PROCESS FOR THE PREPARATION OF BETA-LACTAMS

Abstract: A process for the preparation of a lactam of formula: wherein R¹, R² and R³ may be the same or different and each represents hydrogen or C₁₋₆ alkyl, or R¹ and R² may together complete a carbocyclic ring; R⁴ is hydrogen, -CH -CO₂R P where R P is a carboxy-protecting group, -CH₂-CH₂-OH or a protected derivative thereof, -CH₂-CH₂-CHO or a protected derivative thereof, or R³ and R⁴ together complete a car­ bocyclic ring; R⁴ is hydrogen or C₁₋₆ alkyl; and R⁵ is hydrogen, an organic radical wherein any reactive groups may be pro­ tected or a subgroup of formula-NR α R β wherein R α and R β are the same or different and each is hydrogen or an organic radical, or a subgroup of OR δ wherein R δ is a hydroxyl protect­ ing group, which process comprises treatment of an iron complex of formula with an oxidising agent.

Description: CHEMICAL PROCESS This invention relates to a chemical process for the preparation of P-lactams, which are themselves useful as intermediates in the production of antibacterial compounds. J. Chem. Soc. Chem, Comm., 1977,851 and J. Organometallic Chem., 1979, 182, Cli disclose a process for the preparation of P-and b-lactones, which process comprises oxidation of a compound of formula I: EMI1.1 wherein Ra and Rd are hydrogen and Rb and Rc are methyl, Rb and Rc are hydrogen and Ra and Rd R represent -(CH2)2-, or Ra and Rb together represent (CH2)3- and Rc and Rd are hydrogen; with a cerium IV salt. It has now been found that high yields of (3-lactams may be obtained by oxidation of tricarbonyliron- X-allyl- Cr-lactam complexes. Accordingly the present invention provides a process for the preparation of a lactam of formula (II): EMI2.1 wherein R1, R2 and R3 may be the same or different and each represents hydrogen or C1-6 alkyl, or R1 and R2 may together complete a carbocyclic ring; R is hydrogen, -CH2-CO2RP where RP is a carboxy protecting group, -CH2-CH2-OH or a protected derivative thereof, -CH2-CH2-CHO or a protected derivative thereof, or R and R4 together complete a carbocyclic ring;R4' is hydrogen or C1-6 alkyl; and R is hydrogen, an organic radical wherein any reactive groups may be protected or a subgroup of formula-NR&alpha;Rss wherein R&alpha; and Rss are the same or different and each is hydrogen or an organic radical, or a subgroup of ORb wherein Ras is a hydroxyl protecting group, which process comprises treatment of an iron complex of formula (III): EMI2.2 R1 wherein R1 R2 R3 R4 R4 and R5 wherein RÚ, , Rê, R , , R4' and R5 are as defined with respect to a formula (II),with an oxidising agent. Compounds of formula (II) contain at least one chiral centre viz the carbon atom marked 3 below. When R4 and R4' are not the same the compounds have a second chiral centre carbon 4 EMI3.1 Thus when we refer generally to compounds of formula (II) herein, we mean mixtures of stereochemical isomers as well as pure isomers. This cyclisation may be carried out in a range of organic solvents subject to the solubility of the iron complex (III) and the oxidizing agent. It is convenient to use a polar solvent, preferably a water-miscible solvent such as, for example, tetrahydrofuran, acetone, dimethylformamide, dimethylsulphoxide, hexamethylphosphoramide, acetonitrile, dimethoxyethane, dioxan or an alcohol such as methanol, ethanol, propanol or butanol. Suitable solvents include acetonitrile or ethanol. Preferably the solvent is ethanol The oxidising agent used in the above process should have a finite solubility in the reaction solvent. Suitable oxidising agents include iron III salts, silver I salts, and cerium IV salts. A preferred oxidising agent is