2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid, and a preparation method and application thereof

Abstract

The application belongs to the technical field of small molecule compound synthesis and utilization, and provides 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid as well as a preparation method and application thereof. The method comprises the following steps: taking gamma-valerolactone and lysine as reaction raw materials, reacting at 80-120 DEG C for 5-24 h, cooling to room temperature after the reaction is completed, performing solid-liquid centrifugal separation, and obtaining 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid after purifying the solid. In the application, gamma-valerolactone is both a solvent and a reactant, 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid is synthesized through one-step reaction, and the application has the advantages of simple preparation process, convenient operation, green and environment-friendly preparation process and the like. The prepared product can generate lysine and 4-hydroxyvaleric acid by hydrolyzing the amide group through an enzyme or alkali, and has great potential application in the fields of medicine and chemical industry.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of small molecule compound synthesis utilization, and particularly relates to 2-amino-6-[(4-hydroxy-1-oxylpentyl)amino]hexanoic acid as well as a preparation method and application thereof. BACKGROUND

[0002] Gamma-valerolactone is a biomass-based green chemical, which is a colorless to slightly yellow transparent liquid at room temperature. Gamma-valerolactone has wide industrial application value, and can be used as a fuel additive, a lubricant, a plasticizer, an organic solvent, and a precursor for producing olefins and polymers. In addition, gamma-valerolactone has a vanillin and coconut flavor, and is an edible flavor allowed to be used in China, and is mainly used to prepare peach, coconut, vanilla and other type fragrances.

[0003] Lysine is a very important amino acid in the body, which has positive nutritional significance in promoting human growth and development, enhancing immunity, resisting viruses, promoting fat oxidation, and relieving anxiety. The amino group of lysine has high reactivity, and contains a π electron, which can undergo addition reaction with electrophiles such as cysteine. At the same time, lysine is a typical basic amino acid, which can react with a series of acidic substances to form lysine salt through acid-base reaction.

[0004] CN101012305A discloses the use of amino acids in the preparation of biodegradable medical materials and a method for preparing biodegradable medical materials. The ring-opening homopolymerization or copolymerization reaction of cyclic ester monomers is carried out with polar non-basic amino acids as catalysts to form aliphatic polyesters. In this patent, amino acids are used as catalysts, and aliphatic polyester polymers are formed, which are mainly used for preparing biodegradable medical materials. The polymer does not contain amino acids, and cannot reflect the characteristics of amino acids themselves. A new small molecule containing γ-valerolactone structure and lysine structure has some characteristics of γ-valerolactone and lysine from the structure. By hydrolyzing the amide group through enzyme or alkali, 4-hydroxyvaleric acid and lysine beneficial to the human body are released, which has potential application market in the fields of medicine and chemical industry. Among them, 4-hydroxyvaleric acid is a receptor agonist, which has a sedative effect. However, 4-hydroxyvaleric acid is unstable at room temperature, and can automatically dehydrate into γ-valerolactone, resulting in high preparation and storage cost and limiting its application range. Therefore, it is of great significance and wide application value to develop a green and simple process for preparing a new small molecule containing γ-valerolactone structure and lysine structure and a preparation method thereof. SUMMARY

[0005] To solve the above technical problems, the present application provides a 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid and its preparation method and application. The prepared 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid contains γ-valerolactone structure and lysine structure, which provides basis and technical basis for 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid in the fields of medicine and chemical industry.

[0006] In order to achieve the above purpose, the technical scheme of the present application is realized, and the steps are as follows:

[0007] A preparation method of 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid, γ-valerolactone and lysine are placed in a reactor for reaction, and after the reaction is completed, it is cooled to room temperature, and then solid-liquid centrifugal separation is carried out, and after the solid is purified, light yellow solid 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid is obtained.

[0008] Further, the mass ratio of the γ-valerolactone to lysine is (2-10):1.

[0009] Further, the stirring speed of the reaction is 250 rpm.

[0010] Further, the temperature of the reaction during the reaction process is 80-120℃, and the reaction time is 5-24h.

[0011] Further, the specific steps of the purification are as follows: the solid after solid-liquid centrifugal separation is washed with a solvent by stirring, and the lower solid is taken out after high-speed centrifugation, and the washing and centrifugation process is repeated three times, and then the light yellow product 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid is obtained after drying.

[0012] Further, the solvent is ethyl acetate.

[0013] Further, the drying temperature is 80℃.

[0014] The above method is used to prepare 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid.

[0015] The above 2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid is used in the fields of medicine and chemical industry.

[0016] The reaction mechanism of the present application is as follows:

[0017] The ester bond of γ-valerolactone and the amino group of lysine undergoes amidation reaction to generate amide product (2-amino-6-[(4-hydroxy-1-oxyl pentyl) amino] hexanoic acid).

[0018] The present application has the following beneficial effects:

[0019] (1) The present application provides a 2-amino-6-[(4-hydroxy-1-oxylpentyl)amino] hexanoic acid, which releases 4-hydroxyvaleric acid and lysine beneficial to human body by hydrolyzing its amide group through enzyme or alkali, and has potential application market in the fields of medicine and chemical industry.

[0020] (2) The present application provides a preparation method of 2-amino-6-[(4-hydroxy-1-oxylpentyl)amino] hexanoic acid. The process uses gamma-valerolactone and lysine as raw materials, and obtains 2-amino-6-[(4-hydroxy-1-oxylpentyl)amino] hexanoic acid through a simple reaction at 80-120 DEG C. In the process, gamma-valerolactone is both a solvent and a reactant, and the product 2-amino-6-[(4-hydroxy-1-oxylpentyl)amino] hexanoic acid is insoluble in gamma-valerolactone at room temperature, so that the separation of the solvent gamma-valerolactone and the product can be realized through simple centrifugation. The present application has simple technical process, convenient operation, and the whole process is green and environmentally friendly, and has broad industrial application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the following will briefly introduce the drawings needed to be used in the embodiments or prior art description. Obviously, the drawings in the following description are only some embodiments of the present application, and other drawings can also be obtained by those skilled in the art without creative labor.

[0022] Figure 1 It is the product physical map obtained in Example 1 of the present application.

[0023] Figure 2 It is the high-resolution mass spectrum analysis spectrum diagram of the product obtained in Example 1 of the present application.

[0024] Figure 3 It is the infrared spectrum diagram of the reaction raw material and the product obtained in Example 1 of the present application.

[0025] Figure 4 It is the nuclear magnetic hydrogen spectrum diagram of the product obtained in Example 1 of the present application.

[0026] Figure 5 It is the nuclear magnetic carbon spectrum diagram of the product obtained in Example 1 of the present application.

[0027] Figure 6 It is the structural formula of 2-amino-6-[(4-hydroxy-1-oxylpentyl)amino] hexanoic acid.

[0028] Figure 7 It is the liquid chromatogram of the hydrolysis product of the product obtained in Example 1 of the present application. DETAILED DESCRIPTION

[0029] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments of the present application. Based on the embodiments in the present application, all other embodiments obtained by a person of ordinary skill in the art without creative effort fall within the protection scope of the present application.

[0030] Embodiment 1

[0031] A preparation method of 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid in the embodiment is as follows:

[0032] (1) 16 g of γ-valerolactone and 4 g of lysine were taken into a 50 mL reaction kettle. The mechanical stirring speed was controlled to be 250 rpm, the reaction kettle was heated to 100 ℃, and the temperature was kept for 8 h. After the reaction was completed, the reaction kettle was cooled to room temperature, and the product was transferred to a centrifuge bottle to realize solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0033] (2) The solid product obtained in step (1) was washed with 20 mL of ethyl acetate by stirring, and then centrifuged to obtain a solid product; the solid product was further washed with 40 mL of ethyl acetate (20 mL each time), and then centrifuged, and dried in an 80 ℃ oven to obtain a light yellow solid 6.6 g (see Figure 1 ).

