CN1680292A - 用作4-氨基喹啉衍生物中间体的化合物 - Google Patents
用作4-氨基喹啉衍生物中间体的化合物 Download PDFInfo
- Publication number
- CN1680292A CN1680292A CNA2005100529529A CN200510052952A CN1680292A CN 1680292 A CN1680292 A CN 1680292A CN A2005100529529 A CNA2005100529529 A CN A2005100529529A CN 200510052952 A CN200510052952 A CN 200510052952A CN 1680292 A CN1680292 A CN 1680292A
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- Prior art keywords
- compound
- formula
- benzyl
- methyl
- preparation
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 96
- 239000000543 intermediate Substances 0.000 title abstract 2
- FQYRLEXKXQRZDH-UHFFFAOYSA-N 4-aminoquinoline Chemical compound C1=CC=C2C(N)=CC=NC2=C1 FQYRLEXKXQRZDH-UHFFFAOYSA-N 0.000 title 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims description 31
- 239000003513 alkali Substances 0.000 claims description 15
- -1 trifluoromethyl benzene compound Chemical class 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 230000002829 reductive effect Effects 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 8
- 238000005859 coupling reaction Methods 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
- UTAHFAJHGGPJEQ-UHFFFAOYSA-N (2-phenylphenyl)phosphane Chemical group PC1=CC=CC=C1C1=CC=CC=C1 UTAHFAJHGGPJEQ-UHFFFAOYSA-N 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 3
- ZEMZPXWZVTUONV-UHFFFAOYSA-N 2-(2-dicyclohexylphosphanylphenyl)-n,n-dimethylaniline Chemical group CN(C)C1=CC=CC=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 ZEMZPXWZVTUONV-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 235000010290 biphenyl Nutrition 0.000 claims description 3
- 239000004305 biphenyl Substances 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 239000003446 ligand Substances 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000007516 brønsted-lowry acids Chemical group 0.000 claims description 2
- 150000007528 brønsted-lowry bases Chemical class 0.000 claims description 2
- 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 claims 1
- 229940125782 compound 2 Drugs 0.000 claims 1
- 229940126214 compound 3 Drugs 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 102000012336 Cholesterol Ester Transfer Proteins Human genes 0.000 abstract description 7
- 108010061846 Cholesterol Ester Transfer Proteins Proteins 0.000 abstract description 7
- 239000003112 inhibitor Substances 0.000 abstract description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 23
- 239000000203 mixture Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000003756 stirring Methods 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229910052757 nitrogen Inorganic materials 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000004140 cleaning Methods 0.000 description 8
- 208000029078 coronary artery disease Diseases 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- 108010010234 HDL Lipoproteins Proteins 0.000 description 7
- 102000015779 HDL Lipoproteins Human genes 0.000 description 7
