DK144095B - PROCEDURE FOR THE PRODUCTION OF CEPHALEXIN OR SALTS THEREOF - Google Patents

Description

(19) DENMARK

| J | (12) PUBLICATION OF 144095 B

DIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM

(21) Application No. 2005/77 (51) | nt.CI.3 C07D501 / 10 (22) Filing date 5 · May 1977 (24) Running day 4 May 1972 (41) Aim. available May 5, 1977 (44) Posted May 7, Dec. 1981 (86) International application no.

(86) International filing day (85) Continuation day - (62) Application No. 2206/72

(30) Priority 11 May 1971 in 143683 * US

(71) Applicant BRISTOL-MYERS COMPANY, New York, US.

(72) Inventor Joseph Rubinfeld, US: Raymond Urgel Lemieux, CA: Rin = tje Raap, CA.

(74) Clerk Th. Ostenfeld Patentbureau A / S.

(54) Process for the preparation of cephalexin or its salts.

The present invention relates to a novel process for the preparation of the antibacterial compound, cephalexin. The compound of the invention is valuable as an antibacterial agent, as a nutritional supplement for animal feed and as a therapeutic agent for poultry, animals and humans in the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.

Cephalexin is the generic name for 7- (α-aminophenylacetamido) - O 3-methyl-3-cephem-4-carboxylic acid, which has the structural formula t / "CH" C - NH - p ^ CH3

t COOH

3 2 U4095

Cephalexin is e.g. described in J. Med. Chem., 12, 310-313 (1969), in British Patent No. 1,174,335, in South African Patent No. 67/1260, in the specification for published Japanese Patent Application No. 16871/66 and in Belgian Patent No. 696,026.

An important step in the process of the present invention is a direct rearrangement of 6-acylamidopenicillanic acid 1-oxides to 7-acylamido-3-methylceph-3-em-4-carboxylic acid without the need to first esterify the 3-carboxylic function of the penicillin. There is extensive literature available regarding the rearrangement of penicillin-1-oxide esters to the corresponding 3-methylceph-3-em-4-carboxylate esters, but it is generally recognized that the 3-carboxyl function of penicillin is in form. of a carboxylic acid ester so that decarboxylation does not occur.

The most well-known prior art of this important step is the following: 1. U.S.A. No. 3,275,626, which discloses the rearrangement of 63-aeylamidopenicillanic acid ester. It is further disclosed in the patent that the reaction produces a decarboxylated 3-methyl-3-cephem rearrangement product (column 5, lines 29-36 and column 7, lines 24-33) unless the penicillin sulfoxide used in the rearrangement is in in the form of a 3-carboxylic acid ester.

2. British Patent No. 1,204,394 discloses the rearrangement of 6-acylamidopenicillanic acid sulfoxide esters in a tertiary sulfonamide solvent system.

British Patent No. 1,204,972 discloses the rearrangement of 6-acylamidopenicillanic acid sulfoxide esters in a tertiary carboxamide or tertiary urea solvent system.

4. U.S.A. U.S. Patent No. 3,507,861 discloses, inter alia, decarboxylation of the carboxyl function when the free acid is subjected to the "sulfoxide rearrangement".

5. The Inventors of the Same U.S.A. patent has elaborated on their discoveries in a publication entitled "Chemistry of Cephalosporin Antibiotics. XV. Transformation of Penicillin Sulfoxide", A Synthesis of Cephalosporin Compound, J. Am. Chem. Soc., 91, 1401 (March 12, 1969). It is clearly stated in this publication that "the only product which can be isolated and characterized from the acetic anhydride and acid-catalyzed rearrangement of penicillin sulfoxide free acids was 3-methyl-7- (2-phenoxyacetamido) -3-cephem." 6. I J, Am. Chem. Soc. 85, 1896 (June 20, 1963), Morin, Jackson et al. stated that the rearrangement of penicillin sulfoxic acid results in decarboxylation.

7. In South African Patent No. 68/2780, it is clearly stated that "In all cases, the (known penicillins) must be esterified and converted to the corresponding sulfoxide prior to treatment", i.e. is rearranged into 3-methyl-3-cephem-4-carboxylate derivative.

8. In the U.S.A. U.S. Patent No. 3,197,466 discloses the preparation of penicillin sulfoxides.

9. Suddal, Morch and Tybring describe the preparation of penicillin sulfoxides in an article entitled "Penicillin Oxides, Tetrahedron Letters" 9, page 381 (1962).

10. In South African Patent No. 68/5889 a process for the preparation of penicillin sulfoxide esters is disclosed.

11. South African Patent No. 70/1627 discloses a rearrangement of penicillin sulfoxide esters into 3-methylceph-3-em-4-carboxylic acid esters using acid-amine complexes by heat. There is no revelation at this site that compounds other than penicillin sulfoxide esters can be rearranged without decarboxylation of the carboxyl group. All of the examples and claims shown are directed to the rearrangement of penicillanic acid sulfoxide esters to 3-methylceph-3-em-4-carboxylate esters.

12. Danish Patent Application No. 1677/71 discloses a process for the preparation of cephalexin in which hetacillin is nitrosated or formylated to form N-nitrose or N-formylhetacillin, which is then oxidized to form the corresponding sulfoxide; this blocked sulfoxide can then be redistributed in free acid form to N-nitroso or N-formylhetacephalexin, which can finally be cleaved to release cephalexin.

The present invention provides an improved process for the preparation of cephalexin or non-toxic salts thereof, wherein the rearrangement step of a cephalosporanic acid compound is performed in good yield on the free acid form of a penicillin sulfoxide produced by oxidation of a penicillin produced by fermentation. This avoids the disadvantages of the prior art in rearranging a penicillin sulfoxide ester. Compared to the process using hetacillin as a starting material, one obtains that a penicillin produced by fermentation is a much more readily available starting material and partly that one avoids a nitrosation or fonnylation step and subsequent unblocking. The process according to the invention also uses silylation steps known per se.

More particularly, the process according to the invention is of the kind comprising the following steps: A) Oxidation of a penicillin produced by fermentation or a salt thereof to produce a penicillin sulfoxide of the formula: 0H 3 R - C - NH - f CH3

X-N-1-CO-H

Wherein R is the side chain of a penicillin produced by fermentation? B) Conversion of the penicillin sulfoxide to a cephalosporanoic acid compound of the formula 0 o R - C - NH-r-f

C02H

wherein R has the meaning given above? C) Reaction of the Cephalosporanoic Acid Compound with a Silyl Compound of Formula R 1 / R 1/51> ΝΗ X r 3

1 ί I 1 \ 2 I

I y'B. or R-Si-X

Wherein R, R and R are hydrogen, halogen, (lower) alkyl, halogen (lower) alkyl, phenyl, benzyl, tolyl or dimethylaminophenyl, with at least one of the groups R , R and R are different from halogen or hydrogen? R 1 represents (lower) alkyl; m represents an integer 1 or 2, and X represents halogen or

-N

wherein R is hydrogen or (lower) alkyl and R is hydrogen, (lower) alkyl or R3 is E-Ji in which R, R and R are as defined above, under anhydrous conditions, in an inert solvent, and in the presence of an acid deactivating tertiary amine to form the corresponding silyl ester of the cephalosporanoic acid compound; D) Reaction of the silyl ester with excess of a halogenating agent under anhydrous conditions, in an inert solvent, and in the presence of an acid deactivating tertiary amine to form the corresponding imino halide; E) Reaction of the imino halide with an alcohol selected from aliphatic alcohols of 1-12 carbon atoms and phenylalkyl alcohols of 1-7 alkyl carbon atoms to prepare the corresponding imino ether * F) Breaking of the imino ether's imino bond by hydrolysis or alcoholysis to produce 7-aminodeacetoxycephalosephalic acid epoxy G) Preparation of the mono- or disilyl derivative of 7-aminodeacetoxy-cephalosporanoic acid; H) N-acylation of the mono or disilyl derivative with a phenylglycine derivative and I) Cleavage by hydrolysis or alcoholysis of all silyl groups present to form cephalexin or by subsequent conversion of a non-toxic, pharmaceutically acceptable salt thereof, the process being characterized wherein (1) the conversion step (B) consists of a rearrangement by heating the free acid form of the penicillin sulfoxide in a weak basic solvent in the presence of a catalyst comprising a strong acid, either alone or in combination with a nitrogen base with a pKb value of not less than 4; (2) the monosilyl derivative of 7-aminodeacetoxycephalosporanoic acid is prepared by reacting the 7-aminodeacetoxycephalosporanic acid product of step (F) with approximate or molar amount of a silyl compound as defined in step (C), or by performing hydrolysis or alcoholysis reaction ( ) in the presence of at least approx. a molar excess of a silyl compound as defined in step (C) or by subjecting in step (F) the iminoether imino bond of alcoholysis and thermal decomposition in the presence of at least about a molar excess of a silyl compound as defined in step (C); (3) the disilyl derivative of 7-aminodeacetoxycephalosporanoic acid is prepared by reacting the 7-aminodeacetoxycephalosporanoic acid product of step (F) with at least 2 moles of a silyl compound as defined in step (C) per day. mole of 7-aminodeacetoxycephalosporanoic acid / or by carrying out the hydrolysis or alcoholysis reaction of step (f) in the presence of at least ca. a double molar excess of a silyl compound, as defined in step (C), or subjecting in step (F) the imino-bond of the imino ether to alcoholysis and thermal decomposition in the presence of at least a double molar excess of a silyl compound, as defined in step (C) (C); and (4) performing the acylation reaction by reacting the mono- or disilyl derivative with phenylglycyl chloride, hydrochloride in an inert, non-aqueous organic solvent system.

The non-toxic, pharmaceutically acceptable salts include e.g.

(1) non-toxic, pharmaceutically acceptable salts of the acidic carboxylic acid group such as the sodium, potassium, calcium, aluminum and ammonium salts, and non-toxic substituted ammonium salts with amines such as tri (lower) alkyl amines, procaine, dibenzylamine, N-benzyl-ft-phenethylamine, 1-ephenamine, Ν, Ν'-dibenzylethylenediamine, dehydroabietylamine, N, N'-bis-dehydroabietylethylenediamine, N- (lower) alkylpiperidines such as N-ethylpiperidine and other amines , which has been used to form salts of benzylpenicillin; and (2) nontoxic, pharmaceutically acceptable acid addition salts (i.e., salts of the basic nitrogen atom) such as (a) the mineral acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, sulfate, sulfamate, sulfonate, phosphate, etc., and (b) the organic acid addition salts such as the maleate, acetate, citrate, tartrate, oxalate, succinate, benzoate, fumarate, malate, mandelate, ascorbate, β-naphthalenesulfonate, p-toluenesulfonate and the like. Cephalexin can also exist as the "free acid" which naturally exists as a zwitter ion.

The penicillanic acid sulfoxide used in step (B) is derived from a fermentation penicillin.

The term "penicillin produced by fermentation" shall include in this connection all the penicillins by which it is known to be produced. a fermentation process according to Behren's rule [Medicinal Chemistry, 3rd ed., p. 382, A. Burger, Wiley-Interscience (pub.)], and in particular it includes penicillins of the formula "H ^ X" CH3 R - C - N—- rj ^ -CH3

O = ± -N- CO 2 H

Wherein R represents phenyl, benzyl, phenoxymethyl, phenylmercaptomethyl, such phenyl, benzyl, phenoxymethyl and phenylmercaptomethyl substituted with chloro, methyl, methoxy or nitro groups, as well as heptyl and thiophen-2-methyl. Penicillins with these representative R groups are produced most economically or most easily by fermentation methods.

The preferred penicillins are 6-phenylacetamidopenicillanic acid (penicillin G) and 6-phenoxyacetamidopenicillanic acid (penicillin V):

The oxidation step (A) can be carried out according to the guidelines described by Chow, Hall and Hoover (J. Org. Chem. 1962, 27, 1381), except it is preferred to oxidize the free penicillic acid (or salt thereof) directly in instead of first esterifying the carboxyl group as referred to in said literature site. Direct oxidation of a free penicillic acid or salt is described by Essery et al. in J. Org. Chem. 30, 1965, 4388. The penicillin is mixed with the oxidizing agent in an amount such that at least one atom of active oxygen is present per day. atomic thiazolidine sulfur. Suitable oxidation agents include hydrogen peroxide, peracetic acid, metaperiodic acid, monoperphthalic acid, m-chloro-perbenzoic acid and t-butyl hypochlorite, the latter being preferably used in admixture with a weak base, e.g. pyridine - Excess oxidant can lead to the formation of 1,1-dioxide, the 1-oxide can be obtained in R and / or S form.

The acyl group in the 6-amino position of the penicillanic acid sulfoxide may be any acyl group derived from fermentation, but should preferably be reasonably stable under the rearrangement conditions. Due to the particularly easy availability of penicillin G and V, it is preferred according to the invention that R in the sulfoxide represents benzyl or phenoxymethyl.

The rearrangement step (B) is carried out under catalytic acidic conditions, preferably using polybasic acids, such as ortho-phosphoric acid, which is partially neutralized with basic solvents and most conveniently by adding small amounts of a weak basic substance such as pyridine or quinoline. For convenience, these catalysts are herein described as complexes or salts, although it should be understood that the term "complex" may be substituted for "salts". Furthermore, it should be noted that under the reaction conditions, the salt or complex may exist in a dissociated form.

Thus, according to one embodiment, there is provided a process for the preparation of 7-acylamido-3-methylceph-3-em-4-carboxylic acids, which comprises rearranging a 6-acylamidopenicillanic acid 1-oxide in a weak basic organic solvent such as dioxane or diglyme in the presence of a catalyst comprising a strong acid alone or in combination with a nitrogen base having a pKb value of not less than 4. The catalyst is preferably derived from a nitrogen base and an acid which forms salts or complexes, which salt may be formed in situ in the reaction mixture. The acid should preferably be a polybasic acid, such as a phosphorus-containing acid.

