KR20040029394A - 에포틸론 및 유도체의 합성을 위한 보호3,5-디히드록시-2,2-디메틸-발레로아미드 및 그의 제조방법 및 용도 - Google Patents

에포틸론 및 유도체의 합성을 위한 보호3,5-디히드록시-2,2-디메틸-발레로아미드 및 그의 제조방법 및 용도 Download PDF

Info

Publication number: KR20040029394A
Authority: KR; South Korea
Prior art keywords: formula; benzyl; dimethyl; compound; group
Prior art date: 2001-08-03

Application number

KR10-2004-7001710A

Other languages

English (en)

Korean (ko)

Inventor

쥐르겐 베스터만

올린 페트로브

조한스 프라트젝

Original Assignee

쉐링 악티엔게젤샤프트

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2001-08-03

Filing date

2002-08-05

Publication date

2004-04-06

2002-08-05 Application filed by 쉐링 악티엔게젤샤프트 filed Critical 쉐링 악티엔게젤샤프트

2004-04-06 Publication of KR20040029394A publication Critical patent/KR20040029394A/ko

Links

238000000034 method Methods 0.000 title claims abstract description 38
229930013356 epothilone Natural products 0.000 title claims abstract description 10
150000003883 epothilone derivatives Chemical class 0.000 title claims abstract description 5
238000004519 manufacturing process Methods 0.000 title claims description 7
238000003786 synthesis reaction Methods 0.000 title abstract description 8
230000015572 biosynthetic process Effects 0.000 title abstract description 7
ZYRUAVNMUFDGQT-UHFFFAOYSA-N 3,5-dihydroxy-2,2-dimethylpentanamide Chemical class NC(=O)C(C)(C)C(O)CCO ZYRUAVNMUFDGQT-UHFFFAOYSA-N 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 113
238000002360 preparation method Methods 0.000 claims abstract description 27
HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 claims abstract description 10
150000001408 amides Chemical class 0.000 claims description 37
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
125000006239 protecting group Chemical group 0.000 claims description 25
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
-1 TIP Chemical group 0.000 claims description 16
125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 14
239000003054 catalyst Substances 0.000 claims description 12
RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 12
125000003710 aryl alkyl group Chemical group 0.000 claims description 11
125000003118 aryl group Chemical group 0.000 claims description 11
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 11
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 10
150000002576 ketones Chemical class 0.000 claims description 10
125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 10
125000006241 alcohol protecting group Chemical group 0.000 claims description 9
GQNZGCARKRHPOH-RQIKCTSVSA-N miocamycin Chemical group C1[C@](OC(C)=O)(C)[C@@H](OC(=O)CC)[C@H](C)O[C@H]1O[C@H]1[C@H](N(C)C)[C@@H](O)[C@H](O[C@@H]2[C@H]([C@H](OC(=O)CC)CC(=O)O[C@H](C)C/C=C/C=C/[C@H](OC(C)=O)[C@H](C)C[C@@H]2CC=O)OC)O[C@@H]1C GQNZGCARKRHPOH-RQIKCTSVSA-N 0.000 claims description 9
125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 8
150000002148 esters Chemical class 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
125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 7
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 7
JOCBASBOOFNAJA-UHFFFAOYSA-N N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid Chemical group OCC(CO)(CO)NCCS(O)(=O)=O JOCBASBOOFNAJA-UHFFFAOYSA-N 0.000 claims description 7
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 7
CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical group C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 claims description 7
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
125000004432 carbon atom Chemical group C* 0.000 claims description 6
150000003333 secondary alcohols Chemical class 0.000 claims description 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 5
230000002255 enzymatic effect Effects 0.000 claims description 5
125000000468 ketone group Chemical group 0.000 claims description 4
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
125000000217 alkyl group Chemical group 0.000 claims description 3
238000007127 saponification reaction Methods 0.000 claims description 3
RRDQNXUAYNXDJE-HNNXBMFYSA-N (3S)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2,2-dimethylpentanoic acid Chemical compound [Si](C)(C)(C(C)(C)C)O[C@H](C(C(=O)O)(C)C)CCO[Si](C)(C)C(C)(C)C RRDQNXUAYNXDJE-HNNXBMFYSA-N 0.000 claims description 2
102000004190 Enzymes Human genes 0.000 claims description 2
108090000790 Enzymes Proteins 0.000 claims description 2
