A kind of preparation method of high-purity 6-aminocaproic acid

Abstract

The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing high-purity 6-aminocaproic acid, which is obtained by Fenton oxidation method using 2-(2-aminoethyl)cyclobutane-1-one as a raw material; the method has simple reaction, convenient operation and convenient post-processing; the raw materials of the preparation method of the invention are easy to obtain, no ion exchange resin is needed, the production cost is greatly reduced, and no subsequent treatment of three wastes is needed. The reaction conditions are mild, the obtained 6-aminocaproic acid has high purity and high yield, the yield can reach more than 95.5%, and the HPLC purity exceeds 98.0%, which is suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for preparing 6-aminocaproic acid, a hemostatic drug with a purity of up to 98%. Background Art

[0002] 6-aminocaproic acid is an antifibrinolytic drug. Fibrinogen specifically binds to fibrin through the lysine binding site in its molecular structure, and then turns into plasmin under the action of activators. This enzyme can cleave the arginine and lysine peptide chains in fibrin to form fibrin degradation products, which dissolve blood clots. 6-aminocaproic acid can inhibit the binding of plasminogen to fibrin and prevent its activation, thereby inhibiting fibrinolysis. High concentrations directly inhibit the activity of plasmin and achieve a hemostatic effect.

[0003] 6-aminocaproic acid is generally obtained by direct chemical synthesis, by hydrolyzing caprolactam or its polymer and then refining it. For example, the hydrolysis temperature disclosed in the US patent document, publication number US2453234A, is as high as 250°C, and acetic acid is added as a hydrolysis catalyst. The hydrolysis temperature of this method is too high, which is not conducive to energy saving and consumption reduction, and the safety is relatively low. Therefore, industrial promotion is limited.

[0004] Another example is a Chinese invention patent application, with publication number CN 101125821A, which discloses a method for preparing a hemostatic drug 6-aminocaproic acid, wherein caprolactam is dissolved in dilute hydrochloric acid, heated to reflux, 6-aminocaproic acid hydrochloride is prepared, and spherical macroporous styrene-based weakly alkaline anion exchange resin is used for neutralization, and the product is obtained by post-treatment. The technical solution of this application is to prepare 6-aminocaproic acid by heating and hydrolyzing caprolactam in a hydrochloric acid aqueous solution. The reaction process is relatively violent, and ion exchange resin is also required for neutralization. Due to the limitation of the exchange capacity of the resin, in the process of industrial application, the amount of ion exchange resin used is too large, the cost is very high, the reaction time is long, and the product yield is not high, generally around 80%; in addition, the ion exchange resin needs to be regenerated after neutralization, and a large amount of salt-containing wastewater will be generated during the regeneration process, which will cause great environmental pollution and increase the cost of wastewater treatment, which is not conducive to industrial promotion and application.

[0005] In order to reduce costs and avoid the use of ion exchange resin for neutralization, a Chinese invention patent, with the announcement number CN105238823 B, discloses a method for preparing 6-aminocaproic acid, wherein polyethylene glycol is dissolved in water, polyvinyl alcohol is added, amidase is added after cooling and mixed, and then poured on a plane to form a disc-shaped structure, and then transferred to a 30°C constant temperature incubator for drying, transferred to a Na2SO4 solution for filtration, washed twice, and a phosphate buffer solution is added to obtain a fixed enzyme; caprolactam, ammonium formate and phosphate buffer are added to the container in sequence, concentrated ammonia water is added to the container, and then the fixed enzyme is added, and the reaction is stirred in a 30°C water bath to obtain a reaction solution; activated carbon is added for decolorization, filtered, and then subjected to vacuum distillation, naturally cooled and crystallized, and infrared dried to obtain refined 6-aminocaproic acid. The technical scheme of the invention uses caprolactam as a raw material and amidase as a hydrolysis catalyst to prepare 6-aminocaproic acid. The reaction conditions of this method are mild, and ion exchange resins are not required, which reduces production costs, but the product yield obtained by this method generally does not exceed 90%. Summary of the invention

[0006] In order to overcome the above technical problems, the present invention provides a method for preparing 6-aminocaproic acid with high purity and high yield, which is suitable for industrial production and promotion. The method has simple operation, mild reaction conditions, low production cost and little environmental pollution.

