CN103319305B - 苯并降冰片烯的制备方法 - Google Patents
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Abstract
本发明涉及一种新颖的制备9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-胺的方法,该方法包括a)环戊二烯与CXCl3,其中X是氯或溴,在自由基引发剂的存在下反应为式II化合物,或aa)环戊二烯与CXCl3,其中X是氯,在金属催化剂的存在下,反应为式II化合物,其中X是氯,b)式II化合物在适宜溶剂的存在下与碱反应为式III化合物,c)并且式III化合物在1,2-脱氢-6-硝基苯的存在下转变为式IV化合物,和d)使式IV化合物在金属催化剂的存在下氢化。
Description
本申请是发明名称为“苯并降冰片烯的制备方法”的中国发明专利申请No.200980142361.7的分案申请,其申请日是2009年09月28日,优先权日是2008年10月27日。
本发明涉及9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺的制备。
化合物9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺是苯并降冰片烯杀真菌剂制备中有价值的中间体,例如,如WO2007/048556中所述。
由WO2007/048556知道,通过下述方法制备9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺
a)式A化合物
(A)在亚硝酸烷基酯存在下
与式B化合物
(B)其中R’和R’’是,例如,C1-C4烷基,反应为式C化合物
b)使式C化合物在适当金属催化剂的存在下氢化为式D化合物
c)以臭氧处理式D化合物,随后用还原剂处理为式E化合物
d)使式E化合物与三苯基膦/四氯化碳反应为式F的2,9-二氯亚甲基-5-硝基-苯并降冰片烯
和
e)使式F化合物在金属催化剂的存在下氢化为9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺。
该现有技术方法的一个缺点在于大量的反应步骤降低产物的产率。此外,臭氧解反应难以控制,昂贵的步骤d)需要使用三苯基膦,使得该方法不经济并且不适合大规模生产。
因此本发明的目的是提供一种生产9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺的新方法,以避免已知方法的缺点并且使以一种经济上有利的方式用较少的反应步骤高产量、高质量地制备9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺成为可能。
因此,根据本发明,提供了一种制备式I的9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基胺的方法
该方法包括
a)将环戊二烯与CXCl3,其中X是氯或溴,优选溴,在自由基引发剂的存在下反应为式II化合物
其中X是氯或溴,
或aa)将环戊二烯与CXCl3,其中X是氯,在金属催化剂的存在下反应为式II化合物
其中X是氯,
b)将式II化合物在适宜溶剂中与碱反应为式III化合物
c)并且将式III化合物在1,2-脱氢-6-硝基苯的存在下转化为式IV化合物
以及
d)使式IV化合物在金属催化剂的存在下用氢源氢化。
该方法的一个实施方案包括
a)将环戊二烯与CXCl3,其中X是氯或溴,在自由基引发剂的存在下反应为式II化合物
其中X是氯或溴。
反应步骤a)和aa):
式II化合物可以以下列异构体或它们的混合物的形式出现:
和其中X是氯或溴。
反应步骤a)和aa)的产物可以直接用于接下来的反应步骤b)。式II的特定异构体或异构体混合物的分离或提纯不是必需的。式II化合物及其异构体和式IV化合物是新颖的并且特别为依照本发明的方法而开发的并因此构成本发明进一步主题。
