CN105272927A - Novel method for preparing chlordiazepoxide - Google Patents
Novel method for preparing chlordiazepoxide Download PDFInfo
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- CN105272927A CN105272927A CN201510787661.8A CN201510787661A CN105272927A CN 105272927 A CN105272927 A CN 105272927A CN 201510787661 A CN201510787661 A CN 201510787661A CN 105272927 A CN105272927 A CN 105272927A
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- chlordiazepoxide
- formula
- monomethylamine
- reaction
- novel method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D243/14—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
- C07D243/16—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals
- C07D243/18—1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines substituted in position 5 by aryl radicals substituted in position 2 by nitrogen, oxygen or sulfur atoms
- C07D243/20—Nitrogen atoms
Abstract
The invention discloses a novel method for preparing chlordiazepoxide. The method comprises the step of making 7-cl-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-keto-4-oxide react with a monomethylamine micromolecule fatty alcohol solution in the presence of acetic acid and anhydrous magnesium sulfate so that chlordiazepoxide can be prepared. Compared with existing preparing methods, the method has the advantages that the method is simple, reaction conditions are mild, and yield is high; aftertreatment process is simple, product purity is high, environment pollution is not serious, and the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to a kind of novel method preparing chlordiazepoxide.
Background technology
Chlordiazepoxide, has another name called: zeisin, English name: Chlordiazepoxide, chemical name: the chloro-2-methylamino-of 7--5-phenyl-3H-1,4-Benzodiazepine-4-oxide compound.Chemical structure is:
。
Chlordiazepoxide has calmness, weak stable, of flaccid muscles, anticonvulsant action, is usually used in treating anxious and obsessive compulsive neurosis, hysteria, the insomnia of neurastheniac and the irritated hypertension headache of mood etc.Can be used for ethylism and spasm (convulsive seizure caused by meningitis as various in tetanus) in addition, share with antiepileptic drug, can epilepsy grand mal be suppressed, also effective to petit mal.Once in a while as preanesthetic medication to reduce anxiety and anxiety.Meal with wine is used for the treatment of familial, senile and idiopathic action tremor.This product can strengthen the effect of phenothiazines tranquilizer (as chlorpromazine) and oxidase inhibitor (as Supirdyl) and phenothiazines, barbiturates, alcohol etc. when share, and has the danger strengthening CNS inhibition.Lactating women and pregnant woman should avoid use, and especially gestation starts 3 months and gives a birth first 3 months.
The preparation of chlordiazepoxide be generally with 2-amino-5-chlorobenzophenone for raw material, react in ethanol with oxammonium hydrochloride, obtain 2-amino-5-chlorobenzophenone oxime; React with chloroacetyl chloride, obtain 2-chloro acetylamino-5-chlorobenzophenone oxime; Then ring-closure reaction obtains 2-chloromethyl-4-phenyl-6-chloro-quinazoline-3-oxide compound; Last and Monomethylamine reacts, and obtains chlordiazepoxide.Reaction equation is as follows:
。
Document [US2893992], [JournalofOrganicChemistry (1961), 26,1111-18], [zeisin technological innovation, medicine industry, 01 phase in 1973,46-47], [AnnalesPharmaceutiquesFrancaises, 1986,43 (4), 321-8] and [ArchivderPharmazie (Weinheim, Germany), 1994,327 (2), 77-84] etc. above-mentioned synthetic method is reported.
The synthetic method Problems existing of above-mentioned chlordiazepoxide: (1) the first step, reacts with Hydrochloride Hydroxylamine Oximation, and aftertreatment is complicated, in and time, produce a large amount of gas, easily flash occur.Product contains jelly, and content is low, shade deviation, and yield is low.(2) second step acylation reaction, uses first kind solvent (should avoid the solvent used in pharmaceutical production) benzene; Reaction uses chloroacetyl chloride, requires to avoid water, and moisture is too high directly affects quality and yield, if misoperation also may cause Peril Incident.The moisture that chloroacetyl chloride very easily absorbs in air produces Mono Chloro Acetic Acid, causes content to reduce, affects product yield and quality.(3) the 3rd step ring-closure reactions, crude reaction needs to carry out underpressure distillation, and energy consumption is high.
