WO2001035900A2 - Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide - Google Patents

Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide Download PDF

Info

Publication number
WO2001035900A2
WO2001035900A2 PCT/IB2000/001288 IB0001288W WO0135900A2 WO 2001035900 A2 WO2001035900 A2 WO 2001035900A2 IB 0001288 W IB0001288 W IB 0001288W WO 0135900 A2 WO0135900 A2 WO 0135900A2
Authority
WO
WIPO (PCT)
Prior art keywords
formula
ethoxy
reaction
acetic acid
solvent
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/IB2000/001288
Other languages
English (en)
French (fr)
Other versions
WO2001035900A3 (en
Inventor
Mohammad Salman
Suresh J. Babu
Purna C. Ray
Sujay Biswas
Naresh Kumar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories 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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Priority to AU67210/00A priority Critical patent/AU6721000A/en
Priority to EP00954859A priority patent/EP1751084A2/en
Priority to US10/130,579 priority patent/US6686497B1/en
Publication of WO2001035900A2 publication Critical patent/WO2001035900A2/en
Publication of WO2001035900A3 publication Critical patent/WO2001035900A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups

Definitions

  • the present invention relates to a new and industrially advantageous process for the preparation of 3-ethoxy-4-ethoxycarbonyl-phenyl acetic acid of Formula I:
  • Repaglinide is S (+) 2-ethoxy-4-[N- ⁇ 1 -(2-piperidinophenyl)-3- methyl-1-butyl ⁇ -aminocarbonylmethyl]benzoic acid (Formula II) and is known from US Patent Nos. US 5,216,167 and US 5,312,924.
  • Repaglinide is first member of a new class of oral hypoglycemic agents (Meglitinides) for type II non-insulin dependent diabetes mellitus (NIDDM). It stimulates the secretion of insulin from beta cells in the pancreas, acting via calcium channels. Hypoglycemic events are less with repaglinide as compared with other anti- diabetic agents. It offers significantly better biological profile as compared with sulphonyl urea class of hypoglycemic agents, and has been approved by the US FDA for treatment of non-insulin dependent diabetes mellitus (type-ll diabetes).
  • reaction conditions are unsafe and inconvenient to handle at a commercial scale, as it involves high temperature (150 9 C for O- alkylation) and longer reaction times.
  • the process requires raw materials which are toxic and difficult to handle at commercial scale, e.g. sodium cyanide, carbon tetrachloride and gaseous hydrochloric acid.
  • the present invention relates to a process for the preparation of 3-ethoxy-4-(ethoxycarbonyl)phenyl acetic acid of Formula I, comprising reacting 4-methylsalicylic acid of Formula III, with ethylbromide in a dipolar aprotic solvent at a selected temperature within a range of ambient to 100 S C, preferably 30-40-C during a period of one to several hours.
  • the suitable dipolar aprotic solvent is selected from the group consisting of dimethylsulphoxide, N, N-dimethyl formamide, sulfolane and N-methyl-1- pyrrolidone.
  • the reaction is carried out in the presence of an inorganic base, preferably selected from the group consisting of potassium carbonate and sodium carbonate.
  • the reaction is worked up following the conventional method to afford ethyl 2-ethoxy-4-methylbenzoate of Formula IV in practically quantitative yield.
  • the compound of Formula IV is then reacted with lithium diisopropyl amide (LDA
  • FO RMULA - VIII which in turn is prepared by reacting n-butyllithium and diisopropylamine in anhydrous tetrahydrofuran as a solvent by following the methods known in the prior art. More particularly, ethyl 2-ethoxy-4-methyl-2-benzoate of Formula IV is reacted with lithium diisopropylamide (LDA) of Formula VIII at -40 to -80 9 C, preferably at -60 to -80 Q C for 0.5 to several hours and subsequent decomposition of carbanion with carbondioxide.
  • LDA lithium diisopropylamide
  • the reaction of compounds of Formula IV and VIII is carried out in the presence of a suitable diploar aprotic co-solvent which is selected from the group consisting of hexamethylphosphoramide (HMPA), 1 ,3-dimethyl-3,4,5,6-tetrahydro-2-(1 H) pyrimidinone (DMPU); 1 ,3-dimethyl-2-imidazolidinone (DMEU) and tetramethyl urea.
  • HMPA hexamethylphosphoramide
  • DMPU 1 ,3-dimethyl-3,4,5,6-tetrahydro-2-(1 H) pyrimidinone
  • DMEU 1 ,3-dimethyl-2-imidazolidinone
  • the desired compound, 3-ethoxy-4-(ethoxycarbonyl)phenyl acetic acid of Formula I is isolated at this pH by conventional methods including extraction with a suitable solvent which is selected from the group consisting of dichloromethane, dichloroethane, chloroform, ether, isopropyl ether and toluene.
  • Potassium carbonate (68.0 g, 0.492 mole) was added to a well-stirred solution of 4-methylsalicylic acid (25 g, 0.164 mole) in dimethylsulfoxide (75ml). The mixture was stirred at 35-40 s C and 1 st lot of ethyl bromide (27.0g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0g, 0.247 mole) was added over a period of 30 minutes at 35-40 9 C. The reaction mixture was further stirred at 35-40 s C and 1 st lot of ethyl bromide (27.0g, 0.247 mole) was added slowly over a period of 30 minutes then stirred for two hours and a second lot of ethyl bromide (27.0g, 0.247 mole) was added over a period of 30 minutes at 35-40 9 C. The reaction mixture was further stirred at
  • n-butyllithium 25 ml, 15% w/w solution in hexane
  • diisopropylamine 3.6 g
  • tetrahydrofuran 30 ml
  • n-butyllithium 50 ml, 15% w/w solution in hexane was added to a solution of diisopropylamine (7.25 g) in tetrahydrofuran (90 ml) at -30 °C.
  • the mixture was stirred at -30 °C for 30 minutes, cooled to -75 °C, and 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)- pyrimidinone (DMPU, 30 ml), was added slowly.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/IB2000/001288 1999-11-16 2000-09-11 Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide Ceased WO2001035900A2 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU67210/00A AU6721000A (en) 1999-11-16 2000-09-11 Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, key acid synthon ofrepaglinide
EP00954859A EP1751084A2 (en) 1999-11-16 2000-09-11 Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide
US10/130,579 US6686497B1 (en) 1999-11-16 2000-09-11 Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1483/DEL/99 1999-11-16
IN1483DE1999 IN192862B (OSRAM) 1999-11-16 1999-11-16

