CN113735765A - Preparation method of 2-methyl nicotinate and derivatives thereof - Google Patents
Preparation method of 2-methyl nicotinate and derivatives thereof Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
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Abstract
The invention belongs to the technical field of fine chemical preparation, and discloses a preparation method of 2-methyl nicotinate and derivatives thereof, which comprises the following steps: (1) reacting raw materials including alkyl vinyl ether, 1, 3-dicarbonyl compound and formaldehyde raw materials at 60-100 ℃ for 6-9 hours, and separating reaction products to obtain 2-alkoxy-3, 4-dihydropyran derivatives; (2) reacting 2-alkoxy-3, 4-dihydropyran derivative with ammonium salt in organic solvent under the action of oxidizing agent methylene blue and Lewis acid at certain temperature for 7-10 hr to obtain 2-methyl nicotinate or its derivative. Compared with the traditional preparation method of the 2-methyl nicotinate and the derivatives thereof, the method has the advantages of cheap and easily obtained raw materials, easily separated products, simple steps, high industrial application value and the like by improving the overall reaction flow design and the reaction conditions of the preparation method.
Description
Technical Field
The invention belongs to the technical field of fine chemical preparation, and particularly relates to a preparation method of 2-methyl nicotinate and derivatives thereof, which takes 1, 3-dicarbonyl compounds, alkyl vinyl ether and formaldehyde as raw materials to prepare the 2-methyl nicotinate and the derivatives thereof.
Background
The pyridine derivatives are fine chemicals and bioactive molecules with high added values, and are mainly applied to production of pesticides, medicines, fuels, textiles and surfactants. Nicotinic acid esters, which are pyridine derivatives, are also widely used in the fields of medicines, agricultural chemicals, and the like, and are commonly used for synthesizing hypotensive drugs, anesthetics, analgesics, and the like. Conventional methods for synthesizing nicotinic acid esters include Hantzsch pyridine synthesis, Bohlmann-Rahtz synthesis, Michel addition, and the like. The nicotinate compound generated by the Hantzsch pyridine synthesis method needs to be catalyzed by Pd/C or needs to be synthesized by microwave, so that the method has high production cost and is difficult to realize industrialization; the method for synthesizing nicotinic acid ester compounds by using Bohlmann-Rahtz pyridine synthesis method has the advantages that due to the fact that rare-type and expensive alkynone needs to be used, the method is expensive in raw material price, and the function diversity of synthesized nicotinic acid ester is insufficient; the synthesis of nicotinic acid ester compounds by the Michelal addition method is not environment-friendly and is easy to cause environmental pollution because toluene is often used as a reaction medium. Meanwhile, the method has the problems of low substituent compatibility, difficult position regulation and the like. Therefore, a synthetic route with low production cost, simple synthetic method and diverse functions of target products is urgently needed.
Disclosure of Invention
In view of the above defects or improvement needs of the prior art, the present invention aims to provide a method for preparing 2-methylnicotinate and its derivatives, wherein the overall reaction flow design of the preparation method is improved, methylene blue is used as an oxidant, and reaction conditions (such as substrate, catalyst, temperature, etc.) are preferably set, so that compared with the traditional preparation method of 2-methylnicotinate and its derivatives, the method has the advantages of cheap and easily available raw materials, easy product separation, simple steps, high industrial application value, etc.
To achieve the above object, according to the present invention, there is provided a method for preparing 2-methylnicotinate or a derivative thereof, comprising the steps of:
(1) reacting raw materials including alkyl vinyl ether, 1, 3-dicarbonyl compound and formaldehyde raw materials at 60-100 ℃ for 6-9 hours, and separating reaction products to obtain 2-alkoxy-3, 4-dihydropyran derivatives; wherein the molar ratio of the 1, 3-dicarbonyl compound to the alkyl vinyl ether is 2.5: 1-1.6: 1; the molar ratio of the 1, 3-dicarbonyl compound to the formaldehyde-based raw material is 1: 1-1: 1.3;
(2) and (2) reacting the 2-alkoxy-3, 4-dihydropyran derivative obtained in the step (1) with an ammonium salt in an organic solvent under the action of an oxidant methylene blue and a Lewis acid under the temperature condition that the temperature is 70-85 ℃ and does not exceed the boiling point of the organic solvent for 7-10 hours to obtain the 2-methylnicotinate or the derivative thereof.
