US20080177110A1 - Processes for the synthesis of O-desmethylvenlafaxine - Google Patents
Processes for the synthesis of O-desmethylvenlafaxine Download PDFInfo
- Publication number
- US20080177110A1 US20080177110A1 US11/881,825 US88182507A US2008177110A1 US 20080177110 A1 US20080177110 A1 US 20080177110A1 US 88182507 A US88182507 A US 88182507A US 2008177110 A1 US2008177110 A1 US 2008177110A1
- Authority
- US
- United States
- Prior art keywords
- bodv
- desmethylvenlafaxine
- reaction mixture
- preparing
- combining
- 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.)
- Abandoned
Links
- KYYIDSXMWOZKMP-UHFFFAOYSA-N O-desmethylvenlafaxine Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(O)C=C1 KYYIDSXMWOZKMP-UHFFFAOYSA-N 0.000 title claims abstract description 104
- 238000000034 method Methods 0.000 title claims abstract description 65
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 238000003786 synthesis reaction Methods 0.000 title description 4
- 239000011541 reaction mixture Substances 0.000 claims description 127
- 239000003960 organic solvent Substances 0.000 claims description 82
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 68
- 239000002585 base Substances 0.000 claims description 65
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 48
- 238000004519 manufacturing process Methods 0.000 claims description 42
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical group [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 239000000243 solution Substances 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 19
- 239000003444 phase transfer catalyst Substances 0.000 claims description 19
- 239000003638 chemical reducing agent Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 16
- 229910052751 metal Inorganic materials 0.000 claims description 16
- 239000002184 metal Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- -1 Hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol Chemical class 0.000 claims description 14
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 14
- 239000012022 methylating agents Substances 0.000 claims description 13
- 239000003223 protective agent Substances 0.000 claims description 13
- JTDRMEWIAHOIGB-UHFFFAOYSA-N 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexan-1-ol Chemical compound C1CCCCC1(O)C(CN(C)C)C1=CC=C(Br)C=C1 JTDRMEWIAHOIGB-UHFFFAOYSA-N 0.000 claims description 11
- 230000001376 precipitating effect Effects 0.000 claims description 11
- BXOPMXHGNHQNLT-UHFFFAOYSA-N 2-(4-bromophenyl)-2-(1-hydroxycyclohexyl)acetonitrile Chemical compound C=1C=C(Br)C=CC=1C(C#N)C1(O)CCCCC1 BXOPMXHGNHQNLT-UHFFFAOYSA-N 0.000 claims description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 9
- XUHFBOUSHUEAQZ-UHFFFAOYSA-N bromobenzyl cyanide Chemical compound N#CC(Br)C1=CC=CC=C1 XUHFBOUSHUEAQZ-UHFFFAOYSA-N 0.000 claims description 9
- 238000011084 recovery Methods 0.000 claims description 9
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 7
- 150000001340 alkali metals Chemical class 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 7
- NUDYEFKRVCEEPL-UHFFFAOYSA-N 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexan-1-ol Chemical compound C1CCCCC1(O)C(CN)C1=CC=C(Br)C=C1 NUDYEFKRVCEEPL-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 150000002170 ethers Chemical class 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000012267 brine Substances 0.000 claims description 5
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Chemical compound [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 5
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000007818 Grignard reagent Substances 0.000 claims description 4
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004795 grignard reagents Chemical class 0.000 claims description 4
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 125000001931 aliphatic group Chemical group 0.000 claims description 3
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims description 3
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 3
- 150000001342 alkaline earth metals Chemical class 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003118 aryl group Chemical group 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 239000003880 polar aprotic solvent Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 claims description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000003983 crown ethers Chemical group 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 150000004714 phosphonium salts Chemical group 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 239000002002 slurry Substances 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 125000005207 tetraalkylammonium group Chemical group 0.000 claims description 2
- 125000005497 tetraalkylphosphonium group Chemical group 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 11
- 239000000543 intermediate Substances 0.000 abstract description 8
- 239000000203 mixture Substances 0.000 description 57
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical group [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 38
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 37
- 229910000085 borane Inorganic materials 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 16
- 238000003747 Grignard reaction Methods 0.000 description 13
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- 229960004688 venlafaxine Drugs 0.000 description 8
- 229960004132 diethyl ether Drugs 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000011777 magnesium Substances 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- GUJOJGAPFQRJSV-UHFFFAOYSA-N dialuminum;dioxosilane;oxygen(2-);hydrate Chemical compound O.[O-2].[O-2].[O-2].[Al+3].[Al+3].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O GUJOJGAPFQRJSV-UHFFFAOYSA-N 0.000 description 5
- 229940052303 ethers for general anesthesia Drugs 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 150000007529 inorganic bases Chemical class 0.000 description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-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
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 229910052901 montmorillonite Inorganic materials 0.000 description 3
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 3
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 2
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
- 239000012346 acetyl chloride Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 150000004820 halides Chemical group 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 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
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- 229960002748 norepinephrine Drugs 0.000 description 2
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000005270 trialkylamine group Chemical group 0.000 description 2
- MFHFWRBXPQDZSA-UHFFFAOYSA-N 2-(4-bromophenyl)acetonitrile Chemical compound BrC1=CC=C(CC#N)C=C1 MFHFWRBXPQDZSA-UHFFFAOYSA-N 0.000 description 1
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-UHFFFAOYSA-N 0.000 description 1
- MOHIYTLRUDZQDP-UHFFFAOYSA-N 2-cyclohexyl-2-phenylpropanenitrile Chemical compound C=1C=CC=CC=1C(C#N)(C)C1CCCCC1 MOHIYTLRUDZQDP-UHFFFAOYSA-N 0.000 description 1
- NVAOLENBKNECGF-UHFFFAOYSA-N 2-phenylpropanenitrile Chemical compound N#CC(C)C1=CC=CC=C1 NVAOLENBKNECGF-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
- GELAJAUWKHBCTB-BTMNXFQOSA-N BBC.BC(B)=C.C.CN(C)CC(C1=CC=C(Br)C=C1)C1(C)CCCCC1.CN(C)CC(C1=CC=C(Br)C=C1)C1(O)CCCCC1.CN(C)CC(C1=CC=C(O)C=C1)C1(O)CCCCC1.N#CC(C1=CC=C(Br)C=C1)C1(O)CCCCC1.N#CCC1=CC=C(Br)C=C1.NCC(C1=CC=C(Br)C=C1)C1(O)CCCCC1.O=C1CCCCC1.P[V-].[2H]B=O.[2H]B=O.[V] Chemical compound BBC.BC(B)=C.C.CN(C)CC(C1=CC=C(Br)C=C1)C1(C)CCCCC1.CN(C)CC(C1=CC=C(Br)C=C1)C1(O)CCCCC1.CN(C)CC(C1=CC=C(O)C=C1)C1(O)CCCCC1.N#CC(C1=CC=C(Br)C=C1)C1(O)CCCCC1.N#CCC1=CC=C(Br)C=C1.NCC(C1=CC=C(Br)C=C1)C1(O)CCCCC1.O=C1CCCCC1.P[V-].[2H]B=O.[2H]B=O.[V] GELAJAUWKHBCTB-BTMNXFQOSA-N 0.000 description 1
- QALCRWBCHXIJRH-FNASUAHHSA-N CN(C)CC(C1=CC=C(O)C=C1)C1(O)CCCCC1.COC1=CC=C(C(C#N)C2(O)CCCCC2)C=C1.COC1=CC=C(C(CN(C)C)C2(O)CCCCC2)C=C1.COC1=CC=C(C(CN)C2(O)CCCCC2)C=C1.COC1=CC=C(CC#N)C=C1.O=C1CCCCC1.[2H][2H].[V] Chemical compound CN(C)CC(C1=CC=C(O)C=C1)C1(O)CCCCC1.COC1=CC=C(C(C#N)C2(O)CCCCC2)C=C1.COC1=CC=C(C(CN(C)C)C2(O)CCCCC2)C=C1.COC1=CC=C(C(CN)C2(O)CCCCC2)C=C1.COC1=CC=C(CC#N)C=C1.O=C1CCCCC1.[2H][2H].[V] QALCRWBCHXIJRH-FNASUAHHSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical group [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical class [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 description 1
- 150000002222 fluorine compounds Chemical group 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910000000 metal hydroxide Inorganic materials 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000012154 norepinephrine uptake Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical group 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 229910052615 phyllosilicate Inorganic materials 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000013275 serotonin uptake Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000007711 solidification Methods 0.000 description 1
- 230000008023 solidification Effects 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/29—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- 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
- A61P25/24—Antidepressants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
-
- 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
Definitions
- the invention encompasses a process for the synthesis of O-desmethylvenlafaxine.
