|
【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% |
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 |