CN113121350B - Method for dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylate and application thereof - Google Patents
Method for dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylate and application thereof Download PDFInfo
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Abstract
The invention discloses a method for dynamically and dynamically splitting alpha-aryl-alpha-alkyl carboxylic ester and application thereof, belonging to the technical field of organic synthesis. The method is characterized in that pentafluorophenol ester and benzhydrol are used as reactants, alpha-aryl-alpha-alkyl ester is obtained through dynamic kinetic resolution reaction under the catalysis of chiral DMAP nitrogen oxide derived from benzhydryl amine, and (S) -naproxen, (S) -ibuprofen, (S) -ketoprofen, (S) -fenoprofen and (S) -flurbiprofen are synthesized. The chiral DMAP nitrogen-oxygen catalyst takes oxygen atoms in pyridine nitrogen oxygen as nucleophilic sites to participate in dynamic kinetic resolution reaction, and simultaneously hydrogen in a catalyst molecule plays a key role. The method has the advantages of good yield, high enantioselectivity and the like.
Description
Technical Field
The invention relates to a method for catalyzing dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylic ester by chiral DMAP nitroxide catalyst, belonging to the technical field of asymmetric synthesis in organic chemistry.
Background
Optically active α -aryl- α -alkyl carboxylic acids and derivatives thereof are important bioactive molecules, such as (S) -ibuprofen, (S) -naproxen, (S) -ketoprofen, (S) -fenoprofen, and (S) -flurbiprofen, are widely used non-steroidal anti-inflammatory drugs. The nucleophilic sites in previously reported catalysts are limited to nitrogen or carbon atoms, and the use of oxygen atoms as nucleophilic sites has not been applied to such reactions.
Therefore, the development of efficient synthetic methods for preparing chiral α -aryl- α -alkyl carboxylic acids and derivatives thereof is of great research interest.
Disclosure of Invention
In order to solve the technical problems, the invention discloses a method for catalyzing the dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylic ester by using a chiral DMAP nitroxide catalyst. Unlike available DMAP catalyst with pyridine nitrogen to participate in nucleophilic reaction, the DMAP nitrogen-oxygen chiral catalyst of the present invention utilizes oxygen atom in pyridine nitrogen oxygen as nucleophilic site to participate in dynamic kinetic resolution reaction, and the hydrogen in the catalyst molecule plays a key role.
The invention relates to a method for catalyzing dynamic kinetic resolution of alpha-aryl-alpha-alkyl carboxylic ester by chiral DMAP nitroxide catalyst, which comprises the following steps: the method comprises the steps of taking racemized alpha-aryl-alpha-alkyl ester 1 and benzhydrol as raw materials, and carrying out dynamic kinetic resolution reaction under the catalysis of DMAP nitrogen oxide chiral catalyst to obtain chiral alpha-aryl-alpha-alkyl ester 3; the reaction equation is as follows:
wherein: r is selected from C1-C8 alkyl or benzyl; ar (Ar) 1 Selected from electron-deficient aryl groups; ar (Ar) 2 Selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl; NR (NR) 1 R 2 Is dimethylamine or tetrahydropyrrole; r is R 3 Selected from phenyl, C1-C4 alkyl, substituted phenyl, benzyl or diphenylmethyl; the above-mentioned substituents are C1-C4 alkoxy, C1-C6 alkyl, halogen, nitro, nitrile, carboxylate, etc.
Further, among the above substituents, it is preferable that: r is Me, et and Bn; ar (Ar) 1 Phenyl substituted by one or more of chlorine, fluorine, nitro and trifluoromethyl; ar (Ar) 2 For 4-MeOC 6 H 4 、2-MeOC 6 H 4 、4-CH 3 C 6 H 4 、2-CH 3 C 6 H 4 、4-ClC 6 H 4 、2-ClC 6 H 4 1-naphthyl, 2-naphthyl, and the like.
Further, in the above technical scheme, the DMAP nitroxide chiral catalyst comprises the following structure:
further, in the above technical scheme, the DMAP nitroxide chiral catalyst preferably has a structure of C9f.
