CN117843650A - Refining method of nalmefene hydrochloride - Google Patents
Refining method of nalmefene hydrochloride Download PDFInfo
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- CN117843650A CN117843650A CN202311820519.XA CN202311820519A CN117843650A CN 117843650 A CN117843650 A CN 117843650A CN 202311820519 A CN202311820519 A CN 202311820519A CN 117843650 A CN117843650 A CN 117843650A
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- nalmefene hydrochloride
- nalmefene
- water
- hydrochloride
- purifying
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- GYWMRGWFQPSQLK-OPHZJPRHSA-N (4r,4as,7as,12bs)-3-(cyclopropylmethyl)-7-methylidene-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-4a,9-diol;hydron;chloride Chemical compound Cl.N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 GYWMRGWFQPSQLK-OPHZJPRHSA-N 0.000 title claims abstract description 87
- 229960000677 nalmefene hydrochloride Drugs 0.000 title claims abstract description 87
- 238000000034 method Methods 0.000 title claims abstract description 33
- 238000007670 refining Methods 0.000 title claims abstract description 16
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- 239000002904 solvent Substances 0.000 claims abstract description 15
- 238000001953 recrystallisation Methods 0.000 claims abstract description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000012535 impurity Substances 0.000 claims abstract description 9
- 238000010992 reflux Methods 0.000 claims abstract description 7
- 238000001914 filtration Methods 0.000 claims abstract description 6
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 5
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 239000007787 solid Substances 0.000 claims abstract description 3
- 238000005406 washing Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- WJBLNOPPDWQMCH-MBPVOVBZSA-N Nalmefene Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=C)O)CC1)O)CC1CC1 WJBLNOPPDWQMCH-MBPVOVBZSA-N 0.000 claims description 13
- 229960005297 nalmefene Drugs 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 4
- 238000007239 Wittig reaction Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229960003086 naltrexone Drugs 0.000 claims description 4
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 3
- 238000003786 synthesis reaction Methods 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000007858 starting material Substances 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 5
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 abstract description 4
- 238000010898 silica gel chromatography Methods 0.000 abstract description 2
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000007791 liquid phase Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- ZFSXKSSWYSZPGQ-UHFFFAOYSA-N (2-hydroxycyclopentyl)azanium;chloride Chemical compound Cl.NC1CCCC1O ZFSXKSSWYSZPGQ-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 229960000858 naltrexone hydrochloride Drugs 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000003840 Opioid Receptors Human genes 0.000 description 2
- 108090000137 Opioid Receptors Proteins 0.000 description 2
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000000711 cancerogenic effect Effects 0.000 description 2
- 231100000315 carcinogenic Toxicity 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 101800005049 Beta-endorphin Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102100027467 Pro-opiomelanocortin Human genes 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 206010038678 Respiratory depression Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SLUNEGLMXGHOLY-UHFFFAOYSA-N benzene;hexane Chemical compound CCCCCC.C1=CC=CC=C1 SLUNEGLMXGHOLY-UHFFFAOYSA-N 0.000 description 1
- WOPZMFQRCBYPJU-NTXHZHDSSA-N beta-endorphin Chemical compound C([C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)[C@@H](C)O)C1=CC=CC=C1 WOPZMFQRCBYPJU-NTXHZHDSSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 102000051367 mu Opioid Receptors Human genes 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000003401 opiate antagonist Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000009875 water degumming Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 108020001612 μ-opioid receptors Proteins 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a refining method of nalmefene hydrochloride. According to the method, a crude nalmefene hydrochloride product is utilized, isopropanol and water are mixed to serve as a solvent, active carbon is added for refluxing and filtering, and then cooling crystallization, solid collection, washing and drying are sequentially carried out, so that the high-purity nalmefene hydrochloride is obtained. Wherein, the mass ratio of the nalmefene hydrochloride to the water is 1 (0.5-2), and the mass ratio of the nalmefene hydrochloride to the isopropanol is 1 (1-10). The invention adopts a recrystallization method, and can remove triphenylphosphine oxide and impurity potassium bromide in the crude nalmefene hydrochloride in a targeted manner. The impurity content in the crude nalmefene hydrochloride can be obviously reduced by recrystallization, and the purity of the refined nalmefene hydrochloride product is improved. The recrystallization process is adopted, so that the problems of large solvent consumption and difficult post-treatment caused by reverse silica gel column chromatography are avoided.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry. In particular to a refining method of nalmefene hydrochloride.
