KR100509081B1 - 3,6-디알킬-5,6-디하이드로-4-하이드록시-2에이치-피란-2-온의 합성방법 - Google Patents
3,6-디알킬-5,6-디하이드로-4-하이드록시-2에이치-피란-2-온의 합성방법 Download PDFInfo
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- KR100509081B1 KR100509081B1 KR10-2001-0005462A KR20010005462A KR100509081B1 KR 100509081 B1 KR100509081 B1 KR 100509081B1 KR 20010005462 A KR20010005462 A KR 20010005462A KR 100509081 B1 KR100509081 B1 KR 100509081B1
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- hydroxy
- alkyl
- acid
- ketoester
- Prior art date
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- 230000015572 biosynthetic process Effects 0.000 title description 12
- 238000003786 synthesis reaction Methods 0.000 title description 11
- 238000000034 method Methods 0.000 claims abstract description 110
- 125000000422 delta-lactone group Chemical group 0.000 claims abstract description 62
- 150000001266 acyl halides Chemical class 0.000 claims abstract description 54
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 30
- 238000002360 preparation method Methods 0.000 claims abstract description 27
- 150000004820 halides Chemical group 0.000 claims abstract description 21
- 238000004519 manufacturing process Methods 0.000 claims abstract description 20
- 230000008569 process Effects 0.000 claims abstract description 20
- 125000006239 protecting group Chemical group 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 12
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 5
- 239000002253 acid Substances 0.000 claims description 57
- 239000003054 catalyst Substances 0.000 claims description 47
- 238000005984 hydrogenation reaction Methods 0.000 claims description 46
- -1 ruthenium diacetate compound Chemical class 0.000 claims description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 32
- 125000003118 aryl group Chemical group 0.000 claims description 28
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 27
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 26
- 125000006737 (C6-C20) arylalkyl group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 17
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 17
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- 150000001277 beta hydroxy acids Chemical class 0.000 claims description 14
- ATRNZOYKSNPPBF-UHFFFAOYSA-N D-beta-hydroxymyristic acid Natural products CCCCCCCCCCCC(O)CC(O)=O ATRNZOYKSNPPBF-UHFFFAOYSA-N 0.000 claims description 13
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 13
- ATRNZOYKSNPPBF-CYBMUJFWSA-N (R)-3-hydroxytetradecanoic acid Chemical compound CCCCCCCCCCC[C@@H](O)CC(O)=O ATRNZOYKSNPPBF-CYBMUJFWSA-N 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 11
- 229910052707 ruthenium Inorganic materials 0.000 claims description 11
- LTVRSJBNXLZFGT-UHFFFAOYSA-N 2-silylethenone Chemical compound [SiH3]C=C=O LTVRSJBNXLZFGT-UHFFFAOYSA-N 0.000 claims description 10
- 150000001768 cations Chemical class 0.000 claims description 10
- 150000002560 ketene acetals Chemical class 0.000 claims description 8
- 125000002252 acyl group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 6
- 150000007942 carboxylates Chemical class 0.000 claims description 6
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 6
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims description 6
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 230000002140 halogenating effect Effects 0.000 claims description 5
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 claims description 5
- 229960001243 orlistat Drugs 0.000 claims description 5
- 230000009467 reduction Effects 0.000 claims description 5
- WEGKDKPBTCKBQQ-MRXNPFEDSA-N (3r)-3-trimethylsilyloxytetradecanoyl chloride Chemical group CCCCCCCCCCC[C@H](CC(Cl)=O)O[Si](C)(C)C WEGKDKPBTCKBQQ-MRXNPFEDSA-N 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 4
- 150000004679 hydroxides Chemical class 0.000 claims description 4
- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 claims description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 claims description 3
- DTXSRICYVCKUME-UHFFFAOYSA-L ruthenium(2+);diacetate Chemical compound [Ru+2].CC([O-])=O.CC([O-])=O DTXSRICYVCKUME-UHFFFAOYSA-L 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- HFBHOAHFRNLZGN-LURJTMIESA-N (2s)-2-formamido-4-methylpentanoic acid Chemical compound CC(C)C[C@@H](C(O)=O)NC=O HFBHOAHFRNLZGN-LURJTMIESA-N 0.000 claims description 2
