CN105646508B - A kind of preparation method of nalmefene hydrochloride monohydrate - Google Patents
A kind of preparation method of nalmefene hydrochloride monohydrate Download PDFInfo
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- CN105646508B CN105646508B CN201610088610.0A CN201610088610A CN105646508B CN 105646508 B CN105646508 B CN 105646508B CN 201610088610 A CN201610088610 A CN 201610088610A CN 105646508 B CN105646508 B CN 105646508B
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- preparation
- nalmefene hydrochloride
- organic solvent
- nalmefene
- water
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
Abstract
A kind of preparation method of nalmefene hydrochloride monohydrate, methods described add water and control dosage by the way that nalmefene hydrochloride is dispersed in specific organic solvent, turn crystalline substance, prepared nalmefene hydrochloride monohydrate has high income, purity height, the advantages of stability is high, and non-hygroscopic is good.
Description
Technical field
The present invention relates to a kind of preparation method of nalmefene hydrochloride monohydrate.
Background technology
Nalmefene is a kind of known opioid receptor antagonists, and it can suppress given OPIOIDS activator and by class
The pharmacological effect of both activators caused by opiate system endogenous.Nalmefene comes from it as the Clinical efficacy of antagonist
Quickly (and optionally) reverses the ability of the effect of these opium excitomotors, is included in central nervous system and respiratory system
In common prevent.Nalmefene is a kind of opiate derivative similar in construction to opiate antagonist naltrexone.Phase
Dose-dependant is not found including longer half-life period, larger oral administration biaavailability and for naltrexone, the advantages of nalmefene
Property hepatotoxicity wind agitation.
CN102325778A discloses the preparation method of nalmefene hydrochloride monohydrate, but prepared nalmefene hydrochloride
Monohydrate yield is low, stability is poor and has hygroscopicity.
The content of the invention
The present invention provides a kind of preparation method of nalmefene hydrochloride monohydrate, and methods described is by the way that nalmefene hydrochloride is divided
It is dispersed in specific organic solvent, adds water and control the dosage of water to carry out turning crystalline substance, prepared nalmefene hydrochloride monohydrate tool
There is the advantages of high income, purity is high, and stability is high, and non-hygroscopic is good.
The preparation method of a kind of nalmefene hydrochloride monohydrate of the present invention, it is characterised in that the preparation method includes：
Nalmefene hydrochloride is scattered in organic solvent, add water, turn brilliant obtained nalmefene hydrochloride monohydrate, and it is described organic molten
Agent is selected from least one of dichloromethane, chloroform.
Preferably, above-mentioned organic solvent is dichloromethane.
Preferably, the weight ratio of above-mentioned nalmefene hydrochloride and water is 1：0.1 ~ 0.8, preferably 1：0.24~0.72.
Preferably, the ratio of above-mentioned nalmefene hydrochloride and organic solvent is 1：5~15（g/ml）, preferably 1：8~12（g/
ml）, more preferably 1：10（g/ml）.
Preferably, above-mentioned preparation method includes：Nalmefene hydrochloride is disperseed in organic solvent, to add water, flowed back, cooling,
Filtering, dry, nalmefene hydrochloride monohydrate is made.
Preferably, above-mentioned preparation method includes：According to formula dosage, nalmefene hydrochloride is dispersed in dichloromethane, stirred
Mix down and be slowly dropped into purified water, heat up, flow back 1h, is cooled to 10-15 DEG C, filtering, 40 DEG C of dryings, the water of nalmefene hydrochloride one is made
Compound.
The preparation method of the present invention, by the way that nalmefene hydrochloride is dispersed in specific organic solvent, controls the dosage of water,
Prepared nalmefene hydrochloride monohydrate substantially increases yield, purity, and stability is good, and has the advantages of non-hygroscopic.
Embodiment
The embodiment of the present invention is described in detail below.It is it should be appreciated that described herein specific
Being given for example only property of embodiment description and interpretation the present invention, be not intended to limit the invention.
Embodiment 1
5.0g nalmefene hydrochloride samples（Moisture 3.57%）Disperseed with 50ml dichloromethane, it is pure to be slowly dropped into 2.4g under stirring
Change water, be warming up to backflow keep 1h, after be cooled to 10-15 DEG C of filtering, 40 DEG C of dryings of filter cake obtain nalmefene hydrochloride one to constant weight
Hydrate, the amount of obtaining 4.68g, moisture 5.23%, yield 92.0%.
Embodiment 2
5.0g nalmefene hydrochloride samples（Moisture 3.57%）Disperseed with 50ml dichloromethane, it is pure to be slowly dropped into 1.2g under stirring
Change water, be warming up to backflow keep 1h, after be cooled to 10-15 DEG C of filtering, 40 DEG C of dryings of filter cake obtain nalmefene hydrochloride one to constant weight
Hydrate, the amount of obtaining 4.66g, moisture 5.11%, yield 91.7%.
Embodiment 3
5.0g nalmefene hydrochloride samples（Moisture 3.57%）Disperseed with 50ml dichloromethane, it is pure to be slowly dropped into 3.6g under stirring
Change water, be warming up to backflow keep 1h, after be cooled to 10-15 DEG C of filtering, 40 DEG C of dryings of filter cake obtain nalmefene hydrochloride one to constant weight
Hydrate, the amount of obtaining 4.48g, moisture 5.25%, yield 88.0%.
Embodiment 4
5.0g nalmefene hydrochloride samples（Moisture 3.57%）Disperseed with 50ml chloroforms, 2.4g purified waters be slowly dropped under stirring,
Be warming up to 40-45 DEG C holding 1h, after be cooled to 10-15 DEG C of filtering, 40 DEG C of dryings of filter cake obtain the water of nalmefene hydrochloride one to constant weight
Compound, the amount of obtaining 4.50g, moisture 5.20%, yield 88.5%.
Comparative example 1
5.0g nalmefene hydrochloride samples（Moisture 3.57%）Disperseed with 50ml dichloromethane, it is pure to be slowly dropped into 4.8g under stirring
Change water, be warming up to backflow keep 1h, after be cooled to 10-15 DEG C of filtering, 40 DEG C of dryings of filter cake obtain nalmefene hydrochloride one to constant weight
Hydrate, the amount of obtaining 3.58g, moisture 5.32%, yield 70.3%.
Comparative example 2
5.0g nalmefene hydrochloride samples（Moisture 3.57%）Disperseed with 50ml ethyl acetate, it is pure to be slowly dropped into 2.4g under stirring
Change water, be warming up to 40-45 DEG C of holding 1h, after be cooled to 10-15 DEG C of filtering, 40 DEG C of dryings of filter cake to constant weight, obtain hydrochloric acid and receive U.S.
Fragrant solid, the amount of obtaining 4.60g, moisture 3.90%, nalmefene hydrochloride monohydrate can not be obtained.
Comparative example 3
By 25g nalmefene hydrochlorides（Moisture 3.57%）It is suspended in 32ml water, heats the mixture to 80 DEG C, vacuum distillation
Low boiling point organic solvent, using the linear gradient, solution is cooled to 20 DEG C with 1 hour.Suspension is kept stirring for 2h, Ran Houyong
1h is cooled to 4 DEG C, and is kept stirring for 1h again at such a temperature, crosses filter solid, is washed with 25ml acetone.By wet solid at 30 DEG C
It is dried in vacuum overnight, the amount of obtaining 14.1g, moisture 4.90%, yield 55.6%.
Comparative example 4
To 5.0g nalmefene hydrochloride samples（Moisture 3.57%）4.0g purified waters are added, the water of nalmefene hydrochloride one can not be obtained
Compound.
From above example and comparative example, the present invention is specific organic molten by using nalmefene hydrochloride is dispersed in
In agent, the dosage of specific water is selected to carry out turning crystalline substance, the yield of prepared nalmefene hydrochloride monohydrate substantially increases.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
Claims (8)
1. a kind of preparation method of nalmefene hydrochloride monohydrate, it is characterised in that the preparation method includes：Hydrochloric acid is received into U.S.
Sweet smell is scattered in organic solvent, adds water, the weight ratio of the nalmefene hydrochloride and water is 1：0.1~0.8, turn brilliant obtained hydrochloric acid and receive
U.S. fragrant monohydrate, and described organic solvent is selected from least one of dichloromethane, chloroform.
2. preparation method according to claim 1, it is characterised in that the organic solvent is dichloromethane.
3. preparation method according to claim 1, it is characterised in that the weight ratio of the nalmefene hydrochloride and water is 1：
0.24~0.72.
4. preparation method according to claim 1, it is characterised in that the ratio of the nalmefene hydrochloride and organic solvent with
G/ml is calculated as 1：5~15.
5. preparation method according to claim 4, it is characterised in that the ratio of the nalmefene hydrochloride and organic solvent with
G/ml is calculated as 1：8~12.
6. preparation method according to claim 5, it is characterised in that the ratio of the nalmefene hydrochloride and organic solvent with
G/ml is calculated as 1：10.
7. according to the preparation method any one of claim 1-6, it is characterised in that the preparation method includes：By salt
Sour nalmefene is scattered to add water in organic solvent, flows back, cools, filter, dry, nalmefene hydrochloride monohydrate is made.
8. preparation method according to claim 7, it is characterised in that the preparation method includes：, will according to formula dosage
Nalmefene hydrochloride is dispersed in dichloromethane, and purified water is slowly dropped under stirring, heating, and flow back 1h, is cooled to 10-15 DEG C, mistake
Filter, 40 DEG C of dryings, nalmefene hydrochloride monohydrate is made.
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| CN105646508B true CN105646508B (en) | 2018-02-27 |
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| US10927121B1 (en) * | 2019-12-20 | 2021-02-23 | Southwest Research Institute | Technologies for removing residual solvent from nalmefene hydrochloride and producing crystalline nalmefene hydrochloride monohydrate, monosolvate, or crystalline nalmefene hydrochloride dihydrate |
| CN113354652A (en) * | 2021-06-24 | 2021-09-07 | 无锡济煜山禾药业股份有限公司 | Synthesis method of nalmefene hydrochloride |
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| UA102128C2 (en) * | 2008-12-05 | 2013-06-10 | Х. Луннбек А/С | Nalmefene hydrochloride dihydrate |
| TWI560170B (en) * | 2011-12-06 | 2016-12-01 | Lundbeck & Co As H | Process for recovery of nalmefene hydrochloride |
| CN103204859B (en) * | 2013-04-25 | 2015-12-02 | 四川海思科制药有限公司 | A kind of Nalmefene hydrochloride compound and preparation method thereof |
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Effective date of registration: 20171124 Address after: 210009, five building, Jiangsu Drug Institute, 26 Ma Jia street, Gulou District, Nanjing, Jiangsu Applicant after: Nanjing Zhuo Kang medical science and Technology Co., Ltd. Address before: 210009, Ma Jia street, Gulou District, Jiangsu, 26, Nanjing Applicant before: NANJING ZHUOTAI PHARMACEUTICAL CO., LTD. |
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