CN114736210A - Preparation method of crystal form of morphinan derivative - Google Patents
Preparation method of crystal form of morphinan derivative Download PDFInfo
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- CN114736210A CN114736210A CN202210314901.2A CN202210314901A CN114736210A CN 114736210 A CN114736210 A CN 114736210A CN 202210314901 A CN202210314901 A CN 202210314901A CN 114736210 A CN114736210 A CN 114736210A
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- 239000013078 crystal Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical class C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 title claims abstract description 13
- DJSFYNINGIMKAG-FQJQBBMWSA-N (e)-n-[(4r,4as,7r,7ar,12bs)-3-(cyclopropylmethyl)-4a,9-dihydroxy-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-yl]-3-(furan-3-yl)-n-methylprop-2-enamide;hydron;chloride Chemical compound Cl.C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@H]3N(C)C(=O)\C=C\C1=COC=C1)CN2CC1CC1 DJSFYNINGIMKAG-FQJQBBMWSA-N 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 30
- 238000003756 stirring Methods 0.000 claims description 30
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002904 solvent Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- ZFSXKSSWYSZPGQ-UHFFFAOYSA-N (2-hydroxycyclopentyl)azanium;chloride Chemical compound Cl.NC1CCCC1O ZFSXKSSWYSZPGQ-UHFFFAOYSA-N 0.000 claims description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 4
- 239000005456 alcohol based solvent Substances 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- 239000012046 mixed solvent Substances 0.000 claims description 4
- 239000002808 molecular sieve Substances 0.000 claims description 4
- XGZZHZMWIXFATA-UEZBDDGYSA-N nalfurafine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]1(O)CC[C@H]3N(C)C(=O)\C=C\C1=COC=C1)CN2CC1CC1 XGZZHZMWIXFATA-UEZBDDGYSA-N 0.000 claims description 4
- 229960000858 naltrexone hydrochloride Drugs 0.000 claims description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 238000002156 mixing Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 239000008213 purified water Substances 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 claims description 2
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 7
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 239000000047 product Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 239000012065 filter cake Substances 0.000 description 8
- 238000011160 research Methods 0.000 description 6
- OLUNPKFOFGZHRT-YGCVIUNWSA-N Naftifine hydrochloride Chemical compound Cl.C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OLUNPKFOFGZHRT-YGCVIUNWSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229960003979 naftifine hydrochloride Drugs 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000003556 assay Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000004811 liquid chromatography Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- 208000003251 Pruritus Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001631 haemodialysis Methods 0.000 description 2
- 230000000322 hemodialysis Effects 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000002386 leaching Methods 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical group O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000000634 powder X-ray diffraction Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 206010012335 Dependence Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 208000004880 Polyuria Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 208000007271 Substance Withdrawal Syndrome Diseases 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
- 206010060875 Uraemic pruritus Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003326 anti-histaminergic effect Effects 0.000 description 1
- 239000000043 antiallergic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000035619 diuresis Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000007803 itching Effects 0.000 description 1
- 239000002632 kappa opiate receptor agonist Substances 0.000 description 1
- 229940126470 kappa opioid receptor agonist Drugs 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 238000001126 phototherapy Methods 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229940125379 topical corticosteroid Drugs 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Images
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of a crystal form of a morphinan derivative, which particularly relates to the preparation of high-purity and stable 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride, obtains a crystal form I, and provides crystals comprising the crystal form I and amorphous 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride and a method for preparing the crystals.
Description
Technical Field
The invention relates to the field of drug synthesis, in particular to a preparation method of a crystal form of a morphinan derivative.
Background
Uremic pruritus is a common symptom of many chronic renal failure patients requiring hemodialysis, and the traditional treatment methods include oral antihistamine and antiallergic drugs, topical corticosteroid drugs, phototherapy and skin care. However, some patients do not respond to the above conventional treatments and their quality of life is drastically reduced.
Nalfuraphine hydrochloride is developed by Toray Industries, Inc., Japan, is a kappa-opioid receptor agonist containing a morphine skeleton, can obviously improve pruritus symptoms of hemodialysis patients and chronic liver disease patients who have no effective treatment means, and has no addiction and withdrawal symptoms.
Nalfuraphine hydrochloride, chemical name 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride, having the following chemical structure:
in the field of pharmaceutical synthesis, polymorphism of a drug is an important factor affecting safety and effectiveness of the drug, especially in solid preparations and preparations that are not true solutions. Therefore, the research on drug polymorphism is receiving more and more attention and attention in the fields of medicine research and development and national drug supervision.