a cerium IV salt, in particular cerium IV ammonium nitrate. The initial stage of the process is generally carried out at moderate to low temperatures such as, for example -50 to + 300C, and the reaction mixture allowed to equilibrate to room temperature during the course of the reaction. The period for which the reaction is allowed to proceed depends upon the particular starting materials employed. The course of the reaction may be followed by conventional methods such as thin layer chromatography and terminated when an optimum quantity of product is present in the reaction mixture. Suitably the group R5 is hydrogen, an amino protecting group, such as for example p-nitrobenzyl, or a sub-group of formula: EMI4.1 * wherein R is C1 6 alkyl and R is an organic group such that - C02R is an ester group. Suitable groups R include methyl, ethyl, and nand iso-propyl. Certain compounds within formula (III) are disclosed in Tetrahedron, 1976, 32, 2123, Tetrahedron, 1974, 30, 839, and Chemische Berichte,1979, 112, 3644. Compounds of formula (III) may be prepared by reaction of a metal complex of formula (IV): EMI5.1 wherein R1, R2, R3, R4 and R4' are as defined with respect to formula (II) with a compound of formula (V): R5 - NH2 (V) wherein R5 is as defined with respect to formula (II) in the presence of a Lewis.acid. Suitable Lewis acids include zinc chloride. An excess of the compound of formula (V) is used in the reaction to ensure a reasonable extent of reaction; preferably a 5 to 10-fold excess is used. The 1 2 R2, 3 4 4' 5 groups R , R , R , R , R and R5 are chosen according to the ss-lactam antibiotic to be synthesised using the compound of formula (II) as starting material. Suitably R5NH2is ammonia, hydrazine, hydroxylamine, a primary amine, N-monosubstituted hydrazine, N,N-disubstituted hydrazine or O-substituted hydroxylamine. Compounds of formula (II) are useful intermediates in the synthesis of P-lactam antibiotics. In a preferred embodiment of the present invention the groups R4 and R5 are selected to facilitate ring closure to produce carbapenem derivatives of formula (VI) EMI6.1 wherein R6 is a carboxyl blocking group, R7 is hydrogen, C16 alkyl or a group -S-R9, wherein R9 is an S organic radical, and R is ethyl, ethenyl or a group of sub-formula (a): -CH(CH3)-OR-10 (a) wherein R is hydrogen or an acyl group or a group of formula R11O3S- wherein R is a salting ionor a methyl or ethyl group. Formula (VI) includes compounds with antibacterial activity per se; however further antibacterially active compounds may be produced by removal of the carboxyl blocking group R6 to produce the free carboxyl group. A conventional reaction sequence leading to certain compounds of formula (VI), starting from compound (VII) is illustrated in scheme 1. Compound (VII) is an example of a monocyclic -lactani (II) produced by the process of the present invention. It will be seen from the scheme that the process of the present invention may be used for the preparation of intermediates for pharmaceutically useful compounds. EMI7.1 The starting material (VII): EMI8.1 wherein RZ is an hydroxyl-protecting group removable by base hydrolysis; and RX is an amino-protecting group may be produced by the process of the present invention from the iron complex of formula (XIV): EMI8.2 wherein RZ and RX are as defined hereinbefore. Suitably RZ may be an acetyl group and RX a p-nitrobenzyl group. Conversion of compound (VII) to compound (VIII) comprises (1) ozonolysis of the carbon-carbon double bond, (2) reduction of the ozonide produced with sodium borohydride in ethanol to give a free hydoxyl compound, which may then be (3) treated with a compound