A sort of 14 Application of aminoacetylation of sodium acetate

Abstract

The present invention belongs to the technical field of chemical synthesis and discloses a 14 The aminoacetylation of sodium C acetate is applied to a solvent by adding sodium C acetate, amine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / EDCI in a one-pot method to obtain the desired acetamide; wherein, based on the molar mass ratio of the sodium C acetate: amine: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / EDCI = 1:0.5-3:0.5-5; the solvent is acetonitrile and water in a volume ratio of 1:0.5-5.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a 14 C. Application of aminoacetylation of sodium acetate. Background Art

[0002] The description of the background technology in the present invention belongs to the related technology related to the present invention and is only used to illustrate and facilitate the understanding of the invention content of the present invention. It should not be understood that the applicant explicitly believes or infers that the applicant believes that it is the prior art of the present invention on the filing date of the first application.

[0003] Currently, there are three main methods for conventional aminoacetylation chemical synthesis: the acyl halide method, the acetic acid method, and the anhydride method. Both the acyl halide method and the acetic acid method suffer from reagent instability, volatilization, and decomposition. The anhydride method, which involves the condensation of two molecules of acetic acid, is complex and reduces yield by half.

[0004] Currently, the most commonly used method for amino acetylation is the acyl halide method. Its synthesis process primarily involves synthesizing acyl halides from acetic acid, which are then reacted with various amino groups to produce acetylamino groups. However, most corresponding acyl halides (such as acetyl chloride) are highly reactive and decompose when exposed to moisture. Consequently, further reaction of the acyl halide with an amine results in failure to produce the corresponding amide or a reduced yield. Summary of the Invention

[0005] The purpose of the embodiment of the present invention is to provide a 14 C. Application of aminoacetylation of sodium acetate.

[0006] A sort of 14 The amino acetylation application of sodium acetate comprises the following steps:

[0007] In the solvent, add 14 C sodium acetate, amine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / EDCI to obtain the desired acetamide in one pot;

[0008] Wherein, according to volume ratio, the 14 C sodium acetate: amine: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride / EDCI = 1:0.5-3:0.5-5;

[0009] The solvent is acetonitrile and water in a volume ratio of 1:0.5 to 5

[0010] Furthermore, the amines include: aliphatic amines, aromatic amines, amino acids, etc.

[0011] Furthermore, the application is in the preparation of [ 14 C] application of N-acetyl lysine, comprising the following steps:

[0012] (1) Take 14 C sodium acetate (0.45 mmol), N-Cbz-L-lysine benzyl ester (0.225-1.35 mmol), acetonitrile (3-30 ml) and water (6-60 ml) were stirred to dissolve; EDCI (0.225-2.25 mmol) was added and stirred at 15-45°C for 1-4 h;

[0013] Ethyl acetate (10-100 ml) was added to extract and separate the phases. The organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column to obtain N-acetyl-Cbz-L-lysine benzyl ester;

[0014] (2) Add N-acetyl-Cbz-L-lysine benzyl ester (156.0 mg) to a single-necked reaction flask, add ethanol (5-20 ml), and stir to dissolve. Add 10% palladium on carbon (40-200 mg), replace with a hydrogen balloon four times, and stir under hydrogen pressure at 20-40°C for 24-72 hours.

[0015] Filter, rinse with ethanol / water (4ml / 2ml), concentrate the filtrate to dryness, prepare by reverse phase, and freeze-dry to obtain [ 14 C] N-acetyl lysine.

[0016] Furthermore, the application is in the preparation of [ 14 C] application in the synthesis of N-acetyl-L-cysteine, comprising the following steps:

[0017] (1) Take 14 Sodium acetate (0.45 mmol), L-cystine diethyl ester dihydrochloride (0.225-1.35 mmol), acetonitrile (3-30 ml), and water (6-60 ml) were stirred and dissolved. EDCI (0.225-2.25 mmol) was added and stirred at 15-45°C for 1-4 hours. Ethyl acetate (10-100 ml) was added to extract and separate the phases. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain N-acetyl-L-cystine diethyl ester.