[0034] (3) The light yellow solid was easily dissolved in water, the aqueous solution was diluted to 1 ppm, and high-resolution liquid chromatography-mass spectrometry analysis was performed, and it was found that there was only one main product peak, and the molecular weight of the product was 246 (the recommended molecular formula was C 11 H 22 N2O4) (see Figure 2 ). Further comparative analysis by infrared spectrum (see Figure 3 ) showed that the product obtained by the reaction had new peaks of amide functional groups (3320 cm -1 , 1640 cm -1 ); analysis by nuclear magnetic hydrogen spectrum (see Figure 4 ) and carbon spectrum (see Figure 5 ) showed that the product contained carboxyl, hydroxyl, peptide bond, methyl and amino functional groups. Based on the structural characteristics of the reaction raw materials γ-valerolactone and lysine, comprehensive analysis by high-resolution liquid chromatography-mass spectrometry, infrared spectrum, nuclear magnetic resonance and the like, it was determined that the product was 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid, and the structure is as shown in Figure 6 .

[0035] Example 2

[0036] A method for preparing 2-amino-6-[(4-hydroxy-l-oxopentyl)amino]hexanoic acid according to this example is as follows:

[0037] (1) 8 g of γ-valerolactone and 4 g of lysine were added to a 50 mL reaction kettle. The mechanical stirring speed was controlled at 250 rpm, the reaction kettle was heated to 120°C and reacted at this temperature for 5 h. After the reaction was completed, it was cooled to room temperature, and the product was transferred to a centrifuge bottle to achieve solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0038] (2) The solid product obtained in step (1) was washed with 20 mL of ethyl acetate by stirring thoroughly, and then centrifuged to obtain a solid product; the solid product obtained above was further washed with 40 mL of ethyl acetate (20 mL each time) by centrifugation, and then dried in an 80°C oven to obtain 6.4 g of 2-amino-6-[(4-hydroxy-l-oxopentyl)amino]hexanoic acid.

[0039] Example 3

[0040] A method for preparing 2-amino-6-[(4-hydroxy-l-oxopentyl)amino]hexanoic acid according to this example is as follows:

[0041] (1) 30 g of γ-valerolactone and 3 g of lysine were added to a 50 mL reaction kettle. The mechanical stirring speed was controlled at 250 rpm, the reaction kettle was heated to 80°C and reacted at this temperature for 24 h. After the reaction was completed, it was cooled to room temperature, and the product was transferred to a centrifuge bottle to achieve solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0042] (2) The solid product obtained in step (1) was washed with 20 mL of ethyl acetate by stirring thoroughly, and then centrifuged to obtain a solid product; the solid product obtained above was further washed with 40 mL of ethyl acetate (20 mL each time) by centrifugation, and then dried in an 80°C oven to obtain 5.0 g of 2-amino-6-[(4-hydroxy-l-oxopentyl)amino]hexanoic acid.

[0043] Example 4

[0044] A method for preparing 2-amino-6-[(4-hydroxy-l-oxopentyl)amino]hexanoic acid according to this example is as follows:

[0045] (1) Take 30 g of γ-valerolactone and 6 g of lysine into a 50 mL reaction kettle. Control the mechanical stirring speed at 250 rpm, and heat the reaction kettle to 90°C and react at this temperature for 18 h. After the reaction is completed, cool to room temperature, and transfer the product to a centrifuge bottle to realize solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0046] (2) The solid product obtained in step (1) is washed with 20 mL of ethyl acetate by stirring sufficiently, and then centrifuged to obtain a solid product; the solid product obtained above is further washed with 40 mL of ethyl acetate (in two times, 20 mL each time), and then centrifuged, and dried in an 80°C oven to obtain 10 g of 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid.