- 238000004821 distillation Methods 0.000 description 7
- 239000011521 glass Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000001291 vacuum drying Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 6
- 229940125881 cholesteryl ester transfer protein inhibitor Drugs 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 125000004494 ethyl ester group Chemical group 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 239000010410 layer Substances 0.000 description 6
- 238000012546 transfer Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- JCBPETKZIGVZRE-SCSAIBSYSA-N (2r)-2-aminobutan-1-ol Chemical class CC[C@@H](N)CO JCBPETKZIGVZRE-SCSAIBSYSA-N 0.000 description 4
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 4
- 108010023302 HDL Cholesterol Proteins 0.000 description 4
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 230000001186 cumulative effect Effects 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- NWDUUMKBQJCPDE-UHFFFAOYSA-N 2-aminopentanenitrile;methanesulfonic acid Chemical compound CS(O)(=O)=O.CCCC(N)C#N NWDUUMKBQJCPDE-UHFFFAOYSA-N 0.000 description 3
- 201000001320 Atherosclerosis Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 201000005577 familial hyperlipidemia Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- IRICHAOGAOFEQI-UHFFFAOYSA-N (1-bromo-2,2,2-trifluoroethyl)benzene Chemical compound FC(F)(F)C(Br)C1=CC=CC=C1 IRICHAOGAOFEQI-UHFFFAOYSA-N 0.000 description 2
- GYQJEZJHBPGITN-SNVBAGLBSA-N (3r)-3-[4-(trifluoromethyl)anilino]pentanenitrile Chemical compound N#CC[C@@H](CC)NC1=CC=C(C(F)(F)F)C=C1 GYQJEZJHBPGITN-SNVBAGLBSA-N 0.000 description 2
- 150000005011 4-aminoquinolines Chemical class 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- UOHBMRODJBFDPN-UHFFFAOYSA-N C(C)(C)(C)O.[Li] Chemical compound C(C)(C)(C)O.[Li] UOHBMRODJBFDPN-UHFFFAOYSA-N 0.000 description 2
- PZOYRQKSKTXMRA-IINYFYTJSA-N CC[C@@](C1)(N)N(C(O)=O)C2=CC=C(C(F)(F)F)C=C2[C@H]1C(OC)=O Chemical compound CC[C@@](C1)(N)N(C(O)=O)C2=CC=C(C(F)(F)F)C=C2[C@H]1C(OC)=O PZOYRQKSKTXMRA-IINYFYTJSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 108010028554 LDL Cholesterol Proteins 0.000 description 2
- 238000008214 LDL Cholesterol Methods 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- TXJNLIXEXFOWOC-NNJIEVJOSA-N [(4R)-2-oxo-1-phenyl-4-[4-(trifluoromethyl)anilino]hexyl] carbamate Chemical compound C(N)(OC(C1=CC=CC=C1)C(C[C@@H](CC)NC1=CC=C(C=C1)C(F)(F)F)=O)=O TXJNLIXEXFOWOC-NNJIEVJOSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- PQLFROTZSIMBKR-UHFFFAOYSA-N ethenyl carbonochloridate Chemical compound ClC(=O)OC=C PQLFROTZSIMBKR-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229940125753 fibrate Drugs 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910001425 magnesium ion Inorganic materials 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000012856 packing Methods 0.000 description 2
- 238000005191 phase separation Methods 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