102000004882 Lipase Human genes 0.000 claims description 2
108090001060 Lipase Proteins 0.000 claims description 2
230000007062 hydrolysis Effects 0.000 claims description 2
238000006460 hydrolysis reaction Methods 0.000 claims description 2
125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
WTEXCSCMZWYPJS-KRWDZBQOSA-N (3S)-2,2-dimethyl-3,5-bis(phenylsilyloxy)pentanoic acid Chemical compound C1(=CC=CC=C1)[SiH2]O[C@H](C(C(=O)O)(C)C)CCO[SiH2]C1=CC=CC=C1 WTEXCSCMZWYPJS-KRWDZBQOSA-N 0.000 claims 1
125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
241000349731 Afzelia bipindensis Species 0.000 claims 1
239000004367 Lipase Substances 0.000 claims 1
125000003158 alcohol group Chemical group 0.000 claims 1
238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
235000019421 lipase Nutrition 0.000 claims 1
IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims 1
QBZXOWQOWPHHRA-UHFFFAOYSA-N lithium;ethane Chemical compound [Li+].[CH2-]C QBZXOWQOWPHHRA-UHFFFAOYSA-N 0.000 claims 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
230000001681 protective effect Effects 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
239000000243 solution Substances 0.000 description 26
RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
239000012074 organic phase Substances 0.000 description 18
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
239000003921 oil Substances 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
239000000741 silica gel Substances 0.000 description 13
229910002027 silica gel Inorganic materials 0.000 description 13
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
QGYNXQMBZVRCEO-YFKPBYRVSA-N (3S)-3,5-dihydroxy-2,2-dimethylpentanoic acid Chemical compound O[C@H](C(C(=O)O)(C)C)CCO QGYNXQMBZVRCEO-YFKPBYRVSA-N 0.000 description 8
238000006243 chemical reaction Methods 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 7
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
239000000543 intermediate Substances 0.000 description 6
239000000047 product Substances 0.000 description 6
238000005575 aldol reaction Methods 0.000 description 5
125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 5
238000003818 flash chromatography Methods 0.000 description 5
230000009466 transformation Effects 0.000 description 5
238000000844 transformation Methods 0.000 description 5
VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
150000001298 alcohols Chemical class 0.000 description 4
238000005882 aldol condensation reaction Methods 0.000 description 4
238000002425 crystallisation Methods 0.000 description 4
230000008025 crystallization Effects 0.000 description 4
150000002009 diols Chemical class 0.000 description 4
239000003480 eluent Substances 0.000 description 4
239000013067 intermediate product Substances 0.000 description 4
VDTRJTGFCRZAIA-UHFFFAOYSA-N n,n,2-trimethyl-1-trimethylsilylprop-1-en-1-amine Chemical compound CN(C)C(=C(C)C)[Si](C)(C)C VDTRJTGFCRZAIA-UHFFFAOYSA-N 0.000 description 4
230000003647 oxidation Effects 0.000 description 4
238000007254 oxidation reaction Methods 0.000 description 4
239000012071 phase Substances 0.000 description 4
238000000746 purification Methods 0.000 description 4
239000007787 solid Substances 0.000 description 4
239000000126 substance Substances 0.000 description 4
JRHWHSJDIILJAT-BYPYZUCNSA-N (2s)-2-hydroxypentanoic acid Chemical compound CCC[C@H](O)C(O)=O JRHWHSJDIILJAT-BYPYZUCNSA-N 0.000 description 3
YIPMUTCSUODJOU-AWEZNQCLSA-N (3s)-3-hydroxy-n,n,2,2-tetramethyl-5-phenylmethoxypentanamide Chemical compound CN(C)C(=O)C(C)(C)[C@@H](O)CCOCC1=CC=CC=C1 YIPMUTCSUODJOU-AWEZNQCLSA-N 0.000 description 3
MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 3
AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 3
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
229910017855 NH 4 F Inorganic materials 0.000 description 3
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
229910052799 carbon Inorganic materials 0.000 description 3
239000012230 colorless oil Substances 0.000 description 3
229960004132 diethyl ether Drugs 0.000 description 3
125000004185 ester group Chemical group 0.000 description 3
239000000706 filtrate Substances 0.000 description 3
239000012634 fragment Substances 0.000 description 3
238000010438 heat treatment Methods 0.000 description 3
125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
239000002243 precursor Substances 0.000 description 3
229910052938 sodium sulfate Inorganic materials 0.000 description 3
235000011152 sodium sulphate Nutrition 0.000 description 3
239000002904 solvent Substances 0.000 description 3
239000007858 starting material Substances 0.000 description 3
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
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DSSYKIVIOFKYAU-OIBJUYFYSA-N (S)-camphor Chemical compound C1C[C@]2(C)C(=O)C[C@H]1C2(C)C DSSYKIVIOFKYAU-OIBJUYFYSA-N 0.000 description 2
HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 2
HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
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BHPOKGSFWCXYAD-UHFFFAOYSA-N N,2,2-trimethyl-3-oxo-N-phenyl-5-phenylmethoxypentanamide Chemical compound CN(C(C(C(CCOCC1=CC=CC=C1)=O)(C)C)=O)C1=CC=CC=C1 BHPOKGSFWCXYAD-UHFFFAOYSA-N 0.000 description 2
OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
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VEZXCJBBBCKRPI-UHFFFAOYSA-N beta-propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 2
238000001311 chemical methods and process Methods 0.000 description 2
IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
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239000011261 inert gas Substances 0.000 description 2
239000003120 macrolide antibiotic agent Substances 0.000 description 2
238000013048 microbiological method Methods 0.000 description 2
125000000896 monocarboxylic acid group Chemical group 0.000 description 2
OCLLZBHSVCOSSS-UHFFFAOYSA-N n-(3-methyl-2-trimethylsilylbut-3-en-2-yl)aniline Chemical compound CC(=C)C(C)([Si](C)(C)C)NC1=CC=CC=C1 OCLLZBHSVCOSSS-UHFFFAOYSA-N 0.000 description 2
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
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238000003756 stirring Methods 0.000 description 2
238000006257 total synthesis reaction Methods 0.000 description 2
238000010626 work up procedure Methods 0.000 description 2
229940075963 (-)- camphor Drugs 0.000 description 1
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125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
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XPIJMQVLTXAGME-UHFFFAOYSA-N 1,1-dimethoxycyclohexane Chemical compound COC1(OC)CCCCC1 XPIJMQVLTXAGME-UHFFFAOYSA-N 0.000 description 1
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ADQVHPMMGAMGFP-LBPRGKRZSA-N 2-[(4s)-2,2-dimethyl-1,3-dioxan-4-yl]-2-methylheptan-3-one Chemical compound CCCCC(=O)C(C)(C)[C@@H]1CCOC(C)(C)O1 ADQVHPMMGAMGFP-LBPRGKRZSA-N 0.000 description 1
LRRGYHJHSLSATF-UHFFFAOYSA-N 2-phenylmethoxypropanal Chemical compound O=CC(C)OCC1=CC=CC=C1 LRRGYHJHSLSATF-UHFFFAOYSA-N 0.000 description 1
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NBKNFNAHFNVUOW-UHFFFAOYSA-N 3-ethoxy-3-oxopropanoic acid;hydrochloride Chemical compound Cl.CCOC(=O)CC(O)=O NBKNFNAHFNVUOW-UHFFFAOYSA-N 0.000 description 1
YIPMUTCSUODJOU-UHFFFAOYSA-N 3-hydroxy-n,n,2,2-tetramethyl-5-phenylmethoxypentanamide Chemical compound CN(C)C(=O)C(C)(C)C(O)CCOCC1=CC=CC=C1 YIPMUTCSUODJOU-UHFFFAOYSA-N 0.000 description 1
XJGNRXDOYOEFKR-UHFFFAOYSA-N 3-phenylmethoxypropanoyl chloride Chemical compound ClC(=O)CCOCC1=CC=CC=C1 XJGNRXDOYOEFKR-UHFFFAOYSA-N 0.000 description 1
NBWQEOJFZRTXEM-UHFFFAOYSA-N 3-propanethioyl-1,3-oxazolidin-2-one Chemical compound CCC(=S)N1CCOC1=O NBWQEOJFZRTXEM-UHFFFAOYSA-N 0.000 description 1
DMAYBPBPEUFIHJ-UHFFFAOYSA-N 4-bromobut-1-ene Chemical compound BrCCC=C DMAYBPBPEUFIHJ-UHFFFAOYSA-N 0.000 description 1
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
239000004215 Carbon black (E152) Substances 0.000 description 1
XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
229930182831 D-valine Natural products 0.000 description 1
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
230000005526 G1 to G0 transition Effects 0.000 description 1
238000003747 Grignard reaction Methods 0.000 description 1
WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
206010028980 Neoplasm Diseases 0.000 description 1
241001532577 Sorangium Species 0.000 description 1
JEKXJMDUMGMVCJ-UHFFFAOYSA-N [Li]CCC=C Chemical compound [Li]CCC=C JEKXJMDUMGMVCJ-UHFFFAOYSA-N 0.000 description 1
239000002253 acid Substances 0.000 description 1
150000001299 aldehydes Chemical class 0.000 description 1
230000029936 alkylation Effects 0.000 description 1
