DE2055796A1 - Process for the preparation of 7 aminocephalosporanic acid derivatives - Google Patents

Description

Fujikawa Pharmaceutical Co., Ltd.

Representative: Sabüro Hayakawa

ITo. 3, Dosho-raachi, 4-Chorae, Higashi-ku, Osaka / Japan

Process for the preparation of 7-aminocephalosporanic acid derivatives

The present invention relates to a new process for the preparation of 7-aminocephalosporanic acid derivatives of the general formula

E ₂ -X-OH ₂ -CONH

(D

COOH

wherein R ^ is azido, thiadiazolylthio, oxadiazolylthio or tetrazolylthio; X (Dhio, oxy or a single bond; R _{2 represents} halogen, sydnone, tetrazolyl, oxadiazolyl, thienyl, phenyl or thiadiazolyl., Where X represents a single bond when R _{2 represents} a halogen atom,

and of pharmaceutically acceptable salts of these derivatives, wherein the method according to the invention characterized

- 2-

net is that ε a n aas reaction product (of the formula VII) hydrolyzes, the aan gets, if, a connection öer Eornel

HOOC-GH- (CH ₂ ), - COHH

(II)

COOH

where E ^ has the same meaning as above,

in the presence of a base with chlorotrimethylsilane or a Reacted salt of the compound of the formula II with chlorotrimethylsilane, the compound of the formula III obtained with reacted with a halogenating agent, the resulting compound of formula IV with a lower one Reacted alkanol and the resulting compound of the formula V with a compound of the formula

E ₂ -X-CH ₂ -COOH

(VI)

where E ₂ and X have the same meaning as above,

in the presence of a condensing agent, or with? a derivative / compound reactive with respect to the carboxyl group of the formula V is reacted in the presence of an organic base.

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 Dutch patent application No. 6,805,179. Other analog output connections can also be found in

205579R

in a similar manner as in accordance with that in the cited literature parts described method are produced.

The compounds of the formula I obtained according to the process of the invention are known compounds (compare, for example, Dutch patent application Kr. 6,805,179). According to this reference, the compounds obtained according to the invention have been prepared as follows: For example, the 7- (1H-! Tetrazol-1-yl) acetamido-5- (5-2ie "fcbyl-1,3 * 4-thiadiazole- 2-yl) thiomethyl-3-cephem-4-carboxylic acid prepared by hydrolysis of 7- (5- = fiEunoadipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid (which corresponds to the starting compound of the formula II according to the present invention). Then the 7-amino-3- (5 "" ^ri ethyl-'1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid reacted with "IH-tetrazole-1-acetic acid. According to these known processes, it is unavoidable to isolate the 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid as an intermediate product, since otherwise 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 compound.

The present invention is accordingly a method which is characterized in that the desired Compounds of the formula I can be obtained directly in higher yields without intermediate products, d. H. the connections of the formulas (III), (IV), (V) and (VII) would have to be isolated.

When carrying out the reaction according to the present invention, a compound of the formula II is first used with Chlorotrimethylsilane reacted in the presence of a base or a salt of a compound of the formula II with chlorotrimethylsilane.

Starting compounds for this reaction are those compounds of the formula II in which IL _{1 is} one of the following
Groups: 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),
and tetrazolylthio (e.g. 1H-tetrazolylthio or 2H-tetra-

pi J- '■■■ r>

zolylthio), in which the thiadiazole and oxadiazoP / lower
Can carry alkyl groups or lower alkylthio groups,
and wherein the tetrazole nucleus can carry lower alkyl.
In the sense of the above definition, lower alkyl groups and the lower alkyl parts of the lower alkylthio groups are understood to mean straight-chain and branched monovalent hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl
or pentyl.

Examples of salts of the compounds of formula II are
Alkali metal salts (for example sodium or potassium salts), alkaline earth metal salts (for example salt or magnesium salts) or salts with organic tertiary amines (for example triethylamine, trimethylamine, N-methylpiperazine or pyridine salts).

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

bicarbonate, alkoxide and hydride, an alkaline earth metal (e.g. Calcium or magnesium) alkoxide, carbonate, bicarbonate and

hydride, or an organic tertiary amine (e.g. trimethylamine, Triethylamine, N-methylpiperazine or pyridine).

