Patent Publication Number: US-4056521-A

Title: Penam and cepham derivatives and preparation thereof

Description:
This is a division of application Ser. No. 407,962, filed Oct. 19, 1973, now U.S. Pat. No. 3,954,732. 
    
    
     Having now generally described the invention, a further understanding can be attained by reference to certain specific examples which are provided herein for purposes of illustration only and are not intended to be construed as limiting unless otherwise so indicated. 
     Reaction of: ##STR2## 
     EXAMPLE 1 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.65 g) was dissolved in chloroform (15 ml). To this solution was added cupric chloride (0.16 g) and then the mixture was stirred for 8 hours at room temperature. Precipitates were filtered off and the filtrate was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off to give oily 2,2,2,-trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenoxyacetamido) penam-3-carboxylate (0.56 g). 
     Infrared Absorption Spectrum (Film): 3350, 1785, 1760 1685 cm -1 . 
     EXAMPLE 2 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.63 g) was dissolved in chloroform (15 ml). To this solution was added cupric chloride (0.16 g) and then the mixture was stirred for 8 hours at room temperature. Precipitates were filtered off and the filtrate was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The crystals obtained by distilling off the solvent were washed with ether to give 2,2,2-trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.45 g), mp 108° to b 109° C. 
     Infrared Absorption Spectrum (Nujol): 3300, 1785, 1763, 1656 cm -1 . 
     EXAMPLE 3 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.63 g) was dissolved in acetonitrile (12 ml). To this solution was added mercuric chloride (0.44 g) and then the mixture was stirred for 24 hours at room temperature. After the reaction, precipitates were filtered off and the filtrate was concentrated under reduced pressure and the obtained residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with water, dried and the solvent was distilled off. The obtained residue was purified by chromatography on silica gel to give colorless needles of 2,2,2-trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (190 mg), mp 104° to 105° C, from the third and fourth fractions of fractions each of which was separated into 50 ml. 
     Infrared Absorption Spectrum (Nujol): 3300, 1785, 1763, 1656 cm -1 . 
     EXAMPLE 4 
     To a solution of methyl 2-oxo-3-(2-phenoxy-acetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (0.12 g), in dried methylene chloride (5 ml) was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, methylene chloride was distilled off under reduced pressure from the reaction mixture. The residue was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was distilled off to give oily methyl 2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.085 g). 
     Infrared Absorption Spectrum (Chloroform): 3400, 1790, 1760, 1680 cm -1 . 
     EXAMPLE 5 
     There was obtained oily methyl 2-chloromethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.36 g) by treating in the similar manner as described in Example 4 using methyl 2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenyl-1-azetidineacetate (0.43 g). 
     The following compounds were obtained by using the same procedures as those of the Example 
     1. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamide)penam-3-carboxylate mp 90° to 93° C (dec.). 
     2. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-[N-(2,2,2-trichloroethoxy)-carbonylphenylglycyl]aminopenam-3-carboxylate (powder) 
     3. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (gummy). 
     4. 1-Cyclopropylethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (oil). 
     5. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-[2-(sydnon-3-yl) acetamido]penam-3-carboxylate (amorphous). 
     6. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-[2-(4-hydroxyphenyl)-2-(1-cyclopropylethoxy)carbonyl-aminoacetamido]penam-3-carboxylate (powder). 
     7. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-[2-(2-thienyl)acetamido]-penam-3-carboxylate (oil). 
     8. 3,5-Di-tert.-butyl-4-hydroxybenzyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (white crystalline powder). 
     9. 2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)-carbonylphenylglycyl]aminopenam-3-carboxylate (mp 130° to 135° C). 
     10. 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-cyanoacetamido)-penam-3-carboxylate (amorphous). 
     Reaction of: ##STR3## 
     EXAMPLE 1 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenylazetidine-1-acetate (0.63 g) was dissolved in acetonitrile (12 ml). To this solution was added mercuric chloride (0.44 g) and the mixture was stirred for 24 hours at room temperature. After the reaction precipitates were filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate and the ethyl acetate layer was washed with water and then dried. The solvent was distilled off and the obtained residue was purified by column chromatography on silica gel to give powdery 2,2,2-trichloroethyl 3-chloro-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (70 mg) from the fifth and sixth fractions of fractions each of which was separated into 50 ml. 
     Infrared Absorption Spectrum (Nujol): 3400, 1775, 1760, 1675 cm -1 . 
     EXAMPLE 2 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenyl-acetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenylazetidine-1-acetate (1.26 g) was dissolved in methylene chloride (15 ml). To this solution was added dried zinc chloride (0.40 g) and the mixture was stirred for 2 days at room temperature. After the reaction, the reaction mixture was filtered and the filtrate was washed with sodium bicarbonate aqueous solution and then with water. The residue was subjected to column chromatography on silca gel (20 g) and eluted with chloroform. The third fraction of the fractions each of which was separated in about 30 ml was separated and the solvent was distilled off to give powdery 2,2,2-trichloroethyl 3-chloro-3-methyl-7-(2-phenylacetamido) cepham-4-carboxylate. 
     EXAMPLE 3 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenylazetidine-1-acetate (0.12 g) was dissolved in dry methylene chloride (5 ml). To this solution was added 5% methanolic hydrochloric acid (0.8 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methyl 3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.07 g). 
     Infrared Absorption Spectrum (Chloroform): 3410, 1775, 1742, 1690 cm -1 . 
     EXAMPLE 4 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-propylaminothio-α-isopropenylazetidine-1-acetate (0.43 g) was dissolved in dried methylene chloride. To this solution was added 5% methanolic hydrochloric acid (2 ml) and the mixture was stirred for 10 hours at room temperature. After the reaction, the reaction mixture was concentrated under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was distilled off and the residue was subjected to column chromatography on silica gel using chloroform as developing solvent to give oily methyl 3-chloro-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (310 mg). 
     The following compounds were obtained by using the same procedures as those of the Examples 1 to 4. 
     
         __________________________________________________________________________
 ##STR4##                                                                 
                                  Property of                             
No.                                                                       
   R.sup.1        R.sup.2  R.sup.3                                        
                               Z  the product                             
__________________________________________________________________________
    ##STR5##      COOCH.sub.3                                             
                           CH.sub.3                                       
                               Br amorphous                               
2                                                                         
    ##STR6##      COOCH.sub.3                                             
                           CH.sub.3                                       
                               I  oil                                     
3                                                                         
    ##STR7##      COOH     CH.sub.3                                       
                               Br amorphous                               
4                                                                         
    ##STR8##      COOCH.sub.2 CCp.sub.3                                   
                           CH.sub.3                                       
                               Br mp 90 to 93° C (dec.)            
5  NCCH.sub.2 CONH                                                        
                  COOCH.sub.2 CCl.sub.3                                   
                           CH.sub.3                                       
                               Br amorphous                               
6                                                                         
    ##STR9##       COOCH.sub.2 CCl.sub.3                                  
                           CH.sub.3                                       
                               Br oil                                     
__________________________________________________________________________
 
    
     Reaction of: ##STR10## 
     EXAMPLE 1 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine-acetate (1.06 g) and silver acetate (0.34 g) were suspended in tert-butanol and the mixture was refluxed for 48 hours. After the reaction, precipitates were filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and the solvent was distilled off. The obtained residue was purified by column chromatography on silica gel using chloroform as developing solvent to give pale yellow oil of methyl 2-acetoxymethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (490 mg). 
     Infrared Absorption Spectrum (CHCl 3 ): 3410, 1792, 1745, 1740, 1690 cm -1 . 
     EXAMPLE 2 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidine-acetate (0.63 g) was dissolved in chloroform (10 ml). To this solution was added lead tetraacetate (1.77 g) and the mixture was refluxed for 24 hours. To the reaction mixure was added water and precipitates were filtered off. The filtrate was separated into chloroform layer and aqueous layer and the aqueous layer was extracted with chloroform. The chloroform layer was combined, dried over magnesium sulfate and then the solvent was distilled off. The residue was prufied by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.11 g), mp 122° to 123° C. 
     EXAMPLE 3 
     2,2,2-Trichloroethyl 2-oxo-6-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (1.26 g) was dissolved in a mixture of chloroform (10 ml) and acetic acid (10 ml). To this solution was added lead tetraacetate (1.80 g) and the mixture was stirred for 7 hours at room temperature. Lead tetraacetate (1.80 g) was further added to this solution and the solution was stirred for 8 hours at 50° C. To the reaction mixture was added chloroform, and the solution was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-acetoxymethyl-2-methyl-6-(2- phenylacetamido)penam-3-carboxylate (0.26 g). 
     Infrared Absorption Spectrum (Nujol) 3280, 1792, 1748, 1660 cm -1 . 
     EXAMPLE 4 
     2,2,2-Trichloroethyl 2-oxo-3-[N-(1-cyclopropylethoxy)carbonylphenylglycy]-amino-4-(benzothiazol-2-yl)ditho-α-isopropenyl-1-azetidineacetate (1.52 g) was dissolved in dry methylene chloride (15 ) under ice-cooling. To this solution was dropwise added a solution of thiocyanogen (1m mole) in methylene chloride (10 ml) and the mixture was stirred for 24 hours at the same temperature. Precipitates were filtered off and the filtrate was washed with a saturated sodium bicarbonate aqueous solution and then with water. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure to give oily 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-[N- (1-cyclopropylethoxy)carbonylphenylglycyl]-aminopenam-3-carboxylate (1.3 g). 
     Infrared Absorption Spectrum (Film): 1780, 1765, 1680 cm -1 . 
     EXAMPLE 5 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithioα-isopropenyl-1-azetidineacetate (0.63 g) was dissolved in dried methylene chloride (10 ml) under ice-cooling. To this solution was dropwise added a solution of thiocyanogen (0.6 m mole) in methylene chloride (5 ml). After the mixtue was stirred for 24 hours at the same temperature, precipitates were filtered off. The filtrate was concentrated under reduced pressure and the residue was dissolved in ethyl acetate (10 ml). The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. After the solvent was distilled off, the residue was crystallized by adding a small amount of ether. The crystals were filtered off and the filtrate was concentrated to give oily 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl6-(2-phenoxyacetamido)penam-3-carboxylate (0.49 g). 
     Infrared Absorption Spectrum (Film): 1785, 1760, 1690 cm -1 . 
     EXAMPLE 6 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (5.04 g) was dissolved in dried methylene chloride (20 ml). To this solution was dropwise added a solution of thiocyanogen (4.5 m mole) in methylene chloride for 5 minutes under ice-cooling. After stirring for 7 hours at the same temperature, precipitates were filtered off. The filtrate was washed with a saturated sodium bicarbonate aqueous solution and then with warter and thereafter dried over magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was crystallized by adding a small amount of ether to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (3.58 g), mp 137° to 140° C. 
     EXAMPLE 7 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.63 g) and potassium thiocyanate (150 mg) were dissolved in dried acetone (10 ml). To this solution was added p-toluenesulfonic acid monohydrate (0.19 g) and the mixture was stirred for 24 hours at room temperature. Precipitates were filtered off and the filtrate was concentrated under reduced pressure and then the residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was crystallized by adding a small amount of ether to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (330 mg). 
     EXAMPLE 8 
     2,2,2-Trichloroethyl 2-oxo-3-[3-(2-chlorophenyl)-5-methyl-isoxazol-4-carboxamido]-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.70 g) was dissolved in dried methylene chloride (10 ml) under ice-cooling. To this solution was dropwise added a solution of thiocyanogen (0.5m mole) in methylene chloride (5 ml) and the mixture was stirred for 24 hours at the same temperature. Precipitates were filtered off and the filtrate was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried. The solvent was distilled off and the residue was pulverized by adding petroleum ether (about 10 ml) to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-thiocyanatomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazol-4-carboxamido]-penam-3-carboxylate (500 mg). 
     Infrared Absorption Spectrum (Nujol): 1785, 1770, 1670 cm -1 . 
     EXAMPLE 9 
     Acetic acid (5 ml) was added to a solution of 2,2,2-trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (1.26 g) in ethyl acetate (15 ml) To this solution was added silver acetate (0.68 g) under stirring at room temperature and the mixture was stirred for 4 hours at the same temperature. After the reaction, precipitates was filtered off from the reaction mixture and the filtrate was washed with water, with 5% sodium bicarbonate aqueous solution and then filtered. The filtrate was washed with water, dried and the solvent was distilled off. The oily residue (0.87 g) was purified by thin layer chromatography and recrystallized from ether to give colorless needles of 2,2,2-trichloroethyl 2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, mp 116° to 118° C. 
     EXAMPLE 10 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (454 mg) was dissolved in methylene chloride (20 ml). To this solution were added methanol (5 ml) and then boron trifluoride etherate (0.124 g) under cooling at 0° C. The mixture was stirred for 3 hours at the same temperature and further stirred for 2 hours at 5° to 10° C. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and then with water, dried and the solvent was distilled off. The oily residue (25 g) was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was separated into each 50 ml fraction and the seventh and eighth fractions were combined. The solvent was distilled off to give oily methyl 2-methoxymethyl-2-methy-6-(2-phenoxyacetamido)penam-3-carboxylate. 
     Infrared Absorption Spectrum (CHCl 3 ): 3370, 1787, 1742, 1685 cm -1 . 
     The following compounds were obtained by using the same procedures as those of the Example 1 to 10. 
     
