CN113845443A - 2-氰基-3-氨基丙烯酸酯类化合物的制备方法及中间体 - Google Patents
2-氰基-3-氨基丙烯酸酯类化合物的制备方法及中间体 Download PDFInfo
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
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- -1 cyano, hydroxyl Chemical group 0.000 claims description 8
- 239000000460 chlorine Substances 0.000 claims description 7
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明公开了一种2‑氰基‑3‑氨基丙烯酸酯类化合物的制备方法及中间体。本发明所述的方法包括以下步骤:化合物(I)与化合物(II)在有机溶剂中,碱性条件下反应得到中间体(III);(2)中间体(III)与烷基化试剂在碱性条件下反应得到中间体(IV);(3)中间体(IV)氨化得到2‑氰基‑3‑氨基丙烯酸酯类化合物。本发明的制备工艺简单,减少三废产生,得到含量不小于95%的原药,总收率大于85%,所有原料普通易得,反应条件温和,无高温高压操作。
Description
技术领域
本发明涉及一种化合物的制备方法,特别涉及一种2-氰基-3-氨基丙烯酸酯类化合物的制备方法及中间体。
背景技术
具有生物活性的丙烯酸衍生物是目前新农药开发研究的目标之一,并具有相当的可拓展性和结构改造潜力,其中2-氰基-3-氨基丙烯酸酯类衍生物作为农药杀菌剂的研究,在很大程度上仍属于有待探索并具有丰富拓展与想象空间的一类化合物。
早期公开的方法(J.Am.Chem.Soc..1943,40,388~390),以脒与氰乙酸酯为原料制得,副产较高,方法收率很低,难以提纯;Bull Soc Chim.Fr.(1-2,Pt.2)1976,177~83(Fr)上公开的方法是以(取代)硫代苯甲酰与2-溴代氰乙酸酯直接反应制得,原料不易得;用3-苯基-2-氰基丙烯酸酯与亚磷酸三乙酯(J.Prakt.Chem.Chemie 1983,325(5),876~9)为原料经加成,溴化、消除,最后与氨水反应制备,本方法步骤多,成本高;以苯甲醛与氰乙酸乙酯为起始原料(J.Org.Chem.,1973,33(13),2287~2290),缩合制得3-苯基-氰基丙烯酸酯,再与氯气加成生成2,3-二氯-3-苯基-2-氰基丙烯酸酯,再在缚酸剂存在下或高温下消除反应得到3-氯-3-苯基-2-氰基丙烯酸酯,最后与氨水制得目标产物,该方法需要在高温下进行,在采用该法合成时,在化合物2,3-二氯-3-苯基-2-氰基丙烯酸酯高温消除成3-氯-3-苯基-2-氰基丙烯酸酯时,收率很低,产品大部分是副产品2-氯3-苯基丙烯腈。3-氨基-3-苯基丙烯腈与光气反应(Synthetic Communications.1993,23(16)2293~2302),生成中间体3-氨基-3-苯基丙烯酰氯,然后再和C1~C6脂肪醇反应生成目标化合物,该方法原料3-氨基-3-苯基丙烯腈难得,难以进行3-氨基-3-苯基-氰基丙烯酸酯类化合物中3-氨基系列取代。各种取代的苯甲酰氯与氰乙酸酯在碱(比如乙醇镁、乙醇钠或三乙胺等)存在下反应得到中间体3-羟基-3-取代苯基-2-氰基丙烯酸酯(Synthetic Communications.1996,26(19)3549~3557;US4781750),3-羟基-3-取代苯基-2-氰基丙烯酸酯经三氯氧磷氯化得到3-氯-3-取代苯基-2-氰基丙烯酸酯,随后氯代化合物与氨水反应生成目标产物,反应中用到三氯氧磷,毒性较大,乙醇镁、乙醇钠或三乙胺等价格偏贵。CN101417962B公开的方案以苯甲腈起始原料,通入氯化氢气体,生成亚胺基醚,再与氰乙酸乙酯反应得到产物,盐酸气对设备腐蚀较大,反应周期较长。
发明内容
发明目的:本发明提供了一种2-氰基-3-氨基丙烯酸酯类化合物的制备方法,该方法适用于工业生产,简化工艺流程,减少三废,所得的原药收率高,纯度高。本发明还提供了用于制备2-氰基-3-氨基丙烯酸酯类化合物的中间体。
其中:
R1选自卤素;
R2选自C1~C6烷基;
R3选自甲基、乙基、异丙基、正丙基、取代或者非取代的苯基;所述的取代基为氯、溴、氨基,氰基,羟基,烷氧基,酯基、芳香杂环基、苯基或取代苯基。