Publications (2)

Publication Number Publication Date
WO2001035900A2 true WO2001035900A2 (en) 2001-05-25
WO2001035900A3 WO2001035900A3 (en) 2002-02-07

Family

ID=11092714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2000/001288 Ceased WO2001035900A2 (en) 1999-11-16 2000-09-11 Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide

Country Status (5)

Country Link
US (1) US6686497B1 (OSRAM)
EP (1) EP1751084A2 (OSRAM)
AU (1) AU6721000A (OSRAM)
IN (1) IN192862B (OSRAM)
WO (1) WO2001035900A2 (OSRAM)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019140A1 (en) * 2003-08-26 2005-03-03 Biocon Limited Ethyl 4-(2-tert-butoxy-2-oxoethyl)-2-ethoxybenzoate, intermediate for the preparation of repaglinide
EP2177221A1 (en) 2008-10-20 2010-04-21 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of substantially optically pure Repaglinide and precursors thereof
US8440833B2 (en) 2007-11-20 2013-05-14 Anaconda Pharma Human papilloma virus inhibitors and pharmaceutical compositions containing same

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6818786B2 (en) * 2003-03-31 2004-11-16 Council Of Scientific And Industrial Research Process for the preparation of ethyl 3-ethoxy-4-ethoxycarbonyl-phenylacetate
US20100004293A1 (en) * 2006-12-20 2010-01-07 Bristol-Myers Squibb Company Crystalline forms of aryl-substituted pyrazole-amide compounds
CN101891621B (zh) * 2010-07-15 2015-05-13 启东市沪东化工有限公司 3-乙氧基-4-乙氧羰基苯乙酸的合成方法
CN105198838A (zh) * 2015-10-21 2015-12-30 河南普瑞制药有限公司 一种瑞格列奈的制备方法
CN112209825B (zh) * 2020-11-10 2022-09-20 江苏八巨药业有限公司 一种3-乙氧基-4-乙氧羰基苯乙酸的合成方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5216167A (en) 1983-12-30 1993-06-01 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
US5312924A (en) 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
WO1993000337A1 (de) 1991-06-21 1993-01-07 Dr. Karl Thomae Gmbh (s)(+)-2-äthoxy-4-[n-[1-(2-piperidino-phenyl)-3-methyl-1-butyl]aminocarbonylmethyl]-benzoesäure

