CN1275052A - 取代4-苯基-4-氰基环乙烷羧酸的制备方法 - Google Patents
取代4-苯基-4-氰基环乙烷羧酸的制备方法 Download PDFInfo
- Publication number
- CN1275052A CN1275052A CN98810030A CN98810030A CN1275052A CN 1275052 A CN1275052 A CN 1275052A CN 98810030 A CN98810030 A CN 98810030A CN 98810030 A CN98810030 A CN 98810030A CN 1275052 A CN1275052 A CN 1275052A
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- Prior art keywords
- alkyl
- hydrogen
- compound
- randomly
- lithium
- Prior art date
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- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 22
- XWFKZQVEYDVFTA-UHFFFAOYSA-N 4-cyano-4-phenylcyclohexane-1-carboxylic acid Chemical class C1CC(C(=O)O)CCC1(C#N)C1=CC=CC=C1 XWFKZQVEYDVFTA-UHFFFAOYSA-N 0.000 title 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 48
- 239000002904 solvent Substances 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 229910001507 metal halide Inorganic materials 0.000 claims abstract description 11
- 150000005309 metal halides Chemical class 0.000 claims abstract description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 52
- 239000000203 mixture Substances 0.000 claims description 31
- 238000006243 chemical reaction Methods 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- -1 2-tetrahydro-thienyl Chemical group 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical group [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 14
- 229910052744 lithium Inorganic materials 0.000 claims description 13
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 10
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 9
- 125000003368 amide group Chemical group 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- 238000001556 precipitation Methods 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 239000011777 magnesium Substances 0.000 claims description 5
- CXDHJGCWMIOAQP-UHFFFAOYSA-N 2-pyridin-3-yl-1,4,5,6-tetrahydropyrimidine;hydrochloride Chemical compound Cl.C1CCNC(C=2C=NC=CC=2)=N1 CXDHJGCWMIOAQP-UHFFFAOYSA-N 0.000 claims description 4
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 4
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910052751 metal Chemical group 0.000 claims description 4
- 239000002184 metal Chemical group 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- WFKAJVHLWXSISD-UHFFFAOYSA-N isobutyramide Chemical compound CC(C)C(N)=O WFKAJVHLWXSISD-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- YBYIRNPNPLQARY-UHFFFAOYSA-N 1H-indene Natural products C1=CC=C2CC=CC2=C1 YBYIRNPNPLQARY-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- YPWFISCTZQNZAU-UHFFFAOYSA-N Thiane Chemical compound C1CCSCC1 YPWFISCTZQNZAU-UHFFFAOYSA-N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 125000003454 indenyl group Chemical group C1(C=CC2=CC=CC=C12)* 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 150000003214 pyranose derivatives Chemical class 0.000 claims description 2
- 238000004062 sedimentation Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- 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 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 1
- 150000001408 amides Chemical class 0.000 abstract 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 45
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 18
- 239000000047 product Substances 0.000 description 18
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 16
- 239000000376 reactant Substances 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 11
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 9
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 9
- 150000003839 salts Chemical class 0.000 description 9
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 238000005292 vacuum distillation Methods 0.000 description 8
- 150000001264 acyl cyanides Chemical class 0.000 description 7
- 208000006673 asthma Diseases 0.000 description 7
- NDKBVBUGCNGSJJ-UHFFFAOYSA-M benzyltrimethylammonium hydroxide Chemical compound [OH-].C[N+](C)(C)CC1=CC=CC=C1 NDKBVBUGCNGSJJ-UHFFFAOYSA-M 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 201000010099 disease Diseases 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 6
- 150000002576 ketones Chemical class 0.000 description 6
- 229910003002 lithium salt Inorganic materials 0.000 description 6
- 159000000002 lithium salts Chemical class 0.000 description 6
- WLJVNTCWHIRURA-UHFFFAOYSA-M pimelate(1-) Chemical compound OC(=O)CCCCCC([O-])=O WLJVNTCWHIRURA-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 150000002825 nitriles Chemical class 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 208000035126 Facies Diseases 0.000 description 4
- 108010044467 Isoenzymes Proteins 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- 230000032683 aging Effects 0.000 description 4
- 210000005091 airway smooth muscle Anatomy 0.000 description 4
- 239000003513 alkali Substances 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- VZFUCHSFHOYXIS-UHFFFAOYSA-N cycloheptane carboxylic acid Natural products OC(=O)C1CCCCCC1 VZFUCHSFHOYXIS-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- 150000002500 ions Chemical class 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 102000030621 adenylate cyclase Human genes 0.000 description 3
- 108060000200 adenylate cyclase Proteins 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 150000002118 epoxides Chemical class 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 210000000440 neutrophil Anatomy 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 3
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 description 2
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 210000001616 monocyte Anatomy 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000035479 physiological effects, processes and functions Effects 0.000 description 2
- 229940072033 potash Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 239000001103 potassium chloride Substances 0.000 description 2
- 235000011164 potassium chloride Nutrition 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- HNNQYHFROJDYHQ-UHFFFAOYSA-N 3-(4-ethylcyclohexyl)propanoic acid 3-(3-ethylcyclopentyl)propanoic acid Chemical compound CCC1CCC(CCC(O)=O)C1.CCC1CCC(CCC(O)=O)CC1 HNNQYHFROJDYHQ-UHFFFAOYSA-N 0.000 description 1
- FZFWPURYSWKIRT-UHFFFAOYSA-N 3-cyclopentyloxy-4-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1OC1CCCC1 FZFWPURYSWKIRT-UHFFFAOYSA-N 0.000 description 1
- ZRXHLJNBNWVNIM-UHFFFAOYSA-N 3-methyl-1-benzofuran Chemical compound C1=CC=C2C(C)=COC2=C1 ZRXHLJNBNWVNIM-UHFFFAOYSA-N 0.000 description 1
- HODGGPKVMIMTGQ-UHFFFAOYSA-N 4-(chloromethyl)-2-cyclopentyloxy-1-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1OC1CCCC1 HODGGPKVMIMTGQ-UHFFFAOYSA-N 0.000 description 1
- UPJKSWLLCONYMW-UHFFFAOYSA-N 5'-Adenosine monophosphate Natural products COc1cc(O)c(C(=O)C)c(OC2OC(COC3OC(C)C(O)C(O)C3O)C(O)C(O)C2O)c1 UPJKSWLLCONYMW-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 101710095468 Cyclase Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HGVNXEVNBBVJGZ-UHFFFAOYSA-N O1C2=C(N(C3=CC=CC=C13)C1=CC=C(C3=CC(C#N)=C(C#N)C=C3C3=CC=C(N4C5=CC=CC=C5OC5=C4C=CC=C5)C=C3)C=C1)C=CC=C2 Chemical compound O1C2=C(N(C3=CC=CC=C13)C1=CC=C(C3=CC(C#N)=C(C#N)C=C3C3=CC=C(N4C5=CC=CC=C5OC5=C4C=CC=C5)C=C3)C=C1)C=CC=C2 HGVNXEVNBBVJGZ-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N adenyl group Chemical group N1=CN=C2N=CNC2=C1N GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 229960004217 benzyl alcohol Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 229910052790 beryllium Inorganic materials 0.000 description 1
- ATBAMAFKBVZNFJ-UHFFFAOYSA-N beryllium atom Chemical compound [Be] ATBAMAFKBVZNFJ-UHFFFAOYSA-N 0.000 description 1
- 230000008512 biological response Effects 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 229910010277 boron hydride Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical group 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
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Abstract
本发明涉及一种制备其中R’或R”中的至少一个是羧基的式(Ⅰ)化合物的方法,该方法包括在无质子偶极酰氨基溶剂和水的存在下,用Ⅰ(a)或Ⅱ(a)族金属卤化物处理式(Ⅱ)化合物。
Description
发明领域
本发明涉及制备4-氰基-4-(3-环戊氧基-4-甲氧基苯基)环己烷羧酸和其类似物的中间体和合成路线。该酸及其类似物选择性地抑制磷酸二酯酶同功酶IV(命名的)(下文称PDE IV)中的催化位点,因此该酸用于治疗多种可通过影响PDE IV酶及其亚型缓解的疾病。
发明背景
支气管哮喘是一种复杂的多因素性疾病,其特征在于气道的可逆性狭窄和呼吸道对外部刺激的高反应性。
由于多种介导物在该病的发展中起着作用,使得人们难于识别新的哮喘治疗药物。因此,消除一种介导物的作用将会对所有主要的支气管哮喘成因起明显作用是看似不可能的。“介导物接进”的另一种含义是相应于疾病病理生理学调节细胞反应活性。
一种途径是通过提高cAMP(环3’,5’-一磷酸腺苷)的水平。据显示,环AMP是介导对多种激素、神经递质和药物的生物应答的第二信使;[Krebs Endocrinology Proceedings of the 4th InternationalCongress Excerpta Medica,17-29,1973]。当适宜的拮抗剂与特异性细胞表面受体结合时,腺苷酸环化酶被激活,Mg+2-AIP被加速转化为cAMP。
环AMP调节大多数,但不是全部的对外源性(变应性)哮喘的病理生理学产生作用的细胞活性。因此cAMP水平的提高将产生有益作用,包括:1)气道平滑肌松弛,2)抑制肥大细胞介导物的释放,3)抑制中性细胞脱粒,4)抑制嗜碱细胞脱粒和5)抑制单核细胞和巨噬细胞的活化。因此,激活腺苷酸环化酶或抑制磷酸二酯酶的化合物将有效抑制气道平滑肌和各种炎症细胞的不适当活化。cAMP失活的主要细胞机制是3’-磷酸二酯键被一种或多种称为环核苷酸磷酸二酯酶(PDEs)的一族的同功酶水解。
据示,一种环核苷酸磷酸二酯酶(PDE)同功酶PDE IV对气道平滑肌和炎症细胞中的cAMP断裂起作用。[Torphy,“磷酸二酯酶同功酶:新的抗哮喘药物的潜在靶位”,《哮喘新药》(New Drugs for Asthma),Barnes编辑,IBC Technical Services Ltd.,1989]。研究表明对该酶的抑制作用不仅使气道平滑肌松弛,还抑制肥大细胞、嗜碱细胞和中性细胞的脱粒,并且还抑制单核细胞和中性细胞的活化。此外,在体内,当靶细胞的核苷酸环化酶活性由于适宜的激素或内分泌物提高时,将显著增强PDE IV抑制剂的有益作用。这样,PDE IV抑制剂将对哮喘性肺有效,哮喘性肺中的前列腺素E2和前列腺环素(腺苷酸环化酶的活化剂)水平是升高的。这类化合物将提供独特的药物治疗手段以治疗支气管哮喘,与目前市场上的药物相比,它们具有明显的治疗优越性。
本发明的方法和中间体提供了制备某些4-取代-4-(3,4-二取代苯基)环己烷羧酸的手段,它们用于治疗哮喘和其他可通过影响PDE IV酶及其亚型缓解的疾病。在1996年9月3日出版的美国专利5552483中全面描述了特别令人感兴趣的终产物。其中公开的对于理解本发明和实践本发明所必需的信息和内容全部引入本文以供参考。
发明概述
本发明涉及制备式I化合物的方法,
其中
R1是-(CR4R5)nC(O)O(CR4R5)mR6、-(CR4R5)nC(O)NR4(CR4R5)mR6、-(CR4R5)nO(CR4R5)mR6或-(CR4R5)rR6,其中烷基部分可任选被一个或多个卤素取代;
m是0至2;
n是1至4;
r是0至6;
R4和R5独立地选自氢或C1-2烷基;
R6是氢、甲基、羟基、芳基、卤素取代的芳基、芳氧基C1-3烷基、卤素取代的芳氧基C1-3烷基、2,3-二氢化茚基、茚基、C7-11多环烷基、四氢呋喃、呋喃基、四氢吡喃基、吡喃基、四氢噻吩基、噻吩基、四氢噻喃基、噻喃基、C3-6环烷基或包含一个或两个不饱和键的C4-6环烷基,其中的环烷基和杂环基部分可任选地被1至3个甲基或一个乙基取代;
条件是:
a)当R6是羟基时,则m是2;或者
b)当R6是羟基时,则r是2至6;或者
c)当R6是2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,则m是1或2;或者
d)当R6是2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,则r是1至6;或者
e)当n是1并且m是0时,则-(CR4R5)nO(C3R4R5)m中的R6不是H;
X是YR2、卤素、硝基、NH2或甲酰胺;
X2是O或NR8;
Y是O或S(O)m’;
m’是0、1或2;
R2独立地选自可任选地被一个或多个卤素取代的-CH3或-CH2CH3;
R3是氢、卤素、C1-4烷基、CH2NHC(O)C(O)NH2、卤素取代的C1-4烷基、-CH=CR8’R8’、可任选地被R8’取代的环丙基、CN、OR8、CH2OR8、NR8R10、CH2NR8R10、C(Z’)H、C(O)OR8、C(O)NR8R10或C≡CR8’;
R8是氢或可任选地被一至三个氟取代的C1-4烷基;
R8’是R8或氟;
R10是OR8或R11;
R11是氢或可任选地被一至三个氟取代的C1-4烷基;
Z’是O、NR9、NOR8、NCN、C(-CN)2、CR8CN、CR8NO2、CR8C(O)OR8、CR8C(O)NR8R8、C(-CN)NO2、C(-CN)C(O)OR9或C(-CN)C(O)NR8R8;
R’和R”独立地选自氢或-C(O)OX,其中X是氢或者金属或铵阳离子;
该方法包括:
a)将I(a)族或II(a)族金属卤化物与一种无质子偶极酰胺基溶剂和水和式A或B的化合物混合,
式A和B中,R1、R3、X2和X具有式(I)中相同含义;
b)将所述混合物在至少60℃加热数小时,该加热可任选在惰性气氛下进行;
c)往所述混合物中加入强碱沉淀出式(I)混合物;
d)从所述沉淀中除去酰氨基溶剂和水,并任选地
1)进一步纯化沉淀,或
2)使沉淀酸化,获得游离酸。
发明具体方案
本发明的方法涉及某些4-取代-4-(3,4-二取代苯基)环己烷羧酸的合成。通过I(a)族或II(b)族盐中间体使氰基环氧化物转化为所需的相应酸。
采用该方法制备的化合物是PDE IV抑制剂。它们用于治疗1996年9月3日公开的美国专利5552438中描述的多种疾病。
可采用该方法制备的优选化合物是下列:
所有命名的分子式化合物中,优选的R1取代基是CH2-环丙基、CH2-C5 -6环烷基、未取代的或被OH取代的C4-6环烷基、C7-11多环烷基、(3-或4-环戊烯基)、苯基、四氢呋喃-3-基、苄基或者未取代的或被一个或多个氟取代的C1-2烷基、-(CH2)1-3C(O)O(CH2)0-2CH3、-(CH2)1-3O(CH2)0-2CH3和-(CH2)2-4OH。
式(I)或(II)中,优选的X基团是那些其中X是YR2并且Y是氧的基团。式(I)中,优选的X2基团是那些其中X2是氧的基团。优选的R2基团是未取代的或被一个或多个卤素取代的C1-2烷基。卤原子优选是氟和氯,更优选是氟。更优选的R2基团是甲基或氟取代的烷基,尤其是C1-2烷基,例如-CF3、-CHF2或-CH2CHF2。最优选的是-CHF2和-CH3。
最优选的是那些化合物,其中R1是-CH2-环丙基、环戊基、3-羟基环戊基、甲基或CF2H;X是YR2;Y是氧;X2是氧;R2是CF2H或甲基;且R3是CN的化合物。
这些化合物的锂盐表示一小类优选的化合物。特别是4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸的锂盐,即4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸锂代表了一种优选的方案。特别地,化合物顺式4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸锂是最优选的。
羧酸盐是这样制备的:用I(a)族或II(a)族金属卤化物开环环氧化物,得到酰腈,在水的存在下将酰腈水解为酸。用酰腈制备酸的一个问题是当酰腈形成羧酸盐时,产生氢氰酸(HCN)。要求采用成本-效率合理的手段除去该HCN。本发明的特点在于可更有效地除去HCN。本发明人发现,如果反应在含水的无质子偶极酰胺基溶剂中进行,当加入强碱时,氰化物盐形成并保留在溶液中,在溶液同时形成羧酸盐沉淀。如此收集沉淀并除去溶剂,也即意味着从链烷酸盐沉淀中除去了大部分或基本上所有的氰化物盐。这避免了不得不进行额外的纯化步骤,例如氧化HCN。
本发明中使用的I(a)或II(a)族金属卤化物是任何碱金属或碱土金属,即锂、钠、钾、铷、铯或钫;和铍、镁、钙、锶、钡或镭的卤化物。优选的金属是锂和镁。卤化物包括氟化物、氯化物、溴化物和碘化物。优选的卤化物是溴化物。优选锂和镁的卤化物。溴化锂和溴化镁是最优选的。尤其优选溴化锂。
关于酰胺基溶剂,可列举二甲基甲酰胺(DMF)、二甲基乙酰胺和N-甲基吡咯烷酮。DMF是最优选的。除酰胺基溶剂外,还可使用第二种溶剂。例如乙腈被成功地用于下述反应中。通常将水加到反应罐中,就地水解酰腈,得到链烷酸。本发明的另一个优选方案是使用水可混溶的无质子偶极溶剂。DMF、二甲基乙酰胺和N-甲基吡咯烷酮符合该要求。虽然在反应介质中必需有水,但水的量可以相差很大。甚至当存在较小量的水时,反应仍能进行。在反应容器中,优选存在占容器中任何液体和固体总量的至少0.1%(w/w)的水。更优选的水量至少为约1%w/w,最优选为约1-5%w/w。虽然没有对所有可能的水和酰胺基溶剂的混合溶剂系统进行试验,但获知该反应可在存在20%(w/w)水时进行。因此,认为可使用更高百分比的水。本领域从业者可获知有机溶剂与水的最佳比例。使用任何量的水与酰胺基溶剂混合均被认为是在本发明的范围内。
反应可在高于约60℃的任何温度下进行。由于可以使用多种酰氨基溶剂和水的混合溶剂,因此将温度限制在一个确定的上限是不切合实际的,因为温度随选择的溶剂和选定溶剂的比例不同而不同。
I(a)或II(a)族金属卤化物开环环氧化物,得到酰腈。酰腈在水的存在下被水解为酸。通过往反应容器中加入约2当量或更多的强碱可形成不溶性的羧盐,而不是分离游离酸。该碱形成两种盐,一种环己烷羧酸的盐和一种HCN的盐,HCN是在酰腈基的水解中释放出来的。产生的金属氰化物溶于溶剂,而链烷酸的盐从溶液中沉淀出来。这样可通过简单除去溶剂将链烷酸与氰化物盐分离。本发明可使用少于2当量的碱进行,但这有可能导致链烷酸损失,因此这部分链烷酸不会从溶液中沉淀出来,从经济观点上讲,这是不利的。未反应的HCN可能污染从溶液中沉淀出来的链烷酸。因此,优选的方案是使用2当量或更多当量的链烷酸。
本发明的强碱是可与氰离子形成盐的任何离子。可使用任何强至足以形成这类盐的碱;氰化物盐的形成是在确认该步骤中是否使用特定碱的两个标准中更具决定性。无机氢氧化物是优选的。例如,可使用氢氧化锂、氢氧化钠和氢氧化钾。也可使用铵盐,例如四烷基铵氢氧化物或氢氧化铵。氢氧化锂是优选的,因为氰化锂盐高度溶于含水的无质子偶极酰胺基溶剂,这样当除去酰胺基溶剂时,可更有效和完全地从酸盐中除去氰离子。氰化锂较氰化钠或氰化钾更易溶于DMF中。因此在成盐步骤中,用锂作为强碱中的阳离子是更有利的。
本发明的优选方案是将溶剂装入反应容器中,加入溴化锂,然后加入环氧化物。一旦反应基本上完成,加入两当量或更多当量的氢氧化锂水溶液,将环己烷羧酸盐从沉淀中过滤出来,弃去溶剂。如果需要,环己烷羧酸的锂盐可进一步纯化除残留的杂质如氰化物盐,或者通过将该盐溶解或悬浮于溶剂中并使其酸化转化为游离酸。
该方法的代表性反应路线如图I和图II所示。这些图用具体的实例表示来说明本发明的一般方法。
图11说明本发明可采用的第二种非常相似的条件。该图的流程与图1概括的流程相同,但某些步骤的一些条件有所变化。
图I描述的化学反应记载于登记号为USSN 60/061613(1997年2月12日)的共同未结案的美国申请和特别指定美国的申请号为PCT/US98/02749、公开号为WO 98/34584的PCT申请。这些申请均被引入本文中以供参考,它们尤其与第1-7步的化学反应有关。
图II的化学反应记载于1998年8月26日递交的申请号为PCT/EP98/05504的PCT申请,该申请特别指定美国为指定国。该申请的全部公开内容引入本文以供参考。下面具体描述图II的化学反应。
图I和II中化学反应的一般描述如下:
在约125℃下,将环戊基氯、异香草醛和碳酸钾在二甲基甲酰胺中的混合物搅拌直至认为完全形成了环戊氧基产物(约2小时)。将该混合物冷却到20-25℃,将固体(氯化钾和碳酸氢钾)离心除去并用甲醇洗涤后弃去。将二甲基甲酰胺母液和甲醇洗涤液合并用于下步。
将环戊氧基化合物在二甲基甲酰胺和甲醇中的溶液冷却到约0℃并用硼氢化钠处理(约1.5小时)。使温度保持在低于5℃。将该混合物在0-10℃搅拌30分钟,然后在25-30℃搅拌直至认为还原反应完全(约1小时)。加入乙酸50%以消耗过量硼氢化物,真空蒸馏除去二甲基甲酰胺和甲醇。将混合物冷却至20-25℃后,分配到水和甲苯中。含醇的甲苯相用软化水洗涤,通过过滤器后用于下步反应。
在15-25℃下,醇的甲苯溶液用浓盐酸(最低36%)处理。将含氯化合物的有机相分离并用碳酸氢钠处理以中和痕量盐酸。过滤除去固体(氯化钠、碳酸氢钠)。
氯化物的溶液经真空蒸馏浓缩。冷却至约20℃后,加入软化水、四丁基溴化铵和氰化钠。该混合物加热至80℃后,在该温度下搅拌直至认为氰化反应进行完全(约2小时)。
将混合物冷却到低于60℃后,将其分配到水和甲苯中。在30-25℃下,将含氰基化合物的甲苯相用软化水洗涤,真空蒸馏至最小体积,往其中加入乙腈。该产物的乙腈溶液可直接用于下步。
制备丙烯酸甲酯的乙腈溶液和氢氧化四烃铵(TritonB)和乙腈的溶液。在低于25℃下,将约16.6%的丙烯酸甲酯溶液加到氰基化合物溶液中。加入约12.5%的氢氧化四烃铵溶液,该混合物再搅拌数分钟后,冷却至低于25℃。按该添加顺序重复三次以上,再分两批加入最后33%的丙烯酸甲酯溶液和最后50%的氢氧化四烃铵溶液。将反应混合物在20-25℃下搅拌直至认为反应完全(约2-3小时)。真空蒸馏至最小体积除去乙腈。在50℃下,将该混合物分配到环己烷/甲苯和水中。在约0℃下,使含庚二酸酯的环己烷/甲苯相陈化约1小时。
将产物离心分离并用冷(低于0℃)环己烷/甲苯洗涤。在最高50℃下,使湿的滤饼真空干燥,得到近白色至米色粉末状的庚二酸酯。
将29%甲醇钠的甲醇溶液一次性地加入庚二酸酯的二噁烷溶液中。将该混合物加热至约75℃(回流)并使其在该温度下保持直至2-甲氧羰基环己烷-1-酮全部形成(约1小时)。蒸馏掉大部分甲醇后,用二噁烷代替甲醇。往该混合物中加入碳酸氢钠和软化水,加热至回流(约85-88℃)并使混合物在该温度下保持直至环己烷-1-酮全部形成(约10小时)。
将混合物冷却至低于60℃后,加入浓盐酸溶液使pH由高于10降至7.5。
真空蒸馏除去大部分二噁烷和甲醇。之后,在约70℃下,将该混合物分配到环己烷/甲苯和水中。在约70℃下,含酮的有机相用软化水洗涤两次。
将产物溶液冷却至10℃并在9-11℃下陈化约1小时。将产物过滤分离并用冷的(10℃)环己烷/甲苯洗涤,在不超过50℃下,将湿滤饼真空干燥,得到近白色粉末状的酮。
在无机碱和催化量苄基三乙基氯化铵(BTEAC)的存在下,用氯代乙腈处理酮可由酮制备二腈(dicarbonitrile)。在低温下,例如约0℃左右,将酮和稍稍过量的氯乙腈在适宜溶剂,如THF中的混合液加到强碱(氢氧化钾水溶液)和BTEAC及水混溶性溶剂,如四氢呋喃中的混合物中。在反应期间(通常为约1小时),使反应保持在该温度下进行。分离产物,或以粗品油形式使用该产物。
用I(a)或II(a)族金属卤化物将二腈转化为环己烷甲酸。该反应如下进行:往容器中加入溶剂,在此可列举DMF、乙腈和水以及I(a)或II(a)族金属卤化物(优选约1.5当量),例如LiBr;将惰性气体通入该容器;加入二腈A或B或者A和B的混合物;将容器和其中内容物在约100℃加热数小时,例如8小时。反应物用DMF和任选的水稀释。加入氢氧化锂水溶液(约50%摩尔过量是优选的)。悬浮液形成。在稍稍升高的温度下(40-80℃)搅拌约1小时左右。用常规方法回收锂盐。
例如,通过将锂盐悬浮在有机溶剂,如乙酸乙酯中,用无机酸的水溶液处理该悬浮液来制备酸。然后除去有机溶剂,洗涤并浓缩。用常规方法分离产物。
用下列实施例来说明、而不是限制本发明的具体方案。本发明者保留所附权利要求书中阐明的范围。
实施例1
3-环戊氧基-4-甲氧基苯甲醛的制备
在120-125℃下,将环戊基氯(8.48g,0.08mol)、异香草醛(6.12g,0.04mol)和碳酸钾(1.1g,0.08mol)在二甲基甲酰胺(4.04g)中的混合物在反应器(100ml)中搅拌1.5小时。取样以鉴定批量转化情况。结果(GC):0.5面积%异香草醛(目标:≤1.0面积%)。将该混合物冷却到20℃并过滤除去固体(碳酸氢钾、氯化钾)。湿滤饼用甲醇洗涤。
实施例2
3-环戊氧基-4-甲氧基苄醇的制备
将实施例1得到的二甲基甲酰胺母液和甲醇洗涤液合并并转移到清洁的反应器中。再加入甲醇(8.52g)并使该批物料冷却到0℃。在温度保持在4-9℃下,用1小时10分钟以上少量多次地加入硼氢化钠(0.49g,0.0129mol)。将反应物在7.2-10℃搅拌30分钟,然后加热至25℃。在25-31℃搅拌110分钟后,取样并进行分析(GC),认为反应已经完全。往反应器中加入乙酸50%(1.80g)以消耗剩余的硼氢化钠。操作中将温度保持在24-25℃。真空蒸馏除去二甲基甲酰胺和甲醇(蒸馏终点:58℃,6毫巴).冷却至20-25℃后,将混合物分配到水(3.13g)和甲苯(28.07g)中。甲苯相(含标题化合物)用软化水(2.65g)洗涤。
实施例3
4-氯甲基-2-环戊氧基-1-甲氧基苯的制备
将实施例2的甲苯溶液冷却到20℃,加入浓盐酸(37.5%;9.80g),期间使温度保持在20-22.7℃。添加完40分钟后取样并进行分析(GC),认为反应已经完全。进行相分离并弃去下部的水相。往反应器中加入碳酸氢钠(1.20g)以中和剩余盐酸。搅拌15分钟后,将混合物冷却到23℃,过滤除去固体(碳酸氢钠、氯化钠)。真空蒸馏(蒸馏终点:28℃,7毫巴)除去部分甲苯(17.07g)。
实施例4
4-氰甲基-2-环戊氧基-1-甲氧基苯的制备
将实施例3得到的溶液冷却至低于25℃,加入四丁基溴化铵(0.205g,0.63mol)、软化水(2.775g)和氰化钠(1.976g,0.039mol),并将该混合物加热到80℃,然后在78.1-80.4℃搅拌1小时50分钟。取样以证实反应物的转化。
加入甲苯(5.841g)和软化水(8.76g),进行相分离(在约54℃)并弃去下部水相。甲苯相(含产物)用软化水(13.32g)洗涤。真空蒸馏(蒸馏终点:55℃,1毫巴)除去甲苯。
实施例5
4-氰基-4-(3-环戊氧基-4-甲氧基苯基)庚二酸二甲酯的制备
在室温下,将实施例4制备的氰甲基化合物(纯度85.4%的9.05g;纯度100%的7.73g;0.0334mol)加到反应器(0.5L)中。将乙腈(28.56g)和软化水(0.07g)加到该反应器中。制备丙烯酸甲酯(6.88g,0.029mol)的乙腈(4.02g)溶液和甲醇Triton B(40.2%,50.94g,2.269molTriton B)的乙腈(4.06g)溶液。在20℃下,加入第一批约16.6%的丙烯酸甲酯溶液(1.81g)。然后加入第一批约12.5%的Triton B溶液(0.63kg)。添加后的温度为31℃。在28℃下,加入第二批约16.6%的丙烯酸甲酯溶液(1.82g)。然后加入第二批约12.5%的Triton B溶液(0.63g)。添加后的反应物温度为36℃。在35℃下,加入第三批约16.6%的丙烯酸甲酯溶液(1.81g)。然后加入第三批约12.5%的Triton B溶液(0.62g)。添加后的反应物温度为32℃。在32℃下,加入第四批约16.6%的丙烯酸甲酯溶液(1.81g)。然后加入约12.5%的Triton B溶液(0.63g)。添加后的反应物温度为36℃。在34℃下,加入第五批约33.2%的丙烯酸甲酯溶液(3.64g)。然后加入第五批约25%的Triton B溶液(1.25g)。添加后的反应物温度为38℃。然后加入最后一批约25%的Triton B溶液(1.25g)。添加后的反应物温度为36℃。将反应混合物在20-25℃搅拌1.5小时。真空蒸馏(蒸馏终点:59℃,20毫巴)除去乙腈。然后将该混合物分配到环己烷/甲苯(1145.9/254.6g)和水(559.8g)中。在50-52℃下,环己烷/甲苯相(含产物)用软化水(559.8g)洗涤。为使标题产物结晶,用50分钟使产物溶液冷却到0℃。然后接种庚二酸酯晶种并在-1-1℃陈化1小时。滤出庚二酸酯,用环己烷/甲苯(6.51g/1.44g)洗涤并用常规方法回收。
