CN102212087A - 一种制备3,6位支化葡萄三糖的方法 - Google Patents
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Abstract
本发明公开了一种制备3,6位支化葡萄三糖的方法,属于寡糖的制备领域。该法可用于有免疫调节、抗肿瘤、抗炎及抗菌等作用核心片段3,6位支化葡萄三糖的合成,以酰化的葡萄糖三氯乙酰亚胺酯为糖基供体与烯丙基-α-D-吡喃葡萄糖苷受体一步偶联得三糖。本发明的优点:合成路线简洁,操作简便,产物易结晶提纯,适于大量制备。
Description
技术领域
本发明是关于有生物活性核心片段3,6位支化葡萄三糖的合成,属于寡糖的制备领域。
背景技术
至今,已从真菌中得到多种具有生物活性的多糖类物质,如lentinan(香菇多糖)(源于Lentinus edodes,香菇),Lycium barbarum polysaccharides(枸杞多糖)(源于wolfberry fruit,枸杞子)、schizophyllan(裂褶菌多糖)(源于Schizophyllum commune,裂褶菌)以及pochyman(茯苓多糖)(源于Poria cocos,茯苓)等,并广泛应用于肿瘤及免疫缺陷性疾病的临床治疗。到目前为止,已报道其具有免疫调节、抗肿瘤、抗病毒、抗辐射、延缓衰老及抗感染等多种作用,有的已在临床用于肿瘤、肝炎、心血管疾病的辅助治疗和康复。除了粘附和支持作用外,在细胞识别、信号传导、调控机体免疫功能以及控制细胞的迁移、增殖、分化、代谢等方面都有十分重要的作用。活性最强的多糖是具有分支的β-(1→3)葡聚糖。活性多糖具有一个共同的β-(1→3)连接的葡萄糖基组成的结构主链,沿主链随机分布着β-(1→6)连接的葡萄糖基,呈梳状结构。在具有免疫调节能力的多糖中,含β-(1→6)分支的β-(1→3)-D-葡聚糖,对肿瘤生长有抑制作用。
这类多糖的典型代表是香菇多糖和裂褶菌多糖,香菇多糖常用于治疗中晚期消化系统肿瘤,裂殖菌多糖结合放疗用于宫颈癌晚期的免疫治疗,均可延长患者生命。这导致了一系列关于裂褶多糖及其衍生物合成的报道(参见文献①T Kenichi,Carbohydrate Research,1986,145,293-306.②T Kenichi,Journal of Carbohydrate Chemistry,1993,12,1043-1056.③T Kenichi,Journal of Carbohydrate Chemistry,1994,13,1159-1177.专利CN00122826.9,CN01100099.6)。香菇多糖的合成也是研究的热点(参见YANG Guangbin,Carbohydrate Research,2005,1,39-48.)。此外,1976年Ayers发现从致病菌大雄疫病菌细胞壁降解产物获得的葡聚七糖可以诱导大豆产生植物抗毒素(参见Ayers A,Ebel J,Finelli F,Bergher N,Albersheim P,Plant Physiology,1976,57(5):751)。这是首次被发现的寡糖激活剂,10纳克(1×10-8克)应用于1克植物组织即能产足够的植保素,相当于1克寡糖激活剂可使1000吨作物的组织产生足够量的植保素,迄今为止,它是已发现植保素激活剂中效率最高的。几个著名的实验室都先后进行了寡糖激活剂的合成研究(参见①Sharp,J.K.,Journal of Biological Chemistry,1984,259,11321-11326.② Hong N.Tetrahedron Letter,1990,31:3179-3183.③Nicolaou K C.Journal of the American Chemical Society,1997,119,449-453.)。这些葡聚寡糖均具有3,6位支化葡萄三糖的结构,可见高效简洁的合成具有生物活性的核心片段3,6位支化葡萄三糖有着重要的作用。
