CN1369504A - 枸杞多糖核心糖肽结构衍生物的制备 - Google Patents
枸杞多糖核心糖肽结构衍生物的制备 Download PDFInfo
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Abstract
本发明涉及具有潜在药用价值的枸杞多糖核心糖肽结构衍生物的化学制备。该衍生物保持了天然枸杞多糖核心糖肽的四糖结构单元及一个丝氨酸配糖体、具有所示的结构通式。通式中R1可为氢或半乳吡喃糖基,R2为氢或阿拉伯糖基化合物。
Description
本发明属于有生物活性的糖肽衍生物的制备领域。
枸杞多糖核心糖肽可能是茄科植物枸杞(Lycium Barbarum L.)果实的药效成份,中国药典一部(1995年版)记载枸杞有滋补肝肾、益精明目的功能,用于虚劳精亏、旋晕耳鸣、血虚萎黄、目昏不明等症。枸杞多糖核心糖肽含有一个结构为β-D-半乳吡喃糖基-(1→6)-[β-D-半乳吡喃糖基-(1→3)]-β-D-半乳吡喃糖基-(1→6)-β-D-半乳吡喃糖基-L-丝氨酸的糖肽(“糖复合物的结构和功能”,主编陈惠黎,上海医大出版社,1997年6月第一版)。
本发明的目的在于提供一种简易的枸杞多糖核心糖肽衍生物的化学制备法。核心是用部分苯甲酰化的糖基三氯乙酰亚胺酯供体与3,6位二羟基的β-D-半乳吡喃糖异丙硫苷偶联,一步可得到高产率、立体专一的三糖异丙硫苷衍生物,以它直接作为下一步反应的供体,与6位羟基的β-D-半乳吡喃糖基-L-丝氨酸偶合,能简易而有效地合成枸杞多糖核心糖肽衍生物。(3,6位二羟基的β-D-半乳吡喃糖异丙硫苷的合成见我们以前的专利00107723.6)。
下面结合实施例对本发明进行详细的说明。
氧-(2,3,4,6-四-氧-乙酰基-β-D-半乳吡喃糖基)-N-苄氧羰基-L-丝氨酸甲酯(3)--丝氨酸衍生物2(3克,11.8毫摩尔)和1.02当量的溴代半乳糖1(5克,12.1毫摩尔)溶于20毫升的干燥二氯甲烷,在0℃,无光条件下,氮气氛中,加入1当量的三氟甲磺酸银(AgOTf)(3.03克,11.8毫摩尔)催化反应,反应2小时,滴加三乙胺中和反应体系,蒸干混合物,用硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(2∶1),得到浆状物糖肽3(3.2克,47%).旋光[α]D 25+6(c1,CHCl3);核磁δH(CDCl3)1.95,2.00,2.01,2.11(4s,4x3H,-CH3),3.74(s,3H,-OCH3),3.76-3.82(m,3H,H-5,H-6a,H-6b),3.84-3.88(m,1H,-OCH2),4.20-4.24(m,1H,-OCH2),4.41(d,1H,J1,27.8Hz,H-1),4.44-4.46(m,1H,-OCH),4.94(dd,1H,J2,310.2,J3,43.3Hz,H-3),5.11-5.14(m,3H,-OCH2,H-2),5.33(d,1H,J3,43.2Hz,H-4),5.55(d,1H,J8.1Hz,NH),7.23-7.33(m,5H,Ph).
