FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of Acitretin
SeQuent Scientific Limited
A Company Incorporated Under The Companies Act, 1956
Having Registered Office at
116 Vardhman Industrial Complex, L.B.S Marg,
Thane (W), Mumbai - 400 601, India
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for preparing a retinoid class of drug, specifically Acitretin.
BACKGROUND OF THE INVENTION
Acitretin, an aromatic analogue of retinoic acid, is useful in the treatment of hyperkeratotic skin diseases such as psoriasis. It is a member of the retinoid family, a group of compounds related to retinol (vitamin A). Acitretin is marketed in the brand name "Soriatane" and "Neotigason",
The chemical name of acitretin is (2E,4E,6E,8E)-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid represented by formula I.

There are number of literatures available which describe the process for the preparation of compound of the formula (I), US patent 4105681 describes a process for the preparation of acitretin by reacting 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-mefhyl-penta-2,4-diene-1 -triphenyl phosphonium bromide with 3-formylcrotonic acid butyl ester using DMF and sodium hydride and further hydrolyzing the obtained ester using potassium hydroxide and ethanol. This process gives mixture of cis and trans isomers of the ester in the ratio of 55:45, which is hydrolysed as such. It involves tedious work up and precipitation with huge amount hexane to get pure product.
US7129365 describes a process for the preparation of pure acitretin by contacting crude acitretin with solvent, in the presence of a free radical scavenger such as butylated hydroxy anisole or butylated hydroxy toluene, and

isolating the substantially pure acitretin. In this process huge amount of solvent is required to dissolve the material in THF. In this process butylated hydroxy anisole or butylated hydroxy toluene is added to avoid isomerization of product, since product tends to degrade in THF solution resulting in additional steps of tedious workup.
CN10I26518I provides a process for isomerization of aryl substituted 11- and/or 13-cis-nonatetraenes to obtain all-trans isomers in the presence of a heavy metal catalyst. This patent mentions that when Pd(OAc)2(Ph3P)2 is used as heavy metal catalyst for the isomerisation of 9-(4-methoxy-2.3,6-trimethylphenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-l-oic acid butyl ester (also called as acitretin butyl ester), the desired all -trans isomer achieved is 74.8% and the remaining 25.2% are undesired cis-isomers. This patent also mentions that 99.7% all-trans isomer is obtained when Pd(NO3)2+Ph3P is used as a heavy metal catalyst for the isomerisation. The drawback of this process is that it needs an additional step of isomerisation, which involves isolating the acitretin butyl ester and dissolving in high volume of solvent and further treating with a heavy metal catalyst such as Pd(N03). These heavy metal catalysts are very hygroscopic and costly hence it is not preferred on industrial scale.
The major drawback in the above stated prior arts is the formation of cis-isomers of acitretin butyl ester whose physical properties are very similar to that of trans-isomer. This makes the purification of acitretin butyl ester very tedious and moreover repeated purification is required to get the desired purity. The repeated purification results to the loss of acitretin butyl ester which is very costly hence not preferred on industrial scale.
Therefore, there is a continued need to develop a process which overcomes most of the above stated drawbacks. The present inventors have developed a very cost effective and robust process for preparation of acitretin which overcomes most of the above drawback.

SUMMARY OF THE INVENTION
The principal aspect of the present invention is to provide a process for the preparation of (2E,4E,6E!8E)-9-(4-methoxy-2J3,6-trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid of formula I, which comprises:
a) condensing 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenyl phosphonium bromide of formula III with 3-formylcrotonic acid butyl ester of formula IV using ethyl acetate and base to form acitretin butyl ester of formula II;
b) isolating the acitretin butyl ester of formula II by an alcoholic solvent; and
c) hydro lyzing acitretin butyl ester of formula II using a base in an alcoholic solvent to form acitretin of formula I.
The process of the present invention may be illustrated by the below reaction scheme:


DETAIL DESCRIPTION OF THE INVENTION
Accordingly in an embodiment of the invention, condensation of 5-(4-methoxy-2,3,6-trimethyl-phenyI)-3-methyI-penta-2,4-diene-l-triphenyI phosphonium bromide of formula III with 3-formylcrotonic acid butyl ester in step (a) is carried out in presence of ethyl acetate and a base preferably an organic base selected from ammonia, methylamine, pyridine, triethylamine, imidazole, benzimidazole, histidine, N-methyl morpholine and the like, more preferably triethylamine. The condensation reaction in step (a) is carried out at a temperature in the range of 50 to 90° C, preferably 70-85° C most preferably at reflux temperature.
In another embodiment of the invention, the isolation of acitretin butyl ester of formula II is carried out by an alcoholic solvent like methanol, ethanol, propanol, butanol etc. preferably by methanol to obtain pure acitretin butyl ester of formula II.
In yet another embodiment of the invention, hydrolysis of acitretin butyl ester of formula II in step (c) is carried out using an aqueous solution of base preferably alkali metal hydroxide selected from sodium hydroxide or potassium hydroxide, preferably sodium hydroxide and an alcoholic solvent selected from methanol, ethanol, propanol and the like, preferably ethanol at the temperature range of 60 to 100° C preferably at 75-85° C to obtain acitretin of formula I. The obtained acitretin is further crystallized by water and/or acetone to obtain acitretin of purity more than 99%.
In still another embodiment, the present invention has following advantages over the stat-of-the art:
a) The present invention avoids the use of sodium hydride for condensation, which is highly reactive in presence of water.
b) The present invention avoids the use of free radical scavenger such as butylated hydroxy anisole or butylated hydroxy toluene, which requires high volume of solvent to dissolve the crude acitretin.

