3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine -Drug Synthesis Database

【结构式】

【分子编号】57048

【品名】3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine; 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

【CA登记号】

【分子式】C₁₇H₁₃N₅O

【分子量】303.32332

【元素组成】C 67.32% H 4.32% N 23.09% O 5.27%

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：(VI)

4-Phenoxybenzoic acid (I) is chlorinated with SOCl2, and the resultant acid chloride (II) is then condensed with malononitrile to produce the hydroxybenzylidene malononitrile (III). Subsequent methylation of (III) with trimethylsilyl diazomethane yields the methyl ether (IV), which is cyclized to pyrazole (V) upon treatment with hydrazine hydrate in boiling EtOH. Reaction of the 3-amino-4-cyanopyrazole (V) with hot formamide then produces the key pyrazolopyrimidine intermediate (VI).

参考文献中间体

合成目标

【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
(I)	57044	4-Phenoxybenzoic acid; Diphenyl ether 4-carboxylic acid	2215-77-2	C₁₃H₁₀O₃	详情	详情
(II)	44796	4-phenoxybenzoyl chloride		C₁₃H₉ClO₂	详情	详情
(III)	57045	2-[hydroxy(4-phenoxyphenyl)methylene]malononitrile		C₁₆H₁₀N₂O₂	详情	详情
(IV)	57046	2-[methoxy(4-phenoxyphenyl)methylene]malononitrile		C₁₇H₁₂N₂O₂	详情	详情
(V)	57047	5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile		C₁₆H₁₂N₄O	详情	详情
(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

合成路线2

该中间体在本合成路线中的序号：(VI)

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.

参考文献中间体

合成目标

【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：(VII)

Chlorination of 4-phenoxybenzoic acid (I) with refluxing SOCl2 gives the corresponding acid chloride (II), which is then condensed with malononitrile (III) in the presence of DIEA in toluene/THF, followed by treatment with H2So4 to yield the enol derivative (IV). Methylation of the hydroxy group of compound (IV) by means of Me3SiCHn2 and DIEA in ace tonitrile/MeoH provides the 2-methoxyethene derivative (V), which by cyclization with hydrazine in EtoH affords the pyrazole derivative (VI). Cyclization of compound (VI) with formamide at 180 °C gives 4-amino-3-(4-phenoxyphenyl)pyrazolo[3,4-d]pyrimidine (VII) (1), which is submitted to Mitsunobu coupling with N-Boc-3(S)-hydroxypiperidine (VIII) in THF using DIAD and either polymer-bound triphenylphosphine or PPh3 to provide the 1-[N-Boc-3(R)-piperidinyl]pyrazolopyrimidine derivative (IX). Deprotection of intermediate (IX) by treatment with HCl in dioxane or TFA in CH2Cl2 leads to the free piperidine derivative (X), which is finally acylated with acryloyl chloride (XI) by means of Et3n in CH2Cl2 .

参考文献中间体

合成目标

【1】 Hirst, G.C., Wishart, n., Rafferty, P., Friedman, M.M., Arnold, L.D., Calderwood, D., Ritter, K. (Abbott GmbH & Co. KG). Pyrazolopyrimidines as therapeutic agents. EP 1212327, JP 2003509428, US 6660744, WO 2001019829.
【2】 Pan, Z., Scheerens, H., Li, S.J. et al. Discovery of selective irreversible inhibitors for Bruton’s tyrosine kinase. ChemMedChem 2007, 2(1): 58-61.
【3】 Honigberg, L., Verner, E., Pan, Z. (Pharmacyclics, Inc.). Inhibitors of Bruton’s tyrosine kinase. US 2008139582, US 7825118.
【4】 Honigberg, L., Verner, E., Pan, Z. (Pharmacyclics, Inc.). Inhibitors of Bruton’s tyrosine kinase. KR 2013027536, US 2008076921, US 7732454.
【5】 Honigberg, L., Verner, E., Pan, Z. (Pharmacyclics, Inc.). Inhibitors of Bruton’s tyrosine kinase. CA 266116, Cn 101805341, Cn 102746305, CN 102887900, EP 2081435, EP 2201840, EP 2443929, EP 2526771, EP 2526933, EP 2526934, EP 2529621, EP 21529622, EP 2532234, EP 2532235, JP 2010504324, JP 2010235628, US 2008108636, US 7514444, WO 2008039218.
【6】 Pan, Z., Li, S.J., Schereens, H., Honigberg, L., Verner, E. (Pharmacyclics, Inc.). Bruton’s tyrosine kinase activity probe and method of using. US 2008214501, WO 2008054827.

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)	57044	4-Phenoxybenzoic acid; Diphenyl ether 4-carboxylic acid	2215-77-2	C₁₃H₁₀O₃	详情	详情
(II)	44796	4-phenoxybenzoyl chloride		C₁₃H₉ClO₂	详情	详情
(III)	12061	Malononitrile	109-77-3	C₃H₂N₂	详情	详情
(IV)	57045	2-[hydroxy(4-phenoxyphenyl)methylene]malononitrile		C₁₆H₁₀N₂O₂	详情	详情
(V)	57046	2-[methoxy(4-phenoxyphenyl)methylene]malononitrile		C₁₇H₁₂N₂O₂	详情	详情
(VI)	57047	5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile		C₁₆H₁₂N₄O	详情	详情
(VII)	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
(VIII)	68045	(S)-tert-butyl 3-hydroxypiperidine-1-carboxylate	143900-44-1	C₁₀H₁₉NO₃	详情	详情
(IX)	68047	(R)-tert-butyl 3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate		C₂₇H₃₀N₆O₃	详情	详情
(X)	68046	(R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine		C₂₂H₂₂N₆O	详情	详情
(XI)	11577	Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride	814-68-6	C₃H₃ClO	详情	详情

Extended Information