DE2730580A1 - CEPHALOSPORIN DERIVATIVES AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

PATiNTANWXLTE PROF. DR. DR. J. REITSTÖTTER DR.-ING. WOLFRAM BUNTE DR. WERNER KINZEBACH

D-eOOO MUNICH 40. BAUERSTRASSE 22 ■ FERNRUF <O89) 37 69 83 ■ TELEX BZIS2OO ISAR D POSTAL ADDRESS: D-SOOO MUNICH 43. POST BOX 78O

Munich, July 6, 1977
iM / 18 151

PIERREL SpA
Via Turati, 30, 20121-Milan, Italy

Cephalosporin derivatives and processes for their preparation

The invention relates to a method of manufacturing]

semi-synthetic antibiotics, and in particular an i

Process for the preparation of cephalosporin compounds i

by acylating 7-ACA (7-Air.inocephalosporanic acid). I.

i A specific object of the present invention is the j

Preparation of 7-cyanoacetamido derivatives of 7-ACA. i

The acylation of 7-aminocephalosporanic acid by acid, chlorides or mixed carboxylic acid anhydrides is common
British Patent 1 109 525. I.

7 0 9 HH ? I 1 Π 7 (J

• 1

It has now been found that the acylation of 7-ACA with a
reactive cyanoacetic acid derivative occurs rapidly and
the production of intramuscular antibiotics,
e.g. T-cyanoacetamidocephalosporanic acid (Cephacetril) allowed.

The invention thus provides a method for producing
Cephalosporin compounds of the formula I:

j CN-CH ₂ CONH

(D

CH ₂ OCOCH ₃

(ID

wherein M has the meanings given above,
with an acylating agent of the formulas

CNCH ₂ CO-O-SO ₂ -R or ₂₂

where R is CH ₃ , C ₃ H ₅ , C ₃ H ₇ , CgH ₅ , PCH ₃ -CgH ₄ , etc
or OLi, ONa, OK,

in a reaction inert solvent at a temperature
between -60 ⁰ C and 30 ⁰ C converts.

709882/1070

COOM ^!

wherein M is hydrogen, sodium, potassium, ammonium, a;

Tri- (lower alkyl) - or trimethylsilyl group, which j

is characterized in that a connection of the!

Formula II: (

The purity of the 7-ACA is not critical to the success of method j.

Reaction-inert is the term used to describe a solvent which, under the process conditions, does not react to any significant extent with either the reagents or the product. 'For the inventive method suitable solvent is dimethylformamide, dimethylsulfoxide, dioxane, acetone, tetrahydrofuran, hexamethylphosphoramide, and those> solvent in which 7-ACA can be solubilized either as salt or as j trimethylsilyl derivative \ beispiels-, halogenated solvents, and Lower alkyl carboxylic acid esters.

Since the production of cyanoacetyl chloride in industrial! Scale is critical because of its rapid decomposition during distillation even at relatively low pressure (Schroeter and Zink, Ber. , 71 , 675, (1938) and also its storage (A. Weissberger and HD Porter, J.Amer.Chem.Soc ., 6-5 , 52 (1943), the cyanoacetyl acylation of 7-ACA is carried out using a mixed carboxylic acid anhydride of the CNCH-CO-O-CO-R ^{1 type} , in which R ^{1 is} an alkyl, aryl or aralkyl group .

The amino group of the 7-ACA can, however, also ^{react with the R 1} -CO- radical, resulting in a product of the following structural formula:

R ¹ CONH -

rCX

r CH ₂ OCOCH ₃

COOH

70 Π Β 82/1070

which corresponds to cephacetril (T-cyanoacetamido-cephalosporanic acid) is similar and makes this product difficult to clean.

The inventive method also relates to the synthesis of mixed anhydrides of cyanoacetic acid and sulfonic acid, wherein the following mixed carboxylic acid sulfonic acid anhydride of the general formula

CNCH ₉ CO-O-SO ₉ -RI

; I.

arises, in which R has the meanings given above.