c) The present invention obviates the step of isomerisation which in turn avoids the use of heavy metal catalyst resulting the process very operation friendly and highly specific to formation of the desired product.
d) The process of the present invention is cost effective and provides a very high yield.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Example:
a) Preparation of acitretin butyl ester :
Ethyl acetate (10 L) and 5-(4-methoxy-2,3,6-trimethyl-phenyI)-3-methyl-penta-2,4-diene-l-triphenyl phosphonium bromide (2.0 kg) were stirred for 15 minutes at 25 to 35°C. Triethylamine (1.06 kg) was added and stirred for 15 minutes. 3-Formylcrotonic acid butyl ester (0.84 kg) was added and the reaction mass was heated to reflux temperature (78±2°C) and maintained under stirring for 2.5 hrs. After completion of reaction, the reaction mass was cooled to 25 to 35°C. Water was added to the above reaction mass and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The ethyl acetate was distilled out from the combined ethyl acetate layer. Methanol (16L) was added to the residue at below 50°C and stirred for 30 min at 25 to 35°C. The reaction mass was cooled to -5 to -10°C and stirred for 4 hrs. The product was filtered at -5 to -10°C, washed with chilled methanol and suck dried.
Yield: 0.96 to 1.04 kg.
b) Preparation of acitretin :
Water (14.3 L) and Sodium hydroxide (0.45 kg) were charged into the flask, cooled to 27 ±2°C. Ethanol (21.5 L) and Acitretin butyl ester (1.43 Kg) were added to the above reaction mass, heated to reflux at 80 ±2°C and maintain for 40 minutes. After completion of reaction, the reaction mass was

cooled to 27 ±2°C and filtered. Water (28.6 L) was added to RBF and cooled to 5-10°C. The filtrate was added to above chilled water at 5 to 10°C, pH was adjusted to 2.0 - 3.0 using concentrated hydrochloric acid (1.4 to 1.6 L) at 5-10°C and stirred for one hour at 5 -10°C. The product was filtered and suck dried. The solid was washed with water (19 L) at 27 ±2°C till pH is neutral and suck dried. The obtained acitretin is further purified by water and acetone to obtain pure acitretin having HPLC purity 99.5%.
Yield: 1.0 kg.

We claim:
1. A process for the preparation of (2E34E,6E,8E)-9-(4-methoxy-2,3,6-
trimethylphenyl)-3,7-dimethylnona-2,4,6,8-tetraenoic acid of formula I,
which comprises:

a) condensing 5-(4-methoxy-2,3,6-trimethyl-phenyl)-3-methyl-penta-2,4-diene-1-triphenyl phosphonium bromide of formula III with 3-formylcrotonic acid butyl ester of formula IV using ethyl acetate and base to form acitretin butyl ester of formula II;

b) isolating the acitretin butyl ester of formula II by an alcoholic solvent; and

c) hydrolyzing acitretin butyl ester of formula II using a base in an alcoholic solvent to form acitretin of formula I.

2. A process according to claim 1, where in the base used in step (a) is an organic base selected from methylamine, pyridine, triethylamine, imidazole, benzimidazole, histidine, N-methyl morpholine.
3. A process according to claim 1, wherein the base used in step (a) is triethylamine.
4. A process according to claim 1, wherein the condensation in step (a) is carried out at reflux temperature.
5. A process according to claim 1, wherein alcoholic solvent in step (b) & (c) is selected from methanol, ethanol, propanol, and butanol.
6. A process according to claim 1, wherein alcoholic solvent in step (b) is methanol.
7. A process according to claim 1, wherein alcoholic solvent in step (c) is ethanol.
8. A process according to claim 1, wherein base used in step (c) is alkali metal hydroxide selected from sodium hydroxide or potassium hydroxide.
9. A process according to claim 1, wherein base in step (c) is sodium hydroxide.
10. A process according to claim 1, wherein the acitretin of formula 1 is crystallized by water and acetone.