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WO2008126104A2 - Nouveau procédé de préparation de l'adapalène - Google Patents

Nouveau procédé de préparation de l'adapalène Download PDF

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Publication number
WO2008126104A2
WO2008126104A2 PCT/IN2008/000236 IN2008000236W WO2008126104A2 WO 2008126104 A2 WO2008126104 A2 WO 2008126104A2 IN 2008000236 W IN2008000236 W IN 2008000236W WO 2008126104 A2 WO2008126104 A2 WO 2008126104A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
adamantyl
process according
palladium
methoxy phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2008/000236
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English (en)
Other versions
WO2008126104A3 (fr
Inventor
Ketan Dhansukhlal Vyas
Ranjeet Nair
Pravin Nalawade
Ulhas Digambar Patil
Aditi Milind Panandikar
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Indoco Remedies Ltd
Original Assignee
Indoco Remedies Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Indoco Remedies Ltd filed Critical Indoco Remedies Ltd
Publication of WO2008126104A2 publication Critical patent/WO2008126104A2/fr
Publication of WO2008126104A3 publication Critical patent/WO2008126104A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/56—Ring systems containing bridged rings
    • C07C2603/58—Ring systems containing bridged rings containing three rings
    • C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
    • C07C2603/74—Adamantanes

Definitions

  • 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.
  • Adapalene 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.
  • 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.
  • 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.
  • 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:
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 -
  • 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.
  • 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 - C 4 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 50 0 C to 8O 0 C, 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 - 30 0 C.
  • 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.
  • 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 - 30 0 C 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 - 321 0 C.
  • 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:
  • 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.
  • THF tetrahydrofuran
  • the reaction is carried out in the temperature range of -60 0 C to -40 0 C; 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 - 30 0 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 charged freshly prepared aqueous solution of potassium hydrogen difluoride maintaining the temperature between 25 - 30 0 C.
  • 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 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.
  • 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 45-50 0 C. The hyflow bed was washed with tetrahydrofuran: water (1 : 1) mixture at 45-50 0 C. 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention porte sur un procédé pour la préparation du dérivé adamantylé acide 6-[3-(l-adamantyl)-4-méthoxy, phényl]-2-naphtoïque, connu comme étant l'adapalène, dans lequel on utilise un nouvel intermédiaire, à savoir le 3-adamantyl-4-méthoxyphényl potassium trifluoroborate.
PCT/IN2008/000236 2007-04-11 2008-04-09 Nouveau procédé de préparation de l'adapalène Ceased WO2008126104A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN720/MUM/2007 2007-04-11
IN720MU2007 2007-04-11

Publications (2)

Publication Number Publication Date
WO2008126104A2 true WO2008126104A2 (fr) 2008-10-23
WO2008126104A3 WO2008126104A3 (fr) 2009-07-30

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PCT/IN2008/000236 Ceased WO2008126104A2 (fr) 2007-04-11 2008-04-09 Nouveau procédé de préparation de l'adapalène

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112479867A (zh) * 2020-12-30 2021-03-12 武汉诺安药业有限公司 一种阿达帕林微粉化的化学制备方法
CN112724011A (zh) * 2019-10-28 2021-04-30 东莞东阳光药物研发有限公司 一种精制阿达帕林的方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007012492A (es) * 2005-04-08 2007-12-06 Galderma Res & Dev Nuevo metodo para la preparacion del acido 6-[3-(1-adamantil)-4- metoxifenil]-2-naftoico.
CN1696100B (zh) * 2005-06-01 2010-11-24 黑龙江福和华星制药集团股份有限公司 痤疮治疗药阿达帕林的新型简捷合成方法
CN1872829A (zh) * 2006-04-18 2006-12-06 江苏中丹化工集团公司 一种制备阿达帕林的方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112724011A (zh) * 2019-10-28 2021-04-30 东莞东阳光药物研发有限公司 一种精制阿达帕林的方法
CN112724011B (zh) * 2019-10-28 2024-04-05 广东东阳光药业股份有限公司 一种精制阿达帕林的方法
CN112479867A (zh) * 2020-12-30 2021-03-12 武汉诺安药业有限公司 一种阿达帕林微粉化的化学制备方法
CN112479867B (zh) * 2020-12-30 2024-03-29 武汉诺安药业有限公司 一种阿达帕林微粉化的化学制备方法

Also Published As

Publication number Publication date
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