5-Amino-4-pyrazolecarbonitrile -Drug Synthesis Database

【结构式】

【分子编号】57051

【品名】5-Amino-4-pyrazolecarbonitrile

【CA登记号】

【分子式】C₄H₄N₄

【分子量】108.10272

【元素组成】C 44.44% H 3.73% N 51.83%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XVIII)

Cyclization of ethoxymethylenemalonodinitrile (XVII) with hydrazine gives 5-aminopyrazole-4-carbonitrile (XVIII), which is further cyclized with acetamide (X) in refluxing AcOH to yield the 3-cyanopyrazolo[1,5-a]pyrimidine derivative (XIX). Finally, this compound is condensed with 2-bromothiophene (XX) by means of Mg.

参考文献中间体

合成目标

【1】 Sorbera, L.A.; Castaner, J.; Martin, L.; Indiplon. Drugs Fut 2003, 28, 8, 739.
【2】 Wilcoxen, K.M.; Gross, R.S. (Neurocrine Biosciences Inc.); Synthesis of substd. pyrazolopyrimidines. WO 0110868 .

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)	59947	N-{3-[(E)-3-(dimethylamino)-2-propenoyl]phenyl}-N-methylacetamide		C₁₄H₁₈N₂O₂	详情	详情
(XVII)	13017	Ethoxymethylenemalononitrile; 2-(Ethoxymethylene)malononitrile	123-06-8	C₆H₆N₂O	详情	详情
(XVIII)	57051	5-Amino-4-pyrazolecarbonitrile		C₄H₄N₄	详情	详情
(XIX)	62965	N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-methylacetamide		C₁₆H₁₃N₅O	详情	详情
(XX)	13681	2-Bromothiophene	1003-09-4	C₄H₃BrS	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

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.

参考文献中间体

合成目标

【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3

该中间体在本合成路线中的序号：(I)

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

合成目标

【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

Extended Information