At present, document WO2006109671 reports 3 crystal forms of naftifine hydrochloride and preparation methods thereof, which disclose preparation methods of naftifine hydrochloride of a, B and C forms, wherein the preparation method of the naftifine hydrochloride of the a form needs to add a seed crystal to assist crystallization, the crystallization time is long, the yield is 70% -80% when the crystallization time reaches 16h to 5 days, the B form needs to be placed in a refrigerator or in the dark for 3 days to 8 days to complete crystallization, the yield is 28% -77%, the C form needs to add a seed crystal to assist crystallization or be placed in the dark for 4 days to 12 days, the yield is 80% -90%, the production time is long, the crystallization efficiency is low, and the method is difficult to realize on industrial production.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity and stable 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamide ] morphinan hydrochloride, and provides crystals of the 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamide ] morphinan hydrochloride which comprises a type I and an amorphous form and a preparation method thereof, wherein the crystal forms are used for preparing medicinal active ingredients with functions of diuresis, pain relief and itching relieving.
In order to achieve the above purpose, the invention provides the following technical scheme: a process for preparing a crystalline form of a morphinan derivative, comprising the steps of:
the first step is as follows: dissociating naltrexone hydrochloride by using sodium bicarbonate, uniformly mixing the dissociated naltrexone hydrochloride with benzoic acid, N-methylbenzylamine, p-toluenesulfonic acid monohydrate and benzene, heating to reflux and divide water for 16h, carrying out nitrogen protection, cooling to 25 ℃, adding a 4A molecular sieve, ethanol and sodium cyanoborohydride, reacting for 2h at 25 ℃, concentrating the reaction solution, extracting by using dichloromethane, concentrating to obtain a crude NAHY-1 product, and carrying out the second-step reaction;
the second step is that: dissolving NAHY-1 in methanol, adding 10% Pd/C under stirring at 25 deg.C, displacing hydrogen, reacting at 25 deg.C for 4h, filtering, and extracting with dichloromethane to obtain NAHY-2 product;
the third step: dissolving SM-2 in dichloromethane, adding a catalytic amount of N, N-dimethylformamide under stirring at 25 ℃, dropwise adding thionyl chloride, reacting for 2 hours under stirring at 25 ℃, and directly concentrating the reaction solution to obtain a NAHY-3 product for subsequent reaction;
the fourth step: dissolving NAHY-2 in tetrahydrofuran and water, adding sodium carbonate under stirring at 25 deg.C, dissolving NAHY-3 in tetrahydrofuran, dripping into the reaction system, stirring at 25 deg.C for 30min, adding methanol and 3M sodium hydroxide water solution, stirring at 25 deg.C for 1 hr, extracting with ethyl acetate, concentrating to obtain crude NAHY-4 product, and pulping with ethyl acetate to obtain refined NAHY-4 product;
the fifth step: dissolving 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan (NAHY-4) and hydrogen chloride in a benign solvent, adding a poor solvent, stirring to react to obtain amorphous crystals of 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride, adding an alcohol solvent or purified water to the amorphous crystals, heating to 40-80 ℃, stirring to react for 30 minutes to 2 hours, then cooling and filtering to obtain the crystal form I.
Preferably, the alcohol solvent is a single alcohol solvent or a mixture of two alcohol solvents or three alcohol solvents, and the alcohol solvent includes: methanol, ethanol, isopropanol or n-butanol.
Preferably, the alcohol solvent is a mixed solvent of methanol and isopropanol in a ratio of 1: 1.
Preferably, in the fifth step, the benign solvent is methanol, ethanol, water or isopropanol, wherein the volume of the methanol is 5-15 times of the mass of the amorphous crystal, and the volume of the ethanol or isopropanol is 10-20 times.
Preferably, the volume of methanol is 10 times of the mass of the amorphous crystal, and the volume of ethanol or isopropanol is 15 times of the mass of the amorphous crystal.
Preferably, in the first step, the poor solvent is ethyl acetate, isopropyl acetate, isobutyl acetate or acetone.
Preferably, the poor solvent is ethyl acetate and acetone, and the volume is 3 times to 10 times of that of the benign solvent.
Preferably, form i has high intensity diffraction peaks at 2 θ angular positions of 10.4 °, 10.9 °, 11.4 °, 12 °, 19 °, 20.5 °, 21.6 ° in its X-powder diffraction pattern.