As a further preferred aspect of the present invention, in the step (1), the 1, 3-dicarbonyl compound is specifically:
wherein, R is1The group is selected from methyl, methoxy, ethoxy, isopropoxy, tert-butoxy, allyloxy, benzyloxy.
As a further preferred aspect of the present invention, in the step (1), the alkyl vinyl ether is specifically:
wherein, R is2The radical is ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl.
In a further preferred aspect of the present invention, in the step (1), the formaldehyde-based raw material is specifically an aqueous formaldehyde solution or paraformaldehyde.
In a further preferred embodiment of the present invention, in the step (2), the ammonium salt is any one of ammonium chloride, ammonium bromide, ammonium iodide, ammonium acetate and ammonium bicarbonate.
In a further preferred embodiment of the present invention, in the step (2), the lewis acid is any one of aluminum trichloride, aluminum trichloride hexahydrate, aluminum trifluoromethanesulfonate, and nickel perchlorate hexahydrate.
In a further preferred embodiment of the present invention, in the step (2), the organic solvent is any one of ethanol, isopropanol, and acetonitrile.
As a further preferred aspect of the present invention, in the step (2), the molar ratio of the ammonium salt to the 2-alkoxy-3, 4-dihydropyran derivative is 1: 1-2: 1; the molar ratio of the oxidant methylene blue to the 2-alkoxy-3, 4-dihydropyran derivative is 1: 1-1: 1.5; the molar ratio of the Lewis acid to the 2-alkoxy-3, 4-dihydropyran derivative is 0.5: 1-1.25: 1; the ratio of the volume of the organic solvent to the amount of the substance of the 2-alkoxy-3, 4-dihydropyran derivative is 5: 1L/mol-10: 1L/mol.
As a further preferred aspect of the present invention, in the step (1), the 2-alkoxy-3, 4-dihydropyran derivative is isolated by distillation under reduced pressure;
in the step (2), the 2-methylnicotinate or a derivative thereof is separated by Preparative Thin Layer Chromatography (PTLC).
Through the technical scheme, compared with the prior art, the invention has the following beneficial effects:
(1) the technical scheme is that the 2-alkoxy-3, 4-dihydropyran derivative is synthesized by using alkyl vinyl ether, a 1, 3-dicarbonyl compound and formaldehyde aqueous solution, and then the 2-alkoxy-3, 4-dihydropyran derivative and ammonium salt (such as ammonium acetate) react in an organic solvent (such as ethanol) at the reaction temperature of 70-85 ℃ (the reaction temperature does not exceed the boiling point of the organic solvent), and the reaction condition is mild.
(2) The raw materials of alkyl vinyl ether, 1, 3-dicarbonyl compound, formaldehyde raw material and ammonium salt adopted by the technical scheme are cheap and easy to obtain, and the alkyl vinyl ether and the 1, 3-dicarbonyl compound are various and can be flexibly changed according to actual requirements.
(3) The Lewis acid adopted by the technical scheme is preferably aluminum trichloride or aluminum trichloride hexahydrate, and the yield effect is good; and the catalysts are low in price, compared with the prior art, noble metal catalysts such as gold and palladium are not adopted, so that the preparation cost is greatly reduced, and the economic benefit is favorably improved.
(4) The invention particularly adopts methylene blue as an oxidant, which can effectively ensure the synthesis of a target compound (namely, 2-methyl nicotinate or a derivative thereof); in addition, the oxidant is low in price and wide in source, compared with the prior art, the oxidant with strong corrosivity such as nitric acid is not needed, and the environmental pollution is favorably reduced.
Drawings
FIG. 1 is a schematic diagram of the process for preparing methyl 2-methylnicotinate in example 1 of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
In general, the process of the present invention for the preparation of 2-methylnicotinate esters and derivatives thereof will first include an alkyl vinyl ether
1, 3-dicarbonyl compounds
And formaldehyde raw material (such as formaldehyde aqueous solution or paraformaldehyde) at 60-100 deg.C for 6-9 hr, and separating the reaction product to obtain 2-alkoxy-3, 4-dihydropyran derivative
Then, the obtained 2-alkoxy-3, 4-dihydropyran derivative is reacted with ammonium salt in an organic solvent under the action of methylene blue as an oxidant and Lewis acid at 70-85 ℃ (of course, the reaction temperature does not exceed the boiling point of the organic solvent) for 7-10 hours to obtain 2-methylnicotinate or a derivative thereof
The following are specific examples:
example 1: preparation of methyl 2-methylnicotinate
The preparation method comprises the first step of carrying out Diels-Alder reaction on n-butyl vinyl ether, formaldehyde aqueous solution and methyl acetoacetate to generate 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran, and the second step of carrying out ring opening/condensation cyclization/oxidation on the 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran and ammonium acetate in ethanol by taking aluminum trichloride hexahydrate as a catalyst and methylene blue as an oxidant to obtain the 2-methyl nicotinic acid methyl ester. The main reactions involved in the first to second steps are shown in FIG. 1. The specific operation process is as follows:
step (1): 1.0g (10mmol) of n-butyl vinyl ether, 0.77g (25.5mmol) of formaldehyde as a solute in an aqueous formaldehyde solution and 2.37g (20mmol) of methyl acetoacetate were put into a reactor equipped with magnetic stirring, and after mixing, the reaction was stirred at 60 ℃ for 8 hours. After the reaction, unreacted n-butyl vinyl ether was distilled off, and then, distillation was carried out under reduced pressure to obtain 2.0g (8.9mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝5.04–4.85(m,1H),3.78–3.68(m,1H),3.62(s,3H),3.54–3.39(m,1H),2.41–2.20(m,2H),2.17(s,3H),1.85–1.63(m,2H),1.58–1.39(m,2H),1.37–1.21(m,2H),0.89–0.80ppm(m,3H)；13C NMR(101MHz,CDCl3,25℃)δ＝168.76,161.88,101.82,97.94,68.43,50.95,31.65,26.08,19.92,19.19,17.78,13.78ppm.
Step (2): 47.8mg (0.2mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran obtained in step (1), 28.4mg (0.37mmol) of ammonium acetate, 137mg (0.33mmol) of methylene blue, and 36.2mg (0.15mmol) of aluminum trichloride hexahydrate were put into a reactor equipped with magnetic stirring, and the mixture was stirred at 70 ℃ for 7 hours, and after completion of the TLC detection reaction, heating was stopped. Separating the product and the raw material by Preparative Thin Layer Chromatography (PTLC), wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 5: 1, to finally obtain 20mg (0.13mmol) of the methyl 2-methylnicotinate.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝8.62(dd,J＝4.7,1.4Hz,1H),8.20(dd,J＝7.9,1.5Hz,1H),7.22(dd,J＝7.8,4.9Hz,1H),3.93(s,3H),2.85ppm(s,3H)；13C NMR(100MHz,CDCl3,TMS,25℃)δ＝167.0,159.9,151.9,138.4,125.4,120.9,52.3,24.8ppm；IR(KBr):v＝2956,1726,1577,1441,1378,1283,1251,1083,913cm-1；HRMS(TOF,ESI):m/z calcd for C8H9NO2,[M+H]+152.0706,found 152.0705.
The yield of this example 1 was 63%, wherein the yield of step (1) was 89% and the yield of step (2) was 63%.