1098 ?? /? 216

The reaction is usually carried out in a solvent such as chloroform, dichloromethane. It is also possible to use other solvents which are inert to the reaction. The reaction is preferably carried out in the range between room temperature and 40 ⁰ C. However, there is no particular limitation on the reaction temperature. The chlorotrimethylsilane is preferably used in an amount of more than 3 moles per mole of the compound II. It is also preferred to use the compound of the formula II in anhydrous form. Otherwise it is preferred to use the chlorotrimethylsilane in such an amount that any water contained in compound II is eliminated.

The compound of formula III thus prepared is used without isolation treated with a halogenating agent. Examples of halogenating agents are phosphorus trichloride, phosphorus pentachloride, Phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, Phosgene or thionyl chloride. Here, too, there is no particular limitation with regard to the reaction temperature. Usually, however, the reaction takes place under cooling executed.

The compound of the formula IV thus obtained is subjected to a further reaction with a lower alkanol without being isolated. Examples of lower alkanols are methanol, ethanol, propanol, butanol or pentanol. There is none particular limitation with regard to the reaction temperature. Usually, however, the reaction will take place at room temperature or supercooling.

The compound of the formula V prepared in this way is, without isolation, a further reaction with a compound of Formula VI in the presence of a condensing agent or with

subjected to a reactive derivative thereof in the presence of an organic base. In the compounds of the formula VI, the group IL ^ X- for halogen (e.g. chlorine or bromine), sydnonthio (e.g. sydnon-4 ~ ylthio), sydnonoxy (e.g. sydnon-4-yloxy) , Sydnone, tetrazolyl (e.g. 1H-tetrazolyl or 2H-tetrazolyl), tetrazolylthio (e.g. IH-tetrazolylthio or 2H-tetrazolylthio), tetrazolyloxy (e.g. "IH-tetrazolyloxy or 2H-tetrazolyloxy), oxadiazolyl (e.g. 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl or 1,3,5-oxadiazolyl), oxadiazolylthio (e.g. 1,3,4-oxadiazolylthio, 1,2,5- Oxadiazolylthio or 1,3,5-oxadiazolylthio), oxadiazolyloxy (e.g. 1,3,4-oxadiazolyloxy, 1,2,5-oxadiazolyloxy or 1,3,5-oxadiazolyloxy), thienyl, thienylthio, thienyloxy, phenyl, Phenylthio, phenyloxy, thiadiazolyl (e.g. Λ , 3,4-TMadiazolyl, 1,2,5-thiadiazolyl or 1,3,5-thiadiazolyl), thiadiazolylthio (e.g. 1,2,5-thiadiazolylthio, 1 , 3,4 ~ Ttd.adiazolylthio or 1,3,5-thiadiazolylthio), and thiadiazolyloxy (e.g. 1,2,5-thiadiazolyloxy, 1,3,4-thiadiazolyloxy or 1,3,5-thiadiazolyloxy) . Of the above mentioned These groups can be any of the following groups: sydnone, tetrazolyl, oxadiazolyl, oxadiazolylthio, oxadiazolyloxy, thienyl, thienylthio, thienyloxy, phenyl, phenylthio, phenyloxy, thiadiazolyl, thiadiazolylthio and thiadiazolyloxy or a lower alkylthio group. Each of the groups sydnonthio, sydnonoxy, tetrazolylthio and tetrazolyloxy can carry a lower alkyl group. In this sense, the lower alkyl groups and the lower alkyl parts of the lower alkylthio groups can be straight-chain and branched monovalent hydrocarbon groups having 1 to 6 carbon atoms, such as methyl, propyl, isopropyl, butyl, isobutyl, perityl.

Examples of the above-mentioned derivatives of the compounds 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, white

109827/2216

therhin acid chlorides, active esters v / ie cyanomethyl esters, Pentachlorophenyl ester, methanesulfonyl ester, methoxymethyl ester, Vinyl ester, 1-methoxy vinyl ester, 1-ithoxy vinyl ester, Propargyl ester, p-chlorophenyl ester, trichlorophenyl ester etc.

Examples of organic bases which can be used in this reaction are triethylamine, N, N ~ dimethylbenzylamine or pyridine. Examples of condensing agents that can be used in this reaction are by Alkyl substituted pyridine, N, N-di-cyclohexylcarbodiimide or Ν, Ν-di-isopropylcarbodiimide. The reaction is preferred carried out at room temperature or with warming.

