CN115448865B - 一种不对称合成塞曲西坦中间体的方法 - Google Patents
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/24—Oxygen or sulfur atoms
- C07D207/26—2-Pyrrolidones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明公开了一种不对称合成塞曲西坦中间体的合成方法,属于有机合成技术领域。本方法从简单易得的三氟甲基取代的1,6‑烯炔和苯硼酸出发,经由镍催化的不对称环化脱氟反应和四取代烯烃的臭氧化分解反应为关键步骤,以高产率和高对映选择性的得到塞曲西坦关键合成中间体(R)‑4‑(二氟乙烯基)‑吡咯烷‑2‑酮。本发明反应条件温和、操作简单、路线短、收率高,为药物分子塞曲西坦的不对称合成提供了可行路线。
Description
技术领域
本发明属于有机合成技术领域,具体涉及治疗顽固性癫痫的塞曲西坦药物中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮的不对称合成方法。
背景技术
本发明涉及的塞曲西坦和其关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮结构式如下:
塞曲西坦(Seletracetam)是比利时UCB公司开发的抗癫痫药物Levetiracetam的结构类似药物,在继发性和遗传性癫痫发作模型中具有强效的抑制癫痫发作的活性。研究表明,塞曲西坦能够和突触小泡蛋白2A(SV2A)产生高度立体选择性结合,结合力为Levetiracetam的10倍,同时能和N-型钙通道结合,抑制Ca2+流入所产生的高电压激活(Epilepsia.2009,50,702-710.)。塞曲西坦的Ⅱ期临床试验结果显示其对于治疗难治性、部分发作性癫痫具有良好效果,能有效地减少癫痫发作的频率。目前该药物还处于III期临床试验中。
然而,合成塞曲西坦的关键步骤在于对光学纯的(R)-4-(二氟乙烯基)-吡咯烷-2-酮中间体的制备。在已报道的方法中,主要依赖于对外消旋的4-(二氟乙烯基)-吡咯烷-2-酮通过高效液相色谱进行手性拆分,虽然能够快速得到高纯度单一构型的目标中间体,但是同时拆分的另一对映异构体会造成极大的浪费,降低合成效率。另外,使用价格昂贵的手性柱使得生产成本大大增加。因此,迫切地需要发展不对称合成(R)-4-(二氟乙烯基)-吡咯烷-2-酮的方法。
发明内容
本发明的目的在于解决现有技术存在的问题,提供一种不对称合成塞曲西坦的关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮的方法。
本发明的目的通过下述技术方案实现:
一种不对称合成塞曲西坦关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮的方法,包括下述步骤:
(1)将结构式为的化合物1和苯硼酸2在镍催化下,发生环化脱氟反应,得到结构式为/>的二氟乙烯基取代的手性吡咯烷酮3;
其中,化合物1通过包括如下步骤的方法制备:将2-丁炔酸、结构式为的化合物A和二环己基碳二亚胺在二氯甲烷中缩合,得到化合物1;
(2)将化合物3结构中的偕二氟烯烃通过溴化氢保护,得到结构式为的化合物4;
(3)将化合物4结构中的烯烃通过臭氧切断得到酮,进一步将酮还原成醇,得到结构式为的化合物5;
(4)将化合物5利用三苯基膦和碘单质在碱性作用下,加热发生脱氧反应,得到结构式为的化合物6;
(5)将化合物6在溴化钾和氧化剂作用下实现氧化性的脱苄基化反应,通过四丁基氟化铵进一步脱除HBr保护得到结构式为的(R)-4-(二氟乙烯基)-吡咯烷-2-酮。
进一步地,所述的不对称合成塞曲西坦关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮的方法,包括下述步骤:
