WO2003000652A1 - Process for preparation of cyclohexanol derivatives - Google Patents
Process for preparation of cyclohexanol derivatives Download PDFInfo
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- WO2003000652A1 WO2003000652A1 PCT/US2002/019753 US0219753W WO03000652A1 WO 2003000652 A1 WO2003000652 A1 WO 2003000652A1 US 0219753 W US0219753 W US 0219753W WO 03000652 A1 WO03000652 A1 WO 03000652A1
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- alkyl
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- compound
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- 238000000034 method Methods 0.000 title claims abstract description 31
- HPXRVTGHNJAIIH-PTQBSOBMSA-N cyclohexanol Chemical class O[13CH]1CCCCC1 HPXRVTGHNJAIIH-PTQBSOBMSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 claims description 30
- 238000006243 chemical reaction Methods 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000002524 organometallic group Chemical group 0.000 claims description 18
- PACGLQCRGWFBJH-UHFFFAOYSA-N 2-(4-methoxyphenyl)acetonitrile Chemical compound COC1=CC=C(CC#N)C=C1 PACGLQCRGWFBJH-UHFFFAOYSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 229920000642 polymer Polymers 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 3
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 150000001409 amidines Chemical class 0.000 claims description 3
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004423 acyloxy group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 150000002357 guanidines Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- DIBHLCJAJIKHGB-UHFFFAOYSA-N dec-5-ene Chemical compound [CH2]CCCC=CCCCC DIBHLCJAJIKHGB-UHFFFAOYSA-N 0.000 claims 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 25
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical class OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 24
- 125000004093 cyano group Chemical group *C#N 0.000 description 22
- 238000003756 stirring Methods 0.000 description 21
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000008213 purified water Substances 0.000 description 17
- 239000000243 solution Substances 0.000 description 17
- 239000007787 solid Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 7
- -1 phenylacetonitrile anion Chemical class 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- SUSQOBVLVYHIEX-UHFFFAOYSA-N o-phenylene-diaceto-nitrile Natural products N#CCC1=CC=CC=C1 SUSQOBVLVYHIEX-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 150000001450 anions Chemical class 0.000 description 5
- 238000004880 explosion Methods 0.000 description 5
- SCZNXLWKYFICFV-UHFFFAOYSA-N 1,2,3,4,5,7,8,9-octahydropyrido[1,2-b]diazepine Chemical compound C1CCCNN2CCCC=C21 SCZNXLWKYFICFV-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- UURSXESKOOOTOV-UHFFFAOYSA-N dec-5-ene Chemical compound CCCCC=CCCCC UURSXESKOOOTOV-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000010183 spectrum analysis Methods 0.000 description 3
- ASYJSBPNAIDUHX-UHFFFAOYSA-N 2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetonitrile Chemical compound C1=CC(OC)=CC=C1C(C#N)C1(O)CCCCC1 ASYJSBPNAIDUHX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- 0 *C(*)C1=CC=CCC1 Chemical compound *C(*)C1=CC=CCC1 0.000 description 1
- AXQUONJGMAVWJA-UHFFFAOYSA-N 1,1,2,3,3-pentabutylguanidine Chemical compound CCCCN=C(N(CCCC)CCCC)N(CCCC)CCCC AXQUONJGMAVWJA-UHFFFAOYSA-N 0.000 description 1
- ISNICOKBNZOJQG-UHFFFAOYSA-N 1,1,2,3,3-pentamethylguanidine Chemical compound CN=C(N(C)C)N(C)C ISNICOKBNZOJQG-UHFFFAOYSA-N 0.000 description 1
- OEBXWWBYZJNKRK-UHFFFAOYSA-N 1-methyl-2,3,4,6,7,8-hexahydropyrimido[1,2-a]pyrimidine Chemical compound C1CCN=C2N(C)CCCN21 OEBXWWBYZJNKRK-UHFFFAOYSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- CGWBIHLHAGNJCX-UHFFFAOYSA-N 2-butylguanidine Chemical compound CCCCNC(N)=N CGWBIHLHAGNJCX-UHFFFAOYSA-N 0.000 description 1
- FVKFHMNJTHKMRX-UHFFFAOYSA-N 3,4,6,7,8,9-hexahydro-2H-pyrimido[1,2-a]pyrimidine Chemical compound C1CCN2CCCNC2=N1 FVKFHMNJTHKMRX-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical group CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- VKEQBMCRQDSRET-UHFFFAOYSA-N Methylone Chemical compound CNC(C)C(=O)C1=CC=C2OCOC2=C1 VKEQBMCRQDSRET-UHFFFAOYSA-N 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000002485 combustion reaction Methods 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000002815 homogeneous catalyst Substances 0.000 description 1
