SE438331B - AZETIDINYLBUTENOATE SUBSTANCES AS INTERMEDIATES FOR THE PREPARATION OF 3-SUBSTITUTED CEPHALOSPORINE DERIVATIVES - Google Patents

Description

/.a.fwW-f-Jrfßtma-vf a 7810962 ~ 6 ä among these may be mentioned the very readily available penicillin sulfoxide derivatives of the naturally occurring compounds penicillin C and / or penicillin V. If one tries to carry it out in the U.S. According to U.S. Pat. No. 3,843,682, using an island arnidopenicillin sulfoxide ester as a starting material, the product thus obtained is a complex mixture which does not contain any 2-chlorosulfinylazetidin-4-one product or at best contains product in such an extraordinarily small amount that it cannot be determined by ordinary methods of analysis. Thus, in this prior art, it is necessary 1) to replace the natural 6-substituent of a penicillin with an imido substituent and 2) to cleave the imido substituent to enable re-acylation and introduction of the substituent desired to have in the intended antibiotic end product.

The present invention relates to a compound which is an intermediate in the preparation of 3-substituted cephem derivatives and which does not suffer from the above-mentioned disadvantage. This intermediate compound has the formula O f *, c in-dank // S0 _ (III) I-- [H2 f --N \ /, - CH! H / 1 LOOP, wherein R 1 represents a protecting group for the carboxylic acid group and R 3 represents a) hydrogen, C 1 -C 3 alkylziles 4-nitrobenzyloxy; 1 b) the group R 'where R' represents phenyl; c) a group of the formula R '- (O) m -CH 2 - wherein R' has the meaning given above and m is 0 or 1; or d) a group of the formula n '-clrn- W wherein R' has the meaning given above and W represents protected amino.

The carboxylic acid protecting group (i.e. R 1) may be a preferred pig which can be removed by acid treatment or hydration. Preferred protecting groups for the carboxyl group are, for example, 3 7810962-6 Li.:. the following: G1-G4-alkyl, 2,2,2-trinaiogenethyl, 2-iodoethyl, benzyl, p-nitrohensyl, sucoinimidomethyl, phthalimidomethyl, p-methoxybenzyl, benzhydryl, C2-C6-alkanoyloxymethyl, dimethylallyl, phenacyl or halogen- vßnauyl, where by "halogen" in the above groups is meant chlorine, bromine or iodine.

Particular illustrative examples of preferred carboxylic acid protecting groups of the sulfinyl chlorides III are e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, 2,2,2-trichloroethyl, 2,2,2-tribromethyl, 2-iodoethyl, benzyl, p-nitro benzyl, succinimidomethyl, phthalimidomethyl, p-methoxybersyl, benzhydryl, acetoxymethyl, pivaloyloxymethyl, propionoxymethyl, phenacyl, p-chlorophenacyl, p-bromophenacyl. Highly preferred protecting groups for the carboxyl group are methyl, hensyl, n-nitrobenzyl, p-methoxybenzyl, benzhydryl and 2,2,2-trichloro- why].

Special, illustrative examples of the group R3 are i.a. hydrogen, methyl, ethyl, n-propyl, isopropyl, 4-nitrobenzyloxy, phenyl, benzyl, phenoxymethyl, d .- (2,2,2-trichloroethoxycarbonylamino) -benzyl.

By "protected amino" is meant an amino group which is substituted by one of the usual amino blocking groups, e.g. t-butyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 1-carbomethoxy-2-propenyl formed with methyl acetoacetate, or trimethylsilyl. Additional typical amino protecting groups are described by J.M. Barton and "Protective Groups in Organic Chemistry", J.F. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2. Any of these is useful for inclusion in "protected amino" within the meaning of the present specification and claims.

In the above definitions, the protecting groups for the amino and carboxyl groups have of course not been described in an exhaustive manner.

The function of these groups is to protect reactive functional groups during the production of a desired product. They are then removed without the rest of the molecule breaking. Many such protecting groups Hr are known to fnckmannon, and all of them may equally well be used within the scope of the present invention.

