CN105541931B - 一种氟代糖苷衍生物及其制备方法 - Google Patents
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Abstract
本发明公开了一种氟代糖苷衍生物及其制备方法,氟代糖苷衍生物是以缩水内醚糖化合物为底物,在四烷基氟化铵/氟氢化钾复合氟化剂作用下,进行分子内亲核取代反应,即得;该方法操作简单,反应条件温和、成本低、副产物少、收率高,满足工业化生产要求。
Description
技术领域
本发明涉及一种氟代糖苷衍生物,以及高效合成氟代糖苷衍生物的方法,属于糖类杂环化合物合成领域。
背景技术
近年来,含氟药物的研究取得了令人瞩目的成功。基于氟的特殊效应,在药物设计中氟的引入已成为糖类药物中重要的修饰手段。在氟代糖中,由于氟取代了糖上的羟基,虽然C-F和C-OH在键长和极性上相差不多,但却改变了氢键的性质,表现在对酶的相互影响,对抗体的结合能力不同。氟代糖的化学及生物化学特性已使它们成为抗肿瘤、抗病毒及肿瘤诊断方面的重要药物。目前已有多个用于疾病检测或者治疗的氟代糖的药物上市。具有典型代表如下:2-[18F]-2-脱氧葡萄糖是经典的PET-CT的显影剂,被应用于癌症、心血管疾病及老年痴呆等重大疾病的检测。2013年上市的氟代核苷类药物索非布韦(sofosbuvir)是丙肝病毒RNA聚合酶的抑制剂,2014年的销售额为103亿美元1,为新的“重磅炸弹”药物。氟代的另一核苷类似物吉西他滨(Gemcitabine)也是治疗恶性肿瘤的一线药物。
[Clark,J.L.;Hollecker,L.;Mason,J.C.;Stuyver,L.J.;Tharnish,P.M.;Lostia,S.;McBrayer,T.R.;Schinazi,R.F.;Watanabe,K.A.;Otto,M.J.;Furman,P.A.;Stec,W.J.;Patterson,S.E.;Pankiewicz,K.W.J.Med.Chem.2005,48,5504–5508.]。
近年来氟代糖已在糖类药物新药创制中扮演重要的角色,该类化合物的合成,关键的问题是糖上羟基的氟化。由于氟离子的亲核能力低,并会诱发消除等副反应。因而造成反应复杂、收率低。因此,探索简便、温和并且高效氟化方法合成氟代糖是及其必要的。
发明内容
针对现有的技术存在的缺陷,本发明的一个目的是在于提供一种新型结构的氟代糖药物中间体化合物,为糖类药物的合成提供了新的原料途径。
针对现有的氟代糖苷制备方法存在副反应高,氟化试剂昂贵、且稳定性差,氟化效率低、反应条件苛刻等缺陷,本发明的另一个目的是在于提供一种操作简单,反应条件温和、成本低、副产物少、收率高制备所述氟代糖苷衍生物的方法。
为了实现上述技术目的,本发明提供了一种氟代糖苷衍生物,具有式1或式2结构:
其中,
R1为苄基、苯甲酰基或氢原子;
X为甲氧基、苯氧基、对甲基苯硫基、异丙基硫基、乙基硫基或辛基硫基;
X1和X2各自独立选至氢或氟。
优选的方案,氟代糖苷衍生物为
中一种。
本发明还提供了一种氟代糖苷衍生物的方法,该方法是以缩水内醚糖化合物为底物,在四烷基氟化铵/氟氢化钾复合氟化剂作用下,进行分子内亲核取代反应,即得;
所述的缩水内醚糖化合物具有式3或式4结构:
其中,
R1为苄基、苯甲酰基或氢原子;
X为甲氧基、苯氧基、对甲基苯硫基、异丙基硫基、乙基硫基或辛基硫基。
