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A kind of synthetic method of alogliptin benzoate

A synthesis method and technology of benzoic acid are applied in the fields of carboxylate preparation, organic chemistry, etc., and can solve the problems that the impurity content is difficult to meet the qualified requirements of raw materials, resulting in reduced yield and high reaction temperature, and is convenient for industrial production and easy to control. , the effect of high purity

Active Publication Date: 2016-08-24
JIANGSU DEYUAN PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Its main disadvantages are: sodium hydride is used, and the anhydrous requirements of the reagent are relatively high; methyl iodide is used, which is highly toxic; by-products will be generated in the first step , which is difficult to remove in subsequent steps and will further generate other by-products
The disadvantage of this scheme is that the solvent used in the second step is n-butanol, the reaction temperature is too high, resulting in a decrease in yield, and the impurity content in the product is difficult to meet the qualified requirements of the raw material drug

Method used

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  • A kind of synthetic method of alogliptin benzoate
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Examples

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Embodiment 1

[0039] Embodiment 1, a kind of synthetic method of alogliptin benzoate comprises the following steps:

[0040] (1) 2-Cyanobenzyl bromide and 3-methyl-6-chlorouracil were stirred and reacted in toluene in the presence of tri-n-butylamine, cooled and added with water to stir and crystallize, filtered and washed to obtain 2-(6-chloro- 3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;

[0041] (2) 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile and (R)-3- Aminopiperidine dihydrochloride and alkali were added to ethanol, stirred and reacted, and after purification, it was salified with benzoic acid to obtain 2-({6-[(3R)-3-aminopiperidin-1-yl]-3- Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)-benzonitrile monobenzoate.

Embodiment 2

[0042] Example 2, in the step (2) of the synthetic method of alogliptin benzoate described in Example 1, the amount of the substance used (R)-3-aminopiperidine dihydrochloride is 2-( 1.0 to 1.5 times the amount of 6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile.

Embodiment 3

[0043] Example 3, in the step (2) of the synthesis method of alogliptin benzoate described in Example 1 or 2, the base is sodium bicarbonate or sodium carbonate.

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Abstract

The invention discloses a synthesis method of alogliptin benzoate. The synthesis method comprises the following steps: putting 2-cyano benzyl bromide, 3-3metyl-6-chlorouracil and tri-n-butylamine in methylbenzene and stirring for reaction; cooling, adding water and stirring for crystallization; filtering and washing with water to obtain 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimdine-1-metyl)-benzonitrile; adding 2-(6-chlorine-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimdine-1-metyl)-benzonitrile, (R)-3-piperidinamine dihydrochloride and alkali into ethyl alcohol and stirring for reaction; purifying and salifying with benzoic acid to obtain alogliptin benzoate. The synthesis method disclosed by the invention is mild in condition, easy to control, non-toxic, environment-friendly, high in purity and high in yield.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to alogliptin benzoate: 2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl Synthetic method of base-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)-benzonitrile monobenzoate. Background technique [0002] Dipeptidyl peptidase IV (DPP4) is a type II membrane protein, a nonclassical serine amino dipeptidase. It is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (gut, liver, lung, kidney and placenta) and is also found in body fluids. DPP4 is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell surface antigen CD-26. [0003] According to the introduction of Chinese published patent document CN 101309689, DPP4 is the cause of GLP-1 (7-36) (glucagon) metabolic cracking in vivo, and it has been proved that many other peptides (CHRH, NPY, GLP- 2. VIP) has proteolytic activity. GLP-...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07C51/41C07C63/08
CPCC07D401/04
Inventor 郑家通杨汉跃董超陈学民朱思梅
Owner JIANGSU DEYUAN PHARMA
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