JP5553752B2 - 4−フェニル−6−(2,2,2−トリフルオロ−1−フェニルエトキシ)ピリミジン系化合物を調製する方法 - Google Patents
4−フェニル−6−(2,2,2−トリフルオロ−1−フェニルエトキシ)ピリミジン系化合物を調製する方法 Download PDFInfo
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- JP5553752B2 JP5553752B2 JP2010522057A JP2010522057A JP5553752B2 JP 5553752 B2 JP5553752 B2 JP 5553752B2 JP 2010522057 A JP2010522057 A JP 2010522057A JP 2010522057 A JP2010522057 A JP 2010522057A JP 5553752 B2 JP5553752 B2 JP 5553752B2
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- alkyl
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- -1 4-phenyl-6- (2,2,2-trifluoro-1-phenylethoxy) pyrimidine compound Chemical class 0.000 title claims description 79
- 238000000034 method Methods 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims description 84
- 239000003054 catalyst Substances 0.000 claims description 11
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 8
- 229910052744 lithium Inorganic materials 0.000 claims description 5
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical group [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims description 5
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical group [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 4
- 239000003446 ligand Substances 0.000 claims description 4
- 239000011777 magnesium Substances 0.000 claims description 4
- 229910052749 magnesium Inorganic materials 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- QYIGOGBGVKONDY-UHFFFAOYSA-N 1-(2-bromo-5-chlorophenyl)-3-methylpyrazole Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1Br QYIGOGBGVKONDY-UHFFFAOYSA-N 0.000 claims description 3
- STSCVKRWJPWALQ-UHFFFAOYSA-N TRIFLUOROACETIC ACID ETHYL ESTER Chemical group CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 claims description 3
- UOPFIWYXBIHPIP-NHCUHLMSSA-N n-[(1r,2r)-2-amino-1,2-diphenylethyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H](C=1C=CC=CC=1)[C@H](N)C1=CC=CC=C1 UOPFIWYXBIHPIP-NHCUHLMSSA-N 0.000 claims description 3
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical group [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- MMAGMBCAIFVRGJ-UHFFFAOYSA-J iridium(3+);1,2,3,4,5-pentamethylcyclopenta-1,3-diene;tetrachloride Chemical group Cl[Ir+]Cl.Cl[Ir+]Cl.CC=1C(C)=C(C)[C-](C)C=1C.CC=1C(C)=C(C)[C-](C)C=1C MMAGMBCAIFVRGJ-UHFFFAOYSA-J 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- WGOPGODQLGJZGL-UHFFFAOYSA-N lithium;butane Chemical compound [Li+].CC[CH-]C WGOPGODQLGJZGL-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 2
- 238000006478 transmetalation reaction Methods 0.000 claims 2
- NOIXNOMHHWGUTG-UHFFFAOYSA-N 2-[[4-[4-pyridin-4-yl-1-(2,2,2-trifluoroethyl)pyrazol-3-yl]phenoxy]methyl]quinoline Chemical compound C=1C=C(OCC=2N=C3C=CC=CC3=CC=2)C=CC=1C1=NN(CC(F)(F)F)C=C1C1=CC=NC=C1 NOIXNOMHHWGUTG-UHFFFAOYSA-N 0.000 claims 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- 238000005984 hydrogenation reaction Methods 0.000 claims 1
