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【结 构 式】 
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【分子编号】53567 【品名】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 【CA登记号】n/a |
【 分 子 式 】C20H22FN5O2 【 分 子 量 】383.4255832 【元素组成】C 62.65% H 5.78% F 4.95% N 18.27% O 8.35% |
合成路线1
该中间体在本合成路线中的序号：(VIII)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：(IX)Acid hydrolysis of the ethylene ketal function of (IX) afforded ketone (X). This was subjected to a reductive amination with N-methylpiperazine (XI) in the presence of sodium triacetoxyborohydride to produce the corresponding disubstituted cyclohexane compound as a 3:1 mixture of cis- and trans-isomers. The desired trans-compound (XII) was then isolated by column chromatography. Finally, acylation of (XII) with 2,3-dichlorobenzenesulfonyl chloride (XIII) provided the title sulfonamide.
| 【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 |
|---|---|---|---|---|---|---|
| (IX) | 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 |
| (X) | 53568 | 4-[4-amino-5-(4-amino-3-fluorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclohexanone | n/a | C18H18FN5O | 详情 | 详情 |
| (XI) | 10061 | 1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine | 109-01-3 | C5H12N2 | 详情 | 详情 |
| (XII) | 53569 | 5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine; 5-(4-amino-3-fluorophenyl)-7-[4-(4-methyl-1-piperazinyl)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine | n/a | C23H30FN7 | 详情 | 详情 |
| (XIII) | 53570 | 2,3-Dichlorobenzenesulfonyl chloride | 82417-45-6 | C6H3Cl3O2S | 详情 | 详情 |