枸橼酸托瑞米芬的合成工艺改进
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摘要
以3-羟基-1-苯基丙-1-酮(2)为原料,经氯代反应得3-氯-1-苯基丙-1-酮(3),3与4-羟基二苯甲酮经偶联反应得(Z)-4-氯-1,2-二苯基-1-[(4-羟基)苯基]-1-丁烯(4),4与N,N-二甲胺基溴乙烷氢溴酸盐经亲核取代反应得托瑞米芬,最后与枸橼酸成盐得枸橼酸托瑞米芬,纯度99.45%,总收率17%(以2计)。本研究将氯化亚砜的氯代反应提至第一步,可避免成品的降解及异构化。同时对制备化合物4时的溶剂、反应温度、萃取溶剂及浓缩温度进行优化,确定了最佳反应条件:以乙二醇二甲醚(DME)为反应溶剂,在0～10℃滴加3进行反应,反应后处理用甲苯萃取,并于40～45℃浓缩。该反应条件下得到的粗品4的(Z)-异构体比例高(Z∶E=8∶1),再通过后续简单的析晶纯化即可得到单一构型的中间体4(纯度96.1%)。
3-Chloro-1-phenylpropan-1-one(3) was synthesized from 3-hydroxy-1-phenylpropan-1-one(2)via chlorination, which was followed by a coupling reaction to give(Z)-4-chloro-1,2-diphenyl-1-[(4-hydroxy)phenyl]-1-butene(4). Then the latter was subjected to a nucleophilic substitution with 2-bromo-N,N-dimethylethanamine hydrobromide and salification with citric acid to afford toremifene citrate in a purity of 99.45% and a total yield of 17%(based on 2). In this study, the chlorination with sulfur oxychloride was placed in the first step, which could avoid the degradation and isomerization of the product. At the same time, the reaction solvent, temperature, extraction solvent and concentration temperature for the preparation of compound 4 were optimized, and the optimum reaction conditions were as follows: ethylene glycol dimethyl ether(DME) was used as the reaction solvent with the addition of 3 at 0-10 ℃,toluene was used as the extract solvent after the reaction, and then concentrated at 40-45 ℃. In the crude 4 obtained under this reaction condition, the(Z)-isomer ratio was high(Z∶E=8∶1), and then the(Z)-isomer of 4(purity of 96.1%)could be obtained by the subsequent simple crystallization.
3-Chloro-1-phenylpropan-1-one(3) was synthesized from 3-hydroxy-1-phenylpropan-1-one(2)via chlorination, which was followed by a coupling reaction to give(Z)-4-chloro-1,2-diphenyl-1-[(4-hydroxy)phenyl]-1-butene(4). Then the latter was subjected to a nucleophilic substitution with 2-bromo-N,N-dimethylethanamine hydrobromide and salification with citric acid to afford toremifene citrate in a purity of 99.45% and a total yield of 17%(based on 2). In this study, the chlorination with sulfur oxychloride was placed in the first step, which could avoid the degradation and isomerization of the product. At the same time, the reaction solvent, temperature, extraction solvent and concentration temperature for the preparation of compound 4 were optimized, and the optimum reaction conditions were as follows: ethylene glycol dimethyl ether(DME) was used as the reaction solvent with the addition of 3 at 0-10 ℃,toluene was used as the extract solvent after the reaction, and then concentrated at 40-45 ℃. In the crude 4 obtained under this reaction condition, the(Z)-isomer ratio was high(Z∶E=8∶1), and then the(Z)-isomer of 4(purity of 96.1%)could be obtained by the subsequent simple crystallization.
引文
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[7]吕刚,黄道飞,通过钩型转化法实现高立体选择性合成托瑞米芬:中国,102126969[P].2011-07-20.
[8]徐晓光.枸橼酸托瑞米芬的合成[J].中国医药工业杂志,2002,33(9):417-418.
[9]洪浩,詹姆斯·盖吉,李九远,等.托瑞米芬的合成方法:中国,104230723A[P].2014-12-24.
[10]张瑞仁,刘红,祝红兵,等.枸橼酸托瑞米芬的中间体合成工艺改进[J].黑龙江医药科学,2012,35(4):29-30.
[11]REIJO J T,ARTO J K,KAUKO O A K,et al.Novel triphenyl alkane and alkene derivatives and their preparation and use:US,4696949[P].1987-09-29.
[12]LALIT K,AMIT S,NAND L,et al.Design and synthesis of3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception[J].Bioorg Med Chem Lett,2011,21(1):176-181.
[2]EDWARDS M R,PIETZSCH C,VAUSSELIN T,et al.High-throughput minigenome system for identifying smallmolecule inhibitors of Ebola virus replication[J].ACSInfect Dis,2015,1(8):380-387.
[3]JOHANSEN L M,BRANNAN J M,DELOS S E,et al.FDA-approved selective estrogen receptor modulators inhibit Ebola virus infection[J].Sci Transl Med,2013,5(190):190ra79.
[4]JOHANSEN L M,DEWALD L E,SHOEMAKER C J,et al.A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity[J].Sci Transl Med,2015,7(290):290ra89.
[5]JENNIFER K,WEI S,CARLES M R,et al.Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs[J].Emerg Microbes Infect,2014,3(12):e84.
[6]REIJO J T,ARTO J K,KAUKO O A K,et al.Tri-phenyl alkene derivatives and their preparation and use:US,005491173A[P].1996-02-13.
[7]吕刚,黄道飞,通过钩型转化法实现高立体选择性合成托瑞米芬:中国,102126969[P].2011-07-20.
[8]徐晓光.枸橼酸托瑞米芬的合成[J].中国医药工业杂志,2002,33(9):417-418.
[9]洪浩,詹姆斯·盖吉,李九远,等.托瑞米芬的合成方法:中国,104230723A[P].2014-12-24.
[10]张瑞仁,刘红,祝红兵,等.枸橼酸托瑞米芬的中间体合成工艺改进[J].黑龙江医药科学,2012,35(4):29-30.
[11]REIJO J T,ARTO J K,KAUKO O A K,et al.Novel triphenyl alkane and alkene derivatives and their preparation and use:US,4696949[P].1987-09-29.
[12]LALIT K,AMIT S,NAND L,et al.Design and synthesis of3-(azol-1-yl)phenylpropanes as microbicidal spermicides for prophylactic contraception[J].Bioorg Med Chem Lett,2011,21(1):176-181.