WO2003048104A1 - Methods for preparing o-desmethylvenlafaxine - Google Patents

Methods for preparing o-desmethylvenlafaxine Download PDF

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Publication number
WO2003048104A1
WO2003048104A1 PCT/US2002/038403 US0238403W WO03048104A1 WO 2003048104 A1 WO2003048104 A1 WO 2003048104A1 US 0238403 W US0238403 W US 0238403W WO 03048104 A1 WO03048104 A1 WO 03048104A1
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Prior art keywords
thiolate
venlafaxine
reaction
desmethylvenlafaxine
alcohol
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PCT/US2002/038403
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French (fr)
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Beat Theodor Weber
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Wyeth
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Priority to UA20040705306A priority Critical patent/UA80543C2/en
Priority to BR0214701-7A priority patent/BR0214701A/en
Priority to CA2466779A priority patent/CA2466779C/en
Priority to IL16225302A priority patent/IL162253A0/en
Priority to DK02804479T priority patent/DK1451143T3/en
Priority to NZ533316A priority patent/NZ533316A/en
Priority to HU0402269A priority patent/HUP0402269A3/en
Priority to JP2003549297A priority patent/JP4342312B2/en
Priority to EP02804479A priority patent/EP1451143B9/en
Application filed by Wyeth filed Critical Wyeth
Priority to AU2002357049A priority patent/AU2002357049B2/en
Priority to MXPA04005309A priority patent/MXPA04005309A/en
Priority to DE60228118T priority patent/DE60228118D1/en
Priority to SI200230743T priority patent/SI1451143T1/en
Publication of WO2003048104A1 publication Critical patent/WO2003048104A1/en
Priority to IL162253A priority patent/IL162253A/en
Priority to NO20042680A priority patent/NO20042680L/en
Priority to ZA2004/05250A priority patent/ZA200405250B/en
Priority to HK04108589A priority patent/HK1065778A1/en
Priority to IL194034A priority patent/IL194034A/en

