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Trelagliptin impurity compound and preparation method thereof

A technology of trexagliptin impurity and compound, which is applied in the field of drug synthesis, can solve the problems that the preparation method of trexagliptin impurity K has not been reported in literature, etc., and achieve the effects of high product purity, high reaction yield and short route

Pending Publication Date: 2022-03-01
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] For the preparation method of this trexagliptin impurity K, there is no bibliographical report at present

Method used

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  • Trelagliptin impurity compound and preparation method thereof
  • Trelagliptin impurity compound and preparation method thereof
  • Trelagliptin impurity compound and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0060] Add acetone (60ml) to a 250ml reaction flask, add compound I (R)-3-amino-1-Boc-piperidine (5.08g, 25.36mmol) and potassium carbonate (10.52g, 76.08mmol), and stir for 10min Afterwards, 2-cyano-5-fluorobenzyl bromide (11.94 g, 55.79 mmol) was added and stirring was continued at 20 °C for 16 h. Purified water (50ml) was added and the mixture was extracted with ethyl acetate (2 x 50ml). Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate to obtain compound III (R)-3-(bis(2-cyano-5-fluorobenzyl))amino-1-Boc-piperidine with a yield of 95.5% , HPLC purity 99.91%.

Embodiment 2

[0062] Add acetone (60ml) in the reaction flask of 250ml, add compound I namely (R)-3-amino-1-Boc-piperidine (5.08g, 25.36mmol) and sodium bicarbonate (6.39g, 76.08mmol), stir After 10 min, 2-cyano-5-fluorobenzyl bromide (10.86 g, 50.72 mmol) was added and stirring was continued at 20 °C for 16 h. Purified water (50ml) was added and the mixture was extracted with ethyl acetate (2 x 50ml). Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate to obtain compound III (R)-3-(bis(2-cyano-5-fluorobenzyl))amino-1-Boc-piperidine with a yield of 92.0% , HPLC purity 99.84%.

Embodiment 3

[0064] In the reaction bottle of 250ml, add acetone (60ml), add compound I namely (R)-3-amino-1-Boc-piperidine (5.08g, 25.36mmol) and triethylamine (7.70g, 76.08mmol), stir After 10 min, 2-cyano-5-fluorobenzyl bromide (16.28 g, 76.08 mmol) was added and stirring was continued at 20 °C for 16 h. Purified water (50ml) was added and the mixture was extracted with ethyl acetate (2 x 50ml). Dry the organic phase with anhydrous magnesium sulfate, filter and concentrate to obtain compound III (R)-3-(bis(2-cyano-5-fluorobenzyl))amino-1-Boc-piperidine with a yield of 87.8% , HPLC purity 99.63%.

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Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a trelagliptin impurity compound K and a preparation method thereof. The preparation method comprises the following steps: taking (R)-3-amino-1-Boc-piperidine and 2-cyano-5-fluorobenzyl bromide as raw materials, reacting under the action of alkali to prepare (R)-3-(bis (2-cyano-5-fluorobenzyl)) amino-1-Boc-piperidine, further salifying the (R)-3-(bis (2-cyano-5-fluorobenzyl)) amino-1-Boc-piperidine, reacting with 2-[[6-chloro-3-methyl-2, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4-dioxo-3, 4- The trelagliptin impurity compound K is prepared from 2, 4-dihydro-1 (2H)-pyrimidinyl] methyl]-4-fluorobenzonitrile under the action of alkali. The synthesis method provided by the invention is simple, the trelagliptin impurity compound K obtained by the method is high in purity and high in yield after recrystallization precipitation, and the impurity compound can be used as an impurity reference substance in a trelagliptin finished product detection standard.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a trexagliptin impurity compound and a preparation method thereof. Background technique [0002] Trelagliptin succinate is a dipeptidyl peptidase Ⅳ (DPP-Ⅳ) inhibitor developed by Japan's Takeda (Takeda Pharmaceutical Co., Ltd.), which can selectively and continuously inhibit DPP-Ⅳ and control blood sugar levels . Approved under the trade name in March 2015 Listed for the treatment of type 2 diabetes. Its chemical name is 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H )-yl]methyl]-4-fluoro-benzonitrile succinate, the CAS number is 1029877-94-8, and its structural formula is as follows: [0003] [0004] The patent CN1926128A applied by Yuanyan Takeda Company in China discloses a synthetic route of trexagliptin as follows: 2-bromo-5-fluorotoluene is used as the starting material, and compound C, namely 2-cyano, is obt...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
CPCC07D401/04
Inventor 杨德亮黄文波陈秋英
Owner LUNAN PHARMA GROUP CORPORATION
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