CN106167492A - A kind of purification process of nalmefene hydrochloride - Google Patents
A kind of purification process of nalmefene hydrochloride Download PDFInfo
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- CN106167492A CN106167492A CN201610540285.7A CN201610540285A CN106167492A CN 106167492 A CN106167492 A CN 106167492A CN 201610540285 A CN201610540285 A CN 201610540285A CN 106167492 A CN106167492 A CN 106167492A
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- Prior art keywords
- nalmefene
- nalmefene hydrochloride
- purification process
- dried
- hydrochloride
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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
The invention belongs to pharmaceutical technology field, be specifically related to the purification process of a kind of nalmefene hydrochloride, the method selects nalmefene to be raw material, ethyl acetate, acetone, water equal solvent effect under, prepare purity nalmefene hydrochloride more than 99.95%.
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology.It is specifically related to the improvement synthetic method of nalmefene.
Background technology
Nalmefene is a kind of opiate derivant similar in construction to opiate antagonist naltrexone, be one
The opioid receptor antagonists known, it can suppress given OPIOIDS agonist and by swashing that OPIOIDS system endogenous produces
The pharmacological effect of dynamic both agent.Nalmefene comes from it as the Clinical efficacy of antagonist and quickly and optionally reverses Ah
The ability of sheet excitomotor effect, is included in common preventing in central nervous system and respiratory system.
The nalmefene hydrochloride preparation listed at present is Nalmefene hydrochloride injection, and specification is that 1ml:0.1mg is (with nalmefene
Meter).Owing to injection is directly injected into tissue or blood vessel, so must assure that injection quality, the wherein quality of crude drug
Most important.If it is lower to obtain impurity content by simple and environmentally-friendly low cost process, the higher crude drug of purity will
Ensureing the safety of medication further, this is also that people always pursue and desired.
Nalmefene can according to Hanh etc. (J.Med.Chem., 18,259-262 (1975), Mallinckrodt (US4,751,
307) prepare with the method described in (US4,535,157) such as Meltzner.By using method mentioned above, obtain nalmefene
Free alkali, then can by use conventional method, be translated into hydrochlorate.
According to Brittain (Analytical Profiles of Drug Substances and Excipients (medicine
The parsing feature of product and adjuvant) (1996), Vol 24, pp.351-395), can obtain pure by nalmefene hydrochloride from water recrystallization
Medicine, it inevitably comprises monohydrate crystalline phase.In the summary that this is identical, the monohydrate phase quilt of nalmefene hydrochloride
It is described as the most nonhygroscopic, because it is only capable of absorbing the external moisture being up to 1%.
United States Patent (USP) US3814768 discloses nalmefene hydrochloride crude product benzene-hexane synthesis obtained and enters as solvent
The method of row crystallization, but do not report the situations such as the purity of thus obtained nalmefene hydrochloride.Benzene used in the method is by ICH
(International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use view) is categorized as first kind solvent, the most known can be carcinogenic and by strong doubt
The solvent harmful to human and environment, should avoid using in the production of medicine as far as possible, if used, it is necessary to carry out residual quantity inspection
Survey, residual quantity is controlled within the limits prescribed, and orders into quality standard；The hexane used is that the Equations of The Second Kind that ICH specifies is molten
Agent, i.e. without genotoxicity but have the solvent of animal carcinogenecity, use should be limited, if use, it is necessary to carry out remain quantifier elimination,
And according to circumstances decide whether to order into quality standard this inspection.In industrialized production, the use of benzene and hexane all can be endangered
The health of evil operator, and unfriendly to environment, and the residual quantity in finished product is wayward.
United States Patent (USP) US4535157 discloses uses Gossypol recrystallized from chloroform, and obtains the side of pure hydrochloric acid nalmefene with hexane washing
Method, but do not report the situations such as the purity of thus obtained nalmefene hydrochloride.Chloroform and hexane used in the method broadly fall into
The Equations of The Second Kind solvent that ICH specifies, has certain toxicity, therefore equally exists the problems referred to above.
Therefore, it is presently required and a kind of new, stable and non-hygroscopic nalmefene hydrochloride is provided and prepares its side
Method.
Summary of the invention
The technical problem to be solved is to overcome above-mentioned weak point, research design advantageously industry metaplasia
The nalmefene hydrochloride preparation method produced.
The invention provides the purification process of a kind of nalmefene hydrochloride, the method selects nalmefene to be raw material, in acetic acid second
Ester, acetone, water equal solvent effect under, prepare purity nalmefene hydrochloride more than 99.95%.
