KR850001960B1 - Process for preparing cephalosporin derivatives - Google Patents

Abstract

Cephalosporin derivative(I), used as an anti-biotic, is prepared from thio-ester(II) by reacting with cephalosporanic acid(III) for 8 - 25 hrs at 30 - 90≰C, where R1 - H, methyl, ethyl, or propyl gp.; R2 = 4-hydroxy phenyl, C1 -C5 alkyl, or C1 - C5 alkyl substituted with halogen, hydroxy, or cyano gp.; R3 = methoxy, ethoxy, or propoxy gp.; R4 = 1-methyl-1H-tetrazol-5-yl thio, 1,2,3-triazol-5-yl thio, 1,3,4- thiadiazolyl-2-yl thio, or acetyl oxy gp.; and R5 =H, Na, or protection gp.

Description

Method for preparing cephalosporin derivative

The present invention relates to a novel method for producing cephalosporin derivatives of the following formula (I), which has a broad spectrum of antimicrobial spectrum against Gram-positive bacteria and Gram-negative bacteria and also shows strong resistance to β-lactamase of various bacterial production.

In the above structural formula

R ¹ is hydrogen, a methyl group, an ethyl group, or a propyl group,

R ² is a 4-hydroxyphenyl group, a C ₁ -C ₅ alkyl group, or a C ₁ -C ₅ alkyl group substituted with a halogen element, a hydroxy group or a cyano group,

R ³ is a methoxy group, an ethoxy group, or a furoxy group,

R ⁴ is a 1-methyl-1H-tetrazol-5ylthio group, 1,2,3-triazol-5ylthio group, 1,3,4-thiadiazolyl-2-ylthio group or acetyloxy group,

R ⁵ is hydrogen, sodium or a protecting group.

The present invention relates to a new and advanced method of preparation which is different from the known methods, and some of the cephalosporin derivatives such as the above formula (I) have already been reported. For example, according to U.S. Patent Nos. 3,796,717, 3,828,037, 4,098,888, 4,263,292, 4,321,265, etc., the heterocyclic thio group was first prepared at the 3 position of cephalosporin to produce the 7 position of the cephalosporin derivatives. The amino group and the acid derivative of the acyl derivatives are directly reacted to prepare the target product in a two-stage to three-stage process.

The grooves of the conventional process are economically disadvantageous by reacting expensive cefes more than twice, besides being complicated due to the large number of processes. Also, the purification method according to the increase of the number of processes and the resulting starting materials and intermediate products as impurities The loss was great. The present invention significantly improved this prior manufacturing method and invented the manufacturing method which makes a core process into a single process.

According to the novel preparation method of the present invention, the compound of formula (I) is prepared by reacting the diester of formula (II) with the cephalosporranic acid derivative of formula (III).

In the above structural formula

R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined above.

Solvents used in the reaction include water, ethyl ether, tetrahydrofuran, acetone, methyl ethyl ketone, methyl isobutyl ketone, chloroform, methylene chloride, ethyl acetate, dimethylformamide and the like. Mixed solvents may also be used. Bases used to dissolve the cephalosporan acid derivatives of the above formula (III) include sodium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and the like. The cephalosporranic acid derivative of formula (III) is reacted with a solvent such as acetone, ethyl acetate, methylene chloride, dimethylformamide, and the reaction temperature is 30 ° C to 90 ° C, but preferably 50 ° C to 60 ° C. . The reaction time is 8 hours to 25 hours, but preferably 10 hours or more. At this time, the thioester and cephalosporan acid derivatives used are reacted using the same equivalents, or preferably, the amount of thioester is used slightly higher than that of the cephalosporan acid derivatives.

Thioesters used as starting materials are prepared in the reaction of acyl chloride with thiols, which gives good results when the amount of acyl chloride used is slightly higher than thiol. The reaction solvent is methylene chloride, tetralifurfuran, acetone, ethyl acetate, water and the like, but the reaction is carried out at 0 ° C to 40 ° C, preferably 20 ° C to 25 ° C, and 30 minutes to 5 hours 2 hours is good.

The methoxylation of the cephalosporin derivative at position 7a can be performed before or after the reaction of the thioester and the cephalosporan acid derivative. The new and advanced manufacturing method of the present invention is the same as mentioned above, but is explained in more detail by the following examples, which are not intended to limit the scope as the new method of the present invention.