[0047] Example 5

[0048] The preparation method of one kind of 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid in this example is as follows:

[0049] (1) Take 30 g of γ-valerolactone and 6 g of lysine into a 50 mL reaction kettle. Control the mechanical stirring speed at 250 rpm, and heat the reaction kettle to 90°C and react at this temperature for 18 h. After the reaction is completed, cool to room temperature, and transfer the product to a centrifuge bottle to realize solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0050] (2) The solid product obtained in step (1) is washed with 20 mL of ethyl acetate by stirring sufficiently, and then centrifuged to obtain a solid product; the solid product obtained above is further washed with 40 mL of ethyl acetate (in two times, 20 mL each time), and then centrifuged, and dried in an 80°C oven to obtain 10 g of 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid.

[0051] Example 6

[0052] The preparation method of one kind of 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid in this example is as follows:

[0053] (1) Take 30 g of γ-valerolactone and 6 g of lysine into a 50 mL reaction kettle. Control the mechanical stirring speed at 250 rpm, and heat the reaction kettle to 90°C and react at this temperature for 18 h. After the reaction is completed, cool to room temperature, and transfer the product to a centrifuge bottle to realize solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0054] (2) The solid product obtained in step (1) is washed with 20 mL of ethyl acetate by stirring thoroughly, and then centrifuged to obtain a solid product. The solid product obtained above is further washed with 40 mL of ethyl acetate (20 mL each time) by stirring thoroughly, and then centrifuged. The product is dried in an oven at 80°C to obtain 2-amino-6-[(4-hydroxy-l-oxypentyl)amino]hexanoic acid.

[0055] Example 7

[0056] A method for preparing 2-amino-6-[(4-hydroxy-l-oxypentyl)amino]hexanoic acid according to the present embodiment is as follows:

[0057] (1) 15 g of γ-valerolactone and 5 g of lysine are added to a 50 mL reaction kettle. The mechanical stirring speed is controlled at 250 rpm, the reaction kettle is heated to 80°C, and the reaction is carried out at this temperature for 24 h. After the reaction is completed, the product is cooled to room temperature, and is transferred to a centrifuge bottle to separate the solid product and the liquid (γ-valerolactone) solution by high-speed centrifugation.

[0058] (2) The solid product obtained in step (1) is washed with 20 mL of ethyl acetate by stirring thoroughly, and then centrifuged to obtain a solid product. The solid product obtained above is further washed with 40 mL of ethyl acetate (20 mL each time) by stirring thoroughly, and then centrifuged. The product is dried in an oven at 80°C to obtain 2-amino-6-[(4-hydroxy-l-oxypentyl)amino]hexanoic acid.

[0059] Example 8

[0060] A method for preparing 2-amino-6-[(4-hydroxy-l-oxypentyl)amino]hexanoic acid according to the present embodiment is as follows:

[0061] (1) 21 g of γ-valerolactone and 3 g of lysine are added to a 50 mL reaction kettle. The mechanical stirring speed is controlled at 250 rpm, the reaction kettle is heated to 100°C, and the reaction is carried out at this temperature for 16 h. After the reaction is completed, the product is cooled to room temperature, and is transferred to a centrifuge bottle to separate the solid product and the liquid (γ-valerolactone) solution by high-speed centrifugation.

[0062] (2) The solid product obtained in step (1) is washed with 20 mL of ethyl acetate by stirring thoroughly, and then centrifuged to obtain a solid product. The solid product obtained above is further washed with 40 mL of ethyl acetate (20 mL each time) by stirring thoroughly, and then centrifuged. The product is dried in an oven at 80°C to obtain 2-amino-6-[(4-hydroxy-l-oxypentyl)amino]hexanoic acid.