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 ##STR11##                                                                
 
    
     
         __________________________________________________________________________
                                                  Property                
No.                                                                       
   R.sup.1           R.sup.2  R.sup.3                                     
                                  Y               of the                  
__________________________________________________________________________
                                                  product                 
    ##STR12##        COOCH.sub.2 CCl.sub.3                                
                               ##STR13##                                  
                                  N.sub.3         mp 105 to 106°   
                                                  C                       
2                                                                         
    ##STR14##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR15##      Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3320, 1790, 1765, 1680  
                                                  cm.sup.-1.              
3                                                                         
    ##STR16##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR17##      Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3400, 1790, 1765, 1680  
                                                  cm.sup. -1.             
4                                                                         
    ##STR18##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR19##      Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3300, 1790, 1765, 1680  
                                                  cm.sup.-1.              
5                                                                         
    ##STR20##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                  SCOCH.sub.3     Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3390, 1790, 1765, 1680  
                                                  - 1690 cm.sup.-1.       
6                                                                         
    ##STR21##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR22##      Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3300, 1788, 1764, 1675  
                                                  cm.sup.-1               
7                                                                         
    ##STR23##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR24##      Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3200, 1790, 1770, 1678  
                                                  cm.sup.-1               
8                                                                         
    ##STR25##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR26##      Oil Infrared Absorption 
                                                  pectrum (Film) 3250,    
                                                  1780, 1765, 1665        
                                                  cm.sup.-1               
9                                                                         
    ##STR27##        COOCH.sub.3                                          
                              CH.sub.3                                    
                                   ##STR28##      Infrared Absorption     
                                                  Spectrum (Film) 3300,   
                                                  1785, 1745, 1680        
                                                  cm.sup.-1               
10                                                                        
    ##STR29##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR30##      Oil Infrared Absorption 
                                                  pectrum (Film) 3270,    
                                                  1780, 1760, 1710, 1680  
                                                  cm.sup.-1               
11                                                                        
    ##STR31##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR32##      Oil Infrared Absorption 
                                                  pectrum (Film) 3270,    
                                                  1760, 1710, 1680        
                                                  cm.sup.-1               
12                                                                        
    ##STR33##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                  OCH.sub.3       Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3360, 1785, 1757, 1666  
                                                  cm.sup.-1               
13                                                                        
    ##STR34##        COOCH.sub.3                                          
                              CH.sub.3                                    
                                   ##STR35##      Oil Infrared Absorption 
                                                  pectrum (CHCl.sub.3)    
                                                  3410, 1785, 1748, 1690  
                                                  cm.sup.-1               
14                                                                        
    ##STR36##        COOCH.sub. 2 CCl.sub.3                               
                              CH.sub.3                                    
                                   ##STR37##      Amorphous Infrared      
                                                  Absorption Spectrum     
                                                  (Nujol) 3220, 1780,     
                                                  1760, 1700 cm.sup.-1    
15                                                                        
    ##STR38##        COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                   ##STR39##      Amorphous Infrared      
                                                  Absorption Spectrum     
                                                  (Nujol) 3300, 1780,     
                                                  1770, 1665 cm.sup.-1    
16 H.sub.2 N         COOCH.sub.2 CCl.sub.3                                
                              CH.sub.3                                    
                                  SCN             toluenesulfonate        
                                                  mp 182 to 185° C 
                                                  (dec.)                  
17                                                                        
    ##STR40##        COOH     CH.sub.3                                    
                                  SCOCH.sub.3     N, N&#39;-dibenzyl-         
                                                  ethylenediamine salt    
                                                  mp 105 to 107°   
                                                  C                       
18                                                                        
    ##STR41##        COOH     CH.sub.3                                    
                                   ##STR42##      N,N&#39;-dibenzyl- ethylened
                                                  iamine salt mp          
                                                  100° C (dec.)    
19                                                                        
    ##STR43##        COOH     CH.sub.3                                    
                                   ##STR44##      mp 120° C        
20                                                                        
    ##STR45##        COOH     CH.sub.3                                    
                                   ##STR46##      N,N&#39;-dibenzyl- ethylened
                                                  iamine salt mp 117 to   
                                                  119° C (dec.)    
21                                                                        
    ##STR47##        COOH     CH.sub.3                                    
                                   ##STR48##      mp 152 to 154°   
                                                  C                       
22                                                                        
    ##STR49##        COOH     CH.sub.3                                    
                                   ##STR50##      N,N&#39;-dibenzyl- ethylened
                                                  iamine salt mp 150 to   
                                                  152° C (dec.)    
23                                                                        
    ##STR51##        COOH     CH.sub.3                                    
                                   ##STR52##      Sodium salt mp          
                                                  200° C (dec.)    
24                                                                        
    ##STR53##        COOH     CH.sub.3                                    
                                   ##STR54##      Sodium salt mp 185 to   
                                                  186° C           
__________________________________________________________________________
                                                  (dec.)                  
 