Further, in the above technical scheme, the reaction is performed in an organic solvent, and the organic solvent is selected from one or more of benzotrifluoride, chlorobenzene, dichloromethane or toluene. Preferably, the solvent is a mixed solvent of benzotrifluoride and dichloromethane.
Further, in the above technical scheme, the reaction is performed in an organic base selected from triethylamine, diisopropylethylamine or pyridine. Preferably the organic base is triethylamine or diisopropylethylamine.
Further, in the technical scheme, the molar ratio of the DMAP nitroxide chiral catalyst to the racemization alpha-aryl-alpha-alkyl ester 1 is 0.01-0.2:1. the preferable proportion of the two is 0.05-0.1:1.
further, in the above technical scheme, the reaction temperature is-10 ℃ to 20 ℃.
The invention also provides a method for synthesizing (S) -naproxen, (S) -ibuprofen, (S) -ketoprofen, (S) -fenoprofen or (S) -flurbiprofen, which comprises the following steps: the chiral alpha-aryl-alpha-alkyl ester 3 obtained by adopting the scheme is catalyzed and hydrogenated in palladium carbon to obtain (S) -naproxen, (S) -ibuprofen, (S) -ketoprofen, (S) -fenoprofen or (S) -flurbiprofen, and the specific corresponding reaction structure is as follows:
further, in the above technical scheme, the catalytic hydrogenation reaction solvent is a mixed solvent of tetrahydrofuran and ethanol.
The invention has the beneficial effects that:
1. the method takes racemized alpha-aryl-alpha-alkyl ester and benzhydrol as raw materials, and chiral alpha-aryl-alpha-alkyl ester products can be obtained in one step through dynamic kinetic resolution reaction. Then, catalytic hydrogenation is carried out, and a plurality of chiral drugs such as (S) -naproxen and the like are synthesized. The raw materials of the reaction are easy to obtain, and the highest reaction yield and enantioselectivity can reach 93 percent and 99 percent ee respectively.
2. Unlike available DMAP catalyst with pyridine nitrogen to participate in nucleophilic reaction, the DMAP nitrogen-oxygen chiral catalyst of the present invention utilizes oxygen atom in pyridine nitrogen oxygen as nucleophilic site to participate in dynamic kinetic resolution reaction, and the hydrogen in the catalyst molecule plays a key role.
Detailed Description
Example 1
[a]Unless otherwise indicated, the reaction conditions were as follows: esters (0.05 mmol), 2a (18.4 mg,0.1 mmol), catalyst C9f (2.2 mg,0.005mmol,10 mol%), iPr 2 EtN (17.4. Mu.L, 0.1 mmol) was left in DCM (0.5 mL) for 72h. [ b ]]Nuclear magnetic yield. [ c ]]Determined by chiral HPLC analysis. N.R = no reaction.
Taking pentafluorophenol ester 1b and benzhydrol 2a as raw materials to generate 3a as an example, the reaction condition is optimized, and the reaction equation is as follows:
the specific reaction results are shown in the following table:
[a]reaction conditions 1 (0.05 mmol), 2a (0.1 mmol), catalyst (10 mol%) and base (2 equiv) were reacted in solvent (0.5 mL) for 72h [ b ]]Nuclear magnetic yield. [ c ]]Determined by chiral HPLC analysis. [ d ]]PhCF 3 /DCM(1/1,v/v).[e]Et 3 N(5equiv),PhCF 3 /DCM(1/1,v/v).[f]1b(0.2mmol),2a(0.4mmol),C9f(10mol%),and Et 3 N(5equiv)in PhCF 3 DCM (0.5 mL,1/1, v/v) was reacted for 72h [ g ]]C9f(5mol%).
In the screening process of the reaction conditions, the effect of the catalyst on the reaction was first examined (reference numerals 1 to 10). Meanwhile, by comparing the influences of different leaving esters, alkali, solvents, temperature, raw material equivalent ratios and catalyst consumption on the reaction, the method finally determines that C9f is the optimal catalyst, the addition amount is 10mol%, the mixed solvent of benzotrifluoride and dichloromethane is the optimal reaction solvent, and 5 times of triethylamine is the optimal reaction condition.
Investigation of reaction conditions (exemplified by reference numeral 18): to a dried 5mL reaction tube were added chiral catalyst C9f (8.8 mg,0.02mmol,10 mol%), benzhydrol 2a (73.6 mg,0.4 mmol) and pentafluorophenol ester 1b (63.2 mg,0.2 mmol), followed by benzotrifluoride/dichloromethane (1/1, v/v,0.5 mL) and finally triethylamine (152. Mu.L, 1 mmol), and the reaction was stirred at 0deg.C for 72 hours. Column chromatography gave 57.6mg of yellow oil 3a in 91% yield,93% ee. HPLC CHIRALCEL IA n-hexane/2-pro-nol=98/2, flow rate=0.5 mL/min, λ= 256nm,retention time:24.043min (minor), 25.903min (major) [ α ]] D 21 =+22.5(c=1.7,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.32-7.22(m,10H),7.21-7.15(m,3H),7.08-7.02(m,2H),6.81(s,1H),3.83(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H).
Example 2
To a dried 5mL reaction tube were added chiral catalyst C9f (8.8 mg,0.02mmol,10 mol%), benzhydrol 2a (73.6 mg,0.4 mmol) and pentafluorophenol ester 1b-L (0.2 mmol), followed by benzotrifluoride/dichloromethane (1/1, v/v,0.5 mL) and finally triethylamine (152. Mu.L, 1 mmol), and the reaction was stirred at 0deg.C for 72 hours. And after the reaction is finished, obtaining a product after column chromatography.
The specific results are as follows:
representative nuclear magnetic characterization data are as follows:
(S)-Benzhydryl-2-(o-tolyl)propanoate(3c)
colorless oil, 55.5mg,84% yield,95% ee; r is R f =0.38(Pet/EtOAc,10/1,v/v).HPLC CHIRALCEL ID,n-hexane/2-propanol=90/10,flow rate=0.6mL/min,λ=256nm,retention time:9.060min(minor),9.478min(major).[α] D 21 =+33.4(c=2.0,CHCl 3 ); 1 H NMR(400MHz,CDCl 3 )δ7.32–7.22(m,5H),7.21–7.09(m,7H),7.06–7.00(m,2H),6.83(s,1H),4.07(q,J=7.2Hz,1H),2.35(s,3H),1.50(d,J=7.2Hz,3H).
(S)-Benzhydryl-2-(p-tolyl)propanoate(3d)
White powder, m.p. 48.3-49.7 ℃;57.4mg,87% yield,88% ee;R f =0.34(Pet/EtOAc,10/1,v/v).HPLC CHIRALCEL IG,n-hexane/2-propanol=98/2,flow rate=0.5mL/min,λ=256nm,retention time:33.425min(major),37.690min(minor).[α] D 21 =+17.6(c=2.4,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.32–7.24(m,5H),7.21–7.14(m,5H),7.13–7.06(m,4H),6.82(s,1H),3.80(q,J=7.2Hz,1H),2.33(s,3H),1.50(d,J=7.2Hz,3H).
(S)-Benzhydryl-2-(2-methoxyphenyl)propanoate(3e)
Colorless oil, 56.0mg,81% yield,99% ee; r is R f =0.46(Pet/EtOAc,10/1,v/v).HPLC CHIRALCEL IA,n-hexane/2-propanol=95/5,flow rate=0.5mL/min,λ=256nm,retention time:18.582min(minor),19.865min(major).[α] D 21 =+3.2(c=3.0,CHCl 3 ).
1 H NMR(600MHz,CDCl 3 )δ7.30–7.20(m,9H),7.17–7.12(m,3H),6.90(t,J=7.2Hz,1H),6.87(s,1H),6.81(d,J=8.4Hz,1H),4.10(q,J=7.2Hz,1H),3.59(s,3H),1.49(d,J=7.2Hz,3H).
