A method for synthesizing n,n-diethyl-2-hydroxyphenylacetamide and its analogues and its applications

Abstract

The application provides a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide and analogues thereof, and a reaction route of the method is as follows: the method comprises the following steps: 1) reacting a compound of formula (III) with a compound of formula (IV) in a solvent A under the action of a condensing agent and a base for a certain time to obtain a reaction solution containing a compound of formula (II); 2) adding a reducing agent to the reaction solution containing the compound of formula (II) obtained in step 1), and reacting for a certain time; the reaction is monitored, and after the reaction is completed, the solvent is spun dry, separated and dried to obtain a crude product of the compound of formula (I); 3) purifying the crude product obtained in step 2) to obtain a pure product of the compound of formula (I); wherein R1 and R2 are independently hydrogen, an alkyl group or an aryl group; and A is a substituted or unsubstituted aryl group or a heteroaryl group.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide and its analogues, and their applications. Background Technology

[0002] Swedish patent SE 409808 B, published in 1979, reported N,N-diethyl-2-hydroxyphenylacetamide (DEM) with good anthelmintic activity. Various synthetic methods for DEM have been developed in the prior art. However, all existing methods for synthesizing DEM use mandelic acid as a substrate, resulting in numerous synthetic steps, low overall yield, and low purity. For example, in existing methods for preparing DEM using mandelic acid, after obtaining crude DEM, anhydrous calcium chloride is used for post-treatment purification, utilizing the principle of calcium ion complexation to remove impurities. However, in practice, technicians have found that purifying 1g of crude DEM with a purity of 95% using calcium chloride complexation yields only 0.64g of product, with virtually no change in purity. This indicates that this post-treatment method significantly reduces the yield, and the improvement in purity is not significant. Summary of the Invention

[0003] To address the shortcomings of existing technologies, this invention provides a method for the efficient and high-yield synthesis of N,N-diethyl-2-hydroxyphenylacetamide (DEM) and its analogues using benzoylformic acid and its analogues as synthetic substrates via a one-pot process.

[0004] Therefore, one object of the present invention is to provide a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide and its analogues.

[0005] Another object of the present invention is to provide an application of the above method in the preparation of N,N-diethyl-2-hydroxyphenylacetamide and its analogues.

[0006] The technical solution for achieving the objective of this invention is as follows:

[0007] On one hand, the present invention provides a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide and its analogues (i.e., Method 1), the reaction route of which is as follows:

[0008]

[0009] The method includes the following steps:

[0010] 1) In solvent A, the compound of formula (III) and the compound of formula (IV) are reacted for a certain time under the action of a condensing agent and a base to obtain a reaction solution containing the compound of formula (II).

[0011] 2) Add a reducing agent to the reaction solution containing compound (II) obtained in step 1), react for a certain time, monitor the reaction, and after the reaction is completed, evaporate the solvent, separate and dry to obtain the crude product of compound (I);

[0012] 3) Purify the crude product obtained in step 2) to obtain the pure product of compound (I);

[0013] In this context, R1 and R2 are independently hydrogen, alkyl, or aryl; A is a substituted or unsubstituted aryl or heteroaryl group.

[0014] In the above method,

[0015] Preferably, in step 1), the solvent A includes, but is not limited to, tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, N,N-dimethylformamide or mixtures thereof, and more preferably acetonitrile;

[0016] Preferably, in step 1), the condensing agent includes, but is not limited to, HBTU, HATU, HOBT, PyBOP, TBTU, etc., and more preferably HBTU;

[0017] Preferably, in step 1), the molar ratio of the compound of formula (III) to the condensing agent is about 1:1 to 1:1.2, more preferably 1:1.2;

[0018] Preferably, in step 1), the molar ratio of the compound of formula (III) to the compound of formula (IV) is about 1:1 to 1:3, more preferably 1:1.5;

[0019] Preferably, in step 1), the base is a nitrogen-containing organic base; more preferably, the base includes, but is not limited to, triethylamine, DMAP, DIPEA, pyridine, etc.; more preferably, it is triethylamine.

[0020] Preferably, in step 1), the molar ratio of the compound of formula (III) to the base is about 1:1 to 1:3, more preferably 1:3;

[0021] Preferably, in step 1), the reaction time is 4-6 hours, more preferably 5 hours;

[0022] Preferably, in step 2), the reducing agent is a selective reducing agent; more preferably, the reducing agent includes, but is not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, DIBAL-H, LTBA, Red-Al, etc.; more preferably, the reducing agent is sodium borohydride.

