CN110478360A - 一种用于治疗皮炎的人参皂苷衍生物 - Google Patents
一种用于治疗皮炎的人参皂苷衍生物 Download PDFInfo
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- CN110478360A CN110478360A CN201810462801.8A CN201810462801A CN110478360A CN 110478360 A CN110478360 A CN 110478360A CN 201810462801 A CN201810462801 A CN 201810462801A CN 110478360 A CN110478360 A CN 110478360A
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Abstract
本发明公开了一种人参二醇苷衍生物及其制备方法和应用。该类化合物在体外和动物模型实验中体现出很强的抗炎作用，因此可以用于制备抗炎的药物，尤其是可以用于治疗皮炎。在实验中，本发明化合物对皮炎的作用明显，在远超过有效治疗剂量下，对血常规和血糖也未产生明显的影响，在抗炎药物，尤其是治疗皮炎领域具有很高的应用前景。
Description
技术领域
本发明涉及一种用于治疗皮炎的药物化合物，更具体而言，本发明涉及一种用于治疗皮炎的人参皂苷衍生物。
背景技术
皮炎是一种慢性，复发性，炎症相关的皮肤病，患者往往有剧烈瘙痒，严重影响生活质量。该病呈慢性过程，1岁前发病的患者约占全部患者的50％，但是也有成年发病的。在发达国家，该病儿童发病率可高达10～20％。我国上海地区3～6岁儿童发病率高达8.3％。
皮炎的发病与遗传和环境因素密切相关。父母等家族成员有过敏性疾病史者，患本病的概率显著增加。遗传因素主要是影响皮肤屏障功能和免疫平衡，本病患者往往有Th2为主介导的免疫异常，还可有皮肤屏障功能的减弱或者破坏，如患者中丝聚蛋白的减少或缺失，环境因素包括环境变化，生活方式的改变，过度洗涤，感染或变应原。此外，还有一些心理因素的。
但是该病真正的病因并不清楚，一般认为是在遗传基础，由于变应原进入或者微生物定殖，形成皮肤免疫异常反应，引发皮疹或者瘙痒，而瘙痒和过度洗涤等不良刺激，又可进一步加重皮肤炎症。皮炎异常反应涉及多个环节，如朗格汉斯细胞和皮肤树突细胞对变应原的提呈。Th2为主的异常免疫反应，调节性T细胞功能障碍，IgE过度产生和嗜酸性细胞升高等，角质形成细胞产生的细胞因子和炎症介质也参与了炎症反应，其他如神经、内分泌也参与皮肤炎症反应。
皮炎的临床表现多种多样，但是其基本的特征是皮肤干燥，慢性湿疹样皮炎，剧烈瘙痒，本病绝大多数初发于幼儿期。分为婴儿期、儿童期、青少年期、成人期。根据不同年龄，发病部位，病情现状有所不同，而且40-80％的患者有家族过敏史，如家族成员有皮炎，过敏性哮喘，过敏性鼻炎，过敏性结膜炎等。家族史询问中对于皮炎的诊断非常重要，而且对于重度皮炎患者，血清中IgE升高，酸性粒细胞升高也较为常见。根据病情及检测所见，诊断为特异发性皮炎。需要根据主要的标准和次要标准，并确定疾病的严重程度。对于皮炎的治疗，因为皮炎是慢性复发性疾病，治疗的目的是缓解或者是消除临床症状，消除诱发或加重因，减少和预防复发，提高患者的生活质量，因此对于患者的教育和基础治疗是非常重要的，目前在治疗皮炎方面主要是外用的药物治疗，在一定情况下，给予系统性治疗。
目前，现有技术中治疗皮炎的药物包括，外用药物：局部外用糖皮质激素是皮炎一线疗法。外用激素种类很多，经济方便，疗效首选。根据患者的年龄、皮损性部位及皮损程度，选择不同的剂型和强度的激素制剂，快速有效地控制皮炎，减轻症状。根据外用激素的强度分为四级，一般为初始治疗时应选用强度足够的制剂(强效或者超强效)以求在数日内控制炎症。症状控制后，逐渐过渡到中、弱激素或钙调神经磷酯酶抑制剂。但是长期的大量应用激素，应注意皮肤系统不良反应及其它副作用。
钙调神经磷酯酶抑制剂，对于T淋巴细胞有选择性抑制作用，有较强的抗炎作用，此外尚有抗微生物制剂等系统性治疗药物，例如抗组胺药物及白三烯受体拮抗剂，肥大细胞膜稳定剂。
人参皂苷是传统中药，作用非常广泛，其化学结构属于四环三萜类，化学结构类似糖皮质激素。其药理上一个重要的特点是具有适应原样作用，即其药理作用常因机体功能状态不同呈现双向作用。如对垂体-肾上腺皮质系统，既能阻止促肾上腺皮质激素(ACTH)引起的肾上腺肥大，又可阻止可的松引起的肾上腺萎缩，而且多种人参皂苷对大鼠皮质激素的影响研究结果证明，人参皂苷Rd的作用最强，并证明人参皂苷刺激肾上腺皮质，增加了分泌皮质激素的作用，而且证明不是通过肾上腺素能神经系统或兴奋H1受体所致。因此也显示不同的人参皂苷对皮质激素样的作用是不一致的。事实上，近年来已经证明一些人参皂苷对皮质激素受体有激动作用，而且人参皂苷中的一些作用类似于选择性糖皮质激素的修饰剂。
人参皂苷coumpound K(CK)是人参中原人参二醇型皂苷在人体肠道内的主要代谢产物，属于稀有人参皂苷。人参皂苷CK独特的生物活性已经引起了人们广泛关注，针对它的科学研究也日益增多。
发明内容
本发明是从原人参二醇苷出发研究了一系列化合物，证明该类化合物可以有很强的抗炎作用，在实验中，表现出强大的的抗炎作用，并且在超过有效治疗剂量很大的时候，对血液和血糖未产生明显的影响。
具体而言，本发明的第一个方面涉及一种人参二醇苷衍生物或其药学上可接受的盐，所述人参二醇苷衍生物具有如下所示的通式(I)的结构：
其中，R1选自羟基或非葡萄糖的吡喃糖基或
R2和R3一起表示＝O或＝N-OR8；
或R2为氢且R3为羟基；
R4和R6结合成键，且R5和R7独立选自氢、C1-6烷氧基、羟基、氰基、C1-6酯基、糖基；
或R6和R7一起表示＝O或＝N-OH，且R5和R4独立选自氢、C1-6烷氧基、羟基、氰基；
或R4、R5、R6和R7独立选自氢、C1-6烷氧基、羟基、氰基、C1-6酯基、糖基；
R8选自氢或C1-6烷基。
根据本发明的另一种实施方式，其中，R2和R3一起表示＝N-OH。
根据本发明的另一种实施方式，其中，R4和R6结合成键。
根据本发明的另一种实施方式，其中，R6和R7一起表示＝N-OR8；并且R8表示氢或甲基。
根据本发明的另一种实施方式，其中，R4和R6结合成键，R5选自糖基；并且R1表示羟基。
其中，所述C1-6烷氧基是指RO-基团，其中R是指C1-6烷基，具体包括甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、戊氧基、异戊氧基、叔戊氧基、新戊氧基、己氧基、异己氧基、叔己氧基、新己氧基等。所述烷基可以任选被选自低级烷基、羟基、氰基的取代基取代。
所述C1-6烷氧基优选未取代的甲氧基或乙氧基。
所述C1-6酯基是指RaCOO-基团，其中Ra是指C1-5烷基；所述C1-6酯基优选乙酰氧基。
所述非葡萄糖的吡喃糖基是指：鼠李糖基、岩藻糖基、阿拉伯糖基、木糖基、核糖基、奎诺糖基、半乳糖基、氨基葡萄糖基、6-脱氧-6-氨基葡萄糖基、乳糖基以及纤维二糖基。
所述糖基是指糖苷分子中提供半缩醛羟基的糖部分，根据本发明的糖基优选脱氧糖基或五碳糖基，其具体例子包括：核酮糖基、鼠李糖基、岩藻糖基、阿拉伯糖基、木糖基、核糖基、奎诺糖基、葡萄糖基、半乳糖基、氨基葡萄糖基、6-脱氧-6-氨基葡萄糖基、乳糖基以及纤维二糖基。
根据本发明的另一种实施方式，其中本发明涉及如下化合物：
本发明中，所述的药学上可接受的盐较佳的为本发明化合物与药学上可接受的酸进行反应制得的酸加成盐，或者其中具有酸性基团的化合物和碱性化合物反应生成的盐。其中，所述的酸较佳的选自无机酸(如盐酸、硫酸、磷酸或氢溴酸等)，和有机酸(如草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸或苯甲酸等)；所述的碱性化合物较佳的选自氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠或碳酸氢钾等。上述药学上可接受的盐容易分离，可采用常规分离方法提纯，如溶剂萃取、稀释、重结晶、柱色谱和制备薄层色谱等。
本发明的另一个方面涉及通式(I)化合物的合成方法，具体涉及包括如下的反应：
1)3位和12位选择性二酰基取代的20(S)-人参二醇苷的制备
所述的选择性酰基化处理是指：将20(S)-人参二醇苷(PPD)溶于有机溶剂中，加入催化剂后，再加热3～7当量的酰基化剂，加热反应，即得。
所述的酰基化剂可以选自酸酐、活性酯或酰氯中的一种；优选乙酸酐，苯甲酰氯。
所述的催化剂选自二甲氨基吡啶、三乙胺、吡啶、二异丙基乙胺或N,N,N,N-四甲基乙二胺中的一种或其组合。优选二甲氨基吡啶、三乙胺。
2)酰基取代的20(S)-人参二醇苷的选择性去酰基
3,12-O-二酰基取代的20(S)-人参二醇苷在有机碱的存在性进行选择性脱酰基，得目标化合物。
所述有机碱优选一价碱金属化合物；更优选甲醇钠、乙醇钠、氢氧化钠、氢氧化钾、氢氧化锂中的一种或其组合
所述反应优选在有机溶剂的存在下进行，所述有机溶剂选自二氯甲烷、三氯甲烷、四氯化碳、甲醇、乙醇、丙醇、丁醇、乙腈、THF、DMF、DMSO、吡啶、苯、甲苯、二甲苯、乙醚或其混合物。
3)糖苷化反应
将取代的20(S)-人参二醇苷与糖基供体、路易斯酸催化剂和分子筛在惰性气体保护下，在糖苷处理液中进行糖苷化反应，待反应结束时加入淬灭剂淬灭反应，最后用柱层析纯化或重结晶纯化，获得20-O-糖苷化反应提纯物。
所述的二取代的20(S)-人参二醇苷、糖基供体和路易斯酸催化剂的摩尔比为1：(1.0～5.0)：(0.01～0.5)，所述的二取代的20(S)-人参二醇苷和分子筛的质量比为1：0.1～7：1。
所述的路易斯酸催化剂是指C3-C9的卤代酰胺、C1-C6的氟代烃基磺酸、C2-C8的硅基氟代烃基磺酸酯、C1-C6的氟代烃基磺酸银、三氟化硼-乙醚络合物或三氟化硼-乙醚混合物中的一种或其组合。
所述的分子筛为型硅铝酸盐分子筛。
所述的糖苷处理液是指C1-C4的氯代烷烃、甲苯或乙醚中的一种或其组合。
所述的淬灭剂为三甲胺、三乙胺或硫代硫酸钠中的一种或其组合。
所述的柱层析纯化中采用的洗脱液为：石油醚、二氯甲烷、乙酸乙酯、三氯甲烷、甲醇、正己烷或环己烷中一种其混合。
所述的重结晶纯化中采用的结晶溶剂为：三氯甲烷、C1-C4的烷基醇、乙酸乙酯、丙酮、正己烷、石油醚、环己烷、二氯甲烷或水中一种或其组合。
所述的有机溶剂为：二氯甲烷、三氯甲烷、吡啶、二氯乙烷中一种或其混合。
4)20-O-糖基类化合物的制备
糖苷化反应提纯物可在类似步骤2)的条件下进行选择性脱除保护基反应或完全脱除保护基反应后生成。
所述的极性溶剂为：四氢呋喃、甲醇、乙醇、二氯甲烷或水中的一种或其组合。
5)羟基的氧化
20(S)-人参二醇苷衍生物3位和12位的羟基可以在氧化剂的存在下氧化反应得到对应的氧代衍生物。
所述的所述的氧化剂为重铬酸二吡啶盐、吡啶铬酐、重铬酸钾、重铬酸钠、Dess-Martin氧化剂或三氧化铬中一种或其混合。
所述氧化反应优选在有机溶剂的存在下加热进行。
6)双键的还原
20(S)-人参二醇苷衍生物中的双键可以与氢气在氢化催化剂的作用下发生还原得到对应的氢化产物。
所述氢化催化剂可以选择Pd/C或其它已知的氢化催化剂。
反应优选在极性溶剂的存在下进行，所述极性溶剂优选甲醇、乙醇。
7)20(S)-羟基达玛烷-3,24-二烯-12-酮类化合物的合成