(S)-Benzhydryl-2-(2-chlorophenyl)propanoate(3g)
Colorless oily form; 58.8mg,84% yield,94% ee; r is R f =0.37(Pet/EtOAc,20/1,v/v).HPLC CHIRALCEL OJ-H,n-hexane/2-propanol=70/30,flow rate=0.8mL/min,λ=256nm,retention time:9.200min(minor),10.788min(major).[α] D 21 =+31.8(c=2.40,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.41–7.37(m,1H),7.32–7.29(m,4H),7.27–7.24(m,1H),7.22–7.15(m,6H),7.13–7.09(m,2H),6.86(s,1H),4.37(q,J=7.2Hz,1H),1.51(d,J=7.2Hz,3H).
(S)-Benzhydryl-2-(4-chlorophenyl)propanoate(3h)
Light yellow oily; 49.6-54.7 ℃; (60.9 mg,87% yield,90% ee); r is R f =0.43(Pet/EtOAc,20/1,v/v).HPLC CHIRALCEL IA,n-hexane/2-propanol=99/1,flow rate=0.8mL/min,λ=256nm,retention time:23.290min(major),26.117min(minor).[α] D 21 =+4.6(c=1.50,CHCl 3 ); 1 H NMR(400MHz,CDCl 3 )δ7.33–7.24(m,7H),7.23–7.17(m,5H),7.11–7.05(m,2H),6.82(s,1H),3.81(q,J=7.2Hz,1H),1.50(d,J=7.2Hz,3H).
(S)-Benzhydryl-2-(naphthalen-1-yl)propanoate(3i)
Light yellow oily; 63.2-65.4 ℃;63.6mg,87% yield,97% ee; r is R f =0.42(Pet/EtOAc,50/1,v/v).HPLC CHIRALCEL IA,n-hexane/2-propanol=98/2,flow rate=0.5mL/min,λ=256nm,retention time:29.987min(major),33.043min(minor).[α] D 21 =+67.5(c=2.10,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ8.07(d,J=7.8Hz,1H),7.89(d,J=7.8Hz,1H),7.79(d,J=8.4Hz,1H),7.52–7.44(m,2H),7.42–7.38(m,1H),7.38–7.34(m,1H),7.28–7.22(m,3H),7.21–7.12(m,5H),6.99(d,J=7.2Hz,2H),6.86(s,1H),4.64(q,J=7.2Hz,1H),1.69(d,J=7.2Hz,3H).(S)-Benzhydryl-2-phenylbutanoate(3k)
Colorless oily form; 55.7mg,84% yield,93% ee; r is R f =0.46(Pet/EtOAc,20/1,v/v).HPLC CHIRALCEL IA,n-hexane/2-propanol=98/2,flow rate=0.5mL/min,λ=256nm,retention time:25.242min(minor),28.140min(major).[α] D 21 =+24.5(c=1.00,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.30–7.24(m,10H),7.19–7.18(m,3H),7.07(t,J=3.6Hz,2H),6.81(s,1H),3.57(t,J=7.2Hz,1H),2.14–2.10(m,1H),1.85–1.80(m,1H),0.85(t,J=7.2Hz,3H).
Example 3
To a dry 5mL reaction tube were added chiral catalyst C9f (8.8 mg,0.02mmol,10 mol%), benzhydrol 2a (73.6 mg,0.4 mmol) and pentafluorophenol ester 1m (74.4 mg,0.2 mmol), followed by benzotrifluoride/dichloromethane (1/1, v/v,0.5 mL) and finally triethylamine (152. Mu.L, 1 mmol), and the reaction was stirred at 0deg.C for 72 hours. Column chromatography gave 66.2mg of a colourless oil 3m in 89% yield,90% ee. HPLC CHIRALCEL IA n-hexane/2-pro-nol=99/1, flow rate=0.5 mL/min, λ= 256nm,retention time:27.917min (major), 33.453min (minor) [ α] D 21 =+20.5(c=1.40,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.32-7.21(m,5H),7.21-7.14(m,5H),7.11-7.03(m,4H),6.81(s,1H),3.80(q,J=7.2Hz,1H),2.46(d,J=7.2Hz,2H),1.89-1.82(m,1H),1.51(d,J=7.2Hz,3H),0.91(d,J=7.2Hz,6H).