- Venlafaxine ( ⁇ )-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol is the first of a class of anti-depressants. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin, and is an alternative to the tricyclic anti-depressants and selective re-uptake inhibitors. Venlafaxine has the following chemical formula, Formula I:
- O-desmethylvenlafaxine 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, is reported to be a metabolite of venlafaxine and has been reported to inhibit norepinephrine and serotonin uptake. See Klamerus, K. J. et al., “Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite,” J. Clin. Pharmacol. 32:716-724 (1992).
- O-desmethylvenlafaxine has the following chemical formula, Formula II:
- MCC methyl benzyl cyanide
- CMBC cyclohexyl methylbenzyl cyanide
- DDMV didesmethyl venlafaxine
- ODV O-desmethylvenlafaxine
- the invention encompasses (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
- the present invention provides a process for preparing CBBC comprising reacting BBC with cyclohexanone.
- the present invention provides a process for preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) comprising precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), a dry organic solvent, a base and cyclohexanone.
- CBBC (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile
- the present invention provides a process for obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), a phase transfer catalyst, a base and cyclohexanone.
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and further converting the CBBC to O-desmethylvenlafaxine.
- the invention encompasses 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).
- the present invention provides a process for preparing 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) comprising: combining CBBC, an organic solvent and borane to create a reaction mixture, followed by recovery of the BDDMV from the reaction mixture.
- BDDMV 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine.
- the invention encompasses 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
- the present invention provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, followed by recovery of the BODV from the reaction mixture.
- BODV 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
- the present invention provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, an organic solvent, and a methylating agent to form a mixture, and recovering the BODV from the mixture.
- BODV 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising combining BODV with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocuprate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine.
- the invention encompasses hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
- the present invention provides a process for preparing hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.
- BODV-P hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine.
- the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
- the present invention further provides processes for preparing O-desmethylvenlafaxine via the intermediates described above.
- the invention encompasses a new synthetic route for obtaining O-desmethylvenlafaxine, from 4-bromophenylacetonitrile (BBC), (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC), 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV), 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) and hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
- BCC 4-bromophenylacetonitrile
- CBBC 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol
- BDDMV 1-[1-(4-
- the intermediate bromophenylacetonitrile (BBC) is condensed with cyclohexanone to form the intermediate (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
- the cyano group on the CBBC is subjected to reduction, to form the intermediate 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) which is then subjected to selective alkylation to produce 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV), which is finally converted to O-desmethylvenlafaxine (ODV), by performing halide exchange (optionally, the final conversion step can go via a protected BODV intermediate) as described in the following scheme:
- the invention encompasses (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC). Also provided is CBBC in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The CBBC may have a purity of at least about 50% as measured by HPLC.
- the compound is characterized by NMR 1 H (DMSO-d 6 ) ⁇ : 1.56 (4H, H cyclohexyl), 1.71 (2H, H cyclohexyl), 2.25 (2H, H cyclohexyl), 2.61 (2H, H cyclohexyl), 3.32 (1H, CHCN), 7.27 (2H, H arom.), 7.65 (2H, H arom.).
- the present invention also provides a process for preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) by reacting BBC with cyclohexanone
- This process can comprise precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), organic solvent, a base and cyclohexanone.
- BBC bromophenylacetonitrile
- organic solvent is dry.
- An organic solvent is dry if it is essentially free of water such that the amount of residual water, if detectable, does not interfere with the reaction (e.g. by destroying catalysts or reagents) in a manner that prevents the benefits of the present invention from being realized.
- an organic solvent having less than 1% by water is considered to be dry by one of ordinary skill of art.
- the dry organic solvent is selected from the group consisting of: C 4-8 ethers, polar aprotic solvents (Polarity Index of greater than about 2.0), C 1 -C 8 chlorinated aliphatic, C 6 -C 12 aromatic hydrocarbons, and C 1-6 alcohols.
- the ethers are selected from the group consisting of: diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), the polar aprotic solvents are selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO), the chlorinated organic solvents are selected from the group consisting of methylene chloride and chlorobenzene or chloroform and the aromatic hydrocarbons are selected from the group consisting of toluene and benzene.
- the polar aprotic solvents are selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO)
- the chlorinated organic solvents are selected from the group consisting of methylene chloride and chlorobenzene or chloroform
- the aromatic hydrocarbons are selected from the group consisting of toluene and benzene.
- the dry organic solvent is selected from the group consisting of: tetrahydrofuran (THF), methanol, methylene chloride and toluene.
- THF tetrahydrofuran
- methanol methylene chloride
- toluene tetrahydrofuran
- the organic solvent can be used individually, or in a mixture with another solvent, particularly methanol.
- the base can be an inorganic base, such as an alkali metal or alkaline earth metal. More preferably, the base is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis(trimethyl silyl) amide (LiN[(CH 3 ) 3 Si] 2 ), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH 3 ).
- LDA lithium diisopropyl amide
- LiN[(CH 3 ) 3 Si] 2 potassium hydroxide
- KOH lithium hydroxide
- LiOH lithium hydroxide
- NaH sodium hydride
- t-BuOK potassium tert butoxide
- t-BuOLi lithium tert butoxide
- BuLi butyl lithium
- NaOCH 3
- the process can be carried out by combining a solution or a slurry of BBC and a dry organic solvent with a base to obtain a reaction mixture, followed by combining the reaction mixture with cyclohexanone, to obtain CBBC.
- Cyclohexanone can be added to the reaction mixture in a dropwise manner. After combining the reaction mixture with cyclohexanone, the mixture is further maintained, until completion of the reaction.
- CBBC may then be recovered.
- the solvent can be evaporated and the residue dissolved in a water immiscible solvent such as toluene, EtOAc (ethyl acetate), CH 2 Cl 2 , diethyl ether, MTBE (methyl-t-butyl ether), MEK (methyl ethyl ketone) washed with water or brine, and evaporated to get an oil.
- the oil can then be added to an organic solvent such as methanol to obtain a solution and crystallize CBBC.
- the present invention provides a process for obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), optionally a phase transfer catalyst, a base and cyclohexanone.
- CBBC (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile
- BCC bromophenylacetonitrile
- a phase transfer catalyst optionally a phase transfer catalyst
- a base optionally a phase transfer catalyst
- the phase transfer catalyst can be a tetraalkylammonium, tetraalkylphosphonium, tetraarylammonium or tetraarylphosphonium, preferably wherein the alkyl group can be the same or different and contains from 1 to 10 carbons, and wherein the aryl group can be the same or different and contains from 6 to 8 carbons.
