|Title of Invention||
NOVEL PROCESS FOR PREPARATION OF ADAPALENE
|Abstract||Disclosed herein is a process for the preparation of the adamantyl derivative 6-[3-(1-Adamantyl)-4-methoxy phenyl]-2-naphthoic acid known as adapalene employing a novel intermediate 3 - Adamantyl - 4 - methoxyphenyl potassium trifluoroborate.|
|Full Text||FORM 2THE PATENT ACT 1970(39 of 1970)&The Patents Rules, 2003PROVISIONAL SPECIFICATION(See section 10 and rule l3)
1. TITLE OF THE INVENTION: "Novel process for preparation of Adapalene"
2. APPLICANT(a) NAME: M/S. INDOCO REMEDIES LIMITED.(b) NATIONALITY: Indian Company incorporated under the IndianCompanies ACT, 1956 (c) ADDRESS: Indoco House, 166 C. S. T. Road, Santacruz (East), Mumbai -400 098. Maharashtra, India
3. PREAMBLE TO THE DESCRD7TION
The following specification particularly describes the invention.
Field of invention:
The present invention relates to a novel method for the preparation of the compound 6-[3-(1- 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.
l.KOH: 2. HC1.
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 reaction catalyst a transition metal such as palladium or nickel or one of its complexes with various phosphines. The reaction sequence is as shown in scheme - 1 below:
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 and 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 THF. Finally 3-adamantyl-4-methoxyphenyI 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 firstly involves Grignard reaction. This requires anhydrous condition and a possibility of runaway reaction during Grignard reagent formation. Also the reaction involves the addition of freshly fused ZnC12 and the preparation of the catalyst NiC12 (DPPE) complex, which also needs to be freshly prepared 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-( 1 -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 PdC2 (PPh3)2 for the direct conversion of Grignard reagent employing ZnC12 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 trifluoroborate.
The inventors have observed that Potassium organotrifluoroborates (BF3K) moiety is compatible with sensitive functional groups and is tolerant to hostile reaction conditions such as epoxidation, ozonolysis, osmylation and metal-halogen exchange. Most importantly, these novel nucleophiles perform well in cross coupling and other important reactions. Additionally, Potassium organotrifluoroborates are air and moisture-stable crystalline solids which are readily accessible by a variety of high yielding methods and can be stored for extended periods of time making it more industrial friendly to use on
large scale production. The novel compound 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate, exhibit superb behavior in the Suzuki-Miyaura reaction and provides a powerful method for the preparation of 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid the compound of Formula -1.
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 prepare pharmacopially pure 6-[3-(l-Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid using an improved process.
Another objective of the present invention is to prepare 6-[3-(l- Adamantyl)-4 - methoxy phenyl] - 2 - naphthoic acid by an industrially useful and viable process.
Yet another objective of the present invention is to prepare 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.
Detailed description of the invention:
In one embodiment of the present invention the compound 6 - [3-(l- Adamantyl) - 4 -methoxy phenyl] - 2 - naphthoic acid of Formula -1 is prepared in a one pot process by Suzuki - Miyaura coupling between 3 - Adamantyl - 4 - methoxy phenyl 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) - 4 -methoxy phenyl] - 2 - naphthoic acid can be represented in the reaction sequence Scheme - 2 below:
COOCHj l.5%Pd/C; THF
Formula - II
Formula • III
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 solvents in the presence of a catalyst and a base. The polar solvents 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 THF, the most preferred solvent is THF. The volume of the solvent used is in the range of 3 times to 9 times with most preferred volume is 6 times of 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate used. The volume of water used is 3 times to 6 times, the preferred volume is 3 times of 3 - Adamantyl - 4 - methoxy phenyl potassium trifluoroborate used.
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 hydroxide and potassium hydroxide. The most preferred base is potassium hydroxide.
The preferred range of temperature to carry out the coupling reaction is 50°C to 80°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 supercell in hot condition and the filtrate is collected and cooled to 25 - 30°C. The reaction is further diluted with water and treated with dilute hydrochloric acid to precipitate out 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula -1. 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% meeting all the pharmacopieal specifications.
If required, the product can be recrystallised using the mixed solvent THF and ethyl acetate in the ratio of 1:1 and reflux under stirring and diluting with n - heptane to precipitate out the product. The compound is cooled, chilled to 0 - 5°C and filtered. Finally washed the product with chilled n - heptane and dried to get 6 - [3-(l-Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid of Formula - I having HPLC purity of more than 99.7% having melting range of 318 - 321°C.
In another embodiment of the present invention the compound 3 - Adamantyl - 4 -methoxy phenyl potassium trifluoroborate of Formula- II employed in the synthesis of 6 - [3-(l- Adamantyl) - 4 - methoxy phenyl] - 2 - naphthoic acid compound of Formula -I, prepared by reacting 2 - (1 - Adamantyl) - 4 - bromoanisole of Formula - IV (prepared from 4-bromophenol using reported procedure by Charpentier et al. J. Med Chem, 1995, 38, 4993-5006) with n - Butyl lithium in presence of solvent, tri isopropyl borate and potassium hydrogen difluoride. The reaction sequence can be represented as per the scheme - 3 below:
' L N. ^^ Br 1. THF / n - BuLi / -53°C ± 3°C;
II I 2, Tri isopropyl borate/ dil. HCI / Ethyl acetate
H3C^ ^Is. sf) 3 KHF2/Water
Formula - IV
Scheme - 3
According to the present invention the 2 - (1 - Adamantyl) - 4 - bromoanisole of Formula - IV is reacted with n- butyl lithium in presence of tetra hydro furan (THF) to form a complex. The reaction is carried out in the temperature range of -40°C to -60°C; Tri - isopropyl borate is introduced slowly to the reaction mass by maintaining the same temperature. After the reaction completion the temperature is slowly brought to 25 - 30°C 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 freshly prepared aqueous solution of potassium hydrogen difluoride was charged and maintained the temperature between 0 - 8°C. The molar equivalent of potassium hydrogen difluoride to the 2 - (1 - Adamantyl) - 4 - bromoanisole is 3:1.
The quantity of water for the preparation of the aqueous solution of potassium hydrogen difluoride being 2 times to 6 times, the preferred volume of water is 3 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.
Both the embodiments of the present invention is 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.
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 THF. The reaction mixture was cooled to -55 ± 3°C 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 ± 3°C. Cooling was removed and the temperature was raised slowly to 25 - 30°C. 1.0 L of 1.2N hydrochloric acid was then charged and reaction mass was stirred for 30 minutes. The layer was separated and the aqueous layer was extracted with 2 x 300 ml ethyl acetate. The combined organic layer was charged in 1.0 L round bottom flask and aqueous solution of potassium hydrogen difluoride (230 gm, in 700 ml water) was added at 25 - 30°C and stirring was maintained till white precipitate is obtained. The mixture was continued for another 1 h after maintaining the temperature to 0-5°C. 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 6 vol of THF was charged. After stirring for 15 min, 3.0 gm of 5% Pd / C (50% wet, 5T39K, Johnson-Matthey) was charged. Aqueous potassium hydroxide solution (50.0 gm in 300 ml water) was also added. 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, 4 vol of THF: water (1:1) mixture was further added and then filtered through hyflow bed at 45-50°C. The hyflow bed was washed with 5 vol of THF: water (1:1) mixture at 45-50°C. 500 ml water was then charged and the reaction mass was stirred. The aqueous reaction solution was then
extracted with 2 x 100 ml ethyl acetate. The aqueous layer was separated and acidified with 50% dilute hydrochloric acid. The precipitated mass was filtered, washed with water till neutral pH was obtained. The solid product obtained was dried at 70 - 75°C till constant weight to get 6 - [3-(l- adamantyl) - 4 - methoxyphenyl] - 2 - naphthoic acid having HPLC purity of >99%.
Further, the dried product was taken in 300 ml of THF and ethyl acetate (1:1) mixture and kept for stirring. The temperature was raised to reflux and was maintained for 30 minutes. The heating was stopped and the reaction mass was slowly cooled to 25 - 30°C. 500 ml of n-heptane was charged and the mixture was stirred for another 30 minutes. The reaction mass was then chilled to 0 - 5°C and stirring at this temperature for another 2.0 hours. The precipitated solid was filtered and washed with n - heptane. The pure 6 - [3-(1- adamantyl) - 4 - methoxyphenyl] - 2 - naphthoic acid was then dried. Yield = 34.0 - 36 gms (56 - 60 %) Assay: 99.88% by HPLC.
Dated this 11th day of April 2007
|Indian Patent Application Number||720/MUM/2007|
|PG Journal Number||37/2012|
|Date of Filing||11-Apr-2007|
|Name of Patentee||INDOCO REMEDIES LIMITED|
|Applicant Address||INDOCO HOUSE, 166 C.S.T.ROAD, SANTACRUZ (EAST), MUMBAI 400098|
|PCT International Classification Number||C07C51/353|
|PCT International Application Number||N/A|
|PCT International Filing date|