CN108341821A - A kind of synthetic method of epinastine hydrochloride - Google Patents
A kind of synthetic method of epinastine hydrochloride Download PDFInfo
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- CN108341821A CN108341821A CN201810315907.5A CN201810315907A CN108341821A CN 108341821 A CN108341821 A CN 108341821A CN 201810315907 A CN201810315907 A CN 201810315907A CN 108341821 A CN108341821 A CN 108341821A
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- dibenzo
- azepine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The invention discloses a kind of synthetic methods of epinastine hydrochloride, are related to pharmaceutical technology field, include the following steps：With 6 cyano 6,11 1H dibenzo [b, e] azepineIt, using the methanol solution of ammonia as solvent, is passed through hydrogen generation reduction reaction in the presence of Raney Ni for raw material and obtains 6 (amino methyl) 6,11 dihydro 1H dibenzo [b, e] azepineBy 6 (amino methyl) 6,11 dihydro 1H dibenzo [b, e] azepineWith cyanogen bromide ring-closure reaction, then with alkali neutralization, 3 amino 9,13b dihydro 1H dibenzo [c, f] imidazo [1,5 a] azepine are obtainedBy 3 amino 9,13b dihydro 1H dibenzo [c, f] imidazo [1,5 a] azepines
Description
Technical field
The present invention relates to pharmaceutical technology field more particularly to a kind of synthetic methods of epinastine hydrochloride.
Background technology
The entitled epinastine hydrochloride of epinastine hydrochloride English, entitled 3- amino -9, the 13- dihydro of chemistry
- 1H- dibenzo [c, f]-imidazo [1,5-a] azepineHydrochloride, structure are shown below, be one kind by German Bo Linge
A kind of orally active antihistamine that Yin Gehan companies succeed in developing, with the total further joint development city of pharmacy cooperation of Japan three
, 1994 in Japanese Initial Public Offering, trade name " Alesion ".
Epinastine hydrochloride is for treating bronchial asthma, allergic dermatitis, nettle rash, eczema, dermatitis and common silver bits
Sick (psoriasis) has very strong inhibiting effect for the bronchoconstriction caused by histamine and bradykinin, and to by other
Bronchoconstriction caused by chemical mediator is then the most effective group for acting on perineural no sedation without inhibiting effect
One of amine H1 receptor antagonists.
Currently, the preparation method of epinastine hydrochloride mainly has：
With 6,11- dihydro -5H- dibenzo [b, e] azepineFor starting material, cyano -6 6- are made in the presence of DMSO,
11-1H- dibenzo [b, e] azepineHydrogenated aluminium lithium or hydrogenation aluminium reducing obtain 6- (amino methyl) -6,11- dihydros-again
1H- dibenzo [b, e] azepineAnd after being translated into fumarate processing, 3- ammonia is made with cyanogen bromide cyclization in ethanol
Base -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineIt is suspended in methanol, it is molten with HCl- ether
Liquid handles to obtain epinastine hydrochloride.But this method preparation process is more, and required time is long, and used severe toxicity Cymag and
Expensive and inflammable lithium aluminium hydride reduction or aluminum hydride, and the yield in reduction step is not high, is not suitable for large-scale industrialization
Production；Also it is that starting material is converted into richness through sodium borohydride reduction to have with 6- cyano -6,11-1H- dibenzo [b, e] azepine
Horse hydrochlorate is refined, and 6- (amino methyl) -6,11- dihydro -1H dibenzo [b, e] azepine is obtainedIt is obtained again through cyanogen bromide cyclization
3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineHydrobromate turns it with sodium hydroxide
It turns to epinastine, then through ethanol solution hydrochloride at salt, uses sodium borohydride to have boron for reducing agent in the technique and generate, can draw
Enter impurity phase, and the yield in reduction step is not high.Therefore, the application improves its synthesis technology.
Invention content
Technical problems based on background technology, the present invention propose a kind of synthetic method of epinastine hydrochloride, institute
The purity and yield of epinastine hydrochloride obtained are high, and simple for process, take short.
