3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole -Drug Synthesis Database

【结构式】

【分子编号】11987

【品名】3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole

【CA登记号】16617-46-2

【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 7 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5 合成路线6 合成路线7

合成路线1

该中间体在本合成路线中的序号：(V)

The condensation of N-(3-acetylphenyl)acetamide (I) with dimethylformamide dimethylacetal (II) at reflux temperature gives N-[3-[3-(dimethylamino)-2-propenoyl]phenyl]acetamide (III), which is alkylated with NaH and ethyl iodide to the corresponding N-ethyl derivative (IV). Finally, this compound is cyclized with 3-aminopyrazole-4-carbonitrile (V) in refluxing acetic acid.

参考文献中间体

合成目标

【1】 Mealy, N.; Castaner, J.; Zaleplon. Drugs Fut 1996, 21, 1, 37.
【2】 Dusza, J.P.; Tomcufcik, A.S.; Albright, J.D. (American Cyanamid Co.); [7-(3-Disubstd. amino)phenyl]pyrazolo[1,5-a]pyrimidines. EP 0208846; JP 1986260083; JP 1995084468; US 4626538 .

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)	11983	3'-Acetamidoacetophane; m-Acetamidoacetophenone; N-(3-Acetylphenyl)acetamide	7463-31-2	C₁₀H₁₁NO₂	详情	详情
(II)	11984	N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal	4637-24-5	C₅H₁₃NO₂	详情	详情
(III)	11985	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]acetamide		C₁₃H₁₆N₂O₂	详情	详情
(IV)	11986	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]-N-ethylacetamide		C₁₅H₂₀N₂O₂	详情	详情
(V)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The alkylation of 5-amino-4-cyanopyrazole (I) with n-propyl iodide led to a 4:1 inseparable mixture of regioisomers (II) and (III). This mixture was transformed into the respective imidates (IV) and (V) through refluxing in triethyl orhoformate. Subsequent addition of 2-furoic hydrazide (VI) to the nitrile group of (IV)+(V), followed by thermal cyclization in diphenyl ether at 260 C furnished the corresponding pyrazolotriazolopyrimidines. The desired regioisomer (VII) was then isolated by flash chromatography. Hydrolysis of (VII) with aqueous HCl afforded the aminopyrazole (VIII), which was further converted to the tricyclic compound (IX) by reaction with cyanamide and p-toluenesulfonic acid. Finally, coupling of (IX) with p-methoxyphenyl isocyanate (X) provided the title urea.

参考文献中间体

合成目标

【1】 Cacciari, B.; Klotz, K.-N.; Borea, P.A.; Leung, E.; Merighi, S.; Varani, K.; Gessi, S.; Spalluto, G.; Baraldi, P.G.; Ropmagnoli, R.; Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine derivatives as highly potent and selective human A3 adenosine receptor antagonists. J Med Chem 1999, 42, 22, 4473.

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)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情
(II)	41398	3-amino-1-propyl-1H-pyrazole-4-carbonitrile		C₇H₁₀N₄	详情	详情
(III)	41399	3-amino-2-propyl-1H-2lambda(5)-pyrazole-4-carbonitrile		C₇H₁₂N₄	详情	详情
(IV)	41400	ethyl 4-cyano-1-propyl-1H-pyrazol-3-yliminoformate		C₁₀H₁₄N₄O	详情	详情
(V)	41401	ethyl 4-cyano-2-propyl-1H-2lambda(5)-pyrazol-3-yliminoformate		C₁₀H₁₆N₄O	详情	详情
(VI)	41402	2-furohydrazide	3326-71-4	C₅H₆N₂O₂	详情	详情
(VII)	41403	2-(2-furyl)-8-propyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine		C₁₃H₁₂N₆O	详情	详情
(VIII)	41404	4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-propyl-1H-pyrazol-3-amine; 4-[3-(2-furyl)-1H-1,2,4-triazol-5-yl]-1-propyl-1H-pyrazol-3-ylamine		C₁₂H₁₄N₆O	详情	详情
(IX)	41405	2-(2-furyl)-8-propyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-ylamine; 2-(2-furyl)-8-propyl-8H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine		C₁₃H₁₃N₇O	详情	详情
(X)	41406	4-methoxyphenyl isocyanate; 1-isocyanato-4-methoxybenzene	5416-93-3	C₈H₇NO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【1】 Khamar BM, Modi IA, Shukla MC, et aL. 2006. A process for the preparation of zaleplon. W0 2006070244

