阅读说明：本技术 一种高光学活性α-烷基苯乙酸化合物及其制备方法与应用 (Alpha-alkyl phenylacetic acid compound with high optical activity and preparation method and application thereof ) 是由 陈建平 杨城 郭聪颖 于 2020-06-08 设计创作，主要内容包括：本发明公开了一种高光学活性α-烷基苯乙酸化合物及其制备方法与应用。本发明通过将芳基烷基取代的丙二酸单酯底物与手性环己基二胺衍生的磺酰胺类有机催化剂按摩尔比1∶(0.01～0.30)混合在有机溶剂中,在20～50℃温度下反应2～48h,得到α-烷基苯乙酸化合物。该α-烷基苯乙酸化合物可用于制备非甾体抗炎药、镇痛药和中枢神经兴奋药。本发明制备方法操作简单、条件温和、几乎没有副产物、催化剂易得、对映选择性高,并且反应产物通过简单转化就可用于合成具有重要生物活性医药中间体。(The invention discloses an alpha-alkyl phenylacetic acid compound with high optical activity, a preparation method and application thereof. According to the invention, an aryl alkyl substituted malonic acid monoester substrate and a sulfonamide organic catalyst derived from chiral cyclohexyl diamine are mixed in an organic solvent according to the molar ratio of 1: 0.01-0.30, and react for 2-48 h at the temperature of 20-50 ℃ to obtain an alpha-alkyl phenylacetic acid compound. The alpha-alkylphenylacetic acid compound can be used for preparing non-steroidal anti-inflammatory drugs, analgesics and central nervous stimulants. The preparation method has the advantages of simple operation, mild conditions, almost no by-products, easy obtainment of catalyst and high enantioselectivity, and the reaction product can be used for synthesizing the medicinal intermediate with important biological activity through simple conversion.)

1. An optically active α -alkylphenylacetic acid compound having a chemical formula represented by the following formula (I):

in the formula (I), Ar is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester group, sulfonyl and carbonyl;

R¹is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester group, sulfonyl and carbonyl;

R²the C1-C100 hydrocarbyl containing one or more substituents, wherein the substituents comprise phenyl, carbonyl, cyano, C2-C10 ester, sulfonyl, amido bond, ether bond, hydroxyl, alkynyl, halogen, phthalimide, C1-C10 alkoxy, phenyl-substituted C1-C4 alkyl, C3-C7 cycloalkyl, phenylcarbonyl, benzoyl, N-containing five-membered or six-membered heterocyclic ring and N-containing five-membered or six-membered heterocyclic ring with benzo C1-C6 hydrocarbyl, halogen, ester group and alkoxy.

2. The highly optically active α -alkylphenacetic acid compound of claim 1, wherein R is²Is C1-C20 alkyl containing one or more substituent groups.

3. The method for preparing an optically active α -alkylphenacetic acid compound according to claim 1, characterized by comprising the steps of: mixing an aryl alkyl substituted malonic acid monoester substrate and a sulfonamide organic catalyst derived from chiral cyclohexyl diamine according to the molar ratio of 1: 0.01-0.30 in an organic solvent, and reacting at the temperature of 20-50 ℃ for 2-48 h to obtain the alpha-alkyl phenylacetic acid compound.

4. The method of claim 3, wherein the aryl alkyl substituted malonic acid monoester substrate has a chemical formula as shown in formula (II):

in the formula (II), Ar is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester, sulfonyl and carbonyl;

R¹is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester group, sulfonyl and carbonyl;

R²the C1-C100 hydrocarbyl containing one or more substituents, wherein the substituents comprise phenyl, carbonyl, cyano, C2-C10 ester, sulfonyl, amido bond, ether bond, hydroxyl, alkynyl, halogen, phthalimide, C1-C10 alkoxy, phenyl-substituted C1-C4 alkyl, C3-C7 cycloalkyl, phenylcarbonyl, benzoyl, N-containing five-membered or six-membered heterocyclic ring and N-containing five-membered or six-membered heterocyclic ring with benzo C1-C6 hydrocarbyl, halogen, ester group and alkoxy.