According to the invention it is possible to use the reaction mixture from the previous step as starting material. It is preferred to use the reaction mixture from the excess halogenating agent in this reaction and lower alkanol have been distilled off under reduced pressure. If this is not removed have been, it is preferred to heat the reaction mixture of the previous step to remove excess Halogenation »! ittel and excess lower alkanol to eliminate, or alternatively to add an excess amount of dimethylformamide to the reaction mixture, to eliminate the excess halogenating agent.

The compounds of the formula VII prepared in this way are subjected to hydrolysis without being isolated. The hydrolysis reaction is usually carried out by pouring the reaction mixture from the previous step into water v.'ird, preferably in the form of an acid such as dilute hydrochloric acid or acetic acid, or a base such as an alkali metal bicarbonate or a trialkylamine. the

1098 ?? / ?? 16

obtained compound, the 7-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 preferably carried out under anhydrous conditions with the exception of the last stage of hydrolysis. It is believed, that the intermediates of the formulas III, IV, V and VII, which are used in the above-described reaction stages are obtained, correspond to the following formulas, in which X, R ^ and E2 have the same meaning as above, Rv represents hydrogen or (CHv) ^ Si-, I represents a halogen and Z ~ is an anion and R ^, a lower alkyl group represents.

(CH,), Si-OOC-CH- (CH ₀ ), ~ COKH Jj ι £ J

BH-R,

(III)

COOSi (CH ₅ )

(GH,), Si-OOC-CH- (CH ₀ ), - C = Ii jj j 2 3 ι

NH-R,

COOSi (CH,).

(CH,), Si-OOC- ^ i- (CH ₀ )., - C = H 3 3 Zo

NH-R.

0-R,

NH-R.

(CH _x ), Si-OOC-CH- (CH ₀ ) "- C-0-R,

²³ yt

R ₂ -X-CH ₂ -COlT

COOSi (CH,),

COOSi (CH,)

(V)

(VII)

- 10 -

109822/2216

The invention is further illustrated by the following examples:

example 1

7- (5-Aminoadipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (2.5 g) was dissolved in dichloromethane (50 ml). Triethylamine (0.6 ml), chlorotrimethylsilane (3 ml) and Ν, Ν-dimethylaniline (4.3 ml) were added. The mixture was stirred at room temperature for one hour. Then at - 60 ⁰ C. Phosphorus pentachloride (2.1 g) was added. The mixture was 2.5 hours at - stirred 50 ⁰ C - 40 to. Then, Ν, Ν-dimethylaniline was added (0.3 ml) and n-butanol (18 ml), and the mixture was for one hour at - stirred 50 ⁰ C - 40 to. The dichloromethane was distilled off under reduced pressure at Zimmertempertur, and the residue was concentrated under reduced pressure (2 τηTnH g) 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 at room temperature for 15 minutes. Then the mixed acid anhydride formed from 1H-tetrazole-1-acetic acid 0.9 g) 5 triethylamine (2.1 ml), trimethylacetyl chloride Ο x 7 g) 1 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

- 11 109827/2216 *

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)" acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-car'bonsäure, F. 130 · ⁰ to 140 C (dec.) UV spectrum (phosphate buffer pH 6.4).

71

Max

272 m / rev

,1%
'1 cm

230

Example 2

7- (5-Aminoadipamido) -3- (5-methyl-1,3,4-thiadiaol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (2.5 g) was dissolved in dichloromethane. Triethylamine (0.6 ml), Ghlortrimethylsilan (4 ml) and N, N-dimethylaniline (4.3 ml) was added thereto. The mixture was stirred for one hour at room temperature and phosphorus pentachloride (2.1 g) was then added at -60 ⁰ C. The mixture was stirred 50 ⁰ C. Then, Ν, was added Ν-dimethylaniline (0.3 ml) and n-butanol "(18 ml), and the mixture was for one hour at - - 2.5 hours at - 40 to. stirred 50 ⁰ C - 40 to . The dichloromethane was distilled off under reduced pressure at room temperature, and the residue was further concentrated ^{under reduced pressure (2 mmHg) at 40 ° G.} The residue was suspended in dichloromethane (20 ml). Then, iriethylamine (5.1 ml) was added thereto with cooling. The mixture was stirred at room temperature for 15 minutes. Then the mixed acid anhydride formed from IH-tetrazol-1-acetic acid O.9 g), triethylamine (2.1 ml), trimethylacetyl chloride O-7 g), and tetrahydrofuran (40 ml) was added with cooling. The mixture was stirred for 15 hours and the solvent was then distilled off under reduced pressure. The residue was poured into water and the aqueous solution was extracted with ethyl acetate.