[0063] Example 9

[0064] The preparation method of the 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid of the embodiment is as follows:

[0065] (1) 27 g of γ-valerolactone and 3 g of lysine were taken into a 50 mL reaction kettle. The mechanical stirring speed was controlled at 250 rpm, the reaction kettle was heated to 120°C, and reaction was carried out at this temperature for 8 h. After the reaction was completed, the product was cooled to room temperature and transferred to a centrifuge bottle to realize solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0066] (2) The solid product obtained in step (1) was washed with 20 mL of ethyl acetate by stirring sufficiently, and then centrifuged to obtain a solid product; the solid product obtained above was further washed with 40 mL of ethyl acetate (20 mL each time), and then centrifuged, and dried in an 80°C oven to obtain 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid.

[0067] Example 10

[0068] The preparation method of the 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid of the embodiment is as follows:

[0069] (1) 27 g of γ-valerolactone and 3 g of lysine were taken into a 50 mL reaction kettle. The mechanical stirring speed was controlled at 250 rpm, the reaction kettle was heated to 120°C, and reaction was carried out at this temperature for 8 h. After the reaction was completed, the product was cooled to room temperature and transferred to a centrifuge bottle to realize solid-liquid separation by high-speed centrifugation, to obtain a solid product and a liquid (γ-valerolactone) solution, respectively.

[0070] (2) The solid product obtained in step (1) was washed with 20 mL of ethyl acetate by stirring sufficiently, and then centrifuged to obtain a solid product; the solid product obtained above was further washed with 40 mL of ethyl acetate (20 mL each time), and then centrifuged, and dried in an 80°C oven to obtain 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid.

[0071] Application example:

[0072] Taking the 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid prepared in Example 1 as an example, the application of the 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid prepared in the application is as follows:

[0073] The 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid product was put into a human small intestine simulation environment with a pH of 7.4, a temperature of 37°C, and a porcine trypsin catalyst, and the hydrolysis product was detected. 0.1 g of the 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid product obtained in Example 1 was put into a 20 mL glass bottle, 10 mL of a sodium hydrogen phosphate and sodium dihydrogen phosphate buffer solution with a pH of 7.4 and 0.01 g of a porcine trypsin catalyst were added to the glass bottle, and the mixture was reacted in a 37°C constant temperature shaker (160 r / min) for 3 h. The aqueous solution obtained after the reaction was subjected to liquid chromatography analysis, and it was found that 4-hydroxyvaleric acid was present in the product (see Figure 7 ), indicating that the 2-amino-6-[(4-hydroxy-1-oxypentyl)amino]hexanoic acid product has the function of slowly releasing 4-hydroxyvaleric acid and lysine in the human body, and can be used as a lysine supplement, a precursor drug of the receptor agonist 4-hydroxyvaleric acid.

[0074] The above description is merely preferred embodiments of the present application, and is not intended to limit the present application. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid, characterized in that: The method comprises the following steps: placing gamma-valerolactone and lysine in a reactor for reaction, cooling to room temperature after the reaction is completed, performing solid-liquid centrifugation, and purifying the solid to obtain light yellow solid 2-amino-6-[(4-hydroxy-1-oxyidenepentyl)amino]hexanoic acid.

2. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 1, wherein: The mass ratio of the gamma-valerolactone to lysine is (2-10):

1.

3. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 2, wherein: The stirring speed of the reaction was 250 rpm.

4. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 3, wherein: The reaction temperature is 80-120°C.

5. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 4, wherein: The reaction time is 5-24h.

6. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 5, wherein The specific steps of the purification are: stirring and washing the solid after solid-liquid centrifugation with a solvent, removing the lower layer of solid after high-speed centrifugation, repeating the washing and centrifugation process three times, and drying to obtain a light yellow solid 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid.

7. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 6, wherein: The solvent is ethyl acetate.

8. The method for preparing 2-amino-6-[(4-hydroxy-1-oxypentylene)amino]hexanoic acid according to claim 7, wherein: The drying temperature is 80°C.

9. 2-Amino-6-[(4-hydroxy-1-oxypentylidenepentyl)amino]hexanoic acid prepared by the method of any one of claims 1 to 8.

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