CN111269279B - 一种在温和条件下制备卤代糖的方法 - Google Patents
一种在温和条件下制备卤代糖的方法 Download PDFInfo
- Publication number
- CN111269279B CN111269279B CN202010113910.6A CN202010113910A CN111269279B CN 111269279 B CN111269279 B CN 111269279B CN 202010113910 A CN202010113910 A CN 202010113910A CN 111269279 B CN111269279 B CN 111269279B
- Authority
- CN
- China
- Prior art keywords
- sugar
- halogen
- formula
- iodine
- halo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 235000000346 sugar Nutrition 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 75
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 57
- 239000003960 organic solvent Substances 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- 150000002367 halogens Chemical class 0.000 claims abstract description 12
- 229930182475 S-glycoside Natural products 0.000 claims abstract description 8
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 150000003569 thioglycosides Chemical class 0.000 claims abstract description 6
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 4
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims abstract description 4
- 125000006239 protecting group Chemical group 0.000 claims abstract description 4
- 229910052710 silicon Inorganic materials 0.000 claims abstract description 4
- 239000010703 silicon Substances 0.000 claims abstract description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- 229910052801 chlorine Inorganic materials 0.000 claims abstract description 3
- 125000001475 halogen functional group Chemical group 0.000 claims abstract 7
- 238000003756 stirring Methods 0.000 claims description 17
- 239000002808 molecular sieve Substances 0.000 claims description 15
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 15
- 125000003147 glycosyl group Chemical group 0.000 claims description 6
- HEVMDQBCAHEHDY-UHFFFAOYSA-N (Dimethoxymethyl)benzene Chemical compound COC(OC)C1=CC=CC=C1 HEVMDQBCAHEHDY-UHFFFAOYSA-N 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-IVMDWMLBSA-N D-allopyranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@H](O)[C@@H]1O WQZGKKKJIJFFOK-IVMDWMLBSA-N 0.000 claims description 2
- 125000000824 D-ribofuranosyl group Chemical group [H]OC([H])([H])[C@@]1([H])OC([H])(*)[C@]([H])(O[H])[C@]1([H])O[H] 0.000 claims description 2
- 125000000089 arabinosyl group Chemical group C1([C@@H](O)[C@H](O)[C@H](O)CO1)* 0.000 claims description 2
- 239000012298 atmosphere Substances 0.000 claims description 2
- 125000002519 galactosyl group Chemical group C1([C@H](O)[C@@H](O)[C@@H](O)[C@H](O1)CO)* 0.000 claims description 2
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
- 125000000311 mannosyl group Chemical group C1([C@@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 125000000969 xylosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)CO1)* 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000000203 mixture Substances 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 125000000011 thioglycoside group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 abstract description 24
