CN116804028A - 一类n-烷基取代的沙蚕磷类化合物及其制备方法 - Google Patents
一类n-烷基取代的沙蚕磷类化合物及其制备方法 Download PDFInfo
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Abstract
本发明公开了一类N‑烷基取代的沙蚕磷类化合物及其制备方法,属于有机化学领域。该制备方法以N‑烷基‑1,3‑二氯丙烷、硫代磷酸酯为原料,在NaH的作用下,以乙腈为溶剂,通过取代反应制得该类沙蚕磷类化合物。该方法条件温和,原料易得,操作简单。制得的沙蚕磷类化合物以天然产物沙蚕毒素为先导化合物,通过具有广泛生物活性的硫代磷酸酯加以修饰,可用于生物医药、农药等方面。
Description
技术领域
本发明涉及一类N-烷基取代的沙蚕磷类化合物及其合成方法,属于有机化学领域,用于得到一系列具有生物活性的沙蚕磷类化合物。
背景技术
现代农业的发展得益于农药的广泛使用。随着社会经济的发展,全球对农药的需求尤其是绿色农药的需求与日俱增。从天然产物中分离出具有具有杀虫杀菌等生物活性的有效成分,加以人工修饰,改造后合成可用于商业化大规模生产的仿生农药对绿色农药的研究及现代化农业的推动具有至关重要的作用。因此目前对仿生农药的开发与研究主要集中在对天然产物研究上。
早期人们发现,蚊蝇等昆虫在沙蚕尸体上爬行后会中毒死亡,同时使用沙蚕的垂钓者会产生头痛、恶心呕吐、呼吸异常的症状。因此从海生环节足动物异足索沙蚕Lumbricomerereis hateropoda体内分离出该有效成分沙蚕毒素,并将之作为先导化合物开创了动物源杀虫剂的先河。目前以沙蚕毒素为先导化合物的上市商品化产品仅有五种:易卫杀,杀螟丹,杀虫磺,杀虫单,杀虫双。
沙蚕毒素及其商品化上市产品
沙蚕毒素类杀虫剂的作用靶标与有机磷、氨基甲酸酯等胆碱酯酶抑制剂不同,该类杀虫剂主要作用于nAChR,通过破坏受体的立体结构从而阻断受体正常的神经功能。因此,沙蚕毒素类杀虫剂与有机磷、氨基甲酸酯、拟除虫菊酯等杀虫剂在共同使用时不会产生交互抗性。但随着沙蚕毒素类杀虫剂在农业上的长期、大量的使用,加上使用不科学、害虫对逆环境适应的本能等因素的影响,部分害虫已经对沙蚕毒素类杀虫剂产生了不同程度的抗药性。为了丰富和发展动物源杀虫剂,合成新型的沙蚕毒素类杀虫剂是解决抗药性的有效途径之一。
农药史上曾风靡全球的有机磷农药,因种类多、药效高、用途广、易分解等特点,一度居于农药销量的全球榜首。因其对哺乳动物会产生较高的毒性,且不利于生态环境的安全防护,逐步淡出历史舞台。由于其应用的广泛性和在世界农药市场的稳定性,以及我国农药市场对低毒、低残留、安全的有机磷农药的需求,开发绿色环保的有机磷农药仍是商业合成农药中极其重要的研究领域。
硫代磷酸酯类化合物具有重要的生物活性,广泛应用于医用药物化学和农药化学中。因此将硫代磷酸酯类化合物与沙蚕毒素结合,设计合成新型的沙蚕磷类杀虫剂,逐步探索实现对具有杀虫广谱、高效、对哺乳动物低毒、环境易降解的仿生农药的合成,具有重要的应用价值。
具有生物活性硫代磷酸酯
发明内容
本发明的目的是合成新型沙蚕毒素衍生物并筛选出具有潜在杀虫活性的沙蚕毒素类衍生物解决沙蚕毒素类杀虫剂抗性问题,提供一类新型的沙蚕磷类化合物及其制备方法。
