WO2016197580A1 - α-烷基支链取代的α-氨基酸衍生物的合成方法 - Google Patents

α-烷基支链取代的α-氨基酸衍生物的合成方法 Download PDF

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WO2016197580A1
WO2016197580A1 PCT/CN2015/098519 CN2015098519W WO2016197580A1 WO 2016197580 A1 WO2016197580 A1 WO 2016197580A1 CN 2015098519 W CN2015098519 W CN 2015098519W WO 2016197580 A1 WO2016197580 A1 WO 2016197580A1
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amino acid
acid derivative
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imine
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曾伟
肖新生
卢晓霞
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South China University of Technology SCUT
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/04—Formation of amino groups in compounds containing carboxyl groups
    • C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/28—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/14—Dithiocarbamic acids; Derivatives thereof
    • C07C333/18—Esters of dithiocarbamic acids
    • C07C333/24—Esters of dithiocarbamic acids having nitrogen atoms of dithiocarbamate groups bound to carbon atoms of six-membered aromatic rings

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  • the invention belongs to the field of organic synthesis, and in particular relates to a method for synthesizing ⁇ -alkyl branched-chain substituted ⁇ -amino acid derivatives.
  • Amino acids are not only the basic building blocks of proteins, but their derivatives are also important structural units of many natural products and drug molecules. Amino acids and their derivatives have important applications in the field of biomedicine. Amino acids are also precursors for the synthesis of many catalysts. Therefore, the synthesis methods of ⁇ -amino acid derivatives have been widely recognized.
  • the synthesis methods of the currently reported ⁇ -amino acid derivatives mainly include: first, hydrogenation of the imine under certain conditions by a reducing reagent to obtain a target product.
  • a reducing reagent for example, (1) H 2 is used as a reducing reagent; (2) Hantzsch ester is used as a reducing reagent; and (3) other reagents are used as a reducing agent.
  • the second is the target product obtained by adding an imine under certain conditions by an organometallic reagent.
  • organometallic reagent such as: (1) organoaluminum reagent; (2) organozinc reagent; (3) organoboron reagent.
  • the object of the present invention is to provide a simple and efficient method for synthesizing ⁇ -alkyl branched-chain substituted ⁇ -amino acid derivatives, and the raw materials used in the method are cheap and easy to obtain and have no Poison, the whole process is simple and easy.
  • a method for synthesizing an ⁇ -alkyl branched-substituted ⁇ -amino acid derivative comprising the steps of:
  • the product is separated and purified by column chromatography; the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.
  • the structure of the imine is as shown in the formula A
  • the structure of the olefin is as shown in the formula B
  • the structure of the 9-bbn is as shown in the formula C
  • the structure of the ⁇ -amino acid derivative is as shown in the formula D.
  • R 1 is 4-MeOC 6 H 4 , 2-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC 6 One of H 4 , 4-NO 2 C 6 H 4 , Ph, 4-COOEtC 6 H 4 or 1-naphthyl;
  • R 2 is n-butyl, cyclohexyl, Ph, 4-MeOC 6 H 4 , 4-MeC 6 H 4 , 3-MeC 6 H 4 , 4-ClC 6 H 4 , 4-BrC One of 6 H 4 , 4- t BuC 6 H 4 , 1-naphthyl or 2-thienyl;
  • the molar ratio of the olefin to 9-bbn is 1:1;
  • the molar ratio of the olefin to the imine is (1-3): 1, preferably 1.5: 1.
  • the transition metal salt is palladium dichloride, palladium acetate, palladium trifluoroacetate, palladium dichlorodiacetonitrile, palladium dichloroditriphenylphosphine, copper acetate, copper chloride, copper bromide, trifluoromethanesulfonate.
  • One of copper acid, cuprous chloride, cuprous bromide, cuprous iodide, cuprous cyanide or copper perchlorate, preferably cuprous cyanide has a high yield.
  • the base is one of Cs 2 CO 3 , NaOMe, NaO t Bu, LiOMe, Li 2 CO 3 , Na 2 CO 3 , NaOEt, K 2 CO 3 , LiO t Bu or KOEt, preferably Cs 2 CO 3
  • the yield is higher.
  • the organic solvent is toluene or 1,2-dichloroethane.
  • the method of the invention is simple and efficient, and the raw materials used are simple and easy to obtain and non-toxic.
  • the preparation method is not sensitive to water and air during the reaction.
  • the whole operation process is simple and easy, the steps are simple, and the product is easy to be purified.
  • an olefin and 9-bbn are used to form an alkyl boron reagent in situ, and the reaction conditions are mild, and a wide variety of olefins are available.
  • the existing synthesis methods all require strict anhydrous and anaerobic conditions, the reaction operation is complicated, the reaction needs to be carried out at a low temperature, and the refrigeration cost is high. While the present invention does not require anhydrous anaerobic conditions, the reaction can be carried out at room temperature or at a slightly higher temperature.
  • Figure 1 is a hydrogen spectrum of Compound 1.
  • Figure 3 is a hydrogen spectrum of Compound 2.
  • Figure 5 is a hydrogen spectrum of Compound 3.
  • Figure 6 is a carbon spectrum of Compound 3.
  • Figure 7 is a hydrogen spectrum of Compound 4.
  • Figure 8 is a carbon spectrum of Compound 4.
  • Figure 9 is a hydrogen spectrum of Compound 5.
  • Figure 10 is a carbon spectrum of Compound 5.
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:
  • a method for synthesizing an ⁇ -amino acid derivative comprising the steps of:

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

本发明公开了α-烷基支链取代的α-氨基酸衍生物的合成方法，该方法包括以下步骤：取烯烃与9-bbn在0-80℃下反应0.5-12h，然后加入亚胺，在过渡金属盐、碱和有机溶剂存在的情况下，于0-90℃下反应12-48h，生成α-氨基酸衍生物。本发明中采用烯烃与9-bbn原位生成烷基硼试剂，反应条件温和，烯烃可选种类多。同时现有合成方法都需要严格无水无氧条件，反应操作复杂，反应需要在低温下进行，制冷成本高。而本发明不需无水无氧条件，同时反应可以在室温或稍高一些的温度下进行。

Description

α-烷基支链取代的α-氨基酸衍生物的合成方法 技术领域
本发明属于有机合成领域，具体涉及α-烷基支链取代的α-氨基酸衍生物的合成方法。
背景技术
氨基酸不仅是蛋白质的基本构成单位，其衍生物还是很多天然产物和药物分子的重要结构单元。氨基酸及其衍生物在生物医药领域有着重要用途，氨基酸还是许多催化剂的合成前体，因此α-氨基酸衍生物的合成方法一直得到广泛的重视。
目前报道的α-氨基酸衍生物的合成方法主要有：一是通过还原试剂，在一定条件下对亚胺进行氢化作用得到目标产物。如：(1)以H2作为还原试剂；(2)以Hantzsch酯作为还原试剂；(3)以其他试剂作为还原剂。
二是通过有机金属试剂，在一定条件下对亚胺进行加成从而得到的目标产物。如：(1)有机铝试剂；(2)有机锌试剂；(3)有机硼试剂。
上述试剂制备难度高，保存条件苛刻，可选种类少。
发明内容
为了克服现有技术的缺点与不足，本发明的目的在于提供一种简便、高效的α-烷基支链取代的α-氨基酸衍生物的合成方法，该方法所用到的原料廉价易得且无毒，整个操作过程简单易行。
本发明的目的通过下述技术方案实现：
α-烷基支链取代的α-氨基酸衍生物的合成方法，包括以下步骤：
(1)取烯烃与9-硼双环(3,3,1)-壬烷(简称9-bbn)在0-80℃(优选60℃)下反应0.5-12h，然后加入亚胺，在过渡金属盐、碱和有机溶剂存在的情况下，于0-90℃(优选70℃)下反应12-48h，生成α-氨基酸衍生物；
(2)反应结束后，采用柱层析将产物分离纯化；所述柱层析的洗脱液为石油醚和乙酸乙酯的混合溶剂。
所述亚胺的结构如式A所示，烯烃的结构如式B所示，9-bbn结构如式C所示，α-氨基酸衍生物的结构如式D所示。
Figure PCTCN2015098519-appb-000001
在式A和式D中，R1为4-MeOC6H4、2-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-NO2C6H4、Ph、4-COOEtC6H4或1-萘基中的一种；
在式B和D中，R2为正丁基、环己基、Ph、4-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-tBuC6H4、1-萘基或2-噻吩基中的一种；
所述亚胺式A已有文献报道(Borrione,E.；Prato,M.；Scorrano,G.；Stivanello,M.Synthesis and cycloaddition reaction of ethyl glyoxylate imines.Synthesis of substituted furo-[3,2-c]quinolines and 7H-indeno[2,1-c]quinolines[J].J.Heterocycl.Chem.1988,25,1831)。
所述烯烃与9-bbn的摩尔比为1:1；
所述烯烃与亚胺的摩尔比为(1-3):1，优选1.5:1。
所述的过渡金属盐为二氯化钯、醋酸钯、三氟醋酸钯、二氯二乙腈钯、二氯二三苯基膦钯、醋酸铜、氯化铜、溴化铜、三氟甲磺酸铜、氯化亚铜、溴化亚铜、碘化亚铜、氰化亚铜或高氯酸铜中的一种，优选氰化亚铜，其产率较高。
所述的碱为Cs2CO3、NaOMe、NaOtBu、LiOMe、Li2CO3、Na2CO3、NaOEt、K2CO3、LiOtBu或KOEt中的一种，优选Cs2CO3，其产率较高。
所述的有机溶剂为甲苯或1,2-二氯乙烷。
上述过程中发生的化学反应如下式所示：
Figure PCTCN2015098519-appb-000002
本发明相对于现有技术具有如下的优点及效果：
本发明的方法简便、高效，所用到的原料简单易得且无毒，本制备方法在反应过程中对水和空气都不敏感。另外整个操作过程简单易行，步骤简便，产物易纯化。
本发明中采用烯烃与9-bbn原位生成烷基硼试剂，反应条件温和，烯烃可选种类多。同时现有合成方法都需要严格无水无氧条件，反应操作复杂，反应需要在低温下进行，制冷成本高。而本发明不需无水无氧条件，同时反应可以在室温或稍高一些的温度下进行。
附图说明
图1是化合物1的氢谱图。
图2是化合物1的碳谱图。
图3是化合物2的氢谱图。
图4是化合物2的碳谱图。
图5是化合物3的氢谱图。
图6是化合物3的碳谱图。
图7是化合物4的氢谱图。
图8是化合物4的碳谱图。
图9是化合物5的氢谱图。
图10是化合物5的碳谱图。
具体实施方式
下面结合实施例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实施例1
α-氨基酸衍生物的合成方法，包括以下步骤：