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    • 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
    • C07C213/08—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 not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention relates to methods for preparing O-desmethylvenlafaxine.
  • O-desmethylvenlafaxine is a major metabolite of venlafaxine. Methods to make O-desmethylvenlafaxine are described in U.S. Patent No. 4,535,186. This method uses benzyl blocking groups leading to relatively low throughput.
  • a process of making O-desmethylvenlafaxine is also described in WO 00/59851 in which venlafaxine is allowed to react with diphenyl phosphide in THF (generated by adding n-butyl lithium in THF to diphenylphosphine in THF below 0°C) at reflux for an overnight period.
  • the yield was reported to be 73.8%.
  • the method involved extraction steps involving large volumes of solvent.
  • the present invention provides a process of making O-desmethylvenlafaxine which is both time and material efficient.
  • venlafaxine As described in Scheme I the starting material, venlafaxine (Formula I), is demethylated. Venlafaxine may be prepared in accordance with procedures known in the art such as described in U.S. Patent No. 4,535,186.
  • demethylation is performed using a high molecular weight alkane, arene, or arylalkyl thiolate anion, such as straight or branched chain alkane thiolate anions having 8 to 20 carbon atoms, mono or bicyclic arene thiolate anions having 6 to 10 carbon atoms, or mono or bicyclic arylalkyl thiolate anions having 7 to 12 carbon atoms in the presence of a protic or aprotic solvent.
  • a base such as an alkoxide comprised of a straight or branched chain alkyl group of from 1 to 6 carbon atoms may be present to generate the thiolate anion.
  • the aliphatic thiol has from 10 to 20 carbon atoms and most preferably the aliphatic thiol is dodecanethiol.
  • the aromatic thiol is preferably benzenethiol.
  • the arylalkyl thiolate anion is preferably oc-toluenethiol or naphthylmethanethiol.
  • the alkoxide is preferably a lower alkoxide, e.g., of 1 to 6 carbon atoms (e.g., methoxide, ethoxide and the like) such as sodium methoxide (sodium methylate, sodium methanolate).
  • a lower alkoxide e.g., of 1 to 6 carbon atoms (e.g., methoxide, ethoxide and the like) such as sodium methoxide (sodium methylate, sodium methanolate).
  • the solvent is preferably a hydroxylic or ethereal solvent or mixtures thereof, and more preferably an alcohol, ethylene glycol or ether of ethylene glycol.
  • Ethers of ethylene glycol include, but are not limited to, ethylene glycol monoethyl ether, triethylene glycol dimethyl ether and polyethylene glycol.
  • the solvent is an inert, polar, high boiling point ether of ethylene glycol such as polyethylene glycol and most preferably PEG 400 (polyethylene glycol having a molecular weight range of from about 380-420).
  • the reaction is performed at a temperature of from about 150°C to about 220°C, more preferably from about 170°C to about 220°C, and most preferably from about 180°C to about 200°C.
  • the reaction is generally allowed to progress until, ideally, not more than 1% venlafaxine remains.
  • the reaction is complete in from about 2 hours to about 5 hours and more preferably in from about 2 to about 3.5 hours.
  • the thiolate anion can be prepared separately or in situ.
  • venlafaxine base is dissolved in polyethylene glycol 400 containing dodecanethiol and sodium methylate as a solution in methanol as the temperature is increased to from about 180°C to about 200°C, with stirring for about 2 to about 3.5 hours.
  • venlafaxine base is dissolved in polyethylene glycol containing dodecanethiolate and stirred for about 2 to about 3.5 hours at from about 180°C to about 200°C with stirring.
  • the process may be carried out in a molar excess of thiolate, preferably the molar ratio of thiolate to venlafaxine is up to about 3.0:1, e.g., in the range from about 1.05:1 to about 2.8:1, preferably about 1.15:1 to about 2.5:1.
  • reaction mixture may be cooled to between about 65°C and about 75°C and an alcohol may be added as a diluent before neutralization to the isoelectric point (about pH9.5 to about pH10.0) with an appropriate neutralization agent such as hydrochloric acid.
  • an appropriate neutralization agent such as hydrochloric acid.
  • the alcoholic medium may also aid in the crystallization of the product as neutralization is initiated.
  • the alcohol comprises a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, and the like, and mixtures thereof.
  • the alcohol is isopropanol.
  • Yields of the present invention are greater than about 75% and generally from about 85% to greater than 90%.
  • Example 1 is illustrative but are not meant to be limiting of the present invention.
  • Dodecanethiol (122 g), venlafaxine (111 g), and a methanolic solution of sodium methanolate (30%, 90 g) and PEG 400 are heated to 190°C.
  • the methanol is distilled off and the solution is stirred 2 h at 190°C.
  • 2- propanol (450 g) is added and the pH is adjusted to 9.5 with aqueous HCI.
  • the precipitate is collected by suction filtration, and the cake is washed with 2-propanol, toluene, 2-propanol and water.
  • the wet O-desmethylvenlafaxine is dried in vacuo. Yield: 87g.
  • Venlafaxine (5.6 g) and benzenethiol sodium salt(6.9 g) are charged to PEG 400 (25 g).
  • the reaction mixture is heated to 160°C for 5 h. Then the temperature is lowered and water is added (60 g).
  • the pH is adjusted to 3.5 with H 3 PO 4 .
  • the organic by-products are removed by extraction with heptanes (25 g).
  • the pH of the aqueous layer is then adjusted to 9.5 with aqueous ammonia.
  • the precipitate is collected by suction filtration, re-slurried in water (100 g), isolated by suction filtration and dried in vacuo. Yield 1 g.
  • Step a Formation of the reagent sodium dodecanethiolate.
  • Dodecanethiol (246 g) and sodium methylate in methanol 30% (216 g) are charged to a rotary evaporator. Vacuum is applied and the solvent is abstracted completely using a bath temperature up to 90°C. The remaining sodium dodecanethiolate (272 g) is used without further purification in the subsequent step.

Abstract

The present invention provides an efficient method of making O-desmethylvenlafaxine by demethylating venlafaxine with a thiolate a nion.

