DE2055796C2 - Process for the preparation of 7-aminocephalosporanic acid derivatives - Google Patents

Description

HOOC-CH- (CH;), - NH,

where Ri has the meanings given above,

or a salt thereof in a manner known per se in the presence of a base with chlorotrimethylsilane in reacts with a solvent,

the compound obtained in this way in a manner known per se with phosphorus pentachloride or phosphorus pentabromide converts under cooling,

the compound obtained is reacted with a lower alkanol with cooling,

CH ₂ -R,

COOH

or a pharmaceutically acceptable salt thereof, characterized in that one a compound of the general formula

(U)

the compound obtained thereby with a compound in general formula

R ₂ -CH ₂ -COOH (VI)

wherein R _{2 has} the meaning given above, reacts in the presence of a condensing agent, or with a reactive derivative thereof, in the presence of an organic base and
the compound obtained is hydrolyzed.

The invention relates to the process described in the claim for the preparation of 7-aminocephalosporanic acid derivatives of the general formula I defined according to the claims or a pharmaceutically acceptable salt thereof.

In the BE-Pi! 7 18 824 will manufacture 7-Aminocephalosporanic acids by means of an imide chloride process starting from cephalosporin silyl esters described. In this process, however, the 7-amino compound must be isolated as an intermediate, thereby causing a reduced yield. Those obtained according to the method of the invention Compounds of the formula I are known compounds (compare, for example, NL-OS 68 05 179). According to this reference, the compounds obtained according to the invention are prepared as follows For example, 7- (1H-Tetrazoll-yl) -acetamido-3- (5iTiethyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid produced by hydrolysis of 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-

thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (that of the starting compound of the formula II according to corresponds to the present invention). Then the obtained 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid became reacted with 1H-tetrazole-1-acetic acid. Even after this procedure is it is inevitable, the 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -tbiomethyl-3-cephem-4-carboxylic acid as an intermediate product, otherwise it is impossible to carry out the next stage of the reaction. this naturally complicates the entire process and leads to a low yield of the desired Link.

The process according to the invention does not proceed via the 7-amino intermediate stage; it surrenders the advantage of a considerable increase in yield.

The compounds of formula II used as starting material according to the invention, e.g. B. 7- (5-Aminoadipamido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid can be prepared according to the process described in NL-OS 68 05 179. Other analog output connections can be made in a similar manner.

The groups R \ in the compounds which can be prepared according to the invention and in the starting compounds of the formula II are thiadiazolylthio, e.g. B. 1,3,4-thiadiazolylthio, 1,2,5-thiadiazolylthio or 1,3,5-thiadiazolylthio or tetrazolylthio, for example 1H-tetrazolyithio or 2H-tetrazolylthio, in which the thiadiazole or tetrazole rings can carry lower alkyl. Lower alkyl are straight-chain and branched monovalent hydrocarbon groups with 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl.

Examples of salts of the compounds of the formula II are alkali metal salts (e.g. sodium or potassium salts), Alkaline earth metal salts (e.g. calcium or magnesium salts) or salts with organic tertiary amines (e.g. Triethylamine, trimethylamine, N-methylpiperazine or pyridine salts).

Examples of bases which are used in the reaction between the compound of the formula II and chlorotrimethylsilane can be used are bases which can form a salt with the compound of formula II. Examples these are alkali metal (e.g. potassium or sodium) hydroxide, carbonate, bicarbonate, alkoxide and hydride,

an alkaline earth metal (ζ. B. calcium or magnesium, -) alkoxide, carbonate, bicarbonate and hydride, or a organic tertiary amine (e.g. trimethylamine, triethylamine, N-methylpiperazine or pyridine).

The reaction is carried out in a solvent such as chloroform, dichloromethane. It can also other solvents inert to the reaction can be used. The reaction is preferably carried out in Range between room temperature and 40 ° C carried out With regard to the reaction temperature, there is κι however, there is no particular limitation. The chlorotrimethylsilane is preferably used in an amount greater than or equal to used as 3 moles per mole of compound II. In addition, it is preferred to use the compound of the formula II to be used in anhydrous form. Otherwise it is π preferred, the chlorotrimethylsilane in such a Use amount so that any water contained in the compound II is eliminated.

