WO2019034094A1

WO2019034094A1 - Method for preparing alcoholic compound

Info

Publication number: WO2019034094A1
Application number: PCT/CN2018/100730
Authority: WO
Inventors: 刘勇军; 王仲清; 廖守主; 罗忠华
Original assignee: 东莞东阳光药物研发有限公司
Priority date: 2017-08-17
Filing date: 2018-08-16
Publication date: 2019-02-21
Also published as: CN111065627B; CN111065627A

Abstract

Disclosed is a method for preparing an alcoholic compound, comprising subjecting raw materials, i.e. an amine compound and an acid halide compound, to an amidation reaction, a reduction reaction, an esterification reaction, and/or a hydrolysis reaction to obtain the target product.

Description

Method for preparing alcohol compound

Technical field

The invention relates to a preparation method of an alcohol compound, and belongs to the technical field of pharmacy.

Background technique

Listed on Selexipag, it is an oral prostacyclin receptor agonist that relaxes smooth muscle wall of blood vessels, dilates blood vessels, reduces pulmonary artery pressure, and is clinically used for the treatment of pulmonary hypertension in adults. As shown below:

In the preparation of celecoxib, an important intermediate alcohol compound needs to be prepared, and its structure is as shown in the following formula (1):

In the prior art, there are various methods for preparing the compound represented by the formula (1), but these methods have more or less problems, such as high temperature reaction in WO2011017612, difficult industrialization, or preparation of a specific intermediate. As a raw material, and then the target product is prepared, there are many reaction steps, a long reaction process, a low yield, and the like, and it is difficult to industrially apply. Therefore, it is necessary to study and develop a preparation process of the compound represented by the formula (1).

Summary of the invention

Summary of invention

In one aspect, the present invention provides a process for preparing a compound of the formula (1), which can be easily obtained by subjecting a raw material amine compound and an acid halide compound to an amidation reaction, followed by a reduction reaction, an esterification reaction, and a hydrolysis reaction. product.

In another aspect, the invention provides a novel intermediate compound for use in the preparation of a compound of formula (1).

Detailed description of the invention

The present invention provides a process for preparing a compound of the formula (1), which comprises: hydrolyzing a compound of the formula (2) in an organic solvent under the addition of a base to obtain a compound of the formula (1) ,

Wherein R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl or phenyl.

In some embodiments, R ₁ is methyl. In some embodiments, R ₁ is ethyl.

In the above hydrolysis reaction, the base is at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate, or at least one of them. In some embodiments, the base is sodium hydroxide. In some embodiments, the base is potassium hydroxide.

In the above hydrolysis reaction, the organic solvent is ethanol, methanol, isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), tetrahydrofuran. (THF), 2-methyltetrahydrofuran, or a combination thereof. In some embodiments, the organic solvent is methanol, ethanol, or a combination thereof to facilitate reaction and processing. In some embodiments, the organic solvent is dimethyl sulfoxide, which facilitates reaction and processing.

In some embodiments, a method for preparing a compound of the formula (1), comprising: hydrolyzing a compound of the formula (2) in an organic solvent under the addition of a base to obtain a formula (1) Compound,

Wherein R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl; the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or a hydrate thereof, or a combination thereof; the organic solvent is ethanol, methanol, isopropanol, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethylacetamide (DMAc) ), tetrahydrofuran (THF), 2-methyltetrahydrofuran, or a combination thereof.

Wherein R ₁ is a methyl group or an ethyl group; the base is sodium hydroxide, potassium hydroxide, or a combination thereof; and the organic solvent is methanol, ethanol, dimethyl sulfoxide (DMSO), or a combination thereof.

In the hydrolysis reaction of the present invention, the reaction temperature can be controlled to be from 0 ° C to 80 ° C. In some embodiments, in the hydrolysis reaction, the reaction temperature is controlled to room temperature to 80 °C. In some embodiments, in the hydrolysis reaction, the reaction temperature is controlled to be 35 ° C to 70 ° C. In some embodiments, in the hydrolysis reaction, the reaction temperature is controlled to be 40 ° C to 60 ° C to facilitate the product.

The compound of the formula (1) obtained by the method provided by the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization and/or column chromatography.

The compound of the formula (2) can be obtained by esterification of a compound represented by the formula (3) with a carboxylate in an organic solvent at a certain temperature:

Wherein X ₁ is chlorine, bromine or iodine, and R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl.

