CN109232496A - 一类3,4,6-三-o-取代基-d-葡萄烯糖的制备方法 - Google Patents
一类3,4,6-三-o-取代基-d-葡萄烯糖的制备方法 Download PDFInfo
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
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- FMXIGEXRLSNRMR-NJYVYQBISA-N [(2r,3r,4r)-3,4-bis[[tert-butyl(dimethyl)silyl]oxy]-3,4-dihydro-2h-pyran-2-yl]methoxy-tert-butyl-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)OC[C@H]1OC=C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C FMXIGEXRLSNRMR-NJYVYQBISA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/188—Preparation; Treatments not provided for in C07F7/20 by reactions involving the formation of Si-O linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一类3,4,6‑三‑O‑取代基‑D‑葡萄烯糖的制备方法，包括如下步骤：(1)D‑葡萄烯糖的制备：以3,4,6‑三‑O‑乙酰基‑D‑葡萄烯糖为起始原料，在碱性条件下反应脱除保护基制得D‑葡萄烯糖；(2)3,4,6‑三‑O‑取代基‑D‑葡萄烯糖的制备：D‑葡萄烯糖在碱的作用下与具有较高反应活性的卤化物RX反应制得3,4,6‑三‑O‑取代基‑D‑葡萄烯糖；其中，3,4,6‑三‑O‑取代基‑D‑葡萄烯糖中的取代基为甲基，苯甲酰基，叔丁基二甲基硅基和烯丙基中的一种。与现有技术相比，本发明所述制备方法具有合成路线简洁，操作简便，反应条件温和，反应时间短，所用试剂便宜易得，收率高，成本低等优点，适合于大量工业化生产。
Description
技术领域
本发明属于有机化学合成领域，具体涉及一类3,4,6-三-O-取代基-D-葡萄烯糖的合成方法。
背景技术
糖类是指多羟基的醛、酮类或其衍生物、聚合物，基本的组成元素是C、H、O，有些糖类还含有N、P、S等其它元素。自然界中存在很多糖类化合物，其对于维持有机体的生命活动具有重要意义。糖主要通过与其它生物分子形成糖缀合物参与生命活动，也可以以游离形式参与，在生物体内有着重要的功能，例如：可以为机体提供生命活动所需要的能量、可以作为虾类、蟹类骨骼的结构成分，参与生物活性物质的合成、提供合成其他生物分子的碳架。
糖类化合物对于药物设计与研发等具有重要意义，现今在抗肿瘤、抗氧化、抗菌等多方面得到了较为广泛的应用。例如：D-甘露醇，可以用于制备利尿剂、治疗急性肾衰竭，医治青光眼等多方面。近年来糖类物质被看成是药物先导物的有效来源之一，其中烯糖在有机反应及药物合成中扮演着重要角色，为多数药物合成提供了重要的中间体，烯糖的双键部分可以发生很多反应，如重排、环氧化、加成和取代等。这些反应广泛应用于合成寡糖、糖肽、抗生素、核苷、糖醛酸和天然产物。
烯糖作为一种手性多羟基的化合物，其3,4,6位羟基具有很高的反应活性，因此，在3,4,6位羟基反应引入其他基团制备成3,4,6-三-O-取代基-D-葡萄烯糖，对于糖类化合物的合成及活性研究具有非常重要的意义。
发明内容
本发明的目的在于提供一类3,4,6-三-O-取代基-D-葡萄烯糖的制备方法，其中，取代基为甲基，苯甲酰基，叔丁基二甲基硅基和烯丙基中的一种。该方法合成路线简洁，操作简便，反应条件温和，反应时间短，所用试剂均为工业常用试剂，收率高，成本低，适合大量工业化生产。其反应路线如下：
实现本发明目的的技术方案为：一类3,4,6-三-O-取代基-D-葡萄烯糖的制备方法，包括如下步骤：
(1)D-葡萄烯糖的合成：以3,4,6-三-O-乙酰基-D-葡萄烯糖为起始原料，在碱性条件下反应脱除保护基制得D-葡萄烯糖；
(2)3,4,6-三-O-取代基-D-葡萄烯糖的合成：D-葡萄烯糖在碱的作用下与具有较高反应活性的卤化物RX反应制得3,4,6-三-O-取代基-D-葡萄烯糖；
其中，3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为甲基，苯甲酰基，叔丁基二甲基硅基和烯丙基中的一种。
作为优化，步骤(1)中，D-葡萄烯糖的具体合成步骤为：将3,4,6-三-O-乙酰基-D-葡萄烯糖、甲醇钠、甲醇加入到反应器中，室温下搅拌反应，反应结束，加入酸性树脂调节体系pH为中性后抽滤，滤液减压浓缩即得到D-葡萄烯糖。
作为优化，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为甲基，卤化物RX为碘甲烷，碱为氢化钠、正丁基锂、叔丁醇钾、叔丁醇钠中的一种或几种。
