FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of 2-((4-tert-butyIcycIohexyl)methyI)-3-hydroxy-l,4-naphthoquinone
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 it is to be performed:

FIELD OF INVENTION
The present invention relates to a novel process for preparing 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone of the formula I.

BACKGROUND OF THE INVENTION
2-((4-Tert-butylcyclohexyl)methyl)-3-hydroyx-l,4-naphthoquinone of
formula I is commonly called buparvaquone. Buparvaquone is a hydroxynaphthoquinone antiprotozoal drug related to parvaquone and atovaquone. It is a promising compound for the therapy and prophylaxis of all forms of theileriosis. Buparvaquone has been shown to have anti-leishmanial activity in vitro. It can be used to treat bovine East Coast fever protozoa in-vitro, along with the only other substance known - Peganum Harmala.
There are many process described in the art for the preparation of 2-((4-tert-butylcyclohexyl)methyl)-3-hydroyx-l,4-naphthoquinone. US patent 4485117 describes a process for the preparation of buparvaquone using 1 -(4-tert-butylcyclohexyl) acetic acid. In this process, when racemic mixture of l-(4-tert-butylcyclohexyl) acetic acid were used then racemic buparvaquone was obtained and when cis and trans isomers of l-(4-tert-butylcyclohexyl) acetic acid were used, then the corresponding cis and trans buparvaquone was obtained.

Chinese patent 10265172 discloses a process for preparation of buparvaquone using stereospecific l-(4-tert-buty]cyclohexyl) acetic acid. This patent is silent about the preparation and separation of pure cis and trans forms of l-(4-tert-butylcyclohexyl) acetic acid.
The prior art process either prepare the desired trans-2-((4-Tert-butylcyclohexyl)methyl)-3-hydroyx-l,4-naphthoquinone by using trans- l-(4-tert-butylcyclohexyl) acetic acid starting material or if they use racemic l-(4-tert-butylcyclohexyl) acetic acid they obtain mixture of cis- and trans-2-((4-Tert-butylcyclohexyl)methyl)-3-hydroyx-l,4-naphthoquinone. There is no process reported for the separation of trans-2-((4-Tert-butylcyclohexyl)methyl)-3-hydroyx-M-naphthoquinone from the mixture. Hence usually a pure trans- l-(4-tert-butylcyclohexyl) acetic acid is used to obtain the desired trans form of buparvaquone. The trans-l-(4-tert-butylcyclohexyl) acetic acid is very costly as compared to racemic compound and the process involves use of hazardous reagent like sodium cyanide, hence the reported process are not cost effective at industrial scale.
Thus there is a need to develop an alternative process for the preparation of buparvaquone, which provides a process for separation of desired trans isomer of buparvaquone from their mixture which is very economical at industrial scale.
SUMMARY OF THE INVENTION
The principal aspect of the invention is to provide a novel process for the preparation of pure trans isomer of 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxys-naphthoquinone of the formula I, which comprises:
a) reacting (4-tert-butylcyclohexyl)acetic acid of formula IV with 2-
chloronaphthoquinone of formula III using a catalyst and a reagent in
presence of solvent to give 2-[(4-tert-butylcyclohexyl)methyl]-3-
chloronaphthoquinone of formula II;

b) treating 2-[(4-tert-butylcyclohexyl)methyl]-3-chloronaphthoquinone of formula II with base in a solvent to obtain mixture of cis and trans 2-((4-tert-butyIcycIohexyI)methyl)-3-hydroxy-l,4-naphthoquinone;and
c) purifying insitu the obtain mixture by a ketonic solvent to obtain pure trans 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone of formula I.
The above process can be illustrated by below scheme:

DETAIL DESCRIPTION OF THE INVENTION
In an embodiment of the invention, the catalyst for reaction of (4-tert-butylcyclohexyl)acetic acid and 2-chloronaphthoquinone in step (a) is preferably silver nitrate and reagent is preferably ammonium per sulphate. The reaction is carried out in solvent acetonitrile, propionitrile, methylene chloride, THF, MIBK, MEK, DMF, diglyme, monoglyme, cyclohexane, Heptane, Toluene, Ethyl acetate, ethyl lactate, chloroform, 1,4-dioxane, dimethyl acetamide, chlorobenzene, preferably acetonitrile at temperature 50 °C to 100 °C, preferably at 75 to 80 °C.

In another embodiment of the invention, 2-[(4-tert-butylcyclohexyl)methyl]-3-chloronaphthoquinone in step (b) is treated with a base selected from an alkali metal hydroxide or an alkali metal carbonate preferably potassium hydroxide and in an alcoholic solvent preferably methanol at temperature 50 °C to 80 °C, preferably 60 to 65 °C.
In yet another embodiment of the invention, the obtained mixture of cis and trans 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone is purified insitu by adjusting the pH using concentrated hydrochloric acid and dissolving in a ketonic solvent selected from acetone, ethyl methyl ketone and methyl isobutyl ketone preferably methyl isobutyl ketone .
In still another embodiment of the invention the starting material 2-chloronaphthoquinone is obtained from a commercial source and (4-tert-butylcyclohexyl)acetic acid is made as per the process available in prior art or preferably made insitu as given in the reference example of this invention.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.
Reference example:
(a) Preparation of ethyI-2-( 4-tert butyl cyclohexylidene) acetate:
To a mixture of Toluene (3 L) and Sodium methoxide (275 mL) a solution of triethyl phosphono acetate (1.6 kg) diluted with toluene was slowly added , temperature was maintained between 15- 20°C. After complete addition RM was stirred at 24 - 28°C for 1 hour and cooled. A solution of p-tert butyl cyclohexanone (1 L) diluted with toluene was slowly added to the above RM at 15-20°C, stirred for one hour at 25-30°C. The RM was heated to 40-45°C, maintained for 2hours. After reaction completion RM was quenched into pre-cooled DM Water at 5-10°C, allowed to attain 25-30°C and the layer were separated. The combined toluene layer was washed with DM Water. Toluene was distilled out completely to get thick liquid which is directly used for next step.

