A method for the synthesis of hydroxamic acids using metal salts

Abstract

The present application relates to the field of organic synthesis, and in particular, the present application provides a method for synthesizing hydroxamic acid by using metal salt as a promoter. The specific reaction formula is shown in the description, and the reaction of carboxylate ester and hydroxylamine in the presence of metal salt and alcohol obtains hydroxamic acid derivative shown in formula two. The present application uses specific metal salt as a promoter, and the reaction is carried out in ethanol. The raw material ester is widely available and inexpensive, and no by-product of carboxylic acid caused by ester hydrolysis is generated, which is an environmentally friendly hydroxylamine decomposition reaction system.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, and in particular, the present application provides a method for the synthesis of hydroxamic acid using metal salts. BACKGROUND

[0002] Hydroxamic acid derivatives have a wide range of applications in the chemical discipline. Due to their ability to chelate metal ions, the hydroxamic acid fragment has been extensively studied as a pharmacophore for many metalloprotease inhibitors. In the industrial field, they are often used for metal flotation and wastewater treatment. In the field of organic synthesis, they are efficient synthetic intermediates.

[0003] According to the different raw materials, the synthesis methods of hydroxamic acids can be divided into three categories. 1) Using carboxylic acid as raw material: In 2005, Allegretti et al. proposed that carboxylic acid was converted into acyl chloride with better activity by thionyl chloride or oxalyl chloride, and then reacted with hydroxylamine to generate hydroxamic acid. However, this preparation method not only requires corrosion-resistant equipment, but also increases the potential environmental burden [Allegretti, M.; Bertini, R.; Cesta, M. C.; Bizzarri, C.; Di Bitondo, R.; DiCioccio, V.; Galliera, E.; Berdini, V.; Topai, A.; Zampella, G.; Russo, V.; Di Bello, N.; Nano, G.; Nicolini, L.; Locati, M.; Fantucci, P.; Florio, S.; Colotta, F. J. Med Chem, 2005, 48, 4312-4331.](Eq. 1). In 2013, Locock et al. proposed the use of organic base and dehydrating agent, and the condensation of carboxylic acid with O-protected hydroxylamine followed by deprotection to generate hydroxamic acid. Although this method has no corrosive reagents, the use of condensing agent and protecting group makes the atom economy worse [Locock, K. E. S.; Yamamoto, I.; Tran, P.; Hanrahan, J. R.; Chebib, M.; Johnston, G. A. R.; Allan, R. D. J Med Chem. 2013](Eq. 2). 2) Using ester as raw material: In the presence of strong base, methyl or ethyl ester can react with hydroxylamine aqueous solution at room temperature to generate the corresponding hydroxamic acid salt. However, this method requires more acid to neutralize the excess base in the post-processing, resulting in waste of resources and generation of wastewater. In addition, due to the use of strong base, ester hydrolysis to generate carboxylic acid byproduct may occur during the reaction process [Qin, P.; Ran, Y.; Xie, F.; Liu, Y.; Wei, C.; Luan, X.; Wu, J. bioorgan med chem 2023, 80, 117178](Eq. 3). In 2005, Ho et al. reported that the addition of a catalytic amount of KCN in the THF / MeOH / 50% NH2OH reaction system can improve the efficiency of ester conversion to the corresponding hydroxamic acid, but KCN is highly toxic and poses potential risks to operators and the environment. [Ho, C. Y.; Strobel, E.; Ralbovsky, J. Org. Chem, 2005, 70, 4873-4875.](Eq. 4). In addition, using zinc oxide as a reaction promoter and product separation precipitant, the conversion from ester to hydroxamic acid can be achieved in a deep eutectic solvent (DES) derived from biological sources.However, the reaction system often requires higher reaction temperature and longer reaction time for substrates with larger molecular weight or stronger liposolubility, and the yield of product is reduced due to the use of deep eutectic solvent [Liang, X, ; Lv, B. ; Sun, S. ; Wu, Z. ; Lin, B. ; Bao, X. ; Chen, G. Green Chemistry, 2023, 25, 2446-2452. ] (Eq. 5). 3) Using aldehyde as raw material: In 2013, Pilo et al. proposed that using copper acetate as catalyst, tert-butyl hydroperoxide (TBHP) as oxidant, aldehyde reacts with N-hydroxysuccinimide to generate hydroxamic acid. [Pilo, M. ; Porcheddu, A. ; De Luca L. Org Biomol Chem, 2013, 11, 8241. ] (Eq. 6). In 2016, Papadopoulos et al. reported a photochemical method using diisopropyl azodicarboxylate (DIAD) and phenyl glyoxylic acid as catalyst, and aldehyde can be converted into hydroxamic acid under light. [Papadopoulos, G. N. ; Kokotos, C. G. Chem. Eur. J, 2016, 22, 6964-6967. ] (Eq. 7). The method using aldehyde as raw material uses various types of reagents and is expensive, resulting in complex post-treatment and increased cost of preparing hydroxamic acid.

