Indian Patents. 270430:PREPARATION OF NAPTHOQUINONE COMPOUNDS USING 2,3-DIHALONAPHOQUINONE

Title of Invention	PREPARATION OF NAPTHOQUINONE COMPOUNDS USING 2,3-DIHALONAPHOQUINONE
Abstract	The present invention relates to preparation of napthoquinone compounds by using a 2,3-dihalonapthoquinone intermediate.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 OF 1970) & PATENTS RULES, 2006 PROVISIONAL SPECIFICATION (SECTION 10; RULE 13) 'PREPARATION OF NAPTHOQUINONE COMPOUNDS' ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED FIELD OF THE INVENTION The present invention relates to preparation of napthoquinone compounds by using a 2,3-dihalonapthoquinone intermediate. BACKGROUND OF THE INVENTION A wide range of naphthoquinones is known in the art. Such compounds have been variously described as having antimalarial, anticoccidial and antitheilerial activity. Some compounds have also been described as possessing activity against external parasites. Thus, Fieser et al, J. Amer. Chem. Soc. 1948, 70, 3156-3165 (and references cited therein) describes a large number of 2-substituted-3-hydroxy-l,4-naphthoquinones as having antimalarial activity. A number of these compounds have also been described in U.S. Patent Specification No. 2 553 648. Further classes of 2-substituted-3-hydroxy-l,4-naphthoquinones having activity as antimalarial, anticoccidial and/or antitheilerial agents are described in U.S. Patents Nos. 3 367 830, and 3 347 742, U.K. Patent Specification No. 1553424, and European Patent Specifications Nos. 2 228, 77551, 77550 and 123,238. European Patent No. 123,238 discloses 2-substituted-3-hydroxy-l,4-naphthoquinones which are said to be active against the human malaria parasite Plasmodium falciparum and also against Eimeria species such as E. tenella and E.acervulina, which are causative organisms of coccidiosis. 2-Substituted-3-hydroxy-l,4-naphthoquinones(l) have been described in literature as possessing anti-protozoal activity, in particular anti-malarial. Anti-coccicidal activity has also been reported to a lesser extend. Hundreds of such compounds as possessing anti-malarial activity have been disclosed by Feiser and coworkers. All these compounds use 2-chloro-l,4-naphthoquinone(2) as one of the starting materials. CI OH o O (2) (3) 0=C-OH (4) Synthesis of 2-chloro-l,4-naphthoquinone in the laboratory always resulted in a mixture of monochloro and dichloronaphthoquinone i.e. 2-Chloro and 2,3-Dichloronaphthoquinones. Material procured from market was also found to contain almost 10-12% of 2,3-dichloronaphthoquinone(3). The preparation of pure 2-chloronaphthoquinone from this material is tedious and results in loss, making it expensive. Prior art has used the condensation of trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid(4) with 2-chloro-l, 4-naphthoquinone(2) to give 2-chloro-3-[trans-4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone(5) which on hydrolysis yielded Atovaquone (6). We have however found that condensation of trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid(4) with the abundantly available, commercially inexpensive 2,3-dichloronaphthoquinone(3) gave an improved yield of 2-chloro-3-[trans-4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone(5) which on hydrolysis yielded Atovaquone (6). SUMMARY OF THE INVENTION FORMULA (I) 3 The present invention provides, in a first aspect, use of 2, 3-dihalonaphthoquinone compounds of Formula 1, wherein R1 and R2 are halogens selected from the group comprising CI, Br, I and F, for the preparation of napthoquinone compounds. R1 and R2 may be the same halogen or may contain different halogen groups. The present invention also provides the use of 2, 3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula IA O FORMULA (IA) wherein X is any aryl, heteroaryl, alkyl groups and the like. Particularly the present invention provides the use of 2, 3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof. FORMULA (II) wherein R2 is defined as above and R3 is selected from the group comprising C 1-6 alkoxy; aralkoxy; C 1-6 alkyl- C 1-6 alkoxy; hydrogen; unsubstituted phenyl; phenyl substituted by one or more groups, preferably selected from halogens; C 1-6 linear or branched alkyl, halogen and perhalo- C 1-6 alkyl. It is to be noted that the Formula II will cover the stereoisomers including geometrical and optical isomers of the compounds disclosed above. The napthoquinone compounds of Formula II comprising 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof, may then be optionally used to prepare 2-cyclohexyl -1,4-naphthoquinones compounds of Formula III. FORMULA (III) Wherein R3 is defined as above and R4 is selected from the group comprising hydroxyl; a group OCOR5, wherein R5 is a C1-10 alkyl group, a C3-10 cycloalkyl group, a C1-10 alkoxy group, or a phenyl or naphthyl group, each such R5 group being optionally substituted e.g. by amino, mono or di-C 1 –4 alkylamino, carboxy or hydroxy; a group OR6 or SR6, wherein R6 is an optionally substituted C1-10 alkyl, Cs - 1 o cycloalkyl, phenyl or naphthyl group as defined for R5 or a group NR'R8, wherein R7 and R8 each independently represent hydrogen or C1-6 alkyl, or the group NR R3 represents a 5-7 membered saturated heterocyclic ring, which may optionally contain a further heteroatom selected from nitrogen, oxygen or sulphur; and physiologically acceptable salts and other physiologically functional derivatives thereof. DESCRIPTION OF THE INVENTION The present invention relates to the preparation of napthoquinone compounds by using a 2, 3-dihalonapthoquinone intermediate. More specifically the invention is concerned with the use of novel