Synthesis method of C-19 double-bonded triptolide derivative
阅读说明：本技术 一种c-19位双键化雷公藤内酯醇衍生物的合成方法 (Synthesis method of C-19 double-bonded triptolide derivative ) 是由 张鹏 焦明坤 仇波 肖飞 于 2018-05-31 设计创作，主要内容包括：本发明公开了一种C-19位双键化雷公藤内酯醇衍生物的合成方法,以雷公藤内酯醇及其衍生物为原料,与酰化试剂和缚酸剂在反应溶剂中在-78～0℃反应后升温至-5～5℃,加无机碱溶液和酯类溶剂,得到的有机相经酸洗、浓缩、结晶得到C-19位双键化雷公藤内酯醇衍生物。本发明的合成方法,步骤少,耗时短,收率高,纯度高。(the invention discloses a method for synthesizing a C-19 double-bonded triptolide derivative, which comprises the steps of taking triptolide and triptolide derivatives as raw materials, reacting the triptolide and triptolide derivatives with an acylation reagent and an acid-binding agent in a reaction solvent at-78-0 ℃, heating to-5 ℃, adding an inorganic alkali solution and an ester solvent, and carrying out acid washing, concentration and crystallization on an obtained organic phase to obtain the C-19 double-bonded triptolide derivative. The synthesis method has the advantages of few steps, short time consumption, high yield and high purity.)
1. A synthetic method of C-19 double-bonded triptolide derivatives shown in a general formula I is characterized by comprising the following steps:
i) Triptolide and triptolide derivatives shown in formula V react with an acylation reagent and an acid-binding agent in a reaction solvent at-78-0 ℃,
ii) heating the reaction solution obtained in the step i) to-5 ℃, and adding an inorganic alkali solution and an ester solvent;
iii) carrying out acid washing, concentration and crystallization on the organic phase obtained by the extraction of the ester solvent in the step ii) to obtain the C-19 double-bonded triptolide derivative shown in the general formula I,
In the following formulas, the first and second groups,
r 1 is a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkenyl, C2-C6 alkynyl, C6-C10 aryl, C7-C15 arylalkyl, or 4-8 membered heteroaryl;
R 2 is OR 3, F OR SH, R 3 is selected from H, Boc, TBS, TES, CH 2 SCH 3, CH 2 OCH 3, -CH2OP (═ O) (OH)2, -CH2OP (═ O) (OBn)2, -OP (═ O) (OH)2, -OP (═ O) (OBn)2, -COOH;
Represents the α -configuration or the β -configuration;
Each X is independently H, OH, wherein at most one X is OH;
each of the above substituents independently refers to one or more hydrogen atoms on the group being substituted with a substituent selected from the group consisting of halogen, -OH, NH 2, CN, COOH, -OP (═ O) (OH)2, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated C2-C6 acylamino, unsubstituted or halogenated 5-8 membered aryl, unsubstituted or halogenated 5-8 membered heteroaryl, unsubstituted or halogenated 4-8 membered saturated heterocycle or carbocycle, wherein each of the above heteroaryl groups independently comprises 1-3 heteroatoms selected from the group consisting of N, O or S.
2. The synthetic method of claim 1 wherein R 1 is a substituted or unsubstituted C1-C4 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, or 4-8 membered heteroaryl, said substitution being such that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C1-C3 alkoxy;
R 2 is OH, OBoc, OCH 2 OP (═ O) (OH) 2, -OCH 2 OP (═ O) (OBn) 2, OTBS, OTES, OCH 2 SCH 3 or OCH 2 OCH 3, and/or
each X is H.
3. The synthetic method of claim 1 wherein the reaction solvent is selected from the group consisting of: tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and acetone.
4. The method of claim 1, wherein in step i), the acid-binding agent and the acylating agent are added in sequence after the acylating agent is added.
5. The synthetic method of claim 1 wherein the acylating reagent is selected from the group consisting of: acid chlorides, acid bromides, and acid anhydrides.
6. the synthetic method of claim 1 wherein the acid scavenger is selected from the group consisting of: lithium diisopropylamide, butyl lithium, tert-butyl lithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium 2,2,6, 6-tetramethylpiperidyl magnesium chloride complex.
7. The method of synthesis according to claim 1, wherein the inorganic base solution is selected from the group consisting of: sodium carbonate aqueous solution, potassium carbonate aqueous solution, lithium carbonate aqueous solution, sodium phosphate aqueous solution, potassium phosphate aqueous solution, sodium hydrogen carbonate aqueous solution, potassium hydrogen carbonate aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and lithium hydroxide aqueous solution.
8. The synthetic method of claim 1 wherein the extraction solvent is selected from the group consisting of: ethyl acetate, isopropyl acetate, isobutyl acetate.
9. the synthesis process according to claim 1, characterized in that the solvents used for the crystallization are: dichloromethane/n-hexane, dichloromethane/n-heptane, tetrahydrofuran/ethyl acetate, tetrahydrofuran/n-hexane, or tetrahydrofuran/n-heptane.
10. the synthesis method of claim 1, wherein the amount of the acylating agent is 2.0-4.0 equivalents and the amount of the acid-binding agent is 2.0-6.0 equivalents.
Technical Field
The invention relates to the field of medicinal chemistry, in particular to an improved synthesis method of C-19 double-bonded triptolide derivatives with antitumor activity and immunosuppressive activity.
Background
The natural products are always the main sources of the structures of the novel antitumor drugs, but the compounds have poor pharmacokinetic properties, and only few pure natural products are developed into the antitumor drugs clinically.
Tripterygium Wilfordii (TW) which is a traditional Chinese medicine plant is a common research object of antitumor drugs, and triptolide, which is a compound extracted from the TW, is an important effective component of the Tripterygium wilfordii, and the triptolide is found to have anti-inflammatory, anti-tumor and immunosuppressive activities. Meanwhile, researches find that triptolide also has high toxicity and various adverse reactions, which seriously influences the development and utilization of triptolide. In vivo experiments show that the safety range of triptolide is narrow, 2 times or 4 times of effective dose of triptolide can cause animal death, and even research reports that the effective doses are very close to each other in lethal dose. Toxicological studies have found that adverse reactions of triptolide involve various tissues and organs such as gastrointestinal tract, kidney, heart, liver, hematopoietic system and reproductive system. Therefore, the triptolide is structurally modified to obtain the high-efficiency and low-toxicity triptolide derivative, so that the triptolide derivative can exert antitumor and other biological activities and avoid toxicity, and the triptolide derivative becomes an important research direction in scientific research.
The literature research finds that the structural modification aiming at triptolide at present mainly focuses on C-14 hydroxyl, C-7/C-8 epoxy, C-12/C-13 epoxy and unsaturated lactone ring. The structural modification aiming at the unsaturated lactone ring mainly aims at converting the lactone ring into a furan ring, or converting the lactone ring into lactam, or opening the lactone ring to achieve the aim of increasing water solubility, but the two strategies can cause the reduction or even disappearance of the activity of the derivative.
Disclosure of Invention
The invention aims to provide an improved synthesis method of C-19 double-bonded triptolide derivatives.
The first aspect of the invention provides a method for synthesizing C-19 double-bonded triptolide derivative shown in the general formula I, which comprises the following steps:
i) triptolide and triptolide derivatives shown in formula V react with an acylation reagent and an acid-binding agent in a reaction solvent at-78-0 ℃,
ii) heating the reaction solution obtained in the step i) to-5 ℃, and adding an inorganic alkali solution and an ester solvent;
iii) carrying out acid washing, concentration and crystallization on the organic phase obtained by the extraction of the ester solvent in the step ii) to obtain the C-19 double-bonded triptolide derivative shown in the general formula I,
In the following formulas, the first and second groups,
R 1 is a substituted or unsubstituted C1-C6 alkyl, C3-C8 cycloalkyl, C2-C6 alkenyl, C3-C8 cycloalkenyl, C2-C6 alkynyl, C6-C10 aryl, C7-C15 arylalkyl, or 4-8 membered heteroaryl;
R 2 is OR 3, F OR SH, R 3 is selected from H, Boc, TBS, TES, CH 2 SCH 3, CH 2 OCH 3, -CH 2 OP (═ O) (OH) 2, -CH 2 OP (═ O) (OBn) 2, -OP (═ O) (OH) 2, -OP (═ O) (OBn) 2, -COOH;
represents the α -configuration or the β -configuration;
Each X is independently H, OH, wherein at most one X is OH;
Each of the above substituents independently refers to one or more hydrogen atoms on the group being substituted with a substituent selected from the group consisting of halogen, -OH, NH 2, CN, COOH, -OP (═ O) (OH) 2, unsubstituted or halogenated C1-C8 alkyl, unsubstituted or halogenated C3-C8 cycloalkyl, unsubstituted or halogenated C1-C8 alkoxy, unsubstituted or halogenated C2-C6 alkenyl, unsubstituted or halogenated C2-C6 alkynyl, unsubstituted or halogenated C2-C6 acyl, unsubstituted or halogenated C2-C6 amido, unsubstituted or halogenated 5-8 membered aryl, unsubstituted or halogenated 5-8 membered heteroaryl, unsubstituted or halogenated 4-8 membered saturated heterocycle or carbocycle, wherein each of the above heteroaryl groups independently comprises 1-3 heteroatoms selected from the group consisting of N, O or S.
In another preferred embodiment, R 1 is a substituted or unsubstituted C1-C4 alkyl group, C3-C6 cycloalkyl group, C6-C10 aryl group, or 4-8 membered heteroaryl group, said substitution meaning that one or more hydrogen atoms on the group are substituted with a substituent selected from the group consisting of halogen, -OH, unsubstituted or halogenated C1-C4 alkyl, unsubstituted or halogenated C1-C3 alkoxy.
In another preferred example, R 2 is OH, OBoc, OCH 2 OP (═ O) (OH) 2, -OCH 2 OP (═ O) (OBn) 2, OTBS, OTES, OCH 2 SCH 3, or OCH 2 OCH 3.
In another preferred embodiment, each X is H.
in another preferred embodiment, R 1 is cyclohexyl, n-propyl, n-butyl, phenyl, furyl, methylphenyl, methoxyphenyl, or trifluoromethylphenyl.
In another preferred embodiment, R 1 is cyclohexyl, n-propyl, n-butyl, phenyl, 2-furyl, p-methylphenyl, p-methoxyphenyl, or p-trifluoromethylphenyl.
in another preferred embodiment, R 2 is OH, in another preferred embodiment, R 2 is β -OH, and in another preferred embodiment, R 2 is OBoc, OCH 2 OP (═ O) (OH) 2 or-OCH 2 OP (═ O) (OBn) 2.
in another preferred embodiment, the reaction solvent is selected from: tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile and acetone.
In another preferred embodiment, the solvent is anhydrous tetrahydrofuran or 2-methyltetrahydrofuran.
In another preferred embodiment, in step i), the acid-binding agent and the acylating agent are added in sequence after the acylating agent is added.
In another preferred embodiment, the acylating agent is selected from the group consisting of: acid chlorides, acid bromides, and acid anhydrides.
In another preferred embodiment, the acylating agent is an acyl chloride, including but not limited to benzoyl chloride, p-trifluorobenzoyl chloride, p-methoxybenzoyl chloride, and the like.
In another preferred embodiment, the acylating agent is benzoyl chloride, p-methoxybenzoyl chloride, p-trifluoromethylbenzoyl chloride, 2-furoyl chloride or benzoic anhydride.
in another preferred embodiment, the acid scavenger is selected from the group consisting of: lithium diisopropylamide, butyl lithium, tert-butyl lithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium 2,2,6, 6-tetramethylpiperidyl magnesium chloride complex.
in another preferred example, the acid-binding agent is 2,2,6, 6-tetramethyl piperidyl lithium chloride complex.
in another preferred embodiment, the inorganic base solution is selected from: sodium carbonate aqueous solution, potassium carbonate aqueous solution, lithium carbonate aqueous solution, sodium phosphate aqueous solution, potassium phosphate aqueous solution, sodium hydrogen carbonate aqueous solution, potassium hydrogen carbonate aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, and lithium hydroxide aqueous solution.
In another preferred embodiment, the extraction solvent is selected from: ethyl acetate, isopropyl acetate, isobutyl acetate.
in another preferred embodiment, the solvents used for the crystallization are: dichloromethane/n-hexane, dichloromethane/n-heptane, tetrahydrofuran/ethyl acetate, tetrahydrofuran/n-hexane, or tetrahydrofuran/n-heptane.
In another preferred embodiment, the amount of the acylating agent is 2.0-4.0 equivalents, and the amount of the acid-binding agent is 2.0-6.0 equivalents.
In another preferred embodiment, 1mmol triptolide and triptolide derivatives are added into anhydrous tetrahydrofuran, stirred for 10 minutes at 15-25 ℃ under the protection of nitrogen, and then cooled to-78-0 ℃. Adding 3mmol of acylation reagent, continuing stirring at-78-0 ℃ for 5 minutes after the addition is finished, and then dropwise adding 4mmol of acid-binding agent. And continuing to react for 0.5 hour after dripping is finished, then heating the reaction solution to-5 ℃, adding an inorganic alkali solution and an ester solvent, stirring for 0.5 hour, and carrying out acid washing, concentration and crystallization on an organic phase to obtain the C-19 double-bonded triptolide derivative with high purity.
The synthesis method takes triptolide and the triptolide derivatives as starting raw materials, and prepares the C-19 double-bonded triptolide derivatives by one-step reaction with an acylation reagent, and has the advantages of few synthesis steps, short time consumption and high yield.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Each feature disclosed in this specification may be replaced by an alternative feature serving the same, equivalent, or similar purpose. For reasons of space, they will not be described in detail.
Detailed Description
The inventor of the application researches extensively and deeply to develop an improved synthesis method of C-19 double-bonded triptolide derivative, which takes triptolide and the derivative thereof as starting materials to react with an acylation reagent in one step to prepare the C-19 double-bonded triptolide derivative, and the reaction solution is subjected to post-treatment and crystallization to obtain the C-19 double-bonded triptolide derivative with higher purity, and the synthesis method has the advantages of less synthesis steps, short time consumption and high yield. On the basis of this, the present invention has been completed.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are percentages and parts by weight.
unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.
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