A process for the preparation of L-2,4-diaminobutyric acid dihydrochloride
By using L-homoserine as a raw material and combining steps such as heating and pressurization, acid-binding agent neutralization, esterification and nucleophilic substitution, the preparation process of L-2,4-diaminobutyric acid dihydrochloride has been simplified, solving the problems of complex reaction, high cost and low purity in the existing technology, and realizing efficient and low-cost industrial production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG ACADEMY OF PESTICIDE SCI
- Filing Date
- 2026-02-28
- Publication Date
- 2026-05-19
AI Technical Summary
Existing technologies for preparing L-2,4-diaminobutyric acid dihydrochloride suffer from problems such as complex reaction steps, use of hazardous reagents, high costs, difficulty in separating waste salts, and low product purity.
Using L-homoserine as a raw material, L-2,4-diaminobutyric acid dihydrochloride was prepared by reacting it with a catalyst under heat and pressure, followed by acid-binding agent neutralization, esterification, nucleophilic substitution and hydrolysis. This simplified the reaction process and improved the purification efficiency of the intermediate.
It reduces production costs, simplifies operating procedures, increases product yield, and reduces the generation of waste, making it suitable for large-scale industrial production.
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Figure CN121758308B_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the technical field of organic chemistry, specifically relating to a method for preparing L-2,4-diaminobutyric acid dihydrochloride. Background Technology
[0002] The information disclosed in this background section is intended only to enhance some understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that the information constitutes prior art known to those skilled in the art.
[0003] Ectoine is a water-soluble zwitterionic amino acid derivative discovered in 1985 in halophilic bacteria living in harsh environments. Studies have shown that one molecule of ectoine can complex with 4-5 water molecules, and this water-binding ability can protect cells, proteins, and other biomolecules. Ectoine can penetrate and regulate interfacial stability, thereby increasing the skin's surface water retention and stabilizing the lipid layer. It is widely used in skincare products for moisturizing, sun protection, anti-UV, and anti-aging effects.
[0004] L-2,4-Diaminobutyric acid dihydrochloride is an important intermediate in the synthesis of edodecanin, as well as a pharmacological tool and a potential chiral building block. L-2,4-Diaminobutyric acid has also been used as an internal standard for amino acid analysis. Several methods have been reported in the literature.
[0005] CN201810002838 reports a method for synthesizing the small molecule amino acid derivative ectoine. Using L-acetylasparagine as the starting material, an activated diamide is obtained through ring-closure and protection reactions, which is then reduced with triethylsilane and finally purified by a base ring-opening reaction to obtain L-4-amino-2-acetaminobutyric acid.
[0006] CN201910683022 reports a method for preparing L-2,4-diaminobutyrate salt. Using L-glutamine as a raw material, a Boc-protected reaction is performed under alkaline conditions to obtain N-Boc-L-glutamine, which is then degraded with sodium hypochlorite to obtain crude L-2-N-Boc-4-aminobutyric acid. Finally, under acidic conditions, the protection is removed, followed by desalting with a cation exchange resin, elution with ammonia, pH adjustment with hydrochloric acid, and finally slurrying with ethanol to obtain crude L-2,4-diaminobutyrate salt. This method generates a large amount of waste salt, which is difficult to separate from the product. The desalting with cation exchange resin is costly and inefficient, resulting in low product purity.
[0007] Scheme 1 has a long route, complex reaction and post-processing, and uses the hazardous reagent sodium hydride, resulting in high reaction costs and cumbersome operation, which is not conducive to large-scale application. Scheme 2 generates a large amount of waste salt, and the cost of desalination with cation exchange resin is high and the efficiency is low. It is also difficult to separate the salt from the product, resulting in low product purity. Summary of the Invention
[0008] To address the shortcomings of existing technologies, this invention provides a method for preparing L-2,4-diaminobutyric acid dihydrochloride, using L-homoserine as a raw material. This method is inexpensive and readily available, the intermediates are easy to purify, reducing costs and waste, and achieving a high product yield.
[0009] The technical solution adopted in this invention is as follows:
[0010] This invention provides a method for preparing L-2,4-diaminobutyric acid dihydrochloride, the method comprising the following steps:
[0011] S1: Starting with L-homoserine, it is reacted with concentrated hydrochloric acid under heating and pressure conditions. A catalyst is added, and after the reaction is completed, L-2-amino-4-chlorobutyrate salt is obtained by crystallization and filtration.