intermediate 2,3-dihalonapthoquinone (Formula I) for the preparation of napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof. The napthoquinone compounds of Formula II may then be used for preparation of 2-cyclohexyl-1,4-naphthoquinones compounds of Formula III The invention accordingly provides, in a first aspect, use of 2,3-dihalonaphthoquinone compounds of Formula I, wherein R1 and R2 are halogens selected from the group comprising CI, Br, I and F, for the preparation of napthoquinone compounds. R1 and R2 may be the same halogen or may contain different halogen groups. FORMULA (I) A particularly preferred example of the compound of Formula I is 2,3-dichloro naphthoquinone. The present invention also provides the use of 2,3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula IA FORMULA (IA) Wherein X is any aryl, heteroaryl, alkyl groups and the like. FORMULA (II) Particularly the present invention provides the use of 2,3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof. wherein R2 is defined as above and R3 is selected from the group comprising C 1-6 alkoxy; aralkoxy; C1-6 alkyl- C1-6 alkoxy; hydrogen; unsubstituted phenyl; phenyl substituted by one or more groups, preferably selected from halogens; C1-6 linear or branched alkyl, halogen and perhalo-C 1-6 alkyl. It is to be noted that the Formula II will cover the stereoisomers including geometrical and optical isomers of the compounds disclosed above. Some non-limiting examples of compounds of Formula II include: 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone; 2-Cyclohexyl-3-chloro-l,4-naphthoquinone, and 2-trans-(4-t-Butylcyclohexyl)-3-chloro-l,4-naphthoquinone. The napthoquinone compounds of Formula II, selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof, may then be optionally used to prepare 2-cyclohexyl -1,4-naphthoquinones compounds of Formula III. FORMULA (in) wherein R3 is defined as above and R4 is selected from the group comprising hydroxyl; a group OCOR5, wherein R5 is a C1-10 alkyl group, a C3-10 cycloalkyl group, a C1-10 alkoxy group, or a phenyl or naphthyl group, each such R5 group being optionally substituted e. g. by amino, mono-or di-C 1-4 alkylamino, carboxy or hydroxy; a group OR6 or SR6, wherein R6 is an optionally substituted C1-10 alkyl, C1-10 cycloalkyl, phenyl or naphthyl group as defined for R5; or a group NR7R8, wherein R7 and Rs each independently represent hydrogen or C1-4 alkyl, or the group NR7R8 represents a 5-7 membered saturated heterocyclic ring, which may optionally contain a further heteroatom selected from nitrogen, oxygen or sulphur; and physiologically acceptable salts and other physiologically functional derivatives thereof. Some non-limiting examples of compounds of Formula III include: 2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (Atovaquone); 2-Cyclohexyl-3-hydroxy 1,4-naphthoquinone (Parvaquone) and ; 2-trans-(4-t-Butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone. The 2,3-dihalonaphthoquinone compounds of Formula I is treated with a cyclohexane carboxylic acid or any substituted derivative thereof in the presence of silver nitrate and ammonium persulphate to give the napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof. The napthoquinone compounds of Formula II, may be further converted to 2-cyclohexyl -1,4-naphthoquinones compounds of Formula III using various reagents known in the art. For example the napthoquinone compounds of Formula II may be hydrolyzed with potassium hydroxide to give 2-cyclohexyl-3-hydroxyl-1,4-naphthoquinones compounds. Particularly preferred compounds for use according to the present invention includes use of 2,3-dichloronaphthoquinone for the preparation of 2-chloro-3-trans-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone and subsequently of 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone). In the course of our investigations on the synthesis of Atovaquone (6) we found surprisingly that the condensation of trans-4-(4-chlorophenyl)cyclohexane carboxylic acid (4) with the abundantly available, commercially inexpensive 2,3-dichloronaphthoquinone (3) in the presence of silver nitrate and ammonium perdisulphate gave a reasonable yield of 2-chloro-3-trans-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (5) which on hydrolysis yielded Atovaquone (6). Since position 3 in 2,3-dichloronaphthoquinone was occupied by a chlorine atom, it was not anticipated that it would be displaced by a substituted cyclohexyl group. This surprising finding led us to a systematic study of the reaction using pure 2,3-dichloro naphthoquinone (3) and different mixtures of this with 2-chloronaphthoquinone (2). Table 1 summarizes the results with yields of 2-chloro-3-trans -[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (5) and Atovaquone (6). The table shows clearly that mixtures of 2-chloro-l,4-naphthoquinone (2) and 2,3-dichloro naphthoquinone (3) particularly in the range of (3) : (2) = 9 : 1 to 1 : 9 gave better yields of 2-chloro-3-trans-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (5) and hence of Atovaquone (6) when compared to the use of 2-chloronaphthoquinone (2) or 2,3-dichloronaphthoquinone (3) alone. Since the preparation of pure 2-chloronaphthoquinone goes through a crude product which contains at least 10% 2,3-dichloronaphthoquinone, the process of our invention allows the direct use of this crude mixture. Table 1 s.No. Quantity of 2,3-Dichloro 1,4-napthoquinone (3) Quantity of 2-Chloro-l,4-naphthoquinone (2) Ratio %Wt./ wt. Yield of (5) Yield of Atovaquone 1 5.0 gm - + 98% 1.5 gm 0.999 gm 2 4.5 gm 0.5 gm 90: 10 2.0 gm 1.334 gm 3 3.5 gm 1.5 gm 70:30 2.0 gm 1.334 gm 4 2.5 gm 2.5 gm 50:50 2.1 gm 1.400 gm 5 1.5 gm 3.5 gm 30:70 2.0 gm 1.334 gm 6 0.5 gm 4.5 gm 10 : 90 2.0 gm 1.334 gm 7 - 5.0 gm +98% 1.25 gm 0.833 gm The 2, 3-dichloronaphthoquinone was found to give a product with lesser impurities, for example, from the 2-chloronaphthoquinone reaction, the solid product obtained from the reaction was found to consist of 55-75% of the trans isomer(5), 10-20% of the cis- isomer and 3-7% of an unknown impurity. On the other hand, the solid product from the reaction using 2,3-dichloronaphthoquinone had >90% of the trans isomer (5), The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto. EXAMPLE 1 1. 