[0023] Preferably, in step 2), the molar ratio of the compound of formula (III) to the reducing agent is about 1:1 to 1:3, more preferably 1:3;

[0024] Preferably, in step 2), the reaction time is 18-24 hours, more preferably 20 hours;

[0025] Preferably, in step 2), the method for monitoring the reaction is selected from ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonance, thin-layer chromatography, gas chromatography, and high-performance liquid chromatography, and more preferably high-performance liquid chromatography;

[0026] Preferably, in step 2), the separation method is selected from recrystallization, distillation, chromatography, precipitation, evaporation, and extraction, more preferably extraction; further preferably, the solvents used for extraction include, but are not limited to, dichloromethane, ethyl acetate, and diethyl ether; even more preferably, the solvent used for extraction is dichloromethane; even more preferably, the separation method includes the following steps: adding 50 ml of dichloromethane to the product obtained after evaporating the solvent, extracting twice with water (150 ml × 2), adding 150 ml of water to the organic phase, adjusting the pH to weakly acidic with 1N HCl, releasing the aqueous phase, and washing the organic phase once with 150 ml of water;

[0027] Preferably, in step 3), the purification is performed by chromatography, recrystallization and precipitation; more preferably, the purification is performed by column chromatography; even more preferably, the column chromatography purification is performed using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent.

[0028] Preferably, both R1 and R2 are ethyl;

[0029] Preferably, A is a substituted aryl or heteroaryl group, more preferably an aryl or heteroaryl group substituted with a group selected from the following: halogen, -CN, -NO2, -OH, -SH, -OR, -SR, -R3, -R3OR4, -C(O)R3, -S(O)R3, -S(O)OR3, -NR4R5, -C(O)NR4R5, -OC(O)R4, -NR4C(O)R5, and even more preferably, A is a phenyl group.

[0030] In some embodiments of the present invention, a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide is provided, the reaction route of which is as follows:

[0031]

[0032] The method includes the following steps:

[0033] 1) Benzoylcarboxylic acid and diethylamine are reacted in solvent A for a certain time under the action of a condensing agent and a base to obtain a reaction solution;

[0034] 2) Add a reducing agent to the reaction solution obtained in step 1), react for a certain time, monitor the reaction, and after the reaction is completed, evaporate the solvent, separate and dry to obtain crude N,N-diethyl-2-hydroxyphenylacetamide;

[0035] 3) Purify the crude product obtained in step 2) to obtain pure N,N-diethyl-2-hydroxyphenylacetamide.

[0036] In the method,

[0037] Preferably, in step 1), the solvent A includes, but is not limited to, tetrahydrofuran, dichloromethane, acetonitrile, ethyl acetate, N,N-dimethylformamide or mixtures thereof, and more preferably acetonitrile;

[0038] Preferably, in step 1), the condensing agent includes, but is not limited to, HBTU, HATU, HOBT, PyBOP, TBTU, etc., and more preferably HBTU;

[0039] Preferably, in step 1), the molar ratio of benzoylformic acid to the condensing agent is about 1:1 to 1:1.2, more preferably 1:1.2;

[0040] Preferably, in step 1), the molar ratio of benzoylformic acid to diethylamine is about 1:1 to 1:3, more preferably 1:1.5;

[0041] Preferably, in step 1), the base is a nitrogen-containing organic base; more preferably, the base includes, but is not limited to, triethylamine, DMAP, DIPEA, pyridine, etc.; more preferably, it is triethylamine.

[0042] Preferably, in step 1), the molar ratio of benzoylformic acid to the base is about 1:1 to 1:3, more preferably 1:3;

[0043] Preferably, in step 1), the reaction time is 4-6 hours, more preferably 5 hours;

[0044] Preferably, in step 2), the reducing agent is a selective reducing agent; more preferably, the reducing agent includes, but is not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, DIBAL-H, LTBA, Red-Al, etc.; more preferably, the reducing agent is sodium borohydride.

[0045] Preferably, in step 2), the molar ratio of benzoylformic acid to reducing agent is about 1:1 to 1:3, more preferably 1:3;

[0046] Preferably, in step 2), the reaction time is 18-24 hours, more preferably 20 hours;

[0047] Preferably, in step 2), the method for monitoring the reaction is selected from ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonance, thin-layer chromatography, gas chromatography, and high-performance liquid chromatography, and more preferably high-performance liquid chromatography;

[0048] Preferably, in step 2), the separation method is selected from recrystallization, distillation, chromatography, precipitation, evaporation, and extraction, more preferably extraction; further preferably, the solvents used for extraction include, but are not limited to, dichloromethane, ethyl acetate, and diethyl ether; even more preferably, the solvent used for extraction is dichloromethane; even more preferably, the separation method includes the following steps: adding 50 ml of dichloromethane to the product obtained after evaporating the solvent, extracting twice with water (150 ml × 2), adding 150 ml of water to the organic phase, adjusting the pH to weakly acidic with 1N HCl, releasing the aqueous phase, and washing the organic phase once with 150 ml of water;

[0049] Preferably, in step 3), the purification is performed by chromatography, recrystallization and precipitation; more preferably, the purification is performed by column chromatography; even more preferably, the column chromatography is performed using silica gel H as packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as eluent.

