DE1770980C3 - Process for the N-deacylation of cephalosporanic acid derivatives - Google Patents

Description

COOII

in the

R is a hydrogen atom or an acetyloxy

group and
Ri is a group of the following formulas

Dip invention relates to a method for N-deacylation of cephalosporanic acid derivatives of the general formula

R ₁ NlI

N ^; CII ₂ R
COOH

in the

R is a hydrogen atom or an acetyloxy group

peund
Ri is a group of the following formulas

S \

CH ₁ - CO-

CH ₁ -C ¹ O

CH ₁ -CO

H ₁ N

CH (CH ₂ ) _, CO
COOH

Il

¹ p

Il ο

N-CH (CH ₁ I ₁ CO

'' I.

COOH

mean by treating the esters of these compounds with phosphorus pentachloride in the Cold and in the presence of a tertiary amine, subsequent reaction with an alcohol in Presence of a tertiary amine in the cold, hydrolysis of the imino ether formed and regression the free carboxyl group from the ester obtained, characterized in that one starting from a silyl ester and both the treatment with phosphorus pentachloride and the Reaction with an alcohol at a temperature below -15 ° C carried out.

2. The method according to claim 1, characterized in that the reaction is carried out at a temperature below -30 ⁰ C.

3. The method according to any one of claims 1 and 2, characterized in that the amount of used tertiary amine is only so large that the pH does not exceed 1 after the addition of water.

H ₁ N

CH (CH ₂ )., CO
C ¹ OOH
O

Λ / Cx

N-CH (CH ₂ I ₃ CO-COOH

mean by treating the esters of these compounds with phosphorus pentachloride in the cold and in Presence of a tertiary amine, subsequent reaction with an alcohol in the presence of a tertiary Amine in the cold, hydrolysis of the imino ether formed and regression of the free carboxyl group from the ester obtained.

7-Aminocephalosporanic acid is described in GB-PS 9 53 695 and can be obtained by 7N deacylation from Cephalosporin C.

The 7-aminodeacetoxycephalosporanic acid is disclosed in GB-PS 9 57 659 and can be catalytically ^

ss hydrogenation of cephalosporin C and then Acid hydrolysis of the hydrogenated product can be obtained.

It is known that the 7-amino group of 7-aminocephalosporanic acid and its analogues, the

do with regard to the nature of the substituent in the 3-position differ, for the production of cephalosporins, which differ from the starting material, can acylate. These cephalosporins can too have antibiotic activity. This method

(15 enables the λ-aminoadipoyl side chain of Replace cephalosporin C with various alternative side chains in the 7-position. This method is for example in GB patents 9 53 695,

^ ₄₃ 9 57 569, 9 76 225, 9 88 527 and 10 54 806

hpwritten.

Several methods are known for the 7N deacylation of cephalosporins. A particularly suitable one Method consists in the 7-amido group of a s Cephalosporins to convert into an imino halide group and to convert this into an imino ether rfTnn the "imino ether for obtaining a 7-Am. r tendency to hydrolyze. You have to urge for it

will carry that the 4-carboxylic acid group in the κ;

Cephalosporin protected during deacylation

ird it is known to pre-esterify the group

H r to block the formation of the imino halide and the

Fsterblockierungsgruppe after deacylation to

distant, for example by hydrolysis or by i _: UuHroeeno'.yse. This process is described, for example, in GB patents 10 41985 and 11 19 806

^SC GB-PS 10 41 985 states that the free amino group and the carboxylic acid group of> cephalosporin C or a derivative thereof can be protected from deacylation in a suitable manner by converting the cephalosporin C into the dibenzhydryl ester of Ν, Ν -PhthaloyI-cephalosporin C transferred. The compound with the protected amino acid groups is then treated with an agent which forms an imino halide group in the 7-amino division. Typical iminohalide-forming agents are, for example, acid halides, for example phosphorus pentachloride or phosphorus oxychloride.

The iminohalide is then by reacting with an alcohol, especially an alkanol, such as Methanol or ethanol, converted into an imino ether.