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- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical class C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 2
- FVPPLRDSFQDFLX-RXMQYKEDSA-N (3r)-3-aminopentanenitrile Chemical compound CC[C@@H](N)CC#N FVPPLRDSFQDFLX-RXMQYKEDSA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- CQSGWFMVGDLSSR-UHFFFAOYSA-N 2-(trifluoromethyl)-3,4-dihydro-2h-quinoline-1-carboxylic acid Chemical compound C1=CC=C2N(C(=O)O)C(C(F)(F)F)CCC2=C1 CQSGWFMVGDLSSR-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
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- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- WALYXZANOBBHCI-UHFFFAOYSA-K magnesium sodium trichloride hydrate Chemical compound O.[Cl-].[Na+].[Mg+2].[Cl-].[Cl-] WALYXZANOBBHCI-UHFFFAOYSA-K 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
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- 239000011664 nicotinic acid Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- QULYNCCPRWKEMF-UHFFFAOYSA-N parachlorobenzotrifluoride Chemical compound FC(F)(F)C1=CC=C(Cl)C=C1 QULYNCCPRWKEMF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/24—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the same saturated acyclic carbon skeleton
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
- C07C271/64—Y being a hydrogen or a carbon atom, e.g. benzoylcarbamates
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
Abstract
本发明涉及作为胆固醇酯转移蛋白(CETP)抑制剂的中间体的通式化合物及其制备方法,其中A为CN、CONH2或CONHCOOR,R为甲基或任选取代的苄基。
Description
本申请是中国发明申请(发明名称:用作4-氨基喹啉衍生物中间体的化合物,申请日:2002年4月8日;申请号02809166.3)的分案申请。
发明领域
本发明涉及作为胆固醇酯转移蛋白(CETP)抑制剂的中间体的化合物及其制备方法。
发明背景
动脉粥样硬化及其相关的冠状动脉疾病(CAD)在工业化国家中是死亡率最高的疾病。在美国,尽管人们企图改善次级危险因素(吸烟、肥胖、缺乏锻练)并通过改变饮食和药物疗法来治疗血脂异常,但冠心病(CHD)仍然是死亡的最常见原因。
现已表明这种情况发展的危险性与某些血脂水平有着密切关系。虽然高LDL-C是最明显的血脂异常的指标,但并不表明它是引起CHD的唯一原因。低HDL-C也被认为是CHD的一种危险因素(Gordon,D.J.,等:″High-densityLipoprotein Cholesterol and Cardiovascular Disease″,Circulation,(1989),79:8-15)。
高LDL-胆固醇和甘油三酯水平与心血管疾病发展呈正相关,而高水平的HDL-胆固醇与之呈负相关。因此,血脂异常并不是CHD的单一危险指标,而是包括一种或多种脂质异常。
在控制这类疾病的两种血浆水平的许多因素中,从依赖性原则上讲,胆固醇酯转移蛋白(CETP)活性对这三者均有影响。人们已发现,这种70,000道尔顿血糖蛋白在许多动物物种(包括人)中所起的作用是在脂蛋白颗粒之间转移胆固醇酯和甘油三酯,包括高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、极低密度脂蛋白(VLDL)和乳糜微粒。CETP活性的最终结果是HDL胆固醇降低和LDL胆固醇升高。脂蛋白水平的这种影响被认为是促动脉粥样硬化的,这在脂质状况增加CHD危险的患者中尤其如此。
现有的提高HDL的疗法不完全令人满意。烟酸能显著提高HDL,但它有严重的耐药性导致降低活性。贝特类药物(Fibrates)和HMG-CoA还原酶抑制剂只能少量提高HDL-C。因此,现在这种情况显然不能满足医药上对于耐药性好的、能明显提高血浆HDL水平从而逆转或减缓动脉粥样硬化的发展的药物的需求。
公开号为WO00/02887的PCT申请公开了含有某些新配体的催化剂的应用,这类配体用于过渡金属催化的碳-杂原子和碳-碳键形成中的过渡金属。
本申请引用的共同转让美国专利6,140,343特别公开了CETP抑制剂,顺式-4-[乙酰基-(3,5-双-三氟甲基-苄基)-氨基]-2-乙基-6-三氟甲基-3,4-二氢-2H-喹啉-1-羧酸异丁酯及其制备方法(例如实施例46中所公开的方法)。
本申请引用的共同转让美国专利6,197,786特别公开了CETP抑制剂,顺式-4-[(3,5-双-三氟甲基-苄基)-甲氧基羰基-氨基]-2-乙基-6-三氟甲基-3,4-二氢-2H-喹啉-1-羧酸乙酯及其制备方法(例如实施例7中所公开的方法)。
发明概述
本发明的一个方面是式III化合物。
本发明的另一个方面是式IV化合物。
本发明的再一个方面是式VI化合物,
其中R选自甲基、苄基和取代的苄基。
本发明的又一个方面是式VII化合物,
其中R选自甲基、苄基和取代的苄基。
在本发明这些化合物的一个优选的实施方案中,式VI化合物和式VII化合物的R选自甲基、苄基和被一个或多个取代基取代的苄基,取代基各自独立地选自(C1-C3)烷基、(C1-C3)烷氧基和卤素。
本发明的另一方面是制备上面式III化合物的方法,包括对位被卤素或O-三氟甲基磺酸根(O-triflate)取代的三氟甲苯与式II化合物进行偶联,