Example 4
To a dried 5mL reaction tube were added chiral catalyst C9f (8.8 mg,0.02mmol,10 mol%), benzhydrol 2a (73.6 mg,0.4 mmol) and pentafluorophenol ester 1n (84 mg,0.2 mmol), followed by benzotrifluoride/dichloromethane (1/1, v/v,0.5 mL) and finally triethylamine (152. Mu.L, 1 mmol), and the reaction mixture was stirred at 0℃for 86 hours. The column chromatography gave 72.2mg of 3n as a colorless oil in 86% yield,88% ee. HPLC CHIRALCEL OD-H, n-hexane/2-pro-nol=99/1, flow rate=0.8 mL/min, λ= 256nm,retention time:34.585min (major), 45.472min(minor).[α] D 21 =+20.4(c=1.10,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.72(d,J=7.2Hz,3H),7.69(d,J=7.2Hz,1H),7.56(t,J=7.2Hz,1H),7.50(d,J=7.8Hz,1H),7.42(q,J=7.2Hz,3H),7.30-7.23(m,5H),7.22-7.15(m,3H),7.12-7.06(m,2H),6.83(s,1H),3.91(q,J=7.2Hz,1H),1.55(d,J=7.2Hz,3H).
Example 5
To a dry 5mL reaction tube were added chiral catalyst C9f (2.2 mg,0.005mmol,10 mol%), benzhydrol 2a (36.8 mg,0.1 mmol) and pentafluorophenol ester 1o (20.4 mg,0.05 mmol), followed by benzotrifluoride/dichloromethane (1/1, v/v,0.5 mL) and finally triethylamine (38. Mu.L, 0.25 mmol), respectively, and the reaction mixture was stirred at 0deg.C for 72 hours. Column chromatography gave 17.1mg of colorless oil 3o in 84% yield,94% ee. HPLC CHIRALCEL IA n-hexane/2-pro-nol=98/2, flow rate=0.5 mL/min, λ= 256nm,retention time:18.135min (major), 22.193min (minor) [ α ]] D 21 =+20.6(c=1.42,CHCl 3 ). 1 H NMR(400MHz,CDCl 3 )δ7.33-7.19(m,11H),7.13-6.88(m,8H),6.83(s,1H),3.80(q,J=7.2Hz,1H),1.50(d,J=7.2Hz,3H).
Example 6
To a dried 5mL reaction tube were added chiral catalyst C9f (8.8 mg,0.02mmol,10 mol%), benzhydrol 2a (73.6 mg,0.4 mmol) and pentafluorophenol ester 1p (82.0 mg,0.2 mmol), followed by benzotrifluoride/dichloromethane (1/1, v/v,0.5 mL) and finally triethylamine (152. Mu.L, 1 mmol), and the reaction mixture was stirred at 0deg.C for 72 hours. The column chromatography gave 72.3mg of white powder 3p in 88% yield, 91% ee. HPLC CHIRALCEL OJ-H, n-hexane/2-pro-nol=70/30, flow rate=1.0 mL/min, λ= 256nm,retention time:17.982min (major), 27.502min (minor).[α] D 21 =+6.4(c=1.40,CHCl 3 ). 1 H NMR(600MHz,CDCl 3 )δ7.54(d,J=7.8Hz,2H),7.43(t,J=7.2Hz,2H),7.39-7.35(m,2H),7.32-7.25(m,5H),7.23-7.21(m,3H),7.14-7.07(m,4H),6.86(s,1H),3.86(q,J=7.2Hz,1H),1.55(d,J=7.2Hz,3H).
Example 7
To a 50mL dry round bottom flask was added chiral catalyst C9f (114 mg,0.26mmol,10 mol%), benzhydrol 2a (956.8 mg,5.2 mmol) and pentafluorophenol ester 1q (1.0296 g,2.6 mmol), then benzotrifluoride/dichloromethane (1/1, v/v,7.0 mL) and finally triethylamine (1.4 mL,13 mmol) and stirred at 0deg.C for 85 hours. The column chromatography gave 897.3mg of white solid 3q in 87% yield,93% ee. HPLC CHIRALCEL IA n-hexane/2-pro-nol=98/2, flow rate=0.8 mL/min, λ= 256nm,retention time:32.408min (major), 37.220min (minor) [ α ]] D 21 =+16.6(c=1.60,CHCl 3 ); 1 H NMR(600MHz,CDCl 3 )δ7.67(d,J=8.4Hz,1H),7.62(d,J=9.0Hz,1H),7.59(s,1H),7.36(d,J=9.6Hz,1H),7.28-7.21(m,5H),7.16-7.10(m,5H),7.05(d,J=7.2Hz,2H),6.84(s,1H),3.96(q,J=7.2Hz,1H),3.90(s,3H),1.58(d,J=7.2Hz,3H).
