Patent Publication Number: US-4544755-A

Title: Cleavage of phthalimides to amines

Description:
The present invention relates to a process for the cleavage of phthalimides of the formula I ##STR2## where R is a substituent and the ring A can be further substituted, wherein a compound of the formula I is treated with an alkanolamine. 
     R can be an aliphatic, cycloaliphatic, aromatic or heterocyclic group. 
     Examples of suitable radicals are alkyl which is unsubstituted or substituted by alkoxy, cyano, carboxamido, unsubstituted or substituted amino or aryl; cycloalkyl; aryl which is unsubstituted or substituted by halogen, nitro, alkyl, alkoxy, cyano, carbamyl, formyl, sulfamyl, cyanomethyl, alkoxymethyl, aryloxymethyl, arylthiomethyl, arylsulfonylmethyl, aryl, benzoyl, vinylaryl, vinylimidazolyl or carboxyl; saturated or unsaturated heterocyclic radicals; and alkenyl. 
     Examples of specific radicals R are: CH 3 , C 2  H 5 , C 3  H 7 , C 4  H 9 , C 5  H 11 , C 6  H 13 , C 7  H 15 , C 8  H 17 , C 10  H 21 , C 12  H 25 , C 2  H 4  OCH 3 , C 2  H 4  OC 4  H 9 , C 4  H 8  OCH 3 , (CH 2 ) 5  CN, C 2  H 4  N(CH 3 ) 2 , C 6  H 4  Cl, C 6  H 4  NO 2 , C 6  H 4  CH 3 , C 6  H 4  OCH 3 , C 6  H 3  Cl 2 , C 6  H 3  (NO 2 ) 2 , C 6  H 4  CN, C 6  H 4  COOH, C 6  H 4  CONH 2 , C 6  H 4  CHO, C 6  H 4  SO 2  C 6  H 5 , C 6  H 4  CH 2  CN, C 6  H 4  OCH 3 , C 6  H 4  CH 2  OCH 3 , C 6  H 4  CH 2  SCH 3 , C.sub. 6 H 4  CH 2  SC 6  H 5 , C 6  H 4  CH 2  SO 2  C 6  H 5 , C 6  H 5 , C 6  H 4  COC 6  H 5  and C 2  H 4  C 6  H 5 . 
     The ring A can be further substituted by, for example, chlorine, bromine, nitro, carboxyl, carbamyl or sulfamyl. 
     The compounds of the formula I can be prepared by a conventional method, for example by reacting a halogen compound with potassium phthalimide by the Gabriel method. 
     The cleavage of the phthalimides to give amines and phthalic acids or derivatives thereof is frequently very difficult in practice. Acidic hydrolysis with 20-30% strength hydrochloric acid generally requires prolonged refluxing (Liebig Ann. Chem. 1949, 22) or has to be carried out at 200° C. under superatmospheric pressure (Chem. Ber. 20 (1887), 2224). Alkaline hydrolysis with an aqueous alkali does not in general proceed any further than the phthalamic acid stage. For complete hydrolysis, a downstream treatment with a mineral acid is necessary (Chem. Ber. 37 (1904), 1038). Although the cleavage of the phthalimides of the formula I by means of hydrazine presents scarcely any problems on the laboratory scale, considerable difficulties are encountered on an industrial scale. The sparingly soluble salt of the cyclic phthalic hydrazide is formed in the reaction (Nature (London) 158 (1946), 514) and separates out as a bulky precipitate, the handling of which requires large amounts of solvents and large reaction kettles. The acute toxicity and the high price of hydrazine are also obstacles to the economical use of this method. 
     It was therefore extremely surprising that cleavage of phthalimides can be carried out readily in accordance with the invention. 
     The cleavage of the phthalimide of the formula I is carried out simply by heating the compound in an alkanolamine. This acts both as a solvent and as a reactant. Examples of suitable alkanolamines are monoethanolamine, monoisopropanolamine, 3-aminopropanol and aminoethylethanolamine. Monoethanolamine is preferably used. The reaction temperatures are from 40° to 140° C., preferably from 60° to 100° C. The method of working up the reaction mixture depends on the nature of the amine liberated, and is as a rule very simple. For example, water-insoluble, solid amines can usually be precipitated by adding water. Water-soluble amines can be isolated by extraction with a solvent, such as methylene chloride, ethyl acetate or toluene. The phthalic acid alkanolamides liberated in the reactions remain in the aqueous phase and can therefore be separated off without difficulty. 
     The cleavage can of course also be carried out in the presence of an additional solvent, this being done in particular where the cleavage products are capable of reacting with the alkanolamines, so that an excess of alkanolamine over and above the stoichiometric amount is disadvantageous. For example, where exchangeable halogen atoms are present, it is advisable to carry out the reaction only with about the stoichiometric amount of the alkanolamine. 
     Examples of solvents which can be used in the cleavage are alkanols, glycols, glycol ethers, ketones, halohydrocarbons or hydrocarbons, specific examples being methanol, ethanol, propanol, butanol, glycol, methyl glycol, ethyl glycol, acetone, methyl ethyl ketone, tetrahydrofuran, dioxane, methylene chloride, chlorobenzene and toluene. 
     As a rule, the phthalimido radical serves as a protective group, i.e. its presence permits reactions which are impossible in the presence of a free amino group. For example, when the amino group is protected it is possible to carry out alkylations, acylations, nitrations, halogenations, chlorosulfonations or oxidations. 
     The novel process is particularly useful in the case of compounds possessing aromatic or heteroaromatic radicals R, in particular phenyl, naphthyl, thiazolyl, thiadiazolyl, imidazolyl, benzothiazolyl, benzimidazolyl, indolyl, pyridyl or quinolyl radicals. 
    
