WO2016179932A1 - 阿魏酸冰片酯的合成和应用 - Google Patents

阿魏酸冰片酯的合成和应用 Download PDF

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WO2016179932A1
WO2016179932A1 PCT/CN2015/089396 CN2015089396W WO2016179932A1 WO 2016179932 A1 WO2016179932 A1 WO 2016179932A1 CN 2015089396 W CN2015089396 W CN 2015089396W WO 2016179932 A1 WO2016179932 A1 WO 2016179932A1
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borneol
ferulate
ferulic acid
ester
formula
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PCT/CN2015/089396
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French (fr)
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李云森
陈子珺
邓世平
刘乾
高原
冯海梅
李勇
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苏州沪云肿瘤研究中心股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the invention belongs to the field of chemical medicine, and particularly relates to the synthesis and application of ferulic acid right (left) borneol ester.
  • Ferulic acid (4-hydroxy-3-methoxycinnamic acid), originally found in the seeds and leaves of plants, is a phenolic acid extracted from plants such as Angelica, Chuanxiong, and A. It is widely used in health care products, cosmetics, medicines, pesticides and food additives in the fields of anti-oxidation, anti-thrombosis and various physiological activities.
  • ferulic acid can inhibit platelet aggregation and release, can significantly inhibit experimental thrombosis, regulate immune, clear and inhibit free radical reactions, ferulic acid molecules can be used in a variety of ways to the structure of biological macromolecules in vivo The function is protective.
  • ferulic acid has strong hydrophilicity, poor fat solubility, and its metabolism in the body is fast, the brain is less distributed, and it is difficult to pass through the blood-brain barrier, making it widely restricted in the treatment of cerebrovascular diseases.
  • the current clinical application of the drug sodium ferulate injection is mainly focused on the treatment of cardiovascular diseases. Therefore, the modification of ferulic acid molecules to prepare derivatives to improve the molecular fat solubility is a key to solving the molecular defects of ferulic acid.
  • the reaction of ferulic acid with alcohol to ferulic acid ester is to improve its fat solubility and use effect. The best way.
  • Multi-targeted drugs are drug molecules that are rationally designed based on the overall goal of improving efficacy and/or improving safety and that can act on multiple targets associated with a disease to produce more than one pharmacological activity.
  • the combination of drugs is one of the ways to design multi-target drugs.
  • the present invention provides a synthesis method and application of borneol ferulate.
  • the ferrovic acid borneol ester of the invention has simple synthesis process, easy economical raw materials, non-toxic and harmless, and the synthesis process is easy to be controlled, and the obtained ferulic acid borneol ester has good fat solubility; in addition, the invention also provides ferulic acid borneol.
  • the present invention provides a method for synthesizing borneol ferulate, which comprises:
  • R is a protecting group
  • the borneol is a right-handed borneol shown in Formula 1a or a left-handed borneol shown in Formula 1b;
  • the final preparation is dextrorotatory ferulic acid ester, and its structural formula is:
  • the specific synthetic route is:
  • the final preparation is L- borneol ferulate, and its structural formula is:
  • the specific synthetic route is:
  • the protecting group comprises any one of the following: methyl, tert-butyl, triphenylmethyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, benzyl Base, tetrahydropyranyl.
  • the condensing agent comprises one or more of the following: dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethyl Carbodiimide, 4-dimethylaminopyridine, 1-hydroxybenzotriazole and 4-pyrrolidinopyridine.
  • the present invention provides a method for synthesizing another borneol ferulate, which comprises:
  • the organophosphorus reagent comprises any one of the following: triphenylphosphine, ethoxydiphenylphosphorus and triethyl phosphite.
  • the base comprises one or more of the following: lithium tetrahydrogenate, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide and potassium carbonate.
  • the haloacetyl borneol ester is a haloacetyl dextromethate ester of the formula 4a
  • the wittig phosphorus reagent obtained in the step (1) is as shown in the formula 5a
  • the ferment obtained in the step (2) The borneol ester is dextromethorphanate;
  • X is Cl, Br or I
  • R is PPh 3 X, P(O)Ph 2 or P(O)(OEt) 2 .
  • the specific synthetic route is:
  • the haloacetyl borneol ester is a haloacetyl leucovorin ester of the formula 4b, and the wittig phosphorus reagent obtained in the step (1) is represented by the formula 5b, and the ferment obtained in the step (2)
  • the borneol ester is L- borneol ferulate;
  • X is Cl, Br or I
  • R is PPh 3 X, P(O)Ph 2 or P(O)(OEt) 2 .
  • the specific synthetic route is:
  • the present invention provides the use of borneol ferulate in the preparation of a medicament for treating cerebrovascular diseases
  • the cerebrovascular disease is stroke
  • the borneol ferulate is dextromethorphanate or levofloxacin ferulic acid.
  • the synthetic process of the ferulic acid borneol ester of the invention has the following beneficial effects:
  • the synthesis process of the ferulic acid borneol ester of the invention is simple, the raw material is economically easy to obtain, and the synthesis process is easy to control.
