CN109232187B - 一种手性发卡林醇类似物及其合成方法和应用 - Google Patents
一种手性发卡林醇类似物及其合成方法和应用 Download PDFInfo
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- CN109232187B CN109232187B CN201810961365.9A CN201810961365A CN109232187B CN 109232187 B CN109232187 B CN 109232187B CN 201810961365 A CN201810961365 A CN 201810961365A CN 109232187 B CN109232187 B CN 109232187B
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C33/05—Alcohols containing rings other than six-membered aromatic rings
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Abstract
本发明涉及一种手性发卡林醇类似物及其合成方法和应用。所述手性发卡林醇类似物,其结构通式I如下所示。本发明在常温下将端基1,3‑二炔类化合物在手性氨基醇、金属试剂和有机碱条件下对醛进行不对称加成反应,所得类似物比天然发卡林醇具有更强抗HepG2肿瘤细胞增殖活性。本发明的合成方法反应条件温和,适合特定底物反应,化学产率和立体选择性高,合成特定的产物具有抗HepG2肿瘤细胞增殖活性,适合于此类发卡林醇类化合物的制备及规模化生产。
Description
技术领域
本发明属于医药化工领域,具体地说,涉及氨基醇配体不对称催化合成手性发卡林醇类似物及其合成方法和应用。
背景技术
手性发卡林醇类化合物具有共轭二炔醇类结构,在抗肿瘤,神经保护,抗真菌和抗炎等方面有显著的生物活性,具有巨大的潜在研究价值。其特定构型和其生物活性之间存在很大关系,但由于受到该类化合物结构种类的限制,其生物活性也受到限制,例如天然结构的发卡林醇对HepG2肝癌细胞没有抗增殖活性。
发卡林醇类化合物主要来源于天然植物,如人参、三七、芹菜和胡萝卜等提取物,但植物中此类化合物的含量低、分离困难、成本高,导致提取的法卡林醇类似物价格昂贵,且所需该类化合物结构种类受到限制。
目前,对手性共轭二炔醇类化合物的化学合成主要包括二种方法:一种常用方法是先制备关键中间体手性炔丙醇,再通过炔丙醇与单炔烃之间的偶联反应来合成手性二炔醇类似物;另一种方法是直接通过端基1,3-二炔类化合物对羰基化合物的不对称加成反应合成。后者能在新碳-碳键形成的同时形成手性中心,在操作步骤上更为快捷;但是由于两个碳-碳三键共轭相连,其反应活性限制了在化学合成中的应用。
此外,通过端基1,3-二炔类化合物对醛的不对称加成反应合成发卡林醇类化合物的催化体系主要有两个:一个是手性氨基醇配体催化体系,另一个是手性BINOL(联二萘酚)催化体系;但这两个体系在高对映选择性上和在醛底物适用范围上均有限,例如已有的催化体系均未能在邻位或间位上有卤素取代的苯甲醛底物上发生加成反应,取得相应的光学活性产物。
发明内容
为了解决上述问题,本发明提供一种氨基醇配体高选择性催化合成手性发卡林醇类似物新方法。采用该方法可解决天然来源的手性二炔醇类化合物在植物中含量低、提取分离困难、成本高,以及化学合成方法中结构种类和生物活性受限的问题。
本发明所采用的技术方案如下。
一种手性发卡林醇类似物,其结构通式I如下:
R1选自三异丙基硅基、正己烷基;
R2选自如下取代基中的一种:
其中,X1选自F、Cl、Br等中的一种;
X2选自F、Cl、OCH3中的一种;
n为1或2;
手性炔醇第5号碳原子构型为R或S构型。
进一步优选地,所述手性发卡林醇类似物优选下列结构:
本发明还提供一种手性发卡林醇类似物的合成方法,包括:常温下,在氨基醇配体、金属试剂、有机碱、有机溶剂组成的体系内,端基1,3-二炔类化合物对醛底物进行不对称加成反应。
进一步地,所述氨基醇配体、金属试剂、有机碱的摩尔比为(3.0-0.5):(3.0-0.5):(3.0-0.5);优选(0.5-1.5):(0.5-1.5):(1-2);进一步优选为1.1:1:1.5。