优选的方案,四烷基氟化铵、氟氢化钾和缩水内醚糖化合物的摩尔量比为1~4:1:1;最优选为2:1:1。
进一步优选的方案,四烷基氟化铵为四甲基氟化铵、四乙基氟化铵、四丁基氟化铵;最优选为四丁基氟化铵。
优选的方案,亲核取代反应是在70~140℃下反应2~5h。
本发明的亲核取代反应无需采用溶剂,后处理过程简单。
本发明的氟代糖苷衍生物的具体合成方法:将缩水内醚糖化合物、四丁基氟化铵、氟氢化钾,在隔绝空气环境下加入反应釜中,然后将反应釜放入油浴中在70~140℃下反应2~5h;反应结束后,将反应液冷却至室温,以乙酸乙酯稀释,再用饱和碳酸氢钠和水洗;有机层干燥,过滤,滤液减压蒸馏后经硅胶柱层析分离,即得。
本发明的氟代糖苷衍生物合成路线如下:
相对现有技术,本发明的技术方案带来的有益技术效果:
1、本发明的技术方案中采用的氟化试剂相对稳定、价格便宜,且氟化效果高,适用于各种不同反应条件。
2、本发明的氟代糖苷衍生物通过一锅法即可实现合成,方法简单,消除副反应少,具有较好的选择性,氟化产物收率高,反应条件温和。
3、本发明的氟代糖苷衍生物为糖类药物提供了新的原料途径,具有广泛的应用价值。
具体实施方式
下列实施例旨在进一步说明本发明内容,而不是限制本发明权利要求的保护范围。
实施例1
首先参考文献[Veleti,S.K.;et al.J.Org.Chem,2014,79,9444-9450;Wang,Yuan et al.Org.Lett,2005,7,5577-5579;Kulkarni,S.S.;et al.J.Org.Chem,2005,70,2808-2811.]以全乙酰葡萄糖为原料经五步反应合成内醚糖(1a),然后将TBAF·3H2O(1.26g,4mmol,2eq),KHF2(156mg,2mmol,1eq),缩水内醚糖化合物1a(712mg,2mmol,1equiv)在隔绝空气条件下加入反应釜中;然后将反应釜放入油浴中在70℃下反应2h;反应结束后,将反应液冷却至室温,用乙酸乙酯(50mL)稀释,再用饱和碳酸氢钠(10mL)和水(5mL)洗。有机层用无水硫酸钠干燥,过滤,滤液减压蒸馏后经硅胶快速柱层析分离,即得单一氟代产物1(624mg,1.66mmol)。
化合物1:产率83%,1H NMR(400MHz,CDCl3):δ7.48–7.37(m,6H),7.15(d,J=7.9Hz,2H),5.64(s,1H),5.18(bd,J=32.3Hz,1H,H1),4.87(dd,1H,J=3.6,44.5Hz,H2),4.39–4.34(m,2H,H6and H3),4.02–3.92(m,2H,H4and H5),3.89–3.84(m,1H,H6),2.42(d,1H,J=1.5Hz,OH),2.35(s,3H,CH3);13C NMR(100MHz,CDCl3):δ138.1(CAr),136.9(CAr),132.1(CAr),129.9(CAr),129.4(CAr),128.4(CAr),126.1(CAr),102.2(C7),90.9(d,J=176.5Hz,C2),84.2(d,J=18.4Hz,C1),76.2(C4),68.9(C6),67.2(d,J=29.5Hz,C3),66.4(C5),21.1(CH3);HRMS(ESI):calcd.for C20H21FNaO4S+[Na+]332.1640,found 332.1648.
