阅读说明：本技术 一种还原缩硫醛或缩硫酮脱硫的方法 (Method for reducing mercaptal or thioketone for desulfurization ) 是由 娄红祥 徐泽军 孙斌 于 2019-10-30 设计创作，主要内容包括：本发明提供一种还原缩硫醛或缩硫酮脱硫的方法,该方法以水合肼为还原剂,将缩硫醛或缩硫酮还原为甲基或亚甲基。本发明工艺简便、环境友好,能在克级以上规模安全转化,适用于化工医药领域,可实现规模化生产。(The invention provides a method for reducing mercaptal or thioketone for desulfurization, which takes hydrazine hydrate as a reducing agent to reduce mercaptal or thioketone into methyl or methylene. The method has the advantages of simple and convenient process, environmental protection, capability of safely converting in a gram-level or above scale, suitability for the field of chemical and medical engineering and realization of large-scale production.)

1. A method for reducing mercaptal or thioketal to desulfurize uses hydrazine hydrate as a reducing agent to reduce the mercaptal or thioketal into methyl or methylene.

2. The method according to claim 1, wherein the method comprises mixing the mercaptal or thione with a reaction solvent, adding an alkaline reagent, using hydrazine hydrate as a reducing agent, and heating under nitrogen to reduce the mercaptal or thione to a methyl group or a methylene group.

3. The process according to claim 2, characterized in that the reaction solvent is diethylene glycol and/or ethylene glycol.

4. The process according to claim 2, characterized in that the alkaline agent is selected from cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, preferably cesium carbonate.

5. The process according to claim 1 or 2, characterized in that the molar ratio of mercaptal or thione to hydrazine hydrate is from 1:5 to 1: 15;

preferably, the molar ratio of mercaptal or thione to alkaline agent is from 1:5 to 1: 15.

6. A method of reducing mercaptal or thioketal for desulfurization, the method comprising reducing compound 1 to compound 2 with hydrazine hydrate as a reducing agent:

formula 1:formula 2:

7. the method according to claim 6, wherein the method comprises dissolving compound 1 in an organic solvent, adding an alkaline reagent, using hydrazine hydrate as a reducing agent, and heating under nitrogen to reduce compound 1 to compound 2.

8. The process according to claim 7, characterized in that the organic solvent is diethylene glycol and/or ethylene glycol.

9. The method of claim 7, wherein the alkaline agent is cesium carbonate.

10. The method according to claim 6 or 7, wherein the molar ratio of compound 1 to hydrazine hydrate is from 1:5 to 1: 15;

preferably, the molar ratio of compound 1 to alkaline agent is from 1:5 to 1: 15.

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, in particular to a method for reducing mercaptal or thioketone for desulfurization.

Background

The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.

The reduction of mercaptal or thioketal to desulfurize and prepare methyl or methylene is an important chemical transformation, and is widely used in the synthesis of medicines and intermediates. The applicant has found through research that the current reduction desulfurization reaction can be roughly divided into the following types: (1) taking active metal as a reducing agent, wherein the representative agent is Raney nickel, and nickel derivatives NiCrAs (prepared from nickel acetate, sodium hydride and tertiary amyl alcohol) and Ni₂B (nickel chloride and sodium borohydride preparation) and an ammonia solution of metallic sodium or lithium. The reagent is most widely used, has better functional group compatibility and yield, but needs several times of equivalent of Raney nickel, because the Raney nickel is expensive and extremely flammable, great potential safety hazard exists in gram-level reaction scale, and a large amount of waste residues with high activity and difficult treatment are generated, and the reaction scale is difficult to safely amplify; (2) using metal hydrides as reduction reagentsThe agent, for example, is subjected to reductive desulfurization reaction with a radical initiator, azobisisobutyronitrile, and tri-n-butyltin hydride as a reducing agent. The reaction condition is mild, but tri-n-butyltin hydride has high toxicity and is not suitable for being applied to pharmaceutical chemical production; (3) non-metal compounds such as diphosphorus tetraiodide and sodium ethyl mercaptide are used as reducing agents. This type of reducing agent has poor functional group compatibility and is limited only to compounds of relatively simple structure.

Disclosure of Invention

Therefore, the invention aims to provide a method for reducing mercaptal or thioketal and desulfurizing, which can be produced in an enlarged way.

Specifically, the invention has the following technical scheme:

in a first aspect of the invention, the invention provides a method for reducing desulfurization, wherein hydrazine hydrate is used as a reducing agent to reduce mercaptal or thioketal into methyl or methylene.

In an embodiment of the present invention, the mercaptal or thione refers to a compound obtained by reacting a carbonyl compound with an alcohol or thiol, which is generally referred to as having

And/or

A compound of the group in which n is 0 or 1 and when n is 0, it is a five-membered ring

Or

When n is 1, it is a six-membered ringOr

In an embodiment of the present invention, the method comprises mixing mercaptal or thione with a reaction solvent, adding an alkaline reagent, and heating under nitrogen with hydrazine hydrate as a reducing agent to reduce mercaptal or thione to methyl or methylene.