原则上大量下列类别的自由基引发剂可以用于反应步骤a):有机过氧化物(例如过氧化甲乙酮,过氧化苯甲酰),有机偶氮化合物,金属盐和配合物(Cu,Ru)。优选自由基引发剂选自偶氮二异丁腈、过氧化二苯甲酰及双(叔丁基环己基)过氧化二碳酸酯。特别优选偶氮二异丁腈。
反应步骤a)有利地是在升高的温度下进行,优选温度20至100°C,优选60至100°C,最优选80至90°C。三氯溴甲烷的使用是优选的,特别是在过氧化物或偶氮化合物引发剂的情况下。
在特别优选的反应步骤aa)中,环戊二烯在金属催化剂的存在下与CCl4反应为式II化合物
其中X为氯。对于步骤aa),自由基引发剂的存在不是必需的,但对减少催化剂用量可能是有利的(少用催化剂)。
用于催化的合适金属例如选自钌、铜、铁、钯和铑。优选的催化剂包括钌(II)或铜(I)配合物。特别优选的催化剂选自Ru(PPh3)3Cl2,Ru(异丙基苯)PPh3Cl2,Ru(Cp)PPh3Cl2,Grubbs I(苯亚甲基-双(三环己基磷)-二氯钌)和与胺配体配位的CuCl,所述胺配体特别是双胺或三胺配体。Grubbs I、CuCl/四甲基乙二胺(TMEDA)或五甲基二亚乙基三胺是最优选的催化剂。
反应步骤aa)可以在惰性溶剂的存在下进行,使用Ru-催化剂时,优选不使用溶剂。反应步骤aa)有利地是在升高的温度下进行,特别在温度20至100°C,优选60至100°C,最优选60至80°C进行。反应步骤aa)的产物是三种可能异构体的混合物。特定异构体或异构体混合物的分离或提纯不是必需的。
反应步骤aa)的一个优选实施方案可以这样有效地来进行,在0.5至2mol%,特别是1mol%的铜I催化剂,优选CuCl,和1至4mol%,特别是2mol%的四甲基乙烷-1,2-二胺(TMEDA)的存在下,加热环戊二烯和1.5至3,特别是2当量的四氯化碳在乙腈中的混合物,蒸馏后给出70-80%产物的分离产率。
如上添加催化量(通常为1mol%)的自由基引发剂,特别是N,N-偶氮二异丁腈,到反应混合物,可以减少催化剂用量(少用催化剂)。
反应步骤aa)有更多的优势。CCl4的使用成本较低,与四氯化碳的加成产物(CTCM-环戊烯)远比溴衍生物(BTCM-环戊烯)稳定,反应放热少得多,因而更适合大规模生产,并且下一步也没有产生溴离子。
在反应步骤a)和aa)中,CCl3Br或CCl4以过量于环戊二烯使用,对于1当量环戊二烯优选使用1.5-5当量,特别是2-3当量的CCl3Br或CCl4。
反应步骤b):
用于反应步骤b)优选的碱是碱金属醇化物,例如叔丁醇钠和叔丁醇钾,或者像NaNH2或二异丙基氨基锂的金属胺化物。
除酮和酯外,可以使用所有惰性溶剂。反应步骤b)的适宜溶剂选自甲基叔丁基醚(MTBE)、甲基环己烷(MCH)或其混合物、四氢呋喃(THF)、二乙二醇二甲醚和甲苯。
反应步骤b)其它适宜的溶剂是氯苯。
反应步骤b)有利地是在温度范围-20至+20°C进行,优选温度-10°C至10°C,最优选-5°C至5°C。
本发明一个优选的实施方案中,式III化合物(其溶液)不加分离直接用于下一反应步骤。式III化合物是式I化合物制备中有价值的中间体。式III化合物由(a)Moberg,C.;Nilsson,M.J.Organomet.Chem.1973,49,243-248.(b)Siemionko,R.K.;Berson,J.A.J.Am.Chem.Soc.1980,102,3870-3882而已知。但是,上述参考文献中描述的制备方法是非常不利的,因为:
1)该方法不能如描述再现(得到低产率)。2)使用非常昂贵的自燃的和毒性的起始材料(二茂镍)。3)产生大量金属废弃物(含镍化合物)。4)该方法不能放大到工业应用(大量二茂镍不可得,大量二茂镍操作危险)。
与之相反,从环戊二烯开始制备式III化合物是一种新颖的和非常有效的方法并因此构成了本发明又一主题。
因此,本发明的又一主题是式III化合物的制备方法
该方法包括
a)将环戊二烯在自由基引发剂的存在下,与CXCl3,其中X为氯或溴,优选溴,反应为式II化合物
其中X为氯或溴,
和b)将式II化合物在适宜溶剂的存在下与碱反应。
反应步骤c)
1,2-脱氢-6-硝基苯原位生成[例如,从式(A)的6-硝基邻氨基苯甲酸开始,