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 abstract description 7
- CBEQRNSPHCCXSH-UHFFFAOYSA-N iodine monobromide Chemical compound IBr CBEQRNSPHCCXSH-UHFFFAOYSA-N 0.000 abstract description 7
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 abstract description 6
- 239000011630 iodine Substances 0.000 abstract description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 abstract description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000460 chlorine Substances 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract description 2
- 239000002904 solvent Substances 0.000 abstract description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract 1
- 125000006575 electron-withdrawing group Chemical group 0.000 abstract 1
- 150000002243 furanoses Chemical class 0.000 abstract 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract 1
- 150000003215 pyranoses Chemical class 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- 239000012300 argon atmosphere Substances 0.000 description 14
- 238000012512 characterization method Methods 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- 238000004821 distillation Methods 0.000 description 14
- 239000003480 eluent Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000011259 mixed solution Substances 0.000 description 14
- 239000003208 petroleum Substances 0.000 description 14
- 239000000243 solution Substances 0.000 description 12
- 125000004383 glucosinolate group Chemical group 0.000 description 10
- -1 saccharide compounds Chemical class 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 7
- 239000008103 glucose Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229930182470 glycoside Natural products 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 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 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 235000014633 carbohydrates Nutrition 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 229930182830 galactose Natural products 0.000 description 3
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 2
- SHZGCJCMOBCMKK-JFNONXLTSA-N L-rhamnopyranose Chemical compound C[C@@H]1OC(O)[C@H](O)[C@H](O)[C@H]1O SHZGCJCMOBCMKK-JFNONXLTSA-N 0.000 description 2
- PNNNRSAQSRJVSB-UHFFFAOYSA-N L-rhamnose Natural products CC(O)C(O)C(O)C(O)C=O PNNNRSAQSRJVSB-UHFFFAOYSA-N 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 150000002338 glycosides Chemical class 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229920001542 oligosaccharide Polymers 0.000 description 2
- 150000002482 oligosaccharides Chemical class 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- UGJBHEZMOKVTIM-UHFFFAOYSA-N N-formylglycine Chemical class OC(=O)CNC=O UGJBHEZMOKVTIM-UHFFFAOYSA-N 0.000 description 1
- 239000000370 acceptor Substances 0.000 description 1
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 235000021310 complex sugar Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229930182478 glucoside Natural products 0.000 description 1