2-\|trans-4-(4-Chlorophenyl)cvclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone): Stage 1: Synthesis of 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone (5) CI A mixture of 2, 3-dichloro-l,4-naphthoquinone (5gm), 4-(4-chlorophenyl)-cyclohexane-1-carboxylic acid (6.06 gm) and silver nitrate (2.47 gm) was taken in acetonitrile (60 ml) and the mixture was heated to reflux, maintaining good stirring. Then a solution of ammonium persulphate (14.23 gm) in water (77 ml) was added through a dropping funnel over a period of 1 - 2 hrs. The mixture was refluxed for 4 hrs. Then it was cooled in ice for about 1 hr after which it was filtered. The solid was extracted with hot methylene chloride (100 ml x 3). The organic layer was dried over anhydrous sodium sulphate and concentrated to get light brownish yellow solid. This on crystallization from acetonitrile afforded the trans compound as yellow crystals (1.5 gm). Melting point, IR, NMR etc. fully matched with the product obtained from monochloro naphthoquinone. The same procedure was adopted for all the remaining five composition reported in Table-1. Stage II. 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone) (6) (5) Product from stage I (1.5gm) was taken in methanol and under stirring, potassium hydroxide (1.52 gm) dissolved in water (15 ml) was added over a period of 15 - 20 minutes, dropwise. The mixture was then refluxed approximately for 6 - 7 hrs. During this period the mixture became dark red. The mixture was then cooled in ice and concentrated hydrochloric acid (5.4 ml) was added dropwise to get yellow solid, which is filtered and washed thoroughly with water. The product after crystallization from methanol-acetic acid afforded the title compound as trans isomer (750 mg). Melting point, IR, NMR matched with the product obtained from monochloro naphthoquinone. EXAMPLE 2 Synthesis of 2-cyclohexyl-3-hydroxy-l,4-naphthoquinone (Parvaquone) (8) Stage I. Synthesis of 2-cyclohexyl-3-chloro-l,4-naphthoquinone (7) A mixture of 2,3-dichloro-l,4-naphthoquinone (5gm), 4-t-butylcyclohexane carboxylic acid (2.7629 gm) and silver nitrate (2.095 gm) was taken in acetonitrile (60 ml) and the mixture was heated to reflux. Then a solution of ammonium persulphate (12.06 gm) in 77 ml of water was added through a dropping funnel over a period of 1 to 2 hrs. The mixture was refluxed for 4 hrs and cooled in ice for about I hr after which it was filtered. The solid was extracted with hot methylene chloride (100 ml x 3). The methylene chloride layer was dried over anhydrous sodium sulphate, concentrated to get light brownish yellow solid. This on crystallization from acetonitrile afforded the title compound as yellow crystals (2.5 gm). 300 MHz NMR of the compound fully agreed with the desired compound o CX^C+ H0OC^> Stage II: 2-Cyclohexyl-3-hydroxy-l,4-naphthoquinone (8) o (7) (8) Product from stage I (1 gm) was taken in methanol and under stirring, potassium hydroxide (1.4 gm), dissolved in water (10 ml) was added over a period of 15 - 20 minutes dropwise. The mixture was then refluxed for 6 - 7 hrs, during which period, it became dark red. The mixture was cooled in ice and concentrated hydrochloric acid (3.6 ml) was added dropwise to get yellow solid, which was filtered and washed thoroughly with water. The product after crystallization from dichloromethane/hexane mixture afforded the title compound (0.75 gm), melting point 128 - 130°C. EXAMPLE 3 1. 2-trans-(4-t-Butylcyclohexyl)-3-hydroxy-l,4-naphthoquinone (10) Stage I: Synthesis of 2-trans-(4-t-butylcyclohexyl)-3-chloro-l,4-naphthoquinone (9) A mixture of 2,3-dichloro-l,4-naphthoquinone (1.925gm), l-trans-(4-t-butyl-cyclohexyl)-carboxylic acid (1.8Q6gm) and silver nitrate (0.95gm) in acetonitrile (25ml) was heated to reflux with vigorous stirring whilst a solution of ammonium persulfate (5.48gm) in water (30ml) was added dropwise over a period of 1 to 2 hrs. The mixture was refluxed for 4 hrs and cooled in ice for about 1 hr after which it was filtered. The solid was extracted with hot methylene chloride (25 ml x 3). The methylene chloride layer was dried over anhydrous sodium sulphate and concentrated to give bright yellow solid which on crystallization from acetonitrile afforded the title compound (0.6gm). The 300 MHz NMR fully agreed with the structure. Stage II: 2-trans-(4-t-Butylcyclohexyl)-3-hydroxy-l,4-naphthoquinone (10) Product from stage I (0.2gm) was taken in methanol (6ml) and under stirring, potassium hydroxide (0.2gm) dissolved in water (2ml) was added over a period of 15 to 20 minutes dropwise. The mixture was then refluxed approximately for 3- 4 hrs. The mixture was cooled in ice and concentrated hydrochloric acid (1 ml) was added dropwise to get yellow solid which was filtered and washed thoroughly with water. The product after crystallization from dichloromethane/hexane mixture afforded the title compound (0.12gm), melting point: 130 -132°C. The structure was confirmed by 300 MHz NMR. Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

