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【结 构 式】 
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【分子编号】35573 【品名】tert-butyl 2-([(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]methyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate 【CA登记号】 |
【 分 子 式 】C24H25N5O5S2 【 分 子 量 】527.6252 【元素组成】C 54.63% H 4.78% N 13.27% O 15.16% S 12.15% |
合成路线1
该中间体在本合成路线中的序号：(XII)3-(tert-Butoxycarbonylamino)-2-pyrrolidinone (II), obtained by cyclization of (S)-Boc-2,4-diaminobutyric acid (I) in the presence of EDC, was regioselectively alkylated with propargyl bromide and NaH to give the N-propargyl pyrrolidinone (III). Subsequent acid-promoted deprotection of the Boc group of (III) provided aminopyrrolidinone (IV). Sulfonyl chloride (VII) was prepared by lithiation of thienopyridine (V), followed by addition of SO2, and further chlorination of the resulting sulfinic acid (VI) with sulfuryl chloride. This sulfonyl chloride (VII) was then coupled with aminopyrrolidinone (III), yielding sulfonamide (VIII). Lithiation of 3-(tert-butoxycarbonylamino)pyridine (IX) and subsequent treatment with iodine in cold THF provided the iodopyridine derivative (X). Palladium-mediated coupling of (X) with propargyl pyrrolidinone (VIII) furnished adduct (XI), which was cyclized to the pyrrolopyridine system (XII) upon treatment with DBU. Finally, the Boc protecting group of (XII) was removed using trifluoroacetic acid.
| 【1】 Choi-Sledeski, Y.M.; Becker, M.R.; Pauls, H.W.; et al.; Azaindole pyrrolidinone inhibitors of factor Xa: SAR, synthesis, and X-ray crystal structure of a novel surrogate for basic P1 moieties. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 33. |
| 【2】 Choi-Sledeski, Y.M.; Pauls, H.W.; Green, D.M.; Barton, J.N.; Becker, M.R.; Ewing, W.R. (Aventis Pharmaceuticals, Inc.); Sulfonic acid or sulfonylamino N-(heteroaralkyl)-azaheterocyclylamide cpds.. EP 0944386; WO 9825611 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 | |
| (I) | 29493 | (2S)-4-amino-2-[(tert-butoxycarbonyl)amino]butyric acid | C9H18N2O4 | 详情 | 详情 | |
| (II) | 29492 | tert-butyl (3S)-2-oxopyrrolidinylcarbamate | C9H16N2O3 | 详情 | 详情 | |
| (III) | 35566 | tert-butyl (3S)-2-oxo-1-(2-propynyl)pyrrolidinylcarbamate | C12H18N2O3 | 详情 | 详情 | |
| (IV) | 35567 | (3S)-3-amino-1-(2-propynyl)-2-pyrrolidinone | C7H10N2O | 详情 | 详情 | |
| (V) | 29500 | thieno[3,2-b]pyridine | C7H5NS | 详情 | 详情 | |
| (VI) | 35568 | thieno[3,2-b]pyridine-2-sulfonic acid | C7H5NO3S2 | 详情 | 详情 | |
| (VII) | 29496 | thieno[3,2-b]pyridine-2-sulfonyl chloride | C7H4ClNO2S2 | 详情 | 详情 | |
| (VIII) | 35569 | N-[(3S)-2-oxo-1-(2-propynyl)pyrrolidinyl]thieno[3,2-b]pyridine-2-sulfonamide | C14H13N3O3S2 | 详情 | 详情 | |
| (IX) | 35570 | tert-butyl 3-pyridinylcarbamate | 56700-70-0 | C10H14N2O2 | 详情 | 详情 |
| (X) | 35571 | tert-butyl 4-iodo-3-pyridinylcarbamate | C10H13IN2O2 | 详情 | 详情 | |
| (XI) | 35572 | tert-butyl 4-(3-[(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]-1-propynyl)-3-pyridinylcarbamate | C24H25N5O5S2 | 详情 | 详情 | |
| (XII) | 35573 | tert-butyl 2-([(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]methyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate | C24H25N5O5S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XII)N-alkylation of (S)-3-(benzyloxycarbonylamino)-2-pyrrolidinone (XIII) with propargyl bromide produced (XIV). Palladium-mediated coupling (XIV) with iodopyridine (X) gave adduct (XV), which was cyclized to the pyrrolopyridine (XVI) by means of DBU. The benzyloxycarbonyl protecting group of (XVI) was removed by transfer catalytic hydrogenolysis with formic acid, and the deprotected amine (XVII) was then condensed with sulfonyl chloride (VII) to furnish sulfonamide (XII). Deprotection of the Boc group of (XII) as above gave rise to the title compound.
| 【1】 Choi-Sledeski, Y.M.; Becker, M.R.; Pauls, H.W.; et al.; Azaindole pyrrolidinone inhibitors of factor Xa: SAR, synthesis, and X-ray crystal structure of a novel surrogate for basic P1 moieties. 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 33. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 11176 | 3-Bromopropyne; 3-Bromo-1-propyne | 106-96-7 | C3H3Br | 详情 | 详情 | |
| (VII) | 29496 | thieno[3,2-b]pyridine-2-sulfonyl chloride | C7H4ClNO2S2 | 详情 | 详情 | |
| (X) | 35571 | tert-butyl 4-iodo-3-pyridinylcarbamate | C10H13IN2O2 | 详情 | 详情 | |
| (XII) | 35573 | tert-butyl 2-([(3S)-2-oxo-3-[(thieno[3,2-b]pyridin-2-ylsulfonyl)amino]pyrrolidinyl]methyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate | C24H25N5O5S2 | 详情 | 详情 | |
| (XIII) | 35574 | benzyl (3S)-2-oxopyrrolidinylcarbamate | C12H14N2O3 | 详情 | 详情 | |
| (XIV) | 35575 | benzyl (3S)-2-oxo-1-(2-propynyl)pyrrolidinylcarbamate | C15H16N2O3 | 详情 | 详情 | |
| (XV) | 35576 | benzyl (3S)-1-(3-[3-[(tert-butoxycarbonyl)amino]-4-pyridinyl]-2-propynyl)-2-oxopyrrolidinylcarbamate | C25H28N4O5 | 详情 | 详情 | |
| (XVI) | 35577 | tert-butyl 2-[((3S)-3-[[(benzyloxy)carbonyl]amino]-2-oxopyrrolidinyl)methyl]-1H-pyrrolo[2,3-c]pyridine-1-carboxylate | C25H28N4O5 | 详情 | 详情 | |
| (XVII) | 35578 | tert-butyl 2-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-1H-pyrrolo[2,3-c]pyridine-1-carboxylate | C17H22N4O3 | 详情 | 详情 |