Sign In to Follow Application
View All Documents & Correspondence

"Processes For The Synthesis Of O Desmethylvenlafaxine"

Abstract: Provides are intermediates and processes for preparation of o- desmethylvenlafaxine.

Get Free WhatsApp Updates!
Notices, Deadlines & Correspondence

Patent Information

Application #
Filing Date
22 December 2008
Publication Number
12/2009
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application

Applicants

TEVA PHARMACEUTICALS INDUSTRIES LTD
5 BASEL STREET, P.O. BOC 3190, PETAH TIQVA 49131, ISRAEL.

Inventors

1. VALERIE NIDDAM-HILDESHEIM
P.O.BOX 3948, 60920 KADIMA, ISRAEL.
2. TAMAR NIDAM
RECHOV WEIZMAN 53/40, 56238 YEHUD, ISRAEL.

Specification

PROCESSES FOR THE SYNTHESIS OF O-DESMETHYLVENLAFAXINE CROSS REFERENCE TO RELATED APPLICATIONS [0001] 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 March 13, 2007. The contents of these applications are incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention encompasses a process for the synthesis of O- desmethylvenlafaxine. BACKGROUND OF THE INVENTION [0003] Venlafaxine, (±)-l-[2-(Dimethylamino)-l-(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 antidepressants and selective re-uptake inhibitors. Venlafaxine has the following chemical formula, Formula I: (Formula Removed) [0004] O-desmethylvenlafaxine, 4-[2-(dimethylamino)-l-(l- hydroxycyclohexyl)ethyl]phenol, is reported to be a metabolite of venlafaxuie and has been reported to inhibit norepinephrine and serotonin uptake. See Klameras, K. J. et al., "Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite," J. Clin. Pharmacol. 32:716-724 (1992). O-desmethylvenlafaxine has the following chemical formula, Formula II: (Formula Removed) [0005] Processes for the synthesis of O-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. [0006] The synthesis disclosed in the above references is performed according to the following scheme. (Formula Removed) Wherein "MBC" refers to methyl benzyl cyanide, "CMBC" refers to cyclohexyl methylbenzyl cyanide, "DDMV" refers to didesmethyl venlafaxine, and "ODV" refers to O-desmemylvenlafaxine. [0007] However, the processes disclosed in the above US patents and US patent applications all remain problematic when applied to industrial scale production. The process in US Patent No. 7,026,508 uses L-selectride, a compound which is very problematic when scaling up the process for industrial application. Further, the process disclosed in US Application Publication No. 2005/0197392 uses lithiumdiphenyl phosphine, a compound which handling and use in industrial scale processes is extremely dangerous. Also, the process disclosed in 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. [0008] There is a need in the art for a new synthetic route for obtaining sO- desmethylvenlafaxine, using a precursor of venlafaxine to directly obtain O-desmethylvenlafaxine. SUMMARY OF THE INVENTION [0009] In one embodiment, the invention encompasses (4-bromophenyl)(l- hydroxycyclohexyl)acetonitrile(CBBC). [00010] In one embodiment the present invention provides a process for preparing CBBC comprising reacting BBC with cyclohexanone. [00011] In another embodiment, the present invention provides a process for preparing (4-bromophenylXl-hydroxycyclohexyl)acetonitrile (CBBC) comprising precipitating CBBC from a mixture of: bromophenylacetonitrile (BBC), a dry organic solvent, a base and cyclohexanone. [00012] In another embodiment, the present invention provides a process for obtaining (4-bromophenyl)(l-hydroxycyclohexyl)acetonitrile (CBBC) from a mixture of bromophenylacetonitrile (BBC), a phase transfer catalyst, a base and cyclohexanone. [00013] In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing CBBC in any of the methods described above, and farther converting the CBBC to O-desmethylvenlafaxine. [00014] In another embodiment, the invention encompasses l-[2-amino-l-(4- bromophenyl)ethyl]cyclohexanol (BDDMV). [00015] In another embodiment, the present invention provides a process for preparing l-[2-amino-l-(4-bromophenyl)ethyl]cyclohexanol (BDDMV) comprising: combining CBBC, an organic solvent and borane to create a reaction mixture, followed by recovery of the BDDMV from the reaction mixture. [00016] In another embodiment, the present invention provides a process for obtaining O-desmetaylvenlafaxine comprising preparing BDDMV as described above, and further converting the BDDMV to O-desmethylvenlafaxine. [00017] In another embodiment, the invention encompasses l-[l-(4- bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). [00018] In another embodiment, the present invention provides a process for preparing 1 -{l-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanoI (BODV) comprising: combining BDDMV, formaldehyde and a reducing agent to create a reaction mixture, followed by recovery of the BODV from the reaction mixture. [00019] In another embodiment, the present invention provides a process for preparing l-[l-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV) comprising: combining BDDMV, an organic solvent, and a methylatmg agent to form a mixture, and recovering the BODV from the mixture. [00020] In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV in any of the methods described above, and further converting the BODV to O-desmethylvenlafaxine. [00021] In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV, a hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture. [00022] In another embodiment, the present invention provides a process for converting BODV to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction. [00023] In one embodiment the present invention provides a process for preparing O-desmethylvenlafaxine comprising combining BODV with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocupxate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine. [00024] In another embodiment, the invention encompasses hydroxyprotected-l-[l-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV-P). [00025] In