CN107056849B - 一种全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法 - Google Patents
一种全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法 Download PDFInfo
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Abstract
本发明公开了一种全乙酰基保护α‑2,6‑二脱氧葡萄糖‑O‑糖苷的制备方法,其特点是以全乙酰化2,6‑二脱氧葡萄糖为给体,伯醇、仲醇、叔丁醇、酪醇、酪醇或5‑羟甲基糠醛等为受体,将给体与受体按1:0.2~4的当量比混合,搅拌下按1mol:10~100L的摩尔体积比加入乙腈、二氯甲烷或1,2‑二氯乙烷溶解混合,在I2‑Et3SiH催化体系下进行糖苷化反应。本发明与现有技术相比具有工艺简单、操作方便,生产成本低,产率高,立体选择性高,反应条件更温和,反应时间短等优点,避免了高毒化学原料对环境的污染,是一种受体底物适用范围更广、绿色环保和经济高效的α‑2,6‑二脱氧葡萄糖‑O‑糖苷制备方法。
Description
技术领域
本发明涉及医药中间体合成技术领域,具体地说是一种全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法。
背景技术
2,6-二脱氧-α-糖苷广泛存在于许多具有重要生物活性的天然产物和临床试剂中,并且发挥着非常重要的作用,许多含有2,6-二脱氧糖结构单元的化合物,比如:蒽环类抗生素,大环内酯类抗生素,金霉酸,角环素类抗生素,强心苷等,分别对不同的疾病具有很好的疗效,引起了科学界和医学界的广泛关注。
2,6-二脱氧糖苷键相对于普通的糖类化合物而言,更加容易水解或降解破坏,故而其合成也就相对更加困难。Ye小组发展了一种以硫苷为给体,采用预活化的方法高效和立体选择性地制备2,6-二脱氧糖苷的方法。他们组采用3,4-O-碳酸酯保护的2,6-二脱氧-硫苷为给体,首先在-72℃下在苯亚磺酰吗啉(BSM)和三氟甲磺酸酐(Tf2O)共同作用下充分活化硫苷给体,然后和一系列醇受体反应,并最终以高收率和较好的α-选择性得到目标糖苷。但是该方法采用超低温操作,反应条件苛刻(Lu,Y.;Li,Q.;Zhang,L.;Ye,X.Org.Lett.2008,10,3445.)。
Lowary小组使用2,3-脱水糖的方法,在Lewis酸的作用下先生成2-硫取代糖,随后用三正丁基氢化锡和AIBN作用,还原得到2,6-二脱氧糖,此方法需要在C-2位引入保护基团,在糖苷化反应结束之后再脱除,操作步骤繁琐(Hou,D.;Lowary,T.L.J.Org.Chem.2009,74,2278)。
Bennett小组采用端基裸露的脱氧糖基给体在3,3-二氯-1,2-二苯基环丙烯和四丁基碘化铵(TBAI)的共同催化作用下经氯苷中间体,再经碘苷中间体,然后在与受体反应,并以70-86%的产率和适中的α-选择性得到目标产物。但是该方法所采用的催化剂较为昂贵(Nogueira,J.M.;Nguyen,S.H.;Bennet,C.S.Org.Lett.2011,13,2814.)。
综上所述,现有技术构建α-2,6-二脱氧糖苷的方法有很多,且各有千秋,有些给体不稳定、制备或活化比较困难,有些反应选择性和产率低或者普适性差,而且有些体系所使用的试剂昂贵且不方便,反应条件苛刻,操作步骤繁琐等,难以同时保证较高的最终产率和立体选择性。
发明内容
本发明的目的是针对现有技术的不足而提供的一种全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,采用I2-Et3SiH催化体系对全乙酰化2,6-二脱氧葡萄糖进行糖苷化反应,工艺简单、操作方便、收率高、生产成本低、反应条件较温和以及避免了高毒化学原料的使用,是一种易于制备、受体稳定且能够在较温和的条件下以高收率和高选择性的糖苷化反应,具有绿色环保、经济高效且很有应用前景的α-2,6-二脱氧葡萄糖-O-糖苷的制备方法。
实现本发明目的的具体技术方案是:一种全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,其特点是以全乙酰化2,6-二脱氧葡萄糖为给体,伯醇、仲醇、叔丁醇、酪醇或5-羟甲基糠醛为受体,将给体与受体按1:0.2~4的当量比混合,搅拌下加入乙腈、二氯甲烷或1,2-二氯乙烷,然后在I2-Et3SiH催化体系下进行糖苷化反应,其反应温度为0~50℃,反应时间为5~60分钟,反应结束后经分离、提纯后得产物为全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷,所述伯醇为乙醇、正丁醇、正戊醇、正辛醇、正癸醇、三氟乙醇、三氯乙醇、苯甲醇、丙烯醇或丙炔醇;所述仲醇为异丙醇、薄荷醇、3-戊醇或环己醇;所述给体与乙腈、二氯甲烷或1,2-二氯乙烷(DCE)的摩尔体积比为1mol:10~100L;所述I2-Et3SiH催化体系,其I2与给体的当量比为0.1~2:1,Et3SiH与给体的当量比为0.01~1:1。
所述I2与给体的当量比优选为0.3~1.5:1,Et3SiH与给体的当量比优选为0.05~0.5:1。
所述给体与乙腈、二氯甲烷或1,2-二氯乙烷的摩尔体积比为优选为1mol:30~50L。
所述受体与给体的当量比优选1.0~1.5:1。
所述反应温度优选10~30℃。
本发明与现有技术相比具有工艺简单、操作方便,生产成本低,产率高,立体选择性好,反应条件更温和,避免了高毒化学原料的使用,不污染环境,是一种受体底物适用范围更广、绿色环保和经济高效的α-2,6-二脱氧葡萄糖-O-糖苷制备方法。
具体实施方式
本发明将全乙酰化α-2,6-二脱氧葡萄糖与受体混合后加入乙腈、二氯甲烷或1,2-二氯乙烷,在I2-Et3SiH的催化体系下进行如下反应方程式的糖苷化反应:
其中:结构式1为全乙酰化2,6-二脱氧葡萄糖;结构式2为受体;结构式3为全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷,以下将通过具体的实施例对本发明做进一步的阐述:
实施例1
氮气保护下,将30mg(0.11mmol)1,3,4-三-O-乙酰基-2,6-二脱氧-D-葡萄糖与6.5μL(0.11mmol)炔丙醇混合,搅拌下加入2mL乙腈溶解后,在25℃温度下加入13.97mg(0.055mmol)I2和1.8μL(0.011mmol)Et3SiH催化剂,TLC点板(PE:EA=4:1)跟踪监测反应,15min时TLC监测反应完全,反应液经分离、提纯后得29.0mg产物为α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖炔丙醇苷,其产率为98%,α:β=8.8:1。
对所得产物α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖炔丙醇苷进行分析,测试数据如下:
1H NMR(500MHz,CDCl3)δ5.26(ddd,J=11.5,9.7,5.4Hz,1H),5.07(d,J=3.0Hz,1H),4.75(t,J=9.6Hz,1H),4.20(t,J=1.8Hz,2H),3.87(dq,J=9.9,6.3Hz,1H),2.42(t,J=2.2Hz,1H),2.25(dd,J=13.0,5.2Hz,1H),2.04(s,3H),2.00(s,3H),1.82(td,J=12.8,3.7Hz,1H),1.18(d,J=6.3Hz,3H)。
13C NMR(125MHz,CDCl3)δ170.31,95.52,79.11,74.72,74.65,68.93,66.26,54.34,35.09,21.11,20.94,17.55。
ESI-HRMS:Calcd for C13H18O6Na[M+Na]+:293.0996,found 293.1007。
实施例2
氮气保护下,将300mg(1.1mmol)1,3,4-三-O-乙酰基-2,6-二脱氧-D-葡萄糖与178μL(1.65mmol)3-戊醇混合,搅拌下加入50mL二氯甲烷溶解后,在15℃温度下加入140mg(0.55mmol)I2和1.8μL(0.011mmol)Et3SiH催化剂,TLC点板(PE:EA=4:1)跟踪监测反应,15min时TLC监测反应完全,反应液经分离、提纯后得298mg产物为α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖3-戊醇苷298mg,其产率为90%,α:β=9.1:1。
对所得产物α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖3-戊醇苷进行分析,测试数据如下:
1H NMR(500MHz,CDCl3)δ5.28(ddd,J=11.6,9.5,5.3Hz,1H),4.96(d,J=3.4Hz,1H),4.72(t,J=9.6Hz,1H),3.96(dq,J=10.1,6.3Hz,1H),3.46–3.41(m,1H),2.18(dd,J=12.7,5.3Hz,1H),2.05(s,3H),2.00(s,3H),1.79(td,J=12.3,3.8Hz,1H),1.56–1.47(m,4H),1.15(d,J=6.3Hz,3H),0.91(t,J=7.5Hz,3H),0.85(t,J=7.5Hz,3H)。
13C NMR(125MHz,CDCl3)δ170.43,95.47,79.84,75.20,69.45,65.83,35.95,26.92,25.25,21.19,21.01,17.58,10.10,9.25。
ESI-HRMS:Calcd for C15H26O6Na[M+Na]+:325.1622,found 325.1620。
实施例3
氮气保护下,将30mg(0.11mmol)1,3,4-三-O-乙酰基-2,6-二脱氧-D-葡萄糖与22.8mg(0.165mmol)酪醇(0.165mmol)混合,搅拌下加入10mLDCE溶解后,在50℃温度下加入13.97mg(0.055mmol)I2和1.8μL(0.011mmol)Et3SiH催化剂,TLC点板(PE:EA=3:1)跟踪监测反应,25min时TLC监测反应完全,反应液经分离、提纯后得30.9mg产物为α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖酪醇苷30.9mg,其产率为80%,α:β=7.4:1。
对所得产物α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖3-酪醇苷进行分析,测试数据如下:
1H NMR(500MHz,CDCl3)δ7.08(d,J=8.4Hz,2H),6.77(d,J=8.4Hz,2H),5.45(s,1H),5.24(ddd,J=11.6,9.6,5.4Hz,1H),4.82(d,J=3.1Hz,1H),4.68(t,J=9.6Hz,1H),3.75(dt,J=9.5,7.2Hz,1H),3.63–3.52(m,2H),2.80(t,J=6.9Hz,2H),2.19(dd,J=12.6,5.2Hz,1H),2.04(s,3H),2.00(s,3H),1.74(ddd,J=12.5,11.8,3.6Hz,1H),1.08(d,J=6.3Hz,3H)。
13C NMR(125MHz,CDCl3)δ170.71,170.56,154.41,131.01,130.21,115.35,96.60,74.94,69.37,68.48,65.65,35.40,35.34,21.19,20.97,17.62。
ESI-HRMS:Calcd for C18H24O7Na[M+Na]+:375.1414,found 375.1407。
实施例4
氮气保护下,将30mg(0.11mmol)1,3,4-三-O-乙酰基-2,6-二脱氧-D-葡萄糖与41mg(0.33mmol)5-羟甲基糠醛混合,搅拌下加入10mL二氯甲烷溶解后,在0℃温度下加入在0度下加入13.97mg(0.055mmol)I2和1.8μL(0.011mmol)Et3SiH催化剂,TLC点板(PE:EA=3:1)跟踪监测反应,50min时TLC监测反应完全,反应液经分离、提纯后得33.5mg产物为α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖糠醛5-羟甲醇苷,其产率为90%,α:β=8:1。
对所得产物α-3,4-二-O-乙酰基-2,6-二脱氧-D-葡萄糖3-酪醇苷进行分析,测试数据如下:
1H NMR(500MHz,CDCl3)δ9.64(s,1H),7.22(d,J=3.5Hz,1H),6.55(d,J=3.4Hz,1H),5.26(ddd,J=11.6,9.6,5.4Hz,1H),4.99(d,J=3.1Hz,1H),4.76(t,J=9.6Hz,1H),4.65(d,J=11.7Hz,1H),4.56(d,J=13.5Hz,1H),3.87(dq,J=9.9,6.2Hz,1H),2.28(ddd,J=13.0,5.4,1.0Hz,1H),2.05(s,3H),2.00(s,3H),1.82(ddd,J=13.0,11.8,3.8Hz,1H),1.18(d,J=6.3Hz,3H)。
13C NMR(125MHz,CDCl3)δ177.87,170.35,170.30,157.64,152.8,111.68,96.72,74.67,68.86,66.27,61.29,35.14,21.10,20.94,17.64。
ESI-HRMS:Calcd for C16H20O8Na[M+Na]+:363.1050,found 363.1052。
上述各实施例所得全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷经检测、分析后可以确认为纯的目标产物。以上只是对本发明作进一步的说明,并非用以限制本专利,凡为本发明等效实施,均应包含于本专利的权利要求范围之内。
Claims (5)
1.一种全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,其特征在于以全乙酰化2,6-二脱氧葡萄糖为给体,伯醇、仲醇、叔丁醇、酪醇或5-羟甲基糠醛为受体,将给体与受体按1:0.2~4的当量比混合,搅拌下加入乙腈、二氯甲烷或1,2-二氯乙烷,然后在I2-Et3SiH催化体系下进行糖苷化反应,其反应温度为0~50℃,反应时间为5~60分钟,反应结束后经分离、提纯后得产物为全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷,所述伯醇为甲醇、乙醇、正丁醇、正戊醇、正辛醇、正癸醇、三氟乙醇、三氯乙醇、苯甲醇、丙烯醇或丙炔醇;所述仲醇为异丙醇、3-戊醇、薄荷醇或环己醇;所述给体与乙腈、二氯甲烷或1,2-二氯乙烷的摩尔体积比为1mol:10~100L;所述I2-Et3SiH催化体系,其I2与给体的当量比为0.1~2:1,Et3SiH与给体的当量比为0.01~1:1。
2.根据权利要求1所述全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,其特征在于所述I2与给体的当量比为0.3~1.5:1,Et3SiH与给体的当量比为0.05~0.5:1。
3.根据权利要求1所述全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,其特征在于所述给体与乙腈、二氯甲烷或1,2-二氯乙烷的摩尔体积比为1 mol: 30~50L。
4.根据权利要求1所述全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,其特征在于所述受体与给体的当量比为1.0~1.5:1。
5.根据权利要求1所述全乙酰基保护α-2,6-二脱氧葡萄糖-O-糖苷的制备方法,其特征在于所述反应温度为10~30℃。
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