- 12 -

BATH ORIGINAL

The extract was extracted with a saturated aqueous solution of potassium bicarbonate. Water was added to the extract. The extract was acidified by adding concentrated 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 to give a residue (1.35 g). This residue was dissolved in ethyl acetate. Thereto ether was added and the precipitate was collected by filtration. Pale yellowish red crystals were obtained from (0.47 g) 7-phenylacetaj3iido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, mp 160 bis 165 ⁰ C (dec.).
UV spectrum (95% ethanol):

7V.

Max

274 m / rev

1%

E.

'1 cm

245

Example 3

Sodium 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 s) was added to dichloromethane (50 ml). Triethylamine (0.6 ml), chlorotrimethylsilane (10 ml) and N, N-dimethylaniline were added (4.3 ml) was added and the mixture was stirred under reflux for one hour. Phosphorus pentachloride was added to this mixture (2.1 g) added while cooling with a mixture of dry ice and acetone. At the same temperature were to this mixture N, N-dimethylaniline (0.3 g) and absolute n-propanol (15 ml) added. The mixture was Stirred for 30 minutes at the same temperature and then for 30 minutes at room temperature. Then became the mixture Triethylamine (5.5 ml) was added and it was 15 minutes at Stirred at room temperature. Then the solution

- 13 109827/2216

medium distilled off under reduced pressure. The residue obtained was dissolved in dichloromethane (50 ml) and triethylamine (4 ml) was added thereto. The solution thus obtained was added to a solution which had been prepared by adding a solution of 1H-tetrazole-1-acetic acid (3.2 g), (chloromethylene) dimethylene ammonium chloride (3 x 5 s) and dimethylformamide (4 x ml) stirred in dichloromethane (20 ml) for one hour at room temperature, to this, while cooling with a mixture of dry ice and acetone, triethylamine (4-5 g) was added and the mixture was stirred for 30 minutes at the same temperature. The resulting mixture was stirred for 2 hours, wherein the temperature to rise gradually to -20 ⁰ G was allowed. Then the solvent was distilled off. The residue was poured into water and the aqueous solution was adjusted to pH 1.5 and extracted with ethyl acetate. The ethyl acetate was washed with water and extracted three times with an aqueous saturated solution of potassium bicarbonate. The aqueous solution was washed with ethyl acetate and neutralized by adding concentrated hydrochloric acid in the presence of ethyl acetate. The ethyl acetate was washed twice with water and dried over magnesium sulfate. Then the oily residue was washed with ether and dissolved in ethyl acetate. Ether was added to the solution with cooling, and the deposited precipitate was washed with ether and dried, pale yellowish crystals of (0.933 S) 7- (1H-tetrazol-1-yl) acetamido-3- (5-methyl) being obtained -1.3 * 4- thiadiazol-2-yl) thiomethyl-3-cephem-4 ~ carboxylic acid, mp 129-138 ⁰ C.

Example 4 ■.

Sodium 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 s) would be suspended in dichloromethane (50 ml) and to this mixture were added triethylamine (0.6 ml), chlorotrimethylsilane

109822/2216

(7 ml) and Ν, Ν-dimethylaniline (4.3 ml). The mixture was stirred under reflux for one hour. Then was under.

Cooling to -5P ⁰ C by means of a mixture of acetone and

.f QO ₁ κ nii or

Add dry ice / pentachloride. The mixture was stirred at the same temperature for two hours. Then a solution of N, N-dimethylaniline (0.3 ml) in methanol (16 ml) was added. The mixture was stirred for 30 minutes under cooling to -40 ⁰ G and then 30 minutes at room temperature. To this mixture was then added triethylamine (5 ml) with cooling, and the mixture was stirred for 15 minutes. The solvent was then distilled off under reduced pressure. Dichlorinethane (40 ml) was added to the residue. The solution was added to another solution prepared by stirring a solution of dicyclohexylcarbodiimide (3g) and voletrazole-1-acetic acid (3.84g) in tetrahydrofuran (30ml) with cooling for one hour. The solution was stirred for one hour at 0 to 5 ^° C. and then for one hour at room temperature. The solvent was distilled off under reduced pressure. Water was added to the residue and the aqueous solution was extracted with ethyl acetate. The ethyl acetate layer was 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 washed with an aqueous saturated saline solution, dried and concentrated by distillation. The oily residue was treated with ether, whereby crystals (1,124 g) of 7- (1H-tetrazol-1-yl) acetamido-3 ~ (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3 -cephem-4-carboxylic acid.

