CS196272B2 - Method of producing delta up 3-cephalosporin esters - Google Patents

Abstract

Antibacterial alkanoyloxymethyl cephalosporin esters prepd. from 4-carboxy cpd. and alkanoyloxymethyl halide

Description

The invention relates to a process for the preparation of A3-cephalosporin esters.

The idea of esterifying β-lactam type antibiotics to facilitate oral absorption is known. An explanation of the problems associated with esterification, particularly in the case of cephalosporin antibiotics, is given in Binderup et al., J. Antiblotics, 24, 767 (1971). For example, the cephalotin sodium is converted to a mixture of the ^2- and N-acetoxymethyl ester by reaction with chloromethyl acetate. When it is necessary to obtain pure, orally administered, active? ³ -acetoxymethyl ester, the mixture of isomers is oxidized with m-chloroperbenzoic acid to form a β-sulfoxide ester. This sulfoxide is reduced to sulfide by phosphorus trichloride as described by Kaiser et al., J. Org. Chem., 35, 2430 (1970). Isomeric mixtures of A ^{2 -} and A ^3- esters can also be separated by very laborious chromatographic techniques.

The problem of the above double bonds and their isomerization was discussed by Murphy and Webber in "Cephalosporins and Penicillins, Chemistry and Biology", Ε. H. Flynn, Ed., Academic Press, New York and London, 1972, pp. 147-151 and 172-176.

The proper cause of isomerization. in the known esterification procedures using a cephalosporinic acid salt with the double bond at the 3-position, the presence of relatively high initial acid concentrations in the reaction mixture is present. The presence of the acid anion in excess induces isomerization of the double bond at the 3-position in the ester product. It follows that the initial steps of the esterification processes hitherto known, which are characterized by a high acid anion concentration and a low ester product concentration, give rise to conditions which are very favorable for the formation of the double bond at the 2-position. however, some ester has already been converted to the double bond isomer at the 2-position.

Furthermore, Cocker et al. in J. Chem. Soc., 1142 (1966) have shown that the presence of a base causes isomerisation of the double bond at the 3-position of cephalosporic acid or an ester thereof. Thus, the presence of a base in the esterification mixture can give rise to a mixture of isomeric esters which is very difficult to separate.

Morin et al., J. Am. Chem. Soc., 91, 1401 (1969), have shown that under alkaline conditions the equilibrium state of the double bonds at positions 2 and 3 probably reflects the difference

The ratio of substituents most of which are in position 3 of the cephalosporin compound.

The invention relates to a process for esterification. cephalosporic acid having a double bond at the 3-position and derivatives thereof to form esters with a double bond. The cephalosporin esters obtained by the process of the invention require only simple purification methods, since the amount of ballast substances is very small.

Acyloxymethyl esters of cephalosporin with a double bond at the 3 - position. produced by the method of the invention are antibiotics with very easy absorbability when administered orally. various penicillin derivatives have been described in Daehne et al. in J. Med. Chem. 13, 607 (1970) and U.S. Pat

578 · 570 ', · ··· 2,650,218, 3,250,679, 3,654,265, · 679,663, 3,719,668, 3,720,664, 3,720 · 665.

Acyloxymethyl esters of various cephalosporin compounds have been described in U.S. Patent Nos. 3,485,819, 3,488,729, 3,708,479 and DE Patent Nos. 2,230,620 and BE Patent Nos. 784,800.

The invention thus relates to an improved process for the preparation of cephalosporin esters having a double bond in. position 3 of the general formula I

where. .... . . '

R .. means ·. 2-phenoxyacetyl; N-butoxycarbonylphenyls, cyl,. 2- (2-thlenyl) acetyl; 2- (1,2y33-1H-rl-yl) -acetyl or a radical of the general formula. ;.