The compounds of formula III according to the invention have an acylamino group attached to the C3 atom of the azetidinyl ring. This acylamino group can then be maintained in the use of the compounds III for the preparation of cephem derivatives, which has the advantage that one does not first have to carry out an avacylation and then an aceracylation. The compounds III according to the invention can be prepared according to known procedures starting from a penicillanate sulfoxide of the formula 0 o II E R3-C-NH \\ “M // f- LH3 (V) I l CH o” 3 NOW _ COOR preferably with the formula 1 OO, »: ß H / _ _ _ K \ 4ï>% _ t0 ) m cnz c Nu T s C513, a I rn (VI) o '1' 1 3 COOR1 wherein m, R1 and R3 in these formulas have the meanings given above.

Accordingly, the preferred sulfinyl chlorides of the invention of formula III are the following compounds of formula VII U (J, '"" 7 "' n I." La .nn -ni-C »m1 TU (VII). UI 2 F, H ïü fl a wherein m and R1 have the meanings given above.

As stated above, the sulfinyl chlorides of the invention are intended to be used as intermediates. They can be subjected to cyclization to form the corresponding 3-exomethylenecepham sulfoxides by subjecting the sulfinyl chloride to the action of a Friedcl ~ Crafts ~ catalyst, for example stannous chloride.

The 3-exomethylenecepham sulfoxides obtained as cyclization products are useful as intermediates in the preparation of antibiotic compounds. The sulfoxides can be reduced by known methods, typically with phosphorus trichloride or phosphorus tribromide in dimethylformamide, to give the corresponding 3-methylmethylencephamer.

The exomethylenecepamers can be used in the preparation of novel cephem antibiotics of the formula 7810962-6 O n S R -C-NU 3 -sr / N / “B O COOH wherein B represents, for example, chlorine, bromine or methoxy. such chemical conversions of 3-exomethylenecepham compounds have been reported in the chemical literature, see e.g. Robert R. Chauvette owh Pamela A. Penninqton, Journal of the American Chemical Society, 'L fl, 4086 (1974).

The preparation and use of the compounds III are further illustrated in the following examples. However, the invention is in no way limited to what is stated in these examples. Example gel 1. Preparation of p-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl) -4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate.

A solution of 500 mg (1 mmol) of p-nitrobenzyl-6) * - phenoxyacetamido-2,2-dimethylpenam-3-carboxylate-1-oxide and 13 # mg (1 mmol) of N-chlorosuecinimide in 40 m] well-dried 1,1,2-trichloroethane was boiled for 90 minutes. The mixture was cooled, washed with water and the brine was dried. The solvent was allowed to evaporate in solution, each in vacuo. According to the NMR spectrum, the title compound was obtained in almost quantitative yield. nu: (cnc13) <5'1.91 (broad s, 3), 4.53 (s, z), s, os (with s, 1), 5.23 (m, 2), 5.33 (s, 2), 5.57 (d, 1, J = 4.5 Hz), 6.18 (dd, 1, J = 4.5 Hz) and 6.9-8.1 (m, 9, aromatic H).

Example 2. Preparation of p-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate.

A mixture of 6.0 g (12 mmol) of p-nitrobenzyl-6-phenoxyacetamido-3-carboxylate-1-oxide in 500 ml of dry toluene was boiled Strong-fold for a full -2.2 minutes under reflux using a Dean- removal of traces of water present. When the drying step was followed, 1.8 g of N-chlorosuccinimide was added and the mixture was refluxed for 90 minutes. Then the mixture was cooled to about 50 DEG C. and evaporated to give the sulfinyl chloride product.

Example gel 3. Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosuphinyl] -4-oxo-3-formamido-1-acetidinyl) -3-butenoate.

A solution of 1,43 g of p-nitrobenzyl-6β-formamido-2,2-dimethylpeneam J-carboxylate-1-oxide and 500 mg of N-chlorosuccinimide in 40 ml of dry 1,1,2-trichloroethane was boiled. 90 minutes under reflux. The mixture was cooled, washed with water and brine and dried over MqSO 4; = _ “Mouth |: ~ 1 - ;, | -¿¿ _ = -_ | ¿Kf_y_, 781Û962 ~ 6 b the solvent was allowed to evaporate. The NMR spectrum indicates that conversion to the title compound has taken place.

NMR (CDCl 3) δ 1.91 (broad s, 3), 5.03 (broad s, 1), 5.20 (m, 2), 5.34 (s, 2), 5.62 (d, 1) , J = 4.5 Hz), 6.12 and 6.3 (ABq, 1, J = 4.5 Hz) and 7.4-8.4 (m, 4, aromatic H). Preparation of 2,2,2-trichloroethyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenyl] acetamido-1-azetidinyl) -3-butenoate.

A solution of 500 mg of 2,2,2-chlorochlorutyl-6 [1-phonylacylamide-2-2-dimethylpename-3-carboxylate-1-oxide and 134 mg of N-chlorosuccinimide in 40 ml of dry toluene was refluxed for 90 minutes. The mixture was cooled, washed with H 2 O and brine and dried over MQSO 4; the solvent was evaporated on a Rotavapor apparatus. The title compound was extracted in the form of a colorless foam. mm (coc1311.1,9o (s, 3), 3.55 (s, 2), 4.6 (m, 2), 4.95 (d, 1, J = 4.5 H2), 5, 03-5.21 (m, 3), 5.65 and 5.70 (Aßq, 1, J = 4.5 Hz), 7.3 (s, 5) and 7.5 (d, N11, J = 10 Hz).

Example 5. Preparation of p-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate.

To 150 ml of toluene, which was distilled and dried by molecular sieve, was added 3.0 g (6 mmol) of D-nitrobenzyl-6-phenoxyacetamido-2; 2-dimethylponam-3-carboxylate-1-oxide and 1.3 g ( 6 mmol) The N-chloro-N-methyl-p-toluenes-zero mixture was heated at reflux for 60 minutes.

The reaction mixture then obtained was cooled to room temperature. A portion (15 ml) was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to dryness. The NMR spectrum of the residue indicated that the product was contaminated with some small amount of N-methyl-p-toluenesulfonamide. (min (cncf13) .S 1.88 (s, 3, al1y1-cn3), 5.0 (s, 2, vinyl-cnz) and 9.12 (s, 1,,: 11_1y1_-n). §§ Preparation of p-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azidtidinyl) -3-butenoate 425 ml of toluene were heated in a device containing a Dean - - "dark water trap to remove any moisture present by aznotropic distillation. In this way 25 ml of toluene were removed.

To the remaining toluene was added 10.09 g (20 mmol) of p-nitrobenzyl-G-phenoxyacanthamido-2,2-dimethylpenam-3-carboxylate-1-oxide, keeping the toluene at a temperature slightly below reflux temperature. . The toluene (200 ml) was distilled separately, and 4.0 g (22 mmol) of N-chlorophthalimide were added. The solution thus obtained was added in the hot state dropwise to the solution of the penicillin sulfoxide medium 7810962-'6 over the course of 30 minutes. Throughout the addition time, the mixture remained a light yellow solution. Then the mixture was boiled for 55 minutes under reflux, after which a sample was taken. NMR analysis (CDCl 3) of this sample indicated that virtually all of the penicillin sulfide ester was transferred to the title compound.

Example gel 7. Preparation of benzhydryl-3-methyl-2- (2-chlorosulfonyl-4-oxo-3-phenoxyacetamido-1-aletidinyl) -3-butenoate.

To 800 ml of dried tohun was added 20 g of benzhydryl-6-phenoxyacetamido-2,2-dimethylpename-3-carboxylate-1-oxide. The mixture was refluxed in a Dean-Stark water trap to azeo-ironically remove any moisture that may be present. This removed 100 ml of toluene. To the mixture was then added 13.2 g of N-chlorosuccinimide. The reflux was stopped for 1.5 hours. The product was analyzed by NMR, and the analysis results confirmed the structure of the title compound.

NMR (CDCl 3) 51.88 (s, 3), 4.53 (s, 2), 4.90 (s, 1), 5.14 (s, 2), 5.54 (s, 1, J = 4 Hz), 6.24 (kv, 1, J = 4 Hz and 8 Hz), 6.95 (s, 1), 7.15 ~ 7.4 (m, 15) and 8.0 (d, 1 , J = 8 Hz). Preparation of p-nitrobenzyl 3-methyl-2- (2-chlorosulfinyl-4-oxo-3-acetamido-1-azetidinyl) -3-butenoate. 500 ml of toluene were heated in a Dean-Stark water trap in azeotropic distillation to remove any moisture present. To the thus dried toluene was added 1.0 g (2.4 mmol) of p-nitrobenzyl 6-acetamido-2,2-dimethylpenam-3-carboxylate-1-oxide. The resulting mixture was refluxed, again using a Dean ~ Stark water trap to remove any additional water. The mixture was then cooled, and 400 mg (2.9 mmol) of N-chlorosuccinimide was added. Then the mixture was boiled for 1 hour under reflux. A sample of the reaction mixture was taken out and the solvent was removed. The product thus obtained was the tilel compound, which was shown by NMR analysis. mm (cnc13) 41.86 (rlred s, 3), 2.04, 2.09 (zs, s), 4, sn (m, 1), 5.2 (m, 2), 5.28 (s , 2), 5.63 (m, 1), 6.05 (d, 1, J = 4 Hz), and 7.4 - 8 4 (kv, 4, aromatic H).

Preparation of 2,2,2-trichloroethyl] -3-methyl-2- [2-chlorosulfonyl-4-oxo-3- (4'-nitrobenzyloxycarbamido) -1-azetidinyl] -3-butenoal.

A mixture of 300 ml of 1,1,2-trichloroethane and 10.26 g of 2,2,2-trichloroethyl-6- (4'-nitrobenzyloxycarbamido) -2,2-dimethylpenam-3-carboxylate-1-oxide was prepared. . The mixture was boiled under reflux, removing about 75 ml of the solvent to promote the reaction of the gokumer g koumer. .if 781Û962 ~ 6 2 tionsmedfets torkning. Then the mixture was cooled and propyl oxide was added first and then 4 q N-chlorosuccinimide. The temperature of the mixture was raised to 10,200, and the mixture was refluxed for 2.5 hours. A sample of the reaction mixture was taken, the solvent was evaporated, and NMR analysis of the residue confirmed the structure of the title compound.

NMR (CDCl 3) δ 1.94 (broad s, 3), 4.83 (s, 2), 5.25 (s, 2), 5.0-5.4 (m, 3), 6.20 (d , 1, J = 4 Hz), 7.55 (d, 2, J = 8Hz), and 8.24 (d, 2, J = 9 Hz). Éggmgel 10.

Α-N-nitrobenzyl-3-methyl-2- (2-chlorosulfinyl-4-oxo-3-phenoxyacetamido-1-azetidinyl) -3-butenoate was prepared by making a 30 min. reflux heating a solution of 1 g of p-nitrobenzyl-6-phenoxyacetamidopenicillanate-1-oxide and 0.27 g of N-chlorosuccinimide in 40 ml of 1,1,2-trichloroethane. Then 0.27 g of zinc chloride was added to the reaction mixture. This was followed by another 45 min. heating during reflux.

When the mixture was then cooled to room temperature, it was washed with 1N HCl (2 times) and dried (MgSO 4), then evaporated to dryness in vacuo. An NMR spectrum of the product showed that it consisted of the desired compound p-nitrobenzyl-7-phenoxyacetamido--3-exprethylenecepham-4-carboxylate-1-oxide.

JL The 3-exomethylenecepham compound prepared according to A) could be converted to the corresponding 3-hydroxy-3-cephem derivative according to the following procedure (1) or (2). (1) A solution of 1.25 g of p-nitrobenzyl-7-phenoxyacetamido-3-exomethyl] encephame-4-carboxylate 1-oxide in 150 ml of methylene chloride, containing about 0.31 ml of methanol, was degassed and cooled to -30 ° C under nitrogen.

