CN111484522B - 一种光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法 - Google Patents
一种光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法 Download PDFInfo
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Abstract
本发明公开一种光学纯顺式2‑(二苯基膦)‑1‑环己甲酸的制备方法,由1‑环己烯‑1‑甲酸甲酯与二苯基磷氧发生加成反应得到第一中间体,再由第一中间体经还原制得第二中间体,由第二中间体水解即得到顺式‑2‑(二苯基膦)‑1‑环己甲酸,所述顺式‑2‑(二苯基膦)‑1‑环己甲酸。本发明开创性的研究了光学纯顺式2‑(二苯基膦)‑1‑环己甲酸的制备方法,填补了膦配体中光学活性纯顺式‑2‑(二苯基膦)‑1‑环己甲酸的空缺,有效促进了不对称路易斯酸和过渡金属催化效果。
Description
技术领域
本发明属于化学制备技术领域,具体涉及一种光学纯顺式-2-(二苯基膦)-1-环己甲酸的制备方法。
背景技术
手性是自然界的普遍现象(常见于天然产物和药物)。不对称催化,是构建手性中心的最重要和直接的策略,一直是有机化学领域的研究热点之一。自2000年以来,一方面,手性小分子催化取得了瞩目的成绩;另一方面,不对称路易斯酸和过渡金属催化,依然占据重要地位,是极其有效的补充。而手性配体的设计和开发,是促进不对称路易斯酸和过渡金属催化发展的主要动力。
在众多的配体中,膦配体是最为重要的一类配体之一,受到了各国科学家的关注和深入研究。2001年,Stelzer等报道了消旋反式-2-(二苯基膦)-1-环己甲酸的制备方法(Eur. J.Inorg.Chem.2001,1251-1259)。然而,光学活性顺式-2-(二苯基膦)-1-环己甲酸的合成方法,一直未见报道。
发明内容
发明目的:本发明目的在于针对现有技术的不足,提供一种光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,本发明另一目的在于提供该方法制备的光学纯顺式2-(二苯基膦)-1-环己甲酸。
技术方案:本发明所述的一种光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,由1-环己烯-1-甲酸甲酯与二苯基磷氧发生加成反应得到第一中间体,再由第一中间体经还原制得第二中间体,由第二中间体水解即得到顺式-2-(二苯基膦)-1-环己甲酸,所述顺式-2-(二苯基膦)-1-环己甲酸如式(I)或式(II)所示;
进一步地,所述光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,包括如下步骤:
(1)向反应瓶中加入摩尔比为1~2:1的1-环己烯-1-甲酸甲酯(III)与二苯基膦氧,并加入溶剂与催化剂,在-30~-15℃下反应40~50h,反应结束后加入淬灭剂,萃取后脱溶剂得到第一中间体,如式(IV)或式(VI);
(2)向第一中间体中加入溶剂,并加入复合还原剂,在90~110℃下反应15~20h,加入淬灭剂,反应完成后经以正己烷/乙酸乙酯进行柱层析分离,得到第二中间体,如式(V)或式(VII);
(3)向第二中间体中加入水解剂,水解后得到光学纯顺式-2-(二苯基膦)-1-环己甲酸,式(I)或式(II)所示;
具体反应过程如下方程式:
进一步地,步骤(1)中所述溶剂为四氢呋喃,催化剂为Bu2Mg/(R or S)-H8-BINOL与H2O,淬灭剂为饱和氯化铵。
进一步地,为针对反应体系,提高还原效率,提高产物纯度,步骤(2)中所述复合还原剂为摩尔比为2:3的三氯硅烷和三乙胺混合物;所述溶剂为甲苯。
进一步地,为针对反应体系,提高水解效率,步骤(3)中所述水解剂三氯化铝,所述水解过程以二甲硫醚作为溶剂。
有益效果:本发明开创性的研究了光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,填补了膦配体中光学活性纯顺式-2-(二苯基膦)-1-环己甲酸的空缺,有效促进了不对称路易斯酸和过渡金属催化效果;本发明中,通过发明人对原料特性的研究,针对性的选择加成催化剂、还原催化剂、水解剂,配合相应的溶剂,不仅保证反应过程的顺利进行,还有助于提高产物的产率和纯度。
附图说明
图1为实施例1中产物的1H NMR谱图;
图2为实施例1中产物的13C NMR谱图;
图3为实施例1中产物的31P NMR谱图;
图4为实施例2中产物的1H NMR谱图;
图5为实施例2中产物的13C NMR谱图;
图6为实施例2中产物的31P NMR谱图;
图7为实施例3中产物的1H NMR谱图;
图8为实施例3中产物的13C NMR谱图;
图9为实施例3中产物的31P NMR谱图。
具体实施方式
下面通过附图对本发明技术方案进行详细说明,但是本发明的保护范围不局限于所述实施例。实施例中所使用反应类药品均为常规市售。
实施例1:第一中间体的的制备
在室温及N2保护下,将1.76g(R)-H8-BINOL,72μL H2O加入到40mL无水四氢呋喃中,在室温下剧烈搅拌5min,将溶于庚烷的4mmol二丁基镁逐滴加入到反应体系里,再将8.1g二苯基膦氧加入到反应体系中,在室温下剧烈搅拌5min,搅拌结束将反应体系降温至-20℃,在此温度下保持5min,环己烯甲酸甲酯(5.88g,42mmol)逐滴加入到反应体系中,滴加完毕在-20℃反应48h;反应结束后,用饱和氯化铵溶液淬灭反应,减压脱去溶剂,水相用氯仿萃取三次,萃取得到的有机相用无水硫酸钠干燥,减压脱除溶剂,残余物用乙醚重结晶,得到8.65g化合物第一中间体,产率62.5%,ee 值100%,dr值100%。
实施例1所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ7.89-7.69(m,4H),7.56-7.37(m,6H),3.45(s,3H),2.96-2.91(m,1H),2.60-2.47(m,1H),2.23-2.00(m,2H),1.93-1.74(m,2H),1.67-1.44(m,3H),1.33-1.21(m,1H).
13C NMR(100MHz,CDCl3):δ173.71,173.69,133.44,132.56,132.50,131.63,131.61, 131.60,131.59,131.56,131.48,131.39,128.67,128.56,128.45,51.41,40.48,39.77,38.69, 29.09,29.00,25.97,25.85,22.45,21.64.
31P NMR(161MHz,CDCl3):δ32.28.
通过产物的核磁共振氢谱、碳谱、磷谱,证明成功合成第一中间体。
式(IV)化合物的比旋光度:[α]D 20=-46.3(c=0.10,MeOH).
HRMS:calculated for C20H23O3P(M+H)+:343.1463,found:343.1458.
式(VI)化合物比旋光度:[α]D 20=+46.3(c=0.10,MeOH).
HRMS:calculated for C20H23O3P(M+H)+:343.1463,found:343.1458.
实施例2:第二中间体的制备
在室温及N2保护下,将10.38g,30mmol第一中间体溶解到45mL无水甲苯中,在室温下搅拌,反应体系降温到0℃,将12mL,90mmol三乙胺逐滴加入到反应体系中,逐滴加入8.5mL,60mmol三氯硅烷,加入三氯硅烷时会形成白色沉淀,将混合物在 100℃下搅拌18小时,然后将所得悬浮液移至冰浴冷却,用N2脱气处理的100mL 10%NaOH水溶液淬灭,然后用漏斗过滤除去白色固体,用甲苯洗涤,100mL×3二氯甲烷萃取水相,有机相合并用无水硫酸钠干燥。减压脱去溶剂得到粗产品,并进行柱层析,洗脱液:正己烷:乙酸乙酯=50:1~20:1,纯化粗产物,得到7.5g化合物第二中间体,产率77%;ee值100%。通过手性HPLC分析测定对映体纯度。
实施例2所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ7.51-7.46(m,4H),7.40-7.28(m,6H),3.51(s,3H),2.69-2.59(m,1H),2.39-2.29(m,1H),2.04-1.92(m,1H),1.81-1.65(m,4H),1.41-1.31(m,1H),1.40-1.17(m,1H),1.05-0.91(m,1H).
13C NMR(100MHz,CDCl3):δ175.88,136.44,136.31,135.60,135.45,134.98,134.77, 132.90,132.73,129.19,128.44,128.38,128.32,128.25,51.55,46.46,46.26,35.73,35.58, 30.16,30.06,27.19,27.15,25.60,25.56,24.90.
31P NMR(161MHz,CDCl3):δ-10.92.
通过产物的核磁共振氢谱、碳谱、磷谱,证明成功合成第二中间体。
式(V)化合物的比旋光度:[α]D 20=-41.9(c=0.10,MeOH).
HRMS:calculated for C20H23O2P(M+H)+:327.1514,found:327.1508.
式(VII)化合物的比旋光度:[α]D 20=+41.9(c=0.10,MeOH).
HRMS:calculated for C20H23O2P(M+H)+:327.1514,found:327.1508.
实施例3:纯顺式2-(二苯基膦)-1-环己甲酸
在0℃及N2保护下,将27mL二甲硫醚加入到1.63g,5mmol第二中间体和6.0 g,25mmol三氯化铝中,然后将混合物在室温下搅拌过夜。随后将混合物冷却至0℃,将反应体系逐滴加入到30mL冰水中,然后快速用30mL×3二氯甲烷萃取,合并的有机相用无水硫酸钠干燥,N2氛围,0℃下过滤并减压脱去溶剂得到1.3g化合物纯顺式 2-(二苯基膦)-1-环己甲酸,产率83%。上述所有溶剂在-20℃下提前冷却并用N 2脱气处理。
实施例3所得产物的结构表征数据如下所示:
1H NMR(400MHz,CDCl3):δ7.68-7.52(m,4H),7.39-7.30(m,6H),2.67-2.51(m,2H),2.16-12.12(m,1H),2.01-1.88(m,1H),1.84-1.78(m,1H),1.68-1.50(m,4H),1.38-1.29(m,1H).
13C NMR(100MHz,CDCl3):δ179.81,134.01,133.81,133.75,133.55,129.13,128.95, 128.48,128.41,41.57,41.47,37.46,37.33,29.35,29.29,26.05,25.95,25.41,25.27,22.32.
31P NMR(161MHz,CDCl3):δ-10.64.
通过产物的核磁共振氢谱、碳谱、磷谱,证明成功合成纯顺式2-(二苯基膦)-1-环己甲酸。
式(I)化合物的比旋光度:[α]D 20=-10.3(c=0.10,MeOH).
HRMS:calculated for C19H21O2P(M+H)+:313.1357,found:313.1356.
式(II)化合物的比旋光度:[α]D 20=+10.3(c=0.10,MeOH).
HRMS:calculated for C19H21O2P(M+H)+:313.1357,found:313.1356.
本发明开创性的研究了光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,填补了膦配体中光学活性纯顺式-2-(二苯基膦)-1-环己甲酸的空缺,有效促进了不对称路易斯酸和过渡金属催化效果。
如上所述,尽管参照特定的优选实施例已经表示和表述了本发明,但其不得解释为对本发明自身的限制。在不脱离所附权利要求定义的本发明的精神和范围前提下,可对其在形式上和细节上作出各种变化。
Claims (4)
1.一种光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,其特征在于:由1-环己烯-1-甲酸甲酯与二苯基磷氧发生加成反应得到第一中间体,再由第一中间体经还原制得第二中间体,由第二中间体水解即得到顺式-2-(二苯基膦)-1-环己甲酸,所述顺式-2-(二苯基膦)-1-环己甲酸如式(I)或式(II)所示;
具体包括如下步骤:
(1)向反应瓶中加入摩尔比为1~2:1的1-环己烯-1-甲酸甲酯(III)与二苯基膦氧,并加入溶剂与催化剂,在-30~-15℃下反应40~50h,反应结束后加入淬灭剂,萃取后脱溶剂得到第一中间体,如式(IV)或式(VI);
(2)向第一中间体中加入溶剂,并加入复合还原剂,在90~110℃下反应15~20h,加入淬灭剂,反应完成后经以正己烷/乙酸乙酯进行柱层析分离,得到第二中间体,如式(V)或式(VII);
(3)向第二中间体中加入水解剂,水解后得到光学纯顺式-2-(二苯基膦)-1-环己甲酸,式(I)或式(II)所示;
具体反应过程如下方程式:
2.根据权利要求1所述的光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,其特征在于:步骤(1)中所述溶剂为四氢呋喃,催化剂为Bu2Mg/(R or S)-H8-BINOL与H2O,淬灭剂为饱和氯化铵。
3.根据权利要求1所述的光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,其特征在于:步骤(2)中所述复合还原剂为摩尔比为2:3的三氯硅烷与三乙胺混合物;所述溶剂为甲苯。
4.根据权利要求1所述的光学纯顺式2-(二苯基膦)-1-环己甲酸的制备方法,其特征在于:步骤(3)中所述水解剂为三氯化铝,所述水解过程以二甲硫醚作为溶剂。
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