WO2007049302A2 - An improved process for the preparation of pure venlafaxine - Google Patents
An improved process for the preparation of pure venlafaxine Download PDFInfo
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- WO2007049302A2 WO2007049302A2 PCT/IN2006/000422 IN2006000422W WO2007049302A2 WO 2007049302 A2 WO2007049302 A2 WO 2007049302A2 IN 2006000422 W IN2006000422 W IN 2006000422W WO 2007049302 A2 WO2007049302 A2 WO 2007049302A2
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- venlafaxine
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- hydrochloride
- ethyl acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified 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
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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
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- 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
Abstract
The present invention relates to pure Venlafaxine or salt thereof and a process for preparing highly pure Venlafaxine of structural Formula (I), Formula (I) from N, N-didesmethyl venlafaxine or salt thereof of formula (III).
Description
TITLE OF THE INVENTION
An improved process for the preparation of pure Venlafaxine FIELD OF THE INVENTION
The field of the invention relates to pure Venlafaxine or salt thereof and a process for preparing highly pure Venlafaxine of structural Formula I, or salt thereof.
BACKGROUND OF THE INVENTION
Venlafaxine of Formula-I is a useful antidepressant and is chemically known as (±)-l- [α-[(dimethyl-amino)methyl]-p-methoxybenzyl] cyclohexanol. Venlafaxine has been first disclosed in US patent 4,535,186. The process comprises the reaction of p- methoxy phenyl acetonitrile at -78°C, with cyclohexanone under the influence of n- butyl lithium, following available methods [Sauvetre et al. Tetrahedron 34 2135 (1978)] followed by reduction under high pressure using rhodium on alumina as the catalyst. Symmetrical iV-methylation is accomplished via modified Eschweiler-Clarkes procedure employing formaldehyde, formic acid and a large excess of water.
During methylation under said conditions appreciable amount of a by-product of formula II
Formula II is formed which should be reduced under more energetic conditions to lead to the formation of venlafaxine and long reaction hours are required for the completion of reaction. Further it is difficult to completely convert the compound of formula II to venlafaxine which leads to additional purification steps.
US patent application 2002/0143211 Al discloses a process for the preparation of essentially pure venlafaxine. The process comprises treating AζiV-didesmethyl venlafaxine hydrochloride with sodium hydroxide and subsequently with formaldehyde and formic acid.
PCT patent application 2005/058796 Al discloses a process for the preparation of venlafaxine by treating AζJV-didesmethyl venlafaxine hydrochloride, spiro compound in the presence of a salt of formic acid selected from the group of metal salt and an ammonium salt of formic acid.
In view of the above there is an urgent need to develop a process where the formation of compound of formula II is avoided and reaction moves smoothly to the preparation of venlafaxine.
Accordingly, it is an object of the present invention to provide a simple and efficient process for the preparation of highly pure venlafaxine from JV,JV-didesmethyl venlafaxine of formula III,
Formula III or salt thereof wherein formation of compound of formula II is minimized and reaction time is reduced and hence impurity formation is very less leading to the preparation of highly pure venlafaxine.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided an improved process for preparation of highly pure venlafaxine hydrochloride thereof which comprises:
heating ΛζN-didesmethyl venlafaxine or salt with hexamethylenetetramine and formic acid in aqueous medium at temperature from room temperature to reflux temperature till complete methylation,
treating the reaction mixture with a base,
extracting compound with an organic solvent,
distilling of the organic solvent to obtain venlafaxine as oil,
treating the above reaction mass in an organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
isolating venlafaxine hydrochloride.
In another aspect of the present invention, there is provided an improved process for the preparation of highly pure venlafaxine or salt thereof which comprises:
adding organic base to ΛζiV-didesmethyl venlafaxine of formula III or salt thereof,
Formula III followed by formaldehyde and formic acid,
heating the reaction mixture at 95-1050C till complete conversion to venlafaxine,
treating the reaction mixture with a base,
extracting compound with an organic solvent,
distilling of the organic solvent completely to obtain venlafaxine as oil,
treating the above reaction mass in organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
isolating venlafaxine hydrochloride.
