CN106831348A - 8,11,13‑罗汉松科‑13‑醇及其中间体的制备方法 - Google Patents
8,11,13‑罗汉松科‑13‑醇及其中间体的制备方法 Download PDFInfo
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- CN106831348A CN106831348A CN201710053968.4A CN201710053968A CN106831348A CN 106831348 A CN106831348 A CN 106831348A CN 201710053968 A CN201710053968 A CN 201710053968A CN 106831348 A CN106831348 A CN 106831348A
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- FCMKFNXOHUYWRU-UHFFFAOYSA-N [Cl].[Cr] Chemical compound [Cl].[Cr] FCMKFNXOHUYWRU-UHFFFAOYSA-N 0.000 description 1
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 1
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- 238000005893 bromination reaction Methods 0.000 description 1
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- 229940125797 compound 12 Drugs 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 239000004519 grease Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
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- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
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- 238000005556 structure-activity relationship Methods 0.000 description 1
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Classifications
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- C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
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- C07C1/00—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon
- C07C1/32—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen
- C07C1/321—Preparation of hydrocarbons from one or more compounds, none of them being a hydrocarbon starting from compounds containing hetero-atoms other than or in addition to oxygen or halogen the hetero-atom being a non-metal atom
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Abstract
本发明公开了制备化合物9所示8,11,13‑罗汉松科‑13‑醇,或其药学上可接受的盐,或其溶剂合物的方法,所述方法包括以下步骤:h、在氧化剂和酸的存在下,以化合物8为原料制备得到化合物9;其中,氧化剂选自双氧水或过氧化叔丁醇,酸选自H2SO4、对甲基苯磺酸。本发明的制备化合物9的方法,方法简便,收率高,易于放大,适合于工业化大规模生产。
Description
技术领域
本发明涉及8,11,13-罗汉松科-13-醇及其中间体的制备方法。