Full Text

FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
PROVISIONAL SPECIFICATION (SECTION 10; RULE 13)
'PREPARATION OF NAPTHOQUINONE COMPOUNDS'
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S B.MARG, LOWER PAREL, MUMBAI - 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to preparation of napthoquinone compounds by using a 2,3-dihalonapthoquinone intermediate.
BACKGROUND OF THE INVENTION
A wide range of naphthoquinones is known in the art. Such compounds have been variously described as having antimalarial, anticoccidial and antitheilerial activity. Some compounds have also been described as possessing activity against external parasites. Thus, Fieser et al, J. Amer. Chem. Soc. 1948, 70, 3156-3165 (and references cited therein) describes a large number of 2-substituted-3-hydroxy-l,4-naphthoquinones as having antimalarial activity. A number of these compounds have also been described in U.S. Patent Specification No. 2 553 648. Further classes of 2-substituted-3-hydroxy-l,4-naphthoquinones having activity as antimalarial, anticoccidial and/or antitheilerial agents are described in U.S. Patents Nos. 3 367 830, and 3 347 742, U.K. Patent Specification No. 1553424, and European Patent Specifications Nos. 2 228, 77551, 77550 and 123,238.
European Patent No. 123,238 discloses 2-substituted-3-hydroxy-l,4-naphthoquinones which are said to be active against the human malaria parasite Plasmodium falciparum and also against Eimeria species such as E. tenella and E.acervulina, which are causative organisms of coccidiosis. 2-Substituted-3-hydroxy-l,4-naphthoquinones(l) have been described in literature as possessing anti-protozoal activity, in particular anti-malarial. Anti-coccicidal activity has also been reported to a lesser extend. Hundreds of such compounds as possessing anti-malarial activity have been disclosed by Feiser and coworkers. All these compounds use 2-chloro-l,4-naphthoquinone(2) as one of the starting materials.

