CN102791706A - 制备亲代谢性谷氨酸受体正向变构调节剂-874的方法 - Google Patents
制备亲代谢性谷氨酸受体正向变构调节剂-874的方法 Download PDFInfo
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- CN102791706A CN102791706A CN2011800128476A CN201180012847A CN102791706A CN 102791706 A CN102791706 A CN 102791706A CN 2011800128476 A CN2011800128476 A CN 2011800128476A CN 201180012847 A CN201180012847 A CN 201180012847A CN 102791706 A CN102791706 A CN 102791706A
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- trifluoromethoxy
- carboxylic acid
- methyl
- benzyl
- bromo
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- 230000000946 synaptic effect Effects 0.000 description 1
- 230000003956 synaptic plasticity Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 230000004462 vestibulo-ocular reflex Effects 0.000 description 1
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Abstract
本发明提供了制备7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲氧基苄基)-2,3-二氢异吲哚-1-酮的方法。
Description
技术领域
本发明涉及mGluR2正向变构调节剂(allosteric modulator)的制备方法。
背景技术
亲代谢性谷氨酸受体(mGluR,metabotropic glutamate receptors)构成了由谷氨酸活化的GTP-结合蛋白(G-蛋白)偶联受体家族,且在中枢神经系统的突触活性包括神经可塑性、神经发育和神经变性中具有重要作用。
mGluRs在完整哺乳动物神经元中的活化引起了一种或多种下列的反应:磷脂酶C的活化;磷酸肌醇(PI)水解的增加;细胞内钙释放;磷脂酶D的活化;腺苷酸环化酶的活化或抑制;环腺苷酸(cAMP)形成的增加或减少;鸟苷酸环化酶的活化;环鸟苷酸(cGMP)形成的增加;磷脂酶A2的活化;花生四烯酸释放的增加;以及电压-和配体-门控性离子通道活性的增加或减少(Schoepp等人,1993,Trends Pharmacol.Sci.,14:13;Schoepp,1994,Neurochem.Int.,24:439;Pin等人,1995,Neuropharmacology 34:1;Bordi&Ugolini,1999,Prog.Neurobiol.59:55)。
已鉴定了八种mGluR亚型,根据基本序列相似性、信号转导连接和药理学分布将其分为三组。组-I包括mGluR1和mGluR5,其活化磷脂酶C以及细胞内钙信号的产生。组-II (mGluR2和mGluR3)以及组-III(mGluR4、mGluR6、mGluR7和mGluR8)的mGluR介导腺苷酸环化酶活性和环磷腺苷水平的抑制。参见Pin等人,1999,Eur.J.Pharmacol.,375:277-294。