Background
Nalmefene is an opioid receptor antagonist produced synthetically in 1975 by the Miami pharmaceutical company of florida. As a new generation of highly selective, highly specific opioid receptor antagonists. Nalmefene acts on mu, kappa and alpha opioid receptors, has strong affinity to mu receptor, can competitively antagonize beta-endorphin, and achieves therapeutic effects of relieving respiratory depression, promoting awakening, protecting nerves and the like [ present clinical application of nalmefene, 2012,14 (326) ]. Compared with naltrexone, nalmefene has longer acting time on opioid receptors, higher bioavailability and fewer adverse reactions, thus being widely applied clinically.
The nalmefene hydrochloride preparation which is currently marketed is nalmefene hydrochloride injection with the specification of 0.1mg/1ml (calculated as nalmefene). Since the injection is directly injected into human tissue or blood vessels, the quality of the injection must be ensured, wherein the quality of the raw materials is important. If the crude drug with lower impurity content and higher purity can be obtained by a simple and environment-friendly low-cost process, the safety of drug administration can be further ensured, which is also consistently pursued and expected by people.
Nalmefene can be prepared according to the method described by Hanh et al (j.med.chem., 18,259-262 (1975), mainckrodt (US 4751307) and Meltzner et al (US 4535157) by employing the above mentioned method, the free base of nalmefene is obtained which can then be converted into the hydrochloride salt by using conventional methods.
According to Brittain (Analytical Profiles of Drug Substances and Excipients (analytical characteristics of drugs and excipients) (1996), vol 24, pp.351-395), nalmefene hydrochloride can be recrystallized from water to give a pure drug product, which inevitably contains a monohydrate crystalline phase. In this same review, nalmefene hydrochloride monohydrate is described as being substantially non-hygroscopic in that it is only able to absorb up to 1% of extraneous moisture.
U.S. Pat. No. 3,182,62 discloses a method of crystallizing crude nalmefene hydrochloride obtained by synthesis using benzene-hexane as a solvent, but the purity of nalmefene hydrochloride obtained by this method is not reported. Benzene used in the method is classified into a first type of solvent by ICH (international conference on the registration of human medicines), namely a solvent which is known to be carcinogenic and is suspected to be harmful to human and the environment, is avoided as much as possible in the production of medicines, and if the benzene is used, the residual quantity is detected, controlled within a specified range and bound into a quality standard; the second class of solvents specified by ICH, i.e. solvents which are not genotoxic but are carcinogenic to animals, should be limited in use and if so, a residual quantity study must be carried out and it is determined if the test is to be entered into quality standards. In industrial production, benzene and hexane are harmful to the health of operators, and are not friendly to the environment, and the residual quantity in the finished product is not easy to control.
Thus, there is a need to provide a new, stable and non-hygroscopic nalmefene hydrochloride and a process for its preparation.
Disclosure of Invention
The invention aims to provide a refining method of nalmefene hydrochloride, which is more beneficial to industrial production, on the basis of the prior art.
The technical scheme of the invention is as follows:
the refining method of nalmefene hydrochloride is characterized by adopting a recrystallization mode for refining, and comprises the following steps:
(1) Dissolving pre-refined nalmefene hydrochloride in water, heating to 70-90 ℃, and stirring to obtain nalmefene hydrochloride solution;
(2) Adding active carbon into the nalmefene hydrochloride solution obtained in the step (1), refluxing and thermally filtering;
(3) And (3) adding isopropanol into the filtrate obtained in the step (2), and sequentially cooling and crystallizing, collecting solids, washing and drying to obtain the high-purity nalmefene hydrochloride.
