CN107641103A - A kind of Bendazac preparation method - Google Patents
A kind of Bendazac preparation method Download PDFInfo
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- CN107641103A CN107641103A CN201710406278.2A CN201710406278A CN107641103A CN 107641103 A CN107641103 A CN 107641103A CN 201710406278 A CN201710406278 A CN 201710406278A CN 107641103 A CN107641103 A CN 107641103A
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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
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 (7)
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.
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CN201710406278.2A CN107641103A (en) | 2017-06-01 | 2017-06-01 | A kind of Bendazac preparation method |
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CN201710406278.2A CN107641103A (en) | 2017-06-01 | 2017-06-01 | A kind of Bendazac preparation method |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108383807A (en) * | 2018-04-12 | 2018-08-10 | 深圳市前海博扬研究院有限公司 | A method of reducing the discharge of etherification reaction brine waste |
CN112457300A (en) * | 2020-12-19 | 2021-03-09 | 南京方生和医药科技有限公司 | 3-hydroxy-5-substituted-1H-indazole compound and preparation method thereof |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JPS497278A (en) * | 1972-05-27 | 1974-01-22 | ||
FI49611B (en) * | 1972-07-12 | 1975-04-30 | Medipolar Oy | |
WO2003076408A2 (en) * | 2002-03-08 | 2003-09-18 | Abbott Laboratories | Indazole derivatives that are activators of soluble guanylate cyclase |
CN103641784A (en) * | 2013-12-03 | 2014-03-19 | 杭州民生药业有限公司 | Bendazac lysine synthesis process |
-
2017
- 2017-06-01 CN CN201710406278.2A patent/CN107641103A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS497278A (en) * | 1972-05-27 | 1974-01-22 | ||
FI49611B (en) * | 1972-07-12 | 1975-04-30 | Medipolar Oy | |
WO2003076408A2 (en) * | 2002-03-08 | 2003-09-18 | Abbott Laboratories | Indazole derivatives that are activators of soluble guanylate cyclase |
CN103641784A (en) * | 2013-12-03 | 2014-03-19 | 杭州民生药业有限公司 | Bendazac lysine synthesis process |
Non-Patent Citations (4)
Title |
---|
ARTURO SAN FELICIANO ET AL.: "Regioselective Synthesis of 1-Alkyl- or 1-Aryl-1H-indazoles via Copper-Catalyzed Cyclizations of 2-Haloarylcarbonylic Compounds", 《ORGANIC LETTERS》 * |
DAVID W. GORDON: "An Improved Synthesis of YC-1", 《SYNLETT》 * |
HONG SHEN ET AL.: "Synthesis and biological evaluations of novel bendazac lysine analogues as potent anticataract agents", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
修志明: "苄达赖氨酸合成工艺的研究", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108383807A (en) * | 2018-04-12 | 2018-08-10 | 深圳市前海博扬研究院有限公司 | A method of reducing the discharge of etherification reaction brine waste |
CN108383807B (en) * | 2018-04-12 | 2020-10-27 | 深圳市前海博扬研究院有限公司 | Method for reducing discharge of salt-containing wastewater of etherification reaction |
CN112457300A (en) * | 2020-12-19 | 2021-03-09 | 南京方生和医药科技有限公司 | 3-hydroxy-5-substituted-1H-indazole compound and preparation method thereof |
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