【结 构 式】 |
【药物名称】RPR-120844 【化学名称】4-[3(S)-(7-Methoxy-N-methylnaphthalen-2-ylsulfonamido)-2-oxopyrrolidin-1-ylmethyl]thiophene-2-carboxamidine 【CA登记号】186549-27-9 【 分 子 式 】C22H24N4O4S2 【 分 子 量 】472.58898 |
【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
The reduction of 5-bromothiophene-3-carbaldehyde (I) with NaBH4 in THF gives the corresponding carbinol (II), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to yield 4-(hydroxymethyl)thiophene-2-carbonitrile (III). The reaction of (III) with tetrabromomethane and triphenylphosphine affords the corresponding bromomethyl derivative (IV), which is condensed with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (V) by means of NaH in THF/DMF to give the expected addition product (VI). The deprotection of the amino group of (VI) with HCl in ethyl acetate yields the primary amine (VII), which is acylated with 7-methoxynaphthalene-2-sulfonyl chloride (VIII) and triethylamine in dichloromethane providing the sulfonamide (IX). The methylation of (IX) with methyl iodide and K2CO3 in DMF affords the N-methylsulfonamide (X), which is finally treated first with HCl in ethanol, and then with NH3 in methanol to convert the cyano group of (X) into the amidino group of the target compound.
【1】 Ewing, W.R.; Manetta, V.E.; Becker, M.R.; et al.; Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa. J Med Chem 1999, 42, 18, 3557. |
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) | 31660 | 5-bromo-3-thiophenecarbaldehyde | C5H3BrOS | 详情 | 详情 | |
(II) | 31661 | (5-bromo-3-thienyl)methanol | C5H5BrOS | 详情 | 详情 | |
(III) | 31662 | 4-(hydroxymethyl)-2-thiophenecarbonitrile | C6H5NOS | 详情 | 详情 | |
(IV) | 31663 | 4-(bromomethyl)-2-thiophenecarbonitrile | C6H4BrNS | 详情 | 详情 | |
(V) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
(VI) | 31664 | tert-butyl (3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinylcarbamate | C15H19N3O3S | 详情 | 详情 | |
(VII) | 31665 | 4-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-2-thiophenecarbonitrile | C10H11N3OS | 详情 | 详情 | |
(VIII) | 31666 | 7-methoxy-2-naphthalenesulfonyl chloride | C11H9ClO3S | 详情 | 详情 | |
(IX) | 31667 | N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-2-naphthalenesulfonamide | C21H19N3O4S2 | 详情 | 详情 | |
(X) | 31668 | N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-N-methyl-2-naphthalenesulfonamide | C22H21N3O4S2 | 详情 | 详情 |