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【结 构 式】 
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【分子编号】65443 【品名】(3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; (3aS,4R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine 【CA登记号】155899-66-4 |
【 分 子 式 】C8H15NO3 【 分 子 量 】173.21204 【元素组成】C 55.47% H 8.73% N 8.09% O 27.71% |
合成路线1
该中间体在本合成路线中的序号：(I)4(R)-Aminocyclopentane-(1S,2R,3S)-triol 2,3-acetonide (I) is condensed with 4,6-dichloro-5-nitro-2-propylthiopyrimidine (II) in the presence of diisopropylethylamine in THF to afford the aminopyrimidine adduct (III), which is reduced to the diamine (IV) by means of iron powder in acetic acid. Cyclization of diamine (IV) employing isoamyl nitrite in hot acetonitrile followed by displacement of the resulting 6-chloro-8-azapurine (V) with ammonia in THF gives the azaadenine (VI). The lithium alkoxide of cyclopentanol (VI) is then alkylated with methoxycarbonylmethyl triflate (VII), producing ether (VIII). After conversion of amine (VIII) to the corresponding bromide (IX) by diazotization with isoamyl nitrite in bromoform, bromide displacement with 2-(3,4-difluorophenyl)cyclopropylamine (X) gives adduct (XI). Finally, DIBAL reduction of the ester function of (XI) provides acetonide (XII), which is finally hydrolyzed under acidic conditions to furnish the title compound (1, 2). Scheme 1.
| 【1】 Guile, S., Hardern, D., Willis, P., Springthorpe, B., Ingall, A. (AstraZeneca AB; AstraZeneca plc). Novel triazolo(4,5-d)pyrimidine compounds. EP 1135391, JP 2002531567, JP 2007084551, US 2003144305, US 2006025590, US 6525060, WO 0034283. |
| 【2】 Bohlin, M., Lassen, B., Cosgrove, S. (AstraZeneca AB). New crystalline and amorphous form of triazolo(4,5-d)pyrimidine compound. CA 2408596, EP 1289992, EP 1493745, JP 2003535092, US 2003181469, US 2007173518, WO 0192262. |
| 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) | 65443 | (3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; (3aS,4R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine | 155899-66-4 | C8H15NO3 | 详情 | 详情 |
| (II) | 65444 | 4,6-Dichloro-5-nitro-2-propylthiopyrimidine | 145783-14-8 | C7H7Cl2N3O2S | 详情 | 详情 |
| (III) | 65445 | (3aR,4S,6R,6aS)-6-[[6-Chloro-5-nitro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol | 220241-59-8 | C15H21ClN4O5S | 详情 | 详情 |
| (IV) | 65446 | (3aR,4S,6R,6aS)-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol | 220241-60-1 | C15H23ClN4O3S | 详情 | 详情 |
| (V) | 65447 | (3aR,4S,6R,6aS)-6-[7-Chloro-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol | 220241-61-2 | C15H20ClN5O3S | 详情 | 详情 |
| (VI) | 65448 | (3aR,4S,6R,6aS)-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol | 274693-22-0 | C15H22N6O3S | 详情 | 详情 |
| (VII) | 63493 | methyl 2-{[(trifluoromethyl)sulfonyl]oxy}acetate | C4H5F3O5S | 详情 | 详情 | |
| (VIII) | 65449 | 2-[[(3aR,4S,6R,6aS)-6-[7-Amino-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-acetic acid methyl ester | 274693-23-1 | C18H26N6O5S | 详情 | 详情 |
| (IX) | 65450 | 2-[[(3aR,4S,6R,6aS)-6-[7-Bromo-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-acetic acid methyl ester | 274693-24-2 | C18H24BrN5O5S | 详情 | 详情 |
| (X) | 65451 | (1R,2S)-rel-2-(3,4-Difluorophenyl)cyclopropanamine | 1006614-49-8 | C9H9F2N | 详情 | 详情 |
| (XI) | 65452 | 2-[[(3aR,4S,6R,6aS)-6-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-acetic acid methyl ester | 274693-25-3 | C27H32F2N6O5S | 详情 | 详情 |
| (XII) | 65453 | 2-[[(3aS,4R,6S,6aR)-4-[7-[[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-2,2-dimethyl-tetrahydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy]ethanol | 274693-26-4 | C26H32F2N6O4S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The preparation of the cyclopentylamino intermediates (I) and (XIX) is shown in Scheme 4. Reaction of (1S,4R)-4-acetoxy-2-cyclopentenol (XXX) with di-tert-butyl iminodicarboxylate in the presence of NaH and Pd(PPh3)4 produces the di-Boc-protected aminocyclopentenol (XXXI), which undergoes dihydroxylation to triol (XXXII) by means of N-methylmorpholine N-oxide and a catalytic amount of osmium tetroxide. After acidic deprotection of the di-Boc derivative (XXXII), the resulting amino triol (XXXIII) is converted to the key acetonide (I) upon heating with 2,2-dimethoxypropane and catalytic HCl in acetone (1, 2). The O-hydroxyethyl derivative (XIX) is prepared by protection of aminoalcohol (I) as the benzyl carbamate (XXXIV), followed by O-alkylation with ethyl bromoacetate and potassium tert-butoxide to give (XXXV). Subsequent reduction of ester (XXXV) with LiBH4 in THF furnishes the corresponding hydroxyethyl derivative (XXXVI), from which the N-(benzyloxycarbonyl) group is removed by catalytic hydrogenation over Pd/C (3). Scheme 4.
| 【1】 Guile, S., Hardern, D., Willis, P., Springthorpe, B., Ingall, A. (AstraZeneca AB; AstraZeneca plc). Novel triazolo(4,5-d)pyrimidine compounds. EP 1135391, JP 2002531567, JP 2007084551, US 2003144305, US 2006025590, US 6525060, WO 0034283. |
| 【2】 Bohlin, M., Lassen, B., Cosgrove, S. (AstraZeneca AB). New crystalline and amorphous form of triazolo(4,5-d)pyrimidine compound. CA 2408596, EP 1289992, EP 1493745, JP 2003535092, US 2003181469, US 2007173518, WO 0192262. |
| 【3】 Larsson, U., Magnusson, M., Musil, T., Palmgren, A. (AstraZeneca AB). Triazolo pyrimidine compounds. CA 2408914, EP 1299390, JP 2003535093, US 2003148888, US 2006041132, US 2007049755, US 7067663, WO 0192263. |
| 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) | 65443 | (3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol; (3aS,4R,6S,6aR)-6-Hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine | 155899-66-4 | C8H15NO3 | 详情 | 详情 |
| (XIX) | 65458 | 2-[[(3aR,4S,6R,6aS)-6-Aminotetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]ethanol | 274693-55-9 | C10H19NO4 | 详情 | 详情 |
| (XXX) | 45407 | (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol | 60410-16-4 | C7H10O3 | 详情 | 详情 |
| (XXXI) | 65467 | (1S,4R)-4-[(N,N-di-Boc)amino]-2-cyclopentenol | C15H25NO5 | 详情 | 详情 | |
| (XXXII) | 65468 | C15H27NO7 | 详情 | 详情 | ||
| (XXXIII) | 65469 | C5H11NO3.HCl | 详情 | 详情 | ||
| (XXXIV) | 65470 | N-[(3aS,4R,6S,6aR)-Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]carbamicacid phenylmethyl ester | 274693-53-7 | C16H21NO5 | 详情 | 详情 |
| (XXXV) | 65471 | C20H27NO7 | 详情 | 详情 | ||
| (XXXVI) | 65472 | N-[(3aS,4R,6S,6aR)-Tetrahydro-6-(2-hydroxyethoxy)-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]carbamic acid phenylmethyl ester | 274693-54-8 | C18H25NO6 | 详情 | 详情 |