  • the invention has no harmful by-products in the synthesis process of ferulic acid borneol ester, and is an environmentally-friendly and economical process, and can be widely adapted to the production of drugs for treating cerebrovascular diseases.
  • the ferulic acid borneol ester prepared by the synthetic process of the invention has good fat solubility and can be applied to antithrombotic, hypolipidemic and therapeutic drugs for stroke, and no obvious side effects are observed.
  • Figure 1 is a nuclear magnetic diagram of the dextrorotatory ferulic acid ester of the present invention.
  • Figure 2 is a mass spectrum of the dextrorotatory ferulic acid ester of the present invention.
  • Figure 3 is a nuclear magnetic diagram of the levofloxacin ferulic acid ester of the present invention.
  • Fig. 4 is a brain slice diagram of the blank effect group of the fermented right (left) dextrorotatory ester of ferulic acid of the present invention.
  • Figure 5 is a diagram showing the pharmacodynamics of the ferulic acid dextrorotatory fermentate of the present invention.
  • Figure 6 is a diagram showing the brain test of the nimodipine group of the fermented ferulic acid (left) lyoside ester of the present invention.
  • Fig. 7 is a diagram showing the brain test of the left-handed borneol ester group of the ferulic acid right (left) vortexyl ester of the present invention.
  • Figure 8 is a diagram showing the brain effect of the right-handed borneol ester group of ferulic acid in the present invention.
  • 1a is a right-handed borneol
  • 2 is a phenolic hydroxyl-protected ferulic acid
  • R is a protecting group.
  • the phenolic hydroxyl-protected ferulic acid is condensed with a right-handed borneol under the catalyzed condensate to obtain a phenolic hydroxyl-protected ferulic acid.
  • the borneol ester 3a is deprotected to obtain dextroferric acid dextrofluorate;
  • the above protecting group includes any one of the following: methyl, tert-butyl, triphenylmethyl, methoxymethyl, trimethyl a silyl group, a tert-butyldimethylsilyl group, a benzyl group and a tetrahydropyranyl group;
  • the above condensing agents include: dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide, 4-dimethylaminopyridine, 1-hydroxybenzotriazole and 4-pyrrolidinopyridine.
  • the method for synthesizing the dextrorotatory ferulic acid ester comprises the following steps:
  • the structure of the dextrorotatory ferric acid ester obtained in the present example was confirmed by a nuclear magnetic resonance method, and the spectrum thereof is as shown in Fig. 1.
  • the structural characteristics of the dextrorotatory ferroflavonate are:
  • This example discloses a synthetic route of ferulic acid levonolate, the route is as follows:
  • 1b is a left-handed borneol
  • the phenolic hydroxyl-protected ferulic acid is condensed with L- borneol under the catalysis of a condensing agent to obtain a phenolic hydroxyl-protected L- borneol ester 3b, and then deprotected to obtain a ferulic acid levofloxacin.
  • the above protecting group includes any one of the following: methyl, tert-butyl, triphenylmethyl, methoxymethyl, Trimethylsilyl, tert-butyldimethylsilyl, benzyl and tetrahydropyranyl; phenolic hydroxyl-protected ferulic acid condensed with levofloxacin catalyzed by a condensing agent to give phenolic hydroxyl protected ferulic acid left-handed borneol The ester is then deprotected to give levofloxacin ferulic acid ester.
  • haloacetyl dextrofuryl ester 4a is reacted with an organophosphorus reagent to obtain wittig phosphorus reagent 5a, and then wittig phosphorus reagent 5a is further subjected to wittig reaction with 3-methoxy-4hydroxybenzaldehyde 6 under the action of a base to obtain ferulic acid right.
  • Rotary ester is reacted with an organophosphorus reagent to obtain wittig phosphorus reagent 5a, and then wittig phosphorus reagent 5a is further subjected to wittig reaction with 3-methoxy-4hydroxybenzaldehyde 6 under the action of a base to obtain ferulic acid right.
  • Rotary ester Rotary ester.
  • X is Cl, Br or I
  • R is PPh 3 X, P(O)Ph 2 or P(O)(OEt) 2 .
  • the organophosphorus reagent includes: triphenylphosphine, ethoxydiphenylphosphorus and triethyl phosphite; the base includes: lithium tetrahydrogenate, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, hydrogen Sodium oxide, potassium hydroxide, lithium hydroxide and potassium carbonate.
  • Step 1 Add chloroacetyl dextrorotyl ester 4a (21.5g, 93.2mmol), triphenylphosphine (48.9g, 186mmol), toluene (215ml) to the reaction flask, warm to reflux, reaction 12h, steam under reduced pressure The residue was recrystallized from dichloromethane / petroleum ether to afford compound 5a (34.2 g).