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯(10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。
Figure PCTCN2015098519-appb-000003
(2)在已抽真空充氮气的密封管中加苯乙烯(15.1mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在60℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入碳酸铯(5mg，0.015mmol)、氰化亚铜(0.9mg，0.01mmol)，步骤(1)的亚胺，密封后在70℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品23.5mg，产率为：75％。
本实施例所得产品的结构表征数据如下：
1H NMR(400MHz,CDCl3)δ7.28(t,J＝7.3Hz,2H),7.18(d,J＝7.2Hz,3H),6.75(d,J＝7.9Hz,2H),6.56(d,J＝7.8Hz,2H),4.14(q,J＝7.1Hz,2H),3.97(s,1H),3.91(s,1H),3.71(s,3H),2.77(t,J＝7.7Hz,2H),2.06(ddd,J＝27.9,13.5,6.9Hz,2H),1.22(t,J＝7.1Hz,3H).氢谱图见图1。
13C NMR(101MHz,CDCl3)δ174.35,152.83,141.07,128.58,128.53,126.18,115.30,114.92,61.05,57.38,55.72,34.81,31.93,14.31.碳谱图见图2。
High Resolution MS：计算值C19H23NO3[M+H]+:314.1751,发现:314.1749。
根据以上数据推断所得产品的结构如下所示：
Figure PCTCN2015098519-appb-000004
化合物1
实施例2
α-氨基酸衍生物的合成方法，包括以下步骤：
(1)在密封管中，加入对氯苯胺(12.7mg，0.1mmol)，乙醛酸乙酯(10.2mg， 0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。
Figure PCTCN2015098519-appb-000005
(2)在已抽真空充氮气的密封管中加苯乙烯(15.1mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在0℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入碳酸钠(1.6mg，0.015mmol)、碘化亚铜(1.9mg，0.01mmol)，步骤(1)的亚胺，密封后在90℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品19mg，产率为：60％。
本实施例所得产品的结构表征数据如下：
1H NMR(400MHz,CDCl3)δ7.29(t,J＝7.3Hz,2H),7.20(dd,J＝16.3,7.2Hz,3H),7.10(d,J＝8.3Hz,2H),6.49(d,J＝8.3Hz,2H),4.16(dt,J＝11.7,5.9Hz,3H),4.04–3.97(m,1H),2.75(t,J＝7.8Hz,2H),2.21–2.12(m,1H),2.04(dd,J＝13.7,7.0Hz,1H),1.26(d,J＝6.6Hz,3H).氢谱图见图3。
13C NMR(101MHz,CDCl3)δ173.66,145.42,140.71,129.15,128.53,128.50,126.24,123.01,114.69,61.26,56.19,34.43,31.73,14.25.碳谱图见图4。
High Resolution MS：计算值C18H20ClNO2[M+H]+:318.1255,发现:318.1254.
根据以上数据推断所得产品的结构如下所示：
Figure PCTCN2015098519-appb-000006
化合物2
实施例3
α-氨基酸衍生物的合成方法，包括以下步骤：
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯 (10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。
Figure PCTCN2015098519-appb-000007
(2)在已抽真空充氮气的密封管中加对溴苯乙烯(27mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在80℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入NaOtBu(1.5mg，0.015mmol)、醋酸钯(2.4mg，0.01mmol)，步骤(1)的亚胺，密封后在0℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品22.3mg，产率为：57％。
本实施例所得产品的结构表征数据如下：