Example 2: preparation of ethyl 2-methylnicotinate
Step (1): 1.0g (10mmol) of n-butyl vinyl ether, 0.75g (25mmol) of formaldehyde as a solute in an aqueous formaldehyde solution and 2.6g (20mmol) of ethyl acetoacetate are put into a reactor equipped with magnetic stirring, and after mixing, the reaction is carried out for 7 hours under the condition of 100 ℃. After the reaction, unreacted n-butyl vinyl ether was distilled off, and then, distillation was carried out under reduced pressure to obtain 2.2g (9.0mmol) of 6-methyl-2-n-butoxy-5-carboxyethyl-3, 4-dihydropyran.1H NMR(600MHz,CDCl3,TMS,25℃)δ＝5.02(d,J＝1.0Hz,1H),4.21–4.10(m,2H),3.80(dt,J＝8.5,6.7Hz,1H),3.59–3.48(m,1H),2.42–2.27(m,2H),2.24(s,3H),1.88–1.83(m,1H),1.81–1.71(m,1H),1.64–1.51(m,2H),1.40–1.33(m,2H),1.28(t,J＝7.1Hz,3H),0.91ppm(t,J＝7.4Hz,3H)；13C NMR(150MHz,CDCl3,25℃)δ＝168.32,161.51,102.04,97.92,68.40,59.57,31.64,26.11,19.89,19.18,17.81,14.35,13.7ppm.
Step (2): 6-methyl-2-n-butoxy-5-carboxyethyl-3, 4-dihydropyran 48.5mg (0.2mmol) obtained in step (1), ammonium acetate 15.4mg (0.2mmol), methylene blue 83mg (0.2mmol), and aluminum trichloride hexahydrate 48.3mg (0.2mmol) were put into a reactor equipped with magnetic stirring, and the mixed solution was stirred at 75 ℃ for 8 hours, and after completion of the TLC detection reaction, heating was stopped. Separating the product and the raw material by Preparative Thin Layer Chromatography (PTLC), wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 5: 1, to finally obtain 15.9mg (0.096mmol) of the ethyl 2-methylnicotinate.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝8.61(d,J＝3.3Hz,1H),8.19(dd,J＝7.8,1.5Hz,1H),7.21(dd,J＝7.7,4.9Hz,1H),4.39(q,J＝7.1Hz,2H),2.84(s,3H),1.41ppm(t,J＝7.1Hz,3H)；13C NMR(100MHz,CDCl3,TMS,25℃)δ＝168.7,161.4,159.4,151.7,138.4,120.9,61.3,24.8,14.3ppm；IR(KBr):v＝2969,1722,1573,1441,1367,1283,1251,1086,913cm-1；HRMS(TOF,ESI):m/z calcd for C9H11NO2,[M+H]+166.0863,found 166.0861.
The yield of this example 2 was 48%, wherein the yield of step (1) was 90% and the yield of step (2) was 48%.
Example 3: preparation of 3-acetyl-2-methylpyridine
Step (1): n-butyl ethyl is put into a reactor with magnetic stirring1.0g (10mmol) of alkenyl ether, 0.84g (28mmol) of solute formaldehyde in an aqueous formaldehyde solution, and 2.5g (25mmol) of acetylacetone were mixed and reacted at 80 ℃ for 6 hours with stirring. After the reaction, unreacted n-butyl vinyl ether was distilled off, and then, distillation was carried out under reduced pressure to obtain 1.4g (6.6mmol) of 6-methyl-2-n-butoxy-5-acetyl-3, 4-dihydropyran.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝5.04(dd,J＝3.6,2.8Hz,1H),3.80(dt,J＝9.6,6.7Hz,1H),3.54(dt,J＝9.6,6.6Hz,1H),2.48(dddd,J＝16.1,10.1,6.0,1.5Hz,1H),2.35–2.25(m,1H),2.21(s,6H),2.00–1.74(m,2H),1.60–1.49(m,2H),1.42–1.28(m,2H),0.91ppm(t,J＝7.4Hz,3H)；13C NMR(101MHz,CDCl3,25℃)δ＝198.07,160.11,109.49,96.56,67.44,30.63,28.47,25.22,19.65,18.19,17.97,12.78ppm.
