CN102584812A

CN102584812A - Preparation method of tebipenem pivoxil impurities

Info

Publication number: CN102584812A
Application number: CN2011103704366A
Authority: CN
Inventors: 李瑞远; 刘立力; 张广明; 陈辉; 陈齐阳; 尹志媛; 吕博雅
Original assignee: WANLE PHARMACEUTICAL CO Ltd SHENZHEN
Current assignee: WANLE PHARMACEUTICAL CO Ltd SHENZHEN
Priority date: 2011-11-18
Filing date: 2011-11-18
Publication date: 2012-07-18
Anticipated expiration: 2031-11-18
Also published as: CN102584812B

Abstract

The invention provides a preparation method of tebipenem pivoxil impurities. The preparation method has the advantages that the operation is simple and convenient, the condition that a dry solid product is obtained by using expensive freeze-drying equipment and column chromatography operated complexly to purify is avoided, the degree of purity is high and reaches above 97%, and reference substances of the impurities can be directly used in the quality research on tebipenem pivoxil crude drug.

Description

A kind of Typee is trained the preparation method of southern ester impurity

Technical field

The present invention relates to organic chemistry filed, further relate to the preparation method that a kind of Typee is trained southern ester impurity.

Background technology

A Typee training south volt ester (II) is a kind of novel oral carbapenems medicine by Wyeth Pharmaceuticals's research and development.This compound is that the reactive precursor Typee is trained the prodrug that southern C2 position carboxylic esterification forms.Typee is trained southern has a broad antifungal spectrum; To most of clinical strain separated (except that few part bacterial classification such as Enterococcus faecium (faecium) and Pseudomonas aeruginosa (Pseudomonas aeruginosa)); Typee training south all shows than penicillium mould series and the stronger bacterinertness of cephalo series; And compare with the carbapenem antibiotic of other injections, Typee training south also shows with degree or stronger antibacterial effect.Particularly show extremely strong antibacterial effect to the PRSP (penicillin resistant streptococcus pneumoniae), MRSP (anti-Oxacyclotetradecane,erythromycin deriv streptococcus pneumoniae) and the Haemophilus influenzae (hemophilus influenzae) that caused the childhood infection major cause in recent years.As the prodrug in Typee training south, a Typee training south volt ester has better absorption dynamics than Typee training south, and has satisfactory stability property.Its structural formula is:

Meeting decomposition, polymerization in acid or alkali environment produce some impurity thereby Typee is trained southern ester, show that according to the former related data that grinds company the impurity that possibly exist is as shown in the table:

Table 1

When Typee being trained southern ester bulk drug and carries out quality approach, need to use the reference substance of these impurity that the impurity in the bulk drug is carried out the content monitoring, meet medicinal requirements to guarantee to prepare, can be used in the bulk drug of preparation safe and effective medicine preparation.

The Typee of formula II is trained southern ester beta-lactam nucleus open loop or hydrolysis of ester group is taken place under acidic conditions easily, and open loop produces impurity P2, and it is formula I compound that open loop while hydrolysis of ester group can produce impurity P9.

Summary of the invention

The invention provides a kind of Typee and train the preparation method of southern ester impurity, this method reaction conditions is gentle, and is easy and simple to handle, and the reaction times is short, and product purity is more than 97%.

A kind of method of training southern ester impurity suc as formula the Typee shown in (I) compound for preparing provided by the invention is characterized in that, comprises following steps:

1) reaction: Typee training south is added among the NaOH or HCl solution that concentration is 2N-5～10 ℃ of insulation reaction;

2) neutralization: adding concentration is HCl or NaOH solution adjusting pH to 4～6 of 2N;

3) solidify: add acetone and stir, leave standstill cooling, supernatant liquid inclines;

4) desalination: add ethanol or dissolve with methanol, cooling, suction filtration;

5) crystallization: add the isopropyl ether crystallization in the filtrating;

6) suction filtration, drying.

Further optimize, the step 1) reaction times is 10～30 minutes; The weight/volume (g/ml) of Typee training south and NaOH or HCl solution is than being 1: 2～4 in the step 1), preferred 1: 2.5;

Step 2) pH value preferred 5.6 in;

Step 3) and 4) service temperature is-10～10 ℃, preferred-5～0 ℃;

The step 5) recrystallization temperature is-20～0 ℃, preferred-5～0 ℃;

The said drying means of step 6) is vacuum-drying.

Typee training used in the present invention south can be through any means preparation of the prior art, and purity is more than 99.5%.

Find in the experiment that NaOH that reaction is used or HCl solution are if the low excessively words of concentration react slower, and the volume of required acid of concentration low reaction or alkali is bigger; The water yield is more, add acetone make product and salt out required volume of organic solvent bigger, waste solvent and not easy to operate; If excessive concentration, temperature of reaction rises too high, wayward extent of reaction; Produce other impurity, confirm that therefore the concentration of employed NaOH or HCl solution is that 2N is the most suitable.And when regulating pH value, containing basic center and acid sites owing in formula (I) compound structure, peracid can cause forming hydrochloride; Cross alkali and can form sodium salt; Because the molecule quantitative change is big behind the salify, cause the last yield can be, and product be the mixture of title product formula (I) compound and salt thereof greater than theoretical yield; Through repeatedly the experiment and structural identification confirm that the scope of pH value is preferably between 4～6, most preferably the pH value 5.6.After step 3) adding acetone stirred and leaves standstill, lower floor was the mixture that comprises product and NaCl, and for tightly being attached to the sticky solid of container bottom, the upper strata is the mixed solvent of acetone and water, can directly incline to.

