GUND VITTHAL GENBHAU (IN)
PANDIAN VIJAY KANNAN (IN)
LAL BANSI (IN)
GUND VITTHAL GENBHAU (IN)
PANDIAN VIJAY KANNAN (IN)
| US5894074A | 1999-04-13 | |||
| US6342533B1 | 2002-01-29 | |||
| US5536815A | 1996-07-16 | |||
| US20030139623A1 | 2003-07-24 |
CLAIMS
1. A novel process for the preparation of O-desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof
Formula I
from 2-(4-methoxyphenyl)acetonitrile of formula II comprising, i) reacting 2-(4-methoxyphenyl)acetonitrile of formula II with lewis acid in presence of organic solvent such as substituted or unsubstituted hydrocarbons at a temperature of 50 to 100°C to obtain 2-(4-hydroxyphenyl)acetonitrile of formula III
Formula II Formula III ϋ) reacting compound of formula III with cyclohexanone in the presence of a base such as alkali or alkaline earth metal oxides. The reaction is carried out in the presence of solvent or without adding solvent, preferably without adding solvent to obtain compound of formula V
Formula V iii) reacting compound of formula V with dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure to obtain 0-desmethylvenlafaxine of formula I
Formula V Formula I iv) further 0-desmethylvenlafaxine of formula I is converted to its pharmaceutically acceptable salts
2. A novel single step process for the preparation of 0-desmethylvenlafaxine of formula I from 2-(l-hydroxycyclohexyl)-2-(4-hydroxyphenyl)acetonitrile of formula V using dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure.
Formula V Formula I
3. A novel process for the preparation of O-desmethylvenlafaxine of formula I and pharmaceutically acceptable salt thereof from 2-(4-hydroxyphenyl)acetonitrile of formula III comprising, i) reacting 2-(4-hydroxyphenyl)acetonitrile of formula III with protecting reagent in presence of base such as metal hydrides and aprotic solvent such as tetrahydrofuran to obtain compound of formula IV
Formula III Formula IV wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl ii) reacting compound of formula IV with cyclohexanone in the presence of an inorganic base and phase transfer catalyst, in the presence water, organic solvent . or mixture of water with water immiscible organic solvent to obtain compound of formula VI
Formula VI wherein, R is as defined above in) reacting compound of formula VI with dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure to obtain compound of formula VII
Formula VII wherein, R is as defined above iv) reacting compound of formula VII with a deprotecting reagent to obtain O- desmethylvenlafaxine of formula I
4. A novel single step process for the preparation of compound of formula VII from compound formula VI using dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure.
Formula VI Formula VII
5. The process as claimed in claims 1, 2, 3 or 4 wherein, dimethylamine salt is selected from dimethylamine hydrochloride, dimethylamine hydrobromide, dimethylamine hydroiodide, dimethylamine phosphate or dimethylamine sulfate preferably dimethylamine hydrochloride.
6. The process as claimed in claims 1, 2, 3 or 4 wherein, the tertiary amine is selected from trialkylamine, alkylarylamine, or triarylamine, preferably trialkylamine, more preferably triethylamine
7. The process as claimed in claims 1, 2, 3 or 4 wherein, the transition metal catalyst is selected from palladium, platinum, rhodium, or nickel. The catalyst is supported or unsupported. Preferably the catalyst is selected from palladium hydroxide or 5-20% palladium supported on carbon, alumina, calcium carbonate or barium sulphate, more preferably 5-20% palladium supported on carbon.
8. The process as claimed in claims 1, 2, 3 or 4 wherein, a polar organic solvent used in reductive animation is selected from C 1 -C 10 straight chain or branched alcohol, N,N- dimethylformamide, esters, ethers, halogenated solvents or hydrocarbons, preferably Q-C 4 straight chain or branched alcohol, more preferably methanol.
9. The process as claimed in claim 1 or 2 wherein, the reductive animation reaction is carried out at temperature of 25-15O 0 C, preferably at 60-110 0 C.
10. The process as claimed in claim 1 or 2 wherein, reductive amination is carried out under hydrogen pressure ranging from 0.5-20 Kg/cm 2 , preferably from 8-12 Kg/cm 2 .
11. The process as claimed in claim 3 or 4 wherein, the reductive amination reaction is carried out at temperature of 25-12O 0 C, preferably at 25-60 0 C, more preferably at 25-40 0 C.
12. The process as claimed in claim 3 or 4 wherein, reductive amination is carried out under hydrogen pressure ranging from 0.5-20 Kg/cm 2 , preferably from 0.5 to 5 Kg/cm 2 , more preferably from 0.5 to 1 Kg/cm 2 ,
13. The process as claimed in claims 1, 2, 3 or 4 wherein, the catalyst concentration in the reductive amination reaction with reference to the compound of formula V or compound of formula VI is from 1-20 wt %, preferably the catalyst concentration is from 5-12 wt %.
14. The process as claimed in claim 1 wherein, the molar ratio of the 2-(4- methoxyphenyl)acetonitrile to the lewis acid is from 1 :1 to 1 :5, preferably from 1 :2 to 1 :3.
