盐酸帕唑的中审定

民民局公告号 (21(22(73)专利权人工地址200040市静安区西路号专利权人中国工业研究总(72)发明人唐家 岑均(74)专利机构弼兴人朱水平 JoseBarluengaetal.MonoalkylationofPrimaryAromaticAminesviaN-(Alkoxymethy1)arylAmines.

Society,ChemicalCommunication.1983,19PhilipA.Harrisetal.Discoveryofthyl-benzenesulfonamide(Pazopanib),aNovelandPotentVascularEndothelialGrowthFactorReceptorInhibitor.《JournalofMedicinalChemistry2008,51卷员forfortheFormationofStableMethyleneamines.《Journalofthe权利要求书1页说明书9盐酸帕唑的及其方B本发明公开了一种盐酸帕唑的化合物及其方法。本发明的III和IIIa参与的方法可用于盐酸帕唑的关键BCN

权利 求 1/1一种盐酸帕唑的化合物III或骤：缩合反应，即可；11～101。为0～100℃。盐酸帕唑的及其方 本发明具体的涉及盐酸帕唑的及其方法 [(23-3-二甲基N-(2-氯嘧啶-4-基)-N-甲基-2H-吲唑-6-胺为盐酸帕唑的关键中间 [0006] 本发明所要解决的技术问题是提供了一种与现有技术完全不同的用于盐酸IIIIIIa23-N-(2-4-N-2H-6-并 本发明提供了盐酸帕唑的化合物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)本发明化合物III和IIIa参与的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，缓慢滴加18.6g0.3mol6061-1HNMR(400MHzCDCl3)δ1.28(t3H)，2.56(q7.17(d8.0HzH).4(dz1H)d189(M+Na) 室温下将亚硝酸叔丁酯(25ml0.15mol(100ml)2(25g，0.15mol)500ml)1h。反应结束后将反应液浓缩至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)悬浮于200ml甲苯中在室温下滴加硫酸二甲酯(16.4g，0.13mol)。滴毕加热至回流反应4h。将反应液冷却至室温后滴加饱和碳酸氢钠水溶液调pH至8左右。过滤滤饼用甲苯(10ml×2)洗涤干燥得黄色固体4(15.3g80.1％)。 mp182-183℃(文献[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]钠(3.6g0.156mol(50ml)中，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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，加热回流搅拌至全溶后加入式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