A method for synthesizing l-glutamic acid-5-tert-butyl ester magnesium salt

Abstract

The application discloses a synthesis method of L-glutamic acid-5-tert-butyl ester magnesium salt, which comprises the following steps: (1) using L-glutamic acid as a starting material, reacting in the presence of an acid catalyst in tert-butyl acetate to obtain L-glutamic acid di-tert-butyl ester; (2) selectively hydrolyzing the L-glutamic acid di-tert-butyl ester obtained in the step (1) in the presence of magnesium sulfate to obtain L-glutamic acid-5-tert-butyl ester magnesium salt. Through the selective hydrolysis reaction mediated by the magnesium salt, the selective retention of the 5-position tert-butyl ester is successfully realized, the reaction selectivity is high, the synthesis process is feasible and controllable; the whole process reaction condition is mild, the operation is simple and safe, the post-treatment is simple, the by-product is easy to remove, the product yield is high (more than 64%) and the product purity is high (greater than 97%), and the method is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application relates to a synthesis method of L-glutamic acid-5-tert-butyl ester magnesium salt and belongs to the technical field of organic synthesis. BACKGROUND

[0002] L-glutamic acid-5-tert-butyl ester magnesium salt is a modified amino acid derivative, which can be used as a key intermediate or building block in polypeptide or protein synthesis, can effectively realize the regional selectivity control of the reaction, and can ensure the high efficiency and accuracy of the synthesis process. The compound has important application value in medical research and development and biochemical research, for example, is used for efficiently and selectively constructing specific polypeptide sequences or proteins containing glutamic acid residues. However, there is no report on the synthesis process of L-glutamic acid-5-tert-butyl ester magnesium salt in the prior art, especially a synthesis method suitable for industrial production. SUMMARY

[0003] In order to solve the above problems, the purpose of the present application is to provide a synthesis method of L-glutamic acid-5-tert-butyl ester magnesium salt, which has mild reaction conditions, simple operation, low cost, high yield and is suitable for large-scale production.

[0004] In order to achieve the above purpose, the technical scheme of the present application is as follows:

[0005] A synthesis method of L-glutamic acid-5-tert-butyl ester magnesium salt, comprising the following steps:

[0006] (1) using L-glutamic acid as a starting material, reacting in the presence of an acidic catalyst in tert-butyl acetate to obtain L-glutamic acid di-tert-butyl ester (denoted as intermediate A).

[0007] The amount of tert-butyl acetate is 8-10 times the volume of the mass of L-glutamic acid.

[0008] The acidic catalyst is a mixed acid of perchloric acid and concentrated sulfuric acid (mass ratio of not less than 98% sulfuric acid aqueous solution), wherein the amount of perchloric acid is 0.8-2 equivalents (based on L-glutamic acid), and the amount of concentrated sulfuric acid is 0.8-2 equivalents (based on L-glutamic acid).

[0009] (2) performing selective hydrolysis reaction on the intermediate A obtained in step (1) in the presence of a magnesium salt to obtain L-glutamic acid-5-tert-butyl ester magnesium salt.

[0010] The magnesium salt is magnesium sulfate, and the amount thereof is 1.0-2.0 equivalents (based on L-glutamic acid); the solvent used in the hydrolysis reaction is one or more of water and ethanol; preferably a mixed solvent of water and ethanol, wherein the amount of ethanol is 0.6-2 times the volume of the mass of L-glutamic acid.

[0011] The reaction route thereof is as follows:

[0012]

[0013] The beneficial effects of the present application are:

[0014] 1. The present application uses inexpensive and readily available L-glutamic acid as a starting material to synthesize intermediate A, avoiding the purchase of more expensive intermediate A, effectively reducing production costs.

[0015] 2. The present application completes two-step reactions by one-pot method, selectively removes a single tert-butyl group through unique conditions to obtain the target compound, has high operation feasibility, and is easy to produce.

[0016] 3. The present application realizes high selectivity retention of 5-tert-butyl ester through magnesium salt mediated selective hydrolysis reaction, has less by-products, and has strong controllability.

[0017] 4. The present application has mild reaction conditions, simple and safe operation, only needs crystallization and filtration for post-treatment, does not need complex purification, by-products are easy to remove, has high product yield (can reach more than 64%), high purity (≥97%), and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0018] The present application will be further described in detail below in combination with the drawings and specific embodiments.

[0019] Figure 1 The product spectrum obtained in Example 1 is shown, and the un-integrated peak is the residual solvent peak.

[0020] Figure 2 The product spectrum obtained in Example 2 is shown, and the un-integrated peak is the residual solvent peak.

