WO2011101864A1 - Novel process for the synthesis of phenoxyethyl derivatives - Google Patents

Novel process for the synthesis of phenoxyethyl derivatives Download PDF

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Publication number
WO2011101864A1
WO2011101864A1 PCT/IN2011/000093 IN2011000093W WO2011101864A1 WO 2011101864 A1 WO2011101864 A1 WO 2011101864A1 IN 2011000093 W IN2011000093 W IN 2011000093W WO 2011101864 A1 WO2011101864 A1 WO 2011101864A1
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formula
trifluoroethoxy
ethanol
phenoxy
group
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PCT/IN2011/000093
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French (fr)
Inventor
Rajesh Jain
Rao R. Jagdeeshwar
Rao Siripragada Mahender
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Panacea Biotec Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/16—Preparation of ethers by reaction of esters of mineral or organic acids with hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/26—Preparation of ethers by reactions not forming ether-oxygen bonds by introduction of hydroxy or O-metal groups

Definitions

  • the invention relates to the field of organic chemistry and is directed to improved, commercially viable and industrially advantageous processes for the synthesis of compounds useful as intermediates in the synthesis of a1 adrenoceptor blockers, including (R)-1-(3-hydroxypropyl)-5- [2 - [2 - [2-(2,2,2- trifluoroethoxy) phenoxy] ethylamino] propyl] indoline 7-carboxamide (hereinafter referred to by its generic name "Silodosin”) and its pharmaceutically acceptable salts.
  • Silodosin is a selective alpha-1 adrenergic receptor antagonist, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
  • United States patent 5,436,264 assigned to Syntex Inc also discloses a process for the synthesis of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethanol using 2-hydroxy-1-(2-hydroxyethyloxy) benzene and 2-iodo-1 ,1 ,1-trifluoroethane.
  • the 2-iodo-1 ,1 ,1-trifluoroethane is low boiling reagent (Boiling point 53-55°C) and is very difficult to handle while doing reaction at reflux condition to obtain the product, 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethanol.
  • the present invention provides an improved, commercially viable and industrially advantageous processes for the synthesis of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol using less expensive starting material and reagents such as pyrocatechol and aluminium chloride and also the synthesis of a1 adrenoceptor blockers such as silodosin using 2-[2-(2,2,2-trifluoroethoxy) phenoxyjethanol synthesized by the process of the present invention.
  • the intermediates and the final end products obtained through the improved processes of this invention are expected to be obtained in a superior yield and purity.
  • the present invention relates to an improved, commercially viable and industrially advantageous process for the synthesis of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol and its use in the synthesis of a1 adrenoceptor blockers such as silodosin.
  • the present invention specifically relates to an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy) phenoxy] etha
  • step (d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
  • the present invention further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol of Formula I, its derivatives and/or its pharmaceutically acceptable salts thereof, which comprises the steps of:
  • step (c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
  • the present invention still further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy ) phenoxy] ethanol of Formula I, derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of:
  • step (c) optionally converting the product of step (b) to its derivative and/or its pharmaceutically acceptable salt .
  • the present invention further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl methane sulfonate (Formula IX)
  • the present invention even further discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin (Formula XIII)
  • R is hydrogen or hydroxyl protecting group selected from a group comprising of acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chlor
  • the present invention relates to an improved, commercially viable and industrially advantageous process for the synthesis of 2-[2-(2,2,2- trifluoroethoxy )phenoxy]ethanol, its derivatives and/or its pharmaceutically acceptable salts.
  • 2-[2-(2,2,2-trifluoroethoxy) phenoxyjethanol, its derivatives and/or its pharmaceutically acceptable salts are useful as intermediates in the synthesis of compounds that act as a1 adrenoceptor blockers.
  • solvent refers to solvent selected from the group comprising of polar protic solvents such as n-Butanol, Isopropanol, n-Propanol, ethanol, methanol, water, polar aprotic solvents such as Dichloromethane, Tetrahydrofuran, ethyl acetate, acetone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide, acetonitrile (MeCN), dimethyl sulfoxide and non polar solvents such as hexane, benzene, toluene, 1 ,4- dioxane, chloroform, diethyl ether, methyl t-butyl ether. It may also include inorganic solvents such as ammonia (NH 3 ), concentrated sulfuric acid (H 2 SO 4 ). Prefered solvent is dimethylformamide (DMF) and acetonitrile (MeCN).
  • polar protic solvents such
  • base refers to an organic base or an inorganic base.
  • Suitable organic base include, but are not limited to, lower alkyl amine such as triethylamine, diisopropylethylamine and the like.
  • Suitable inorganic base include, but are not limited to, an alkali metal carbonate (for example, cesium carbonate, potassium carbonate, sodium carbonate, etc.), an alkali phosphate (for examples Sodium hydrogen diphospate, sodium dihydrogen monophospate, potassium dihydrogen phosphate, potassium mohydrogen phosphate) an alkali metal alkoxide (for example, potassium t-butoxide, sodium ethoxide, etc.), an alkali metal hydride (for example, potassium hydride, sodium hydride, etc.), or an alkali metal hydroxide (for example, potassium hydroxide, sodium hydroxide, etc.).
  • an alkali metal carbonate for example, cesium carbonate, potassium carbonate, sodium carbonate, etc.
  • appropriate alcohol refers to alcohol selected from a group comprising of 2-bromoethenol, 2-chloroethenol, 2-iodoethanol, 2- methanesulfonyloxy ethanol, 2-(p-toulenesulfonyloxy) ethanol, 2-(p- triflurormethanesulfonyloxy) ethanol.