- ZPLNOBKZFHEVGA-SSYAZFEXSA-N C[Si](OC([C@H](C(=O)OC)CCCCCC)=CC(CCCCCCCCCCC)O[Si](C)(C)C)(C)C Chemical compound C[Si](OC([C@H](C(=O)OC)CCCCCC)=CC(CCCCCCCCCCC)O[Si](C)(C)C)(C)C ZPLNOBKZFHEVGA-SSYAZFEXSA-N 0.000 claims description 2
- RUIZXJNYLMYDLB-UHFFFAOYSA-N [P].C1=CC=CC=C1C1=CC=CC=C1 Chemical class [P].C1=CC=CC=C1C1=CC=CC=C1 RUIZXJNYLMYDLB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001805 chlorine compounds Chemical group 0.000 claims description 2
- JWBISEOOIYWJAR-IKOFQBKESA-N ethyl (5r)-2-hexyl-3-oxo-5-trimethylsilyloxyhexadecanoate Chemical compound CCCCCCCCCCC[C@@H](O[Si](C)(C)C)CC(=O)C(C(=O)OCC)CCCCCC JWBISEOOIYWJAR-IKOFQBKESA-N 0.000 claims description 2
- 150000002596 lactones Chemical class 0.000 claims description 2
- BMSVIOWGXQIDOX-MIHMCVIASA-N methyl (5r)-2-hexyl-3-oxo-5-trimethylsilyloxyhexadecanoate Chemical group CCCCCCCCCCC[C@@H](O[Si](C)(C)C)CC(=O)C(C(=O)OC)CCCCCC BMSVIOWGXQIDOX-MIHMCVIASA-N 0.000 claims description 2
- 238000007142 ring opening reaction Methods 0.000 claims description 2
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 claims 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 claims 1
- MFWAUQYJVQZMFL-UHFFFAOYSA-N ethyl 3-oxo-5-trimethylsilyloxydecanoate Chemical compound CCCCCC(O[Si](C)(C)C)CC(=O)CC(=O)OCC MFWAUQYJVQZMFL-UHFFFAOYSA-N 0.000 claims 1
- 150000001261 hydroxy acids Chemical class 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 120
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 81
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 64
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 49
- 239000011541 reaction mixture Substances 0.000 description 43
- 239000000203 mixture Substances 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 33
- 239000000243 solution Substances 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 32
- 239000000725 suspension Substances 0.000 description 31
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 27
- 239000007787 solid Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 22
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- MNDIARAMWBIKFW-UHFFFAOYSA-N 1-bromohexane Chemical compound CCCCCCBr MNDIARAMWBIKFW-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- VURFVHCLMJOLKN-UHFFFAOYSA-N diphosphane Chemical class PP VURFVHCLMJOLKN-UHFFFAOYSA-N 0.000 description 11
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- HSHMTDVEKPAEGS-UHFFFAOYSA-N diethyl 2-hexylpropanedioate Chemical compound CCCCCCC(C(=O)OCC)C(=O)OCC HSHMTDVEKPAEGS-UHFFFAOYSA-N 0.000 description 9
- 229910052751 metal Inorganic materials 0.000 description 9
- 239000002184 metal Substances 0.000 description 9
- 239000003960 organic solvent Substances 0.000 description 9
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000004821 distillation Methods 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 8
- 150000003512 tertiary amines Chemical class 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- ZIYVHBGGAOATLY-UHFFFAOYSA-N methylmalonic acid Chemical compound OC(=O)C(C)C(O)=O ZIYVHBGGAOATLY-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 239000004809 Teflon Substances 0.000 description 6
- 229920006362 Teflon® Polymers 0.000 description 6
- 229910052786 argon Inorganic materials 0.000 description 6
- 238000009876 asymmetric hydrogenation reaction Methods 0.000 description 6
- UCZHVONNLSXXCI-UHFFFAOYSA-N dimethyl 2-hexylpropanedioate Chemical compound CCCCCCC(C(=O)OC)C(=O)OC UCZHVONNLSXXCI-UHFFFAOYSA-N 0.000 description 6
- 238000011067 equilibration Methods 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 238000006884 silylation reaction Methods 0.000 description 6
- 238000000967 suction filtration Methods 0.000 description 6
- 229940086542 triethylamine Drugs 0.000 description 6
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- BLXCWAINNUGTQE-LJQANCHMSA-N (2r)-5-hexyl-4-hydroxy-2-undecyl-2,3-dihydropyran-6-one Chemical compound CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1 BLXCWAINNUGTQE-LJQANCHMSA-N 0.000 description 5
- FQKGSCOHCDSKAC-UHFFFAOYSA-N 4-[3-cyanopropyl(dimethoxy)silyl]butanenitrile Chemical compound N#CCCC[Si](OC)(CCCC#N)OC FQKGSCOHCDSKAC-UHFFFAOYSA-N 0.000 description 5
- BLXCWAINNUGTQE-UHFFFAOYSA-N 5-hexyl-4-hydroxy-2-undecyl-2,3-dihydropyran-6-one Chemical compound CCCCCCCCCCCC1CC(O)=C(CCCCCC)C(=O)O1 BLXCWAINNUGTQE-UHFFFAOYSA-N 0.000 description 5