CI

OH

o O
(2) (3) 0=C-OH (4)

Synthesis of 2-chloro-l,4-naphthoquinone in the laboratory always resulted in a mixture of monochloro and dichloronaphthoquinone i.e. 2-Chloro and 2,3-Dichloronaphthoquinones. Material procured from market was also found to contain almost 10-12% of 2,3-dichloronaphthoquinone(3). The preparation of pure 2-chloronaphthoquinone from this material is tedious and results in loss, making it expensive. Prior art has used the condensation of trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid(4) with 2-chloro-l, 4-naphthoquinone(2) to give 2-chloro-3-[trans-4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone(5) which on hydrolysis yielded Atovaquone (6). We have however found that condensation of trans-4-(4-chlorophenyl)cyclohexanecarboxylic acid(4) with the abundantly available, commercially inexpensive 2,3-dichloronaphthoquinone(3) gave an improved yield of 2-chloro-3-[trans-4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone(5) which on hydrolysis yielded Atovaquone (6).
SUMMARY OF THE INVENTION

FORMULA (I)
3
The present invention provides, in a first aspect, use of 2, 3-dihalonaphthoquinone compounds of Formula 1, wherein R1 and R2 are halogens selected from the group comprising CI, Br, I and F, for the preparation of napthoquinone compounds. R1 and R2 may be the same halogen or may contain different halogen groups.

The present invention also provides the use of 2, 3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula IA

O FORMULA (IA)
wherein X is any aryl, heteroaryl, alkyl groups and the like.
Particularly the present invention provides the use of 2, 3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof.

FORMULA (II)
wherein R2 is defined as above and R3 is selected from the group comprising C 1-6 alkoxy; aralkoxy; C 1-6 alkyl- C 1-6 alkoxy; hydrogen; unsubstituted phenyl; phenyl substituted by one or more groups, preferably selected from halogens; C 1-6 linear or branched alkyl, halogen and perhalo- C 1-6 alkyl.
It is to be noted that the Formula II will cover the stereoisomers including geometrical and optical isomers of the compounds disclosed above.
The napthoquinone compounds of Formula II comprising 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof, may then be optionally used to prepare 2-cyclohexyl -1,4-naphthoquinones compounds of Formula III.

FORMULA (III)
Wherein R3 is defined as above and R4 is selected from the group comprising hydroxyl; a group OCOR5, wherein R5 is a C1-10 alkyl group, a C3-10 cycloalkyl group, a C1-10 alkoxy group, or a phenyl or naphthyl group, each such R5 group being optionally substituted e.g. by amino, mono or di-C 1 –4 alkylamino, carboxy or hydroxy; a group OR6 or SR6, wherein R6 is an optionally substituted C1-10 alkyl, Cs - 1 o cycloalkyl, phenyl or naphthyl group as defined for R5 or a group NR'R8, wherein R7 and R8 each independently represent hydrogen or C1-6 alkyl, or the group NR R3 represents a 5-7 membered saturated heterocyclic ring, which may optionally contain a further heteroatom selected from nitrogen, oxygen or sulphur; and physiologically acceptable salts and other physiologically functional derivatives thereof.
DESCRIPTION OF THE INVENTION
The present invention relates to the preparation of napthoquinone compounds by using a 2, 3-dihalonapthoquinone intermediate. More specifically the invention is concerned with the use of novel intermediate 2,3-dihalonapthoquinone (Formula I) for the preparation of napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof. The napthoquinone compounds of Formula II may then be used for preparation of 2-cyclohexyl-1,4-naphthoquinones compounds of Formula III
The invention accordingly provides, in a first aspect, use of 2,3-dihalonaphthoquinone compounds of Formula I, wherein R1 and R2 are halogens selected from the group comprising CI, Br, I and F, for the preparation of napthoquinone compounds. R1 and R2 may be the same halogen or may contain different halogen groups.