  • 2-bromoethenol is preferred alcohol.
  • salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, butyrate, camphorsulphonate, difluconae, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, tirchloracetat, glutamate, p- toluenesulphonate, hydrochloric, , hydro
  • lewis acid refers to any compound that can accept an electron pair. Few examples of lewis acid include, but are not limited to aluminum chloride, aluminum bromide, tribromoborane, stannous chloride.
  • nucleophile refers to any molecule possessing an electron rich functional group. Specifically the term nucleophile as used herein would mean "sulphur containing nucleophiles". Few examples of sulphur containing nucleophiles include, but are not limited to, methanethiol, ethanethiol, isopropanethiol, butanethiol, dodecanethiol, benzenethiol or Cn 2 thiols.
  • Lewis acid - nucleophile system refers to a combination of Lewis acid and a nucleophile used in the reaction system for the demethylation reaction.
  • Lewis acid and nucleophile can be selected from those specifies within the meaning of Lewis acid and nucleophile in the present invention.
  • Specific examples of Lewis acid - nucleophile system include, but are not limited to, AICI 3 -Ethanethiol system, AICI 3 -methanethiol system, AICI 3 - isopropanethiol, AlCU-dodecanethiol system and the like.
  • alkylating agent refers to substituted and unsubstituted linear or cyclic alkyl sulfonates such as 2,2,2-trifluoroethyl toluenesulfonate, 2,2,2- trifluoroethyl methane sulfonate, 2,2,2-trifluoroethyl trifluoromethanesulfonate; substituted and unsubstituted methyl and ethyl benzenesulfonate, 2,2,2- trifluoroethyl chloride, 2,2,2-trifluoroethyl bromide, 2,2,2-trifluoroethyl iodide.
  • alkylating agents may be preferably substituted with one or more halogen atoms.
  • hydroxyl protecting group means any moiety that can react with hydroxyl group to form a protected hydroxyl moiety to protect it in a reaction. Suitable examples of hydroxyl protecting group include, but not limited to acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1- ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyl
  • the present invention provides a improved, commercially viable and industrially advantageous process for preparation of 2-[2-(2,2,2- trifluoroethoxy) phenoxy]ethanol comprising:
  • the starting material 2-methoxy phenol can be obtained commercially.
  • the present invention relates to an improved, commercially viable and industrially advantageous process for preparation of 2- [2-(2,2,2-trifluoroethoxy) phenoxy]ethanol of Formula I
  • step (d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
  • X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like.
  • Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
  • the present invention relates to an improved, commercially viable and industrially advantageous process for preparation of 2- [2-(2,2,2-trifluoroethoxy) pheno ula I
  • step (d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
  • the present invention provides a improved, commercially viable and industrially advantageous process of preparation of 2- [2-(2,2,2-trifluoroethoxy) phenoxy] ethanol comprising the steps of :
  • the present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of: (a) preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula VII)
  • step (c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
  • X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
  • Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
  • the present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of: (a) preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula VII)
  • step (c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
  • the present invention provides an improved, commercially viable and industrially advantageous process of preparation of 2- [2-(2,2,2-trifluoroethoxy) phenoxy] ethanol comprising the steps of:
  • the present invention is to provide an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, comprising the steps of:
  • step (c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
  • X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
  • Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
  • the present invention is to provide an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, comprising the steps of:
  • step (c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
  • the present invention further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl methane sulfonate Formula IX)
  • the 2-[2-(2,2,2-trifluoroethoxy) phenoxyjethanol (Formula I) or its derivatives and/or its pharmaceutically acceptable salt obtained by following the process of any of the embodiments of the present invention, can be used as intermediate for the synthesis of a1 adrenoceptor blockers such as silodosin, either by isolating it or without the need of isolating it as intermediate (one pot process).
  • a1 adrenoceptor blockers such as silodosin
  • the above compound of formula I can be used in preparation of silodosin with or without isolating it.
  • the present invention provides an improved, commercially viable and industrially advantageous process for the synthesis of silodosin (Formula XIII)
  • the compounds of Formula X can be prepared by methods disclosed in any of the prior art.
  • R is hydrogen or hydroxyl protecting group selected from a group comprising of acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chlor

Abstract

The present invention provides an improved process for the synthesis of 2-[2- (2,2,2-trifluoroethoxy)phenoxy]ethanol intermediate, its derivatives and/or its pharmaceutically acceptable salts, useful in the synthesis of α-1 adrenoceptor blockers such as silodosin.

Description

NOVEL PROCESS FOR THE SYNTHESIS OF PHENOXYETHYL
DERIVATIVES
Field of the invention
The invention relates to the field of organic chemistry and is directed to improved, commercially viable and industrially advantageous processes for the synthesis of compounds useful as intermediates in the synthesis of a1 adrenoceptor blockers, including (R)-1-(3-hydroxypropyl)-5- [2 - [2 - [2-(2,2,2- trifluoroethoxy) phenoxy] ethylamino] propyl] indoline 7-carboxamide (hereinafter referred to by its generic name "Silodosin") and its pharmaceutically acceptable salts.
Background
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary however reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Silodosin is a selective alpha-1 adrenergic receptor antagonist, indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH).
Till date very few processes for the manufacture of Silodosin have become known.
United States patent 5,387,603 assigned to Kissei pharmaceuticals discloses the synthesis of silodosin from 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methanesulfonate and 1-acetyl-5-(2-aminopropyl) indoline-7-carbonitrile. It also discloses a multistep synthesis of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethanol and its salt, specifically mesylate derivative from 2-methoxy phenol using expensive and hazardous reagents like 1 ,1 ,1-trifluoro ethyl iodide and boron tribromide and Lithium aluminium hydride.
United States patent 5,436,264 assigned to Syntex Inc also discloses a process for the synthesis of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethanol using 2-hydroxy-1-(2-hydroxyethyloxy) benzene and 2-iodo-1 ,1 ,1-trifluoroethane. The 2-iodo-1 ,1 ,1-trifluoroethane is low boiling reagent (Boiling point 53-55°C) and is very difficult to handle while doing reaction at reflux condition to obtain the product, 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethanol.
Japanese patents and applications JP3331047, JP3331048, and JP09221473 .assigned to Kissei pharmaceuticals .disclose the synthesis of 2-[2-(2,2,2- trifluoroethoxy)phenoxy] ethanol from 2-methoxy phenol and 1 ,1 ,1 -trifluoro-2- iodoethane using boron tribromide.
Thus, the general strategies for making the target compound exist, they are not practical for large-scale synthesis, because they employ reagents which are either expensive or difficult to handle or both, as well as specialized equipments are required for the desired operating conditions. These drawbacks make them ill- suited to be employed on common multipurpose industrial plants. Specifically these processes utilize components like 1 , 1 , 1-trifluoro-2- iodoethane and boron tribromide which are very expensive and hence are not economical for use on the industrial scale. Also it is desirable that, impurities introduced during commercial manufacturing processes must be limited to very small amounts, and preferably be substantially absent. Hence there is a need for developing processes which are commercially feasible and have simple process that allow the preparation of highly pure intermediates in a facile manner on an industrial scale, which may yield Silodosin and other end products in high yield and purity.
The present invention provides an improved, commercially viable and industrially advantageous processes for the synthesis of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol using less expensive starting material and reagents such as pyrocatechol and aluminium chloride and also the synthesis of a1 adrenoceptor blockers such as silodosin using 2-[2-(2,2,2-trifluoroethoxy) phenoxyjethanol synthesized by the process of the present invention. The intermediates and the final end products obtained through the improved processes of this invention are expected to be obtained in a superior yield and purity.
Summary of the invention
The present invention relates to an improved, commercially viable and industrially advantageous process for the synthesis of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol and its use in the synthesis of a1 adrenoceptor blockers such as silodosin.
The present invention specifically relates to an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy) phenoxy] etha
Figure imgf000004_0001
Formula I
or its derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of:
(a) preparation of 1-methoxy-2-(2 -trifluoroethoxy)benzene (Formula IV )
Figure imgf000004_0002
Formula IV
by reacting 2-methoxy phenol (Formula II)
Figure imgf000004_0003
Formula II with 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III); Formula III
(b) demethylating the compound of Formula IV to yield 2-(2,2,2- trifluoroethoxy)phenol (Formula VI);
Figure imgf000005_0001
Formula VI
(c) reacting compound of formula VI with 2-bromoethanol (Formula VII)
.OH
Formula VII
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000005_0002
Formula I
(d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
The present invention further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol of Formula I, its derivatives and/or its pharmaceutically acceptable salts thereof, which comprises the steps of:
(a) preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula VI)
Figure imgf000005_0003
Formula VI
by reacting pyrocatechol (Formula V)
Figure imgf000005_0004
Formula V with 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III ) ;
Figure imgf000006_0001
Formula III
(b) reacting compound of Formula VI with 2-bromoethanol (formula VII )
.OH
Br-
Formula VII
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000006_0002
Formula I
(c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
The present invention still further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy ) phenoxy] ethanol of Formula I, derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of:
(a) preparation of 2-(2-hydroxyethoxy)phenol (Formula VIII)
Figure imgf000006_0003
Formula VIII
by reacting pyrocatechol (formula V)
Figure imgf000006_0004
Formula V
with 2 bromoethanol (formula VII );
Formula VII (b) reacting the compound of Formula VIII with 2,2,2-trifluoroethyl p- toluenesulfonate (Formula III)
Tscr F,
Formula III
to yield 2-[2-(2,2,2-trifluoroetho ol (Formula I);
Figure imgf000007_0001
Formula I
(c) optionally converting the product of step (b) to its derivative and/or its pharmaceutically acceptable salt .
The present invention further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl methane sulfonate (Formula IX)
Figure imgf000007_0002
Formula IX
by reacting 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Fomnula I) obtained by following the processes as disclosed in any of the embodiments of the present invention with methanesulfonyl chloride.
The present invention even further discloses an improved, commercially viable and industrially advantageous process for the preparation of silodosin (Formula XIII)
Figure imgf000007_0003
Formula XIII
or its pharmaceutically acceptable salt thereof, comprising the following steps (a) reacting 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I) obtained by following the processes as disclosed in any of the embodiments of the present invention with methanesulfonyl chloride to obtain 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl methane sulfonate Formula IX)
Figure imgf000008_0001
Formula IX
(b) reacting compound of formula IX with Compound represented by the structural formula X
Figure imgf000008_0002
Formula X
to obtain compound of formula XI
Figure imgf000008_0003
Formula XI
wherein R is hydrogen or hydroxyl protecting group selected from a group comprising of acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenyl-methyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl or substitutedpixyl, preferred hydroxyl protecting group is benzoyl.
(c) removing the hydroxyl protecting group of compound of formula XI to yield compound of formula XII
Figure imgf000009_0001
Formula XII
(d) hydrolyzing compound of formula XII to obtain silodosin (formula XIII) These and other features, aspects, and advantages of the present subject matter will become better understood with reference to the following description and appended claims. This summary is provided to introduce a selection of concepts in a simplified form. This summary is not intended to limit the scope of the claimed subject matter.
Detailed description of the invention
The present invention relates to an improved, commercially viable and industrially advantageous process for the synthesis of 2-[2-(2,2,2- trifluoroethoxy )phenoxy]ethanol, its derivatives and/or its pharmaceutically acceptable salts. 2-[2-(2,2,2-trifluoroethoxy) phenoxyjethanol, its derivatives and/or its pharmaceutically acceptable salts are useful as intermediates in the synthesis of compounds that act as a1 adrenoceptor blockers.
Definitions:
The invention described herein in detail using the terms defined below unless otherwise specified.
The term " solvent" refers to solvent selected from the group comprising of polar protic solvents such as n-Butanol, Isopropanol, n-Propanol, ethanol, methanol, water, polar aprotic solvents such as Dichloromethane, Tetrahydrofuran, ethyl acetate, acetone, methyl isobutyl ketone, dimethylformamide (DMF), dimethylacetamide, acetonitrile (MeCN), dimethyl sulfoxide and non polar solvents such as hexane, benzene, toluene, 1 ,4- dioxane, chloroform, diethyl ether, methyl t-butyl ether. It may also include inorganic solvents such as ammonia (NH3), concentrated sulfuric acid (H2SO4). Prefered solvent is dimethylformamide (DMF) and acetonitrile (MeCN).
The term "base" refers to an organic base or an inorganic base. Suitable organic base include, but are not limited to, lower alkyl amine such as triethylamine, diisopropylethylamine and the like. Suitable inorganic base include, but are not limited to, an alkali metal carbonate (for example, cesium carbonate, potassium carbonate, sodium carbonate, etc.), an alkali phosphate (for examples Sodium hydrogen diphospate, sodium dihydrogen monophospate, potassium dihydrogen phosphate, potassium mohydrogen phosphate) an alkali metal alkoxide (for example, potassium t-butoxide, sodium ethoxide, etc.), an alkali metal hydride (for example, potassium hydride, sodium hydride, etc.), or an alkali metal hydroxide (for example, potassium hydroxide, sodium hydroxide, etc.).
The term "appropriate alcohol" refers to alcohol selected from a group comprising of 2-bromoethenol, 2-chloroethenol, 2-iodoethanol, 2- methanesulfonyloxy ethanol, 2-(p-toulenesulfonyloxy) ethanol, 2-(p- triflurormethanesulfonyloxy) ethanol. 2-bromoethenol is preferred alcohol.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic inorganic or organic acids. The salts may be prepared during the final isolation and purification of the compounds by making acidic addition salts. Representative salts of basic compounds of the present invention can be prepared by reacting free base form of the compound with a suitable acid, including, but not limited to acetate, trifluoroacetate, adipate, citrate, aspartate, benzoate, benzenesulphonate, bisulfate, besylate, butyrate, camphorsulphonate, difluconae, hemisulfate, heptanoate, formate, fumarate, lactate, maleate, methanesulfonate, naphthylsulfonate, nicotinate, oxalate, picrate, pivalate, succinate, tartrate, tirchloracetat, glutamate, p- toluenesulphonate, hydrochloric, , hydrobromic, sulphuric, phosphoric and the like. The term "derivatives" refers to any compounds prepared from the Formula I. The term "Lewis acid" refers to any compound that can accept an electron pair. Few examples of lewis acid include, but are not limited to aluminum chloride, aluminum bromide, tribromoborane, stannous chloride.
The term "nucleophile" refers to any molecule possessing an electron rich functional group. Specifically the term nucleophile as used herein would mean "sulphur containing nucleophiles". Few examples of sulphur containing nucleophiles include, but are not limited to, methanethiol, ethanethiol, isopropanethiol, butanethiol, dodecanethiol, benzenethiol or Cn2 thiols.
The term "Lewis acid - nucleophile system" refers to a combination of Lewis acid and a nucleophile used in the reaction system for the demethylation reaction. Lewis acid and nucleophile can be selected from those specifies within the meaning of Lewis acid and nucleophile in the present invention. Specific examples of Lewis acid - nucleophile system include, but are not limited to, AICI3-Ethanethiol system, AICI3-methanethiol system, AICI3- isopropanethiol, AlCU-dodecanethiol system and the like.
The term "alkylating agent" refers to substituted and unsubstituted linear or cyclic alkyl sulfonates such as 2,2,2-trifluoroethyl toluenesulfonate, 2,2,2- trifluoroethyl methane sulfonate, 2,2,2-trifluoroethyl trifluoromethanesulfonate; substituted and unsubstituted methyl and ethyl benzenesulfonate, 2,2,2- trifluoroethyl chloride, 2,2,2-trifluoroethyl bromide, 2,2,2-trifluoroethyl iodide. These entire alkylating agents may be preferably substituted with one or more halogen atoms.
The term "hydroxyl protecting group" means any moiety that can react with hydroxyl group to form a protected hydroxyl moiety to protect it in a reaction. Suitable examples of hydroxyl protecting group include, but not limited to acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1- ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyi, 9-fluorenyl-methyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl or substitutedpixyl. Preferred hydroxyl protecting group is benzoyl.
It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. As well, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein. It is also to be noted that the terms "comprising", "including", "characterized by" and "having" can be used interchangeably.
