【结 构 式】 |
【药物名称】YM-75466, YM-466(free base), YM-60828(free base) 【化学名称】2-[N-(7-Amidinonaphthalen-2-ylmethyl)-N-[4-[1-(1-iminoethyl)piperidin-4-yloxy]phenyl]sulfamoyl]acetic acid methanesulfonate 【CA登记号】201933-41-7 (free base) 【 分 子 式 】C28H35N5O8S2 【 分 子 量 】633.74785 |
【开发单位】Yamanouchi (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
The intermediate aniline (IV) was synthesized by Mitsunobu coupling between N-Boc-4-piperidinol (I) and p-nitrophenol (II), followed by catalytic hydrogenation of the resultant nitrophenyl ether (III). 7-Formyl-2-naphthalenecarbonitrile (VI) was prepared by oxidation of the bromomethyl(naphthalene) (V) employing either trimethylamine N-oxide or dimethylsulfoxide in the presence of silver tetrafluoroborate. Reductive alkylation of aniline (IV) with aldehyde (VI) by means of sodium triacetoxyborohydride produced the secondary amine (VII), which was subsequently acylated with ethyl 2-(Chlorosulfonyl)acetate (VIII) to furnish sulfonamide (IX). The required amidine (X) was then obtained by Pinner reaction of nitrile (IX) with ethanolic HCl, followed by treatment with ammonium acetate. The deprotected piperidine moiety of (X) was further subjected to condensation with ethyl acetimidate to give the bis-amidine compound (XI). The ethyl ester group of (XI) was finally hydrolyzed under acidic conditions, yielding the target carboxylic acid.
【1】 Hirayama, F.; et al.; The discovery of YM-60828: A potent, selective and orally-bioavailable factor Xa inhibitor. Bioorg Med Chem 2002, 10, 5, 1509. |
【2】 Hirayama, F.; Koshio, H.; Matsumoto, Y.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Yamanouchi Pharmaceutical Co., Ltd.); Novel amidinonaphthyl derivs. or salt thereof. EP 0798295; US 5869501; WO 9616940 . |
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) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
(II) | 11236 | 4-Nitrophenol; p-Nitrophenol | 100-02-7 | C6H5NO3 | 详情 | 详情 |
(III) | 55852 | tert-butyl 4-(4-nitrophenoxy)-1-piperidinecarboxylate | C16H22N2O5 | 详情 | 详情 | |
(IV) | 55853 | tert-butyl 4-(4-aminophenoxy)-1-piperidinecarboxylate | C16H24N2O3 | 详情 | 详情 | |
(V) | 24988 | 7-(bromomethyl)-2-naphthonitrile | C12H8BrN | 详情 | 详情 | |
(VI) | 55854 | 7-formyl-2-naphthonitrile | C12H7NO | 详情 | 详情 | |
(VII) | 55855 | tert-butyl 4-(4-{[(7-cyano-2-naphthyl)methyl]amino}phenoxy)-1-piperidinecarboxylate | C28H31N3O3 | 详情 | 详情 | |
(VIII) | 55856 | ethyl 2-(chlorosulfonyl)acetate | C4H7ClO4S | 详情 | 详情 | |
(IX) | 55857 | tert-butyl 4-(4-{[(7-cyano-2-naphthyl)methyl][(2-ethoxy-2-oxoethyl)sulfonyl]amino}phenoxy)-1-piperidinecarboxylate | C32H37N3O7S | 详情 | 详情 | |
(X) | 55858 | ethyl 2-{[({7-[amino(imino)methyl]-2-naphthyl}methyl)-4-(4-piperidinyloxy)anilino]sulfonyl}acetate | C27H32N4O5S | 详情 | 详情 | |
(XI) | 55859 | ethyl 2-({({7-[amino(imino)methyl]-2-naphthyl}methyl)-4-[(1-ethanimidoyl-4-piperidinyl)oxy]anilino}sulfonyl)acetate | C29H35N5O5S | 详情 | 详情 |