Novel asymmetric catalytic synthesis method of (S)-naproxen

A synthetic method and asymmetric technology, applied in the field of medicine, can solve the problems of cumbersome reaction steps and harsh reaction conditions, and achieve the effect of short synthetic route and high optical purity of the product

Inactive Publication Date: 2014-04-30
CHINA AGRI UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Although there have been many reports on the asymmetric synthesis of (S)-naproxen, there are still some problems, such as the need for enzyme reagents, stoichiometric chirality Reagents, reaction conditions are harsh, reaction steps are cumbersome, etc. Therefore, it is of great significance to study efficient, environmentally friendly, and simple new asymmetric synthesis methods

Method used

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  • Novel asymmetric catalytic synthesis method of (S)-naproxen
  • Novel asymmetric catalytic synthesis method of (S)-naproxen
  • Novel asymmetric catalytic synthesis method of (S)-naproxen

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Embodiment 1

[0021] Under the protection of argon, add CoI in a dry Schlenk bottle 2 (62.4mg, 0.2mmol), after vacuum drying for 2h, add anhydrous tetrahydrofuran (6mL) and bisoxazoline chiral ligand L1 (88.0mg, 0.24mmol), and stir at room temperature for 1h. Add racemic benzyl 2-bromophenylpropionate (485.0mg, 2.0mmol) to the mixed solution, reduce the reaction temperature to -80°C, and add 6-methoxy-2-naphthylmagnesium bromide dropwise ( 8.0 mL, 0.5M solution in THF, 4.0 mmol). Stirring was continued at -80°C for 12 h, and the reaction was quenched by adding saturated ammonium chloride aqueous solution. The reaction solution was extracted with ether (15mL×4), the organic layers were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane / ethyl acetate 40:1) to obtain (S)-naphthalene as a white solid Proxanthate 2 (364.8 mg, yield 57%, optical purity 90%). The ee value of (S)-naproxen ester 2 was incre...

Embodiment 2

[0027] Under the protection of argon, add Pd / C (21mg, 10%, 0.02mmol) in a dry Schlenk tube, vacuum dry for 10min, add (S)-naproxen ester 2 (64mg, 0.2mmol) in methanol (1mL) solution. Continue to stir the reaction for 6h and filter. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane / ethyl acetate 3:2) to obtain (S)-naproxen (34.9 mg, yield 76%, optical purity > 99%) as a white solid. [α] D 20 =+70.0(c1.0,CHCl 3 ); 1 H NMR (300MHz, CDCl 3 )δ:7.70–7.68(m,3H),7.42–7.39(m,1H),7.15–7.10(m,2H),3.90(s,3H),3.85(q,J=7.2Hz,1H),1.58 (d,J=7.2Hz,3H); 13C NMR (75MHz, CDCl 3 )δ: 180.7, 157.7, 134.9, 133.8, 129.3, 128.9, 127.2, 126.2, 126.1, 119.0, 105.7, 55.3, 45.3, 18.1; HRMS (ESI-TOF): calcd for C 14 h 15 o 3 [M+H] + :231.1021, found 231.1016.

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Abstract

The invention discloses a novel asymmetric catalytic synthesis method of (S)-naproxen. According to the method, racemic 2-halogenated propionate is used as an initial raw material to perform an asymmetric Kumada cross-coupling reaction with 6-methoxyl-naphthyl grignard reagent in the catalysis of bisoxazoline/cobalt to prepare (S)-naproxen ester, and the ee value is increased by using a re-crystallization method, and the (S)-naproxen is prepared by catalytic hydrogenation. The synthetic route is simple and short, is a two-step reaction, the total yield of the whole synergetic route is 43 percent, and the optical purity of the product is more than 99 percent.

Description

technical field [0001] [0002] The invention relates to the technical field of medicine, in particular to a new method for asymmetric catalytic synthesis of (S)-naproxen. Background technique [0003] Naproxen is an arylpropionic acid non-steroidal anti-inflammatory drug with a wide range of clinical applications, mainly for the treatment of chronic arthritis, osteoarthritis, and acute upper respiratory tract inflammation. Naproxen has a chiral carbon atom in its structure and has a pair of enantiomers with different biological activities. Studies have shown that the analgesic effect of (S)-naproxen (formula 1) is 28 times that of (R)-isomer (Shen, T.Y.Angew.Chem, Int.Ed.Engl.1972,11(6), 460–472. Roszkowski, A.P.; Rooks, W.H.; Tomolonis, A.J.; Miller, L.M.J. Pharmacol. Exp. Ther. 1971, 179(1), 114–123.). Therefore, (S)-naproxen is its active ingredient. At present, (S)-naproxen can be obtained mainly by racemate resolution, chiral induction, enzymatic catalysis and asym...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C59/64C07C51/09C07C67/343C07C69/734
CPCC07C51/09C07C67/343C07C59/64C07C69/734
Inventor 边庆花钟江春王敏郑冰刘飞鹏毛建友杨燕青
Owner CHINA AGRI UNIV
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