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)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(II)	66968	1-(3-bromophenyl)ethanone	2142-63-4	C₈H₇BrO	详情	详情
(III)	66969	sodium 1-(3-bromophenyl)-1,3-dioxopropan-2-ide		C₉H₆BrNaO₂	详情	详情
(IV)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情
(V)	66970	7-(3-bromophenyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile	933054-30-9	C₁₃H₇BrN₄	详情	详情
(VI)	66971	N-(3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl)acetamide	115931-01-6	C₁₅H₁₁N₅O	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

参考文献中间体

合成目标

【1】 Koradi F. Feher F. Magyar E, Singer C. 2005. Preparation of N-[3-(3-cyanopyrazolo [1,5-a] pyrimidin-5-yl) phenyll-N-ethylacetamide, regioisamer of Zaleplon, and crystalline forms of Zaleplon. US 2005032818
【2】 Kankan RN, Rao DR. 2005. Zaleplon Synthesis, W0 2005023813
【3】 Korycinska M, Stawinski T, Wieczorek M. 2003. A process for the preparation of zaleplon via the cyclocondensation reaction of 3-dimethylamino-l-(3-N-ethyl-N-aoetylaminophenyl) -2-propen-l-one with 3- aminopyrazole-4-carborutrile in an aqueous solution of formic acid. W0 2003095456
【4】 Subramanian RS, Sathyanarayanan N, Janardhana PNR, et aL. 2005. Process for prepantion of N-[3-(3- cyanopynzolo [1,5-a] pyrimidin-7-yl) phenyl]-n-ethylacetamide. W0 2005099712

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)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情
(II)	11986	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]-N-ethylacetamide		C₁₅H₂₀N₂O₂	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

参考文献中间体

合成目标

【1】 Shen JS，Li JF，Li FW，et al. 2002．Synthesis of zaleplon.中国医药工业杂卷．33(7): 313～314

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)	49701	Acetic anhydride; Acetyl oxide	108-24-7	C₄H₆O₃	详情	详情
(II)	66972	3-Aminoacetophenone;3-Amino acetophenone;m-Aminoacetophenone;1-(3-Aminophenyl)ethanone	99-03-6	C₈H₉NO	详情	详情
(III)	11983	3'-Acetamidoacetophane; m-Acetamidoacetophenone; N-(3-Acetylphenyl)acetamide	7463-31-2	C₁₀H₁₁NO₂	详情	详情
(IV)	11985	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]acetamide		C₁₃H₁₆N₂O₂	详情	详情
(V)	11986	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]-N-ethylacetamide		C₁₅H₂₀N₂O₂	详情	详情
(VI)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情

合成路线6

该中间体在本合成路线中的序号：(IV)

参考文献中间体

合成目标

【1】 Horns S. 2003. Method for producing N-ethyl-N-[3-(3-cyanopyrazolo [1, 5α] pyrimidin-7-yl) phenyl] acetamide (zaleplon). W0 2003068775

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)	16602	ethyl formate	109-94-4	C₃H₆O₂	详情	详情
(II)	66973	N-(3-acetylphenyl)-N-ethylacetamide		C₁₂H₁₅NO₂	详情	详情
(III)	66974	sodium 1-(3-(N-ethylacetamido)phenyl)-1,3-dioxopropan-2-ide		C₁₃H₁₄NaNO₃	详情	详情
(IV)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情

合成路线7

该中间体在本合成路线中的序号：(VII)

参考文献中间体

合成目标

【1】 Zheng LY, Wang SQ, Li BC, et aL. 2001.Improvement on the synthetic technology of zaleplon as a new sedative and hypnoticdrug. 中国药物化学杂志，11 (6)：353～355

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)	10317	Acetophenone	98-86-2	C₈H₈O	详情	详情
(II)	61934	1-(3-nitrophenyl)-1-ethanone；3-Nitroacetophenone;m-Nitroacetophenone	121-89-1	C₈H₇NO₃	详情	详情
(III)	66972	3-Aminoacetophenone;3-Amino acetophenone;m-Aminoacetophenone;1-(3-Aminophenyl)ethanone	99-03-6	C₈H₉NO	详情	详情
(IV)	11983	3'-Acetamidoacetophane; m-Acetamidoacetophenone; N-(3-Acetylphenyl)acetamide	7463-31-2	C₁₀H₁₁NO₂	详情	详情
(V)	11985	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]acetamide		C₁₃H₁₆N₂O₂	详情	详情
(VI)	11986	N-[3-[(E)-3-(Dimethylamino)-2-propenoyl]phenyl]-N-ethylacetamide		C₁₅H₂₀N₂O₂	详情	详情
(VII)	11987	3-Amino-4-pyrazolecarbonitrile; 3-Amino-1H-pyrazole-4-carbonitrile; 3-Amino-4-cyanopyrazole	16617-46-2	C₄H₄N₄	详情	详情

Extended Information