Therefore, the preparation method of exploitation chlordiazepoxide, optimum synthesis technique, reduces the generation of side reaction, improves the quality of products and yield, reduce costs, have great importance for suitability for industrialized production.
Summary of the invention
Object of the present invention is exactly the defect for prior art, provides a kind of novel method preparing chlordiazepoxide.Compare with existing preparation method, it is easy that present method has preparation method, and reaction conditions is gentle, and yield is high; Last handling process is simple, and product purity is high, and environmental pollution is little, is suitable for the advantages such as suitability for industrialized production.
For reaching above-mentioned purpose, the invention provides following technical scheme:
Prepare a novel method for chlordiazepoxide, 7-chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound (II), under acetic acid and anhydrous magnesium sulfate exist, reacts with the small molecules fatty alcohol solution of Monomethylamine, prepare chlordiazepoxide (I), reaction equation is as follows:
。
Prepare a novel method for chlordiazepoxide, formula II is prepared in the reaction of formula I, and the small molecules fatty alcohol solution of described Monomethylamine is the methanol solution of Monomethylamine or the ethanolic soln of Monomethylamine.
A kind of novel method preparing chlordiazepoxide, formula II is prepared in the reaction of formula I, the methanol solution of described Monomethylamine, its concentration is the mass percent concentration of Monomethylamine is 30 ~ 40%, and the ratio of the methanol solution of Monomethylamine and the weight consumption of formula II is 1:1 ~ 2:1.
A kind of novel method preparing chlordiazepoxide, formula II is prepared in the reaction of formula I, the ethanolic soln of described Monomethylamine, its concentration is the mass percent concentration of Monomethylamine is 30 ~ 40%, and the ratio of the ethanolic soln of Monomethylamine and the weight consumption of formula II is 1:1 ~ 2:1.
Prepare a novel method for chlordiazepoxide, formula II is prepared in the reaction of formula I, and the volumetric usage of described acetic acid and the ratio of formula II weight consumption are 0.05:1 ~ 0.1:1.
Prepare a novel method for chlordiazepoxide, formula II is prepared in the reaction of formula I, and the ratio of described anhydrous magnesium sulfate and the weight consumption of formula II is 0.07:1 ~ 0.1:1.
The present invention compared with prior art tool has the following advantages:
1) adopt acetic acid and anhydrous magnesium sulfate to be catalyzer, improve the yield of reaction, reduce cost.
2) preparation method is easy, and reaction conditions is gentle, and process easily controls, and feed stock conversion is high.
3) byproduct of reaction is water, and product is easy to separation and purification, and can obtain the end product that purity is higher, yield is high, pollutes little, is suitable for suitability for industrialized production.
Embodiment
Illustrate the present invention with example below, these examples are intended to help to understand technological method of the present invention.But should be understood that these examples are exemplary, the present invention is not limited thereto.
Embodiment 1:
The chloro-5-phenyl-1 of 7-is added successively in reaction flask, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 286.7g, acetic acid 14.4mL, anhydrous magnesium sulfate 24g and methyl alcohol 600mL, be cooled to 10 ~ 15 DEG C, stir the methanol solution 430.1g that lower slowly dropping mass percent concentration is the Monomethylamine of 35%, control temperature of reaction below 25 DEG C.After dropwising, be incubated 20 ~ 25 DEG C, continue stirring 5 hours.Be cooled to 5 ~ 10 DEG C, insulated and stirred crystallization 1 hour, filter, methanol wash filter cake, is filtered dry, and filter cake adds water making beating, filters, and washing, to neutrality, obtains chlordiazepoxide crude product.After oven dry, add gac and ethanol, heating for dissolving is decoloured, and filtrate cooling crystallization, obtains chlordiazepoxide 244.2g, yield 81.5%, HPLC purity 99.4%.
Embodiment 2:
The chloro-5-phenyl-1 of 7-is added successively in reaction flask, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 286.7g, acetic acid 28.6mL, anhydrous magnesium sulfate 20g and methyl alcohol 500mL, be cooled to 10 ~ 15 DEG C, stir the methanol solution 573.4g that lower slowly dropping mass percent concentration is the Monomethylamine of 30%, control temperature of reaction below 25 DEG C.After dropwising, be incubated 20 ~ 25 DEG C, continue stirring 6 hours.Be cooled to 5 ~ 10 DEG C, insulated and stirred crystallization 1 hour, filter, methanol wash filter cake, is filtered dry, and filter cake adds water making beating, filters, and washing, to neutrality, obtains chlordiazepoxide crude product.After oven dry, add gac and ethanol, heating for dissolving is decoloured, and filtrate cooling crystallization, obtains chlordiazepoxide 251.4g, yield 83.9%, HPLC purity 99.6%.
