CN110526950B - 一种alpha-五-O-乙酰基甘露糖的制备方法 - Google Patents
一种alpha-五-O-乙酰基甘露糖的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 3
- 238000000034 method Methods 0.000 claims abstract description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims abstract description 10
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000047 product Substances 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 6
- 238000000746 purification Methods 0.000 claims description 5
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000012065 filter cake Substances 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 4
- 238000001308 synthesis method Methods 0.000 claims description 4
- 239000005457 ice water Substances 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 abstract description 4
- UAOKXEHOENRFMP-KLHDSHLOSA-N [(2r,3r,4s,5s)-2,3,4,5-tetraacetyloxy-6-oxohexyl] acetate Chemical compound CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)C=O UAOKXEHOENRFMP-KLHDSHLOSA-N 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 239000007787 solid Substances 0.000 abstract description 3
- 229960005486 vaccine Drugs 0.000 abstract description 3
- 230000021736 acetylation Effects 0.000 abstract description 2
- 238000006640 acetylation reaction Methods 0.000 abstract description 2
- 230000003197 catalytic effect Effects 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 2
- HRYLCRMCPOGATF-ZJIFWQFVSA-N (4R,5S,6R,7R)-4,5,6-triacetyl-4,5,6,7-tetrahydroxy-7-(hydroxymethyl)nonane-2,3,8-trione Chemical compound C(C)(=O)[C@@]([C@]([C@@]([C@@](C(=O)C(C)=O)(O)C(C)=O)(O)C(C)=O)(O)C(C)=O)(O)CO HRYLCRMCPOGATF-ZJIFWQFVSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 150000002703 mannose derivatives Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
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Abstract
本发明提供了一种alpha‑五‑O‑乙酰基甘露糖的制备方法，以天然甘露糖为原料在传统的醋酸酐乙酰化工艺基础上进行了探索，添加催化量氟化铯为催化剂，在催化剂的作用下抑制了beta‑五‑O‑乙酰基甘露糖的生成，从而直接析晶分离得到高纯度的固态alpha‑五‑O‑乙酰基甘露糖，克服传统方法制备的五‑O‑乙酰基甘露糖难以析晶纯化和大规模产业化的困难。该方法工艺简单、成本低、适合大规模生产，能够促进甘露糖在药物和疫苗开发领域的应用。
Description
技术领域
本发明属于糖化学合成领域，具体涉及一种alpha-五-O-乙酰基甘露糖的合成方法。
背景技术
五-O-乙酰基甘露糖是开发制备一系列甘露糖药物和疫苗寡糖片段的重要原料。传统的从甘露糖制备五乙酰基甘露糖的方法得到的是两种异构体1-alpha和1-beta两个产物混合物，这样的混合产物呈油状，难以纯化和商品化。
现有可行的制备单一构型固态五-O-乙酰基甘露糖的方法是通过两步法获得：
。
但是该方法成本较高，此外反应过程无法完全避免beta异构体的产生，重结晶过程单一alpha构型产品收率较低。目前国内市场alpha-五-O-乙酰基甘露糖还仅限于试剂级，价格较高限制了下游功能产品的开发利用。
发明内容
针对现有固体alpha-五-O-乙酰基甘露糖生产工艺纯化困难、成本高、难以工业化生产的问题，本发明提供了一种alpha-五-O-乙酰基甘露糖的合成方法，收率高、母液可以套用，适于工业化生产。
为实现上述目的，本发明采用如下技术方案。
一种alpha-五-O-乙酰基甘露糖的合成方法，包括以下步骤：浓硫酸存在下，氟化铯催化甘露糖和醋酸酐反应，分离纯化获得产物alpha-五-O-乙酰基甘露糖。
所述分离纯化步骤为：反应结束后的体系降温至0-10℃倒入冰水中，然后过滤，滤饼用0-10℃甲醇洗涤2-3次后过滤并干燥，获得产物。
合成路线如下：
。
本发明具有以下优点：
本发明的合成方法以天然甘露糖为原料在传统的醋酸酐乙酰化工艺基础上进行了探索，添加催化量氟化铯为催化剂，在催化剂的作用下抑制了beta-五-O-乙酰基甘露糖的生成，从而直接析晶分离得到高纯度的固态alpha-五-O-乙酰基甘露糖，克服传统方法制备的五-O-乙酰基甘露糖难以析晶纯化和大规模产业化的困难。该方法工艺简单、成本低、适合大规模生产，能够促进甘露糖在药物和疫苗开发领域的应用。
具体实施方式
下面结合实施例对本发明做进一步说明，但本发明不受下述实施例的限制。
实施例1
（1）搅拌下往6L醋酸酐中加入10g浓硫酸，体系搅拌均匀后分批加入1000g甘露糖，加料过程控制体系温度低于50℃；待加料完毕温度稳定后往体系加入1g氟化铯，然后继续搅拌反应，经HPLC检测12h后体系反应完全；
（2）将反应后的体系降温至4℃，然后将体系缓慢倒入剧烈搅拌的10L冰水中，目标产物析出，过滤，滤饼用3L甲醇在0℃下搅洗，然后再过滤，滤饼用甲醇充分淋洗，固体产物经干燥得alpha-五-O-乙酰基甘露糖1985g，收率91.6%，HPLC纯度99.2%。
Claims (2)
1.一种alpha-五-O-乙酰基甘露糖的合成方法，其特征在于，包括以下步骤：浓硫酸存在下，氟化铯催化甘露糖和醋酸酐反应，分离纯化获得产物alpha-五-O-乙酰基甘露糖。
2.根据权利要求1所述的合成方法，其特征在于，所述分离纯化步骤为：反应结束后的体系降温至0-10℃倒入冰水中，然后过滤，滤饼用0-10℃甲醇洗涤2-3次后过滤并干燥，获得产物。
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| CN201910896615.XA CN110526950B (zh) | 2019-09-23 | 2019-09-23 | 一种alpha-五-O-乙酰基甘露糖的制备方法 |
| PCT/CN2019/108395 WO2021056382A1 (zh) | 2019-09-23 | 2019-09-27 | 一种alpha-五-O-乙酰基甘露糖的制备方法 |
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996027379A1 (en) * | 1995-03-08 | 1996-09-12 | The Scripps Research Institute | Carbopeptoids and carbonucleotoids |
| CN101213170A (zh) * | 2005-05-06 | 2008-07-02 | 迈克罗比亚公司 | 制备4-联苯基氮杂环丁烷-2-酮化合物的方法 |
| WO2014152718A1 (en) * | 2013-03-15 | 2014-09-25 | Arizona Board Of Regents, For And On Behalf Of Arizona State University | Saccharide conjugates |
| CN107286207A (zh) * | 2017-08-10 | 2017-10-24 | 济南山目生物医药科技有限公司 | 一种龙胆二糖的合成方法 |
| CN107325133A (zh) * | 2017-08-11 | 2017-11-07 | 济南山目生物医药科技有限公司 | 一种1,2,3‑三‑o‑乙酰基‑5‑脱氧‑d核糖的合成方法 |
| CN107446004A (zh) * | 2017-08-10 | 2017-12-08 | 济南山目生物医药科技有限公司 | 一种2‑(4’‑甲基伞形酮)‑alpha‑N‑乙酰基神经氨酸钠的合成方法 |
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| AU2005285045B2 (en) * | 2004-09-14 | 2011-10-13 | Gilead Sciences, Inc. | Preparation of 2'fluoro-2'- alkyl- substituted or other optionally substituted ribofuranosyl pyrimidines and purines and their derivatives |
| US9938312B2 (en) * | 2011-03-25 | 2018-04-10 | University Of Georgia Research Foundation, Inc. | Compounds and methods for chemical and chemo-enzymatic synthesis of complex glycans |
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- 2019-09-23 CN CN201910896615.XA patent/CN110526950B/zh active Active
- 2019-09-27 WO PCT/CN2019/108395 patent/WO2021056382A1/zh not_active Ceased
Patent Citations (6)
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| WO1996027379A1 (en) * | 1995-03-08 | 1996-09-12 | The Scripps Research Institute | Carbopeptoids and carbonucleotoids |
| CN101213170A (zh) * | 2005-05-06 | 2008-07-02 | 迈克罗比亚公司 | 制备4-联苯基氮杂环丁烷-2-酮化合物的方法 |
| WO2014152718A1 (en) * | 2013-03-15 | 2014-09-25 | Arizona Board Of Regents, For And On Behalf Of Arizona State University | Saccharide conjugates |
| CN107286207A (zh) * | 2017-08-10 | 2017-10-24 | 济南山目生物医药科技有限公司 | 一种龙胆二糖的合成方法 |
| CN107446004A (zh) * | 2017-08-10 | 2017-12-08 | 济南山目生物医药科技有限公司 | 一种2‑(4’‑甲基伞形酮)‑alpha‑N‑乙酰基神经氨酸钠的合成方法 |
| CN107325133A (zh) * | 2017-08-11 | 2017-11-07 | 济南山目生物医药科技有限公司 | 一种1,2,3‑三‑o‑乙酰基‑5‑脱氧‑d核糖的合成方法 |
Non-Patent Citations (1)
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