CN104803864B - β-羟基-α-氨基酸衍生物及其合成方法和应用 - Google Patents
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Abstract
本发明涉及如式(I)所示的β‑羟基‑α‑氨基酸衍生物及其化学合成方法,以α‑芳基重氮酯、芳胺与芳醛为原料,以一价金属铑为催化剂,以有机溶剂为溶剂,在室温条件下经过一步反应,柱层析提纯即得到产物。本发明制备方法具步骤经济性高、原子经济性强、非对映选择性较高、收率较高等优势,且反应条件温和,操作简单安全。本发明β‑羟基‑α‑氨基酸新型衍生物是一类构筑多种生物活性天然产物和药物的重要化合物。本发明还公开了式(I)所示的β‑羟基‑α‑氨基酸衍生物在抑制蛋白酪氨酸磷酸酯酶活性中的应用。本发明在医药化工领域具有广阔的应用前景。
Description
技术领域
本发明属于药物合成技术领域,涉及一种新型β-羟基-α-氨基酸衍生物及其化学合成方法和应用。
背景技术
β-羟基-α-氨基酸衍生物是一类构筑多种生物活性天然产物和药物的重要化合物,在抗帕金森氏病药物屈昔多巴,肽类抗生素Chloramphenicol和Vancomycin中都含有β-羟基-α-氨基酸骨架。
本发明人课题组在2003-2004年已经公开了α-芳基重氮酯、芳胺与芳醛的三组份反应(Chem.Commun.,2004,2486-2487),在醋酸铑的催化下,α-芳基重氮酯与芳胺生成的铵基叶立德成功地被芳醛捕捉,一步构建了β-羟基-α-氨基酸衍生物这一重要骨架。但是该方法具有若干局限性,例如:1)总体来说,反应的化学选择性较低;2)只有中等的非对映选择性;3)反应底物范围比较局限,只有缺电子的芳醛才适用于该方法,大大减少了产物α-氨基-β-羟基酸酯衍生物的多样性。因此,探索及发展一种成本低、步骤经济、收率高、选择性好、底物适用性广、操作安全的α-氨基-β-羟基酸酯衍生物合成方法就显得十分重要。
发明内容
本发明克服现有技术的缺点,公开一种式(I)所示的α-氨基-β-羟基酸酯衍生物及其合成方法,具有原料价廉易得、操作简单、高收率、高非对映选择性、底物适应性广等优点。
本发明提出了一种新的α-氨基-β-羟基酸酯衍生物,其结构如式(I)所示:
其中,
R1为苄基、甲基、正丙基、氢原子;
R2为乙基、叔丁基;
Ar1为邻甲氧基苯基、2,4,6-三甲基苯基、苯基、对乙氧基苯基、邻乙氧基苯基、对甲氧基苯基;
Ar2为对硝基苯基、对溴苯基、间溴苯基、邻溴苯基、对氰基苯基、苯基、对甲氧基苯基。
本发明还提出了一种α-氨基-β-羟基酸酯衍生物的制备方法,以α-芳基重氮酯、芳胺与芳醛为原料,以一价金属铑为催化剂,以有机溶剂为溶剂,在室温条件下经过一步反应,柱层析提纯即得到产物式(I)所示的α-氨基-β-羟基酸酯衍生物。
本发明α-氨基-β-羟基酸酯衍生物制备方法的反应方程式为:
其中,R1为苄基、甲基、正丙基、氢原子;R2为乙基、叔丁基;Ar1为邻甲氧基苯基、2,4,6-三甲基苯基、苯基、对乙氧基苯基、邻乙氧基苯基、对甲氧基苯基;Ar2为对硝基苯基、对溴苯基、间溴苯基、邻溴苯基、对氰基苯基、苯基、对甲氧基苯基。
其中,所述芳醛、芳胺、烷基重氮酯、(1,5-环辛二烯)氯铑(I)二聚体的用量比例为:按摩尔比称取芳醛∶芳胺∶烷基重氮酯∶(1,5-环辛二烯)氯铑(I)二聚体=1.0∶1.2∶2.0∶0.01。
其中,所述芳醛为对硝基苯甲醛、对溴苯甲醛、间溴苯甲醛、邻溴苯甲醛、对氰基苯甲醛、苯甲醛、对甲氧基苯甲醛。
其中,所述芳胺为邻甲氧基苯胺、2,4,6-三甲基苯胺、苯胺、对乙氧基苯胺、邻乙氧基苯胺、对甲氧基苯胺。
其中,所述烷基重氮酯为苄基重氮乙酯、甲基重氮乙酯、正丙基重氮乙酯、重氮叔丁酯。
其中,所述溶剂为二氯甲烷。
