CA2656166A1 - Processes for the synthesis of o-desmethylvenlafaxine - Google Patents
Processes for the synthesis of o-desmethylvenlafaxine Download PDFInfo
- Publication number
- CA2656166A1 CA2656166A1 CA002656166A CA2656166A CA2656166A1 CA 2656166 A1 CA2656166 A1 CA 2656166A1 CA 002656166 A CA002656166 A CA 002656166A CA 2656166 A CA2656166 A CA 2656166A CA 2656166 A1 CA2656166 A1 CA 2656166A1
- Authority
- CA
- Canada
- Prior art keywords
- cobc
- obc
- organic solvent
- cyclohexanone
- group
- 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
- 238000000034 method Methods 0.000 title claims abstract description 112
- 230000008569 process Effects 0.000 title claims abstract description 105
- 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 32
- 238000003786 synthesis reaction Methods 0.000 title description 8
- 230000015572 biosynthetic process Effects 0.000 title description 7
- BHCUWXACHAFFSK-UHFFFAOYSA-N 4-[2-amino-1-(1-hydroxycyclohexyl)ethyl]phenol Chemical compound C1CCCCC1(O)C(CN)C1=CC=C(O)C=C1 BHCUWXACHAFFSK-UHFFFAOYSA-N 0.000 claims abstract description 61
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- IZSWBXTYTALSOZ-UHFFFAOYSA-N 2-cyclohexyl-2-phenylacetonitrile Chemical compound C=1C=CC=CC=1C(C#N)C1CCCCC1 IZSWBXTYTALSOZ-UHFFFAOYSA-N 0.000 claims abstract description 16
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 116
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 60
- 239000003960 organic solvent Substances 0.000 claims description 54
- 239000011541 reaction mixture Substances 0.000 claims description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 50
- 239000002585 base Substances 0.000 claims description 38
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical group FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- NNICRUQPODTGRU-UHFFFAOYSA-N mandelonitrile Chemical compound N#CC(O)C1=CC=CC=C1 NNICRUQPODTGRU-UHFFFAOYSA-N 0.000 claims description 35
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 25
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 20
- 229910015900 BF3 Inorganic materials 0.000 claims description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 18
- 239000003638 chemical reducing agent Substances 0.000 claims description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 15
- 239000011968 lewis acid catalyst Substances 0.000 claims description 15
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 14
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 12
- 239000003444 phase transfer catalyst Substances 0.000 claims description 12
- HUCVOHYBFXVBRW-UHFFFAOYSA-M caesium hydroxide Inorganic materials [OH-].[Cs+] HUCVOHYBFXVBRW-UHFFFAOYSA-M 0.000 claims description 10
- -1 cyclohexylbenzylcyanide compound Chemical class 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical group [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 9
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 8
- 150000007529 inorganic bases Chemical class 0.000 claims description 7
- 230000009467 reduction Effects 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- LZWQNOHZMQIFBX-UHFFFAOYSA-N lithium;2-methylpropan-2-olate Chemical compound [Li+].CC(C)(C)[O-] LZWQNOHZMQIFBX-UHFFFAOYSA-N 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 5
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000008096 xylene Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 239000012448 Lithium borohydride Substances 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 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
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 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
- 150000002170 ethers Chemical class 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 239000002002 slurry Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000006239 protecting group Chemical group 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- MFGOFGRYDNHJTA-UHFFFAOYSA-N 2-amino-1-(2-fluorophenyl)ethanol Chemical compound NCC(O)C1=CC=CC=C1F MFGOFGRYDNHJTA-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
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 229910000085 borane Inorganic materials 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
- 238000005984 hydrogenation reaction 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
- 239000012022 methylating agents Substances 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 2
- 150000004714 phosphonium salts Chemical group 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid group Chemical group C(CCC(=O)O)(=O)O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 5
- 229940052303 ethers for general anesthesia Drugs 0.000 claims 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 2
- 230000002152 alkylating effect Effects 0.000 claims 1
- 229960004132 diethyl ether Drugs 0.000 claims 1
- 235000015320 potassium carbonate Nutrition 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 32
- 238000004128 high performance liquid chromatography Methods 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229960004688 venlafaxine Drugs 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- 239000000243 solution Substances 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 8
- AYKYOOPFBCOXSL-UHFFFAOYSA-N (4-hydroxyphenyl)acetonitrile Chemical compound OC1=CC=C(CC#N)C=C1 AYKYOOPFBCOXSL-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000011084 recovery Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 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
- GCDPXEFXIBVRBS-UHFFFAOYSA-N 2-cyclohexyl-2-hydroxy-2-phenylacetonitrile Chemical compound C=1C=CC=CC=1C(C#N)(O)C1CCCCC1 GCDPXEFXIBVRBS-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- BUDQDWGNQVEFAC-UHFFFAOYSA-N Dihydropyran Chemical compound C1COC=CC1 BUDQDWGNQVEFAC-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 239000000908 ammonium hydroxide Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 230000017858 demethylation Effects 0.000 description 2
- 238000010520 demethylation reaction Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229940093499 ethyl acetate Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000003223 protective agent 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
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- 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
- RRXSYZFVDIRTFB-UHFFFAOYSA-N C[CH]C1=CC=C(OC)C=C1 Chemical group C[CH]C1=CC=C(OC)C=C1 RRXSYZFVDIRTFB-UHFFFAOYSA-N 0.000 description 1
- 101150026303 HEX1 gene Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001412 amines Chemical class 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
- 238000004364 calculation method Methods 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 239000012351 deprotecting agent Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000012154 norepinephrine uptake Effects 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 230000013275 serotonin uptake Effects 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 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
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/36—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrane Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
The present invention describes processes for the preparation of O-desmethylvenlafaxine and the intermediates cyclohexylbenzylcyanide and tridesmethylvenlafaxine, which may be used as intermediates in preparing O- desmethylvenlafaxine.
Description
PROCESSES FOR THE SYNTHESIS OF O-DESMETHYLVENLAFAXINE
CROSS REFERENCE TO RELATED APPLICATIONS
[1] The present application claims the benefit of the following United States Provisional Patent Application Nos.: 60/833,616, filed July 26, 2006;
60/837,879, filed August 14, 2006; 60/849,216, filed October 3, 2006;
60/843,998, filed September 11, 2006; 60/849,255, filed October 3, 2006; 60/906,639, filed March 12, 2007; and 60/906,879, filed 1Vlarch 13, 2007. The contents of these applications are incorporated herein by reference.
FIELD OF THE INVENTION
CROSS REFERENCE TO RELATED APPLICATIONS
[1] The present application claims the benefit of the following United States Provisional Patent Application Nos.: 60/833,616, filed July 26, 2006;
60/837,879, filed August 14, 2006; 60/849,216, filed October 3, 2006;
60/843,998, filed September 11, 2006; 60/849,255, filed October 3, 2006; 60/906,639, filed March 12, 2007; and 60/906,879, filed 1Vlarch 13, 2007. The contents of these applications are incorporated herein by reference.
FIELD OF THE INVENTION
[2] The inverition encompasses processes for the synthesis of O-desmethylvenlafaxine.
BACKGROUND OF THE INVENTION
BACKGROUND OF THE INVENTION
[3] Venlafaxine, (t)-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:
iH3 H3C'N
OH
Formula I
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:
iH3 H3C'N
OH
Formula I
[4] 0-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," .I. Clzn. Pharmacol. 32:716-724 (1992). 0-desmethylvenlafaxine has the following chemical formula, Formula II:
OH
` ~ .
OH
C76Hz5NO2 Mol. Wt-- 263.38 Forrnula II
[51 Processes for the synthesis of 0-desmethylvenlafaxine, comprising a step of demethylation of the methoxy group of venlafaxine, are described in U.S.
patent No. 7,026,508 and 6,689,912, and in U.S. publication No. 2005/0197392.
[6] The synthesis disclosed in the above references is performed according to the following scheme:
O UM:s un!le.
OM:e ~ =~ `.: ;j . . . .
,.~ HO .r ' Reduction HO
. ,...,CN . .
`= .,~~ .
~...:~.
DOiMV
p"Me OH
Methylation Demethylation HO ~CH3 HO ~H3 amine 0'LCH3 phenol C N
Venlefaitine VNL ONV
Wherein "MBC" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl methylbenzyl cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV"
refers to 0-desmethylvenlafaxine.
[7] However, the processes disclosed in the above US patents and US
patent applications all remain problematic when applied to industrial scale production.
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 US Patent 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.
[8] There is a need in the art for a new synthetic route for obtaining 0-desmethylvenlafaxine, using a precursor of venlafaxine to obtain 0-desmethylvenlafaxine rather than by preparing venlafaxine and subsequently demethylating venlafaxine to obtain 0-desmethyl venlafaxine.
SUMMARY OF THE INVENTION
[9] In one embodiment, there is provided cyclohexylbenzylcyanide (COBC) of the formula:
OH
OH
CN .
COBC
[10] In another embodiment, the present invention provides a process for preparing cyclohexy.lbenzylcyanide (COBC) comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the reaction comprises combining OBC, an organic solvent, preferably a dry organic solvent, a base and cyclohexanone.
[11] In another embodiment, the present invention provides a process for obtaining cyclohexylbenzylcyanide (COBC) comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone in the presence of a phase transfer catalyst and a base_ [12] In another embodiment, the present invention provides a process for obtaining 0-desmethylvenlafaxine comprising preparing COBC as described above, and further converting the COBC to O-desmethylvenlafaxine.
[13] In another embodiment, the present invention provides a process for preparing tridesmethyl venlafaxine (TDMV) comprising: reducing COBC, preferably the step of reducing COBC comprises combining COBC, a reducing agent, an organic solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to create a reaction mixture, optionally followed by recovery of the TDMV from the reaction mixture.
[14] In another embodiment, the present invention provides a process for obtaining 0-desmethylvenlafaxine comprising preparing TDMV as described above, and further converting the TDMV to 0-desmethylvenlafaxine.
1151 In another embodiment, the present invention provides a process for preparing 0-desmethylvenlafaxine comprising: reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the step of reacting with cyclohexanone comprises combining OBC, an organic solvent, a base and cyclohexanone;
reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to create a reaction mixture; optionally recovering TDMV from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[161 In another embodiment, the present invention provides a process for preparing 0-desmethylvenlafaxine comprising: providing a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone, to obtain COBC; reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to create a reaction mixture; optionally recovering TDMV
from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[17] In another embodiment, the present invention provides a process of preparing 0-desmethyl venlafaxine (ODV) comprising combining hydroxybenzylcyanid (OBC) with a protecting reagent to obtain a hydroxyl protected hydroxybenzylcyanide (POBC), converting POBC to hydroxy protected O-desmethy.lvenlafaxine (PODV), and deprotecting PODV to form ODV.
[18] In yet another embodiment there is provided a hydroxyl protected hydroxybenzylcyanide (POBC). Also provided is a process of preparing POBC from hydroxybenzyl cyanide (OBC).
[19] In another embodiment there is provided a hydroxyl protected cyclcobexylbenzylcyanide (PCOBC). Also provided is a process of preparing PCOBC.
[20] In another embodiment there is provided a hydroxyl protected tridesmethyl venlafaxine (PTDMV). Also provided is a process of preparing PTDMV).
[21] In another embodiment there is provided a hydroxyl protected 0-desmethyl venlafaxine (PODV).
