DK147597B - PROCEDURE FOR THE PREPARATION OF 7-AMINOCEPHALOSPORANIC ACID DERIVATIVES - Google Patents

Description

147597

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

R-X-CH 2 -CONH i i o ^ ~ Y ^ ch 2-Bi

000h

wherein R 1 represents azido, thiadiazolylthio or oxadiazolylthio, wherein the thiadiazole and oxadiazole nuclei are optionally substituted with C 1-6 alkyl or C 1-6 alkylthio, or tetrazolylthio, where the tetrazole cores are optionally substituted with C 1-6 alkyl, X is bet - or oxygen atom or a single bond, and R 2 represents halogen or sydnyl, tetrazolyl, oxadiazolyl, thienyl, phenyl or thiadiazolyl, which groups are optionally substituted with C 1-6 alkyl or C 1-6 alkylthio, with however, Sydnyl and tetrazolyl are optionally substituted with C 1-6 alkyl when X represents sulfur or oxygen, with the proviso that when R 2 is halogen, X represents a single bond, or salts thereof, thereby reacting a compound of general formula II

^ rYs> H00C-CH- (OH «)» -C0NH ^ A χχ | 1 KH2 0 2

C00H

wherein R 1 has the meaning given above, with chlorotrimethylsilane in the presence of a base or reacting a salt of the compound of the general formula II with chlorotrimethylsilane, reacting the resulting 2

compound with a halogenating agent and reacting the resulting compound with a lower alkanol, the process being characterized in that the resulting compound having the general formula V

. S.

(CH3) 3Si-OOC-CH- (CH2) 5-C = N- | -f> γ

Le5 Lrψ H

0 COOSi (CH3) 3

5 wherein R 1 is as defined above, R 3 is hydrogen or (CH 2 S 5, and R 1 is lower alkyl, then reacted with a compound of general formula VI

r2-x-ch2-cooh VI

wherein R * and X have the above meanings, in the presence of a condensing agent, or the compound V is reacted with a reactive carboxyl group derivative of the compound of the general formula VI in the presence of an organic base, after which the compound obtained is hydrolyzed.

By "C 1-6 alkyl" is meant herein a straight or branched hydrocarbon group, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl or pentyl.

The starting compounds of general formula II, for example 7- (5-aminoadipinamido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid, can be prepared as described in Dutch patent application No. 6,805,179 or in analogy thereof.

Compounds of general formula I are known, for example, from Dutch Patent Application No. 6,805,179, according to which, for example, 7- (1H-tetrazol-3-yl) -acetamido-3- (5-methyl-1,3, 4-Thiadiazol-2-yl) -thiomethyl-3-ceph-em-4-carboxylic acid is prepared by hydrolysis of 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazole-2 -yl) -thiomethyl-3-cephem-4-carboxylic acid (corresponding to a starting compound of the general formula II 5 by the process herein) and subsequent reaction of the resulting 7-amino-3- (5-methylM 3,4-thiadiazol-2-yl) -thio-methyl-3-cephem-4-carboxylic acid with 1H-tetrazole-1-acetic acid. In this known method, it is necessary to isolate 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid as intermediate, since otherwise, the subsequent reaction cannot be carried out and this causes the complexity of this known reaction sequence and leads to the lower yield of the desired compound.

In the process of the present invention, the desired compound of general formula I is obtained directly in a higher yield 15 without isolating the intermediates, i.e. the compounds of formulas Ilf, IV, V and VII (cf. pp. 6-7).

In the process of the present invention, a compound of the general formula II is first reacted with chlorotrimethylsilane in the presence of a base, or a salt of the compound of the general formula II is reacted with chlorotrimethylsilane.

In the starting compounds of general formula II, R 1 may be azido, thiadiazolylthio (e.g., 1,3,4-thiadiazolylthio, 1,2,5-thiadiazolylthio or 1,3,5-thiadiazolylthio), oxadiazolylthio (e.g., 1.3 , 4-oxadiazolylthio, 1,2,5-oxadiazolylthio or 1,3,5-oxadiazolylthio) or tetrazolylthio (e.g., 1H-tetrazolylthio or 2H-tetrazolylthio).