The formation of the imino halide and / or the minoether is preferably in the presence of a tertiary amine, such as triethylamine, pvridine or dimethylaniline, performed.

In the next stage, the imino ether is treated with water in the presence of an acidic or basic catalyst hydrolyzed to form the corresponding 4-ester of 7-aminocephalosporanic acid. Examples of suitable Catalysts are mineral acids such as sulfuric acid, phosphoric acid or hydrochloric acid, or organic acids such as trifluoroacetic acid or p-toluenesulfonic acid.

To obtain the corresponding compound with a free 4-carboxyl group, the protective group must subsequently removed by hydrogenolysis or acid hydrolysis.

GB-PS U 19 806 describes an iminohalide / iminoether deacylation process which is similar that of GB-PS 10 41985, which, however, m specifically, starts from the dibenzhydryl ester of NN-phthaloyl-cephalosporin C. After Implementation of the dibenzhydryl ester of 7-aminocephalosporanic acid with trifluoroacetic acid is the latter Compound then by reacting with a tertiary amine in a polar solvent into a Trifluoroacetate converted. By re-installation 7-aminocephalosporanic acid is then obtained from the solvent.

From the Belgian patents 6 28 231 and 6 15 344 it is already known in the acylation of Aminopenicillanic acids to protect the carboxyl groups and the amino groups with silyl groups.

n; p Aofpabe of the invention now consists of a Process for the N-deacylation of cephalosporanic acid derivatives to indicate that with particularly high Yields and without side reactions to the pure N-deacylated cephalosporanic acid derivatives leads.

It has now surprisingly been found that the N-deacylation of cephalosporanic acid derivatives is successful Perform smoothly with high yield when talking about a silyl ester of cephalosporanic acid derivatives goes out and the treatment with phosphorus pentachloride and the reaction with an alcohol at a temperature below - 15 ° C.

The invention therefore relates to a process for the N-deacylation of cephalosporanic acid derivatives general formula

R ₁ NIl-]

- N } - CH ₂ R

COOH

in the

R is a hydrogen atom or an acetyloxy group

pe and
Ri is a group of the following formulas

S '

.is

• 40

45 Vh ₂ -co -

H, N

CH (CH, IjCO-

COOH
O

Il / Vc \

N-CHlCH ₂ ) JCO--

COOH

mean by treating the esters of these compounds with phosphorus pentachloride in the cold and in Presence of a tertiary amine, subsequent reaction with an alcohol in the presence of a tertiary Amine in the cold, hydrolysis of the formed iminoether and regression of the free carboxyl group from the ester obtained, which is characterized in that one starts out from a Silylesier and both the treatment with phosphorus pentachloride and the reaction with an alcohol in one Carries out a temperature below - 15 ° C.

The treatment with phosphorus pentachloride and the reaction with an alcohol are preferably carried out at a temperature of below -30 ^° C., in which, according to a further preferred embodiment, the amount of tertiary amine used is only so large that, after the addition of water, the pH Value does not exceed 1.

A large number of silylating agents can be used to form the 4-silylating agent, for example compounds of the general formula R ₂ RjRiSiX, in which X is a halogen atom, an amino group or an HNSiR ₂ R ₃ R4 group and R ₂ , R ₃ < : nd R <mean hydrocarbon radicals, such as alkyl groups or aryl groups. When X represents a halogen atom, one or more groups R ₂ , R ₃ and Ra can represent not only hydrocarbon groups but also halogen atoms or hydrogen atoms. ' °

E «is therefore also possible to use bifunctional silylating agents such as dialkyldihalosilanes, and trifunctional securing agents such as Alkyltrihalosilanes to use. Dialkyldihalosilanes are particularly suitable. Hexaalkylcyclotrisilazanes and octaalkylcyclotetrasilazanes can also be used be used. Further suitable silylating agents are trialkylsilylacetamides or bistrialkylsilylacetamides.

As a solvent for the treatment with phosphorus pentachloride, for example, methylene chloride, Use (alcohol-free) chloroform, dialkyl ether, tetrachloroethane and nitromethane.

During the conversion of the imino halide into the imino ether or during the cleavage of the imino ether, the 4-silyl group is also split off and the free 4-carboxylic acid group is formed. The imino ether can also be cleaved as it is formed during treatment of the imino halide with an alcohol. The alcoholysis of the imiro halide can be carried out using ethanol or methanol, but it is preferably carried out with an alkano! performed with 3 or more carbon atoms, wherein one brings about the reaction is preferably conducted at a temperature below -3O ⁰ C.

In order to bind the acid set free during the reaction, a tertiary amine is preferably used, such as trialkylamine, dimethylaniline, quinoline, lutidine or pyridine, added. The amount of used tertiary amine can be such that only part of the acid formed is bound by this amine. Preferably, such an amount of tertiary amine is used that the pH of the reaction mixture is not greater than 1 if only water and no further neutralizing agents are added. So is the amount of tertiary ainine, on PCI5 as well based on a small excess of an acid generating halosilane derivative, preferably less than 4 equivalents and advantageously less than 3 equivalents.

The following examples serve to further illustrate the invention.

example 1

55

2.51 g of the sodium salt of cefalotin is converted into the dimethylsilyl ester with 0.6 ml of dimethyldichlorosilane in 35 ml of methylene chloride to which 1.6 ml of dimethylaniline have been added. After the solution has cooled to about -55.degree. C., 1.35 g of PCl _{5 are} added, with the result that the temperature rises to -40.degree.

^{The temperature is kept at -40.degree. C.} for 2½ hours and the mixture is then cooled to -70.degree.

Then 0.30 ml of dimethylaniline are added and after about 1.5 minutes 15 ml of butanol.

The temperature is - held 4O ⁰ C.

After about 2½ hours, the reaction mixture is poured into a mixture of 33 liters of water and 16.5 ml of methanol poured. The pH of the mixture is then brought to 3.5 with ammonium bicarbonate. To Allowing to stand for about 20 hours, the precipitate is filtered off with suction at 5 ° C. Purification of the reaction product is achieved by dissolving in water at a pH of 7.3 and treating with activated charcoal.

After filtration, 1.5 times its volume of methanol is added to the aqueous solution. then the pH is brought to 3.5 with 4 η hydrochloric acid.

After standing for 2 hours at about 5 ° C., the crystals are filtered off with suction.

The yield is 1.51 g (92.5%) of 7-aminocephalosporanic acid.

Example 2

3.12 g of anhydrous cephalosporin C, which is suspended in 42 ml of methylene chloride, are stirred with stirring 1.1ml triethylamine, 3.15 ml trimethylchlorosilane and 6.7 ml of dimethylaniline were added.

After a reaction time of 1 hour, the mixture is cooled to about ⁰ C -6O. Then 3.3 g of phosphorus pentachloride are added with constant stirring. The temperature then rises to around - 40 ° C.

After a reaction time of 2 '/ 2 hours at this temperature, the mixture to about - Cooled 70 ° C and with stirring 0.4 ml of dimethylaniline and 30 ml of n-ButanoI quickly added, resulting in has that the temperature rises. This is kept at -40 ° C for 2 1/2 hours.

The reaction mixture is then poured into a mixture of 33 ml of water and with constant stirring Poured 16.5 ml of methanol. Then the pH of the mixture is suddenly adjusted to 3.5 with ammonium bicarbonate brought.

After 20 hours standing at 5 ⁰ C, the precipitate is filtered off with suction and washed with methylene chloride and acetone.

The product is cleaned by dissolving it in water at a pH of 7.3 and treating it with activated charcoal. After filtration, 1½ times its volume of methanol is added to the aqueous solution. Then the pH is brought to 3.5 with 4 η hydrochloric acid. After 2 hours of standing, the crystals are filtered off with suction at about 5 ⁰ C.

The yield is 1.86 g (about 91%) of 7-aminocephalosporanic acid.

Example 3

2.80 g of N-phthaloyl-cephalosporin C are in 40 ml Suspended methylene chloride and 3.2 ml of a 20 wt .-% solution of triethylamine in methylene chloride and 2.85 ml of dimethylaniline were added. The essentially clear solution is added with 0.6 ml of dimethyldichlorosilane N-Phthaloylcephalosporin C implemented, both of which COOH groups are silylated.