将20(S)-羟基达玛烷-3-羟基-24-烯-12-酮与酰氯在碱性条件下反应，然后与溴化锂、碳酸锂在DMF中加热反应，得目标化合物。
所述酰氯可以选自苯磺酰氯、对甲苯磺酰氯。
8)12-β-羟基-20(S)-羟基达玛烷-24-烯-3-酮类化合物的制备
PPD与活性酰氯在有机溶剂中，有机碱的存在下，低温反应，在PPD的12位引入酰基。该酰基取代的PPD在有机溶剂中，PDC和醋酐的存在下室温反应，将化合物3位的羟基氧化为羰基。然后将其在醇钠/醇的存在下脱去12位的酰基，即得目标化合物。
9)20(S)-达玛烷-3,12-羟基亚胺基-24-烯类化合物的合成
将20(S)-达玛烷-3,12-二氧代-24-烯类化合物与盐酸羟胺在碱性条件下反应，得相应的羟基亚胺类化合物。
本发明的另一方面涉及一种药物组合物，其包括上述本发明的人参二醇苷衍生物或其药学上可接受的盐及药学上可接受的辅料。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、软膏、霜剂、乳膏丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油等；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。如果需要的话，还可以用通常的涂渍材料使片剂作为糖衣片剂、肠衣片剂、涂膜片剂(如涂明胶膜片剂)、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液和悬浮液消毒，并最好加入适量的氯化钠，葡萄糖或甘油等，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明的如式I所示的化合物及其药学上可接受的盐在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比1-70％，较佳的为质量百分比1-30％。
本发明中，所述的药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择合适剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂和胶囊是口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射，如有必要可以单纯用针剂进行肌肉、皮内、皮下或腹内注射；栓剂为给药到直肠。
本发明的另一方面涉及上述化合物的医药用途，具体而言，该类化合物在体外和动物模型实验中体现出很强的抗炎作用，因此可以用于制备抗炎的药物。在实验中，其表现出很强的抗炎作用，在超过治疗指数很大的剂量下，对血液和血糖也未产生明显的影响。因此，其在抗炎药物，尤其是治疗和/或预防皮炎，特别是特异性皮炎领域具有很高的应用前景。
具体实施方式
实施例1 3-O-乙酰基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-12-酮(IA)
1.1 3,12-二-O-乙酰基-20(S)-人参二醇苷(I-1a)的合成
将20(S)-人参二醇苷(120.0g,0.26mol)溶于干燥吡啶(750.0mL)，加入催化量的DMAP，冰浴条件下滴加Ac2O(99.1mL,1.04mol)，自然恢复至室温反应6.0h。将反应液减压浓缩，再以乙酸乙酯(2.0L)稀释，依次用稀盐酸，饱和NaHCO3水溶液，饱和NaCl水溶液洗涤，有机层用无水Na2SO4干燥，过滤，减压浓缩，得微黄色固体，重结晶(乙酸乙酯/石油醚)得白色晶体I-1a(110.3g，收率77.8％)。1H NMR(CDCl3)δ5.15(t,J＝6.6Hz,1H,H-24),4.72(td,J＝10.8,4.8Hz,1H,H-12),4.48(dd,J＝12.0,4.2Hz,1H,H-3),2.04(s,3H,H-COCH 3),2.03(s,3H,H-COCH 3),1.70(s,3H),1.63(s,3H),1.12(s,3H),1.00(s,3H),0.94(s,3H),0.87(s,3H),0.85(s,3H),0.84(s,3H)。
1.2 3-β-O-乙酰基-20(S)-人参二醇苷(I-2a)的合成
将化合物I-1a(110.0g,0.20mol)溶于100.0mL CH2Cl2，加入400.0mL甲醇和MeONa(1.1g,0.02mol)，室温反应3.0h。加入适量阳离子树脂调节pH至7，过滤除去树脂，浓缩，得浅黄色固体I-2a(91.7g,90.3％)。1H NMR(CDCl3)δ5.15(t,J＝6.6Hz,1H,H-24),4.47(dd,J＝11.0,5.5Hz,1H,H-3),3.60(td,J＝10.5,5.0Hz,1H,H-12),2.04(s,3H,H-COCH 3),1.69(s,3H),1.63(s,3H),1.19(s,3H),0.98(s,3H),0.90(s,3H),0.87(s,3H),0.85(s,6H)。
1.3 3-β-O-乙酰基-20(S)-羟基达玛烷-24-烯-12-酮(I-3a)的合成
将化合物I-2a(91.0g,0.18mol)溶于干燥的500.0mL CH2Cl2中，加入PDC(101.6g,0.27mol)和醋酐(34.0mL,0.36mol)室温反应约5.0h，抽滤除去不溶物，滤液浓缩，柱层析分离(乙酸乙酯/正己烷＝1/10)得白色晶体I-3a(63.4g,70.0％)。1H NMR(CDCl3)δ5.10(s,1H,H-24),4.48(dd,J＝11.6,4.4Hz,1H,H-3),2.85(d,J＝10.2Hz,1H,H-13),2.44-2.37(m,1H,H-17),2.28(d,J＝14.3Hz,1H),2.23(d,J＝14.0Hz,1H),2.05(s,3H),1.68(s,3H),1.62(s,3H),1.17(s,3H),1.12(s,3H),0.95(s,3H),0.87(s,6H),0.80(s,3H)。
1.4 3-β-O-乙酰基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-12-酮(IA)的合成
将I-3a(25.0g,49.92mmol)和2,3,4,6-四-O-乙酰基葡萄糖三氯亚胺酯(36.9g,74.88mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(901.69μL,4.99mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体。将四分之一浓缩物溶于二氯甲烷和甲醇的混合溶剂(400.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IA(6.7g,两步收率81.0％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.5Hz,1H,H-24),4.47-4.43(m,1H),4.44(d,J＝7.6Hz,1H,H-1’),3.80(dd,J＝11.7,1.8Hz,1H),3.64(dd,J＝11.8,5.3Hz,1H),3.36-3.32(m,2H),3.27(t,J＝8.8Hz,1H),3.22-3.18(m,1H),3.10(t,J＝8.2Hz,1H),2.51(dd,J＝9.7,4.4Hz,1H),2.44(t,J＝13.2Hz,1H),2.11(dd,J＝12.8,3.3Hz,1H),2.02(s,3H),1.66(s,3H),1.62(s,3H),1.27(s,3H),1.11(s,3H),1.02(s,3H),0.91(s,3H),0.88(s,3H),0.76(s,3H)；13C NMR(150MHz,CD3OD)δ215.2,172.8,132.0,126.0,98.3,82.5,82.1,78.8,77.4,75.7,71.8,62.9,57.5,57.2,57.1,56.1,43.0,41.9,40.7,40.7,39.4,39.0,38.8,35.5,33.0,28.5,25.9,25.0,24.7,24.6,22.9,21.2,19.4,17.8,17.2,16.9,16.7,16.3。MALDI-HRMS calcd for C38H62NaO9[M+Na]+685.4286,found685.4293。
实施例2 3-β-O-乙酰基-20(S)-O-β-D-吡喃葡萄糖醛酸甲酯达玛烷-24-烯-12-酮(IA-1)的制备
将I-3a(4.4g,8.79mmol)和2,3,4-三-O-乙酰基葡萄糖醛酸甲酯三氯亚胺酯(5.0g,10.44mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(157.21μL,0.87mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(150.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IA-1(3.3g,两步收率54.1％)。1H NMR(400MHz,CD3OD)δ5.06(t,J＝6.8Hz,1H),4.51(d,J＝7.6Hz,1H),4.45(dd,J＝10.2,6.0Hz,1H),3.79(d,J＝9.7Hz,1H),3.75(s,3H),3.51(t,J＝9.4Hz,1H),3.36(t,J＝9.1Hz,1H),3.30-3.28(m,1H),3.14(t,J＝8.4Hz,1H),2.50(dd,J＝10.1,4.3Hz,1H),2.43(t,J＝13.2Hz,1H),2.11(dd,J＝12.8,3.3Hz,1H),2.02(s,3H),1.66(s,3H),1.60(s,3H),1.27(s,3H),1.10(s,3H),1.01(s,3H),0.91(s,3H),0.88(s,3H),0.75(s,3H)。13C NMR(150MHz,CD3OD)δ215.1,172.8,171.3,132.0,125.9,98.7,83.0,82.1,77.9,76.4,75.2,73.1,57.4,57.2,57.1,56.1,52.8,43.2,41.9,40.7,40.4,39.4,38.9,38.8,35.4,33.0,28.4,25.9,25.0,24.5,24.4,22.7,21.1,19.4,17.8,17.1,16.9,16.7,16.3。
实施例3 3β-羟基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-12-酮(IB)
将实施例步骤1.4中四分之二的浓缩物溶于二氯甲烷和甲醇的混合溶剂(400.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，50℃下反应6.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IB(11.6g,两步收率74.8％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.2Hz,1H),4.44(d,J＝7.6Hz,1H,H-1’),3.80(d,J＝11.5Hz,1H),3.64(dd,J＝11.7,5.3Hz,1H),3.34-3.31(m,2H),3.28(t,J＝8.8Hz,1H),3.21-3.18(m,1H),3.16-3.08(m,2H),2.52-2.40(m,2H),1.67(s,3H),1.62(s,4H),1.27(s,3H),1.11(s,3H),0.98(s,3H),0.97(s,3H),0.79(s,4H),0.74(s,3H)。