Yield: 1.4 kg
(b) Preparation of (4-tert-butylcydohexylidene)acetic acid:
Methanol (4.5 L) and step a material were charged into a reactor at 25-30°C. A solution of Potassium hydroxide (625 g) in DM water was added to the above RM at 20-30°C, heated to 60 - 65°C and maintained for 5 hrs. After reaction completion methanol was distilled out completely. RM was cooled to 20-25°C, DM Water was added and aqueous layer was acidified slowly with concentrated HC1 to maintain pH 1.0-2.0. Solids were separated and stirred for one hour at 20-25°C. Solids were filtered and washed with DM water till neutral pH.
Yield: 1.1 kg
(c) Preparation of (4-tert-butylcycIohexyl)acetic acid:
(4-tert-butylcyclohexylidene)acetic acid and Pd/C slurry was charged into an Autoclave at 20-30°. Methanol (3 L) was added under nitrogen. Nitrogen gas was purged and pressure was released. Hydrogen gas was purged and pressure was released. After completion of reaction RM was filtered, Pd/C was recovered and filtrate was distilled to remove methanol completely. Acetonitrile was added, heated to get clear solution and cooled to 25-30°C slowly and further maintained for 2 hours at 0-5°C. Solids were filtered and washed with chilled Acetonitrile.
Yield: 0.8 kg
Example : Preparation of 2-((4-tert-butvl cyclohexyl) methyl)-3-hydroxy-l,4-naphthoquinone :
a) Preparation of 2-[(4-tert-butyIcyclohexyI) methyl]-3-
chloronaphthoquinone:
Acetonitrile (8 L), 2-chloro-l,4-napthoquinone and (4-tert-butylcyclohexyl) acetic acid (1.06 kg) were charged into a reactor. A solution of Silver nitrate (250 g) in DM water and ammonium per sulphate (2.31 kg) solution in DM water were

added into the above reaction mass RM and the mixture heated slowly to 75-80°C for 2 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C and further to 0-5°C. The reaction mass was filtered and washed with DM water. The obtained wet solid was dissolved in toluene, filtered and washed with toluene. The reaction mass was distilled and the reaction mass was heated to make a clear solution and then cooled slowly to 25-30°C and further to 0-5°C for 2 hours. Solids were filtered and washed with chilled Toluene.
Yield: 1.2 kg
b) Preparation of 2-[(4-tert-butylcyclohexyl)methyl]-3-
hydroxynaphthoquinone:
Methanol (10 L) and 2-[(4-tert-butylcyclohexyl) methyl]-3-chloronaphthoquinone were charged into a reactor at 25-30°C. A solution of KOH solution in DM water was added drop wise, heated to at 60-65°C and maintained for 5 hours at 60-65°C. Cone. HC1 was added to adjust the pH 1.0-2.0. DM water was added and cooled to 0-5°C.RM was filtered, washed with DM water.
MIBK and the crude solids obtained above were charged into a RBF,
heated to 80-85°C. DM water was added and stirred for 30 minutes. The Aqueous
Layer was separated, DM water was again added and stirred for 30 minutes. Two
layers were separated, organic layer is taken for distillation. RM was distilled to a
residual volume, heated to form a clear solution and slowly cooled to 15-20°C for
2 hours. Solids were filtered and washed with chilled MIBK. MIBK and the
above solids were charged into the flask and heated to form a clear solution, heated to 95-100°C.RM was slowly cooled to 15-20°C for 2 hours. Solids were filtered, washed with chilled MIBK and dried at 70-75°C vacuum.
Yield: 0.6 kg

We claim:
1. A process for the preparation of pure trans 2-((4-tert-butyIcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone of the formula I comprising :

a) reacting (4-tert-butylcyclohexyl)acetic acid of formula JV with 2-chloronaphthoquinone of formula III using a catalyst and a reagent in presence of solvent to give 2-[(4-tert-butylcyclohexyI)methyl]-3-chloronaphthoquinone of formula II;

b) treating 2-[(4-tert-butylcyclohexyl)methyl]-3-chloronaphthoquinone of formula II with base in a solvent to obtain mixture of cis and trans 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone; and

c) purifying insitu the obtain mixture by a ketonic solvent to obtain pure trans
2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone of
formula I.
2. A process according to claim 1, wherein the reaction in step (a) is carried out in presence of a catalyst preferably silver nitrate and reagent preferably ammonium per sulphate.
3. A process according to claim 1, wherein the solvent in step (a) is acetonitrile.
4. A process according to claim 1, wherein the base for treatment in step (b) is selected from an alkali metal hydroxide or an alkali metal carbonate.
5. A process according to claim 4, wherein the base for treatment in step (b) is
potassium hydroxide.
6. A process according to claim 1, wherein the solvent for treatment in step (b) is an alcoholic solvent preferably methanol.
7. A process according to claim 1, wherein the treatment in step (b) is carried out at temperature 50 0C to 80 0C, preferably 60 to 65 OC.
8. A process according to claim 1, wherein the ketonic solvent for purification in step (c) selected from acetone, ethyl methyl ketone and methyl isobutyl ketone.
9. A process according to claim 1, wherein the ketonic solvent for purification in step (c) is methyl isobutyl ketone.