15. The process as claimed in claim 3 or 4 wherein, the protecting group is selected from well-known phenol protecting groups such as methoxyethoxymethyl, methoxymethyl, aryloyl, arylsulfonyl, dihydropyrane or trimethylsilyl, alkyl, and aralkyl, preferably the protecting group is methoxyethoxymethyl.
16. The process as claimed in claim 3 or 4 wherein, the organic or inorganic base used in the condensation reaction is selected form inorganic base such as alkali metal hydroxide or alkaline earth metal hydroxide, preferably alkali hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, more preferably sodium hydroxide and potassium hydroxide.
17. The process as claimed in claim 3 or 4 wherein, the phase transfer catalyst used is such as, but not restricted to quaternary ammonium salts or polyethylene glycols, preferably quaternary ammonium salts such as tetrabutylammonium hydrogensulphate, tetralkylammonium halide, wherein the alkyl group can be same or different and contains Ci- Cβ carbon atoms, such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide or tetraethylammonium bromide more preferably tetrabutylammonium bromide.
18. The process as claimed in claim 3 or 4 wherein, deprotecting reagent is selected from known for such groups, but not restricted to zinc bromide, cerium trichloride, titanium tetrachloride, diisopinocampheylchloroborane, dimethylboron bromide, diphenylboron bromide, pyridinium p-toluenesulfoante, formic acid or trifluoroacetic acid preferably trifluoroacetic acid. |
NOVEL PROCESS FOR PREPARATION OF O-DESMETHYLVENLAFAXINE
FIELD OF INVENTION
The present invention relates to the novel processes for the preparation of 4-(2- (dimethylamino)-l-(l-hydroxycyclohexyl)ethyl)phenol, commonly known as O- desmethylvenlafaxine of formula I and its pharmaceutically acceptable salts of formula IA.
Formula I Formula IA
BACKGROUND OF THE INVENTION
O-Desmethylvenlafaxine is a major metabolite of well known antidepressant drug venlafaxine. O-Desmethylvenlafaxine was first disclosed in EPl 12669. Succinate salt of O- desmethylvenlafaxine has been found to be a serotonin-norepinephrine reuptake inhibitor
(SNRI) and is pre-registered as a treatment for adult patients with major depressive disorder
(MDD) in men and women and as a treatment for moderate to severe vasomotor symptoms
(VMS) associated with menopause. It is in clinical trials of phase II/III to evaluate its potential use in fibromyalgia and neuropathic pain respectively.
Various methods are known for making O-desmethylvenlafaxine. Many of these processes start from venlafaxine, in which O-desmethylvenlafaxine is obtained by O-demethylation of venalafaxine as shown in the scheme below,
US 6,342,533 describes O-demethylation of venlafaxine by reacting with lithium diphenylphosphide (prepared in situ from diphenyl methane and butyl lithium) in tetrahydrofuran to get O-desmethylvenlafaxine. The disadvantage of this process is that it requires very high volume of solvent. The molar ratio of venlafaxine to diphenyl methane is 1:4.5
US 6,689,912 discloses the preparation of O-desmethylvenlafaxine by reacting venlafaxine with a high molecular weight alkane or arenethiolate anion in an alcohol such as ethylene glycol, polyethylene glycol, or their mixtures at 150-220 0 C. The drawback of this process is, it requires very high temperature and also thiol derivatives used are hazardous.
WO 2007071404 describes a process for preparing O-desmethylvenlafaxine by demethylation of venlafaxine by using metal sulfide and optionally using selenium as a demethylating agent.
WO 2007/147564 discloses a process for preparation of O-desmethylvenlafaxine. The process has following steps: (1) protection of 4-hydroxyphenylacetonitrile using benzyl bromide, (2) the product of step-1 is condensed with cyclohexanone in presence of butyl lithium at -70 0 C, (3) the product of step-2 is simultaneously reduced and deprotected using 10% PdVC at hydrogen pressure of 3-4 kg/cm 2 , 23 hours, and (4) the product of step-3 is N- methylated (Eschweiler-Clarke reaction) using formic acid and 37% formaldehyde solution at 100 0 C for 5 hrs to yield O-desmethylvenlafaxine
The reaction is as shown in scheme below:
Reduction/ deprotection
where R is benzyl
WO 200700294 describes a process for condensation of optionally substituted 4-hydroxyphenylacetonitrile with cyclohexanone using bases such as alkali metal alcoholates, alkaline earth metal alcoholates and aluminium alcoholates.
The above mentioned processes suffer from many drawbacks. Most of the prior art processes for the preparation of 0-desmethylvenlafaxine start from venlafaxine.
Another disadvantage is most of the prior art processes employ formaldehyde as a reactant for N-methylation step which is known to be a carcinogen. Acute exposure of the same is highly irritating to the eyes, nose and throat. Ingestion of formaldehyde is fatal and long term exposure causes respiratory problems and skin irritation.