FORMULA (I)
A particularly preferred example of the compound of Formula I is 2,3-dichloro naphthoquinone.
The present invention also provides the use of 2,3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula IA

FORMULA (IA)
Wherein X is any aryl, heteroaryl, alkyl groups and the like.
FORMULA (II)
Particularly the present invention provides the use of 2,3-dihalonaphthoquinone compounds of Formula I for the preparation of napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof.

wherein R2 is defined as above and R3 is selected from the group comprising C 1-6 alkoxy; aralkoxy; C1-6 alkyl- C1-6 alkoxy; hydrogen; unsubstituted phenyl; phenyl substituted by one or more groups, preferably selected from halogens; C1-6 linear or branched alkyl, halogen and perhalo-C 1-6 alkyl.
It is to be noted that the Formula II will cover the stereoisomers including geometrical and optical isomers of the compounds disclosed above.
Some non-limiting examples of compounds of Formula II include:
2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone;
2-Cyclohexyl-3-chloro-l,4-naphthoquinone, and 2-trans-(4-t-Butylcyclohexyl)-3-chloro-l,4-naphthoquinone.
The napthoquinone compounds of Formula II, selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof, may then be optionally used to prepare 2-cyclohexyl -1,4-naphthoquinones compounds of Formula III.

FORMULA (in)
wherein R3 is defined as above and R4 is selected from the group comprising hydroxyl; a group OCOR5, wherein R5 is a C1-10 alkyl group, a C3-10 cycloalkyl group, a C1-10 alkoxy group, or a phenyl or naphthyl group, each such R5 group being optionally substituted e. g. by amino, mono-or di-C 1-4 alkylamino, carboxy or hydroxy; a group OR6 or SR6, wherein R6 is an optionally substituted C1-10 alkyl, C1-10 cycloalkyl, phenyl or naphthyl group as defined for R5; or a group NR7R8, wherein R7 and Rs each independently represent hydrogen or C1-4 alkyl, or the group NR7R8 represents a 5-7 membered saturated heterocyclic ring, which may optionally contain a further heteroatom selected from nitrogen, oxygen or sulphur; and physiologically acceptable salts and other physiologically functional derivatives thereof.
Some non-limiting examples of compounds of Formula III include:

2-[trans-4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone (Atovaquone); 2-Cyclohexyl-3-hydroxy 1,4-naphthoquinone (Parvaquone) and ; 2-trans-(4-t-Butylcyclohexyl)-3-hydroxy-1,4-naphthoquinone.
The 2,3-dihalonaphthoquinone compounds of Formula I is treated with a cyclohexane carboxylic acid or any substituted derivative thereof in the presence of silver nitrate and ammonium persulphate to give the napthoquinone compounds of Formula II selected from 2-cyclohexyl-3-halo-l,4-naphthoquinones or substituted cyclohexyl derivatives thereof. The napthoquinone compounds of Formula II, may be further converted to 2-cyclohexyl -1,4-naphthoquinones compounds of Formula III using various reagents known in the art. For example the napthoquinone compounds of Formula II may be hydrolyzed with potassium hydroxide to give 2-cyclohexyl-3-hydroxyl-1,4-naphthoquinones compounds.
Particularly preferred compounds for use according to the present invention includes use of 2,3-dichloronaphthoquinone for the preparation of 2-chloro-3-trans-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone and subsequently of 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone).
In the course of our investigations on the synthesis of Atovaquone (6) we found surprisingly that the condensation of trans-4-(4-chlorophenyl)cyclohexane carboxylic acid (4) with the abundantly available, commercially inexpensive 2,3-dichloronaphthoquinone (3) in the presence of silver nitrate and ammonium perdisulphate gave a reasonable yield of 2-chloro-3-trans-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (5) which on hydrolysis yielded Atovaquone (6). Since position 3 in 2,3-dichloronaphthoquinone was occupied by a chlorine atom, it was not anticipated that it would be displaced by a substituted cyclohexyl group. This surprising finding led us to a systematic study of the reaction using pure 2,3-dichloro naphthoquinone (3) and different mixtures of this with 2-chloronaphthoquinone (2). Table 1 summarizes the results with yields of 2-chloro-3-trans -[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (5) and Atovaquone (6). The table shows clearly that mixtures of 2-chloro-l,4-naphthoquinone (2) and 2,3-dichloro naphthoquinone (3) particularly in the range of (3) : (2) = 9 : 1 to 1 : 9 gave better yields of 2-chloro-3-trans-[4-(4-chlorophenyl)cyclohexyl]-l,4-naphthoquinone (5) and hence of Atovaquone (6) when compared to the use of 2-chloronaphthoquinone (2) or 2,3-dichloronaphthoquinone (3) alone. Since the preparation of pure 2-chloronaphthoquinone

