DK142912B - Process for the preparation of 7-aminocephalosporanoic acid or derivatives thereof. - Google Patents

Description

(11) PUBLICATION 142912 DENMARK (BDlnt. Cl.3 C 07 D 501/18 UMΠίνίΜΠΙΝ. C 07 D 501/04 '(21) Application No 5720/68 (22) Filed on 1st au® * 1 ^ 68 ( 24) Running day, 1 Aug 1968 (44) The application submitted and 1 ng) the petition published on 25 · leu * -7

DIRECTORATE OF

PATENT AND TRADEMARKET <3 °> Priority requested from it

Aug 7 · 1967, 6710855, NL

(71) ROYAL NETHERLANDS GIST AND SPIRITUS FACTORY N.V., Delft, NL.

(72) Inventor: Helmut Wilhelm Otto Weissenburger, 52, Cromhoutlaan, Rijs® district (Z.H.), NL.

(74) Proxy during the proceedings:

The engineering company Budde, Schou & Co.

(54) Process for the preparation of 7-aminocephalosporanoic acid or its derivatives.

The present invention relates to a particular process for the preparation of 7-aminocephalosporanoic acid or derivatives thereof of the formula

S

H, N -.- S '' 'V,

/ CH 2 -N, N ^ ~ "R

0 COOH

wherein R represents hydrogen, acyloxy or -SR 2, wherein R 2 represents an optionally substituted aliphatic, aromatic or heterocyclic group, wherein a corresponding 7N-acylamidocephalo-sporanoic acid whose functional group ex- in the acyl moiety is blocked is esterified. at its free carboxylic acid group, is treated with an agent which forms an imino bond, then an ether bond is introduced at the iminocarbon atom, then the imino double bond is hydrolyzed or alcoholized and the ester group is cleaved to form a free carboxylic acid group.

7-Aminocephalosporanoic acid is prepared according to British Patent No. 953695 by 7N deacylation of cephalosporin C, having the formula I wherein R is acetoxy and the 7-amino group is acylated with a 4-amino-adipoyl group.

7-Aminodesacetoxycephalosporanoic acid is obtained according to British Patent No. 957569, by catalytic hydrogenation of cephalosporin C followed by acid hydrolysis. In the resulting product, R is hydrogen of formula I.

7-aminocephalosporanoic acid and its derivatives wherein R in the 3-position of formula I has the above meanings are. known compounds for use as starting material in the preparation of a number of known cephalosporins (the so-called semi-synthetic cephalosporins) by 7-acylation, which cephalosporins usually also have antibiotic activity of the same kind as cephalosporin C.

This makes it possible to replace the α-aminoadipoyl side chain in cephalosporin C with various alternative side chains at the 7-position. This technique is e.g. disclosed in the specifications of British Patent Nos. 953695, 957543, 957569, 976225, 988527, and 1054806, which aim to provide other cephalosporins in addition to those obtained by pure fermentation methods.

It is known to perform 7N deacylation of cephalosporins by converting the 7-amido group of a cephalosporin into an imino halide group, which in turn is hydrolyzed to produce the 7-amino compound, according to French Patent No. 1394820. The 4-carboxyl group of the cephalosporin must be carefully protected during deacylation, and it is known to block the group by esterification prior to the formation of the imino halide and to remove the blocking ester group after deacylation, e.g. by hydrolysis or hydrogenolysis, e.g. as described in the specifications of British Patent Nos. 1041985 and 1119806 (similar to the disclosures of publicly available Dutch applications Nos. 6401421 and 6513095}.

According to British Patent No. 104,1985, the free amino and carboxylic acid groups of cephalosporin C or a derivative thereof of the formula 3 are protected.

CH- (CH2) 3-CO-HN --........ s' X

h2n

1-

0 COOH

wherein R represents an acyloxy group (optionally derived from the 4-carboxyl group to form a lactone ring) prior to deacylation. This protection of the free amino and carboxylic acid groups serves to prevent undesirable side reactions with the reagents. The amino group is particularly protected with phenacetyl, carbobenzoxy, 2,4-dinitrophenyl, N, N - phthaloyl or N-benzoyl, and the carboxylic acid group is particularly protected with benzyl, methyl, p-methoxybenzyl, benzhydryl, tetrahydropyranyl or p-nitrophenyl. First of all, these reactive groups in the 7-acyl chain are protected by conversion of cephalosporin C to the dibenzhydryl ester of Ν, Ν-phthaloylcephalosporin C.