DETAILED DESCRIPTION OF THE INVENTION
The inventors have developed an efficient process for the preparation of highly pure venlafaxine hydrochloride of formula I.
In one aspect of the present invention, the conversion of ΛζiV-didesmethyl venlafaxine or salt thereof to venlafaxine in the presence of hexamethylenetetramine is the inventive part of this invention. Generally methylation of ΛζTV-didesmethyl venlafaxine or salt thereof is carried out in the presence of hexamethylenetetramine and formic acid in aqueous medium. The salt can be any acid addition salt such as hydrochloride, formate, acetate, propionate, sulphate or the like. Specifically, ΛfJV-didesmethyl venlafaxine hydrochloride is converted to venlafaxine hydrochloride.
It is advantageous to use slight excess of hexamethylenetetramine in the ratio of 1.0-2.5 mole equivalent with respect to AζiV-didesmethyl venlafaxine hydrochloride. Preferably 1.0- 1.5 mole equivalent of hexamethylenetetramine is used. The reaction is conducted at a temperature of 80-1050C and it takes 8-10 hours for completion of the reaction. Specifically, iV.iV-didesmethyl venlafaxine hydrochloride is treated with formic acid and hexamethylenetetramine in the presence of water at a temperature of 95-1050C. After completion of the reaction, pH of reaction mass is adjusted to 10-11 using sodium hydroxide. Thereafter the product is extracted with an organic solvent. Organic solvent can be selected from isopropyl ether, ethyl acetate and preferably ethyl acetate is used. Organic layer is dried over sodium sulphate and solvent is concentrated to obtain oil. The crude oil can be dissolved in alcohol such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof. The hydrochloride formation is achieved using isopropanolic hydrochloric acid. The reaction is carried out at ambient temperature and pH is adjusted to 1-2. Venlafaxine hydrochloride is isolated by filtration and optionally purified by slurring at^ temperature of 25-50°C in a solvent selected from alcohol such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof
In another aspect of the present invention, the conversion of ΛζN-didesmethyl venlafaxine or salt thereof to venlafaxine in the presence of organic base is the inventive part of this invention. Generally, methylation of ΛζN-didesmethyl venlafaxine or salt thereof is carried out in the presence of organic base using formaldehyde and formic acid. The salt can be any acid addition salt such as hydrochloride, formate, acetate, propionate, sulphate or the like. Specifically, N,N- didesmethyl venlafaxine hydrochloride is converted to venlafaxine hydrochloride. The organic base used is selected from trialkyl amines, tertiary alkyl amines, pyridine and the like. The trialkyl amines can be tributyl amine, triethyl amine or the like. Preferably triethyl amine is used.
It is advantageous to use excess of organic base in the ratio of 3-7 moles equivalent with respect to ΛζiV-didesmethyl venlafaxine hydrochloride. Preferably 4-5 moles equivalent of base is used. The reaction is conducted at a temperature of 80-100°C and it takes 3-6 hours for completion of the reaction. Specifically iV,iV-didesmethyl venlafaxine hydrochloride is treated with formic acid and formaldehyde in the presence of triethylamine at a temperature of 95-1050C. After completion of reaction, pH of reaction mass is adjusted to 10-11 using sodium hydroxide. Thereafter product is extracted with organic solvent. Organic solvent can be selected from isopropyl ether, ethyl acetate and preferably ethyl acetate is used. Organic layer is dried over sodium sulphate and solvent is concentrated to obtain oil. The crude oil can be dissolved in alcohol such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof.
The hydrochloride formation is achieved using isopropanolic-hydrochloric acid. Isopropanolic-hydrochloric acid is prepared by passing hydrochloric acid gas in isopropanol till concentration of hydrochloric acid in isopropanol reached the ratio of 20-22%. The hydrochloride formation is carried out at ambient temperature and pH is adjusted to 1-2. Venlafaxine hydrochloride is isolated by filtration and optionally purified by slurring at a temperature of 25-5O0C in a solvent selected from alcohol such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and are not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Examnle-1
Preparation of l-[2-(di-methylamino')-l-(4-methoxyphenyl')ethyllcvclohexanoI hydrochloride (Venlafaxine Hydrochloride)
To a solution of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (25.0 g; 87.56 mmol) in purified water (200 ml) was added hexamethylenetetramine (15.5 g; 110.56 mmol), and formic acid ( 45.0 ml; 1193.47 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then the temperature was raised to 98 - 1020C. The reaction mixture was stirred at 98 - 1020C till completion of methylation. After completion of reaction, the reaction mass was cooled to 15 — 2O0C and pH was adjusted to 10 — 11 using sodium hydroxide solution (20%). The reaction mass was extracted with ethyl acetate. The organic layer was dried over sodium sulphate (13.0 g) and ethyl acetate was distilled out under vacuum. Isopropyl alcohol: ethyl acetate (4:1, 50.0 ml) was added to the residue with stirring and pH was adjusted to 1-2 using isopropanolic-hydrochloric acid (20- 22%) yielded a thick white suspension. This was diluted with isopropyl alcohol: ethyl acetate (4:1, 62.5 ml) and the temperature of reaction mass was raised to 40 - 450C and stirred at this temperature for 3.0 hours. The reaction mass was cooled to 0 - 50C, stirred and filtered to afford crude venlafaxine hydrochloride. Crude material was slurred in isopropyl alcohol: ethyl acetate (4:1, 50.0 ml) at 40 - 450C. Thereafter the reaction mixture was cooled to 0 - 50C, filtered, washed with chilled isopropyl alcohol: ethyl acetate (4:1, 25 ml) and dried under vacuum at 45-5O0C for 9 hours to obtain 19. Ig of l-[2-(dimethyl)-l-(4-
methoxyphenyl) ethyl] cyclohexanol hydrochloride having purity 99.7 9% by high performance liquid chromatography.
Example-2
Preparation of l-f2-(di-methylaminoVl-(4-methoxyDhenyl) ethyllcyclohexanol hydrochloride (Venlafaxine Hydrochloride)
To a solution of l-[2-amino-l-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride (10.0 g; 35.02 mmol) in purified water (80 ml) was added hexamethylenetetramine (6.2 g; 59.50 mmol), and formic acid ( 18.0 ml; 477.39 mmol). The reaction mixture was stirred at room temperature for 15 minutes. Thereafter the temperature was raised to 98 - 1020C. The reaction mixture was stirred at 98 - 1020C till completion of methylation. After completion of reaction, the reaction mass was cooled to 15 - 2O0C and pH was adjusted to 10 - 11 using sodium hydroxide solution (20%). The reaction mass was extracted with ethyl acetate. The organic layer was dried over sodium sulphate and ethyl acetate was distilled out under vacuum. Isopropyl alcohol: ethyl acetate (4:1, 20.0 ml) was added to the residue with stirring and pH was adjusted to 1- 2 using isopropanolic-hydrochloric acid (20- 22%) to yield a thick white suspension. This was diluted with isopropyl alcohol: ethyl acetate (4:1, 25 ml) and the temperature of reaction mass was raised to 40 - 450C and stirred at this temperature for 3.0 hours. The reaction mass was cooled to 0 - 50C, stirred and filtered to afford crude venlafaxine hydrochloride. Crude material was slurred in isopropyl alcohol: ethyl acetate (4:1, 20.0 ml) at 40 — 450C. Thereafter the reaction mixture was cooled to 0 - 50C, filtered, washed with chilled isopropyl alcohol: ethyl acetate (4:1, 10 ml) and dried under vacuum at 45-5O0C for 8 - 10 h to obtain 6.8 g of l-[2-(dimethyl)-l-(4- methoxyphenyl) ethyl] cyclohexanol hydrochloride having purity 99.88% by high performance liquid chromatography.