- 238000006418 Brown reaction Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000004817 gas chromatography Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000001632 sodium acetate Substances 0.000 description 5
- 235000017281 sodium acetate Nutrition 0.000 description 5
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 4
- DRSSRPWTPHIRJG-UHFFFAOYSA-N 2-ethoxycarbonyloctanoic acid Chemical compound CCCCCCC(C(O)=O)C(=O)OCC DRSSRPWTPHIRJG-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- PBYRAYONARLAQJ-UHFFFAOYSA-N [2-[2-bis(3,5-ditert-butylphenyl)phosphanyl-6-methoxyphenyl]-3-methoxyphenyl]-bis(3,5-ditert-butylphenyl)phosphane Chemical compound COC=1C=CC=C(P(C=2C=C(C=C(C=2)C(C)(C)C)C(C)(C)C)C=2C=C(C=C(C=2)C(C)(C)C)C(C)(C)C)C=1C=1C(OC)=CC=CC=1P(C=1C=C(C=C(C=1)C(C)(C)C)C(C)(C)C)C1=CC(C(C)(C)C)=CC(C(C)(C)C)=C1 PBYRAYONARLAQJ-UHFFFAOYSA-N 0.000 description 4
- 125000005233 alkylalcohol group Chemical group 0.000 description 4
- WDECIBYCCFPHNR-UHFFFAOYSA-N chrysene Chemical compound C1=CC=CC2=CC=C3C4=CC=CC=C4C=CC3=C21 WDECIBYCCFPHNR-UHFFFAOYSA-N 0.000 description 4
- 238000005828 desilylation reaction Methods 0.000 description 4
- PWSLBMVNVSADMI-UHFFFAOYSA-N diethyl 2,2-dihexylpropanedioate Chemical compound CCCCCCC(C(=O)OCC)(C(=O)OCC)CCCCCC PWSLBMVNVSADMI-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000005270 trialkylamine group Chemical group 0.000 description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 4
- 239000003039 volatile agent Substances 0.000 description 4
- MDLJTYLCQPZADW-UHFFFAOYSA-N 2-methoxycarbonyloctanoic acid Chemical compound CCCCCCC(C(O)=O)C(=O)OC MDLJTYLCQPZADW-UHFFFAOYSA-N 0.000 description 3
- WEGKDKPBTCKBQQ-UHFFFAOYSA-N 3-trimethylsilyloxytetradecanoyl chloride Chemical compound CCCCCCCCCCCC(CC(Cl)=O)O[Si](C)(C)C WEGKDKPBTCKBQQ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 244000309464 bull Species 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- WUXHROCHHBXGDN-UHFFFAOYSA-N dimethyl 2,2-dihexylpropanedioate Chemical compound CCCCCCC(C(=O)OC)(C(=O)OC)CCCCCC WUXHROCHHBXGDN-UHFFFAOYSA-N 0.000 description 3
- RXVHBWZRZUBQSM-UHFFFAOYSA-N ethyl 2-hexyl-5-hydroxy-3-oxohexadecanoate Chemical compound CCCCCCCCCCCC(O)CC(=O)C(C(=O)OCC)CCCCCC RXVHBWZRZUBQSM-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- CQRPUKWAZPZXTO-UHFFFAOYSA-M magnesium;2-methylpropane;chloride Chemical compound [Mg+2].[Cl-].C[C-](C)C CQRPUKWAZPZXTO-UHFFFAOYSA-M 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000000526 short-path distillation Methods 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- OSAHWADQQULDAE-UHFFFAOYSA-N 1-methoxyoct-1-enoxy(trimethyl)silane Chemical compound CCCCCCC=C(OC)O[Si](C)(C)C OSAHWADQQULDAE-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- NMLZYEWNUCRSRJ-UHFFFAOYSA-L [1-(2-diphenylphosphanylnaphthalen-1-yl)naphthalen-2-yl]-diphenylphosphane;ruthenium(2+);diacetate Chemical compound [Ru+2].CC([O-])=O.CC([O-])=O.C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 NMLZYEWNUCRSRJ-UHFFFAOYSA-L 0.000 description 2
- NWFDYJDCSIHFAB-UHFFFAOYSA-M [Cl-].CCC(C)(C)[Mg+] Chemical compound [Cl-].CCC(C)(C)[Mg+] NWFDYJDCSIHFAB-UHFFFAOYSA-M 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 150000004729 acetoacetic acid derivatives Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 2
- 239000000920 calcium hydroxide Substances 0.000 description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 2
- OEERIBPGRSLGEK-UHFFFAOYSA-N carbon dioxide;methanol Chemical compound OC.O=C=O OEERIBPGRSLGEK-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 235000008504 concentrate Nutrition 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- RXVHBWZRZUBQSM-ZMFCMNQTSA-N ethyl (5r)-2-hexyl-5-hydroxy-3-oxohexadecanoate Chemical compound CCCCCCCCCCC[C@@H](O)CC(=O)C(C(=O)OCC)CCCCCC RXVHBWZRZUBQSM-ZMFCMNQTSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- BNHFWQQYLUPDOG-UHFFFAOYSA-N lithium;1,2,2,3-tetramethylpiperidine Chemical compound [Li].CC1CCCN(C)C1(C)C BNHFWQQYLUPDOG-UHFFFAOYSA-N 0.000 description 2
- 229910001629 magnesium chloride Inorganic materials 0.000 description 2
- 159000000003 magnesium salts Chemical class 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UOZZAMWODZQSOA-CQSZACIVSA-N methyl (3r)-3-hydroxytetradecanoate Chemical compound CCCCCCCCCCC[C@@H](O)CC(=O)OC UOZZAMWODZQSOA-CQSZACIVSA-N 0.000 description 2
