阅读说明：本技术 一种羧酸酯化合物的制备方法 (Preparation method of carboxylic ester compound ) 是由 万小兵 郑永高 陶苏艳 李星星 成雄略 于 2020-12-25 设计创作，主要内容包括：本发明涉及一种羧酸酯化合物的制备方法：在亚硝酸酯的催化下,羧酸与甲醇在空气下反应,得到酯化合物。本发明的制备方法具有原料来源丰富、催化剂廉价易得、反应条件温和且操作简便等优点,可高收率的修饰一系列脂肪羧酸,特别要说明的是,传统的酯化方法一般不适合药物分子的酯化。利用本方法,可以对一系列已知药物分子进行修饰,从而为发现新的药物分子提供捷径。(The present invention relates to a method for producing a carboxylic acid ester compound: under the catalysis of nitrite ester, carboxylic acid reacts with methanol under air to obtain ester compound. The preparation method of the invention has the advantages of abundant raw material sources, cheap and easily-obtained catalyst, mild reaction conditions, simple and convenient operation and the like, can modify a series of aliphatic carboxylic acids with high yield, and particularly indicates that the traditional esterification method is not suitable for esterification of drug molecules. By using the method, a series of known drug molecules can be modified, thereby providing a shortcut for discovering new drug molecules.)

1. A preparation method of a carboxylic ester compound is characterized in that a carboxylic acid compound and methanol are used as raw materials to react in the presence of nitrite to prepare the carboxylic ester compound.

2. The method for producing a carboxylic acid ester compound according to claim 1, wherein the carboxylic acid compound has the formula(ii) a In the formula R¹One selected from hydrogen, C1-C12 alkyl, alkoxy, phenyl, benzyl, substituted phenyl, thienyl, indolyl, phenolic group, naphthyl, biphenyl and amido; r²One selected from hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl and phenyl; r³One selected from hydrogen, methyl, methylene, ethyl, isopropyl, propyl, butyl and phenyl; the substituent on the substituted phenyl is selected from one or more of hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetamido, fluorine, chlorine, bromine, iodine and the like.

3. The method for preparing a carboxylic ester compound according to claim 1, wherein the nitrite is one or more selected from the group consisting of isopropyl nitrite, butyl nitrite, isobutyl nitrite and tert-butyl nitrite.

4. The method for producing a carboxylic acid ester compound according to claim 1, wherein the molar ratio of the carboxylic acid compound to the nitrous acid ester is 10: 1 to 10.

5. The method for producing a carboxylic acid ester compound according to claim 1, wherein the molar ratio of the carboxylic acid compound to the nitrite is 5: 2.

6. The method for producing a carboxylic acid ester compound according to claim 1, wherein the reaction time is 20 to 50 hours; the reaction temperature is 25-50 ℃.

7. The process for producing a carboxylic acid ester compound according to claim 1, wherein the reaction is carried out in air.

8. The carboxylate compound prepared by the method for preparing carboxylate compound according to claim 1.

9. The application of nitrite in preparing carboxylic ester compound by catalyzing the reaction of carboxylic acid compound and methanol.

10. Use according to claim 9, wherein the reaction is free of metals or metal compounds.

Technical Field

The invention relates to the technical field of carboxylate synthesis, in particular to a preparation method for synthesizing a methyl carboxylate compound.

Background

It is well known that esterification is one of the most basic and important chemical reactions, widely used in organic synthesis and in the synthesis of pharmaceuticals and natural products, such as esters accounting for 25% of all chemical operations involved in the synthesis of pharmaceuticals. Although there are many reports on the synthesis of carboxylic ester compounds, they have some disadvantages, such as harsh reaction conditions, narrow substrate range, poor atom economy, the need of strong acid and strong base which are harmful to equipment and heavy metal catalyst which is not environment-friendly, oxidant or catalyst or polymer which is relatively high in cost and relatively complex. For example:

(1) acid-catalyzed esterification of carboxylic acids with alcohols is the classical method for synthesizing esters, however, acids can be damaging to equipment and harmful to the environment, and the method is not applicable when acid-sensitive ingredients are present. (see: E. Emmet Reid;Ind. Eng. Chem;1948, 40, 1596–1601; Junzo Otera; Chem. Rev.1993, 93. 1449-1470）；

(2) debases Manna et al, 2013 reported a method of producing carboxylic acid esters from carboxylic acids and alcohols as substrates. However, the heavy metal zinc is used as an acid catalyst, and the triphenyl phosphine and the iodine participate in the reaction, so that the reaction is more complicated, and by-products of phosphorus oxide and hydrogen iodide are generated, so that the purification of the reaction is more difficult. (see: Debasis Manna;J. Org. Chem. 2013, 78, 2386−2396）；

(3) in 2013, Yasuhiro Uozumi et al reported a method for preparing carboxylic esters. The polymeric acid catalyst used in the method is not a commercial reagent, needs further preparation, is not practical for acid-sensitive substances, and has a narrow substrate range. (see: Yasuhiro Uozumi;Org. Lett. 2013, 15, 5798–5801）；

(4) asit K, Chakraborti et alA method for preparing methyl carboxylate was reported in 1999. However, the methylating agent used in the method has higher toxicity and is harmful to the environment and people; also, the method uses a strong base. This limits the substrate range, and the operation is relatively cumbersome, and the atom economy of the reaction is not high, causing serious contamination. (see: Asit k. Chakraborti;J. Org. Chem. 1999, 64, 8014-8017）；

(5) shannon s. Stahl et al reported a method of preparing carboxylic esters in 2017. The method uses a noble metal palladium catalyst, and has high cost and relatively complex reaction conditions. (see: Shannon s. Stahl;J. Am. Chem. Soc. 2017, 139, 1690−1698）；

(6) aiwen Lei et al also reported a method of making carboxylic acid esters in 2012. However, the reaction needs expensive and complex palladium-containing catalyst, and meanwhile, the reaction conditions are relatively complex, the substrate range is narrow, the used raw materials are easy to decompose, and the price is generally several times of that of the corresponding carboxylic acid. (see: Aiwen Lei;Angew.Chem. Int. Ed.2012, 51,1-6）。

in summary, most of the currently reported methods for synthesizing esters have the following disadvantages: the raw materials need to be pre-activated, the reaction conditions are harsh, the used substrate is harmful to the environment, the used catalyst is noble metal or heavy metal, the price is expensive, the substrate range is narrow, and the atom economy is poor; more importantly, because a general drug molecule has a plurality of functional groups, including sensitive functional groups, and the functional groups are poorly tolerated by conventional esterification methods, conventional esterification methods are generally not suitable for the esterification of drug molecules.