The superiority of the mixed carboxylic acid-sulfonic acid anhydrides over the mashed carboxylic acid anhydrides is based on the complete acylation of a nucleophilic group, such as the amino group of 7-ACA, only by the carboxylic acid group, whereby the sulfonyl radical does not react under these conditions (cf.CG. Overberger and E. Sarlo, J. Amer. Chem. Soc. , 85 , 2446, (1963)).

The method according to the invention thus enables production of cephacetril, which is free of similar or closely related cephalosporin compounds.

Another advantage of the method according to the invention is the possibility of producing the cephacetrile in one step, since the mixed anhydride can be produced directly "in situ" avoiding any handling of the active intermediates.

The cyanoacetic acid is converted into the desired mixed carboxylic acid-sulfonic acid- ^ nhydride by adding a salt thereof (M ¹ = sodium, potassium, lithium, tertiary organic amine, preferably pyridine or triethylamine) with a

709882/1070

m / 18 151 --S-- 273058Q j

In practice, the mixed anhydride is not isolated per se but is formed in situ by using the Sulfonyl halide is added to a solution or suspension of the cyanoacetic acid salt. The response will be in one

reaction-inert solvent system, for example dimethyl; formamide or methylene chloride, carried out at temperatures of -60 ° C. to 30 ^° C. for 5 minutes to half an hour. The two reagents are used in molar proportions from 0% to 300% molar excess over 7-ACA.

The desired inorganic salt of cyanoacetic acid is obtained by adding an equivalent amount of the required

MetaUhydroxyds to the acid dissolved in ethanol, after which , it is filtered off and the salt precipitates. Alternatively, it can be made directly in the same solution in which the mixed anhydride is synthesized using an organic base.

• The reaction takes place preferably in an organic water- ', free solvent in which the 7-ACA is a salt of an organic base or as a trimethylsilyl or dimethylsilyl derivative is resolved.

Any organic base that forms a salt with 7-ACA can be used. Suitable organic bases are tri- (C.-C.) -Alky! Amines, N- (C ₁ -C ₄ ) -alky! Piperidines, N- (Cj-C ^

709882/1070

Sulfonyl halide according to the following equation

CNCH ₀ COOM ¹ + RSO-Cl > CNCH ₀ COOSO ₀ R + M ¹ Cl '

wherein M ¹ and R have the meanings given above, I converts. 1

273058Q

m / 18.5, - «- 273058Q j

morpholine. However, it is advantageous to use a TrI- (C ₁ -C ₄ ) - j

alkylamine, preferably triethylamine, as the organic base. !

Such bases have the advantage that they are a salt j with 7-ACA

form that in many of the above solvents;

is soluble. i

The salts prepared in this way are particularly suitable if a non-aqueous solvent system, such as methylene chloride, used.

This part of the reaction can be carried out over a wide range of temperatures. Temperatures from about 0 ° C to _; j about 30 ⁰ C are appropriate. The temperatures are preferably kept; but between about 0 C to about 10 C to avoid decomposition of the product.

The two solutions prepared in this way (the solution of 7-ACA and the solution of the mixed anhydrides) are now given for about half an hour at a temperature between -40 C and O C to each other.

After the reaction has ended, the conversion of 7-ACA to cephacetril is in the range from 90 to 100% of the stoichiometric amount. ■

The order of addition of the two solutions is very critical because only the addition of the 7-ACA salt solution to the Solution of the mixed anhydrides gives very high yields of cephacetrile, while otherwise yields in the range of 10 to 30% would be received.

709882/1070

Μ / ιβ 151 -χ- 273058Q

In view of the very high rate of both the formation of the mixed carboxylic acid-sulfonic acid anhydride and its subsequent reaction with 7-ACA, the reaction; participant, cyanoacetic acid, 7-ACA, triethylamine and sulfonyl halide in a different than the one described above! Admit order. When sulfonyl halide is added dropwise to the mixture of all the other reactants, cephacetrile is formed in practically the same yields as in the previously described method. In this case, triethylamine or similar bases can also be partially replaced by pyridine. ^!