- 230000036571 hydration Effects 0.000 description 1
- 238000006703 hydration reaction Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910000069 nitrogen hydride Inorganic materials 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000004445 quantitative analysis Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- PNVNVHUZROJLTJ-UHFFFAOYSA-N venlafaxine Chemical compound C1=CC(OC)=CC=C1C(CN(C)C)C1(O)CCCCC1 PNVNVHUZROJLTJ-UHFFFAOYSA-N 0.000 description 1
- 229960004688 venlafaxine Drugs 0.000 description 1
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
Abstract
A process for the preparation of cyclohexanol derivatives of formula (I) by reacting a compound of formula (II) with a compound of formula (III) in the presence of a base catalyst of formula (IV) or (V). In the above formula, R1-R9, A, B, X and p have tghe meanings given in the specification.
Description
PROCESS FOR PREPARATION OF CYCLOHEXANOL DERIVATIVES
BACKGROUND OF THE INVENTION
Field of the Invention
[01] The present invention relates to a process for preparation of cyclohexanol derivatives such as l-[cyano (4-methoxyphenyl)methyl] cyclohexanol.
Background of the Related Art
[02] 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. As disclosed in U.S. Patent No. 4,535,186, cyclohexanol derivatives can be produced by reaction of a cycloalkanone or cycloalkenone with an appropriately substituted (ortho or para) phenylacetonitrile anion.
[03] 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.
[04] U.S. Patent No. 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. 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.
1— -CH2 j
[05] Chinese Patent Publication No. 1225356 (CNO1225356A) 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 . However, 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.
[06] The known processes above involve two steps, i.e. reacting phenylacetonitrile with a base to produce an anion and coupling the anion with a ketone compound. In particular, the reaction in the anion-producing step involves some difficulties with regard to determination of the end point of the step and quantitative analysis of the anion produced. Such problems give rise to variations in yield in the
coupling step and therefore they are also difficult for industrial application for this reason.
SUMMARY OF THE INVENTION
[07] Accordingly, the present invention is directed to a process for preparation of cyclohexanol derivatives that substantially overcomes problems and disadvantages of the conventional art.
[08] 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.
[09] 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.
[10] One aspect of the present invention is a process for preparation of cyclohexanol derivatives of formula I,
(I)
wherein R6 and R are ortho or para substituents, independently selected from the group consisting of hydrogen, hydroxyl, Cι-C6 alkyl, Ci-Cβ alkoxy, C7-C9 aralkoxy, C -C7 alkanoyloxy, -Cδ alkylmercapto, halo or trifluoromethyl; R8 is hydrogen or -Cg alkyl; p is one of the integers 0, 1, 2, 3 or 4; and R9 is hydrogen or -C6 alkyl; comprising reacting a compound of formula II with a compound of formula III,
(II) (πi)
in the presence of non-organometallic base catalysts represented by the formula IV or V, in the presence or absence of a reaction solvent,
(IV) (V)
wherein A is -(CH2 ) n -where n is an integer from 2 to 4; B is - (CH2)m- where m is an integer from 2 to 5 ; X is CH2, O, NH or NR' where R' is a C1-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 R5 is an alkyl, a cycloalkyl or an alkyl or cyloalkyl supporting polymer, and where R9 is an alkyl, alkyl group is introduced by alkylation.
[11] 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. tetra methyl guanidine (TMG), tetra butyl guanidine, penta methyl guanidine, penta butyl guanidine and N'- butyl-N",N"-dicyclohexylguanidine. 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.