具体地,本发明制备方法为:先按摩尔比称取芳醛∶芳胺∶烷基重氮酯∶(1,5-环辛二烯)氯铑(I)二聚体=1.0∶1.2∶2.0∶0.01;在反应瓶中加入芳醛、(1,5-环辛二烯)氯铑(I)二聚体和有机溶剂,让芳醛和(1,5-环辛二烯)氯铑(I)二聚体溶解;接着,将烷基重氮酯和芳胺用有机溶剂溶解,得到烷基重氮酯和芳胺的混合溶液;其中,用于溶解烷基重氮酯和芳胺的有机溶剂的量为10-15ml/mmol;然后,在室温下,通过蠕动泵在0.5小时内将烷基重氮酯和芳胺的混合溶液慢慢滴加到反应瓶中,反应结束后,30℃-40℃旋蒸去除溶剂,得到粗产品;将粗产品进行柱层析,例如,用体积比为乙酸乙酯∶石油醚=1∶30~1∶20的溶液进行柱层析,得到β-羟基-α-氨基酸衍生物纯品。
本发明制备方法的反应机理包括:金属催化下重氮分解形成金属卡宾,金属卡宾与芳胺形成的叶立德被芳醛所捕捉,一步形成具有高收率、高非对映选择性的β-羟基-α-氨基酸衍生物。本发明设计的合成方法具有步骤经济性高、原子经济性强、非对映选择性较高、收率较高等优势,并且反应条件温和,操作简单安全。
本发明还提出了式(I)所示α-氨基-β-羟基酸酯衍生物在抑制蛋白酪氨酸磷酸酯酶活性中的应用。本发明式(I)所示α-氨基-β-羟基酸酯衍生物可作为蛋白酪氨酸磷酸酯酶抑制剂。
本发明有益效果还包括:制备方法所用的原料重氮化合物、芳醛、芳胺和有机溶剂均价廉易得,成本低;合成路线简单,反应条件温和,可以一步构建目标产物;具有原子经济性,高选择性,高收率等,符合绿色化学的要求;能简单快捷地合成光学活性的β-羟基-α-氨基酸衍生物。本发明式(I)β-羟基-α-氨基酸新型衍生物是一类构筑多种生物活性天然产物和药物的重要化合物。本发明提供多样性的化合物骨架,对新药筛选和制药工艺具有非常重要的意义。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
本发明提出的式(I)所示β-羟基-α-氨基酸化合物的全新制备方法,其反应路线具体包括:先按摩尔比称取芳醛∶芳胺∶烷基重氮酯∶(1,5-环辛二烯)氯铑(I)二聚体=1.0∶1.2∶2.0∶0.01,将芳醛、(1,5-环辛二烯)氯铑(I)二聚体和有机溶剂加入反应瓶中,让芳醛和(1,5-环辛二烯)氯铑(I)二聚体溶解,接着,将烷基重氮酯和芳胺用有机溶剂溶解,得到烷基重氮酯和芳胺的混合溶液,用于溶解烷基重氮酯和芳胺的有机溶剂的量为10-15ml/mmol;然后在室温下,通过蠕动泵0.5小时将烷基重氮酯和芳胺的混合溶液慢慢滴加到反应瓶中,反应结束后,30℃-40℃旋蒸去除溶剂,得到粗产品;将粗产品用体积比为乙酸乙酯∶石油醚=1∶30~1∶20的溶液进行柱层析,得到β-羟基-α-氨基酸衍生物的纯品。
实施例1 制备本发明化合物4a
先称取对硝基苯甲醛3a(0.1mmol),邻甲氧基苯胺2a(0.12mmol),苄基重氮乙酯1a(0.2mmol),(1,5-环辛二烯)氯铑(I)二聚体(5.0mg,0.01mmol),将对硝基苯甲醛3a、(1,5-环辛二烯)氯铑(I)二聚体和1ml二氯甲烷加入小试管反应器中,让对硝基苯甲醛3a和(1,5-环辛二烯)氯铑(I)二聚体溶解,接着,将苄基重氮乙酯1a和邻甲氧基苯胺2a用1ml二氯甲烷溶解,得到1ml苄基重氮乙酯1a和邻甲氧基苯胺2a的混合溶液,然后在室温下,通过蠕动泵0.5小时将苄基重氮乙酯1a和邻甲氧基苯胺2a的混合溶液慢慢滴加到反应瓶中,反应结束后,30℃-40℃旋蒸去除溶剂,得到粗产品;将粗产品用体积比为乙酸乙酯∶石油醚=1∶30~1∶20的溶液进行柱层析,得到β-羟基-α-氨基酸衍生物的纯品4a。收率为65%,dr为13∶1。见表1。
产物β-羟基-α-氨基酸衍生物的4a表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ8.16(d,J=7.0Hz,2H),7.54(d,J=7.0Hz,2H),7.21(m,J=2.8Hz,3H),7.00(m,2H),6.89-6.86(m,2H),6.85-6.78(m,2H),5.69(s,1H),5.14(s,1H),4.57(s,1H),4.02-3.96(m,1H),3.85(d,J=6.0Hz,1H),3.81(s,J=6.0Hz,3H),3.49(d,J=11.3Hz,1H),3.00(d,J=11.3Hz,1H),0.87(t,J=5.7Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ174.17,147.70,147.41,146.34,135.10,134.54,129.95,128.69,128.05,126.96,122.48,120.85,112.98,110.42,74.14,68.04,61.63,55.70,37.61,13.34.
实施例2-13 制备化合物β-羟基-α-氨基酸衍生物(4b~4m)
实施例2-13中,反应中取代基的变化、化合物编号、d.r.值、产率等详见表1,其他实验步骤及条件同实施例1。
表1
产物β-羟基-α-氨基酸衍生物4b~4m的表征,见以下:
4b的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ7.36(d,J=12.0Hz,2H),7.14(d,J=12.0Hz,2H),7.08(m,3H),6.94(m,2H),6.84-6.81(m,2H),6.79-6.71(m,2H),5.32-5.26(m,2H),4.04-3.97(m,2H),3.85(d,J=8.0Hz,1H),3.72-3.68(m,4H),3.53-3.49(d,J=8.0Hz,1H),1.05(t,J=8.0Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ172.54,147.86,138.86,135.66,134.73,130.77,130.19,128.78,127.89,126.68,121.75,120.90,117.75,113.40,110.47,74.45,69.65,61.93,55.78,37.76.13.75.
4c的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ7.47-7.40(m,2H),7.29(s,1H),7.16(d,J=7.4Hz,4H),7.00(s,2H),6.86-6.82(m,2H),6.79-6.73(m,J=6.5Hz,4H),5.47(s,1H),5.15(s,1H),4.27(s,1H),4.03-3.93(m,1H),3.86(d,J=7.6Hz,1H),3.81(s,J=8.5Hz,3H),3.46(d,J=14.2Hz,1H),3.03(d,J=14.2Hz,1H),0.91(t,J=7.1Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ129.84,129.10,128.06,127.05,125.84,119.86,117.24,109.40,73.28,60.66,36.57,28.69,12.44.
4d的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ7.58(d,J=8.0Hz,2H),7.45(d,J=8.0Hz,2H),7.18(m,3H),6.97(s,2H),6.84-6.81(m,2H),6.78-6.73(m,2H),5.61(s,1H),5.10(s,1H),4.49(s,1H),3.96(m,J=4.0Hz,1H),3.77(s,3H),3.48-3.44(d,J=16.0Hz,1H),1.05(d,J=16.0Hz,1H),0.84(t,J=8.0Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ174.16,147.66,144.30,135.16,134.55,131.17(s),129.95,128.54,128.06,126.95,120.84,118.85,118.30,112.98,111.39,110.36,74.27,68.03,61.64,55.69,37.53,13.34.
