Abstract:
The present invention belongs to the technical field of chemical catalysts, and particularly relates to a zinc 2-arylpropionate catalyst, a preparation method therefor and use thereof The structural formula of the zinc 2-arylpropionate catalyst of the present invention is one of the following structures. The catalyst can be used for homogeneous catalysis of a 1,2-aryl rearrangement reaction of α-haloarylketal, and especially for synthesis of high yield and environmentally friendly 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs, such as, ibuprofen, ketoprofen, loxoprofen, flurbiprofen, fenoprofen, or naproxen and the like.

Description:
FIELD OF THE INVENTION 
       [0001]    The present invention belongs to the technical field of chemical catalysts, and particularly relates to a zinc 2-arylpropionate catalyst, a preparation method therefor and use thereof, especially the use thereof in the syntheses of 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs. 
       BACKGROUND ARTS 
       [0002]    2-Arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs, such as ibuprofen, ketoprofen, loxoprofen, flurbiprofen, fenoprofen, naproxen, etc., are clinically widely used for treating arthritis, rheumatoid arthritis, and the relief of various fever and pain symptoms. 
         [0003]    In the presence of a catalyst, 1,2-aryl rearrangement of an α-haloarylketal is a classical method for preparing a 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drug. Giordano used AgBF 4  to catalyze the 1,2-aryl rearrangement of an α-haloarylketal, but AgBF 4  has a too expensive price, and is not suitable for industrial productions (J. Chem. Soc. Perkin Trans. 1, 1982, 11, 2575; Tetrahedron, 1982, 23, 1385). There are documents reporting that lewis acids, such as anhydrous ZnCl 2 , ZnBr 2  or SnCl 4 , can catalyze the 1,2-aryl rearrangement of an α-haloarylketal, but there are colloidal black insolubles produced during the reaction, and the separating operation is relatively complex (European patent EP 0035305, 0034871, and 0163338; U.S. Pat. No. 4,414,405; J. Org. Chem. 1983, 48, 4658; and Chinese Journal of Pharmaceuticals, 1988, 19, 483). CHEN, Fener et al. (Chinese patent ZL 00127293.4; Chinese Journal of Pharmaceuticals, 1998, 29, 531; West China Journal of Pharmaceutcal Sciences, 1995, 10, 129); and Piccolo (J. Org. Chem., 1987, 52, 10) and European patent 0174844 describe the use of ZnO, ZnS or Zn(OH) 2  to catalyze such a rearrangement reaction, with a higher rearrangement yield, but due to the presence of a heterogeneous catalyst, the reaction needs a higher temperature, material outshoot easily occurs, and the product quality is relatively poor. US patent U.S. Pat. No. 4,623,736 discloses the rearrangement of an α-chlorinated isobutylphenyl phenyl ketal under the catalysis of zinc 2-ethylhexanoate to prepare ibuprofen, but this reaction has strict conditions and is carried out almost without a solvent, and the product is a black oily substance and has a poorer quality. Zinc tosylate or a mixture of same and ZnO is used in Chinese patent ZL 92106667.8 to catalyze the molecular rearrangement so as to prepare ibuprofen, which needs to be performed at a high temperature of 140-150° C. 
       SUMMARY OF THE INVENTION 
       [0004]    An object of the present invention lies in overcoming the drawbacks in the prior art, and providing a homogeneous catalyst of zinc 2-arylpropionate, a preparation therefor and use thereof, especially the use thereof in the syntheses of 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs. 
         [0005]    Such a zinc 2-arylpropionate catalyst provided by the present invention has one of the following structures: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0006]    wherein R 1  and R 2  are respectively selected from hydrogen, a C 1 -C 4  alkyl, a methoxyl, a trifluoromethyl, a halogen, a phenyl, and a benzyl; R 1  is ortho-substituted, meta-substituted or para-substituted, mono-substituted or polysubstituted; and R 2  is C-5, C-6, C-7, or C-8 substituted, mono-substituted or polysubstituted. 
         [0007]    The synthetic route of such a zinc 2-arylpropionate catalyst of the present invention is as follows: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0008]    the specific steps are: 
         [0009]    (1) at room temperature, an alkaline earth hydroxide is dissolved in a C 1 -C 4  alcohol, 2-arylpropionic acid is added, and reacted at room temperature to 100° C. for 0.5-2 h to obtain a solution of alkaline earth 2-arylpropionate. Said alkaline earth hydroxide is sodium hydroxide, potassium hydroxide or calcium hydroxide, and the molar ratio of the 2-arylpropionic acid to the alkaline earth hydroxide is 1:0.8-1:1.5. 
         [0010]    (2) a zinc salt or zinc oxide is added into the above-mentioned alkaline earth 2-arylpropionate solution, and reacted at room temperature to 100° C. for 0.5-20 h to obtain zinc 2-arylpropionate; said zinc salt is zinc chloride, zinc sulphate or zinc acetate; and the molar ratio of said zinc salt or zinc oxide to the alkaline earth 2-arylpropionate is 0.5:1-0.5:1.2. 
         [0011]    Preferred reaction conditions of the present invention are: in step (1), the alkaline earth hydroxide is sodium hydroxide, the C 1 -C 4  alcohol is methanol or ethanol, the reaction temperature is 45-55° C., the reaction time is 0.5-2 h, and the molar ratio of the 2-arylpropionic acid to the alkaline earth hydroxide is 1:1-1:1.1. In step (2), said zinc salt is zinc acetate, and the molar ratio of the zinc acetate to the sodium 2-arylpropionate is 0.5:1-0.5:1.1. 
         [0012]    The zinc 2-arylpropionate catalyst of the present invention can be used for catalyzing the 1,2-aryl rearrangement reaction of the corresponding α-haloarylketal (III). Especially, by said rearrangement reaction, 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs are synthesized by catalysis. Particularly, the zinc 2-arylpropionate and α-haloarylketal are reacted in a single or mixed aromatic hydrocarbon solvent at 80-160° C. for 1-10 h. Said aromatic hydrocarbon solvent is benzene, mono-substituted benzene or multisubstituted benzene, etc. The molar ratio of said zinc 2-arylpropionate catalyst to the α-haloarylketal is 0.01:1-0.5:1. 
         [0013]    In the present invention, preferred reaction conditions of the rearrangement reaction are: the aromatic hydrocarbon solvent is toluene, the reaction temperature is 110-120° C., and the molar ratio of the catalyst to the α-haloarylketal is 0.02:1-0.1:1. The α-haloarylketal can be prepared with reference to methods in the following documents: U.S. Pat. No. 4,623,736; J. Chem. Soc. Perkin Trans. 1, 1986, 1983; CHEN, Fener et al., Chinese Journal of Pharmaceuticals, 1996, 27, 195; Chinese Journal of Pharmaceuticals, 1998, 29, 531; West China Journal of Pharmaceutcal Sciences, 1995, 10, 129; and XIONG Xianqiang et al., Chinese Journal of Pharmaceuticals, 2000, 31, 436. The α-haloarylketal can be selected from one of the following structures: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein Ar is 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    and X is Cl, Br or I. The zinc 2-arylpropionate catalyst provided by the present invention is simple to be synthesized, and can be used for synthesis of 2-arylpropanonic acid non-steroidal anti-inflammatory analgesic drugs by homogeneous catalysis in a high yield under moderate conditions. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0014]    The present invention is further described below in detail in combination with particular embodiments, but the scope of protection of the present invention is not limited thereto. 
       Embodiment 1 Synthesis of zinc 2-phenylpropionate 
       [0015]    0.4 g (0.01 mol) of sodium hydroxide and 15 mL of methanol are added into a 100 mL round-bottom flask, and dissolved at room temperature under stirring, thereafter 1.5 g (0.01 mol) of 2-phenylpropionic acid is added and reacted at 50° C. for 0.5 h, and cooled to room temperature. 1.1 g (0.005 mol) of a solution of zinc acetate dihydrate dissolved in methanol (10 mL) is dropwise added and reacted at 50° C. for 1 h after the completion of the addition, the majority of the solvent is recovered, and a white solid is filtered out, washed with a methanol solution, and dried at 150° C. under a reduced pressure for 7 h to obtain 1.81 g of zinc 2-phenylpropionate with a yield of 99.5% and m.p. 262-264° C. 
