Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
1. TITLE OF THE INVENTION
"A process for the preparation of Adapalene"
2. APPLICANT
(a) NAME: USV LIMITED
(b) NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c) ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088,
Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the nature of this invention and the
manner in which it is to be performed.

A process for the preparation of Adapalene
TECHNICAL FIELD:
The present invention relates to an improved process for the preparation of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (Adapalene) having formula I.

BACKGROUND OF INVENTION:
Adapalene is a benzonaphthalene derivative used in the treatment of Acne Vulgaris. It is a retinoid and when used in small concentrations is a moderator of cellular differentiation, keratinization, and inflammatory processes.
US 4,717,720 / Re 34,440 describes a process for the preparation of Adapalene (I). 1-Adamantol is reacted with 4-bromophenol (II) in presence of concentrated sulfuric acid in dichloromethane to give crude 2-(l-adamantyl)-4-bromophenol (III), which after recrystallization in isooctane provides pure 2-(l-adamantyl)-4-bromophenoI (III). The compound (III) is alkylated with iodomethane in presence of sodium hydride in tetrahydrofuran to obtain crude 2-(l-adamantyl)-4-bromoanisole (IV). The crude product (IV) is purified by column chromatography using mixture of hexane-dichloromethane to get pure compound (IV). The compound (IV) when treated with magnesium, followed by zinc chloride, methyl-6-bromo-2-naphthoate in presence of
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[l,2-bis(diphenylphosphino)ethane]dichloronickel(II) or NiCl2-DPPE in THF provides crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V). The crude product (V) is purified by column chromatography using mixture of heptane-dichloromethane and recystallized in ethyl acetate to obtain pure compound (V). The compound (V) was further treated with a solution of soda in methanol to obtained crude 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I). The crude product (I) is recystallized in a mixture of THF and ethyl acetate to obtain pure compound (I). (Scheme I)
SCHEME I:



HO
1. l-Adamantol,
CH 2CI 2, H 2SO 4
— ^
2. NaHCO 3

l.NaH, THF
2.CH3I

(II)

(III)

COOCH,
Br 1. Mg, THF
NaOH, CH 3OH
(IV)

2. methyl-6-bromo D naphthoate
3.ZnCI 2,NiCl j/DPPE

COOH

3

The main disadvantage of this process is the purification of compound (IV) and (V) using column chromatography, which is expensive, time consuming and impractical at industrial scale. Another major disadvantage of the process for preparation of compound (I) from compound (V) by hydrolysis using soda in methanol for 48 hrs, which is expensive, unproductive and time consuming at industrial scale.
US 5015758 discloses another process for the preparation of methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid wherein 1-acetoxyadamantane is reacted with methyl-(4-hydroxyphenyl)-2-naphthoate in presence of sulphuric acid to obtain the ester compound. The patent does not however describe the further process of conversion to Adapalene.
OBJECTS OF THE INVENTION:
An object of the present invention is to provide a process for the preparation of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (Adapalene) having formula I, in high yield and high purity.
Another object of the invention is to provide a simple, economical and industrially feasible process for the preparation of 6-[3-(l-adamantyl)-4-methoxy phenyls-naphthoic acid of the formula (I).
SUMMARY OF THE INVENTION:
The present invention provides a process for preparation of highly pure 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (Adapalene) (I) in high yield. 1-Adamantol is reacted with 4-bromophenol (II) in presence of concentrated sulfuric acid in dichloromethane to give 2-(l-adamantyl)-4-bromophenol (III). The compound
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(Ill) alkylated with iodomethane in presence of phase transfer catalyst, base in organic solvent and water to obtain 2-(l-adamantyl)-4-bromoanisole (IV). Optionally compound (III) is alkylated using Dimethyl sulphate, in presence of a base. The compound (IV) is treated with magnesium, followed by zinc chloride, methyl-6-bromo-2-naphthoate in presence of [l,2-bis(diphenylphosphino)ethane]dichl-oronickel(II) or NiCl2-DPPE in THF to give crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V). The crude product (V) is recystallized in a mixture of organic solvents to obtain pure compound (V). The compound (V) was further treated with a solution of soda in organic solvent to obtained crude 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I). The crude product (I) is recystallized using a mixture of organic solvents to obtain pure compound (I).
DETAILED DESCRIPTION OF THE INVENTION:
Formula (I)
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According to the invention there is provided a process for the preparation of Adapalene OR 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid having formula I comprising:


Reacting 1-Adamantol with 4-bromophenol (II) in presence of concentrated sulfuric acid in dichloromethane and isolating 2-(l-adamantyl)-4-bromophenol (III);


HO

Formula (III)
Treating the compound of formula (III) with iodomethane in presence of phase transfer catalyst in dichloromethane and aqueous alkaline solution to give 2-(l-adamantyl)-4-bromoanisole (IV);

Formula (IV)
Treating the compound of formula (III) with Dimethyl sulphate in presence of a base to yield compound III.
C-C coupling the compound of formula (IV) with methyl-6-bromo-2-naphthoate using magnesium, zinc chloride and NiCb-DPPE to obtain methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V);
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Formula (V)
e. Purifying the compound of formula (V) by recrystallization in
organic solvents;
f. Hydrolysing the compound of formula (V) with base in a higher
boiling solvent to obtain the crude Adapalene (I);
g. Purifying the crude Adapalene by recrystallization using organic
solvents
According to an embodiment of the present invention the isolation of 2-(l-adamantyl)-4-bromophenol (III), is carried out by diluting the reaction mixture with water, distilling dichloromethane and filtering the white solid and drying. Thus, the process avoids basification and the tedious extractive work up.
According to the present invention the phase transfer catalyst used for methylation of 2-(l-adamantyl)-4-bromophenol (III) to yield 2-(l-adamantyl)-4-bromoanisole (IV) is a quarternary ammonium salt. The crude compound (IV) thus obtained is treated with hydrocarbon solvents selected form pentane, hexane, heptane, isooctane or mixture thereof.

According to another embodiment of the present invention, methylation is achieved using Dimethyl sulphate in presence of a base.
According to the present invention the C-C coupling is carried out by converting, 2-(l-adamantyl)-4-bromoanisole (IV) to a Grignard reagent using magnesium, exchanging Magnesium with Zinc using Zinc chloride and reacting with methyl-6-bromo-2-naphthoate in presence of NiCl2-DPPE in THF to give crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V).
According to the present invention the organic solvent used for the purification of crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V) is an ester selected from ethyl acetate, methyl acetate, isopropyl acetate or mixture thereof.
According to the present invention the solvent used for hydrolyzing methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V) may be selected from 1,4-Dioxane, n-butanol, 1,2-dimethoxymethane, 2-ethoxyethanol or ethylene glycol. The base may be selected from sodium hydroxide, potassium hydroxide or lithium hydroxide.
According to another embodiment of the present invention the crude Adapalene is purified using a mixture of tetrahydrofuran and ethyl acetate.
The following experimental example is illustrative of the invention but not limitative of the scope thereof.
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EXAMPLES:
Preparation of 2-(l-adamantyI)-4-bromophenol (III):
To a solution of (10.0 g, 57.8 mmol) p-bromophenol and 1-adamantanol (8.78 g, 57.76 mmol) in dichloromethane (50 ml) and concentrated sulphuric acid (3 ml) was added slowly. The reaction mixture was stirred for 4-6 hrs at room temperature (RT). Water (50 ml) was added to the reaction mixture, dichloromethane was distilled and white solid formed. The solid obtained was filtered, washed with water and dried. [Yield: 15.5 g, 87.3 %]
Preparation of 2-(l-adamantyl)-4-bromoanisole (IV):
A mixture of 2-(l-adamantyl)-4-bromophenol (III) (15.5 g, 50 mmol) in dichloromethane (100 ml), tetrabutylammonium bromide (1.0 g) and sodium hydroxide (20 g, 500 mmol in 100 ml water) were stirred at 10°C. Then iodomethane (4.71 ml, 75mmol) was added in a drop wise manner for 15 min into the reaction mixture at 10°C. The reaction mixture was stirred for 2-4 hrs. The dichloromethane layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated to obtained desired compound IV. [Yield: 15.5 g, 86%]
Preparation of 2-(l-adamantyl)-4-bromoanisole (IV):
To a solution of 2-(l-adamantyl)-4-Bromophenol (III) (50 g, 162 mmole) in acetone 200 ml, Potassium carbonate ( 33.7 g, 216 mmole) was added and stirred at RT. Dimethyl sulphate (20.53 ml, 244 mmole) was added dropwise for 15 min at RT. The reaction mixture was then refluxed for 4 hrs. The reaction mixture was further cooled to RT, water was added, and the solid separated, was filtered and washed with acetone. The solid was then treated with 3N HC1 till pH is about 5 to 6, filtered and washed with water and acetone and then finally dried to obtain compound (IV). [Yield: 44g, 84%]
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Preparation of methyl ester of 6-[3-(l-adamantyl)-4methoxy phenyl]-2 naphthoate (V):
A mixture of magnesium turnings (1.26 g, 51.85 mmol) in THF (10 ml) was stirred at room temperature and 2-(l-adamantyl)-4-bromoanisole (IV) (1.4 g, 4.36 mmol) and 1,2-dibromoethane (0.56 ml) were added under nitrogen atmosphere. The reaction mixture was heated at 40°C for initiation, and then 2-(l-adamantyl)-4-bromoanisole (12.6 g, 39.25 mmol) in tetrahydrofuran (40 ml) was added in a drop wise manner for 30 min at reflux temperature. Zinc chloride (8.4 g, 61 mmol) in tetrahydrofuran (30 ml) was added in a drop wise manner for 15 min at reflux temperature. The reaction mixture was refluxed for 1 hr. Methyl 6-bromo-2-naphthoate (8.0 g, 30mmol) was added, stirred for 10 min, followed by the addition of NiCb/DPPE catalyst (0.21 g). The reaction mixture was stirred at same temperature for 2 hrs and concentrated to obtain a residue, which was treated with dichloromethane (100 ml) and 1 N HC1 (100 ml). The dichloromethane layer washed with 10 % EDTA disodium salt, water, dried over anhydrous sodium sulfate and distilled to obtained crude compound. The crude compound was stirred in ethyl acetate (140 ml) for 1 hr at 25-30°C and the solid obtained was filtered and dried. [Yield: 9.45 g, 50%]
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Preparation of 6-[3-(l-adamantyl)-4methoxy phenyl]-2 naphthoic acid (Adapalene) (I):
The compound (V) (9.45 g, 22mmol) was dissolved in 1,4-Dioxane (95 ml) at reflux temperature and KOH (6.3 g, l lmmol in 30 ml water) was added in a drop wise manner for 15 min. The reaction mixture was refluxed for 2-4 hrs and then cooled when the potassium salt of adapalene is precipitated, filtered and washed with methanol (25 ml). This salt of adapalene was acidified with 2 N HC1, solid separated, filtered and dried to obtained crude adapalene. The crude was recrystallized from THF-ethyl acetate. [Yield: 5.0 g, 81 %; Purity: HPLC > 99 %]
Dated this the 3™ day of May, 2006
Dr K G Rajendran
Head-Knowledge Cell
USV Limited
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Abstract:
The present invention provides a process for preparation of highly pure Adapalene OR 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I).
The synthesis as described herein comprises, (1) the preparation and isolation 2-(l-adamantyl)-4-bromophenol (III); (2) the compound (III) is alkylated with iodomethane in presence of base in organic solvent to obtain 2-(l-adamantyl)-4-bromoanisole (IV); (3) the crude methyl ester of 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (V) is recystalhzed in a mixture of organic solvent to obtain pure compound (V); (4) the compound (V) was further heated for 2 to 4 hrs with a solution of soda in organic solvent to obtained crude 6-[3-(l-adamantyl)-4-methoxy phenyl]-2-naphthoic acid (I); (5) the crude product (I) is recystalhzed in a organic solvent to obtain pure Adapalene (I).
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