A process for the preparation of (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propanoic acid

Abstract

The application discloses a preparation method of (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propanoic acid and belongs to the technical field of organic synthesis. The application adopts an oxazole ring as a raw material, removes a proton under the action of a deprotonating agent under low-temperature conditions, is then complexed with CuBr-Me2S under the catalysis of potassium iodide to form a stable copper lithium complex, then is reacted with N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester, and finally is removed of a methyl group under the action of lithium hydroxide to generate (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propanoic acid. The route improves product yield, is simple and efficient, product separation and purification are simple, and is suitable for industrial amplification conditions.

Description

Technical Field

[0001] This invention relates to a method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid, belonging to the field of organic synthesis technology. Background Technology

[0002] Oxazole rings (1,3-oxonium heterocycles) are an important class of building blocks for pharmaceuticals and materials. Pure oxazole ring monomers are rarely used directly as end products due to their weak stability and high reactivity. Their core value lies in the irreplaceable role of their derivative structural units in drug design and functional materials.

[0003] Amino acids containing oxazole rings possess unique structural characteristics and have wide applications. They serve as building blocks for peptide synthesis: as protecting amino acid monomers in solid / liquid phase peptide synthesis, they are used to introduce oxazole ring side chains to construct bioactive peptides with special heterocyclic structures (such as enzyme inhibitors and receptor ligand mimics); and as pharmaceutical research intermediates: used to screen or synthesize lead compounds with antitumor, antibacterial, and neuromodulatory activities (oxazole rings are commonly found in drug molecules and can enhance metabolic stability and target binding affinity).

[0004] A review of existing literature revealed few reports on the synthesis of (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid. The main method reported is as follows: using 2-bromooxazole as a starting material, it is coupled with (R)-2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxopropyl zinc iodide under palladium catalysis (configuration inversion), followed by removal of the methyl group to generate (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid [WO2024 / 54603A1].

[0005] Currently, the lack of an efficient and convenient synthetic method for (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid limits its application and promotion. Therefore, developing a simple and high-yield synthetic method is of significant practical importance. Summary of the Invention

[0006] The purpose of this invention is to provide a method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid in high yield.

[0007] To achieve the above objectives, this invention uses an oxazole ring as a raw material. Under low temperature conditions, the ring is deprotonated by a deprotonating agent, and then complexed with CuBr-Me2S under potassium iodide catalysis to form a stable copper-lithium complex. This complex then reacts with N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester to generate (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate methyl ester. Finally, the methyl group is removed under lithium hydroxide to generate (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid.

[0008] The synthetic route for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid according to the present invention is as follows:

[0009] Includes the following steps: A. The oxazole ring is mixed in THF. Under low temperature conditions, a deprotonating agent is slowly added, followed by CuBr-Me2S and potassium iodide. After complexation is complete, N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester is added to generate (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate methyl ester.

[0010] B. Methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate and lithium hydroxide are mixed in a solvent and reacted at room temperature to produce (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid.

[0011] In a preferred embodiment, in the above technical solution, in step A, the low temperature condition is -20°C to -78°C; the organic solvent is selected from tetrahydrofuran or 2-methyltetrahydrofuran.

[0012] In a preferred embodiment, in the above technical solution, in step A, the deprotonating agent is selected from n-butyllithium, LDA, isopropyl magnesium bromide, or isopropyl magnesium chloride.

[0013] In a preferred embodiment of the above technical solution, in step A, the molar ratio of the oxazole ring, deprotonating reagent, CuBr-Me2S, potassium iodide, and N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester is 1:1-1.1:1-1.1:0.05-0.15:1-1.2. After screening and optimization, it was found that the addition of the deprotonating reagent to the oxazole ring directly reacts with N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester, producing a product, but the yield is relatively low. The presumed reason is that under strongly alkaline conditions, N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester undergoes the removal of the -OTs group to form an olefin, thus reducing the yield.