The thus produced compound of the Forme) JIJ is reacted without isolation with phosphorus pentachloride or phosphorus pentabromide with cooling.

The compound of formula IV thus obtained is without isolation of a further reaction with a subjected to lower alkanol. Examples of lower alkanols are methanol, ethanol, propanol, butanol 2-1 or pentanol. The reaction is carried out with cooling.

The compound of formula V prepared in this way is without isolation of a further reaction with a Compound of formula VI in the presence of such a condensing agent or with a reactive derivative subjected thereof in the presence of an organic base.

Examples of the above-mentioned derivatives of compounds y, of the formula VI, which are reactive with regard to the carboxyl group are acid anhydrides and mixed acid anhydrides with lower alkyl carbonates or aliphatic carboxylic acids, furthermore acid chlorides, active esters such as cyanomethyl esters, pentachlorophenyl esters, methanesulfonyl esters, methoxymethyl esters, vinyl esters, 1-methoxy vinyl esters, 1-ethoxy vinyl ester, propargyl ester, p-chlorophenyl ester and trichlorophenyl ester.

Examples of organic bases which can be used in this reaction are triethylamine, N, N-dimethylbenzylamine or pyridine. Examples of condensing agents which can be used in this reaction are pyridine substituted by alkyl, N ₁ N-dicyclohexylcarbodiimide or NN-di-isopropylcarbodiimide. The reaction is preferably carried out at room temperature or with heating.

According to the invention it is possible to use the reaction mixture of the previous step as the starting material to be used for the next procedural stage. It is preferred to use the reaction mixture in this reaction use, from the excess halogenating agent and lower alkanol under reduced Pressure have been distilled off. If these have not been removed, it is preferred to use the reaction mixture of the previous step to remove excess halogenation agent! and excess to eliminate lower alkanol, or in alternative Way to add an excess amount of dimethylformamide to the reaction mixture to remove the excess Eliminate halogenating agents.

The compounds of the formula VIl prepared in this way are subjected to hydrolysis without being isolated. The hydrolysis reaction is usually carried out in that the reaction mixture of the preceding Step is poured into water, preferably in the presence of an acid such as dilute hydrochloric acid or acetic acid, or a base such as an alkali metal bicarbonate or a trialkylamine. The received Compound, the Z-aminocephalosporanic acid derivative of the formula I can be purified and isolated in the customary manner.

The reaction steps according to the present invention are carried out under anhydrous conditions with the exception of the last step of hydrolysis. It is assumed that the intermediates of the formulas III, IV, V and VII which are obtained in the reaction steps described above correspond in each case to the following formulas, in which R 1 and R 2 have the same meaning as above, R j for hydrogen or (CH j ) ₃ Si - is, Y is chlorine or bromine and Z- is an anion and R _{4 is} a lower alkyl group.

(CHj) ₃ Si-OOC -CH- (CH _{2) 3} -CONH
NH-R ₃

COOSi (CH ₃ ) ₃

(CHj) ₃ Si-OOC - CH- (CHj) ₃ - C = N -r- {

I Y-N

γ / ^

NH-R ₃

CH ₂ -R,

(IV)

COOSi (CH ₃ ) ₃

(CHj) jSi - OOC _{- CH - (CH 2} ) j - C =

NH-R ₃ 0 -R ₄

COOSi (CH ₃ ) ₃

NH - R ₃

(CHj) ₃ Si-OOC-CH- (CH ₂ ) JCOR ₄

R ₂ -X-CH ₂ -CON "

(VK)

COOSi (CHj) ₃

The invention is further explained using the following examples:

example 1

7- (5-aminodipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid (2.5 g) was dissolved in dichloromethane (50 ml) solved. To this were added triethylamine (0.6 ml), chlorotrimethylsilane (3 ml) and N, N-dimethylaniline (4.3 ml). The mixture was stirred at room temperature for one hour. Phosphorus pentachloride (2.1 g) was then added at -60 ° C. The mixture was stirred at -40 to -50 ° C for 2.5 hours. Then N, N-dimethylaniline were added (0.3 ml) and n-butanol (18 ml), and the mixture was for one hour at -40 to - 50 ⁰ C stirred. The dichloromethane was distilled off under reduced pressure at room temperature, and the residue was concentrated under reduced pressure (2 mmHg) at 40 ⁰ C. The residue was suspended in dichloromethane (20 ml) and triethylamine (5.1 ml) was then added with cooling. The mixture was stirred for 15 minutes at room temperature. Then the mixed acid anhydride formed from 1H-tetrazole-1-acetic acid (1.9 g), triethylamine (2.1 ml), trimethylacetyl chloride (1.7 g), and tetrahydrofuran (40 ml) was added with cooling . The mixture was stirred at room temperature for 15 hours and the solvent was distilled off under reduced pressure. The residue was poured into water and the aqueous solution was extracted with ethyl acetate. Then the ethyl acetate layer was extracted with a saturated aqueous solution of sodium bicarbonate. Ethyl acetate was added to the extract and the mixture was acidified by adding hydrochloric acid. The ethyl acetate layer was separated, washed with water and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and ether was added to the solution. The crystal precipitated was collected by filtration. Yellowish crystals were obtained, namely (0.23 g) 7- (1H-tetrazol-1-yl) -acet-

amido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, m.p. 130 to 140 ⁰ C (dec.).
UV spectrum (phosphate buffer pH 6.4);

272 ηιμ

230

Example 2

Sodium 7- (5-aminoadipamido) -3- (5-methyll, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 g) was added to dichloromethane (50 ml). To this were added triethylamine (0.6 ml), chlorotrimethylsilane (10 ml) and N, N-dimethylaniline (4.3 ml) were added, and the mixture was stirred under reflux for one hour, To this mixture was added phosphorus pentachloride (2.1 g) while cooling with a mixture of dry ice and Given acetone. At the same temperature, N, N-dimethylaniline (0.3 g) and absolute n-propanol (15 ml) added. The mixture was kept at the same temperature and for 30 minutes then stirred for 30 minutes at room temperature. then

ι ■> was added to the mixture triethylamine (5.5 ml), and it was stirred for 15 minutes at room temperature. Then the solvent was under distilled off under reduced pressure. The residue obtained was dissolved in dichloromethane (50 ml), and added was added triethylamine (4 ml). The solution thus obtained was added to a solution which thereby that a solution of 1H-tetrazole-1-acetic acid had been prepared (3.2 g), (chloromethylene) dimethylammonium chloride (3.5 g) and dimethylformamide (4 ml) in

2> dichloromethane (20 ml) for one hour at room temperature stirred, added triethylamine (4.5 g) while cooling with a mixture of dry ice and acetone and the mixture was stirred at the same temperature for 30 minutes. The resulting mixture

jo was stirred for 2 hours, with the temperature gradually increased to - 20 ⁰ C was allowed to rise. Then the solvent was distilled off. The residue was poured into water and the aqueous solution was adjusted to pH 1.5 and with ethyl acetate

r> extracted. The ethyl acetate was washed with water and three times with an aqueous saturated one Extracted solution of potassium carbonate. The aqueous solution was washed with ethyl acetate and washed through Addition of concentrated hydrochloric acid in the presence of

4 (i ethyl acetate neutralized. The ethyl acetate was twice washed with water and dried over magnesium sulfate. Then the oily residue was washed with ether washed and dissolved in ethyl acetate. Ether was added to the solution while cooling, and the precipitated

ne precipitate was washed with ether and dried, giving pale yellowish crystals were of (0.933g) 7- (1H-tetrazol-1-yl) acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 129 to 138 ° C.

B e i s ρ i e 1 3

Sodium 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate
(2.55 g) was suspended in dichloromethane (50 ml) and to this mixture were added triethylamine (0.6 ml), chlorotrimethylsilane (7 ml) and N, N-dimethylaniline (4.3 ml). The mixture was stirred under reflux for one hour. Then while cooling to -50 ° C by means of a mixture of acetone and dry ice

bo added phosphorus pentachloride. The mixture was stirred for two hours at the same temperature. Then a solution of N, N-dimethylani-Hn (0.3 ml) in methanol (16 ml!) Was added. The mixture was cooled to -40 ° C for 30 minutes and then 30 minutes Stirred minutes at room temperature. Triethylamine (5 ml) was then added to this mixture with cooling. was added and the mixture was stirred for 15 minutes. Then the solvent was reduced

distilled off under the pressure. Dichloromethane (40 ml) was added to the residue. The solution became too added to another solution which had been prepared by using a solution of dicyclohexolcarbodiimide (3 g) and 1H-tetrazol-1-acetic acid (3.84 g) in tetrahydrofuran (30 ml) for one hour with cooling had been stirred. The solution was left at 0-5 ° C for one hour and then at room temperature for one hour touched. The solvent was distilled off under reduced pressure. Water became the residue given, and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was washed with Washed with water and extracted with an aqueous saturated solution of potassium bicarbonate. The extract was acidified by adding hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was with a aqueous saturated saline solution, dried and concentrated by distillation. The oily one The residue was treated with ether, whereby crystals (1.124 g) of 7- (l H-tetrazol-1-yl) acetamido-3- (5-me-

thyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid.

Example 4

Triethylamine (0.6 ml), chlorotrimethylsilane (6 ml) and N, N-Dimethylaniline (4.3 ml) were added to a solution of sodium 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-

thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 g) in dichloromethane (50 ml). The mixture was stirred under reflux for one hour. Then phosphorus pentachloride (2.1 g) was added with vigorous stirring at ⁰ -5o C. The mixture was stirred for an additional two hours at the same temperature. Then a mixture of N, N-dimethylaniline (0.3 ml) and methanol (15 ml) was added with cooling to -20 ° C. The solution was stirred for 30 minutes at -40 to -50 ⁰ C and then 30 minutes at room temperature. The solvent was then distilled off under reduced pressure. The residue was suspended in dichloromethane (50 ml), and triethylamine (6 ml) was added with cooling to -10 to -15 ° C. The mixture was stirred for 10 minutes and then thiophene-2-acetyl chloride (4 g) was added. The mixture was stirred at the same temperature for two hours. Then the solvent was distilled off under reduced pressure. The residue was poured into water and the aqueous solution was extracted with ethyl acetate. The extract was washed with water and extracted with an aqueous saturated solution of potassium bicarbonate. The aqueous solution was acidified by adding hydrochloric acid while cooling, and washed with an aqueous solution of sodium chloride and dried. The solvent was distilled off under reduced pressure. The residue was treated with ether whereby crystals were obtained from (133 g) 7- (a-thienyl) -acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid.
IR spectrum (Ntijol):

3300,1780,1720.1655 and 1530 cm- '

Example 5

Sodium 7- (5-aminoadipamido) -3- (5-methyl-13,4-

thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate

(2.55 g) was suspended in dichloromethane (30 ml)

Triethylamine (0.4 ml), N, N-dimethylaniline, 30 ml) and chlorotrimethylsilane (0.4 ml) were added. The mixture was stirred under reflux for one hour. Then was added with cooling to ⁰ C -5o phosphorus pentachloride (2.2 g). The mixture was stirred at the same temperature for two hours. . Then, "N, N-dimethylaniline (0.3 ml) and methanol (15 ml) was added The mixture was stirred for 30 minutes at -.. Stirred for 50 to -40 ⁰ C and 30 minutes at room temperature then the reaction mixture under reduced pressure was The residue was concentrated

given in dichloromethane (30 ml). This mixture was added all at once to a solution which had been prepared by reacting 1 H-tetrazole-1-acetic acid (2.0 g) with pivaloyl chloride (1.9 g) in a solution of triethylamine (2.2 ml) and tetrahydrofuran (50 ml)

ι) while cooling to -5 to 0 ^° C. Immediately thereafter, triethylamine (5.5 ml) was added to this mixture at the same temperature, and the mixture was stirred for one hour at the same temperature and left to stand overnight. The solvent was distilled off under reduced pressure and water was added to the residue. The aqueous solution was extracted with ethyl acetate. The ethyl acetate was washed with an aqueous saturated saline solution. Then was saturated with an aqueous

2 "i solution of sodium bicarbonate extracted. The extract was acidified to pH 2.0 by adding hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with an aqueous saturated saline solution, dried and under reduced pressure

ίο concentrated. The oily residue was washed with ether washed, leaving a yellowish powder of (1.19 g)

7- (1 H-tetrazol-1 -ylJacetamido-S-iS-methyl-1,3,4-thiadiazol-2-yl) -thiomethy! -3-cephem-4-carboxylic acid, obtained 95 F. to 100 ⁰ C. became.

^i] B eis ρ ie 1 6

Sodium 7- (5-aminoadipamido) -3- (1-methyl-1H-tetrazol-S-ylJ-thiomethyl-S-cephem ^ -carboxylate (2.55 g) was suspended in dichloromethane (30 ml) 4Ii suspension were added triethylamine (0.4 ml), N, N-dimethylaniline (3.0 ml) and chlorotrimethylsilane (4.0 ml). The mixture was stirred under reflux for one hour. Then, while cooling to -50 to - 4O added ⁰ C. phosphorus pentachloride (2.2 g). the mixture • ji was stirred for two hours at the same temperature. Then N were N-Dimethyianilin (3.0 ml) and methanol (15 ml) was added. the mixture was 30 minutes at -50 to -.. ^D stirred for 40 C and 30 minutes at room temperature the reaction mixture was then concentrated under reduced pressure, and the P.ückstand (30 mL) using dichloromethane and triethylamine (5.5 ml) was added This mixture was to a solution of α-thienylacetyl chloride (2.5 g) in tetrahydrofuran (50 ml) at -5 to 0 ⁰ C, and the reaction mixture was one hour at the same temperature stirred and then left to stand overnight. Then the solvent was distilled off under reduced pressure, and water was added to the residue. The aqueous solution was extracted with ethyl acetate and the ethyl acetate was washed with water. Then it was extracted with an aqueous saturated solution of sodium bicarbonate. The extract was acidified by adding hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was washed with an aqueous saturated solution of sodium chloride, dried and concentrated under reduced pressure. The oily residue was washed with ether, whereby a

Powder of (0.249 g) 7- (oc-thienyl) -acetamido-3- (1-methyl-1H-tetrazol-S-ylJthiomethyl-S-cephem ^ -carboxylic acid, M.p. 87 to 91 ° C.

Comparative tests:

The following comparative experiments show that the 7-aminocephalospo-

HOOC

ransic acid derivatives are obtained in a significantly higher yield than by the process of BE-PS 7 18 824.

a) The process described in BE-PS 7 18 824 can be represented by the following reaction scheme will:

(A)

N - N

CH ₂ -S-

COONa

-CH ₃ (B)

N N -CH _{2 CONH}

Ν —Ν

110 g of the sodium salt of 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid were obtained (Purity 79%) of the formula (A) silylated and then treated with phosphorus pentachloride for production of an imino halide which was then treated with methanol to produce an imino ether. The resulting solution of the imino ether was separated into two portions, of which one for carrying out the method known from the above-mentioned patent specification and the other to carry out the inventive method

HOOC - CH- (CH ₂ J ₃ - CONH NH _{2 0}

b)

-Sv CH ₃

(C)

rens was used.

In carrying out the known process, the imino ether was hydrolyzed for production of the 7-ACA derivative of the formula (B), which was then acylated with (1H-tetrazol-1-yl) acetic acid under Formation of cefazolin of formula (C) in a yield of 11.7 g with a purity of 95%, corresponding to a total yield of 28.8% of theory.

The process according to the invention can be represented by the following reaction scheme:

N-N

"Tn! -Cn, -s-4 _s JL-ch

(A)

COONa

N-N

COOH '-CH ₃

(C)

The imino ether given in section (a) above was acylated and then hydrolyzed, where one cefalozin in an amount of 26.5 g with a purity of 95%, corresponding to a Overall yield of 65.5% of theory was obtained

The tests were carried out in detail as follows:

g of the compound (A) (with a purity of 79%) was suspended in 750 ml of dichloromethane. 27.5 ml of triethylamine were added to the suspension and the resulting mixture was stirred for 10 minutes. 200 ml of chlorotrimethylsilane and 180 ml of dimethylaniline were then added. The resulting mixture was refluxed for one hour with stirring and then cooled to -20 to -25 ° C, then 55 g of phosphorus pentachloride were added. The mixture was stirred at the same temperature for a further 2 hours, and then 750 ml of methanol was added. The solution obtained was divided into two portions, one of which was used to carry out the known process (a) and the other was used to carry out the process (b) according to the invention.
The known method (a) became as follows

carried out: One half of the reaction mixture obtained above was cooled to -20 ° C and 30 Minutes after the addition of 200 ml of water warmed to room temperature. The mixture was made with Triethylamine adjusted to pH 3.5, then 200 ml of water were added. The resulting mixture was stirred and the precipitate was separated by filtration. To a suspension of the Precipitation in 180 ml of water, 15 ml of triethylamine were slowly added with stirring. After Addition of 225 ml of acetone was slowly added 25% acetic acid. The precipitated crystals were collected by filtration and dried.

For the purpose of comparison, this compound was further acylated to give compound (C). The product obtained was dissolved in 180 ml of dichloromethane by adding 25 g of triethylamine and the solution was cooled to -20 ° C. while stirring. To the cooled solution, a solution was added, the g by cooling a solution of 9.6 lH-tetrazole-1-acetic acid and 9.1 g of triethylamine in 300 ml dichloromethane at - 10 ^c C and addition of 9.0 g prepared Pivaloylcliloriu had been. The solution was then allowed to react for 30 minutes at the same temperature, for an additional hour at 5 ° C, and for 4 hours at room temperature. The reaction mixture was treated in a conventional manner to give 11.7 g of the desired product (cefalozin) with a purity of 95%.

Since the theoretical yield was 38.5 g, the overall yield was as follows:

11.7 x 0.95
38.5

x 100 = 28.8% of theory.

Process (b) according to the invention was carried out as follows: The other half of that obtained above Reaction mixture was for 30 minutes at -40 to -50 ° C and then for an additional 30 minutes at Treated at room temperature. After the addition of triethylamine, the solvent was distilled off and a suspension of the residue in dichloromethane was stirred at 0 to -5 ° C. This solution became a dichloromethane solution of 1H-tetrazole-1-acetic acid and pivaloyl chloride were added and the solution was kept at the same temperature for 2 hours and more Reacted for 5 hours at room temperature. The reaction mixture was conventional Treated manner to obtain 26.5 g of the desired product cefalozin in a purity of 95%.

Taking into account the theoretical yield of 38.5 g, the following was obtained Total yield:

26.5 x 0.95
38.5

x 100 - 65.5% of theory.

As the results of the comparative experiments described above show, Cefalozin was used in the Manufactured using the method according to the invention in a bulge obtained by more than was twice as high as when using the method known from Belgian patent specification 718824. The considerable increase in yield that can be achieved by the process according to the invention is noticeable in practice Weight and is quite surprising even for the specialist.

Claims (1)

Claim: Process for the preparation of 7-aminocephalosporanic acid derivatives of the general formula R, -CH, -CONH where mean: Ri thiadiazolylthio or tetrazolylthio, which can each carry lower alkyl, and
R ₂ tetrazolyl or thienyl, ι ί