BR112018013249B1 - Method of preparation of pyridyl pyrazolidinone carboxylate compounds - Google Patents

Abstract

This invention relates to the field of organic synthesis and specifically relates to the method of preparing pyridyl pyrazolidinone carboxylate compounds. The reaction scheme is as follows; where the groups are defined in the description. The invention provides a method for the preparation of pyridinylpyrinone carboxylate compounds as key intermediates of phenylcarboxamide insecticides. The method of the invention improves product yield, reduces energy consumption and is more convenient for industrial production.

Description

FIELD OF INVENTION

[0001] This invention belongs to the field of organic synthesis and specifically relates to the method of preparing pyridyl pyrazolidinone carboxylate compounds.

BACKGROUND OF THE INVENTION

Ciclaniliprole Tetraclorantraliniprole[0002] Phenylcarboxamides are a kind of new insecticides with high efficacy and safety. 3-Bromo-N-(4-chloro-2-methyl-6-(methylcarbamoyl)phenyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide is highly effective against insects and is marketed by DuPont and generic name of chlorantraniliprole; 3-bromo-1-(3-chloropyridin-2-yl)-N-(4-cyano-2-methyl-6-(methylcarbamoyl)phenyl)-1H-pyrazole-5-carboxamide is also highly effective against insects, the its generic name being cyantraniliprole. 3-Bromo-N-(4-chloro-2-methyl-6-(1-cyclopropylethyl)carbamoyl)phenyl)-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide under development shows a broad-spectrum insecticidal activity, which is marketed by Ishihara. 3-Bromo-N-(2,4-dichloro-6-(methylcarbamoyl)phenyl)-1-(3,5-chloro-2-pyridyl)-1H-pyrazole-5-carboxamide is highly effective against insects, being commercialized by the Shenyang Research Institute of Chemical Industry.

Cyclaniliprole Tetrachloranthraliniprole

[0003] Ethyl 1-(3-Chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate is a key intermediate in the synthesis of chlorantraniliprole, cyantraniliprole, cyclaniliprole. WO2004011453 discloses that 3-chloro-2-hydrazinylpyridine reacts with diester maleate to provide 1-(3-chloropyridin-2-yl)-3-pyrazolidinone-5-carboxylate in 55% yield.

[0004] Fengbo Xu of NanKai University describes the use of anthracycline diamine complex as a catalyst for the synthesis of 1-(3-chloropyridin-2-yl)-3-pyrazolidinone-5-carboxylate in 70% yield ( reference: Research and Application of Pesticide 14 (2), 14-15, 2009 ). The structure of the anthracycline diamine complex is as follows:

[0005] Researchers continually strive to research and develop new, more advanced, more favorable, and safer for the environment to prepare pyridyl pyrazinone carboxylate compounds so as to manufacture the highly effective and safe phenylcarboxamide insecticides with higher quality and lower cost.

SUMMARY OF THE INVENTION

[0006] The object of this invention is to provide a new method for the preparation of pyridylpyrinone carboxylate compounds, which is more concise and safer for the environment.

[0007] In order to achieve the above objective, the technical embodiments of this invention are as follows:

em que: R1 é H ou Cl; R2 é alquila C1-C6, alquenila C2-C4, alquinila C2-C4, cicloalquila C3-C6 halogenada, ou grupo benzila não substituído ou substituído de menos de 6 grupos alquila C1-C4;[0008] Method for the preparation of pyridyl pyrazinone carboxylate compounds as represented by formula (I), the reaction scheme being as follows:

wherein: R1 is H or Cl; R2 is C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogenated C3-C6 cycloalkyl, or unsubstituted benzyl group or substituted with less than 6 C1-C4 alkyl groups;

[0009] Pyridyl pyrazolidinone (I) carboxylate compounds were synthesized by reacting diester maleate (III) with hydrazopyridine (II) in the presence of a catalyst base.

em que L2 é selecionado do que se segue:

em que o catalisador é selecionado de Cu (L1) Br, Cu (L1) I, Cu (L2)2 Br Cu (L2)2I: em que L1 é selecionado do que se segue:

em que L2 é selecionado do que se segue:

em que o catalisador é selecionado de Cu (L1)I ou Cu (L2)2 I; em que L1 é selecionado do que se segue:

em que L2 é selecionado do que se segue:

[0010] Wherein the catalyst is selected from Cu (L1)Cl, Cu (L1) Br, Cu (L1) I, Cu (L2)2 Cl, Cu (L2)2 Br, Cu (L2)2 I, Ni (L1) Cl2 , Ni (L1 ) Br2 , Ni (L1 ) I2 , Ni (L2 )2 Cl2 , Ni (L2 )2 Br2 or Ni (L2 )2 I2 ; Where L1 is selected from the following:

where L2 is selected from the following:

wherein the catalyst is selected from Cu(L1)Br, Cu(L1)I, Cu(L2)2Br Cu(L2)2I: wherein L1 is selected from the following:

where L2 is selected from the following:

wherein the catalyst is selected from Cu(L1)I or Cu(L2)2I; where L1 is selected from the following:

where L2 is selected from the following:

[0011] Pyridyl pyrazolidinone (I) carboxylate compounds were synthesized by reacting diester maleate (III) with hydrazopyridine (II) in the presence of a catalyst base.

[0012] The molar ratio of hydrazopyridine (II), base, diester maleate (III), to catalyst is 1: 1-2: 1-5: 0.00001-0.01o

[0013] The molar ratio of hydrazopyridine (II), base, diester maleate (III), to catalyst is 1: 1.2-1.5: 1.5-2: 0.0001-0.001.

[0014] Pyridyl pyrazolidinone (I) carboxylate compounds were synthesized by reacting diester maleate (III) with hydrazopyridine (II) in the presence of a base with catalyst at temperatures between 20 and 50°C.

[0015] Pyridyl pyrazolidinone (I) carboxylate compounds were synthesized by reacting diester maleate (III) with hydrazopyridine (II) in the presence of a base and a solvent with catalyst.

[0016] The solvent is selected from toluene, chlorobenzene, carboxylic ether, alkyl alcohol, ether or other polar aprotic solvent.

[0017] The base is selected from alkali metal hydride, alkali metal ammonia or alkoxide salts.

[0018] The alkali metal hydride is selected from LiH, NaH or KH.

[0019] The alkali metal ammonium salt is selected from LiNH2, NaNH2 or KNH2.

[0020] The metal alkoxide salts are selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium pentoxide, sodium isopropoxy, sodium isobutoxide, sodium sec-butoxide, sodium t-butoxide sodium, potassium methoxide, potassium ethoxide, potassium propoxide or potassium t-butoxide. The carboxylic ester is selected from acetate, fumarate ester or maleate ester. The alkyl alcohol is selected from methanol, ethanol, propanol, butanol, amyl alcohol, isopropanol, iso-butanol, sec-butyl alcohol or t-butyl alcohol. The ether is selected from tetrahydrofuran, 2-methyl-tetrahydrofuran or dioxane. The polar aprotic solvent is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide.

[0021] The base is selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium pentoxide, sodium isopropoxide, sodium isobutoxide, sodium sec-butoxide, sodium t-butoxide.

[0022] The appropriate solvent is selected from methanol, ethanol, propanol, butanol, amyl alcohol, isopropanol, isobutanol, sec-butyl alcohol or t-butyl alcohol.

[0023] The base is selected from sodium methoxide, sodium ethoxide. The preferred solvent is selected from ethanol.

[0024] In the above definitions of compounds of the formula, the term "alkyl" denotes straight or branched alkyl such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl , n-pentyl, i-pentyl, n-hexyl, etc. "Cycloalkyl" denotes ring of bond form, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl and cyclopropylcyclopropyl, etc. "Alkenyl" denotes linear or branched alkenyl such as 1-propenyl, 2-propenyl and different isomers of butenyl, pentenyl and hexenyl. "Alkenyl" also includes polyene, such as 1,2-propidienyl and 2,4-hexadiene. "Halogen" includes fluorine, chlorine, bromine and iodine.

[0025] The invention adopts non-nitrogenated phenylphosphine compounds as catalyst in the synthesis of pyridyl pyrazolidinones carboxylic ester, which can greatly improve the yield, thus completing the invention. The reaction temperature of the invention can be carried out at 20-50°C. The temperature is easy to control and the safety of the reaction is greatly improved. The catalyst of the invention is easy to synthesize and low in price and can be prepared just by reacting the metal salt and phenylphosphine in ethanol. Therefore, the catalyst of the invention is easier to apply in industrial production.

EXAMPLES

[0026] The following preparation examples are used to further illustrate the method for preparing the pyridyl pyrazinone carboxylate compounds provided in the present invention, but not to limit it. EXAMPLE 1: Synthesis of Ethyl 1-(3-Chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate

[0027] To a 2000 mL flask was added 1000 mL of anhydrous ethanol, sodium ethoxide (65.7 g, 0.966 mol), 3-chloro-2-hydrazinylpyridine (101.04 g, 98%, 0.69 mol) and Cu(PPh3)2I catalyst (0.15 g, 0.00021 mol. The reaction mixture was heated to 40°C. Diethyl maleate (145.7 g, 0.83 mol) was added dropwise. After maintaining the temperature at 40°C for 4 h, the reaction mixture was neutralized with glacial acetic acid (60 g) and diluted with 1000 mL of water. The mixture was cooled to room temperature and the precipitate formed. The solid was isolated by filtration, washed with 40% aqueous ethanol solution (3 x 150 mL) and dried to provide the product ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate ( 149.91 g) as an orange solid in 79% yield, 98% quantitative analysis content. 1H NMR (300 MHz, DMSO): 8.289-8.269 (q, 1H), 7.956-7.190 (q, 1H) , 7.231-7.190 (q, 1H), 4.862-4.816 (q, 1H), 4.236-4.165 (q, 2H), 2.967-2.879 (q , 1H), 2.396-2.336 (q, 1H), 1.250-1.202 (t, 3H).

[0028] The catalyst synthesis method is as follows:

[0029] To a 2000 mL flask, 1000 mL of anhydrous ethanol, triphenylphosphine (500 g, 1.9 mol) and CuI (181 g, 0.95 mol) were added. The reaction mixture was heated at 80°C for 1 h. The mixture was cooled to room temperature and the precipitate formed. The solid was isolated by filtration and dried to give the product (644.9 g) in 95% yield.

[0030] The following other catalysts can be prepared in this way by selecting suitable raw materials. EXAMPLE 2: Synthesis of ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate

[0031] To a 1000 mL flask was added 300 mL of anhydrous ethanol, sodium ethoxide (16.97 g, 0.249 mol), 3-chloro-2-hydrazinylpyridine (30.75 g, 98%, 0.21 mol ) and Cu(binap)I catalyst (0.017 g, 0.00021mol). The reaction mixture was heated to 30°C. Diethyl maleate (44.23 g, 0.252 mol) was added dropwise. After maintaining the temperature at 30°C for 4 h, the reaction mixture was neutralized with glacial acetic acid (15 g) and diluted with 300 mL of water. The mixture was cooled to room temperature and a precipitate formed. The solid was isolated by filtration, washed with 40% aqueous ethanol solution (3 x 50 mL) and dried to give the product ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate ( 47.06 g) as an orange solid in 79% yield, the quantitative analysis content was 95%. EXAMPLE 3: Synthesis of ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate

[0032] To a 1000 mL flask was added 300 mL of anhydrous ethanol, sodium ethoxide (16.97 g, 0.249 mol), 3-chloro-2-hydrazinylpyridine (30.75 g, 98%, 0.21 mol) and Cu catalyst (PPhaHBr (0.042 g, 0.000063 mol (Cu Reference (PPh3)2Br. The reaction mixture was heated to 35°C. Diethyl maleate (44.23 g, 0.252 mol) dropwise. After maintaining the temperature at 35°C for 4 hours, the reaction mixture was neutralized with glacial acetic acid (15 g) and diluted with 300 mL of water. The mixture was cooled to room temperature. The solid was isolated by filtration, washed with 40% aqueous ethanol (3 x 50 mL) and dried to give the product 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone Ethyl-5-carboxylate (45.98 g) as an orange solid in 78% yield, quantitative analysis content was 96%.EXAMPLE 4: Synthesis of 1-(3-chloro-2-pyridinyl)-3 -pyrazolidinone-5-ethyl carboxylate

[0033] To a 1000 mL flask were added 300 mL anhydrous ethanol, sodium ethoxide (16.97 g, 0.249 mol), 3-chloro-2-hydrazinylpyridine (30.75 g, 98%, 0.21 mol ) and Ni(PPh3)2Br2 catalyst (0.047 g, 0.000063mol) (Ni PPh3)2Br2 reference: Appl. Organometal. Chem., 23, 455-459, 2009). The reaction mixture was heated to 45°C. Diethyl maleate (44.23 g, 0.252 mol) was added dropwise. After maintaining the temperature at 45°C for 4 hours, the reaction mixture was neutralized with glacial acetic acid (15 g) and diluted with 300 ml of water. The mixture was cooled to room temperature and the precipitate formed. The solid was isolated by filtration, washed with 40% aqueous ethanol solution (3 x 50 mL) and dried to provide the product ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate ( 45.98 g) as an orange solid in 78% yield, the quantitative analysis content was 96%.

[0034] According to the method in example 1, Cu(PPh3)2I as the catalyst, 1-(3,5-dichloro-2-pyridinyl)-ethyl 3-pyrazolidinone-5-carboxylate was synthesized in high yields . 1H NMR (300 MHz, CDCl3): 8.146 (q, 1H), 7.658 (q, 1H), 5.073 (dd, 1H), 4.241 (q, 2H), 3.029 (dd, 1H), 2.721 (dd, 1H) , 1.258 (t, 3H). EXAMPLE 5: Synthesis of ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate

(3-cloropiridin-2-il)-3-hidróxi-1H-pirazol-5- carboxilato foi sintetizado de acordo com o método público da Nankai University (referência: Research and Application of Pesticide. 14(2), 14-15, 2009). Foram adicionados a um frasco de 1.000 mL, 300 mL de etanol anidro, etóxido de sódio (5,22 g, 0,227 mol), 3-cloro-2-hidrazinilpiridina (30 g, 0,205 mol) e adicionou-se o catalisador gota a gota. Adicionou-se maleato de dietila (44,23 g, 0,252 mol) gota a gota. Depois de manter o refluxo durante 30 min., a mistura reacional foi resfriada a 65 e neutralizada com ácido acético glacial (25,2 g) e diluída com 300 mL de água. A mistura foi resfriada até à temperatura ambiente e o precipitado foi formado. O sólido foi isolado por filtração, lavado com solução aquosa a 40% de etanol (3 x 50 mL) e seco para fornecer o produto 1- (3-cloro-2- piridinil)-3-pirazolidinona-5-carboxilato de etila (45,2 g), como um sólido laranja. O teor do método de normalização por área de HPLC é de 96% e o teor de análise quantitativa é de 85,4 %%, em 70% de rendimento.[0035] To a 1000 L reaction flask were added 600 L of anhydrous ethanol, sodium ethoxide (34.6 kg, 500 mol), 3-chloro-2-hydrazinylpyridine (61.5 kg, 98%, 420 mol ) and the catalyst Cu(PPh3)2 I (90 g). The reaction mixture was heated to 35°C. Diethyl maleate (88.4 kg, 500 mol) was added dropwise. After maintaining the temperature at 35 °C for 4 h, the reaction mixture was neutralized with glacial acetic acid (20 kg) and diluted with 300 L of water. The mixture was cooled to room temperature and the precipitate formed. The solid was isolated by filtration, washed with 40% aqueous ethanol solution (100 L) and dried to give the product ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate (92 kg ) as an orange solid in 78% yield, the quantitative analysis content being 96%. EXAMPLE FOR COMPARISON

(3-chloropyridin-2-yl)-3-hydroxy-1H-pyrazol-5-carboxylate was synthesized according to the public method of Nankai University (reference: Research and Application of Pesticide. 14(2), 14-15, 2009). To a 1000 mL flask was added 300 mL of anhydrous ethanol, sodium ethoxide (5.22 g, 0.227 mol), 3-chloro-2-hydrazinylpyridine (30 g, 0.205 mol) and the catalyst was added dropwise. drop. Diethyl maleate (44.23 g, 0.252 mol) was added dropwise. After refluxing for 30 min., the reaction mixture was cooled to 65°C and neutralized with glacial acetic acid (25.2 g) and diluted with 300 mL of water. The mixture was cooled to room temperature and a precipitate formed. The solid was isolated by filtration, washed with 40% aqueous ethanol solution (3 x 50 mL) and dried to give the product ethyl 1-(3-chloro-2-pyridinyl)-3-pyrazolidinone-5-carboxylate ( 45.2 g) as an orange solid. The HPLC area normalization method content is 96% and the quantitative analysis content is 85.4%%, in 70% yield.

[0036] As can be seen from the above examples and comparison examples, the invention adopts a simple, inexpensive and readily available nitrogen-free phenyl phosphine compound as a catalyst, pyridyl pyrazolidinone carboxylate compounds can be synthesized in high yields. The method was applied in the industrial expansion production process. After using the catalyst of the invention, the reaction can be carried out at a lower temperature, thus reducing production energy consumption and greatly improving reaction safety, which plays an important role in reducing production cost and improving the safety of the reaction in the production process. APPLICATION EXAMPLE

[0037] According to the above reaction formula, 3-bromo-1-pyridyl pyrazole-5-carboxylic acid was prepared by bromination and hydrolyzed from 1-(pyridin-2-yl)-3-hydroxy-1H ethyl -pyrazole-5-carboxylate. Pyrazolyl chloride was prepared by the above pyrazole carboxylic acid after acylation and oxidation. Pyrazolyl chloride and 2-amino-5-chloro-N,3-dimethylbenzamide were subjected to condensation reaction to provide chlorantraniliprole in a 56.7% yield (the yield calculated by 1-(3-chloro-2-pyridinyl) -3-pyrazolidinone-5-ethyl carboxylate.

Claims (5)

1. Method for the preparation of pyridyl pyrazolidinone carboxylate compounds as represented by formula (I), characterized in that the reaction scheme is:

wherein: R1 is H or Cl; R2 is C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halogenated C3-C6 cycloalkyl, or benzyl group substituted by less than 6 C1-C4 alkyl groups; pyridyl pyrazolidinone carboxylate compounds (I) were synthesized by reacting diester maleate (III) with hydrazopyridine (II) in the presence of a base with catalyst; wherein the molar ratio of hydrazopyridine (II), base, diester maleate (III), to catalyst is 1: 1-2:15:0.00001-0.01; wherein the catalyst is selected from Cu(L1)Cl, Cu(L1)Br, Cu(L1)I, Cu(L2)2Cl, Cu(L2)2Br, Cu(L2)2I, Ni(L1)Cl2, Ni (L1)Br2, Ni(L1)I2, Ni(L2)2Cl2, Ni(L2)2Br2 or Ni(L2)2I2 ; where L1 is selected from the following:

where L2 is selected from the following:

the appropriate solvent is selected from toluene, chlorobenzene, carboxylic esters, alkyl alcohols, ethers or polar aprotic solvents; the base is selected from alkali metal hydrides, alkali metal ammonia or alkoxide salts; alkali metal hydrides are selected from LiH, NaH or KH; the alkali metal ammonium salts are selected from LiNH2, NaNH2 or KNH2; the metal alkoxide salts are selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium pentoxide, sodium isopropoxy, sodium isobutoxide, sodium sec-butoxide, sodium t-butoxide, methoxide potassium, potassium ethoxide, potassium propoxide or potassium t-butoxide; the carboxylic esters are selected from acetates, fumarate diesters or maleate diesters; alkyl alcohols are selected from methanol, ethanol, propanol, butanol, amyl alcohol, isopropanol, isobutanol, sec-butyl alcohol or t-butyl alcohol; the ethers are selected from tetrahydrofuran, 2-methyl-tetrahydrofuran or dioxane; the polar aprotic solvent is selected from acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or dimethylsulfoxide. 2. Method according to claim 1, characterized in that the pyridyl pyrazolidinone carboxylate compounds (I) were synthesized by the reaction of diester maleate (III) with hydrazopyridine (II) in the presence of a base with catalyst in temperatures between 20 and 50°C; the molar ratio of hydrazopyridine (II), base, diester maleate (III), to catalyst is 1:1.21.5:1.5-2:0.0001-0.001. wherein the catalyst is selected from Cu(L1)Br, Cu(L1)I, Cu(L2)2Br or Cu(L2)2I: wherein L1 is selected from the following:

where L2 is selected from the following:

3. Method according to claim 2, characterized in that the catalyst is selected from Cu(L1)I or Cu(L2)2I; where L1 is selected from the following:

where L2 is selected from the following:

4. Method according to claim 1, characterized in that the base is selected from sodium methoxide, sodium ethoxide, sodium propoxide, sodium butoxide, sodium pentoxide, sodium isopropoxide, sodium isobutoxide, secbutoxide sodium, sodium t-butoxide; the appropriate solvent is selected from methanol, ethanol, propanol, butanol, amyl alcohol, isopropanol, isobutanol, secbutyl alcohol or t-butyl alcohol. 5. Method according to claim 4, characterized in that the base is selected from sodium methoxide, sodium ethoxide; the preferred solvent is selected from ethanol.