[12] 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.
[13] 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.
[14] In preparation of the cyclohexanol derivatives such as l-[cyano(4- methoxyphenyl)methyl]cyclohexanol represented by formula I according to the present invention, 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.
[15] 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.
Catalyst
(I)
[16] In the above reaction, R6 to R9, and p are the same as defined above, and where R9 is an alkyl, it is introduced by alkylation.
[17] In the preparation of the cyclohexanol derivatives such as l-[cyano(4- methoxyphenyl)methyl]cyclohexanol represented formula I, 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. The use of a 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.
[18] The present process is also more simplified and environment-friendly without production of organometallic byproducts as use of organic solvents is avoided.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[19] The present invention will now be described in detail with reference to the following examples, which are not intended to limit the scope of the present invention.
r201 Example 1
[21] 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 100 g (1.02 mole) of cyclohexanone and 32 g (0.21 mole) of 1,8-diazabicyclo [5,4,0] undec-7-ene (DBU) were added to a flask and kept at 15 to 20 °C with stirring for 48 hours. IN HCl was then added to the resulting solution to regulate the pH to acid level. After one hour of stirring at room temperature, the formed precipitate was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane, to yield 140 g of a white solid as, the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 84%, melting point 123.7 °C).
[22] 1H NMR Analysis (DMSO-d6) : δ 7.27-6.93 (4H, q, aromatic). 4.85 (1H, s, OH), 4.05 (3H, s, OCH3), 3.76 (1H, s, CHCN), 1.69-1.08 (10H, m, cyclohexyl)
[23] 1H NMR Analysis (CDC13) : δ 7.23-6.89 (4H, q, aromatic). 3.82 (3H, s, OCH3), 3.73 (1H, s, CHCN), 1.72-1.16 (10H, m, cyclohexyl)
[24] 13C NMR Analysis (DMSO-d6) : δ 159.4, 131.3, 125.8, 121.4, 114.1, 72.2, 55.8, 48.8, 36.0, 34.7, 25.9, 22.0, 21.9
[25] Mass Spectral Analysis: Molecular weight 245 [M+ by C.I.M.S.]
[26] R (KBr pallet) : 3408 cm"1 (-OH), 2249 cm"1 (-CN)
T271 Example 2
[28] 52.7 g (0.36 mole) of p-methoxyphenylacetonitrile, 35.8 g (0.36 mole) of cyclohexanone and 28.6 g (0.19 mole) of l,8-diazabicyclo[5,4,0]undec-7-ene were added to a flask and kept at 15 to 20 °C with stirring for 90 hours. IN HCl was then added to the resulting solution to regulate the pH to acid level. After one hour of stirring at room temperature, the formed precipitate was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane to yield 62 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 70%).
[291 Example 3
[30] The procedures were performed in the same manner as described in Example 1, except that 0.5 equivalent of 1,8-diazabicyclo [5, 4, 0]undec-7-ene was used in the 6-day reaction to yield 67 g of a white solid as the target compound, l-[cyano(4- methoxyphenyl)methyl]cyclohexanol (yield 80%).
[31] Example 4
[32] 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 167 g (1.70 mole) of cyclohexanone and 52 g (0.34 mole) of l,8-diazabicyclo[5,4,0]undec-7-ene were added to a flask and kept at 0 °C with stirring for 60 hours. IN HCl was then added to the
resulting solution to regulate the pH to acid level. After one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane to yield 147 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 88%).
T331 Example 5
[34] The procedures were performed in the same manner as described in Example 1, except that 0.5 equivalent of l,8-diazabicyclo[5,4,0]undec-7-ene was used, in the 8-hour reaction to yield 116 g of a white solid as the target compound, 1- [cyano(4-methoxyphenyl)methyl] cyclohexanol (yield 70%).