238000005804 alkylation reaction Methods 0.000 description 1
150000001413 amino acids Chemical class 0.000 description 1
230000000259 anti-tumor effect Effects 0.000 description 1
238000013459 approach Methods 0.000 description 1
238000009876 asymmetric hydrogenation reaction Methods 0.000 description 1
238000011914 asymmetric synthesis Methods 0.000 description 1
125000004429 atom Chemical group 0.000 description 1
239000008280 blood Substances 0.000 description 1
210000004369 blood Anatomy 0.000 description 1
229910052796 boron Inorganic materials 0.000 description 1
239000007853 buffer solution Substances 0.000 description 1
201000011510 cancer Diseases 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
238000013375 chromatographic separation Methods 0.000 description 1
238000004440 column chromatography Methods 0.000 description 1
238000009833 condensation Methods 0.000 description 1
230000005494 condensation Effects 0.000 description 1
OSXYHAQZDCICNX-UHFFFAOYSA-N dichloro(diphenyl)silane Chemical compound C=1C=CC=CC=1[Si](Cl)(Cl)C1=CC=CC=C1 OSXYHAQZDCICNX-UHFFFAOYSA-N 0.000 description 1
FAMGJMYDHOESPR-UHFFFAOYSA-M dilithium;carbanide;bromide Chemical compound [Li+].[Li+].[CH3-].[Br-] FAMGJMYDHOESPR-UHFFFAOYSA-M 0.000 description 1
239000001177 diphosphate Substances 0.000 description 1
235000019820 disodium diphosphate Nutrition 0.000 description 1
BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
GYQBBRRVRKFJRG-UHFFFAOYSA-L disodium pyrophosphate Chemical compound [Na+].[Na+].OP([O-])(=O)OP(O)([O-])=O GYQBBRRVRKFJRG-UHFFFAOYSA-L 0.000 description 1
238000001035 drying Methods 0.000 description 1
238000006911 enzymatic reaction Methods 0.000 description 1
230000032050 esterification Effects 0.000 description 1
238000005886 esterification reaction Methods 0.000 description 1
125000001033 ether group Chemical group 0.000 description 1
238000001704 evaporation Methods 0.000 description 1
230000008020 evaporation Effects 0.000 description 1
238000013467 fragmentation Methods 0.000 description 1
238000006062 fragmentation reaction Methods 0.000 description 1
238000004128 high performance liquid chromatography Methods 0.000 description 1
229930195733 hydrocarbon Natural products 0.000 description 1
150000002430 hydrocarbons Chemical class 0.000 description 1
229910052739 hydrogen Inorganic materials 0.000 description 1
239000001257 hydrogen Substances 0.000 description 1
125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
239000005457 ice water Substances 0.000 description 1
238000002955 isolation Methods 0.000 description 1
229910052744 lithium Inorganic materials 0.000 description 1
150000002642 lithium compounds Chemical class 0.000 description 1
UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
YTJXGDYAEOTOCG-UHFFFAOYSA-N lithium;di(propan-2-yl)azanide;oxolane Chemical compound [Li+].C1CCOC1.CC(C)[N-]C(C)C YTJXGDYAEOTOCG-UHFFFAOYSA-N 0.000 description 1
229940041033 macrolides Drugs 0.000 description 1
239000000463 material Substances 0.000 description 1
230000001404 mediated effect Effects 0.000 description 1
DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 description 1
125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
235000019796 monopotassium phosphate Nutrition 0.000 description 1
GXMIHVHJTLPVKL-UHFFFAOYSA-N n,n,2-trimethylpropanamide Chemical compound CC(C)C(=O)N(C)C GXMIHVHJTLPVKL-UHFFFAOYSA-N 0.000 description 1
230000003287 optical effect Effects 0.000 description 1
150000007530 organic bases Chemical class 0.000 description 1
150000002902 organometallic compounds Chemical class 0.000 description 1
PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
RPTKMZRQBREOMV-UHFFFAOYSA-N propoxymethylbenzene Chemical compound CCCOCC1=CC=CC=C1 RPTKMZRQBREOMV-UHFFFAOYSA-N 0.000 description 1
238000012552 review Methods 0.000 description 1
230000011218 segmentation Effects 0.000 description 1
238000010561 standard procedure Methods 0.000 description 1
238000003860 storage Methods 0.000 description 1
238000006467 substitution reaction Methods 0.000 description 1
238000001308 synthesis method Methods 0.000 description 1
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
150000003568 thioethers Chemical class 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
125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
239000004474 valine Substances 0.000 description 1

Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/16—Preparation of optical isomers
- C07C231/18—Preparation of optical isomers by stereospecific synthesis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
- C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
- 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
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P13/00—Preparation of nitrogen-containing organic compounds
- C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/002—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by oxidation/reduction reactions
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction

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Chemical & Material Sciences (AREA)
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Pharmacology & Pharmacy (AREA)
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Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Preparation Of Compounds By Using Micro-Organisms (AREA)
Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

KR10-2004-7001710A 2001-08-03 2002-08-05 에포틸론 및 유도체의 합성을 위한 보호3,5-디히드록시-2,2-디메틸-발레로아미드 및 그의 제조방법 및 용도 KR20040029394A (ko)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
DE10138348A DE10138348A1 (de)	2001-08-03	2001-08-03	Geschützte 3,5-Dihydroxy-2,2-dimethyl-valeroamide für die Synthese von Epothilonen und Derivaten und Verfahren zur Herstellung und die Verwendung
DE10138348.7		2001-08-03
PCT/EP2002/008726 WO2003014063A2 (de)	2001-08-03	2002-08-05	Geschützte 3,5-dihydroxy-2,2-dimethyl-valeroamide für die synthese von epothilonen und derivaten und verfarhen zur herstellung und die verwendung

Publications (1)

Publication Number	Publication Date
KR20040029394A true KR20040029394A (ko)	2004-04-06

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KR10-2004-7001710A KR20040029394A (ko)	2001-08-03	2002-08-05	에포틸론 및 유도체의 합성을 위한 보호3,5-디히드록시-2,2-디메틸-발레로아미드 및 그의 제조방법 및 용도

Country Status (16)

Country	Link
EP (1)	EP1412322A2 (no)
JP (1)	JP2004537589A (no)
KR (1)	KR20040029394A (no)
CN (2)	CN1538952A (no)
AR (1)	AR036207A1 (no)
BR (1)	BR0211649A (no)
CA (1)	CA2456255A1 (no)
DE (1)	DE10138348A1 (no)
IL (1)	IL160159A0 (no)
MX (1)	MXPA04000954A (no)
NO (1)	NO20040912L (no)
PE (1)	PE20030345A1 (no)
PL (1)	PL367430A1 (no)
RU (1)	RU2004106530A (no)
WO (1)	WO2003014063A2 (no)
ZA (1)	ZA200401727B (no)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6867305B2 (en)	1996-12-03	2005-03-15	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto and analogues thereof
US6242469B1 (en)	1996-12-03	2001-06-05	Sloan-Kettering Institute For Cancer Research	Synthesis of epothilones, intermediates thereto, analogues and uses thereof
WO2003029195A1 (fr)	2001-09-28	2003-04-10	Sumika Fine Chemicals Co., Ltd.	Intermediaires pour l'elaboration d'un derive de l'epothilone, et leur procede de production
DE10326195A1 (de) *	2003-06-07	2004-12-23	Schering Ag	Geschützte 5,7-Dihydroxy-4,4-dimethyl-3-oxoheptansäureester und 5,7-Dihydroxy-2-alkyl-4,4-dimethyl-3-oxoheptansäureester für die Synthese von Epothilonen- und Derivaten und Verfahren zur Herstellung dieser Ester
CN110857276B (zh) *	2018-08-22	2021-03-02	中国科学院化学研究所	一类手性β-羟基酰胺类化合物及其制备方法与应用

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US4824980A (en) *	1988-09-02	1989-04-25	Dow Corning Corporation	Process to produce O-silyl O,N-ketene acetals
US6211412B1 (en) *	1999-03-29	2001-04-03	The University Of Kansas	Synthesis of epothilones

