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【结 构 式】 
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【药物名称】RPR-208566 【化学名称】2(R)-(3-Amidinobenzyl)-3(R)-(3',4'-dimethoxybiphenyl-4-ylcarboxamido)butyric acid methyl ester trifluoroacetate 【CA登记号】219672-61-4, 219672-60-3 (free base) 【 分 子 式 】C30H32F3N3O7 【 分 子 量 】603.60064 |
【开发单位】Aventis Pharma (Originator) 【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Coagulation Factor Xa Inhibitors |
合成路线1
Organozinc reagent (II), prepared from 4-bromo-1,2-dimethoxybenzene (I), was coupled with methyl iodobenzoate (III) in the presence of bis(triphenylphosphine) palladium dichloride and diisobutylaluminum hydride to furnish biphenyl derivative (IV). After saponification of the methyl ester group of (IV), treatment with thionyl chloride yielded acid chloride (V).
| 【1】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 . |
| 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) | 38452 | 4-bromo-1,2-dimethoxybenzene; 4-bromo-2-methoxyphenyl methyl ether | 2859-78-1 | C8H9BrO2 | 详情 | 详情 |
| (II) | 38453 | chloro(3,4-dimethoxyphenyl)zinc | C8H9ClO2Zn | 详情 | 详情 | |
| (III) | 16123 | methyl 4-iodobenzoate | 619-44-3 | C8H7IO2 | 详情 | 详情 |
| (IV) | 38454 | methyl 3',4'-dimethoxy[1,1'-biphenyl]-4-carboxylate | C16H16O4 | 详情 | 详情 | |
| (V) | 38455 | 3',4'-dimethoxy[1,1'-biphenyl]-4-carbonyl chloride | C15H13ClO3 | 详情 | 详情 |
合成路线2
Protection of methyl (R)-3-aminobutyrate (VI) with di-tert-butyl dicarbonate provided the Boc derivative (VII), which was alkylated with 3-cyanobenzyl bromide (VIII) in the presence of lithium bis(trimethylsilyl)amide at -78 C to afford adduct (IX). Acid deprotection of the Boc group of (IX) yielded amino ester (X). Alternatively, (X) was obtained by protection of methyl 3-aminobutyrate (VI) with benzyl chloroformate, followed by alkylation with 3-cyanobenzyl bromide to give (XI). The carbobenzoxy group of (XI) was then deprotected by hydrogenation over Pd/C. Coupling of amino ester (X) with acid chloride (V) gave rise to amide (XII). Conversion of (XII) to the required amidine was then achieved by treatment with methanolic HCl, followed by reaction of the resulting imidate with ammonia in boiling MeOH. The title compound was isolated after conversion to the trifluoroacetate salt.
| 【1】 Gong, Y.; Guertin, K.R.; McGarry, D.G.; Pauls, H.W.; Klein, S.I.; Spada, A.P. (Aventis Pharmaceuticals, Inc.); Substd. N-[(aminoiminomethyl or aminomethyl)phenyl]propyl amides. CA 2264556; EP 0931060; WO 9900356 . |
| 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) | 38455 | 3',4'-dimethoxy[1,1'-biphenyl]-4-carbonyl chloride | C15H13ClO3 | 详情 | 详情 | |
| (VI) | 38456 | methyl (3R)-3-aminobutanoate | C5H11NO2 | 详情 | 详情 | |
| (VII) | 38457 | methyl (3R)-3-[(tert-butoxycarbonyl)amino]butanoate | C10H19NO4 | 详情 | 详情 | |
| (VIII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
| (IX) | 38458 | methyl (2R,3R)-3-[(tert-butoxycarbonyl)amino]-2-(3-cyanobenzyl)butanoate | C18H24N2O4 | 详情 | 详情 | |
| (X) | 38459 | methyl (2R,3R)-3-amino-2-(3-cyanobenzyl)butanoate | C13H16N2O2 | 详情 | 详情 | |
| (XI) | 38460 | methyl (2R,3R)-3-[[(benzyloxy)carbonyl]amino]-2-(3-cyanobenzyl)butanoate | C21H22N2O4 | 详情 | 详情 | |
| (XII) | 38461 | methyl (2R,3R)-2-(3-cyanobenzyl)-3-[[(3',4'-dimethoxy[1,1'-biphenyl]-4-yl)carbonyl]amino]butanoate | C28H28N2O5 | 详情 | 详情 |