AT404726B - Crystalline salts of derivatives of 3-vinyl-3-cephem-4- carboxylic acid and process for their preparation - Google Patents

Abstract

The invention relates to novel crystalline salts of 7-[2- (aminothiazol-4-yl)-2-(tert- butoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4- carboxylic acid with amines of the formula I <IMAGE> in which either R1, R2 and R3 are each an ethyl group, or R1 and R2 are cyclohexyl and R3 is hydrogen, or R1 and R2 are hydrogen and R3 is the tert-octyl group, and process for the preparation of these novel compounds and their use.

Description

AT 404 726 B

The invention relates to new crystalline salts of 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid with amines of the formula

= CH, / n-R2

I in which R 1, R 2 and R 3 are each an ethyl group or R 1 and R 2 are cyclohexyl and R 3 are hydrogen or R 1 and R 2 are hydrogen and R 3 are the teitoctyl group, and processes for the preparation of these new compounds and their use.

Cefixime as a trihydrate of the formula

CH = CH, 3H20 fa is a modern, orally available cephalsoporin antibiotic with excellent antibacterial properties and high / S-lactamase stability (see, for example, H.Yamanaka et al., J.Antibiotics (1985), Seil 2), p 1738-1751).

Cefixime can be prepared in various ways, the most cost-effective way being the linking of 7-amino-3-vinyl-3-cephem-4-carboxylic acid of the formula III with a reactive derivative of 2- (aminothiazol-4-yl) - 2- (tert.butoxycarbonylmethoxyimino) acetic acid1, for example 2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester of formula IV to 7- [2- (aminothiazol-4-yl) -2- (tert-Butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid of the formula V and subsequent cleavage of the tert-butoxy group. H2N-N-0-CH2-COO.tBu

NI CH = CH,

COOH l -c — co — S— &lt; ·

aO

IV

H, N

CH ~ CH, 2nd

AT 404 726 B

However, the compound of formula V can only be obtained in amorphous form and is excellently soluble in the common organic solvents, such as halogenated hydrocarbons, alcohols, ketones and esters, so that undesirable solvents such as hydrocarbons or ethers are used to isolate them (compare EP 0360630, example 133 ) must be used. The free acid of the formula V can also be isolated from water, the compound being difficult and time-consuming to dry. Due to the unfavorable dissolving properties of the compound of formula V, which make it necessary to isolate it from extreme anti-solvents such as ether or water, undesirable by-products are naturally also precipitated, which under certain circumstances have to be carried along into the active ingredient cefixime or have to be laboriously removed.

Accordingly, there is a need for an efficient cleaning method for the compound of the formula V or for an easily isolatable crystalline derivative with a cleaning effect directly from synthesis solutions. This object is achieved by using the salts of the formula I.

The salts of the compound of formula I can be prepared by 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid of formula V in a ester, for example in ethyl acetate or butyl acetate, in a ketone, for example in methyl isobutyl ketone, or in a chlorinated hydrocarbon, for example in dichloromethane, optionally with the aid of an alcohol, for example methanol, ethanol or isopropanol, as cosolvent, triethylamine, dicyclohexylamine or tert .Ocrylamine is added, the corresponding compound of the formula I crystallizing out.

However, the reaction mixture can also be diluted with the corresponding ester, ketone or halogenated hydrocarbon, in which case the desired crystallization occurs or is completed, or the alcohol added is removed by distillation, in turn the crystallization occurs or is completed and the by-products remain in solution.

The amount of amine is not critical, but stoichiometric amounts up to a double excess are preferred, based on 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3 used -cephem-4-carboxylic acid used.

After isolation of the compounds of the formula I, these can either be converted into the purified compounds of the formula V with the aid of an acid or used as such in the process for cleaving the tert-butyl protecting group to prepare cefixime.

