A method for synthesizing a malonic acid derivative

Abstract

The present invention discloses a method for synthesizing malonic acid derivatives, which comprises the following steps: dispersing cyclopropanol compounds, bases and organozinc in a solvent, and then introducing carbon dioxide for reaction to obtain malonic acid derivatives. The method for synthesizing malonic acid derivatives of the present invention has the advantages of easily available raw materials, no need for transition metal catalysts, mild reaction conditions, high atom economy, good adaptability to functional groups, wide substrate applicability, etc., and is safe and simple to operate, facilitating industrial production and having great potential application value.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a method for synthesizing malonic acid derivatives. Background Art

[0002] Carbon dioxide (CO2) is a non-toxic, inexpensive, and abundant atmospheric resource, which can be converted into valuable chemical substances such as alcohols, aldehydes and ketones, carboxylic acids, etc. through a reduction process as a renewable C1 synthon (Klankermayer, J.; Wesselbaum, S.; Beydoun, K.; Leitner, Walter. Angew. Chem. Int. Ed. 2016, 55, 7296 - 7343; Janes, T.; Yang Y.; Song, D. Chem. Commun. 2017, 53, 11390 - 11398.).

[0003] Carboxylic acid compounds have important applications in human production and life. They are important intermediates for many drugs and active molecules, and their synthesis processes have attracted much attention (Fan, Z.; Zhang, Z.; Xi, C. ChemSusChem 2020, 13, 6201 - 6218). Malonic acid is an important synthon and is widely used in the construction of pharmaceuticals, pesticides, fragrances, natural products, and other molecules. Functionalized malonic acids are commonly present in various bio-related molecules. For example, luminal is an important drug for treating epilepsy; carboplatin is a broad-spectrum anti-tumor drug; norfloxacin is commonly used to treat enteritis and dysentery; isopropyl mercaptan is a low-toxicity and highly effective rice fungicide. With the wide application of malonic acid derivatives, it is crucial to develop highly selective and flexible synthetic routes for malonic acid derivatives. In recent years, researchers have synthesized dicarboxylation products by using some activated alkenes (Xu, P.; Wang, S.; Xu, H.; Liu, Y.-Q.; Li, R.-B.; Liu, W.-W.; Wang, X.-Y.; Zou, M.-L.; Zhou, Y.; Guo, D.; Zhu, X. ACS Catal. 2023, 13, 2149 - 2155; Ju, T.; Zhou, Y.-Q.; Cao, K.-G.; Fu, Q.; Ye, J.-H.; Sun, G.-Q.; Liu, X.-F.; Chen, L.; Liao, L.-L.; Yu, D.-G. Nat. Chem. 2021, 4, 304 - 311; You, Y.; Kanna, W.; Takano, H.; Hayashi, H.; Maeda, S.; Mita, T. J. Am. Chem. Soc. 2022, 144, 3685 - 3695.), alkynes (Liao, L.-L.; Wang, Z.-H.; Cao, K.-G.; Sun, G.-Q.; Zhang, W.; Ran, C.-K., Li, Y.; Chen, L.; Cao, G.-M.; Yu, D.-G. J. Am. Chem. Soc. 2022, 144, 2062 - 2068.), cycloalkanes (Fujihara, T.; Horimoto, Y.; Mizoe, T.; Sayyed, F. B.; Tani, Y.; Terao, J.; Sakaki, S.; Tsuji, Y. Org. Lett. 2014, 16, 4960 - 4963.), and a few unactivated alkenes and alkynes under transition metal catalysis, photocatalysis, electrocatalysis, and base-promoted conditions (Song, L.; Wang, W.; Yue, J.-P.; Jiang, Y.-X.; Wei, M.-K.; Zhang, H.-P.; Yan, S.-S.; Liao, L.-L.; Yu, D.-G. Nat. Chem.2022, 5, 832 - 838; Takahashi, K.; Sakurazawa, Y.; Iwai, A.; Iwasawa, N. ACS Catal. 2022, 12, 3776 - 3781.), but currently there are only the following two methods for synthesizing malonic acid derivatives using CO₂: 1) In 2017, the Skrydstrup research group first performed initial boration of terminal alkynes using 9 - BBN, and then synthesized malonic acid derivatives through copper - catalyzed gem - dicarboxylation (Juh, M.; Laursen, S. L. R.; Huang, Y.; Nielsen, D. U.; Daasbjerg, K.; Skrydstrup, T. ACS Catal. 2017, 7, 1392 - 1396); 2) Based on the Ni - catalyzed insertion of two molecules of CO₂ into olefins (Hoberg, H.; Ballesteros, A.; Sigan, A.; Jégat, C.;. D.; Milchereit, A. J. Organomet. Chem. 1991, 407, C23 - C29), the Iwasawa research group effectively converted ethylene into malonates using Ni / Ir catalysis (Takahashi, K.; Sakurazawa, Y.; Iwai, A.; Iwasawa, N. ACS Catal. 2022, 12, 3776 - 3781). However, the above two methods generally have problems such as high reaction temperature, cumbersome operation, and narrow substrate scope, and their applications are greatly limited.