[0007] The technical solutions to the above technical problems are as follows:

[0008] It is obtained from 2-(2-aminoethyl)cyclobutane-1-one by Fenton oxidation method.

[0009] The synthetic route is as follows:

[0010]

[0011] The reaction mechanism is as follows:

[0012]

[0013] The following steps are involved:

[0014] Step 1): Under ice-water bath conditions, 2-(2-aminoethyl)cyclobutane-1-one is dissolved in methanol at a volume ratio of 1:1-1.2, the solution temperature is controlled at 0-5°C, and after being stirred and dissolved uniformly, 8% hydrogen peroxide solution is added dropwise, wherein the volume ratio of 2-(2-aminoethyl)cyclobutane-1-one to 8% hydrogen peroxide solution is 1:1-1.1; the dropping frequency is controlled to be 30-60 d / min, preferably 40-45 d / min; after the dropping is completed, stirring is continued for 5-10 min to obtain peroxide solution A;

[0015] Step 2): dissolving ferrous sulfate in concentrated sulfuric acid to prepare a ferrous sulfate solution B with a mass volume ratio of 500 g / L to 1000 g / L;

[0016] Step 3): under ice-water bath conditions, peroxide solution A is added dropwise to ferrous sulfate solution B, the reaction temperature is controlled to be 0±5° C., and the dropping frequency is controlled to be 30 to 60 d / min, preferably 45 to 50 d / min; after the dropwise addition is completed, the stirring reaction is continued for at least 30 min; an off-white solid is obtained by filtration, and the solid is washed with a 10% NaHCO3 aqueous solution and water in sequence until the pH value is 6±0.5 to obtain a crude 6-aminocaproic acid product; and the crude 6-aminocaproic acid product is recrystallized and purified with a mixed solvent of water, methanol and ethanol in equal volumes to obtain a pure 6-aminocaproic acid product.

[0017] The beneficial effects of the present invention are:

[0018] The synthesis method of the present invention uses 2-(2-aminoethyl)cyclobutane-1-one as a raw material, and uses Fenton oxidation method to open the ring of the cyclic reactant to obtain 6-aminocaproic acid, and H2O2 is reacted in the presence of Fe 2+ In the presence of , a hydroxyl radical ·OH with strong oxidizing ability is generated, which triggers more other reactive oxygen species. The generation of ·OH is the beginning of the chain, while other reactive oxygen species and reaction intermediates constitute the nodes of the chain. Each reactive oxygen species is consumed and the reaction chain terminates.

[0019] The carbon-carbon bond of 2-(2-aminoethyl)cyclobutane-1-one is broken under the action of the oxidant, and the carbonyl carbon after the break carries a lone electron, and HO· combines with the carbonyl carbon to become a carboxyl group. The synthesis method is simple in reaction, easy to operate, and convenient for post-processing. In this reaction, the amino group on the structure of 2-(2-aminoethyl)cyclobutane-1-one is alkaline and will form a salt with sulfuric acid in the system. After the reaction is completed, it will be neutralized by alkaline water to return to the original state of the amino group. Therefore, it is just right to use 2-(2-aminoethyl)cyclobutane-1-one as the raw material.

[0020] The present invention controls the reasonable reaction drop speed, because H2O2 is a strong oxidant, and too fast a drop speed will cause the temperature of the reaction system to rise rapidly by more than 5°C, making it difficult to control the appropriate temperature of the reaction system, resulting in an increase in side reactions. In addition, controlling the reasonable drop speed can make H2O2 / Fe 2+ The ratio is relatively low, which increases the yield of ·OH, improves the utilization rate of hydrogen peroxide, and improves the overall oxidation effect.