5. The method for preparing an optically active α -alkylphenyl acetic acid compound according to claim 3, wherein the catalyst has a chemical formula represented by the following formula (III) or formula (IV):

in the formulae (III) and (IV), R³Is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one to more substituents including trifluoromethyl, fluorine, halogen, ester group, sulfonyl, carbonyl, nitro;

R⁴is C1-C100 alkyl or cyclic hydrocarbon including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

6. The method of claim 5 wherein R is α -alkylphenacetic acid compound with high optical activity³Is 3, 5-bis (trifluoromethyl) phenyl, heteroaryl, 1-naphthyl or 2-naphthyl; r⁴Is a hydrocarbon group of C1-C20, and the cyclic hydrocarbon is- (CH)₂)₅-。

7. The method for preparing α -alkylphenacetic acid compound with high optical activity according to claim 3, wherein the organic solvent is a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent, a ketone solvent or an alcohol solvent.

8. The method of claim 7, wherein the organic solvent is dichloromethane, 1, 2-dichloroethane chloroform, toluene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 4-dioxane or acetone.

9. The method of claim 8, wherein the organic solvent is t-butyl methyl ether.

10. Use of the high optical activity α -alkylphenylacetic acid compound of claim 1 or 2 for the preparation of non-steroidal anti-inflammatory drugs, analgesics and central nervous stimulants.

Technical Field

The invention belongs to the field of asymmetric synthesis, and particularly relates to an alpha-alkylphenylacetic acid compound with high optical activity, and a preparation method and application thereof.

Background

Optically active alpha-alkylphenylacetic acid derivatives are ubiquitous building blocks in natural products, biologically active compounds and pharmaceuticals. For example, ibuprofen (ibuprofen) and naproxen (naproxen), optically active carboxylic acids containing a chiral center at the α -position, are widely used as non-steroidal anti-inflammatory drugs and analgesics; ritalin (methylphenidate) as a central nervous stimulant, and the like. Since optically active α -alkylphenylacetic acid compounds having a chiral center at the α -position are widely used in the medical field, their preparation is receiving increasing attention from organic chemists.

The asymmetric decarboxylation protonation reaction is an effective mode for synthesizing the α -alkyl phenylacetic acid with optical activity, and the reaction conditions are mild, the operation is simple, and the reaction has almost no by-product (only CO)₂Production), thus the green and environmentally friendly nature of the reaction is favored by chemists (1.j.t.mohr, a.y.hong andb.m.stoltz, nat.chem.,2009,1,359.) although bio-enzyme catalyzed asymmetric decarboxylation protonation of α -alkyl, aryl substituted malonic acids is a highly efficient method for preparing optically active α -alkylphenoacetic acid derivatives, biomimetic small organic molecule catalyzed asymmetric decarboxylation protonation, particularly for open chain malonic acid substrates, successful reaction examples are still few, and neither the control of the catalyst on the reaction activity nor the reaction enantioselectivity is very desirable.

Disclosure of Invention

The invention aims to provide an alpha-alkylphenylacetic acid compound with high optical activity, a preparation method and application thereof, and aims to overcome the defects of the prior art in the background technology so as to meet the preparation requirements of key intermediates of a series of chiral drugs.

The invention is realized by the following steps that the alpha-alkyl phenylacetic acid compound with high optical activity has a chemical structural formula shown as the following formula (I):

in the formula (I), Ar is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester group, sulfonyl and carbonyl;

R¹is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester group, sulfonyl and carbonyl;

R²the compound is a C1-C100 hydrocarbon group containing one or more substituents, wherein the substituents comprise phenyl, carbonyl, cyano, C2-C10 ester, sulfonyl, amido bond, ether bond, hydroxyl, alkynyl, halogen, phthalimide, C1-C10 alkoxy, phenyl-substituted C1-C4 alkyl, C3-C7 cycloalkyl, phenylcarbonyl, benzoyl, N-containing five-membered or six-membered heterocyclic ring and N-containing five-membered or six-membered heterocyclic ring with benzo-C1-C6 hydrocarbon group, halogen, ester group and alkoxy;

refers to the chiral center of a chiral compound, whose absolute configuration may be (R) or (S).