本发明解决上述问题采用的技术方案:N-烷基-1,3-二氯丙烷与硫代磷酸酯,在碱性条件下,通过取代反应得到式I所示化合物;
反应式中,R1为甲基、乙基或正丙基;R2为甲基、乙基、正丙基、异丙基、正丁基或苯基。
制备具有通式I的沙蚕磷类化合物的方法步骤如下:
采用的原料为中间体I:N-甲基-1,3-丙二醇、N-乙基-1,3-丙二醇、N-丙基-1,3-丙二醇,结构式如下所示:
中间体II:
R2为甲基、乙基、正丙基、异丙基、正丁基或苯基。
本发明提供的制备通式I所示沙蚕磷类化合物的方法步骤如下:
中间体1a以2,2-甲基-1,3-二噁烷-5-酮与甲胺缩合后,经NaBH4还原得2,2-甲基-1,3-二噁烷-5-甲胺并用Boc2O保护甲氨基,通过HCl酸化后得到N-甲基-1,3-丙二醇,再由SOCl2卤代,重结晶后得到中间体N-甲基-1,3-二氯丙烷盐酸盐;
以2-氨基-1,3-丙二醇为原料,对氨基进行烷基化得到N-乙基-1,3-丙二醇及N-丙基-1,3-丙二醇,经SOCl2卤代,重结晶后得到中间体N-乙基-1,3-二氯丙烷盐酸盐、N-丙基-1,3-二氯丙烷盐酸盐;
中间体部分硫代磷酸酯以醇为原料,与PCl3在碱的催化下通过取代反应合成对应的亚磷酸二酯,再与S和Et3N,在乙醚中反应一晚得到硫代磷酸酯的三乙胺盐,稀盐酸酸化后得到中间体硫代磷酸酯。
中间体N-甲基-1,3-二氯丙烷、N-乙基-1,3-二氯丙烷、N-丙基-1,3-二氯丙烷与硫代磷酸酯在碱性条件下发生亲核取代反应得到该类沙蚕磷化合物。
上述反应的溶剂为:乙腈、四氢呋喃、甲苯、丙酮、乙酸乙酯或二氯甲烷等;碱为:NaH、Et3N、DMAP或NaOH;
反应的温度变化范围为25℃~110℃,反应时间1~6h;N-烷基取代的1,3-二氯丙烷与硫代磷酸酯、碱的用量物质的量比为1∶3∶3。硫代磷酸酯的物质的量为N-烷基-1,3-二氯丙烷的2倍及以上,碱的用量与硫代磷酸酯的用量相同。
以下为本发明方法合成的化合物一览表1:
表1 沙蚕磷类化合物的名称编号与结构
本发明的有益效果:沙蚕磷类化合物是一类仿生农药,其结构中包含的硫代磷酸酯的一个特性是其在植物、动物和土壤微生物中的相对低稳定性和快速代谢分解,从而形成对人类和家畜环境相对安全的产品。沙蚕磷类化合物制备过程简单,纯化手段简便,可实现商业化大规模生产。
具体实施方式
以下结合具体实施例对本发明作进一步的描述。
实施例1
制备中间体I中2-甲氨基-1,3-丙二醇1a
制备方法步骤如下:
Step 1:250ml圆底烧瓶中加入2,2-甲基-1,3-二噁烷-5-酮(0.8g,6.15mmol),加入30ml二氯甲烷,加入甲胺(3.7ml,7.38mmol)。室温搅拌1h,加入NaBH4(0.31g,8.2mmol),室温搅拌12h,用甲醇淬灭,然后加入Boc2O(1.34g,6.15mmol),室温反应4h,用饱和Na2CO3稀释,DCM萃取(3×30ml),合并有机相并用MgSO4干燥,浓缩。过柱纯化(石油醚∶乙酸乙酯=6∶1,v/v)得(2,2-二甲基-1,3-二噁烷-5-基)(甲基)氨基甲酸叔丁酯0.9g(60%yield)
该产物为无色透明液体;
1H NMR(300MHz,CDCl3)δ3.88(ddd,J=18.0,13.6,8.0Hz,5H),2.97(s,3H),1.41(s,9H),1.38(d,J=5.0Hz,6H).