The beneficial effects are that the technical scheme of this application possesses following technological effect:
the invention researches the structural characteristics of naftifine hydrochloride and the solubility in different solvents in detail, optimizes the crystallization scheme on the basis of the original research, does not need to add seed crystals for auxiliary crystallization, only needs crystallization time within 4h, avoids the crystallization operation in dark or a refrigerator for a long time, can obtain the crystal form A consistent with the original research, has equivalent yield, can reach 75-90 percent, has consistent product quality, can reach all single impurities within 0.10 percent, has stable pH value, is consistent with the original research, is suitable for industrial production, and is effective for optimizing the preparation method of the crystal form A of the original research.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings will be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
figure 1 is an X-ray powder diffraction pattern of crystalline form i of 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride of the present invention.
Figure 2 is an XPRD pattern of crystalline form i of 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride according to the present invention, including specific data for angle 2 θ.
Figure 3 is an X-ray powder diffraction pattern of amorphous crystals of 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride of the present invention.
FIG. 4 is a liquid chromatography assay of example 5 of the present invention.
FIG. 5 is a liquid chromatography assay of example 7 of the present invention.
FIG. 6 is a liquid chromatography assay of example 8 of the present invention.
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings. In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not necessarily defined to include all aspects of the invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
The example route is as follows:
example 1:
SM-1(550g) was suspended in 5.5L DCM and 5.5L saturated NaHCO was added with stirring at 25 deg.C3Stirring the aqueous solution at 25 deg.C for 15min, standing for layering, and extracting the water layer with 2L DCM; combining organic layers, concentrating at 40 ℃ outside to obtain 470g of free raw materials in total, suspending the free raw materials in benzene (15L), adding benzoic acid-1 (178g) and N-methylbenzylamine (264g), stirring at 25 ℃ to dissolve, sequentially adding benzoic acid-2 (267g) and p-toluenesulfonic acid monohydrate (14g), gradually turbidity the system, separating out solids, heating the outside to 110 ℃, refluxing at 79 ℃ inside for 16h, gradually changing the system into a yellow clear solution, protecting with nitrogen, cooling to 25 ℃ inside, adding 4A molecular sieve (200g) and ethanol (15L), adding sodium cyanoborohydride (137g) once, having no obvious heat release phenomenon, stirring for 2h, completely reacting, adding methanol (10L) into the system, stirring at 25 ℃ to substantially dissolve the solids, concentrating at 45 ℃ to obtain a semi-solid, adding DCM (10L) into the residue, saturated NaHCO3Aqueous solution (7.5L), stirring at 25 deg.C until it is substantially clear, filtering to remove molecular sieve and a small amount of viscous solid, filtering to remove the filtrate, separating the filtrate into layers, back-extracting the aqueous layer with DCM (5L), combining the organic layers, and concentrating to obtain product as off-white foaming solid with a total of 471.2g and a yield of 64%.
Example 2:
dissolving NAHY-1(430g) in 9LAdding 10% Pd/C (86g) into methanol, pumping out hydrogen for three times, reacting at 25 deg.C, adding diatomaceous earth for 4 hr, filtering, washing filter cake with methanol (4L), mixing filtrates, concentrating at 40 deg.C, adding 4L saturated NaHCO into residue3Aqueous solution, DCM extraction (4L x 3), organic layer was combined and concentrated at external temperature 40 ℃ to obtain the product as a pale yellow foamy solid in total 284g with 80% yield.
Example 3:
suspending SM-2(88g) in DCM (1L), stirring uniformly at 25 ℃, adding N, N-dimethylformamide (2g), dropwise adding thionyl chloride (113g), deflating in the dropwise adding process, keeping the temperature at 25 ℃ for reaction, gradually dissolving the system clear after 2h, stopping deflation, concentrating the reaction liquid at the external temperature of 40 ℃ to obtain a product which is an earthy yellow solid and accounts for 110g in total, and directly putting the product in the next step with the yield calculated by 100%.
Example 4:
dissolving NAHY-2(206g) in THF/water (1L/1L), adding sodium carbonate (123g), stirring at 25 deg.C, dissolving NAHY-3 in THF (1L), dropwise adding into the reaction system, reacting at 25 deg.C for 0.5h, adding methanol (6L) and 3M NaOH aqueous solution (8L), reacting at 25 deg.C for 1h, adding saturated NaHCO into the reaction system3Water solution (3.5L) and 5L of ethyl acetate are stirred and layered, a water layer is extracted by 5L of ethyl acetate, organic phases are combined, saturated saline (5L) is washed, organic phase anhydrous sodium sulfate is dried, filtered and concentrated to obtain a crude product, 7L of ethyl acetate is added, pulping is carried out at 25 ℃ for 30min, filtering is carried out, 1L of EA of a filter cake is rinsed, the filter cake is dried to obtain a product, the total amount is 244g, white-like solid is obtained, and the yield is 90%.