another embodiment, the present invention provides a process for preparing hydroxyprotected-l-[l-(4-bromophenyl)-2- (dimemylamiiio)ethyl]cyclohexanol (BODV-P) comprising: combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture. [00026] In another embodiment, the present invention provides a process for obtaining O-desmethylvenlafaxine comprising preparing BODV-P as described above, and further converting the BODV-P to O-desmethylvenlafaxine. [00027] In another embodiment, the present invention provides a process for converting BODV-P to O-desmethylvenlafaxine, using a Grignard reaction or organocuprate reaction. [00028] In another embodiment, the present invention provides a process for preparing O-desmethylvenlafaxine comprising: combining BODV-P, hydroxide donor base and a metal salt to create a reaction mixture, followed by recovery of the O- desmethylvenlafaxine from the reaction mixture. [00029] The present invention further provides processes for preparing O- desmethylvenlaiaxine via the intermediates described above. DETAILED DESCRIPTION OF THE INVENTION [00030] The invention encompasses a new synthetic route for obtaining O- desmethylvenlafaxine, from 4-bromophenylacetonitrile (BBC), (4-bromophenyl)(l- hydroxycyclohexyi)acetonitriIe (CBBC), l-[2-amino-l-(4- bromophenyl)ethyl]cyclohexanol (BDDMV), l-[l-(4-bromophenyl)-2- (dimethylamino)ethyljcyclohexanol (BODV) and hydroxyprotected-l-[l-(4- bromophenyl)-2-(dimethylamino)ethyl] cyclohexanol (BODV-P). [00031] In the process of the invention, the intermediate bromophenylacetonitrile (BBC) is condensed with cyclohexanone to form the intermediate (4-bromophenyl)(l-hydroxycyclohexyl)acetonitrile (CBBC). Further, the cyano group on the CBBC is subjected to reduction, to form the intermediate l-[2- amino-l-(4-bronw|>henyl)e potassium hydroxide (KOH), lithium hydroxide (LiOH), sodium hydride (NaH), potassium tert butoxide (t-BuOK), lithium tert butoxide (t-BuOLi), butyl lithium (BuLi) and sodium methoxide (NaOCH3). 12. The process of any one of claims 5-11, wherein the process is carried out by combining a solution or a slurry of BBC and a dry organic solvent with a base to obtain a reaction mixture, followed by combining the reaction mixture with cyclohexanone, to obtain CBBC. 13. The process of any one of claims 5-12, further comprising recovering CBBC. 14. The process of any one of claims 13, wherein recovery comprises evaporating the solvent, dissolving the residue in a water immiscible solvent such as toluene, washing with water or brine, and evaporated to get a residue. 15. The process of any one of claims 13-14, further comprising crystallizing CBBC from the residue. 16. The process of any one of claims 4-15, wherein the process comprises combining bromophenylacetonitrile (BBC), a phase transfer catalyst, optionally a base and cyclohexanone. 17. The process of claim 16, wherein the reaction occurs in the presence of water. 18. The process of any one of claims 16-17, wherein the phase transfer catalyst is a tetraalkylammonium, tetraalkylphosphoiuum, tetraarylanimonium or tetraarylphosphonium, wherein the alkyl group can be the same or different and contains from 1 to 10 carbons, and wherein the aryl group can be the same or different and contains from 6 to 8 carbons 19. The process of any one of claims 16-17, wherein the phase transfer catalyst is selected from the group consisting of: tetrabutylammonium hydrogensulphate, tetrabutylammonium bromide, tetrabutylammormirn chloride, tetrabutylammonium iodide, benzyltriethyl ammonium chloride, aliquot, quaternary ammonium salt, quaternary phosphonium salt and crown ether. 20. The process of any one of claims 16-18, wherein the phase transfer catalyst is tetra butyl ammonium bromide (TBAB). 21. The process of any one of claims 5-20, wherein the base is an alkali metal or alkaline earth metal hydroxide or carbonate. 22. The process of any one of claims 16-21, wherein the base is NaOH, KOH, LiOH, CsOH, K2CO3, NaCOs or Cs2CO3 23. A process for preparing O-desmethylvenlafaxine comprising preparing CBBC as described in any one of claims 4-22, and further converting the CBBC to O-desmethylvenlafaxine. 24. l-[2-amino-l-(4-bromophenyl)ethyl]cyclohexanol (BDDMV). 25. The compound of claim 24, wherein the compound is in isolated or purified form. 26. The compound of any one of claims 24-25, wherein the compound has a purity of at least about 50% as measured by HPLC. 27. A process for preparing a compound according to any of claims 24 to 26 comprising reacting CBBC with a reducing agent. 28. The process of claim 27, comprising combining CBBC and an organic solvent to obtain a solution, and adding a reducing agent to the solution. 29. The process of claim 28, wherein the solvent is a dry organic solvent. 30. The process of any one of claims 28-29, wherein the reducing agent is Borane or hydride. 31. The process of claim 30, wherein the reducing agent is Borane dimeflrylsulfide. 32. The process of any one of claims 28-29, wherein the reducing agent is Kb in presence of catalyst such as Ni, Co or Pt. 33. The process of any one of claims 27-32, wherein the solvent is tetrahydrofuran (THF). 34. The process of claim 31, wherein the borane is present in an amount of about 1 to about 3 moles per mole of CBBC. 35. The process of any one of claims 27-34, further comprising quenching, acidifying resulting organic layer, and extracting CBBC from the organic layer. 36. The process of any one of claims 27-35, further comprising drying the organic layer over Na2SO4 or under a pressure of less than one atmosphere, or both. 37. A process for preparing O-desmethylvenlafaxine, comprising preparing BDDMV as described in any one of claims 27-36, and further converting the BDDMV to O-desmethylvenlafaxine. 38. l-[l-(4-bromophenyl)-2-(dimethylamino)ethyl]cyclohexanol (BODV). 