[0018] (2) Add N-acetyl-L-cystine diethyl ester (129.5 mg) to a single-necked reaction flask, add ethanol / water (5-20 ml / 5-20 ml), stir to dissolve, add lithium hydroxide (100-500 mg), and stir at 15-35°C for 2-5 hours. After stirring and cooling in an ice-water bath, add citric acid dropwise until neutral, and concentrate to dryness to obtain N-acetyl-L-cystine diacetic acid.

[0019] (3) Add N-acetyl-L-cystine diacetic acid, tetrahydrofuran / water (9-18 ml / 1-2 ml), and triphenylphosphine (2-6 mmol) to the reaction flask. After nitrogen replacement three times, stir at 45-55°C for 10-15 hours. Concentrate the reaction solution under reduced pressure, add water (5-50 ml), stir, and filter. Wash the filter cake with water (5 ml x 3). Concentrate the filtrate to dryness and prepare [ 14 C] N-acetyl-L-cysteine.

[0020] Furthermore, the application is in the preparation of [ 14 C] application in the synthesis of N-acetyl-DL-O-methylserine, comprising the following steps:

[0021] Pick 14 Sodium acetate (1.19 mmol), DL-O-methylserine (0.60-3.57 mmol), acetonitrile (3-30 ml) and water (6-60 ml) were stirred and dissolved. EDCI (0.60-3.57 mmol) was added and stirred at 15-45°C for 1-4 hours. Ethyl acetate (10-100 ml) was added to extract and separate the phases. The organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and reversed to obtain [ 14 C] N-acetyl-DL-O-methylserine.

[0022] The embodiments of the present invention have the following beneficial effects:

[0023] The sodium acetate used in this method is stable, and the one-step synthesis is easy to perform. Amines can be acetylated to produce acetamide at room temperature without the need for strictly anhydrous conditions. This method is simple, uses stable and readily available reagents, and offers good process reproducibility and yield.

[0024] The method of the present application is characterized in that stable sodium acetate is used as a raw material, acetonitrile and water are used as a mixed solvent to efficiently dissolve the raw material, and EDCI is used to achieve one-step acetylation of the amino group at room temperature. The method mainly solves the main difficulties of the current amino acetylation process, such as complex multi-step reaction, unstable reagents used, and low reaction yield, and has good application for the amino acetylation of most amino acids and other amino acetylations. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 The synthetic process flow chart of Example 1 of the present invention is as follows;

[0026] Figure 2 Flow chart of the synthesis process of Example 2 of the present invention;

[0027] Figure 3 This is a flow chart of the synthesis process of Example 3 of the present invention. DETAILED DESCRIPTION

[0028] The present application will be further described below with reference to the embodiments.

[0029] To more clearly illustrate the embodiments of the present invention or technical solutions in the prior art, different "one embodiment" or "embodiment" in the following description do not necessarily refer to the same embodiment. Different embodiments may be replaced or combined. Those skilled in the art can also derive other implementation methods based on these embodiments without inventive effort.

[0030] Example 1

[0031] [ 14 C] N-acetyl lysine synthesis (e.g. Figure 1 shown)

[0032] This embodiment includes the following steps:

[0033] (1) Add the 14 Sodium acetate (38.2 mg, 0.45 mmol), SM-2 (185.0 mg, 0.45 mmol), acetonitrile (3 ml) and water (6 ml) were stirred and dissolved, and EDCI (87.1 mg, 0.45 mmol) was added and stirred at 25°C for 3 h.

[0034] Ethyl acetate (20 ml) was added to extract the separated phases. The organic phase was collected, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified on a silica gel column to obtain 156.0 mg of N-acetyl-Cbz-L-lysine benzyl ester (yield: 82%).