[0004] Therefore, it is of great significance to develop a method for synthesizing malonic acid derivatives with the advantages of mild reaction conditions, wide substrate applicability, safe and simple operation, etc. Summary of the Invention

[0005] The purpose of the present invention is to provide a method for synthesizing malonic acid derivatives.

[0006] The technical solution adopted by the present invention is as follows:

[0007] A method for synthesizing malonic acid derivatives, which comprises the following steps: dispersing cyclopropanol compounds, a base, and organozinc in a solvent, and then introducing carbon dioxide for reaction to obtain malonic acid derivatives; the structural formula of the cyclopropanol compounds is: In the formula, R 1 is one of phenyl, p - tolyl, m - tolyl, o - tolyl, p - methoxyphenyl, p - chlorophenyl, p - fluorophenyl, p - bromophenyl, p - trifluoromethylphenyl, 3,4 - difluorophenyl, naphthyl, thiophenyl, furyl, cyclohexyl, pentyl, methyl, and R 2 is one of phenyl and naphthyl.

[0008] Preferably, the molar ratio of the cyclopropanol compound, the base, and the organozinc is 1:1.0-1.5:1.5-2.2.

[0009] Preferably, the base is at least one of potassium carbonate, triethylamine, 1,4-diazabicyclo[2.2.2]octane (DABCO), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0010] More preferably, the base is 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0011] Preferably, the organozinc is at least one of diethylzinc and dimethylzinc.

[0012] Preferably, the solvent is at least one of tetrahydrofuran (THF), toluene, dimethyl sulfoxide (DMSO), dichloromethane (DCM), and N,N-dimethylformamide (DMF).

[0013] Preferably, the reaction is carried out at 25°C to 60°C, and the reaction time is 6 h to 24 h.

[0014] More preferably, the reaction is carried out at 35°C to 40°C, and the reaction time is 10 h to 15 h.

[0015] Preferably, the reaction is carried out under the condition that the carbon dioxide pressure is 0.8 atm to 1.2 atm (0.8 to 1.2 atmospheres).

[0016] Preferably, the reaction is carried out under the condition that the stirring rate is 400 rpm to 700 rpm.

[0017] Preferably, after the reaction, the reaction solution is separated and purified.

[0018] Preferably, the specific operation of the separation and purification is as follows: washing and acidifying the reaction solution, extracting with ethyl acetate, taking the organic layer for drying, filtering and concentrating under reduced pressure, and then performing column chromatography purification.

[0019] Preferably, the eluent for the column chromatography is composed of dichloromethane and methanol in a volume ratio of 10-20:1.

[0020] Preferably, the specific operation of the separation and purification is as follows: washing and acidifying the reaction solution, extracting with ethyl acetate, taking the organic layer for drying, filtering and concentrating under reduced pressure, dissolving in a methanol-ether mixed solution, placing in a protective atmosphere and adding trimethylsilyldiazomethane for an esterification reaction, then concentrating under reduced pressure, and then performing column chromatography purification.

[0021] Preferably, the volume ratio of methanol to diethyl ether in the methanol-diethyl ether mixed solution is 3-5:1.

[0022] Preferably, the protective atmosphere is a nitrogen atmosphere.

[0023] Preferably, the esterification reaction is carried out at room temperature (25°C ± 5°C), and the reaction time is 1.5 h - 2.5 h.

[0024] Preferably, the eluent for column chromatography is composed of ethyl acetate and petroleum ether in a volume ratio of 3-5:1.

[0025] The synthesis reaction formula of the malonic acid derivative of the present invention is as follows:

[0026]

[0027] The beneficial effects of the present invention are as follows: The synthesis method of the malonic acid derivative of the present invention has the advantages of easily available raw materials, no need for transition metal catalysts, mild reaction conditions, high atom economy, good adaptability to functional groups, wide substrate applicability, etc., and the operation is safe and simple, facilitating industrial production, and has great potential application value. Description of the Drawings

[0028] Figure 1 1H NMR spectrum of the malonic acid derivative synthesized in Example 1.

[0029] Figure 2 13C NMR spectrum of the malonic acid derivative synthesized in Example 1.

[0030] Figure 3 1H NMR spectrum of the malonic acid derivative synthesized in Example 11.

[0031] Figure 4 13C NMR spectrum of the malonic acid derivative synthesized in Example 11.