(1)将结构式为的化合物1、苯硼酸2、镍催化剂和配体L加入到溶剂中,在加热下反应完全,经柱层析分离得到结构式为/>的二氟乙烯基取代的手性吡咯烷酮3;
(2)将化合物3加入溴化氢水溶液加热回流反应,反应结束后萃取、浓缩、柱层析分离得到结构式为的化合物4;
(3)将化合物4溶于溶剂中,向其鼓入臭氧气体直至出现持续蓝色现象,再通入氧气消除多余臭氧,随后加入还原剂并继续反应,直至反应结束,柱层析分离得到结构式为的化合物5;
(4)将化合物5、三苯基膦、碘单质和碱加入到溶剂中,加热回流反应,反应结束后,柱层析分离得到结构式为的化合物6;
(5)将化合物6、溴化钾和氧化剂加入到溶剂中进行反应,反应结束后,过滤、浓缩得到脱苄基粗产物,向溶有粗产物的四氢呋喃溶液中加入四丁基氟化铵,继续反应,反应结束后,经薄层色谱分离得到结构式为的(R)-4-(二氟乙烯基)-吡咯烷-2-酮。
优选的,步骤(1)中,所述的镍催化剂为醋酸镍;所述的配体L为(S,Sp)-iPr-phosferrox,其结构式为所述的溶剂为乙腈、三氟乙醇、1,4-二氧六环中的一种或者其混合;所述化合物1:苯硼酸2:镍催化剂:配体L的摩尔比例为1:2:0.1:0.12;所述的反应的条件为80-100℃反应24-26小时。
优选的,步骤(2)中,所述的溴化氢水溶液为质量分数48%的溴化氢水溶液;所述的加热回流反应的条件为80-110℃回流18-24小时。
优选的,步骤(3)中,所述的溶剂为二氯甲烷、甲醇其中一种;所述的还原剂选自三苯基膦、二甲硫醚和硼氢化钠中的一种;所述化合物4与还原剂的摩尔比例为1:5;所述的反应的温度为-78~0℃。
优选的,步骤(4)中,所述的碱为有机碱,选自三乙胺、二异丙基胺、吡啶其中的一种;所述的溶剂为甲苯;所述化合物5、三苯基膦、碘单质、碱的摩尔比例为1.0:1.5:0.5:1.0;所述的反应的温度为100-110℃。
优选的,步骤(5)中,所述的氧化剂为过氧单磺酸钾;所述的溶剂为硝基甲烷、二氯甲烷和水中的一种或其混合;所述化合物6、溴化钾、氧化剂的摩尔比例为1:1.0:1.5;所述的四丁基氟化铵选自含其1.0M浓度的四氢呋喃溶液;所述的反应的温度为10-30℃。
本发明相对于现有技术具有如下优点和有益效果:
本发明从简单的起始原料三氟甲基取代的1,6-烯炔1和苯硼酸2出发,以六步、高产率和高对映选择性的得到塞曲西坦的关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮。本发明反应条件温和、操作简单、路线短、收率高,为该药物分子的不对称合成提供了可行路线。
具体实施方式
本发明提供一种不对称合成塞曲西坦关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮的方法。该方法以三氟甲基取代的1,6-烯炔1和苯硼酸2为起始原料,经由镍催化的不对称环化脱氟反应和四取代烯烃的臭氧化分解反应为关键步骤,以高产率和高对映选择性的得到(R)-4-(二氟乙烯基)-吡咯烷-2-酮。其合成路线如下:
其中,所用底物1三氟甲基取代的1,6-烯炔通过包括如下步骤的方法制备:
在装有聚四氟乙烯磁子的圆底烧瓶中加入2-丁炔酸(15.0mmol,1.3mg)、化合物A(15.0mmol,3.2g)、DCC(18.0mmol,3.7g)和二氯甲烷(50mL)。将反应混合物在30℃下搅拌反应12小时。反应完毕,将反应液浓缩,柱层析分离得到3.4g无色油状液体即化合物1(产率为81%)。其中,化合物A的制备参见文献J.Flourine.Chem.,2015,180,216–221。
1H NMR(400MHz,CDCl3)δ7.44-7.15(m,5H),6.33-6.14(m,1H),5.74-5.52(m,1H),4.75(s,2H),4.18(dd,J=4.7,2.4Hz,2H),2.01(dd,J=3.9,1.4Hz,3H);19NMR(376MHz,CDCl3)δ-64.17.
实施例1
(1)化合物3的合成:
在装有聚四氟乙烯磁子的烘干密封管中加入Ni(OAc)2·4H2O(0.02mmol,5.0mg)、(S,Sp)-iPr-phosferrox(0.024mmol,11.6mg)和三氟乙醇(1mL)。将反应混合物在氩气氛的手套箱中搅拌15分钟。然后加入底物1(0.2mmol,56.2mg)和苯硼酸2(0.4mmol,48.8mg)。封闭密封管,并从手套箱中取出,然后在80℃下搅拌反应24h。反应完毕,将反应液浓缩,柱层析分离得到42.1mg无色油状液体即化合物3(产率为62%,ee值为98%)。
1H NMR(400MHz,CDCl3)δ7.37-7.26(m,8H),7.13(d,J=7.9Hz,2H),4.60-4.48(m,2H),3.90(ddd,J=23.9,10.4,2.3Hz,1H),3.58(t,J=9.7Hz,1H),3.42(t,J=9.0Hz,1H),2.85(dd,J=9.9,3.0Hz,1H),2.60(s,3H);13C NMR(101MHz,CDCl3)δ168.2,156.2(t,J=290.0),148.8,142.9,136.4,128.9,128.5,128.4,127.8,127.6,126.6,81.2(dd,J=22.6,18.8Hz),50.2,47.0,31.0(d,J=5.5Hz),20.5;19F NMR(376MHz,CDCl3)δ-89.61(d,J=42.7Hz),-90.15(dd,J=48.0,23.9Hz);HRMS:(ESI)calcd for C21H20F2NO+[M+H]+340.1507found 340.1501.
[α]D 28 91.5(c 5.0,iPrOH).
光学纯度分析:产物的对映体过量98%,手性OD-H柱(正己烷/异丙醇为95:5,v:v),
1mL/min,254nm,30℃,保留时间为t1=12.0分钟,t2=12.8分钟。
(2)化合物4的合成:
在装有聚四氟乙烯磁子的反应管中加入偕二氟烯烃底物3(40.8mg,0.12mmol)和2mL质量分数为48%的HBr水溶液,然后在110℃下回流24小时。反应完毕,乙酸乙酯萃取,合并有机相并用无水硫酸钠干燥,浓缩,柱层析分离得到34.8mg无色油状液体即化合物4(产率为69%,ee值为97%)。
1H NMR(600MHz,CDCl3)δ7.42-7.38(m,2H),7.38-7.33(m,2H),7.33-7.27(m,4H),7.21-7.17(m,2H),4.56(d,J=14.6Hz,1H),4.53(d,J=14.6Hz,1H),3.42(dd,J=10.5,7.4Hz,1H),3.34-3.29(m,1H),3.12-3.05(m,1H),2.62(d,J=1.4Hz,3H),2.20-2.08(m,2H);13C NMR(151MHz,CDCl3)δ168.0,148.4,142.5,136.2,129.0,128.8,128.32,128.29,127.8,127.7,121.6(t,J=306.2Hz),48.6,48.0(t,J=20.1Hz),47.0,31.7(d,J=3.9Hz),20.4;19F NMR(565MHz,CDCl3)δ-41.47(dt,J=159.1,11.2Hz),-45.48(dt,J=158.8,16.8Hz);HRMS:(ESI)calcd for C21H21BrF2NO+[M+H]+420.0769found 420.0770.
[α]D 32 11.27(c 0.1,iPrOH).
光学纯度分析:产物的对映体过量97%,手性AD-H柱(正己烷/异丙醇为5:1,v:v),1mL/min,254nm,30℃,保留时间为t1=4.9分钟,t2=5.3分钟。
(3)化合物5的合成:
在装有聚四氟乙烯磁子的反应管中加入底物4(21.0mg,0.05mmol)和2mL二氯甲烷,将反应液冷却至-78℃,持续向混合液鼓入臭氧,直到出现持续的蓝色现象。然后鼓入氧气以消除多余的臭氧,随后立即加入NaBH4(9.5mg,0.25mmol)。混合物在-78℃搅拌过夜。反应完毕恢复至室温,加入水淬灭,用乙酸乙酯萃取,有机相经干燥浓缩后柱层析分离得到12.5mg白色固体即化合物5(产率为75%,ee值为97%)。
1H NMR(600MHz,CDCl3)δ7.38-7.29(m,3H),7.25-7.20(m,2H),4.51(d,J=14.7Hz,1H),4.42(d,J=14.7Hz,1H),4.08(d,J=9.8Hz,1H),3.46-3.39(m,1H),3.08-2.97(m,2H),2.66-2.57(m,1H),2.53-2.40(m,1H);19F NMR(565MHz,CDCl3)δ-42.49(ddd,J=159.8,16.3,8.4Hz),-44.74(dt,J=159.9,16.3Hz);13C NMR(151MHz,CDCl3)δ173.4,135.2,128.9,128.1,128.0,121.1(t,J=305.0Hz),73.6,47.9,47.1,46.0(t,J=22.3Hz),38.1(d,J=3.0Hz);HRMS:(ESI)calcd for C13H15BrF2NO2 +[M+H]+334.0249found 420.0254.
[α]D 32 4.32(c 0.1,iPrOH).
光学纯度分析:产物的对映体过量97%,手性OD-H柱(正己烷/异丙醇为7:3,v:v),1mL/min,204nm,30℃,保留时间为t1=6.5分钟,t2=8.1分钟。
(4)化合物6的合成:
在装有聚四氟乙烯磁子的密封管中加入底物5(12.5mg,0.037mmol)和PPh3(14.5mg,0.056mmol)溶解于0.5mL超干甲苯中。然后在氩气保护下加入吡啶(3.5mg,0.044mmol)和碘单质(4.7mg,0.019mmol)。将混合物在110℃下回流反应8小时。反应完毕加入饱和Na2S2O3溶液,用乙酸乙酯萃取,有机相干燥并浓缩,柱层析分离得到8.2mg无色油状液体即化合6(产率为70%,ee值为97%)。
1H NMR(600MHz,CDCl3)δ7.37-7.32(m,2H),7.32-7.28(m,1H),7.25-7.21(m,2H),4.47(d,J=14.6Hz,1H),4.43(d,J=14.7Hz,1H),3.45(dd,J=10.0,7.9Hz,1H),3.03(dd,J=10.0,7.6Hz,1H),2.82-2.66(m,2H),2.64-2.41(m,2H),2.26(dd,J=16.3,8.7Hz,1H);13CNMR(151MHz,CDCl3)δ173.0,136.0,128.8,128.2,127.8,121.3(t,J=305.4Hz),51.6,48.2(t,J=21.5Hz),46.5,37.2,28.2(t,J=2.5Hz);19F NMR(565MHz,CDCl3)δ-43.11--43.55(m),-43.82(dt,J=159.7,14.4Hz);HRMS:(ESI)calcd for C13H15BrF2NO+[M+H]+318.0300found 318.0300.
[α]D 32 7.94(c 0.1,iPrOH).
光学纯度分析:产物的对映体过量97%,手性IA-H柱(正己烷/异丙醇为17:3,v:v),1mL/min,194nm,30℃,保留时间为t1=8.3分钟,t2=8.8分钟。
(5)(R)-4-(二氟乙烯基)-吡咯烷-2-酮的合成
在装有聚四氟乙烯磁子的密封管中加入底物6(7.1mg,0.022mmol)和KBr(2.6mg,0.022mmol),置换氩气,加入1.0mL DCM/H2O(9/1,v/v)的混合溶剂,最后加入过氧单磺酸钾(11.4mg,0.033mmol)。将混合物在30℃下反应24h。反应完毕,将反应液通过硅藻土过滤,旋干滤液得到粗产品,向粗产品中加入15μL四丁基氟化铵(2.0M in THF)和超干的THF(300μL),并在氩气保护下室温反应2小时。反应完毕直接通过薄层色谱分离得到1.6mg无色油状液体即(R)-4-(二氟乙烯基)-吡咯烷-2-酮(产率为50%ee值为97%)。
1H NMR(600MHz,CDCl3)δ5.58(s,1H),4.29(ddd,J=24.5,9.4,2.0Hz,1H),3.59(ddd,J=9.2,7.9,1.1Hz,1H),3.30(dtt,J=9.7,8.5,7.2Hz,1H),3.14(dd,J=9.5,7.2Hz,1H),2.55(dd,J=16.8,8.7Hz,1H),2.15(dd,J=16.8,8.6Hz,1H);19F NMR(376MHz,CDCl3)δ-86.75(d,J=41.8Hz),-88.00(dd,J=41.7,24.0Hz);13C NMR(151MHz,CDCl3)δ176.8,156.6(dd,J=294.5,288.2Hz)80.0(dd,J=23.7,19.3Hz),47.9(t,J=3.0Hz),36.7,30.3.
[α]D 32 2.44(c 0.1,iPrOH).
