CN114890908A - 一种γ位三氟甲基氨基酸衍生物及制备方法 - Google Patents
一种γ位三氟甲基氨基酸衍生物及制备方法 Download PDFInfo
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- CN114890908A CN114890908A CN202210590236.XA CN202210590236A CN114890908A CN 114890908 A CN114890908 A CN 114890908A CN 202210590236 A CN202210590236 A CN 202210590236A CN 114890908 A CN114890908 A CN 114890908A
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- Prior art keywords
- trifluoromethyl
- amino acid
- gamma
- acid derivative
- aryl
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 238000006243 chemical reaction Methods 0.000 claims abstract description 74
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- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- HVAPLSNCVYXFDQ-UHFFFAOYSA-N 3,3-dimethyl-1-(trifluoromethyl)-1$l^{3},2-benziodoxole Chemical compound C1=CC=C2C(C)(C)OI(C(F)(F)F)C2=C1 HVAPLSNCVYXFDQ-UHFFFAOYSA-N 0.000 claims description 62
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 15
- 125000003118 aryl group Chemical group 0.000 claims description 15
- 239000003446 ligand Substances 0.000 claims description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
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- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- PNNRZXFUPQQZSO-UHFFFAOYSA-N pyran Chemical compound [CH]1OC=CC=C1 PNNRZXFUPQQZSO-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- MECAHFSQQZQZOI-UHFFFAOYSA-N tert-butyl 3-methylideneazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(=C)C1 MECAHFSQQZQZOI-UHFFFAOYSA-N 0.000 description 1
- PDTZMULNKGUIEJ-UHFFFAOYSA-N tert-butyl 4-methylidenepiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=C)CC1 PDTZMULNKGUIEJ-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005979 thermal decomposition reaction Methods 0.000 description 1
- HYWCXWRMUZYRPH-UHFFFAOYSA-N trimethyl(prop-2-enyl)silane Chemical compound C[Si](C)(C)CC=C HYWCXWRMUZYRPH-UHFFFAOYSA-N 0.000 description 1
- 229960002703 undecylenic acid Drugs 0.000 description 1
- 229960000834 vinyl ether Drugs 0.000 description 1
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Abstract
本发明公开了一种γ位三氟甲基氨基酸衍生物及制备方法。所示氨基酸衍生物制备方法包括:将三氟甲基源、N‑芳基甘氨酸衍生物、烯烃加入有机溶剂中,然后加入催化剂或光引发剂,发生串联反应得到γ位三氟甲基氨基酸衍生物;其中,所述烯烃不包括共轭烯烃。本发明提供的制备方法以甘氨酸衍生物为底物,以烯烃作为烷基化主体,加入三氟甲基源,在催化剂或光引发剂的作用下,将甘氨酸衍生物直接转化为γ位三氟甲基的氨基酸衍生物。本发明不需要添加当量的氧化剂、原料简单易得,反应条件温和,底物范围广,产物结构类型丰富,产物应用范围广,产率和化学选择性高。
Description
技术领域
本发明属于非天然氨基酸领域,更具体地,涉及一种γ位三氟甲基氨基酸衍生物及制备方法。
背景技术
氟代化合物具有优异的理化性质,在氨基酸中引入含氟基团以改善其理化性质的研究已经成为了生物、化学以及多种交叉学科的热点研究课题。例如,氟代的异亮氨酸和苯丙氨酸在合成多肽或蛋白质后能够极大地提升热稳定性。另一方面在分子中引入含氟基团能大大提升分子的脂溶性,这种性质在以大脑为靶器官的药物分子设计中经常使用。
