Method for preparing 3-pyridyl-2-methyl naphthoate compound through catalysis

Abstract

The method comprises the following steps: fully reacting a substituted pyridine compound as shown in a formula (I) and a 2-naphthoic acid methyl ester compound as shown in a formula (II) in a DMSO (Dimethylsulfoxide) solvent by taking palladium acetate and copper acetate as catalysts and taking cesium carbonate as alkali to obtain the 3-pyridyl-2-naphthoic acid methyl ester compound. The product, namely the 3-pyridyl-2-naphthoic acid methyl ester compound, as shown in a formula (III) is prepared. The method has the advantages of low cost, simplicity in operation, excellent yield and the like, and meets the requirement of green synthesis of drug intermediates. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical chemical intermediate preparation, and specifically relates to a method for catalytically preparing 3-pyridyl-2-benzoic acid methyl ester compounds. Background Art

[0002] 3-pyridyl-2-naphthoic acid methyl ester compounds are an important class of pharmaceutical chemical intermediates, and their structural skeletons have various pharmacological activities, including anti-cancer, anti-tumor, immune regulation and other effects, and have been used to synthesize a series of important drugs and pesticides. The reported preparation method of 3-pyridyl-2-naphthoic acid methyl ester compounds is mainly obtained by multi-step coupling and oxidation, and there are many reaction steps, low reaction efficiency and a series of difficult-to-handle by-products in the reaction process, which cause irreversible pollution and damage to the environment, do not meet the requirements of green synthesis, and urgently need to improve and innovate the existing preparation process. The present invention adopts a bimetallic salt with high catalytic efficiency as a catalyst, and realizes the efficient preparation of 3-pyridyl-2-naphthoic acid methyl ester compounds by one-step reaction. The method has important application prospects in the field of pharmaceutical intermediate synthesis industry related to 3-pyridyl-2-naphthoic acid methyl ester compounds. Summary of the invention

[0003] In view of the shortcomings and disadvantages of the existing preparation technology, the purpose of the present invention is to provide a method for catalytically preparing 3-pyridyl-2-naphthoic acid methyl ester compounds, which is specifically achieved by the following technical scheme:

[0004] A method for catalytically preparing 3-pyridyl-2-naphthoic acid methyl ester compounds, the method comprising: fully reacting a substituted pyridine compound represented by formula (I) with a 2-naphthoic acid methyl ester compound represented by formula (II) in an organic solvent using a bimetallic acetate as a catalyst and a carbonate as a base to obtain a reaction product, and treating the product to obtain a 3-pyridyl-2-naphthoic acid methyl ester compound represented by formula (III); the bimetallic acetate is palladium acetate and copper acetate, the carbonate is cesium carbonate, and the organic solvent is dimethyl sulfoxide (DMSO);

[0005]

[0006] In the reaction formula, the substituent R1 is selected from one of the following: nitro, methoxy, chlorine, bromine; the substituent R2 is selected from one of the following: hydrogen, methoxy.

[0007] Furthermore, the ratio of the substituted pyridine compound to the 2-naphthoic acid methyl ester compound is 10mmol:15mmol.

[0008] Furthermore, the ratio of the substituted pyridine compound, the 2-naphthoic acid methyl ester compound to palladium acetate and copper acetate is 10mmol:15mmol:1mmol:1mmol.

[0009] Furthermore, the ratio of the substituted pyridine compound, the 2-naphthoic acid methyl ester compound and the cesium carbonate is 10mmol:15mmol:20mmol.

[0010] Furthermore, the ratio of the substituted pyridine compound, the 2-naphthoic acid methyl ester compound and the organic solvent is 10 mmol: 15 mmol: 30 mL.

[0011] Furthermore, the equivalent ratio of the substituted pyridine compound to the 2-naphthoic acid methyl ester compound is 1:(1-1.5).

[0012] Furthermore, the reaction temperature is 100° C. and the reaction time is 12 hours.

[0013] Furthermore, the specific steps of post-processing are:

[0014] 1) Extraction: After the reaction product is cooled to room temperature, 20 mL of saturated sodium chloride aqueous solution is added to the reaction product, and then extracted with ethyl acetate for 3 times, 20 mL each time, and the extracts are combined;

[0015] 2) Concentration: Dry the extract with anhydrous sodium sulfate and spin dry with a rotary evaporator to obtain a concentrate;

[0016] 3) The obtained concentrate is adsorbed on column chromatography silica gel, added to a 200-300 mesh chromatography silica gel column, and subjected to rapid column chromatography with ethyl acetate:acetone in a certain ratio. The eluents are combined, dried by rotary evaporation, and the product 3-pyridyl-2-naphthoic acid methyl ester compounds are extracted by oil pump.

[0017] Furthermore, the drying time in step 2) is 8 hours.

[0018] Furthermore, in step 3), the volume ratio of ethyl acetate:acetone is 2-3:1.

[0019] The method of the invention adopts a bimetallic salt with high catalytic efficiency as a catalyst, realizes the efficient preparation of 3-pyridyl-2-naphthoic acid methyl ester compounds through a one-step reaction, has the advantages of low cost, simple operation, high yield, meets the requirements of green synthesis, and the like. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 is the 1H NMR spectrum of product 3a in the present invention;

[0021] Figure 2 is the 13C NMR spectrum of product 3a in the present invention;

[0022] Figure 3 1H NMR spectrum of product 3b in the present invention;

[0023] Figure 4 is the 13C NMR spectrum of product 3b in the present invention;

[0024] Figure 5 is the 1H NMR spectrum of the product 3c in the present invention;

[0025] Figure 6 is the 13C NMR spectrum of the product 3c in the present invention;

[0026] Figure 7 is the 1H NMR spectrum of product 3d in the present invention;

[0027] Figure 8 is the 13C NMR spectrum of product 3d in the present invention;

[0028] Fig. 9 is the 1H NMR spectrum of the product 3e in the present invention;

[0029] Fig.10 is the 13C NMR spectrum of the product 3e in the present invention;

[0030] Fig.11 is the 1H NMR spectrum of the product 3f in the present invention;

[0031] Fig.12 This is the 13C NMR spectrum of product 3f in the present invention. DETAILED DESCRIPTION

[0032] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments to provide a better understanding of the present technical solution.

[0033] The synthesis steps of the present invention are as follows: 10 mmol of substituted pyridine compound 1 and 15 mmol of 2-naphthoic acid methyl ester 2 are added in a 50 mL round-bottom flask, and then 30 mL of DMSO, 1 mmol of palladium acetate, 1 mmol of copper acetate, and 20 mmol of cesium carbonate are added in sequence, and the mixture is stirred at 100 ° C for 12 hours. After the reaction is completed and cooled, 20 mL of saturated sodium chloride aqueous solution is added to the system, and the mixture is extracted with ethyl acetate 3 times, 20 mL each time, and the organic phases are combined, dried with anhydrous sodium sulfate, and the solvent is evaporated. 200-300 mesh silica gel column chromatography, ethyl acetate: acetone solution gradient elution, to obtain a pure product of 3-pyridyl-2-naphthoic acid methyl ester compound 3, with a yield of 79-91%. Specific embodiments and characterization data are as follows:

[0034]

[0035] Example 1: Preparation of product 3a

[0036] At room temperature, 10 mmol 2-nitropyridine and 15 mmol methyl 2-naphthoate were added to a 50 mL round-bottom flask, followed by 30 mL DMSO, 1 mmol palladium acetate, 1 mmol copper acetate, and 20 mmol cesium carbonate, and stirred at 100 ° C for 12 hours. After the reaction was completed and cooled, 20 mL saturated sodium chloride aqueous solution was added to the system, and extracted with ethyl acetate 3 times, 20 mL each time, and the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated. 200-300 mesh silica gel column chromatography, ethyl acetate: acetone solution gradient elution, to obtain the pure product of 3-pyridyl-2-naphthoic acid methyl ester compound 3a.

[0037] 3a 1 H NMR spectrum see Figure 1 , 3a 13 C NMR spectrum see Figure 2 .

[0038] Methyl 3-(3-nitropyridin-2-yl)-2-naphthoate (3a), yield 79%, yellow solid powder, melting point 113.8-114.3°C.

