A-420983, -Drug Synthesis Database

【结构式】

【药物名称】A-420983

【化学名称】N-[4-[4-Amino-1-[trans-4-(4-methylpiperazin-1-yl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl]-1-methyl-1H-indole-2-carboxamide

【CA登记号】330789-03-2, 330788-65-3 (cis-isomer), 330789-04-3 (maleate)

【分子式】C₃₃H₃₉N₉O₂

【分子量】593.73788

【开发单位】Abbott (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Treatment of Autoimmune Diseases, Treatment of Transplant Rejection, Tyrosine Kinase Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

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.

参考文献中间体

【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

合成路线2

Suzuki coupling between the pyrazolopyrimidinyl iodide (IX) and the pinacol arylboronate derivative (XI) provides the 3-aryl pyrazolopyrimidine (XII). The N-Boc protecting group of (XII) is then removed under acidic conditions to give aniline (XIII). Acid chloride (XV), prepared by chlorination of 1-methyl-2-indolecarboxylic acid (XIV) is finally coupled to aniline (XIII) to furnish the title amide.

参考文献中间体

【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
(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
(XI)	58341	tert-butyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate		C₁₈H₂₈BNO₅	详情	详情
(XII)	58342	tert-butyl 4-{4-amino-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenylcarbamate		C₂₈H₄₀N₈O₃	详情	详情
(XIII)	58343	3-(4-amino-3-methoxyphenyl)-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine; 3-(4-amino-3-methoxyphenyl)-1-[4-(4-methyl-1-piperazinyl)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine		C₂₃H₃₂N₈O	详情	详情
(XIV)	58344	1-methyl-1H-indole-2-carboxylic acid; 1-methylindole-2-carboxylic acid	16136-58-6	C₁₀H₉NO₂	详情	详情
(XV)	58545	3-ethyl-7,8-dihydro-3H-pyrazolo[4',3':5,6]pyrido[3,4-d]pyridazine-6,9-dione		C₁₀H₉N₅O₂	详情	详情

合成路线3

In a related procedure, the pyrazolopyrimidinyl iodide (IX) is coupled to the (indolecarboxamido)phenyl boronate (XVI) under Suzuki reaction conditions, leading directly to the title compound.

参考文献中间体

【1】 Ferraris, D.; et al.; Design, synthesis and SAR of PARP-1 inhibitors. Drugs Fut 2002, 27, Suppl. A.

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)	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
(XVI)	58346	N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-indole-2-carboxamide		C₂₃H₂₇BN₂O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)