CN103159765A

CN103159765A - Indisetron purification method suitable for industrialization

Info

Publication number: CN103159765A
Application number: CN2011104212693A
Authority: CN
Inventors: 程凯; 陈立云
Original assignee: BEIJING JIALIN PHARMACEUTICAL Co Ltd
Current assignee: BEIJING JIALIN PHARMACEUTICAL Co Ltd
Priority date: 2011-12-15
Filing date: 2011-12-15
Publication date: 2013-06-19
Anticipated expiration: 2031-12-15
Also published as: CN103159765B

Abstract

The invention discloses an indisetron purification method suitable for industrialization. The method comprises the following steps: pouring a crude indisetron product or a dimethyl formamide (DMF) solution or aqueous DMF solution of a crude product of a pharmaceutically acceptable salt of indisetron into an aqueous solution of an alkali metal hydroxide or carbonate; allowing indisetron solid to be precipitated; carrying out filtering; washing the indisetron solid until the indisetron solid is neutral; and carrying out drying so as to obtain high-purity indisetron. The method provided by the invention has the advantages of easy and convenient operation, low cost, good safety, high yield and capacity of preparing high-purity indisetron.

Description

A kind of indisetron purification process that is suitable for industrialization

Technical field

The invention belongs to the medical chemistry technical field, relate to a kind of indisetron purification process that is suitable for industrialization, more particularly, relate to the reaction solution mixture from a kind of synthetic indisetron, impure (mainly containing the export-oriented isomer of indisetron) indisetron or its salt, the purification process of the high-quality indisetron of preparation.

Background technology

Indisetron (Indisetron) is a kind of novel 5-HT ₃Receptor blocking agent is used for the nauseating and vomiting that the anti-malignant tumor treatment causes.Indisetron is developed jointly by Japan's day clear pharmacy and the pharmacy of apricot woods, and its structural formula is as follows:

In the process of preparation indisetron, inevitably to produce its export-oriented isomer impurities, because it and the character of indisetron are close, very difficultly with common purification process, it be removed.

EP0469449A1 discloses two kinds of methods of preparation indisetron: 1) take pyridine as solvent, and by introversion-3,9-dimethyl-3,9-diazabicyclo [3.3.1] nonane-7-amine and 1H-indazole-3-formyl chloride reaction preparation.Its post-treating method is first concentrated dried reaction solution, and raffinate is transferred pH to 1 with acid, and ethyl acetate extraction is carried assorted, then uses adjusting PH with base 〉=11, chloroform extraction, drying, concentrated.Residue obtains indisetron through column chromatography for separation, and yield is 15.4%.2) take DMF as solvent, by interior to 3,9-dimethyl-3,9-diazabicyclo [3,3,1] nonane-7-amine and two indazoles [2,3-a, 2 ', 3 '-d] piperazine-7,14-two reactive ketones preparations.Its post-treating method is dried for being evaporated to, and then adds entry, crystallization, filtration, and the solid that obtains is through column chromatography purification, and yield is 60%.

It is all through column chromatography purification that two kinds of methods prepare indisetron, and obviously the method complex operation, be unfavorable for suitability for industrialized production.

Summary of the invention

The inventor has been surprisingly found out that a kind of indisetron purification process that is suitable for industrialization after deliberation, thereby obtains high-quality indisetron, has overcome above shortcomings in prior art.

The purpose of this invention is to provide a kind of purification process that is suitable for the indisetron of industrialization.

Specifically, the invention provides a kind of purification process that is suitable for the indisetron of industrialization, it comprises the steps:

(1) with dimethyl formamide (DMF) solution or the DMF aqueous solution of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product, in the aqueous solution of impouring alkali metal hydroxide or carbonate; The indisetron solid is separated out;

(2) filter: can adopt strainer decompress filter, plate filter press filtration or dry with whizzer;

(3) washing: filter cake is washed with water to filtrate for neutral, but also appropriate ethanol drip washing 1-2 time after water washing;

(4) drying: atmospheric pressure at room is air-dry, or 40-60 ℃ dry 8-16 hour; Perhaps 30-50 ℃ vacuum-drying 8-12 hour.

In embodiments of the invention, described indisetron crude product or indisetron pharmaceutically-acceptable salts crude product contain the indisetron of the export-oriented isomer of 0.5 to 40 % by weight, here, described pharmacy acceptable salt is selected from the salt of hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, formic acid or acetic acid.

