DK2635586T3 - PROCEDURE FOR THE PREPARATION OF NALTREXON - Google Patents
PROCEDURE FOR THE PREPARATION OF NALTREXON Download PDFInfo
- Publication number
- DK2635586T3 DK2635586T3 DK11785301.0T DK11785301T DK2635586T3 DK 2635586 T3 DK2635586 T3 DK 2635586T3 DK 11785301 T DK11785301 T DK 11785301T DK 2635586 T3 DK2635586 T3 DK 2635586T3
- Authority
- DK
- Denmark
- Prior art keywords
- noroxymorphone
- naltrexone
- mixture
- acid
- mixing
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 78
- 238000002360 preparation method Methods 0.000 title claims description 5
- 229960003086 naltrexone Drugs 0.000 claims description 51
- 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 47
- HLMSIZPQBSYUNL-IPOQPSJVSA-N Noroxymorphone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 HLMSIZPQBSYUNL-IPOQPSJVSA-N 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 42
- 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 26
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 25
- 229960005297 nalmefene Drugs 0.000 claims description 24
- -1 cyclopropylmethyl halide Chemical class 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 238000002156 mixing Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 18
- AEILLAXRDHDKDY-UHFFFAOYSA-N bromomethylcyclopropane Chemical group BrCC1CC1 AEILLAXRDHDKDY-UHFFFAOYSA-N 0.000 claims description 16
- 239000007787 solid Substances 0.000 claims description 16
- 239000003586 protic polar solvent Substances 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 14
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical group CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 11
- 238000007239 Wittig reaction Methods 0.000 claims description 8
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical group 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 4
- 239000003245 coal Substances 0.000 claims 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 23
- 238000004128 high performance liquid chromatography Methods 0.000 description 13
- 239000002516 radical scavenger Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 239000012458 free base Substances 0.000 description 9
- 230000029936 alkylation Effects 0.000 description 7
- 238000005804 alkylation reaction Methods 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 6
- 239000011736 potassium bicarbonate Substances 0.000 description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 6
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- 239000000908 ammonium hydroxide Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 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 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 206010012335 Dependence Diseases 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- 229940127450 Opioid Agonists Drugs 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 239000003401 opiate antagonist Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- QMFVIJMHPXUVOL-RCGDHTHDSA-N (4r,4as,7ar,12bs)-4a,9-dihydroxy-1,2,3,4,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;hydrochloride Chemical compound Cl.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4 QMFVIJMHPXUVOL-RCGDHTHDSA-N 0.000 description 1
- 208000001613 Gambling Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 206010034158 Pathological gambling Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- USDJGQLNFPZEON-UHFFFAOYSA-N [[4,6-bis(hydroxymethylamino)-1,3,5-triazin-2-yl]amino]methanol Chemical compound OCNC1=NC(NCO)=NC(NCO)=N1 USDJGQLNFPZEON-UHFFFAOYSA-N 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 150000005323 carbonate salts Chemical class 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- ZVTQWXCKQTUVPY-UHFFFAOYSA-N chloromethylcyclopropane Chemical compound ClCC1CC1 ZVTQWXCKQTUVPY-UHFFFAOYSA-N 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 235000019788 craving Nutrition 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- JHKJQWFHNIOUKY-UHFFFAOYSA-N iodomethylcyclopropane Chemical compound ICC1CC1 JHKJQWFHNIOUKY-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 230000007056 liver toxicity Effects 0.000 description 1
- 229940127240 opiate Drugs 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41040510P | 2010-11-05 | 2010-11-05 | |
| DKPA201001007 | 2010-11-05 | ||
| US201161489701P | 2011-05-25 | 2011-05-25 | |
| DKPA201100396 | 2011-05-25 | ||
| PCT/DK2011/000128 WO2012059103A1 (en) | 2010-11-05 | 2011-11-04 | Method for the manufacturing of naltrexone |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DK2635586T3 true DK2635586T3 (en) | 2017-03-27 |
Family
ID=45001588
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK11785301.0T DK2635586T3 (en) | 2010-11-05 | 2011-11-04 | PROCEDURE FOR THE PREPARATION OF NALTREXON |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP2635586B1 (enExample) |
