Preparation method of 2-(2-aminoethyl)cyclobutane-1-one for synthesizing 6-aminocaproic acid

Abstract

The invention belongs to the field of drug synthesis, and in particular to a method for preparing 2-(2-aminoethyl)cyclobutane-1-ketone, a raw material for synthesizing 6-aminocaproic acid, using 4-aminobutyryl chloride as a raw material, and purifying to obtain 2-(2-aminoethyl)cyclobutane-1-ketone after substitution and ring-closure reaction, and the substance can be ring-opened in one step to obtain 6-aminocaproic acid. The method is simple to react, easy to operate, and has a simple post-processing purification process, low production cost investment, and is conducive to industrial promotion. The obtained 2-(2-aminoethyl)cyclobutane-1-ketone has high purity and high yield, and the yield can reach more than 80%, and the purity is up to more than 97%.

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a method for synthesizing 2-(2-aminoethyl)cyclobutane-1-one (Formula 1), a raw material for synthesizing 6-aminocaproic acid. 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] At present, 6-aminocaproic acid is generally prepared by direct chemical synthesis, which is obtained by hydrolyzing caprolactam or its polymer and then refining it. For example, U.S. Patent No. US2453234A and Chinese Patent Applications CN101125821A, CN109369430A, CN110256268A, CN111100025A, CN106632474A, etc. have all been reported.

[0004] 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 has low safety.

[0005] The Chinese invention patent application, with publication number CN 101125821A, discloses a method for preparing 6-aminocaproic acid, a hemostatic drug, wherein caprolactam is dissolved in dilute hydrochloric acid, heated to reflux, 6-aminocaproic acid hydrochloride is prepared, spherical macroporous styrene weakly alkaline anion exchange resin is used for neutralization, and the product is obtained by post-treatment. The technical solution of the 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, the amount of ion exchange resin used in the industrial application process 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 pollutes the environment greatly, and also increases the cost of wastewater treatment, which is not conducive to industrial promotion and application.

[0006] Relatively speaking, the production method of 6-aminocaproic acid is relatively simple, but the application range of 6-aminocaproic acid is constantly expanding, and the production demand is also increasing. Therefore, if a new industrialized method of 6-aminocaproic acid can be developed, it will have extensive social and economic benefits.

[0007] 2-(2-aminoethyl)cyclobutane-1-one can be ring-opened to obtain 6-aminocaproic acid. Therefore, 2-(2-aminoethyl)cyclobutane-1-one is a key raw material for preparing 6-aminocaproic acid. However, there is no report on the method for preparing 2-(2-aminoethyl)cyclobutane-1-one. Therefore, it is necessary to solve the problem of preparing the raw material 2-(2-aminoethyl)cyclobutane-1-one, so as to solve the problem of industrialization of 6-aminocaproic acid from the source. Summary of the invention

[0008] In order to overcome the above technical problems, the present invention provides a method for synthesizing 2-(2-aminoethyl)cyclobutane-1-one (Formula 1), a key raw material for the industrial production of 6-aminocaproic acid, with a yield of more than 80% and a purity of more than 97%, thereby providing a guarantee for the subsequent industrialization of 6-aminocaproic acid.

[0009] The technical solutions to the above technical problems are as follows:

[0010] Using 4-aminobutyryl chloride as the raw material, it is purified after substitution and cyclization reaction;

[0011] The synthetic route is as follows:

[0012]

[0013] The following steps are involved:

[0014] Step 1): Substitution reaction:

[0015] 4-aminobutyryl chloride and sodium azide are prepared in a molar ratio of 1:2.5-3.5, and 4-aminobutyryl chloride is prepared by chlorinating 4-aminobutyric acid; anhydrous DMF is used as a reaction solvent, and the molar volume ratio of 4-aminobutyryl chloride to anhydrous DMF is 1:1-1.5; the mixture is added into a reaction container with a heating function, heated and stirred until dissolved, the reaction temperature is controlled at 70-80°C, and the reaction is stirred for 8-12 hours, and the mixture after the stirring reaction is diluted with dichloromethane, washed with 10% hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered, and vacuum rotary evaporated to obtain the 4-aminobutyryl chloride nitride shown in formula 2; the amount of dichloromethane used is such that the molar volume ratio of 4-aminobutyryl chloride to dichloromethane is 1:1-1.2; the amount of 10% hydrochloric acid solution used is such that the molar volume ratio of 4-aminobutyryl chloride to 10% hydrochloric acid solution is 1:1-1.3.