目前,现有的含氟氨基酸制备方法通常为通过不同的单体合成含氟氨基酸,其通常需要化学计量的氧化剂,造成原子利用率低,产生大量副产物或预先在分子中组装官能团然后通过过渡金属催化交叉偶联,反应条件苛刻(例如高于100℃),且反应底物的选择范围通常比较有限,普适性不强等技术问题。
发明内容
针对现有技术的以上缺陷或改进需求,本发明提供了一种γ位三氟甲基氨基酸衍生物及制备方法,其目的在于不使用化学计量的氧化剂的条件下,以烯烃为烷基化主体直接实现甘氨酸的α位C-H烷基化,由此解决现有的含氟氨基酸制备方法通常需要化学计量的氧化剂或预先在分子中组装官能团然后通过过渡金属催化交叉偶联,反应条件苛刻,且反应底物的选择范围通常比较有限,普适性不强等技术问题。
为实现上述目的,按照本发明的一个方面,提供了一种γ位三氟甲基氨基酸衍生物的制备方法,所述方法包括:将三氟甲基源、N-芳基甘氨酸衍生物、烯烃加入有机溶剂中,然后加入催化剂或光引发剂,发生串联反应得到γ位三氟甲基氨基酸衍生物;其中,所述烯烃不包括共轭烯烃。
优选地,所述N-芳基甘氨酸衍生物包括N-芳基甘氨酸酯、N-芳基氨基酮以及N-端芳基保护的甘氨酸多肽;所述三氟甲基源通过下式I或II表示:
其中,R为芳环上单取代或多取代的氢原子、芳基、烷基或卤素。
优选地,所述三氟甲基源为1-(三氟甲基)-1,2-苯碘酰-3(1H)-酮或3,3-二甲基-1-(三氟甲基)-1,2-苯并碘氧杂戊环。
优选地,所述催化剂包括过渡金属盐和配体,所述过渡金属盐包括Fe(NTf2)2、CuCl、CuBr、CuI、Cu(OTf)2、Cu(CH3CN)4PF6、CoCl2,Co(OAc)2和Co(acac)2中的一种,所述配体包括吡啶双噁唑啉类配体、吡啶噁唑啉类配体、双噁唑啉类配体、连噁唑啉类配体或Xantphos中的一种;当采用加入催化剂时,所述串联反应条件为在惰性气体保护下,0-60℃的温度下进行;所述光引发剂包括Ir(ppy)3、Ru(bpy)3Cl2、曙红、Mes-Acr+中的一种;当采用加入光引发剂时,所述串联反应条件为在惰性气体保护下,在波长为420-500nm的蓝光照射下进行。
优选地,所述烯烃、N-芳基甘氨酸衍生物、三氟甲基源与光引发剂的摩尔比为(1.0-3.0):1:(1.0-2.0):(0.002-0.1)。
优选地,所示烯烃、N-芳基甘氨酸衍生物、三氟甲基源、过渡金属盐与配体的摩尔比为(1.0-3.0):1:(1.0-2.0):(0.01-0.1):(0.012-0.12)。
优选地,所述有机溶剂为三氟甲苯、甲苯、对二甲苯、间二甲苯、邻二甲苯、乙酸乙酯、乙醚、甲基叔丁基醚、二氯甲烷、1,2-二氯乙烷和乙腈中的一种或多种。
按照本发明的另一个方面,提供一种γ位三氟甲基氨基酸衍生物如下所示:
其中,Ar为芳基;R1、R2和R3为各自独立地为氢原子、芳基、烷基、烷氧基或氨基。
按照本发明的又一个方面,提供一种γ位三氟甲基氨基酸盐酸盐的制备方法,所述方法包括:将硝酸铈铵加入γ位三氟甲基氨基酸衍生物中,将γ位三氟甲基氨基酸衍生物的芳基进行氧化脱除,然后利用盐酸HCl进行酸化处理,得到γ位三氟甲基非天然氨基酸盐酸盐。
按照本发明的再一个方面,提供一种γ位三氟甲基氨基酸盐酸盐如下所示:
其中,R1、R2和R3为各自独立地为氢原子、芳基、烷基、烷氧基或氨基。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,至少能够取得下列有益效果。
(1)本发明提供的制备方法以甘氨酸衍生物为底物,以烯烃作为烷基化主体,加入三氟甲基源,在催化剂或光引发剂的作用下,将甘氨酸衍生物直接转化为γ位三氟甲基的氨基酸衍生物。解决了现有的含氟氨基酸制备方法通常需要化学计量的氧化剂或预先在分子中组装官能团然后再交叉偶联,反应条件苛刻,且反应底物的选择范围通常比较有限,普适性不强等技术问题。
(2)本发明制备过程中使用了三氟甲基的三价碘试剂,利用此类高价碘试剂的氧化性使反应不断循环,从而仅仅添加催化剂量的金属盐或光引发剂,即能使甘氨酸衍生物直接转化为γ位三氟甲基的氨基酸衍生物。
(3)本发明制备得到的γ位三氟甲基的氨基酸衍生物能进一步衍生制备氨基醇、氨基酸酯盐酸盐等。
(4)本发明γ位三氟甲基的氨基酸衍生物的制备方法具有不需要添加当量的氧化剂、原料简单易得,反应条件温和,底物范围广,产物结构类型丰富,产物应用范围广,产率和化学选择性高等优点。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。此外,下面所描述的本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
本发明提供一种γ位三氟甲基氨基酸衍生物的制备方法,所述方法包括:将三氟甲基源、N-芳基甘氨酸衍生物、烯烃加入有机溶剂中、然后加入催化剂或光引发剂,发生串联反应得到γ位三氟甲基氨基酸衍生物;其中,所述烯烃不包括共轭烯烃。
示例性地:本发明的合成路线如下:
其中,R1、R2和R3为各自独立地为氢原子、芳基、烷基、烷氧基或氨基。示例性地,烷基可以为C数1-200的烷基,烯烃可以为含有碳碳双键,且C数1-200。该些示例不应理解为对本发明的限制。
其串联反应原理为:催化剂将高价碘试剂单电子还原为三氟甲基自由基,然后三氟甲基自由基与烯烃加成生成烷基自由基,而高价态的催化剂将甘氨酸酯两次氧化为亚胺,最后烷基自由基与亚胺加成得到γ位三氟甲基的氨基酸衍生物。
以下为实施例:
需要说明的是,实施例2-58以及对比例1-2在反应结束后,对产品的后处理,均与实施例1相同。
实施例1
