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【结 构 式】 
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【分子编号】23180 【品名】methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate 【CA登记号】 |
【 分 子 式 】C17H23NO5 【 分 子 量 】321.37336 【元素组成】C 63.54% H 7.21% N 4.36% O 24.89% |
合成路线1
该中间体在本合成路线中的序号：(VI)Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished the target amidine, which was isolated as the hydrochloride salt.
| 【1】 Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.; New platelet fibrinogen receptor glycoprotein IIb-. J Med Chem 1998, 41, 21, 4036. |
| 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) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (II) | 23176 | 6-nitro-2,3-dihydro-4H-chromen-4-one | C9H7NO4 | 详情 | 详情 | |
| (III) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (IV) | 23178 | 2-[6-nitro-4-oxo-2H-chromen-3(4H)-ylidene]acetic acid | C11H7NO6 | 详情 | 详情 | |
| (V) | 23179 | methyl 2-(6-amino-3,4-dihydro-2H-chromen-3-yl)acetate | C12H15NO3 | 详情 | 详情 | |
| (VI) | 23180 | methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C17H23NO5 | 详情 | 详情 | |
| (VII) | 23181 | ethyl 2-[(3S)-6-amino-3,4-dihydro-2H-chromen-3-yl]acetate | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (IX) | 23183 | ethyl 2-[(3S)-6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C21H20N2O4 | 详情 | 详情 | |
| (X) | 23184 | ethyl 2-[(3S)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate | C23H26N2O5 | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)Nitration of chromanone (I) with fuming HNO3 at -35 C afforded 6-nitro-4-chromanone (II). Subsequent aldol condensation of (II) with glyoxylic acid (III) in the presence of H2SO4 produced the alpha-beta-unsaturated acid (IV). Further hydrogenation of the nitro, keto, and olefin groups of (IV) with concomitant esterification produced the benzopyranylacetate (V). After protection of (V) as the N-Boc derivative (VI), optical resolution was achieved by preparative HPLC on a Chiralcel-OD column. The desired (S)-enantiomer (VI) was deprotected using ethanolic HCl to afford amine (VII), which was condensed with 4-cyanobenzoyl chloride (VIII) to give amide (IX). Treatment of (IX) with HCl-EtOH produced imidate (X), and subsequent treatment with morpholine (XI) furnished amidine (XII). Finally, basic hydrolysis of the ester function provided the target amidinoacid, which was isolated as the hydrochloride salt.
| 【1】 Okumura, K.; Shimazaki, T.; Aoki, Y.; Yamashita, H.; Tanaka, E.; Banba, S.; Yazawa, K.; Kibayashi, K.; Banno, H.; New platelet fibrinogen receptor glycoprotein IIb-. J Med Chem 1998, 41, 21, 4036. |
| 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) | 14461 | 2,3-Dihydro-4H-chromen-4-one; 4-Chromanone | 491-37-2 | C9H8O2 | 详情 | 详情 |
| (II) | 23176 | 6-nitro-2,3-dihydro-4H-chromen-4-one | C9H7NO4 | 详情 | 详情 | |
| (III) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (IV) | 23178 | 2-[6-nitro-4-oxo-2H-chromen-3(4H)-ylidene]acetic acid | C11H7NO6 | 详情 | 详情 | |
| (V) | 23179 | methyl 2-(6-amino-3,4-dihydro-2H-chromen-3-yl)acetate | C12H15NO3 | 详情 | 详情 | |
| (VI) | 23180 | methyl 2-[(3S)-6-[(tert-butoxycarbonyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C17H23NO5 | 详情 | 详情 | |
| (VII) | 23181 | ethyl 2-[(3S)-6-amino-3,4-dihydro-2H-chromen-3-yl]acetate | C13H17NO3 | 详情 | 详情 | |
| (VIII) | 19280 | 4-cyanobenzoyl chloride | 6068-72-0 | C8H4ClNO | 详情 | 详情 |
| (IX) | 23183 | ethyl 2-[(3S)-6-[(4-cyanobenzoyl)amino]-3,4-dihydro-2H-chromen-3-yl]acetate | C21H20N2O4 | 详情 | 详情 | |
| (X) | 23184 | ethyl 2-[(3S)-6-([4-[ethoxy(imino)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate | C23H26N2O5 | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
| (XII) | 23186 | ethyl 2-[(3S)-6-([4-[imino(4-morpholinyl)methyl]benzoyl]amino)-3,4-dihydro-2H-chromen-3-yl]acetate | C25H29N3O5 | 详情 | 详情 |