WO2016045415A1 - Method for asymmetrically catalyzed synthesis of nitropyrazole amide compound - Google Patents

Abstract

A method for asymmetrically catalyzed synthesis of a γ-nitropyrazole amide compound, where a nitroalkene and an α,β-unsaturated pyrazole amide are employed as raw materials, a complex formed by a chiral amine oxide and a rare earth metal compound serves as a catalyst, a 4 Å molecular sieve serves as an additive, and the γ-nitropyrazole amide compound is produced after a reaction, which has a yield as high as 99% and an enantiomeric excess as high as 99% ee. The catalytic system not only has the advantages of a simple operation, mild reaction conditions, not requiring any acidic/basic additive, convenient product purification, high yield and enatioselectivity, compliance with green atomic economy, and great prospects for industrial application, but also allows the γ-nitropyrazole amide compound produced via the reaction to undergo some simple chemical conversions to produce some molecules having physiological activities.

Description

Method for asymmetrically catalyzing synthesis of nitropyrazole amide compound

This application is submitted to the Chinese Patent Office on September 22, 2014, the application number is 201410486209.3, and the invention is entitled “A method for asymmetric catalytic synthesis of γ-nitropyrazole amide compounds”, which was submitted on February 12, 2015. Priority of the Chinese Patent Office, Application No. 201510075076.5, entitled "A Method for Asymmetric Catalytic Synthesis of γ-Nitropyrazolamide Compounds", the entire contents of which are incorporated herein by reference. .

Technical field

The invention relates to a method for synthesizing γ-nitropyrazole amide by asymmetric Michael addition reaction of α,β-unsaturated pyrazole amide with nitroalkane by chiral amine oxide-rare earth metal complex.

Background technique

The γ-nitropyrazole amide compound plays an important role in organic synthesis. It can not only undergo methyl esterification reaction with methanol under the catalysis of alkali, but also has simple operation, high synthesis efficiency, and can be converted into a simple chemical reaction. Biologically active compounds such as γ-amino acid, 2-pyridone, and 2-pyrrolidone. There have been some reports of asymmetric catalytic synthesis of γ-nitropyrazole amide.

Carlos F. Barbas III and others used the thiourea derivative XIV as a chiral catalyst and chloroform as a solvent to achieve the asymmetric Michael addition reaction of the following nitroene with pyrazole amide at -20 ° C. The product obtained 34%- 99% yield, dr value of 10:1->20:1 (dr value: diastereoselectivity of compounds containing two or more chiral centers) and ee value of 78%-97% (Angew. Chem. Int. Ed. 2012, 51, 5381).

Long Lu et al. used the thiourea derivative 2d as a chiral catalyst and toluene as a solvent to achieve asymmetric Michael addition reaction of the following nitroalkane with trifluoromethyl substituted pyrazole amide at room temperature. -91% yield, dr value of 4.4:1 - 9.9:1 (dr value: diastereoselectivity of compounds containing two or more chiral centers) and ee values of 80%-93% (ACS Catal .2013, 3, 502).

Shuji Kanemasa et al. used R, R-DBFOX/Ph _* Ni(ClO ₄ ) _2* 3H ₂ O(A) and 2,2,6,6-tetramethylpiperidine (TMP) as a combined catalyst, nitromethane and tetrahydrofuran (v/ v=1/1) is a mixed solvent, and the following asymmetric addition reaction of nitromethane to unsaturated pyrazole amide is achieved at -20 ° C to room temperature, and the product can obtain a yield of 39%-97% and 77. An ee value of %-97% (J. Am. Chem. Soc. 2002, 124, 13394).