goes through a crude product which contains at least 10% 2,3-dichloronaphthoquinone, the process of our invention allows the direct use of this crude mixture.
Table 1

s.No. Quantity of 2,3-Dichloro 1,4-napthoquinone (3) Quantity of 2-Chloro-l,4-naphthoquinone (2) Ratio %Wt./ wt. Yield of (5) Yield of Atovaquone
1 5.0 gm - + 98% 1.5 gm 0.999 gm
2 4.5 gm 0.5 gm 90: 10 2.0 gm 1.334 gm
3 3.5 gm 1.5 gm 70:30 2.0 gm 1.334 gm
4 2.5 gm 2.5 gm 50:50 2.1 gm 1.400 gm
5 1.5 gm 3.5 gm 30:70 2.0 gm 1.334 gm
6 0.5 gm 4.5 gm 10 : 90 2.0 gm 1.334 gm
7 - 5.0 gm +98% 1.25 gm 0.833 gm
The 2, 3-dichloronaphthoquinone was found to give a product with lesser impurities, for example, from the 2-chloronaphthoquinone reaction, the solid product obtained from the reaction was found to consist of 55-75% of the trans isomer(5), 10-20% of the cis- isomer and 3-7% of an unknown impurity. On the other hand, the solid product from the reaction using 2,3-dichloronaphthoquinone had >90% of the trans isomer (5), The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.
EXAMPLE 1

1. 2-|trans-4-(4-Chlorophenyl)cvclohexyl]-3-hydroxy-l,4-naphthoquinone (Atovaquone):
Stage 1: Synthesis of 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-chloro-l,4-naphthoquinone (5)

CI

A mixture of 2, 3-dichloro-l,4-naphthoquinone (5gm), 4-(4-chlorophenyl)-cyclohexane-1-carboxylic acid (6.06 gm) and silver nitrate (2.47 gm) was taken in acetonitrile (60 ml) and the mixture was heated to reflux, maintaining good stirring. Then a solution of ammonium persulphate (14.23 gm) in water (77 ml) was added through a dropping funnel over a period of 1 - 2 hrs. The mixture was refluxed for 4 hrs. Then it was cooled in ice for about 1 hr after which it was filtered. The solid was extracted with hot methylene chloride (100 ml x 3). The organic layer was dried over anhydrous sodium sulphate and concentrated to get light brownish yellow solid. This on crystallization from acetonitrile afforded the trans compound as yellow crystals (1.5 gm).
Melting point, IR, NMR etc. fully matched with the product obtained from monochloro naphthoquinone. The same procedure was adopted for all the remaining five composition reported in Table-1.
Stage II. 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-l,4-naphthoquinone

(Atovaquone) (6)

(5)
Product from stage I (1.5gm) was taken in methanol and under stirring, potassium hydroxide (1.52 gm) dissolved in water (15 ml) was added over a period of 15 - 20 minutes, dropwise. The mixture was then refluxed approximately for 6 - 7 hrs. During this period the mixture became dark red. The mixture was then cooled in ice and concentrated hydrochloric acid (5.4 ml) was added dropwise to get yellow solid, which is filtered and washed thoroughly with water. The product after crystallization from methanol-acetic acid afforded the title compound as trans isomer (750 mg).
Melting point, IR, NMR matched with the product obtained from monochloro naphthoquinone.
EXAMPLE 2
Synthesis of 2-cyclohexyl-3-hydroxy-l,4-naphthoquinone (Parvaquone) (8)
Stage I. Synthesis of 2-cyclohexyl-3-chloro-l,4-naphthoquinone (7)
A mixture of 2,3-dichloro-l,4-naphthoquinone (5gm), 4-t-butylcyclohexane carboxylic acid (2.7629 gm) and silver nitrate (2.095 gm) was taken in acetonitrile (60 ml) and the mixture was heated to reflux. Then a solution of ammonium persulphate (12.06 gm) in 77 ml of water was added through a dropping funnel over a period of 1 to 2 hrs. The mixture was refluxed for 4 hrs and cooled in ice for about I hr after which it was filtered. The solid was extracted with hot methylene chloride (100 ml x 3). The methylene chloride layer was dried over anhydrous sodium sulphate, concentrated to get light brownish yellow solid. This on crystallization from acetonitrile afforded the title compound as yellow crystals (2.5 gm). 300 MHz NMR of the compound fully agreed with the desired compound