39. The compound of claim 38, wherein BODV is in isolated or purified form. 40. The compound of any one of claims 38-39, wherein BODV has a purity of at least about 50% as measured by HPLC. 41. A process for preparing the compound of any one of claims 38-40 comprising combining BDDMV, formaldehyde and a reducing agent. 42. The process of claim 41, wherein BDDMV is dissolved or suspended in an organic solvent, preferably a C1-6 alcohol such as MeOH, followed by addition of formaldehyde and the reducing agent. 43. The process of any one of claims 41-42, wherein the reducing agent is NaBH4. 44. The process of any one of claims 41 -42, wherein the reducing agent is formic acid. 45. The process of any one of claims 41-44, further comprising recovering BODV from an organic solvent. 46. The process of any one of claims 41-45, wherein recovery comprises evaporating the organic solvent to obtain a residue, optionally dissolving the residue in a second organic solvent, acidifying, evaporating the second organic solvent. 47. A process for preparing the compound of claim 38 comprising combining BDDMV, an organic solvent, and a methylating agent. 48. The process of claim 47 wherein the process comprises optionally dissolving BDDMV in an organic solvent to obtain a solution, adding a base and a methylating agent to the solution to obtain BODV. 49. The process of any one of claims 47-48, wherein the solvent is dichloromethane or dimethylsulfoxide, THF, ACN or toluene. 50. The process of any one of claims 48-49 wherein the base is BuLi or a C3-C9 trialkylamine. 51. The process of claim 50, wherein the base is triethylamine. 52. The process of any one of claims 43-51 wherein the methylating agent is a methyl halide or dimethylsulfate. 53. The process of claim 52 wherein the methylating agent is methyl iodide. 54. The process of claim 53, wherein the Nal is a neat reagent. 55. The process of any one of claims 41-54 further comprising recovering BODV from the obtained reaction mixture. 56. A process for preparing O-desmethylvenlafaxine comprising preparing BODV according to any one of claims 41-55, and further converting the BODV to O-desmethy Ivenlafaxine. 57. A process for preparing O-desmethylvenlafaxine comprising hydrolyzing BODV of any one of claims 38-40. 58. A process for preparing O-desmethylvenlafaxine comprising: combining BODV of any one of claims 38-40, a hydroxide donor base and a metal salt to obtain a reaction mixture, followed by recovery of the O-desmethylvenlafaxine from the reaction mixture. 59. The process of claim 58, wherein the hydroxide donor base is an alkali metal or alkaline earth metal hydroxide. 60. The process of claim 59, wherein the base is a potassium hydroxide (KOH), lithium hydroxide (LiOH) or sodium hydroxide (NaOH), CsOH, 61. The process of any one of claims 58-60, wherein the metal salt is silver nitrate (AgNCb). 62. The process of claim 61, wherein the metal salt is AgNOa optionally on a support. 63. The process of any one of claims 56-62, wherein the process comprises combining AgNCb in water with solid support (montmorillonite or silica) to obtain a reaction mixture, heating the mixture, removing the water to obtain a residue, combining BODV, a base and the residue to obtain ODV. 64. The process of claim 63, further comprising recovering ODV by extracting ODV with an organic solvent. 65. The process of claim 64, wherein the solvent is a mixture of chloroform and methanol. 66. A process for preparing O-desmethylvenlafaxine comprising combining BQDV of any one of claims 38-40 with Mg or Cu, and an organic solvent to obtain a grignard reagent or an organocuprate reagent, and combining the reagent with borate and an acid to provide O-desmethylvenlafaxine. 67. The process of claim 66, wherein the process comprises combining Mg or Cu and a halogen when Cu is not used with BODV in an organic solvent such as THF. 68. The process of claim 67, wherein the halogen is I2- 69. The process of any one of claims 66-68, wherein the borate is fcriraethylborate. 70. The process of any one of claims 66-69, wherein the acid is glacial acetic acid. 71. The process of any one of claims 66-70, further comprising quenching with hydrogen peroxide. 72. The process of claim 66-71, further comprising adding a water immiscible organic solvent in which O-desmethylvenlafaxine is soluble in, preferably diethylether, to recover O-desmethylvenlafaxine. 73. The process of any of the preceding claims which synthesize O-desmetiaylvenlafaxine, wherein a hydroxy! protected BODV is used to synthesize O-desmethylvenlafaxine. 74. The process of claim 73, wherein the protected intermediate of BODV has a suitable hydroxyl protecting group selected from the group consisting of silyl, acetyl and dihydropyran (DHP). 75. The process of claim 74, wherein the BODV is protected with an acetyl group. 76. Hydroxyprotected-l-[l-(4-brornophenyl)-2-(dimethylarruno)ethyl]cyclohexanol (BODV-P). 77. The BODV-P of claim 76 in isolated or purified form. 78. The BODV-P of claim 76 or 77, wherein the protecting group is acetyl group. 79. The BODV-P of claim 76 or 77, wherein the protecting group is silyl, acetyl or dihydropyran (DHP). 80. The BODV-P of claim 76-79 having a purity of at least about 50% as measured by HPLC. 81. A process for preparing the hydroxyprotected-l-[l-(4-brqmophenyl)-2-(diniethylarnino)ethyl]cyclohexanol (BODV-P) of claim 76 comprising combining BODV an organic solvent, a base and a protecting agent to create a reaction mixture, and recovering the BODV-P from the reaction mixture. 82. The process of claim 81 wherein the organic solvent is ethyl acetate. 83. The process of claim 81 -82 wherein the process is performed under basic conditions. 84. The process of claim 81-83 wherein the base is a C3-C9 trialkyl amine such as triethylamine, or imidazole or lutidine or pyridine or inorganic base such K2C03. 85. The process of claim 81-84 wherein the protecting agent is selected from the group consisting of: silyl, acetyl, DHP and derivatives thereof.

