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【结 构 式】 
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【分子编号】41250 【品名】3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine 【CA登记号】 |
【 分 子 式 】C5H4IN5 【 分 子 量 】261.02493 【元素组成】C 23.01% H 1.54% I 48.62% N 26.83% |
合成路线1
该中间体在本合成路线中的序号：(II)The iodination of 1H-pyrazolo[3,4-d]pyrimidine-4-amine (I) with N-yodosuccinimide (NIS) gives 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (II), which is condensed with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (III) by means of BF3/ethyl ether in nitromethane to yield the benzoylated adduct (IV). Finally this compound is deprotected with sodium methoxide.
| 【1】 Robins, R.K.; Potential purine antagonists. I. Synthesis of some 4,6-substituted pyrazolo[3,4-d]pyrimidines. J Am Chem Soc 1956, 78, 784-790. |
| 【2】 Cottam, H.B.; New adenosine kinase inhibitors with oral antiinflammatory activity. Drugs Fut 1994, 19, 5, 485. |
| 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) | 41249 | 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine | 2380-63-4 | C5H5N5 | 详情 | 详情 |
| (II) | 41250 | 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C5H4IN5 | 详情 | 详情 | |
| (III) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (IV) | 41251 | [(2R,3R,4R,5R)-5-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | C31H24IN5O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)The reaction of methyl D-ribofuranoside (I) with SOCl2 gives methyl 5-chloro-5-deoxy-2,3-O-sulfinyl-D-ribofuranoside (II), which is treated with ammonia to yield methyl 5-chloro-5-deoxy-D-ribofuranoside (III). The reaction of (IV) with benzoyl chloride and pyridine affords the dibenzoate (IV), which is treated with lithium azide in DMF to provide the 5'-azido derivative (V). The condensation of 3-iodo-1H-pyrazolo[3,4-d]pyrimidine-4-amine (VII) (prepared by iodination of (1H-pyrazolo[3,4-d]pyrimidine-4-amine (VI) with N-iodosuccinimide (NIS)) with the azido derivative (V) by means of BF3/Et in nitromethane gives the adduct (VIII), which is debenzoylated with sodium methoxide yielding the azido nucleoside (IX). Finally this compound is reduced with triphenylphosphine and ammonia to furnish the target 5'-amino-nucleoside.
| 【1】 Cottam, H.B.; New adenosine kinase inhibitors with oral antiinflammatory activity. Drugs Fut 1994, 19, 5, 485. |
| 【2】 Kasukhin, L.F.; Gololobov, Yu.G.; Zhmurova, I.N.; Sixty years of Staudinger reaction. Tetrahedron 1981, 37, 437-472. |
| 【3】 Browne, C.E.; Ugarkar, B.G.; Mullane, K.M.; Gruber, H.E.; Bullough, D.A.; Erion, M.D.; Castellino, A. (Sicor Inc.); Adenosine kinase inhibitors. EP 0496617; JP 1993112595; WO 9212718 . |
| 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) | 41258 | (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydro-3,4-furandiol | C6H12O5 | 详情 | 详情 | |
| (II) | 41252 | (4S)-4-(chloromethyl)-6-methoxytetrahydro-2lambda(4)-furo[3,4-d][1,3,2]dioxathiol-2-one | C6H9ClO5S | 详情 | 详情 | |
| (III) | 41253 | (2S,3S,4R)-2-(chloromethyl)-5-methoxytetrahydro-3,4-furandiol | C6H11ClO4 | 详情 | 详情 | |
| (IV) | 41254 | (3R,4R,5S)-4-(benzoyloxy)-5-(chloromethyl)-2-methoxytetrahydro-3-furanyl benzoate | C20H19ClO6 | 详情 | 详情 | |
| (V) | 41255 | (3R,4R,5R)-5-(azidomethyl)-4-(benzoyloxy)-2-methoxytetrahydro-3-furanyl benzoate | C20H19N3O6 | 详情 | 详情 | |
| (VI) | 41249 | 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine | 2380-63-4 | C5H5N5 | 详情 | 详情 |
| (VII) | 41250 | 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C5H4IN5 | 详情 | 详情 | |
| (VIII) | 41256 | (2R,3R,4R,5R)-2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(azidomethyl)-4-(benzoyloxy)tetrahydro-3-furanyl benzoate | C24H19IN8O5 | 详情 | 详情 | |
| (IX) | 41257 | (2R,3R,4S,5R)-2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-5-(azidomethyl)tetrahydro-3,4-furandiol | C10H11IN8O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(III)In an alternative synthetic route, cyclization of the aminopyrazole (I) with formamide gives the pyrazolopyrimidine (II), which is then iodinated to (III) by means of N-iodosuccinimide. Mitsunobu coupling of (III) with 4,4-(ethylenedioxy)cyclohexanol (IV) produces the cyclohexyl pyrazolopyrimidine derivative (V), and further ketal hydrolysis leads to ketone (VI). This is subjected to reductive amination with N-methylpiperazine (VII) in the presence of NaBH(OAc)3 to yield (VIII). Finally, Suzuki coupling of iodopyrazolopyrimidine (VIII) with 4-phenoxyphenylboronic acid (IX) gives rise to the title compound.
