CN1944387A - 一种含有二取代金刚烷基的维甲酸类化合物制备方法 - Google Patents
一种含有二取代金刚烷基的维甲酸类化合物制备方法 Download PDFInfo
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- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
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Abstract
本发明公开了一种含有二取代金刚烷基的维甲酸类化合物制备方法，该方法包括以下步骤：将金刚醇和4－溴苯酚在5－60℃下，在卤化溶剂中与硫酸反应生成二取代的金刚烷二酚衍生物。本发明所提供了的方法可能是更具有药用前景的含有二取代金刚烷基的新型维甲酸类药物分子的合成方法，方法简单，原料易得，工艺可放大生产，得率和纯度高。
Description
一、技术领域
本发明涉及一种含有二取代金刚烷基的维甲酸类化合物制备方法。
二、背景技术
在含有金刚烷基的维甲酸类化合物中，阿达帕林(Adapalene，化合物1)是其典型代表(J.Med.Chem.，2005，48，5875-5882以及所引的文献)。阿达帕林可与对皮肤角质细胞增长与分化有调节作用的维甲酸γ受体选择性结和，调节毛囊，皮脂腺上皮细胞的分化，减少粉刺形成。也可抑制人体多形白细胞的化学趋化，抑制花生四烯酸经脂氧化反应转化为炎症介质而导致的炎性反应，改善炎性皮损。类以结构的其它维甲酸类化合物如化合物2和3还有抑制和治疗癌症的作用。
这类化合物在结构上有一共同点，即含有一个疏水单取代金刚烷基，一个芳香连接基和苯甲酸。而含有二取代金刚烷基的这类分子(化合物4)尚未见报道。这类分子是一种新型维甲酸类化合物，可能有更好的药用前途。
三、发明内容
1、发明目的：本发明的目的是提供一种新型的维甲酸类化合物制备方法。
2、技术方案：本发明所述的一种维甲酸类化合物的制备方法，包括以下步骤：将金刚醇和4-溴苯酚在5-60℃下，在卤化溶剂中与硫酸反应生成二取代的金刚烷二酚衍生物。
所述的金刚醇、4-溴苯酚、硫酸三者之间的摩尔比是1∶0.5∶0.5至1∶5∶5，最佳摩尔比是1∶1∶1至1∶2.5∶2.5。
所述的卤化溶剂是二氯甲烷、氯仿、或二氯乙烷，最佳是二氯甲烷或氯仿。
所述的温度最佳为20-40℃。
所述的金刚烷二酚衍生物，与CH3I或(CH3)2SO4反应醚化，以与(CH3)2SO4反应最为合适。
所述的金刚烷二酚醚化衍生物，形成格氏试剂，通过NiCl2(DPPE)或PdCl2(PPh3)2催化与6-溴-2-萘甲酸甲酯偶合形成金刚烷二酯衍生物，以PdCl2(PPh3)2催化最为合适。
所述的金刚烷二酯衍生物，碱性水解得到含有二取代金刚烷基的维甲酸类化合物。
3、有益效果：本发明提供了一种新的可能更具有药用前景的含有二取代金刚烷基的新型维甲酸类药物分子的合成方法，该方法简单，原料易得，工艺可放大生产，得率和纯度高。
四、具体实施方式
以下的实施例仅在于详细说明本发明，而非限制本发明。
化合物7的制备：化合物5(3.05g，0.020mol)、化合物6(8.65g，0.050mol)溶于CH2Cl2(18ml)，逐滴加入浓硫酸(1.07ml，0.020mol)，保持反应温度在25度。反应在25-30度搅拌3小时后倒入100毫升水中，用碳酸钠中和至pH 6。反应用CH2Cl2(3×100ml)萃取，洗涤，干燥，过虑，蒸干。粗产品用二甲烷和甲醇(95∶5)作溶剂，柱色谱分离得6.2g淡黄色化合物6(99.5％ HPLC)，收率65％。粗产物在氯仿和环己烷中重结晶，产率约为35％
以上反应用CH2Cl2作溶剂，反应温度在5度，收率20％。
以上反应用CHCl3作溶剂，反应温度在40度，收率40％。
以上反应用二氯乙烷作溶剂，反应温度在25度，收率35％。
以上反应用二氯乙烷作溶剂，反应温度在20度，收率35％。
以上反应用CHCl3作溶剂，反应温度在60度，收率40％。
以上反应当金刚醇、4-溴苯酚、硫酸三者之间的摩尔比是1∶1∶1时，收率45％
以上反应中，金刚醇、4-溴苯酚、硫酸三者之间的摩尔比也可以是1∶0.5∶0.5至1∶5∶5之间的任一数值，最佳是在1∶1∶1至1∶2.5∶2.5之间的数值。
1H NMR(CDCl3，400MHz)：7.33(s，1H)，7.18(d，1H)，6.55(d，1H)，4.81(s，1H)，2.42(s，1H)，2.30(s，1H)，2.19(d，2H)，2.05(d，2H)，1.79(s，1H)。
化合物8的制备：化合物7(4.78g，0.010mol)和无水碳酸钠(6.61g，0.063mol)加入无水丙酮(100ml)中。搅拌下加入(CH3)2SO4(2.0ml，0.021mol)。加热回流过夜。将反应倒入200毫升水中，用CH2Cl2(2×100ml)萃取.。有机相用1MNaOH(2×100ml)，盐水(2×100ml)洗涤，干燥，过虑。将200毫升环己烷加入，浓缩过程中形成固体，过滤得化合物84.35g(98.5％ HPLC)，收率86％。1HNMR(DMSO-d6，400MHz)：7.35(d，1H)，7.20(s，1H)，6.95(d，1H)，3.79(s，3H)，2.27(s，1H)，2.20(s，1H)，2.15(d，2H)，1.87(d，2H)，1.70(s，1H)。
化合物10的制备：化合物8(2.53g，0.0050mol)在无水THF(25ml)的溶液在氮气保护下滴入镁(0.292g，0.012mol)和少许碘中，控制温度在40度以下。滴毕反应在40度保持45分钟。制得的格氏试剂备用。
另一反应器中加入化合物9(3.18g，0.012mol)，PdCl2(PPh3)2(1.73g，0.0024mol)和无水ZnCl2(1.64g，0.012mol)以及无水THF(50ml)。搅拌加热至50-55度，1小时内加入如上所得格氏试剂。同温反应1小时。反应在冰浴中冷却，加入20毫升水，反应浓缩至糊状，在冰浴中冷却，1M HCl溶液(100ml)缓慢加入。反应用CH2Cl2(3×100ml)萃取洗涤，干燥，过滤，蒸干。粗产品用二氯甲烷和甲醇(95∶5)作溶剂，柱色谱分离得2.45g白色固体化合物10(99％ HPLC).收率68％。1H NMR(CDCl3，400MHz)：8.61(s，1H)，8.00(m，3H)，7.91(d，1H)，7.81(d，1H)，7.67(s，1H)，7.57(d，1H)，7.00(d，1H)，3.99(s，3H)，3.91(s，3H)，2.60(s，1H)，2.36(d，3H)，2.17(d，2H)，1.85(s，1H)。
化合物4的制备：化合物8(1.2g，0.0017mol)悬浮在甲醇(120ml)中，加入氢氧化钾粉末(0.34g，0.0084ml)。混合物回流2小时，蒸发至干，加入1M HCl溶液(50ml)。过滤形成的白色固体，干燥。固体在THF中重结晶得0.95g白色化合物4(99％ HPLC)。收率81％.M-：688。1H NMR(DMSO-d6，400MHz)：12.82(b，1H)，8.57(s，1H)，8.19(s，1H)，8.14(d，1H)，8.05(d，1H)，7.97(d，1H)，7.89(d，1H)，7.66(m，2H)，7.14(d，1H)，3.89(s，3H)，2.53(s，1H)，2.34(m，3H)，2.09(d，2H)，1.82(s，1H)。
Claims (6)
1、一种含有二取代金刚烷基的维甲酸类化合物制备方法，其特征是该方法包括以下步骤：将金刚醇和4-溴苯酚在5-60℃下，在卤化溶剂中与硫酸反应生成二取代的金刚烷二酚衍生物。
2、根据权利要求1所述的制备方法，其特征是所述的金刚醇、4-溴苯酚、硫酸三者之间的摩尔比是1∶0.5∶0.5至1∶5∶5。
3、根据权利要求1所述的制备方法，其特征是所述的金刚醇、4-溴苯酚、硫酸三者之间的摩尔比是1∶1∶1至1∶2.5∶2.5。
4、根据权利要求1所述的制备方法，其特征是所述的卤化溶剂是二氯甲烷、氯仿、或二氯乙烷。
5、根据权利要求1所述的制备方法，其特征是所述的卤化溶剂是二氯甲烷或氯仿。
6、根据权利要求1所述的制备方法，其特征是所述的温度为20-40℃。
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610097378A CN100588643C (zh) | 2006-11-02 | 2006-11-02 | 一种含有二取代金刚烷基的维甲酸类化合物制备方法 |
| US11/699,704 US7473799B2 (en) | 2006-11-02 | 2007-01-29 | Process for the preparation of synthetic retinoids with disubstituted adamantyl radical |
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| CN200610097378A CN100588643C (zh) | 2006-11-02 | 2006-11-02 | 一种含有二取代金刚烷基的维甲酸类化合物制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110483284A (zh) * | 2019-08-26 | 2019-11-22 | 浙江工业大学 | 一种1-金刚烷甲酸-2-(取代苯甲酰氧基)乙酯类化合物及其合成方法和应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2636061B1 (fr) * | 1988-09-07 | 1990-11-09 | Cird | Procede de preparation de derives de l'adamantane-1 |
| FR2698871B1 (fr) * | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | Nouveau taxoïdes, leur préparation et les compositions pharmaceutiques qui les contiennent. |
| CN1827582A (zh) * | 2006-04-18 | 2006-09-06 | 江苏中丹化工集团公司 | 6－[3－(1－金刚烷基)－4－甲氧基苯基]－2－萘甲酸甲酯的制备方法 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110483284A (zh) * | 2019-08-26 | 2019-11-22 | 浙江工业大学 | 一种1-金刚烷甲酸-2-(取代苯甲酰氧基)乙酯类化合物及其合成方法和应用 |
| CN110483284B (zh) * | 2019-08-26 | 2022-05-13 | 浙江工业大学 | 一种1-金刚烷甲酸-2-(取代苯甲酰氧基)乙酯类化合物及其合成方法和应用 |
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| Publication number | Publication date |
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| CN100588643C (zh) | 2010-02-10 |
| US7473799B2 (en) | 2009-01-06 |
| US20080108848A1 (en) | 2008-05-08 |
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