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, with 6- cyano -6,11-1H- dibenzo [b, e] azepineFor raw material, in the presence of Raney-Ni, with the first of ammonia
Alcoholic solution is solvent, is passed through hydrogen generation reduction reaction and obtains 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] nitrogen
It is miscellaneous
S2, by 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepine3- ammonia is generated with cyanogen bromide cyclization
Base -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineHydrobromate obtain 3- amino-with alkali neutralization
9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
S3, by 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineWith hydrochloric acid at salt, i.e.,
.
Preferably, in the S1, by 6- cyano -6,11-1H- dibenzo [b, e] azepineIt is added in autoclave, then
The methanol solution of Raney-Ni, ammonia is added, is passed through hydrogen, is stirred to react, filters, by filtrate concentration and recovery methanol, extraction is washed
It washs, it is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepine
Preferably, in the S1, by 100 parts of 6- cyano -6,11-1H- dibenzo [b, e] azepinesAutoclave is added
In, the methanol solution of 4-8 parts of Raney-Ni, 400-500 parts of ammonia is added, hydrogen is passed through, 4- is stirred to react at 25-30 DEG C
Filtrate concentration and recovery methanol is added dichloromethane and is extracted, extract liquor saturated common salt water washing is done by 7h, filtering
It is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepine
Preferably, in the S1, it is passed through hydrogen, it is 2.5-3.0MPa to control pressure in autoclave.
Preferably, in the S1, preparing for the methanol solution of ammonia is as follows：Under ice bath, ammonia is passed into methanol directly
To saturation to get.
Preferably, in the S2, by 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepineUse dichloromethane
Alkane dissolves, and cyanogen bromide is added, is stirred to react, cools down after reaction, and crystallization filters, is dissolved in water and suspension is made, and uses
NaOH solution adjusts pH value to 10-11, stirs, and cooling, crystallization, filtering, filter cake is washed with water to neutrality, dry, obtains 3- amino-
9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
Preferably, in the S2, by 100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepineWith
300-400 parts of dichloromethane dissolvings, are added 30-40 parts of cyanogen bromides, 12-15h are stirred to react at 25-30 DEG C, after reaction
It is cooled to 0-5 DEG C, crystallization filters, is dissolved in 200-300 parts of water and suspension is made, and pH value is adjusted with 10% NaOH solution
To 10-11,2-3h is stirred, is cooled to 0-5 DEG C, crystallization, filtering, filter cake is washed with water to neutrality, dry, obtains amino -9 3-,
13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
Preferably, in the S3, by 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
It is added in ethyl alcohol, stirring and dissolving, concentrated hydrochloric acid is added dropwise and adjusts pH value to 2-3, stirs, cooling, crystallization filters, recrystallization, mistake
Filter, it is dry to get.
Preferably, in the S3, by 100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazos [1,5-a]
AzepineIt is added in 400-500 parts of ethyl alcohol, stirring and dissolving, concentrated hydrochloric acid is added dropwise and adjusts pH value to 2-3,3-5h is stirred at room temperature, it is cold
But to 0-5 DEG C, crystallization, filtering, 60% ethyl alcohol recrystallization of filter cake, filtering, dry to get.
Advantageous effect：The present invention is with 6,11- dihydro -5H- dibenzo [b, e] azepineFor starting material, avoid using play
The Cymag of poison, and use Raney-Ni as catalyst in reduction step, catalytic hydrogenation is carried out in the methanol solution of ammonia
Reaction, reaction condition is mild, and the reaction time is shorter, and reduzate yield up to 90% or more, stablize by entire synthesis technology, reaction
Step is simple, and the used time is short, the purity and high income of obtained epinastine hydrochloride.
Specific implementation mode
In the following, technical scheme of the present invention is described in detail by specific embodiment.
Embodiment 1
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, with 6- cyano -6,11-1H- dibenzo [b, e] azepineFor raw material, in the presence of Raney-Ni, with the first of ammonia
Alcoholic solution is solvent, is passed through hydrogen generation reduction reaction and obtains 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] nitrogen
It is miscellaneous
S2, by 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepine3- ammonia is generated with cyanogen bromide cyclization
Base -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineHydrobromate obtain 3- amino-with alkali neutralization
9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
S3, by 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineWith hydrochloric acid at salt, i.e.,
.
Embodiment 2
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, by 100 parts of 6- cyano -6,11-1H- dibenzo [b, e] azepinesIt is added in autoclave, adds 4 parts
The methanol solution of Raney-Ni, 400 parts of ammonia are passed through hydrogen, and it is 2.5MPa to control pressure in autoclave, is stirred at 25 DEG C
4h is reacted, filtrate concentration and recovery methanol is added dichloromethane and is extracted by filtering, by extract liquor saturated common salt water washing,
It is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepineCross chromatography, yield 90.1%；Wherein,
Preparing for the methanol solution of ammonia is as follows：Under ice bath, by ammonia be passed into methanol until be saturated to get；
S2, by 100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepinesWith 300 parts of dichloromethane
Dissolving is added 30 parts of cyanogen bromides, 12h is stirred to react at 25 DEG C, is cooled to 0 DEG C after reaction, and crystallization filters, its is molten
Suspension is made in 200 parts of water, adjusts pH value to 10 with 10% NaOH solution, stirs 2h, be cooled to 0 DEG C, crystallization filters,
Filter cake is washed with water to neutrality, dry, obtains 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
S3, by 100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepinesIt is added to
In 400 parts of ethyl alcohol, stirring and dissolving is added dropwise concentrated hydrochloric acid and adjusts pH value to 2,3h is stirred at room temperature, is cooled to 0 DEG C, and crystallization filters, filter
60% ethyl alcohol recrystallization of cake, filtering, it is dry to get.
Embodiment 3
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, by 100 parts of 6- cyano -6,11-1H- dibenzo [b, e] azepinesIt is added in autoclave, adds 5 parts
The methanol solution of Raney-Ni, 420 parts of ammonia are passed through hydrogen, and it is 2.6MPa to control pressure in autoclave, is stirred at 27 DEG C
Reaction 5h is mixed, filtrate concentration and recovery methanol is added dichloromethane and is extracted, extract liquor is washed with saturated common salt by filtering
It washs, it is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepineCross chromatography, yield 91.8%；Its
In, preparing for the methanol solution of ammonia is as follows：Under ice bath, by ammonia be passed into methanol until be saturated to get；
S2, by 100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepinesWith 320 parts of dichloromethane
Dissolving is added 32 parts of cyanogen bromides, 13h is stirred to react at 25 DEG C, is cooled to 2 DEG C after reaction, and crystallization filters, its is molten
Suspension is made in 230 parts of water, adjusts pH value to 10 with 10% NaOH solution, stirs 2h, be cooled to 2 DEG C, crystallization filters,
Filter cake is washed with water to neutrality, dry, obtains 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
S3, by 100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepinesIt is added to
In 420 parts of ethyl alcohol, stirring and dissolving is added dropwise concentrated hydrochloric acid and adjusts pH value to 2,3.5h is stirred at room temperature, is cooled to 2 DEG C, and crystallization filters,
60% ethyl alcohol recrystallization of filter cake, filtering, it is dry to get.
Embodiment 4
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, by 100 parts of 6- cyano -6,11-1H- dibenzo [b, e] azepinesIt is added in autoclave, adds 6 parts
The methanol solution of Raney-Ni, 450 parts of ammonia are passed through hydrogen, and it is 2.8MPa to control pressure in autoclave, is stirred at 28 DEG C
Reaction 6h is mixed, filtrate concentration and recovery methanol is added dichloromethane and is extracted, extract liquor is washed with saturated common salt by filtering
It washs, it is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepineCross chromatography, yield 93.3%；Its
In, preparing for the methanol solution of ammonia is as follows：Under ice bath, by ammonia be passed into methanol until be saturated to get；
S2, by 100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepinesWith 350 parts of dichloromethane
Dissolving is added 35 parts of cyanogen bromides, 14h is stirred to react at 28 DEG C, is cooled to 3 DEG C after reaction, and crystallization filters, its is molten
Suspension is made in 250 parts of water, adjusts pH value to 10.5 with 10% NaOH solution, stirs 2.5h, is cooled to 3 DEG C, crystallization,
Filtering, filter cake are washed with water to neutrality, dry, obtain 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a]
Azepine
S3, by 100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepinesIt is added to
In 450 parts of ethyl alcohol, stirring and dissolving is added dropwise concentrated hydrochloric acid and adjusts pH value to 2.5,4h is stirred at room temperature, is cooled to 3 DEG C, and crystallization filters,
60% ethyl alcohol recrystallization of filter cake, filtering, it is dry to get.