[0016] Step 2): Cyclization reaction:

[0017] The substitution product obtained in step 1) and copper acetylacetonate are mixed in a molar ratio of 1:0.02-0.03, and anhydrous toluene is used as a reaction solvent, and the molar volume ratio of the substitution product to the anhydrous toluene is 1:0.9-1.1; the mixture is added to a reaction vessel with a heating function, heated and stirred to reflux temperature, and the reaction is continued for 2-3 hours, the mixture after the stirring reaction is subjected to reduced pressure rotary evaporation to recover the solvent, and anhydrous dichloromethane is injected into the reaction vessel, and the molar volume ratio of the substitution product to the anhydrous dichloromethane is 1:3-5; toluenesulfonyl chloride and potassium carbonate are added, and the molar ratio of the substitution product, toluenesulfonyl chloride and potassium carbonate is 1:1-1.1:1-1.1; the mixture is heated to 40°C and stirred for reaction for 45-60 minutes, and then sodium hydride is added to the reaction system, and the molar ratio of the substitution product to the sodium hydride is 1:1-1.1; the reaction is continued for 1-2 hours. The stirred reaction mixture is cooled to room temperature and filtered, and the filtrate layer is rapidly purified by medium pressure to obtain a cyclization product, i.e., 2-(2-aminoethyl)cyclobutane-1-one as shown in Formula 1; the solvent used for the medium pressure rapid purification is a mixed solvent of ethyl acetate, petroleum ether and methyl tert-butyl ether in a volume ratio of 1:5:0.5.

[0018] The specific reaction mechanism is as follows:

[0019]

[0020] Another object of the present invention is to provide a 2-(2-aminoethyl)cyclobutane-1-one shown in Formula 1 prepared by the above method as a raw material or intermediate for producing 6-aminocaproic acid, and to obtain 6-aminocaproic acid through a ring-opening reaction. The method has the advantages of simple reaction steps, good reaction yield in each step, and suitability for industrial application.

[0021] The beneficial effects of the present invention are:

[0022] The present invention uses 4-aminobutyryl chloride as a raw material, and purifies after substitution and cyclization reaction to obtain 2-(2-aminoethyl)cyclobutane-1-one shown in Formula 1, and the substance can be ring-opened in one step to obtain 6-aminocaproic acid. The method has simple reaction, convenient operation, simple post-treatment purification process, low production cost investment, and is conducive to industrial promotion.

[0023] The preparation method of the invention has readily available raw materials and mild reaction conditions. The prepared 2-(2-aminoethyl)cyclobutane-1-one has high purity and high yield, the yield can reach more than 80%, and the purity is as high as more than 97%. The invention can provide a reference for a new idea for the preparation of 2-(2-aminoethyl)cyclobutane-1-one.

[0024] The present invention is further described in detail below in conjunction with specific implementation modes. 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): Substitution reaction:

[0028] 121.6 g of 4-aminobutyryl chloride (1 mol), 162.5 g of sodium azide (2.5 mol), and 1 L of anhydrous DMF were added to a reaction vessel with a heating function, heated and stirred until dissolved, the reaction temperature was controlled at 70° C., and the reaction was stirred for 12 h. The mixture after the stirring reaction was diluted with 1 L of dichloromethane, washed with 1 L of 10% hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain 4-aminobutyryl azide shown in Formula 2;

[0029] Step 2): Cyclization reaction:

[0030] Take 128.1g of 4-aminobutyryl azide (1mol) obtained in step 1), 5.24g of copper acetylacetonate (0.02mol), and 0.9L of anhydrous toluene, add them to a reaction vessel with a heating function, heat and stir to reflux temperature, continue to react for 3h, reduce the pressure and rotary evaporate the mixture after stirring and reacting to recover the solvent, inject 3L of dichloromethane into the reaction vessel, add 190.65g of tosyl chloride (1mol) and 138.21g of potassium carbonate (1mol), heat to 40℃ and stir to react for 45min, then add 24g of sodium hydride (1mol) to the reaction system, and continue to react for 1h. Cool the mixture after stirring and reacting to room temperature, filter, and quickly purify the filtrate layer by medium pressure to obtain the cyclization product, i.e., 2-(2-aminoethyl)cyclobutane-1-one shown in Formula 1; yield 80.5%, HPLC purity 97.1%. The medium-pressure rapid purification uses a mixed solvent of ethyl acetate, petroleum ether and methyl tert-butyl ether in a volume ratio of 1:5:0.5.

[0031] Embodiment 2:

[0032] Step 1): Substitution reaction:

[0033] 121.6 g of 4-aminobutyryl chloride (1 mol), 227.5 g of sodium azide (3.5 mol), and 1.5 L of anhydrous DMF were added to a reaction vessel with a heating function, heated and stirred until dissolved, the reaction temperature was controlled at 80° C., and the reaction was stirred for 8 h. The mixture after the stirring reaction was diluted with 1.2 L of dichloromethane, washed with 1.3 L of 10% hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain 4-aminobutyryl azide shown in Formula 2;

[0034] Step 2): Cyclization reaction:

[0035] Take 128.1g of 4-aminobutyryl azide (1mol) obtained in step 1), 7.85g of copper acetylacetonate (0.03mol), and 1.1L of anhydrous toluene, add them to a reaction vessel with a heating function, heat and stir to reflux temperature, continue to react for 2h, reduce the pressure and rotary evaporate the mixture after stirring and reacting to recover the solvent, inject 4L of dichloromethane into the reaction equipment, add 200.18g of tosyl chloride (1.05mol) and 145.12g of potassium carbonate (1.05mol), heat to 40℃ and stir to react for 50min, then add 25.2g of sodium hydride (1.05mol) to the reaction system, and continue to react for 1.5h. Cool the mixture after stirring and reacting to room temperature, filter, and quickly purify the filtrate layer by medium pressure to obtain the cyclization product, i.e., 2-(2-aminoethyl)cyclobutane-1-one shown in Formula 1; yield 83.2%, HPLC purity 97.5%. The medium-pressure rapid purification uses a mixed solvent of ethyl acetate, petroleum ether and methyl tert-butyl ether in a volume ratio of 1:5:0.5.

[0036] Embodiment 3:

[0037] Step 1): Substitution reaction:

[0038] 121.6 g of 4-aminobutyryl chloride (1 mol), 201.5 g of sodium azide (3.1 mol), and 1.25 L of anhydrous DMF were added to a reaction vessel with a heating function, heated and stirred until dissolved, the reaction temperature was controlled at 75° C., and the reaction was stirred for 10 hours. The mixture after the stirring reaction was diluted with 1.1 L of dichloromethane, washed with 1.15 L of 10% hydrochloric acid solution, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to obtain 4-aminobutyryl azide shown in Formula 2;

[0039] Step 2): Cyclization reaction:

[0040] Take 128.1g of 4-aminobutyryl azide (1mol) obtained in step 1), 6.55g of copper acetylacetonate (0.025mol), and 1.05L of anhydrous toluene, add them to a reaction vessel with a heating function, heat and stir to reflux temperature, continue to react for 2.5h, reduce the pressure and rotary evaporate the mixture after stirring and reacting to recover the solvent, inject 5L of dichloromethane into the reaction equipment, add 209.72g of tosyl chloride (1.1mol) and 152.03g of potassium carbonate (1.1mol), heat to 40℃ and stir to react for 60min, then add 26.4g of sodium hydride (1.1mol) to the reaction system, and continue to react for 2h. The mixture after stirring and reacting is cooled to room temperature, filtered, and the filtrate layer is quickly purified by medium pressure to obtain the cyclization product, i.e. 2-(2-aminoethyl)cyclobutane-1-one shown in formula 1; the yield is 82.8%, and the HPLC purity is 97.3%. The medium-pressure rapid purification uses a mixed solvent of ethyl acetate, petroleum ether and methyl tert-butyl ether in a volume ratio of 1:5:0.5.

[0041] Comparative Example 1:

[0042] According to the steps of Example 2, only the solvent of the cyclization reaction was changed to anhydrous DMF, and the yield of 2-(2-aminoethyl)cyclobutane-1-one was 44.5% and the HPLC purity was 67.4%.

[0043] Comparative Example 2:

[0044] According to the steps of Example 2, only 4-aminobutyryl azide and copper acetylacetonate were reacted in anhydrous toluene solvent for 1 h. The yield of 2-(2-aminoethyl)cyclobutane-1-one was 23.5% and the HPLC purity was 77.6%.

[0045] Comparative Example 3:

[0046] According to the steps of Example 2, only 4-aminobutyryl azide and copper acetylacetonate were reacted in anhydrous toluene solvent for 5 hours, and the yield of 2-(2-aminoethyl)cyclobutane-1-one was 79.8% and the HPLC purity was 67.6%.

[0047] Comparative Example 4:

[0048] According to the steps of Example 2, only the solvent was recovered by rotary evaporation after the cyclization reaction, and the medium-pressure rapid purification step was omitted. The yield of the obtained 2-(2-aminoethyl)cyclobutane-1-one was 79.4% and the HPLC purity was 18.6%.

[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 2-(2-aminoethyl)cyclobutane-1-one as shown in formula 1, characterized in that: Using 4-aminobutyryl chloride as the raw material, it is purified after substitution and cyclization reaction; The synthetic route is as follows: The following steps are involved: Step 1): Substitution reaction: 4-aminobutyryl chloride and sodium azide are mixed in a molar ratio of 1:2.5-3.5, and anhydrous DMF is used as a reaction solvent. The mixture is added into a reaction vessel with a heating function, heated and stirred until dissolved, and the reaction temperature is controlled at 70-80° C. The mixture is stirred for 8-12 hours, and the substitution product is obtained by post-treatment, i.e., 4-aminobutyryl azide shown in Formula 2; Step 2): Cyclization reaction: The substitution product obtained in step 1) and copper acetylacetonate are mixed in a molar ratio of 1:0.02-0.03, and anhydrous toluene is used as a reaction solvent. The mixture is heated and stirred to reflux temperature, and the reaction is continued for 2-3 hours. The mixture after the stirring reaction is subjected to reduced pressure rotary evaporation to recover the solvent, and anhydrous dichloromethane is injected into the reaction container, and toluenesulfonyl chloride and potassium carbonate are added, wherein the molar ratio of the substitution product, toluenesulfonyl chloride and potassium carbonate is 1:1-1.1:1-1.1; the mixture is heated to 40°C and stirred for reaction for 45-60 minutes, and then sodium hydride is added to the reaction system, wherein the molar ratio of the substitution product to sodium hydride is 1:1-1.1; the reaction is continued for 1-2 hours, and the cyclization product, i.e. 2-(2-aminoethyl)cyclobutane-1-one shown in Formula 1, is obtained by post-treatment; The specific reaction mechanism is as follows:

2. The preparation method according to claim 1, characterized in that: The amount of anhydrous DMF added in step 1) is such that the molar volume ratio of 4-aminobutyryl chloride to anhydrous DMF is 1:1-1.

5.

3. The preparation method according to claim 1, characterized in that: The post-treatment in step 1) is to dilute the mixture after the stirring reaction with dichloromethane, wash it with 10% hydrochloric acid solution, dry it over anhydrous sodium sulfate, filter it, and evaporate it under reduced pressure to obtain 4-aminobutyryl azide shown in formula 2, wherein the amount of dichloromethane used is such that the molar volume ratio of 4-aminobutyryl chloride to dichloromethane is 1:1 to 1.2; the amount of 10% hydrochloric acid solution used is such that the molar volume ratio of 4-aminobutyryl chloride to 10% hydrochloric acid solution is 1:1 to 1.

3.

4. The preparation method according to claim 1, characterized in that: The amount of anhydrous toluene added in step 2) is such that the molar volume ratio of the substitution product obtained in step 1) to anhydrous toluene is 1:0.9-1.

1.

5. The preparation method according to claim 1, characterized in that: The amount of anhydrous dichloromethane added in step 2) is such that the molar volume ratio of the substitution product obtained in step 1) to anhydrous dichloromethane is 1:3-5.

6. The preparation method according to claim 1, characterized in that: The post-treatment in step 2) is to cool the mixture after the stirring reaction to room temperature, filter it, and quickly purify the filtrate layer by medium pressure to obtain the cyclization product. The solvent used for the medium pressure rapid purification is a mixed solvent, and the mixed solvent is a mixture of ethyl acetate, petroleum ether and methyl tert-butyl ether in a volume ratio of 1:5:0.

5.

7. Use of 2-(2-aminoethyl)cyclobutane-1-one of formula 1 prepared by the method according to any one of claims 1 to 6, characterized in that: As a raw material or intermediate for synthesizing 6-aminocaproic acid.

8. The use according to claim 7, characterized in that: Using 2-(2-aminoethyl)cyclobutane-1-one as shown in formula 1 as a raw material or intermediate, 6-aminocaproic acid is synthesized in one step through a ring-opening reaction; The specific synthetic route is as follows:

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