[0050] In some preferred embodiments of the present invention, a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide is provided, the method comprising the following steps:

[0051] 1) Add 1.5g benzoylformic acid and 4.55g HBTU to a 250ml round-bottom flask, add 100ml acetonitrile, stir and dissolve at room temperature, then add 1.54ml diethylamine, stir for 3min, then add 4.16ml triethylamine, react at room temperature for 5h to obtain the reaction solution;

[0052] 2) Add 1.11 g NaBH4 to the reaction solution obtained in step 1), stir at room temperature, monitor the reaction with HPLC, and the reaction is complete in about 24 h; evaporate the solvent, add 50 ml dichloromethane, extract twice with water (150 ml × 2), add 150 ml water to the organic phase, adjust the pH to weakly acidic with 1N HCl, release the aqueous phase, wash the organic phase once with 150 ml water, dry the organic phase with anhydrous sodium sulfate, filter, and obtain crude N,N-diethyl-2-hydroxyphenylacetamide;

[0053] 3) The crude N,N-diethyl-2-hydroxyphenylacetamide obtained in step 2) is purified by column chromatography to obtain pure N,N-diethyl-2-hydroxyphenylacetamide, wherein the column chromatography purification is carried out using silica gel H as packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as eluent.

[0054] On the other hand, the present invention also provides the application of the above-described method in the preparation of N,N-diethyl-2-hydroxyphenylacetamide and its analogues. Preferably, the present invention provides the application of the above-described method in the preparation of N,N-diethyl-2-hydroxyphenylacetamide.

[0055] Furthermore, the present invention also provides a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide (i.e., Method Two), the reaction route of which is as follows:

[0056]

[0057] The method includes the following steps:

[0058] (i) In solvent C, add the compound of formula (III), stir in an ice bath, and then react with an acyl chloride reagent for a certain time under the catalysis of a small amount of DMF, and evaporate to dryness to obtain the compound of formula (X);

[0059] (ii) Add solvent C to the compound of formula (X) obtained in step (i), then add the compound of formula (IV), react for a certain time under the action of alkali, and evaporate to dryness to obtain the compound of formula (II).

[0060] (iii) Add solvent D and reducing agent to the compound of formula (II) obtained in step (ii), react for a certain time, monitor the reaction, and after the reaction is completed, evaporate the solvent, separate and dry to obtain the crude product of compound (I);

[0061] (iv) Purify the crude product obtained in step (iii) to obtain the pure product of compound (I);

[0062] In this context, R1 and R2 are independently hydrogen, alkyl, or aryl; A is a substituted or unsubstituted aryl or heteroaryl group.

[0063] In the above method,

[0064] Preferably, in step (i) and / or step (ii), the solvent C includes, but is not limited to, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate or mixtures thereof, more preferably dichloromethane;

[0065] Preferably, in step (i), the acyl chloride reagent includes, but is not limited to, oxalyl chloride, thionyl chloride, etc., and more preferably oxalyl chloride;

[0066] Preferably, in step (i), the molar ratio of the compound of formula (III) to the acyl chloride reagent is about 1:1 to 1:1.2, more preferably 1:1.2 or 1:1;

[0067] Preferably, in step (i), the molar ratio of the acyl chloride reagent to DMF is about 10:1 to 20:1, more preferably 10:1;

[0068] Preferably, in step (i), the ice bath is at 0°C;

[0069] Preferably, in step (i), the ice bath stirring time is 10 to 20 minutes, more preferably 10 minutes;

[0070] Preferably, in step (i), the reaction time is 1 to 2 hours, more preferably 1 hour;

[0071] Preferably, in step (ii), the molar ratio of the compound of formula (III) to the compound of formula (IV) is about 1:1 to 1:3, more preferably 1:1.5;

[0072] Preferably, in step (ii), the base is a nitrogen-containing organic base, and more preferably the base includes, but is not limited to, triethylamine, DMAP, DIPEA, pyridine, etc., and more preferably triethylamine;

[0073] Preferably, in step (ii), the molar ratio of the compound of formula (III) to the base is about 1:1 to 1:2, more preferably 1:1;

[0074] Preferably, in step (ii), the reaction time is 15 to 30 minutes;

[0075] Preferably, in step (iii), the reducing agent is a selective reducing agent; more preferably, the reducing agent includes, but is not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, DIBAL-H, LTBA, Red-Al, etc.; more preferably, sodium borohydride.

[0076] Preferably, in step (iii), the molar ratio of the compound of formula (III) to the reducing agent is about 1:1 to 1:3, more preferably 1:3;

[0077] Preferably, in step (iii), the solvent D includes, but is not limited to, acetonitrile, ethanol, methanol, water or mixtures thereof, more preferably acetonitrile;

[0078] Preferably, in step (iii), the reaction time is 18 to 24 hours; more preferably, it is 20 hours.

[0079] Preferably, the reaction in the above method is monitored by a method selected from the following: ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonance, thin-layer chromatography, gas chromatography and high-performance liquid chromatography, more preferably high-performance liquid chromatography;

[0080] Preferably, in step (iii), the separation method is selected from recrystallization, distillation, chromatography, precipitation, evaporation and extraction, more preferably extraction; further preferably, the solvents used for extraction include, but are not limited to, dichloromethane, ethyl acetate and diethyl ether; even more preferably, the solvent used for extraction is dichloromethane; even more preferably, the separation method includes the following steps: adding 50 ml of dichloromethane to the product obtained after evaporating the solvent, and extracting with water 3 times (150 ml × 3); adding 150 ml of water to the organic phase, adjusting the pH to weakly acidic with 1N HCl, washing away the remaining diethylamine and triethylamine, releasing the aqueous phase, and washing the organic phase once with 150 ml of water;

[0081] Preferably, in step (iv), the purification is performed by chromatography, recrystallization and precipitation; more preferably, the purification is performed by column chromatography; even more preferably, the column chromatography purification is performed using silica gel H as packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as eluent.

