3-chloro-2-pyrazinecarbonitrile -Drug Synthesis Database

【结构式】

【分子编号】42535

【品名】3-chloro-2-pyrazinecarbonitrile

【CA登记号】55557-52-3

【分子式】C₅H₂ClN₃

【分子量】139.5438

【元素组成】C 43.04% H 1.44% Cl 25.41% N 30.11%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XIV)

Treatment of carboxylic acid (I) with MeOH and H2SO4 yields methyl ester (II), which is then converted into cyano derivative (III) by reaction with LiCN in DMF and AcOH. Hydrolysis of (III) with aqueous KOH in EtOH provides dicarboxylic acid (IV), which is cyclized by means of Ac2O to give the dicarboxylic anhydride (V). Alternatively, (V) can be obtained by condensation of ester (VI) with diethyl oxalate (A) in Et2O in the presence of t-BuOK to afford (VII), which is cyclized with H2SO4 and submitted to catalytic hydrogenation over Pd/C. Condensation of anhydride (V) with (S)-alpha-methylbenzylamine yields a mixture of imides, from which (3aR,9bR)-(IX) is obtained by crystallization. Reduction of (3aR,9bR)-(IX) with BH3·THF followed by hydrogenation over Pd/C affords isoindole derivative (X), which is then alkylated with chloroacetonitrile (XI) in acetonitrile in the presence of DIEA and reduced with LiAlH4 to give the primary amine (XII). Treatment of (XIII) with POCl3 and Et3N yields 2-chloro-3-cyanopyrazine (XIV), which is oxidized to provide (XV) by means of K2S2O8 in H2SO4. Treatment of N-oxide (XV) with ethyl thioglycolate (XVI) and NaOEt in DMF affords pyrazinothiophene (XVII), which is then chlorinated with POCl3 to give (XVIII). Finally, reaction of amine (XII) with (XVIII) and triphosgene in toluene and Et3N affords the desired product.