13C NMR(75MHz,CDCl3)δ155.53(s),98.24(s),79.78(s),61.49(s),28.39(s).
Step 2:25ml圆底烧瓶中加入(2,2-二甲基-1,3-二噁烷-5-基)(甲基)氨基甲酸叔丁酯(600mg,2.446mmol),加入THF与H2O的混合液(20ml,v/v=1∶1),加入4.0M的盐酸1,4-二氧六环溶液(1.834ml,7.34ml),室温反应一晚后旋除溶剂,残留液体溶于氯仿与异丙醇的混合液(v/v=1∶1)15ml中,加入Na2CO3(2g),室温搅拌1h。过滤,浓缩滤液得2-甲氨基-1,3-丙二醇1a,粗品直接进行下一步。
实施例2
制备中间体I中2-乙氨基-1,3-丙二醇1b
制备方法步骤如下:
将2-氨基-1,3-丙二醇(9.1g,0.1mol)加入到的250ml圆底烧瓶中,加入碳酸钾(13.82g,0.1mol)、溴乙烷(16.35g,0.15mol),然后加入适量甲苯作溶剂,回流搅拌3小时,冷却到室温,旋除甲苯,氯仿洗固体不溶物,过滤旋干得2-乙氨基-1,3-丙二醇粗品,为淡黄色油状液体。
实施例3
制备中间体I中2-丙氨基-1,3-丙二醇1c
制备方法步骤如下:
将2-氨基-1,3-丙二醇(9.1g,0.1mol)加入到的250ml圆底烧瓶中,加入碳酸钾(13.82g,0.1mol)、溴丙烷(18.45g,0.15mol),然后加入适量甲苯作溶剂,回流搅拌3小时,冷却到室温,旋除甲苯,氯仿洗固体不溶物,过滤旋干得2-丙氨基-1,3-丙二醇1c粗品,为黄色油状液体。
实施例4
制备中间体中2-甲氨基-1,3-二氯丙烷2a
制备方法步骤如下:
在50ml圆底烧瓶中加入1a粗品2g,冰浴条件下缓慢滴加SOCl2(6.9ml,0.1mol),滴加完毕后回流搅拌0.5h,冷却后旋除多余的氯化亚砜,氯仿重结晶得2-甲氨基-1,3-二氯丙烷2a的盐酸盐0.68g(20%yield)。
该产物为白色固体;
1H NMR(300MHz,D2O)δ4.07-4.01(m,4H),4.00-3.89(m,1H),2.86(s,3H).
13C NMR(75MHz,D2O)δ59.46(s),40.33(s),30.66(s).
MS(HRMS-ESI):Calcd for C4H9Cl2N,[M+H]+:142.0185,found:142.0168.
实施例5
制备中间体2-乙氨基-1,3-二氯丙烷2b
制备方法步骤如下:
在50ml圆底烧瓶中加入1b粗品2g,冰浴条件下缓慢滴加SOCl2(7.1ml,0.08mol),滴加完毕后回流搅拌0.5h,冷却后旋除多余的氯化亚砜,氯仿重结晶得2-乙氨基-1,3-二氯丙烷2b的盐酸盐1.36g(42%yield)。
该产物为白色固体;
1H NMR(300MHz,D2O)δ4.06-3.86(m,5H),3.25(q,J=7.2Hz,2H),1.31(t,J=7.2Hz,3H).
13C NMR(75MHz,D2O)δ57.94(s),41.28(s),40.32(s),10.38(s).
MS(HRMS-ESI):Calcd for C5H11Cl2N,[M+H]+:156.0341,found:156.0328.
实施例6
制备中间体2-丙氨基-1,3-二氯丙烷2c
制备方法步骤如下:
在50ml圆底烧瓶中加入1c粗品2g,冰浴条件下缓慢滴加SOCl2(5.5ml,0.075mol),滴加完毕后回流搅拌0.5h,冷却后旋除多余的氯化亚砜,氯仿重结晶得2-丙氨基-1,3-二氯丙烷2c的盐酸盐1.40g(45%yield)
该产物为白色固体;
1H NMR(300MHz,D2O)δ4.06-3.85(m,5H),3.21-3.06(m,2H),1.80-1.60(m,2H),0.95(t,J=7.4Hz,3H).