o
CX^C+ H0OC^>
Stage II: 2-Cyclohexyl-3-hydroxy-l,4-naphthoquinone (8)
o

(7) (8)
Product from stage I (1 gm) was taken in methanol and under stirring, potassium hydroxide (1.4 gm), dissolved in water (10 ml) was added over a period of 15 - 20 minutes dropwise. The mixture was then refluxed for 6 - 7 hrs, during which period, it became dark red. The mixture was cooled in ice and concentrated hydrochloric acid (3.6 ml) was added dropwise to get yellow solid, which was filtered and washed thoroughly with water. The product after crystallization from dichloromethane/hexane mixture afforded the title compound (0.75 gm), melting point 128 - 130°C.
EXAMPLE 3 1. 2-trans-(4-t-Butylcyclohexyl)-3-hydroxy-l,4-naphthoquinone (10)
Stage I: Synthesis of 2-trans-(4-t-butylcyclohexyl)-3-chloro-l,4-naphthoquinone (9)
A mixture of 2,3-dichloro-l,4-naphthoquinone (1.925gm), l-trans-(4-t-butyl-cyclohexyl)-carboxylic acid (1.8Q6gm) and silver nitrate (0.95gm) in acetonitrile (25ml) was heated to reflux with vigorous stirring whilst a solution of ammonium persulfate

(5.48gm) in water (30ml) was added dropwise over a period of 1 to 2 hrs. The mixture was refluxed for 4 hrs and cooled in ice for about 1 hr after which it was filtered. The solid was extracted with hot methylene chloride (25 ml x 3).
The methylene chloride layer was dried over anhydrous sodium sulphate and concentrated to give bright yellow solid which on crystallization from acetonitrile afforded the title compound (0.6gm). The 300 MHz NMR fully agreed with the structure.

Stage II: 2-trans-(4-t-Butylcyclohexyl)-3-hydroxy-l,4-naphthoquinone (10)

Product from stage I (0.2gm) was taken in methanol (6ml) and under stirring, potassium hydroxide (0.2gm) dissolved in water (2ml) was added over a period of 15 to 20 minutes

dropwise. The mixture was then refluxed approximately for 3- 4 hrs. The mixture was cooled in ice and concentrated hydrochloric acid (1 ml) was added dropwise to get yellow solid which was filtered and washed thoroughly with water. The product after crystallization from dichloromethane/hexane mixture afforded the title compound (0.12gm), melting point: 130 -132°C. The structure was confirmed by 300 MHz NMR.
Although the invention has been described in terms of particular embodiments and applications, one of ordinary skill in the art, in light of this teaching, can generate additional embodiments and modifications without departing from the spirit of or exceeding the scope of the claimed invention. It should be emphasized that the above-described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of the principles of the invention. Accordingly, it is to be understood that the drawings and descriptions herein are proffered by way of example to facilitate comprehension of the invention and should not be construed to limit the scope thereof.

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Patent Number

270430

Indian Patent Application Number

473/MUM/2008

PG Journal Number

52/2015

Publication Date

25-Dec-2015

Grant Date

21-Dec-2015

Date of Filing

07-Mar-2008

Name of Patentee

ALKEM LABORATORIES LTD.

Applicant Address

DEVASHISH, ALKEM HOUSE, SENAPATI BAPAT MARG, LOWER PAREL, MUMBAI

Inventors:

#	Inventor's Name	Inventor's Address
1	VEERASAMY ANANTHALAKSHMI	KUMAR ORGANIC PRODUCTS RESEARCH CENTRE PVT LTD USHA KRISHNA TOWERS, PLOT NO.36, ROAD NO.3 AND 5, JIGANI INDUSTRIAL AREA, ANEKAL TALUK, BANGALORE-562106.
2	GOVINDARAJALU JEYARAMAN	KUMAR ORGANIC PRODUCTS RESEARCH CENTRE PVT LTD USHA KRISHNA TOWERS, PLOT NO.36, ROAD NO.3 AND 5, JIGANI INDUSTRIAL AREA, ANEKAL TALUK, BANGALORE-562106.
3	KOOTTUNGALMADHOM RAMASWAMY RANGANATHAN	KUMAR ORGANIC PRODUCTS RESEARCH CENTRE PVT LTD USHA KRISHNA TOWERS, PLOT NO.36, ROAD NO.3 AND 5, JIGANI INDUSTRIAL AREA, ANEKAL TALUK, BANGALORE-562106.
4	KUPPUSWAMY NAGARAJAN	ALKEM LABORATORIES LTD. 473 D2, 13TH CROSS, IVTH PHASE, PEENYA INDUSTRIAL AREA, BANGALORE-560058.

PCT International Classification Number

C07C225/30; A61K31/12; A61K31/13

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA