阅读说明：本技术 一种高非对映选择性2-（羟基（苯基）甲基）环己酮衍生物及其制备方法 (High diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and preparation method thereof ) 是由 刘艳 吕嘉敏 卢汉彬 丸冈启二 于 2019-08-27 设计创作，主要内容包括：本发明属于合成化学技术领域,公开了一种高非对映选择性2-(羟基(苯基)甲基)环己酮衍生物及其制备方法。所述2-(羟基(苯基)甲基)环己酮衍生物的化学结构如式(1)所示,其中,R为硝基；<Image he="267" wi="334" file="DDA0002181544880000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>所述2-(羟基(苯基)甲基)环己酮衍生物是在苯甲醛衍生物中加入路易斯酸、催化剂、二甲基亚砜和环己酮,在室温下搅拌反应；反应结束后加入水充分稀释体系中的二甲基亚砜,再用乙酸乙酯萃取,合并萃取得到的有机相,减压蒸馏浓缩,得到粗产品；在40～55℃下用乙酸乙酯将粗产品溶解,加入正己烷后放入-10～10℃下静置重结晶,经过滤、洗涤后制得。本发明方法制备条件温和,操作步骤简单,能有效提高产物的非对映选择性。(The invention belongs to the technical field of synthetic chemistry, and discloses a high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and a preparation method thereof. The chemical structure of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is shown as a formula (1), wherein R is nitro; the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is prepared by adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and stirring for reaction at room temperature; after the reaction is finished, adding water to fully dilute the dimethyl sulfoxide in the system, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product; dissolving the crude product with ethyl acetate at 40-55 ℃, adding n-hexane, standing at-10 ℃, and performing heavy cakingAnd (4) filtering and washing the crystal to obtain the crystal. The method has mild preparation conditions and simple operation steps, and can effectively improve the diastereoselectivity of the product.)

1. A high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is characterized in that the chemical structure of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is shown as a formula (1), wherein R is a nitro group;

the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is prepared by adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and fully stirring at room temperature to react; after the reaction is finished, adding water to fully dilute the dimethyl sulfoxide in the system, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product; and (3) completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane, standing at-10 ℃ for recrystallization, filtering and washing to obtain the product.

2. The highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has a formula:

3. the highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the Lewis acid is one or more of ferrous chloride tetrahydrate, ferric chloride, zinc chloride, aluminum chloride, and antimony pentafluoride.

4. The highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the catalyst is racemic D, L-proline, D-proline or L-proline.

5. The high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the cyclohexanone is 1 to 3 equivalents of benzaldehyde derivative.

6. The high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to claim 1, wherein the catalyst is 10 to 30 mol% of the benzaldehyde derivative, and the Lewis acid is 10 to 30 mol% of the benzaldehyde derivative.

7. Process for the preparation of highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivatives according to any of claims 1 to 6, characterized in that it comprises the following specific steps:

s1, adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and fully stirring at room temperature to react;

s2, adding water to fully dilute the dimethyl sulfoxide in the system after the reaction in the step S1 is finished, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product;

s3, completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane while the crude product is hot, and standing at-10 ℃ for recrystallization; after filtration and washing of the remaining solid with n-hexane, a 2- (hydroxy (phenyl) methyl) cyclohexanone derivative was obtained.

8. The method for preparing 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity according to claim 7, wherein the reaction time in step S1 is 24-168 h.

9. The method for preparing 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity according to claim 7, wherein the standing time in step S3 is 0.5-168 h.

10. Use of the highly diastereoselective 2- (hydroxy (phenyl) methyl) cyclohexanone derivative according to any one of claims 1 to 6 in the field of catalytic chemistry or medicine.

Technical Field

The invention belongs to the technical field of synthetic chemistry, and particularly relates to a high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative and a preparation method thereof.

Background

Chiral organic compounds and their properties are important research directions in stereochemistry, and play important roles in natural product chemistry, biochemistry, pharmaceutical chemistry, and polymer chemistry. When a chiral drug molecule acts on an organism, the enantiomeric interactions produced by drug molecules of different configurations tend to be different and even diametrically opposed, resulting in distinct pharmacological and toxicological effects. A typical example is the "reaction stop" event occurring in Europe at the end of the 50 th century, the tragic nature of seal malformation of pregnant women caused by taking thalidomide (also known as "reaction stop"), and it was subsequently discovered that the reaction stop drug contained two different optical isomers, the (R) -isomer had a sedative effect and the (S) -isomer had a teratogenic effect. Therefore, in the preparation process of organic molecules, the method for solving the stereochemistry problem and developing a high-selectivity method has important significance.

The aldol condensation reaction is an important synthetic method for increasing a carbon chain in organic synthesis, and plays an important role in drug synthesis and functional molecule construction. Wherein the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is an important fine chemical intermediate, and the compound is prepared by developing a high-selectivity method, is particularly suitable for developing a method for industrial production, and has important economic value.

At present, the main methods for obtaining the compounds with high stereoselectivity are as follows: (1) racemate resolution, by which racemate is the most commonly used method in the acquisition of chiral drugs. (2) Asymmetric synthesis methods, which mainly comprise chemical asymmetric catalytic synthesis and biological asymmetric catalytic synthesis. At present, the first method is mainly separation by chromatography, but is not suitable for industrial production; the second method is difficult, expensive and time-consuming to develop. Therefore, the development of a method for obtaining 2- (hydroxy (phenyl) methyl) cyclohexanone derivatives with high diastereoselectivity, which can be industrially produced, is an urgent problem to be solved.