Example 1

A) A solution of 13 g of 7-aminocephalos formic acid suspended in 100 mM acetonitrile was stirred at 20 ° C. to 25 ° C., followed by addition of 12 mM N, O-bis-trimethylsilyl acetamide, followed by stirring for 2 hours. After adding 7 g of D-2-amino-hydroxybutylyl chloride, the mixture is stirred at room temperature for 1 hour. 400mι distilled water is added to the above reaction mixture at 0 ° C to 5 ° C, and vigorous stirring results in precipitation. Since this precipitate is not filtered well, 100mι methylene chloride is added to dissolve the precipitate, which is then filtered to remove insoluble matters.The organic layer is separated using a separatory funnel, washed twice with 100mι distilled water, and 8g of sodium carbonate in 100mι distilled water. Was added to an aqueous solution, and then the aqueous layer was separated, washed twice with 50 mι of methylene chloride, separated from the aqueous layer, 100 mι of distilled water and 50 mι of acetonitrile were added, and gradually adjusted to pH 4.0 with 1N hydrochloric acid. do. Continue to vigorously stir to pH 2.0 and filter. After washing with a sufficient amount of distilled water and drying under reduced pressure, 15 g of 7β- [D-α-amino-β (S) -hydroxybutyramido] -cephalosporonic acid was obtained.

B) Add 12 g of a) compound to 50mι methylene chloride at room temperature, stir, add 7 g of diphenyldiazomethane, stir at room temperature for 2 hours or more, evaporate the solvent under reduced pressure, and dissolve the residue in ethyl acetate. After washing with 5% sodium bicarbonate solution, washing with water, dehydrating with magnesium sulfate, and then anhydrous solution was concentrated to give 18 g of diphenylmethyl 7β- [D-αamino-β (S) -hydroxy solid foam. Butyramido] -cephalosporanate.

C) Add 17 g of the compound produced in b) to 200mι of methylene chloride and 20mι of tetrahydrofuran, melt and cool to -70 ℃, add 80mι of methanol solution (33mmol) of lithium methoxide, and after 5 minutes, 9mι of t -Butyl hypochloride is added quickly to the reaction mixture. After 30 minutes, 18 mM acetic acid is added followed by 5 mM trimethyl phosphite to stop the reaction and to decompose the excess oxidant. The mixed solution was raised to room temperature, added to 400mι citrate buffer (pH7), stirred, the organic layer was separated, washed twice with 250mι distilled water, the organic layer was separated, dehydrated with magnesium sulfate, and the organic solvent was concentrated under reduced pressure. 15 g of diphenylmethyl 7β- [D-α-amino-β (S) -hydroxybutyramido] -7α-methoxycephalosporanate is obtained as a solid foam.

D) 6 g of 4-methyl-2,3-dioxopiperazin-1-yl-carbonyl chloride and 4.5 g of triethylamine were added to 90 mι of methylene chloride, and 3 g of 1 g of 50 mι of methylene chloride was stirred at room temperature. Mixture containing methyltetrazole-5-thiol was added over 30 minutes while maintaining at 20 ° C to 25 ° C, and then stirred for 2 hours, maintained at 0 ° C to 5 ° C, stirred for 2 hours, filtered, and dried under reduced pressure. -Methyltetrazol-5-yl-4-ethyl-2,3-dioxopiperazin-1-ylcarbonylthiolate is obtained. Jungjung: 223 ℃

E) Add 15 g of c) and 8 g of d) to 100 mM acetone and stir vigorously, cool to room temperature after 15 hours at 50 ° C to 60 ° C, and deposit 200mI of isopropanol to precipitate. After stirring for 2 hours at 0 ° C to 5 ° C, filtered, washed with isopropanol, and dried under reduced pressure, 13 g of diphenylmethyl 7β- [D-α- (4-ethyl-2,3-dioxo-1-piperazine carboxane Mido) -β- (S) -hydroxybutyramido] -7α-methoxy-3-[-5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -Δ ³ Obtain cefem-4-carboxylate.

Example 2

A) 3 g of 7β- [D-α-amino-β (S) -hydroxybutyramido] -cephalospotanic acid and 0.5 g of sodium carbonate were dissolved in 40 mM distilled water, and 0.5 g of 1-methylmol was dissolved. After adding porin, 2.5 g of 1-methyltetrazol-5-yl-4-ethyl-2,3-dioxopiperazin-1-ylcarbonylthiolate was added thereto, followed by stirring at 50 ° C. to 60 ° C. for at least 10 hours. Then add 40mι ethyl acetate, adjust the pH to 2.0 with 1N hydrochloric acid, separate the organic layer, dehydrate with magnesium sulfate, filter, distill the organic solvent under reduced pressure, dissolve the remaining solid in 10mι acetone, and add 60mι isopropanol. Crystals precipitate. The crystals were filtered off, washed with isopropanol, and dried overnight at 40 ° C., and then 4.1 g of 7β- [D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -β- (S ) -Hydroxybutyramido] -3-[-5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] -Δ ³ -cefe-4-carboxylic acid.