Example 5

Triethylamine (0.6 ml), chlorotrimethylsilane (6 ml) and N, N-dimethylaniline (4.3 ml) were added to a solution of

- 15 -

109822/2216.

'Sodium 7 ~ (5-aminoadipamido) -3- (5-methyl-1,3,4-- · fcüiadiazol-2-yl) tMQmethyl-3-ceph.em-4-carboxylate (2.55 s) in. Given dichloromethane (50 ml). The mixture was stirred under reflux for one hour. Phosphorus pentachloride (2.1 g) was then added at -50 ° G with vigorous stirring. The mixture was stirred for a further two hours at the same temperature. Then, a mixture of N, N-dimethylaniline (0.3 ml) and methanol (15 ml) under cooling to -20 ⁰ 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 for two hours at the same temperature. 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, washed with an aqueous solution of sodium chloride and dried. The solvent was distilled off under reduced pressure. The residue was treated with ether to obtain crystals of (1.33 g) 7- (oc-thienyl) acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-ceph .em-4-carboxylic acid. IR spectrum (Nujol) :

3300, 1780, 1720, 1655 and 1530 cm

-1

- 16 -

109822/2216

Example 6

Sodium 7- (5-aminoadipamido) -3- (5-methyl-1,3 »4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 g) was dissolved in dichloromethane (30 ml) suspended. Triethylamine (0.4 ml), Ν, Ν-dimethylaniline (30 ml) and chlorotrimethylsilane (4.0 ml) were added. The mixture was stirred under reflux for one hour. Then was added (2.2 g) under cooling to -50 ⁰ C phosphorus pentachloride. The mixture was stirred at the same temperature for two hours. Then Ν, Ν-dimethylaniline (0.3 ml) and methanol (15 ml) were added. The mixture was stirred at -50 30 minutes - stirred -40 ⁰ C and 30 minutes at room temperature. Then the reaction mixture was concentrated under reduced pressure. Dichloromethane (30 ml) was added to the residue. This mixture was added all at once to a solution which had been prepared by reacting 1H-tetrazole-1-acetic acid (2.0 g) with pivaroyl chloride (1.9 g) in a solution of triethylamine (2.2 ml) and tetrahydrofuran (50 ml) with cooling to -5 to 0 ⁰ G. Immediately thereafter was added triethylamine (5.5 ml) at the same temperature to this mixture, and the mixture was one hour at the

touched

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, it was extracted with an aqueous saturated solution of sodium bicarbonate. 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 concentrated under reduced pressure. The oily residue was washed with Ether washed, leaving a yellowish powder of (1.19 g) 7- (1H-tetrazol-1-yl) acetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem -4-carboxylic acid, m.p. 95 "to 100 ^° C.

became.
- 17 -

109822/2216

Example y ■

Sodium 7- (5-aminoadipamido) -5- (5-iQe'biiyl-1 »3, 4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 s) was dissolved in dichloromethane (30 ml ) suspended. Triethylamine (0.4 ml), N, N-dimethylaniline (30 ml) and chlorotrimethylsilane (4.0 ml) were added. The mixture was stirred under reflux for one hour. Then was added under cooling at -50 to -40 ⁰ C 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) were added. The mixture was stirred for 30 minutes at -50 to -40 ⁰ C and 30 minutes at room temperature. Triethylamine (2.5 ml) was added and the reaction mixture was concentrated under reduced pressure. Became the residue. Given dichloromethane (30 ml). This mixture was added all at once to a solution which had been prepared by adding 1,3,4-thiadiazol-2-thioacetic acid (2.75 g) with pivaroyl chloride (1.9 g) in a mixture of triethylamine (2.2 ml) and tetrahydrofuran (50%) ml) was treated with cooling to -5 to 0 ⁰ G for one hour and then triethylamine (3.0 ml) was added. The reaction mixture was stirred at the same temperature for one hour and then 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 and the ethyl acetate was washed with water. The ethyl acetate layer was extracted with an aqueous saturated solution of sodium bicarbonate. The extract was acidified by adding hydrochloric acid while cooling and then 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, a yellowish powder of (0.549 g) 7- (1,3, ^z * -Thiadiazol-2-yl) thioacetamido-3- (5-

- 18 109822/2216

methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, m.p. 90 to 95 ⁰ G was obtained.

