DK142418B - Process for the preparation of 6-acylamidopenicillin or 7-acylamidocephalosporin compounds. - Google Patents

Description

[(11) PROCEDURE WRITTEN 1 ^ 2418 DENMARK, 5,, lntC '· c II l null § (21) Appendix No. 1819/72 (22) Filed on 1 ^ 1 ·· Spr · 1972 (24) uh due 14. April 1972 (44) The claim presented and - Qpn

the petition published on <- I «0KT3. you

PATENT AND TRADEMARKET SYSTEM (30) Priority requested from it,

Apr 15 1971a 24140/71, JP

Apr 15 1971a 24141/71, JP

(71) TOYAMA CHEMICAL CO. LTD., 18, 1-chome, Nihonbashi Kayaba-cho, Chuo-ku, Tokyo, JP.

(72) Inventor: Toshlyasu Ishimaru, 2-7 Momoyamadai, Suita-shi, Osaka-fu, JP: Yutaka Kodama, 6 ^ 13-5 * Shimizu-machi, Toyama-shi, Toyama-ken, JP: Toyoo MaedaJ 6- 2-2 1-chome, Shimookul, Toyama-shi, Toyama-ken, JP:

Shuntaro Takano, 10-5 1-chome, Shimookul, Toyama-shi, Toyama-ken, JP.

(74) Plenipotentiary in the proceedings:

Hofman-Bang & Boutard Engineering Company.

(54) Process for preparing 6-acylamidopenicillin or 7-acyl = amidocephalosporin compound is.

The invention relates to a particular process for the preparation of 6-acylamidopenicillin or 7-acylamidocephalosporin compounds of the general formula I set forth in the preamble of the claim.

JCH, V / 3

The compounds of formula I wherein Y is Cv are penicillins of the following formula 'ί3' / CH3

R1 - C - CONH - ^ SxpcH U-D

wherein R, n, R and R have the meaning set forth in the preamble of the claim.

These penicillins, such as α-α-phenoxyethylpenicillin, α-phenoxy-propylpenicillin, methylphenylisoxazolylpenicillin, methylchlorophenylisoxazolylpenicillin, methyldichlorophenylisoxazolylpenicillin, α-aminobenzylpenicillin, α-amino-α-( shows strong antibacterial properties against Gram-positive bacteria and Gram-negative bacteria, and is highly suitable as drugs for human and animal diseases.

^ CH2

The compounds of formula I wherein Y is X are cephalosporins of the following formula Η3 "R - C - CONH-1-C] -2 J - ch2r (1-2)

- Jn 0 T

COOH

1 2 3 wherein R, R, n, R and R are as defined in the preamble of claim.

These cephalosporins, e.g. 7- (2-thienylacetamido) -3-acetoxy-methyl-3-cephem-4-carboxylic acid, 7- (α-aminophenylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid, 7- (α-aminophenylacetamido) - 3-methyl-3-cephem-4-carboxylic acid, 7- (α-aminophenylacetamido) -3-methoxymethyl-3-cephem-4-carboxylic acid, 7- (α-aminophenylacetamido) - 3-methylth ± omethyl-3 cephem-4-carboxylic acid, 7- [Ϊ- (1H) -tetrazolyl-ac etamido7-3- [2- (5-methyl-1,3,4-thiadiazolyl 1) -thiome thyl7 * 3 - »- c ephem - 4-carboxylic acid and 7- [α-amino (p-hydroxyphenyl) -ac etamido7-3-methyl-3-cephem-4-carboxylic acid, show strong antibacterial properties against Gram-positive and Gram-negative bacteria and are highly suitable as medicines for human and animal diseases.

Methods for preparing these penicillins or cephalosporins are known, such as e.g. The Schotten-Baumann process, whereby an alkali metal salt of 6-aminopenicillanic acid or 7-aminocephalo- 3 U2418 sporanoic acid of the general formula (id

V

COOH

wherein Y is as defined in the preamble of the claim, dissolved in water and reacted with acid halides, or a process wherein a trialkylamine salt of a compound of formula (II) is dissolved in an organic solvent and reacted with a reactive derivative of a carboxylic acid in the presence of an acid binding agent.

However, since the reaction of the former process is usually carried out under alkaline conditions, cleavage of the unstable β-lactam ring occurs in the compound of formula (II), so that the purity of the resulting compound of formula (I) becomes extremely poor and the yield thus low . Although the reaction of the latter process is carried out in a non-aqueous solvent and is homogeneous, the β-lactam ring cleavage nevertheless occurs and the yield is low, and therefore complicated steps are required for the separation and purification of the desired product, and it is very difficult to carry out these practices on an industrial scale.