Examples of salts of the compound of general formula II include the alkali metal salts such as the sodium or potassium salts, the alkaline earth metal salts, e.g., the calcium or magnesium salts, or the organic tertiary amine salts, e.g., triethylamine, trimethylamine, N-methylpiperazine or the like. 30 clays the pyridine salts.

Examples of bases which may be used in the reaction of the compound of general formula II with chlorotrimethylsilane are those bases which can form a salt of the compound of general formula II, in particular such bases as hydroxides, carbonates, bicarbonates , alkoxides or hydrides of alkali metals, eg of potassium or sodium, alkoxides, carbonates, bicarbonates and hydrides of alkaline earth metals, eg of calcium or magnesium, or organic tertiary amines, for example trimethylamine, triethylamine, N-methylpiperazine or pyridine.

The reaction is usually carried out in a solvent such as chloroform, dichloromethane or any other solvent which is inert under the reaction conditions. The reaction is carried out for stepwise in the range of room temperature up to 40 ° C, but the reaction temperature is not otherwise critical. Chlorotrimethylsilane is preferably used in an amount greater than 3 moles per ml. moles of the compound of general formula II. It is preferred to use the compound of general formula II in anhydrous form or to use chlorotrimethylsilane in a sufficient amount to eliminate the water contained in the compound of general formula II.

The compound (III) thus prepared is not isolated, but subjected to treatment with a halogenating agent. Examples of suitable halogenating agents are phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, phosgene or thionyl chloride. The reaction temperature is not critical, but the reaction is usually carried out under cooling.

The compound (IV) thus prepared is not isolated, but reacted with a lower alkanol. Examples of such lower alkanols are methanol, ethanol, propanol, butanol and pentanol. The reaction temperature is not critical, but the reaction is usually carried out in a range from room temperature down to cooling temperature.

The compound (V) thus prepared is not isolated, but is reacted with a compound of general formula VI in the presence of a condensing agent, or reacted with a reactive derivative of the compound of formula VI in the presence of an organic base. The compound having a carboxyl group is a compound of formula VI, wherein R2X- may be halogen, e.g. chloro or bromo, sydnylthio, eg sydnon-4-ylthio, sydnyloxy, eg sydnon-4-yloxy, sydnyl, tetrazolyl, e.g. tetrazolyl or 2H-tetrazolyl, tetrazolylthio, eg 1H-tetrazolylthio or 2H-tetrazolylthio, tetrazolyloxy, eg 1H-tetrazolyloxy or 2H-tetrazolyloxy, oxadiazolyl, eg 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl or 1,3,5-oxadiazolyl, oxadiazolylthio, e.g., 1,3,4-oxadiazolylthio, 1,2,5-oxa-diazolylthio, or 1,3,5-oxadiazolylthio, oxadiazolyloxy, e.g., 1,3,4-oxa-diazolyloxy, e.g. , 2,5-oxadiazolyloxy or 1,3,5-oxadiazolyloxy, thienyl, thienylthio, thienyloxy, phenyl, phenylthio, phenyloxy, thiadiazolyl, e.g., 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl or 1.3 , 5-thiadiazolyl, thia-diazolylthio, e.g., 1,2,5-thiadiazolylthio, 1,3,4-thiadiazolylthio or 1,3,5-thiadiazolylthio, and thiadiazolyloxy, e.g., 1,2,5-thiadiazolyloxy, thiadiazolyloxy or 1,3,5-thiadiazolyloxy.

Examples of the above reactive carboxyl group derivatives of the compounds of general formula VI are acid anhydrides, e.g. mixed anhydrides with lower alkyl carbonates or aliphatic carboxylic acids, acid chlorides or active esters, e.g. -ethoxyvinyl esters, propargy I esters, p-chlorophenyl esters and trichlorophenyl esters.

Examples of organic bases that can be used in this reaction are triethylamine, Ν, Ν-dimethylbenzylamine and pyridine. Examples of condensing agents which can be used in the reaction are alkyl-substituted pyridines, N, N-di-cyclohexylcarbodiimide or 25 Ν, di-diisopropylcarbodiimide. The reaction is preferably carried out at a temperature between room temperature and heating temperature.

