阅读说明：本技术 一种醋酸四烯物制备方法 (Preparation method of tetraene acetate ) 是由 张金峰 张天杰 蒋澄宇 顾向忠 郭晔堃 钟静芬 于 2018-05-28 设计创作，主要内容包括：本发明公开了一种醋酸四烯物的制备方法。本发明提供了一种醋酸四烯物的制备方法,包括以下步骤：在有机溶剂中,将化合物2、自由基型卤代试剂、二氧化硫和缚酸剂进行反应,得到化合物1,即可。本发明的制备方法,以廉价易得的市售泼尼松龙为起始原料,两种不同类型羟基在一步反应中同时消除并形成环内烯,减少了反应步骤,且反应条件温和、后处理简单、收率高和粗品的化学纯度较高,适合工业化生产。<Image he="219" wi="700" file="DDA0001675692120000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of a tetraene acetate. The invention provides a preparation method of a tetraene acetate, which comprises the following steps: and (2) reacting the compound 2, a free radical type halogenating reagent, sulfur dioxide and an acid-binding agent in an organic solvent to obtain a compound 1. The preparation method of the invention takes the cheap and easily available commercially available prednisolone as the initial raw material, two different types of hydroxyl are simultaneously eliminated in one-step reaction to form the cyclopropene, so that the reaction steps are reduced, the reaction conditions are mild, the post-treatment is simple, the yield is high, the chemical purity of the crude product is high, and the method is suitable for industrial production.)

1. a process for the preparation of compound 1, comprising the steps of: reacting the compound 2, a free radical type halogenating reagent, sulfur dioxide and an acid-binding agent in an organic solvent to obtain a compound 1,

2. The method according to claim 1, wherein the organic solvent is a polar organic solvent;

and/or the volume-to-mass ratio of the volume of the organic solvent to the mass of the compound 2 is 2-20 mL/g, for example 6-10 mL/g;

And/or the free radical type halogenating reagent is N-halogen succinimide reagent and/or halogenated dimethyl hydantoin reagent;

and/or the molar ratio of the free radical type halogenating agent to the compound 2 is 2.0-8.0;

And/or the sulfur dioxide is introduced into the organic solvent in a gas form;

and/or the molar ratio of the sulfur dioxide to the compound 2 is 8 to 20, such as 8 to 16;

And/or the acid-binding agent is an organic weak base acid-binding agent;

And/or the molar ratio of the acid-binding agent to the compound 2 is 10-50;

And/or the temperature of the reaction is-25 to-5 ℃;

and/or the reaction time is 0.2-1 h, such as 0.5-2 h.

3. The method according to claim 2, wherein the organic solvent is one or more of a nitrile solvent, an ether solvent, an amide solvent, a pyridine solvent and a sulfoxide solvent;

And/or the free radical type halogenating reagent is an N-halogen succinimide reagent;

And/or the molar ratio of the free radical halogenating agent to the compound 2 is 1.9-3.0;

And/or the acid-binding agent is a pyridine acid-binding agent or a tertiary amine acid-binding agent;

and/or the molar ratio of the acid-binding agent to the compound 2 is 16-50;

And/or the temperature of the reaction is-15 to-10 ℃.

4. The method according to claim 3, wherein the organic solvent is one or more of a nitrile solvent, an ether solvent, an amide solvent and a pyridine solvent; preferably an amide-based solvent and/or a pyridine-based solvent;

And/or the molar ratio of the free radical halogenating agent to the compound 2 is 3.0;

and/or the acid-binding agent is a pyridine acid-binding agent.

5. The production method according to claim 2, wherein the nitrile-based solvent is acetonitrile; the ether solvent is tetrahydrofuran; the amide solvent is N, N-dimethylformamide or N, N-dimethylacetamide; the pyridine solvent is pyridine; the sulfoxide solvent is dimethyl sulfoxide;

And/or the halogenated dimethyl hydantoin reagent is one or more of dichlorodimethyl hydantoin, dibromodimethyl hydantoin and bromochlorodimethyl hydantoin; the N-halogen succinimide reagent is N-chlorosuccinimide and/or N-bromosuccinimide; preferably N-chlorosuccinimide;

and/or the pyridine acid-binding agent is pyridine; the tertiary amine acid-binding agent is triethylamine or N, N-diisopropylethylamine.

6. The preparation method according to any one of claims 1 to 5, wherein the reaction comprises the following post-treatment steps after the reaction is finished: pouring the reaction solution into ice water, adjusting the pH value to be weakly acidic, stirring and filtering.