Embodiment 5
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, by 100 parts of 6- cyano -6,11-1H- dibenzo [b, e] azepinesIt is added in autoclave, adds 7 parts
The methanol solution of Raney-Ni, 480 parts of ammonia are passed through hydrogen, and it is 3.0MPa to control pressure in autoclave, is stirred at 30 DEG C
Reaction 6h is mixed, filtrate concentration and recovery methanol is added dichloromethane and is extracted, extract liquor is washed with saturated common salt by filtering
It washs, it is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepineCross chromatography, yield 93.5%；Its
In, preparing for the methanol solution of ammonia is as follows：Under ice bath, by ammonia be passed into methanol until be saturated to get；
S2, by 100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepinesWith 350 parts of dichloromethane
Dissolving is added 38 parts of cyanogen bromides, 14h is stirred to react at 25 DEG C, is cooled to 3 DEG C after reaction, and crystallization filters, its is molten
Suspension is made in 250 parts of water, adjusts pH value to 10.5 with 10% NaOH solution, stirs 3h, is cooled to 2 DEG C, crystallization, mistake
Filter, filter cake are washed with water to neutrality, dry, obtain 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] nitrogen
It is miscellaneous
S3, by 100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepinesIt is added to
In 450 parts of ethyl alcohol, stirring and dissolving is added dropwise concentrated hydrochloric acid and adjusts pH value to 3,4h is stirred at room temperature, is cooled to 2 DEG C, and crystallization filters, filter
60% ethyl alcohol recrystallization of cake, filtering, it is dry to get.
Embodiment 6
A kind of synthetic method of epinastine hydrochloride proposed by the present invention, includes the following steps：
S1, by 100 parts of 6- cyano -6,11-1H- dibenzo [b, e] azepinesIt is added in autoclave, adds 8 parts
The methanol solution of Raney-Ni, 500 parts of ammonia are passed through hydrogen, and it is 3.0MPa to control pressure in autoclave, is stirred at 30 DEG C
Reaction 7h is mixed, filtrate concentration and recovery methanol is added dichloromethane and is extracted, extract liquor is washed with saturated common salt by filtering
It washs, it is dry, obtain 6- (amino methyl) -6,11-1H- dibenzo [b, e] azepineCross chromatography, yield 93.0%；Its
In, preparing for the methanol solution of ammonia is as follows：Under ice bath, by ammonia be passed into methanol until be saturated to get；
S2, by 100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepinesWith 400 parts of dichloromethane
Dissolving is added 40 parts of cyanogen bromides, 15h is stirred to react at 30 DEG C, is cooled to 5 DEG C after reaction, and crystallization filters, its is molten
Suspension is made in 300 parts of water, adjusts pH value to 11 with 10% NaOH solution, stirs 3h, be cooled to 5 DEG C, crystallization filters,
Filter cake is washed with water to neutrality, dry, obtains 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
S3, by 100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepinesIt is added to
In 500 parts of ethyl alcohol, stirring and dissolving is added dropwise concentrated hydrochloric acid and adjusts pH value to 3,5h is stirred at room temperature, is cooled to 5 DEG C, and crystallization filters, filter
60% ethyl alcohol recrystallization of cake, filtering, it is dry to get.
The foregoing is only a preferred embodiment of the present invention, but scope of protection of the present invention is not limited thereto,
Any one skilled in the art in the technical scope disclosed by the present invention, according to the technique and scheme of the present invention and its
Inventive concept is subject to equivalent substitution or change, should be covered by the protection scope of the present invention.
Claims (9)
1. a kind of synthetic method of epinastine hydrochloride, which is characterized in that include the following steps：
S1, with 6- cyano -6,11-1H- dibenzo [b, e] azepineIt is molten with the methanol of ammonia in the presence of Raney-Ni for raw material
Liquid is solvent, is passed through hydrogen generation reduction reaction and obtains 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepine
S2, by 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepineAmino -9 3- are generated with cyanogen bromide cyclization,
13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineHydrobromate obtain 3- amino -9,13b- with alkali neutralization
Dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepine
S3, by 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineWith hydrochloric acid at salt to get.