生成式III化合物。
在本发明关于式III化合物制备方法的一个优选实施方案中,所述三氟甲苯化合物与所述的式II化合物之间的偶联反应是在过渡金属优选钯的存在下进行的。
在本发明关于式III化合物制备方法的另一个优选实施方案中,所述三氟甲基苯化合物与所述的式II化合物之间的偶联反应是在膦配体,优选二烷基膦基联苯配体,更优选是选自2-二环己基膦基-2′-(N,N-二甲基氨基)联苯和2-二环己基膦基-2′-甲基联苯配体的存在下进行的。
在本发明关于式III化合物制备方法的一个优选实施方案中,所述三氟甲基苯化合物与所述的式II化合物之间的偶联反应是在碱,优选碳酸铯存在下发生的。
本发明的另一方面是制备上面式IV化合物的方法,包括将上面式III化合物用水解剂进行水解,水解剂选自酸和碱,优选为酸,更优选为硫酸和水,从而生成式IV化合物。
本发明的又一方面是制备上面式VI化合物的方法,包括将上面式IV化合物与式V化合物在碱优选叔丁醇锂存在下偶联形成式VI化合物,
其中R选自甲基、苄基和取代的苄基。
本发明的另一方面是制备上面式VII化合物的方法,包括将上面式VI化合物(其中R选自甲基、苄基和取代苄基),在路易斯酸优选钙离子或镁离子存在下,用还原剂优选硼氢化钠,进行还原,生成还原的化合物,并在酸性条件下使该还原的化合物环化生成式VII化合物。
有关式V、VI和VII化合物中的术语“取代的苄基”是指在苯环上被一个或多个取代基取代的苄基,该取代基不会阻碍下列反应:(a)适当的式V化合物与式IV化合物反应生成适当的式VI化合物,(b)还原和环化适当的式VI化合物生成适当的式VIIB化合物,(c)式VTIB化合物酰化生成式VIIIB化合物,或(d)从式VIIIB化合物进行脱保护步骤去除适当取代的苄氧基羰基基团生成式IB化合物。优选的取代基是(C1-C3)烷基和(C1-C3)烷氧基和卤素。
发明详述
反应方案A例举说明了从(R)-2-氨基-1-丁醇制备式II的手性异构体的方法。反应方案B例举说明了制备式IA和式IB的胆固醇酯转移蛋白抑制剂的方法。
方案A
方案B
根据方案B,式III化合物是通过将式II的手性异构体化合物((R)-3-氨基-戊腈)在金属催化剂优选Pd的存在下,与对位被卤素或O-三氟甲基磺酸根(O-triflate,-O-S(O)2CF3)取代的三氟甲基苯进行偶联而制备。为了优化偶联,该偶联反应在配体(优选膦配体)和碱的存在下进行。优选的膦配体是二烷基膦基联苯配体,优选的是选自2-二环己基膦基-2′-(N,N-二甲基氨基)联苯和2-二环己基膦基-2′-甲基联苯。该反应优选在约60℃至约110℃进行。式II的手性异构体可以按照方案A,用本领域技术人员已知的方法从(R)-2-氨基-1-丁醇(CAS#005856-633)制备,如以下实验方法的实施例9所述。
式IV化合物是式III化合物的腈通过水解而制备的。该水解可在酸性或碱性条件下进行。优选的水解方法是在酸性条件下进行,优选使用硫酸和水。对于用碱水解而言,优选的碱是羟基碱,优选氢氧化锂、氢氧化钠和氢氧化钾,或者烷氧基碱,优选甲醇盐和乙醇盐。同样,对于用碱水解而言,优选的是使用过氧化物。该水解反应优选地在约20℃至约40℃进行。
式VI化合物是通过式IV化合物的酰胺与式V的氯甲酸酯在碱优选叔丁醇锂存在下进行反应而制备的。该反应优选的是在约0℃至约35℃的温度下进行。如果需要式VI化合物中的R是甲基,则将氯甲酸甲酯用作式V化合物。如果需要式VI化合物中的R是苄基,则用氯甲酸苄酯。
式VII化合物的制备是通过将式VI化合物的亚酰胺与还原剂,优选硼氢化钠,在路易斯酸活化剂优选钙或镁离子的存在下,进行反应生成还原的中间体。生成还原的中间体的该反应优选在约-20℃至约20℃进行。在酸性条件下,该中间体进行非对映选择性地环化形成式VII的四氢喹啉环。该环化步骤优选在约20℃至约50℃进行。
式IA的CETP抑制剂的制备是用氯甲酸乙酯对式VII化合物(R为甲基)上的四氢喹啉的氮,在碱优选吡啶的存在下进行酰化,生成式VIIIA化合物。该反应优选在约0℃至约25℃进行。
式IA的CETP抑制剂是通过在碱(优选烷氧化物,更优选氢氧化物)的存在下,用3,5-双(三氟甲基)苄基卤化物,优选3,5-双(三氟甲基)苄基溴化物烷化R为甲基的式VII化合物而进行制备。该反应优选在约25℃至约75℃的温度范围进行。
式IB的CETP抑制剂的制备是将R为苄基或取代的苄基的式VII化合物的四氢喹啉的氮,在碱优选吡啶的存在下,用氯甲酸异丙酯进行酰化生成式VIIIB化合物。该反应优选在约0℃至约25℃进行。
然后从式VIIIB化合物制备式IB的CETP抑制剂,首先用过量的氢源(如环己烯、氢气或甲酸铵)在适当的催化剂存在下,在极性溶剂(如乙醇)中对式VIIIB化合物进行处理除去苄氧基羰基。式IB中的3,5-双-三氟甲基苄基基团则可以通过用3,5-双-三氟甲基-苯甲醛与胺和酸如乙酸进行处理,接着用氢化物如三乙酰氧基硼氢化钠处理而引入。然后,用本领域技术人员已知的方法将氨基酰化生成式IB化合物。从式VIIIB化合物制备式IB化合物的方法在共同转让的US6,140,343中也有说明。US6,140,343的公开在此引用作为参考。
实验方法
熔点是用Buchi熔点测量仪测定。NMR谱在Varian Unity 400(Varian Co.,Palo Alto,CA)上记录。化学位移从溶剂的低磁场以ppm表示。峰型以如下符号表示:s=单峰;d=双重峰;t=三重峰;q=四重峰;m=多重峰;bs=宽单峰。
实施例1
(3R)-3-(4-三氟甲基-苯氨基)-戊腈
在一个清洁、干燥充氮气的100L玻璃罐中装入(R)-3-氨基戊腈甲磺酸盐(3000g,15.44mol)、碳酸钠(2.8kg,26.4mol)和二氯甲烷(21L)。将该非均相混合物充分搅拌至少2小时。将混合物过滤,滤液用二氯甲烷(3×2L)淋洗。将所得的滤出物放在一个清洁、干燥并充氮气的50L玻璃反应罐中。蒸馏除去二氯甲烷直至内部温度达到50-53℃,得到游离碱胺,为一种稀薄的油。然后将罐冷却到室温并加入甲苯(20L)、氯代-4-(三氟甲基)苯(4200g,23.26mol)和碳酸铯(7500g,23.02mol)。将该溶液用氮气充气1小时。充气接近完毕时,通过将2-二环己基膦基-2’-(N,N-二甲基氨基)联苯(68g,0.17mol)、苯基硼酸(28g,0.23g)和四氢呋喃(1.2L)装入一个配有搅拌捧并用氮气冲气的2L圆底烧瓶中,接着装入乙酸钯(26g,0.12mol),制成新鲜的催化剂溶液。在室温和氮气氛下将该催化剂溶液搅拌15分钟。将该溶液加到50L用套管(排空气)的反应罐中。将该混合物在氮气氛下内部温度为79℃加热16小时。反应溶液冷却到室温并经Celite过滤。固体用甲苯(3×2L)洗涤并收集滤液。合并所有的滤液,得到粗的标题化合物溶液。
实施例2
(3R)-3-(4-三氟甲基-苯氨基)-戊酸酰胺
将硫酸水溶液(8.2L硫酸和1.1L水预混并冷却到35℃或更低)加到实施例1的(3R)-3-(4-三氟甲基-苯氨基)-戊腈的粗制甲苯溶液中。将所得的二层溶液充分搅拌并在35℃加热17小时。收集下层的水层并用氢氧化钠水溶液(95L水和10.7kg氢氧化钠)和二异丙醚(IPE)(40L)中止。萃取和除去水层后,将有机层合并并用饱和NaHCO3水溶液(10L)萃取。将所得双层中的有机相蒸馏浓缩至19L体积。然后将该溶液冷却到室温并放入(3R)-3-(4-三氟甲基-苯氨基)-戊酸酰胺晶种,在搅拌下让其粒化3小时。向非均相的混合物中加入环己烷(38L),并使该混合物再粒化11小时。滤出固体,用环己烷(4L)洗涤,在40℃真空干燥得到3021g(75%)标题化合物。
1HNMR(400MHz,CDCl3):0.98(t,3,J=7.5),1.60-1.76(m,2),2.45(d,2,J=5.8),3.73-3.80(m,1),5.53(br s,1),5.63(brs,1),6.65(d,2,J=8.7),7.39(d,2,J=8.7)13CNMR(100MHz,CDCl3):10.74,27.80,40.02,51.95,112.63,118.9(q,J=32.7),125.18(q,J=271.0),126.93(q,J=3.8),150.17,174.26
实施例3
(3R)-[3-(4-三氟甲基-苯氨基)-戊酰基]-氨基甲酸甲酯
在一个清洁、干燥充氮气的100L玻璃罐中,装入(3R)-3-(4-三氟甲基-苯氨基)-戊酸酰胺(6094g,23.42mol)、异丙醚(30L)和氯甲酸甲酯(2.7kg,29mol)。将所得的浆料冷却到2℃。然后在该反应罐中装入叔丁醇锂溶液(18-20%的THF溶液,24.6kg,约58mol),其装料速度要使内部温度维持在10℃以下,优选约5℃。加碱完成后10分钟,加1.5M盐酸(36L)使反应骤停。除去水层,有机层用饱和NaCl/水溶液(10L)萃取。除去水层,有机相在真空和约50℃下蒸馏浓缩直至体积减少到约24L。在反应釜中加环己烷(48L),并在釜内温度约45-50℃下再真空蒸馏直至釜中溶液体积减少至24L。在该反应釜中加第二份环己烷(48L),再重复在釜内温度约45-50℃下再真空蒸馏直至釜中溶液体积减少至24L。将温度保持在50℃时种入(3R)-[3-(4-三氟甲基-苯氨基)-戊酰基]-氨基甲酸甲酯晶种,并搅拌2小时形成晶粒。然后将溶液缓慢冷却(1.5小时)到室温,搅拌15小时使其成粒。将该混合物过滤。所得固体用环己烷(10L)洗涤,在40℃真空干燥得到7504g(94%)标题化合物。
m.p.=142.3-142.4℃
1HNMR(400MHz,d6-丙酮):0.96(t,3,J=7.4),1.55-1.75(m,2),2.86(dd,1,J=6.6,16.2),2.96(dd,1,J=6.2,16.2),3.69(s,3),3.92-3.99(m,1),5.49(br d,1,J=8.7),6.76(d,2,J=8.7),7.37(d,2,J=8.7),9.42(br s,1)。
13CNMR(100MHz,CDCl3):10.62,28.10,40.19,51.45,53.42,112.54,118.98(q,J=32.70),125.16(q,J=270.2),126.90(q,J=3.8),150.10,152.71,173.40。
实施例4
(2R,4S)-(2-乙基-6-三氟甲基-1,2,3,4-四氢-喹啉-4-基)-氨基甲酸甲酯
在一个清洁、干燥充氮气的100L玻璃罐中,装入(3R)-[3-(4-三氟甲基-苯氨基)-戊酰基]-氨基甲酸甲酯(7474g),接着加2B乙醇(46L)和水(2.35L)。将硼氢化钠(620g)一次地加到上述溶液中。不断充氮气。在室温下搅拌混合物20分钟,然后将其冷却到-10℃。加入3.3M氯化镁水溶液(4.68kgMgCl2·6H2O溶于7L水中),加入的速度要保持内部温度不超过-5℃。一旦加完后,将反应溶液温热到0℃持续45分钟。将反应混合物转移到一个200L装有二氯甲烷(70L)和1M盐酸/柠檬酸溶液(5.8L浓盐酸,64L水,和10.5kg柠檬酸)的罐中中止反应。罐的上面空间充氮气。在室温下搅拌该双层2小时。分离各相,转移下层有机产物。除去水层后,将有机相返回到反应釜中并用柠檬酸水溶液(6.3kg柠檬酸,34L水)萃取。将该混合物搅拌1小时,放置过夜。分层并在有机相中加Darco活性炭(G-60级,700g,Atlas PowderCo.,Wilmington,DE)并搅拌溶液30分钟。然后通过Celite过滤混合物,并用二氯甲烷(14L和8L)洗涤二次。蒸馏滤液同时周期性地加入己烷,从而用己烷替换二氯甲烷至最后的总体积为70L(己烷总用量为112L)。在替换过程中结晶出产物。一旦达到稳定的蒸馏温度后,将溶液冷却并在室温搅拌下粒化10小时。滤出固体,用己烷(14L)洗涤,在40℃真空干燥得到标题化合物(5291g)(80%)。
m.p.=139.0-140.5℃
1HNMR(400MHz,d6-丙酮):1.00(t,3,J=7.5),1.51-1.67(m,3),2.19(ddd,1,J=2.9,5.4,12.4),3.44-3.53(m,1),3.67(s,3),4.89-4.96(m,1),5.66(br s,1),6.56(br d,1,J=8.7),6.65(d,1,J=8.7),7.20(d,1,J=8.7),7.30(br s,1)。
13CNMR(100MHz,CDCl3):9.88,29.24,35.47,48.09,52.42,52.60,113.66,118.90(q,J=33.1),121.40,124.08(q,J=3.8),125.08(q,J=270.6),125.70(q,J=3.8),147.68,157.30。
实施例5
(2R,4S)-2-乙基-4-甲氧基羰基氨基-6-三氟甲基-3,4-二氢-2H喹啉-1-羧酸乙酯
在一个清洁、干燥充氮气的100L玻璃罐中,装入(2R,4S)-(2-乙基-6-三氟甲基-1,2,3,4-四氢-喹啉-4-基)-氨基甲酸甲酯(5191g,17.17mol)、二氯甲烷(21L)和吡啶(4.16L,51.4mol)。将反应釜冷却到-10℃。缓慢加氯甲酸乙酯(4.10L,42.9mol),加入速度要使釜内温度不超过-5℃。使反应溶液的温度到0℃并保持20小时。通过加入二异丙醚(IPE)(36L)、二氯甲烷(6.2L)和1.5M盐酸溶液(52L)使反应骤停。反应分层并用1M氢氧化钠溶液(15L)萃取有机层。反应分层并用饱和氯化钠NaCl水溶液(15L)洗涤有机层。分离所得的各相,有机层通过蒸馏浓缩至40L体积。低于该体积,开始出现结晶。通过蒸馏混合物并周期性地加IPE从而用IPE代替二氯甲烷,直到温度保持在68℃情况下体积仍恒定在40L(IPE共用46L)。冷却混合物并在室温搅拌下粒化19小时。过滤固体,用IPE(8L)洗涤,并在40℃真空干燥得到5668g标题化合物(88%)。
m.p.=157.3-157.6℃.
1H(400MHz,d6-丙酮):0.84(t,3,J=7.5),1.26(t,3,J=7.0),1.44-1.73(m,3),2.59(ddd,1,J=4.6,8.3,12.9),3.67(s,3),4.14-4.28(m,2),4.46-4.54(m,1),4.66-4.74(m,1),6.82(br d,1,J=9.1),7.53(s,1),7.58(d,1,J=8.3),7.69(d,1,J=8.3)。13CNMR(100MHz,CDCl3):9.93,14.55,28.46,38.08,46.92,52.64,53.70,62.42,120.83(q,J=3.4),124.32(q,J=271.7),124.36(q,J=3.4),126.38,126.46(q,J=32.7),134.68,139.65,154.66,156.85。
实施例6
(2R,4S)-4-[(3,5-双-三氟甲基-苄基)-甲氧基羰基-氨基]-2-乙基-6-
三氟甲基-3,4-二氢-2H-喹啉-1-羧酸乙酯
在一个清洁、干燥充氮气的100L玻璃罐中,在室温下装入(2R,4S)-2-乙基-4-甲氧基羰基氨基-6-三氟甲基-3,4-二氢-2H-喹啉-1-羧酸乙酯(5175g,13.82mol)、CH2Cl2(20L)和叔丁醇钾(1551g,13.82mol)。将混合物搅拌5分钟。向混合物中一次加入3,5-双(三氟甲基)苄基溴(3.50L,19.1mol)。将内部温度在20-25℃保持1.5小时。反应2.3小时后,另外加入叔丁醇钾(46.10g,0.41mol)。反应共进行4.5小时后将其停止。在反应溶液中加1,4-二氮杂双环[2,2,2]辛烷(DABCO)(918g,8.18mol),并将混合物搅拌1小时。在反应混合物中加入IPE(40L)和0.5M盐酸(30L)。分离所得的有机相和水相并将有机层用0.5M盐酸(2×30L)萃取。然后分离有机和水相,并用饱和氯化钠水溶液(15L)萃取有机相,再将所得的有机和水相分离。在有机层中加入无水硫酸镁(3.5kg)并将混合物搅拌30分钟。然后将该混合物过滤(0.5微米滤器)到一个50L玻璃罐中,用IPE洗(8L)二次。在内部温度35℃下真空浓缩滤液至12L体积,得到油状物。在该油中加入2B乙醇(25L),并将溶液在真空下浓缩至体积为12L。再在该溶液中加入2B乙醇(15L),在真空下浓缩至体积为12L。将溶液冷却至室温,并种下(2R,4S)-4[(3,5-双-三氟甲基-苄基)-甲氧基羰基-氨基]-2-乙基-6-三氟甲基-3,4-二氢-2H-喹啉-1-羧酸乙酯(3g)晶种。溶液粒化约38小时,过滤,并用2B乙醇(4L+2L)洗涤。真空干燥(不加热)得到4610g(55%)标题化合物。真空浓缩上述过滤中的母液(溶液温度62℃)至终体积6L,并冷却至38℃。在溶液中种下(2R,4S)-4[(3,5-双-三氟甲基-苄基)-甲氧基羰基-氨基]-2-乙基-6-三氟甲基-3,4-二氢-2H-喹啉-1-羧酸乙酯(0.5g)晶种,将其冷却并搅拌粒化19小时。将混合物过滤,将该固体用2B乙醇(2.5L)洗涤。所得滤饼真空干燥(不加热),得到1422g(17%)的第二批标题化合物。合并共收6032g(73%)。
实施例7
(3R)-[3-(4-三氟甲基-苯氨基)-戊酰基]-氨基甲酸苄酯
在一个清洁、干燥充氮气的烧瓶中,装入(3R)-3-(4-三氟甲基-苯氨基)-戊酸酰胺(20.11g,77.27mmol)和异丙醚(100mL),并将混合物冷却到-12℃。然后加氯甲酸苄酯(13.25mL,92.8mmol),接着缓慢加1.0M叔丁醇锂的THF溶液(185.5mL)。叔丁醇锂THF溶液加入速度要使内部温度保持在0℃以下。加完碱后15分钟,通过加入异丙醚(100mL)和1.5M盐酸(130mL)的混合物使反应骤停。分离各相,有机层用饱和氯化钠水溶液(130mL)洗涤。再分离各相并将有机层干燥(MgSO4)、过滤、并在部分真空下(40℃)浓缩至总体积为100mL。再加入异丙醚(200mL)并再将该溶液在部分真空下(40℃)浓缩至总体积为100mL。冷却后,在溶液中种下(3R)-[3-(4-三氟甲基-苯氨基)-戊酰基]-氨基甲酸苄基酯晶种,并将其在室温下搅拌过夜。剩余溶剂通过部分真空蒸馏(45℃浴温,200mL后再加100mL)用环己烷替换。将所得的浆液冷却并搅拌40分钟,过滤并干燥,得到25.8714g(85%)标题化合物。
m.p.100.6-101.4℃.
1HNMR(400MHz d6-丙酮):0.96(t,3,J=7.5),1.57-1.75(m,2),2.87(dd,1,J=6.6,16.2),2.97(dd,1,J=6.2,16.2),3.94-4.00(m,1),5.16(s,2),5.50(br s,1),6.75(d,2,J=5.7),7.33-7.43(m,7),9.52(br s,1)。
13CNMR(100MHz CDCl3):10.66,28.13,40.28,51.47,68.25,112.52,118.91(q,J=32.3),125.21(q,J=269.9),126.92(q,J=3.8),128.64,128.98,129.04,135.05,150.12,152.12,173.52。
实施例8
(2R,4S)-(2-乙基-6-三氟甲基-1,2,3,4-四氢-喹啉-4-基)-氨基甲酸苄酯
在一个清洁、干燥充氮气的烧瓶中,装入(3R)-[3-(4-三氟甲基-苯氨基)-戊酰基]-氨基甲酸苄酯(11.51g,29.18mmol)和95%乙醇(80mL),并将溶液在冰/丙酮浴(约-12℃)中冷却。然后将硼氢化钠(0.773g,20.4mmol)加到溶液中。反应内部温度为-11.5℃。向反应瓶中缓慢加MgCl2·6H2O(6.23g,30.6mmol,溶解在13mL水中)的溶液。调节加入速度使内部温度保持在-5℃以下。全部加入后,将溶液温度升高到0℃并搅拌30分钟。然后通过加二氯甲烷(115mL)、1N盐酸(115mL)和柠檬酸(14.02g,72.97mmol)骤停反应。在室温下搅拌该分层溶液。3.75小时后,反应经HPLC分析观察到环化反应已经完成,并分层。向有机层中加水(58mL)和柠檬酸(8.41g,43.77mmol),并将混合物在室温下搅拌45分钟。分离各相并在有机层中加g-60 Darco活性炭(1.52g)(Atlas PowderCo.,Wilmington,DE)。搅拌45分钟后,溶液经Celite过滤并用二氯甲烷(2×15mL)洗涤。然后经大气压下蒸馏浓缩,用己烷(约350mL)置换滤液至总体积为230mL。在室温下搅拌该混合物14小时,过滤,并干燥,得到9.0872g(82%)标题化合物。
m.p.154.0-155.2℃
1HNMR(400MHz,d6-丙酮):1.00(t,3,J=7.5),1.51-1.69(m,3),2.17-2.26(m,1),3.46-3.54(m,1),4.96(ddd,1,J=5.4,9.5,11.6),5.14(d,1,J=12.9),5.20(d,1,J=12.9),5.66(br s,1),6.65(d,1,J=8.3),6.71(br d,1,J=9.1),7.20(dd,1,J=1.9,8.9),7.30-7.43(m,6)。
13CNMR(100MHz,CDCl3):9.89,29.24,35.34,48.16,52.44,67.27,113.70,118.85(q,J=32.7),121.37,124.12(q,J=3.8),125.14(q,J=270.6),125.72(q,J=3.8),128.38,128.51,128.86,136.57,147.71,156.74。
实施例9
(R)-3-氨基戊腈甲磺酸盐
步骤1:甲磺酸2-叔丁氧基羰基氨基-丁酯
批次#1:将BOC酸酐(515.9g)的乙酸乙酯溶液(400mL),通过加液漏斗加到R-(-)-2-氨基-1-丁醇(200.66g)的乙酸乙酯溶液(1105mL)中。将该反应混合物搅拌约30分钟。加入四甲基乙二胺(TMEDA)(360mL),并将反应混合物冷却到大约10℃。用30分钟向该反应混合物加入甲磺酰氯(184.7mL)。搅拌1小时后将反应混合物过滤,收集滤液。
批次#2:将BOC酸酐(514.5g)的乙酸乙酯溶液(400mL),通过加液漏斗加到R-(-)-2-氨基-1-丁醇(200.12g)的乙酸乙酯中溶液(1101mL)中。将该反应混合物搅拌约30分钟。加入四甲基乙二胺(TMEDA)(359.1mL),并将反应混合物冷却到大约10℃。用30分钟向该反应混合物中加入甲磺酰氯(184.1mL)。搅拌1小时后将该反应混合物与批次#1的滤液合并并过滤。将固体用400mL乙酸乙酯洗涤。在滤液中加入己烷(12L)。将混合物在冰/水浴中冷却。约2.5小时后过滤分离固体,用己烷(2L)洗涤并在真空下干燥得到标题化合物(971.57g)。
步骤2:(1-氰甲基-丙基)-氨基甲酸叔丁酯
将氰化钠(24.05g)加到二甲基甲酰胺(DMF)(500L)中,并将该混合物在35℃搅拌30分钟。加入四丁基溴化铵并将该反应混合物在此35℃搅拌2小时。加入甲磺酸2-叔丁氧基羰基氨基-丁酯(101.23g)并将该反应混合物在35℃搅拌过夜。然后该混合物在2升水与1升异丙醚之间分配。将所有机相和水相分离,并依次用水和用氯化钠饱和水溶液洗涤。有机层经硫酸镁干燥,过滤并浓缩得到固体(65.22g)。将(61.6g)固体转移到顶部装有搅拌器的一个烧瓶中。加入己烷并将该烧瓶加热到65℃。所有固体均溶解后,将该混合物冷却到环境温度。将该混合物搅拌过夜。过滤分离出所得固体,得到标题化合物(52.32g)。
步骤3:(R)-3-氨基戊腈甲磺酸盐
向(1-氰甲基-丙基)-氨基甲酸叔丁酯的四氢呋喃(530mL)溶液中,加入甲磺酸(71g)。将反应混合物40℃加热约30分钟。将温度升到45℃并搅拌约1小时。再将温度升到65℃,并搅拌该反应混合物约5小时。使混合物冷却到环境温度。过滤分离所得固体,得到标题化合物(41.53g)。
Claims (15)
3.式VI化合物,
其中R选自甲基、苄基和取代的苄基。
5.权利要求3或4的化合物,其中R选自甲基、苄基和被一个或多个取代基取代的苄基,取代基各自独立地选自(C1-C3)烷基、(C1-C3)烷氧基和卤素。
7.权利要求6的方法,其中所述的三氟甲基苯化合物在膦配体的存在下与式II化合物进行偶联。
8.权利要求7的方法,其中所述的膦配体是二烷基膦基联苯配体。
9.权利要求8的方法,其中所述的膦配体选自2-二环己基膦基-2′-(N,N-二甲基氨基)联苯和2-二环己基膦基-2′-甲基联苯。
10.权利要求6的方法,其中所述的偶联包括将所述的三氟甲基苯化合物在碱存在下与式II化合物进行偶联。
11.式IV化合物的制备方法,
包括用水解剂水解式III化合物,
水解剂选自酸和碱,从而生成式IV化合物。
13.权利要求12的方法,其中所述的碱是叔丁醇锂。
15.权利要求14的化合物,其中所述的还原剂是在路易斯酸存在下的硼氢化钠。
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CNB028091442A Expired - Fee Related CN1297541C (zh) | 2001-04-30 | 2002-04-08 | 制备胆固醇酯转运蛋白抑制剂的方法 |
CNB028091663A Expired - Fee Related CN1267411C (zh) | 2001-04-30 | 2002-04-08 | 用作4-氨基喹啉衍生物中间体的化合物 |
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CNB028091663A Expired - Fee Related CN1267411C (zh) | 2001-04-30 | 2002-04-08 | 用作4-氨基喹啉衍生物中间体的化合物 |
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US (3) | US6600045B2 (zh) |
EP (2) | EP1425270B1 (zh) |
JP (2) | JP3924251B2 (zh) |
KR (2) | KR100591998B1 (zh) |
CN (3) | CN100357265C (zh) |
AR (3) | AR036331A1 (zh) |
AT (2) | ATE321755T1 (zh) |
AU (1) | AU2002253448B2 (zh) |
BR (2) | BR0209291A (zh) |
CA (2) | CA2445623A1 (zh) |
CZ (2) | CZ20032900A3 (zh) |
DE (2) | DE60210265T2 (zh) |
DK (2) | DK1425270T3 (zh) |
ES (2) | ES2256461T3 (zh) |
HK (1) | HK1062294A1 (zh) |
HU (2) | HU225777B1 (zh) |
IL (2) | IL157544A0 (zh) |
MX (2) | MXPA03009936A (zh) |
PL (2) | PL366700A1 (zh) |
PT (1) | PT1425270E (zh) |
RU (2) | RU2259355C2 (zh) |
TW (1) | TWI250974B (zh) |
WO (2) | WO2002088085A2 (zh) |
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DE102004031656A1 (de) * | 2004-06-30 | 2006-01-19 | Merck Patent Gmbh | Tetrahydrochinoline |
WO2006069162A1 (en) * | 2004-12-20 | 2006-06-29 | Reddy Us Therapeutics, Inc. | Novel heterocyclic compounds and their pharmaceutical compositions |
UA90706C2 (ru) | 2005-02-24 | 2010-05-25 | Милленниум Фармасьютикалз, Инк. | Антагонисты рецептора pgd2 для лечения воспалительных заболеваний |
BRPI0611838A2 (pt) * | 2005-06-20 | 2012-08-28 | Astrazeneca Ab | processo para a preparação de um composto |
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DE102006032391A1 (de) * | 2006-07-04 | 2008-01-17 | Merck Patent Gmbh | Fluortenside |
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AR065670A1 (es) | 2007-03-09 | 2009-06-24 | Indigene Pharmaceuticals Inc | Combinacion de metformina r-(+) lipoato y agentes antihiperlipidemicos para el tratamiento de hiperglucemia diabetica y complicaciones diabeticas |
JP2011256110A (ja) * | 2008-09-30 | 2011-12-22 | Takeda Chem Ind Ltd | ヘキサヒドロピロロキノリンの製造法 |
TWI450896B (zh) * | 2009-06-30 | 2014-09-01 | Lilly Co Eli | 反式-4-〔〔(5s)-5-〔〔〔3,5-雙(三氟甲基)苯基〕甲基〕(2-甲基-2h-四唑-5-基)胺基〕-2,3,4,5-四氫-7,9-二甲基-1h-1-苯并氮呯-1-基〕甲基〕-環己基羧酸 |
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CN105706289A (zh) * | 2013-11-11 | 2016-06-22 | 隆萨有限公司 | 利用路易斯酸制备第13族元素的氰基化合物的方法 |
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