[0021] Figure 3 The product spectrum obtained in Example 3 is shown, and the un-integrated peak is the residual solvent peak. DETAILED DESCRIPTION

[0022] In the following implementation, the materials are respectively (name / manufacturer / CAS number):

[0023] L-glutamic acid / Shanghai Haohong Biomedicine Technology Co., Ltd. / 56-86-0; tert-butyl acetate / Shanghai Macklin Biochemical Technology Co., Ltd. / 540-88-5; magnesium sulfate / Shanghai Macklin Biochemical Technology Co., Ltd. / 7487-88-9; ethanol / Shanghai Macklin Biochemical Technology Co., Ltd. / 64-17-5.

[0024] Example 1

[0025] (1) L-glutamic acid (14.7 g, 0.1 mol) and tert-butyl acetate (10 V, 147 mL) were added to a four-necked flask and cooled to 0±5℃ under nitrogen protection. After stirring for 30 minutes, perchloric acid (20.0 g, 0.2 mol) and concentrated sulfuric acid (7.84 g, 0.08 mol) were added sequentially. The reaction was maintained at 0±5℃ for 16 hours, and the reaction progress was monitored by ELSD. When the content of intermediate A was ≥90% and the remaining raw material was ≤2%, sodium hydroxide aqueous solution (80 mL) was added to quench the reaction, and the mixture was stirred at 20±5℃ for 0.5 hours. The pH was adjusted to 4~5 with sodium hydroxide aqueous solution. Then, the tert-butyl acetate was removed by concentration in a water bath at 40℃ to obtain an aqueous solution of intermediate A.

[0026] (2) Add ethanol (0.6 V, 8.8 mL) and magnesium sulfate (18.0 g, 0.15 mol) to the aqueous solution of intermediate A obtained in step (1), add water until the system is clear, and keep the reaction at 50±5℃ for 16 hours. When ELSD monitoring shows that the target compound is ≥90% and intermediate A is ≤2%, cool the reaction system to 0±5℃ to crystallize, keep it at the temperature and stir for 0.5~1 hours, filter, wash the filter cake with water (150 mL), and dry it at room temperature to obtain 15.8 g of white solid (i.e., magnesium salt of L-glutamic acid-5-tert-butyl ester), with a yield of 69.91% and a purity of 99.17% as determined by ELSD (see the chromatogram for details). Figure 1 ).

[0027] Example 2

[0028] (1) Add L-glutamic acid (50 g, 0.34 mol) and tert-butyl acetate (9 V, 450 mL) to a four-necked flask and cool to 0±5℃ under nitrogen protection. After stirring for 30 minutes, add perchloric acid (48.8 g, 0.34 mol) and concentrated sulfuric acid (33.30 g, 0.34 mol) sequentially. Maintain the temperature at 0±5℃ for 16 hours and monitor the reaction progress by ELSD. When the content of intermediate A is ≥90% and the remaining raw material is ≤2%, add sodium hydroxide aqueous solution (100~200 mL) to quench the reaction, stir at 20±5℃ for 0.5 hours, and adjust the pH to 4~5 with sodium hydroxide aqueous solution. Then concentrate in a water bath at 40℃ to remove tert-butyl acetate, and obtain an aqueous solution of intermediate A.

[0029] (2) Add ethanol (1.6 V, 80 mL) and magnesium sulfate (40.8 g, 0.34 mol) to the aqueous solution of intermediate A obtained in step (1), add water until the system is clear, and keep the reaction at 50±5℃ for 16 hours. When ELSD monitoring shows that the target compound is ≥90% and intermediate A is ≤2%, cool the reaction system to 0±5℃ to crystallize, keep it at the temperature and stir for 0.5~1 hours, filter, wash the filter cake with water (400 mL), and dry it at room temperature to obtain 53.8 g of white solid (i.e., magnesium salt of L-glutamic acid-5-tert-butyl ester), with a yield of 70.00% and a purity of 99.93% as determined by ELSD (see the chromatogram). Figure 2 ).

[0030] Example 3

[0031] (1) L-glutamic acid (14.7 g, 0.1 mol) and tert-butyl acetate (8 V, 117.6 mL) were added to a four-necked flask and cooled to 0±5℃ under nitrogen protection. After stirring for 30 minutes, perchloric acid (8.0 g, 0.08 mol) and concentrated sulfuric acid (19.6 g, 0.2 mol) were added sequentially. The reaction was maintained at 0±5℃ for 16 hours, and the reaction progress was monitored by ELSD. When the content of intermediate A was ≥90% and the remaining raw material was ≤2%, sodium hydroxide aqueous solution (80 mL) was added to quench the reaction, and the mixture was stirred at 20±5℃ for 0.5 hours. The pH was adjusted to 4~5 with sodium hydroxide aqueous solution. Then, the tert-butyl acetate was removed by concentration in a water bath at 40℃ to obtain an aqueous solution of intermediate A.