As phosphorous acid may be used orthophosphoric acid, polyphosphoric acid, pyrophosphoric acid or phosphoric acid or a phosphonic acid. The phosphonic acid may be an aliphatic, araliphatic or aryl phosphonic acid; the aliphatic group, araliphatic group or aryl group for such a phosphonic acid may be a hydrocarbon group (e.g., a lower alkyl, phenyl lower alkyl or phenyl group) or a hydrocarbon group substituted by e.g. a halogen atom or a nitro group. Examples of aliphatic phosphonic acids include the lower alkyl phosphonic acids and substituted (e.g. halogen) lower alkyl phosphonic acids such as methane phosphonic acid, ethane phosphonic acid, dichloromethane phosphonic acid, trichloromethane phosphonic acid and iodomethane phosphonic acid. Examples of arylphosphonic acids include benzene phosphonic acids and substituted (e.g. halogen or nitro) benzene phosphonic acids, e.g. bromobenzene phosphonic acids and nitrobenzenephosphonic acids. The term "a phosphorus-containing acid" also includes the anhydrides of the acids listed above, e.g. ^ 2 ^ 5 ·

The term "nitrogen base" is used herein as a convenient term for a basic substance containing nitrogen, although it may contain other heteroatoms, e.g. oxygen. However, it is preferred to use weakly basic and organic amines. Bases which can be used have a pKb value for protonization of not less than 4 (i.e., when measured in water at 25 ° C). The base may be a polyfunctional base having a nitrogen function having such pKb value for the first protonation step.

The organic base may be primary, secondary or tertiary; however, it is preferred to use weak tertiary organic bases. Examples of such tertiary organic bases are the unsaturated heterocyclic bases such as pyridine, quinoline, isoquinoline, benzimidazole and homologues thereof, e.g. the alkyl-substituted pyridines and quinolines such as α-, β- and γ-picolines and 2- and 4-methylquinolines. Other substituted heterocyclic bases which may be used include those with halogen (e.g., chlorine or bromine), acyl (e.g., formyl or acetyl), acylamido (e.g., acetamido), cyano, carboxy, aldoximino, and the like. substituted.

Other organic bases which may be used include aniline and nucleus substituted anilines such as halo anilines (e.g., o-chloroaniline, m-chloroaniline and p-chloroaniline); anilines (eg o-methylaniline and m-methylaniline); hydroxy and (lower) alkoxyanilines (eg o-methoxy-aniline and m-hydroxyaniline); nitroanilines (e.g., m-nitroaniline) and carboxyanilines (e.g., m-carboxyaniline), as well as N- (lower) alkylanilines (e.g., N-methylaniline) and N, N-di (lower) alkylanilines.

Preferred groups of catalytic systems are those obtained by reacting a phosphorus-containing acid with a nitrogen base. Advantageous results have been obtained with the process of the invention when salts of orthophosphoric acid have been used as catalysts. Equally advantageous results, however, have been obtained when the catalyst is formed in situ. Catalyst systems are obtained by converting practically molar equivalents of an acid and an aromatic heterocyclic tertiary organic nitrogen base into a weak basic solvent system. Advantageous results have been obtained with the process of the invention when complexes of pyridine, quinoline, isoquinoline or derivatives thereof substituted with lower alkyl, halogen, acyl, acylamido, cyano, carboxy or aldoximino have been used as catalysts.

Particularly preferred complexes of nitrogen bases are those obtained by reaction of a phosphorus-containing acid with an aromatic heterocyclic tertiary organic nitrogen base. Advantageous results have been obtained with the process of the invention when using salts of orthophosphoric acid or a phosphonic acid with pyridine, quinoline, isoquinoline or such bases substituted e.g. lower alkyl, halogen, acyl, acylamido, cyano, carboxy or aldoxymino. Valuable catalysts thus include pyridine; 2-methyl- and 4-methyl-pyridine; quinoline and isoquinoline salts of orthophosphorus, methane phosphone, ethane phosphone, iodomethane phosphone, dichloromethane phosphone, trichloromethane phosphone, bromobenzene phosphone and nitrobenzen phosphonic acids.

In particular, it is preferred that the catalyst comprises a complex formed of phosphoric acid or P2 ° 5 ° 9 a nitrogen base selected from pyridine or quinoline.

The catalytic system used in the process of the invention can be designed from such amounts of the acid and the base that a portion of U4G95 or more of the acidic functions is partially neutralized by the base and / or the solvent. Generally, less than the molar amount of nitrogen base is used so that the catalyst, in addition to the salt, also contains some free acid.

The optimal ratio of acid to base in the catalytic system depends on various factors, including the nature of the acid and the base, as well as the nature of the penicillanic acid sulfoxide. The optimum ratio can be determined by prior experiments.

A preferred catalytic system for use in the process of the present invention is that obtained by reacting 1 mole of pyridine and 2 moles of orthophosphoric acid in dioxane.

Another preferred catalytic system for use in the process of the invention is obtained from quinoline and orthophosphoric acid in a weak basic solvent (i.e., dioxane). It occurs by reacting practically one mole equivalent of quinoline and two mole equivalent of orthophosphoric acid.

Another preferred catalytic system that can be used for step (B) is that obtained by the combination of ° 9 PY 2 idin in a weakly basic solvent, e.g. dioxane.

A particularly preferred catalyst according to the invention comprises a pyridine-di (phosphoric acid) complex which is present in a molar ratio of approx. 0.05 to approx. 0.5 moles per mole of penicillin sulfoxide.

Step (B) is carried out in a weak basic organic solvent to control acidity, homogeneity and temperature.

Usually, the penicillanic acid sulfoxide will be dissolved in the organic solvent. The solvent should be substantially inert to the penicillanic acid sulfoxide used in the process and to the 3-methylceph-3-em-4-carboxylic acid produced by the process.

Solvents which may be used include those disclosed in U.S.A. No. 3,275,626 and other publications with descriptions of the rearrangement reaction. Particularly suitable solvents, however, include ketones boiling from 75-120 ° C (e.g. 100-120 ° C), esters boiling from 75-140 ° C (e.g. 100-130 ° C), dioxane and diethylene glycol dimethyl ether (diglyme). Illustrative examples of the ketones and esters which can be used in the process of the present invention are aliphatic ketones and esters with appropriate boiling points, including ethyl methyl ketone, isobutyl methyl ketone, methyl n-propyl ketone, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and diethyl carbonate. These solvents are capable of being protonated by a strong acid and are considered as such "weakly basic organic solvents". The most preferred solvent is dioxane.