实施例4 3β-羟基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-12-酮(IB-1)
将IB(7.5g,12.08mmol)溶于MeOH(200.0mL)中，加入Pd/C(750.0mg),H2置换后室温反应2h，TLC检测反应完毕后，硅藻土滤除Pd/C，反应液浓缩，柱层析分离(CH2Cl2/MeOH＝10/1)得白色固体IB-1(4.6g,61.3％)。1H NMR(400MHz,CD3OD)δ4.43(d,J＝7.7Hz,1H),3.80(dd,J＝11.6,1.5Hz,1H),3.64(dd,J＝11.6,5.4Hz,1H),3.36-3.31(m,2H),3.27(d,J＝8.8Hz,1H),3.21-3.17(m,1H),3.15(t,J＝6.4,4.8Hz,1H),3.09(t,J＝8.4Hz,1H),2.50-2.40(m,2H),2.11(dd,J＝12.7,3.5Hz,1H),1.9-1.91(m,1H),1.84-1.78(m,1H),1.27(s,3H),1.08(s,3H),0.98(s,3H),0.97(s,3H),0.89(s,3H),0.88(s,3H),0.79(s,3H),0.74(s,3H)；13C NMR(150MHz,CD3OD)δ215.6,98.3,82.6,79.3,78.8,77.4,75.6,71.8,62.9,57.5,57.2,57.1,56.3,42.9,41.9,41.0,40.7,40.0,40.0,38.8,35.6,33.0,29.0,28.6,27.9,24.9,23.8,23.0,22.9,19.5,17.1,16.7,16.3,16.0。MALDI-HRMS calcd for C36H62NaO8[M+Na]+645.4337,found 645.4354。
实施例5 3β,25-二羟基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-12-酮(IB-2)
5.1 24-溴-25-羟基-3β-O-乙酰基-20(S)-O-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基)达玛烷-12-酮(I-3A-2)的合成
将I-3A(7.5g,9.02mmol)溶于四氢呋喃150mL，加入水15mL，冰浴下分批加入N-溴代丁二酰亚胺(2.4g,13.53mmol)，冰浴继续反应1h。TLC检测反应完毕后，加入乙酸乙酯200mL稀释反应液，依次用5％硫代硫酸钠溶液，饱和食盐水洗涤，有机层以无水硫酸钠干燥，过滤，浓缩，柱层析分离(乙酸乙酯/石油醚＝1/2)得白色固体I-3A-2(7.6g,90.5％)。1HNMR(400MHz,CDCl3)δ5.20(t,J＝9.4Hz,1H,H-3’),5.01(t,J＝9.8Hz,1H,H-4’),4.95(t-like,J＝9.0,8.2Hz,1H,H-2’),4.68(d,J＝7.8Hz,1H,H-1’),4.46(dd,J＝11.4,4.7Hz,1H,H-3),4.12-4.18(m,2H,H-6’),3.89(d,J＝9.8Hz,1H,H-24),3.70-3.68(m,1H,H-5’),2.97(d,J＝9.8Hz,1H,H-13),2.38-2.44(m,1H,H-17),2.16(d,J＝8.6Hz,2H,H-11),2.10(s,3H,H-Ac),2.04(s,3H,H-Ac),2.02(s,3H,H-Ac),1.98(s,6H,H-Ac*2),1.35(s,3H,H-26,H-27),1.19(s,3H,H-20),1.04(s,3H,H-Me),0.95(s,3H,H-Me),0.87(s,3H,H-Me),0.85(s,3H,H-Me),0.72(s,3H,H-Me)；13C NMR(125MHz,CDCl3)δ211.3(C-12),170.9,170.7,170.2,169.5,169.1,94.7(C-1’),81.8,80.3,73.1,72.6,72.1,71.8,71.7,68.6,62.4,56.2,55.8,55.7,54.3,41.4,40.5,39.7,38.6,38.2,37.8,37.5,34.2,31.6,29.1,27.9,26.5,26.2,23.7,23.4,22.8,21.3,20.8,20.6,18.2,16.7,16.4,16.2,15.6。MALDI-HRMS calcd forC46H71O14BrNa[M+Na]+949.3919,found 949.3919。
5.2 25-羟基-3β-O-乙酰基-20(S)-O-(2,3,4,6-四-O-乙酰基-β-D-吡喃葡萄糖基)达玛烷-12-酮(I-3A-3)的合成
将I-3A-2(7.2g,7.76mmol)溶于EtOAc 150mL中加入DIEA 3mL，Pd/C 720.0mg,H2置换后室温反应2h，TLC检测反应完毕后，硅藻土滤除Pd/C，反应液浓缩，柱层析分离(乙酸乙酯/石油醚＝1/1)得白色固体I-3A-3(6.0g,90.9％)。1HNMR(400MHz,CDCl3)δ5.17(t,J＝9.4Hz,1H,H-3’),5.00(t-like,J＝9.9,9.3Hz,1H,H-4’),4.93(t,J＝8.8Hz,1H,H-2’),4.61(d,J＝7.7Hz,1H,H-1’),4.46(dd,J＝11.5,4.4Hz,1H,H-3),4.16(dd,J＝12.1,6.1Hz,1H,H-6’-1),4.09(dd,J＝12.1,2.0Hz,1H,H-6’-2),3.64(ddd,J＝9.9,6.1,2.2Hz,1H,H-5’),2.98(d,J＝9.9Hz,1H,H-13),2.45(td,J＝10.4,5.5Hz,1H,H-17),2.07(s,3H,H-Ac),2.03(s,3H,H-Ac),2.01(s,3H,H-Ac),1.98(s,6H,H-Ac,H-Ac),1.21(s,6H,H-26,H-27),1.19(s,3H,H-21),1.02(s,3H,H-Me),0.95(s,3H,H-Me),0.87(s,3H,H-Me),0.85(s,3H,H-Me),0.72(s,3H,H-Me)；13CNMR(125MHz,CDCl3)δ211.6(C-12),170.8(C-Ac),170.6(C-Ac),170.2(C-Ac),169.5(C-Ac),169.0(C-Ac),94.6(C-1’),82.3,80.4,73.2,71.9,71.5,70.7,68.8,62.6,56.1,55.8,55.6,54.5,44.7,41.2,40.5,39.7,39.6,38.3,37.9,37.5,34.3,29.4,29.3,27.9,23.5,23.5,23.2,21.2,20.8,20.6,19.6,18,2,16.8,16.4,16.2,15.6。MALDI-HRMS calcd for C46H72O14Na[M+Na]+871.4820,found 871.4824。
5.3 3β,25-二羟基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-12-酮(IB-2)的合成
将I-3A-3(6.0g,7.07mmol)溶于干燥CH2Cl2(60mL)，加入60mL CH3OH，加入MeONa调节pH至10，48℃反应约6h。用适量阳离子树脂调节pH至中性，滤除树脂，浓缩，柱层析分离(CHCl3/CH3OH＝15/1)得白色固体IB-2(3.9g,86.6％)。1H NMR(400MHz,CD3OD)δ4.44(d,J＝7.7Hz,1H),3.81(dd,J＝11.8,1.8Hz,1H),3.63(dd,J＝11.8,5.5Hz,1H),3.34-3.31(m,2H),3.27(t,J＝9.0Hz,1H),3.23–3.18(m,1H),3.15(t,J＝6.0,4.8Hz,1H),3.09(t,J＝8.4Hz,1H),2.50(dd,J＝9.5,4.3Hz,1H),2.43(t,J＝13.2Hz,1H),2.11(dd,J＝12.7,3.3Hz,1H),1.95-1.90(m,1H),1.27(s,3H),1.17(s,6H),1.11(s,3H),0.98(s,3H),0.97(s,3H),0.79(s,3H),0.75(s,3H)；13C NMR(150MHz,CD3OD)δ215.6,98.3,82.7,79.3,78.7,77.5,75.6,71.8,71.5,62.9,57.5,57.2,57.2,56.3,45.5,43.3,41.9,41.3,40.7,40.0,39.9,38.8,35.6,33.0,29.4,29.2,28.6,27.9,25.0,22.9,20.6,19.5,17.1,16.7,16.3,16.0。MALDI-HRMS calcd for C36H62O9Na[M+Na]+661.4292,found661.4304。
根据以上相同的方法制备其他连接不同糖基的人参二醇苷类衍生物。
实施例6 3β-羟基-20(S)-O-β-D-吡喃半乳糖基达玛烷-24-烯-12-酮(IC)
白色固体，5.2g，两步收率70.3％。1H NMR(400MHz,CD3OD)δ5.08(t,J＝6.8Hz,1H,H-24),4.39(d,J＝6.2Hz,1H,H-1’),3.82(s,1H),3.71(dd,J＝10.6,6.6Hz,1H),3.64(dd,J＝10.8,6.4Hz,1H),3.46-3.42(m,3H),3.35(d,J＝9.4Hz,1H),3.14(dd,J＝10.7,4.5Hz,1H),2.52-2.40(m,2H),2.11(dd,J＝12.7,2.3Hz,1H),1.66(s,4H),1.62(s,3H),1.27(s,3H),1.11(s,3H),0.98(s,3H),0.97(s,3H),0.80(s,3H),0.74(s,3H)；13C NMR(150MHz,CD3OD)δ215.6,131.9,126.0,98.8,82.4,79.3,76.1,75.6,73.1,70.1,62.1,57.5,57.2,57.1,56.4,43.0,41.9,40.7,40.6,40.0,39.9,38.8,35.6,33.0,28.6,27.9,25.9,24.9,24.7,22.9,19.5,17.8,17.1,16.7,16.3,16.0。
MALDI-HRMS calcd for C36H60NaO8[M+Na]+643.4180,found 643.4190。
实施例7 3β-羟基-20(S)-O-α-D-吡喃甘露糖基达玛烷-24-烯-12-酮(ID)
白色固体，4.9g，两步收率66.2％。1H NMR(400MHz,CD3OD)δ5.11(t,J＝6.5Hz,1H),5.05(s,1H,H-1’),3.79(d,J＝11.5Hz,1H),3.76-3.64(m,4H),3.59(t,J＝9.2Hz,1H),3.22(d,J＝9.3Hz,1H),3.14(dd,J＝10.5,4.2Hz,1H),2.50(t,J＝9.1Hz,1H),2.41(t,J＝13.2Hz,1H),2.14(dd,J＝13.0,2.2Hz,1H),1.68(s,3H),1.63(s,4H),1.29(s,3H),1.13(s,3H),0.98(s,3H),0.97(s,3H),0.80(s,3H),0.76(s,3H)；13C NMR(150MHz,CD3OD)δ214.6,132.5,125.4,95.4,81.9,79.3,75.0,73.7,72.9,68.7,63.0,57.4,57.4,57.1,56.2,42.4,41.8,40.7,40.0,39.9,39.4,38.8,35.4,33.2,28.6,27.9,25.9,24.9,24.6,23.8,19.5,17.7,17.0,16.7,16.6,16.0。MALDI-HRMS calcd for C36H60NaO8[M+Na]+643.4180,found643.4185。
实施例8 3β-羟基-20(S)-O-β-D-吡喃木糖基达玛烷-24-烯-12-酮(IE)
白色固体，4.5g，两步收率63.4％。1H NMR(400MHz,CD3OD)δ5.08(t,J＝6.4Hz,1H),4.39(d,J＝7.3Hz,1H,H-1’),3.77(dd,J＝11.2,5.2Hz,1H),3.49-3.42(m,1H),3.33(d,J＝9.4Hz,1H),3.27(t,J＝8.8Hz,1H),3.16-3.11(m,2H),3.07(t,J＝8.8Hz,1H),2.49(dd,J＝10.0,4.4Hz,1H),2.43(t,J＝13.2Hz,1H)2.11(dd,J＝12.8,2.4Hz,1H),1.67(s,4H),1.61(s,5H),1.26(s,3H),1.09(s,3H),0.97(s,6H),0.79(s,3H),0.74(s,3H)；13C NMR(150MHz,CD3OD)δ215.5,132.1,125.8,98.9,82.4,79.3,78.4,75.5,71.3,66.5,57.5,57.2,57.1,56.3,42.9,41.9,40.7,40.7,40.0,39.9,38.8,35.6,33.0,28.6,27.9,25.9,24.9,24.7,23.0,19.5,17.7,17.1,16.7,16.3,16.0。MALDI-HRMS calcd for C35H58NaO7[M+Na]+613.4075,found 613.4078。
实施例9 3β-羟基-20(S)-O-α-L-吡喃鼠李糖基达玛烷-24-烯-12-酮(IF)
白色固体，4.8g，两步收率66.7％。1H NMR(400MHz,(CD3)2SO)δ5.05(t,J＝6.4Hz,1H),4.78(s,1H),4.74(s,1H),4.60(s,1H),4.50(s,1H),4.35(s,1H),3.55-3.48(m,2H),3.44(d,J＝8.4Hz,1H),3.15(t,J＝9.2Hz,1H),2.98(m,1H),2.94(d,J＝9.2Hz,1H),2.36(t,J＝12.8Hz,2H),1.64(s,4H),1.57(s,3H),1.14(s,3H),1.07(d,J＝6.4Hz,3H),0.96(s,3H),0.89(s,3H),0.88(s,3H),0.70(s,3H),0.66(s,3H)；13C NMR(150MHz,(CD3)2SO)δ201.4,130.5,124.6,94.0,79.9,76.5,72.2,72.0,71.0,68.6,55.3,55.3,55.1,53.9,40.7,38.9,38.6,38.1,37.1,33.9,31.7,28.1,27.,25.5,23.7,23.1,21.0,18.1,17.9,17.45,16.4,15.7,15.7,15.3。MALDI-HRMS calcd for C37H62NaO6[M+Na]+625.4439,found 625.4444。
实施例10 3-β-甲氧基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-12-酮(IG)
10.1 3-β-羟基-20(S)-羟基达玛烷-24-烯-12-酮(I-4)的合成
将化合物I-3a(16.0g,31.96mmol)溶于80.0mL CH2Cl2，加入80.0mL甲醇，加入甲醇钠至pH＝9-10，50℃下反应6.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析分离，得浅黄色固体I-4(14.1g,96.2％)。1H NMR(400MHz,CDCl3)δ5.10(s,1H),3.20(d,J＝9.0Hz,1H),2.85(d,J＝10.3Hz,1H),2.40(q,J＝9.0Hz,1H),2.28(d,J＝13.6Hz,1H),2.21(t,J＝14.4Hz,1),1.68(s,3H),1.62(s,3H),1.17(s,3H),1.11(s,3H),0.99(s,3H),0.93(s,3H),0.80(s,6H)。
10.2 3-β-甲氧基-20(S)-羟基达玛烷-24-烯-12-酮(I-5a)的合成
将I-4(7.3g,15.91mmol)溶于干燥的DMF(200.0mL)中，加入碘甲烷(1.99mL,31.96mmol),冰浴下分批加入60％氢化钠(1.9g,47.94mmol)，于室温下反应。反应结束后，缓慢滴加水淬灭反应，乙酸乙酯稀释，依次用1mol/L盐酸，饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，柱层析分离(EA/PE,1:6)得淡黄色液体I-5a(5.9g,78.4％)。1H NMR(400MHz,CDCl3)δ5.61(s,1H),5.06(t,J＝7.1Hz,1H),3.52(s,3H),3.23(dd,J＝11.0,4.4Hz,1H),2.94-2.86(m,1H),1.66(s,3H),1.60(s,3H),1.17(s,3H),1.00(s,3H),0.99(s,3H),0.97(s,3H),0.84(s,3H),0.80(s,3H)；13C NMR(150MHz,CDCl3)δ214.3,142.7,125.7,79.0,74.5,55.8,55.2,54.0,52.4,48.9,39.0,38.9,38.5,37.3,36.7,34.6,31.6,28.3,28.2,27.3,26.8,25.9,25.2,22.7,22.2,18.3,17.9,16.9,15.8,15.7。
10.3 3-β-甲氧基-20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-12-酮(IG)
将I-5a(5.8g,12.27mmol)和2,3,4,6-四-O-乙酰基葡萄糖三氯亚胺酯(9.1g,18.41mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(222.3μL,1.23mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(150.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IG(4.0g,两步收率52.0％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.7Hz,1H),4.48(d,J＝7.6Hz,1H),3.81(d,J＝11.3Hz,1H),3.64(dd,J＝11.8,7.6Hz,1H),3.48(s,3H),3.38(t,J＝8.9Hz,1H),3.23-3.14(m,4H),3.09-3.07(m,1H),2.18-1.95(m,5H),1.66(s,3H),1.62(s,3H),1.33(s,3H),1.03(s,3H),1.00(s,3H),0.97(s,3H),0.88(s,3H),0.79(s,3H)。
实施例11 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3,24-二烯-12-酮(IH)
11.1 3-β-O-对甲苯磺酰基-20(S)-羟基达玛烷-24-烯-12-酮(I-6)的合成
将I-4(3.3g,7.19mmol)溶于干燥的CH2Cl2和吡啶中，冰浴下加入对甲苯磺酰氯(13.7g,71.90mmol)，80℃下反应6.0h。反应结束后，缓慢滴加水淬灭反应，乙酸乙酯稀释，依次用1mol/L盐酸，饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，柱层析分离，得白色固体I-6(3.8g,87.5％)。1H NMR(400MHz,CDCl3)δ7.79(d,J＝7.3Hz,2H),7.33(d,J＝7.4Hz,2H),5.09(s,1H),4.18(d,J＝11.2Hz,1H),3.18(s,1H),2.83(d,J＝10.0Hz,1H),2.44(s,3H),2.41-2.34(m,1H),2.20(d,J＝11.2Hz,2H),1.68(s,3H),1.61(s,3H),1.15(s,3H),1.10(s,3H),0.90(s,3H),0.83(s,6H),0.77(s,3H)；13C NMR(150MHz,CDCl3)δ213.8,144.5,134.9,131.7,129.8,127.8,125.0,90.3,73.3,56.3,56.0,54.8,53.3,46.2,40.3,39.3,38.8,38.4,38.0,37.3,33.9,30.9,28.0,26.5,25.9,24.8,24.6,22.6,21.8,18.5,17.8,17.6,16.3,16.0,15.9。MALDI-HRMS calcd for C37H57O5S[M+H]+613.3921,found 613.3927。
11.2 20(S)-羟基达玛烷-3,24-二烯-12-酮(I-7)的合成
将I-6(3.8g,6.20mmol)溶于DMF(50.0mL)中，加入溴化锂(5.2g,49.60mmol)和碳酸锂(3.7g,49.60mmol)，于153℃条件下反应1.5h。将反应液冷却至室温，加入水终止反应，乙酸乙酯稀释，依次用1mol/L盐酸、饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，柱层析分离(EA/PE,1:6)得到I-7(2.3g,84.2％)。1H NMR(400MHz,CDCl3)δ5.40(s,2H),5.11(s,1H),2.89(d,J＝9.9Hz,1H),2.42(s,1H),2.32-1.96(m,5H),1.69(s,3H),1.62(s,3H),1.21(s,3H),1.13(s,3H),0.96(s,6H),0.92(s,3H),0.81(s,3H)；13C NMR(150MHz,CDCl3)δ214.4,138.2,131.6,125.0,121.1,73.3,56.3,55.1,52.5,52.4,46.2,40.9,40.4,39.4,37.9,36.8,34.8,33.3,31.8,30.9,26.5,25.9,24.8,22.7,22.6,19.6,17.8,17.5,16.2,15.5。MALDI-HRMS calcd for C30H48NaO2[M+Na]+463.3547,found463.3543。
11.3 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3,24-二烯-12-酮(IH)
将I-7(2.3g,5.22mmol)和2,3,4,6-四-O-苯甲酰基葡萄糖三氯亚胺酯(4.6g,6.26mmol)溶于干燥的CH2Cl2(60.0mL)，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(94.3μL,0.52mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(50.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应4.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IH(2.5g,两步收率79.5％)。1H NMR(400MHz,CD3OD)δ5.44-5.36(m,2H),5.09(t,J＝6.6Hz,1H),4.44(d,J＝7.6Hz,1H),3.80(dd,J＝11.7,1.5Hz,1H),3.65(dd,J＝11.7,5.5Hz,1H),3.37-3.34(m,2H),3.28(t,J＝8.8Hz,1H),3.20(dd,J＝8.3,6.0Hz,1H),3.10(t,J＝8.1Hz,1H),2.54-2.45(m,2H),2.08(dd,J＝12.8,3.2Hz,1H),1.66(s,3H),1.62(s,3H),1.30(s,3H),1.12(s,3H),1.00(s,3H),0.97(s,3H),0.93(s,3H),0.76(s,3H)；13C NMR(150MHz,CD3OD)δ215.5,139.2,131.9,126.0,122.2,98.3,82.5,78.7,77.4,75.6,71.7,62.9,57.8,57.1,55.1,53.9,42.9,42.2,41.9,40.8,40.7,38.0,35.7,34.8,33.0,32.1,25.9,24.9,24.7,23.0,22.9,20.7,17.8,17.1,16.9,15.7。MALDI-HRMS calcd for C36H58NaO7[M+Na]+625.4075,found625.4080。
实施例12 20-O-β-D-吡喃木糖基-20(S)-人参二醇苷(IJ)
白色固体。1H NMR(CD3OD):5.09(t,J＝7.1Hz,1H,H-24),4.52(d,J＝7.7Hz,1H,H-1’),3.78(dd,J＝11.5,5.5Hz,1H,H-5’-2),3.68(td,J＝10.4,4.9Hz,1H,H-12),3.45(ddd,J＝10.4,8.8,5.5Hz,1H,H-4’),3.29(t,J＝8.8Hz,1H,H-3’),3.14(dd,J＝11.5,10.4Hz,1H,H-5’-1),3.13(dd,J＝11.0,4.4Hz,1H,H-3),3.07(dd,J＝8.8,7.7Hz,1H,H-12),1.67(s,3H),1.61(s,3H),1.32(s,3H),1.00(s,3H),0.96(s,3H),0.91(s,3H),0.90(s,3H),0.70(s,3H)；13C NMR(CDCl3):132.3(C-25),128.2(C-24),98.9(C-1’),84.8(C-20),79.6(C-3),78.4(C-3’),75.3(C-2’),71.8(C-12),71.1(C-4’),66.8(C-5’),57.3,53.1,52.4,51.0,40.9,40.2,40.0,38.1,36.7,35.9,31.5,30.8,28.6,28.0,27.2,25.9,23.9,22.4,19.4,18.3,17.8,17.3,16.7,16.3,16.1。
实施例13 20-O-β-L-吡喃鼠李糖基-20(S)-人参二醇苷(IK)
白色固体。1H NMR(CD3OD):5.13(d,J＝1.4Hz,1H,H-1’),5.13(t,J＝7.1Hz,1H,H-24),3.79(m,1H,H-2’),3.79(m,1H,H-5’),3.60(td,J＝10.1,5.5Hz,1H,H-12),3.56(dd,J＝9.6,3.2Hz,1H,H-3’),3.38(t-like,J＝9.6,9.2Hz,1H,H-4),3.13(dd,J＝11.5,4.6Hz,1H,H-3),1.69(s,3H),1.62(s,3H),1.36(s,3H),1.24(d,J＝6.0Hz,3H,H-5’),1.00(s,3H),0.96(s,3H),0.93(s,3H),0.91(s,3H),0.77(s,3H)；MS:629[M+Na]+,607[M+H]+,589.5[M-OH]+,443.4,425.4,407.4。
实施例14 20-O-α-L-吡喃阿拉伯糖基-20(S)-人参二醇苷(IL)
白色固体。1H NMR(CD3OD):5.10(d,J＝7.3Hz,1H,H-24),4.50(d,J＝7.3Hz,1H,H-1),3.84(dd,J＝12.4,1.4Hz,1H,H-5’-1),3.79(brs,1H,H-4’),3.71(td,J＝10.6,5.5Hz,1H,H-12),3.53(dd,J＝12.4,1.4Hz,1H,H-5’-2),3.51(dd,J＝6.4,3.2Hz,1H,H-3’),3.45(dd,J＝9.1,7.3Hz,1H,H-2’),3.14(dd,J＝11.5,4.6Hz,1H,H-3),1.67(s,3H),1.62(s,3H),1.34(s,3H),1.01(s,3H),0.96(s,3H),0.92(s,3H),0.91(s,3H),0.78(s,3H)。
实施例15、16 20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-3,12-二酮(IIA)和20(S)-羟基-3-O-β-D-吡喃葡萄糖基达玛烷-3,24-二烯-12-酮(IIA-1)的合成
15.1 20(S)-羟基达玛烷-24-烯-3,12-二酮(II-1)的合成
将PPD(40.0,86.82mmol)溶于干燥的500.0mL二氯甲烷中，加入PDC(98.0g,260.46mmol)和醋酐(32.8mL,347.28mmol)室温反应约5.0h，抽滤除去不溶物，滤液浓缩柱层析分离(EA/PE,1:8)得到淡黄色泡沫状固体II-1(24.3g,61.2％)。1H NMR(400MHz,CDCl3)δ5.11(t,J＝7.1Hz,1H,H-24),2.90(d,J＝9.6Hz,1H,H-13),2.55-2.40(m,3H),2.29(d,J＝7.7Hz,2H),1.69(s,3H),1.62(s,3H),1.23(s,3H),1.11(s,6H)1.07(s,3H),1.04(s,3H),0.81(s,3H)。
15.2 20(S)-O-β-D-吡喃葡萄糖基达玛烷-24-烯-3,12-二酮(2A)和20(S)-羟基-3-O-β-D-吡喃葡萄糖基达玛烷-3,24-二烯-12-酮(2A-1)的合成
将II-1(11.0g,24.08mmol)和2,3,4,6-四-O-乙酰基葡萄糖三氯亚胺酯(17.8g,36.12mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(435.5μL,2.41mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(150.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IIA(5.8g,两步收率38.9％)和IIA-1(5.6g,两步收率37.6％)。IIA:1H NMR(400MHz,CD3OD)δ5.10(t,J＝6.4Hz,1H),4.45(d,J＝7.7Hz,1H),3.80(dd,J＝11.8,1.4Hz,1H),3.65(dd,J＝11.7,5.4Hz,1H),3.40-3.33(m,2H),3.28(d,J＝8.9Hz,1H),3.21(dd,J＝7.4,5.1Hz,1H),3.11(t,J＝8.2Hz,1H),2.54-2.48(m,4H),2.14(dd,J＝12.8,3.2Hz,1H),1.67(s,3H),1.62(s,3H),1.31(s,3H),1.12(s,3H),1.09(s,3H),1.07(s,6H),0.77(s,3H)；13C NMR(150MHz,CD3OD)δ220.0,214.8,131.9,126.0,98.3,82.5,78.8,77.4,75.6,71.8,62.9,57.5,57.2,56.1,55.4,43.0,41.8,40.8,40.7,40.3,38.5,34.8,33.0,27.1,25.9,24.9,24.7,22.9,21.4,20.9,17.8,17.1,16.3,15.8。MALDI-HRMS calcd for C36H58NaO8[M+Na]+641.4024,found 625.4041。
IIA-1:1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.7Hz,1H),4.94(d,J＝7.3Hz,1H),4.59(d,J＝8.1Hz,1H),3.83(d,J＝12.2Hz,1H),3.66(dd,J＝12.1,4.7Hz,1H),3.39-3.29(m,3H),3.07(d,J＝9.5Hz,1H),2.46–2.35(m,2H),2.14(d,J＝14.8Hz,1H),2.06-1.92(m,3H),1.66(s,3H),1.61(s,3H),1.27(s,3H),1.15(s,3H),1.01(s,6H),0.99(s,3H),0.77(s,3H)；13C NMR(150MHz,CD3OD)δ215.2,160.6,132.1,125.8,102.1,97.2,78.3,77.9,75.1,75.0,71.4,62.5,57.5,57.3,55.0,54.6,44.4,42.1,41.6,40.7,40.6,38.6,37.6,34.7,32.7,28.8,25.9,25.7,24.9,23.9,20.6,20.0,17.7,17.3,16.4,15.7。MALDI-HRMS calcdfor C36H58NaO8[M+Na]+641.4024,found 625.4040。
实施例17 20(S)-O-β-D-吡喃葡萄糖基达玛烷-1,24-二烯-3,12-二酮(IIB)
17.1 20(S)-羟基达玛烷-1,24-二烯-3,12-二酮(II-2)的合成
将II-1(12.0g,26.27mmol)溶于DMSO(88.0mL)中，加入IBX(24.0g,39.41mmol)，于70℃条件下反应24.0h。将反应液冷却至室温，加入水终止反应，乙醚稀释，依次用饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，柱层析分离(EA/PE,1:7)得到II-2(8.4g,70.5％)。1H NMR(400MHz,CDCl3)δ6.98(d,J＝10.0Hz,1H),5.81(d,J＝9.9Hz,1H),5.07(s,1H),2.88(d,J＝10.8Hz,1H),2.47(d,J＝13.8Hz,1H),2.38(t,J＝12.5Hz,2H),1.65(s,3H),1.59(s,3H),1.23(s,3H),1.13(s,6H),1.09(s,6H),0.78(s,3H)。
17.2 20(S)-O-β-D-吡喃葡萄糖基达玛烷-1,24-二烯-3,12-二酮(IIB)的合成
将II-2(8.3g,18.25mmol)和2,3,4,6-四-O-乙酰基葡萄糖三氯亚胺酯(13.5g,27.37mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(330.7μL,1.83mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(100.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体2B(5.1g,两步收率45.3％)。1H NMR(400MHz,CD3OD)δ7.21(d,J＝10.1Hz,1H),5.81(d,J＝10.1Hz,1H),5.10(t,J＝6.3Hz,1H),4.45(d,J＝7.4Hz,1H),3.80(d,J＝12.0Hz,1H),3.65(dd,J＝12.0,4.9Hz,1H),3.40(d,J＝9.7Hz,1H),3.35(t,J＝9.2Hz,1H),3.27(d,J＝9.6Hz,1H),3.22-3.19(m,1H),3.11(t,J＝7.9Hz,1H),2.64(t,J＝13.0Hz,1H),2.54-2.49(m,2H),2.39(d,J＝12.4Hz,1H),1.66(s,3H),1.62(s,3H),1.35(s,3H),1.21(s,3H),1.14(s,6H),1.11(s,4H),0.76(s,3H)；13C NMR(150MHz,CD3OD)δ213.8,207.3,160.6 131.9,126.1,126.0,98.3,82.4,78.7,77.4,75.6,71.7,62.8,57.3,55.0,50.1,45.9,42.9,42.7,41.3,40.7,40.4,34.9,32.8,28.1,25.9,24.9,24.7,22.9,21.8,20.2,19.7,17.8,17.1,16.5。MALDI-HRMS calcd for C36H56NaO8[M+Na]+639.3867,found 639.3873。
实施例18 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3-甲氧亚胺基-24-烯-12-酮(IIIA)
18.1 3-β-羟基-12-β-O-三甲基乙酰基-20(S)-人参二醇苷(III-1)的合成
将PPD(45.0g,97.68mmol)溶于500.0mL二氯甲烷中，加入三乙胺(27.1mL,195.36mmol)，将反应体系温度降至-5℃，冰浴下滴加三甲基乙酰氯(24.1mL,195.36mmol)，-5℃下反应3.0h。加入水终止反应，依次用水洗，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，得粗产物36.6g，直接用于下一步反应。
18.2 12-β-O-三甲基乙酰基-20(S)-羟基达玛烷-24-烯-3-酮(III-2)的合成
将III-1(36.6g,67.17mmol)溶于干燥的600.0mL二氯甲烷中，加入PDC(37.9g,100.76mmol)和醋酐(19.0mL,201.51mmol)室温反应约5.0h，抽滤除去不溶物，滤液浓缩直接用于下一步反应。1H NMR(400MHz,CDCl3)δ5.15(t,J＝7.2Hz,1H),4.82(t,J＝10.4Hz,1H),2.47-2.45(m,2H),2.22(s,1H),1.71(s,3H),1.63(s,3H),1.21(s,9H),1.12(s,3H),1.09(s,3H),1.06(s,3H),1.04(s,3H),0.98(s,3H),0.93(s,3H)。
18.3 12-β-羟基-20(S)-羟基达玛烷-24-烯-3-酮(III-3)的合成
将上步反应浓缩物溶于二氯甲烷和甲醇的混合溶剂(400.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，50℃下反应6.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体III-3(17.9g,三步收率39.9％)。1H NMR(400MHz,CDCl3)δ5.16(s,1H,H-24),3.62-3.57(m,1H,H-3),2.54-2.41(m,2H),1.70(s,3H),1.64(s,3H),1.20(s,3H),1.08(s,3H),1.04(s,3H),1.03(s,3H),0.98(s,3H),0.89(s,3H)。
18.4 12-β-羟基-20(S)-羟基达玛烷-3-甲氧亚胺基-24-烯(III-4a)的合成
将III-3(2.3g,5.01mmol)溶于吡啶(60.0mL)中，加入O-甲基羟胺盐酸盐(628.1mg,7.52mmol)，于80℃条件下反应4.0h。将反应液冷却至室温，加入水终止反应，乙酸乙酯稀释，依次用1mol/L盐酸、饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，直接用于下一步。
18.5 20(S)-羟基达玛烷-3-甲氧亚胺基-24-烯-12-酮(III-5a)的合成
将III-4a溶于干燥的120.0mL二氯甲烷中，加入PDC(2.8g,7.52mmol)和醋酐(1.4mL,15.03mmol)室温反应约5.0h，抽滤除去不溶物，滤液浓缩柱层析分离得到淡黄色泡沫状固体III-5a(1.1g,两步收率45.2％)。1H NMR(400MHz,CDCl3)δ5.10(s,1H,H-24),3.81(s,3H),3.25(s,1H),2.92(d,J＝14.8Hz,1H),2.86(d,J＝10.4Hz,1H),2.40(d,J＝8.0Hz,1H),1.69(s,3H),1.62(s,3H),1.20(s,3H),1.16(s,3H),1.12(s,3H),1.07(s,3H),1.01(s,3H),0.78(s,3H)；13C NMR(150MHz,CDCl3)δ214.0,165.2,131.7,125.0,73.2,61.2,56.4,56.0,54.9,53.1,46.2,40.3,40.2,39.3,38.5,37.9,37.5,33.7,30.9,27.5,26.5,25.9,24.8,23.2,22.6,19.2,17.8,17.5,15.9,15.6。MALDI-HRMS calcd for C31H51NNaO3[M+Na]+508.3761,found 508.3760。
18.6 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3-甲氧亚胺基-24-烯-12-酮(IIIA)的合成
将III-5a(1.1g,2.26mmol)和2,3,4,6-四-O-乙酰基葡萄糖三氯亚胺酯(1.3g,2.71mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(40.8μL,0.23mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(50.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析，得到白色固体IIIA(860.0mg,两步收率58.5％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.7Hz,1H),4.44(d,J＝7.7Hz,1H),3.80(d,J＝11.7Hz,1H),3.76(s,3H),3.64(dd,J＝11.7,5.3Hz,1H),3.36-3.31(m,2H),3.27(t,J＝8.9Hz,1H),3.20(dd,J＝7.3,5.1Hz,1H),3.10(t,J＝8.2Hz,1H),2.88(dt,J＝8.5,4.8Hz,1H),2.52-2.43(m,2H),2.31-2.22(m,1H),2.10(dd,J＝12.7,2.9Hz,1H),1.66(s,3H),1.62(s,3H),1.29(s,3H),1.14(s,3H),1.11(s,3H),1.07(s,3H),1.05(s,3H),0.74(s,3H)；13C NMR(150MHz,CD3OD)δ215.1,166.5,131.9,126.0,98.3,82.5,78.7,77.4,75.6,71.7,62.8,61.3,57.5,57.2,57.1,55.8,42.9,41.9,41.1,40.8,40.7,39.6,38.7,35.1,33.0,28.1,25.9,24.9,24.7,23.5,22.9,20.3,18.4,17.8,17.1,16.2,16.1。MALDI-HRMS calcd for C37H61NNaO8[M+Na]+670.4289,found 670.4294。
实施例19 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3-羟基亚胺基-24-烯-12-酮(IIIB)
19.1 12-β-羟基-20(S)-羟基达玛烷-3-烯丙氧亚胺基-24-烯(III-4b)的合成
将III-3(5.0g,10.90mmol)溶于吡啶(120.0mL)中，加入O-烯丙基羟胺盐酸盐(1.8g,16.35mmol)，于80℃条件下反应4.0h。将反应液冷却至室温，加入水终止反应，乙酸乙酯稀释，依次用1mol/L盐酸、饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，直接用于下一步。
19.2 20(S)-羟基达玛烷-3-烯丙氧亚胺基-24-烯-12-酮(III-5b)的合成
将III-4b溶于干燥的120.0mL二氯甲烷中，加入PDC(6.2g,16.35mmol)和醋酐(3.1mL,32.70mmol)室温反应约5.0h，抽滤除去不溶物，滤液浓缩柱层析分离得到淡黄色泡沫状固体III-5b(3.6g,两步收率64.6％)。1H NMR(400MHz,CDCl3)δ5.99(dd,J＝17.4,11.4Hz,1H),5.26(d,J＝17.3Hz,1H),5.17(d,J＝10.5Hz,1H),5.09(t,J＝6.8Hz,1H),4.52(d,J＝2.6Hz,2H),3.24(s,1H),2.97(d,J＝15.8Hz,1H),2.86(d,J＝10.3Hz,1H),2.43-2.36(m,1H),1.69(s,3H),1.62(s,3H),1.20(s,3H),1.16(s,3H),1.12(s,3H),1.06(s,3H),1.01(s,3H),0.79(s,3H)；13C NMR(150MHz,CDCl3)δ214.0,165.3,134.9,131.7,125.0,117.0,74.4,73.2,56.4,56.0,54.9,53.1,46.2,40.3,40.3,39.3,38.4,37.9,37.5,33.7,30.9,27.6,26.5,25.9,24.8,23.2,22.6,19.2,17.8,17.8,17.5,15.9,15.5。MALDI-HRMScalcd for C33H53NNaO3[M+Na]+534.3918,found 534.3921。
19.3 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3-羟基亚胺基-24-烯-12-酮(IIIB)的合成
将III-5b(3.6g,7.03mmol)和2,3,4,6-四-O-乙酰基葡萄糖三氯亚胺酯(4.2g,8.44mmol)溶于干燥的CH2Cl2，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至-40℃，滴加TMSOTf(127.0μL,0.70mmol)，-40℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(100.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应1.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，将浓缩物溶于乙醇和水的混合溶剂中(50.0mL,v:v＝4:1)，加入三苯基膦(256.5mg,0.98mmol)、醋酸钯(73.2mg,0.33mmol)、三乙胺(4.1mL,29.34mmol)和甲酸(1.1mL,29.34mmol)，加热回流1.5h，反应液浓缩，柱层析纯化，得到白色固体IIIB(1.8g,三步收率40.4％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.5Hz,1H),4.44(d,J＝7.5Hz,1H),3.80(d,J＝11.6Hz,1H),3.65(dd,J＝11.8,5.3Hz,1H),3.36-3.31(m,2H),3.28(t,J＝9.2Hz,1H),3.22-3.19(m,1H),3.10(t,J＝8.2Hz,1H),2.96(dt,J＝14.6,3.9Hz,1H),2.53-2.44(m,2H),2.33-2.24(m,1H),2.11(dd,J＝12.2,2.4Hz,1H),1.66(s,3H),1.62(s,3H),1.30(s,3H),1.14(s,3H),1.11(s,3H),1.07(s,3H),1.06(s,3H),0.74(s,3H)；13C NMR(150MHz,CD3OD)δ215.2,166.5,131.9,126.,98.3,82.5,78.7,77.4,75.6,71.7,62.8,57.5,57.2,57.1,55.9,42.9,41.9,41.1,40.8,40.7,39.6,38.8,35.1,33.0,28.1,25.9,24.9,24.7,23.4,22.9,20.3,17.8,17.7,17.1,16.12,16.1。MALDI-HRMS calcd for C36H59NNaO8[M+Na]+656.4133,found 656.4139。
实施例20 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3-羟基-2-氰基-2,24-二烯-12-酮(IIIC)
20.1 20(S)-羟基达玛烷-3-羟基-2-氰基-2,24-二烯-12-酮(III-9)
将III-3(10.0g,21.80mmol)溶于干燥的甲酸乙酯中(150.0mL)中，加入30％甲醇钠(30mL)，于室温下反应3.0h。反应结束后，乙酸乙酯稀释，依次用1mol/L盐酸，饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，浓缩物溶于乙醇(150.0mL)和水(26.4mL)的混合溶剂中，加入羟胺盐酸盐(3.0g,43.60mmol)和三乙胺(3.0mL,21.80mmol)，于55℃下反应10.0h。反应结束后，乙酸乙酯稀释，依次用1mol/L盐酸，饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，粗产物溶于干燥的150.0mL二氯甲烷中，加入PDC(12.3g,32.70mmol)和醋酐(4.1mL,43.60mmol)室温反应6.0h，抽滤除去不溶物，滤液浓缩，浓缩物溶于干燥的甲醇中(130.0mL)中，加入30％甲醇钠(5.4mL)，于55℃下反应3.5h。反应结束后，乙酸乙酯稀释，依次用1mol/L盐酸，饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，柱层析分离，得白色固体III-9(3.0g,四步收率28.6％)。1H NMR(600MHz,(CD3)2SO)δ9.78(s,1H),5.06(brs,1H),3.92(s,1H),2.97(d,J＝9.3Hz,1H),2.40(t,J＝13.1Hz,1H),2.20(brs,1H),1.63(s,3H),1.57(s,3H),1.17(s,3H),1.10(s,3H),1.01(s,3H),0.90(s,3H),0.87(s,3H),0.66(s,3H)；13C NMR(150MHz,(CD3)2SO)δ210.3,171.5,130.1,125.1,119.9,77.9,72.3,55.4,55.4,51.8,51.7,42.3,41.5,40.5,38.1,35.9,32.8,31.4,26.9,25.5,25.3,23.3,22.6,19.0,17.5,16.5,15.2,14.8。MALDI-HRMS calcd for C31H47NNaO3[M+Na]+504.3448,found 504.3452。
20.2 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3-羟基-2-氰基-2,24-二烯-12-酮(IIIC)
将III-9(2.0g,4.15mmol)和2,3,4,6-四-O-苯甲酰基葡萄糖三氯亚胺酯(3.7g,4.98mmol)溶于干燥的CH2Cl2(90.0mL)，加入适量分子筛，氩气保护，室温搅拌30min后将反应体系温度降至0℃，滴加TMSOTf(75.0μL,0.42mmol)，0℃反应。TLC检测反应完毕后，加入Et3N终止反应，恢复至室温，抽滤除去分子筛，反应液浓缩成固体，将浓缩物溶于二氯甲烷和甲醇的混合溶剂(50.0mL,v:v＝1:1)中，加入甲醇钠至pH＝9-10，室温下反应4.0h后，TLC检测反应完全，加入阳离子树脂中和反应液，过滤浓缩，柱层析。得到白色固体IIIC(1.6g,两步收率59.9％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.5Hz,1H),4.44(d,J＝7.7Hz,1H),3.80(dd,J＝11.8,1.9Hz,1H),3.64(dd,J＝11.9,5.3Hz,1H),3.38-3.34(m,2H),3.27(d,J＝8.8Hz,1H),3.22-3.17(m,1H),3.10(t,J＝8.2Hz,1H),2.56-2.48(m,2H),1.66(s,3H),1.62(s,3H),1.29(s,3H),1.16(s,3H),1.12(s,3H),1.09(s,4H),1.02(s,3H),0.76(s,3H)；13C NMR(150MHz,CD3OD)δ214.7,173.6,131.9,126.0,120.6,98.3,82.5,79.4,78.7,77.4,75.6,71.7,62.8,57.6,57.1,54.4,53.9,42.9,42.4,41.6,40.7,40.6,39.7,37.7,34.5,33.0,27.9,25.9,24.9,24.7,22.9,20.6,19.8,17.8,17.0,16.0,15.7。MALDI-HRMS calcd for C37H57NNaO8[M+Na]+666.3976,found 666.3973。
实施例21 20(S)-O-β-D-吡喃葡萄糖基达玛烷-3,12-羟基亚胺基-24-烯-12-酮(IVA)
将IIA(1.25g,2.02mmol)溶于吡啶(60.0mL)中，加入羟胺盐酸盐(421.1mg,6.06mmol)，于80℃条件下反应4.0h。将反应液冷却至室温，加入水终止反应，乙酸乙酯稀释，依次用1mol/L盐酸、饱和碳酸氢钠，饱和氯化钠洗涤，有机层用无水硫酸钠干燥，减压浓缩，柱层析纯化，得白色固体IVA(913.0mg,69.7％)。1H NMR(400MHz,CD3OD)δ5.09(t,J＝6.8Hz,1H),4.46(d,J＝7.6Hz,1H),3.80(d,J＝11.4Hz,1H),3.65(dd,J＝11.5,5.1Hz,1H),3.37-3.33(m,2H),3.30-3.28(m,1H),3.20(dd,J＝14.6,7.8Hz,1H),3.11(t,J＝8.0Hz,1H),2.94-2.88(m,1H),2.85(d,J＝9.6Hz,1H),2.59(dd,J＝11.0,6.9Hz,1H),2.38-2.30(m,1H),1.66(s,3H),1.60(s,3H),1.22(s,3H),1.18(s,3H),1.13(s,3H),1.06(s,3H),1.03(s,3H),0.77(s,3H)；13C NMR(150MHz,CD3OD)δ166.9,161.8,131.8,126.2,98.4,83.4,78.6,77.3,75.4,71.8,62.9,57.0,55.5,53.2,43.4,41.9,41.1,40.5,39.9,38.8,35.6,32.5,28.2,25.9,24.4,23.4,22.7,20.2,17.8,17.3,16.3,15.8。MALDI-HRMS calcd forC36H60N2NaO8[M+Na]+671.4242,found 671.4246。
实施例22化合物对小鼠慢性皮炎湿疹模型的作用研究
本实验选择前述的人参二醇苷衍生物(下称GR衍生物)，及人参皂苷CK。
药物配制：取相应量受试样品，置于研钵研磨，再用0.5％CMCNa以等量倍增法配制至相应体积。
阳性对照：
本系列是口服，选择皮质激素类药物醋酸泼尼松(生产单位：浙江仙琚制药股份有限公司，批号、规格：161105，5mg)作为阳性药。
外用的阳性对照：复方醋酸地塞米松乳膏，批号1702052H，华润三九医药股份有限公司。
试剂
2,4-二硝基氯苯(DNCB)，梯希爱(上海)化成工业发展有限公司。
橄榄油：化学纯CP，批号20160325，国药集团化学试剂有限公司。
甲醛溶液，分析纯AR，性状：无色透明液体，含8％-14％的甲醇以防聚合。
二乙二醇乙醚：上海麦克林生化科技有限公司，批号：C10005375，室温保存。
蓖麻油：批号P1040114,Shanghai Titan chem.Co.Ltd.
仪器
Nicon eclipse 90i显微镜，软件NIS-Elements BR3.2。
实验动物
动物购自上海西普尔-必凯实验动物有限公司。许可证号码：SCXK(沪)2013-0016。
试验方法
分组及给药方法
(1)balb/c小鼠，适应性饲养2天后，每组5只，即模型组、泼尼松组、GR衍生物各组。实验前1天腹部去毛3cm×3cm，实验当天以7％DNCB丙酮橄榄油(体积比为4:1)100μL涂于腹部致敏，实验第5天于小鼠右耳内外侧涂0.5％DNCB 20μL激发，每3天激发一次，共激发4次。于致敏当天开始口服给药，受试样品和CK组给药剂量为20mg/kg，泼尼松片给药剂量为6mg/kg，至末次激发后第2天，结果见表1和表2。
(2)方法同上，balb/c小鼠，每组5只，即模型组、泼尼松组和受试样品IB、IE、IVA、IIIA、CK的15mg/kg、30mg/kg、60mg/kg组，结果见表3。
(3)balb/c小鼠，每组5只，即模型组、醋酸地塞米松乳膏组、GR衍生物各组(外用制剂配制方法：加入占总体积5％的二乙二醇乙醚溶解，然后用蓖麻油稀释至所需浓度)。实验前1天腹部去毛3cm×3cm，实验当天以7％DNCB丙酮橄榄油(体积比为4:1)100μL涂于腹部致敏，实验第5天于小鼠右耳内外侧涂0.5％DNCB 20μL激发，每3天激发一次，共激发4次。各组小鼠在激发24h、48h和72h后，分别外涂相应的药物于小鼠右耳内侧，每天2次，并于第5次激发后72h处死小鼠，结果见表4。
取材及观察检测指标
初次激发前、每次激发后24h及末次激发后2天用螺旋测微仪测量小鼠右耳厚度。于实验最后一天取耳部标本，石蜡包埋固定，HE染色，显微镜观察病理情况并测量皮肤厚度。第二次实验仅测量皮肤厚度。第三次实验仅测量皮肤厚度。
数据分析
数据以均数和标准差表示，采用SPSS16.0软件进行单因素方差分析(oneway ANOVA)比较各组差异，如果p<0.05则被认为具有统计学意义。
试验结果
表1 GR衍生物口服对小鼠慢性皮炎湿疹模型不同天数耳厚度卡尺测量结果
注：与模型组比较，P*<0.05,P**<0.01
本实验条件下，表1显示，与模型组比较，泼尼松组在实验12天能减轻小鼠耳厚度，泼尼松组为0.324±0.028(P<0.05)，IB组为0.314±0.002(P<0.01)，IIA-1组为0.308±0.028(P<0.01)，IE组为0.307±0.018(P<0.01)，IVA组为0.299±0.022(P<0.01)。其中IIA-1组从试验第8天就能减轻小鼠耳厚度，IVA组从第10天开始减轻耳厚度。
表2 GR衍生物口服对小鼠慢性皮炎湿疹模型病理切片耳表皮厚度
| 组别 | 耳表皮厚度(μm) |
| 模型组 | 29.183±4.348 |
| 泼尼松组 | 22.140±4.286<sup>*</sup> |
| CK | 21.573±3.077<sup>**</sup> |
| IB | 20.037±3.327<sup>**</sup> |
| IB-2 | 22.018±3.765<sup>*</sup> |
| IC | 20.537±6.325<sup>*</sup> |
| IE | 19.438±4.369<sup>**</sup> |
| IIA | 20.690±2.674<sup>*</sup> |
| IA-1 | 21.884±2.763<sup>*</sup> |
| IA | 21.489±4.118<sup>*</sup> |
| IVA | 19.624±3.131<sup>**</sup> |
| IIIA | 19.156±2.074<sup>**</sup> |
注：与模型组比较，P*<0.05,P**<0.01
表2显示，与模型组比较，泼尼松组能减轻小鼠耳表皮厚度，为22.140±4.286(P<0.05)，CK组为21.573±3.077(P<0.01)，IB为20.037±3.327(P<0.01)，IE为19.438±4.369(P<0.01)，IVA为19.624±3.131(P<0.01)，IIIA为19.156±2.074(P<0.01)。
表3 GR衍生物口服对小鼠慢性皮炎湿疹模型病理切片耳表皮厚度
注：与模型组比较，P*<0.05,P**<0.01
表3显示，IB、IE、IVA、IIIA各组能不同程度减轻小鼠耳表皮厚度。
病理：HE染色显示，模型组小鼠耳片表皮角化过度增生，增厚真皮以单核细胞浸润为主，血管扩张。泼尼松组能减轻炎症细胞浸润，减少表皮角化过度，改善耳片病理改变。IB，IE，IVA，IIIA均可减轻炎症细胞浸润，减轻表皮过度角化，改善耳片的病理改变，而且有一定的剂量依赖关系。
表4 GR衍生物外用对小鼠慢性皮炎湿疹模型病理切片耳表皮厚度
注：与模型组比较，P*<0.05,P**<0.01
结论
本试验条件下，IA、IC、IB、IVA、ID和IA-1能够明显抑制耳厚度和耳表皮厚度，显示其对小鼠慢性皮炎湿疹有明显的效果。
实施例23血液学相关变化研究
33只ICR小鼠，随机分为11组，即生理盐水组，1.8mg/kg醋酸地塞米松组，CK、IB、IC、ID、IVA、IH、IJ、IK、IL组均给予225mg/kg。分别灌胃给予小鼠，连续6天，于末次给药后1h取足量血测血常规，结果见表5。
表5 GR系列化合物血液学检查数据
注：与空白相比，*P＜0.05，**P＜0.01
血液学数据显示，与空白对照相比，地塞米松1.8mg/kg剂量组的淋巴细胞百分比均显著降低、中性粒细胞百分比显著增加，白细胞计数显著降低、单核细胞百分比显著增加；而CK和GR衍生物均未引起血液学相关变化。
实施例24血糖相关变化研究
33只ICR小鼠，随机分为11组，即生理盐水组，1.8mg/kg醋酸地塞米松组，CK、IB、IC、ID、IVA、IH、IJ、IK、IL组均给予225mg/kg。分别灌胃给予小鼠，连续6天，于第6天晨8:00左右开始禁食，于次日4:00左右，测尾静脉血糖。
表4 GR系列化合物血糖数据
| 组别 | 血糖值(mmol/L) |
| 空白组 | 3.05±0.11 |
| 醋酸地塞米松组 | 5.78±0.36<sup>**</sup> |
| CK | 3.18±0.28 |
| IB | 3.10±0.19 |
| IC | 3.25±0.26 |
| ID | 2.79±0.56 |
| IVA | 3.02±0.23 |
| IH | 2.98±0.37 |
| IJ | 3.11±0.43 |
| IK | 3.09±0.28 |
| IL | 3.03±0.21 |
注：与空白相比，*P＜0.05，**P＜0.01
血糖数据显示，与空白对照相比，地塞米松引起小鼠血糖升高；而CK和GR衍生物未引起血糖相关变化。
Claims (10)
1.通式(I)的结构所示的人参二醇苷衍生物或其药学上可接受的盐在制备预防和/或治疗皮炎的药物中的应用
其中，R1选自羟基或非葡萄糖的吡喃糖基或
R2和R3一起表示＝O或＝N-OR8；
或R2为氢且R3为羟基；
R4和R6结合成键，且R5和R7独立选自氢、C1-6烷氧基、羟基、氰基、C1-6酯基、糖基；
或R6和R7一起表示＝O或＝N-OH，且R5和R4独立选自氢、C1-6烷氧基、羟基、氰基；
或R4、R5、R6和R7独立选自氢、C1-6烷氧基、羟基、氰基、C1-6酯基、糖基；
R8选自氢或C1-6烷基。
2.根据权利要求1所述的应用，其中，通式(I)中，R2和R3一起表示＝N-OH。
3.根据权利要求1所述的应用，其中，通式(I)中，R4和R6结合成键。
4.根据权利要求3所述的应用，其中，通式(I)中，R5选自糖基；并且R1表示羟基。
5.根据权利要求1所述的应用，其中，通式(I)中，R6和R7一起表示＝N-OR8；并且R8表示氢或甲基。
6.根据权利要求1所述的应用，其中，通式(I)中，R1中所述非葡萄糖的吡喃糖基选自鼠李糖基、岩藻糖基、阿拉伯糖基、木糖基、核糖基、奎诺糖基、半乳糖基、氨基葡萄糖基、6-脱氧-6-氨基葡萄糖基、乳糖基以及纤维二糖基。
7.根据权利要求1-6任一项所述的应用，其中，通式(I)中，所述糖基独立选自脱氧糖基或五碳糖基。
8.根据权利要求1所述的应用，其中，所述人参二醇苷衍生物结构如下：
9.根据权利要求1所述的应用，其中，所述人参二醇苷衍生物的药学上可接受的盐选自其钠盐、钾盐、钙盐、铵盐。
10.根据权利要求1-9任一项所述的应用，其特征在于，所述皮炎优选特异性皮炎。
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| KR19990015091A (ko) * | 1997-08-01 | 1999-03-05 | 박원훈 | 인삼 사포닌 또는 사포게닌을 함유하는 보체활성 조절제 |
| CN102743402A (zh) * | 2012-07-15 | 2012-10-24 | 浙江大学 | 人参二醇皂苷组分在制备防治皮炎和疤痕药物中的用途 |
| WO2012173452A1 (ko) * | 2011-06-16 | 2012-12-20 | 한국생명공학연구원 | 진세노사이드 컴파운드 ｋ 또는 이의 유도체로 된 항균제 |
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| KR19990015091A (ko) * | 1997-08-01 | 1999-03-05 | 박원훈 | 인삼 사포닌 또는 사포게닌을 함유하는 보체활성 조절제 |
| WO2012173452A1 (ko) * | 2011-06-16 | 2012-12-20 | 한국생명공학연구원 | 진세노사이드 컴파운드 ｋ 또는 이의 유도체로 된 항균제 |
| CN102743402A (zh) * | 2012-07-15 | 2012-10-24 | 浙江大学 | 人参二醇皂苷组分在制备防治皮炎和疤痕药物中的用途 |
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Application publication date: 20191122 |