实施例6
4-氰基-4-(3-环戊氧基-4-甲氧基苯基)环己烷-1-酮的制备
将实施例5制备的庚二酸酯(76.52g,1.8112mol)加到反应器(100ml)中。加入二噁烷(2214g)和29.1%甲醇钠的甲醇溶液(0.44g,24mmol)。将该混合物加热至回流(77℃)并在该温度下搅拌1小时。取样以证实反应物的转化。蒸馏除去甲醇(16.82g馏出物)至反应器底部温度为97℃。加入新鲜的二噁烷(121.6g)以补充蒸馏期间损失的二噁烷。加入碳酸氢钠(22.2g,26.mmol)和软化水(2.47g)。将该混合物加热至回流(87℃)并在约87℃下搅拌10小时。取样以证实反应物的转化。将反应物冷却到78℃。加入二噁烷(0.13g)和软化水(0.12g)以使反应物齐平。冷却至低于60℃后,加入浓盐酸(37%,0.265g)以调整pH至7.5。真空蒸馏(蒸馏终点:66℃,305毫巴)除去二噁烷、甲醇和部分水(27.73g馏出物)。
搅拌下,将环己烷(180.0g)和甲苯(65.5g)加到反应器中。将反应物加热到70℃并在70℃或稍低的温度下进行相分离,弃去水相。在约70℃下,将含标题酮的有机相用两份软化水(总计169.4g)洗涤。往反应器中加入环己烷(165.0g)以使反应物齐平。为使产物结晶,用1小时以上使反应物冷却到10℃。然后在9-11℃陈化6小时以使结晶完全。将产物过滤并用环己烷/甲苯(81.5g/27.2g)洗涤。
实施例7
顺-6-[3-(环戊氧基)-4-甲氧基苯基]-1-氧杂螺环[2.5]辛烷-
2,6-二腈的制备
将上端安装有搅拌器、内部温度计的500ml园底烧瓶通入氮气清洗。烧瓶中加入50%氢氧化钾水溶液(22.0g)和四氢呋喃(55.0ml)。在室温搅拌下,加入苄基三乙基氯化铵(0.81g,35mmol,0.05当量)。使该溶液冷却到0℃。在室温下,往等压加料漏斗中加入含四氢呋喃(55.0ml)、4-氰基-4-(3-环戊氧基-4-甲氧基苯基)环己烷-1-酮(23.0g,73mmol,1.0当量)和氯乙腈(5.9g,78mmol,1.07当量)的溶液。将烧瓶内容物在0℃搅拌下,用15分钟添加等压加料漏斗中的溶液。使反应温度保持在0-5℃并搅拌1小时。将反应物温热到25℃,用水(90.0ml)和乙酸乙酯(90.0ml)稀释。搅拌溶液并使其放置30分钟。分层,分离有机层并真空浓缩得到残余物。加入甲基环己烷/THF(5∶1)(54.0ml),将该溶液加热到60℃,然后在90分钟以上再冷却到20℃;在约40℃时产物开始结晶。然后将该悬浮液冷却到0℃并在0-5℃保持2小时。在0℃下,将产物过滤并用甲醇混合液(46.0ml)洗涤。干燥产物,得到白色结晶固体状的标题产物。
实施例8
顺-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-
γ-1-环己烷羧酸锂,2的制备
往与碱洗气器相连的上端安装有搅拌器、内部温度计和回流冷凝器的1.0L三颈园底烧瓶中加入二甲基甲酰胺(200ml)、乙腈(200ml)、溴化锂(32.4g.0.37mol)和水(5.6g,0.31mol)。搅拌该悬浮液直至获得溶液,之后加入顺-6-[3-(环戊氧基)-4-甲氧基苯基]-1-氧杂螺环[2.5]辛烷-2,6-二腈,1(90.0g,0.25mol)。将烧瓶中的反应物在90-95℃下加热8-12小时。将反应物冷却到60℃并用二甲基甲酰胺(270ml)稀释。往该琥珀色溶液(60℃)中快速加入氢氧化锂水溶液(21.65g,0.51mol一水合氢氧化锂溶于112.5ml水中)。该悬浮液在60℃搅拌1小时,冷却至5℃,并在5℃保持1小时。将该悬浮液过滤,用乙酸乙酯(100ml)洗涤并进行空气干燥,以79.5%校准产率获得2。
实施例9
顺-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸,3
往上端安装有搅拌器和内部温度计的1.0L三颈园底烧瓶中加入顺-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸锂,2(58.5g,0.167mol)和乙酸乙酯(500ml)。在室温搅拌该浅色悬浮液,然后加入3N盐酸水溶液(70ml,0.21mol)。将反应物搅拌10分钟后转移到分液漏斗中。分离有机相并用水洗涤一次(100ml)。分离有机层并过滤至清洁的安装有蒸馏头和上端安装有搅拌器的1.0L三颈园底烧瓶中。蒸除乙酸乙酯(200ml)浓缩反应物。将烧瓶中的浓缩物冷却至60℃,然后加入庚烷(275ml)。将该悬浮液冷却至5℃并在5℃保持2小时,过滤并用冷(5℃)庚烷(50ml)洗涤。产物在真空箱中干燥至衡重,得到50.0g(85%)3。
Claims (12)
其中
R1是-(CR4R5)nC(O)O(CR4R5)mR6、-(CR4R5)nC(O)NR4(CR4R5)mR6、-(CR4R5)nO(CR4R5)mR6或-(CR4R5)rR6,其中烷基部分可任选地被一个或多个卤素取代;
m是0至2;
n是1至4;
r是0至6;
R4和R5独立地选自氢或C1-2烷基;
R6是氢、甲基、羟基、芳基、卤素取代的芳基、芳氧基C1-3烷基、卤素取代的芳氧基C1-3烷基、2,3-二氢化茚基、茚基、C7-11多环烷基、四氢呋喃基、呋喃基、四氢吡喃基、吡喃基、四氢噻吩基、噻吩基、四氢噻喃基、噻喃基、C3-6环烷基或包含一个或两个不饱和键的C4-6环烷基,其中的环烷基和杂环部分可任选地被1至3个甲基或一个乙基取代;
条件是:
a)当R6是羟基时,则m是2;或者
b)当R6是羟基时,则r是2至6;或者
c)当R6是2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,则m是1或2;或者
