Sitagliptin synthesis method

A synthetic method and step-by-step technology, applied in the field of medicine and chemical industry, can solve the problems of resource waste, many steps, expensive raw materials, etc., and achieve the effects of avoiding toxic and dangerous chemical reagents, mild reaction conditions, and easy-to-obtain raw materials

Inactive Publication Date: 2018-06-19
安庆奇创药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method needs to obtain a single chiral intermediate by resolution, which is a great waste of resources for industrial production, and there are also expensive raw materials and more steps for the synthesis of formula IV compounds. question

Method used

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Experimental program
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Embodiment 1

[0034] Embodiment 1, the preparation of formula II compound

[0035] In a 50mL single-necked bottle, add 2,4,5-trifluorobromobenzene (I) (2.10g, 10mmol), diethyl malonate (4.80g, 30mmol), cuprous iodide (0.19g, 1mmol), L-proline (0.23g, 2mmol), potassium phosphate (7.43g, 35mmol) and 20mL of anhydrous DMSO, and the reaction system was replaced with nitrogen three times. Raise the temperature to 90°C and react for 24h. After that, spread a layer of diatomaceous earth on the filter paper, filter, and wash the filter cake with 10 mL of ethyl acetate to obtain the mother liquor. Add 70 mL of ethyl acetate to dilute the mother liquor, wash three times with saturated ammonium chloride aqueous solution, once with saturated sodium chloride aqueous solution, and finally wash once with water, and spin evaporate the ethyl acetate under reduced pressure to obtain the crude product. The crude product was recrystallized from methanol at 0° C. to obtain 2.28 g of a light yellow solid, name...

Embodiment 2

[0036] Embodiment 2, the preparation of formula III compound

[0037] Into a 50 mL single-necked flask, 1-tert-butoxycarbonylpiperazine (1.87 g, 10 mmol), trifluoroacetic anhydride (3.15 g, 15 mmol) and 15 mL of anhydrous dioxane were sequentially added, and stirred at room temperature for one hour. Then hydrazine hydrate (80%, 1.25g, 20mmol), tetrabutylammonium iodide (0.37g, 1mmol) and morpholine (0.17g, 2mmol) were added successively, and then the temperature was raised to 70°C. Hydrogen peroxide (30%, 4.53g, 40mmol) was dissolved in 5mL of dioxane, and the hydrogen peroxide solution was slowly added dropwise to the above reaction solution for 4h, and then the reaction was continued for 2h. Afterwards, 80 mL of ethyl acetate was added to dilute the mother liquor, washed three times with saturated aqueous sodium sulfite solution, once with saturated aqueous sodium chloride solution, and finally washed once with water, and the ethyl acetate was rotary evaporated under reduced p...

Embodiment 3

[0038] Embodiment 3, the preparation of formula IV compound

[0039] In a 100 mL single-necked bottle, potassium tert-butoxide (2.24 g, 20 mmol) was dissolved in 40 mL of tetrahydrofuran, and stirred at room temperature for one minute. Then compound III (1.91 g, 10 mmol) and compound II (2.60 g, 10 mmol) were added sequentially, and stirring was continued at room temperature for 60 min. Afterwards, the reaction solvent tetrahydrofuran was distilled off under reduced pressure, and 50 mL of water and 50 mL of dichloromethane were added to extract an organic phase. The organic phase was dried with anhydrous sodium sulfate, and then distilled under reduced pressure to obtain a yellow crude product solid. The crude product was recrystallized from dichloromethane and cyclohexane to obtain 3.33 g of compound IV with a yield of 82% and a purity of 99%.

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Abstract

The invention discloses a sitagliptin synthesis method, which comprises: carrying out a reaction on a compound represented by a formula IV, (R)-(+)-tert-butyl sulfinamide and hydrogen under the catalysis of a catalyst to obtain a compound represented by a formula V; and carrying out a hydrolysis reaction on the compound represented by the formula V to obtain a compound represented by a formula VI,ie., sitagliptin. According to the present invention, the method has advantages of easily available raw materials, simple steps, high yield and mild reaction conditions, and is suitable for industrial production. The formulas IV, V and VI are defined in the specification.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis method of sitagliptin. Background technique [0002] The chemical name of sitagliptin is 7-[(3R)-3amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetra Hydrogen-3-trifluoromethyl-1,2,4-triazolo[4,3-a]pyrazine is an oral DPP-IV inhibitor for the treatment of type II diabetes. Sitagliptin was approved for marketing in 2006 and is the best-selling variety. In 2015, the total sales of Januvia and Janumet reached US$6.29 billion, making it the largest variety among DPP-IV inhibitors. [0003] Initially, Merck applied for the patent CN1761642 for the preparation method of the compound, which disclosed that 2,4,5-trifluorophenylacetic acid was used as the starting material, and first reacted with cyclo(ethylene)isopropyl malonate to form The corresponding enol compound is followed by substitution and decarboxylation with the corresponding pyraz...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 吴学平邢继刚严东洋陈耀
Owner 安庆奇创药业有限公司
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