13C NMR(75MHz,D2O)δ58.25(s),47.33(s),40.22(s),19.04(s),10.07(s).
MS(HRMS-ESI):Calcd for C6H13Cl2N,[M+H]+:170.0498,found:170.0482.
实施例7
制备2-甲氨基-1,3-二(硫代磷酸二甲酯基)丙烷4a
制备方法步骤如下:
将硫代磷酸二甲酯3a(0.4262g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-甲氨基-1,3-二氯丙烷2a(0.1785g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥。
说明:化合物4a不稳定,在分离过程中即发生变质。
实施例8
制备2-甲氨基-1,3-二(硫代磷酸二乙酯基)丙烷4b
制备方法步骤如下:
将硫代磷酸二乙酯3b(0.5105g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-甲氨基-1,3-二氯丙烷2a(0.1785g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(15ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(乙酸乙酯∶甲醇=15∶1)得黄色油状物4b 147mg(36%yield)。
31P NMR(121MHz,CDCl3)δ27.43(s).
1H NMR(300MHz,CDCl3)δ4.25-4.04(m,8H),3.10-2.91(m,5H),2.42(s,3H),1.33(t,J=7.1Hz,12H).
13C NMR(75MHz,CDCl3)δ63.79(d,J=6.3Hz),59.23(t,J=4.7Hz),33.52(s),33.49(s),16.06(d,J=7.2Hz).
MS(HRMS-ESI):Calcd for C12H29NO6P2S2,[M+H]+:410.0984,found:410.0983.
实施例9
制备2-甲氨基-1,3-二(硫代磷酸二丙酯基)丙烷4c
制备方法步骤如下:
将硫代磷酸二丙酯3c(0.5947g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-甲氨基-1,3-二氯丙烷2a(0.1785g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(乙酸乙酯∶甲醇=30∶1)得黄色油状物4c 223mg(48%yield)。
31P NMR(121MHz,CDCl3)δ27.61(s).
1H NMR(300MHz,CDCl3)δ4.15-3.90(m,8H),3.12-2.94(m,5H),2.43(s,3H),1.80-1.60(m,8H),1.02-0.87(m,12H).
13C NMR(75MHz,CDCl3)δ69.27(d,J=6.7Hz),59.28(t,J=4.7Hz),34.56-32.36(m),23.56(d,J=7.3Hz),10.06(s).
MS(HRMS-ESI):Calcd for C16H37NO6P2S2,[M+H]+:466.1610,found:466.1611.
实施例10
制备2-甲氨基-1,3-二(硫代磷酸二异丙酯基)丙烷4d
制备方法步骤如下:
将硫代磷酸二异丙酯3d(0.5947g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-甲氨基-1,3-二氯丙烷2a(0.1785g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(乙酸乙酯∶甲醇=30∶1)得黄色油状物4d 405mg(87%yield)。
31P NMR(121MHz,CDCl3)δ25.02(s).
1H NMR(300MHz,CDCl3)δ4.83-4.64(m,4H),3.15-2.91(m,5H),2.43(s,3H),1.41-1.27(m,24H).
13C NMR(75MHz,CDCl3)δ72.98(dd,J=6.7,1.5Hz),59.21(t,J=5.0Hz),33.65(d,J=2.8Hz),33.49(s),23.87(d,J=4.1Hz),23.68(dd,J=5.4,1.4Hz).
MS(HRMS-ESI):Calcd for C16H37NO6P2S2,[M+H]+:466.1610,found:466.1619.
实施例11
制备2-甲氨基-1,3-二(硫代磷酸二丁酯基)丙烷4e
制备方法步骤如下:
将硫代磷酸二丁酯3e(0.6788g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-甲氨基-1,3-二氯丙烷2a(0.1785g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(100%乙酸乙酯)得黄色油状物4e 235mg(45%yield)。
31P NMR(121MHz,CDCl3)δ27.61(s).
1H NMR(300MHz,CDCl3)δ4.17-3.97(m,8H),3.08-2.94(m,5H),2.43(s,3H),1.75-1.56(m,8H),1.48-1.29(m,8H),1.01-0.83(m,12H).
13C NMR(75MHz,CDCl3)δ67.54(d,J=6.7Hz),59.30(t,J=4.7Hz),33.51(s),33.40(d,J=3.6Hz),32.17(d,J=7.2Hz),18.73(s),13.57(s).
MS(HRMS-ESI):Calcd for C20H45NO6P2S2,[M+H]+:522.2136,found:522.2238.
实施例12
制备2-甲氨基-1,3-二(硫代磷酸二苯酯基)丙烷4f
制备方法步骤如下:
将硫代磷酸二苯酯3f(0.7988g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-甲氨基-1,3-二氯丙烷2a(0.1785g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(反相C18制备柱,水∶乙腈=30∶70)得白色油状物4f 60mg(10%yield)。
31P NMR(121MHz,CDCl3)δ21.21(s).
1H NMR(300MHz,CDCl3)δ7.53-6.96(m,20H),2.97(dd,J=15.7,5.3Hz,4H),2.73(d,J=5.5Hz,1H),2.19(s,3H).
13C NMR(75MHz,CDCl3)δ149.99(s),129.92(s),125.82(s),120.75(dd,J=4.9,2.3Hz),59.02(s),33.26(s).
MS(HRMS-ESI):Calcd for C28H29NO6P2S2,[M+H]+:602.0984,found:602.0942.
实施例13
制备2-乙氨基-1,3-二(硫代磷酸二甲酯基)丙烷5a
制备方法步骤如下:
将硫代磷酸二甲酯3a(0.4262g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-乙氨基-1,3-二氯丙烷2b(0.1925g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(乙酸乙酯∶甲醇=20∶1)得黄色油状物5a 88mg(24%yield)。
31P NMR(121MHz,CDCl3)δ30.97(s).
1H NMR(300MHz,CDCl3)δ3.94-3.67(m,12H),3.14-2.92(m,5H),2.66(q,J=7.1Hz,2H),1.15-1.03(m,3H).
13C NMR(75MHz,CDCl3)δ57.57(t,J=4.4Hz),54.04(d,J=6.2Hz),41.26(s),33.88(d,J=3.6Hz),15.31(s).
MS(HRMS-ESI):Calcd for C9H23NO6P2S2,[M+H]+:368.0515,found:368.0493.
实施例14
制备2-乙氨基-1,3-二(硫代磷酸二乙酯基)丙烷5b
制备方法步骤如下:
将硫代磷酸二乙酯3b(0.5105g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-乙氨基-1,3-二氯丙烷2b(0.1925g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(乙酸乙酯∶甲醇=30∶1)得黄色油状物5b 216mg(51%yield)。
31P NMR(121MHz,CDCl3)δ27.57(s).
1H NMR(300MHz,CDCl3)δ4.32-4.02(m,8H),3.22-2.86(m,5H),2.67(q,J=7.1Hz,2H),1.35(t,J=7.1Hz,12H),1.10(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl3)δ63.80(d,J=6.2Hz),57.57(t,J=4.6Hz),41.32(s),33.97(d,J=3.6Hz),16.11(d,J=7.3Hz),15.35(s).
MS(HRMS-ESI):Calcd for C13H31NO6P2S2,[M+H]+:424.1141,found:424.1152.
实施例15
制备2-乙氨基-1,3-二(硫代磷酸二丙酯基)丙烷5c
制备方法步骤如下:
将硫代磷酸二丙酯3c(0.5947g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-乙氨基-1,3-二氯丙烷2b(0.1925g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(石油醚∶乙酸乙酯=1∶10)得黄色油状物5c 278mg(58%yield)。
31P NMR(121MHz,CDCl3)δ27.74(s).