[0035] (2) Add N-acetyl-Cbz-L-lysine benzyl ester (156.0 mg) to a single-necked reaction flask, add ethanol (8 ml), and stir to dissolve. Add 10% palladium on carbon (70 mg), replace the mixture with a hydrogen balloon four times, and stir under hydrogen pressure at 30°C for 48 h.

[0036] Filter, rinse with ethanol / water (4ml / 2ml), concentrate the filtrate to dryness, prepare by reverse phase, and freeze-dry to obtain [ 14 C] N-acetyl lysine 50 mg. (Yield: 71%)

[0037] Example 2

[0038] [ 14 C] N-acetyl-L-cysteine ​​synthesis (such as Figure 2 shown)

[0039] This embodiment includes the following steps:

[0040] (1) Add the 14Sodium acetate (38.2 mg, 0.45 mmol), L-cystine diethyl ester dihydrochloride (167.84 mg, 0.45 mmol), acetonitrile (10 ml), and water (20 ml) were stirred and dissolved. EDCI (174.3 mg, 0.90 mmol) was added and stirred at 25°C for 3 h. TLC indicated the formation of a clear product. Ethyl acetate (20 ml) was added for extraction and phase separation. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 129.5 mg of N-acetyl-L-cystine diethyl ester (yield: 75%).

[0041] (2) Add N-acetyl-L-cystine diethyl ester (129.5 mg) to a single-necked reaction flask, add ethanol / water (8 ml / 8 ml), stir to dissolve, add lithium hydroxide (200 mg), and stir at 25°C for 3 h. After stirring and cooling in an ice-water bath, add citric acid dropwise until neutral, and concentrate to dryness to obtain N-acetyl-L-cystine diacetic acid.

[0042] (3) Add N-acetyl-L-cystine diacetic acid, tetrahydrofuran / water (13.5 ml / 1.5 ml), and triphenylphosphine (870.8 mg, 3.32 mmol) to the reaction flask. After nitrogen replacement three times, stir at 50°C for 13 h. Concentrate the reaction solution under reduced pressure, add water (10 ml), stir, and filter. Wash the filter cake with water (5 ml × 3). Concentrate the filtrate to dryness and prepare [ 14 C] N-acetyl-L-cysteine ​​44.5 mg. (Yield: 80%)

[0043] Example 3

[0044] [ 14 C]N-acetyl-DL-O-methylserine synthesis (such as Figure 3 shown)

[0045] This embodiment includes the following steps:

[0046] (1) Add the 14 Sodium acetate (100.0 mg, 1.19 mmol), DL-O-methylserine (141.0 mg, 1.19 mmol), acetonitrile (6 ml) and water (12 ml) were stirred and dissolved. EDCI (456.2 mg, 2.38 mmol) was added and stirred at 25 ° C for 3 h. Ethyl acetate (40 ml) was added to extract and separate the phases. The organic phase was taken, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and reversed to obtain [ 14 C] N-acetyl-DL-O-methylserine 147.5 mg (yield: 76%).

[0047] Comparative Examples with This Patent

[0048] [ 14C]N-acetyl-DL-O-methylserine synthesis

[0049] This embodiment includes the following steps:

[0050] (1) Add the 14 C acetic anhydride (123.8 mg, 1.19 mmol), DL-O-methylserine (141.0 mg, 1.19 mmol), 4-dimethylaminopyridine (145.4 mg, 1.19 mmol) and anhydrous dichloromethane (6 ml) were stirred and dissolved. Stirred at 25 ° C for 12 h. Concentrated under reduced pressure and reversed to obtain [ 14 C] N-acetyl-DL-O-methylserine 67.9 mg (yield: 35%).

[0051] The sodium acetate used in this method is stable, and the one-step synthesis is easy to perform. Amines can be acetylated to produce acetamide at room temperature without the need for strictly anhydrous conditions. This method is simple, uses stable and readily available reagents, and offers good process reproducibility and yield.

[0052] The method of the present application is characterized in that stable sodium acetate is used as a raw material, acetonitrile and water are used as a mixed solvent to efficiently dissolve the raw material, and EDCI is used to achieve one-step acetylation of the amino group at room temperature. The method mainly solves the main difficulties of the current amino acetylation process, such as complex multi-step reaction, unstable reagents used, and low reaction yield, and has good application for the amino acetylation of most amino acids and other amino acetylations.

[0053] It should be noted that the above embodiments can be freely combined as needed. The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Those skilled in the art will readily appreciate that the present invention is susceptible to various modifications and variations. Any modifications, equivalent substitutions, or improvements made within the spirit and principles of the present invention are intended to be included within the scope of protection of the present invention.

Claims

1. A 14 The application of sodium acetate in amino acetylation reaction is characterized in that: The application is in the preparation of [ 14 C] application of N-acetyl lysine, comprising the following steps: (1) Take 14 Dissolve 0.45 mmol of sodium C acetate, 0.225-1.35 mmol of N-Cbz-L-lysine benzyl ester, 3-30 ml of acetonitrile, and 6-60 ml of water in agitation; add 0.225-2.25 mmol of EDCI and stir at 15-45°C for 1-4 hours; Add 10-100 ml of ethyl acetate to extract and separate the phases. Take the organic phase, dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify it on a silica gel column to obtain N-acetyl-Cbz-L-lysine benzyl ester; (2) Add N-acetyl-Cbz-L-lysine benzyl ester (156.0 mg) to a single-necked reaction flask, add 5-20 ml of ethanol, and stir to dissolve; add 40-200 mg of 10% palladium carbon, replace the mixture with a hydrogen balloon four times, and stir under hydrogen pressure at 20-40°C for 24-72 hours; Filter, rinse with ethanol / water 4ml / 2ml, concentrate the filtrate to dryness, prepare by reverse phase, and freeze-dry to obtain [ 14 C] N-acetyl lysine.

2. A 14 The application of sodium acetate in amino acetylation reaction is characterized in that: The application is in the preparation of [ 14 C] application in the synthesis of N-acetyl-L-cysteine, comprising the following steps: (1) Take 14 Stir and dissolve 0.45mmol of sodium acetate, 0.225-1.35mmol of L-cystine diethyl ester dihydrochloride, 3-30ml of acetonitrile, and 6-60ml of water; add 0.225-2.25mmol of EDCI and stir at 15-45℃ for 1-4h; add 10-100ml of ethyl acetate for extraction and separation; take the organic phase, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain N-acetyl-L-cystine diethyl ester; (2) Add 129.5 mg of N-acetyl-L-cystine diethyl ester to a single-necked reaction flask, add 5-20 ml of ethanol / 5-20 ml of water, stir to dissolve, add 100-500 mg of lithium hydroxide, and stir at 15-35°C for 2-5 hours; after stirring and cooling in an ice-water bath, add citric acid dropwise until neutral, and concentrate to dryness to obtain N-acetyl-L-cystine diacetic acid; (3) Add N-acetyl-L-cystine diacetic acid, tetrahydrofuran / water 9-18 ml / 1-2 ml, add triphenylphosphine 2-6 mmol, replace with nitrogen three times, stir at 45-55 ° C for 10-15 hours; concentrate the reaction solution under reduced pressure, add water 5-50 ml, stir and filter, wash the filter cake with water 5 ml × 3 times, concentrate the filtrate to dryness, and prepare by reverse phase. 14 C] N-acetyl-L-cysteine; 3. A 14 The application of sodium acetate in amino acetylation reaction is characterized in that: The application is in the preparation of [ 14 C] application in the synthesis of N-acetyl-DL-O-methylserine, comprising the following steps: Pick 14 C sodium acetate 1.19mmol, DL-O-methylserine 0.60-3.57mmol and acetonitrile 3-30ml and water 6-60ml, stirred and dissolved; added EDCI 0.60-3.57mmol, stirred at 15℃-45℃ for 1-4h; added ethyl acetate 10-100ml to extract and separate the phases, took the organic phase, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and reversed to prepare [ 14 C] N-acetyl-DL-O-methylserine.

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