氧-(2,3,4-三-氧-苯甲酰基-6-三苯基甲基-β-D-半乳吡喃糖基)-N-苄氧羰基-L-丝氨酸甲酯(5).--化合物3(3.2克,5.6毫摩尔)溶于甲醇,滴加0.5N的甲醇钠的甲醇溶液调节PH值至9-10,反应4小时后,加入树脂调节PH值至7,过滤除去树脂,滤液浓缩,上硅胶柱色谱纯化分离,淋洗液为甲醇/乙酸乙酯(1∶4),得到浆状物氧-(β-D-半乳吡喃糖基)-N-苄氧羰基-L-丝氨酸甲酯4(2.2克,95%)将化合物4(2.2克,5.3毫摩尔)溶于10毫升吡啶中,加入催化量的DMAP(20毫克),然后加入1.1当量的三苯基氯甲烷(1.57克,5.83毫摩尔),50℃下搅拌24小时再向反应体系中一次加入3.5当量的苯甲酰氯(2.2毫升,18.5毫摩尔)和3毫升吡啶的混合液,升温至50℃后,搅拌过夜,混合物中加入甲苯,蒸去吡啶,剩余物用150毫升二氯甲烷稀释,然后加入冰水洗两次以除去吡啶盐,水相再用50毫升二氯甲烷反萃取一次,合并有机相,浓缩后,上硅胶柱色谱纯化分离,淋洗液为甲苯/石油醚/乙酸乙酯(0.2∶1.5∶1),得到泡沫状物氧-(2,3,4-三-氧-苯甲酰基-6-三苯基甲基-β-D-半乳吡喃糖基)-N-苄氧羰基-L-丝氨酸甲酯5(600毫克,0.62毫摩尔),以及α,β混合物(3.2克,3.3毫摩尔),总产率75%.旋光[α]D 25+8(c1,CHCl3);核磁δH(CDCl3)3。24(dd,1H,J5,6a8.7,J6a,6b12Hz,H-6a),3.42(dd,1H,J5,6b5.7,J6a,6b9Hz,H-6b),3.57(s,1H,-OCH3),3.87-3.91(m,1H,-OCH2),3.96(t,J5,6a7.5,J5,6b6.0Hz,H-5),4.29(dd,1H,J10.2Hz,-OCH2),4.40-4.43(m,1H,-OCH),4.67(d,1H,J1,27.2Hz,H-1),4.96,5.04(2d,2H,J12.3Hz,-OCH2),5.44(d,1H,J7.5Hz,NH),5.56-5.62(m,2H,H-2,H-3),6.02(s,1H,H-4),7.05-8.05(m,35H,ph).
氧-(2,3,4-三-氧-苯甲酰基-β-D-半乳吡喃糖基)-N-苄氧羰基-L-丝氨酸甲酯(6).--化合物5(600毫克,0.62毫摩尔)溶于10毫升二氯甲烷中,加入>2.5当量的六水合三氯化铁,反应3小时后,用50毫升的二氯甲烷稀释反应体系,用冰水洗去六水合三氯化铁,水相再用20毫升二氯甲烷反萃取一次,合并有机相,浓缩后,上硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(1.5∶1),得到泡沫状产物6(400毫克,85%).旋光[α]D 25+1(c1,CHCl3);核磁δH(CDCl3)3.35(s,1H,-OCH3),3.56-3.62(m,1H,H-5),3.77(dd,1H,J5,6a7.2,J6a,6b11.7Hz;H-6a),3.99(dd,1H,J5,6b5.7,J6a,6b11.4Hz,H-6b),4.09-4.12(m,2H,-OCH2),4.50-4.53(m,1H,-OCH),4.74(d,1H,J1,27.8Hz,H-1),5.02(d,1H,J8.4Hz,NH),5.09(s,2H,-OCH2),5.51-5.55(m,2H,H-2,H-3),5.73(s,1H,H-4),7.20-8.09(m,20H,ph)