发明内容
本发明的目的是提供一种有生物活性核心片段3,6位支化葡萄三糖合成的方法,该合成路线简洁,操作简便,原料成本低,产物易结晶提纯,适于大量制备。
本发明采取的合成方法在于:
一种制备3,6位支化葡萄三糖的方法,其特征在于:以D-葡萄糖A为起始原料,经三步反应制得单糖供体三氯乙酰亚胺酯片段D(D′),再以2.0~2.5摩尔的酰基葡萄糖的三氯乙酰亚胺酯片段D(D′)为糖基给体,以1摩尔的烯丙基-α-D-吡喃葡萄糖苷片段F为糖基受体,将糖基供体与糖基受体溶于二氯甲烷、二甲基甲酰胺、乙腈、甲苯或1,2-二氯乙烷中,经路易斯酸三氟甲磺酸三甲基硅酯,或三氟化硼·乙醚催化,-40~0℃搅拌下偶联,反应1~3小时,经乙醇结晶得三糖片段G(G′)。反应如下:
其中,B,C,D,E,G中R为乙酰基;B′,C′,D′,E′,G′中R为苯甲酰基。
所述的以烯丙基-α-D-吡喃葡萄糖苷为原料,一步合成三糖。
所述的路易斯酸为三氟甲磺酸三甲基硅酯,或为三氟化硼·乙醚。
所述的一步合成三糖,反应溶剂为二氯甲烷、二甲基甲酰胺、乙腈、甲苯或1,2-二氯乙烷。
所述的三糖产物片段G′纯化用乙醇重结晶。
所述的酰基葡萄糖的三氯乙酰亚胺酯片段D(D′)与烯丙基-α-D-吡喃葡萄糖苷片段F反应得到目标产物的工艺为:在有机溶剂中,三氯乙酰亚胺酯片段D(D′)与烯丙基-α-D-吡喃葡萄糖苷片段F以1∶1~2∶2.5的摩尔比,于-40~0℃下反应1~3小时。
附图说明:
图1为Allyl O-(2,3,4,6-Tetra-O-benzoyl-β-D-glucopyranosyl)-(1→3)-O-[2,3,4,6-tetra-O-benzoyl-β-D-glucopyranosyl-(1→6)]-β-D-glucopyranoside(G′)1H-NMR谱图
具体实施方式
下面结合实施例对本发明的方法进行详细地说明。
实施例1
(1)、单糖给体D的制备
0.81ml高氯酸在搅拌下于0℃小心滴入60ml乙酸酐,半小时后,分批加入无水葡萄糖A(18.01g,100.06mmol),待加A完继续搅拌反应半小时。反应液倾入冰水中,析出白色固体,过滤,固体用二氯甲烷溶解后,依次用1当量盐酸溶液、饱和NaHCO3溶液、饱和食盐水洗涤。在无水乙醇中重结晶,得全乙酰化葡萄糖B(36.12g,92.59mmol),产率93%。
将上述化合物B(10.05g,25.76mmol)溶于38ml二甲基甲酰胺溶液,向体系中加入乙酸铵(3.89g,50.47mmol),25℃下反应20小时。浓缩后乙酸乙酯提取,依次用1当量盐酸溶液、饱和NaHCO3溶液、饱和食盐水洗涤。浓缩后上柱层析分离(环己烷∶乙酸乙酯=2∶1)得到白色固体C(8.23g,23.64mmol),产率91%。
化合物C(2.13g,6.12mmol)溶于30ml无水二氯甲烷中,加入1.9ml三氯乙腈并加入0.12ml DBU,室温下搅拌2小时。浓缩后上柱层析分离(环己烷∶乙酸乙酯=2∶1)得到浅黄色糖浆D(2.79g,5.69mmol),产率93%。
D:1H NMR(500MHz,CDCl3):δ:8.76(s,1H),6.59(d,J=3.3Hz,1H,H-1),5.47(t,J=9.8Hz,1H),5.18(t,J=9.8Hz,1H),5.16(m,1H),4.21-4.29(m,2H),4.16(m,1H),2.08(s,3H),2.05 (s,3H),2.03(s,3H),2.02(s,3H).