The compound with the amino and acid groups thus protected is then treated with an agent to produce an imino halide group in the 7-amido position of the sub-formula -C = N- lial where hal means halogen atom. Typical iminohalide forming agents are such acid halides as phosphorus pentachloride (PClg) or phosphorus oxychloride (POCll) or phosgene (COC ^).

The imino halide is then converted to an imino ether of the partial formula -C = N- 1 -alkyl by treatment with an alcohol, especially methanol or ethanol.

The formation of the imino halide and / or imino ether is preferably carried out in the presence of a tertiary amine such as triethylamine, pyridine or dimethylaniline.

In the next step, the imino ether group is hydrolyzed in aqueous acidic or basic solution. Examples of suitable acids are sulfuric acid, phosphoric acid or hydrochloric acid, or organic acids such as trifluoroacetic acid or p-toluenesulfonic acid. This gives the corresponding 4-ester of 7-aminocephalosporanoic acid.

To obtain the corresponding compound containing a free 4-carboxyl group, one must then remove the blocking group by hydrogenolysis or acid hydrolysis, e.g. hydrogenolysis in ice cream 4142912 ke with Pd on coal or with aqueous trifluoroacetic acid in anisole. The yield thus becomes 24-59%.

British Patent Specification No. 1119806 discloses a similar imino halide / imino ether deacylation process, but provides as starting material specifically Ν, Ν-phthaloyl-cephalosporin C-dibenzhydryl ester. The dibenzhydryl ester of 7-aminocephalosporanoic acid is hydrolyzed with trifluoroacetic acid which is then converted to a trifluoroacetate by reaction with a tertiary amine in a polar solvent and the 7-aminocephalosporanoic acid is obtained by crystallization from the solvent. However, it is still necessary to cleave the ester group at the 4-carb-oxyl position in a later separate step.

The process of the present invention, relative to the above prior art, represents an improvement in 7N deacylation of cephalosporins, in which better yields of the desired products are obtained than the methods described in British Patent Nos. 104,1985 and 11,19806, namely an improvement of yield to well over 90% of theory. At the same time, the hitherto necessary implementation of a separate step to remove the protecting group for 4-carboxyl is avoided.

The process of the invention is characterized in that said esterification of the free carboxylic acid group in the starting material is carried out to form a di- or trialkylsilyl ester group, and that the formation of the imino bond and the ether bond introduction are carried out at a temperature below -15 ° C.

In particular, the process of the invention introduces a dialkyl or trialkylsilyl ester group as protection for the free carboxylic acid group in the 4-position of the cephalosporanoic acid (counted from S), and this proceeds without significant side reactions when the temperature is simply kept below -15 ° C. Also, the formation of the imino bond per se known as precursor to the deacylation in the 7-N-amido group proceeds without particular side reactions when the temperature is simply kept below -15 ° C. However, for the sake of obtaining optimal yields, it is preferred according to the invention that the formation of the imino ether be carried out at a temperature below -30 ° C.

For the formation of the imino halide, the usual acid halides are used, cf. the prior art, and in particular phosphorus pentachloride or phosphorus oxychloride. However, it was not without doubt to foresee that this known reaction was also smoothly feasible with the 4-carboxy-protected groups of 7-acylamidocephalosporanoic acid-protected 4-carboxy groups. It is reported in i.a. Tetrahedron Letters No. 7, pages 885-888 (1969) by L. Birkhofer and K. Krebs, U2912 that PC15 can convert silyl esters to acid chlorides. This side reaction would not be particularly favorable here as it would uncontrollably interfere with the above imidohalide formation and subsequent imino ether formation and final deacylation.

It has now been found that no such uncontrollable side reaction occurs; but, on the contrary, one obtains a far more favorable and simpler course of reaction, the hydrolysis or alcoholysis of the imino ether bond at the 7-N-imino ether group being cleaved while simultaneously separating the silyl ester group from the 4-carboxy group, thereby saving the above-mentioned separate deesterification in a subsequent step. As a whole, the process sequence is simplified and the yield is drastically increased (from 25-60% in the prior art to about 90% in the process according to the invention). This represents a clear technical advance and a surprising improvement.

The compounds of formula I according to the invention can be used as intermediates in the above-mentioned preparation of semi-synthetic cephalosporins of the formula

RCHN -N

III

j-ά 4, J-CH2-R

° COOH

wherein R is as defined under formula I and Rc is a conventional 7N-acyl group within the cephalosporan chemistry by conventional acylation procedures, by introducing a desired acyl group of the 7-amino group into compounds of formula I.

It could appear backward first to deacylate and then to acylate the same site (at the 7N amino group of cephalosporanoic acid and its derivatives); but partly it is difficult to make all the known cephalosporins by cheap fermentation methods, and partly some semi-synthetic cephalosporins are more readily available, cheaper and / or purer (easier to isolate) than others perhaps more active or for other technical reasons more desirable cephalosporins. Therefore, such re-acylation is often desired and, with the now good yields obtained and the smooth course of the process according to the invention, can be made economically advantageous as a whole.

In this way, a wide variety of valuable pharmaceutically active cephalosporins of known structure or, optionally, precursors thereof, can be prepared using the purely prepared compounds of formula I as intermediate in the process of the invention.

6 142912

Suitable starting materials for use in the process of the invention are cephalosporin C and its 3-substituted derivatives and other 7-N-acylamidocephalosporanoic acids or 3-substituted derivatives thereof such as cephalothin having the formula in [2 -ch 2 -co-hn - / 'N .

y, -N 4 Å -CH 2 -OCOCH

/ 2 3 COOH

and N-phenylacetyl-3-desacetoxy-7-aminocephalosporanoic acid. It is also possible to assume the salts of a 7N-acylamido-cephalosporanoic acid or 3-substituted derivatives thereof, e.g. a sodium salt. Such cepha losporins are e.g. also cephaloridine (known from, for example, French Patent No. 1329119 and Belgian Patent No. 641338) and the semi-synthetic cephalosporins disclosed in Irish Application No. 528/65, British Patent No. 1104937, Canadian Patent No. 793322, Swiss Patent No. 469740, U.S. Pat.

3502665 and 3252973 and Belgian Patent No. 664645, Dutch Application No. 65/06818 and French Patent No. 1465394. These known cephalosporins can be treated by the method according to the invention, i.e. when the 4-carboxylic acid group in the 7-aminocephalo-sporanoic acid moiety is protected by conversion to a di- or trialkyl ester group, during deacylation at the 7N-acylamido group, namely at the known steps of forming an imino halide group which is then converted to an imino ether group (but at low temperature) followed by cleavage of the imino ether group (but with simultaneous cleavage of the cilyl ester group). In these starting materials, the acyl moiety in the cephalosporins may be modified by chemical or fermentation methods, e.g. by substituting the 4-amino group in the amino-adipoyl moiety (of cephalosporin C) to e.g. a 4-carboxylbutanamido group, or with a phenylacetyl or phenoxy group derived from the acyl group of penicillin G or penicillin V of desacetoxy-cephalosporins obtained by ring extension of penicillin sulfoxides.

Important for the choice of starting material is that it must be capable of being converted to an imino halide without the group R reacting. Such inert R substituents are also commonly known in cephalosporins which, in the 3-position, e.g. may be modified to a heterocyclic thiomethyl group or a carbamoyloxymethyl group wherein acyl oxy under the definition of R e.g. means acetoxy or carbamoyloxy, and 7, e.g. comprises the 1,1-dimethyl-2-amino-2-carboxyethylthio group and heterocyclic thio groups such as thiadiazolylthio, optionally substituted by alkyl, e.g. 5-methyl-1,3,4-thiadiazyl-2-ylthio, or azido.

The 4-silyl ester can be formed using various known silylating agents such as bifunctional silylating agents such as dialkyl dihalo silanes and trifunctional silylating agents such as di-alkyl dihalo silanes. Dialkyl dihalo silanes are particularly suitable, for example: hexaalkylcyclotrisilazanes and octaalkylcyclotetrasilanes, and other suitable silylating agents are trialkylsilylacetamides or bis-trialkylsilylacetamides.

Due to reliability, low cost and good reactivity, the invention is preferred to carry out the esterification by treatment with trimethylchlorosilane or with dimethyldichlorosilane.

The imino halide can be prepared from the silyl ester by methods known per se in reaction with an acid halide such as phosphorus pentachloride or phosphorus oxychloride, at a temperature below -15 ° C and especially below -30 ° C. Suitable solvents for use in this process step are e.g. methylene chloride, chloroform (non-alcoholic), dialkyl ether, tetrachloroethane and nitromethane.

During conversion of the imino halide to the imino ether or during the decomposition of the imino ether, the 4-silyl group is decomposed simultaneously, forming the free carboxylic acid. The imino ether can also be cleaved as it forms during the treatment of the imino halide with an alcohol. The alcoholysis of the imino halide can be carried out with ethanol or methanol, but is preferably carried out with an alkanol having 2 or more carbon atoms and preferably at a temperature below -30 ° C.

To bind the acid released during the reactions, a tertiary amine, e.g. a trialkylamine, dimethylaniline, quinoline, lutidine or pyridine for the reaction mixture. The amount of tertiary amine used may be such that only a portion of the acid formed is bound to the acid binding agent. Preferably, the amount of tertiary amine used is such that the pH of the reaction mixture would not be greater than 1 if only water and no additional neutralizing agent were added thereto. The amount of tertiary amine, calculated on e.g.

Thus, PCl 2 and a small excess of acid-forming halogen silane derivative are less than four equivalents and advantageously less than three equivalents.

8 142912

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

Example 1 2.51 g of sodium salt of cephalotine is converted into 35 ral of methylene chloride, to which has been added 1.60 ml of dimethylaniline, with 0.6 ml of dimethyldichlorosilane to the 4-dimethylchlorosilyl ester of cephalotine.

After cooling the solution to ca. -55 ° C is added 1.35 g of PCI ^, as a result of which the temperature rises to -40 ° C. For 2 1/4 hours, the temperature is kept at -40 ° C, after which the mixture is cooled to -70 ° C.

Then 0.30 ml of dimethylaniline is added to the solution and after approx. For 1 1/2 minutes add 15 ml of butanol. The temperature is then kept at -40 ° C.

After approx. For 2 1/2 hours, the reaction mixture is poured into a mixture of 33 ml of water and 16.5 ml of methanol, and the pH of the mixture is adjusted to 3.5 by means of ammonium bicarbonate. After approx. 20 hours of storage, the precipitate is filtered at 5 C. Purification of the product is carried out by dissolving in water at a pH of 7.3 and treatment with activated carbon.

After filtration, the aqueous solution is added 3/2 times its volume of methanol, and the pH is adjusted to 3.5 by means of 4 N hydrochloric acid. The crystals formed are filtered off at ca. 5 ° C after 2 hours of storage.

The yield is 1.51 g of 7-aminocephalosporanoic acid (92.5 $ of theory).

Example 2 3.12 g of anhydrous cephalosporin C are suspended in 42 ml of methylene chloride and stirred with stirring 1.1 ml of triethylamine, 3.15 ml of trimethylchlorosilane and 6.7 ml of dimethylaniline to give the corresponding 4-trimethylsilyl ester.

After a reaction time of 1 hour, the mixture is cooled to ca. -60 ° C, then 3.3 S phosphorus pentachloride is added with thorough stirring. The temperature then rises to approx. -40 ° C.

After 2 1/2 hours of reaction at this temperature, the mixture is cooled to ca. -70 ° C and 0.4 ml of dimethylaniline and 30 ml of n-butanol are rapidly added with stirring as a result of which the temperature rises again. The temperature is kept at -40 ° C for 2 1/2 hours.

9 142912

Then, with thorough stirring, the reaction mixture is poured into a mixture of 33 ml of water and 16.5 ml of methanol, and the pH of the mixture is immediately adjusted to 3.5 by means of ammonium bicarbonate.

