FI58132B - FRAMING PROOF FOR 3-METHYL- 3-CEFEM-4-CARBOXYLSYRAFOERENINGAR - Google Patents

Description

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4¾¾¾ ^ ^ Patent fi: C - (! Dclat ^ (51) Kv.ik.3 / tot.a.3 c 07 D 501/0 * SUOMI — FINLAND 01) ** «**»> »" »» - pnwwwekunt T83277 (22) Hakemhpihri — AmeknlRpdag 27.10.78 '' (23) Alkepliv · —GIMgh «Tad | 25.02.72 (41) Interpreters

Patent and Registration Office ________ .__.

Patent · och regietaretyreleen ^ Aurtku utkjd och utUdcriftan pubUoirad 29 · 08.80 "(32) (33) (31) satisfied mtolkmu-Begird priorttet 25.02.71 USA (US) 1189 ^ 1 ^ (71) Eli Lilly and Company, 307 East McCarty Street, Indianapolis, Indiana U6206, USA (72) Robert Raymond Chauvette, Indianapolis, Indiana, USA (7 ^) Oy Kolster Ab (5M Method for the preparation of 3 “methyl - ^ - cephem - ^ - carboxylic acid compounds - Förfarande The present invention relates to a process for the preparation of compounds of formula II. The present invention relates to a process for the preparation of compounds of formula II. The present invention relates to a process for the preparation of 3-methyl- [3-cephem-U-carboxylic acid derivatives (62) separated by application 500/72 (publication 57 ^ 19) -Avdelad fr & n ansokan 500/72 for the preparation of 3-methyl-cephem-1 + -carboxylic acid compounds according to

B

R - N- ^ ^

^ - CH0 II

Wherein R is hydrogen, C 1 -C 4 alkyl, a carboxylic acid protecting group, preferably benzyl, nitrobenzyl or C 1 -C 4 alkoxybenzyl or a pharmaceutically acceptable cation, and R is hydrogen or oC-thienylacetyl.

2 531 32

The process according to the invention is characterized in that the 3-methylene-cepham compound of the formula

B

R - N - | - ^ S'X · # - IL CH2 o coor1 wherein R and R1 are as defined above is reacted with a tertiary amine having a pK'a value of at least 9> 5 in the presence of an aprotic solvent having a dielectric constant is great. ~

According to the cephalos nomenclature system for cephalosporin antibiotics, Morin et al.

J. Am. Chem. Soc. 8U, 3,00 (1962) 7-ADCA is termed 3-methyl-7-amino-cephem-A-carboxylic acid, where & denotes the endocyclic position of the carbon-carbon double bond. 7-Aminodesacetoxycephalosporanic acid is a useful intermediate in the preparation of desacetoxycephalosporanic acid antibiotics. For example, acylation of 7-ADCA in a mixed anhydride reaction with tert-butyloxycarbonyl (t-BOC) -protected D-phenylglycine using methyl chloroformate followed by removal of the t-BOC group gives 7 - (oC-D-aminophenylacetamido) deacetoxaco-deacetoxy-deacetoxy commonly referred to as cefalexin. Other useful cephalosporin intermediates in which the carbon-carbon double bond is located in the 2-position (Δ) of the cephem ring are also known, for example, the 7-acyl, Δ-cephem-1 + carboxylic acid esters disclosed in U.S. Patent 3,536,705 and J. Org. .

Chem., 35 2U29 (1970). However, cepham-structured compounds having an exocyclic double bond represented by the following formula have not been previously described in the art.

6 \ ΓΠ I2 CHa

The term "C 1 -C 4 alkyl" means methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tert-butyl.

"Carboxylic acid protecting group" means an organic ester or anhydride that forms radicals commonly used to protect the carboxylic acid group of penicillin and cephalosporin antibiotics, and more generally to protect the carboxylic acid group of amino acids and peptides. Such protecting groups are relatively labile and readily cleaved by acidic or basic hydrolysis or hydrogenolysis, such as tert-butyl, benzyl, p-methoxybenzyl, 2,2,2-trichloroethyl, p-nitrobenzyl, benzhydryl. -, N-methoxybenzhydryl, phenazyl, p-bromophenyl, tetrahydropyran-3,5132 and mixed anhydrides of acetic and propionic acids.