Embodiment 3:
The chloro-5-phenyl-1 of 7-is added successively in reaction flask, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 286.7g, acetic acid 21.5mL, anhydrous magnesium sulfate 28.6g and methyl alcohol 550mL, be cooled to 10 ~ 15 DEG C, stir the methanol solution 286.7g that lower slowly dropping mass percent concentration is the Monomethylamine of 40%, control temperature of reaction below 25 DEG C.After dropwising, be incubated 20 ~ 25 DEG C, continue stirring 6.5 hours.Be cooled to 5 ~ 10 DEG C, insulated and stirred crystallization 1 hour, filter, methanol wash filter cake, is filtered dry, and filter cake adds water making beating, filters, and washing, to neutrality, obtains chlordiazepoxide crude product.After oven dry, add gac and ethanol, heating for dissolving is decoloured, and filtrate cooling crystallization, obtains chlordiazepoxide 248.3g, yield 82.8%, HPLC purity 99.3%.
Embodiment 4:
The chloro-5-phenyl-1 of 7-is added successively in reaction flask, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 286.7g, acetic acid 14.4mL, anhydrous magnesium sulfate 28.6g and ethanol 500mL, be cooled to 10 ~ 15 DEG C, stir the ethanolic soln 573.4g that lower slowly dropping mass percent concentration is the Monomethylamine of 30%, control temperature of reaction below 25 DEG C.After dropwising, be incubated 20 ~ 25 DEG C, continue stirring 5.5 hours.Be cooled to 5 ~ 10 DEG C, insulated and stirred crystallization 1 hour, filter, washing with alcohol filter cake, is filtered dry, and filter cake adds water making beating, filters, and washing, to neutrality, obtains chlordiazepoxide crude product.After oven dry, add gac and ethanol, heating for dissolving is decoloured, and filtrate cooling crystallization, obtains chlordiazepoxide 256.1g, yield 85.4%, HPLC purity 99.5%.
Embodiment 5:
The chloro-5-phenyl-1 of 7-is added successively in reaction flask, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 286.7g, acetic acid 28.7mL, anhydrous magnesium sulfate 20.0g and ethanol 600mL, be cooled to 10 ~ 15 DEG C, stir the ethanolic soln 480.7g that lower slowly dropping mass percent concentration is the Monomethylamine of 33%, control temperature of reaction below 25 DEG C.After dropwising, be incubated 20 ~ 25 DEG C, continue stirring 5.5 hours.Be cooled to 5 ~ 10 DEG C, insulated and stirred crystallization 1 hour, filter, washing with alcohol filter cake, is filtered dry, and filter cake adds water making beating, filters, and washing, to neutrality, obtains chlordiazepoxide crude product.After oven dry, add gac and ethanol, heating for dissolving is decoloured, and filtrate cooling crystallization, obtains chlordiazepoxide 250.1g, yield 83.4%, HPLC purity 99.7%.
Embodiment 6:
The chloro-5-phenyl-1 of 7-is added successively in reaction flask, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound 286.7g, acetic acid 22.3mL, anhydrous magnesium sulfate 24.5g and ethanol 550mL, be cooled to 10 ~ 15 DEG C, stir the ethanolic soln 286.7g that lower slowly dropping mass percent concentration is 40% Monomethylamine, control temperature of reaction below 25 DEG C.After dropwising, be incubated 20 ~ 25 DEG C, continue stirring 6 hours.Be cooled to 5 ~ 10 DEG C, insulated and stirred crystallization 1 hour, filter, washing with alcohol filter cake, is filtered dry, and filter cake adds water making beating, filters, and washing, to neutrality, obtains chlordiazepoxide crude product.After oven dry, add gac and ethanol, heating for dissolving is decoloured, and filtrate cooling crystallization, obtains chlordiazepoxide 247.6g, yield 82.6%, HPLC purity 99.4%.