| JP (2) | JP6246589B2 (enExample) |
| AP (1) | AP3415A (enExample) |
| AU (1) | AU2011325563B2 (enExample) |
| CA (1) | CA2815093C (enExample) |
| CY (1) | CY1118742T1 (enExample) |
| DK (1) | DK2635586T3 (enExample) |
| EA (1) | EA022266B1 (enExample) |
| ES (1) | ES2620660T3 (enExample) |
| HR (1) | HRP20170379T1 (enExample) |
| HU (1) | HUE033596T2 (enExample) |
| LT (1) | LT2635586T (enExample) |
| ME (1) | ME02621B (enExample) |
| MX (1) | MX2013005009A (enExample) |
| PL (1) | PL2635586T3 (enExample) |
| PT (1) | PT2635586T (enExample) |
| RS (1) | RS55777B1 (enExample) |
| SI (1) | SI2635586T1 (enExample) |
| SM (1) | SMT201700177T1 (enExample) |
| WO (1) | WO2012059103A1 (enExample) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20140005216A1 (en) | 2012-06-27 | 2014-01-02 | H. Lundbeck A/S | Nalmefene for reduction of alcohol consumption in specific target populations |
| AR096851A1 (es) | 2013-07-11 | 2016-02-03 | H Lundbeck As | Sales que no forman hidratos ni solvatos de nalmefeno |
| KR20160093025A (ko) | 2013-12-20 | 2016-08-05 | 하. 룬트벡 아크티에 셀스카브 | 멜랑코리성 특색을 갖는 우울 장애의 치료를 위한 카파-활성을 갖는 오피오이드 수용체 길항제 및 보티옥세틴의 용도 |
| JP6797691B2 (ja) | 2014-04-22 | 2020-12-09 | 大塚製薬株式会社 | ブレクスピプラゾールとナルメフェンの組み合わせ剤及び物質関連障害を治療するためのその用途 |
| US9701687B2 (en) * | 2014-05-05 | 2017-07-11 | Noramco, Inc. | Process for the preparation of opioid compounds |
| US9701688B2 (en) * | 2014-05-05 | 2017-07-11 | Noramco, Inc. | Process for the preparation of opioid compounds |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4535157A (en) | 1983-11-01 | 1985-08-13 | Key Pharmaceuticals, Inc. | Process for making 6-desoxy-6-methylenenaloxone and 6-desoxy-6-methylenenaltrexone |
| US4751307A (en) | 1985-01-17 | 1988-06-14 | Mallinckrodt, Inc. | Wittig-reaction processes |
| ATE178329T1 (de) * | 1989-10-16 | 1999-04-15 | Us Health | Totale synthese von northebain-, normorphin-, noroxymorphon-enantiomeren und -derivaten via n- nor-zwischenverbindungen |
| FR2906252B1 (fr) * | 2006-09-21 | 2008-11-28 | Sanofi Aventis Sa | Procede de preparation d'halogenures de n-aklyl naltrexone |
| WO2008138383A1 (de) | 2007-05-16 | 2008-11-20 | Cilag Ag | Verfahren zur herstellung von n-methylnaltrexonbromid |
| CN102227433B (zh) * | 2008-09-30 | 2015-01-07 | 马林克罗特有限公司 | 烷基化吗啡喃衍生物的仲胺基团的方法 |
| PL2435439T3 (pl) | 2009-05-25 | 2016-05-31 | H Lundbeck As | Wytwarzanie chlorowodorku nalmefenu z naltreksonu |
-
2011
- 2011-11-04 AU AU2011325563A patent/AU2011325563B2/en not_active Ceased
- 2011-11-04 EP EP11785301.0A patent/EP2635586B1/en active Active
- 2011-11-04 JP JP2013537002A patent/JP6246589B2/ja active Active
- 2011-11-04 AP AP2013006897A patent/AP3415A/xx active
- 2011-11-04 HU HUE11785301A patent/HUE033596T2/hu unknown
- 2011-11-04 SM SM20170177T patent/SMT201700177T1/it unknown
- 2011-11-04 CA CA2815093A patent/CA2815093C/en active Active
- 2011-11-04 DK DK11785301.0T patent/DK2635586T3/en active
- 2011-11-04 PL PL11785301T patent/PL2635586T3/pl unknown
- 2011-11-04 HR HRP20170379TT patent/HRP20170379T1/hr unknown
- 2011-11-04 PT PT117853010T patent/PT2635586T/pt unknown
- 2011-11-04 ES ES11785301.0T patent/ES2620660T3/es active Active
- 2011-11-04 RS RS20170244A patent/RS55777B1/sr unknown
- 2011-11-04 MX MX2013005009A patent/MX2013005009A/es active IP Right Grant
- 2011-11-04 SI SI201131131A patent/SI2635586T1/sl unknown
- 2011-11-04 ME MEP-2017-57A patent/ME02621B/me unknown
- 2011-11-04 LT LTEP11785301.0T patent/LT2635586T/lt unknown
- 2011-11-04 WO PCT/DK2011/000128 patent/WO2012059103A1/en not_active Ceased
- 2011-11-04 EA EA201390658A patent/EA022266B1/ru not_active IP Right Cessation
-
2016
- 2016-06-24 JP JP2016125389A patent/JP6215399B2/ja active Active
-
2017
- 2017-03-17 CY CY20171100341T patent/CY1118742T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2635586B1 (en) | 2017-02-08 |
| HUE033596T2 (hu) | 2017-12-28 |
| HRP20170379T1 (hr) | 2017-05-05 |
| JP2016199566A (ja) | 2016-12-01 |
| EA022266B1 (ru) | 2015-11-30 |
| PL2635586T3 (pl) | 2017-06-30 |
| CA2815093A1 (en) | 2012-05-10 |
| AP2013006897A0 (en) | 2013-05-31 |
| MX2013005009A (es) | 2013-08-01 |
| LT2635586T (lt) | 2017-04-10 |
| AP3415A (en) | 2015-09-30 |
| EP2635586A1 (en) | 2013-09-11 |
| JP6246589B2 (ja) | 2017-12-13 |
| PT2635586T (pt) | 2017-03-30 |
| AU2011325563B2 (en) | 2015-08-20 |
| JP2013541564A (ja) | 2013-11-14 |
| JP6215399B2 (ja) | 2017-10-18 |
| RS55777B1 (sr) | 2017-07-31 |
| SI2635586T1 (sl) | 2017-07-31 |
| ME02621B (me) | 2017-06-20 |
| AU2011325563A1 (en) | 2013-05-02 |
| CA2815093C (en) | 2019-08-06 |
| CY1118742T1 (el) | 2017-07-12 |
| EA201390658A1 (ru) | 2013-11-29 |
| WO2012059103A1 (en) | 2012-05-10 |
| ES2620660T3 (es) | 2017-06-29 |
| SMT201700177T1 (it) | 2017-05-08 |
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