CN117658967A - 一种黄烷-3,4-二醇类衍生物的制备方法 - Google Patents
一种黄烷-3,4-二醇类衍生物的制备方法 Download PDFInfo
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- 150000005832 flavan-3,4-diol derivatives Chemical class 0.000 title claims abstract description 14
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 17
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 13
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- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
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- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- AHSBSUVHXDIAEY-UHFFFAOYSA-K manganese(iii) acetate Chemical compound [Mn+3].CC([O-])=O.CC([O-])=O.CC([O-])=O AHSBSUVHXDIAEY-UHFFFAOYSA-K 0.000 claims description 2
- MOVBJUGHBJJKOW-UHFFFAOYSA-N methyl 2-amino-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=CC=C1N MOVBJUGHBJJKOW-UHFFFAOYSA-N 0.000 claims description 2
- FIYYMXYOBLWYQO-UHFFFAOYSA-N ortho-iodylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1I(=O)=O FIYYMXYOBLWYQO-UHFFFAOYSA-N 0.000 claims description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 claims description 2
- 229910001923 silver oxide Inorganic materials 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
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- 235000011121 sodium hydroxide Nutrition 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- QSUJAUYJBJRLKV-UHFFFAOYSA-M tetraethylazanium;fluoride Chemical compound [F-].CC[N+](CC)(CC)CC QSUJAUYJBJRLKV-UHFFFAOYSA-M 0.000 claims description 2
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- XIMADJWJJOMVID-UHFFFAOYSA-N 2-phenyl-3,4-dihydro-2h-chromene-3,4-diol Chemical class OC1C(O)C2=CC=CC=C2OC1C1=CC=CC=C1 XIMADJWJJOMVID-UHFFFAOYSA-N 0.000 abstract description 34
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Abstract
本发明公开了一种黄烷‑3,4‑二醇类衍生物的制备方法。该制备方法成本低,产量高,反应时间短,可用于大规模制备黄烷‑3,4‑二醇类衍生物。本发明的制备方法可以连续操作,反应条件温和,每一步都无须柱层析纯化,降低了人力物力成本。
Description
技术领域
本发明涉及一种黄烷-3,4-二醇类衍生物的制备方法。
背景技术
黄烷-3,4-二醇类衍生物是一类性质不稳定,易氧化和聚合的化合物,因其具有抑菌、抗炎症、抗氧化、增强免疫等生物学功能,被广泛地应用于医药领域。
现有技术中已公开过一些此类化合物的制备方法。
专利申请CN 102503922 A中公开了一类黄烷-3,4-二醇类衍生物的制备方法,但是该专利申请中所涉及的制备方法反应条件苛刻,所采用的LiAlH4试剂遇水会剧烈反应,需要反应溶剂的绝对无水,难以规模化放大生产,且后处理中LiAlH4的淬灭会导致最终产物发生聚合反应。
“Chem.Pharm.Bull.53(12)1565—1569(2005)”公开了一种制备方法,但是其涉及内生真菌提取过程,工艺复杂,目前只适用于实验室毫克级别,不能用于工业化放大生产,同时收率低下,且不能绝对的控制氧化的选择性。
“HETEROCYCLES,Vol.84,No.1,2012,pp.349—354.”公开了一种制备方法,其工艺流程如下:
该工艺中每步反应的后处理的比较复杂,都需要进行一次柱层析纯化,总体收率偏低,不能实现公斤级的合成;同时,该工艺中只使用TBS对酚羟基进行保护,未对3-OH醇羟基进行保护,放大生产过程中会得到不同构型的产物杂质。
因此,亟待一种更为高效环保的黄烷-3,4-二醇类衍生物的制备方法。
发明内容
本发明以黄烷-3-醇为起始原料,通过三步反应获得黄烷-3,4-二醇类衍生物;先对所述起始原料黄烷-3-醇进行酚羟基和醇羟基保护,得羟基保护中间体产物;再对得到的羟基保护中间体产物进行氧化反应,得4-O-氧化中间体;最后对得到的4-O-氧化中间体进行脱保护反应,得最终目标化合物:黄烷-3,4-二醇类衍生物。
具体地,本发明提供了一种如下式(I)所示的黄烷-3,4-二醇类衍生物的制备方法,
其中,R1、R2和R3各自独立地为氢或羟基;R4选自H、甲基、乙基、-C(O)CH3、-CH2CH2OSi(CH3)2C(CH3)3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2OCH2CH3;优选地,R4选自甲基、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2OCH2CH3;
所述制备方法包括如下步骤:
(1)化合物a与化合物RaCl或(Ra)2NH发生取代反应,得到化合物b;所述反应在路易斯碱存在下进行,所述路易斯碱可以选自三乙胺、咪唑、碳酸氢钠、碳酸钠、碳酸铯中的一种或多种;式中Ra选自三甲基硅基、三乙基硅基、二甲基苯基硅基;当R1为氢时,R1a为氢;当R1为羟基时,R1a与Ra相同;当R2为氢时,R2a为氢;当R2为羟基时,R2a与Ra相同;当R3为氢时,R3a为氢;当R3为羟基时,R3a与Ra相同;
(2)化合物b与化合物R4OH发生氧化反应,得到化合物c;所述反应在氧化剂以及亲核试剂存在下进行;所述氧化剂可以选自DDQ、MnO2、过氧单磺酸钾、K2S2O8、2-碘酰苯甲酸、氧化银、硝酸铈铵、三醋酸锰中的一种或多种;所述亲核试剂可以选自水、甲醇、乙醇、乙酸、叔丁基二甲基羟乙氧基硅烷、乙二醇单乙醚、二乙二醇乙醚;
(3)化合物c在反应溶剂中发生硅醚脱保护反应,得到化合物(I);所述反应在脱保护试剂存在下进行,所述脱保护试剂可以选自氟化铵、四丁基氟化铵、四甲基氟化铵、四乙基氟化铵、氟化氢吡啶等含氟离子试剂以及氢氧化钠、碳酸氢钠、碳酸钠、乙酸钠、三乙胺等路易斯碱试剂。
优选地,
上述步骤(1)中,化合物a与化合物RaCl或(Ra)2NH的摩尔比为1:5~1:7;
上述步骤(2)中,化合物b与化合物R4OH的摩尔比为1:1.5~1:20;化合物b与氧化剂的摩尔比为1:1.5~1:6;
上述步骤(3)中,化合物c与脱保护试剂的摩尔比为1:1~1:6。
优选地,
上述步骤(1)在乙腈、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺、丙酮中的一种或多种作为溶剂,0℃~30℃作为反应温度范围,1-12小时作为反应时间下进行;
上述步骤(2)在正己烷、正庚烷、正戊烷、二氯甲烷、氯仿、1,2-二氯乙烷、1,1-二氯乙烷、1,1-二氯乙烯、1,2-二氯乙烯、环己烷、乙苯、甲苯、二甲苯、氯苯、乙腈、叔丁基甲醚、1,4-二氧六环、水中的一种或多种作为反应溶剂,0℃~30℃作为反应温度范围,1-12小时作为反应时间下进行;
上述步骤(3)所述反应溶剂选自甲醇、乙醇、乙酸乙酯、1,4-二氧六环、丙酮、乙腈、三氯乙烷中的一种或多种,0℃~30℃作为反应温度范围,1-3小时作为反应时间下进行。
优选地,
上述步骤(1)中,反应后所得的反应液经过蒸除溶剂后,加入石油醚、正己烷,正庚烷、正戊烷和二氯甲烷中的一种或多种,冷却1-12小时后,可得高纯度的羟基保护中间体结晶产物(纯度>95%)。
上述步骤(2)中,反应后所得的反应液直接通过净化媒介过滤,然后用有机试剂洗涤,可得较高纯度的4-O-氧化中间体(化合物c的纯度>70%);
所述净化媒介为:硅胶粉、硅藻土、中性三氧化二铝、碱性三氧化二铝/活性炭或离子交换树脂。洗涤所用的有机试剂选自正己烷、正庚烷、正戊烷、二氯甲烷、环己烷、乙苯、甲苯、二甲苯、乙腈、氯苯、叔丁基甲醚和乙酸乙酯的一种或多种;
上述步骤(3)中,反应所得的终产物粗液溶解于异丙醇、甲醇、乙醇、乙酸乙酯、1,4-二氧六环、丙酮、乙腈或三氯乙烷中的一种或多种,重结晶两次,得高纯度的最终产物黄烷-3,4-二醇类衍生物(化合物(I)纯度>98%)。
本发明所用试剂和原料均市售可得。
本发明以黄烷-3-醇为底物,合成黄烷-3,4-二醇类衍生物。通过硅醚羟基保护、苄位氧化、羟基脱保护,连续三步操作,高选择性合成目标化合物,无须柱层析,适合工业上大规模合成。
有益效果
1、本发明可以连续操作,反应条件温和,每一步都无须柱层析纯化,降低了人力物力成本;
2、本发明所用反应原料价格低廉,操作简便,可以实现大规模的放大;
3、本发明的合成路线合成的黄烷-3,4-二醇类衍生物,纯度高达98%,连续操作综合产率可达到50%;
4、在本发明中由于3号位醇羟基被保护,因此,由于位阻的影响,可以高立体选择性的得到4-O-氧化中间体产物,实现对手性的精准控制,得到单一构型的黄烷-3,4-二醇类衍生物;
5、本发明利用含多个硅醚保护基中间体极性偏小的特性,通过简单操作实现氧化产物中间体与极性大的副产物的分离纯化,从而得到较高纯度(>70%)的4-O-氧化产物中间体。
附图说明
图1为实施例1中(2R,3R,4S)-黄烷-3,4-二醇核磁1H-NMR;
图2为实施例1中(2R,3R,4S)-黄烷-3,4-二醇核磁13C-NMR;
图3为实施例2中(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇核磁1H-NMR;
图4为实施例2中(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇核磁13C-NMR;
图5为实施例2中(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇中间体核磁1H-NMR;
图6为实施例2中(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇中间体核磁13C-NMR;
图7为实施例2中(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇核磁1H-NMR;
图8为实施例2中(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇核磁13C-NMR;
图9为实施例3中(2S,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇核磁1H-NMR;
图10为实施例3中(2S,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇核磁13C-NMR;
图11为实施例4中(2R,3R,4S)-4-甲氧基黄烷-3,4-二醇核磁1H-NMR;
图12为实施例4中(2R,3R,4S)-4-甲氧基黄烷-3,4-二醇核磁13C-NMR;
图13为实施例1中(2R,3R,4S)-黄烷-3,4-二醇LC-MS谱图;
图14为实施例2中(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇LC-MS谱图;
图15为实施例4中(2R,3R,4S)-4-甲氧基黄烷-3,4-二醇LC-MS谱图;
图16为实施例6中(2S,3R,4S)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇LC-MS谱图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
各实施例中,1HNMR由BRUKER AVANCE NEO 600MHz,JNM-ECZ400s型核磁共振仪记录,化学位移以δ(ppm)表示:液质联用(LCMS)由Shimadzu LC-20AD,Agilent 1260型和Agilent 1200型质谱仪记录。
缩写
实施例1:(2R,3R,4S)-黄烷-3,4-二醇的合成
(1)(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇
在N2氛围下,将20g(2R,3R)-黄烷-3-醇溶于200mL乙腈溶液中。然后在0℃下,将72mL HMDS(5eq)逐滴加入到反应瓶中,并在室温下反应3h,直到原料消失。反应结束后,减压浓缩,剩余残渣在石油醚中重结晶得到98%收率的(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.93(dd,J=8.2,2.1Hz,1H),6.88(d,J=2.1Hz,1H),6.81(d,J=8.2Hz,1H),6.14(d,J=2.3Hz,1H),5.97(d,J=2.3Hz,1H),4.89-4.85(m,1H),4.14(td,J=4.3,2.0Hz,1H),2.80(dd,J=16.5,4.5Hz,1H),2.58(dd,J=16.6,4.0Hz,1H),0.26(s,9H),0.25(s,9H),0.24(s,9H),0.23(s,9H),-0.11(s,9H);13C NMR(125MHz,CDCl3)δ155.84,154.64,154.37,146.21,145.95,132.93,120.74,120.62,119.86,105.21,104.24,101.87,78.82,67.48,29.08,0.58,0.52,0.43,0.41,-0.08.
(2)(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将DDQ(2.0eq)分批次加入到反应瓶中。随后,逐滴加入24.3mL去离子水(20eq)并在室温下继续反应12个小时,直到原料消失。随后,在0℃下,将10g DMAP(1.2eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段硅藻土垫进行快速过滤,并用石油醚和乙腈20:1的混合溶剂进行洗涤,最终以54%的收率得到(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ6.93(dd,J=8.2,2.1Hz,1H),6.67(d,J=2.1Hz,1H),6.65(d,J=8.2Hz,1H),6.01(d,J=2.3Hz,1H),5.98(d,J=2.3Hz,1H),4.88(s,1H),4.86(d,J=2.7Hz,1H),4.76(dd,J=2.7,1.3Hz,1H),0.33(s,9H),0.27(s,18H),0.23(s,9H),-0.06(s,9H);13C NMR(125MHz,CDCl3)δ159.1,155.2,155.3,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,88.9,80.5,65.6,3.9,3.7,3.6,3.5,3.4.
(3)(2R,3R,4S)-黄烷-3,4-二醇(见图1、图2和图13)
将步骤(2)中合成的(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-黄烷-3,4-二醇溶于200mL的甲醇溶液中,向反应溶液中加入60mL TBAF(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在乙醇溶剂中重结晶,最终以97%的收率得到目标产物(2R,3R,4S)-黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ7.00(d,J=2.1Hz,1H),6.83(dd,J=8.3,2.1Hz,1H),6.78(d,J=8.1Hz,1H),5.98(d,J=2.2Hz,1H),5.93(d,J=2.3Hz,1H),4.97(d,J=1.0Hz,1H),4.73(d,J=2.8Hz,1H),3.83(dd,J=2.8,1.2Hz,1H);13C NMR(125MHz,MeOD)δ160.1,159.0,157.8,145.8,144.6,131.5,121.0,116.1,115.2,103.0,95.3,94.8,84.4,74.0,70.0.
实施例2:(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇的合成
(1)(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇(见图3和图4)
在N2氛围下,将20g(2R,3R)-黄烷-3-醇溶于200mL乙腈溶液中。然后在0℃下,将72mL HMDS(5eq)逐滴加入到反应瓶中,并在室温下反应3h,直到原料消失。反应结束后,减压浓缩,剩余残渣在石油醚中重结晶得到98%收率的(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.93(dd,J=8.2,2.1Hz,1H),6.88(d,J=2.1Hz,1H),6.81(d,J=8.2Hz,1H),6.14(d,J=2.3Hz,1H),5.97(d,J=2.3Hz,1H),4.89-4.85(m,1H),4.14(td,J=4.3,2.0Hz,1H),2.80(dd,J=16.5,4.5Hz,1H),2.58(dd,J=16.6,4.0Hz,1H),0.26(s,9H),0.25(s,9H),0.24(s,9H),0.23(s,9H),-0.11(s,9H);13C NMR(125MHz,CDCl3)δ155.84,154.64,154.37,146.21,145.95,132.93,120.74,120.62,119.86,105.21,104.24,101.87,78.82,67.48,29.08,0.58,0.52,0.43,0.41,-0.08.
(2)(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇(见图5和图6)
在N2氛围下,将步骤(1)中合成的(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将DDQ(2.0eq)分批次加入到反应瓶中。随后,逐滴加入67mL乙二醇乙醚(10eq)并在室温下继续反应3个小时,直到原料消失。随后,在0℃下,将10g DMAP(1.2eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段硅藻土垫进行快速过滤,并用石油醚和乙腈20:1的混合溶剂进行洗涤,最终以49%收率得到(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ6.97(dd,J=8.2,2.1Hz,1H),6.92(d,J=2.1Hz,1H),6.84(d,J=8.2Hz,1H),6.12(d,J=2.3Hz,1H),5.98(d,J=2.3Hz,1H),5.06(s,1H),4.25(d,J=2.8Hz,1H),3.91(dd,J=2.8,1.4Hz,1H),3.85(dd,J=6.0,4.2Hz,2H),3.62(dd,J=5.7,4.3Hz,2H),3.56(qt,J=7.0,3.3Hz,2H),1.23(t,J=7.0Hz,3H),0.31(s,9H),0.25(s,18H),0.24(s,9H),-0.21(s,9H);13C NMR(125MHz,CDCl3)δ156.8,156.6,156.2,146.3,146.0,132.9,120.9,120.8,120.1,105.7,103.6,101.6,75.2,71.8,70.2,69.4,69.1,66.8,15.4,0.7,0.6,0.4,-0.21.
(3)(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇(见图7、图8和图14)
将步骤(2)中合成的(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇中间体溶于200mL的乙醇溶液中,向反应溶液中加入2.5gNH3F(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在丙酮溶剂中重结晶,最终以99%的收率得到目标产物(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ7.00(d,J=1.9Hz,1H),6.83(dd,J=8.3,1.8Hz,1H),6.78(d,J=8.1Hz,1H),5.98(d,J=2.2Hz,1H),5.92(d,J=2.3Hz,1H),4.94(s,1H),4.47(d,J=2.7Hz,1H),3.97(dd,J=2.7,1.1Hz,1H),3.91(ddd,J=5.4,4.2,1.6Hz,2H),3.68-3.62(m,2H),3.58(q,J=7.0Hz,2H),1.22(t,J=7.0Hz,3H);13C NMR(125MHz,MeOD)δ160.1,159.0,157.8,145.8,144.6,131.5,116.1,115.2,103.0,95.3,94.8,84.7,72.7,71.7,71.8,70.4,66.6,15.2.
实施例3:(2S,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇的合成
(1)(2S,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇
在N2氛围下,将20g(2S,3R)-黄烷-3-醇溶于200mL乙腈溶液中。然后在0℃下,将72mL HMDS(5eq)逐滴加入到反应瓶中,并在室温下反应3h,直到原料消失。反应结束后,减压浓缩,剩余残渣在石油醚中重结晶得到98%收率的(2S,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.90(d,J=5.4Hz,2H),6.84(d,J=8.6Hz,1H),6.11(s,1H),5.98(s,1H),4.55(d,J=8.7Hz,1H),3.84(q,J=8.1Hz,1H),2.93(dd,J=16.2,5.7Hz,1H),2.53(dd,J=16.3,9.7Hz,1H),0.28(s,9H),0.25(s,27H),-0.15(s,9H);13C NMR(125MHz,CDCl3)δ155.8,154.6,154.3,146.4,133.2,121.0,120.9,120.4,106.2,104.4,101.6,81.7,69.6,30.8,0.6,0.5,0.4,0.3,-0.1.
(2)(2S,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2S,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将DDQ(2.0eq)分批次加入到反应瓶中。随后,逐滴加入67mL乙二醇乙醚(10eq)并在室温下继续反应3个小时,直到原料消失。随后,在0℃下,将10g DMAP(1.2eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段硅藻土垫进行快速过滤,并用石油醚和乙腈20:1的混合溶剂进行洗涤,最终以53%的收率得到(2S,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ6.97(dd,J=8.2Hz,1H),6.84(d,J=6.2Hz,2H),6.12(d,J=1.2Hz,1H),5.98(d,J=1.2Hz,1H),5.06(d,J=8.7Hz,1H),4.25(dd,J=8.7,2.8Hz,1H),3.91(d,J=2.8Hz,1H),3.85(dd,J=6.0,4.2Hz,2H),3.62(dd,J=5.7,4.3Hz,2H),3.56(q,J=7.0Hz,2H),1.23(t,J=7.0Hz,3H),0.31(s,9H),0.25(s,27H),-0.21(s,9H);13C NMR(125MHz,CDCl3)δ159.1,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,80.8,72.7,71.2,70.4,66.6,15.2,0.6,0.5,0.4,0.3,-0.1.
(3)(2S,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇(见图9和图10)
将步骤(2)中合成的(2S,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)黄烷-3,4-二醇中间体溶于200mL的乙醇溶液中,向反应溶液中加入2.5gNH3F(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在丙酮溶剂中重结晶,最终以99%的收率得到目标产物(2R,3R,4S)-4-(2-乙二醇)黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ6.88(d,J=1.3Hz,1H),6.77(d,J=1.5Hz,2H),5.94(d,J=2.3Hz,1H),5.79(d,J=2.3Hz,1H),4.85(s,1H),4.69(d,J=3.5Hz,1H),3.97(dd,J=2.7,1.1Hz,2H),3.82(dd,J=10.2,3.4Hz,1H),3.64(dd,J=2.7,1.1Hz,1H),3.57(q,J=7.0Hz,2H),1.21(t,J=7.0Hz,3H);13C NMR(125MHz,MeOD)δ160.3,160.0,158.1,146.0,145.9,131.8,119.5,115.9,115.5,101.1,96.6,95.6,76.2,73.1,71.2,69.5,69.5,67.6,15.4.
实施例4:(2R,3R,4S)-4-甲氧基黄烷-3,4-二醇的合成
(1)(2R,3R)-(3’,4’,3,5,7)-五(三乙基硅氧基)黄烷-3-醇
在N2氛围下,将20g(2R,3R)-黄烷-3-醇和47g咪唑(10eq)溶于200mL THF(四氢呋喃)和DCM(二氯甲烷)(体积比3:1)的混合溶剂中。然后在室温下,将58mL TESCl(5eq)逐滴加入到反应瓶中,并在室温下继续反应6h,直到原料消失。反应结束后,减压浓缩,剩余残渣在正己烷中重结晶得到98%收率的(2R,3R)-(3’,4’,3,5,7)-五(三乙基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.87(dd,J=8.4,2.3Hz,1H),6.79(d,J=2.3Hz,1H),6.65(d,J=8.4Hz,1H),5.98(d,J=2.3Hz,1H),5.95(d,J=2.3Hz,1H),4.95(s,1H),4.45(td,J=4.3,1.3Hz,1H),2.97(dd,J=16.6,4.4Hz,1H),2.63(dd,J=16.6,4.5Hz,1H),1.21(t,J=7.8Hz,9H),1.09(t,J=7.9Hz,18H),1.06(t,J=8.0Hz,9H),1.01(t,J=7.9Hz,9H),0.83(q,J=7.8Hz,6H),0.80(q,J=7.9Hz,12H),0.78(q,J=8.0Hz,6H),0.76(q,J=7.9Hz,6H);13C NMR(125MHz,CDCl3)δ156.3,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,84.5,29.1,11.2,10.8,10.7,10.6,10.5,7.0,6.9,6.8,6.7,6.6.
(2)(2R,3R,4S)-(3’,4’,3,5,7)-五(三乙基硅氧基)-4-甲氧基黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2R,3R)-(3’,4’,3,5,7)-五(三乙基硅氧基)黄烷-3-醇溶解在500mL的乙腈溶剂中。而后,在室温下,将溶于100mL水中的19g K2S2O8(1.0eq)以及9g KH2PO4(1.0eq)加入到反应瓶中。随后,逐滴加入28.5mL甲醇并在室温下继续搅拌3个小时,直到原料消失。反应结束后,将反应液用乙酸乙酯提取有机相,盐水洗涤,干燥,减压浓缩。将残余物通过一段中性氧化铝柱进行快速过滤,并用正己烷和乙腈20:1的混合溶剂进行洗涤,最终以51%的收率得到(2R,3R,4S)-(3’,4’,3,5,7)-五(三乙基硅氧基)-4-甲氧基黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ7.03(d,J=2.2Hz,1H),6.91(dd,J=8.3,2.2Hz,1H),6.85(d,J=8.2Hz,1H),6.14(d,J=2.2Hz,1H),6.01(d,J=2.2Hz,1H),5.92(d,J=2.7Hz,1H),4.95(s,1H),4.01(dd,J=5.8,2.6Hz,2H),3.17(s,3H),1.24(t,J=7.8Hz,9H),1.12(t,J=7.9Hz,18H),1.09(t,J=8.0Hz,9H),1.05(t,J=7.9Hz,9H),0.83(q,J=7.8Hz,6H),0.80(q,J=7.9Hz,12H),0.77(q,J=8.0Hz,6H),0.75(q,J=7.9Hz,6H);13C NMR(125MHz,CDCl3)δ156.3,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,84.5,29.1,11.2,10.8,10.7,10.6,10.5,7.0,6.9,6.8,6.7,6.6.
(3)(2R,3R,4S)-4-甲氧基黄烷-3,4-二醇(见图11和图12)
将步骤(2)中合成的(2R,3R,4S)-(3’,4’,3,5,7)-五(三乙基硅氧基)-4-甲氧基黄烷-3,4-二醇中间体溶于200mL的甲醇溶液中,向反应溶液中加入7.8gNH3F(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在异丙醇中重结晶,最终以98%的收率得到目标产物(2R,3R,4S)-4-甲氧基黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ7.01(d,J=2.0Hz,1H),6.84(dd,J=8.3,1.8Hz,1H),6.80(d,J=8.1Hz,1H),6.00(d,J=2.3Hz,1H),5.93(d,J=2.3Hz,1H),4.38(d,J=2.8Hz,1H),3.96(d,J=2.8,1.2Hz,1H),3.55(s,3H);13C NMR(125MHz,MeOD)δ160.1,159.0,157.8,145.8,144.6,131.5,121.0,116.1,115.2,103.0,95.3,94.8,84.7,73.9,71.5,57.0.
实施例5:(2R,3R,4R)-4-乙酰氧基黄烷-3,4-二醇的合成
(1)(2R,3S)-(3’,4’,3,5,7)-五(苯基二甲基硅氧基)黄烷-3-醇
在N2氛围下,将20g(2R,3S)-黄烷-3-醇和47g咪唑(10eq)溶于200mL THF(四氢呋喃)和DCM(二氯甲烷)(体积比3:1)的混合溶剂中。然后在室温下,将57mL DMPSCl(5eq)逐滴加入到反应瓶中,并在室温下继续反应6h,直到原料消失。反应结束后,减压浓缩,剩余残渣在正己烷中重结晶得到95%收率的(2R,3S)-(3’,4’,3,5,7)-五(苯基二甲基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ7.61-7.57(m,20H),7.43-7.21(m,5H),6.93(dd,J=8.2,2.1Hz,1H),6.67(d,J=2.1Hz,1H),6.65(d,J=8.2Hz,1H),5.98(d,J=2.3Hz,1H),5.95(d,J=2.3Hz,1H),4.97(d,J=11.0Hz,1H),4.45(dt,J=11.1,4.3Hz,1H),2.97(dd,J=16.6,4.4Hz,1H),2.63(dd,J=16.6,4.5Hz,1H),1.21(s,18H),1.09(s,6H),0.79(s,6H).
(2)(2R,3R,4R)-(3’,4’,3,5,7)-五(苯基二甲基硅氧基)-4-乙酰氧基黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2R,3S)-(3’,4’,3,5,7)-五(苯基二甲基硅氧基)黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将15.6g DDQ(1.0eq)分批次加入到反应瓶中。随后,逐滴加入4mL乙酸溶液,并在室温下继续反应3个小时,直到原料消失。在0℃下,将10g DMAP(1.2eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段硅胶粉垫进行快速过滤,并用正庚烷和乙酸乙酯20:1的混合溶剂进行洗涤,最终以57%的收率得到(2R,3R,4R)-(3’,4’,3,5,7)-五(苯基二甲基硅氧基)-4-乙酰氧基黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ7.58-7.32(m,20H),7.28-7.23(m,5H),7.03(d,J=2.2Hz,1H),6.91(dd,J=8.3,2.2Hz,1H),6.85(d,J=8.2Hz,1H),6.14(d,J=2.3Hz,1H),6.01(d,J=2.3Hz,1H),5.92(d,J=11.2Hz,1H),4.95(d,J=7.9Hz,1H),4.01(dd,J=11.2,8.0Hz,1H),2.09(s,3H),1.23(s,18H),1.10(s,6H),0.59(s,6H).
(3)(2R,3R,4R)-4-乙酰氧基黄烷-3,4-二醇
将步骤(2)中合成的(2R,3R,4R)-(3’,4’,3,5,7)-五(苯基二甲基硅氧基)-4-乙酰氧基黄烷-3,4-二醇中间体溶于200mL的甲醇溶液中,向反应溶液中加入60mL TBAF(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在二氯甲烷和乙腈的混合溶剂中重结晶,最终以95%的收率得到目标产物(2R,3R,4R)-4-乙酰氧基黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ6.77(d,J=2.0Hz,1H),6.60(dd,J=8.2,2.0Hz,1H),6.57(d,J=8.1Hz,1H),5.76(d,J=2.3Hz,1H),5.70(d,J=2.3Hz,1H),5.27(s,1H),4.24(d,J=10.3Hz,1H),3.70(dd,J=10.5,1.2Hz,1H),3.13(s,3H);13CNMR(125MHz,MeOD)δ170.2,160.1,159.0,157.8,145.8,144.6,131.5,121.0,116.1,115.2,103.0,95.3,94.8,65.2,21.0.
实施例6:(2S,3R,4S)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇的合成
(1)(2S,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇
在N2氛围下,将20g(2S,3R)-黄烷-3-醇溶于200mL乙腈溶液中。然后在0℃下,将72mLHMDS(5eq)逐滴加入到反应瓶中,并在室温下继续反应3h,直到原料消失。反应结束后,减压浓缩,剩余残渣在正己烷中重结晶得到96%收率的(2S,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.93(dd,J=8.3,2.1Hz,1H),6.89(d,J=2.0Hz,1H),6.81(d,J=8.2Hz,1H),6.20(d,J=2.3Hz,1H),6.01(d,J=2.3Hz,1H),4.86(d,J=10.3Hz,1H),4.14(dt,J=10.3,4.5Hz,1H),2.80(dd,J=16.5,4.6Hz,1H),2.58(dd,J=16.6,4.5Hz,1H),0.26(s,9H),0.25(s,9H),0.24(s,9H),0.23(s,9H),-0.11(s,9H);13C NMR(125MHz,CDCl3)δ155.84,154.64,154.37,146.21,145.95,132.93,120.74,120.62,119.86,105.21,104.24,101.87,78.82,67.48,29.08,0.58,0.52,0.43,0.41,-0.08.
(2)(2S,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2S,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将15.6g DDQ(1.0eq)分批次加入到反应瓶中。随后,逐滴加入28mL叔丁基二甲基硅氧基乙醇(2.0eq),并在室温下继续反应3个小时,直到原料消失。在0℃下将10gDMAP(1.2eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段硅胶粉垫进行快速过滤,并用甲苯溶剂进行洗涤,最终以60%的收率得到(2S,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ6.93(dd,J=8.2,2.1Hz,1H),6.89(d,J=2.1Hz,1H),6.81(d,J=8.2Hz,1H),6.20(d,J=2.3Hz,1H),6.01(d,J=2.3Hz,1H),5.06(d,J=12.0Hz,1H),4.25(d,J=6.0Hz,1H),3.91(dd,J=12.1,6.3Hz,1H),3.56(t,J=7.0Hz,2H),1.23(t,J=7.0Hz,2H),0.98(s,9H),0.26(s,9H),0.25(s,9H),0.24(s,9H),0.23(s,9H),0.22(s,3H),0.21(s,3H),-0.11(s,9H);13C NMR(125MHz,CDCl3)δ159.1,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,80.8,72.7,71.3,64.3,30.6,25.9,3.9,3.7,3.6,3.5,3.4,-2.3.
(3)(2S,3R,4S)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇
将步骤(2)中合成的(2S,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇中间体溶于200mL的甲醇溶液中,向反应溶液中加入3.8g TMAF(1.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在乙醇中重结晶,最终以98%的收率得到目标产物(2S,3R,4S)-4-(2-((叔丁基二甲基硅烷基)氧基)乙氧基)黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ7.00(d,J=1.9Hz,1H),6.83(dd,J=8.3,1.8Hz,1H),6.78(d,J=8.1Hz,1H),5.98(d,J=2.2Hz,1H),5.92(d,J=2.3Hz,1H),4.94(d,J=12.2Hz,1H),4.47(d,J=6.2Hz,1H),3.97(dd,J=12.2,6.3Hz,1H),3.58(t,J=7.0Hz,2H),1.22(t,J=7.0Hz,2H);0.98(s,9H),0.22(s,3H),0.21(s,3H);13CNMR(125MHz,MeOD)δ160.1,159.0,157.8,145.8,144.6,131.5,121.0,116.1,115.2,103.0,95.3,94.8,84.7,71.8,71.7,71.3,64.3,30.6,25.9,-2.2,-2.3.
实施例7:(2R,3R,4S)-4-(2-(2-乙二醇)乙氧基)黄烷-3,4-二醇的合成
(1)(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇
在N2氛围下,将20g(2R,3R)-黄烷-3-醇溶于200mL乙腈溶液中。然后在0℃下,将72mL HMDS(5eq)逐滴加入到反应瓶中,并在室温下反应3h,直到原料消失。反应结束后,减压浓缩,剩余残渣在石油醚中重结晶得到98%收率的(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.93(dd,J=8.2,2.1Hz,1H),6.88(d,J=2.1Hz,1H),6.81(d,J=8.2Hz,1H),6.14(d,J=2.3Hz,1H),5.97(d,J=2.3Hz,1H),4.89-4.85(m,1H),4.14(td,J=4.3,2.0Hz,1H),2.80(dd,J=16.5,4.5Hz,1H),2.58(dd,J=16.6,4.0Hz,1H),0.26(s,9H),0.25(s,9H),0.24(s,9H),0.23(s,9H),-0.11(s,9H);13C NMR(125MHz,CDCl3)δ155.84,154.64,154.37,146.21,145.95,132.93,120.74,120.62,119.86,105.21,104.24,101.87,78.82,67.48,29.08,0.58,0.52,0.43,0.41,-0.08.
(2)(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-(2-乙二醇)乙氧基)黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2R,3R)-(3’,4’,3,5,7)-五(三甲基硅氧基)黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将31.2g DDQ(2.0eq)分批次加入到反应瓶中。随后,逐滴加入94mL二乙二醇乙醚(10eq),并在室温下继续反应3个小时,直到原料消失。随后,在0℃下,将20g DMAP(2.4eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段硅藻土垫进行快速过滤,并用石油醚和乙腈20:1的混合溶剂进行洗涤,最终以45%的收率得到(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-(2-乙二醇)乙氧基)黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ6.97(dd,J=8.2,2.1Hz,1H),6.92(d,J=2.1Hz,1H),6.84(d,J=8.2Hz,1H),6.12(d,J=2.3Hz,1H),5.98(d,J=2.3Hz,1H),5.06(s,1H),4.25(d,J=2.8Hz,1H),3.91(dd,J=2.8,1.4Hz,1H),3.85(dd,J=6.0,4.2Hz,2H),3.83(t,J=6.8Hz,2H),3.75(t,J=6.8Hz,2H),3.62(dd,J=5.7,4.3Hz,2H),3.56(qt,J=7.0,3.3Hz,2H),1.23(t,J=7.0Hz,3H),0.31(s,9H),0.25(s,18H),0.24(s,9H),-0.21(s,9H);13C NMR(125MHz,CDCl3)δ159.1,155.3,155.2,147.2,144.4,131.3,122.3,120.8,119.1,107.7,104.1,99.5,86.7,80.8,72.7,70.7,70.4,70.1,66.6,15.2,3.9,3.7,3.6,3.5,3.4.
(3)(2R,3R,4S)-4-(2-(2-乙二醇)乙氧基)黄烷-3,4-二醇
将步骤(2)中合成的(2R,3R,4S)-(3’,4’,3,5,7)-五(三甲基硅氧基)-4-(2-(2-乙二醇)乙氧基)黄烷-3,4-二醇中间体溶于200mL的甲醇溶液中,向反应溶液中加入28g TEAF(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在丙酮溶剂中重结晶,最终以96%的收率得到目标产物(2R,3R,4S)-4-(2-(2-乙二醇)乙氧基)黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ7.00(d,J=1.9Hz,1H),6.83(dd,J=8.3,1.8Hz,1H),6.78(d,J=8.1Hz,1H),5.98(d,J=2.2Hz,1H),5.92(d,J=2.3Hz,1H),4.94(s,1H),4.47(d,J=2.7Hz,1H),3.97(dd,J=2.7,1.1Hz,1H),3.85(dd,J=6.0,4.2Hz,2H),3.83(t,J=6.8Hz,2H),3.75(t,J=6.8Hz,2H),3.62(dd,J=5.7,4.3Hz,2H),3.56(qt,J=7.0,3.3Hz,2H),1.23(t,J=7.0Hz,3H);13C NMR(125MHz,MeOD)δ160.1,159.0,157.8,145.8,144.6,131.5,121.0,116.1,115.2,103.0,95.3,94.8,84.7,72.7,71.8,71.7,70.7,70.4,70.1,66.6,15.2.
实施例8:(2R,3R,4S)-4-(2-(2-乙二醇)乙氧基)没食子黄烷-3,4-二醇的合成
(1)(2R,3R)-(3’,4’,5’,3,5,7)-五(三甲基硅氧基)没食子黄烷-3-醇
在N2氛围下,将20g(2R,3R)-没食子黄烷-3-醇溶于200mL乙腈溶液中。然后在0℃下,将86.4mL HMDS(6eq)逐滴加入到反应瓶中,并在室温下反应3h,直到原料消失。反应结束后,减压浓缩,剩余残渣在石油醚中重结晶得到98%收率的(2R,3R)-(3’,4’,5’,3,5,7)-五(三甲基硅氧基)没食子黄烷-3-醇。
1H NMR(600MHz,CDCl3)δ6.90(s,2H),6.34(d,J=2.3Hz,1H),6.03(d,J=2.3Hz,1H),5.06-4.95(m,1H),4.23(td,J=4.5,1.8Hz,1H),2.93(dd,J=16.5,3.9Hz,1H),2.72(dd,J=16.6,4.0Hz,1H),0.28(s,9H),0.27(s,18H),0.26(s,9H),-0.11(s,9H);13C NMR(125MHz,CDCl3)δ156.3,155.3,155.2,148.1,135.8,130.2,112.0,107.7,104.1,99.5,87.0,83.6,29.1,0.6,0.5,0.4,0.3,-0.1.
(2)(2R,3R,4S)-(3’,4’,5’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)没食子黄烷-3,4-二醇
在N2氛围下,将步骤(1)中合成的(2R,3R)-(3’,4’,5’,3,5,7)-五(三甲基硅氧基)没食子黄烷-3-醇溶解在500mL的二氯甲烷中。而后,在0℃下,将DDQ(2.0eq)分批次加入到反应瓶中。随后,逐滴加入67mL乙二醇乙醚(10eq)并在室温下继续反应3个小时,直到原料消失。随后,在0℃下,将10gDMAP(1.2eq)加入到反应瓶中,继续搅拌10min后,通过硅藻土垫进行过滤、减压浓缩。将残余物通过一段中性氧化铝垫进行快速过滤,并用正己烷和乙腈20:1的混合溶剂进行洗涤,最终以49%的收率得到(2R,3R,4S)-(3’,4’,5’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)没食子黄烷-3,4-二醇中间体产物。
1H NMR(600MHz,CDCl3)δ7.01(s,2H),6.54(d,J=2.1Hz,1H),6.37(d,J=2.1Hz,1H),5.21(s,1H),4.78(d,J=2.8Hz,1H),3.99(dd,J=2.8,1.4Hz,1H),3.87(dd,J=6.0,4.2Hz,2H),3.64(dd,J=5.7,4.3Hz,2H),3.56(q,J=7.0Hz,2H),1.27(t,J=7.0Hz,3H),0.37(s,9H),0.29(s,18H),0.27(s,9H),-0.15(s,9H);13CNMR(125MHz,CDCl3)δ159.1,155.2,155.3,148.1,135.8,130.2,112.0,107.7,104.1,99.5,86.7,81.1,72.7,72.6,70.4,66.6,15.2,1.1,0.7,0.6,0.4,-0.1.
(3)(2R,3R,4S)-4-(2-乙二醇)没食子黄烷-3,4-二醇
将步骤(2)中合成的(2R,3R,4S)-(3’,4’,5’,3,5,7)-五(三甲基硅氧基)-4-(2-乙二醇)没食子黄烷-3,4-二醇中间体溶于200mL的乙醇溶液中,向反应溶液中加入28g TEAF(6.0eq),并在室温下继续反应2h,直到原料消失。反应结束后,减压浓缩。将残余物溶解于乙酸乙酯和水(各100mL)中,用乙酸乙酯提取有机物,盐水洗涤,干燥,减压浓缩。将残余物在丙酮溶剂中重结晶,最终以96%的收率得到目标产物(2R,3R,4S)-4-(2-乙二醇)没食子黄烷-3,4-二醇。(根据耦合常数以及NMR判断,该反应产物为目标产物)
1H NMR(600MHz,MeOD)δ6.83(s,2H),6.12(d,J=2.2Hz,1H),5.98(d,J=2.3Hz,1H),4.73(s,1H),4.28(d,J=2.7Hz,1H),3.93(dd,J=2.7,1.1Hz,1H),3.91(dd,J=5.4,1.6Hz,2H),3.68-3.62(m,2H),3.58(q,J=7.0Hz,2H),1.22(t,J=7.0Hz,3H);13C NMR(125MHz,MeOD)δ160.1,159.0,157.8,145.8,144.6,131.5,116.1,115.2,103.0,95.3,94.8,84.7,72.7,71.7,71.8,70.4,66.6,15.2。
Claims (9)
1.一种如下式(I)所示的黄烷-3,4-二醇类衍生物的制备方法,
其中,R1、R2和R3各自独立地为氢或羟基;R4选自H、甲基、乙基、-C(O)CH3、-CH2CH2OSi(CH3)2C(CH3)3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2OCH2CH3;
其特征在于,所述制备方法包括如下步骤:
(1)化合物a与化合物RaCl或(Ra)2NH发生取代反应,得到化合物b;所述反应在路易斯碱存在下进行;式中Ra选自三甲基硅基、三乙基硅基、二甲基苯基硅基;当R1为氢时,R1a为氢;当R1为羟基时,R1a与Ra相同;当R2为氢时,R2a为氢;当R2为羟基时,R2a与Ra相同;当R3为氢时,R3a为氢;当R3为羟基时,R3a与Ra相同;
(2)化合物b与化合物R4OH发生氧化反应,得到化合物c;所述反应在氧化剂以及亲核试剂存在下进行;
(3)化合物c在反应溶剂中发生硅醚脱保护反应,得到化合物(I);所述反应在脱保护试剂存在下进行。
2.如权利要求1所述的制备方法,其特征在于:R4选自H、甲基、乙基、-C(O)CH3、-CH2CH2OSi(CH3)2C(CH3)3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2OCH2CH3。
3.如权利要求1或2所述的制备方法,其特征在于:步骤(1)中所述路易斯碱选自三乙胺、咪唑、碳酸氢钠、碳酸钠、碳酸铯中的一种或多种。
4.如权利要求1或2所述的制备方法,其特征在于:步骤(2)中所述氧化剂选自DDQ、MnO2、过氧单磺酸钾、K2S2O8、2-碘酰苯甲酸、氧化银、硝酸铈铵、三醋酸锰中的一种或多种;步骤(2)中所述亲核试剂选自水、甲醇、乙醇、乙酸、叔丁基二甲基羟乙氧基硅烷、乙二醇单乙醚、二乙二醇乙醚。
5.如权利要求1或2所述的制备方法,其特征在于:步骤(3)中所述脱保护试剂选自含氟离子试剂或路易斯碱试剂;所述含氟离子试剂选自氟化铵、四丁基氟化铵、四甲基氟化铵、四乙基氟化铵、氟化氢吡啶;所述路易斯碱试剂选自氢氧化钠、碳酸氢钠、碳酸钠、乙酸钠、三乙胺。
6.如权利要求1或2所述的制备方法,其特征在于:
步骤(1)中,化合物a与化合物RaCl或(Ra)2NH的摩尔比为1:5~1:7;
步骤(2)中,化合物b与化合物R4OH的摩尔比为1:1.5~1:20;化合物b与氧化剂的摩尔比为1:1.5~1:6;
步骤(3)中,化合物c与脱保护试剂的摩尔比为1:1~1:6。
7.如权利要求1或2所述的制备方法,其特征在于:
步骤(1)在乙腈、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺、丙酮中的一种或多种作为溶剂,0℃~30℃作为反应温度范围,1-12小时作为反应时间下进行。
8.如权利要求1或2所述的制备方法,其特征在于:步骤(2)在正己烷、正庚烷、正戊烷、二氯甲烷、氯仿、1,2-二氯乙烷、1,1-二氯乙烷、1,1-二氯乙烯、1,2-二氯乙烯、环己烷、乙苯、甲苯、二甲苯、氯苯、乙腈、叔丁基甲醚、1,4-二氧六环、水中的一种或多种作为反应溶剂,0℃~30℃作为反应温度范围,1-12小时作为反应时间下进行。
9.如权利要求1或2所述的制备方法,其特征在于:步骤(3)所述反应溶剂选自甲醇、乙醇、乙酸乙酯、1,4-二氧六环、丙酮、乙腈、三氯乙烷中的一种或多种,0℃~30℃作为反应温度范围,1-3小时作为反应时间下进行。
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