Example 8

Sodium 7- (5-aminoadipamido) -3-0-methyl-1H-tetrazol-5-yl) thiomethyl-J-cephem- ^ - carboxylate (2.55 s) was suspended in dichloromethane (30 ml). Triethylamine (0.4 ml), N, N-dimethylaniline (3-0 ml) and chlorotrimethylsilane (4.0 ml) were added to this suspension. The mixture was stirred under reflux for one hour. Then was added with cooling to -50 to -40 ⁰ C Phosphorus pentachloride (2.2 g). The mixture was stirred at the same temperature for two hours. Then N, N-dimethylaniline (3-0 ml) and methanol (15. ml) were added. The mixture was stirred for 30 minutes at -50 to -40 ⁰ G and 30 minutes at room temperature. The reaction mixture was then concentrated under reduced pressure and dichloromethane (30 ml) and triethylamine (5 x 5 ml) were added to the residue. This mixture was added to a Lösirg of -Thienylacetylchlorid cc (2.5 g) in tetrahydrofuran (50 ml) at -5 to 0 ⁰ C, and the reaction mixture was stirred for one hour at der.gleichen temperature and then allowed 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, a powder of (0.249 g) 7- («-thienyl) -acetamido-3- (1-methyl-1H-tetrazol-5-yi) thiomethyl-3-cephem-4-carbon - acid, F. 8? until 9I ⁰ C was obtained.

Example 9

Sodium 7- (5-amino adipamido) -3- (5-methylt] iio-1, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate (2.55 s) was dissolved in dichloromethane (30 ml) .suspended. Triethylamine (0.3 ml) · »N, N-dimethylaniline (2.2 ml) and chlorotrimethylsilane (3-0 ml) were added. The mixture was stirred under reflux for one hour. Phosphorus pentachloride (1.0 g) was then added with cooling to -4-0 to -50 ° 0. The mixture was stirred at the same temperature for two hours. Then N, N-Dime thy 1 anil in (0.15 ml) and methanol (7.5 ml) were added. The mixture was stirred for 30 minutes at -50 to -40 ⁰ C and then 30 minutes at room temperature. Then the mixture was concentrated under reduced pressure. Dichloromethane (30 ml) was added to the residue. and added triethylamine (2.3 ml). This mixture was added to a solution prepared by mixing a solution of sydnone-3-acetic acid (1.76 g) in tetrahydrofuran (50 ml) with a solution of dicyclohexylcarbodiimide (2.5 g) in tetrahydrofuran (20 ml) for 10 minutes had been treated with cooling to -5 to 0 ^{0 C.} This reaction mixture was stirred at the same temperature for one hour and then allowed 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. The ethyl acetate was then 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 a saturated aqueous solution of sodium chloride, dried and concentrated under reduced pressure. The oily residue was washed with ether, a powder of (0.234 g) 7- (sydnon-3-yl) acetamido-3- ■

- 20 - ■ 109827/2216

(5-methylthio-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, m.p. 163 "to 168 ⁰ G was obtained.