7. the method of claim 1, further comprising the steps of: in a solvent, carrying out esterification reaction on a compound 3 and acetic anhydride (Ac2O) in the presence of a catalyst to prepare a compound 2,

8. The method according to claim 7, wherein the haloalkane-type solvent and/or amide-type solvent; the chloroalkane solvent is preferably dichloromethane; the amide solvent is preferably N, N-dimethylacetamide or N, N-dimethylformamide;

And/or the volume-mass ratio of the volume of the solvent to the mass of the compound 3 is 3-8; preferably 5 to 8;

And/or the catalyst is 4-dimethylaminopyridine;

And/or the molar ratio of the catalyst to the compound 3 is 0.1 to 1.5, such as 1.0 to 1.5;

And/or the molar ratio of the acetic anhydride to the compound 3 is 1.1-1.5;

And/or the reaction temperature is 25-50 ℃, such as 35-45 ℃;

and/or the reaction time is 0.5-3 h, preferably 0.5-1 h;

And/or after the esterification reaction is finished, the method comprises the following post-treatment steps: the reaction solution was poured into ice water, stirred and filtered.

9. The method of claim 1, comprising the steps of:

(1) Under the protection of gas, reacting the compound 2 with the free radical type halogenating reagent in the organic solvent to obtain an intermediate compound 2A;

(2) under the action of the acid-binding agent and the sulfur dioxide, the intermediate compound 2A is subjected to elimination reaction to obtain a compound 1,

wherein, X is selected from one of Cl, Br and I, and X' is selected from one of Cl, Br and I.

10. An intermediate compound 2A having the structure shown below:

Wherein, X is selected from one of Cl, Br and I, and X' is selected from one of Cl, Br and I.

Technical Field

The invention relates to a preparation method of a tetraene acetate.

Background

The compound of tetraene acetate, the chemical name of which is 21-hydroxypregna-1, 4,9(11), 16-tetraene-3, 20-diketone-21-acetic ester, is a very important corticosteroid medicine intermediate, and can be used as a starting raw material to synthesize various medicaments such as triamcinolone acetonide, triamcinolone, budesonide, dexamethasone, flumethasone, fluticasone propionate, and Allolone, and the market prospect is good.

The following four methods are mainly reported in the literature for synthesizing tetraene acetate.

The method comprises the following steps: (reference, Steroids 2013(78): 1281-1287)

the method relates to two-step rearrangement reaction, has complex mechanism and complex operation, is not easy to control the quality of an intermediate, and has lower yield of only 63 percent in the first step.

The second method comprises the following steps: (ref.J.Am.chem.Soc.1959 (81):4962-4968)

The method takes 16-dehydroprogesterone as a raw material, synthesizes the tetraene acetate through four-step reaction, has extremely low total yield (5.6 percent), and has high price of the 16-dehydroprogesterone.

the third method comprises the following steps: (reference, CN 102603843)

The preparation method is prepared by ethynylation, esterification, oxidation and rearrangement, the total yield is 54.1 percent, the purity after refining is only 96 percent, and the oxidation process uses noble metal catalysis, so the production cost is high.

the method four comprises the following steps: (reference, CN 105622699)

The preparation method is prepared by 5 steps of reaction, has longer route, harsher reaction conditions and lower total yield which is only 36.1 percent.

Disclosure of Invention

the invention aims to overcome the defects that the preparation method of the tetraene acetate in the prior art is long in reaction route, harsh in reaction condition, high in cost, not suitable for industrial production and the like, and expensive reagents are possibly used. The preparation method of the invention takes the cheap and easily available commercially available prednisolone as the initial raw material, two different types of hydroxyl are simultaneously eliminated in one-step reaction to form the cyclopropene, so that the reaction steps are reduced, the reaction conditions are mild, the post-treatment is simple, the yield is high, the chemical purity of the crude product is high, and the method is suitable for industrial production.

The invention provides a preparation method of a compound 1, which comprises the following steps: reacting the compound 2, a free radical type halogenating reagent, sulfur dioxide and an acid-binding agent in an organic solvent to obtain a compound 1,

Wherein the organic solvent may be a polar organic solvent; preferably one or more of nitrile solvents, ether solvents, amide solvents, pyridine solvents and sulfoxide solvents; more preferably one or more of nitrile solvents, ether solvents, amide solvents and pyridine solvents; most preferred are amide solvents and/or pyridine solvents. The nitrile solvent is preferably acetonitrile. The ethereal solvent is preferably Tetrahydrofuran (THF). The amide solvent is preferably N, N-Dimethylformamide (DMF) or N, N-Dimethylacetamide (DMA). The pyridine solvent is preferably pyridine. The sulfoxide-based solvent is preferably dimethyl sulfoxide (DMSO).

The amount of the organic solvent used is not particularly limited, as long as the compound 2 can be dissolved without affecting the reaction. The volume of the organic solvent is preferably 2 to 20mL/g, for example 6 to 10mL/g, in comparison with the volume mass of the compound 2.

