CN105646508A - Preparation method of nalmefene hydrochloride monohydrate - Google Patents
Preparation method of nalmefene hydrochloride monohydrate Download PDFInfo
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- CN105646508A CN105646508A CN201610088610.0A CN201610088610A CN105646508A CN 105646508 A CN105646508 A CN 105646508A CN 201610088610 A CN201610088610 A CN 201610088610A CN 105646508 A CN105646508 A CN 105646508A
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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
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Abstract
The invention discloses a preparation method of a nalmefene hydrochloride monohydrate. According to the method, nalmefene hydrochloride is dispersed in a specific organic solvent, water is added, the dosage is controlled, and crystal transformation is performed. The prepared nalmefene hydrochloride monohydrate has the advantages of high yield, high purity, high stability and good nonabsorbent property.
Description
Technical field
The present invention relates to the preparation method of a kind of Revex monohydrate.
Background technology
Nalmefene is a kind of known opioid receptor antagonists, and it can suppress the OPIOIDS agonist given and the pharmacological effect of the agonist by the endogenous property generation of OPIOIDS system. Nalmefene as the Clinical efficacy of antagonist come from its fast (and optionally) reverse the ability of the effect of these opiates agonists, be included in central nervous system and unify common preventing in respiratory system. Nalmefene is the opiate derivative being similar to opiate antagonist naltrexone in a kind of structure. Relative to TREXUPONT, the advantage of Nalmefene comprises longer transformation period, bigger oral administration biaavailability and does not find dose-dependently liver toxicity.
CN102325778A discloses the preparation method of Revex monohydrate, but prepared Revex monohydrate receipts rate is low, stability is poor and has water absorbability.
Summary of the invention
The present invention provides the preparation method of a kind of Revex monohydrate, described method by being dispersed in specific organic solvent by Revex, the consumption added water and control water carries out turning brilliant, prepared Revex monohydrate has receipts rate height, purity height, stability height, the advantage that non-hygroscopic is good.
The preparation method of a kind of Revex monohydrate of the present invention, it is characterized in that, described preparation method comprises: disperseed in organic solvent by Revex, add water, turn brilliant obtained Revex monohydrate, and at least one that described organic solvent is selected from methylene dichloride, chloroform.
Preferably, above-mentioned organic solvent is methylene dichloride.
Preferably, the weight ratio of above-mentioned Revex and water is 1:0.1 ~ 0.8, it is preferable to 1:0.24 ~ 0.72.
Preferably, the ratio of above-mentioned Revex and organic solvent is 1:5 ~ 15(g/ml), it is preferable to 1:8 ~ 12(g/ml), it is more preferable to it is 1:10(g/ml).
Preferably, above-mentioned preparation method comprises: is disperseed in organic solvent by Revex, adds water, backflow, and cooling is filtered, dry, obtained Revex monohydrate.
Preferably, above-mentioned preparation method comprises: according to formula consumption, be dispersed in methylene dichloride by Revex, stirs lower slow and enters purified water, heats up, and backflow 1h, is cooled to 10-15 DEG C, filters, 40 DEG C of dryings, obtains Revex monohydrate.
The preparation method of the present invention, by being dispersed in by Revex in specific organic solvent, the consumption of control water, prepared Revex monohydrate substantially increases receipts rate, purity, good stability, and has non-hygroscopic advantage.
Embodiment
Hereinafter the specific embodiment of the present invention is described in detail. Should be understood that, embodiment described herein only for exemplarily description and interpretation the present invention, is not limited to the present invention.
Embodiment 1
5.0g Revex sample (moisture 3.57%) disperses with 50ml methylene dichloride, stir lower slow and enter 2.4g purified water, it is warming up to backflow and keeps 1h, after be cooled to 10-15 DEG C of filtration, filter cake 40 DEG C is dried to constant weight, obtains Revex monohydrate, the amount of obtaining 4.68g, moisture content 5.23%, receipts rate 92.0%.
Embodiment 2
5.0g Revex sample (moisture 3.57%) disperses with 50ml methylene dichloride, stir lower slow and enter 1.2g purified water, it is warming up to backflow and keeps 1h, after be cooled to 10-15 DEG C of filtration, filter cake 40 DEG C is dried to constant weight, obtains Revex monohydrate, the amount of obtaining 4.66g, moisture content 5.11%, receipts rate 91.7%.
Embodiment 3
5.0g Revex sample (moisture 3.57%) disperses with 50ml methylene dichloride, stir lower slow and enter 3.6g purified water, it is warming up to backflow and keeps 1h, after be cooled to 10-15 DEG C of filtration, filter cake 40 DEG C is dried to constant weight, obtains Revex monohydrate, the amount of obtaining 4.48g, moisture content 5.25%, receipts rate 88.0%.
Embodiment 4
5.0g Revex sample (moisture 3.57%) disperses with 50ml chloroform, stir lower slow and enter 2.4g purified water, it is warming up to 40-45 DEG C and keeps 1h, after be cooled to 10-15 DEG C of filtration, filter cake 40 DEG C is dried to constant weight, obtains Revex monohydrate, the amount of obtaining 4.50g, moisture content 5.20%, receipts rate 88.5%.