Keeping in view the difficulties of above mentioned processes, present inventors have surprisingly found out the novel process for preparation of O-desmethylvenlafaxine from 2- (4-methoxyphenyl)acetonitrile of formula II. The process is cost effective and provides O-
desmethylvenlafaxine in better yield and purity. The present inventors have also found out another novel process for preparation of O-desmethylvenlafaxine from and by protecting 2- (4-hydroxyhenyl)acetonitrile of formula III.
OBJECTIVES OF THE INVENTION
An objective of the present invention is to provide a novel process for the preparation of O- desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof from 2-(4- methoxyρhenyl)acetonitrile of formula II.
Another objective of the present invention is to provide a novel single step process for the synthesis of O-desmethylvenlafaxine of formula I from 2-(l -hydroxy cy clohexyl)-2-(4- hydroxyphenyl)acetonitrile of formula V.
Yet another objective of the present invention is to provide a novel process for the preparation of O-desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof from 2-(4-hydroxyphenyl)acetonitrile of formula III .
Another objective of the present invention is to provide an improved process for preparation of 2-(4-hydroxyphenyl)acetonitrile of formula III from 2-(4-methoxyphenyl)acetonitrile of formula II.
Further objective of the present invention is to provide a better yielding and cost effective process for the preparation of O-desmethylvenlafaxine with better purity.
Yet further objective of present invention is to make O-desmethylvenlafaxine succinate salt with purity >99.9%
SUMMARY OF THE INVENTION
The present invention provides a novel process for the preparation of O- desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof from 2-(4- methoxyphenyl)acetonitrile of formula II
Formula I
The present invention also provides a novel single step process for the preparation of O-desmethylvenlafaxine of formula I from 2-(l-hydroxycyclohexyl)-2-(4- hydroxyphenyl)acetonitrile of formula V using dimethylamine and/or its salt in the presence of transition metal catalyst, in the presence of tertiary amine or without adding tertiary amine, in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure.
Formula V Formula I
The present invention also provide a novel single step process for the preparation of compound of formula VII from compound formula VI using dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure.
Formula VI Formula VII wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl
The present invention further provides a novel process for the preparation of
O-desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof from 2- (4-hydroxyphenyl)acetonitrile of formula III.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel processes for the preparation of O- desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof.
Formula I
In one aspect of the present invention there is provided a novel process for the preparation of O-desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof from 2- (4-methoxyphenyl)acetonitrile of formula II.
The process of present invention for the preparation of O-desmethylvenlafaxine of formula I is as depicted in Scheme 1:
Formula II Formula III Formula V
Formula IA Formula I
Scheme 1 wherein, HX is succinic acid or other pharmaceutically acceptable salts.
According to the present invention a novel process for the preparation of O- desmethylvenlafaxine of formula I and pharmaceutically acceptable salts thereof from 2-(4- methoxyphenyl)acetonitrile of formula II comprising, i) reacting 2-(4-methoxyphenyl)acetonitrile of formula II with lewis acid in presence of organic solvent at a temperature of 50 to 100 0 C to obtain 2-(4- hydroxyphenyl)acetonitrile of formula III ii) reacting compound of formula III with cyclohexanone in the presence of a base. The reaction is carried out in the presence of solvent or without adding solvent to obtain compound of formula V iii) reacting compound of formula V with dimethylamine and/ or it's salt in the presence of transition metal catalyst, in the presence of tertiary amine or without
adding tertiary amine in a polar organic solvent under, hydrogen pressure at room temperature or at an elevated temperature to obtain O-desmethylvenlafaxine of formula I iv) further O-desmethylvenlafaxine of formula I is converted to its pharmaceutically acceptable salts
The present invention also provides an improved process for the preparation of 2-(4- hydroxyphenyl)acetonitrile of formula III from 2-(4-methoxyphenyl)acetonitrile formula II by reacting compound of formula II with lewis acid in presence of organic solvent at a temperature of 50 to 100°C.
Formula II Formula III
In an embodiment of the present invention the lewis acid is selected from aluminium chloride, aluminium bromide, zinc chloride, zinc bromide, iron chloride, preferably aluminium chloride.
In further embodiment of the present invention the organic solvent is selected from substituted or unsubstituted aromatic hydrocarbons such as toluene, xylene, chlorobenzene, benzene, preferably toluene.
The molar ratio of the 2-(4-methoxyphenyl)acetonitrile to the lewis acid is from 1:1 to 1:5, preferably from 1:2 to 1:3.
The reaction is carried out at temperature of 50 to 100° C, preferably at 60 to 8O 0 C.
The compound of formula III is condensed with cyclohexanone in presence of a base, in presence of solvent or without adding solvent, preferably without adding solvent using the process as described in the prior art to obtain the compound of formula V.
In an embodiment of the present invention base used in the condensation step is selected from alkali or alkaline earth metal oxides, preferably potassium tert-butoxide.
Second aspect of the present invention is to provide a novel single step process for the preparation of O-desmethylvenlafaxine of formula I from 2-(l -hydroxy cyclohexy l)-2-(4- hydroxyphenyl)acetonitrile of formula V using dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure.