Step (2): 42.5mg (0.2mmol) of 6-methyl-2-n-butoxy-5-acetyl-3, 4-dihydropyran obtained in step (1), 15.4mg (0.2mmol) of ammonium acetate, 83mg (0.2mmol) of methylene blue, and 20mg (0.15mmol) of aluminum trichloride were put into a reactor equipped with magnetic stirring, and the mixture was stirred at 80 ℃ for reaction for 9 hours, and after the completion of the TLC detection reaction, heating was stopped. Separating the product and the raw material by Preparative Thin Layer Chromatography (PTLC), wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 5: 1, to finally obtain 11.9mg (0.088mmol) of the 3-acetyl-2-methylpyridine.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝8.60(d,J＝3.6Hz,1H),7.97(dd,J＝7.8,1.1Hz,1H),7.25(dd,J＝7.7,4.9Hz,1H),2.76(s,3H),2.61ppm(s,3H)；13C NMR(100MHz,CDCl3,TMS,25℃)δ＝200.4,158.1,151.3,136.7,132.9,120.8,29.4,24.7ppm；IR(KBr):v＝2963,1722,1578,1368,1260cm-1；HRMS(TOF,ESI):m/z calcd for C8H9NO,[M+H]+136.0757,found 136.0757.
The yield of this example 3 was 44%, wherein the yield of step (1) was 66% and the yield of step (2) was 44%.
Example 4: preparation of benzyl 2-methyl-nicotinate
Step (1): 1.25g (12.5mmol) of n-butyl vinyl ether, 0.75g (25mmol) of formaldehyde as a solute and 3.9g (20mmol) of benzyl acetylacetonate in an aqueous formaldehyde solution were put into a reactor equipped with magnetic stirring, and after mixing, the reaction was stirred at 80 ℃ for 9 hours. After the reaction, unreacted n-butyl vinyl ether was distilled off, and then, distillation was carried out under reduced pressure to obtain 1.6g (5.3mmol) of 6-methyl-2-n-butoxy-5-carboxybenzyl-3, 4-dihydropyran.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝7.40–7.28(m,5H),5.16(s,2H),5.03(dd,J＝3.9,2.7Hz,1H),3.80(dt,J＝9.6,6.7Hz,1H),3.53(dt,J＝9.6,6.6Hz,1H),2.45–2.34(m,2H),2.26(s,3H),1.91–1.72(m,2H),1.61–1.51(m,2H),1.42–1.30(m,2H),0.91ppm(t,J＝7.4Hz,3H)；13C NMR(101MHz,CDCl3,25℃)δ＝168.06,162.35,136.84,128.47,127.86,101.81,98.06,68.51,65.49,31.67,26.12,20.08,19.22,17.88,13.82ppm.
Step (2): 6-methyl-2-n-butoxy-5-carboxybenzyl-3, 4-dihydropyran 59.5mg (0.2mmol), ammonium acetate 15.4mg (0.23mmol), methylene blue 122mg (0.3mmol), and aluminum trichloride 26.7mg (0.25mmol) were put into a reactor equipped with magnetic stirring, and the mixed solution was stirred at 85 ℃ for 10 hours, and after completion of the TLC detection reaction, heating was stopped. Separating the product and the raw material by Preparative Thin Layer Chromatography (PTLC), wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 10: 1, finally obtaining 21.0mg (0.088mmol) of benzyl 2-methylnicotinate.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝8.61(dd,J＝4.7,1.4Hz,1H),8.22(dd,J＝7.9,1.4Hz,1H),7.48–7.32(m,5H),7.20(dd,J＝7.8,4.9Hz,1H),5.36(s,2H),2.85ppm(s,3H)；13C NMR(100MHz,CDCl3,TMS,25℃)δ＝166.3,160.0,151.9,138.5,135.6,128.7,128.4,125.3,120.9,77.4,77.1,76.7,67.1,24.9ppm；IR(KBr):v＝3032,2966,1723,1671,1651,1574,1378,1245，912,743，699cm-1；HRMS(TOF,ESI):m/z calcd for C14H13NO2,[M+H]+228.1019,found 228.1016.
The yield of this example 4 was 46%, wherein the yield of step (1) was 54% and the yield of step (2) was 46%.