如L.Paquette et al,J.Amer.Chem.Soc.99,3734(1977)和H.Seidel,Chemische Berichte,34,4351(1901)所描述的那样。
反应步骤c)在升高的温度,优选30°C至60°C,最优选30至40°C的温度下进行。
反应步骤d)
氢化反应的优选金属催化剂选自下组:兰尼镍,铂,优选在载体如碳上的铂,钯,优选在载体如碳上的钯,但不限于上述组。特别优选催化剂是兰尼镍。合适的氢源是氢或肼,优选氢。
反应步骤d)在低到升高的温度下进行,优选温度0至80°C,优选30至60°C。
根据本发明的方法的一个优选变化方案,包括
aa)将环戊二烯与CXCl3,其中X为氯,在金属催化剂的存在下,其中催化剂的金属成分选自钌、铜、铁、钯和铑,反应为式II化合物
其中X是氯,
b)将式II化合物在适宜溶剂的存在下与选自碱金属醇化物的碱反应为式III化合物
c)并且将式III化合物在1,2-脱氢-6-硝基苯的存在下转化为式IV化合物
以及
d)将式IV化合物在金属催化剂的存在下用氢源氢化。
制备实例:
例P1:式IIa化合物的制备:
将偶氮二异丁腈(2.5g)溶于一溴三氯甲烷(250g)。
将一溴三氯甲烷(650g)在惰性气氛(氮气)下加入到玻璃反应器中并加热至85°C。1/3的偶氮二异丁腈溶液(84g)立即被加到该反应器中并将反应器内容物再次加热至85°C,随后在85°C用2.5小时同时加入剩余的2/3偶氮二异丁腈溶液(168.5g)和环戊二烯(100g,新鲜蒸馏)与甲基环己烷(10g)的混合物。反应混合物在85°C再搅拌一小时,随后冷却到环境温度。真空蒸发(60→70°C,150→50mbar)大量溶剂(一溴三氯甲烷)。将甲基环己烷(50g)加到蒸馏残余物中,蒸馏继续(60→70°C,150→15mbar)。粗产品(蒸馏残余物)再真空干燥30分钟(70°C,15mbar)。式IIa化合物产量389g,呈棕色油状,94%纯度,92%产率,区域异构体混合物。
例P2:式III化合物的制备:
在惰性气氛(氮气)下将溴(三氯甲基)环戊烯(27.83g,化合物IIa)、甲基环己烷(62mL)、甲基叔丁基醚(62mL)和二(2-甲氧基乙基)醚(二乙二醇二甲醚,6.7g)加入到玻璃反应器。该混合物在冰/氯化钠浴中冷却至-10°C。将叔丁醇钠(20.3g)以固体形式加入到反应器中,用时10分钟,同时保持温度低于+5°C。添加完毕后,反应混合物在0-5°C搅拌2小时。反应混合物用冰冷水(80mL)和冰(40g)处理,随后水相的pH值用32%盐酸(约3mL)调整至≤2。分离水相,有机相用无水碳酸钾在0°C干燥。滤去碳酸钾并用甲基叔丁基醚(10mL)漂洗。甲基乙基酮(10g)作为内标被添加到合并滤液中,6,6-二氯亚甲基环戊二烯(式III化合物)的浓度由1H核磁共振光谱确定。产率81%[9.7g的9.9%(约0.53M)溶液]。溶液储存在冷藏室内,然后用于下一步。
例P3:式IV化合物的制备:
将在上一步中获得的6,6-二氯亚甲基环戊二烯的冷溶液(9%,在甲基叔丁基醚/甲基环己烷=1:1溶液中)放置在玻璃反应器中,并迅速加热至35°C。将亚硝酸叔戊酯(2.66g)加入到该反应器中,随后在温度35°C用80分钟同时加入亚硝酸叔戊酯(9.46g)和在甲基乙基酮(42mL)中的6-硝基邻氨基苯甲酸溶液(11.6g,96.6%)。反应混合物在该同一温度再搅拌30分钟,随后所有的挥发物用旋转蒸发除去。剩余残留物在+5°C从甲醇(20mL)中结晶15小时。褐色结晶物被过滤,用冷甲醇(15mL)洗涤,在空气中干燥。产量7.10g(42%,98%纯产物)。
例P4:式IV化合物的氢化:
高压釜加装四氢呋喃(130ml)、湿兰尼镍(2g)和式IV化合物(20g)。封闭高压釜,开始搅拌内容物,用氮气吹扫三次以清除氧气,然后用氢气吹扫三次。反应器用氢气加压至5巴。然后将高压釜内容物加热至40°C,并在需要时加入氢气以维持压力。当氢气吸收停止时,通常在3-4小时后,将反应物料在40°C再维持30分钟。这段时间后,释放压力,将内容物冷却至环境温度。在真空下去除溶剂,产生的油状物放置结晶,得到18g浅黄色至浅棕色的式I化合物(96%,94%纯产物)。