After a reaction time of 1 hour, the mixture is cooled to -50 ° C. and 1.4 g of PCl _{5 are} added. By continued constant stirring, the temperature is maintained for 2 hours ¹ A to -40 ⁰ C, whereupon the mixture to - 65 ° C cools.

Now quickly a mixture of 0.2 ml of dimethylaniline and 25 ml of n-butanol were added.

The temperature is then held at -40 ° C. for 2 hours. The mixture is then turned into a Mixture of 30 ml of water and 15 ml of methanol

poured and brought the pH to 3.5 with ammonium bicarbonate. After standing for about 20 hours at 5 ° C, the precipitate is filtered off with an acetone / water mixture (1: 1), methylene chloride and Acetone washed and dried.

The yield is 1.18 g (84%) of 7-aminocephalosporanic acid.

Example 4

2.23 g of the N-ethylpiperidine salt of N-phenacetyl-3-deacetoxy-7-aminocephalosporanic acid are suspended in 18 ml of methylene chloride and after adding 1.3 ml of dimethylaniline with ImI trimethylchlorosilane in converted to the 4-silyl ester.

After 1 hour, the mixture is cooled to -5o ⁰ C and treated with 1.1 g PCU. The temperature is kept at -40 ° C for 2½ hours and then lowered to -65 ° C.

To the cooled mixture was added a solution of 0.3 ml of dimethylaniline and 12 ml of butanol is added and then the temperature maintained for 2 hours ¹ A to -40 ° C.

The reaction mixture is poured into a mixture of 35 ml of water and 17 ml of methanol and mixed with Ammonium bicarbonate brought to a pH of 3.5. After standing at 5 ° C for 20 hours the precipitate is filtered off with suction, with a methanol / water mixture (1: 1), methylene chloride and acetone washed and dried.

The yield is 0.936 g (92%) of 3-deacetoxy-7-aminocephalosporanic acid.

Example 5

3.3 g (10 mmol) of 7-phenylacetamido-S-desacetoxycephalosporanic acid are added to a mixture of 27 ml of methylene chloride and 2.9 ml of dimethylaniline and

1.3 ml of triethylamine. After stirring for 15 minutes at 10 ^° C., 2.5 ml of trimethylchlorosilane are added, the mixture is stirred for a further 30 minutes, and the mixture is cooled

.s mixture to -15 ° C and adds 2.4 g of PCI5. The mixture is stirred for an additional 2 hours at - 15 ⁰ C. and 27 ml of isobutanol at this temperature.

The mixture is then stirred for a further 1/2 hour at -15 ° C., and the reaction mixture is then poured into 70 ml Water and adjusts to a pH of 3.5 by adding ammonium bicarbonate.

After standing for 20 hours at 5 ° C., the mixture is filtered

remove the precipitate, wash it with an acetone / water mixture and acetone and dry it. the The yield of 7-aminodeacetoxycephalosporanic acid is 1.95 g (91%).

Example 6

5.30 g of N-phthaloyl-cephalosporin are added to a mixture of 40 ml of methylene chloride and 2.9 ml of dimethylaniline C and 1.3 ml of triethylamine and then continues

2.4 ml of trimethylchlorosilane are added. After stirring for 1 hour, the reaction mixture is cooled to -15 ° C. and 2.4 g of PCl ₅ are added.

Then the mixture is stirred for 2 hours at ¹ A -15 ° C, 26 ml of isobutanol is added and stirred for a further 2 hours at -15 ° C.

The reaction mixture is then poured into 60 ml of water and adjusted by adding ammonium bicarbonate to a pH of 3.5.

After standing for 20 hours at 5 ° C., the mixture is filtered remove the precipitate, wash it with an acetone / water mixture and acetone and dry it. Man receives 2.45 g (yield = 90%) 7-aminocephalosporanic acid.

Claims (1)

Patent claims: 1. Process for the H-deacylation of cephalosporanic acid derivatives the general formula R ₁ - NH S- . ^u - - N C ¹ H ₁ R