EP1397344A1 - Procede de preparation de derives de cyclohexanol - Google Patents

Procede de preparation de derives de cyclohexanol

Info

Publication number
EP1397344A1
EP1397344A1 EP02744526A EP02744526A EP1397344A1 EP 1397344 A1 EP1397344 A1 EP 1397344A1 EP 02744526 A EP02744526 A EP 02744526A EP 02744526 A EP02744526 A EP 02744526A EP 1397344 A1 EP1397344 A1 EP 1397344A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
process according
ene
compound
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.)
Withdrawn
Application number
EP02744526A
Other languages
German (de)
English (en)
Inventor
Keun-Sik Kim
Kwang-Il Kim
Sung-Woo Lee
Jin-Soo Park
Ki-Byung Chai
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.)
Wyeth LLC
Original Assignee
Wyeth LLC
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 Wyeth LLC filed Critical Wyeth LLC
Publication of EP1397344A1 publication Critical patent/EP1397344A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to a process for preparation of cyclohexanol derivatives such as l-[cyano (4-methoxyphenyl)methyl] cyclohexanol.
  • Cyclohexanol derivatives such as l-[cyano(4-methoxyphenyl)methyl] cyclohexanol are useful intermediates for making compounds like venlafaxine which have anti-depressant effects by inhibiting re-uptake of neurotransmitters, norepinephrine and serotonin.
  • cyclohexanol derivatives can be produced by reaction of a cycloalkanone or cycloalkenone with an appropriately substituted (ortho or para) phenylacetonitrile anion.
  • the preparation method disclosed in the US '186 patent involves the use of an organometallic base such as n-butyl lithium in order to induce phenylacetonitrile anion in the reaction.
  • the organometallic base is expensive, has to be used in an amount of at least one equivalent of the reactant at a low temperature below -50 °C , is characteristically susceptible to water in air with the risk of fire or explosion, and provides a low production yield of less than 50 percent. Therefore, organometallic bases are considered impractical for industrial scale synthesis.
  • 5,043,466 discloses a process for preparation of cyclohexanol derivatives which use an organometallic base such as a lithium di- isopropylamide as illustrated in the following reaction mechanism.
  • organometallic base such as a lithium di- isopropylamide
  • the US '466 patent varies the mixed ratio of hydrocarbon solvents in an attempt to improve reaction temperature and yield, but there still remains the problem of the base, lithium di- isopropylamide being impractical for industrial scale synthesis as it too is expensive, hard to handle, and can be a fire or explosion risk.
  • CiNO1225356A Chinese Patent Publication No. 1225356 discloses the use of bases such as sodium methoxide, sodium ethoxide, sodium hydride and sodium amide in the preparation of cyclohexanol derivatives to enhance the reaction temperature in the range of 0 to 5 ° C .
  • bases such as sodium methoxide, sodium ethoxide, sodium hydride and sodium amide
  • the disclosed bases were used in amounts of at least one equivalent of the reactant, and are also dangerous as they too are prone to combustion or explosion.
  • the present invention is directed to a process for preparation of cyclohexanol derivatives that substantially overcomes problems and disadvantages of the conventional art.
  • An object of the present invention is to provide a process for preparation of cyclohexanol derivatives by reaction of phenylacetonitrile with cyclohexanone to enable economical and reasonable mass quantity production.
  • Another object of the present invention is to provide a process for preparation of cyclohexanol derivatives that is safe and environmentally friendly without the risk of fire or explosion and simpler than conventional syntheses because the reactants are all mixed in one reaction.
  • One aspect of the present invention is a process for preparation of cyclohexanol derivatives of formula I,
  • R 6 and R are ortho or para substituents, independently selected from the group consisting of hydrogen, hydroxyl, C ⁇ -C 6 alkyl, Ci-C ⁇ alkoxy, C 7 -C 9 aralkoxy, C -C 7 alkanoyloxy, -C ⁇ alkylmercapto, halo or trifluoromethyl;
  • R 8 is hydrogen or -Cg alkyl;
  • p is one of the integers 0, 1, 2, 3 or 4;
  • R 9 is hydrogen or -C 6 alkyl; comprising reacting a compound of formula II with a compound of formula III,
  • A is -(CH 2 ) n -where n is an integer from 2 to 4; B is - (CH 2 ) m - where m is an integer from 2 to 5 ;