[0039] 1 H NMR (500MHz, CDCl3) δ8.59(d,J=8.53Hz,1H),8.47(dd,J=8.30,0.90Hz,1H),8.34(s,1H),8.05– 8.15(m,2H),7.92–8.01(m,2H),7.83-7.90(m,1H),7.65(dd,J=7.40,1.12Hz,1H),4,10(s,3H); 13 C NMR (125MHz, CDCl3) δ169.4,151.4,150.2,150.1,141.1,138.7,137.0,136. 1,135.7,134.4,134.1,132.9,132.7,132.1,131.2,128.3,80.8,80.6,56.9;

[0040] HRMS(ESI)m / z calcd for C 17 H 12 O4N2Na[M+Na]+:331.0679,found:331.0677.

[0041] Example 2: Preparation of product 3b

[0042] At room temperature, 10 mmol 2-nitro-4-chloropyridine and 15 mmol methyl 2-naphthoate were added to a 50 mL round-bottom flask, followed by 30 mL DMSO, 1 mmol palladium acetate, 1 mmol copper acetate, and 20 mmol cesium carbonate. The mixture was stirred at 100°C for 12 hours. After the reaction was completed and cooled, 20 mL saturated sodium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate 3 times, 20 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated. The mixture was chromatographed on a 200-300 mesh silica gel column. The mixture was eluted with a gradient of ethyl acetate:acetone solution to obtain the pure product of methyl 3-pyridyl-2-naphthoate compound 3b.

[0043] 3b 1 H NMR spectrum see Figure 3 , 3b 13 C NMR spectrum see Figure 4 .

[0044] Methyl 3-(6-chloro-3-nitropyridin-2-yl)-2-naphthoate (3b), yield 85%, yellow solid powder, melting point 180.5-181.6°C.

[0045] 1 H NMR (500MHz, CDCl3) δ8.59(d,J=8.5Hz,1H),8.47(d,J=2.0Hz,1H),8.31(s,1H),8.16-8.06(m,2H),8.00(m,2H),7.50(d,J=8.1Hz,1H),4.14(s,3H); 13 C NMR (125MHz, CDCl3) δ169.4,151.7,151.3,149.7,141.2,138.5,137.3,137.1 ,136.7,135.1,134.7,134.1,133.1,132.0,131.2,128.5,57.0; HRMS(ESI)m / z calcd for C 17 H 11 O4N2ClNa[M+Na]+:365.0303, found:365.0202.

[0046] Example 3: Preparation of product 3c

[0047] At room temperature, 10 mmol 2-nitro-4-methoxypyridine and 15 mmol methyl 2-naphthoate were added to a 50 mL round-bottom flask, followed by 30 mL DMSO, 1 mmol palladium acetate, 1 mmol copper acetate, and 20 mmol cesium carbonate. The mixture was stirred at 100°C for 12 hours. After the reaction was completed and cooled, 20 mL saturated sodium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate 3 times, 20 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated. The mixture was chromatographed on a 200-300 mesh silica gel column. The mixture was eluted with a gradient of ethyl acetate:acetone solution to obtain the pure product of methyl 3-pyridyl-2-naphthoate compound 3c.

[0048] 3c 1 H NMR spectrum see Figure 5 , 3c 13 C NMR spectrum see Figure 6 .

[0049] Methyl 3-(5-methoxy-3-nitropyridin-2-yl)-2-naphthoate (3c) yield 83%, yellow solid powder, melting point 177.4-178.7°C.

[0050] 1 H NMR(500MHz, CDCl3)δ8.58(d,J=8.5Hz,1H),8.52(d,J=9.2Hz,1H),8.31(s,1H),8.15-8.04(m, 2H),7.93(s,1H),7.28(dd,J=2.7,9.2Hz,1H),7.05(d,J=2.9Hz,1H),4.16(s,3H),4.12(s,3H); 13 C NMR (125MHz, CDCl3) δ169.6,167.1,150.3,150.3,144.7,141.8,140.9,13 6.8,134.6,134.3,133.0,132.3,131.4,131.2,121.1,117.2,60.0,57.1;

[0051] HRMS(ESI)m / z calcd for C 18 H 14 O5N2Na[M+Na]+:361.0796,found:361.0795.

