CN103073496B - The preparation method of Dextromethorphane Hbr - Google Patents
The preparation method of Dextromethorphane Hbr Download PDFInfo
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- MKXZASYAUGDDCJ-NJAFHUGGSA-N dextromethorphan Chemical compound C([C@@H]12)CCC[C@]11CCN(C)[C@H]2CC2=CC=C(OC)C=C21 MKXZASYAUGDDCJ-NJAFHUGGSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 230000002829 reductive effect Effects 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 238000001514 detection method Methods 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000007787 solid Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 239000012452 mother liquor Substances 0.000 claims description 4
- 239000012279 sodium borohydride Substances 0.000 claims description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 4
- 238000010792 warming Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 4
- 238000006170 formylation reaction Methods 0.000 description 4
- -1 methane amide Chemical class 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 230000000954 anitussive effect Effects 0.000 description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012046 mixed solvent Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- 229940124584 antitussives Drugs 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- HADKRTWCOYPCPH-UHFFFAOYSA-M trimethylphenylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)C1=CC=CC=C1 HADKRTWCOYPCPH-UHFFFAOYSA-M 0.000 description 2
- YBYCJQQRZPXLHU-UHFFFAOYSA-N 1,2,3,4,5,6,7,8-octahydroisoquinoline Chemical compound C1CNCC2=C1CCCC2 YBYCJQQRZPXLHU-UHFFFAOYSA-N 0.000 description 1
- QYXMTRMBTVDSOQ-UHFFFAOYSA-N 1-benzyl-1,2,3,4,5,6,7,8-octahydroisoquinoline Chemical compound N1CCC(CCCC2)=C2C1CC1=CC=CC=C1 QYXMTRMBTVDSOQ-UHFFFAOYSA-N 0.000 description 1
- ZYYDNMRUDMCOHG-UHFFFAOYSA-N 1-benzyl-2-methyl-3,4,5,6,7,8-hexahydro-1h-isoquinoline Chemical compound CN1CCC(CCCC2)=C2C1CC1=CC=CC=C1 ZYYDNMRUDMCOHG-UHFFFAOYSA-N 0.000 description 1
- XUDUTRMKKYUAKI-UHFFFAOYSA-N 3-[1-(1-phenylethyl)piperidin-4-yl]-1h-benzimidazol-2-one Chemical compound C1CC(N2C(NC3=CC=CC=C32)=O)CCN1C(C)C1=CC=CC=C1 XUDUTRMKKYUAKI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- UPARLEVJTRQMJB-QAPCUYQASA-N CNCC[C@@](CCCC1)([C@H]1CC1)c2c1ccc(OC)c2 Chemical compound CNCC[C@@](CCCC1)([C@H]1CC1)c2c1ccc(OC)c2 UPARLEVJTRQMJB-QAPCUYQASA-N 0.000 description 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- JAQUASYNZVUNQP-USXIJHARSA-N Levorphanol Chemical compound C1C2=CC=C(O)C=C2[C@]23CCN(C)[C@H]1[C@@H]2CCCC3 JAQUASYNZVUNQP-USXIJHARSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- QNEFNFIKZWUAEQ-UHFFFAOYSA-N carbonic acid;potassium Chemical compound [K].OC(O)=O QNEFNFIKZWUAEQ-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 231100000025 genetic toxicology Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 229960003406 levorphanol Drugs 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical group O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Present invention is disclosed the preparation method of a kind of Dextromethorphane Hbr (I), its comprise the steps: with intermediate ent-3-methoxyl group mutter (II) carry out N-methylate generate described Dextromethorphane Hbr (I).This preparation method is simple and convenient, be conducive to the production cost reducing Dextromethorphane Hbr, and can improve the quality of product.
Description
Technical field
The invention belongs to methodology of organic synthesis design and bulk drug and Intermediate Preparation technical field, particularly a kind of preparation method of Dextromethorphane Hbr.
Background technology
Dextromethorphane Hbr ((+)-3-methoxyl group-17-methyl-(9 α, 13 α, 14 α)-mutter, I) be the dextrorotatory isomer of m orphine levo-dromoran methyl ether, central antitussive effect is played by suppressing oblongata coughing centre, be a kind of powerful central antitussive, its antibechic intensity is equal with morphine monomethyl ether or slightly strong.Due to this kind resistance and additive all lower, because of but the antitussive medicine that uses of a kind of applicable long-term taking or high dosage.This medicine is recorded by multinational pharmacopeia, and Ye Shi China needs one of kind given priority in this field.
