CN114539168B - 一种合成Piragliatin及其类似物的方法 - Google Patents
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- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
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- 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
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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Abstract
本发明公开了一种合成Piragliatin及其类似物的方法。具体来说,是以芳基卤化物、丙烯酸衍生物以及烷烃为原料,通过十聚钨酸盐与金属镍络合物的协同催化来高效构建Piragliatin及其类似物的方法;即在光照下首先实现烯烃的芳基烷基化,再将酯水解成酸进而制成酰氯,最后与2‑氨基吡嗪缩合得到Piragliatin。本发明中使用了一种新颖的烯烃烷基芳基化的方法学,与之前的合成方法相比,原料商业可得、步骤简洁高效并且易于进一步衍生化,操作简单,适用于大量Piragliatin及其类似物的合成。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种合成Piragliatin及其类似物的合成方法。
背景技术
Piragliatin可以通过激活葡萄糖激酶(GK)实现治疗II型糖尿病。Sarabu等人的实验证明了Piragliatin能够减少空腹以及口服葡萄糖耐量试验后的血糖水平,改善胰岛素分泌状况,增加β细胞对葡萄糖的敏感性,并降低肝葡萄糖输出量(Science 2003,301,370;J.Med.Chem.2010,53,3618;J.Med.Chem.2012,55,7021)。目前该药物开发正处于二期临床阶段。
然而,目前合成Piragliatin的方法步骤冗长,底物上复杂的结构需要预先构建并保护,大量金属试剂的使用以及苛刻的条件不仅给环境带来污染也增加了生产成本。基于本发明人课题组长期致力于烯烃双官能团化方面的研究,本发明提出了以芳基卤化物、丙烯酸衍生物与环戊烷或环戊酮为原料,通过烯烃的烷基芳基化、酸化和酰胺化三步高效地实现Piragliatin及其类似物的合成。
发明内容
为了解决上述技术问题,本发明提供一种简单,高效,快捷,高选择性的合成Piragliatin及其类似物的方法。
本发明提供的技术方案如下:
一种使用烯烃烷基芳基化策略的合成Piragliatin方法,其特征在于,包括下述步骤:
(1)将芳基卤代物A、环戊烷/酮B与丙烯酸酯C在可见光照射下,通过十聚钨酸盐与金属镍络合物催化,得到双官能团化产物中间体D;
所述芳基卤化物A的结构式为:其中R1选自甲硫基(-SMe)、甲磺酰基(-SO2Me)、氟基(-F)中的一种,X选自Br、I中的一种;
所述丙烯酸酯C的结构式为:其中R2选自氢、C1-12的烷基或含杂原子的烷基、C6-30的烷基取代的芳基或含杂原子的烷基取代的芳基中的一种;
所述双官能团化产物中间体D结构式为:
(2)将双官能团化产物中间体D在碱性条件下水解,得到羧酸E;
所述羧酸E的结构式为
(3)将羧酸E与草酰氯反应得到对应的酰氯,再与2-氨基哌嗪缩合,得到Piragliatin及其类似物F;
所述Piragliatin及其类似物F结构式为
进一步,所述步骤(1)的步骤如下:在惰性气体的保护下,向反应管中加入光催化剂十聚钨酸盐和金属镍络合物、芳基卤代物A、环戊烷/环戊酮B、丙烯酸酯C、碱金属盐GH以及有机溶剂,封闭反应管,在紫光灯照射下室温反应完全,经柱层析分离得到双官能团化产物D。
更进一步,所述步骤(1)中碱金属GH中,G为K+,Na+,Li+或Cs+,H选自[PO4 3-]、[CO3 2-]、[HCO3 -]和[HPO4 2-]中的一种。
更进一步,所述步骤(1)中有机溶剂为丙酮和乙腈中的一种或其混合。
进一步,所述步骤(1)中十聚钨酸盐为十钨酸四丁基铵。
进一步,所述步骤(1)中金属镍络合物选自金属镍络合物选自(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍、(4,4'-二甲氧基-2,2'-联吡啶)二溴化镍、二溴化镍与4,4'-二叔丁基-2,2'-联吡啶的混合物或二溴化镍与4,4'-二甲氧基-2,2'-联吡啶的混合物中的一种。
更进一步,所述步骤(1)中,芳基卤代物A的浓度为1~0.1mol/L;环戊烷或环戊酮B的浓度为10~0.1mol/L;丙烯酸酯C的浓度为3~0.3mol/L;十聚钨酸盐的浓度为0.001~0.0001mol/L;金属镍络合物的浓度为0.1~0.01mol/L;无机碱的浓度为2~0.2mol/L。
更进一步,所述步骤(1)中,反应辐照光的波长为300-500nm之间。
进一步,所述步骤(2)的步骤如下:双官能团化产物D溶解于THF与水的混合溶液,0℃下加入氢氧化锂,室温反应至完全,酸化萃取,干燥浓缩得到羧酸E。
进一步,所述步骤(3)的步骤如下:羧酸E加入DCM,0℃下加入草酰氯以及1滴DMF,室温反应30min后,加入含有2-氨基哌嗪和吡啶的THF溶液,室温反应24小时,经柱层析分离得到Piragliatin及其类似物F。优选的,该步骤中DCM和THF均经过除水处理。
本发明的合成路线如下
本发明的有益效果如下:
与之前的方法相比,本方法可以通过商业可得的原料只需通过三步实现Piragliatin的合成,并且也为其类似物的合成提供了一个高效的途径。
本方法利用300-500nm的光作为驱动力,所使用的光催化剂十聚钨酸盐价格便宜,是一种有效、绿色、廉价合成Piragliatin及其类似物的方法。
具体实施方式
通过下述实施例将有助于理解本发明,但并不限制本发明的内容。
实施例1
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸苄酯(97.2mg,0.6mmol),环戊酮(168.2mg,2mmol),4-溴-2-氯-1-(甲基磺酰基)苯(53.9mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(3-氯-4-(甲基磺酰基)苯基)-3-(3-氧代环戊基)丙酸苄酯41.8mg(产率为48%,d.r.=1:1,无色透明液体。
1H NMR(600MHz,CDCl3)δ8.11-8.08(m,1H),7.54-7.51(m,1H),7.42-7.38(m,1H),7.37-7.31(m,4H),7.28-7.26(m,1H),5.19-5.15(m,1H),5.11-5.07(m,1H),3.75-3.70(m,1H),3.27(s,3H),2.37-2.23(m,3H),2.15-2.05(m,2H),2.01-1.88(m,2H),1.85-1.75(m,1H),1.56-1.47(m,1H);13C NMR(151MHz,CDCl3)δ217.8,171.91,171.85,146.09,146.05,137.2,135.1,132.98,132.97,131.29,131.27,131.23,128.7,128.41,128.38,127.12,127.11,67.4,49.74,49.72,44.8,44.5,42.8,39.14,39.07,38.4,38.3,35.02,35.96,29.5,29.2;HRMS:(ESI)calcd for C22H24ClO5S+[M+H]+435.1027;found 435.1013.
在上述产物的基础上进一步合成Piragliatin:
合成路径如下:
制备方法如下:
向2-(3-氯-4-(甲基磺酰基)苯基)-3-(3-氧代环戊基)丙酸苄酯(43.5mg,0.1mmol)中加入四氢呋喃(0.75mL),水(0.25mL),在0℃下加入氢氧化锂(12.0mg,0.5mmol),室温反应18小时,0℃下用1M KHSO4溶液将pH调至2,用乙酸乙酯萃取,真空干燥过夜。随后0℃加入超干二氯甲烷(2mL),草酰氯(14.0mg,0.11mmol)和N,N-二甲基甲酰胺(1滴),室温反应30分钟后,加入含有2-氨基哌嗪(20.9mg,0.22mmol)与吡啶(17.4mg,0.22mmol)的四氢呋喃溶液(2mL),室温反应24小时,浓缩,快速柱层析,得产物Piragliatin19.4mg(产率为46%,d.r.=1:1,白色固体)。
1H NMR(600MHz,CDCl3)δ9.55-9.45(m,1H),8.40-8.33(m,2H),8.22-8.19(m,1H),8.14-8.10(m,1H),7.64-7.59(m,1H),7.52-7.48(m,1H),3.79-3.70(m,1H),3.32-3.23(m,3H),2.48-2.29(m,3H),2.22-2.13(m,2H),2.10-2.05(m,1H),1.98-1.82(m,2H),1.64-1.56(m,1H);13C NMR(151MHz,CDCl3)δ217.9,169.9,147.8,146.6,146.4,142.2,141.0,137.2,133.4,131.7,131.4,131.3,127.1,127.1,45.0,44.7,43.0,39.6,39.68,39.53,39.64,39.49,35.3,35.1,29.8,29.6.
实施例2
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸甲酯(51.7mg,0.6mmol),环戊烷(140.2mg,2mmol),4-溴-2-氯-1-(甲基磺酰基)苯(53.9mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(3-氯-4-(甲基磺酰基)苯基)-3-环戊基丙酸甲酯31.0mg(产率为45%,无色透明液体)。
1H NMR(600MHz,CDCl3)δ8.08(d,J=8.2Hz,1H),7.53(d,J=1.7Hz,1H),7.44-7.37(m,1H),3.68(s,3H),3.66(t,J=7.8Hz,1H),3.26(s,3H),2.12-2.05(m,1H),1.84-1.78(m,1H),1.77-1.70(m,2H),1.62-1.55(m,3H),1.53-1.44(m,2H),1.15-1.04(m,2H);13C NMR(151MHz,CDCl3)δ173.3,147.2,136.9,132.8,131.5,131.1,127.4,52.5,50.6,42.9,39.9,37.9,32.8,32.3,25.2.
在上述产物的基础上进一步合成Piragliatin类似物:
合成路线如下:
制备方法如下:
将2-(3-氯-4-(甲基磺酰基)苯基)-3-环戊基丙酸甲酯(34.5mg,0.1mmol)中加入四氢呋喃(0.75mL),水(0.25mL),在0℃下加入氢氧化锂(12.0mg,0.5mmol),室温反应18小时,0℃下用1M KHSO4溶液将pH调至2,用乙酸乙酯萃取,真空干燥过夜。随后0℃加入超干二氯甲烷(2mL),草酰氯(14.0mg,0.11mmol)和N,N-二甲基甲酰胺(1滴),室温反应30分钟后,加入含有2-氨基哌嗪(20.9mg,0.22mmol)与吡啶(17.4mg,0.22mmol)的四氢呋喃溶液(2mL),室温反应24小时,浓缩,快速柱层析,得产物2-(3-氯-4-(甲基磺酰基)苯基)-3-环戊基-N-(吡嗪-2-基)丙酰胺21.1mg(产率为52%,无色透明液体)。
1H NMR(600MHz,CDCl3)δ9.52(s,1H),8.35(d,J=2.5Hz,1H),8.21(dd,J=2.6,1.6Hz,1H),8.15-8.07(m,2H),7.62(d,J=1.7Hz,1H),7.49(dd,J=8.2,1.7Hz,1H),3.67(t,J=7.5Hz,1H),3.27(s,3H),2.27-2.18(m,1H),1.93-1.86(m,1H),1.83-1.73(m,2H),1.70-1.66(m,1H),1.65-1.58(m,2H),1.55-1.45(m,2H),1.19-1.10(m,2H);13C NMR(151MHz,CDCl3)δ170.5,147.8,147.0,142.1,140.8,137.2,137.1,133.2,131.4,131.4,127.2,53.0,42.9,40.2,37.8,32.9,32.5,25.2.
实施例3
合成路线如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸甲酯(51.7mg,0.6mmol),环戊烷(140.2mg,2mmol),4-溴-2-氯-1-氟苯(41.8mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(3-氯-4-氟苯基)-3-环戊基丙酸甲酯30.6mg(产率为54%,无色透明液体)。
1H NMR(600MHz,CDCl3)δ7.37(dd,J=7.0,2.3Hz,1H),7.20-7.16(m,1H),7.08(t,J=8.7Hz,1H),3.67(s,3H),3.56(t,J=7.8Hz,1H),2.07-2.01(m,1H),1.80-1.70(m,3H),1.65-1.60(m,2H),1.58(dd,J=5.2,1.4Hz,1H),1.52-1.45(m,2H),1.14-1.05(m,2H);13CNMR(151MHz,CDCl3)δ174.1,157.3(d,J=248.2Hz),136.3(d,J=3.9Hz),130.1,127.7(d,J=7.1Hz),121.0(d,J=17.6Hz),116.6(d,J=21.1Hz),52.2,49.9,39.9,37.8,32.7,32.2,25.1;19F NMR(565MHz,CDCl3)δ-117.8.HRMS:(ESI)calcd for C15H18ClFO2H+[M+H]+285.1052;found 285.1042.
实施例4
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸甲酯(51.7mg,0.6mmol),环戊酮(140.2mg,2mmol),4-溴-2-氯-1-氟苯(41.8mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(3-氯-4-氟苯基)-3-(3-氧代环戊基)丙酸甲酯28.6mg(产率为48%,d.r.=1:1,无色透明液体)。
1H NMR(600MHz,CDCl3)δ7.38-7.34(m,1H),7.20-7.15(m,1H),7.12-7.08(m,1H),3.69-3.66(m,3H),3.60-3.54(m,1H),2.38-2.27(m,2H),2.25-2.14(m,2H),2.13-2.10(m,1H),2.09-1.97(m,1H),1.97-1.85(m,1H),1.85-1.75(m,1H),1.57-1.49(m,1H);13C NMR(151MHz,CDCl3)δ218.3,173.5,173.5,157.5(d,J=249.2Hz),135.5(d,J=3.9Hz),135.4(d,J=3.9Hz),130.0,130.0,127.6(d,J=7.5Hz),127.6(d,J=7.5Hz),121.4(d,J=18.1Hz),121.3(d,J=18.1Hz),116.9(d,J=21.0Hz),52.4,52.4,49.1,49.1,44.9,44.5,39.3,39.2,38.4,38.4,35.1,35.0,29.6,29.3;19F NMR(565MHz,CDCl3)δ-116.9,-116.9.HRMS:(ESI)calcd for C15H16ClFO3H+[M+H]+299.0845;found 299.0840.
