阅读说明：本技术 一种手性催化剂及其制备方法和应用 (Chiral catalyst and preparation method and application thereof ) 是由 刘畅 黄静 梁建林 师旭东 于 2019-06-05 设计创作，主要内容包括：本发明提供了一种手性催化剂及其制备方法和应用,本发明提供的手性催化剂用于惕格酸的催化加氢反应,实验结果表明,其得到的加成产物R-2-甲基丁酸或S-2-甲基丁酸的光学纯度ee值可高达99.2％,手性纯度高,且加成反应完毕后,只需要经过蒸馏即可实现纯化,后处理方便,易于实现工业化生产。(The chiral catalyst is used for catalytic hydrogenation reaction of tiglic acid, and experimental results show that the ee value of the optical purity of the obtained addition product R-2-methylbutyric acid or S-2-methylbutyric acid can be as high as 99.2%, the chiral purity is high, purification can be realized only by distillation after the addition reaction is finished, the post-treatment is convenient, and the industrial production is easy to realize.)

1. A chiral catalyst has a structure shown in formula (VI-R) or a structure shown in formula (VI-S),

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or alkyl of C1-C8;

x is Cl, Br or I.

2. The chiral catalyst of claim 1 wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or alkyl of C2-C6.

3. The chiral catalyst of claim 1 wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, or n-octyl.

4. The chiral catalyst of claim 1, wherein the chiral catalyst is specifically of formula (VI-R-1), formula (VI-R-2), formula (VI-R-3), formula (VI-S-1), formula (VI-S-2) or formula (VI-S-3).

5. A method of preparing the chiral catalyst of claim 1, comprising:

reacting a compound with a structure shown in a formula (V-R) or a formula (V-S) with p-cymene ruthenium dihalide to obtain a compound with a structure shown in a formula (VI-R) or a structure shown in a formula (VI-S),

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or C1-C8 alkyl

X is Cl, Br or I.

6. The method according to claim 5, wherein the compound having the structure of formula (V-R) or the structure of formula (V-S) is prepared by the following method:

reacting a compound with a structure shown in a formula (III-R) or a compound with a structure shown in a formula (III-S) with diphenyl phosphorus chloride to obtain a compound with a structure shown in a formula (IV-R) or a compound with a structure shown in a formula (IV-S);

converting the compound with the structure of the formula (IV-R) or the compound with the structure of the formula (IV-S) into the compound with the structure of the formula (V-R) or the structure of the formula (V-S).

7. The method according to claim 6, wherein the compound of formula (III-R) or the compound of formula (III-S) is prepared by the following method:

converting a compound of formula (I-R) or a compound of formula (I-S) into a compound of formula (II-R) or a compound of formula (II-S),

and (3) reacting the compound with the structure of the formula (II-R) or the compound with the structure of the formula (II-S) with trifluoromethanesulfonic anhydride to obtain the compound with the structure of the formula (III-R) or the compound with the structure of the formula (III-S).

8. The preparation method according to claim 7, wherein the compound of formula (I-R) or the compound of formula (I-S) is obtained by reacting R-gossypol acetate or S-gossypol acetate with sodium hydroxide solution.

9. A method for preparing chiral 2-methylbutyric acid, comprising:

carrying out catalytic hydrogenation reaction on tiglic acid under the condition of a chiral catalyst with a structure shown as a formula (VI-R) or a structure shown as a formula (VI-S) in any one of claims 1-3 to obtain R-2-methylbutyric acid or S-2-methylbutyric acid;

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or C1-C8 alkyl,

x is Cl, Br or I.

10. The method according to claim 9, wherein the solvent used in the reaction is an alcohol solvent.

Technical Field

The invention relates to the field of organic synthesis, in particular to a chiral catalyst and a preparation method and application thereof.

Background

2-methylbutyric acid and its ester are important flavor substances with apple and pineapple flavors, so that it has great market demand as essence and perfume, in addition, chiral 2-methylbutyric acid can also be used as intermediate for chiral synthesis of chiral building blocks and the like in medicine, daily chemicals and organic chemical industry, for example, high optical purity 2-methyl alkanoic acid can also be used as synthesis intermediate with high value in synthesis of many optical purification compounds such as biological pheromone and the like, so that the synthesis of high optical purity chiral 2-methyl butyric acid has great interest in academic circles.

At present, as for the obtaining methods of high-optical purity 2-methylbutyric acid, patent EP0673911A describes that tiglic acid is asymmetrically reduced by a complex formed by an optically active 5, 5 ', 6, 6', 7, 7 ', 8, 8' -octahydrobinaphthyl phosphorus ligand and a ruthenium compound, and S-2-methylbutyric acid with an ee value of 99.2-97% is obtained; also, for example, j.am.chem.soc.2008, 130, 8584-.