- UOZZAMWODZQSOA-UHFFFAOYSA-N methyl 3-hydroxytetradecanoate Chemical compound CCCCCCCCCCCC(O)CC(=O)OC UOZZAMWODZQSOA-UHFFFAOYSA-N 0.000 description 2
- JGHZJRVDZXSNKQ-UHFFFAOYSA-N methyl octanoate Chemical compound CCCCCCCC(=O)OC JGHZJRVDZXSNKQ-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 description 2
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 2
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RRKODOZNUZCUBN-CCAGOZQPSA-N (1z,3z)-cycloocta-1,3-diene Chemical compound C1CC\C=C/C=C\C1 RRKODOZNUZCUBN-CCAGOZQPSA-N 0.000 description 1
- VYXHVRARDIDEHS-QGTKBVGQSA-N (1z,5z)-cycloocta-1,5-diene Chemical compound C\1C\C=C/CC\C=C/1 VYXHVRARDIDEHS-QGTKBVGQSA-N 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- UZGRZSHGRZYCQV-UHFFFAOYSA-N 4,6-dichloro-1,3-benzothiazol-2-amine Chemical compound C1=C(Cl)C=C2SC(N)=NC2=C1Cl UZGRZSHGRZYCQV-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 229940127470 Lipase Inhibitors Drugs 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 239000005641 Methyl octanoate Substances 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 150000001216 Samarium Chemical class 0.000 description 1
- 229910052772 Samarium Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910001508 alkali metal halide Inorganic materials 0.000 description 1
- 150000008045 alkali metal halides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 229910000024 caesium carbonate Inorganic materials 0.000 description 1
- BRPQOXSCLDDYGP-UHFFFAOYSA-N calcium oxide Chemical compound [O-2].[Ca+2] BRPQOXSCLDDYGP-UHFFFAOYSA-N 0.000 description 1
- 239000000292 calcium oxide Substances 0.000 description 1
- ODINCKMPIJJUCX-UHFFFAOYSA-N calcium oxide Inorganic materials [Ca]=O ODINCKMPIJJUCX-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001734 carboxylic acid salts Chemical class 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000000078 claw Anatomy 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 125000005265 dialkylamine group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002085 enols Chemical class 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- YHYANIKYZIYYHG-PLYLYKGUSA-N ethyl (2R)-2-hexyl-3,5-bis(trimethylsilyloxy)hexadec-3-enoate Chemical compound C[Si](OC([C@H](C(=O)OCC)CCCCCC)=CC(CCCCCCCCCCC)O[Si](C)(C)C)(C)C YHYANIKYZIYYHG-PLYLYKGUSA-N 0.000 description 1
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 description 1
- 229910052808 lithium carbonate Inorganic materials 0.000 description 1
- HQRPHMAXFVUBJX-UHFFFAOYSA-M lithium;hydrogen carbonate Chemical compound [Li+].OC([O-])=O HQRPHMAXFVUBJX-UHFFFAOYSA-M 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 150000002696 manganese Chemical class 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- UOGMEBQRZBEZQT-UHFFFAOYSA-L manganese(2+);diacetate Chemical class [Mn+2].CC([O-])=O.CC([O-])=O UOGMEBQRZBEZQT-UHFFFAOYSA-L 0.000 description 1
- 238000006140 methanolysis reaction Methods 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000003495 polar organic solvent Substances 0.000 description 1
- 239000005373 porous glass Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- BPEVHDGLPIIAGH-UHFFFAOYSA-N ruthenium(3+) Chemical compound [Ru+3] BPEVHDGLPIIAGH-UHFFFAOYSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- BABPEPRNSRIYFA-UHFFFAOYSA-N silyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O[SiH3] BABPEPRNSRIYFA-UHFFFAOYSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- SJRDNQOIQZOVQD-UHFFFAOYSA-M sodium;2,2-dimethylpropanoate Chemical compound [Na+].CC(C)(C)C([O-])=O SJRDNQOIQZOVQD-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 125000005208 trialkylammonium group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract
Description
Claims (50)
- (a) 하기 화학식 2의 아실 할라이드를 하기 화학식 3의 케텐 아세탈로 처리하여 하기 화학식 4의 δ-하이드록시-보호된-β-에놀 에테르 에스테르를 제조한다음 하나 이상의 보호기 R3 및 R6를 제거하고, 상기 생성물을 산과 접촉시켜 하기 화학식 1의 δ-락톤을 제조하거나, (b) 하기 화학식 2의 아실 할라이드를 하기 화학식 5의 말로네이트 하프산으로 처리하여 하기 화학식 6의 δ-하이드록시-β-케토에스테르를 제조한다음 δ-하이드록시-보호된-β-에놀 에테르 에스테르를 산으로 처리하여 하기 화학식 1의 δ-락톤을 제조함을 포함하는, 하기 화학식 1의 δ-락톤의 제조방법:화학식 1화학식 2화학식 3화학식 4화학식 5화학식 6상기 식들에서,R1은 C1-C20 알킬이고,R2는 H 또는 C1-C10 알킬이고,R3는 하이드록시 보호기이고,화학식 3 및 4에서 R4 및 R5는 독립적으로 C1-C6 알킬, C5 -C20 아릴, C6-C20 아릴알킬 또는 식 -SiR8R9R10(여기서, R8, R9 및 R10 은 독립적으로 C1-C6 알킬 또는 페닐이다)이고,R5는 C1-C6 알킬, C5-C20 아릴 또는 C6-C 20 아릴알킬이고,R6은 H 또는 R4이고,R7은 H 또는 R3이고,X는 할라이드이다.