Example 5: preparation of methyl 2-methylnicotinate
Step (1): 1.0g (10mmol) of n-butyl vinyl ether, 0.77g (25.5mmol) of formaldehyde as a solute in an aqueous formaldehyde solution and 2.37g (20mmol) of methyl acetoacetate were put into a reactor equipped with magnetic stirring, and after mixing, the reaction was stirred at 60 ℃ for 8 hours. After the reaction, unreacted n-butyl vinyl ether was distilled off, and then, distillation was carried out under reduced pressure to obtain 2.0g (8.9mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝5.04–4.85(m,1H),3.78–3.68(m,1H),3.62(s,3H),3.54–3.39(m,1H),2.41–2.20(m,2H),2.17(s,3H),1.85–1.63(m,2H),1.58–1.39(m,2H),1.37–1.21(m,2H),0.89–0.80ppm(m,3H)；13C NMR(101MHz,CDCl3,25℃)δ＝168.76,161.88,101.82,97.94,68.43,50.95,31.65,26.08,19.92,19.19,17.78,13.78ppm.
Step (2): 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran 71.7mg (0.3mmol), ammonium acetate 23.1mg (0.3mmol), methylene blue 125mg (0.3mmol) and aluminum trifluoromethanesulfonate 27mg (0.15mmol) obtained in step (1) were put into a reactor equipped with magnetic stirring, and the mixture was dissolved in 2mL of ethanol and reacted at 75 ℃ for 8 hours with stirringAnd stopping heating after TLC detection reaction is finished. Separating the product and the raw material by Preparative Thin Layer Chromatography (PTLC), wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 5: 1, to finally obtain 16.8mg (0.11mmol) of the methyl 2-methylnicotinate.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝8.62(dd,J＝4.7,1.4Hz,1H),8.20(dd,J＝7.9,1.5Hz,1H),7.22(dd,J＝7.8,4.9Hz,1H),3.93(s,3H),2.85ppm(s,3H)；13C NMR(100MHz,CDCl3,TMS,25℃)δ＝167.0,159.9,151.9,138.4,125.4,120.9,52.3,24.8ppm；IR(KBr):v＝2956,1726,1577,1441,1378,1283,1251,1083,913cm-1；HRMS(TOF,ESI):m/z calcd for C8H9NO2,[M+H]+152.0706,found 152.0705.
The yield of this example 5 was 37%, wherein the yield of step (1) was 89% and the yield of step (2) was 37%.
Example 6: preparation of methyl 2-methylnicotinate
Step (1): 1.0g (10mmol) of n-butyl vinyl ether, 0.77g (25.5mmol) of formaldehyde as a solute in an aqueous formaldehyde solution and 2.37g (20mmol) of methyl acetoacetate were put into a reactor equipped with magnetic stirring, and after mixing, the reaction was stirred at 60 ℃ for 8 hours. After the reaction, unreacted n-butyl vinyl ether was distilled off, and then, distillation was carried out under reduced pressure to obtain 2.0g (8.9mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝5.04–4.85(m,1H),3.78–3.68(m,1H),3.62(s,3H),3.54–3.39(m,1H),2.41–2.20(m,2H),2.17(s,3H),1.85–1.63(m,2H),1.58–1.39(m,2H),1.37–1.21(m,2H),0.89–0.80ppm(m,3H)；13C NMR(101MHz,CDCl3,25℃)δ＝168.76,161.88,101.82,97.94,68.43,50.95,31.65,26.08,19.92,19.19,17.78,13.78ppm.
Step (2): in a reactor equipped with magnetic stirring, 71.7mg (0.3mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran obtained in step (1), 16.05mg (0.3mmol) of ammonium chloride, 125mg (0.3mmol) of methylene blue, and 55mg (0.15mmol) of nickel perchlorate hexahydrate were charged and dissolved in 2mL of ethanol, and the mixture was stirred at 75 ℃ for reaction for 7 hours, and after completion of the TLC detection reaction, heating was stopped. Separating the product and the raw material by Preparative Thin Layer Chromatography (PTLC), wherein the eluent is a mixed solvent of petroleum ether and ethyl acetate, and the volume ratio is 5: 1, to finally obtain 17.7mg (0.117mmol) of the methyl 2-methylnicotinate.1H NMR(400MHz,CDCl3,TMS,25℃)δ＝8.62(dd,J＝4.7,1.4Hz,1H),8.20(dd,J＝7.9,1.5Hz,1H),7.22(dd,J＝7.8,4.9Hz,1H),3.93(s,3H),2.85ppm(s,3H)；13C NMR(100MHz,CDCl3,TMS,25℃)δ＝167.0,159.9,151.9,138.4,125.4,120.9,52.3,24.8ppm；IR(KBr):v＝2956,1726,1577,1441,1378,1283,1251,1083,913cm-1；HRMS(TOF,ESI):m/z calcd for C8H9NO2,[M+H]+152.0706,found 152.0705.