RYC1 such that RY is a hydroxyl protecting group. Compound (IX) may be prepared by catalytic hydrogenolysis of the fully protected compound (VIII). Compound (X) may be produced from (IX) in three steps. the first being reaction with a suitably protected derivative of glyoxylate hydrate. Suitably Rw may be a p-nitrobenzyl group0 The second step comprises treatment with thionyl chloride in the presence of 2,6-lutidine; the third step being treatment with a phosphine such as triphenylphosphine in the presence of 2,6-lutidine. The compound of formula (X) should then be treated with sodium methoxide in methanol to remove the hydroxyl protecting group RZ, giving the compound of formula (XI). The free hydroxyl group in compound (XI) may be cyclised to give the carbapenem derivative (XII) via an oxidation step using acetic anhydride in dimethylsulphoxide. The compound of formula (XIII) is obtained by reaction of the carbapenem derivative (XII) with a thiol of formula RVSH, such that Rv is an organic radical wherein any reactive groups may be protected, in the presence of an inorganic base. Suitably the inorganic base is a carbonate, in particular an alkali metal carbonate such as potassium carbonate0 The reaction is conveniently carried out in a polar organic solvent such as dimethylformamide at moderate temperatures i.e. not in excess of 400C, room temperature being most appropriate. Compounds of formula (II) wherein R5 is a hydroxyl protected derivative of -CH2CH2OH and R5 is a sub group of formula: EMI9.1 wherein R and R are as hereinbefore defined, are useful intermediates in a further process for preparing bicyclic P-lactam compounds. A conventional reaction sequence leading to a class of compounds within formula (VI) is illustrated in scheme 2. EMI10.1 The compounds of the formula (XViII), wherein RZ t and R are as described hereinbefore, may be obtained from compound of formula (XVII), wherein RZ., RY, R+ and Rt are as described hereinbefore, by a process which comprises (1) removal of the hydroxyl-protecting group RZ by base hydrolysis with sodium methoxide in methanol, (2) treatment with acetic anhydride in dimethylsulphoxide and (3) treatment with sodium hydride. Compounds of formula (XVII) are prepared in turn from compounds of formula (XVI), wherein R , R and R* are as described hereinbefore, by a conventional sequence of reactions such as described in Scheme 1 for the conversion of compound (VII) to (VIII). The following examples illustrate this invention. The following descriptions relate to the preparation of useful starting materials. M.p.'s were determined with a Kofler hot-stage apparatus. 1H nmr spectra were obtained for solutions in CDCl3 (Me4Si as internal standard). Petroleum ether refers to the fraction b.p. 40-60 . Solutions were dried over sodium sulphate, and solvents by standard methods. Chromatography was performed on Merck-Kieselgel 60 (0.04-0.063 mm) and (0.063-0.2 mm). General Procedure for Tricarbonyl Iron Lactam Complex ¯reParation Benzylamine was added to a solution of the tricarbonyl iron lactone complex and zinc chloride in tetrahydrofuran (THF)/ether or ether. When the reaction was complete (as indicated by thin layer chromatography) the mixture was filtered and the solvent removed under reduced pressure to give the crude product, which was purified by chromatography and subsequent recrystallisation from petroleum ether. Description 1 Tricarbonyl- (2,3, 4--3-buten-2-yl )-l-benzylaminocarbonvl iron (1) Tricarbonyl-(2,3,4-v-3-buten-2yl)-1-oxycarbonyl iron (100 mg, 0.42 mmol) with zinc chloride (110 mg, 0.84 mmol) and benzylamine (540 mg, 5 mmol) in THF/ether (1:3, 5 ml) gave