mGluR家族受体的活性牵涉于哺乳动物CNS中的多种正常过程中,且为多种神经学和精神病学病症的化合物治疗的重要靶标。海马长期增强效应和小脑长期消退的诱导需要mGluR的活化(Bashir等人,1993,Nature,363:347;Bortolotto等人,1994,Nature,368:740;Aiba等人,1994,Cell,79:365;Aiba等人,1994,Cell,79:377)。也已经证实了伤害感受和痛觉缺失中mGluR活化的作用(Meller等人,1993,Neuroreport,4:879;Bordi&Ugolini,1999,Brain Res.,871:223)。此外,mGluRs的活化已经暗示了在多种其它正常过程中起到调节性作用,这些过程包括突触传递、神经元发育、凋亡神经元死亡、突触可塑性、空间学习、嗅觉记忆、心搏的中心控制、醒觉、运动控制及前庭眼球反射的控制(Nakanishi,1994,Neuron,13:1031;Pin等人,1995,Neuropharmacology,supra;Knopfel等人,1995,J Med.Chem.,38:1417)。
在阐明mGluR的神经生理学作用时,最新进展已将这些受体确定为治疗急性和慢性神经障碍、急性和慢性精神障碍以及慢性和急性疼痛障碍的有希望的药物靶标。由于mGluR的生理学和病理生理学意义,因而需要能够调节mGluR功能的新药和化合物。
发明内容
本申请所述的方案和方法示例说明了具有如下结构的7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲氧基苄基)-2,3-二氢异吲哚-1-酮的制备:
本领域的技术人员应该理解的是,通过本申请所述的方法制备的化合物可以溶剂化物例如水合物的形式以及非溶剂化物的形式存在。还应该理解,本发明包括化合物的所有这些溶剂化物形式。此外,本领域技术人员应该理解的是可通过改变或者修改本申请所述的方法来制备化合物。特别地,本领域技术人员应该理解的是可改变或者变更例如溶剂、温度或者具体试剂且所述改变在本发明的范围内。
本发明的范围也包括化合物的盐。一般来说,使用本领域熟知的标准操作来获得通过本发明方法制备的化合物的药用盐。
在本发明的一个实施方案中,化合物可为药用盐或者其溶剂化物。特别地,药用盐可为酸加成盐诸如盐酸盐、氢溴酸盐、磷酸盐、乙酸盐、富马酸盐、马来酸盐、酒石酸盐、枸橼酸盐、甲磺酸盐或者对甲苯磺酸盐。
具体实施方式
本发明通过以下的方案和实施例进一步说明,其描述了本发明的几个实施方案。本申请提供的合成方案和合成方法通过示例说明来提供且不应理解为限制本发明。本领域技术人员应该清楚的是可通过所述方法的变化形式来制备所述化合物或者其中间体。
方案A
方案B
方案C
方案D
定义:
下述定义在本申请方案和实施内容中使用:
来自方案的NB,必要时请检查和校正。
″PG″-保护基,例如BOC基团
″BrCH2CN″-溴乙腈
″NH2OH″-羟胺
″iPrMgCl″-异丙基氯化镁
″NBS″-N-溴琥珀酰亚胺
″(PhC(CO)O)2″-过氧苯甲酰
″AlMe3″-三甲基铝
″Ms2O″-甲磺酸酐
″NaOPt″-叔戊醇钠
″ZnCN2″-氰化锌
″R″-短链烷基,例如乙基
″POCl3″-三氯氧化磷
″DMF″-二甲基甲酰胺
″NaBH4″-四氢硼酸钠
″SOCl2″-亚硫酰氯
″NaOEt″-乙醇钠
″TBAF″-四丁基氟化铵
″MsOH″-甲磺酸
″rel vol″或者″rel vols″-相对体积
对于本申请所述的所有实施例和方法,物质的量、溶剂、体积、温度和时间为示例说明的且不应作为限定可进行所述反应的方式或者本发明的范围。当进行所述方法且实施本申请所述的发明时,可进行对物质的量、溶剂、体积、温度和时间的改变。
实施例1:4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯(A3a)的制备
(A3a)
标题化合物根据如下方案A来制备。溴乙腈(1.20摩尔当量)加至哌嗪-1-羧酸叔丁酯(A1a)(1.00摩尔当量)和四甲基胍(1.45摩尔当量)在四氢呋喃(3.6倍相对体积)中的冷却的溶液中。当反应完成时,将混合物温热,加入2-甲基四氢呋喃(5.0倍相对体积)然后用水(1.50倍相对体积)洗涤。将有机溶液通过真空蒸馏浓缩,之后加入甲醇(1.10倍相对体积)并将混合物冷却。加入羟胺盐酸盐(1.70摩尔当量)、四甲基胍(1.70摩尔当量)和水(0.25摩尔当量),并将混合物加热。当反应完成时,向混合物中加入氯化钠(0.15相对重量)并允许分离为两相。将较低相除去并用2-甲基四氢呋喃(1.40倍相对体积)反萃取两次。将合并的有机相与庚烷(8.0倍相对体积)混合,冷却,并种晶。将混合物保持,之后进一步冷却且加入更多的庚烷。标题化合物(A3a)经滤过回收,用冷水洗涤一次且用庚烷洗涤两次,然后真空干燥(69%)。