d)当R6是2-四氢吡喃基、2-四氢噻喃基、2-四氢呋喃基或2-四氢噻吩基时,则r是1至6;或者
e)当n是1并且m是0时,则-(CR4R5)nO(CR4R5)m中的R6不是H;
X是YR2、卤素、硝基、NH2或甲酰胺;
X2是O或NR8;
Y是O或S(O)m’;
m’是0、1或2;
R2独立地选自可任选地被一个或多个卤素取代的-CH3或-CH2CH3;
R3是氢、卤素、C1-4烷基、CH2NHC(O)C(O)NH2、卤素取代的C1-4烷基、-CH=CR8’R8’、可任选地被R8’取代的环丙基、CN、OR8、CH2OR8、NR8R10、CH2NR8R10、C(Z’)H、C(O)OR8、C(O)NR8R10或C≡CR8’;
R8是氢或可任选地被一至三个氟取代的C1-4烷基;
R8’是R8或氟;
R10是OR8或R11;
R11是氢或或可任选地被一至三个氟取代的C1-4烷基;
Z’是O、NR9、NOR8、NCN、C(-CN)2、CR8CN、CR8NO2、CR8C(O)OR8、CR8C(O)NR8R8、C(-CN)NO2、C(-CN)C(O)OR9或C(-CN)C(O)NR8R8;
R’和R”独立地选自氢或-C(O)OX,其中X是氢或者金属或铵阳离子;
该方法包括:
式II(a)和II(b)中,R1、R3、X2和X具有式(I)中相同含义;
b)将所述混合物在至少约60℃加热数小时,该加热可任选在惰性气氛下进行;
c)往所述混合物中加入强碱沉淀出式(I)化合物;
d)从所述沉淀中除去酰氨基溶剂和水,并任选地
1)进一步纯化沉淀,或
2)使沉淀酸化,获得游离酸。
2、权利要求1的方法,其中产物化合物中,R1是-CH2-环丙基环戊基、3-羟基环戊基、甲基或CF2H;X是YR2;Y是氧;X2是氧;并且R2是CF2H或甲基;且R3是CN。
3、权利要求1或2的方法,其中I(a)或II(a)族的金属卤化物是卤化锂或卤化镁。
4、权利要求1-3任一项的方法,其中I(a)或II(a)族的金属卤化物是溴化锂或溴化镁。
5、权利要求1-4任一项的方法,其中的无质子偶极酰氨基溶剂是二甲基甲酰胺、二甲基乙酰胺或N-甲基吡咯烷酮。
6、权利要求1-5任一项方法,其中的I(a)或II(a)族的金属卤化物是溴化锂并且酰氨基溶剂是二甲基甲酰胺。
7、权利要求1-6任一项的方法,其中水的存在量占反应容器中内容物重量0.1%(重量)以上。
8、权利要求1-7任一项的方法,其中的强碱是氢氧化锂。
9、权利要求1-8任一项的方法,其中的式II(a)或II(b)的化合物是顺-6-[3-(环戊氧基)-4-甲氧基苯基]-1-氧杂螺环[2.5]辛烷-2,6-二腈。
10、权利要求1-9任一项的方法的产物,它是顺-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸锂。
11、一种化合物,它是顺-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸锂。
12、一种组合物,它含有基本上纯净的顺-4-氰基-4-(3-环戊氧基-4-甲氧基苯基)-γ-1-环己烷羧酸锂。
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PE (1) | PE121599A1 (zh) |
PL (1) | PL191974B1 (zh) |
SA (1) | SA99191000A (zh) |
SK (1) | SK4902000A3 (zh) |
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MXPA02007300A (es) * | 2000-01-26 | 2002-11-29 | Smithkline Beecham Corp | Monohidrato de 4-ciano-4-[3-(ciclopentiloxi)-4-metoxifenil]ciclohexancarboxilato de cis-litio. |
CA2402384A1 (en) | 2000-03-16 | 2001-09-20 | Inflazyme Pharmaceuticals Ltd. | Benzylated pde4 inhibitors |
HUP0302891A2 (hu) | 2001-01-31 | 2003-12-29 | Pfizer Products Inc. | PDE4 izoenzimek inhibitoraiként alkalmazható éterszármazékok, alkalmazásuk és ezeket tartalmazó gyógyszerkészítmények |
CA2436535A1 (en) | 2001-01-31 | 2002-08-08 | Prizer Products Inc. | Nicotinamide biaryl derivatives useful as inhibitors of pde4 isozymes |
EE200300362A (et) | 2001-01-31 | 2003-12-15 | Pfizer Products Inc. | PDE4 isosüümide inhibiitoritena kasutatavad tiasolüül-, oksasolüül-, pürrolüül- ja imidasolüülhappeamiidi derivaadid |
US7250518B2 (en) | 2001-01-31 | 2007-07-31 | Pfizer Inc. | Nicotinamide acids, amides, and their mimetics active as inhibitors of PDE4 isozymes |
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CN102491959A (zh) * | 2011-12-19 | 2012-06-13 | 江苏澄扬作物科技有限公司 | 一种环氧乙烷衍生物的制备方法 |
CN102491959B (zh) * | 2011-12-19 | 2015-03-25 | 江苏澄扬作物科技有限公司 | 一种环氧乙烷衍生物的制备方法 |
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