对比实施例1
其它条件都和实施例1一样,不同之处将反应釜放入油浴中在160℃下反应2h;最终只得到消除产物1aa(570mg,1.6mmol)。
1H NMR(400MHz,CDCl3):δ7.50–7.47(m,2H),7.40–7.37(m,3H),7.35(d,2H,J=8.1Hz),7.15(d,2H,J=8.0Hz),5.65(s,1H),5.17(d,1H,J=5.8Hz,H2),4.43(dd,1H,J=5.3,10.6Hz,H6),4.31–4.25(m,2H,H3,H5),3.89–3.83(m,2H,H4 and H6),2.47(d,1H,J=1.5Hz,OH),2.35(s,3H,CH3);13C NMR(125MHz,CDCl3):δ153.6(C1),138.3,136.9,132.4,130.0,129.4,128.4,127.6,126.2,102.8(C2),101.7,77.5(C4),68.4(C6),65.8(C5),61.5(C3),21.2(CH3);
对比实施例2
其它条件都和实施例1一样,不同之处将TBAF·3H2O代替四烷基氟化铵/氟氢化钾复合氟化剂,在密闭环境下加入反应釜反应,在70℃下反应2h,无氟代产物生成,回收原料(406mg),得到消除产物1aa(270mg),NMR表征与对比实施例1吻合。
对比实施例3
其它条件都和实施例1一样,不同之处将KHF2代替四烷基氟化铵/氟氢化钾复合氟化剂,在密闭环境下加入反应釜反应,在90℃下反应2h,无氟代产物生成,也无消除产物1aa。
实施例2
参考文献[Yun,H.C.;Synthetic Communications,2003,33,2349-2363;Anker,D.;Giudicelli,M.B.;Journal of Carbohydrate Chemistry,1991,10,1991.].以甲基-α-D-木糖苷为原料,经五步反应合成内醚糖(2a),然后将TBAF·3H2O(1.26g,4mmol,2eq),KHF2(156mg,2mmol,1eq),缩水内醚糖化合物2a(472mg,2mmol,1equiv)在隔绝空气条件下加入反应釜中;然后将反应釜放入油浴中在110℃下反应3h;反应结束后,将反应液冷却至室温,用乙酸乙酯(80mL)稀释,再用饱和碳酸氢钠(20mL)和水(10mL)洗。有机层用无水硫酸钠干燥,过滤,滤液减压蒸馏后经硅胶快速柱层析分离,即得单一氟代产物2(417mg,1.63mmol)。
化合物2:产率83%,1H NMR(400MHz,CDCl3):δ7.39–7.26(m,5H,HAr),4.95(bs,1H,H1),4.88(bd,J=52.4Hz,1H,H3e),4.60(ABq,J=11.7Hz,1H,C6H5CH2-),4.45(ddd,J=2.3,3.8,27.4Hz,1H,H4a),4.17(bd,J=13.1Hz,1H,H2e),3.75–3.67(m,2H,H5a and H5e),3.41(s,3H,OCH3);13C NMR(100MHz,CDCl3):δ136.5(CAr),128.7(CAr),128.4(CAr),128.0(CAr),110.0(C1),97.3(d,J=185.7Hz,C3),83.2(d,J=27.3Hz,C4),77.5(d,J=24.5Hz,C2),74.0(C6H5CH2-),69.2(d,J=9.9Hz,C5),55.2(OCH3);HRMS(ESI):calcd.for C13H17FNaO4+,279.1003,found 279.1006.
实施例3
参考文献[Coppola,Y.;Lorenzo,D.N.;J.Org.Chem.2007,72,9679-9689;Wang,H.;She,J.;Zhang,L.-H.;Ye,X.-S.J.Org.Chem.2004,69,5774-5777.].以甲基-α-D-葡萄糖苷为原料,经四步反应合成内醚糖(3a),然后将TBAF·3H2O(1.58g,2mmol,2eq),KHF2(156mg,2mmol,1eq),缩水内醚糖化合物3a(528mg,2mmol,1equiv)在隔绝空气条件下加入反应釜中;然后将反应釜放入油浴中在130℃下反应2h;反应结束后,将反应液冷却至室温,用乙酸乙酯(80mL)稀释,再用饱和碳酸氢钠(20mL)和水(10mL)洗。有机层用无水硫酸钠干燥,过滤,滤液减压蒸馏后经硅胶快速柱层析分离,即得单一氟代产物3(477mg,1.68mmol)。
化合物3:产率84%,1H NMR(400M Hz,CDCl3):δ7.51–7.35(m,5H),5.60(s,1H,H7),4.80(ddd,J=3.0,3.0,49.9Hz,1H,H3e),4.61(s,1H,H1),4.36–4.25(m,2H,H5and H6),4.06(ddd,J=3.0,6.5,9.6Hz,1H,H2),3.96(ddd,J=2.5,9.6,30.3Hz,1H,H4a),3.79(td,1H,J=1.4,10.4Hz,H6),3.42(s,3H),2.38(d,J=5.6Hz,OH);13C NMR(100MHz,CDCl3):δ137.1(CAr),129.3(CAr),128.4(CAr),126.3(CAr),102.2(C7),101.4(C1),87.0(d,J=185.3Hz,C3),74.8(d,J=16.9Hz,C4),69.2(C6),68.9(d,J=25.5Hz,C2),58.4(d,J=3.0Hz,C5),55.7(OCH3);HRMS(ESI):calcd.for C14H17FNaO5+307.0952,found 307.0958.