异丙硫基2,4-二-氧-苯甲酰基-3-氧-叔丁基二甲基硅烷基-6-氧-三苯基甲基-β-D-半乳吡喃糖苷(8)--将异丙硫基的6-氧-三苯基甲基-β-D-半乳吡喃糖苷7(1.30克,2.73毫摩尔)溶于5毫升的N,N-二甲基甲酰胺,冷却到0℃,加入2当量的咪唑(0.37克,4.54毫摩尔),把预先溶于1毫升的N,N-二甲基甲酰胺的1.0当量的叔丁基二甲基氯硅烷(0.41克,2.73毫摩尔)在1.5小时内分部分加入反应体系.搅拌反应3小时后,再向混合物中一次加入2.5当量的苯甲酰氯和5毫升吡啶的混合液,升温至50℃后,搅拌40小时.混合物中加入甲苯,蒸去吡啶,剩余物用100毫升乙酸乙酯稀释,然后加入冰水洗两次以除去吡啶盐和N,N-二甲基甲酰胺,水相再用50毫升乙酸乙酯反萃取一次,合并有机相,浓缩后,上硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(1.5∶1),得到泡沫状中间体8(1.65克,2.07毫摩尔),总产率76%.旋光[α]D 25+17(c1,CHCl3);核磁δH(CDCl3)-0.12,0.11(2s,2x3H,-Si(CH3)2),0.61(s,9H,t-Bu),1.26,1.32(2d,6.8Hz,2x3H,SCH(CH3)2),3.18(dd,J5,6a6.8,J6a,6b9.6Hz,1H,H-6a),3.22-3.31(m,1H,SCH(CH3)2),3.44(dd,J5,6b6.4,J6a,6b9.6Hz,1H,H-6b),3.80(t,J5,6a6.8,J5, 6b6.5Hz,H-5),4.06(dd,1H,J2.37.2,J3,43.2Hz,H-3);4.68(d,1H,J1,210.0Hz,H-1),5.46(t,1H,J1,29.2,J2,39.2Hz,H-2),5.71(d,1H,J3,43.2Hz,H-4),7.14-8.17(m,25H,Ph)。
异丙硫基2,4-二-氧-苯甲酰基-β-D-半乳吡喃糖苷(9).--向化合物8(1.65克,2.07毫摩尔)加入92%的三氟乙酸水溶液(25毫升),搅拌反应2小时后,加入甲苯,蒸去溶剂,剩余物上硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(2∶1),得到浆状物10(765毫克,1.6毫摩尔),产率80%.旋光[α]D 25+15(c1,CHCl3);核磁δH(CDCl3)1.34,1.28(2d,6.8Hz,2x3H,SCH(CH3)2),3.23-3.30(m,1H,SCH(CH3)2),3.58(dd,J5,6a7.2,J6a,6b12Hz,1H,H-6a),3.77(dd,J5,6a6.4,J6a,6b11.6Hz,1H,H-6b),3.86-3.90(m,1H,H-5),4.14(dd,J2,39.6,J3,43.4Hz,1H,H-3),4.80(d,1H,J1,210.0Hz,H-1),5.43(t,J1,210.0,J2,310.0Hz,1H,H-2),5.62(d,J3,43.3Hz,1H,H-4),7.26-8.14(m,10H,ph).
2,3,4,6-四-氧-苯甲酰基-α-D-半乳吡喃糖基2,2,2-三氯乙酰亚胺酯(10)--D-半乳糖(5克,27.8毫摩尔)溶于40毫升吡啶中,加入催化量的DMAP(50毫克),再向混合物中一次加入5.5当量的苯甲酰氯(20毫升),升温至50℃后,搅拌置夜混合物中加入甲苯,蒸去吡啶,剩余物用150毫升二氯甲烷稀释,然后加入1N盐酸洗两次以除去吡啶盐,水相再用50毫升二氯甲烷反萃取一次,合并有机相,浓缩后,上硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(3∶1),得到产物苯甲酰基2,3,4,6-四-氧-苯甲酰基-D-半乳吡喃糖苷(18.5克,95%).