作为优化，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为苯甲酰基，卤化物RX为苯甲酰氯，碱为醋酸钠、甲醇钠、吡啶中的一种或几种。
作为优化，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为叔丁基二甲基硅基，卤化物RX为叔丁基二甲基氯硅烷，碱为咪唑，反应溶剂为DMF、甲醇、正丁醇、DMSO中的一种或几种。
作为优化，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为烯丙基，卤化物RX为烯丙基溴，碱为氢化钠、正丁基锂、叔丁醇钾、叔丁醇钠中的一种或几种，反应溶剂为DMF、甲醇、正丁醇、丙酮中的一种或几种。
本发明与现有技术相比具有以下有益效果：本发明所述3,4,6-三-O-取代基-D-葡萄烯糖的制备方法，其中，取代基为甲基，苯甲酰基，叔丁基二甲基硅基和烯丙基中的一种，具有合成路线简洁，操作简便，反应条件温和，反应时间短，所用试剂便宜易得，收率高，成本低等优点，适合于大量工业化生产。
具体实施方式
下面通过具体实施例对本发明进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明的一部分实施例，而不是全部的实施例。基于本发明的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本发明的保护范围。
实施例1
D-葡萄烯糖的制备
以3mL甲醇为溶剂，将3,4,6-三-O-乙酰基-D-葡萄烯糖(272mg,1mmol)加入25mL的圆底烧瓶中，完全溶解后加入1mol/L的甲醇钠的甲醇溶液(1mL，1mmol)，室温下均匀搅拌4h。用薄层硅胶板检测反应完全后，加入酸性树脂调节体系pH变为中性。抽滤，收集滤液，减压浓缩得到D-葡萄烯糖(146mg,1mmol)。
实施例2
3,4,6-三-O-甲基-D-葡萄烯糖的制备
以5mL DMF为溶剂，将反应生成的D-葡萄烯糖(146mg,1mmol)加入圆底烧瓶中，冰浴搅拌下分次加入氢化钠(60％)(180mg,4.5mmol)，反应0.5h后向体系逐滴加入碘甲烷(639mg,4.5mmol)，撤去冰浴，反应过夜。薄层硅胶板监测反应完全后，加入3mL饱和NH4Cl使反应停止。体系用水和二氯甲烷萃取，收集有机相，用Na2SO4干燥，过滤、减压浓缩、柱层析分离得到无色油状液体3,4,6-三-O-甲基-D-葡萄烯糖(150mg,产率80％)。
1H NMR(CDCl3,600MHz):δ6.38(d,J＝6.0Hz,1H),4.82(dd,J＝6.0,2.4Hz,1H),3.97-3.93(m,1H),3.88-3.85(dd,J＝4.8,1.2Hz,1H),3.69-3.60(m,2H),3.53(s,3H),3.45(dd,J＝7.8,6.0Hz,1H),3.41(s,3H),3.39(s,3H).
实施例3
3,4,6-三-O-苯甲酰基-D-葡萄烯糖的制备
以1.3mL吡啶为溶剂，将D-葡萄烯糖(146mg,1mmol)加入圆底烧瓶中，置于室温搅拌器上搅拌。然后逐滴加入苯甲酰氯(460mL,4mmol)，反应过夜。薄层硅胶板检测反应完全，体系用二氯甲烷和1mol/L的HCl萃取，将有机相用饱和碳酸钠溶液和蒸馏水洗涤，Na2SO4干燥，过滤、减压浓缩、柱层析分离得到白色固体3,4,6-三-O-苯甲酰基-D-葡萄烯糖(357mg,产率78％)。
1H NMR(CDCl3,400MHz):δ8.17-8.0(m,6H),7.57(m,3H),7.44(m,6H),6.53(dd,J＝6.4,1.2Hz,1H),5.61-5.59(dt,J＝6.8,2.0Hz,1H),4.89(dd,J＝6.0,2.8Hz,1H),4.84-4.80(dd,J＝12.4,4.8Hz,1H),4.68(dd,J＝12.0,2.4Hz,1H),4.20-4.26(m,1H),4.13-4.08(m,1H)。
实施例4
3,4,6-三-O-叔丁基二甲基硅基-D-葡萄烯糖的制备
以5mL DMF为溶剂，将葡萄烯糖(146mg,1mmol)、咪唑(612mg,9mmol)和叔丁基二甲基氯硅烷(906mg,6mmol)加入圆底烧瓶中，在50℃的反应浴中搅拌，反应过夜。薄层硅胶板检测反应完全，加入3mL饱和NH4Cl使反应停止。体系用水和二氯甲烷萃取，收集有机相，用Na2SO4干燥，过滤、减压浓缩、柱层析分离得到油状液体3,4,6-三-O-叔丁基二甲基硅基-D-葡萄烯糖(380mg,产率77％)。
1H NMR(CDCl3,600MHz):δ6.32(d,J＝6.0Hz,1H),4.69(t,J＝5.4Hz,1H),3.99(d,J＝3.6Hz,1H),3.96-3.88(m,2H),3.81-3.75(m,2H),0.90(d,J＝4.8Hz,27H),0.10(s,6H),0.08(s,6H),0.06(s,3H),0.05(s,3H).
