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【结 构 式】

【药物名称】Rosuvastatin calcium, ZD-4522, S-4522, Crestor

【化学名称】(+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)-heptenoic acid calcium salt (2:1)

【CA登记号】147098-20-2, 287714-41-4 (free acid), 147098-18-8 (monoNa salt)

【 分 子 式 】C44H54CaF2N6O12S2

【 分 子 量 】1001.15878

【开发单位】Shionogi (Originator), AstraZeneca (Licensee)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, HMG-CoA Reductase Inhibitors

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9

合成路线1

　

参考文献 中间体
【1】 Niddam-Hildesheim V, Shenkar N, Chen KB, et aL. 2007. Diastereomeric purification of rosuvastatin after stereoselective reduction. W0 2007040940(本专利属于Teva Pharmaceutical Industries Ltd, Israel. Teva Pharmaceuticals USA, Inc)
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) 66662 (R,E)-tert-butyl 6-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)-2-hydroxy-4-oxohex-5-enoate 　 C25H32FN3O6S 详情 详情

合成路线2

　

参考文献 中间体
【1】 Balanov A, Shenkar N, Niddam-Hildeshehnv. 2007. Process for producing rousuvastatin. W0 2007041666(本专利属于Teva Pharmaceutical Industries Ltd．Isnel; Teva Pharmaceuticals USA, Inc)
【2】 Hiddam-Hijldesheim V, Balanov A, Shenkar N, et al. 2006. Preparation of rosuvastatin. W0 2006091771 (本专利属于Teva Pharmaceutial Industries Ltd，Israel; Teva Pharmaceuticals USA, Inc)
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) 66663 (R)-1-tert-butyl 5-ethyl 3-((tert-butyldimethylsilyl)oxy)pentanedioate 　 C17H34O5Si 详情 详情
(II) 66664 (R)-5-(tert-butoxy)-3-((tert-butyldimethylsilyl)oxy)-5-oxopentanoic acid 　 C15H30O5Si 详情 详情
(III) 66665 (S)-5-(tert-butoxy)-3-((tert-butyldimethylsilyl)oxy)-5-oxopentanoic propionic anhydride 　 C18H34O6Si 详情 详情
(IV) 66666 (R)-tert-butyl 3-((tert-butyldimethylsilyl)oxy)-6-(diethoxyphosphoryl)-5-oxohexanoate 　 C20H41O7PSi 详情 详情
(V) 23882 N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-2-pyrimidinyl]-N-methylmethanesulfonamide 147118-37-4 C16H18FN3O3S 详情 详情
(VI) 66667 (R,E)-tert-butyl 2-((tert-butyldimethylsilyl)oxy)-6-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-4-oxohex-5-enoate 　 C31H46FN3O6SSi 详情 详情
(VII) 66662 (R,E)-tert-butyl 6-(4-(4-fluorophenyl)-6-isopropyl-2-(N- methylmethylsulfonamido)pyrimidin-5-yl)-2-hydroxy-4-oxohex-5-enoate 　 C25H32FN3O6S 详情 详情
(VIII) 66668 (2R,4S,E)-tert-butyl 6-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-2,4-dihydroxyhex-5-enoate 　 C25H34FN3O6S 详情 详情

合成路线3

　

参考文献 中间体
【1】 Zlicar M. 2007. Process for the synthesis of rosuvastatin calcium using L-malic acid for the side chain chirality. W0 2007017117(本专利属于Lek Pharmaceuticals D D, Slovenia)
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) 11058 (S)-(+)-Hydroxysuccinic acid; (S)-(+)-Malic acid; (S)-(+)-2-Hydroxybutanedioic acid; L-(-)-Apple acid 97-67-6 C4H6O5 详情 详情
(II) 11806 dimethyl (2S)-2-hydroxybutanedioate 617-55-0 C6H10O5 详情 详情
(III) 66669 (S)-dimethyl 2-((tert-butyldimethylsilyl)oxy)succinate 　 C12H24O5Si 详情 详情
(IV) 66670 (S)-methyl 3-((tert-butyldimethylsilyl)oxy)-4-oxobutanoate 　 C11H22O4Si 详情 详情
(V) 66671 　 　 C27H40F4N3O5PS 详情 详情
(VI) 66672 (S,E)-methyl 4-((tert-butyldimethylsilyl)oxy)-6-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)hex-5-enoate 　 C27H40FN3O5SSi 详情 详情
(VII) 66673 (S,E)66670-tert-butyl 5-((tert-butyldimethylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3-oxohept-6-enoate 　 C32H48FN3O6SSi 详情 详情
(VIII) 66674 (3R,5S,E)-tert-butyl 5-((tert-butyldimethylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3-hydroxyhept-6-enoate 　 C32H50FN3O6SSi 详情 详情
(IX) 66675 (3R,5S,E)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate 355806-00-7 C26H36FN3O6S 详情 详情

合成路线4

　

参考文献 中间体
【1】 Zhao ZQ，Peng LZ 2006．Preparation of Rosuvastatin and its salt. 发明专利申请公开说明书，CN(本专利属于Lunan Pharmaceutical Group Co，Ltd．Peop Rep China)
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) 66676 (R,E)-(R)-2-(benzyloxy)-2-oxo-1-phenylethyl 3-((tert-butyldimethylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-5-oxohept-6-enoate 　 C43H52FN3O8SSi 详情 详情
(II) 66677 (3R,5S,E)-(R)-2-(benzyloxy)-2-oxo-1-phenylethyl 3-((tert-butyldimethylsilyl)oxy)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-5-hydroxyhept-6-enoate 　 C43H54FN3O8SSi 详情 详情
(III) 66678 (3R,5S,E)-(R)-2-(benzyloxy)-2-oxo-1-phenylethyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate 　 C37H40FN3O8S 详情 详情
(IV) 66679 (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid 　 C22H28FN3O6S 详情 详情

合成路线5

　

参考文献 中间体
【1】 Wang SQ, Wu B,Xu SX. 2006. Process for preparation of rosuvastatin calcium as HMG-CoA reductase inhibitor.发明专利申请公开说明书，CN 1821242(本专利属于Yabang Chenucal Group Co, Ltd, Peop Rep China; Changzhou Yabang Pharmaceutical Research Institute Co, Ltd)
【2】 Joshi N, Bhirud SB, Chandrasekhar B, et aL. 2005. An impmved process for preparation of rosuvastatin derivatives, useful as HMG-CoA inhibitor. US 2005124639
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) 66681 tert-butyl 2-((4R,6S)-6-(bromomethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 　 C13H23BrO4 详情 详情
(II) 66680 tert-butyl 2-((4R,6S)-6-((dimethoxyphosphoryl)methyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 　 C15H29O7P 详情 详情
(III) 23882 N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl-2-pyrimidinyl]-N-methylmethanesulfonamide 147118-37-4 C16H18FN3O3S 详情 详情
(IV) 66682 tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 　 C29H40FN3O6S 详情 详情
(V) 66675 (3R,5S,E)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate 355806-00-7 C26H36FN3O6S 详情 详情
(VI) 66679 (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoic acid 　 C22H28FN3O6S 详情 详情

合成路线6

　

参考文献 中间体
【1】 Crabb JM, Horbury JT, Nigel P. 2004. An improved production of calcium salt of rosuvastatin, useful in the treatment of hypercholesterolemia, hyperlipoproteinenua, and atherosclerosis. W0 2004108691(本专利属于Astrazeneca UK Limited, UK)
【2】 Huang QY. 2006. Process for preparation of Rovstatin calcium. W0 2006Q76845(本专利属于Anhui Qingrun Pharmaceutical and Chemical Co, Ltd, Peop,Rep China)
【3】 Kumar Y, Meeran HNPN, De S, et aL. 2004. Process for the preparation of rosuvastatin hemicalcium salt. W0 2004052867(本专利属于Ranbaxy Labontories Limited, India)
【4】 Sebek P, Radl S. Stach J. 2005. A trans-salification method for the preparation of the rosuvastatin calaum from its potassium or sodium salt. W0 2005068435(本专利属于Zentiva,A S．C,,ech Rep)
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) 66683 (E)-N-(5-(3-cyanoprop-1-en-1-yl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide 　 C19H21FN4O2S 详情 详情
(III) 66684 (E)-N-(4-(4-fluorophenyl)-6-isopropyl-5-(4-oxobut-1-en-1-yl)pyrimidin-2-yl)-N-methylmethanesulfonamide 　 C19H22FN3O3S 详情 详情
(IV) 66685 (S,E)-ethyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-5-hydroxy-3-oxohept-6-enoate 　 C24H30FN3O6S 详情 详情
(V) 66686 (3R,5S,E)-ethyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate 　 C24H32FN3O6S 详情 详情

合成路线7

　

参考文献 中间体
【1】 Mei GY．Cai QF. 2005．Preparation for rosurrastatin and its intermediates. 发明专利申请公开说明书，CN 1687087(本专利属于Zhqiang HiSIm Pharmaceutical Co，Ltd，Peop Rep China)
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) 66687 N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide 　 C16H19BrFN3O2S 详情 详情
(II) 66688 ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)triphenylphosphonium 　 C34H34FN3O2PS 详情 详情
(III) 66689 tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate 　 C13H22O5 详情 详情
(IV) 66682 tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate 　 C29H40FN3O6S 详情 详情

合成路线8

　

参考文献 中间体
【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

合成路线9

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.

参考文献 中间体
【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
Extended Information
Drug NewChemical Entity Original Patent(1)