- the phase transfer catalyst can be a tetraalkylammonium halide, preferably wherein the alkyl group can be the same or different and contains from 1 to 6, preferably from 1 to 4 carbon atoms, and the halide is fluoride, chloride, bromide or iodide, preferably chloride, bromide or iodide.
- the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot, quaternary ammonium salt, quaternary phosphonium salt and crown ether. More preferably, the phase transfer catalyst is tetra butyl ammonium bromide (TBAB).
- TBAB tetra butyl ammonium bromide
- the base may be an inorganic base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, preferably, NaOH, KOH, LiOH, CsOH, K 2 CO 3 or NaCO 3 , Cs 2 CO 3 , KHCO 3 or NaHCO 3
- an alkali metal or alkaline earth metal hydroxide or carbonate preferably, NaOH, KOH, LiOH, CsOH, K 2 CO 3 or NaCO 3 , Cs 2 CO 3 , KHCO 3 or NaHCO 3
- BBC cyclohexanone
- the phase transfer catalyst such as TBAB
- the base such as NaOH
- the base is added in an amount of about 0.5 to about 1 mole per mole of BBC.
- the cyclohexanone is added in an amount of about 1 to about 1.15 moles per mole of BBC.
- the reaction is then maintained to get CBBC.
- the reaction can be maintained from about 1 to about 24 hours. It can also be stirred while maintained.
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and further converting the CBBC to O-desmethylvenlafaxine.
- the invention encompasses 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV). Also provided is BDDMV in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BDDMV may have a purity of at least about 50% as measured by HPLC.
- BDDMV can be prepared by reacting CBBC with a reducing agent. More specifically, BDDMV can be prepared by combining CBBC an organic solvent such as THF to obtain a solution, to which a reducing agent is added.
- the solvent is a dry organic solvent, as described above, more preferably THF.
- Chlorinated solvents such as C 1 -C 8 chlorinated hydrocarbons and C 4 -C 8 ethers can also be used.
- the reducing agent is borane or a hydride, more preferably a Borane dimethylsulfide complex, which is added dropwise.
- the borane is present in an amount of about 1 to about 3 moles per mole of CBBC.
- the reducing agent may be H 2 in presence of catalyst such as Ni or Co or Pt.
- the resulting reaction mixture can then be maintained, preferably for about 1 hr to about 48 hrs, such as about 12 hours. This mixture can then be quenched such as by adding NH 4 Cl and hydrogen peroxide.
- the BDDMV can then be recovered.
- the resulting layers may be separated and the organic layer acidified, such as with citric acid.
- the aqueous phase can be basified such as with NH 4 OH and extracted with diethylether to recover more of the product.
- the organic layer can then be washed with brine or water to remove water soluble impurities, and dried. Drying can be carried out over Na 2 SO 4 or under a pressure of less than one atmosphere, or both.
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine.
- the invention encompasses 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). Also provided is BODV in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BODV may have a purity of at least about 50% as measured by HPLC.
- the present invention also provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
- BODV may be prepared by reductive amination reaction of BDDMV and a formaldehyde source in the presence of a reducing agent. In one embodiment this process comprises combining BDDMV, formaldehyde and a reducing agent. BODV is then recovered from the obtained reaction mixture.
- BDDMV such as that prepared above
- a C 1-4 alcohol such as MeOH
- Formaldehyde preferably in the form of a formalin solution is then added to obtain a solution.
- Formaldehyde in water can also be used as a solvent.
- a reducing agent preferably NaBH 4 or formic acid is then added.
- the reaction is an exothermic reaction, so prior to combining the sodium borohydride with the formaldehyde solution, formaldehyde solution is preferably cooled to a temperature of less than about 10° C.
- the reaction mixture is maintained, while stirring, for about 1 to about 24 hours, such as about 12 hours.
- the formaldehyde is present in an amount of from about 1 mole per mole of BDDMV, to an excess amount, such as about 50 moles.
- the sodium borohydride is present in an amount of about 1 mole per mole of BDDMV.
- the BODV can then be recovered. Recovery can be carried out by evaporating the organic solvent, such as under reduced pressure, to obtain a residue.
- the residue can then be dissolved in a water immiscible organic solvent such as methylene chloride EtOAc, toluene, MEK, TBME, diethyl ether and acidified to a pH of about 2 to about 6.
- An inorganic acid such as HCl or H2SO4 can be used.
- the aqueous phase is basified to a pH of about 8 to about 10 to facilitate extraction of additional amounts of BODC.
- NH 4 OH can be used as a base and methylene chloride as a solvent for extraction.
- the organic phase can then be evaporated, such as under a pressure of less than about one atmosphere, to obtain BODV.
- BODV can also be prepared by a process which comprises combining BDDMV, an organic solvent, and a methylating agent. BODV is then recovered from the obtained reaction mixture.
- BDDMV such as that prepared above
- an organic solvent preferably dichloromethane or dimethylsulfoxide.
- a base is added to the solution.
- the base can be BuLi or a C 3 -C 9 trialkylamine such as triethylamine.
- Alkali metal or alkaline earth metal hydrides or hydroxides such as NaH and NaOH can also be used.
- an inert organic solvent may also be added.
- BuLi can be added as a solution in a C 5 -C 12 saturated (aliphatic) or aromatic hydrocarbon, such as hexane.
- a methylating agent is added.
- the methylating agent is a methyl halide, preferably methyl iodide.
- Dimethylsulfate can also be used.
- the reaction can be done as neat reaction, methyliodide being the solvent and the reagent.
- the organic solvent is dichloromethane or dimethylsulfoxide or THF.
- the mixture can then be maintained for about 30 minutes to about 16 hours to obtain BODV. The BODV can then be recovered.
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
- the hydroxide donor base is an alkali metal or alkaline earth metal hydroxide, such as potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydroxide (NaOH), cesium hydroxide.
- the metal salt is silver nitrate (AgNO 3 ).
- the AgNO 3 is employed into the reaction mixture, as a supported AgNO 3 .
- the term “supported AgNO 3 ” as used herein refers to Montmorillonite. Silica can also be used as support. Montmorillonite is a very soft phyllosilicate mineral that typically forms in microscopic crystals, forming a clay.
- the hydroxide donor base is present in an amount of about 1 to about 20 moles per mole of BODV.
- the metal salt is present in an amount of about 1 to about 20 by weight of BODV.
- a solution of AgNO 3 in water montmorillonite is added and the resulting mixture is heated. Heating is preferably carried out to a temperature of about 40 to about 150° C., such as about 100° C. for 1 hour.
- the solution can then be dried, such as by heating, or reducing the pressure to less than about one atmosphere.
- BODV, and a base such as NaOH and the supported AgNO 3 are combined.
- the reaction mixture is heated to a temperature of above 20° C.; more preferably, the reaction mixture is heated to about 100° C.
- the obtained reaction mixture is maintained, while stirring, for about 18 hours.
- ODV can then be extracted from the reaction mixture with an organic solvent, such as with a mixture of chloroform and methanol. Other solvents such as EtOAc, THF, or acetone can also be used.
- the present invention further provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or a organocuprate reaction.
- BODV is combined with Mg, a halogen (only Mg or Cu in case of organo cuprate reaction) and a dry organic solvent to provide a Grignard reagent.
- a Grignard reaction Such synthetic step is known by one skilled in the art as Grignard reaction.
- the Grignard reagent is then combined with borate and an acid to provide O-desmethylvenlafaxine.
