鹽酸帕唑的中審定

民民局公告號 (21(22(73)專利權(quán)人工地址200040市靜安區(qū)西路號專利權(quán)人中國工業(yè)研究總(72)發(fā)明人唐家 岑均(74)專利機構(gòu)弼興人朱水平 JoseBarluengaetal.MonoalkylationofPrimaryAromaticAminesviaN-(Alkoxymethy1)arylAmines.

Society,ChemicalCommunication.1983,19PhilipA.Harrisetal.Discoveryofthyl-benzenesulfonamide(Pazopanib),aNovelandPotentVascularEndothelialGrowthFactorReceptorInhibitor.《JournalofMedicinalChemistry2008,51卷員forfortheFormationofStableMethyleneamines.《Journalofthe權(quán)利要求書1頁說明書9鹽酸帕唑的及其方B本發(fā)明公開了一種鹽酸帕唑的化合物及其方法。本發(fā)明的III和IIIa參與的方法可用于鹽酸帕唑的關(guān)鍵BCN

權(quán)利 求 1/1一種鹽酸帕唑的化合物III或驟：縮合反應，即可；11～101。為0～100℃。鹽酸帕唑的及其方 本發(fā)明具體的涉及鹽酸帕唑的及其方法 [(23-3-二甲基N-(2-氯嘧啶-4-基)-N-甲基-2H-吲唑-6-胺為鹽酸帕唑的關(guān)鍵中間 [0006] 本發(fā)明所要解決的技術(shù)問題是提供了一種與現(xiàn)有技術(shù)完全不同的用于鹽酸IIIIIIa23-N-(2-4-N-2H-6-并 本發(fā)明提供了鹽酸帕唑的化合物III或 的化合物III 0.11～10111～410～的(2，3-二甲基-N-(2-氯嘧啶-4-基)-N-甲基-2H-吲唑-6-胺)：40～160℃；的、的、DMF(NNIII5～50ml/g。1∶1～61。所示： 唑的。[0029](2)本發(fā)明化合物III和IIIa參與的2，3-二甲基-N-(2-氯嘧 [0032]II[0033]2-乙基-5-胺[0034]224.2g0.2mol(100ml)0℃以下，緩慢滴加18.6g0.3mol6061-1HNMR(400MHzCDCl3)δ1.28(t3H)，2.56(q7.17(d8.0HzH).4(dz1H)d189(M+Na) 室溫下將亞硝酸叔丁酯(25ml0.15mol(100ml)2(25g，0.15mol)500ml)1h。反應結(jié)束后將反應液濃縮至3(25.5g95.73 3δ2.64(s3H)7.78(d8.8Hz1H)8.01(ddJ1.6Hz1H)8.38(dJ1H)10.22(s1H)。176(M- 3(17.7g0.1mol)懸浮于200ml甲苯中在室溫下滴加硫酸二甲酯(16.4g，0.13mol)。滴畢加熱至回流反應4h。將反應液冷卻至室溫后滴加飽和碳酸氫鈉水溶液調(diào)pH至8左右。過濾濾餅用甲苯(10ml×2)洗滌干燥得黃色固體4(15.3g80.1％)。 mp182-183℃(文獻[4]183.6-185.4℃)。1HNMR(400MHzCDCl3)δ2.67(s3H)，4.17(s7.63(d9.2Hz1H)d2.0zH)8.6(d192(M+H 34(15.30.08mol(12.3g95.δ2.49(s，3rs2H)3.97(s3H6.52(ddJ20Hz1H)7.71(dJ8.8Hz1H184(M+Na[0044]鈉(3.6g0.156mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(2.g.09mo(3.6g0.093mol(4.5g82.899 2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 7.2g0.313mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.6g84.699 2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 6.1g0.156mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.4g81.099 2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H (12.2g0.313mol(50ml)II(5g0.031mol)(.g.9ml0ml4.5g82.899 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 3.6g0.156mol) g(4.4g81.099 2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 7.2g0.313mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.4g81.099 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 6.1g0.156mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.2g77.399 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 7.2g0.313mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.4g81.099 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H (3.6g0.156molII(5g0.031mol)(.g.9ml0ml4.2g77.399 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 10N23- 3.6g0.156mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.1g75.499 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 11N23- 6.1g0.156mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.2g77.399 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 12N23- 6.1g0.156mol(50ml)中，加熱回流攪拌至全溶后加入式II(5g0.031mol)(.g.9ml0ml4.1g75.499 mp147-159℃。1HNMR(400MHz，CDCl3)δ2.51(s3H2.89(s3H3.75(s1H)，H)J20Hz1H)6.55(dJ2.2Hz1H)7.31(dJ176(M+H 1323III(5g0.029mol7.2g0.086mol7(6.7g81.699 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1H)6.87(ddJ2.0Hz1H7.49(dJ0.8Hz1H)7.31(ddJ1H7.93(dJ6.0Hz1H)288(M+H)1423III(5g0.029mol(9.8g0.117mol7(6.7g81.699 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1H)6.87(ddJ2.0Hz1H7.49(dJ0.8Hz1H)7.31(ddJ1H7.93(dJ6.0Hz1H)288(M+H)1523III(5g0.029mol(7.2g0.086mol7(6.3g76.799 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1H)6.87(ddJ2.0Hz1H7.49(dJ0.8Hz1H)7.31(ddJ1H7.93(dJ6.0Hz1H)288(M+H)1623III(5g0.029mol(9.8g0.117mol7(6.3g76.799 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1H)6.87(ddJ2.0Hz1H7.49(dJ0.8Hz1H)7.31(ddJ1H7.93(dJ6.0Hz1H)288(M+H)1723[0092]III(5g0.029mol9.1g0.086molTHF(20ml)(20ml×2)7(6.6g80.499 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1H)6.87(ddJ2.0Hz1H7.49(dJ0.8Hz1H)7.31(ddJ1H7.93(dJ6.0Hz1H)288(M+H)1823[0095III(5g0.029mol12.4g0.117molTHF(20ml7(6.6g80.499 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1H)6.87(ddJ2.0Hz1H7.49(dJ0.8Hz1H)7.31(ddJ1H7.93(dJ6.0Hz1H)288(M+H)1923III(5g0.029mol(7.2g0.086mol7(6.2g75.599 1HNMR(400MHzO-δ2.62(s3H3.43(s3H4.06(s3H)，J6.0Hz1