背景技术
松香是一种重要的化工原料,广泛应用于肥皂、造纸、油漆、橡胶等行业。松香是多种树脂酸和少量脂肪酸以及中性物质的混合物,其中松香酸是主要成分,具有三环二萜结构,松香酸在工业上具有广泛的应用。近年来,研究表明松香酸及其衍生物具有重要的生物学功能。
发明内容
为解决上述问题,本发明提供了一种制备化合物9所示8,11,13-罗汉松科-13-醇,或其药学上可接受的盐,或其溶剂合物的方法,所述方法包括以下步骤:
h、在氧化剂和酸的存在下,以化合物8为原料制备得到化合物9;
其中,氧化剂选自双氧水或过氧化叔丁醇,酸选自H2SO4、对甲基苯磺酸。
进一步地,氧化剂选自过氧化叔丁醇,酸选自H2SO4。
进一步地,过氧化叔丁醇与化合物8的摩尔比为1~3:1,优选3:1。
进一步地,所述步骤h中,溶剂为二氯甲烷、四氢呋喃、乙酸或水。
进一步地,所述步骤h中,反应的温度为0~80℃,优选50℃。
进一步地,所述方法还包括下述步骤:
(1)将化合物1转化为化合物5;
(2)将化合物5转化为化合物8。
进一步地,所述步骤(1)包括以下步骤:
a、将化合物1与溴化氢反应,制备得到化合物2;
b、在碱性环境下,将化合物2转化为化合物3;
c、将化合物3转化为化合物4;
d、将化合物4转化为化合物5。
进一步地,所述步骤a中,溶剂为乙酸,优选的反应温度为20~30℃;
所述步骤b中,所用的碱为LiOH,溶剂为二甲基甲酰胺;优选的反应温度为80℃;
所述步骤c中,包括将化合物3与碘乙烷在碱性环境下反应的步骤;优选的,所用的碱为碳酸钾,溶剂为丙酮;进一步优选的反应温度为60℃;
所述步骤d中,包括将化合物4与LiAlH4反应的步骤;优选的,溶剂为四氢呋喃;进一步优选的反应温度为20~30℃。
进一步地,所述步骤(2)包括以下步骤:
e、将化合物5转化为化合物6;
f、将化合物6转化为化合物7;
g、将化合物7转化为化合物8。
进一步地,所述步骤e中,包括将化合物5与对甲基苯磺酰氯反应的步骤;优选的,所述的溶剂选自二氯甲烷、吡啶、四氢呋喃、乙腈,更优选吡啶;进一步优选的反应温度为20~30℃;
所述步骤f中,包括将化合物6与碘化钠和锌粉反应的步骤;优选的,所述的溶剂选自N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰三胺,优选六甲基磷酰三胺;进一步优选的反应温度为105℃;
所述步骤g中,包括将化合物7与SeO2反应的步骤;优选的溶剂选自二氯甲烷、四氢呋喃、乙腈,更优选四氢呋喃;进一步优选的反应温度为0℃。
本发明的制备化合物9的方法,方法简便,收率高,易于放大,适合于工业化大规模生产。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
下述实施例中:
松香酸1购于安耐吉化学;氢氧化锂、氢化铝锂、石油醚、乙酸乙酯、二氯甲烷、甲醇、丙酮、吡啶、四氢呋喃、碳酸钾、对甲苯磺酰氯、过氧化叔丁醇、冰醋酸、碘乙烷、N,N-二甲基甲酰胺、33%氢溴酸等购于成都市科龙化工试剂厂;锌粉、碘化钠、六甲基磷酰三胺、氯铬酸吡啶嗡盐、二氧化硒等试剂购于成都瑞欧克科技有限公司。试验中所应用的试剂除特殊说明外,其余均为市面所售分析纯,无水试剂与溶剂均按要求处理;薄层层析所用的硅胶预制板为青岛海洋化工有限公司所生产的硅胶GF254预制板;快速硅胶柱层析采用青岛海洋化工厂生产的硅胶H。
实施例1
化合物8的合成路线如下:
(a)33%HBr/AcOH,rt.,6h,81%;(b)LiOH,N,N-二甲基甲酰胺,80℃,7h,100%;(c)EtI,K2CO3,丙酮,60℃,3h,98%;(d)LiAlH4,四氢呋喃,rt.,3h,92%;(e)TsCl,吡啶,rt,5h,80%;(f)Zn,NaI,六甲基磷酰三胺,105℃,6h,75%;(g)SeO2,四氢呋喃,0℃,5-10h,80%;(h)t-BuOOH,H2SO4,50℃,1h,90%.
1、二溴化物(2)的合成
将化合物(1)(20.00g,66.40mmol)溶于64ml冰醋酸中,冰浴下滴加33%HBr/AcOH溶液(64ml,132.80mmol),室温搅拌6h,析出大量固体,TLC显示原料完全反应。过滤,滤饼经冰醋酸洗涤至近白色,真空干燥过夜,得固体(25.00g,收率81%),未经纯化直接投下一步。
2、脱溴化物(3)的合成
将二溴化物(2)(12.00g,25.88mmol)溶于244ml N,N-二甲基甲酰胺中,在常温搅拌下加入LiOH(2.64g,64.72mmol),升温至80℃,反应液基本呈无色透明,随着反应的进行,反应液又变为深褐色,反应7h,TLC显示完全反应。旋去DMF,加水用稀盐酸将反应液的pH调至2~3,用乙酸乙酯萃取3次,用饱和食盐水洗涤,干燥,浓缩,得淡黄色油状物,真空干燥过夜,收率定量。未经纯化直接投下一步。
3、化合物(4)的合成
将化合物(3)(15.00g,49.67mmol)用150ml丙酮溶解,常温下加入K2CO3(20.00g),搅拌反应15min。将碘乙烷(11.12ml,149.01mmol)逐滴加入到反应液中,升温至60℃,随着反应的进行反应液变为乳黄色。反应24h,TLC显示完全反应。旋尽丙酮,加水,用乙酸乙酯提取3次,用饱和食盐水洗涤,干燥,浓缩,粗品经柱层析(PE:EA=20:1)纯化得淡黄色固体(16.15g,收率98%)。
4、化合物5的合成
将化合物(4)(16.00g,48.78mmol)用50ml THF溶解,在冰浴搅拌下加入到LiAlH4(7.00mg,195.12mmol)的50ml THF混合液中,有气体产生,室温搅拌反应3h,TLC显示完全反应。冰浴下用稀盐酸将pH调至6,过滤。旋尽滤液,加水,用乙酸乙酯提取3次,用饱和食盐水洗涤,干燥,浓缩,得无色透明油状物(13.45g,收率92%)。
5、化合物6的合成
将化合物(5)(13.00g,45.14mmol)和TsCl(52.00g,270.8mmol)在100ml吡啶中室温搅拌反应5h,TLC显示完全反应。旋去吡啶,加水,用二氯甲烷提取3次,用饱和食盐水洗涤,干燥,浓缩,粗品经柱层析(PE:EA=60:1)纯化得无色透明透明油状物(15.87g,收率80%)。
6、化合物7的合成
将化合物(6)(0.05g,0.11mmol)的1ml六甲基磷酰三胺溶液逐滴加入到NaI(0.08g,0.54mmol)和Zn(0.07g,1.07mmol)中,升温至105℃搅拌反应6h,TLC显示完全反应。用石油醚(乙酸乙酯不好分层)提取3次,用饱和食盐水洗涤,干燥,浓缩,粗品经柱层析(PE:EA=60:1)纯化得无色透明油状物(200mg,收率75%)。
7、化合物8的合成
将化合物(7)(0.37g,1.36mmol)溶于265ml THF中,原料完全溶解,在0℃下加入SeO2(300mg,2.72mmol)显示多数原料反应完全,有少量大极性杂质生成。过滤,滤液用乙酸乙酯提取3次,用饱和食盐水洗涤,干燥,浓缩,粗品经柱层析(PE:EA=5:1)纯化得淡黄色油状物(310mg,收率80%)。
1H NMR(400MHz,CDCl3)δ7.80(d,J=8.2Hz,1H),7.37(d,J=8.0Hz,1H),7.22(s,1H),5.32(s,1H),3.85(d,J=9.3Hz,1H),3.62(d,J=9.4Hz,1H),2.93~2.73(m,2H),2.48(s,3H),1.71(m,2H),1.60(s,3H),1.58(s,3H),1.51~1.30(m,6H),1.20(s,3H),0.91(s,3H).13C NMR(101MHz,CDCl3)δ147.84,144.70,1f34.55,133.00,127.92,124.82,72.29,43.52,38.01,37.39,37.18,37.09,35.02,31.63,29.96,29.71,25.15,21.67,18.80,18.30,17.14.HRMS(AP-ESI)Calcd.for C20H30NaO:309.2195(M+Na)+.Found:309.2185.
8、化合物9的合成
将化合物8(0.11g,0.40mmol)溶于1.6ml AcOH中,在室温搅拌下依次加入t-BuOOH(115.2μL,1.20mmol)和H2SO4(2.0μL,0.04mmol),室温搅拌24h。TLC显示完全反应。旋去溶剂,用二氯甲烷提取3次,有机层用饱和NaHCO3洗涤三次,又取饱和NaHCO3层用稀盐酸将pH调至3,再用二氯甲烷提取水层两次,干燥,浓缩,粗品经柱层析(PE:EA=10:1)纯化得淡黄色油状物(88mg,收率90%)。
1H NMR(400MHz,CDCl3)δ7.14(d,J=8.6Hz,1H),6.64(dd,J=8.5,2.7Hz,1H),6.53(d,J=2.6Hz,1H),4.77(s,1H),3.02~2.65(m,2H),1.88(m,1H)1.81~1.56(m,4H),1.54~1.23(m,4H),1.19(s,3H),0.97(s,3H),0.95(s,3H).13C NMR(300MHz,CDCl3)δ148.12,138.14,132.15,120.92,110.14,108.16,45.84,36.98,34.31,32.55,28.66,28.59,25.73,20.23,16.86,14.59,14.25HRMS(AP-ESI)Calcd.for C17H25O:245.1878(M+H)+.Found:245.1895.
化合物9的合成,过氧化重排试剂可为H2O2、p-TsOH,t-BuOOH、H2SO4,最优为t-BuOOH、H2SO4;溶剂可用THF、冰醋酸,以冰醋酸为最优;t-BuOOH的当量可为1eq、2eq、3eq,以3eq为最优。结果如表1所示。
表1化合物9的合成条件摸索
序号 | 氧化重排试剂 | 酸 | 溶剂 | 收率 |
1 | 过氧化氢(3eq) | 对甲苯磺酸(0.5eq) | 四氢呋喃 | 70% |
2 | 过氧化氢(2eq) | 对甲苯磺酸(0.5eq) | 冰醋酸 | 46% |
3 | 过氧化氢(1eq) | 对甲苯磺酸(0.5eq) | 冰醋酸 | 34% |
4 | 过氧化氢(3eq) | 对甲苯磺酸(0.5eq) | 冰醋酸 | 79% |
5 | 过氧化叔丁醇(3eq) | 浓硫酸(0.1eq) | 冰醋酸 | 90% |
6 | 过氧化叔丁醇(2eq) | 浓硫酸(0.1eq) | 冰醋酸 | 55% |
7 | 过氧化叔丁醇(1eq) | 浓硫酸(0.1eq) | 冰醋酸 | 48% |
8 | 过氧化叔丁醇(3eq) | 浓硫酸(0.1eq) | 四氢呋喃 | 79% |
对比例1化合物8的制备路线
发明人探索了多条化合物8的制备路线,其中的一条制备路线如下:
(a)33%HBr/AcOH,rt.,6h,88%;(b)LiOH,二甲基甲酰胺,80℃,7h,100%;(c)SeO2,四氢呋喃,0℃,5h,80%;(d)EtI,K2CO3,丙酮,60℃,3h,92%;(e)LiAlH4,四氢呋喃,rt.,3h,84%;(f)氯铬酸吡啶嗡盐,CH2Cl2,rt.,4h,90%.
具体为:
化合物2的合成:将松香酸1溶于溶剂中,再加入溴化氢,松香酸:溴化氢的摩尔比为1:2,于常温下搅拌反应5h~7h,过滤,用结冰状的冰醋酸洗涤,洗涤后真空干燥12小时,得中间体2;
化合物3的合成:将步骤(a)中得到得中间体2溶于溶剂中,在常温下加入碱,中间体2与氢氧根离子摩尔比为1:2.5,升温至80℃搅拌反应4h~6h,加稀盐酸将pH调至2~3,萃取、洗涤、浓缩,得到中间体3;
化合物10的合成:将步骤(b)中得到得中间体3溶于溶剂中,在0℃搅拌下加入二氧化硒,中间体3:二氧化硒的摩尔比为1:2~8,0℃下恒温搅拌反应4h~12h,过滤、萃取、洗涤、浓缩,得到中间体4;
化合物11的合成:将步骤(c)中得到得中间体4溶于丙酮中,在常温搅拌下加入碱,搅拌十五分钟,在加入碘乙烷,中间体10:碘乙烷的摩尔比为1:2,升温至60℃反应4h~6h,萃取、洗涤、浓缩,得到松香酸衍生物11;
化合物12的合成:将步骤(d)得到的中间体11用四氢呋喃溶解,在冰浴搅拌下加入到四氢铝锂的四氢呋喃混合液中,中间体4:四氢铝锂的摩尔比为1:4,室温搅拌反应3h,调pH至6,过滤、萃取、洗涤、浓缩,得到松香酸衍生物12;
化合物13的合成:分别用二氯甲烷将步骤(e)得到的中间体12和氯铬酸吡啶鎓盐溶解,中间体与氯铬酸吡啶鎓盐的摩尔比为1:1.5,25℃搅拌下将中间体12的二氯甲烷溶液逐滴滴加到氯铬酸吡啶鎓盐得二氯甲烷溶液中,常温搅拌反应4h,过滤,萃取,洗涤,干燥,浓缩,纯化得松香酸衍生物13。
但是在合成过程中,从化合物13合成化合物14十分困难。采用黄鸣龙还原时,原料13基本反应完全,但点很杂没有明显的主点,且反应温度接近二甲基硅油的沸点。因此,该条路线不适合于化合物8的制备。
对比例2化合物8的制备路线
发明人探索了多条化合物8的制备路线,其中的一条制备路线如下:
(a)EtI,K2CO3,丙酮,60℃,3h,94%;(b)LiAlH4,THF,rt.,3h,84%;(c)TsCl,吡啶,rt,5h,84%;(d)Zn,NaI,六甲基磷酰三胺,105℃,6h,98%.
化合物15的合成:将松香酸1溶于丙酮中,在常温搅拌下加入碱,搅拌十五分钟,在加入碘乙烷,中间体10:碘乙烷的摩尔比为1:2,升温至60℃反应4h~6h,萃取、洗涤、浓缩,得到松香酸衍生物15;
化合物16的合成:将步骤(a)得到的中间体15用四氢呋喃溶解,在冰浴搅拌下加入到四氢铝锂的四氢呋喃混合液中,中间体15:四氢铝锂的摩尔比为1:4,室温搅拌反应3h,调pH至6,过滤、萃取、洗涤、浓缩,得到松香酸衍生物16;
化合物17的合成:将步骤(b)得到的中间体16和对甲苯磺酰氯用吡啶溶解,中间体16与对甲苯磺酰氯的摩尔比为1:5,室温搅拌反应5h。旋去吡啶,萃取、洗涤、浓缩、柱层析纯化得松香酸衍生物17;
化合物18的合成:将步骤(c)得到的中间体17用六甲基磷酰三胺溶解,逐滴加入到碘化钠和锌粉中,升温至105℃搅拌反应6h。用石油醚萃取,干燥,浓缩,柱层析纯化得松香酸衍生物18;
化合物19的合成:将步骤(d)得到的中间体18溶于冰醋酸中,冰浴下滴加33%溴化氢的冰醋酸溶液,室温搅拌,当放大投料量时反应杂质明显增多,导致产品无法从冰醋酸溶液中析出,而产品、未反应原料与杂质的极性均很小,对产品的纯化变得十分困难,收率极低。因此,该条路线不适合于化合物8的制备。
试验例本发明化合物的生物活性
应用购买的PTP1B重组蛋白(Sigma),以对硝基苯磷酸二钠(pNPP)为底物检测PTP1B活性。采用的阳性参照化合物为齐墩果酸。利用PTP1B能水解底物nNPP的磷酸酯键,得到的产物对硝基苯酚在碱性条件下于410nm处有很强的光吸收,通过直接检测410nm处光吸收的变化以观察化合物对酶活性的抑制情况,具体操作方法如下:将底物pNPP的水溶液48μL、PTP1B缓冲溶液50μL(25Mm HEPES,PH 7.2、1MmEDTA、1.5Mm DTT、50Mm NaCl)、化合物的DMSO溶液2μL依次加入96孔板中构成100μL的反应体系。37℃反应30min后,每孔加入5μL1N的NaOH水溶液,利用EnSpire酶标仪于410nm处测吸光度值。在不含待测化合物的反应液中,吸光度(At)定义为100%活性。在不含PTP1B的反应液中,吸光度(Ab)定义为0%活性。对于待测化合物,抑制率(%)=[1-(A-Ab)/(At-Ab)]×100,其中A为含待测化合物的反应液的吸光度。
表2化合物在100μM浓度下的PTP1B抑制率
以齐墩果酸OA作为阳性对照,对合成的松香酸衍生物的PTP1B抑制活性进行测定。化合物相应的PTP1B在100μM浓度下的抑制率如表1所示。实验数据表明,所合成的一系列松香酸衍生物中,大部分都具有一定的PTP1B抑制活性。通过实验结果分析构效关系,可以得出以下结论:当松香酸衍生物的C-4位为羧基时,将萜类骨架部分进行芳香化,引入羟基或叔丁醇,引入叔丁醇的化合物PTP1B抑制活性更好;而当C-4位的羧基转变为偕二甲基时,萜类骨架同时芳香化,酚羟基化合物较叔丁醇化合物抑制活性好;当松香酸衍生物的萜类骨架部分保持不变,C-4位基团的变化对于化合物抑制活性的影响不明显。