T351 Example 6
[36] 25.4 g (0.17 mole) of p-methoxyphenylacetonitrile, 41.8 g (0.42 mole) of cyclohexanone and 13.2 g (0.087 mole) of l,8-diazabicycle[5,4,0]undec-7-ene were added to a flask and kept at 25 °C with stirring for 24 hours. IN HCl was then added to the resulting solution to regulate pH to acid level. After adding 50ml of methyl alcohol and one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane to yield 23.7 g of a white solid as the target compound, l-[cyano(4- methoxyphenyl)methyl]cyclohexanol (yield 56.1%).
[37] Example 7
[38] 50.3 g (0.34 mole) of p-methoxyphenylacetonitrile, 34.8 g (0.35 mole) of
cyclohexanone and 43.3g (0.35 mole) of l,5-diazabicyclo[4,3,0]none-5-ene (DBN) were added to a flask and kept at 20 to 25 °C with stirring for 90 hours. To the resulting solution were added 50 ml of methyl alcohol and 200 ml of purified water. After one hour stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane to yield 116 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl) methyl]cyclohexanol (yield 70%).
[391 Example 8
[40] 20 g (0.14 mole) of p-methoxyphenylacetonitrile, 13.7 g (0.14 mole) of cyclohexanone and 21.2 g (0.14 mole) of l,8-diazabicyclo[5,4,0]undec-7-ene were added to a flask, diluted with 100 ml of methyl alcohol and kept at 15 to 20 °C with stirring for 20 hours. To the resulting solution were added 20 ml of methyl alcohol and 150 ml of purified water. After one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then ethyl acetate and n-hexane to yield 17.4 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 52%).
T411 Example 9
[42] The procedures were performed in the same manner as described in Example 1, except that 0.1 equivalent of l,8-diazabicyclo[5,4,0]undec-7-ene was used in the 6-day reaction to yield 76.1 g of a white solid as the target compound, 1- [cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 90.5%).
[431 Example 10
[44] 25.4 g (0.17 mole) of p-methoxyphenylacetonitrile, 83.6 g (0.85 mole) of cyclohexanone and 26.7 g (0.17 mole) of l,8-diazabicyclo[5,4,0] undec-7-ene were added to a flask and kept at 20 to 25 °C with stirring for 24 hours. To the resulting solution were added 50 ml of methyl alcohol and 200 ml of purified water. After one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then ethyl acetate and n-hexane to yield 18.0 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl) methyl] cyclohexanol (yield 42.6%).
[451 Example 11
[46] The procedures were performed in the same manner as described in Example 1, except that the reaction temperature was kept in the range from 35 to 40 °C to yield 30.6 g of a white solid as the target compound, l-[cyano(4-methoxy- phenyl)methyl]cyclohexanol (yield 36.8%).
[471 Example 12
[48] 100 g (0.68 mole) of p-methoxyphenylacetonitrile, 100 g (1.02 mole) of cyclohexanone and 0.47 g (0.0034 mole) of l,5,7-triazabicyclo[4,4,0] dec-5-ene (TBD) were added to a flask and kept at 20 to 25 °C with stirring for 10 to 12 hours. IN HCl was then added to the resulting solution to regulate the pH to acid level. After one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then ethyl acetate and n-hexane to yield 128 g of a
white target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 77%).
T491 Example 13
[50] The procedures were performed in the same manner as described in Example 1, except that 0.03 equivalent of 7- methyl-1, 5, 7-triazabicyclo [4, 4, 0] dec- 5-ene (MTBD) was used in the 20 to 22-hour reaction to yield 128 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol(yield 77%).
rsπ Example 14
[52] 50 g (0.34 mole) of p-methoxyphenylacetonitrile, 50 g (0.51 mole) of cyclohexanone and 0.24 g (0.0017 mole) of 1, 5, 7-triazabicyclo [4, 4, 0] dec-5-ene (TBD) were added to a flask and kept at 20 to 25°C with stirring for 19 hours. The reaction mixture was dissolved in 500 ml of ethyl acetate and, after addition of 200 ml of purified water, was neutralized with 6N HCl. Following phase separation at 30 to 35 °C, the organic solvent was removed under vacuum and 500 ml of ethyl acetate and 200 ml of purified water were added to the filtrate. After one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane to yield 74g of a white solid as the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 89%).
