WO2013000277A1

WO2013000277A1 - Method for preparing broad-spectrum long-acting penicillin antibiotic ticarcillin disodium

Info

Publication number: WO2013000277A1
Application number: PCT/CN2012/000876
Authority: WO
Inventors: 隋巍峰; 郭顺; 刘志; 陆祖昆; 朱炜
Original assignee: 苏州二叶制药有限公司
Priority date: 2011-06-28
Filing date: 2012-06-27
Publication date: 2013-01-03
Also published as: CN102268017A; DE112012000225B4; CN102268017B; DE112012000225T5; BR112013008592A2

Abstract

Provided is a method for preparing ticarcillin disodium with less side reaction and strong controllability in mild reaction condition using fewer steps, which comprises (1) reacting 3-thiophene malonic acid with N-hydroxyl succinimide in an organic solvent and under catalysis of DCC and DMAP to obtain an intermediate 1 that is separated and purified by column chromatography, (2) dissolving the intermediate 1 in methylene dichloride and adding 6-APA and an alkali to obtain ticarcillin, and (3) reacting ticarcillin with a salt forming agent to obtain ticarcillin disodium.

Description

Preparation method of broad-spectrum long-acting penicillin antibiotic ticarcillin sodium

The invention relates to a preparation method of a broad-spectrum long-acting penicillin antibiotic ticarcillin sodium, and belongs to the technical field of medicine. Background technique

Penicillin is extracted from Penicillium culture medium. There are 7 kinds of penicillin G. Penicillin G has the strongest effect, the highest yield and clinical application value. Penicillin G has been used clinically for more than half a century. It is characterized by strong antibacterial action and is used in various cocci and Gram-positive bacteria, but it also has major disadvantages, mainly because it is not resistant to acid, can not be taken orally, and is not resistant to enzymes. Causes drug resistance and narrow spectrum of antibacterial.

Penicillin G

6-APA

In order to solve the defects of penicillin, many semi-synthetic penicillins were developed using 6-Aminopenicillanic acid (6-APA) obtained from penicillin fermentation broth, including broad-spectrum long-acting penicillin antibiotics. Ticardllin Disodium, chemical name: ( ² S,5R, ⁶ R)-3, ³ _dimethyl-6-[2-carboxy-2-(2-thienyl)acetylamino]-7- Oxo-4-thiazepine Heterobicyclo[3.2.0]heptan-2-carboxylic acid disodium salt), the structural formula is:

Ticarcillin sodium

At present, there are various synthetic routes for obtaining ticarcillin sodium through 6-APA side chain. In general, the condensation reaction is carried out after 6-APA or 3-thiophenemalonic acid is protected by carboxyl or amino groups, and then the reaction is carried out. The product is hydrolyzed and salted to obtain a final product. After protecting the amino group and carboxyl group of 6-APA with trimethylsilyl silane, it is condensed with 3-thienylmalonyl chloride to obtain the intermediate N-trimethylsilyl- 6-[ α -Chlorocarbonyl-2-(3-thienyl)-acetamide]-picamic acid trimethylsilyl ester, after hydrolysis, with sodium 2-ethylhexanoate, with ethyl acetate After the refining, the final product is obtained. This method requires first protecting the group and then hydrolyzing the reaction product. The steps are cumbersome, and the hydrolysis reaction is difficult to carry out and difficult to control. Summary of the invention

SUMMARY OF THE INVENTION An object of the present invention is to provide a process for preparing ticarcillin sodium which has mild reaction conditions, few side reactions, few steps, and high controllability.

In view of the prior art technical bias for 6- or 3-thiophenemalonic acid prior to carboxyl or amino protection followed by subsequent reactions, the present invention provides a novel synthesis method:

(1) 3-thiophene malonic acid is reacted with N-hydroxysuccinimide in an organic solvent under the catalysis of DC (by DMAP to obtain intermediate 1, which is purified by column chromatography; the organic solvent is preferably alcohol a solvent-like, more preferably ethanol;

(2) Dissolving Intermediate 1 in dichloromethane, adding 6-APA and a base to obtain ticarcillin; the base is sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, triethylamine, diethylamine One type, preferably triethylamine;

(3) ticarcillin is reacted with a salt forming agent to obtain ticarcillin sodium. The salt forming agent is sodium acetate, sodium ethoxide, sodium isooctanoate, sodium isohexanoate, sodium hydrogencarbonate or sodium hydroxide, potassium hydroxide, preferably hydrogen carbonate. sodium.

Compared to existing methods, this synthetic route has the following advantages:

After activation of a carboxyl group of 3-thiophene malonic acid, it directly reacts with the amino group of 6-APA without water [removing the protecting group. The reaction conditions are mild, the side reactions are few, the steps are small, and the controllability is strong. detailed description

The invention is further described by the following examples, which are intended to be illustrative only and not to limit the scope of the invention, and obvious modifications and It is also included in the scope of the invention. Example 1:

3-The thiophene malonic acid (0.74 g, 4.0 mmol) was dissolved in 10 ml of ethanol, and DMAP (730 mg, 6 mmol) and DCC (1.2 g, 6.0 mmol) were added and stirred at room temperature for half an hour, then N-hydroxysuccinimide was added. (0.47g, 4mmol), after stirring at room temperature for half an hour, and then added to a saturated solution of EtOAc (EtOAc). Column chromatography (ethyl acetate / methanol = 10:1) eluted to afford Intermediate 1 1.05 g, yield 93%.

Intermediate 1 (1.05 g, 3.7 mmol) was dissolved in 20 ml of dichloromethane, and 6-APA (0.8 g, 3.7 mmol) and triethylamine 10 ml were added and stirred at room temperature for 8 hours, then adjusted with 1 mol/l hydrochloric acid solution. Acidic (pH = 2.0) and reacted at -5 °C for 2 h. Extraction of dichloromethane, decolorization of activated carbon, thickening after drying 1.37 g of ticarcillin was obtained, yield 95%, MS (m/z): 385 (M+H)+. Ticarcillin (1.35 g, 3.5 mmol) was dissolved in 10 ml of ethyl acetate, and 20 ml of ethyl acetate dissolved in 5 g of sodium hydrogencarbonate was added dropwise thereto, and the mixture was stirred and crystallized at 25 ° C, and dried under reduced pressure at 30 ° C to obtain white crystals. 1.45 g, yield 97%, melting point 201 ° C, HPLC purity: 98.89%, MS (m/z): 429 (M+H)+.

Claims

Claim

1. A method for preparing ticarcillin sodium, comprising the steps of:

(1) 3-thiophene malonic acid is reacted with N-hydroxysuccinimide in an organic solvent under the catalysis of DC and DMAP to obtain an intermediate, which is separated and purified by column chromatography;

(2) dissolving the intermediate in dichloromethane, adding 6-APA and a base to obtain ticarcillin;

(3) ticarcillin is reacted with a salt forming agent to obtain ticarcillin sodium.

The method according to claim 1, wherein the organic solvent is an alcohol solvent.

3. The method according to claim 2, wherein the alcohol solvent is ethanol.

The method according to claim 1, wherein the base (2) is one of sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, triethylamine, and diethylamine.

5. Method according to claim 4, characterized in that the base is triethylamine.

The method according to claim 1, wherein the salt forming agent is sodium acetate, sodium ethoxide, sodium isooctanoate, sodium isohexanoate, sodium hydrogencarbonate or sodium hydroxide, potassium hydroxide. .

7. The method according to claim 6, wherein the salt forming agent is sodium hydrogencarbonate.