Alpha-alkylphenylacetic acid compound with high optical activity as well as preparation method and application thereof

An optically active, alkylbenzene technology, which is applied in the field of high optically active α-alkylphenylacetic acid compounds and their preparation, can solve the problem that the control of the enantioselectivity of the reaction activity of the catalyst is not very ideal, and achieves that the catalyst is easy to obtain. , the reaction operation is simple, the effect of high enantioselectivity

Active Publication Date: 2020-09-04
NANJING UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although enzyme-catalyzed asymmetric decarboxylation and protonation of α, α-alkyl, aryl-substituted malonates is an efficient method for preparing optically active α-alkylphenylacetic acid derivatives, biomimetic organic small molecule catalysis The asymmetric decarboxylation protonation reaction, especially for the open-chain malonate substrate, there are still few successful reaction examples, neither the catalyst's control of the reaction activity nor the enantioselectivity of the reaction is very ideal

Method used

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  • Alpha-alkylphenylacetic acid compound with high optical activity as well as preparation method and application thereof
  • Alpha-alkylphenylacetic acid compound with high optical activity as well as preparation method and application thereof
  • Alpha-alkylphenylacetic acid compound with high optical activity as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0031] The preparation method of highly optically active α-alkylphenylacetic acid compound is as follows:

[0032]

Embodiment 1

[0034] The synthesis of embodiment 1 (R)-2-phenylbutyric acid phenyl ester (2a)

[0035] 2-(Phenoxycarbonyl)-2-phenylbutanoic acid (1a, 28.4mg, 0.1mmol, 1equiv.), N-((1R,2R)-2-(piperidin-1-yl)cyclohexyl) -3,5-Bis(trifluoromethyl)benzenesulfonamide (4.6mg, 0.01mmol, 0.1equiv) was added to a 4mL reaction flask, methyl tert-butyl ether (1.0mL) was added, and the reaction was mixed at 22°C Stir until the reaction of the raw materials is complete; the organic phase is spin-dried, and the remaining residue is purified by silica gel chromatography (petroleum ether / ethyl acetate=20 / 1) to obtain the corresponding product 2a, yield: 98%, ee: 91%. [α] D 20 =-65(c0.23, CHCl 3 ); IR (film) 3414, 2932, 1753, 1610, 1592, 1511, 1252, 816, 750cm -1 ; 1 HNMR (400MHz, CDCl 3 ) , δ7.36–7.29(m,4H),7.22–7.16(m,1H),7.00–6.96(m,2H),6.93–6.87(m,2H),3.81(s,3H),3.64(t,J =7.7Hz,1H),2.26–2.13(m,1H),2.07-1.78(m,1H),0.99(t,J=7.4Hz,3H); 13 CNMR (100MHz, CDCl 3 )δ172.9, 159.0, 150.9, 130.8, 129.5, 1...

Embodiment 2

[0036] The synthesis of embodiment 2 (R)-2-(4-methoxyphenyl) phenyl butyrate (2b)

[0037] Starting from the raw material 1b, the experimental reaction steps were the same as the synthetic method of 2a in Example 1 to obtain the product 2b, the yield: 96%, ee: 90%. [α] D 20 =-65(c0.23, CHCl 3); IR (film) 3414, 2932, 1753, 1610, 1592, 1511, 1252, 816, 750cm -1 ; 1 HNMR (400MHz, CDCl 3 ) , δ7.36–7.29(m,4H),7.22–7.16(m,1H),7.00–6.96(m,2H),6.93–6.87(m,2H),3.81(s,3H),3.64(t,J =7.7Hz,1H),2.26–2.13(m,1H),2.07-1.78(m,1H),0.99(t,J=7.4Hz,3H); 13 CNMR (100MHz, CDCl 3 )δ172.9, 159.0, 150.9, 130.8, 129.5, 129.2, 125.9, 121.6, 114.2, 55.4, 52.8, 26.9, 12.3; HRMS (ESI) CalcdforC 17 h 19 o 3 (M+H): 271.1334.Found: 271.1338.HPLC: ChiralcelOJ-H (25cm×0.46cm), hexane / 2-propanol=90 / 10, 1.0mL / min, 204nm, 25℃, t R =27.54min(minor), 38.92min(major).

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Abstract

The invention discloses an alpha-alkylphenylacetic acid compound with high optical activity as well as a preparation method and application of the alpha-alkylphenylacetic acid compound. The preparation method comprises the following steps: mixing an aryl alkyl substituted malonic acid monoester substrate and a sulfonamide organic catalyst derived from chiral cyclohexylenediamine according to a molar ratio of 1: (0.01-0.30) in an organic solvent, and reacting for 2-48 hours at the temperature of 20-50 DEG C to obtain the alpha-alkylphenylacetic acid compound. The alpha-alkylphenylacetic acid compound can be used for preparing non-steroidal anti-inflammatory drugs, analgesics and central nervous excitants. The preparation method has the advantages of simple operation, mild conditions, almostno by-product, easily available catalyst and high enantioselectivity, and the reaction product can be used for synthesizing medical intermediates with important biological activity through simple conversion.

Description

technical field [0001] The invention belongs to the field of asymmetric synthesis, and in particular relates to a highly optically active α-alkylphenylacetic acid compound and its preparation method and application. Background technique [0002] Optically active α-alkylphenylacetic acid derivatives are ubiquitous structural units in natural products, bioactive compounds and pharmaceuticals. For example, the optically active carboxylic acid ibuprofen (ibuprofen) and naproxen (naproxen), which contain a chiral center in the α-position, are widely used as non-steroidal anti-inflammatory drugs and analgesics; Ritalin (methylphenidate) acts as a central Nervous stimulants, etc. Because optically active α-alkylphenylacetic acids containing chiral centers at the α-position are widely used in the field of medicine, their preparation has received more and more attention from organic chemists. [0003] Asymmetric decarboxylation and protonation reaction is an effective way to synthe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/612C07C69/616C07C69/65C07C69/736C07C67/32C07C51/09C07C59/68
CPCC07B2200/07C07C51/09C07C69/612C07C69/616C07C69/65C07C69/736C07C59/68
Inventor 陈建平杨城郭聪颖
Owner NANJING UNIV OF TECH
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