Formula V Formula I
In an embodiment of the present invention dimethylamine salt is selected from dimethylamine hydrochloride, dimethylamine hydrobromide, dimethylamine hydroiodide, dimethylamine phosphate or dimethylamine sulfate preferably dimethylamine hydrochloride.
In further another embodiment of the present invention the tertiary amine is selected from trialkylamine, alkylarylamine, or triarylamine, preferably trialkylamine, more preferably triethylamine.
In yet another embodiment of the present invention the transition metal catalyst is selected from palladium, platinum, rhodium, or nickel. The catalyst is supported or unsupported. Preferably the catalyst is selected from palladium hydroxide or 5-20% palladium supported on carbon, alumina, calcium carbonate or barium sulphate, more preferably 5-20% palladium supported on carbon.
The catalyst concentration with reference to the compound of formula V is from 1-20 wt %, preferably the catalyst concentration is from 5-12 wt %
In an embodiment of the present invention the polar organic solvent is selected from Ci-C 10 straight chain or branched alcohol, N,N-dimethylformamide, esters, ethers, halogenated solvents or hydrocarbons. The preferred polar organic solvent of the present invention is C 1 - C 4 straight chain or branched alcohol, preferably C 1 -C 2 alcohol, more preferably methanol.
The concentration of compound of formula V in the reaction mixture is in the range of 5-15 % with reference to the solvent, preferably 10-15% with reference to the solvent.
The single step reductive amination reaction is carried out at temperature of 25-15O 0 C, preferably at 60-110°C.
The single step reductive amination reaction is carried out under hydrogen pressure ranging from 0.5-20 Kg/cm 2 , preferably from 8-12 Kg/cm 2 .
The single step reductive amination reaction time varies from 3 to 20 hours, preferably between 8 to 12 hours.
In an aspect of the invention the crude product of formula I is isolated by acidifying the crude residue with aqueous dil HCl, extracting the crude residue with ethyl acetate, separating the
aqueous layer, cooling the aqueous layer to 5-10 0 C, adjusting the pH to 7-8 using base and stirring the solution for 2-3 hrs at 0-5 0 C to obtain the crude O-desmethylvenlafaxine.
In an embodiment of the invention the base used for adjusting the pH to 7-8 is selected from alkali metal hydroxides, alkali metal carbonates, preferably alkali metal carbonates such as potassium carbonate, sodium carbonate, magnesium carbonate or calcium carbonate more preferably sodium carbonate.
In an aspect of the invention the crude O-desmethylvenlafaxine is then purified in presence of polar solvent to obtain pure O-desmethylvenlafaxine with HPLC purity >99.8 %.
In an embodiment of present invention the polar solvent used in purification step is selected from tetrahydrofuran, dichloromethane, dimethylformamide, acetone, acetonitrile or C 1 -C 5 straight chain or branched alcohols such as methanol, ethanol, isopropyl alcohol, preferably acetone.
The pharmaceutically acceptable salts of O-desmethylvenlafaxine of formula I is prepared in accordance with the procedures known to the art or conventionally by reaction of free base of formula I with an equivalent amount of any acid (HX) which forms non-toxic salts. Pharmaceutically acceptable inorganic or organic salts include, but are not limited to hydrochloric, hydrobromic, fumaric, maleic, succinic, tartarate, sulfuric, phosphoric.
In an aspect of the invention O-desmethylvenlafaxine of formula I is converted to its pharmaceutically acceptable succinate salt of formula IA using succinic acid in presences of acetone. The process comprising, (i) heating the mixture of O-desmethylvenlafaxine, succinic acid, acetone and water at a temperature of 50-60°C for 30 minutes to obtain a clear solution, (ii) charcoal treatment to the clear solution, (iii) cooling the filtrate at 25-30°C for 2-3 hours, further cooling to 0-5°C with stirring for 1 hour to obtain O-desmethylvenlafaxine succinate with purity >99.9%
Third aspect of the present invention is to provide a novel process for the preparation of O- desmethylvenlafaxine of formula I and pharmaceutically acceptable salt thereof from 2-(4- hydroxyphenyl)acetonitrile of formula III
The process of the present invention for preparation of O-desmethylvenlafaxine from and by protecting 2-(4-hydroxyphenyl)acetonitrile of formula III is as depicted in Scheme-2:
Formula I Formula VII
Scheme 2 wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM) 5 aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl
According to the present invention a novel process for the preparation of O- desmethylvenlafaxine of formula I and pharmaceutically acceptable salt thereof from 2-(4- hydroxyphenyl)acetonitrile of formula III comprising,
i) reacting 2-(4-hydroxyphenyl)acetonitrile of formula III with protecting reagent in presence of base and aprotic solvent to obtain compound of formula IV ii) reacting compound of formula IV with cyclohexanone in the presence of an organic or inorganic base and phase transfer catalyst, in the presence water, organic solvent or mixture of water with water immiscible organic solvent to obtain compound of formula VI iii) reacting compound of formula VI with dimethylamine and/ or it's salt in the presence of transition metal catalyst, in the presence of tertiary amine or without adding tertiary amine, in a polar organic solvent under hydrogen pressure at room temperature or at an elevated temperature to obtain compound of formula VII iv) reacting compound of formula VII with a deprotecting reagent to obtain O- desmethylvenlafaxine of formula I
Another aspect of the present invention is to provide a process for the preparation of 2-(l- hydroxycyclohexyl)-2-(4-hydroxyphenyl)acetonitrile of formula V from compound of formula VI in the presence of deprotecting reagents.