2. the synthetic method of epinastine hydrochloride according to claim 1, which is characterized in that in the S1, by 6- cyano-
6,11-1H- dibenzo [b, e] azepineIt is added in autoclave, adds the methanol solution of Raney-Ni, ammonia, be passed through hydrogen
Gas is stirred to react, filtering, and filtrate concentration and recovery methanol extracts, washs, dry, obtains 6- (amino methyl) -6,11-1H- bis-
Benzo [b, e] azepine
3. the synthetic method of epinastine hydrochloride according to claim 1 or 2, which is characterized in that in the S1, by 100
Part 6- cyano -6,11-1H- dibenzo [b, e] azepineIt is added in autoclave, adds 4-8 parts of Raney-Ni, 400-
The methanol solution of 500 parts of ammonia, is passed through hydrogen, and 4-7h is stirred to react at 25-30 DEG C, and filtering by filtrate concentration and recovery methanol, adds
Enter dichloromethane to be extracted, it is dry by extract liquor saturated common salt water washing, obtain 6- (amino methyl) -6,11-1H- hexichol
And [b, e] azepine
4. according to the synthetic method of any epinastine hydrochlorides of claim 1-3, which is characterized in that in the S1, lead to
Enter hydrogen, it is 2.5-3.0MPa to control pressure in autoclave.
5. according to the synthetic method of any epinastine hydrochlorides of claim 1-4, which is characterized in that in the S1, ammonia
Methanol solution prepare it is as follows：Under ice bath, by ammonia be passed into methanol until be saturated to get.
6. according to the synthetic method of any epinastine hydrochlorides of claim 1-5, which is characterized in that, will in the S2
6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepineIt is dissolved with dichloromethane, cyanogen bromide is added, stirring is anti-
It answers, cools down after reaction, crystallization filters, is dissolved in water and suspension is made, and adjusts pH value to 10-11 with NaOH solution, stirs
It mixes, cooling, crystallization, filtering, filter cake is washed with water to neutrality, dry, obtains 3- amino -9,13b- dihydro -1H- dibenzo [c, f]
Imidazo [1,5-a] azepine
7. according to the synthetic method of any epinastine hydrochlorides of claim 1-6, which is characterized in that, will in the S2
100 parts of 6- (amino methyl) -6,11- dihydro -1H- dibenzo [b, e] azepinesIt is dissolved, is added with 300-400 parts of dichloromethane
30-40 parts of cyanogen bromides, are stirred to react 12-15h at 25-30 DEG C, are cooled to 0-5 DEG C after reaction, and crystallization filters, by it
It is dissolved in 200-300 parts of water and suspension is made, adjust pH value to 10-11 with 10% NaOH solution, stir 2-3h, be cooled to 0-5
DEG C, crystallization, filtering, filter cake is washed with water to neutrality, dry, obtains 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo
[1,5-a] azepine
8. according to the synthetic method of any epinastine hydrochlorides of claim 1-7, which is characterized in that, will in the S3
3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepineIt is added in ethyl alcohol, stirring and dissolving, is added dropwise
Concentrated hydrochloric acid adjusts pH value to 2-3, stirs, cooling, and crystallization filters, and recrystallizes, filtering, it is dry to get.
9. according to the synthetic method of any epinastine hydrochlorides of claim 1-8, which is characterized in that, will in the S3
100 parts of 3- amino -9,13b- dihydro -1H- dibenzo [c, f] imidazo [1,5-a] azepinesIt is added to 400-500 parts of ethyl alcohol
In, stirring and dissolving is added dropwise concentrated hydrochloric acid and adjusts pH value to 2-3,3-5h is stirred at room temperature, is cooled to 0-5 DEG C, and crystallization filters, and filter cake is used
60% ethyl alcohol recrystallization, filtering, it is dry to get.
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| 郭建锋等: "盐酸依匹斯汀的合成工艺研究", 《现代药物与临床》 * |
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