- Mg and a halogen such as I 2 are combined with BODV in an inert solvents organic solvent such as THF, CH 2 Cl 2 , ACN, ethers.
- the BODV can be added dropwise.
- the mixture can then be heated, such as to a temperature of about 30 to about reflux, more preferably about reflux.
- the mixture is preferably cooled, such as to about ⁇ 20 C, to about 10 C, preferably about ⁇ 10 C.
- Trimethylborate is then added.
- an organic or inorganic acid such as glacial acetic acid is added.
- the reaction mixture can then be quenched, such as by adding hydrogen peroxide.
- a water immiscible solvents organic solvent such as Diethylether, EtOAc, TBME, toluene, MEK
- the solvent can then be removed such as by reducing the pressure to less than one atmosphere.
- the new synthetic route for obtaining O-desmethylvenlafaxine can go via a protected intermediate of BODV.
- the protected intermediate of BODV may contain any suitable hydroxyl protecting group, such as silyl, acetyl and dihydropyran (DHP).
- hydroxyl protecting group such as silyl, acetyl and dihydropyran (DHP).
- the invention encompasses hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
- BODV-P hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
- the BODV is protected with an acetyl.
- BODV-P particularly acetyl protected, in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms.
- the BODV-P including acetyl protected may have a purity of at least about 50% as measured by HPLC.
- the present invention provides a process for preparing hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.
- BODV-P hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol
- the solvent used can be any organic solvent.
- the organic solvent is ethyl acetate.
- Other organic solvents such as CH 2 Cl 2 , ethers such THF, toluene, hexane or ACN can also be used.
- the process is performed under basic conditions.
- the basic source is organic or inorganic base.
- the basic source is a C 3 -C 9 trialkyl amine such as triethylamine or imidazole or lutidine or pyridine.
- An inorganic base such as an alkali metal or alkaline earth metal carbonate such as K 2 CO 3 can also be used,
- the protecting agent is selected from the group consisting of: silyl, acetyl, DHP and derivatives thereof. More preferably, the protecting agent is acetyl chloride or acetic anhydride.
- the reaction mixture is optionally maintained for about 30 minutes to about 24 hours to obtain BODV-P. BODV-P may then be recovered from the reaction mixture by any method known in the art.
- the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine.
- the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction.
- the conversion can be performed as described above for BODV.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, a hydroxide donor base and a metal salt. O-desmethylvenlafaxine is then be recovered from the reaction mixture.
- hydroxide donor base and a metal salt used in the reaction are as described above.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- the aqueous phase was basified with NH 4 OH and extracted with diethylether. The organic layer was then washed with brine, dried over Na 2 SO 4 and evaporated under reduced pressure to get BDDMV.
- BDDMV (0.2 g, 0.68 mmol) is dissolved in DMSO (2.5 ml). The solution is cooled into an ice bath causing its solidification. 1.6 M BuLi solution in hexane (0.4 mmol) is added, and the temperature is allowed to heat to room temperature. Then MeI (0.25 mmol) is added. The reaction mixture is stirred until we get BODV (HPLC monitoring).
- BDDMV (0.5 g, 1.67 mmol) is suspended in CH 2 Cl 2 .
- the reaction mixture is stirred under nitrogen atmosphere at room temperature for 6 hours.
- MeI (5 mmol) and NEt 3 (3 ml) are added.
- the addition caused the temperature to rise. After 16 hours, the analysis shows the presence of BODV.
Abstract
Provides are intermediates and processes for preparation of o-desmethylvenlafaxine.
Description
- The present application claims the benefit of the following U.S. Provisional Patent Application Nos. 60/833,616, filed Jul. 26, 2006; 60/837,879, filed Aug. 14, 2006; 60/849,216, filed Oct. 3, 2006; 60/843,998, filed Sep. 11, 2006; 60/849,255, filed Oct. 3, 2006; 60/906,639, filed Mar. 12, 2007; and 60/906,879, filed Mar. 13, 2007. The contents of these applications are incorporated herein by reference.
- The invention encompasses a process for the synthesis of O-desmethylvenlafaxine.
- Venlafaxine, (±)-1-[2-(Dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol is the first of a class of anti-depressants. Venlafaxine acts by inhibiting re-uptake of norepinephrine and serotonin, and is an alternative to the tricyclic anti-depressants and selective re-uptake inhibitors. Venlafaxine has the following chemical formula, Formula I:
- O-desmethylvenlafaxine, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenol, is reported to be a metabolite of venlafaxine and has been reported to inhibit norepinephrine and serotonin uptake. See Klamerus, K. J. et al., “Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite,” J. Clin. Pharmacol. 32:716-724 (1992). O-desmethylvenlafaxine has the following chemical formula, Formula II:
- Processes for the synthesis of O-desmethylvenlafaxine, comprising a step of demethylation of the methoxy group of venlafaxine, are described in U.S. Pat. Nos. 7,026,508 and 6,689,912, and in U.S. publication No. 2005/0197392.
- The synthesis disclosed in the above references is performed according to the following scheme:
- Wherein “MBC” refers to methyl benzyl cyanide, “CMBC” refers to cyclohexyl methylbenzyl cyanide, “DDMV” refers to didesmethyl venlafaxine, and “ODV” refers to O-desmethylvenlafaxine.
- However, the processes disclosed in the above U.S. patents and U.S. patent applications all remain problematic when applied to industrial scale production. The process in U.S. Pat. No. 7,026,508 uses L-selectride, a compound which is very problematic when scaling up the process for industrial application. Further, the process disclosed in US Application Publication No. 2005/0197392 uses lithiumdiphenyl phosphine, a compound which handling and use in industrial scale processes is extremely dangerous. Also, the process disclosed in U.S. Pat. No. 6,689,912 uses methanol as a solvent, which use is problematic when traces of methanol remain and in subsequent process steps when high temperatures are applied.
- There is a need in the art for a new synthetic route for obtaining sO-desmethylvenlafaxine, using a precursor of venlafaxine to directly obtain O-desmethylvenlafaxine.
- In one embodiment, the invention encompasses (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
- In one embodiment the present invention provides a process for preparing CBBC comprising reacting BBC with cyclohexanone.
- In another embodiment, the present invention provides a process for preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) comprising precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), a dry organic solvent, a base and cyclohexanone.
- In another embodiment, the present invention provides a process for obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), a phase transfer catalyst, a base and cyclohexanone.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and further converting the CBBC to O-desmethylvenlafaxine.
- In another embodiment, the invention encompasses 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).
- In another embodiment, the present invention provides a process for preparing 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) comprising: combining CBBC, an organic solvent and borane to create a reaction mixture, followed by recovery of the BDDMV from the reaction mixture.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine.
- In another embodiment, the invention encompasses 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
- In another embodiment, the present invention provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, followed by recovery of the BODV from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, an organic solvent, and a methylating agent to form a mixture, and recovering the BODV from the mixture.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In one embodiment the present invention provides a process for preparing O-desmethylvenlafaxine comprising combining BODV with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocuprate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine.
- In another embodiment, the invention encompasses hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
- In another embodiment, the present invention provides a process for preparing hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine.
- In another embodiment, the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
- The present invention further provides processes for preparing O-desmethylvenlafaxine via the intermediates described above.
- The invention encompasses a new synthetic route for obtaining O-desmethylvenlafaxine, from 4-bromophenylacetonitrile (BBC), (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC), 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV), 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) and hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
- In the process of the invention, the intermediate bromophenylacetonitrile (BBC) is condensed with cyclohexanone to form the intermediate (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC). Further, the cyano group on the CBBC is subjected to reduction, to form the intermediate 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) which is then subjected to selective alkylation to produce 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV), which is finally converted to O-desmethylvenlafaxine (ODV), by performing halide exchange (optionally, the final conversion step can go via a protected BODV intermediate) as described in the following scheme:
- where x is a suitable hydroxy protecting group.
- The use of precursors of venlafaxine which contain a halogen group, in the new synthetic route for obtaining O-desmethylvenlafaxine, highly improves the yield of the reaction.
- In one embodiment, the invention encompasses (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC). Also provided is CBBC in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The CBBC may have a purity of at least about 50% as measured by HPLC. The compound is characterized by NMR 1H (DMSO-d6) δ: 1.56 (4H, H cyclohexyl), 1.71 (2H, H cyclohexyl), 2.25 (2H, H cyclohexyl), 2.61 (2H, H cyclohexyl), 3.32 (1H, CHCN), 7.27 (2H, H arom.), 7.65 (2H, H arom.).
- The present invention also provides a process for preparing (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) by reacting BBC with cyclohexanone
- This process can comprise precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), organic solvent, a base and cyclohexanone. Preferably the organic solvent is dry. An organic solvent is dry if it is essentially free of water such that the amount of residual water, if detectable, does not interfere with the reaction (e.g. by destroying catalysts or reagents) in a manner that prevents the benefits of the present invention from being realized. Typically an organic solvent having less than 1% by water is considered to be dry by one of ordinary skill of art.
- Preferably, the dry organic solvent is selected from the group consisting of: C4-8 ethers, polar aprotic solvents (Polarity Index of greater than about 2.0), C1-C8 chlorinated aliphatic, C6-C12 aromatic hydrocarbons, and C1-6 alcohols. More preferably, the ethers are selected from the group consisting of: diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), the polar aprotic solvents are selected from the group consisting of dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO), the chlorinated organic solvents are selected from the group consisting of methylene chloride and chlorobenzene or chloroform and the aromatic hydrocarbons are selected from the group consisting of toluene and benzene. Most preferably, the dry organic solvent is selected from the group consisting of: tetrahydrofuran (THF), methanol, methylene chloride and toluene. The organic solvent can be used individually, or in a mixture with another solvent, particularly methanol.
- The base can be an inorganic base, such as an alkali metal or alkaline earth metal. More preferably, the base is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis(trimethyl silyl) amide (LiN[(CH3)3Si]2), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH3). The base is preferably present in an amount of about 1 to about 5 moles per mole of BBC.
- The process can be carried out by combining a solution or a slurry of BBC and a dry organic solvent with a base to obtain a reaction mixture, followed by combining the reaction mixture with cyclohexanone, to obtain CBBC. Cyclohexanone can be added to the reaction mixture in a dropwise manner. After combining the reaction mixture with cyclohexanone, the mixture is further maintained, until completion of the reaction.
- CBBC may then be recovered. The solvent can be evaporated and the residue dissolved in a water immiscible solvent such as toluene, EtOAc (ethyl acetate), CH2Cl2, diethyl ether, MTBE (methyl-t-butyl ether), MEK (methyl ethyl ketone) washed with water or brine, and evaporated to get an oil. The oil can then be added to an organic solvent such as methanol to obtain a solution and crystallize CBBC.
- In another embodiment, the present invention provides a process for obtaining (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), optionally a phase transfer catalyst, a base and cyclohexanone. The reaction may occur with or without the presence of an organic solvent or water. Preferably, the reaction occurs in the presence of water. The use of water allows for obtaining a product that otherwise would be contaminated with residual organic solvent.
- The phase transfer catalyst can be a tetraalkylammonium, tetraalkylphosphonium, tetraarylammonium or tetraarylphosphonium, preferably wherein the alkyl group can be the same or different and contains from 1 to 10 carbons, and wherein the aryl group can be the same or different and contains from 6 to 8 carbons.
- The phase transfer catalyst can be a tetraalkylammonium halide, preferably wherein the alkyl group can be the same or different and contains from 1 to 6, preferably from 1 to 4 carbon atoms, and the halide is fluoride, chloride, bromide or iodide, preferably chloride, bromide or iodide.
- Preferably, the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot, quaternary ammonium salt, quaternary phosphonium salt and crown ether. More preferably, the phase transfer catalyst is tetra butyl ammonium bromide (TBAB).
- The base may be an inorganic base, such as an alkali metal or alkaline earth metal hydroxide or carbonate, preferably, NaOH, KOH, LiOH, CsOH, K2CO3 or NaCO3, Cs2CO3, KHCO3 or NaHCO3
- BBC, cyclohexanone, the phase transfer catalyst such as TBAB and the base such as NaOH are combined. Preferably, the base is added in an amount of about 0.5 to about 1 mole per mole of BBC. The cyclohexanone is added in an amount of about 1 to about 1.15 moles per mole of BBC. The reaction is then maintained to get CBBC. The reaction can be maintained from about 1 to about 24 hours. It can also be stirred while maintained.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and further converting the CBBC to O-desmethylvenlafaxine.
- In another embodiment, the invention encompasses 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV). Also provided is BDDMV in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BDDMV may have a purity of at least about 50% as measured by HPLC.
- BDDMV can be prepared by reacting CBBC with a reducing agent. More specifically, BDDMV can be prepared by combining CBBC an organic solvent such as THF to obtain a solution, to which a reducing agent is added. Preferably the solvent is a dry organic solvent, as described above, more preferably THF. Chlorinated solvents, such as C1-C8 chlorinated hydrocarbons and C4-C8 ethers can also be used. Preferably the reducing agent is borane or a hydride, more preferably a Borane dimethylsulfide complex, which is added dropwise. Preferably, the borane is present in an amount of about 1 to about 3 moles per mole of CBBC. Alternatively, the reducing agent may be H2 in presence of catalyst such as Ni or Co or Pt. The resulting reaction mixture can then be maintained, preferably for about 1 hr to about 48 hrs, such as about 12 hours. This mixture can then be quenched such as by adding NH4Cl and hydrogen peroxide.
- The BDDMV can then be recovered. The resulting layers may be separated and the organic layer acidified, such as with citric acid. Optionally, the aqueous phase can be basified such as with NH4OH and extracted with diethylether to recover more of the product. The organic layer can then be washed with brine or water to remove water soluble impurities, and dried. Drying can be carried out over Na2SO4 or under a pressure of less than one atmosphere, or both.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine.
- In another embodiment, the invention encompasses 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). Also provided is BODV in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BODV may have a purity of at least about 50% as measured by HPLC.
- The present invention also provides a process for preparing 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). BODV may be prepared by reductive amination reaction of BDDMV and a formaldehyde source in the presence of a reducing agent. In one embodiment this process comprises combining BDDMV, formaldehyde and a reducing agent. BODV is then recovered from the obtained reaction mixture.
- BDDMV, such as that prepared above, can be dissolved or suspended (preferably dissolved) in a C1-4 alcohol such as MeOH. Formaldehyde, preferably in the form of a formalin solution is then added to obtain a solution. Formaldehyde in water can also be used as a solvent. A reducing agent, preferably NaBH4 or formic acid is then added. The reaction is an exothermic reaction, so prior to combining the sodium borohydride with the formaldehyde solution, formaldehyde solution is preferably cooled to a temperature of less than about 10° C. Preferably, the reaction mixture is maintained, while stirring, for about 1 to about 24 hours, such as about 12 hours. Preferably, the formaldehyde is present in an amount of from about 1 mole per mole of BDDMV, to an excess amount, such as about 50 moles. Preferably, the sodium borohydride is present in an amount of about 1 mole per mole of BDDMV.