优选地,上述的2-氰基-3-氨基丙烯酸酯类化合物的制备流程如下:
(1)化合物(I)与化合物(II)在有机溶剂中,碱性条件下反应得到中间体(III);
(2)中间体(III)经烷基化反应后得到中间体(IV):
(3)中间体(IV)氨化反应得到2-氰基-3-氨基丙烯酸酯类化合物:
优选地,步骤(1)或步骤(2)中,所述的碱性条件为在碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钙、氧化钙中其中一种或一种以上的混合物存在的条件下。
优选地,步骤(2)中,所述的烷基化试剂选自硫酸二甲酯、硫酸二乙酯、氯甲烷、溴甲烷、溴乙烷、氯乙烷、溴代正丙烷、氯代正丙烷、氯代异丙烷、溴代异丙烷、取代苄基氯或取代苄基溴,其中,取代基为氯、溴、氨基、氰基、羟基、烷氧基、酯基、芳香杂环基、苯基或取代苯基。
优选地,所述的有机溶剂为苯、甲苯、二甲苯、二氯甲烷、二氯乙烷、四氢呋喃、甲基四氢呋喃、二氧戊环、乙二醇二甲醚、乙二醇二乙醚、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇中一种或一种以上的混合溶剂。
优选地,步骤(1)中,反应温度为-20~150℃;化合物(I)的摩尔数是化合物(II)的摩尔数的1~4倍,所用碱的摩尔数是化合物(I)的摩尔数的1~3倍;和/或步骤(3)中,氨化试剂的摩尔数是中间体(IV)的摩尔数的1~3倍。
优选地,步骤(2)中,反应温度为0~150℃;所述的烷基化试剂的摩尔数是中间体(III)摩尔数的1~2.5倍,所用碱的摩尔数是烷基化试剂摩尔数的1~3倍。
优选地,步骤(3)中,氨化反应的温度为0~100℃;氨化的氨化试剂为氨气或氨水;氨化试剂的摩尔数是中间体(IV)的摩尔数的1~3倍。
优选地,步骤(1)中,反应温度为0~120℃;和/或步骤(2)中,反应温度为0~100℃;和/或步骤(3)中,反应温度为0~60℃。
更优选地,步骤(1)中,反应温度为10-65℃;步骤(2)中,反应温度为0~45℃;步骤(3)中,反应温度为30~40℃。
优选地,步骤(1)中,反应时间为1-4h;步骤(2)中,反应时间为2-8h;步骤(3)中,反应时间为0.5-3h。
更优选地,步骤(1)中,反应时间为1-3h;步骤(2)中,反应时间为3-6h;步骤(3)中,反应时间为0.5-2h。
本发明还提供了一种用于制备2-氰基-3-氨基丙烯酸酯类化合物的中间体,所述中间体结构为R3选自甲基、乙基、异丙基、正丙基、取代或者非取代的苯基;所述的取代基为氯、溴、氨基,氰基,羟基,烷氧基,酯基、芳香杂环基、苯基或取代苯基。
有益效果:(1)本发明的整个工艺流程在碱性或弱碱性条件下进行,减少对设备的腐蚀,减少废水、废气和固体废弃物的产生;(2)本发明的尾气易于处理,尾气中的氨气直接用反应三的反应液吸收,再接入水吸收,几乎没有尾气;(3)本发明的制备方法得到的产物纯度高,制备得到的原药含量不小于95%,总收率大于85%;(4)本发明所有原料普通易得,反应条件温和,无高温高压操作。
具体实施方式
实施例1:将氰乙酸乙酯114克(1摩尔,99%),氢氧化钠60.6克(1.5摩尔,99%),99%乙醇300克投入反应瓶中,控制温度在10~15℃,滴入苯甲酰氯185克(1.3摩尔,99%),一小时左右滴完,滴完后,在10~15℃保持2小时,反应完成后,得到中间体(III)的反应液,再加入氢氧化钠44.4克(1.1摩尔,99%),将内温降至0~5℃,温度稳定10分钟后,滴入硫酸二甲酯152.7克(1.2摩尔,99%),1小时内滴完,在0~5℃反应3小时,得到中间体(IV)的反应液,将温度升至35~40℃,0.5~1小时内通入氨气25.5克,保温半小时,将乙醇蒸出,加入100克水,化合物(V)2-氰基-3-氨基丙烯酸乙酯析出后过滤,烘干得105克,含量96%。
中间体(III):1HNMR(CDCl3)δ1.44(t,J=7.2Hz,3H)4.46(q,J=7.2Hz,2H)8.35~8.38(m,5H),14.3(s,1H)。
中间体(IV):1HNMR(CDCl3)δ1.14(t,J=7.0Hz,3H)3.68(s,3H),4.05(q,J=7.0Hz,2H),7.26~7.57(m,5H)。
化合物(V):1HNMR(CDCl3)δ1.36(t,J=7.2Hz,3H),4.28(q,J=7.2Hz,2H),6.01(s,1H),7.44~7.58(m,5H),9.38(s,1H)。