苯甲酰基2,3,4,6-四-氧-苯甲酰基-D-半乳吡喃糖苷在四氢呋喃-甲醇的混合溶剂中(6∶4),0℃通氨气20分钟,室温反应15小时,蒸干混合物,用硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(3∶1),得到2,3,4,6-四-氧-苯甲酰基-D-半乳吡喃糖苷,产率80%2,3,4,6-四-氧-苯甲酰基-D-半乳吡喃糖苷(5克,8.39毫摩尔)溶于25毫升干燥二氯甲烷中,加入0.3当量的DBU(0.5毫升)和3当量的三氯乙腈(4毫升),反应2小时,蒸干混合物,用硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(3∶1),得到泡沫状物10(5.58克,90%).旋光[α]D 25+122(c1,CHCl3);核磁δH(CDCl3)4.49(dd,1H,J5,6a6.0,J6a,6b11.4Hz,H-6a),4.66(dd,1H,J5,6b6.9,J6a, 6b11.1Hz,H-6b),4.92(t,1H,J5,6a6.0,J5,6b6.9Hz,H-5),6.03(dd,1H,J1,23.6,J2,310.5Hz,H-2),6.14(dd,1H,J2,310.5,J3,43.0Hz,H-3),6.22(d,1H,J3,42.4Hz,H-4),6.98(d,1H,J1,23.6Hz,H-1),7.22-8.13(m,20H,Ph),8.69(s,1H,NH);
异丙硫基2,3,4,6-四-氧-苯甲酰基-β-D-半乳吡喃糖基-(1→6)-2,3,4,6-四-氧-苯甲酰基-β-D-半乳吡喃糖基-(1→3)-2,4-二-氧-苯甲酰基-β-D-半乳吡喃糖苷(11).--化合物9(300毫克,0.65毫摩尔)和2.2当量的化合物10(1.06克,1.43毫摩尔)溶于5毫升的干燥二氯甲烷,在0℃,氮气氛中,滴加0.10当量(12微升)的TMSOTf催化偶联反应,反应2小时,滴加三乙胺(1滴)中和反应体系,蒸干混合物,用硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(2∶1),得到泡沫状物三糖11(5.58克,90%).旋光[α]D 25+14(c1,CHCl3);核磁δH(CDCl3)1.01,1.13(2d,2x3H,J6.5Hz,SCH(CH3)2),2.97-3.01(m,1H,SCH(CH3)2),3.88(dd,J5,6a8.4,J6a,6b10.8Hz,H-6a),4.04-4.06(m,1H,H-6),4.19-4.49(m,5H,H-3,H-5,H-5,H-5,H-6),4.50(dd,1H,J5,6 6.0,J6a,6b11.4Hz,H-6),4.64(d,1H,J1,2 10.2Hz,H-1),4.69-4.63(m,1H,H-6),4.75(dd,1H,J5,65.7,J6a,6b10.8Hz,H-6),5.00(t,1H,J1,27.8,J2,39.6Hz,H-2),5.00(d,1H,J1,27.8Hz,H-1),5.43(dd,1H,J2,310.5,J3,43.3Hz,H-3),5.61(t,1H,J1,28.7,J2,39.9Hz,H-2),5.58-5.64(m,2H,H-3,H-1),5.91(t,1H,J1,29.0,J2,39.6Hz,H-2),5.92(d,1H,J3,43.0Hz,H-4),5.98(d,1H,J3,43.0Hz,H-4),6.06(d,1H,3.3Hz)7.05-8.23(m,50H,ph).
