阅读说明：本技术 (5r)-5-羟基雷公藤内酯醇的制备方法 (Preparation method of (5R) -5-hydroxy triptolide ) 是由 李柏俊 谢建树 夏文宏 夏广新 刘彦君 于 2018-07-27 设计创作，主要内容包括：本发明公开了一种(5R)-5-羟基雷公藤内酯醇的制备方法,其包括如下步骤：在溶剂中,将如式I所示的化合物在碱性试剂的存在下进行水解反应,即可；其中,R为甲酰基或苯甲酰基,所述的碱性试剂可为肼和/或碱金属氢氧化物。本发明的制备方法具有较佳的收率、无需使用剧毒试剂、避免了手性拆分并且易于实现工业化生产。<Image he="202" wi="700" file="DDA0001746599740000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of (5R) -5-hydroxyl triptolide, which comprises the following steps: in a solvent, carrying out hydrolysis reaction on a compound shown as a formula I in the presence of an alkaline reagent; wherein R is formyl or benzoyl, and the alkaline reagent can be hydrazine and/or alkali metal hydroxide. The preparation method has better yield, does not need to use a highly toxic reagent, avoids chiral resolution and is easy to realize industrial production.)

1. A method for preparing a compound shown as a formula I comprises the following steps: in a solvent, adding a compound shown as a formula II in CrO₃Carrying out oxidation reaction under the existing condition;

wherein R is acetyl or benzoyl.

2. A process for the preparation of a compound of formula I according to claim 1, wherein: CrO₃The molar ratio to the compound of formula II is 6-30:1, such as 12-25:1, and further such as 18-22: 1.

3. A process for the preparation of a compound of formula I according to claim 1, wherein: the oxidation reaction is carried out on CrO₃And in the presence of a catalyst; wherein the catalyst is one or more of N-hydroxysuccinimide, N-hydroxyphthalimide and N-hydroxymaleimide, such as N-hydroxysuccinimide and/or N-hydroxyphthalimide, and further such as N-hydroxysuccinimide.

4. A process for the preparation of a compound of formula I according to claim 3, wherein: the molar ratio of the catalyst to the compound shown as the formula II is 0.6-10:1, such as 0.8-2: 1;

and/or, CrO₃The molar ratio of the compound of formula II to the compound of formula II is 1-30:1, such as 3-12:1, and such as 4-8: 1.

5. A process for the preparation of a compound of formula I according to any one of claims 1 to 4, wherein: the solvent is a mixed solvent of acetonitrile and water, a mixed solvent of methanol and water or a mixed solvent of ethanol and water;

and/or the volume-mass ratio of the solvent to the compound shown in the formula II is 2-100mL/g, such as 10-60 mL/g;

and/or the reaction temperature of the oxidation reaction is 10-70 ℃, such as 20-50 ℃;

and/or the post-treatment of the oxidation reaction comprises the following steps: after the reaction is finished, adding water, extracting, washing an organic phase by a sodium bisulfite water solution and water, and concentrating.

6. A process for the preparation of a compound of formula I according to claim 1, wherein: it further comprises the following steps: in the presence of an acid-binding agent, carrying out acylation reaction on a compound shown as a formula III and an acylation reagent to obtain a compound shown as a formula II;

7. a preparation method of (5R) -5-hydroxyl triptolide is characterized by comprising the following steps:

(1) preparing a compound of formula I according to the process for the preparation of a compound of formula I as claimed in any one of claims 1 to 6;

(2) in a solvent, carrying out hydrolysis reaction on a compound shown as a formula I in the presence of an alkaline reagent;

8. the method for preparing (5R) -5-hydroxytriptolide according to claim 7, wherein the solvent in the hydrolysis reaction is one or more of alcohol solvent, ether solvent and water;

and/or in the hydrolysis reaction, the volume-mass ratio of the solvent to the compound shown in the formula I is 5-100 mL/g;

and/or, in the hydrolysis reaction, the alkaline reagent is hydrazine and/or alkali metal hydroxide;

and/or the reaction temperature of the hydrolysis reaction is-25-20 ℃;

and/or the post-treatment of the hydrolysis reaction comprises the following steps: adding acid to adjust pH to 5-7.