实施例2:将氰乙酸乙酯114克(1摩尔,99%),氢氧化钾72.1克(1.3摩尔,99%),99%四氢呋喃300克投入反应瓶中,控制温度在20~25℃,滴入苯甲酰氯170.3克(1.2摩尔,99%),一小时左右滴完,滴完后,在20~25℃保持2小时,反应完成后,得到中间体(III)的反应液,再加入氢氧化钾56.6克(1.0摩尔,99%),将内温降至10~15℃,温度稳定10分钟后,滴入硫酸二甲酯152.7克(1.2摩尔,99%),1小时内滴完,在10~15℃反应3.5小时,得到中间体(IV)的反应液,将温度升至30~40℃,0.5~1小时内通入氨气34.5克,保温半小时,将四氢呋喃蒸出,加入100克水,化合物(V)2-氰基-3-氨基丙烯酸乙酯析出后过滤,烘干得102.7克,含量98%。
实施例3:将氰乙酸乙酯114克(1摩尔,99%),氢氧化钠48.5克(1.2摩尔,99%),99%二氯乙烷450克投入反应瓶中,控制温度在60~65℃,滴入苯甲酰氯170.3克(1.2摩尔,99%),一小时左右滴完,滴完后,在60~65℃保持2小时,反应完成后,得到中间体(III)的反应液,再加入氢氧化钠48.5克(1.2摩尔,99%),将内温降至40~45℃,温度稳定10分钟后,滴入硫酸二乙酯186.6克(1.2摩尔,99%),1小时内滴完,在40~45℃反应5小时,得到中间体(IV)的反应液,将温度降至30~40℃,加入氨水200克(质量浓度17%,2摩尔氨气),保温半小时,将二氯乙烷蒸出,加入100克水,化合物(V)2-氰基-3-氨基丙烯酸乙酯析出后过滤,烘干得106.5克,含量95.7%。
中间体(IV)1HNMR(CDCl3)δ1.14(t,J=7.0Hz,3H),1.31(t,J=7.0Hz,3H),3.93(q,J=7.0Hz,2H),4.06(q,J=7.0Hz,2H),7.27~7.55(m,5H)。
Claims (10)
2.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,步骤(1)或步骤(2)中,所述的碱性条件为在碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、氢氧化钠、氢氧化钾、氢氧化钙、氧化钙中其中一种或一种以上的混合物存在的条件下。
3.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,步骤(2)中,所述的烷基化试剂选自硫酸二甲酯、硫酸二乙酯、氯甲烷、溴甲烷、溴乙烷、氯乙烷、溴代正丙烷、氯代正丙烷、氯代异丙烷、溴代异丙烷、取代苄基氯或取代苄基溴,其中,取代基为氯、溴、氨基、氰基、羟基、烷氧基、酯基、芳香杂环基、苯基或取代苯基。
4.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,所述的有机溶剂为苯、甲苯、二甲苯、二氯甲烷、二氯乙烷、四氢呋喃、甲基四氢呋喃、二氧戊环、乙二醇二甲醚、乙二醇二乙醚、甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇中一种或一种以上的混合溶剂。
5.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,步骤(1)中,反应温度为-20~150℃;化合物(I)的摩尔数是化合物(II)的摩尔数的1~4倍,所用碱的摩尔数是化合物(I)的摩尔数的1~3倍。
6.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,步骤(2)中,反应温度为0~150℃;所述的烷基化试剂的摩尔数是中间体(III)摩尔数的1~2.5倍,所用碱的摩尔数是烷基化试剂摩尔数的1~3倍。
7.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,步骤(3)中,氨化反应的温度为0~100℃;氨化的氨化试剂为氨气或氨水;氨化试剂的摩尔数是中间体(IV)的摩尔数的1~3倍。
8.根据权利要求1所述的2-氰基-3-氨基丙烯酸酯类化合物的制备方法,其特征在于,步骤(1)中,反应温度为0~120℃;和/或步骤(2)中,反应温度为0~100℃;和/或步骤(3)中,反应温度为0~60℃。
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