Formula VI Formula V wherein, R is methoxyethoxymethyl (MEM) 5 methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl
The present invention also provide a process for the preparation of compound of formula IV using protecting reagents in the presence base and aprotic solvent from compound of formula III.
Formula III Formula IV
wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM) 5 aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl
In an embodiment of the present invention the protecting group is selected from well-known phenol protecting groups such as methoxyethoxymethyl, methoxymethyl, aryloyl, arylsulfonyl, dihydropyrane or trimethylsilyl, alkyl, and aralkyl, preferably the protecting group is methoxyethoxymethyl.
In further embodiment of present invention the base used in phenol protection reaction is selected from metal hydrides or carbonates such as sodium hydride, potassium hydride, sodium carbonate or potassium carbonate, preferably the base is selected metal hydrides such as sodium hydride.
In yet further embodiment of present invention the aprotic solvent used in protection reaction is selected from tetrahydrofuran, diethyl ether, isopropyl ether, preferably tetrahydrofuran.
In another embodiment of present invention the intermediate of formula VI is obtained by the condensation reaction of compound of formula IV with cyclohexanone using organic or inorganic base and phase transfer catalyst in the presence water, organic solvent or mixture of water with water immiscible organic solvent.
Formula IV Formula VI wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl,
The organic or inorganic base is selected form alkali metal hydroxide or alkaline earth metal hydroxide, preferably alkali hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, more preferably sodium hydroxide and potassium hydroxide.
The phase transfer catalyst used is such as but not restricted to quaternary ammonium salts or polyethylene glycols, preferably quaternary ammonium salts such as tetrabutylammonium hydrogensulphate, tetralkylammonium halide, wherein the alkyl group can be same or different and contains C 1 -C 6 carbon atoms, such as tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, tetraethylammonium bromide more preferably tetrabutylammonium bromide.
In an embodiment of the invention the solvent used is selected from water, organic solvent or mixture of water with water immiscible organic solvents such as ethers, esters, halogenated solvent, aliphatic and aromatic hydrocarbon, preferably the reaction is carried out in water.
Fourth aspect of the present invention is to provide a novel single step process for the preparation of compound of formula VII from compound formula VI using dimethylamine and/or its salt in the presence of transition metal catalyst and with or without using tertiary
amine in a polar organic solvent at room temperature or at an elevated temperature under hydrogen pressure.
Formula VI Formula VII wherein, R is methoxyethoxymethyl (MEM), methoxymethyl (MOM), aryloyl, arylsulfonyl, tetrahydropyranyl or substituted silyl
In an embodiment of the present invention dimethylamine salt is selected from dimethylamine hydrochloride, dimethylamine hydrobromide, dimethylamine hydroiodide, dimethylamine phosphate or dimethylamine sulfate preferably dimethylamine hydrochloride
In further another embodiment of the present invention the tertiary amine is selected from trialkylamine, alkylarylamine, or triarylamine, preferably trialkylamine, more preferably triethylamine
In yet another embodiment of the present invention the transition metal catalyst is selected from palladium, platinum, rhodium, or nickel. The catalyst is supported or unsupported. Preferably the catalyst is selected from palladium hydroxide or 5-20% palladium supported on carbon, alumina, calcium carbonate or barium sulphate, more preferably 5-20% palladium supported on carbon.
The catalyst concentration with reference to the compound of formula VI is from 1-20 wt %, preferably the catalyst concentration is from 5-12 wt %
In an embodiment of the present invention the polar organic solvent is selected from C 1 -C 10 straight chain or branched alcohol, N,N-dimethylformamide, esters, ethers, halogenated solvents or hydrocarbons. The preferred polar organic solvent of the present invention is C 1 - C 4 straight chain or branched alcohol, preferably C 1 -C 2 alcohol, more preferably methanol.
The concentration of compound of formula VI in the reaction mixture is in the range of 5-15 % with reference to the solvent, preferably 10-15% with reference to the solvent.
The single step reductive animation reaction is carried out at temperature of 25-12O 0 C, preferably at 25-60 0 C 5 preferably at 25-40°C.
The single step reductive animation is carried out under hydrogen pressure ranging from 0.5 to 20 Kg/cm 2 , preferably from 0.5 to 5 Kg/cm 2 , more preferably from 0.5 to 1 Kg/cm 2
The single step reductive amination reaction time varies from 3 to 20 hours, preferably between 8 to 12 hours.
In an aspect of the invention the product obtained is isolated by adjusting the pH of crude aqueous solution to 8-10, extracting with ethyl acetate to obtain crude product of formula VII. The crude product is then purified to obtain pure compound of formula VII with HPLC purity >99%.
In an aspect of the present invention intermediate of formula VI or formula VII is deprotected by using deprotecting reagents to obtain compound of formula V or O- desmethylvenlafaxine of formula I respectively.
Deprotecting reagent is selected from known for such groups, but not restricted to zinc bromide, cerium trichloride, titanium tetrachloride, diisopinocarnpheylchloroborane,
dimethylboron bromide, diphenylboron bromide, pyridinium p-toluenesulfoante, formic acid or trifluoroacetic acid preferably trifluoroacetic acid.
The invention is now demonstrated by the following non limiting illustrative example.
Example 1:
2-(4-Hydroxyphenyl)acetonitrile (Formula III):
1 H NMR in DMSO d 6 (δppm): 9.55 (s, IH, ArOH) 5 7.15 (d, 2H, ArH) 5 6.80 (d, 2H, ArH) 5 3.84 (s, 2H 5 CH 2 ) 1 3 C NMR in DMSO-d 6 (δppm): 156.99, 129.40, 121.21, 119.80, 115.85, 21.73
IR (KBr): 3340.71, 2268.29, 19.9, 1614.42, 1516.05, 1446.61, 1408.04, 1263.37, 1222.87, 1105.21, 943.19, 819.75, 759.95, 707.88, 578.64 cm "1 . GCMS: 133 (base peak), 106, 90, 78.
Example 2:
2-(l-Hydroxycyclohexyl)-2-(4-hydroxyphenyI)acetonitrile (Formula V):
To the stirred solution of cyclohexanone (294.85g, 3.004 moles) and 2-(4- hydroxyphenyl)acetonitrile (100.Og, 0.751 moles) was added potassium tert-butoxide (101.19g, 0.90 moles) in lots at room temperature and reaction mixture was allowed to stir at room temperature for 4-5 hrs. Water . (500 ml) and ethyl acetate (500 ml) were added to above reaction mixture and acidified with dilute HCl to pH 3-4. Organic layer was separated out and aqueous portion was extracted with ethyl acetate (250 ml). Combined ethyl acetate layer was washed with brine (250 ml) and dried over sodium sulphate. Solvent was evaporated under reduced pressure to obtain thick residue. Heptane (200 ml) & ethyl acetate (15 ml) was added to the residue and was heated at 50-55 0 C for 2 hrs. After which time it was cooled to room temperature and the crude off-white solid was filtered out, washed with heptane and dried under vacuum at 40-45°C to obtain pure product. Yield: 114g (65.63%); HPLC: 99.36%; MP: 191-192 0 C. 1H NMR in DMSO-d 6 (δppm): 9.51 (s, IH 5 ArOH ) 7.14 (d, 2H, ArH), 6.75 (d, 2H, ArH), 4.81 (s, IH, OH), 3.96 (s, IH, CH) 5 1.67-1.04 (4 x m, 1OH, cyclohexane protons). 1 3 C NMR in DMSO-d 6 (δppm): 157.06, 130.71, 123.40, 121.08, 114.94, 71.48, 48.03, 35.31, 33.80, 25.09, 21.19, 21.06. IR (KBr):3369.64, 3284.77, 2941.44, 2249.00, 1616.35, 1597.06, 1519.91, 1460.11; 1415.75, 1269.16, 1236.37, 1151.50, 966.34, 837.11, 690.52, 590.22, 540!07 crn 1 GCMS: 133 (Base peak), 115, 106, 90, 78.
Example 3:
4-(2-(Dimethylamino)-l-(l-hydroxycyclohexyl)ethyl)phenol (O-Desmethylvenlafaxine of Formula I):
1 H NMR in DMSO-d 6 (δppm): 9.19 (brd, IH, Ar-OH), 6.95 (d, 2H, ArH), 6.63 (d, 2H, ArH), 5.45 (brd, IH, -OH), 3.0 (dd, IH, CH), 2.71 (t, IH, CH), 2.32 (dd, IH, CH), 2.13 (s,
6H, -N(CHs) 2 ), 1.58-1.27 (m, 7H, CH 2 ), 1.14-1.09 (m, IH, CH 2 ), 1.0-0.95 (m, IH, CH 2 ), 0.91-0.85 (m, IH, CH 2 ).
13 C NMR in DMSO-d 6 (δppm): 155.62, 131.69, 130.11, 114.44, 72.62, 60.47, 51.64, 45.35, 37.21, 32.36, 25.75, 21.31, 21.26 IR (KBr):3014.74, 2937.59, 2833.43, 1620.21, 1595.13, 1505, 1271.09, 1240.23, 1184.29, 1147.65, 1037.70, 964.41, 850, 700.16, cm "1
Example 4:
4-(2-(Dimethylamino)-l -(I -hydroxycyclohexyl)ethyl)phenol succinate (O- Desmethylvenlaf axine succinate of Formula IA) :
O-Desmethylvenlafaxine free base (6Og, 0.2278 moles), acetone (506ml) & water (160 ml) was stirred at 25 0 C for 30 minutes. The solution of succinic acid (27.7g, 0.2345 moles) in acetone (56.6ml) & water (18 ml) was added to above reaction mixture at 25 0 C then it was heated to 58 0 C for 30 minutes to get clear solution. Activated charcoal (1.5g) was added & stirred for 30 minutes at same temperature. Reaction mixture was filtered through celite, washed with acetone (50 ml). Filtrate was cooled to 25-30 0 C and stirred for 2-3 hrs, it was then cooled to 0-5 0 C & stirred for 1.0 hr. White colored product was filtered through Buchnner funnel & washed with acetone. Yield: 82g (94.36%), HPLC Purity: 99.95%, MP: 128-129 0 C
1 H NMR in DMSO-d 6 : 7.02(d, 2H, ArH), 6.66 (d, 2H, ArH), 3.20-3.16 (m, IH 5 CH), 2.79- 2.69 (m, 2H, CH 2 -N(CH 3 ) 2 ), 2.35 (s, 4H 5 2 x -CH 2 COOH), 2.30 (s, 6H, -N(CH 3 ) 2 ), 1.56- 1.34 (2 x m, 7H, cyclohexane protons), 1.13-0.89 (2 x m 5 3H, cyclohexane protons) 1H NMR in DMSO-d 6 + D 2 O(δppm): 7.04 (d, 2H, Ar-H), 6.98 (d, 2H, Ar-H) 5 3.32-3.27 (m, IH 5 -CH), 2.97-2.92 (m, IH, -CH), 2.82-2.79 (m, IH, -CH), 2.41 (s, 6H 5 -N(CHs) 2 ), 2.33
(s, 4H, 2 x -CH 2 COOH), 1.51-1.31 (2 x m, 7H, CH 2 ), 1.10-1.03 (m, 2H, -CH 2 ), 0.91-0.88 (m, IH, -CH 2 )
13 C NMR in DMSO-d 6 (δppm): 174.11, 155.67, 130.28, 130.02, 114.41, 72.16, 59.39, 50.88, 44.37, 36.60, 32.39, 29.96, 25.36, 21.04, 20.95. IR (KBr): 3456.44, 2931.80, 1604.77, 1469.76, 1415.75, 1271.09, 952.84 cm- 1 GCMS: 263, 165, 120, 58 (base peak)
Example 5:
2-(4-((2-Methoxyethoxy)methoxy)phenyl)acetonitirle (formula IV)
The NaH (25.2g; 65% dipersion in oil, 0.6302 moles) was washed with hexane (2 x 100 ml) under nitrogen atmosphere. Dry tetrahydrofuran (300 ml) was added to NaH and the suspension was cooled with stirring to 0-5°C. A solution of 2-(4-hydroxyphenyl)acetonitirle (50g, 0.3755 moles) in dry tetrahydrofuran (150 ml) was added drop wise over a period of 1 hr at 0-5° C. Reaction mixture was stirred for 25-30 minutes. Methoxyethoxyniethyl chloride (MEM-Cl) (59.2g, 0.4752 moles) in dry tetrahydrofuran (50 ml) was added drop wise at 0-5° C over a period of 30 minutes and was stirred for further 15 minutes at the same temperature. Reaction mixture was then gradually warmed to 25-30° C and stirred for another 24 hrs at room temperature. Reaction progress was monitored by TLC. After completion of reaction, it was quenched by drop wise addition of methanol (100 ml) at 0-5° C. Reaction solvent was removed completely under reduced pressure and the residue was poured into ice-water (400 ml). Aqueous portion was extracted with ethyl acetate (3 x 200 ml). Combined organic layer was washed with water (200 ml) followed by brine (200 ml). Organic layer was dried over sodium sulphate. Solvent was distilled off under vacuum to obtain crude product (9Og, HPLC purity: 95%). Crude product was then purified by flash column chromatography using ethyl
acetate/hexane as a gradient eluent. Evaporation of the column fractions gave pure liquid compound.
Yield: 72.25g (87%); HPLC purity: 97.18%
1 H NMR in CDCl 3 : δ 7.24 (dd, 2H 5 Ar-H), 7.06 (dd, 2H, Ar-H), 5.27 (s, 2H, -OCH 2 O-),
3.82 (t, 2H 5 -OCH 2 ), 3.69 (s, 2H 5 -CH 2 CN) 5 3.55 (t, 2H ; -OCH 2 ), 3.38 (s, 3H 5 -OCH 3 ),
IR (KBr): 2926.01, 2893.22, 2249.0, 1612.49, 1512.19, 1454.33, 1367.53, 1309.67, 1282.66,
1228.66, 1103.28, 999.13, 846.75, 813.96 cm "1 .
GC-MS: 221 (M + ), 89, 59 (100%).
Example 6:
(l-Hydroxycyclohexyl)-(4-(2-methoxyethoxy)methoxy)phenyl acetonitrile (formula VI)
To the stirred solution of sodium hydroxide (10.4g, 0.26 moles) in water (300 ml) was added TBAB (3g, 0.0093 moles) and allowed to stir for 10 minutes at room temperature. A clear solution thus obtained was then cooled to 0-5° C and mixture of cyclohexanone (34.5g, 0.3515 moles) & 2-(4-((2-methoxyethoxy)methoxy)phenyl) acetonitirle (30g, 0.1356 moles) was added drop wise over a period of 1 hr at 0-5° C. Reaction mixture was then stirred for 10 hrs at 0-5° C. After completion of reaction, aqueous portion was extracted with ethyl acetate (3 x 200 ml). Combined organic layer was washed with water (200 ml) followed by brine (200 ml) and dried over anhydrous sodium sulphate. Solvent was distilled off under vacuum to obtain crude oily product (46g, HPLC purity: 71%). Small amount of crude product was purified by flash chromatography using ethyl acetate/hexane as a gradient eluent. Evaporation of the column fractions gave pure liquid compound. (Note: Crude product with 71% purity was used as such for the next step.) 1H NMR in CDCl 3 : 57.26 (d, 2H, Ar-H), 7.06 (d, 2H, Ar-H), 5.27 (s , 2H, -OCH 2 O-), 3.82 (t, 2H 5 -OCH 2 ), 3.74 (s, IH, -CHCN) 5 3.56 (t, 2H, -OCH 2 ), 3.37 (s, 3H, -OCH 3 ), 1.83-1.50 (3
x m, 10H, 5 x -CH 2 ).
13 C NMR in CDCl 3 : δ 157.42, 130.69, 125.01, 119.84, 116.38, 93.46, 72.74, 71.64, 67.79,
59.04, 49.42, 35.01, 34.87, 25.21, 21.58, 21.51.
IR (KBr): 3469.94, 3458.37, 3444.87, 2933.73, 2860.43,. 2239.36, 1737.86, 1610.56,
1512.19, 1450.47, 1228.66, 1001.06, 989.48, 840.96, 786.96, 540.07 cm "1
GC-MS: 221 (M + - cyclohexanone), 89, 59 (100%).
HPLC Purity: 99.27 %
Example 7: l-(2-(Dimethylamino)-l-(4-((2-methoxyethoxy)methoxy)phenyl)e thyl) cyclohexanol
(formula VII):
purified by flash column chromatography using methanol/ dichloromethane as a gradient eluent. Evaporation of the column fractions gave pure liquid compound.
Yield: 2.7g (43%), HPLC purity - >98%
1 H NMR in CDCl 3 : δ 7.05 (d, 2H 5 Ar-H), 6.96 (d, 2H, Ar-H), 5.26 (s, 2H 5 -OCH 2 O-), 3.85-
3.82 (m, 2H 5 -OCH 2 ), 3.59-3.55 (m, 2H, -OCH 2 ), 3.38 (s, 3H 5 -OCH 3 ), 3.29 (t, IH 5 -CHPh) 5
2.95 (dd, IH 5 -CHN(Me) 2 ), 2.33 (s, 6H 5 2 x -NCH 3 ), 2.28 (dd 5 IH 5 -CHN(Me) 2 ), 1.76-0.85 (3
X m 5 IOH 5 5 x -CH 2 ).
IR (KBr): 2935.66, 2858.51, 2825.72, 1610.56, 1510.26, 1465.9, 1224.80, 1103.28,
1008.77, 842.89 cm -1
Example 8:
4-(2-(Dimethylamino)-l-(l-hydroxycycIohexyl)ethyl)phenol (O-Desmethylvenlafaxine, of formula I)
To the stirred solution of l-(2-(dimethylamino)-l-(4-((2-methoxyethoxy) methoxy)phenyl)ethyl) cyclohexanol (0.6g, 0.00170 moles), in dichloromethane (50 ml) was added trifluoroacetic acid (3 ml) in dichloromethane (3 ml) at 0-5° C over a period of 5 minutes. Reaction mixture was continued to stir at the same temperature for 4-5 hrs. Reaction progress was monitored by TLC. After completion of reaction, pH was adjusted to 10-12 with dilute sodium hydroxide solution and stirred for 5 minutes. Dichloromethane layer was separated out to recover starting material. The pH of the aqueous layer was adjusted to 4-5 using dilute hydrochloric acid and again basified to pH 8-9 using aqueous sodium bicarbonate. This basic aqueous layer was extracted with dichloromethane (3 x 50 ml). Combined organic layer was washed with water (50 ml) followed by brine (50 ml). ). Dichloromethane layer was dried over anhydrous sodium sulphate. Solvent was distilled out
completely under vacuum to obtain a product (0.4 Ig, 91%). Crude product was then purified by flash column chromatography using methanol/ dichloromethane as a gradient eluent. Evaporation of the column fractions gave pure white solid of 0-desmethylvenlafaxine. Yield: 0.3 Ig (70%); HPLC Purity: >98.0%.
Next Patent: IMPROVED PROCESS FOR THE PREPARATION OF 0-DESMETHYL-VENLAFAXINE