- The BODV can then be recovered. Recovery can be carried out by evaporating the organic solvent, such as under reduced pressure, to obtain a residue. The residue can then be dissolved in a water immiscible organic solvent such as methylene chloride EtOAc, toluene, MEK, TBME, diethyl ether and acidified to a pH of about 2 to about 6. An inorganic acid such as HCl or H2SO4 can be used. Optionally the aqueous phase is basified to a pH of about 8 to about 10 to facilitate extraction of additional amounts of BODC. NH4OH can be used as a base and methylene chloride as a solvent for extraction. The organic phase can then be evaporated, such as under a pressure of less than about one atmosphere, to obtain BODV.
- BODV can also be prepared by a process which comprises combining BDDMV, an organic solvent, and a methylating agent. BODV is then recovered from the obtained reaction mixture.
- BDDMV, such as that prepared above, is dissolved in an organic solvent, preferably dichloromethane or dimethylsulfoxide. Optionally a base is added to the solution. The base can be BuLi or a C3-C9 trialkylamine such as triethylamine. Alkali metal or alkaline earth metal hydrides or hydroxides such as NaH and NaOH can also be used. If an inorganic base is used, an inert organic solvent may also be added. For example, with BuLi can be added as a solution in a C5-C12 saturated (aliphatic) or aromatic hydrocarbon, such as hexane. A methylating agent is added. Preferably the methylating agent is a methyl halide, preferably methyl iodide. Dimethylsulfate can also be used. The reaction can be done as neat reaction, methyliodide being the solvent and the reagent. Preferably, the organic solvent is dichloromethane or dimethylsulfoxide or THF. The mixture can then be maintained for about 30 minutes to about 16 hours to obtain BODV. The BODV can then be recovered.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
- Preferably, the hydroxide donor base is an alkali metal or alkaline earth metal hydroxide, such as potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydroxide (NaOH), cesium hydroxide. Preferably, the metal salt is silver nitrate (AgNO3). Optionally, the AgNO3 is employed into the reaction mixture, as a supported AgNO3. The term “supported AgNO3” as used herein refers to Montmorillonite. Silica can also be used as support. Montmorillonite is a very soft phyllosilicate mineral that typically forms in microscopic crystals, forming a clay. Preferably, the hydroxide donor base is present in an amount of about 1 to about 20 moles per mole of BODV. Preferably, the metal salt is present in an amount of about 1 to about 20 by weight of BODV.
- As exemplified, to a solution of AgNO3 in water montmorillonite is added and the resulting mixture is heated. Heating is preferably carried out to a temperature of about 40 to about 150° C., such as about 100° C. for 1 hour. The solution can then be dried, such as by heating, or reducing the pressure to less than about one atmosphere. Then, BODV, and a base such as NaOH and the supported AgNO3 are combined. Preferably, the reaction mixture is heated to a temperature of above 20° C.; more preferably, the reaction mixture is heated to about 100° C. Preferably, the obtained reaction mixture is maintained, while stirring, for about 18 hours. ODV can then be extracted from the reaction mixture with an organic solvent, such as with a mixture of chloroform and methanol. Other solvents such as EtOAc, THF, or acetone can also be used.
- The present invention further provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or a organocuprate reaction. In one embodiment, BODV is combined with Mg, a halogen (only Mg or Cu in case of organo cuprate reaction) and a dry organic solvent to provide a Grignard reagent. Such synthetic step is known by one skilled in the art as Grignard reaction. The Grignard reagent is then combined with borate and an acid to provide O-desmethylvenlafaxine.
- In one embodiment, Mg and a halogen such as I2 are combined with BODV in an inert solvents organic solvent such as THF, CH2Cl2, ACN, ethers. The BODV can be added dropwise. The mixture can then be heated, such as to a temperature of about 30 to about reflux, more preferably about reflux. Before adding borate, the mixture is preferably cooled, such as to about −20 C, to about 10 C, preferably about −10 C. Trimethylborate is then added. After stirring an organic or inorganic acid, such as glacial acetic acid is added. The reaction mixture can then be quenched, such as by adding hydrogen peroxide. For recovery, a water immiscible solvents organic solvent, such as Diethylether, EtOAc, TBME, toluene, MEK, is added to the reaction mixture to obtain ODV. The solvent can then be removed such as by reducing the pressure to less than one atmosphere.
- Optionally, the new synthetic route for obtaining O-desmethylvenlafaxine can go via a protected intermediate of BODV.
- The protected intermediate of BODV may contain any suitable hydroxyl protecting group, such as silyl, acetyl and dihydropyran (DHP).
- In another embodiment, the invention encompasses hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P). Preferably, the BODV is protected with an acetyl. Also provided is BODV-P, particularly acetyl protected, in isolated or purified form. Isolated refers to being separated from the reaction mixture in which it forms. The BODV-P including acetyl protected may have a purity of at least about 50% as measured by HPLC.
- In another embodiment, the present invention provides a process for preparing hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.
- Typically, the solvent used can be any organic solvent. Preferably, the organic solvent is ethyl acetate. Other organic solvents such as CH2Cl2, ethers such THF, toluene, hexane or ACN can also be used.
- Preferably, the process is performed under basic conditions. Typically, the basic source is organic or inorganic base. Preferably, the basic source is a C3-C9 trialkyl amine such as triethylamine or imidazole or lutidine or pyridine. An inorganic base such as an alkali metal or alkaline earth metal carbonate such as K2CO3 can also be used,
- Preferably, the protecting agent is selected from the group consisting of: silyl, acetyl, DHP and derivatives thereof. More preferably, the protecting agent is acetyl chloride or acetic anhydride. The reaction mixture is optionally maintained for about 30 minutes to about 24 hours to obtain BODV-P. BODV-P may then be recovered from the reaction mixture by any method known in the art.
- One of ordinary skill of art would appreciate that each of the above processes described for preparation of CBBC, BDDMV, BODV, BODV-P and ODV can be combined. Such combination can be combining the process of CBBC, with BDDMV to prepare BODV, and further to prepare BODV-P if desired, and further to prepare ODV. Such process can also start with BDDMV, BODV or BODV-P. Such combinations are provided in further detail below.
- In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine.
- In another embodiment, the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction.
- The conversion can be performed as described above for BODV.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, a hydroxide donor base and a metal salt. O-desmethylvenlafaxine is then be recovered from the reaction mixture.
- The hydroxide donor base and a metal salt used in the reaction are as described above.
- One of ordinary skill of art would appreciate that each of the above processes described for preparation of CBBC, BDDMV, BODV, BODV-P and ODV can be combined. Such combination can be combining the process of CBBC, with BDDMV to prepare BODV, and further to prepare BODV-P if desired, and further to prepare ODV. Such process can also start with BDDMV, BODV or BODV-P. Such combinations are provided in further detail below.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: precipitating CBBC from a mixture of: BBC, a dry organic solvent, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, recovering BODV from the reaction mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture; combining BODV-P, a hydroxide donor base and a metal salt to create a reaction mixture and recovering O-desmethylvenlafaxine from the reaction mixture.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture and converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: obtaining CBBC from a mixture of BBC, a phase transfer catalyst, a base and cyclohexanone; combining CBBC, an organic solvent and borane to create a reaction mixture, recovering BDDMV from the reaction mixture; combining BDDMV, an organic solvent, and a methylating agent to form a mixture; recovering the BODV from the mixture; combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture; recovering BODV-P from the reaction mixture and converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction.
- The invention in certain of its embodiments is illustrated by the following non-limiting examples.
- A 250 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged slowly with MeOH (50 ml) and NaOCH3 (10 g, 185 mmol) at ambient temperature. DMF (4 ml) and Bromophenylacetonitrile (20 g, 102 mmol) were added. The reaction mixture was stirred at ambient temperature until complete dissolution. Cyclohexanone (20 g, 203 mmol) was then added dropwise and the reaction was stirred at ambient temperature overnight. The solvent was evaporated and the residue was dissolved in toluene, washed with brine and evaporated to get an oil which on crystallization from MeOH yielded CBBC.
- A 100 ml three necked flask equipped with, thermometer and mechanical stirrer is charged with BBC (2 g, 10 mmol), cyclohexanone (2 g, 20.3 mmol), TBAB (0.2 g) and NaOH (6 ml 10%). The reaction is stirred at RT overnight to get CBBC.
- A 250 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with CBBC (7 g, 23.79 mmol) and THF (100 ml). This solution was stirred at ambient temperature. Then a solution of Borane dimethylsulfide complex (20 ml 2M in THF, 39.89 mmol) was added dropwise. This mixture was stirred overnight at ambient temperature and poured into saturated solution of NH4Cl. A 30% solution of hydrogen peroxide was then added. The layers were separated and the organic layer was acidified with citric acid.
- The aqueous phase was basified with NH4OH and extracted with diethylether. The organic layer was then washed with brine, dried over Na2SO4 and evaporated under reduced pressure to get BDDMV.
- BDDMV (0.81 g, 2.72 mmol) was dissolved in MeOH (20 ml). A formalin solution (1.3 ml, 16.25 mmol) was added and the solution was cooled with an ice bath. To the cold solution NaBH4 (0.25 g, 6.5 mmol) was added. The reaction mixture was stirred at ambient temperature overnight and the solvent was then evaporated under reduced pressure. The residue was dissolved in methylene chloride and acidified with 10% HCl. The aqueous phase was basified with NH4OH and extracted with methylene chloride. The organic phase was then evaporated under reduced pressure to get BODV.
- BDDMV (0.2 g, 0.68 mmol) is dissolved in DMSO (2.5 ml). The solution is cooled into an ice bath causing its solidification. 1.6 M BuLi solution in hexane (0.4 mmol) is added, and the temperature is allowed to heat to room temperature. Then MeI (0.25 mmol) is added. The reaction mixture is stirred until we get BODV (HPLC monitoring).
- BDDMV (0.5 g, 1.67 mmol) is suspended in CH2Cl2. Methyl Iodide (2.65 mmol) and Triethylamine (2.9 mmol) are added. The reaction mixture is stirred under nitrogen atmosphere at room temperature for 6 hours. At this stage MeI (5 mmol) and NEt3 (3 ml) are added. The addition caused the temperature to rise. After 16 hours, the analysis shows the presence of BODV.
- Preparation of ODV from BODV
- To a solution of AgNO3 (3.38 g in 100 ml H2O), montmorillonite K10 (15 g) was added and the mixture was stirred for 30 min. at ambient temperature. The solution was then evaporated to dryness and the residue was dried in an oven at 100° C. for 1 hour.
- 0.4 g of BODV (1.26 mmol), 0.2 g of NaOH (5 mmol) and 2 g of supported AgNO3 were mixed thoroughly in a mortar. The mixture was heated to 100° C. overnight under mechanical stirring. The mixture was then extracted with chloroform and with methanol to get ODV.
- A 100 ml three-necked flask equipped with nitrogen inlet, thermometer, mechanical stirrer and condenser was charged with Mg (0.2 g, 8.23 mmol) and 12 (0.1 g 0.39 mmol). BODV (0.3 g, 0.92 mmol) in THF (30 ml) was added dropwise and the mixture was heated to reflux for 1 hour. The mixture was cooled to −10° C. and trimethylborate (1 ml, 8.8 mmol) was added. After stirring for 30 min glacial acetic acid (2 ml, 34.9 mmol) was added. Then a cold solution of 30% hydrogen peroxide (2 ml 19.64 mmol) was also added. Diethylether was added and the organic phase was filtered to get ODV.
- A 100 ml three-necked flask equipped with Nitrogen inlet, thermometer, mechanical stirred and condenser was charged with BODV (0.37 g 1.13 mmol), EtOAc (20 ml) and Et3N (1 ml 7.16 mmol). Acetylchloride (1 ml 14 mmol) was added slowly. The reaction mixture was stirred 1 hour at ambient temperature and the organic phase was washed with water, dried over magnesium sulfate and evaporated to get BODV-P.
- Preparation of ODV from BODV-P
- A 250 ml three-necked flask equipped with Nitrogen inlet, thermometer, mechanical stirred and condenser was charged with Mg (0.7 g, 28.80 mmol) and 12 (0.2 g 0.78 mmol). BODV-P (1 g, 2.71 mmol) in THF (30 ml) was added dropwise and the mixture was heated to reflux for 2 hours. The mixture was then cooled to −10° C. and trimethylborate (20 ml, 176 mmol) was added. After stirring for 30 min at this temperature glacial acetic acid (15 ml, 261.75 mmol) was added. Then a cold solution of 30% hydrogen peroxide (20 ml 196.4 mmol) was added. The organic phase was washed with saturated ferrous ammonium sulfate, dried over magnesium sulfate and concentrated to get ODV.
- To a solution of AgNO3 (3.38 g in 100 ml H2O), montmorillonite K10 (15 g) is added and the mixture is stirred for 30 min. at ambient temperature. The solution is then evaporated to dryness and the residue is dried in an oven at 100° C. for 1 hour.
- 0.4 g of P-BODV, 0.2 g of NaOH (5 mmol) and 2 g of supported AgNO3 are mixed thoroughly in a mortar. The mixture is heated to 100° C. overnight under mechanical stirring. The mixture is then extracted with chloroform and with methanol to get ODV.
Claims (45)
1. (4-bromophenyl)(1-hydroxycyclohexyl)acetonitrile (CBBC).
2-3. (canceled)
4. A process for preparing compound of claim 1 , 2 or 3 comprising reacting BBC with cyclohexanone.
5. The process of claim 4 , wherein the process comprises combining bromophenylacetonitrile (BBC), an organic solvent, a base and cyclohexanone to precipitating CBBC.
6. The process of claim 5 , wherein the organic solvent is selected from the group consisting of: C2-8 ethers, polar aprotic solvents (Polarity Index of greater than about 2.0), C1-C8 chlorinated aliphatic and aromatic, C6-C12 aromatic hydrocarbons, and C1-6 alcohols.
7. The process of claim 5 , wherein the organic solvent is selected from the group consisting of diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), methylene chloride, chlorobenzene, toluene and benzene.
8. The process of claim 5 , wherein the organic solvent is selected from the group consisting of tetrahydrofuran (THF), methanol, methylene chloride and toluene.
9. The process of claim 5 , wherein the organic solvent contains less than 1% water by volume.
10. The process of claim 5 , wherein the base is an alkali metal or alkaline earth metal.
11. The process of claim 5 , wherein the base is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis(trimethyl silyl) amide (LiN[(CH3)3Si]2), potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH3).
12. The process of claim 5 , wherein the process is carried out by combining a solution or a slurry of BBC and a dry organic solvent with a base to obtain a reaction mixture, followed by combining the reaction mixture with cyclohexanone, to obtain CBBC.
13. The process of claim 5 , further comprising recovering CBBC.
14. The process of claim 13 , wherein recovery comprises evaporating the solvent, dissolving the residue in a water immiscible solvent such as toluene, washing with water or brine, and evaporated to get a residue.
15. The process of claim 13 , further comprising crystallizing CBBC from the residue.
16. The process of claim 4 , wherein the process comprises combining bromophenylacetonitrile (BBC), a phase transfer catalyst, optionally a base and cyclohexanone.
17. The process of claim 16 , wherein the reaction occurs in the presence of water.
18. The process of claim 16 , wherein the phase transfer catalyst is a tetraalkylammonium, tetraalkylphosphonium, tetraarylammonium or tetraarylphosphonium, wherein the alkyl group can be the same or different and contains from 1 to 10 carbons, and wherein the aryl group can be the same or different and contains from 6 to 8 carbons
19. The process of claim 16 , wherein the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot, quaternary ammonium salt, quaternary phosphonium salt and crown ether.
20. The process of claim 16 , wherein the phase transfer catalyst is tetra butyl ammonium bromide (TBAB).
21. The process of claim 5 , wherein the base is an alkali metal or alkaline earth metal hydroxide or carbonate.
22. The process of claim 16 , wherein the base is NaOH, KOH, LiOH, CsOH, K2CO3, NaCO3 or Cs2CO3
23. A process for preparing O-desmethylvenlafaxine comprising preparing CBBC as described in claim 4 , and further converting the CBBC to O-desmethylvenlafaxine.
24. 1-[2-amino-1-(4-bromophenyl)ethyl]cyclohexanol (BDDMV).
25-26. (canceled)
27. A process for preparing a compound according to claim 24 comprising reacting CBBC with a reducing agent.
28-37. (canceled)
38. 1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV).
39-40. (canceled)
41. A process for preparing the compound of claim 38 comprising combining BDDMV, formaldehyde and a reducing agent.
42-46. (canceled)
47. A process for preparing the compound of claim 38 comprising combining BDDMV, an organic solvent, and a methylating agent.
48-55. (canceled)
56. A process for preparing O-desmethylvenlafaxine comprising preparing BODV according to claim 47 , and further converting the BODV to O-desmethylvenlafaxine.
57. A process for preparing O-desmethylvenlafaxine comprising hydrolyzing BODV of claim 38 .
58. A process for preparing O-desmethylvenlafaxine comprising: combining BODV of claim 38 , a hydroxide donor base and a metal salt to obtain a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture.
59-65. (canceled)
66. A process for preparing O-desmethylvenlafaxine comprising combining BODV of claim 38 with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocuprate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine.
67-72. (canceled)
73. The process of any of claims 56 -58 and 66 which synthesize O-desmethylvenlafaxine, wherein a hydroxyl protected BODV is used to synthesize O-desmethylvenlafaxine.
74-75. (canceled)
76. Hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P).
77-80. (canceled)
81. A process for preparing the hydroxyprotected-1-[1-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P) of claim 76 comprising combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture.
82-85. (canceled)
86. A process for preparing O-desmethylvenlafaxine comprising preparing BODV according to claim 41 , and further converting the BODV to O-desmethylvenlafaxine
Priority Applications (1)
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US11/881,825 US20080177110A1 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of O-desmethylvenlafaxine |
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US83361606P | 2006-07-26 | 2006-07-26 | |
US83787906P | 2006-08-14 | 2006-08-14 | |
US84399806P | 2006-09-11 | 2006-09-11 | |
US84921606P | 2006-10-03 | 2006-10-03 | |
US84925506P | 2006-10-03 | 2006-10-03 | |
US90663907P | 2007-03-12 | 2007-03-12 | |
US90687907P | 2007-03-13 | 2007-03-13 | |
US11/881,825 US20080177110A1 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of O-desmethylvenlafaxine |
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US11/881,799 Abandoned US20090062572A1 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of O-desmethylvenlafaxine |
US11/881,731 Expired - Fee Related US7605290B2 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of O-desmethylvenlafaxine |
US11/881,825 Abandoned US20080177110A1 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of O-desmethylvenlafaxine |
US11/881,826 Abandoned US20080183016A1 (en) | 2006-07-26 | 2007-07-26 | Process for the synthesis of O-desmethylvenlafaxine |
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US11/881,731 Expired - Fee Related US7605290B2 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of O-desmethylvenlafaxine |
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US (4) | US20090062572A1 (en) |
EP (4) | EP1934168A2 (en) |
JP (3) | JP2008044936A (en) |
KR (3) | KR101019455B1 (en) |
CA (1) | CA2656161A1 (en) |
IL (1) | IL196403A0 (en) |
WO (1) | WO2008013990A2 (en) |
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MX2007016179A (en) * | 2006-04-17 | 2008-03-11 | Teva Pharma | Polymorphic forms of tegaserod maleate. |
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US20090069601A1 (en) * | 2006-07-26 | 2009-03-12 | Valerie Niddam-Hildesheim | Processes for the synthesis of O-desmethylvenlafaxine |
KR101019455B1 (en) * | 2006-07-26 | 2011-03-07 | 테바 파마슈티컬 인더스트리즈 리미티드 | Processes for the synthesis of o-desmethylvenlafaxine |
US20080221356A1 (en) * | 2006-07-26 | 2008-09-11 | Valerie Niddam-Hildesheim | Processes for the synthesis of O-desmethylvenlafaxine |
EP2061750A2 (en) * | 2006-08-04 | 2009-05-27 | Medichem, S.A. | Improved process for synthesizing desvenlafaxine free base and salts or solvates thereof |
US20100076086A1 (en) * | 2007-01-31 | 2010-03-25 | Merck Development Centre Private Limited Plot 1 A/2 | Process for the preparation of o-desmethyl venlafaxine |
WO2010008735A2 (en) * | 2008-06-16 | 2010-01-21 | Teva Pharmaceutical Industries Ltd. | Solid states of o-desmethylvenlaf axine salts |
CN101781221A (en) * | 2010-02-11 | 2010-07-21 | 上海凯米侬医药科技有限公司 | Preparation method of O-desmethylvenlafaxine |
WO2011121452A2 (en) * | 2010-03-29 | 2011-10-06 | Pliva Hrvatska D.O.O. | Crystal forms of o-desmethylvenlafaxine fumarate |
JP5858581B2 (en) * | 2012-09-27 | 2016-02-10 | 国立大学法人 東京大学 | Method for producing indole 3-carboxylic acids |
CN108499614B (en) * | 2018-04-28 | 2021-06-04 | 西南医科大学附属医院 | Method for preparing drug intermediate for central nervous system from modified nickel catalytic material |
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Also Published As
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WO2008013990A3 (en) | 2008-03-27 |
EP1917237A2 (en) | 2008-05-07 |
IL196403A0 (en) | 2009-11-18 |
JP2008088159A (en) | 2008-04-17 |
CA2656161A1 (en) | 2008-01-31 |
KR20080037715A (en) | 2008-04-30 |
US7605290B2 (en) | 2009-10-20 |
KR20080037713A (en) | 2008-04-30 |
EP1934167A2 (en) | 2008-06-25 |
US20090062572A1 (en) | 2009-03-05 |
US20080139849A1 (en) | 2008-06-12 |
US20080183016A1 (en) | 2008-07-31 |
EP1934168A2 (en) | 2008-06-25 |
KR101019455B1 (en) | 2011-03-07 |
KR20080037714A (en) | 2008-04-30 |
JP2008044936A (en) | 2008-02-28 |
KR101019453B1 (en) | 2011-03-07 |
WO2008013990A2 (en) | 2008-01-31 |
EP2046725A2 (en) | 2009-04-15 |
JP2008546850A (en) | 2008-12-25 |
KR101019454B1 (en) | 2011-03-07 |
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