Example 3
Step I: Preparation of l-[2-amino-l-(4-mcthoxy phenyl) ethyll cyclohexanol hydrochloride l-[Cyano-l-(4-methoxyphenyl)methyl]cyclohexanol (100.0 g) was dissolved in formic acid (800 ml; 98%) in an autoclave and cooled to 10-150C. Palladium catalyst (Pd/C 15%, 15.0 g: 50% wet) slurred in formic acid (45.0 ml) was added to the reaction mass and the reaction mass was stirred at 10 - 150C under hydrogen pressure 3.5 - 4.0 kg/cm2 for 4.0 hours. After complete conversion of l-[cyano-l-(4-methoxyphenyl) methyl] cyclohexanol, the reaction mass was filtered and formic acid was recovered under vacuum at 40 - 450C to obtain a viscous oily product. The oily product was dissolved in purified water (500 ml) and washed with ethyl acetate (3 x 100 ml). The aqueous layer was basified with 10% aqueous sodium hydroxide to pH 9.5 at 15 - 2O0C. The reaction mixture was extracted with ethyl acetate (750 ml x 3). The organic layer was combined and concentrated under vacuum at temperature of 45 - 5O0C. Ethyl acetate (450 ml) was added to the oil (115.0 g) with stirring and pH was adjusted with ethyl acetate-hydrochloric acid at 20 - 3O0C to pH 1 - 2. A thick white suspension was formed. The temperature of reaction mass was raised to 40 - 450C and stirred for 2.0 hours at this temperature, cooled to 10 - 150C and filtered. The wet product was slurred in ethyl acetate (200 ml) for 2.0 hours, filtered, washed with chilled ethyl acetate (100 ml) and dried under vacuum at 40 - 450C for 8 - 10 hours to obtain 70.5 g of title compound having purity 99.0% by high performance liquid chromatography.
Step II: Preparation of l-f2-(di-methylamino)-l-(4-methoxyphenyl)ethyn cyclohexanol hydrochloride (Venlafaxine hydrochloride)
Triethyl amine (121.96 g; 1.20 mol) was added to a solution of l-[2-amino-l-(4- methoxyphenyl)ethyl]cyclohexanol hydrochloride (70.0 g; 0.245 mol) in purified water (210 ml) followed by addition of formic acid (140 ml; 3.71 mol) and formaldehyde (101.5 ml; 1.25 mol). The reaction mixture was stirred at ambient temperature for 15
minutes and temperature was raised to 98 - 1020C. The reaction mixture was stirred at 98 - 1020C till complete conversion to venlafaxine (4.5 hours). After completion of reaction, the reaction mass was cooled to 15 - 2O0C and pH was adjusted to 10 - 11 with sodium hydroxide solution (20%). The product was extracted with ethyl acetate (2000ml) and ethyl acetate was recovered under vacuum at temperature 45 - 5O0C to obtain crude Venlafaxine as oil.
A mixture of isopropyl alcohol and ethyl acetate (4:1, 140 ml) was added to the oil with stirring and pH was adjusted to 1 — 2 with isopropanolic-hydrochloric acid (20 - 22%, 50 ml). A thick white suspension was formed. To this suspension isopropyl alcohol: ethyl acetate (4:1, 175 ml) was added and the temperature was raised to 40 - 450C and stirred for 2.0 hours at the same temperature. The reaction mass was cooled to 0 - 50C and stirred for 2.0 hours. The white suspension was filtered and wet product was slurred in isopropyl alcohol: ethyl acetate (4:1, 140 ml). The slurry was stirred for 1.0 hour at 40 - 450C and for 1.0 hour at 0 - 50C. The cooled suspension was filtered, washed with isopropyl alcohol: ethyl acetate (4:1) 70 ml and dried under vacuum at 45-5O0C for 10 hours to obtain 53.4 g of Venlafaxine hydrochloride having purity: 99.89% by high performance liquid chromatography.
Example 4
Step I: Preparation of l-f2-amino-l-(4-methoxy phenyl) ethyllcyclohexanol hydrochloride l-[Cyano-l-(4-methoxyphenyl)methyl]cyclohexanol (100.0 g) was dissolved in formic acid (800 ml; 98%) in an autoclave and cooled to 10-150C. Palladium catalyst (Pd/C 15%, 15.0 g: 50% wet) slurred in formic acid (45.0 ml) was added to the reaction mass and the reaction mass was stirred at 10 - 150C under hydrogen pressure 3.5 - 4.0 kg/cm2 for 4.15 hours. After complete conversion of l-[cyano-l-(4-methoxyphenyl) methyl] cyclohexanol, the reaction mass was filtered and formic acid was recovered
under vacuum at 40 - 450C to obtain a viscous oily product. The oily product was dissolved in purified water (500 ml) and washed with ethyl acetate (3 x 100 ml). The aqueous layer was basified with 10% aqueous sodium hydroxide to pH 9.5 at 15 - 2O0C. The reaction mixture was extracted with ethyl acetate (750 ml x3). The organic layer was combined and concentrated under vacuum at temperature 45 - 5O0C. Ethyl acetate (450 ml) was added to the oil (115.0 g) with stirring and pH was adjusted with ethyl acetate-hydrochloric acid at 20 - 3O0C to pH 1 - 2. A thick white suspension was formed. The temperature of reaction mass was raised to 40 - 450C and stirred for 2.0 hours at this temperature, cooled to 10 - 150C and filtered. The wet product was slurred in ethyl acetate (200 ml) for 2.0 hours, filtered, washed with chilled ethyl acetate (100 ml) and dried under vacuum at 40 - 450C for 8 - 10 hours to obtain 65.2 g of title compound having purity 99.45 % by high performance liquid chromatography.
Step II: Preparation of Venlafaxine hydrochloride
Triethyl amine (111.51 g; 1.10 mol) was added to a solution of l-[2-amino-l-(4- methoxyphenyl)ethyl]cyclohexanol hydrochloride (64.0 g; 0.224 mol) in purified water (192 ml) followed by addition of formic acid (128 ml; 3.39 mol) and formaldehyde (92.2ml; 1.13 mol). The reaction mixture was stirred at ambient temperature for 15 minutes and temperature was raised to 98 - 1020C. The reaction mixture was stirred at 98 - 1020C till complete conversion to venlafaxine (4 hours). After completion of reaction, the reaction mass was cooled to 15 - 2O0C and pH was adjusted to 10.5 with sodium hydroxide solution (20%). The product was extracted with ethyl acetate (1800ml) and ethyl acetate was recovered under vacuum at temperature 45 - 5O0C to obtain crude Venlafaxine as oil. A mixture of isopropyl alcohol and ethyl acetate (4:1, 120 ml) was added to the oil with stirring and pH was adjusted to 1 - 2 with isopropanolic-hydrochloric acid (20 - 22%, 45 ml). A thick white suspension was formed. To this suspension isopropyl alcohol: ethyl acetate (4:1, 160 ml) was added and the temperature was raised to 40 - 450C and stirred for 2.0 hours at the same temperature. The reaction mass was cooled to 0 — 50C and stirred for 2.0 hours. The
while suspension was filtered and wet product was slurred in isopropyl alcohol: ethyl acetate (4:1, 128ml). The slurry was stirred for 1.0 hour at 40 - 450C and for 1.0 hour at 0 - 50C. The cooled suspension was filtered, washed with isopropyl alcohol: ethyl acetate (4:1) 64 ml and dried under vacuum at 45-5O0C for 8 hours to obtain 53.7 g of Venlafaxine hydrochloride having purity 99.90% by high performance liquid chromatography.