Claims (10)
1.一种制备化合物9所示8,11,13-罗汉松科-13-醇,或其药学上可接受的盐,或其溶剂合物的方法,其特征在于:所述方法包括以下步骤:
h、在氧化剂和酸的存在下,以化合物8为原料制备得到化合物9;
其中,氧化剂选自双氧水或过氧化叔丁醇,酸选自H2SO4、对甲基苯磺酸。
2.根据权利要求1所述的方法,其特征在于:氧化剂选自过氧化叔丁醇,酸选自H2SO4。
3.根据权利要求2所述的方法,其特征在于:过氧化叔丁醇与化合物8的摩尔比为1~3:1,优选3:1。
4.根据权利要求1或2所述的方法,其特征在于:所述步骤h中,溶剂为二氯甲烷、四氢呋喃、乙酸或水。
5.根据权利要求1-4任一项所述的方法,其特征在于:所述步骤h中,反应的温度为0~80℃,优选50℃。
6.根据权利要求1-5任一项所述的方法,其特征在于:所述方法还包括下述步骤:
(1)将化合物1转化为化合物5;
(2)将化合物5转化为化合物8。
7.根据权利要求6所述的方法,其特征在于:所述步骤(1)包括以下步骤:
a、将化合物1与溴化氢反应,制备得到化合物2;
b、在碱性环境下,将化合物2转化为化合物3;
c、将化合物3转化为化合物4;
d、将化合物4转化为化合物5。
8.根据权利要求7所述的方法,其特征在于:所述步骤a中,溶剂为乙酸,优选的反应温度为20~30℃;
所述步骤b中,所用的碱为LiOH,溶剂为二甲基甲酰胺;优选的反应温度为80℃;
所述步骤c中,包括将化合物3与碘乙烷在碱性环境下反应的步骤;优选的,所用的碱为碳酸钾,溶剂为丙酮;进一步优选的反应温度为60℃;
所述步骤d中,包括将化合物4与LiAlH4反应的步骤;优选的,溶剂为四氢呋喃;进一步优选的反应温度为20~30℃。
9.根据权利要求1所述的方法,其特征在于:所述步骤(2)包括以下步骤:
e、将化合物5转化为化合物6;
f、将化合物6转化为化合物7;
g、将化合物7转化为化合物8。
10.根据权利要求9所述的方法,其特征在于:所述步骤e中,包括将化合物5与对甲基苯磺酰氯反应的步骤;优选的,所述的溶剂选自二氯甲烷、吡啶、四氢呋喃、乙腈,更优选吡啶;进一步优选的反应温度为20~30℃;
所述步骤f中,包括将化合物6与碘化钠和锌粉反应的步骤;优选的,所述的溶剂选自N,N-二甲基甲酰胺、二甲亚砜、六甲基磷酰三胺,优选六甲基磷酰三胺;进一步优选的反应温度为105℃;
所述步骤g中,包括将化合物7与SeO2反应的步骤;优选的溶剂选自二氯甲烷、四氢呋喃、乙腈,更优选四氢呋喃;进一步优选的反应温度为0℃。
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