CN105294582A - Method for preparing chlordiazepoxide hydrochloride with small hygroscopicity - Google Patents
Method for preparing chlordiazepoxide hydrochloride with small hygroscopicity Download PDFInfo
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- CN105294582A CN105294582A CN201510787683.4A CN201510787683A CN105294582A CN 105294582 A CN105294582 A CN 105294582A CN 201510787683 A CN201510787683 A CN 201510787683A CN 105294582 A CN105294582 A CN 105294582A
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- chlordiazepoxide
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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
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A disclosed method for preparing chlordiazepoxide hydrochloride with small hygroscopicity comprises the following steps: (1) successively adding chlordiazepoxide and a micromolecule linear-chain aliphatic ketone, and stirring to raise the temperature to a reaction temperature, slowly dropwise adding a hydrogen chloride acetone solution, after dropwise adding is finished, performing warm-keeping reaction, and filtering while hot, washing, filtering thoroughly and drying, so as to obtain a chlordiazepoxide hydrochloride crude product; and (2) adding the chlordiazepoxide hydrochloride crude product into the micromolecule linear-chain aliphatic ketone, and stirring to raise the temperature to a reaction temperature, performing warm-keeping reaction, filtering while hot, washing, filtering thoroughly and drying, so as to obtain chlordiazepoxide hydrochloride. Compared with a conventional preparation method, the method possesses the advantages of being mild in reaction conditions, simple production technology, easily controllable in process, high in reaction yield, convenient for mother liquor recovery, substantially reduced in cost and suitable for industrialized production, and using a single solvent. The prepared chlordiazepoxide hydrochloride possesses the advantages of small hygroscopicity, high purity and good stability.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, relate to and a kind ofly prepare the method for drawing moist little chlordiazepoxide.
Background technology
Chlordiazepoxide grinds by the international drugmaker (ValeantPharmaceuticalsInc.) of Wa Lante is former, and nineteen sixty goes on the market in the U.S..English name: Chlordiazepoxidehydrochloride; Chemical name: the hydrochloride of chloro-3H-1, the 4-Benzodiazepine of N-methyl-5-phenyl-7--2-amine-4-oxide compound.Chemical structure is:
。
Chlordiazepoxide is mainly used in treating anxiety neurosis, alleviates the symptoms such as anxiety, anxiety, worry, uneasiness and insomnia; Treatment of insomnia patients; The disease of the too high or muscular rigidity for the treatment of muscular tension; Control epileptic seizures is share with antiepileptic drug.The Reposans clinical application of U.S.'s listing is in management anxiety disorder, and short-term relief anxiety symptom, acute alcohol Withrawal symptom and operation consent are frightened.Britain's listing Reposans clinical application is in alleviation generalized anxiety, and its anxiety disorder is severe, cannot bears the misery self occurred, or concurrent insomnia, the psychosoma of short duration, body or mental disorder.The muscle spasm that the various cause of disease causes.Alleviation of alcohol gives up acute generalised symptom.Chlordiazepoxide is not also had to go on the market in other countries such as Japan.
Little about the bibliographical information preparing chlordiazepoxide.The existing preparation method of chlordiazepoxide is mainly raw material with chlordiazepoxide, by obtaining with hydrochloric acid salt-forming reaction.Easily there is degraded and generate the impurity such as 2-amino-5-chlorobenzophenone in chlordiazepoxide, reduces product yield and purity in the presence of water with acid-respons.Contain mass crystallization solvent with the chlordiazepoxide that existing preparation method obtains, by ordinary methods such as dryings except desolventizing, the product that content is qualified cannot be difficult to obtain; The product that content is qualified, fusing point is lower than normal value 5 DEG C, and draw moist higher, poor stability, placement can turn yellow gradually.Affect its standing storage and use.Draw moist height simultaneously and also directly affects the compressing tablet production of chlordiazepoxide tablet and the use of other formulation.
Therefore, develop and a kind ofly prepare the method for drawing moist little chlordiazepoxide, improve its standing storage security and formulated performance, avoid producing hidden danger of quality, industrial production is had great importance.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind ofly prepares the method for drawing moist little chlordiazepoxide.Compare with existing preparation method, present method has reaction conditions gentleness, and production technique is simple, and process easily controls, and reaction yield is high, uses single solvent, and mother liquor is convenient to reclaim, and cost reduces greatly, is suitable for the advantage of suitability for industrialized production.Chlordiazepoxide prepared by present method have draw moist little, purity is high, the advantage of good stability.
For reaching above-mentioned purpose, the invention provides following technical scheme:
Prepare a method of drawing moist little chlordiazepoxide, comprise the steps:
(1) add chlordiazepoxide and small molecules straight chain fatty ketone successively, stir and be warming up to temperature of reaction.Slow dropping hydrogenchloride acetone soln.After dropwising, insulation reaction, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide crude product;
(2) chlordiazepoxide crude product is added in small molecules straight chain fatty ketone, stir and be warming up to temperature of reaction.Insulation reaction, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide.