Disclosure of Invention

In order to solve the above-mentioned disadvantages and drawbacks of the prior art, the present invention is primarily directed to a 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity. The derivative is a product with high diastereoselectivity in a trans-configuration, has higher diastereoselectivity, and has a ratio of the trans-configuration to a cis-configuration (anti: syn) of 50: 1.

the invention also aims to provide a preparation method of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity. The method has the advantages of lower requirements on equipment, mild reaction conditions, simple operation, no need of using expensive chiral catalysts, environmental friendliness and the like, can efficiently carry out chiral resolution, and simultaneously obtains the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity. The multiple asymmetric aldol condensation products can directly obtain high diastereoselectivity products by using a recrystallization method through the method, are suitable for industrial production, and provide a basis for mass production and subsequent research of fine chemical engineering and biological medicine.

The purpose of the invention is realized by the following technical scheme:

a high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has a chemical structure shown in a formula (1), wherein R is nitro;

the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is prepared by adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and fully stirring at room temperature to react; after the reaction is finished, adding water to fully dilute the dimethyl sulfoxide in the system, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product; and (3) completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane, standing at-10 ℃ for recrystallization, filtering, and washing to obtain the product.

Preferably, the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has the structural formula:

preferably, the lewis acid is one or more of ferrous chloride tetrahydrate, ferric chloride, zinc chloride, aluminum chloride or antimony pentafluoride.

Preferably, the catalyst is racemic D, L-proline, D-proline or L-proline.

Preferably, the cyclohexanone accounts for 1-3 equivalents of the benzaldehyde derivative.

Preferably, the catalyst is 10-30 mol% of the benzaldehyde derivative, and the Lewis acid is 10-30 mol% of the benzaldehyde derivative.

The preparation method of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative with high diastereoselectivity comprises the following specific steps:

s1, adding Lewis acid, a catalyst, dimethyl sulfoxide and cyclohexanone into a benzaldehyde derivative, and stirring at room temperature for full reaction;

s2, adding water to fully dilute the dimethyl sulfoxide in the system after the reaction in the step S1 is finished, extracting with ethyl acetate, combining organic phases obtained by extraction, and carrying out reduced pressure distillation and concentration to obtain a crude product;

s3, completely dissolving the crude product by using ethyl acetate at 40-55 ℃, adding n-hexane while hot, and standing at-10 ℃; filtering while the solution is cold, washing the residual solid with n-hexane, and then using the washed residual solid to prepare the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative.

Preferably, the reaction time in the step S1 is 24-168 h.

Preferably, the standing time in the step S3 is 0.5-168 h.

The high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative is applied to the field of catalytic chemistry or medicines.

Compared with the prior art, the invention has the following beneficial effects:

1. the invention takes cyclohexanone and benzaldehyde derivatives as raw materials, Lewis acid and a catalyst are added, and the diastereoselectivity of the product is improved directly by a recrystallization method after the synthesized crude product is extracted and concentrated. The method has mild conditions, and is safe and reliable; the method has the advantages of greatly reducing the consumption of solvents consumed in the purification by silica gel column chromatography in the traditional method, along with simple operation steps, environmental protection, and improvement of efficiency and resource utilization rate.

2. The invention utilizes cheap and easily obtained solvents, such as n-hexane and ethyl acetate, to carry out recrystallization so as to directly and effectively improve the diastereoselectivity of the 2- (hydroxy (phenyl) methyl) cyclohexanone derivative. Compared with the enzymatic resolution, the high diastereoselectivity 2- (hydroxy (phenyl) methyl) cyclohexanone derivative has lower cost and does not need to carry out complicated enzyme screening process; compared with the preparative chromatography, the method has the advantages of less resolving solvent consumption and less time.

3. In the prior art, the common diastereoisomer resolution mode of the compounds is to use chromatography for purification and separation, the chromatography resolution is suitable for a small amount of compounds, the separation difficulty is high, and the industrial production is difficult to realize. Besides high requirements on equipment and sites, the use of a large amount of eluent increases the production cost and does not accord with the industrial concept of environmental protection; it is also a waste of time and human resources, however, the purification results are often not very desirable. The invention carries out diastereoisomer resolution by recrystallization, improves the diastereoisomer ratio (dr) more efficiently, can complete the resolution of a large amount of compounds, and is suitable for industrial production; the method has the advantages of less solvent, low equipment and instrument requirements, environmental protection and good purification effect, and the trans-configuration and cis-configuration (anti: syn) can reach 50: 1.

drawings

FIG. 1 shows NMR of 2- (hydroxy (2-nitrophenyl) methyl) cyclohex-1-one in example 1: (¹H-NMR) profile;

FIG. 2 shows NMR of 2- (hydroxy (2-nitrophenyl) methyl) cyclohex-1-one in example 1: (¹³C-NMR) profile;

FIG. 3 shows 2- (hydroxy (3-nitrophenyl) methyl) group in example 2Nuclear magnetic resonance of cyclohex-1-ones (¹H-NMR) profile;

FIG. 4 is the NMR of 2- (hydroxy (3-nitrophenyl) methyl) cyclohex-1-one in example 2: (NMR)¹³C-NMR) profile;

FIG. 5 is the NMR of 2- (hydroxy (4-nitrophenyl) methyl) cyclohex-1-one in example 3: (NMR)¹H-NMR) profile;

FIG. 6 shows NMR of 2- (hydroxy (4-nitrophenyl) methyl) cyclohex-1-one in example 3: (¹³C-NMR).

Detailed Description

The following examples are presented to further illustrate the present invention and should not be construed as limiting the invention. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art. The reagents, methods and apparatus employed in the present invention are conventional in the art, except as otherwise indicated.