CN103204859B - A kind of Nalmefene hydrochloride compound and preparation method thereof - Google Patents
A kind of Nalmefene hydrochloride compound and preparation method thereof Download PDFInfo
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- CN103204859B CN103204859B CN201310148272.1A CN201310148272A CN103204859B CN 103204859 B CN103204859 B CN 103204859B CN 201310148272 A CN201310148272 A CN 201310148272A CN 103204859 B CN103204859 B CN 103204859B
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Abstract
The invention belongs to medical art.Specifically, the present invention relates to a kind of Nalmefene hydrochloride compound and preparation method thereof.Revex is the derivative of water-soluble TREXUPONT, the chemical structure of its 6 methylene radical makes that it has long action time, route of administration is many, bioavailability is high, few side effects, physiologically active penetrate the characteristics such as microbial film more by force, more easily, all there is effect in various degree to Hold up voltage, circulation, digestion, internal secretion and neural normal function, be applied to the antagonism of opioid analgesics respiration inhibition, the treatment of heart failure and shock, the treatment of alcoholism and habituation and fat-reducing etc. at present.Invention increases the stability of medicine, ensure drug safety.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of Nalmefene hydrochloride compound and preparation method thereof.
Background technology
Revex in 1975 synthesis, No. CAS: 58895 ?64 ?0, English name: Nalmefenehydrochloride; It is the another new pure opiate receptor antagonist of synthesis after naloxone (NAL) and TREXUPONT (NTX).It and opiate receptor μ, κ, δ all can be in conjunction with, wherein the strongest with the effect of μ receptors bind.
Revex is the derivative of water-soluble TREXUPONT, the chemical structure of its 6 methylene radical makes that it has long action time, route of administration is many, bioavailability is high, few side effects, physiologically active penetrate the characteristics such as microbial film more by force, more easily, all there is effect in various degree to Hold up voltage, circulation, digestion, internal secretion and neural normal function, be applied to the antagonism of opioid analgesics respiration inhibition, the treatment of heart failure and shock, the treatment of alcoholism and habituation and fat-reducing etc. at present.Meanwhile, Revex poisoningly also has certain antagonistic action for some non-opiums are drug-induced, such as, reverse the excessive respiration inhibition that causes of alcohol and stupor etc.
About the process for purification of Revex, bibliographical information is few.US Patent No. 3814768 discloses Revex benzene-hexane synthesis obtained carries out crystallization method as solvent, but does not report the situations such as the purity of Revex obtained thus.The benzene used in the method is discussed by ICH(International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human use) be categorized as first kind solvent, namely known can be carcinogenic and by the strong doubt solvent harmful to human and environment, should avoid using in the production of medicine as far as possible, if used, residues detection must be carried out, residual quantity is controlled within the limits prescribed, and orders into quality standard; The Equations of The Second Kind solvent that the hexane used specifies for ICH, namely has the solvent of animal carinogenicity without genotoxicity, should limit use, if used, must carry out residual quantifier elimination, and according to circumstances determine whether order this inspection into quality standard.In suitability for industrialized production, the use of benzene and hexane all can endanger the health of operator, and unfriendly to environment, and the residual quantity in finished product is wayward.
US Patent No. 4535157 discloses with Gossypol recrystallized from chloroform, and obtains the method for pure hydrochloric acid Nalmefene with hexanes wash, but does not report the situations such as the purity of Revex obtained thus.The chloroform used in the method and hexane all belong to the Equations of The Second Kind solvent that ICH specifies, have certain toxicity, therefore there are the problems referred to above equally.
Summary of the invention
The object of the present invention is to provide a kind of Nalmefene hydrochloride compound of following structural formula:
Above-mentioned compound, is characterized in that, has generation 2 θ=7.1239 °, the X ray diffracting characteristic peak of 13.5001 °, 14.2413 °, 16.5438 °, 21.5263 °, 22.4357 °.
Above-mentioned compound, is characterized in that, has the X ray diffracting characteristic peak similar with accompanying drawing 1.