Ozone was bubbled into the cold solution for about 4 minutes. at -30 ° C; the blue reaction mixture was heated to 0 ° C, degassed under reduced pressure and diluted with about 80 ml of toluene. The diluted mixture was evaporated to a small volume under reduced pressure in a water bath maintained at about 45 DEG C. The product, p-nitrobenzyl-7-phenoxyacutamide-3-hydroxy-3-cephem-4-carboxylate-1-oxide, was formed as a gel in the concentrate. It was filtered and dried under vacuum at GOOC. The yield of the product was 1.1 q (88%), and the product melted at about 130 DEG-140 DEGC. The identity of the product was confirmed by analysis data. (2) 20 g of p-nitrobenzyl-7-phenoxyacetamido-3-exomethylenecepham-4-carboxylate-1-oxide were dissolved in 400 ml of acetonitrile, which contained 10 ml of § 3 »lf 0" 7810962-6 acetic acid. The solution was cooled to - For 1 3/4 hours, a stream of air with about 2% ozone from an ozone generator was passed through the cold solution, at a rate of about 400 ml / min, and a small portion of the cold reaction solution was chromatographed on thin sieves. Calcium plates using ethyl acetate: acetic acid (20: 1, v / v) for the development The developed chromatogram showed only a trace of the starting material 3.0 ml of dimethyl sulfide was then added to the cold reaction solution, which was stirred for 30 minutes. at -15 DEG C. The then precipitated product, p-nitrobenzyl-7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate-1-oxide, was filtered off and washed on the filter with 100 ml of cold acetonitrile. The product was dried in vacuo to give 17.85 g of dry weight (89.1%).

C The product prepared according to B) (Procedure (1) or (2) could be converted into the corresponding 3-chloro-3-cephem-4-carboxylate in the following manner: c, 1.31 ml (d = 1.57) of phosphorus trichloride were added with stirring. Stirring was continued for 10 minutes. and cooled the solution to -55 ° C by means of a dry ice-acetone bath. To the cold solution was added dropwise a cold solution of 2.51 g (5 mmol) of p-nitrobenzyl 7-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylate-1-oxide in 40 ml of DMF. After this addition, the mixture was stirred in an ice-salt bath at -7 ° C for 1 hour and then at room temperature likewise for 1 hour. The reaction mixture was extracted with ethyl acetate, and the extract was washed twice with a dilute sodium bicarbonate solution and twice with brine, then dried. The extract was then evaporated in vacuo. The crude product was purified by chromatography on 10 g of silica gel using the gradient of 600 ml of toluene to 600 ml of 1: 1 ethyl acetate: toluene, v / v.

The yield of the purified product, p-nitrobenzyl 7-phenoxyacetamido-3-chloro-3-cephem-4-carboxylate, was 0.967 g (38.5% yield). An NMR spectrum of the product confirmed its identity. 1: L-nn:

Claims (6)

7810962 ~ 6 ID Élâ "EJL3aEJíJíiLX Mullan product for use in the preparation of 3-substituted cephem derivatives, characterized in that it is a compound of the formula: 0 | || f () Rg-rï-rxrg / JJ ~ ___ * MIT Lä ”, f, _” f '' n (III) 0 \ t + r In COOR wherein R1 represents a protecting group for the carboxylic acid group and R3 represents a) hydrogen , C 1 -C 3 alkyl or 4-nitrobenzyloxy; b) the group R 'where R' represents phenyl; c) a group of the formula R '- (O) m -CH 2 - wherein R' has the meaning given above and m is 0 or 1; or d) a group of the formula R, -CH- in which R 'has the meaning given above and W represents protected amino. Intermediate according to claim 1, characterized in that R 3 is a group of the formula R '- (O) m ~ CH 2 -. Intermediate according to Claim 1 or 2, characterized in that R 3 represents phenyl. Intermediate product according to one of Claims 1 to 3, characterized in that m is O. Intermediate product according to one of Claims 1 to 3, characterized in that m is 1. Intermediate according to one of Claims 1 to 5, characterized in that R 1 is C 1 -C 4 alkyl, 2,2,2-trihaloethyl, 2-iodoethyl, benzyl, p-nitrobenzyl, succinimidomethyl, phthalimidomethyl, p-methoxy benzyl, benzhydryl, C 2 -C 6 alkanoyloxymethyl, dimethylallyl, phenacyl, or p-halophenacyl. J ä ~