    
     Reaction of: ##STR55## 
     EXAMPLE 1 
     Potassium thiocyanate (1.17 g) was dissolved in a mixture of water (20 ml) and acetone (100 ml). To this solution was added 2,2,2-trichlorothyl 2-bromomethyl-2-methyl-6-(2-phenyl-acetamido) penam-3-carboxylate (5.45 g) at room temperature and the mixture was stirred for 5.5 hours at room temperature. After removing acetone under reduced pressure at room temperature, precipitates were collected by filtration, washed with water and further washed with ethanol to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (4.10 g). This substance was recrystallized from isopropylether containing 5% acetone to give pure compound, mp 133° to 135° C. 
     Analysis for C 19  H 18  N 3  O 4  S 2  Cl 3  : Calc&#39;d. : C43.64, H3.47, N8.04, S12.27, Cl 20.34. Found: : C43.84, H3.26, N7.99, S12.31, Cl20.3l. 
     EXAMPLE 2 
     A mixture of 2,2,2-trichloroethyl 2-bromomethyl-b 2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After removing acetone under reduced pressure, the residue was extracted with ethy acetate. The ethyl acetate layer was washed with water, with a saturated sodium bicarbonate queous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small amount of ether was added to the residue. Precipitated crystals were filtered off and the solvent was distilled off from the filtrate. The crystalline residue was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-azidomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (150 mg). This substance was crystallized by adding a small amount of a mixture of ether and petroleum ether and the crystals were recrystallized from ether to give pure compound, mp 105° to 106° C. 
     Analysis for C 18  H 18  N 5  O 4  SCl 3  : Calc&#39;d: C42.66, H3.58, N13.82, S6.33, Cl20.99. Found: C42.66, H3.40, H13.69, Cl20.74. 
     EXAMPLE 3 
     5-Methyl-1,3,4-thiadiazole-2-thiol (0.16 g) was dissolved in a mixture of pH 6.5 phosphate buffer (5 ml) and acetone (10 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamide)penam-3-carboxylate (0.54 g) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and acetone was distilled off and thereafter the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.09 g) from the second and third fractions each of which was separated into about 30 ml. 
     Infrared Absorption Spectrum (CHCl 3 ): 3320, 1790, 1765, 1680 cm -1 . 
     EXAMPLE 4 
     5-Methyl-1,3,4-thiadiazole-2-thiol (0.20 g) and sodium bicarbonate (0.85 g) were dissolved in formamide (7 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.54 g), and the mixture was stirred for 5 hours at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.20 g) from the third fractions each of which was separated into about 30 ml. 
     EXAMPLE 5 
     Benzothiazole-2-thiol (0.20 g) was dissolved in a mixture of pH 6.7 phosphate buffer (15 ml) and dioxane (15 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 7 hours at room temperature. After the reaction was completed, dioxane was distilled off and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with a 2% potassium carbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.15 g) from the second fraction of fractions each of which was separated into 30 ml. 
     Infrared Absorption Spectrum (CHCl 3 ). 3400, 1790, 1765, 1680 cm -1 . 
     EXAMPLE 6 
     To a solution of 1-methyl-1H-tetrazole-5-thiol (0.23 g) in a mixture of pH 6.9 phosphate buffer (15 ml) and acetone (20 ml) was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), and the mixture was stirred for 5 hours at room temperature. Acetone was distilled off from the reaction mixture. The aqueous layer was extracted with ethyl acetate and the extract was washed with sodium bicarbonate aqueous solution and then with a saturated sodium chloride aqueous solution. After the extract was dried over magnesium sulfate, the solvent was distilled off. The residue was purified by column chromatography on silica gel to give oily 2,2,2-trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylate (0.27 g). 
     Infrared Absorption Spectrum (CHCl 3 ). 3300, 1790, 1765, 1680 cm -1 . 
     EXAMPLE 7 
     Acetone (20 ml) and thioacetic acid (0.12 g) were added to pH 6.7 phosphate buffer (20 ml). To a mixture was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) under stirring. After stirring for 5 hours at room temperature, the reaction mixture was post-treated in the similar manner as described in Example 6 to give oily 2,2,2-trichloroethyl 2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.173 g). 
     Infrared Absorption Spectrum (CHCl 3 ): 3390, 1790, 1965, 1690 ˜ 1685 cm -1 . 
     EXAMPLE 8 
     Sodium piperidine-1-dithiocarboxylate (0.37 g) was dissolved in a mixture of pH 6.7 phosphate buffer (20 ml) and acetone (25 ml) and then to this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g). After stirring for 3 hours at room temperature, the reaction mixture was post-treated in the similar manner as described in Example 6 to give oily 2,2,2-trichloroethyl 2-piperidinothiocarbonyl-thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.11 g). 
     Infrared Absorption Spectrum (CHCl 3 ): 3300, 1788, 1764, 1675 cm -1 . 
     EXAMPLE 9 
     Acetone (25 ml) was added to a solution of 1-methylimidazole-2-thiol (0.23 g) in pH 6.9 phosphate buffer (20 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), and the mixture was stirred for 3 hours at room temperature. 
     The reaction mixture was post-treated in the similar manner as described in Example 6 to give oily 2,2,2-trichloroethyl 2-(1-methylimidazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.29 g). 
     Infrared Absorption Spectrum (CHCl 3 ): 3200, 1790, 1770, 1678 cm -1 . 
     EXAMPLE 10 
     Acetone (25 ml) was added to a solution of pyridine-4-thiol (0.22 g) in pH 6.8 phosphate buffer (20 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), and the mixture was stirred for 3 hours at room temperature. 
     The reaction mixture was post-treated in the similar manner as described in Example 6 to give oily 2,2,2-trichloroethyl 2-(4-pyridyl)-thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.15 g). 
     Infrared Absorption Spectrum (Film): 3250, 1780, 1765, 1665 cm -1 . 
     EXAMPLE 11 
     5-Methyl-1,3,4-thiadiazole-2-thiol (0.4 g) was dissolved in a mixture of pH 7.3 phosphate buffer (20 ml) and acetone (20 ml). To this solution was added a solution of methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.80 g) in acetone (10 ml) and the mixture was stirred for 4 hours at room temperature. After the reaction was completed, acetone was distilled off from the reaction mixture and the residue was extracted with ethyl acetate. The extract was washed with sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to column chromatography on silica gel (60 g) and eluted with chloroform. The eluate was separated into fractions of each about 30 ml to give methyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.28 g) from the fourth to seventh fractions. 
     Infrared Absorption Spectrum (Film): 3300, 1785, 1745, 1690 cm -1 . 
     EXAMPLE 12 
     Acetic acid (2 ml) was added to a solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) in methylene chloride (10 ml). And to this solution was added silver acetate (0.34 g) water stirring at room temperature and then the mixture was stirred for 2.5 hours. After the reaction was completed, the reaction mixture was filtered under reduced pressure and the filtrate was washed with 5% hydrochloric acid and then filtered again. The oily residue was crystallized by treating with ether and the crystals were collected by filtration and then dried to give colorless needles of 2,2,2-trichloroethyl-2-acetoxymethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.21 g), mp 116° to 118° C. 
     EXAMPLE 13 
     A solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]-aminopenam-3-carboxylate (6.75 g) in acetone (50 ml) was added to a solution of 1-methyl-1H-tetramole-5-thiol (2.6 g) in a mixture of phosphate buffer (200 ml) and acetone (200 ml), under cooling at 5° C, and the mixture was stirred for 5 hours at the same temperature. After the reaction was completed, acetone was distilled off from the reaction mixture under reduced pressure and the residue was extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate aqueous solution and then with water, dried. The solvent was distilled off. The oily residue was subjected to column chromatography on silica gel (180 g) and eluted with chloroform. The eluate was separated into fractions of each 50 ml and after collecting the fractions of the eleventh to sixteenth, the solvent was distilled off to give oily 2,2,2-trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl) thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl] aminopenam-3-carboxylate (3.15 g). 
     Infrared Absorption Spectrum (Film): 3270, 1780, 1760, 1710, 1680 cm -1 . 
     EXAMPLE 14 
     By treating in the similar manner as described in Example 13 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (6.72 g), 5-methyl-1,3,4-thiadiazole-2-thiol (1.98 g), pH 6.8 phosphate buffer (200 ml) and acetone (250 ml), there was obtained oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (1.16 g). 
     Infrared Absorption Spectrum (CHCl 3 ): 3420, 1790, 1770, 1708, 1687 cm -1 . 
     EXAMPLE 15 
     A solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (3.6 g) in formamide (40 ml) was added to a solution of sodium bicarbonate (0.66 g) and 5-methyl-1,3,4-thiadiazole-2-thiol (1.1 g) in formamide (60 ml) under ice-cooling, after which the mixture was stirred for 4.5 hours at the same temperature. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% sodium bicarbonate aqueous solution and then with water, dried, after which the solvent was distilled off. The oily residue was subjected to column chromatography on silica gel (110 g) and eluted with chloroform. The eluate was separated into fractions of each 50 ml and after collecting the fractions of the fifteenth and sixteenth. the solvent was distilled off to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3-thiadiazol-2-yl)thiomethyl-2-methyl-6-[N-(1-cyclopropylethoxy)carbonylphenylglycyl]aminopenam-3-carboxylate (0.-2 g). 
     EXAMPLE 16 
     2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.10 g) dissolved in methylene chloride (15 ml). To this solution was added aniline (0.28 g) under cooling at -10° C and then silver fluoroborate (0.-3 g), after which the mixture was stirred for 2 hours. After the reaction was completed, the reaction mixture was washed with a dilute phosphoric acid aqueous solution and then with water, dried over magnesium sulfate, after which the solvent was distilled off. The residue was subjected to column chromatography at silica gel (20 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml. The second to seventh fractions were collected and the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.8- g), mp 148° to 149° C. 
     Infrared Absorption Spectrum (CHCl 3 ): 3400, 1780, 1765, 1680 cm -1 . 
     EXAMPLE 17 
     By treating in the similar manner as described in Example 16 using methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.88 g), aniline (0.28 g), silver fluoroborate (0.43 g) and methylene chloride (15 ml), there was obtained oily methyl 2-anilinomethyl-2-methyl-6-(2-phenoxyacetamido)-penam-3-carboxylate (0.41 g) from the fractions of the third to seventh. 
     Infrared Absorption Spectrum (CHCl 3 ); 3410, 1785, 1748, 1690 cm -1 . 
     EXAMPLE 18 
     2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (1.10 g) was dissolved in methylene chloride (12 ml) and to this solution was added methanol (3 ml). And to the solution was added silver fluoroborate (0.45 g) under stirring under cooling at -10° C and the mixture was stirred for 2 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered and the filtrate was washed with sodium bicarbonate aqueous solution and then with water, dried over magnesium sulfate and thereafter concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was seprated into fractions of about 20 ml and the first and second fractions were collected. After distilling off the solvent, the residue was dried to give oily 2,2,2-trichloroethyl 2-methoxymethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate. 
     Infrared Absorption Spectrum (CHCl 3 ); 3360, 1785, 1757, 1666 cm -1 . 
     EXAMPLE 19 
     By treating in the similar manner as described in Example 18 using methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate instead of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate, there was obtained oily methyl 2-methoxymethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate. 
     Infrared Absorption Spectrum (CHCl 3 ) 3370, 1787, 1742, 1685 cm -1 . 
     EXAMPLE 20 
     By treating the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamino[penam-3-carboxylate and 1-methyl-IH-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl 2-(1-methyl-IH-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate. 
     Infrared Absorption Spectrum (Nujol); 3300, 1780, 1770, 1665 cm -1 . 
     EXAMPLE 21 
     By treating in the similar manner as described in Example 11 using 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)-acetamido]penam-3-carboxylate and 1-methyl-IH-tetrazole-5-thiol in a mixture of pH 6.85 phosphate buffer and acetone, there was obtained amorphous 2,2,2-trichloroethyl-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carboxylate. 
     Infrared Absorption Spectrum (Nujol) 3220, 1780, 1760, 1700 cm -1 . 
     
         __________________________________________________________________________
 ##STR56##                                                                
No.                                                                       
    R.sup.1         R.sup.2 R.sup.3                                       
                                Y            Property of the              
__________________________________________________________________________
                                             products                     
    ##STR57##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          Oil Infrared Absorption      
                                             Spectrum (Film) 1785, 1760,  
                                             1690 cm.sup.-1.              
2                                                                         
    ##STR58##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          Oil Infrared Absorption      
                                             Spectrum (Film) 1780, 1765,  
                                             1680 cm.sup.-1.              
3                                                                         
    ##STR59##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          Powder Infrared Absorption   
                                             Spectrum (Nujol) 1785, 1770, 
                                             1670 cm.sup.-1.              
4  H.sub.2 N       COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          toluenesulfanate             
                                             mp 182 to 185° C      
                                             (dec.)                       
5                                                                         
    ##STR60##      COOH     CH.sub.3                                      
                                SCOCH.sub.3  N,N&#39;-dibenzylethylenediamine 
                                             salt mp 105 to 107°   
                                             C                            
6                                                                         
    ##STR61##      COOH     CH.sub.3                                      
                                 ##STR62##   N,N&#39;-dibenzylethylenediamine 
                                             salt mp 100° C        
                                             (dec.)                       
7                                                                         
    ##STR63##      COOH     CH.sub.3                                      
                                 ##STR64##   mp 120° C             
8                                                                         
    ##STR65##      COOH     CH.sub.3                                      
                                 ##STR66##   N,N&#39;-dibenzylethylenediamine 
                                             salt mp 117 to 119° C 
                                             (dec.)                       
9                                                                         
    ##STR67##      COOH     CH.sub.3                                      
                                 ##STR68##   mp 152 to 154° C      
10                                                                        
    ##STR69##      COOH     CH.sub.3                                      
                                 ##STR70##   N,N&#39;-dibenzylethylenediamine 
                                             salt mp 150 to 152°   
                                             (dec.)                       
11                                                                        
    ##STR71##      COOH     CH.sub.3                                      
                                 ##STR72##   Sodium salt mp 200° C 
                                             (dec.)                       
12                                                                        
    ##STR73##      COOH     CH.sub.3                                      
                                 ##STR74##   Sodium salt mp 185 to        
                                             186° C                
__________________________________________________________________________
                                             (dec.)                       
 
    
     Reaction of: ##STR75## 
     EXAMPLE 1 
     2,2,2-Trichloroethyl-3-bromo-3-methyl-7-(2-phenylacetamido)cepham---carboxylate (1.10 g) was dissolved in methylene chloride 15 ml) and to this solution was added aniline (0.28 g). And to the solution was added silver fluoroborate (0.45 g) under stirring under ice-cooling and the mixture was stirred for - hours at the same temperature. After the reaction was completed, the reaction mixture was filtered. The filtate was washed with a dilute aqueour solution of phosphoric acid and then with water, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml and the second to eighth fractions were collected and then the solvent was distiled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), mp 148° to 149° C. 
     Infrared Absorption Spectrum (CHCl 3 ): 3400, 1780 1765, 1680 cm -1 . 
     