It is possible to use the reaction mixture from the previous step as starting material. It is preferred as starting material for this reaction to use a reaction mixture from which excess 30 of halogenating agent and lower alkanol is distilled off under reduced pressure. If a reaction mixture is used from which excess halogenating agent has not been removed, it is preferable, prior to the reaction, to heat this reaction mixture to remove excess halogenating agent and excess alkanol or alternatively to add an excess amount of dimethylformamide to the reaction mixture. the excess of halogenating agent.

The compound (VII) thus prepared is not isolated but subjected to hydrolysis. The hydrolyzing reaction is usually carried out by pouring the reaction mixture from the previous step into water, preferably in the presence of an acid such as dilute hydrochloric acid or acetic acid, or a base, for example an alkali metal bicarbonate or a trialkylamine. The resulting compound, the 7-aminocephalosporanoic acid derivative of general formula I, can be isolated and purified in conventional manner.

The reactions of the present invention are preferably carried out under anhydrous conditions with the exception of the last hydrolysis reaction.

It is believed that the intermediates III, IV, V and VII resulting from the above reactions can be represented by the following formulas, wherein X, R1, R2 have the meanings given above, R3 represents hydrogen or (CH , Z "represents an anion and R * represents lower alkyl:

(CH3) 3Si-00C-CH- (CH2) 5-00NH —- ζ S N

HH-R3 J Jv 111 0 ^ 7 CH.-R1 COOSi (CH3) 5

(CH,), Si-00C-CH- (CH9), - C = N-j-S S N

1, 3 In Dr. JL IV

1 Cr ^ OHj-R1 COOSi (CH3) 3 (CH3) 3Si-00C-CH- (CH2) 3-C = N - | - <Snj I, I in NH-R3 0-R4) / ^ GHg-R1 0 COOSi (CH3) 3 77575 ra-R5 (OH,), Si-OOC-CH- (CHg), - CO-R4 \

2 vv + S

R -X-CH 2 -COH - {N VII

XCH2-R1 7Γ COOSi (CH3) 3

The process of the invention is further illustrated by the following examples: EXAMPLE 1 2.5 g of 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thio-5-methyl-3- cephem-4-carboxylic acid is suspended in 50 ml of dichloromethane.

0.6 ml of triethylamine, 3 ml of chlorotrimethylsilane and 4.3 ml of Ν, Ν-dimethylaniline are added. The mixture is stirred for 1 hour at room temperature, then 2.1 g of phosphorus pentachloride is added at -60 ° C. The mixture is stirred for 2 1/2 hours at a temperature between -40 and -50 ° C.

0.3 ml of Ν, Ν-dimethylaniline and 18 ml of n-butanol are added and the mixture is stirred for 1 hour at a temperature between -40 and -50 ° C. The dichloromethane is distilled off under reduced pressure at room temperature and the residue is concentrated under reduced pressure (2 mm Hg) at 40 ° C. The residue is suspended in 20 ml of dichloromethane, and 15 ml, with cooling, 5.1 ml of triethylamine are added. The mixture is stirred for 15 minutes at room temperature and then, with cooling, the mixed acid anhydride formed using 1.9 g of 1H-tetra-1-acetic acid, 2.1 ml of triethylamine, 1.7 g of trimethylacetyl chloride and 40 ml of tetrahydrofuran. The resulting mixture is stirred for 15 hours at room temperature and the solvent is distilled off under reduced pressure. The residue is poured into water and the aqueous solution is extracted with ethyl acetate, then the ethyl acetate phase is extracted with a saturated aqueous solution of sodium bicarbonate. To the extract is added ethyl acetate and the mixture is acidified by addition of hydrochloric acid. The ethyl acetate phase is separated, washed with water and dried over magnesium sulfate. The ethyl acetate is distilled off under reduced pressure. The residue is dissolved in ethyl acetate and ether is added to the solution. The precipitate is collected by filtration to give 0.23 g of yellow crystals of 7- (1H-tetrazol-1-yl) -acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) - thiomethyl-3-cephem-4-carboxylic acid, mp 130-140 ° C (dec.). UV Spectrum (Phosphate Buffer at pH 6.4): X 272 ΓΠ9Χ 15 nm, ε | Example 230 2.5 g of 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thio-methyl-3-cephem-4-carboxylic acid suspended in dichloromethane. Add 0.6 ml of triethylamine, 4 ml of chlorotrimethylsilane and 4.3 ml of N, N-dimethylaniline. The mixture is stirred for 1 hour at room temperature, then 2.1 g of phosphorus pentachloride is added at -60 ° C. The mixture is stirred for 2 1/2 hours at a temperature between -40 and -50 ° C. 0.3 ml of Ν, Ν-dimethylaniline and 18 ml of n-butanol are added and the mixture is stirred for 1 hour at a temperature between -40 ° C and -50 ° C. The dichloromethane 25 is distilled off under reduced pressure at room temperature and the residue is concentrated under reduced pressure (2 mm Hg) at 40 ° C. The residue is suspended in 20 ml of dichloromethane and 5.1 ml of triethylamine is added under cooling. The mixture is stirred for 15 minutes at room temperature and then, with cooling, the mixed acid anhydride obtained using 1.9 g of phenylacetic acid, 2.1 ml of triethylamine, 1.7 g of trimethylacetyl chloride and 40 ml of tetrahydrofuran is added.