[0082] Preferably, both R1 and R2 are ethyl;

[0083] Preferably, A is a substituted aryl or heteroaryl group, more preferably an aryl or heteroaryl group substituted with a group selected from the following: halogen, -CN, -NO2, -OH, -SH, -OR, -SR, -R3, -R3OR4, -C(O)R3, -S(O)R3, -S(O)OR3, -NR4R5, -C(O)NR4R5, -OC(O)R4, -NR4C(O)R5, and even more preferably, A is a phenyl group.

[0084] In some embodiments of the present invention, a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide is provided, the method comprising the following steps:

[0085] (i) Add benzoylformic acid to solvent C, stir in an ice bath, and then react with an acyl chloride reagent for a certain time under the catalysis of a small amount of DMF. Dry the mixture to obtain the acyl chloride.

[0086] (ii) Add solvent C to the acyl chloride obtained in step (i), then add diethylamine, react for a certain time under the action of a base, and evaporate to dryness to obtain...

[0087] (iii) to the result obtained in step (ii) Solvent D and reducing agent were added to the mixture, and the reaction was carried out for a certain period of time. The reaction was monitored, and after the reaction was completed, the solvent was evaporated, the mixture was separated, and dried to obtain the crude product of compound (I).

[0088] (iv) Purify the crude product obtained in step (iii) to obtain the pure product of compound (I);

[0089] In the above method,

[0090] Preferably, in step (i) and / or step (ii), the solvent C includes, but is not limited to, acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate or mixtures thereof, more preferably dichloromethane;

[0091] Preferably, in step (i), the acyl chloride reagent includes, but is not limited to, oxalyl chloride, thionyl chloride, etc., and more preferably oxalyl chloride;

[0092] Preferably, in step (i), the molar ratio of benzoylformic acid to acyl chloride reagent is about 1:1 to 1:1.2, more preferably 1:1.2 or 1:1;

[0093] Preferably, in step (i), the molar ratio of the acyl chloride reagent to DMF is about 10:1 to 20:1, more preferably 10:1;

[0094] Preferably, in step (i), the ice bath is at 0°C;

[0095] Preferably, in step (i), the ice bath stirring time is 10 to 20 minutes, more preferably 10 minutes;

[0096] Preferably, in step (i), the reaction time is 1 to 2 hours, more preferably 1 hour;

[0097] Preferably, in step (ii), the molar ratio of benzoylformic acid to diethylamine is about 1:1 to 1:3, more preferably 1:1.5;

[0098] Preferably, in step (ii), the base is a nitrogen-containing organic base, and more preferably the base includes, but is not limited to, triethylamine, DMAP, DIPEA, pyridine, etc., and more preferably triethylamine;

[0099] Preferably, in step (ii), the molar ratio of the benzoylformic acid to the base is about 1:1 to 1:2, more preferably 1:1;

[0100] Preferably, in step (ii), the reaction time is 15 to 30 minutes;

[0101] Preferably, in step (iii), the reducing agent is a selective reducing agent; more preferably, the reducing agent includes, but is not limited to, sodium borohydride, lithium borohydride, sodium cyanoborohydride, DIBAL-H, LTBA, Red-Al, etc.; more preferably, sodium borohydride.

[0102] Preferably, in step (iii), the molar ratio of benzoylformic acid to the reducing agent is about 1:1 to 1:3, more preferably 1:3;

[0103] Preferably, in step (iii), the solvent D includes, but is not limited to, acetonitrile, ethanol, methanol, water or mixtures thereof, more preferably acetonitrile;

[0104] Preferably, in step (iii), the reaction time is 18 to 24 hours; more preferably, it is 20 hours.

[0105] Preferably, the reaction in the above method is monitored by a method selected from the following: ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonance, thin-layer chromatography, gas chromatography and high-performance liquid chromatography, more preferably high-performance liquid chromatography;

[0106] Preferably, in step (iii), the separation method is selected from recrystallization, distillation, chromatography, precipitation, evaporation and extraction, more preferably extraction; further preferably, the solvents used for extraction include, but are not limited to, dichloromethane, ethyl acetate and diethyl ether; even more preferably, the solvent used for extraction is dichloromethane; even more preferably, the separation method includes the following steps: adding 50 ml of dichloromethane to the product obtained after evaporating the solvent, and extracting with water 3 times (150 ml × 3); adding 150 ml of water to the organic phase, adjusting the pH to weakly acidic with 1N HCl, washing away the remaining diethylamine and triethylamine, releasing the aqueous phase, and washing the organic phase once with 150 ml of water;

[0107] Preferably, in step (iv), the purification is performed by chromatography, recrystallization and precipitation; more preferably, the purification is performed by column chromatography; even more preferably, the column chromatography purification is performed using silica gel H as packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as eluent.

[0108] In some preferred embodiments of the present invention, a method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide is provided, the method comprising the following steps:

[0109] 1) Add 1.50g of benzoylformic acid to a 250ml round-bottom flask, add 50ml of dichloromethane, stir in an ice bath at 0℃ for 10min, add 0.85ml of oxaloyl chloride, stir for 1min, then add 2 drops of DMF, stir and react for 1h, monitor the reaction by TLC until complete; evaporate the solvent and the remaining oxaloyl chloride.

[0110] 2) Then add 50 ml of dichloromethane, stir well, add 1.54 ml of diethylamine, stir for 1 min, add 1.37 ml of triethylamine, stir at room temperature for 0.5 h, monitor the reaction for completeness by TLC, and evaporate the solvent.

[0111] 3) Then add 50 ml of acetonitrile and 1.11 g of NaBH4, stir at room temperature, monitor the reaction with HPLC, and after about 20 h, the reaction is complete. Dry the solvent by rotary evaporation. Then add 50 ml of dichloromethane and extract three times with water (150 ml × 3). Add 150 ml of water to the organic phase, adjust the pH to weakly acidic with 1N HCl, and wash away the remaining diethylamine and triethylamine. Discard the aqueous phase, and wash the organic phase once more with 150 ml of water. Dry the organic phase with anhydrous sodium sulfate, filter, and obtain crude N,N-diethyl-2-hydroxyphenylacetamide.

[0112] 4) The crude N,N-diethyl-2-hydroxyphenylacetamide was purified by column chromatography to obtain pure N,N-diethyl-2-hydroxyphenylacetamide. The column chromatography purification was carried out using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent.

[0113] Furthermore, the present invention also provides the application of the above-described method in the preparation of N,N-diethyl-2-hydroxyphenylacetamide and its analogues. Preferably, the present invention provides the application of the above-described method in the preparation of N,N-diethyl-2-hydroxyphenylacetamide.

[0114] The advantages of this invention are as follows: Using benzoylcarboxylic acid as the substrate, compared to the traditional method using mandelic acid, avoids the interference of the hydroxyl group in the substrate on the condensation reaction. In methods one and two of this invention, the condensation product of benzoylcarboxylic acid and amine in the first step is singular and has a high yield. The product does not need to be separated; combined with the selective reduction of the carbonyl group by a reducing agent, a one-pot synthesis of compound DEM is achieved. Compared with existing DEM synthesis methods, this reduces the number of synthesis steps and improves the synthesis efficiency and overall yield. Furthermore, in existing technologies, using DCC as a condensing agent generates DCU, increasing the difficulty of post-processing. However, this invention uses HBTU as a condensing agent, and the byproduct can be removed through simple post-processing, which is beneficial to improving the product yield and purity.

[0115] Terms and / or definitions

[0116] The term [alkyl] refers to a straight-chain or branched monovalent hydrocarbon (e.g., C1-C4). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isobutyl, n-butyl, isobutyl, and tert-butyl.

[0117] The term "aryl" refers to an aromatic ring system with a monocyclic 6-carbon ring, a bicyclic 10-carbon ring, or a tricyclic 14-carbon ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracene.

[0118] The term "heterocyclic group" refers to a monovalent aromatic 5- to 8-membered monocyclic, 8- to 12-membered bicyclic, or 11- to 14-membered tricyclic ring system having one or more heteroatoms (such as O, N, S, or Se). Examples of aromatic heterocyclic groups include, but are not limited to, pyridyl, pyrroleyl, furanyl, thiopheneyl, imidazolyl, oxazolyl, thiazolyl, benzimidazolyl, pyrimidinyl, quinolinyl, and indoleyl.

[0119] The alkyl, aryl, and heteroaryl groups described herein include both substituted and unsubstituted groups. Substituents on alkyl groups include, but are not limited to, C2-C... 10 alkynyl group, C3-C 20 cycloalkyl, C3-C 20 Heterocyclic alkyl, C1-C 10 Alkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, amino, alkylamino, arylamino, hydroxyl, halogen, ketone, thionyl, silyl, mercapto, thio (-S-), alkylthio, arylthio, alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioyl, formamidinyl, amide, thiourea, cyanothio, sulfonamide, guanidine, urea, cyano, nitro, acyl, thioyl, acyloxy, aminoformamide, aminoformamide, carboxyl, and carboxylic acid esters. On the other hand, possible substituents on aryl and heteroaryl groups, besides C1-C... 10 Alkyl groups, including all the substituents mentioned above. Aryl and heteroaryl groups may also be fused together. Attached Figure Description

[0120] The embodiments of the present invention will now be described in detail with reference to the accompanying drawings, wherein:

[0121] Figure 1 DEM prepared in Example 1 1 H NMR;

[0122] Figure 2 DEM prepared in Example 1 13 C NMR;

[0123] Figure 3 DEM prepared in Example 3 1 H NMR;

[0124] Figure 4 DEM prepared in Example 3 13 C NMR;

[0125] Figure 5 Mass spectrometry of the DEM prepared in Example 3. Detailed Implementation

[0126] The following embodiments are provided to illustrate the present invention, but are not intended to limit its scope of protection. All equivalent changes and modifications made in accordance with the content of the claims of the present invention should be within the technical scope of the present invention.

