FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
The patent Rules, 2003
COMPLETE SPECIFICATION
A Process for Preparation of 2-((4-tert-butylcyclohexyl)methyl)-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-butylcydohexyI)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 l-(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 were obtained.

Chinese patent 10265172 discloses a process for preparation of buparvaquone using stereospecific l-(4-tert-butylcyclohexyl) acetic acid. This patent is silent about the preparation and separation of pure cis and trans forms of l-(4-tert-butylcyclohexyl) acetic acid.
Our other pending patent application 356/MUM/2012 Al describes a
process for preparation of pure trans isomer of 2-((4-tert-butylcyclohexyl)methyl)-
3-hydroxy-l,4-naphthoquinone by reacting (4-tert-butylcyclohexyl)acetic acid
with 2-chloronaphthoquinone using silver nitrate as a catalyst and ammonium per
sulphate as a reagent in acetonitrile to give 2-[(4-tert-butylcyclohexyl)methyl]-3-
chloronaphthoquinone; treating 2-[(4-tert-butylcyclohexyl)methyl]-3-
chloronaphthoquinone with potassium hydroxide in methanol at temperature 60 to 65 °C to obtain a mixture of cis and trans 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone; and purifying the obtain mixture by methyl isobutyl ketone to obtain pure trans 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone.
All most all the processes reported in prior art including the process disclosed in our above mentioned pending application, use costly silver nitrate as catalyst, ammonium persulphate as reagent and acetonitrile as solvent. Moreover the process involves the free radical reaction, which always results to low yield. The recovery of silver from the process is lengthy and tedious.
Thus there is a need to develop an alternative process for the preparation of buparvaquone, which avoids silver nitrate and other costly reagents and solvents.
SUMMARY OF THE INVENTION
The principal aspect of the invention is to provide a novel process for the preparation of 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l ,4-naphthoquinone of the formula I, which comprises:

a) condensing lH-isochromene-l,4(3H)-dione of formula IV with (4-tert-butylcyclohexyl)acetaldehyde of formula III using a base in presence of solvent to give 3-[(4-tert-butylcyclohexyl)methylene]-lH-sochromene-l,4(3H)-dione of formula II; and
b) treating 3-[(4-tert-butylcyclohexyl)methylene]-lH-isochromene-1,4(3H)-dione of formula II with base in a solvent to obtain 2-((4-tert-butylcyclohexyl)methyl)-3-hydr0xy-1,4-naphthoquinone of formula I.
The above process can be illustrated by below scheme 1:

DETAIL DESCRIPTION OF THE INVENTION
In an embodiment of the invention, condensation of lH-isochromene-l,4(3H)-dione of formula IV with (4-tert-butylcyclohexyl)acetaldehyde of formula

III is carried out using a base preferably Isobutyl amine in presence of solvent selected from methanol, ethanol, isopropanol, acetic acid preferably acetic acid to give 3-[(4-tert-butylcyclohexyl)methylene]-lH-isochromene-l ,4(3H)-dione of formula II.
In another embodiment of the invention, 3-[(4-tert-butylcyclohexyl)methylene]-lH-isochromene-l,4(3H)-dione of formula II in step (b) is treated with a base which is an alkoxide selected from sodium methoxide, sodium ethoxide, sodium propoxide, preferably sodium methoxide in presence of solvent selected from methanol, ethanol, isopropanol, preferably methanol to form 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone of formula I.
In yet another embodiment of the invention, the starting material 4-tert-butylcyclohexyl)acetate of formula III may be prepared by the process available in the art or it can be prepared by the condensation of 4-tert-butylcyclohexanone with triethyl phosphono acetate using sodium methoxide in presence toluene to give ethyl-2-(4-tert-butylcyclohexylidene) acetate, which can be reduced using palladium on carbon in presence of methanol to obtain ethyl(4-tert-butylcyclohexyl)acetate. Ethyl(4-tert-butylcyclohexyl)acetate thus obtained can be hydrolyzed using lithium aluminium hydride in presence of chlorobenzene to form 4-tert-butylcyclohexyl)acetate.
In still another embodiment, the process of the present invention obviates the use of costly catalyst, reagents and solvents viz. silver nitrate, ammonium persulphate and acetonitrile. Moreover, the process of the prior art involves the free radical reaction, which always results in lower yield.
The present invention is illustrated by the following examples, which are not to limit the scope of the invention.

Example 1 : Preparation of 2-((4-tert-butyl cyclohexyl) mcthvn-3-hydroxy-1,4-naDhthoquinone:
a) Preparation of 3-[(4-tert-butylcyclohexyl)methylene]-lH-isochromene-l,4(3H)-dione:
1,4-Isochromandione lOg was taken in acetic acid l00mL and (4-tert butyl cyclohexyl) acetaldehyde 11.2g was added, the mixture was treated with Isobutyl amine 1.5g in acetic acid. The reaction mixture was heated to 35-40 °C and stirred for 10-15 hours to completion of reaction. The reaction mixture was diluted with water (50 mL) and stirred. The solid was filtered and washed with water and dried. The solid was further crystallized with IP A.
Yield: 11.Og.
b) Preparation of 2-[(4-tert-butylcyclohexyi)methyI]-3-
hydroxynaphthoquinone:
The step-1 9g. was taken in methanol 90mL. sodium methoxide 2.8g was added and the reaction mixture was stirred at 25-30°C for 15-20 hours. The reaction mixture was diluted with water 90mL, a yellow solid precipitated,. The solid was filtered and washed with water and dried. The solid product was-recrystallised with MIBK to get the pure title compound as yellow crystals.
Yield: 4.5 g. HPLC purity more than 99.5%

We claim:
1. A process for the preparation of 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-l,4-naphthoquinone of the formula I, which comprises:

a) condensing li/-isochromene-l,4(3H)-dione of formula IV with (4-tert-butylcyclohexyl)acetaldehyde of formula III using a base in presence of solvent to give 3-[(4-tert-butylcyclohexyl)methylene]-lH-isochiomene-l,4(3H)-dione of formula II; and

b) treating 3-[(4-tert-butylcyclohexyl)methylene]-lH-isochromene-l,4(3H)-dione of formula II with base in a solvent to obtain 2-((4-tert-butylcyclohexyl)methyl)-3-hydroxy-1,4-naphthoquinone of formula I.
2. A process according to claim 1, wherein base for condensation in step a) is Isobutyl amine.
3. A process according to claim 1. wherein the solvent is selected from methanol, ethanol, isopropanol and acetic acid.

4. A process according to claim 1, wherein the solvent is acetic acid.
5. A process according to claim 1, wherein the base in step b) is an alkoxide selected from sodium methoxide, sodium ethoxide and sodium propoxide.
6. A process according to claim 1, wherein the base in step b) is sodium methoxide,
7. A process according to claim 1, wherein the solvent in step b) is selected from methanol, ethanol and isopropanol.
8. A process according to claim 1, wherein the solvent in step b) is methanol.