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Preparation method of leucine dipeptide

A technology of leucine dipeptide and leucine, which is applied in the preparation methods of peptides, chemical instruments and methods, peptides, etc., can solve the problems of high safety hazards in reaction operations, heavy metal residues, and inability to crystallize and purify, and avoid the Column chromatography, less three wastes, easy to control effect

Inactive Publication Date: 2018-12-07
NANJING NUTRABUILDING BIO TECH CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] The main problems of this route are as follows: the p-toluenesulfonate of leucine benzyl ester is used in the reaction, there is no commercial source and the atom economy is poor; the yield of the first step reported in the literature is only 70-75%, and the product is an oil Unable to crystallize and purify; polymers are formed during the reaction, which are difficult to remove; palladium black / hydrogen gas is used for deprotection, which has high cost, great safety hazards in reaction operation, and heavy metal residues

Method used

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  • Preparation method of leucine dipeptide
  • Preparation method of leucine dipeptide
  • Preparation method of leucine dipeptide

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Embodiment 1

[0025] The preparation of embodiment 1 leucine dipeptide

[0026] Under nitrogen protection, dissolve L-leucine (10g, 76mmol) in acetonitrile, cool to 0-10°C, add potassium carbonate (10.5g, 76mmol), stir for half an hour; dropwise add L-leucine-N- Acetonitrile solution of acid anhydride (11.9g, 76mmol) in the carboxyl ring, after the addition, keep stirring at the temperature for 2h, TLC detects that the reaction is complete, adjust the pH to 5-6 with acetic acid, filter, beat with water, and dry to obtain an off-white solid 16.7g, molar yield 90%, liquid phase purity 98%. 1H NMR (water-d2, 400MHz): δ4.43 (dd, J = 8.8, 5.6Hz, 1H), 4.03 (t, J = 7.0Hz, 1H), 1.86-1.61 (m, 6H), 1.04-0.86 (m,12H).

Embodiment 2

[0027] The preparation of embodiment 2 leucine dipeptide

[0028] Under the protection of nitrogen, dissolve L-leucine (10g, 76mmol) in tetrahydrofuran, cool to 0-10°C, add potassium hydroxide (4.3g, 76mmol), stir for half an hour; dropwise add L-leucine-N - A solution of carboxycyclic anhydride (11.9 g, 76 mmol) in tetrahydrofuran. After the addition, heat up to 20-30°C and stir for 1 hour. TLC detects that the reaction is complete. Adjust the pH to 5-6 with phosphoric acid. After filtering, beat with water. After filtering, dry to obtain 15.8 g of off-white solid with a molar yield of 85%. 98% purity.

Embodiment 3

[0029] The preparation of embodiment 3 leucine dipeptide

[0030] Under nitrogen protection, suspend L-leucine (10g, 76mmol) in toluene, cool to 0-10°C, add potassium carbonate (21g, 152mmol), stir for half an hour; dropwise add L-leucine-N-carboxyl Toluene solution of internal acid anhydride (7.7g, 49.4mmol), after adding, keep stirring at this temperature for 2h, TLC detects that the reaction is complete, adjust the pH to 5-6 with acetic acid, filter and beat with water, filter and dry to obtain off-white solid 10.8g, molar yield 90%, liquid phase purity 98%.

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Abstract

The invention provides a preparation method of leucine dipeptide. L-leucine-N-carboxyl cyclic anhydride is dissolved in a certain solvent to react with a compound (which is described in the spefication) to produce leucine dipeptide. The preparation method provided by the invention has the beneficial effects that the route is short, the operation is simple and convenient, the atomic economy is highand three wastes are less; raw materials and auxiliary materials are low in price and easy in obtaining or preparation; the reaction conditions are mild, the impurities are fewer and the yield is high; by crystallization and purification of a product, the column chromatography is avoided, the process is stable, the control is easy, the treatment after reaction is convenient and the preparation method can be economically and conveniently used for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of leucine dipeptide. Background technique [0002] Metabolic syndrome is a pathological state of metabolic disorders of protein, fat, carbohydrates and other substances in the human body. The main features are overweight or obesity, insulin resistance, high blood pressure, and lipid metabolism disorders. risk factor. The incidence of metabolic syndrome in the population is increasing year by year, and the incidence in obese people is much higher than that in the general population. Studies have shown that the common pathological basis of this group of diseases is insulin resistance and lipid metabolism disorder, which is a chronic subclinical inflammatory process. Patent US9371276B reports that metformin salts of leucine dipeptides can be used to prevent and treat metabolic syndromes such as diabetes, obesity, lipid metabolism disor...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/062C07K1/02
CPCC07K5/06043
Inventor 张健廖琪林
Owner NANJING NUTRABUILDING BIO TECH CO LTD
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