[0127] Example 1

[0128] 1.5 g of benzoylformic acid and 4.55 g of HBTU were added to a 250 ml round-bottom flask, followed by 100 ml of acetonitrile. The mixture was stirred and dissolved at room temperature (approximately 24°C). Then, 1.54 ml of diethylamine was added, and the mixture was stirred for 3 min. Next, 4.16 ml of triethylamine was added, and the mixture was reacted at room temperature for 5 h. 1.11 g of NaBH4 was added, and the mixture was stirred at room temperature (approximately 24°C). The reaction was monitored by HPLC, and the reaction was completed in approximately 20 h. The solvent was evaporated, and 50 ml of dichloromethane was added. The mixture was extracted twice with water (150 ml × 2). 150 ml of water was added to the organic phase, and the pH was adjusted to weakly acidic with 1N HCl. The aqueous phase was discharged, and the organic phase was washed once with 150 ml of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The crude product was purified by column chromatography using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent. The yield of the prepared product (DEM) was 95%, and the purity was 99%.

[0129] The prepared DEM 1 H NMR, 13 C NMR shows Figure 1 and Figure 2 .

[0130] Example 2

[0131] 1.5 g benzoylformic acid and 4.55 g HBTU were added to a 250 ml round-bottom flask, followed by 100 ml THF. The mixture was stirred and dissolved at room temperature (approximately 24°C). Then, 1.54 ml diethylamine was added, and the mixture was stirred for 3 min. Next, 4.16 ml triethylamine was added, and the mixture was reacted at room temperature for 5 h. Finally, 1.11 g NaBH4 was added, and the mixture was stirred at room temperature (approximately 24°C). The reaction was monitored by HPLC, and the reaction was complete in approximately 20 h. The solvent was evaporated, and 50 ml dichloromethane was added. The mixture was extracted twice with water (150 ml × 2). 150 ml water was added to the organic phase, and the pH was adjusted to weakly acidic with 1 N HCl. The aqueous phase was discharged, and the organic phase was washed once with 150 ml water. The organic phase was dried over anhydrous sodium sulfate and filtered. The crude product was purified by column chromatography using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent. The yield of the prepared product (DEM) was 60%.

[0132] Example 3

[0133] Add 1.50 g of benzoylformic acid to a 250 ml round-bottom flask, add 50 ml of dichloromethane, stir in an ice bath at 0 °C for 10 min, add 0.85 ml of oxaloyl chloride, stir for 1 min, then add 2 drops of DMF, stir for 1 h, and monitor the reaction by TLC until complete. Dry the solvent and the remaining oxaloyl chloride, add 50 ml of dichloromethane, stir well, add 1.54 ml of diethylamine, stir for 1 min, add 1.37 ml of triethylamine, stir at room temperature (around 24 °C) for 0.5 h, and monitor the reaction by TLC until the acyl chloride disappears, indicating complete aminolysis. Dry the solvent, add 50 ml of acetonitrile, add 1.11 g of NaBH4, stir at room temperature (around 24 °C), and monitor the reaction by HPLC. The reaction is complete in approximately 20 h. Dry the solvent, add 50 ml of dichloromethane, and extract three times with water (150 ml × 3). Add 150 ml of water to the organic phase, adjust the pH to weakly acidic with 1N HCl, and wash away the remaining diethylamine and triethylamine. Dispose of the aqueous phase, and wash the organic phase once more with 150 ml of water. Dry the organic phase with anhydrous sodium sulfate and filter. Purify the crude product by column chromatography using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent. The yield of the prepared product DEM was 80%, and the purity was 99%.

[0134] The prepared DEM 1 H NMR, 13 C NMR and mass spectrometry are shown in the figures. Figure 3 , Figure 4 and Figure 5 .

[0135] Example 4

[0136] 1.50 g of benzoylformic acid was added to a 250 ml round-bottom flask, followed by 50 ml of dichloromethane. The mixture was stirred in an ice bath at 0 °C for 10 min. Then, 0.85 ml of oxaloyl chloride was added, and the mixture was stirred for 1 min. Two drops of DMF were then added, and the mixture was stirred for 1 h. TLC monitoring showed the reaction was complete. The solvent and remaining oxaloyl chloride were evaporated, and 50 ml of dichloromethane was added. The mixture was stirred thoroughly, followed by 1.54 ml of diethylamine. The mixture was stirred for 1 min, followed by 1.37 ml of triethylamine. The mixture was stirred at room temperature (approximately 24 °C) for 0.5 h. TLC monitoring showed the disappearance of the acyl chloride, indicating complete aminolysis. 1.11 g of NaBH4 was added, and the mixture was stirred at room temperature (approximately 24 °C). HPLC monitoring showed that no product was formed after 20 h of reaction, and the yield of the prepared product (DEM) was 0%.

[0137] Example 5

[0138] Add 1.50 g of benzoylformic acid to a 250 ml round-bottom flask, add 50 ml of dichloromethane, stir in an ice bath at 0 °C for 10 min, add 0.85 ml of oxaloyl chloride, stir for 1 min, then add 2 drops of DMF, stir for 1 h, and monitor the reaction for completeness by TLC. Dry the solvent and remaining oxaloyl chloride, add 50 ml of dichloromethane, stir well, add 1.54 ml of diethylamine, stir for 1 min, add 1.37 ml of triethylamine, stir at room temperature (around 24 °C) for 0.5 h, and monitor the reaction for completeness by TLC. Dry the solvent again, add 50 ml of THF, add 1.11 g of NaBH4, stir at room temperature (around 24 °C), and monitor the reaction by HPLC. The reaction is complete in approximately 20 h. Dry the solvent again, add 50 ml of dichloromethane, and extract three times with water (150 ml × 3). Add 150 ml of water to the organic phase, adjust the pH to weakly acidic with 1N HCl, and wash away the remaining diethylamine and triethylamine. The aqueous phase was discharged, and the organic phase was washed once with 150 ml of water. The organic phase was dried over anhydrous sodium sulfate and filtered. The crude product was purified by column chromatography using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent. The yield of the prepared product in DEM was approximately 60%.

Claims

1. A method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide, wherein the reaction route of the method is as follows: The method includes the following steps: 1) In solvent A, the compound of formula (III) and the compound of formula (IV) are reacted for a certain time under the action of a condensing agent and a base to obtain a reaction solution containing the compound of formula (II). 2) Add a reducing agent to the reaction solution containing compound (II) obtained in step 1), react for a certain time, monitor the reaction, and after the reaction is completed, evaporate the solvent, separate and dry to obtain the crude product of compound (I); 3) Purify the crude product obtained in step 2) to obtain the pure product of compound (I); Where R1 and R2 are both ethyl groups; A is a phenyl group; In step 1), solvent A is acetonitrile; In step 2), the reducing agent is sodium borohydride or lithium borohydride.

2. The method according to claim 1, wherein, In step 1), the condensing agent is selected from HBTU, HATU, HOBT, PyBOP and TBTU.

3. The method according to claim 2, wherein, The condensing agent is HBTU.

4. The method according to claim 1, wherein, In step 1), the molar ratio of the compound of formula (III) to the condensing agent is 1:1 to 1:1.

2.

5. The method according to claim 4, wherein, In step 1), the molar ratio of the compound of formula (III) to the condensing agent is 1:1.

2.

6. The method according to claim 1, wherein, In step 1), the molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1 to 1:

3.

7. The method according to claim 6, wherein, In step 1), the molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1.

5.

8. The method according to claim 1, wherein, In step 1), the base is a nitrogen-containing organic base.

9. The method according to claim 8, wherein, In step 1), the base is selected from triethylamine, DMAP, DIPEA and pyridine.

10. The method according to claim 9, wherein, In step 1), the base is triethylamine.

11. The method according to claim 1, wherein, In step 1), the molar ratio of the compound of formula (III) to the base is 1:1 to 1:

3.

12. The method according to claim 11, wherein, In step 1), the molar ratio of the compound of formula (III) to the base is 1:

3.

13. The method according to claim 1, wherein, In step 1), the reaction time is 4-6 hours.

14. The method according to claim 13, wherein, In step 1), the reaction time is 5 hours.

15. The method according to claim 1, wherein, In step 2), the molar ratio of the compound of formula (III) to the reducing agent is 1:1 to 1:

3.

16. The method according to claim 15, wherein, In step 2), the molar ratio of the compound of formula (III) to the reducing agent is 1:

3.

17. The method according to claim 1, wherein, In step 2), the reaction takes 18-24 hours.

18. The method according to claim 17, wherein, In step 2), the reaction takes 20 hours.

19. The method according to claim 1, wherein, In step 2), the method for monitoring the reaction is selected from ultraviolet spectrophotometry, infrared spectrophotometry, nuclear magnetic resonance, thin-layer chromatography, gas chromatography and high-performance liquid chromatography.

20. The method according to claim 19, wherein, In step 2), the method for monitoring the reaction is high-performance liquid chromatography.

21. The method according to claim 1, wherein, In step 2), the separation method is selected from recrystallization, distillation, chromatography, precipitation, evaporation and extraction.

22. The method according to claim 21, wherein, In step 2), the separation method is extraction.

23. The method according to claim 22, wherein, The solvents used for extraction were selected from dichloromethane, ethyl acetate, and diethyl ether.

24. The method according to claim 23, wherein, The solvent used for extraction was dichloromethane.

25. The method according to claim 1, wherein, In step 2), the separation method includes the following steps: adding 50 ml of dichloromethane to the product obtained after evaporating the solvent, extracting twice with 150 ml of water, adding 150 ml of water to the organic phase, adjusting the pH to weakly acidic with 1N HCl, releasing the aqueous phase, and washing the organic phase once with 150 ml of water.