In the esterification reaction of the present invention, the carboxylate may be a sodium carboxylate or a potassium carboxylate. In some embodiments, the carboxylate is potassium acetate, which facilitates reaction and processing. In some embodiments, the carboxylate is sodium acetate. In some embodiments, the carboxylate is sodium formate. In some embodiments, the carboxylate is potassium formate.

In the esterification reaction of the present invention, the organic solvent may be dimethyl sulfoxide, DMF, DMAc, ethanol, methanol, tetrahydrofuran or a combination thereof. In some embodiments, the organic solvent is dimethyl sulfoxide to facilitate the reaction.

In the esterification reaction of the present invention, the reaction temperature may be from room temperature to 120 °C.

In some embodiments, the compound of formula (2) can be prepared by esterification of a compound of formula (3) with a carboxylate in an organic solvent at a temperature:

Wherein X ₁ is chlorine, bromine or iodine, R ₁ is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl; the carboxylate may be a carboxylic acid a sodium salt or a potassium salt; the organic solvent may be dimethyl sulfoxide, DMF, DMAc, ethanol, methanol, tetrahydrofuran or a combination thereof; the reaction temperature is from room temperature to 120 °C.

In the above esterification reaction, in some embodiments, the reaction temperature is from 40 ° C to 120 ° C. In the above esterification reaction, in some embodiments, the reaction temperature is from 60 ° C to 100 ° C, which is advantageous for reaction control and progress.

In some embodiments, the compound of formula (2) is prepared by esterification of a compound of formula (3) with a carboxylate in an organic solvent at a temperature:

Wherein X ₁ is chlorine or bromine, R ₁ is hydrogen or methyl; the carboxylate is potassium acetate; the organic solvent is dimethyl sulfoxide; and the reaction temperature is from 60 ° C to 100 ° C.

Wherein X ₁ is chlorine, R ₁ is methyl; the carboxylate is potassium acetate; the organic solvent is dimethyl sulfoxide; and the reaction temperature is from 60 ° C to 100 ° C.

The compound of the formula (2) prepared according to the method of the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization and/or column chromatography.

The compound represented by the formula (3) can be produced by a reduction reaction of a compound represented by the formula (4) under a reducing agent and a Lewis acid in an organic solvent at a certain temperature:

Wherein X ₁ is chlorine, bromine or iodine.

In the reduction reaction of the present invention, the reducing agent may be lithium aluminum hydride, sodium borohydride or potassium borohydride, or a combination thereof.

In the reduction reaction of the present invention, the Lewis acid may be aluminum trichloride, zinc chloride, iron chloride, cobalt chloride, or a combination thereof. In some embodiments, the Lewis acid is aluminum trichloride, facilitating the reaction to proceed and the product.

In the reduction reaction of the present invention, the organic solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether or ethylene glycol dimethyl ether, or a combination thereof. In some embodiments, the organic solvent for the reduction reaction is tetrahydrofuran or 2-methyltetrahydrofuran or a combination thereof to facilitate the reaction and the product.

In the reduction reaction of the present invention, the reaction temperature of the reduction reaction may be from -25 ° C to 50 ° C. In some embodiments, the reaction temperature of the reduction reaction is from -25 °C to 40 °C. In some embodiments, the reaction temperature of the reduction reaction is from -25 °C to 30 °C. In some embodiments, the reaction temperature of the reduction reaction is from -20 °C to 40 °C. In some embodiments, the reaction temperature of the reduction reaction is from -20 °C to 30 °C. In some embodiments, the reaction temperature of the reduction reaction is from 0 °C to 30 °C. In some embodiments, the reaction temperature of the reduction reaction is from -20 °C to 5 °C.

In some embodiments, the compound of the formula (3) is prepared by a reduction reaction of a compound of the formula (4) by adding a reducing agent and a Lewis acid in an organic solvent at a certain temperature:

Wherein, the X ₁ is chlorine, bromine or iodine; the reducing agent is lithium tetrahydrogen aluminum, sodium borohydride or potassium borohydride, or a combination thereof; the Lewis acid may be aluminum trichloride, zinc chloride, Iron chloride, cobalt chloride, or a combination thereof; the organic solvent for the reaction is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether or ethylene glycol dimethyl ether, or a combination thereof; reaction temperature It is -25 ° C - 50 ° C.