  • X is CH 2 , O, NH or NR' where R' is a C 1 -C alkyl or acyl, or an alkyl supporting polymer ; each of and Ri to R is independently hydrogen, an alkyl, a cycloalkyl or an alkyl or cycloalkyl supporting polymer, and all of to R are not hydrogen, and R 5 is an alkyl, a cycloalkyl or an alkyl or cyloalkyl supporting polymer, and where R 9 is an alkyl, alkyl group is introduced by alkylation.
  • the non-organometallic base used in the present invention comprises amidines or guanidines represented by formula IV or V. More specifically, examples of non- organometallic bases of the present invention include amidines, e.g. 1,8- diazabicyclo [5,4,0]undec-7-ene (DBU) and l,5-diazabicyclo[4,3,0]non-5-ene (DBN); cyclic guanidines, e.g. l,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD) and 7-methyl-l,5,7- triazabicyclo[4,4,0]dec-5-ene (MTBD); alkyl guanidines, e.g.
  • the base catalyst of the present invention may be a homogeneous catalyst or may be a catalyst containing an amidine- or guanidine- based organic amine base immobilized on a polymer support (e.g. polystyrene) or an inorganic support (e.g. silica).
  • the non-organometallic base of the present invention is at least one selected from the group consisting of the above-mentioned bases.
  • the amount of the non-organometallic base used is not specifically limited and may be in the range from about 0.0001 to about 2 equivalents, and more preferably, from about 0.005 to 0.5 equivalents relative to one equivalent of the compound of formula II.
  • the reaction of the present invention can be successfully accomplished with the base catalysts used only in a catalytic amount, which is advantageous.
  • the present invention may optionally not use an organic solvent comprising hydrocarbons or ethers that are required in conventional synthesis. Whether to use an organic solvent or not is optimally decided by those skilled in the art, but it is generally preferred not to use an organic solvent.
  • the reaction temperature is preferably in the range of about -20 to 80 ° C , more preferably about 10 to 30 ° C .
  • the process of the present invention can be ' conducted even at room temperature, which is advantageous.
  • the present invention presents a process for preparation of cyclohexanol derivatives by reaction of an appropriately substituted, para-phenylacetonitrile with a cyclohexanone in the presence of a non-organometallic amine base (e.g. DBU, DBN, TBN, MTBD, TMG or N'-butyl-N",N"-dicyclohexylguanidine) in accordance with reaction mechanism I.
  • a non-organometallic amine base e.g. DBU, DBN, TBN, MTBD, TMG or N'-butyl-N",N"-dicyclohexylguanidine
  • R 6 to R 9 , and p are the same as defined above, and where R 9 is an alkyl, it is introduced by alkylation.
  • a non-organo metallic base such as DBU, DBN, TBD, MTBD, TMG or N'-butyl-N",N"-dicyclohexylguanidine that is an amine base is used instead of an organometallic base such as n-butyl lithium or lithium diisopropyl amide used in conventional processes to induce a phenylacetontirile anion.
  • non-organometallic base in a relatively small amount that is relatively inexpensive, less susceptible to hydration, operable at room temperature, with no risk of fire or explosion, enables mass quantity production through a safe and relatively simple industrial process. Only catalytic amounts of non-organometallic base are needed in the present invention, which produces highly pure, high yield cyclohexanol derivatives.
  • the present invention provides a safe and relatively simple process for industrial scale mass quantity production of cyclohexanol derivatives such as l-[cyano4-methoxyphenyl]methyl]cyclohexanol represented by formula I.
  • the present invention uses a relatively inexpensive, non-metallic base in small amounts, which is environment-friendly and avoids organic solvents, to produce highly pure l-[cyano4-methoxyphenyl] methyl] cyclohexanol in high yield.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de cyclohexanol de formule (I) par mise en réaction d'un composé de formule (II) avec un composé de formule (III) en présence d'un catalyseur basique de formule (IV) ou (V). Dans la formule susmentionnée, R1-R9, A, B, X et p ont les significations énoncées dans les spécifications.
EP02744526A 2001-06-22 2002-06-21 Procede de preparation de derives de cyclohexanol Withdrawn EP1397344A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
KR2001035889 2001-06-22
KR1020010035889A KR20030000217A (ko) 2001-06-22 2001-06-22 시클로헥사놀 유도체의 제조방법
PCT/US2002/019753 WO2003000652A1 (fr) 2001-06-22 2002-06-21 Procede de preparation de derives de cyclohexanol