4e的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ7.48-7.39(m,2H),7.29(s,1H),7.18(dd,J=6.0,2.1Hz,4H),7.00(dd,J=6.4,2.8Hz,2H),6.87-6.80(m,2H),6.76(dd,J=15.4,7.0Hz,2H),5.47(s,1H),5.15(s,1H),4.26(s,1H),3.98(dd,J=10.7,7.2Hz,1H),3.86(dt,J=6.6,5.5Hz,1H),3.80(s,3H),3.46(d,J=14.2Hz,1H),3.03(d,J=14.2Hz,1H),0.91(t,J=7.2Hz,4H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ172.19,146.18,135.54,128.27,127.37,125.81,120.12,116.53,109.52,108.93,59.90,56.81,54.48,37.86,13.05.
4f的表征:
1HNMR(400MHz,CDCl3,25℃,TMS)δ8.20(d,J=8.0Hz,2H),7.60(d,J=8.0Hz,2H),7.05(d,J=4.0Hz,1H),6.92-6.96(m,J=8.0Hz,2H),6.72(s,2H),6.55(d,J=8.0Hz,2H),5.12(s,1H),4.74(s,2H),4.11-4.07(m,J=8.0Hz,1H),3.83-3.88(m,J=8.0Hz,1H),3.34(d,J=16.0Hz,1H),3.00(d,J=16.0Hz,1H),2.11(s,6H),0.97(t,J=8.0Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ172.13,148.19,147.31,139.32,135.11,133.66,133.64,129.84,129.75,128.51,127.51,126.51,122.67,72.36,61.67,38.78,20.47,19.96,13.44.
4g的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ8.09(d,J=7.0Hz,2H),7.41(d,J=7.0Hz,2H),7.23(m,J=13.1Hz,2H),7.17-7.15(m,3H),6.97(m,2H),6.83(m,J=5.8Hz,2H),5.59(d,J=7.3Hz,1H),4.58(s,1H),4.06-3.99(m,3H),3.83(d,J=11.3Hz,1H),3.56(d,J=11.3Hz,1H),1.09(t,J=5.7Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ172.02,147.50,147.34,144.08,135.23,130.19,129.64,128.17,127.97,127.02,122.85,118.69,115.73,73.89,69.84,62.51,36.71,29.69,13.88.
4h的表征:
1HNMR(400MHz,CDCl3,25℃,TMS)δ8.10(d,J=8.8Hz,2H),7.49(d,J=8.7Hz,2H),7.13(d,J=3.0Hz,3H),6.91-6.86(m,2H),6.75-6.70(m,2H),6.63-6.58(m,2H),5.51(s,1H),4.26(s,1H),4.21(s,1H),3.96-3.88(m,3H),3.77(mJ=10.7,7.2Hz,1H),3.36(d,J=14.2Hz,1H),2.94(d,J=14.2Hz,1H),1.33(t,J=7.0Hz,3H),0.83(t,J=7.2Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ172.91,145.60,136.99,134.19,129.00,127.79,127.26,126.11,121.65,116.85,115.43,114.65,73.77,67.81,62.92,60.79,36.49,28.69,13.94,12.49.
4i的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ8.14(d,J=8.0Hz,2H),7.54(d,J=8.7Hz,2H),7.20(d,J=4.0Hz,3H),6.96(s,2H),6.81-6.78(mJ=8.0Hz,2H),6.69(m,J=8.0Hz,2H),5.58(s,1H),4.40(s,1H),4.33(s,1H),4.01-3.96(m,J=8.0Hz,1H),3.87-3.82(m,J=8.0Hz,1H),3.43(s,3H),3.41(d,J=12.0Hz,1H),3.04d,J=12.0Hz,1H),0.90(t,J=8.0Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ173.79,153.13,147.37,137.99,135.13,129.90,128.70,128.17,127.02,122.57,117.69,114.71,74.65,68.73,61.75,55.33,37.33,13.44.
4j的表征:
1HNMR(400MHz,CDCl3,25℃,TMS)δ8.09(d,J=8.6Hz,2H),7.43(d,J=8.6Hz,2H),7.16(d,J=5.1Hz,3H),6.98-6.93(m,2H),6.88-6.74(m,4H),5.50(d,J=8.8Hz,1H),5.35(s,1H),4.27(d,J=8.9Hz,1H),4.02-3.87(m,4H),3.75(d,J=14.0Hz,1H),3.52(d,J=14.0Hz,1H),1.22(t,J=6.9Hz,3H),1.01(t,J=7.1Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ171.55,146.51,146.28,134.27,133.51,129.25,127.11,125.92,121.69,119.93,117.29,112.45,110.64,73.43,68.56,63.20,61.12,36.17,28.69,13.83.12.69.