[22] In yet other embodiments of the invention each of the other embodiments provide one of each of the following compounds in isolated form:
cyclohexylbenzylcyanide (COBC), hydroxyl protected 4-hydroxybenzylcyanide (POBC), hydroxyl protected cyclohexylbenzylcyanide (PCOBC), hydroxyl protected tridesmethyl venlafaxine (PTDMV), and hydroxyl protected 0-desmethyl venlafaxine (PODV).
DETAILED DESCRIPTION OF THE INVENTION
[23] In one embodiment of the invention there is provided a cyclohexylbenzylcyanide compound COBC of the following formula OH
CN
j COBC
COBC may be obtained by any of the processes described below. Preferably, COBC
is substantially, pure, preferably at least 95% pure, more preferably at least 99% pure.
[24] The invention encompasses a synthetic route for obtaining O-desmethylvenlafaxine, from hydroxybenzylcyanide (OBC) and cyclohexylbenzylcyanide (COBC). As used herein, hydroxybenzylcyanide or OBC
refers to the compound 4-hydroxybenzylcyanide and cyclohexylbenzylcyanide or COBC refers to the compound 4-[1-cyano-l-(1-hydroxycyclohexy.l)methyl]phenol.
[25] As used herein, the term "reduced pressure" refers to a pressure less than atmospheric pressure. As used. herein, the term "substantially pure"
means a compound of very high purity as is understood by one of skill in the art, such as a purity of about 95%, or greater, as determined, for example, by HPLC area percent.
As used herein the term "room temperature" or "RT" means the ambient temperature of an typical laboratory, which is usually about that of Standard Temperature and Pressure (STP). As used herein, an "isolated" compound means the compound has been separated from the reaction mixture in which it was formed.
1261 In the process of the invention, the intermediate hydroxybenzylcyanide (OBC) is condensed with cyclohexanone to form the intermediate (hydroxy)cyclohexylbenzylcyanide (COBC). Further, the cyano group on the COBC
is subjected to reduction, to form the intermediate tridesmethyl venlafaxine (TDMV) which is then subjected to selective alkylation to produce 0-desmethylvenlafaxine (ODV).
[27] Alternatively, a protected hydroxy-benzylcyanide (POBC) intermediate is condensed with cyclohexanone to form the protected intermediate (hydroxy)cyclohexylbenzylcyanide (PCOBC). Further, the cyano group on the PCOBC is subjected to reduction, to form the protected intermediate tridesmethyl venlafaxine (PTDMV) which is then subjected to selective alkylation to produce desmethylvenlafaxine (ODV).
1281 The two pathways are as described in the following scheme:
OH o H OH OH
l("v'lJ
Condensation Reduction Methylatfon OH OH OH i H3 CN CN NHZ N"ICH
OBC COBC TDMV ODV
ectI:otb0n0 o)C OX
\ ~ \ \
-' ( Condensation Reduation OH OH
POBC PCOBC PTDMV
wherein X is a hydroxyl protecting group.
[29] In one embodiment, the present invention provides a process for preparing cyclohexylbenzylcyanide (COBC) comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably in the presence of an organic solvent and/or a base. The organic solvent is preferably a "dry organic solvent." As used herein the term "dry organic solvent" refers to an organic solvent that 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) in a manner that prevents the benefits of the present invention from being realized. Such dry organic solvent useful in the process of the present invention preferably comprises less about 1% by weight, more preferably less than about 0.1 % by weight water, such as about 0.05% by weight to about 0.1% by weight of water.
1301 A suitable organic solvent is selected from the group consisting of:
ethers, polar aprotic solvents, aromatic hydrocarbons, and alcohols, acetonitrile, and mixtures thereof. More preferably, the ethers contain 2-8 carbon atoms, more .preferably 4-8 carbon atoms, or are selected from the group consisting of:
diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF); preferably, the polar aprotic solvents are selected from the group consisting of dimethyiformamide (DMF), dimethylacetamide (DMA) and dimethy.lsulfoxide (DMSO); and the aromatic hydrocarbons are selected from the group consisting of toluene, xylene, and benzene;
preferably the aromatic hydrocarbons contain 6-14 carbon atoms, more preferably from 6-10 carbon atoms, even more preferably toluene, xylene or benzene;
preferably, the alcohols contain 1-6 carbon atoms, more preferably 1-4 carbon atoms or are selected from the group consisting of methanol, ethanol,.isopropanol (IPA), and butanol. Most preferably, the organic solvent is selected from the group consisting of:
tetrahydYofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO). Preferably, the organic solvent is a dry organic solvent.
[311 The organic solvent can be employed as such, or it can be employed in mixture with another organic solvent such as methanol or toluene.
[32] Preferably, the cyclohexanone is present in an amount of about 1 to about 2 moles per mole of OBC, more preferably from about 1.1 mole to about 1.5 mole per mole of OBC.
[33] Preferably, the base is an inorganic base.lVlore preferably, the inorganic base is an alkali metal base. A suitable base for use in the process of the present invention is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis (trimethyl silyl) amide (LiN[(CH3)3Si]2), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (CsOH), sodium hydride (NaH), potassium hydride (KH), cesium hydride (CsH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium metoxide (NaOMe). When the organic solvent is tetrahydrofuran (THF), the base is preferably lithium diisopropyl amide (LDA), and when the organic solvent is a polar aprotic solvent, such as for example DMSO, the base is preferably sodium methoxide (NaOMe).
[34] Preferably, the base is present in an amount of about 1 to about 5 moles per mole of OBC, more preferably in an amount of about 1.5 to about 3.5 moles per mole of OBC, even more preferably the amount is from about 2 to about 3 moles per mole of OBC.
[35] In one embodiment of the invention, a solution or a slurry of hydroxybenzylcyanide (OBC) and an organic solvent may be first combined with a base, followed by combining the obtained reaction mixture with cyclohexanone, to obtain COBC. The initial reaction mixture may be cooled prior to adding cyclohexanone, preferably cooling is to a temperature of about -50 C to about -80 C, preferably about -65 C. Preferably, cyclohexanone is added to the reaction mixture in a dropwise manner.
[36] After combining the reaction mixture with cyclohexanone, the mixture may be further maintained, preferably at a constant temperature of about -40 C
to about 35 C, preferably with stirring, for a sufficient time to obtain a useful amount of COBC, which is generally at least 10 minutes, preferably at least 45 min, more preferably from about 1 hour to an overnight period (about 8 to 18 hours), even more preferably from about 2 hours to about 5 hours.
[37] COBC may be further recovered from the reaction mixture by any method known in the art. In one embodiment, recovery of COBC from the reaction mixture comprises the steps of extracting COBC from the reaction mixture, preferably with ethylacetate, washing the obtained organic layer, preferably with a saturated ammonium chloride solution and brine, and evaporating the solvent, preferably under reduced pressure, to obtain crude COBC. Such recovery may further comprise the steps of slurrying the crude COBC in a chlorinated hydrocarbon, preferably methylene chloride, filtering the slurry, washing the solid with methylene chloride, and drying to obtain substantially pure COBC.
[38] In another embodiment, the present invention provides a process for obtaining cyclohexylbenzylcyanide (COBC) from a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone.
[39] Preferably, the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate; a tetraalkylammonium halide wherein the alkyl group can be the same or different and contains from I to 6, such as for example tetrabutylammonium bromide, tetrabutylammonium chloride, or tetrabutylanimonium iodide; benzyltriethyl ammonium chloride; a quaternary ammonium salt; a quatemary phosphonium salt and a crown ether. More preferably, the phase transfer catalyst is tetrabutylammonium bromide (TBAB).
[40] The base in this embodiment is preferably an inorganic base. Suitable inorganic bases are, for example, metal oxides and metal carbonates.
Preferably, the inorganic base is selected from the group consisting of: NaOH, KOH, LiOH, CsOH, K2C03, Na2CO3, and Cs2CO3. Other bases suitable for use in the process of the invention are, for example, metal alkanoxides such as sodium methoxide (NaOMe) or sodium ethanoxide (NaOEt). Preferably, the base is present in an amount of about 0.5 to about 3 mole per mole of OBC, more preferably from about I mole to about 2 mole per mole of OBC.
[41] Preferably, the cyclohexanone is present in an mnount of about 1 to about 2 moles per mole of OBC, more preferably from about 1.1 mole to about 1.5 mole per mole of OBC.
[42] The reaction may occur with or without the presence of an organic solvent or water. Preferably, the reaction occurs in the presence of water.
[43] Preferably, the reaction mixture is maintained, preferably with stirring, for a sufficient period of time to obtain a useful amount of COBC. A
sufficient period of tirne may be from about 1 hour to about 24 hours, preferably an overnight period (about 8 to about 18 hours). One of ordinary skill in the art could easily monitor the reaction to determine whether a sufficient period of time has elapsed.
[44] The present invention also provides hydroxyl protected hydroxybenzylcyanide (POBC) of the following formula:
x CN
POBC
wherein X is a hydroxyl protecting group. The hydroxyl protecting group may be removed by deprotection.
[45] The hydroxyl group on the 4-hydroxybenzylcyanide (OBC) may be prepared by a process comprising combining OBC with a protecting reagent to form a reaction mixture, optionally in an organic solvent and in the presence of a catalyst, a base or both, to obtain the hydroxyl protected POBC.
[46] A suitable protecting agent can be any known hydroxyl protecting agent. Suitable hydroxyl protecting groups are listed in T.W. Greene, Protecting Groups in Organic Synthesis, (2 d Ed.), which is incorporated herein by reference.
Preferably, the hydroxyl protecting group can be a silyl, acetyl, or 3,4-dihydro-2H-puran (DHP). The silyl protecting group is preferably tert-butyldimethylsilyl (TBDMS). The protection reaction may be carried out at any suitable temperature depending on reagent used, preferably the temperature is between about 0 C to about 100 C, more preferably between about room temperature to about 55 C. A
preferred base added to the reaction mixture is selected from the group selected from imidazole, pyridine, triethylamine, lutidine, and dimethylaminopyridine. A catalyst may be added to the mixture, such as for example Pyridinium p-toluene sulfonate (PPTS).
[47] Preferably, POBC is substantially pure, preferably at least 95% pure, more preferably at least 99% pure.
[48] The present invention also provides hydroxyl protected cyclohexylbenzylcyanide (PCOBC). of the following formula:
ox H
CN
PCOBC
wherein X is as described above. Preferably, PCOBC is substantially pure, preferably at least 95% pure, more preferably at least 99% pure.
[491 In another embodiment, the present invention provides a process for preparing a hydroxyl protected COBC (PCOBC), according to the processes for preparing COBC, wherein the starting material 4-hydroxybenzylcyanide (OBC) is a hydroxyl protected OBC (POBC) as described in the scheme above.
[50] In another embodiment, the present invention provides a process for obtaining 0-desmethylvenlafaxine comprising preparing COBC or PCOBC in any of the methods described above, and further converting them to 0-desmethylvenlafaxine.
[51] In another embodiment of the process of the present invention 0-desmethyl venlafaxine, salts thereof or hydroxyl protected derivatives thereof may be prepared from hydroxybenzylcyanide by first protecting the hydroxyl group on the hydroxybenzylcyanide (OBC). The hydroxyl protected hydroxybenzylcyanide (POBC) may then be condensed with cyclohexanone to obtain a hydroxyl protected cyclohexylbenzylcyanide (PCOBC) which is reduced to form the hydroxyl protected tridesmethyl venlafaxine (PTDMV) and methylated to form a hydroxyl protected 0-desmethyl venlafaxine (PODV) as is shown in the schematic above.
