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Preparation method for trelagliptin

A methyl-reaction technology, applied in the field of preparation of trelagliptin, can solve the problems of harsh reaction conditions and low yield, and achieve the effects of high product purity and yield, high yield and shortening reaction time.

Inactive Publication Date: 2018-02-16
SHIJIAZHUANG DUEN MEDICINE SCI & TECHCO
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AI Technical Summary

Problems solved by technology

The reaction of synthesizing 3-methyl-6-chlorouracil includes the cyclization and halogenation reaction of diethyl malonate and methylurea, and the reaction of preparing 1-methylpyrimidine-2,4,6-trione , the reaction conditions are harsh, the reaction time reaches 72h, and the yield is low

Method used

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  • Preparation method for trelagliptin
  • Preparation method for trelagliptin

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Embodiment

[0028] A preparation method of Trexagliptin, comprising the following steps:

[0029] (1) Preparation of 1-methylpyrimidine-2,4,6-trione

[0030] Methylurea (97.14 g, 1.31 mol), absolute ethanol 1.2 L, sodium metal (30.4 g, 1.32 mol) were added in batches, and stirred for 1 h. A solution of diethyl malonate (273.0 g, 1.70 mol) in 100 mL of absolute ethanol was slowly added dropwise to the reaction liquid, heated to reflux, and reacted for 24 h. The solvent was distilled off under reduced pressure, 1L of water was added, the pH was adjusted to 3-4 with 2N HCl, and the mixture was crystallized by cooling. Suction filtration, washing with water, and drying gave light yellow powder, 152.8 g of 1-methylpyrimidine-2,4,6-trione, yield 82%, mp.129-130°C.

[0031] (2) Preparation of 3-methyl-6-chlorouracil

[0032] 1-Methylpyrimidine-2,4,6-trione (80g, 0.564mol), 400g of phosphorus oxychloride, cooled to 0°C, controlled temperature at 0-5°C and stirred for 0.5h, heated to 60°C for 1...

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Abstract

The invention discloses a preparation method for trelagliptin and belongs to the field of organic synthesis. The preparation method comprises the following steps: (1) taking methylurea and diethyl malonate as initial raw materials and performing cyclization and chlorination reaction, thereby acquiring 3-methyl-6-chlorouracil; (2) acquiring 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-methyl)-4-fluorobenzonitrile from the nucleophilic substitution reaction of 3-methyl-6-chlorouracil and 2-bromine methyl-4-fluorobenzonitrile; (3) generating a target compound (R)-2-((6-(3-aminopiperidines-1-group)-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-group) methyl-4-fluorobenzonitrile (trelagliptin) through the reaction of 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-methyl)-4-fluorobenzonitrile and (R)-3-aminopiperidine. The preparation method has the characteristics of low-cost and easily acquired initial raw materials, convenient after-treatment, mild condition, operation convenience, and the like.

Description

technical field [0001] The invention relates to a preparation method of trexagliptin, which belongs to the field of organic synthesis. Background technique [0002] Trelagliptin succinate, chemical name: (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo- 3,4-Dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile succinate is a new DPP-IV inhibitor developed by Takeda Pharmaceutical Company. On March 26, 2015, it was approved for marketing in Japan. It is mainly used for the treatment of long-term type Ⅱ diabetes mellitus. It is used once a week, which can effectively improve the patient's condition, is convenient to use and improves patient compliance, and has few adverse reactions. Therefore, it is a A novel and promising drug for the treatment of type 2 diabetes. [0003] The structure of Trexagliptin is as follows: [0004] [0005] Generally in the prior art, the synthesis method of trexagliptin reported in US2012197018, US20090275750, US2008108807 and WO2015092...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 方瑜杜玉民
Owner SHIJIAZHUANG DUEN MEDICINE SCI & TECHCO
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