实施例5
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸甲酯(51.7mg,0.6mmol),环戊烷(140.2mg,2mmol),4-溴联苯(46.6mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-([1,1'-联苯]-4-基)-3-环戊基丙酸甲酯37.0mg(产率为60%,无色透明液体)。
1H NMR(600MHz,CDCl3)δ7.51-7.45(m,4H),7.36-7.29(m,4H),7.27-7.23(m,1H),3.61-3.56(m,4H),2.06-2.00(m,1H),1.81-1.75(m,1H),1.74-1.65(m,2H),1.63-1.57(m,1H),1.55-1.49(m,2H),1.44-1.36(m,2H),1.09-1.00(m,2H).13C NMR(151MHz,CDCl3)δ174.8,140.8,140.1,138.4,128.8,128.4,127.3,127.3,127.1,52.0,50.5,40.0,37.9,32.8,32.4,25.1,25.1;HRMS:(ESI)calcd for C21H25O2 +[M+H]+309.1849;found 309.1844.
实施例6
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸甲酯(51.7mg,0.6mmol),环戊酮(140.2mg,2mmol),2-溴二苯并[b,d]噻吩(52.6mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(二苯并[b,d]噻吩-2-基)-3-(3-氧代环戊基)丙酸甲酯40.8mg(产率为58%,d.r.=1:1,无色透明液体)。
1H NMR(600MHz,CDCl3)δ8.19-8.16(m,1H),8.10-8.07(m,1H),7.86-7.80(m,2H),7.49-7.45(m,2H),7.44-7.40(m,1H),3.84-3.77(m,1H),3.69(d,J=0.9Hz,3H),2.47-2.26(m,3H),2.23-2.05(m,4H),1.90-1.79(m,1H),1.61-1.50(m,1H);13C NMR(151MHz,CDCl3)δ218.6,218.6,174.2,174.1,139.8,138.6,136.0,135.1,135.1,134.9,134.8,127.0,126.9,126.4,126.4,124.4,124.4,123.1,122.8,121.7,121.6,120.8,52.2,50.0,49.9,45.0,44.6,39.5,39.4,38.4,38.4,35.1,35.0,29.6,29.2;HRMS:(ESI)calcd for C21H21O3S+[M+H]+353.1206;found 353.1206.
实施例7
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯酸异丙酯(68.4mg,0.6mmol),环戊酮(140.2mg,2mmol),2-溴二苯并[b,d]噻吩(52.6mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(二苯并[b,d]噻吩-2-基)-3-(3-氧代环戊基)丙酸异丙酯52.6mg(产率为50%,d.r.=1:1,无色透明液体)。
1H NMR(600MHz,CDCl3)δ8.20-8.07(m,2H),7.87-7.78(m,2H),7.49-7.40(m,3H),5.04-4.97(m,1H),3.78-3.70(m,1H),2.46-2.19(m,4H),2.13-2.02(m,3H),1.92-1.80(m,1H),1.61-1.52(m,1H),1.25(dd,3H),1.12(dd,J=6.2,1.3Hz,3H);13C NMR(151MHz,CDCl3)δ218.7,218.7,173.2,139.8,138.5,135.9,135.2,135.1,126.9,126.9,126.5,126.5,124.4,124.4,123.0,122.9,121.6,121.6,120.8,120.7,68.4,50.4,50.3,45.0,44.7,39.5,39.5,38.5,38.4,35.2,35.1,29.6,29.3,21.8,21.7,21.5;HRMS:(ESI)calcd forC21H21O3S+[M+H]+353.1206;found 353.1206.
实施例8
合成路径如下:
制备方法如下:
惰性气氛下,向反应管中加入十钨酸四丁基铵(13.3mg,0.004mmol),(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍(9.8mg,0.02mmol),磷酸钾(84.8mg,0.4mmol),丙烯腈(31.8mg,0.6mmol),环戊酮(140.2mg,2mmol),2-溴二苯并[b,d]噻吩(52.6mg,0.2mmol)和丙酮(0.5mL)。紫光灯(10w,390nm)照射下室温反应18小时,浓缩,快速柱层析,得产物2-(二苯并[b,d]噻吩-2-基)-3-(-3-氧代环戊基)丙腈37.0mg(产率为58%,d.r.=1:1,无色透明液体)。
1H NMR(600MHz,CDCl3)δ8.20-8.17(m,2H),8.13-8.10(m,2H),7.91-7.80(m,4H),7.52-7.47(m,4H),7.41-7.37(m,2H),4.05-3.96(m,2H),2.53-2.24(m,10H),2.23-2.14(m,2H),2.11-2.01(m,2H),1.92-1.84(m,2H),1.62-1.56(m,2H);13C NMR(151MHz,CDCl3)δ217.48,217.41,140.0,139.5,136.3,134.8,131.7,127.4,125.52,125.51,124.7,123.7,123.0,121.8,120.2,120.1,44.6,44.4,42.2,42.0,38.4,38.3,36.4,35.9,35.1,34.8,29.5,29.2;HRMS:(ESI)calcd for C20H18NOS+[M+H]+320.1059;found 320.1095.
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 (7)
1.一种合成Piragliatin及其类似物的方法,其特征在于,包括下述步骤:
(1)将芳基卤代物A、环戊烷或环戊酮B与丙烯酸酯C在光照射下,在碱金属盐GH和有机溶剂中通过十聚钨酸盐与金属镍络合物催化,得到双官能团化产物中间体D;
所述芳基卤化物A的结构式为:其中R1选自甲硫基(-SMe)、甲磺酰基(-SO2Me)、氟基(-F)中的一种,X选自Br、I中的一种;
所述丙烯酸酯C的结构式为:其中R2选自氢、C1-12的烷基或含杂原子的烷基、C6-30的烷基取代的芳基或含杂原子的烷基取代的芳基中的一种;
所述双官能团化产物中间体D结构式为:
碱金属盐GH中,G为K+,Na+,Li+或Cs+,H选自[PO4 3-]、[CO3 2-]、[HCO3 -]和[HPO4 2-]中的一种;
金属镍络合物选自(4,4'-二叔丁基-2,2'-联吡啶)二溴化镍、(4,4'-二甲氧基-2,2'-联吡啶)二溴化镍、二溴化镍与4,4'-二叔丁基-2,2'-联吡啶的混合物或二溴化镍与4,4'-二甲氧基-2,2'-联吡啶的混合物中的一种;
反应辐照光的波长为300-500nm;
(2)将双官能团化产物中间体D在碱性条件下水解,得到羧酸E;
所述羧酸E的结构式为
(3)将羧酸E与草酰氯反应得到对应的酰氯,再与2-氨基哌嗪缩合,得到Piragliatin及其类似物F;
所述Piragliatin及其类似物F结构式为
2.根据权利要求1所述的方法,其特征在于,所述步骤(1)的步骤如下:在惰性气体的保护下,向反应管中加入光催化剂十聚钨酸盐和金属镍络合物、芳基卤代物A、环戊烷/环戊酮B、丙烯酸酯C、碱金属盐GH以及有机溶剂,封闭反应管,在光照下室温反应完全,经柱层析分离得到双官能团化产物D。
3.根据权利要求2所述的方法,其特征在于:所述步骤(1)中有机溶剂为丙酮和乙腈中的一种或其混合。
4.根据权利要求1所述的方法,其特征在于:所述步骤(1)中十聚钨酸盐为十钨酸四丁基铵。
5.根据权利要求2所述的方法,其特征在于:所述步骤(1)中,芳基卤代物A的浓度为1~0.1mol/L;环戊烷或环戊酮B的浓度为10~0.1mol/L;丙烯酸酯C的浓度为3~0.3mol/L;十聚钨酸盐的浓度为0.001~0.0001mol/L;金属镍络合物的浓度为0.1~0.01mol/L;碱金属盐的浓度为2~0.2mol/L。
6.根据权利要求1所述的方法,其特征在于,所述步骤(2)的步骤如下:双官能团化产物D溶解于THF与水的混合溶液,0℃下加入氢氧化锂,室温反应至完全,酸化萃取,干燥浓缩得到羧酸E。
7.根据权利要求1所述的方法,其特征在于,所述步骤(3)的步骤如下:羧酸E加入DCM,0℃下加入草酰氯以及1滴DMF,室温反应30min,加入含有2-氨基哌嗪和吡啶的THF溶液,室温反应24小时,经柱层析分离得到Piragliatin及其类似物F。
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