Documents

Application Documents

# Name Date
1 10547-delnp-2008-pct-304.pdf 2011-08-21
1 10547-DELNP-2008_EXAMREPORT.pdf 2016-06-30
2 10547-delnp-2008-pct-210.pdf 2011-08-21
2 10547-delnp-2008-abstract.pdf 2011-08-21
3 10547-delnp-2008-gpa.pdf 2011-08-21
3 10547-delnp-2008-claims.pdf 2011-08-21
4 10547-delnp-2008-correspondence-others.pdf 2011-08-21
4 10547-delnp-2008-form-5.pdf 2011-08-21
5 10547-delnp-2008-form-3.pdf 2011-08-21
5 10547-delnp-2008-description (complete).pdf 2011-08-21
6 10547-delnp-2008-form-2.pdf 2011-08-21
6 10547-delnp-2008-form-1.pdf 2011-08-21
7 10547-delnp-2008-form-18.pdf 2011-08-21
8 10547-delnp-2008-form-2.pdf 2011-08-21
8 10547-delnp-2008-form-1.pdf 2011-08-21
9 10547-delnp-2008-form-3.pdf 2011-08-21
9 10547-delnp-2008-description (complete).pdf 2011-08-21
10 10547-delnp-2008-correspondence-others.pdf 2011-08-21
10 10547-delnp-2008-form-5.pdf 2011-08-21
11 10547-delnp-2008-claims.pdf 2011-08-21
11 10547-delnp-2008-gpa.pdf 2011-08-21
12 10547-delnp-2008-pct-210.pdf 2011-08-21
12 10547-delnp-2008-abstract.pdf 2011-08-21
13 10547-DELNP-2008_EXAMREPORT.pdf 2016-06-30
13 10547-delnp-2008-pct-304.pdf 2011-08-21