- 제 1 항에 있어서,R1이 운데실인 방법.
- 제 1 항 또는 제 2 항에 있어서,R2가 헥실인 방법.
- 제 1 항 또는 제 2 항에 있어서,R3가 식 -SiR11R12R13(여기서, R11, R12 및 R13은 각각 독립적으로 C1-C6 알킬 또는 페닐이다)의 잔기인 방법.
- 제 1 항 또는 제 2 항에 있어서,X가 클로라이드인 방법.
- 제 1 항 또는 제 2 항에 있어서,R5가 C1-C6 알킬인 방법.
- 제 1 항 또는 제 2 항에 있어서,R4 및 R6이 각각 식 -SiR8R9R10의 잔기인 방법.
- 제 1 항 또는 제 2 항에 있어서,R7이 H인 방법.
- 제 1 항 또는 제 2 항에 있어서,단계 (a)가 δ-하이드록시-보호된-β-에놀 에테르 에스테르를 제조한다음 R6 보호기를 제거하여 하기 화학식 102의 δ-하이드록시-보호된-β-케토에스테르를 제조함을 포함하는 방법:화학식 102상기 식에서,R1, R2, R3 및 R5는 각각 제 1 항 또는 제 2 항에서 정의한 바와 같다.
- 제 1 항 또는 제 2 항에 있어서,(i) 하기 화학식 103의 β-하이드록시 산을 하이드록시 보호기로 처리하여 하기 화학식 104의 β-하이드록시-보호된 에스테르를 제조하고, (ii) 상기 β-하이드록시-보호된 에스테르를 아실 할로겐화제로 처리하여 아실 할라이드를 제조함을 포함하는 아실 할라이드 제조 단계를 추가로 포함하는 방법:화학식 103화학식 104상기 식들에서,R1 및 R3는 제 1 항 또는 제 2 항에서 정의한 바와 같고,R14은 H, R3 또는 카복실레이트 반대 양이온이다.
- 제 10 항에 있어서,R3 및 R14이 각각 식 -SiR15R16R17(여기서, R15 , R16 및 R17은 각각 독립적으로 C1-C6 알킬 또는 페닐이다)의 잔기인 방법.
- 제 10 항에 있어서,(a) 하기 화학식 105의 β-케토에스테르를 에난티오선택적으로 환원시켜 하기 화학식 106의 β-하이드록시 에스테르를 에난티오선택적으로 제조하고, (b) 상기 β-하이드록시 에스테르를 비누화시켜 β-하이드록시 산을 제조함을 포함하는 β-하이드록시 산의 에난티오선택적 제조 단계를 추가로 포함하는 방법:화학식 105화학식 106상기 식들에서,R1은 제 1 항 또는 제 2 항에서 정의한 바와 같고,R18은 C1-C6 알킬, C5-C20 아릴 또는 C6-C 20 아릴알킬이다.
- 제 12 항에 있어서,하기 화학식 7의 입체화학 구조를 갖는 δ-락톤을 제조하는 방법:화학식 7상기 식에서,R1 및 R2는 각각 제 1 항 또는 제 2 항에서 정의한 바와 같다.
- 제 13 항에 있어서,90% 이상의 에난티오머 과량으로 δ-락톤을 제조하는 방법.
- 제 12 항에 있어서,β-케토에스테르의 에난티오선택적 환원 단계가 수소화 촉매의 존재하에서의 β-케토에스테르의 수소화를 포함하는 방법.
- 제 15 항에 있어서,수소화 촉매가 본원 명세서중 표 4에 나타낸 촉매로부터 선택되는 방법.
- 제 16 항에 있어서,수소화 촉매가 디(η2-클로로)[(R)-(6,6'-디메톡시비페닐-2,2'-디일)비스(디페닐포스핀)]루테늄(II)(식 RuCl2((R)-MeOBIPHEP))의 화합물인 방법.
- 제 17 항에 있어서,수소화 촉매가 디(η2-아세타토)[(R)-(6,6'-디메톡시비페닐-2,2'-디일)비스(디페닐포스핀)]루테늄(II)(식 Ru(OAc)2((R)-MeOBIPHEP))의 루테늄 디아세테이트 화합물을 할라이드 공급원과 접촉시킴으로써 제조된 생성물인 방법.
- 제 18 항에 있어서,할라이드 공급원 대 루테늄 디아세테이트의 몰비가 20:1 이상인 방법.
- 할라이드와 키랄 치환된 비페닐 인 리간드를 포함하는 루테늄 수소화 촉매 및 40바아 이하의 수소 기체 압력의 존재하에서 하기 화학식 105의 β-케토에스테르를 수소화시킴을 포함하는, 제 12 항에서 정의한 바와 같은 하기 화학식 106의 β-하이드록시 에스테르의 에난티오선택적 제조방법:화학식 105화학식 106상기 식들에서,R1은 C1-C20 알킬이고,R18은 H, C1-C6 알킬, C5-C20 아릴 또는 C6-C20 아릴알킬이다.
- 제 20 항에 있어서,수소 기체가 공업용 수소 기체인 방법.
- 제 20 항 또는 제 21 항에 있어서,R1이 운데실인 방법.
- 제 20 항 또는 제 21 항에 있어서,R18이 C1-C6 알킬인 방법.
- 제 20 항 또는 제 21 항에 있어서,수소화 촉매가 제 16 항 내지 제 19 항중 어느 한 항에서 정의한 바와 같은 촉매로부터 선택되는 방법.
- (a) 하기 화학식 107의 아실 할라이드를 하기 화학식 108의 실릴 케텐 아세탈로 처리하여 하기 화학식 109의 δ-실록시-β-실릴 에놀 에테르 에스테르를 제조하고, (b) 상기 δ-실록시-β-실릴 에놀 에테르 에스테르를 염기로 처리하여 하나 이상의 실릴기를 제거하고, (c) 상기 단계 (b)의 생성물을 산과 접촉시켜 하기 화학식 7의 δ-락톤을 제조함을 포함하는, 하기 화학식 7의 δ-락톤의 에난티오선택적 제조방법:화학식 7화학식 107화학식 108화학식 109상기 식들에서,R1은 C11H23이고,R2는 C6H13이고,R5는 C1-C6 알킬, C5-C20 아릴 또는 C6-C 20 아릴알킬이고,R8, R9, R10, R11, R12 및 R13은 각각 독립적으로 C1-C6 알킬 또는 페닐이다.
- 제 25 항에 있어서,90% 이상의 에난티오머 과량으로 δ-락톤을 제조하는 방법.
- 제 25 항 또는 제 26 항에 있어서,R5가 C1-C6 알킬인 방법.
- 제 25 항 또는 제 26 항에 있어서,단계 (b)가 δ-실록시-β-실릴 에놀 에테르 에스테르를 수산화물 및 탄산염으로 이루어진 군으로부터 선택되는 염기로 처리하여 양쪽 2개의 실릴기를 탈실릴화시킴을 포함하는 방법.
- 제 25 항 또는 제 26 항에 있어서,단계 (b)가 δ-실록시-β-실릴 에놀 에테르 에스테르를 중탄산염으로 처리하여 하기 화학식 110의 δ-실록시-β-케토에스테르를 제조함을 포함하는 방법:화학식 110상기 식에서,R5, R11, R12 및 R13은 각각 제 25 항에서 정의한 바와 같다.
- 제 25 항 또는 제 26 항에 있어서,산이 염산인 방법.
- 제 25 항에 있어서,(i) (R)-3-하이드록시 테트라데칸산을 실릴화제로 처리하여 하기 화학식 111의 β-실록시 테트라데카노에이트 실릴 에스테르를 제조하고, (ii) 상기 β-실록시 테트라데카노에이트 실릴 에스테르를 아실 할로겐화제와 접촉시켜 아실 할라이드를 제조함을 포함하는 아실 할라이드 제조 단계를 추가로 포함하는 방법:화학식 111상기 식에서,R11, R12 및 R13은 각각 제 25 항에서 정의한 바와 같다.
- 제 31 항에 있어서,R11, R12 및 R13이 각각 메틸인 방법.
- 제 31 항에 있어서,실릴화제가 트리메틸실릴 클로라이드 및 헥사메틸디실라잔으로 이루어진 군으로부터 선택되는 방법.
- 제 31 항에 있어서,아실 할로겐화제가 티오닐 클로라이드인 방법.
- 제 31 항에 있어서,(a) 하기 화학식 112의 β-케토에스테르를 에난티오선택적으로 환원시켜 하기 화학식 113의 β-하이드록시 에스테르를 제조하고, (b) 상기 β-하이드록시 에스테르를 비누화시켜 (R)-3-하이드록시 테트라데칸산을 제조함을 포함하는 (R)-3-하이드록시 테트라데칸산 제조 단계를 추가로 포함하는 방법:화학식 112화학식 113상기 식들에서,R18은 C1-C6 알킬, C5-C20 아릴 또는 C6-C 20 아릴알킬이다.
- 제 35 항에 있어서,β-케토에스테르의 에난티오선택적 환원 단계가 수소화 촉매의 존재하에서의 β-케토에스테르의 수소화를 포함하는 방법.
- 제 36 항에 있어서,수소화 촉매가 제 15 항 내지 제 19 항중 어느 한 항에서 정의한 바와 같은 군으로부터 선택되는 방법.