4k的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ8.10(d,J=8.0Hz,2H),7.41(d,J=8.0Hz,2H),6.86-6.76(m,J=8.0Hz,3H),6.68(m,J=8.0Hz,2H),5.60(d,J=4.0Hz,1H),4.45(m,2H),4.22-4.16(d,J=8.0Hz,2H),3.80(s,3H),1.39(s,3H),1.11(t,J=8.0Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ176.59,147.41,146.06,134.51,128.54,122.40,121.01,118.60,112.40,110.20,73.11,63.13,62.00,55.50,19.45,13.81.
4l的表征:
1HNMR(400MHz,CDCl3,25℃,TMS)δ8.19(d,J=8.4Hz,2H),7.56(d,J=8.3Hz,2H),6.84(s,2H),5.18(s,1H),4.89(s,1H),4.85(s,1H),4.01(dd,J=10.5,7.2Hz,1H),3.55(dd,J=10.5,7.2Hz,1H),2.31(s,6H),2.25(s,3H),1.84-1.71(m,1H),1.64-1.56(m,1H),0.85(t,J=7.1Hz,4H),0.74-0.58(m,1H),0.50(t,J=7.2Hz,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ172.61,148.27,147.37,139.12,133.46,133.03,129.76,128.18,122.75,71.61,63.31,33.75,20.52,19.91,17.18,14.40,13.8408.
4m的表征:
1H NMR(400MHz,CDCl3,25℃,TMS)δ8.22(dd,J=12.0,8.8Hz,2H),7.62(d,J=8.1Hz,2H),6.92-6.61(m,3H),6.44(d,J=8.3Hz,1H),5.15(dd,J=41.7,24.8Hz,2H),4.24(d,J=79.8Hz,1H),3.87(s,3H),3.48(d,J=37.2Hz,1H),1.33(s,6H),1.24(s,3H).
13C NMR(400MHz,CDCl3,25℃,TMS)δ147.86,147.46,136.15,127.59,127.11,123.39,121.05,118.86,111.57,110.11,83.10,77.34,77.03,76.71,73.46,73.13,63.82,55.61,27.85.
实施例14 本发明β-羟基-α-氨基酸衍生物4a、4b、4f、4g、4k、4l、4m对蛋白酪氨酸磷酸酯酶活性的抑制
PTP1B是第一个被鉴定的蛋白酪氨酸磷酸酯酶(protein tyrosinephosphatase),通过PTP1B剔除的老鼠实验表明,PTP1B通过对胰岛素受体的脱磷酰化,进而在调节胰岛素敏感性和脂肪代谢过程中起着非常重要的作用。因而,选择性的、高活性的PTP1B抑制剂在糖尿病和肥胖症的治疗中有重要的价值。
筛选方法:
Protocol id:25
Protocol name:PTP1B activity assay,absorbance
仪器:VERSAmax(Molecular Devices,USA).
材料:PTP1B,本实验室应用大肠杆菌表达系统得到GST融合蛋白。
底物,pNPP.