参考文献中间体

合成目标

【1】 Meyer, M.D.; Altenbach, R.J.; Basha, F.Z.; Carroll, W.A.; Drizin, I.; Kerwin, J.F. Jr.; Lebold, S.A.; Lee, E.L.; Elmore, S.W.; Sippy, K.B.; Tietje, K.R.; Wendt, M.D.; Yamamoto, D.M. (Abbott Laboratories Inc.); Tricyclic substd. hexahydrobenz[e]isoindole alpha-1 adrenergic antagonists. EP 0808318; US 5597823; WO 9622992 .
【2】 Basha, F.Z.; Meyer, M.D.; Altenbach, R.J.; et al.; Structure-activity studies for a novel series of tricycic substituted hexahydrobenz[e]isoindole alpha1A adrenoceptor antagonists as potential agents for the symptomatic treatment of bening prostatic hyperplasia (BPH). J Med Chem 2000, 43, 8, 1586.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	17571	Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate	95-92-1	C₆H₁₀O₄	详情	详情
(I)	42524	5-methoxy-3,4-dihydro-1-naphthalenecarboxylic acid		C₁₂H₁₂O₃	详情	详情
(II)	42525	methyl 5-methoxy-3,4-dihydro-1-naphthalenecarboxylate		C₁₃H₁₄O₃	详情	详情
(III)	42526	methyl 2-cyano-5-methoxy-1,2,3,4-tetrahydro-1-naphthalenecarboxylate		C₁₄H₁₅NO₃	详情	详情
(IV)	42527	5-methoxy-1,2,3,4-tetrahydro-1,2-naphthalenedicarboxylic acid		C₁₃H₁₄O₅	详情	详情
(V)	42528	(3aR,9bR)-6-methoxy-3a,4,5,9b-tetrahydronaphtho[1,2-c]furan-1,3-dione		C₁₃H₁₂O₄	详情	详情
(VI)	42529	ethyl 4-(2-methoxyphenyl)butanoate		C₁₃H₁₈O₃	详情	详情
(VII)	42530	diethyl 2-(2-methoxyphenethyl)-3-oxosuccinate		C₁₇H₂₂O₆	详情	详情
(VIII)	20042	(1S)-1-phenyl-1-ethanamine; (1S)-1-phenylethylamine		C₈H₁₁N	详情	详情
(IX)	42531	(3aR,9bR)-6-methoxy-2-[(1S)-1-phenylethyl]-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione		C₂₁H₂₁NO₃	详情	详情
(X)	42532	(3aR,9bR)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindol-6-yl methyl ether; (3aR,9bR)-6-methoxy-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]isoindole		C₁₃H₁₇NO	详情	详情
(XI)	14443	2-chloroacetonitrile; chloroacetonitrile	107-14-2	C₂H₂ClN	详情	详情
(XII)	42533	(3aR,9bR)-2-(2-aminoethyl)-6-methoxy-3a,4,5,9b-tetrahydro-1H-benzo[e]isoindole-1,3(2H)-dione		C₁₅H₁₈N₂O₃	详情	详情
(XIII)	42534	3-hydroxy-2-pyrazinecarboxamide	55321-99-8	C₅H₅N₃O₂	详情	详情
(XIV)	42535	3-chloro-2-pyrazinecarbonitrile	55557-52-3	C₅H₂ClN₃	详情	详情
(XV)	42536	3-chloro-2-cyanopyrazin-1-ium-1-olate		C₅H₂ClN₃O	详情	详情
(XVI)	23995	ethyl 2-sulfanylacetate	2713-34-0	C₄H₈O₂S	详情	详情
(XVII)	42537	7-amino-6-(ethoxycarbonyl)thieno[2,3-b]pyrazin-1-ium-1-olate		C₉H₉N₃O₃S	详情	详情
(XVIII)	42538	ethyl 7-amino-2-chlorothieno[2,3-b]pyrazine-6-carboxylate		C₉H₈ClN₃O₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Condensation of 3-chloropyrazine-2-carbonitrile (I) with N-methylmethanesulfonamide (II) in the presence of Cs2CO3 in acetonitrile at 80 °C gives N-(3-cyano-2-pyrazinyl)-N-methylmethanesulfonamide (III), which by nitrile reduction using H2 over Pd/C in methanolic ammonia, followed by treatment with AcOH in EtOAc provides the primary amine (IV). Condensation of 2,4-dichloro-5-(trifluoromethyl) pyrimidine (V) with 4-amino-N-methylbenzamide (VI) by means of ZnBr2 and Et3N in DCE/t-BuOH affords diaryl amine (VII). Finally, (aminomethyl)pyrazine (IV) is coupled with chloropyrimidine (VII) in the presence of DIEA in DCE/t-BuOH at 80 °C and the resulting free base is treated with HCl in MeOH .

参考文献中间体

合成目标

【1】 Luzzio, M.J., Autry, C.L., Bhattacharya, S.K. et al. (Pfizer Products Inc. ). Sulfonyl amide derivatives for the treatment of abnormal cell growth. US 2014100368; US 8247411; EP 2146779; US 2013005964; JP 2010524914; CN 103951658; US 2011166120; US 8440822; WO 2008129380.

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)	42535	3-chloro-2-pyrazinecarbonitrile	55557-52-3	C₅H₂ClN₃	详情	详情
(II)	67859	N-methylmethanesulfonamide	1184-85-6	C₂H₇NO₂S	详情	详情
(III)	67860	N-(3-cyano-2-pyrazinyl)-N-methylmethanesulfonamide		C₇H₈N₄O₂S	详情	详情
(IV)	67861	N-(3-(aminomethyl)pyrazin-2-yl)-N-methylmethanesulfonamide acetate		C₇H₁₂N₄O₂S.C₂H₄O₂	详情	详情
(V)	67477	2,4-dichloro-5-(trifluoromethyl)pyrimidine	3932-97-6	C₅HCl₂F₃N₂	详情	详情
(VI)	67862	4-amino-N-methylbenzamide	6274-22-2	C₈H₁₀N₂O	详情	详情
(VII)	67863	4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzamide		C₁₃H₁₀ClF₃N₄O	详情	详情
(VIII)	67864	N-methyl-4-((4-(((3-(N-methylmethylsulfonamido)pyrazin-2-yl)methyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzamide		C₂₀H₂₁F₃N₈O₃S	详情	详情

Extended Information