CN107641103A

CN107641103A - A kind of Bendazac preparation method

Info

Publication number: CN107641103A
Application number: CN201710406278.2A
Authority: CN
Inventors: 邵杨; 蒋维; 胡孟奇
Original assignee: HEFEI YUANZHI PHARMACEUTICAL R & D Co Ltd
Current assignee: HEFEI YUANZHI PHARMACEUTICAL R & D Co Ltd
Priority date: 2017-06-01
Filing date: 2017-06-01
Publication date: 2018-01-30

Abstract

A kind of Bendazac preparation method.O-Halogen benzoic acids, inorganic base, catalyst, hydrazine compound, solvent are added in reactor, 20~48h is stirred at 75~110 DEG C, after being spin-dried for, then intermediate III is obtained after being extracted and washed with alcohol kind of extractants；Intermediate III, benzyl chloride, sodium hydroxide, water are sequentially added in reactor, kept at 20~75 DEG C, filtered through cooling, intermediate IV is obtained after washing；Intermediate formula IV, potassium hydroxide, glycol dimethyl ether are first added in reactor, chloroacetic ethylene glycol dimethyl ether solution is added dropwise after the dissolved clarification that heats up again, is kept at 60~85 DEG C, 4h is stirred, white solid precipitation is had after being spin-dried for, after acid adjustment, centrifuged after purification through soda acid again, obtain white solid Bendazac.The inventive method raw material sources are cheap, and technological operation is easy to control, high income, stay in grade, and cost substantially reduces than existing methods, be adapted to industrialized production the advantages that.

Description

A kind of Bendazac preparation method

Technical field

The invention belongs to field of pharmaceutical preparations, and specifically, the present invention relates to a kind of Bendazac preparation method.

Background technology

Bendazac, benzyl bacteria ether indazole, bendazac, English name:Bendazac, fusing point:161-163 DEG C, relative density: 1.27g/cm3,508.2 DEG C of at 760mmHg, 261.1 DEG C, 25 DEG C of 3.78E-11mmHg at, molecular formula is C16H14N2O3, Analgesic agent is commonly used for, existing preparation method complex operation, is difficult to control, yield is low, and cost is higher.

Bendazac (Lacosamide) structural formula is as follows：

The content of the invention

The invention provides a kind of Bendazac preparation method, the inventive method raw material sources are cheap, and technological operation is easy to control, High income, stay in grade, cost substantially reduce than existing methods, be adapted to industrialized production the advantages that.

To achieve the above object, the present invention uses following technical scheme：

A kind of Bendazac preparation method, this method comprise the following steps：

(a) o-Halogen benzoic acids, inorganic base, catalyst, hydrazine compound, solvent are added in reactor, stirred at 75~110 DEG C 20~48h is mixed, after being spin-dried for, then intermediate III is obtained after being extracted and washed with alcohol kind of extractants；

(b) by intermediate III, benzyl chloride, sodium hydroxide, water, sequentially add in reactor, keep at 20~75 DEG C, through cooling Filter, intermediate IV is obtained after washing；

(c) intermediate formula IV, potassium hydroxide, glycol dimethyl ether are first added in reactor, are added dropwise again after the dissolved clarification that heats up Chloroacetic ethylene glycol dimethyl ether solution, keep at 60~85 DEG C, stir 4h, white solid precipitation is had after being spin-dried for, after acid adjustment, Centrifuged after purification through soda acid again, obtain white solid Bendazac.

Preferably, o-Halogen benzoic acids described in step (a) can be in 0-chloro-benzoic acid, o-bromobenzoic acid, o-iodobenzoic acid It is any.

Preferably, the inorganic base described in step (a) can be appointing in natrium carbonicum calcinatum, Anhydrous potassium carbonate, sodium hydroxide One kind, equivalent are 1~1.5 equivalent of raw material.

Preferably, the hydrazine compound described in step (a) can be any of hydrazine hydrate, hydrazine hydrochloride, and equivalent is raw material 3~6 equivalents.

Preferably, the alcohol kind of extractants described in step (a) can be any of methanol, ethanol or isopropanol, extract Taken amount is 3~5 times of raw material.

Preferably, the catalyst described in step (a) is any of cupric oxide or cuprous oxide, addition 0.01 ~0.02 equivalent.

Preferably, the solvent described in step (a) is any of toluene or dimethylbenzene, addition for raw material 5~ 10 times.

The raw material sources of the inventive method are cheap, and technological operation is easy to control, high income, stay in grade, the more existing side of cost Method substantially reduces, be adapted to industrialized production the advantages that.

Embodiment

In order to which the present invention is apparent to understand, with reference to specific embodiment, the invention will be further described, to help Understand present disclosure.

Embodiment one

1. the preparation of intermediate III, the chemical formula of intermediate III is as follows：

10Kg 0-chloro-benzoic acids, 85g cuprous oxide, 12Kg natrium carbonicum calcinatums, 21Kg hydrazine hydrates, 80Kg toluene are added anti- Answer in device, be warming up at 85 DEG C and stir 36h, add 24Kg ethanol when 20 DEG C are cooled to after reaction completely, stir 0.5h, centrifuge, Mother liquor is evaporated, and is steamed the mashing washing of solid water, is dried 12h at 50 DEG C, obtain the 6.5Kg of white solid intermediate III, yield 75.8%, the 0-chloro-benzoic acid can be replaced any of o-bromobenzoic acid, o-iodobenzoic acid, and the natrium carbonicum calcinatum can Any of Anhydrous potassium carbonate, sodium hydroxide are replaced with, equivalent is 1~1.5 equivalent of raw material, and the hydrazine hydrate can be replaced Hydrazine hydrochloride, equivalent are 3~6 equivalents of raw material, and the ethanol can be replaced any of methanol or isopropanol, and extraction quantity is original 3~5 times of material, the cuprous oxide can be replaced cupric oxide, measures and can be replaced diformazan for 0.01~0.02 equivalent, the toluene Benzene, addition are 5~10 times of raw material.

2. the preparation of intermediate IV, the chemical formula of intermediate IV is as follows：

6.5Kg intermediates III, 2.1Kg sodium hydroxides, 4.8Kg water are taken, 40 DEG C of stirring 0.5h is warming up to, 6.1Kg chlorine is added dropwise Benzyl, 70 DEG C are stirred 2 hours, are cooled to and are centrifuged at room temperature, filter cake washing, are dried 12h at 50 DEG C, are obtained white solid intermediate IV 9.9Kg, yield 91.2%.

3. the preparation of Bendazac：

9.0Kg intermediates IV, 122.6Kg potassium hydroxide are taken, 86Kg glycol dimethyl ethers rise temperature refers to 85 DEG C of dissolvings and stirred 0.5h is mixed, monoxone 18.9Kg is added dropwise and is dissolved in 18Kg glycol dimethyl ethers, 85 DEG C are stirred at reflux 4h, and kettle internal solvent is evaporated, PH=2~3, centrifugation are adjusted with 1M HCl, filter cake adds sodium bicarbonate aqueous solution, 50 DEG C of heating for dissolving, and aqueous phase adds 1M HCl to adjust PH=2 ~3, centrifuge, washing, drying 10h at 50 DEG C obtains white solid Bendazac 10.2Kg, yield 90%.

General principle, principal character and the advantages of the present invention of the present invention, the technology of the industry has been shown and described above Personnel under the premise without departing from the spirit and scope of the present invention, can also it will be appreciated that the present invention is not limited to the above embodiments There are various changes and modifications, these changes and improvement all fall within the protetion scope of the claimed invention.

Claims

1. a kind of Bendazac preparation method, it is characterised in that this method comprises the following steps：

(a) o-Halogen benzoic acids, inorganic base, catalyst, hydrazine compound, solvent are added in reactor, 20 is stirred at 75~110 DEG C ~48h, after being spin-dried for, then intermediate III is obtained after being extracted and washed with alcohol kind of extractants；

(b) by intermediate III, benzyl chloride, sodium hydroxide, water, sequentially add in reactor, keep at 20~75 DEG C, taken out through cooling Filter, obtains intermediate IV after washing；

(c) intermediate formula IV, potassium hydroxide, glycol dimethyl ether are first added in reactor, chloroethene is added dropwise again after the dissolved clarification that heats up The ethylene glycol dimethyl ether solution of acid, keep at 60~85 DEG C, stir 4h, white solid precipitation is had after being spin-dried for, after acid adjustment, then pass through Soda acid centrifuges after purification, obtains white solid Bendazac.

2. according to the method for claim 1, it is characterised in that o-Halogen benzoic acids described in step (a) can be adjacent chlorobenzene first Any of acid, o-bromobenzoic acid, o-iodobenzoic acid.

3. according to the method for claim 1, it is characterised in that inorganic base described in step (a) can be natrium carbonicum calcinatum, Any of Anhydrous potassium carbonate, sodium hydroxide, equivalent are 1~1.5 equivalent of raw material.

4. according to the method for claim 1, it is characterised in that the hydrazine compound described in step (a) can be hydrazine hydrate, salt Any of sour hydrazine, equivalent are 3~6 equivalents of raw material.

5. according to the method for claim 1, it is characterised in that alcohol kind of extractants described in step (a) can be methanol, Any of ethanol or isopropanol, extraction quantity are 3~5 times of raw material.

6. according to the method for claim 1, it is characterised in that the catalyst described in step (a) is cupric oxide or oxidation Any of cuprous, addition is 0.01~0.02 equivalent.

7. according to the method for claim 1, it is characterised in that the solvent described in step (a) is in toluene or dimethylbenzene It is any, addition is 5~10 times of raw material.