WO2009093776A1 - Method for the preparation of atorvastatin and intermediates used therein - Google Patents
Method for the preparation of atorvastatin and intermediates used therein Download PDFInfo
- Publication number
- WO2009093776A1 WO2009093776A1 PCT/KR2008/002373 KR2008002373W WO2009093776A1 WO 2009093776 A1 WO2009093776 A1 WO 2009093776A1 KR 2008002373 W KR2008002373 W KR 2008002373W WO 2009093776 A1 WO2009093776 A1 WO 2009093776A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- phenyl
- formula
- compound
- carbon atoms
- oxygen
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 77
- 238000002360 preparation method Methods 0.000 title abstract description 76
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 title abstract description 22
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 title abstract description 22
- 229960005370 atorvastatin Drugs 0.000 title abstract description 22
- 239000000543 intermediate Substances 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims description 147
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 53
- 125000004432 carbon atom Chemical group C* 0.000 claims description 52
- 229910052760 oxygen Inorganic materials 0.000 claims description 52
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 45
- 239000001301 oxygen Substances 0.000 claims description 45
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 239000001257 hydrogen Substances 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- -1 methoxy, ethoxy Chemical group 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 27
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 20
- 229910052717 sulfur Inorganic materials 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 14
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 13
- 239000011593 sulfur Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052740 iodine Inorganic materials 0.000 claims description 8
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 8
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000006501 nitrophenyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 150000001340 alkali metals Chemical class 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- 125000005106 triarylsilyl group Chemical group 0.000 claims description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 69
- 238000005160 1H NMR spectroscopy Methods 0.000 description 56
- 238000006243 chemical reaction Methods 0.000 description 45
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 27
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 239000000203 mixture Substances 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 235000011121 sodium hydroxide Nutrition 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 239000004210 ether based solvent Substances 0.000 description 5
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000003849 aromatic solvent Substances 0.000 description 4
- 229960004132 diethyl ether Drugs 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000008096 xylene Substances 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 0 CC1C*CC1 Chemical compound CC1C*CC1 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229940000635 beta-alanine Drugs 0.000 description 3
- VSGNNIFQASZAOI-UHFFFAOYSA-L calcium acetate Chemical compound [Ca+2].CC([O-])=O.CC([O-])=O VSGNNIFQASZAOI-UHFFFAOYSA-L 0.000 description 3
- 239000001639 calcium acetate Substances 0.000 description 3
- 229960005147 calcium acetate Drugs 0.000 description 3
- 235000011092 calcium acetate Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 239000007810 chemical reaction solvent Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 2
- MPJZTKDCDOWZTJ-UHFFFAOYSA-N 6-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-4-phenylmethoxyoxan-2-one Chemical compound C1C(OCC=2C=CC=CC=2)CC(=O)OC1CCN1C(C(C)C)=CC(C=2C=CC=CC=2)=C1C1=CC=C(F)C=C1 MPJZTKDCDOWZTJ-UHFFFAOYSA-N 0.000 description 2
- DFGKGUXTPFWHIX-UHFFFAOYSA-N 6-[2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]acetyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)C1=CC2=C(NC(O2)=O)C=C1 DFGKGUXTPFWHIX-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 159000000007 calcium salts Chemical class 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 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
- 238000004440 column chromatography Methods 0.000 description 2
- 238000006114 decarboxylation reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- MWVFCEVNXHTDNF-UHFFFAOYSA-N hexanedione Natural products CCCC(=O)C(C)=O MWVFCEVNXHTDNF-UHFFFAOYSA-N 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- YKGLXIQPXNGEAY-UHFFFAOYSA-N methyl 2-benzylidene-4-methyl-3-oxopentanoate Chemical compound COC(=O)C(C(=O)C(C)C)=CC1=CC=CC=C1 YKGLXIQPXNGEAY-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 2
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- VVRPOCPLIUDBSA-CNZCJKERSA-M sodium;(3r,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoate Chemical compound [Na+].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 VVRPOCPLIUDBSA-CNZCJKERSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- ZGGHKIMDNBDHJB-NRFPMOEYSA-M (3R,5S)-fluvastatin sodium Chemical compound [Na+].C12=CC=CC=C2N(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O)=C1C1=CC=C(F)C=C1 ZGGHKIMDNBDHJB-NRFPMOEYSA-M 0.000 description 1
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- DRXSXLRHAVJPFZ-LOYHVIPDSA-N tert-butyl 2-[(2r,4r)-2-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-1,5-dioxaspiro[5.5]undecan-4-yl]acetate Chemical compound C([C@H]1OC2(CCCCC2)O[C@@H](CC(=O)OC(C)(C)C)C1)CN1C(C(C)C)=CC(C=2C=CC=CC=2)=C1C1=CC=C(F)C=C1 DRXSXLRHAVJPFZ-LOYHVIPDSA-N 0.000 description 1
- BCSHQPLDVLPKSH-FIRIVFDPSA-N tert-butyl 2-[(4r,6r)-2,2-ditert-butyl-6-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-1,3,2-dioxasilinan-4-yl]acetate Chemical compound C([C@H]1O[Si](O[C@@H](CC(=O)OC(C)(C)C)C1)(C(C)(C)C)C(C)(C)C)CN1C(C(C)C)=CC(C=2C=CC=CC=2)=C1C1=CC=C(F)C=C1 BCSHQPLDVLPKSH-FIRIVFDPSA-N 0.000 description 1
- HWSHVKNLMBMKSR-GHMZBOCLSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound CC(C)(C)OC(=O)C[C@H]1C[C@@H](CCN)OC(C)(C)O1 HWSHVKNLMBMKSR-GHMZBOCLSA-N 0.000 description 1
- ZTCXOUMUHOQUMW-HUUCEWRRSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2-(3-nitrophenyl)-1,3,2-dioxaborinan-4-yl]acetate Chemical compound O1[C@@H](CC(=O)OC(C)(C)C)C[C@@H](CCN)OB1C1=CC=CC([N+]([O-])=O)=C1 ZTCXOUMUHOQUMW-HUUCEWRRSA-N 0.000 description 1
- DUKXPCHOTMGQPU-HZPDHXFCSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2-(4-methoxyphenyl)-1,3,2-dioxaborinan-4-yl]acetate Chemical compound C1=CC(OC)=CC=C1B1O[C@@H](CC(=O)OC(C)(C)C)C[C@@H](CCN)O1 DUKXPCHOTMGQPU-HZPDHXFCSA-N 0.000 description 1
- KGBPIGPMMHZOOV-GHMZBOCLSA-N tert-butyl 2-[(4r,6r)-6-(2-aminoethyl)-2-ethyl-1,3,2-dioxaborinan-4-yl]acetate Chemical compound CCB1O[C@H](CCN)C[C@H](CC(=O)OC(C)(C)C)O1 KGBPIGPMMHZOOV-GHMZBOCLSA-N 0.000 description 1
- OULFWIYRQCCNNG-KAYWLYCHSA-N tert-butyl 2-[(4r,6r)-6-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate Chemical compound C([C@H]1OC(C)(C)O[C@@H](CC(=O)OC(C)(C)C)C1)CN1C(C(C)C)=CC(C=2C=CC=CC=2)=C1C1=CC=C(F)C=C1 OULFWIYRQCCNNG-KAYWLYCHSA-N 0.000 description 1
- VAUBPFVSXXRASB-FIRIVFDPSA-N tert-butyl 2-[(4r,6r)-6-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-2-(3-nitrophenyl)-1,3,2-dioxaborinan-4-yl]acetate Chemical compound C([C@H]1OB(O[C@@H](CC(=O)OC(C)(C)C)C1)C=1C=C(C=CC=1)[N+]([O-])=O)CN1C(C(C)C)=CC(C=2C=CC=CC=2)=C1C1=CC=C(F)C=C1 VAUBPFVSXXRASB-FIRIVFDPSA-N 0.000 description 1
- KFNAPXFHUVINIA-CLJLJLNGSA-N tert-butyl 2-[(4r,6r)-6-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-2-methoxy-1,3,2-dioxaborinan-4-yl]acetate Chemical compound C1[C@H](CC(=O)OC(C)(C)C)OB(OC)O[C@@H]1CCN1C(C=2C=CC(F)=CC=2)=C(C=2C=CC=CC=2)C=C1C(C)C KFNAPXFHUVINIA-CLJLJLNGSA-N 0.000 description 1
- BUPMQTZQXMAGGP-FIRIVFDPSA-N tert-butyl 2-[(4r,6r)-6-[2-[2-(4-fluorophenyl)-3-phenyl-5-propan-2-ylpyrrol-1-yl]ethyl]-2-phenyl-1,3,2-dioxaborinan-4-yl]acetate Chemical compound C([C@H]1OB(O[C@@H](CC(=O)OC(C)(C)C)C1)C=1C=CC=CC=1)CN1C(C(C)C)=CC(C=2C=CC=CC=2)=C1C1=CC=C(F)C=C1 BUPMQTZQXMAGGP-FIRIVFDPSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Definitions
- the present invention relates to a compound of formula 7a, which is a novel intermediate, and to a preparation method thereof.
- the reaction solvent is one or more selected from the group consisting of: halogen solvents, such as methylene chloride, chloroform, and carbon tetrachloride, aromatic solvents, such as toluene, benzene, nitrobenzene and xylene, and ether solvents, such as tetrahydrofuran, diethylether, dioxane and diisopropylether.
- halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride
- aromatic solvents such as toluene, benzene, nitrobenzene and xylene
- ether solvents such as tetrahydrofuran, diethylether, dioxane and diisopropylether.
- the solvent is preferably a halogen solvent or an aromatic solvent, and most preferably methylene chloride.
- the compound of formula 7a is a compound of the following formula 7b: [Formula 7b]
- the organic solvent that is used in the reaction is one or more selected from the group consisting of hydrocarbon solvents, such as hexane, cyclohexane or heptane, aromatic solvents, such as toluene, benzene or xylene, ether solvents, such as tetrahydrofuran, diethylether, dioxane or diisopropylether, alcoholic solvents, such as methanol, ethanol, propanol or butanol, and polar solvents, such as dimethylformamide or N,N-dimethylacetamide.
- the solvent is preferably an aromatic solvent, and most preferably toluene.
- the acid is pivalic acid, trifluoromethylsulfonic acid, methanesulfonic acid, p- toluenesulfonic acid or acetic acid, and preferably pivalic acid.
- the water removal agent may be molecular sieve, anhydrous magnesium sulfate or anhydrous sodium sulfate, and the water removal device may be a Dean-Stark trap. In the present invention, the Dean-Stark trap is preferably used to remove water.
- the reaction temperature is 50-110 ° C , preferably a reflux temperature suitable for the solvent, and more preferably 80- 100 ° C .
- reaction temperature is low or exceeds 110 ° C , the reaction does not occur or byproducts are produced, leading to a significant decrease in the yield of the reaction.
- the reaction time is about 1-48 hours, preferably 5-30 hours, and more preferably 10-20 hours.
- the compound of formula 6 may be used in 1-3 molar equivalents, and preferably 1-1.5 molar equivalents.
- the compound of formula 5 can be prepared by subjecting a compound of formula 2 to a Knoevenagel condensation reaction with benzaldehyde in a n-hexane solvent in the presence of beta- alanine and acetic acid using a Dean-Stark trap, to prepare a compound of formula 3, subjecting the compound of formula 3 to a Stetter reaction with 4-fluorobenzaldehyde in reflux conditions in an ethanol solvent in the presence of a thiazolmm catalyst to prepare a compound of formula 4, and subjecting the compound of formula 4 to decarboxylation in tetrahydrofuran in the presence of sodium hydroxide.
- reaction Scheme 5 benzaldehyde beta-alanine, acetic acid n-hexane, Dean-Stark trap
- Example 1 Preparation of methyl 4-methyl-3-oxo-2- (phenylmethylene)pentanoate 100 g of isobutylacetate was added to 1.5 L of hexane, and 6.2 g of beta-alanine,
- Example 2 Preparation of ( ⁇ )meth ⁇ l-2-(2-(4-fluorophenyl)-2-oxo-l- phenylethyl)-4-methyl-3-oxopentanoate of fR-(R* ,R*Y1. rR-(R ⁇ S*TI, rS-(R*.R*)l and rS-(R*.S*)l isomers
- Example 4-1 Preparation of t-butyl 2-(T4R.6R)-6-(2-r2-r4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-2-phenyl-l,3,2-dioxaborinan-4-yl)acetate
- Example 4-2 Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t- butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxane-4-yl)acetate.
- Example 4-3 Preparation of 2-(HR,6R)-6-(2-(2-(4-fluorophenyl')-5-isopropyl- 3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yDacetic acid
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid.
- Example 4-4 Preparation of ethyl 2-(r4R,6R)-6-(2-(2-r4-fluorophenvn-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and ethyl 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate.
- 1H-NMR 400 MHz, CDCl 3 ) ⁇ 1.02 - 1.29 (m, 10H), 1.41 - 1.49 (m, 6H), 1.59 -
- Example 4-5 Preparation of benzyl 2-((4R,6RV6-(2-(2-f4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1.3 -dioxan-4-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and benzyl 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate.