1H NMR(400MHz,CDCl3)δ:1.46(s,9H),2.42(m,4H),3.00(s,2H),3.43(m,4H),5.10(s,2H)。
实施例2:4-溴-2,6二甲基苯甲酸(B2)的制备
标题化合物根据如下方案B来制备。将5-溴-2-碘-1,3-二甲基-苯(B1)(1.0摩尔当量)在甲基-叔丁醚(6.0倍相对体积)中的溶液加至异丙基氯化镁(2.0摩尔当量)在甲基-叔丁醚(2.0倍相对体积)中的溶液中,保持温度<0℃。加入二氧化碳气体直到显示反应完成。加入2N盐酸水溶液(4倍相对体积)淬灭反应混合物,分离各相并弃去水相。将产物在1M氢氧化钠水溶液(6.5倍相对体积)中萃取,然后用甲基叔丁醚(4倍相对体积)洗涤。通过加入2N盐酸水溶液(4.5倍相对体积)将标题化合物(B2)沉淀,之后滤过,用水然后庚烷洗涤,并干燥得到白色晶状固体(85%)。
1H NMR(400MHz,CDCl3)δH 2.28(6H,s),7.35(2H,s),13.30(1H,s)。
实施例3:5-溴-7-甲基-3H-异苯并呋喃-1-酮(B3)的制备
标题化合物根据如下方案B来制备。将4-溴-2,6-二甲基苯甲酸(B2)(1.0摩尔当量)、N-溴琥珀酰亚胺(2.5摩尔当量)和过氧苯甲酰(0.1摩尔当量)在氯苯(10倍相对体积)中的溶液加热至≥70℃直到显示反应完成。将40%w/w亚硫酸钠水溶液(4倍相对体积)加至反应混合物中,分离各相并将水相弃去。将有机相用饱和碳酸氢钠水溶液(6倍相对体积)洗涤。将氯苯相通过真空蒸馏浓缩(为3倍相对体积)并加入二甲基乙酰胺(2.5倍相对体积),之后将该溶液加至硼氢化钠(1.6摩尔当量)在二甲基乙酰胺(3倍相对体积)中的混合物中。将混合物搅拌直到显示反应完成。然后将混合物用36%w/w氯化氢(2.5摩尔当量)在水(3.5倍相对体积)中的溶液淬灭。通过真空蒸馏除去溶剂,沉淀得到标题化合物(B3),其为白色晶状固体,将其滤过并干燥(59%)。
1H NMR(400MHz,DMSO)δH 2.57(s,3H),5.32(s,2H),7.60(s,1H),7.73(s,1H)。
实施例4:4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺(B4)
的制备
(B4)
标题化合物根据如下方案B来制备。将4-(三氟甲氧基)-苄基胺(1.2摩尔当量)加至5-溴-7-甲基-3H-异苯并呋喃-1-酮(B3)(1.0摩尔当量)在2-甲基四氢呋喃(10倍相对体积)中的溶液中并惰化。加入三甲基铝(1.2摩尔当量)并将所得的溶液加热至≥40℃直到反应完成。然后将有机溶液加至酒石酸钾钠(1.5摩尔当量)在水(3倍相对体积)中的冷却的溶液中并搅拌。分离该两相混合物,并将水相弃去。将有机相用水(3.33倍相对体积)洗涤,然后加入壬烷(3倍相对体积)并通过真空蒸馏除去2-甲基四氢呋喃,结晶(B4),其为白色晶状固体,将其滤过,用壬烷洗涤并干燥(73.5%)。
1H NMR(400MHz,DMSO)δH 2.19(s,3H),4.44(dd,4H,13.4Hz,5.78Hz),5.33(t,1H,5.76Hz),7.34(s,1H),7.35(s,2H),7.47(s,1H),7.49(s,2H),8.85(t,1H,5.76Hz).
实施例5:5-溴-7-甲基-2-(4-三氟甲氧基-苄基)-2,3-二氢-异吲哚-1-酮(B5)
的制备
标题化合物根据如下方案B来制备。将三乙胺(1.4摩尔当量)加至4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺(B4)(1.0摩尔当量)在2-甲基四氢呋喃(5倍相对体积)中的溶液中。将甲磺酰氯(1.1摩尔当量)加至该溶液中,保持温度<5℃。将其搅拌直到显示反应完成。加入叔戊醇钠(2.5摩尔当量)同时保持温度<5℃,并将反应混合物搅拌直到反应完成。加入水(10倍相对体积)并分离所得的两相混合物,弃去水相。加入2.7M盐酸水溶液(4倍相对体积)并分离各相,弃去水相。将有机相浓缩干燥并将所得的蜡状物在庚烷(4倍相对体积)中重结晶。滤过,用庚烷洗涤并干燥,得到标题化合物(B5),其为白色固体(77%)。
1H NMR(400MHz,DMSO)δH 2.64(s,3H),4.33(s,2H),4.73(s,2H),7.34(d,2H,8.40Hz),7.42(d,2H,8.40Hz),7.47(s,1H),7.59(s,1H).