- 150000008131 glucosides Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000008494 α-glucosides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—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 directly attached to carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/18—Acyclic radicals, substituted by carbocyclic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
- C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
- C07H9/04—Cyclic acetals
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Saccharide Compounds (AREA)
Abstract
本发明公开了一种在温和条件下制备卤代糖的方法，利用易于制备的硫苷供体与卤素单质或卤素互化物在室温下反应，即可得到卤代糖(氯、溴、碘)。其中所述的卤素单质和卤素互化物分别是商业易得碘单质、溴化碘以及氯化碘。该方法适用于各类吡喃糖和呋喃糖。且该方法对于硫苷供体的保护基没有限制，可以是吸电子基团如乙酰基、苯甲酰基等，也可以是供电子的基团如苄基、硅基等。同时该反应在二氯甲烷、乙腈、甲苯等多种有机溶剂中均可发生。本发明卤代糖的制备方法简单，反应条件温和，原料易得，适用范围广，对于酸不稳定的基团如异亚丙基缩酮和硅基等具有兼容性，而且对于分离过程不稳定的卤代糖除去溶剂即可得到纯净的产物。
Description
技术领域
本发明属于糖苷的合成技术领域，具体涉及一种在温和条件下制备卤代糖的方法。
背景技术
糖类化合物是生命体重要的结构物质、能源物质及信息传递物质，在复杂的生命活动中发挥着十分重要的作用。自然界中，糖类化合物的存在形式有：单糖、寡糖、聚糖及糖缀合物。然而由于其化学结构的复杂性及微观不均一性，使得研究糖类化合物的结构及其功能的关系变得十分困难。获取独特且单一的碳水化合物材料对于了解其物理特性，生物学功能和疾病相关特征非常重要。目前，从天然来源中以可接受的纯度和量分离糖类化合物依然是个难点。因此，最方便地获得具有明确结构的复杂糖往往只能通过化学合成。
卤代糖在糖苷键的合成中扮演了历史性的角色，因为糖苷的第一次合成(1879年)就是用的卤代糖，几年后koenigs和knorr发展了该方法。卤代糖不仅可以合成氧苷、氮苷、碳苷、硫苷类化合物，还能合成烯糖等化合物，在糖类的化学合成中具有不可替代的作用。
目前，典型的合成卤代糖的方法是利用各种卤化试剂如溴化氢乙酸溶液、四氯化钛等与保护的糖反应，由于这类卤化试剂存在酸性强、毒性大或者价格昂贵等问题。因此亟待发展一种在温和条件下制备卤代糖的方法并能够广泛应用于寡糖的制备。
发明内容
本发明所要解决的技术问题在于克服使用强酸性、高毒性卤化剂制备卤代糖的缺点，提供一种制备方法简便、反应条件温和、后处理简单的卤代糖的制备方法。
解决上述技术问题所采用的技术方案是：在无水无氧的惰性气氛下，将式a所示的端基硫苷供体溶解于有机溶剂中，再加入卤素单质或卤素互化物，在室温下搅拌至端基硫苷供体反应完全，得到式b所示的卤代糖；
式中G代表全保护的糖基，X代表Cl、Br或I。
上述方法中，所述的糖基为葡萄糖基、半乳糖基、甘露糖基、鼠李糖基、阿洛糖基、核糖基、阿拉伯糖基、木糖基中任意一种，糖基上的保护基为乙酰基、苯甲酰基、新戊酰基、苄基、异亚丙基缩酮、硅基、苯亚甲基缩醛中任意一种或多种的组合。
上述方法中，所述的有机溶剂为二氯甲烷、乙腈、甲苯中任意一种。
上述方法中，优选端基硫苷供体与卤素单质或卤素互化物的摩尔比为1:1.0～1.5。
上述方法中，进一步优选室温搅拌反应的时间为0.5～5小时。
与现有技术相比，本发明具有的有益效果如下：
1、本发明以稳定的S-2,2-二甲基-3-丁炔基硫代糖苷为前体，以氯化碘、溴化碘、碘单质等卤素互化物或卤素单质作为温和的卤化试剂进行反应制备卤代糖，该反应具有反应条件温和、反应彻底、后处理简便等优点。
2、本发明制备卤代糖过程简便，使用范围广(可用于不同种类保护基保护的多种糖类化合物)，为卤代糖的合成提供了新思路。
3、本发明反应彻底，制备卤代糖后，可以不经分离以及不更换溶剂，直接在反应液中加入不同的添加剂和受体一锅法以高立体选择性得到α-和β-糖苷化合物。
具体实施方式
下面结合实施例对本发明进一步详细说明，但本发明的保护范围并不仅限于这些实施例。
实施例中，氢谱1H-NMR和碳谱13C-NMR在布鲁克公司(Bruker)400MHz核磁共振谱仪上测定，室温是指20℃至30℃的温度。
实施例1
将32.80mg(0.074mmol)式1a所示的全乙酰化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.7mL二氯甲烷，然后加入90μL 1mol/L 氯化碘的二氯甲烷溶液，室温下搅拌反应2h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式1b所示的氯代全乙酰化葡萄糖23.0mg，收率85％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.37(d,J＝4.0Hz,1H),5.52(dd,J＝3.2,1.2Hz, 1H),5.42(dd,J＝10.8,3.2Hz,1H),5.25(dd,J＝10.8,4.0Hz,1H),4.54-4.49(m,1H),13C NMR(400MHz,CDCl3)δ170.41,170.22,170.01,169.87,91.26,69.44,67.94,67.30, 67.18,61.11,20.81,20.78,20.72,20.69.
实施例2
将41.71mg(0.094mmol)式1a所示的全乙酰化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.9mL二氯甲烷，然后加入110μL 1mol/L 溴化碘的二氯甲烷溶液，室温下搅拌反应1h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式2b所示的溴代全乙酰化葡萄糖33.5mg，收率78％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.61(d,J＝4.0Hz,1H),5.55(t,J＝9.6Hz,1H), 5.16(t,J＝9.6Hz,1H),4.83(dd,J＝10.0,4.0Hz,1H),4.35-4.26(m,2H),4.12(d,J＝10.8 Hz,1H),2.10(s,3H),2.09(s,3H)2.05(s,3H),2.03(s,3H)；13C NMR(400MHz,CDCl3)δ 170.57,169.91,169.85,169.52,86.63,72.21,70.68,70.23,67.23,61.02,20.78,20.77, 20.74,20.67.
