|Title of Invention||
AN IMPROVED PROCESS FOR THE PREPARATION OF VENLAFAXINE AND ITS ANALOGS
|Abstract||A novel single step process for the synthesis of venlafaxine of formula I and N-desmethylvenlafaxine of formula II from 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile [cyano-intermediate] of formula V comprising reacting 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile with an alkylamine and/or its salt in a solvent in the presence of a transition metal catalyst, under hydrogen atmosphere.|
THE PATENTS ACT, 1970
(39 of 1970)
The Patents Rules, 2006
(See section 10; rule 13)
1. Title of the invention. "AN IMPROVED PROCESS FOR THE PREPARATION OF
VENLAFAXINE AND ITS ANALOGS"
(a) NAME: CALYX CHEMICALS AND PHARMACEUTICALS LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 5, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E),
Mumbai-400 072, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.
FIELD OF INVENTION
The present invention relates to a novel process for synthesis of l-[2-dimethylamino-l-(4-methoxyphenyl) ethyl] cyclohexanol, commonly known as venlafaxine, and its analogs of formula I.
BACKGROUND OF THE INVENTION
Venlafaxine (represented by Formula I) and pharmaceutically acceptable salts thereof are new generation antidepressants, which are quite different from other antidepressants having a unique structure and morphological effects. In humans, venlafaxine is transformed by a metabolic pathway into two minor metabolites, N-desmethyl venlafaxine and N, O-didesmethyl venlafaxine and one major metabolite, O-desmethyl venlafaxine.
R = alkyl, aralkyl, H, R1 = alkyl, aralkyl, H R and R1 = removable protecting group
R' = alkyl, aralkyl, H
R1 = removable protecting group
The preparation of venlafaxine from its cyano-intermediate (represented by Formula II) involving two step synthesis is known in prior art. The first step is the reduction of R-CN to R-CH2NH2 and the second step is methylation of the amine by Eschweiler-Clarke reaction. The same is schematically shown as under:
However the above mentioned processes have many disadvantages. The use of
expensive catalyst like rhodium on alumina is one of the important ones. BF3
etherate is highly corrosive & a reducing agent like NaBH4 is again not
Yet another disadvantage is the formation of an impurity of Formula III, which is
formed during methylation using formaldehyde as reagent.
US 6,350,912 disclose a one pot process for the preparation of venlafaxine in 15-28 % yield from the cyano-intermediate. In the said patent venlafaxine of formula I has been prepared by the reduction of cyano-intermediate of formula II (R1 = -CH3) in the presence of formaldehyde and Raney nickel at 60°C and 200 psi pressure of hydrogen.
US2005033088 discloses a two step process for venlafaxine starting from the cyano-intermediate. The cyano-intermediate is reduced in the presence of palladium on charcoal in an organic acid like acetic acid in an autoclave at a pressure of 5-25 kg/cm2 at a temperature in the range of 30-75°C. The product of step 1 is methylated using formic acid, 40% formaldehyde solution and water at a temperature of 90-98°C for 19 hrs to yield venlafaxine hydrochloride.
WO2006035457 discloses a process for the preparation of venlafaxine and its intermediates. The said publication discloses a two step process for the preparation of the venlafaxine from the cyano-intermediate. The process
comprises the step of hydrogenating the cyano-intermediate in the presence of toluene, water, and raney nickel wherein said process yields 66% of an intermediate with 99% HPLC purity. This reaction is carried out at 10-12°C/4-5kg for 2 hours and further at 50°C/7-8kg for 7-8 hours. This intermediate is methylated using formaldehyde and formic acid mixture to form venlafaxine followed by the treatment with HC1 gas dissolved in isopropanol.
Thus, venlafaxine is either prepared from the cyano-intermediate in two steps or is prepared in one pot with poor yield in the prior art. Further all the prior art processes employ formaldehyde as a reactant, which is known to be a carcinogen. Acute exposure is highly irritating to the eyes, nose and throat. Ingestion of formaldehyde is fatal and long term exposure causes respiratory problems and skin irritation.
Hence there is a need to develop an alternative process with better yield, purity and environmentally safe process for the synthesis of venlafaxine and its analogs.
The present inventors have found that compounds of formula I can be prepared in a single step by hydrogenating the cyano-intermediate of formula II in the presence of alkylamine and / or its salt and transition metal catalyst in a solvent.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a one-pot process for the synthesis of venlafaxine and its analogues employing the cyano-intermediate of formula II as the starting material.
It is another object of the present invention to provide an economically viable process for the synthesis of venlafaxine and its analogues.
It is yet another object of the present invention to provide a better yielding process for the synthesis of venlafaxine and its analogues.
It is yet another object of the present invention to provide a process for the synthesis of venlafaxine and its analogues with better purity.
It is a further object of the present invention to provide an environmentally safe process for the synthesis of venlafaxine and its analogues avoiding the use of formaldehyde.
SUMMARY OF THE INVENTION
According to an aspect of the present invention there is provided a novel single step process for synthesis of venlafaxine, and its analogs of formula I from 1-[cyano(aryl)methyl]cyclohexanol of formula II comprising reaction of 1-[cyano(aryl)methyl]cyclohexanol with an alkylamine or its salt in a solvent in presence of a catalyst.
Formula I Formula II
DETAILED DESCRIPTION OF THE PRESENT INVENTION
Venlafaxine is a representative of a new class of antidepressants with a novel chemical structure. The present invention describes a one-pot process for venlafaxine and its analogues starting from the cyano-intermediate of Formula II. The present invention circumvents all the difficulties encountered in the prior art and is an economically viable process.