过程:采用光吸收检测法,在96孔或384孔平底透明微孔板中检测酶活性。底物pNPP经PTP1B水解得到的游离产物在405nm处有很强的光吸收。通过酶标仪监测405nm处光吸收强度的变化,计算得到反应初速度。实验中采用的对照化合物为齐墩果酸。
样品处理:各样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。
数据处理及结果说明:初筛选择单浓度条件下,例如20μg/ml,对样品的活性进行测试。以上述实施例制得的产物作为各样品。对于在一定条件下表现出活性的样品,例如,抑制率%Inhibition大于50,测试活性剂量依赖关系,即IC50/EC50值,通过样品活性对样品浓度进行非线性拟和得到,计算所用软件为Graphpad Prism4,拟合所使用的模型为sigmoidal dose-response(varible slope),对于大多数抑制剂筛选模型,将拟合曲线底部和顶部设定为0和100。一般情况下,每个样品在测试中均设置复孔(n≥2),在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。
实验结果见下表2,实验结果表明,本发明β-羟基-α-氨基酸衍生物均可有效抑制蛋白酪氨酸磷酸酯酶。较佳地,本发明β-羟基-α-氨基酸衍生物4a、4b、4g、4l对蛋白酪氨酸磷酸酯酶具有更佳的活性抑制效果。可见,本发明β-羟基-α-氨基酸衍生物可作为有效的蛋白酪氨酸磷酸酯酶抑制剂应用于医药领域。
表2
ID | 样品编号 | 浓度 | 类型 | 单位 | 结果 | 误差 | 备注 |
1 | 4a | 20μg/mL | %Inhibition | percent | 56.35 | 19.00 | |
2 | 4a | IC50 | μg/mL | 10.04 | 0.62 | ||
3 | 4b | 20μg/mL | %Inhibition | percent | 85.08 | 1.42 | |
4 | 4b | IC50 | μg/mL | 5.73 | 0.74 | ||
5 | 4f | 20μg/mL | %Inhibition | percent | 26.08 | 2.39 | |
6 | 4g | 20μg/mL | %Inhibition | percent | 53.53 | 3.20 | |
7 | 4g | IC50 | μg/mL | 14.92 | 1.98 | ||
8 | 4k | 20μg/mL | %Inhibition | percent | 7.94 | 9.91 | |
9 | 4l | 20μg/mL | %Inhibition | percent | 71.24 | 8.09 | |
10 | 4l | IC50 | μg/mL | 14.46 | 1.38 | ||
11 | 4m | 20μg/mL | %Inhibition | percent | 40.10 | 11.41 |
Claims (9)
1.一种α-氨基-β-羟基酸酯衍生物,其特征在于,其结构如式(I)所示:
其中,
R1为苄基、甲基、正丙基、氢原子;
R2为乙基、叔丁基;
Ar1为邻甲氧基苯基、2,4,6-三甲基苯基、苯基、对乙氧基苯基、邻乙氧基苯基、对甲氧基苯基;
Ar2为对硝基苯基、对溴苯基、间溴苯基、邻溴苯基、对氰基苯基、苯基、对甲氧基苯基;
其中,
所述α-氨基-β-羟基酸酯衍生物不包括以及式(I)中基团取代如下的化合物:R1=H,R2=乙基,Ar1=苯基或邻甲氧基苯基,Ar2=对硝基苯基;R1=H,R2=乙基,Ar1=对甲氧基苯基,Ar2=苯基。
2.一种如权利要求1中式(I)所示的α-氨基-β-羟基酸酯衍生物的制备方法,其特征在于,以烷基重氮酯1、芳胺2与芳醛3为原料,以一价金属铑[Rh(COD)Cl2]为催化剂,以有机溶剂为溶剂,在室温条件下经过一步反应,柱层析提纯即得到式(I)所示的α-氨基-β-羟基酸酯衍生物;所述制备方法的反应式为:
3.如权利要求2所述的制备方法,其特征在于,所述芳醛:芳胺:烷基重氮酯:一价金属铑[Rh(COD)Cl2]的摩尔比为1.0:1.2:2.0:0.01。
4.如权利要求2所述的制备方法,其特征在于,所述芳醛为对硝基苯甲醛、对溴苯甲醛、间溴苯甲醛、邻溴苯甲醛、对氰基苯甲醛、苯甲醛、对甲氧基苯甲醛。
5.如权利要求2所述的制备方法,其特征在于,所述芳胺为邻甲氧基苯胺、2,4,6-三甲基苯胺、苯胺、对乙氧基苯胺、邻乙氧基苯胺、对甲氧基苯胺。
6.如权利要求2所述的制备方法,其特征在于,所述烷基重氮酯为苄基重氮乙酯、甲基重氮乙酯、正丙基重氮乙酯、重氮叔丁酯。
7.如权利要求2所述的制备方法,其特征在于,所述溶剂为二氯甲烷。
8.一种如权利要求1中式(I)所示的α-氨基-β-羟基酸酯衍生物在制备蛋白酪氨酸磷酸酯酶活性抑制剂中的应用。
9.如权利要求8所述的应用,其特征在于,式(I)所示的α-氨基-β-羟基酸酯衍生物作为蛋白酪氨酸磷酸酯酶抑制剂。
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