[0052] Example 4: Preparation of product 3d

[0053] At room temperature, 10 mmol 2-nitro-4-bromopyridine and 15 mmol methyl 2-naphthoate were added to a 50 mL round-bottom flask, followed by 30 mL DMSO, 1 mmol palladium acetate, 1 mmol copper acetate, and 20 mmol cesium carbonate, and the mixture was stirred at 100°C for 12 hours. After the reaction was completed and cooled, 20 mL saturated sodium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate 3 times, 20 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated. The mixture was chromatographed on a 200-300 mesh silica gel column. The mixture was eluted with a gradient of ethyl acetate:acetone solution to obtain the pure product of 3-pyridyl-2-naphthoic acid methyl ester compound 3d.

[0054] 3d 1 H NMR spectrum see Figure 7 , 3d 13 C NMR spectrum see Figure 8 .

[0055] Methyl 3-(5-bromo-3-nitropyridin-2-yl)-2-naphthoate (3d) yield 90%, yellow solid powder, melting point 184.5-185.4°C.

[0056] 1 H NMR (500MHz, CDCl3) δ8.62(d,J=2.0Hz,1H),8.59(d,J=8.5Hz,1H),8.31(s,1 H),8.05-8.08(m,3H),8.00-7.94(m,1H),7.54(d,J=8.3Hz,1H),4.04(s,3H); 13 C NMR (125MHz, CDCl3) δ169.4,151.8,150.3,149.6,141.1,140.0,137.7,136.9,135.2,134.7,134.1,133.1,132.0,131.4,131.2,126.0,57.0;

[0057] HRMS(ESI)m / zcalcd for C 17 H 12 O4N2Br[M+H]+:386.9973,found:386.9970.

[0058] Example 5: Preparation of product 3e

[0059] At room temperature, 10 mmol of 2-nitro-4-methyl-formylpyridine and 15 mmol of methyl 2-naphthoate were added to a 50 mL round-bottom flask, followed by 30 mL of DMSO, 1 mmol of palladium acetate, 1 mmol of copper acetate, and 20 mmol of cesium carbonate. The mixture was stirred at 100 °C for 12 hours. After the reaction was completed and cooled, 20 mL of saturated sodium chloride aqueous solution was added to the system, and the mixture was extracted with ethyl acetate 3 times, 20 mL each time. The organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated. The mixture was chromatographed on a 200-300 mesh silica gel column. The mixture was eluted with a gradient of ethyl acetate:acetone solution to obtain the pure product of methyl 3-pyridyl-2-naphthoate compound 3e.

[0060] 3e 1 H NMR spectrum see Fig. 9 , 3e 13 C NMR spectrum see Fig.10 .

[0061] Methyl 6-(3-(methoxycarbonyl)naphthalen-2-yl)-5-nitronicotin ate (3e) yield 82%, yellow solid powder, melting point 180.2-181.7°C.

[0062] 1 H NMR(500MHz, CDCl3)δ9.10(s,1H),8.64-8.57(m,2H),8.34(s,1H),8.15-8.0 5(m,2H),7.99-7.93(m,1H),7.75(d,J=7.9Hz,1H),4.27(s,3H),4.12(s,3H); 13 C NMR (125MHz, CDCl3) δ169.3,168.5,151.4,150.3,149.4,143.1,140.9,137.6 ,136.0,135.4,134.9,134.7,134.1,133.2,131.9,131.3,129.4,57.0,56.6;

[0063] HRMS(ESI)m / z calcd for C 19 H 14 O6N2Na[M+Na]+:389.0745,found:389.0744.

[0064] Example 6: Preparation of product 3f

[0065] At room temperature, 10 mmol 2-nitro-4-cyanopyridine and 15 mmol methyl 2-naphthoate were added to a 50 mL round-bottom flask, followed by 30 mL DMSO, 1 mmol palladium acetate, 1 mmol copper acetate, and 20 mmol cesium carbonate, and stirred at 100 ° C for 12 hours. After the reaction was completed and cooled, 20 mL saturated sodium chloride aqueous solution was added to the system, and extracted with ethyl acetate 3 times, 20 mL each time, and the organic phases were combined, dried with anhydrous sodium sulfate, and the solvent was evaporated, and chromatographed on a 200-300 mesh silica gel column. Ethyl acetate: acetone solution was used as a gradient elution to obtain the pure product of 3-pyridyl-2-naphthoic acid methyl ester compound 3f.

[0066] 3f 1 H NMR spectrum see Fig.11 , 3f 13 C NMR spectrum see Fig.12 .

[0067] Methyl 3-(5-cyano-3-nitropyridin-2-yl)-2-naphthoate(3f), yield 91%, yellow solid powder, melting point 209.3-210.5℃.

[0068] 1 H NMR (500MHz, CDCl3) δ8.60(d,J=8.5Hz,1H),8.54(d,.J=8.5Hz,1H),8.35(s,1H),8.15-8.11(m,3H),8.02-7.95(m,2H),4.15(s,3H); 13 C NMR (125MHz, CDCl3) δ169.5,153.7,151.7,148.2,142.6,140.4,139.4,13 6.5,135.3,134.4,134.1,133.7,132.1,131.5,129.2,121.0,120.5,57.3;

[0069] HRMS(ESI)m / z calcd for C 18 H 11 O4N3Na[M+Na]+:356.0643,found:356.0635.

Claims

1. A method for catalytically preparing 3-pyridyl-2-naphthoic acid methyl ester compounds, characterized in that The method comprises: a substituted pyridine compound represented by formula (I) and a 2-naphthoic acid methyl ester compound represented by formula (II) are fully reacted in an organic solvent using a bimetallic acetate as a catalyst and a carbonate as a base to obtain a reaction product, and the product is treated to obtain a 3-pyridyl-2-naphthoic acid methyl ester compound represented by formula (III); the bimetallic acetate is palladium acetate and copper acetate, the carbonate is cesium carbonate, and the organic solvent is dimethyl sulfoxide (DMSO); In the reaction formula, the substituent R1 is selected from one of the following: nitro, methoxy, chlorine, bromine; the substituent R2 is selected from one of the following: hydrogen, methoxy.

2. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The ratio of the substituted pyridine compound to the 2-naphthoic acid methyl ester compound is 10mmol:15mmol.

3. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The ratio of the substituted pyridine compound, 2-naphthoic acid methyl ester compound to palladium acetate and copper acetate is 10mmol:15mmol:1mmol:1mmol.

4. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The ratio of the substituted pyridine compound, the 2-naphthoic acid methyl ester compound and the cesium carbonate is 10mmol:15mmol:20mmol.

5. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The ratio of the substituted pyridine compound, the 2-naphthoic acid methyl ester compound and the organic solvent is 10mmol:15mmol:30mL.

6. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The equivalent ratio of the substituted pyridine compound to the 2-naphthoic acid methyl ester compound is 1:(1-1.5).

7. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The reaction temperature is 100° C. and the reaction time is 12 hours.

8. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 1, characterized in that The specific steps of the post-processing are: 1) Extraction: After the reaction product is cooled to room temperature, 20 mL of saturated sodium chloride aqueous solution is added to the reaction product, and then extracted with ethyl acetate for 3 times, 20 mL each time, and the extracts are combined; 2) Concentration: Dry the extract with anhydrous sodium sulfate and spin dry with a rotary evaporator to obtain a concentrate; 3) The obtained concentrate is adsorbed on column chromatography silica gel, added to a 200-300 mesh chromatography silica gel column, and subjected to rapid column chromatography with ethyl acetate:acetone in a certain ratio. The eluents are combined, dried by rotary evaporation, and the product 3-pyridyl-2-naphthoic acid methyl ester compounds are extracted by oil pump.

9. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 8, characterized in that The drying time in step 2) is 8 hours.

10. A method for preparing 3-pyridyl-2-naphthoic acid methyl ester compounds by catalysis as claimed in claim 8, characterized in that In step 3), the volume ratio of ethyl acetate to acetone is 2-3:1.

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