Later, a process for preparing compounds of formula (I) was found by dissolving the compound of formula (II) in a non-aqueous solvent and acylating without using the trialkylamine salt to prevent the cleavage of the (3-lactam ring and obtaining a good Several reports have been published so far regarding this process, a method for protecting the carboxy group in 6-ara -openicillanic acid with a trialkylsilyl group / TErrn 675. 166-170 (1964) 7, a method for protecting the carboxy group and the amino group of 6-aminopenicillanic acid together with a trialkylsilyl group / Japanese Patent Specification No. 4046/65 and No. 8353/65, BE Patent No. 615,344 (1962) and U.S. Patent No. 3,249,622 (1966/7; and a method of protection of 7-aminocephalosporanoic acids with 4,22418 a trialkylsilyl group / GB Patent No. 1 073 530 (1967) and CA 68, 12 9847 · According to these methods, the compound having The moiety (II), protected by the trialkylsilyl group, has a good solubility in various solvents and the removal of the protective group after the acylation is very easy and the yield of the desired product is thus excellent.

However, these known methods require the reaction of the compound of formula (II) with excess trialkylsilyl chloride, N-trimethylsilyldiethylamine, hexamethyldisilazane, etc. in the form of cooperative solvent at a temperature of 60-90 ° C or more for a long time to prepare the trialkylsilyl derivatives. of formula (II) and the yield of the product is low since the compound of formula (II) is decomposed by heating, with the result that these processes are disadvantageous from an industrial point of view.

In addition, a method for protecting the carboxy group in 6-aminopenicillanic acid with dihalogen silane derivatives has been published / DE DE Publication No. 1 923 642 (196917 * However, since this method does not always provide a satisfactory yield and the handling of the dihalogen silane derivatives is troublesome due to their toxicity for the skin, it is disadvantageous from an industrial point of view.

The object of the present invention is to provide a process for the preparation of penicillins and cephalosporins by acylation of 6-aminopenicillanic acid or 7-aminocephalosporoic acid, using a protecting group which allows the compound of formula (II) to readily dissolve in aqueous solvents and acylated, which are easy to introduce and easy to remove after acylation.

This is achieved by the method according to the invention, which is characterized by the characterizing part of the claim.

According to DK Patent Specification No. 133,046, 6-aminopenicillanic acid is prepared from 6-acylamidopenicillanic acid, while the carboxy group in the starting material is protected with e.g. a trivalent phosphorus compound. According to DK Patent Application No. 5025/71, 5-aminocephalosporanoic acids are prepared from 7-acylamidocephalosporanoic acids, while the carboxyl group in the starting material is protected with e.g. a trivalent phosphorus compound.

Thus, the above two methods are characteristic of using a trivalent phosphorus compound to protect the carboxy group during cleavage of the amide bond (cleavage of the acyl group). In contrast, the present invention lies in the use of a trivalent phosphorus compound for the acylation reaction of the amino group in a compound having a free amino group and a free carboxy group in a molecule. Therefore, it is clear that the present method is quite different from the above mentioned methods, not only in terms of purpose and basic requirements but also in the technical idea.

To date, a trivalent phosphorus compound has been used in peptide synthesis as an activating agent for the carboxy group or amino group in the synthesis of an acid amide (see J. Aså, Chm. Soc. Vol. 7Θ (1956), pages 2121-2131). However, since the amino acid has a free amino group and a free carboxy group in a molecule, it has been well known that either the amino or carboxy group is always protected by a protecting group which does not contribute to the reaction (the amidation reaction). The reason for this is that polycondensation takes place between several molecules of the compound, thereby reducing the yield and the purpose could not be achieved.

According to this prior art, even with the process of the present invention, polycondensation should occur when a trivalent phosphorus compound was used and therefore it would be foreseen that the desired compound would be difficult to obtain. However, the inventors broke with this assumption so far and they succeeded in obtaining high yield penicillins and cephalosporins. Therefore, the present invention could not be predicted, either from the two above-mentioned writings or from the general knowledge of peptide synthesis.

Furthermore, the method according to the invention provides better yields than in the prior art.

Salts of compounds of formula (II) which may be used in the process of the invention include, e.g. alkali metal salts; such as sodium and potassium salts;

Trivalent phosphorus compounds of formula (III) which may be used in the process of the invention include, e.g. the following compounds: CH2PClg, C2H5PC12, C2H5PBr2, PC1 £, C ^ PCl ^ Cg ^ PClg, Cg ^ PBrg, C / -HcCH0PClo »(CHj-PCl, CH, \ 6 5 2 2 '3'2 21> PC1, > PC1, (C, H.), PC1, ° 6H5 CH30PC12, C2H50PC12, C ^ OPClg, C4Hg0PCl2, C1CH2CH20PC12, C6H50PC12, cl - ^ - 0PCl2, C6H5CH20PC12, C1CH2CH2CH20PC12, C1CH2CH

