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【结 构 式】 
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【分子编号】53564 【品名】1,4-dioxaspiro[4.5]decan-8-ol 【CA登记号】22428-87-1 |
【 分 子 式 】C8H14O3 【 分 子 量 】158.19736 【元素组成】C 60.74% H 8.92% O 30.34% |
合成路线1
该中间体在本合成路线中的序号：(VI)4-Bromo-2-fluoroaniline (I) was protected as the N-Boc derivative (II) upon treatment with di-tert-butyl dicarbonate. Subsequent palladium-catalyzed bromide displacement in (II) with bis-pinacolatodiborane (III) furnished the arylboronate derivative (IV). The (dioxaspirodecyl)pyrimidine (VII) was prepared by coupling between 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (V) and 4-hydroxycyclohexanone ethylene ketal (VI) under Mitsunobu conditions. Subsequent Suzuki coupling of iodopyrrolopyrimidine (VII) with boronate (IV) afforded adduct (VIII). Displacement of the 4-chloro of (VIII) with simultaneous N-Boc group cleavage with ammonium hydroxide in dioxan at 120 C in a sealed vessel furnished the diamino compound (IX).
| 【1】 Wishart, N.; Barlozzari, T.; Arnold, L.D.; et al.; Structure activity relationships for a novel series of pyrrolo[2,3-d]pyrimidine Tie-2 inhibitors. Proc Am Assoc Cancer Res 2002, 43, Abst 4205. |
| 【2】 Hirst, G.C.; Ritter, K.; Arnold, L.D.; Wishart, N.; Calderwood, D. (BASF AG); Pyrrolopyrimidines as protein kinase inhibitors. EP 1114053; WO 0017203 . |
| 【3】 Hirst, G.C.; Rafferty, P.; Arnold, L.D.; Johnston, D.N.; Calderwood, D.; Munschaufer, R. (BASF AG); Pyrrolopyrimidines as tyrosine kinase inhibitors. WO 0172751 . |
| 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) | 14723 | 4-Bromo-2-fluorophenylamine; 4-Bromo-2-fluoroaniline | 367-24-8 | C6H5BrFN | 详情 | 详情 |
| (II) | 53560 | tert-butyl 4-bromo-2-fluorophenylcarbamate | n/a | C11H13BrFNO2 | 详情 | 详情 |
| (III) | 53561 | n/a | C12H26B2O4 | 详情 | 详情 | |
| (IV) | 53562 | tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate | n/a | C17H25BFNO4 | 详情 | 详情 |
| (V) | 53563 | 4-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine | 123148-78-7 | C6H3ClIN3 | 详情 | 详情 |
| (VI) | 53564 | 1,4-dioxaspiro[4.5]decan-8-ol | 22428-87-1 | C8H14O3 | 详情 | 详情 |
| (VI) | 53565 | 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine | n/a | C14H15ClIN3O2 | 详情 | 详情 |
| (VII) | 53566 | tert-butyl 4-[4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylcarbamate | n/a | C25H28ClFN4O4 | 详情 | 详情 |
| (VIII) | 53567 | 5-(4-amino-3-fluorophenyl)-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 4-[4-amino-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-2-fluorophenylamine | n/a | C20H22FN5O2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Reduction of 1,4-cyclohexanedione mono-ethylene ketal (VII) with NaBH4 gives alcohol (VIII). This is then coupled with the pyrazolopyrimidine (VI) under Mitsunobu conditions to afford adduct (IX). Subsequent acidic ketal hydrolysis in (IX) leads to ketone (X). Finally, reductive condensation of (X) with N-methylpiperazine (XI) in the presence of NaBH(OAc)3 produces a mixture of cis and trans disubstituted cyclohexanes, from which the title trans isomer is isolated by flash column chromatography.
| 【1】 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 |
|---|---|---|---|---|---|---|
| (VI) | 57048 | 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine | C17H13N5O | 详情 | 详情 | |
| (VII) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (VIII) | 53564 | 1,4-dioxaspiro[4.5]decan-8-ol | 22428-87-1 | C8H14O3 | 详情 | 详情 |
| (IX) | 57049 | 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | C25H25N5O3 | 详情 | 详情 | |
| (X) | 57050 | 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexanone | C23H21N5O2 | 详情 | 详情 | |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(IV)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：(V)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 |