[0012] S2: Dissolve the L-2-amino-4-chlorobutyrate salt obtained in step S1 in water, neutralize it with an acid-binding agent, and react it with ethyl chloroformate. After the reaction is completed, extract the solution to obtain N-ethoxycarbonyl-L-4-chlorobutyric acid.
[0013] S3: The solution of N-ethoxycarbonyl-L-4-chlorobutyric acid obtained in step S2 is subjected to esterification reaction with ethanol under acid catalysis. After the reaction is completed, the solvent is removed to obtain N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester.
[0014] S4: The N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester obtained in step S3 is reacted with potassium phthalimide in an organic solvent under the catalysis of sodium iodide to carry out a nucleophilic substitution reaction to obtain L-2-[(ethoxycarbonyl)amino]-4-phthalimide ethyl butyrate;
[0015] S5: The L-2-[(ethoxycarbonyl)amino]-4-phthalimide ethyl butyrate obtained in step S4 is subjected to hydrolysis to remove the ethoxycarbonyl and phthalimide protecting groups. The resulting reaction solution is concentrated, crystallized, filtered, and dried to obtain L-2,4-diaminobutyric acid dihydrochloride.
[0016] In one or more embodiments of the present invention, in step S1, the catalyst is a mixture of zinc chloride and ferrous chloride, wherein the mass ratio is (1~2):(1~2), and the amount of the catalyst is 0.5~1.5% of the mass of L-homoserine.
[0017] In one or more embodiments of the present invention, in step S1, the reaction temperature is 90~110°C, the reaction time is 4~6h, and the pressure is 0.4~0.6MPa, preferably 0.5MPa.
[0018] In one or more embodiments of the present invention, in step S1, the mass ratio of L-homoserine to concentrated hydrochloric acid is 1:(1.2~1.8).
[0019] In one or more embodiments of the present invention, in step S1, the mass concentration of the concentrated hydrochloric acid is 36% to 38%.
[0020] In one or more embodiments of the present invention, in step S2, the mass ratio of L-2-amino-4-chlorobutyrate, water, acid-binding agent, and ethyl chloroformate is (75~95):(150~250):(80~120):(50~80).
[0021] In one or more embodiments of the present invention, in step S2, the reaction temperature is 2~8°C and the reaction time is 2~6h.
[0022] In one or more embodiments of the present invention, in step S2, the acid-binding agent is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, and sodium hydroxide; and the solvent used for extraction is any one of ethyl acetate, dichloroethane, and toluene.
[0023] In one or more embodiments of the present invention, in step S3, the mass ratio of the solution of N-ethoxycarbonyl-L-4-chlorobutyric acid, ethanol and acid catalysis is (300~400):(20~60):(2~15).
[0024] In one or more embodiments of the present invention, in step S3, the reaction temperature is 40~80℃ and the reaction time is 2~6h.
[0025] In one or more embodiments of the present invention, in step S3, the acid catalyst is concentrated hydrochloric acid; the mass concentration of the concentrated hydrochloric acid is 36% to 38%.
[0026] In one or more embodiments of the present invention, in step S4, the mass ratio of N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester, potassium phthalimide salt and sodium iodide is (50~70):(50~80):(0.05~0.20).
[0027] In one or more embodiments of the present invention, in step S4, the organic solvent is any one of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone.
[0028] In one or more embodiments of the present invention, the reaction temperature in step S4 is 55~65°C.
[0029] In one or more embodiments of the present invention, in step S4, after the nucleophilic substitution reaction is completed, water is added dropwise to the reaction solution at 45~55°C to crystallize, and after filtration, a high-purity L-2-[(ethoxycarbonyl)amino]-4-phthalimide ethyl butyrate intermediate is obtained.
[0030] In one or more embodiments of the present invention, in step S5, the hydrolysis reaction is carried out using a hydrochloric acid solution with a mass concentration of 15-25% at reflux temperature, and the amount used is 80-85% of the mass of ethyl L-2-[(ethoxycarbonyl)amino]-4-phthalimide butyrate, preferably 83%.
[0031] In one or more embodiments of the present invention, the reaction time in step S5 is 7 to 12 hours.
[0032] Compared with the related technologies known to the inventors, one of the technical solutions of the present invention has the following beneficial effects:
[0033] This invention uses L-homoserine as a raw material, which is inexpensive and readily available, reducing production costs. The reaction steps are simple, the intermediates are easy to purify, the product yield is high, and there is minimal waste from mother liquor reuse. The method of this invention is simple to operate, convenient to prepare, low in cost, and suitable for large-scale industrial production. Attached Figure Description
[0034] The accompanying drawings, which form part of this specification, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.
[0035] Figure 1 Flowchart of the preparation process of L-2,4-diaminobutyric acid dihydrochloride.
[0036] Figure 2 : 1H NMR spectrum of L-2,4-diaminobutyric acid dihydrochloride. Detailed Implementation
[0037] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
[0038] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the exemplary embodiments of the present invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, and / or combinations thereof.
[0039] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.
[0040] Example 1: As Figure 1 The preparation method of L-2,4-diaminobutyric acid dihydrochloride specifically includes the following steps:
[0041] S1: 60g of L-homoserine (0.5mol) was added to a hydration pressure vessel (0.5 MPa), along with 91.25g of 37% concentrated hydrochloric acid, 0.32g of zinc chloride, and 0.3g of ferrous chloride as catalysts. The mixture was heated to 100℃ and reacted for 5h. Samples were taken for monitoring. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed, and dried to obtain 85.3g (0.475mol) of solid L-2-amino-4-chlorobutyrate salt, with a yield of 95%.
[0042] S2: Add the solid S1 to a 1L reaction flask, then add 200g of water to dissolve it. Cool to 5℃ and stir. Add 100g of sodium bicarbonate, then add 60g of ethyl chloroformate dropwise. After the addition is complete, keep the reaction at 5℃ for 3h. Take a sample to track the reaction. After the reaction is complete, add 230g of dichloroethane. Heat to room temperature and stir to dissolve the solid. Let it stand to separate the layers. The lower layer yields 310.14g of N-ethoxycarbonyl-L-4-chlorobutyric acid solution (0.45mol, quantitative content 30.18%, yield 94%).
[0043] S3: Add the N-ethoxycarbonyl-L-4-chlorobutanine solution from the S2 reaction to a 500ml reaction flask, add 31g of ethanol, then add 5g of 37% concentrated hydrochloric acid, heat to 50℃ and react for 3h, take samples for monitoring, after the reaction is completed, first remove the solvent under normal pressure to recover the solvent, then remove the solvent under reduced pressure to dichloroethane, to obtain 105.2g of N-ethoxycarbonyl-L-4-chlorobutanine ethyl ester, yield 97.7%.
[0044] S4: Add 60.39 g (0.25 mol) of N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester to a 500 ml reaction flask, dissolve it in 125 g of DMF, add 0.1 g of sodium iodide as a catalyst, and then add 60.2 g (0.325 mol) of potassium phthalimide. Heat to 60 °C and stir to react. The gas phase is monitored to ensure complete reaction.
[0045] S5: Cool to room temperature, filter, wash, add 200g of water dropwise to the filtrate at 50℃, precipitating a large amount of solid, then cool to room temperature for crystallization for 3h; filter, wash, add the obtained solid to 250g of 20w / w% hydrochloric acid solution, heat to reflux, control the reflux ratio, react for 8h, and monitor the reaction until completion. After concentration of the reaction solution, crystallize at room temperature, filter, wash, dry, and reuse the mother liquor to obtain 40.2g of crude L-2,4-diaminobutyric acid dihydrochloride, yield 80% (S4-S5). The 1H NMR spectrum is shown below. Figure 2 .
[0046] Example 2: S1: 150g of L-homoserine (1.25mol) was added to a hydration pressure vessel (0.5 MPa), along with 228.13g of 37% concentrated hydrochloric acid, 1g of zinc chloride, and 0.8g of ferrous chloride as catalysts. The mixture was heated to 100℃ and reacted for 5h. Samples were taken for monitoring. After the reaction was completed, the mixture was cooled to room temperature, filtered, washed, and dried to obtain 215.33g (1.19mol) of solid L-2-amino-4-chlorobutyrate salt, with a yield of 96%.
[0047] S2: Add the solid S1 to a 2L reaction flask, then add 500g of water to dissolve it. Cool to 5℃ and stir. Add 250g of sodium bicarbonate, then add 150g of ethyl chloroformate dropwise. After the addition is complete, keep the reaction at 5℃ for 4 hours and take a sample for monitoring. After the reaction is complete, add 600g of dichloroethane, raise the temperature to room temperature, stir to dissolve, and let stand to separate the layers. The lower layer yields 850.5g of N-ethoxycarbonyl-L-4-chlorobutyric acid solution (1.1mol, quantitative content 27.1%, yield 93%).
