A method for synthesizing D-2,3-diaminopropionic acid

Abstract

This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing D-2,3-diaminopropionic acid. The method includes first reacting D-Boc asparagine and sodium hypohalate in a solvent to obtain an intermediate solution; then adjusting the pH of the intermediate solution to 4-8, removing the solvent to obtain a solid; finally, reacting the solid with acid and purifying it to obtain the final product; wherein the solvent in step (1) is a sodium hydroxide solution. This invention ensures a rapid and complete reaction by controlling the temperature and time of the reaction process; and by adding concentrated hydrochloric acid in stages, it can obtain the deprotected target product in high yield. The method of this invention avoids the use of expensive iodine reagents, uses inexpensive and readily available raw materials, has a high overall reaction yield, low cost, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of compound synthesis, specifically relating to a method for synthesizing D-2,3-diaminopropionic acid. Background Technology

[0002] D-2,3-diaminopropionic acid has the following structure: As a non-natural amino acid, it has a wide range of applications, such as the synthesis of Merck's novel cholesterol-lowering drug MK0616 and the synthesis of the hemostatic compound D-glucan.

[0003] Several synthetic methods for 2,3-diaminopropionic acid have been reported. For example, 2,3-diaminopropionic acid was obtained from aspartic acid via the Schmidt reaction. Upender K. Nadir et al. also obtained 2,3-diaminopropionic acid from azacyclopropane derivative and (R)-(+)-α-methylbenzyl isocyanate through ring-opening, reduction, and acidification steps. Vicente Gotor et al. also obtained 2,3-diaminopropionic acid from azacyclopropane derivative as a starting material through ring-opening, hydrogenation reduction, amine group protection, and acidification steps (see synthetic route 1).

[0004]

[0005] The method disclosed in Chinese patent CN109180532B uses D-serine as a raw material to first synthesize D-Boc-serine, and then esterifies it with methanesulfonyl chloride in the presence of an acid-binding agent. The Boc-D-serine methanesulfonate undergoes an ammonolysis reaction to generate N-α-Boc-D-α,β-diaminopropionic acid (see synthetic route 2).

[0006]

[0007] Chinese patent CN113754551A discloses a method of adding laccase solution to a weakly acidic solution at room temperature, then adding tryptophan and phenol under stirring and reacting for 2-4 hours to obtain diaminopropionic acid (see synthetic route 3).

[0008]

[0009] The methods disclosed above have problems such as harsh reaction conditions, difficulty in obtaining starting materials, and complicated synthetic routes, making it difficult to achieve large-scale preparation of diaminopropionic acid.

[0010] The preparation of diaminopropionic acid via Hoffmann degradation is a simple method. For example, Chinese patent CN105439883A discloses a method using D-asparagine monohydrate as a raw material, reacting it with 9-fluorenylmethyl-N-succinimide carbonate to obtain an intermediate, which then undergoes degradation under the action of [bis(trifluoroacetoxy)iodo]benzene for 60 hours to obtain Fmoc-D-2,3-diaminopropionic acid. Finally, it is deprotected under the action of diethylamine to obtain D-2,3-diaminopropionic acid. Chinese patent CN102234240B discloses the Hoffmann degradation of L-benzyloxycarbonyl asparagine under the action of diacetyliodobenzene to obtain Cbz-D-2,3-diaminopropionic acid, with a reaction time of 12 hours (see synthetic route 4).

[0011]

[0012] Existing methods for preparing 2,3-diaminopropionic acid using the Hoffmann degradation reaction all use expensive iodine reagents as raw materials, resulting in high costs and generally long reaction times, which makes industrial implementation difficult. Summary of the Invention

[0013] This invention addresses the problems existing in the prior art by providing a method for synthesizing D-2,3-diaminopropionic acid. The method uses readily available raw materials, has low cost, short reaction time, high yield, and is suitable for industrial production.

[0014] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0015] A method for synthesizing D-2,3-diaminopropionic acid, comprising the following steps:

[0016] (1) Reaction of D-Boc asparagine and sodium hypohalite in a solvent yields an intermediate solution;

[0017] (2) Add acid to the intermediate solution to remove the solvent and obtain a solid;

[0018] (3) React the solid with acid to obtain the product;

[0019] Furthermore, in step (1), the solvent is a sodium hydroxide solution.

[0020] Further, the sodium hypohalite mentioned in step (1) is sodium hypochlorite or sodium hypobromite.

[0021] Further, the molar ratio of D-Boc asparagine to sodium hypohalite in step (1) is 1:1.05-1.5.

[0022] Further, step (1) involves mixing D-Boc asparagine with a solvent, then adding sodium hypohalite solution dropwise at a temperature controlled at -5 to -5℃ until the reaction is complete.

[0023] Furthermore, the temperature of the reaction in step (1) is 0-50℃, and the reaction time is 1-5 hours.

[0024] Further, the reaction described in step (1) is to first react at 0-30℃ for 1-3 hours, and then raise the temperature to 30-50℃ for 1-3 hours.