The time for obtaining optimum yields in the process of the invention varies according to the solvent and temperature used. The rearrangements are conveniently carried out at the boiling point of the selected solvent, and for the solvents boiling in the lower part of the intervals listed above, correspondingly longer reaction times may be required, e.g. up to 48 hours, than for the solvents boiling at higher temperatures. Eg. dioxane rearrangements generally require times from 7 to 15 hours to obtain optimal results, whereas those performed in methyl isobutyl ketone generally require times from 1 to 8 hours. The yields of the rearrangements depend, but to a lesser extent, on the concentration of catalyst in the solvent and correspondingly longer reaction times are required at lower catalyst concentrations.

It is particularly preferred to use dioxane as an organic solvent because penicillanic acid sulfoxides can be dissolved in this solvent in high concentration and there is generally no decrease in the yield by increasing the concentration to the order of 35%.

The amount of strong acid used in the rearrangement should generally not exceed 1.0 mole per day. moles of penicillanic acid sulfoxide; however, it is generally preferred to use it in amounts of 0.05 to 0.5 moles per day. mole of penicillanic acid sulfoxide.

The amount of nitrogenous base used in the rearrangement should generally not exceed 1.0 mole per moles of penicillanic acid sulfoxide; however, it is generally preferred to use it in amounts of from 0.025 to 0.25 mol per liter. mole of penicillanic acid sulfoxide.

The appropriate duration of a given reaction can be determined by examining the reaction solution by one or more of the following methods: 1. Thin layer chromatography, e.g. on silica gel, development with 3: 1: 1 n-butanol-acetic acid-water and visualization of the spots by treatment with a sulfuric acid spray.

2. Determination of the rotation after appropriate dilution of the reaction mixture with e.g. chloroform.

3. Determination of the ultraviolet spectrum of a sample of the reaction mixture suitably diluted with ethyl alcohol. This determination cannot be applied when ketonic solvents are used as reaction media.

12 NMR (nuclear magnetic resonance).

Although satisfactory yields can be obtained by carrying out the reaction under normal reflux, it may be possible to improve the yields by introducing a desiccant (e.g., alumina, calcium oxide, sodium hydroxide or molecular sieves) which is inert to the solvent in the reflux return line for removal of water formed during the reaction. Alternatively, water formed during the reaction can be removed using a fractionation column, the water formed being removed by fractional distillation.

It should also be noted that the process in question can be carried out at elevated pressures. Hereby, lower boiling solvents can be used at temperatures above their boiling point. For example, If the reaction is carried out in a sealed container, the process using tetrahydrofuran can be carried out at 150 ° C if desired, even if this temperature is above the reflux temperature of the tetrahydrofuran at atmospheric pressure. Thus, within the scope of the invention, the said reaction conditions also fall using elevated pressures.

After carrying out the reaction, the salt can be removed either before or after concentrating the reaction mixture. If the reaction solvent is immiscible with water, the complex can be removed by a simple washout. If, on the other hand, the reaction medium is miscible with water, it is appropriate for purification purposes to remove the reaction solvent (this can be done by distillation under reduced pressure) and then purify the residue by an appropriate method, e.g. chromatography on silica gel, etc., or precipitation by salt formation, fractional crystallization, etc.

It has been found that the degree of conversion achieved by the process of the invention may be such that complicated purification methods can be avoided and the residue can be concentrated to a solution and used directly in the next step of the reaction without isolation or purification, or the can be isolated and purified using the methods highlighted above.

The product can be extracted into a solvent and used directly for the following step or, if desired, purified by recrystallization from a suitable solvent.

Thus, it has surprisingly been found that, notwithstanding the known teachings, it is possible and practically feasible to rearrange the penicillanic acid sulfoxide to 3-methylceph-3-em-4-carboxylic acids with minimal decarboxylation. This discovery presents a myriad of advantages over the process of rearranging penicillan sulfoxide esters, avoiding the need to first esterify the penicillanic acid or penicillanic acid sulfoxide and, after the rearrangement, to deesterify the 3-methylceph-3-em-4-carboxylate ester.

After the rearrangement, the 7-acylamido compound formed in step (B) can be N-deacylated to form a corresponding 7-amino compound and the latter can then be silylated as described below and acylated with an appropriate acylating agent.

Methods for N-deacylation of cephalosporin derivatives with 7-acyl amido groups are known, and a suitable method comprises treating a 7-acylamidoceph-3-em-4-carboxylic acid silyl ester with an imidhalogenide-forming component, conversion of the imide halogen thus obtained. -nid to the imino ether and decomposition of the latter. The ester group can then be cleaved by hydrolysis or alcoholysis to form the 4-carboxylic acid. This N-deacylation method is described in more detail in Belgian Patent No. 719,712 and in U.S.A. U.S. Patent Nos. 3,499,909 and 3,575,970. British Patent Specification No. 1,227,014 discloses an N-deacylation method similar to that described in the aforementioned literature sites, except that other 4-carboxylic acid esters, i.e. other than silyl esters, is used in the 7-acylamidodesacetoxycephalosporin starting material.

The formation of the silyl ester in step (C) occurs by reacting, under anhydrous conditions, a silyl compound as defined in step (C) with the 7-acylamido compound or a salt thereof, in an inert organic solvent in the presence of an acid deactivating tertiary amine.

Suitable inert solvents include methylene chloride, dichloromethane, chloroform, tetrachloroethane, nitromethane, benzene and diethyl ether.

Suitable acid deactivating tertiary amines include triethylamine, dimethylamine, quinoline, lutidine, pyridine, etc .. The amount of acid deactivating amine used is preferably equivalent to approx.

75% of the total acid that is developed during the process.

Examples of some suitable silyl compounds for step (C) are: trimethylchlorosilane, hexamethyldisilazane, triethylchlorosilane, methyltrichlorosilane, dimethyldichlorosilane, triethylbromosilane, tri-n-propylchlorosilane, bromomethyl dimethylchlorosilane, tri benzylmethylethylchlorosilane, phenylethylmethylchlorosilane, triphenylchlorosilane, triphenylfluorosilane, tri-o-tolyl-chlorosilane, tri-p-dimethylaminophenylchlorosilane, N-ethyltriethylsilylamine, hexaethyldisilazane, triphenylsilane

Tetramethyldiethyldisilazane, tetramethyldiphenyldisilazane, hexaphenyl-disilazane, hexa-p-tolyl-disilazane, etc. The same effect is produced by hexa-alkylcyclotrisilazanes or octa-alkylcyclotetrasilazanes.

Other suitable silylating agents are silylamides and silylurides such as trialkylsilylacetamide and a bis-trialkylsilylacetamide. The most preferred silyl compounds are trimethylchlorosilane and dimethyldichlorosilane.

The imino halide produced in step (D) is preferably an imino chloride or bromide / which can be prepared by reacting the silyl ester of step (C) with an excess, e.g. 2 or more moles per moles of silyl ester, of a halogenating agent such as phosphorus pentachloride, phosphorus pentabromide, phosphorus tribromide, phosphorus trichloride, oxalyl chloride, p-toluenesulfonic acid halide, phosphorus oxychloride, phosgene, etc. under anhydrous conditions in an inert organic solvent in the presence of an acid reactant, is below 0 ° C and most preferably approx. -20 ° C to approx. -60 ° C.