Wherein the X ₁ is chlorine or bromine; the reducing agent is sodium borohydride or potassium borohydride, or a combination thereof; the Lewis acid is aluminum trichloride, zinc chloride or ferric chloride, or a combination thereof; The organic solvent for the reaction is tetrahydrofuran, 2-methyltetrahydrofuran or a combination thereof; the reaction temperature is -25 ° C to 30 ° C.

The compound of the formula (3) obtained by the method of the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization, and/or column chromatography.

The compound represented by the formula (4) can be produced by subjecting the compound represented by the formula (5) and the compound of the formula (01) to an amidation reaction at a certain temperature under an alkali condition in an organic solvent:

Wherein X ₁ is chlorine, bromine or iodine; and X is chlorine, bromine or iodine.

In the amidation reaction, the organic solvent may be toluene, xylene, THF, 2-methyltetrahydrofuran, DMF, DMAc, ethylene glycol dimethyl ether (DME), or a combination thereof. In some embodiments, in the amidation reaction, the organic solvent is toluene, DMF, ethylene glycol dimethyl ether (DME), or a combination thereof.

In the amidation reaction, the base may be 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP). ), N-methylmorpholine (NMM), potassium carbonate, sodium carbonate or a combination thereof. In some embodiments, in the amidation reaction, the base is 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-di Methylaminopyridine (DMAP), N-methylmorpholine (NMM) or a combination thereof. In some embodiments, in the amidation reaction, the base is 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-di Methylaminopyridine (DMAP), N-methylmorpholine (NMM) or a combination thereof.

In the amidation reaction, the reaction temperature may be from room temperature to 100 °C.

In some embodiments, the compound of the formula (4) is prepared by amidating a compound of the formula (5) and a compound of the formula (01) in an organic solvent under a base condition at a certain temperature. :

Wherein X ₁ is chlorine, bromine or iodine; the X is chlorine, bromine or iodine; the organic solvent may be toluene, THF, 2-methyltetrahydrofuran, DMF, DMAc, ethylene glycol dimethyl ether ( DME), or a combination thereof; the base may be 1,8-diazabicycloundec-7-ene (DBU), triethylamine, diisopropylethylamine, 4-dimethylaminopyridine (DMAP), N-methylmorpholine (NMM), potassium carbonate, sodium carbonate or a combination thereof; the reaction temperature is from room temperature to 100 °C.

Wherein X ₁ is chlorine or bromine; X is chlorine or bromine; the organic solvent is toluene, xylene or a combination thereof; and the base is 1,8-diazabicycloundec-7 -ene (DBU); the temperature of the reaction is from room temperature to 100 °C.

The compound of the formula (4) obtained by the method of the present invention can be directly used in the next reaction, or can be used in the next reaction after purification by washing, crystallization, and/or column chromatography.

In another aspect, the invention provides novel intermediate compounds which can be used in the preparation of compounds of formula (1).

A compound having the structure shown in formula (2):

In some embodiments, the compound of formula (2) has the structure:

A compound having the structure shown in formula (4):

Wherein X ₁ is chlorine, bromine or iodine. In some embodiments, X ₁ is chlorine or bromine. In some embodiments, X ₁ is chlorine.

In some embodiments, the compound of formula (4) has the structure:

The invention provides a method for preparing the compound of the formula (1), which is cheap and easy to obtain, has high yield, mild reaction condition, simple operation and convenient industrial production, and is also provided for preparing the formula (1). A novel intermediate compound of the compound, which is easy to prepare, can simplify the process for preparing the compound represented by the formula (1), and can be used in industrial production.

Detailed ways

In order to make those skilled in the art better understand the technical solutions of the present invention, the present invention will be further described in detail below by way of non-limiting embodiments.

The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.

In the present invention, g: gram; mL: ml; °C: Celsius; h: hour; Ph: phenyl.

In the present invention, room temperature refers to an ambient temperature of 15 ° C to 38 ° C or 20 ° C to 35 ° C or 20 ° C to 30 ° C.

In the following examples, X is chlorine, X ₁ is chlorine, and R ₁ is a methyl group. When X, X ₁ and R ₁ are other groups, the target product is prepared by the method of the following examples.

The compound of the formula (5) can be produced by a known method such as the method in the patent application CN106316967.

Example 1

5 g of the compound of the formula (5), 4.7 g of DBU and 50 mL of toluene were added to the reaction vessel, and 5.6 g of 4-chlorobutyryl chloride was added dropwise with stirring at room temperature (20 ° C to 30 ° C), and the mixture was heated to 50 ° C for 12 h. The reaction is over. Then, the reaction system was cooled to room temperature, stirred with 30 mL of a saturated aqueous solution of sodium hydrogencarbonate and stirred for 0.5 h, and the mixture was allowed to stand for liquid separation. The organic layer was washed twice with 30 mL of water, and the organic layer was concentrated to give 6 g of crude material, The compound represented by the formula (4) has a yield of 88.2% and a purity of 97.96%. The obtained crude product can be subjected to silica gel column chromatography, and the mixture of ethyl acetate and petroleum ether in a volume ratio of 1:9 is used as an eluent, and can also be directly used in the next step.

The crude product was detected as: ¹ H NMR (600 Mz CDCl3): δ 8.47 (s, 1H), δ 7.51 to 7.46 (m, 4H), δ 7.36 to 7.32 (m, 6H), δ 5.00 to 4.96 (m) , 1H), δ 3.58 to 3.55 (m, 2H), δ 2.31 to 2.28 (m, 2H), δ 2.12 to 2.09 (m, 2H), δ 1.24 to 1.23 (d, 6H);

ESI/MS+ (M/z): 394.1.

Example 2

10 g of the compound of the formula (5), 10 g of DBU and 100 mL of toluene were added to the reaction vessel, and 11 g of 4-chlorobutyryl chloride was added dropwise with stirring at room temperature, and the mixture was heated to 80 ° C for 8 h, and the reaction was completed. Then, the reaction system was cooled to room temperature, 60 mL of a 15% sodium carbonate (mass fraction) aqueous solution was added and stirred for 0.5 h, and the mixture was allowed to stand for separation. The organic layer was washed twice with 60 mL of water and then concentrated to give a crude product of 13.1 g. The compound is a compound of the formula (4), the yield is 96.3%, and the purity is 98.73%.

Example 3

8 g of the compound of the formula (5), 13.8 g of DBU and 70 mL of toluene were added to the reaction vessel, and 11.7 g of 4-chlorobutyryl chloride was added dropwise with stirring at room temperature, and the mixture was heated to 60 ° C for 8 h, and the reaction was completed. The reaction system was cooled to room temperature, 60 mL of a 10% sodium carbonate (mass fraction) aqueous solution was added and stirred for 0.5 h, and the mixture was allowed to stand for liquid separation. The organic layer was washed twice with 60 mL of water, and then the organic layer was concentrated to obtain 10.2 g of crude material. The compound represented by the formula (4) has a yield of 93.6% and a purity of 97.63%.

Example 4

5 g of the compound of the formula (4), 50 mL of tetrahydrofuran and 1.4 g of sodium borohydride were added to the reaction vessel, 2.5 g of aluminum trichloride was added thereto with stirring at room temperature, and stirring was continued at room temperature for 4 hours, and the reaction was completed. The reaction system was cooled to 10 ° C, and a mixture of 3.2 g of sodium hydroxide and 20 mL of water was added, and the mixture was stirred at room temperature for 0.5 h, and the mixture was allowed to stand for separation. The organic layer was washed twice with 30 mL of brine, and then,克, yellow solid, detected, is a compound of formula (3), yield 83.3%, purity 98.72%. The obtained crude product can be directly used for the next reaction, or can be subjected to silica gel column chromatography, and a mixture of ethyl acetate and petroleum ether in a volume ratio of 1:10 is used as an eluent.

The obtained crude product was detected: ¹ H NMR (600 Mz CDCl3): δ 8.02 (s, 1H), δ 7.47 to 7.45 (m, 2H), δ 7.38 to 7.35 (m, 2H), δ 7.28 to 7.23 (m) , 6H), δ 4.78 ~ 4.71 (m, 1H), δ 3.61 ~ 3.58 (m, 2H), δ 3.46 ~ 3.43 (m, 2H), δ 1.88 ~ 1.86 (m, 4H), δ 1. 30 to 1.28 (d, 6H);

ESI/MS+(M/z): 380.3.

Example 5

To the reaction vessel were added 12 g of the compound of the formula (4), 110 mL of tetrahydrofuran and 2.9 g of sodium borohydride, and the mixture was cooled to -15 ° C with stirring, and 5.3 g of aluminum trichloride was added thereto, and stirring was continued at -15 ° C for 24 hours, and the reaction was completed. The reaction was quenched by adding 10 mL of water, and then a mixture of 6.5 g of sodium hydroxide and 40 mL of water was added, and then stirred at room temperature for 0.5 h, and the mixture was allowed to stand for separation. The organic layer was washed twice with 40 mL of brine, and then, The crude product was recrystallized from 30 mL of ethanol and 70 mL of water in ethanol to give 10.3 g of a pale yellow solid as a compound of formula (3), yield: 89.0%, purity 98.11%.

Example 6

15 g of the compound of the formula (4), 160 mL of 2-methyltetrahydrofuran and 5.0 g of sodium borohydride were added to the reaction vessel, and the mixture was stirred and cooled to 0 ° C, and 10.1 g of aluminum trichloride was added in portions, and stirring was continued at 0 ° C for 24 h. The reaction is over. The reaction was quenched by adding 20 mL of water, and then a mixture of 12.2 g of sodium hydroxide and 50 mL of water was added, and then stirred at room temperature for 0.5 h, and the mixture was allowed to stand for separation. The organic layer was washed twice with 50 mL of brine, and the organic layer was concentrated to give crude. The crude product was recrystallized from 40 mL of ethanol and 100 mL of water in ethanol to give 14.1 g of pale yellow solid as a compound of formula (3), yield 97.5%, purity 99.47%.

Example 7

4 g of the compound of the formula (3), 20 mL of dimethyl sulfoxide and 1.4 g of potassium acetate were added to the reaction vessel, and the reaction was kept at 70 ° C for 14 h, and the reaction was completed. The reaction system was cooled to room temperature, 40 mL of ethyl acetate and 40 mL of water were added and stirred for 0.5 h, and the mixture was allowed to stand for liquid separation. The organic layer was washed twice with 20 mL of water, and then the organic layer was concentrated to give 4 g of crude product. The compound of the formula (2) had a yield of 94.3% and a purity of 98.71%. The obtained crude product can be directly used for the subsequent reaction, or can be subjected to silica gel column chromatography, eluent: ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain a product.

The crude product was obtained as follows: ¹ H NMR (600 Mz CDCl3): δ 8.01 (s, 1H), δ 7.46 - 7.44 (m, 2H), δ 7.38 - 7.35 (m, 2H), δ 7.27 - 7.23 (m) , 6H), δ 4.78 ~ 4.75 (m, 1H), δ 4.15 ~ 4.12 (m, 2H), δ 3.45 ~ 3.42 (m, 2H), δ 2.05 (s, 3H), δ 1.76 ~ 1.68 (m, 4H), δ 1.29 to 1.27 (d, 6H);

ESI/MS+(M+1/z): 404.3, (M+23/z): 426.3.

Example 8

7 g of the compound of the formula (3), 20 mL of dimethyl sulfoxide and 2.7 g of potassium acetate were added to the reaction vessel, and the reaction was kept at 95 ° C for 4 h, and the reaction was completed. The reaction system was cooled to room temperature, and then added with 80 mL of ethyl acetate and 40 mL of water and stirred for 0.5 hr, and the mixture was stood still, and the organic layer was washed twice with 30 mL of water, and the organic layer was concentrated to give 7.2 g of crude oil as a yellow oil. 2) Compound shown, yield 96.9%, purity 98.64%.

Example 9

10 g of the compound of the formula (3), 35 mL of dimethyl sulfoxide and 4.39 g of potassium acetate were added to the reaction vessel, and the reaction was kept at 100 ° C for 3 h, and the reaction was completed. The reaction system was cooled to room temperature, and 90 mL of methyl tert-butyl ether and 60 mL of water were added and stirred for 0.5 h, and the mixture was allowed to stand for separation. The organic layer was washed twice with 30 mL of water, and then the organic layer was concentrated to give 10.3 g of crude oil. (2) Compound shown, yield 97.1%, purity 98.92%.

Example 10

5 g of the compound of the formula (2), 15 mL of dimethyl sulfoxide, 1 mL of water and 0.75 g of sodium hydroxide were added to the reaction vessel, and the reaction was kept at 40 ° C for 3 h, and the reaction was completed. The reaction system was cooled to room temperature, and 40 mL of water was added dropwise with stirring to precipitate a large amount of solid, which was filtered, washed with water, and dried in vacuo at 50 ° C to give the product 4.12 g of a yellow solid, which was found to be a compound of formula (1), yield 91.9%. The purity is 98.79%.

The product was detected: ESI/MS+(M+1/z): 362.2;

¹ H NMR (600Mz CDCl3): δ 8.02 (s, 1H), δ 7.46 to 7.43 (m, 2H), δ 7.37 to 7.34 (m, 2H), δ 7.27 to 7.20 (m, 6H), Δ4.79～4.76(m,1H),δ3.71～3.68(m,2H),δ3.46～3.42(m,2H),δ1.81～1.73(m,2H),δ1.68～1.63( m, 2H), δ 1.66 (s, 1H), δ 1.29 to 1.27 (d, 6H).

Example 11

5 g of the compound of the formula (2), 15 mL of ethanol, 1 mL of water and 0.6 g of sodium hydroxide were added to the reaction vessel, and the reaction was kept at 60 ° C for 2 h, and the reaction was completed. The reaction system was cooled to room temperature, and 45 mL of water was added dropwise with stirring to precipitate a large amount of solid, which was filtered, washed with water, and dried in vacuo at 50 ° C to give product 4.3 g, yellow solid as compound of formula (1), yield 95.9%, purity 97.98%.

Example 12

8 g of the compound of the formula (2), 30 mL of methanol, 2 mL of water and 2 g of potassium hydroxide were added to the reaction vessel, and the reaction was kept at 45 ° C for 5 h, and the reaction was completed. After cooling at room temperature, 85 mL of water was added dropwise with stirring to precipitate a large amount of solid, which was filtered, washed with water, and dried in vacuo at 50 ° C to give the product 6.95 g, as a yellow solid as a compound of formula (1), yield 97.0%, purity 98.46%.

The method of the present invention has been described by the preferred embodiments, and it is obvious that those skilled in the art can make modifications and/or changes and combinations of the methods and applications described herein to implement and apply the techniques of the present invention. . Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.

Claims

A method for preparing a compound of the formula (1), which comprises: hydrolyzing a compound of the formula (2) in an organic solvent under a base condition to obtain a compound of the formula (1),

Wherein R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl or phenyl.
The method according to claim 1, further comprising: a compound represented by the formula (3) and a carboxylate, which are subjected to an esterification reaction at a certain temperature in an organic solvent to prepare a compound of the formula (2).

Wherein X 1 is chlorine, bromine or iodine, and R 1 is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or phenyl.
The method according to claim 1 or 2, further comprising: the compound represented by the formula (4) is subjected to a reduction reaction at a certain temperature in an organic solvent under the addition of a reducing agent and a Lewis acid to obtain the formula (3). Compound,

Wherein X 1 is chlorine, bromine or iodine.
The method according to claim 3, which further comprises: a compound represented by the formula (5) and a compound of the formula (01) are subjected to amidation reaction at a certain temperature in an organic solvent under an alkali addition to obtain a formula (4). ) the compound shown,

Wherein X 1 is chlorine, bromine or iodine; and X is chlorine, bromine or iodine.
The method according to claim 1, wherein the base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or a hydrate thereof, or a combination thereof.
The method according to claim 1, wherein the organic solvent is ethanol, methanol, isopropanol, dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide, tetrahydrofuran, or combination.
The method according to claim 1, wherein in the hydrolysis reaction, the reaction temperature is from 0 °C to 80 °C.
The method of claim 2 wherein the carboxylate is a sodium or potassium carboxylate.
The method according to claim 2, wherein in the esterification reaction, the organic solvent is dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, ethanol, methanol. , tetrahydrofuran or a combination thereof.
The method according to claim 2, wherein the reaction temperature in the esterification reaction is from room temperature to 120 °C.
The method of claim 3 wherein the reducing agent is lithium aluminum hydride, sodium borohydride or potassium borohydride, or a combination thereof.
The method of claim 3 wherein the Lewis acid is aluminum trichloride, zinc chloride, iron chloride, cobalt chloride, or a combination thereof.
The method according to claim 3, wherein in the reducing reaction, the organic solvent is tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, methyl tert-butyl ether or ethylene glycol dimethyl ether, or a combination thereof.
The method according to claim 3, wherein the reaction temperature of the reduction reaction is from -25 ° C to 50 ° C.
The method according to claim 4, wherein in the amidation reaction, the organic solvent is toluene, xylene, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N,N-dimethyl Acetylamine, ethylene glycol dimethyl ether, or a combination thereof.
The method according to claim 4, wherein in the amidation reaction, the base is 1,8-diazabicycloundec-7-ene, triethylamine, diisopropylethylamine, 4 - dimethylaminopyridine, N-methylmorpholine, potassium carbonate, sodium carbonate or a combination thereof.
The method according to claim 4, wherein in the amidation reaction, the reaction temperature is from room temperature to 100 °C.