Prepare a method of drawing moist little chlordiazepoxide, in step (1), described small molecules straight chain fatty ketone is acetone or butanone, and the ratio of the weight consumption of small molecules straight chain fatty ketone and chlordiazepoxide is 4:1 ~ 6:1.
Prepare a method of drawing moist little chlordiazepoxide, in step (1), described temperature of reaction is 50 ~ 60 DEG C.
A kind ofly prepare the method for drawing moist little chlordiazepoxide, in step (1), described hydrogenchloride acetone soln, its concentration is the mass percent concentration of hydrogenchloride is 20 ~ 30%, and the ratio of the acetone soln of hydrogenchloride and the weight consumption of chlordiazepoxide is 0.6:1 ~ 0.8:1.
Prepare a method of drawing moist little chlordiazepoxide, in step (2), described small molecules straight chain fatty ketone is acetone or butanone, and the ratio of the weight consumption of small molecules straight chain fatty ketone and chlordiazepoxide is 6:1 ~ 7:1.
Prepare a method of drawing moist little chlordiazepoxide, in step (2), described temperature of reaction is 50 ~ 60 DEG C.
The present invention compared with prior art tool has the following advantages:
1) chlordiazepoxide that prepared by present method have draw moist little, purity is high, the advantage of good stability;
2) reaction conditions is gentle, and production technique is simple, and process easily controls, and reaction yield is high;
3) reaction uses single solvent, and mother liquor is convenient to reclaim, and cost reduces greatly, is suitable for suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Embodiment 1:
Add chlordiazepoxide 50g and acetone 200g successively, stir and be warming up to 50 ~ 60 DEG C.Under stirring, in 3.0 hours, slowly drip 20 ~ 30% hydrogenchloride acetone soln 35g.After dropwising, be incubated 50 ~ 60 DEG C of reactions 1.5 hours, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide crude product 53g;
Chlordiazepoxide crude product 53g is added in acetone 318g, stirs and be warming up to 50 ~ 60 DEG C.Be incubated 50 ~ 60 DEG C to stir 1.0 hours, filtered while hot.Washing, be filtered dry, drying obtains hydrochloric acid chlorine nitrogen 48g, total recovery 85.6%, content 99.7%, fusing point: 215.5 ~ 216.1 DEG C.
Embodiment 2:
Add chlordiazepoxide 50g and acetone 300g successively, stir and be warming up to 50 ~ 60 DEG C.Under stirring, in 3.0 hours, slowly drip 20 ~ 30% hydrogenchloride acetone soln 40g.After dropwising, be incubated 50 ~ 60 DEG C of reactions 2.0 hours, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide crude product 50g;
Chlordiazepoxide crude product 50g is added in acetone 300g, stirs and be warming up to 50 ~ 60 DEG C.Be incubated 50 ~ 60 DEG C to stir 1.0 hours, filtered while hot.Washing, be filtered dry, drying obtains hydrochloric acid chlorine nitrogen 46g, total recovery 82.0%, content 99.8%, fusing point: 215.1 ~ 215.6 DEG C.
Embodiment 3:
Add chlordiazepoxide 50g and acetone 250g successively, stir and be warming up to 50 ~ 60 DEG C.Under stirring, in 2.5 hours, slowly drip 20 ~ 30% hydrogenchloride acetone soln 30g.After dropwising, be incubated 50 ~ 60 DEG C of reactions 1.5 hours, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide crude product 51g;
Chlordiazepoxide crude product 51g is added in acetone 357g, stirs and be warming up to 50 ~ 60 DEG C.Be incubated 50 ~ 60 DEG C to stir 1.0 hours, filtered while hot.Washing, be filtered dry, drying obtains hydrochloric acid chlorine nitrogen 47g, total recovery 83.8%, content 99.6%, fusing point: 215.3 ~ 215.8 DEG C.
Embodiment 4:
Secondaryly add chlordiazepoxide 50g and butanone 200g, stir and be warming up to 50 ~ 60 DEG C.Under stirring, in 2.0 hours, slowly drip 20 ~ 30% hydrogenchloride acetone soln 30g.After dropwising, be incubated 50 ~ 60 DEG C of reactions 2.0 hours, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide crude product 52g;
Chlordiazepoxide crude product 52g is added in butanone 312g, stirs and be warming up to 50 ~ 60 DEG C.Be incubated 50 ~ 60 DEG C to stir 1.0 hours, filtered while hot.Washing, be filtered dry, drying obtains hydrochloric acid chlorine nitrogen 47g, total recovery 83.8%, content 99.7%, fusing point: 214.3 ~ 214.9 DEG C.
Embodiment 5:
Secondaryly add chlordiazepoxide 50g and butanone 300g, stir and be warming up to 50 ~ 60 DEG C.Under stirring, in 3.0 hours, slowly drip 20 ~ 30% hydrogenchloride acetone soln 40g.After dropwising, be incubated 50 ~ 60 DEG C of reactions 1.5 hours, filtered while hot.Washing, be filtered dry, drying obtains chlordiazepoxide crude product 52g;
Chlordiazepoxide crude product 52g is added in butanone 364g, stirs and be warming up to 50 ~ 60 DEG C.Be incubated 50 ~ 60 DEG C to stir 1.0 hours, filtered while hot.Washing, be filtered dry, drying obtains hydrochloric acid chlorine nitrogen 48g, total recovery 85.6%, content 99.9%, fusing point: 214.6 ~ 215.2 DEG C.
Draw moist experiment:
Draw moist experiment instruction principle according to Chinese Pharmacopoeia 2010 editions annex Ⅺ Ⅹ J medicines to carry out drawing moist experimental result as following table:
| Embodiment | Percentage weight increase | Draw moist feature description |
| 1 | 0.27% | Slightly draw moist |
| 2 | 0.28% | Slightly draw moist |
| 3 | 0.32% | Slightly draw moist |
| 4 | 0.30% | Slightly draw moist |
| 5 | 0.27% | Slightly draw moist |
Claims (6)
1. prepare a method of drawing moist little chlordiazepoxide, it is characterized in that: comprise the steps:
(1) add chlordiazepoxide and small molecules straight chain fatty ketone successively, stir and be warming up to temperature of reaction, slowly drip hydrogenchloride acetone soln, after dropwising, insulation reaction, filtered while hot, washing, be filtered dry, drying obtains chlordiazepoxide crude product;
(2) added by chlordiazepoxide crude product in small molecules straight chain fatty ketone, stir and be warming up to temperature of reaction, insulation reaction, filtered while hot, washing, be filtered dry, drying obtains chlordiazepoxide.
2. a kind ofly as claimed in claim 1 prepare the method for drawing moist little chlordiazepoxide, it is characterized in that: in step (1), described small molecules straight chain fatty ketone is acetone or butanone, and the ratio of the weight consumption of small molecules straight chain fatty ketone and chlordiazepoxide is 4:1 ~ 6:1.
3. a kind ofly as claimed in claim 1 prepare the method for drawing moist little chlordiazepoxide, it is characterized in that: in step (1), described temperature of reaction is 50 ~ 60 DEG C.
4. a kind ofly as claimed in claim 1 prepare the method for drawing moist little chlordiazepoxide, it is characterized in that: in step (1), described hydrogenchloride acetone soln, its concentration is the mass percent concentration of hydrogenchloride is 20 ~ 30%, and the ratio of the acetone soln of hydrogenchloride and the weight consumption of chlordiazepoxide is 0.6:1 ~ 0.8:1.
5. a kind ofly as claimed in claim 1 prepare the method for drawing moist little chlordiazepoxide, it is characterized in that: in step (2), described small molecules straight chain fatty ketone is acetone or butanone, and the ratio of the weight consumption of small molecules straight chain fatty ketone and chlordiazepoxide is 6:1 ~ 7:1.
6. a kind ofly as claimed in claim 1 prepare the method for drawing moist little chlordiazepoxide, it is characterized in that: in step (2), described temperature of reaction is 50 ~ 60 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510787683.4A CN105294582A (en) | 2015-11-17 | 2015-11-17 | Method for preparing chlordiazepoxide hydrochloride with small hygroscopicity |
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| CN201510787683.4A CN105294582A (en) | 2015-11-17 | 2015-11-17 | Method for preparing chlordiazepoxide hydrochloride with small hygroscopicity |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL95335B1 (en) * | 1973-09-19 | 1977-10-31 | METHOD OF PREPARING NON-HYGROSCOPIC CHLORINE RHYAZEPOXIDE | |
| 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 |
-
2015
- 2015-11-17 CN CN201510787683.4A patent/CN105294582A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL95335B1 (en) * | 1973-09-19 | 1977-10-31 | METHOD OF PREPARING NON-HYGROSCOPIC CHLORINE RHYAZEPOXIDE | |
| 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 |
Non-Patent Citations (1)
| Title |
|---|
| L.H.STERNBACH ET AL.: "Quinazolines and 1,4-Benzodiazepines.Ⅱ.The Rearrangement of 6-Chloro-2-chloromethyl-4-phenylquinazoline 3-Oxide into 2-Amino Derivatives of 7-Chloro-5-phenyl-3H-1,4-benzodiazepine4-Oxide", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
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Inventor after: Feng Xuan Inventor after: Fu Lin Inventor after: Liu Yuting Inventor after: Wang Yong Inventor after: Dai Xianpeng Inventor after: Zeng Wei Inventor after: Tian Yulin Inventor before: Feng Xuan Inventor before: Fu Lin Inventor before: Dai Xianpeng Inventor before: Zeng Wei Inventor before: Tian Yulin Inventor before: Wang Yong |
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Application publication date: 20160203 |
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