The present invention relates to a single step synthesis of venlafaxine (la), and N-desmethyl venlafaxine (lb), O-desmethyl venlafaxine (Ic) and N,0-didesmethyl venlafaxine (Id) from compound having formula (II).
la: R = CH3, R1 = CH3 Ib:R = H,R'=CH3
Ic:R = CH3,R' = H Id: R = H, R1 = H
The present inventors have found that compounds of formula I can be prepared in a single step by hydrogenating the cyano-intermediate of formula II in the presence of alkylamine and/or its salt and transition metal catalyst in a solvent under mild reaction conditions.
The present invention avoids an impurity of Formula HI, which is formed during methylation using formaldehyde as reagent.
The reaction is as shown in Scheme-1:
II: R = as specified above Amidine intermediate
I: R1 and R = as specified above
The alkylamine used may be in the form of free base as gas, solution in a solvent such as alcohol or may be in the form of its salt or may be as combination of any of the above.
The molar ratio of the cyano-compound to the alkylamine is from 1:1 to 1:10, more preferably from 1:1 to 1:5.
The catalyst is selected from transition metals like nickel or cobalt, noble metals like platinum, palladium or metal like rhodium. The catalyst may be supported or unsupported. Preferably the catalyst is 5-20% palladium on alumina or 5-20% palladium on carbon or 5-20% palladium on barium sulfate.
The catalyst concentration with reference to the cyano-compound is from 5-100 wt%.
The organic solvent is selected from Q-C4 alcohol, water, N, N-dimethylformamide, esters, ethers, halogenated solvents, hydrocarbons, alone or in combination. The preferred solvent of the present invention is alcohol preferably methanol.
The cyano-compound concentration in the reaction mixture is in the range of 2-20% with reference to the solvent.
Hydrogen pressure is between 1 to 15 atmosphere, more preferably between 1 to 5 atmosphere.
The reaction time varies from 3 to 75 hours, preferably between 10 to 20 hours.
HPLC of the crude reaction mixture showed 10-81 % of required product
depending upon reaction conditions, reagents and their ratio, catalyst and reaction
The reaction conditions like time, temperature, hydrogen pressure and the
concentration of the cyano-compound, alkylamine and the catalyst are to the large
Venlafaxine and its analogs are further converted to their salts by methods known in the literature.
The invention is now demonstrated by the following non limiting illustrative example
General Procedure for preparation of compounds of formula I:
To the stirred solution of l-[cyano(aryl)methyl]cyclohexanol (1.0 equiv) in methanol (10-15 volumes) alkylamine (3 equiv.) was added and the mixture was stirred for 5-10 minutes to get a clear solution. Palladium catalyst (10-20 wt%) was added under nitrogen atmosphere to the above reaction mixture. The reaction mixture was purged with hydrogen gas (three times) and allowed to stir under hydrogen (1-2 atm. press.) at room temperature for 3-75 hrs. The progress of the reaction was monitored by TLC and HPLC. After completion of the reaction, the catalyst was filtered through celite and washed with methanol. The combined filtrate was concentrated to dryness under reduced pressure and the residue was poured in water. The aqueous layer was basified with 10% aq. NaOH to pH 8-10 and extracted with ethyl acetate (3 times). The combined ethyl acetate layers were washed with brine (2 times) and dried over sodium sulphate. Ethyl acetate was evaporated in vacuo to give light yellow gum that turned slowly into pale yellow solid.
1 eq. of the cyano compound, 4 eq. of dimethylamine hydrochloride, 5% palladium on alumina (40 wt% with reference to the cyano compound) in methanol were stirred for 24 hours and worked up as above, showed 81% yield of venlafaxine (by HPLC) in the crude reaction mixture.
Crude reaction mixture was purified using well-known methods reported in the art.
Spectroscopic characterization of Venlafaxine free base and its HCl salt, obtained from above process:
(+)-Venlafaxine-free base (la):
1H NMR in CDC13: 8 7.05 (d, 2H), 6.81 (d, 2H), 3.79 (s, 3H), 3.27 (t, IH), 2.94
(dd, IH), 2.31 (s, 6H), 2.28 (dd, IH), 1.71-0.94 (m, 10H).
13C NMR in CDC13: 6 158.16, 132.65, 130.01, 113.20, 74.14, 61.14, 55.05,
51.52, 45.37, 37.99, 31.07, 25.91, 21.52, 21.23.
HPLC Purity: 99.37 % (area %).
GC-MS: 178 (M+H+).
(+)-Venlafaxine. HCl Salt:
1H NMR in D20: 8 7.23 (d, 2H), 6.91 (d, 2H), 3.71 (s, 3H), 3.54 (t, IH), 3.48 (dd,
IH), 2.97 (dd, IH), 2.69 (s, 6H), 1.41-1.0 (m, 10H).
13C NMR in D20: 8 158.52, 130.86, 128.16, 114.25, 73.23, 58.26, 55.25, 50.38,
44.87, 41.41, 35.07, 33.34, 24.76, 21.08, 20.86.
HPLC Purity: 99.64 % (area %).
GC-MS: 178 (M+H+).
Dated this 29th day of September 2006
OF S.MAJUMDAR & CO Applicants' Agent
|Indian Patent Application Number||1610/MUM/2006|
|PG Journal Number||47/2013|
|Date of Filing||29-Sep-2006|
|Name of Patentee||CALYX CHEMICALS AND PHARMACEUTICALS LTD.|
|Applicant Address||5, MARWAH'S COMPLEX, SAKIVIHAR ROAD, SAKINAKA, ANDHERI(E), MUMBAI-400 072.|
|PCT International Classification Number||C07C213/12,C07C217/64|
|PCT International Application Number||N/A|
|PCT International Filing date|