|
【结 构 式】 
|
【药物名称】YM-128, YM-68128 【化学名称】2-[4-[4-[4-(N-Hydroxyamidino)phenyl]-3-oxopiperazin-1-yl]piperidin-1-yl]acetic acid ethyl ester 【CA登记号】199801-52-0 【 分 子 式 】C20H29N5O4 【 分 子 量 】403.48523 |
【开发单位】Merck KGaA (Originator), Yamanouchi (Originator) 【药理作用】Antiplatelet Therapy, Chemical Delivery Systems, Coagulation Disorders Therapy, DRUG DELIVERY, Drug Delivery Systems, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists |
合成路线1
Alkylation of methyl 4-oxo-3-piperidinecarboxylate (I) with ethyl bromoacetate provided piperidineacetate (II). Subsequent decarbomethoxylation of (II) using LiCl in boiling DMF produced piperidone (III). On the other hand, coupling between 4-aminobenzonitrile (IV) and N-Boc-glycine (V) via activation with carbonyldiimidazole gave amide (V). The Boc group of (V) was then deprotected with HCl in EtOAc to yield 2-amino-N-(4-cyanophenyl)acetamide (VI). Reductive condensation of amine (VI) with piperidone (III) employing NaBH(OAc)3 furnished adduct (VII), which was further reductocondensed with chloroacetaldehyde to give chloroethyl amine (VIII). Cyclization of (VIII) in the presence of NaH generated piperazinone (IX). Finally, addition of hydroxylamine to the cyano group of (IX) provided the corresponding hydroxyamidine.
| 【1】 Suzuki, K.; Tsukamoto, S.; Yanagisawa, I.; Matsumoto, Y.; Ichihara, M.; Akamatsu, S.; Kaku, S.; Kawasaki, T.; Novel orally active GPIIb/IIIa antagonists: Synthesis and structure-activity relationship studies of oxopiperazine derivatives. Symp Med Chem 1999, Abst 1P-02. |
| 【2】 Matsumoto, Y.; Akamatsu, S.; Ichihara, M.; Kawasaki, T.; Kaku, S.; Yanagisawa, I. (Merck Patent GmbH; Yamanouchi Pharmaceutical Co., Ltd.); Substd. amidinobenzene derivs. and medicinal compsns. thereof. EP 0905129; US 6057324; WO 9745413 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 | |
| 18066 | N-alpha-t-BOC-glycine; 2-[(tert-butoxycarbonyl)amino]acetic acid | 4530-20-5 | C7H13NO4 | 详情 | 详情 | |
| (I) | 28106 | methyl 4-oxo-3-piperidinecarboxylate | 56026-52-9 | C7H11NO3 | 详情 | 详情 |
| (II) | 37983 | methyl 1-(2-ethoxy-2-oxoethyl)-4-oxo-3-piperidinecarboxylate | C11H17NO5 | 详情 | 详情 | |
| (III) | 37984 | ethyl 2-(4-oxo-1-piperidinyl)acetate | C9H15NO3 | 详情 | 详情 | |
| (IV) | 15361 | 4-Aminobenzonitrile | 873-74-5 | C7H6N2 | 详情 | 详情 |
| (V) | 37985 | tert-butyl 2-(4-cyanoanilino)-2-oxoethylcarbamate | C14H17N3O3 | 详情 | 详情 | |
| (VI) | 37986 | 2-amino-N-(4-cyanophenyl)acetamide | C9H9N3O | 详情 | 详情 | |
| (VII) | 37988 | ethyl 2-(4-[[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate | C18H24N4O3 | 详情 | 详情 | |
| (VIII) | 37987 | ethyl 2-(4-[(2-chloroethyl)[2-(4-cyanoanilino)-2-oxoethyl]amino]-1-piperidinyl)acetate | C20H27ClN4O3 | 详情 | 详情 | |
| (IX) | 37989 | ethyl 2-[4-[4-(4-cyanophenyl)-3-oxo-1-piperazinyl]-1-piperidinyl]acetate | C20H26N4O3 | 详情 | 详情 |