[53] Example 15
[54] 25 g (0.17 mole) p-methoxyphenylacetonitrile, 25 g (0.25 mole) cyclohexanone and 2.5g (0.0090 mole) N'-butyl-N",N"-dicyclohexylguanidine were added
to a flask and kept at 20 to 25 °C with stirring for 24 hours. IN HCl was then added to the resulting solution to regulate the pH to acid levels. After one hour of stirring at room temperature, the precipitate produced was separated by filtration and washed with purified water and then with ethyl acetate and n-hexane to yield 30 g of a white solid as the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 72%).
T551 Comparative Example 1
[56] 50g (0.34 mole) of p-methoxyphenylacetonitrile was diluted with 250ml of dry tetrahydrofuran (THF) and cooled to -70°C under a nitrogen atmosphere. 210ml (0.34 mole) of n-butyl lithium (n-BuLi) was dropped into the resulting solution while maintaining the temperature of the solution below -50°C. The solution was then stirred for 30 minutes and, after addition of 50 g (0.51 mole) of cyclohexanone, was stirred for 45 minutes more, while the temperature of the solution was kept at less than -50°C. Thereafter, the temperature of the reaction solution was raised to 0°C, and a saturated ammonium chloride solution was added to cause phase separation. The aqueous layer was extracted with diethyl ether and combined with the organic layer. The organic solvent was then removed under reduced pressure to yield 25.2 g of the target compound, l-[cyano(4-methoxyphenyl)methyl]cyclohexanol (yield 34.2%).
[57] Melting point: 123 to 126 °C.
[58] Mass Spectral Analysis: Molecular weight 245 [M+ by C.I.M.S.]
[59] 1H NMR Analysis (DMSO-d6): δ 7.32, 6.95 (4H, q, p-substituted aromatic), 3.8 (3H, s, O-CH3), 3.76 (1H, s, CH-CN), 1.56 (10H, m, aliphatic cyclohexyl)
[60] Comparative Example 2
[61] While maintaining internal temperature below 10°C, 76.5 g of p- methoxyphenylacetonitrile diluted with 75 ml of toluene was slowly added to lithium diisopropylamide solution made by adding 73 ml of diisopropylamine to 325 ml of 6M BuLi and 300 ml of toluene under a nitrogen atmosphere. After 30 minutes of stirring, 46. Og of cyclohexanone diluted with 50ml of toluene was slowly added with the internal temperature kept below 10°C, and stirred for more than about 30 minutes. The resulting solution was then added to 100ml of 12N HCl aqueous solution and 1 L of cold purified water. After filtration, the filtrate was diluted with dichloromethane and washed with purified water. With the dichloromethane replaced with diisopropyl ether, the solvent was removed under reduced pressure and the filtrate was cooled down and filtered to yield 91.0g of a white solid as the target compound, l-[cyano(4- methoxyphenyl)methyl] methyl] cyclohexanol (yield 79%).
[621 Reference Example
[63] 12 g (0.05 mole) of l-[cyano(4-methoxyphenyl)methyl]cyclohexanol prepared in Example 1 was dissolved in 250ml of a mixture of ammonia and ethanol, with the mixing ratio of 2:8 (v/v), and 2.8 g of 5% rhodium on alumina was added to cause a hydrogenation reaction. The catalyst was filtered out and washed with ethanol and the filtrate was concentrated under reduced pressure to provide a compound in the
form of oil, which was then diluted with 100ml of toluene and acidified to pH 2. After filtration, 9 g of a white solid was obtained as the target compound, l-[2-amino- l-(4-methoxyphenyl)ethyl] cyclohexanol (yield 57%).
[64] Melting point: 168 to 172 °C.
[65] Mass Spectral Analysis: Molecular weight 250 [M+ by C.I.M.S.]
[66] 1H NMR Analysis (DMSO-d6): δ 7.85 (3H, s, NH3+), 3.75(3H, s, O- CH3), 3.20 (3H, m, CHCH2), 1.35 (10H, m, aliphatic cyclohexyl)
[67] As described above, 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.