       Embodiment 2 Synthesis of zinc 2-p-tolylpropionate 
       [0016]    0.44 g (0.011 mol) of sodium hydroxide and 15 mL of methanol are added into a 100 mL round-bottom flask, and dissolved at room temperature under stirring, thereafter 1.64 g (0.01 mol) of 2-p-tolylpropionic acid is added and reacted at 50° C. for 2 h, and cooled to room temperature. 1.1 g (0.005 mol) of a solution of zinc acetate dihydrate dissolved in methanol is dropwise added (10 mL) and undergoes a reflux reaction for 7 h after the completion of the addition, the majority of the solvent is recovered, and a white solid is filtered out, washed with a methanol solution, and dried at 150° C. under a reduced pressure for 7 h to obtain 1.66 g of zinc 2-p-tolylpropionate with a yield of 84.7% and m.p. 256-258° C. 
       Embodiment 3 Synthesis of zinc 2-p-isobutylphenylpropionate 
       [0017]    44 mg (1.1 mmol) of sodium hydroxide and 8 mL of methanol are added into a 25 mL round-bottom flask, and dissolved at room temperature under stirring, thereafter 206 mg (1 mmol) of 2-p-isobutylphenylpropionic acid is added and reacted at 50° C. for 2 h, and cooled to room temperature. 110 mg (0.5 mmol) of a solution of zinc acetate dihydrate dissolved in methanol is dropwise added (2 mL) and undergoes a reflux reaction for 10 h after the completion of the addition, the majority of the solvent is recovered, and a white solid is filtered out, washed with a methanol solution, and dried at 150° C. under a reduced pressure for 7 h to obtain 192 mg of zinc 2-p-isobutylphenylpropionate with a yield of 80.8% and m.p. 203-206° C. 
       Embodiment 4 Synthesis of zinc 2-(6-methoxylnaphthyl)propionate 
       [0018]    40 mg (1 mmol) of sodium hydroxide and 8 mL of methanol are added into a 25 mL round-bottom flask, and dissolved at room temperature under stirring, thereafter 230 mg (1 mmol) of 2-(6-methoxylnaphth-2-yl)propionic acid is added and reacted at 50° C. for 2 h, and cooling is performed to room temperature. 110 mg (0.5 mmol) of a solution of zinc acetate dihydrate dissolved in methanol is dropwise added (2 mL) and undergoes a reflux reaction for 7 h after the completion of the addition, the majority of the solvent is recovered, and a white solid is filtered out, washed with a methanol solution, and dried at 150° C. under a reduced pressure for 7 h to obtain 183 mg of zinc 2-(6-methoxylnaphth-2-yl)propionate with a yield of 69.8% and m.p. 205-207° C. 
         [0019]    Examples of the use of zinc 2-arylpropionate in the catalysis of 1,2-aryl rearrangement reaction of the corresponding α-haloarylketal are as follows. 
       Embodiment 5 Synthesis of 2-(6-methoxylnaphth-2-yl)naphthylpropionic acid ((±)naproxen) under catalysis of zinc 2-(6-methox-2-yl)naphthyl propionate 
       [0020]    16.7 g (0.05 mol) of 2-(1 -bromoethyl)-2-(6-methoxylnaphth-2-yl)-5,5-dimethyl-1,3 -epoxyhexane, 0.523 g (0.001 mol) of zinc 2-(6-methoxylnaphthyl)propionate and 50 mL of toluene are added into a 500 mL round-bottom flask and undergo a reflux reaction for 5.5 h, a 30% sodium hydroxide solution (50 mL) is added, after refluxing under stirring for 3.5 h and cooling to 50° C., water (30 mL) and a small amount of activated carbon are added, and the stirring refluxing is continued for 0.5 h. After cooling, filtration and standing, an aqueous layer is separated, a toluene layer is washed with water (50 mL×3), the aqueous layers are combined and adjusted with concentrated hydrochloric acid to a pH of 1-2 to separate a white solid, and the white solid is filtered, the crude product is washed with water and dried. Recrystallization is performed using ethanol-water to obtain 11.14 g of a white powder with a yield of 96.9%. The m.p. is 152-154° C. 
       Embodiment 6 Synthesis of 2-(4-methoxylphenyl)propionic acid (critical intermediate of loxoprofen) under catalysis of zinc 2-(4-methylphenyl)propionate 
       [0021]    13.4 g (0.05 mol) of 2-(1-chloroethyl)-5,5-dimethyl-2-p-tolyl-1,3-epoxyhexane, 0.523 g (0.001 mol) of zinc 2-(6-methoxylnaphthyl)propionate and 50 mL of toluene are added into a 500 mL round-bottom flask and undergo reflux reaction for 3.5 h, a 30% sodium hydroxide solution (50 mL) is added, after reflux under stirring for 3.5 h and cooling to 50° C., water (30 mL) and a small amount of activated carbon are added, and agitation reflux continues for 0.5 h. After cooling, filtration and standing, aqueous layer is separated, a toluene layer is washed with water (50 mL×3), the aqueous layers are combined and adjusted with a concentrated hydrochloric acid to a pH of 1-2 extracted with chloroform (30 mL×3), dried using an anhydrous sodium sulphate, the chloroform is distilled off to obtain 7.92 g of a white solid with a yield of 96.6%. The m.p. is 37-38° C. 