In an embodiment of the present invention, the reaction solvent is diethylene glycol and/or ethylene glycol.

In an embodiment of the invention, the alkaline agent is selected from cesium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide.

In an embodiment of the invention, the molar ratio of mercaptal or thioketal to hydrazine hydrate is from 1:5 to 1: 15.

In an embodiment of the invention, the molar ratio of mercaptal or thione to alkaline agent is from 1:5 to 1: 15.

In some embodiments of the invention, mercaptal or thioketal is added to a reaction flask with an agitated reflux condenser, dissolved in an organic solvent, and hydrazine hydrate (5-15eq.) and alkaline reagent (5-15eq.) are added sequentially. Stirring, placing in 80-180 deg.C oil bath (nitrogen atmosphere), reacting for 2-8h, cooling to room temperature after reaction, adding water to quench reaction, extracting water phase with ethyl acetate for three times, combining organic phases, washing organic phases with water and saturated salt water, concentrating organic solvent, and performing flash column chromatography to obtain desired methyl or methylene product. Unless otherwise specified, the eq. in the present invention means a chemical equivalent.

In a second aspect of the invention, the invention provides a method for reducing mercaptal or thioketal for desulfurization, the method comprising reducing compound 1 to compound 2:

compound 1:

compound 2:

in an embodiment of the present invention, the method comprises dissolving compound 1 in an organic solvent, adding an alkaline reagent, using hydrazine hydrate as a reducing agent, and heating under nitrogen to reduce compound 1 to compound 2.

In an embodiment of the present invention, the organic solvent is diethylene glycol and/or ethylene glycol.

In an embodiment of the invention, the alkaline agent is cesium carbonate. In the implementation process of preparing the compound 2 from the compound 1, the invention discovers that when hydrazine hydrate is used as a reducing agent, potassium carbonate, sodium hydroxide and potassium hydroxide are used as alkaline substances, the reaction is difficult to carry out, the yield is low, and particularly when potassium tert-butoxide is used as the alkaline substance, only a trace amount of product can be generated.

In an embodiment of the invention, the molar ratio of compound 1 to hydrazine hydrate is from 1:5 to 1: 15.

Preferably, the molar ratio of compound 1 to alkaline agent is from 1:5 to 1: 15.

In an embodiment of the present invention, the hydrazine hydrate is preferably 80% to 98% hydrazine hydrate, more preferably 98% hydrazine hydrate.

In some embodiments, the concentration of hydrazine hydrate can affect the choice of alkaline material, such as when 80% hydrazine hydrate is used, the alkaline material is potassium hydroxide and the reaction is not as easy as with 98% hydrazine hydrate.

In some embodiments, when the alkaline reagent is cesium carbonate, the reaction can occur under a wider range of reaction conditions and can be performed more easily, and therefore, cesium carbonate is a preferred alkaline reagent in the present invention. For example, when hydrazine hydrate is used as a catalyst, cesium carbonate is used as an alkaline reagent, and diethylene glycol is used as an organic solvent (reaction solvent), the reaction can be carried out within the range of 140 ℃ to 180 ℃, and the reaction time is 2 to 6 hours. When the reaction temperature is lower than 140 ℃, the reaction is difficult to proceed.

Further, in some embodiments, when the basic agent is cesium carbonate, the reaction yield increases significantly as the reaction temperature increases, such as from 140 ℃ to 170 ℃, but decreases as the temperature continues to increase to 180 ℃, but the yield at 180 ℃ is still higher than the yield at 140 ℃; in still other embodiments, when the basic agent is cesium carbonate, the reaction yield increases significantly with increasing reaction time, such as when the reaction time increases from 2 hours to 4 hours, but continues to increase to 6 hours, the reaction yield decreases, but the yield at 6 hours is still higher than the yield at 2 hours.

Therefore, in some embodiments of the present invention, the reductive desulfurization method uses hydrazine hydrate as a reducing agent to reduce mercaptal or thioketone into corresponding methyl or methylene, the alkaline reagent is cesium carbonate, the organic solvent is diethylene glycol, the reaction temperature is 170-. And, in some embodiments, a reaction temperature of 170 ℃ and a reaction time of 4 hours is more preferred.

In the embodiment of the invention, the experiment is amplified to be more than gram level, the reaction yield is still stable, and no obvious reduction is caused. For example, in some embodiments of the present invention, the amount of compound 1 (i.e., substrate) is increased from 120mg to 5.3g (i.e., 5300mg) under the same conditions, i.e., the molar ratio of compound 1 to hydrazine hydrate is 1:15, the alkaline reagent is cesium carbonate, the molar ratio of compound to cesium carbonate is 1:15, the reaction temperature is 170 ℃, and the reaction time is 4 hours, the reaction is safe and the yield is stable without significant decrease.