Claims
WHAT IS CLAIMED IS:
A process for preparation of cyclohexanol derivatives of formula I
(I) wherein R6 and R7 are ortho or para substituents, independently selected from the group consisting of hydrogen, hydroxyl, Cι-C6 alkyl, -Cό alkoxy, C7-C9 aralkoxy, C2-C alkanoyloxy, C^ alkylmercapto, halo or trifluoromethyl; R8 is hydrogen or Ci-C6 alkyl; p is one of the integers 0, 1, 2, 3 or 4; and R is hydrogen or - alkyl; comprising reacting a compound of formula II with a compound of formula HI,
(π) n) in the presence of a non-organometallic base catalyst represented by formula IV or V, in the presence or absence of a reaction solvent:
(IV) (V) wherein A is - (CH2)n - where n is an integer from 2 to 4; B is - (CH )m - where m is an integer from 2 to 5; X is CH2, O, NH or NR', where R' is a -C4 alkyl or acyl, or an alkyl supporting polymer; and each of Ri to R4 is independently hydrogen, an alkyl, a cycloalkyl or an alkyl or cycloalkyl supporting polymer and all of R] to R are not hydrogen, and R5 is an alkyl, a cycloalkyl or an alkyl or cycloalkyl supporting polymer, and where R9 is an alkyl, alkyl group is introduced by alkylation.
2. The process of claim 1 , wherein the compound of formula II is p-methoxyphenylacetonitrile.
3. The process of claim 1, wherein the compound of formula III is cyclohexanone.
4. The process according to any one of claims 1 to 3, wherein the non- organometallic base catalyst is a mixture of catalysts selected from one or more amidines or guanidines of formula (IV) or (V).
5. The process according to any one of claims 1 to 4, wherein the base catalyst is either homogeneous or immobilized on a polymer support.
6. The process according to any one of claims 1 to 5, wherein the non-organometallic base is selected from the group consisting of l,8-diazabicyclo[5,4,0]undec-7- ene (DBU), l,5-diazabicyclo[4,3,0]non-5-ene (DBN), l,5,7-triazabicyclo[4,4,0]dec-5- ene (TBD), 7-methyl-l,5,7-triazabicyclo[4,4,0]dec-5-ene (MTBD), tetra methyl guanidine (TMG) and N'-butyl-N",N"-dicyclohexylguanidine.
7. The process according to any one of claims 1 to 6, wherein the amount of the non-organometallic base used is in the range from about 0.005 to about 0.5 equivalents relative to one equivalent of the compound of formula π.
8. The process according to any one of claims 1 to 7, wherein no solvent is used.
9. The process according to any one of claims 1 to 8, wherein the reaction temperature is in the range of about -20 to 80°C.
10. The process of claim 9, wherein the reaction temperature is in the range of about 10 to 30 °C
11. The process according to any one of claims 1 to 10, wherein the compounds of formulas II and III and the base catalysts are used in equivalent ratios of 1 : 1 ~ 1.5 : 0.005 ~ 0.5.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA002450914A CA2450914A1 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
| EP02744526A EP1397344A1 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
| NZ530594A NZ530594A (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cycloalkanol (and cycloalkenol) derivatives |
| IL15944802A IL159448A0 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
| US10/481,679 US20040186310A1 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
| HU0400867A HUP0400867A3 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
| MXPA03011401A MXPA03011401A (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives. |