B) To 20 mι of methylene chloride, add 3.6 g of the compound produced in a) at room temperature and stir, add 1.26 g of diphenyldiazomethane, stir at room temperature for 2 hours or more, evaporate the solvent under reduced pressure, and remove the residue with ethyl acetate. After dissolving in water, washed with 5% sodium bicarbonate solution, washed with water, dehydrated with magnesium sulfate, concentrated anhydrous solution to a small amount, left to filter, and dried overnight to remove 4.2 g of diphenylmethyl 7β- [D-α. -[4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -β- (S) -hydroxybutyramido] -3-[-5- (1-methyl-1,2 , 3,4-tetrazolyl) -thiomethyl] -Δ ³ -cepem-4-carboxylate. Melting Point: 124 ℃

C) Melt the compound produced in 4.2 g of b) in a 50 mι mixture of methylene chloride and 5 mι tetrahydrofuran, and then cool it to -70 ° C and add 18 ml of methanol solution of lithium methoxide (6 mmol) for 3 minutes. After stirring, 0.8mι of t-butyl hypochloride was added, and after 15 minutes of stirring, 1.6mι of acetic acid was added, 0.5mι of triethylphosphite was added, and the mixed solution was raised to room temperature. The mixed solution was added to 110mι citrate buffer (pH7), stirred for 30 minutes or more, the organic layer was separated, washed with 50mι distilled water, the organic layer was separated, dehydrated with magnesium sulfate, and the organic solvent was concentrated under reduced pressure. The remaining residue was dissolved in a 1: 1 solution of benzene and ethyl acetate and chromatographed to 2.8 g of diphenylmethyl 7β- [D-α- (4 ethyl-2,3-dioxo-1-piperazinecarboxamido). -β- (S) - hydroxy-butyramide amido] -7α--methoxy-3 - [- 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] - △ ³ - cephem Obtain 4-carboxylate. IR (KBr) cm ^-1 : C = 0.1780,1710, 1670,

D) Dissolve the compound produced in 2.8g of c) in 30mι of anisole, maintain 0 ℃ to 5 ℃, add 30mι of trifluoroacetic acid, stir for 1 hour, remove the solvent by distillation under reduced pressure, and then remove the remaining residue. To the mixture, add 60mι distilled water and 60mι ethyl acetate, slowly add 15% sodium carbonate solution to pH7.0, separate the aqueous layer, add 120mι methyl acetate, adjust pH to 2.0 with 2N hydrochloric acid, and separate the organic sulfate magnesium sulfate. After dehydration, the mixture was concentrated under reduced pressure and 1.9 g of 7β- [D-α- (4 ethyl-2,3-dioxo-1-piperazinecarboxamido) -β- (S) -hydroxybutyramido ] -7α--methoxy-3 - [- 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] - △ ³ - to obtain a cephem-4-carboxylic acid. Melting Point: 119 ℃

ιR (KBr) cm ^-1 : C = 0,1770,1705,1675.

E) Dissolve 1.9 g of the compound produced in d) in 15 mι of acetone and 4 mι of n-butanol mixed solvent, and then dissolve 1.2 g of sodium 2-ethylhexanoate in 15 mι of n-butanol and stir for at least 1 hour. Crystals precipitate. The crystals were filtered off, washed with acetone, and dried in vacuo at room temperature to yield 1.25 g of 7β- [D-α- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -β- (S the cephem-4-carboxylic acid sodium -) hydroxy-butyramide amido] -7α--methoxy-3 - [- 5- (1-methyl-1,2,3,4-tetrazolyl) thiomethyl] - △ ³ Get

Claims (1)

A process for preparing the cephalosporin derivative of formula (I), characterized by reacting a compound of formula (II) with a cephalosporan acid derivative of formula (III):

In the above structural formula, R ¹ is hydrogen, a methyl group, an ethyl group or a furo handwriting, R ² is 4-hydroxy phenyl, C ₁ ~ C ₅ alkyl group, or a halogen atom, a hydroxy-substituted C ₁ ~ C to the lock time, or a cyano group _{5 is an} alkyl group, R ³ is a methoxy group, an ethoxy group, or a furoxy group, R ⁴ is a 1-methyl-1H-tetrazol-5ylthio group, 1,2,3-triazol-5ylthio group, 1, 3,4-thiadiazolyl-2-ylthio group or an acetyloxy group, R ⁵ is hydrogen, sodium or a protecting group.