阅读说明：本技术 一种n-甲基-d-苏氨酸的合成方法 (Synthesis method of N-methyl-D-threonine ) 是由 徐红岩 马敬祥 于 2021-10-09 设计创作，主要内容包括：本发明涉及一种N-甲基-D-苏氨酸的合成方法。主要解决一种N-甲基-D-苏氨酸合成和放大生产的技术问题。本发明合成方法包括以下步骤：在甲醇溶液中,D-苏氨酸和无水碳酸钾、苯甲醛、甲醇、三乙酰氧基硼氢化钠反应,生成化合物1；在甲醇溶液中,化合物1和多聚甲醛、氰基硼氢化钠反应,生成化合物2；在含有碳酸氢钠的N,N-二甲基甲酰胺溶液中,化合物2和溴化苄发生脂化反应,生成化合物3；在甲醇溶液中,化合物3经过钯炭氢化,同时脱去两个苄基,生成目标化合物4。作为D-苏氨酸的衍生物,N-甲基-D-苏氨酸在合成抗菌肽和治疗癌症、糖尿病等多肽药物研究中越来越受到重视。(The invention relates to a synthetic method of N-methyl-D-threonine. Mainly solves the technical problems of synthesis and scale-up production of N-methyl-D-threonine. The synthesis method comprises the following steps: in a methanol solution, D-threonine reacts with anhydrous potassium carbonate, benzaldehyde, methanol and sodium triacetoxyborohydride to generate a compound 1; reacting the compound 1 with paraformaldehyde and sodium cyanoborohydride in a methanol solution to generate a compound 2; in an N, N-dimethylformamide solution containing sodium bicarbonate, carrying out esterification reaction on the compound 2 and benzyl bromide to generate a compound 3; in a methanol solution, the compound 3 is hydrogenated by palladium-carbon, and two benzyl groups are removed simultaneously to generate a target compound 4. As a derivative of D-threonine, N-methyl-D-threonine has been gaining increasing attention in the synthesis of antibacterial peptides and the research of polypeptide drugs for the treatment of cancer, diabetes, and the like.)

1. A method for synthesizing N-methyl-D-threonine is characterized by comprising the following steps: the method comprises the following steps: step one, in a methanol solution, reacting D-threonine with anhydrous potassium carbonate, benzaldehyde, methanol and sodium triacetoxyborohydride to generate a compound 1; secondly, reacting the compound 1 with paraformaldehyde and sodium cyanoborohydride in a methanol solution to generate a compound 2; thirdly, carrying out esterification reaction on the compound 2 and benzyl bromide in an N, N-dimethylformamide solution containing sodium bicarbonate to generate a compound 3; fourthly, in a methanol solution, hydrogenating the compound 3 by palladium carbon, and simultaneously removing two benzyl groups to generate a target compound 4; the synthesis route is as follows:

。

2. the method for synthesizing N-methyl-D-threonine as claimed in claim 1, wherein the method comprises the following steps: in the first step, sodium triacetoxyborohydride is added as a reducing agent at the end.

3. The method for synthesizing N-methyl-D-threonine as claimed in claim 1, wherein the method comprises the following steps: and step 2, adding sodium cyanoborohydride as a reducing agent finally.

4. The method for synthesizing N-methyl-D-threonine as claimed in claim 1, wherein the method comprises the following steps: and in the third step, stirring and reacting for 24 hours at 30 ℃.

5. The method for synthesizing N-methyl-D-threonine as claimed in claim 1, wherein the method comprises the following steps: and the fourth step, stirring and reacting for 5 hours at room temperature.

Technical Field

The present invention relates to a method for synthesizing N-methyl-D-threonine (CAS: 2812-27-3).

Background

With the increasing maturity of biotechnology and polypeptide synthesis technology, more and more polypeptide drugs are developed and applied clinically. Since the first discovery by swedish scientist g.boman in the world of 1980 of Cecropins, a polypeptide active substance having an antibacterial effect, antibacterial peptides have been extensively and intensively studied. Petriellin A is a cyclic depsipeptide with antifungal effect, the three-dimensional structure of which is determined, and is synthesized by a solid phase. N-methyl-D-threonine has been reported to date as one of the monomers for synthesizing Petriellin A.

Disclosure of Invention

The invention mainly aims to provide a method for synthesizing N-methyl-D-threonine, which mainly solves the technical problem that the prior method for synthesizing N-methyl-D-threonine by amplification is lacked.

