CN113735765B - Preparation method of 2-methylnicotinate and derivatives thereof - Google Patents
Preparation method of 2-methylnicotinate and derivatives thereof Download PDFInfo
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- CN113735765B CN113735765B CN202111068712.3A CN202111068712A CN113735765B CN 113735765 B CN113735765 B CN 113735765B CN 202111068712 A CN202111068712 A CN 202111068712A CN 113735765 B CN113735765 B CN 113735765B
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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
- C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D213/24—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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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
- C07D213/04—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—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 having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
The invention belongs to the technical field of fine chemical preparation, and discloses a preparation method of 2-methylnicotinate 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 for 7-10 hours at a certain temperature to obtain 2-methylnicotinate or derivative thereof. Compared with the traditional preparation method of the 2-methylnicotinate and the derivatives thereof, the preparation method has the advantages of low-cost 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 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-methylnicotinate and derivatives thereof, which takes 1, 3-dicarbonyl compounds, alkyl vinyl ether and formaldehyde raw materials as raw materials to prepare the 2-methylnicotinate and the derivatives thereof.
Background
Pyridine derivatives are fine chemicals and bioactive molecules with high added value, and are mainly applied to the production of pesticides, medicines, fuels, textiles and surfactants. Nicotinic acid esters, which are pyridine derivatives, are also widely used in the fields of medicine, pesticides, etc., and are commonly used for synthesizing antihypertensives, anesthetics, analgesics, etc. Conventional methods for synthesizing nicotinic acid esters include Hantzsch pyridine synthesis, bohlmann-Rahtz synthesis, michel addition, and the like. The synthesis of nicotinic acid esters by Hantzsch pyridine synthesis method needs Pd/C catalysis or microwave condition to realize the synthesis of nicotinic acid esters, thus leading to higher production cost and difficult realization of industrialization; the nicotinic acid ester compound is synthesized by a Bohlmann-Rahtz pyridine synthesis method, and the raw materials of the method are high in price and the synthesized nicotinic acid ester has insufficient functional diversity due to the need of using the alkyne ketone with rare types and high price; the nicotinic acid ester compound is synthesized by a Michelia addition method, and toluene is often used as a reaction medium, so that the method is not environment-friendly and is easy to cause environmental pollution. Meanwhile, the method has the problems of low compatibility of substituent groups, difficult position regulation and control and the like. Therefore, a synthetic route with low production cost, simple synthetic method and functional diversity of target products is urgently needed at present.
Disclosure of Invention
Aiming at the defects or improvement demands of the prior art, the invention aims to provide a preparation method of 2-methylnicotinate and derivatives thereof, wherein the overall reaction flow design of the preparation method is improved, methylene blue is used as an oxidant, and reaction conditions (such as a substrate, a catalyst, temperature and the like) are preferably set.
In order to achieve the above object, according to the present invention, there is provided a method for producing 2-methylnicotinate or a derivative thereof, characterized by 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 to 1.6:1, a step of; taking the amount of substances containing carbon elements in formaldehyde components in the formaldehyde raw material as the amount of the substances in the formaldehyde raw material, the molar ratio of the 1, 3-dicarbonyl compound to the formaldehyde raw material is 1:1 to 1:1.3;
(2) Reacting the 2-alkoxy-3, 4-dihydropyran derivative obtained in the step (1) with ammonium salt in an organic solvent under the action of oxidizing agent methylene blue and Lewis acid at a temperature of 70-85 ℃ and a temperature not exceeding the boiling point of the organic solvent for 7-10 hours to obtain 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 the R is 1 The group is selected from methyl, methoxy, ethoxy, isopropoxy, tert-butoxy, allyloxy and benzyloxy.
As a further preferred aspect of the present invention, in the step (1), the alkyl vinyl ether is specifically:
wherein the R is 2 The group 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 aspect 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.
As a further preferred aspect of the present invention, in the step (2), the lewis acid is any one of aluminum trichloride, aluminum trichloride hexahydrate, aluminum trifluoromethane sulfonate, and nickel perchlorate hexahydrate.
In a further preferred aspect 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, a step of; the molar ratio of the oxidizing agent methylene blue to the 2-alkoxy-3, 4-dihydropyran derivative is 1:1 to 1:1.5; the molar ratio of the lewis acid to the 2-alkoxy-3, 4-dihydropyran derivative is 0.5:1 to 1.25:1, a step of; 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 derivative thereof is isolated by Preparative Thin Layer Chromatography (PTLC).
