阅读说明：本技术 一种(r,e)-4-苯基丁基-3-烯-2-醇衍生物的制备方法 (Preparation method of (R, E) -4-phenylbutyl-3-ene-2-alcohol derivative ) 是由 钟为慧 陈佳琛 凌飞 肖霄 于 2020-07-30 设计创作，主要内容包括：本发明公开了一种(R,E)-4-苯基丁基-3-烯-2-醇衍生物的制备方法。具体为,采用手性二茂铁骨架的PNN配体与五羰基溴化锰组成的催化剂对(E)-4-苯基-3-烯-2-酮衍生物进行不对称氢化,高收率和高对映选择性地生成(R,E)-4-苯基丁基-3-烯-2-醇衍生物。与传统拆分法相比,本发明有益效果主要体现在：反应条件温和、操作简便、立体选择性好、收率高、生产周期短、“三废”量少、易于工业化,具有较大的实施价值和社会经济效益。<Image he="136" wi="700" file="DDA0002610075910000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a preparation method of (R, E) -4-phenylbutyl-3-ene-2-ol derivatives. Specifically, the (E) -4-phenyl-3-alkene-2-ketone derivative is subjected to asymmetric hydrogenation by adopting a catalyst consisting of a PNN ligand of a chiral ferrocene skeleton and manganese pentacarbonyl bromide, and the (R, E) -4-phenylbutyl-3-alkene-2-alcohol derivative is generated with high yield and high enantioselectivity. Compared with the traditional splitting method, the method has the following beneficial effects: mild reaction conditions, simple and convenient operation, good stereoselectivity, high yield, short production period, less three wastes and easy industrialization, and has great implementation value and social and economic benefits.)

1. A method for producing a (R, E) -4-phenylbutyl-3-en-2-ol derivative, comprising the steps of:

1) under the argon atmosphere, the manganese pentacarbonyl bromide and the chiral ligand L are reacted^*Sequentially adding the mixture into a solvent A, and reacting for 0.5 to 6 hours at the temperature of between 0 and 60 ℃ to prepare a catalyst [ M]/L^*；

2) Under argon atmosphere, sequentially adding (E) -4-phenylbutyl-3-alkene-2-ketone derivative shown in formula (1) and catalyst [ M ] prepared in step 1) into a reaction kettle]/L^*The solvent B and the alkaline substance, replacing hydrogen, then carrying out asymmetric hydrogenation reaction at 10-60 ℃ and 1.0-6.0 MPa for 2-24 hours, and passing the reaction liquid through siliconFiltering with diatomite, concentrating the filtrate under reduced pressure to recover solvent B, and making into (R, E) -4-phenylbutyl-3-ene-2-ol derivative shown in formula (2);

the reaction equation is as follows:

in the formulas (1) and (2): ar is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; wherein the substituent in the substituted aryl or the substituted heterocyclic aryl is halogen, alkyl of C1-C6, cycloalkyl of C3-C6, alkoxy of C1-C6, aryl of C6-C10 or heterocyclic aryl.

2. The process for the preparation of (R, E) -4-phenylbutyl-3-en-2-ol derivatives according to claim 1, characterized in that the chiral ligand L^*As shown in the general formula (I):

in the general formula (I): r¹Is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl or C1-C6 alkyl, R²Is hydrogen, C1-C6 alkyl, aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; the imidazole group is substituted imidazole or substituted benzimidazole; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl.

3. Process for the preparation of (R, E) -4-phenylbutyl-3-en-2-ol derivatives according to claim 1 or 2, characterized in that the chiral ligand L^*The structure comprises the following structures:

4. the method for preparing (R, E) -4-phenylbutyl-3-en-2-ol derivative of claim 1, wherein solvent A and solvent B are independently selected from one or more of dichloromethane, tetrahydrofuran, toluene, methanol, ethanol, n-propanol, isopropanol, and tert-butanol.

