A method for preparing 6-aminocaproic acid by one-step synthesis of cyclohexanone

Abstract

The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing 6-aminocaproic acid by one-step synthesis of cyclohexanone. The method uses cyclohexanone and hydroxylamine, which are abundant in source, as raw materials, and obtains 6-aminocaproic acid by one-step ring-opening reaction. The reaction process is simple and the post-treatment is convenient. Excessive addition of cyclohexanone allows the cyclohexanone to serve as both a reaction raw material and a reaction reagent during the reaction, thereby ensuring that the reaction can proceed in a forward direction and improving the conversion rate. The preparation method of the invention has mild reaction conditions, and the yield of the obtained 6-aminocaproic acid can reach more than 85%, and the purity is as high as more than 97%, 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 by synthesizing cyclohexanone in one step. 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. Summary of the invention

[0005] In order to overcome the above technical problems, the present invention provides a method for preparing 6-aminocaproic acid by one-step synthesis using cyclohexanone. The raw materials are easily available and the reaction conditions are mild. The yield of the prepared 6-aminocaproic acid can reach more than 85% and the purity is as high as more than 97%, which is suitable for large-scale production.

[0006] The technical solutions to the above technical problems are as follows:

[0007] A method for preparing 6-aminocaproic acid by one-step synthesis using cyclohexanone, wherein cyclohexanone and hydroxylamine are used as raw materials, and 6-aminocaproic acid is obtained by one-step ring-opening reaction;

[0008] The synthetic route is as follows:

[0009]

[0010] Specifically, cyclohexanone and hydroxylamine undergo a condensation reaction to obtain cyclohexanone oxime, which is then rearranged in sulfuric acid to obtain 1,6-caprolactam, which is then ring-opened in fuming sulfuric acid to obtain 6-aminocaproic acid;

[0011] The reaction mechanism is:

[0012]

[0013] The following steps are involved:

[0014] Cyclohexanone and hydroxylamine are mixed in a molar ratio of 1:2-3, 2 / 3 of the cyclohexanone and hydroxylamine are mixed and added into a stirring reaction container with a heating device, and the reaction temperature is controlled to be 150-155° C.; after sealing the tube and stirring the reaction for at least 1 hour, the temperature is naturally lowered to below 60° C., and the remaining cyclohexanone is added. When the temperature of the reaction material is below 40° C., water and concentrated sulfuric acid are slowly added into the reaction container, and then the temperature is increased to 110-115° C., and after stirring the reaction for at least 10 minutes, all the materials in the reaction container are transferred into water, and after stirring evenly, the solid is collected, fuming sulfuric acid is added, and the mixture is heated to 100° C. and sealed the tube and stirred the reaction for at least 30 minutes. After the reaction, centrifugation is performed to obtain a crude 6-aminocaproic acid product, and the crude 6-aminocaproic acid product is obtained by recrystallization with ethanol at least twice to obtain a pure 6-aminocaproic acid product.

[0015] Furthermore, the molar volume ratio of the hydroxylamine to water is 1 mol: 6-8 mL.

[0016] Furthermore, the molar weight ratio of the hydroxylamine to the concentrated sulfuric acid is 1 mol: 200-230 g.

[0017] Furthermore, the molar weight ratio of the hydroxylamine to the oleum is 1 mol: 160-180 g.

[0018] The beneficial effects of the present invention are:

[0019] The synthesis method involved in the invention uses cyclohexanone and hydroxylamine, which are abundant in source, as raw materials, and obtains 6-aminocaproic acid through a one-step ring-opening reaction. The reaction process is simple and the post-treatment is convenient. Cyclohexanone is added in excess. During the reaction, the cyclohexanone serves as both a reaction raw material and a reaction reagent, thereby ensuring that the reaction can proceed in a forward direction and improving the conversion rate. The preparation method of the invention has mild reaction conditions, and the yield of the obtained 6-aminocaproic acid can reach more than 85%, and the purity is as high as more than 97%, which is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] The present invention will be further described in detail below in conjunction with the accompanying drawings and specific embodiments.

[0021] Figure 1 This is the H NMR spectrum of the pure 6-aminocaproic acid obtained in Example 1 of the present invention;

[0022] Figure 2 This is the NMR carbon spectrum of the pure 6-aminocaproic acid obtained in Example 1 of the present invention. DETAILED DESCRIPTION

[0023] The reagents and raw materials used in the synthesis steps of the present invention are available on the market.

[0024] Embodiment 1:

[0025] 196 g of cyclohexanone (2 mol) and 33 g of hydroxylamine (1 mol) were mixed and added to a stirred reaction vessel with a heating device, and the reaction temperature was controlled to be 155° C.; after the tube was sealed and stirred for 1 hour, the temperature was naturally lowered to below 60° C., and then 98 g of cyclohexanone (1 mol) was added. When the temperature of the reaction material was below 40° C., 6 mL of water and 200 g of concentrated sulfuric acid were slowly added to the reaction vessel, and then the temperature was raised to 110° C. After stirring for 10 minutes, in order to facilitate the precipitation of the product, all the materials in the reaction vessel were transferred to water, stirred evenly, the solid was collected, 180 g of fuming sulfuric acid was added, heated to 100° C., sealed and stirred for 30 minutes, and centrifuged after the reaction to obtain crude 6-aminocaproic acid, which was recrystallized from ethanol at least twice to obtain pure 6-aminocaproic acid with a yield of 89.9%.

[0026] The NMR spectrum data of the pure 6-aminocaproic acid prepared in this example are as follows:

[0027] Melting point 207~208℃; MS (m / z): [M+H] + :132.