[0032] (2) Add ethanol (2 V, 29.4 mL) and magnesium sulfate (24.0 g, 0.2 mol) to the aqueous solution of intermediate A obtained in step (1), add water until the system is clear, and keep the reaction at 50±5℃ for 16 hours. When ELSD monitoring shows that the target compound is ≥90% and intermediate A is ≤2%, cool the reaction system to 0±5℃ to crystallize, keep it at the temperature and stir for 0.5~1 hours, filter, wash the filter cake with water (150 mL), and dry it at room temperature to obtain 14.5 g of white solid (i.e., magnesium salt of L-glutamic acid-5-tert-butyl ester), with a yield of 64.15% and a purity of 97.84% as determined by ELSD (see the chromatogram). Figure 3 ).

[0033] The above embodiments do not limit the present invention in any way. All technical solutions obtained by equivalent substitution or equivalent transformation fall within the protection scope of the present invention.

Claims

1. A method for synthesizing magnesium salt of L-glutamic acid-5-tert-butyl ester, characterized in that, Includes the following steps: (1) Add 14.7 g of L-glutamic acid and 147 mL of tert-butyl acetate to a four-necked flask and cool to 0±5℃ under nitrogen protection; after stirring for 30 minutes, add 20.0 g of perchloric acid and 7.84 g of concentrated sulfuric acid in sequence; keep the temperature at 0±5℃ and monitor the reaction progress by ELSD; when the content of intermediate A is ≥90% and the raw material is ≤2%, add 80 mL of sodium hydroxide aqueous solution to quench the reaction, stir at 20±5℃ for 0.5 hours, and adjust the pH to 4~5 with sodium hydroxide aqueous solution; then concentrate in a 40℃ water bath to remove tert-butyl acetate and obtain an aqueous solution of intermediate A; (2) Add 8.8 mL of ethanol and 18.0 g of magnesium sulfate to the aqueous solution of intermediate A obtained in step (1), add water until the system is clear, and keep the reaction at 50±5℃. When the ELSD monitoring shows that the target compound is ≥90% and intermediate A is ≤2%, cool the reaction system to 0±5℃ to crystallize, keep it warm and stir for 0.5~1 hours, filter, wash the filter cake with 150 mL of water, and dry it at room temperature to obtain a white solid.

2. A method for synthesizing magnesium salt of L-glutamic acid-5-tert-butyl ester, characterized in that, Includes the following steps: (1) Add 50 g of L-glutamic acid and 450 mL of tert-butyl acetate to a four-necked flask and cool to 0±5℃ under nitrogen protection; after stirring for 30 minutes, add 48.8 g of perchloric acid and 33.30 g of concentrated sulfuric acid in sequence; keep the temperature at 0±5℃ and monitor the reaction progress by ELSD; when the content of intermediate A is ≥90% and the raw material is ≤2%, add 100~200 mL of sodium hydroxide aqueous solution to quench the reaction, stir at 20±5℃ for 0.5 hours, and adjust the pH to 4~5 with sodium hydroxide aqueous solution; then concentrate in a 40℃ water bath to remove tert-butyl acetate and obtain an aqueous solution of intermediate A; (2) Add 80 mL of ethanol and 40.8 g of magnesium sulfate to the aqueous solution of intermediate A obtained in step (1), add water until the system is clear, and keep the reaction at 50±5℃. When the ELSD monitoring shows that the target compound is ≥90% and intermediate A is ≤2%, cool the reaction system to 0±5℃ to crystallize, keep it warm and stir for 0.5~1 hours, filter, wash the filter cake with 400 mL of water, and dry it at room temperature to obtain a white solid.

3. A method for synthesizing magnesium salt of L-glutamic acid-5-tert-butyl ester, characterized in that, Includes the following steps: (1) Add 14.7 g of L-glutamic acid and 117.6 mL of tert-butyl acetate to a four-necked flask and cool to 0±5℃ under nitrogen protection; after stirring for 30 minutes, add 8.0 g of perchloric acid and 19.6 g of concentrated sulfuric acid in sequence; keep the temperature at 0±5℃ and monitor the reaction progress by ELSD; when the content of intermediate A is ≥90% and the raw material is ≤2%, add 80 mL of sodium hydroxide aqueous solution to quench the reaction, stir at 20±5℃ for 0.5 hours, and adjust the pH to 4~5 with sodium hydroxide aqueous solution; then concentrate in a 40℃ water bath to remove tert-butyl acetate and obtain an aqueous solution of intermediate A; (2) Add 29.4 mL of ethanol and 24.0 g of magnesium sulfate to the aqueous solution of intermediate A obtained in step (1), add water until the system is clear, and keep the reaction at 50±5℃. When the ELSD monitoring shows that the target compound is ≥90% and intermediate A is ≤2%, cool the reaction system to 0±5℃ to crystallize, keep it warm and stir for 0.5~1 hours, filter, wash the filter cake with 150 mL of water, and dry it at room temperature to obtain a white solid.

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