Cl cH3r0cH2opci2, ch3och2ch2opci2, c2h5och2ch2opci2, (ch50) 2pci, (C2 ^ 0) 2PC1, (C1CH2CH20) 2PC1, (C6H50) 2PC1, (C6H5CH20) 2PC1, "C, H-0 CXOv

((^ -0) 9PC1, ^ 5> PC1, * 15 ^ .PCl, 5 ^ PCl, (CH ^) pN-PClp, C2 <^ (CS ^ rio Γ ^ pci, _r / K1> i- ° ~ ^ ρα, _T z1'01 · i — Cr CH ^ —O '' C1CH2j CK CHjOCHg-1—0 ^ cJlo> PC1 'C> C1' OCo-rcl ·

Examples of carboxylic acids of general formula (IV) include e.g. phenylacetic acid, α-phenoxyacetic acid, α-phenoxypropionic acid, α-phenoxyacetic acid, diphenoxyacetic acid, diphenylacetic acid, naphthylacetic acid, naphthoxyacetic acid, α-aminophenylacetic acid, α-chlorophenylacetic acid, α-bromophenylacetic acid, α-bromophenylacetic acid, α-bromophenylacetic acid carbonylphenylacetic acid, thienylacetic acid, tetrazolylacetic acid, 1-aminocyclohexanecarboxylic acid, 2,6-dimethoxybenzoic acid, α-benzyl-oxycarbonylphenylacetic acid, α-amino- (4-hydroxyphenyl) acetic acid, α-amino-4-hydroxy (3 acetic acid, α-amino- (3-chloro-4-hydroxyphenyl) acetic acid, α-amino- (4-nitrophenyl) acetic acid, α-amino- (4-chlorophenyl) acetic acid, α-amino- (4-methoxyphenyl) acetic acid, Α-Amino (4-methylthiophenyl) acetic acid, α-amino (4-acetamidophenyl) acetic acid, cc-aminocyclohexadienylacetic acid, cc -5-methyl-4-isoxazolylcarboxylic acid, 3- (2-chlorophenyl) l) -5-methyl-4-isoxazolylcarboxylic acid, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarboxylic acid, 3- (2-chloro-6-fluorophenyl) -5-methyl-4-isoxazolylcarboxylic acid, 3 -phenyl-5-methyl-4-isothiazolyl-carboxylic acid and α-amino- (optionally substituted-thiazolyl) acetic acid.

The reactive derivatives thereof include e.g. acid halides, acid anhydrides, mixed acid anhydrides with organic or inorganic acids, active esters, acid azides, acid cyanides, and active acid amides; especially preferred are acid chlorides, mixed acid anhydrides and active acid amides. The mixed acid anhydrides include those with substituted acetate, alkyl carbonate, arylcarbonate and aralkyl carbonate. The active esters include e.g. cyanmethyl esters, substituted-phenyl esters, substituted-benzyl esters, and substituted-thiophenyl esters. The active acid amides include e.g. those with N-acylsaccharin, N-acylimidazole, N-acylbenzcylamide, N, N-dicyclohexyl-N-acylurea and N-acylsulfoamide. When the compound of formula (IV) is an α-amino acid, the desired product can be prepared in high yield by reaction with it in the form of a cyclic anhydride such as oxazolidine-2,5-dione, a mixed acid anhydride wherein the amino group is protected by a diphenylmethyl group, a trityl group, a bis (p-methoxyphenyl) methyl group, a bis (p-mothc :: yphenyl) phenylmethyl group, a trifluoroacetyl group, a salicylilidene group, a benzylilidene group, a p-nitrobenzylidene group or a p-nitrobenzylidene group with β-diketones or β-ketoacid derivatives, e.g. with acetoacetic acid ester, acetoacetamides, acetylacetone, benzoylacetone, α-formylpropionic acid ester, α-acetylcyclopentanone and α-acetylcyclohexanone; or the hydrochloride of an acid chloride.

In carrying out the process of the invention, the salt of the compound of formula (II) is dissolved or suspended in a suitable solvent such as methylene chloride, chloroform, carbon tetrachloride, ethylene chloride, trichloroethane, trichlen (trile), acetonitrile, acetone, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, formamide, dimethylformamide and dimethylacetamide, and this solution or suspension is added to a solution containing the compound of formula (III). Alternatively, the compound of formula (III) is added to the salt of the compound of formula (II). This reaction is carried out at below room temperature, and preferably at a gf temperature between -50 and 0 ° C. Preferred mole ratios of compounds (II) to (III) are between 1: 0.5 and 1: 2. It is preferred that the reaction be carried out in the presence of an acid-binding agent such that a slight excess amount of an acid-binding agent relative to the compound of formula (II) is added to the solution containing the compound of formula (III).