5. The process for the preparation of (R, E) -4-phenylbutyl-3-en-2-ol derivative according to claim 1, characterized in that the catalyst [ M ] in step 2)]/L^*The molar ratio of the substrate (E) -4-phenylbutyl-3-en-2-one derivative to the substrate (E) -1: 100-1: 100000.

6. The process for producing (R, E) -4-phenylbutyl-3-en-2-ol derivative according to claim 1, characterized in that the asymmetric hydrogenation in step 2) is carried out at a temperature of 40 ℃ to 60 ℃; the hydrogen pressure is 2.0-3.0 Mpa; the reaction time is 10-16 hours.

7. The process for producing a (R, E) -4-phenylbutyl-3-en-2-ol derivative as claimed in claim 1, wherein the basic substance in step 2) is one selected from the group consisting of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, sodium hydroxide, and potassium hydroxide.

Technical Field

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of a (R, E) -4-phenylbutyl-3-ene-2-ol derivative.

Background

Over the past decades, there has been considerable progress in asymmetric hydrogenation, one of the most important processes for the preparation of chiral alcohols being the asymmetric hydrogenation of prochiral ketones. Chiral enols, as important pharmaceutical intermediates, are widely used in the synthesis of various natural products, pharmaceuticals, agrochemicals, and bioactive compounds. For example, allyl alcohol is a key pharmacophore of the side chain of statins and is also a key intermediate of cannabidiol (cannabidiol), and therefore, it is important to develop an effective asymmetric synthesis method for the compounds. In general, asymmetric synthesis methods of chiral enols can be divided into three main categories: (i) chemical asymmetric addition, (ii) biocatalytic asymmetric reduction, (iii) chemocatalytic asymmetric reduction. Among them, chemical catalysis is most attractive from the viewpoint of practical use and economical utilization. Several methods have been successfully developed for chiral oxazaborolidine catalyzed hydroboration, chiral ruthenium/diphosphine/diamine catalyzed asymmetric hydrogenation or chiral iridium/chiral phosphine ligand catalyzed asymmetric hydrogenation. However, the synthesis method is still limited overall, and in most cases, the substrate has limitations, and the central metal is a precious metal which is scarce in reserves and toxic and harmful to human bodies. The manganese element is one of 18 trace elements for human life and health, and the residual quantity of the manganese in the human body can be 250 ppm. Therefore, it is desired to develop an asymmetric synthesis method having high enantioselectivity by using manganese metal as a central metal.

As early as 2002, professor Noyori, a scientist in japan, reported that for asymmetric catalytic hydrogenation of 3-nonen-2-one, designing a class of chiral ruthenium/diphosphine/diamine catalyzed asymmetric hydrogenation to obtain the corresponding chiral alcohol in 99% ee and 95% yield, which is promising for the originally difficult topic, but the substrate was limited to a substrate with aliphatic groups at both ends (j.am.chem.soc.,2002,124, 6508-. Subsequently, in 2008, Ohkuma teaches group modification of its ligand to form a more active chiral ruthenium/diphosphine/diamine catalytic system, the ligand is used for asymmetric catalytic hydrogenation reduction of chalcone substrates, the substrates are limited to aromatic group substrates at both ends, the highest yield is 99%, and the corresponding chiral alcohol is obtained in 98% ee (angelw.chem.int.ed., 2008,120, 7457-one). In 2018, professor James reported a process for asymmetric boration reduction of α, β -unsaturated ketones to obtain cannabidiol drug intermediates (org. lett.,2018,20,381-384.) in 78% ee, 94% yield.

Although the limitations of the substrate appear to have been addressed, there are several important problems that have not yet been addressed: 1) the double bond side connection is that the asymmetric hydrogenation of polysubstituted substrates or condensed ring substrates such as quinoline ring, benzothiophene ring and the like on the benzene ring is not reported; 2) the catalyst conversion number (TON) is too low to meet the requirements of industrial production; 3) the catalytic system is limited to the combination of noble metals such as ruthenium or iridium and chiral ligands; 4) the highly stereoselective preparation of key intermediates of cannabidiol using asymmetric catalytic hydrogenation remains challenging. Therefore, the development of a great variety of chiral ligands and catalytic systems thereof is urgently needed to solve these problems.