实施例6:7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-
腈(B6)的制备
标题化合物根据如下方案B来制备。将5-溴-7-甲基-2-(4-三氟甲氧基-苄基)-2,3-二氢-异吲哚-1-酮(B5)(1.0摩尔当量)、氰化锌(0.6摩尔当量)、1,1’-二(二苯基膦基)二茂铁(0.012摩尔当量)、三(二亚苄基丙酮)-二钯(0)(0.005摩尔当量)、二甲基甲酰胺(5倍相对体积)和水(0.25摩尔当量)加至容器中并用氮气彻底惰化,之后加热至≥90℃直到反应完成。将反应混合物冷却并加入甲基叔丁醚(13倍相对体积),随后滤过。将得到的有机相用8.75%w/w氢氧化铵水溶液(14倍相对体积)洗涤两次。加入庚烷(14倍相对体积),结晶得到标题化合物(B6)。用9:1庚烷/MTBE混合物洗涤并干燥,得到标题化合物(B6),其为棕色固体(40%)。
1H NMR(400MHz,DMSO)δH 2.69(d,3H),4.41(s,2H),4.76(s,2H),7.34(s,1H),7.36(s,1H),7.42(s,1H),7.44(s,1H),7.74(s,1H),7.86(s,1H).
实施例7:7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-
羧酸(B7)的制备
标题化合物根据如下方案B来制备。将7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-腈(B6)与甲醇(10倍相对体积)和49%氢氧化钾水溶液(3.0摩尔当量)混合并加热,直到反应完成。将混合物真空浓缩,除去甲醇,然后用盐酸水溶液稀释,沉淀得到产物,将其用乙酸异丙酯萃取。将有机相浓缩除去溶剂,然后用庚烷研磨,滤过并干燥,得到标题化合物(B7)(85%)。
1H NMR(400MHz,DMSO)δ:2.71(s,3H),4.42(s,2H),4.77(s,2H),7.35(d,2H,8.73Hz),7.43(d,2H,8.73Hz),7.81(s,1H),7.91(s,1H),13.19(s,1H,br)。
实施例8a:5-甲酰基-呋喃-3-羧酸乙酯(C2a)的制备
标题化合物根据如下方案C来制备。向3-糠酸乙酯(C1a)(1摩尔当量)在N,N-二甲基甲酰胺(4摩尔当量)中的溶液中加入磷酰氯(4摩尔当量)。将所得的溶液加热至60℃,直到确认反应完成。然后将该反应混合物加至碳酸钠(8.25摩尔当量)在水(18倍相对体积)中的溶液中。加入甲苯(7倍相对体积),并分离各相。将有机相在大气压力浓缩(为4.2倍相对体积,总体积)。得到22.1%w/w标题化合物(C2a)溶液,其为3.5%w/w甲苯溶液(73%)。
1H NMR(400MHz,CDCl3)δH 1.37(3H,t,7.2Hz),4.33(2H,q,7.2Hz),7.54(1H,m),8.22(1H,m)和9.69(1H,m)。
实施例8b:5-甲酰基-呋喃-3-羧酸乙酯(C2a)的制备
标题化合物根据方案C通过使用流动反应器(例如2-系列连续搅拌槽型反应器(CSTR))来制备。将CSTR用3-糠酸乙酯(C1a)(1摩尔当量)、N,N-二甲基甲酰胺(3.833摩尔当量)和磷酰氯(4.167摩尔当量)装填。将反应温度保持在105℃,并调节装填速率,获得2小时的平均滞留时间。将留在反应器中的溶液在碳酸氢钾(8.33摩尔当量)在水(3.13L/g碳酸钾)中的溶液中淬灭。加入甲苯(0.26L/L水),并分离各相。将有机相通过大气压力蒸馏浓缩(3.2体积)。得到22.4%w/w标题化合物(C2a)在甲苯中的溶液。
1H NMR(400MHz,CDCl3)δH 1.37(3H,t,7.2Hz),4.33(2H,q,7.2Hz),7.54(1H,m),8.22(1H,m)和9.69(1H,m)。
实施例9:5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸乙酯盐酸盐
(C3a)的制备
标题化合物根据如下方案C来制备。向22.1%w/w 5-甲酰基-呋喃-3-羧酸乙酯(C2a)(1摩尔当量)在甲苯中的溶液中加入4-(三氟甲氧基)-苄基胺(1.1摩尔当量),并将反应混合物搅拌,直到反应完成。加入硼氢化钠(1.25摩尔当量)并将所得的淤浆冷却至≥-5℃。加入乙醇(16.0倍相对体积)并将所得的溶液用盐酸水溶液(3.0摩尔当量)淬灭,结晶得到标题化合物(C3a)。将该淤浆加热至≥60℃,然后冷却以改善晶型。滤过并用甲苯洗涤,然后用乙醇水溶液洗涤,得到标题化合物(C3a),其为晶状白色固体(85%)。
1H NMR(400MHz,DMSO)δH 1.28(3H,t),4.24(6H,m),6.97(1H,d),7.44(1H,d),7.70(1H,d),8.46(1H,d)。
实施例10:7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚
-5-羧酸乙酯(C4a)的制备
标题化合物根据如下方案C来制备。在环境温度将丁烯酰氯(1.05摩尔当量)加至5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸乙酯盐酸盐(C3a)(1.0摩尔当量)、二异丙基乙基胺(2.5摩尔当量)和甲苯(10倍相对体积)的混合物中。反应完成时,将混合物用水(5倍相对体积)洗涤,浓缩(为5倍相对体积,总体积)并加热回流且保持>12小时。加入甲磺酸(1.0摩尔当量),然后将反应混合物在Dean&Stark条件下加热回流直到确认反应完成。然后将溶液用氢氧化钠水溶液(5倍相对体积)、然后水(5倍相对体积)洗涤。加入庚烷(10倍相对体积),并将混合物冷却,允许结晶发生。将混合物滤过并将回收的固体干燥,得到标题化合物(C4a),其为白色晶状固体(73%)、
1H NMR(400MHz,CDCl3)δ:1.40(t,3H,7.12Hz),2.81(s,3H),4.27(s,2H),4.39(q,2H,7.12Hz),4.78(s,2H),7.18(d,2H,8.60Hz),7.35(d,2H,8.19Hz),7.87(s,1H),7.90(s,1H)。
实施例11:7-甲基-1-氧代-2-[4-(三氟甲氧基)-苄基]-2,3-二氢-1H-异吲哚
-5-羧酸(B7)的制备
标题化合物根据如下方案C来制备。将7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸乙酯(C4a)与2-丙醇(4倍相对体积)和49%氢氧化钾水溶液(1.5摩尔当量)混合并加热直到反应完成。加入36%w/w盐酸水溶液(2.00摩尔当量),将反应混合物冷却至环境温度并加入水(5倍相对体积)。标题化合物(B7)通过滤过收集并干燥(98%)。
1H NMR(400MHz,DMSO)δ:2.71(s,3H),4.42(s,2H),4.77(s,2H),7.35(d,2H,8.73Hz),7.43(d,2H,8.73Hz),7.81(s,1H),7.91(s,1H),13.19(s,1H,br)。
实施例12a:4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异
吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯(D1a)的制备
标题化合物根据如下方案C来制备。将4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯(A3a)(1.0摩尔当量)和7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸乙酯(C4a)(1.0摩尔当量)在乙腈(14倍相对体积)中在60℃混合。历时20分钟加入乙醇钠(0.2mols)并使反应混合物保持在60℃直到反应完成。加入水(10倍相对体积)并将反应混合物冷却至环境温度。将标题化合物(D1a)经滤过收集并用水洗涤,之后干燥(84%)。
1H NMR(400MHz,CDCl3)δ:1.46(9H,s),2.58(4H,m),2.84(3H,s),3.50(4H,m),3.79(2H,s),4.33(2H,s),4.81(2H,s),7.20(2H,m),7.36(2H,m),7.99(1H,s),8.04(1H,s)。
实施例12b:4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异
吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯(D1a)的制备
标题化合物根据如下方案C来制备。将7-甲基-1-氧代-2-[4-(三氟甲氧基)-苄基]-2,3-二氢-1H-异吲哚-5-羧酸(B7)(1.00摩尔当量)在甲苯(8.0倍相对体积)中的淤浆加热并加入亚硫酰氯(1.50摩尔当量)。当反应完成时,将过量的亚硫酰氯和甲苯通过常压蒸馏除去。将该溶液加至4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯(A3a)(1.1摩尔当量)和碳酸钾(1.25摩尔当量)在2-甲基四氢呋喃(19.0倍相对体积)中的淤浆中。加入四丁基氟化铵(1.0摩尔当量)在四氢呋喃(0.5倍相对体积)中的溶液并将内容物加热直到环化反应完成。冷却后,将有机相用水洗涤,之后通过蒸馏浓缩。加入甲基-叔丁醚以诱导结晶。冷却后,标题化合物(D1a)经滤过回收,用甲基叔丁醚洗涤并在真空烘箱中干燥为恒重。
1H NMR(400MHz,CDCl3)δ:1.46(9H,s),2.58(4H,m),2.84(3H,s),3.50(4H,m),3.79(2H,s),4.33(2H,s),4.81(2H,s),7.20(2H,m),7.36(2H,m),7.99(1H,s),8.04(1H,s)。
实施例13:7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲
氧基-苄基)-2,3-二氢-异吲哚-1-酮甲磺酸盐(D2)的制备