In summary, in the catalytic reaction system of Carlos F. Barbas III, the reaction must be carried out at -20 ° C, which consumes a lot of energy; in the catalytic reaction system of Long Lu, the α,β-unsaturated amide extended substrate is The terminal has a trifluoromethyl substitution, and the restriction is relatively large; in the catalytic reaction system of Shuji Kanemasa, it needs to be activated at -78 °C before the reaction, and the reaction temperature of 11 substrates in the extended 16 substrates is -20. °C, 3 substrates need 0 °C, only two substrates can be reacted at room temperature, the reaction time of 11 substrates needs 96h, 6 substrates need 168h reaction time, and the yield is not Ideally, after the reaction is completed, the product is washed with saturated ammonium chloride and then separated and purified by column chromatography. The reaction conditions are harsh, the operation is complicated, and the amount of nitromethane is too large (0.1 mmol α, β-unsaturated pyrazole amide compound is needed) 9.1 mmol nitromethane), the most important thing is that the reaction results obtained are not good. Therefore, an efficient, simple operation, energy-saving and environmentally friendly approach needs to be developed.

Summary of the invention

The object of the present invention is to develop a Michael addition reaction of an asymmetrically catalyzed α,β-unsaturated pyrazole amide compound with a nitroalkane to provide an efficient, simple, energy-saving and environment-friendly synthetic γ-nitropyrazole. A method of an amide compound.

The invention provides a method for asymmetrically synthesizing a γ-nitropyrazole amide compound, characterized in that a nitroalkane and an α,β-unsaturated pyrazole amide are used as raw materials, and a chiral amine oxide and a rare earth metal are used. The complex formed by the compound is a catalyst,

The molecular sieve is an additive, and a chiral γ-nitropyrazole amide compound is obtained, wherein:

The structure of the nitroalkane is RCH ₂ NO ₂ , R=H, CH ₃ , Et, Bn;

The structure of the α,β-unsaturated pyrazole amide compound is:

R ¹ =C ₆ H ₅ ,4-FC ₆ H ₄ ,4-ClC ₆ H ₄ ,4-BrC ₆ H ₄ ,4-MeC ₆ H ₄ ,4-MeOC ₆ H ₄ ,3-BrC ₆ H ₄ , 3-MeC ₆ H ₄ ,2-BrC ₆ H ₄ ,2-MeOC ₆ H ₄ ,3,4–Cl ₂ C ₆ H ₃ ,3,4-(MeO) ₂ C ₆ H ₃ ,2-Furyl,2 -Thienyl, CH ₃ , Pr, Pent, ⁱ Bu, EtO, EtOOC; R ² =CH ₃ , Ph; R ³ =H, Cl, Br, I;

The γ-nitropyrazole amide compound has the following structure:

Wherein R, R ¹ , R ² , R ^{3 have} the same definitions as defined above.

The structure of the chiral amine oxide ligand is:

n=1,2; R=Ph-,2,6-Me ₂ C ₆ H ₃ -,2,6-Et ₂ C ₆ H ₃ -,2,6-iPr ₂ C ₆ H ₃ -,Ph ₂ CH -;

The reaction solvent is selected from the group consisting of alkanes such as pentane, hexane, heptane, etc.; halogenated hydrocarbons such as dichloroethane, chloroform, etc.; aromatic hydrocarbons such as toluene, ethylbenzene, cumene; ethers For example, tetrahydrofuran, methyl tert-butyl ether, 2-methyltetrahydrofuran, etc., esters such as ethyl acetate, isopropyl acetate and the like.

Preferably, the reaction temperature is 25-50 °C.

Preferably, the solution of the present invention is: a method for asymmetrically synthesizing a γ-nitropyrazole amide compound, characterized by using a nitroalkane and an α,β-unsaturated pyrazole amide as a raw material, a chiral amine oxide a complex formed with a rare earth metal compound is a catalyst,

The molecular sieve is an additive, dichloromethane is used as a solvent, and the reaction is carried out at 25-50 ° C under normal pressure for 12-120 h to obtain a chiral γ-nitropyrazole amide compound.

The above method was used to detect the end point of the reaction by TLC, and the chiral γ-nitropyrazole amide compound was isolated by silica gel column chromatography.