The mixture is stirred for 15 hours and the solvent is distilled off under reduced pressure. The residue is poured into water and the aqueous solution is extracted with ethyl acetate, the extract in turn U7597 g being extracted with saturated aqueous solution of potassium bicarbonate and water being added to the extract. The extract is acidified by the addition of concentrated hydrochloric acid, whereupon the ethyl acetate phase is separated, washed with water and dried over magnesium sulfate. The ethyl acetate is distilled off under reduced pressure to give 1.35 g of a residue. This residue is dissolved in ethyl acetate and ether is added to the ethyl acetate phase. The precipitate is collected by filtration to give 0.47 g of pale yellow-red crystals of 7-phenylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4 carboxylic acid, mp 160-165 ° C (dec.). UV Spectrum (95% ethanol): Xmgx = 274 nm, = 245.

EXAMPLE 3 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate are added to 50 ml of dichloromethane. .

Add 0.6 ml of triethylamine, 10 ml of chlorotrimethylsilane and 4.3 ml of Ν, Ν-dimethylaniline and stir the mixture for 1 hour under reflux. 2.1 g of phosphorus pentachloride is added to the mixture, which is cooled with a mixture of dry ice and acetone, and then 0.3 g of Ν, Ν-dimethylaniline and 15 ml of absolute n-propanol are added at the same temperature.

The mixture is stirred for 30 minutes at the same temperature and then for 30 minutes at room temperature. To the mixture is added 5.5 ml of triethylamine and stirred for 15 minutes at room temperature, whereupon the solvent is distilled off under reduced pressure. A solution prepared by dissolving the residue thus obtained in 50 ml of dichloromethane and the addition of 4 ml of triethylamine is added to a solution prepared by stirring a solution of 3.2 g of 1H-tetrazole -1-acetic acid, 3.5 g (chloromethylene) dimethylene ammonium chloride and 4 ml dimethylformamide in 20 ml dichloromethane for 1 hour at room temperature and add 4.5 g triethylamine thereto under cooling with a mixture of dry ice and acetone with subsequent stirring of the mixture for 30 minutes at the same temperature. The resulting mixture is stirred for 2 hours, gradually allowing the temperature to rise to -20 ° C and then distilling off the solvent. The residue is poured into water and the aqueous solution is adjusted to pH 1.5 and extracted with ethyl acetate. The ethyl acetate phase is washed with water and extracted 3 times with water saturated with potassium bicarbonate solution.

The aqueous solution is washed with ethyl acetate and adjusted to neutral reaction by the addition of concentrated hydrochloric acid in the presence of ethyl acetate. The ethyl acetate phase is washed twice with water and dried over magnesium sulfate. The solvent is distilled off and the oily residue is washed with ether and dissolved in ethyl acetate. To the solution is added ether under cooling and the precipitate is washed with ether and dried to give 0.933 g of pale yellow crystals of 7- (1H-tetrazol-1-yl) -acetamido-3- (5-methyl-1,3,4). -thiadiazo-2-yl) -thio-methyl-3-cephem-4-carboxylic acid, mp 129-138 ° C.