标题化合物根据如下方案D来制备。在85℃向4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯(D1a)(0.170mol)在1-丁醇(250mL)和水(30mL)的混合物中的溶液中加入甲磺酸(0.187mol)。加入额外的水(10mL)后,将反应混合物保持在85℃直到反应完成。将反应混合物冷却至65-70℃,之后在结晶器中进行筛选滤过。将反应容器和管线在结晶器中用热(80℃)的1-丁醇(1x200mL)淋洗。然后将所得的反应混合物保持在85℃,之后加入1-丁醇(800mL),冷却至78℃并用(D2)(0.1g,1%w/w)种晶。然后将反应混合物冷却至15℃并将温度在65-70℃循环两次,之后滤过,得到标题化合物(D2),将其用1-丁醇(2x 200mL)洗涤,之后真空干燥,得到标题化合物,其为白色固体(87.38g,88.0%的收率)。
1H NMR(400MHz,DMSO)δ:2.36(3H,s),2.81(4H,m),3.15(4H,m),3.91(2H,s),4.46(2H,s),4.78(2H,s),7.37(2H,m),7.45(2H,m),8.00(1H,m),8.12(1H,m)和8.59(1H,宽单峰)。
Claims (7)
1.制备具有以下结构的7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲氧基苄基)-2,3-二氢异吲哚-1-酮或者其酸加成盐的方法:
所述方法包括:
使哌嗪-1-羧酸叔丁酯与溴乙腈在有机溶剂中在碱的存在下反应且随后与羟胺或者其酸加成盐反应,形成4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯;
使在醚溶剂中的5-溴-2-碘-1,3-二甲基-苯与格氏试剂和二氧化碳气体反应,形成4-溴-2,6-二甲基苯甲酸;
使4-溴-2,6-二甲基苯甲酸与N-溴琥珀酰亚胺和自由基引发剂在有机溶剂中加热且随后将过度溴化产物用还原剂还原,形成5-溴-7-甲基-3H-异苯并呋喃-1-酮;
使5-溴-7-甲基-3H-异苯并呋喃-1-酮与4-(三氟甲氧基)-苄基胺在含有三甲基铝的无水溶剂中加热,形成4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺;
使4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺与甲磺酰氯和碱在有机溶剂中反应,形成5-溴-7-甲基-2-(4-三氟甲氧基-苄基)-2,3-二氢-异吲哚-1-酮;
使5-溴-7-甲基-2-(4-三氟甲氧基-苄基)-2,3-二氢-异吲哚-1-酮在氰化锌、1,1’-二(二苯基膦基)二茂铁和三(二亚苄基丙酮)-二钯的存在下在有机溶剂中加热,形成7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-腈;
将7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-腈在溶剂中用氢氧化物溶液水解,形成7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸;
使在有机溶剂中的7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸与亚硫酰氯或者另外的氯化剂反应并使产物与4-[(2Z)-2-氨基-2-羟基亚氨基)乙基]-哌嗪-1-羧酸叔丁酯在碱的存在下反应,形成4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯,以及
通过与在溶剂中的酸加热对4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯进行脱羧,形成7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲氧基-苄基)-2,3-二氢-异吲哚-1-酮或者其酸加成盐。
2.制备具有以下结构的7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲氧基苄基)-2,3-二氢异吲哚-1-酮或者其酸加成盐的方法:
所述方法包括:
使哌嗪-1-羧酸叔丁酯与溴乙腈在有机溶剂中在碱的存在下反应且随后与羟胺或者其酸加成盐反应,形成4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯;
将3-糠酸乙酯用Vilsmeier试剂进行甲酰化,形成5-甲酰基-呋喃-3-羧酸乙酯,所述Vilsmeier试剂是通过使磷酰氯与二甲基甲酰胺或者另外的甲酰化剂反应形成的;
使在有机溶剂中的5-甲酰基-呋喃-3-羧酸乙酯与4-(三氟甲氧基)-苄基胺反应并将产物还原,形成5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸乙酯或者其酸加成盐;
使5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸乙酯或者其酸加成盐与丁烯酰氯在碱的存在下以及随后的加热或者其它条件下反应来进行DielsAlder转化且随后将产物用酸或者碱进行脱水,形成7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸乙酯;
使7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸乙酯与4-[(2Z)-2-氨基-2-羟基亚氨基)乙基]-哌嗪-1-羧酸叔丁酯在含有碱的有机溶剂中反应,形成4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯,以及
通过与在有机溶剂中的酸加热,对4-{5-[7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-基]-[1,2,4]噁二唑-3-基甲基}-哌嗪-1-羧酸叔丁酯进行脱羧,形成7-甲基-5-(3-哌嗪-1-基甲基-[1,2,4]噁二唑-5-基)-2-(4-三氟甲氧基-苄基)-2,3-二氢-异吲哚-1-酮或者其酸加成盐。
3.化合物,选自:
5-溴-7-甲基-3H-异苯并呋喃-1-酮;
4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺;
5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸或者其烷基酯,和
7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸或者其烷基酯。
5.制备4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺的方法,
所述方法包括:
使哌嗪-1-羧酸叔丁酯与溴乙腈在有机溶剂中在碱的存在下反应且随后与羟胺或者其酸加成盐反应,形成4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯;
使在醚溶剂中的5-溴-2-碘-1,3-二甲基-苯与格氏试剂和二氧化碳气体反应,形成4-溴-2,6-二甲基苯甲酸;
使4-溴-2,6-二甲基苯甲酸与N-溴琥珀酰亚胺和自由基引发剂在有机溶剂中加热且随后将过度溴化产物用还原剂还原,形成5-溴-7-甲基-3H-异苯并呋喃-1-酮;
使5-溴-7-甲基-3H-异苯并呋喃-1-酮与4-(三氟甲氧基)-苄基胺在含有三甲基铝的无水溶剂中加热,形成4-溴-2-羟基甲基-6-甲基-N-(4-三氟甲氧基-苄基)-苯甲酰胺。
7.制备7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸乙酯的方法,
所述方法包括:
使哌嗪-1-羧酸叔丁酯与溴乙腈在有机溶剂中在碱的存在下反应且随后与羟胺或者其酸加成盐反应,形成4-(N-羟基甲脒基甲基)-哌嗪-1-羧酸叔丁酯;
将3-糠酸乙酯用Vilsmeier试剂进行甲酰化,形成5-甲酰基-呋喃-3-羧酸乙酯,所述Vilsmeier试剂是通过使磷酰氯与二甲基甲酰胺或者另外的甲酰化剂反应形成的;
使在有机溶剂中的5-甲酰基-呋喃-3-羧酸乙酯与4-(三氟甲氧基)-苄基胺反应并将产物还原,形成5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸乙酯或者其酸加成盐;
使5-[(4-三氟甲氧基-苄基氨基)-甲基]-呋喃-3-羧酸乙酯或者其酸加成盐与丁烯酰氯在碱的存在下以及随后的加热或者其它条件下反应来进行DielsAlder转化且随后将产物用酸或者碱进行脱水,形成7-甲基-1-氧代-2-(4-三氟甲氧基-苄基)-2,3-二氢-1H-异吲哚-5-羧酸乙酯。
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CN107935842A (zh) * | 2017-12-27 | 2018-04-20 | 珠海奥博凯生物医药技术有限公司 | 一种2‑氯‑4‑溴‑6‑甲基苯甲酸的制备方法 |
CN110498783A (zh) * | 2019-08-02 | 2019-11-26 | 成都蓝蜻蜓生物技术有限公司 | 一种合成罗沙司他中间体的方法 |
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US11123310B2 (en) | 2017-02-24 | 2021-09-21 | Pharmapotheca, Llc | Amphetamine controlled release, prodrug, and abuse-deterrent dosage forms |
US11396502B2 (en) | 2018-11-13 | 2022-07-26 | Incyte Corporation | Substituted heterocyclic derivatives as PI3K inhibitors |
WO2020102150A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Heterocyclic derivatives as pi3k inhibitors |
WO2020102198A1 (en) | 2018-11-13 | 2020-05-22 | Incyte Corporation | Heterocyclic derivatives as pi3k inhibitors |
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