[0032] Figure 5 1H NMR spectrum of the malonic acid derivative synthesized in Example 12.

[0033] Figure 6 13C NMR spectrum of the malonic acid derivative synthesized in Example 12.

[0034] Figure 7 1H NMR spectrum of the malonic acid derivative synthesized in Example 13.

[0035] Figure 8 13C NMR spectrum of the malonic acid derivative synthesized in Example 13.

[0036] Figure 91H NMR spectrum of the malonic acid derivative synthesized in Example 14.

[0037] Figure 10 13C NMR spectrum of the malonic acid derivative synthesized in Example 14.

[0038] Figure 11 1H NMR spectrum of the malonic acid derivative synthesized in Example 15.

[0039] Figure 12 13C NMR spectrum of the malonic acid derivative synthesized in Example 15.

[0040] Figure 13 1H NMR spectrum of the malonic acid derivative synthesized in Example 16.

[0041] Figure 14 13C NMR spectrum of the malonic acid derivative synthesized in Example 16.

[0042] Figure 15 1H NMR spectrum of the malonic acid derivative synthesized in Example 17.

[0043] Figure 16 13C NMR spectrum of the malonic acid derivative synthesized in Example 17.

[0044] Figure 17 1H NMR spectrum of the malonic acid derivative synthesized in Example 18.

[0045] Figure 18 13C NMR spectrum of the malonic acid derivative synthesized in Example 18.

[0046] Figure 19 1H NMR spectrum of the malonic acid derivative synthesized in Example 19.

[0047] Figure 20 13C NMR spectrum of the malonic acid derivative synthesized in Example 19.

[0048] Figure 21 1H NMR spectrum of the malonic acid derivative synthesized in Example 20.

[0049] Figure 22 13C NMR spectrum of the malonic acid derivative synthesized in Example 20.

[0050] Figure 23 1H NMR spectrum of the malonic acid derivative synthesized in Example 21.

[0051] Figure 24 13C NMR spectrum of the malonic acid derivative synthesized in Example 21. Detailed implementation mode

[0052] The present invention will be further explained and illustrated below in conjunction with specific embodiments.

[0053] Example 1:

[0054] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0055] Add 0.3 mmol of 1-phenylcyclopropanol, 0.3 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir and react at 40 °C for 12 h, the stirring rate is 600 rpm, then stop heating and stirring and cool to room temperature, then add 5 mL of water for washing, then add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases and dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol according to a volume ratio of 20:1, and the malonic acid derivative is obtained (yield: 81%).

[0056] The nuclear magnetic resonance hydrogen spectrum of the malonic acid derivative synthesized in this example is as Figure 1 shown, and the nuclear magnetic resonance carbon spectrum is as Figure 2 shown. The spectral data are as follows:

[0057] 1 H NMR (400 MHz, DMSO-d6): δ = 12.77 (s, 2H), 8.38 - 7.87 (m, 2H), 7.70 - 7.60 (m, 1H), 7.57 - 7.46 (m, 2H), 3.81 (t, J = 6.8 Hz, 1H), 3.54 (d, J = 7.2 Hz, 2H).

[0058] 13 C NMR (100 MHz, DMSO-d6): δ = 197.74, 171.07, 136.61, 134.12, 129.43, 128.60, 47.86, 38.24.

[0059] The infrared data and mass spectrum data of the malonic acid derivative synthesized in this example are as follows:

[0060] IR (KBr): 2925, 2211, 1664, 1578, 1466, 1009, 757, 526 cm -1 .

[0061] HRMS-ESI (m / z): Calcd for C11 H 11 O5[M+H] + : 223.0601; found: 223.0599.

[0062] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0063]

[0064] Example 2:

[0065] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0066] Add 0.3 mmol of 1-phenylcyclopropanol, 0.3 mmol of DABCO, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir at 40 °C for 12 h with a stirring rate of 600 rpm, stop heating and stirring, cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 40%; the product is the same as that in Example 1).

[0067] Example 3:

[0068] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0069] Add 0.3 mmol of 1-phenylcyclopropanol, 0.3 mmol of triethylamine, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, then stir at 40 °C for 12 h with a stirring rate of 600 rpm, stop heating and stirring, cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 26%; the product is the same as that in Example 1).

[0070] Example 4:

[0071] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0072] Add 0.3 mmol of 1-phenylcyclopropanol, 0.3 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of toluene into a reaction vessel (Schlenk tube). After evacuation, introduce carbon dioxide until the pressure inside the reaction vessel reaches 1 atm. Then, stir the reaction at 40 °C for 12 h with a stirring rate of 600 rpm. After stopping heating and stirring, cool to room temperature. Then, add 5 mL of water for washing, add 3 mL of 2 mol / L hydrochloric acid for acidification. Extract the aqueous layer with ethyl acetate three times. Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 75%; the product is the same as in Example 1).