氩气气氛下,在Schlenk反应管中加入4-苯基-1-丁烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Cu(CH3CN)4PF6(0.002mmol)、吡啶双噁唑啉(0.0024mmol)、干燥的二氯乙烷(1mL),室温下搅拌6h(TLC监测)。反应结束后,加入饱和硫代硫酸钠水溶液(1mL)和饱和碳酸氢钠水溶液(1mL)结束反应,以二氯甲烷萃取(2mL×3),无水硫酸钠干燥,减压除去溶剂得到粗产品,以石油醚:乙酸乙酯=50:1的混合溶剂作为展开剂,通过200-300目的硅胶柱层析分离得到产物1。产率为93%。1H NMR(400MHz,Chloroform-d)δ7.27–7.15(m,2H),7.15–7.04(m,3H),6.74–6.63(m,2H),6.59–6.50(m,2H),4.18–3.91(m,3H),3.89–3.68(m,1H),3.65(s,3H),3.64(s,1.5H),2.76–2.37(m,1.5H),2.29–1.97(m,2H),1.95–1.82(m,1H),1.73–1.52(m,1.5H),1.15(t,J=7.2Hz,1.5H),1.06(t,J=7.1Hz,1.5H);13C{1H}NMR(101MHz,Chloroform-d)δ173.0,172.9,153.4,153.2,141.2,141.0,140.7,128.6,128.5,128.5,128.3,127.2(q,J=276.9),126.2,126.1,116.2,115.8,115.0,114.9,61.5,61.4,60.6,60.3,55.7,55.7,35.8,34.9,34.3(q,J=27.7),34.2(q,J=27.9),33.0,32.9,32.7,31.6,14.2,14.2;19F NMR(376MHz,Chloroform-d)δ-63.6(t,J=11.3Hz,3F);高分辨质谱[ESI]:计算值为C22H26F3NNaO3 +[M+Na]+432.1757,实际测量值432.1760。
实施例2
氩气气氛下,在Schlenk反应管中加入1-辛烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、氯化亚铜(0.002mmol)、吡啶双噁唑啉(0.0024mmol)、干燥的二氯乙烷(1mL),0℃下搅拌6h(TLC监测)。最后通过200-300目的硅胶柱层析分离得到产物2。产率为95%。
1H NMR(400MHz,Chloroform-d)δ6.84–6.71(m,2H),6.70–6.57(m,2H),4.27–4.10(m,2H+1H),4.05–4.00(m,1H),4.00–3.77(m,1H),3.74(s,3H+3H),2.61–2.40(m,1H),2.33–2.22(m,1H),2.21–1.96(m,1H+1H),1.46–1.17(m,13H),0.95-0.75(m,3H);13C{1H}NMR(101MHz,Chloroform-d)δ173.1,173.1,153.3,153.1,141.3,140.8,127.2(q,J=276.4),116.1,115.7,114.9,114.9,61.3,61.3,60.6,60.2,55.7,55.7,36.0,35.6,34.2(q,J=27.6),34.1(q,J=28.2),31.6,31.6,30.7,29.6,29.2,29.1,26.8,26.4,22.6,14.2,14.2,14.0;19F NMR(376MHz,Chloroform-d)δ-63.82(t,J=11.2Hz),-63.89(t,J=11.5Hz);高分辨质谱[ESI]:计算值为C20H30F3NNaO3 +[M+Na]+412.2070,实际测量值412.2076。
实施例3
氩气气氛下,在Schlenk反应管中加入丙烯(0.6mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、溴化亚铜(0.002mmol)、连噁唑啉(0.0024mmol)、干燥的二氯乙烷(1mL),0℃下搅拌6h(TLC监测)。最后通过柱层析分离得到产物3。产率为96%。
实施例4
氩气气氛下,在Schlenk反应管中加入烯丙苯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、碘化亚铜(0.002mmol)、双噁唑啉(0.0024mmol)、干燥的二氯乙烷(1mL),60℃油浴下搅拌6h(TLC监测)。最后通过层析分离得到产物4。产率为93%。
1H NMR(400MHz,Chloroform-d)δ7.38–7.10(m,5H),6.76–6.64(m,2H),6.55–6.42(m,2H),4.26–4.06(m,2H+1H),4.05–3.80(m,1H+1H),3.70(s,3H),3.69(s,3H),2.99–2.86(m,1H),2.83–2.65(m,1H+1H),2.65–2.53(m,1H),2.53–2.33(m,1H),2.20–2.05(m,1H),2.05–1.89(m,1H),1.28(t,J=7.1Hz,3H),1.21(t,J=7.1Hz,3H);13C{1H}NMR(101MHz,Chloroform-d)δ173.0,172.8,153.2,153.1,140.9,140.7,138.5,138.3,129.4,129.3,128.7,127.1(q,J=276.9Hz),127.0(q,J=276.9Hz),126.9,115.9,115.8,114.9,61.5,61.4,59.3,59.1,55.6,37.8(q,J=2.3Hz),37.5(q,J=2.2Hz),37.1,35.9,33.7(q,J=28.3Hz),33.5(q,J=28.1Hz),14.3,14.2;19F NMR(376MHz,Chloroform-d)δ-63.42(t,J=11.2Hz),-63.53(t,J=11.2Hz);高分辨质谱[ESI]:计算值为C21H24F3NNaO3 +[M+Na]+418.1600,实际测量值为418.1597。
实施例5