Based on this, it is important to develop an esterification method including, but not limited to, carboxylic acid of drug molecules.

Disclosure of Invention

In order to solve the above technical problems, the present invention aims to provide a method for preparing a carboxylate compound, which has mild reaction conditions; the raw material source is rich; the reaction substrate has wide universality; simple operation and the like, and can modify a series of carboxylic acids with pharmaceutical properties and fatty carboxylic acids such as amino acids with biological activity and the like.

The invention discloses a preparation method of a carboxylic ester compound, which takes a carboxylic acid compound and methanol as raw materials to prepare the carboxylic ester compound by reaction in the presence of nitrite.

The invention discloses application of nitrite in preparation of a carboxylic ester compound by catalyzing a reaction of a carboxylic acid compound and methanol.

The preparation method of the carboxylic ester compound comprises the following steps: sequentially adding nitrite, carboxylic acid compound and methanol into air in a reaction test tube; and then reacting for 20-50 hours at the temperature of 25-49 ℃ to obtain the carboxylate compound.

In the present invention, the carboxylic acid compound has the general formula:

in the formula R¹One selected from hydrogen, C1-C12 alkyl, alkoxy, phenyl, benzyl, substituted phenyl, thienyl, indolyl, phenolic group, naphthyl, biphenyl and amido; r²One selected from hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl and phenyl; r³One selected from hydrogen, methyl, methylene, ethyl, isopropyl, propyl, butyl and phenyl; the substituent on the substituted phenyl is selected from one or more of hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetamido, fluorine, chlorine, bromine, iodine and the like;

the nitrite is one or more of isopropyl nitrite, butyl nitrite, isobutyl nitrite and tert-butyl nitrite, preferably, the nitrite is tert-butyl nitrite (b), (c), (d^tBuONO）。

The carboxylate compound has the general formula:

in the formula R¹Selected from hydrogen, C1-C12 alkyl, alkoxy, phenyl, benzyl, substituted phenyl, thiaOne of a thiophenyl group, an indolyl group, a phenolyl group, a naphthyl group, a biphenyl group and an amide group; r²One selected from hydrogen, methyl, methylene, ethyl, isopropyl, hydroxyl, hydroxymethyl and phenyl; r³One selected from hydrogen, methyl, methylene, ethyl, isopropyl, propyl, butyl and phenyl; the substituent on the substituted phenyl is selected from one or more of hydrogen, methyl, methoxy, hydroxyl, nitro, phenyl, acetamido, fluorine, chlorine, bromine, iodine and the like.

Further, the molar ratio of the carboxylic acid compound to the nitrous acid ester is 10: 1-10; preferably, the molar ratio of carboxylic acid compound to nitrite is 5: 2.

Further, the ratio of the amount of the carboxylic acid compound to the amount of the alcohol was 0.5 mmol: 2 mL.

Further, the reaction time is 20-50 hours, preferably 48 hours; the reaction temperature is 25-50 ℃, and preferably, the reaction temperature is 40 ℃.

Further, the reaction was carried out in air.

Further, after the reaction is finished, quenching the reaction by using sodium thiosulfate, and conventionally separating the carboxylic ester compound, for example, after the quenching reaction, extracting the product by using ethyl acetate, removing the solvent and adsorbing by using silica gel, and then carrying out column chromatography to obtain the product carboxylic ester compound.

The invention has at least the following advantages:

1. the reaction substrate used in the invention is commercially available, and has good medical and industrial application prospects.

2. The invention can react without the presence of additives such as metal, strong base, strong acid and the like, can be carried out under the air condition as low as room temperature, and meets the requirement of green safety.

3. The method has high atom economy, and the byproduct is water; the method has the advantages of simple reaction system, wide substrate range, good functional group compatibility, mild reaction conditions, convenient post-operation treatment operation and capability of overcoming the defects of the conventional synthesis method.

4. Can be operated and simply synthesized into a series of esterified compounds of aliphatic carboxylic acids such as carboxylic acid with pharmaceutical properties and bioactive amino acid.

The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a preferred embodiment of the present invention and is described in detail below.

Detailed Description

The raw materials of the invention are all the existing commercial products, and the specific preparation operation and the test method are all conventional methods. The following examples are given to further illustrate the embodiments of the present invention. The method only takes the nitrite, the carboxylic acid compound and the methanol as raw materials to carry out the reaction without adding other substances, can prepare the carboxylic ester in the air under mild conditions, solves the problem that the prior art needs metal or metal compound to catalyze the reaction, and further overcomes the problem that the traditional esterification method is not suitable for the esterification of drug molecules; the following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Example one

To a reaction tube were added the drug molecule 1a (Naproxen) (0.5 mmol, 115.2 mg) and methanol containing 40mol% of t-butyl nitrite (2 mL of methanol and 0.2mmol of t-butyl nitrite, the same as in the following example) in this order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent, silica gel is used for adsorption, and finally column chromatography is carried out by using a mixed solvent (1: 1) of ethyl acetate and petroleum ether to obtain a product 3a, wherein the yield is 95% (separation yield). The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.76 – 7.68 (m, 3H), 7.45 – 7.43 (m, 1H), 7.20 – 7.11 (m, 2H), 3.93 – 3.86 (m, 4H), 3.69 (s, 3H), 1.62 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 175.0, 157.5, 135.6, 133.6, 129.2, 128.8, 127.1, 126.1, 125.8, 118.9, 105.4, 55.1, 51.9, 45.2, 18.5; HRMS (ESI-TOF): Anal. Calcd. For C₁₄H₂₀O₂+Na⁺: 267.0992, Found: 267.1007; IR (neat, cm^-1): υ 3005, 2975, 2932, 1733, 1603, 1504, 1448, 1173, 1027, 855, 823.

Replacing tert-butyl nitrite with isopropyl nitrite, butyl nitrite or isobutyl nitrite, wherein the rest is unchanged, and the product yield is respectively 13%, 42% and 35%; the tert-butyl nitrite is replaced by an oxidant, such as tert-butyl hydroperoxide, hydrogen peroxide and tert-butyl hypochlorite, and the rest is unchanged, and the product yield is respectively less than 5%, less than 5% and 60%.

Example two

To a reaction tube were added the drug molecule 1a (Naproxen) (0.5 mmol, 115.2 mg) and methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at the temperature of 25 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent, silica gel is used for adsorption, and finally column chromatography is carried out by using a mixed solvent (1: 1) of ethyl acetate and petroleum ether to obtain the product 3a, wherein the yield is 63%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

EXAMPLE III

To a reaction tube were added drug molecule 1b (Carprofen) (0.5 mmol, 136.9 mg), methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3b, wherein the yield is 90%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.34 – 7.29 (m, 2H), 7.25 – 7.21 (m, 1H), 7.18 (dd, J = 8.1, 1.4 Hz, 1H), 3.90 (q, J = 7.2 Hz, 1H), 3.72 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 175.5, 140.3, 139.0, 138.0, 125.7, 124.7, 124.1, 121.5, 120.5, 119.8, 119.4, 111.5, 109.5, 52.2, 45.7, 18.8; HRMS (ESI-TOF): Anal. Calcd. For C₁₆H₁₄ ³⁵ClNO₂+Na⁺: 310.0605, Found: 310.0600. Anal. Calcd. For C₁₆H₁₄ ³⁷ClNO₂+Na⁺: 312.0576, Found: 312.0570; IR (neat, cm^-1): υ 3407, 2985, 1731,1605, 1449, 1376, 1174, 1153, 810.

Example four

To a reaction tube were added drug molecules 1c (ibuprofen) (0.5 mmol, 103.2 mg), methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3c can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 85%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.21 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 3.71 (q, J = 7.2 Hz, 1H), 3.67 (s, 3H), 2.46 (d, J = 7.2 Hz, 2H), 1.93 – 1.80 (m, 1H), 1.50 (d, J = 7.2 Hz, 3H), 0.92 (d, J = 6.6 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 175.2, 140.5, 137.7, 129.3, 127.1, 51.9, 44.98, 44.96 , 30.1, 22.3, 18.6; HRMS (ESI-TOF): Anal. Calcd. For C₁₄H₂₀O₂+Na⁺: 243.1356, Found: 243.1365; IR (neat, cm^-1): υ 2953, 2869, 1737, 1512, 1457, 1434, 1334, 1204, 1162, 1068, 847.

EXAMPLE five

To a reaction tube were added drug molecule 1d (Ketoprofen) (0.5 mmol, 127.2 mg), methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3d can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 86%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.82 – 7.73 (m, 3H), 7.67 – 7.65 (m, 1H), 7.60 – 7.51 (m, 2H), 7.49 – 7.39 (m, 3H), 3.80 (q, J = 7.2 Hz, 1H), 3.66 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 196.3, 174.3, 140.7, 137.7, 137.3, 132.4, 131.4, 129.9, 129.0, 128.9, 128.4, 128.1, 52.0, 45.1, 18.4; HRMS (ESI-TOF): Anal. Calcd. For C₁₇H₁₆O₃+Na⁺: 291.0992, Found: 291.0987; IR (neat, cm^-1): υ 3061, 2980, 2951, 1734, 1657, 1597, 1447, 1281, 1165, 1074, 950, 704.

EXAMPLE six

To a reaction tube were added sequentially drug molecules 1e (indomethcin) (0.5 mmol, 178.9 mg), methanol containing 40mol% of tert-butyl nitrite; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3e can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 86%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.68 – 7.63 (m, 2H), 7.48 – 7.43 (m, 2H), 6.96 (d, J = 2.5 Hz, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.66 (dd, J = 9.0, 2.5 Hz, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.66 (s, 2H), 2.38 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.2, 168.1, 155.9, 139.1, 135.8, 131.1, 130.7, 130.5, 129.0, 114.8, 112.4, 111.5, 101.2, 55.6, 52.0, 30.0, 13.2; HRMS (ESI-TOF): Anal. Calcd. For C₂₀H₁₈ ³⁵ClNO₄+H⁺: 372.0997, Found: 372.0994. Anal. Calcd. For C₂₀H₁₈ ³⁷ClNO₄+H⁺:374.0968, Found: 374.0947; IR (neat, cm^-1): υ 2984, 1736, 1687, 1594, 1479, 1372, 1325, 1044, 846, 755.

EXAMPLE seven

To the reaction tube were added the drug molecule 1f (Flurbiprofen) (0.5 mmol, 122.2 mg), methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3f can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 87%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.58 – 7.55 (m, 2H), 7.49 – 7.36 (m, 4H), 7.20 – 7.14 (m, 2H), 3.79 (q, J = 7.2 Hz, 1H), 3.72 (s, 3H), 1.57 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 174.4, 159.6 (J = 248.2 Hz), 141.8 (J = 7.6 Hz),135.4, 130.8 (J = 3.8 Hz), 128.9 (J = 2.9 Hz), 128.4, 127.8 (J = 13.7 Hz), 127.6, 123.5 (J = 3.5 Hz), 115.2 (J = 23.5 Hz), 52.1, 44.8, 18.3; ¹⁹F NMR (376 MHz, CDCl₃) δ -117.52; MS (EI) calculated for [C₁₆H₁₅FO₂]: 258.1, Found: 258.1; IR (neat, cm^-1): υ 2982, 2920, 2850, 1734, 1561, 1482, 1416, 1170, 910, 694.

Example eight

To a reaction tube were added sequentially 1g of drug molecule (Cipro fibrate) (0.5 mmol, 144.6 mg), methanol containing 40mol% t-butyl nitrite; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing the solvent by silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain 3g of a product, wherein the yield is 79%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.11 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.7 Hz, 2H), 3.75 (s, 3H), 2.82 (dd, J = 10.7, 8.4 Hz, 1H), 1.92 (dd, J = 10.7, 7.4 Hz, 1H), 1.81 – 1.72 (m, 1H), 1.59 (s, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 174.6, 154.7, 129.6, 128.2, 118.7, 79.1, 60.8, 52.4, 34.7, 25.7, 25.29, 25.28; HRMS (ESI-TOF): Anal. Calcd. For C₁₄H₁₆ ³⁵Cl₂O₃+Na⁺: 325.0369, Found: 325.0370. Anal. Calcd. For C₁₄H₁₆ ³⁵Cl³⁷ClO₃+Na⁺: 327.0339, Found: 327.0346. Anal. Calcd. For C₁₄H₁₆ ³⁷Cl³⁷ClO₃+Na⁺: 329.0310, Found: 329.0300; IR (neat, cm^-1): υ 2995, 2951, 1735, 1611, 1510, 1287, 1241, 1136, 831, 760.

Example nine

To a reaction tube were added drug molecules 1h (Bendazac) (0.5 mmol, 141.2 mg), methanol containing 40mol% tert-butyl nitrite in sequence; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product for 3 hours, wherein the yield is 96%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J = 8.1 Hz, 1H), 7.29 – 7.16 (m, 4H), 7.13 – 7.08 (m, 3H), 7.04 – 6.98 (m, 1H), 5.29 (s, 2H), 4.95 (s, 2H), 3.68 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.2, 154.6, 141.6, 137.2, 128.4, 127.36, 127.32, 126.8, 119.9, 119.3, 112.3, 108.8, 65.2, 52.1, 51.8; HRMS (ESI-TOF): Anal. Calcd. For C₁₇H₁₆N₂O₃+Na⁺: 319.1053, Found: 319.1068; IR (neat, cm^-1): υ 3061, 3031, 2940, 2851, 1748, 1527, 1494, 1224, 1055, 742, 720.

Example ten

Adding drug molecule 1i (Nateglinide) (0.5 mmol, 158.8 mg) and methanol containing 40mol% of tert-butyl nitrite into a reaction tube in sequence; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3i can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 87%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.30 – 7.20 (m, 3H), 7.10 – 7.06 (m, 2H), 6.01 (d, J = 7.7 Hz, 1H), 4.91 – 4.86 (m, 1H), 3.71 (s, 3H), 3.16 (dd, J = 13.8, 5.8 Hz, 1H), 3.07 (dd, J = 13.8, 5.8 Hz, 1H), 2.05 – 1.97 (m, 1H), 1.92 – 1.81 (m, 2H), 1.80 – 1.72 (m, 2H), 1.46 – 1.33 (m, 3H), 1.09 – 0.90 (m, 3H), 0.85 (d, J = 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 175.5, 172.1, 135.8, 129.2, 128.3, 126.9, 52.6, 52.1, 45.3, 43.1, 37.7, 32.6, 29.6, 29.3, 28.85, 28.76, 19.6; HRMS (ESI-TOF): Anal. Calcd. For C₂₀H₂₉NO₃+Na⁺: 354.2040, Found: 354.2044; IR (neat, cm^-1): υ 3314, 3064, 3027, 2940, 2853, 1730, 1636, 1542, 1441, 1227, 1175, 696, 667.

EXAMPLE eleven

To a reaction tube were added drug molecules 1j (MCPA) (0.5 mmol, 100.4 mg) and methanol containing 40mol% t-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for column chromatography to obtain a product 3j, wherein the yield is 99%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.12 (d, J = 2.1 Hz, 1H), 7.08 – 7.05 (m, 1H), 6.60 (d, J = 8.7 Hz, 1H), 4.61 (s, 2H), 3.78 (s, 3H), 2.25 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 169.2, 154.6, 130.8, 129.2, 126.27, 126.17, 112.3, 65.7, 52.2, 16.1; MS (EI) calculated for [C₁₀H₁₁ClO₃]: 214.0, Found: 214.0; IR (neat, cm^-1): υ 2955, 2927, 1759, 1490, 1437, 1177, 800, 647.

Example twelve

To a reaction tube were added drug molecule 1k (Myristic acid) (0.5 mmol, 114.2 mg), methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain a product 3k, wherein the yield is 99%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 3.63 (s, 3H), 2.27 (t, J = 7.6 Hz, 2H), 1.63 – 1.55 (m, 2H), 1.26 – 1.23 (m, 20H), 0.85 (t, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 174.2, 51.3, 34.0,31.9, 29.63, 29.60, 29.55, 29.4, 29.3, 29.2, 29.1, 24.9, 22.6, 14.0; MS (EI) calculated for [C₁₅H₃₀O₂]: 242.2, Found: 242.3; IR (neat, cm^-1): υ 2923, 2853, 1742, 1465, 1436, 1362, 1169, 1016, 722.

EXAMPLE thirteen

To a reaction tube were added sequentially drug molecules 1m (Aceclofenac) (0.5 mmol, 117.1 mg), methanol containing 40mol% of tert-butyl nitrite; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3m can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 63%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.32 (d, J = 8.1 Hz, 2H), 7.26 – 7.24 (m, 1H), 7.14 – 7.10 (m, 1H), 6.96 (t, J = 8.0 Hz, 2H), 6.70 (s, 1H), 6.55 (d, J= 8.0 Hz, 1H), 4.67 (s, 2H), 3.93 (s, 2H), 3.71 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 167.8, 142.6, 137.7, 130.9, 129.4, 128.8, 128.1, 124.0, 123.8, 122.1, 118.4, 61.1, 52.2, 37.9; HRMS (ESI-TOF): Anal. Calcd. For C₁₇H₁₅ ³⁵Cl₂NO₄+Na⁺: 390.0270, Found: 390.0280. Anal. Calcd. For C₁₇H₁₅ ³⁵Cl³⁷ClNO₄+Na⁺: 392.0241, Found: 392.0237. Anal. Calcd. For C₁₇H₁₅ ³⁷Cl³⁷ClNO₄+Na⁺: 394.0211, Found: 394.0190; IR (neat, cm^-1): υ 3353, 2955, 1743, 1718, 1505, 1454, 1279, 1228, 1148, 1003, 778, 745.

Example fourteen

Adding drug molecules 1n (Isoxepac) (0.5 mmol, 134.2 mg) and methanol containing 40mol% of tert-butyl nitrite into a reaction tube in sequence; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3n, wherein the yield is 96%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 2.3 Hz, 1H), 7.86 – 7.83 (m, 1H), 7.51 – 7.47 (m, 1H), 7.43 – 7.37(m, 2H), 7.30 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.12 (s, 2H), 3.66 (s, 3H), 3.61 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 190.5, 171.6, 160.3, 140.19, 136.1, 135.4, 132.6, 132.2, 129.2, 129.0, 127.6, 127.5, 124.9, 120.9, 73.4, 51.9, 39.8; HRMS (ESI-TOF): Anal. Calcd. For C₁₇H₁₄O₄+Na⁺: 291.0992, Found: 291.0987; IR (neat, cm^-1): υ 2952, 1733, 1645, 1489, 1299, 1138, 1012, 829, 760.

Example fifteen

Add compound 1o (0.5 mmol, 109.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3o can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 86%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.81 – 7.75 (m, 2H), 7.69 – 7.64 (m, 2H), 3.93 (t, J = 7.2 Hz, 2H), 3.62 (s, 3H), 2.68 (t, J = 7.2 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 167.8, 133.9, 131.8, 123.1, 51.7, 33.6, 32.6; HRMS (ESI-TOF): Anal. Calcd. For C₁₂H₁₁NO₄+Na⁺: 256.0580, Found: 256.0594; IR(neat, cm^-1): υ 3034, 2954, 1775, 1709, 1444, 1373, 1206, 1114, 1007, 891, 715.

Example sixteen

Add compound 1p (0.5 mmol, 155.7 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3p, wherein the yield is 95%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.75 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.4 Hz, 2H), 7.41 – 7.37 (m, 2H), 7.32 – 7.29 (m, 2H), 5.50 (s, 1H), 4.40 (d, J = 7.0 Hz, 2H), 4.20 (t, J = 7.0 Hz, 1H), 3.68 (s, 3H), 3.49 –7.35 (m, 2H), 2.55 (t, J = 5.9 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 172.6, 156.2, 143.7, 141.1, 127.5, 126.8, 124.9, 119.8, 66.5, 51.5, 47.0, 36.4, 34.0; HRMS (ESI-TOF): Anal. Calcd. For C₁₉H₁₉NO₄+Na⁺: 348.1206, Found: 348.1216; IR(neat, cm^-1): υ 3440, 3307, 3063, 3039, 3001, 2952, 1736, 1686, 1549, 1266, 734.

Example seventeen

Add compound 1q (0.5 mmol, 148.7 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3q, wherein the yield is 95%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 7.5 Hz, 2H), 7.62 (d, J = 7.4 Hz, 2H), 7.42 – 7.39 (m, 2H), 7.34 – 7.30 (m, 2H), 5.61 – 5.44 (m, 1H), 4.43 – 4.42 (m, 2H), 4.25 – 4.22 (m, 1H), 3.99 –3.85 (m, 2H), 3.73 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 156.2, 143.6, 141.1, 127.5, 126.9, 124.9, 119.8, 66.9, 52.1, 46.9, 42.4; HRMS (ESI-TOF): Anal. Calcd. For C₁₈H₁₇NO₄ +Na⁺: 334.1050, Found: 334.1063; IR (neat, cm^-1): υ 3285, 2952, 1739, 1690, 1551, 1438, 1247, 1000, 748.

EXAMPLE eighteen

Add compound 1r (0.5 mmol, 205.8 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3r, wherein the yield is 71%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.77 – 7.75 (m, 2H), 7.61 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.31 – 7.29 (m, 2H), 5.85 (d, J = 8.1 Hz, 1H), 4.61 – 4.51 (m, 1H), 4.44 – 4.34 (m, 2H), 4.23 (t, J = 7.2 Hz, 1H), 3.70 (s, 3H), 3.00 (dd, J = 16.8, 4.6 Hz, 1H), 2.85 (dd, J = 16.8, 4.8 Hz, 1H), 1.48 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 171.1, 169.5, 155.8, 143.8, 143.6, 141.4, 127.6, 126.9, 125.0, 119.8, 82.5, 67.0, 51.8, 50.8, 47.0, 36.6, 27.7; HRMS (ESI-TOF): Anal. Calcd. For C₂₄H₂₇NO₆ +Na⁺: 448.1731, Found: 448.1725; IR (neat, cm^-1): υ 3319, 2946, 1749, 1690, 1530, 1445, 1310, 1253, 1036, 737.

Example nineteen

Add compound 1s (0.5 mmol, 205.3 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product is obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 66 percent. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.76 – 7.74 (m, 2H), 7.59 (s, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (m, 2H), 6.08 (d, J = 7.2 Hz, 1H), 5.95 – 5.79 (m, 1H), 5.44 (s, 1H), 5.22 (dd, J = 35.1, 13.8 Hz, 2H), 4.61 – 4.34 (m, 5H), 4.21 (t, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.61 (d, J = 5.0 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 170.8, 156.7, 156.0, 143.64, 143.55, 141.13, 141.11, 132.4, 127.6, 126.9, 125.0, 119.8, 117.7, 67.0, 65.7, 54.5, 52.6, 46.9, 42.4; HRMS (ESI-TOF): Anal. Calcd. For C₂₃H₂₄N₂O₆ +Na⁺: 447.1527, Found: 447.1530; IR (neat, cm^-1): υ 3368, 2977, 2952, 2853, 1723, 1536, 1446, 1404, 1228, 1151, 1040, 845.

Example twenty

Adding 1t (0.5 mmol, 104.6 mg) of the compound and methanol containing 40mol% of tert-butyl nitrite into a reaction test tube in sequence; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3t, wherein the yield is 92%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.39 – 7.27 (m, 5H), 5.50 (s, 1H), 5.11 (s, 2H), 3.94 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4, 156.2, 136.1, 128.6, 128.0, 127.9, 66.9, 52.1, 42.5; HRMS (ESI-TOF): Anal. Calcd. For C₁₁H₁₃NO₄ +Na⁺: 246.0737, Found: 246.0755; IR (neat, cm^-1): υ 3347, 2954, 2923, 2851, 1703, 1522, 1438, 1367, 1205, 1053, 1003, 697.

Example twenty one

Add compound 1u (0.5 mmol, 89.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain a product 3u, wherein the yield is 95%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.79 – 7.77 (m, 2H), 7.49 – 7.43 (m, 1H), 7.39 – 7.35 (m, 2H), 7.09 (s, 1H), 4.17 (d, J = 5.3 Hz, 2H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.4,167.6, 133.4, 131.6, 128.4, 127.0, 52.2, 41.5; HRMS (ESI-TOF): Anal. Calcd. For C₁₀H₁₁NO₃ +Na⁺: 216.0631, Found: 216.0636; IR (neat, cm^-1): υ 3337, 2955, 1748, 1652, 1540, 1489, 1438, 1372, 1211, 906, 725.

Example twenty two

Add compound 1v (0.5 mmol, 111.7 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3v, wherein the yield is 93%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.37 – 7.26 (m, 5H), 5.53 (d, J = 6.5 Hz, 1H), 5.17 – 5.04 (m, 2H), 4.41 – 4.34 (m, 1H), 3.71 (s, 3H), 1.38 (d, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.4, 155.5, 136.2, 128.3, 127.97, 127.93, 66.7, 52.2, 49.4, 18.3; HRMS (ESI-TOF): Anal. Calcd. For C₁₂H₁₅NO₄ +Na⁺: 260.0893, Found: 260.0899; IR (neat, cm^-1): υ 3338, 3036, 2992, 2957, 1751, 1682, 1524, 1463, 1212, 1171, 1071, 751, 698.

Example twenty three

Add compound 1w (0.5 mmol, 155.7 mg), methanol containing 40mol% of tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3w, wherein the yield is 80%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.77 (d, J = 7.5 Hz, 2H), 7.62 (t, J = 6.6 Hz, 2H), 7.42 – 7.39 (m, 2H), 7.34 – 7.30 (m, 2H), 5.58 (d, J = 7.4 Hz, 1H), 4.52 – 4.33 (m, 3H), 4.24 (t, J = 7.0 Hz, 1H), 3.75 (s, 3H), 1.44 (d, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.4, 155.6, 143.8, 143.6, 141.1, 127.5, 126.9, 124.9, 119.8, 66.8, 52.3, 49.4, 47.0, 18.4; HRMS (ESI-TOF): Anal. Calcd. For C₁₉H₁₉NO₄+Na⁺: 348.1206, Found: 348.1208; IR (neat, cm^-1): υ 3328, 2956, 2919, 1726, 1604, 1590, 1465, 1317, 1163, 1026, 849.

Example twenty-four

Add compound 1x (0.5 mmol, 77.1 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3x, wherein the yield is 65%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.27 – 7.21 (m, 2H), 7.04 – 6.97 (m, 2H), 3.69 (s, 3H), 3.60 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 162.0 (d, J = 245.4 Hz), 130.8 (d, J = 8.1 Hz), 129.6 (d, J = 3.3 Hz), 115.4 (d, J = 21.5 Hz), 52.1, 40.2; ¹⁹F NMR (376 MHz, CDCl₃) δ -115.73; MS (EI) calculated for [C₉H₉FO₂]: 168.1, Found: 168.1; IR (neat, cm^-1): υ 3044, 2976, 2955, 1736, 1604, 1509, 1436, 1259, 1221, 1154, 1014, 823.

Example twenty-five

Add Compound 1y (0.5 mmol, 107.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3y can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 92%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.46 – 7.41 (m, 2H), 7.17 – 7.14 (m, 2H), 3.69 (s, 3H), 3.57 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.4, 132.8, 131.6, 130.9, 121.1, 52.1, 42.4; MS (EI) calculated for [C₉H₉BrO₂]: 228.0, Found: 228.0; IR (neat, cm^-1): υ 2951, 1734, 1489, 1435, 1253, 1158, 1071, 1012, 802.

Example twenty-six

To a reaction tube were added compound 1z (0.5 mmol, 131.1 mg) and methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3z, wherein the yield is 90%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 8.2 Hz, 2H), 3.68 (s, 3H), 3.56 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.3, 137.5, 133.5, 131.2, 92.6, 52.1, 40.5; MS (EI) calculated for [C₉H₉IO₂]: 276.0, Found: 276.0; IR (neat, cm^-1): υ 3002, 2955, 1487, 1437, 1343, 1164, 1008, 800.

Example twenty-seven

Add compound 1aa (0.5 mmol, 75.1 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3aa, wherein the yield is 73%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.17 (q, J = 8.1 Hz, 4H), 3.70 (s, 3H), 3.60 (s, 2H), 2.35 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.2, 136.7, 130.9, 129.2, 129.1, 51.9, 40.7, 21.0; MS (EI) calculated for [C₁₀H₁₂O₂]: 169.1, Found: 169.1; IR (neat, cm^-1): υ 3024, 2952, 2924, 1736, 1516, 1435, 1255, 1152, 1015, 807, 722.

Example twenty-eight

Add compound 1ab (0.5 mmol, 83.1 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3ab can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 93%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.24 – 7.21 (m, 1H), 6.88 – 6.78 (m, 3H), 3.78 (s, 3H), 3.68 (s, 3H), 3.59 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.8, 159.6, 135.3, 129.4, 121.5, 114.8, 112.5, 55.1, 51.9, 41.1; HRMS (ESI-TOF): Anal. Calcd. For C₁₀H₁₂O₃ +Na⁺: 203.0679, Found: 203.0694; IR (neat, cm^-1): υ 2952, 2838, 1734, 1600, 1491, 1435, 1259, 1148, 1049, 770, 690.

Example twenty-nine

Add compound 1ac (0.5 mmol, 76.1 mg), methanol containing 40mol% of tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3ac, wherein the yield is 72%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.40 (s, 1H), 7.21 – 7.15 (m, 1H), 7.10 – 7.12 (m, 1H), 6.86 – 6.91(m, 2H), 3.74 (s, 3H), 3.69 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 174.2, 154.9, 130.9, 129.0, 120.7, 120.5, 117.2, 52.6, 37.2; HRMS (ESI-TOF): Anal. Calcd. For C₉H₁₀O₃+Na⁺: 189.0522, Found: 189.0529; IR (neat, cm^-1): υ 3420, 2985, 2956, 1734, 1599, 1459, 1374, 1239, 1043, 755.

Example thirty

Add compound 1ad (0.5 mmol, 82.1 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3ad with the yield of 88%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.12 – 7.00 (m, 3H), 3.71 (s, 3H), 3.63 (s, 2H), 2.33 (s, 3H), 2.30 (s, 3H); ¹³C NMR (100MHz, CDCl₃) δ 172.0, 135.5, 133.5, 132.4, 130.8, 130.2, 128.0, 51.9, 38.9, 20.8, 19.0; HRMS (ESI-TOF): Anal. Calcd. For C₁₁H₁₄O₂ +Na⁺: 201.0886, Found: 201.0884; IR (neat, cm^-1): υ 3002, 2952, 2923, 1734, 1506, 1435, 1253, 1153, 1014, 810.

Example thirty one

Add Compound 1ae (0.5 mmol, 76.1 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain the product 3ae, wherein the yield is 90%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.46 – 7.28 (m, 5H), 5.18 (s, 1H), 3.74 (s, 3H);¹³C NMR (100 MHz, CDCl₃) δ 174.0, 138.2, 128.52, 128.41, 126.5, 72.8, 52.9; HRMS (ESI-TOF): Anal. Calcd. For C₉H₁₀O₃+Na⁺: 189.0522, Found: 189.0531; IR (neat, cm^-1): υ 3438, 2952, 1737, 1490, 1455, 1261, 1200, 1095, 1067, 981, 733.

Example thirty-two

Add compound 1af (0.5 mmol, 115.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain a product 3af, wherein the yield is 93%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.51 – 7.44 (m, 2H), 7.32 – 7.27 (m, 2H), 5.13 (d, J = 4.2 Hz, 1H), 3.74 (s, 3H), 3.67 (d, J = 5.0 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 173.5, 137.1, 131.6, 128.2, 122.4,72.2, 53.1; MS (EI) calculated for [C₉H₉BrO₃]: 244.0, Found: 244.0; IR (neat, cm^-1): υ 3329, 2950, 1732, 1484, 1435, 1213, 1088, 1003, 981, 762.

Example thirty-three

Add compound 1ag (0.5 mmol, 115.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3ag, wherein the yield is 91%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 8.34 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 3.66 (s, 3H), 3.56 (s, 2H), 2.08 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.2, 168.9, 137.1, 129.53, 129.38, 120.1, 51.9, 40.4, 24.1; HRMS (ESI-TOF): Anal. Calcd. For C₁₁H₁₃NO₃+Na⁺: 230.0788, Found: 230.0804; IR (neat, cm^-1): υ 3285, 3287, 3064, 3005, 2954, 1727, 1662, 1507, 1432, 1251, 1014.

Example thirty-four

Add compound 1ah (0.5 mmol, 116.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product of 3ah with the yield of 85%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.45 – 7.25 (m, 5H), 4.52 (s, 1H), 3.73 (s, 1H), 3.69 (s, 3H), 3.04 (s, 2H), 2.60 (tt, J = 10.7, 3.9 Hz, 1H), 2.11 – 1.55 (m, 4H); ¹³C NMR (100 MHz, CDCl₃) δ 174.4, 170.2, 135.7, 129.4, 128.2, 126.5, 51.6, 46.6, 41.2, 40.6, 28.2, 27.7; HRMS (ESI-TOF): Anal. Calcd. For C₁₄H₁₇NO₃+Na⁺: 270.1101, Found: 270.1111; IR (neat, cm^-1): υ 3058, 2999, 2859, 1729, 1625, 1432, 1176, 1146, 1038, 708.

Example thirty-five

Add Compound 1ai (0.5 mmol, 96.2 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3ai can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 95%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.95 – 7.89 (m, 2H), 7.55 – 7.49 (m, 1H), 7.43 – 7.40 (m, 2H), 3.64 (s, 3H), 3.01 (t, J = 7.2 Hz, 2H), 2.41 (t, J = 7.2 Hz, 2H), 2.07 – 2.00 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 199.2, 173.5, 136.6, 132.9, 128.4, 127.9, 51.4, 37.3, 32.9, 19.2; HRMS (ESI-TOF): Anal. Calcd. For C₁₂H₁₄O₃+Na⁺: 229.0835, Found: 229.0836; IR (neat, cm^-1): υ 2952, 1732, 1683, 1598, 1448, 1210, 1001, 741, 690.

Example thirty-six

Add compound 1aj (0.5 mmol, 88.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3aj, wherein the yield is 88%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.70 – 7.67 (m, 1H), 7.58 – 7.48 (m, 2H), 7.32 – 7.28 (m, 1H), 4.04 (s, 2H), 3.72 (s, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 168.6, 163.2, 152.3, 129.9, 123.6, 121.6, 121.1, 109.8, 52.4, 31.3; HRMS (ESI-TOF): Anal. Calcd. For C₁₀H₉NO₃+Na⁺: 214.0475, Found: 214.0466; IR (neat, cm^-1): υ 2955, 2849, 1739, 1610, 1522, 1437, 1204, 1007, 748.

Example thirty-seven

To a reaction tube were added compound 1ak (0.5 mmol, 97.6 mg) and methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain a product 3ak, wherein the yield is 89%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 8.09 (d, J = 8.8 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H), 3.63 (s, 3H), 3.02 (t, J = 7.5 Hz, 2H), 2.65 (t, J = 7.5 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 172.4, 148.2, 146.5, 129.1, 123.6, 51.6, 34.6, 30.5; HRMS (ESI-TOF): Anal. Calcd. For C₁₀H₁₁NO₄+Na⁺: 232.0580, Found: 232.0580; IR (neat, cm^-1): υ 3083, 2958, 1728, 1514, 1345, 1296, 1191, 1170, 854, 750.

Example thirty-eight

Add compound 1al (0.5 mmol, 114.6 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3al, wherein the yield is 93%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.42 – 7.35 (m, 2H), 7.10 – 7.03 (m, 2H), 3.65 (s, 3H), 2.89 (t, J = 7.7 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 172.9, 139.4, 131.4, 130.0, 120.0, 51.5,35.3, 30.2; MS (EI) calculated for [C₁₀H₁₁BrO₂]: 242.0, Found: 242.0; IR (neat, cm^-1): υ 2951, 1734, 1489, 1436, 1363, 1171, 1156, 1011, 814.

Example thirty-nine

Add Compound 1am (0.5 mmol, 105.2 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, the mixed solvent of ethyl acetate and petroleum ether is used for carrying out column chromatography to obtain the product 3am, wherein the yield is 95%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 6.76 – 6.73 (m, 1H), 6.70 – 6.68 (m, 2H), 3.81 (d, J = 7.1 Hz, 6H), 3.62 (s, 3H), 2.85 (t, J = 7.8 Hz, 2H), 2.57 (t, J= 7.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 173.1, 148.7, 147.3, 132.9, 119.9, 111.4, 111.1, 55.7, 55.6, 51.3, 35.7, 30.4; HRMS (ESI-TOF): Anal. Calcd. For C₁₂H₁₆O₄+Na⁺: 247.0941, Found: 247.0949; IR (neat, cm^-1): υ 2996, 2966, 2840, 1730, 1589, 1514, 1153, 1026, 810.

Example forty

Adding 0.5mmol of compound 1an, 175.7 mg) and methanol containing 40mol% of tert-butyl nitrite into a reaction test tube in sequence; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3an, wherein the yield is 78%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.39 – 7.27 (m, 5H), 5.21 – 5.06 (m, 2H), 4.20 (d, J = 35.8 Hz, 1H), 3.97 (dt, J = 13.2, 3.8 Hz, 1H), 3.66 (s, 3H), 3.07 (d, J = 33.2 Hz, 1H), 2.95 – 2.83 (m, 1H), 2.47 (s, 1H), 2.08 – 1.98 (m, 1H), 1.78 – 1.37 (m, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 173.5, 155.0, 136.6, 128.4, 127.9, 127.8, 51.7, 45.7, 44.1, 41.1, 27.1, 24.0; HRMS (ESI-TOF): Anal. Calcd. For C₁₅H₁₉NO₄+Na⁺: 300.1206, Found: 300.1216; IR (neat, cm^-1): υ 3032, 2950, 2861, 1732, 1695, 1469, 1428, 1233, 1138, 1017, 697.

Example forty one

To a reaction tube were added compound 1ao (0.5 mmol, 84.6 mg), methanol containing 40mol% of tert-butyl nitrite in that order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, quenching the reaction product by using a saturated sodium chloride solution, extracting the reaction product by using ethyl acetate, removing a solvent by using a rotary evaporator, adsorbing the solvent by using silica gel, and finally performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3ao, wherein the yield is 96%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 6.66 (s, 2H), 3.76 (t, J = 7.1 Hz, 2H), 3.60 (s, 3H), 2.57 (t, J = 7.1 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.0, 170.2, 134.1, 51.7, 33.4, 32.5; HRMS (ESI-TOF): Anal. Calcd. For C₈H₉NO₄ +Na⁺: 206.0424, Found: 204.0411; IR (neat, cm^-1): υ 3101, 2955, 2850, 1735, 1699, 1443, 1408, 1374, 1199, 826.

Example forty two

Add compound 1ap (0.5 mmol, 82.1 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, the solvent is removed by a rotary evaporator, silica gel is used for adsorption, and finally, the product 3ap can be obtained by performing column chromatography by using a mixed solvent of ethyl acetate and petroleum ether, wherein the yield is 86%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.33 – 7.27 (m, 2H), 7.23 – 7.17 (m, 3H), 3.68 (s, 3H), 2.67 (t, J = 7.6 Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 2.04 – 1.92 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 173.9, 141.3, 128.44, 128.34, 125.9, 51.5, 35.1, 33.3, 26.4; MS (EI) calculated for [C₁₁H₁₄O₂]: 178.1, Found: 178.1; IR (neat, cm^-1): υ 3029, 2950, 2859, 1735, 1603, 1497, 1202, 1144, 745, 699.

Example forty-three

To a reaction tube were added compound 1aq (0.5 mmol, 83.1 mg), methanol containing 40mol% of tert-butyl nitrite in sequence; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally, column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain a product 3aq, wherein the yield is 90%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.29 – 7.24 (m, 2H), 6.99 – 6.94 (m, 1H), 6.89 – 6.84 (m, 2H), 4.76 (q, J = 6.8 Hz, 1H), 3.74 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 172.7, 157.5, 129.5, 121.5, 115.0, 72.4, 52.2, 18.5; HRMS (ESI-TOF): Anal. Calcd. For C₁₀H₁₂O₃ +Na⁺: 203.0679, Found: 203.0687; IR (neat, cm^-1): υ 2992, 2954, 1736, 1588, 1493, 1376, 1282, 1132, 977, 751, 690.

Example forty-four

Add Compound 1ar (0.5 mmol, 106.2 mg), methanol containing 40mol% tert-butyl nitrite to the reaction tube in order; then reacting for 48 hours at 40 ℃ in the air; after the reaction is finished, sodium thiosulfate is added for stirring and quenching, a rotary evaporator is used for removing the solvent and adsorbing silica gel, and finally column chromatography is carried out by using a mixed solvent of ethyl acetate and petroleum ether to obtain the product 3ar with the yield of 98%. The main test data of the prepared product are as follows, and the actual synthesized product is consistent with the theoretical analysis through analysis.

¹H NMR (400 MHz, CDCl₃) δ 7.66 – 7.59 (m, 4H), 7.50 – 7.46 (m, 2H), 7.44 – 7.36 (m, 3H), 3.76 (s, 3H), 3.72 (s, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 171.9, 140.6, 140.0, 132.9, 129.6, 128.7, 127.21, 127.17, 126.9, 52.0, 40.7; HRMS (ESI-TOF): Anal. Calcd. For C₁₅H₁₄O₂ +Na⁺: 249.0886, Found: 249.0890; IR (neat, cm^-1): υ 3029, 2951, 1733, 1488, 1435, 1250, 1154, 1009, 754, 697.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, it should be noted that, for those skilled in the art, many modifications and variations can be made without departing from the technical principle of the present invention, and these modifications and variations should also be regarded as the protection scope of the present invention. The method has the advantages of rich raw material sources, simple and convenient operation, strong functional group compatibility, good substrate universality, greenness and safety, can carry out methyl esterification modification on a series of known drug molecules, and is a shortcut | for developing and discovering new drug molecules or physiologically active molecules!