Disclosure of Invention

Aiming at the defects in the prior art, the invention aims to provide a preparation method of (R, E) -4-phenylbutyl-3-alkene-2-alcohol derivatives, which has the advantages of high purity, high enantioselectivity and the like and can meet the requirement of industrial production.

The process for preparing the (R, E) -4-phenylbutyl-3-en-2-ol derivative with high purity and high enantioselectivity comprises the following steps:

the preparation process of the (R, E) -4-phenylbutyl-3-ene-2-ol derivative is characterized by comprising the following steps of:

1) at the temperature of 0-60 ℃ and under the argon atmosphere, the manganese pentacarbonyl bromide and the chiral ligand L are reacted^*Sequentially adding the mixture into a solvent A, and reacting for 0.5-6 hours to obtain a catalyst [ M]/L^*；

2) Sequentially adding a catalyst [ M ] obtained in the step 1) of (E) -4-phenylbutyl-3-alkene-2-ketone-derivative shown in the formula (1) into a reaction kettle under the argon atmosphere]/L^*After hydrogen is replaced by the solvent B and alkali, carrying out asymmetric hydrogenation reaction for 2-24 hours at 10-60 ℃ and 1.0-6.0 MPa, filtering the reaction liquid by diatomite, and carrying out reduced pressure concentration to recover the solvent B, thus obtaining the (R, E) -4-phenylbutyl-3-ene-2-ol derivative shown in the formula (2);

the preparation process route is represented by the following reaction formula:

in the formulas (1) and (2): ar is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; wherein the substituent in the substituted aryl or the substituted heterocyclic aryl is halogen, alkyl of C1-C6, cycloalkyl of C3-C6, alkoxy of C1-C6, aryl of C6-C10 or heterocyclic aryl.

The chiral ligand L^*As shown in the general formula (I):

in the general formula (I): r¹Is aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl or C1-C6 alkyl, R²Is hydrogen, C1-C6 alkyl, aryl or substituted aryl, heterocyclic aryl or substituted heterocyclic aryl; the imidazole group is substituted imidazole or substituted benzimidazole; the substituent on the benzene ring of the substituted benzimidazole group is one or more, and each substituent is independently selected from H or C1-C4 alkyl.

The preferred 6 chiral ligands L^*The structure is as follows:

the solvent A for preparing the catalyst and the solvent B for asymmetric hydrogenation are respectively selected from one or more of dichloromethane, tetrahydrofuran, toluene, methanol, ethanol, n-propanol, isopropanol and tert-butanol, and the solvents A and B can be the same.

The molar ratio of the catalyst to the (R, E) -4-phenylbutyl-3-ene-2-ol derivative is 1: 100-1: 100000.

Further, the temperature of the asymmetric hydrogenation reaction is 40-60 ℃.

Further, the pressure of the hydrogen for the asymmetric hydrogenation reaction is 2.0-3.0 MPa.

The base used in the asymmetric hydrogenation reaction is selected from one of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate, sodium methoxide, sodium hydroxide and potassium hydroxide.

By adopting the technology, compared with the prior art, the invention has the beneficial effects that:

the invention provides a novel catalytic system [ M ] composed of chiral ferrocene PNN ligand and manganese pentacarbonyl bromide]/L^*The method is used for catalyzing asymmetric hydrogenation of (E) -4-phenylbutyl-3-ene-2-ketone derivatives to generate (R, E) -4-phenylbutyl-3-ene-2-alcohol derivatives with high stereoselectivity, the dosage of the catalyst is small and can be reduced to less than ten thousandth, and the method has the characteristics of mild reaction conditions, easily obtained raw materials, simple experimental operation, high catalytic efficiency, capability of obtaining target products with better yield and ee value and the like, and can be used for preparing key cannabidiol drug intermediates.

Detailed Description

The present invention will be described with reference to examples, but the present invention is not limited to the examples.