实施例5
3,4,6-三-O-烯丙基-D-葡萄烯糖的制备
以5mL DMF为溶剂，将葡萄烯糖(146mg,1mmol)加入25mL圆底烧瓶中，冰浴搅拌下分次加入加入氢化钠(60％)(180mg,4.5mmol)，反应0.5h后向体系中逐滴加入烯丙基溴(544.5mg,4.5mmol)，撤去冰浴，反应过夜。薄层硅胶板监测反应完全，加入3mL饱和NH4Cl使反应停止。体系用水和二氯甲烷萃取，收集有机相，用Na2SO4干燥，过滤、减压浓缩、柱层析分离得到无色油状液体3,4,6-三-O-烯丙基-D-葡萄烯糖(207mg,产率78％)。
1H NMR(CDCl3,400MHz):δ6.38(d,J＝6.0Hz,1H),5.92(m 3H),5.34-5.23(m,3H),5.21-5.13(m,3H),4.83-4.77(m,1H),4.34-4.27(m,1H),4.20-3.96(m,7H),3.73(d,J＝3.2Hz,2H),3.68(dd,J＝8.0,6.4Hz,1H)。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所有的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一类3,4,6-三-O-取代基-D-葡萄烯糖的制备方法，其特征在于，包括如下步骤：
(1)D-葡萄烯糖的制备：以3,4,6-三-O-乙酰基-D-葡萄烯糖为起始原料，在碱性条件下反应脱除保护基制得D-葡萄烯糖；
(2)3,4,6-三-O-取代基-D-葡萄烯糖的制备：D-葡萄烯糖在碱的作用下与具有较高反应活性的卤化物RX反应制得3,4,6-三-O-取代基-D-葡萄烯糖；
其中，3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为甲基，苯甲酰基，叔丁基二甲基硅基和烯丙基中的一种。
2.如权利要求1所述的制备方法，其特征在于，所述步骤(1)中，D-葡萄烯糖的具体合成步骤为：将3,4,6-三-O-乙酰基-D-葡萄烯糖、甲醇钠、甲醇加入到反应器中，室温下搅拌反应，反应结束，加入酸性树脂调节体系pH为中性后抽滤，滤液减压浓缩即得到D-葡萄烯糖，其中，3,4,6-三-O-乙酰基-D-葡萄烯糖与甲醇钠的投料摩尔比为1:1。
3.如权利要求1所述的制备方法，其特征在于，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为甲基，卤化物RX为碘甲烷，碱为氢化钠、正丁基锂、叔丁醇钾、叔丁醇钠中的一种或几种。
4.如权利要求3所述的制备方法，其特征在于，步骤(2)的碱为氢化钠，反应溶剂为DMF，D-葡萄烯糖、氢化钠、碘甲烷的投料摩尔比为1:4.5:4.5，反应温度为室温，淬灭液为饱和氯化铵溶液，后处理萃取溶剂为二氯甲烷。
5.如权利要求1所述的制备方法，其特征在于，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为苯甲酰基，卤化物RX为苯甲酰氯，碱为醋酸钠、甲醇钠、吡啶中的一种或几种。
6.如权利要求5所述的制备方法，其特征在于，步骤(2)中直接用吡啶作为碱和溶剂，D-葡萄烯糖、吡啶、苯甲酰氯的投料摩尔比为1:16:4，反应温度为室温，反应淬灭液为盐酸，后处理萃取溶剂为二氯甲烷。
7.如权利要求1所述的制备方法，其特征在于，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为叔丁基二甲基硅基，卤化物RX为叔丁基二甲基氯硅烷，碱为咪唑，反应溶剂为DMF、甲醇、正丁醇、DMSO中的一种或几种。
8.如权利要求7所述的制备方法，其特征在于，步骤(2)中反应溶剂为DMF,D-葡萄烯糖、咪唑、叔丁基二甲基氯硅烷的投料摩尔比为1:9:6，反应温度为50±5℃,反应淬灭液为饱和氯化铵溶液，后处理萃取溶剂为二氯甲烷。
9.如权利要求1所述的制备方法，其特征在于，步骤(2)中3,4,6-三-O-取代基-D-葡萄烯糖中的取代基为烯丙基，卤化物RX为烯丙基溴，碱为氢化钠、正丁基锂、叔丁醇钾、叔丁醇钠中的一种或几种，反应溶剂为DMF、甲醇、正丁醇、丙酮中的一种或几种。
10.如权利要求9所述的制备方法，其特征在于，步骤(2)中，反应溶剂为DMF,碱为氢化钠，D-葡萄烯糖、烯丙基溴、氢化钠的投料摩尔比为1:4.5:4.5，反应温度为室温，反应淬灭液为饱和氯化铵溶液，后处理萃取溶剂为二氯甲烷。
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