In one embodiment, the present invention provides a improved, commercially viable and industrially advantageous process for preparation of 2-[2-(2,2,2- trifluoroethoxy) phenoxy]ethanol comprising:
(a) alkylating 2-methoxy phenol by treating it with a suitable alkylating agent in the presence of a suitable base (s) and solvent to obtain 1-methoxy-2-(2,2,2- trifluoroethoxy)benzene ;
(b) demethylating 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene using a Lewis acid - nucleophile system in a suitable solvent (s) to obtain 2-(2,2,2- trifluoroethoxy)phenol, and
(c) subjecting 2-(2,2,2-trifluoroethoxy)phenol to a condensation reaction with a appropriate alcohol in presence of a suitable base and solvent to yield 2-[2-
(2 ,2 ,2-trif luoroethoxy) phenoxy]ethanol .
The starting material 2-methoxy phenol can be obtained commercially.
In another embodiment the present invention relates to an improved, commercially viable and industrially advantageous process for preparation of 2- [2-(2,2,2-trifluoroethoxy) phenoxy]ethanol of Formula I
Figure imgf000012_0001
Formula I
or its derivatives and/or its pharmaceutically acceptable salts thereof, which comprises the steps of:
(a) preparation of 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (Formula IV )
Figure imgf000013_0001
Formula IV
by reacting 2-methoxy phenol (Formula II)
Figure imgf000013_0002
Formula II
with suitable alkylating agent (Formula IMA);
Formula IMA
(b) treating the compound of Formula IV with aluminium chloride in the presence of ethanethiol and methylene chloride to yield 2-(2,2,2- trifluoroethoxy)phenol (Formula VI);
Figure imgf000013_0003
Formula VI
(c) reacting compound of formula VI with 2 substituted ethanol (formula VI IA );
ΌΗ
Formula VIIA
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000013_0004
Formula I
(d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
wherein X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like. wherein Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
In a preferred embodiment the present invention relates to an improved, commercially viable and industrially advantageous process for preparation of 2- [2-(2,2,2-trifluoroethoxy) pheno ula I
Figure imgf000014_0001
Formula I
or its derivatives and/or its pharmaceutically acceptable salts thereof, which comprises the steps of:
(a) preparation of 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (Formula IV )
Figure imgf000014_0002
Formula IV
by reacting 2-methoxy phenol (Formula II)
Figure imgf000014_0003
Formula II
with 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III);
Formula III
(b) treating the compound of Formula IV with aluminium chloride in the presence of ethanethiol and methylene chloride to yield 2-(2,2,2- trifluoroethoxy)phenol (Formula V
Figure imgf000014_0004
Formula VI
(c) reacting compound of formula VI with 2 bormoethanol (Formula VIII) Formula VII
to yield 2-[2-(2 ,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000015_0001
Formula I
(d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
In another embodiment, the present invention provides a improved, commercially viable and industrially advantageous process of preparation of 2- [2-(2,2,2-trifluoroethoxy) phenoxy] ethanol comprising the steps of :
(a) alkylating pyrocatechol to corresponding aralkylether by reacting it with an alkylating agent in the presence of a suitable base and a solvent; and
(b) reacting the aralkylether with an appropriate alcohol in the presence of a suitable base and solvent.
In still another embodiment, the present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of: (a) preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula VII)
Formula VI
by reacting pyrocatechol (Formula V)
Figure imgf000015_0003
Formula V
with suitable alkylating agent (Formula IIIA ) ;
Formula IIIA (b) reacting compound of Formula VII with 2 substituted ethanol (formula VIIA
);
OH
Formula VIIA
to yield 2-[2-(2,2,2-trifluoroetho l (Formula I);
Figure imgf000016_0001
Formula I
(c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
wherein X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
wherein Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
In another preferred embodiment, the present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, which comprises the steps of: (a) preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula VII)
Figure imgf000016_0002
Formula VI
by reacting pyrocatechol (Formula V)
Figure imgf000016_0003
Formula V
with 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III ) ; TsO^ F3
Formula III
(b) reacting compound of Formula VII with 2 bormoethanol (formula VIII )
OH
Br^
Formula VII
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000017_0001
Formula I
(c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
In a further embodiment, the present invention provides an improved, commercially viable and industrially advantageous process of preparation of 2- [2-(2,2,2-trifluoroethoxy) phenoxy] ethanol comprising the steps of:
(a) reaction between pyrocatechol and a appropriate alcohol in the presence of a suitable base and solvent to obtain a hydroxylated aralkylether;
(b) alkylating the hydroxylated aralkylether by reacting it with an alkylating agent in the presence of a suitable base and solvent.
In a still further embodiments the present invention is to provide an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, comprising the steps of:
(a) preparation of 2-(2-hydroxyethoxy)phenol (Formula VIII)
Figure imgf000017_0002
Formula VIII
by reacting pyrocatechol (Formula V
Figure imgf000017_0003
Formula V
with 2 substituted ethanol (formula VI I A );
.OH
Y
Formula VI I A
(b) reacting the compound of Formula VIII with suitable alkylating agent (Formula IMA)
Figure imgf000018_0001
Formula I HA
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000018_0002
Formula I
(c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
wherein X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
wherein Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
In a further preferred embodiments the present invention is to provide an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts, comprising the steps of:
(a) preparation of 2-(2-hydroxyeth rmula VIII)
Figure imgf000018_0003
Formula VIII
by reacting pyrocatechol (Formula V)
Figure imgf000019_0001
Formula V
with 2 bormoethanol (formula VII);
ΩΗ
Br'
Formula VII
(b) reacting the compound of Formula VIII with 2,2,2-trifluoroethyl toluenesulfonate (Formula III)
TsO^ F3
Formula III
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000019_0002
Formula I
(c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
The present invention further discloses an improved, commercially viable and industrially advantageous process for the preparation of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethyl methane sulfonate Formula IX)
Figure imgf000019_0003
Formula IX
by reacting 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I) obtained by following the processes as disclosed in any of the embodiments of the present invention with methanesulfonyl chloride.
The 2-[2-(2,2,2-trifluoroethoxy) phenoxyjethanol (Formula I) or its derivatives and/or its pharmaceutically acceptable salt obtained by following the process of any of the embodiments of the present invention, can be used as intermediate for the synthesis of a1 adrenoceptor blockers such as silodosin, either by isolating it or without the need of isolating it as intermediate (one pot process).
The above compound of formula I can be used in preparation of silodosin with or without isolating it.
In a particularly preferred embodiment, the present invention provides an improved, commercially viable and industrially advantageous process for the synthesis of silodosin (Formula XIII)
Figure imgf000020_0001
Formula XIII
or its pharmaceutically acceptable salt thereof, comprising the steps of ;
(a) reacting 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I) obtained by following the processes as claimed in any of the preceding claim , with methanesulfonyl chloride to obtain 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate (Formula IX
Figure imgf000020_0002
Formula IX
(b) reacting compound of formula IX with Compound represented by the structural formula X
Figure imgf000020_0003
Formula X
to obtain compound of formula XI
Figure imgf000021_0001
Formula XI
(c) removing the hydroxyl protecting group of compound of formula XI to yield compound of formula XII
Figure imgf000021_0002
Formula XII
(d) hydrolyzing compound of formula XII to obtain silodosin, and optionally converting to its pharmaceutically acceptable salts.
The compounds of Formula X can be prepared by methods disclosed in any of the prior art.
wherein R is hydrogen or hydroxyl protecting group selected from a group comprising of acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenyl-methyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl or substitutedpixyl.
Examples:
The invention is explained in detail in the following examples which are given solely for the purpose of illustration only and therefore should not be construed to limit the scope of the invention. The following terms/symbols/abbreviations/chemical formulae are emproyecrin the examples:
ml : Millilitre
g : Gram
mg : Milligram
h : Hours
min : Minute
mM : Millimole
μΜ : Micromole
DMF : Dimethyl formamide
K2CO3 : Potassium Carbonate
Example 1:
Preparation of 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (IV)
To a solution of 2-methoxy phenol (II) (1.75 g, 14.1 mmol) in DMF (10 ml) was added K2CO3 (3.9 g, 28.2 mmol) and 2,2,2-trifluoroethyl p-toluenesulfonate (III) (3.58 g, 14.1 mmol) at room temperature. The mixture was stirred at 100°C in a sealed vessel for 12 h. The mixture was diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The solvent was evaporated under vacuum and purified by column chromatography to give 1.7 g of 1-methoxy-2-(2,2,2- trifluoroethoxy)benzene (IV) as an oil.
Example 2:
Preparation of 2-(2,2,2-Trifluoroethoxy)phenol (VI):
a) Route-1 : To a mixture of ethanethiol (2 ml) in methylene chloride (4 ml) was added aluminum chloride (6.77 g, 50.9 mmol) slowly at 0 °C. The resulting solution was stirred for 10 min and 1-methoxy-2-(2,2,2-trifluoroethoxy) benzene (IV) (3.5 g, 16.9 mmol) in methylene chloride (4 ml) was added at 0°C. The mixture was warmed to room temperature and stirred for 4 h. The mixture was diluted with water (50 ml), extracted with methylene chloride (3 X 100 ml) and concentrated under reduced pressure. The product was purified by column chromatography to give 3 g of 2-(2,2,2-trifluoroethoxy) phenol (VI) as a thick gel.
b) Route-2: To a solution of Pyrocatechol (50 g, 454.5 mmol) in DMF (400 ml) was added K2C03 (188.1 g, 1363 mmol) and 2,2,2-trifluoroethyl p- toluenesulfonate (III) (115.4 g, 454.5 mmol) at room temperature. The mixture was stirred at 1 0°C in a sealed vessel for 24 hrs. The mixture was diluted with water (750 ml) and extracted with ethyl acetate (250 ml). The ethyl acetate layer was washed with water (500 ml) and the solvent was evaporated under vacuum. The obtained crude material was purified by column chromatography to give 37 g of 2-(2,2,2-trifluoroethoxy)phenol (VI) as a thick gel.
Example 3:
Preparation of 2-(2-Hydroxyethoxy)phenol (VIII):
To a solution of Pyrocatechol (100 g, 909.09 mmol) in acetonitrile (800 ml) was added K2CO3 (376.3 g, 2727.27 mmol) and followed by addition of 2- bromoethanol (VII) (227.2 gm, 1818.18 mmol) at room temperature. The mixture was stirred for 24 hrs at 110-120°C. The reaction mixture was filtered and washed the solid with acetonitrile (200 ml). The filtrate was concentrated under reduced pressure. The obtained crude was dissolved in ethyl acetate (750 ml) and washed with water (1000 ml). The water layer was extracted twice with ethyl acetate (2 X 750 ml). The combined organic layers were distilled at 40-45°C to become thick mass and added mixture of ethyl acetate and pet ether (3:7) (200 ml). The obtained solid was filtered and washed with mixture of ethyl acetate and pet ether (3:7) (100 ml) and dried the solid under vacuum at 45°C to give 45 g of 2-(2-hydroxyethoxy) phenol (VIII) as a white solid.
Example 4:
Preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (I):
a) Route-1 : To a solution of 2-(2,2,2-trifluoroethoxy) phenol (VI) (37 g, 192.7 mmol) in acetonitrile (370 ml) was added K2CO3 (79.7 g, 578.1 mmol) and followed by addition of 2-bromoethanol (VII) (48.17 g, 385.1 mmol) at room temperature. The mixture was stirred for 66 hrs at 90-100°C. The reaction mixture was filtered and the solvent was evaporated under vacuum. The crude was diluted with ethyl acetate (400 ml) and washed with water (200 ml). The solvent was evaporated under vacuum to give 35 g of 2-[2-(2,2,2- trifluoroethoxy)phenoxy]ethanol (I) as an oil. (HPLC purity is 85-90%).
b) Route-2: To a solution of 2-(2-hydroxyethoxy) phenol (VIII) (250 g, 1623 mmol) in DMF (1250 ml) was added K2C03 (676 g, 4899 mmol) and 2,2,2- trifluoroethyl p-toluenesulfonate (III) (414 g, 1623 mmol) at room temperature. The mixture was stirred at 120°C for 24-30 hrs and was diluted with water (9370 ml). The product was extracted twice with ethyl acetate (2 x 1500 ml) and the combined organic layers were washed with water (500 ml). The solvent was evaporated under vacuum to give 225 g of 2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethanol (I) as a colourless oil (HPLC purity is 95-98%).
1H NMR: δ 7.06-6.91 (m, 4H), 4.37 (q, 2H), 4.12 (t, 2H), 3.94 (t, 2H) Example 5:
Preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate (IX): To a solution of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (287 g, 1216 mmol) in methylene chloride (1435 ml) were added triethyl amine (307 g, 3040 mmol) and methane sulfonyl chloride (145.5 g, 1276 mmol) under ice cooling. The mixture was stirred at room temperature for 1 hrs and water (700 ml) was added to it. The organic layer was separated and washed with water (700 ml). The solvent was evaporated under reduced pressure and the obtained thick gel was crystallized from Hexane (860 ml) at low temperature to give 193 g of 2-[2- (2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate (IX) as a white solid (HPLC purity is 97-98%).
Example 6:
Preparation of Silodosin
The conversion of 2-[2-(2,2,2-trifluoroethoxy)phenoxy] ethyl methane sulfonate (IX) to Silodisn was followed by procedures disclosed in any of the prior art including United States patent application 20070197627 and United States patent 5,387,603.

Claims

1. A process for preparation of 2-[2-(2,2,2-trifluoroethoxy) phenoxy]ethanol of Formula I
Figure imgf000025_0001
Formula I
or its derivatives and/or its pharmaceutically acceptable salts thereof, comprising the steps of:
(a) preparation of 1-methoxy-2-(2,2,2-trifluoroethoxy)benzene (Formula IV )
Figure imgf000025_0002
by reacting 2-methoxy phenol (Formula II)
Figure imgf000025_0003
Formula II
with suitable alkylating agent of formula IMA
Formula IMA
(b) demethylating the compound of Formula IV to yield 2-(2,2,2- trifluoroethoxy)phenol (Formula VI);
Figure imgf000025_0004
Formula VI
(c) reacting compound of formula VI with 2 substituted ethanol (Formula VI I A)
OH
Formula VIIA to yield 2-[2-(2,2,2-trifluoroethox l (Formula I);
Figure imgf000026_0001
Formula I
(d) optionally converting the product of step (c) to its derivatives and/or its pharmaceutically acceptable salts.
wherein X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
wherein Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
2. A process as claimed in claim 1 , wherein suitable alkylating agent of formula MIA is 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III);
Formula III
3. A process as claimed in claim 1 , wherein 2 substituted ethanol (Formula VI I A) is 2 bromoethanol (formula VII)
/\ OH Formula VII
4. A process as claimed in claim 1 , wherein either or both of step (a) and step (c) are carried out in presence of a base selected from a group comprising of lower alkyl amine such as triethylamine, diisopropylethylamine and the like, an alkali metal carbonate such as cesium carbonate, potassium carbonate, sodium carbonate and the like, an alkali metal alkoxide such as potassium t- butoxide, sodium ethoxide and the like, an alkali metal hydride such as potassium hydride, sodium hydride and the like, or an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide and the like.
5. A process as claimed in claim 4, wherein either or both of step (a) and step (c) are carried out in presence of potassium carbonate.
6. A process as claimed in claim 1 , wherein step (b) is carried out in presence of a Lewis acid - nucleophile system selected from a group comprising of AICI3- Ethanethiol system, AlC -methanethiol system, AlC -isopropanethiol, AICI3- dodecanethiol system and the like.
7. A process as claimed in claim 6, wherein step (b) is carried out in presence of AICI3-Ethanethiol system.
8. A process as claimed in claim 1 , wherein either or both of step (a) and step (c) are carried out in presence of potassium carbonate and wherein the step (b) is carried out in presence of AICU-Ethanethiol system.
9. A process for preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts thereof, comprising the steps of:
(a) preparation of 2-(2,2,2-trifluoroethoxy)phenol (Formula VI)
Figure imgf000027_0001
Formula VI
by reacting pyrocatechol (Formula V)
Figure imgf000027_0002
Formula V
with suitable alkylating agent of formula IIIA
Figure imgf000027_0003
Formula IIIA (b) reacting compound of Formula VI with 2 substituted ethanol (formula VIIA);
OH
Formula VIIA
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000028_0001
Formula I
(c) optionally converting the product of step (b) to its derivatives and/or its pharmaceutically acceptable salts.
wherein X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
wherein Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
10. A process as claimed in claim 9, wherein suitable alkylating agent of formula IMA is 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III);
Formula III
11. A process as claimed in claim 9, wherein 2 substituted ethanol (Formula VIIA) is 2 bromoethanol (formula VII)
OH
Formula VII
12. A process as claimed in claim 9, wherein either or both of step (a) and step (b) are carried out in presence of a base selected from a group comprising of lower alkyl amine such as triethylamine, diisopropylethylamine and the like, an alkali metal carbonate such as cesium carbonate, potassium carbonate, sodium carbonate and the like, an alkali metal alkoxide such as potassium t- butoxide, sodium ethoxide and the like, an alkali metal hydride such as potassium hydride, sodium hydride and the like, or an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide and the like.
13. A process as claimed in claim 12, wherein either or both of step (a) and step (b) are carried out in presence of potassium carbonate.
14. A process for preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol of Formula I or its derivatives and/or its pharmaceutically acceptable salts thereof, comprising the steps of:
(a) preparation of 2-(2-hydroxyethoxy)phenol (Formula VIII)
Figure imgf000029_0001
Formula VIII
by reacting pyrocatechol (formula V)
Figure imgf000029_0002
with 2 substituted ethanol (formula VI IA );
Formula VIIA
(b) reacting the compound of Formula VIII with suitable alkylating agent of formula MIA
Formula IIIA
to yield 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I);
Figure imgf000029_0003
Formula I
(c) optionally converting the product of step (b) to its derivative and/or its pharmaceutically acceptable salts.
wherein X is selected from a group comprising of substituted or unsubstituted linear or cyclic group such as toluenesulfonate, trifluoromethanesulfonate, ethylbenzenesulphonate, chlorine, bromine and the like,
wherein Y is selected from a group comprising of bromine, chlorine, Iodine and the like.
15. A process as claimed in claim 14, wherein suitable alkylating agent of formula IMA is 2,2,2-trifluoroethyl p-toluenesulfonate (Formula III);
Formula III
16. A process as claimed in claim 14, wherein 2 substituted ethanol (Formula VIIA) is 2 bromoethanol (formula VII)
^ . .OH
Formula VII
17. A process as claimed in claim 14, wherein either or both of step (a) and step (b) are carried out in presence of a base selected from a group comprising of lower alkyl amine such as triethylamine, diisopropylethylamine and the like, an alkali metal carbonate such as cesium carbonate, potassium carbonate, sodium carbonate and the like, an alkali metal alkoxide such as potassium t- butoxide, sodium ethoxide and the like, an alkali metal hydride such as potassium hydride, sodium hydride and the like, or an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide and the like.
18. A process as claimed in claim 17, wherein either or both of step (a) and step (b) are carried out in presence of potassium carbonate.
19. A process for preparation of 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate (Formula IX)
Figure imgf000031_0001
Formula IX
by reacting 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I) obtained by the processes claimed in any of the preceding claim
Figure imgf000031_0002
Formula I
with methanesulfonyl chloride.
20. A process for preparation of silodosin (Formula XIII)
Figure imgf000031_0003
Formula XIII
or its pharmaceutically acceptable salts thereof, comprising the steps of ;
(a) reacting 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethanol (Formula I) obtained by following the processes as disclosed in any of the preceding claim with methanesulfonyl chloride to obtain 2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl methane sulfonate (Formula IX)
Figure imgf000031_0004
Formula IX
(b) reacting compound of formula IX with Compound represented by the structural formula X
Figure imgf000032_0001
Formula X
to obtain compound of formula XI
Figure imgf000032_0002
Formula XI
wherein R is hydrogen or hydroxyl protecting group selected from a group comprising of acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4- dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4-methoxytrityl, 4,4'- dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyi, 9-fluorenyl-methyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl or substitutedpixyl and the like.
(c) removing the hydroxyl protecting group of compound of formula XI to yield compound of formula XII
Figure imgf000032_0003
Formula XII (d) hydrolyzing compound of formula XII to obtain silodosin (formula XIII) and optionally converting to its pharmaceutically acceptable salts.
21. A process as claimed in claim 20, wherein the compound of formula X is 3- {7-cyano-5-[(2R)-2-aminopropyl]-2,3-dihydro-1 H-indol-1 -yl}propyl benzoate.
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WO2013072935A2 (en) 2011-10-10 2013-05-23 Cadila Healthcare Limited Process for the preparation of silodosin
CN103396352A (en) * 2013-08-07 2013-11-20 苏州明锐医药科技有限公司 Preparation method of Silodosin
CN109516933A (en) * 2018-10-29 2019-03-26 安徽省庆云医药股份有限公司 A kind of preparation method of Silodosin intermediate
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WO2013072935A2 (en) 2011-10-10 2013-05-23 Cadila Healthcare Limited Process for the preparation of silodosin
CN103396352A (en) * 2013-08-07 2013-11-20 苏州明锐医药科技有限公司 Preparation method of Silodosin
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CN109516933A (en) * 2018-10-29 2019-03-26 安徽省庆云医药股份有限公司 A kind of preparation method of Silodosin intermediate
CN109516933B (en) * 2018-10-29 2021-03-02 安徽省庆云医药股份有限公司 Preparation method of silodosin intermediate
CN114478202A (en) * 2022-02-16 2022-05-13 江苏飞宇医药科技股份有限公司 Method for continuously preparing 2- (2,2, 2-trifluoroethoxy) phenol

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