【结 构 式】 |
【药物名称】RPR-131247 【化学名称】4-Hydroxy-3-[2-oxo-3(S)-(thieno[3,2-b]pyridin-2-ylsulfonamido)pyrrolidin-1-ylmethyl]benzamidine 【CA登记号】205054-04-2, 205054-05-3 (trifluoroacetate) 【 分 子 式 】C19H19N5O4S2 【 分 子 量 】445.52238 |
【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
Reaction of salicylaldehyde (I) with iodine monochloride produced 2-hydroxy-5-iodobenzaldehyde (II), which was protected with (2-methoxyethoxy) methyl chloride to give ether (III). Reduction of the aldehyde group of (III) with NaBH4 yielded alcohol (IV) and subsequent treatment with N-bromosuccinimide and triphenylphosphine generated bromide (V). N-Boc-3-aminopyrrolidinone (VII) was prepared by cyclization of (S)-alpha-Boc-2,4-diaminobutyric acid (VI) in the presence of EDC and HOBt. Subsequent alkylation of (VII) with bromide (V) produced the N-benzylpyrrolidinone derivative (VIII). Displacement of iodide group of (VIII) by zinc cyanide gave nitrile (IX). Then, acid cleavage of both Boc and MEM protecting groups furnished intermediate (X).
【1】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
40670 | 2-(chloromethoxy)ethyl methyl ether; 1-(chloromethoxy)-2-methoxyethane; (2-methoxyethoxy)methyl chloride | 3970-21-6 | C4H9ClO2 | 详情 | 详情 | |
(I) | 21351 | 2-Hydroxybenzaldehyde;Salicylic aldehyde;2-Formylphenol;salicylaldehyde | 90-02-8 | C7H6O2 | 详情 | 详情 |
(II) | 31671 | 2-hydroxy-5-iodobenzaldehyde | C7H5IO2 | 详情 | 详情 | |
(III) | 31672 | 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde; 5-iodo-2-[(2-methoxyethoxy)methoxy]benzaldehyde | C11H13IO4 | 详情 | 详情 | |
(IV) | 31673 | [5-iodo-2-[(2-methoxyethoxy)methoxy]phenyl]methanol | C11H15IO4 | 详情 | 详情 | |
(V) | 31674 | 2-[[2-(bromomethyl)-4-iodophenoxy]methoxy]ethyl methyl ether; 2-(bromomethyl)-4-iodo-1-[(2-methoxyethoxy)methoxy]benzene | C11H14BrIO3 | 详情 | 详情 | |
(VI) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
(VII) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
(VIII) | 31675 | tert-butyl (3S)-1-[5-iodo-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C20H29IN2O6 | 详情 | 详情 | |
(IX) | 31676 | tert-butyl (3S)-1-[5-cyano-2-[(2-methoxyethoxy)methoxy]benzyl]-2-oxopyrrolidinylcarbamate | C21H29N3O6 | 详情 | 详情 | |
(X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 |
合成路线2
The reaction of 5-chlorothieno[3,2-b]pyridine (XI) with n-BuLi and SO2 in THF and further oxidation with SO2Cl2 gives sulfonyl chloride (XII), which was coupled with aminopyrrolidinone (X) by means of TEA in dichloromethane to yield sulfonamide (XIII). Conversion of the nitrile of (XIII) to the corresponding imidate with HCl in methanol, followed by reaction with ammonia produced benzamidine (XIV). Finally, hydrogenolytic dechlorination of (XIV) over Pd/C provided the title compound.
【1】 Ewing, W.R.; Davis, R.S.; Becker, M.R.; et al.; Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 18, 2753. |
【2】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(X) | 31677 | 3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile | C12H13N3O2 | 详情 | 详情 | |
(XI) | 38295 | 5-chlorothieno[3,2-b]pyridine | C7H4ClNS | 详情 | 详情 | |
(XII) | 38296 | 5-chlorothieno[3,2-b]pyridine-2-sulfonyl chloride | C7H3Cl2NO2S2 | 详情 | 详情 | |
(XIII) | 38297 | 5-chloro-N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide | C19H15ClN4O4S2 | 详情 | 详情 | |
(XIV) | 38298 | 3-[((3S)-3-[[(5-chlorothieno[3,2-b]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidamide | C19H18ClN5O4S2 | 详情 | 详情 |