CN115109104B - 一种3’-脱氧腺苷的合成方法 - Google Patents
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
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Abstract
本发明公开了一种3’‑脱氧腺苷的合成方法,本发明中的3’‑脱氧腺苷合成方法基于苯甲酰基在酸性环境中会发生定向迁移的特性进行,整个过程反应条件温和,处理简单,所需药品廉价易得,中间产物多采用一锅法进行合成,并且很少有中间产物需要硅胶柱层析法分离纯化,省去了后续实验处理及分离纯化的操作时间,使整个反应过程时间大幅缩短。而且由于不需要多次纯化,最终产率得到保证,总产率可达30%,可一次性达到十克级。
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种3’-脱氧腺苷的合成方法。
背景技术
现有技术中一般采用下述方法合成虫草素(3-脱氧腺苷,化合物13):
该方法存在以下缺陷:
a)在每一步实验反应结束后都需要利用硅胶柱层析进行分离纯化,必然会浪费大量的时间和造成实验产物的浪费,从来造成总产率不高;
b)化合物4的制备反应中涉及到1,2:5,6-二-O-异亚丙基以及化合物7的1,2:3,5-二-O-异亚丙基选择性脱除,对于实验药品的用量及反应需要十分精确的掌握,这步反应尚不成熟,会造成化合物4的分离纯化会繁琐复杂进而影响实验产率;并且高碘酸和硼氢化钠属于易制毒易制爆物品,在药品采购过程中也会比较麻烦;
c)化合物8的制备过程中,需要选择性保护伯醇,在此过程中会生成副反应产物,由于副产物和主产物的极性差距不大,在分离纯化中会占用大量时间。
综上所述,在现有制备3-脱氧核糖过程中,存在保护官能团的选择性保护和选择性脱除、实验药品采购困难以及中间产物全部需要硅胶柱层析分离纯化等问题,造成整个生产过程时间较长以及实验总产率较低。
发明内容
针对上述现有技术,本发明提供一种3’-脱氧腺苷的合成方法,以解决现有虫草素合成方法耗时长、产率低的问题。
为了达到上述目的,本发明所采用的技术方案是,提供一种3’-脱氧腺苷的合成方法,包括以下步骤:
S1:对D-木糖进行甲基化修饰,得到如式(I)所示的化合物;
S2:对如式(I)所示化合物进行脱羟基处理,得到如式(II)所示的化合物;
S3:将如式(II)所示的化合物溶于有机酸中,加入乙酸酐和浓硫酸,于冰浴下反应0.5~2h,然后分离纯化产物;
S4:将N6-苯甲酰基腺嘌呤溶于乙腈中,然后于惰性气体氛围中加入N,O-双(三甲基甲硅烷基)乙酰胺,搅拌至反应体系澄清;随后加入S3中分离纯化后的产物,再滴加三氟甲磺酸三甲基硅酯,滴毕室温搅拌反应10~20min,随后将体系升温至75~85℃,保温反应1~2h,再分离纯化,然后将纯化后的物质与甲醇混合,,通入氨气后,于50~60℃反应2~4h,即得。
在上述技术方案的基础上,本发明还可以做如下改进。
进一步,D-木糖的甲基化修饰包括以下步骤:
S11:将D-木糖溶于有机溶剂中,冰浴下加入乙酰氯,再于室温下反应35~45min,然后浓缩、纯化,得产物一;
S12:将产物一溶于有机溶剂中,加入三乙烯二胺,于室温下反应10~20min后加入三苯基氯甲烷,继续搅拌反应1.5~2.5h;然后于冰浴条件下向反应体系中加入吡啶,搅拌反应0.5h后加入苯甲酰氯,再升温至40℃,继续搅拌反应2h,随后萃取、浓缩,得产物二;
S13:将产物二溶解于二氯甲烷和甲醇的混合溶剂中,加入对甲苯磺酸一水合物,于室温下搅拌反应8~12h,然后萃取、浓缩、纯化,完成D-木糖的甲基化修饰。
进一步,产物一与三乙烯二胺、三苯基氯甲烷、吡啶和苯甲酰氯的摩尔比为0.2~0.25:0.45~0.5:0.45~0.5:2.9~2.95:0.95~1。
进一步,如式(I)所示化合物的脱羟基处理包括以下步骤:
S21:将如式(I)所示化合物和二硫化碳溶解于有机溶剂中,加入氢化钠,搅拌反应45~55min,然后加入碘甲烷,继续搅拌反应1h,然后浓缩、纯化,得产物三;
S22:将偶氮二异丁腈和三丁基氢化锡共溶于有机溶剂中,得混合溶液;将产物三溶解于有机溶剂中,于100~120℃下回流0.5h,然后将混合溶液滴加至反应体系中,继续搅拌反应1~3h,再浓缩、纯化,完成如式(I)所示化合物的脱羟基处理。
进一步,如式(I)所示化合物与二硫化碳、氢化钠和碘甲烷的摩尔比为0.05~0.1:0.35~0.45:0.1~0.2:0.1~0.2。
进一步,产物三与偶氮二异丁腈和三丁基氢化锡的摩尔比为0.05~0.1:0.01~0.05:0.05~0.1。
进一步,如式(II)所示化合物与乙酰溴和N6-苯甲酰基腺嘌呤的摩尔比为0.005~0.01:0.001~0.005:0.01~0.015。
本发明的有益效果是:本发明中的3’-脱氧腺苷(虫草素)合成方法基于苯甲酰基在酸性环境中会发生定向迁移的特性进行,整个过程反应条件温和,处理简单,所需药品廉价易得,中间产物多采用一锅法进行合成,并且很少有中间产物需要硅胶柱层析法分离纯化,省去了后续实验处理及分离纯化的操作时间,使整个反应过程时间大幅缩短。而且由于不需要多次纯化,最终产率得到保证,总产率可达30%,可一次性达到十克级。
具体实施方式
下面结合实施例对本发明的具体实施方式做详细的说明。
实施例1
一种3’-脱氧腺苷(虫草素)的制备方法,包括以下步骤:
(1)合成甲基-2,3-二-O-苯甲酰基-5-三苯基甲基-α/β-D-呋喃核糖(化合物1)
反应方程式如下:
a)称取D-木糖(60.00g,0.40mol)放入干燥圆底烧瓶中,加入甲醇(500mL)后冰浴条件下缓慢滴入乙酰氯(32mL)后移除冰浴条件室温反应40min。TLC[V(MeOH):V(EA)=1:5]检测反应完成。加入干燥碳酸氢钠粉末中和体系中多余的有机酸,过滤除掉大部分盐后在真空条件下浓缩收集,配制2500mL[V(MeOH):V(EA)=1:4]的混合溶液溶解产物后用带有硅藻土(3cm)的抽滤漏斗快速抽滤两次(除盐),真空浓缩收集,得到无色糖浆状产物。
b)将步骤a)制得的产物(40.00g,0.24mol)经乙腈(1330mL)溶解后,加入三乙烯二胺(54.70g,0.49mol)室温搅拌15min后加入三苯基氯甲烷(135.90g,0.49mol)室温搅拌2h。
c)然后将反应体系移至冰浴条件中并加入吡啶(235mL,2.92mol)搅拌0.5h后缓慢滴入苯甲酰氯(113mL,0.98mol),滴毕,升至40℃搅拌2h。处理:真空浓缩体系后加入二氯甲烷(1000mL)和水(1000mL)混合搅拌,加入分液漏斗混合液分为三层,从上至下分别为水层,白色的苯甲酸层,以及溶解产物后的二氯甲烷层。取下层有机相后,再用二氯甲烷(2*500mL)洗涤水层两次后合并有机相,经饱和食盐水和无水硫酸钠干燥后真空浓缩得到化合物1(140.80g,91%)。
(2)合成甲基-2,5-二-O-苯甲酰基-α/β-D-呋喃核糖(化合物2)
反应方程式如下:
将化合物1(120.00g,0.195mol)用二氯甲烷(975mL)和甲醇(1.95mL)溶解搅拌10min后加入对甲苯磺酸一水合物(74.10g,0.39mol)室温搅拌10h。处理:加研磨后的无水碳酸钠粉末中和体系多余的有机酸,过程中体系会出现大量气泡并从黄色液体变成无色液体。当反应体系酸碱度调至接近中性后加纯净水进行萃取,有机相依次经饱和碳酸钠溶液和饱和氯化钠溶液洗涤后真空浓缩收集后经硅胶色谱柱分离纯化,洗脱液极性:[V(PE):V(EA)=6:1],得到无色糖浆状化合物2(34.80g,48%)。
化合物2的检测谱图数据为:1H NMR(400MHz,CDCl3)δ8.02-7.88(m,6H),7.47(q,J=8.4,8.0Hz,3H),7.38-7.29(m,6H),7.18(d,J=6.4Hz,1H),5.22(s,1H),5.17(s,1H),5.02(s,1H),4.72-4.56(m,3H),4.46(ddd,J=23.6,11.6,6.4Hz,2H),4.34(d,J=4.4Hz,1H),3.37(s,3H),3.32(s,1H).13C NMR(100MHz,CDCl3)δ166.74,166.65,166.5,165.5,133.6,133.4,133.2,133.1,129.96,129.90,129.8,129.7,129.0,128.5,128.43,128.37,127.95,127.86,127.2,106.7,100.9,81.76,81.2,81.1,75.9,74.5,73.9,64.2,63.3,60.4,55.7,55.5,53.4.
(3)合成甲基-2,5-二-O-苯甲酰基-3-脱氧-α/β-D-呋喃核糖合成(化合物3)
反应方程式如下:
a)0℃下,将化合物2(28.72g,0.08mmol)和二硫化碳(24mL,0.40mol)溶解在无水四氢呋喃(195mL)中后缓慢加入氢化钠(3.70g,0.15mol),加完搅拌50min后滴入碘甲烷(10mL,0.15mol)搅拌1h。处理:滴加冰醋酸中和反应体系的pH后真空浓缩收集后利用硅胶短色谱柱除掉盐和不溶性杂质,洗脱液极性:[V(PE):V(EA)=10:1],得到黄色糖浆状化合物。
b)取步骤a)制得的产物(34.90g,0.08mol)用无水甲苯(400mL)溶解后置于110℃冷凝回流0.5h,采用无水甲苯(50mL)溶解偶氮二异丁腈(3.10g,0.02mmol)和三丁基氢化锡(24mL,0.09mol)后滴入反应体系反应2h。处理:反应体系真空浓缩后收集,利用硅胶短色谱柱除掉盐和不溶性杂质,洗脱液极性:[V(PE):V(EA)=100:1→V(PE):V(EA)=10:1]。得到无色糖浆状化合物3(25.8g,94%)。
化合物3的检测谱图数据为:1H NMR(600MHz,CDCl3)δ8.12-8.02(m,5H),7.60-7.56(m,2H),7.48-7.43(m,5H),5.41(d,J=4.2Hz,1H),5.08(s,1H),4.78(m,1H),4.51(dd,J=11.4,4.2Hz,1H),4.36(dd,J=11.4,6.0Hz,1H),3.39(s,3H),2.37-2.27(m,2H);13C NMR(150MHz,CDCl3)δ166.4,165.7,133.3,133.1,129.9,129.73,129.71,128.44,128.39,107.0,78.2,77.5,67.2,54.7,32.0.
(4)合成3-脱氧-N6-苯甲酰基-9-(2’,5’-二-O-苯甲酰基-3’-脱氧-β-D-核糖)腺苷(化合物4)
反应方程式如下:
a)将化合物3(23.0g,0.06mmol)利用冰乙酸(190mL)在室温下溶于圆底烧瓶中,搅拌10min后加入乙酸酐(26mL,0.28mol)后移至冰浴环境中,缓慢滴加浓硫酸(13mL,0.25mol),滴闭搅拌1h。反应完全后,准备一个500mL烧杯,加入100mL饱和碳酸钠冰水溶液,并在上层加入为1/3饱和碳酸钠冰水溶液体积的乙酸乙酯溶液,将反应体系用100mL乙酸乙酯稀释后缓慢滴加进烧杯搅拌中和酸碱度后分液取有机层,用乙酸乙酯洗水层两次后用无水硫酸钠干燥,真空减压浓缩。得到黄色糖浆状产物。
b)将N6-苯甲酰基腺嘌呤(11.5g,0.05mol)溶于新重蒸的无水乙腈(200mL)中,然后通入惰性气体(氮气)10min,再加入N,O-双(三甲基甲硅烷基)乙酰胺(BSA)(30.0g,0.15mol),搅拌至反应体系全部透明澄清,继续反应10min;随后加入上述a)中制备的黄色糖浆状产物(12.0g,0.004mol),再缓慢滴加三氟甲磺酸三甲基硅酯(49g,0.22mol),滴毕室温搅拌反应15min,随后将体系升温至80℃反应1h,TLC检测(VPE:VEA=5:4)反应过程结束后减压浓缩,得到的粗品经硅胶层析柱层析分离纯化(洗脱液极性:VPE:VEA=10:1),得到产物4(14.4g,82%)。
化合物4的检测谱图数据为:1H NMR(600MHz,CDCl3)δ8.75(s,1H),8.20(s,1H),8.07(dd,J=7.8,1.2Hz,2H),8.02(dd,J=8.4,1.2Hz,2H),7.99(dd,J=8.4,1.2Hz,2H),7.74-7.35(m,10H),6.28(d,J=1.2Hz,1H),6.13(d,J=6.0Hz,1H),4.90(m,1H),4.75(dd,J=12.0,3.0Hz,1H),4.59(dd,J=12.0,5.4Hz,1H),3.01(ddd,J=14.4,10.2,6.0Hz,1H),2.53-2.48(m,1H);13C NMR(150MHz,CDCl3)δ166.3,165.8,152.7,151.1,149.7,142.1,133.8,133.7,133.4,132.8,129.8,129.6,129.4,128.9,128.8,128.6,128.5,127.9,123.6,90.6,79.2,78.4,64.9,33.6.