Example 4 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate are suspended in 50 ml of dichloromethane -15 an, and to the mixture are added 0.6 ml of triethylamine, 7 ml of chlorotrimethylsilane and 4.3 ml of Ν, Ν-dimethylaniline. The mixture is stirred for 1 hour under reflux, then phosphorus pentachloride is added under cooling at -50 ° C with a mixture of acetone and dry ice. The mixture is stirred for 2 hours at the same temperature, then a solution of 0.3 ml of Ν, Ν-dimethylaniline in 16 ml of methanol is added. The resulting mixture is stirred for 30 minutes at room temperature. To the mixture is added, under cooling, 5 ml of triethylamine and stirred for 15 minutes, after which the solvent is distilled off under reduced pressure. To the residue is added 40 ml of dichloromethane. This solution 25 is added to a solution prepared by stirring a solution of 3 g of dicyclohexylcarbodiimide and 3.84 g of 1 H-tetrazole-1-acetic acid in 30 ml of tetrahydro uranium under cooling for 1 hour. The resulting solution is stirred for 1 hour at 0-5 ° C and then for 1 hour at room temperature. The solvent is evaporated under reduced pressure, and to the residue is added water, and the aqueous solution is extracted with ethyl acetate. The ethyl acetate phase is washed with water and extracted with potassium bicarbonate saturated water. The extract is acidified by addition of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with water saturated with sodium chloride, dried and concentrated by distillation. The oily residue is treated with ether to give 1.124 g of crystals of 7- (1H-tetrazol-1-yl) -acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl 3-cephem-4-carboxylic acid.

EXAMPLE 5 0.6 ml of triethylamine, 6 ml of chlorotrimethylsilane and 4.3 ml of N, N-dimethyl-aniline are added to a solution of 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5- methyl, 3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate in 50 ml of dichloromethane. The mixture is stirred for 1 hour under reflux and 2.1 g of phosphorus pentachloride is added under vigorous stirring at -50 ° C. The resulting mixture is further stirred for 2 hours at the same temperature and then, with cooling at -20 ° C, a mixture of 0.3 ml of Ν, Ν-dimethylaniline and 15 ml of methanol is added.

The solution is stirred for 30 minutes at a temperature between -40 and 15 -50 ° C and then for 30 minutes at room temperature, whereupon the solvent is distilled off under reduced pressure. The residue is suspended in 50 ml of dichloromethane and 6 ml of triethylamine is added under cooling at a temperature between -10 and -15 ° C. The mixture is stirred for 10 minutes and 4 g of thiophene-2-acetyl chloride is added. The mixture 20 is stirred for 2 hours at the same temperature and the solvent is distilled off under reduced pressure. The residue is poured into water and the aqueous solution is extracted with ethyl acetate. The extract is washed with water and extracted with water saturated with potassium bicarbonate. The aqueous solution is acidified by the addition of hydrochloric acid with cooling, washed with water saturated with sodium chloride and dried. The solvent is distilled off under reduced pressure. The residue is treated with ether to give 1.33 g of crystals of 7- (2-thienyl) -acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid. IR Spectrum (nujol): 3300, 1780, 1720, 1655 and 1530 cm -1.

EXAMPLE 6 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate are suspended for 30 minutes. ml of dichloromethane, and 0.4 ml of triethylamine, 30 ml of N, N-dimethylaniline 5 and 4.0 ml of chlorotrimethylsilane are added. The mixture is stirred for 1 hour under reflux and 2.2 g of phosphorus pentachloride is added under cooling at -50 ° C. The mixture is stirred for 2 hours at the same temperature and 0.3 ml of Ν, Ν-dimethylaniline and 15 ml of methanol are added. The mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. The reaction mixture is concentrated under reduced pressure and 30 ml of dichloromethane are added to the residue. The resulting mixture is added at once to a solution prepared by reacting 2.0 g of 1H-tetrazole-1-acetic acid with 1.9 g of pivaloyl chloride in a solution of 2.2 ml of triethylamine and 50 ml of tetrahydrofuran , under cooling at a temperature between -5 and 0 ° C. Immediately thereafter, 5.5 ml of triethylamine are added to the mixture at the same temperature and the mixture is stirred for 1 hour at this temperature, where it is left to stand overnight. The solvent is evaporated under reduced pressure and water is added to the residue. The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water saturated with sodium chloride and then extracted with water saturated with sodium bicarbonate. The extract is acidified by adding hydrochloric acid to pH 2.0 and extracted with ethyl acetate. The ethyl acetate phase is washed with water saturated with sodium chloride, dried and concentrated under reduced pressure. The oily residue is washed with ether to give 1.19 g of a yellow powder of 7- (1H-tetrazol-1-yl) -acetamido-3- (5-methyl-1,3,4-thiadiazole) - 2-yl) -thiomethyl-3-cephem-4-carboxylic acid, mp 95-100 ° C.