- VVOFSHARRCJLLA-CHWSQXEVSA-N n-[(1r,2r)-2-aminocyclohexyl]-4-methylbenzenesulfonamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@H]1[C@H](N)CCCC1 VVOFSHARRCJLLA-CHWSQXEVSA-N 0.000 claims 1
- 239000000243 solution Substances 0.000 description 69
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
- 239000000203 mixture Substances 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- 125000000217 alkyl group Chemical group 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 27
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 125000003118 aryl group Chemical group 0.000 description 21
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 239000001257 hydrogen Substances 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- 125000000623 heterocyclic group Chemical group 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 12
- 238000004821 distillation Methods 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 125000000547 substituted alkyl group Chemical group 0.000 description 11
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000002877 alkyl aryl group Chemical group 0.000 description 9
- 238000006243 chemical reaction Methods 0.000 description 9
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 238000000634 powder X-ray diffraction Methods 0.000 description 8
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 7
- 229910052736 halogen Inorganic materials 0.000 description 7
- 150000002367 halogens Chemical class 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 239000002002 slurry Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 235000019260 propionic acid Nutrition 0.000 description 6
- 125000006633 tert-butoxycarbonylamino group Chemical group 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- YBMVIGVXVXAKDM-LLVKDONJSA-N (1r)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanol Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1[C@@H](O)C(F)(F)F YBMVIGVXVXAKDM-LLVKDONJSA-N 0.000 description 5
- JPZOAVGMSDSWSW-UHFFFAOYSA-N 4,6-dichloropyrimidin-2-amine Chemical compound NC1=NC(Cl)=CC(Cl)=N1 JPZOAVGMSDSWSW-UHFFFAOYSA-N 0.000 description 5
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 235000001014 amino acid Nutrition 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 238000004440 column chromatography Methods 0.000 description 5
- 125000005842 heteroatom Chemical group 0.000 description 5
- 229910052741 iridium Inorganic materials 0.000 description 5
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 5
- 229910052760 oxygen Inorganic materials 0.000 description 5
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 5
- 235000015497 potassium bicarbonate Nutrition 0.000 description 5
- 239000011736 potassium bicarbonate Substances 0.000 description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 235000011181 potassium carbonates Nutrition 0.000 description 5
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 5
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- SGRRXMOSJYUMBY-NSHDSACASA-N (2s)-3-(4-boronophenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(B(O)O)C=C1 SGRRXMOSJYUMBY-NSHDSACASA-N 0.000 description 4
- YNKKCYYJEALSKL-UHFFFAOYSA-N 1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethanone Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1C(=O)C(F)(F)F YNKKCYYJEALSKL-UHFFFAOYSA-N 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 108010031944 Tryptophan Hydroxylase Proteins 0.000 description 4
- 102000005506 Tryptophan Hydroxylase Human genes 0.000 description 4
- 238000002441 X-ray diffraction Methods 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 4
- NFIVJOSXJDORSP-QMMMGPOBSA-N (2s)-2-amino-3-(4-boronophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(B(O)O)C=C1 NFIVJOSXJDORSP-QMMMGPOBSA-N 0.000 description 3
- KOGJTURHFMAARC-ZDUSSCGKSA-N (2s)-3-[4-(2-amino-6-chloropyrimidin-4-yl)phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound C1=CC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CC=C1C1=CC(Cl)=NC(N)=N1 KOGJTURHFMAARC-ZDUSSCGKSA-N 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical group [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 208000037765 diseases and disorders Diseases 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 3
- 235000021317 phosphate Nutrition 0.000 description 3
- 125000002577 pseudohalo group Chemical group 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000005855 radiation Effects 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 229910052717 sulfur Chemical group 0.000 description 3
- 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 description 3
- BTANRVKWQNVYAZ-BYPYZUCNSA-N (2S)-butan-2-ol Chemical group CC[C@H](C)O BTANRVKWQNVYAZ-BYPYZUCNSA-N 0.000 description 2
- WSJJQZIMUAGKSW-WIOPSUGQSA-N (2s)-3-[4-[2-amino-6-[(1r)-1-[4-chloro-2-(3-methylpyrazol-1-yl)phenyl]-2,2,2-trifluoroethoxy]pyrimidin-4-yl]phenyl]-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound N1=C(C)C=CN1C1=CC(Cl)=CC=C1[C@H](C(F)(F)F)OC1=CC(C=2C=CC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CC=2)=NC(N)=N1 WSJJQZIMUAGKSW-WIOPSUGQSA-N 0.000 description 2
- SCQBKVUSRQRUTD-UHFFFAOYSA-N 4-phenyl-6-(2,2,2-trifluoro-1-phenylethoxy)pyrimidine Chemical compound C=1C=CC=CC=1C(C(F)(F)F)OC(N=CN=1)=CC=1C1=CC=CC=C1 SCQBKVUSRQRUTD-UHFFFAOYSA-N 0.000 description 2
- XKVUYEYANWFIJX-UHFFFAOYSA-N 5-methyl-1h-pyrazole Chemical compound CC1=CC=NN1 XKVUYEYANWFIJX-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 101100441092 Danio rerio crlf3 gene Proteins 0.000 description 2