Sodium 7- (5-aminoadipamido) -3- (5-methyl-1,3,4-thiadia-.zol-2-yl) -thiomethyl-3-cephem-4-carboxylate (2.55 g) was dissolved in dichloromethane ( 30 ml) suspended. Triethylamine (0.4 ml), N, N-dimethylaniline (3.0 ml) and chlorotrimethylsilane (4.0 ml) were added. The mixture was stirred under reflux for one hour. Then was added under cooling at -40 to -50 ⁰ C Phosphorus pentachloride (2.2 g). This mixture was stirred at the same temperature for two hours. Then N, N ~ dimethylaniline (0.3 ml) and methanol (15 ml) were added. The mixture was stirred for 30 minutes at -50 to -40 ⁰ C and 30 minutes at room temperature. The mixture was concentrated under reduced pressure and dichloromethane (15 ml), tetrahydrofuran (50 ml) and triethylamine (5.5 ml) were added to the residue. The solution was -Bromacetylcblorid · (2.4 g) in dichloromethane (15 ml) was added to a solution of c * under cooling to -5 to 0 ⁰ C, and the reaction mixture was stirred for 3 hours at the same temperature and then allowed 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, and the ethyl acetate was washed with water and then extracted with an aqueous saturated solution of sodium bicarbonate. The extract was acidified by adding hydrochloric acid while cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried and concentrated under reduced pressure. The oily residue was washed with ether, a powder of (0.525 g) 7- ( ⁰ ^ -Bromacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) -3-cephem-4 -carboxylic acid,

F. 135 Ms 143 C was obtained.

21 -

109827/2216

Example 11

Sodium 7- (5-amii ^l oadipinamido) -3- (5-nietliyl-1,3,4-ox.3diazol-2-yl) thiomethyl-.3-cephem-4-carboxylate (2.55 s) was dissolved in dichloromethane (30 ml) suspended. Triethylamine (0.4 ml), N, N-dimethylaniline (3.0 ml) and chlorotrimethylsilane (4.0 ml) were added. The mixture was stirred under reflux for one hour. Then it was cooled to -40. up to -50 ⁰ C phosphorus pentachloride (2.2 g) added. The mixture was stirred at the same temperature for two hours. Then were Ν, Ν-dimethylaniline. (0.3 ml) and methanol (15 ml) · added. The mixture was stirred for 30 minutes at -50 to -40 ⁰ C and 30 minutes at room temperature. It was then concentrated under reduced pressure and dichloromethane (50 ml) and triethylamine (3 «0 ml) were added to the residue. This solution was cooled to -10 to 15 ⁰ O and added dropwise to phenylacetyl chloride (4.0 g). The reaction mixture was stirred for two hours at the same temperature 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 and then extracted with an aqueous saturated solution of sodium bicarbonate. The extract was acidified by adding hydrochloric acid while cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried and concentrated under reduced pressure. The oily residue was washed with ether, a powder of (0.284 g) 7-pkenylacetamido-3- (5-methyl-1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4-carbacic acid , F. 105 to 113 ⁰ C was obtained.

ΤΤΓΒΤΓΤΤΤΤΤΤίΓ

Example 12

Sodium 7- (5-amindadipamido) -3-azidQmethyl-3-cephem-4-carboxylate (2.0 g) was suspended in dichloromethane (30 ml). Triethylamine (0.4 ml), N, N-dimethylaniline (3.0 ml) and chlorotrimethylsilane (4-0 ml) were added. The mixture was stirred under reflux for one hour. Then phosphorus pentachloride was added (2.2 g) under cooling at -40 to -50 ⁰ C. The mixture was stirred at the same temperature for two hours. Then N, N-dimethylaniline (0.3 ml) and methanol (15 ml) were added. The mixture was at -50 for 30 minutes. to -40 ⁰ C and stirred for 30 minutes at room temperature. Then it was concentrated under reduced pressure. Dichloromethane (50 ml) and triethylamine (3 x 0 ml) were added to the residue. This solution was cooled to -5 to 0 ⁰ C was added dropwise to 3-methyl-1,2,5-oxadiazol-4-acetyl chloride (1.5 g). The mixture was stirred for two hours at the same temperature and then 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, and the ethyl acetate was washed with water and then extracted with an aqueous saturated solution of sodium carbonate. The extract was acidified by adding hydrochloric acid while cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried and concentrated under reduced pressure. The oily residue was dissolved in dichloromethane. A small amount of ether was added to this. The mixture was left to stand under cooling. The deposited precipitate was collected by filtration and washed with ether, whereby crystals of (0.434 g) 7- (3-methyl-1,2,5-oxadiazol-4-yl) acetamido-3-azidomethyl-3-cephem-4 -carboxylic acid, m.p. 115 to 120 ⁰ C were obtained.