1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.8Hz,1H),7.06(d,J＝7.8Hz,1H),6.76(d,J＝8.2Hz,1H),6.57(d,J＝8.3Hz,1H),4.15(q,J＝7.1Hz,1H),3.93(t,J＝6.3Hz,1H),3.86(s,1H),3.74(s,1H),2.73(t,J＝7.7Hz,1H),2.05(ddd,J＝21.1,13.7,7.0Hz,1H),1.23(t,J＝7.1Hz,2H).氢谱图见图5。
13C NMR(101MHz,CDCl3)δ174.17,152.90,140.87,139.95,131.54,130.30,119.92,115.33,114.91,61.10,57.17,55.71,34.54,31.25,14.25.碳谱图见图6。
High Resolution MS：C19H22BrNO3计算值[M+H]+:392.0856,发现:392.0848.
根据以上数据推断所得产品的结构如下所示：
Figure PCTCN2015098519-appb-000008
化合物3
实施例4
α-氨基酸衍生物的合成方法，包括以下步骤：
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯(10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。
Figure PCTCN2015098519-appb-000009
(2)在已抽真空充氮气的密封管中加1-己烯(12.6mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在60℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入NaOMe(0.8mg，0.015mmol)、溴化亚铜(1.4mg，0.01mmol)，步骤(1)的亚胺，密封后在70℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品21.1mg，产率为：72％。
本实施例所得产品的结构表征数据如下：
1H NMR(400MHz,CDCl3)δ6.76(d,J＝8.7Hz,2H),6.59(d,J＝8.6Hz,2H),4.16(q,J＝7.1Hz,2H),3.94(t,J＝6.4Hz,1H),3.81(d,J＝4.0Hz,1H),3.73(s,3H),1.82–1.70(m,2H),1.42(s,2H),1.33–1.26(m,6H),1.23(t,J＝7.1Hz,3H),0.88(t,J＝6.4Hz,3H).氢谱图见图7。
13C NMR(101MHz,CDCl3)δ174.62,152.69,141.16,115.12,114.88,60.86,57.92,55.72,33.26,31.62,29.02,25.60,22.54,14.25,14.03.碳谱图见图8。
High Resolution MS：C17H27NO3计算值[M+H]+:294.2064,发现:294.2063.
根据以上数据推断所得产品的结构如下所示：
Figure PCTCN2015098519-appb-000010
化合物4
实施例5
α-氨基酸衍生物的合成方法，包括以下步骤：
(1)在密封管中，加入对甲氧基苯胺(12.3mg，0.1mmol)，乙醛酸乙酯 (10.2mg，0.1mmol)，无水硫酸钠(71mg，0.5mmol)，二氯甲烷(2mL)，混合液在室温下搅拌反应0.5h。然后过滤除去硫酸钠用二氯甲烷洗涤滤渣，旋干溶剂二氯甲烷，得到0.1mmol亚胺。
Figure PCTCN2015098519-appb-000011
(2)在已抽真空充氮气的密封管中加环己烯(12.3mg，0.15mmol)，9-bbn(0.3mL，0.15mmol，9-bbn为0.5mol/L的THF溶液)，无水甲苯1mL，混合液在60℃搅拌反应1h后，停止加热，冷却到室温。然后依次加入碳酸锂(1mg，0.015mmol)、二氯化钯(1.8mg，0.01mmol)，步骤(1)的亚胺，密封后在70℃下反应24h。反应完毕后，待反应体系冷却到室温后，过滤，旋干，采用柱层析进一步分离纯化，得到产品21mg，产率为：72％。
本实施例所得产品的结构表征数据如下：
1H NMR(400MHz,CDCl3)δ6.75(d,J＝8.3Hz,2H),6.60(d,J＝8.4Hz,2H),4.15(q,J＝7.1Hz,2H),3.85(s,1H),3.75(d,J＝6.0Hz,1H),3.73(s,3H),1.86(d,J＝12.1Hz,1H),1.77(d,J＝11.5Hz,2H),1.67(d,J＝11.6Hz,3H),1.27–1.12(m,8H).氢谱图见图9。
13C NMR(101MHz,CDCl3)δ174.02,152.64,141.68,115.22,114.87,63.41,60.69,55.74,41.33,29.68,29.23,26.23,26.11,26.09,14.30.碳谱图见图10。
High Resolution MS：C17H25NO3计算值[M+H]+:292.1907,发现:292.1906。
根据以上数据推断所得产品的结构如下所示：
Figure PCTCN2015098519-appb-000012
化合物5
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (7)