tricarbonyl-(2,3,4-y-3-buten-2-yl)-1-benzylamino- carbonyl iron (1) (117 mg, 81%), m.p. 76-78 , smax 3080, 2980, 2850, 2070, 2010, 1585, 1570, 1405 and 1165 cm 5 7.35-7.04 (5H, m), 4.84 (1H, ddd, J 14, 8 and 8 Hz), 4.40 (1H, m), 4.26 (1H, ABq, J 15 Hz); 4.14 (1H, ABq; J 15 Hz), 3.73 (1H, ddd, J 8, 2 and 2 Hz), 3.46-3.20 (2H, m), aril 2.88 (1H, dd, J 12 and 2 Hz) (Found: C, 54.81; H, 3.93; N, 4.25. C15H13N04Fe requires C, 55.08; H, 4.01; N, 4.28%.) Description 2 Tricarbonyl-(2,3,4-#-3-methyl-3-buten-2-yl)-1-benzylamino- carbonyl iron (2) Tricarbonyl-(2,3,4-q-2-methyl-3-buten-2-yl)-1-oxy- carbonyl iron (100 mg, 0.4 mmol) with zinc chloride (107 mg, 0.8 mmol) and benzylamine (510 mg, 4.7 mmol) in THF/ether (1:3, 5 ml) gave tricarbonyl-(2,3,4-#-3-methyl-3- 2-yl)-l-benzylaminocarbonyl iron (2) (131 mg, 97%), m.p. 70-720, ';max. 3025, 2920, 2850, 2000, 1980, 1590, 1175, 700 and 665 cm-l; 6 7.34-.7.06 (5H, m), 4.24 (3H, m), 3.56 (lH,dd J 2 and 2 Hz) 3.33 (1H, ABX, J 13 and 6 Hz) 3.14 (1H, ABX, J 13 and 2 Hz), 2.70 (1H, d, J 2 Hz), and 1.94 (3H, s) (Found: C, 56.04; H, 4.40; N, 4.07. C16H15NO4Fe requires C, 56.33; H, 4.43; N, 4.12%). Description 3 TriCarbOnvl-(2,3,4-R-2,3-dimethyl-3-buten-2-yl)-1-benzYl- aminocarbonyl iron (3) Tricarbonyl-(2,3,4-#-2,3-dimethyl-3-buten-2-yl)-1- oxycarbonyl iron (100 mg, 0.37 mmol) with zinc chloride (100 mg, 0.735 mmol) and benzylamine (483 mg, 4.5 mmol) in ether (6 ml) gave tricarbonyl-(2,3,4--2,3-dimethyl-3- buten-2-yl)-l-benzylaminocarbonyl iron (3) (100 mg, 75%), m.p. 98-1000, smax 2900, 2025, 1990, 1570, 1440, 1185 and 705 cm 1; b 7.33-7.08 (5H, m), 4.28 (2H, s), 3.42 (1H, d, J 2 Hz), 3.14 (2H, s), 2.44 (1H, d, J 2 Hz), 2.08 (3H, s), and 1.89 (3H, s) (Found: C, 57.55; H, 4.80; N, 3.90. C17Hl7NO4 Fe requires C, 57.50; H, 4.80; N, 3.95%). Description 4 E-tricarbonyl-(2,3,4-#-3-nonen-2-yl)-l-benzylaminocarbonyl iron (4) A mixture of cis-and trans tricarbonyl-(l,2,3-#-1 nonen -3-yl)-4-oxycarbonyl iron (460 mg, 1.49 mmol) with zinc chloride (200 mg, 1.47 mmol) and benzylamine (750 mg, 7 mmol) in ether (10 ml) gave E-tricarbonyl-(2,3,4-p-3-nonen- 2-yl)-l-benzylaminocarbonyl iron (4) (500 mg, 82%) m.p. 80-86 , Vmax. 2900, 2850, 2030, 1995, 1980 and 1590 cm 6 7.31-7.10 (5H, m), 4.64 (1H, dd, J 12 and 8 Hz), 4.31 (1H, ABq, J 14 Hz), 4.17 (1H, m), 4.16 (1H, ABq, J 14 Hz); 3.78 (1H, m), 3.26 (1H, ABX, J 11 and 6 Hz), 3.10 (1H, ABX, J 11 Hz), 2.3402.24 (1H, m), 1.79-1.68 (1H, m), 1.65-1.41 (2H, m), 1.35 (4H, bd, s), and 0.91 (3H, t, J 6 Hz), (Found: C, 60.5; H, 5.80; N, 3.50. C20H23N04Fe requires, C, 60.6; H, 5.90; N, 3.5%). Description 5 TricarbonYS 2-t-ethylevelopent-l-ene-ll-yl)-2X-benzvl- aminocarbonyl iron (5) A mixture of syn and anti tricarbonyl (1,1',2'-5-1-vinyl-cyclopentan-1-yl)-2-oxycarbonyl iron (lg, 3.6 mmol) with zinc chloride (1 g, 7.35 mmol) and benzylamine (5.0 9, 46.7 mmol) in ether (70 ml) gave tricarbonyl-(1,1',2-¯-ethylcyclopent-1-en - 1'-yl)-2'- benzylaminocarbonyl iron (5) (0.5 g, 38%) (48% based on starting material) m.p. 98-100 dec., v max. 2900, 2020, 1990, 1980, 1580 and 680 cm ; 5 7.39-7.09 (5H, m), 4.30-4.06 (4H, m), 3.27 (2H, m), 2.60-2.26 (2H, m), and 2.14-1.60 (4H, m) (Found: C, 58.60; H, 4.55; N, 3.75 C18H17NO4Fe requires C, 58.88; H, 4.66; N, 3.80%). Description 6 Tricarbonyl (1,1',2'-#-1-vinyl-cyclopentan-1-yl)-2-benzyl aminocarbonvl iron (6a) and tricarbonvl (1.1'-2-#-ethyl- cyclosent-1-ene-1'-yl)-2'-benzylaminocarbonyl iron (6b) Tricarbonyl-(1,1',2- < -ethylcyclopent-1-en-1-yl)-2'- oxycarbonyl iron (100 mg, 0.36 mmol) with zinc chloride (98 mg, 0.72 mmol) and benzylamine (385 mg, 3.6 mmol) in THF/ether (1:4, 10 ml) gave tricarbonyl (1,1',2'- < -1- vinyl-cyclopentan-l-yl)-2-benzylaminocarbonyl