| KR1020037016739A KR100874835B1 (en) | 2001-06-22 | 2002-06-21 | Process for preparing cyclohexanol derivative |
| EA200400069A EA007486B1 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
| JP2003507059A JP2004531577A (en) | 2001-06-22 | 2002-06-21 | Preparation of cyclohexanol derivatives |
| UA2004010467A UA78511C2 (en) | 2001-06-22 | 2002-06-21 | A process for the preparation of cyclohexanol derivatives |
| BR0210542-0A BR0210542A (en) | 2001-06-22 | 2002-06-21 | Process for preparing cyclohexanol derivatives |
| NO20035586A NO20035586L (en) | 2001-06-22 | 2003-12-15 | Process for the preparation of cyclohexanol derivatives |
| ZA2004/00451A ZA200400451B (en) | 2001-06-22 | 2004-01-21 | Process for preparation of cyclohexanol derivatives |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2001-35889 | 2001-06-22 | ||
| KR1020010035889A KR20030000217A (en) | 2001-06-22 | 2001-06-22 | Process for the preparation of cyclohexanol derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2003000652A1 true WO2003000652A1 (en) | 2003-01-03 |
| WO2003000652A8 WO2003000652A8 (en) | 2004-05-21 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/US2002/019753 WO2003000652A1 (en) | 2001-06-22 | 2002-06-21 | Process for preparation of cyclohexanol derivatives |
Country Status (21)
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|---|---|
| EP (1) | EP1397344A1 (en) |
| JP (1) | JP2004531577A (en) |
| KR (2) | KR20030000217A (en) |
| CN (1) | CN1267410C (en) |
| AR (1) | AR034609A1 (en) |
| BR (1) | BR0210542A (en) |
| CA (1) | CA2450914A1 (en) |
| CO (1) | CO5540339A2 (en) |
| EA (1) | EA007486B1 (en) |
| EC (1) | ECSP034920A (en) |
| HU (1) | HUP0400867A3 (en) |
| IL (1) | IL159448A0 (en) |
| MX (1) | MXPA03011401A (en) |
| NO (1) | NO20035586L (en) |
| NZ (1) | NZ530594A (en) |
| PL (1) | PL366613A1 (en) |
| SG (1) | SG156520A1 (en) |
| TW (1) | TWI250973B (en) |
| UA (1) | UA78511C2 (en) |
| WO (1) | WO2003000652A1 (en) |
| ZA (1) | ZA200400451B (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005035483A1 (en) * | 2003-10-02 | 2005-04-21 | Wyeth | Process for the preparation of 1-[cyano(phenyl)methyl]-cyclohexanol compounds |
| WO2005049560A2 (en) * | 2003-09-29 | 2005-06-02 | Sun Pharmaceutical Industries Limited | Process for the preparation of anti-depressant compound |
| WO2007000294A1 (en) * | 2005-06-29 | 2007-01-04 | Wyeth | Process for the preparation of 1-[cyano (4-hydroxyphenyl)methyl]cyclohexanol compounds |
| WO2008013993A2 (en) * | 2006-07-26 | 2008-01-31 | Teva Pharmaceutical Industries Ltd. | Processes for the synthesis of o-desmethylvenlafaxine |
| JP2008088159A (en) * | 2006-07-26 | 2008-04-17 | Teva Pharmaceutical Industries Ltd | Process for synthesis of o-desmethylvenlafaxine |
| US7674935B2 (en) | 2006-04-17 | 2010-03-09 | Teva Pharmaceutical Industries Ltd. | Crystal forms of O-desmethylvenlafaxine |
| US8569371B2 (en) | 2010-03-29 | 2013-10-29 | Pliva Hrvatska D.O.O. | Crystal forms of O-desmethylvenlafaxine fumarate |
| WO2015148301A1 (en) * | 2014-03-28 | 2015-10-01 | Cummins Filtration Ip, Inc. | Ashless oil additives and their use as tbn boosters |
| WO2019137978A1 (en) | 2018-01-10 | 2019-07-18 | Huntsman International Llc | Polyurethane comprising formulations with isocyanate functionality |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100651353B1 (en) * | 2002-02-01 | 2006-11-28 | 에스케이 주식회사 | A continuous method for preparing venlafaxine intermediates with high yield |