         __________________________________________________________________________
 ##STR76##                                                                
No.                                                                       
   R.sup.1          R.sup.2 R.sup.3                                       
                                 Y           Property of the              
__________________________________________________________________________
                                             product                      
 1                                                                        
    ##STR77##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                N.sub.3      mp 105 to 106 ° C     
 2                                                                        
    ##STR78##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR79##   Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3320,  
                                             1790, 1765, 1680 cm.sup.-1   
 3                                                                        
    ##STR80##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR81##   Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3400,  
                                             1790, 1765, 1680 cm.sup.-1   
 4                                                                        
    ##STR82##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR83##   Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3300,  
                                             1790, 1765, 1680 cm.sup.-1   
    ##STR84##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCOCH.sub.3  Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3390,  
                                             1790, 1765, 1690 - 1680      
                                             cm.sup.1                     
 6                                                                        
    ##STR85##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR86##   Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3300,  
                                             1788, 1764, 1675 cm.sup.-1   
 7                                                                        
    ##STR87##      COOCH.sub.2 CCl.sub. 3                                 
                            CH.sub.3                                      
                                 ##STR88##   Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3200,  
                                             1790, 1770, 1678 cm.sup.-1   
 8                                                                        
    ##STR89##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR90##   Oil Infrared Absorption      
                                             Spectrum (Film) 3250, 1780,  
                                             1765, 1665 cm.sup.-1         
 9                                                                        
    ##STR91##      COOCH.sub.3                                            
                            CH.sub.3                                      
                                 ##STR92##   Infrared Absorption Spectrum 
                                             (Film) 3300, 1785, 1745,     
                                             1690 cm.sup.-1               
10                                                                        
    ##STR93##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR94##   Oil Infrared Absorption      
                                             Spectrum (Film) 3270, 1780,  
                                             1760, 1710, 1680 cm.sup.-1   
11                                                                        
    ##STR95##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR96##   Oil Infrared Absorption      
                                             Spectrum (Film) 3270, 1760,  
                                             1710, 1680 cm.sup.-1         
12                                                                        
    ##STR97##      COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                OCH.sub.3    Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3360,  
                                             1785, 1757, 1666 cm.sup.-1   
13                                                                        
    ##STR98##      COOCH.sub.3                                            
                            CH.sub.3                                      
                                 ##STR99##   Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3410,  
                                             1785, 1748, 1690 cm.sup.-1   
14                                                                        
    ##STR100##     COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR101##  Amorphous Infrared           
                                             Absorption Spectrum (Nujol)  
                                             3220, 1780, 1760, 1700       
                                             cm.sup.-1                    
15                                                                        
    ##STR102##     COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                 ##STR103##  Amorphous Infrared           
                                             Absorption Spectrum (Nujol)  
                                             3300, 1780, 1770, 1665       
                                             cm.sup.-1                    
16                                                                        
    ##STR104##     COOCH.sub.3                                            
                            CH.sub.3                                      
                                OCH.sub.3    Oil Infrared Absorption      
                                             Spectrum (CHCl.sub.3) 3370,  
                                             1787, 1742, 1685 cm.sup.-1   
17                                                                        
    ##STR105##     COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          Oil  Infrared Absorption     
                                             Spectrum (Film) 1785, 1760,  
                                             1690 cm.sup.-1               
18                                                                        
    ##STR106##     COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          Oil Infrared Absorption      
                                             Spectrum (Film) 1780, 1765,  
                                             1680 cm.sup.-1               
19                                                                        
    ##STR107##     COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          Powder Infrared Absorption   
                                             Spectrum (Nujol) 1785, 1770, 
                                             1670 cm.sup.-1               
20                                                                        
    ##STR108##     COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          mp 137 to 140° C      
21 H.sub.2 N       COOCH.sub.2 CCl.sub.3                                  
                            CH.sub.3                                      
                                SCN          toluenesulfonate             
                                             mp 182 to 185° C      
                                             (dec.)                       
22                                                                        
    ##STR109##     COOH     CH.sub.3                                      
                                SCOCH.sub.3  N,N&#39;-dibenzylethylenediamine 
                                             salt  mp 105 to 107°  
                                             C                            
23                                                                        
    ##STR110##     COOH     CH.sub.3                                      
                                 ##STR111##  N,N&#39;-dibenzylethylenediamine 
                                             salt mp 100° C        
                                             (dec.)                       
24                                                                        
    ##STR112##     COOH     CH.sub.3                                      
                                 ##STR113##  mp 120° C             
25                                                                        
    ##STR114##     COOH     CH.sub.3                                      
                                 ##STR115##  N,N&#39;-dibenzylethylenediamine 
                                             salt mp 117 to 119° C 
                                             (dec.)                       
26                                                                        
    ##STR116##     COOH     CH.sub.3                                      
                                 ##STR117##  mp 152 to 154°  C     
27                                                                        
    ##STR118##     COOH     CH.sub.3                                      
                                 ##STR119##  N,N&#39;-dibenzylethylenediamine 
                                             salt mp 150 to 152° C 
                                             (dec.)                       
28                                                                        
    ##STR120##     COOH     CH.sub.3                                      
                                 ##STR121##  Sodium salt mp 200° C 
                                             (dec.)                       
29                                                                        
    ##STR122##     COOH     CH.sub.3                                      
                                 ##STR123##  Sodium salt mp 185 to        
                                             186° C                
__________________________________________________________________________
                                             (dec.)                       
 
    
     Reaction of: ##STR124## 
     EXAMPLE 1 
     A solution of m-chloroperbenzoic acid (1.39 g) in chloroform (15 ml) was added to a solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (3.74 g) in chloroform (35 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour, and precipitates were filtered off. The filtrate was washed with a saturated sodium bicarbonate aqueous solution and water in turn and dried over magnesium sulfate. After the solvent was removed uner reduced pressure, the residue was crystallized by adding a little of ether. The Crystals were filtered to give colorless crystals of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-β-oxide (3.15 g), mp 114°-115° C (dec.). 
     Analysis -- C 18  H 18  O 5  N 2  SCl 3  Br: Calcd. : C38.55, H3.24, N4.99. Found : C38.40, H3.12, N 4.68. 
     EXAMPLE 2 
     2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (540 mg) was suspended in a mixed solution of pyridine (10 ml) and water (1 ml) at -35°-40° C. To the suspension was dropwise added isocyanuroyl chloride (110 mg). The mixture was stirred for an hour and 20 minutes and then the mixture was poured into a mixed solution of 20% aqueous phosphoric acid (50 ml) and ethyl acetate (20 ml) under ice-cooling. The ethyl acetate fraction was separated. After the water layer was extracted with ethyl acetate, the ethyl acetate extract was combined with the above-obtained ethyl acetate layer. The extract was washed with 5% phosphoric acid, water, saturated sodium bicarbonate aqueous solution and water in turn, and then dried over magnesium sulfate. After the solvent was removed, the residue was subjected to column chromatography on silica gel with chloroform. The 3rd fraction was concentrated to give 2,2,2-trichloroethyl-2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-β-oxide (130 mg). The 5th fraction was concentrated to give 2,2,2-trichloroethyl 2-bromomethyl- 2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate-1-α-oxide (170 mg). 
     Infrared Absorption Spectrum (CHCl 3 ) of the α-oxide compound: 3420, 1795, 1770, 1665 cm -1 . 
     EXAMPLE 3 
     m-Chloroperbenzoic acid (210 mg) was dropwise added to a solution of 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (522 mg) in chloroform (10 ml) under ice-cooling. The mixture was stirred under ice-cooling for 1 hour and the solid was filtered off. The filtrate was washed with a saturated sodium bicarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. The solvent was removed to give colorless power of 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-.beta.-oxide (540 mg). 
     Infrared Absorption Spectrum (Nujol): 3330, 2130, 1797, 1778(sh.), 1677 cm -1 . 
     EXAMPLE 4 
     2,2,2-Trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (522 mg) was suspended in a mixed solution of pyridine (10 ml) and water (1 ml) at -35°-40° C. To the suspension was dropwise added isocyanuroyl chloride (110 mg) at -35°--40° C. The mixture was stirred at -35°--40° C for 1 hour, and then poured into a mixed solution of ice-cooled 20% phosphoric acid (50 ml) and ethyl acetate (20 ml), and then the ethyl acetate layer was separated. After the water layer was extracted with ethyl acetate, the extract was combined with the above-obtained ethyl acetate layer. The extract was washed with 5% phosphoric acid, water, saturated sodium bicarbonate aqueous solution and water, in turn, and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography on silica gel with chloroform to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-.beta.-oxide (140 mg). 
     EXAMPLE 5 
     2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (522 mg) was suspended in a mixed solution of pyridine (12 ml) and water (12 ml) at -25°--35° C. To the suspension was added phenyliododichloride (550 mg). And the mixture was stirred at -25°--35° C for 3 hours, phenyliododichloride (550 mg) was further added to the mixture. After stirring for 1 hour, phenyliododichloride (550 mg) was added to the mixture again. The reaction mixture was stirred for additional 1 hour, poured into a mixed solution of 20% phosphoric acid (50 ml) and ethyl acetate (20 ml), and then the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate, which was combined with the above-obtained ethyl acetate layer. The combined ethyl acetate layer was washed with 5% phosphoric acid, water saturated sodium bicarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. After the solvent was removed under reduced pressure, the residue was subjected to column chromatography on silica gel with a mixed solution of benzene (2 parts) and ethyl acetate (1part). The 3rd to 7th fractions were concentrated to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-p-oxide (250 mg). 
     EXAMPLE 6 
     A solution of m-chloroperbenzoic acid (2.03 g) in chloroform (30 ml) was added dropwise to a solution of 2,2,2-trichloroethyl-2-chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (5.0 g) in chloroform (40 ml) at -10°--5° C under stirring and then the mixture was stirred at -10°--5° C for 1 hour. After the solid was filtered off, the filtrate was washed with a saturated sodium becarbonate aqueous solution and water, in turn, and then dried over magnesium sulfate. After removal of solvent, the residue was crystallized by adding ethanol. The crystal was filtered and recrystallized from ethanol to give 2,2,2-trichloroethyl 2chloromethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate-1-oxide (4.10 g), mp 130°--131° C. 
     Analysis -- C 18  H 18  O 5  N 2  SCl 4  : Calcd. : C 41.87, H3.51, N 5.43, S 6.21. Found : C 41.80, H3.45, N 5.50, S 6.44. 
     EXAMPLE 7 
     Sodium tungstate (0.02 g) was added to a solution of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid (3.1 g) in acetic acid (8 ml) at 7°-10° C under stirring and then to the mixture was added 30% aqueous hydrogen peroxide (1.2 ml). The mixture was stirred at 7°-10° C for 1 hour. After the reaction, ice-water (50 ml) was added to the reaction mixture and then extracted with ethyl acetate. The extract was washed with water and back-extracted with 5% sodium bicarbonate aqueous solution. The aqueous layer was washed with ethyl acetate twice, acidified with 5% hydrochloric acid to pH2 and then extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give powder of 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid-1-oxide (2 g). 
     Infrared Absorption Spectrum (CHCl 3 ). 3350, 1795, 1740, 1688 cm -1 . 
     EXAMPLE 8 
     A solution of m-chloroperbenzoic acid (0.445 g) in chloroform (5ml) was added to a solution of 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido) cepham-4-carboxylate (1.21 g) under stirring at -5° to -10° C, and the mixture was stirred for an hour at the same temperature. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and with water in turn and then dried. After the solvent was distilled off, the residue was crystallized by adding ether. Thus obtained crystals were recrystallized from ethanol to give 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate-1-oxide (1.10 g), mp 159° to 161° C. 
     reaction of: ##STR125## 
     EXAMPLE 1 
     2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate-1-oxide (1.12 g) was dissolved in dried methylene chloride (10 ml). To this solution were added dimethyl aniline (0.36 g) under cooling at -15° C and then phosphorus pentachloride (0.6 g), and the mixture was stirred for 3 hours. To the solution was added anhydrous methanol (0.7 g) under cooling at -40° C and the solution was stirred for 2 hours and further stirred for 1 hour at -15° C. After the reaction, precipitated crystals were collected by filtration, washed with a small amount of methylene chloride and then dried to give 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate-1-oxide hydrochloride (0.70 g), mp 147° to 154° C (dec.). 
     Infrared Absorption Spectrum (Nujol): 1820, 1800, 1760 cm -1 . 
     EXAMPLE 2 
     2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (10.8 g) was dissolved in dried methylene chloride (300 ml). To this solution were added under cooling at -35° C dried dimethylaniline (3.6 g) and then phosphorus pentachloride (6.4 g) and the mixture was stirred for 2.5 hours at the same temperature. To the solution was added dropwise anhydrous methanol (6.4 g) at the same temperature and the mixture was stirred for 1 hour at -15° C. Water (6.3 ml) was added to the solution and the solution was vigorously stirred for 30 minutes. After the reaction, precipitates were collected by filtration, washed with methylene chloride and further with ether and then dried to give powdery 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (7.8 g). 
     Infrared Absorption Spectrum (Nujol): 3330 - 3400, 1790, 1770 cm -1 . 
     EXAMPLE 3 
     2,2,2-Trichloroethyl 2-thiocyanatomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.53 g) was dissolved in dried methylene chloride (10 ml). To this solution were added under cooling at -20° to -30° C dimethylaniline (0.43 g) and then phosphorus pentachloride (0.23 g) and the mixture was stirred for 1.5 hours. Further, to the solution was added dropwise anhydrous methanol (0.3- g) and the solution was stirred for 5 hours. Water (7 ml) was added to the solution at 0° C and the mixture was stirred for 10 minutes. Aqueous layer was separated from the mixture. The aqueous layer was adjusted to pH9 by adding 1N-sodium hydroxide aqueous solution and extracted with ethyl acetate (10 ml). The extract was dried over magnesium sulfate and the solvent was distilled off. The residue was dissolved in a small amount of ethyl acetate and to the solution were added toluene-sulfonic acid monohydrate (0.1 g) and ethyl acetate (5 ml). The mixture was cooled and precipitated crystals were collected by filtration to give 2,2,2-trichloroethyl 2-thiocyanatomethyl-2-methyl-6-aminopenam-3-carboxylate toluenesulfonate (0.06 g), mp 182° to 185° C (dec.). 
     Infrared Absorption Spectrum (Nujol): 2150, 1795, 1750 cm -1 . 
     Reaction of: ##STR126## 
     EXAMPLE 1 
     To a sodium of ethyl chlorocarbonate (1.95 g) in dried methylene chloride (120 ml) was added dropwise under cooling -5° C a solution of N-(1-cyclopropylethoxy)carbonylphenylglycine (4.74 g) and triethylamine (1.83 g) in dried methylene chloride (50 ml). The solution containing a mixed anhyride of N-(1-cyclopropylethoxy)carbonylphenylglycine and ethyl chlorocarbonte prepared by stirring the above mixture for 1 hour at eht same temperature was cooled at -30° to -35° C. To this solution were added dropwise a solution of 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g) and triethylamine (3.0 g) in dried methylene chloride (100 ml), and the mixture was stirred for 3 hours. After the reaction was completed, the reaction mixture was washed with 5% hydrochloric acid, water, 5% sodium bicarbonate aqueous solution andwater in turn and then dried. The solvent was distilled off to give amorphous, 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-[N-(1-cyclopropylethoxy)-phenylglycyl]aminopenam-3 -carboxylate (9.7 g). 
     Infrared Absorption Spectrum (CHCl 3 ): 3410, 1785, 1765, 1690 cm -1 . 
     EXAMPLE 2 
     To a solution of pivaloyl chloride (1.4 g) in dried methylene chloride (100 ml) was added dropwise under cooling at -5° C a solution of 1H-tetrazol-1-acetic acid (1.81 g) and triethylamine (1.4 g) in dried methylene chloride (30 ml), and the mixture was stirred for 2 hours at the same temperature. The solution containing a mixed anhydride of 1H-tetrazole-1-acetic acid and pivalic acid prepared above was cooled at -35° C and to the solution were added dropwise a solution of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (4.0 g) and triethlamine (2.0 g) in dried methylene chloride (80 ml), after which the mixture was stirred for 4 hours at the same temperature. After the reaction was completed, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily 2,2,2-tricloroethyl 2-bromoethyl-2-methyl-6-[2-(1H-tetrazol-1-yl)acetamido]penam-3-carbodylate (3.85 g). 
     Infrared Absorption Spectrum (Film): 3250, 1783, 1765, 1635 cm -1 . 
     EXAMPLE 3 
     A solution of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-aminopenam-3-carboxylate hydrochloride (6.95 g) and triethylamine (3.0 g) in dried methylene chloride (100 ml) was cooled at -25° C. To this solution was added dropwise a solution of 3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl chloride (4.5 g) in dried methylene chloride (30 ml), and the mixture was stirred for 33 hours at the same temperature. After the reaction was completed, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (6.75 g). 
     Infrared Absorption Spectrum (Film): 3370, 1790, 1765, 1670 cm -1 . 
     
         __________________________________________________________________________
 ##STR127##                                                               
No.    R.sup.1&#34;  R.sup.2       R.sup.3                                    
                                   Y&#39;          X   Property of the        
__________________________________________________________________________
                                                   product                
    ##STR128##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   N.sub.3     S   mp. 105 to 106° 
                                                   C                      
2                                                                         
    ##STR129##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR130## S   Oil  Infrared          
                                                   Absorption  Spectrum(CH
                                                   Cl.sub.3) 3320,  1790, 
                                                   1765, 1680 cm.sup.-1   
3                                                                         
    ##STR131##   COOCH.sub.2 CCl.sub. 3                                   
                               CH.sub.3                                   
                                    ##STR132## S                          
                                                    ##STR133##            
4                                                                         
    ##STR134##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR135## S   Oil  Infrared          
                                                   Absorption  Spectrum(CH
                                                   Cl.sub.3) 3300,  1790, 
                                                   1765, 1680 cm.sup.-1   
5                                                                         
    ##STR136##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   SCOCH.sub.3 S                          
                                                    ##STR137##            
6                                                                         
    ##STR138##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR139## N   Oil  Infrared          
                                                   Absorption  Spectrum(CH
                                                   Cl.sub.3) 3300,  1788, 
                                                   1764, 1675 cm.sup.-1   
7                                                                         
    ##STR140##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR141## S   Oil  Infrared          
                                                   Absorption  Spectrum(CH
                                                   Cl.sub.3) 3200,  1790, 
                                                   1770, 1678 cm.sup.-1   
8                                                                         
    ##STR142##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR143## S   Oil  Infrared          
                                                   Absorption  Spectrum(Fi
                                                   lm) 3250,   1780,      
                                                   1765, 1665 cm.sup.-1   
9                                                                         
    ##STR144##   COOCH.sub.3   CH.sub.3                                   
                                    ##STR145## S   Oil  Infrared          
                                                   Absorption  Spectrum(Fi
                                                   lm) 3300,  1785, 1745, 
                                                   1690 cm.sup.-1         
10                                                                        
    ##STR146##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR147## S   Oil Infrared           
                                                   Absorption Spectrum(Fil
                                                   m) 3270, 1780, 1760,   
                                                   1710, 1680 cm.sup.-1   
11                                                                        
    ##STR148##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR149## S   Oil Infrared           
                                                   Absorption Spectrum(Fil
                                                   m) 3270, 1760, 1710,   
                                                   1680 cm.sup.-1         
12                                                                        
    ##STR150##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   OCH.sub.3   S                          
                                                    ##STR151##            
13                                                                        
    ##STR152##   COOCH.sub.3   CH.sub.3                                   
                                    ##STR153## S                          
                                                    ##STR154##            
14                                                                        
    ##STR155##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR156## S   Amorphous              
15                                                                        
    ##STR157##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR158## S   Amorphous Infrared     
                                                   Absorption Spectrum(Nuj
                                                   ol) 3300, 1780, 1770,  
                                                   1665 cm.sup.-1         
16                                                                        
    ##STR159##   COOCH.sub.3   CH.sub.3                                   
                                   OCH.sub.3   S                          
                                                    ##STR160##            
17                                                                        
    ##STR161##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    ##STR162## S   mp 148 to 149°  
                                                   C                      
18                                                                        
    ##STR163##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   SCN         S   Oil Infrared           
                                                   Absorption Spectrum(Fil
                                                   m) 1785, 1760, 1690    
                                                   cm.sup.-1              
19                                                                        
    ##STR164##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   SCN         S   Oil Infrared           
                                                   Absorption  Spectrum(Fi
                                                   lm) 1780, 1765, 1680   
                                                   cm.sup.-1              
20                                                                        
    ##STR165##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   SCN         S   Powder Infrared        
                                                   Absorption Spectrum(Nuj
                                                   ol) 1785, 1770, 1670   
                                                   cm.sup.-1              
21                                                                        
    ##STR166##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   SCN         S   mp 137 to 140°  
                                                   C                      
22                                                                        
    ##STR167##   COOH          CH.sub.3                                   
                                   SCOCH.sub.3 S   N,N&#39;-dibenzylethyl-    
                                                   enediamine salt mp 105 
                                                   to 107° C       
23                                                                        
    ##STR168##   COOH          CH.sub.3                                   
                                    ##STR169## S   N,N&#39;-dibenzylethyl-    
                                                   enediamine salt mp     
                                                   100° C (dec.)   
24                                                                        
    ##STR170##   COOH          CH.sub.3                                   
                                    ##STR171## S   mp 120° C       
25                                                                        
    ##STR172##   COOH          CH.sub.3                                   
                                    ##STR173## S   N,N&#39;-dibenzylethyl-    
                                                   enediamine salt mp 117 
                                                   to 119° C       
                                                   (dec.)                 
26                                                                        
    ##STR174##   COOH          CH.sub.3                                   
                                    ##STR175## S   mp 152 to 154°  
                                                   C                      
27                                                                        
    ##STR176##   COOH          CH.sub. 3                                  
                                    ##STR177## S   N,N&#39;-dibenzylethyl-    
                                                   enediamine salt mp 150 
                                                   to 152° C       
                                                   (dec.)                 
28                                                                        
    ##STR178##   COOH          CH.sub.3                                   
                                    ##STR179## S   Sodium salt mp         
                                                   200° C (dec.)   
29                                                                        
    ##STR180##   COOH          CH.sub.3                                   
                                    ##STR181## S   Sodium salt mp 185 to  
                                                   186° C (dec.)   
30                                                                        
    ##STR182##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   SCN                                    
                                                ##STR183##                
                                                   Colourless powder      
31                                                                        
    ##STR184##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                    Br                                    
                                                ##STR185##                
                                                   mp 114 to 115°  
                                                   C (dec.)               
32                                                                        
    ##STR186##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br                                     
                                                ##STR187##                
                                                   Amorphous              
33                                                                        
    ##STR188##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br          S   mp 90 to 93° C  
34                                                                        
    ##STR189##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Cl          S   mp 104 to 105°  
                                                   C                      
35                                                                        
    ##STR190##   COOH          CH.sub.3                                   
                                   Br          S   mp 164.5 to            
                                                   165.5° C        
36                                                                        
    ##STR191##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br          S   Powder                 
37                                                                        
    ##STR192##   COOCH.sub.3   CH.sub.3                                   
                                   Br          S                          
                                                    ##STR193##            
38                                                                        
    ##STR194##                                                            
                  ##STR195##   CH.sub.3                                   
                                   Br          S   Oil                    
39                                                                        
    ##STR196##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br          S   Amorphous              
40                                                                        
    ##STR197##                                                            
                  ##STR198##   CH.sub.3                                   
                                   Br          S   White crystalline      
                                                   powder                 
41                                                                        
    ##STR199##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br          S   Powder                 
42 CH.sub.3 SCH.sub.2 CONH                                                
                 COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br          S   mp 71 to 73° C  
                                                   (dec.)                 
43                                                                        
    ##STR200##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Br                                     
                                                ##STR201##                
                                                   mp 115 to 116°  
                                                   C (dec.)               
44                                                                        
    ##STR202##   COOCH.sub.2 CCl.sub.3                                    
                               CH.sub.3                                   
                                   Cl                                     
                                                ##STR203##                
                                                   mp 130 to 131°  
__________________________________________________________________________
                                                   C                      
 
