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【结 构 式】

【分子编号】23885

【品名】methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoate

【CA登记号】147118-40-9

【 分 子 式 】C23H30FN3O6S

【 分 子 量 】495.5722232

【元素组成】C 55.74% H 6.1% F 3.83% N 8.48% O 19.37% S 6.47%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XI)

The condensation of 4-fluorobenzaldehyde (I) with 4-methyl-3-oxopentanoic acid ethyl ester (II) by means of piperidine/AcOH in refluxing benzene gives the corresponding benzylidene derivative (III), which is cyclized with S-methylisothiourea (IV) and oxidized with DDQ, affording the pyrimidine derivative (V). The oxidation of (V) with m-chloroperbenzoic acid (m-CPBA) gives the expected methanesulfonyl derivative (VI), which is treated first with methylamine and then with methanesulfonyl chloride to provide the N-methylmethanesulfonamide (VII). The reduction of the ester group of (VII) with DIBAL in toluene, followed by selective oxidation of the resulting alcohol with TPAP, affords the aldehyde (VIII), which is submitted to a Wittig condensation with the phosphorane (IX) in acetonitrile to give the protected heptenoate (X). The deprotection of (X) with FH and the controlled reduction of the resulting keto alcohol with Et2BOMe and NaBH4 affords the chiral dihydroxyheptenoate (XI), which is hydrolyzed with NaOH in ethanol, yielding the corresponding sodium salt (XII). Finally, this compound is treated with calcium chloride.

1 Watanabe, M.; et al.; Synthesis and biological activity of methanesulfonamide pyrimidine- and N-methanesulfonyl pyrrole-substituted 3,5-dihydroxy-6-heptenoates, a novel series of HMG-CoA reductase inhibitors. Bioorg Med Chem 1997, 5, 2, 437.
2 Castañer, J.; Graul, A.; ZD-4522. Drugs Fut 1999, 24, 5, 511.
3 Hirai, K.; Ishiba, T.; Koike, H.; Watanabe, M. (Shionogi & Co. Ltd.); Pyrimidine derivs. as HMG-CoA reductase inhibitors. EP 0521471; JP 1993178841; US 5260440 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 12337 4-fluorobenzaldehyde 459-57-4 C7H5FO 详情 详情
(II) 19408 ethyl 4-methyl-3-oxopentanoate 7152-15-0 C8H14O3 详情 详情
(III) 15877 ethyl (Z)-3-(4-fluorophenyl)-2-isobutyryl-2-propenoate C15H17FO3 详情 详情
(IV) 10272 [[Amino(imino)methyl]sulfanyl]methane 2986-19-8 C2H6N2S 详情 详情
(V) 23879 ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfanyl)-5-pyrimidinecarboxylate C17H19FN2O2S 详情 详情
(VI) 23880 ethyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)-5-pyrimidinecarboxylate C17H19FN2O4S 详情 详情
(VII) 23881 ethyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinecarboxylate C18H22FN3O4S 详情 详情
(VIII) 23882 N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-2-pyrimidinyl]-N-methylmethanesulfonamide 147118-37-4 C16H18FN3O3S 详情 详情
(IX) 23884 methyl (3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidene)hexanoate 147118-35-2 C31H39O4PSi 详情 详情
(X) 23883 methyl (3R,6E)-3-[[tert-butyl(dimethyl)silyl]oxy]-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-5-oxo-6-heptenoate 147118-38-5 C29H42FN3O6SSi 详情 详情
(XI) 23885 methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoate 147118-40-9 C23H30FN3O6S 详情 详情
(XII) 23887 sodium (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoate 147098-18-8 C22H27FN3NaO6S 详情 详情

合成路线2

该中间体在本合成路线中的序号:(IX)

 

1 Deshpande PB, Ramakrishnan A, Nilesh BS, et aL 2006. Process for preparation of calcium salt of rosuvastatin. W0 2006106526(本专利属于Unichem Laboratories Limited, India)
2 Deshpande PB, Ramakrishnan A, Nilesh BS, et al. 2006. Process for preparation of Rasuvastatin and its calcium salt. W0 2006100689(本专利属于Unichem Laboratories Limited, India)
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 23882 N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-2-pyrimidinyl]-N-methylmethanesulfonamide 147118-37-4 C16H18FN3O3S 详情 详情
(II) 66690 (E)-ethyl 4-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)but-3-enoate   C21H26FN3O4S 详情 详情
(III) 66691 (E)-4-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)but-3-enoic acid   C19H22FN3O4S 详情 详情
(IV) 66692 (E)-methyl 6-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3-oxohex-5-enoate   C22H26FN3O5S 详情 详情
(V) 66693 (E)-methyl 6-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3-hydroxyhex-5-enoate   C22H28FN3O5S 详情 详情
(VI) 66694 (E)-6-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3-hydroxyhex-5-enoic acid   C21H26FN3O5S 详情 详情
(VII) 66695 (S,E)-6-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3-hydroxyhex-5-enoic acid   C21H26FN3O5S 详情 详情
(VIII) 66696 (S,E)-methyl 8-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-5-hydroxy-3-oxooct-7-enoate   C24H30FN3O6S 详情 详情
(IX) 23885 methyl (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoate 147118-40-9 C23H30FN3O6S 详情 详情
Extended Information