The yield of this example 6 was 39%, wherein the yield of step (1) was 89% and the yield of step (2) was 39%.
In the present invention, methylene blue is used as an oxidizing agent, and other oxidizing agents (such as t-butyl hydroperoxide, 2, 3-dichloro-5, 6-dicyanobenzoquinone, di-t-butyl peroxide, 2-iodoxybenzoic acid, manganese dioxide, and silver carbonate) are used to simulate the processes of the above examples, so that the target product cannot be obtained.
The above examples are all examples and the various reaction starting materials employed are commercially available in analytically pure grades.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A method for preparing 2-methylnicotinate or a derivative thereof, characterized by comprising the following steps:
(1) reacting raw materials including alkyl vinyl ether, 1, 3-dicarbonyl compound and formaldehyde raw materials at 60-100 ℃ for 6-9 hours, and separating reaction products to obtain 2-alkoxy-3, 4-dihydropyran derivatives; wherein the molar ratio of the 1, 3-dicarbonyl compound to the alkyl vinyl ether is 2.5: 1-1.6: 1; the molar ratio of the 1, 3-dicarbonyl compound to the formaldehyde-based raw material is 1: 1-1: 1.3;
(2) and (2) reacting the 2-alkoxy-3, 4-dihydropyran derivative obtained in the step (1) with an ammonium salt in an organic solvent under the action of an oxidant methylene blue and a Lewis acid under the temperature condition that the temperature is 70-85 ℃ and does not exceed the boiling point of the organic solvent for 7-10 hours to obtain the 2-methylnicotinate or the derivative thereof.
2. The method according to claim 1, wherein in step (1), the 1, 3-dicarbonyl compound is specifically:
wherein, R is1The group is selected from methyl, methoxy, ethoxy, isopropoxy, tert-butoxy, allyloxy, benzyloxy.
3. The process according to claim 1, wherein in step (1), the alkyl vinyl ether is in particular:
wherein, R is2The radical is ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl.
4. The method according to claim 1, wherein in the step (1), the formaldehyde-based raw material is an aqueous formaldehyde solution or paraformaldehyde.
5. The method according to claim 1, wherein in the step (2), the ammonium salt is any one of ammonium chloride, ammonium bromide, ammonium iodide, ammonium acetate and ammonium bicarbonate.
6. The method according to claim 1, wherein in the step (2), the Lewis acid is any one of aluminum trichloride, aluminum trichloride hexahydrate, aluminum trifluoromethanesulfonate and nickel perchlorate hexahydrate.
7. The method according to claim 1, wherein in the step (2), the organic solvent is any one of ethanol, isopropanol, and acetonitrile.
8. The process according to any one of claims 1 to 7, wherein in the step (2), the molar ratio of the ammonium salt to the 2-alkoxy-3, 4-dihydropyran derivative is 1: 1-2: 1; the molar ratio of the oxidant methylene blue to the 2-alkoxy-3, 4-dihydropyran derivative is 1: 1-1: 1.5; the molar ratio of the Lewis acid to the 2-alkoxy-3, 4-dihydropyran derivative is 0.5: 1-1.25: 1; the ratio of the volume of the organic solvent to the amount of the substance of the 2-alkoxy-3, 4-dihydropyran derivative is 5: 1L/mol-10: 1L/mol.
9. The production process according to any one of claims 1 to 8, wherein in the step (1), the 2-alkoxy-3, 4-dihydropyran derivative is isolated by distillation under reduced pressure;
in the step (2), the 2-methylnicotinate or a derivative thereof is separated by Preparative Thin Layer Chromatography (PTLC).
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| US5081247A (en) * | 1987-05-05 | 1992-01-14 | Basf Aktiengesellschaft | Preparation of pyridines |
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