  • Step 2 Add compound 5a (34.2 g, 69.4 mmol) to anhydrous tetrahydrofuran under nitrogen. (342 ml), cooled to -78 ° C, n-butyllithium (11.0 g, 173 mmol) was added dropwise, and the reaction was carried out for 0.5 h after the dropwise addition. 3-methoxy-4-hydroxybenzaldehyde 6 (13.3 g, A solution of 87.5 mmol) in tetrahydrofuran (70 ml) was added and maintained at -78 ° C for 3 h.
  • haloacetyl leucovorin ester 4b is reacted with an organophosphorus reagent to obtain wittig phosphorus reagent 5b, and then wittig phosphorus reagent 5b is further subjected to wittig reaction with 3-methoxy-4-hydroxybenzaldehyde under the action of a base to obtain levonate ferulic acid ester. ;
  • the organophosphorus reagent includes: triphenylphosphine, ethoxydiphenylphosphorus and triethyl phosphite; the above base includes: lithium tetrahydrogenate, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, hydroxide Sodium, potassium hydroxide, lithium hydroxide and potassium carbonate.
  • Step 1 2-chloroacetyl lyoferred ester 4b (21.5g, 93.2mmol), triphenylphosphine (48.9g, 186mmol), toluene (215ml) was added to the reaction flask, heated to reflux, 12h, decompression Evaporation and recrystallization from methylene chloride / petroleum ether afforded compound 5b (35.8 g).
  • Step 2 Under a nitrogen atmosphere, the compound 5b (35.8 g, 72.6 mmol) was added to anhydrous tetrahydrofuran (358 ml), cooled to -78 ° C, and n-butyllithium (11.6 g, 182 mmol) was added dropwise. After the reaction was carried out for 0.5 h, a solution of 3-methoxy-4-hydroxybenzaldehyde 6 (13.9 g, 91.4 mmol) in tetrahydrofuran (70 ml) was added dropwise, and the mixture was stirred at -78 ° C for 3 h.
  • the ferulic acid dextrocarbate and the ferulic acid levonolate obtained in the above examples were tested for pharmacological effects on the brain caused by permanent cerebral ischemia in rats by treatment with borneol ferulate. The effects of injury were evaluated for its efficacy in the treatment of stroke disorders.
  • the distal carotid artery is ligated at the distal end, and the external carotid artery is severed to make the trunk free. Then, the internal carotid artery was separated, and a loose buckle was applied to the root of the external carotid artery with a wire to clamp the common carotid artery and the internal carotid artery.
  • the fishing line (length 40mm, diameter 0.26mm) was incision through the main carotid artery and slowly moved into the neck. The vein advances in the direction of the cranium, and when the fishing line enters the internal carotid artery, the artery clip on the internal carotid artery is released.
  • the rats were divided into 5 groups, 20 in each group, respectively: sodium ferulate group, dextromethorphanate group, levofloxacin ferulic acid ester, positive control nimodipine Groups and blank groups (administered with an equal volume of physiological saline); once daily administered intravenously for 3 consecutive days at a dose volume of 0.2 ml/100 g body weight.
  • Neurological deficit scores The neurological deficits of animals were graded according to Bederson's method. The criteria are as follows:
  • Nimodipine group 10 1.40 ⁇ 0.52* 20.0 ⁇ 5.13* Ferulic acid levofloxacin 9 1.60 ⁇ 0.55* 21.8 ⁇ 4.78* Ferulic acid dextrorotatory ester group 10 1.40 ⁇ 0.50* 18.1 ⁇ 5.43*
  • the synthesis process of the ferulic acid borneol ester of the invention is short, the raw material is economical and easy to obtain, non-toxic and harmless, and the synthesis process is easy to control; no harmful by-products are produced, and the environment is economical and economical.
  • the type of process can be widely adapted to the production of drugs for the treatment of cerebrovascular diseases.
  • the borneol ferulate of the present invention has good water solubility and can be applied to antithrombotic, hypolipidemic and therapeutic drugs for cerebrovascular diseases, and no significant side effects are observed.

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Abstract

提供一种阿魏酸冰片酯的合成和应用。其中一种合成工艺使酚羟基保护的阿魏酸与冰片发生缩合反应，所得产物再经脱保护，得到阿魏酸冰片酯；另一种合成工艺采用卤代乙酰冰片酯与有机磷试剂反应，所得wittig磷试剂再与3-甲氧基-4-羟基苯甲醛进行wittig反应，得到阿魏酸冰片酯。本发明的合成工艺简单，原料经济易得，无毒无害，并且合成过程易受控制，适用于工业化大规模生产。此外，本发明还提供了阿魏酸冰片酯在制备治疗脑血管疾病的药物中的应用；特别地，发明人发现，阿魏酸冰片酯能有效改善脑卒中病人的脑血液循环障碍病症，对病人的大脑神经起到良好的保护作用，具有良好的临床应用前景。

Description

阿魏酸冰片酯的合成和应用 技术领域
本发明属于化学医药领域，具体的涉及阿魏酸右(左)旋冰片酯的合成和应用。
背景技术
阿魏酸(4-羟基-3-甲氧基肉桂酸)，最初在植物的种子和叶子中发现，是一种存在当归、川穹、阿魏等植物中提取的酚酸，其具有抗炎、抗氧化、抗血栓和多种生理活性，广泛应用于保健品、化妆品、医药、农药和食品添加剂等领域。
经过研究发现，阿魏酸能够抑制血小板聚集和释放，能够明显抑制实验性血栓形成，调节机体免疫、清楚和抑制自由基反应，阿魏酸分子可以通过多种途径对体内生物大分子的结构和功能起到保护作用。
但是阿魏酸分子亲水性强，脂溶性差，且其体内代谢速度快，脑分布少，较难透过血脑屏障发挥作用，使其在治疗脑血管疾病领域应用大受限制，已上市药物阿魏酸钠注射液目前在临床上的应用主要偏重于心血管疾病的治疗。因此，对阿魏酸分子进行修饰制备衍生物以提高分子脂溶性的研究是解决阿魏酸分子缺陷的一个关键，阿魏酸与醇反应成阿魏酸酯是改进其脂溶性和使用效果的最佳方法。
传统中药冰片具有开窍醒神、促进药物透过血脑屏障、对中枢神经系统有双向调节和保护作用等功效，对于脑卒中疾病治疗也有不错的疗效，这为本发明提供了一个极佳的研究思路。
近来的研究显示，许多疾病的发生原因不只一种，相应的治疗手段也可以有多种，如果同时抑制疾病的发生的多个靶点，能够产生更好的疗效。多靶点药物是基于提高疗效和(或)改善安全性的总体目标而合理设计的、可作用于与某个疾病相关的多个靶点而产生一种以上药理活性的药物分子。药物的组合是多靶药物设计的途径之一。
发明内容
为解决上述技术问题，本发明提供了阿魏酸冰片酯的合成方法和应用。本发明的阿魏酸冰片酯合成工艺简单，原料经济易得，无毒无害，且合成过程易受控制，所得阿魏酸冰片酯脂溶性好；此外，本发明还提供了阿魏酸冰片酯在制备治疗脑血管疾病尤其是脑卒中的药物中的应用。
具体地，第一方面，本发明提供了一种阿魏酸冰片酯的合成方法，其包括：
(1)使冰片与式2所示酚羟基保护的阿魏酸在缩合剂的作用下发生缩合反应，得到酚羟基保护的阿魏酸冰片酯；
Figure PCTCN2015089396-appb-000001
式2中，R为保护基；
(2)所得酚羟基保护的阿魏酸冰片酯经脱保护，得到阿魏酸冰片酯。
上述合成方法中，所述冰片为式1a所示右旋冰片或式1b所示左旋冰片；
Figure PCTCN2015089396-appb-000002
当所述冰片为式1a所示右旋冰片时，最终制得的是阿魏酸右旋冰片酯，其结构式为：
Figure PCTCN2015089396-appb-000003
其具体合成路线为：
Figure PCTCN2015089396-appb-000004
当所述冰片为式1b所示左旋冰片时，最终制得的是阿魏酸左旋冰片酯，其结构式为：
Figure PCTCN2015089396-appb-000005
其具体合成路线为：
Figure PCTCN2015089396-appb-000006
优选地，所述保护基包括以下中的任意一种：甲基、叔丁基、三苯基甲基、甲氧基甲基、三甲基硅基、叔丁基二甲基硅基、苄基、四氢吡喃基。
优选地，所述缩合剂包括以下中的一种或几种：二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺、4-二甲氨基吡啶、1-羟基苯并三唑和4-吡咯烷基吡啶。
第二方面，本发明提供了另一种阿魏酸冰片酯的合成方法，其包括：
(1)使卤代乙酰冰片酯与有机磷试剂反应，得到wittig磷试剂；
(2)所得wittig磷试剂与3-甲氧基-4-羟基苯甲醛在碱的作用下进行wittig反应，得到阿魏酸冰片酯。
作为优选，所述有机磷试剂包括以下中的任意一种：三苯基磷、乙氧基二苯基磷和亚磷酸三乙酯。
作为优选，所述碱包括以下中的一种或几种：四氢铝锂、甲醇钠、乙醇钠、叔丁醇钾、氢化钠、氢氧化钠、氢氧化钾、氢氧化锂和碳酸钾。
在一个优选的具体实施方案中，所述卤代乙酰冰片酯为式4a所示卤代乙酰右旋冰片酯，步骤(1)所得wittig磷试剂如式5a所示，步骤(2)所得阿魏酸冰片酯为阿魏酸右旋冰片酯；
Figure PCTCN2015089396-appb-000007
其中，X为Cl、Br或I；
Figure PCTCN2015089396-appb-000008
其中，R为PPh3X、P(O)Ph2或P(O)(OEt)2。其具体合成路线为：
Figure PCTCN2015089396-appb-000009
在另一个优选的具体实施方案中，所述卤代乙酰冰片酯为式4b所示卤代乙酰左旋冰片酯，步骤(1)所得wittig磷试剂如式5b所示，步骤(2)所得阿魏酸冰片酯为阿魏酸左旋冰片酯；
Figure PCTCN2015089396-appb-000010
其中，X为Cl、Br或I；
Figure PCTCN2015089396-appb-000011
其中，R为PPh3X、P(O)Ph2或P(O)(OEt)2。其具体合成路线为：
Figure PCTCN2015089396-appb-000012
第三方面，本发明提供了阿魏酸冰片酯在制备治疗脑血管疾病的药物中的应用；
优选地，所述脑血管疾病为脑卒中；
优选地，所述阿魏酸冰片酯为阿魏酸右旋冰片酯或阿魏酸左旋冰片酯。
有益效果
相比于现有技术，本发明的阿魏酸冰片酯的合成工艺具备如下有益效果：
(1)本发明阿魏酸冰片酯的合成工艺简单，原料经济易得，并且合成工艺过程易控制。
(2)本发明阿魏酸冰片酯的合成过程中无有害副产物的产生，是环保经济型工艺，可以广泛适应于治疗脑血管疾病药物的生产中。
(3)本发明合成工艺所制得的阿魏酸冰片酯脂溶性好，能够应用到抗血栓、降血脂和治疗脑卒中的药物中，并且未见明显副作用。
附图说明
为了更清楚地说明本发明实施例技术中的技术方案，下面将对实施例技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一 些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明的阿魏酸右旋冰片酯的核磁图。
图2为本发明的阿魏酸右旋冰片酯的质谱图。
图3为本发明的阿魏酸左旋冰片酯的核磁图。
图4为本发明的阿魏酸右(左)旋冰片酯的药效实验空白组脑切片图。
图5为本发明的阿魏酸右(左)旋冰片酯的药效实验阿魏酸钠组脑切片图。
图6为本发明的阿魏酸右(左)旋冰片酯的药效实验尼莫地平组脑切片图。
图7为本发明的阿魏酸右(左)旋冰片酯的药效实验左旋冰片酯组脑切片图。
图8为本发明的阿魏酸右(左)旋冰片酯的药效实验右旋冰片酯组脑切片图。
具体实施方式
下面将结合本发明实施例中的附图，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
本实施例中公开了一种阿魏酸右旋冰片酯的合成路线以及具体合成方法，其中合成路线为：
Figure PCTCN2015089396-appb-000013
其中，1a为右旋冰片，2为酚羟基保护的阿魏酸，R为保护基，酚羟基保护的阿魏酸在缩合剂催化下与右旋冰片缩合得到酚羟基保护的阿魏酸右旋冰片酯3a，再经脱保护得到阿魏酸右旋冰片酯；上述的保护基包括以下中的任意一种：甲基、叔丁基、三苯基甲基、甲氧基甲基、三甲基硅基、叔丁基二甲基硅基、苄基和四氢吡喃基；上述缩合剂包括：二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺、4-二甲氨基吡啶、1-羟基苯并三唑和4-吡咯烷基吡啶。
所述阿魏酸右旋冰片酯的合成方法包括以下几步：
A.将4-苄基阿魏酸(7.5g，0.026mol)投入到二氯甲烷(50ml)中，冰盐浴降温至0℃后，加入二环己基碳二亚胺(5.43g，0.026mol)和4-二甲氨基吡啶(0.96g，0.008mol)，加上干燥管，反应1h；将右旋冰片(4.065g，0.026mol)溶解于二氯甲烷中(25ml)中，滴加到反应液中；滴加完毕后，撤去冰盐浴，自然升温，反应过夜；反应结束后，过滤固体，滤饼用适量二氯甲烷洗涤，滤液蒸干，残余物经柱层析得化合物3a(9.8g)。
B.将化合物3a(9g，0.021mol)投入到四氢呋喃(90ml)中，搅拌均匀，加入甲酸铵(6.84g，0.105mol)，在加入钯炭(1.8g，0.147mol)，反应3h。反应结束后，用硅藻土过滤钯炭，并用适量四氢呋喃洗涤，滤液蒸干。残余物用石油醚或者异丙醇 重结晶，得到化合物阿魏酸右旋冰片酯。
将本实施例中获得的阿魏酸右旋冰片酯的结构用核磁共振方法进行确证，其图谱如图1中所示，所述阿魏酸右旋冰片酯的结构特征为：
1H-NMR(CDCl3,500MHz)0.88，0.90，0.94(各3H，s，H-8，9，10)，1.05(1H，dd,J＝13.3，3.3Hz，H-3b)，1.29(1H，m，H-5b)，1.31(1H，m，H-6b)，1.71(1H，m，H-4)，1.78(1H，m，H-5a)，2.06(1H，m，H-6a)，2.41(1H，dddd,J＝13.8，10.0，4.0，3.5Hz，H-3a)，3.94(3H，s，OMe)，5.01(1H，ddd,J＝10.0，3.3，1.8Hz，H-2)，6.31(1H，d，J＝15.9Hz，H-8′)，6.92(1H，d，J＝8.5Hz，H-5′)，7.04(1H，dd，J＝8.5，2.0Hz，H-6′)，7.06(1H，d，J＝2.0Hz，H-2′)，7.59(1H，d，J＝15.9Hz，H-7′)。鉴定化合物为阿魏酸右旋冰片酯。
本实施例中获得的阿魏酸右旋冰片酯的结构信息通过质谱法进行确证，如图2所示，EI-MS M/Z 331.6[M+]，329.6[M-]。
实施例2
本实施例公开了一种阿魏酸左旋冰片酯的合成路线，路线如下所示：
Figure PCTCN2015089396-appb-000014
其中，1b为左旋冰片，酚羟基保护的阿魏酸在缩合剂催化下与左旋冰片缩合得到酚羟基保护的阿魏酸左旋冰片酯3b，再经脱保护得到阿魏酸左旋冰片酯。
上述的保护基包括以下中的任意一种：甲基、叔丁基、三苯基甲基、甲氧基甲基、 三甲基硅基、叔丁基二甲基硅基、苄基和四氢吡喃基；酚羟基保护的阿魏酸在缩合剂催化下与左旋冰片缩合得到酚羟基保护的阿魏酸左旋冰片酯，再经脱保护得到阿魏酸左旋冰片酯。
具体合成方法：
A.将4-苄基阿魏酸(7.5g，0.026mol)投入到二氯甲烷(50ml)中，冰盐浴降温至0℃后，加入二异丙基碳二亚胺(5.43g，0.026mol)和1-羟基苯并三唑和4-吡咯烷基吡啶(0.96g，0.008mol)，加上干燥管，反应1h；将左旋冰片(4.065g，0.026mol)溶解于二氯甲烷中(25ml)中，滴加到反应液中；滴加完毕后，撤去冰盐浴，自然升温，反应过夜；反应结束后，过滤固体，滤饼用适量二氯甲烷洗涤，滤液蒸干，残余物经柱层析得化合物3b(10.5g)。
B.将化合物3b(9g，0.021mol)投入到四氢呋喃(90ml)中，搅拌均匀，加入甲酸铵(6.84g，0.105mol)，在加入钯炭(1.8g，0.147mol)，反应3h。反应结束后，用硅藻土过滤钯炭，并用适量四氢呋喃洗涤，滤液蒸干。残余物用石油醚或者异丙醇重结晶，得到化合物阿魏酸左旋冰片酯。
对上述获得的阿魏酸左旋冰片酯采用核磁法对其结构进行确证，如图3所示，得到的结果为：
1H-NMR(CDCl3,500MHz)0.88，0.90，0.95(各3H，s，H-8，9，10)，1.05(1H，dd,J＝13.9，3.4Hz，H-3b)，1.29(1H，m，H-5b)，1.31(1H，m，H-6b)，1.71(1H，m，H-4)，1.78(1H，m，H-5a)，2.06(1H，m，H-6a)，2.41(1H，dddd,J＝13.3，9.7，3.8，3.4Hz，H-3a)，3.94(3H，s，OMe)，5.07(1H，dd,J＝9.7.3.0.H-2)，6.31(1H，d，J＝15.9Hz，H-8′)，6.92(1H，d，J＝8.5Hz，H-5′)，7.04(1H，dd，J＝8.5，2.0Hz，H-6′)，7.06(1H，d，J＝2.0Hz，H-2′)，7.59(1H，d，J＝15.9Hz，H-7′)。鉴定化合物为阿魏酸右旋冰片酯。
实施例3
本实施例中公开了一种阿魏酸右旋冰片酯的合成路线：
Figure PCTCN2015089396-appb-000015
卤代乙酰右旋冰片酯4a与有机磷试剂反应得到wittig磷试剂5a，然后wittig磷试剂5a再与3-甲氧基-4羟基苯甲醛6在碱的作用下进行wittig反应得到阿魏酸右旋冰片酯。
其中，X为Cl、Br或I，R为PPh3X、P(O)Ph2或P(O)(OEt)2。
有机磷试剂包括：三苯基磷、乙氧基二苯基磷和亚磷酸三乙酯中；所述碱包括：四氢铝锂、甲醇钠、乙醇钠、叔丁醇钾、氢化钠、氢氧化钠、氢氧化钾、氢氧化锂和碳酸钾。
上述合成路线的具体方法步骤为：
步骤一：将氯乙酰右旋冰片酯4a(21.5g，93.2mmol)、三苯基膦(48.9g，186mmol)、甲苯(215ml)加入到反应瓶中，升温至回流，反应12h，减压蒸干，残余物用二氯甲烷/石油醚重结晶，得到化合物5a(34.2g)。
步骤二：在氮气保护下，将化合物5a(34.2g，69.4mmol)加入到无水四氢呋喃 (342ml)中，冷却至-78℃，滴加正丁基锂(11.0g，173mmol)，滴加完后反应0.5h，滴加3-甲氧基-4-羟基苯甲醛6(13.3g，87.5mmol)的四氢呋喃(70ml)溶液，加完后保持-78℃反应3h。反应完后自然升温至室温，向反应液中滴加饱和碳酸氢钠溶液(200ml)，乙酸乙酯(150ml×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥4h，过滤，滤液浓缩至干，残余物用石油醚或者异丙醇重结晶，得到化合物阿魏酸右旋冰片酯。
实施例4
本实施例中公开了阿魏酸左旋冰片酯的合成线路，如下：
Figure PCTCN2015089396-appb-000016
卤代乙酰左旋冰片酯4b与有机磷试剂反应得到wittig磷试剂5b，然后wittig磷试剂5b再与3-甲氧基-4羟基苯甲醛在碱的作用下进行wittig反应得到阿魏酸左旋冰片酯；
其中X为Cl、Br或I，R为PPh3X、P(O)Ph2或P(O)(OEt)2。有机磷试剂包括：三苯基磷、乙氧基二苯基磷和亚磷酸三乙酯中；上述碱包括：四氢铝锂、甲醇钠、乙醇钠、叔丁醇钾、氢化钠、氢氧化钠、氢氧化钾、氢氧化锂和碳酸钾。
上述合成路线的具体方法步骤为：
步骤一：将2-氯乙酰左旋冰片酯4b(21.5g，93.2mmol)、三苯基膦(48.9g，186mmol)、甲苯(215ml)加入到反应瓶中，升温至回流，反应12h，减压蒸干，残余物用二氯甲烷/石油醚重结晶，得到化合物5b(35.8g)。
步骤二：在氮气保护下，将化合物5b(35.8g，72.6mmol)加入到无水四氢呋喃(358ml)中，冷却至-78℃，滴加正丁基锂(11.6g，182mmol)，滴加完后反应0.5h，滴加3-甲氧基-4-羟基苯甲醛6(13.9g，91.4mmol)的四氢呋喃(70ml)溶液，加完后保持-78℃反应3h。反应完后自然升温至室温，向反应液中滴加饱和碳酸氢钠溶液(200ml)，乙酸乙酯(150ml×3)萃取，合并有机相，饱和食盐水洗涤，无水硫酸钠干燥4h，过滤，滤液浓缩至干，残余物用石油醚或者异丙醇重结晶，得到化合物阿魏酸左旋冰片酯。
实施例5
本实施例中将上述实施例中获得的阿魏酸右旋冰片酯和阿魏酸左旋冰片酯进行药效实验，通过阿魏酸冰片酯治疗给药对大鼠永久性脑缺血所致脑损伤的影响评价其在脑卒中疾病治疗中的药效。
上述实验方案为：
1、准备清洁级雄性SD大鼠100只(成模率为50％)，体重250-300g，采用颈内动脉线栓法制备大鼠大脑中动脉闭塞(MCAO)模型：大鼠用3％水合三氯乙醛(300mg/kg)腹腔注射(ip)麻醉，仰卧手术台上，颈部正中切口，暴露右侧颈总动脉，向外牵引二腹肌及胸锁乳突肌，由颈总动脉分叉处向头端依次游离，结扎并剪断颈外动脉的分支：枕骨下动脉和甲状腺上动脉。在颈外动脉远端结扎，切断颈外动脉使其主干游离备用。然后分离颈内动脉，用丝线在颈外动脉根部打一松扣，夹闭颈总动脉和颈内动脉。将渔线(长40mm，直径0.26mm)经颈外动脉主干切口，缓慢向颈内动 脉入颅方向推进，当渔线进入颈内动脉后松开颈内动脉上的动脉夹。以颈总动脉分叉处为标记，推进18mm左右时感到阻力，即达到了较细的大脑前动脉内，阻断了MCA的所有血供来源，扎紧颈外动脉根部松扣。缝合皮肤，完成MCAO导致永久性脑缺血模型。
2、假手术组大鼠麻醉后，仅暴露颈内外动脉分叉，不闭塞MCA。于模型完成后2h尾静脉给药，分为5组，每组20只，分别为：阿魏酸钠组、阿魏酸右旋冰片酯组，阿魏酸左旋冰片酯，阳性对照尼莫地平组和空白组(给以等容积的生理盐水)；每天静脉给药一次，连续给药3天，给药容积为0.2ml/100g体重。
3、神经功能缺陷评分标准：按Bederson的方法对动物的神经功能缺陷进行分级评分，标准如下：
0分：未观察到神经症状。
1分：提尾悬空时，动物的手术对侧前肢表现为腕肘屈曲，肩内旋，肘外展，紧贴胸壁。
2分：将动物置于光滑平面上，推手术侧肩向对侧移动时，阻力降低。
3分：动物自由行走时向手术对侧环转或转圈。
4分；软瘫，肢体无自发活动。
实验结束后对上述四组实验进行初步药效结果统计，行为学评分和脑梗体积统计结果如表1所示：
表1、药效学实验结果统计表
组别 n 行为学评分 脑梗体积(mm2)
空白对照组 10 2.50±0.53 35.2±4.38
阿魏酸钠组 10 2.30±0.54 33.8±4.85
尼莫地平组 10 1.40±0.52* 20.0±5.13*
阿魏酸左旋冰片酯组 9 1.60±0.55* 21.8±4.78*
阿魏酸右旋冰片酯组 10 1.40±0.50* 18.1±5.43*
*P＜0.05,与空白组比较。
由图4-8和表1中的行为学评分和脑梗体积统计可知，上市药物阿魏酸钠对于脑卒中疾病几乎不存在治疗效果，而阿魏酸左旋冰片酯和阿魏酸右旋冰片酯均表现出良好的药效，其中阿魏酸左旋冰片酯与阳性对照药尼莫地平相当，而阿魏酸右旋冰片酯优于阳性对照药尼莫地平。
通过本发明的上述实施例中可以得到，本发明阿魏酸冰片酯的合成工艺简短，原料经济易得，无毒无害，并且合成工艺过程易控制；无有害副产物的产生，是环保经济型工艺，可以广泛适应于治疗脑血管疾病药物的生产中。
本发明的阿魏酸冰片酯水溶性好，能够应用到抗血栓、降血脂和治疗脑血管疾病的药物中，并且未见明显副作用。
对所公开的实施例的上述说明，使本领域专业技术人员能够实现或使用本发明。对这些实施例的多种修改对本领域的专业技术人员来说将是显而易见的，本文中所定义的一般原理可以在不脱离本发明的精神或范围的情况下，在其它实施例中实现。因此，本发明将不会被限制于本文所示的这些实施例，而是要符合与本文所公开的原理和新颖特点相一致的最宽的范围。

Claims (10)

  1. 阿魏酸冰片酯的合成方法，其包括：
    (1)使冰片与式2所示酚羟基保护的阿魏酸在缩合剂的作用下发生缩合反应，得到酚羟基保护的阿魏酸冰片酯；
    Figure PCTCN2015089396-appb-100001
    式2中，R为保护基；
    (2)所得酚羟基保护的阿魏酸冰片酯经脱保护，得到阿魏酸冰片酯。
  2. 根据权利要求1所述的合成方法，其特征在于，所述冰片为式1a所示右旋冰片或式1b所示左旋冰片；
    Figure PCTCN2015089396-appb-100002
  3. 根据权利要求1或2所述的合成方法，其特征在于，所述保护基包括以下中的任意一种：甲基、叔丁基、三苯基甲基、甲氧基甲基、三甲基硅基、叔丁基二甲基硅基、苄基、四氢吡喃基。
  4. 根据权利要求1-3任一项所述的合成方法，其特征在于，所述缩合剂包括以下中的一种或几种：二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺、4-二甲氨基吡啶、1-羟基苯并三唑和4-吡咯烷基吡啶。
  5. 阿魏酸冰片酯的合成方法，其包括：
    (1)使卤代乙酰冰片酯与有机磷试剂反应，得到wittig磷试剂；
    (2)所得wittig磷试剂与3-甲氧基-4-羟基苯甲醛在碱的作用下进行wittig反应，得到阿魏酸冰片酯。
  6. 根据权利要求5所述的合成方法，其特征在于，所述有机磷试剂包括以下中的任意一种：三苯基磷、乙氧基二苯基磷和亚磷酸三乙酯。
  7. 根据权利要求5或6所述的合成方法，其特征在于，所述碱包括以下中的一种或几种：四氢铝锂、甲醇钠、乙醇钠、叔丁醇钾、氢化钠、氢氧化钠、氢氧化钾、氢氧化锂和碳酸钾。
  8. 根据权利要求5-7任一项所述的合成方法，其特征在于，所述卤代乙酰冰片酯为式4a所示卤代乙酰右旋冰片酯，步骤(1)所得wittig磷试剂如式5a所示，步骤(2)所得阿魏酸冰片酯为阿魏酸右旋冰片酯；
    Figure PCTCN2015089396-appb-100003
    其中，X为Cl、Br或I；
    Figure PCTCN2015089396-appb-100004
    其中，R为PPh3X、P(O)Ph2或P(O)(OEt)2。
  9. 根据权利要求5-7任一项所述的合成方法，其特征在于，所述卤代乙酰冰片酯为式4b所示卤代乙酰左旋冰片酯，步骤(1)所得wittig磷试剂如式5b所示，步骤(2)所得阿魏酸冰片酯为阿魏酸左旋冰片酯；
    Figure PCTCN2015089396-appb-100005
    其中，X为Cl、Br或I；
    Figure PCTCN2015089396-appb-100006
    其中，R为PPh3X、P(O)Ph2或P(O)(OEt)2。
  10. 阿魏酸冰片酯在制备治疗脑血管疾病的药物中的应用；
    优选地，所述脑血管疾病为脑卒中；
    优选地，所述阿魏酸冰片酯为阿魏酸右旋冰片酯或阿魏酸左旋冰片酯。
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