| 【1】 Burchat, A.F.; et al.; Pyrazolo[3,4-d]pyrimidines containing an extended 3-substituent as potent inhibitors of Lck - A selective insight. Bioorg Med Chem Lett 2002, 12, 12, 1687. |
| 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) | 57051 | 5-Amino-4-pyrazolecarbonitrile | C4H4N4 | 详情 | 详情 | |
| (II) | 41249 | 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine | 2380-63-4 | C5H5N5 | 详情 | 详情 |
| (III) | 41250 | 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C5H4IN5 | 详情 | 详情 | |
| (IV) | 53564 | 1,4-dioxaspiro[4.5]decan-8-ol | 22428-87-1 | C8H14O3 | 详情 | 详情 |
| (V) | 57052 | 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C13H16IN5O2 | 详情 | 详情 | |
| (VI) | 57053 | 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone | C11H12IN5O | 详情 | 详情 | |
| (VII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (VIII) | 57054 | 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C16H24IN7 | 详情 | 详情 | |
| (IX) | 57055 | 4-Phenoxyphenylboronic acid | 51067-38-0 | C12H11BO3 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(III)Treatment of 3-aminopyrazole-4-carbonitrile (I) with formamide at 180 C gives rise to the pyrazolopyrimidinyl amine (II). Subsequent iodination of (II) with N-iodosuccinimide in hot DMF affords 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (III). Reduction of 1,4-cyclohexanedione mono-ethylene ketal (IV) with NaBH4 furnishes alcohol (V). This is then subjected to Mitsunobu coupling with the pyrazolopyrimidine (III) to produce adduct (VI). Acidic hydrolysis of the ethylene ketal (VI) leads to the cyclohexanone (VII). The reductive amination of ketone (VII) with N-methylpiperazine (VIII), either employing NaBH(OAc)3 or via condensation in hot NMP, and then reduction of the resultant enamine with formic acid, produces a mixture of trans- (IX) and cis- (X) disubstituted cyclohexanes, with different ratios in each case.
| 【1】 Ferraris, D.; et al.; Design, synthesis and SAR of PARP-1 inhibitors. Drugs Fut 2002, 27, Suppl. A. |
| 【2】 Hirst, G.C.; Rafferty, P.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D.; Friedman, M.M. (BASF AG); Pyrazolopyrimidines as therapeutic agents. EP 1212327; WO 0119829 . |
| 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) | 57051 | 5-Amino-4-pyrazolecarbonitrile | C4H4N4 | 详情 | 详情 | |
| (II) | 41249 | 4-amine-1H-pyrazolo[3,4-d]pyrimidine; 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1H-pyrazolo[3,4-d]pyrimidin-4-amine | 2380-63-4 | C5H5N5 | 详情 | 详情 |
| (III) | 41250 | 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C5H4IN5 | 详情 | 详情 | |
| (IV) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (V) | 53564 | 1,4-dioxaspiro[4.5]decan-8-ol | 22428-87-1 | C8H14O3 | 详情 | 详情 |
| (VI) | 57052 | 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C13H16IN5O2 | 详情 | 详情 | |
| (VII) | 57053 | 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)cyclohexanone | C11H12IN5O | 详情 | 详情 | |
| (VIII) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (IX) | 57054 | 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C16H24IN7 | 详情 | 详情 | |
| (X) | 58340 | 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 3-iodo-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C16H24IN7 | 详情 | 详情 |