In the embodiment of the present invention, in the reaction of reducing and desulfurizing compound 1 to produce compound 2, hydrazine hydrate is used as a reducing agent, and the applicant tried to set the reaction temperature to be lower than 140 ℃, for example, 80 ℃, 100 ℃ and 135 ℃, and the reaction is difficult to proceed, and no compound 2 is produced.

In the embodiment of the present invention, in the reaction of reducing and desulfurizing compound 1 to produce compound 2, hydrazine hydrate is used as a reducing agent, and the applicant tried to replace the catalyst with potassium carbonate, sodium hydroxide or potassium hydroxide, and found that the reaction is difficult to proceed, and even if the reaction temperature and the amount of the reactant are adjusted on the basis of the catalyst, the reaction is still difficult to proceed, and the yield is low, and can reach 4% at the minimum.

In the embodiment of the present invention, in the reaction of reducing and desulfurizing compound 1 to produce compound 2, the applicant has tried to replace hydrazine hydrate with other commonly used reducing agents (such as diphosphorus tetraiodide, sodium ethanethiol, tri-n-butyltin hydride, etc.), and the reaction system is disturbed except for raney nickel, so that the desired reduction product compound 2 cannot be obtained; even if applicants attempted to adjust other reaction conditions, compound 2, the desired product, was not obtained.

In the embodiment of the present invention, in the reaction of producing compound 2 by reductive desulfurization of compound 1, the applicant has tried to change hydrazine hydrate to raney nickel and the reaction proceeds, but the yield is unstable, the reaction scale can be maintained only at about 100mg, and the reaction cannot be scaled up, and it is difficult to industrially produce the hydrazine hydrate.

In some embodiments of the present invention, the method for obtaining compound 2 by reductive desulfurization of compound 1 comprises dissolving compound 1 in diethylene glycol and/or ethylene glycol (diethylene glycol is more preferred) as an organic solvent, adding hydrazine hydrate and cesium carbonate, and reacting in nitrogen at 140-180 ℃ for 2-6 hours to generate compound 2, wherein the molar ratio of compound 1 to hydrazine hydrate is 1:5-1: 15; the molar ratio of the compound 1 to the alkaline reagent is 1:5-1: 15. After the reaction is finished, adding water to quench the reaction, separating and purifying to obtain the compound 2.

And, in an embodiment of the present invention, the present invention provides an amplification method for reductive desulfurization of compound 1 to compound 2, the method comprising: dissolving a compound 1 in an organic solvent diethylene glycol, adding hydrazine hydrate and cesium carbonate, and reacting for 3-6 hours in nitrogen at 170-180 ℃ to generate a compound 2, wherein the molar ratio of the compound 1 to the hydrazine hydrate is 1:5-1: 15; the molar ratio of the compound 1 to the alkaline reagent is 1:5-1: 15. After the reaction is finished, adding water to quench the reaction, separating and purifying to obtain the compound 2.

Compared with the prior art, the invention has the following advantages:

the invention creatively adopts hydrazine hydrate as a reducing agent to carry out reduction desulfurization on mercaptal and thioketone, and compared with the conventional method, the method has the advantages thatE.g. as compared to the use of active metals such as Raney nickel, NiCras, Ni₂B. The ammonia solution of metal sodium or lithium is a reducing reagent, the reagent cost of hydrazine hydrate is cheaper, taking Raney nickel as an example, the price difference of the two is 30-50 times, and the Raney nickel has larger activity difference and unstable yield according to the difference of a preparation method, and belongs to high-risk materials and is extremely flammable, large-scale reaction above gram level has larger potential safety hazard, and generates a large amount of waste residues with high activity and difficult treatment, the post-treatment is difficult, the reaction scale is difficult to realize safe amplification, and the scale is only about 100 mg; for example, compared with metal hydride as a reducing agent (such as tri-n-butyl tin hydride), tri-n-butyl tin hydride is a highly toxic substance although the reaction temperature is moderate, is colorless and tasteless, and is not suitable for pharmaceutical chemical production; for example, compared with a non-metal compound as a reducing agent (such as diphosphorus tetraiodide or sodium ethyl mercaptide), the reducing agent of the type has poor functional group compatibility, and is only limited to a compound with a simpler structure, such as the compound 1 shown in the invention, so that the compound 2 cannot be obtained under the reducing agent.

The invention uses cheap and easily obtained hydrazine hydrate as a reducing reagent, conveniently converts mercaptal or thioketone into corresponding methyl or methylene, has simple and convenient process and environmental protection, can safely convert on a scale of more than gram level, is suitable for the field of chemical engineering and medicine, and can realize large-scale production.

Detailed Description

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 defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. The reagents or starting materials used in the present invention can be purchased from conventional sources, and unless otherwise specified, the reagents or starting materials used in the present invention can be used in a conventional manner in the art or in accordance with the product specifications. 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.

The invention can be carried out according to the following reaction: