CN1019395B - 麦维诺素及其类似物8-酰基的α-碳烷基化的方法 - Google Patents
麦维诺素及其类似物8-酰基的α-碳烷基化的方法Info
- Publication number
- CN1019395B CN1019395B CN88104227A CN88104227A CN1019395B CN 1019395 B CN1019395 B CN 1019395B CN 88104227 A CN88104227 A CN 88104227A CN 88104227 A CN88104227 A CN 88104227A CN 1019395 B CN1019395 B CN 1019395B
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- compound
- alkyl
- osi
- keys
- methyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 title abstract description 5
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 title abstract description 5
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000005804 alkylation reaction Methods 0.000 title description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 32
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- -1 ammonia compound Chemical class 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000003513 alkali Substances 0.000 claims description 8
- 150000002596 lactones Chemical class 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000004215 Carbon black (E152) Substances 0.000 claims description 6
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 150000003863 ammonium salts Chemical class 0.000 claims description 6
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 6
- 229930195733 hydrocarbon Natural products 0.000 claims description 6
- 150000002430 hydrocarbons Chemical class 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 4
- 150000001408 amides Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229910052744 lithium Inorganic materials 0.000 claims description 4
- IKAACYWAXDLDPM-UHFFFAOYSA-N 1,2,3,4,4a,5-hexahydronaphthalene Chemical compound C1=CCC2CCCCC2=C1 IKAACYWAXDLDPM-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 3
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000003973 alkyl amines Chemical class 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Chemical group 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- BRPMJMJJONIAHU-UHFFFAOYSA-N lithium;pyrrolidine Chemical compound [Li].C1CCNC1 BRPMJMJJONIAHU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004210 ether based solvent Substances 0.000 claims 2
- 239000002798 polar solvent Substances 0.000 claims 2
- 238000010306 acid treatment Methods 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims 1
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
- 229940083608 sodium hydroxide Drugs 0.000 claims 1
- 230000002152 alkylating effect Effects 0.000 abstract description 2
- 150000001350 alkyl halides Chemical class 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- 239000000243 solution Substances 0.000 description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- 239000000047 product Substances 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 238000003483 aging Methods 0.000 description 13
- 230000032683 aging Effects 0.000 description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 12
- 239000002994 raw material Substances 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical group CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000029936 alkylation Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- MSZJEPVVQWJCIF-UHFFFAOYSA-N butylazanide Chemical compound CCCC[NH-] MSZJEPVVQWJCIF-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 150000002148 esters Chemical group 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical group C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000010926 purge Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 3
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 2
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000855 fermentation Methods 0.000 description 2
- 230000004151 fermentation Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- UAXOELSVPTZZQG-UHFFFAOYSA-N tiglic acid Natural products CC(C)=C(C)C(O)=O UAXOELSVPTZZQG-UHFFFAOYSA-N 0.000 description 2
- IKAACYWAXDLDPM-JTQLQIEISA-N (4aR)-1,2,3,4,4a,5-hexahydronaphthalene Chemical compound C1CCC[C@@H]2CC=CC=C12 IKAACYWAXDLDPM-JTQLQIEISA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical group O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- WMHRYMDGHQIARA-UHFFFAOYSA-N 4-hydroxyoxan-2-one Chemical compound OC1CCOC(=O)C1 WMHRYMDGHQIARA-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- VGMFHMLQOYWYHN-UHFFFAOYSA-N Compactin Natural products OCC1OC(OC2C(O)C(O)C(CO)OC2Oc3cc(O)c4C(=O)C(=COc4c3)c5ccc(O)c(O)c5)C(O)C(O)C1O VGMFHMLQOYWYHN-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- YBCVMFKXIKNREZ-UHFFFAOYSA-N acoh acetic acid Chemical compound CC(O)=O.CC(O)=O YBCVMFKXIKNREZ-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 1