实施例3
将39.25mg(0.088mmol)式1a所示的全乙酰化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.9mL二氯甲烷，然后加入27.9mg(0.11 mmol)碘单质，室温下搅拌反应2h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式3b所示的碘代全乙酰化葡萄糖37.1mg，收率92％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.99(d,J＝4.4Hz,1H),5.46(t,J＝9.6Hz,1H), 5.21-5.15(m,1H),4.34(dd,J＝12.8,4.0Hz,1H),4.20(dd,J＝10.0,4.4Hz,1H),4.11(dd, J＝12.4,2.0Hz,1H),4.05(ddd,J＝10.4,3.6,2.0Hz,1H),2.10(s,3H),2.10(s,3H),2.06 (s,3H),2.03(s,3H)；13C NMR(400MHz,CDCl3)δ170.44,169.78,169.54,169.42,74.91, 72.92,71.74,70.29,66.93,60.86,20.78,20.62,20.57,20.52.
实施例4
将41.21mg(0.093mmol)式2a所示的全乙酰化半乳糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.9mL二氯甲烷，然后加入27.9mg(0.11 mmol)碘单质，室温下搅拌反应2h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式4b所示的碘代全乙酰化半乳糖40.3mg，收率95％。所得产物的结构表征数据为：1H NMR(600MHz,CDCl3)δ7.08(d,J＝4.2Hz,1H),5.49(d,J＝3.0Hz,1H),5.30 (dd,J＝10.2,3.0Hz,1H),4.36(dd,J＝10.8,4.2Hz,1H),4.26-4.18(m,2H),4.11(dd,J＝ 11.4,6.6Hz,1H),2.15(s,3H),2.11(s,3H),2.06(s,3H),2.01(s,3H)；13C NMR(400MHz, CDCl3)δ170.42,169.97(2C),169.85,75.26,73.68,69.81,67.58,66.63,60.74,21.08,20.79, 20.73(2C).
实施例5
将53.52mg(0.12mmol)式3a所示的全乙酰化甘露糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入1.2mL二氯甲烷，然后加入33.0mg(0.13mmol) 碘单质，室温下搅拌反应2h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式5b 所示的碘代全乙酰化甘露糖40.30mg，收率95％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ7.07(d,J＝4.4Hz,1H),5.49(d,J＝3.2Hz,1H),5.28(dd,J＝ 10.4,3.2Hz,1H),4.35(dd,J＝10.8,3.6Hz,1H),4.28-4.17(m,2H),4.10(dd,J＝10.8,6.4 Hz,1H).2.14(s,3H),2.10(d,J＝4.5Hz,3H),2.05(s,3H),2.00(s,3H).13C NMR(400 MHz,CDCl3)δ170.36,169.93,169.92,169.80,75.27,73.70,69.82,67.59,66.65,60.72, 21.03,20.74,20.68(2C).
实施例6
将34.52mg(0.089mmol)式4a所示的全乙酰化鼠李糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.9mL二氯甲烷，然后加入110μL 1mol/L 氯化碘的二氯甲烷溶液，室温下搅拌反应3h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式6b所示的氯代全乙酰化鼠李糖67mg，收率84％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.67(s,1H),5.74(dd,J＝10.0,3.6Hz,1H),5.47 (dd,J＝3.6,1.6Hz,1H),5.17(t,J＝10.4Hz,1H),3.86-3.77(m,1H),2.16(s,3H),2.09(s, 3H),2.00(s,3H),1.30(d,J＝6.0Hz,3H)；13C NMR(400MHz,CDCl3)δ169.93,169.85, 169.66,73.81,73.67,70.39,68.59,67.39,20.91,20.76,16.92.
实施例7
将55.76mg(0.080mmol)式5a所示的全苯甲酰化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.8mL二氯甲烷，然后加入24.4mg(0.096 mmol)碘单质，室温下搅拌反应4h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比6:1的混合液)，得到式7b所示的碘代全苯甲酰化葡萄糖49.40mg，收率87％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ8.07(d,J＝7.2Hz,2H),8.00(d,J＝7.2Hz,2H),7.95 (d,J＝7.2Hz,2H),7.88(d,J＝7.2Hz,2H),7.61-7.49(m,3H),7.49-7.41(m,4H), 7.41-7.35(m,3H),7.30(t,J＝8Hz,2H),6.87(d,J＝4.0Hz,1H),6.27(t,J＝10Hz,1H), 5.82(t,J＝10.0Hz,1H),5.33(dd,J＝10.0,4.0Hz,H),4.78-4.71(m,1H),4.67(dd,J＝ 12.4,3.6Hz,1H),4.51(dd,J＝12.4,4.4Hz,1H)；13C NMR(400MHz,CDCl3)δ166.12, 165.65,165.40,165.18,133.90,133.74,133.45,133.36,130.17(2C),130.03(2C), 129.92(3C),129.84(2C),129.53,128.87(2C),128.66(2C),128.59(2C),128.55(2C), 128.46(3C),86.95,72.79,71.55,70.69,68.06,62.02.
实施例8
将36.27mg(0.057mmol)式6a所示的全苄基化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.6mL二氯甲烷，然后加入69μL1mol/L 氯化碘的二氯甲烷溶液，室温下搅拌反应0.5h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比8:1的混合液)，得到式8b所示的氯代全苄基化葡萄糖25.71mg，收率81％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ7.38-7.26(m,18H),7.18-7.11(m,2H),6.06 (d,J＝3.6Hz,1H),4.97(d,J＝10.8Hz,1H),4.83(dd,J＝10.8,6.0Hz,2H),4.76-4.67(m, 2H),4.58(d,J＝12.4Hz,1H),4.53-4.43(m,2H),4.11-4.00(m,2H),3.79-3.69(m,3H), 3.65(d,J＝10.8Hz,1H)；13C NMR(400MHz,CDCl3)δ138.50,138.01,137.66,137.45, 128.58,128.44,128.12,128.07,127.99,127.96,127.88,127.82,127.72,93.53,81.40,79.82, 76.41,75.85,75.23,73.51,73.38,72.99,67.76.
实施例9
将40.82mg(0.11mmol)式7a所示的异亚丙基缩酮保护的甘露糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入1.1mL二氯甲烷，然后加入120μL 1mol/L氯化碘的二氯甲烷溶液，室温下搅拌反应3h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比6:1 的混合液)，得到式9b所示的氯代异亚丙基缩酮保护的甘露糖26.49mg，收率83％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.26(s,1H),4.44(d,J＝5.2 Hz,1H),4.31(dd,J＝7.6,5.2Hz,1H),3.96-3.72(m,5H),1.55(s,3H),1.52(s,3H),1.45(s, 3H),1.37(s,3H)；13C NMR NMR(400MHz,CDCl3)δ108.47,100.01,92.44,83.13, 79.14,71.49,69.13,43.19,42.69,41.22,35.59,20.89.
实施例10
将45.84mg(0.10mmol)式8a所示的全乙酰化甘露糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入1.0mL二氯甲烷，然后加入110μL 1mol/L溴化碘的二氯甲烷溶液，室温下搅拌反应1h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式10b所示的溴代全乙酰化甘露糖37.31mg，收率88％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.29(d,J＝1.0Hz,1H),5.71(dd,J＝10.4,3.6Hz, 1H),5.44(dd,J＝3.6,1.6Hz,1H),5.36(t,J＝10.0Hz,1H),4.32(dd,J＝12.4,4.8Hz,1H), 4.21(ddd,J＝10.0,4.8,1.6Hz,1H),4.13(dd,J＝12.8,2.2Hz,1H),2.17(s,3H),2.10(s, 3H),2.07(s,3H),2.00(s,3H)；13C NMR(400MHz,CDCl3)δ170.59,169.77,169.64(2C), 83.13,72.91,72.21,68.01,65.36,61.52,20.90,20.81,20.78,20.71.