例P5:用Grubbs-I催化剂制备式IIa的CTCM-环戊烯:
将环戊二烯(2.0g)、偶氮二异丁腈(0.5g)、苯基亚甲基-双(三环己基磷)二氯化钌(Grubbs'1代催化剂,12.2mg,0.05mol%)和四氯化碳(14g)的混合物在惰性气氛(氩气)下在75°C加热。通过气相色谱监测转化。4小时后反应完成,生成氯(三氯甲基)环戊烯,为三种异构体的混合物,产率85%(气相色谱,使用十二烷作为标准)。
例P6:用CuCl/TMEDA催化剂制备式IIa的CTCM-环戊烯:
催化剂溶液:
将氯化铜(I)(0.99g)、四甲基乙二胺(TMEDA,2.32g)和乙腈(100mL)的混合物在氮气气氛下于75°C加热25分钟,然后冷却到室温。
环戊二烯溶液:
将新鲜配制的环戊二烯(66.0g)溶于四氯化碳(307g)。
反应:
在氮气气氛下将乙腈(80g)和40%的催化剂溶液放入氮气下的玻璃反应器中。将该混合物加热到温度75°C。然后将40%的环戊二烯溶液以一批加入反应器中,随后同时加入剩余的催化剂溶液和环戊二烯溶液并保持温度在60至70°C。该环戊二烯溶液用1小时添加,催化剂溶液用1.5小时。反应混合物在70°C再搅拌一小时,冷却至环境温度并过滤。用旋转蒸发除去溶剂,真空蒸馏(40-45°C,0.1mbar)分馏残余物。产量170g(75%,97-98%纯度),三种区域异构体的混合物。
例P7:式III化合物的制备:
将叔丁醇钠(69.2g)与氯苯(175ml)在室温下搅拌30分钟,产生精细悬浮液。
在惰性气氛(氮气)下将氯(三氯甲基)环戊烯(69.1g)、氯苯(275ml)和二(2-甲氧基乙基)醚(二甘醇二甲醚,21.1g)装入玻璃反应器。将该混合物冷却至-20°C,将叔丁醇钠悬浮液用35分钟按份加入该反应器,同时保持温度低于+3°C。添加完成后,反应混合物在-5°C搅拌3小时。反应混合物用0.5M盐酸水溶液(300ml)和冰(200g)的混合物淬处理。水相的pH值控制在pH≤2。分离水相,有机相用相同的冰水混合物提取2次(这对完全除去叔丁醇和二乙二醇二甲醚是必需的)。6,6-二氯亚甲基环戊二烯的浓度由1H核磁共振光谱确定,用氯苯(溶剂)作为内标。产率75%[510g的6.8%(约0.52M)溶液]。溶液储存在冷藏室或干冰内,然后用于下一步。
注:刚刚淬灭处理后的产率(没有进一步提取)是85%。该溶液在相分离中失去。
可有利地使用根据本发明的方法制备的优选的苯并降冰片烯杀真菌剂是式V的3-二氟甲基-1-甲基-1H-吡唑-4-羧酸(9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基)酰胺
式V化合物描述在,例如,WO2007/048556中。式V化合物可以两种对映体形式出现。式Va化合物
其化学名称为3-二氟甲基-1-甲基-1H-吡唑-4-羧酸((1S,4R)-9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基)-酰胺,和式Vb化合物
其化学名称为3-二氟甲基-1-甲基-1H-吡唑-4-羧酸((1R,4S)-9-二氯亚甲基-1,2,3,4-四氢-1,4-桥亚甲基-萘-5-基)酰胺。旋光角[α]23.5分别为-119.26°和+119.23°(在四氢呋喃中)。
Claims (2)
1.制备式III化合物的方法
该方法包括
a)将环戊二烯与CXCl3,其中X为氯或溴,在自由基引发剂的存在下反应为式II化合物,其中所述自由基引发剂选自有机过氧化物、有机偶氮化合物、金属盐和配合物
其中X是氯或溴,所述反应在20至100℃的温度进行并且CXCl3以过量于环戊二烯使用,和
b)将式II化合物在适宜溶剂的存在下与碱反应,所述碱选自碱金属醇化物和金属胺化物,所述溶剂是除酮和酯外的惰性溶剂并且所述反应在-20至+20℃的温度进行。
2.根据权利要求1的方法,其中X为溴。
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