In a preferred scheme, the solvent is a mixed solvent of water and isopropanol, the mass ratio of the nalmefene hydrochloride to the water is 1 (0.1-4), and the mass ratio of the nalmefene hydrochloride to the isopropanol is 1 (1-15).
Preferably, the volume ratio of the nalmefene hydrochloride to the water for recrystallization is 1 (0.5-2), the mass volume ratio of the nalmefene hydrochloride to the isopropanol is 1 (1-10), and all volume ratios are calculated in g/mL.
In a preferred embodiment, the volume ratio of water to isopropanol is 1 (1-20).
In a preferred embodiment, the pre-refined nalmefene hydrochloride is dissolved in water, heated to 80-90 ℃, and stirred for 10 minutes until the solution is clarified, thus obtaining the nalmefene hydrochloride solution.
In a preferred scheme, in the step (2), the crude nalmefene hydrochloride is decolorized by adding activated carbon for refluxing, and impurities are removed by hot filtration.
In a preferred scheme, in the step (3), the crystallization temperature is 0-10 ℃, and the precipitated crystals are dried under reduced pressure under the conditions that the temperature is 60-70 ℃ and the pressure is less than or equal to 0.09 MPa.
In a preferred embodiment, after refining, the naltrexone hydrochloride content of the nalmefene hydrochloride-containing solution is controlled to be less than or equal to 0.2%.
In a preferred embodiment, the synthesis procedure for nalmefene hydrochloride is as follows:
(1) Taking naltrexone as a starting material, and carrying out Wittig reaction with a ylide reagent to obtain a nalmefene concentrated solution;
(2) Dissolving the obtained concentrated nalmefene solution with ethyl acetate, and then dropwise adding concentrated hydrochloric acid to prepare nalmefene hydrochloride;
(3) The ylide reagent is prepared by reacting methyl triphenylphosphine bromide with potassium tert-butoxide;
in a preferred scheme, in the step of synthesizing the nalmefene hydrochloride, the Wittig reaction is carried out in the presence of 2-methyltetrahydrofuran as a solvent, wherein the mole ratio of the nalmefene to the methyltriphenylphosphine bromide to the potassium tert-butoxide is 1:2.5:2.5, and the reaction temperature is 20-30 ℃.
The technical scheme of the invention has the following advantages:
1. the refining method of nalmefene hydrochloride provided by the invention comprises the steps of recrystallization, wherein the recrystallized solvent is water and isopropanol, the mass ratio of the nalmefene hydrochloride to the water is 1 (0.5-2), and the mass ratio of the nalmefene hydrochloride to the isopropanol is 1 (1-10). By adopting a recrystallization method, triphenylphosphine oxide and impurity potassium bromide in the crude nalmefene hydrochloride can be removed in a targeted manner. The impurity content in the crude nalmefene hydrochloride can be obviously reduced by recrystallization, and the purity of the refined nalmefene hydrochloride product is improved. The recrystallization process is adopted, so that the problems of large solvent consumption and difficult post-treatment caused by reverse silica gel column chromatography are avoided.
2. According to the refining method of nalmefene hydrochloride, in the step of recrystallization, the content of naltrexone hydrochloride in the nalmefene hydrochloride-containing solution is controlled to be less than or equal to 0.2%. The content of naltrexone hydrochloride in the nalmefene hydrochloride crude product can be obviously reduced in the recrystallization process. The invention provides key process control conditions for refining nalmefene hydrochloride.
3. The refining method of nalmefene hydrochloride provided by the invention further comprises the steps of adding active carbon, refluxing and hot filtering. The active carbon is added for refluxing, so that the crude nalmefene hydrochloride can be decolorized, the clarity of the refined nalmefene hydrochloride product is effectively improved, and impurities are removed, so that the nalmefene hydrochloride can be used for preparing a nalmefene hydrochloride preparation.
Drawings
FIG. 1 is the liquid phase data of crude nalmefene hydrochloride, and the liquid phase detection method is shown in example 1.
FIG. 2 is liquid phase data of the finished product after refining in example 10.
Detailed Description
The present invention is further illustrated by the following description of specific embodiments, which are not intended to be limiting, and various modifications and improvements can be made by those skilled in the art based on the basic idea of the invention, without departing from the invention
The basic idea of the invention is within the scope of the invention.
Example 1:
methyl triphenylphosphonium bromide (0.732 mol,262 g) and potassium tert-butoxide (0.732 mol,82 g) were dissolved in 2-methyltetrahydrofuran (0.7L) under an inert atmosphere. The suspension turned yellow, the temperature was maintained in the range of 20-30℃and stirred for 2 hours. Then naltrexone (0.293 mol,100 g) was dissolved in 2-methyltetrahydrofuran (0.4L), and added to the reaction solution at 20-30℃over 0.5 hours, and reacted for 3 hours. The reaction was monitored by HPLC and quenched by addition of saturated ammonium chloride solution (0.5L), and the reaction was extracted twice with ethyl acetate. The organic phase was collected and washed 2 times with water (0.5 l) and once with saturated sodium chloride solution (0.5 l). The organic phase was concentrated under reduced pressure, and then diluted with ethyl acetate (0.4L) to give a clear solution. Concentrated hydrochloric acid (37%, 0.05L) was added over 1 hour at 20-30 ℃. The suspension was stirred at the same temperature for at least 3 hours, filtered, and the filter cake was washed with a small amount of ethyl acetate. The filter cake is dried in a vacuum drying oven at 40 ℃ for 2 hours, 89.1g of crude nalmefene hydrochloride can be obtained, and the yield is 81.05%.
5g of crude nalmefene hydrochloride (content 98.38%) is stirred with 50ml of ethyl acetate at room temperature for 1 hour, suction filtration is carried out, filter cakes are collected, 4.78g of refined nalmefene hydrochloride is dried, the yield is 95.6%, the purity of nalmefene hydrochloride is 98.536%, the content of naltrexone hydrochloride is 0.232%, and the maximum single impurity is 0.571%.
HPLC chromatographic conditions
The chromatographic column is kromasil 100-5-C18, and octadecyl bonded silica gel is used as filler; taking 1900mL of water, weighing 15.6g of anhydrous sodium dihydrogen phosphate, adding 5mL of triethylamine, regulating the pH to 5.4 by using phosphoric acid, adding 100mL of tetrahydrofuran, uniformly mixing to obtain a mobile phase A and acetonitrile as a mobile phase B, and performing linear gradient elution according to the following table; the flow rate is 1.0ml/min and the column temperature is 30 ℃; the detection wavelength is 230nm; the sample volume was 10. Mu.l, and the sample was injected into a liquid chromatograph to record a chromatogram.
TABLE 1 elution gradient
Examples 2 to 10:
5g of crude nalmefene hydrochloride (98.38%) are stirred with dichloromethane (50 ml), ethyl acetate/methanol (50 ml:1 ml), dichloromethane/methanol (50 ml:1 ml), methanol (50 ml), ethanol (50 ml), isopropanol (50 ml), water (5 ml) and isopropanol/water (50 ml:1 ml), respectively, at room temperature for 1 hour. In the example 10, isopropanol/water (50 ml:10 ml) is used as a solvent, the crude nalmefene hydrochloride is heated to 80 ℃ to be dissolved, the solution is clarified, isopropanol is slowly added, and then the solution is slowly cooled to room temperature for crystallization and stirred for 1 hour. And (3) carrying out suction filtration on the crystallized reaction liquid, collecting a filter cake, and drying to obtain the nalmefene hydrochloride refined product. The liquid phase data and yields of the refined product are shown in the following table, and the liquid phase data of crude product and example 10 are shown in figures 1 and 2, respectively, of the appendix.
