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【结 构 式】 
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【药物名称】Ticagrelor, AR-C126532, AZD6140 【化学名称】(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-Difluorophenyl)cyclopropylamino]-5-(propylsulfanyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol 【CA登记号】274693-27-5, 377093-13-5 (hydrate) 【 分 子 式 】C23H28F2N6O4S 【 分 子 量 】522.5693 |
【开发单位】AstraZeneca (GB). 【药理作用】Antiplatelet Therapy P2Y12 (P2T) Receptor Antagonist. |
合成路线1
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
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
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 |
合成路线4
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 |