(2)、三糖G的制备
i D(2.67g,5.42mmol)及F(0.48g,2.17mmol)溶于78ml干燥1,2-二氯乙烷中,加入4克 分子筛,在-40℃,氮气保护下,加入三甲基硅三氟甲磺酸酯(0.32ml),继续反应1小时,加入三乙胺终止反应,过滤,饱和碳酸氢钠水溶液及水洗涤,浓缩,柱层析分离得到G(0.48g,0.54mmol),产率25%。
ii D(2.43g,4.93mmol)及F(0.47g,2.14mmol)溶于73ml干燥二氯甲烷中,加入4克 分子筛,在-20℃,氮气保护下,加入三甲基硅三氟甲磺酸酯(0.25ml),继续反应2h,加入三乙胺终止反应,过滤,饱和碳酸氢钠水溶液及水洗涤,浓缩,柱层析分离得到G(0.60g,0.68mmol),产率32%。
iii D(3.21g,6.52mmol)及F(0.717g,3.26mmol)溶于75ml干燥甲苯中,加入4克 分子筛,在0℃,氮气保护下,加入三甲基硅三氟甲磺酸酯(0.37ml),继续反应3小时,加入三乙胺终止反应,过滤,饱和碳酸氢钠水溶液及水洗涤,浓缩,柱层析分离得到G(1.06g,1.21mmol),产率37%。
G:13C NMR(125MHz CDCl3),δ:170.25-168.6(C=O),133.2,117.2(CH=CH2),100.7(2C,C-lb,c),99.2(C-la),61.8(C-6a,b,c),20.9-20.3(COCH3).
实施例2
(1)、单糖给体D′的制备
无水葡萄糖A(20.01g,111.17mmol)溶于280ml吡啶溶液,加入催化剂DMAP(0.738g,6.04mmol),冰浴冷却至0℃,滴加80ml苯甲酰氯25℃下反应24h。加入70ml甲醇停止反应。将反应液倾入500ml的50℃水中析出白色固体,过滤,固体用二氯甲烷溶解后,依次用1当量盐酸溶液、饱和NaHCO3溶液、饱和食盐水洗涤。在无水乙醇中重结晶,得全苯甲酰化葡萄糖B′(73.22g,104.50mmol),产率94%。
将乙二胺(5.61ml,0.84mmol)、乙酸(2.394ml,0.42mmol)依次滴入500ml四氢呋喃 溶液。再向体系中加入上述化合物B′(30.15g,43.03mmol),25℃下反应16~20h。浓缩后二氯甲烷提取,依次用1当量盐酸溶液、饱和NaHCO3溶液、饱和食盐水洗涤。浓缩后上柱层析分离(环己烷∶乙酸乙酯=4∶1)得到白色固体C′(23.10g,38.73mmol),产率90%。
化合物C′(3.26g,5.46mmol)溶于30ml无水二氯甲烷中,加入1.7ml三氯乙腈并加入0.10ml DBU,室温下搅拌2小时。浓缩后上柱层析分离(环己烷∶乙酸乙酯=4∶1)得到白色泡沫D′(4.93g,5.19mmol),产率95%。
D′:1H NMR(500MHz,CDCl3),δ:8.65(s,1H),8.04(d,2H J=7.4Hz),7.99(dd,4H,J=8.3,3.1Hz),7.87(d,2H,J=7.4Hz),7.52~7.29(m,12H),6.88(s,1H),6.30(t,IH,J=10.1Hz),5.80(t,1H,J=9.8Hz),5.62(dd,1H,J=10.2,3.52Hz),4.68(d,2H,J=10.3Hz),4.45(dd,1H,J=12.8,5.4Hz).