Claims (6)
1. prepare the novel method of chlordiazepoxide for one kind, it is characterized in that: the chloro-5-phenyl-1 of 7-, 3-dihydro-2H-1,4-benzodiazepine-2-ketone-4-oxide compound (II), under acetic acid and anhydrous magnesium sulfate exist, react with the small molecules fatty alcohol solution of Monomethylamine, prepare chlordiazepoxide (I), reaction equation is as follows:
。
2. a kind of novel method preparing chlordiazepoxide as claimed in claim 1, it is characterized in that: formula II is prepared in the reaction of formula I, the small molecules fatty alcohol solution of described Monomethylamine is the methanol solution of Monomethylamine or the ethanolic soln of Monomethylamine.
3. a kind of novel method preparing chlordiazepoxide as claimed in claim 2, it is characterized in that: formula II is prepared in the reaction of formula I, the methanol solution of described Monomethylamine, its concentration is the mass percent concentration of Monomethylamine is 30 ~ 40%, and the ratio of the methanol solution of Monomethylamine and the weight consumption of formula II is 1:1 ~ 2:1.
4. a kind of novel method preparing chlordiazepoxide as claimed in claim 2, it is characterized in that: formula II is prepared in the reaction of formula I, the ethanolic soln of described Monomethylamine, its concentration is the mass percent concentration of Monomethylamine is 30 ~ 40%, and the ratio of the ethanolic soln of Monomethylamine and the weight consumption of formula II is 1:1 ~ 2:1.
5. a kind of novel method preparing chlordiazepoxide as claimed in claim 1, it is characterized in that: formula II is prepared in the reaction of formula I, the volumetric usage of described acetic acid and the ratio of formula II weight consumption are 0.05:1 ~ 0.1:1.
6. a kind of novel method preparing chlordiazepoxide as claimed in claim 1, it is characterized in that: formula II is prepared in the reaction of formula I, the ratio of described anhydrous magnesium sulfate and the weight consumption of formula II is 0.07:1 ~ 0.1:1.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060003995A1 (en) * | 2004-06-30 | 2006-01-05 | Wisys Technology Foundation, Inc. | Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects |
| CN101228135A (en) * | 2005-07-21 | 2008-07-23 | 霍夫曼-拉罗奇有限公司 | Pyridazinone derivatives as thyroid hormone receptor agonists |
| US20100261711A1 (en) * | 2009-03-20 | 2010-10-14 | Wisys Technology Foundation | Selective anticonvulsant agents and their uses |
| CN102249946A (en) * | 2011-05-13 | 2011-11-23 | 上海海嘉诺医药发展股份有限公司 | Preparation method of N-alkyloxy oxalyl alanine alkyl ester |
| CN102482280A (en) * | 2009-05-11 | 2012-05-30 | 阿斯利康(瑞典)有限公司 | [1,2,4] triazolo [4,3-b] pyridazines as ligands of the androgen receptor |
-
2015
- 2015-11-17 CN CN201510787661.8A patent/CN105272927A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20060003995A1 (en) * | 2004-06-30 | 2006-01-05 | Wisys Technology Foundation, Inc. | Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedative-hypnotic and ataxic effects |
| CN101228135A (en) * | 2005-07-21 | 2008-07-23 | 霍夫曼-拉罗奇有限公司 | Pyridazinone derivatives as thyroid hormone receptor agonists |
| US20100261711A1 (en) * | 2009-03-20 | 2010-10-14 | Wisys Technology Foundation | Selective anticonvulsant agents and their uses |
| CN102482280A (en) * | 2009-05-11 | 2012-05-30 | 阿斯利康(瑞典)有限公司 | [1,2,4] triazolo [4,3-b] pyridazines as ligands of the androgen receptor |
| CN102249946A (en) * | 2011-05-13 | 2011-11-23 | 上海海嘉诺医药发展股份有限公司 | Preparation method of N-alkyloxy oxalyl alanine alkyl ester |
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Inventor after: Feng Xuan Inventor after: Liu Yuting Inventor after: Zhao Chengan Inventor after: Fu Lin Inventor after: Dai Xianpeng Inventor before: Feng Xuan Inventor before: Fu Lin Inventor before: Dai Xianpeng Inventor before: Zhao Chengan |
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Application publication date: 20160127 |