实施例11
将55.24mg(0.12mmol)式2a所示的全乙酰化半乳糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入1.2mL二氯甲烷，然后加入132μL 1mol/L溴化碘的二氯甲烷溶液，室温下搅拌反应1h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式11b所示的溴代全乙酰化半乳糖48.52mg，收率95％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.69(d,J＝4.0Hz,1H),5.51(dd,J＝3.6,1.2Hz, 1H),5.39(dd,J＝10.4,3.6Hz,1H),5.04(dd,J＝10.8,4.0Hz,1H),4.47(t,J＝6.4Hz,1H), 4.20–4.07(m,2H),2.14(s,3H),2.10(s,3H),2.05(s,3H),2.00(s,3H)；13C NMR(400 MHz,CDCl3)δ156.32,156.11,155.98,155.87,90.55,76.89,74.44,74.26,73.62,68.72, 36.66,36.58,36.53,36.51.
实施例12
将55.24mg(0.087mmol)式9a所示的全苄基化半乳糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入0.6mL二氯甲烷，然后加入95μL 1mol/L 氯化碘的二氯甲烷溶液，室温下搅拌反应0.3h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比8:1的混合液)，得到式12b所示的氯代全苄基化半乳糖38.03mg，收率78％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ7.36–7.27(m,18H),7.21-7.16(m,2H),6.11 (s,1H),4.90(d,J＝10.8Hz,1H),4.72(d,J＝4.8Hz,2H),4.68(d,J＝4.8Hz,1H),4.66– 4.61(m,2H),4.58(d,J＝10.8Hz,1H),4.52(d,J＝11.6Hz,2H),4.19(dd,J＝9.6,3.2Hz, 1H),4.10(t,J＝10.0Hz,1H),4.02(dd,J＝9.6,2.8Hz,1H),3.89(t,J＝2.4Hz,1H),3.82 (dd,J＝11.2,4.4Hz,1H),3.71(dd,J＝11.2,1.2Hz,1H)；13C NMR(400MHz,CDCl3)δ 138.26,138.14,137.70,128.56,128.53,128.43,128.08,128.00,127.97,127.93,127.91, 127.87,127.80,127.68,91.67,78.46,77.83,75.41,74.67,74.16,73.49,73.00,72.61,68.38.
实施例13
将53.42mg(0.12mmol)式1a所示的全乙酰化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入1.2mL甲苯，然后加入130μL 1mol/L溴化碘的二氯甲烷溶液，室温下搅拌反应2.5h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式2b所示的溴代全乙酰化葡萄糖37.0mg，收率75％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.61(d,J＝4.0Hz,1H),5.55(t,J＝9.6Hz,1H),5.16 (t,J＝9.6Hz,1H),4.83(dd,J＝10.0,4.0Hz,1H),4.35-4.26(m,2H),4.12(d,J＝10.8Hz, 1H),2.10(s,3H),2.09(s,3H)2.05(s,3H),2.03(s,3H)；13C NMR(400MHz,CDCl3)δ 170.57,169.91,169.85,169.52,86.63,72.21,70.68,70.23,67.23,61.02,20.78,20.77, 20.74,20.67.