Description

METHODS FOR PREPARING O-DESMETHYLVENLAFAXINE
This invention relates to methods for preparing O-desmethylvenlafaxine.
BACKGROUND OF THE INVENTION
O-desmethylvenlafaxine is a major metabolite of venlafaxine. Methods to make O-desmethylvenlafaxine are described in U.S. Patent No. 4,535,186. This method uses benzyl blocking groups leading to relatively low throughput.
A process of making O-desmethylvenlafaxine is also described in WO 00/59851 in which venlafaxine is allowed to react with diphenyl phosphide in THF (generated by adding n-butyl lithium in THF to diphenylphosphine in THF below 0°C) at reflux for an overnight period. The yield was reported to be 73.8%. Furthermore, the method involved extraction steps involving large volumes of solvent.
The present invention provides a process of making O-desmethylvenlafaxine which is both time and material efficient.
DESCRIPTION OF THE INVENTION
In accordance with the present invention is provided a method of making O- desmethylvenlafaxine comprising the steps of demethylating a compound of Formula I to provide a compound of Formula II as described in Scheme I.
thiol
Figure imgf000002_0001
Figure imgf000002_0002
C17H27N02 C16H25N02 Mol. Wt.: 277.40 Mol. Wt.: 263.38
Formula I Formula II
Scheme I As described in Scheme I the starting material, venlafaxine (Formula I), is demethylated. Venlafaxine may be prepared in accordance with procedures known in the art such as described in U.S. Patent No. 4,535,186.
In accordance with the present invention, demethylation is performed using a high molecular weight alkane, arene, or arylalkyl thiolate anion, such as straight or branched chain alkane thiolate anions having 8 to 20 carbon atoms, mono or bicyclic arene thiolate anions having 6 to 10 carbon atoms, or mono or bicyclic arylalkyl thiolate anions having 7 to 12 carbon atoms in the presence of a protic or aprotic solvent. Optionally, a base such as an alkoxide comprised of a straight or branched chain alkyl group of from 1 to 6 carbon atoms may be present to generate the thiolate anion.
Preferably the aliphatic thiol has from 10 to 20 carbon atoms and most preferably the aliphatic thiol is dodecanethiol. The aromatic thiol is preferably benzenethiol. The arylalkyl thiolate anion is preferably oc-toluenethiol or naphthylmethanethiol.
When present, the alkoxide is preferably a lower alkoxide, e.g., of 1 to 6 carbon atoms (e.g., methoxide, ethoxide and the like) such as sodium methoxide (sodium methylate, sodium methanolate).
The solvent is preferably a hydroxylic or ethereal solvent or mixtures thereof, and more preferably an alcohol, ethylene glycol or ether of ethylene glycol. Ethers of ethylene glycol include, but are not limited to, ethylene glycol monoethyl ether, triethylene glycol dimethyl ether and polyethylene glycol. Preferably, the solvent is an inert, polar, high boiling point ether of ethylene glycol such as polyethylene glycol and most preferably PEG 400 (polyethylene glycol having a molecular weight range of from about 380-420).
The reaction is performed at a temperature of from about 150°C to about 220°C, more preferably from about 170°C to about 220°C, and most preferably from about 180°C to about 200°C. The reaction is generally allowed to progress until, ideally, not more than 1% venlafaxine remains. In some aspects of the invention the reaction is complete in from about 2 hours to about 5 hours and more preferably in from about 2 to about 3.5 hours.
The thiolate anion can be prepared separately or in situ. In some preferred embodiments of the present invention, venlafaxine base is dissolved in polyethylene glycol 400 containing dodecanethiol and sodium methylate as a solution in methanol as the temperature is increased to from about 180°C to about 200°C, with stirring for about 2 to about 3.5 hours. In other preferred embodiments of the present invention, venlafaxine base is dissolved in polyethylene glycol containing dodecanethiolate and stirred for about 2 to about 3.5 hours at from about 180°C to about 200°C with stirring.