The invention provides a kind of preparation and train the method for southern ester impurity suc as formula the Typee shown in (I) compound; This method is easy and simple to handle; Avoided using the column chromatography purification of expensive freeze-drier and complex operation and having obtained the exsiccant solid phase prod; Product purity is high, reaches more than 97%, the impurity reference substance in the time of can directly being used as Typee and training southern ester bulk drug quality approach.

Embodiment below in conjunction with embodiment does further explain to the present invention.

Embodiment

Embodiment 1

Typee is trained southern 20g join precooling to-5～0 ℃ 2N NaOH solution 50ml ,-5～0 ℃ of insulation 30min.In reaction solution, be added dropwise to 2N HCl solution and transfer pH to 4.5, finishing adds acetone 800ml, is as cold as-5～0 ℃, leaves standstill the upper solution of inclining.Resistates adds 0 ℃ of ethanol 200ml dissolving, is chilled to-5 ℃, and suction filtration is removed insolubles, and filtrating is added dropwise to isopropyl ether 600ml, 0 ℃ of crystallization.Suction filtration, filter cake is transferred to room temperature vacuum-drying in the vacuum drying oven rapidly with the washing of 50ml isopropyl ether after draining, get white products 16.8g, and HPLC 98.2%, yield 95.5%.

Embodiment 2

Typee is trained among the 2N NaOH solution 50ml that southern 20g joins precooling to 0～5 ℃-5～0 ℃ of insulation 15min.In reaction solution, be added dropwise to 2N HCl solution and make PH5.6, finishing adds acetone 800ml, is chilled to-5～0 ℃, leaves standstill the upper solution of inclining.Resistates adds 0 ℃ of methyl alcohol 200ml dissolving, is chilled to-10 ℃, and suction filtration is removed insolubles, and filtrating is added dropwise to isopropyl ether 600ml ,-20 ℃ of crystallizatioies.Suction filtration, filter cake is transferred to room temperature vacuum-drying in the vacuum drying oven rapidly with the washing of 50ml isopropyl ether after draining, get white products 17.2g, and HPLC 97.5%, yield 97.8%.

Embodiment 3

Typee is trained southern 20g join precooling to-5～0 ℃ 2N HCl solution 50ml, 5～0 ℃ of insulation 30min.In reaction solution, be added dropwise to 2N NaOH solution and make PH5.6, finishing adds acetone 800ml, is chilled to-5～0 ℃, leaves standstill the upper solution of inclining.Resistates adds 0 ℃ of ethanol 200ml dissolving, is chilled to-5 ℃, and suction filtration is removed insolubles, and filtrating is added dropwise to isopropyl ether 600ml ,-5 ℃ of crystallizatioies.Suction filtration, filter cake is transferred to room temperature vacuum-drying in the vacuum drying oven rapidly with the washing of 50ml isopropyl ether after draining, get white products 15.7g, and HPLC 97.2%, yield 89.3%.

Embodiment 4

Typee is trained southern 20g join precooling to-5～0 ℃ 2N HCl solution 50ml, 0～10 ℃ of insulation 20min.In reaction solution, be added dropwise to 2N NaOH solution and make PH6, finishing adds acetone 800ml, is chilled to-5～0 ℃, leaves standstill the upper solution of inclining.Resistates adds 0 ℃ of ethanol 200ml dissolving, is chilled to-5 ℃, and suction filtration is removed insolubles, and filtrating is added dropwise to isopropyl ether 600ml ,-10 ℃ of crystallizatioies.Suction filtration, filter cake is transferred to room temperature vacuum-drying in the vacuum drying oven rapidly with the washing of 50ml isopropyl ether after draining, get white products 16.6g, and HPLC 97.6%, yield 94.4%.

Claims

1. one kind prepares the method for training southern ester impurity suc as formula the Typee shown in (I) compound, it is characterized in that, comprises following steps:

5) crystallization: add the isopropyl ether crystallization in the filtrating;

6) suction filtration, drying.

2. method according to claim 1 is characterized in that the step 1) reaction times is 10～30 minutes.

3. method according to claim 1 is characterized in that the southern by weight/volume with NaOH or HCl solution of Typee training is 1: 2～5 in the step 1).

4. method according to claim 3 is characterized in that the southern by weight/volume with NaOH or HCl solution of Typee training is 1: 2.5 in the step 1).

5. method according to claim 1 is characterized in that step 2) in the pH value be 5.6.

6. method according to claim 1 is characterized in that step 3) and 4) service temperature be-10～10 ℃.

7. method according to claim 6 is characterized in that step 3) and 4) service temperature be-5～0 ℃.

8. method according to claim 1 is characterized in that the step 5) recrystallization temperature is-20～0 ℃.

9. method according to claim 1 is characterized in that the said drying means of step 6) is vacuum-drying.