"" Pharmaceutically acceptable cation "means an alkali metal cation such as lithium, sodium and potassium cations and alkaline earth cations such as calcium and magnesium cations and zinc cations.

Examples of starting compounds to be used in the process of the invention are the following: β-methylene-T-aminocepham-β-carboxylic acid 3-methylene-7- (2 '- (α-thienyl) acetamido) cefam-U-carboxylic acid p-nitrobenzyl-3-methylene -7- (2 '- (oC-thienyl) acetamido) cefam-k-carboxylate Said 3-methylenecepham-U-carboxylic acids are generally highly crystalline compounds which in many cases are more soluble in water than the correspondingly substituted 3-methyl-22-cephem-U -carboxylic acids (deacetoxy-

O

cephalosporan acids). In contrast to 3-methyl-N-cephem-k-carboxylic acids, the 3-methylene-cepham compounds do not have an absorption in the range of 260 m, ultra-. . . ~. 3 in the violet spectrum, but as with the 3-methyl-Δ-cephem compounds, they exhibit absorption in the infrared region at about 1790 cm -1 in the region typical of the β-lactam carbonyl group. The nuclear magnetic resonance spectrum of the 3-methylene cepham compounds shows an allyl-type hydrogen attached to the N-carbon and two vinyl hydrogens attached to the carbon substituent on the C-carbon, these properties being consistent with the structure of the 3-methylenecepham-U-carboxylic acid disclosed herein.

Said 3-methylene cephalosporin compounds are prepared by reduction of 7 to 3 amino- or 7-acylamido-Zr-cephem-1-carboxylic acid or ester in which the 3-carbon of the cephem core is substituted with -CH 2 -S-R 2, wherein e.g. a hydrocarbon group or a SO 2 M 2 group in which M + is a metal cation (see parent application).

The isomerization is carried out by mixing 3-methylenecephamic acid or an ester thereof prepared from a 3-substituted methylcephalosporinic acid or ester by a reductive substitution reaction with an aprotic solvent having a high dielectric constant and a strongly basic tertiary organic amine. Aprotic solvents that can be used in the isomerization process have a high dielectric constant, such as dimethyl sulfoxide, dimethylacetamide, and dimethylformamide. Preferably dimethylacetamide (DMA) is used.

Tertiary organic amines that can be used in the isomerization process with an aprotic solvent include amines having a pKa of about 9-5 or greater, such as tertiary alkylamines containing C 1 -C 4 alkyl groups. Examples of such amines are trimethylamine, triethylamine, tri-n-propylamine, methyldiethylamine, tri-n-butylamine, tri-n-octylamine and tri-n-decylamine. Preferably triethylamine is used.

The amine is preferably used in excess of the amount of 3-methylenephepham compound, but even a smaller amount of amine is sufficient for the necessary isomerization.

k 58132

In many cases, the isomerization proceeds satisfactorily with the addition of a few drops of amine as a catalyst.

The isomerization is preferably carried out at room temperature and has been found to proceed rapidly in the temperature range of about 20 ° C to 35 ° C. However, the isomerization mixture is usually stirred at room temperature for about 12 hours to completely isomerize the double bond from the exo position to the endo position.

The present invention thus relates to a process for the preparation of deacetoxycephalosporanic acids or esters from 3-methylenecephalamic acids or esters. As mentioned in the main application, the reduction of 3-substituted methylcephalosporins in many cases results in an isomeric mixture containing both 3 ~. ... 3. .

a methylemephepham compound and an isomeric Δ-cephem compound. Mixture of isomers - may be fractionated into individual isomers by known chromatographic or crystallization methods. The 3-methylene cepham isomer can then be subjected to 3 ...

isomerization as described above to give the desired α-cephem antibiotic. "

Alternatively, it can be for a reduction product mixture containing 3-exos. ...... 3 ....

3-endoisomers, the isomerization is performed mainly to obtain the desired cephem antibiotic, which is generally separable by partition crystallization.

The latter alternative method is preferable to the former because it does not require slow chromatography or fractional crystallization as an intermediate.

Examples of compounds of formula I are: 3-methylene-7-aminocepham-1 + -carboxylic acid

A particularly useful compound of formula I in the preparation of the 7-amino-deacetoxycephalosporanic acid backbone is 3-methylene-7-aminocepham-U-carboxylic acid trimethylsilyl ester (R = trimethylsilyl). In this case, a trimethylsilylating agent such as N- (trimethylsilyl) acetamide or bis-trimethylsilylacetamide is added to the suspension of 3-methylene-7-aminocepham-1j-carboxylic acid and acetonitrile with stirring to form a trimethylsilyl ester. The formation of the ester gives a solution. A tertiary organic amine, such as triethylamine, is then added to isomerize the carbon-carbon double bond from the exo position to the endo position to form a solution of trimethylsilyl ester of 7-ADCA. The solution is diluted with water and the pH is adjusted to about 3.5 to hydrolyze the trimethylsilyl ester of 7-ADCA to form a crystalline precipitate of 7-ADCA.

The 7-ADCA is filtered off and can then be acylated with the desired acyl group, for example an amino protecting group with a phenylglycine acyl group to give the antibiotic k <- f'alexin ash.

Alternatively, the acylation can be performed on the trimethylsilyl ester of 7-ADCA in situ, followed by recovery of the trimethylsilyl ester of cefalexin. The ester is hydrolyzed with water to give cefalexin. The acylation of 7-ADCA with an amino-protected phenylglycine, for example an phenylglycine protected with an N- (t-butyloxycarbonyl) group, can be carried out according to methods of acylation 5,581,32 known per se. Accordingly, the hydrolysis of the trimethylsilyl esters of 7_ADCA and cefalexin is carried out according to methods known per se.

The following examples further illustrate this invention.

Example 1 To 5 ml of dimethylacetamide containing U drops of triethylamine was added 100 mg of p-nitrobenzyl 3-methylene-7- (2 '- (o-thienyl) acetamido) cepham-1-carboxylate, and the solution thus obtained was kept at room temperature. temperature overnight. The reaction mixture was poured into water-ethyl acetate, the ethyl acetate layer was separated, washed with 5 ~ hydrochloric acid and water, and dried over magnesium sulfate. The dried ethyl acetate layer was evaporated to dryness to give p-nitro

O

benzyl 3-methyl-7- (21- (cC-thienyl) acetamido) -Δ-cephem-U-carboxylate as a white crystalline solid.

Example 2 "To 5 ml of dimethylacetamide containing 15 drops of triethylamine was added 100 mg of 3-methylene-7- (2 '- (oC'-thienyl) -acetamido) cepham-1-carboxylic acid, and the solution was kept at room temperature. The reaction mixture was poured into a mixture of water and ethyl acetate, and the pH of the mixture was immediately adjusted to 2 with 5% hydrochloric acid, the ethyl acetate layer was separated and washed with 5% hydrochloric acid and water, and then dried over magnesium sulfate, and the dried ethyl acetate layer was evaporated to dryness. which contained 70% of the isomeric product by NMR spectrum and thin layer chromatographic analysis on an absorbent silica gel, 3-methyl-7- (2 '- (οζ-thienyl) -

O

acetamido)) -A-cephem-1H-carboxylic acid.

Example 3

To a suspension of 1 g of 3-methylene-7-aminocepham-k-carboxylic acid and 20 ml of acetonitrile was added, with good stirring, 3 g of N- (trimethylsilyl) acetamide. To the resulting solution was added 3 drops of triethylamine, and the reaction mixture was stirred at room temperature for two hours. The reaction solution was diluted with water, and the pH of the solution was adjusted to 3.5 with hydrochloric acid. The reaction product, 3-methyl-7-amino-A-cephem-1-carboxylic acid (7-ADCA), formed as a crystalline precipitate from the acidic reaction solution.

Claims (2)

6 58132 A process for preparing a 3-methyl-N-cephem-U-carboxylic acid compound of the formula H! q II R - N - ^ N 0y-ny ^ -ch3 C00R1 wherein R1 is hydrogen, C1-4-alkyl, a carboxylic acid protecting group, preferably benzyl, nitrobenzyl or C1-C6-alkoxybenzyl, or a pharmaceutically acceptable cation; R is hydrogen, or N-thienylacetyl, characterized in that a 3-methylenephepham compound of the formula HR-N - p * S "N. R 1 COOR 1 in which R and R 1 are as defined above is reacted with a tertiary amine thereof. , having a pK'a value of at least 9.5, in the presence of an aprotic solvent having a high dielectric constant. Process according to Claim 1, characterized in that the tertiary amine is triethylamine and the aprotic solvent is dimethylacetamide.