The compounds of formula I according to the invention can also be obtained in high purity directly from acylation solutions starting from 7-amino-3-vinyl-3-cephem-4-carboxylic acid of formula III with a reactive derivative of 2- (aminothiazol-4-y! ) -2- (tert.butoxycarbonylmethoxyimino) acetic acid, for example 2- (aminot-hiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester of formula IV can be obtained. Here, 7-amino-3-vinyl-3-cephem-4-carboxylic acid of the formula III as a salt with an amine in an organic solvent, for example in a halogenated hydrocarbon such as dichloromethane, in an ester such as ethyl acetate or butyl acetate or in a ketone as Methyl isobutyl ketone, optionally with the addition of an alcohol, for example ethanol or methanol, or water or an amide such as dimethylformamide as cosolvent and dissolved with 2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester of the formula IV transferred. After the reaction has taken place, the compounds of the formula I are obtained directly from the corresponding solvent (mixture). It is also possible to first suspend the two reactants in the corresponding solvent or solvent mixture, then to add the amine necessary for dissolving 7-amino-3-vinyl-3-cephem-4-carboxylic acid and to react the reaction with subsequent crystallization of the compounds of the formula I. perform.

A further embodiment of the invention consists in the 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid from the organic solvent after the acylation reaction has taken place by extraction with a base, for example with sodium bicarbonate or sodium hydroxide solution, in an aqueous phase, then extract the product again after pH correction as free acid in one of the solvents mentioned and then crystallize the compounds of the formula I. If this procedure is followed, ethyl acetate is the preferred solvent. Suitable amines for dissolving the 7-amino-3-vinyl-3-cephem-4-carboxylic acid are, for example, tertiary amines such as triethylamine or tributylamine, amidines such as 1,5-diazabicyclo [4.3.0Jnon-5-ene (DBN) or 1 , 8-diazabicyclo (5.4.0] undec-7-ene (DBU) or guanidines such as tetramethylguanidine.

The salts of the compound of formula I are crystalline, sparingly soluble in common organic solvents such as esters, for example ethyl acetate, ketones, for example methyl isobutyl ketone, and chlorinated hydrocarbons, for example dichloromethane. The salts of the compounds of the formula I have an enormous cleaning power with regard to by-products and are therefore particularly suitable for cleaning compounds of the formula V from by-products. 3rd

AT 404 726 B

In the following examples, which are intended to explain the invention in greater detail without, however, restricting the scope, all temperatures are given in degrees Celsius.

Example 1: 7- [2- (Aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid. Triethylammonium salt

10 g of 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid are placed in a 500 ml Erlenmeyer flask and stirred with 250 ml of ethyl acetate transferred. Then as much methanol is added as is necessary to bring the starting material into solution (approx. 15 ml). The mixture is stirred for 45 minutes at room temperature and then filtered through a pleated filter. A solution of 2.1 g of triethylamine in 20 ml of ethyl acetate is slowly added dropwise to the filtrate over the course of about 20 minutes, the product beginning to crystallize out. The suspension is then stirred for one hour at room temperature and for a further hour at 0, then the title compound is isolated using a suction filter and the product is washed with 20 ml of ice-cold ethyl acetate. After drying overnight in a vacuum drying cabinet at 30 *, the title compound is obtained.

By-product content: 0.18%

Free cefixime content: 1.68%

Decomposition from 200 · 1H NMR (MeOH-d „): 7.08 (dd, J = 11.2 and 17.6 Hz, 1H); 6.92 (s, 1H); 5.84 (d, 1H); 5.45 (d, 1H): 5.22 (d, 1H); 5.17 (d, 1H); 4.66 (s, 2H); 3.73 and 3.59 (AB, d, J = 17.5 Hz, 1H); 3.19 (q, 2H); 1.48 (s, 9H); 1.30 (t, 3H).

Example 2: 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid dicyclohexylamine salt 5.1 g 7- [2- (aminothiazole -4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-car-bonic acid are dissolved in 50 ml of ethyl acetate, 5 ml of ethanol and 0.25 ml of water at 35 '. 2 ml of dicyclohexylamine are added with stirring and inoculated. The mixture is further stirred at 35 * for 30 minutes and at ambient temperature for a further 30 minutes. The title compound is then isolated at 25 * on a suction filter and the filter cake is washed twice with 10 ml of ethyl acetate. The product is dried in a desiccator in a vacuum overnight.

By-product content: 0.16%

Free cefixime content: 1.0% ’H NMR (MeOH-d *): 7.02 (dd, J = 11.2 and 17.7 Hz, 1H); 6.92 (s, 1H); 5.79 (d. 1H); 5.31 (d, 1H); 5.12 (d, 1H); 5.10 (i.e. 1H); 4.65 (s, 2H); 3.65 and 3.54 (AB, d, J * 17.3 Hz, 1H); 3.21-3.14 (m, 2H); 2.05 (m, 4H); 1.8 (m, 4H); 1.6 (m. 2H); 1.48 (s, 9H); 1.2-1.4 (m, 10H).

Example 3: 7- [2- (aminothiazol-4-yl) -2- (tertbutoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-ce-phem-4-carboxylic acid tert-octylamine salt 5.1 g 7- [2- (aminothiazol-4 -yl) -2- (tert.butoxycarbonylmethoxyimino) acetamidoh3-vinyl-3-cephem-4-car-bonic acid are dissolved in 50 ml of ethyl acetate, 10 ml of ethanol and 1 ml of water. The solution is warmed to 35 * and inoculated. 1.7 ml of tert-octylamine are added with stirring, then the stirring is switched off. The mixture is left to crystallize for 15 minutes, stirred and a further 50 ml of ethyl acetate are added dropwise in about 30 minutes with stirring. The precipitation is stirred for 15 minutes, then isolated at 35 * and the filter cake washed twice with 5 ml of ethyl acetate. The product is dried overnight in a vacuum.

By-product content: 0.15%

Free cefixime content: 1.0% 1H NMR (MeOH-d4): 7.02 (dd, J = 11.2 and 17.7 Hz, 1H); 6.92 (s, 1H); 5.79 (d. 1H); 5.32 (d, 1H); 5.13 (d, 1H); 5.11 (i.e. 1H); 4.65 (s, 2H); 3.66 and 3.55 (AB, d, J = 17.3 Hz, 1H); 1.66 (s, 2H); 1.49 (s, 9H); 1.43 (s, 6H); 1.06 (s, 9H).

Example 4: 7- [2- (Aminothiazol-4-yl) -2- (tertbutoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-ceprtem-4-carboxylic acid.terLOctylamine salt (preparation directly from acylation solutions of 7-amino-3-vinyl -3-cephem-4-carboxylic acid and 2- (aminot-hiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzthiazoiylester) 4

AT 404 726 B

20 g of 7-amino-3-vinyl-3-cephem-4-carboxylic acid are suspended in 200 ml of dichloromethane at room temperature in a 250 ml three-necked flask equipped with a magnetic stirrer, dropping funnel, reflux condenser and thermometer, a thin suspension being formed. Then 45 g of 2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester are added and the mixture is mixed with 4 ml of water. 10 g of triethylamine are then added in the course of 10 minutes, the temperature rising by 5-10 *. After the exothermic reaction has subsided, the batch is heated to the reflux temperature (30-35 *). The reaction mixture becomes almost completely clear in the course of about 2 hours. After 3.5 hours, 5 ml of methanol are added, the mixture is filtered and the filter layer is washed with 50 ml of dichloromethane. The combined filtrates are placed in a 500 ml three-necked flask with stirrer, reflux condenser, dropping funnel and thermometer, to approx. 35 &quot; warmed and within about 35 minutes a freshly prepared solution of 22 g of tert-acrylamine in 100 ml of dichloromethane was added, inoculating with seed crystals of the title compound at the beginning of the addition. When the addition has ended, about 100 ml of solvent are distilled off and at the same time about 200 ml of dichloromethane are added. Then the suspension is reduced to -10 &quot; cooled and stirred for 40 minutes at this temperature. The title compound is then isolated on a suction filter, washed with cooled (-20 °) dichloromethane and dried in a vacuum drying cabinet at 30 * overnight.

M.p .: 190 &quot; (Dec.)

By-product content: 0.23%

Free cefixime content: 0.03%

Example 5: 7- {2- (Aminothiazol-4-yl) -2- (tertbutoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-ce-phem-4-carboxylic acid. Triethylammonium salt (preparation directly from acylation solutions of 7-amino-3 -vinyl-3-cephem-4-carboxylic acid and 2- (aminot-hiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester)

In a 250 ml three-necked flask equipped with a stirrer, dropping funnel, thermometer and ice bath, 10 g of 7-amino-3-vinyl-3-cephem-4-carboxylic acid are suspended in 100 ml of dichloromethane and brought to 0 &quot; chilled. Then 10 ml of water are added and 10 g of triethylamine are then quickly added dropwise. The reaction mixture is then brought to room temperature (20%) and 22 g of 2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester are added. The reaction mixture is stirred for a further 3 hours at room temperature and then the product is isolated on a suction filter, stirred as a moist product in 100 ml dichloromethane again, suction filtered and dried overnight in a vacuum drying cabinet at 40 &quot; dried.

Reference example: 7- [2- (aminothiazol-4-yl) -2-tertbutoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid

25.4 liters of ethyl acetate, 0.94 liters of water and 2.4 liters of methanol are placed in a 30 liter vessel with a stirrer and cooled to 10 *. Then 1,044 kg of 7-amino-3-vinyl-cephem-4-carboxylic acid are added with stirring. Then 0.982 kg of triethylamine is added to the reaction mixture, followed by 2.56 kg of 2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzothiazolylester. The cooling is set to 2 &quot; Set internal temperature and the reaction mixture was stirred at this temperature for 20 hours. This creates a clear orange solution from the yellowish suspension. After the reaction has ended, the solution is filtered through a suction filter and transferred to a 50 liter vessel. The reaction solution is mixed with 23.4 l of water and stirred for 20 minutes and at the same time warmed to 20 ×. Then the pH is adjusted to between 2.0 and 2.3 by adding 3.5 N hydrochloric acid. The phases are separated and the water phase is extracted three times with ethyl acetate. The combined ethyl acetate phases are mixed with 0.234 kg of activated carbon (NORIT CG1) and stirred for 10 minutes. Then it is filtered through a pressure filter and the coal cake is washed with 1.5 l of ethyl acetate. The filtrate is overlaid with 23.4 l of water and the pH is adjusted to 8.0 with about 0.93 l of 5 N sodium hydroxide solution while stirring. The phases are separated and the organic phase is extracted three times with water. The combined water phases are on the rotary evaporator at 45 &quot; freed of ethyl acetate residues and then mixed with 0.053 kg of activated carbon (NORIT CG1). It is filtered through a pressure filter and the coal cake is washed twice with 1.6 l of water each. The title compound is then precipitated by adding 6 N hydrochloric acid to a pH of 2.3. The suspension is cooled to 5 * and stirred at this temperature for 30 minutes. Then the product is isolated on a centrifuge, washed with 10 l of water and then dried in a vacuum drying cabinet under vacuum at 45 * 90 hours over Blaugel. 5

Claims (4)

AT 404 726 B content HPLC: 85.9%, H20: 4.3% purity in Fl%: 92.84% content of free cefixime: 1.6% Claims 1. Crystalline salts of 7- [2- (aminothiazol-4 * yl) -2 '( tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid of the formula N-0-CH2-COO.tBu COOH in which R1t R2 and R3 either each represent an ethyl group or Rt and R2 represent cyclohexyl and R3 represent hydrogen or Rt and R2 represent hydrogen and R3 represent the tertiary acrylic group. 2. 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid. Triethylammonium salt 3. 7- [2- (aminothiazol-4- yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid dicyclohexylammonium salt 4. 7- [2- (aminothiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid, tert-octylammonium salt 5. A process for the preparation of the compounds of formula I, characterized in that 7- [2- (aminothiazol-4-yl) -2- (tert.butoxvcarbonylmethoxyimino) acetamido] -3-vinyl-3-cephem-4-carboxylic acid of formula V crystallized in the presence of triethylamine, oicyclohexylamine or tert-acrylamine. 6. A process for the preparation of the compounds of formula I, characterized in that 7-amino-3-vinyl-3-cephem-4-carboxylic acid with a reactive derivative of 2- (aminothiazol-4-yl) -2- (tert .butoxycarbonylmethoxyimino) acetic acid and the reaction product with triethylamine, dicyclohexylamine or tert.Ocrylamine crystallized. 7. The method according to claim 6, characterized in that as a reactive derivative of 2- (aminot-hiazol-4-yl) -2- (tert.butoxycarbonylmethoxyimino) acetic acid 2- (aminothiazol-4-yl) -2- (tert .butoxycarbonylmethoxyimino) acetic acid S-mercaptobenzthiazolylester used. 6