氩气气氛下,在Schlenk反应管中加入烯丙基苄醚(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、CuI(0.002mmol)、Xantphos(0.0024mmol)、干燥的二氯甲烷(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物5。产率为81%。
1H NMR(400MHz,Chloroform-d)δ7.45–7.28(m,5H),6.82–6.68(m,2H+2H),6.65–6.56(m,2H),4.58–4.43(m,2H),4.24(d,J=4.3Hz,1H),4.19(d,J=4.5Hz,1H),4.16–4.06(m,2H),3.78–3.69(m,3H),3.67–3.54(m,2H),2.71–2.53(m,1H),2.53–2.35(m,2H),2.32–2.17(m,2H),1.25–1.14(m,3H);13C{1H}NMR(101MHz,Chloroform-d)δ172.60,172.4,153.7,153.1,137.7,137.6,128.8,128.4,127.8,127.5,127.7,127.2(q,J=278.1Hz),127.0(q,J=277.0Hz),116.5,115.7,114.8,73.5,73.3,69.3,68.9,61.6,61.3,60.1,59.4,55.7,36.5,35.8,32.7(q,J=28.5Hz),31.8(q,J=28.7Hz),14.2,14.1;19F NMR(376MHz,Chloroform-d)δ-64.06(t,J=11.3Hz),-64.16(t,J=11.4Hz);高分辨质谱[ESI]:计算值为C22H26F3NNaO4 +[M+Na]+448.1706,实际测量值为448.1700。
实施例6
氩气气氛下,在Schlenk反应管中加入(but-3-eN-1-yloxy)(tert-butyl)dimethylsilane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Ir(ppy)3(0.002mmol)、干燥的乙腈(1mL),然后将反应管放置在420nm蓝光的照射下,室温下搅拌12h(TLC监测)。最后通过柱层析分离得到产物6。产率为95%。
实施例7
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(pent-4-eN-1-yloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Ru(bpy)3Cl2(0.002mmol)、干燥的乙腈(1mL),然后将反应管放置在450nm蓝光的照射下,室温下搅拌12h(TLC监测)。最后通过柱层析分离得到产物7。产率为97%。
实施例8
氩气气氛下,在Schlenk反应管中加入4-戊烯醇(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、曙红(0.02mmol)、干燥的乙腈(1mL),然后将反应管放置在500nm可见光的照射下,室温下搅拌12h。最后通过柱层析分离得到产物8。产率为94%。
实施例9
氩气气氛下,在Schlenk反应管中加入1-十一烯酸(0.24mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Mes-Acr+(0.002mmol)、干燥的乙腈(1mL),然后将反应管放置在450nm蓝光的照射下,室温下搅拌12h(TLC监测)。最后通过柱层析分离得到产物9。产率为95%。
实施例10
氩气气氛下,在Schlenk反应管中加入2-(pent-4-eN-1-yl)isoindoline-1,3-dione(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.02mmol)、吡啶噁唑啉(0.024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物10。产率为92%。
实施例11
氩气气氛下,在Schlenk反应管中加入4-戊烯酰苯胺(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物11。产率为86%。
实施例12
氩气气氛下,在Schlenk反应管中加入2-(but-3-eN-1-yl)-2-methyl-1,3-dioxolane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、CuI(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物12。产率为77%。
实施例13
氩气气氛下,在Schlenk反应管中加入三甲基烯丙基硅烷(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物13。产率为95%。
实施例14
氩气气氛下,在Schlenk反应管中加入3,3-二甲基-1-丁烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物14。产率为54%。
实施例15
氩气气氛下,在Schlenk反应管中加入5-咔唑基-1-戊烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物15。产率为57%。
实施例16
氩气气氛下,在Schlenk反应管中加入3-丁烯酸(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物16。产率为66%。
实施例17
氩气气氛下,在Schlenk反应管中加入ethyl but-3-enoylglycinate(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物17。产率为64%。
实施例18
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物18。产率为85%。
