CLIAMS:We Claim:

1. A process for the preparation of dehydroatovaquone of formula II

Formula II
which comprises:

a) halogenation of 2-Chloro-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione with halogenating agent in presence of solvent to provide 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione; and

b) reaction of 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione with a base in presence of a solvent to provide dehydroatovaquone of formula I.

2. The process of claim 1, wherein the halogenating agent is N-chlorosuccinimide (NCS) or N-bromosuccinimide (NBS).

3. The process of claim 1, wherein the halogenation reaction of step a) is performed in presence of catalyst such as azobisisobutyronitrile or dibenzoyl peroxide.

4. The process of claim 1, wherein the solvent for step a) is selected from chlroinated solvent such as dichloromethane, chloroform, dichloroethane and chlorobenzene.

5. The process of claim 1, wherein the base used in the step b) is selected from inorganic base or organic base.

6. The process of claim 1, wherein the base used in the step b) is potassium hydroxide.

7. The process of claim 5, wherein the solvent of step b) is alcohol such as methanol.
,TagSPECI:4. DESCRIPTION

The present invention provides a chemical process for preparing dehydroatovaquone of Formula II, which is useful as intermediate and reference marker for atovaquone.

Formula II

Atovaquone, chemically known as trans-2-[4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthalenedione of Formula I:

Formula I

Atovaquone is a widely used antiprotozoal and is potently active (in animals and in vitro) against Pneumocystis carinii, Plasmodia, and tachyzoite and cyst forms of Toxoplasma gondii. It is a highly lipophilic compound resembling ubiquinone and has a low aqueous solubility. This is the reason for the poor bioavailability of atovaquone after oral administration.

U.S. Patent No. 4,981,874 discloses the use of atovaquone against Pneumocystis carinii infection in a mammal. EP Patent No. 0 123 238 and U.S. Patent No. 5,053,432 disclose the use of atovaquone against Plasmodium falciparum and also against Eimeria species such as E. tenella and E. acervulina which are causative organisms of coccidiosis. Further, use of atovaquone against Toxoplasmosis and Cryptosporidiosis is disclosed in EP Patent No. 0 445 141 and 0 496 729 respectively.

Currently, atovaquone suspension marketed under trade name MEPRON is a formulation of micro-fine particles of atovaquone.

The skilled in the art of drug manufacturing research and development understand that a compound in a relatively pure state can be used as a "reference standard." A reference standard is similar to a reference marker, which is used for qualitative analysis only, but is used to quantify the amount of the compound of the reference standard in an unknown mixture, as well. A reference standard is an "external standard," when a solution of a known concentration of the reference standard and an unknown mixture are analyzed using the same technique. (Strobel p. 924, Snyder p. 549, Snyder, L. R.; Kirkland, J. J. Introduction to Modern Liquid Chromatography, 2nd ed. (John Wiley & Sons: New York 1979)). The amount of the compound in the mixture can be determined by comparing the magnitude of the detector response.

The reference standard can also be used to quantify the amount of another compound in the mixture if a "response factor," which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined. (Strobel p. 894). For this purpose, the reference standard is added directly to the mixture, and is known as an "internal standard." (Strobel p. 925, Snyder p. 552).

Use of a compound as a reference marker requires recourse to a sample of substantially pure compound. Therefore, there is a need to develop an efficient process to provide Dehydroatovaquone of Formula II, which can be used as reference marker to establish the level of the purity of Atovaquone.

The inventors of the present invention developed a new process to provide dehydroatovaquone of Formula II from new intermediate of 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione, which is industrially feasible.

In an aspect, the present invention provides a process for the preparation of dehydroatovaquone of Formula II. The process comprises:

a) halogenation of 2-Chloro-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione with halogenating agent in presence of solvent to provide 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione; and

b) reaction of 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione with a base in presence of a solvent to provide dehydroatovaquone of formula I.

In an embodiment, the process of the present invention comprises halogenation of 2-Chloro-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione with halogenating agent in presence of solvent to provide 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione.

The halogenating agent may suitably be used 1 to 3 equivalents of the 2-Chloro-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione compound to be halogenated, in order to get desirable yields. Preferably 1-2 equivalents of halogenating agent are used.

The halogenating agent is selected from the group of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), or 1,3-dibromo-5,5-dimethylhydantoin (DBDMH)

The halogenation with NBS may be performed in presence of catalyst, for example Azobisisobutyronitrile (AIBN) or dibenzoyl peroxide.

The solvent for the halogenation reaction is selected from chlroinated solvent such as dichloromethane, chloroform, dichloroethane, chlorobenzene and the like; ester such as ethyl acetate, isopropyl acetate and the like. In embodiment, the solvent is chloroform for the halogenation reaction of the present invention.

The reaction may be performed at a temperature of about 35 to reflux. The reaction may be performed at reflux for a period of at least 2 hours to complete the conversion of starting material.

After completion of the reaction, the reaction mixture may be cooled to room temperature or to 0°C to provide 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione. The compound may be recrystallized from alcohol, for example, methanol, ethanol, isopropyl alcohol and the like.

In another embodiment, the process of the present invention comprises reaction of 2-(4-halo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione with a base in presence of a solvent to provide dehydroatovaquone of formula I.

The suitable base used for reaction includes but are not limited to inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and the like; organic base such as triethyl amine, pyridine, N-methyl pyrrolidine (NMP) and the like.

The solvent for conducting the reaction is selected from alcohol such as methanol, ethanol, isopropyl alcohol and n-butanol. The reaction is conducted at above 35 °C or at reflux temperature for a period of at least 1 hour.

After completion of the reaction, the reaction mixture is cooled to room temperature and treated with acid, for example, acetic acid to provide dehydroatovaquone.

The obtained compound may be purified by using conventional techniques such as recrystallization, column chromatography, anti-solvent technique and the like.

The resultant of the present invention, dehydroatovaquone, can be utilized for the preparation of atovaquone by using known process in the art. Further, the dehydroatovaquone is utilized as reference marker for analysis.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

EXAMPLES:

Example-1:
Process for 2-(4-Bromo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione

2-Chloro-3-(4-(4-chlorophenyl)cyclohexyl)naphthalene-1,4-dione (50.0 g) was dissolved in carbon tetrachloride (2.25 L) and treated with N-bromosuccinimide (24.5 g) in presence of catalytic Azobisisobutyronitrile (0.5 g). The reaction mixture was stirred at reflux for 10 hours. The reaction mixture cooled to room temperature and filtered the reaction mixture. The resultant filtrate recovered under reduced pressure. The remaining yellow solid was recrystallized from methanol to get 56.0 g. The crude product used in next stage without purification.

Example-2:
Process for Dehydroatovaquone

2-(4-Bromo-4-(4-chlorophenyl)cyclohexyl)-3-chloronaphthalene-1,4-dione (55.0 g) was dissolved in methanol (800 mL) and treated with 10 % potassium hydroxide solution (290 mL). The reaction mixture was stirred at reflux for 4 hours. The reaction mixture cooled to room temperature and acidify with acetic acid (100 mL). The resultant suspension was filered and washed with the mixture of methanol and water to get 25.1 g. The desired product was isolated by column chromatography.

HPLC purity: more than 85 %