1H NMR(300MHz,CDCl3)δ4.20-3.90(m,8H),3.19-2.90(m,5H),2.67(q,J=7.1Hz,2H),1.82-1.61(m,8H),1.10(t,J=7.1Hz,3H),0.96(t,J=7.4Hz,12H).
13C NMR(75MHz,CDCl3)δ69.24(d,J=6.7Hz),57.56(t,J=4.7Hz),41.32(s),33.92(d,J=3.6Hz),23.58(d,J=7.3Hz),15.35(s),10.09(s).
MS(HRMS-ESI):Calcd for C17H39NO6P2S2,[M+H]+:480.1767,found:480.1784.
实施例16
制备2-乙氨基-1,3-二(硫代磷酸二异丙酯基)丙烷5d
制备方法步骤如下:
将硫代磷酸二异丙酯3d(0.5947g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-乙氨基-1,3-二氯丙烷2b(0.1925g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(石油醚∶乙酸乙酯=1∶10)得黄色油状物5d 278mg(58%yield)。
31P NMR(121MHz,CDCl3)δ25.14(s).
1H NMR(300MHz,CDCl3)δ4.88-4.65(m,4H),3.21-2.90(m,5H),2.70(dd,J=13.7,6.7Hz,2H),1.44-1.32(m,24H),1.13(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl3)δ73.36-72.30(m),57.56(s),41.34(s),34.08(s),24.30-23.26(m),15.24(s).
MS(HRMS-ESI):Calcd for C17H39NO6P2S2,[M+H]+:480.1767,found:480.1784.
实施例17
制备2-乙氨基-1,3-二(硫代磷酸二丁酯基)丙烷5e
制备方法步骤如下:
将硫代磷酸二丁酯3e(0.6788g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-乙氨基-1,3-二氯丙烷2b(0.1925g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(石油醚∶乙酸乙酯=1∶1)得黄色油状物5e 279mg(52%yield)。
31P NMR(121MHz,CDCl3)δ27.87(d,J=31.2Hz).
1H NMR(300MHz,CDCl3)δ4.23-3.96(m,8H),3.17-2.92(m,5H),2.67(q,J=7.1Hz,2H),1.68(dt,J=14.6,6.6Hz,8H),1.40(dq,J=14.5,7.3Hz,8H),1.11(t,J=7.1Hz,3H),0.93(t,J=7.4Hz,12H).
13C NMR(75MHz,CDCl3)δ67.50(d,J=6.7Hz),57.57(s),41.33(s),33.92(d,J=3.5Hz),32.19(d,J=7.2Hz),18.75(s),15.35(s),13.61(s).
MS(HRMS-ESI):Calcd for C21H47NO6P2S2,[M+H]+:536.2393,found:536.2372.
实施例18
制备2-乙氨基-1,3-二(硫代磷酸二苯酯基)丙烷5f
制备方法步骤如下:
将硫代磷酸二苯酯3f(0.7988g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-乙氨基-1,3-二氯丙烷2b(0.1925g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(石油醚∶乙酸乙酯=2∶3)得黄色油状物5f 443mg(72%yield)。
31P NMR(121MHz,CDCl3)δ21.24(s).
1H NMR(300MHz,CDCl3)δ7.50-7.10(m,20H),2.98(dd,J=15.7,5.6Hz,4H),2.84(dd,J=11.1,5.5Hz,1H),2.43(q,J=7.1Hz,2H),0.92(t,J=7.1Hz,3H).
13C NMR(75MHz,CDCl3)δ150.05(dd,J=8.2,3.8Hz),129.86(s),125.74(s),120.68(dd,J=4.8,3.7Hz),57.31(t,J=4.5Hz),41.04(s),34.64(d,J=3.7Hz),15.09(s).
MS(HRMS-ESI):Calcd for C29H31NO6P2S2,[M+H]+:616.1141,found:616.1101.
实施例19
制备2-丙氨基-1,3-二(硫代磷酸二甲酯基)丙烷6a
制备方法步骤如下:
将硫代磷酸二甲酯3a(0.4262g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-丙氨基-1,3-二氯丙烷2c(0.2065g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(乙酸乙酯∶甲醇=25∶1)得黄色油状物6a 107mg(28%yield)。
31P NMR(121MHz,CDCl3)δ31.02(s).
1H NMR(300MHz,CDCl3)δ3.82(d,J=12.6Hz,12H),3.16-2.95(m,5H),2.62(dd,J=9.1,5.2Hz,2H),1.59-1.44(m,2H),1.02-0.88(m,3H).
13C NMR(75MHz,CDCl3)δ57.71(t,J=4.4Hz),54.07(d,J=6.2Hz),48.74(s),33.86(d,J=3.6Hz),23.22(s),11.73(s).
MS(HRMS-ESI):Calcd for C10H25NO6P2S2,[M+H]+:382.0671,found:382.0649.
实施例20
制备2-丙氨基-1,3-二(硫代磷酸二乙酯基)丙烷6b
制备方法步骤如下:
将硫代磷酸二乙酯3b(0.5105g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-丙氨基-1,3-二氯丙烷2c(0.2065g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(正己烷∶乙酸乙酯=1∶2)得黄色油状物6b 284mg(65%yield)。
31P NMR(121MHz,CDCl3)δ27.60(s).
1H NMR(300MHz,CDCl3)δ4.31-4.05(m,8H),3.16-2.94(m,5H),2.60(t,J=7.1Hz,2H),1.63-1.44(m,2H),1.37(t,J=7.1Hz,12H),0.94(t,J=7.4Hz,3H).
13C NMR(75MHz,CDCl3)δ63.76(d,J=6.2Hz),57.60(t,J=4.7Hz),48.80(s),34.02(d,J=3.6Hz),23.30(s),16.10(d,J=7.2Hz),11.74(s).
MS(HRMS-ESI):Calcd for C14H33NO6P2S2,[M+H]+:438.1297,found:438.1299.
实施例21
制备2-丙氨基-1,3-二(硫代磷酸二丙酯基)丙烷6c
制备方法步骤如下:
将硫代磷酸二丙酯3c(0.5947g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-丙氨基-1,3-二氯丙烷2c(0.2065g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(正己烷∶乙酸乙酯=1∶2)得黄色油状物6c 385mg(78%yield)。
31P NMR(121MHz,CDCl3)δ27.76(s).
1H NMR(300MHz,CDCl3)δ4.17-3.94(m,8H),3.06(td,J=14.6,5.7Hz,5H),2.60(t,J=7.1Hz,2H),1.90-1.63(m,5H),1.58-1.41(m,2H),1.09-0.85(m,15H).
13C NMR(75MHz,CDCl3)δ69.21(d,J=6.6Hz),57.60(t,J=4.7Hz),48.81(s),33.95(d,J=3.5Hz),23.56(d,J=7.3Hz),23.29(s),11.73(s),10.07(s).
MS(HRMS-ESI):Calcd for C18H41NO6P2S2,[M+H]+:494.1923,found:494.1918.
实施例22
制备2-丙氨基-1,3-二(硫代磷酸二异丙酯基)丙烷6d
制备方法步骤如下:
将硫代磷酸二异丙酯3d(0.5947g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-丙氨基-1,3-二氯丙烷2c(0.2065g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(正己烷∶乙酸乙酯=1∶2)得黄色油状物6d 385mg(78%yield)。
31P NMR(121MHz,CDCl3)δ25.19(s).
1H NMR(300MHz,CDCl3)δ4.79-4.61(m,4H),3.13-2.91(m,5H),2.56(t,J=7.1Hz,2H),1.46(dd,J=14.5,7.3Hz,2H),1.32(dd,J=5.9,5.2Hz,24H),0.88(t,J=7.4Hz,3H).
13C NMR(75MHz,CDCl3)δ72.82(dd,J=6.6,2.0Hz),57.54(t,J=5.1Hz),48.82(s),34.23(d,J=3.6Hz),24.06-23.45(m),23.27(s),11.73(s).
MS(HRMS-ESI):Calcd for C18H41NO6P2S2,[M+H]+:494.1923,found:494.1952.