(5)合成虫草素(化合物5)
反应方程式如下:
在高压反应瓶中依次加入无水甲醇180mL和化合物4(3.19g,0.01mol),搅拌使其溶解;通入氨气后55℃反应3h。缓慢冷却至室温,温度小于35摄氏度真空浓缩后加水100mL和二氯甲烷100mL后萃取取水相冰冻后经冻干得淡黄色固体虫草素(化合物5,2.05g,85.1%)。
虫草素(化合物5)的检测谱图数据为:1H NMR(400MHz,DMSO-d6)δ:8.36(s,1H),8.15(s,1H),7.30(s,2H),5.87(d,J=6.0Hz,1H),5.69(d,J=5.6Hz,1H),5.19-5.17(m,1H),4.57(s,1H),4.34(s,1H),3.69-3.66(m,1H),3.51-3.46(m,1H),2.27-2.20(m,2H),1.93-1.90(m,2H);13C NMR(100MHz,DMSO-d6)δ:156.1,152.2,149.0,139.1,119.1,90.8,80.8,74.7,62.7,34.4。虽然结合实施例对本发明的具体实施方式进行了详细地描述,但不应理解为对本专利的保护范围的限定。在权利要求书所描述的范围内,本领域技术人员不经创造性劳动即可作出的各种修改和变形仍属本专利的保护范围。
Claims (5)
1.一种3’-脱氧腺苷的合成方法,其特征在于,包括以下步骤:
S1:对D-木糖进行甲基化修饰,得到如式(I)所示的化合物;
;
D-木糖的甲基化修饰包括以下步骤:
S11:将D-木糖溶于有机溶剂中,冰浴下加入乙酰氯,再于室温下反应35~45 min,然后浓缩、纯化,得产物一;
S12:将产物一溶于有机溶剂中,加入三乙烯二胺,于室温下反应10~20 min后加入三苯基氯甲烷,继续搅拌反应1.5~2.5 h;然后于冰浴条件下向反应体系中加入吡啶,搅拌反应0.5 h后加入苯甲酰氯,再升温至40 ℃,继续搅拌反应2 h,随后萃取、浓缩,得产物二;
S13:将产物二溶解于二氯甲烷和甲醇的混合溶剂中,加入对甲苯磺酸一水合物,于室温下搅拌反应8~12 h,然后萃取、浓缩、纯化,完成D-木糖的甲基化修饰;
S2:对如式(I)所示化合物进行脱羟基处理,得到如式(II)所示的化合物;
;
如式(I)所示化合物的脱羟基处理包括以下步骤:
S21:将如式(I)所示化合物和二硫化碳溶解于有机溶剂中,加入氢化钠,搅拌反应45~55 min,然后加入碘甲烷,继续搅拌反应1 h,然后浓缩、纯化,得产物三;
S22:将偶氮二异丁腈和三丁基氢化锡共溶于有机溶剂中,得混合溶液;将产物三溶解于有机溶剂中,于100~120 ℃下回流0.5 h,然后将混合溶液滴加至反应体系中,继续搅拌反应1~3 h,再浓缩、纯化,完成如式(I)所示化合物的脱羟基处理;
S3:将如式(II)所示的化合物溶于有机酸中,加入乙酸酐和浓硫酸,于冰浴下反应0.5~2 h,然后分离纯化产物;
S4:将N6-苯甲酰基腺嘌呤溶于乙腈中,然后于惰性气体氛围中加入N,O-双(三甲基甲硅烷基)乙酰胺,搅拌至反应体系澄清;随后加入S3中分离纯化后的产物,再滴加三氟甲磺酸三甲基硅酯,滴毕室温搅拌反应10~20 min,随后将体系升温至75~85 ℃,保温反应1~2h,再分离纯化,然后将纯化后的物质与甲醇混合,通入氨气后,于50~60 ℃反应2~4 h,即得。
2.根据权利要求1所述的3’-脱氧腺苷的合成方法,其特征在于:产物一与三乙烯二胺、三苯基氯甲烷、吡啶和苯甲酰氯的摩尔比为0.2~0.25:0.45~0.5:0.45~0.5:2.9~2.95:0.95~1。
3.根据权利要求1所述的3’-脱氧腺苷的合成方法,其特征在于:如式(I)所示化合物与二硫化碳、氢化钠和碘甲烷的摩尔比为0.05~0.1:0.35~0.45:0.1~0.2:0.1~0.2。
4.根据权利要求1所述的3’-脱氧腺苷的合成方法,其特征在于:产物三与偶氮二异丁腈和三丁基氢化锡的摩尔比为0.05~0.1:0.01~0.05:0.05~0.1。
5.根据权利要求1所述的3’-脱氧腺苷的合成方法,其特征在于:如式(II)所示化合物与乙酰溴和N6-苯甲酰基腺嘌呤的摩尔比为0.005~0.01:0.001~0.005:0.01~0.015。
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