The imino ether in step (E) is formed by reacting the imino halide, preferably under anhydrous conditions, with a primary or secondary alcohol, preferably at temperatures below 0 ° C and most preferably between -10 ° C and -70 ° C.

Examples of suitable alcohols to form the imino ethers are 7 7 primary and secondary alcohols of the general formula R OH, wherein R is selected from the group consisting of (A) (lower) alkyl of 1-12 carbon atoms, preferably 1-3 carbon atoms such as methanol, ethanol, propanol, isopropanol, n-butanol, amyl alcohol, decanol, etc.? (B) phenylalkyl of 1-7 alkyl carbon atoms, such as benzyl alcohol, 2-phenyl-ethanol-1, etc .; (C) cycloalkyl, such as cyclohexyl alcohol, etc; (D) hydroxyalkyl of 2-12 carbon atoms, preferably at least 3 carbon atoms such as 1,6-hexanediol, etc .; (E) alkoxyalkyl of 3-12 carbon atoms such as 2-methoxyethanol, 2-isopropoxyethanol, 2-butoxyethanol, etc .; (F) aryloxyalkyl of 3-7 carbon atoms in the aliphatic chain such as 2-p-chlorophenoxyethanol, etc .; (G) aralkoxyalkyl of 3-7 carbon atoms in the aliphatic chain such as 2- (p-methoxybenzyloxy) ethanol, etc .; (H) hydroxyalkoxyalkyl of 4-7 carbon atoms such as diglycol. Mixtures of these alcohols are also suitable for forming the imino ethers.

After formation of the imino ethers, the imino bond must be broken to form 7-aminodeacetoxycephalosporanoic acid (7-ADCA) or, as explained below, a silyl derivative thereof. This process is carried out by mild hydrolysis or alcoholysis. The use of the silyl esters simplifies the process as the silyl ester hydrolyses simultaneously with the cleavage of the imino bond, thus avoiding the necessity of a separate step for cleavage of the 4-carboxy esters.

15 U4095

The formation of 7-ADCA by the process of the invention is illustrated in the following example: 2.23 g of the N-ethylpiperidine salt of N-phenacetyl ~ 3 -'-desacetoxy-7-aminocephalosporanoic acid was suspended in 18 ml of methylene chloride and after addition of 1.3 ml of dimethylaniline was added to 1 ml of trimethylchlorosilane to give the corresponding trimethylsilyl ester. After 1 hour, the mixture was cooled to -50 ° C, and 1/1 g of PCI 2 was added.

For 2 1/4 hours the temperature was kept at -40 ° C and then lowered to -65 ° C. A solution of 0.3 ml of dimethylaniline and 12 ml of butanol was added to the cooled mixture and then the temperature was maintained at -40 ° C for 2 1/4 hour. The reaction mixture was poured onto a mixture of 35 ml of water and 17 ml of methanol and brought to pH 3.5 at one time by means of ammonium bicarbonate. After approx. The precipitate was filtered off for 20 hours at 5 ° C, washed with ice water (1: 1) / methylene chloride and acetone, and dried to give 0.936 g (92% yield) of desacetoxy-7-aminocephalosporanoic acid.

The monosilyl derivative of 7-ADCA can be prepared by reacting the 7-ADCA formed in step (F) with ca. one mole of a silyl compound as defined in step (C) per mole 7-ADCA. As an example, 7-ADCA can be reacted with approx. an equimolar amount of trimethyl chlorosilane in a suitable anhydrous, inert organic solvent, in the presence of triethylamine to form the monosilylated derivative of formula H2N-I-fS ") / -CH3 COOSi (CH3) 3

Alternatively, this monosilylated 7-ADCA can be prepared by carrying out the imine cleavage reaction in step (F) in the presence of at least about one molar excess of a silyl compound as defined in step (C). In this process, the desired monosilyl derivative can be prepared without the need to first isolate 7-ADCA.

Yet another process for preparing monosilylated 7-ADCA involves subjecting the imino ether derivative in step (F) to the alcoholysis and thermal decomposition in the presence of at least ca. one molar excess of a silyl compound as defined in step (C). This method also allows the monosilyl derivative to be formed without first preparing and isolating 7-ADCA.

The disilyl derivative of 7-ADCA can be prepared analogously to the methods discussed above for the preparation of monosilylated 7-ADCA. Thus, the 7-ADCA formed in step (F) can be reacted with at least about one double molar excess of a silyl compound as defined in step (C) under the same reaction conditions as described above for step (C) and in the preparation of monosilylated 7-ADCA, i.e. in an essentially anhydrous inert organic solvent and in the presence of an acid deactivating tertiary amine. By way of example, 7-ADCA may be reacted with trimethylchlorosilane in methylene chloride in the presence of triethylamine and in a ratio of approx. two moles of trimethylchlorosilane per mole of 7-ADCA to form the disilylated 7-ADCA of the formula

Si (CH,), 3 3 η-n ——— r> -— ch 3

0 T

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Alternatively, the imine cleavage reaction step (F) may be carried out in the presence of at least ca. double molar excess of a silyl compound as defined in step (C) to form the disilylated 7-ADCA derivative. This method allows formation of the desired disilyl derivative without the need to first form and isolate 7-ADCA.

Yet another method of preparing disilylated 7-ADCA causes the imino ether derivative in step (F) to be subjected to alcoholysis and thermal decomposition in the presence of at least ca. a double molar excess of a silyl compound, as defined in step (C). This method also allows preparation of the desired disilyl derivative without the need to first isolate 7-ADCA.

Either the mono- or disilylated 7-ADCA or an N-protected derivative thereof can then be N-acylated with phenylglycyl chloride, hydrochloride to form silylated cephalexin. All silyl groups present after the acylation reaction are then removed in a conventional manner, e.g. by hydrolysis or alcoholysis to form the desired cephalexin end product.

Belgian Patent No. 737,761 discloses N-acylation with conventional acylating agents of mono- or disilylated 7-ADCA, which have been prepared by a different and more complicated method. None of the aforementioned novel processes for preparing monosilylated or disilylated 7-ADCA are disclosed in this patent, nor is the novel and valuable chloride, hydrochloride-acylation step disclosed. British Patent No. 1,227,014 discloses N-acylation of 7-ADCA esters, but only 2,2,2-trichloroethyl, benzyloxymethyl, t-butyl, p-methoxy, 3,5-dimethoxybenzyl and p The methoxybenzyl esters are used in this process.

Although any of the phenylglycine derivatives commonly used for acylation of 6-APA or 7-ACA or derivatives thereof can be used to acylate the subject mono- or disylated 7-ADCA, phenylglycyl chloride, hydrochloride as used herein is used. acylating. The acylation step (H) of the process of the present invention is a novel step, since no prior art discloses the acylation of acylated 7-ADCA with acid halide, hydrohalide acylating agents. The use of the particular acylation process in question leads to higher yields than the use of conventional acylating agents.

The solvents useful for the acylation reaction are well known to those skilled in the art and include inert, non-aqueous organic solvents such as tetrahydrofuran, dimethylformamide, methylene chloride, ethylene chloride and acetonitrile.

The preferred temperature range for the acylation step is from approx. -20 ° C to approx. + 70 ° C. However, the temperature is not critical and temperatures higher or lower than those within the preferred limits can be used.

Although some reaction will take place, regardless of the molar ratio used between the reactants, it is preferable to use a molar excess of acylating agents to obtain the greatest yields.

The cephalexinsilyl ester formed in step (H) can be treated by hydrolysis or alcoholysis to decompose the functional sily groups and to form the desired cephalexin end product. A preferred silyl cleavage method consists of treating the product of step (H) with methanol or a mixture of methanol and water.

Cephalexin prepared in accordance with the present invention may, if desired, be converted in a manner known per se to a non-toxic, pharmaceutically acceptable salt thereof.

18 144095

Example 1

Preparation of 7- (phenoxyacetamido) desacetoxycephalosporanoic acid (2) by rearrangement of penicillin V acid sulfoxide (1).

The pyridine-di (phosphoric acid) complex (PDPA) was prepared as follows: Pyridine (7.9 g, 0.10 mol) was added portionwise to a stirred and ice-cooled solution of 85% orthophosphoric acid (23.0 g, 0.20 mol) ) in 100 ml of tetrahydrofuran. The white solid precipitate was collected by filtration, washed with THF and ether, and dried in vacuo over 25 ° C yield: 25.4 g (92%).

A mixture of penicillin V sulfoxide (18.3 g, 0.050 mol), PDPA (1.38 g, 0.005 mol) and anhydrous dioxane (300 ml) was heated under reflux (oil bath) for 8 hours. The refluxing dioxane was passed through Linde 4A molecular sieves (^ 100 g) in a Soxhlet apparatus before being returned to the flask. The solvent was removed under reduced pressure and the residue was treated with a mixture of ethyl acetate (200 ml) and water (50 ml). The ethyl acetate layer was extracted with 1N aqueous sodium bicarbonate (60 ml). The bicarbonate extract was cooled and acidified with dilute hydrochloric acid. The semi-solid precipitate was extracted into ethyl acetate (125 ml). This solution was dried (MgSO4) and concentrated to dryness to give 14.0 g of a yellow solid foam. By nm spectroscope! using o-toluic acid as an international standard, the amount of the desired product was estimated to be 6.30 g (36%). To a cold solution of the crude product in 25 ml of methanol was added dibenzylamine (7.9 g, 0.040 mol). After the addition of some seed crystals, the dibenzylamine salt of 2 crystallized slightly. After cooling overnight at -15 °, the solid was collected by filtration and washed successively with cold methanol and ether. 7.5 g (28%) of a white, airy solid, mp 135-136 ° (dec) were obtained. The infrared spectrum of this salt coincided with that of the authentic 2 dibenzylamine salt (mp 141-142 ° (dec) after recrystallization from methanol).

The dibenzylamine salt was briefly shaken with 75 ml of ethyl acetate and 30 ml of 1 N hydrochloric acid. Dibenzylamine hydrochloride crystallized from this mixture and collected by filtration and dried (2.5 g, 78%). The ethyl acetate layer was dried (MgSO 4) and concentrated to a volume of ca.

20 ml. A white solid crystallized easily and collected by filtration after cooling, yield 4.1 g (24%), mp 173-175 ° (dec), Nujol 3450 (NH) f 1760 (β-lactam carbonyl), 1730 (amide carbonyl) and H13.X-j 1670 cm (carbonyl). The infrared spectrum and the nm spectrum coincided with the corresponding spectra for an authentic sample of 2, melting point 197-178 ° (dec.) Prepared from phenoxyacetyl chloride and 7-aminodesacetoxycephalosporanoic acid.

Example 2

Rearrangement of penicillin V acid sulfoxide (1) to 7- (phenoxyacetamido) -desacetoxycephalosporanoic acid (2) under different conditions.

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Example 3

Conversion of (1) to dibenzylamine salt of (2)

A mixture of penicillin V sulfoxide (18.3 g, 0.05 mol) and (2.84 g, 0.02 mol) was stirred with dioxane (300 ml) and heated at reflux for 8 hours. The reaction mixture was then filtered and the solid washed out with dioxane. The combined filtrates were concentrated and the residue was collected in ethyl acetate (100 ml) and washed with water (2 x 50 ml). After drying over MgSO 4, the solvent was removed and 15.3 g of a yellowish-brown foam was obtained. A sample mixed with o-toluic acid was analyzed by NMR spectroscope! and indicated a yield of 22% of 2. The crude 2 was then converted to the pure dibenzylamine salt of 2 as follows. The foam (14.8 g) was dissolved in methanol (35 ml) and dibenzylamine (7.9 g, 0.04 mol) was added. After cooling overnight at -10 ° C, the resulting precipitate was filtered off, washed with a little cold methanol and dried to yield 5.8 g (22%) of a light colored solid, mp 135-136 ° C (dec). . The solid was identified as the dibenzylamine salt of 7- (phenoxyacetamido) desacetoxycephalosporanoic acid.

Example 4

Rearranging (1) to (2)

A mixture of penicillin V sulfoxide (18.3 g, 0.050 mol), PDPA (1.38 g, 0.005 mol) and bis (2-methoxyethyl) ether (diglyme; 300 ml) was stirred at 110-115 ° for 2 hours. The reaction mixture was worked up as in Experiment 3 to give 4.75 g (17%) of the dibenzylamine salt, mp 130-134 ° (dec), from which 1.75 g (10%) of 7- (phenoxyacetamido) -desacetoxycephalosporanoic acid, m.p. 170 ° (dec.), Isolated.

Example 5

Rearranging (1) to (2)

A mixture of penicillin V sulfoxide (18.3 g, 0.050 mol) 85% orthophosphoric acid (0.49 g, 0.0043 mol) and dioxane (300 ml) was heated at reflux for 16 hours. The reaction mixture was worked up as in Experiment 3 to obtain 4.0 g (15%) of the dibenzylamine salt, m.p. 130-132 ° (dec), from which 1.13 g (6.5%) of 7- (phenoxyacetamido) -desacetoxycephalosporanoic acid, m.p. 172-173 ° (dec.) Was isolated.

25 1U095

Example 6

Rearranging (1) to (2)

A mixture of penicillin V sulfoxide (18.3 g, 0.050 mol), quinoline (0.65 g, 0.0050 mol), 85% orthophosphoric acid (0.98 g, 0.0085 mol) and dioxane (300 ml ) was heated at reflux for 8 hours. The reaction mixture was worked up as in Experiment 3 to give 6.3 g (23%) of the dibenzylamine salt, mp 135-136 ° (dec), from which 3.5 g (20%) of 7- (phenoxyacetamido) desacetoxycephalosporanoic acid, mp 174-175 ° (dec.) Was isolated.

Example 7

Reduction of penicillin V acid sulfoxide to 7- (phenoxyacetamido) desacetoxycephalosporanoic acid P205 (123.0 g, 0.866 mol) was added to 5.0 liters of dry dioxane and then 47.0 ml (2.60 mol) of deionized water and 27 4 ml of pyridine. The slurry is stirred and refluxed. To the reflux slurry is added a dioxane solution of 1000 g (2.60 mole) of penicillin V sulfoxide monohydrate in 10 liters of dioxane, continuously at constant speed, to take 8 hours. When the reaction is complete (by T.L.C.), the slurry is cooled to 30-50 ° and then filtered and washed with dioxane to complete the transfer of materials. The filtrate of the washings is combined and the volume reduced in vacuo to remove most of the dioxane. Add 10.0 liters of methylene chloride (MeCl2) to the oil and stir the solution. 15 liters of deionized water are added to the MeCl2 solution and the phases are thoroughly stirred. The pH should be set to 1.8 with HCl. The phases are separated and the aqueous phase is discarded. The MeCl2-rich phase is stirred and 15.0 liters of deionized water are added. 460 g (5.5 moles) of NaHCO 3 is added to the stirred mixture. The pH is adjusted to 8.3-8.4 with 10% NaOH and the phases are stirred for 15-20 minutes (20 ° C) and the MeCl2 phase discarded.

The aqueous phase is stirred and 10.0 liters of new MeCl2 is added and the pH is adjusted to 1.8 with 6N HCl. The phases are stirred for 15 minutes and the MeCl2-rich layer is separated and stored. Another extraction on the aqueous phase is carried out with 5 liters of MeCl2 · The combined dewatered MeCl2 phases are dried. The MeCl2 solution is frozen for MeCl2 by vacuum distillation into a glass. The yield is 400 g of a compound analyzed by IR, NMR and iodometric examination as pure 7- (phenoxyacetamido) desacetoxycephalosporanoic acid.

144095 26

Example 8

Penicillin V acid sulfoxide rearrangement to 7- (phenoxyacetamido) -desacetoxycephalosporanoic acid / dibenzylamine salt

Penicillin V sulfoxide (18.3 g, 0.05 mole), pyridine (0.40 g, 0.005 mole) and orthophosphoric acid (3 g of an 85% solution, 0.026 mole) in anhydrous dioxane (300 ml) were stirred and heated under reflux for 6 hours on oil bath at approx. 135 °. Next, the solvent was removed, ethyl acetate (100 ml) was added to the residue and the solution was washed with water (2 x 50 ml). The organic layer was dried over MgSO 4 and the solvent removed to give 17 g of a yellowish-brown foam. The foam was dissolved in methanol (35 ml) and dibenzylamine (7.9 g, 0.040 mol) was added and the resulting mixture was cooled for 1 hour at -10 to -15 °. The resulting precipitate was filtered off, washed with cold methanol and dried to give 7.6 g (28.2%) of a light tan solid, mp 133-135 ° dec.

Example 9

Preparation of 7-Aminodeacetoxycephalosporanoic acid (7-amino-3-methyl-ceph-3-em-4-carboxylic acid) (3) from 7- (phenoxyacetamido) -desacetoxy-cephalosporanoic acid (7-phenoxyacetamido) -3-methylceph-3 em-4-carboxylic acid) (2)

A solution of trimethyl chlorosilane (0.65 g, 6.0 mmol) in 5 mL of CH 2 Cl 2 was added dropwise over 3.5 minutes to a stirred mixture of 2 (1.74 g, 5.0 mmol), trimethylamine ( 50 g, 5.0 mmol) and N, N-dimethylaniline (1.2 g, 10.0 mmol) in 30 ml of C ^C C at room temperature with stirring. The mixture was stirred a further 30 minutes and then cooled to -55 ° C. Phosphorus pentachloride (1.15 g, 5.5 mmol) was added and the temperature maintained at -40 ° with stirring for 2 hours, then cooled again to 60 ° C and 15 ml of methyl alcohol and 0.3 g of dimethyl-aniline were quickly added. in 3 minutes (the temperature rose to -50 ° C). The resulting mixture was stirred at -40 ° ± 4 ° C for 2 hours and poured onto an ice-cold mixture of water (25 ml) and methanol (12 ml) with stirring. The pH of the stirred mixture was adjusted to 3.5 (from start 1) with ammonium carbonate. The mixture was cooled in the refrigerator for 18 hours and the solid precipitate collected by filtration. The solid was washed with - 15 ml portions of ice water (2 times), methanol (2 times) and ether.

The solid was dried in vacuo over P 2 5 exchange of 0.83 g (78%) of a white crystalline substance determined to be identical to authentic 3.

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Example 10

Acylation of disllylated 7-ADCA to produce cephalexin

Trimethylchlorosilane (2.28 g, 0.021 mol) in methylene chloride (5 ml) is added to a stirred cold mixture of 7-ADCA (2.14 g, 0.01 mol), triethylamine (2.02 g, 0 2 mol) and N, N-dimethylaniline (1.34 g, 0.011 mol) in methylene chloride (25 ml) such that the reaction temperature remains below 10 ° C. After 2 hours at 5-10 ° C, the mixture is cooled to 0 ° C and phenylglycyl chloride, HCl (2.16 g, 0.0105 mol) is added portionwise. Stirring at 0 - 5 ° C is continued for 2 hours, methanol (1.6 g, 0.05 mol) is added dropwise and after 15 minutes the mixture is concentrated to dryness. The resulting white substance (9.3 g) was stirred with cold water (20 ml). The pH of the solution is adjusted to 4.5 with concentrated ammonia and the mixture is left at 0 ° for 3 hours and filtered. The solid is washed with ice water, acetone and ether and dried in vacuo over P 2 ° 5 + weight 2.3 g (66%), m.p. 165-167 ° dec., [Α] D + 128.8 ° (c, 1.56 in AcOH); [α] D 25 + 118.2 ° (c, 1.54 in 1N-HCl) IR and NMR confirm that the compound is essentially pure cephalexin.

Example 11

Preparation of di (trimethylsilyl) -7-aminodeacetoxycephalosporanoic acid

Trimethyl chlorosilane (2.5 g, 0.022 mol) in dry methylene chloride (5 ml) was slowly added to a stirred, cold (id bath) mixture of 7-ADCA (2.14 g, 0.01 mol) and triethylamine (2.22 g (0.022 mol) in dry methylene chloride (25 ml) at such a rate that the temperature of the reaction mixture was kept below 10 ° C. When the addition is over, stirring is maintained at 5 - 10 ° C for a further 2 hours and the reaction mixture is concentrated under vacuum. n-Hexane (30 ml) was added to the residue and the mixture was stirred and filtered. The filtrate was concentrated under reduced pressure to give 3.1 g (88%) of an oil which solidified by scraping. The solid was dissolved in the least amount of hexane and cooled to form silky white crystals. Part was centrifuged and the solid was found to have a melting point of 64-80 ° C. The IR spectrum and the NMR spectrum (benzene) of the compound are consistent with the putative structure. The compound is fairly soluble in benzene and n-hexane.

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Example 12

Preparation of 7- (D-α-aminophenylacetamido) -3-methylceph-3-em-4-carboxylic acid

A. "In Situ" Preparation of Monosilyl Derivative of 7-ADCA

1000 g (4.67 mol) of 7-ADCA are added to 20 liters of dry methylene chloride (MeCl2) K.F. H2 O (less than or equal to 0.01%). The slurry is stirred.

425 g (2.67 mol) of hexamethyldisilazane are added and nitrogen gas is bubbled through the slurry by immersing capillary tubes. The slurry is heated to reflux. Complete solution is obtained after approx. 4 hours reaction.

B. Preparation of Cephalexin from Monosilylated 7-ADCA

The above solution is cooled to 10 ° C and 782 ml of DMA, HCl (30% in MeCl2) is added to the reaction mixture followed by 627 ml (4.95 mol) of DMA. The solution is cooled to 0 ° C and 1020 g (4.95 mol) of phenylglycyl chloride hydrochloride is added. The slurry is stirred at 0 ° C for 1 hour. The temperature is then brought to 24 - 25 ° C and kept for approx. 2 hours. The reaction mixture is cooled to 0 ° C and 282 ml (7.0 moles) of dry methanol are added. The reaction mixture is heated to 20 ° C and an oily phase begins to separate. 30.0 liters of cold water are added to the mixture and the phases are stirred until the oil dissolves in the aqueous phase. Adjust the pH to 2.3 - 2.6 with TEA. The methylene chloride phase is extracted and the aqueous phase is extracted three times with 30 liters of MeCl2 each time. The methylene chloride is placed under vacuum and concentrated to a volume of 10 liters. The solution is stirred and 10 liters of acetonitrile are added and the solution is heated to 40 ° C. The pH is adjusted with TEA to 4.5. The slurry is filtered and the cake is then dried at 50 ° C. A weight of 1300-1400 g (80-86% yield) of cephalexin is obtained.

Example 13

Preparation of Mono- and Disilylated 7-ADCA Derivatives 3 4.2 g of phenoxyacetamidodesacetoxycephalosporin was stirred in 90 cm 3 of methylene chloride and 2.1 cm of triethylamine was added followed by 7.0 cm 3 of DMA. The solution was cooled to 10 ° C and 3 Trimethylchlorosilane was added at a temperature below 25 ° C. The reaction mixture was cooled to -40 ° C and 4.9 g of PCl 2 were added. 125 cc of methanol was added and the temperature was allowed to rise to 38 ° C over 4 hours.

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The solvents were removed by vacuum distillation at 20 ° C and the residue redissolved in 30 cm of methylene chloride. Next, 3.33 g of triethylamine were added at 0-10 ° C, followed by 3.6 g of trimethylchlorosilane at 5-10 ° C. Stirring was continued for 2 hours at 10-15 ° C. Next, 30 cc of n-hexane was added and the mixture was filtered. The filtrate was concentrated to a residue under reduced pressure and, after scraping and triturating with hexane, yielded 3.1 g of a solid; mp 64-80 ° C. NMR and IR were consistent with the putative structure of di (trimethylsilyl) -7-ADCA. A small portion of the solid was also distilled at 140 ° / 0.1 mm to give a viscous rubber which solidified by scraping and whose IR and NMR were consistent with the putative structure. The compound was very soluble in benzene, CH 2 Cl 2 and hexane. Then, if the monosilylated derivative is desired, then 1.45 g of dimethyldichlorosilane is added instead of 3.6 g of TMS, and the product is similarly worked up except that when the filtrate is concentrated to a residue, the residue is used directly in the next acylation step and is not isolated as a solid or a distillable rubber. The mono- or disilylated derivatives are valuable compounds which can be used directly in subsequent acylation reactions.

Claims (2)

30 144095 A process for the preparation of cephalexin or non-toxic, pharmaceutically acceptable salts thereof, comprising the steps of: A) Oxidation of a penicillin or salt thereof prepared by fermentation to produce a penicillin sulfoxide of the formula O n T CH Wherein R represents the side chain of a penicillin produced by fermentation; B) converting the penicillin sulfoxide to a cephalosporanoic acid compound of the formula 0 5 R - C - NH Wherein R is as defined above, C) reacting the cephalosporanoic acid compound with a silyl compound of the formula E \ / r1 ^ / Si R ™ or R2 - li-X R1 'si * 4 2 3 4 wherein R, R and R are hydrogen, halogen, (lower) alkyl, halogen (lower) alkyl, phenyl, benzyl, tolyl or dimethylaminophenyl, with at least one of the groups R, R and R being different from halogen or hydrogen, R 1 represents (lower) alkyl, m represents an integer of 1 or 2, and X represents halo gene or R 5 -N 31 wherein R represents hydrogen or (lower) alkyl, and R represents hydrogen, (lower) alkyl or R 3 R 2 -Si · - wherein R, R and R have the above significance, under anhydrous conditions, in an inert solvent, and in the presence of an acid-deactivating tertiary amine, formation of the corresponding cilyl ester of the cephalosporanoic acid compound, D) reacting the cilyl ester with an excess of a halogen energy agent under anhydrous conditions, solvent, and in the presence of an acid deactivating tertiary amine, to form the corresponding imino halide, E) reacting the imino halide with an alcohol selected from aliphatic alcohols of 1-12 carbon atoms, and phenylalkyl alcohols of 1-7 alkyl carbon atoms, to produce the corresponding imino ether, F) breaking the imino ether bond imino bond by hydrolysis or alcoholysis to produce 7-aminoacetoxycephalosporanoic acid G) mono- or disilyld preparation the derivative of 7-aminodeacetoxy-cephalosporanoic acid, H) N-acylation of the mono- or disilyl derivative with a phenylglycine derivative, and I) cleavage by hydrolysis or alcoholysis of all silyl groups to form cephalexin or by subsequent conversion to produce a non-toxic, pharmaceutically acceptable salt thereof; characterized in that (1) the conversion step (B) consists of a rearrangement by heating the free acid form of the penicillin sulfoxide in a weak basic solvent in the presence of a catalyst comprising a strong acid either alone or in combination with a nitrogen base having a pKb value of not less than 4, (2) the monosilyl derivative of 7-aminode-acetoxycephalosporanoic acid is prepared either by reacting the 7-aminodeace toxycephalosporanoic acid product of step (F) with ca. a molar amount of a silyl compound, as defined in step (C), or by performing the hydrolysis or alcoholysis reaction of step (F) in the presence of at least ca. a molar excess of a silyl compound as defined in step (C), or by subjecting the imino ether imino bond in step (F) to alcoholysis and thermal decomposition in the presence of at least ca. a molar excess of a silyl compound as defined in step (C), (3) disilyl