阅读说明：本技术 一种3,4-二甲基吡唑-5-甲酸酯类化合物的制备方法 (Preparation method of 3, 4-dimethylpyrazole-5-formate compound ) 是由 胡向平 陈修帅 于 2019-11-21 设计创作，主要内容包括：本发明提供一种3,4-二甲基吡唑-5-甲酸酯类化合物的制备方法。该方法以2-丁酮与草酸二酯为原料,在有机环状仲胺催化剂催化下高收率、高区域选择性地制备3-甲基乙酰丙酮酸酯化合物,3-甲基乙酰丙酮酸酯化合物再与肼反应,高收率制备3,4-二甲基吡唑-5-甲酸酯类化合物。该制备方法以吡咯啉、哌啶、吗啡啉等有机含氮环状仲胺化合物为催化剂,以甲醇、乙醇等醇类为溶剂进行反应。本发明具有反应条件相对温和、操作简便、区域选择性高、收率高等特点,合成的3,4-二甲基吡唑-5-甲酸酯类化合物可用于制备腈吡螨酯类杀螨剂。(The invention provides a preparation method of 3, 4-dimethylpyrazole-5-formate compounds. The method takes 2-butanone and oxalic acid diester as raw materials, prepares a 3-methyl acetyl pyruvate ester compound with high yield and high regioselectivity under the catalysis of an organic cyclic secondary amine catalyst, and then reacts the 3-methyl acetyl pyruvate ester compound with hydrazine to prepare the 3, 4-dimethyl pyrazole-5-formate compound with high yield. The preparation method takes organic nitrogenous cyclic secondary amine compounds such as pyrroline, piperidine and morpholine as catalysts and alcohols such as methanol and ethanol as solvents for reaction. The method has the characteristics of relatively mild reaction conditions, simple and convenient operation, high regioselectivity, high yield and the like, and the synthesized 3, 4-dimethylpyrazole-5-formic ester compound can be used for preparing the cyenopyrafen acaricide.)

1. a preparation method of 3, 4-dimethylpyrazole-5-formate compounds is characterized by comprising the following steps: the method comprises the steps of catalyzing high-regioselectivity reaction between 2-butanone and oxalic acid diester by using an organic cyclic secondary amine catalyst to prepare a 3-methyl acetylacetonate compound, carrying out condensation cyclization reaction on 3-methyl acetylacetonate and hydrazine, and preparing the 3, 4-dimethylpyrazole-5-formate compound with high yield.

2. The method for producing a 3, 4-dimethylpyrazole-5-carboxylic acid ester compound according to claim 1, wherein: the method comprises the following specific steps:

(1) dissolving 2-butanone and oxalic acid diester in an alcohol reaction medium to obtain a mixed solution, then adding an organic cyclic secondary amine catalyst into the mixed solution under the protection of nitrogen, and stirring and reacting at the reflux temperature for not less than 12 hours; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, washing with water, extracting with ethyl acetate, drying, and concentrating to obtain a crude product of 3-methylacetoacetate, wherein the crude product can be directly used for subsequent cyclization reaction without purification, and can also be used for subsequent cyclization reaction after reduced pressure distillation purification;

(2) dissolving a 3-methylacetylpyruvate ester compound in an alcohol reaction medium, keeping the reaction temperature at-10-0 ℃, dropwise adding hydrazine hydrate or hydrazine alcohol solution while stirring, keeping the temperature for reaction for 0.5-12 hours after dropwise adding, removing the solvent, and distilling the residue under reduced pressure to obtain a 3, 4-dimethylpyrazole-5-formate compound;

the molar ratio of the organic cyclic secondary amine catalyst to the 2-butanone in the step (1) is 0.001-1: 1;

the molar ratio of the 2-butanone to the oxalic acid diester compound is 0.1-10: 1;

the molar ratio of the 3-methyl acetylacetonate compound to hydrazine in the step (2) is 0.5-2: 1.

3. The method for producing a 3, 4-dimethylpyrazole-5-carboxylate compound according to claim 1 or 2, characterized in that:

the 3, 4-dimethylpyrazole-5-formate compound has the following structure:

in the formula: r¹、R²Is one or two of H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.

4. The method for producing a 3, 4-dimethylpyrazole-5-carboxylate compound according to claim 1 or 2, characterized in that:

the 3-methyl acetylacetonate compound II has the following structure:

in the formula: r¹Is one or two of H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.