(2)、三糖G′的制备
i D′(4.13g,5.57mmol)及F(0.614g,2.79mmol)溶于65ml干燥乙腈中,加入4克 分子筛,在0℃,氮气保护下,加入三甲基硅三氟甲磺酸酯(0.25ml),继续反应1小时,加入三乙胺终止反应,过滤,浓缩,乙醇重结晶得到G′(1.35g,0.98mmol),产率35%。
ii D′(4.02g,5.42mmol)及F(0.52g,2.36mmol)溶于70ml干燥二氯甲烷∶乙腈=1∶1中,加入4克 分子筛,在-30℃,氮气保护下,加入三甲基硅三氟甲磺酸酯(0.30ml),继续反应2小时,加入三乙胺终止反应,过滤,浓缩,乙醇重结晶得到G′(1.72g,1.25mmol),产率53%。
iii D′(3.93g,5.30mmol)及F(0.35g,2.12mmol)溶于80ml干燥二甲基甲酰胺中,加入4克 分子筛,在-40℃,氮气保护下,加入三甲基硅三氟甲磺酸酯(0.35ml),继续反应3小时,加入三乙胺终止反应,过滤,浓缩,乙醇重结晶得到G′(1.35g,0.98mmol),产率46%。
G′:1H NMR(500MHz,CDCl3),δ:7.256-8.030(m,40H,Ph),5.85-5.90(m,2H,H-4,CH2=CH-CH2-),5.56-5.75(m,3H,H-4,H-4,H-3)5.49-5.55(m,2H,H-3,H-2),5.12(m,2H,CH2=CH-CH2-),5.02(d,1H,J1,2=8Hz,H-1),4.91(d,1H,J1,2=7.8Hz,H-1),4.80(d,1H,J1,2=8.3Hz,H-1),4.64-4.67(m,2H,H-3,CH2=CH-CH2-),4.50(dd,1H,H-6)4.39(dd,1H,H-6)4.09-4.11(m,3H,H-5)3.93(dd,1H,H-6)3.77-3.84(m,2H,CH2=CH-CH2-,H-5)3.69(dd,2H,H-6)3.34-3.41(m,2H,H-6a,H-6b)2.62(br d,H,1OH,)2.25(br d,H,1OH,).
13C NMR(125Hz,CDCl3),δ:165.8-164.1(C=O),133.2,116.9(CH=CH2),101.3,100.5(C-lb,c),99.1(C-la),and 63.2 and 62.9(C-6b,c).
Claims (6)
2.如权利要求1所述的一种有生物活性核心片段3,6位支化葡萄三糖的合成方法,其特征在于所述的以烯丙基-α-D-吡喃葡萄糖苷为原料,一步合成三糖。
3.如权利要求1所述的一种有生物活性核心片段3,6位支化葡萄三糖的合成方法,其特征在于所述的路易斯酸为三氟甲磺酸三甲基硅酯,或为三氟化硼·乙醚。
4.如权利要求1所述的一种有有生物活性核心片段3,6位支化葡萄三糖的合成方法,其特征在于:一步合成三糖,反应溶剂为二氯甲烷、二甲基甲酰胺、乙腈、甲苯或1,2-二氯乙烷。
5.如权利要求1所述的一种有生物活性核心片段3,6位支化葡萄三糖的合成方法,其特征在于:三糖产物片段G用乙醇重结晶。
6.如权利要求1所述的一种有生物活性核心片段3,6位支化葡萄三糖的合成方法,其特征在于:在有机溶剂中,三氯乙酰亚胺酯片段D(D′)与烯丙基-α-D-吡喃葡萄糖苷片段F以1∶1~2∶2.5的摩尔比,于-40~0℃下反应1~3小时。
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CN108892740A (zh) * | 2018-06-19 | 2018-11-27 | 朱玉亮 | 一种3,6位支化葡聚六糖的合成方法 |
CN108912239A (zh) * | 2018-06-19 | 2018-11-30 | 朱玉亮 | 一种3,6位支化葡聚七糖的合成方法 |
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