; R 3 represents a hydrogen atom or an alkanoyl 0-1; about carbon atoms,

R1 represents a hydrogen atom, an acetoxy group, (2-methyl-1,3,4-thiadiazol-5-yl) thio, or (1-methyl-1,2,3,4-tetrazole). When R is N-tert-butoxycarbonylphenylglycyl, R 1 is hydrogen, R 2 is alkyl of 1 to 4 carbon atoms, by the reaction of ^{3 3} -cephalosporinic acid with a double bond in the ^5- yl group; position 3 of formula II.

where

R @ 1 and R @ 1 are as defined above with an alkanoic acid halomethyl ester of formula (III)

O

II

X — CH2O — C — R2 (III) where ··· ·, ........- -..............

R 2 is as defined above and

X represents a chlorine or bromine atom, in the presence of a base in an inert solvent at a temperature of less than 50 ° C, followed by isolation of the product, which comprises adding an equivalent of a base to an equimolar mixture of acid and halomethyl ester such as fast that. , the rate of formation of the acid anion is approximately equivalent to the esterification rate over a period of 2 to 24 hours.

A wide variety of novel compounds can be obtained by the process of the present invention, wherein the preferred compounds of the present invention are represented by the formula (I):

R is a radical of formula

where

R3 represents a hydrogen atom or an alkanoyl having 1 to 4 carbon atoms,

R 1 represents (1-methyl-1,2,3,4-tetrazol-5-yl) thio and a

R2 represents methyl, ethyl, isopropyl or t-butyl. .

After esterification, the N-t-butoxycarbonyl group can be removed by treatment with formic acid or trifluorobutic acid to give the antibiotic active 7- (N-phenylglycylamino)] cephalosporin ester.

The term "halogen" used with respect to a halomethyl ester means a chlorine or bromine atom. Typical examples of alkanoic acid halomethyl esters which can be used in the process of the invention are: chloromethyl acetate, bromomethyl acetate, bromomethyl n-propionate, bromomethyl pivalate and chloromethyl pivalate. Preferred halo-alkanoic acids are chloromethyl acetate, bromomethyl acetate, chloromethyl pivalate and bromomethyl pivalate.

1'9 6'272

The esterification is preferably carried out in an inert organic solvent in the presence of a suitable base. Suitable inert solvents are amides, halogenated hydrocarbons, sulfoxides, ethers and ketones. Examples of inert solvents are acetonitrile, Ν, Ν-dimethylformamide (DMF), N, N-dimethylacetamide (DMAC), dichloromethane, chloroform, dimethylsulfoxide (DMSO), diethylsulfoxide, diethyl ether, dioxane, tetrahydrofuran (THF), acetone and methyl ethyl ketone. . Any solvent can be used, preferred solvents are dimethylformamide, acetone and acetonitrile. .

The base that it uses to carry out the esterification helps to form the acid anion while acting as an acid binding agent. The base used may be of organic or inorganic origin. Suitable organic bases are, for example, secondary and tertiary amines, such as dicyclohexylamine, N-ethylaniline, morpholine, diethylamine, Ν, Ν-diethylaniline, N-methylmorpholine, pyridine and triethylamine. Secondary amines may also be used in the process of the present invention, since they react more readily with cephalosporinic acid than with halomethyl ether.

Inorganic bases such as alkali metal bicarbonates, alkali metal carbonates or hydroxides such as sodium bicarbonate, lithium carbonate and potassium hydroxide may also be used in the process of the invention. Preferably, alkali metal hydroxides dissolved in as little water as possible are used, and this solution is then diluted with preferred solvents to form homogeneous solutions. ^r

Preferred bases for use in the process of the invention are dicyclohexylamine, triethylamine and pyridine.

The preferred amount of the base in the esterification process is 1 equivalent to cephalosporic acid. The cephalosporinic acid and the halogen ester reactant are preferably mixed in equimolar amounts. In some cases, however, an excess of the halomethyl ester may be used to increase the esterification efficiency.

Under the conditions of the process of the invention, the base is never present in excess, since it immediately reacts with the acid in the esterification mixture to form the acid anion. The rate of addition of the base must be controlled because rapid addition would cause too much acid anion. Since this amount should be as low as possible in the esterification mixture,. the rate of formation of the acid anion should be approximately the same as the esterification rate. The rate of formation of the acid anion is dependent on the concentration of the base and the rate of addition.

The rate of esterification of the acid depends on the total amount of substituent at the 3-position of the cephalosporic acid and on the reactivity of the halogen ester used. For example, cephalosporin acids with methyl groups, acetoxymethyl groups, or methylthio groups at the 3-position can be esterified much faster than those with heterocyclic substituents.

The relative reactivity of the halomethyl esters depends more on the electronegativity of the halogen substituent than on the ester group. Iodomethyl and bromomethyl esters are more reactive than chlorinated esters and are therefore more preferred. The ester group as such may also have 'steric effects' when, for example, it is a pivalate. Otherwise, the slower rate due to the steric effect can be counterbalanced by using more reactive iodomethyl pivalate or bromomethyl pivalate.

It will be appreciated by those skilled in the art of cephalosporin chemistry that in individual cases the rate of base addition will depend upon the cephalosporinic acid used and the halomethyl ester used. The base is added so quickly that the formation of the acid anion proceeds approximately as fast as the etherification, the esterification rate being different for different acids. The rate of formation of the acid anion can be approximately matched to the rate of esterification, for example, by adjusting the rate of esterification

1. dilute the solution accordingly; or

2nd principle adds at a very slow speed or down

3. the base adds at a rate approximately equivalent to the rate at which the salt precipitates; or

4. Use a bromide ion to increase the rate of esterification of low reactive esters.

The process of the invention is preferably carried out using highly dilute base solutions which are added at a controlled rate.

The base is used in a dilute solution in an inert solvent or a mixture thereof. Although the concentration of the base is not a critical value, a concentration of 0.10 to 1.0 mmol is usually used relative to the range used. desert. Even more dilute solutions may be used if desired. The base is further diluted by addition to the reaction mixture. The rate of addition of the alkali solution can be controlled by the pump associated with. spraying device or by adding the base dropwise. In the case of iodomethyl and bromomethyl esters, the rate of addition of the base is preferably 5 to 20 drops per minute. A slower base addition is useful when one of the reactants is chloromethyl ester. The bromide ion in the form of a soluble salt can be added to the esterification mixture to increase the reactivity of the chloromethyl ester. Furthermore, the rate of precipitation of the salt of the base from the solution is an indirect indicator of the rate of esterification and the addition of the base can therefore be controlled according to this precipitation. The addition of the base should generally take a very long time, for example several hours using dimethylformamide as the preferred solvent, the rate being determined by the appearance of a precipitate of the resulting salt.

While maintaining the aforementioned advantageous conditions for the slow addition of the dilute base, sufficiently low concentrations of the anion of the acid in the esterification mixture are produced, thereby minimizing the double bond isomerization. '

The reaction is usually carried out at a temperature below 50 ° C, preferably 20-30 ° C. The reaction is substantially complete after 2 to 24 hours, usually 4 to 14 hours. The product is usually reacted for 4 to 14 hours to obtain better results. The product may be isolated by pouring the reaction mixture into a suitable water-immiscible organic solvent such as ethyl acetate or chloroform and washing the resulting solution with an excess of water to dispose of the resulting reaction solvent. and salts. The unreacted carboxylic acid in the organic phase is eluted with a dilute base, for example dilute sodium hydroxide or sodium bicarbonate, without isomerization of the ester formed. The ester is usually isolated as a solid and can be further purified by conventional means such as crystallization or chromatography.

The cephalosporinic acids of formula (II) which are the starting materials for carrying out the process of the invention can be prepared by the methods described in great detail in U.S. Pat. Nos. 3,516,997, 3,610,221, 3,743,644 and 3,766,175.

The alkanoic acid halomethyl esters of formula (III) are easily obtainable. For example, chloromethyl acetate can be produced according to M. Descude, Bull. Soc. Chim. France [3], 27, 867 (1902). ·.

Examples of cephalosporin acids which can be used in the process of the invention are the following:

7-acetamido-3-methyl-3-cephem-4-carboxylic acid, 7-acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid, 7-acetamido-3-methylthiomethyl-3-cephem-4- ' 7-acetamido-3- (2-methyl-1,3,4-thiadiazol-5-yl-thiomethyl) -3-methyl-4-carboxylic acid, 7-acetamido-3- ( 1-methyl-1,2,3,4-tetrazol-5-yl-thiomethyl) -3-cephem-4-carboxylic acid; 7- (2-phenylacetamido) -3-methyl-3-cephem-4 7- (2-Phenylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid 7-: 2-Phenylacetamido-3-methylthiomethyl-3-cephem-4-carboxylic acid 7 - (2-phenylacetamido) -3- [2-methyl-1,3,4-thiadiazole-5-yl] -4- (2-phenylacetamido) -3-methyl-4- carboxylic acid 7- (2-phenylacetamido) -3- (1-methyl-1,2,3,4-telrazol-5-ylthlomethyl) -3-cephem-4-carboxylic acid 7- (2-phenoxyacetamido) -3-methyl-4-cephem-d-carboxylic acid; .

7- (2-phenoxyacetamido) -3-acetoxymethyl-3-cephem-4-carboxylate, 7- (2-phenoxyacetamido) -3-methylthiomethyl) -3-cephem-4- carboxyl,. 7- (2-phenoxyacetamido) -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid 7- (2-phenoxyacetamido) -3- (1) -methyl-1,2,2,4,4-aza-5-ylthiomethyl) -3-cephem-4-carboxylic acid 7- (2- (2-thienyl) acetamido] -3-methyl-3-methyl-3-carboxylic acid 4-carboxylic acid, 7- (2- (2-thienyl) acetamido] -3-aceloxymelhyl-3-cephem-4-carboxylic acid, 7- (2- (2-thienyl) acetamido] -3-methylthiomethyl-3-cephem -4- carboxylic acid, 7- [2- (2-thienyl) acelamido] -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 7- (2- (2-thienyl Jacetamido) -3- (1-methyl-1, 1,3,4-tetrazol-5-ylmethyl) -3-methyl-4-carboxylic acid, acid 7-mandlamido-3-methyl-3-cephem-4-carboxylic acid, 7-mandlamido-3-acetoxymethyl-4-cephem-4-carboxylic acid, 7-mandlamido-3-methylthlomethyl-3-cephem-4-carboxylic acid, 7-Mandlamido-3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid

7-Mandlamido-3- (1-nitro-1,2,3,4-triazol-5-ylthiomethyl) -1H-tert-4-carboxylic acid, 4-carboxylic acid.

7- (α-phenyl-Nt-butoxycarbonylpolyglycino) -3-methyl-3-methyl-4-carboxylic acid, 7- (α'-phenyl-Nt-butoxycarbonylglycylamino) -3-methyl 7- [2- [1,2,3,4-tetrazol-1-yl) acetamido] -3-methyl-3-cephem-4-carboxylic acid, thylthiomethyl-3-cephem-4-carboxylic acid, 7- (2- (1,2,3,4-tetrazol-1-yl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid 7- (2- (1,2,3,4-tetrazole- 1-yl) acetamido] -3-methylthiomethyl-3-cephem-4-carboxylic acid 7- (2- (1,2,3,4-tetrazol-1-yl) acetamido] -3- (2- methyl-1,3,4-thiadiazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid 7- [2- (1,2,3,4-tetrazol-1-yl) acetamido] - 3- (1-Methyl-1,2,3,4-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid 7-O-N-imandlamido) -3-methyl-3-cephem-4 -carboxylic acid, 7- (Ofmylmandlamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid, 7- (Ofmylmandlamido) -3-methylthiomethyl-3-cephem-4-carboxylic acid, 7- (O --ormy ymand lamid o) -3-

- (2-Methyl-3,4,4-thiadiazol-5-ylthiomethyl) -3-methyl-4-carboxylic acid and 7- (O-methylmandlamido) -3-

- (1-methyl-1,2,3,4-tetriazol-5-ylthiomathyl) -3-cephem-4-carboxylic acid.