Therefore, it is important to provide 2-methylbutyric acid which is inexpensive to prepare and has high optical purity.

Disclosure of Invention

In view of the above, the technical problem to be solved by the present invention is to provide a chiral catalyst, a preparation method and an application thereof, the chiral catalyst provided by the present invention is used for synthesizing chiral 2-methylbutyric acid, and the obtained chiral 2-methylbutyric acid has high optical purity and a simple preparation process.

The invention provides a chiral catalyst which has a structure shown as a formula (VI-R) or a structure shown as a formula (VI-S),

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or C1-C8 alkyl,

x is Cl, Br or I.

Preferably, said R is₁、R₂、R₃And R₄Independently selected from hydrogen or alkyl of C2-C6.

Preferably, said R is₁、R₂、R₃And R₄Independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, or n-octyl.

Preferably, the chiral catalyst is specifically of the formula (VI-R-1), the formula (VI-R-2), the formula (VI-R-3), the formula (VI-S-1), the formula (VI-S-2) and the formula (VI-S-3).

The invention also provides a preparation method of the chiral catalyst, which comprises the following steps:

reacting a compound with a structure shown in a formula (V-R) or a formula (V-S) with p-cymene ruthenium dihalide to obtain a compound with a structure shown in a formula (VI-R) or a structure shown in a formula (VI-S),

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or C1-C8 alkyl,

x is Cl, Br or I.

Preferably, the compound with the structure of formula (V-R) or (V-S) is prepared by the following method: reacting the compound with the structure of formula (III-R) or (III-S) with diphenyl phosphorus chloride to obtain a compound with the structure of formula (IV-R) or (IV-S);

converting the compound with the structure of the formula (IV-R) or (IV-S) into the compound with the structure of the formula (V-R) or (V-S).

Preferably, the compound with the structure of formula (III-R) or (III-S) is prepared by the following method:

converting a compound having a structure of formula (I-R) or (I-S) into a compound having a structure of formula (II-R) or (II-S),

reacting the compound with the structure of the formula (II-R) or (II-S) with trifluoromethanesulfonic anhydride to obtain the compound with the structure of the formula (III-R) or (III-S).

Preferably, the compound with the structure of formula (I-R) or (I-S) is obtained by reacting R-gossypol acetate or S-gossypol acetate with sodium hydroxide solution.

The invention also provides a preparation method of chiral 2-methylbutyric acid, which comprises the following steps:

carrying out catalytic hydrogenation reaction on tiglic acid under the condition of a chiral catalyst according to any one of claims 1-3 to obtain R-2-methylbutyric acid or S-2-methylbutyric acid;

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or C1-C8 alkyl,

x is Cl, Br or I.

Preferably, the solvent used for the reaction is an alcohol solvent.

Compared with the prior art, the chiral catalyst provided by the invention is used for catalytic hydrogenation reaction of tiglic acid, and experimental results show that the optical purity ee value of the obtained addition product R-2-methylbutyric acid or S-2-methylbutyric acid can be as high as 99.2, the ee value is high, purification can be realized only by distillation after the addition reaction is finished, the post-treatment is convenient, and the industrial production is easy to realize.

Detailed Description

The invention provides a chiral catalyst which has a structure shown in a formula (I-a) or a structure shown in a formula (I-b),

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or alkyl of C1-C8; (ii) a

X is Cl, Br or I.

In the present invention, R is₁Preferably hydrogen or alkyl of C2 to C6, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl or n-octyl.

In the present invention, R is₂Preferably hydrogen or alkyl of C2 to C6, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl or n-octyl.

In the present invention, R is₃Preferably hydrogen or alkyl of C2 to C6, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl or n-octyl.

In the present invention, R is₄Preferably hydrogen or alkyl of C2 to C6, more preferably hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl or n-octyl.

In the present invention, X is preferably I.

The invention also provides a preparation method of the chiral catalyst, which comprises the following steps:

reacting a compound with a structure shown in a formula (V-R) or a formula (V-S) with p-cymene ruthenium dihalide to obtain a compound with a structure shown in a formula (VI-R) or a structure shown in a formula (VI-S),

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or alkyl of C1-C8;

x is Cl, Br or I.

According to the invention, the compound with the structure of formula (V-R) or the structure of formula (V-S) is reacted with p-cymene ruthenium dihalide to obtain the compound with the structure of formula (VI-R) or the structure of formula (VI-S), wherein the p-cymene ruthenium dihalide is preferably p-cymene ruthenium diiodide; the molar ratio of the compound having the structure of formula (V-R) or the structure of formula (V-S) to the ruthenium p-cymene dihalide is preferably 1: the invention has no special requirements on reaction conditions, and a person skilled in the art can select appropriate reaction conditions according to actual needs.

In the present invention, the compound of formula (V-R) or formula (V-S) is preferably prepared by the following method:

reacting a compound with a structure shown in a formula (III-R) or a compound with a structure shown in a formula (III-S) with diphenyl phosphorus chloride and zinc powder to obtain a compound with a structure shown in a formula (IV);

converting the compound with the structure of the formula (IV-R) or the compound with the structure of the formula (IV-S) into the compound with the structure of the formula (V-R) or the structure of the formula (V-S).

Wherein the molar ratio of the compound with the structure of formula (III-R) or the compound with the structure of formula (III-S) to the diphenyl phosphorus chloride is preferably 1: 2-5, and more preferably 1: 3-4; the catalyst for the reaction is preferably diphenylphosphinoethane nickel dichloride, and the solvent for the reaction is preferably DMF; the reaction temperature is preferably 105-110 ℃.

The invention also converts the compound with the structure of formula (IV-R) or the compound with the structure of formula (IV-S) into the compound with the structure of formula (V-R) or the compound with the structure of formula (V-S), wherein, the invention has no special requirement on the conversion method, and a person skilled in the art can select proper acid or alkane compounds according to actual needs to react to obtain the compound with the desired structure of formula (V-R) or the compound with the structure of formula (V-S).

In the invention, the compound with the structure of formula (III-R) or the compound with the structure of formula (III-S) is prepared according to the following method:

converting a compound of formula (I-R) or a compound of formula (I-S) into a compound of formula (II-R) or a compound of formula (II-S),

and (3) reacting the compound with the structure of the formula (II-R) or the compound with the structure of the formula (II-S) with trifluoromethanesulfonic anhydride to obtain the compound with the structure of the formula (III-R) or the compound with the structure of the formula (III-S).

Wherein, the invention has no special requirement on the method for converting the compound with the structure of formula (I-R) or the compound with the structure of formula (I-S) into the compound with the structure of formula (II-R) or the compound with the structure of formula (II-S), and the skilled person can select the appropriate reaction condition according to the actual requirement; wherein the compound with the structure of formula (I-R) or the compound with the structure of formula (I-S) is preferably obtained by reacting R-gossypol acetate or S-gossypol acetate with sodium hydroxide solution; wherein, the sodium hydroxide solution is preferably 35 wt% to 45 wt% of sodium hydroxide solution.

The compound with the structure of formula (II-R) or the compound with the structure of formula (II-S) is reacted with trifluoromethanesulfonic anhydride to obtain the compound with the structure of formula (III-R) or the compound with the structure of formula (III-S), wherein the ratio of the mole number of hydroxyl groups in the compound with the structure of formula (II-R) or the compound with the structure of formula (II-S) to the mole number of trifluoromethanesulfonic anhydride is preferably 1: 2-1: 4, and the reaction is preferably completed at-5 ℃, and more preferably at 0 ℃.

Specifically, the specific preparation process of the chiral catalyst of the invention is as follows:

the invention also provides a preparation method of chiral 2-methylbutyric acid, which comprises the following steps:

carrying out catalytic hydrogenation reaction on tiglic acid under the condition of the chiral catalyst to obtain R-2-methylbutyric acid or S-2-methylbutyric acid;

wherein R is₁、R₂、R₃And R₄Independently selected from hydrogen or C1-C8 alkyl,

x is Cl, Br or I.

According to the invention, tiglic acid is subjected to catalytic hydrogenation reaction under the condition of the chiral catalyst to obtain R-2-methylbutyric acid or S-2-methylbutyric acid; wherein, the solvent of the reaction is preferably an alcohol solvent, and more preferably one or more of methanol, ethanol and isopropanol; the pressure of hydrogen in the reaction system is preferably 0.1MPa to 5MPa, more preferably 0.1MPa to 1 MPa; the reaction temperature is preferably 0-120 ℃, and more preferably 30-80 ℃.

More specifically, the preparation process of the methyl butyric acid of the invention is as follows:

in the chiral catalyst and the preparation method and application thereof provided by the invention, the chiral catalyst is used for catalytic hydrogenation reaction of tiglic acid, and the result shows that the ee value of the optical purity of the obtained addition product R-2-methylbutyric acid can be as high as 99.2%, and the ee value of the optical purity of S-2-methylbutyric acid can be as high as 99.0%, which are higher than the ee values of the products obtained by the two technical schemes in the prior art indicated in the background technology, and after the addition reaction is finished, the purification can be realized only by distillation, the post-treatment is convenient, and the industrial production is easy to realize.

The following will clearly and completely describe the technical solutions of the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.