iron (6a) (52 mg, 39%) m.p. 95-98 , may 3020, 2960, 2860, 2070, max -l 2010, 1960, 1590, 1170, 700, and 665 cm 1; 6 7.34-7.18 (3H, m), 7.17-7.04 (2H, m), 5.07 (1H, dd, J 8 and 12 Hz), 4.88 (1H, ABq, J 14 Hz), 3.68 (1H, ABq, J 14 Hz), 3.443.32 (3H, m), and 2.65-1.52 (6H, m) (Found: C, 58.92; H, 4.66; N, 3.80. C18H17NO4Fe requires C, 58.88; H, 4.66; N, 3.80%) and tricarbonyl-(1,1'-2-#-ethylcyclopent-1 ene-1'-yl)-2'-benzylaminocarbonyl iron(6b) (9 mg, 7%) m.p. 95-8 , #max 2900, 2020, 1990, 1980, 1580 and 680 cm-1; 6 7.39-7.18 (3H, m), 7.16-7.07 (2H, m), 4.35 (1H ABq, J 15 Hz), 4.27 (1H, d, J 6 Hz), 4.22 (1H, bd,s), 4.13 (1H, ABq, J 15 Hz), 3.37 (1H, ABX, J 13 and 6 Hz), 3.21 (1H, ABq, J 13 Hz), 2.92-2.75 (1H, m), 2.48-2.37 (2H, m), 2.02 (1H, dd, J 15 and 8 Hz), 1.96-1.82 (1H, m), and 1.58-1.37 (1H, m) as an inseparable mixture. Description 7 Tricarbonyl-(2,3,4-#-3-buten-2-yl)1-(carbomethoxy-p-benzvloxy- phenyl)methylaminocarbonyl iron (7) Tricarbonyl-(2,3,4-n,-3-buten-zyl)-1-oxycarbonyl iron (38 mg, 0.16 mmol) with zinc chloride (43 mg, 0.3 mmol) and methyl-p-benzyloxyphenyl-C-glycinate (0.6 g, 2.2 mmol) in THF/ether (1: :4, 13 ml) gave tricarbonyl-(2,3,4-t-3-buten- 2-yl)-1-(carbomethoxy-p-benzyloxyphenyl)methylaminocarbonyl iron (7) (61 mg, 80%) as an oil, vJmax 3060, 3030, 2950, 2870, 2090, 2010, 2000, 1740, 1610, 1590, 1510, 1240, 1160, -l 690 and 665 cm Description 8 Tricarbonvl-(2,3.4-h-3-methvl-3-buten-2-ol)-1-p-nitro- benzylaminocarbonyl iron (8) Tricarbonyl-(2,3,4- < -3-methyl-3-buten-2-yl)-1-oxy- carbonyl iron (70 mg, 0.3 mmol) with zinc chloride (76mg, 0.6 mmol) and p-nitrobenzylamine (45.6 mg, 3 mmol) in THF/ether (2: :1, 9 ml) gave tricarbonyl-(2,3,4-n-3-methyl-3- buten-2-yl)-l-p-nitrobenzylaminocarbonyl iron (8) (89 mg, 85%), m.p. 118-123 , may 3040, 3000, 2950, 2870, 2095, 2025, 2000, 1580, 1525, 1355, 1215 and 750 cm ; 6 8.20 (2H, ABq, 5.8 Hz), 7.25 (2H, ABq, J 8 Hz), 4.39 (1H, ABq, J 15 Hz), 4.20 (1H, ABq, J 15 Hz), 3.68-3.51 (1H, m), 3.34-3.18 (2H, m), 2.66 (1H, bd, s) and 2.03 (3H, s) (Found: C, 50.02; H, 3.74; N, 7.25. C16Hl4N206Fe requires C, 49.77; H. 3.65; N, 7.26%). Description 9 Tricarbonyl-(2,3,4-#-3-methyl-3-buten-2-yl)-1-2,4-dimethoxy benzylaminocarbonyl iron (9! Tricarbonyl-(2,3,4- < -3-methyl-3-buten-2-yl)-1-oxy- carbonyl iron (150 mg, 0.6 mmol) with zinc chloride (81 mg, 0.6 mmol) and 2,4-dimethoxybenzylamine (500 mg, 3 mmol) in ether (5 ml) gave tricarbonyl-(2,3,4- < -3-methyl-3-buten-2-yl)- 1-2,4-dimethoxy benzylaminocarbonyl iron (9) (226 mg, 95%) m.p. 95-8 Vmax 3000, 2955, 2945, 2060, 2000, 1960, 1610, 1585, 1505, 1210, 1035, 910 and 740 cm 1 6 7.06-6.94 (1H, m), 6.50-6.32 (2H, m), 4.16 (3H, m), 3.80 (6H, s), 3.56 (1H, m), 3.31-3.10 (2H, m), 2.73 (1H, bd, s) and 1.98 (3H, s) (Found: C, 54.01; H, 4.81; N, 3.51. C18HlgNO6Fe requires C, 53.89; H, 4.77; N, 3.49%). Description 10 Tricarbonvl-(2,3.4- < -3-methvl-3-buten-2-vl)-1-carbobenzoXv- p-benzyloxyphenyl)methylaminocarbonyl iron (10) Tricarbonyl-(2,3,4¯4-3-methyl-3-buten-2-yl)-l-oxy- carbonyl iron (100 mg, 0.4 mmol) with zinc chloride (108 mg, 0.8 mmol) and benzyl-p-benzyloxyphenyl-cglymate (1.4 g, 4 mmol) in THF/ether (1: :1, 10 ml) gave tricarbonyl-(2, 3,4- -3-methyl-3-buten-2-yl)-l-carbobenzoxy-p-benzyloxyphenyl)methylaminocarbonyl iron (10) (103 mg, 45%) as an oil, #max 3090, 3070, 3040, 2960, max 2930, 2070, 2020, 1980, 1740, 1610, 1588, 1510, 1250 and -1 1170 cm General Procedure for the Oxidation of Tricarbonvl iron Lactam Complexes Ceric ammonium nitrate in ethanol was added to a solution of the tricarbonyl iron lactam complex in ethanol at low temperature. The mixture was warmed to room temperature slowly and stirred until the reaction was complete (as indicated by thin layer chromatography). The solvent was removed under reduced pressure and water added. The aqueous layer was extracted with ether, the combined ethereal extracts dried and the solvent removed under reduced pressure to give the crude product, which was purified by chromatography. Example 1 l-Benzyl-3-ethenyl-3-methvl-azetidinone (1) (110 mg, 0.34 mmol) with ceric ammonium nitrate (820 mg, 1.5 mmol) in ethanol (10 ml) at -300C gave l-benzyl-3ethenyl-3-methyl-azetidinone (45 mg, 72%) as an oil; vmax 3085, 3030, 3000, 2980, 2965, 2920, 2900, 1745, 1645, 1400, 940, and 700 cm 5 7.39-7.21 (5H, m), 6.12-5.78 (1H, m), 5.42-5.16 (2H, m), 4.40 (2H, s), 3.98-3.76 (1H, m), 3.39 (1H, dd, J 5 and 5 Hz), and 3.06 (1H, dd, J 5 and 3 Hz) (Found: M+ 187.0999, C12Hl3NO requires M 187.0997). Example 2 l-benzyl-3-isoprenyl azetidinone (2) (90 mg, 0.26 mmol) with ceric ammonium nitrate (0.9 9, 1.64 mmol)in ethanol (10 ml) at 300 gave 1-benzyl-3- isoprenyl-azetidinone (40mg, 75%) as an oil, ';max. 3080, 3060, 3030, 2970, 2900, 1745, 1645, 1605, 1400, 900, 730 and -l 700 cm 1; 6 7.36-7.17 (5H, m), 4.92 (2H, bd, s), 4.38 (2H, s), 3.90-3.72 (m, 1H), 3.26 (1H, dd, J 6 and 6 Hz), 3.04 (1H, dd, J 6 and 3 Hz), and 1.78 (3H, s) (Found: M 201.1153, C13Hl5NO requires M 201.1154). Example 3 1-benzyl-3-isoprenyl-3-methyl-azetidinone (3) (0.32 g, 0.9 mmol) with ceric ammonium nitrate (2.28 g, 4.00 mmol) in ethanol (10 ml) at O C gave l-benzyl-3- isoprenyl-3-methyl-azetidinone (65 mg, 33.5%) as an oil, #max 2860, 1740, 1640, 1400 and 700 cm ; 6 7.37-7.17 (SM, m), 3.02 (1H, bd, s), 4.86 (1H, m), 4.40 (2H, s), 3.16 (1H, ABq, J 5 Hz), 2.90 (1H, ABq, J 5 Hz), 1.77 (3H, s) and 1.45 (3H, s) (Found: M+ 215.1310. C14Hl7NO requires M 215.1309) and 1-benzyl-3,6-dihydro-4,5-dimethyl- 2-pyridone (20) (109 mg, 56.3%) m.p. 78-800, sm #max. 2900, 1640, 1495, 1450, 1320, 1265, 725 and 715 cm ; # 7.35-7.18 (5H, m), 4.73 (2H, s), 3.73 (2H, bd, s), 3.03 (2H, bd, s) and 1.70 (6H, s) (Found: C, 78.00; H, 8.15; N, 6.35. C14H17NO requires C, 78.15; H, 7.90; N, 6.50%). Example 4 l-benzyl-3-(1-heptenyl)-azetidinone (4) (0.63 9, 1.58 mmol) with ceric ammonium nitrate (4.1 g, 7.5 mmol) in ethanol (10 ml) at -5 give cisand trans-1-benzyl-3-(1-heptenyl)-azetidinone (0.26 g, -l 64%) as an oil, 9max 2900, 1745, and 1390 cm ; b 7.36-7.20 (5H, m) 6.00-5.24 (2H, m), 4.38 (2H, s), 3.88-3.66 (1H, m) 3.32 (1H, dd, J 6 and 6 Hz), 2.93 (1H, dd, J6 and 2.5 Hz), 2.28-1.90 (2H, m), 1.68-1.04 (6H, m), and 1.00-0.72 (3H, m) (Found: M+ 257.1772, C17H23NO requires M 257.1779). Example 5 l-benzyl-3-(cyclopenten-1'-yl)-azetidinone (5) (190 mg, 0.517 mmol) with ceric ammonium nitrate (1.35 9, 2.46 mmol) in ethanol (23 ml) at ambient temperature gave l-benzyl-3-(cyclopenten-l'-yl)-azetidinone (99 mg, 84%) -1 as an oil, vmax 2860 and 1740 cm ; 6 7.38-7.20 (5H, m), 5.66 (1H, bd, s), 4.45 (2H, s), 4.10-3.86 (1H, m), 3.34 (1H, dd, J 5 and 5 Hz), 3.08 (1H, dd J 5 and 3 Hz), and 2.56-1.84 (6H, m) (Found: C, 79.00; H, 7.70; N, 6.20. C15H17NO requires C, 79.25; H, 7.55; N, 6.15). Example 6 l-vintl-(N-benzvl1-6-azabicyclo [3.2.0]hept-7-one A mixture of (6a) and (6b) (80 mg, 0. 