[52] The protected POBC may be converted by any of the above processes to a hydroxyl protected PCOBC, which can be reduced to a hydroxyl protected PTDMV by a process described above, and the protected PTDMV may be methylated to obtain the hydroxyl protected PODV. Subsequently, the PODV is preferably deprotected with an appropriate deprotecting agent depending on the protecting group used. Preferably such deprotection agent can be an acid, such as for example methanesulfonic acid.
[53] The present invention also provides a process for preparing tridesmethyl venlafaxine (TDMV). TDMV may be prepared by reducing COBC.
Preferably, COBC is combined with a reducing agent in the presence of an organic solvent and/or a Lewis acid catalyst, preferably boron trifluoride (BF3) to create a reaction mixture. TDMV may be further recovered from the reaction mixture.
[54] In one embodiment, a solution of COBC, a reducing agent and an organic solvent are combined with a Lewis acid catalyst to obtain a reaction mixture, followed by recovery of the TDMV from the reaction mixture.
[55] Preferably, the solution of COBC, reducing agent and organic solvent is cooled prior to combining it with a Lewis acid catalyst. A preferred temperature to which the mixture is cooled is to a temperature of less than about 10 C, more preferably from about -10 C to about 10 C.
[56] A preferred Lewis acid catalyst is boron trifluoride (BF3). When BF3 is used, it is preferably added as a complex in ether (BF3Et2O), or else the complex may be formed in situ.
[57] In some embodiments, COBC may be prepared by precipitation from a mixture of hydroxybenzylcyanide (OBC), an organic solvent, a base and cyclohexanone; or from a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone.
[58] Preferably, the reducing agent is selected from the group consisting of:
sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiA1H4), L-selectride (lithium tri-sec-butylborohydride), and borane.
More preferably, the reducing agent is NaBH4.
[59] Alternatively, the reduction can be performed by hydrogenation in the presence of a catalyst, e.g. Ni, Co, Pd/C, or Pt catalyst.
[60] Preferably, the organic solvent is a dry organic solvent. The organic solvent is as described above. More preferably, the organic solvent is THF.
[61] Preferably, the reducing agent is present in an amount of about 1 to about 10 moles per mole of COBC, more preferably in an amount of about 4 to about moles per mole of COBC. A preferred amount of the Lewis acid catalyst, such as BF3, is an amount of about 1 to about 5 moles per mole of COBC, more preferably from about 2 to about 3 mole per mole of COBC.
[62] The reaction mixture in the process of the present invention may be maintained, preferably at a constant temperature, such as at room temperature, preferably while stirring, for a sufficient period of time to obtain TDMV. A
preferred period of time is from about 1 hour to about 24 hours, more preferably from about 3 hours to about 12 hours, even more preferably, from about 8 hours to about 10 hours.
[63] TDMV may then be recovered from the reaction mixture by any method known in the art. In one embodiment, recovery of TDMV from the reaction mixture comprises the steps of basifying and optionally extracting TDMV from the reaction mixture, preferably with ethylacetate, washing the obtained organic solution, preferably with water andlor brine, and drying to obtain= TDMV, preferably by evaporating the solvent for example under reduced pressure.
[64] The present invention also provides the hydroxyl protected tridesmethyl venlafaxine (PTDMV) of the following formula:
x OH
NHa PTDMV
wherein X is as described above. Preferably, PCOBC is substantially pure, preferably at least 95% pure, more preferably at least 99% pure.
[65] In another embodiment, the present invention provides a process for preparing hydroxyl protected tridesmethyl venlafaxine (PTDMV), according to the preparation of TDMV, wherein the starting material the hydroxyl protected PCOBC
as described above.
[66] In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising preparing TDMV or PTDMV as described above, and further converting them to 0-desmethylvenlafaxine.
[67] The conversion of TDMV to 0-desmethylvenlafaxine can be performed, for example as described in co-pending United States Patent Application No. --/-------- filed July 26, 2007, entitled "Processes for the Synthesis of Desmethylvenlafaxine"(Atty Docket No 1662/03304), which is incorporated herein by reference. For example, TDMV may be combined with an organic solvent and a methylating agent to form a mixture, and recovering the 0-desmethylvenlafaxine from the mixture. Also, TDMV may be subjected to selective reductive amination to produce 0-desmethylvenlafaxine ("ODV"). PTDMV is converted to PO-desmethylvenlafaxine in a similar manner.
[68] In another embodiment, the present invention provides a process for preparing 0-desmethylvenlafaxine comprising: reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the step of reacting with cyclohexanone comprises combining OBC, an organic solvent, a base and cyclohexanone;
reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and boron trifluoride (BF3).to create a reaction mixture;
recovering TDMV from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[69] In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: providing a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone, to obtain COBC; reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and boron trifluoride (BF3) to create a reaction mixture; recovering TDMV from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[70] In another embodiment of the present invention a hydroxyl protected 0-desmethyl venlafaxine (PODV) may be prepared by any of the above processes wherein the starting material is a hydroxyl protected intermediate as described above.
The present invention also provides the hydroxyl protected 0-desmethyl venlafaxine (PODV).
[71] The 0-desmethyl venlafaxine prepared by any of above process can be prepared in the form of a salt, preferably a succinate salt.
[72] . Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the synthesis of the compound COBC, tridesmethyl venlafaxine and further their conversion to 0-desmethylvenlafaxine. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may. be practiced without departing from the scope of the invention.
EXAMPLES
HPLC Method:
Column & Packing: Zorbax SB C-18 4.6*250mm Part No.28105-020 or equivalent column Column Temperature: 25 C
Buffer Add 4.Oml of trifluoroacetic acid and 7.Oml of triethylamine to 1L of water adjust the pH to3.0 with triethylarnine.
Eluent:
ReservoirA 30 JoAcetonitrile and 70% Buffer Reservoir B To a mixture of 700m1 Acetonitrile and 300m1 buffer add 1.6m1 of trifluoroacetic acid and 2.9rn1 of triethylamine measure the pH it should be about 3_0 (correct the pH with triethylamine or trifluoroacetic acid if necessary).
Gradient Time Reservoir A Reservoir B
0 100% 0%
21 min 100% 0%
55 min 45% 55%
Equilibrium time: 10min Flow Rate: 1.0 ml/min Detector: 230 nm Sample Volume: 10 l Diluent: Eluent A
Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
Sample Preparation Weigh accurately about 10 mg of sample in a 20m1 amber volumetric flask.
Dissolve with eluent A.
Method Inject the sample solutions into the chromatograph, continuing the chromatogram of sample up to the end of the gradient. Determine the areas for each peak in each solution using a suitable integrator.
Calculation Impurity Profile Determination % impurity _ area impurity in sample x 100 Total area Preparation of COBC
Example 1:
A 100 ml, three necked flask equipped with Nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and THF (15 ml). This solution was cooled to -78 C and LDA (2M in THF, 16.5 ml, 33 mmol) was added slowly, keeping temperature under -65 C. A white solid precipitated during LDA
addition. Afler the end of the addition, the mixture was stirred for 30 minutes.
Cyclohexanone (1.62 g, 16.5 mmol) was then added, and the mixture continued in the same conditions for 5 hours. The reaction was quenched by pouring it into 100 ml of a saturated ammonium chloride solution containing ice.
The product was extracted to EtOAc (3x30 ml). The organic layer was washed with a saturated ammonium chloride solution and brine. Finally the solvent was evaporated under reduced pressure to get 3.5 g of a mixture of OBC (30%) and COBC
(60%) (Yield =60%).
This mixture was suspended in 10 ml methylene chloride, where a solid precipitated. The slurry was stirred at room temperature-for 2 hours, the solid filtered, washed with methylene chloride and vacuum dried at room temperature, to get 1.9g COBC (purity 99% by HPLC area, yield=55%).
Examgle 2:
A 100 ml, three necked flask equipped with Nitrogen inlet, thermometer and magnetic stirrer was charged with OBC (5g, 37.5 mmol) and DMSO (5 ml). The contents of the flask were stirred to complete dissolving (brown color). KOH
(3.2g, 56 mmol ) was added and the reaction mixture stirred vigorously (exothermic).
Cyclohexanone (5.52 g, 56 mmol) was then added dropwise. The reaction was quenched with HC1 5% and methylene chloride was added. The layers were separated and a solid precipitated. The solid was then filtered under reduced pressure and washed with a small amount of methylene chloride to yield 3.2g of COBC.
Example 3:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), toluene (15 ml) and DMF
(2ml). The reaction mixture was stirred at about room temperature (RT) until dissolution was complete and NaH (1.2g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise. The reaction was stirred at RT for an additional lhr to get 21% COBC (% area HPLC).
Example 4:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), THF (30 ml) and DMF
(2m1). The reaction mixture was stirred at RT until dissolution was complete and t-BuOK (3.3 g, 30 mmol) was added. Cyclohexanone (1.65 g, 16.8 mmol) was then added dropwise and the reaction was stirred at RT for an additiona13.5hrs to get 19%COBC (% area HPLC).
Example 5:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), THF (15 ml) and DMF
(2m1). The mixture was stirred at RT until complete dissolution and NaH (1.2g, mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise and the reaction was stirred at RT for and additional 2hrs to get 34%COBC (% area HPLC).
Example 6:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) MeOH (15 ml) and DMF
(2ml). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1.7g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise and the reaction was stirred at RT overnight to obtain 30% COBC
(%
area HPLC).
Example 7:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), MeOH (10 ml) and DMSO
(lOml). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1.7g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was added dropwise. The reaction was stirred at RT overnight to obtain 32% COBC ( 'o area HPLC).
Example 8:
A 100 ml, three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (l Ornl). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (2.65g, 47 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 10 min to get 43% COBC (% area HPLC).
Example 9:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (10m1). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1 g, 17.6 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 45 min to get 55% of COBC (% area HPLC).
Example 10:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (lOml). The reaction mixture was stirred at RT until complete dissolution and LiOH (1g, 23.8 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 8.5hrs to get 35% of COBC (% area HPLC).
Example 11:
A 100 ml three necked flask equipped with, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), cyclohexanone (1.7 g, 17.3 mmol), TBAB (0.26g) and NaOH (6m1 10%). The reaction was stirred at RT overnight to .get 44% COBC (HPLC).
Example 12:
A 100 ml three necked flask equipped with nitrogen inlet, thennometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and THF (15m1). The reaction mixture was stirred at RT until complete dissolution and t-BuOLi (2g, mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 45min to get 19% COBC (% area HPLC).
Example 13:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer,and mechanical stirrer was charged with OBC (2g, 15 mmol), THF(15m1) and DMF
(1.5m1). The reaction mixture was stiured at RT until complete dissolution and t-BuOLi (2.5g, 30 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 1.15 hr to get 23.5% COBC (%
area HPLC).
Example 14:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2 g, 20.37 mmol), TBAB (0.5g) and NaOH (13m1 10%) were added. The reaction was stirred at RT
overnight to get 40%COBC (% area HPLC).
Examule 15:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2.2g, 22.4 mmol).
Water (l Oml), TBAB (0.3g) and KOH (1.9g, 30.5 mmol) were then added. The reaction was stirred at RT overnight to get 39% COBC (% area HPLC).
Examule 16:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2.2g, 22.4 mmol).
Water (10m1), TBAB(0.3gr) and LiOH (2g, 47.6mmo1) were then added. The reaction was stirred at RT overnight to get 39% COBC (% area HPLC)_ Example 17:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), DMA (10m1) and LiOH (2g, 47.7 mmol). Cyclohexanone (2.2g, 22:4 mmol) was then added dropwise. The reaction mixture was stirred at RT overnight to get 10% COBC (% area HPLC).