[0073] Example 5:

[0074] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0075] Add 0.3 mmol of 1-phenylcyclopropanol, 0.3 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of dimethyl sulfoxide into a reaction vessel (Schlenk tube). After evacuation, introduce carbon dioxide until the pressure inside the reaction vessel reaches 1 atm. Then, stir the reaction at 40 °C for 12 h with a stirring rate of 600 rpm. After stopping heating and stirring, cool to room temperature. Then, add 5 mL of water for washing, add 3 mL of 2 mol / L hydrochloric acid for acidification. Extract the aqueous layer with ethyl acetate three times. Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 63%; the product is the same as in Example 1).

[0076] Example 6:

[0077] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0078] Add 0.3 mmol of 1-phenylcyclopropanol, 0.3 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube). After evacuation, introduce carbon dioxide until the pressure inside the reaction vessel reaches 1 atm. Then, stir the reaction at 35 °C for 12 h with a stirring rate of 600 rpm. After stopping heating and stirring, cool to room temperature. Then, add 5 mL of water for washing, add 3 mL of 2 mol / L hydrochloric acid for acidification. Extract the aqueous layer with ethyl acetate three times. Combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 70%; the product is the same as in Example 1).

[0079] Example 7:

[0080] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0081] Add 0.3 mmol of 1-phenylcyclopropanol, 0.36 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir and react at 35 °C for 12 h with a stirring rate of 600 rpm, stop heating and stirring and then cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then carry out column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 82%; the product is the same as that in Example 1).

[0082] Example 8:

[0083] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0084] Add 0.3 mmol of 1-phenylcyclopropanol, 0.45 mmol of DBU, 0.45 mmol of diethylzinc and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir and react at 35 °C for 12 h with a stirring rate of 600 rpm, stop heating and stirring and then cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then carry out column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 64%; the product is the same as that in Example 1).

[0085] Example 9:

[0086] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0087] 0.3 mmol of 1-phenylcyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran were added to a reaction vessel (Schlenk tube). After evacuation, carbon dioxide was introduced until the pressure in the reaction vessel reached 1 atm. The mixture was stirred at 35 °C for 12 h at a stirring rate of 600 rpm. Then, heating and stirring were stopped and the mixture was cooled to room temperature. 5 mL of water was added for washing, and then 3 mL of 2 mol / L hydrochloric acid was added for acidification. The aqueous layer was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was composed of dichloromethane and methanol in a volume ratio of 20:1, to obtain the malonic acid derivative (yield: 95%; the product was the same as in Example 1).

[0088] Example 10:

[0089] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0090] 0.3 mmol of 1-phenylcyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran were added to a reaction vessel (Schlenk tube). After evacuation, carbon dioxide was introduced until the pressure in the reaction vessel reached 1 atm. The mixture was stirred at 35 °C for 14 h at a stirring rate of 600 rpm. Then, heating and stirring were stopped and the mixture was cooled to room temperature. 5 mL of water was added for washing, and then 3 mL of 2 mol / L hydrochloric acid was added for acidification. The aqueous layer was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was composed of dichloromethane and methanol in a volume ratio of 20:1, to obtain the malonic acid derivative (yield: 96%; the product was the same as in Example 1).

[0091] Example 11:

[0092] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0093] 0.3 mmol of 1-(4-methylphenyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran were added to a reaction vessel (Schlenk tube). After evacuation, carbon dioxide was introduced until the pressure in the reaction vessel reached 1 atm. The mixture was stirred at 40 °C for 14 h at a stirring rate of 600 rpm. Then, heating and stirring were stopped and the mixture was cooled to room temperature. 5 mL of water was added for washing, and then 3 mL of 2 mol / L hydrochloric acid was added for acidification. The aqueous layer was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was composed of dichloromethane and methanol in a volume ratio of 20:1, to obtain the malonic acid derivative (yield: 91%).

[0094] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as follows Figure 3 shown, and the 13C NMR spectrum is as follows Figure 4 shown. The spectral data are as follows:

[0095] 1 H NMR (400 MHz, CDCl3): δ = 12.83 (s, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 3.78 (t, J = 6.8 Hz, 1H), 3.50 (d, J = 7.2 Hz, 2H), 2.37 (s, 3H).

[0096] 13 C NMR (100 MHz, CDCl3): δ = 197.13, 171.04, 144.49, 134.13, 129.92, 128.67, 47.80, 38.07, 21.75.

[0097] The infrared data and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0098] IR (KBr): 2925, 2211, 1720, 1676, 1572, 1267, 1011, 823, 755 cm -1 .