[0048] S3: Add the N-ethoxycarbonyl-L-4-chlorobutanine solution from the S2 reaction to a 2L reaction flask, add 80g of ethanol, then add 13g of 37% concentrated hydrochloric acid, heat to 50℃ and react for 4h, take samples for monitoring, after the reaction is completed, first remove the solvent under normal pressure to recover the solvent, then remove the dichloroethane under reduced pressure to obtain 257.44g (1.06mol) of N-ethoxycarbonyl-L-4-chlorobutanine ethyl ester, with a yield of 96.5%.
[0049] S4: Add 241.56 g (1 mol) of N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester to a 2 L reaction flask, dissolve it in 500 g DMF, add 0.4 g sodium iodide as a catalyst, and then add 240.8 g (1.3 mol) of potassium phthalimide. Heat to 60 °C and stir the reaction. The gas phase is monitored to ensure the reaction is complete.
[0050] S5: Cool to room temperature, filter, wash, add 800g of water dropwise to the filtrate at 50℃, precipitating a large amount of solid, then cool to room temperature for crystallization for 5h; filter, wash, add the obtained solid to 1000g of 20% hydrochloric acid solution, heat to reflux, control the reflux ratio, react for 10h, and monitor the reaction until completion. After concentration of the reaction solution, crystallize at room temperature, filter, wash, dry, and reuse the mother liquor to obtain 160.8g of crude L-2,4-diaminobutyric acid dihydrochloride, yield 82% (S4-S5).
[0051] Comparative Example 1: S1: 60g of L-homoserine (0.5mol) and 91.25g of 37% concentrated hydrochloric acid were added to a hydration pressure vessel (0.5 MPa). (1) No catalyst was added / (2) Only 0.62g of zinc chloride (ZnCl2) was added / (3) Only 0.62g of ferrous chloride (FeCl2) was added. The temperature was raised to 100℃ and reacted for 5h. Samples were taken for tracking. After the reaction was completed, the temperature was lowered to room temperature, filtered, washed and dried to obtain solid L-2-amino-4-chlorobutyrate salt.
[0052] S2~S5 are the same as in Example 1.
[0053] (1) Compared with Example 1, the only difference is that in S1, no catalyst was added, and 70.5 g (0.39 mol) of solid L-2-amino-4-chlorobutyrate was obtained, with a yield of 78.5%.
[0054] (2) Compared with Example 1, the only difference is that in S1, only 0.62g of zinc chloride (ZnCl2) was added. 75.3g (0.42mol) of solid L-2-amino-4-chlorobutyrate was obtained, with a yield of 83.86%.
[0055] (3) Compared with Example 1, the only difference is that in S1, only 0.62g of ferrous chloride (FeCl2) was added. 74.5g (0.41mol) of solid L-2-amino-4-chlorobutyrate was obtained, with a yield of 82.97%.
[0056] Comparative Example 2: S1~S3 are the same as in Example 1, except that no nucleophilic reagent is added.
[0057] S4: Add 60.39 g (0.25 mol) of N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester to a 500 ml reaction flask, dissolve it in 125 g of DMF, add 60.2 g (0.325 mol) of potassium phthalimide salt, heat to 60 °C and stir to react. The gas phase is monitored to ensure the reaction is complete.
[0058] S5: Cool to room temperature, filter, wash, add 200g of water dropwise to the filtrate at 50℃, precipitating a large amount of solid, then cool to room temperature for crystallization for 3h; filter, wash, add the obtained solid to 250g of 20w / w% hydrochloric acid solution, heat to reflux, control the reflux ratio, react for 8h, and monitor the reaction until completion. After concentration of the reaction solution, crystallize at room temperature, filter, wash, dry, and reuse the mother liquor to obtain 25.2g of crude L-2,4-diaminobutyric acid dihydrochloride, yield 50.1% (S4-S5).
[0059] Comparative Example 3: S1~S4 are the same as in Example 1, but the crystallization conditions in S5 are different.
[0060] S5: Cool to room temperature, filter, wash, add 200g of water dropwise to the filtrate at room temperature, precipitating a large amount of solid, then cool to 0℃ for 3h to crystallize; filter, wash, add the obtained solid to 250g of 20w / w% hydrochloric acid solution, heat to reflux, control the reflux ratio, react for 8h, and monitor the reaction until completion. After concentration of the reaction solution, crystallize at room temperature, filter, wash, dry, and reuse the mother liquor to obtain 35.2g of crude L-2,4-diaminobutyric acid dihydrochloride, containing many impurities, with a yield of 70.05% (S4-S5).
[0061] Comparative Example 4: S1~S4 are the same as in Example 1, except for the hydrochloric acid equivalent number in the S5 hydrolysis reaction.
[0062] S5: Cool to room temperature, filter, wash, add 200g of water dropwise to the filtrate at 50℃, precipitating a large amount of solid, then cool to room temperature for crystallization for 3h; filter, wash, add the obtained solid to 150g of 20w / w% hydrochloric acid solution, heat to reflux, control the reflux ratio, react for 8h, and monitor the reaction until completion. After concentration of the reaction solution, crystallize at room temperature, filter, wash, dry, and reuse the mother liquor to obtain 35.8g of crude L-2,4-diaminobutyric acid dihydrochloride, yield 71.24% (S4-S5).
[0063] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A method for preparing L-2,4-diaminobutyric acid dihydrochloride, characterized in that, The method includes the following steps: S1: Starting with L-homoserine, it is reacted with concentrated hydrochloric acid under heating and pressure. A catalyst is added, and after the reaction is completed, L-2-amino-4-chlorobutyrate is obtained by crystallization and filtration. The catalyst is a mixture of zinc chloride and ferrous chloride in a mass ratio of (1~2):(1~2), and the amount of catalyst used is 0.5~1.5% of the mass of L-homoserine. The mass ratio of L-homoserine to concentrated hydrochloric acid is 1:(1.2~1.8). The reaction temperature is 90~110℃, the reaction time is 4~6h, and the pressure is 0.4~0.6MPa; S2: Dissolve the L-2-amino-4-chlorobutyrate salt obtained in step S1 in water, neutralize with an acid-binding agent, and react with ethyl chloroformate. After the reaction is completed, extract to obtain a solution of N-ethoxycarbonyl-L-4-chlorobutyric acid. The mass ratio of L-2-amino-4-chlorobutyrate salt, water, acid-binding agent, and ethyl chloroformate is (75~95):(150~250):(80~120):(50~80). The acid-binding agent is any one of sodium carbonate, sodium bicarbonate, potassium carbonate, and sodium hydroxide; the solvent used for extraction is any one of ethyl acetate, dichloroethane, and toluene; the reaction temperature is 2~8℃, and the reaction time is 2~6h; S3: The solution of N-ethoxycarbonyl-L-4-chlorobutyric acid obtained in step S2 is subjected to esterification reaction with ethanol under acid catalysis. After the reaction is completed, the solvent is removed to obtain N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester. S4: The N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester obtained in step S3 is reacted with potassium phthalimide in an organic solvent under the catalysis of sodium iodide to carry out a nucleophilic substitution reaction. After the nucleophilic substitution reaction is completed, water is added dropwise to the reaction solution to crystallize the mixture. After filtration, L-2-[(ethoxycarbonyl)amino]-4-phthalimide butyric acid ethyl ester is obtained. The mass ratio of N-ethoxycarbonyl-L-4-chlorobutyric acid ethyl ester, potassium phthalimide, and sodium iodide is (50~70):(50~80):(0.05~0.20). The organic solvent is any one of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone; The reaction temperature is 55~65℃; S5: The L-2-[(ethoxycarbonyl)amino]-4-phthalimide ethyl butyrate obtained in step S4 is subjected to hydrolysis to remove the ethoxycarbonyl and phthalimide protecting groups. The resulting reaction solution is concentrated, crystallized, filtered, and dried to obtain L-2,4-diaminobutyric acid dihydrochloride.
2. The method for preparing L-2,4-diaminobutyric acid dihydrochloride as described in claim 1, characterized in that, In step S3, the mass ratio of the solution of N-ethoxycarbonyl-L-4-chlorobutyric acid, ethanol, and acid catalysis is (300~400):(20~60):(2~15). The acid catalyst is concentrated hydrochloric acid; The reaction temperature is 40~80℃, and the reaction time is 2~6h.
3. The method for preparing L-2,4-diaminobutyric acid dihydrochloride as described in claim 1, characterized in that, In step S5, the hydrolysis reaction is carried out using a hydrochloric acid solution with a mass concentration of 15-25% at reflux temperature, and the amount used is 80-85% of the mass of ethyl L-2-[(ethoxycarbonyl)amino]-4-phthalimide butyrate.
4. The method for preparing L-2,4-diaminobutyric acid dihydrochloride as described in claim 1, characterized in that, In step S5, the reaction time is 7~12h.