Publications (1)

Publication Number Publication Date
EP1397344A1 true EP1397344A1 (fr) 2004-03-17

Family

ID=36604137

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02744526A Withdrawn EP1397344A1 (fr) 2001-06-22 2002-06-21 Procede de preparation de derives de cyclohexanol

Country Status (21)

Country Link
EP (1) EP1397344A1 (fr)
JP (1) JP2004531577A (fr)
KR (2) KR20030000217A (fr)
CN (1) CN1267410C (fr)
AR (1) AR034609A1 (fr)
BR (1) BR0210542A (fr)
CA (1) CA2450914A1 (fr)
CO (1) CO5540339A2 (fr)
EA (1) EA007486B1 (fr)
EC (1) ECSP034920A (fr)
HU (1) HUP0400867A3 (fr)
IL (1) IL159448A0 (fr)
MX (1) MXPA03011401A (fr)
NO (1) NO20035586D0 (fr)
NZ (1) NZ530594A (fr)
PL (1) PL366613A1 (fr)
SG (1) SG156520A1 (fr)
TW (1) TWI250973B (fr)
UA (1) UA78511C2 (fr)
WO (1) WO2003000652A1 (fr)
ZA (1) ZA200400451B (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100651353B1 (ko) * 2002-02-01 2006-11-28 에스케이 주식회사 고수율로 벤라팩신 중간체를 연속적으로 제조하는 방법
WO2005049560A2 (fr) * 2003-09-29 2005-06-02 Sun Pharmaceutical Industries Limited Procede de preparation d'un compose antidepresseur
PE20050954A1 (es) * 2003-10-02 2005-12-20 Wyeth Corp Proceso para la preparacion de compuestos de 1-[ciano(fenil)metil]-ciclohexanol
WO2007000294A1 (fr) * 2005-06-29 2007-01-04 Wyeth Procede de preparation de composes de 1-[cyano (4-hydroxyphenyl)methyl]cyclohexanol
MX2007016179A (es) 2006-04-17 2008-03-11 Teva Pharma Formas cristalinas de o-desmetilvenlafaxina.
JP4763788B2 (ja) * 2006-07-26 2011-08-31 テバ ファーマシューティカル インダストリーズ リミティド Ｏ−デスメチルベンラファキシンの合成方法
JP2008044936A (ja) * 2006-07-26 2008-02-28 Teva Pharmaceutical Industries Ltd Ｏ−デスメチルベンラファキシンの合成方法
KR101409554B1 (ko) 2010-03-29 2014-06-19 플리바 흐르바츠카 디.오.오. Ｏ-데스메틸벤라팍신 푸마레이트의 결정형
BR112016021706A2 (pt) * 2014-03-28 2018-07-10 Cummins Filtration Ip Inc aditivos de óleo sem cinzas e uso dos mesmos como reforçadores de tbn.
PL3737726T3 (pl) 2018-01-10 2024-04-22 Huntsman International Llc Formulacje zawierające poliuretan o funkcjonalności izocyjanianu

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4535186A (en) * 1983-04-19 1985-08-13 American Home Products Corporation 2-Phenyl-2-(1-hydroxycycloalkyl or 1-hydroxycycloalk-2-enyl)ethylamine derivatives
GB8902209D0 (en) * 1989-02-01 1989-03-22 Wyeth John And Brother Limited Preparation of cyclohexanol derivatives and novel thioamide intermediates
TWI228118B (en) * 2000-08-30 2005-02-21 Ciba Sc Holding Ag Process for the preparation of substituted phenylacetonitriles

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03000652A1 *

Also Published As

Publication number Publication date
UA78511C2 (en) 2007-04-10
ECSP034920A (es) 2004-02-26
CN1267410C (zh) 2006-08-02
MXPA03011401A (es) 2004-04-05
CO5540339A2 (es) 2005-07-29
EA007486B1 (ru) 2006-10-27
WO2003000652A8 (fr) 2004-05-21
ZA200400451B (en) 2005-06-29
BR0210542A (pt) 2004-06-22
HUP0400867A2 (hu) 2004-08-30
PL366613A1 (en) 2005-02-07
KR20030000217A (ko) 2003-01-06
WO2003000652A1 (fr) 2003-01-03
CA2450914A1 (fr) 2003-01-03
KR100874835B1 (ko) 2008-12-19
EA200400069A1 (ru) 2004-06-24
SG156520A1 (en) 2009-11-26
JP2004531577A (ja) 2004-10-14
IL159448A0 (en) 2004-06-01
NZ530594A (en) 2006-06-30
CN1531524A (zh) 2004-09-22
NO20035586L (no) 2003-12-15
AR034609A1 (es) 2004-03-03
HUP0400867A3 (en) 2005-04-28
TWI250973B (en) 2006-03-11
NO20035586D0 (no) 2003-12-15
KR20040011548A (ko) 2004-02-05

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