26. The method according to claim 1, wherein, In step 3), the purification is performed using chromatography, recrystallization, and precipitation.

27. The method according to claim 26, wherein, In step 3), the purification is performed using column chromatography.

28. The method according to claim 27, wherein, The column chromatography purification was performed using silica gel H as the packing material and petroleum ether / ethyl acetate at a volume ratio of 5:1 as the eluent.

29. A method for synthesizing N,N-diethyl-2-hydroxyphenylacetamide, wherein the reaction route of the method is as follows: The method includes the following steps: (i) Add the compound of formula (III) to solvent C, stir in an ice bath, and then react with an acyl chloride reagent for a certain time under the catalysis of a small amount of DMF, and evaporate to dryness to obtain the compound of formula (X); (ii) Add solvent C to the compound of formula (X) obtained in step (i), then add the compound of formula (IV), react for a certain time under the action of base, and evaporate to dryness to obtain the compound of formula (II). (iii) Add solvent D and reducing agent to the compound of formula (II) obtained in step (ii), react for a certain time, monitor the reaction, and after the reaction is completed, evaporate the solvent, separate and dry to obtain the crude product of compound (I); (iv) Purify the crude product obtained in step (iii) to obtain the pure product of compound (I); Where R1 and R2 are both ethyl groups; A is a phenyl group; In step (iii), the solvent D is acetonitrile; In step (iii), the reducing agent is sodium borohydride or lithium borohydride.

30. The method according to claim 29, wherein, In step (i) and / or step (ii), the solvent C is acetonitrile, tetrahydrofuran, dichloromethane, ethyl acetate, or a mixture thereof.

31. The method according to claim 30, wherein, In step (i) and / or step (ii), the solvent C is dichloromethane.

32. The method according to claim 29, wherein, In step (i), the acyl chloride reagent is selected from oxalyl chloride and thionyl chloride.

33. The method according to claim 32, wherein, In step (i), the acyl chloride reagent is oxalyl chloride.

34. The method according to claim 29, wherein, In step (i), the molar ratio of the compound of formula (III) to the acyl chloride reagent is 1:1 to 1:1.

2.

35. The method according to claim 34, wherein, In step (i), the molar ratio of the compound of formula (III) to the acyl chloride reagent is 1:1.2 or 1:

1.

36. The method according to claim 29, wherein, In step (i), the molar ratio of the acyl chloride reagent to DMF is 10:1 to 20:

1.

37. The method of claim 36, wherein, In step (i), the molar ratio of the acyl chloride reagent to DMF is 10:

1.

38. The method according to claim 29, wherein, In step (i), the ice bath is at 0°C.

39. The method according to claim 29, wherein, In step (i), the ice bath stirring time is 10 to 20 minutes.

40. The method according to claim 39, wherein, In step (i), the ice bath stirring time is 10 minutes.

41. The method according to claim 29, wherein, In step (i), the reaction takes a certain time of 1 to 2 hours.

42. The method according to claim 41, wherein, In step (i), the reaction time is 1 hour.

43. The method according to claim 29, wherein, In step (ii), the molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1 to 1:

3.

44. The method according to claim 43, wherein, In step (ii), the molar ratio of the compound of formula (III) to the compound of formula (IV) is 1:1.

5.

45. The method according to claim 29, wherein, In step (ii), the base is a nitrogen-containing organic base.

46. ​​The method according to claim 45, wherein, In step (ii), the base is selected from triethylamine, DMAP, DIPEA and pyridine.

47. The method according to claim 46, wherein, In step (ii), the base is triethylamine.

48. The method according to claim 29, wherein, In step (ii), the molar ratio of the compound of formula (III) to the base is 1:1 to 1:

2.

49. The method according to claim 48, wherein, In step (ii), the molar ratio of the compound of formula (III) to the base is 1:

1.

50. The method according to claim 29, wherein, In step (ii), the reaction takes a certain time of 15 to 30 minutes.

51. The method according to claim 29, wherein, In step (iii), the molar ratio of the compound of formula (III) to the reducing agent is 1:1 to 1:

3.

52. The method according to claim 51, wherein, In step (iii), the molar ratio of the compound of formula (III) to the reducing agent is 1:

3.

53. The method according to claim 29, wherein, In step (iii), the reaction takes a certain time of 18 to 24 hours.

54. The method according to claim 53, wherein, In step (iii), the reaction takes 20 hours.

55. The method according to claim 29, wherein, In step (iii), the separation method is selected from recrystallization, distillation, chromatography, precipitation, evaporation and extraction.

56. The method according to claim 55, wherein, In step (iii), the separation method is extraction.

57. The method according to claim 56, wherein, The solvents that can be used for extraction are selected from dichloromethane, ethyl acetate, and diethyl ether.

58. The method according to claim 57, wherein, The solvent used for extraction was dichloromethane.

59. The method according to claim 29, wherein, In step (iv), the purification is performed using chromatography, recrystallization, and precipitation.

60. The method according to claim 59, wherein, In step (iv), the purification is performed using column chromatography.

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