- 150000001656 butanoic acid esters Chemical group 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- NEHMKBQYUWJMIP-NJFSPNSNSA-N chloro(114C)methane Chemical compound [14CH3]Cl NEHMKBQYUWJMIP-NJFSPNSNSA-N 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 235000019628 coolness Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000002019 doping agent Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000004900 laundering Methods 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 1
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010129 solution processing Methods 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Peptides Or Proteins (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cephalosporin Compounds (AREA)
Abstract
本发明公开了一种使麦维诺素及其类似物中8-酰基侧链α-位烷基化的方法,按此方法操作时只需将碱和烷基卤一次加在一起即可得到纯度符合药用的产品。
Description
结构(Ⅰ)的化合物是已知的,并具有抑制B-羟-B-甲基戊二酸单酰辅酶A还原酶的性质,
它们是天然发酵产物麦维诺素(mevinolin,R=CH3,美国专利4,231,938)和康巴克素(Compactin,R=H,美国专利3,983,140)及它们的衍生物,所有的都含有天然的α-甲基丁酸酯侧链。已知含有2,2-二甲基丁酸酯侧链并且R=CH3的结构式为(Ⅱ)的化合物是比其2-甲基丁酸酯类似物更具活性的B-羟-β-甲基戊二酸单酰辅酶A学原酶抑制剂。
某些结构式(Ⅱ)的化合物及它们的制备方法已公开于美国专利4,444,784和欧洲专利申请公开33538中。但其中所公开的方法包括4个不同的化学步骤:(1)除去2-甲基丁酸酯侧链酯基;(2)保护吡喃酮环上的羟基;(3)重新酯化以形成所要求的2,2-二甲基丁酸酯;以及(4)除去4-羟基的保护基。该反应路线长而总产率低。
美国专利4,582,915(“915”)分开了一种用烷氨基金属和卤代甲烷直接使天然可得的甲基丁酸
酯侧链的α-碳烷基化而得到二甲基丁酸酯侧链的新方法,但发现此方法在药物的商业制造中有一定缺陷。为了使原料有较高的转化率需要采用重复加入氨基碱和甲基卤,该方法产率低而费时。另外,还需要选择性的水解,以使未甲基化的原料少于0.7%。这一步骤很费时间,因为未转化的原料水解很慢,一般需20小时。在原料是麦维诺素时,该方法的总产率是属于中等水平的。在甲基化和水解的过程中,除了未转化的原料外,还产生一些其他杂质。当原料为麦维诺素时,其中包括去丁酸酯基麦维诺素和双甲基化合物(其中除了8′-碳酯侧链外还有内酯的α-碳被甲基化),以及一种甲醚)此时已成为开链的内酯的环氧原子被甲基化)。从总过程中分离出的最终产物的纯度接近作为维护人类健康的产品的边缘。一种使杂质种类少于所述范围的方法应保证每批产品变化不大,不必采用耗费大的反复重结晶,并且所制得的最终药物的纯度不出问题。
本发明是使酰基部分α-位置烷基化的新方法,可描述如下:
更具体地说,本方法可用于甲基化麦维诺素以生产比麦维诺素本身更加活泼的β-羟-β-甲基戊二酸单酰辅酶A还原酶抑制剂,反应进行时只需一次加入碱和甲基卤即可形成纯度符合制药要求的产品。
本发明提供一种使麦维诺素及其类似物8′-碳酯侧链的α-碳甲基化的新方法,只需一次加入碱和烷基卤,即可形成比用“915”路线所得的类似产物产率更高,特别是纯度更高的产物。本发明方法可用反应式表示如下:
式中R1为C1-5烷基;
R2为选自H,CH3,OH或CH2OH的基:
R3为H或C1-3烷基:
R4为C3-5烷基:
R′2与R2相同,但当R2是OH或CH2OH时,R′2是OSi(Me)2t-C4H9或CH2OSi(Me)2t-C4H9;
R5为C1-3烷基;
R6和R7各自为
(ⅰ)C1-3烷基或
(ⅱ)R6和R7一起和与它们相连的氮形成5或6员杂环,如四氢吡咯或哌啶;
R8选自H,OH,或CH2OH:条件是
R2或R8中至少有一个是H;
R′8与R8相同,但当R8是OH或CH2OH时,R′8为OSi(Me)2t-C4H9或CH2OSi(Me)2t-C4H9;
X为氯、溴或碘;
M+为由锂、钠或钾产生的阳离子;
a,b和c各代表单键或者a,b和
c中之一代表一个双键或者a和c都代表双键。
除非特别另有规定外,术语烷基代表直链和支链的两种烷基。
本发明的一个实施例是制备结构(Ⅴ)的化合物,其中:R1为乙基,R3为甲基,R5为甲基。
属于这一实例的一类化合物中,R′2为氢、CH3或CH2OSi(Me)2t-C4H9。其中的一类化合物,它们中的a和c都代表双键,这一类化合物的实例有:
其中R1为乙基,R3为甲基,R4为正丁基,R5为甲基以及
a,R′2为CH3和R′3为H;或
b,R′2为CH2OSi(Me)2t-C4H9和R′8为H;或
c,R′2为H和R′8为CH2OSi(Me)2t-C4H9。
其中的另一类化合物,它们中的a、b和c都是单键。