[0004]

[0005] In summary, there is still a lack of a method for preparing hydroxamic acid that is inexpensive and easy to obtain, green and environmentally friendly, and can effectively avoid the byproduct of carboxylic acid. SUMMARY

[0006] The purpose of the present application is to provide a method for promoting the synthesis of hydroxamic acid using metal salt.

[0007] To achieve the above purpose, the technical scheme adopted by the present application is:

[0008] A method for promoting the synthesis of hydroxamic acid derivatives using metal salt,

[0009]

[0010] The carboxylic acid ester represented by Formula I reacts with hydroxylamine in the presence of metal salt and alcohol to obtain the hydroxamic acid derivative represented by Formula II.

[0011] The metal salt is one or more of zinc chloride, zinc bromide, and zinc iodide; and the alcohol is one or more of methanol, ethanol, and isopropanol.

[0012] R' is selected from C1-C6 alkyl or benzyl;

[0013] A is selected from the group consisting of: C1-C6 alkyl, C1-C6 alkenyl, C6-C20 aryl; 3-20 membered heteroaryl; wherein the substituent is one or more hydrogen atoms on the alkyl, alkenyl, aryl or heteroaryl group is replaced by a substituent selected from the group consisting of: halogen, nitro, cyano, amino unsubstituted or substituted by one or two C1-C6 alkyl or C2-C10 acyl, hydroxyl, C1-C6 alkyl unsubstituted or substituted by halogen or hydroxyl, C1-C6 alkoxy, C6-C10 aryl, 3-20 membered heteroaryl, C6-C10 aryloxy, carboxyl, sulfone, sulfonamide; wherein two hydrogen atoms on two adjacent carbon atoms of the aryl group can be replaced by -(CH)n-; the heteroaryl group contains 1-3 N, O, or S heteroatoms;

[0014] n is 2, 3, 4, 5 or 6.

[0015] R' is selected from the group consisting of: methyl, ethyl, isopropyl or benzyl;

[0016] A is selected from the group consisting of:

[0017]

[0018] The carboxylic acid ester of formula I is reacted with hydroxylamine in the presence of a metal salt and an alcohol at 0-80°C for 6-24 hours to obtain the hydroxamic acid derivative of formula II;

[0019] The molar ratio of zinc chloride to the carboxylic acid ester of formula I is 1-4:1; the volume of alcohol added is 20 times the mass of the carboxylic acid ester; the hydroxylamine used is a 50% hydroxylamine aqueous solution, and the amount added is equal to the volume of alcohol used.

[0020] The carboxylic acid ester of formula I is reacted with hydroxylamine in the presence of a metal salt and an alcohol at 0-80°C for 6-24 hours to obtain the hydroxamic acid derivative of formula II;

[0021] The molar ratio of zinc chloride to the carboxylic acid ester of formula I is 1-4:1; the volume of alcohol added is 20 times the mass of the carboxylic acid ester; the hydroxylamine used is a 50% hydroxylamine aqueous solution, and the amount added is equal to the volume of alcohol used.

[0022] The present application has the advantages of:

[0023] The present application uses specific metal salt as promoter, and matches specific material ratio to react in ethanol. Different from the hydroxylamine decomposition reaction of ester promoted by alkali, the present application does not generate carboxylic acid byproduct caused by ester hydrolysis, and only needs to use acid with equal molar amount of metal salt in the post-treatment process, which is different from the method promoted by alkali, which needs to consume more acid to neutralize excess alkali in the post-treatment process. The molar amount of metal salt used in the method of the present application is significantly reduced compared with the molar amount of alkali used in the alkali promotion method, the amount of acid used in the post-treatment process is greatly reduced, and the yield and purity of the obtained product are higher. In addition, compared with the zinc oxide-deep eutectic solvent reaction system, the solvent ethanol of the present application has better solubility for esters with large molecular weight and high fat solubility, so that the present application uses specific metal salt in ethanol to match specific conditions to further improve the solubility. Therefore, for esters with large molecular weight and high fat solubility, the present method can obtain higher yield under lower reaction temperature and shorter reaction time. Specific implementation method

[0024] In order to make the above-mentioned purposes, features, technical solutions and advantages of the present application more clear and obvious, the specific implementation of the present application will be described in detail below with specific examples.

[0025] In the following description, many specific details are set forth in order to provide a thorough understanding of the present application. However, the present application can be practiced in other embodiments that are different from those described herein. Temperatures, catalysts, concentrations, reactant compositions, and other process conditions can vary, and appropriate reactants and conditions can be readily selected by those skilled in the art of the present disclosure, so the specific examples described herein are only used to explain the present application, and do not constitute any limitation on the present application.

[0026] Secondly, the "one embodiment" or "embodiment" referred to herein means that the specific features, structures or characteristics can be included in at least one implementation of the present application. "In one embodiment" appearing in different places in the specification does not mean the same embodiment, nor is it an independent or alternative embodiment that excludes other embodiments.

[0027] The various reaction raw materials in the embodiments of the present application are from commercial or literature reported synthesis. Unless otherwise specified, the professional and scientific terms used herein have the same meaning as those mastered by those skilled in the art.

[0028] Example 1: Preparation of N-hydroxy-[1,1'-biphenyl]-4-carboxamide:

[0029] Methyl [1,1'-biphenyl]-4-carboxylate (0.106 g, 0.5 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 12 hours. After the reaction, the product was isolated by adding equal volume of 10% dilute hydrochloric acid and then filtered. N-hydroxy-[1,1'-biphenyl]-4-carboxamide was obtained as a white solid, 0.10 g, yield 96%, product purity 97% (HPLC area normalization method). 1 H NMR (600 MHz, DMSO-d6) δ 11.28 (s, 1H), 9.07 (s, 1H), 7.86 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 7.6 Hz, 2H), 7.49 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.4 Hz, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 164.27, 143.09, 139.57, 131.98, 129.43, 128.43, 127.91, 127.23, 127.00. HRMS (ESI): m / z [M-H] - calculated for C 13 H 10 NO2: 212.0717; found: 212.0720. m.p. 186-190 °C.

[0030] Comparative Example 1: Methyl [1,1'-biphenyl]-4-carboxylate (0.106 g, 0.5 mmol) and zinc oxide (0.08 g, 1 mmol) were added to deep eutectic solvent (choline chloride: glycerol = 1:2) (2 g) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at 45 °C for 36 hours. After the reaction, the product was isolated by adding equal volume of water and then filtered. The complex of the product and zinc oxide was added to 20 mL of ethanol containing oxalic acid (2 mmol), stirred for 2 hours and then filtered. The filtrate was evaporated and washed with water to obtain N-hydroxy-[1,1'-biphenyl]-4-carboxamide as a white solid, 0.09 g, yield 82%.

[0031] In Example 1, compared with Comparative Example 1, the reaction time was shortened from 36 hours to 12 hours, the reaction temperature was reduced from 45 °C to room temperature, and the reaction yield was improved from 82% to 96% using zinc oxide-deep eutectic solvent reaction system.

[0032] Example 2: Preparation of N-hydroxy-1-(4-methoxyphenyl)-7-oxo-6-(4-(2- oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- carboxamide:

[0033] Methyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7- tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (0.237 g, 0.5 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 12 hours. After the reaction was complete, the reaction was filtered and the filtrate was diluted with water. The pH of the solution was adjusted to 5 with 10% dilute hydrochloric acid. The resulting precipitate was collected by filtration to give N-hydroxy-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide as a white solid, 0.19 g, 79% yield. 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.03 (s, 1H), 7.50 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 4.06 (t, J = 6.6 Hz, 2H), 3.80 (s, 3H), 3.59 (t, J = 5.7 Hz, 2H), 3.18 (t, J = 6.6 Hz, 2H), 2.38 (t, J = 6.3 Hz, 2H), 1.90 - 1.78 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 169.33, 166.61, 159.60, 157.05, 141.89, 140.73, 140.29, 133.10, 133.00, 127.24, 126.81, 126.50, 125.50, 113.87, 55.95, 51.38, 51.30, 33.06, 23.47, 21.36, 21.30. HRMS (ESI): m / z [M-H] - calculated for C 25 H 24 N5O5: 474.1783; found: 474.1802. m.p. 133-136 °C.

[0034] Comparative Example 2: Methyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (0.237 g, 0.5 mmol) and zinc oxide (0.08 g, 1 mmol) were added to a deep eutectic solvent (choline chloride:glycerol = 1:2) (2 g) and stirred for 10 minutes. Then, 50% hydroxylamine aqueous solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then carried out at 45 °C for 36 hours. After diluting the reaction solution with an equal volume of water, the mixture was filtered to obtain a complex of the product and zinc oxide. This complex was added to 20 mL of ethanol containing oxalic acid (2 mmol), stirred for 2 hours, and then filtered. The filtrate was evaporated to dryness and washed with water to give N-hydroxy-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiridin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, a white solid, 0.15 g, yield 62%.

[0035] Compared with Comparative Example 2, in Example 2, the reaction time was shortened from 24 hours to 12 hours, the reaction temperature was reduced from 45°C to room temperature, and the reaction yield was increased from 62% to 79% compared with the reaction system using zinc oxide-deep eutectic solvent.

[0036] Example 3: N 1 -hydroxy-N 8 Preparation of phenyloctanoic acid diamide:

[0037] Methyl 8-oxo-8-(phenylamino)octanoate (0.263 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (5 mL) and stirred for 10 minutes. Then, 50% hydroxylamine aqueous solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed for 10 hours at room temperature. An equal volume of 10% dilute hydrochloric acid was added to the reaction solution, and the mixture was filtered to obtain N. 1 -hydroxy-N 8 1-Phenylacetic acid diamide, white solid, 0.23 g, yield 88%, product purity 98% (HPLC area normalization method). 1 HNMR (400MHz, DMSO-d6) δ10.33(s,1H),9.84(s,1H),8.66(s,1H),7.58(d,J=7.3Hz,2H),7.35-7.21(m,2H),7.02(t,J=7 .4Hz,1H),2.29(t,J=7.5Hz,2H),1.94(t,J=7.4Hz,2H),1.57(p,J=7.2Hz,2H),1.49(p,J=7.2Hz,2H),1.36-1.20(m,4H).13 C NMR (101 MHz, DMSO-d6) δ 171.69, 169.57, 139.81, 129.10, 123.38, 119.49, 36.84, 32.71, 28.88, 25.49.

[0038] Example 4: Preparation of (E)-N-hydroxy-3-(3-(N-phenylsulfamoyl)phenyl)acrylamide:

[0039] (E)-3-(3-(N-phenylsulfamoyl)phenyl)acrylate methyl ester (0.317 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed for 10 hours at room temperature. After the reaction was complete, an equal volume of 10% dilute hydrochloric acid was added to the reaction and it was then filtered under suction to give (E)-N-hydroxy-3-(3-(N-phenylsulfamoyl)phenyl)acrylamide as a light yellow solid, 0.26 g, 83% yield, product purity 97% (HPLC area normalization method). 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 10.32 (s, 1H), 9.12 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 7.9 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.46 (d, J = 15.9 Hz, 1H), 7.26 - 7.19 (m, 2H), 7.14 - 7.07 (m, 2H), 7.06 - 7.01 (m, 1H), 6.50 (d, J = 15.8 Hz, 1H). 13 C NMR (101 MHz, DMSO-d6) δ 162.51, 140.75, 137.98, 136.97, 136.36, 132.45, 130.49, 129.68, 127.53, 125.20, 124.80, 121.83, 120.83. HRMS (ESI): m / z [M-H] - calculated for C 15 H 13 N2O4S: 317.0602; found: 317.0620. m.p. 168-171 °C.

[0040] Example 5: Preparation of (E)-N-hydroxy-3-(4-iodophenyl)acrylamide:

[0041] Methyl (E)-3-(4-iodophenyl)acrylate (0.144 g, 0.5 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 10 hours. After the reaction was complete, an equal volume of 10% dilute hydrochloric acid was added to the reaction and it was then filtered under suction to give (E)-N-hydroxy-3-(4-iodophenyl)acrylamide as a white solid, 0.11 g, 75% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.05 (s, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.53 - 7.26 (m, 3H), 6.48 (d, J = 15.8 Hz, 1H). 13 CNMR (101 MHz, DMSO-d6) δ 162.84, 138.22, 137.73, 134.91, 129.89, 120.39, 96.38. HRMS (ESI): m / z [M-H] - calculated for C9H7INO2: 287.9527; found: 287.9534. m.p. 189-192 °C.

[0042] Example 6: Preparation of (R)-2-((l-(tert-butoxy)vinyl)amino)-N-hydroxy-3- phenylpropanamide:

[0043] Methyl (l-(tert-butoxy)vinyl)-D-phenylalaninate (0.277 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was complete, an equal volume of 10% dilute hydrochloric acid was added to the reaction and it was then filtered under suction to give (R)-2-((l-(tert-butoxy)vinyl)amino)-N-hydroxy-3-phenylpropanamide as a white solid, 0.24 g, 86% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (d, J = 1.6 Hz, 1H), 8.83 (d, J = 1.6 Hz, 1H), 7.36 - 7.12 (m, 5H), 6.96 (d, J = 8.6 Hz, 1H), 4.07 - 4.01 (m, 1H), 2.91 - 2.71 (m, 2H), 1.31 (s, 9H). 13C NMR (101 MHz, DMSO-d6) δ 168.88, 155.56, 138.52, 129.64, 128.49, 126.67, 78.38, 53.99, 38.17, 28.63, 28.31. MS (ESI): m / z [M+Na] + : 303.1. m.p. 136-138 °C.

[0044] Example 7: Preparation of (S)-2-((l-(tert-butoxy)vinyl)amino)-N- hydroxy-3-phenylpropanamide:

[0045] (1-(tert-butoxy)vinyl)-L-phenylalanine methyl ester (0.277 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was filtered by suction after adding equal volume of 10% dilute hydrochloric acid to the reaction solution, (S)-2-((l-(tert-butoxy)vinyl)amino)-N-hydroxy-3-phenylpropanamide was obtained as a white solid, 0.23 g, yield 82%. 1 HNMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.83 (s, 1H), 7.34-7.12 (m, 5H), 6.96 (d, J = 8.6 Hz, 1H), 4.07-4.01 (m, 1H), 2.92-2.70 (m, 2H), 1.31 (s, 9H). 13 C NMR (101 MHz, DMSO-d6) δ 168.88, 155.55, 138.52, 129.63, 128.49, 126.67, 78.38, 53.98, 38.18, 28.63, 28.32. MS (ESI): m / z [M+Na] + : 303.1. m.p. 140-143 °C.

[0046] Example 8: Preparation of N-hydroxybenzamide:

[0047] Methyl benzoate (0.136 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was filtered by suction after adding equal volume of 10% dilute hydrochloric acid to the reaction solution, N-hydroxybenzamide was obtained as a light pink solid, 0.13 g, yield 92%. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.03 (s, 1H), 7.79-7.71 (m, 2H), 7.55-7.48 (m, 1H), 7.48-7.41 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.64, 133.25, 131.58, 128.84, 127.31. HRMS (ESI): m / z [M-H] - Calculated for C7H6O2: 136.0404; Found: 136.0412. m.p. 104-106 °C.