The preparation of existing Dextromethorphane Hbr is mostly by the following method: optically pure intermediate (+)-1-(4-methoxyl group) benzyl-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 (V), through N-formylation reaction, sodium borohydride reduction, obtain the formylated intermediate (+) of N--1-(4-methoxyl group) benzyl-N-formyl radical-1 successively, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 (VI) and the methylated intermediate (+) of N--1-(4-methoxyl group) Benzyl-N-methyl-1, 2, 3, 4, 5, 6, 7, 8-octahydro isoquinoline 99.9 (VII), intermediate (VII) obtains intermediate ent-3-hydroxyl-17-methyl through acid catalyzed annulation and mutters (III), intermediate (III) obtains target product Dextromethorphane Hbr by O-methylation reaction again.
The above-mentioned operational path preparing Dextromethorphane Hbr via intermediate (III) solves the Industrialized processing technique of this bulk drug substantially.But, by intermediate (III) prepare Dextromethorphane Hbr carry out O-methylation reaction time, as methyl-sulfate, methyl iodide etc., N-can be there is to some extent and to methylate side reaction, form quaternary ammonium salt by product (VIII) in conventional methylating reagent.So, in actual production process, have to use selectivity good, but the special methylating reagent that price is high, as trimethylphenyl ammonium hydroxide controls the process of side reaction, and carry out in toluene and methanol mixed solvent (see " pharmacy today " 18 volumes the 4th phase in 2008 the 63rd page).Because trimethylphenyl ammonium hydroxide price is higher, and difficult acquisition, methylated yield only has about 50%, thus makes the production cost of Dextromethorphane Hbr significantly improve.More outstanding, the by product DMA of this reaction belongs to genotoxicity material, and its residual quantity will directly affect the quality of bulk drug.At present, the residual control of DMA has been listed among USP, EP, JP and Chinese Pharmacopoeia as a crucial rigid index.So, if another succinct convenient, with low cost and Dextromethorphane Hbr route of nontoxicity residue can be designed, there is important actual application value.
Summary of the invention
The object of the invention is to the defect overcoming prior art, a kind of preparation method of new Dextromethorphane Hbr is provided, this preparation method is simple and convenient, be conducive to reducing the production cost of Dextromethorphane Hbr, and the quality of product can be improved.
To achieve these goals, the present invention adopts following main technical schemes: the preparation method of a kind of Dextromethorphane Hbr (I), it is characterized in that described preparation method comprise the steps: with intermediate ent-3-methoxyl group mutter (II) carry out N-methylate generate described Dextromethorphane Hbr (I).
In addition, the present invention also provides following attached technical scheme:
Described N-methylates and comprises the reduction reaction of N-formylation reaction and methane amide.
Described formylation reagent is formaldehyde, paraformaldehyde, formic acid or alkyl formate.
The alkyl of described alkyl formate is the common allcyl groups that methyl, ethyl, propyl group, sec.-propyl or carbon atom are less than 10.
The solvent of described formylation reaction is methyl alcohol, ethanol, Virahol, methyl-formiate, ethyl formate, methylene dichloride, trichloromethane, toluene, the mixed solvent between dimethylbenzene, water or aforementioned solvents.
The reductive agent of described formamide is sodium borohydride, POTASSIUM BOROHYDRIDE, sodium cyanoborohydride, borine, Lithium Aluminium Hydride or catalytic hydrogenation.
The catalyzer of described catalytic hydrogenation is Raney's nickel, palladium charcoal or palladium hydroxide charcoal.
The solvent of described catalytic hydrogenation is the mixed solvent between methyl alcohol, ethanol, Virahol, water or aforementioned solvents.
Compared to prior art, the preparation method of Dextromethorphane Hbr provided by the present invention, its advantage is mainly muttered by the intermediate ent-3-methoxyl group be easy to get can obtain Dextromethorphane Hbr through the N-preparation that methylates.The method is conducive to reducing the production cost of Dextromethorphane Hbr and improving the quality of product, and the Dextromethorphane Hbr obtained by the method meets or exceeds standards of pharmacopoeia both domestic and external, thus facilitates the economic technology development of this bulk drug.
Embodiment
Foregoing invention is utilized to carry out obtained Dextromethorphane Hbr how simply and easily by being set forth by three concrete preparation process and method below.
Embodiment one: add intermediate (II) (25.7g, 0.1mol), 40% formaldehyde (15.0g, 0.2mol) and methyl alcohol 200mL in 500mL three-necked bottle successively, low rate mixing reacts 12 hours.Reaction solution is proceeded to hydrogenation reaction cauldron, adds Raney's nickel 3g, the gentle 2-4 kilogram of pressure of holding chamber, react 4 hours, TLC detection reaction terminates.Filtering recovering catalyst, mother liquor concentrating under reduced pressure, residuum recrystallizing methanol obtains off-white color solid Dextromethorphane Hbr (I) 22.5g, yield 83.0%.
Embodiment two: add intermediate (II) (25.7g in 500mL three-necked bottle successively, 0.1mol), paraformaldehyde (6.0g, 0.2mol), solid carbonic acid potassium (13.8g, 0.1mol), methyl alcohol 150mL and water 50mL, be warming up to 65-75 DEG C, start stirring reaction 6 hours.Reaction solution is proceeded to hydrogenation reaction cauldron, adds palladium charcoal 3g, be warming up to 40-45 DEG C, keep 2-4 kilogram of pressure, react 6 hours, TLC detection reaction terminates.Filtering recovering catalyst, mother liquor concentrating under reduced pressure, residuum recrystallizing methanol obtains off-white color solid Dextromethorphane Hbr (I) 23.8g, yield 87.8%.
Embodiment three: add intermediate (II) (25.7g in 500mL three-necked bottle successively, 0.1mol), sodium methylate (10.8g, 0.2mol), methyl-formiate 150mL, be warming up to 50-55 DEG C, stirring reaction 6 hours, TLC detection reaction terminates.Removal of solvent under reduced pressure, residue dissolve with ethanol.Add sodium borohydride (4.6g, 0.12mol), fall room temperature reaction 12 hours, TLC detection reaction terminates in batches.Mother liquor concentrations, residue with Ethyl acetate dissolves, and with using dilute hydrochloric acid and water washing to neutral successively, anhydrous sodium sulfate drying.Concentrating under reduced pressure, residuum recrystallizing methanol obtains off-white color solid Dextromethorphane Hbr (I) 21.6g, yield 79.6%.
It is pointed out that above-mentioned preferred embodiment is only and technical conceive of the present invention and feature are described, its object is to person skilled in the art can be understood content of the present invention and implement according to this, can not limit the scope of the invention with this.All equivalences done according to spirit of the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (1)
1. a preparation method for Dextromethorphane Hbr (I),
It is characterized in that described preparation method comprises the steps:
The 0.1mol intermediate (II) of 25.7g, the 0.2mol sodium methylate of 10.8g, 150mL methyl-formiate is added successively in three-necked bottle, be warming up to 50-55 DEG C, stirring reaction 6 hours, TLC detection reaction terminates, removal of solvent under reduced pressure, residue dissolve with ethanol; Add the 0.12mol sodium borohydride of 4.6g, fall room temperature reaction 12 hours, TLC detection reaction terminates in batches; Mother liquor concentrations, residue with Ethyl acetate dissolves, and with using dilute hydrochloric acid and water washing to neutral successively, anhydrous sodium sulfate drying; Concentrating under reduced pressure, residuum recrystallizing methanol obtains off-white color solid Dextromethorphane Hbr (I).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104119273B (en) * | 2014-04-24 | 2017-11-21 | 上海天慈生物谷生物工程有限公司 | A kind of method for preparing dextromethorphan |
| CN106432079A (en) * | 2016-08-31 | 2017-02-22 | 江苏宝众宝达药业有限公司 | Synthesis method of impurity 3-methoxy-17-methylmorphinan-10-one enantiomer of dextromethorphan |
| CN115557891A (en) * | 2022-10-28 | 2023-01-03 | 上海万巷制药有限公司 | Preparation method of dextromethorphan |
| CN116444433B (en) * | 2023-03-31 | 2025-12-09 | 浙江九洲药业股份有限公司 | Right Meisha Process for the preparation of a compound containing a compound selected from the group consisting of |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634429A (en) * | 1969-09-30 | 1972-01-11 | Hoffmann La Roche | Morphinan derivatives and preparation thereof |
| US3819635A (en) * | 1971-09-08 | 1974-06-25 | Bristol Myers Co | 14-hydroxymorphinan derivatives |
| EP0834506A1 (en) * | 1996-10-02 | 1998-04-08 | F. Hoffmann-La Roche Ag | Process for the preparation of (9alpha, 13alpha, 14alpha)-1-(3-Methoxymorphinan-17-yl)alkanones |
| HK1076052A1 (en) * | 2002-07-17 | 2006-01-06 | Avanir Pharmaceuticals | Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2364151A1 (en) * | 2008-10-30 | 2011-09-14 | Concert Pharmaceuticals Inc. | Combination of morphinan compounds and antidepressant for the treatment of pseudobulbar affect, neurological diseases, intractable and chronic pain and brain injury |
-
2013
- 2013-02-18 CN CN201310051880.0A patent/CN103073496B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3634429A (en) * | 1969-09-30 | 1972-01-11 | Hoffmann La Roche | Morphinan derivatives and preparation thereof |
| US3819635A (en) * | 1971-09-08 | 1974-06-25 | Bristol Myers Co | 14-hydroxymorphinan derivatives |
| EP0834506A1 (en) * | 1996-10-02 | 1998-04-08 | F. Hoffmann-La Roche Ag | Process for the preparation of (9alpha, 13alpha, 14alpha)-1-(3-Methoxymorphinan-17-yl)alkanones |
| HK1076052A1 (en) * | 2002-07-17 | 2006-01-06 | Avanir Pharmaceuticals | Pharmaceutical compositions comprising dextromethorphan and quinidine for the treatment of neurological disorders |
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