[0099] HRMS-ESI (m / z): Calcd for C 12 H 13 O5 [M+H] + : 237.0757; found: 237.0754.

[0100] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0101]

[0102] Example 12:

[0103] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0104] 0.3 mmol of 1-(4-methoxyphenyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran were added to a reaction vessel (Schlenk tube). After evacuation, carbon dioxide was introduced until the pressure in the reaction vessel reached 1 atm. The mixture was then stirred at 40 °C for 14 h at a stirring rate of 700 rpm. After stopping heating and stirring, it was cooled to room temperature. Then 5 mL of water was added for washing, and 3 mL of 2 mol / L hydrochloric acid was added for acidification. The aqueous layer was extracted with ethyl acetate three times. After combining the organic phases, they were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was composed of dichloromethane and methanol in a volume ratio of 15:1, and the malonic acid derivative was obtained (yield: 90%).

[0105] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as shown in Figure 5 the following, and the 13C NMR spectrum is as shown in Figure 6 the following. The spectral data are as follows:

[0106] 1 H NMR (400 MHz, DMSO-d6): δ = 12.72 (s, 2H), 8.24 - 7.67 (m, 2H), 7.32 - 6.68 (m, 2H), 3.82 (s, 3H), 3.78 (t, J = 7.2 Hz, 1H), 3.47 (d, J = 7.2 Hz, 2H).

[0107] 13 C NMR (100 MHz, DMSO-d6): δ = 196.01, 171.15, 163.98, 130.94, 129.61, 114.58, 56.16, 47.91, 37.88.

[0108] The IR data and MS data of the malonic acid derivative synthesized in this example are as follows:

[0109] IR (KBr): 2920, 2208, 1577, 1473, 1091, 1004, 828, 504 cm -1 .

[0110] HRMS-ESI (m / z): Calcd for C 12 H 13 O6 [M + H] + : 253.0707; found: 253.0704.

[0111] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0112]

[0113] Example 13:

[0114] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0115] Add 0.3 mmol of 1-(4-chlorophenyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran to a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir at 40 °C for 14 h at a stirring rate of 700 rpm, stop heating and stirring, cool to room temperature, add 5 mL of water for washing, add 3 mL of 2 mol / L hydrochloric acid for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 82%).

[0116] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as shown in Figure 7 shown, and the 13C NMR spectrum is as shown in Figure 8 shown, and the spectral data are as follows:

[0117] 1 H NMR (400 MHz, DMSO-d6): δ = 12.82 (s, 2H), 8.03 - 7.98 (m, 2H), 7.61 - 7.57 (m, 2H), 3.77 (t, J = 7.2 Hz, 1H), 3.52 (d, J = 6.8 Hz, 2H).

[0118] 13 C NMR (100 MHz, DMSO-d6): δ = 196.74, 170.82, 138.95, 135.19, 130.45, 129.44, 47.74, 38.15.

[0119] The infrared data and mass spectrum data of the malonic acid derivative synthesized in this example are as follows:

[0120] IR (KBr): 3249, 2934, 2213, 1585, 1467, 1470, 1228, 1026, 875, 777, 690 cm -1 .

[0121] HRMS-ESI (m / z): Calcd for C 11 H 10 ClO5 [M + H] +: 257.0211; found: 257.0207.

[0122] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0123]

[0124] Example 14:

[0125] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0126] Add 0.3 mmol of 1-(4-bromophenyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir at 40 °C for 14 h with a stirring rate of 700 rpm, stop heating and stirring, cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 94%).

[0127] The nuclear magnetic resonance hydrogen spectrum of the malonic acid derivative synthesized in this example is as Figure 9 shown, and the nuclear magnetic resonance carbon spectrum is as Figure 10 shown. The spectral data are as follows:

[0128] 1 H NMR (400 MHz, DMSO-d6): δ = 12.75 (s, 2H), 7.94 - 7.89 (m, 2H), 7.74 - 7.69 (m, 2H), 3.78 (t, J = 7.2 Hz, 1H), 3.52 (d, J = 7.2 Hz, 2H).

[0129] 13 C NMR (100 MHz, DMSO-d6): δ = 197.01, 170.93, 135.57, 132.47, 130.61, 128.24, 47.82, 38.21.

[0130] The infrared data and mass spectrum data of the malonic acid derivative synthesized in this example are as follows:

[0131] IR (KBr): 3465, 2928, 2212, 1582, 1460, 1362, 1124, 1005, 824 cm -1 .

[0132] HRMS-ESI(m / z): Calcd for C 11 H 10 BrO5[M+H] + : 300.9706; found: 300.9702.

[0133] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0134]

[0135] Example 15:

[0136] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0137] Add 0.3 mmol of 1-(4-trifluoromethylphenyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir and react at 40 °C for 14 h, the stirring rate is 700 rpm, stop heating and stirring, then cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 75%).

[0138] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as Figure 11 shown, and the 13C NMR spectrum is as Figure 12 shown. The spectral data are as follows:

[0139] 1 1H NMR (400 MHz, DMSO-d6): δ = 12.90 (s, 2H), 8.19 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.4 Hz, 2H), 3.81 (t, J = 7.2 Hz, 1H), 3.59 (d, J = 6.8 Hz, 2H).

[0140] 13 13C NMR (100 MHz, DMSO-d6): δ = 197.29, 170.81, 139.66, 133.38 (q, J = 31.7 Hz), 129.40, 126.34 (q, J = 3.7 Hz), 124.31 (d, J = 271.0 Hz), 47.80, 38.49.

[0141] The infrared data and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0142] IR(KBr): 3232, 2934, 2216, 1584, 1464, 1010, 734 cm -1 .

[0143] HRMS-ESI(m / z): Calcd for C 12 H 10 F3O5[M+H] + : 291.0475; found: 291.0470.

[0144] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0145]

[0146] Example 16:

[0147] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0148] Add 0.3 mmol of 1-(3,4-difluorophenyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir and react at 40 °C for 14 h, the stirring rate is 700 rpm, stop heating and stirring and then cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases and dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then carry out column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 90%).

[0149] The nuclear magnetic resonance hydrogen spectrum of the malonic acid derivative synthesized in this example is as Figure 13 shown, and the nuclear magnetic resonance carbon spectrum is as Figure 14 shown. The spectral data are as follows:

[0150] 1 H NMR(400 MHz, DMSO-d6): δ = 12.52(s, 2H), 8.04 - 7.97(m, 1H), 7.92 - 7.87(m, 1H), 7.60 - 7.50(m, 1H), 3.77(t, J = 7.2 Hz, 1H), 3.53(d, J = 7.2 Hz, 2H).

[0151] 13 13C NMR(100MHz, DMSO-d6): δ = 195.79, 170.92, 153.45 (dd, J = 252.4, 12.6 Hz), 150.18 (dd, J = 246.5, 13.0 Hz), 134.10 (t, J = 4.0 Hz), 126.51 (dd, J = 7.7, 3.4 Hz), 118.61 (d, J = 17.7 Hz), 117.95 (d, J = 17.9 Hz), 47.85, 38.28.

[0152] The infrared data and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0153] IR (KBr): 3479, 2925, 2211, 1627, 1572, 1443, 1365, 1005, 776 cm -1 .

[0154] HRMS-ESI (m / z): Calcd for C 11 H9F2O5 [M + H] + : 259.0413; found: 259.0409.

[0155] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0156]

[0157] Example 17:

[0158] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0159] Add 0.3 mmol of 1-(2-naphthyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir the reaction at 40 °C for 14 h with a stirring rate of 500 rpm, stop heating and stirring, cool to room temperature, add 5 mL of water for washing, add 3 mL of 2 mol / L hydrochloric acid for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 92%).

[0160] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as Figure 15 shown, and the 13C NMR spectrum is as Figure 16As shown below, the spectral data is as follows:

[0161] 1 H NMR (400 MHz, DMSO-d6): δ = 12.75 (s, 2H), 8.76 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.05 - 7.94 (m, 3H), 7.74 - 7.56 (m, 2H), 3.86 (t, J = 7.2 Hz, 1H), 3.69 (d, J = 6.8 Hz, 2H).

[0162] 13 C NMR (100 MHz, DMSO-d6): δ = 195.85, 170.91, 148.61, 143.76, 130.16, 122.57, 117.70, 117.38, 65.09, 64.47, 47.78, 37.76.

[0163] The infrared data and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0164] IR (KBr): 3271, 2950, 2206, 1720, 1569, 1466, 1359, 1005, 679 cm -1 .

[0165] HRMS-ESI (m / z): Calcd for C 15 H 13 O5 [M + H] + : 273.0757; found: 273.0752.

[0166] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0167]

[0168] Example 18:

[0169] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0170] 0.3 mmol of 1-(2-thienyl)cyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran were added to a reaction vessel (Schlenk tube). After evacuation, carbon dioxide was introduced until the pressure in the reaction vessel reached 1 atm. The mixture was then stirred at 40 °C for 14 h at a stirring rate of 500 rpm. After stopping heating and stirring, it was cooled to room temperature. Then 5 mL of water was added for washing, and 3 mL of 2 mol / L hydrochloric acid was added for acidification. The aqueous layer was extracted with ethyl acetate three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography. The eluent for column chromatography was composed of dichloromethane and methanol in a volume ratio of 20:1, and the malonic acid derivative was obtained (yield: 83%).

[0171] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as shown in Figure 17 and the 13C NMR spectrum is as shown in Figure 18 . The spectral data are as follows:

[0172] 1 H NMR (400 MHz, DMSO-d6): δ = 12.77 (s, 2H), 8.02 (dd, J = 3.6, 1.2 Hz, 1H), 7.98 (dd, J = 5.2, 1.2 Hz, 1H), 7.25 - 7.21 (m, 1H), 3.78 (t, J = 7.2 Hz, 1H), 3.48 (d, J = 7.2 Hz, 2H).

[0173] 13 C NMR (100 MHz, DMSO-d6): δ = 190.80, 170.88, 143.50, 135.56, 134.27, 129.50, 47.76, 38.42.

[0174] The IR data and MS data of the malonic acid derivative synthesized in this example are as follows:

[0175] IR (KBr): 3276, 2933, 2209, 1579, 1492, 1250, 1175, 1031, 833 cm -1 .

[0176] HRMS-ESI (m / z): Calcd for C9H9O5S [M+H] + : 229.0165; found: 229.0163.

[0177] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0178]

[0179] Example 19:

[0180] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0181] Add 0.3 mmol of 1-cyclohexylcyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran to a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir the reaction at 40 °C for 14 h at a stirring rate of 500 rpm, stop heating and stirring, and then cool to room temperature. Add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 87%).

[0182] The nuclear magnetic resonance hydrogen spectrum of the malonic acid derivative synthesized in this example is as shown in Figure 19 shown, and the nuclear magnetic resonance carbon spectrum is as shown in Figure 20 shown, and the spectral data are as follows:

[0183] 1 H NMR (400 MHz, DMSO-d6): δ = 12.78 (s, 2H), 3.55 (t, J = 7.2 Hz, 1H), 2.95 (d, J = 7.2 Hz, 2H), 2.46 - 2.35 (m, 1H), 1.81 - 1.53 (m, 5H), 1.33 - 1.06 (m, 5H).

[0184] 13 C NMR (100 MHz, DMSO-d6): δ = 210.96, 170.85, 49.82, 47.41, 28.46, 25.99, 25.56.

[0185] The infrared data and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0186] IR (KBr): 3253, 2925, 2213, 1720, 1574, 1472, 1379, 1272, 1021, 910, 764, 696 cm -1 .

[0187] HRMS-ESI (m / z): Calcd for C 11 H 15 O5[M-H] - : 227.0925; found: 227.0919.

[0188] As described above, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0189]

[0190] Example 20:

[0191] A method for synthesizing a malonic acid derivative, comprising the following steps:

[0192] Add 0.3 mmol of 1-pentylcyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc, and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir and react at 40 °C for 14 h, the stirring rate is 500 rpm, stop heating and stirring, cool to room temperature, add 5 mL of water for washing, add 3 mL of hydrochloric acid with a concentration of 2 mol / L for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of dichloromethane and methanol in a volume ratio of 20:1, thus obtaining the malonic acid derivative (yield: 74%).

[0193] The nuclear magnetic resonance hydrogen spectrum of the malonic acid derivative synthesized in this example is as Figure 21 shown, and the nuclear magnetic resonance carbon spectrum is as Figure 22 shown. The spectral data interpretation is as follows:

[0194] 1 H NMR (400 MHz, DMSO-d6): δ = 11.91 (s, 2H), 3.55 (t, J = 7.2 Hz, 1H), 2.90 (d, J = 7.2 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.45 (p, J = 7.2 Hz, 2H), 1.33 - 1.14 (m, 4H), 0.84 (t, J = 6.8 Hz, 3H).

[0195] 13 C NMR (100 MHz, DMSO-d6): δ = 208.36, 170.89, 47.44, 42.09, 41.38, 31.25, 23.41, 22.47, 14.36.

[0196] The infrared data and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0197] IR (KBr): 3721, 3315, 3084, 2936, 2208, 1731, 1562, 1042, 756 cm -1 .

[0198] HRMS-ESI(m / z): Calcd for C 10 H 15 O5[M-H] - : 215.0925; found: 215.0920.

[0199] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0200]

[0201] Example 21:

[0202] A method for synthesizing a malonic acid derivative, which comprises the following steps:

[0203] Add 0.3 mmol of 1-methyl-2-phenylcyclopropanol, 0.45 mmol of DBU, 0.6 mmol of diethylzinc and 2 mL of tetrahydrofuran into a reaction vessel (Schlenk tube), evacuate and then introduce carbon dioxide until the pressure in the reaction vessel is 1 atm, stir at 40 °C for 14 h with a stirring rate of 500 rpm, stop heating and stirring and then cool to room temperature, add 5 mL of water for washing, add 3 mL of 2 mol / L hydrochloric acid for acidification, extract the aqueous layer with ethyl acetate 3 times, combine the organic phases and dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure, dissolve in a mixed solution of 2 mL of methanol and ether (volume ratio of methanol to ether is 4:1), evacuate and then place in a nitrogen atmosphere, add 2.4 mmol of trimethylsilyldiazomethane at 0 °C, stir at room temperature for 2 h, concentrate under reduced pressure, and then perform column chromatography purification. The eluent for column chromatography is composed of ethyl acetate and petroleum ether in a volume ratio of 3:1, thus obtaining the malonic acid derivative (yield: 67%).

[0204] The 1H NMR spectrum of the malonic acid derivative synthesized in this example is as Figure 23 shown, and the 13C NMR spectrum is as Figure 24 shown. The spectral data are as follows:

[0205] 1 1H NMR (400 MHz, CDCl3): δ = 87.35 - 7.27 (m, 3H), 7.24 - 7.18 (m, 2H), 4.46 (d, J = 11.6 Hz, 1H), 4.24 (d, J = 11.6 Hz, 1H), 3.75 (s, 3H), 3.42 (s, 3H), 2.14 (s, 3H).

[0206] 1313C NMR (100 MHz, CDCl3): δ = 205.41, 168.56, 168.01, 133.82, 129.05, 128.75, 128.26, 57.93, 54.43, 52.85, 52.35, 28.84.

[0207] The infrared and mass spectrometry data of the malonic acid derivative synthesized in this example are as follows:

[0208] IR (KBr): 3465, 2922, 1648, 1235, 1142, 690 cm -1 .

[0209] HRMS-ESI (m / z): Calcd for C 14 H 15 O5 [M-H] - : 263.0925; found: 263.0924.

[0210] In summary, the structural formula of the malonic acid derivative synthesized in this example is as follows:

[0211]

[0212] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications made without departing from the spirit and principle of the present invention shall be equivalent replacement methods and shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a malonic acid derivative, characterized in that, It includes the following steps: dispersing a cyclopropanol compound, a base and an organozinc in a solvent, and then introducing carbon dioxide for reaction to obtain a malonic acid derivative; the structural formula of the cyclopropanol compound is: , wherein, R 1 is one of phenyl, p-tolyl, m-tolyl, o-tolyl, p-methoxyphenyl, p-chlorophenyl, p-fluorophenyl, p-bromophenyl, p-trifluoromethylphenyl, 3,4-difluorophenyl, naphthyl, thienyl, furyl, cyclohexyl, pentyl, methyl, and R 2 is one of phenyl and naphthyl; the base is at least one of triethylamine, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]undec-7-ene; the organozinc is at least one of diethylzinc and dimethylzinc.

2. The synthesis method of the malonic acid derivative according to claim 1, characterized in that: The molar ratio of the cyclopropanol compound, the base, and the organozinc is 1:1.0 - 1.5:1.5 - 2.

2.

3. The method for synthesizing the malonic acid derivative according to claim 1 or 2, characterized in that: The solvent is at least one of tetrahydrofuran, toluene, dimethyl sulfoxide, dichloromethane, and N,N-dimethylformamide.

4. The method for synthesizing the malonic acid derivative according to claim 1 or 2, characterized in that: The reaction is carried out at 25°C - 60°C, and the reaction time is 6h - 24h.

5. The method for synthesizing a malonic acid derivative according to claim 4, wherein: The reaction is carried out under the condition that the carbon dioxide pressure is 0.8 atm - 1.2 atm.

6. The synthesis method of the malonic acid derivative according to claim 5, wherein: The reaction is carried out under the condition that the stirring rate is 400 rpm - 700 rpm.

7. The method for synthesizing the malonic acid derivative according to claim 1 or 2, characterized in that: After the reaction is completed, the reaction solution is also separated and purified.

8. The synthesis method of the malonic acid derivative according to claim 7, wherein: The specific operation of the separation and purification is as follows: The reaction solution is washed with water and acidified, then extracted with ethyl acetate. Then the organic layer is taken for drying, filtration, and concentration under reduced pressure, and then purified by column chromatography; Alternatively, the reaction solution is washed with water and acidified, then extracted with ethyl acetate. Then the organic layer is taken for drying, filtration, and concentration under reduced pressure, and then dissolved in a methanol-ether mixed solution. Then it is placed in a protective atmosphere and trimethylsilyldiazomethane is added for an esterification reaction. Then it is concentrated under reduced pressure, and then purified by column chromatography.

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