5. The method for producing a 3, 4-dimethylpyrazole-5-carboxylate compound according to claim 1 or 2, characterized in that:

the oxalic acid diester III has the following structure:

in the formula: r¹Is one or two of H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.

6. The method for producing a 3, 4-dimethylpyrazole-5-carboxylate compound according to claim 1 or 2, characterized in that:

the 2-butanone IV has the following structure:

7. the method for producing a 3, 4-dimethylpyrazole-5-carboxylate compound according to claim 1 or 2, characterized in that:

the hydrazine V has the following structure:

in the formula: r²Is one or two of H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.

8. The method for producing a 3, 4-dimethylpyrazole-5-carboxylate compound according to claim 1 or 2, characterized in that:

the organic cyclic secondary amine catalyst Cat has the following structural characteristics:

in the formula: x is a C-C single bond, O, NR³、S、CH₂、CH₂CH₂Etc. wherein R³Is H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl.

9. The method for producing a 3, 4-dimethylpyrazole-5-carboxylic acid ester compound according to claim 2, wherein:

the reaction medium is alcohol protonic solvent such as methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol, etc.

10. Use of 3, 4-dimethylpyrazole-5-carboxylic acid esters prepared by a process as claimed in any one of claims 1 to 9, wherein: the prepared 3, 4-dimethylpyrazole-5-formate compound can be used for synthesizing the cyenopyrafen acaricide.

Technical Field

The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of a 3, 4-dimethylpyrazole-5-formate compound.

Background

The efficient, highly selective construction of heterocyclic compounds is one of the leading and challenging areas of organic synthetic chemistry research. 3, 4-dimethylpyrazole-5-formate compounds are used as important heterocyclic compounds and have wide application in synthesis of pesticides, medicines, materials and the like, particularly 3, 4-dimethylpyrazole-5-ethyl formate or 1,3, 4-trimethylpyrazole-5-ethyl formate is a raw material for synthesizing novel acaricide cyenopyrafen, so that the synthesis of the acaricide cyenopyrafen is widely concerned. The traditional method for preparing 1,3, 4-trimethylpyrazole-5-ethyl formate uses acetone and diethyl oxalate as raw materials, and needs 5 steps of reactions such as Claisen condensation, cyclization with hydrazine hydrate, N-methylation preparation, 4-site chloromethylation, Pd/C dechlorination and the like [ (a) D.Huang, M.Huang, A.Liu, X.Liu, W.Liu, X.Chen, H.Xue, J.Sun, D.Yin, X.Wang, Design, Synthesis, and acrylic Activities of Novel Pyrazole acrylic acid triene Compounds contents.J.heterocyclic Chem.2017,54,1121; (b) kamal, a.b.sharp, s.polepalli, v.s.reddy, g.b.kumar, s.gupta, k.v.s.r.krishna, a.nagab hushana, r.k.mishra, n.jain, Pyrazole-oxydazo conjugates: synthesis, antipollogenic activity and inhibition of tubulin.org.biomol.chem.2014,12,7993; (c) chen xiaoyang, liu xing ping, li modest, cao lidan, gaodera, liu folk, xun, lieepin, nitrile pyrantel and its isomer synthesis and bioactivity research, fine chemical intermediates 2014,44, 17. The preparation method has the advantages of multiple reaction steps, complex operation and high production cost, and limits the large-scale application of the preparation method in industrial production.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a method for preparing a 3-methyl acetyl acetonate compound by catalyzing 2-butanone and oxalic acid diester to react by an organic cyclic secondary amine catalyst in a high regioselectivity manner, and then performing a condensation cyclization reaction with hydrazine to prepare the 3, 4-dimethyl pyrazole-5-formate compound in a high yield. The method adopts organic cyclic secondary amine as a catalyst, takes 2-butanone, oxalic acid diester and hydrazine as reaction raw materials, and prepares the 3, 4-dimethylpyrazole-5-formate compound through two-step reaction under mild conditions with high yield and high regioselectivity, thereby providing a new synthetic route with simple operation, high yield and high regioselectivity for the 3, 4-dimethylpyrazole-5-formate compound, in particular for the 1,3, 4-trimethylpyrazole-5-formate compound, and having industrial application prospect. The reaction is carried out in an alcohol solvent such as methanol or ethanol using a commercially available, inexpensive, organic cyclic secondary amine as a catalyst.

The method comprises the following specific steps:

(1) dissolving 2-butanone and oxalic acid diester in an alcohol reaction medium to obtain a mixed solution, then adding an organic cyclic secondary amine catalyst into the mixed solution under the protection of nitrogen, and stirring and reacting at the reflux temperature for not less than 12 hours; after the reaction is finished, concentrating under reduced pressure until no solvent exists basically, washing with water, extracting with ethyl acetate, drying, and concentrating to obtain a crude product of 3-methylacetoacetate, wherein the crude product can be directly used for subsequent cyclization reaction without purification, and can also be used for subsequent cyclization reaction after reduced pressure distillation purification;

(2) dissolving a 3-methylacetylpyruvate ester compound in an alcohol reaction medium, keeping the reaction temperature at-10-0 ℃, dropwise adding hydrazine hydrate or hydrazine alcohol solution while stirring, keeping the temperature for reaction for 0.5-12 hours after dropwise adding, removing the solvent, and distilling the residue under reduced pressure to obtain the 3, 4-dimethylpyrazole-5-formate compound.

The 3, 4-dimethylpyrazole-5-formate compound I has the following structure:

in the formula: r¹、R²Is one or two of H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; the substituents on the C3-C12 naphthenic base, the substituents on the phenyl and the substituents on the benzyl are one or more than two of C1-C40 alkyl, C1-C40 alkoxy, halogen, nitro, ester group or cyano.

The 3-methyl acetylacetonate compound II has the following structure:

in the formula: r¹And R in the above formula I¹Are equivalent groups.

The oxalic acid diester III has the following structure:

in the formula: r¹And R in the above formula I¹Are equivalent groups.

The 2-butanone IV has the following structure:

the hydrazine V has the following structure:

in the formula: r²And R in the above formula I²Are equivalent groups.

The organic cyclic secondary amine catalyst has the following structural characteristics:

in the formula: x is a C-C single bond, O, NR³、S、CH₂、CH₂CH₂Etc. of the foregoing R³Is H, C1-C40 alkyl, C3-C12 cycloalkyl, substituted C3-C12 cycloalkyl, phenyl, substituted phenyl, benzyl and substituted benzyl; the organocyclic secondary amine catalyst is preferably of the structure:

the reaction medium is one or more of methanol, ethanol, isopropanol, n-propanol, n-butanol, tert-butanol and other alcoholic protic solvents; methanol and ethanol are preferred.

The catalytic reaction conditions in the step (1) are preferably as follows: the temperature is the reflux temperature of the reaction medium; the reaction medium is ethanol; the pressure is normal pressure; the time period required was 24 hours.

The molar ratio of the organic cyclic secondary amine catalyst to the 2-butanone in the step (1) is 0.001-1: 1;

the molar ratio of the 2-butanone to the oxalic acid diester compound in the step (1) is 0.1-10: 1;

the molar ratio of the 3-methyl acetylacetonate compound to hydrazine in the step (2) is 0.5-2: 1;

the reaction conditions in the step (2) are preferably as follows: the temperature is-5 ℃; the dropping time is 1 hour; the pressure is normal pressure; the time period required was 2 hours.

The reaction equation of the invention is as follows:

the prepared 3, 4-dimethylpyrazole-5-formate compound can be used for synthesizing the cyenopyrafen acaricide.

The invention has the following advantages:

1. the initial raw materials are cheap and easy to obtain, the reaction steps are short, and the operation is simple and convenient;

2. the catalyst is cheap and easy to obtain, and the using amount is small;

3. the reaction activity is good, the regioselectivity is high, and the reaction condition is easy to realize;

4. the substrate has wide application range, can carry out cycloaddition reaction on various hydrazine compounds and obtain ideal effect.

5. The invention can provide a new synthesis route with simple operation, high yield and high regioselectivity for 3, 4-dimethylpyrazole-5-formate compounds.

Drawings

In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.

FIG. 1 is a NMR spectrum of ethyl 3, 4-dimethylpyrazole-5-carboxylate compound I-1 prepared in example 1;

FIG. 2 is a NMR spectrum of methyl 3, 4-dimethylpyrazole-5-carboxylate compound I-2 prepared in example 4;

FIG. 3 is a NMR spectrum of ethyl 1,3, 4-trimethylpyrazole-5-carboxylate compound I-3 prepared in example 5.

FIG. 4 is a NMR spectrum of methyl 1,3, 4-trimethylpyrazole-5-carboxylate compound I-4 prepared in example 6.

Detailed Description

The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker 400 NMR.

Example 1

Diethyl oxalate and hydrazine hydrate are used as raw materials to prepare the 3, 4-dimethylpyrazole-5-ethyl formate compound I-1.

0.21g (3mmol) pyrroline Cat-1 and 50mL ethanol are added into a 100mL three-neck flask equipped with a thermometer, a magnetic stirring device and a constant pressure dropping funnel, a mixed solution of 2.16g (30mmol) 2-butanone IV and 4.6g (32mol) diethyl oxalate III-1 is dropped into the flask from the constant pressure dropping funnel within 1.0 hour at room temperature, after the dropping is finished, the reaction solution is heated to a reflux state, and the reaction is continued for 12 hours. Removing volatile components, extracting with ethyl acetate (50mL multiplied by 2), washing with water for 2 times, drying with anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of 3-methyl ethyl acetoacetate II-1, which is directly used for the next synthesis without purification.

In a 100mL three-necked flask equipped with a thermometer, magnetic stirring and a constant pressure dropping funnel, 5.16g (30mmol) of the crude product of ethyl 3-methylacetoacetate II-1 is dissolved in 50mL of ethanol, 2.35g (37.5mmol) of 80% hydrazine hydrate V-1 is dropwise added within 1.5h at the temperature of-5 ℃, and after the dropwise addition is finished, the reaction is continued for 1h under heat preservation. Vacuum desolventizing, extracting with ethyl acetate (250 mL. times.2), washing with water for 2 times, drying with anhydrous sodium sulfate, desolventizing, and vacuum distilling and purifying the residue to obtain 4.60g of 3, 4-dimethylpyrazole-5-methyl formate with a yield of 91%. The NMR spectrum of product I-is shown in FIG. 1:¹H NMR(400MHz,CDCl₃)δ1.38(t,J＝7.1Hz,3H),2.24(s,3H),2.30(s,3H),4.35-4.40(q,J＝7.2Hz,2H).

the structural formulas of Cat-1, III-1, IV and V-1 are as follows:

example 2

The organic catalyst Cat-1 in example 1 was replaced with piperidine Cat-2, and the procedure was otherwise the same as in example 1. The reaction gave compound I-1 in 78% yield.

The structural formula of Cat-2 is as follows:

example 3

The organic catalyst Cat-1 of example 1 was replaced with morpholine Cat-3, and the procedure of example 1 was repeated. Compound I-1 was obtained in 85% yield.

The structural formula of Cat-3 is as follows:

example 4

The same procedures used in example 1 were repeated except for using dimethyl oxalate III-2 instead of diethyl oxalate III-1 used in example 1 to give methyl 3, 4-dimethylpyrazole-5-carboxylate compound I-2 in a yield of 84%. The NMR spectrum of product IV-2 is shown in FIG. 2:¹H NMR(400MHz,CDCl₃)δ2.22(s,3H),2.25(s,3H),3.90(s,3H).

the structural formula of III-2 and I-2 is as follows:

example 5

The hydrazine hydrate V-1 in example 1 was replaced with N-methylhydrazine V-2, and the same procedure as in example 1 was repeated to give ethyl 1,3, 4-trimethylpyrazole-5-carboxylate compound I-3 in 89% yield. The NMR spectrum of product I-3 is shown in FIG. 3:¹H NMR(400MHz,CDCl₃)δ1.39(t,J＝7.2Hz,3H),2.18(s,3H),2.19(s,3H),4.07(s,3H),4.33-4.38(q,J＝7.2Hz,2H).

the structural formulas of I-3 and V-2 are as follows:

example 6

The hydrazine hydrate V-1 in example 1 was replaced with N-methylhydrazine V-2, and diethyl oxalate III-1 was replaced with dimethyl oxalate III-2, and the same procedure as in example 1 was repeated to give methyl 1,3, 4-trimethylpyrazole-5-carboxylate compound I-4 in 91% yield. The NMR spectrum of product I-4 is shown in FIG. 4:¹H NMR(400MHz,CDCl₃)δ1.39(t,J＝7.2Hz,3H),2.18(s,3H),2.19(s,3H),4.07(s,3H),4.33-4.38(q,J＝7.2Hz,2H).

the structural formulas of I-4, III-2 and V-2 are as follows: