+

WO2009008000A2 - Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène - Google Patents

Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène Download PDF

Info

Publication number
WO2009008000A2
WO2009008000A2 PCT/IN2008/000273 IN2008000273W WO2009008000A2 WO 2009008000 A2 WO2009008000 A2 WO 2009008000A2 IN 2008000273 W IN2008000273 W IN 2008000273W WO 2009008000 A2 WO2009008000 A2 WO 2009008000A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
benzo
benzoyl
thiophene
Prior art date
Application number
PCT/IN2008/000273
Other languages
English (en)
Other versions
WO2009008000A3 (fr
Inventor
Rajamannar Thennati
Srinivasu Kilaru
Nileshkumar Sureshbhai Patel
Yesha Vijaykumar Patel
Original Assignee
Sun Pharmaceutical Industries 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 Sun Pharmaceutical Industries Ltd. filed Critical Sun Pharmaceutical Industries Ltd.
Publication of WO2009008000A2 publication Critical patent/WO2009008000A2/fr
Publication of WO2009008000A3 publication Critical patent/WO2009008000A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/56—Radicals substituted by oxygen atoms

Definitions

  • the present invention relates to a process for the preparation of 6-hydroxy-2-(4- hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, compound of formula I, and its pharmaceutically acceptable salts.
  • Compound of formula I commonly known as raloxifene (INN Name) is used in the treatment and prevention of osteoporosis in post-menopausal women.
  • United States Patent No.4,418,068 (Assigned to: Eli Lilly and company; referred to herein as '068) describes the preparation of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethoxy)benzoyl]benzo[b]thiophene, compound of formula I, and its pharmaceutically acceptable salts by various methods.
  • the dealkylation is carried out in presence of Lewis acid like aluminum chloride and boron trichloride.
  • Dealkylations with aluminum chloride require addition of mercaptan compounds which give an offensive odour.
  • aluminum chloride produces large quantity of aluminum based by-products which are soluble in raloxifene processing solvents and are detected in the final product.
  • Boron trichloride overcomes the disadvantages of aluminum chloride but is corrosive, toxic gas with pungent irritating odor and hence difficult to handle. Also the cost is prohibitive as it is six-fold expensive than aluminum trichloride. Further, the purity and yield of the compound of formula I obtained using these dealkylation methods are not reported.
  • the workup involves ether wash, treatment with aqueous methanesulfonic acid followed by basification with ammonia to give crude 6-hydroxy-2- (4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, compound of formula I.
  • the crude compound of formula I is then subjected to column purification to get compound of formula I as a yellow foam which is recrystallized from acetone, to get purified compound of formula I.
  • This process is disadvantageous as the workup involves multiple purification steps using different solvents and results in lower yield of the compound of formula I.
  • the present invention provides such a process for preparing 6-hydroxy- 2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, compound of formula I from 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3[4-(2- piperidinoethoxy)-benzoyl]benzo[b]thiophene compound of formula II.
  • An object of the invention is to provide a simple and commercially feasible process for the preparation of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo[b]thiophene, compound of formula I, in high yields in substantially pure form from compound of formula II using lower volumes of solvent, without the need for chromatographic methods of purification.
  • the substantially pure 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl] benzo[b]thiophene compound of formula I, or its hydrochloride salt referred to herein has HPLC purity 99% or more, preferably 99.5% or more.
  • substantially pure compound of formula I may be prepared by deprotecting compound of formula II with base in dimethyl sulfoxide.
  • the base for deprotection reaction may be selected from aqueous solution of alkali metal alkoxides such as sodium methoxide, potassium methoxide, potassium tertiary butoxide and the like; alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like; alkali metal amide such as sodium amide and the like; ammonia, hydroxylamine, hydrazine, dimethylamine and the like.
  • alkali metal alkoxides such as sodium methoxide, potassium methoxide, potassium tertiary butoxide and the like
  • alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like
  • alkali metal amide such as sodium amide and the like
  • the deprotection reaction maybe carried out by heating at 50 0 C or above, preferably at about 50 -100°C.
  • the deprotection reaction maybe carried out for 3 or more hours, preferably 3 -7 hours.
  • the volume of dimethyl sulfoxide for deprotection reaction may range from 3 to 8 volumes per gram of compound of formula II.
  • the reaction mixture may be subjected to simple acid base purification.
  • the acid for purification may be selected from inorganic acid like hydrochloric acid, sulfuric acid and the like or organic acid like acetic acid and the like.
  • the base for purification maybe selected from inorganic base like sodium carbonate, sodium bicarbonate and the like; or organic base such as ammonia and the like.
  • the process of the present invention yields substantially pure 6-hydroxy-2-(4- hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, compound of formula I, by deprotecting compound of formula II with base in dimethyl sulfoxide without chromatographic purification.
  • 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl]benzo[b]thiophene, compound of formula I may be converted to its pharmaceutically acceptable salts by using appropriate acid.
  • the pharmaceutically acceptable salts may be selected from mineral acid salts such as hydrochloride, hydrobromide, sulfate and the like; organic acid salts such as acetate, oxalate, citrate, succinate, maleate, fumarate, malate, tartrate, and the like; and sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate and the like; preferably hydrochloride.
  • mineral acid salts such as hydrochloride, hydrobromide, sulfate and the like
  • organic acid salts such as acetate, oxalate, citrate, succinate, maleate, fumarate, malate, tartrate, and the like
  • sulfonates such as methanesulfonate, benzenesulfonate, toluenesulfonate and the like; preferably hydrochloride.
  • the hydrochloride salt of compound of formula I may be prepared by dissolving hydrochloric acid in alcoholic solvent like methanol, ethanol, isopropanol, n- propanol, n-butanol, t-butanol, isobutanol or by passing HCl gas at a temperature ranging from about -10 to 100°C.
  • the hydrochloride salt of compound of formula I obtained may be recrystallized from polar aprotic solvent and water so as to remove any residual solvents.
  • the polar aprotic solvent may be selected from dimethyl sulfoxide, dimethyl formamide, ethylacetate, acetone and the like.
  • the recrystallization of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4- (2piperidinoethoxy)benzoyl]benzo[b]thiophene hydrochloride may be carried out by dissolving in polar aprotic solvent followed by addition of water to facilitate crystallization.
  • the dissolution may be carried at 50-80 ° C followed by addition of water.
  • the preferred ratio of volume of polar aprotic solvent to volume of water may be selected from the range of 1 : 20 to 1 : 80.
  • the resulting mixture is stirred for 0.5 to 5 hours to crystallize the hydrochloride of compound of formula I having HPLC purity 99% or more, preferably 99.5% or more.
  • the hydrochloride salt of 6- hydroxy-2-(4-hydroxyphenyl)-3-[4-(2piperidinoethoxy)benzoyl]benzo[b]thiophene may be prepared by reacting 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-
  • the substantially pure hydrochloride salt of 6-hydroxy-2-(4-hydroxyphenyl)-3-[4- (2piperidinoethoxy)benzoyl] benzo[b]thiophene compound of formula I, referred to herein, has HPLC purity 99% or more, preferably 99.5% or more.
  • 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3[4-(2-piperidinoethoxy) benzoyl]benzo[b]thiophene hydrochloride, compound of formula II may be prepared by any method known to those skilled in the art such as United States Patent No 4,418,068.
  • reaction mixture was stirred at room temperature for 1.0 hour and basified using aqueous ammonia, and stirred overnight at room temperature, filtered and dried to get 2.84g of 6-hydroxy-2-(4-hydroxyphenyl)-3- [4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene HPLC purity > 99% by area.
  • the above material was dissolved in methanol and filtered to remove undissolved solid. Aqueous HCl was added to the filtrate at room temperature.
  • reaction mixture was stirred at room temperature and basified using aqueous ammonia, and stirred at room temperature, filtered and dried to get compound of formula I, 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2- piperidinoethoxy)benzoyl]benzo[b]thiophene HPLC purity > 99% by area.
  • the above material was dissolved in methanol and filtered to remove undissolved solid. Aqueous HCl was added to the filtrate at room temperature.
  • the precipitated solid was filtered at room temperature, washed with methanol and dried to give the hydrochloride salt of 6- hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene compound of formula I (HPLC purity 99.64% by area).
  • the hydrochloride salt was recrystallized by dissolving in 7.0 L of dimethyl sulfoxide at 60-70° C followed by addition of 456 L water.
  • the reaction mixture was diluted with DM water at room temperature and acidified using concentrated HCl.
  • the reaction mixture was stirred at room temperature for 1.0 hour and basified with liquor ammonia, and stirred overnight at room temperature, filtered and suck dried to get a crude solid.
  • the reaction mixture was evaporated to dryness under vacuum.
  • the residue on HPLC analysis revealed 72.3 % compound of formula I with impurities of compounds of formula III a to c.
  • the residue is dissolved in water and washed with diethyl ether.
  • the water layer was degassed under vacuum and nitrogen was bubbled to remove traces of ether.
  • the aqueous mixture was acidified and followed by basification with excess sodium bicarbonate.
  • the crude product (2.4 gm, HPLC analysis of 98.86% by area) was filtered and purified by column chromatography to get 1.78 g yellow oil, which is dissolved in 6.0 ml acetone, cooled and filtered to get 1.2 g (42.2% theory) purified product.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène, un composé de formule (I), ledit procédé comprenant la déprotection d'un composé de formule (II) avec une base dans du diméthylsulfoxyde pour donner un composé de formule (I) essentiellement pur avec une pureté par HPLC de 99 % ou plus par surface et la conversion facultative en son sel pharmaceutiquement acceptable.
PCT/IN2008/000273 2007-04-12 2008-04-15 Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène WO2009008000A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN723MU2007 2007-04-12
IN723/MUM/2007 2007-04-12