Finally, the formation of the mixed anhydride can occur in pyridine as solvent, although it is likely that the real acylating agent is the symmetrical anhydride (CNCH _? CO _? ) _O, which a priori can also be present in the possible processes mentioned above.

Cephacetril is isolated by conventional methods known to those skilled in the art. A typical procedure is for example the addition of water to the reaction mixture, separation of the solvent if it is not with water is miscible, adjusting the pH of the reaction mixture to about 2 in the presence of the appropriate organic solvent (e.g. ethyl acetate), with which the cephalosporin compound can be extracted. The product will by removing the solvent or by adding a suitable organic solvent through which the Cephacetrile is precipitated, won.

Alternatively, the cephalosporin can be used as an alkali metal or amine salt by adding the appropriate inorganic or organic base can be isolated to the dry ethyl acetate extract.

703882/1070

Jar

example

17 g (0.2 mol) of cyanoacetic acid are added to 0.5 liters of methylene chloride at -10 ° C. under a nitrogen atmosphere. then 28 ml (0.2 mol) of triethylamine are added dropwise with stirring and then 15.7 ml (0.2 mol) Methanesulfonyl chloride so that the temperature can be kept below -10 C.

After 30 minutes, a solution is added, prepared by dissolving 27.2 g (0.1 mol) of 7-ACA and 42 ml (0.3 mol) of triethylamine in the same solvent as before (0.25 l) at one temperature between -15 C and -5 ⁰ C to the first solution.

The reaction is complete when a test shows the absence of 7-ACA (5-10 minutes after the addition is complete) while using UV or colorimetric analysis 95-bis

100% conversion to cephacetrile is indicated. ;

1 liter of water is then added to the cold mixture with stirring and the two layers are separated (about pH 4-5). Is discarded, the organic layer (Cephacetrilgehalt <2%. Of theoretical amount) and coating the water again with 1 liter of ethyl acetate, cooled to zero ⁰ C and the pH is adjusted by adding a suitable inorganic acid to 2. After the first separation, the aqueous phase is extracted twice with fresh solvent. Collect the organic layers, treat with activated charcoal and a drying agent such as anhydrous sodium sulfate, and filter. A solution of sodium acetate in methanol (about 10% by weight) with sodium cephacetrile seed crystals is then added to the organic extract.

709882/1070

j The precipitate is left to stand for ^{12 hours at 0 ° C., j}

filtered off, washed with ethyl acetate and methanol and j

dried in vacuo, leaving 21.7 g of sodium cephacetril '■

; receives ^,!

.

^E 1cm ^{230 at 260 nm} ' ^{water <} 3 ^econtains 0.9%,

ι i

!

colorimetric content test: 96.7%. ;

example

The same amounts of reagents are used as in Example 1; the working method is changed only insofar as one
the solution of the mixed anhydrides to the solution of the 7-ACA
admits. After the reaction has ended, it is colorimetric
certain yield only 30%.

example

12.75 g (0.15 mol) of cyanoacetic acid are suspended under
Nitrogen atmosphere in 250 ml of methylene chloride (KF <0.01%). , Are then added at - 15 ⁰ C was added dropwise 12 ml (0.148 mol) of pyridine and then dropwise 11.75 ml (0.153 mole) of methanesulfonic onylchlorid to, wherein the temperature at -15 ⁰ C.
holds. The mixture is then stirred for a further 20 minutes
this temperature.

The mixture is then added over the course of 20 minutes
-15 ⁰ C a solution of 13.6 g (0.05 mol) of 7-ACA and 21 ml '(0.15 mol) of triethylamine in 125 ml of methylene chloride. After this
the mixture has been stirred for 1 hour, the colored suspension is coated with 150 ml of water and the pH is adjusted to 3.1

709882/1070

m / 18 151- ygr- 273058Q

Add sodium hydroxide to about 6 and discard the! organic layer. The red-brown aqueous solution coated

one with ethyl acetate and gives at 0 ° C up to pH 2 j

13% HCl too. The ethyl acetate layer is separated off and:

treats them with anhydrous sodium sulfate and activated charcoal. ^;

After filtering, the organic solvent is removed in vacuo and the semisolid residue was triturated with diethyl ether be ¹ -

a yellow solid forms which is filtered off and dried (11.1 g); determined colorimetrically, yield 94.3%. '

1% '

E ₁ 254 at 260 nm (NaHCO, 0.1 n) with a yield of lern 3

example

6.8 g (80 mmol) of cyanoacetic acid, 6.4 ml (80 mmol) of pyridine, 10.9 g (40 mmol) of 7-ACA and 16.85 ml (120 mmol) of triethylamine are dissolved in 250 ml of methylene chloride, whereby ^{while stirring at 0 °} C., the organic bases are added dropwise under a nitrogen atmosphere.

The solution is cooled to -20 ⁰ C. and for one hour dropwise 6.26 ml (80 mmol) of methanesulfonyl chloride. The reaction mixture is stirred for 3 hours at a temperature lower than 0 ^° C. and then 250 ml of water are added. The organic layer is discarded as usual after adjusting the pH to about 4 while the aqueous solution is adjusted to pH 2 in the presence of an organic solvent such as ethyl acetate.

The organic layer is separated, dried over magnesium sulfate and treated with activated charcoal; after evaporation of the

709882/1070

Solvent obtained in vacuo is prepared with diethyl ether, 9.0 g being filtered off
Receives cephacetril. (Purity determined by colorimetric analysis 95%, EJ _cm 251 at 264 nm).
The yield is 66%.

example

1.7 g (20 mmol) of cyanoacetic acid are dissolved in 50 ml of pyridine! and outputs to the cooled to -10 ⁰ C solution of 0.8 ml (10.35 mmol) of 'methanesulfonyl chloride. After stirring for 1/2 hour, a solution of 2.72 g (10 mmol) of 7-ACA and 4.2 ml (30 mmol) of triethylamine in 25 ml of methylene chloride is added
Temperature below 0 ⁰ C too.

The mixture is stirred for 1 hour at room temperature and then coated with 100 ml of water. You reject them
Methylene chloride layer and the aqueous layer is coated again with ethyl acetate, the pH being adjusted from 6.6 to 2
adjusts. After drying and treating with activated charcoal
the organic layer is evaporated in vacuo. The solid obtained is prepared with diethyl ether, 0.9 g of 99% pure cephacetril being obtained. :

e] _ciii 270 at 262 nm.

709882/1070

Claims (4)

Claims '(D CH ₂ OCOCH ₃ where M for H, Na, K, NH ,, a tri- (lower alkyl) amine or trimethylsilyl group, characterized in that a compound of the general formula II: (ID CH ₂ OCOCH ₃ COOM in which M has the meanings given above, with an anhydride of the formulas CNCH ₂ CO-O-SO ₂ -R or (CNCH ₂ O) ₂ 0 where R is CH ₀ , C-Hj-, C-, Η. ,, C, H _C , DCH ₀ C ₁ -H. or OLi, J ^ b SI ob * "j ο 4 ONa or OK, acylated. 2. The method according to claim 1, characterized in that the reaction in a reaction-inert solvent system at a temperature between -60 ⁰ C and 30 C, preferably -20 ⁰ C and 0 ⁰ C is carried out. 709882/1070 ORIGINAL INSPECTED 3. The method according to any one of the preceding claims / characterized in that the reaction-inert Solvents in which the acylation reaction is carried out, preferably methylene chloride, dimethylformamide and pyridine are. 4. The method according to any one of the preceding claims, characterized in that the used for the acylation Mixed anhydride is made by adding a salt of cyanoacetic acid with sulfonyl halide implements. 70988? / 10 7 0