       Embodiment 7 Synthesis of 2-(4-isobutylphenyl)propionic acid (ibuprofen) under catalysis of zinc 2-(4-isobutylphenyl)propionate 
       [0022]    15.6 g (0.05 mol) of 2-(1-bromoethyl)-2-p-butylphenyl-1,3-epoxypentane, 0.784 g (0.0015 mol) of zinc 2-(6-methoxylnaphthyl)propionate and 50 mL of toluene are added into a 500 mL round-bottom flask and undergo a reflux reaction for 3.0 h, a 30% sodium hydroxide solution (50 mL) is added, after refluxing under stirring for 3.5 h and cooling to 50° C., water (30 mL) and a small amount of activated carbon are added, and the stirring refluxing is continued for 0.5 h. After cooling, filtration and standing, an aqueous layer is separated, a toluene layer is washed with water (50 mL×3), the aqueous layers are combined and adjusted with concentrated hydrochloric acid to a pH of 1-2 to separate a white solid, and the white solid is filtered, the crude product is washed with water and dried. Recrystallization is performed using ethanol-water to obtain 10.01 g of a white powder with a yield of 97.2%. The m.p. is 74-75° C. 
       Embodiment 8 Synthesis of 2-(3-phenoxyl)propionic acid (fenoprofen) under catalysis of zinc 2-(3-phenoxyl)propionate 
       [0023]    8.52 g (0.02 mol) of 1-(1,1-diethyoxyl-2-iodopropyl)-3-phenoxybenzene, 0.219 g (0.0004 mol) of zinc 2-(6-methoxylnaphthyl)propionate and 30 mL of toluene are added into a 500 mL round-bottom flask and undergo a reflux reaction for 3.5 h, a 30% sodium hydroxide solution (50 mL) is added, after refluxing under stirring for 3.5 h and cooling to 50° C., water (15 mL) and a small amount of activated carbon are added, and the stirring refluxing is continued for 0.5 h. After cooling, filtration and standing, an aqueous layer is separated, a toluene layer is washed with water (30 mL×3), the aqueous layers are combined and adjusted with concentrated hydrochloric acid to a pH of 1-2 extracted with chloroform (30 mL×3), dried using an anhydrous sodium sulphate, the chloroform is distilled off to obtain 4.48 g of a light yellow liquid with a yield of 92.5%.  1 H NMR (CDCl 3 ) δ 1.49 (d, 3H, CH 3 ), 3.71 (q, 1H, CH), 6.87-7.37 (m, 9H, ArH), 7.50-8.40 (brs, COOH). 
       Embodiment 9 Synthesis of 2-(3-fluoro-4-phenyl)phenylpropionic acid (flurbiprofen) under catalysis of zinc 2-(3-fluoro-4-phenyl)propionate 
       [0024]    7.84 g (0.02 mol) of 2-(1 -bromoethyl)-2-(2-fluoro-(1,1′-biphen-4-yl)-5,5-dimethyl-1,3-dioxocyclohexan e, 0.276 g (0.0005 mol) of zinc 2-(6-methoxylnaphthyl)propionate and 30 mL of toluene are added into a 500 mL round-bottom flask and undergo a reflux reaction for 3.5 h, a 30% sodium hydroxide solution (50 mL) is added, after refluxing under stirring for 3.5 h and cooling to 50° C., water (15 mL) and a small amount of activated carbon are added, and the stirring refluxing is continued for 0.5 h. After cooling, filtration and standing, an aqueous layer is separated, a toluene layer is washed with water (30 mL×3), the aqueous layers are combined and adjusted with concentrated hydrochloric acid to a pH of 1-2 to separate a white solid, and the white solid is filtered, the crude product is washed with water and dried. Recrystallization is performed using ethanol-water to obtain 4.45 g of a white powder with a yield of 91.2%. The m.p. is 110-112° C.