    
     Reaction of: ##STR204## 
     EXAMPLE 1 
     Acetic acid (1 ml) and zinc powder (0.75 g) were added to a solution of 2,2,2-trichloroethyl 2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylate (0.65 g) in dimethylformamide (3 ml) under ice-cooling and the mixture was stirred for 2 hours at the same temperature. After the reaction, the reaction mixture was filtered and the filtrate was poured into 5% hydrochloric acid (20 ml) and then extracted with ethy acetate. The extract was washed with water, dried and the solvent was distilled off to give oil (0.365 g). After dissolving the oil in acetone (0.7 ml), to this solution was added a solution of N,N&#39;-dibenzylethylenediamine diacetate (0.142 g) in water (5 ml) and precipitated powder was filtered. The powder has purified by reprecipitation method from a mixture of methanol and water to give N,N&#39;-dibenzyl-ethylenediamine 2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.211 g) mp. 105° t 107° C. 
     Analysis for C 18  H 19  N 2  O 5  S 2 .1/2 C 16  H 22  N 2 .H 2  O: Calc&#39;d C 57.19, H 5.87, N 7.69. Found: C 57.18, H 5.58, N 7.44. 
     Infrared Absorption Spectrum (Nujol): 3300, 1772, 1690, 1670 cm -1 . 
     EXAMPLE 2 
     Acetic acid (1 ml) and zinc powder (0.80 g) were added to a solution of 2,2,2-trichloroethyl-2-piperidinethiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.95 g) in dimethylformamide (5 ml) under ice-cooling and the mixture was stirred for 1 hour and 40 minutes. After the reaction, zinc powder was filtered off and the filtrate was poured into ethyl acetate. The solution was washed with 3% hydrochloric acid and then with water (four times) and dried over magnesium sulfate. After dryng, the solvent was distilled off and the residue was dissolved in a small amount of methanol. To this solution was added on aqueous solution of N,N&#39;-dibenzylethylenediamine diacetate and precipitates were collected by filtration, washed with water to give N,N&#39;-dibenzylethylenediamine2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.30 g), mp. 100° C (dec.). 
     Analysis for C 22  H 26  O 4  N 3  S 3 .1/2 C 16  H 22  N: Calc&#39;d: C 57.03, H 6.22, N 8.87. Found: C 57.00, H, 5.87, N, 8.60. 
     Infrared Absorption Spectrum (Nujol): 3280, 1777, 1660 cm -1 . 
     EXAMPLE 3 
     2,2,2-Trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylate (1.00 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.5 ml) and then zinc powder under cooling at -15° C and the mixture was stirred for 6 hours. After the reaction, zinc powder was filtered off and the filtrate was poured into ethyl acetate. The solution was washed 4 times with water and dried pver magnesium sulfate. After drying, the solvent was distilled off and and the residue was dissolved in a small amount of methanol and then pulverized by adding water to the solution. The powder was collected by filtration, washed with water and dried to give 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylic acid (0.50 g), mp. 120° C. 
     Analysis for C 22  H 23  O 4  N 3  S.1/2 H 2  O: Calc&#39;d: C 60.81, H 5.56, N 9.67. Found: C 60.49, H 5.40, N 9.44. 
     Infrared Absorption Spectrum (Nujol): 3400, 1780, 1745 cm -1 . 
     EXAMPLE 4 
     2,2,2-Trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (0.67 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.8 ml) and zinc powder (0.7 g) under cooling at -15° C and the mixture was stirred for 2 hours at the same temperature. After the reaction, zinc powder was filtered off and the filtrate was poured into 5% hydrochloric acid (20 ml) and then extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was dissolved in methanol (0.8 ml) and to this solution was added a solution of N,N&#39;-dibenzylethylenediamine diacetate (0.18 g) in water (5 ml) and precipitates were collected by filtration, washed with water and dried to give N,N&#39;-dibenzylethylenediamine 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[3-(2-chlorophenyl)-5-methylisoxazole-4-carboxamido]penam-3-carboxylate (0.24 g), mp. 117° to 119° C (dec.). 
     Infrared Absorption Spectrum (Nujol): 3400, 1778, 1665 cm -1 . 
     EXAMPLE 5 
     2,2,2-Trichloroethyl 2-(1methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) acetamido]-penam-3-carboxylate (0.6 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.9 ml) and zinc powder (0.8 g) under cooling at -15° C and the mixture was stirred for 1.5 hours at the same temperature. After the reaction, zinc powder was filtered off and the filtrate was poured into 5% hydrochloric acid (20 ml) and then extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue was crystallized from ether to give 2-(1-methyl-1H-tetrazol-5-thiomethyl-2-methyl-6-[2-(1H-tetrazol-1-yl) acetamido]penam-3-carboxylic acid (0.25 g), mp. 152° l to 154° C. 
     Infrared Absorption Spectrum (Nujol): 3230, 1780, 1738, 1692 cm -1 . 
     EXAMPLE 6 
     2,2,2-Trichloroethyl 2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.94 g) was dissolved in dimethylformamide (5 ml). To this solution were added under ice-cooling acetic acid (0.7 ml) and then zinc powder (0.80 g) under stirring and the mixture was stirred for 2.5 hours. After the reaction, zinc powder was filtered off and the filtrate was dissolved in ethyl acetate. The solution was washed with 3% hydrochloric acid, 3 times with water and dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was dissolved in a small amount of methanol and then crystallized by adding an aqueous solution of N,N&#39;-dibenzylethylenediamine diacetate (0.36 g). Crystals were collected by filtration and washed with a mixture of ethanol and water and dried to give N,N&#39;-dibenzylethylenediamine 2-(1-methyl-1H-tetrazol-5-yl) thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.50 g), mp. 150° to 152° C (dec.). 
     Analysis for C 18  H 18  O 4  N 6  S 2 .1/2 O 16  H 22  N 2 .1/2 H 2  O: Calc&#39;d: C 54.48, H 5.28, N 17.17. Found: C 54.45, H 5.29, N 17.00. 
     Infrared Absorption Spectrum (Nujol): 3370, 1763, 1674 cm -1 . 
     EXAMPLE 7 
     2,2,2-Trichloroethyl 2-chloromethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylate (1.5 g) was dissolved in dried dimethylformamide (8 ml) and to this solution were added formic acid (1.5 ml) and then zinc powder (1.5 g) under stirring while ice-cooling. After stirring for 2 hours at the same temperature, zinc powder was filtered off and washed with dimethylformamide (5 ml). The filtrate and the washings were added to a mixed cool solution of ethylacetate (30 ml) and 5% hydrochloric acid (15 ml). After extracting with ethyl acetate, the extract was washed with water and dried over magnesium sulfate. The gummy substance (1.16 g) obtained by distilling off the solvent inder reduced pressure was crystallized from a mixed solvent of ethyl acetate and isopropyl ether to give 2-chloromethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylic acid (660 mg) mp. 110° to 112° C (dec.). 
     Analysis for C 16  H 17  N 2  O 4  SCl: Calc&#39;d: 52.10, H 4.65, N 7.60, S 8.69, Cl 9.61. Found: C 51.90, N 4.73, N 7.46, S 8.67, Cl 9.34. 
     Infrared Absorption Spectrum (Nujol): 3325, 1788, 1730, 1635 cm -1 . 
     EXAMPLE 8 
     2,2,2-Trichloroethyl 2-(benzothiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.90 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.7 ml) under ice-cooling and then zinc powder (0.80 g) under stirring, and then the mixture was stirred for 2 hours. After zinc powder was filtered off, the filtrate was dissolved in ethyl acetate and the solution was wshed with 3% hydrochloric acid and then 3 times with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was dissolved in a small amount of acetone. To this solution was added a solution of sodium 2-ethylhexanoate (250 mg) in acetone (5 ml) and the solution was again concentrated. The residue was crystallized by adding ethanol and the crystals were collected by filtration, washed with a small amount of ethanol and dried to give sodium 2-(benzothizol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.50 g), mp. 200° C (dec.). 
     Infrared Absorption Spectrum (Nujol): 3400, 1760, 1670, 1600 cm -1 . 
     EXAMPLE 9 
     2,2,2-trichloroethyl 2-(5-metyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.80 g) was dissolved in dimethylformamide (5 ml). To this solution were added acetic acid (0.5 ml) and then zinc powder (0.80 g) under ice-cooling and the mixture was stirred for 2 hours. Zinc powder was filtered off and the filtrate was dissolved in ethyl acetate. The solution was washed with 5% hydrochloric acid and then 4 times with water and thereafter dried over magnesium sulfate. The residue obtained by distilling off the solvent was dissolved in a small amount of ethyl acetate and to the solution was added a solution of sodium 2-ethylhexanoate (250 mg) in acetone (5 ml), and then the solution was concentrated. The residue was pulverized from ethyl acetate and further the powder was crystallized from ethanol. The crystals were collected by filtration, washed with ethanol and dried to give sodium 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.28 g), mp. 185°  to 186° C (dec.). 
     Infrared Absorption Spectrum (Nujol): 3200, 1757, 1670, 1625 cm -1 . 
     In the similar manner, the following compound was obtained. (1) 2-Bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylic acid (mp. 164.5° to 165.5° C). 
     reaction of: ##STR205## 
     EXAMPLE 1 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidineacetate (454 mg) was dissolved in methylene chloride (20 ml). To this solution was added methanol (5 ml) and thereafter added boron trifluoride etherate (0.124 g) at 0° C. The mixture was stirred for 3 hours at the same temperature and further stirred for 2 hours at 5° to 10° C. After the reaction, the mixture was washed with 5% sodium bicarbonate aqueous solution and with water. After drying the mixture, the mixture was concentrated ane the oily residue (250 mg) was purified by column chromatography on silica gel to give oily methyl 3-methyl-3-methoxy-7-(2-phenoxyacetamido)-cepham-4-carboxylate. 
     Infrared Absorption Spectrum (CHCl 3 ): 3400,1772, 1739, 1688 cm -1 . 
     EXAMPLE 2 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (1.06 g) was dissolved in methylene chloride (20 ml). To this solution were added aniline (0.28 g) and then silver fluoroborate (0.80 g) and thereafter the mixture was stirred for 2 days at room temperature. After the reaction, the reaction mixture was filtered and the filtrate was washed with a dilute phosphoric acid aqueous solution and then with water. After drying the mixture, the mixture was concentrated and the residue was purified by column chromatography on silica gel (25 g) to give methyl 3-metyl-3-anilino-7-(2-phenoxyacetamido)cepham-4-carboxylate )0.38 g), mp. 129° to 130° C. 
     EXAMPLE 3 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (1.26 g) was dissolved in ethyl acetate (15 ml). To this solution was added acetic acid (5 ml) and then silver acetate (0.68 g) under stirring at room temperature. The mixture was stirred for 4 hours at the same temperature. After the reaction, the reaction mixture was filtered and the filtrate was washed with water and then with 5% sodium bicarbonate aqueous solution. The solution was filtered again and the filtrate was washed with water and then dried. The solvent was distilled off and the residue was purified by thin layer chromatography using a mixture of acetone: benzene (1:9) to give amorphous 2,2,2-trichloroethyl 3-acetoxy-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate. 
     Infrared Absorption Spectrum (CHCl 3 ): 3425, 1780, 1750, 1680 cm -1 . 
     EXAMPLE 4 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (2.12 g) was dissolved in methanol (80 ml). To this solution was added silver nitrate (0.68 g) and the mixture was refluxed for 28 hours. After the reaction, precipitates were filtered and the filtrate was concentrated. The obtained residue was extracted with ethyl acetate and the extract was washed with water and then dried. The solvent was distilled off and the obtained residue was purified by column chromatography on silica gel using chloroform as developing solvent to give pale yellow oil of methyl 3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (620 mg.). 
     Infrared Absorption Spectrum (CHCl 3 ): 3400, 1772, 1739, 1688 cm -1 . 
     Similar result was obtained using methylene chloride as solvent and silver fluoroborate instead of silver nitrate. 
     EXAMPLE 5 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.53 g) was idssolved in methanol (20 ml). To this solution was added silver acetate (0.17 g) and the mixture was refluxed for 39 hours. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily methyl 3-methyl-3-methoxy-7-(2-phenoxyacetamido)-cepham-4-carboxylate (200 mg). 
     EXAMPLE 6 
     A mixture of methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidineacetate (0.53 g), mercuric acetate (0.3 g) and methanol (20 ml) were refluxed for 48 hours. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily methyl 3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate (180 mg). 
     EXAMPLE 7 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.53 g) was dissolved in methanol (20 ml). To this solution was added mercuric chloride (0.27 g) and the mixture was refluxed for 24 hours. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily methyl 3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate (220 mg). 
     EXAMPLE 8 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-benzothiazol-2-yl)-dithio-α-isopropenyl-1-azetidineacetate (0.53 g) was dissolved in methanol (20 ml). To this solution was added cupric oxide (0.15 g), and the mixture was refluxed for 72 hours. After the reaction, the reaction mixture was post-treated in the similar manner as described in Example 1 to give oily methyl 3-methyl-3-methoxy-7-(2-phenoxyacetamido)cepham-4-carboxylate (50 mg). 
     EXAMPLE 9 
     2,2,2-Trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-isopropenyl-1-azetidineacetate (0.63 g) and p-toluenesulfonic acid monohydrate (0.19 g) were dissolved in a mixture of methanol (15 ml) and methylene chloride (5 ml). The mixture was stirred for 4.5 hours at 50° C. After the reaction, methanol and methylene chloride were distilled off and the residue was dissolved in ethyl acetate (10 ml). The ethyl acetate layer was washed with a saturated sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The residue obtained by removing the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 3-methyl-3-methoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (120 mg), mp. 132° to 133° C. 
     The following compounds were obtained by using the same procedures as those of the Examples 1 to 9. 
     1. 2,2,2-Trichloroethyl 3-methyl-3-azido-7-(2-phenylacetamido)cepham-4-carboxylate (mp. 136° to 140° C). 
     2. 2,2,2-trichloroethyl 3-methyl-3-hydroxy-7-(2-phenylacetamido)cepham-4-carboxylate (mp. 169° to 171° C). 
     3. 2,2,2-trichloroethyl 3-methyl-3-isopropoxy-7-(2-phenylacetamido)cepham-4-carboxylate (oil). 
     4. 1-Cyclopropylethyl 3-methyl-3-anilino-7-(2-phenylacetamido)cepham-4-carboxylate (colorless oil). 
     5. 2,2,2-Trichloroethyl 3-methyl-3-anilino-7-(2-phenylacetamido)cepham-4-carboxylate (oil). 
     6. 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylic acid (mp. 119° to 123° C (dec). 
     Reaction of: ##STR206## 
     EXAMPLE 1 
     A mixture of 2,2,2-trichloroethyl 2-bromoethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (1.08 g), sodium azide (0.26 g), acetone (20 ml) and water (4 ml) was stirred for 4 hours at room temperature. After acetone was distilled off under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water, with saturated sodium bicarbonate aqueous solution and further with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and a small quantity of ether was added to the residue to give colorless crystals of 2,2,2,-trichloroethyl 3-azido-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (170 mg). This substance was recrystallized from carbon tetrachloride to give crystals melting at 136° to 140° C. 
     Infrared Absorption Spectrum (Nujol): 3310, 2110, 1770, 1746, 1658 cm -1 . 
     EXAMPLE 2 
     2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) was dissolved in absolute dimethylsulfoxide (5 ml). To this solution was added silver fluoroborate (0.20 g) and then the mixture was stirred under shielding from light for 3 hours at room temperature. To the solution was added a solution of triethylamine (0.1 g) in dimethylsulfoxide (0.5 ml) and the solution was further stirred for 5 hours and then allowed to stand overnight at room temperature. Precipitates were filtered off and the filtrate was poured into ice-water and then extracted with ethyl acetate. The extract was washed with water and dried. The residue obtained by distilling off the solvent under reduced pressure was crystallized by a small amount of ether to give colorless crystals of 2,2,2-trichloroethyl 3-hydroxy-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (280 mg) (58%). This substance was recrystallized from a mixed solvent of benzene-n-hexane to give colorless needles melting at 169° to 171° C. 
     Analysis for C 18  H 19  N 2  O 5  SCl 3  : Calc&#39;d: C 44.87, H 3.97, N 5.81, S 6.66, Cl 22.08. Found: C 45.08, H 3.93, N 5.75, S 6.45, Cl 21.96. 
     EXAMPLE 3 
     2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.55 g) was dissolved in a mixture of tetrahydrofuran (5 ml) and methanol (5 ml). To this solution was added silver fluoroborate (0.24 g) under cooling and then the mixture was stirred for 1 hour. The reaction mixture was concentrated and the obtained residue was dissolved in chloroform. This solution was washed with a saturated sodium bicarbonate aqueous solution and with water and dried over magnesium sulfate. The residue obtained by distilling off the solvent was subjected to chromatography on silica gel using chloroform as developing solvent. The obtained crystals were recrystallized from carbon tetrachloride to give 2,2,2-trichloroethyl 3-methyl-3-methoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (0.27 g), mp. 132° to 133° C. 
     The similar result was obtained using methylene chloride instead of tetrahydrofuran in the above example. 
     Infrared Absorption Spectrum (Nujol): 3300, 1780, 1760, 1683 cm -1 . 
     EXAMPLE 4 
     2,2,2-Trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido) penam-3-carboxylate (0.55 g) was dissolved in a mixture of tetrahydrofuran (5 ml) and isopropanol (5 ml). To this solution was added silver fluoroborate (0.24 g) under ice-cooling and the mixture was stirred for 1 hour. The reaction mixture was concentrated and the obtained residue was dissolved in chloroform. This solution was washed with a saturated sodium bicarbonate aqueous solution and with water and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 3-methyl-3-isopropoxy-7-(2-phenylacetamido)-cepham-4-carboxylate (0.10 g). 
     Infrared Absorption Spectrum (Film): 3300, 1760, 1750, 1670 cm -1 . 
     EXAMPLE 5 
     Methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.88 g) was dissolved in methylene chloride (13 ml) containing methanol. To the solution was added silver fluoroborate (0.45 g), and the mixture was stirred for 2 hours. After the reaction, the reaction mixture was filtered and the filtrate was washed with a dilute sodium bicarbonate aqueous solution and then with water. The solution was dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The elute was separated into fractions of each about 20 ml and the seventh to tenth fractions were collected. The solvent was distilled off to give Methyl 3-methoxy-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (0.60 g). 
     Infrared Absorption Spectrum (CHCl 3 ): 3400, 1772, 1739, 1688 cm -1 . 
     The following compounds were obtained by using the same procedures as those of the Examples 1 to 5. 
     1. Methyl 3-aniline-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (mp. 129° to 130° C). 
     2. 1-cyclopropylethyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (colorless oil). 
     3. 2,2,2-Trichloroethyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (oil). 
     4. 3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylic acid. 
     Reaction of: ##STR207## 
     EXAMPLE 1 
     Anilino (0.28 g) was added to a solution of 2,2,2-trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.10 l g) in methylene chloride (15 ml). To the solution was added silver fluoborate 0.45 g under ice-cooling under stirring and stirred at the same temperature for 4 hours. After the reaction, the mixture was filtered and the filtrate was washed with dilute phosphoric acid aqueous solution and water in turn. The solution was dried over magnesium sulphate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) using chloroform. The 12th to 13th fractions of fractions, each of which was separated into 20 cc, were concentrated to give oily 2,2,2-trichlocoethyl 3-anilino-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate. 
     Infrared Absorption Spectrum (CHCl 3 ): 3420, 1772, 1750, 1680 cm -1 . 
     The following compounds were obtained by using the same procedure as that of the Example 1. 
     
         __________________________________________________________________________
                                       Property of                        
No.                                                                       
        R.sup.1   R.sup.2   R.sup.3                                       
                                Y      the product                        
__________________________________________________________________________
    ##STR208##   COOCH.sub.2 CCl.sub.3                                    
                           CH.sub.3                                       
                               N.sub.3 mp. 136 - 140° C            
2                                                                         
    ##STR209##   COOCH.sub.2 CCl.sub.3                                    
                           CH.sub.3                                       
                               OH      mp. 169 - 171° C            
3                                                                         
    ##STR210##   COOCH.sub.2 CCl.sub.3                                    
                           CH.sub.3                                       
                               OCH.sub.3                                  
                                       mp. 132 - 133° C            
4                                                                         
    ##STR211##   COOCH.sub.2 CCl.sub.3                                    
                           CH.sub.3                                       
                                ##STR212##                                
                                       oily                               
5                                                                         
    ##STR213##   COOCH.sub.3                                              
                           CH.sub.3                                       
                               OCH.sub.3                                  
                                       oily                               
6                                                                         
    ##STR214##   COOCH.sub.3                                              
                           CH.sub.3                                       
                                ##STR215##                                
                                       mp. 129 - 130° C            
7                                                                         
    ##STR216##                                                            
                  ##STR217##                                              
                           CH.sub.3                                       
                                ##STR218##                                
                                       colorless oily                     
8                                                                         
    ##STR219##   COOH      CH.sub.3                                       
                                ##STR220##                                
                                       mp. 119 - 123° C            
                                       (dec)                              
__________________________________________________________________________
 