更进一步,所述端基1,3-二炔类化合物与氨基醇配体、金属试剂、有机碱、醛底物的摩尔比为(3.0-0.5):(3.0-0.5):(3.0-0.5):(3.0-0.5):(3.0-0.5);优选(1-1.5):(0.5-1.5):(0.5-1.5):(1-2):(0.5-1.5);进一步优选为1.2:1.1:1:1.5:1。
进一步地,所述氨基醇配体选自如下物质中的一种或多种:
(1)(1S,2S)-2-氨基-3-(4-硝基苯)丙烷-1,3-二醇;
(2)(1S,2S)-N,N-二甲氨基-3-(4-硝基苯)丙烷-1,3二醇;
(3)(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇;
(4)(1S,2S)-3-(三苯甲基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇;
(5)(1S,2S)-N,N-二正丁氨基-3-(4-硝基苯)丙烷-1,3二醇;
(6)(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二正丁氨基-1-(4-硝基苯)丙烷-1-醇;
(7)(1S,2R)-2-二甲基氨基-苯丙基-1-醇;
其中,所述(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇由如下方法制得:
(1)将(1S,2S)-2-氨基-3-(4-硝基苯)丙烷-1,3-二醇,甲醛和甲酸混合,回流;在减压条件下,去除溶剂,滤渣调节pH为中性,再萃取,除溶剂,浓缩液用三氧化二铝层析柱分离纯化,得到(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇;
(2)在氮气条件下,向含有(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇的CH2Cl2溶液中加入TBDMSCL,咪唑和催化剂量的DMPA;在室温条件下,反应过夜;反应液倒入水中,调节pH=8;水相用CH2Cl2萃取,收集有机相,加入碳酸钾饱和溶液,干燥,过滤,去除溶剂,浓缩液分离纯化,得到氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇。
进一步地,所述醛底物为芳基醛底物或脂肪醛底物,优选被F、Cl、OCH3取代的苯甲醛,进一步优选为2-氟苯甲醛、2-氯苯甲醛或3-甲氧基苯甲醛。
进一步地,所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、氯仿、乙醚、乙酸乙酯或正己烷中的任意一种或多种。
进一步地,所述金属试剂选自二甲基锌、二乙基锌、三氟甲磺酸锌、三氟甲磺酸铜、三氟甲磺酸钴中的一种或多种。
进一步地,所述有机碱选自1,4-二甲基哌嗪、二环己基胺、六甲基磷酰三胺、乙二胺、三乙胺、吡啶、氮甲基吡啶中的一种或多种。
进一步地,所述端基1,3-二炔类化合物选自:1-(三异丙基硅基)-1,3-丁二炔和/或1-(正己烷基)-1,3-丁二炔。
所述1-(三异丙基硅基)-1,3-丁二炔由如下方法制得:
(1)0℃下,将溴滴加到饱和KOH水溶液中,搅拌,加入2-甲基-3-丁炔-2-醇,继续搅拌;萃取,干燥,蒸去溶剂,硅胶柱层析分离得到4-溴2-甲基丁-3-炔-2醇;
(2)将CuCl加入到丁胺水溶液中,加入盐酸羟胺及三异丙基硅基乙炔进行反应,反应结束后置于冰浴冷却;
(3)将步骤(1)所得加入步骤(2)所得体系中,于0℃反应,继续搅拌,并每隔2分钟加入盐酸羟胺;萃取,洗涤,干燥,分离得到2-甲基-6-三异丙基-己3,5-二炔-2-醇;
(4)将2-甲基-6-三异丙基-己3,5-二炔-2-醇置于含KOH的甲苯溶液中回流,除去溶剂,分离得到1-(三异丙基硅基)-1,3-丁二炔。
进一步地,所述不对称加成反应是在干燥空气中进行,反应时间为0.5~24小时。
作为本发明优选的实施方式之一,所述手性发卡林醇类似物的合成方法,包括:
(1)常温下,将1-(三异丙基硅基)-1,3-丁二炔或1-(正己烷基)-1,3-丁二炔、氨基醇配体、金属试剂和有机碱按一定比例在有机溶剂中混合,室温搅拌;
(2)加入芳基醛或脂肪醛底物,室温再搅拌数小时,即得。
反应结束后,可用饱和氯化铵溶液淬灭,并采用常规后处理程序包括干燥、过滤和浓缩;经柱层析分离纯化,手性HPLC验证以及旋光测定后,获得光学活性发卡林醇类似物,该类型化合物具有抗肝癌细胞HepG2活性。
作为本发明优选的另一实施方式,所述手性发卡林醇类似物的合成方法,包括:
(1)常温下,将三异丙基硅基1,3-丁二炔、氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇、金属试剂三氟甲磺酸锌和有机碱三乙胺按比例在有机溶剂中混合,室温搅拌;
(2)加入醛底物,室温搅拌,即得;
所述醛底物选自2-氟苯甲醛、2-氟苯甲醛或3-甲氧基苯甲醛中的一种。
本发明还提供上述手性发卡林醇类似物在抗HepG2肝癌细胞方面的应用;
和/或,所述手性发卡林醇类似物在制备抗HepG2肝癌细胞药物中的应用。
本发明所述方案取得的有益效果如下:
(1)本发明通过混合端基1,3-二炔类化合物、氨基醇配体、金属试剂和有机碱后,对相应芳香醛或脂肪醛进行不对称加成反应,高产率高选择性地合成系列特定构型的手性发卡林醇类似物。该类型特定手性发卡林醇类似物比天然发卡林醇具有更强抗HepG2肿瘤细胞活性。
(2)本发明所述的合成方法反应条件温和(室温反应),适合特定底物反应,化学产率和立体选择性高,合成特定的产物具有强的抗HepG2肿瘤细胞活性,适合于此类发卡林醇类化合物的制备及规模化生产。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
若未特别指明,实施例中所用的技术手段为本领域技术人员所熟知的常规手段,所用原料均为市售商品。
以下实施例中使用的金属试剂、有机碱、醛等均购自阿拉丁试剂网、探索平台、伊诺凯、安耐吉试剂公司、北京百灵威科技有限公司等。
实施例1:(S)-1-(2-氟苯基)-5-(三异丙基硅基)-戊烷-2,4-二炔-1-醇,即S-1的制备
1、1-(三异丙基硅基)-1,3-丁二炔的制备
0℃下,将溴5mL(97.6mmol)滴加到饱和KOH水溶液中搅拌30分钟后,加入2-甲基-3-丁炔-2-醇10mL(108.2mmol)并继续搅拌30分钟。反应混合物用乙醚萃取后干燥,蒸去溶剂,硅胶柱层析分离得到4-溴2-甲基丁-3-炔-2醇黄色油状液体待用,收率90%。
将CuCl加入到丁胺水溶液中,加入10g盐酸羟胺及三异丙基硅基乙炔40.3g(220.8mmol)后进行反应,反应结束后置于冰浴冷却。向上述反应体系中加入4-溴2-甲基丁-3-炔-2醇30.0g(184.0mmol)后,于0℃反应,继续搅拌,并每隔2分钟加入2g盐酸羟胺。反应2小时后,用乙醚萃取。合并有机相并用饱和氯化钠溶液洗涤,干燥后硅胶柱层析分离得到2-甲基-6-三异丙基-己3,5-二炔-2-醇黄色油状液体,收率89%。
将2-甲基-6-三异丙基-己3,5-二炔-2-醇置于含KOH的甲苯溶液中回流4小时,除去溶剂后经柱层析分离得到1-(三异丙基硅基)-1,3-丁二炔浅黄色液体,收率89%,1H NMR(400MHz,CDCl3):δ2.07(s,1H),1.09(s,21H)。
2、氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇的制备
(1S,2S)-2-氨基-3-(4-硝基苯)丙烷-1,3-二醇(1)(5g,23.6mmol),甲醛(37-40%,7.5mL)和甲酸(98%,10mL)加入到25mL的烧瓶中回流8h。在减压条件下去除溶剂,滤渣使用1N氢氧化钠(30mL)调节PH为中性,再用CH2Cl2(3×30mL)萃取。除溶剂,浓缩液用三氧化二铝层析柱分离纯化(CH2Cl2/CH2OH=10:1),得到棕色的液体为(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇(2),5.2g,产率93%。1H NMR(400MHz,CDCl3)δ8.20(d,J=7.9Hz,2H),7.59(d,J=8.0Hz,2H),4.58(d,J=9.6Hz,1H),3.60(s,2H),2.56(d,J=19.3Hz,9H).13C NMR(100MHz,CDCl3)δ149.98,147.53,128.02,123.64,71.28,69.87,57.81,41.61.
在氮气条件下,(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇(2)(1.95g,8.1mmol)的CH2Cl2溶液(30mL)中,加入TBDMSCL(1.28g,8.5mmol),咪唑(1.4g,20.6mmol)和催化剂量的DMPA(10mg),在室温条件下,反应过夜。反应液倒入20mL水中,用低温的盐酸(0.5M)调节PH=8。水相用CH2Cl2(2×10mL)萃取,收集有机相,加入碳酸钾饱和溶液,无水硫酸钠干燥,过滤。去除溶剂后,浓缩液硅胶柱(CH2Cl2/CH3OH=20:1)分离纯化后为棕色油状液体产物氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇(3),2.07g,产率90%。1H NMR(400MHz,CDCl3)δ8.40(d,J=8.1Hz,2H),7.80(d,J=7.9Hz,2H),4.83(d,J=9.6Hz,1H),3.85(d,J=11.2Hz,1H),3.67(d,J=3.3Hz,1H),2.69(s,7H),1.07(s,9H),0.17(s,6H).13C NMR(100MHz,CDCl3)δ150.29,147.45,128.11,123.45,71.42,69.07,57.11,41.77,25.79,17.99,-5.75.
3、(S)-1-(2-氟苯基)-5-(三异丙基硅基)-戊烷-2,4-二炔-1-醇,即S-1的制备
将氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇(3)(1.1equiv)、三氟甲磺酸锌(1.0equiv,181mg)、三乙胺(1.5equiv,104μL)、三异丙基硅基1,3-丁二炔(1.2equiv,0.6mL,150μL)加入到10mL支管中,然后加入1mL二氯甲烷,室温下搅拌0.5h;
再加入2-氟苯甲醛(1equiv,0.5mmol),室温下搅拌24h,反应最后用饱和NH4Cl淬灭,抽滤,CH2Cl2(3×5mL)萃取,有机相用无水硫酸钠干燥,之后再抽滤,除溶剂得粗品,柱层析(300~400目,PE/EA=10:1)得到产物(S)-1-(2-氟苯基)-5-(三异丙基硅基)-戊烷-2,4-二炔-1-醇,即S-1,化学收率99%。
产物经HPLC分析检测,采用手性Chiracel AD-H柱子,流动相正己烷/异丙醇为90/10,流速1mL/min,检测波长254nm,保留时间为t minor=9.73min,t major=10.44min,对映选择性ee值为96%,旋光值为[α]D 20=-18.9(c=1.10,CHCl3)。
1H NMR(400MHz,CDCl3)δ7.63(s,1H),7.35(s,1H),7.20(d,J=4.7Hz,1H),7.09(d,J=8.7Hz,1H),5.80(s,1H),2.42(s,1H),1.08(s,21H).13C NMR(100MHz,CDCl3)δ161.28,158.81,130.62,130.53,128.45,128.42,124.56,124.53,115.85,115.65,88.59,86.15,74.45,71.77,59.49,59.44,18.53,11.21。
4、S-1的抗HepG2肿瘤细胞活性评价
HepG2肿瘤细胞培养液为DMEM高糖培养基,胎牛血清,青霉素-链霉素溶液,配制比例依次为10:1:89。在超净工作台上取对数生长期的细胞,用无菌吸管吸出瓶内旧培养液,PBS缓冲液清洗2次,用胰蛋白酶消化液1.5ml消化HepG2细胞2min左右,倒置显微镜下观察细胞,当细胞回缩变圆、间隙增大,加4ml各自对应的培养液终止消化。细胞悬液加入10ml无菌离心管中,离心机离心后弃上清液,加入4ml培养液吹打成细胞悬液,吸取适量细胞悬液于细胞计数板。倒置显微镜下观察细胞计数板上4个大格子里的细胞数目,细胞的密度按照下列计算公式计算:细胞密度=(4大格细胞数目之和/4)×10000,调节细胞种板密度为4-60000个/ml于细胞加样槽,用3ml无菌吸管吹打,用100μl的移液枪加100μl细胞悬液于96孔板,每加7孔,吹打50-60次,再继续加另外的孔,周围一圈加100μl的PBS。细胞最终种板密度为4000-6000个/孔,将96孔板放入37℃、5%CO2培养箱中常规培养。
准确称量样品S-1质量16.4毫克,加入DMSO体积数为248微升,配置成为母液,放入超净工作台,用注射器吸取,过滤到一个无菌EP管中,标记,封口胶封口,4℃冰箱保存。用10μl的移液枪吸取上述母液10μl,用纯培养基稀释,涡旋震荡仪震荡,为工作液,用10μl的移液枪吸取过滤后的工作液,用纯培养基稀释,涡旋震荡仪震荡,即补加液。样品的稀释采用现用现配,96孔板在37℃,5%CO2培养箱中培养23h-25h后,加入配好的样品,用羊水负压器吸除每孔培养液,向每孔加入药品100μl,药品复孔数目为2个和4个。加完样品后放入培养箱中培养47h-49h,用纯培养基调节CCK-8的浓度,调节成7%浓度的CCK-8工作液。用羊水负压器吸除每孔含药培养基,向每孔加入100μLCCK-8工作液,放入培养箱中孵育40min,于酶标仪上检测,检测波长450nm,测定各孔吸光度OD值。
用excel 2016和graphpad prism 5.01算出,S-1样品对HepG2肿瘤细胞的IC50值(165.6±1.1uM)。
实施例2:(S)-1-(2-氯苯基)-5-(三异丙基硅基)-戊烷-2,4-二炔-1-醇,即S-2的制备
1、1-(三异丙基硅基)-1,3-丁二炔的制备
同实施例1的描述。
2、氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇(3)的制备
同实施例1的描述。
3、(S)-1-(2-氯苯基)-5-(三异丙基硅基)-戊烷-2,4-二炔-1-醇,即S-2的制备
同实施例1的描述,所加入底物为2-氯苯甲醛(1equiv,0.5mmol),得到产物为(S)-1-(2-氯苯基)-5-(三异丙基硅基)-戊烷-2,4-二炔-1-醇,即S-2,化学收率82%。
产物通过HPLC分析检测,采用手性Chiralcel OD柱子,流动相正己烷/异丙醇为95/5,流速1mL/min,检测波长220nm,保留时间为tmajor=14.3min,tminor=9.7min,对映选择性ee值为92%,旋光值为[α]D 20=-63.8(c=1.01,CHCl3)。
1H NMR(400MHz,CDCl3)δ7.73(d,J=5.7Hz,1H),7.38(s,1H),7.36–7.28(m,2H),5.89(d,J=3.7Hz,1H),2.52(s,1H),1.08(s,21H).13C NMR(101MHz,CDCl3)δ136.99,132.78,130.11,129.93,128.58,127.51,88.76,86.20,74.58,71.96,62.45,18.65,11.33。
4、S-2的抗HepG2肿瘤细胞活性评价
同实施例1的描述。
准确称量S-2质量为19.5毫克,加入DMSO的体积数为281微升,测定S-2样品对HepG2肿瘤细胞的IC50值(110.9±1.0uM)。
实施例3:(R)-1-(3-甲氧基苯基)十一烷-2,4-二炔-1-醇,即R-16的制备
1、1-(正己烷基)-1,3-丁二炔的制备
替换相应的原料,制备方法同实施例1的描述。
实施例1中所述偶合炔烃为1-辛炔,产率89%。
1H NMR(400MHz,CDCl3):δ2.26(t,2H,J=7.0Hz),1.95(s,1H),1.34(m,6H),0.89(t,3H,J=6.6Hz),1.54(p,2H,J=6.6Hz)。
2、氨基醇配体(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇(3)的制备
同实施例1的描述。
3、(R)-1-(3-甲氧基苯基)十一烷-2,4-二炔-1-醇,即R-16制备
同实施例1的描述,所加入底物为3-甲氧基苯甲醛(1equiv,0.5mmol),得到产物为(S)-1-(3-甲氧基苯基)十一烷-2,4-二炔-1-醇,即R-16,产率80%。
产物通过HPLC分析检测,采用手性Chiralcel OD柱,流动相正己烷/异丙醇为80/20,流速0.9mL/min,检测波长254nm,保留时间为tmajor=7.9min,tminor=5.8min,ee值为94%,旋光值为[α]D 20=-11.1(c=1.13,CHCl3)。
1H NMR(400MHz,CDCl3):δ7.29(s,1H),7.09(d,J=8.8Hz,2H),6.88(d,J=6.7Hz,1H),5.49(s,1H),3.83(s,3H),2.29(d,J=5.6Hz,2H),2.21(s,1H),1.54(d,J=6.1Hz,1H),1.43–1.21(m,6H),0.89(d,J=5.1Hz,3H);13C NMR(101MHz,CDCl3):δ159.85,141.45,129.78,118.89,114.28,112.00,82.82,74.53,71.78,64.98,64.32,55.34,31.28,28.53,28.08,22.53,19.33,14.08。
4、R-16的抗HepG2肿瘤细胞活性评价
同实施例1的描述。
准确称量R-16质量为14.4毫克,加入DMSO的体积数为265微升,测定R-16药品对HepG2肿瘤细胞的IC50值(103.0±1.1μM)。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
Claims (5)
1.一种手性发卡林醇类似物的合成方法,其特征在于,包括:常温下,在由氨基醇配体、金属试剂、有机碱、有机溶剂组成的催化体系内,端基1,3-二炔类化合物对醛底物进行不对称加成反应;
所述氨基醇配体为(1S,2S)-3-(叔-丁基二甲基硅醇基)-2-N,N-二甲氨基-1-(4-硝基苯)丙烷-1-醇;
所述金属试剂选自三氟甲磺酸锌;
所述醛底物为2-氟苯甲醛、2-氯苯甲醛或3-甲氧基苯甲醛;
所述端基1,3-二炔类化合物选自:1-(三异丙基硅基)-1,3-丁二炔和/或1-(正己烷基)-1,3-丁二炔;
所述氨基醇配体、金属试剂、有机碱的摩尔比为(3.0-0.5):(3.0-0.5):(3.0-0.5)。
2.根据权利要求1所述的合成方法,其特征在于,所述氨基醇配体、金属试剂、有机碱的摩尔比为(0.5-1.5):(0.5-1.5):(1-2)。
3.根据权利要求1或2任一所述的合成方法,其特征在于,所述有机溶剂选自甲苯、二氯甲烷、四氢呋喃、氯仿、乙醚、乙酸乙酯或正己烷中的任意一种或多种;
所述有机碱选自1,4-二甲基哌嗪、二环己基胺、六甲基磷酰三胺、乙二胺、三乙胺、吡啶、氮甲基吡啶中的一种或多种。
4.根据权利要求1所述的合成方法,其特征在于,所述1-(三异丙基硅基)-1,3-丁二炔由如下方法制得:
(1)0℃下,将溴滴加到饱和KOH水溶液中,搅拌,加入2-甲基-3-丁炔-2-醇,继续搅拌;萃取,干燥,蒸去溶剂,硅胶柱层析分离得到4-溴2-甲基丁-3-炔-2醇;
(2)将CuCl加入到丁胺水溶液中,加入盐酸羟胺及三异丙基硅基乙炔进行反应,反应结束后置于冰浴冷却;
(3)将步骤(1)所得加入步骤(2)所得体系中,于0℃反应,继续搅拌,并每隔2分钟加入盐酸羟胺;萃取,洗涤,干燥,分离得到2-甲基-6-三异丙基-己3,5-二炔-2-醇;
(4)将2-甲基-6-三异丙基-己3,5-二炔-2-醇置于含KOH的甲苯溶液中回流,除去溶剂,分离得到1-(三异丙基硅基)-1,3-丁二炔。
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