DE69913955T2 - Ein verbessertes synthese- und reinigungsverfahren für (r*,r*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochlorid - Google Patents
Ein verbessertes synthese- und reinigungsverfahren für (r*,r*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochlorid Download PDFInfo
- Publication number
- DE69913955T2 DE69913955T2 DE69913955T DE69913955T DE69913955T2 DE 69913955 T2 DE69913955 T2 DE 69913955T2 DE 69913955 T DE69913955 T DE 69913955T DE 69913955 T DE69913955 T DE 69913955T DE 69913955 T2 DE69913955 T2 DE 69913955T2
- Authority
- DE
- Germany
- Prior art keywords
- tramadol
- trans
- hydrochloride
- amine
- ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000015572 biosynthetic process Effects 0.000 title claims description 13
- 238000003786 synthesis reaction Methods 0.000 title claims description 11
- 238000000746 purification Methods 0.000 title description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 96
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 86
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims abstract description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 48
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims abstract description 46
- 229960004380 tramadol Drugs 0.000 claims abstract description 46
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 claims abstract description 46
- 239000000654 additive Substances 0.000 claims abstract description 29
- 238000003747 Grignard reaction Methods 0.000 claims abstract description 27
- 230000000996 additive effect Effects 0.000 claims abstract description 23
- 150000001412 amines Chemical class 0.000 claims abstract description 22
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 238000001953 recrystallisation Methods 0.000 claims abstract description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000002825 nitriles Chemical class 0.000 claims abstract description 8
- PLDWAJLZAAHOGG-UHFFFAOYSA-N 1-bromo-3-methoxybenzene Chemical compound COC1=CC=CC(Br)=C1 PLDWAJLZAAHOGG-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 38
- 239000000047 product Substances 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- RXYPXQSKLGGKOL-UHFFFAOYSA-N 1,4-dimethylpiperazine Chemical compound CN1CCN(C)CC1 RXYPXQSKLGGKOL-UHFFFAOYSA-N 0.000 claims description 8
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 8
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 8
- QWCGXANSAOXRFE-UHFFFAOYSA-N 2-(2-methoxyethoxy)ethanamine Chemical compound COCCOCCN QWCGXANSAOXRFE-UHFFFAOYSA-N 0.000 claims description 6
- 239000007983 Tris buffer Substances 0.000 claims description 6
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical group OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 6
- 230000002194 synthesizing effect Effects 0.000 claims description 6
- SNICXCGAKADSCV-JTQLQIEISA-N (-)-Nicotine Chemical compound CN1CCC[C@H]1C1=CC=CN=C1 SNICXCGAKADSCV-JTQLQIEISA-N 0.000 claims description 4
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 claims description 4
- GIWQSPITLQVMSG-UHFFFAOYSA-N 1,2-dimethylimidazole Chemical compound CC1=NC=CN1C GIWQSPITLQVMSG-UHFFFAOYSA-N 0.000 claims description 4
- SGUVLZREKBPKCE-UHFFFAOYSA-N 1,5-diazabicyclo[4.3.0]-non-5-ene Chemical compound C1CCN=C2CCCN21 SGUVLZREKBPKCE-UHFFFAOYSA-N 0.000 claims description 4
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 4
- KKKDZZRICRFGSD-UHFFFAOYSA-N 1-benzylimidazole Chemical compound C1=CN=CN1CC1=CC=CC=C1 KKKDZZRICRFGSD-UHFFFAOYSA-N 0.000 claims description 4
- MCMFEZDRQOJKMN-UHFFFAOYSA-N 1-butylimidazole Chemical compound CCCCN1C=CN=C1 MCMFEZDRQOJKMN-UHFFFAOYSA-N 0.000 claims description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 4
- XQABVLBGNWBWIV-UHFFFAOYSA-N 4-methoxypyridine Chemical compound COC1=CC=NC=C1 XQABVLBGNWBWIV-UHFFFAOYSA-N 0.000 claims description 4
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 4
- UKODFQOELJFMII-UHFFFAOYSA-N pentamethyldiethylenetriamine Chemical compound CN(C)CCN(C)CCN(C)C UKODFQOELJFMII-UHFFFAOYSA-N 0.000 claims description 4
- 229920000570 polyether Polymers 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- WMGVPDQNPUQRND-UHFFFAOYSA-N (2-methylphenyl)acetonitrile Chemical compound CC1=CC=CC=C1CC#N WMGVPDQNPUQRND-UHFFFAOYSA-N 0.000 claims description 3
- -1 diglycol ethers Chemical class 0.000 claims description 3
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 150000003512 tertiary amines Chemical class 0.000 claims 1
- HFNCOTSLOKKPHU-UHFFFAOYSA-N cyclohexanol;hydrochloride Chemical compound Cl.OC1CCCCC1 HFNCOTSLOKKPHU-UHFFFAOYSA-N 0.000 abstract 1
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 15
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 239000012071 phase Substances 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- XGLVDUUYFKXKPL-UHFFFAOYSA-N 2-(2-methoxyethoxy)-n,n-bis[2-(2-methoxyethoxy)ethyl]ethanamine Chemical compound COCCOCCN(CCOCCOC)CCOCCOC XGLVDUUYFKXKPL-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 5
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000011777 magnesium Substances 0.000 description 5
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 229910052749 magnesium Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 238000004140 cleaning Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 238000006683 Mannich reaction Methods 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 150000004795 grignard reagents Chemical class 0.000 description 2
- 150000003840 hydrochlorides Chemical group 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- TVYLLZQTGLZFBW-HOCLYGCPSA-N (1r,2s)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol Chemical compound COC1=CC=CC([C@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-HOCLYGCPSA-N 0.000 description 1
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 1
- YUMSFEDUCCHSIV-UHFFFAOYSA-N 2-methyl-2-methylperoxypropane Chemical compound COOC(C)(C)C YUMSFEDUCCHSIV-UHFFFAOYSA-N 0.000 description 1
- 241000857902 Bursera graveolens Species 0.000 description 1
- 206010012373 Depressed level of consciousness Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000007818 Grignard reagent Substances 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- PPKXEPBICJTCRU-UHFFFAOYSA-N [2-hydroxy-2-(3-methoxyphenyl)cyclohexyl]methyl-dimethylazanium;chloride Chemical compound Cl.COC1=CC=CC(C2(O)C(CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008378 aryl ethers Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- QCAWEPFNJXQPAN-UHFFFAOYSA-N methoxyfenozide Chemical compound COC1=CC=CC(C(=O)NN(C(=O)C=2C=C(C)C=C(C)C=2)C(C)(C)C)=C1C QCAWEPFNJXQPAN-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000012485 toluene extract Substances 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B49/00—Grignard reactions
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8649898P | 1998-05-22 | 1998-05-22 | |
| US86498P | 1998-05-22 | ||
| PCT/US1999/011336 WO1999061405A1 (en) | 1998-05-22 | 1999-05-20 | An improved synthesis and purification of (r*,r*)-2-[ (dimethylamino) methyl]-1-( 3-methoxyphenyl) cyclohexanol hydrochloride |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69913955D1 DE69913955D1 (de) | 2004-02-05 |
| DE69913955T2 true DE69913955T2 (de) | 2004-12-16 |
Family
ID=22198976
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69913955T Expired - Fee Related DE69913955T2 (de) | 1998-05-22 | 1999-05-20 | Ein verbessertes synthese- und reinigungsverfahren für (r*,r*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochlorid |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US6399829B1 (https=) |
| EP (1) | EP1077923B1 (https=) |
| JP (1) | JP2002516302A (https=) |
| AT (1) | ATE257147T1 (https=) |
| CA (1) | CA2330142A1 (https=) |
| DE (1) | DE69913955T2 (https=) |
| DK (1) | DK1077923T3 (https=) |
| ES (1) | ES2212849T3 (https=) |
| WO (1) | WO1999061405A1 (https=) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001510180A (ja) * | 1997-07-15 | 2001-07-31 | ラシンスキィ・リミテッド | トラマドール、その塩酸塩、及びそれらの製造方法 |
| KR100342919B1 (ko) * | 1999-10-21 | 2002-07-04 | 박노중 | 트랜스체 염산 트라마돌의 분리 제조방법 |
| RU2165922C1 (ru) * | 2000-07-19 | 2001-04-27 | Государственный научно-исследовательский институт органической химии и технологии | Способ получения трамадола |
| DE10049483A1 (de) * | 2000-09-29 | 2002-05-02 | Gruenenthal Gmbh | Substituierte 1-Aminobutan-3-ol-Derivate |
| DE10049481A1 (de) | 2000-09-29 | 2002-05-02 | Gruenenthal Gmbh | Substituierte C-Cyclohexylmethylamin-Derivate |
| DE10108308A1 (de) | 2001-02-21 | 2002-08-29 | Gruenenthal Gmbh | Verfahren zur Isolierung und Reinigung von (1RS,2RS)-2[(Dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol |
| US6649783B2 (en) | 2001-10-03 | 2003-11-18 | Euro-Celtique, S.A. | Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols |
| DE10236510A1 (de) * | 2002-08-09 | 2004-02-19 | Grünenthal GmbH | Verfahren zur Herstellung von 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol |
| JP2004115510A (ja) * | 2002-09-05 | 2004-04-15 | Toray Fine Chemicals Co Ltd | ピペラジン誘導体の製造方法 |
| EP1785412A1 (en) * | 2005-11-14 | 2007-05-16 | IPCA Laboratories Limited | Tramadol recovery process |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3652589A (en) * | 1967-07-27 | 1972-03-28 | Gruenenthal Chemie | 1-(m-substituted phenyl)-2-aminomethyl cyclohexanols |
| IL103096A (en) * | 1992-09-08 | 1996-12-05 | Chemagis Ltd | Process for purification 2 -]) Dimethylamino (methyl-1-) 3-methoxycinyl (cyclohexanol and its salts. |
| IL116281A (en) * | 1995-12-07 | 1999-06-20 | Chemagis Ltd | Process for the purification of (rr,ss)-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol and its salts |
-
1999
- 1999-05-20 EP EP99930115A patent/EP1077923B1/en not_active Expired - Lifetime
- 1999-05-20 WO PCT/US1999/011336 patent/WO1999061405A1/en not_active Ceased
- 1999-05-20 US US09/700,889 patent/US6399829B1/en not_active Expired - Fee Related
- 1999-05-20 DK DK99930115T patent/DK1077923T3/da active
- 1999-05-20 CA CA002330142A patent/CA2330142A1/en not_active Abandoned
- 1999-05-20 ES ES99930115T patent/ES2212849T3/es not_active Expired - Lifetime
- 1999-05-20 DE DE69913955T patent/DE69913955T2/de not_active Expired - Fee Related
- 1999-05-20 AT AT99930115T patent/ATE257147T1/de not_active IP Right Cessation
- 1999-05-20 JP JP2000550815A patent/JP2002516302A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| EP1077923A1 (en) | 2001-02-28 |
| WO1999061405A1 (en) | 1999-12-02 |
| JP2002516302A (ja) | 2002-06-04 |
| EP1077923B1 (en) | 2004-01-02 |
| US6399829B1 (en) | 2002-06-04 |
| DE69913955D1 (de) | 2004-02-05 |
| ES2212849T3 (es) | 2004-08-01 |
| CA2330142A1 (en) | 1999-12-02 |
| ATE257147T1 (de) | 2004-01-15 |
| DK1077923T3 (da) | 2004-04-13 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69716767T2 (de) | Verfahren zur herstellung von tolterodin | |
| DE69109514T2 (de) | 4-(4-Alkoxyphenyl)-2-Butylaminderivate und deren Herstellungsverfahren. | |
| DE19619665C2 (de) | Racemattrennung von Ketamin | |
| DE69913955T2 (de) | Ein verbessertes synthese- und reinigungsverfahren für (r*,r*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol hydrochlorid | |
| DE20216835U1 (de) | Racemisches Tamsulosin in Form der freien Base | |
| DE112020001032T5 (de) | Verfahren zur Herstellung von Levoamphetamin | |
| DE69116237T2 (de) | Derivate von Hexahydroazepine, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel | |
| EP3271337B1 (de) | Verfahren zur herstellung von (4s)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluormethyl)phenyl]-1,2,3,4-tetrahydro pyrimidin-5-carbonitril | |
| EP0176856B1 (de) | Verfahren zur Herstellung optisch aktiver Amine | |
| EP1073634B1 (de) | Verfahren zur herstellung von enantiomerenreinem n-methyl- n- (1s)- 1-phenyl- 2-((3s)-3- hydroxypyrrolidin- 1-yl)ethyl]- 2,2- diphenylacetamid | |
| EP1067129B1 (de) | Racemisierung von R,S-Dioxo-benzylpyrrolopiperidin | |
| DD266349A5 (de) | Verfahren zur herstellung von 2-acyloxypropylamin-2-acyloxypropylamin-derivaten | |
| DE602004009831T2 (de) | Verfahren zur gewinnung von tolterodin | |
| DE69932269T2 (de) | Herstellung optisch aktiver Cyclohexylphenylglykolsäureester | |
| EP0612745B1 (de) | Verfahren zur Herstellung von 1,2,3,4,10,14b-Hexahydro-2-methyl-dibenzo[c,f]pyrazino[1,2-a]azepin und seiner Salze | |
| DE60002303T2 (de) | Verfahren zur herstellung von paroxetin | |
| EP1389188B1 (de) | Verfahren zur herstellung von biperiden ii | |
| DE112020004177B4 (de) | Verfahren zur herstellung des natriumsalzes von 4-[[(1r)-2-[5-(2-fluor-3-methoxyphenyl)-3-[[2-fluor-6-(trifluormethyl)-phenyl]methyl]-3,6-dihydro-4-methyl-2,6-dioxo-1(2h)-pyrimidinyl]-1-phenylethyl]amino]butansäure (elagolix-natriumsalz) und zwischenstufen dieses verfahrens | |
| EP0367205B1 (de) | 2-Aminocarbonsäuren und deren Derivate, Verfahren zu deren Herstellung und deren Verwendung als Arzneimittel | |
| DE69030774T2 (de) | Optisch aktive Diastereoisomersalze von Tetrahydro-2-furancarbonsäure | |
| DE69804853T2 (de) | Verfahren zur herstellung von mequitazin und zwischenprodukt der synthese | |
| WO2005049570A1 (de) | Verfahren zur synthese optisch aktiver piperidine durch hydrierung optisch aktiver pyridine | |
| DE69916269T2 (de) | Neues verfahren | |
| DE102004034682A1 (de) | Verkürztes Verfahren zur Herstellung von chiralem Lobelin | |
| EP0180890A2 (de) | Verfahren zur diastereoselektiven Reduktion von 3-Amino-1-benzoxepin-5(2H)-onen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| 8339 | Ceased/non-payment of the annual fee |