WO2008126104A2

WO2008126104A2 - Novel process for preparation of adapalene

Info

Publication number: WO2008126104A2
Application number: PCT/IN2008/000236
Authority: WO
Inventors: Ketan Dhansukhlal Vyas; Ranjeet Nair; Pravin Nalawade; Ulhas Digambar Patil; Aditi Milind Panandikar
Original assignee: Indoco Remedies Ltd
Current assignee: Indoco Remedies Ltd
Priority date: 2007-04-11
Filing date: 2008-04-09
Publication date: 2008-10-23
Anticipated expiration: 2009-10-11
Also published as: WO2008126104A3

Abstract

Disclosed herein is a process for the preparation of the adamantyl derivative 6-[3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid known as adapalene employing a novel intermediate 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate.

Description

NOVEL PROCESS FOR PREPARATION OF ADAPALENE

Field of invention:

The present invention relates to a novel process for the preparation of adamantyl derivative 6-[3-(l - Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid known as adapalene employing a novel intermediate 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate.

Background and Prior art:

The compound 6-[3-(l - Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I known as Adapalene is used in dermatology, particularly in the treatment of acne vulgaris and psoriasis.

Formula - 1

Adapalene was first time disclosed in the US patent No. 4,717,720 (herein after referred as '720) describe the preparation of compound of Formula - I using Negishi cross Coupling. In this reaction, 2-(l-adamantyl)-4-bromoanisole is converted to its organomagnesium compound followed by conversion to organozinc compound using zinc chloride and reacted with 6-bromo-2-methylnaphthoate employing transition metal as reaction catalyst such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme - 1 below:

Scheme - 1 Another US patent No. 5,015,758 describe the process for preparation of 6[3-(l- Adamantyl) - 4 - methoxyphenyl] - 2 - naphthoate a penultimate step for preparation of Adapalene using Friedel - Crafts alkylation by reacting 1 - acetoxy adamantane with methyl - 6 - (4 - hydroxyphenyl) - 2 - naphthoate in presence of cone. Sulfuric acid in solvent n - heptane.

Another improved process was published in the journal, Organic Process Research & Development, 2006, 10, 285 - 288 for the preparation of Adapalene. The process involves the preparation of intermediates followed by Negishi cross Coupling, where in 2-(l-adamantyl)-4-bromophenol was prepared using 1 - adamentol and 4- bromo phenol in presence of 98% sulphuric acid and acetic acid, which on methylation with dimethyl sulfate and potassium carbonate in dry acetone yields 2-(l -adamantyl)-4-bromoanisole. The compound is reacted with magnesium to form Grignard reagent and then coupled with 6-bromo-2-methylnaphthoate in presence of novel Pd - Zn double metal catalyst to yield ester, which on saponification followed by treatment with acid yields Adapalene.

The recent published application WO 2006/108717 describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula - 1. The application describes the preparation of 3-adamantyl-4-methoxyphenyl boronic acid from 2-(l-adamantyl)-4- bromoanisole using n-Butyl Lithium and triisopropyl borate in solvent tetrahydrofuran. Finally 3-adamantyl-4-methoxyphenyl boronic acid is reacted with 6-bromo-2-naphthoic acid involving Suzuki coupling in presence of Palladium acetate catalyst, a ligand 2 - (dicyclohexyl - phosphino) biphenyl, an inorganic base in solvent to get the compound adapalene.

Some of the drawbacks of the prior art processes include:

- The reported process in US patent 4717720, using Negishi cross coupling involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which needs to be freshly prepared increases the reaction step and has to be thoroughly dried before its use for coupling. Further the coupling reaction, results in the formation of dimer impurities during the organozinc compound reaction, with 2-(I -adamantyl)-4-bromoanisole and 6-bromo-2-methylnaphthoate respectively, which are difficult to remove. All these operations make the entire synthesis extremely sensitive and difficult to handle.

Some of the above drawbacks were addressed by the authors in the article published in Organic Process Research & Development, 2006, 10, 285 - 288 for the preparation of Adapalene. But the use of Pd catalyst with the ligand like PdCl₂ (PPh₃)₂ for the direct conversion of Grignard reagent employing ZnCYl in catalytic amount has its own limitations. The use of Grignard reagent, palladium catalyst with ligand and hygroscopic ZnCl₂ demerits this process for industrial application.

The recent published application WO 2006/108717; describes the use of Suzuki coupling for the synthesis of adapalene the compound of formula - I. The use of organo boronic acids for the Suzuki reaction has some limitations because of the indeterminate stoichiometry associated with the use of boronic acid, and its difficulty in purification and the byproducts formed during the reaction.

Therefore there remains a need for an improved process for preparing adapalene that eliminates or substantially reduces the impurities, decreases the number of steps, and employs a more robust process which is convenient and cost efficient.

The present inventors have come out with a novel process which ameliorates the problems in the prior art with a one - pot process for the preparation of adapalene by employing Suzuki - Miyaura coupling involving the use of novel reactant 3-adamantyl-4- methoxyphenyl potassium trifiuoroborate.

The novel compound 3 - Adamantyl - 4 - methoxy phenyl potassium trifiuoroborate, exhibit superb behavior in the Suzuki-Miyaura reaction and provides a powerful method for the preparation of 6 - [3-(I - Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid, the compound of Formula - I.

Formula - 1

Potassium organotrifluoroborates are air and moisture-stable crystalline solids which can be stored for extended periods of time making it more industrial friendly to use on large scale production.

The other advantage of the present invention is in the use of methyl ester of 6 - Bromo - 2 -naphthoic acid and isolating adapalane directly from the reaction instead of its methyl ester, the above process becomes more robust and eliminates the saponification step as reported in prior art. Also the use of readily and cheaply available Pd catalyst on carbon over the conventional and costlier Pd-catalyst with ligands offers further advantage to the current process.

Objectives of the invention:

The objective of the present invention is to provide a novel process to prepare adamantyl derivative 6-[3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula -

Another objective of the present invention is to prepare 6-[3-(l - Adamantyl}-4 - methoxy phenyl] - 2 - naphthoic acid by an industrially viable and useful process.

Yet another objective of the present invention is to prepare adamantyl derivative 6-[3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid by using the novel compound 3 - adamantly - 4 - methoxyphenyl potassium trifluoroborate.

Yet another objective of the present invention is the preparation of pure 3-adamantyl-4- methoxyphenyl potassium trifluoroborate compound. Summary of the invention:

The present invention provides a process for the preparation of adamantyl derivative 6 [3 - (1 - Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid compound of Formula -

Formula - 1

Comprising of; coupling reaction of the compound 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate of Formula - II

K*

Formula - Il with 6 - Bromo - 2 - methyl naphthoate of Formula - III

Formula - III Wherein; a) Coupling of 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate of Formula - II with 6 - bromo - 2 - methyl naphthoate of Formula - III in presence of palladium catalyst and base in a polar solvent at temperature of 50 - 80⁰C; b) Cooling the reaction and treating with an acid to isolate compound of Formula - I and; c) Purifying the compound to isolate pure crystalline 6-[3-(l- Adamantyl) - A - methoxy phenyl] - 2 - naphthoic acid. The invention further provides the process to prepare novel intermediate 3-adamantyl-4- methoxyphenyl potassium trifluoroborate compound of Formula - II.;

Wherein; a) reacting 2 - (1 - Adamantyl) - 4 - bromoanisol with n - butyl lithium and triisopropyl borate in tetrahydrofuran at temperature of - 60 to - 40 ⁰C, b) quenching the reaction mass in acid solution and extracting with solvent ethyl acetate and; c) charging potassium hydrogen difluoride to ethyl acetate layer at temperature of 20 - 30⁰C to get 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate of Formula - II;

Detailed description of the invention:

In one embodiment of the present invention, the adamantyl derivative 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I is prepared in a one pot process by employing Suzuki - Miyaura coupling between 3 - Adamantyl - A - methoxyphenyl potassium trifluoroborate of Formula II and 6 - bromo - 2 - methyl naphthoate of Formula - III.

According to the present invention the preparation of 6 - [3-(l- Adamantyl) - A - methoxy phenyl] - 2 - naphthoic acid can be represented in the reaction sequence Scheme - 2 below:

Formula - 1

Formula - Il Formula - 111

Scheme - 2

The preparation of 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I is carried out using Suzuki Miyaura coupling in one - pot, by reacting 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate of Formula - II and 6 - bromo - 2 - methyl naphthoate of Formula - III in a polar solvent in the presence of a catalyst and base. The polar solvent used for the coupling reaction is selected from Ci - C₄ alcohol, aliphatic acetates, tetrahydrofuran (THF) either single or mixture thereof with water. The preferred solvents are methanol, ethyl acetate and tetrahydrofuran, the most preferred solvent is tetrahydrofuran with water. The volume of the solvent used is in the range of three times to nine times with most preferred volume is six times of charged 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate. The volume of water used is three times to six times, the preferred volume is three times of charged 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate.

The catalyst used for the coupling reaction is palladium catalyst selected from Palladium on carbon, Palladium (II) acetate, tris (dibenzyldieneacetone) dipalladium (0), Dichloro bis(triphenylphosphine)palladium (II), tetrakis(triphenylphosphine)palladium (0) and Diacetatobis(triphenylphosphine) palladium (II). The most preferred catalyst for the coupling reaction is palladium on carbon. Further the reaction is carried out in presence of an inorganic base selected from potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide. The most preferred base used is potassium hydroxide.

The preferred range of temperature to carry out the coupling reaction is 50⁰C to 8O⁰C, the most preferred range of temperature for the coupling reaction is 65 ± 3°C. The reaction is maintained at 65 ± 3°C for 6 - 10 hours by monitoring the reaction using thin layer chromatography for the disappearance of 6 - bromo - 2 - methyl naphthoate. After completion of the reaction the reaction mass is passed through hyflow in hot condition, the filtrate is collected and cooled to 25 - 30⁰C. The reaction is further diluted with water and treated with 1 - 2N hydrochloric acid to isolate 6 - [3-(I- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I. The product separated is filtered and washed with water till pH of the washings are 6.5 to 7.1. The compound obtained has HPLC purity of more than 99.50%.

The product is further purified using solvent selected from tetrahydrofuran, ethyl acetate, dimethyl sulfoxide, acetone, n - heptane and water either single or mixture thereof. The preferred solvent for purification is tetrahydrofuran and n - heptane. The purification is carried out at reflux temperature in tetrahydrofuran, cooled the solution to 25 - 30⁰C and charged n - heptane to isolate pure crystalline 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I. The product 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I after purification has HPLC purity of more than 99.7% having melting range of 318 - 321⁰C.

In another embodiment of the present invention the compound 3 - Adamantyl - A - methoxy phenyl potassium trifluoroborate of Formula - II employed in the synthesis of 6 - [3-(I - Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid compound of Formula - I, prepared by reacting 2 - (1 - Adamantyl) - 4 - bromoanisole of Formula - IV with n - Butyl lithium in presence of solvent, tri isopropyl borate and potassium hydrogen difluoride. The compound 4-bromophenol was prepared using reported procedure by Charpentier et al. J. Med Chem, 1995, 38, 4993 - 5OO6.The reaction sequence can be represented as per the scheme - 3 below:

Scheme - 3

According to the present invention the compound 2 - (1 - Adamantyl) - A - bromoanisole of Formula - IV is reacted with n- butyl lithium in presence of tetrahydrofuran (THF) to form a complex. The reaction is carried out in the temperature range of -60⁰C to -40⁰C; most preferred range of temperature for the reaction is -55°C ± 5°C. Tri - isopropyl borate is introduced slowly to the reaction mass by maintaining the temperature at -55°C ± 5°C. After the reaction completion the temperature is slowly brought to 25 - 30⁰C and 1 - 6 N hydrochloric acid is slowly charged. The most preferred dilution is 1 - 2 N hydrochloric acid. The reaction mass is stirred and separated the organic layer. To the organic layer charged freshly prepared aqueous solution of potassium hydrogen difluoride maintaining the temperature between 25 - 30⁰C. The molar equivalent of potassium hydrogen difluoride to the 2 - (1 - Adamantyl) - 4 - bromoanisole is 3: 1 , more preferred molar ratio being 0.9: 1. The quantity of water for the preparation of the aqueous solution of potassium hydrogen difluoride being two to six times, the preferred volume of water is three times the quantity of potassium hydrogen difluoride. The reaction mixture is stirred for 1 - 3 hour during which the solid 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate precipitates out. The product is filtered and washed with fresh ethyl acetate. The solid product is dried at 55 - 65°C till constant weight.

The 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate is further characterized by elememtal analysis and Infrared spectrum.

The FT infrared absorption spectra of 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate of Formula - II showed the absorption at the wavelength 2902 cm²; 2848 cm²; 1596 cm²; 1491 cm²; 1226 cm²; 1 166 cm²; 1 139 cm²; 997 cm²; 974 cm²; 869 cm²; 820 cm². The result of elemental analysis shows 58.6% C, 6.26 % H and 4.53% O and the rational formula of the resultant compound is determined to be CnH_2IBF₃KO as calculated values OfC₁₇H_2I BF₃KO agrees with 58.58% C, 6.03% H and 4.59% O.

The intermediate compound [3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate] of Formula - II, as prepared and characterized above can be used in the preparation of adamantyl derivatives.

All embodiments of the present invention are carried out in presence of an inert atmosphere using Nitrogen or Argon gas.

The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respect as illustrative and non restrictive to the invention.

Examples:

Example 1: Preparation of 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate:

In a 2.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 100.0 gm of 2-(l- adamantyl) 4-bromo anisole was charged in 600 ml tetrahydrofuran. The reaction mixture was cooled to -55 ± 5⁰C and 302 ml of 1.6 M n - butyl Lithium was slowly added and stirred. 87 ml of tri isopropyl borate was then charged and stirring was continued for 30 minutes at -55 ± 5°C. Cooling was removed and the temperature raised slowly to 25 - 30⁰C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes and separated the organic layer. The organic layer was charged in 1.0 L round bottom flask and freshly prepared aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 - 30⁰C and stirring was maintained till white precipitate is obtained. The mixture was continued under stirring and cooled to 0 - 5⁰C. The product, 3 - adamantyl - 4 - methoxyphenyl potassium trifluoroborate obtained was filtered, washed with 100 ml of ethyl acetate. The product was dried at 60 - 65°C till constant weight. Yield: 90.5 gm (83%), Purity: 99.0 % by HPLC.

Example 2: Preparation of 6 - [3-(l- Adamantyl) - 4 - methoxyphenyl] - 2 - naphthoic acid:

In a 1.0 L round bottom flask equipped with stirring and under nitrogen atmosphere 50.0 gm of 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate, 23 gm of 6- bromo -2-methyl napthoate in 300 ml tetrahydrofuran (THF) was charged. Stirred for 15 min and charged 3.0 gm of 5% Pd / C was and aqueous potassium hydroxide solution (50.0 gm in 300 ml water). Stirring was continued and the temperature was raised to reflux. The reaction mass was maintained for 10 hours at reflux and after the completion of the reaction, 200 ml of tetrahydrofuran: water (1 : 1) mixture was added and then filtered through hyflow bed at 45-50⁰C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50⁰C. 500 ml water was charged and the reaction mass was stirred. The aqueous layer was acidified with 1.2N hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH. The solid product obtained was dried at 70 - 75°C till constant weight to get 6 - [3-(l- adamantyl) - 4 - methoxyphenyl] - 2 - naphthoic acid.

The dried product was taken in 300 ml of tetrahydrofuran and stirred. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and cooled the reaction mass to 25 - 30⁰C. 500 ml of n - heptane was charged to the reaction mass and stirred for 30 minutes. The reaction mass was then chilled to 0 - 5°C and maintained stirring at 0 - 5°C temperature for 2.0 hours. The precipitated solid was filtered and washed with n - heptane. The pure crystalline 6 - [3-(l- adamantyl) - 4 methoxyphenyl] - 2 - naphthoic acid thus obtained was then dried till constant weight. Yield = 40 - 42 gms (68 - 72 %)

Claims

We claim,

1) A process for the preparation of adamantyl derivative 6-[3-(l - Adamantyl) - 4 methoxy phenyl] - 2 - naphthoic acid of Formula - I;

Formula - 1 Comprising of; coupling of the compound 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate of Formula - Il

K*

Formula - II with 6 - Bromo - 2 - methyl naphthoate of Formula - III

Formula - III

2) The process according to claim 1, wherein, coupling of 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate of Formula - II with 6 - bromo - 2 - methyl naphthoate of Formula - III is carried out in presence of palladium catalyst and base in a polar solvent at temperature of 50 - 80⁰C.

3) The process according to claims I and 2, wherein, the palladium catalyst used is selected from Palladium on carbon, Palladium (II) acetate, Tris - (dibenzyldieneacetone) dipalladium (0), Dichloro bis (triphenylphosphine) palladium (II), Tetrakis (triphenylphosphine) palladium (0) and Diacetatobis (triphenylphosphine) palladium (II). 4) The process according to claims 1 to 3, wherein; the palladium catalyst used is Palladium on carbon.

5) The process according to claims 1 and 2, wherein, the polar solvent used for C - C coupling is selected from C l - C4 alcohol, aliphatic acetates, tetrahydrofuran and water either single or mixture thereof.

6) The process according to claims 1 and 5, wherein, the preferred solvents are methanol, ethyl acetate and tetrahydrofuran used either alone or mixture thereof with water.

7) The process according to claims 1 , 5 & 6, wherein, the solvent for coupling reaction used is tetrahydrofuran with water.

8) The process according to claims 1 and 2 wherein; the base used in the coupling reaction is selected from potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.

9) The process according to claims 1, 2 and 8, wherein, the preferred base used is potassium hydroxide.

10) The process according to claim 1 , wherein, coupling reaction is carried out at preferred temperature of 65 ± 5°C.

H) A process for the preparation of adamantyl derivative 6-[3-(l - Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - 1

Formula - 1 Comprising of the steps of; a) coupling of 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate of Formula - II with 6 - bromo - 2 - methyl naphthoate of Formula - III in presence of palladium catalyst and base in a polar solvent; at temperature of 50 - 8O⁰C; b) cooling the reaction mass and treating with an acid to isolate compound of Formula - I; and c) purifying the compound to isolate pure crystalline 6-[3-(l - Adamantyl) — 4 - methoxy phenyl] - 2 - naphthoic acid. 12) The process according to claim 1 1 , wherein, the said acid is dilute hydrochloric acid.

13) The process according to claim 1 1 , wherein, the said solvent for purification are tetrahydrofiiran, ethyl acetate, dimethyl sulfoxide, acetone, n - heptane and water used either alone or mixture thereof.

14) The use of intermediate compound [3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate] of Formula - 11, as claimed in claim 1, for the preparation of adamantyl derivatives.

Formula II