Publications (2)

Publication Number Publication Date
WO2009008000A2 true WO2009008000A2 (fr) 2009-01-15
WO2009008000A3 WO2009008000A3 (fr) 2011-08-11

Family

ID=40229220

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2008/000273 WO2009008000A2 (fr) 2007-04-12 2008-04-15 Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène

Country Status (1)

Country Link
WO (1) WO2009008000A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029088A2 (fr) * 2009-09-07 2011-03-10 Dr. Reddy's Laboratories Ltd. Préparation de raloxifène et de ses sels
ITMI20101967A1 (it) * 2010-10-25 2012-04-26 Fidia Farmaceutici Nuova forma polimorfa di raloxifene cloridrato

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4418068A (en) * 1981-04-03 1983-11-29 Eli Lilly And Company Antiestrogenic and antiandrugenic benzothiophenes

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011029088A2 (fr) * 2009-09-07 2011-03-10 Dr. Reddy's Laboratories Ltd. Préparation de raloxifène et de ses sels
WO2011029088A3 (fr) * 2009-09-07 2011-11-24 Dr. Reddy's Laboratories Ltd. Préparation de raloxifène et de ses sels
ITMI20101967A1 (it) * 2010-10-25 2012-04-26 Fidia Farmaceutici Nuova forma polimorfa di raloxifene cloridrato

Also Published As

Publication number Publication date
WO2009008000A3 (fr) 2011-08-11

Similar Documents

Publication Publication Date Title
US20080167498A1 (en) Crystalline venlafaxine base and novel polymorphs of venlafaxine hydrochloride, processes for preparing thereof
JP2008239629A (ja) 新規なベンラファクシン塩酸塩多型形状、ならびにその調製方法
CN111630049A (zh) 用于制备2-(5-甲氧基异色满-1-基)-4,5-二氢-1h-咪唑及其硫酸氢盐的方法
WO2009008000A2 (fr) Procédé de préparation de 6-hydroxy-2-(4-hydroxyphényl)-3-[4-(2-pipéridinoéthoxy)benzoyl]benzo[b]thiophène
US10336706B2 (en) Crystalline form of Eltrombopag free acid
WO2019150383A1 (fr) Procédé de préparation de luliconazole
EP0511019B1 (fr) Procédé pour la fabrication d'acides cétoniques
US20170362161A1 (en) Process for the preparation of indanamine derivatives and new synthesis intermediates
WO2022097115A1 (fr) Procédé amélioré de préparation de prohéxadione et de son sel de calcium
KR20020052213A (ko) 6-메틸-2-(4-메틸-페닐)-이미다조[1,2-ａ]피리미딘-3-(Ｎ,Ｎ-디메틸-아세트아미드) 및 중간체의 제조 방법
EP3280701A1 (fr) Procédé de résolution chirale de l'intermédiaire clé de la synthèse d'aprémilast et son utilisation pour la préparation d'aprémilast pur
US8183392B2 (en) (E)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine and process for producing the same and process for producing (E,Z)-N-monoalkyl-3-oxo-3-(2-thienyl) propenamine
BR112012029363B1 (pt) Processo para preparar 1-alquil-3-difluorometil-5 -hidroxipirazóis
CA2584349A1 (fr) Procede de preparation de 2-methylspiro(1,3-oxathiolane- 5,3')quinuclidine
US10538479B2 (en) Process for the preparation of indanamine derivatives and new synthesis intermediates
KR100241089B1 (ko) 2-메르캅토-4-메틸-1,3-티아졸-5-아세트산의 신규한제조방법
EP2058303B1 (fr) Procédé de production d'un dérivé de pipéridine-4-one
US20070129414A1 (en) Process for preparing 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1h-imidazole-1-yl)methyl]- 4h-carbbazol-4-one or its salt
US20060252940A1 (en) Crystalline 1-[2-(2,4-difluorophenyl)-oxiranyl methyl]-1h-1,2,4-triazole
HU226683B1 (en) Intermediat product of fluoxetine and process for its production
KR19990085334A (ko) 벤질옥시칼콘 유도체의 제조방법 및 그의 정제방법
BE538899A (fr)

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08826121

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08826121

Country of ref document: EP

Kind code of ref document: A2

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载