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- 2002-06-21 MX MXPA03011401A patent/MXPA03011401A/en not_active Application Discontinuation
- 2002-06-21 HU HU0400867A patent/HUP0400867A3/en unknown
- 2002-06-21 EP EP02744526A patent/EP1397344A1/en not_active Withdrawn
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- 2002-06-21 UA UA2004010467A patent/UA78511C2/en unknown
- 2002-06-21 BR BR0210542-0A patent/BR0210542A/en not_active IP Right Cessation
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| WO2005049560A2 (en) * | 2003-09-29 | 2005-06-02 | Sun Pharmaceutical Industries Limited | Process for the preparation of anti-depressant compound |
| WO2005049560A3 (en) * | 2003-09-29 | 2005-09-15 | Sun Pharmaceutical Ind Ltd | Process for the preparation of anti-depressant compound |
| WO2005035483A1 (en) * | 2003-10-02 | 2005-04-21 | Wyeth | Process for the preparation of 1-[cyano(phenyl)methyl]-cyclohexanol compounds |
| WO2007000294A1 (en) * | 2005-06-29 | 2007-01-04 | Wyeth | Process for the preparation of 1-[cyano (4-hydroxyphenyl)methyl]cyclohexanol compounds |
| US7674935B2 (en) | 2006-04-17 | 2010-03-09 | Teva Pharmaceutical Industries Ltd. | Crystal forms of O-desmethylvenlafaxine |
| JP2008088159A (en) * | 2006-07-26 | 2008-04-17 | Teva Pharmaceutical Industries Ltd | Process for synthesis of o-desmethylvenlafaxine |
| WO2008013993A3 (en) * | 2006-07-26 | 2008-04-10 | Teva Pharma | Processes for the synthesis of o-desmethylvenlafaxine |
| US7605290B2 (en) | 2006-07-26 | 2009-10-20 | Teva Pharmaceutical Industries Ltd. | Processes for the synthesis of O-desmethylvenlafaxine |
| WO2008013993A2 (en) * | 2006-07-26 | 2008-01-31 | Teva Pharmaceutical Industries Ltd. | Processes for the synthesis of o-desmethylvenlafaxine |
| US8569371B2 (en) | 2010-03-29 | 2013-10-29 | Pliva Hrvatska D.O.O. | Crystal forms of O-desmethylvenlafaxine fumarate |
| WO2015148301A1 (en) * | 2014-03-28 | 2015-10-01 | Cummins Filtration Ip, Inc. | Ashless oil additives and their use as tbn boosters |
| CN106170536A (en) * | 2014-03-28 | 2016-11-30 | 康明斯过滤Ip公司 | Ashless lubricating oil additive and the application as total base number reinforcing agent thereof |
| US10428291B2 (en) | 2014-03-28 | 2019-10-01 | Cummins Filtration Ip, Inc. | Ashless oil additives and their use as TBN boosters |
| WO2019137978A1 (en) | 2018-01-10 | 2019-07-18 | Huntsman International Llc | Polyurethane comprising formulations with isocyanate functionality |
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| ZA200400451B (en) | 2005-06-29 |
| NZ530594A (en) | 2006-06-30 |
| NO20035586D0 (en) | 2003-12-15 |
| EP1397344A1 (en) | 2004-03-17 |
| EA007486B1 (en) | 2006-10-27 |
| KR20040011548A (en) | 2004-02-05 |
| JP2004531577A (en) | 2004-10-14 |
| MXPA03011401A (en) | 2004-04-05 |
| CO5540339A2 (en) | 2005-07-29 |
| HUP0400867A2 (en) | 2004-08-30 |
| BR0210542A (en) | 2004-06-22 |
| CN1531524A (en) | 2004-09-22 |
| HUP0400867A3 (en) | 2005-04-28 |
| CN1267410C (en) | 2006-08-02 |
| SG156520A1 (en) | 2009-11-26 |
| UA78511C2 (en) | 2007-04-10 |
| CA2450914A1 (en) | 2003-01-03 |
| NO20035586L (en) | 2003-12-15 |
| AR034609A1 (en) | 2004-03-03 |
| PL366613A1 (en) | 2005-02-07 |
| IL159448A0 (en) | 2004-06-01 |
| WO2003000652A8 (en) | 2004-05-21 |
| TWI250973B (en) | 2006-03-11 |
| KR100874835B1 (en) | 2008-12-19 |
| EA200400069A1 (en) | 2004-06-24 |
| KR20030000217A (en) | 2003-01-06 |
| ECSP034920A (en) | 2004-02-26 |
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