Comparative example 1
5.0g Revex sample (moisture 3.57%) disperses with 50ml methylene dichloride, stir lower slow and enter 4.8g purified water, it is warming up to backflow and keeps 1h, after be cooled to 10-15 DEG C of filtration, filter cake 40 DEG C is dried to constant weight, obtains Revex monohydrate, the amount of obtaining 3.58g, moisture content 5.32%, receipts rate 70.3%.
Comparative example 2
5.0g Revex sample (moisture 3.57%) disperses by 50ml ethyl acetate, stir lower slow and enter 2.4g purified water, it is warming up to 40-45 DEG C and keeps 1h, after be cooled to 10-15 DEG C of filtration, filter cake 40 DEG C is dried to constant weight, obtains Revex solid, the amount of obtaining 4.60g, moisture content 3.90%, cannot obtain Revex monohydrate.
Comparative example 3
25g Revex (moisture 3.57%) is suspended in 32ml water, mixture is heated to 80 DEG C, vacuum distilling low boiling point organic solvent, adopts the linear gradient, with 1 hour, solution is cooled to 20 DEG C. Keep stirring 2h by suspension, then it is cooled to 4 DEG C with 1h, and keep again at such a temperature stirring 1h, cross filter solid, use 25ml washing with acetone. By wet solid dried in vacuo overnight at 30 DEG C, the amount of obtaining 14.1g, moisture content 4.90%, receipts rate 55.6%.
Comparative example 4
Add 4.0g purified water to 5.0g Revex sample (moisture 3.57%), Revex monohydrate cannot be obtained.
By above embodiment and comparative example it will be seen that Revex is dispersed in specific organic solvent by the present invention by adopting, selecting the consumption of specific water to carry out turning brilliant, the receipts rate of prepared Revex monohydrate substantially increases.
Below the preferred embodiment of the present invention is described in detail; but, the detail that the present invention is not limited in above-mentioned enforcement mode, within the scope of the technical conceive of the present invention; the technical scheme of the present invention can being carried out multiple simple variant, these simple variant all belong to protection scope of the present invention.
Claims (6)
1. the preparation method of a Revex monohydrate, it is characterized in that, described preparation method comprises: is disperseed in organic solvent by Revex, adds water, turn brilliant obtained Revex monohydrate, and at least one that described organic solvent is selected from methylene dichloride, chloroform.
2. preparation method according to claim 1, it is characterised in that, described organic solvent is methylene dichloride.
3. preparation method according to claim 1 and 2, it is characterised in that, the weight ratio of described Revex and water is 1:0.1 ~ 0.8, it is preferable to 1:0.24 ~ 0.72.
4. preparation method according to any one of claim 1-3, it is characterised in that, the ratio of described Revex and organic solvent is 1:5 ~ 15(g/ml), it is preferable to 1:8 ~ 12(g/ml), it is more preferable to be 1:10(g/ml).
5. preparation method according to any one of claim 1-4, it is characterised in that, described preparation method comprises: is disperseed in organic solvent by Revex, adds water, backflow, and cooling is filtered, dry, obtained Revex monohydrate.
6. preparation method according to any one of claim 1-5, it is characterized in that, described preparation method comprises: according to formula consumption, be dispersed in methylene dichloride by Revex, stirs lower slow and enters purified water, heat up, backflow 1h, is cooled to 10-15 DEG C, filters, 40 DEG C of dryings, obtained Revex monohydrate.
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| CN201610088610.0A CN105646508B (en) | 2016-02-17 | 2016-02-17 | A kind of preparation method of nalmefene hydrochloride monohydrate |
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| CN201610088610.0A CN105646508B (en) | 2016-02-17 | 2016-02-17 | A kind of preparation method of nalmefene hydrochloride monohydrate |
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| CN105646508B CN105646508B (en) | 2018-02-27 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN117986261A (en) * | 2024-04-02 | 2024-05-07 | 成都瑞尔医药科技有限公司 | Method for recycling nalmefene hydrochloride mother liquor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102325778A (en) * | 2008-12-05 | 2012-01-18 | H.隆德贝克有限公司 | Nalmefene hydrochloride dihydrate |
| CN103204859A (en) * | 2013-04-25 | 2013-07-17 | 四川海思科制药有限公司 | Nalmefene hydrochloride compound and preparation method thereof |
| CN104093721A (en) * | 2011-12-06 | 2014-10-08 | H.隆德贝克有限公司 | Process for recovery of nalmefene hydrochloride |
-
2016
- 2016-02-17 CN CN201610088610.0A patent/CN105646508B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102325778A (en) * | 2008-12-05 | 2012-01-18 | H.隆德贝克有限公司 | Nalmefene hydrochloride dihydrate |
| CN104093721A (en) * | 2011-12-06 | 2014-10-08 | H.隆德贝克有限公司 | Process for recovery of nalmefene hydrochloride |
| CN103204859A (en) * | 2013-04-25 | 2013-07-17 | 四川海思科制药有限公司 | Nalmefene hydrochloride compound and preparation method thereof |
Non-Patent Citations (1)
| Title |
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| 杜玍妮，等，: "纳美芬的研究进展", 《中国医院药学杂志》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN117986261A (en) * | 2024-04-02 | 2024-05-07 | 成都瑞尔医药科技有限公司 | Method for recycling nalmefene hydrochloride mother liquor |
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| CN105646508B (en) | 2018-02-27 |
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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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