    
     EXAMPLE 1 
     2-Aminobenzylcyanide 
     100 g of 2-cyanomethyl-N-phenylphthalimide were introduced, a little at a time, into 100 g of monoethanolamine at 80° C. After 10 minutes, the mixture was cooled to 20° C., and 400 g of ice water were added dropwise. The precipitated product was filtered off under suction and washed neutral with ice water. 
     Yield: 40 g (80% of theory); m.p. 70° C. 
     EXAMPLE 2 
     1-(2-Aminobenzyl)-imidazole 
     30 g of 2-(1-imidazolylmethyl)-N-phenylphthalimide in 60 g of monoethanolamine were stirred for 1 hour at 70° C. The mixture was cooled to 20° C., after which 200 g of ice water were added dropwise and the mixture was extracted with three times 150 g of ethyl acetate. The combined extracts were dried, and evaporated down under reduced pressure. 
     Yield: 13 g (75% of theory); m.p. 42° C. 
     EXAMPLE 3 
     4,4&#39;-Diaminobenzophenone 
     20 g of bis-[4,4&#39;-(carboxyphthalimidoyl)]-benzophenone in 30 g of monoethanolamine were stirred for 15 minutes at 80° C., after which 200 g of ice water were added dropwise at 20° C. The precipitate was filtered off under suction, washed with water and dried. 
     Yield: 7 g (92% of theory); m.p. 236° C. 
     The following amines were prepared from the compounds of the formula I, using methods similar to those described in Examples 1 to 3: 
     
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 ##STR3##                                                                 
Ex-                                                                       
am-                                   mp.                                 
ple  R.sup.1              R.sup.2     [°C.]                        
______________________________________                                    
      ##STR4##            H            38                                 
5                                                                         
      ##STR5##            H            86                                 
6                                                                         
      ##STR6##            H            64                                 
7                                                                         
      ##STR7##            H           150                                 
8    2-CN                 H            48                                 
9                                                                         
      ##STR8##            H           223                                 
10   2-CH.sub.2 OCH.sub.3 H           oil                                 
11                                                                        
      ##STR9##            H            90                                 
12                                                                        
      ##STR10##           H           106                                 
13   2-CH.sub.2 SH        H           oil                                 
14   2-CH.sub.2 SC.sub.6 H.sub.5                                          
                          H            75                                 
15   2-CH.sub.2 SO.sub.2C.sub.6 H.sub.5                                   
                          H           178                                 
16                                                                        
      ##STR11##           3-Cl         76                                 
17   2-CH.sub.2 OCH.sub.3 3-Cl        oil                                 
18                                                                        
      ##STR12##           3-Cl         97                                 
19                                                                        
      ##STR13##           3-Cl        158                                 
20   2-CH.sub.2 SO.sub.2 C.sub.6 H.sub.5                                  
                          6-CH.sub.2 SO.sub.2 C.sub.6 H.sub.5             
                                      216                                 
21                                                                        
      ##STR14##           4-NO.sub.2  227                                 
22                                                                        
      ##STR15##           H            72                                 
23                                                                        
      ##STR16##           H           201                                 
24   2-CHCHCN             4-NO.sub.2  266                                 
25   2-CHO                4-NO.sub.2  200                                 
26   2-CHO                4-Cl         90                                 
27   2-CH.sub.2 OH        3-Cl         75                                 
28   2-CN                 4-NO.sub.2  209                                 
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     The following heterocyclic amines can also be prepared by methods similar to those described: 
     2-amino-4-phenylthiazole, 
     2-amino-5-nitrothiazole, 
     2-amino-3-cyano-4-methyl-5-aminocarbonylthiophene and 
     2-amino-5-nitrobenzothiazole.