Example 5:
suspending 160.0g of 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan in 0.65L of ethanol, stirring uniformly at 25 ℃, adding 150ml of HCl/MeOH solution (4mol/L), continuing stirring for 30 minutes, then adding 8L of acetone, stirring for crystallization for 2 hours, filtering, leaching the filter cake with a small amount of acetone, and drying to obtain a white-like solid, wherein the total amount is 165.2g, and the yield is 95%. To obtain amorphous 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride. HPLC purity 98.9%.
Example 6:
suspending 100.0g of 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan in 0.5L of methanol, stirring uniformly at 25 ℃, adding 107ml of HCl/MeOH solution (4Mol/L), stirring for 30 minutes, adding 5L of ethyl acetate, stirring for crystallization for 2 hours, filtering, leaching the filter cake with a small amount of ethyl acetate, and drying to obtain an off-white solid with a total yield of 96.4g and 89.6%. To obtain amorphous 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride.
Example 7:
amorphous 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride obtained in example 1 was charged into a three-necked flask 100g, added to 100ml of a mixed solvent of methanol and isopropanol (1:1), heated to 40 ℃ under nitrogen, stirred for 2 hours, filtered, and the filter cake was dried to give a white crystalline powder, yield: 82.7g, yield 82.7%. The crystal form I is obtained. HPLC purity 99.4%.
Example 8:
amorphous 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride obtained in example 1 was charged into a three-necked flask 100g, added to a mixed solvent of methanol, ethanol and isopropanol (1:1:1), heated to 50 ℃ under nitrogen, stirred for 2 hours, filtered, and the filter cake was dried to obtain a white crystalline powder, yield: 79.7g, yield 79.7%. The crystal form I is obtained. HPLC purity 99.8%.
Example 9:
amorphous 17-cyclopropylmethyl-3, 14 β -dihydroxy-4, 5 α -epoxy-6 β - [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride obtained in example 1 was taken out and added to a three-necked flask 100g, purified water (550mL) was added thereto, the mixture was stirred to a clear solution at 25 ℃, heated to an internal temperature of 55 ℃ and stirred for 15min, the temperature was reduced, the internal temperature was 30 ℃ and filtered, and the filter cake was dried to obtain a white crystalline powder, yield: 85.2g, yield 85.2%. The crystal form I is obtained. As shown in figure 2, the crystal form I has high-intensity diffraction peaks at 2 theta angular positions of 10.4 degrees, 10.9 degrees, 11.4 degrees, 12 degrees, 19 degrees, 20.5 degrees and 21.6 degrees in an X-powder diffraction pattern.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (8)
1. A process for the preparation of a crystalline form of a morphinan derivative, characterized in that: the method comprises the following steps:
the first step is as follows: dissociating naltrexone hydrochloride by using sodium bicarbonate, uniformly mixing the dissociated naltrexone hydrochloride with benzoic acid, N-methylbenzylamine, p-toluenesulfonic acid monohydrate and benzene, heating to reflux and divide water for 16h, carrying out nitrogen protection, cooling to 25 ℃, adding a 4A molecular sieve, ethanol and sodium cyanoborohydride, reacting for 2h at 25 ℃, concentrating the reaction solution, extracting by using dichloromethane, concentrating to obtain a crude NAHY-1 product, and carrying out the second-step reaction;
the second step is that: dissolving NAHY-1 in methanol, adding 10% Pd/C under stirring at 25 deg.C, displacing hydrogen, reacting at 25 deg.C for 4 hr, filtering, and extracting with dichloromethane to obtain NAHY-2 product;
the third step: dissolving SM-2 in dichloromethane, adding a catalytic amount of N, N-dimethylformamide under stirring at 25 ℃, dropwise adding thionyl chloride, reacting for 2 hours under stirring at 25 ℃, and directly concentrating the reaction solution to obtain a NAHY-3 product for subsequent reaction;
the fourth step: dissolving NAHY-2 in tetrahydrofuran and water, adding sodium carbonate under stirring at 25 deg.C, dissolving NAHY-3 in tetrahydrofuran, dripping into the reaction system, stirring at 25 deg.C for 30min, adding methanol and 3M sodium hydroxide water solution, stirring at 25 deg.C for 1 hr, extracting with ethyl acetate, concentrating to obtain crude NAHY-4 product, and pulping with ethyl acetate to obtain refined NAHY-4 product;
the fifth step: dissolving 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan (NAHY-4) and hydrogen chloride in a benign solvent, adding a poor solvent, stirring to react to obtain amorphous crystals of 17-cyclopropylmethyl-3, 14 beta-dihydroxy-4, 5 alpha-epoxy-6 beta- [ N-methyl-trans-3- (3-furyl) -acrylamido ] morphinan hydrochloride, adding an alcohol solvent or purified water to the amorphous crystals, heating to 40-80 ℃, stirring to react for 30 minutes to 2 hours, then cooling and filtering to obtain the crystal form I.