[0021] The preparation method of the invention has readily available raw materials and mild reaction conditions. The prepared 6-aminocaproic acid has high purity and high yield, the yield can reach more than 95.5%, and the HPLC purity exceeds 98.0%, and is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0023] Figure 1 This is the H NMR spectrum of the pure 6-aminocaproic acid obtained in Example 2 of the present invention;

[0024] Figure 2 This is the NMR carbon spectrum of the pure 6-aminocaproic acid obtained in Example 2 of the present invention. DETAILED DESCRIPTION

[0025] The reagents and raw materials used in the synthesis steps of the present invention are available on the market.

[0026] Embodiment 1:

[0027] Step 1): Under ice-water bath conditions, 1 L of 2-(2-aminoethyl)cyclobutane-1-one was dissolved in 1 L of methanol, the solution temperature was controlled to be 0°C, and after being stirred and dissolved evenly, 1 L of 8% hydrogen peroxide solution was added dropwise, and the dropping frequency was controlled to be 60 d / min; after the dropping was completed, stirring was continued for 5 min to obtain peroxide solution A;

[0028] Step 2): 500 g of ferrous sulfate was dissolved in 1 L of concentrated sulfuric acid to obtain ferrous sulfate solution B;

[0029] Step 3): Under ice-water bath conditions, peroxide solution A is added dropwise to ferrous sulfate solution B, the reaction temperature is controlled to 0±5°C, and the dropping frequency is controlled to 30d / min; after the dropping is completed, the stirring reaction is continued for 30min; an off-white solid is obtained by filtration, and washed with 10% NaHCO3 aqueous solution and water in sequence until the pH is 6±0.5 to obtain crude 6-aminocaproic acid, which is then recrystallized and purified with a mixed solvent of water, methanol and ethanol in equal volumes to obtain pure 6-aminocaproic acid. The yield is 95.5%, and the HPLC purity is 98.1%.

[0030] Embodiment 2:

[0031] Step 1): Under ice-water bath conditions, 1 L of 2-(2-aminoethyl)cyclobutane-1-one was dissolved in 1.2 L of methanol, the solution temperature was controlled at 5°C, and after being uniformly dissolved by stirring, 1.1 L of 8% hydrogen peroxide solution was added dropwise, and the dropping frequency was controlled to be 45 d / min; after the dropping was completed, stirring was continued for 10 min to obtain peroxide solution A;

[0032] Step 2): 1000 g of ferrous sulfate was dissolved in 1 L of concentrated sulfuric acid to obtain ferrous sulfate solution B;

[0033] Step 3): Under ice-water bath conditions, peroxide solution A is added dropwise to ferrous sulfate solution B, the reaction temperature is controlled to 0±5°C, and the dropping frequency is controlled to 50d / min; after the dropping is completed, the stirring reaction is continued for 40min; an off-white solid is obtained by filtration, and washed with 10% NaHCO3 aqueous solution and water in sequence until the pH is 6±0.5 to obtain a crude 6-aminocaproic acid product, which is recrystallized and purified with a mixed solvent of water, methanol and ethanol in an equal volume ratio to obtain a pure 6-aminocaproic acid product. The yield is 97.5%, and the HPLC purity is 98.4%. The pure 6-aminocaproic acid prepared in this embodiment has the following nuclear magnetic spectrum data:

[0034] Melting point 207℃; MS (m / z): [M+H] + :132.

[0035] 1 H NMR (300MHz, H2O) δ: 2.83 (t, J=6.0Hz, 2H), 2.03 (t, J=6.0Hz, 2H), 1.65-1.17 (m, 6H);

[0036] 13 C NMR (75MHz, H2O) δ: 183.53, 39.23, 37.13, 26.36, 25.32, 25.10.

[0037] Embodiment 3:

[0038] Step 1): Under ice-water bath conditions, 1 L of 2-(2-aminoethyl)cyclobutane-1-one was dissolved in 1.1 L of methanol, the solution temperature was controlled at 2°C, and after being stirred and dissolved evenly, 1 L of 8% hydrogen peroxide solution was added dropwise, and the frequency of addition was controlled to be 30 d / min; after the addition was completed, stirring was continued for 8 min to obtain peroxide solution A;

[0039] Step 2): 700 g of ferrous sulfate was dissolved in 1 L of concentrated sulfuric acid to obtain ferrous sulfate solution B;

[0040] Step 3): Under ice-water bath conditions, peroxide solution A is added dropwise to ferrous sulfate solution B, the reaction temperature is controlled to 0±5°C, and the dropping frequency is controlled to 45d / min; after the dropping is completed, the stirring reaction is continued for 45min; an off-white solid is obtained by filtration, and washed with 10% NaHCO3 aqueous solution and water in sequence until the pH is 6±0.5 to obtain crude 6-aminocaproic acid, which is then recrystallized and purified with a mixed solvent of water, methanol and ethanol in equal volumes to obtain pure 6-aminocaproic acid. The yield is 96.7%, and the HPLC purity is 98.0%.

[0041] The invention uses 2-(2-aminoethyl)cyclobutane-1-one as a raw material, and uses a Fenton oxidation method to open the ring of the cyclic reactant to obtain 6-aminocaproic acid. No ion exchange resin is required, so there is no subsequent three wastes treatment, and the production cost can be reduced. The yield can reach more than 95.5%, the HPLC purity exceeds 98.0%, and it is suitable for large-scale production.

[0042] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Any simple modification or equivalent changes made to the above embodiments based on the technical essence of the present invention shall fall within the protection scope of the present invention.

Claims

1. A method for preparing 6-aminocaproic acid, characterized in that: It is obtained from 2-(2-aminoethyl)cyclobutane-1-one by Fenton oxidation method. The synthetic route is as follows: The following steps are involved: Step 1): Under ice-water bath conditions, 2-(2-aminoethyl)cyclobutane-1-one is dissolved in a solvent at a volume ratio of 1:1-1.2, the solution temperature is controlled at 0-5°C, and after being stirred and dissolved uniformly, 8% hydrogen peroxide solution is added dropwise, wherein the volume ratio of 2-(2-aminoethyl)cyclobutane-1-one to 8% hydrogen peroxide solution is 1:1-1.1; the dropping frequency is controlled at 30-60 d / min; after the dropping is completed, stirring is continued for 5-10 min to obtain a peroxide solution A; Step 2): dissolving ferrous sulfate in concentrated sulfuric acid to prepare a ferrous sulfate solution B with a mass volume ratio of 500 g / L to 1000 g / L; Step 3): Under ice-water bath conditions, peroxide solution A is added dropwise to ferrous sulfate solution B, the reaction temperature is controlled to 0±5° C., and the dropping frequency is controlled to 30-60 d / min; after the dropping is completed, the stirring reaction is continued for at least 30 min; an off-white solid is obtained by filtration, and the solid is washed with 10% NaHCO3 aqueous solution and water in sequence until the pH is 6±0.5 to obtain 6-aminocaproic acid.

2. The preparation method according to claim 1, characterized in that: The solvent in step 1) is methanol.

3. The preparation method according to claim 1, characterized in that: The dropping frequency of step 1) is 40 to 45 d / min.

4. The preparation method according to claim 1, characterized in that: Step 3) The dropping frequency is 45 to 50 d / min.

5. The preparation method according to claim 1, characterized in that: Step 3) obtains crude 6-aminocaproic acid, and further comprises recrystallizing and purifying the crude 6-aminocaproic acid with a mixed solvent to obtain pure 6-aminocaproic acid.

6. The preparation method according to claim 5, characterized in that: The mixed solvent is a mixture of water, methanol and ethanol in equal volume ratios.

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