A method for preparing 6-aminocaproic acid using pimelic acid as raw material

Abstract

The present invention belongs to the field of drug synthesis, and is particularly related to a novel method for preparing 6-aminocaproic acid using pimelic acid as a raw material, using pimelic acid with abundant sources as a reaction raw material, undergoing acylation and cyclization reaction with acetic anhydride, and then undergoing substitution reaction with ammonia, and finally purifying after ring opening in an alkaline system to obtain 6-aminocaproic acid pure product. The reaction process is simple and post-processing is convenient; acetic anhydride is added in excess, and during the reaction process, acetic anhydride serves as both a reaction raw material and a reaction reagent, ensuring that the reaction can proceed in a positive direction and improving the conversion rate; the 6-aminocaproic acid obtained by the present invention has a purity of more than 97%, a yield of more than 85%, and 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 by taking pimelic acid as a raw material. Background Art

[0002] 6-Aminocaproic acid, also known as aminocaproic acid, aminocaproic acid, ε-aminocaproic acid, and antifibrinolytic acid, is a commonly used antiplasmin hemostatic drug for SAH. It has an antifibrinolytic effect and can produce competitive inhibition with plasminogen activators, thereby inhibiting the process of converting plasminogen into plasmin. It also has a weak direct inhibitory effect on plasmin, slowing down the cleavage of fibrin into polypeptides and amino acids.

[0003] The drug is rapidly and completely absorbed in the gastrointestinal tract, with a bioavailability of 80%. The blood concentration reaches its peak 2 hours after taking it. Most of it is excreted in the urine in its original form. 1 / 2 About 103 minutes. It is suitable for bleeding caused by primary or secondary hyperfibrinolysis, such as bleeding caused by severe infection, gynecological accidents, leukemia, malignant tumors and severe liver disease; other bleeding such as major surgical operations, gynecological bleeding, bleeding in the lungs, upper digestive tract, prostate, liver, pancreas, etc. The drug can be used during or before surgery to reduce intraoperative bleeding and reduce the amount of blood transfusion.

[0004] 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.

[0005] 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. Summary of the invention

[0006] In order to overcome the above technical problems, the present invention provides a method for synthesizing 6-aminocaproic acid by using pimelic acid, which has a wide range of sources, as a reaction raw material. The method has a purity of more than 97%, a yield of more than 85%, a low production cost, little environmental pollution, and is suitable for large-scale production.

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

[0008] A method for preparing 6-aminocaproic acid using pimelic acid as a raw material, wherein pimelic acid and an excess of acetic anhydride undergo acylation and cyclization reactions, and then undergo substitution reactions with ammonia water, and finally undergo ring opening in an alkaline system to obtain the product;

[0009] The reaction mechanism is as follows:

[0010]

[0011] The following steps are involved:

[0012] Pimelic acid and acetic anhydride are added into a stirred reaction vessel equipped with a heating device in a molar volume ratio of 1:0.25-0.3, heated to 135-140° C., reacted for at least 60 minutes, and then distilled under reduced pressure to remove unreacted acetic anhydride and generated acetic acid;

[0013] Then, the material in the stirred reaction container is added dropwise to ammonia water with a mass concentration of 20%, wherein the ammonia water is such that the molar volume ratio of pimelic acid to ammonia water is 1:0.5-0.8, and the dropping speed is controlled to be 30-60 d / min, preferably 40-45 d / min; after the dropwise addition is completed, the temperature of the reactant is controlled to be 180-185° C., and stirring is continued for 5-10 min. Then, all the material in the reaction container is poured into water with an equal volume to the ammonia water, the stirred mixture is filtered through diatomaceous earth, the filtrate is concentrated, 5% sodium hydroxide solution is added to the system, stirring is continued for at least 30 min at room temperature, the solid product is collected, washed with water for at least three times, and dried to obtain a crude 6-aminocaproic acid product, which is recrystallized with 95% ethanol to obtain a pure 6-aminocaproic acid product.

[0014] Wherein, the molar volume ratio of pimelic acid to 5% sodium hydroxide solution is 1:6-8.

[0015] The beneficial effects of the present invention are:

[0016] The synthesis method involved in the present invention uses pimelic acid, which is abundant in source, as a reaction raw material, undergoes acylation and cyclization reaction with acetic anhydride, and then undergoes substitution reaction with ammonia water, and then obtains a crude 6-aminocaproic acid product after ring opening in an alkaline system, and then obtains a pure 6-aminocaproic acid product through recrystallization with 95% ethanol. The reaction process is simple and the post-treatment is convenient; acetic anhydride is added in excess, and during the reaction process, acetic anhydride serves as both a reaction raw material and a reaction reagent, ensuring that the reaction can proceed in a forward direction and improving the conversion rate; the purity of the 6-aminocaproic acid prepared by the present invention is as high as more than 97%, and the yield can reach more than 85%, which is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0018] Figure 1 This is the H NMR spectrum of the pure 6-aminocaproic acid obtained in Example 2 of the present invention;

[0019] Figure 2 This is the NMR carbon spectrum of the pure 6-aminocaproic acid obtained in Example 2 of the present invention. DETAILED DESCRIPTION

[0020] The reagents and raw materials used in the synthesis steps of the present invention are available on the market.

[0021] Embodiment 1:

[0022] 160 g of pimelic acid (1 mol) and 250 mL of acetic anhydride were added to a stirred reaction vessel equipped with a heating device, heated to 140° C., reacted for 60 min, and then the unreacted acetic anhydride and the generated acetic acid were removed by distillation under reduced pressure;

[0023] Then, the material in the stirred reaction vessel is added dropwise to 500 mL of ammonia water with a mass concentration of 20%, and the dropping speed is controlled to be 30 d / min; after the dropwise addition is completed, the temperature of the reactant is controlled to be 180° C., and stirring is continued for 10 min, and then all the material in the reaction vessel is poured into 500 mL of water, stirred evenly, and the stirred mixture is filtered through diatomaceous earth, the filtrate is concentrated, 6 L of 5% sodium hydroxide solution is added to the system, and stirring is continued for 30 min at room temperature, and the solid product is collected, washed with water three times, and dried to obtain crude 6-aminocaproic acid, which is recrystallized with 95% ethanol to obtain pure 6-aminocaproic acid. The yield is 85.6%, and the HPLC purity is 97.3%.

[0024] Embodiment 2:

[0025] 160 g of pimelic acid (1 mol) and 300 mL of acetic anhydride were added to a stirred reaction vessel equipped with a heating device, heated to 135° C., reacted for 70 min, and then the unreacted acetic anhydride and the generated acetic acid were removed by distillation under reduced pressure;

[0026] Then, the material in the stirred reaction vessel is added dropwise to 800 mL of ammonia water with a mass concentration of 20%, and the dropping speed is controlled to be 60 d / min; after the dropwise addition is completed, the temperature of the reactant is controlled to be 185°C, and stirring is continued for 5 min, then all the material in the reaction vessel is poured into 800 mL of water, stirred evenly, the stirred mixture is filtered with diatomaceous earth, the filtrate is concentrated, 8 L of 5% sodium hydroxide solution is added to the system, stirring is continued for 45 min at room temperature, the solid product is collected, washed with water three times, and dried to obtain crude 6-aminocaproic acid, which is recrystallized with 95% ethanol to obtain pure 6-aminocaproic acid. The yield is 88.1%, and the HPLC purity is 98.0%. The pure 6-aminocaproic acid prepared in this embodiment has the following nuclear magnetic spectrum data:

[0027] Melting point 208℃; MS (m / z): [M+H] + :132.

[0028] 1 H NMR (300MHz, H2O) δ: 2.82 (t, J=6.0Hz, 2H), 2.02 (t, J=6.0Hz, 2H), 1.65-1.17 (m, 6H);

[0029] 13 C NMR (75MHz, H2O) δ: 183.54, 39.23, 37.13, 26.36, 25.32, 25.10.