In embodiments of the invention, the DMF of the described DMF aqueous solution and the ratio of water (by weight) should be more than or equal to 1, are preferably greater than to equal 10.

In embodiments of the invention, the DMF solution of described indisetron crude product or indisetron pharmaceutically-acceptable salts crude product or the DMF aqueous solution, wherein, the content of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product is the 1-20 % by weight, be more preferably the 5-15 % by weight, (with respect to the DMF solution of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product or the per-cent of the DMF aqueous solution).

In embodiments of the invention, described alkali metal hydroxide is potassium hydroxide or sodium hydroxide; Described alkaline carbonate is salt of wormwood or sodium carbonate, preferred salt of wormwood.

In embodiments of the invention, the aqueous solution of alkali metal hydroxide or carbonate, preferably, its concentration is the 1-10 % by weight, preferred 2-5 % by weight.

In embodiments of the invention, described preparation method's step (1) is with in the aqueous solution of the DMF solution of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product or DMF aqueous solution impouring alkali metal hydroxide or carbonate the time, temperature is usually at 0-50 ℃, preferred 10-30 ℃, and stir or standing crystallization 1-8 hour at this temperature.

In embodiments of the invention, as selectable scheme, the preparation of the solution of indisetron crude product DMF described in step (1), can adopt the indisetron crude product, first with DMF, it is dissolved, then in the alkali lye of impouring proper concn, the indisetron solid is separated out; Perhaps, the preparation of the DMF aqueous solution of described indisetron pharmaceutically-acceptable salts crude product can be adopted indisetron pharmaceutically-acceptable salts crude product, and is first directly soluble in water, then after adding appropriate DMF, then in the alkali lye of impouring proper concn, separate out the indisetron solid; Perhaps, with the reaction solution (for example EP0469449A1 embodiment 14, react complete rear) of preparation indisetron, directly in impouring alkali lye, separate out the indisetron solid.In embodiments of the invention, the indisetron solution before impouring alkali lye, the content of indisetron is generally 1-20%, preferred 5-15%.

Compared with prior art, the invention has the advantages that: the reaction solution that 1) EP0469449A1 method 2 is prepared indisetrons, directly just can separate out the very high indisetron of purity in impouring alkali lye, and yield is 70-75%, apparently higher than the column chromatography purification method (yield is 60%) of bibliographical information.2) for the high indisetron of export-oriented content of isomer, use the inventive method purifying, can remove well export-oriented isomer, obtain the high indisetron of purity.The method is easy and simple to handle, and cost is low, and security is good, and yield is high, is more suitable for suitability for industrialized production.

Embodiment

Be further elaborated below in conjunction with specific embodiment, still, these embodiment limit the scope of the invention.

The preparation of embodiment 1 indisetron reaction solution

Add respectively in 60g to-3 in the 3L there-necked flask, 9-dimethyl-3,9-diazabicyclo [3,3,1] nonane-7-amine and 1900ml DMF, ice bath is cooled to below 5 ℃, then adds 74g salt of wormwood, 2.3g DMAP (DMAP) and 51.4g two indazoles [2,3-a, 2 ', 3 '-d] piperazine-7, the 14-diketone.Finish stirring at room 24 hours.

Embodiment 2 uses wet chemical as alkali lye, the indisetron reaction solution to be carried out purifying

The slow impouring of reaction solution that embodiment 1 obtains is filtered with ice in the wet chemical of cooling 4kg 2%, control temperature below 30 ℃.Finish, 10-30 ℃ of stirring and crystallizing 5 hours.Filter, filter cake is washed to neutrality, dries to get solid 85.4g.Yield: 76.87%, purity: 99.35%, the content of export-oriented isomer is 0.18%.

Embodiment 3 uses aqueous sodium hydroxide solution as alkali lye, the indisetron reaction solution to be carried out purifying

Filter with ice in the aqueous sodium hydroxide solution of cooling 4kg 2% by the slow impouring of reaction solution that embodiment 1 obtains, control temperature below 30 ℃.Finish, 10-30 ℃ of stirring and crystallizing 5 hours.Filter, filter cake is washed to neutrality, dries to get solid 82.2g.Yield: 73.99%, purity: 99.24%, the content of export-oriented isomer is 0.21%.