Wherein the free radical type halogenating reagent is N-halogen succinimide reagent and/or halogenated dimethyl hydantoin reagent; preferably N-halosuccinimide reagents. The halogenated dimethyl hydantoin reagent is preferably one or more of dichlorodimethyl hydantoin, dibromodimethyl hydantoin and bromochlorodimethyl hydantoin. The N-halogen succinimide reagent is preferably N-chlorosuccinimide (NCS) and/or N-bromosuccinimide (NBS); more preferably N-chlorosuccinimide.

Wherein, the molar ratio of the free radical type halogenating agent to the compound 2 can be 2.0-8.0, preferably 1.9-3.0, and more preferably 3.0.

wherein the sulfur dioxide is preferably introduced into the organic solvent in the form of a gas.

Wherein the molar ratio of the sulfur dioxide to the compound 2 can be 8 to 20, such as 8 to 16.

Wherein the acid-binding agent can neutralize acid generated by the reaction without participating in the reaction, and the reaction is not influenced. Preferably an organic weak base acid-binding agent; more preferably a pyridine acid-binding agent or a tertiary amine acid-binding agent; most preferably a pyridine acid-binding agent. The pyridine acid-binding agent is preferably pyridine. The tertiary amine acid-binding agent is preferably Triethylamine (TEA) or N, N-Diisopropylethylamine (DIPEA).

wherein the dosage of the acid-binding agent is at least the dosage of acid generated by neutralization reaction; the molar ratio of the acid-binding agent to the compound 2 is preferably 10-50; more preferably 16 to 50.

wherein the temperature of the reaction can be-25 to-5 ℃; preferably-15 to-10 ℃.

Wherein the reaction time is 0.2-1 h, such as 0.5-2 h, preferably until the compound 2 is not reacted or completely reacted by detection (such as TLC).

in the present invention, after step 2 is finished, the following post-processing steps may be further included: pouring the reaction solution into ice water, adjusting the pH value to be weakly acidic, stirring and filtering.

wherein, preferably, the operation of washing the filter cake is further included after the suction filtration; more preferably, the operation of drying the filter cake is also included after washing the filter cake.

In the present invention, the preparation method of compound 1 may further comprise the following steps: in a solvent, carrying out esterification reaction on a compound 3 and acetic anhydride (Ac2O) in the presence of a catalyst to prepare a compound 2,

Among them, the solvent may be a solvent conventionally used in such reactions in the art. Preferably a haloalkane solvent and/or an amide solvent. The chloroalkane solvent is preferably dichloromethane. The amide solvent is preferably N, N-Dimethylacetamide (DMA) or N, N-Dimethylformamide (DMF).

the amount of the solvent used is not particularly limited, as long as the compound 3 can be dissolved without affecting the reaction. The volume-to-mass ratio of the volume of the solvent to the mass of the compound 3 may be 3 to 8, and more preferably 5 to 8.

Among them, the catalyst may be one conventionally used in such reactions in the art, and is preferably 4-Dimethylaminopyridine (DMAP).

Wherein the molar ratio of the catalyst to the compound 3 may be 0.1 to 1.5, for example 1.0 to 1.5.

wherein the molar ratio of the acetic anhydride (Ac2O) to the compound 3 can be 1.1-1.5.

Wherein the temperature of the reaction may be a temperature conventional in the art for such reactions. Preferably 25 to 50 ℃; for example 35 to 45 ℃.

Wherein the esterification reaction proceeds until the compound 3 is no longer reacted or is completely reacted by detection (e.g., TLC). The reaction time may be 0.5 to 3 hours, preferably 0.5 to 1 hour.

in the invention, the esterification reaction can also comprise the following post-treatment steps after the esterification reaction is finished: the reaction solution was poured into ice water, stirred and filtered.

Wherein, preferably, the operation of washing the filter cake is included after the suction filtration; more preferably, said washing of the filter cake comprises an operation of drying the filter cake.

In the present invention, the preparation method of the compound 1 preferably comprises the steps of:

(1) under the protection of gas, reacting the compound 2 with the free radical type halogenating reagent in the organic solvent to obtain an intermediate compound 2A;

(2) under the action of the acid-binding agent and the sulfur dioxide, the intermediate compound 2A is subjected to elimination reaction to obtain a compound 1,

X is selected from one of Cl, Br and I, and X' is selected from one of Cl, Br and I.

Wherein, the gas in the gas protection can be inert gas; preferably nitrogen (N2) or argon (Ar 2).

The invention also provides an intermediate compound 2A, the structure of which is shown as follows:

Wherein, X is selected from one of Cl, Br and I, and X' is selected from one of Cl, Br and I.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

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

The positive progress effects of the invention are as follows:

The method takes commercially available prednisolone as an initial raw material, synthesizes a tetraene acetate through two steps of reactions, wherein one step is to eliminate two hydroxyls with different configurations, namely 11 beta and 17 alpha, simultaneously to form cycloolefine, so that the synthesis route is shortened, the total yield and the purity of a crude product are high, the post-reaction treatment is simple, the cost is reduced, and the method is suitable for industrial production.

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.