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【结 构 式】 
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【分子编号】65451 【品名】(1R,2S)-rel-2-(3,4-Difluorophenyl)cyclopropanamine 【CA登记号】1006614-49-8 |
【 分 子 式 】C9H9F2N 【 分 子 量 】169.1740064 【元素组成】C 63.9% H 5.36% F 22.46% N 8.28% |
合成路线1
该中间体在本合成路线中的序号：(X)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：(X)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 |
合成路线3
该中间体在本合成路线中的序号：(X)The cyclopropylamine building block (X) is obtained as follows. Knoevenagel condensation of 3,4-difluorobenzaldehyde (XXII) with malonic acid in the presence of piperidine in hot pyridine produces 3,4-difluorocinnamic acid (XXIII). After conversion of (XXIII) to the corresponding acid chloride (XXIV) by means of SOCl2, condensation with L-menthol (XXV) provides the menthyl difluorocinnamate (XXVI). Cyclopropanation of (XXVI) employing dimethylsulfoxonium methylide (generated from trimethylsulfoxonium iodide and NaOH in DMSO) gives the cyclopropanecarboxylate ester (XXVII), which is hydrolyzed to the carboxylic acid (XXVIII) by means of NaOH in aqueous ethanol. Subsequent chlorination of acid (XXVIII) followed by treatment with aqueous NaN3 in the presence of Na2CO3 and Bu4NBr yields the acyl azide (XXIX), which is converted to the target amine (X) by Curtius rearrangement in hot toluene (3). Scheme 3.
| 【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 |
| (XXII) | 26654 | 3,4-difluorobenzaldehyde | 34036-07-2 | C7H4F2O | 详情 | 详情 |
| (XXIII) | 65461 | trans-3,4-Difluorocinnamic acid | 112897-97-9 | C9H6F2O2 | 详情 | 详情 |
| (XXIV) | 65462 | C9H5ClF2O | 详情 | 详情 | ||
| (XXV) | 41803 | (1R,2S,5R)-2-isopropyl-5-methylcyclohexanol; L-menthol | 2216-51-5 | C10H20O | 详情 | 详情 |
| (XXVI) | 65463 | menthyl 3，4-difluorocinnamate | C19H24F2O2 | 详情 | 详情 | |
| (XXVII) | 65464 | C20H26F2O2 | 详情 | 详情 | ||
| (XXVIII) | 65465 | C10H8F2O2 | 详情 | 详情 | ||
| (XXIX) | 65466 | C10H7F2N3O | 详情 | 详情 |