After approx. 20 hours of storage at 5 ° C, the precipitate is filtered off and washed with methylene chloride and acetone. Purification of the crystals is effected by dissolving in water at a pH of 7.3 and treatment with activated carbon.

After filtration, the aqueous solution is added 3/2 times its volume of methanol, and the pH is adjusted to 3.5 by means of 4 N hydrochloric acid. After 2 hours of storage, the crystals are filtered off at approx. 5 ° C.

The yield is 1.86 g of 7-aminocephalosporanoic acid (about $ 91).

Example 5 2.80 g of N-phthaloylcephalosporin C are suspended in 40 ml of methylene chloride and 3.2 ml of a 20 wt.% Solution of triethylamine in methylene chloride and 2.85 ml of dimethylaniline are added. The practically clear solution is then converted with 0.6 ml of dimethyldichlorosilane to produce N-phataloylcephalosporin C, whose carboxylic acid groups are both silylated.

After a reaction time of 1 hour, the mixture is cooled to -50 ° C and 1.4 g of PC1 is added. With continued thorough stirring, the temperature is maintained for 2 1/4 hours at -40 ° C and then the mixture is cooled to -65 ° C. Now a mixture of 0.2 ml of dimethylaniline and 25 ml of n-butanol is rapidly added to the reaction mixture.

The temperature of the mixture is then maintained for 2 hours at -40 ° C and then poured into a mixture of 30 ml of water and 15 ml of methanol. The pH of the new mixture is then adjusted to 3.5 by means of ammonium bicarbonate. After approx. 20 hours of storage at 5 ° C, the precipitate is filtered off, washed with acetone / water (1: 1), methylene chloride and acetone and then dried.

The yield is 1.18 g of crystals of 7-aminocephalosporanoic acid (84 *).

Example 4 2.23 g of N-ethylpiperidine salt of N-phenacetyl-3-desacetoxy-7- 142912-aminocephalosporanoic acid are suspended in 18 ml of methylene chloride and converted after the addition of 1.5 ml of dimethylaniline with 1 ml of trimethyl-ehlorosilane. silylester.

After 1 hour, the mixture is cooled to -50 ° C and 1.1 g of PCI is added. For 2 1/4 hours, the temperature of the mixture is kept at -40 ° C and then lowered to -65 ° C. To the cooled mixture is added a solution of 0.5 ml of dimethylaniline and 12 ml of butanol, and then the temperature is maintained at -40 ° C. 2 1/4 hours.

The reaction mixture is then poured into a mixture of 55 ml of water and 17 ml of methanol and the pH is immediately adjusted to 5.5 by means of ammonium bicarbonate. After approx. 20 hours of storage at 5 ° C, the precipitate is filtered off, washed with methanol / water (1: 1), methylene chloride and acetone and dried.

The yield is 0.956 g of 5-desacetoxy-7-amino-cephalosporanoic acid crystals ($ 92).

Example 5 3.5 g (10 mmol) of N-phenoxyacetyl-3-desacetoxy-7-aminocephalo-sporanoic acid are suspended in 20 ml of methylene chloride. After the addition of 4.4 ml (35 mmol) of dimethylaniline at 25 ° C and 2.1 ml (17 mmol) of trimethyl-ehlorsilane, the reaction mixture is stirred for 15 minutes at 32 ° C. The mixture is then cooled to -45 ° C, then 2.2 g (11 mmol) of PC15 is added. The mixture is then stirred for a further 75 minutes at -30 ° C. The temperature is then lowered to -65 ° C, after which the mixture is stirred for a further 30 minutes.

To the cooled mixture is added 11 ml of isobutanol (118 mmol), raising the temperature to -50 ° C. The mixture is stirred for an additional 2 hours at this temperature.

After pouring the mixture into still 15 ml of water while stirring, the resulting pH of the mixture is adjusted to 7.8 with an 8% NH 2 OH solution. The resulting layers are separated and the aqueous layer is washed with 20 ml of methylene chloride. The pH of the aqueous layer is then rapidly adjusted with 1N hydrochloric acid to 3.6. After cooling to 0 ° C, the 7-aminodesacetoxycephalosporanoic acid is filtered off on a nutshell filter, washed with water and acetone and dried in vacuo. The yield is 1.97 g (92%).