Example 1

To a solution of 4.62 g of 7-D-mandlamido-3- (1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid, 1.53 g of chloromethyl pivalate and 1.03. g of sodium bromide in 25 ml of dimethylformamide was added dropwise a solution of 1.81. g of dicyclohexylamine in 15 ml of dimethylformamide. The reaction mixture is stirred for 12 hours at room temperature, then filtered and the filtrate is added to 700 ml of ethyl acetate. The organic solutions were washed successively with saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution, 1 N aqueous hydrochloric acid solution and water. The organic solution was drained and the solvent was evaporated under reduced pressure to give 1.6 g of a crystalline residue. This residue was recrystallized from fresh ethyl acetate to give pivaloyloxymethyl-7-D-nanidlamido-3- (1-methyl-1,2,3,4-octetrazol-5-ylthiomethyl) -3-cephem-4 -kar-. m.p. 174-176 ° C.

Analysis for C24H28N6O7S2, (576) calculated:

49.99% C, 4.89. % H, 14.57 0/0 N;

found :. .

% C, 49.72;% H, 4.83;% N, 14.37%.

NMR (CDCl 3):

1.5 [s, 9H, -C (CH 8) 3]

3.7 (d, 2H, C-2 H),

3.95 (s, 3H, N-CH 3),

8.70 to 8.75 (d, 1H, N-H).

Example 2

4,25 g. (9.35 mmol) of 7- (2- (1,2,3, -)

4-triazol-1-yl) acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) -3-methyl-4-carboxylic acid and 4 ml of bromomethyl acetate, 12 g (40 mmol) was dissolved in a mixture of 50 ml of acetone and 25 ml of dimethylformamide. The reaction mixture was stirred at room temperature and a solution of 1.26 ml, 0.92 g (9.2 mmol) of triethylamine in 30 ml of acetone was added dropwise over 2 hours. After the addition was complete, the reaction mixture was further stirred overnight. The mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was extracted with 1 L of ethyl acetate (200 mL aliquots). The extracts are filtered and combined, and the filtrate is washed successively with water, a 3N aqueous hydrochloric acid solution, a saturated aqueous sodium bicarbonate solution and a saturated sodium chloride solution. The ethyl acetate phase was dehydrated with sodium sulfate and the solvent was then evaporated to dryness in vacuo. The remaining oily liquid crystallizes on standing, and the crystals are recrystallized from methanol to yield. 0.4 g acetoxymethyl-7- [2- (1,2,3,4-tetrazol-1-yl) acetamido] -3- (2-methyl-1,3,4-thladiazol-5-ythiomethyl) 115 DEG-117.5 DEG C. 3-Cef-4-carboxylate. This product was uniform in preparative chromatography. The NMEOpectrum demonstrates the presence of the ester with the double bond at the 3-position as the only product.

Analysis for C17H16N8S3O6, (524.56) calculated:

C 38.93, H 3.07, N 21.36, S 18.34; found *

38.74% C, 3.29% H, 21.10% N, 18.09% S.

Example 3 g (4.3 mmol) of 7-mandlamido-3- [1-methyltetrazol-S-yl) thiomethyl-3-cephem-4-carboxylic acid and 1.72 ml (17.2 mmol) of bromomethyl acetate are dissolved in the mixture ml of acetone and 10 ml of dimethylformamide.

ϋ

The mixture was stirred at room temperature and a solution of 0.595 ml was added dropwise over 1/2 hour. (4.2 mmol) of triethylamine in 30 ml of acetone. After the addition was complete, the mixture was filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in chloroform and the solution was washed successively with water, saturated sodium bicarbonate solution and finally saturated sodium chloride solution. The chloroform phase was dehydrated with sodium sulfate and evaporated in vacuo to give a foamy residue. the crude product by thin layer chromatography on silica gel with ethyl acetate gives two spots. The product was then recrystallized from methanol to give 0.151 g of acetoxymethyl-7-D-mandlamldo-3- (1-methyl-1,2,3,4-tetrazol-5-ylthiomethyl) -3-cephem-4- 126 DEG-130 DEG C. with decomposition. The NMR spectrum of the crystalline product shows the presence of the double bond ester at the 3-position as the only product.

Analysis for C 21 H 22 N 6 O 7 S 2, (534).

calculated:

% C, 47.18;% H, 4.15;% N, 15.72; found:

H, 4.11; N, 15.45; S, 12.05.