[0014] In a preferred embodiment, in the above technical solution, in step B, the solvent is a mixture of THF and water.

[0015] In a preferred embodiment, in the above technical solution, in step B, the molar ratio of (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate to lithium hydroxide is 1:0.9-1.1.

[0016] Beneficial effects of the invention

[0017] 1. This invention uses readily available oxazole rings as raw materials, which are then complexed with CuBr-Me2S under the action of a deprotonating reagent and subsequently under the catalysis of potassium iodide to form a stable copper-lithium complex, greatly reducing the generation of by-product olefins. The route is simple and efficient.

[0018] 2. This invention uses lithium hydroxide to remove the methyl group from methyl esters. The reaction conditions are mild, the efficiency is high, and the operation is simple.

[0019] 3. The reaction system of this invention has good process stability and is easy to implement industrially. Specific Implementation

[0020] Although the present invention has been described in detail by way of preferred embodiments, the present invention is not limited thereto. Various equivalent modifications or substitutions can be made to the embodiments of the present invention by those skilled in the art without departing from the spirit and essence of the invention, and such modifications or substitutions should all be within the scope of the present invention. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should also be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be determined by the scope of the claims.

[0021] Example 1

[0022] Under nitrogen protection, 0.2 mol (13.8 g) of oxazole ring was mixed in 120 mL of THF solvent. The mixture was cooled to -60 °C, and 100 mL of n-BuLi (2 M THF solution) was slowly added. After the addition was complete, the mixture was stirred for 30 min. Then, 0.22 mol (82.2 g) of N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester was added, and the reaction was allowed to proceed for 2 hours. The mixture was then quenched with 50 mL of saturated ammonium chloride aqueous solution, heated to room temperature, and extracted twice with 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated (the residue...). 1Quantitative analysis using external standard HNMR showed that the molar ratio of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate to byproduct was 1.3:1.

[0023] Example 2

[0024] Under nitrogen protection, 0.2 mol (13.8 g) of oxazole ring was mixed in 120 mL of THF solvent. The mixture was cooled to -40 °C, and 100 mL of LDA (2 M THF and n-hexane solution) was slowly added. After the addition was complete, the mixture was stirred for 1 hour. Then, 0.22 mol (82.2 g) of N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester was added, and the reaction was allowed to proceed for 4 hours. The reaction was quenched with 50 mL of saturated ammonium chloride aqueous solution, and the mixture was heated to room temperature. The mixture was extracted twice with 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated (the residue...). 1 Quantitative detection by external standard using ¹H NMR showed that the molar ratio of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate to byproduct was 1.1:1.

[0025] Example 3

[0026] Under nitrogen protection, 0.2 mol (13.8 g) of oxazole ring was mixed in 120 mL of THF solvent. The mixture was cooled to -20 °C, and 100 mL of Grignard reagent (2 M THF solution) of isopropyl magnesium bromide was slowly added. After the addition was complete, the mixture was stirred for 2 hours. Then, 0.22 mol (82.2 g) of N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester was added, and the reaction was allowed to proceed for 7 hours. The reaction was quenched with 50 mL of saturated ammonium chloride aqueous solution, and the mixture was heated to room temperature. The mixture was extracted twice with 100 mL of ethyl acetate. The combined organic layers were washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated (the residue...). 1 Quantitative analysis by external standard using HNMR showed that the conversion rate of methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate was 31%.

[0027] Example 4

[0028] Under nitrogen protection, 0.2 mol (13.8 g) of oxazole ring was mixed in 120 mL of THF solvent. The mixture was cooled to -60 °C, and 100 mL of n-BuLi (2 M THF solution) was slowly added. After the addition was complete, the mixture was stirred for 30 min. Subsequently, 0.2 mol (41.1 g) of CuBr-Me₂S was added. The mixture was heated to -20°C and stirred for 1 hour. After complexation, N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (0.22 mol, 82.2 g) was added and reacted for 5 hours. The mixture was then quenched with 50 mL of saturated ammonium chloride aqueous solution and heated to room temperature. The mixture was extracted twice with 100 mL of ethyl acetate, and the organic layers were combined and washed with 100 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated, and then distilled under reduced pressure to produce methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate, 48.7 g, yield 90%, GC content 99.2%. 1 HNMR (400 MHz, CDCl3): 7.92 (s, 1H), 7.12 (d, 1H), 7.08 (s, 1H), 4.38-4.34 (m, 1H), 3.66 (s, 3H), 3.19-3.16 (m, 1H), 3.08-3.03 (m, 1H), 1.33 (s, 9H).

[0029] Example 5

[0030]

[0031] Under nitrogen protection, 0.2 mol (13.8 g) of oxazole ring was mixed in 220 mL of THF solvent. The mixture was cooled to -40 °C, and 100 mL of LDA (2 M THF and n-hexane solution) was slowly added. After the addition was complete, the mixture was stirred for 1 hour. Subsequently, 0.2 mol (41.1 g) of CuBr-Me₂S was added. The mixture was heated to -20°C and mechanically stirred rapidly for 1 hour. After complexation, N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester (0.22 mol, 82.2 g) was added, and the reaction was carried out for 7 hours. The mixture was then quenched with 50 mL of saturated ammonium chloride aqueous solution, heated to room temperature, and extracted twice with 100 mL of ethyl acetate. The organic layers were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and then distilled under reduced pressure to produce methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate, 45.9 g, yield 85%, GC content 98.8%.

[0032] Example 6

[0033] Under nitrogen protection, methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate (0.1 mol, 27 g) and lithium hydroxide (0.1 mol, 2.4 g) were mixed in 120 mL of THF and 20 mL of water. The mixture was reacted at room temperature for 10 hours. The THF was concentrated under reduced pressure, and then 50 mL of water was added. The mixture was cooled to 0 °C, and 1 M HCl solution was added to adjust the pH to 5-6. The solid precipitated, and the mixture was filtered. The product was slurried with 100 mL of n-hexane for 1 hour, filtered, and dried to yield 25.1 g of (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid, with a yield of 98% and an HPLC purity of 99%. 1 HNMR (400MHz, DMSO- d 6): 12.72 (s, 1H), 7.98 (s, 1H), 7.14 (d, 1H), 7.09 (s, 1H), 4.37-4.35 (m, 1H), 3.19-3.16 (m, 1H), 3.07-3.04 (m, 1H), 1.33 (s, 9H).

[0034] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid, characterized in that, Includes the following steps: ； A. Mix the oxazole ring in an organic solvent, slowly add a deprotonating agent under low temperature conditions, then add CuBr-Me2S and potassium iodide. After complexation is complete, add N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester to generate (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate methyl ester; B. Methyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate and lithium hydroxide are mixed in a solvent and reacted at room temperature to produce (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid.

2. The method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid according to claim 1, characterized in that: In step A, the low temperature condition is -20°C to -78°C.

3. The method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid according to claim 1, characterized in that: In step A, the deprotonating agent is selected from n-butyllithium, LDA, isopropyl magnesium bromide, or isopropyl magnesium chloride.

4. The method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid according to claim 1, characterized in that: In step A, the molar ratio of the oxazole ring, deprotonating reagent, CuBr-Me2S, potassium iodide, and N-(tert-butoxycarbonyl)-O-toluenesulfonyl-L-serine methyl ester is 1:1-1.1:1-1.1:0.05-0.15:1-1.

2.

5. The method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid according to claim 1, characterized in that: In step B, the solvent is a mixture of tetrahydrofuran and water.

6. The method for preparing (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionic acid according to claim 1, characterized in that: In step B, the molar ratio of (2S)-2-((tert-butoxycarbonyl)amino)-3-(oxazol-2-yl)propionate to lithium hydroxide is 1:0.9-1.1.

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