Above-mentioned compound, is characterized in that, has the TG-DTA differential thermogram similar with accompanying drawing 2.
The object of the present invention is to provide the preparation method of above-claimed cpd, adopt following methods: added by Revex in mixed solvent (ether: acetone: water=3-5:1:1), keep 20-30 DEG C, stir and Revex is dissolved, obtain Revex solution; Add gac, decolouring 10-20 minute, filters, and with mixed solvent (ether: acetone: water=3-5:1:1) washing leaching cake, collects filtrate; Filtrate naturally cools to room temperature (15-25 DEG C), and crystallization is fully separated out; Crystallization suction filtration, filter cake washes rear drying with water, to obtain final product.
The weightmeasurement ratio (g: ml) of the Revex in step described in above-mentioned preparation method (1) and mixed solvent (ether: acetone: water=3-5:1:1) is 1: 1-3.
The weightmeasurement ratio (g: ml) of the Revex in step described in above-mentioned preparation method (1) and mixed solvent (ether: acetone: water=3-5:1:1) is 1: 2.
Under study for action, contriver is surprised to find, although Revex is soluble in water, by temperature and the consumption of water during control high-temperature digestion, and the cooling rate of solution and final recrystallization temperature, still can reach gratifying recrystallization effect and purification effect.
The advantage of preparation method of the present invention is that technique is simple, and easy and simple to handle, cost is low, is suitable for suitability for industrialized production.In addition, due to not with an organic solvent, can not endanger the health of operator when therefore producing, also non-environmental-pollution problem, obtained Revex finished product simplifies the quality test process of finished product, has also ensured drug safety.
Accompanying drawing explanation
The x-ray diffractogram of powder of Fig. 1 embodiment 1 Revex crystal formation;
The TG-DTA differential thermogram of Fig. 2 embodiment 1 Revex crystal formation;
Embodiment
Below in conjunction with embodiment and experimental example, the present invention is further illustrated.
Comparative example 1
In there-necked flask, add 100.0g Revex (HPLC content 95.16%) and 200.0ml acetone, reflux makes Revex dissolve completely.After dissolving, add gac 0.1g, decolour 20 minutes, then filtered while hot, with a small amount of hot acetone washing leaching cake, collect filtrate.Filtrate Temperature fall, to room temperature, has a large amount of white crystals to separate out.Suction filtration, a small amount of washing with acetone of filter cake, 40 DEG C of vacuum-dryings, obtain Revex 93.0g, HPLC analytical results is in table 1.
Comparative example 2
In there-necked flask, add 100.0g Revex (HPLC content 95.16%) and 100.0ml ethanol, reflux makes Revex dissolve completely.After dissolving, add gac 0.1g, decolour 20 minutes, then filtered while hot, with a small amount of hot ethanol washing leaching cake, collect filtrate.Filtrate Temperature fall, to room temperature, has a large amount of white crystals to separate out.Suction filtration, a small amount of washing with alcohol of filter cake, 40 DEG C of vacuum-dryings, obtain Revex 87.4g, HPLC analytical results is in table 1.
Embodiment 1
In there-necked flask, add 100.0g Revex (HPLC content 95.16%) and mixed solvent (ether: acetone: water=4:1:1) 200.0ml, keep 20-30 DEG C, stir and Revex is dissolved, obtain Revex solution; Add gac, decolouring 10-20 minute, filters, and with mixed solvent (ether: acetone: water=4:1:1) washing leaching cake, collects filtrate; Filtrate naturally cools to room temperature (15-25 DEG C), and crystallization is fully separated out; Crystallization suction filtration, filter cake washes rear drying with water, obtains Revex 94.2g, and HPLC analytical results is in table 1.Fig. 1 and Fig. 2 is shown in powder diffraction spectrum and TG-DTA differential thermal analysis.
Embodiment 2
In there-necked flask, add 100.0g Revex (HPLC content 95.16%) and mixed solvent (ether: acetone: water=3:1:1) 300.0ml, keep 20-30 DEG C, stir and Revex is dissolved, obtain Revex solution; Add gac, decolouring 10-20 minute, filters, and with mixed solvent (ether: acetone: water=3:1:1) washing leaching cake, collects filtrate; Filtrate naturally cools to room temperature (15-25 DEG C), and crystallization is fully separated out; Crystallization suction filtration, filter cake washes rear drying with water, obtains Revex 90.9g, and HPLC analytical results is in table 1.Fig. 1 and Fig. 2 is shown in powder diffraction spectrum and TG-DTA differential thermal analysis.
Embodiment 3
In there-necked flask, add 100.0g Revex (HPLC content 95.16%) and mixed solvent (ether: acetone: water=5:1:1) 250.0ml, keep 20-30 DEG C, stir and Revex is dissolved, obtain Revex solution; Add gac, decolouring 10-20 minute, filters, and with mixed solvent (ether: acetone: water=5:1:1) washing leaching cake, collects filtrate; Filtrate naturally cools to room temperature (15-25 DEG C), and crystallization is fully separated out; Crystallization suction filtration, filter cake washes rear drying with water, obtains Revex 93.3g, and HPLC analytical results is in table 1.Fig. 1 and Fig. 2 is shown in powder diffraction spectrum and TG-DTA differential thermal analysis.
Embodiment 4
In there-necked flask, add 100.0g Revex (HPLC content 95.16%) and mixed solvent (ether: acetone: water=4:1:1) 250.0ml, keep 20-30 DEG C, stir and Revex is dissolved, obtain Revex solution; Add gac, decolouring 10-20 minute, filters, and with mixed solvent (ether: acetone: water=5:1:1) washing leaching cake, collects filtrate; Filtrate naturally cools to room temperature (15-25 DEG C), and crystallization is fully separated out; Crystallization suction filtration, filter cake washes rear drying with water, obtains Revex 91.3g, and HPLC analytical results is in table 1.Fig. 1 and Fig. 2 is shown in powder diffraction spectrum and TG-DTA differential thermal analysis.
The HPLC analytical results of each embodiment of table 1
Experimental example 1
The Revex of Example 1-4 and comparative example 1-2 is appropriate, 25 DEG C ± 2 DEG C are placed on respectively with pipe-produced glass bottle sealing, place 24 months under the condition of relative humidity 60% ± 10%, Comparative result embodiment 1 and 2 was all observed appearance character and is become micro-yellow crystalline powder from white crystalline powder when 0 month 6th month time.And embodiment 1-5 is to being still white crystalline powder when 24 months, other index also all meets the requirement of quality standard.
Experimental example 2-heredity and genotoxicity
(1) genetoxic: in embodiment 1 external bacterial gene mutagenicity test, vitro human lymphocyte chromosome aberration test, mouse bone marrow micronucleus test, body and external rat unscheduled assay (UDS) result be feminine gender.In mouse lymph lymphoma in vitro tests, under metabolism activation condition, visible mutation rate has slight increase (about 2 times).
(2) genotoxicity: embodiment 1 pharmaceutical quantities 40mg/ (kgd) (be equivalent to 116 times that the mankind recommend AUC under maximum per daily dose) on the mating of male mouse and fertility without impact.This medicine can change oestrus cycle [the dosage 2mg/ (kgd) of female rats, 20 times that are equivalent to that the mankind recommend AUC under maximum per daily dose], reduce fertility [the dosage 40mg/ (kgd) of female rats, 200 times that are equivalent to that the mankind recommend AUC under maximum per daily dose], and accompany progestogen in blood, oestrogenic hormon to reduce, but when dosage is 0.2mg/ (kgd) (be equivalent to 3 times that the mankind recommend AUC under maximum per daily dose) without above-mentioned change.Dosage be 0.6mg/ (kgd), 4.6mg/ (kgd) (be equivalent to respectively 3 times, 15 times that the mankind recommend AUC under maximum per daily dose) time, monkey serum estradiol level follicular phase can be reduced, then progestin level and progesterone level decline luteal phase is made, and there is amenorrhoea, this directly may suppress the generation of ovary steroid hormone relevant with this medicine.In gestation, late period gives this medicine, can cause rat and rabbit embryonic death and growth retardation.When giving rat 3mg/ (kgd), placenta can be made to occur pathological change.Rat Pregnancy and lactation successive administration Cluth size can be caused to reduce, newborn rat viability decline and postnatal growth slow, but growth retardation can recover after pubescence.
(3) carinogenicity: mouse mixes 12 months [0.46mg/ (kgd), 1.56mg/ (kgd) and the 6mg/ (kgd) that food gives embodiment 1, high dosage 12 times of being equivalent to that the mankind recommend AUC under maximum per daily dose], have no carcinogenesis, but when dosage is greater than 1.5mg/ (kgd), can adipose tissure hyperplasia be caused.Rat oral gives this medicine 2 years [0.05mg/ (kgd), 0.3mg/ (kgd) and 2mg/ (kgd), high dosage is equivalent to 10 times (male) and 20 times (female) that the mankind recommend AUC under maximum per daily dose respectively], when dosage is 0.3mg/ (kgd) and under more high dosage, the incidence of the optimum fatty tissue knurl of rat obviously can be increased.Above-mentioned proliferation response is relevant to the pharmacological action that fatty tissue is excessive and lasting with this medicine.
Claims (5)
1. a Nalmefene hydrochloride compound, is characterized in that, has the X ray diffracting characteristic peak identical with accompanying drawing 1.
2. compound according to claim 1, is characterized in that, has the TG-DTA differential thermogram identical with accompanying drawing 2.
3. the preparation method of compound described in claim 1-2: it is characterized in that adopting following methods:
Revex being added proportion of composing is ether: acetone: in the mixed solvent of water=3-5:1:1, keeps 20-30 DEG C, stirs and Revex is dissolved, obtain Revex solution; Add gac, decolouring 10-20 minute, filter, proportion of composing is ether: acetone: the mixed solvent washing leaching cake of water=3-5:1:1, collects filtrate; Filtrate naturally cools to the room temperature of 15-25 DEG C, and crystallization is fully separated out; Crystallization suction filtration, filter cake washes rear drying with water, to obtain final product.
4. preparation method according to claim 3, is characterized in that, the Revex in described step (1) and the weightmeasurement ratio of above-mentioned mixed solvent are 1: 1-3.
5. preparation method according to claim 4, is characterized in that, the Revex in described step (1) and the weightmeasurement ratio of above-mentioned mixed solvent are 1: 2.
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| CN106167492B (en) * | 2016-07-11 | 2018-08-10 | 西藏易明西雅医药科技股份有限公司 | A kind of purification process of nalmefene hydrochloride |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3814768A (en) * | 1971-11-26 | 1974-06-04 | Lewenstein E | 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts |
| US4535157A (en) * | 1983-11-01 | 1985-08-13 | Key Pharmaceuticals, Inc. | Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone |
| CN102459276A (en) * | 2009-05-25 | 2012-05-16 | H.隆德贝克有限公司 | Preparation of nalmefene hydrochloride from naltrexone |
| 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 |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3814768A (en) * | 1971-11-26 | 1974-06-04 | Lewenstein E | 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts |
| US4535157A (en) * | 1983-11-01 | 1985-08-13 | Key Pharmaceuticals, Inc. | Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone |
| CN102459276A (en) * | 2009-05-25 | 2012-05-16 | H.隆德贝克有限公司 | Preparation of nalmefene hydrochloride from naltrexone |
| 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 |
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Effective date of registration: 20201229 Address after: 620010 No.53, south section of Shunjiang Avenue, East District, Meishan Economic Development Zone, Sichuan Province Patentee after: Haisike Pharmaceutical (Meishan) Co.,Ltd. Address before: 611130 No.136 Baili Road, Chengdu cross strait science and Technology Industrial Development Park, Wenjiang District, Chengdu City, Sichuan Province Patentee before: SICHUAN HAISCO PHARMACEUTICAL Co.,Ltd. |