CN105567746B - 一种酶法合成菊酯类杀虫剂中间体的方法 - Google Patents
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Abstract
本发明公开了一种酶法合成菊酯类杀虫剂中间体的方法,以具有化合物5结构的顺式、反式菊酸异构体的混合DV菊酸甲酯为底物,底物的投加浓度为1~50g/L,在温度25~50℃、pH为6.0~8.0的缓冲溶液中,在水解酶的作用下,水解反应生成菊酯类杀虫剂中间体,其中,混合DV菊酸甲酯中顺式异构体与反式异构体的投料质量比为2:8‑6:4,所述的水解酶为蛋白酶或酯酶,所述的水解酶的投加质量为所述底物质量的10~100%。采用本发明的方法进行制备菊酯类杀虫剂中间体,其过程简单、反应时间短、转化率高、产品纯度高、绿色环保,适于工业化生产。
Description
技术领域
本发明涉及生物化工技术领域,尤其涉及一种酶法合成菊酯类杀虫剂中间体的方法。
背景技术
(1R,3R)-2,2-二甲基-3-(2,2-二氯乙烯基)环丙烷羧酸(式1)又名二氯菊酸,DV菊酸,是菊酸中的甲基被氯原子取代的衍生物,用于生产菊酯类农药的中间体,比菊酯类农药(甲基未被氯所取代)活性更高,用量更低。根据Marketsand Markets发布的最新报告显示,2014年拟除虫菊酯杀虫剂市场的价值约为25.5962亿美元,预计到2019年将以4.8%的复合年增长率增长至32.3324亿美元。
制备1的方法有化学法和生物法,其关键点在于从产物的其他三种异构体(2,3,4)中获得高纯度的1。化学法路线有拆分法(Journal of Agriculturaland Food Chemistry,1997,45(11),4466-4473,US 6150404,CN 200610015694)、合成法(CN 201010593321.9,201010141980)等,化学方法面临的问题是,收率和产物的光学纯度低,且需要用到等当量的手性拆分试剂,或难以回收利用的金属催化剂。生物方法如J.Org.Chem.2003,68,621-624报道的路线,利用微生物中的腈水解酶和腈水合酶对氯氰菊酯底物进行拆分,由于微生物中既有腈水解酶又有腈水合酶,因此酶用量较大(为底物质量的20倍),产物为酸和酰胺的混合物,产物1的ee值〈90%。WO8706269公开了一种利用微生物拆分二氯菊酸甲酯的方法,该方法利用微生物菌体对底物进行拆分,菌体用量为底物浓度的50%,反应时间96小时,且产物纯度〈93%,应用困难。以上方法面临的问题在于,野生型微生物催化剂中含有的目的蛋白量较低,且含有其他蛋白,其中的水解酶对反应可能会造成干扰,因此产物纯度低。
综上所述,目前尚无利用酶法拆分获得1的有效方法。
发明内容
本发明的目的是提供了一种反应转化率高、产物纯度高、对环境友好的酶法合成菊酯类杀虫剂中间体的方法。解决了现有技术中无游离酶法制备菊酯类杀虫剂中间体的方法。
为达到上述目的,本发明采用的技术方案是:一种酶法合成菊酯类杀虫剂中间体的方法,以具有化合物5结构的顺式、反式菊酸异构体的混合DV菊酸甲酯为底物,底物的投加浓度为1~50g/L,在温度25~50℃、pH为6.0-8.0的缓冲溶液中,在水解酶的作用下,水解反应生成菊酯类杀虫剂中间体,其中,混合DV菊酸甲酯中顺式异构体与反式异构体的投料质量比为2:8~6:4,所述的水解酶为蛋白酶或酯酶,所述的水解酶的投加质量为所述底物质量的10~100%,
化合物5的结构式如下:
菊酯类杀虫剂中间体的结构式如下:
优选地,混合DV菊酸甲酯中顺式异构体与反式异构体的投料质量比为4:6。
优选地,所述的缓冲溶液的pH为6.0~7.0。
优选地,所述的缓冲溶液为磷酸盐缓冲溶液。
优选地,所述反应在助溶剂条件下进行,所述的助溶剂为乙腈、丙酮或二者的组合。
进一步优选地,所述助溶剂的投料体积为反应体系总体积的1~10%。
优选地,所述的酯酶购自AMAN0/天野酶公司的酯酶CES-E2。
优选地,所述的蛋白酶为购自sigma公司的Aspergillus saitoi蛋白酶。
优选地,具体的实施过程如下:将所述的底物、水解酶加入到所述的缓冲溶液中,控制反应温度在25~50℃间,水解反应生成菊酯类杀虫剂中间体,反应结束后,采用等体积乙酸乙酯萃取,经旋蒸得到菊酯类杀虫剂中间体的纯品,并采用气相色谱检测纯品转化率及纯度。
由于上述技术方案的运用,本发明与现有技术相比具有下列优点:
1)解决了化学法制备DV菊酸的过程中,所造成的收率与产物的光学纯度低的问题,同时解决了需要用到等量的手性拆分试剂或难以回收利用的金属催化剂对环境造成污染的问题;
2)解决了采用微生物拆分法制备DV菊酸过程中,所使用的酶用量大、产物纯度低、反应时间长的问题;
3)本发明的酶法制备DV菊酸,解决了采用水解酶水解过程中对反应造成干扰、导致产物纯度低的问题,其反应转化率高、产物纯度高、产品分离简单、绿色环保,适于工业化生产。
附图说明
附图1为实施例7得到的(1R,3R)-2,2-二甲基-3-(2,2-二氯乙烯基)环丙烷羧酸的气相色谱图。
具体实施方式
下面结合具体实施例对本发明做进一步详细的说明,但本发明并不限于以下实施例。实施例中采用的实施条件可以根据具体使用的不同要求做进一步调整,未注明的实施条件为常规实验中的条件。
实施例1
取投料质量比为4:6的顺式、反式DV菊酸甲酯异构体的混合甲酯(产物1的理论收率为30%,下同)1g,加入pH 7.0,0.1M磷酸盐缓冲溶液19mL,乙腈lmL,脂肪酶Lipase PS(购自AMAN0/天野酶公司)lg,30℃下反应2小时后等体积乙酸乙酯萃取,气相色谱检测,转化率为4.5%,四种产品的比例(1:2:3:4)为2:94.5:0:3.5。
实施例2
取顺式、反式DV菊酸甲酯异构体的混合甲酯lg,加入pH 7.0,0.1M磷酸盐缓冲溶液19mL,乙腈lmL,Aspergillus saitoi蛋白酶(购自sigma公司)lg,30℃下反应2小时后等体积乙酸乙酯萃取,气相色谱检测,转化率为5.3%,四种产品的比例(1:2:3:4)为94.4:0.7:0:4.9。
实施例3
取顺式、反式DV菊酸甲酯异构体的混合甲酯lg,加入pH 7.0,0.1M磷酸盐缓冲溶液19mL,乙腈1ml,酯酶CES-E2(购自AMANO/天野酶公司,下同)lg,30℃下反应2小时后等体积乙酸乙酯萃取,气相色谱检测,转化率为24.8%,四种产品的比例(1:2:3:4)为93.1:4:0:2.9。
从实施例1、2、3中可看出,选用sigma公司生产的Aspergillus saitoi蛋白酶或AMANO/天野酶公司生产的酯酶CES-E2作为水解酶,其产物1的收率要明显高于选用购自AMANO/天野酶公司的脂肪酶Lipase PS作为水解酶所得到的收率。
实施例4
取顺式、反式DV菊酸甲酯异构体的混合甲酯lg,加入pH 6.0、7.0、8.0和9.0,0.1M缓冲溶液19mL,乙腈lmL,酯酶CES-E2 0.lg,30℃下反应16小时后等体积乙酸乙酯萃取,气相色谱检测,结果如下:
表1
pH | 6.0 | 7.0 | 8.0 | 9.0 |
转化率% | 12 | 27 | 25 | 24 |
产物纯度% | 95 | 97.8 | 91.9 | 57.5 |
从表1中可看出,在其余条件不变的情况下,当体系pH为7.0时,底物的转化率最高,且产物的纯度最高。
实施例5
取顺式、反式DV菊酸甲酯异构体的混合甲酯1g,加入pH 7.0,0.1M磷酸盐缓冲溶液19mL,乙腈1mL,酯酶CES-E20.1g,分别在25、30、35、40、50℃下反应16小时后等体积乙酸乙酯萃取,气相色谱检测,结果如下:
表2
温度℃ | 25 | 30 | 35 | 40 | 50 |
转化率% | 25 | 25.2 | 25.1 | 25.5 | 26.1 |
产物纯度% | 98.7 | 98.7 | 98.8 | 98.7 | 98.7 |
从表2中可看出,在其余条件不变的情形下,在50℃温度条件下,底物的转化率最高,而在35℃温度条件下,产物的纯度最高。
实施例6
取顺式、反式DV菊酸甲酯异构体的混合甲酯1g,加入pH 7.0,0.1M磷酸盐缓冲溶液19mL,不同有机溶剂1mL,酯酶CES-E20.1g,35℃下反应16小时后等体积乙酸乙酯萃取,气相色谱检测,结果如下:
表3
有机溶剂 | 空白 | 乙腈 | 丙酮 | MTBE |
转化率% | 26.4 | 26.8 | 29.2 | 18 |
产物纯度% | 97.9 | 97.8 | 97.9 | 97.8 |
从表3中可看出,如在丙酮存在的有机溶剂中进行所述反应,在确保产品纯度的情况下,底物的转化率有所提高。
实施例7
取顺式、反式DV菊酸甲酯异构体的混合甲酯10g,加入pH 7.0,0.1M磷酸盐缓冲溶液190mL,丙酮10mL,酯酶CES-E2lg,35℃下反应20小时后气相色谱检测,转化率为24.8%,四种产品的比例(1:2:3:4)为98.1:0.7:0:1.2,调节pH至3.5~2.0后等体积乙酸乙酯萃取三次,旋蒸得到产品2.7g,收率95%。
从附图1中可知,产物1、2、3、4的甲酯的出峰时间分别为4.684,4.541,4.392,4.430min,产物1的出峰时间为6.164min。
上述实施例中产品纯度的测定方法采用了气相色谱检测方法,该检测方法所采用的色谱仪为岛津GC-2014,气化室温度220℃,FID检测器温度250℃,载气为氮气,流速为4.5mL/min,分流比为10:1,色谱柱为Supelcoβ-Dex 120,升温程序为100℃3min,40℃/min至180℃,保持2min后结束。
上述实施例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人士能够了解本发明的内容并加以实施,并不能以此限制本发明的保护范围,凡根据本发明精神实质所作的等效变化或修饰,都应涵盖在本发明的保护范围内。
Claims (6)
1.一种酶法合成菊酯类杀虫剂中间体的方法,其特征在于,以具有化合物5结构的顺式、反式二氯菊酸甲酯异构体的混合物为底物,底物的投加浓度为1~50g/L,在温度25~50℃、pH为6.0~8.0的缓冲溶液中,在水解酶的作用下,水解反应生成菊酯类杀虫剂中间体,其中,混合二氯菊酸甲酯中顺式异构体与反式异构体的投料质量比为2:8~6:4,所述的水解酶为酯酶CES-E2或Aspergillus saitoi蛋白酶,所述的水解酶的投加质量为所述底物质量的10~100%,
化合物5的结构式如下:
菊酯类杀虫剂中间体的结构式如下:
2.根据权利要求1所述的酶法合成菊酯类杀虫剂中间体的方法,其特征在于:所述的缓冲溶液的pH为6.0~7.0。
3.根据权利要求1所述的酶法合成菊酯类杀虫剂中间体的方法,其特征在于:所述的缓冲溶液为磷酸盐缓冲溶液。
4.根据权利要求1所述的酶法合成菊酯类杀虫剂中间体的方法,其特征在于:所述反应在助溶剂条件下进行,所述的助溶剂为乙腈、丙酮或二者的组合。
5.根据权利要求4所述的酶法合成菊酯类杀虫剂中间体的方法,其特征在于:所述助溶剂的投料体积为反应体系总体积的1~10%。
6.根据权利要求1至5中任一项权利要求所述的酶法合成菊酯类杀虫剂中间体的方法,其特征在于,具体的实施过程如下:将所述的底物、水解酶加入到所述的缓冲溶液中,控制反应温度在25~50℃间,水解反应生成菊酯类杀虫剂中间体,反应结束后,采用等体积乙酸乙酯萃取,经旋蒸得到菊酯类杀虫剂中间体的纯品,并采用气相色谱检测纯品转化率及纯度。
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