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 2
- 238000010268 HPLC based assay Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L PdCl2(PPh3)2 Substances [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 2
- 125000005213 alkyl heteroaryl group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
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- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000000862 serotonergic effect Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940066765 systemic antihistamines substituted ethylene diamines Drugs 0.000 description 1
- MMGOTUAZCTWZKP-UHFFFAOYSA-N tert-butyl-chloro-cyclohexylphosphane Chemical compound CC(C)(C)P(Cl)C1CCCCC1 MMGOTUAZCTWZKP-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003567 thiocyanates Chemical class 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 150000004764 thiosulfuric acid derivatives Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000009901 transfer hydrogenation reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 1
- 125000003652 trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 description 1
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- 238000005292 vacuum distillation Methods 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Description
本発明は、4−フェニル−6−(2,2,2−トリフルオロ−1−フェニルエトキシ)ピリミジン系化合物を作製する方法に関する。
或る特定の4−フェニル−6−(2,2,2−トリフルオロ−1−フェニルエトキシ)ピリミジン系化合物は、トリプトファンヒドロキシラーゼ(TPH)酵素の阻害剤であり、これはセロトニン生合成の律速段階を触媒する。共に2006年12月12日付で出願された特許文献1及び特許文献2を参照されたい。これらの化合物は、セロトニン作動系に関連する広範な疾患及び障害を治療するのに使用することができると考えられている(同上)。結果として、効率的なこれらの製造方法が望まれる。
本発明は、式I:
本発明は、式Iの化合物を調製する新規の方法、及びそれに有用な中間体の発見に基づく。哺乳類に投与する場合、好ましくは、式Iの化合物はTPHを阻害し、様々な疾患及び障害の治療に使用され得る。概して、共に2006年12月12日付で出願された特許文献1及び特許文献2を参照されたい。
特に明示のない限り、「アルケニル」という用語は、2個〜20個(例えば2個〜10個又は2個〜6個)の炭素原子を有し、少なくとも1つの炭素−炭素二重結合を含む直鎖、分岐、及び/又は環状の炭化水素を意味する。代表的なアルケニル部分としては、ビニル、アリル、1−ブテニル、2−ブテニル、イソブチレニル、1−ペンテニル、2−ペンテニル、3−メチル−1−ブテニル、2−メチル−2−ブテニル、2,3−ジメチル−2−ブテニル、1−ヘキセニル、2−ヘキセニル、3−ヘキセニル、1−ヘプテニル、2−ヘプテニル、3−ヘプテニル、1−オクテニル、2−オクテニル、3−オクテニル、1−ノネニル、2−ノネニル、3−ノネニル、1−デセニル、2−デセニル、及び3−デセニルが挙げられる。
本発明は、式I:
6.1. 1−(4−クロロ−2−(3−メチル−1H−ピラゾール−1−イル)フェニル)−2,2,2−トリフルオロエタノンの調製
(S)−2−アミノ−3−(4−ボロノフェニル)プロピオン酸(Ryscor Science, Inc.、North Carolina、1.0g、4.8mmol)及び炭酸カリウム(1.32g、2当量)を、エタノール水溶液(15mlのエタノール及び8mlの水)中で混合した。ジ−tert−ブチルジカーボネート(1.25g、1.2当量)を一度に添加した。室温で30分間かき混ぜた後、HPLC分析によって、出発化合物の完全な消費及び(S)−3−(4−ボロノフェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸の形成が示された。2−アミノ−4,6−ジクロロピリミジン(1.18g、1.5当量)及び触媒のビス(トリフェニルホスフィン)パラジウム(II)ジクロリド(34mg、1mol%)を添加して、得られた混合物を65℃〜70℃で3時間加熱した。HPLC分析によって、中間体である(S)−3−(4−ボロノフェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸の完全な消費が示された。濃縮及び濾過した後、表題化合物の標準溶液に対する得られた水溶液のHPLC分析により、1.26g(収率67%)であることが示された。