2 mmol) with ceric ammonium nitrate (0.5 g, 0.91 mmol) in ethanol (15 ml) at -30 gave 1-vinyl-(N-benzyl)-6-azabicyclo [3.2.0]heptan- 7-one (37 mg) 75%) as an oil, 9max 2950, 2900, 1740, 1635, 1300 and 650 cm ; 6 7.42-7.16 (5H, m), 6.18-5.90 (1H, m), 5.46-5.08 (2H, m), 4.49 (1H, ABq, J 15 Hz), 4.22 (1H, ABq, J 15 Hz), 3.71 (1H, d, J 4 Hz) and 2.24-1.12 (6H, m) (Found: M+ 227.1312. C15H17NO requires M 227.1310. Example 7 1- (carbomethoxv-p-benzylphenyl )methvl-3-ethyl-3-ethynyl- azetidinone (7) (61 mg, 0.12 mmol) with ceric ammonium nitrate (0.5 g, 0.9 mmol) in ethanol (23 ml) at -30 gave l-carbomethOxy-p-benzyloxyphenyl)methyl-3-ethyl-3-ethynyl- azetidinone (35 mg, 81%) as an oil, ';max. 3090, 3060, 3030, 3000, 2980, 2955, 2900, 1755, 1740, 1640, 1610, 1585, 1510, -l 1230, 1180, 735 and 695 cm ; b 7.40-7.26 (5H, m), 7.24 (2H, ABq, J 8 Hz), 7.00 (2H, ABq, J 8 Hz), 6.18-5.80 (1H, m), 5.60 (1H, s), 5.44-5.20 (2H, m), 5.08 (2H, s), 3.92-3.70 (4H, m), 3.56-3.42 (1H, m), and 3.38-3.28 (1H, m) (Found: M+ 351.1468. C21H2lNO4 requires M 351.1470). Example 8 1-p-nitrobenzyl-3-isopropenvlazetidinone (8) (150 mg, 0.4 mmol) with ceric ammonium nitrate (853 g, 1.6 mmol) in ethanol (20 ml) at -30 gave l-pnitrobenzyl-3-isopropenylazetidinene (70 mg, 74%) as an oil; Vmax 3080, 2950, 2915, 2850, 1740, 1640, 1600, 1520, 1340 and 1100 cm-1 ; 8.20 (2H, ABq, 9 Hz), 7.42 (2H, ABq, 9 Hz), 4.96 (2H, m), 4.59 (1H, ABq, J 16 Hz), 4.41 (1H, ABq, J 16 Hz), 3.89 (1H, m), 3.36 (1H, dd, J 5.6 and 5.5 Hz), 3.10 (1H, dd, J 5.6 and 2.8 Hz), and 1.78 (3H, s) (found M+ 246.1007. C13H14N203 requires 246.1004). Example 9 1-2,4-dimethoxybenzy-3-isopropenyl azetidinone (9) (226 mg, 0.56 mmol) with ceric ammonium nitrate (1.24 g, 2.2 mmol) in ethanol (15 ml) at -30 gave 1-2, 4-dimethoxybenzy-3-isopropenyl azetidinone (8 mg, 13%) as an oil; may 3075, 2950, 2925, 1740, max -1 1640, 1405, 1500, 1200, 1030 and 830 cm ; 6 7.16-6.97 (lH, m), 6.52-6.30 (2H, m), 4.97-4.82 (2H, m), 4.38 (1H, ABq, J 14 Hz), 4.25 (1H, ABq, J 14 Hz), 3.90-3.66 (7H, m), 3.22 (1H, dd, J 5 and 5 Hz), 2.97 (1H, dd, J 5 and 3 Hz). Example 10 1-(carbobenzoxv-D-benzvloxvphenyl)methYl-3-isopropenY azet idone (10) (100 mg, 0.17 mmol) with ceric ammonium nitrate (0.4 g, 0.7 mmol) in ethanol (10 ml) at -30 gave 1- ( carbobenzoxy-p-benzyloxyphenyl ) methyl-3-isopropenylazetidinone (36) (46 mg, 60%) as a diastereomeric mixture of oils. may 2970, 1750, 1740, 1645, 1610, 1370 and -1 max 695 cm ; 6 7.26 (5H, s), 7.17 (5H, s), 7.10-6.70 (4H, m), 5.50 (1H, s), 5.15 (2H, s), 5.01 (2H, s), 4.98-4.84 (2H, bd, s), 3.79-2.90 (3H, m) and 1.60 (3H, s). General method for Ozonolysis of ss-lactams A solution of the ss-lactam in dichloromethane at -78 was exposed to ozone until an excess of ozone was seen (as indicated by the blue colour of the solution). The excess ozone was removed with argon and triphenyl phosphine added. The solution was warmed to room temperature, the solvent removed under reduced pressure and the crude product chromatographed. Example 11 l-p-nitrobenzvlamino-3-acetyl azetidinone l-p-nitrobenzylamino-3-isopropenylazetidinone (40 mg, 0.16 mmol) in dichloromethane (10 ml) at -78 with ozone gave l-p-nitrobenzyl-3-acetyl azetidinone (32 mg, 80%) as an oil, may 1760, 1720, 1615, 1525 and 1355 cm 6 8.20 (2H, ABq, J 9 Hz), 7.36 (2H, ABq, J 9 Hz), 4.56 (2H, s), 4.29 (1H, dd, J 3 and 5 Hz), 3.64 (1H, dd, J 5 and 3 Hz), 3.19 (1H, dd, J 5 and 5 Hz), and 2.33 (3H, s) (Found: M+ 248.0792. C12H12N204 requires M 248.0797). Example 12 1- ( carbobenzoxy-p-benzyloxyphenyl -methyl- 3-isopronenyl azet idinone l-(Carbobenzoxy-p-benzyloxyphenyl)methyl-3-acetyl azetidinone (150 mg, 0.34 mmol) in methylene chloride (15 ml) at -780 with ozone gave l-(carbobenzoxy-pbenzyloxyphenyl)-methyl-3-acetyl azetidinone (111 mg, 74%) as a mixture of diastereomeric oils, Vmax 1760, 1740, 1720, 1610, 1510, 1250 and 695 cam ^; 6 7.476.80 (14H, m), 5.48 (1H, s), 5.14(2H, s), 5.00 (2H, s), 4.24-3.83 (2H, m), 3.67-3.32 (1H, m) and 2.30 (3H, s). Example 13 Ibenzyl-3-1',2'-epoxyethyl-azetidinone l-Benzyl-3-ethenyl-3-methyl-azetidinone (205 mg, 1.1 mmol) in dichloromethane (10 ml) with sodium carbonate (200 mg, 2 mmol) and m-chloroper- benzoic acid (260 mg, 80%, 1.2 mmol) was stirred for 24 h. The suspension was filtered, washed with aqueous sodium bicarbonate solution (5 ml) and the organic layers dried (MgS04). Removal of the solvent under reduced pressure and chromatography of the resulting oil (silica, ethyl acetate/petroleum ether (60/80) gave l-benzyl-3-l',2'- epoxyethyl-azetidinone (80 mg, 36%) (50% based on recovered starting material) as an oil, V 3060, 2980, -1 max 1750, 1600, 1395 and 700 cm ; 5 7.52-7.15 (5H, m), 4.36 (2H, s), 3.7-3.50 (1H, m) and 3.33-2.46 (5H, m). Example 14 l-p-nitrobenzylamino-3-1'-hydroxvethyl azetidinone (32) l-p-nitrobenzylamino-3-acetyl azetidinone (70 mg, 0.3 mmol) with sodium borohydride (5 mg, 0.15 mmol) in ethanol at 00 was stirred for 1 h. Removal of the solvent and chromatography of the resulting oil (silica ethyl acetate) gave l-p-nitrobenzylamino-3-1'- hydroxyethyl azetidinone (50 mg, 71%) as an oil, smax 3450, 3060, 2940, 2910, 1740, 1610, 1525, 1350, 1050, and 640 cm1; 6 8.16 (2H, ABq, J 8 Hz), 7.47 (2H, ABq, J 8 Hz), 4.57 (1H, ABq, J 16 Hz), 4.36 (1H, ABq, J 16 Hz), 4.30-3.90 (1H, m), 3.40-2.78 (4H, bd, m) and 1.32 (3H, d, J 9 Hz). Example 15 l-benzvl-3-l' -hydroxyethyl azetidinone (34) l-Benzyl-3-1',2'-epoxyethyl-azetidinone (55 mg, 0.3 mmol) with K-selectrode (0.6 ml, solution in THF, 0.3 mmol) in THF (5 ml) at -780 was warmed to room temperature and stirred for 6 h. The reaction mixture was washed with water (40 ml), extracted with ethyl acetate (3 x 40 ml) and the combined organic layers dried (MgS04). Removal of the solvent under reduced pressure and chromatographed of the resulting oil gave l-benzyl-3-1'-hydroxyethyl azetidinone (22 mg, 40%) as an oil, V 3240, 3060, 2990, 1740, 1440, 1265 and 705 cm -1; # max730 (5H, m), 4.36-4.00 (3H, 1440, 1265 and 705 cm -1; 6 m), 3.31-2.88 (3H, m) and 1.25 (3H, d, J 6 Hz).

Claims: CLAIMS 1. A process for the preparation of a lactam of formula (II): EMI26.1 wherein R1, R2 and R3 may be the same or different and each represents hydrogen or C16 alkyl, or R1 and R2 may together complete a carbocyclic ring; R is hydrogen, -CH2-CO2RP where where RP is a carboxy protecting group, -CH2-CH2-OH or a protected derivative thereof, -CH2-CH2-CHO or a protected derivative thereof, or R and R4 together 4' hydrogen or C1-6 alkyl; complete a carbocyclic ring; R is hydrogen or C1 6 alkyl; and R5 is hydrogen, an organic radical wherein any reactive groups may be protected or a subgroup of formula NRaRP wherein Ra and Rss are the same or different and each is hydrogen or an organic radical, or a subgroup of OR wherein R# is a hydroxyl protecting group, which process comprises treatment of an iron complex of formula (III): EMI26.2 Wherein R1, R2, R3, R4, R4', and R5 are as defined with respect to a formula (II), with an oxidising agent. 2. A process as claimed in claim 1 wherein the oxidising agent is an iron III salt, silver I salt or a cerium IV salt. 3. A process as claimed in claim 1 or claim 2 wherein the oxidising agent is a cerium IV salt. 4. A process as claimed in any one of claim 1 to 3 wherein the oxidising agent is cerium IV ammonium nitrate. 5. A process as claimed in any one of claims 1 to 4 wherein R is hydrogen, an amino protecting group, szch EMI27.1 or a sub-group of formula: EMI27.2 wherein R+ is C16 alkyl and R is an organic group such * that - C02R is an ester group. 6. A process as set forth in claim 1 substantially as hereinbefore described.

Inventors: HEBBLETHWAITE, ELIZABETH MARY, LEY, STEVEN VICTOR
Applicants: BEECHAM GROUP PLC
Application year: 1981
Main classification: C07D205
IPC codes: C07F15, C07D205, C07D477