2-(4-溴甲基苯基)丙酸合成工艺的优化?
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摘要
采用气相循环与反应-萃取技术,优化了2-(4-溴甲基苯基)丙酸(BMPPA)的合成工艺,解决了现有工艺废酸量大、套用困难的问题。在气-液-液反应体系中,水相2-苯基丙酸(PPA)与多聚甲醛(PFA),氢溴酸(HBr)在溴化锌(ZnBr2)催化下反应生成的BMPPA被萃取至有机相,气相与通入的溴化氢气体强制循环,维持体系溴化氢浓度并促进传质。反应结束后,有机相冷却结晶后析出产物,结晶母液和水相套用。优化后工艺条件为ZnBr2:HBr:PFA:PPA的摩尔比为0.5:2.5:1.5:1,反应温度为80℃,时间为8h,萃取剂为正庚烷,纯化后BMPPA收率为86.7%,纯度为98%,水相和有机相套用多次,产品收率仍稳定。相比于现有工艺,该工艺的废酸量排放减少80%。
The synthesis process of 2-(4-bromomethylphenyl) propionic acid(BMPPA) was optimized by gas cycle and reaction-extraction, which solved the problems of large waste acid amounts and re-usage difficulty of traditional processes. In the gas-liquid-liquid reaction system, BMPPA was produced by the reaction of2-phenylpropionic acid(PPA) with polyformaldehyde(PFA),which was catalyzed by zinc bromide(ZnBr2) in aqueous phase. BMPPA was extracted with organic phase. The gas phase was forced to circulate with the incoming hydrogen bromide gas to maintain hydrogen bromide concentration in the system, which also promoted mass transfer. The product was precipitated by organic phase cooling crystallization after reaction.The bulk liquor and aqueous phase were recycled. The optimized process conditions are as follows: molar ratio of ZnBr2:HBr:PFA:PPA is 0.5:2.5:1.5:1 and reaction at 80 ℃ for 8 hours with extractant of n-heptane. The yield of BMPPA is 86.7% after purification and the purity is 98%. This yield is stable even with water and organic phases are reused. Comparing with traditional processes, the waste acid emission is reduced by 80%.
The synthesis process of 2-(4-bromomethylphenyl) propionic acid(BMPPA) was optimized by gas cycle and reaction-extraction, which solved the problems of large waste acid amounts and re-usage difficulty of traditional processes. In the gas-liquid-liquid reaction system, BMPPA was produced by the reaction of2-phenylpropionic acid(PPA) with polyformaldehyde(PFA),which was catalyzed by zinc bromide(ZnBr2) in aqueous phase. BMPPA was extracted with organic phase. The gas phase was forced to circulate with the incoming hydrogen bromide gas to maintain hydrogen bromide concentration in the system, which also promoted mass transfer. The product was precipitated by organic phase cooling crystallization after reaction.The bulk liquor and aqueous phase were recycled. The optimized process conditions are as follows: molar ratio of ZnBr2:HBr:PFA:PPA is 0.5:2.5:1.5:1 and reaction at 80 ℃ for 8 hours with extractant of n-heptane. The yield of BMPPA is 86.7% after purification and the purity is 98%. This yield is stable even with water and organic phases are reused. Comparing with traditional processes, the waste acid emission is reduced by 80%.
引文
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[5]马秀玲.2-(4-溴甲基苯基)丙酸合成工艺研究[D].青岛:青岛科技大学,2015.MA X L.Study on synthesis of 2-(4-bromomethyl)phenylpropionic acid[D].Qingdao:Qingdao University of Science and Technology,2015.
[6]BRENNA E,CROTTI M,GATTI F G,et al.Enantioselective synthesis of(R)-2-arylpropanenitriles catalysed by ene-reductases in aqueous media and in biphasic ionic liquid-water systems[J].Chemcatchem,2014,6(8):2425-2431.
[7]THIYAGARAJAN S,GUNANATHAN C,THIYAGA R S,et al.Facile ruthenium(II)-catalyzedα-alkylation of arylmethyl nitriles using alcohols enabled by metal-ligand cooperation[J].Acs Catalysis,2017,7(8):5483-5490.
[8]DANG T T,SEAYAD A M.A convenient ruthenium-catalysedα-methylation of carbonyl compounds using methanol[J].Advanced Synthesis&Catalysis,2016,358(21):3373-3380.
[9]徐新良,何昆仑,卢鑫,等.非甾体抗炎药洛索洛芬钠的合成研究[J].中国药物化学杂志,2014,24(5):380-383.XU X L,HE K L,LU X,et al.Study on the synthesis of nonsteroidal anti-inflammatory drug loxoprofen sodium[J].Chinese Journal of Medicinal Chemistry,2014,24(5):380-383.
[10]冯姣,潘鹤林,禹艳坤,等.洛索洛芬钠的合成新工艺研究[J].化学试剂,2016,38(1):88-90.FENG J,PAN H L,YU Y K,et al.Study on the new synthetic process of loxoprofen sodium[J].Chemical Reagent,2016,38(1):88-90.
[11]OGAWA S,OBORA Y.Iridium-catalyzed selectiveα-methylation of ketones with methanol[J].Chemical Communications:cambridge,2014,50(19):2491-2493.
[12]THIYAGARAJAN S,GUNANATHAN C,THIYAGA R S,et al.Facile ruthenium(II)-catalyzedα-alkylation of arylmethyl nitriles using alcohols enabled by metal-ligand cooperation[J].Acs Catalysis,2017,7(8):5483-5490.
[13]LIU Z,YANG Z,YU X,et al.Methylation of C(sp3)-H/C(sp2)-H bonds with methanol catalyzed by cobalt system.[J].Organic Letters,2017,19(19):5228-5231.
[14]HARTMANN R W,BATZL C.Aromatase I.Synthesis and evaluation of mammary tumor inhibiting activity of 3-alkylated3-(4-aminophenyl)piperidine-2,6-diones[J].Cheminform,1987,18(3):1362-1369.
[15]FUJIHARA H,IMAOKA K,FURUKAWA N,et al.Tetrakis-sulphoxides:A new type of phase-transfer catalyst for nucleophilic displacements and alkylations[J].Chemischer Informationsdienst,1986,17(24):333-336.
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[17]HSI R S,STELZER L S,STOLLE W T.Synthesis of carbon-13 labeled ibuprofen[J].Journal of Labelled Compounds and Radiopharmaceuticals,1989,27(10):1115-1125.
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