Example 8
To a 10mL dry reaction tube were added naproxen ester 3q (79.2 mg,0.2 mmol) and 10% Pd/C (40 mg) and dissolved in ethanol/tetrahydrofuran (1/1, v/v,2.0 mL). The hydrogen is replaced by vacuum pumping, so that the reaction tube is completely filled with hydrogen. The reaction was stirred at 0deg.C for 10 hours. After completion of the detection reaction, the reaction solution was passed through celite, and then washed with methanol thoroughly. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography (Pet/etoac=3/1) and finally obtained as a white solid in 82% yield and 93% ee valueAcid 4q. HPLC CHIRALCEL OD-H, n-hexane/2-pro anol=50/1, flow rate=1.0 mL/min with 0.1% TFA; λ= 256nm,retention time:33.072min (minor), 40.233min (major) [ α ]] D 21 =+66.2(c=2.50,CHCl 3 )。
The foregoing embodiments illustrate the basic principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments, and that the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the scope of the principles of the invention, which are defined in the appended claims.
Claims (5)
1. A method for dynamic kinetic resolution of an α -aryl- α -alkyl carboxylate, comprising the steps of: the method comprises the steps of taking racemized alpha-aryl-alpha-alkyl ester 1 and benzhydrol as raw materials, and carrying out dynamic kinetic resolution reaction under the catalysis of DMAP nitrogen oxide chiral catalyst to obtain chiral alpha-aryl-alpha-alkyl ester 3; the reaction equation is as follows:
wherein R is selected from C1-C8 alkyl or benzyl; ar (Ar) 1 Selected from electron-deficient aryl groups; ar (Ar) 2 Selected from phenyl, substituted phenyl, naphthyl, substituted naphthyl; the substitution refers to C1-C4 alkoxy, C1-C6 alkyl, halogen, nitro, nitrile group and carboxylic ester group; the DMAP nitroxide chiral catalyst isThe organic solvent is selected from mixed solvents of benzotrifluoride and dichloromethane; the reaction is carried out in an organic base, wherein the organic base is triethylamine, and the addition amount of the triethylamine is 5eq of racemized alpha-aryl-alpha-alkyl ester 1.
2. The method for dynamic kinetic resolution of α -aryl- α -alkyl carboxylic acid esters according to claim 1, characterized in that: the molar ratio of the DMAP nitroxide chiral catalyst to the racemization alpha-aryl-alpha-alkyl ester 1 is 0.01-0.2:1.
3. the method for dynamic kinetic resolution of α -aryl- α -alkyl carboxylic acid esters according to claim 1, characterized in that: the reaction temperature is-10 ℃ to 20 ℃.
4. A method for synthesizing (S) -naproxen, (S) -ibuprofen, (S) -ketoprofen, (S) -fenoprofen, or (S) -flurbiprofen, comprising the steps of: a chiral α -aryl- α -alkyl ester 3 obtained by the process of any one of claims 1-3, followed by catalytic hydrogenation of the chiral α -aryl- α -alkyl ester 3 in palladium on carbon to obtain (S) -naproxen, (S) -ibuprofen, (S) -ketoprofen, (S) -fenoprofen or (S) -flurbiprofen.
5. A process for the synthesis of (S) -naproxen, (S) -ibuprofen, (S) -ketoprofen, (S) -fenoprofen or (S) -flurbiprofen according to claim 4, characterized in that: the catalytic hydrogenation reaction solvent is a mixed solvent of tetrahydrofuran and ethanol.
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