  1. α-烷基支链取代的α-氨基酸衍生物的合成方法，其特征在于包括以下步骤：
    取烯烃与9-硼双环(3,3,1)-壬烷在0-80℃下反应0.5-12h，然后加入亚胺，在过渡金属盐、碱和有机溶剂存在的情况下，于0-90℃下反应12-48h，生成α-氨基酸衍生物；
    所述亚胺的结构如式A所示，烯烃的结构如式B所示，9-bbn结构如式C所示，α-氨基酸衍生物的结构如式D所示：
    Figure PCTCN2015098519-appb-100001
    在式A和式D中，R1为4-MeOC6H4、2-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-NO2C6H4、Ph、4-COOEtC6H4或1-萘基中的一种；
    在式B和D中，R2为正丁基、环己基、Ph、4-MeOC6H4、4-MeC6H4、3-MeC6H4、4-ClC6H4、4-BrC6H4、4-tBuC6H4、1-萘基或2-噻吩基中的一种；
    所述烯烃与亚胺的摩尔比为(1-3):1；
    所述的碱为Cs2CO3、NaOMe、NaOtBu、LiOMe、Li2CO3、Na2CO3、NaOEt、K2CO3、LiOtBu或KOEt中的一种。
  2. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述烯烃与9-硼双环(3,3,1)-壬烷的摩尔比为1:1。
  3. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述烯烃与亚胺的摩尔比为1.5:1。
  4. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述的过渡金属盐为二氯化钯、醋酸钯、三氟醋酸钯、二氯二乙腈钯、二氯二三苯基膦钯、醋酸铜、氯化铜、溴化铜、三氟甲磺酸铜、氯化亚铜、溴化亚铜、碘化亚铜、氰化亚铜或高氯酸铜中的一种。
  5. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述 的过渡金属盐为氰化亚铜。
  6. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述的碱为Cs2CO3。
  7. 根据权利要求1所述的α-氨基酸衍生物的合成方法，其特征在于：所述的有机溶剂为甲苯或1,2-二氯乙烷。
PCT/CN2015/098519 2015-06-12 2015-12-23 α-烷基支链取代的α-氨基酸衍生物的合成方法 Ceased WO2016197580A1 (zh)

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