[0025] Further, the reaction described in step (1) is to first react at 20-30℃ for 1-2 hours, and then raise the temperature to 40-50℃ for 1-2 hours.

[0026] Further, in step (2), the temperature of the intermediate solution is lowered to -5 to -5°C, the acid is concentrated hydrochloric acid, the pH is adjusted to 4 to 8 after adding the acid, and the mass of the added concentrated hydrochloric acid is 1.05 to 1.5 times the mass of D-Boc aspartic acid.

[0027] Further, the acid mentioned in step (3) is concentrated hydrochloric acid, hydrobromic acid or trifluoroacetic acid.

[0028] Furthermore, the acid mentioned in step (3) is concentrated hydrochloric acid.

[0029] Furthermore, the molar ratio of the acid to D-Boc asparagine in step (3) is 5-8:1.

[0030] Furthermore, in step (3), the molar ratio of acid to D-Boc asparagine is 5.8:1.

[0031] Furthermore, the temperature of the reaction in step (3) is 72-105℃, and the reaction is a reflux reaction for 2-10 hours.

[0032] Furthermore, the reaction in step (3) also includes a purification step, which includes removing the solvent from the solution after the reaction, dissolving it, crystallizing it, filtering it, and drying it to obtain the final product.

[0033] Furthermore, the dissolution is carried out by adding water, and the crystallization is carried out by adding ethanol or acetone dropwise at 20-50°C to precipitate a solid, then cooling to -5-5°C and holding at that temperature for 0.5-2 hours.

[0034] The reaction route of this invention is as follows:

[0035]

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] The method for synthesizing D-2,3-diaminopropionic acid provided by this invention uses readily available raw materials, has low cost, short reaction time, high yield, and is suitable for industrial production. Detailed Implementation

[0038] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention. In addition, it is worth noting that the raw materials involved in the present invention are all commercially available products unless otherwise specified.

[0039] Example 1

[0040] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, heat to 25℃ and maintain the temperature for 1 hour. Then heat to 50℃ and stir to react, maintaining the temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid, adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 100g of concentrated hydrochloric acid, stir and heat to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, heat to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and maintain the temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 20.6g of product (hydrochloride), with a yield of 85%.

[0041] Example 2

[0042] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, heat to 25℃ and maintain the temperature for 1 hour. Then heat to 50℃ and stir to react, maintaining the temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid, adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 100g of concentrated hydrochloric acid, stir and heat to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, heat to 50℃, add 100ml of acetone, and a solid precipitates. Cool to 0℃ and maintain the temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 19.1g of product (hydrochloride), with a yield of 79%.

[0043] Example 3

[0044] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 266g of sodium hypobromite solution (10%) (freshly prepared with bromine and sodium hydroxide solution). After the addition is complete, raise the temperature to 25℃ and keep it at that temperature for 1 hour. Then raise the temperature to 50℃ and stir to react, keeping it at that temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid, adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 100g of concentrated hydrochloric acid, stir and raise the temperature to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, raise the temperature to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and keep it at that temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 20.1g of product (hydrochloride salt), with a yield of 83%.

[0045] Example 4

[0046] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, raise the temperature to 25℃ and keep it at that temperature for 1 hour. Then raise the temperature to 50℃ and stir to react, keeping it at that temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid to adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 80g of 48% hydrobromic acid, stir and raise the temperature to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, raise the temperature to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and keep it at that temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 26.6g of product (hydrobromide), with a yield of 83.8%.

[0047] Example 5

[0048] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to -5℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, heat to 25℃ and keep at this temperature for 1 hour. Then heat to 50℃ and stir to react, keeping the temperature for 1 hour. After the reaction is complete, cool to 5℃, add 52g of concentrated hydrochloric acid to adjust the pH to 4, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 80g of trifluoroacetic acid, stir and heat to 72℃, and reflux for 10 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, heat to 50℃, add 100ml of ethanol to precipitate a solid, cool to 5℃ and keep at this temperature for 2 hours, filter to obtain a wet product, and dry to obtain 23.2g of product (trifluoroacetate), with a yield of 62%.

[0049] Example 6

[0050] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 5℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, heat to 20℃ and maintain the temperature for 3 hours, then heat to 40℃ and stir to react, maintaining the temperature for 2 hours. After the reaction is complete, cool to -5℃, add 40g of concentrated hydrochloric acid, adjust the pH to 8, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 138g of concentrated hydrochloric acid, stir and heat to 90℃ (external temperature), reflux for 2 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, heat to 20℃, add 100ml of ethanol, precipitating a solid. Cool to -5℃ and maintain the temperature for 0.5 hours, filter to obtain a wet product, and dry to obtain 15.8g of product (hydrochloride), yield 65%.

[0051] Comparative Example 1

[0052] Add 40g of D-Boc-asparagine and 276ml of 2.5M potassium carbonate solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, heat to 25℃ and maintain the temperature for 1 hour, then heat to 50℃ and stir to react, maintaining the temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid, adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 100g of concentrated hydrochloric acid, stir and heat to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, heat to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and maintain the temperature for 1 hour, filter to obtain a wet product, and dry to obtain 3.2g of product (hydrochloride), yield 13%.

[0053] Comparative Example 2

[0054] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, raise the temperature to 25℃ and keep it at that temperature for 1 hour. Then raise the temperature to 50℃ and stir to react, and keep it at that temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid, adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 100g of concentrated hydrochloric acid, stir and raise the temperature to 60℃ (external temperature), and keep it at that temperature for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, raise the temperature to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and keep it at that temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 10.5g of product (hydrochloride), with a yield of 43%.

[0055] Comparative Example 3

[0056] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, raise the temperature to 25℃ and keep it at that temperature for 1 hour. Then raise the temperature to 50℃ and stir to react, keeping it at that temperature for 1 hour. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid to adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 140g of 70% phosphoric acid, stir and raise the temperature to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, raise the temperature to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and keep it at that temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 7.2g of product (phosphate), with a yield of 21%.

[0057] Comparative Example 4

[0058] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, heat to 50℃ and stir to react. Maintain the temperature for 2 hours. After the reaction is complete, cool to 0℃, add 49g of concentrated hydrochloric acid, adjust the pH to 5, and evaporate the reaction solvent under reduced pressure to obtain a pale yellow solid. Add 100g of concentrated hydrochloric acid, stir and heat to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure to dryness, add 50ml of water to dissolve, heat to 50℃, add 100ml of ethanol, and a solid precipitates. Cool to 0℃ and maintain the temperature for 1 hour. Filter to obtain a wet product, and dry to obtain 8.7g of product (hydrochloride), with a yield of 36%.

[0059] Comparative Example 5

[0060] Add 40g of D-Boc-asparagine and 276ml of 2.5M sodium hydroxide solution to a four-necked flask, stir to dissolve, cool to 0℃, and slowly add 166g of sodium hypochlorite solution (10%). After the addition is complete, raise the temperature to 25℃ and keep it at that temperature for 1 hour. Then raise the temperature to 50℃ and stir to react, and keep it at that temperature for 1 hour. After the reaction is complete, add 100g of concentrated hydrochloric acid, stir and raise the temperature to 105℃ (external temperature), and reflux for 6 hours. After the reaction is complete, evaporate the solvent under reduced pressure until dry, add 50ml of water to dissolve, raise the temperature to 50℃, add 100ml of ethanol dropwise, and a solid precipitates. Cool to 0℃ and keep it at that temperature for 1 hour. Filter to obtain the wet product, and dry to obtain 13.3g of product (hydrochloride), yield 55%.

[0061] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A method for synthesizing D-2,3-diaminopropionic acid, characterized in that, Includes the following steps: (1) React D-Boc asparagine and sodium hypohalite in a solvent to obtain an intermediate solution; (2) Add acid to the intermediate solution to remove the solvent and obtain a solid; (3) React the solid with acid to obtain, In step (1), D-Boc asparagine is first mixed with sodium hydroxide solution as a solvent, and then sodium hypohalite solution is added dropwise at a temperature controlled at -5-5℃. After the reaction is completed, the reaction temperature in step (1) is 0-50℃ and the reaction time is 1-5 hours. In step (2), the temperature of the intermediate solution is lowered to -5 to -5℃, the acid is concentrated hydrochloric acid, and the pH is adjusted to 4 to -8 after adding the acid; The acid mentioned in step (3) is concentrated hydrochloric acid, hydrobromic acid or trifluoroacetic acid, the reaction temperature is 72-105℃, and the molar ratio of the acid to D-Boc asparagine is 5-8:

1.

2. The synthesis method according to claim 1, characterized in that, The sodium hypohalite mentioned in step (1) is sodium hypochlorite or sodium hypobromite.

3. The synthesis method according to claim 2, characterized in that, The reaction described in step (1) is to first react at 20-30℃ for 1-2 hours, and then raise the temperature to 40-50℃ for 1-2 hours.

4. The synthesis method according to claim 1, characterized in that, The molar ratio of D-Boc asparagine to sodium hypohalite in step (1) is 1:1.05-1.

5.

5. The synthesis method according to claim 1, characterized in that, The mass of concentrated hydrochloric acid added in step (2) is 1.05-1.5 times the mass of D-Boc aspartic acid.

6. The synthesis method according to claim 1, characterized in that, The reaction described in step (3) is a reflux reaction, and the reflux reaction time is 2-10h.

7. The synthesis method according to claim 1, characterized in that, The reaction described in step (3) also includes a purification step, which includes removing the solvent from the solution after the reaction, dissolving it, crystallizing it, filtering it, and drying it to obtain the final product.

8. The synthesis method according to claim 7, characterized in that, The dissolution is carried out by adding water, and the crystallization is carried out by adding ethanol or acetone dropwise at 20-50℃ to precipitate a solid, then cooling to -5-5℃ and keeping it at that temperature for 0.5-2 hours.

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