氧-(2,3,4,6-四-氧-苯甲酰基-β-D-半乳吡喃糖基-(1→6)-[2,3,4,6-四-氧-苯甲酰基-β-D-半乳吡喃糖基-(1→3)]-2,4-二-氧-苯甲酰基-β-D-半乳吡喃糖基(1→6)-2,3,4-三-氧-苯甲酰基-β-D-半乳吡喃糖基)-N-苄氧羰基-L-丝氨酸甲酯(12).--供体化合物6(334毫克,0.21毫摩尔)和1当量的受体化合物11(152毫克,0.21毫摩尔)溶于3毫升的干燥二氯甲烷,在0℃,无光条件下,氮气氛中,加入3当量的碘化琥珀酰胺(NIS)(140毫克,0.62毫摩尔)和1当量(37微升)的TMSOTf催化偶联反应,反应2小时,滴加三乙胺中和反应体系,蒸干混合物,用硅胶柱色谱纯化分离,淋洗液为石油醚/乙酸乙酯(2∶1),得到泡沫状物四糖肽12(400毫克,90%).旋光[α]D 25+87(c1,CHCl3);核磁δH(CDCl3)3.50(s,3H,OCH3),3.50-3.65(m,3H,H-5,H-6a,H-6),3.89-3.95(m,4H,H-6,H-6,H-5,-OCH2),4.08-4.11(m,2H,H-3II,-OCH2),4.24-4.40(m,5H,H-6,H-6,H-6,H-5,H-5),4.53(d,1H,J1,28.0Hz,H-1),4.52-4.55(m,2H,H-1,-OCH),4.70(dd,J5,66.4,J6a,6b11.4Hz,H-6b),4.80(d,1H,J1,27.6Hz,H-1III),4.93(d,1H,J1,28.8Hz,H-1IV),4.94,5.01(2d,2H,J12.4Hz,-OCH2),5.37(d,1H,J7.8Hz,NH),5.37(dd,1H,J2,39.2,J3,43.2Hz,H-3IV),5.42(dd,1H,J2,39.6,J3,43.2Hz,H-3I),5.51-5.55(m,3H,H-2I,H-2II,H-2IV),5.64(dd,1H,J2,39.6,J3,43.2Hz,H-3III),5.70(d,1H,J3,43.2Hz,H-4I),5.75(t,J1,28.0,J2,39.2Hz,H-2III),5.84(d,1H,J3,43.2Hz,H-4IV),5.89(d,1H,J3,42.8Hz,H-4II),5.99(d,1H,J3,43.2Hz,H-4III),7.03-8.15(m,70H,Ph),δC(100MHz,CDCl3)170(CO),165.95,165.92,165.86,165.54,165.44(2C),165.36,165.19(2C),165.15(2C),164.39(2C)(13PhCO),154(PhCH2OCO),100.55,101.40,101.40,101.65(4C-1),52.46,53.74,54.12,61.46,61.93,66.69,66.88,67.55,68.12,68.31,68.63,69.35,69.49,69.87(2C),70.61,70.92,71.04,71.29(2C),71.48,71.62,72.89,73.95(24C,C-O)MALDI-TOF-MS C127H107O38NNa+found m/z 2276.9(M+Na+),C127H107O38NK+found m/z 2292.9(M+K+).
氧-(β-D-半乳吡喃糖基-(1→6)-β-D-半乳吡喃糖基-(1→3)]-β-D-半乳吡喃糖基(1→6)-β-D-半乳吡喃糖基)-L-丝氨酸(13).
将400毫克化合物12溶于10毫升(1∶1)乙酸乙酯-甲醇中,加入Pd/C 40毫克,室温搅拌下反应4小时后完成,移除苄氧羰基,过滤反应物,蒸干滤液,将其溶于20毫升丙酮,加入2N NaOH,使pH到达10,3小时后反应完成,用Biogel-P2柱精致产物,得到不保护的四糖肽13,产率75%。旋光[α]D 25+27(c1,H2O);核磁δH(D2O):4.71,4.60,4.54,4.53.
Claims (2)
2.权利1中的偶联反应催化剂为三甲基硅三氟甲磺酸酯(TMSOTf)或三氟化硼乙醚溶液。溶剂可为无水二氯甲烷、乙腈、乙醚、甲苯等。反应温度为-42-零度。
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CN100457766C (zh) * | 2006-09-26 | 2009-02-04 | 重庆邮电大学 | 非天然活性葡聚四糖烷基苷类化合物及其制备方法和应用 |
CN115141237A (zh) * | 2021-03-29 | 2022-10-04 | 上海医药工业研究院 | 一种络塞维中间体的制备方法 |
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CN100457766C (zh) * | 2006-09-26 | 2009-02-04 | 重庆邮电大学 | 非天然活性葡聚四糖烷基苷类化合物及其制备方法和应用 |
CN115141237A (zh) * | 2021-03-29 | 2022-10-04 | 上海医药工业研究院 | 一种络塞维中间体的制备方法 |
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