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019140A1 (en) * 2003-08-26 2005-03-03 Biocon Limited Ethyl 4-(2-tert-butoxy-2-oxoethyl)-2-ethoxybenzoate, intermediate for the preparation of repaglinide
US8440833B2 (en) 2007-11-20 2013-05-14 Anaconda Pharma Human papilloma virus inhibitors and pharmaceutical compositions containing same
EP2177221A1 (en) 2008-10-20 2010-04-21 Krka Tovarna Zdravil, D.D., Novo Mesto Process for the preparation of substantially optically pure Repaglinide and precursors thereof

Also Published As

Publication number Publication date
WO2001035900A3 (en) 2002-02-07
EP1751084A2 (en) 2007-02-14
US6686497B1 (en) 2004-02-03
AU6721000A (en) 2001-05-30
IN192862B (OSRAM) 2004-05-22

Similar Documents

Publication Publication Date Title
KR101257217B1 (ko) 1-(2-할로비페닐-4-일)-시클로프로판카르복실릭 엑시드 유도체를 제조하는 방법
WO2001035900A2 (en) Synthesis of 3-ethoxy-4-ethoxycarbonyl phenyl acetic acid, a key acid synthon of repaglinide
CN115784927B (zh) 一种烷烃三腈的制备方法
US4154757A (en) Process for the manufacture of p-hydroxybenzyl cyanide
GB2217323A (en) 3,5-Dichloro-4-(1,1,2,3,3,3-hexafluoropropyloxy) aniline
US4376866A (en) Process for the preparation of α-hydroxymethylene arylacetic acid
US6753444B2 (en) Method for producing 2,3,5,6-tetrahalogen-xylyidene compounds
US4948916A (en) Process for producing aminooxyacetic acid salts
EP0423991B1 (en) Process for the preparation of 2-trifluoromethyl-4-hydroxybenzoic acid
US6215022B1 (en) Method for producing 3-hydroxy-2-methylbenzoic acid
JP2002187878A (ja) チオサリチル酸の製造方法
JP2561480B2 (ja) ４，６−ジアルコキシ−２−アルキルチオピリミジン類の製造方法
US11958801B2 (en) Process for preparing 6-isopropenyl-3-methyl-9-decenyl acetate and intermediates thereof
EP1200379B1 (en) Process for the production of cyclopropylmethyl halides
JP2002167342A (ja) アダマンタンジオール類の製造方法
US4508913A (en) Dialkoxymethyl-butyrolactones
JP2008303173A (ja) チオジグリコール酸ジメチルの製造方法
US5994553A (en) Method for preparing 2-mercaptothiazole
US4087464A (en) α-Halogeno-acetals of ethylenically unsaturated aldehydes and their preparation
GB2159156A (en) Process for the preparation of alkyl 3-chlorosulfonylthiophene-2-carboxylate
JPH08217779A (ja) ヘキサヒドロチエノ〔３，４−ｄ〕イミダゾール−２，４−ジオン類の製造法
JP5170987B2 (ja) 新規な含フッ素不飽和シリルエーテル化合物及び該化合物を中間体とする含フッ素不飽和アルコール誘導体の製造方法
CN1409697A (zh) 制备三氟甲基乙酰苯的方法
CN120271515A (zh) 一种瑞司美替罗中间体的合成方法
JP2508790B2 (ja) １−ビフェニリルエタノ―ル誘導体およびその製造法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 2000954859

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 10130579

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: JP

WWP Wipo information: published in national office

Ref document number: 2000954859

Country of ref document: EP