2. A process for preparing a crystalline form of a morphinan derivative according to claim 1, wherein: the alcohol solvent is a single alcohol solvent or a mixture of two alcohol solvents or three alcohol solvents, and the alcohol solvent comprises: methanol, ethanol, isopropanol or n-butanol.
3. A process for preparing a crystalline form of a morphinan derivative according to claim 2, wherein: the alcohol solvent is a mixed solvent of methanol and isopropanol with the ratio of 1: 1.
4. A process for preparing a crystalline form of a morphinan derivative according to claim 2, wherein: in the fifth step, the benign solvent is methanol, ethanol, water or isopropanol, wherein the volume of the methanol is 5-15 times of the mass of the amorphous crystal, and the volume of the ethanol or isopropanol is 10-20 times.
5. A method of preparing a crystalline form of a morphinan derivative according to claim 4, wherein: wherein the volume of the methanol is 10 times of the mass of the amorphous crystal, and the volume of the ethanol or the isopropanol is 15 times of the mass of the amorphous crystal.
6. A method of preparing a crystalline form of a morphinan derivative according to claim 5, wherein: in the first step, the poor solvent is ethyl acetate, isopropyl acetate, isobutyl acetate or acetone.
7. A method of preparing a crystalline form of a morphinan derivative according to claim 6, wherein: the poor solvent is ethyl acetate and acetone, and the volume of the poor solvent is 3-10 times that of the good solvent.
8. A process for preparing a crystalline form of a morphinan derivative according to claim 1, wherein: the crystal form I has high-intensity diffraction peaks at 2 theta angular positions of 10.4 degrees, 10.9 degrees, 11.4 degrees, 12 degrees, 19 degrees, 20.5 degrees and 21.6 degrees in an X-powder diffraction pattern.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1111900A (en) * | 1993-06-30 | 1995-11-15 | 东丽株式会社 | Antitussive |
| US6177438B1 (en) * | 1993-07-23 | 2001-01-23 | Toray Industries, Inc. | Morphinan derivatives and pharmaceutical use thereof |
| CN101155814A (en) * | 2005-04-06 | 2008-04-02 | 东丽株式会社 | Crystals of morphinan derivative and process for producing the same |
| US20140031543A1 (en) * | 2009-02-23 | 2014-01-30 | Mallinckrodt Llc | (+)-6-Hydroxy-Morphinan or (+)-6-Amino-Morphinan Derivatives |
| CN104119348A (en) * | 2013-04-26 | 2014-10-29 | 台湾永光化学工业股份有限公司 | Crystal of morphinan derivative, method for producing same, and pharmaceutical composition using same |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1111900A (en) * | 1993-06-30 | 1995-11-15 | 东丽株式会社 | Antitussive |
| US6177438B1 (en) * | 1993-07-23 | 2001-01-23 | Toray Industries, Inc. | Morphinan derivatives and pharmaceutical use thereof |
| CN101155814A (en) * | 2005-04-06 | 2008-04-02 | 东丽株式会社 | Crystals of morphinan derivative and process for producing the same |
| US20140031543A1 (en) * | 2009-02-23 | 2014-01-30 | Mallinckrodt Llc | (+)-6-Hydroxy-Morphinan or (+)-6-Amino-Morphinan Derivatives |
| CN104119348A (en) * | 2013-04-26 | 2014-10-29 | 台湾永光化学工业股份有限公司 | Crystal of morphinan derivative, method for producing same, and pharmaceutical composition using same |
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