9. The method of claim 8, wherein the alcohol solvent is methanol and/or ethanol;

and/or, in the hydrolysis reaction, the ether solvent is tetrahydrofuran;

and/or in the hydrolysis reaction, the volume-mass ratio of the solvent to the compound shown in the formula I is 10-60 mL/g;

and/or, in the hydrolysis reaction, the alkali metal hydroxide is lithium hydroxide;

and/or, when the alkaline reagent is hydrazine, the molar ratio of hydrazine to the compound shown in the formula I is 10-100: 1;

and/or, when the alkaline reagent is an alkali metal hydroxide, the molar ratio of the alkali metal hydroxide to the compound shown in the formula I is 1.2-2: 1;

and/or the reaction temperature of the hydrolysis reaction is-20-0 ℃;

and/or, in the post-treatment of the hydrolysis reaction, the acid is sulfuric acid or hydrochloric acid;

and/or in the post-treatment of the hydrolysis reaction, the temperature of the process control system for adding the acid is-20-0 ℃.

10. A preparation method of (5R) -5-hydroxyl triptolide is characterized by comprising the following steps: in a solvent, carrying out hydrolysis reaction on a compound shown as a formula I in the presence of an alkaline reagent;

wherein R is acetyl or benzoyl;

the alkaline reagent is hydrazine, and other reaction conditions of the hydrolysis reaction are as defined in any one of claims 7 to 9.

11. A compound having the structure:

Technical Field

The invention relates to a preparation method of (5R) -5-hydroxyl triptolide.

Background

Triptolide (TP) belongs to diterpene epoxy compounds, is one of main active ingredients of Triptolide, shows outstanding pharmacological activity in the aspects of Cancer resistance, inflammation resistance, fertility resistance, angiogenesis resistance, immunosuppression and the like, and has good antitumor activity on all 60 Cancer cells listed in National Cancer Institute (NCI), and thus, Triptolide shows a huge application prospect in the aspects of tumor and immunosuppressive drug development. However, the serious toxic and side effects and the extremely low water solubility of triptolide in the digestive system, the blood circulation system and the urogenital system limit the development process and clinical application of triptolide.

Scholars at home and abroad successfully apply a chemical method to carry out modification and transformation of hydroxylation and methylation on triptolide, wherein the derivative synthesized by the chemical synthesis method comprises the following steps:

(1) CN1511838A discloses (5R) -5-hydroxytriptolide alcohol and a preparation method thereof:

the preparation method comprises the steps of taking triptolide as a raw material, oxidizing the triptolide by selenium dioxide (virulent strain) to generate (5R) -5-hydroxy triptolide (the yield is 82%), and performing reduction and column chromatography to obtain a pair of chiral (5R) -5-hydroxy triptolide (the yield is 38%) and chiral (5R) -5-hydroxy triptolide (the yield is 56%). The method needs to use a highly toxic chemical selenium dioxide, has high difficulty in separating later chiral substances, has a total yield of only 30 percent of target compounds, and is not suitable for the requirement of industrial production.

(2) WO 2005/000291A 1 discloses a preparation method of (5R) -5-hydroxytriptolide alcohol:

the triptolide is used as a raw material, and is oxidized by selenium dioxide to obtain (5R) -5-hydroxyl triptolide (the yield is 46.3%). The method also uses the highly toxic chemical selenium dioxide, and increases the process safety and the drug safety risk in the process of preparing the bulk drug.

Disclosure of Invention

The technical problem to be solved by the invention is to overcome the defects of chiral resolution, low yield or use of highly toxic chemicals and the like in the preparation method of (5R) -5-hydroxyl triptolide in the prior art. Therefore, the invention provides a preparation method of (5R) -5-hydroxyl triptolide, which has better yield, does not need to use a virulent reagent, avoids chiral resolution and is easy to realize industrial production.

The invention provides a preparation method of a compound shown as a formula I, which comprises the following steps: in a solvent, adding a compound shown as a formula II in CrO₃Carrying out oxidation reaction under the existing condition;

wherein R is acetyl or benzoyl.

In the oxidation reaction, CrO₃Can be used in the amounts customary in the art for such reactions, for example CrO₃The molar ratio of the amount of (c) to the compound of formula II may be 6-30:1 (e.g. 12-25:1, further e.g. 18-22: 1).

The oxidation reaction can also be carried out in CrO₃And a catalyst, wherein the catalyst is one or more of N-hydroxysuccinimide, N-hydroxyphthalimide, and N-hydroxymaleimide (e.g., the catalyst may be N-hydroxysuccinimide and/or N-hydroxyphthalimide). When the catalyst is present in the system of the oxidation reaction, CrO can be reduced₃In an amount of, for example, CrO₃The molar ratio of the compound of formula II to the compound of formula II may be 1-30:1 (e.g., 3-12:1, and further e.g., 4-8: 1). The amount of the catalyst may be the amount conventionally used in such reactions in the art, for example, the molar ratio of the catalyst to the compound of formula II may be 0.6-10:1 (e.g., 0.8-2: 1).

In one embodiment of the invention, the catalyst is N-hydroxysuccinimide.

In one embodiment of the invention, the catalyst is N-hydroxyphthalimide.

In the oxidation reaction, the solvent can be a conventional solvent for the reaction in the field, and can also be one or more of a nitrile solvent, an alcohol solvent and water. The nitrile solvent may be acetonitrile. The alcohol solvent can be methanol and/or ethanol. For example, the solvent may be a mixed solvent of acetonitrile and water, a mixed solvent of methanol and water, or a mixed solvent of ethanol and water, and may also be a mixed solvent of acetonitrile and water. When the solvent is a mixed solvent of a nitrile solvent and water, or a mixed solvent of an alcohol solvent and water, the volume ratio of the nitrile solvent or the alcohol solvent to the water can be 5-20:1 (such as 8-15:1, and further such as 10-11: 1).

In the oxidation reaction, the amount of the solvent can be the amount conventionally used in such reactions in the art, and for example, the volume-to-mass ratio of the solvent to the compound represented by the formula II can be 2-100mL/g (e.g., 10-60mL/g, and further e.g., 18-40 mL/g).

The oxidation reaction may be carried out at a temperature which is conventional in the art and which may be from 10 ℃ to 70 ℃ (e.g., from 20 ℃ to 50 ℃, further e.g., from 30 ℃ to 40 ℃).

The progress of the oxidation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC or NMR, preferably TLC), and the end point of the reaction is generally determined as the point at which the compound of formula II is no longer reacted.

The post-treatment of the oxidation reaction can adopt the post-treatment steps conventional in the reaction in the field, and can also comprise the following steps: after the reaction is finished, adding water, extracting, washing an organic phase by a sodium bisulfite water solution and water, and concentrating. The aqueous sodium bisulfite solution may be a 5% aqueous sodium bisulfite solution.

In one embodiment of the invention, the oxidation is in CrO₃And N-hydroxysuccinimide in the presence of a mixed solvent of acetonitrile and water, wherein the volume ratio of the acetonitrile to the water is 8-15:1, and CrO is₃The mol ratio of the N-hydroxysuccinimide to the compound shown in the formula II is 3-12:1, and the mol ratio of the N-hydroxysuccinimide to the compound shown in the formula II is 0.8-2: 1.

The preparation method of the compound shown in the formula I can further comprise the following steps: in the presence of an acid-binding agent, carrying out acylation reaction on a compound shown as a formula III and an acylation reagent to obtain a compound shown as a formula II;

the acylation reaction can be carried out in an organic solvent, which can be a conventional solvent in the art, and can be one or more of a halogenated hydrocarbon solvent (such as dichloromethane and/or chloroform), a ketone solvent (such as acetone), and an ether solvent (such as tetrahydrofuran) (such as dichloromethane).

In the acylation reaction, the amount of the organic solvent can be the amount conventionally used in the reactions in the field, and for example, the volume-to-mass ratio of the organic solvent to the compound shown in the formula III can be 2-15mL/g (for example, 8-12 mL/g).

In the acylation reaction, the acid-binding agent can be one or more of the acid-binding agents conventional in the reaction in the field, such as pyridine, triethylamine and diisopropylethylamine. The dosage of the acid-binding agent can be the conventional dosage of the reaction in the field, and can also be directly used as a solvent of the reaction.

In the acylation reaction, the acylation reagent can be an acylation reagent which is conventional in the reaction in the field, and can also be acetic anhydride, acetyl chloride, benzoic anhydride or benzoyl chloride. The amount of the acylating agent can be the amount conventionally used in the reactions of this type in the art, and for example, the molar ratio of the acylating agent to the compound of formula III can be 1.1-10.

The acylation reaction may also be carried out with the addition of a catalyst, which may be a catalyst conventional in the art for such reactions (e.g., p-dimethylaminopyridine).

The reaction temperature of the acylation reaction can be the reaction temperature which is conventional in the reaction of the type in the field, and can also be 10-50 ℃.

The progress of the acylation reaction can be monitored by conventional testing methods in the art (e.g., TLC, HPLC, GC or NMR, preferably TLC), and the end point of the reaction is generally determined as the point at which the compound of formula III is no longer reacted.

The invention also provides a preparation method a of (5R) -5-hydroxyl triptolide, which comprises the following steps:

(1) preparing the compound shown in the formula I according to the preparation method of the compound shown in the formula I;

(2) in a solvent, carrying out hydrolysis reaction on a compound shown as a formula I in the presence of an alkaline reagent;

in the preparation method a of (5R) -5-hydroxytriptolide, in the hydrolysis reaction, the solvent may be a conventional solvent in the art, and may also be one or more of an alcohol solvent (such as methanol and/or ethanol), an ether solvent (such as tetrahydrofuran) and water (for example, the solvent may be methanol, "a mixed solvent of methanol and water" or "a mixed solvent of methanol, tetrahydrofuran and water"). When the solvent is a mixed solvent of an alcohol solvent and water, or a mixed solvent of an ether solvent and water, the volume ratio of the alcohol solvent or the ether solvent to the water may be 1-5:1 (e.g., 2-4: 1).

In the preparation method a of (5R) -5-hydroxytriptolide, in the hydrolysis reaction, the amount of the solvent may be an amount conventionally used in the reaction in the art, and for example, the volume-to-mass ratio of the solvent to the compound represented by formula I may be 5-100mL/g (e.g., 10-60 mL/g).

In the preparation method a of (5R) -5-hydroxytriptolide, in the hydrolysis reaction, the alkaline reagent may be an alkaline reagent conventional in the reaction in the art, such as hydrazine and/or an alkali metal hydroxide (e.g., lithium hydroxide).

The amount of the alkaline reagent can be the conventional amount in the reaction in the field, when the alkaline reagent is hydrazine, the molar ratio of the hydrazine to the compound shown in the formula I can be 10-100:1 (such as 60-80: 1); when the alkaline agent is an alkali metal hydroxide, the molar ratio of the alkali metal hydroxide to the compound of formula I may be 1.2-2:1 (e.g., 1.4-1.6: 1).

In the preparation method a of (5R) -5-hydroxy triptolide, the reaction temperature of the hydrolysis reaction can be the conventional temperature of the reaction in the field, and can also be-25-20 ℃ (such as-15-10 ℃, and further such as-20-0 ℃).

In the preparation method a of (5R) -5-hydroxytriptolide, the progress of the hydrolysis reaction can be monitored by conventional testing methods in the art (such as TLC, HPLC, GC or NMR, preferably TLC), and the reaction end point is generally determined as the point at which the compound represented by formula I does not react any more.

In the preparation method a of (5R) -5-hydroxytriptolide, the hydrolysis reaction can be performed according to the conventional procedures in the art, for example, the following steps are included: dissolving the compound shown in the formula I in the solvent, and adding the alkaline reagent. When the alkaline reagent is hydrazine, the hydrazine can be hydrazine hydrate (such as 40-80% of hydrazine hydrate, and more such as 40-60% of hydrazine hydrate, the percentage is mass percent), and the addition mode of the hydrazine hydrate can be dropwise addition. When the alkaline agent is an alkali metal hydroxide, the alkali metal hydroxide may be added in the form of an aqueous solution of an alkali metal hydroxide (the concentration may be 0.2 to 2moL/L, for example, 1moL/L), and the addition may be carried out in divided portions (for example, three or more portions).

In the preparation method a of (5R) -5-hydroxy triptolide, the post-treatment of the hydrolysis reaction can adopt the post-treatment steps conventional in the reaction in the field, and can also comprise the following steps: adding acid to adjust pH to 5-7. The acid can be sulfuric acid or hydrochloric acid (the concentration can be 1-5moL/L), and the temperature of the system can be controlled to be-20-0 ℃ in the acid adding process.

In a certain scheme of the invention, in the hydrolysis reaction, the solvent is a mixed solvent of methanol and water, the volume ratio of the methanol to the water is 2-4:1, the alkaline reagent is hydrazine, and the molar ratio of the hydrazine to the compound shown in the formula I is 60-80: 1.

The invention also provides a preparation method b of (5R) -5-hydroxyl triptolide, which comprises the following steps: in a solvent, carrying out hydrolysis reaction on a compound shown as a formula I in the presence of an alkaline reagent;

wherein R is acetyl or benzoyl;

the alkaline reagent is hydrazine, and other reaction conditions of the hydrolysis reaction are as described above.

The invention also provides a compound having the structure:

on the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: provides a preparation method of (5R) -5-hydroxyl triptolide, which has better yield, does not need to use highly toxic reagents, avoids chiral resolution and is easy to realize industrial production.

Drawings

FIG. 1 is an XRPD pattern of (5R) -5-hydroxytriptolide prepared in example 3

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

In the following examples, the yield was calculated using the following formula: yield (mass of product obtained x purity of product obtained)/theoretical product mass.