Claims
1. A process for the preparation of highly pure venlafaxine Formula I or salt thereof,
Formula III with hexamethylenetetramine and formic acid in aqueous medium at temperature from room temperature to reflux till completion of methylation,
b) treating the reaction mixture with a base,
c) extracting compound with an organic solvent,
d) distilling of the organic solvent to obtain venlafaxine as an oil,
e) treating the above reaction mass in an organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
f) isolating venlafaxine hydrochloride.
2. The process according to claim 1, wherein in step-a, ΛζJV-didesmethyl venlafaxine is used in the form of hydrochloride, formate or acetate salt.
3. The process according to claim 2, wherein in step-a, ΛζiV-didesmethyl venlafaxine is used in the form of hydrochloride salt.
4. The process according to claim 1, wherein hexamethylenetetramine is used in molar ratio of 1.0-2.5.
5. The process according to claim 4, wherein hexamethylenetetramine is used in molar ratio of 1.0-1.5.
6. The process according to claim 1, wherein the base used in step-b, is selected from alkaline hydroxides.
7. The process according to claim 5, wherein the base used in step-b is sodium hydroxide.
8. The process according to claim 1, wherein the organic solvent used in step-c is selected from isopropyl ether and ethyl acetate.
9. The process according to claim 1, wherein organic solvent used in step-e is selected from alcohols such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof.
10. A process for the preparation of highly pure Venlafaxine of structural Formula I or salt thereof
which comprises:
a) adding an organic base to τV,7V-didesmethyl venlafaxine of formula III or salt thereof,
Formula III
followed by addition of formaldehyde and formic acid,
b) heating the reaction mixture at 95-105°C till complete conversion to venlafaxine,
c) treating the reaction mixture with a base,
d) extracting compound with an organic solvent,
e) distilling of the organic solvent completely to obtain venlafaxine as oil,
f) treating the above reaction mass in an organic solvent with isopropanolic hydrochloric acid to prepare venlafaxine hydrochloride,
g) isolating venlafaxine hydrochloride.
11. The process according to claim 10, wherein in step-a, ΛζiV-didesmethyl venlafaxine is used in the form of its hydrochloride salt
12. The process according to claim 10, wherein in step-a, the organic base used is selected from trialkyl amines, tertiary alkyl amines and pyridine.
13. The process according to claim 12, wherein organic base is triethylamine.
14. The process according to claim 10, wherein the base used in step-c is selected from alkaline hydroxides.
15. The process according to claim 14, wherein the base used in step-c is sodium hydroxide.
16. The process according to claim 10, wherein the organic solvent used in step-d is selected from isopropyl ether and ethyl acetate.
17. The process according to claim 10, wherein the organic solvent used in step-f is selected from alcohols such as methanol, ethanol, isopropyl alcohol, ethyl acetate or mixture thereof.
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| IN2888DE2005 | 2005-10-28 | ||
| IN2887DE2005 | 2005-10-28 | ||
| IN2887/DEL/2005 | 2005-10-28 | ||
| IN2888/DEL/2005 | 2005-10-28 |
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| WO2007049302A2 true WO2007049302A2 (en) | 2007-05-03 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
| CN111675671A (en) * | 2020-07-15 | 2020-09-18 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine impurity E |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020143211A1 (en) * | 2000-10-19 | 2002-10-03 | Ben-Zion Dolitzky | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
-
2006
- 2006-10-26 WO PCT/IN2006/000422 patent/WO2007049302A2/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020143211A1 (en) * | 2000-10-19 | 2002-10-03 | Ben-Zion Dolitzky | Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochlorid, processes for preparing thereof |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103483210A (en) * | 2012-06-13 | 2014-01-01 | 成都弘达药业有限公司 | New compound and preparation method thereof |
| CN103483210B (en) * | 2012-06-13 | 2016-01-13 | 成都弘达药业有限公司 | A kind of new compound and preparation method thereof |
| CN111675671A (en) * | 2020-07-15 | 2020-09-18 | 苏州第四制药厂有限公司 | Preparation method of venlafaxine impurity E |
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| WO2007049302A3 (en) | 2009-04-09 |
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