Acid binding agents for use in the process of the invention include, e.g. trialkylamine, Ν, dial-dialkylaniline, pyridine and its homologue, quinoline and its homologue, N-alkylmorpholine and N-alkylpiperidine, and in particular pyridine, picolines, lutidines, collidines and Ν, Ν-dimethylaniline are preferred. As a solvent for the compound of formula (III), e.g. benzene, toluene, xylene and ethyl acetate are used in addition to the aforementioned solvents.

The reaction takes place quickly and the reaction solution becomes colorless or pale yellow.

Then at a temperature between -50 and 50 ° C sufficient of the reactive derivative of the compound of formula (IV) to be reacted is added. The reaction is completed in between 30 minutes and 2 hours at the same temperature. This reaction is preferably carried out in the presence of an acid-binding agent, but since sufficiently the acid-binding agent is generally added in the first step, it is not always necessary to add acid-binding agent in this final step.

Then the reaction solution is added water and / or alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol and butyl alcohol, so that the phosphorus derivative is broken down. This solar volysis is usually carried out at room temperature or under low cooling.

The following examples serve to illustrate the method of the invention.

EXAMPLE_1 0.46 g of 2-chloro-4-methyl-1,3,2-dioxaphosphorane was dissolved in 7 ml of methylene chloride and 0.8 g of Ν, Ν-dimethylaniline was added under cooling in ice. To the mixture was added a solution of 1 g of triethylamine salt of 6-aminopenicillanic acid and 0.4 g of Ν, Ν-dimethylaniline in 7 ml of methylene chloride at 0 ° C. After reaction for 10 minutes, a solution of 0.63 g of phenoxypropionyl chloride in 3 ml of methylene chloride. After the reaction mixture temperature was raised to room temperature over about 30 minutes and the reaction allowed to proceed for an additional 30 minutes, the mixture was poured into 10 ml of water. After stirring for 20 minutes, the organic layer was collected, washed with water and evaporated under reduced pressure. The residue was dissolved in 3 ml of butyl acetate and a concentrated aqueous solution of 0.32 g of potassium acetate was added and the mixture was stirred to precipitate white crystals. The precipitated crystals were filtered off and washed with acetone. 1.24 g (98 90 potassium salt of phenoxyethylpenicillin was obtained. When recrystallized from aqueous acetone 1.2 g (95 90 crystals), which showed a decomposition point of 220 ° C, were obtained.

The infrared absorption spectrum of the product was identical to that of a standard sample.

Preview function £ L_2

The procedure of Example 1 was repeated under the same reaction conditions except that 0.49 g of 2-chloro-1,3,2-dioxaphosphorinane was used instead of 2-chloro-4-methyl-1,3,2-dioxaphosphorane. and 1.24 g (98 90 crude crystals of the potassium salt of phenoxyethylpenicillin were obtained.

EXAMPLE 3 0.94 g of triethylamine was added to a suspension of 1 g of 6-aminopenicilanoic acid in 7 ml of methylene chloride and the mixture was allowed to react at room temperature for 30 minutes to form a transparent solution and then added to 0.5 g dimethyl chlorophosphite and allowed to react for 30 minutes. The precipitated triethylamine hydrochloride. was filtered off and the filtrate was evaporated under reduced pressure. The residue was dissolved in a solution of 1.1 g of dimethyl-aniline in 10 ml of methylene chloride, and to the solution was added dropwise a solution of 1 g of α-phenoxybutyryl chloride in 3 ml of methylene chloride. After reacting for 1 hour, the reaction mixture was poured into 10 ml of water and hydrolyzed at a pH of 1.0 for 15 minutes. The organic layer was collected, washed with water and evaporated under reduced pressure. The residue was dissolved by the addition of 3 ml of butyl acetate and 1 ml of acetone. To the mixture was added 0.45 g of finely powdered potassium acetate to gradually precipitate white crystals as it dissolved. The precipitated crystals were filtered off and washed with acetone to give 1.65 g (85.5%) of potassium salt of phenoxypropylpenicillin. By recrystallization from aqueous acetone, white crystals were obtained which showed a decomposition point of 215 ° C.

The infrared absorption spectrum of the product was identical to that of a standard sample.

EKSEMPEL_4

The procedure of Example 3 was repeated under the same reaction conditions except that 0.34 g of dimethyl phosphinochloride was used instead of dimethyl chlorophosphite and 1.6 g (82.7%) of potassium salt of phenoxypropylpenicillin was obtained.