实施例19
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl((2-methylallyl)oxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物19。产率为95%。
实施例20
氩气气氛下,在Schlenk反应管中加入N-Boc-4-亚甲基哌啶(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、连噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物20。产率为90%。
实施例21
氩气气氛下,在Schlenk反应管中加入1-Boc-3-亚甲基氮杂环丁烷(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、双噁唑啉(0.0024mmol)、三氟甲苯(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物21。产率为73%。
实施例22
氩气气氛下,在Schlenk反应管中加入环己烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物22。产率为86%。
实施例23
氩气气氛下,在Schlenk反应管中加入1-甲基环己烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物23。产率为69%。
实施例24
氩气气氛下,在Schlenk反应管中加入降冰片烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物24。产率为92%。
实施例25
氩气气氛下,在Schlenk反应管中加入1,5-环辛二烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、甲苯(1mL),室温下搅拌6h(TLC监测)。
最后通过柱层析分离得到产物25。产率为83%。
实施例26
氩气气氛下,在Schlenk反应管中加入β-蒎烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物26。产率为99%。
实施例27
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰苯胺(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物27。产率为94%。
实施例28
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰异亮氨醇胺(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、邻二甲苯(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物28。产率为88%。
实施例29
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)苯乙酮(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物29。产率为83%。
实施例30
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物30。产率为84%。
实施例31
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰苯丙氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物31。产率为78%。
实施例32
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰甲硫氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物32。产率为91%。
实施例33
氩气气氛下,在Schlenk反应管中加入2-甲基丙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰缬氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、对二甲苯(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物33。产率为88%。
实施例34
氩气气氛下,在Schlenk反应管中加入1-((4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy)methyl)tetrahydrofuraN-2-yl)-5-methyl-3-(pent-4-eN-1-yl)pyrimidine-2,4(1H,3H)-dione(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物34。产率为75%。
实施例35
氩气气氛下,在Schlenk反应管中加入2,2,7,7-tetramethyl-5-(((2-methylallyl)oxy)methyl)tetrahydro-5H-bis([1,3]dioxolo)[4,5-b:4',5'-d]pyran(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Cu(CH3CN)4PF6(0.002mmol)、吡啶噁唑啉(0.0024mmol)、甲基叔丁基醚(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物35。产率为82%。
实施例36