可例举的这类化合物是,它们中的;
R1为乙基,R3为甲基,R4为正丁基,R5为甲基和
a、R′2为CH3及R′8为H;或
b、R′2为CH2OSi(Me)2tC4H9和R′8为H;或
c、R′2为H及R′8为CH2OSi(Me)2t-C4H9。
本发明的第二个实施例是制备结构(Ⅵ)的化合物,其中R1为乙基,R3为甲基和R5为甲基。
属于此实例的一类化合物,它们中的R2为CH3或CH2OH。这些化合物中的一类是,其中a和c皆为双键,可例举的这一类化合物有:
(1)6R-[2-[8(S)-(2,2-二甲丁酰氧基)-2(S),6(R)-二甲基-1,2,6,7,8,8a(R-六氢萘基-1(S)]乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮;
(2)6R-[2-[8(S)-(2,2-二甲丁酰氧基)-2(S)-甲基-6(R)-羟甲基-1,2,6,7,8,8a(R)-六氢萘基-1(S)]乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮。这些化合物中的另一类是其中a,b和c皆为单键。可以列举的这类化合物有:
(1)6(R)-[2-[8(S)-(2,2-二甲丁酰氧基)-2(S),6(S)-二甲基]-1,2,3,4,4a(S),5,6,7,8,8a(S)-十氢萘基-1(S)]乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮,
(2)6(R)-[2-[8(S)-(2,2-二甲丁酰氧基)-2(S)-甲基]-6(R)-羟甲基-1,2,3,4,4a(S),5,6,7,8,8a(S)-十氢萘基-1(S)乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮。
本发明的新方法包括:在结构(Ⅲ)多氢萘基的8′-酰基侧链α-位上选择性的烷基化,该烷基化是在β羟基戊内酯(以烷基酰胺-双叔丁基二甲基甲硅烷基醚形式被保护)存在下进行的,一次加入碱和烷基卤即可得到好的产率。烷基化后,烷基酰胺可顺利地转变成戊内酯而不影响碳烷基化了的酰基侧链。保护、碳烷基化和除去保护基的全部过程在同一反应器中进行。
原料内酯转变成酰胺,是在惰性气体(如氮)保护下,与烷基胺反应,最好用正丁胺。羟基用叔
丁基二甲基甲硅烷基氯或类似的试剂和碱(如咪唑)来保护。
氨基碱金属的形成是使正丁基碱金属的烃类溶液与R6R7NH的无水醚类溶液作用,所述的碱金属是锂、钠或钾,最好用锂;其中的R6R7NH为二乙胺,二甲胺、二异丙胺或四氢吡咯,最好用四氢吡咯,醚类溶剂,如四氢呋喃、乙醚、1,2-二甲氧基乙烷、最好用四氢呋喃,反应温度约为-20℃。
将先生成的羟基被保护的烷基酰胺溶液冷却到约-35℃,而后加入氨基碱金属溶液,加入速度控制在保护温度低于-30℃。使溶液在约-35℃陈化约两小时。将无水的烷基卤(较好的是氯甲烷、溴甲烷或碘甲烷、最好是碘甲烷)一次加到上述混合物中,加入烷基卤后将混合物冷却至约-30℃近1小时,然后在约20分钟内将加热到-10℃,并在此温度陈化约20分钟。于反应混合物中加入过量的水使反应终止,并用烃溶剂,如环己烷或其同类物提取。
用酸例如氢氟酸水溶液处理,除去叔丁基二甲基甲硅烷基保护基,加入氢氧化钠水溶液以使溶液的pH恰好是6.5,但不要使温度超过10℃。
于上述溶液中加入2.0N氢氧化钠并回流1至6小时,最好3小时。将混合物冷却至25℃用水稀释,减压蒸去溶剂。将混合物冷至约10℃,小心地用3.0NHCL酸化至pH为7.0,加入乙酸乙酯,分去水层,乙酸乙酯层用水洗。加入甲醇,将混合物加热至约20℃,加入氨水在约15分钟内结晶出内酯的铵盐。在进行结晶时,将混合物热至35至50℃,5至60分钟,最好是45℃,15分钟,然后冷至+10至-20℃,0.5至12小时,最好-10℃,2.5小时。铵盐用乙酸乙酸/甲醇洗并在氮吹扫下真空干燥。
将铵盐粗品悬浮于烃溶剂,如甲苯中,在氮保护下于90-110℃加热2至12小时,最好在100℃加热3.5小时。将混合物冷至25℃过滤,真空浓缩滤液并保持其内温低于40℃,加入烃溶剂,如环己烷,并将该混合物加热回流0.1至1小时,最好是0.25小时,然后在25至10℃冷却1至12小时,最好在10-15℃冷却两小时。滤出产品内酯并用冷的烃溶剂如环己烷洗,然后真空干燥,得到高纯度的产品。
用含水的甲醇重结晶以上得到的产品,得到经高压液相色谱测定纯度符合制药要求的产品。
原料劳瓦斯达素(Lovastatin)(其中R1为乙基,R2为甲基,R3为甲基以及a和c皆为双键)容易得到或者可按美国专利4,231,938专利公开的发酵方法制得,劳瓦斯达素的氢化衍生物按美国专利4,444,784提出的方法制备。原料康巴克素(其中R1为乙基,R2为H以及R3为CH3,a和c皆为双键)是按照美国专利4,231,938提出的发酵方法制得的。R2为CH2OH的原料按照1987年5月15日申请的共同未决的美国专利申请系列号048136所述的方法制得。R2或R8为OH的化合物按照美国专利4,537,859和4,517,373中的方法制备。
以下实例用以说明本发明,并非用以限制在权利要求中所阐述的本发明。
实例1
6(R)-[2-[8-(S)-(2,2-二甲基丁酰氧基)-2(S),6(R)-二甲基-1,2,6,7,8,8a(R)-六氢-1(S)]-乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2酮的制备:
(1a),3,5-双(叔丁基二甲基甲硅烷基)劳瓦斯达素丁基酰胺(式(Ⅳ)的化合物,其中R1为乙基,R′2为甲基,R3为甲基,R4为正丁基,R′8为H以及a和c皆为双键)
(所有操作皆在氮气氛中进行)。
在25℃,将劳瓦斯达素(53.0克,0.128摩尔)溶于正丁胺中(210毫升2.12摩尔),并在80℃温和地加热回流。一小时后,将溶液冷至25℃,减压至120mm/Hg,于浴温60℃蒸出丁胺。将浓缩后的溶液冷至25℃,加入二甲基甲酰胺(263毫升,经分子筛干燥,K.F.=43)(反应器内体积为373毫升),再减压至120mm/Hg,并于110℃(浴温)加热混合物45分钟,其间收集蒸出液17毫升。然后将混合物冷至25℃,加入咪唑(19.59克,0.288摩尔),然后再加入叔丁基二甲基甲硅烷基氯(44.4克,0.288摩尔)。将混合物于60℃加热8-14小时,直至甲硅烷基化进行完全。将混合物冷至12℃,加入无水甲醇
(5.8毫升0.143摩尔),混合物于10-15℃陈化0.5小时。然后在激烈搅拌下使混合物于环己烷
(1.5升)和蒸馏水(750毫升)中分配,层分开后,用饱和碳酸氢钠水溶液(750毫升)洗上层(环己烷),再用水洗(750毫升)
常压下蒸出环己烷层,收集蒸出液1320毫升后。(容器内体积为580毫升),溶液用分子筛干燥的四氢呋喃(600毫升)稀释,然后在常压下蒸馏收集110毫升蒸出液。将溶液冷至25℃于下一步使用。
(1b)3,5-双(叔丁基二甲基甲硅烷基)森维诺素丁酰胺(式(Ⅴ)的一种化合物,其中R1为乙基,R′2为甲基,R3为甲基,R4为正丁基,R′8为H以及a和c皆为双键)。
将分子筛干燥的四氢吡咯(25.13毫升)和分子筛干燥的四氢呋喃(192毫升)的溶液冷至-18℃,于其中加入正丁基锂在己烷中的溶液(1.65M182.5毫升,0.301摩尔),加入速度以保持温度低于-10℃为准(约15分钟),加完后,混合物在-20℃陈化15分钟。
将3,5-双(叔丁基二甲基甲硅烷基劳瓦斯达素丁基酰胺在四氢呋喃/环己烷中的溶液冷至-35℃,然后将四氢吡咯化锂的溶液于-20℃,在激烈搅拌下加入其中,加入速度控制在整个加入过程中温度保持低于-30℃。然后使该溶液在-35℃陈化两小时。将分子筛干燥的碘甲烷(12.2毫升,0.196摩尔)一次加到混合物中,然后将混合物再冷至-30℃,并陈化1小时。在23分钟内将混合物热至-10℃,并于此温度陈化20分钟。
于混合物中加入水(550毫升)使反应终止并迅速搅拌10分钟,分出各相,下相(水)用环己烷(465毫升)提取。合并有机相,用1NHCl(500毫升)和10%亚硫酸氢钠水溶液(500毫升)洗,将有机相在120mm/Hg下浓缩至300毫升,此浓缩液直接用于下一步反应。
(1c)森维诺素丁基酰胺
用乙腈(600毫升)稀释前一步的浓缩溶液,再在120mm/Hg下将此混合物浓缩至300毫升。将混合物冷至25℃,加入乙腈(300毫升)。将得到的溶液冷至+70℃,加入氢氟酸(79毫升,50%的水溶液)然后把此混合物在1小时内热至25℃,混合物在25℃陈化1.5小时,随后冷却至+5℃。在激烈地搅拌下,小心地加入氢氧化钠水溶液(3N),使溶液的pH恰好为6.5,在加入碱的任何时刻,决不要使温度升高到10℃以上,分出层后,将下层(水)用788毫升(四氢呋喃/环己烷)溶液反提取,(563毫升四氢呋喃/225毫升环己烷)。将四氢呋喃/环己烷提取液与开始的乙腈层合并在一起,并将合并的提取液在120mm/Hg浓缩至290毫升。加入乙醇(无水的1000毫升)并在120mm/Hg蒸至体积为788毫升,此溶液直接用于下一步反应。
(1d)森维诺素铵盐
在25℃,于前一步得到的森维诺素-丁基酰胺的乙醇溶液中加入2N氢氧化钠(164毫升)并将所得的溶液进行温和地回流(81℃)。3小时后将混合物冷至25℃,并用789毫升蒸馏水稀释,减压至120mm/Hg,蒸出乙醇。当收集蒸出液达840毫升时,容器中的体积减至788毫升。将混合物冷至+11℃并小心地加入3.0NHCl进行酸化,使pH至7。加入乙酸乙酯(925毫升),并将水相进一步酸化至pH等于2.5,将混合物迅速搅拌5-10分钟并分开各层,下层(水相)用乙酸乙酯(463毫升)再提取,并与第一次的乙酸乙酯层合并。合并的乙酸乙酯层用水(360毫升)洗,加入甲醇(无水的,533毫升),并当在15分钟内将28%氨水(18.0毫升)加入时,把混合物加热到+20℃。一旦有结晶出现时,将混合物热至45℃陈化15分钟,然后在2.5小时内将其冷至-10℃。陈化1小时后,滤出产品并用3∶1乙酸乙酯/甲醇(338毫升乙酸乙酯/112毫升甲醇,-10℃)洗。于30-35℃,在氮吹扫下,将产品真空干燥,得(1d)步的标题化合物。
(1e)·6(R)-[2-[8(S)-(2,2-二甲基丁酰氧基)-2(S),6(R)-二甲基-1,2,6,7,8,8a(R)-六氢-1(S)]乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮
内酯化
将(1d)步中粗的铵盐(25克,52.35毫摩尔)悬浮于甲苯(500毫升)中并在氮气氛中于100℃加热3.5小时。
将溶液冷至25℃并加入活性炭(1.25克),混合物经在25℃搅拌0.5小时,过滤(用硅藻土),滤液在保持内温小于40℃时真空浓缩至50毫升。加入环己烷(300毫升),该混合物经加热回流0.25小时后,在两小时内将其冷至10-15℃,并
陈化1小时。滤出产品,用冷的环己烷(115毫升)洗,然后于30-35℃真空干燥,得所要的结晶固体化合物。
重结晶:
在25℃和氮气保护下将内酯化的产物(20克)溶于甲醇(240毫升)中,然后经过垫有活性炭在由纤维构成的载体上的均匀混合物(Ecosorb-C)(15克)的滤板过滤(0.25小时),滤板另用甲醇(40毫升)轻洗。将合并的滤液加热至35℃,在0.25小时内加入水(90毫升)。将混合物逐渐冷却(速度5℃/0.25小时)至开始有结晶析出。
将混合物陈化0.5小时,然后再加热到40℃,在1小时内慢慢再加入水(190毫升)。将该混合物于15小时内冷至15℃,陈化1小时,过滤并用甲醇∶水(1.1体积/体积,90毫升)洗涤产品。将产品于30-35℃、在氮气吹扫下真空干燥,得纯度符合制药要求的标题化合物,为无色细长棒状,标题化合物经过高压液相色谱鉴定。
实例2-4
基本上是按实例1的方法,只是替换了其中所用的原料劳瓦斯达素,如下所示,几乎是等摩尔量的结构(Ⅲ)的化合物用以制备2,2-二甲基丁酸酯产物如下表:
R1R2R3a b c R5
实例:2 CH3CH2CH3CH3- - - CH3
实例:3 CH3CH2CH2OH CH3双键 - 双键 CH3
实例:4 CH3CH2CH2OH CH3- - - CH3
Claims (9)
1、一种制备结构式(Ⅵ)化合物的方法:
其中:
R1是C1-5烷基;
R2选自H,CH3,OH或CH2OH;
R3是H或C1-3烷基;
R4是C3-C5烷基;
R5是C1-3烷基;以及
R8选自H,OH,或CH2OH,条件是R2或R8中至少有一个为H;
a,b和c分别代表单键或a,b或c之一代表双键或a和c均代表双键;
该方法包括:
(A)在惰性气氛下,用烷胺R4NH2处理结构式(Ⅲ)化合物:
然后用叔丁基二甲基甲硅烷基氯和咪唑保护羟基,然后
(B)用式M+N-R6R7的碱金属氨化物处理,其中M+是取自钠、钾或锂的阳离子,R6和R7独立地为C1-3烷基,或R6和R7与它们所连的氮原子一起构成5或6元杂环;然后与R5X接触(其中X是氯,溴或碘)以形成结构式(Ⅴ)化合物:
其中:
R1是C1-5烷基;
R′ 2选自H,CH3,OSi(Me)2t-C4H9或CH2OSi(Me)2t-C4H9;
R3是H或C1-3烷基;
R4是C3-5烷基;
R5是C1-3烷基;以及
R′ 8选自H或OSi(Me)2tC4H9或CH2OSi(Me)2tC4H9;条件是R′ 2或R′ 8中的至少一个是H;
a,b和c分别代表单键或a,b和c之一代表双键或a和c代表双键;
还包括以下步骤:
(C)在极性溶剂中用酸处理式(Ⅴ)化合物以除去甲硅烷基保护基;然后
(D)用稀碱处理以水解该烷基氨化物;然后
(E)在烃溶剂中加热内酯的羧酸盐,以形成结构式Ⅵ化合物。
2、按照权利要求1的方法,其中(C)步中的酸是氢氟酸,极性溶剂为乙腈;和(D)步中的稀碱是2.0NNaOH;以及其中(E)步的羧酸盐是在甲苯中于100℃加热。
3、按照权利要求2的方法,其中还包括:经氢氧化钠处理后,与氨水反应以形成内酯的铵盐。
4、按照权利要求3的方法,其中a和c二者皆代表双键。
5、按照权利要求4的方法,其中所制备的化合物选自下列一组化合物:
(a)6(R)-[2-[8(S)-(2,2-二甲基丁酰氧基)-2-(S),6(R)-二甲基-1,2,6,7,8,8a(R)-六氢萘基-1(S)]乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮;
(b)6(R)-[2-[8(S)-(2,2-二甲基丁酰氧基)-2-(S)-甲基-6(R)-羟甲基-1,2,6,7,8,8a(R)-六氢萘基-1(S)]乙基]-4(R)-羟基-3,4,5,6-四氢-2H-吡喃-2-酮;
6、按照权利要求1的方法,其中(B)步在一种醚溶剂中进行,R5为甲基,与R5X的反应是在温度-30至-10℃下进行的。
7、按照权利要求1的方法,其中的醚溶剂是四氢呋喃,烷基胺是丁胺,氨基碱金属是四氢吡咯化锂;R1是乙基,R3是甲基;R′2是H、CH3或CH2OSi(Me)2t-C4H9;
R′是H或CH2OSi(Me)2t-C4H9;条件是R′2或R′8中至少有一个是H。
8、按照权利要求1的方法,其中a和c二者皆代表双键。
9、按照权利要求1的方法,其中所制得的式(Ⅴ)化合物选自具有下列基团的化合物;
a.R′2为CH3和R′8为H;或
b.R′2为CH2OSi(Me)2t-C4H9和R′8为H;或
c.R′2为H为R′8为CH2OSi(Me)2tC4H9。
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EP0094443A1 (en) * | 1982-05-17 | 1983-11-23 | Merck & Co. Inc. | 6(R)-(2-(8(S) (2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S))ethyl)-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one, process for preparing and pharmaceutical composition containing the same |
US4584389A (en) * | 1983-10-11 | 1986-04-22 | Merck & Co., Inc. | Processes for preparing 6(R)-[2-[8(S)(2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one |
EP0137444B1 (en) * | 1983-10-11 | 1990-01-31 | Merck & Co. Inc. | Processes for preparing 6(R)-[2-[8(S)(2,2-dimethylbutyryloxy)-2(S),6(S)-dimethyl-1,2,3,4,4a(S),5,6,7,8,8a(S)-Decahydronaphthyl-1(S)]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one |
DE3480923D1 (de) * | 1983-10-11 | 1990-02-08 | Merck & Co Inc | Verfahren zur c-methylierung von 2-methylbutyraten. |
US4582915A (en) * | 1983-10-11 | 1986-04-15 | Merck & Co., Inc. | Process for C-methylation of 2-methylbutyrates |
US4588820A (en) * | 1984-06-11 | 1986-05-13 | Merck & Co., Inc. | Process for epimerization at C6 of 3,4,5,6-tetrahydro-2H-pyran-2-one |
-
1987
- 1987-07-10 US US07/072,066 patent/US4820850A/en not_active Expired - Lifetime
-
1988
- 1988-07-01 EP EP88306050A patent/EP0299656B1/en not_active Expired - Lifetime
- 1988-07-01 AT AT88306050T patent/ATE59036T1/de not_active IP Right Cessation
- 1988-07-01 ES ES88306050T patent/ES2018710B3/es not_active Expired - Lifetime
- 1988-07-01 DE DE8888306050T patent/DE3861270D1/de not_active Expired - Fee Related
- 1988-07-04 IL IL86968A patent/IL86968A/xx not_active IP Right Cessation
- 1988-07-04 FI FI883184A patent/FI88719C/fi not_active IP Right Cessation
- 1988-07-04 PT PT87909A patent/PT87909B/pt not_active IP Right Cessation
- 1988-07-06 NZ NZ225306A patent/NZ225306A/xx unknown
- 1988-07-08 CA CA000571603A patent/CA1287063C/en not_active Expired - Lifetime
- 1988-07-08 ZA ZA884924A patent/ZA884924B/xx unknown
- 1988-07-08 DK DK198803807A patent/DK172811B1/da not_active IP Right Cessation
- 1988-07-08 AU AU18850/88A patent/AU604937B2/en not_active Expired
- 1988-07-08 NO NO883062A patent/NO172239C/no not_active IP Right Cessation
- 1988-07-08 IE IE210688A patent/IE61025B1/en not_active IP Right Cessation
- 1988-07-09 JP JP63170054A patent/JPH0717663B2/ja not_active Expired - Fee Related
- 1988-07-09 KR KR1019880008564A patent/KR950009314B1/ko not_active IP Right Cessation
- 1988-07-10 CN CN88104227A patent/CN1019395B/zh not_active Expired
-
1991
- 1991-01-21 GR GR91400059T patent/GR3001351T3/el unknown
- 1991-10-11 SG SG846/91A patent/SG84691G/en unknown
- 1991-12-05 HK HK989/91A patent/HK98991A/xx not_active IP Right Cessation
-
1992
- 1992-07-10 CY CY1613A patent/CY1613A/xx unknown
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1994
- 1994-07-25 JP JP6172765A patent/JP2527535B2/ja not_active Expired - Fee Related
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