(S)−2−アミノ−3−(4−ボロノフェニル)プロピオン酸(10g、48mmol)及び重炭酸カリウム(14.4g、3当量)を、エタノール水溶液(250mlのエタノール及び50mlの水)中で混合した。ジ−tert−ブチルジカーボネート(12.5g、1.2当量)を一度に添加した。HPLC分析により、室温で一晩攪拌した後も反応が完了していないことが示された。炭酸カリウム(6.6g、1.0当量)及びさらなるジ−tert−ブチルジカーボネート(3.1g、0.3当量)を添加した。室温で2.5時間かき混ぜた後、HPLC分析によって、出発化合物の完全な消費及び(S)−3−(4−ボロノフェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸の形成が示された。2−アミノ−4,6−ジクロロピリミジン(11.8g、1.5当量)及び触媒のビス(トリフェニルホスフィン)−パラジウム(II)ジクロリド(0.34g、1mol%)を添加して、得られた混合物を75℃〜80℃で2時間加熱した。HPLC分析によって、中間体である(S)−3−(4−ボロノフェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸の完全な消費が示された。混合物を減圧下で濃縮し、濾過した。濾液を酢酸エチル(200ml)で洗浄し、3:1のTHF/MTBE(120ml)で希釈した。この混合物を6N塩酸を用いてpH約2.4まで酸性化した。有機層を塩水で洗浄して、減圧下で濃縮した。残渣をイソプロパノール中で析出させて、濾過し、真空下、50℃で乾燥させて、表題化合物をオフホワイトの固体(9.0g、収率48%)として得た。HPLC分析による純度:92.9%。母液の濃縮によりさらなるオフホワイトの粉末が2.2g生じた(収率12%)。HPLC分析による純度:93.6%。
反応器にエタノール(330kg)、(S)−2−(tert−ブトキシカルボニルアミノ)−3−(4−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)フェニル)プロピオン酸(55kg)、2−アミノ−4,6−ジクロロピリミジン(70kg)、トリフェニルホスフィン(0.55kg)、酢酸パラジウム(0.24kg)、及びTHF(720kg)を投入した。この混合物に、炭酸水素カリウム水溶液(水320kg中50.1kg)をゆっくりと投入した。得られた混合物を68℃〜72℃で20時間〜23時間加熱して、冷却した。真空蒸留及び水による希釈を繰り返すことにより、エタノールを水に置き換えた。不溶性物質を室温で濾過して、湿ケーキを水で洗浄した。濾液を酢酸エチルで2回洗浄した。水層をTHF(664kg)及びトルエン(512kg)と混合し、6N HClを用いてpHを約2.5〜3.5に調節した。水層を酢酸エチルで2回抽出した。合わせた有機層を40℃〜50℃で炭で処理して、セルロース及び硫酸ナトリウムのパッドを通して濾過した。ケーキを1:1のTHF/トルエンで洗浄した。濾液を濃縮して、生成物をトルエン/THFから結晶化させた。真空下、40℃〜45℃で乾燥させると、(S)−3−(4−(2−アミノ−6−クロロピリミジン−4−イル)フェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸トルエン溶媒和物がオフホワイトの固体(収率65%)として得られた。
(S)−3−(4−(2−アミノ−6−((R)−1−(4−クロロ−2−(3−メチル−1H−ピラゾール−1−イル)フェニル)−2,2,2−トリフルオロエトキシ)ピリミジン−4−イル)フェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸(2.0mmol)のエタノール溶液に、塩化チオニル(6当量)を0℃で添加し、得られた混合物をこの温度で30分間、次に室温で24時間攪拌した。HPLC分析により、98%超が(S)−エチル 2−アミノ−3−(4−(2−アミノ−6−((R)−1−(4−クロロ−2−(3−メチル−1H−ピラゾール−1−イル)フェニル)−2,2,2−トリフルオロエトキシ)ピリミジン−4−イル)フェニル)プロピオネートに変換されたことが示された。
反応器に20℃のジャケット温度で、(R)−1−(4−クロロ−2−(3−メチル−1H−ピラゾール−1−イル)フェニル)−2,2,2−トリフルオロエタノール(4.23kg;1.1当量)及びジオキサン(52L;10容量)を投入した。80℃のジャケット温度及び減圧(160mbar〜150mbar;対応する内部温度:52℃〜53℃)下で、2.5容量のジオキサン(13L)を蒸留により除去して、水分除去した。溶液を20℃に冷却した。炭酸セシウム(6.52kg;1.5当量)を添加して、混合物を95℃に加熱した。(S)−3−(4−(2−アミノ−6−クロロピリミジン−4−イル)フェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸(6.95kg;1.0当量)を少量ずつ慎重に添加した。混合物を101℃に2時間加熱した。95℃に冷却した後、さらなる炭酸セシウム(8.65kg;2.0当量)を添加した。反応混合物を101℃に24時間加熱した。水(39L;7.5容量)を添加し、混合物を22℃に急冷した。ジ−t−ブチルジカーボネート(289g;0.1当量)を添加し、混合物を22℃で2時間攪拌した。トルエン(26L;5容量)を添加して、混合物を15分間攪拌した。層を分離した(生成物は有機層中)。水(26L;5容量)を有機層に添加し、混合物を15分間攪拌した。層を分離した(生成物は水層中)。5N HCl(2L)を添加することによって、水層のpHを約7.0に調節した。酢酸エチル(26L;5容量)を添加し、5N HCl(2L)の添加によりpHを4.0に調節した。層を分離した。水層を酢酸エチル(26L;5容量)で抽出した。合わせた有機層を塩水(26L;5容量)で洗浄した。有機層を65℃のジャケット温度及び減圧(230mbar〜95mbar;内部温度を40℃より低く維持)下で3容量まで濃縮した。エタノール(31.5L;6容量)を添加し、65℃のジャケット温度及び減圧(110mbar〜100mbar;内部温度を40℃より低く維持)下で蒸留を続けた。5.5容量の溶媒を蒸留により除去した。エタノール(44L;8.5容量)を添加し、65℃のジャケット温度及び減圧(100mbar〜110mbar;内部温度を40℃より低く維持)下で蒸留を続けて、6.5容量の溶媒を除去した。(S)−3−(4−(2−アミノ−6−((R)−1−(4−クロロ−2−(3−メチル−1H−ピラゾール−1−イル)フェニル)−2,2,2−トリフルオロエトキシ)ピリミジン−4−イル)フェニル)−2−(tert−ブトキシカルボニルアミノ)プロピオン酸を、エタノール溶液として得た。
Claims (9)
- 前記不斉配位子が
(1R,2R)−(−)−N−(4−トルエンスルホニル)−1,2−ジフェニルエチレンジアミン、又は
N−((1R,2R)−2−アミノシクロヘキシル)−4−メチルベンゼンスルホンアミド)である、請求項1に記載の製造方法。 - 前記白金族金属触媒がジクロロ(ペンタメチルシクロペンタジエニル)イリジウム(III)ダイマーである、請求項1又は2に記載の製造方法。
- 前記式IVで表される化合物が、1−(2−ブロモ−5−クロロフェニル)−3−メチル−1H−ピラゾールをトランスメタル化条件下でトリフルオロアセチル化剤と反応させることにより製造したものである、請求項1〜3のいずれかに記載の製造方法。
- 前記トリフルオロアセチル化剤がトリフルオロ酢酸エチルである、請求項4に記載の製造方法。
- 前記トランスメタル化条件がアルキルリチウム試薬又はアルキルマグネシウム試薬の使用を含む、請求項4又は5に記載の製造方法。
- 前記アルキルリチウム試薬が、n−ブチルリチウム、sec−ブチルリチウム又はt−ブチルリチウムである、請求項6に記載の製造方法。
- 前記アルキルマグネシウム試薬が、塩化イソプロピルマグネシウム又は塩化トリブチルマグネシウムである、請求項6に記載の製造方法。
- 前記式II(a)で表される化合物が結晶性(R)−1−(4−クロロ−2−(3−メチル−1H−ピラゾール−1−イル)フェニル)−2,2,2−トリフルオロエタノールである、請求項1〜8のいずれかに記載の製造方法。
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TWI439457B (zh) * | 2007-09-28 | 2014-06-01 | Lexicon Pharmaceuticals Inc | (s)-2-胺基-3-(4-(2-胺基-6-((r)-1-(4-氯-2-(3-甲基-1h-吡唑-1-基)苯基)-2,2,2-三氟乙氧)-嘧啶-4-基)苯基)丙酸乙酯之固體形式與其使用方法 |
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2008
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- 2008-08-22 US US12/196,341 patent/US20090062540A1/en not_active Abandoned
- 2008-08-22 WO PCT/US2008/073950 patent/WO2009029499A1/en active Application Filing
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- 2008-08-22 CN CN200880104288XA patent/CN101801384B/zh active Active
- 2008-08-22 EP EP12180934A patent/EP2529740A1/en not_active Withdrawn
- 2008-08-22 ES ES17201452T patent/ES2848152T3/es active Active
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EP2187887A1 (en) | 2010-05-26 |
CA2697368A1 (en) | 2009-03-05 |
ES2656798T3 (es) | 2018-02-28 |
US7968729B2 (en) | 2011-06-28 |
CN101801384B (zh) | 2012-03-21 |
JP2010536879A (ja) | 2010-12-02 |
US8575362B2 (en) | 2013-11-05 |
EP2529740A1 (en) | 2012-12-05 |
MX2010001938A (es) | 2010-03-11 |
HK1143749A1 (en) | 2011-01-14 |
RU2010111125A (ru) | 2011-09-27 |
BRPI0815754A2 (pt) | 2017-05-30 |
EP3318260B1 (en) | 2020-09-23 |
EP2187887B1 (en) | 2017-11-15 |
RU2493156C2 (ru) | 2013-09-20 |
NZ583017A (en) | 2012-02-24 |
IL226441A0 (en) | 2013-06-27 |
ES2848152T3 (es) | 2021-08-05 |
US20100240906A1 (en) | 2010-09-23 |
AU2008293679A1 (en) | 2009-03-05 |
BRPI0815754B1 (pt) | 2022-03-22 |
WO2009029499A1 (en) | 2009-03-05 |
EP3318260A1 (en) | 2018-05-09 |
CN101801384A (zh) | 2010-08-11 |
AU2008293679B2 (en) | 2013-09-12 |
US20090062540A1 (en) | 2009-03-05 |
US20110301349A1 (en) | 2011-12-08 |
CA2697368C (en) | 2016-06-21 |
KR101582697B1 (ko) | 2016-01-05 |
IL226441A (en) | 2014-06-30 |
ZA201000785B (en) | 2011-04-28 |
KR20100046026A (ko) | 2010-05-04 |
IL203669A (en) | 2015-07-30 |
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