Preparation of TDMV
Example 18:
A100 ml three necked flask equipped with nitrogen inlet thenmometer and mechanical stirrer was charged with COBC (2 g, 8.64 mmol), MeOH (50 ml) and CoCl anhydrous (2.25 g, 17.32 mmol). The resulting solution was cooled to-10 C
with an ice-bath. NaBH4 (3.35 g, 88.62mmol) was added portionwise at this temperature. The ice-bath was removed one hour after the end of addition.
The reaction mixture was stirred 3 hours at room temperature and then quenched with 10%HCI. MeOH was removed under reduced pressure and the aqueous phase was basified with ammonium hydroxide (25%) and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get 0.4 g of TDMV.
Example 19:
A 100 ml three necked flask equipped with nitrogen inlet thermometer and mechanical stirrer was charged with NaBH4 (1.2 g, 31.74 mmol) THF (lOml).
This solution was cooled to10 C with an ice-bath. BF3Et2O (3.95g, 27.86mmol) and COBC (2 g, 8.64 mmol) were then added. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was quenched with formic acid and water. The organic phase was basified with NaOH (25%), washed with water and evaporated under reduced pressure to get TDMV.
Preparation of O-desmethylvenlafaxine Example 20:
TDMV (0.5 g, 2.12 mmol) was suspended in CH2C12. Methyl iodide (0.26 ml, 4.3 mmol) and triethylamine (0.66 ml, 4.73 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 6 hours. At this stage methyl iodide (0.5 ml) and NEt3 (1.2 ml) were added. The addition caused the temperature to rise. After 16 hours, BPLC analysis indicated the presence of ODV.
Preparation of POBC
Example 21: Preparation of OBC-DHP
OBC (0.5g, 3.7 mmol) was dissolved at room temperature in 3,4-dihydro-2H-pyran (DHP) (approx. 2 ml) under N2. Pyridinium p-toluene sulfonate (PPTS, catalytic amount) was added and heated to 55 C for 45 min. The end of reaction was determined by TLC (eluent EtOAc:Hex 1:1). The product was extracted in EtOAc, washed with brine and dried over MgSO4. A pale yellow powder was obtained (0.74g, purity= 98% by area % of HPLC, yield= 91%) Example 22: Preparation of OBC-TBDMS
OBC (5g, 37 mmol), 11 g of TBDMS-Cl, 12g of imidazole and 25m1 of CH2Cla were stirred together for 2 hours at ambient temperature under N2 atmosphere.
The product was washed with brine, a 10% aqueous solution of citric acid, brine and dried over MgSO4. After removal of the solvent 4g of product was obtained.
Preparation of PCOBC
Example 23: Preparation of COBC-DHP
OBC-DHP (0.74g, 3.4 mmol), cyclohexanone (0.5 g), TBAB (0.15g) and a 10% aqueous solution of NaOH (4 ml) were mixed and stirred at room temperature, forming two phases. After 30 minutes of stirring, the organic phase was analyzed by HPLC, containing 46% COBC-DHP and 48% unreacted OBC-DHP.
Example 24:
OBC-DHP (3.25g, 15 mmol) was dissolved in dry THF under N2 and cooled to -80 C. LDA 2M in THF/heptane/ethyl benzene (8 ml, 16 mmol) was added dropwise, keeping the temperature under -60 C. The mixture was stirred at -80 C for 30 minutes. Cyclohexanone (1.65g, 16.5 mmol) was added dropwise. After 1 hour stirring a sample was analyzed by HPLC, containing 41% COBC-DHP and 42%
unreacted OBC-DHP.
Preparation of PTDMV
Example 25:
A 100 ml three necked flask equipped with nitrogen inlet thermometer and mechanical stirrer is charged with PCOBC (8.64 mmol), MeOH (50 ml) and CoCI
anhydrous (17.32 mmol). The resulting solution is cooled to-10 C with an ice-bath.
NaBH4 (88.62mmol) is added portionwise at this temperature. The ice-bath is removed one hour after the end of addition.
The reaction mixture is stirred 3 hours at room temperature and then quenched with 10%HCI. MeOH is removed under reduced pressure and the aqueous phase is basified with ammonium hydroxide (25%) and extracted with EtOAc. The organic phase is washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get PTDMV.
Example 26:
A 100 ml three necked flask-equipped with nitrogen inlet thermometer and mechanical stirrer is charged with NaBH4 (31.74 mmol) and THF (lOml).
This solution is cooled to10 C with an ice-bath. BF3Et2O (27.86nunol) and PCOBC
(8.64 mmol) are then added. The reaction mixture is stirred at room temperature overnight.
The reaction mixture is quenched with formic acid and water. The organic phase is basified with NaOH (25 Jo), washed with water and evaporated under reduced pressure to get PTDMV.
Preparation of PODV
Exarnple 27:
P-TDMV (2.12 mmol) is suspended in CH2Cl2. Methyl iodide (4.3 mmol) and triethylamine (4.73 mmol) are added. The reaction mixture is stirred under nitrogen atmosphere at room temperature for 6 hours. At this stage methyl iodide (0.5 ml) and NEt3 (1.2 ml) are added. After 16 hours, HPLC analysis indicated the presence of PODV.
Preparation of 0-desmethylvenlafaxine Example 28:
PODV (2.12 mmol) is suspended in THF in presence of methanesulfonic acid (6 mmol).The reaction is stirred at ambient temperature overnight. To the mixture so-obtained is first added EtOAc and the organic phase is washed with brine, Na2CO3 saturated and water. The organic phase is then concentrated under reduced pressure to get ODV.
J. et al., "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite," .I. Clzn. Pharmacol. 32:716-724 (1992). 0-desmethylvenlafaxine has the following chemical formula, Formula II:
OH
` ~ .
OH
C76Hz5NO2 Mol. Wt-- 263.38 Forrnula II
[51 Processes for the synthesis of 0-desmethylvenlafaxine, comprising a step of demethylation of the methoxy group of venlafaxine, are described in U.S.
patent No. 7,026,508 and 6,689,912, and in U.S. publication No. 2005/0197392.
[6] The synthesis disclosed in the above references is performed according to the following scheme:
O UM:s un!le.
OM:e ~ =~ `.: ;j . . . .
,.~ HO .r ' Reduction HO
. ,...,CN . .
`= .,~~ .
~...:~.
DOiMV
p"Me OH
Methylation Demethylation HO ~CH3 HO ~H3 amine 0'LCH3 phenol C N
Venlefaitine VNL ONV
Wherein "MBC" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl methylbenzyl cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV"
refers to 0-desmethylvenlafaxine.
[7] However, the processes disclosed in the above US patents and US
patent applications all remain problematic when applied to industrial scale production.
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 US Patent 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.
[8] There is a need in the art for a new synthetic route for obtaining 0-desmethylvenlafaxine, using a precursor of venlafaxine to obtain 0-desmethylvenlafaxine rather than by preparing venlafaxine and subsequently demethylating venlafaxine to obtain 0-desmethyl venlafaxine.
SUMMARY OF THE INVENTION
[9] In one embodiment, there is provided cyclohexylbenzylcyanide (COBC) of the formula:
OH
OH
CN .
COBC
[10] In another embodiment, the present invention provides a process for preparing cyclohexy.lbenzylcyanide (COBC) comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the reaction comprises combining OBC, an organic solvent, preferably a dry organic solvent, a base and cyclohexanone.
[11] In another embodiment, the present invention provides a process for obtaining cyclohexylbenzylcyanide (COBC) comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone in the presence of a phase transfer catalyst and a base_ [12] In another embodiment, the present invention provides a process for obtaining 0-desmethylvenlafaxine comprising preparing COBC as described above, and further converting the COBC to O-desmethylvenlafaxine.
[13] In another embodiment, the present invention provides a process for preparing tridesmethyl venlafaxine (TDMV) comprising: reducing COBC, preferably the step of reducing COBC comprises combining COBC, a reducing agent, an organic solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to create a reaction mixture, optionally followed by recovery of the TDMV from the reaction mixture.
[14] In another embodiment, the present invention provides a process for obtaining 0-desmethylvenlafaxine comprising preparing TDMV as described above, and further converting the TDMV to 0-desmethylvenlafaxine.
1151 In another embodiment, the present invention provides a process for preparing 0-desmethylvenlafaxine comprising: reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the step of reacting with cyclohexanone comprises combining OBC, an organic solvent, a base and cyclohexanone;
reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to create a reaction mixture; optionally recovering TDMV from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[161 In another embodiment, the present invention provides a process for preparing 0-desmethylvenlafaxine comprising: providing a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone, to obtain COBC; reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and a Lewis acid catalyst, preferably boron trifluoride (BF3), to create a reaction mixture; optionally recovering TDMV
from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[17] In another embodiment, the present invention provides a process of preparing 0-desmethyl venlafaxine (ODV) comprising combining hydroxybenzylcyanid (OBC) with a protecting reagent to obtain a hydroxyl protected hydroxybenzylcyanide (POBC), converting POBC to hydroxy protected O-desmethy.lvenlafaxine (PODV), and deprotecting PODV to form ODV.
[18] In yet another embodiment there is provided a hydroxyl protected hydroxybenzylcyanide (POBC). Also provided is a process of preparing POBC from hydroxybenzyl cyanide (OBC).
[19] In another embodiment there is provided a hydroxyl protected cyclcobexylbenzylcyanide (PCOBC). Also provided is a process of preparing PCOBC.
[20] In another embodiment there is provided a hydroxyl protected tridesmethyl venlafaxine (PTDMV). Also provided is a process of preparing PTDMV).
[21] In another embodiment there is provided a hydroxyl protected 0-desmethyl venlafaxine (PODV).
[22] In yet other embodiments of the invention each of the other embodiments provide one of each of the following compounds in isolated form:
cyclohexylbenzylcyanide (COBC), hydroxyl protected 4-hydroxybenzylcyanide (POBC), hydroxyl protected cyclohexylbenzylcyanide (PCOBC), hydroxyl protected tridesmethyl venlafaxine (PTDMV), and hydroxyl protected 0-desmethyl venlafaxine (PODV).
DETAILED DESCRIPTION OF THE INVENTION
[23] In one embodiment of the invention there is provided a cyclohexylbenzylcyanide compound COBC of the following formula OH
CN
j COBC
COBC may be obtained by any of the processes described below. Preferably, COBC
is substantially, pure, preferably at least 95% pure, more preferably at least 99% pure.
[24] The invention encompasses a synthetic route for obtaining O-desmethylvenlafaxine, from hydroxybenzylcyanide (OBC) and cyclohexylbenzylcyanide (COBC). As used herein, hydroxybenzylcyanide or OBC
refers to the compound 4-hydroxybenzylcyanide and cyclohexylbenzylcyanide or COBC refers to the compound 4-[1-cyano-l-(1-hydroxycyclohexy.l)methyl]phenol.
[25] As used herein, the term "reduced pressure" refers to a pressure less than atmospheric pressure. As used. herein, the term "substantially pure"
means a compound of very high purity as is understood by one of skill in the art, such as a purity of about 95%, or greater, as determined, for example, by HPLC area percent.
As used herein the term "room temperature" or "RT" means the ambient temperature of an typical laboratory, which is usually about that of Standard Temperature and Pressure (STP). As used herein, an "isolated" compound means the compound has been separated from the reaction mixture in which it was formed.