EXAMPLE 7 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate are suspended in 30 ml. dichloromethane, and to the suspension are added 0.4 ml of triethylamine, 30 ml of N, N-dimethylaniline and 4.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux, then 2.2 g of phosphorus pentachloride is added under cooling at a temperature between -50 and -40 ° C. The mixture is stirred for 2 hours at the same temperature and 0.3 ml of Ν, Ν-dimethylaniline and 15 ml of methanol are added. The mixture is then stirred for 5 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. After the addition of 2.5 ml of triethylamine, the reaction mixture is concentrated under reduced pressure and 30 ml of dichloromethane are added to the residue. The resulting mixture is added at once to a solution prepared by treating 2.75 g of 1,3,4-thiadiazole-2-thioacetic acid with 1.9 g of pivaloyl chloride in a mixture of 2.2 ml of triethylamine and 50 ml of tetrahydro uranium for 1 hour under cooling at a temperature between -5 and 0 ° C and then add 3.0 ml of triethylamine. The reaction mixture is stirred for 1 hour at the same temperature and then left overnight. The solvent is distilled off under reduced pressure and water is added to the residue. The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water. The ethyl acetate phase is extracted with water saturated with sodium bicarbonate. The extract is acidified by addition of hydrochloric acid under cooling and extracted with ethyl acetate. The ethyl acetate phase is washed with 20 saturated sodium chloride water, dried and concentrated under reduced pressure. The oily residue is washed with ether to give 0.549 g of a yellow powder of 7- (1,3,4-thiadiazol-2-yl) -thioacetamido-3- (5-methyl-1,3,4-thiadiazole). 2-yl) -thiomethyl-3-cephem-4-carboxylic acid, m.p. 90-95 ° C.

EXAMPLE 8 2.55 g of sodium 7- (5-aminoadipinamido) -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylate are suspended in 30 ml of dichloromethane and added The suspension is added 0.4 ml of triethylamine, 3.0 ml of Ν, Ν-dimethylaniline and 4.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux, then 2.2 g of phosphorus pentachloride is added under cooling at a temperature between -50 and -40 ° C. The resulting mixture is stirred for 2 hours at the same temperature, then 3.0 ml of ml, Ν-dimethylaniline and 15 ml of methanol are added. The mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. The reaction mixture is concentrated under reduced pressure and 30 ml of dichloromethane and 5.5 ml of triethylamine are added to the residue. The resulting mixture is added to a solution of 2.5 g of 2-thienylacetyl chloride in 50 ml of tetrahydro-uranium at a temperature between 5 and 0 ° C, and the reaction mixture is stirred for 1 hour at room temperature and then left overnight. The solvent is distilled off under reduced pressure and water is added to the residue. The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water and then extracted with water saturated with sodium bicarbonate. The extract is acidified by addition of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with water saturated with sodium chloride, dried and concentrated under reduced pressure. The oily residue is washed with ether to give 0.249 g of powdered 7- (2-thienyl) -acetamido-3-n-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid, m.p. 87-91 ° C.