- Example 4-6 Preparation of 2-phenylpropan-2-yl 2-(Y4R,6R)-6-(2-(2-(4- fluorophenyl)-5-isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4- vDacetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and 2- phenylpropan-2-yl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate.
- Example 4-7 Preparation of t-butyl 2-(f4R.6R)-6-f2-(2-(4-fmorophenyl)-5- isoprop yl-3 -phenyl- 1 H-pyrrol- 1 -ypethvD-2-f 3 -nitrophenyl " )- 1 , 3 ,2-dioxaborinan-4- yPacetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-(3 -nitrophenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
- Example 4-8 Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl1ethylV2-(4-methoxyphenylV 1.3.2-dioxaborinan-4- yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl- 1,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-(4-methoxyphenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
- Example 4-9 Preparation of t-butyl 2-(f4R.6R1-2-ethyl-6-(2-(2-(4- fluorophenyl)-5 -isopro ⁇ yl-3-phenyl- 1 H-pyrrol- 1 -yliethylV 1.3.2-dioxaborinan-4- yl * )acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-ethyl- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
- Example 4-10 Preparation of t-butyl 2-f(4R.6RV6-(2-(2-(4-fluoro ⁇ henvn-5- isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2-(methylphosphateV 1 ,3-dioxan-4-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1 ,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-methylphosphate-l,3-dioxan-4-yl)acetate.
- Example 4-11 Preparation of l-(2-(4-(benzyloxy)-6-methoxytetrahydro-2H- pyran-2-yl)ethyl)-2-(4-fluorophenvD-5-isopropyl-3-phenyl-lH-pyrrole According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2-(4- (benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)ethanamine.
- Example 4-12 Preparation of 4-(benzyloxy)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)tetrahydro-2H-pyran-2-one
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 6-(2- aminoethyl)-4-(benzyloxy)tetrahydro-2H-pyran-2-one.
- Example 4-13 Preparation of t-butyl 2-(Y4R.6R)-2,2-di-t-butyl-6-(2-(2-(4- fluorophenyl)-5-isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yDethyl)- 1 ,3 ,2-dioxasilinan-4- vDacetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2,2-di-t-butyl-l,3,2-dioxasilinan-4-yl)acetate.
- 1H-NMR 400MHz, CDCl 3 ) ⁇ 0.99 (s, 18H), 1.29 -1.38 (m, 7H), 1.53 (s, 9H),
- Example 4-14 Preparation of t-butyl 2-((4R.6RV6-(2-(2-f4-fluorophenvn-5- isopropyl-3 -phenyl- 1 H-pyrrol- 1 -vDethyl)-2-(sulfite * )- 1 ,3 -dioxan-4-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-sulfite-l,3-dioxan-4-yl)acetate.
- 1H-NMR 400MHz, CDCl 3 ) ⁇ 1.29 -1.38 (m, 7H), 1.53 (s, 9H), 1.51 - 1.61 (m,
- Example 4-15 Preparation of ethyl 2-((2R.4R)-4-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yPethyl)- 1 ,5-dioxaspiror5.51undecan-2-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and ethyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
- Example 4-16 Preparation of t-butyl 2-f(2R,4R)-4-(2-r2-f4-fluorophenv ⁇ -5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethy ⁇ -l,5-dioxaspiror5.51undecan-2-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
- Example 4-17 Preparation of cyclohexyl 2-((2R,4R)-4-(2-(2-(4-fluoro ⁇ henyl)- 5-isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiror5.51undecan-2-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and cyclohexyl 2-((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
- Example 4-18 Preparation of phenyl 2-((2R.4R)-4-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiror5.51undecan-2-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and phenyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
- 1H-NMR 400 MHz, CDCl 3
- Example 4-19 Preparation of benzyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl ' )-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yDethyl)- 1 ,5-dioxaspiro[5.51undecan-2-yl)acetate
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and benzyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- phenylpropan-2-yl 2-((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2- yl)acetate.
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)-N,N-dimethylacetamide.
- Example 4-22 Preparation of N,N-dicvclohexyl-2-(f4R.6RV6-f2-(2-f4- fluorophenylVS -isopropyl-3-phenyl- 1 H-pyrrol- 1 - yl " )ethylV2,2-dimethyl- 1 ,3 -dioxan-4- vDacetamide
- the tiotle compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)-N,N-dicyclohexylacetamide.
- Example 4-23 Preparation of 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl- 3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-vD- 1 -(piperidin- 1 - ypethanone
- the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)- 1 -(piperidin- 1 -yl)ethanone.
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)-l-mo ⁇ holinoethanone.
- Example 4-1 the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-methoxy-l,3,2-dioxaborinan-4-yl)acetate.
- 1H-NMR 400 MHz, CDCl 3 ) ⁇ 1.30 - 1.35 (m, 7H), 1.49 (s, 9H), 1.54 - 1.63 (m,
- Example 4-26 Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-2-(chloro)-l,3-dioxaphosphorinan-4- yPacetate
- Example 4-1 the title compound was synthesized using 1 -(4- fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and t-butyl 2-
- Example 5-1 Preparation of t-butyl 2-(f4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3 - ⁇ henyl-4-(phenylcarbamo yl )- 1 H-pyrrol- 1 -yDethvD- ⁇ -phenyl- 1 ,3,2- dioxaborinan-4-yl)acetate
- 150 g of aluminum chloride and 1.5 L of methylene chloride were placed in a reactor in a nitrogen atmosphere and stirred.
- 121 ml of phenyl isocyanate was slowly added dropwise over 1 hour.
- the reaction temperature was lowered to a temperature between -50 ° C and -
- Example 5-2 The title compound as a light yellow solid was obtained in the same manner as in Example 5-1, except that zinc chloride was instead of aluminum chloride.
- Example 5-3 Preparation of t-butyl 2-((4R.6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3 -phenyl-4-(phenylcarbamothioyiy 1 H-pyrrol- 1 -yl * )ethyl)-2-phenyl- 1,3,2- dioxaborinan-4-yl)acetate
- Example 5-4 Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenylV5- isopropyl-3 -phenyl-4-(phenylcarbamoyl)- 1 H-pyrrol- 1 -yl)ethyl)-2-phenyl- 1.3,2- dioxaborinan-4-yl)acetate
- Example 5-5 Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbomyl)-lH-pyrrol-l-vDethyl)-2,2-dimethyl-l,3-dioxan- 4-yl)acetate
- Example 5-1 the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol-1 -yl)ethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate.
- Example 5-6 Preparation of 2-((4R.6R>6-(2-(2-(4-fluorot>henvl)-5-isopropyl- 3-phenyl-4-( " phenylcarbamoylVlH-pyrrol-l-yl)ethyl " )-2.2-dimethyl-l,3-dioxan-4- yPacetie acid
- Example 5-1 the title compound was synthesized using 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3 -phenyl- lH-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid.
- Example 5-7 Preparation of ethyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl ' )-5- isopropyl-3 -phenyl-4-(phen ⁇ lcarbamoyl * )- 1 H-pyrrol- 1 -yl)ethyl ' )-2,2-dimethyl- 1,3- dioxan-4-yl)acetate
- Example 5-1 the title compound was synthesized using ethyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate.
- 1H-NMR 400 MHz, DMSO-d 6 ) ⁇ 1.22 - 1.38 (m, 15H), 1.53 - 1.78 (m, 3H),
- Example 5-8 Preparation of benzyl 2-ff4R,6RV6-f2-(2-(4-fluorophenylV5- isopro ⁇ yl-3- ⁇ henyl-4-(phenyl carbamoyl)- 1 H-pyrrol- 1 -yl ' )ethyl s )-2,2-dimethyl- 1,3- dioxan-4-yl)acetate
- Example 5-1 the title compound was synthesized using benzyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate.
- Example 5-9 Preparation of 2-phenylprot>an-2-yl 2-ff4R,6R)-6-(2-(2-(4- fluorophenylV 5 -isopropyl-3 -phenyl-4-(phenylcarbamoyl> 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl- 1 ,3 -dioxan-4-yl)acetate
- the title compound was synthesized using 2-phenylpropan-2-yl 2-((4R,6R)-6-(2-(2-(4-fiuorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate.
- Example 5-10 Preparation of t-butyl 2-(f4R,6RV6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl)ethyl)-2-(3-nitrophenyl)-l,3,2- dioxaborinan-4-yl)acetate
- Example 5-1 the title compound was synthesized using t-butyl 2-((4R,6R)-2-ethyl-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3- phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2-(4-methoxyphenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
- Example 5-13 Preparation of t-butyl 2-fC4R.6RV6-r2-r2-r4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl)ethylV2-fmethylphosphate)- 1 ,3 ,2-dioxan-4-yl)acetate
- the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2-(methylphosphate)- 1 ,3 ,2-dioxan-4-yl)acetate.
- Example 5-16 Preparation of phenyl l-(2-((4R.6R)-6-(2-t-butoxy-2-oxoethyl)- 2,2-di-t-butyl-L3,2-dioxasilinan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenvl- 1 H-py ⁇ ol-3 -carboxylate
- Example 5-22 Preparation of benzyl 2-(T2R.4RV4-(2-(2-(4-fluorophenylV5- isopropyl-3 -phenyl-4-( ' phenylcarbamoylV 1 H-pyrrol- 1 - vDethylV 1,5- dioxaspiror5.51undecan-2-yl * )acetate
- the title compound was synthesized using benzyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
- Example 5-1 the title compound was synthesized using 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH-pyrrol- 1 -yl)etbyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)- 1 -(piperidin- 1 -yl)ethanone.
- 1H-NMR 400 MHz, DMSO-d 6 ) ⁇ 1.22 - 1.42 (m, 12H), 1.43 - 1.55(m, 7H),
- Example 5-27 Preparation of 5-(4-flt ⁇ orophenyl)-2-isopropyl-l-(2-((2R 1 4R)-4- (2-morpholino-2-oxoethyl)-L5-dioxaspiror5.51undecan-2-yl)ethyl)-N,4-diphenyl-lH- pyrrol-3-carboxamide.
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Abstract
The present invention relates to a novel method for preparing atorvastatin. According to the present invention, provided are a novel intermediate of the preparation of atorvastatin and a method of preparing large amounts of atorvastatin in a safe manner using the intermediate.
Description
METHOD FOR THE PREPARATION OF ATORVASTATIN AND INTERMEDIATES USED THEREIN
[Technical Field]
The present invention relates to a method for preparing atorvastatin. More specifically, the present invention relates to a novel intermediate for the preparation of atorvastatin and a method of preparing atorvastatin using the same.
[Background Art] Drugs, which show cholesterol lowering effects through a mechanism of inhibiting the activity of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG- CoA reductase), are generally called "statin". Among them, the first generation compounds, developed earliest, include simvastatin, lovastatin, pravastatin and the like, which Eire fermentation products, and the second generation compounds, which are synthetic drugs, include atorvastatin, fluvastatin, rosuvastatin, pitavastatin and the like.
Among them, atorvastatin is a very promising compound, which showed the highest growth rate during the recent three years and had a market size of 13.2 billion dollars in the year 2006. Also, the annual average growth rate was more than 20%.
International Patent Publication No. WO 89/07598, assigned to Warner- Lambert Company commercially producing atorvastatin, discloses a process for the preparation of atorvastatin. In this patent, as can be seen in the following reaction scheme (1), a 1,4-dione compound represented by formula A is allowed to react with a chiral intermediate represented by formula B, to obtain a compound represented by formula C, which is then converted to atorvastatin: [Reaction Scheme 1]
atorvastatin
In the reaction scheme 1 , the first reaction comprises refluxing the compound of formula A and the compound of formula B in a hydrocarbon solvent, such as toluene, cyclohexane or a mixture thereof, and allowing the resulting compound of formula C into contact with aqueous acid solution such as aqueous hydrochloric acid solution.
However, the preparation process according to the reaction scheme 1 has problems in that the reaction time in the first reaction is very long (about 100 hours), leading to an increase in side reactions, and the total yield of the product is as very low as about 15%, because it is not easy to remove produced byproducts.
International Patent Publication No. WO 02/057274 discloses a process for preparing atorvastatin, in which, as shown in the following reaction scheme 2, a compound of formula (A) and a compound of formula (D) are allowed to reflux and condensate by using acetic acid in a xylene solvent to prepare a compound of formula (E), which is then hydrolyzed, thus preparing atorvastatin. [Reaction Scheme 2]
However, in the preparation process according to the reaction scheme 2, the reaction time is very long (about 44 hours) and, in addition, intensive reaction
conditions are required, because the reaction must be carried out at high temperature (not less than 110 "C) using xylene, having a high boiling point, as a reaction solvent. Also, it is difficult to remove the remaining solvent, the toxicity of the solvent itself can cause a serious problem in terms of the safety of workers, and thus it is unsuitable to apply the preparation process in actual industrial fields. In addition, there are problems in that the production of byproducts increases due to a very long reaction time and that it is not easy to remove byproducts.
International Patent Publication No. WO 04/106299 discloses a process for preparing atorvastatin, in which, as shown in the following reaction scheme 3, a compound of formula F and a compound of formula B are allowed to reflux and condensate by using pivalic acid in a mixed solvent of heptane, toluene and tetrahydrofuran. [Reaction Scheme 3]
pivalic acid heptane/toluene/ tetrahydrofuran
F B However, in the preparation process according to the reaction scheme 3, the reaction time is very long (22-25 hours), a high reaction temperature is required, leading to an increase in side reactions, and a separation and purification process is carried out using column chromatography in order to remove produced byproducts, leading to a decrease in the yield of the reaction. Thus, it is not suitable to apply the preparation process in actual industrial fields.
International Patent Publication No. WO 05/012246 discloses a process for preparing atorvastatin, in which, as shown in the following reaction scheme 4, a compound of formula H and a compound of formula I are allowed to reflux in a tetrahydrofuran solvent, and the reaction product is separated and purified using column chromatography:
[Reaction Scheme 4]
Unlike the 1 ,4-dione compound disclosed in International Patent Publication No. WO 89/07598, the 1,4-dione compound of formula H shown in the reaction scheme 4 has a structure very similar to a 1,4-dione compound, which is used in the present invention. However, similarly to the preparation process disclosed in International Patent Publication No. WO 89/07598, the preparation process according to the reaction scheme 4 is difficult to apply in actual industrial fields, because the reaction time is very long (about 2 days) and, in addition, the yield of the product is as very low as about 19%. Also, preparation processes, disclosed in US patent Nos. 4,647,576 and
4,681,893, have problems in that optically pure products cannot be produced and, even though the products can be separated into pure products, the separation and purification process is very expensive. In addition, there are problems in that the reaction time is long, and not less than 50% of the starting material is lost, leading to a decrease in the yield of the reaction.
The reason for the results (long reaction time and low yield) of the prior preparation processes as described above is that a substituent group (e.g., an amide or ester compound) is present at carbon location 3 of the reactant 1,4-dione compound (formula A, F or H), and thus, during the reaction, a structural arrangement resulting from the steric hindrance of carbon locations 2 and 3 in the molecule of the 1 ,4-dione compound inhibits a cyclization reaction with the chiral intermediate (formula B, D or I), resulting in a decrease in the total reaction yield (J. Med. Chem., 1991, 34, 357 ~ 366). [Disclosure of Invention] [Technical Problem]
The present inventors have conducted many studies to a method for preparing atorvastatin, which can overcome the above-described problems occurring in the prior art, and, as a result, have synthesized a novel intermediate (formula 7a) using a 1 ,4-
dione compound (formula 5), which contains no a substituent group at carbon location 3 and has a structural arrangement, which can be easily cyclized with a chiral intermediate, and have developed a method of preparing atorvastatin or a pharmaceutically acceptable salt thereof by using the intermediate in high efficiency and high yield, thereby completing the present invention. [Technical Solution]
The present invention relates to a novel method for preparing atorvastatin and provides a method for preparing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof, which comprises the steps of:
(1) reacting a compound of the following formula 7 with a compound of the following formula 8 to obtain a compound of the following formula 9, and
(2) deprotecting and hydrolyzing the compound of formula 9: [Formula 1]
[Formula 8]
OH, a straight or branched chain alkyl having 1-8 carbon atoms, phenyl or V_/ , wherein R6 is hydrogen, methyl, ethyl, tetrahydropyranyl, benzyl, trialkylsilyl or triarylsilyl, or Ri and R2 together form oxygen (=0) or -(CH2),,-, wherein n is 4 or 5, R3 is oxygen or sulfur, R4 Is Cl, Br, F, I, a straight or branched chain alkyl having 1-8 carbon atoms, phenyl, trityl, OH, an alkoxy having 1 -8 carbon atoms, or phenoxy, and R5 is oxygen (=O), a straight or branched chain alkyl having 1-8 carbon atoms, an alkoxy having 1-8 carbon atoms, an aryl or aryloxy, wherein an aryl or aryloxy is unsubstituted or substituted with an alkyl having 1-4 carbon atoms, an alkoxy having 1- 4 carbon atoms, nitro or halogen, or a Cό-Cio heteroaryl comprising one or two heteroatoms selected from a group consisting of N, O and S; and
Z is oxygen (=O),
, wherein R7 is hydrogen, methyl, ethyl or acetyl, or -
CH2COR8, wherein R8 is
, R9 is hydrogen, a
straight or branched chain alkyl having 1-8 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, phenyl, benzyl or α,α-dimethylbenzyl, and Rio and Rn are each independently hydrogen, a straight or branched chain alkyl having 1-8 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, benzyl or phenyl, or Rio and Rn together form -(CHz)4-, -(CH2)5-, -(CH(Ri2)CHz)3-, -(CH(R12)CHz)4-, -(CH(R12)(CHz)ZCH(R12))-, -(CH(R12)(CH2)SCH(Ri2))-, -CH2CH2-O-CH2CH2-, -CH(Ri2)CH2-O-CH2CH2- or - CH(RI2)CH2-O-CH2CH(RI2)-, wherein Ri2 is an alkyl having 1-4 carbon atoms, and A4 is oxygen or sulfur.
In another aspect, the present invention provides a method for preparing the compound of formula 7a by cyclocondensing a compound of the following formula 5 and a compound of the following formula 6: [Formula 7a]
[Formula 5]
[Formula 6]
wherein Ai and A2 are oxygen;
A3 is CH2;
Z is -CH2COR8, wherein R8 is
or , R9 is hydrogen, a straight or branched chain alkyl having 1-8 carbon atoms, a cycloalkyl group having 3- 6 carbon atoms, phenyl, benzyl or α,α-dimethylbenzyl, and Rio and Rn are each independently hydrogen, a straight or branched chain alkyl having 1-8 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, benzyl or phenyl, or Rio and Rn together form -(CHa)4-, -(CH2)5-, -(CH(Ri2)CHa)3-, -(CH(Ri2)CHa)4-, -(CH(RI2)(CH2)2CH(R12))-, -(CH(Ri2)(CHa)3CH(Ri2))-, -CH2CH2-O-CH2CH2-, -CH(Ri2)CH2-O-CH2CH2- or - CH(RI2)CH2-O-CH2CH(RI2)-, wherein Ri2 is an alkyl having 1 -4 carbon atoms. [Advantageous Effects]
According to the present invention, there is provided a method capable of producing a large amount of atorvastatin at high purity and high yield under mild reaction conditions. [Mode for Invention]
The present invention relates to a method of preparing a compound of formula 1 at high efficiency and high yield using a compound of formula 7 and a compound of
formula 8, which are key intermediates.
Also, the present invention relates to a compound of formula 7a, which is a novel intermediate, and to a preparation method thereof.
Specifically, the present invention relates to a method for preparing a compound of formula 1 or a pharmaceutically acceptable salt thereof, which comprises the steps of:
(1) reacting a compound of the following formula 7 with a compound of the following formula 8 to obtain a compound of the following formula 9, and
(2) deprotecting and hydrolyzing the compound of formula 9: [Formula 1]
[Formula 7]
[Formula 8]
Preferably, when Ai and A2 are oxygen; A3 is CH2; A4 is oxygen; W is
CH2CORg, wherein R8 is
or , R9 is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclohexyl, phenyl, benzyl or α,α-dimethylbenzyl, and Rio and Rn are each independently hydrogen, methyl, ethyl, t-butyl, isopropyl, cyclohexyl, benzyl or phenyl, or Ri0 and Rn together form -(CH2)4-, -(CH2)S-, - (CH(R12)CH2)S-, -(CH(R12)CHz)4-, -(CH(R12)(CH2)2CH(R12))-,
(CH(Ri2)(CHa)3CH(R12))-, -CH2CH2-O-CH2CH2-, -CH(Ri2)CH2-O-CH2CH2- or - CH(RI2)CH2-O-CH2CH(RI2)-, wherein Ri2 is an alkyl having 1-4 carbon atoms.
When Ai and A2 are CH2, A3 is oxygen; A4 is oxygen; W is C
wherein Ri is hydrogen, R2 is
, wherein R6 is hydrogen, benzyl, trimethylsilyl, t-butyldimethylsilyl or t-butyldiphenylsilyl; and Z is oxygen (=0) or
[Formula 9b]
More specifically, in the reaction step (1), the compound of formula 9 can be prepared by reacing the compound of formula 7 with the compound of formula 8 in the presence of a selected reaction solvent and a selected acid. In the step (1), the compound of formula 8 can be used in 1-10 molar
equivalents, preferably 1-8 molar equivalents, and most preferably 2-6 molar equivalents. The reaction solvent is one or more selected from the group consisting of: halogen solvents, such as methylene chloride, chloroform, and carbon tetrachloride, aromatic solvents, such as toluene, benzene, nitrobenzene and xylene, and ether solvents, such as tetrahydrofuran, diethylether, dioxane and diisopropylether. The solvent is preferably a halogen solvent or an aromatic solvent, and most preferably methylene chloride.
As a selected acid, Lewis acid, preferably aluminum chloride, zinc chloride, trifluoroborane, tribromoborane, titanium tetrachloride, iron chloride or tin tetrachloride, and most preferably aluminum chloride is used. Herein, aluminum chloride is used in 1-10 molar equivalents, preferably 1-8 molar equivalents, and more preferably 2-6 molar equivalents. The reaction temperature is in the range from -78 °C to room temperature, preferably from -78 °C to 0 °C , and most preferably from -78 °C to - 40 °C . The reaction time is between 10 minutes and 48 hours, and preferably between 10 minutes and 8 hours.
Meanwhile, in case that A4 in the compound of formula 8 is sulfur, the compound of formula 9 can be prepared by carrying out the reaction between peroxide, such as m-chloroperoxybenzoic acid (m-CPBA) and hydrogen peroxide (H2O2) and the compound of formula 8, in a solvent selected from the group consisting of halogen solvents, such as methylene chloride and chloroform, alcoholic solvents, such as methanol and ethanol, and ether solvents, such as dioxane and tetrahydrofuran.
The reaction step (2) of synthesizing the compound of formula 1 by deprotecting and hydrolyzing the obtained compound of formula 9 can be carried out according to any method known in the art (see WO 02/057274), and the compound of formula 1 can be converted to a pharmaceutically acceptable salt thereof through a salt formation step.
Pharmaceutically acceptable salts include organic salts and inorganic salts. Preferred examples of organic salts include, but are not limited to, morpholine, piperazine, trimethylamine, triethylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibenzylamine, dicyclohexylamine, lysine, ornitine, threonine, arginine, metformin, N-benzyl-2-phenylethanamine, 2-amino-2-methyl-l-propanol, 1-
phenylethanamine, 1 ,2-ethanediamine, ammonia, 2-methyl-2-propanamine, phenethylamine and 2-(3,4-dimethoxyphenyl)ethanamine, and preferred examples of inorganic salts include, but are not limited to, alkali metals, such as lithium, sodium, potassium and cesium, alkaline earth metals, such as magnesium and calcium, aluminum, bismuth and iron.
The deprotection and/or hydrolysis reaction may be carried out by using alkali metal, preferably lithium hydroxide, sodium hydroxide, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or potassium hydroxide, and most preferably sodium hydroxide. Herein, sodium hydroxide can be used in 1-10 molar equivalents, preferably 3-7 molar equivalents, and most preferably 4-5 molar equivalents. The reaction temperature is 0-100 °C, and preferably 0-50 °C , and the reaction time is about 1 -6 hours, and preferably about 2-4 hours.
A solvent, which is used in the reaction of step (2), is one or more selected from the group consisting of, for example, alcoholic solvents, such as methanol, ethanol, propanol or butanol, ether solvents, such as tetrahydrofuran, diethylether, dioxane or diisopropylether, and water. Preferably, a mixture of an ether solvent and water is used, and more preferably, a mixture of tetrahydrofuran and water is used.
The hydrolysis reaction may be carried out at the same time as the deprotection reaction, and a calcium salt formation reaction may be carried out without a separate purification process.
After the above-described deprotection and hydrolysis reactions conducted by using sodium hydroxide, a compound in the form of sodium salt is collected, and may then be prepared into atorvastatin hemicalcium salt in a selected solvent by using any one selected from the group consisting of calcium carbonate, calcium hydroxide, calcium acetate, calcium sulfate and calcium chloride. The equivalent of calcium acetate for the formation of calcium salt is preferably 0.5 mole.
The solvent that is used in the salt formation reaction is one or more selected from the group consisting of, for example, alcoholic solvents, such as methanol, ethanol, propanol or butanol, ether solvents, such as tetrahydrofuran, diethylether, dioxane or diisopropylether, and water. The solvent is preferably is a mixture of an alcoholic solvent and water, and more preferably a mixture of methanol and water.
The reaction temperature is 10-80 "C , and preferably 10-60 °C , and the
reaction temperature is about 1-6 hours, and preferably about 1-3 hours.