实施例14
将46.38mg(0.10mmol)式1a所示的全乙酰化葡萄糖硫苷供体与甲苯共沸三遍，加入
分子筛，在氩气气氛下加入1.0mL乙腈，然后加入110μL 1mol/L溴化碘的二氯甲烷溶液，室温下搅拌反应4h，反应结束后，过滤，通过减压蒸馏除去有机溶剂，残余物经柱层析纯化(洗脱剂为石油醚与乙酸乙酯体积比3:1的混合液)，得到式2b所示的溴代全乙酰化葡萄糖30.9mg，收率75％。所得产物的结构表征数据为：1H NMR(400MHz,CDCl3)δ6.61(d,J＝4.0Hz,1H),5.55(t,J＝9.6Hz,1H),5.16(t, J＝9.6Hz,1H),4.83(dd,J＝10.0,4.0Hz,1H),4.35-4.26(m,2H),4.12(d,J＝10.8Hz, 1H),2.10(s,3H),2.09(s,3H)2.05(s,3H),2.03(s,3H)；13C NMR(400MHz,CDCl3)δ 170.57,169.91,169.85,169.52,86.63,72.21,70.68,70.23,67.23,61.02,20.78,20.77, 20.74,20.67。
Claims (5)
1.一种在温和条件下制备卤代糖的方法，其特征在于：将式a所示的端基硫苷供体与甲苯共沸三遍，加入4 Å分子筛，在无水无氧的惰性气氛下，将式a所示的端基硫苷供体溶解于有机溶剂中，再加入卤素单质或卤素互化物，在室温下搅拌至端基硫苷供体反应完全，得到式b所示的卤代糖；
式中G代表全保护的糖基，X代表Cl、Br或I；
所述的糖基为葡萄糖基、半乳糖基、甘露糖基、鼠李糖基、阿洛糖基、核糖基、阿拉伯糖基、木糖基中任意一种。
2.根据权利要求1所述的制备卤代糖的方法，其特征在于：所述糖基上的保护基为乙酰基、苯甲酰基、新戊酰基、苄基、异亚丙基缩酮、硅基、苯亚甲基缩醛中任意一种或多种的组合。
3.根据权利要求1所述的制备卤代糖的方法，其特征在于：所述的有机溶剂为二氯甲烷、乙腈、甲苯中任意一种。
4.根据权利要求1所述的制备卤代糖的方法，其特征在于：所述端基硫苷供体与卤素单质或卤素互化物的摩尔比为1:1.0～1.5。
5.根据权利要求1所述的制备卤代糖的方法，其特征在于：室温搅拌反应的时间为0.5～5小时。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010113910.6A CN111269279B (zh) | 2020-02-24 | 2020-02-24 | 一种在温和条件下制备卤代糖的方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010113910.6A CN111269279B (zh) | 2020-02-24 | 2020-02-24 | 一种在温和条件下制备卤代糖的方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN111269279A CN111269279A (zh) | 2020-06-12 |
| CN111269279B true CN111269279B (zh) | 2022-08-05 |
Family
ID=70993971
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010113910.6A Expired - Fee Related CN111269279B (zh) | 2020-02-24 | 2020-02-24 | 一种在温和条件下制备卤代糖的方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111269279B (zh) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5218097A (en) * | 1988-12-07 | 1993-06-08 | Ciba-Geigy Corporation | Process for the preparation of protected mono-sugar and oligo-sugar halides |
| WO2015006740A2 (en) * | 2013-07-11 | 2015-01-15 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide-ligand conjugates and process for their preparation |
| CN106167496A (zh) * | 2016-07-20 | 2016-11-30 | 陕西师范大学 | 一种桥环内酯类化合物及其制备方法和在构建β‑甘露糖苷键中的应用 |
| CN109678915A (zh) * | 2018-11-29 | 2019-04-26 | 蔡霈 | 卤代苯二酚葡萄糖苷的制备方法及其药用用途 |
-
2020
- 2020-02-24 CN CN202010113910.6A patent/CN111269279B/zh not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5218097A (en) * | 1988-12-07 | 1993-06-08 | Ciba-Geigy Corporation | Process for the preparation of protected mono-sugar and oligo-sugar halides |
| WO2015006740A2 (en) * | 2013-07-11 | 2015-01-15 | Alnylam Pharmaceuticals, Inc. | Oligonucleotide-ligand conjugates and process for their preparation |
| CN106167496A (zh) * | 2016-07-20 | 2016-11-30 | 陕西师范大学 | 一种桥环内酯类化合物及其制备方法和在构建β‑甘露糖苷键中的应用 |
| CN109678915A (zh) * | 2018-11-29 | 2019-04-26 | 蔡霈 | 卤代苯二酚葡萄糖苷的制备方法及其药用用途 |
Non-Patent Citations (2)
| Title |
|---|
| BRAIN UPTAKE OF HALOGENATED PRODUCTS OF D-GLUCAL;Y. HOMMA et al.;《Journal of Radioanalytical Chemistry》;19831231;第76卷(第2期);第283-288页 * |
