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Synthetic method of chiral 2-aryl propionate

A technology of aryl propionate and aryl acrylate, which is applied in the field of enantioselective synthesis of 2-aryl propionate, can solve the problems of high pressure, high transition metal price, limited industrial application, etc. cheap effect

Active Publication Date: 2020-03-24
DALIAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the transition metals used in the catalyst are expensive and require high pressure, which limit its industrial application

Method used

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  • Synthetic method of chiral 2-aryl propionate
  • Synthetic method of chiral 2-aryl propionate
  • Synthetic method of chiral 2-aryl propionate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Add Cu(OAc) to nitrogen-purged, dry reaction flask 2 ·H 2 O (2.0mg), (R,R)-L1(Ar'=Ph) (2.0mg) and toluene (2.0mL) were stirred at room temperature to a blue solution. Add poly(methylhydrogensiloxane) (120 μL) and n-butanol (118 μL) to the above mixture, stir for 5 min, then add methyl 2-phenylacrylate (0.065 g), and stir for another 2 h. Afterwards, saturated NH 4 F solution (4.0mL), continued to stir for 60min, separated, the aqueous phase was extracted with ethyl acetate (3×5.0mL), the combined organic phase was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, concentrated, and separated by column to obtain 0.046 g of methyl 2-phenylpropionate, the yield is 70%; the enantiomeric composition is analyzed by chiral GC, ee is 8%, and the dominant configuration is (S)-configuration. 1 H NMR (500MHz, CDCl 3 )δ7.32–7.20(m,5H),3.66(q,J=7.1Hz,1H),3.59(s,3H),1.43(d,J=7.2Hz,3H). 13 C NMR (126MHz, CDCl 3 )δ175.13, 140.67, 128.77, 127.59, 127.26, 52....

Embodiment 2

[0042] Add Cu(OAc) to a nitrogen-purged, dry reaction flask 2 ·H 2 O (2.0 mg), (R)-L2 (Ar'=Ph) (3.0 mg) and tetrahydrofuran (2.0 mL) were stirred at room temperature to a blue solution. Poly(methylhydrogensiloxane) (180 μL) and tert-butanol (140 μL) were added to the above system, after stirring, methyl 2-phenylacrylate (162 mg) was added, and the reaction was stirred for 2 h. Add saturated NH to the reaction mixture 4 Cl solution (4.0mL), continued to stir for 20min, separated, the aqueous phase was extracted with ethyl acetate (3×5.0mL), the combined organic phase was washed with NaCl saturated solution, dried over anhydrous sodium sulfate, concentrated, and column separated to obtain 101 mg of colorless liquid methyl 2-phenylpropionate, yield 62%; analyzed by chiral GC, the ee value was 19%, and the dominant configuration was (S)-configuration.

Embodiment 3

[0044] Add Cu(OAc) to a nitrogen-purged, dry reaction flask 2 ·H 2 O (2.0 mg), (S)-L3 (Ar'=Ph) (6.1 mg), toluene (2.0 mL), stirred at room temperature to a blue solution. Add Ph to the above liquid 2 SiH 2 (184μL), neopentylbutanol (132mg), and after stirring for 5min, 2-phenylmethylacrylate (152mg) was added, and the stirring reaction was continued for 2h. Add saturated NH to the reaction mixture 4 Cl solution (4.0mL), continued to stir for 20min, separated, the aqueous phase was extracted with ethyl acetate (3×5.0mL), the combined organic phase was washed with NaCl saturated solution, dried over anhydrous sodium sulfate, concentrated, and column separated to obtain Methyl 2-phenylpropanoate (111 mg, 72% yield), GC chiral analysis, ee 22%), the (S)-configuration was predominant.

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Abstract

The invention belongs to the technical field of chemical synthesis, and relates to a synthetic method of chiral 2-aryl propionate, in particular to enantioselective synthesis of 2-aryl propionate. Thesynthetic method comprises the following steps: adding a copper salt, a chiral phosphine ligand, a silicon-hydrogen compound (in terms of SiH), R<1>OH and 2-aryl acrylate in a certain ratio into a reaction bottle, carrying out a reaction in a reaction solvent at -50 to 40 DEG C for 0.25-6 h, and successively performing hydrolyzing, liquid separating, extracting, washing, drying and column chromatography after the reaction is finished, thereby obtaining the target compound 2-aryl propionate. Compared with the prior art, the method has the advantages that the 2-aryl acrylate is reduced by adopting a Cu catalytic system, a catalyst, namely a Cu compound is low in price, and the limitation of hydrogen high-pressure reduction and a noble metal catalyst is broken through. Chiral 2-aryl propionic acid can be obtained through a simple hydrolysis reaction of 2-aryl propionate, and a part of the compounds of 2-aryl propionate are effective components of current commercially-available drugs suchas ibuprofen and naproxen.

Description

technical field [0001] The invention belongs to the technical field of chemical synthesis and relates to enantiomeric selective synthesis of 2-aryl propionate. Background technique [0002] 2-Arylpropionic acid is a common analgesic and anti-inflammatory drug. Among them, ibuprofen is an OTC non-steroidal anti-inflammatory drug [1] , Widely used in the treatment of headaches, neuralgia, rheumatoid arthritis and rheumatoid arthritis and other diseases. Its active ingredient is (S)-(+)-ibuprofen, while (R)-(-)-ibuprofen isomer is invalid. Naproxen (Naproxen) is a PG synthase inhibitor, a variety of acute pain analgesics, anti-inflammatory, antipyretic, analgesic effects, for rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, gout , chronic degenerative diseases of the motor system and mild and moderate pain, etc., all have positive curative effects, and are used for the relief of migraine, tension headache, postoperative pain and pain associated with various gyne...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/303C07C69/734C07C69/65C07C69/612
CPCC07C67/303C07B2200/07C07C69/734C07C69/65C07C69/612
Inventor 李争宁赵晓媛白瑞李泉城姜岚
Owner DALIAN UNIV
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