光学纯度分析:产物的对映体过量97%,手性OD-H柱(正己烷/异丙醇为4:1,v:v),1mL/min,205nm,30℃,保留时间为t1=8.0分钟,t2=9.3分钟。
以上所述,仅为本发明较佳的具体实施方式,但本发明保护的范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内所做的任何修改,等同替换和改进等,均应包含在发明的保护范围之内。
Claims (11)
1.一种不对称合成塞曲西坦关键中间体(R)-4-(二氟乙烯基)-吡咯烷-2-酮的方法,其特征在于,包括下述步骤:
(1)结构式为的化合物1、苯硼酸2、镍催化剂和配体L在溶剂中,发生环化脱氟反应,得到结构式为/>的二氟乙烯基取代的手性吡咯烷酮3;所述的镍催化剂为醋酸镍,所述的配体L为(S,S p)-iPr-phosferrox,所述的溶剂为三氟乙醇;
(2)将化合物3结构中的偕二氟烯烃通过溴化氢保护,得到结构式为的化合物4;
(3)将化合物4结构中的烯烃通过臭氧切断得到酮,进一步将酮还原成醇,得到结构式为的化合物5;
(4)将化合物5利用三苯基膦和碘单质在碱性作用下,加热发生脱氧反应,得到结构式为的化合物6;
(5)将化合物6在溴化钾和氧化剂作用下实现氧化性的脱苄基化反应,通过四丁基氟化铵进一步脱除HBr保护得到结构式为 的(R)-4-(二氟乙烯基)-吡咯烷-2-酮。
2.根据权利要求1所述的方法,其特征在于,步骤(1)包括如下步骤:将化合物1、苯硼酸2、镍催化剂和配体L加入到溶剂中,在加热下反应完全,得到二氟乙烯基取代的手性吡咯烷酮3。
3. 根据权利要求2所述的方法,其特征在于,所述化合物1、苯硼酸2、镍催化剂、配体L的摩尔比例为1 : 2 : 0.1 : 0.12;所述的反应的条件为80-100 ℃反应24-26小时。
4.根据权利要求1所述的方法,其特征在于,步骤(2)包括如下步骤:将化合物3加入溴化氢水溶液加热回流反应,得到化合物4。
5. 根据权利要求4所述的方法,其特征在于,所述的溴化氢水溶液为质量分数48%的溴化氢水溶液;所述的加热回流反应的条件为80-110 ℃回流18-24小时。
6.根据权利要求1所述的方法,其特征在于,步骤(3)包括如下步骤:将化合物4的溶于溶剂中,向其鼓入臭氧气体直至出现持续蓝色现象,再通入氧气,加入还原剂并继续反应,得到化合物5。
7. 根据权利要求6所述的方法,其特征在于,所述的溶剂选自二氯甲烷、甲醇其中一种;所述的还原剂选自三苯基膦、二甲硫醚和硼氢化钠中的一种;所述化合物4与还原剂的摩尔比例为1:5;所述的反应的温度为-78~0 ℃。
8.根据权利要求1所述的方法,其特征在于,步骤(4)包括如下步骤:将化合物5、三苯基膦、碘单质和碱加入到溶剂中,加热回流反应,得到化合物6。
9. 根据权利要求8所述的方法,其特征在于,所述的碱为有机碱,选自三乙胺、二异丙基胺、吡啶中的一种;所述的溶剂为甲苯;所述化合物5、三苯基膦、碘单质、碱的摩尔比例为1.0 : 1.5 : 0.5 : 1.0;所述的反应的温度为100-110 ℃。
10.根据权利要求1所述的方法,其特征在于,步骤(5)包括如下步骤:将化合物6、溴化钾和氧化剂加入到溶剂中进行反应,反应结束后,过滤、浓缩得到脱苄基粗产物,向溶有粗产物的四氢呋喃溶液中加入四丁基氟化铵,继续反应,得到(R)-4-(二氟乙烯基)-吡咯烷-2-酮。
11. 根据权利要求10所述的方法,其特征在于,所述的氧化剂为过氧单磺酸钾;所述的溶剂为硝基甲烷、二氯甲烷和水中的一种或其混合;所述化合物6、溴化钾、氧化剂的摩尔比例为1 : 1.0 : 1.5;所述的四丁基氟化铵选自含其1.0 M浓度的四氢呋喃溶液;所述的反应的温度为10-30 ℃。
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