| Gold-Catalyzed Synthesis of 2‑Deoxy Glycosides Using S‑But-3-ynyl Thioglycoside Donors;Surya Adhikari et al.;《ACS Catal.》;20131231;第3卷;第57-60页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN111269279A (zh) | 2020-06-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Zhou et al. | Radical dehydroxymethylative fluorination of carbohydrates and divergent transformations of the resulting reverse glycosyl fluorides | |
| JP2004509902A5 (zh) | ||
| Eisink et al. | Regioselective oxidation of unprotected 1, 4 linked glucans | |
| Tamura et al. | Synthesis of chondroitin sulfate E octasaccharide in a repeating region involving an acetamide auxiliary | |
| CN110776544B (zh) | 一类2,3-不饱和半乳糖硫苷类化合物及其合成方法 | |
| Abronina et al. | Novel benzyl-free glycosyl donors for highly stereoselective 1, 2-cis-fucosylation | |
| CN113527388A (zh) | 一种β-2-脱氧糖、2-脱氧-2-叠氮糖和葡萄糖苷键立体选择性合成的方法 | |
| Kováč et al. | Synthesis and NMR Spectra of Methyl 2-Deoxy-2-fluoro-and 3-Deoxy-3-fluoro-α-and β-D-Glucopyranosides | |
| Gola et al. | Influence of the solvent in low temperature glycosylations with O-(2, 3, 5, 6-tetra-O-benzyl-β-d-galactofuranosyl) trichloroacetimidate for 1, 2-cis α-d-galactofuranosylation | |
| Wang et al. | Synthesis of β-d-arabinofuranosides: stereochemical differentiation between d-and l-enantiomers | |
| CN111269279B (zh) | 一种在温和条件下制备卤代糖的方法 | |
| Alvarez-Mico et al. | A new glycosidation method through nitrite displacement on substituted nitrobenzenes | |
| Gandolfi-Donadío et al. | Synthesis of α-d-Galf-(1→ 2)-d-galactitol and α-d-Galf-(1→ 2)[β-d-Galf-(1→ 3)]-d-galactitol, oligosaccharide derivatives from Bacteroides cellulosolvens glycoproteins | |
| Shibata et al. | Total synthesis of acarbose and adiposin-2 | |
| Pang et al. | Synthesis of neamine-derived pseudodisaccharides by stereo-and regio-selective functional group transformations | |
| Amin et al. | Synthesis of asparagine-linked bacillosamine | |
| EP2852607B1 (en) | Synthesis of steroid saponins | |
| JP2540400B2 (ja) | Ｌ−タロピラノシド誘導体の製造方法 | |
| CN112375108B (zh) | 一种选择性合成1,2-顺式糖苷化合物的方法 | |
| Guillemineau et al. | Synthesis of 6-thio pseudo glycolipids and their orientation on a gold slide studied by IRRAS | |
| Liang et al. | Efficient one-pot syntheses of α-D-arabinofuranosyl tri-and tetrasaccharides present in cell wall polysaccharide of Mycobacterium tuberculosis | |
| Zhang et al. | Practical synthesis of a tetrasaccharide derivative corresponding to ristomycin A and ristocetin A | |
| JPH03264595A (ja) | 新規なグリコシル化方法 | |
| Kumar et al. | Reagent-controlled chemo/stereoselective glycosylation of ʟ-fucal to access rare deoxysugars | |
| CH683771A5 (de) | Verfahren zur Herstellung von Sialoglykosylverbindungen. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20220805 |