实施例23
制备2-丙氨基-1,3-二(硫代磷酸二丁酯基)丙烷6e
制备方法步骤如下:
将硫代磷酸二丁酯3e(0.6788g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-丙氨基-1,3-二氯丙烷2c(0.2065g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(石油醚∶乙酸乙酯=1∶1)得黄色油状物6e 154mg(28%yield)。
31P NMR(121MHz,CDCl3)δ27.70(s).
1H NMR(300MHz,CDCl3)δ4.11-3.86(m,8H),3.05-2.83(m,5H),2.49(t,J=7.1Hz,2H),1.68-1.50(m,8H),1.45-1.20(m,10H),0.83(td,J=7.4,3.4Hz,15H).
13C NMR(75MHz,CDCl3)δ67.36(d,J=6.6Hz),57.54(t,J=4.7Hz),48.75(s),33.90(d,J=3.5Hz),32.09(d,J=7.2Hz),23.24(s),18.66(s),13.51(s),11.66(s).
MS(HRMS-ESI):Calcd for C22H49NO6P2S2,[M+H]+:550.2549,found:550.2542.
实施例24
制备2-丙氨基-1,3-二(硫代磷酸二苯酯基)丙烷6f
制备方法步骤如下:
将硫代磷酸二苯酯3f(0.7988g,3mmol)和NaH(0.12g,3mmol)溶于10ml乙腈中,室温搅拌10min,加入2-丙氨基-1,3-二氯丙烷2c(0.2065g,1mmol),50℃下搅拌至原料反应完全。反应完毕后过滤,滤液浓缩,二氯甲烷(50ml×3)与水进行萃取,合并有机相用无水硫酸镁干燥,过滤旋干后过柱纯化(石油醚∶乙酸乙酯=4∶1)得黄色油状物6f233mg(37%yield)。
31P NMR(121MHz,CDCl3)δ21.26(s).
1H NMR(300MHz,CDCl3)δ7.45-7.08(m,20H),2.98(dd,J=15.5,5.6Hz,4H),2.88-2.76(m,1H),2.34(t,J=7.1Hz,2H),1.28(dt,J=14.5,7.2Hz,2H),0.80(t,J=7.4Hz,3H).
13C NMR(75MHz,CDCl3)δ150.07(dd,J=8.2,3.6Hz),129.87(s),125.74(s),120.69(dd,J=4.9,3.4Hz),57.38(t,J=4.5Hz),48.49(s),34.70(d,J=3.7Hz),23.05(s),11.60(s).
MS(HRMS-ESI):Calcd for C30H33NO6P2S2,[M+H]+:630.1297,found:630.1258.。
Claims (2)
1.一类N-烷基取代的沙蚕磷类化合物,其特征在于该类化合物结构通式如下:
式中:
R1为甲基、乙基或正丙基;
R2为甲基、乙基、正丙基、异丙基、正丁基或苯基。
2.根据权利要求1所述的一类N-烷基取代的沙蚕磷类化合物,其特征是,该类化合物制备方法步骤如下:
N-烷基-1,3-二氯丙烷与硫代磷酸酯,在碱性条件下,通过取代反应得到式I所示化合物;
所述N-烷基-1,3-二氯丙烷为2-甲氨基-1,3-二氯丙烷、2-乙氨基-1,3-二氯丙烷或2-丙氨基-1,3-二氯丙烷;
硫代磷酸酯为硫代磷酸二甲酯、硫代磷酸二乙酯、硫代磷酸二丙酯、硫代磷酸二异丙酯、硫代磷酸二丁酯或硫代磷酸二苯酯;
溶剂为乙腈、四氢呋喃、甲苯、丙酮、乙酸乙酯或二氯甲烷;
碱为NaH、Et3N、DMAP、或NaOH;
反应温度25℃~110℃;反应时间1~6h;N-烷基-1,3-二氯丙烷、硫代磷酸酯及碱三者的物质的量比为1∶3∶3,硫代磷酸酯的物质的量为N-烷基-1,3-二氯丙烷的2倍以上,碱的用量与硫代磷酸酯的用量相同。
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