Preferably, R²Is C1-C20 alkyl containing one or more substituent groups.

The invention further discloses a preparation method of the alpha-alkylphenyl acetic acid compound with high optical activity, which comprises the following steps: mixing an aryl alkyl substituted malonic acid monoester substrate and a sulfonamide organic catalyst derived from chiral cyclohexyl diamine according to the molar ratio of 1: 0.01-0.30 in an organic solvent, and reacting at the temperature of 20-50 ℃ for 2-48 h to obtain the alpha-alkyl phenylacetic acid compound.

Preferably, the chemical formula of the aryl alkyl substituted malonic acid monoester substrate is shown as the following formula (II):

in the formula (II), Ar is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester, sulfonyl and carbonyl;

R¹is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one or more substituents, wherein the substituents comprise C1-C10 alkyl, C1-C10 alkoxy, halogen, hydroxyl, ester group, sulfonyl and carbonyl;

R²the C1-C100 hydrocarbyl containing one or more substituents, wherein the substituents comprise phenyl, carbonyl, cyano, C2-C10 ester, sulfonyl, amido bond, ether bond, hydroxyl, alkynyl, halogen, phthalimide, C1-C10 alkoxy, phenyl-substituted C1-C4 alkyl, C3-C7 cycloalkyl, phenylcarbonyl, benzoyl, N-containing five-membered or six-membered heterocyclic ring and N-containing five-membered or six-membered heterocyclic ring with benzo C1-C6 hydrocarbyl, halogen, ester group and alkoxy.

Preferably, the compound structural formula of the catalyst is shown as the following formula (III) or formula (IV):

in the formulae (III) and (IV), R³Is phenyl, heteroaryl, 1-naphthyl or 2-naphthyl containing one to more substituents including trifluoromethyl, fluorine, halogen, ester group, sulfonyl, carbonyl, nitro;

R⁴is C1-C100 alkyl or cyclic hydrocarbon including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Preferably, R³Is 3, 5-bis (trifluoromethyl) phenyl, heteroaryl, 1-naphthyl or 2-naphthyl; r⁴Is a hydrocarbon group of C1-C20, and the cyclic hydrocarbon is- (CH)₂)₅-。

Preferably, the organic solvent is a halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an ether solvent, a ketone solvent or an alcohol solvent.

Preferably, the organic solvent is dichloromethane, 1, 2-dichloroethane chloroform, toluene, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, cyclopentyl methyl ether, 1, 4-dioxane or acetone.

Preferably, the organic solvent is tert-butyl methyl ether.

The invention overcomes the defects of the prior art and provides an alpha-alkylphenoacetic acid compound with high optical activity and a preparation method thereof, in the invention, the alpha-alkylphenoacetic acid compound with optical activity is synthesized by using an asymmetric decarboxylation protonation reaction technology of a sulfonamide catalyst derived from chiral cyclohexyl diamine, and the reaction general formula is as follows:

compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects: the invention utilizes the technology of organic catalytic asymmetric decarboxylation protonation reaction to synthesize a series of alpha-alkyl phenylacetic acid compounds with high optical activity in one step, the reaction has simple operation, mild condition, almost no by-products, easily obtained catalyst and high enantioselectivity, and the reaction products can be used for synthesizing the pharmaceutical intermediates with important biological activity through simple conversion.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.

General examples of the embodiments

The preparation method of the alpha-alkylphenylacetic acid compound with high optical activity is as follows:

the above 1a to 1k and 2a to 2k correspond to the compounds of examples 1 to 13 described below.