EXAMPLE 5 0.46 g of 2-chloro-4-methyl-1,3,2-dioxaphosphorane was dissolved in 7 ml of methylene chloride and 0.8 g of Ν, Ν-dimethylaniline was added under cooling in ice. To this solution was added a mixture of 1 g of triethylamine salt of 6-aminopenicillanic acid and 0.4 g of N, N-dimethyl-aniline in 7 ml of methylene chloride at 0 ° C. After reaction for 10 minutes, a solution of 0.77 g of 3 was added dropwise. -phenyl-5-methyl-4-isoxazolylcarbonyl chloride in 3 ml of methylene chloride. The reaction mixture temperature was raised to room temperature over about 30 minutes and allowed to react for an additional 30 minutes. Then, the reaction mixture was poured into 10 ml of water and stirred for 15 minutes, and the organic layer was collected, washed with water and evaporated under reduced pressure. The residue was dissolved by the addition of 3 ml of butyl acetate, 1 ml of acetone and 1 drop of water. When finely powdered sodium acetate was added, this dissolved and eventually crystals precipitated. The crystals were filtered off and sufficiently washed with acetone to give 1.15 g (87.5%) of white crystals of the sodium salt of methylphenylisoxazolylpenicillin.

By recrystallization from aqueous acetone, white crystals were obtained which showed a decomposition point of 188 - 190 ° C.

The infrared absorption spectrum of the product was identical to that of a standard sample.

EXAMPLE 6 0.46 g of 2-chloro-4-methyl-1,3,2-dioxaphosphorane was dissolved in 7 ml of methylene chloride and 0.8 g of Ν, Ν-dimethylaniline was added. To the solution was added a mixture of 1 g of triethylamine salt of 6-aminopenicillanic acid and 0.4 g of Ν, Ν-dimethylaniline in 7 ml of methylene chloride at 0 ° C. After reaction for 10 minutes, a solution of 1.0 g of 3- ( 2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl chloride in 3 ml of methylene chloride. The temperature of the reaction mixture was raised to room temperature over about 30 minutes and allowed to react for another 30 minutes, after which the mixture was poured into 10 ml of water. After stirring for 20 minutes, the organic layer was collected, washed with water and evaporated under reduced pressure. To the residue was added dropwise 3 ml of butyl acetate, 1 ml of acetone and 1 drop of water, and 0.27 g of finely powdered sodium acetate was added to precipitate white crystals as it dissolved. The precipitated crystals were filtered off and washed with acetone to give 1.4 g (87.5%) of sodium salt of methyldichlorophenyl-isoxazolylpenicillin. Recrystallization from aqueous acetone yielded 1.25 g of white crystals, showing a decomposition point of 220 - 222 ° C.

EXAMPLE 7 0.4 g of 2-chloro-1,3,2-dioxaphosphorane was dissolved in 5 ml of dioxane and 0.8 g of Ν, Ν-dimethylaniline was added. To the mixture was added a solution of 1 g of triethylamine salt of 6-aminopenicillanic acid and 0.4 g of Ν, Ν-dimethylaniline in 5 ml of dioxane at 10 ° C. After reaction for 10 minutes, a solution of 1.0 g was added dropwise. 3- (2,6-Dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl chloride in 2 ml of dioxane. The temperature of the reaction mixture was raised to room temperature over about 30 minutes and allowed to react for an additional 30 minutes, after which the mixture was poured into 20 ml of water. After stirring for 20 minutes, the precipitated gel-like crystals were dissolved in 3 ml of butyl acetate and 1 ml of acetone, and to the mixture was added 0.27 g of finely powdered sodium acetate to precipitate white crystals as it dissolved. The precipitated crystals were filtered off and washed with acetone to give 1.3 g (81.4%) of sodium salt of methyldichlorophenylisoxazolylpenicillin. By recrystallization from aqueous acetone, 1.2 g of white crystals were obtained, showing a decomposition point of 220 - 222 ° C.

Example 8 0.92 g of 2-chloro-4-methyl-1,3,2-dioxaphosphorane was dissolved in 10 ml of methylene chloride and 1.6 g of N, N-dimethylaniline was added.

This mixture was cooled to 4-40 ° C and a solution of 2 g of triethylamine salt of 6-aminopenicillanic acid and 0.8 g of N, N-dimethylaniline in 10 ml of methylene chloride was added and the mixture was allowed to react for 1 hour. On the other hand, 1 g of potassium W- (W ', Ν'-dimethylaminocarbonylpropen-2-yl) -Qβ-amino-phenyl acetate was suspended in 10 ml of methylene chloride and cooled to 440 ° C, with two drops of N-methylmorpholine added. and, further, a solution of 0.84 g of ethyl chlorocarbonate in 2 ml of methylene chloride was added dropwise. The resulting mixture was stirred at the same temperature for 90 minutes to obtain a mixed anhydride.

This was added at once to the previously prepared solution and the mixture allowed to react at 440 ° C for one hour, after which the temperature was raised to 0 ° C over one hour.

The reaction solution was filtered and the filtrate was concentrated at low temperature under reduced pressure. The residue was dissolved in 5 ml of water and 20 ml of methyl isobutyl ketone and the pH of the solution was adjusted to 2.5 with dilute hydrochloric acid with stirring and allowed to stand for 15 minutes. The water layer was collected and adjusted to pH 5.2 with triethylamine to precipitate the crystals. The precipitated crystals were filtered off and washed sufficiently with cold water to give white crystals of D (-) - 06-aminobenzylpenicillin trihydrate.

By recrystallization by the conventional method, 1.9 g (74 g) of white crystals were obtained.

EXAMPLE 9 2 g of triethylamine salt of 6-aminopenicillanic acid and 1.6 g of N, N-dimethylaniline were mixed with 15 ml of methylene chloride and to the mixture was added dropwise 0.92 g of 2-chloro-4-methyl-1,3,2-dioxide. phosphoran at ^ 20 ° C and the mixture was allowed to react at the same temperature for 30 minutes. Then 1.3 g of D (-) - aminophenylacetyl chloride hydrochloride was added and the mixture was allowed to react at 20 ° C for 1.5 hours. Then, the reaction mixture was poured into 250 ml of water and stirred for 10 minutes, after which the water layer was collected. An additional 10 ml of water was added to the organic layer to extract the resulting product.

These water layers were combined and 10 ml of ethyl acetate were added and the mixture was then adjusted to a pH of 5.5 with 10% sodium hydroxide solution. The water layer was collected and 12 g of ammonium sulfate was added to precipitate crystals.

The precipitated crystals were filtered off to give 2.5 g (98.4%) of crude crystals of D (-) - e6-aminobenzylpenicillin trihydrate. By recrystallization by the conventional method, 2.15 g (84.6 g) of the desired product was obtained.

The results when using other trivalent phosphorus compounds in the same manner were as follows:

Trivalent phosphorus compound Mole ratio Yield (%) [3 £> PC1 1.05 82.6 CH50PC12 0.6 74.2 (CH30) 2PC1 1.05 76.8 (C1CH2CH2O) 2PC1 1.05 78.6 (C6H5 ° EXAMPLE 10 2 g of triethylamine salt of 6-aminopenicillanic acid and 0.8 g of N, N-dimethylaniline were mixed with 10 ml of methylene chloride, and 2 g of C1 1.05 73.0 (C6H5) 2PC1 1.05 63.0 14. To the mixture was added dropwise 0.92 g of 2-chloro-4-methyl-1,3,2-dioxa-phosphorane at -5-40 ° C and the mixture was then allowed to react at the same temperature for 30 minutes.

On the other hand, 1 g of sodium D (-) - N (N ', Ν'-dimethylamino-carbonylpropen-2-yl) -o-amino (p-hydroxyphenyl) acetate was suspended in 10 ml of methylene chloride which was added two drops of N-methylmorpholine at ^ 40 ° C, and a further drop of 0.84 g of ethyl chlorocarbonate in 2 ml of methylene chloride was added dropwise, and the mixture was allowed to react at the same temperature for 90 minutes to form a mixed anhydride. This was added at once to the pre-prepared solution, and the mixture was allowed to react at -j-40 ° C for 1 hour, then its temperature was raised to 0 ° C over 1 hour. The reaction mixture was filtered and the filtrate concentrated under reduced pressure. Then, the residue was dissolved in 10 ml of water and 20 ml of methyl isobutyl ketone and the solution was adjusted to a pH of 2.5 with dilute hydrochloric acid with stirring and allowed to stand for 15 minutes.

The aqueous layer was collected and adjusted to pH 5 »2 with 10% sodium hydroxide solution to precipitate crystals. The precipitated crystals were filtered off and washed with cold water to give 2.94 g (70%) crystals of 6 - [] D (-) - (] β -amino- (p-hydroxyphenyl) acetamido] penicillanic acid. trihydrate.

The infrared absorption spectrum of the product and thin layer chromatograms were identical to those of a standard sample.

EXAMPLE 11 2.72 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methylene chloride, 2 g of triethylamine was added to form a transparent solution, and then a solution of 2 was added. 4 g of Ν, Ν-dimethylaniline and 1.7 g of Ν, Ν-dimethylaniline hydrochloride in 7 ml of methylene chloride. The mixture was cooled to -r20 ° C and 1.4 g of 2-chloro-1,3,2-dioxaphosphorane was added dropwise. After reaction at the same temperature for 30 minutes, the reaction mixture was added dropwise with a solution of 1.9 g of thienylacetyl chloride in 5 ml of methylene chloride.

After the reaction mixture temperature was raised to 20 ° C and allowed to react for 2 hours, the mixture was poured into 20 ml of water and stirred for 15 minutes, and the organic layer was collected, washed with water and evaporated under reduced pressure. pressure. The residue was dissolved in butyl acetate and to the solution was added a concentrated aqueous solution of 0.9 g of sodium acetate with stirring to precipitate crystals. The precipitated crystals were filtered off and washed with butyl acetate and then with acetone to give 3.6 g of the sodium salt crystals of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid.

The infrared absorption spectrum of the product and the thin layer chromatogram were identical to those of a standard sample.

EKSEMPEL_12

The procedure of Example 11 was repeated under the same reaction conditions except that 1.5 g of 2-chloro-1,3,2-dioxaphosphorinane was used instead of 2-chloro-1,3,2-dioxa-phosphorane, whereby 3.5 g of crystals of the sodium salt of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid were obtained.

EKSEMPEL_13

The procedure of Example 11 was repeated under the same reaction conditions except that 1.7 g of diethyl chlorophosphite was used instead of 2-chloro-1,3,2-dioxaphosphorane to give 3.2 g of the crystals of the sodium salt of 7 - (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid.

EXAMPLE 14 2.72 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid was suspended in 20 ml of methylene chloride and 2 g of triethylamine was added to form a transparent solution.

Then, the mixture was added a solution of 2.4 g of N, N-dimethyl-aniline and 1.7 g of Ν, Ν-dimethylaniline hydrochloride in 7 ml of methylene chloride. After cooling the mixture to 4-30 ° C, 1.5 g of 4-methyl-2-chloro-1,3,2-dioxaphosphorane was added and the mixture was allowed to react at the same temperature for 30 minutes.

On the other hand, 3.5 g of sodium N- (N ', N'-dimethylaminocarbonylpropen-2-yl) -D (-) - oc-aminophenyl acetate was suspended in 30 ml of methylene chloride and two drops of N were added. -Methylmorpholine, whereupon the mixture was cooled to 4-30 ° C, a solution of 1.2 g of ethyl chlorocarbonate in 3 ml of methylene chloride was added dropwise and the mixture was allowed to react at the same temperature for 2 hours. This mixture was added at once to the pre-prepared solution and reacted with it at 4-30 ° C for 1 hour, after which the temperature was raised to 0 ° C over 1 hour. After completion of the reaction, insoluble material was filtered off and the filtrate was concentrated under reduced pressure. To the residue was added 10 ml of water and 25 ml of methyl isobutyl ketone which were dissolved and the pH of the mixture was adjusted to 2.5 with dilute hydrochloric acid with stirring and allowed to stand for 15 minutes. The water layer was collected and adjusted to pH 5, 5 with triethylamine to give 2.9 g of crystals of 7 - (& - aminophenylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate.

The infrared absorption spectrum of the product and the thin layer chromatogram were identical to those of a standard sample.

EXAMPLE_15 2 »72 g of 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid were suspended in 20 ml of methylene chloride and 2 g of triethylamine which was dissolved was added. To the mixture was then added a solution of 2.4 g of N, N-dimethylaniline and 1.7 g of N, N-dimethylaniline hydrochloride in 7 ml of methylene chloride. Then the mixture was cooled to 4-20 ° C and 1.5 g of 4-methyl-2-chloro-1,3,2-dioxaphosphorane was added dropwise, and the mixture was allowed to react at the same temperature for 30 minutes.

To the reaction mixture was added 2.1 g of D (-) - α-aminophenylacetyl chloride hydrochloride, the temperature was raised to 20 ° C and the mixture allowed to react for 2 hours. After completion of the reaction, the reaction mixture was added with 50 ml of water and stirred for 10 minutes, adjusted to pH 5.2 with 10% sodium hydroxide solution to precipitate crystals. The precipitated crystals were filtered off and washed with water to give 3.97 g (90%) crystals of 7- (T) (-) - α-aminophenylacetamido7-3-acetoxymethyl-3-cephem-4-carboxylic acid dihydrate .

The results when similarly used other trivalent? phosphorus compounds were as follows:

Trivalent Phosphorus Compound Mole Ratio Yield% 1-4 PC1 1.05 88 (CH30) 2PC1 1.05 80.5 (C1-CH2CH2O) 2PC1 1.05 83.9 (CgH50) 2PCl 1.05 74 (C6H5) 2PC1 1, EXAMPLE 16 2.86 g of diethylamine salt of 7-amino-3-methyl-3-cephem-4-carbopcyl acid and 1.2 g of Ν, Ν-dimethylaniline were mixed with 25 ml of methylene chloride and dropwise 1 was added. 5 g of 4-methyl-2-chloro-1,3,2-dioxaphosphorane at -20 ° C over 15 minutes, after which the mixture was allowed to react at the same temperature for 30 minutes. To the reaction mixture was added 2.1 g of D (-) - α-aminophenylacetyl chloride hydrochloride, the temperature was raised to 20 ° C and the mixture was allowed to react for 2 hours. After completion of the reaction, the reaction mixture was added 50 ml of methanol and the pH was adjusted to 1.0 with 10% hydrochloric acid. Insoluble material was filtered off and then the pH of the filtrate was adjusted to 5.2 with triethylamine and stirred for 15 minutes. After filtration of the precipitated material, the filtrate was concentrated to one third of the original volume under reduced pressure and the residue was diluted with 50 ml of acetone to precipitate crystals. The precipitated crystals were filtered off to give 2.7 g (73.5%) crystals of 7- [n (-) - oc-aminophenylacetamide [7-3-phenethyl-3-cephem-4-carboxylic acid monohydrate.

The infrared absorption spectrum of the product and thin layer chromatogram were identical to those of a standard sample.

EXAMPLE_17 2.36 g of sodium salt of 7-amino-3-methyl-3-cephem-4-carboxylic acid were suspended in 25 ml of methylene chloride, and to the mixture was added 1.2 g of Ν, Ν-dimethylaniline, the temperature was raised to 20 And 1.5 g of 4-methyl-2-chloro-1,3,2-dioxaphosphorane was added dropwise over 15 minutes. After reaction at the same temperature for 1 hour, the mixture was added with 2.1 g of D (-) - α-aminophenylacetyl chloride hydrochloride and allowed to react at 20 ° C for 2 hours. After completion of the reaction, the reaction mixture was added 50 ml of methanol and the pH of the mixture was adjusted to 5 »2 with 10% hydrochloric acid. After filtration of insoluble material, the filtrate was adjusted to pH 5.2 with triethylamine and stirred for 15 minutes. After filtration of the precipitated material, the filtrate was concentrated to a third of the original volume under reduced pressure and the residue was diluted with 50 ml of acetone to precipitate crystals to give 2.6 g (71%) crystals of 7- Ώ (_) - α-Aminophenylac etamido7-3-methyl-3-c ephem-4-carboxylic acid e monohydrate.

Example 18 In 25 ml of methylene chloride, 2 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid was suspended and 1.36 g of diethylamine was added to give a clear solution. Furthermore, 2.6 g of triethylamine and 1.13 g of N, N-dimethylaniline were added to the solution. The reaction mixture was cooled to -15 ° C and 2.6 g of 4-methyl-2-chloro-1,3,2-dioxaphosphorane was added dropwise over 15 minutes and at the above temperature. The reaction was allowed to proceed for 30 minutes, after which 2.12 g of D (-) - α-aminophenylacetyl chloride hydrochloride was added. The temperature of the resulting solution was raised to 20 ° C and at this temperature the reaction was continued for 1.5 hours, then 0.8 g of n-butanol was added dropwise to the reaction solution at 0 ° C and the solution was subjected to alcoholysis for 20 minutes. 10 ml of water was added to the solution while the temperature was controlled so as not to exceed 10 ° C and shaken for 10 minutes, the aqueous layer was separated and 40 ml of acetone added to the layer. Thereafter, triethylamine was added to adjust the pH of the resulting solution to 5.5. The solution was stirred at 0-5 ° C for 15 hours and the crystals thus precipitated were collected at

Claims (2)

191 * 241 $ filtration to give 2.4 g of 7-ZD (-) - α-aminophenylacetamide g7-3-methyl-3-cephem-4-carboxylic acid monohydrate (75,390, Crystalline Infrared Absorption Spectrum and Thin Layer Chromatography Method for Preparation of 6-Acylamidopenicillin or 7-Acylamidocephalosporin Compounds of the General Formula Vj R1 - C - CONH-p - S '^ r2 Y (I) 4 Z "V COOH wherein \ ^ ch 2 Y means or 1 _ CH R> where R means ^ -OH 2 ^ 2 hydrogen, halogen, azido, acyloxy, alkoxy, aryloxy or -S-R 'where R' represents an alkyl , aryl or heterocyolic group, R and R each independently means hydrogen or an optionally substituted alkyl, aryl, aralkyl, aryloxy, cycloalkyl or heterocyclic group, n is 0 or 1 2 11 and, when n is 1, R is by itself the same meaning as R, or R and 2 3 R together form a ring and R 2 represents hydrogen, halogen, hydroxy, amino, alkylamino, azido, cyano, alkoxy, alkylthio, aryloxycarbonyl , aralkyloxycarbonyl or alkoxycarbonyl,