Also, the present invention relates to a compound of the following formula 7a, which is a novel intermediate, and a preparation method thereof: [Formula 7a]
Preferably, Ai and A2 are oxygen; A3 are CH2; W is
,
difluorophenyl or quinolinyl; and Z is -CH2CORs, wherein R8 is π V-/ or
Most preferably, the compound of formula 7a is a compound of the following formula 7b: [Formula 7b]
In the present invention, the compound of formula 7a can be prepared by cyclocondensing a compound of the following formula 5 and a compound of the following formula 6. [Formula 7a]
[Formula 5]
[Formula 6]
wherein A1, A2, A3, W and Z are as defined above.
In the preparation method, the condensation of the compound of formula 5 with the compound of formula 6 is carried out in a selected organic solvent in the presence of acid to prepare the compound of formula 7a, and a water removal agent or a water removal device may be used to remove water during the reaction.
The organic solvent that is used in the reaction is one or more selected from the group consisting of hydrocarbon solvents, such as hexane, cyclohexane or heptane, aromatic solvents, such as toluene, benzene or xylene, ether solvents, such as tetrahydrofuran, diethylether, dioxane or diisopropylether, alcoholic solvents, such as methanol, ethanol, propanol or butanol, and polar solvents, such as dimethylformamide or N,N-dimethylacetamide. The solvent is preferably an aromatic solvent, and most preferably toluene.
The acid is pivalic acid, trifluoromethylsulfonic acid, methanesulfonic acid, p- toluenesulfonic acid or acetic acid, and preferably pivalic acid. The water removal agent may be molecular sieve, anhydrous magnesium sulfate or anhydrous sodium sulfate, and the water removal device may be a Dean-Stark trap. In the present invention, the Dean-Stark trap is preferably used to remove water.
In the cyclocondensation reaction, the reaction temperature is 50-110 °C , preferably a reflux temperature suitable for the solvent, and more preferably 80- 100 °C .
If the reaction temperature is low or exceeds 110 °C , the reaction does not occur or byproducts are produced, leading to a significant decrease in the yield of the reaction.
The reaction time is about 1-48 hours, preferably 5-30 hours, and more preferably 10-20 hours. Herein, the compound of formula 6 may be used in 1-3 molar equivalents, and preferably 1-1.5 molar equivalents.
In the preparation method of the present invention, the known compound of formula 5 can be obtained according to any method known in the art (see J. Med. Chem., 1991, 34, 357-366, and US Patent No. 5,003,081). Also, the known compound of formula 6 can be obtained according to the methods known in US Patent No. 5,003,081,
and International Publication Nos. WO 05/012246, WO 03/070733, WO 89/07598 and WO 94/20492.
For example, according to the following reaction scheme 5, the compound of formula 5 can be prepared by subjecting a compound of formula 2 to a Knoevenagel condensation reaction with benzaldehyde in a n-hexane solvent in the presence of beta- alanine and acetic acid using a Dean-Stark trap, to prepare a compound of formula 3, subjecting the compound of formula 3 to a Stetter reaction with 4-fluorobenzaldehyde in reflux conditions in an ethanol solvent in the presence of a thiazolmm catalyst to prepare a compound of formula 4, and subjecting the compound of formula 4 to decarboxylation in tetrahydrofuran in the presence of sodium hydroxide. [Reaction Scheme 5] benzaldehyde beta-alanine, acetic acid
n-hexane, Dean-Stark trap
Hereinafter, the present invention will be described in further detail with reference to examples, but the scope of the present invention is not limited by these examples.
Example 1: Preparation of methyl 4-methyl-3-oxo-2- (phenylmethylene)pentanoate 100 g of isobutylacetate was added to 1.5 L of hexane, and 6.2 g of beta-alanine,
63 ml of benzaldehyde and 22 ml of glacial acetic acid were added thereto with stirring in a nitrogen atmosphere. The resulting mixture was heated to reflux using a Dean- Stark trap for 20 hours to remove water. The reaction mixture was cooled to 20-25 °C
and washed with 1.5 L of IN hydrochloric acid solution and 1.5 L of 10% sodium bicarbonate aqueous solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, thus obtaining 144 g of a geometric isomer mixture of methyl 4-methyl-3-oxo-2- (phenylmethylene)pentanoate as yellow oil.
1H-NMR (400 MHz, CDCl3) δ geometric isomer (isomer 1, 60 %) 0.98 (d, J = 6.8 Hz, 6H), 2.58 (m, IH), 3.70 (s, 3H), 7.28 (m, 5H), 7.68 (s, IH). (isomer 2, 40 %) 1.14 (d, J = 6.8 Hz, 6 H), 3.14 (m, IH), 3.70 (s, 3H), 7.80 (s, 5H), 7.48 (s, 1 H). MS(ESI) m/z 233.0 (M+l). Example 2: Preparation of (±)methγl-2-(2-(4-fluorophenyl)-2-oxo-l- phenylethyl)-4-methyl-3-oxopentanoate of fR-(R* ,R*Y1. rR-(RΛS*TI, rS-(R*.R*)l and rS-(R*.S*)l isomers
To a solution of 31.4 g of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide in 47 ml of anhydrous ethanol, 144 g of methyl 4-methyl-3-oxo-2- (phenylmetnylene)pentanoate, 87 ml of triethanolamine and 74 ml of A- fluorobenzaldehyde were added in an argon atmosphere. The resulting solution was stirred and heated at 70-80 °C for 20 hours. The reaction mixture was cooled to 20- 25 °C , and 2.0 L of ethyl acetate was added thereto. The resulting mixture was washed with 2.0 L of 1 N hydrochloric acid solution, 1.5 L of 10 % sodium bicarbonate aqueous solution and 1.5 L of 10 % sodium chloride aqueous solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, thus obtaining 206 g of (±)methyl 2-(2-(4-fiuorophenyl)-2-oxo- l-phenylethyl)-4-methyl-3-oxopentanoate mixture of [R-(R*,R*)], [R-(R*,S*)], [S- (R*,R*)] and [S-(R*,S*)] isomers as yellow oil. In addition, the obtained oil compound was crystallized from ethanol, thus obtaining 198 g of the title compound as a light white solid.
1H-NMR (400 MHz, CDCl3) δ optical isomer (isomer 1, 95 %) 1.01 (d, J = 6.8 Hz, 3H), 1.26 (d, J= 6.8 Hz, 3H), 2.92 (m, IH), 3.51 (s, 3H), 4.72 (d, J = 11.1 Hz, IH), 5.32 (d, J = 11.1 Hz, IH), 7.01 - 7.21 (m, 2H), 7.28 - 7.30 (m, 5H), 7.98 - 8.01 (m, 2H). (isomer 2, 5 %) 0.52 (d, J= 6.8 Hz, 3H), 0.89 (d, J= 6.8 Hz, 3H), 2.29 (m, IH), 3.70 (s, 3H), 4.73 (d, J = 11.1 Hz, IH), 5.32 (d, J = 11.1 Hz, IH), 7.01 - 7.21 (m, 2H), 7.21 - 7.27 (m, 5H), 7.98 - 8.01 (m, 2H). MS(ESI) m/z 357.2 (M+l).
Example 3: Preparation of l-(4-fluorophenylV5-methyl-2-phenyl-l ,4- hexanedione
(±)methyl 2-(2-(4-fluorophenyl)-2-oxo- 1 -phenylethyl)-4-methyl-3 - oxopentanoate of [R-(R* ,R*)], [R-(R*,S*)]5 [S-(R*,R*)] and [S-(R*,S*)] isomers, obtained in Example 2, was dissolved in 600 ml of tetrahydrofϊiran, and 300 mL of purified water and 41 g of sodium hydroxide were added to the mixture solution. The reaction solution was stirred at room temperature for 24 hours. 2.0 L of isopropylether was added to the reaction product to separate the organic layer, which was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, thus 141 g of the title compound as yellow oil.
1H-NMR (400 MHz, CDCl3) S 1.08 (d, J= 6.9 Hz, 3H), 1.13 (d, J = 6.9 Hz, 3H), 2.65 (m, IH), 2.77 (dd, J= 3.8, 18.0 Hz, IH), 3.63 (dd, J= 10.2, 18.0 Hz, IH), 5.07 (dd, J = 3.8, 10.2 Hz, IH), 7.10 (m, 2H), 7.27 (m, 5H), 7.98 (m, 2H). MS(ESI) m/z 299.0 (M+l). Example 4-1 ; Preparation of t-butyl 2-(T4R.6R)-6-(2-r2-r4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-2-phenyl-l,3,2-dioxaborinan-4-yl)acetate
To a nitrogen-filled flask, 126 g of l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4- hexanedione, 2.5 L of toluene, 41 ml of triethylamine, 160 g of t-butyl 2-((4R,6R)-6-(2- aminoethyl)-2-phenyl-l,3,2-dioxaborinan-4-yl)acetate and 33 ml of pivalic acid were added. The mixture was heated to reflux with stirring for 14 hours while removing water with a Dean-Stark trap. The reaction mixture was cooled slowly to 20-25 "C and washed with purified water, and the organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining 194 g of the title compound as yellow oil. IR (KBr) 2922, 1761, 1740, 1600, 1515 cm"1, 1H-NMR (400 MHz, CDCl3) δ
1.32 - 1.39 (m, 7H), 1.53 (s, 9H), 1.59 - 1.73 (m, 2H), 1.84 - 1.87 (m, IH), 2.39 (dd, J = 15.2, 4.1 Hz, IH), 2.55 (dd, IH), 3.16 (m, IH), 3.93 - 4.03 (m, 2H), 4.21 - 4.28 (m, IH), 4.41 . 4.44 (m, m), 6.22 (s, IH), 7.03 - 7.16 (m, 7H), 7.27 - 7.36 (m, 4H), 7.41 - 7.45 (m, IH), 7.64 - 7.66 (d, J= 6.8 Hz, 2H), MS(ESI) m/z 582.2 (M+l). Example 4-2: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate
According to the same method as described in Example 4-1, the title compound
was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t- butyl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxane-4-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 7H), 1.41 - 1.49 (m, 6H), 1.52 (s, 9H), 1.59 - 1.73 (m, 2H), 1.84 - 1.87 (m, IH), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, 2H), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 9H), MS(ESI) m/z 536.2 (M+l).
Example 4-3: Preparation of 2-(HR,6R)-6-(2-(2-(4-fluorophenyl')-5-isopropyl- 3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yDacetic acid
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.29 (m, 7H), 1.32 - 1.39 (m, 6H), 1.73 - 1.84 (m, 3H), 2.45 (m, 2H), 3.76 (m, IH), 3.93 - 4.05 (m, 3H), 4.42 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 9H), MS(ESI) m/z 480.1 (M+l). Example 4-4: Preparation of ethyl 2-(r4R,6R)-6-(2-(2-r4-fluorophenvn-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and ethyl 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 1.02 - 1.29 (m, 10H), 1.41 - 1.49 (m, 6H), 1.59 -
1.73 (m, 2H), 1.84 - 1.87 (m, IH), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, 2H), 4.21 - 4.28 (m, 3H), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 9H), MS(ESI) m/z 508.0(M+l).
Example 4-5: Preparation of benzyl 2-((4R,6RV6-(2-(2-f4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1.3 -dioxan-4-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and benzyl 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.30 - 1.37 (m, 7H), 1.43 - 1.49 (m, 6H), 1.59 - 1.85 (m, 3H), 2.52 - 2.65 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, 2H), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 5.42 (s, 2H), 6.22 (s, IH), 7.11 - 7.59 (m, 14H), MS(ESI) m/z 570.1 (M+l).
Example 4-6: Preparation of 2-phenylpropan-2-yl 2-(Y4R,6R)-6-(2-(2-(4- fluorophenyl)-5-isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4- vDacetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and 2- phenylpropan-2-yl 2-((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate.
1H-NMR (400 MHz, CDCl3) «5 1.29 - 1.37 (m, 7H), 1.44 - 1.53 (m, 12H), 1.59 - 1.85 (m, 3H), 2.52 - 2.65 (m, 2H), 3.22 (m, IH), 3.93 - 4.03 (m, 2H), 4.21 - 4.28 (m, IH), 4.42 - 4.46 (m, IH), 6.20 (s, IH), 7.19 - 7.64 (m, 14H), MS(ESI) m/z 598.3 (M+l).
Example 4-7: Preparation of t-butyl 2-(f4R.6R)-6-f2-(2-(4-fmorophenyl)-5- isoprop yl-3 -phenyl- 1 H-pyrrol- 1 -ypethvD-2-f 3 -nitrophenyl")- 1 , 3 ,2-dioxaborinan-4- yPacetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-(3 -nitrophenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.32 - 1.37 (m, 7H), 1.48 (s, 9H), 1.57 - 1.70 (m, 2H), 1.79 - 1.84 (m, IH), 2.35 (m, IH), 2.45 - 2.53 (m, IH), 3.14 - 3.28 (m, IH), 3.90 - 4.01 (m, 2H), 4.18 - 4.25 (m, IH), 4.39 - 4.44 (m, IH), 5.98 (s, IH), 7.10 - 7.29 (m, 4H), 7.31 - 8.03 (m,9H), MS(ESI) m/z 627.3 (M+l).
Example 4-8: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl1ethylV2-(4-methoxyphenylV 1.3.2-dioxaborinan-4- yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl- 1,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-(4-methoxyphenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.30 - 1.35 (m, 7H), 1.45 (s, 9H), 1.55 - 1.69 (m, 2H), 1.80 (m, IH), 2.33 - 2.40 (m, IH), 2.56 (m, IH), 3.09 - 3.23 (m, IH), 3.90 - 4.01 (m, 2H), 4.18 - 4.25 (m, 4H), 4.30 - 4.39 (m, IH), 6.01 (s, IH), 6.95 - 7.01 (m, 2H), 7.30 - 7.41 (m, 5H), 7.51 - 8.02 (m, 6H), MS(ESI) m/z 612.3 (M+l).
Example 4-9: Preparation of t-butyl 2-(f4R.6R1-2-ethyl-6-(2-(2-(4- fluorophenyl)-5 -isoproρyl-3-phenyl- 1 H-pyrrol- 1 -yliethylV 1.3.2-dioxaborinan-4-
yl*)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-ethyl- 1 ,3 ,2-dioxaborinan-4-yl)acetate. 1H-NMR (400 MHz, CDCl3)(S 0.61 (q, J= 7.2 Hz, 2H), 0.93 (t, J= 7.2 Hz, 3H),
1.30 - 1.35 (m, 7H), 1.49 (s, 9H), 1.55 - 1.63 (m, 2H), 1.81 - 1.85 (m, IH), 2.33 (m, IH), 2.53 (m, IH), 3.15 - 3.18(m, IH), 4.00 (m, 2H), 4.21 - 4.25 (m, IH), 4.39 - 4.43 (m, IH), 6.19 (s, IH), 7.19 - 7.30 (m, 3H), 7.41 - 7.68 (m, 6H), MS(ESI) m/z 534.4 (M+ 1).
Example 4-10: Preparation of t-butyl 2-f(4R.6RV6-(2-(2-(4-fluoroρhenvn-5- isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2-(methylphosphateV 1 ,3-dioxan-4-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1 ,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-methylphosphate-l,3-dioxan-4-yl)acetate.
1H-NMR (400 MHz, CDC13)<5 1.30 - 1.36 (m, 7H), 1.45 (s, 9H), 1.55 - 1.63 (m, 2H), 1.77 - 1.82 (m, IH), 2.33 - 2.56 (m, 2H), 3.08 - 3.17 (m, IH), 3.91 - 4.00 (m, 5H), 4.21 - 4.26 (m, IH), 4.34 - 4.40 (m, IH), 6.03 (s, IH), 7.20 - 7.31 (m, 4H), 7.39 - 7.59 (m, 5H), MS(ESI) m/z 572.3 (M+l).
Example 4-11 : Preparation of l-(2-(4-(benzyloxy)-6-methoxytetrahydro-2H- pyran-2-yl)ethyl)-2-(4-fluorophenvD-5-isopropyl-3-phenyl-lH-pyrrole According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2-(4- (benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)ethanamine.
1H-NMR (400MHz, CDCl3) δ 1.26 - 1.31 (m, 6H), 1.50 - 1.53 (m, IH), 1.74 - 1.81 (m, 2H), 1.88 - 1.92 (m, 3H), 2.80 (m, IH), 3.38 (m, IH), 3.48 (s, 3H), 3.61 (m, IH), 3.86 - 3.89 (m, 2H), 4.80 (s, 2H), 4.91 - 4.93 (m, IH), 6.39 (s, IH), 7.13 - 7.49 (m, 12H), 7.62 - 7.69 (m, 2H), MS(ESI) m/z 528.7 (M+l).
Example 4-12: Preparation of 4-(benzyloxy)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)tetrahydro-2H-pyran-2-one
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 6-(2- aminoethyl)-4-(benzyloxy)tetrahydro-2H-pyran-2-one.
1H-NMR (400MHz, CDCl3) δ 1.26 - 1.31 (m, 6H), 1.76 - 1.82 (m, IH), 1.91 -
1.99 (m, 2H), 2.15 - 2.41 (m, 3H), 3.30 - 3.40 (m, 2H), 3.86 - 3.89 (m, 2H), 4.21 (m, IH), 4.82 (s, 2H), 6.46 (s, IH), 7.10 - 7.42 (m, 12H), 7.56 - 7.65 (m, 2H), MS(ESI) m/z 512.7 (M+l).
Example 4-13: Preparation of t-butyl 2-(Y4R.6R)-2,2-di-t-butyl-6-(2-(2-(4- fluorophenyl)-5-isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yDethyl)- 1 ,3 ,2-dioxasilinan-4- vDacetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2,2-di-t-butyl-l,3,2-dioxasilinan-4-yl)acetate. 1H-NMR (400MHz, CDCl3) δ 0.99 (s, 18H), 1.29 -1.38 (m, 7H), 1.53 (s, 9H),
1.56 - 1.65 (m, 2H), 1.84 - 1.88 (m, IH), 2.43 (dd, J = 15.0, 4.3 Hz, IH), 2.58(dd, J = 15.2, 4.3Hz, IH), 3.16 - 3.18 (m, IH), 3.85 - 3.92 (m, 2H), 4.18 - 4.20 (m, IH), 4.29 - 4.33 (m, IH), 6.31 (s, IH), 7.13 - 7.28 (m, 7H), 7.62 - 7.69 (m, 2H), MS(ESI) m/z 636.9 (M+l). Example 4-14: Preparation of t-butyl 2-((4R.6RV6-(2-(2-f4-fluorophenvn-5- isopropyl-3 -phenyl- 1 H-pyrrol- 1 -vDethyl)-2-(sulfite*)- 1 ,3 -dioxan-4-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-sulfite-l,3-dioxan-4-yl)acetate. 1H-NMR (400MHz, CDCl3) δ 1.29 -1.38 (m, 7H), 1.53 (s, 9H), 1.51 - 1.61 (m,
2H), 1.84 - 1.88 (m, IH), 2.41 (dd, J = 15.4, 4.1 Hz, IH), 2.56 (dd, J = 15.1, 4.3 Hz, IH), 3.36 - 3.39 (m, IH), 3.89 - 3.96 (m, 2H), 4.16 - 4.19 (m, IH), 4.32 - 4.41 (m, IH), 6.38 (s, IH), 7.16 - 7.35 (m, 7H), 7.60 - 7.68 (m, 2H), MS(ESI) m/z 542.0 (M+l).
Example 4-15: Preparation of ethyl 2-((2R.4R)-4-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yPethyl)- 1 ,5-dioxaspiror5.51undecan-2-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and ethyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.12 - 1.16 (m, 3H), 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m,
IH), 3.93 - 4.03 (m, IH), 4.03 - 4.14 (m, 2H), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH),
6.22 (s, IH), 7.23 - 7.79 (m, 9H), MS(ESI) m/z 548.3 (M+l).
Example 4-16: Preparation of t-butyl 2-f(2R,4R)-4-(2-r2-f4-fluorophenvπ-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyπ-l,5-dioxaspiror5.51undecan-2-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and t-butyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.52 (s, 9H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 9H), MS(ESI) m/z 576.3 (M+l).
Example 4-17: Preparation of cyclohexyl 2-((2R,4R)-4-(2-(2-(4-fluoroρhenyl)- 5-isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiror5.51undecan-2-yl)acetate
According the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and cyclohexyl 2-((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 12H), 1.59 - 1.73 (m, 9H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.78 - 3.86 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 9H), MS(ESI) m/z 602.3 (M+l). Example 4-18: Preparation of phenyl 2-((2R.4R)-4-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiror5.51undecan-2-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and phenyl 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate. 1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 -
1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 14H), MS(ESI) m/z 596.3(M+1).
Example 4-19: Preparation of benzyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl')-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yDethyl)- 1 ,5-dioxaspiro[5.51undecan-2-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and benzyl 2-
((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m5 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 5.20 - 5.26 (m, 2H), 6.22 (s, IH), 7.23 - 7.79 (m, 14H), MS(ESI) m/z 610.3 (M+l).
Example 4-20: Preparation of 2-phenvIpropan-2-yl 2-((2R.4R)-4-(2-(2-(4- fluorophenylV5-isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.51undecan- 2-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- phenylpropan-2-yl 2-((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2- yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, HH), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 14H), MS(ESI) m/z 638.3 (M+l).
Example 4-21 : Preparation of 2-f(4R,6R)-6-(2-(2-(4-fluorophenylV5-isopropyl- 3 -phenyl- 1 H-pyrrol- 1 -vDethyl-2,2-dimethyl- 1 ,3-dioxan-4-yl)-N,N-dimethylacetamide
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)-N,N-dimethylacetamide.
1H-NMR (400 MHz, CDCl3) δ 1.28 - 1.48 (m, 13H), 1.73 - 1.90 (m, 3H), 2.18 - 2.43 (m, 2H), 2.9 - 3.0 (m, 6H), 3.12 - 3.14 (m, IH), 3.79 - 4.02 (m, 4H) 6.26 (s, IH), 7.03 - 7.48 (m, 9H), MS(ESI) m/z 507.2 (M+l). Example 4-22: Preparation of N,N-dicvclohexyl-2-(f4R.6RV6-f2-(2-f4- fluorophenylVS -isopropyl-3-phenyl- 1 H-pyrrol- 1 - yl")ethylV2,2-dimethyl- 1 ,3 -dioxan-4- vDacetamide
According to the same method as in Example 4-1, the tiotle compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)-N,N-dicyclohexylacetamide.
1H-NMR (400 MHz, CDCl3) δ 1.25 - 1.42 (m, 16H), 1.44 - 1.53 (m, 13H), 1.73 - 1.94 (m, 7H), 2.22 (m, IH), 2.43 (m, IH), 3.1 - 3.54 (m, 3H), 3.79 - 4.03 (m, 4H), 6.27
(s, IH), 7.03 - 7.49 (m, 9H), MS(ESI) m/z 643.2 (M+l)
Example 4-23: Preparation of 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl- 3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-vD- 1 -(piperidin- 1 - ypethanone According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2-phenyl-l,4-hexanedione and 2- ((4R,6R)-6-(2-aminoethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)- 1 -(piperidin- 1 -yl)ethanone.
1H-NMR (400 MHz, CDCl3) δ 1.24 - 1.41 (m, 12H), 1.48 - 1.52 (m, 7H),1.73 - 1.95 (m, 3H), 2.15 - 2.44 (m, 2H), 3.12 - 3.34 (m, 5H), 3.78 - 4.02 (m, 4H), 5.61 (s, IH), 7.01 - 7.47 (m, 9H), MS(ESI) m/z 547.0 (M+l)
Example 4-24: Preparation of 2-f(2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl- 3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiror5.51undecan-2-yl)-l- morpholinoethanone
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and 2- ((2R,4R)-4-(2-aminoethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)-l-moφholinoethanone.
1H-NMR (400 MHz, CDCl3) δ 1.28 - 1.30 (m, 6H), 1.39 - 1.58 (m, 9H), 1.73 - 1.92 (m, 5H), 2.14 - 2.42 (m, 2H), 3.12 - 3.22 (m, IH), 3.41 - 3.67 (m, 8H), 3.68 - 4.10 (m, 4H), 6.25 (s, IH), 7.01 - 7.45 (m, 9H), MS(ESI) m/z 589.0 (M+l) Example 4-25: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-f4-fluorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2-methoxy- 1 ,3 ,2-dioxaborinan-4-yl)acetate
According to the same method as in Example 4-1, the title compound was synthesized using l-(4-fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and t-butyl 2- ((4R,6R)-6-(2-aminoethyl)-2-methoxy-l,3,2-dioxaborinan-4-yl)acetate. 1H-NMR (400 MHz, CDCl3)^ 1.30 - 1.35 (m, 7H), 1.49 (s, 9H), 1.54 - 1.63 (m,
2H), 1.81 - 1.86 (m, IH), 2.33 (m, IH), 2.53 (m, IH), 3.15 - 3.18 (m, IH), 4.00 (m, 2H), 4.12 (m, 3H), 4.21 - 4.25 (m, IH), 4.39 - 4.43 (m, IH), 6.20 (s, IH), 7.19 - 7.31 (m, 3H), 7.40 - 7.66 (m, 6H), MS(ESI) m/z 536.0 (M+l).
Example 4-26: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-2-(chloro)-l,3-dioxaphosphorinan-4- yPacetate
According to the same method as in Example 4-1, the title compound was
synthesized using 1 -(4- fluorophenyl)-5-methyl-2 -phenyl- 1,4-hexanedione and t-butyl 2-
((4R,6R )-6-(2-aminoethyl)-2-chloro- 1 ,3 -dioxaphosphorinan-4-yl)acetate.
1H-NMR (400 MHz, CDCl3)(S 1.29 - 1.38 (m, 7H), 1.48 (s, 9H), 1.56 - 1.63 (m,
2H), 1.77 - 1.82 (m, IH), 2.36 - 2.57 (m, 2H), 3.08 - 3.16 (m, IH), 3.90 - 4.01 (m, 2H), 4.21 - 4.27 (m, IH), 4.34 - 4.41 (m, IH), 6.03 (s, IH), 7.20 - 7.31 (m, 4H), 7.39 - 7.62
(m, 5H), MS(ESI) m/z 577.1 (M+l).
Example 5-1 : Preparation of t-butyl 2-(f4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3 -ρhenyl-4-(phenylcarbamo yl )- 1 H-pyrrol- 1 -yDethvD-Σ-phenyl- 1 ,3,2- dioxaborinan-4-yl)acetate 150 g of aluminum chloride and 1.5 L of methylene chloride were placed in a reactor in a nitrogen atmosphere and stirred. To the suspension, 121 ml of phenyl isocyanate was slowly added dropwise over 1 hour.
The reaction temperature was lowered to a temperature between -50 °C and -
60 °C , and a solution of 160 g of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isoprop yl-3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2-phenyl- 1 ,3 ,2-dioxaborinan-4-yl)acetate in
1.2 L of methylene chloride was slowly added dropwise to the reaction material over 1 hour and was then stirred for 1 hour. After the completion of the reaction, purified water was added to the reaction product, and the mixture was stirred for 30 minutes, heated slowly to room temperature, and then stirred for 30 minutes. The organic layer was separated three times with purified water and one time with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining oil.
The oil was crystallized from isopropyl ether and heptane, thus obtaining 147 g of the title compound as a solid. IR (KBr) 2916, 1741, 1662, 1598, 1507 cm"1, 1H-NMR (400 MHz, DMSOd6) δ
1.35 (m, 6H), 1.40 (s, 9H), 1.47 - 1.97 (m, 4H), 2.36 (dd, J = 15.0, 8.2 Hz, IH), 2.52 (dd,
J = 15.0, 4.6 Hz, IH), 3.29 (m, IH), 3.96 (m, IH), 4.14 (m, 2H), 4.40 (m, IH), 6.93 -
7.52 (m, 19H), 9.83 (s, IH), MS(ESI) m/z 701.0 (M+l).
Example 5-2 The title compound as a light yellow solid was obtained in the same manner as in Example 5-1, except that zinc chloride was instead of aluminum chloride.
Example 5-3: Preparation of t-butyl 2-((4R.6R)-6-(2-(2-(4-fluorophenyl)-5-
isopropyl-3 -phenyl-4-(phenylcarbamothioyiy 1 H-pyrrol- 1 -yl*)ethyl)-2-phenyl- 1,3,2- dioxaborinan-4-yl)acetate
The title compound was obtained in the same manner as in Example 5-1, except that phenylisothiocyanate was used instead of phenylisocyanate. IR (KBr) 2912, 2181, 1761, 1662, 1600, 1507, 1211, 1024 cm"1, 1H-NMR (400
MHz, DMSOd6) δ 1.34 (m, 6H), 1.39 (s, 9H), 1.51 - 1.98 (m, 4H), 2.35 (dd, J = 15.0, 8.2 Hz, IH), 2.54 (dd, J = 15.0, 4.6 Hz, IH), 3.31 (m, IH), 3.93 (m, IH), 4.13 (m, 2H), 4.40 (m, IH), 6.89 - 7.52 (m, 19H), 10.59 (s, IH), MS(ESI) m/z 717.1(M+1).
Example 5-4: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenylV5- isopropyl-3 -phenyl-4-(phenylcarbamoyl)- 1 H-pyrrol- 1 -yl)ethyl)-2-phenyl- 1.3,2- dioxaborinan-4-yl)acetate
2 g of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-4- (phenylearbamothioyl)- 1 H-pyrrol- 1 -yl)ethyl)-2-phenyl- 1 ,3 ,2-dioxaborinan-4-yl)acetate obtained in Example 5-3 was dissolved in 70 ml of ethanol, and 0.83 g of sodium hydroxide and 35 ml of 30% hydrogen peroxide were added thereto. The mixture was stirred at room temperature for 3 hours. 300 ml of ethyl acetate and 200 ml of purified water were added to the reaction mixture and stirred slowly for 30 minutes, and the organic layer was separated and washed one time with a saturated aqueous sodium chloride solution. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, thus obtaining oil. The oil was crystallized from isopropylether and heptane, thus obtaining the target compound as a solid compound.
Example 5-5: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbomyl)-lH-pyrrol-l-vDethyl)-2,2-dimethyl-l,3-dioxan- 4-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol-1 -yl)ethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate.
1H-NMR (400 MHz, DMSOd6) δ 1.38 (m, 12H), 1.42 (s, 9H), 1.53 - 1.78 (m, 3H), 1.84 - 1.87 (m, IH), 2.15 (m, IH), 2.85 (m, IH), 3.29 (m, IH), 3.98 - 4.11 (m, 3H), 4.32 (m, IH), 7.01 - 7.79 (m, 14H), 9.65 (s, IH), MS(ESI) m/z 655.1 (M+l).
Example 5-6: Preparation of 2-((4R.6R>6-(2-(2-(4-fluorot>henvl)-5-isopropyl-
3-phenyl-4-("phenylcarbamoylVlH-pyrrol-l-yl)ethyl")-2.2-dimethyl-l,3-dioxan-4- yPacetie acid
According to the same method as in Example 5-1, the title compound was synthesized using 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3 -phenyl- lH-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetic acid.
1H-NMR (400 MHz, DMSOd6) δ 1.32 - 1.47 (m, 12H), 1.57 - 1.78 (m, 3H), 1.84 - 1.87 (m, IH), 2.25 (m, IH), 2.85 (m, IH), 3.33 (m, IH), 3.98 - 4.13 (m, 3H), 4.32 (m, IH), 7.01 - 7.79 (m, 14H), 9.65 (s, IH), 10.57 (s, IH) , MS(ESI) m/z 599.0 (M+l).
Example 5-7: Preparation of ethyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl')-5- isopropyl-3 -phenyl-4-(phenγlcarbamoyl*)- 1 H-pyrrol- 1 -yl)ethyl')-2,2-dimethyl- 1,3- dioxan-4-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using ethyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)acetate. 1H-NMR (400 MHz, DMSO-d6) δ 1.22 - 1.38 (m, 15H), 1.53 - 1.78 (m, 3H),
1.84 - 1.87 (m, IH), 2.25 (m, IH), 2.64 (m, IH), 3.29 (m, IH), 3.98 - 4.21 (m, 5H), 4.32 (m, IH), 7.05 - 7.79 (m, 14H), 9.56 (s, IH), MS(ESI) m/z 637.0 (M+l).
Example 5-8: Preparation of benzyl 2-ff4R,6RV6-f2-(2-(4-fluorophenylV5- isoproρyl-3-ρhenyl-4-(phenyl carbamoyl)- 1 H-pyrrol- 1 -yl')ethyls)-2,2-dimethyl- 1,3- dioxan-4-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using benzyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetate.
1H-NMR (400 MHz, DMSOd6) δ 1.29 - 1.41 (m, 12H), 1.56 - 1.84 (m, 4H), 2.25 (m, IH), 2.64 (m, IH), 3.25 (m, IH), 3.96 - 4.12 (m, 3H), 4.32 (m, IH), 5.12 (s, 2H), 7.03 - 7.78 (m, 19H), 9.52 (s, IH), MS(ESI) m/z 689.2 (M+l).
Example 5-9: Preparation of 2-phenylprot>an-2-yl 2-ff4R,6R)-6-(2-(2-(4- fluorophenylV 5 -isopropyl-3 -phenyl-4-(phenylcarbamoyl> 1 H-pyrrol- 1 -yl)ethyl)-2,2- dimethyl- 1 ,3 -dioxan-4-yl)acetate According to the same method as in Example 5-1, the title compound was synthesized using 2-phenylpropan-2-yl 2-((4R,6R)-6-(2-(2-(4-fiuorophenyl)-5- isopropyl-3-phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl-l ,3-dioxan-4-yl)acetate.
1H-NMR (400 MHz, DMSOd6) S 1.25 - 1.79 (m, 22H), 2.23 (m, IH), 2.63 (m, IH), 3.25 (m, IH), 3.92 - 4.13 (m, 3H), 4.32 (m, IH), 7.11 - 7.85 (m, 19H), 9.61 (s, IH), MS(ESl) m/z 717.0 (M+ 1).
Example 5-10: Preparation of t-butyl 2-(f4R,6RV6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl)ethyl)-2-(3-nitrophenyl)-l,3,2- dioxaborinan-4-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2-(3 -nitrophenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate. 1H-NMR (400 MHz, DMSOd6) δ 1.30 - 1.34 (m, 6H), 1.40 (s, 9H), 1.45 - 2.00
(m, 4H), 2.33 - 2.38(m, IH), 2.50 - 2.55 (m, IH), 3.26 - 3.29 (m, IH), 3.94 - 4.00 (m, IH), 4.11 - 4.20 (m, 2H), 4.38 - 4.42 (m, IH), 7.22 - 7.68 (m, 18H), 9.52 (s, IH), MS(ESl) m/z 746.3 (M+ 1).
Example 5-11 : Preparation of t-butyl 2-((4R,6R)-6-f2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-rphenylcarbamoyl)-lH-pyrrol-l-yl)ethyl)-2-(4-methoxyphenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2-(4-methoxyphenyl)-l ,3,2-dioxaborinan-4-yl)acetate. 1H-NMR (400 MHz, DMSOd6) δ 1.32 (d, J = 7.3 Hz, 6H), 1.39 (s, 9H), 1.43 -
2.19 (m, 4H), 2.32 - 2.37(m, IH), 2.49 - 2.54 (m, IH), 3.22 - 3.28 (m, IH), 3.82 - 4.01 (m, 4H), 4.12 - 4.18 (m, 2H), 4.37 - 4.42 (m, IH), 6.99 - 7.05 (m, 2H), 7.20 - 7.82 (m, 16H), 9.32 (s, IH), MS(ESI) m/z 731.3 (M+l).
Example 5-12: Preparation of t-butyl 2-((4R.6RV2-ethyl-6-(2-(2-(4- fluorophenyl)-5 -isopropyl-3-phenyl-4-(phenyl carbamoyl)- 1 H-pyrrol- 1 -ypethyl)- 1.3,2- dioxaborinan-4-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-2-ethyl-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3- phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2-(4-methoxyphenyl)- 1 ,3 ,2-dioxaborinan-4-yl)acetate. 1H-NMR (400 MHz, DMSO-d6)<5 0.64 (q, J = 7.2 Hz, 2H), 0.95 (t, J = 7.2 Hz,
3H), 1.32 (d, J = 7.3 Hz, 6H), 1.41 (s, 9H), 1.42 - 2.08 (m, 4H), 2.34 - 2.41 (m, IH), 2.26 - 2.49 (m, IH), 3.25 - 3.31 (m, IH), 3.85 - 3.93 (m, IH), 4.15 - 4.21 (m, 2H), 4.36 -
4.41 (m, IH), 7.19 - 7.64 (m, 14H), 9.25 (s, IH), MS(ESI) m/z 653.4 (M+l).
Example 5-13: Preparation of t-butyl 2-fC4R.6RV6-r2-r2-r4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)-lH-pyrrol-l-yl)ethylV2-fmethylphosphate)- 1 ,3 ,2-dioxan-4-yl)acetate According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2-(methylphosphate)- 1 ,3 ,2-dioxan-4-yl)acetate.
1H-NMR (400 MHz, DMSOd6)(S 1.35 (d, J = 7.3 Hz, 6H), 1.45 (s, 9H), 1.96 - 2.10 (m, 4H), 2.32 - 2.42(m, IH), 2.44 - 2.50 (m, IH), 3.20 - 3.29 (m, IH), 3.76 - 3.98 (m, 4H), 4.12 - 4.19 (m, 2H), 4.32 - 4.38 (m, IH), 7.10 - 7.81(m, 14H), 9.20 (s, IH), MS(ESI) m/z 691.3 (M+l).
Example 5-14: Preparation of l-(2-(4-("benzyloxy)-6-methoxytetrahydro-2H- pyran-2-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-lH-pyrrol-3- carboxamide According to the same method as in Example 5-1, the title compound was synthesized using 1 -(2-(4-(benzyloxy)-6-methoxytetrahydro-2H-pyran-2-yl)ethyl)-2-(4- fluorophenyl)-5-isopropyl-3-phenyl-lH-pyrrole.
1H-NMR (400MHz, DMSOd6) δ 1.25 - 1.33 (m, 6H), 1.51 - 1.53 (m, IH), 1.74
- 1.81 (m, 2H), 1.88 - 1.90 (m, 3H), 2.79 - 2.83 (m, IH), 3.42 - 3.51 (m, 4H), 3.59 - 3.62 (m, IH), 3.86 - 3.89 (m, 2H), 4.80 (s, 2H), 4.91 - 4.93 (m, IH), 7.13 - 7.38 (m, 7H), 7.45
- 7.55 (m, 10), 7.62 - 7.69 (m, 2H), 9.56 (s, IH), MS(ESI) m/z 647.7 (M+l).
Example 5-15: Preparation of l-(2-(4-(benzyloxy)-6-oxotetrahvdro-2H-pyran-2- yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl- 1 H-pyrrol-3 -carboxamide
According to the same method as in Example 5-1, the title compound was synthesized using 4-(benzyloxy)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)tetrahydro-2H-pyran-2-one.
1H-NMR (400MHz, DMSOd6) δ 1.31 - 1.39 (m, 6H), 1.74 - 1.80 (m, IH), 1.91
- 1.97 (m, 2H), 2.20 - 2.43 (m, 3H), 3.30 - 3.35 (m, IH), 3.41 - 3.46 (m, IH), 3.84 - 3.87 (m, 2H), 4.25 (m, IH), 4.80 (s, 2H), 7.02 - 7.35 (m, 7H), 7.42 - 7.56 (m, 10H), 7.64 - 7.75 (m, 2H), 9.48 (s, IH), MS(ESI) m/z 631.7 (M+l).
Example 5-16: Preparation of phenyl l-(2-((4R.6R)-6-(2-t-butoxy-2-oxoethyl)- 2,2-di-t-butyl-L3,2-dioxasilinan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-4-phenvl-
1 H-pyπol-3 -carboxylate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-2,2-di-t-butyl-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3 -phenyl- 1 H-pyrrol- 1 -yl)ethyl)- 1 ,3 ,2-dioxasilinan-4-yl)acetate. 1H-NMR (400MHz, DMSO-d6) δ 0.97 (s, 18H), 1.28 -1.39 (m, 7H), 1.53 (s, 9H),
1.51 - 1.63 (m, 2H), 1.82 - 1.87 (m, IH), 2.42 (dd, J = 15.0, 4.3Hz, IH), 2.53 (dd, J = 15.2, 4.3Hz, IH), 3.16 - 3.18 (m, IH), 3.81 - 3.91 (m, 2H), 4.19 - 4.22 (m, IH), 4.26 - 4.31 (m, IH), 6.89 - 7.09 (m, 6H), 7.18 - 7.25 (m, 6H), 7.67 - 7.75 (m, 2H), 9.41 (s, IH), MS(ESI) m/z 756.0 (M+l). Example 5-17: Preparation of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)- 1 H-pyrrol- 1 -yl)ethyl)-2-(sulfite)- 1 ,3 -dioxan-4- vDacetate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2-(sulfϊte)- 1 ,3 -dioxan-4-yl)acetate.
1H-NMR (400MHz, DMSOd6) δ 1.29 -1.38 (m, 7H), 1.53 (s, 9H), 1.51 - 1.61
(m, 2H), 1.84 - 1.88 (m, IH), 2.41 (dd, J= 15.3, 4.1 Hz, IH), 2.56 (dd, J= 15.2, 4.0 Hz,
IH), 3.36 - 3.40 (m, IH), 3.89 - 3.96 (m, 2H), 4.16 - 4.19 (m, IH), 4.32 - 4.41 (m, IH),
6.89 - 7.09 (m, 6H), 7.18 - 7.25 (m, 6H), 7.67 - 7.75 (m, 2H), 9.67 (s, IH), MS(ESI) m/z 661.2 (M+l).
Example 5-18: Preparation of ethyl 2-((2R.4RV4-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-fphenylcarbamoyl)- 1 H-pyrrol- 1 -vDethyl)- 1,5- dioxaspiro \5.5 ]undecan-2-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using ethyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.12 - 1.16 (m, 3H), 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.03 - 4.14 (m, 2H), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 14H), 9.21 (br, IH), MS(ESI) m/z 548.3 (M+l).
Example 5-19: Preparation of t-butyl 2-((2R,4R)-4-(2-(2-(4-fluorophenvl)-5-
isoρropyl-3 -phenyl-4-(phenylcarbamoylV 1 H-pyrrol- 1 -vDethyD- 1,5- dioxaspiror5.51undecan-2-yl)acetate
According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)- 1 ,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.52 (s, 9H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 14H), 9.21 (br, IH), MS(ESI) m/z 695.3 (M+l). Example 5-20: Preparation of cyclohexyl 2-((2R.4RV4-(2-(2-(4-fluorophenylV
5-isopropyl-3-phenyl-4-(phenylcarbamoyl1-lH-pyrrol-l-yl)ethyl)-l15- dioxaspiro[5. Sjundecan-Σ-yDacetate
According to the same method as in Example 5-1, the title compound was synthesized using cyclohexyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3- ρhenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 12H), 1.59 - 1.73 (m, 9H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.78 - 3.86 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 14H), 9.21 (br, IH), MS(ESI) m/z 721.4 (M+l). Example 5-21 : Preparation of phenyl 2-((2R,4RV4-f2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenyl carbamoyl)- 1 H-pyrrol- 1 -yPethyD-l ,5- dioxaspiro["5.5"|undecan-2-vDacetate
According to the same method as in Example 5-1, the title compound was synthesized using phenyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl- lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 19H), 9.21 (br, IH), MS(ESI) m/z 715.3(M+1). Example 5-22: Preparation of benzyl 2-(T2R.4RV4-(2-(2-(4-fluorophenylV5- isopropyl-3 -phenyl-4-('phenylcarbamoylV 1 H-pyrrol- 1 - vDethylV 1,5- dioxaspiror5.51undecan-2-yl*)acetate
According to the same method as in Example 5-1, the title compound was synthesized using benzyl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, 5H), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 5.20 - 5.26 (m, 2H), 6.22 (s, IH), 7.23 - 7.79 (m, 19H), 9.21 (br, IH), MS(ESI) m/z 729.4 (M+ 1).
Example 5-23: Preparation of 2-phenylpropan-2-yl 2-«2R,4R)-4-(2-(2-(4- fluorophenyiy 5-isopropyl-3 -phenyl-4-(phenylcarbamoyl)- 1 H-pyrrol- 1 -yl)ethyl)- 1,5- dioxaspiro[5.51undecan-2-yl)acetate
According to the same method as in Example 5-1 , the title compound was synthesized using 2-phenylpropan-2-yl 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-lH-pyrrol-l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate.
1H-NMR (400 MHz, CDCl3) δ 1.22 - 1.35 (m, 6H), 1.41 - 1.49 (m, 6H), 1.59 - 1.73 (m, HH), 1.84 - 1.87 (m, 4H), 2.39 - 2.55 (m, 2H), 3.16 (m, IH), 3.93 - 4.03 (m, IH), 4.21 - 4.28 (m, IH), 4.41 - 4.44 (m, IH), 6.22 (s, IH), 7.23 - 7.79 (m, 19H), 9.21 (br, IH), MS(ESI) m/z 757.4 (M+ 1).
Example 5-24: Preparation of l-f2-((4R.6R)-6-(2-(dimethylamino)-2-oxoethvn- 2,2-dimethyl- 1 ,3 -dioxan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl- IH- ρyrrol-3-carboxamide
According to the same method as in Example 5-1, the title compound was synthesized using 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl- 1 H-pyrrol- l-yl)ethyl-2,2-dimethyl-l,3-dioxan-4-yl)-N,N-dimethylacetamide.
1H-NMR (400 MHz, DMSOd6) δ 1.27 - 1.50 (m, 13H), 1.71 - 1.92 (m, 3H), 2.16 - 2.45 (m, 2H), 2.89 - 2.94 (m, 6H), 3.10 - 3.12 (m, IH), 3.77 - 4.04 (m, 4H), 7.01 - 7.64 (m, 14H), 9.11 (s, IH), MS(ESI) m/z 626.1 (M+l)
Example 5-25: Preparation of l-(2-(r4R,6R)-6-(2-(dicvclohexylamino')-2- oxoethyl)-2,2-dimethyl-l,3-dioxan-4-yl')ethyl)-5-r4-fluorophenyl)-2-isopropyl-N,4- diphenyl- 1 H-pyrrol-3 -carboxamide According to the same method as in Example 5-1, the title compound was synthesized using N,N-dicyclohexyl-2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5 -isopropyl-3 - phenyl- 1 H-pyrrol- 1 -yl)ethyl)-2,2-dimethyl- 1 ,3-dioxan-4-yl)acetamide.
1H-NMR (400 MHz, DMSOd6) δ 1.24 - 1.40 (m, 16H), 1.45 - 1.56 (m, 13H), 1.71 - 1.95 (m, 7H), 2.18 - 2.45 (m, 2H), 3.15 - 3.55 (m, 3H), 3.72 - 4.05 (m, 4H), 7.00 - 7.65 (m, 14H), 9.12 (s, IH), MS(ESI) m/z 763.0 (M+l).
Example 5-26: Preparation of l-(2-((4R.6R)-2,2-dimethyl-6-(2-oxo-2-(pyridin- l-yl)ethyl)-l,3-dioxan-4-yl)ethyl)-5-(4-fluorophenyl)-2-isopropyl-N,4-diphenyl-lH- pyrrol-3 -carboxamide
According to the same method as in Example 5-1, the title compound was synthesized using 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH-pyrrol- 1 -yl)etbyl)-2,2-dimethyl- 1 ,3 -dioxan-4-yl)- 1 -(piperidin- 1 -yl)ethanone. 1H-NMR (400 MHz, DMSO-d6) δ 1.22 - 1.42 (m, 12H), 1.43 - 1.55(m, 7H),
1.76 (m, IH), 1.85 (m, 2H), 2.18 - 2.42 (m, 2H), 3.10 - 3.35 (m, 5H), 3.75 - 4.04 (m, 4H), 7.03 - 7.68 (m, 14H), 9.21 (s, IH), MS(ESI) m/z 666.1 (M+l).
Example 5-27: Preparation of 5-(4-fltιorophenyl)-2-isopropyl-l-(2-((2R14R)-4- (2-morpholino-2-oxoethyl)-L5-dioxaspiror5.51undecan-2-yl)ethyl)-N,4-diphenyl-lH- pyrrol-3-carboxamide.
According to the same method as in Example 5-1, the title compound was synthesized using 2-((2R,4R)-4-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl- 1 H-pyrrol- l-yl)ethyl)-l,5-dioxaspiro[5.5]undecan-2-yl)-l-morpholinoethanone.
1H-NMR (400 MHz, DMSOd6) δ 1.25 - 1.33 (m, 6H), 1.34 - 1.55 (m, 9H),1.74 - 1.90 (m, 5H), 2.13 - 2.52 (m, 2H), 3.11 - 3.32 (m, IH), 3.41 - 3.65 (m,8H), 3.78 - 4.15 (m, 4H), 7.03 - 7.73 (m, 14H), 9.02 (s, IH), MS(ESI) m/z 708.0 (M+l).
Example 5-28: Preparation of t-butyl 2-((4R.6RV6-(2-(2-(4-fluorophenyl)-5- isopropyl-3-phenyl-4-(phenylcarbamoyl)-l H-pyrrol- 1 -yl)ethyl')-2-methoxy- 1 ,3 ,2- dioxaborinan-4-yl)acetate According to the same method as in Example 5-1, the title compound was synthesized using t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-lH- pyrrol- 1 -yl)ethyl)-2-methoxy- 1 ,3 ,2-dioxaborinan-4-yl)acetate.
1H-NMR (400 MHz, DMSOd6)^S 1.32 (d, J = 7.3 Hz, 6H), 1.41 (s, 9H), 1.42 - 2.08 (m, 4H), 2.34 - 2.41 (m, IH), 2.26 - 2.49 (m, IH), 3.25 - 3.31 (m, IH), 3.40 (s, 3H), 3.85 - 3.93 (m, IH), 4.15 - 4.21 (m, 2H), 4.36 - 4.41 (m, IH), 7.19 - 7.64 (m, 14H), 9.25 (s, IH), MS(ESI) m/z 655.0 (M+l).
Example 6: Preparation of (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropvl-3-phenvl-
4-(phenylcarbamoyl)-lH-pyrrol-l-yl)-3,5-dihydroxyheptanoate sodium salt
In a reactor, 288 g of t-butyl 2-((4R,6R)-6-(2-(2-(4-fluorophenyl)-5-isopropyl- 3 -phenyl-4-(phenylcarbamoyl)- 1 H-pyrrol- 1 -yl)ethyl)-2-phenyl- 1 ,3 ,2-dioxaborinan-4- yl)aceta.te was dissolved in 2 L of tetrahydrofuran, and then 2 L of purified water and 74 g of sodium hydroxide were added thereto. The reaction mixture was stirred at room temperature for 3 hours, and then extracted by addition of 2 L of ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, thus obtaining oil. The obtained oil was crystallized from heptane, thus obtaining 213 g of the title compound as a white solid. Example 7: Preparation of (3R,5R)-7-(2-(4-fluorophenyl)-5-isopropyl-3-phenyl-
4-(phenylcarbamovQ- 1 H-pyrrol-1 -vD-3 ,5-dihydroxyheptanoate hemicalcium salt
In a reactor, 213 g of the atorvastatin sodium salt, obtained in Example 6, was mixed with 1.0 L of methanol and 6.0 L of purified water, and the solution was then heated to 50 °C . Then, the heated solution was slowly added dropwise to a solution of 0.5 molar equivalents of calcium acetate in 0.6 L of water in another reactor. After the completion of the addition, the mixture was slowly cooled to 15 °C with stirring for 2 hours, and then was filtered. The resulting solid was washed with 2 L of purified water, and then dried in a vacuum at 50 °C, thus obtaining 205 g of atorvastatin hemicalcium salt. IR (KBr) 3406, 1651, 1600, 1565, 1510, 1441, 1412, 1316, 1222, 1154, 843,
752 cm"1, 1H-NMR (400 MHz, DMSOd6) δ 1.23 (m, IH), 1.36 (d, J= 6.5 Hz, 6H), 1.38 - 1.63 (m, 3H), 1.99 (m, IH), 2.12 (m, IH), 3.17 - 4.05 (m, 7H), 6.96 - 7.27 (m, 12H), 7.51 (d, J= 7.8 Hz, 2H), 9.85 (s, IH), MS(ESI) m/z 559.2 (M+l).
Claims
1. A method for preparing a compound of the following formula 1 or a pharmaceutically acceptable salt thereof, which comprises the steps of:
(1) reacting a compound of the following formula 7 with a compound of the following formula 8 to obtain a compound of the following formula 9, and
(2) deprotecting and hydrolyzing the compound of formula 9 obtained in the step (1):
[Formula 1]
[Formula 7]
[Formula 8]
^o ON^O O or O 5 wherein Ri and R2 are each independently hydrogen,
OH, a straight or branched chain alkyl having 1-8 carbon atoms, phenyl or
*~ ' , wherein Rg is hydrogen, methyl, ethyl, tetrahydropyranyl, benzyl, trialkylsilyl or triarylsilyl, or Ri and R2 together form oxygen (=0) or -(CH2)n-, wherein n is 4 or 5, R3 is oxygen or sulfur, R4 Is Cl, Br, F, I, a straight or branched chain alkyl having 1-8 carbon atoms, phenyl, trityl, OH, an alkoxy having 1 -8 carbon atoms, or phenoxy, and R5 is oxygen (=0), a straight or branched chain alkyl having 1-8 carbon atoms, an alkoxy having 1-8 carbon atoms, an aryl or aryloxy, wherein an aryl or aryloxy is unsubstituted or substituted with an alkyl having 1-4 carbon atoms, an alkoxy having 1- 4 carbon atoms, nitro or halogen, or a C6-C1O heteroaryl comprising one or two heteroatoms selected from a group consisting of N, O and S; and
Z is oxygen (=0),
, wherein R7 is hydrogen, methyl, ethyl or acetyl, or -
CH2COR8, wherein R8 is
R9 is hydrogen, a straight or branched chain alkyl having 1-8 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, phenyl, benzyl or α,α-dimethylbenzyl, and Rio and Rn are each independently hydrogen, a straight or branched chain alkyl having 1-8 carbon atoms, a
cycloalkyl group having 3-6 carbon atoms, benzyl or phenyl, or Rio and Rn together form -(CHz)4-, -(CH2)5-, -(CH(R12)CH2)3-, -(CH(R12)CHa)4-, -(CH(R12)(CH2)2CH(R12))-, -(CH(Rl2χCH2)3CH(Ri2))-, -CH2CH2-O-CH2CH2-, -CH(R12)CH2-O-CH2CH2- or - CH(R12)CH2-O-CH2CH(R12)-, wherein R12 is an alkyl having 1-14 carbon atoms.
2. The method of Claim 1, wherein, in formula 7 to 9, Ai and A2 are oxygen;
A3 is CH2; A4 is oxygen; W is
,
difluorophenyl or quinolinyl; and Z is -CH2CORs, wherein R8 is π V— ' or
M I " , R9 is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclohexyl, phenyl, benzyl or α,α-dimethylbenzyl, and Rio and Ri1 are each independently hydrogen, methyl, ethyl, t-butyl, isopropyl, cyclohexyl, benzyl or phenyl, or Rio and Rn together form -(CH2)4-, -(CH2)S-, -(CH(R12)CH2)3-, -(CH(R12)CH2),-, -(CH(Ri2)(CH2)2CH(R12))-, -(CH(R12)(CH2)3CH(Ri2))-, -CH2CH2-O-CH2CH2-, -CH(R12)CH2-O-CH2CH2- or - CH(R12)CH2-O-CH2CH(R12)-, wherein R!2 is an alkyl having 1 -4 carbon atoms.
3. The method of Claim 1, wherein, in formula 7 to 9, Ai and A2 are CH2; A3
is oxygen; A4 is oxygen; W is v> , wherein R1 is hydrogen, R2 is
wherein R6 is hydrogen, benzyl, trimethylsilyl, t-butyldimethylsilyl or
R7 butyldiphenylsilyl; and Z is oxygen (=O) or GT , wherein R7 is hydrogen, methyl or ethyl.
4. The method of Claim 2, wherein the compound of formula 9 is a compound of the following formula 9a: [Formula 9a]
5. The method of Claim 2, wherein the compound of formula 9 is a compound of the following formula 9b. [Formula 9b]
6. The method of Claim 1, wherein A4 in the compound of formula 9 obtained in the step (1) is sulfur, and the method further comprises a step of converting A4 being sulfur to oxygen.
7. The method of any one of Claims 1 to 6, wherein the deprotection and/or hydrolysis in the step (2) is carried out by using alkali metal.
8. A compound of the following formula 7a: [Formula 7a]
A3 is CH2;
1-4 carbon atoms, an alkoxy having 1-4 carbon atoms, nitro or halogen, or a C6-Ci0 heteroatyl comprising one or two heteroatoms selected from a group consisting of N, O and S; and
a straight or branched chain alkyl having 1-8 carbon atoms, a chcloalkyl group having 3- 6 carbon atoms, phenyl, benzyl or α,α-dimethylbenzyl, and Rio and Rn are each independently hydrogen, a straight or branched chain alkyl having 1-8 carbon atoms, a cycloalkyl group having 3-6 carbon atoms, benzyl or phenyl, or R1O and Rn together form -(CHz)4-, -(CH2)S-, -(CH(Ri2)CHz)3-, -(CH(R12)CHa)4-, -(CH(R12)(CHa)2CH(R12))-, -(CH(R12)(CH2)3CH(Ri2))-, -CH2CH2-O-CH2CH2-, -CH(Ri2)CH2-O-CH2CH2- or - CH(RI2)CH2-O-CH2CH(RI2)-, wherein Rn is an alkyl having 1-4 carbon atoms.
9. The compound of Claim 8, which is a compound of the following formula 7a:
[Formula 7a]
wherein Ai and A2 are oxygen; A3 is CH2;
O , wherein R1 and R2 are each independently hydrogen, OH, methyl, t-butyl, isopropyl or phenyl, or Ri and R2 together form oxygen (=O) or -(CH2)n-, wherein n is 4 or 5, R3 is oxygen or sulfur, R4 is Cl, Br, F, I, methyl, ethyl, t-butyl, isopropyl, trityl, phenyl, OH, methoxy, ethoxy or phenoxy, and R5 is oxygen (=O), methyl, ethyl, t-butyl, isopropyl, methoxy, ethoxy, phenoxy, t-butoxy, phenyl,
naphthalenyl, methoxyphenyl, ethoxyphenyl, nitrophenyl, difluorophenyl or quinolinyl; and
Z is -CH2COR8, wherein R8 is
or , R9 is hydrogen, methyl, ethyl, isopropyl, t-butyl, cyclohexyl, phenyl, benzyl or α,α- dimethylbenzyl, and R1O and R11 are each independently hydrogen, methyl, ethyl, t-butyl, isopropyl, cyclohexyl, benzyl or phenyl, or R^ and R11 together form -(CH2)4-, -(CH2)S-, -(CH(R12)CH2)S-, -(CH(Ri2)CHz)4-, -(CH(R12)(CH2)2CH(R12))-,
(CH(R12)(CH2)SCH(R12))-, -CH2CH2-O-CH2CH2-, -CH(Ri2)CH2-O-CH2CH2- or - CH(RI2)CH2-O-CH2CH(RI2)-, wherein R12 is an alkyl having 1-4 carbon atoms.
10. The compound of Claim 9, which is a compound of the following formula 7b: [Formula 7b]
11. A method for preparing a compound of the following formula 7a, which comprises cyclocondensing a compound of the following formula 5 and a compound of the following formula 6 to obtain a compound of formula 7a:
[Formula 7a]
[Formula 5]
[Formula 6]
wherein A1, A2, A3, W and Z are as defined in Claim 8.
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| US12/864,139 US8178697B2 (en) | 2008-01-25 | 2008-04-25 | Method for the preparation of atorvastatin and intermediates used therein |
| ES08753187T ES2407506T3 (en) | 2008-01-25 | 2008-04-25 | Procedure for the preparation of atorvastatin and intermediates used in said procedure |
| EP08753187A EP2245008B1 (en) | 2008-01-25 | 2008-04-25 | Method for the preparation of atorvastatin and intermediates used therein |
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|---|---|---|---|---|
| WO2002043667A2 (en) * | 2000-11-16 | 2002-06-06 | Teva Pharmaceutical Industries Ltd. | HYDROLYSIS OF [R(R*,R*)]-2-(4-FLUOROPHENYL)-β,δ -DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID ESTERS WITH CALCIUM HYDROXIDE |
| WO2005118536A1 (en) * | 2004-05-31 | 2005-12-15 | Ranbaxy Laboratories Limited | Process for the preparation of atorvastatin |
| WO2006032959A2 (en) * | 2004-08-06 | 2006-03-30 | Glenmark Pharmaceuticals Limited | Processes for the preparation of pyrrole derivatives |
| WO2006097909A1 (en) * | 2005-03-14 | 2006-09-21 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate using a paal-knorr condensation |
| WO2007029216A1 (en) * | 2005-09-09 | 2007-03-15 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate |
| WO2007028412A1 (en) * | 2005-09-10 | 2007-03-15 | Ulkar Kimya Sanayii Ve Ticaret A.S. | Method for producing lactones |
| WO2007099552A2 (en) * | 2006-03-02 | 2007-09-07 | Matrix Labaratories Ltd | Novel crystalline form of atovastatin hemi-magnesium |
-
2008
- 2008-01-25 KR KR1020080007757A patent/KR100850850B1/en active IP Right Grant
- 2008-04-25 ES ES08753187T patent/ES2407506T3/en active Active
- 2008-04-25 WO PCT/KR2008/002373 patent/WO2009093776A1/en active Application Filing
- 2008-04-25 EP EP08753187A patent/EP2245008B1/en active Active
- 2008-04-25 US US12/864,139 patent/US8178697B2/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002043667A2 (en) * | 2000-11-16 | 2002-06-06 | Teva Pharmaceutical Industries Ltd. | HYDROLYSIS OF [R(R*,R*)]-2-(4-FLUOROPHENYL)-β,δ -DIHYDROXY-5-(1-METHYLETHYL)-3-PHENYL-4-[(PHENYLAMINO)CARBONYL]-1H-PYRROLE-1-HEPTANOIC ACID ESTERS WITH CALCIUM HYDROXIDE |
| WO2005118536A1 (en) * | 2004-05-31 | 2005-12-15 | Ranbaxy Laboratories Limited | Process for the preparation of atorvastatin |
| WO2006032959A2 (en) * | 2004-08-06 | 2006-03-30 | Glenmark Pharmaceuticals Limited | Processes for the preparation of pyrrole derivatives |
| WO2006097909A1 (en) * | 2005-03-14 | 2006-09-21 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate using a paal-knorr condensation |
| WO2007029216A1 (en) * | 2005-09-09 | 2007-03-15 | Pfizer Science And Technology Ireland Limited | Preparation of an atorvastatin intermediate |
| WO2007028412A1 (en) * | 2005-09-10 | 2007-03-15 | Ulkar Kimya Sanayii Ve Ticaret A.S. | Method for producing lactones |
| WO2007099552A2 (en) * | 2006-03-02 | 2007-09-07 | Matrix Labaratories Ltd | Novel crystalline form of atovastatin hemi-magnesium |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2012034958A1 (en) * | 2010-09-16 | 2012-03-22 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Esters of hexanoic acids as intermediates for the preparation of atorvastatin |
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| EP2245008A1 (en) | 2010-11-03 |
| ES2407506T3 (en) | 2013-06-12 |
| US8178697B2 (en) | 2012-05-15 |
| EP2245008B1 (en) | 2013-02-20 |
| US20110015407A1 (en) | 2011-01-20 |
| KR100850850B1 (en) | 2008-08-06 |
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