Embodiment 4 uses wet chemical as alkali lye, the low-purity indisetron to be carried out purifying

The indisetron of low-purity is 87.3% by the content of high-performance liquid chromatogram determination indisetron, and the content of export-oriented isomer is 11.5%.

Above-mentioned indisetron 10.0g is dissolved in 170ml DMF, then with in the wet chemical of its slow impouring with the cooling 360g 2% of ice filter, controls temperature below 30 ℃.Finish, 10-30 ℃ of stirring and crystallizing 5 hours.Filter, filter cake washing is dried to get solid 5.4g, yield to neutral: 61.85%, and purity is 99.40%, the content of export-oriented isomer is 0.19%.

Embodiment 5 uses potassium hydroxide aqueous solution as alkali lye, the low-purity indisetron to be carried out purifying

The indisetron 10.0g of embodiment 4 low-purity is dissolved in 170ml DMF, in the potassium hydroxide aqueous solution of its slow impouring with the cooling 360g 2% of ice filter, controls temperature below 30 ℃.Finish, 10-30 ℃ of standing crystallization 8 hours.Filter, filter cake washing is dried to get solid 5.0g, yield to neutral: 57.3%, and purity is 99.25%, the content of export-oriented isomer is 0.20%.

Embodiment 6 uses wet chemical as alkali lye, low-purity indisetron hydrochloride to be carried out purifying

The indisetron hydrochloride of low-purity is 92.4% by the content of high-performance liquid chromatogram determination indisetron, and the content of export-oriented isomer is 6.9%.

Above-mentioned indisetron hydrochloride 10g is dissolved in 20ml water, adds 170ml DMF, in the wet chemical of the 340g 2% that its slow impouring ice filter is cooling, control temperature below 30 ℃.Finish, 10-30 ℃ of stirring and crystallizing 5 hours.Filter, filter cake washing is dried to get solid 4.6g, yield to neutral: 61.4%, and purity is 99.33%, the content of export-oriented isomer is 0.14%.

Embodiment 7 uses aqueous sodium carbonate as alkali lye, low-purity indisetron hydrochloride to be carried out purifying

The indisetron hydrochloride 10g of embodiment 6 low-purity is dissolved in 20ml water, adds 170mlDMF, in the aqueous sodium carbonate of the 340g 2% that its slow impouring ice filter is cooling, control temperature below 30 ℃.Finish, 10-30 ℃ of stirring and crystallizing 5 hours.Filter, filter cake washing is dried to get solid 4.4g, yield to neutral: 58.7%, and purity is 99.30%, the content of export-oriented isomer is 0.15%.

Claims

1. the purification process of an indisetron, it comprises the steps:

(1) with DMF solution or the DMF aqueous solution of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product, in the aqueous solution of impouring alkali metal hydroxide or carbonate; The indisetron solid is separated out;

(2) filter;

(3) washing is to neutral;

(4) drying.

2. purification process according to claim 1, wherein, in the DMF solution or the DMF aqueous solution of described indisetron crude product or indisetron pharmaceutically-acceptable salts crude product, the content of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product is the 1-20 % by weight.

3. purification process according to claim 2, wherein, the content of indisetron crude product or indisetron pharmaceutically-acceptable salts crude product is the 5-15 % by weight.

4. purification process according to claim 1, wherein, described pharmacy acceptable salt is selected from the salt of hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, formic acid or acetic acid.

5. purification process according to claim 1, wherein, described alkali metal hydroxide is potassium hydroxide or sodium hydroxide; Described alkaline carbonate is salt of wormwood or sodium carbonate, preferred salt of wormwood.

6. purification process according to claim 1, wherein, described alkaline carbonate is salt of wormwood.

7. purification process according to claim 1, wherein, the aqueous solution of described alkali metal hydroxide or carbonate, its concentration is the 1-10 % by weight.

8. purification process according to claim 7, wherein, the aqueous solution of described alkali metal hydroxide or carbonate, its concentration is the 2-5 % by weight.

9. purification process according to claim 1, wherein, in step (1) during impouring temperature be 0-50 ℃.

10. purification process according to claim 6, wherein, in step (1) during impouring temperature be 10-30 ℃.