- (a) 하기 화학식 107의 아실 할라이드를 하기 화학식 114의 말로네이트 하프산으로 처리하여 하기 화학식 115의 δ-하이드록시-β-케토에스테르를 제조하고, (b) 상기 δ-하이드록시-β-케토에스테르를 산과 접촉시켜 하기 화학식 7의 δ-락톤을 제조함을 포함하는, 하기 화학식 7의 δ-락톤의 제조방법:화학식 7화학식 107화학식 114화학식 115상기 식들에서,R1은 C11H23이고,R2는 C6H13이고,R5는 C1-C6 알킬, C5-C20 아릴 또는 C6-C 20 아릴알킬이고,R11, R12 및 R13은 각각 독립적으로 C1-C6 알킬 또는 페닐이다.
- 제 38 항에 있어서,90% 이상의 에난티오머 과량으로 δ-락톤을 제조하는 방법.
- 제 38 항 또는 제 39 항에 있어서,R5가 C1-C6 알킬인 방법.
- 제 38 항 또는 제 39 항에 있어서,산이 염산인 방법.
- 제 38 항 또는 제 39 항에 있어서,제 31 항 내지 제 37 항중 어느 한 항에서 정의한 바와 같은 아실 할라이드 제조 단계를 추가로 포함하는 방법.
- 제 1 항 또는 제 2 항에 있어서,(c) 하기 화학식 7의 화합물을 수소화시켜 하기 화학식 8의 화합물을 수득하는 단계, (d) 수득된 화합물을 염기성 조건하에서 개환 반응시키고 에난티오머적으로 분리시켜 하기 화학식 9의 화합물을 수득하는 단계, (e) 수득된 하기 화학식 9의 화합물의 유리산을 제조하고, 고리를 형성시키고, 기 PG를 절단하여 하기 화학식 10의 화합물을 수득하는 단계, 및 (f) 수득된 화합물을 미쓰노부(Mitsunobu) 조건하에서 N-포르밀-S-류신으로 탈보호 및 반응시켜 하기 화학식 11의 화합물을 수득하는 단계를 추가로 포함하는 방법:화학식 7화학식 8화학식 9화학식 10화학식 11상기 식들에서,R1 및 R2는 각각 제 1 항 또는 제 2 항에서 정의한 바와 같고,X+는 양이온이고,PG는 OH-보호기이다.
- 제 43 항에 있어서,R1이 C11H23이고, R2가 C6H13인 방법.
- (a) 하기 화학식 116의 β-실록시 아실 할라이드, (b) 하기 화학식 117의 δ-실록시-β-실릴 에놀 에테르 에스테르 및 (c) 하기 화학식 118의 δ-실록시-β-케토에스테르로 이루어진 군으로부터 선택되는 화합물 (단, 에틸 5-(트리메틸실록시)-3-옥소-데카노에이트는 제외됨):화학식 116화학식 117화학식 118상기 식들에서,R1은 C1-C20 알킬이고,R2는 H 또는 C1-C10 알킬이고,R5는 C1-C6 알킬, C5-C20 아릴 또는 C6-C20 아릴알킬이고,R8, R9, R10, R11, R12 및 R13은 각각 독립적으로 C1-C6 알킬 또는 페닐이고,X는 할라이드이다.
- 제 45 항에 있어서,β-실록시 아실 할라이드가 (R)-3-트리메틸실록시 테트라데카노일 클로라이드인 화합물.
- 제 45 항에 있어서,δ-실록시-β-실릴 에놀 에테르 에스테르가 메틸 (R)-3,5-비스-(트리메틸실록시)-2-헥실-3-헥사데세노에이트 및 에틸 (R)-3,5-비스-(트리메틸실록시)-2-헥실-3-헥사데세노에이트로 이루어진 군으로부터 선택되는 화합물.
- 제 45 항에 있어서,δ-실록시-β-케토에스테르가 메틸 (5R)-5-(트리메틸실록시)-2-헥실-3-옥소-헥사데카노에이트 및 에틸 (5R)-5-(트리메틸실록시)-2-헥실-3-옥소-헥사데카노에이트로 이루어진 군으로부터 선택되는 화합물.
- 제 1 항 또는 제 2 항에 있어서,오를리스타트(orlistat)를 제조하기 위한 방법.
- 삭제
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US6552204B1 (en) * | 2000-02-04 | 2003-04-22 | Roche Colorado Corporation | Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one |
US8932136B2 (en) | 2000-08-25 | 2015-01-13 | Opentv, Inc. | Method and system for initiating an interactive game |
WO2004065346A1 (ja) * | 2003-01-21 | 2004-08-05 | Sumitomo Chemical Company, Limited | (-)-テトラヒドロリプスタチンおよびその中間体の製造方法 |
EP1651627A2 (en) * | 2003-07-15 | 2006-05-03 | Ranbaxy Laboratories Limited | Process for preparation of oxetan-2-ones |
WO2006017045A2 (en) | 2004-07-08 | 2006-02-16 | Merck & Co., Inc. | Formation of tetra-substituted enamides and stereoselective reduction thereof |
WO2006090377A1 (en) * | 2005-02-22 | 2006-08-31 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | One-pot non-symmetric heterobifunctional coupling of organic molecules through malonic acid derivatives |
US7935829B2 (en) * | 2005-04-15 | 2011-05-03 | Dsm Ip Assets B.V. | Manufacture of thiolactones |
US20080113325A1 (en) * | 2006-11-09 | 2008-05-15 | Sony Ericsson Mobile Communications Ab | Tv out enhancements to music listening |
CN101066924B (zh) * | 2007-06-08 | 2011-01-12 | 中国科学院上海有机化学研究所 | 2-己基-3-羟基-5-r1氧基十六羧酸r2酯,制备方法及用于制备减肥药物奥利司他的用途 |
KR101076680B1 (ko) * | 2007-11-01 | 2011-10-26 | 한미홀딩스 주식회사 | (6r)-3-헥실-4-히드록시-6-운데실-5,6-다이히드로피란-2-온의 제조방법 및 이에 사용되는 중간체 |
CA2744511A1 (en) | 2008-12-16 | 2010-06-24 | F.Hoffmann-La Roche Ag | Process for the preparation of pyrollidine-3-carboxylic acids |
JP5933529B2 (ja) * | 2010-05-21 | 2016-06-08 | フイルメニツヒ ソシエテ アノニムFirmenich Sa | ルテニウムをベースとする錯体 |
CN102947320B (zh) * | 2010-06-22 | 2015-11-25 | 弗门尼舍有限公司 | 钌基络合物 |
US8598925B1 (en) * | 2012-07-16 | 2013-12-03 | Nanowave Technologies Inc. | Frequency determination circuit and method |
JP7161316B2 (ja) | 2018-06-11 | 2022-10-26 | クノールブレムゼ商用車システムジャパン株式会社 | 不純物分離装置 |
WO2024008605A2 (en) | 2022-07-04 | 2024-01-11 | F. Hoffmann-La Roche Ag | Process for the preparation of [ru(oac)2(ligand)] catalysts |
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ES2021058B3 (es) * | 1986-10-24 | 1991-10-16 | Merck & Co Inc | Procedimiento para la sintesis de una azetidinona quiral. |
EP0333268A1 (en) * | 1988-03-18 | 1989-09-20 | Merck & Co. Inc. | Process for synthesis of a chiral 3-beta hydrogen (3R) 4-aroyloxy azetidinone |
ATE128140T1 (de) * | 1989-05-18 | 1995-10-15 | Hoffmann La Roche | Phosphorverbindungen. |
CA2035972C (en) * | 1990-02-23 | 2006-07-11 | Martin Karpf | Process for the preparation of oxetanones |
JPH04316538A (ja) * | 1991-01-22 | 1992-11-06 | Chisso Corp | 光学活性3,5−アンチ−ジヒドロキシカルボン酸エステル誘導体の製造法 |
WO1992014692A1 (en) * | 1991-02-11 | 1992-09-03 | Rhone-Poulenc Rorer International (Holdings) Inc. | Enantioselective preparation of acetylenic or olefinic substituted cycloalkenyl dihydroxybutyrates and 4-hydroxy-tetrahydropyran-2-ones |
DE19636974A1 (de) * | 1996-09-12 | 1998-03-19 | Hoechst Ag | 2-Cyano-3,5-dihydroxy-hex-2-en- carbonsäureamidderivate |
JP3445074B2 (ja) * | 1996-09-20 | 2003-09-08 | 高砂香料工業株式会社 | ルテニウム−ホスフィン錯体の製造方法 |
KR20010021645A (ko) * | 1997-07-11 | 2001-03-15 | 로렌스 티. 마이젠헬더 | 티아디아졸릴 및 옥사디아졸릴 페닐 옥사졸리디논 항균제 |
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US6552204B1 (en) * | 2000-02-04 | 2003-04-22 | Roche Colorado Corporation | Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one |
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DE60100238T2 (de) | 2004-04-01 |
JO2249B1 (en) | 2004-10-07 |
JP2009173635A (ja) | 2009-08-06 |
EP1127886B1 (en) | 2003-05-07 |
JP2004346078A (ja) | 2004-12-09 |
CA2333192C (en) | 2007-01-23 |
MXPA01001187A (es) | 2002-06-04 |
CN1193992C (zh) | 2005-03-23 |
JP4666454B2 (ja) | 2011-04-06 |
DE60100238D1 (de) | 2003-06-12 |
CN1319596A (zh) | 2001-10-31 |
KR20010078336A (ko) | 2001-08-20 |
US6552204B1 (en) | 2003-04-22 |
JP5173775B2 (ja) | 2013-04-03 |
EP1127886A1 (en) | 2001-08-29 |
ATE239716T1 (de) | 2003-05-15 |
DK1127886T3 (da) | 2003-09-01 |
JP2001220387A (ja) | 2001-08-14 |
ES2197128T3 (es) | 2004-01-01 |
CA2333192A1 (en) | 2001-08-04 |
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