The technical scheme of the invention is as follows: the method for synthesizing the N-methyl-D-threonine is characterized by comprising the following steps of: step one, in a methanol solution, reacting D-threonine with anhydrous potassium carbonate, benzaldehyde, methanol and sodium triacetoxyborohydride to generate a compound 1; secondly, reacting the compound 1 with paraformaldehyde and sodium cyanoborohydride in a methanol solution to generate a compound 2; thirdly, carrying out esterification reaction on the compound 2 and benzyl bromide in an N, N-dimethylformamide solution containing sodium bicarbonate to generate a compound 3; fourthly, in a methanol solution, hydrogenating the compound 3 by palladium-carbon, and simultaneously removing two benzyl groups to generate a target compound 4; the synthesis route is as follows:

。

in the first step, sodium triacetoxyborohydride is added as a reducing agent at last; in the step 2, adding cyano sodium borohydride serving as a reducing agent finally; in the third step, stirring and reacting for 24 hours at 30 ℃; and the fourth step, stirring and reacting for 5 hours at room temperature.

The invention has the beneficial effects that: in the research, the invention discovers that in the process of carrying out four-step reaction by using D-threonine, benzaldehyde, sodium triacetoxyborohydride, sodium cyanoborohydride and the like as raw materials, in order to solve the problem of difficult extraction and purification caused by the large water solubility of the intermediate compound 2, compared with sodium bicarbonate, the anhydrous potassium carbonate is adopted in the first step, so that the obtained crude product has high purity and high yield; and in the third step, the compound 2 and benzyl bromide are subjected to esterification reaction, the polarity of the compound 3 is weakened, and the purification and the separation are easy. Compound 3 generated by generating an esterification product is finally hydrogenated by palladium carbon, and two benzyl groups are removed simultaneously, so that a novel method for synthesizing the N-methyl-D-threonine is provided. Compared with the reported method, the intermediate and the target compound avoid the purification of a chromatographic column and are suitable for the scale-up production of the N-methyl-D-threonine.

Detailed Description

Step 1:

d-threonine (20 g, 0.168 mol), anhydrous potassium carbonate (23.2 g, 0.168 mol), benzaldehyde (21.6 g, 0.204 mol) and methanol (400 mL) were added to a 1L four-neck reaction flask, stirred and dissolved, the temperature of the oil bath was raised to 30 ℃ for 4 hours, sodium triacetoxyborohydride (84.78 g, 0.40 mol) was added in portions, and the reaction was continued for 16 hours. Suction filtration and oven drying at 50 ℃ gave a white solid, compound 1 (28.77 g, 0.137 mol, 82%). LC-MS (ESI) M/z 210.13 [ M + H [ ]]⁺。

Step 2:

in a 1L four-necked reaction flask, the white solid (28.77 g, 0.137 mol) obtained in the above step was dissolved in methanol (150 mL), and paraformaldehyde (5.1 g, 0.17 mol) was added thereto, followed by stirring at 30 ℃ to effect a reaction. After 6 hours, sodium cyanoborohydride (10.7 g, 0.17 mol) was added and the reaction was continued for 16 hours. The reaction was spun dry to give compound 2 (30.23 g, 0.136 mol, 99%) as an oily liquid. LC-MS (ESI) M/z 224.19 [ M + H [ ]]⁺。

And step 3:

compound 2 (30.23 g, 0.136 mol) obtained in the previous step was dissolved in DMF (250 mL) in a 1L four-necked reaction flask. Sodium bicarbonate (36.8 g, 0.438 mol) was added and benzyl bromide (37.60 g, 0.219 mol) was slowly added dropwise, controlling the temperature below 20 ℃. After the addition was completed, the mixture was stirred at 30 ℃ for 24 hours. After the reaction was complete, 500 mL of water was added, extracted with ethyl acetate (3X 300 mL), the organic phases combined and washed with brine (2X 300 mL). The solvent was removed to give compound 3 (39.17 g, 0.125 mol, 92% in the freezer, as a white solid) as a colorless oily liquid. LC-MS (ESI) M/z 314.22 [ M + H [ ]]⁺。

And 4, step 4:

compound 3 (24 g, 0.077 mol) obtained in the previous step was dissolved in methanol (200 mL) in a 500 mL three-necked flask. Nitrogen was replaced 3 times, and palladium on charcoal (10%, 5 g) was added. The hydrogen gas was used for the substitution 3 times,stirred at room temperature for 5 hours. The palladium on carbon was removed by suction filtration and the filtrate was spin-dried to give the title compound 4 (10.11 g, 0.076 mol, 99%) as a white solid.¹H NMR (400 MHz,CDCl₃) 11.25（br s, 1H），5.42（br s, 1H），4.05-4.12（m, 1H），3.70-3.81（m, 1H），3.52-3.60（br s, 1H），2.16（s, 3H），1.18（d, J = 6.5 Hz, 3H）；LC-MS (ESI): m/z 134.21 [M+H]⁺。