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.

Applications Claiming Priority (3)

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• 2001
  • 2001-06-22 KR KR1020010035889A patent/KR20030000217A/ko not_active Application Discontinuation
• 2002
  • 2002-06-21 CA CA002450914A patent/CA2450914A1/en not_active Abandoned
  • 2002-06-21 WO PCT/US2002/019753 patent/WO2003000652A1/en active Application Filing
  • 2002-06-21 TW TW091113830A patent/TWI250973B/zh not_active IP Right Cessation
  • 2002-06-21 CN CNB028124669A patent/CN1267410C/zh not_active Expired - Fee Related
  • 2002-06-21 EP EP02744526A patent/EP1397344A1/en not_active Withdrawn
  • 2002-06-21 PL PL02366613A patent/PL366613A1/xx not_active Application Discontinuation
  • 2002-06-21 BR BR0210542-0A patent/BR0210542A/pt not_active IP Right Cessation
  • 2002-06-21 UA UA2004010467A patent/UA78511C2/uk unknown
  • 2002-06-21 JP JP2003507059A patent/JP2004531577A/ja not_active Ceased
  • 2002-06-21 HU HU0400867A patent/HUP0400867A3/hu unknown
  • 2002-06-21 SG SG200508264-9A patent/SG156520A1/en unknown
  • 2002-06-21 IL IL15944802A patent/IL159448A0/xx unknown
  • 2002-06-21 AR ARP020102341A patent/AR034609A1/es unknown
  • 2002-06-21 NZ NZ530594A patent/NZ530594A/en not_active IP Right Cessation
  • 2002-06-21 KR KR1020037016739A patent/KR100874835B1/ko not_active IP Right Cessation
  • 2002-06-21 MX MXPA03011401A patent/MXPA03011401A/es not_active Application Discontinuation
  • 2002-06-21 EA EA200400069A patent/EA007486B1/ru not_active IP Right Cessation
• 2003
  • 2003-12-15 NO NO20035586A patent/NO20035586D0/no not_active Application Discontinuation
  • 2003-12-22 CO CO03111625A patent/CO5540339A2/es not_active Application Discontinuation
  • 2003-12-22 EC EC2003004920A patent/ECSP034920A/es unknown
• 2004
  • 2004-01-21 ZA ZA2004/00451A patent/ZA200400451B/en unknown

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