Compared with the prior art, the technical scheme of the invention has the following beneficial effects:
(1) The technical scheme is that alkyl vinyl ether, 1, 3-dicarbonyl compound and formaldehyde aqueous solution are used for synthesizing 2-alkoxy-3, 4-dihydropyran derivative, and then the 2-alkoxy-3, 4-dihydropyran derivative and ammonium salt (such as ammonium acetate) react in organic solvent (such as ethanol), wherein the reaction temperature is 70-85 ℃ (the reaction temperature is not higher than 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 materials and ammonium salt adopted by the technical scheme are cheap and easy to obtain, the types of the alkyl vinyl ether and the 1, 3-dicarbonyl compound are various and can be flexibly changed according to actual demands, compared with the prior art, the method does not need to use the alkyne ketone with rare types and high price, and simultaneously solves the problem of insufficient functional diversity of the synthesized nicotinic acid derivative.
(3) The Lewis acid adopted in the technical scheme is preferably aluminum trichloride and aluminum trichloride hexahydrate, so that the yield effect is good; and the catalyst has low price, compared with the prior art, noble metal catalysts such as gold, palladium and the like are not adopted, the preparation cost is greatly reduced, and the economic benefit is improved.
(4) The invention particularly adopts methylene blue as an oxidant, and can effectively ensure the synthesis of target compounds (namely, 2-methylnicotinate or derivatives thereof); in addition, the oxidant is low in price and wide in source, compared with the prior art, the oxidant with strong corrosiveness such as nitric acid is not needed, and the environment pollution is reduced.
Drawings
FIG. 1 is a schematic diagram of the process for preparing methyl 2-methylnicotinate according to example 1 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to the drawings and examples, in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the invention. In addition, the technical features of the embodiments of the present invention described below may be combined with each other as long as they do not collide with each other.
In general, the process for preparing 2-methylnicotinate and its derivatives in the present invention will first comprise alkyl vinyl ether
1, 3-dicarbonyl Compound->
Raw materials including formaldehyde raw materials (such as formaldehyde aqueous solution or paraformaldehyde) react for 6 to 9 hours at the temperature of between 60 and 100 ℃, and the reaction products are separated to obtain the 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 oxidizing agent methylene blue and Lewis acid at 70 to 85 ℃ for 7 to 10 hours (of course, the reaction temperature is not higher than the boiling point of the organic solvent) to obtain 2-methylnicotinate or derivative thereof>
The following are specific examples:
example 1: preparation of methyl 2-methylnicotinate
According to the preparation method of the embodiment of the invention, in the first step, n-butyl vinyl ether, formaldehyde aqueous solution and methyl acetoacetate are subjected to Diels-Alder reaction to generate 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran, and in the second step, 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran and ammonium acetate are subjected to ring opening/condensation cyclization/oxidation in ethanol by taking aluminum trichloride hexahydrate as a catalyst and methylene blue as an oxidant to obtain 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): into a magnetically stirred reactor, 1.0g (10 mmol) of n-butyl vinyl ether and 0.77g (25.5 mmol) of formaldehyde as a solute were charged, and 2.37g (20 mmol) of methyl acetoacetate was mixed and reacted at 60℃for 8 hours with stirring. After completion of the reaction, unreacted raw material n-butyl vinyl ether was distilled off, followed by distillation under reduced pressure to obtain 2.0g (8.9 mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(101MHz,CDCl 3 ,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): into a reactor equipped with magnetic stirring, 47.8mg (0.2 mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran obtained in the step (1), 28.4mg (0.37 mmol) of ammonium acetate, 137mg (0.33 mmol) of methylene blue, 36.2mg (0.15 mmol) of aluminum trichloride hexahydrate were charged in 2mL of ethanol, and the mixed solution was stirred at 70℃for 7 hours to stop heating after completion of TLC detection. Separating the product and the raw material by using 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, 20mg (0.13 mmol) of methyl 2-methylnicotinate was finally obtained. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(100MHz,CDCl 3 ,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 C 8 H 9 NO 2 ,[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): into a magnetically stirred reactor, 1.0g (10 mmol) of n-butyl vinyl ether was charged, and the aqueous formaldehyde solution contained 0.75g (25 mmol) of formaldehyde as a solute and 2.6g (20 mmol) of ethyl acetoacetate, and after mixing, the mixture was stirred at 100℃for 7 hours. After completion of the reaction, unreacted raw material n-butyl vinyl ether was distilled off, followed by distillation under reduced pressure to obtain 2.2g (9.0 mmol) of 6-methyl-2-n-butoxy-5-carboxyethyl-3, 4-dihydropyran. 1 H NMR(600MHz,CDCl 3 ,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)； 13 C NMR(150MHz,CDCl 3 ,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): 48.5mg (0.2 mmol) of 6-methyl-2-n-butoxy-5-carboxyethyl-3, 4-dihydropyran obtained in the step (1), 15.4mg (0.2 mmol) of ammonium acetate, 83mg (0.2 mmol) of methylene blue, 48.3mg (0.2 mmol) of aluminum trichloride hexahydrate and 1mL of acetonitrile were charged into a reactor equipped with magnetic stirring, and the mixed solution was stirred at 75℃for 8 hours to react, and after completion of the TLC detection, the heating was stopped. Separating the product and the raw material by using 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, 15.9mg (0.096) of ethyl 2-methylnicotinate was finally obtainedmmol)。 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(100MHz,CDCl 3 ,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 C 9 H 11 NO 2 ,[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): into a magnetically stirred reactor, 1.0g (10 mmol) of n-butyl vinyl ether was charged, and the aqueous formaldehyde solution contained 0.84g (28 mmol) of formaldehyde as a solute and 2.5g (25 mmol) of acetylacetone, and after mixing, the mixture was stirred at 80℃for reaction for 6 hours. After completion of the reaction, unreacted raw material n-butyl vinyl ether was distilled off, followed by distillation under reduced pressure to obtain 1.4g (6.6 mmol) of 6-methyl-2-n-butoxy-5-acetyl-3, 4-dihydropyran. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(101MHz,CDCl 3 ,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): charging the 6-methyl-2-n-butoxy-5-acetyl obtained in step (1) into a reactor equipped with magnetic stirring42.5mg (0.2 mmol) of 3, 4-dihydropyran, 15.4mg (0.2 mmol) of ammonium acetate, 83mg (0.2 mmol) of methylene blue and 20mg (0.15 mmol) of aluminum trichloride are dissolved in 2mL of isopropanol, and the mixed solution is stirred at 80℃for 9 hours, and heating is stopped after the TLC detection reaction is completed. Separating the product and the raw material by using 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, 11.9mg (0.088 mmol) of the 3-acetyl-2-methylpyridine was finally obtained. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(100MHz,CDCl 3 ,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 C 8 H 9 NO,[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 2-methyl-nicotinic acid benzyl ester
Step (1): into a magnetically stirred reactor, 1.25g (12.5 mmol) of n-butyl vinyl ether, 0.75g (25 mmol) of formaldehyde as a solute, 3.9g (20 mmol) of benzyl acetylacetonate, and the mixture was stirred at 80℃for 9 hours. After completion of the reaction, unreacted raw material n-butyl vinyl ether was distilled off, followed by distillation under reduced pressure to obtain 1.6g (5.3 mmol) of 6-methyl-2-n-butoxy-5-carboxybenzyl-3, 4-dihydropyran. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(101MHz,CDCl 3 ,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): into a reactor equipped with magnetic stirring, 59.5mg (0.2 mmol) of 6-methyl-2-n-butoxy-5-carboxybenzyl-3, 4-dihydropyran obtained in the step (1), 15.4mg (0.23 mmol) of ammonium acetate, 122mg (0.3 mmol) of methylene blue, and 26.7mg (0.25 mmol) of aluminum trichloride were charged into 1mL of isopropanol, and the mixed solution was stirred at 85℃for 10 hours, and after completion of the TLC detection, heating was stopped. Separating the product and the raw material by using 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, 21.0mg (0.088 mmol) of said benzyl 2-methylnicotinate was finally obtained. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(100MHz,CDCl 3 ,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 C 14 H 13 NO 2 ,[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): into a magnetically stirred reactor, 1.0g (10 mmol) of n-butyl vinyl ether and 0.77g (25.5 mmol) of formaldehyde as a solute were charged, and 2.37g (20 mmol) of methyl acetoacetate was mixed and reacted at 60℃for 8 hours with stirring. Evaporating unreacted raw material n-butyl after the reaction is finishedVinyl ether was distilled under reduced pressure to give 2.0g (8.9 mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(101MHz,CDCl 3 ,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): into a reactor equipped with magnetic stirring, 71.7mg (0.3 mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran obtained in the step (1), 23.1mg (0.3 mmol) of ammonium acetate, 125mg (0.3 mmol) of methylene blue, and 27mg (0.15 mmol) of aluminum triflate were charged into 2mL of ethanol, and the mixed solution was stirred at 75℃for 8 hours, and after completion of the TLC detection, heating was stopped. Separating the product and the raw material by using 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, 16.8mg (0.11 mmol) of methyl 2-methylnicotinate was finally obtained. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(100MHz,CDCl 3 ,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 C 8 H 9 NO 2 ,[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): into a magnetically stirred reactor, 1.0g (10 mmol) of n-butyl vinyl ether and 0.77g (25.5 mmol) of formaldehyde as a solute were charged, and 2.37g (20 mmol) of methyl acetoacetate was mixed and reacted at 60℃for 8 hours with stirring. After completion of the reaction, unreacted raw material n-butyl vinyl ether was distilled off, followed by distillation under reduced pressure to obtain 2.0g (8.9 mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(101MHz,CDCl 3 ,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): into a reactor equipped with magnetic stirring, 71.7mg (0.3 mmol) of 6-methyl-2-n-butoxy-5-carboxymethyl-3, 4-dihydropyran obtained in the step (1), 16.05mg (0.3 mmol) of ammonium chloride, 125mg (0.3 mmol) of methylene blue, 55mg (0.15 mmol) of nickel perchlorate hexahydrate were charged in 2mL of ethanol, and the mixed solution was stirred at 75℃for 7 hours to react, and after completion of the TLC detection, heating was stopped. Separating the product and the raw material by using 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, 17.7mg (0.117 mmol) of methyl 2-methylnicotinate as described was finally obtained. 1 H NMR(400MHz,CDCl 3 ,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)； 13 C NMR(100MHz,CDCl 3 ,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 C 8 H 9 NO 2 ,[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%.
According to the invention, methylene blue is used as an oxidant, and other oxidants (such as tert-butyl hydroperoxide, 2, 3-dichloro-5, 6-dicyanobenzoquinone, di-tert-butyl peroxide, 2-iodoxybenzoic acid, manganese dioxide and silver carbonate) can not obtain target products according to the processes of the above examples.
The above examples are illustrative and the various reaction materials used are commercially available in analytical grade purity.
It will be readily appreciated by those skilled in the art that the foregoing description is merely a preferred embodiment of the invention and is not intended to limit the invention, but any modifications, equivalents, improvements or alternatives falling within the spirit and principles of the invention are intended to be included within the scope of the invention.
Claims (5)
1. A method for preparing 2-methylnicotinate or derivatives 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 to 1.6:1, a step of; taking the amount of substances containing carbon elements in formaldehyde components in the formaldehyde raw material as the amount of the substances in the formaldehyde raw material, the molar ratio of the 1, 3-dicarbonyl compound to the formaldehyde raw material is 1:1 to 1:1.3;
(2) Reacting the 2-alkoxy-3, 4-dihydropyran derivative obtained in the step (1) with ammonium salt in an organic solvent under the action of oxidizing agent methylene blue and Lewis acid at a temperature of 70-85 ℃ and a temperature not exceeding the boiling point of the organic solvent for 7-10 hours to obtain 2-methylnicotinate or a derivative thereof;
in the step (1), the 1, 3-dicarbonyl compound is specifically:
wherein the R is 1 The group is selected from methyl, methoxy, ethoxy, isopropoxy, tert-butoxy, allyloxy and benzyloxy;
the alkyl vinyl ether is specifically:
wherein the R is 2 The group is ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl;
the formaldehyde raw material is specifically formaldehyde aqueous solution or paraformaldehyde;
in the step (2), the ammonium salt is any one of ammonium chloride, ammonium bromide, ammonium iodide, ammonium acetate and ammonium bicarbonate;
the Lewis acid is any one of aluminum trichloride, aluminum trichloride hexahydrate, aluminum trifluoromethane sulfonate and nickel perchlorate hexahydrate.
2. The method according to claim 1, wherein in the step (2), the organic solvent is any one of ethanol, isopropanol, and acetonitrile.
3. The process according to any one of claims 1 to 2, wherein in step (2), the molar ratio of the ammonium salt to the 2-alkoxy-3, 4-dihydropyran derivative is 1: 1-2: 1, a step of; the molar ratio of the oxidizing agent methylene blue to the 2-alkoxy-3, 4-dihydropyran derivative is 1:1 to 1:1.5; the molar ratio of the lewis acid to the 2-alkoxy-3, 4-dihydropyran derivative is 0.5:1 to 1.25:1, a step of; 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.
4. The process according to any one of claims 1 to 2, wherein in step (1), the 2-alkoxy-3, 4-dihydropyran derivative is isolated by distillation under reduced pressure;
in the step (2), the 2-methylnicotinate or derivative thereof is isolated by Preparative Thin Layer Chromatography (PTLC).
5. The process according to claim 3, 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 derivative thereof is isolated by Preparative Thin Layer Chromatography (PTLC).
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