KR20030066204A - A process for the preparation of an intermediate useful in the synthesis of cefditoren - Google Patents

Abstract

PURPOSE: A process for the preparation of an intermediate useful in the synthesis of cefditoren is provided, thereby preparing the high quality cefditoren intermediate without using any organic solvent at room temperature. CONSTITUTION: A process for the preparation of 7 - amino - 3 - £2 - (4 - methylthiazol - 5 - yl) vinyl| - 3 - cephem carboxylic acid of the formula (I) as an intermediate useful in the synthesis of cefditoren comprises reacting 7 - phenylacetamido - 3 - £2 - (4 - methylthiazol - 5 - yl) vinyl| - 3 - cephem carboxylic acid of the formula (II) with penicillin G amidase to remove a phenylacet group at 7-site, wherein the reaction temperature is 5 to 40 deg. C and the reaction pH is 8 to 8.5; a filtration process of the immobilized penicillin G amidase is optionally added after the completion of the reaction; and a crystallization process by adding an organic solvent into the filtered solution to control pH of the solution is optionally added.

Description

A process for producing ceftitorene intermediate {A PROCESS FOR THE PREPARATION OF AN INTERMEDIATE USEFUL IN THE SYNTHESIS OF CEFDITOREN}

The present invention relates to a method for preparing 7-amino-3- [2- (4-methylthiazol-5-yl) -3-cefe carboxylic acid of formula (I), and more specifically, formula (II) 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem carboxylic acid of is reacted with penicillin G amidase to provide 7-amino- A method for preparing 3- [2- (4-methylthiazol-5-yl) -3-cefe carboxylic acid.

The compound of formula (I) can be used as an important intermediate of the ceftitorene pivoxil of formula (V), a third generation oral cephaic antibiotic.

Ceftitorene of formula (V) can generally be prepared by reacting a compound of formula (IV) at the 7-amino position of a compound of formula (I):

Wherein R ₁ is a protecting group of a common amino group, including a case where there is no protecting group (hydrogen), and X is a general group which is easily released by reaction with structural formula (B).

A general method for preparing the compound of formula (I) is a strong acid such as phosphorus / pyridine which is a phenylacetyl group which is an amino protecting group at position 7 from the compound of formula (III), in which the position 7 of the cefe ring is protected by phenylacetyl. After hydrolysis at, the R group which is a protecting group of the carboxyl group 4 is deprotected under a strong acid catalyst.

R = diphenylmethyl or p-methoxybenzyl

The conventional method for deprotecting the amino protecting group at position 7 is generally violent, and reacts at a low temperature of about -20 degrees, and reacts phosphorus / pyridine with solvent end point under solvent conditions such as methylene chloride. After about 1-2 hours), a small amount of water is added, further stirred at room temperature, and then neutralized with a base to convert the resulting product into a water layer. More organic solvent is added to the water layer and the pH is adjusted to acid to obtain the desired product.

In this conventional method, the reaction temperature must be maintained at a low temperature of about -20 ° C, and the reaction by-product phosphate is present in the water layer, so that the yield and purity of the target compound of formula (I) also present in the water layer are reduced. There is a problem.

U.S. Pat.No. 5,441,874 discloses a 7-amido-[(2-N-phenylacetylamino-4-thiazolyl as a synthetic intermediate of the cefe derivative in which the 7-position of cefem is a (2-amino-4-thiazolyl) acetyl-substituted derivative. ) -2-acetyl] -3-acetoxymethyl-3-cepem-4-carboxylic acid by immobilized enzyme reaction with penicillin G amidase 7-[(2-amino-thiazolyl-4-yl)] A method for preparing acetamido cephalosporic acid is disclosed.

However, a method for preparing a compound of formula (I), which is an important intermediate in the preparation of ceftitorene, using an enzyme is not known at present.

In view of this, the present inventors can stably react at a lower temperature when the compound of formula (II) is reacted with penicillin G amidase to prepare a compound of formula (I), It has been found that the compounds of formula (I) can be prepared in high purity and the present invention has been completed.

The invention provides 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] of formula (II).

Reacting 3-cefem carboxylic acid with penicillin G amidase to remove the phenylacet group at the 7-position, wherein 7-amino-3- [2- (4-methyl) Provided is a process for preparing thiazol-5-yl) vinyl] -3-cefe carboxylic acid.

The penicillin G amidase used in the present invention can be used irrespective of the type of immobilized carrier. For example, PGA-450 sold by Roche, which has an enzyme attached to a spherical carrier, is used. Penicillin G amidase immobilized enzyme can be reused by filtration after reaction type.

The present method for preparing the compound of formula (I) using penicillin G amidase can proceed the reaction in water or inorganic salt buffer, not an organic solvent, unlike in the conventional chemical preparation method. The conventional method for preparing the compound of formula (I) is to deprotect the compound of formula (III) at 7-amino position at low temperature (-20 ° C.) in an organic solvent and then deprotect the protecting group at the 4-carboxy position. However, in the present method, the compound of formula II may be used as a starting material at room temperature in aqueous solution.

The compound of formula II is completely dissolved by adding an inorganic salt buffer and adjusting the pH with a base. Penicillin G amidase was added to the aqueous layer and the mixture was reacted by simple stirring while maintaining the pH at 8.0 to 8.5 using an inorganic salt solution at a temperature of 5 to 40 ° C. to produce a compound of formula (I). After completion of the reaction, the aqueous layer was filtered to recover the penicillin G amidase, a suitable organic solvent was added to the filtrate, and the pH was adjusted to acid to recrystallize the target compound of formula (I) to obtain a large amount of the target compound.

Compounds of formula (II) may be prepared by deprotecting the protecting group of the 4-carboxy group in the compound of formula (III). The deprotection method is a conventionally known method. Diphenylmethyl 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cepem carboxylate and p-methoxybenzyl 7- as compounds of formula (III) Phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cepem carboxylate can be prepared by known methods, for example US Pat. No. 4,918,068 And US Pat. No. 6,288,223.

The invention provides 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] of formula (II).

7-amino-3- [2- (4-methylthiazol-5-yl) of formula (I) prepared by reacting -3-cefem carboxylic acid with penicillin G amidase to remove the phenylacetyl group at the 7-position. Also provided is a method of preparing a compound of formula (V) comprising reacting a) vinyl] -3-cefe carboxylic acid with a compound of formula (IV).

Hereinafter, the configuration and operation of the present invention will be described in detail by way of examples. The present invention is not limited to these examples.

Reference Example 1 Preparation of Compound of Structural Formula (II)

200 ml of anisole in 40 g of p-methoxybenzyl 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefe carboxylate (compound of formula (III)) After dissolving,

Cool down to -15 ~ -10 ℃. Into this solution, slowly add 160 ml of trifluoroacetic acid while maintaining the temperature above. When the dropping is completed, slowly raise the temperature to room temperature and stir at this temperature for 2 hours. TLC confirms the end of the reaction (developing solvent: acetonitrile: water = 4: 1). The reaction solution was slowly added dropwise to diisopropyl ether at room temperature to form a solid, which was then stirred at this temperature for 1 hour, filtered and dried under vacuum at room temperature to yield 7-phenylacetylamido-3- [2- as a solid. 28 g of (4methylthiazol-5-yl) vinyl] -3-cefe carboxylic acid (compound of formula (II)) were obtained.

¹ H NMR (CDCl ₃ ): 2.19 (3H, s), 3.18 (1H, d, J = 18 Hz), 3.3 (1H, d, J = 18 Hz),

3.62 (2H, s), 5.05 (1H, d, J = 5 Hz), 5.85 (1H, m), 6.4 (1H, d, J = 12 Hz), 6.6 (1H, d, J = 12 Hz), 7.2 to 7.35 (5H, m)

Reference Example 2: Preparation of Compound of Structural Formula (II)

200 ml of anisole 43.2 g of diphenylmethyl 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem carboxylate (compound of formula (III)) After dissolution,

Cool down to -15 ~ -10 ℃. Into this solution, slowly add 160 ml of trifluoroacetic acid while maintaining the temperature above. When the dropping is completed, slowly raise the temperature to room temperature and stir at this temperature for 2 hours. TLC confirms the end of the reaction (developing solvent: acetonitrile: water = 4: 1).

The reaction solution was slowly added dropwise to diisopropyl ether at room temperature to form a solid. The mixture was stirred at this temperature for 1 hour, and the resulting crystal was filtered to give 7-phenylacetylamido-3- [2- ( 48.5 Methylthiazol-5-yl) vinyl] -3-cefe carboxylic acid (compound of formula (II)) was dried in vacuo at room temperature to give 28.5 g as a dry matter.

¹ H NMR (CDCl ₃ ): 2.19 (3H, s), 3.18 (1H, d, J = 18 Hz), 3.3 (1H, d, J = 18 Hz), 3.62 (2H, s), 5.05 (1H, d, J = 5Hz), 5.85 (1H, m), 6.4 (1H, d, J = 12Hz), 6.6 (1H, d, J = 12Hz), 7.2 ~ 7.35 (5H, m)

Example 1

28 g of 7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefe carboxylic acid (

1.6 mol) is added to 4 g of boric acid, 200 ml of methylene chloride, and 200 ml of water, and a 10% sodium carbonate aqueous solution is added thereto while stirring to dissolve by adjusting the pH to 7.8-8.0. It is left at room temperature to obtain an aqueous layer. The organic layer is reextracted with 50 ml of water. The water layers thus obtained were combined and 1.44 KU (10 g, wet weight) of penicillin G amidase was added and the temperature was increased to 28-30 ° C. While maintaining this temperature, add a mixture of 28% ammonia water / water = 1: 1 to maintain the pH of 8.1 ~ 8.3. TLC (developing solvent: acetonitrile: water = 4: 1) confirms the completion of the reaction.

The solution is filtered to isolate immobilized enzyme and washed with 20 ml of water. 125 ml of acetone was added to the filtrate, and the pH was adjusted to 3.0 with 12.5% aqueous hydrochloric acid solution, followed by stirring at 20-25 ° C. for 30 minutes to form crystals. The resulting solid was filtered off, washed with 200 ml of acetone, and dried in vacuo at 35 ° C. to yield 12.0 g of 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefe carboxylic acid. (Yield 66%) was obtained.

¹ H NMR (DMSO-d ₆ ): 2.38 (3H, s), 3.31 (1H, d, J = 18 Hz), 3.49 (1H, d, J = 18 Hz), 4.84 (1H, d, J = 5 Hz), 5.08 (1H, d, J = 5 Hz), 6.37 (1H, d, J = 12 Hz), 6.69 (1H, d, J = 12 Hz), 8.91 (1H, s)

As described above, the present invention is a method for preparing a compound of formula (I) using penicillin G amidase from a compound of formula (II) in which a 7-amino group is protected, without using an organic solvent, It can be used as a solvent and can be reacted at room temperature, the product obtained by the present method is significantly better color than the sample prepared by the chemical method, there is an advantage that the quality of the side reaction is less progressed. In addition, the penicillin G amidase immobilized enzyme used in the reaction has the advantage that it can be recovered and used by a simple process of washing with water after filtration.

Claims (7)

7-phenylacetamido-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefem carboxylic acid of formula II is reacted with penicillin G amidase to A process for preparing 7-amino-3- [2- (4-methylthiazol-5-yl) vinyl] -3-cefe carboxylic acid of formula (I), comprising removing the acet group. . The method of claim 1, wherein the compound of formula II is reacted with penicillin G amidase at a temperature of 5-40 ° C. and pH 8-8.5. The process of claim 1 wherein penicillin G amidase is used in 5 × 10 ⁻³ to 1.5 × 10 ⁻¹ units for 1 mol of compound of formula II. The method according to claim 2, wherein the immobilized enzyme is filtered after completion of the reaction, and the penicillin G amidase is recovered. 4. The method of claim 3, further comprising crystallizing the compound of formula (I) by adding an organic solvent to the filtrate obtained after filtration to adjust the pH to acidic. The method of claim 1, wherein the compound of formula (II) is obtained by removing R which is a protecting group of a carboxyl group in the compound of formula (III). Wherein R is diphenylmethyl or p-methoxybenzyl. A process for preparing a compound of formula (V) comprising the step of reacting a compound of formula (I) obtained according to the method of claim 1 with a compound of formula (IV). [Wherein R ₁ is a protecting group of H, or a common amino group, and X is a general group that is easily released by reaction with structural formula (B).