    
     Reaction of: ##STR221## 
     EXAMPLE 1 
     1-Cyclopropylethyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (0.4) was dissolved in dried methylene chloride (10 ml). To this solution was added dropwise a solution of boron trifluoride etherate (50 mg) in dried methylene chloride (3 ml) at 0° C and the mixture was stirred for 5 hours at the same temperature. After the reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and several times with water and then dried. The oil obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give colorless oil of 1-cyclopropylethyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylate (198 mg.). 
     Infrared Absorption Spectrum (Film) 3300, 1777, 1740, 1690 cm 31  1. 
     EXAMPLE 2 
     Methyl 2-oxo-3-(2-phenoxyacetamido)-4-anilinothio-α-isopropenyl-1-azetidineacetate (170 mg) was disolved in dried methylene chloride (4 ml). To this solution was added dropwise a solution of boron trifluoride etherate (25 mg) in dried methylene chloride (2 ml) under ice-cooling and the mixture was stirred for 1 hour at the same temperature. After reaction, the reaction mixture was washed with 5% sodium bicarbonate aqueous solution and with water and then dried. The oil obtained by distilling off the solvent was subjected to column chromatography on silica gel using chloroform as developing solvent to give methyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylate (80 mg), mp 129° to 130° C, from the fifth to eighth fractions of fractions each of which was separated into 50 ml. 
     Infrared Absorption Spectrum (CHCl 3 ) 3420, 1775, 1736, 1691 cm 31  1. 
     In the silimar manner, the following compound was obtained. 
     1. 3-anilino-3-methyl-7-(2-phenoxyacetamido)cepham-4-carboxylic acid (mp 119° to 123° C (dec)). 
     Reaction of: ##STR222## 
     EXAMPLE 1 
     1-Cyclopropylethyl 3-anilino-3-methyl-7-(2-phenoxyacetamido)-cepham-4-carboxylate (142mg) was dissolved in ice-cooled trifluoroacetic acid (1.5 ml) and the mixture was stirred for 1 hour under ice-cooling. After the reaction, the reaction mixture was concentrated under reduced pressure. The residue was dissolved by adding ethyl acetate and extracted with 5% sodium bicarbonate aqueous solution. The extract was adjusted to pH2 with 5% hydrochloric acid and back-extracted with ethyl acetate. The extract was washed with water, dried and the solvent was distilled off. The residue (amorphous) was dissolved in methanol and to this solution was added water little by little. Precifitates were collected by filtration and dried to give powder of 3-anilino-3-methyl-7-(2-phenoxy-acetamido)cepham-4-carboxylic acid (62 mg), mp 119 to 123° C (dec.). 
     Analysis for C 22  H 23  O 5  N3S. 3/2 H 2  O: Calc&#39;d: C 56.40, H 4.95, N 8.97, Found: C 56.57, H 5.05, N 8.97. 
     IR spectrum (Nujol) 3300, 1770, 1735, 1665 cm -1 . 
     In the similar manner, the following compound was obtained. 
     1. 3-bromo-3-methyl-7-(2-phenoxy-acetamido)cepham-4-carboxylic acid (amorphous). 
     Reaction of: ##STR223## 
     EXAMPLE 1 
     5-Methyl-1,3,4-thiadiazole-2-thiol (0.16 g) was dissolved in a mixture of pH 6.5 phosphate buffer (5 ml) and acetone (10 ml). To the solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was washed with sodium bicarbonate aqueous solution and with water and then dried over magnesium sulfate. The solvent was distilled off from the extract and the residue was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(5-methyl-1,3,4-thiadiazol-2-yl)dithio-.alpha.-propenyl-1-azetidineacetate (0.24 g), mp 108° to 109° C, from the fifth to ninth fractions of fractions each of which was separated into 30 ml. 
     Infrared Absorption Spectrum (Nujol): 3280, 1788, 1760, 1654 cm -1 . 
     EXAMPLE 2 
     2-Mercaptobenzothiazole (0.20 g) was dissolved in a mixture of pH 6.7 phosphate buffer (15 ml) and dioxane (15 ml). To the solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.54 g) and the mixture was stirred for 7 hours at room temperature. Dioxane was distilled off from the mixture and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with 2% potassium carbonate aqueous solution and with water and then dried over magnesium sulfate. The residue obtained by distilling off the solvent was purified by column chromatography on silica gel using chloroform as developing solvent to give 2,2,2-trichloroethyl 2-oxo-3-(2-phenylacetamido)-4-(benzothiazol-2-yl)dithio-α-propenyl-1-azetidineacetate (0.10 g), mp 140° to 141° C, from the fourth to sixth fractions of fractions each of which was separated into 30 ml. 
     EXAMPLE 3 
     5-Methyl-1,3-thiadiazole-2-thiol (0.4 g) was dissolved in a mixture of pH 7.3 phosphate buffer (20 ml) and acetone (20 ml). To the solution was added a solution of methyl 2-bromomethyl-2-methyl-6-(2-phenoxyacetamido)penam-3-carboxylate (0.80 g) in acetone (10 ml) and the mixture was stirred for 4 hours at room temperature. After the reaction was completed, acetone was distilled off from the reaction mixture and the residue was extracted with ethyl acetate. The extract was washed with sodium bicarbonate aqueous solution and with water, dried over magnesium sulfate and then the solvent was distilled off. The residue was subjected to column chromatography on silica gel (60 g) and eluted with chloroform. The eluate was separated into about 30 ml fraction to give oily methyl 2-oxo-3-(2phenoxyacetamido)-4-(5-methyl-1,3,4-thiadiazol-2-yl)dithio-.alpha.-propenyl-1 -azetidineacetate (0.22 g) from the eleventh to thirteenth fractions. 
     Inferred Absorption Sprectrum (Chloroform): 3430, 1779, 1742, 1692 cm -1 . 
     Further, oily 4,4-dithiobis[methyl-2-oxo-3-(2-phenoxyacetamido)-α-propenyl-1-azetidineacetate] (0.30 g) was obtained from the eighth to tenth fractions of the above fractions. 
     Infrared Absorption Spectrum (Film) 3280, 1770, 1740, 1680 cm -1 . 
     The following compounds were obtained by using the same procedures as those of the Examples 1 to 3. 
     
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 ##STR224##                                                               
No.                                                                       
   R.sup.1     R.sup.2        R.sup.3                                     
                                  R.sup.4      Property of the            
__________________________________________________________________________
                                               product                    
    ##STR225## COOH           CH.sub.3                                    
                                   ##STR226##  mp 142 to 144° C    
2                                                                         
    ##STR227## COOCH.sub.2 CCl.sub.3                                      
                              &#34;   &#34;            mp 108 to 109° C    
3                                                                         
    ##STR228## COOCH.sub.3    &#34;                                           
                                   ##STR229##  mp 146 to 147 ° C   
4  &#34;           COOH           &#34;   &#34;            mp 146 to 148°  C   
                                               (dec.)                     
5  &#34;           COOCH.sub.2 CCl.sub.3                                      
                              &#34;   &#34;            mp 171 to 174.5° C  
6                                                                         
    ##STR230## COOCH.sub.2 CCl.sub.3                                      
                              &#34;   &#34;            mp 159 to 161° C    
7                                                                         
    ##STR231##                                                            
                ##STR232##    &#34;   &#34;            Oil                        
8                                                                         
    ##STR233## COCH           &#34;   &#34;            mp 76 to 80°  C     
9  &#34;                                                                      
                ##STR234##    &#34;   &#34;            mp 114 to 117° C    
10                                                                        
    ##STR235## COOCH.sub.2 CCl.sub.3                                      
                              &#34;   &#34;            Amorphous                  
11                                                                        
    ##STR236## COOCH.sub.2 CCl.sub.3                                      
                              &#34;   &#34;            Oil                        
12                                                                        
    ##STR237## &#34;              &#34;   &#34;            Amorphous                  
13                                                                        
    ##STR238## &#34;              &#34;   &#34;            mp 136 to 137° C    
14                                                                        
    ##STR239## &#34;              &#34;   &#34;            mp 164 to 165° C    
15 NCCH.sub.2 CONH                                                        
               &#34;              &#34;   &#34;            mp 117 to 119° C    
16                                                                        
    ##STR240##                                                            
                ##STR241##    &#34;   &#34;            mp 149 to 152° C    
17                                                                        
    ##STR242## COOCH.sub.2 CCl.sub.3                                      
                              &#34;   &#34;            mp 175 to 176° C    
18                                                                        
    ##STR243##                                                            
                ##STR244##    &#34;   &#34;            mp 127 to 129° C    
19 &#34;           COOCH.sub.3    &#34;                                           
                                   ##STR245##  Oil                        
20                                                                        
    ##STR246## COOCH.sub.3    &#34;   SCOCH.sub.3  Oil                        
21 &#34;           &#34;              &#34;                                           
                                   ##STR247##  Oil                        
22 &#34;           &#34;              &#34;                                           
                                   ##STR248##  Oil                        
23 &#34;           &#34;              &#34;                                           
                                   ##STR249##  Oil                        
24                                                                        
    ##STR250## COOCH.sub.2 CCl.sub.3                                      
                              &#34;                                           
                                   ##STR251##  Oil                        
__________________________________________________________________________