109827/2216

- ■ 25 -

Example 13 '

Sodium 7- (5-aininoadipamido) -3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylate (2.5 g) was suspended in dichloromethane (30 ml). Triethylamine (0.4 ml), N, N-dimethylaniline (3.0 ml) and chlorotrimethylsilane (4.0 ml) were added. The mixture was stirred under reflux for one hour. Then was added (2.2 g) under cooling to -50 ⁰ C phosphorus pentachloride. This mixture was stirred at the same temperature for two hours. Then N, N-dimethylaniline (0.3 ml) and methanol (15 ml) were added. The mixture was stirred for 30 minutes at -50 to -40 ⁰ C and 30 minutes at room temperature. Then it was concentrated under reduced pressure and dichloromethane (30 ml) was added to the residue. This solution was poured all at once into a solution which had been prepared by mixing 5-methyl-1,3,4-oxadiazole-2-oxyacetic acid (2.7 g) with pivaroyl chloride (1.9 g) in a mixture of triethylamine (2.2 ml) and tetrahydrofuran (50 ml) had been treated ^{with cooling to -5 to 0 0 G.} Immediately thereafter, triethylamine (3-0 ml) was added and the reaction mixture was stirred at the same temperature for one hour and then allowed 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, and the ethyl acetate was washed with water and then extracted with an aqueous saturated solution of sodium bicarbonate. The extract was acidified by adding hydrochloric acid while cooling and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried and concentrated under reduced pressure. The oily residue was dissolved in ether. Another amount of ether was then added until the solution turned white. Then the solution was cooled. The precipitate was through

- 24 109829/2 716

Filtration collected, leaving crystals of (5 * 84- s) 7- (5 ~ Methyl-1,3,4-tmadiazol-2-yl) oxyace.tamido-3-O, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 105 "to

110 C were obtained.

Patent claims:

1098? 7/2? 16

Claims (1)

Patent claims: wherein E ^ is azido, TMadiazolylthio, oxadiazolylthio or tetrazolylthio; X represents thio, oxy or a single bond "; Ro represents halogen, sydnone, tetrazolyl, oxadiazolyl, thienyl, phenyl or thiadiazolyl, where X represents a single bond when R _{2 represents} a halogen atom, and of pharmaceutically acceptable salts of these derivatives, characterized in that one the reaction product of the formula VII is hydrolyzed, which one receives when connecting the forrael HOOC-CH- (CH _{2) 5} -C0NH CHp-RyI COOH (ID where R ^ has the same meaning as above, 109827/2216 2055736 in the presence of a base with chlorotrimethylsilane or a salt of the compound of formula II with chlorotrimethylsilane implemented the compound obtained from Foxmel III with brought a halogenating agent to Eeaktion, the resulting compound of formula IV with a lower Reacted alkanol and the resulting compound of the formula V with a compound of the formula R ₂ -X-CH ₂ -COOH (VI) wherein E ₂ and X have the same meaning as above,. . · in the presence of a condensing agent, or with a reacted with respect to the carboxyl group-reactive derivative of this compound in the presence of an organic Ease v / ird. Process according to claim 1, characterized in that the reaction product of the formula VII is hydrolyzed, the one obtains if the j? onael II 7- (5-Aminoadipinamido) -3- (5 ~ -rae thyl-1,3 »4-thiadiasol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and used as the reagent of the formula VI IH-tetrasol-1-acetic acid. 3. The method according to claim 1, characterized in that a compound of the formula HOOC-CH- (CHo) v-CONH I ^{2 3} (ID CIj »5 -E ^ C. 3 COOH wherein R _{1 has} the same meaning as above, - 27 - 1098 2 7/2216 in the presence of a base with chlorotriraethylsilane or a Salt of the compound of formula II with chlorotrimethylsilaii reacted, the compound of formula III obtained with brought a halogenating agent to the reaction, the resulting / compound of formula IV with a lower Alkaiiol reacted and the resulting compound of formula V with the compound of formula R ₂ -X-CH ₂ -GOOH (VI) . v / orin R ₂ and X have the same meaning as above. to have, in the presence of a condensing agent, or with a reacted with respect to the carboxyl group-reactive derivative of this compound in the presence of an organic base and the compound of formula VII obtained is then hydrolyzed. Process according to claim 3, characterized in that the starting material of the formula II is 7- (5-aminoadipamido) -3- (5-raetlryl-1,3> 4-thiadiasol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and as a reagent of the formula VI 1H-tetrazole-1-acetic acid be used. ■ Dr.T. / Ke 109822/2216