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【结 构 式】

【药物名称】AR-0510

【化学名称】trans-2-[4-(5-Amidino-1-benzofuran-2-ylcarboxamido)cyclohexyloxy]acetic acid ethyl ester

【CA登记号】174774-03-9, 174774-04-0 (monomethanesufonate salt)

【 分 子 式 】C20H25N3O5

【 分 子 量 】387.43935

【开发单位】Mitsubishi Pharma (Originator)

【药理作用】Antiplatelet Therapy, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Integrin alphaIIbbeta3 (Fibrinogen gpIIb/IIIa) Antagonists

合成路线1

Selective O-alkylation of trans-4-aminocyclohexanol (I) was effected by protection of the amino group as the triazinone (III) upon treatment with N,N-dimethylurea and formaldehyde. Subsequent alkylation of (III) with tert-butyl bromoacetate under phase-transfer conditions afforded ether (IV). The protecting group of (IV) was then removed by treatment with ammonium chloride.

1 Ono, S.; Yoshida, T.; Ashimori, A.; Kosaka, K.; Okada, T.; Maeda, K.; Eda, M.; Mori, F.; Inoue, Y.; Ebisu, H.; Imada, T.; Ikegawa, R.; Wang, F.; Nakamura, N. (Welfide Corporation); Novel fused-ring carboxylic acid cpds. or salt thereof,and medicinal use thereof. EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720 .
2 Nakamura, N.; Imada, T.; Inoue, Y.; Kosaka, K.; Yoshida, T.; Ono, S.; Fukaya, C.; Maeda, K.; Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives. Chem Pharm Bull 1999, 47, 12, 1694.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
17430 2-Bromoacetic acid tert-butyl ester; tert-butyl 2-bromoacetate; tert-Butyl bromoacetate 5292-43-3 C6H11BrO2 详情 详情
(I) 19581 trans-4-Aminocyclohexanol;trans-4-Amino-1-cyclohexanol;trans-4-Amino-1-cyclohexanol; 27489-62-9 C6H13NO 详情 详情
(II) 21488 N,N'-dimethylurea 96-31-1 C3H8N2O 详情 详情
(III) 37350 5-(4-hydroxycyclohexyl)-1,3-dimethyl-1,3,5-triazinan-2-one C11H21N3O2 详情 详情
(IV) 37351 tert-butyl 2-[[4-(3,5-dimethyl-4-oxo-1,3,5-triazinan-1-yl)cyclohexyl]oxy]acetate C17H31N3O4 详情 详情
(V) 37352 tert-butyl 2-[(4-aminocyclohexyl)oxy]acetate C12H23NO3 详情 详情

合成路线2

Pinner reaction of ethyl 5-cyano-2-benzofurancarboxylate (VI) gave imidate (VII) and subsequent treatment with ethanolic ammonia afforded amidine (VIII). After basic hydrolysis of the ester group of (VIII), protection with benzyl chloroformate provided the benzyloxycarbonyl derivative (IX). Coupling of (IX) with aminoester (V) in the presence of EDC and HOBt yielded amide (X). Sequential cleavage of benzyloxycarbonyl and tert-butyl groups orf (X) provided amidino acid (XI), which was finally esterified with EtOH and methanesulfonic acid.

1 Ono, S.; Yoshida, T.; Ashimori, A.; Kosaka, K.; Okada, T.; Maeda, K.; Eda, M.; Mori, F.; Inoue, Y.; Ebisu, H.; Imada, T.; Ikegawa, R.; Wang, F.; Nakamura, N. (Welfide Corporation); Novel fused-ring carboxylic acid cpds. or salt thereof,and medicinal use thereof. EP 0712844; JP 1996053398; JP 1996231548; US 5635527; US 5753670; WO 9533720 .
2 Nakamura, N.; Imada, T.; Inoue, Y.; Kosaka, K.; Yoshida, T.; Ono, S.; Fukaya, C.; Maeda, K.; Preparation and pharmacological evaluation of novel glycoprotein (Gp) IIb/IIIa antagonists. 2. Condensed heterocyclic derivatives. Chem Pharm Bull 1999, 47, 12, 1694.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
10101 Benzyloxycarbonyl chloride; Benzyl chloroformate; 1-[[(Chlorocarbonyl)oxy]methyl]benzene 501-53-1 C8H7ClO2 详情 详情
(V) 37352 tert-butyl 2-[(4-aminocyclohexyl)oxy]acetate C12H23NO3 详情 详情
(VI) 37353 ethyl 5-cyano-1-benzofuran-2-carboxylate C12H9NO3 详情 详情
(VII) 37354 ethyl 5-[ethoxy(imino)methyl]-1-benzofuran-2-carboxylate C14H15NO4 详情 详情
(VIII) 37355 ethyl 5-[amino(imino)methyl]-1-benzofuran-2-carboxylate C12H12N2O3 详情 详情
(IX) 37356 5-[[[(benzyloxy)carbonyl]amino](imino)methyl]-1-benzofuran-2-carboxylic acid C18H14N2O5 详情 详情
(X) 37357 ethyl 2-([4-[([5-[[[(benzyloxy)carbonyl]amino](imino)methyl]-1-benzofuran-2-yl]carbonyl)amino]cyclohexyl]oxy)acetate C28H31N3O7 详情 详情
(XI) 37358 2-([4-[([5-[amino(imino)methyl]-1-benzofuran-2-yl]carbonyl)amino]cyclohexyl]oxy)acetic acid C18H21N3O5 详情 详情
Extended Information