CN105001154A - Method for synthesizing 2-halogenated nicotinate and intermediate thereof through ionic liquid method - Google Patents

Abstract

The invention discloses a method for synthesizing 2-halogenated nicotinic acid ester and its intermediate by ionic liquid method. The cyanoacetate, ionic liquid, and substituted aminoacrolein are evenly mixed, heated to a set temperature for reaction, and traced reacting until the substituted aminoacrolein disappears, cooling the reaction solution to room temperature, extracting with an organic solvent for several times, washing and drying the remaining phase of the ionic liquid, and then reuse it, evaporating the organic solvent from the organic phase to obtain the intermediate of 2-halogenated nicotinic acid ester; When synthesizing 2-halogenated nicotinic acid ester, it is not necessary to separate the organic solvent and the 2-halogenated nicotinic acid ester intermediate, add hydrogen halide to the organic phase to continue the reaction, and track and monitor until the reaction is complete; after separation, 2-halogenated nicotinic acid ester is obtained Ester products. The synthesis method of the 2-halonicotinic acid ester of the invention has the advantages of environmental protection, simple operation, high product yield and good quality of the synthetic product.

Description

A method for synthesizing 2-halogenated nicotinic acid ester and its intermediate by ionic liquid method

technical field

The invention relates to the technical field of organic chemistry, in particular to a method for synthesizing 2-halogenated nicotinic acid ester and its intermediate by an ionic liquid method.

Background technique

In chemical production, a large amount of organic solvents are often used in the production of chemical products, but organic solvents are highly volatile and easy to cause environmental pollution. Ionic Liquids (Ionic Liquids) are completely composed of ions, and now mostly refer to molten salts that are in a liquid state below 100 degrees Celsius. Ionic liquids have low vapor pressure, non-flammability, good stability, large heat capacity, good electrical conductivity, "designable" properties, and special solubility to many inorganic salts and organic substances. In recent years, they have been used as environmentally friendly solvents. It has great potential, so it is also called "green solvent".

2-halogenated nicotinic acid esters can be hydrolyzed to prepare 2-halogenated nicotinic acid, among which, 2-chloronicotinic acid is an important drug and pesticide intermediate, mainly used for the preparation of highly effective anti-inflammatory and analgesic drugs niflumic acid, Pranoprofen, HIV reverse transcriptase inhibitor nevirapine and new high-efficiency herbicide nicosulfuron, etc. The main preparation methods of 2-chloronicotinic acid in the prior art are:

(1) Ethyl cyanoacetate chlorination method (Tony Y Z, Eric F V, Scriven.Processes for Producing 2-Halonicotonic Acid Derivatives and Precursors Thereto: US, 5493028[P].1994; MayerJ.Process of Preparing 2-Halogenonicotinic acids: US, 4081451[P].1977; Liang Wangen, Xie Qiuping, Du Jianhua. Improvement of 2-chloronicotinic acid synthesis process [J]. Chemical World, 2012, 8: 491-493), ethyl cyanoacetate and acrolein are The starting material is synthesized by ring closure and hydrolysis to obtain 2-chloronicotinic acid. The method needs to be heated to reflux and has the disadvantages of large solvent consumption, complex process route and the like.

(2) Cyclization of malondialdehyde and ethyl cyanoacetate (Yoshitomi Pharmaceutical Industries Ltd. Japan. 2-Chloronicotinic acid: JP, 55076863 [P]. 1980; Xu Xiaohua, Lu Pei, Xie Longguan, et al. 2-Chloronicotinic acid Synthetic method of acid [P].CN 101367760, 2009; Chen Zhiwei, Zheng Lidong, Su Guodong. Improved synthesis process of 2-chloronicotinic acid [J]. Synthetic Chemistry, 2011, 19(2): 285-286; Du Xiaohua, Hu Fei, Xu Zhenyuan. A synthetic method of 2-chloronicotinic acid and its derivatives [P].CN 103193705A, 2013; Lu Sunbin, Ji Honglou, Gao Xiaoshan. A synthetic method of 2-chloronicotinic acid [P].CN102993092A, 2013 ), using ethyl cyanoacetate and malondialdehyde as starting materials, through ring closure and hydrolysis to synthesize 2-chloronicotinic acid. This synthetic route malondialdehyde is unstable and the raw material is not easy to get, so this synthetic route is also not suitable for industrialized production.

(3) Use acetaldehyde, sodium methoxide, and methyl formate as raw materials to generate sodium aldehyde vinyl alcoholate, which is then reacted with methanol to generate 1,1-dimethoxypropionaldehyde, and then reacted with malononitrile to generate cyclized precursor body, and then undergo cyclization, chlorination, and cyanohydrolysis to generate 2-chloronicotinic acid (Gao Qian, Qian Yong, Xue Yi, etc. A method for preparing 2-chloronicotinic acid [P].CN 104592104A, 2015) , the disadvantage of this method is that there is a lot of waste liquid and it is difficult to handle.

(4) Nitrogen oxidation-chlorination-hydrolysis method (Gedeon R, Vegyeszeti G R T.2-Chloronicotinic acid: HU, 22161[P].1982; Ference N, Bela S, Teljes H.2-Chloronicotinic acid: HU , 33464[P].1984; Adel S, Wallis B.Process for Pure White 2-Chloronicotinic Acid: DE, 2713316[P].1977; Zhang Min, Wang Zhangjiu, Wei Junfa, et al. 2-Chloronicotinic acid and its derivatives Synthesis of 2-chloronicotinic acid [J]. Chinese Journal of Pharmaceutical Industry, 2004, 35 (5): 11-12; Yang Guiqiu, Yu Chunrui, Yu Xiulan. Preparation of 2-chloro-N, N-dimethylnicotinamide [J]. Chinese Journal of Pharmaceutical Industry, 2004, 35(9): 11 -12), using nicotinic acid as the starting material, oxidizing the nitrogen atom on the ring by H ₂ O ₂ to generate N-oxide, and then using POCl ₃ as the chlorination reagent to carry out nucleophilic substitution reaction. The raw material nicotinic acid in this synthetic route is expensive, and the cost of the prepared product is relatively high, the product is difficult to separate, and the purity is also low, which does not meet the requirements of drugs and pesticides.

(5) 2-Chloro-3-picoline oxidation method (Nie Wenna. Study on the synthesis process of 2-chloronicotinic acid [J]. Hebei Chemical Industry, 2006, (10): 14-15, 18; Wang Wenkui, et al. A Synthesis method of 2-chloronicotinic acid [P].CN 201410703012, 2014; Yang Shouhai, et al. A method for one-step oxidation synthesis of 2-chloronicotinic acid [P].CN 201410015351, 2014), 2-chloro-3 -Picthylpyridine is oxidized with potassium permanganate, the alkyl side chain of the pyridine ring is oxidized to potassium carboxylate, and 2-chloronicotinic acid is acidified with concentrated hydrochloric acid to precipitate. The disadvantage of this method is that the raw material 2-chloro-3-picoline is not easy to get, and the environmental pollution is great, so it is not suitable for large-scale industrial production.

(6) 3-cyanopyridine-chlorination-hydrolysis method (Fumiya H.Preparation of 2-Chloro-3-cyanopyridine and 2-Chloronicotinic Acid: JP, 56-169672[P].1981; Naoi Kacheng.2- Preparation of chloronicotinic acid: JP, 59-144759 [P].1984; Liu Junan, Wei Xiaolei. Synthesis of 2-chloronicotinic acid [J]. Chemical and Bioengineering, 2010, 27(4): 36-37) This route Oxidize 3-cyanopyridine with H ₂ O ₂ to generate N-oxide, then use POCl ₃ as chlorination reagent to carry out nucleophilic substitution reaction, and then hydrolyze and neutralize to obtain the product. The disadvantage of this method is that the waste liquid is large and difficult to handle.

It can be seen that the existing 2-halogenated nicotinic acid preparation methods all have many "three wastes" and are difficult to handle. Therefore, it is necessary to develop green and environmentally friendly synthetic methods for 2-halogenated nicotinic acid esters and 2-halogenated nicotinic acid is very necessary.

Contents of the invention

The object of the present invention is to overcome the problems of the prior art and provide a method for synthesizing 2-halogenated nicotinic acid ester and its intermediate by ionic liquid method. The method is environmentally friendly, simple in operation and high in product yield.

To achieve the above object, the technical scheme adopted in the present invention is as follows:

A method for synthesizing 2-halogenated nicotinic acid ester intermediates by ionic liquid method, mixing cyanoacetate, ionic liquid, and substituted aminoacrolein evenly, heating to a set temperature for reaction, and tracking the reaction to substituted aminoacrolein Disappear, cool down to room temperature, extract with organic solvent for many times, wash and dry the remaining phase ionic liquid and reuse it, evaporate the organic solvent from the organic phase to obtain 2-halogenated nicotinic acid ester intermediate, 5-(N,N-dihydrocarbyl) Amino-2-cyano-2,4-pentadienoate, the structure of which is the compound of formula (II).

A method for synthesizing 2-halogenated nicotinate by ionic liquid method, comprising the following steps:

(1) Mix cyanoacetate, ionic liquid, and substituted aminoacrolein evenly, heat to a set temperature for reaction, track the reaction until the substituted aminoacrolein disappears, cool the reaction solution to room temperature, and extract with an organic solvent for several times, The remaining phase ionic liquid is washed and dried and reused, and the organic phase contains a compound with a structure such as formula (II);

(2) Add hydrogen halide to the organic phase in step (1) to continue the reaction, follow up and monitor until the reaction is complete; add lye to the reaction solution to adjust the pH value to 5-6, and leave to separate to obtain an aqueous layer and an organic layer , the aqueous layer was extracted with an organic solvent, and then the organic layers were combined, and the extractant was separated to obtain the 2-halonicotinic acid ester product shown in formula (I).

In formula (I), X represents F or Cl or Br or I, preferably Cl or Br. R ₃ in formula (I) and formula (II) represents C ₁ -C ₁₈ hydrocarbon group or benzyl group, preferably ethyl group or n-propyl group or n-butyl group. In formula (II), R ₁ and R ₂ are each independently H or C ₁ -C ₁₈ hydrocarbon group or phenyl or benzyl, preferably both R ₁ and R ₂ are methyl or ethyl.

In step (1), the ratio of the substituted aminoacrolein, the ionic liquid, and the cyanoacetate is: 1 mol: (100-500) mL: (0.5-1.5) mol.

In step (1) or step (2), the reaction temperature is 0-200°C, preferably 50-100°C.

In step (1) and step (2), the heating method is ultrasonic radiation, electric heating, microwave, water bath, oil bath, etc., preferably the heating method is microwave.

In step (1), the treatment method of the residual phase ionic liquid is washing with deionized water and vacuum drying.

The tracking monitoring adopts chromatographic tracking monitoring.

The cyanoacetate is methyl cyanoacetate, ethyl cyanoacetate, n-propyl cyanoacetate, n-butyl cyanoacetate, n-pentyl cyanoacetate, n-octyl cyanoacetate, cyano Lauryl acetate or octadecyl cyanoacetate.

The type of described ionic liquid is imidazoles or pyridines or quaternary phosphoniums or pyrrolidines or piperidines, the present invention selects the main purpose of this type of ionic liquids to be (1) improve reaction yield; (2) product and ion The liquid is easy to separate, and the ionic liquid can be reused. In addition, compared with traditional organic solvents and electrolytes, the ionic liquid of the present invention also has a series of outstanding advantages: (1) almost no vapor pressure, non-volatile, colorless, and odorless; (2) a larger stable temperature range , better chemical stability and wider electrochemical stable potential; (3) through the design of anions and cations, its solubility to inorganic substances, water, organic substances and polymers can be adjusted, and its acidity can be adjusted to superacid; (4) exhibit good solubility for both inorganic and organic substances; (5) usually contain weakly complexing ions, and have high polarization potential rather than complexing ability.

Wherein, the imidazole ionic liquid is 1-butyl-3-methylimidazolium chloride or 1-butyl-3-methylimidazolium bromide or 1-butyl-3-methylimidazolium trifluoroacetate or 1 -Hydroxyethyl-3-methylimidazolium chloride or 1-butyl-3-methylimidazolium dinitrile amine salt or 1-hexyl-3-methylimidazolium chloride or 1-pentyl-3-methylimidazolium Bromide or 1-allyl-3-butylimidazolium tetrafluoroborate, etc.;

Wherein, the pyridine ionic liquid is N-hexyl-pyridinium chloride or N-hexylpyridine bromide or N-dodecyl-pyridine chloride or N-dodecyl-pyridine bromide or N-ethylpyridine tetra Fluoroborate or N-butylpyridine tetrafluoroborate, etc.;

Wherein, the piperidine ionic liquid is N-butyl-N-methylpiperidinium chloride or N-butyl-N-methylpiperidinium bromide or N-butyl-N-ethylpiperidinium chloride or N-butyl-N-ethylpiperidinium bromide, etc.;

Wherein, the quaternary phosphonium ionic liquid is tributylethylphosphine bromide or tributylethylphosphine bis(trifluoromethanesulfonyl) imide salt or tributylhexylphosphine bromide or tributylhexylphosphine bis( Trifluoromethanesulfonyl)imide or trimethylhydroxyethylammonium hexafluorophosphate or trimethylhydroxyethylammonium bis(trifluoromethanesulfonyl)imide or trimethylhydroxyethylammonium tetrafluoro Borate or tetrabutylphosphine bromide or tetrabutylphosphine bis(trifluoromethanesulfonyl)imide salt, etc.;

Wherein, the pyrrolidine ionic liquid is 1-methyl-1-ethylpyrrolidine chloride or 1-methyl-1-ethylpyrrolidine bromide, 1,1-diethylpyrrolidine chloride or 1,1 -Diethylpyrrolidine bromide or 1-methyl-1-octylpyrrolidine chloride or 1-methyl-1-octylpyrrolidine bromide or 1-methyl-1-dodecylpyrrolidine chloride Pyrrolidine or 1-methyl-1-dodecylpyrrolidine bromide or N-methyl-N-butylpyrrolidine bis(trifluoromethanesulfonyl)imide or N-methyl-N-butyl N-methylpyrrolidine triflate or N-methyl-N-butylpyrrolidine methanesulfonate or N-methyl-N-butylpyrrolidine p-toluenesulfonate.

The substituted aminoacrolein is 3-dimethylaminoacrolein or 3-diethylaminoacrolein or N-methyl-N-benzyl-3-aminoacrolein or N-methyl-N-hexyl-3- Aminoacrolein or N-methyl-N-isooctyl-3-aminoacrolein or N-methyl-N-n-octyl-3-aminoacrolein or N-methyl-N-dodecyl- 3-aminoacrolein or N-dodecyl-3-aminoacrolein or N-octadecyl-3-aminoacrolein.

Described organic solvent is dichloromethane or 1,2-ethylene dichloride or chloroform or carbon tetrachloride or benzene or toluene or chlorobenzene or methyl acetate or ethyl acetate or propyl acetate or butyl acetate or ether or petroleum ether.

The lye is sodium hydroxide solution or potassium hydroxide solution or potassium carbonate solution or sodium carbonate solution or potassium bicarbonate solution or sodium bicarbonate solution or ammonia water, preferably the lye is that the mass fraction is 10%-20% sodium hydroxide solution.

The separation method is as follows: the organic layer is rectified to collect appropriate fractions to obtain the product or the product is obtained through drying, filtering and distillation. At the same time, the organic solvent can be recycled and reused.

The chemical reaction involved in the present invention is shown in reaction formula (I) and reaction formula (II):

The beneficial effects of the present invention are: (1) the ionic liquid adopted when synthesizing the compound of formula (II) is both a solvent and a catalyst, and the ionic liquid has suitable alkalinity and has a good catalytic effect on the reaction formula (I) ; Almost no vapor pressure, non-volatile, colorless, odorless, good chemical stability, soluble reaction raw materials, easy to separate from the product, and can be recycled. (2) The operation is simple, usually the reaction can be completed within 4 hours, and the product is easy to separate and purify; (3) The product yield is high and the quality is good, and the yield can reach more than 90%, which is higher than the yield of the traditional solvent heating reflux method (85%).

Detailed ways

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

Example 1 5-(N,N-dimethyl)amino-2-cyano-2,4-pentadienoic acid ethyl ester

Add 59mL (0.5mol) of ethyl cyanoacetate, 50mL of N-butyl-N-ethylpiperidinium bromide, and 62mL (0.5mol) of 3-dimethylaminoacrolein into the reactor, mix well, and heat to 55°C with ultrasonic waves Temperature and keep warm for 1h to react, TLC detection (petroleum ether:dichloromethane 1:2, sublimation iodine color development) 3-dimethylaminoacrolein reaction is complete, cooled to room temperature, organic solvent dichloromethane 60mL extraction 3 times, The remaining phase ionic liquid was washed with water and dried in vacuum for repeated use. The organic phase was evaporated to remove the solvent methylene chloride and recovered to obtain a crude product, which was then recrystallized with absolute ethanol to obtain 101.7g of white powder with a melting point of 134-135°C and a product yield of 94.2%. The product was characterized by HRMS, ¹ H NMR, and ¹³ C NMR spectra, namely ethyl 5-(N,N-dimethyl)amino-2-cyano-2,4-pentadienoate. ESI-MS: m/z Calcd for C ₁₀ H ₁₄ N ₂ O ₂ 217.0947[M+Na] ⁺ ,found217.0955[M+Na] ⁺ ; ¹ HNMR(300MHz,CDCl ₃ )δ(ppm):1.32( t,J=9Hz,3H,CH ₃ ),2.99(s,3H,NCH ₃ ),3.19(s,3H,NCH ₃ ),4.25(q,J=6Hz.2H,OCH ₂ ),5.57(t, J=12Hz, 1H, CH), 7.08(d, J=12Hz, 1H, CH), 7.78(d, J=12Hz, 1H, CH); ¹³ CNMR(75MHz, CDCl ₃ ) δ(ppm): 14.41( *CH ₃ ), 37.51(N*CH ₃ ), 45.33(N*CH ₃ ), 60.67(*CH ₂ CH ₃ ), 86.69(CH＝*CH-CH), 96.84(*CH＝C-CN), 117.96 (*C-CN), 156.89 (CN), 157.31 (N( _CH3 ) _2- *CH), 165.31 (C=O).

Example 2 5-(N,N-diethyl)amino-2-cyano-2,4-pentadienoic acid butyl ester

Add 59mL (0.5mol) of butyl cyanoacetate, 50mL of N-butyl-N-ethylpiperidinium chloride salt, and 62mL (0.5mol) of 3-diethylaminoacrolein into the reactor, mix well, and heat to 65°C in a water bath Temperature and keep warm for 10h for reaction, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) 3-diethylaminoacrolein reaction is complete, cooled to room temperature, organic solvent toluene 60mL extraction 3 times, the remaining phase The ionic liquid was washed with water and vacuum-dried for repeated use. After adding 10 mL of water to the organic phase to remove impurities, the solvent toluene was evaporated under reduced pressure for recovery, and 126.7 g of a light brown oil was obtained with a yield of 93.1%. The product was characterized by HRMS as butyl 5-(N,N-diethyl)amino-2-cyano-2,4-pentadienoate. ESI-MS: m/z Calcd for C ₁₄ H ₂₂ N ₂ O ₂ 273.3265[M+Na] ⁺ , found 273.32652[M+Na] ⁺ .

Example 3 Synthesis of ethyl 2-chloronicotinate

Add 59 mL (0.5 mol) of ethyl cyanoacetate, 50 mL of N-butyl-N-methylpiperidinium chloride salt, and 62 mL (0.5 mol) of 3-dimethylaminoacrolein into the reactor, mix well, and heat the oil bath to 80 ℃ temperature and keep warm for 6h for reaction, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color development) 3-dimethylaminoacrolein reaction is complete, cooled to room temperature, organic solvent methyl acetate 60mL extraction 3 times , the residual phase ionic liquid was washed with water and vacuum dried and reused, the organic phase was fed with dry HCl gas, and the reaction was tracked by HPLC until the end of the reaction. Add a 10% sodium hydroxide solution to adjust the pH to 5-6, separate the layers, extract the aqueous layer with 20 mL of methyl acetate x 3 times, combine the organic layers, add anhydrous Na ₂ SO ₄ to dry, filter, and evaporate the solvent Methyl acetate was recovered, the residue was rectified under reduced pressure, and the 110-115°C/1mmHg fraction was collected to obtain ethyl 2-chloronicotinate, 85.8g of colorless liquid, with a yield of 92.7%. The HRMS and NMR characterization of the product are as follows:

ESI-MS: m/z Calcd for C ₈ H ₈ NClO ₂ 186.0316[M+H] ⁺ , found 186.0310[M+H] ⁺ .

¹ HNMR (300MHz, CDCl ₃ ) δ(ppm): 1.39(t, J=6Hz, CH ₃ ), 4.39(q, J=6Hz, CH ₂ ), 7.31(t, J=6Hz, 1H, CH), 8.13(d, J=6Hz, 1H.CH), 8.48(d, J=6Hz, 1H,CH).

¹³ CNMR (75MHz, CDCl ₃ )δ(ppm): 14.09(*CH ₃ ), 62.07(*CH ₂ CH ₃ ), 122.04(CH=*CH-CH), 127.22(*C-COOCH ₂ CH ₃ ), 140.11(*CH=C-COO), 149.92(Cl-*C=N), 151.33(N-*CH=CH), 164.51(*C=O).

The synthesis of embodiment 4 2-ethyl bromonicotinate

Add 59mL (0.5mol) of ethyl cyanoacetate, 50mL of 1-dodecyl-3-methylimidazolium chloride salt, and 62mL (0.5mol) of 3-dimethylaminoacrolein into the reactor, mix well, and heat the oil bath to 90 ℃ temperature and keep it warm for 4 hours for reaction, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color development) 3-dimethylaminoacrolein reaction is complete, cooled to room temperature, organic solvent 1,2-dichloroethane Extract with 60mL of alkane for 3 times, wash the remaining phase ionic liquid with water and dry it in vacuum and reuse it. The organic phase is fed with dry HBr gas, and the reaction is tracked by HPLC until the end of the reaction. Add a 20% sodium carbonate solution to adjust the pH to 5-6, separate the layers, extract the aqueous layer with 20 mL of 1,2-dichloroethane x 3 times, combine the organic layers, wash with water, separate the layers, dry over molecular sieves, and filter. The solvent was distilled off under reduced pressure, and 1, 2-dichloroethane was recovered to obtain ethyl 2-bromonicotinate, 108.4 g of light brown liquid, with a yield of 94.0%. The HRMS and NMR characterization of the product are as follows:

ESI-MS: m/z Calcd for C ₈ H ₈ NBrO ₂ 231.0666[M+H] ⁺ , found 231.0659 [M+H] ⁺ .

¹ HNMR (300MHz, CDCl ₃ ) δ(ppm): 1.38(t, J=6Hz, CH ₃ ), 4.37(q, J=6Hz, CH ₂ ), 7.30(t, J=6Hz, 1H, CH), 8.11(d, J=6Hz, 1H.CH), 8.47(d, J=6Hz, 1H,CH).

The synthesis of embodiment 5 2-iodonicotinic acid ethyl esters

Add 59mL (0.5mol) of ethyl cyanoacetate, 50mL of 1-hydroxyethyl-3-methylimidazolium chloride salt, and 62mL (0.5mol) of 3-dimethylaminoacrolein into the reactor, mix well, and heat the electric furnace cover to 110 ℃ temperature and keep warm for 3h to react, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color development) 3-dimethylaminoacrolein reaction is complete, cooled to room temperature, organic solvent ethyl acetate 60mL extraction 3 times , the residual phase ionic liquid was washed with water and vacuum-dried and reused, the organic phase was fed with dry HI gas, and the reaction was tracked by HPLC until the end of the reaction. Add 10% ammonia water to adjust the pH to 5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, and evaporate the solvent ethyl acetate under reduced pressure The ester was recovered to obtain ethyl 2-iodonicotinate, 128.7 g of light brown liquid, and the yield was 92.9%. The HRMS and NMR characterization of the product are as follows:

ESI-MS: m/z Calcd for C ₈ H ₈ NIO ₂ 278.0671[M+H] ⁺ , found 278.0665[M+H] ⁺ .

¹ HNMR (300MHz, CDCl ₃ ) δ(ppm): 1.37(t, J=6Hz, CH ₃ ), 4.37(q, J=6Hz, CH ₂ ), 7.31(t, J=6Hz, 1H, CH), 8.10 (d, J=6Hz, 1H.CH), 8.46 (d, J=6Hz, 1H, CH).

Embodiment 6 Synthesis of ethyl 2-fluoronicotinate

Add 59mL (0.5mol) of ethyl cyanoacetate, 50mL of 1-butyl-3-methylimidazole trifluoroacetate, and 62mL (0.5mol) of 3-dimethylaminoacrolein into the reactor, mix well, and heat the Reaction at a temperature of 120°C and incubated for 2 hours, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) 3-dimethylaminoacrolein has completely reacted, cooled to room temperature, organic solvent toluene 60mL extraction 3 times , the remaining phase ionic liquid was washed with water and vacuum dried and reused, the organic phase was fed with dry HF gas, and the reaction was followed by HPLC until the end of the reaction. Add a 20% potassium carbonate solution to adjust the pH to 5-6, separate the layers, extract the water layer with 20 mL of toluene x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, evaporate the solvent under reduced pressure to recover the toluene , obtained 2-fluoronicotinic acid ethyl ester, light brown liquid 76.5g, the yield was 90.4%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₈ H ₈ NFO ₂ 170.1610[M+H] ⁺ , found 170.1613[M+H] ⁺ .

Example 7 Synthesis of 2-chloronicotinic acid methyl ester

Add 59mL (0.5mol) of methyl cyanoacetate, 50mL of N-ethylpyridine tetrafluoroborate, and 62mL (0.5mol) of 3-dimethylaminoacrolein into the reactor, mix well, heat to 140°C with microwave and keep it warm React for 1 hour, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) 3-dimethylaminoacrolein reaction is complete, cool down to room temperature, organic solvent diethyl ether 60mL extraction 3 times, remaining phase ionic liquid wash After drying in vacuum, it was reused, and the organic phase was fed with dry HCl gas, and the reaction was followed by HPLC until the end of the reaction. Add a 20% sodium hydroxide solution to adjust the pH to 5-6, separate the layers, extract the aqueous layer with 20 mL of ether x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, distill off the solvent and recover the ether, The residue was rectified under reduced pressure, and the 110-115°C/1mmHg fraction was collected to obtain 2-chloronicotinic acid methyl ester, 80.6g of colorless liquid, with a yield of 93.9%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₇ H ₆ NClO ₂ 172.5887[M+H] ⁺ , found 172.5883 [M+H] ⁺ .

Example 8 Synthesis of n-butyl 2-chloronicotinate

Add 59mL (0.5mol) of n-butyl cyanoacetate, 50mL of 1-hexyl-3-methylimidazolium chloride salt, and 69mL (0.5mol) of N-methyl-(N-benzyl)aminoacrolein into the reactor. Uniform, microwave heating to 160°C temperature and keep it warm for 1h to react, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color development) N-methyl-(N-benzyl)aminoacrolein reaction is complete , cooled to room temperature, organic solvent ethyl acetate 60mL extracted 3 times, the remaining phase ionic liquid was washed with water and vacuum-dried and reused, the organic phase was fed with dry HCl gas, and the reaction was tracked by HPLC until the end of the reaction. Add a 10% sodium hydroxide solution to adjust the pH to 5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, and distill off the acetic acid solvent After recovering the ethyl ester, n-butyl 2-chloronicotinate was obtained as 100.5 g of colorless liquid with a yield of 94.1%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₀ H ₁₂ NClO ₂ 214.6685[M+H] ⁺ , found 214.6679 [M+H] ⁺ .

Embodiment 9 The synthesis of 2-chloronicotinic acid n-octadecyl ester

Add 73 mL (0.5 mol) of octadecyl cyanoacetate, 50 mL of 1-hexyl-3-methylimidazolium chloride salt, and 61 mL (0.5 mol) of 3-diethylaminoacrolein into the reactor, mix well, and heat to 200°C with microwave And keep warm for 0.5h to react, TLC detection (petroleum ether:dichloromethane 1:2, sublimation iodine color development) 3-diethylaminoacrolein has completely reacted, cooled to 50°C, separated, washed with ionic liquid phase and dried in vacuum After repeated use, dry HCl gas was fed into the organic phase, and the reaction was tracked by HPLC until the end of the reaction. Add a 10% sodium hydroxide solution to adjust the pH to 5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, and distill off the acetic acid solvent After recovering the ethyl ester, n-octadecyl 2-chloronicotinic acid was obtained as 186.8 g of colorless liquid with a yield of 91.1%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₂₄ H ₄₀ NClO ₂ 411.0406[M+H] ⁺ , found 411.0401[M+H] ⁺ .

Example 10 Synthesis of n-pentyl bromonicotinate

Add 62mL (0.5mol) of n-pentyl cyanoacetate, 600mL of 1-methyl-1-octylpyrrolidine chloride, 45mL (0.4mol) of N-methyl-N-octyl-3-aminopropenal in the reactor ) mixed evenly, microwave heated to 85°C and kept warm for 3h for reaction, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimated iodine color development) N-methyl-N-octyl-3-aminoacrolein After the reaction was complete, the temperature was lowered to room temperature, and the organic solvent ethyl acetate was extracted three times with 60 mL of ethyl acetate. The remaining phase ionic liquid was washed with water and vacuum-dried and then reused. Add 5% potassium hydroxide solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, distill off the solvent and recover the ethyl acetate Finally, n-pentyl 2-bromonicotinate was obtained as 78.9 g of colorless liquid with a yield of 96.5%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₁ H ₁₄ O ₂ NBr 295.1282[M+Na] ⁺ , found 295.1277[M+Na] ⁺ .

Example 11 Synthesis of n-hexyl 2-chloronicotinate

Add 63mL (0.5mol) of n-hexyl cyanoacetate, 200mL of 1-methyl-1-dodecylpyrrolidine chloride, 35mL (0.3mol) of N-methyl-N-hexyl-3-aminoacrolein into the reactor ) mixed evenly, microwave heated to 85°C and kept warm for 3h for reaction, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color) N-methyl-N-hexyl-3-aminoacrolein reaction Completely, cool down to room temperature, extract 3 times with 60 mL of organic solvent ethyl acetate, wash the remaining phase ionic liquid with water and dry it in vacuum before reuse, inject HCl gas into the organic phase, and follow the reaction by HPLC until the end of the reaction. Add 5% potassium hydroxide solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, distill off the solvent and recover the ethyl acetate Finally, n-hexyl 2-bromonicotinate was obtained as 69.4 g of colorless liquid with a yield of 95.7%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₂ H ₁₆ O ₂ NCl 264.7034[M+Na] ⁺ , found 264.7027[M+Na] ⁺ .

Example 12 Synthesis of 2-bromonicotinic acid n-heptyl ester

Add 64mL (0.5mol) of n-heptyl cyanoacetate, 150mL of 1-methyl-1-dodecylpyrrolidine bromide, and 45mL of N-methyl-N-octyl-3-aminoacrolein ( 0.4mol) mixed evenly, microwave heated to 82°C and kept warm for 3h to react, TLC detection (petroleum ether: dichloromethane 1:2, sublimation iodine color development) N-methyl-N-octyl-3-amino The acrolein was completely reacted, cooled to room temperature, and extracted three times with 60 mL of organic solvent ethyl acetate. The remaining phase ionic liquid was washed with water and vacuum-dried and reused. The organic phase was fed with HBr gas, and the reaction was tracked by HPLC until the reaction was completed. Add 5% potassium hydroxide solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of ethyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry over anhydrous sodium sulfate, filter, and distill off the solvent acetic acid After recovering the ethyl ester, n-heptyl 2-bromonicotinate was obtained as 113.4 g of colorless liquid, with a yield of 94.5%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₃ H ₁₈ O ₂ NBr 323.1813[M+Na] ⁺ , found 323.1807 [M+Na] ⁺ .

Example 13 Synthesis of n-octyl 2-chloronicotinate

Add 64mL (0.5mol) of n-octyl cyanoacetate, 100mL of N-methyl-N-butylpyrrolidine bis(trifluoromethanesulfonyl)imide salt, 62mL of 3-diethylaminoacrolein (0.5 mol) mixed evenly, microwave heating to 110°C temperature and keep warm for 3h to react, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color development) 3-diethylaminoacrolein reacted completely, cooled to room temperature, The organic solvent butyl acetate was extracted for 3 times, and the remaining phase ionic liquid was washed with water and vacuum-dried and reused. The organic phase was fed with HCl gas, and the reaction was followed by HPLC until the reaction was completed. Add 5% potassium hydroxide solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of butyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, distill off the solvent and recover the butyl acetate Finally, n-octyl 2-chloronicotinate was obtained as 122.8 g of a colorless liquid with a yield of 91.1%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₄ H ₂₀ O ₂ NCl 292.7566[M+Na] ⁺ , found 292.7558[M+Na] ⁺ .

Example 14 Synthesis of 2-chloronicotinic acid 2-ethylhexyl ester

Add 66mL (0.5mol) of 2-ethylhexyl cyanoacetate, 500mL of N-butyl-N-ethylpiperidinium bromide, and 62mL (0.5mol) of 3-diethylaminoacrolein into the reactor, mix well, microwave Heat to 110°C and keep it warm for 3 hours to react, TLC detection (petroleum ether: methylene chloride 1:2, sublimation iodine color development) 3-diethylaminoacrolein has completely reacted, cooled to room temperature, organic solvent butyl acetate 60mL Extracted 3 times, the remaining phase ionic liquid was washed with water and vacuum dried, and then reused. The organic phase was fed with HCl gas, and the reaction was tracked by HPLC until the end of the reaction. Add 5% potassium hydroxide solution to adjust the pH=5-6, separate the layers, extract the aqueous layer with 20 mL of butyl acetate x 3 times, combine the organic layers, wash with water, separate the layers, dry with molecular sieves, filter, distill off the solvent and recover the butyl acetate Finally, 2-ethylhexyl 2-chloronicotinate was obtained as 121.9 g of colorless liquid, with a yield of 90.4%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₄ H ₂₀ O ₂ NCl 292.7566[M+Na] ⁺ , found 292.7555[M+Na] ⁺ .

Example 15 Synthesis of 2-chloronicotinic acid benzyl ester

Add 63 mL (0.5 mol) of benzyl cyanoacetate, 126 mL of 1-butyl-3-methylimidazole trifluoroacetate, and 19 mL (0.1 mol) of N-octadecyl-3-aminoacrolein into the reactor. Evenly, heat the oil bath to 90°C and keep it warm for 4 hours to react, TLC detection (petroleum ether: dichloromethane 1:2 development, sublimation iodine color development) N-octadecyl-3-aminoacrolein reaction is complete, cool down To room temperature, the organic solvent 1,2-dichloroethane 60mL was extracted three times, and the remaining phase ionic liquid was washed with water and vacuum-dried and then reused. Add concentrated ammonia water to adjust pH=5-6, separate the layers, extract the aqueous layer with 20 mL of 1,2-dichloroethane x 3 times, combine the organic layers, wash with water and separate the liquids, evaporate the solvent 1,2-dichloro Ethane was recovered to obtain benzyl 2-chloronicotinate, 23.7 g of light yellow liquid, and the yield was 95.5%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₃ H ₁₀ O ₂ NCl 270.6665[M+Na] ⁺ , found 270.6657[M+Na] ⁺ .

Example 16 Synthesis of 2-bromonicotinic acid benzyl ester

Add 63mL (0.5mol) of benzyl cyanoacetate, 300mL of 1-methyl-1-hexylpyrrolidine bromide, and 62mL (0.5mol) of 3-dimethylaminoacrolein into the reactor, mix well, and heat the oil bath to 120 ℃ temperature and keep warm for 3h to react, TLC detection (petroleum ether:dichloromethane 1:2 development, sublimation iodine color development) 3-dimethylaminoacrolein complete reaction, cool down to room temperature, organic solvent 1,2-dichloroethane Extract 3 times with 60 mL of alkane, wash the remaining phase ionic liquid with water and dry it in a vacuum, and reuse it. HBr gas is introduced into the organic phase, and the reaction is tracked by HPLC until the reaction is completed. Add concentrated ammonia water to adjust pH=5-6, separate the layers, extract the aqueous layer with 20 mL of 1,2-dichloroethane x 3 times, combine the organic layers, wash with water and separate the liquids, evaporate the solvent 1,2-dichloro Ethane was recovered to obtain benzyl 2-bromonicotinate, 134.8 g of light brown liquid with a yield of 92.3%. The HRMS characterization of the product is as follows:

ESI-MS: m/z Calcd for C ₁₃ H ₁₀ O ₂ NBr 315.1178[M+Na] ⁺ , found 315.1167[M+Na] ⁺ .

Claims (10)

1. A method for synthesizing 2-halogenated nicotinic acid esters by ionic liquid method, is characterized in that, comprises the following steps: (1) Mix cyanoacetate, ionic liquid, and substituted aminoacrolein evenly, heat to a set temperature for reaction, track the reaction until the substituted aminoacrolein disappears, cool the reaction solution to room temperature, and extract with an organic solvent for several times, The remaining phase ionic liquid is washed and dried and reused, and the organic phase contains a 2-halogenated nicotinic acid ester intermediate with the structure shown in the compound of formula (II); (2) Add hydrogen halide to the organic phase in step (1) to continue the reaction, follow up and monitor until the reaction is complete; add lye to the reaction solution to adjust the pH value to 5-6, and leave to separate to obtain an aqueous layer and an organic layer , the aqueous layer is extracted with an organic solvent, then the organic layers are combined, and the extractant is separated to obtain a 2-halonicotinic acid ester product as shown in formula (I); In formula (I), X represents F or Cl or Br or I; In formula (I) and formula (II), R ₃ represents C ₁ -C ₁₈ hydrocarbon group or benzyl; In formula (II), R ₁ and R ₂ are each independently H or a C ₁ -C ₁₈ hydrocarbon group or a phenyl group or a benzyl group. 2. A method for synthesizing 2-halogenated nicotinate intermediates as claimed in claim 1, characterized in that: mix cyanoacetate, ionic liquid, and substituted aminoacrolein evenly, and heat to 0-200 Perform the reaction at ℃, track the reaction until the substituted aminoacrolein disappears, cool down to room temperature, extract the organic solvent for several times, wash and dry the remaining phase ionic liquid and reuse it, evaporate the organic solvent from the organic phase to obtain the compound with the structure shown in formula (II) 2-halogenated nicotinic acid ester intermediate. 3. The method according to claim 1, characterized in that: in step (1), the heating method is ultrasonic radiation, electric heating, microwave, water bath or oil bath. 4. The method according to claim 1 or 2, characterized in that: the ratio of the substituted aminoacrolein, ionic liquid, and cyanoacetate is: 1mol: (100-500) mL: (0.5-1.5) mol. 5. The method according to claim 1, characterized in that: in step (1), the temperature of the reaction is 0-200°C. 6. The method according to claim 1 or 2, characterized in that: the cyanoacetate is methyl cyanoacetate or ethyl cyanoacetate or n-propyl cyanoacetate or n-butyl cyanoacetate Or n-pentyl cyanoacetate or n-octyl cyanoacetate or dodecyl cyanoacetate or octadecyl cyanoacetate. 7. The method according to claim 1 or 2, characterized in that: the type of the ionic liquid is imidazoles or pyridines or quaternary phosphoniums or pyrrolidines or piperidines. 8. The method according to claim 1 or 2, characterized in that: the substituted aminoacrolein is 3-dimethylaminoacrolein or 3-diethylaminoacrolein or N-methyl-N-benzyl- 3-aminoacrolein or N-methyl-N-hexyl-3-aminoacrolein or N-methyl-N-isooctyl-3-aminoacrolein or N-methyl-N-n-octyl-3 - aminoacrolein or N-methyl-N-dodecyl-3-aminoacrolein or N-dodecyl-3-aminoacrolein or N-octadecyl-3-aminoacrolein. 9. the method as claimed in claim 1 or 2 is characterized in that: described organic solvent is methylene dichloride or 1,2-dichloroethane or chloroform or carbon tetrachloride or benzene or toluene or chlorobenzene or Methyl acetate or ethyl acetate or propyl acetate or butyl acetate or diethyl ether or petroleum ether. 10. The method according to claim 1, characterized in that: the lye is sodium hydroxide solution or potassium hydroxide solution or potassium carbonate solution or sodium carbonate solution or potassium bicarbonate solution or sodium bicarbonate solution or ammoniacal liquor.