CN103755554B - Novel method for asymmetric catalytic synthesis of (S)-fenoprofen - Google Patents

Abstract

The invention discloses a new method for asymmetrically synthesizing (S)-fenoprofen. The method generates (S)-fenoprofen by the Kumada cross-coupling reaction of racemic 2-halopropionate and self-made 3-phenoxyphenyl Grignard reagent in bisoxazoline/cobalt catalysis Esters, and then catalytic hydrogenation to obtain (S)-fenoprofen. The synthesis route of the present invention is short and only has three steps of reaction, the total yield of the whole synthesis route is 70%, and the optical purity of the product is high (92% ee).

Description

Asymmetric Catalytic Synthesis of (S)-Fenoprofen

technical field

The invention relates to the technical field of medicine, in particular to a novel asymmetric catalytic synthesis method of (S)-fenoprofen. the

Background technique

Fenoprofen is an aryl propionic acid non-steroidal anti-inflammatory drug, which is widely used clinically, mainly for the treatment of rheumatoid arthritis and osteoarthritis. There is a chiral carbon atom in the structure of fenoprofen, and there are a pair of enantiomers with different biological activities. Studies have shown that the analgesic effect of (S)-fenoprofen (Formula 1) is 35 times that of (R)-isomer (Rubin, A.; Knadler, M.P.; Ho, P.P.K.; Bechtol, L.D.; Wolen, R.L.J. Pharm. Sci. 1985, 74(1), 82–84.). Therefore, (S)-fenoprofen is its active ingredient. Obtaining (S)-fenoprofen mainly includes racemate resolution, chiral induction, enzyme catalysis and asymmetric catalysis. the

(1) The racemate resolution method mainly includes the kinetic resolution of two-9-phenanthrenylmethanol to racemic fenoprofen (Nakata, K.; Onda, Y.-s., Ono, K,; Shiina, I.Tetrahedron Lett.2010,51(43),5666–5669.), and the kinetic resolution of di-alpha-naphthylcarbinol to racemic fenoprofen (Shiina, I.; Nakata, K. ;Onda,Y.-s.Eur.J.Org.Chem.2008,(35),5887–5890.Shiina,I.;Nakata,K;Ono,K.;Onda,Y.-s.;Itagaki, M.J.Am.Chem.Soc.2010,132(33),11629–11641.)

(2) The chiral induction method is mainly the asymmetric alkylation reaction of aryl acids with chiral lithium amide as the chiral inducing reagent (Stivala, C.E.; Zakarian, A.J.Am.Chem.Soc.2011,133(31), 11936–11939.). the

(3) The research of enzyme-catalyzed method mainly comprises the asymmetric hydrolysis reaction of enzyme-catalyzed fenoprofen thioester (Chen, C.-Y.; Cheng, Y.-C.; Tsai, S.-W.J.Chem.Technol. Biotechnol.2002,77(6),699–705.), and enzyme-catalyzed asymmetric hydrolysis of fenoprofen butyl ester (Ghanem, A.; Aboul-Enein, M.N.; El-Azzouny, A.; El- Behairy, M.F.J. Chromatogr. A2010, 1217(7), 1063–1074.)

(4) asymmetric catalysis mainly comprises the asymmetric hydroformylation reaction (Chelucci, G.; Marchetti, M.; Sechi, B.J.Mol.Catal.A:Chem.1997,122(2-3) of the alkene of rhodium catalysis ),111–114.), asymmetric epoxidation of enones (Carde,L.; Davies,H.; Geller,T.P.;Roberts,S.M.Tetrahedron Lett.1999,40(29), 5421–5424.) , and nickel-catalyzed asymmetric hydrovinylation of alkenes (Smith, C.R.; Rajan Babu T.V.J.Org. Chem. 2009, 74(8), 3066–3072.). the

Although there have been some reports on the asymmetric synthesis of (S)-fenoprofen, there are still some problems, such as the need for enzyme reagents, stoichiometric chiral reagents, harsh reaction conditions, and cumbersome reaction steps. Therefore, research Efficient, environmentally friendly, and simple new asymmetric synthesis methods are of great significance. the

Contents of the invention

The invention provides a new method for synthesizing (S)-fenoprofen by cobalt-catalyzed asymmetric Kumada cross-coupling reaction. The present invention adopts the method of asymmetric catalyzed Kumada cross-coupling, generates (S)-non- Noprofen axetil, prepared by catalytic hydrogenation (S)-fenoprofen. The synthesis route of this method is short, with only three steps of reaction, the total yield of the whole synthesis route is 70%, and the optical purity of the product is high (92% ee). Refer to formula 2 for the synthesis route of (S)-fenoprofen synthesized by asymmetric catalysis in the present invention. the

The specific synthetic method of the asymmetric catalytic synthesis (S)-fenoprofen of the present invention comprises the following steps. the

(1) Synthesis of 3-phenoxy Grignard reagent 2

Under the protection of argon, add anhydrous THF and 3-phenoxyhalogenated benzene to the magnesium powder, and heat to reflux for 3 hours to obtain 3-phenoxyphenyl Grignard reagent. the

(2) Synthesis of (S)-fenoprofen axetil 4

Under the protection of argon, add racemic 2-halogenated phenylpropionate 3 to the solution of cobalt salt and bisoxazoline chiral ligand, and stir at room temperature. After lowering the reaction temperature, 3-phenoxy Grignard reagent was added, and the stirring reaction was continued. The reaction was quenched, extracted and dried, concentrated under reduced pressure and purified by silica gel column chromatography to obtain (S)-fenoprofen axetil 4. the

(3) Synthesis of (S)-fenoprofen

Under the protection of argon, a methanol solution of (S)-fenoprofen axetil was added in Pd/C. The reaction was stirred for 6h and filtered. The filtrate was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain (S)-fenoprofen. the

Detailed ways

Example 1

Synthesis of 3-phenoxy Grignard reagent 2

Under argon protection, magnesium powder (109.4 mg, 4.5 mmol) and anhydrous THF (3.0 mL) were added to a dry Schlenk tube, followed by 3-phenoxybromobenzene (249.0 mg, 1.0 mmol). The reaction was stirred, heated carefully to initiate the reaction, and the remaining 3-phenoxybromobenzene (498.0 mg, 2 mmol) was added slowly. The reaction solution was heated to reflux for 3 h to obtain a gray-black THF solution of 3-phenoxymagnesium bromide. the

Example 2

Synthesis of (S)-fenoprofen axetil 4

Under argon protection, CoI ₂ (62.4mg, 0.2mmol) was added to a dry Schlenk bottle, and after vacuum drying for 2h, anhydrous tetrahydrofuran (6.0mL) and bisoxazoline chiral ligand L1 (88.0mg, 0.24 mmol), stirred at room temperature for 1 h. Add racemic benzyl 2-bromophenylpropionate (485.0mg, 2.0mmol) to the mixture, lower the reaction temperature to -80°C, and add homemade 3-phenoxyphenylmagnesium bromide THF solution dropwise . 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 (30mL×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 a colorless oil (S) - Fenoprofen axetil 4 (578.4 mg, 87% yield, 92% optical purity). [α] _D ²⁵ =+13.5(c1.0,CHCl ₃ ); ¹ H NMR(300MHz,CDCl ₃ )δ:7.34–7.26(m,5H),7.25–6.89(m,9H),5.13(d, J=12.6Hz,1H),5.08(d,J=12.6Hz,1H),3.74(q,J=7.2Hz,1H),1.50(d,J=7.2Hz,3H); ¹³ C NMR(75MHz, CDCl ₃ ) δ: 173.9, 157.3, 157.1, 142.3, 135.9, 129.8, 129.7, 128.4, 128.0, 127.8, 123.2, 122.3, _118.8 , 118.2, 117.4, 66.4, 45.4, 18.2; ₂₁ O ₃ [M+H] ⁺ 333.1491, found 333.1490.

Refer to formula 3 for the structure of bisoxazoline chiral ligand L1. the

Synthesis of (S)-fenoprofen

Under argon protection, add Pd/C (21.0mg, 10%, 0.02mmol) in the dry Schlenk tube, vacuum dry 10min, add (S)-fenoprofen axetil (66.5mg, 0.2mmol) methanol ( 1 mL) 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)-fenoprofen (39.2 mg, yield 81%, optical purity 92%) as a colorless oil. [α] _D ²⁰ =+43.0(c1.2,CHCl ₃ ); ¹ H NMR(300MHz,CD ₃ COCD ₃ )δ:10.8(br s,1H),7.41–7.31(m,3H),7.15–7.11 (m,2H),7.04–7.00(m,3H),6.89–6.86(m,1H),3.76(q,J=7.1Hz,1H),1.44(d,J=7.1Hz,3H); ¹³ C NMR (75MHz, CD ₃ COCD ₃ ) δ: 175.3, 158.3, 158.1, 144.4, 130.7, 124.2, 123.3, 119.6, 118.8, 117.9, 45.6, 19.0; HRMS (ESI-TOF) calcd for C ₁₅ H ₁₅ O ₃ [ M+H] ⁺ 243.1021, found 243.1016.

Claims (5)

1. asymmetric catalytic synthesis (S)-fenoprofen method is characterized in that: 3-bromodiphenyl ether or 3-chlorinated diphenyl ether generate Grignard reagent with metal magnesium earlier, then adopt the following formula to represent Asymmetric catalyzed Kumada cross-coupling method, under bisoxazoline/cobalt catalysis, racemic 2-halopropionate is reacted with 3-phenoxyphenyl Grignard reagent to prepare 3-phenoxyphenyl Propionate, finally obtained (S)-fenoprofen by catalytic hydrogenation The substituent R' of the bisoxazoline chiral ligand in the above formula is phenyl, benzyl, isopropyl, isobutyl, tert-butyl and phenethyl; the cobalt salt is CoI ₂ , CoBr ₂ , CoCl ₂ , Co(OAc) ₂ , Co(acac) ₂ , Co(acac) ₃ , Co(dppe)Cl ₂ and Co(PPh ₃ )Cl ₂ ; the halogen atoms of 2-halopropionate are Cl, Br and I , the substituent R is methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl, cyclopentyl, cyclohexyl, cyclohexyl, bromoethyl and isopentenyl; the Grignard reagent is 3-phenoxyphenyl magnesium bromide and 3-phenoxyphenyl magnesium chloride; R of the product 3-phenoxyphenyl propionate is methyl, ethyl, isopropyl, tert-butyl, phenyl, benzyl , cyclopentyl, cyclohexyl, cyclohexyl, bromoethyl and isopentenyl. 2. The synthesis method according to claim 1, characterized in that the organic solvent used in the asymmetric catalytic Kumada cross-coupling reaction is tetrahydrofuran, toluene, ether, dichloromethane and 1,2-dimethoxyethane. the 3. The synthesis method according to claim 1, characterized in that the reaction temperature of the asymmetric catalyzed Kumada cross-coupling reaction is -60°C to -100°C. the 4. The synthetic method according to claim 1, characterized in that the molar equivalent ratio of bisoxazoline chiral ligand and cobalt salt in the asymmetric catalyzed Kumada cross-coupling reaction is 1:1 to 1:3. the 5. The synthetic method according to claim 1, characterized in that the molar equivalent ratio of halogenated carboxylic acid ester and Grignard reagent in the asymmetric catalyzed Kumada cross-coupling reaction is 1:1 to 1:3. the