1261 In the process of the invention, the intermediate hydroxybenzylcyanide (OBC) is condensed with cyclohexanone to form the intermediate (hydroxy)cyclohexylbenzylcyanide (COBC). Further, the cyano group on the COBC
is subjected to reduction, to form the intermediate tridesmethyl venlafaxine (TDMV) which is then subjected to selective alkylation to produce 0-desmethylvenlafaxine (ODV).
[27] Alternatively, a protected hydroxy-benzylcyanide (POBC) intermediate is condensed with cyclohexanone to form the protected intermediate (hydroxy)cyclohexylbenzylcyanide (PCOBC). Further, the cyano group on the PCOBC is subjected to reduction, to form the protected intermediate tridesmethyl venlafaxine (PTDMV) which is then subjected to selective alkylation to produce desmethylvenlafaxine (ODV).
1281 The two pathways are as described in the following scheme:
OH o H OH OH
l("v'lJ
Condensation Reduction Methylatfon OH OH OH i H3 CN CN NHZ N"ICH
OBC COBC TDMV ODV
ectI:otb0n0 o)C OX
\ ~ \ \
-' ( Condensation Reduation OH OH
POBC PCOBC PTDMV
wherein X is a hydroxyl protecting group.
[29] In one embodiment, the present invention provides a process for preparing cyclohexylbenzylcyanide (COBC) comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably in the presence of an organic solvent and/or a base. The organic solvent is preferably a "dry organic solvent." As used herein the term "dry organic solvent" refers to an organic solvent that 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) in a manner that prevents the benefits of the present invention from being realized. Such dry organic solvent useful in the process of the present invention preferably comprises less about 1% by weight, more preferably less than about 0.1 % by weight water, such as about 0.05% by weight to about 0.1% by weight of water.
1301 A suitable organic solvent is selected from the group consisting of:
ethers, polar aprotic solvents, aromatic hydrocarbons, and alcohols, acetonitrile, and mixtures thereof. More preferably, the ethers contain 2-8 carbon atoms, more .preferably 4-8 carbon atoms, or are selected from the group consisting of:
diisopropyl ether, diethyl ether, dioxane, tetrahydrofuran (THF); preferably, the polar aprotic solvents are selected from the group consisting of dimethyiformamide (DMF), dimethylacetamide (DMA) and dimethy.lsulfoxide (DMSO); and the aromatic hydrocarbons are selected from the group consisting of toluene, xylene, and benzene;
preferably the aromatic hydrocarbons contain 6-14 carbon atoms, more preferably from 6-10 carbon atoms, even more preferably toluene, xylene or benzene;
preferably, the alcohols contain 1-6 carbon atoms, more preferably 1-4 carbon atoms or are selected from the group consisting of methanol, ethanol,.isopropanol (IPA), and butanol. Most preferably, the organic solvent is selected from the group consisting of:
tetrahydYofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA) and dimethylsulfoxide (DMSO). Preferably, the organic solvent is a dry organic solvent.
[311 The organic solvent can be employed as such, or it can be employed in mixture with another organic solvent such as methanol or toluene.
[32] Preferably, the cyclohexanone is present in an amount of about 1 to about 2 moles per mole of OBC, more preferably from about 1.1 mole to about 1.5 mole per mole of OBC.
[33] Preferably, the base is an inorganic base.lVlore preferably, the inorganic base is an alkali metal base. A suitable base for use in the process of the present invention is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis (trimethyl silyl) amide (LiN[(CH3)3Si]2), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (CsOH), sodium hydride (NaH), potassium hydride (KH), cesium hydride (CsH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium metoxide (NaOMe). When the organic solvent is tetrahydrofuran (THF), the base is preferably lithium diisopropyl amide (LDA), and when the organic solvent is a polar aprotic solvent, such as for example DMSO, the base is preferably sodium methoxide (NaOMe).
[34] Preferably, the base is present in an amount of about 1 to about 5 moles per mole of OBC, more preferably in an amount of about 1.5 to about 3.5 moles per mole of OBC, even more preferably the amount is from about 2 to about 3 moles per mole of OBC.
[35] In one embodiment of the invention, a solution or a slurry of hydroxybenzylcyanide (OBC) and an organic solvent may be first combined with a base, followed by combining the obtained reaction mixture with cyclohexanone, to obtain COBC. The initial reaction mixture may be cooled prior to adding cyclohexanone, preferably cooling is to a temperature of about -50 C to about -80 C, preferably about -65 C. Preferably, cyclohexanone is added to the reaction mixture in a dropwise manner.
[36] After combining the reaction mixture with cyclohexanone, the mixture may be further maintained, preferably at a constant temperature of about -40 C
to about 35 C, preferably with stirring, for a sufficient time to obtain a useful amount of COBC, which is generally at least 10 minutes, preferably at least 45 min, more preferably from about 1 hour to an overnight period (about 8 to 18 hours), even more preferably from about 2 hours to about 5 hours.
[37] COBC may be further recovered from the reaction mixture by any method known in the art. In one embodiment, recovery of COBC from the reaction mixture comprises the steps of extracting COBC from the reaction mixture, preferably with ethylacetate, washing the obtained organic layer, preferably with a saturated ammonium chloride solution and brine, and evaporating the solvent, preferably under reduced pressure, to obtain crude COBC. Such recovery may further comprise the steps of slurrying the crude COBC in a chlorinated hydrocarbon, preferably methylene chloride, filtering the slurry, washing the solid with methylene chloride, and drying to obtain substantially pure COBC.
[38] In another embodiment, the present invention provides a process for obtaining cyclohexylbenzylcyanide (COBC) from a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone.
[39] Preferably, the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate; a tetraalkylammonium halide wherein the alkyl group can be the same or different and contains from I to 6, such as for example tetrabutylammonium bromide, tetrabutylammonium chloride, or tetrabutylanimonium iodide; benzyltriethyl ammonium chloride; a quaternary ammonium salt; a quatemary phosphonium salt and a crown ether. More preferably, the phase transfer catalyst is tetrabutylammonium bromide (TBAB).
[40] The base in this embodiment is preferably an inorganic base. Suitable inorganic bases are, for example, metal oxides and metal carbonates.
Preferably, the inorganic base is selected from the group consisting of: NaOH, KOH, LiOH, CsOH, K2C03, Na2CO3, and Cs2CO3. Other bases suitable for use in the process of the invention are, for example, metal alkanoxides such as sodium methoxide (NaOMe) or sodium ethanoxide (NaOEt). Preferably, the base is present in an amount of about 0.5 to about 3 mole per mole of OBC, more preferably from about I mole to about 2 mole per mole of OBC.
[41] Preferably, the cyclohexanone is present in an mnount of about 1 to about 2 moles per mole of OBC, more preferably from about 1.1 mole to about 1.5 mole per mole of OBC.
[42] The reaction may occur with or without the presence of an organic solvent or water. Preferably, the reaction occurs in the presence of water.
[43] Preferably, the reaction mixture is maintained, preferably with stirring, for a sufficient period of time to obtain a useful amount of COBC. A
sufficient period of tirne may be from about 1 hour to about 24 hours, preferably an overnight period (about 8 to about 18 hours). One of ordinary skill in the art could easily monitor the reaction to determine whether a sufficient period of time has elapsed.
[44] The present invention also provides hydroxyl protected hydroxybenzylcyanide (POBC) of the following formula:
x CN
POBC
wherein X is a hydroxyl protecting group. The hydroxyl protecting group may be removed by deprotection.
[45] The hydroxyl group on the 4-hydroxybenzylcyanide (OBC) may be prepared by a process comprising combining OBC with a protecting reagent to form a reaction mixture, optionally in an organic solvent and in the presence of a catalyst, a base or both, to obtain the hydroxyl protected POBC.
[46] A suitable protecting agent can be any known hydroxyl protecting agent. Suitable hydroxyl protecting groups are listed in T.W. Greene, Protecting Groups in Organic Synthesis, (2 d Ed.), which is incorporated herein by reference.
Preferably, the hydroxyl protecting group can be a silyl, acetyl, or 3,4-dihydro-2H-puran (DHP). The silyl protecting group is preferably tert-butyldimethylsilyl (TBDMS). The protection reaction may be carried out at any suitable temperature depending on reagent used, preferably the temperature is between about 0 C to about 100 C, more preferably between about room temperature to about 55 C. A
preferred base added to the reaction mixture is selected from the group selected from imidazole, pyridine, triethylamine, lutidine, and dimethylaminopyridine. A catalyst may be added to the mixture, such as for example Pyridinium p-toluene sulfonate (PPTS).
[47] Preferably, POBC is substantially pure, preferably at least 95% pure, more preferably at least 99% pure.
[48] The present invention also provides hydroxyl protected cyclohexylbenzylcyanide (PCOBC). of the following formula:
ox H
CN
PCOBC
wherein X is as described above. Preferably, PCOBC is substantially pure, preferably at least 95% pure, more preferably at least 99% pure.
[491 In another embodiment, the present invention provides a process for preparing a hydroxyl protected COBC (PCOBC), according to the processes for preparing COBC, wherein the starting material 4-hydroxybenzylcyanide (OBC) is a hydroxyl protected OBC (POBC) as described in the scheme above.
[50] In another embodiment, the present invention provides a process for obtaining 0-desmethylvenlafaxine comprising preparing COBC or PCOBC in any of the methods described above, and further converting them to 0-desmethylvenlafaxine.
[51] In another embodiment of the process of the present invention 0-desmethyl venlafaxine, salts thereof or hydroxyl protected derivatives thereof may be prepared from hydroxybenzylcyanide by first protecting the hydroxyl group on the hydroxybenzylcyanide (OBC). The hydroxyl protected hydroxybenzylcyanide (POBC) may then be condensed with cyclohexanone to obtain a hydroxyl protected cyclohexylbenzylcyanide (PCOBC) which is reduced to form the hydroxyl protected tridesmethyl venlafaxine (PTDMV) and methylated to form a hydroxyl protected 0-desmethyl venlafaxine (PODV) as is shown in the schematic above.
[52] The protected POBC may be converted by any of the above processes to a hydroxyl protected PCOBC, which can be reduced to a hydroxyl protected PTDMV by a process described above, and the protected PTDMV may be methylated to obtain the hydroxyl protected PODV. Subsequently, the PODV is preferably deprotected with an appropriate deprotecting agent depending on the protecting group used. Preferably such deprotection agent can be an acid, such as for example methanesulfonic acid.
[53] The present invention also provides a process for preparing tridesmethyl venlafaxine (TDMV). TDMV may be prepared by reducing COBC.
Preferably, COBC is combined with a reducing agent in the presence of an organic solvent and/or a Lewis acid catalyst, preferably boron trifluoride (BF3) to create a reaction mixture. TDMV may be further recovered from the reaction mixture.
[54] In one embodiment, a solution of COBC, a reducing agent and an organic solvent are combined with a Lewis acid catalyst to obtain a reaction mixture, followed by recovery of the TDMV from the reaction mixture.
[55] Preferably, the solution of COBC, reducing agent and organic solvent is cooled prior to combining it with a Lewis acid catalyst. A preferred temperature to which the mixture is cooled is to a temperature of less than about 10 C, more preferably from about -10 C to about 10 C.
[56] A preferred Lewis acid catalyst is boron trifluoride (BF3). When BF3 is used, it is preferably added as a complex in ether (BF3Et2O), or else the complex may be formed in situ.
[57] In some embodiments, COBC may be prepared by precipitation from a mixture of hydroxybenzylcyanide (OBC), an organic solvent, a base and cyclohexanone; or from a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone.
[58] Preferably, the reducing agent is selected from the group consisting of:
sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiA1H4), L-selectride (lithium tri-sec-butylborohydride), and borane.
More preferably, the reducing agent is NaBH4.
[59] Alternatively, the reduction can be performed by hydrogenation in the presence of a catalyst, e.g. Ni, Co, Pd/C, or Pt catalyst.
[60] Preferably, the organic solvent is a dry organic solvent. The organic solvent is as described above. More preferably, the organic solvent is THF.
[61] Preferably, the reducing agent is present in an amount of about 1 to about 10 moles per mole of COBC, more preferably in an amount of about 4 to about moles per mole of COBC. A preferred amount of the Lewis acid catalyst, such as BF3, is an amount of about 1 to about 5 moles per mole of COBC, more preferably from about 2 to about 3 mole per mole of COBC.
[62] The reaction mixture in the process of the present invention may be maintained, preferably at a constant temperature, such as at room temperature, preferably while stirring, for a sufficient period of time to obtain TDMV. A
preferred period of time is from about 1 hour to about 24 hours, more preferably from about 3 hours to about 12 hours, even more preferably, from about 8 hours to about 10 hours.
[63] TDMV may then be recovered from the reaction mixture by any method known in the art. In one embodiment, recovery of TDMV from the reaction mixture comprises the steps of basifying and optionally extracting TDMV from the reaction mixture, preferably with ethylacetate, washing the obtained organic solution, preferably with water andlor brine, and drying to obtain= TDMV, preferably by evaporating the solvent for example under reduced pressure.
[64] The present invention also provides the hydroxyl protected tridesmethyl venlafaxine (PTDMV) of the following formula:
x OH
NHa PTDMV
wherein X is as described above. Preferably, PCOBC is substantially pure, preferably at least 95% pure, more preferably at least 99% pure.
[65] In another embodiment, the present invention provides a process for preparing hydroxyl protected tridesmethyl venlafaxine (PTDMV), according to the preparation of TDMV, wherein the starting material the hydroxyl protected PCOBC
as described above.
[66] In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising preparing TDMV or PTDMV as described above, and further converting them to 0-desmethylvenlafaxine.
[67] The conversion of TDMV to 0-desmethylvenlafaxine can be performed, for example as described in co-pending United States Patent Application No. --/-------- filed July 26, 2007, entitled "Processes for the Synthesis of Desmethylvenlafaxine"(Atty Docket No 1662/03304), which is incorporated herein by reference. For example, TDMV may be combined with an organic solvent and a methylating agent to form a mixture, and recovering the 0-desmethylvenlafaxine from the mixture. Also, TDMV may be subjected to selective reductive amination to produce 0-desmethylvenlafaxine ("ODV"). PTDMV is converted to PO-desmethylvenlafaxine in a similar manner.
[68] In another embodiment, the present invention provides a process for preparing 0-desmethylvenlafaxine comprising: reacting hydroxybenzylcyanide (OBC) with cyclohexanone, preferably the step of reacting with cyclohexanone comprises combining OBC, an organic solvent, a base and cyclohexanone;
reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and boron trifluoride (BF3).to create a reaction mixture;
recovering TDMV from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[69] In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: providing a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone, to obtain COBC; reducing COBC, preferably the step of reducing COBC comprises combining a reducing agent, an organic solvent and boron trifluoride (BF3) to create a reaction mixture; recovering TDMV from the reaction mixture and converting the TDMV to 0-desmethylvenlafaxine.
[70] In another embodiment of the present invention a hydroxyl protected 0-desmethyl venlafaxine (PODV) may be prepared by any of the above processes wherein the starting material is a hydroxyl protected intermediate as described above.
The present invention also provides the hydroxyl protected 0-desmethyl venlafaxine (PODV).
[71] The 0-desmethyl venlafaxine prepared by any of above process can be prepared in the form of a salt, preferably a succinate salt.
[72] . Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail the synthesis of the compound COBC, tridesmethyl venlafaxine and further their conversion to 0-desmethylvenlafaxine. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may. be practiced without departing from the scope of the invention.
EXAMPLES
HPLC Method:
Column & Packing: Zorbax SB C-18 4.6*250mm Part No.28105-020 or equivalent column Column Temperature: 25 C
Buffer Add 4.Oml of trifluoroacetic acid and 7.Oml of triethylamine to 1L of water adjust the pH to3.0 with triethylarnine.
Eluent:
ReservoirA 30 JoAcetonitrile and 70% Buffer Reservoir B To a mixture of 700m1 Acetonitrile and 300m1 buffer add 1.6m1 of trifluoroacetic acid and 2.9rn1 of triethylamine measure the pH it should be about 3_0 (correct the pH with triethylamine or trifluoroacetic acid if necessary).
Gradient Time Reservoir A Reservoir B
0 100% 0%
21 min 100% 0%
55 min 45% 55%
Equilibrium time: 10min Flow Rate: 1.0 ml/min Detector: 230 nm Sample Volume: 10 l Diluent: Eluent A
Mobile phase composition and flow rate may be varied in order to achieve the required system suitability.
Sample Preparation Weigh accurately about 10 mg of sample in a 20m1 amber volumetric flask.
Dissolve with eluent A.
Method Inject the sample solutions into the chromatograph, continuing the chromatogram of sample up to the end of the gradient. Determine the areas for each peak in each solution using a suitable integrator.
Calculation Impurity Profile Determination % impurity _ area impurity in sample x 100 Total area Preparation of COBC
Example 1:
A 100 ml, three necked flask equipped with Nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and THF (15 ml). This solution was cooled to -78 C and LDA (2M in THF, 16.5 ml, 33 mmol) was added slowly, keeping temperature under -65 C. A white solid precipitated during LDA
addition. Afler the end of the addition, the mixture was stirred for 30 minutes.
Cyclohexanone (1.62 g, 16.5 mmol) was then added, and the mixture continued in the same conditions for 5 hours. The reaction was quenched by pouring it into 100 ml of a saturated ammonium chloride solution containing ice.
The product was extracted to EtOAc (3x30 ml). The organic layer was washed with a saturated ammonium chloride solution and brine. Finally the solvent was evaporated under reduced pressure to get 3.5 g of a mixture of OBC (30%) and COBC
(60%) (Yield =60%).
This mixture was suspended in 10 ml methylene chloride, where a solid precipitated. The slurry was stirred at room temperature-for 2 hours, the solid filtered, washed with methylene chloride and vacuum dried at room temperature, to get 1.9g COBC (purity 99% by HPLC area, yield=55%).
Examgle 2:
A 100 ml, three necked flask equipped with Nitrogen inlet, thermometer and magnetic stirrer was charged with OBC (5g, 37.5 mmol) and DMSO (5 ml). The contents of the flask were stirred to complete dissolving (brown color). KOH
(3.2g, 56 mmol ) was added and the reaction mixture stirred vigorously (exothermic).
Cyclohexanone (5.52 g, 56 mmol) was then added dropwise. The reaction was quenched with HC1 5% and methylene chloride was added. The layers were separated and a solid precipitated. The solid was then filtered under reduced pressure and washed with a small amount of methylene chloride to yield 3.2g of COBC.
Example 3:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), toluene (15 ml) and DMF
(2ml). The reaction mixture was stirred at about room temperature (RT) until dissolution was complete and NaH (1.2g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise. The reaction was stirred at RT for an additional lhr to get 21% COBC (% area HPLC).
Example 4:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), THF (30 ml) and DMF
(2m1). The reaction mixture was stirred at RT until dissolution was complete and t-BuOK (3.3 g, 30 mmol) was added. Cyclohexanone (1.65 g, 16.8 mmol) was then added dropwise and the reaction was stirred at RT for an additiona13.5hrs to get 19%COBC (% area HPLC).
Example 5:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), THF (15 ml) and DMF
(2m1). The mixture was stirred at RT until complete dissolution and NaH (1.2g, mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise and the reaction was stirred at RT for and additional 2hrs to get 34%COBC (% area HPLC).
Example 6:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) MeOH (15 ml) and DMF
(2ml). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1.7g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was then added dropwise and the reaction was stirred at RT overnight to obtain 30% COBC
(%
area HPLC).
Example 7:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), MeOH (10 ml) and DMSO
(lOml). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1.7g, 30 mmol) was added. Cyclohexanone (1.7 g, 17.3 mmol) was added dropwise. The reaction was stirred at RT overnight to obtain 32% COBC ( 'o area HPLC).
Example 8:
A 100 ml, three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (l Ornl). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (2.65g, 47 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 10 min to get 43% COBC (% area HPLC).
Example 9:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (10m1). The reaction mixture was stirred at RT until complete dissolution and NaOCH3 (1 g, 17.6 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 45 min to get 55% of COBC (% area HPLC).
Example 10:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and DMSO (lOml). The reaction mixture was stirred at RT until complete dissolution and LiOH (1g, 23.8 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 8.5hrs to get 35% of COBC (% area HPLC).
Example 11:
A 100 ml three necked flask equipped with, thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), cyclohexanone (1.7 g, 17.3 mmol), TBAB (0.26g) and NaOH (6m1 10%). The reaction was stirred at RT overnight to .get 44% COBC (HPLC).
Example 12:
A 100 ml three necked flask equipped with nitrogen inlet, thennometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and THF (15m1). The reaction mixture was stirred at RT until complete dissolution and t-BuOLi (2g, mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 45min to get 19% COBC (% area HPLC).
Example 13:
A 100 ml three necked flask equipped with nitrogen inlet, thermometer,and mechanical stirrer was charged with OBC (2g, 15 mmol), THF(15m1) and DMF
(1.5m1). The reaction mixture was stiured at RT until complete dissolution and t-BuOLi (2.5g, 30 mmol) was added. Cyclohexanone (2 g, 20.37 mmol) was then added dropwise. The reaction was stirred at RT 1.15 hr to get 23.5% COBC (%
area HPLC).
Example 14:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2 g, 20.37 mmol), TBAB (0.5g) and NaOH (13m1 10%) were added. The reaction was stirred at RT
overnight to get 40%COBC (% area HPLC).
Examule 15:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2.2g, 22.4 mmol).
Water (l Oml), TBAB (0.3g) and KOH (1.9g, 30.5 mmol) were then added. The reaction was stirred at RT overnight to get 39% COBC (% area HPLC).
Examule 16:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol) and cyclohexanone (2.2g, 22.4 mmol).
Water (10m1), TBAB(0.3gr) and LiOH (2g, 47.6mmo1) were then added. The reaction was stirred at RT overnight to get 39% COBC (% area HPLC)_ Example 17:
A 100 ml three necked flask equipped with thermometer and mechanical stirrer was charged with OBC (2g, 15 mmol), DMA (10m1) and LiOH (2g, 47.7 mmol). Cyclohexanone (2.2g, 22:4 mmol) was then added dropwise. The reaction mixture was stirred at RT overnight to get 10% COBC (% area HPLC).
Preparation of TDMV
Example 18:
A100 ml three necked flask equipped with nitrogen inlet thenmometer and mechanical stirrer was charged with COBC (2 g, 8.64 mmol), MeOH (50 ml) and CoCl anhydrous (2.25 g, 17.32 mmol). The resulting solution was cooled to-10 C
with an ice-bath. NaBH4 (3.35 g, 88.62mmol) was added portionwise at this temperature. The ice-bath was removed one hour after the end of addition.
The reaction mixture was stirred 3 hours at room temperature and then quenched with 10%HCI. MeOH was removed under reduced pressure and the aqueous phase was basified with ammonium hydroxide (25%) and extracted with EtOAc. The organic phase was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get 0.4 g of TDMV.
Example 19:
A 100 ml three necked flask equipped with nitrogen inlet thermometer and mechanical stirrer was charged with NaBH4 (1.2 g, 31.74 mmol) THF (lOml).
This solution was cooled to10 C with an ice-bath. BF3Et2O (3.95g, 27.86mmol) and COBC (2 g, 8.64 mmol) were then added. The reaction mixture was stirred at room temperature overnight.
The reaction mixture was quenched with formic acid and water. The organic phase was basified with NaOH (25%), washed with water and evaporated under reduced pressure to get TDMV.
Preparation of O-desmethylvenlafaxine Example 20:
TDMV (0.5 g, 2.12 mmol) was suspended in CH2C12. Methyl iodide (0.26 ml, 4.3 mmol) and triethylamine (0.66 ml, 4.73 mmol) were added. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 6 hours. At this stage methyl iodide (0.5 ml) and NEt3 (1.2 ml) were added. The addition caused the temperature to rise. After 16 hours, BPLC analysis indicated the presence of ODV.
Preparation of POBC
Example 21: Preparation of OBC-DHP
OBC (0.5g, 3.7 mmol) was dissolved at room temperature in 3,4-dihydro-2H-pyran (DHP) (approx. 2 ml) under N2. Pyridinium p-toluene sulfonate (PPTS, catalytic amount) was added and heated to 55 C for 45 min. The end of reaction was determined by TLC (eluent EtOAc:Hex 1:1). The product was extracted in EtOAc, washed with brine and dried over MgSO4. A pale yellow powder was obtained (0.74g, purity= 98% by area % of HPLC, yield= 91%) Example 22: Preparation of OBC-TBDMS
OBC (5g, 37 mmol), 11 g of TBDMS-Cl, 12g of imidazole and 25m1 of CH2Cla were stirred together for 2 hours at ambient temperature under N2 atmosphere.
The product was washed with brine, a 10% aqueous solution of citric acid, brine and dried over MgSO4. After removal of the solvent 4g of product was obtained.
Preparation of PCOBC
Example 23: Preparation of COBC-DHP
OBC-DHP (0.74g, 3.4 mmol), cyclohexanone (0.5 g), TBAB (0.15g) and a 10% aqueous solution of NaOH (4 ml) were mixed and stirred at room temperature, forming two phases. After 30 minutes of stirring, the organic phase was analyzed by HPLC, containing 46% COBC-DHP and 48% unreacted OBC-DHP.
Example 24:
OBC-DHP (3.25g, 15 mmol) was dissolved in dry THF under N2 and cooled to -80 C. LDA 2M in THF/heptane/ethyl benzene (8 ml, 16 mmol) was added dropwise, keeping the temperature under -60 C. The mixture was stirred at -80 C for 30 minutes. Cyclohexanone (1.65g, 16.5 mmol) was added dropwise. After 1 hour stirring a sample was analyzed by HPLC, containing 41% COBC-DHP and 42%
unreacted OBC-DHP.
Preparation of PTDMV
Example 25:
A 100 ml three necked flask equipped with nitrogen inlet thermometer and mechanical stirrer is charged with PCOBC (8.64 mmol), MeOH (50 ml) and CoCI
anhydrous (17.32 mmol). The resulting solution is cooled to-10 C with an ice-bath.
NaBH4 (88.62mmol) is added portionwise at this temperature. The ice-bath is removed one hour after the end of addition.
The reaction mixture is stirred 3 hours at room temperature and then quenched with 10%HCI. MeOH is removed under reduced pressure and the aqueous phase is basified with ammonium hydroxide (25%) and extracted with EtOAc. The organic phase is washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to get PTDMV.
Example 26:
A 100 ml three necked flask-equipped with nitrogen inlet thermometer and mechanical stirrer is charged with NaBH4 (31.74 mmol) and THF (lOml).
This solution is cooled to10 C with an ice-bath. BF3Et2O (27.86nunol) and PCOBC
(8.64 mmol) are then added. The reaction mixture is stirred at room temperature overnight.
The reaction mixture is quenched with formic acid and water. The organic phase is basified with NaOH (25 Jo), washed with water and evaporated under reduced pressure to get PTDMV.
Preparation of PODV
Exarnple 27:
P-TDMV (2.12 mmol) is suspended in CH2Cl2. Methyl iodide (4.3 mmol) and triethylamine (4.73 mmol) are added. The reaction mixture is stirred under nitrogen atmosphere at room temperature for 6 hours. At this stage methyl iodide (0.5 ml) and NEt3 (1.2 ml) are added. After 16 hours, HPLC analysis indicated the presence of PODV.
Preparation of 0-desmethylvenlafaxine Example 28:
PODV (2.12 mmol) is suspended in THF in presence of methanesulfonic acid (6 mmol).The reaction is stirred at ambient temperature overnight. To the mixture so-obtained is first added EtOAc and the organic phase is washed with brine, Na2CO3 saturated and water. The organic phase is then concentrated under reduced pressure to get ODV.
Claims (87)
1. Cyclohexylbenzylcyanide (COBC) of the following formula
2. The cyclohexylbenzylcyanide compound of claim Error! Reference source not found.1, wherein the cyclohexylbenzylcyanide is at least 95% pure.
3. A process of preparing cyclohexylbenzylcyanide (COBC) of claim 1 or claim 2 comprising reacting hydroxybenzylcyanide (OBC) with cyclohexanone.
4. The process of claim 3, wherein the reaction comprises combining OBC, an organic solvent, a base and cyclohexanone.
5. The process of claim 4, wherein the organic solvent is selected from the group consisting of: C2-8 ethers, polar aprotic solvents, aromatic hydrocarbons, C1-
6 alcohols, and acetonitrile.
6. The process of claim 5, wherein the organic solvent is selected from the group consisting of diisopropyl ether, diethylether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), toluene, xylene, benzene, methanol, ethanol, isopropanol, butanol and acetonitrile.
6. The process of claim 5, wherein the organic solvent is selected from the group consisting of diisopropyl ether, diethylether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), toluene, xylene, benzene, methanol, ethanol, isopropanol, butanol and acetonitrile.
7. The process of claim 6, wherein the organic solvent is selected from the group consisting of: diisopropyl ether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), xylene, benzene, methanol, ethanol, isopropanol, butanol and acetonitrile.
8. The process of claim 7, wherein the organic solvent is selected from the group consisting of: THF, DMF, DMA, and DMSO.
9. The process of any of claims 4 to 8, wherein the organic solvent is a dry organic solvent.
10. The process of any of claims 3 to 9, wherein the cyclohexanone is present in an amount of about 1 to about 2 moles per mole of OBC.
11. The process of claim 10, wherein the cyclohexanone is present in an amount of about 1.1 to about 1.5 moles per mole OBC.
12. The process of any of claims 4 to 11, wherein the base is an inorganic base.
13. The process of any of claims 4 to 11, wherein the base is selected from the group consisting of: lithium diisopropyl amide (LDA), lithium bis (trimethyl silyl) amide (LiN[(CH3)3Si]2), sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (CsOH), sodium hydride (NaH), potassium hydride (KH), cesium hydride (CsH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium metoxide (NaOMe).
14. The process of any of claims 4 to 13, wherein the base is present in an amount of about 1 to about 5 moles per mole of OBC.
15. The process of claim14, wherein the base is present in an amount of about 1.5 to about 3.5 moles per mole of OBC.
16. The process of any of claims 4 to 15, wherein the combining step comprises combining a solution or a slurry of OBC, the organic solvent and the base, followed by combining the obtained reaction mixture with cyclohexanone.
17. The process of claim 16, wherein the cyclohexanone is added to the reaction mixture in a dropwise manner.
18. The process of any of claims 4 to 17, wherein the reaction mixture is maintained for a period of at least 10 minutes.
19. The process of claim 18, wherein the period is from about 1 hour to about hours.
20. The process of claim 19, wherein the mixture is maintained at a temperature of about -40°C to about 35°C.
21. The process of any of claims 3 to 20, comprising reacting OBC and cyclohexanone in the presence of a phase transfer catalyst and a base.
22. The process of claim 21, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium hydrogensulphate, a tetraalkylammonium halide wherein the alkyl group can be the same or different and contains from 1 to 6, benzyltriethyl ammonium chloride, a quaternary ammonium salt, a quaternary phosphonium salt and a crown ether.
23. The process of claim 22, wherein the phase transfer catalyst is tetrabutyl ammonium bromide (TBAB).
24. The process of any of claims 21 to 23, wherein the base is an inorganic base.
25. The process of any of claims 21 to 23, wherein the base is selected from the group consisting of: NaOH, KOH, LiOH, CsOH, K2CO3, Na2CO3, Cs2CO3, sodium metoxide (NaOMe), and sodium ethoxide (NaOEt).
26. The process of any of claims 21 to 25, wherein the base is present in an amount of about 0.5 to about 3 mole per mole of OBC.
27. The process of claim 26, wherein cyclohexanone is present in an amount of about 1 to about 2 moles per mole of OBC.
28. The process of any of claims 21 to 27, wherein the reaction mixture is maintained for a sufficient period of time to obtain COBC.
29. The process of claim 28, wherein the period of time is from about 1 hour to about 24 hours.
30. The process of claim 29, wherein the period of time is from about 8 hours to about 18 hours.
31. The process of claim 30, wherein the mixture is maintained at a temperature of about -40°C to about 35°C.
32. The process of any of claims 3 to 31, further comprising converting COBC
to O-desmethylvenlafaxine or a salt thereof.
to O-desmethylvenlafaxine or a salt thereof.
33. The process of claim 32, wherein the O-desmethyl vanlafaxine salt is a succinic acid salt.
34. The process of any of claims 3 to 33, wherein the hydroxybenzylcyanide (OBC) is a hydroxyl protected hydroxybenzylcyanide (POBC) to obtain hydroxyl protected cyclohexylbenzylcyanide (PCOBC).
35. Hydroxyl protected hydroxybenzylcyanide (POBC) of the following formula:
wherein X is a hydroxyl protecting group.
wherein X is a hydroxyl protecting group.
36. The hydroxyl protected hydroxybenzylcyanide (POBC) of claim 35, wherein the protecting reagent is selected from the group consisting of dihydropuran and TBDMS.
37. The hydroxyl protected hydroxybenzylcyanide (POBC) of any of claims 35 or 36, having a purity of at least 95%.
38. A process for preparing the hydroxyl protected hydroxybenzylcyanide (POBC) of any of claims 35 to 37 comprising combining OBC with a protecting reagent.
39. Hydroxyl protected cyclobenzylcyanide (PCOBC) of the following formula:
wherein X is a hydroxyl protecting group.
wherein X is a hydroxyl protecting group.
40. The hydroxyl protected cyclobenzylcyanide of claim 39, wherein the protecting reagent is selected from the group consisting of dihydropuran and TBDMS.
41. The hydroxyl protected cyclobenzylcyanide (PCOBC) of any of claim 39 or 40, having a purity of at least 95%.
42. A process of preparing the hydroxyl protected cyclobenzylcyanide (PCOBC) of any of claims 39 to 41 comprising reacting hydroxyl protected hydroxybenzylcyanide (POBC) with cyclohexanone.
43. The process of claim 42, wherein the reaction comprises combining POBC, an organic solvent, a base and cyclohexanone.
44. The process of claim 42, comprising reacting POBC and cyclohexanone in the presence of a phase transfer catalyst and a base.
45. The process of any of claims 42 to 44, further comprising converting PCOBC
to O-desmethylvenlafaxine or a salt thereof.
to O-desmethylvenlafaxine or a salt thereof.
46. The process of claim 45, wherein the O-desmethylvenlafaxine salt is a succinic acid salt.
47. A process for preparing tridesmethyl venlafaxine (TDMV) comprising reducing COBC.
48. The process of claim 47, wherein the reduction of COBC comprises combining COBC with a reducing agent, an organic solvent and a Lewis acid catalyst.
49. The process of claim 48, wherein the combining step comprises combining COBC, a reducing agent and an organic solvent to form a solution, followed by combining the solution with the Lewis acid catalyst.
50. The process of claim 49, wherein the solution is cooled to a temperature less than about 10°C prior to combining the solution with the Lewis acid catalyst.
51. The process of any of claims 48 to 50, wherein the Lewis acid catalyst is boron trifluoride (BF3).
52. The process of any of claims 48 to 51, wherein the reducing agent is selected from the group consisting of: sodium borohydride (NaBH4), lithium borohydride (LiBH4), lithium aluminum hydride (LiAlH), L-selectride, and borane.
53. The process of claim 52, wherein the reducing agent is NaBH4.
54. The process of any of claims 48 to 53, wherein the organic solvent is selected from the group consisting of: C2-8 ethers, polar aprotic solvents, aromatic hydrocarbons, and C1-6 alcohols, and acetonitrile.
55. The process of claim 54, wherein the organic solvent is selected from the group consisting of: diisopropyl ether, dioxane, tetrahydrofuran (THF), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), xylene and benzene.
56. The process of claim 55, wherein the organic solvent is THF.
57. The process of any of claims 48 to 56, wherein the organic solvent is a dry organic solvent.
58. The process of any of claims 48 to 57, wherein the reducing agent is present in an amount of about 1 to about 10 moles per mole- of COBC and the Lewis acid catalyst is BF3, present in an amount of about 1 to about 5 moles per mole of COBC.
59. The process of any of claims 48 to 58, wherein the reaction mixture is maintained for a sufficient period of time to obtain TDMV.
60. The process of claim 59, wherein the period of time is from about 1 hour to about 24 hours.
61. The process of claim 60, wherein the mixture is maintained at a temperature of about 15°C to about 35°C.
62. The process of any of claims 47 to 61, wherein the reduction is carried out by hydrogenation in the presence of a catalyst.
63. The process of claim 62, wherein the catalyst is a Ni, Co, Pd/C, or Pt catalyst.
64. The process of any of claims 47 to 63, further comprising converting TDMV
to O-desmethylvenlafaxine or a salt thereof.
to O-desmethylvenlafaxine or a salt thereof.
65. The process of claim 64, wherein the O-desmethylvenlafaxine salt is a succinic acid salt.
66. Hydroxyl protected tridesmethyl venlafaxine (PTDMV) of the following formula:
wherein X is a hydroxyl protecting group.
wherein X is a hydroxyl protecting group.
67. The hydroxyl protected tridesmethyl venlafaxine of claim 66, wherein the protecting group is selected from the group consisting of dihydropuran and TBDMS.
68. The hydroxyl protected tridesmethyl venlafaxine (PTDMV) of any of claim 66 or 67, having a purity of at least 95%.
69. A process of preparing the hydroxyl protected tridesmethyl venlafaxine (PTDMV) of any of claims 66 to 68 comprising reducing PCOBC.
70. The process of claim 69, further comprising converting PTDMV to O-desmethylvenlafaxine or a salt thereof.
71. The process of claim 70, wherein the O-desmethylvenlafaxine salt is a succinic acid salt.
72. A process of preparing O-desmethyl venlafaxine (ODV) comprising:
a) reacting hydroxybenzylcyanide (OBC) with cyclohexanone to obtain cyclohexylbenzylcyanide (COBC);
b) reducing the cyano group of COBC to obtain tri-desmethyl venlafaxine (TDMV); and c) converting TDMV to ODV.
a) reacting hydroxybenzylcyanide (OBC) with cyclohexanone to obtain cyclohexylbenzylcyanide (COBC);
b) reducing the cyano group of COBC to obtain tri-desmethyl venlafaxine (TDMV); and c) converting TDMV to ODV.
73. The process of claim 72, wherein the reaction of step a) comprises combining OBC, an organic solvent, a base, and cyclohexanone.
74. The process of claim 72, wherein the reaction of step a) comprises providing a mixture of hydroxybenzylcyanide (OBC), a phase transfer catalyst, a base and cyclohexanone, to obtain COBC.
75. The process of any of claims 72 to 74, wherein reducing COBC in step b) comprises combining COBC with a reducing agent, an organic solvent and a Lewis acid catalyst to create a reaction mixture.
76. The process of claim 75, wherein the Lewis acid catalyst is boron fluoride (BF3).
77. The process of any of claims 72 to 76, wherein converting TDMV to ODV
comprises selectively alkylating TDMV.
comprises selectively alkylating TDMV.
78. The process of claim 77, wherein converting TDMV to ODV comprises combining TDMV with a methylating agent.
79. The process of claim 78, wherein converting TDMV to ODV is in the presence of a base.
80. The process of claim 79, wherein the base is triethylamine.
81. The process of any of claims 72 to 80, further comprising converting ODV
to a ODV salt.
to a ODV salt.
82. The process of claim 81, wherein the ODV salt is succinic acid salt.
83. A process of preparing O-desmethyl venlafaxine (ODV) comprising combining hydroxybenzylcyanid (OBC) with a protecting reagent to obtain a hydroxyl protected hydroxybenzylcyanide (POBC), reacting POBC with cyclohexanone to obtain hydroxyl protected cyclohexylbenzylcyanide-(PCOBC), reducing PCOBC to obtain hydroxyl protected tridesmethyl venlafaxine (PTDMV), converting PTDMV to hydroxyl protected O-desmethylvenlafaxine (PODV), and deprotecting PODV to form ODV.
84. The process of claim 83, wherein OBC and the protecting reagent are provided in a mixture further comprising an organic solvent, a catalyst, a base or a mixture thereof.
85. The process of any of claims 83 or 84, wherein the protecting reagent is selected from the group consisting of dihydropuran and TBDMS-Cl.
86. Use of OBC or COBC, either in a hydroxyl protected or unprotected form, in a process for the preparation of TDMV or for the preparation of O-desmethylvenlafaxine (ODV).
87. Use of PTDMV for the preparation of O-desmethylvenlafaxine (ODV).
Applications Claiming Priority (15)
Application Number | Priority Date | Filing Date | Title |
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US83361606P | 2006-07-26 | 2006-07-26 | |
US60/833,616 | 2006-07-26 | ||
US83787906P | 2006-08-14 | 2006-08-14 | |
US60/837,879 | 2006-08-14 | ||
US84399806P | 2006-09-11 | 2006-09-11 | |
US60/843,998 | 2006-09-11 | ||
US84921606P | 2006-10-03 | 2006-10-03 | |
US84925506P | 2006-10-03 | 2006-10-03 | |
US60/849,255 | 2006-10-03 | ||
US60/849,216 | 2006-10-03 | ||
US90663907P | 2007-03-12 | 2007-03-12 | |
US60/906,639 | 2007-03-12 | ||
US90687907P | 2007-03-13 | 2007-03-13 | |
US60/906,879 | 2007-03-13 | ||
PCT/US2007/017009 WO2008013993A2 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of o-desmethylvenlafaxine |
Publications (1)
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CA2656166A1 true CA2656166A1 (en) | 2008-01-31 |
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ID=39750811
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CA002656166A Abandoned CA2656166A1 (en) | 2006-07-26 | 2007-07-26 | Processes for the synthesis of o-desmethylvenlafaxine |
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JP (1) | JP4763788B2 (en) |
CA (1) | CA2656166A1 (en) |
IL (1) | IL196405A0 (en) |
WO (1) | WO2008013993A2 (en) |
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CN109012737B (en) * | 2018-06-19 | 2021-09-17 | 陕西蒲城万德科技有限公司 | Catalytic synthesis method of antidepressant drug intermediate |
Family Cites Families (17)
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US3494954A (en) * | 1967-06-19 | 1970-02-10 | Cutter Lab | 3,3-bis(phenyl)-2-(4-hydroxyphenyl)acrylonitriles |
JPS57149257A (en) * | 1981-03-13 | 1982-09-14 | Nissan Chem Ind Ltd | 4-benzyloxyphenylacetamide |
ZA839073B (en) * | 1982-12-13 | 1984-09-26 | American Home Prod | Phenethylamine derivatives and intermediates therefor |
IE56324B1 (en) * | 1982-12-13 | 1991-06-19 | American Home Prod | Phenethylamine derivatives and intermediates therefor |
JPH10204057A (en) * | 1997-01-27 | 1998-08-04 | Tosoh Corp | Halogenated thioformate derivative and its production |
US6197828B1 (en) * | 1998-12-01 | 2001-03-06 | Sepracor, Inc. | Derivatives of (+)-venlafaxine and methods of preparing and using the same |
EP1905757A1 (en) * | 1999-04-06 | 2008-04-02 | Sepracor Inc. | Derivatives of Venlafaxine and methods of preparing and using the same |
TWI228118B (en) * | 2000-08-30 | 2005-02-21 | Ciba Sc Holding Ag | Process for the preparation of substituted phenylacetonitriles |
EP1343750B1 (en) * | 2000-12-20 | 2005-01-26 | Ciba SC Holding AG | Process for the preparation of phenethylamine derivatives |
DE10065442A1 (en) * | 2000-12-27 | 2002-07-04 | Bayer Ag | Improved process for the preparation of 2- (4-trifluoromethoxyphenyl) ethylamine and 4-bromomethyl and 4-chloromethyl-1-trifluoromethoxy-benzene |
US6673838B2 (en) * | 2001-02-12 | 2004-01-06 | Wyeth | Succinate salt of O-desmethyl-venlafaxine |
US6504044B2 (en) * | 2001-02-28 | 2003-01-07 | Council Of Scientific And Industrial Research | Process for the preparation of 1-[cyano(aryl)methyl] cyclohexanol |
KR20030000217A (en) * | 2001-06-22 | 2003-01-06 | 와이어쓰 | Process for the preparation of cyclohexanol derivatives |
UA80543C2 (en) * | 2001-12-04 | 2007-10-10 | Wyeth Corp | Method for the preparation of o-desmethylvenlafaxine |
CN1232501C (en) * | 2002-11-29 | 2005-12-21 | 重庆凯林制药有限公司 | Preparing technology for cyclohexanol derivatives used to prepare the intermediate of Venlafaxine |
CN101238094A (en) * | 2005-06-29 | 2008-08-06 | Wyeth公司 | Process for the preparation of 1-[cyano(4-hydroxyphenyl)methyl]cyclohexanol compounds |
EP1870395A1 (en) * | 2006-06-19 | 2007-12-26 | KRKA, D.D., Novo Mesto | Process for preparation of o-desmethylvenlafaxine and its analogue |
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- 2007-07-26 CA CA002656166A patent/CA2656166A1/en not_active Abandoned
- 2007-07-26 JP JP2008527229A patent/JP4763788B2/en not_active Expired - Fee Related
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JP2008545807A (en) | 2008-12-18 |
WO2008013993A3 (en) | 2008-04-10 |
WO2008013993A2 (en) | 2008-01-31 |
IL196405A0 (en) | 2009-11-18 |
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