NMR (CDCl3):

2.05 (s, 3H, C-CH3)

3.6 (s, 2H, C-2H);

3.82 (s, 3H, N-CH 3).

8.05 (d, 1 H, N-H). ...·' OF

He attaches

When an equivalent amount of 7- (D-2-formyloxy-2-enylacetamide) -3- (1-methyl-1H-tetrazol-4-ylthiomethyl-4-carboxylic acid 4-carboxylic acid) is used instead of the starting 7 Of the -D-mandlamide derivative and the procedure is otherwise carried out according to Example 1, obtained after recrystallization of pivaloyloxymethyl-7- (D-2-formoxy-2-enylacetamido) -3- (1-methyl-1,2,3) tetrazol-5-ylthiomethyl) -3-cephem-4-carboxylate, m.p. 155-156 ° C.

Analysis for C 25 H 28 N 6 O 8 S 2, (604).

calculated:

% C, 49.66;% H, 4.67;% N, 13.00; found:

% C, 49.47;% N, 4.69;% N, 13.73.

NMR - (CDCl3):

α 1.23 [s, 9, (CH 3) 3 C-],

3.74 (s, 2, C-2 methylene),

3.92 (s, 3, N-CH 3),

4.25 [d, 1 (J = 13) C-3]

4.47 [d, 1 (J = 13) C-3].

4.97 [d, 1 (J = 5) C-6),

5.82 [d, 1 (] = 5, J = 9) - C-7], • 5.85 [d, 1 (J = 6) OCH 2 O),

5.94 [d, 1 (J = 6) OCH 2 O].

6.23 (w, 1, αΗ),

6.87 [d, 1 (J = 9) 7-NH),

7.38 (s, 5, aromatic),

8.17 (s, 1, OCHO).

Example 5

In the case where an equivalent amount of 7- (D-2-ogmyloxy-2-enylacetamido) -3- (1-methyl-1,2,3, -tetrazol-5-ylthlomethyl) acid is used, 3-cep-4-carboxylic acid - starting material instead of the 7-D-mandlamide derivative and the procedure is otherwise carried out according to Example 3, acetoxymethyl-7- (D-2-formyloxy-2-phenylacetamido) is obtained after crystallization -3- (1-methyl-1,1'-tetrazol-5-ylthiomethyl) -3-cephemarboxylate.

Analysis for C 22 H 22 N 6 O 8 S 2, (562). calculated:

46.97 θ / ο - C, 3.94 θ / ο H, 14.94% N;

found:

H, 4.06; N, 14.74.

NMR (CDCl3):

and 2.14 (s, 3, CH 3 -CO 2 -CH 2),

3.73 - (s, 2, C-2),

3.9 (s, 3, N-CH 3).

4.23. (D, 1 (J = 13) C-3)

4.53 [d, 1 (J = 13) C-3).

4.95 (d, 1 (J = 5) C-6),

5.9 (m, 3, C-7 and OCH 2 O -).

6.25 (s, 1, aCH);

7.4 (s, 5, aromatic),

6.92 [d, 1 (1 = 8) 7 NH],

O y

8.15 (s, 1, C).

\ H

Example 6

3.96 g (0.01 mol) of 7- [2- (2-thienyl) acetamido] -3-acetoxymethylcephalosporanic acid and 6.12 g (0.04 mol) of bromomethyl acetate are dissolved in 75 ml of acetone and stirred while stirring. a solution of 1.73 ml of 0.0097 moles of diisopropylamine in 25 ml of acetone was added dropwise over 3 hours. After the addition was complete, the reaction mixture was filtered and the filtrate slurried with ethyl acetate and filtered again. The filtrate was washed successively with water, saturated sodium bicarbonate solution and dried. The solvent was evaporated to dryness in vacuo. The product crystallizes on standing and is recrystallized from benzene-hexane to give 0.25 g of acetoximethyl 7- [2- (2-thienyl) acetamido] -3-acetoxymethyl-S-cephem-4-carboxylate. mp 134-137 ° C. '

Analysis for C 18 H 20 N 2 O 2 S (408.5).

calculated:

48.71 o / o c, 4.30 o / o H, 5.38% N;

found:

H, 4.53; N, 6.16.