The rare earth metal compound is: bismuth triflate [Gd(OTf) ₃ ], bismuth triflate [Sc(OTf) ₃ ], bismuth triflate [Ho(OTf) ₃ ], trifluoromethyl Sulfonium sulfonate [Yb(OTf) ₃ ], ytterbium triflate [Er(OTf) ₃ ], yttrium triflate [Y(OTf) ₃ ];

The molar ratio of the nitroalkane to the α,β-unsaturated pyrazole amide compound is 1.86:1-55.8:1, and the optimum molar ratio is 9.3:1.

The most preferred catalyst for the reaction is a complex of chiral amine oxide L6 (n=2, R=2,6-iPr ₂ C ₆ H ₃ -) with ytterbium triflate [Gd(OTf) ₃ ], The molar ratio of chiral amine oxide to rare earth metal compound is 0.8:1.0-1.5:1.0, and the optimum molar ratio is 1.2:1.0;

The molecular sieve was activated at 450 ° C for 3 hours, corresponding to 0.1 mmol of α,β-unsaturated pyrazole amide.

The molecular sieve amount is 10-100 mg;

Dichloromethane was dried by refluxing with GaH ₂ , and the corresponding amount of 0.1 mmol of α,β-unsaturated pyrazole amide was 6.2 mmol;

The reaction temperature is 30 ° C;

The reaction time is 72-96 h.

Further, the γ-nitropyrazole amide compound prepared by the above method is reacted with methanol in the presence of an organic base to obtain an esterified product.

The esterification product has the following structure:

Wherein R, R ^{1 have} the same definitions as before.

The organic base is selected from the group consisting of triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, dimethylbenzylamine, diethylbenzylamine. 1,8-diazahetero[5,4,0]undecene-7 (DBU).

Compared with the background art, the present invention has the following outstanding advantages:

1. The operation is simple, the catalyst does not need to be activated, and the product is easily separated from the catalyst, the additive and the raw material.

2. The reaction conversion rate and enantioselectivity are high, the reaction yield is as high as 99%, and the enantioselectivity is as high as 99% ee.

3. The reaction system is simple and clean, and no acid or alkali additives are needed.

4. The reaction conditions are mild and the reaction is carried out at a normal pressure of 30 °C.

5. The amount of nitroalkane is small, saving raw materials.

detailed description

Example 1: Chiral amine oxide and rare earth metal complex catalyzed Michael addition reaction of asymmetric α,β-unsaturated pyrazole amide with nitroalkane

A rare earth metal compound (No. 1-11: 0.01 mmol, No. 12-16: 0.0075 mmol) and a chiral amine oxide ligand (No. 1-11: 0.012 mmol, serial number 12-16: 0.009 mmol) are added to the reaction vessel. α,β-unsaturated pyrazole amide 1a (0.1 mmol),

Molecular sieve 30mg, stirrer, after replacing nitrogen for 3 times, add dichloromethane (6.2mmol), nitromethane (No. 1-11: 5.6mmol, serial number 12-16: 0.93mmol), stir at 25-50 ° C for 12-120h . The reaction was monitored by TLC. The column was separated and purified, and the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IE, V _n-hexane : V _isopropanol = 90:10, flow rate: 1.0 mL/min), as shown in Table 1. The reactive and chiral amine oxide ligand structures are as follows:

Table 1. Optimization of asymmetric Michael addition conditions for asymmetric α,β-unsaturated pyrazole amide and nitromethane catalyzed by chiral amine oxides and rare earth metal complexes (n.d.: undetected)

Example 2: Chiral amine oxide L6-Gd(OTf) ₃ complex catalyzes the Michael addition reaction of asymmetric α,β-unsaturated pyrazole amide with nitroalkane

Gd(OTf) ₃ (No. 1-16, 20-23, 25-27: 0.0075 mmol, No. 17-19, 24: 0.01 mmol) and chiral amine oxide L6 (No. 1-16, 20) were added to the reaction vessel. -23, 25-27: 0.009 mmol, No. 17-19, 24: 0.012 mmol) (The molar ratio of chiral amine oxide L6 to ytterbium triflate (Gd(OTf) ₃ ) is 1.2:1.0), α , β-unsaturated amide (0.1 mmol),

Molecular sieve (No. 1-16, 20-27: 30mg, serial number 18: 100mg, serial number 17, 19: 60mg), stirrer, after replacing nitrogen for 3 times, add 6.2mmol dichloromethane and 0.93mmol nitroalkane at 30 °C Stir for 72 h. Separation and purification by column chromatography, the enantiomeric excess of the product is determined by chiral high performance liquid chromatography, and the reaction formula is as follows:

The reaction results are shown in Table 2: (d.r: diastereoselectivity of compounds containing two or more chiral centers)

Table 2. Michael addition reaction of asymmetric α,β-unsaturated pyrazole amide with nitroalkane catalyzed by chiral amine oxide L6-Gd(OTf) ₃ complex

Serial number	R, R1, R2, R3	Yield (%)	Enantioselectivity (%ee)
				1	H, C 6 H 5 , CH 3 , H	99	99
2	H,4-FC 6 H 4 ,CH 3 ,H	99	99
				3	H,4-ClC 6 H 4 ,CH 3 ,H	98	98
4	H,4-BrC 6 H 4 ,CH 3 ,H	96	98
				5	H,4-MeC 6 H 4 ,CH 3 ,H	95	99
6	H,4-MeOC 6 H 4 ,CH 3 ,H	89	99
				7	H,3-BrC 6 H 4 ,CH 3 ,H	98	98
8	H,3-MeC 6 H 4 ,CH 3 ,H	96	99
				9	H,2-BrC 6 H 4 ,CH 3 ,H	99	99
10	H,2-MeOC 6 H 4 ,CH 3 ,H	99	99
				11	H,3,4–Cl 2 C 6 H 3 ,CH 3 ,H	96	99
12	H,3,4-(MeO) 2 C 6 H 3 ,CH 3 ,H	83	99
				13	H,2-Furyl,CH 3 ,H	56	97
14	H,2-Thienyl, CH 3 , H	58	98
				15	H, CH 3 , CH 3 , H	69	98

16	H, Pr, CH 3 , H	87	98
				17	H, Pent, CH 3 , H	65	98
18	H, i Bu, CH 3 , H	77	98
				19	H, EtO, CH 3 , H	53	95
20	H, EtOOC, CH 3 , H	67	95
				twenty one	H,4-ClC 6 H 4 ,CH 3 ,Cl	94	99
twenty two	H,4-ClC 6 H 4 ,CH 3 ,Br	96	99
				twenty three	H,4-ClC 6 H 4 ,CH 3 ,I	97	99
twenty four	H,4-ClC 6 H 4 ,C 6 H 5 ,H	39	81
				25	CH 3 ,4-ClC 6 H 4 ,CH 3 ,H	94	98/98 (d.r.1.6/1)
26	Et,4-ClC 6 H 4 ,CH 3 ,H	87	99/98 (d.r.1.2/1)
				27	PhCH 2 ,4-ClC 6 H 4 ,CH 3 ,H	98	99/98 (d.r.1.1/1)

Example 3: Michael addition reaction of asymmetric α,β-unsaturated pyrazole amide with nitroalkane catalyzed by chiral amine oxide and rare earth metal complex

A rare earth metal compound (No. 1-11: 0.01 mmol, No. 12-16: 0.0075 mmol) and a chiral amine oxide ligand (No. 1-11: 0.012 mmol, serial number 12-16: 0.009 mmol) are added to the reaction vessel. α,β-unsaturated pyrazole amide 1a (0.1 mmol),

Molecular sieve 30mg, stirrer, after replacing nitrogen for 3 times, add dichloromethane (6.2mmol), nitromethane (No. 1-11: 5.6mmol, serial number 12-16: 0.93mmol), stir at 25-50 ° C for 12-120h . The reaction was monitored by TLC. The column was separated and purified, and the enantiomeric excess of the product was determined by high performance liquid chromatography (Daicel chiralcel IE, V _n-hexane : V _isopropanol = 90:10, flow rate: 1.0 mL/min), as shown in Table 1. The reactive and chiral amine oxide ligand structures are as follows:

Table 3. Michael addition reaction of asymmetric α,β-unsaturated pyrazole amide with nitroalkane in chiral amine oxide L6-Gd(OTf) ₃ complex at different solvents and temperatures

Example 4: Amplification amount experiment 1

In a round bottom flask equipped with a magnetic stirring device, an amine oxide ligand L6 (0.24 mmol), ytterbium triflate (0.2 mmol), an unsaturated amide of No. 2 (0.976 g, 4 mmol),

Molecular sieve 1.2 g, nitrogen gas was exchanged 3 times, then 186 mmol of dichloromethane, 37.2 mmol of nitromethane were added, and stirred at 30 ° C for 96 h. Silica gel column chromatography, to obtain a catalytic product as a white solid, 1.217 g, yield: 99%; by HPLC (Daicel chiralcel IE, V _{n-hexane: isopropyl alcohol} = 90 V: 10, flow rate 1.0mL / min The assay gave an enantioselective ee value of 99% of the product.

Example 5: Magnification Experiment 2

In a round bottom flask equipped with a magnetic stirring device, an amine oxide ligand L6 (0.36 mmol), ytterbium triflate (0.3 mmol), and an unsaturated amide of No. 3 (1.04 g, 4 mmol) were added.

Molecular sieve 1.2 g, nitrogen was exchanged 3 times, then 186 mmol of dichloromethane, 37.2 mmol of nitromethane were added, and stirred at 30 ° C for 72 h. Silica gel column chromatography, to obtain a catalytic product as a white solid, 1.278g, yield: 99%; by HPLC (Daicel chiralcel IE, V _{n-hexane: isopropyl alcohol} = 90 V: 10, flow rate 1.0mL / min The assay gave an enantioselective ee value of 98% for the product.

Example 6: Magnification Experiment 3

In a round bottom flask equipped with a magnetic stirrer, an amine oxide ligand L6 (0.72 mmol), ytterbium triflate (0.6 mmol), an unsaturated amide of No. 18 (1.236 g, 6 mmol),

Molecular sieve 6.5 g, nitrogen gas was exchanged 3 times, then 325.5 mmol dichloromethane, 55.8 mmol nitromethane was added, and stirred at 30 ° C for 72 h. Separation by silica gel column chromatography gave the product as a colorless liquid, 1.34 g, yield: 83%; using high performance liquid chromatography (Daicel chiralcel IE, V _n-hexane : V _isopropanol = 90:10, flow rate 1.0 mL / Min) Determination gave the product an enantioselective ee value of 99%.

Application of γ-nitropyrazole amide compound in synthesis:

Example 7: Esterification of catalytic products

After the completion of the catalytic reaction (starting α,β-unsaturated pyrazole amide is 0.1 mmol), DBU (0.067 mmol) and methanol (2.5 mmol) were added to the tubes containing the reaction solutions of 3b and 3a, respectively, and stirred at room temperature. overnight. Separation and purification by column chromatography, and analyzed by high performance liquid chromatography (3a: Daicel chiralcel IB, V _n-hexane : V _isopropanol = 90:10, flow rate 1.0 mL/min), (3b: Daicel chiralcel IC, V _-hexane : V _isopropanol = 95:5, flow rate 0.8 mL/min). The results are as follows:

5a and 5b can synthesize drug molecules, baclofen and paroxetine, according to methods reported in the literature (Org. Lett. 2012, 14, 1516).

After the completion of the catalytic reaction (starting α,β-unsaturated pyrazole amide is 0.1 mmol), triethylamine (0.067 mmol) and methanol (2.5 mmol) were separately added to the tube containing the 3b reaction solution, and stirred at room temperature. overnight. Separation and purification by column chromatography, and analyzed by high performance liquid chromatography (3a: Daicel chiralcel IB, V _n-hexane : V _isopropanol = 90:10, flow rate 1.0 mL/min), (3b: Daicel chiralcel IC, V _-hexane : V _isopropanol = 95:5, flow rate 0.8 mL/min) gave (S)-5b, 94.2% yield, 99% ee.

After completion of the catalytic reaction (starting α,β-unsaturated pyrazole amide is 0.1 mmol), dimethylaniline (0.08 mmol) and methanol (2.5 mmol) were separately added to the tube containing the 3a reaction solution at room temperature. Stir overnight. Separation and purification by column chromatography, and analyzed by high performance liquid chromatography (3a: Daicel chiralcel IB, V _n-hexane : V _isopropanol = 90:10, flow rate 1.0 mL/min), (3b: Daicel chiralcel IC, V _-hexane : V _isopropanol = 95:5, flow rate 0.8 mL/min) gave (S)-5a, 92% yield, 98.6% ee.

Since the fatty ester compounds are not easy to detect and separate and purify, a stepwise process is carried out to complete the esterification process: 3t (46.2mg, 0.173mmol, 98% ee,) is added to the reaction vessel, and then added sequentially. 7.8 mmol of dichloromethane, DBU (0.1 mmol), methanol (3.72 mmol). Separation and purification by column chromatography, using high performance liquid chromatography (Daicel chiralcel IE, V _n-hexane : V _isopropanol = 95:5, flow rate 1.0 mL / min), product yield 95%, enantioselectivity 98% Ee. The results are as follows:

Example 8: Synthesis of pregabalin

Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, announced the conversion of racemic 5c to racemic 6c. They used Raney nickel-H ₂ as a hydrogenating reagent to reduce and shut down 5c, and obtained 6c in 97% yield. Although the results were good, the operation was complicated, and Raney nickel and hydrogen were used in the process. Hazardous reagents (CN 102115449A.06, 07, 2011).

Here we provide the following method for synthesizing 6c from 5c: the reaction conditions are mild, simple, and efficient.

In a round bottom flask equipped with a magnetic stirrer, 5c (68.82 mg, 0.34 mmol), NiCl ₂ ·6H ₂ O (80.6 mg, 0.34 mmol), EtOH (33.9 mmol), and then placed in an ice bath for 5 minutes Then, NaBH ₄ (140.9 mg, 3.74 mmol) was slowly added, and the reaction solution was further stirred under ice bath for 2 hr. Then, the reaction was quenched by adding 1 mL of ethanol, and returned to room temperature. 1 mL of a 6 mol/L sodium hydroxide solution was added to the reaction mixture, and stirring was continued for 1 hour. After 1 h, a 2 mol/L hydrochloric acid solution was added to the reaction solution to adjust the pH to less than 7, and then extracted with dichloromethane (4×6 mL), and the organic layer was combined, dried over anhydrous sodium sulfate, and then filtered and dried. 6c, yield: 95%, using high performance liquid chromatography (Daicel chiralcel AD-H, V _n-hexane : V _isopropanol = 96:4, flow rate 1.0 mL / min), the enantioselective ee value of the product was obtained. 97%.

According to the literature report (Tetrahedron, 2011, 67, 636), in 6 mol/L hydrochloric acid, refluxing at 100 ° C for 10 hours, the salt of pregabalin can be obtained in 95% yield and the ee value is maintained. .

Claims (15)

1. A method for asymmetrically synthesizing a γ-nitropyrazole amide compound, characterized by using a nitroalkane and an α,β-unsaturated pyrazole amide as a raw material, a complex of a chiral amine oxide and a rare earth metal compound As a catalyst,

   

   The molecular sieve is an additive, and a chiral γ-nitropyrazole amide compound is obtained after the reaction, wherein:

   The structure of the nitroalkane is RCH2NO2, R=H, CH3, Et, Bn;

   The structure of the α,β-unsaturated pyrazole amide compound is:

   

   The γ-nitropyrazole amide compound has the following structure:

   

   The structure of the chiral amine oxide ligand is:

   

   Wherein R ¹ =C ₆ H ₅ ,4-FC ₆ H ₄ ,4-ClC ₆ H ₄ ,4-BrC ₆ H ₄ ,4-MeC ₆ H ₄ ,4-MeOC ₆ H ₄ ,3-BrC ₆ H ₄ , 3-MeC ₆ H ₄ ,2-BrC ₆ H ₄ ,2-MeOC ₆ H ₄ ,3,4-Cl ₂ C ₆ H ₃ ,3,4-(MeO) ₂ C ₆ H ₃ ,2-Furyl, 2-Thienyl, CH ₃ , Pr, Pent, ⁱ Bu, EtO, EtOOC; R ² =CH ₃ , Ph; R ³ =H, Cl, Br, I;

   n=1,2; R=Ph-,2,6-Me2C6H3-,2,6-Et2C6H3-,2,6-iPr2C6H3-,Ph2CH-;

   The rare earth metal compound is: bismuth triflate [Gd(OTf) ₃ ], bismuth triflate [Sc(OTf) ₃ ], bismuth triflate [Ho(OTf) ₃ ], trifluoromethyl ytterbium [Yb (OTf) _3], erbium trifluoromethanesulfonate [Er (OTf) _3], yttrium trifluoromethanesulfonate [Y (OTf) _3].
2. The process according to claim 1, wherein the reaction is carried out in the following solvents: pentane, hexane, dichloroethane, chloroform, toluene, ethylbenzene, cumene, tetrahydrofuran, methyl t-butyl ether, 2- Methyltetrahydrofuran, ethyl acetate or isopropyl acetate.
3. The process according to claim 1, wherein the reaction temperature is 25 to 50 °C.
4. The preparation method according to claim 1, characterized in that a complex of a chiral amine oxide and a rare earth metal compound is used as a catalyst, and a nitroalkane and an α,β-unsaturated pyrazole amide are used as a raw material.

   

   The molecular sieve is an additive, dichloromethane is used as a solvent, and the reaction is carried out at 25-50 ° C under normal pressure for 12-120 h to obtain a chiral γ-nitropyrazole amide compound.
5. The process according to claim 1 or 4, wherein the molar ratio of the nitroalkane to the α,β-unsaturated pyrazole amide compound is 1.86:1-55.8:1.
6. According to the production method of claim 5, the molar ratio of the nitroalkane to the α,β-unsaturated pyrazole amide compound is 9.3:1.
7. The process according to claim 1 or 4, wherein the molar ratio of the chiral amine oxide to the rare earth metal compound is from 0.8:1.0 to 1.5:1.0.
8. The process according to claim 7, wherein the molar ratio of the chiral amine oxide to the rare earth metal compound is 1.2:1.0.
9. The preparation method according to claim 1 or 4, wherein said

   

   The amount of molecular sieve is: 0.1mmol of α,β-unsaturated pyrazole amide

   

   The molecular sieve is 10-100 mg.
10. The method according to claim 1 or 4, wherein the rare earth metal compound is lanthanum triflate [Gd(OTf)3].
11. The process according to claim 1 or 4, wherein the chiral amine oxide ligand has n = 2, R = 2,6-iPr2C6H3-.
12. The process according to claim 1 or 4, wherein the molar ratio of the α,β-unsaturated pyrazole amide compound to the rare earth metal compound is from 20:1 to 10:1.
13. The production method according to claim 1 or 4, characterized in that 0.1 mmol of α,β-unsaturated pyrazole amide compound is required

    

    Molecular sieve 30-100mg.
14. The preparation method according to any one of claims 1 to 4, further comprising the following steps:

    The γ-nitropyrazole amide compound is reacted with methanol in the presence of an organic base to obtain an esterified product;

    The esterification product has the following structure:

    

    Wherein R, R ^{1 has} the same definition as in claim 1.
15. The process according to claim 10, wherein the organic base is selected from the group consisting of triethylamine, diisopropylethylamine, trimethylamine, tri-n-propylamine, tri-n-butylamine, dimethylaniline, diethylaniline, and Methylbenzylamine, diethylbenzylamine or 1,8-diazacyclo[5,4,0]undecene-7.