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【结 构 式】

【分子编号】65453

【品名】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

【CA登记号】274693-26-4

【 分 子 式 】C26H32F2N6O4S

【 分 子 量 】562.6409264

【元素组成】C 55.5% H 5.73% F 6.75% N 14.94% O 11.37% S 5.7%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XII)

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:(XII)

In an alternative method, 2-thiobarbituric acid (XIII) is alkylated with 1-iodopropane and NaOH in N-methylpyrrolidone to afford the 2-(propylsulfanyl)pyrimidine (XIV). Diazotization of p-toluidine (XV) with NaNO2 and HCl, followed by coupling of the intermediate diazonium salt with pyrimidine (XIV) in the presence of NaOAc, produces the diazo adduct (XVI). After chlorination of (XVI) with POCl3, reductive cleavage of the diazo compound (XVII) with H2 and Pt/C gives 5-amino-4,6-dichloro-2-(propylsulfanyl)pyrimidine (XVIII). Subsequent condensation of (XVIII) with the cyclopentylamino compound (XIX) in ethanolic triethylamine at 120 °C in a pressure vessel provides the diaminopyrimidine (XX), which is further converted to the azapurine (XXI) by treatment with NaNO2 in acetic acid. Then, substitution of chloride (XXI) with 2-(3,4-difluorophenyl)cyclopropylamine (X) in the presence of triethylamine in acetonitrile affords the acetonide (XII), which is finally hydrolyzed to the title compound as in the above method (3). Scheme 2.

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
(X) 65451 (1R,2S)-rel-2-(3,4-Difluorophenyl)cyclopropanamine 1006614-49-8 C9H9F2N 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
(XIII) 25623 2-Thiobarbituric acid; 4,5-Dihydroxy-2-mercaptopyrimidine; 2-sulfanyl-4,6-pyrimidinediol 504-17-6 C4H4N2O2S 详情 详情
(XIV) 65454 6-Hydroxy-2-(Propylsulfanyl)-4(3H)-Pyrimidinone 145783-12-6 C7H10N2O2S 详情 详情
(XV) 31228 p-toluidine; 4-methylphenylamine 106-49-0 C7H9N 详情 详情
(XVI) 65455     C14H16N4O2S 详情 详情
(XVII) 65456     C14H14Cl2N4S 详情 详情
(XVIII) 65457 5-amino-4,6-dichloro-2-(propylsulfanyl)pyrimidine 145783-15-9 C7H9Cl2N3S 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
(XX) 65459 2-[[(3aR,4S,6R,6aS)-6-[[5-Amino-6-chloro-2-(propylthio)-4-pyrimidinyl]amino]tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol 376608-74-1 C17H27ClN4O4S 详情 详情
(XXI) 65460 2-[[(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-yl]oxy]-ethanol 376608-75-2 C17H24ClN5O4S 详情 详情
Extended Information