Process for the preparation of 2,5-dimethylpyrrole-protected alpha-amino-epsilon-caprolactam and use thereof

Abstract

The application relates to the field of organic matter synthesis methodology, and provides a preparation method and application of 2,5-dimethylpyrrole-protected alpha-amino-epsilon-caprolactam, wherein the 2,5-dimethylpyrrole-protected alpha-amino-epsilon-caprolactam is post-treated by using a standing-recrystallization method, and the preparation efficiency is improved. The standing is used instead of multiple extraction and washing in the prior art, and the consumption of reagents is reduced. Compared with the complex post-treatment steps in the prior art, only necessary solvents and catalysts are needed in the application, the consumption of reagents is reduced, the reagents used are all bulk industrial products, are cheap and easy to obtain, production cost is low, the environment is friendly, and the application can be applied to industrial production. The total yield of the application is high (up to 95% at most), the reaction condition is mild, the application can be used for further preparation of poly(epsilon-lysine), and is favorable to promote the industrial application of chemical synthesis of poly(epsilon-lysine).

Description

Technical Field

[0001] This invention relates to the field of organic synthesis methodology, and more particularly to a method for preparing and applying 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam. Background Technology

[0002] Poly(ε-lysine) is safe and non-toxic, edible, and possesses excellent antibacterial properties. It has been approved by the U.S. Food and Drug Administration (FDA) for use as a food preservative and cosmetic additive. Currently, it is mainly prepared through microbial fermentation, but its molecular weight is less than 4000, which limits its application to some extent. On the other hand, lysine is a natural, renewable resource with wide availability and low price. With the development of bioengineering technology, lysine production has encountered overcapacity. Therefore, developing new pathways to convert inexpensive lysine resources into high-value-added poly(ε-lysine) is of great significance. In previous work, the applicant developed a complete set of new amino acid polymerization routes using lysine as raw material, involving seven-membered ring cyclization, pyrrole protection, and ring-opening polymerization. This resulted in the world's first chemical synthesis of high-molecular-weight poly(ε-lysine), overcoming the limitation that antibacterial poly(ε-lysine) can only be synthesized through bio-fermentation (Reference: Chemical Science, 2015, 6, 6385-6391 and Chinese Invention Patent: 201510047405.5).

[0003] In the above-mentioned process of preparing high molecular weight poly(ε-lysine) from lysine, α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is an excellent intermediate. In the existing methods for synthesizing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole, the post-processing steps mainly include: first, evaporating the reaction solvent to dryness, then dissolving it in dichloromethane, washing repeatedly with saturated sodium bicarbonate solution to remove the acidic catalyst, then washing with saturated brine, extracting and separating the liquids, combining the organic phases, drying with anhydrous sodium sulfate, concentrating the solvent, and then purifying by column chromatography to obtain the final product, α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole. This post-processing is complex, time-consuming, inefficient, and consumes large quantities of solvents and reagents, resulting in high costs, which is not conducive to industrial-scale production. Summary of the Invention

[0004] In view of this, the present invention provides a method for preparing and applying 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam. The method utilizes a static-recrystallization method to post-treat the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam, thereby improving the preparation efficiency.

[0005] To achieve the above-mentioned objective, the first technical solution provided by this invention is: a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole, comprising the following steps:

[0006] S1. Dissolve α-amino-ε-caprolactam in its solvent, add catalyst and 2,5-hexanedione, heat under reflux to obtain the first product;

[0007] S2. Let the first product stand until the liquid and impurities separate into layers. Take the liquid, concentrate it, and then cool it to crystallize, thus obtaining the second product.

[0008] S3. Filter and dry the second product to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam.

[0009] Step S1 is one of the known Paal-Knorr pyrrole synthesis reactions in the prior art, and the reaction route is as follows:

[0010]

[0011] The selection of the catalyst and solvent described herein conforms to the commonalities of the Paal-Knorr pyrrole synthesis reaction. Those skilled in the art can refer to known catalysts and solvents and select them according to specific circumstances, which does not determine the achievement of the purpose of this invention.

[0012] Furthermore, in step S1, the solvent is a substance that can azeotropically react with water and has a water-carrying effect. For example, at least one of dichloromethane, toluene, cyclohexane, and dioxane.

[0013] Furthermore, in step S1, the catalyst can be a substance that can provide an acidic environment for the reaction, such as organic acids like formic acid, acetic acid, and p-toluenesulfonic acid, as well as inorganic acids like sulfuric acid, hydrochloric acid, and phosphoric acid.

[0014] Furthermore, in step S1, the amount of catalyst added is sufficient to adjust the pH of the system to be less than or equal to 5.5. Under these conditions, the yield is relatively ideal.

[0015] Furthermore, in step S1, the molar ratio of α-amino-ε-caprolactam to 2,5-hexanedione is 1:(0.8–1.1). Under these conditions, the yield is relatively ideal.

[0016] Furthermore, in step S1, the concentration of α-amino-ε-caprolactam is 0.1–1 mol / L. Under these conditions, the yield is relatively ideal.

[0017] Furthermore, in step S1, the temperature of the heating reflux is 120–160°C, and the time is 4–9 hours. Under these conditions, the yield is relatively ideal.

[0018] Furthermore, in step S2, the settling time is 3 to 16 hours. To ensure sufficient separation of the liquid and impurities in the first product, the settling time is typically at least 3 hours, and settling for more than 16 hours usually does not further improve the yield.

[0019] Furthermore, in step S2, the mass of solvent removed by concentration is 30-80% of the mass of solvent used in step S1.

[0020] Furthermore, in step S2, the cooling crystallization temperature is -128 to 5°C and the time is 8 to 16 hours.

[0021] Furthermore, the α-amino-ε-caprolactam is prepared by the following method:

[0022] S11. Dissolve lysine hydrochloride in methanol and react it with a chlorinating agent or concentrated sulfuric acid at room temperature;

[0023] S12. Add methanol and alkali to the reaction solution obtained in S11 and react.

[0024] S13. Distill off the methanol in the reaction solution obtained in S12, and then add ethyl acetate for reflux reaction;

[0025] S14. Dry the ethyl acetate in the reaction solution obtained from S13 to obtain solid α-amino-ε-caprolactam.

[0026] To achieve the above-mentioned objective, the second technical solution provided by the present invention is: to prepare α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole using the preparation method of the α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole.

[0027] The present invention has the following beneficial effects:

[0028] 1. The present invention simplifies the post-treatment steps, reduces the complexity and time consumption of the operation, and improves the preparation efficiency by using a static-recrystallization method to post-treat α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole.

[0029] 2. The 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam prepared by this invention has a high overall yield (up to 95%) and mild reaction conditions.

[0030] 3. This invention uses a static settling process instead of the multiple extractions and washing steps in existing technologies, thus reducing reagent consumption. Compared to the complex post-processing steps in existing technologies, this invention only requires necessary solvents and catalysts, reducing reagent consumption. All reagents used are readily available and inexpensive industrial products, resulting in low production costs and an environmentally friendly approach, making it promising for industrial production.

[0031] 4. The 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam prepared by the method provided in this invention can be used to further prepare poly(ε-lysine), which is beneficial to promoting the industrial application of poly(ε-lysine) chemical synthesis. Attached Figure Description

[0032] Figure 1 The α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole obtained in Example 1 of this invention in deuterated chloroform 1 H NMR spectrum. Detailed Implementation

[0033] The following embodiments are provided merely to illustrate the invention and are not intended to limit the scope of protection defined by the appended claims. The embodiments of the invention described below are generally only some, not all, of the embodiments of the invention. Therefore, all other embodiments obtained by those skilled in the art based on the embodiments of the invention without inventive effort should fall within the scope of protection of the invention.

[0034] This invention can be implemented using any α-amino-ε-caprolactam. To provide the fullest possible disclosure, the preparation methods of the α-amino-ε-caprolactam used in Examples 1-9 are described in detail below:

[0035] S11. Dissolve 2245g of lysine hydrochloride in methanol, add concentrated sulfuric acid dropwise at room temperature, react for 3 hours, and then reflux for 8 hours; the amount of methanol used is sufficient to dissolve the lysine hydrochloride, and the amount of concentrated sulfuric acid used is added dropwise until the lysine hydrochloride dissolves.

[0036] S12. Transfer the reaction solution obtained in step S11 to a large reactor, and add 20 times the amount of methanol used in step S11. Then dissolve NaOH in methanol and add it dropwise to react for 12 hours. After that, distill off the methanol, and then add ethyl acetate to reflux for 5 hours. The amount of ethyl acetate used is 10 times the amount of methanol used in step S11. The concentration of NaOH is 7 mol / L.

[0037] S13. The product obtained in step 12 was recrystallized with ethyl acetate to obtain 1023g of α-amino-ε-caprolactam, with a yield of 65%.

[0038] Unless otherwise specified, all other reagents used in Examples 1-9 are commercially available reagents that can be purchased directly.

[0039] The freezing recrystallization temperature described in Examples 1-9 was -20°C and the time was 12 hours.

[0040] Example 1

[0041] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0042] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it by heating at 90℃ in a 2L round-bottom flask containing 1.5L of toluene solvent. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water, and react for 6h to obtain the first product.

[0043] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0044] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 1.

[0045] Example 1 yielded 95%.

[0046] Example 2

[0047] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0048] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it in a 2L round-bottom flask containing 1.5L of toluene solvent at 90℃. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 140℃ for 6 hours to obtain the first product.

[0049] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0050] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 2.

[0051] Example 2 yielded 90%.

[0052] Example 3

[0053] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0054] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it at 90℃ in a 2L round-bottom flask containing 1.5L of dioxane solvent. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the dioxane at 110℃ to remove water, and react for 6h to obtain the first product.

[0055] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill 1 L of dioxane from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0056] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 3.

[0057] Example 3 yielded 85%.

[0058] Example 4

[0059] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0060] S1. Weigh 48g of α-amino-ε-caprolactam and dissolve it by heating at 90℃ in a 2L round-bottom flask containing 1.5L of toluene solvent. Then add 40.5ml of 2,5-hexanedione and 7.1g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water, and react for 6h to obtain the first product.

[0061] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0062] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 4.

[0063] Example 4 yielded 91%.

[0064] Example 5

[0065] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0066] S1. Weigh 192g of α-amino-ε-caprolactam and dissolve it by heating at 90℃ in a 2L round-bottom flask containing 1.5L of toluene solvent. Then add 162ml of 2,5-hexanedione and 28.4g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water, and react for 6h to obtain the first product.

[0067] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0068] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 5.

[0069] Example 5 yielded 87%.

[0070] Example 6

[0071] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0072] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it in a 2L round-bottom flask containing 1.5L of toluene solvent at 90℃. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water, and react for 9h to obtain the first product.

[0073] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0074] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 6.

[0075] Example 6 yielded 88%.

[0076] Example 7

[0077] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0078] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it in a 2L round-bottom flask containing 1.5L of toluene solvent at 90℃. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water and react for 4h to obtain the first product.

[0079] S2. Allow the first product to stand for 12 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0080] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 7.

[0081] Example 7 yielded 80%.

[0082] Example 8

[0083] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0084] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it by heating at 90℃ in a 2L round-bottom flask containing 1.5L of toluene solvent. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water, and react for 6h to obtain the first product.

[0085] S2. Allow the first product to stand for 6 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0086] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 8.

[0087] Example 8 yielded 94%.

[0088] Example 9

[0089] Firstly, a method for preparing α-amino-ε-caprolactam protected by 2,5-dimethylpyrrole is provided, comprising the following steps:

[0090] S1. Weigh 96g of α-amino-ε-caprolactam and dissolve it by heating at 90℃ in a 2L round-bottom flask containing 1.5L of toluene solvent. Then add 81ml of 2,5-hexanedione and 14.2g of p-toluenesulfonic acid monohydrate. Reflux the mixture with toluene at 125℃ to remove water, and react for 6h to obtain the first product.

[0091] S2. Allow the first product to stand for 16 hours to allow impurities to settle to the bottom of the flask. Remove the impurities from the bottom using a separatory funnel. Distill off 1 L of toluene from the supernatant using a rotary evaporator. Recrystallize the remaining liquid by freezing to obtain a solid-liquid mixture, which is the second product.

[0092] S3. The second product is filtered, and the resulting solid is dried in a vacuum oven to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam obtained in Example 9.

[0093] Example 9 yielded 95%.

[0094] 2,5-Dimethylpyrrole-protected α-amino-ε-caprolactam prepared according to Examples 1-9 in deuterated chloroform 1 The HNMR spectra showed no significant differences. Taking Example 1 as an example, its spectrum is shown in the attached figure. Figure 1 , 1 H NMR (300MHz CDCl3) δ7.14(s,1H),6.01(s,2H),5.02-5.06(t,1H),3.50-3.52(t,2H),2.54-2.37(m,6H),1.65-2.13(m,6H).

[0095] As can be seen, the yields of 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam prepared in Examples 1-9 reached 80-95%, and the standing time was not a major factor affecting the yield when the product was allowed to stand for more than 12 hours. The preparation method provided by this invention is applicable to a wide range of reaction conditions. Compared with the prior art involving operations such as rotary evaporation, dissolution, washing, extraction, liquid-liquid separation, combining organic phases, drying, solvent concentration, and column chromatography purification of the first product, this invention provides a simple and economical preparation method with a high yield.

[0096] Example 10

[0097] First, a method for preparing poly(ε-lysine) is provided, comprising the following steps:

[0098] S4. Dry a 50ml single-necked flask, add 1g of 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam prepared in Example 1, add 1mg of elemental Na, evacuate to purge with nitrogen three times, and react at 300℃ for 0.5h under nitrogen protection. After the reaction is complete, allow the reaction solution to cool to room temperature, and precipitate with dimethylformamide (DMF) and water to obtain poly(2,5-dimethylpyrrole-protected α-amino-ε-lysine).

[0099] S5. Take a 500ml three-necked flask and add 0.75g of α-amino-ε-lysine protected by poly-2,5-dimethylpyrrole. Dissolve in 300ml of dioxane, then add 5.02g of hydroxylamine hydrochloride in 120ml of aqueous solution. Vacuum the mixture three times to purge with nitrogen, then add 5.15ml of triethylamine. Heat to 110℃ and reflux for 30 days. The resulting yellow solution is concentrated, freeze-dried, and 5ml of water is added to remove inorganic salts. After centrifugation and drying again, 0.35g of a yellow solid is obtained, with a yield of 76%.

[0100] It can be seen that the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam provided by the present invention can be used to prepare poly(ε-lysine) with a relatively ideal yield.

Claims

1. A process for the preparation of 2,5-dimethylpyrrole protected α-amino-ε- caprolactam, characterized in that, The method comprises the following steps: S1. dissolving α-amino-ε-caprolactam in its solvent, adding a catalyst and 2,5-hexanedione, heating to reflux to obtain a first product; S2. standing the first product until the liquid and impurities are layered, taking the liquid, concentrating and cooling to crystallize to obtain a second product; S3. filtering and drying the second product to obtain 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam; In the step S1, the solvent is toluene, the catalyst is p-toluenesulfonic acid, and the heating temperature is 125°C, and the heating time is 6 hours; In the step S2, the cooling temperature is -128~5°C, and the cooling time is 8~16h. In the step S1, the amount of the catalyst added is adjusted to less than or equal to 5.

5.

2. The production method according to claim 1, characterized by, In the step S1, the molar ratio of α-amino-ε-caprolactam to 2,5-hexanedione is 1: (0.8~1.1).

3. The preparation method according to claim 1, characterized in that, In the step S1, the concentration of α-amino-ε-caprolactam is 0.1~1mol / L.

4. The production method according to claim 1, characterized by, In the step S2, the standing time is 3~16h.

5. The method of claim 1, wherein, In the step S2, the mass of the solvent removed by concentration is 30~80% of the mass of the solvent used in the step S1.

6. The method of claim 1, wherein, The method comprises using the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam prepared by the method of any one of claims 1-6 to prepare 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam.

7. A process for the preparation of poly(ε-lysine) characterized in that, The method comprises using the 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam prepared by the method of any one of claims 1-6 to prepare 2,5-dimethylpyrrole-protected α-amino-ε-caprolactam.

Images