The NMR spectrum carried out in -CDCl3 has the following properties 5:

2.1 (d, acetate, acetate)

3.4 (AB-q, C-2 methylene)

3.8

4.9 (AB-q, G-3 methylene)

5.0 (d, C-6)

5.7 to 5.9 (m, C-7 and OCH 2 O)

6.7 (d. 7-NH)

6.95 to 7.4 (aromatic). .

Example 7

8.0 g (20 mmol) of 7- (2- (2-thienyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid and 3.3 g (22 mmol) of chloromethyl pivalate are dissolved in 100 ml of acetone. The mixture was stirred at room temperature and 2.5 ml (18 mmol) of triethylamine was added dropwise over 1 hour, and the resulting mixture was treated in a similar manner to Example 3 to give pivaloyloxymethyl-7- ( 2- (2-thienyl) acetamido] -3-acetoxymethyl-3-cephem-4-carboxylate.

NMR spectrum performed. in CDCI3 has the following features &

1.05 (s, C (CH 3) ₃ ],

2.0 (s, CH 2 OCCH 3). .

Example 1 a d 8

3.48 g (10 mmol) of 7-phenoxyaldehyde-3-methyl-3-cephem-4-carboxylic acid; and

1.65 g of chloromethyl pivalate (11 mmol) is dissolved in 60 ml of acetone. The mixture was stirred at room temperature while being stirred. the solution was added dropwise over 1 hour

1.25 ml (9 mmol) of triethylamine in acetone The reaction mixture was then treated in a manner analogous to Example 3 to give pivaloyloxymethyl-7-phenoxyacetamidol-3-methyl-11-Cefem 14-carboxylate.

The NMR spectrum performed in CDCl 3 has the following properties δ:

1.05 (s, -C (CH3) 3).

2.05 (s, C-3 CH 3)

3.30 (AB-q, C-Z methylene).

4,5

4.95 (d, C-6).

5.2 to 6.0 (m, C-7, OCH 2 O)

6.7 to 7.7 (aromatic)

8.2 (7-NH).

Claims (3)

What is claimed is: 1. A process for the preparation of N @ 2 -pha. VYNALEZU II CH-Cl CH ₃ coocho-cd ^of II * o (!) where R is 2-phenoxyacetyl, Nt-butoxycarbonylphenylglycyl, 2- (2-thienyl Jacetyl, 2- (1,2 _L 3,4-otrazo) 11-yl acetyl or a radical of formula wherein: R3 represents a hydrogen atom or an alkanoyl group having from 1 to 4 carbon atoms, R 1 is hydrogen, acetoxycluoro, (2-methyl-0,3,4-ahiadiazol-5-yl) thio or (11-methyl-1,2,3,4-tetrazollyl) thio when R is Nterter butoxycarbonynyl glycyl, R 1 represents a hydrogen atom, R 2 represents alkyl of 1 to 4 carbon atoms 196272 to the reaction of A ³ -cephalosporinic acid of the general formula II wherein: R and R 1 are as defined above with the halo-methyl ester of the alkanoic acid III O II X - CH 2 - C - R 2 (III) wherein R 2 has the above meaning and X represents a chlorine or bromine atom in the presence of a base in an inert solvent at a temperature below 50 ° C, followed by isolation of the product, characterized in that The base is added to the equimolar mixture of the acid and the halomethyl ester at a rate at which the formation of the acid anion is equivalent to the rate of esterification within 2 to 24 hours. 2. A process according to claim 1, wherein R is 2-phenoxyacetyl, N-butoxycarbonylphenylglycyl, 2- (2-thienyl) acetyl or 2- (1,2,3,4- tetrazol-1-yl) acetyl. 3. A process according to claim 1, wherein the starting material is a compound of formula (II) wherein R is a radical of formula (I). 9 CH-Cl where R3 represents a hydrogen atom or an alkanoyl group having from 1 to 4 carbon atoms, R 1 is (1-methyl-1,2,3,4-tetrazol-5-yl) thio and compounds of formula III wherein R 2 is methyl, ethyl, isopropyl or t-butyl.