2001
- 2001-08-03 DE DE10138348A patent/DE10138348A1/de not_active Withdrawn
2002
- 2002-08-02 PE PE2002000704A patent/PE20030345A1/es not_active Application Discontinuation
- 2002-08-02 AR ARP020102940A patent/AR036207A1/es unknown
- 2002-08-05 CN CNA028152379A patent/CN1538952A/zh active Pending
- 2002-08-05 KR KR10-2004-7001710A patent/KR20040029394A/ko not_active Application Discontinuation
- 2002-08-05 WO PCT/EP2002/008726 patent/WO2003014063A2/de active Application Filing
- 2002-08-05 CA CA002456255A patent/CA2456255A1/en not_active Abandoned
- 2002-08-05 IL IL16015902A patent/IL160159A0/xx unknown
- 2002-08-05 MX MXPA04000954A patent/MXPA04000954A/es unknown
- 2002-08-05 PL PL02367430A patent/PL367430A1/xx unknown
- 2002-08-05 CN CNA2005100764590A patent/CN1807403A/zh active Pending
- 2002-08-05 BR BR0211649-9A patent/BR0211649A/pt not_active IP Right Cessation
- 2002-08-05 EP EP02774500A patent/EP1412322A2/de not_active Withdrawn
- 2002-08-05 RU RU2004106530/04A patent/RU2004106530A/ru not_active Application Discontinuation
- 2002-08-05 JP JP2003519015A patent/JP2004537589A/ja active Pending
2004
- 2004-03-02 NO NO20040912A patent/NO20040912L/no not_active Application Discontinuation
- 2004-03-02 ZA ZA200401727A patent/ZA200401727B/xx unknown

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Publication number	Publication date
BR0211649A (pt)	2004-07-13
IL160159A0 (en)	2004-07-25
NO20040912L (no)	2004-03-02
CN1538952A (zh)	2004-10-20
PL367430A1 (en)	2005-02-21
EP1412322A2 (de)	2004-04-28
WO2003014063A2 (de)	2003-02-20
CN1807403A (zh)	2006-07-26
DE10138348A1 (de)	2003-02-27
AR036207A1 (es)	2004-08-18
CA2456255A1 (en)	2003-02-20
WO2003014063A3 (de)	2003-05-01
MXPA04000954A (es)	2004-04-20
RU2004106530A (ru)	2005-07-27
JP2004537589A (ja)	2004-12-16
ZA200401727B (en)	2005-04-12
PE20030345A1 (es)	2003-04-10

Publication	Publication Date	Title
US4970313A (en)	1990-11-13	Optically active 3-demethylmevalonic acid derivatives, and intermediates
US4946999A (en)	1990-08-07	Novel intermediates for synthesis of trichostatic acid or trichostatin A, and processes for preparing trichostatic acid and trichostatin A
US20030158412A1 (en)	2003-08-21	Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for the production and the use
KR100876036B1 (ko)	2008-12-26	에포틸론 및 유도체의 합성을 위한 보호3,5-디히드록시-2,2-디메틸-발레로니트릴 및 그의 제조방법 및 용도
KR20040029394A (ko)	2004-04-06	에포틸론 및 유도체의 합성을 위한 보호3,5-디히드록시-2,2-디메틸-발레로아미드 및 그의 제조방법 및 용도
KR100598079B1 (ko)	2006-07-07	신규의 보로네이트 에스테르
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WO2008103016A1 (en)	2008-08-28	Atorvastatin intermediates and method for producing the same
US5214197A (en)	1993-05-25	2,4-dihydroxyadipic acid derivative
US7368568B2 (en)	2008-05-06	Protected 3,5-dihydroxy-2,2-dimethyl-valeroamides for the synthesis of epothilones and derivatives and process for production and the use
US5292946A (en)	1994-03-08	In-situ preparation of diisopinocamphenyl chloroborane
Ito et al.	2006	Enantioselective total synthesis of both diastereomers of preclavulone-A methyl ester
WO2005058861A1 (en)	2005-06-30	Process for preparing simvastatin.
US4501909A (en)	1985-02-26	Aminopolyol derivatives
CN101842363A (zh)	2010-09-22	制备(6r)-3-己基-4-羟基-6-十一烷基-5,6-二氢吡喃-2-酮的方法及该方法中所用的中间体
JP2709807B2 (ja)	1998-02-04	３−クロロ−４−シリルオキシ−２−シクロペンテン−１−オン類の製造法
AU704196B2 (en)	1999-04-15	Preparation of cis-4-O-protected-2-cyclopentenol derivatives
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JP5059355B2 (ja)	2012-10-24	オキサゾリジン誘導体の製造方法
JPH0525089A (ja)	1993-02-02	２−ヒドロキシ酸誘導体の製造法
MXPA98002923A (en)	1999-06-01	Intermediary compounds for the detaxanism semisintesis and the preparation procedures of the mis
KR20050060281A (ko)	2005-06-22	심바스타틴의 제조 방법

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