实施例4
参考文献[Sous,E.I.;Mark A,M.R.;Tetrahedron Letters,2005,46,293-295;Wieslaw,S.;Carbohydrate Research,1986,158,245-8;Raphael,M.M.;Harry,S.H.;J.Org.Chem.1976,41,1832-6.]按照上所述合成路线合成内醚糖(4a),然后将TBAF·3H2O(630mg,2mmol,2eq),KHF2(78mg,1mmol,1eq),缩水内醚糖化合物4a(326mg,1mmol,1equiv)在隔绝空气条件下加入反应釜中;然后将反应釜放入油浴中在140℃下反应2h;反应结束后,将反应液冷却至室温,用乙酸乙酯(35mL)稀释,再用饱和碳酸氢钠(8mL)和水(3mL)洗。有机层用无水硫酸钠干燥,过滤,滤液减压蒸馏后经硅胶快速柱层析分离,即得单一氟代产物4(301mg,0.87mmol)。
化合物4:产率87%,1H NMR(400MHz,CDCl3):δ7.49–7.47(m,2H),7.36–7.28(m,5H),7.05–7.02(m,3H),5.58(s,1H,H7),5.37(s,1H,H1),4.85(ddd,J=2.7,2.7,49.9Hz,1H,H3e),4.39(td,J=5.2,10.2Hz,1H,H5),4.24–4.18(m,2H,H2e and H6),4.02(ddd,J=2.7,10.2,30.1Hz,1H,H4a),3.74(t,J=10.3Hz,1H,H6),2.72(bs,OH);13C NMR(100MHz,CDCl3):δ156.1(CAr),137.0(CAr),129.6(CAr),129.4(CAr),128.5(CAr),126.3(CAr),122.6(CAr),116.6(CAr),102.6(C7),97.9(C1),86.9(d,J=185.1Hz,C3),74.8(d,J=16.8Hz,C4),69.0(C6),68.8(d,J=24.4Hz,C2),59.1(d,J=3.3Hz,C5);HRMS(ESI):calcd.for C19H19FNaO5 +369.1109,found369.1115.
对比实施例4
其它条件都和实施例4一样,不同之处将TBAF·3H2O(1.89 g,6mmol,6eq),KHF2(78mg,1mmol,1eq),缩水内醚糖化合物4a(326mg,1mmol,1equiv)在密闭环境下加入反应釜反应,最终得单一氟代产物4(173 mg,0.5mmol),产率50%,NMR表征与实施例5吻合。
实施例5
参考文献[Wang,Yuan et al.Org.Lett,2005,7,5577-5579;Wang H.;She,J.;Zhang,L.-H.;Ye,X.-S.J.Org.Chem.2004,69,5774-5777.].以4,6-O-苯亚甲基-β–D-葡萄糖苷为原料按照上所述合成路线合成内醚糖(5a),然后将TBAF·3H2O(472.5mg,1.5mmol,2eq),KHF2(58.5mg,0.75mmol,1eq),缩水内醚糖化合物5a(198mg,0.75mmol,1equiv)在隔绝空气条件下加入反应釜中;然后将反应釜放入油浴中在130℃下反应3h;反应结束后,将反应液冷却至室温,用乙酸乙酯(45mL)稀释,再用饱和碳酸氢钠(15mL)和水(7mL)洗。有机层用无水硫酸钠干燥,过滤,滤液减压蒸馏后经硅胶快速柱层析分离,即得单一氟代产物5(166mg,0.59mmol),
化合物5:产率78%,1H NMR(400MHz,CDCl3):δ7.52–7.34(m,5H),5.58(bs,1H,H7),5.00(ddd,J=1.9,3.7,49.9 Hz,1H,H3),4.75(dd,J=1.3,2.8 Hz,1H,H1),4.39(dd,J=4.9,10.5 Hz,1H,H5),4.09–3.97(m,3H,H2,H6 and H4),3.84–3.79(m,1H,H6),3.59(s,3H,OCH3),2.48(bs,OH);13C NMR(100MHz,CDCl3):δ137.0(CAr),129.2(CAr),128.3(CAr),,126.2(CAr),102.5(C7),99.0(C1),87.8(d,J=177.3Hz,C3),75.2(d,J=16.5 Hz,C4),69.3(d,J=27.7 Hz,C5),69.0(C6),63.1(d,J=3.3Hz,C2),57.2(OCH3);HRMS(ESI):calcd.forC14H17FNaO5+307.0952,found 307.0960.
通过上述实验步骤,将四甲基氟化铵代替四丁基氟化铵(TBAF·3H2O),同样得到单一氟代产物5(127.8mg,0.45mmol),产率60%。
实施例6
参考文献[Knapp,S.;Naughton,A.B.J.;Jaramillo,C.;Pipik,B.J.Org.Chem.1992,57,7328―7334;Wang,Yuan et al.Org.Lett,2005,7,5577-5579.],以甲基-β-D-葡萄糖苷为原料,按照所述合成路线合成内醚糖(6a),然后将TBAF·3H2O(157.5mg,0.5mmol,2eq),KHF2(19.5mg,0.25mmol,1eq),缩水内醚糖化合物6a(66mg,0.25mmol,1equiv)在隔绝空气条件下加入反应釜中;然后将反应釜放入油浴中在130℃下反应5h;反应结束后,将反应液冷却至室温,用乙酸乙酯(25mL)稀释,再用饱和碳酸氢钠(7mL)和水(3mL)洗。有机层用无水硫酸钠干燥,过滤,滤液减压蒸馏后经硅胶快速柱层析分离,得氟代产物6和7(6:7=2:1),产率76%。
化合物6:(36mg,0.127mmol),1H NMR(400MHz,CDCl3):7.52–7.35(m,5H,HAr),5.56(s,1H,H7),4.63(dt,J=8.9,53.5Hz,1H,H3),4.40(ddd,J=2.0,5.1,10.7Hz,1H,H6),4.34(d,J=7.7Hz,1H,H1),3.85–3.75(m,2H,H2and H6),3.73–3.65(m,1H,H4),3.59(s,3H),3.45(dddd,J=1.5,5.1,9.7,14.7Hz,1H,H5),2.64(bs,1H,OH);13C NMR(100MHz,CDCl3):136.7(CAr),129.3(CAr),128.3(CAr),126.2(CAr),103.8(d,J=9.8Hz,C1),101.7(C7),92.2(d,J=187.7Hz,C3),78.9(d,J=17.8Hz,C2),73.5(d,J=18.4Hz,C4),68.5(d,J=9.2Hz,C5),65.2(d,J=1.6Hz,C6),57.8(OCH3);
化合物7:(18mg,0.063mmol),1H NMR(400MHz,CDCl3):δ7.50–7.37(m,5H,HAr),5.63(s,1H,H7),4.80(bd,J=21.9Hz,1H,H1),4.63(dd,J=3.9,46.1Hz,1H,H2),4.40(dd,J=3.9,10.2Hz,1H,H3),4.37–4.34(m,1H,H6),3.98(td,J=4.8,9.7 Hz,1H,H5),3.93–3.83(m,2H,H4 and H6),3.60(s,3H,OCH3),2.51(bs,1H,OH);13C NMR(100MHz,CDCl3):δ136.9(CAr),129.4(CAr),128.4(CAr),126.1(CAr),102.2(C7),98.5(d,J=15.2 Hz,C1),88.2(d,J=183.9 Hz,C2),76.5(C4),68.9(C6),67.4(d,J=27.6 Hz,C3),63.4(C5),57.8(OCH3)。
Claims (4)
1.一种制备氟代糖苷衍生物的方法,其特征在于:以缩水内醚糖化合物为底物,在四烷基氟化铵/氟氢化钾复合氟化剂作用下,进行分子内亲核取代反应,即得;所述的分子内亲核取代反应是在70~140℃下反应2~5h;四烷基氟化铵、氟氢化钾和缩水内醚糖化合物的摩尔量比为1~4:1:1;
所述的缩水内醚糖化合物具有式4结构:
所述的氟代糖苷衍生物具有式2结构:
2.根据权利要求1所述的制备氟代糖苷衍生物的方法,其特征在于:四烷基氟化铵、氟氢化钾和缩水内醚糖化合物的摩尔量比为2:1:1。
3.根据权利要求2所述的制备氟代糖苷衍生物的方法,其特征在于:所述的四烷基氟化铵为四甲基氟化铵、四乙基氟化铵、四丁基氟化铵。
4.根据权利要求3所述的制备氟代糖苷衍生物的方法,其特征在于:所述的四烷基氟化铵为四丁基氟化铵。
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