[0048] Example 9: Preparation of N-hydroxy-4-methoxybenzamide:

[0049] Methyl 4-methoxybenzoate (0.166 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was complete, the reaction was filtered by suction after adding equal volume of 10% dilute hydrochloric acid to the reaction. N-hydroxy-4-methoxybenzamide was obtained as a light brown solid, 0.15 g, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1H), 8.88 (s, 1H), 7.73 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H), 3.80 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.52, 161.97, 129.10, 125.42, 114.09, 55.79. HRMS (ESI): m / z [M-H] - Calculated for C8H8NO3: 166.0510; Found: 166.0526. m.p. 140-143 °C.

[0050] Example 10: Preparation of 2-chloro-N-hydroxybenzamide:

[0051] Methyl 2-chlorobenzoate (0.170 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was complete, the reaction was filtered by suction after adding equal volume of 10% dilute hydrochloric acid to the reaction. 2-chloro-N-hydroxybenzamide was obtained as a white solid, 0.16 g, yield 94%. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.21 (s, 1H), 7.54-7.42 (m, 2H), 7.42-7.35 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 163.74, 135.10, 131.55, 131.08, 130.15, 129.82, 127.57. HRMS (ESI): m / z [M-H] - Calculated for C7H5CINO2: 170.0014; Found: 170.0012. m.p. 120-122 °C.

[0052] Example 11: Preparation of N-hydroxy-2-methylbenzamide:

[0053] Methyl 2-methylbenzoate (0.136 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was filtered under suction after the addition of an equal volume of 10% dilute hydrochloric acid, N-hydroxy-2-methylbenzamide was obtained as a white solid, 0.13 g, in 93% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 9.01 (s, 1H), 7.35-7.31 (m, 1H), 7.28-7.15 (m, 3H), 2.33 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 166.62, 136.17, 135.19, 130.89, 129.96, 127.80, 125.96, 19.65. HRMS (ESI): m / z [M-H] - Calculated for C8H8NO2: 150.0561; Found: 150.0546. m.p. 116-120 °C.

[0054] Example 12: Preparation of 2,4-difluoro-N-hydroxybenzamide:

[0055] Methyl 2,4-difluorobenzoate (0.172 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was complete, the reaction was filtered by suction after the addition of an equal volume of 10% dilute hydrochloric acid to the reaction. This resulted in 2,4-difluoro-N-hydroxybenzamide, white solid, 0.15 g, 88% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.24 (s, 1H), 7.62 (q, J = 7.8 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.20 - 7.14 (m, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 164.51 (d, J = 12.5 Hz), 162.86 (d, J = 12.0 Hz), 160.91, 160.79 (d, J = 13.0 Hz), 159.12 (d, J = 13.0 Hz), 132.01 (d, J = 4.9 Hz), 131.94 (d, J = 4.7 Hz), 119.48 (d, J = 15.5 Hz), 112.21 (d, J = 20.1 Hz), 104.96 (t, J = 26.3 Hz). HRMS (ESI): m / z [M-H] - calculated for C7H4F2NO2: 172.0216; found: 172.0222. m.p. 142-146 °C.

[0056] Example 13: Preparation of 4-fluoro-N-hydroxybenzamide:

[0057] Ethyl 4-fluorobenzoate (0.168 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was complete, the reaction was filtered by suction after the addition of an equal volume of 10% dilute hydrochloric acid to the reaction. This resulted in 4-fluoro-N-hydroxybenzamide, white solid, 0.15 g, 89% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.24 (s, 1H), 9.06 (s, 1H), 7.90 - 7.77 (m, 2H), 7.38 - 7.23 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 164.98, 163.61, 163.34, 129.87, 129.81, 129.64, 115.81, 115.66. HRMS (ESI): m / z [M-H]- C7H5FNO2: 154.0310; found: 154.0307. m.p. 153-156 °C.

[0058] Example 14: Preparation of N-hydroxy-4-methylbenzamide:

[0059] Ethyl 4-methylbenzoate (0.164 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was filtered by suction after adding equal volume of 10% dilute hydrochloric acid to the reaction, N-hydroxy-4-methylbenzamide was obtained as a white solid, 0.14 g, yield 88%. 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.97 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 2.34 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.69, 141.44, 130.44, 129.35, 127.32, 21.40. HRMS (ESI): m / z [M-H] - C8H8NO2: 150.0561; found: 150.0595. m.p. 136-138 °C.

[0060] Example 15: Preparation of 2-bromo-N-hydroxybenzamide:

[0061] Methyl 2-bromobenzoate (0.214 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. Then 50% aqueous hydroxylamine solution (2 mL) was slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the reaction was filtered by suction after adding equal volume of 10% dilute hydrochloric acid to the reaction, 2-bromo-N-hydroxybenzamide was obtained as a white solid, 0.19 g, yield 90%. 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.20 (s, 1H), 7.66 (dd, J = 8.1, 1.4 Hz, 1H), 7.48 - 7.33 (m, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.60, 137.21, 133.28, 131.69, 129.84, 128.04, 120.21. HRMS (ESI): m / z [M-H] - calculated for C7H5BrNO2: 213.9509, 215.9489; found: 213.9519, 215.9500. m.p. 161-164 °C.

[0062] Example 16: Preparation of N-hydroxy-3-methoxybenzamide:

[0063] Methyl 3-methoxybenzoate (0.166 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous hydroxylamine solution (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then left to stir at room temperature for 8 hours. After the reaction was filtered off by suction after the addition of an equal volume of 10% dilute hydrochloric acid to the reaction, N-hydroxy-3-methoxybenzamide was obtained as a light brown solid, 0.15 g, 88% yield.1H NMR (600 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.03 (s, 1H), 7.38-7.27 (m, 3H), 7.08 (dd, J = 7.9, 1.5 Hz, 1H), 3.79 (s, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 164.28, 159.52, 134.54, 129.93, 119.44, 117.34, 112.42, 55.60. HRMS (ESI): m / z [M-H] - calculated for C8H8NO3: 166.0510; found: 166.0524. m.p. 86-88 °C.

[0064] Example 17: Preparation of 2-ethoxy-N-hydroxybenzamide:

[0065] Methyl 2-ethoxybenzoate (0.180 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous hydroxylamine solution (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then left to stir at room temperature for 8 hours. After the reaction was filtered off by suction after the addition of an equal volume of 10% dilute hydrochloric acid to the reaction, 2-ethoxy-N-hydroxybenzamide was obtained as a light brown solid, 0.16 g, 88% yield. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.07 (s, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 6.99 (t, J = 7.3 Hz, 1H), 4.12 (q, J = 6.9 Hz, 2H), 1.34 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.83, 156.30, 132.15, 130.28, 123.32, 120.76, 113.25, 64.43, 14.96. HRMS (ESI): m / z [M-H] - calculated for C9H 10 NO3: 180.0666; found: 180.0659. m.p. 108-110 °C.

[0066] Example 18: Preparation of N-hydroxy-3-methoxy-4-methylbenzamide:

[0067] Methyl 3-methoxy-4-methylbenzoate (0.180 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous hydroxylamine solution (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 8 hours. After the addition of an equal volume of 10% dilute hydrochloric acid to the reaction, it was filtered under suction to give N-hydroxy-3-methoxy-4-methylbenzamide as a white solid, 0.15 g, 81% yield. 1 H NMR (400 MHz, DMSO-d6) δ 11.14 (s, 1H), 8.95 (s, 1H), 7.30 (d, J = 1.6 Hz, 1H), 7.26 (dd, J = 7.7, 1.6 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 3.82 (s, 3H), 2.17 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.58, 157.58, 132.15, 130.63, 129.57, 119.28, 109.07, 55.79, 16.44. HRMS (ESI): m / z [M-H] - calculated for C9H 10 NO3: 180.0666; found: 180.0679. m.p. 147-150 °C.

[0068] Example 19: Preparation of N-hydroxy-lH-indole-2-carboxamide:

[0069] Methyl 1H-indole-2-carboxylate (0.175 g, 1 mmol) and zinc chloride (0.14 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 10 hours. After the reaction was complete, the reaction was filtered by adding an equal volume of 10% dilute hydrochloric acid to the reaction and then filtering. This resulted in N-hydroxy-1H-indole-2-carboxamide as a light brown solid, 0.15 g, 83% yield. 1 H NMR (600 MHz, DMSO-d6) δ 11.62 (s, 1H), 11.24 (s, 1H), 9.12 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.98 (s, 1H). 13 C NMR (151 MHz, DMSO-d6) δ 160.00, 136.69, 129.93, 127.45, 123.53, 121.78, 120.13, 112.61, 102.00. HRMS (ESI): m / z [M-H] - calculated for C9H7N2O2: 175.0513; found: 175.0515. m.p. 131-134 °C.

[0070] Example 20: Preparation of N-hydroxybenzamide:

[0071] Methyl benzoate (0.136 g, 1 mmol) and zinc iodide (0.33 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 6 hours. After the reaction was complete, the reaction was filtered by adding an equal volume of 10% dilute hydrochloric acid to the reaction and then filtering. This resulted in the product N-hydroxybenzamide as a light pink solid, 0.12 g, 87% yield.

[0072] Example 21: Preparation of N-hydroxybenzamide:

[0073] Methyl benzoate (0.136 g, 1 mmol) and zinc bromide (0.23 g, 1 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous solution of hydroxylamine (2 mL) was then slowly added to the stirred solution at room temperature. The reaction was then allowed to proceed at room temperature for 6 hours. After the reaction was complete, the reaction was filtered by adding an equal volume of 10% dilute hydrochloric acid to the reaction and then filtering. This resulted in the product N-hydroxybenzamide as a light pink solid, 0.11 g, 82% yield.

[0074] Comparative Example 3

[0075] Methyl benzoate (0.136 g, 1 mmol) and magnesium oxide (0.08 g, 2 mmol) were added to ethanol (2 mL) and stirred for 10 minutes. A 50% aqueous hydroxylamine solution (2 mL) was then slowly added to the stirred solution at room temperature. After 48 hours at room temperature, 10 mL of ethanol was added, the solution was filtered and evaporated to dryness to give the product, N-hydroxybenzamide, as a light pink solid, 0.07 g, 48% yield.

[0076] From the above Example 8, Examples 20 and 21 and Comparative Example 3, it can be seen that the present application uses specific metal salts as accelerators and formulates specific material ratios to react in ethanol, which can obtain higher yield of product under lower reaction temperature and shorter reaction time conditions.

Claims

1. A method for promoting the synthesis of isohydroxamic acid derivatives using metal salts, characterized in that: The carboxylic acid ester shown in Formula 1 reacts with hydroxylamine in the presence of a metal salt and an alcohol to obtain the isohydroxamic acid derivative shown in Formula 2. The metal salt is one or more of zinc chloride, zinc bromide, and zinc iodide; The alcohol is ethanol; The R' is selected from C1-C6 alkyl or benzyl groups; A is selected from 。 2. The method for promoting the synthesis of isohydroxamic acid using metal salts according to claim 1, characterized in that: The R' is selected from the group consisting of methyl, ethyl, isopropyl, or benzyl.

3. The method for promoting the synthesis of isohydroxamic acid using metal salts according to claim 1 or 2, characterized in that: The carboxylic acid ester of Formula 1 is reacted with hydroxylamine in the presence of a metal salt and an alcohol at 0-80°C for 6-24 hours to obtain the isohydroxamic acid derivative of Formula 2. The molar ratio of zinc chloride to the carboxylic acid ester shown in Formula 1 is 1~4:1; the volume of alcohol added is 20 times the mass of the carboxylic acid ester; and the hydroxylamine used is a 50% aqueous solution of hydroxylamine, the amount of which added is equal to the volume of alcohol used.

4. The method for promoting the synthesis of isohydroxamic acid using metal salts according to claim 3, characterized in that: The carboxylic acid ester shown in Formula 1 is reacted with a base in the presence of a metal salt and an alcohol at 20-40°C for 8-12 hours to obtain the isohydroxamic acid derivative shown in Formula 2. The molar ratio of zinc chloride to the carboxylic acid ester shown in Formula 1 is 1~2:1; the volume of alcohol added is 20 times the mass of the carboxylic acid ester; hydroxylamine is a 50% aqueous solution, and the volume ratio of its added amount to the volume of alcohol used is 0.8~1.5:1.

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