Specifically, the invention provides:
The purification process of a kind of nalmefene hydrochloride, comprises the following steps:
Step 1: nalmefene hydrochloride crude product, by 20～40 times of re-crystallizing in ethyl acetate, is dried, obtains nalmefene alkali sterling；
Step 2: be dissolved in the acetone of about 20-30 times by nalmefene alkali, is added dropwise to ether solution of hydrogen chloride to pH2 after filtration
± 0.5, filter collection solid, first use washing with acetone solid, then wash solid with absolute ether, after drying, obtain nalmefene hydrochloride crude product；
Step 3: be completely dissolved in the water of 50-100 DEG C by nalmefene hydrochloride crude product, is cooled to room temperature after heat filter, separates out white
Color crystallizes, sucking filtration, washing, is dried, obtains nalmefene hydrochloride.
Wherein, in described step 1 30 times of the weight more preferably nalmefene of ethyl acetate.
Wherein, 25 times of the weight of the acetone in described step 2 more preferably nalmefene alkali.
Wherein, described step 2 is dried after being preferably first natural drying, is vacuum dried at 55-65 DEG C.
Wherein, described step 3 is more preferably: is completely dissolved in hot water by nalmefene hydrochloride crude product, cools down after heat filter
To room temperature, separate out white crystals, cold preservation at 0-5 DEG C, sucking filtration, washing, be dried, obtain nalmefene hydrochloride.
The invention provides the production method of a kind of high-purity nalmefene, whole production can be implemented under conditions of stable
Journey, and economical and practical, safe high-purity nalmefene production method.
Detailed description of the invention
Below by way of the description of detailed description of the invention, the invention will be further described, but this is not the limit to the present invention
System, those skilled in the art are according to the basic thought of the present invention, and various modifications may be made or improves, but without departing from this
The basic thought of invention, the most within the scope of the present invention.
Embodiment 1
Step 1: nalmefene hydrochloride crude product (content 62.3%) 10g 200g re-crystallizing in ethyl acetate, is dried, obtains nalmefene
Alkali sterling 5.6g；
Step 2: nalmefene alkali 5.6g is dissolved in the acetone of about 112g, is added dropwise to ether solution of hydrogen chloride after filtration extremely
PH2 ± 0.5, filter collection solid, first use washing with acetone solid, then wash solid with absolute ether, after drying, obtain nalmefene hydrochloride thick
Product 5.35g；
Step 3: be completely dissolved in the water of 50 DEG C by nalmefene hydrochloride crude product, is cooled to room temperature after heat filter, separates out white knot
Crystalline substance, sucking filtration, washing, it is dried, obtains nalmefene hydrochloride 4.8g.
Embodiment 2
Step 1: nalmefene hydrochloride crude product (content 62.3%) 10g 300g re-crystallizing in ethyl acetate, is dried, obtains nalmefene
Alkali sterling 6.1g；
Step 2: nalmefene alkali is dissolved in the acetone of about 150g, be added dropwise to after filtration ether solution of hydrogen chloride to pH2 ±
0.5, filter collection solid, first use washing with acetone solid, then wash solid with absolute ether, after drying, obtain nalmefene hydrochloride crude product
5.85g；
Step 3: be completely dissolved in the water of 100 DEG C by nalmefene hydrochloride crude product, is cooled to room temperature after heat filter, separates out white knot
Crystalline substance, sucking filtration, washing, it is dried, obtains nalmefene hydrochloride 5.34g.
Embodiment 3
Step 1: nalmefene hydrochloride crude product (content 62.3%) 10g 400g re-crystallizing in ethyl acetate, is dried, obtains nalmefene
Alkali sterling 6.03g；
Step 2: nalmefene alkali is dissolved in the acetone of about 180g, be added dropwise to after filtration ether solution of hydrogen chloride to pH2 ±
0.5, filter collection solid, first use washing with acetone solid, then wash solid with absolute ether, after drying, obtain nalmefene hydrochloride crude product
5.62g；
Step 3: be completely dissolved in the water of 100 DEG C by nalmefene hydrochloride crude product, is cooled to room temperature after heat filter, separates out white knot
Crystalline substance, sucking filtration, washing, it is dried, obtains nalmefene hydrochloride 5.28g.