TABLE 2 liquid phase data and yields after different solvent refinements
Examples 11 to 16:
5g of crude nalmefene hydrochloride (content 98.38%) are dissolved in isopropanol/water (50 ml:5 ml), isopropanol/water (35 ml:5 ml), isopropanol/water (25 ml:5 ml), isopropanol/water (15 ml:5 ml), isopropanol/water (5 ml:5 ml) and isopropanol/water (5 ml:2.5 ml) respectively in different proportions, the crude nalmefene hydrochloride is heated to 80 ℃ with water to dissolve, the solution is clarified, isopropanol is slowly added, and then the solution is slowly cooled to room temperature for crystallization and stirred for 1 hour. And (3) carrying out suction filtration on the crystallized reaction liquid, collecting a filter cake, and drying to obtain the refined nalmefene hydrochloride product. The liquid phase data and yields of the finished product are shown in the following table.
TABLE 3 liquid phase data and yields after isopropanol/Water refining at different ratios
The above embodiments are only for illustrating the technical solution of the present invention, and are not limiting; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments may be modified or some technical features may be replaced equivalently; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. The refining method of nalmefene hydrochloride is characterized by adopting a recrystallization mode for refining, and comprises the following steps:
(1) Dissolving pre-refined nalmefene hydrochloride in water, heating to 70-90 ℃, and stirring to obtain nalmefene hydrochloride solution;
(2) Adding active carbon into the nalmefene hydrochloride solution obtained in the step (1), refluxing and thermally filtering;
(3) And (3) adding isopropanol into the filtrate obtained in the step (2), and sequentially cooling and crystallizing, collecting solids, washing and drying to obtain the high-purity nalmefene hydrochloride.
2. The method for purifying nalmefene hydrochloride according to claim 1, wherein in the step (3), the solvent is a mixed solvent of water and isopropyl alcohol, the mass ratio of nalmefene hydrochloride to water is 1 (0.1-4), and the mass ratio of nalmefene hydrochloride to isopropyl alcohol is 1 (1-15).
3. The method for refining nalmefene hydrochloride according to claim 2, wherein the volume ratio of the pre-refined nalmefene hydrochloride to water is 1 (0.5-2), the mass volume ratio of the nalmefene hydrochloride to isopropanol is 1 (1-10), and all volume ratios are calculated in g/mL.
4. The method for purifying nalmefene hydrochloride according to claim 1, wherein the volume ratio of water to isopropyl alcohol is 1 (1-20).
5. The method for purifying nalmefene hydrochloride according to claim 1, wherein in the step (1), the pre-purified nalmefene hydrochloride is dissolved in water, heated to 80 to 90 ℃, and stirred for 10 minutes to clarify to obtain a nalmefene hydrochloride solution.
6. The method for purifying nalmefene hydrochloride according to claim 1, wherein in step (2), the crude nalmefene hydrochloride is decolorized by adding activated carbon and refluxing, and the impurities are removed by hot filtration.
7. The method for purifying nalmefene hydrochloride according to claim 1, wherein in the step (3), the crystallization temperature is 0 to 10 ℃, and the precipitated crystals are dried under reduced pressure at 60 to 70 ℃ and a pressure of 0.09MPa or less.
8. The method for purifying nalmefene hydrochloride according to claim 1, wherein the nalmefene hydrochloride content in the nalmefene hydrochloride-containing solution is controlled to be less than or equal to 0.2% after the purification.
9. The method for purifying nalmefene hydrochloride according to claim 1, wherein the synthesis steps of nalmefene hydrochloride are as follows:
(1) Taking naltrexone as a starting material, and carrying out Wittig reaction with a ylide reagent to obtain a nalmefene concentrated solution;
(2) Dissolving the obtained concentrated nalmefene solution with ethyl acetate, and then dropwise adding concentrated hydrochloric acid to prepare nalmefene hydrochloride;
(3) The ylide reagent is prepared by reacting methyl triphenylphosphine bromide with potassium tert-butoxide;
10. the method for purifying nalmefene hydrochloride according to claim 9, wherein in the step of synthesizing the nalmefene hydrochloride, the Wittig reaction is performed in the presence of 2-methyltetrahydrofuran as a solvent, wherein the molar ratio of nalmefene, methyltriphenylphosphine bromide and potassium tert-butoxide is 1:2.5:2.5, and the reaction temperature is 20-30 ℃.
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