氩气气氛下,在Schlenk反应管中加入(8R,9S)-13-methyl-3-(pent-4-eN-1-yloxy)-6,7,8,9,11,12,13,14,15,16-decahydrospiro[cyclopenta[a]phenanthrene-17,2'-[1,3]dioxolane](0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Fe(NTf2)2(0.002mmol)、吡啶噁唑啉(0.0024mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物36。产率为84%。
实施例37
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物37。产率为84%。
实施例38
氩气气氛下,在Schlenk反应管中加入醋酸乙烯酯(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.24mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物38。产率为69%。
实施例39
氩气气氛下,在Schlenk反应管中加入三甲基乙烯氧基硅烷(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.24mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物39。产率为40%。
实施例40
氩气气氛下,在Schlenk反应管中加入乙烯基乙醚(0.6mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(acac)2(0.02mmol)、二氯甲烷(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物40。产率为74%。
实施例41
氩气气氛下,在Schlenk反应管中加入二氢呋喃(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(acac)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物41。产率为72%。
实施例42
氩气气氛下,在Schlenk反应管中加入二氢吡喃(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物42。产率为68%。
实施例43
氩气气氛下,在Schlenk反应管中加入N-乙烯基吡咯烷酮(0.3mmol)、N-(4-氯苯基)氨基苯乙酮(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物43。产率为92%。
实施例44
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(prop-1-eN-1-yloxy)silane(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物44。产率为70%。
实施例45
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(prop-1-eN-2-yloxy)silane(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物45。产率为77%。
实施例46
氩气气氛下,在Schlenk反应管中加入tert-butyl(cyclobut-1-eN-1-yloxy)dimethylsilane(0.3mmol)、N-(4-氯苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物46。产率为68%。
实施例47
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-溴苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物47。产率为77%。
实施例48
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-氟苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、间二甲苯(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物48。产率为66%。
实施例49
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌6h(TLC监测)。最后通过柱层析分离得到产物49。产率为79%。
实施例50
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物50。产率为74%。
实施例51
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(3-甲基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、乙醚(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物51。产率为75%。
实施例52
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(3-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物52。产率为50%。
实施例53
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-苯基甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、CoCl2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物53。产率为72%。
实施例54
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酰苯胺(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物54。产率为70%。
实施例55
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-氯基苯基)氨基苯乙酮(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物55。产率为79%。
实施例56
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸叔丁酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物56。产率为69%。
实施例57
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酰甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、乙酸乙酯(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物57。产率为81%。
实施例58
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酰苯丙氨酸甲酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。最后通过柱层析分离得到产物58。产率为75%。
实施例59
0℃下向搅拌的CAN(硝酸铈铵,6mmol,溶于10.5ml水)溶液中缓慢加入2-甲基丙烯、N-(4-甲氧基)甘氨酸乙酯、Togni I试剂三组分串联的产物(1.5mmol溶于4.5ml乙腈)溶液。将反应在相同温度下保持搅拌2小时,然后用饱和碳酸钠水溶液将其调节至碱性。然后将混合物用二氯甲烷(10mL×3)萃取3次,用饱和食盐水洗涤,再用无水硫酸钠干燥并真空浓缩。然后将残余物溶解在乙醚(5mL)中,将5mL 1M HCl(aq.)缓慢加入到上述溶液中,同时剧烈搅拌。除去有机相后,水相用乙醚(5mL×3)洗涤3次。最后减压除去水,然后将残余物真空干燥,得到米黄色粉末状的氨基酯盐酸盐59。两步产率为86%。
对比例1
氩气气氛下,在Schlenk反应管中加入苯乙烯(0.3mmol)、N-(4-甲氧基苯基)甘氨酰苯丙氨酸甲酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),室温下搅拌0.5h(TLC监测)。从反应结果上看,该反应并不能得到三者串联的产物,目标产物产率为0%。分析可能是由于共轭烯烃氧化电位较低导致的。
对比例2
氩气气氛下,在Schlenk反应管中加入tert-butyldimethyl(vinyloxy)silane(0.3mmol)、N-(4-甲氧基苯基)甘氨酸乙酯(0.2mmol)、Togni试剂(0.3mmol)、Co(OAc)2(0.02mmol)、DMF(1mL),100℃下搅拌0.5h(TLC监测)。从反应结果上看,该反应并不能得到三者串联的产物,目标产物产率为0%。分析可能是由于温度较高,Togni试剂自身热分解导致的。
以上实施例的结构如下所示:
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.一种γ位三氟甲基氨基酸衍生物的制备方法,其特征在于,所述方法包括:
将三氟甲基源、N-芳基甘氨酸衍生物、烯烃加入有机溶剂中,然后加入催化剂或光引发剂,发生串联反应得到γ位三氟甲基氨基酸衍生物;
其中,所述烯烃不包括共轭烯烃。
3.如权利要求2所述的制备方法,其特征在于,所述三氟甲基源为1-(三氟甲基)-1,2-苯碘酰-3(1H)-酮或3,3-二甲基-1-(三氟甲基)-1,2-苯并碘氧杂戊环。
4.如权利要求1-3任一项所述的制备方法,其特征在于,所述催化剂包括过渡金属盐和配体,所述过渡金属盐包括Fe(NTf2)2、CuCl、CuBr、CuI、Cu(OTf)2、Cu(CH3CN)4PF6、CoCl2,Co(OAc)2和Co(acac)2中的一种,所述配体包括吡啶双噁唑啉类配体、吡啶噁唑啉类配体、双噁唑啉类配体、连噁唑啉类配体或Xantphos中的一种;当采用加入催化剂时,所述串联反应条件为在惰性气体保护下,0-60℃的温度下进行;所述光引发剂包括Ir(ppy)3、Ru(bpy)3Cl2、曙红、Mes-Acr+中的一种;当采用加入光引发剂时,所述串联反应条件为在惰性气体保护下,在波长为420-500nm的蓝光照射下进行。
5.如权利要求1-3任一项所述的制备方法,其特征在于,所述烯烃、N-芳基甘氨酸衍生物、三氟甲基源与光引发剂的摩尔比为(1.0-3.0):1:(1.0-2.0):(0.002-0.1)。
6.如权利要求4所述的制备方法,其特征在于,所示烯烃、N-芳基甘氨酸衍生物、三氟甲基源、过渡金属盐与配体的摩尔比为(1.0-3.0):1:(1.0-2.0):(0.01-0.1):(0.012-0.12)。
7.如权利要求1-3任一项所述的制备方法,其特征在于,所述有机溶剂为三氟甲苯、甲苯、对二甲苯、间二甲苯、邻二甲苯、乙酸乙酯、乙醚、甲基叔丁基醚、二氯甲烷、1,2-二氯乙烷和乙腈中的一种或多种。
9.一种γ位三氟甲基氨基酸盐酸盐的制备方法,其特征在于,所述方法包括:根据权利要求1-7任一项所述的制备方法制备得到γ位三氟甲基氨基酸衍生物后,将硝酸铈铵加入所述γ位三氟甲基氨基酸衍生物中,将γ位三氟甲基氨基酸衍生物的芳基进行氧化脱除,然后利用盐酸HCl进行酸化处理,得到γ位三氟甲基非天然氨基酸盐酸盐。
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