Embodiment 4
Step 1: nalmefene hydrochloride crude product (content 62.3%) 10g 300g re-crystallizing in ethyl acetate, is dried, obtains nalmefene
Alkali sterling 6.13g；
Step 2: nalmefene alkali is dissolved in the acetone of about 150g, be added dropwise to after filtration ether solution of hydrogen chloride to pH2 ±
0.5, filter collection solid, first to use washing with acetone solid, then wash solid with absolute ether, after natural drying, at 60 DEG C, vacuum is done
Dry 4 hours, obtain nalmefene hydrochloride crude product 5.21g；
Step 3: be completely dissolved in the water of 60 DEG C by nalmefene hydrochloride crude product, is cooled to room temperature after heat filter, separates out white knot
Crystalline substance, puts into refrigerator (4 DEG C) refrigerated overnight, sucking filtration, washing, is dried, obtains nalmefene hydrochloride 5.21g.
Test example
Chromatographic condition and system suitability octadecylsilane chemically bonded silica be filler (Kromasil C 18,
The chromatographic column that 4.6mm × 250mm, 5 μm or usefulness are suitable)；(sodium dihydrogen phosphate 7.8g, three second are taken with acetonitrile-phosphate buffer
Amine 2ml, adds water to 1000ml, the phosphorus acid for adjusting pH value with 85% to 4.2) (20: 80) for flowing phase；Detection wavelength is 210nm；
Column temperature is 30 DEG C.Take nalmefene hydrochloride reference substance appropriate, add 0.1mol/L hydrochloric acid solution dissolve and dilute make in every 1ml containing about
The solution of 0.2mg, takes 10ml, puts in 25ml measuring bottle, adds 0.4% liquor ferri trichloridi 1ml, puts in water-bath and heats 10 minutes, puts
Cold, it is diluted with water to scale, shakes up, as system suitability solution, take 10 μ l and inject chromatograph of liquid, regulate mobile phase ratio
Making nalmefene peak retention time be about 7 minutes, impurity II peak is about 1.6 relative to the retention time at nalmefene peak.
Algoscopy takes this product, accurately weighed, is dissolved in water and quantitatively dilution is made in every 1ml containing about nalmefene hydrochloride
The solution of 0.1mg, as need testing solution, precision measures 20 μ 1, injects chromatograph of liquid, records chromatogram；Separately take hydrochloric acid to receive
U.S. fragrant reference substance is appropriate, is measured in the same method.By external standard method with calculated by peak area, to obtain final product.
Have related substance to take this product appropriate, accurately weighed, add flowing phased soln and quantitatively dilution make in every 1ml containing about 1mg
Solution, as need testing solution；It is appropriate that another precision weighs Naltrexone Hydrochloride (impurity I) reference substance, adds flowing phased soln and determines
Amount dilution makes the solution of the most impure I1mg in every 1ml, as reference substance solution；Precision measures need testing solution 1ml with right
According to product solution 2ml, putting in same 100ml measuring bottle, with flowing phase dilution to scale, shake up, precision measures 5ml, puts 50ml measuring bottle
In, with flowing phase dilution to scale, shake up, as contrast solution.According to the chromatographic condition under assay item, precision measures for examination
Product solution and each 10ml of contrast solution, respectively note people's chromatograph of liquid, 3 times of record chromatogram to main peak retention time.For examination
If any the chromatographic peak consistent with impurity I retention time in product solution chromatogram, by external standard method with calculated by peak area, impure I is not
0.2% must be crossed；If any with double nalmefene (impurity II) chromatographic peak that retention time is consistent, its peak area cannot be greater than after being multiplied by 2
The peak area (0.1%) of nalmefene in contrast solution；Other single impurity peak area cannot be greater than nalmefene in contrast solution
Peak area (0.1%)；Other each impurity peak area and cannot be greater than 5 times (0.5%) of nalmefene peak area in contrast solution.
Impurity I (Naltrexone Hydrochloride)
C20H24ClNO4377.86
17-(Cvclopropvlmethvl)-4,5a-epoxy-3,14-dihydroxy morphinan-6-ones hydrochlorate
Impurity II (double nalmefene)
C42H48N2O6676.84
Residual solvent takes this product about 0.1g, accurately weighed, puts in 20ml ml headspace bottle, accurate addition N, N-dimethyl formyl
Amine 1ml makes dissolving, seals, shakes up, as need testing solution；Precision weighs acetone, dichloromethane, ethyl acetate and tetrahydrochysene respectively
Furan is each in right amount, adds DMF and makes in every 1ml respectively containing about acetone 500 μ g, dichloromethane 60 μ g, acetic acid second
The solution of ester 500 μ g and oxolane 72 μ g, precision measures 1ml, puts in 20ml ml headspace bottle, seals, as reference substance solution.According to
Residual solvent algoscopy (general rule 0,861 second method) measures, with 6% cyanogen propyl group phenyl-94% dimethyl polysiloxane (or polarity
Close) be the capillary column of fixative be chromatographic column；Initial temperature is 40 DEG C, maintains 8 minutes, with the speed liter of 20 DEG C per minute
Temperature, to 120 DEG C, maintains 5 minutes；Injector temperature is 220 DEG C；Detector temperature is 250 DEG C；Ml headspace bottle equilibrium temperature is 80 DEG C,
Equilibration time is 30 minutes.Taking reference substance solution headspace sampling, record chromatogram, the peak-to-peak separating degree of each composition all should conform to
Ask.Take need testing solution and reference substance solution headspace sampling respectively, record chromatogram.
Result of the test see table.
| Experimental example | Content (%) | There is related substance I | There is related substance II |
| Embodiment 1 | 99.98 | 0.01 | - |
| Embodiment 2 | 99.98 | 0.01 | - |
| Embodiment 3 | 99.98 | 0.01 | - |
| Embodiment 4 | 99.99 | 0.01 | - |
Claims (5)
1. a purification process for nalmefene hydrochloride, comprises the following steps:
Step 1: nalmefene hydrochloride crude product, by 20～40 times of re-crystallizing in ethyl acetate, is dried, obtains nalmefene alkali sterling；
Step 2: nalmefene alkali is dissolved in the acetone of about 20-30 times, be added dropwise to after filtration ether solution of hydrogen chloride to pH2 ±
0.5, filter collection solid, first use washing with acetone solid, then wash solid with absolute ether, after drying, obtain nalmefene hydrochloride crude product；
Step 3: be completely dissolved in the water of 50-100 DEG C by nalmefene hydrochloride crude product, is cooled to room temperature after heat filter, separates out white knot
Crystalline substance, sucking filtration, washing, it is dried, obtains nalmefene hydrochloride.
The purification process of nalmefene hydrochloride the most according to claim 1, it is characterised in that ethyl acetate in described step 1
30 times of weight more preferably nalmefene.
The purification process of nalmefene hydrochloride the most according to claim 1, it is characterised in that the acetone in described step 2
25 times of weight more preferably nalmefene alkali.
The purification process of nalmefene hydrochloride the most according to claim 1, it is characterised in that be dried preferably in described step 2
After first natural drying, it is vacuum dried at 55-65 DEG C.
The purification process of nalmefene hydrochloride the most according to claim 1, it is characterised in that described step 3 is further preferred
For: nalmefene hydrochloride crude product is completely dissolved in hot water, after heat filter, is cooled to room temperature, separate out white crystals, cold at 0-5 DEG C
Hide, sucking filtration, washing, be dried, obtain nalmefene hydrochloride.
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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 |
| CN113493468A (en) * | 2020-03-18 | 2021-10-12 | 四川海思科制药有限公司 | Novel nalmefene dimer and preparation method and application thereof |
| WO2022165040A1 (en) | 2021-01-28 | 2022-08-04 | Rhodes Technologies | Process for crystallizing nalmefene hydrochloride |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
| CN102584840A (en) * | 2011-12-28 | 2012-07-18 | 南京优科生物医药有限公司 | Method for preparing nalmefene compound |
| CN103012416A (en) * | 2011-09-28 | 2013-04-03 | 辽宁海思科制药有限公司 | Method for preparing high-purity 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 |
| CN104513251A (en) * | 2014-11-28 | 2015-04-15 | 安徽悦康凯悦制药有限公司 | Nalmefene hydrochloride preparation method |
-
2016
- 2016-07-11 CN CN201610540285.7A patent/CN106167492B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4322426A (en) * | 1980-04-28 | 1982-03-30 | E. I. Du Pont De Nemours And Company | 17-Substituted-6-desoxy-7,8-dihydro-6α-methylnoroxymorphone narcotic antagonists |
| CN103012416A (en) * | 2011-09-28 | 2013-04-03 | 辽宁海思科制药有限公司 | Method for preparing high-purity nalmefene hydrochloride |
| CN102584840A (en) * | 2011-12-28 | 2012-07-18 | 南京优科生物医药有限公司 | Method for preparing nalmefene compound |
| 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 |
| CN104513251A (en) * | 2014-11-28 | 2015-04-15 | 安徽悦康凯悦制药有限公司 | Nalmefene hydrochloride preparation method |
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 |
| CN113493468A (en) * | 2020-03-18 | 2021-10-12 | 四川海思科制药有限公司 | Novel nalmefene dimer and preparation method and application thereof |
| WO2022165040A1 (en) | 2021-01-28 | 2022-08-04 | Rhodes Technologies | Process for crystallizing nalmefene hydrochloride |
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| CN106167492B (en) | 2018-08-10 |
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