Example 9 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methylthio-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate are suspended. in 30 ml of di-20 chloromethane and to the suspension are added 0.3 ml of triethylamine, 2.2 ml of Ν, Ν-dimethylaniline and 3.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux and 1.0 g of phosphorus pentachloride is added under cooling at a temperature between -40 and -50 ° C. The resulting mixture is stirred for 2 hours at the same temperature and 0.15 ml of Ν, Ν-dimethylaniline and 7.5 ml of methanol are added. The mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. The mixture is concentrated at reduced pressure and 30 ml of dichloromethane and 2.3 ml of triethylamine are added to the residue. The resulting mixture is added to a solution prepared by treating a solution of 1.76 g of sydnon-3-acetic acid in 50 ml of tetrahydrofuran with a solution of 2.5 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran in 10 ml. minutes under cooling at a temperature between -5 ° C and 0 ° C. The resulting reaction mixture is stirred for 1 hour at the same temperature and then left overnight. The solvent is equilibrated under reduced pressure and water is added to the residue. The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water and extracted with water saturated with sodium bicarbonate. The extract is acidified by the addition of hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is washed with water which is saturated with sodium chloride, dried and concentrated under reduced pressure. The oily residue is washed with ether to give 0.234 g of powdered 7- (sydnon-3-yl) -acetamido-3- (5-methylthio-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -10 4-carboxylic acid, mp 163-168 ° C.

EXAMPLE 10 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate are suspended in 30 ml of dichloromethane. -an, and to the suspension are added 0.4 ml of triethylamine, 3.0 ml of N, N-dimethylaniline and 4.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux, then 2.2 g of phosphorus pentachloride is added under cooling at a temperature between -40 and -50 ° C. The mixture is stirred for 2 hours at the same temperature and 0.3 ml of Ν, Ν-dimethylaniline and 15 ml of methanol are added. The resulting mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. The mixture is concentrated under reduced pressure and to the residue are added 15 ml of dichloromethane, 50 ml of tetrahydrofuran and 5.5 ml of triethylamine. The resulting solution is added to a suspension of 2.4 g of 2-bromoacetyl chloride in 15 ml of dichloromethane 25 under cooling at a temperature between -5 and 0 ° C, and the reaction mixture is stirred for 3 hours at the same temperature and then left overnight. The solvent is distilled off under reduced pressure and water is added to the residue. The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water and then extracted with water saturated with sodium bicarbonate. The extract is acidified by addition of hydrochloric acid under cooling and extracted with ethyl acetate. The ethyl acetate phase is washed with water saturated with sodium chloride, dried and concentrated under reduced pressure. The oily residue is washed with ether to give 0.525 g of powdered 7- (2-bromoacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid, mp 135-143 ° C.

Example 11 2.55 g of sodium 7- (5-aminoadipinamido) -3- (5-methyl-1,3,4-oxadiazol-2-5-yl) -thiomethyl-3-cephem-4-carboxylate are suspended in 30 ml. dichloromethane, and to the suspension are added 0.4 ml of triethylamine, 3.0 ml of N, N-dimethylaniline and 4.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux, then 2.2 g of phosphorus pentachloride is added under cooling at a temperature between -40 and -50 ° C. The mixture is stirred for 2 hours at the same temperature and 0.3 ml of Ν, Ν-dimethylaniline and 15 ml of methanol are added. The mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. The resulting mixture is concentrated under reduced pressure and 50 ml of dichloromethane and 3.0 ml of triethylamine are added to the residue. The resulting solution is cooled to a temperature between -10 and -15 ° C and added dropwise to 4.0 g of phenylacetyl chloride, and the reaction mixture is stirred for 2 hours at the same temperature and left overnight. The solvent is distilled off under reduced pressure and water is added to the residue. The aqueous solution 20 is extracted with ethyl acetate and the ethyl acetate phase is washed with water and extracted further with water saturated with sodium bicarbonate.

The extract is acidified by addition of hydrochloric acid under cooling and then extracted with ethyl acetate. The ethyl acetate phase is washed with water saturated with sodium chloride, dried and concentrated under reduced pressure. The oily residue is washed with ether to give 0.284 g of powdered 7-phenylacetamido-3- (5-methyl-1,3,4-oxadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid, m.p. 113 ° C.

EXAMPLE 12 2.0 g of sodium 7- (5-aminoadipinamido) -3-azidomethyl-3-cephem-4-carboxylate are suspended in 30 ml of dichloromethane and to the suspension 0.4 ml of triethylamine, 3, is added. 0 ml of N, N-dimethylaniline and 4.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux, then 2.2 g of phosphorus pentachloride is added under cooling at a temperature between -40 and -50 ° C. The resulting mixture is stirred for 2 hours at the same temperature and 0.3 ml of N, N-dimethylaniline and 15 ml of methanol are added. The mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and then for 30 minutes at room temperature. The mixture is concentrated under reduced pressure and 50 ml of dichloromethane and 3.0 ml of triethylamine are added to the residue. The resulting solution is cooled to a temperature between -5 and 0 ° C and added dropwise to 1.5 g of 3-methyl-1,2,5-oxadiazole-4-acetyl chloride, then the reaction mixture is stirred for 2 hours at the same temperature and then left over overnight. The solvent is evaporated under reduced pressure and water is added to the residue. The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water and further extracted with water saturated with sodium bicarbonate. The extract is acidified by adding hydrochloric acid under cooling and then extracted with ethyl acetate. The ethyl acetate phase is washed with water saturated with sodium chloride, dried and concentrated under reduced pressure. The oily residue is dissolved in dichloromethane and a small amount of ether is added. The mixture is left to cool. The precipitate is isolated by filtration and washed with ether to give 0.434 g of crystals of 7- (3-methyl-1,2,5-oxadiazol-4-yl) -acetamido-3-azidomethyl-3-cephem-4-carboxylic acid, Mp 115-120 ° C.

EXAMPLE 13 2.5 g of sodium 7- (5-aminoadipinamido) -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate are suspended in 30 ml of dichloromethane, and To the suspension are added 0.4 ml of triethylamine, 3.0 ml of N, N-dimethylaniline and 4.0 ml of chlorotrimethylsilane. The mixture is stirred for 1 hour under reflux, then 2.2 g of phosphorus pentachloride is added under cooling at -50 ° C. The resulting mixture is stirred for 2 hours at the same temperature and 0.3 ml of N, N-dimethylaniline and 15 ml of methanol are added. The mixture is stirred for 30 minutes at a temperature between -50 and -40 ° C and for 30 minutes at room temperature. The mixture is then concentrated under reduced pressure and 30 ml of dichloromethane are added to the residue. The resulting solution is added at once to a solution prepared by treating 2.7 g of 5-methyl-1,3,4-thiadiazo-2-oxyacetic acid with 1.9 g of pivaloyl chloride in a mixture of 2 , 2 ml of triethylamine and 50 ml of tetrahydro uranium under cooling at a temperature between -5 and 0 ° C. Immediately thereafter, 3.0 ml of triethylamine is added and the reaction mixture is stirred for 1 hour at the same temperature and then left overnight. The solvent 10 is distilled off under reduced pressure and water is added to the residue.

The aqueous solution is extracted with ethyl acetate and the ethyl acetate phase is washed with water and extracted with water saturated with sodium bicarbonate. The extract is acidified by addition of hydrochloric acid under cooling and extracted with ethyl acetate. Ethyl acetate is washed with 15 saturated sodium chloride water, dried and concentrated under reduced pressure. The oily residue is dried in ether and additional ether is added until the solution turns white and the solution is cooled. The precipitate formed is isolated by filtration to give 5.84 g of crystals of 7- (5-methyl-1,3,4-thiadiazol-2-20 yl) oxyacetamido-3- (1,3,4-thiadiazole) 2-yl) -thiomethyl-3-cephem-4-carboxylic acid, mp 105-110 ° C.

Claims (2)

147597 A process for the preparation of 7-aminocephalosporanic acid derivatives of the general formula I R2-X-CH2-CONH - | - ^ New Ny CH2-R1 COOH wherein R 1 represents azido, thiadiazolylthio or oxadiazolylthio, wherein the 5 thiadiazole and oxadiazole nuclei substituted with C 1-6 alkyl or C 1-6 alkylthio, or tetrazolylthio, wherein the tetrazole cores are optionally substituted with C 1-6 alkyl, X represents a sulfur or oxygen atom or a single bond, and R 2 represents halogen or southnyl, tetrazolyl, oxadiazolyl, thienyl, phenyl or thiadiazolyl, which groups are optionally substituted with C1-6 alkyl or C1-6 alkylthio, however, where nitrile and tetrazolyl are only optionally substituted with C1-6 alkyl when X represents sulfur or oxygen, with the proviso that when R 2 is halogen, X represents a single bond, or salts thereof, thereby reacting a compound of the general formula II hooc-ch- (ch 2) 3-conh - τ 'SS I L_N J 11 ^ 1 2. gh2-r COOH