[0028] 1 H NMR (300MHz, H2O) δ: 2.82 (t, J=6.0Hz, 2H), 2.03 (t, J=6.0Hz, 2H), 1.65-1.18 (m, 6H);

[0029] 13 C NMR (75MHz, H2O) δ: 183.53, 39.24, 37.13, 26.36, 25.32, 25.10;

[0030] The purity was determined by HPLC to be 97.8%.

[0031] Embodiment 2:

[0032] 128g cyclohexanone (1.3mol) and 33g hydroxylamine (1mol) were mixed and added to a stirred reaction vessel with a heating device, and the reaction temperature was controlled to be 150°C; after the tube was sealed and stirred for 1.5h, the temperature was naturally lowered to below 60°C, and then 68g cyclohexanone (0.7mol) was added. When the temperature of the reaction material was below 40°C, 8mL water and 230g concentrated sulfuric acid were slowly added to the reaction vessel, and then the temperature was raised to 115°C. After stirring for 15min, in order to facilitate the precipitation of the product, all the materials in the reaction vessel were transferred to water. After stirring evenly, the solid was collected, 160g fuming sulfuric acid was added, heated to 100°C, sealed and stirred for 45min, and centrifuged after the reaction to obtain crude 6-aminocaproic acid, which was recrystallized from ethanol at least twice to obtain pure 6-aminocaproic acid with a yield of 88.1% and a purity of 98.4% determined by HPLC.

[0033] Embodiment 3:

[0034] 196 g of cyclohexanone (2 mol) and 33 g of hydroxylamine (1 mol) were mixed and added to a stirred reaction vessel with a heating device, and the reaction temperature was controlled to be 152° C.; after the tube was sealed and stirred for 1 hour, the temperature was naturally lowered to below 60° C., and then 98 g of cyclohexanone (1 mol) was added. When the temperature of the reaction material was below 40° C., 7 mL of water and 215 g of concentrated sulfuric acid were slowly added to the reaction vessel, and then the temperature was raised to 110° C. After stirring for 10 minutes, in order to facilitate the precipitation of the product, all the materials in the reaction vessel were transferred to water, stirred evenly, the solid was collected, 170 g of fuming sulfuric acid was added, heated to 100° C., sealed and stirred for 30 minutes, and centrifuged after the reaction to obtain crude 6-aminocaproic acid, which was recrystallized from ethanol at least twice to obtain pure 6-aminocaproic acid, with a yield of 86.9% and a purity of 97.2% determined by HPLC.

[0035] Comparative Example 1:

[0036] According to the steps of Example 1, only the total amount of cyclohexanone was changed to 98 g, i.e. 1 mol, 64 g was added first and then 34 g. The yield of 6-aminocaproic acid was 59.8% and the HPLC purity was 96.6%.

[0037] Comparative Example 2:

[0038] According to the steps of Example 1, only the total amount of cyclohexanone used was changed to 147 g, i.e. 1.5 mol, 98 g was added first and then 49 g was added. The yield of 6-aminocaproic acid obtained was 69.1% and the HPLC purity was 97.1%.

[0039] Comparative Example 3:

[0040] According to the steps of Example 1, only the amount of water was changed to 3 mL, and the yield of 6-aminocaproic acid was 71.2% and the HPLC purity was 88.3%.

[0041] Comparative Example 4:

[0042] According to the steps of Example 1, only the amount of concentrated sulfuric acid was changed to 100 g, and the yield of 6-aminocaproic acid was 68.4% and the HPLC purity was 89.0%.

[0043] Comparative Example 5:

[0044] According to the steps of Example 1, only the amount of oleum was changed to 100 g, the yield of 6-aminocaproic acid was 78.6%, and the HPLC purity was 78.1%.

[0045] Comparative Example 6:

[0046] According to the steps of Example 1, only the recrystallization step was omitted, and the yield of 6-aminocaproic acid was 81.8% and the HPLC purity was 54.6%.

[0047] Comparative Example 6:

[0048] According to the steps of Example 1, the post-treatment was performed with only one recrystallization, and the yield of 6-aminocaproic acid was 83.4% and the HPLC purity was 79.6%.

[0049] 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 by one-step synthesis of cyclohexanone, characterized in that: Cyclohexanone and hydroxylamine are used as raw materials to obtain 6-aminocaproic acid through a one-step ring-opening reaction; The synthetic route is as follows: The following steps are involved: Cyclohexanone and hydroxylamine are mixed in a molar ratio of 2 to 3:1, 2 / 3 of the cyclohexanone and hydroxylamine are mixed and added into a stirring reaction vessel equipped with a heating device, and the reaction temperature is controlled to be 150 to 155°C; after the tube is sealed and stirred for at least 1 hour, the temperature is naturally lowered to below 60°C, and the remaining cyclohexanone is added. When the temperature of the reaction material is below 40°C, water and concentrated sulfuric acid are slowly added into the reaction vessel, wherein the molar volume ratio of the hydroxylamine to the water is 1 mol: 6 to 8 mL; and the molar weight ratio of the hydroxylamine to the concentrated sulfuric acid is 1 mol: 200 to 230 g; Then, the temperature is raised to 110-115°C, and the reaction is stirred for at least 10 minutes. Then, all the materials in the reaction container are transferred to water, and after stirring evenly, the solid is collected, fuming sulfuric acid is added, and the mixture is heated to 100°C, sealed and stirred for at least 30 minutes. After the reaction is completed, centrifugation is performed to obtain 6-aminocaproic acid. The reaction mechanism is as follows:

2. The method according to claim 1, characterized in that The molar weight ratio of the hydroxylamine to the fuming sulfuric acid is 1 mol: 160-180 g.

3. The method according to claim 1, characterized in that The obtained 6-aminocaproic acid is a crude product, and the method further comprises a recrystallization purification step, wherein the recrystallization is performed by using ethanol for at least two times to obtain a pure 6-aminocaproic acid product.

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