Conveniently the process may be carried out in a molar excess of thiolate, preferably the molar ratio of thiolate to venlafaxine is up to about 3.0:1, e.g., in the range from about 1.05:1 to about 2.8:1, preferably about 1.15:1 to about 2.5:1.
Thereafter the reaction mixture may be cooled to between about 65°C and about 75°C and an alcohol may be added as a diluent before neutralization to the isoelectric point (about pH9.5 to about pH10.0) with an appropriate neutralization agent such as hydrochloric acid. The alcoholic medium may also aid in the crystallization of the product as neutralization is initiated.
Preferably the alcohol comprises a straight or branched chain alkyl group of 1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, butanol, and the like, and mixtures thereof. In some preferred embodiments of the invention, the alcohol is isopropanol.
Yields of the present invention are greater than about 75% and generally from about 85% to greater than 90%.
The following Examples are illustrative but are not meant to be limiting of the present invention. Example 1
Dodecanethiol (122 g), venlafaxine (111 g), and a methanolic solution of sodium methanolate (30%, 90 g) and PEG 400 are heated to 190°C. The methanol is distilled off and the solution is stirred 2 h at 190°C. Then the temperature is lowered, 2- propanol (450 g) is added and the pH is adjusted to 9.5 with aqueous HCI. The precipitate is collected by suction filtration, and the cake is washed with 2-propanol, toluene, 2-propanol and water. The wet O-desmethylvenlafaxine is dried in vacuo. Yield: 87g.
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd, J = 12.3 and 8.5, 1H), 2.73 (dd, J = 8.5 and 6.3, 1 H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 2
Venlafaxine (5.6 g) and benzenethiol sodium salt(6.9 g) are charged to PEG 400 (25 g). The reaction mixture is heated to 160°C for 5 h. Then the temperature is lowered and water is added (60 g). The pH is adjusted to 3.5 with H3PO4. The organic by-products are removed by extraction with heptanes (25 g). The pH of the aqueous layer is then adjusted to 9.5 with aqueous ammonia. The precipitate is collected by suction filtration, re-slurried in water (100 g), isolated by suction filtration and dried in vacuo. Yield 1 g.
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd, J = 12.3 and 8.5, 1 H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 3
Dodecanethiol (69 g) venlafaxine (55 g) and an ethanolic solution of sodium ethanolate (21%, 82 g) are charged to a pressure vessel. The temperature is raised to 150°C and the reaction mixture is stirred for 2 days. Then the temperature is lowered and the solution is filtered. The pH of the filtrate is adjusted to 9.5 with aqueous hydrogen chloride. The crystals are collected by suction filtration. The cake is washed with ethanol and dried in vacuo. Yield: 42g
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1 H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd, J = 12.3 and 8.5, 1 H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1 H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).
Example 4
Step a - Formation of the reagent sodium dodecanethiolate.
Dodecanethiol (246 g) and sodium methylate in methanol 30% (216 g) are charged to a rotary evaporator. Vacuum is applied and the solvent is abstracted completely using a bath temperature up to 90°C. The remaining sodium dodecanethiolate (272 g) is used without further purification in the subsequent step.
Step b - Demethylation
A mixture of sodium dodecanethiolate (272 g) venlafaxine (256 g) and PEG 400 (185 g) is stirred 3 h at 190°C. Then the temperature is lowered and 2-propanol (915 g) is added and the pH is adjusted to 9.5 with aqueous HCI. The precipitate is collected by suction filtration, and the cake is washed with 2-propanol and water. The wet O- desmethylvenlafaxine is dried in vacuo. Yield: 200 g.
1H-NMR: (Gemini 200, Varian, 200 MHz) (DMSO-d6) δ = 9.11 (s, br, 1 H; OH), 6.98 (d, br, J = 8.4, 2H; arom.), 6.65 (d, br, J = 8.4, 2H; arom.), 5.32 (s, br, 1H; OH), 3.00 (dd, J = 12.3 and 8.5, 1H), 2.73 (dd, J = 8.5 and 6.3, 1H), 2.36 (dd, J = 12.3 and 6.3, 1H), 2.15 (s, 6H, 2 x Me), 1.7-0.8 (m, 10H, c-hex).

Claims

1. A method of preparing O-desmethylvenlafaxine which comprises demethylating venlafaxine with a high molecular weight alkane, arylalkyl or arene thiolate anion in a hydroxylic or ethereal solvent, or mixture thereof.
2. A method according to Claim 1 which is carried out in alcohol, ethylene glycol, ether of ethylene glycol, or mixture thereof.
3. A method according to Claim 1 in which the solvent is ethylene glycol monoethyl ether, tri-ethylene glycol, dimethyl ether or polyethylene glycol.
4. A method according to Claim 1 in which the solvent is polyethylene glycol 400.
5. A method according to any one of Claims 1 to 4 wherein the reaction is performed at about 150°C to about 220°C.
6. A method according to any one of Claims 1 to 4 wherein the reaction is performed at from about 170°C to about 220° C.
7. A method according to any one of Claims 1 to 4 wherein the reaction is performed at from about 180°C to about 200° C.
8. A method according to any one of Claims 1 to 8 wherein the reaction is carried out for about 2 to about 5 hours.
9. A method according to any one of Claims 1 to 8 wherein the thiolate anion is a straight or branched chain alkane thiolate anion having 8 to 20 carbon atoms.
10. A method according to Claim 9 wherein the alkane thiolate anion is dodecanethiolate.
11. A method according to any one of Claims 1 to 8 wherein the thiol is an arene thiolate anion having from 6 to 10 carbon atoms.
12. A method according to Claim 11 wherein the arene thiolate anion is benzene- thiolate.
13. A method according to any one of Claims 1 to 12 wherein the thiolate anion is generated in the presence of an alkoxide.
14. A method according to Claim 13 wherein the alkoxide is methoxide.
15. A method according to any one of Claims 1 to 14 which is carried out in a stoichiometric excess of thiolate:venlafaxine up to about 3.0:1.
16. A method according to any one of Claims 1 to 14 in which the molar ratio of thiolate:venlafaxine is from about 1.15:1 to about 2.5:1.
17. A method according to any one of Claims 1 to 16 further comprising neutralizing the product to the isoelectric point in the presence of an alcohol comprising a straight or branched chain alkyl group of from 1 to 6 carbon atoms.
18. A method according to Claim 18 wherein the alcohol is isopropanol.
19. A method according to Claim 18 or Claim 19 in which the reaction mixture is cooled to between about 65°C and about 75°C before the an alcohol is added
20. A method according to any one of Claims 18 to 20 wherein the isoelectric point is from about pH9.5 to about pH10.
21. A method of preparing O-desmethylvenlafaxine which comprises the steps of demethylating venlafaxine with dodecyl thiolate and polyethylene glycol 400 in the presence of sodium methylate in methanol at about 180°C to about 200°C for about 2 to about 5 hours; and neutralizing the product to about pH 9.5 in the presence of isopropanol.
PCT/US2002/038403 2001-12-04 2002-12-03 Methods for preparing o-desmethylvenlafaxine WO2003048104A1 (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
UA20040705306A UA80543C2 (en) 2001-12-04 2002-03-12 Method for the preparation of o-desmethylvenlafaxine
SI200230743T SI1451143T1 (en) 2001-12-04 2002-12-03 Methods for preparing o-desmethylvenlafaxine
AU2002357049A AU2002357049B2 (en) 2001-12-04 2002-12-03 Methods for preparing 0-desmethylvenlafaxine
IL16225302A IL162253A0 (en) 2001-12-04 2002-12-03 Venlafaxine hydrochloride monohydrate and methods for the preparation thereof
DK02804479T DK1451143T3 (en) 2001-12-04 2002-12-03 Methods for the preparation of O-desmethylvenlafaxine
NZ533316A NZ533316A (en) 2001-12-04 2002-12-03 Process of making O-desmethylvenlafaxine that is both time and material efficient
HU0402269A HUP0402269A3 (en) 2001-12-04 2002-12-03 Methods for preparing o-desmethylvenlafaxine
JP2003549297A JP4342312B2 (en) 2001-12-04 2002-12-03 Method for producing O-desmethylvenlafaxine
EP02804479A EP1451143B9 (en) 2001-12-04 2002-12-03 Methods for preparing o-desmethylvenlafaxine
BR0214701-7A BR0214701A (en) 2001-12-04 2002-12-03 Methods for the preparation of o-desmethylvenlafaxine
CA2466779A CA2466779C (en) 2001-12-04 2002-12-03 Methods for preparing o-desmethylvenlafaxine
MXPA04005309A MXPA04005309A (en) 2001-12-04 2002-12-03 Methods for preparing o-desmethylvenlafaxine.
DE60228118T DE60228118D1 (en) 2001-12-04 2002-12-03 PROCESS FOR THE PREPARATION OF O-DESMETHYLVENLAFAXINE
IL162253A IL162253A (en) 2001-12-04 2004-05-31 Method for preparing o-desmethylvenlafaxine
NO20042680A NO20042680L (en) 2001-12-04 2004-06-25 Processes for the preparation of O-demethylvenflaxine
ZA2004/05250A ZA200405250B (en) 2001-12-04 2004-07-01 Methods for preparing o-desmethylvenlafaxine
HK04108589A HK1065778A1 (en) 2001-12-04 2004-11-01 Methods for preparing o-desmethylvenlafaxine
IL194034A IL194034A (en) 2001-12-04 2008-09-11 Method for preparing o-desmethylvenlafaxine

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US60/334,953 2001-12-04

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Cited By (18)

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Publication number Priority date Publication date Assignee Title
WO2007071404A1 (en) * 2005-12-20 2007-06-28 Synthon B.V. Process for making desvenlafaxine
WO2007120925A2 (en) 2006-04-17 2007-10-25 Teva Pharmeceutical Industries Ltd. Crystal forms of o-desmethylvenlafaxine
WO2007120923A1 (en) 2006-04-17 2007-10-25 Teva Pharmaceutical Industries Ltd. Substantially pure o-desmethylvenlafaxine and processes for preparing it
WO2008035369A2 (en) * 2006-06-30 2008-03-27 Alembic Limited Novel form of o-desmethyl venlafaxine
WO2009053731A1 (en) 2007-10-26 2009-04-30 Generics [Uk] Limited Process for preparing o-desmethylvenlafaxine
WO2009084038A2 (en) * 2007-12-28 2009-07-09 Ind-Swift Laboratories Limited Improved process for the preparation of 0-desmethyl-venlafaxine
US7605290B2 (en) 2006-07-26 2009-10-20 Teva Pharmaceutical Industries Ltd. Processes for the synthesis of O-desmethylvenlafaxine
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