[0030] Embodiment 3:

[0031] 160 g of pimelic acid (1 mol) and 280 mL of acetic anhydride were added to a stirred reaction vessel equipped with a heating device, heated to 137° C., reacted for 65 min, and then the unreacted acetic anhydride and the generated acetic acid were removed by distillation under reduced pressure;

[0032] Then, the material in the stirred reaction vessel is added dropwise to 650 mL of ammonia water with a mass concentration of 20%, and the dropping speed is controlled to be 45 d / min; after the dropwise addition is completed, the temperature of the reactant is controlled to be 182° C., and stirring is continued for 8 min, and then all the material in the reaction vessel is poured into 650 mL of water, stirred evenly, and the stirred mixture is filtered through diatomaceous earth, and the filtrate is concentrated, and 7 L of 5% sodium hydroxide solution is added to the system, and stirring is continued for 35 min at room temperature, and the solid product is collected, washed with water four times, and dried to obtain crude 6-aminocaproic acid, and recrystallized with 95% ethanol to obtain pure 6-aminocaproic acid. The yield is 85.1%, and the HPLC purity is 97.4%.

[0033] Comparative Example 1:

[0034] According to the steps of Example 2, only the amount of acetic anhydride was changed to 100 mL, and the yield of 6-aminocaproic acid was 21.8% and the HPLC purity was 94.6%.

[0035] Comparative Example 2:

[0036] According to the steps of Example 2, only the amount of acetic anhydride was changed to 200 mL, and the yield of 6-aminocaproic acid was 64.4% and the HPLC purity was 92.6%.

[0037] Comparative Example 3:

[0038] According to the steps of Example 2, only the amount of ammonia water and water was changed to 350 mL, and the yield of 6-aminocaproic acid was 41.2% and the HPLC purity was 88.3%.

[0039] Comparative Example 4:

[0040] The steps of Example 2 were followed, except that the dropping speed was changed to 90 d / min. The yield of 6-aminocaproic acid was 66.1% and the HPLC purity was 89.0%.

[0041] Comparative Example 5:

[0042] The steps of Example 2 were followed, except that the dropping speed was changed to 15 d / min. The yield of 6-aminocaproic acid was 38.6% and the HPLC purity was 88.1%.

[0043] Comparative Example 6:

[0044] According to the steps of Example 2, only the amount of 5% sodium hydroxide was changed to 3.5 L, and the yield of 6-aminocaproic acid was 81.5%, and the HPLC purity was 84.7%.

[0045] Comparative Example 7:

[0046] According to the steps of Example 2, only the post-treatment step was omitted, and the yield of 6-aminocaproic acid was 71.8% and the HPLC purity was 24.6%.

[0047] 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 using pimelic acid as a raw material, characterized in that: The product is obtained by acylation and cyclization of pimelic acid and excess acetic anhydride, followed by substitution reaction with ammonia water, and finally ring opening in an alkaline system. The reaction mechanism is as follows: The following steps are involved: Pimelic acid and acetic anhydride are added into a stirred reaction vessel equipped with a heating device in a molar volume ratio of 1:0.25-0.3, heated to 135-140° C., reacted for at least 60 minutes, and then distilled under reduced pressure to remove unreacted acetic anhydride and generated acetic acid; Then, the material in the stirred reaction container is added dropwise to ammonia water, wherein the ammonia water is such that the molar volume ratio of pimelic acid to ammonia water is 1:0.5-0.8, and the dropping speed is controlled to be 30-60 d / min; after the dropwise addition is completed, the temperature of the reactant is controlled to be 180-185° C., and stirring is continued for 5-10 min. Then, all the material in the reaction container is poured into water of equal volume to the ammonia water, and stirred evenly. The stirred mixture is filtered through diatomaceous earth, and the filtrate is concentrated. A 5% sodium hydroxide solution is added to the system, and stirring is continued for at least 30 min at room temperature. The solid product is collected, washed with water for at least three times, and dried to obtain a crude 6-aminocaproic acid product, and 6-aminocaproic acid is obtained by post-treatment.

2. The method according to claim 1, characterized in that The mass concentration of the ammonia water is 20%.

3. The method according to claim 1, characterized in that The dropping speed is 40-45 d / min.

4. The method according to claim 1, characterized in that The post-treatment is to recrystallize the crude 6-aminocaproic acid with 95% ethanol to obtain the pure 6-aminocaproic acid.

5. The method according to claim 1, characterized in that The added amount of the 5% sodium hydroxide solution is such that the molar volume ratio of pimelic acid to the 5% sodium hydroxide solution is 1:6-8.

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