Synthesis method of teneligliptin-related impurity

A synthesis method and impurity technology are applied in the field of pharmaceutical synthesis to achieve the effects of easy availability of raw materials, simple operation method and reasonable process design

Inactive Publication Date: 2019-07-19
TLC NANJING PHARMA RANDD CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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  • Synthesis method of teneligliptin-related impurity
  • Synthesis method of teneligliptin-related impurity
  • Synthesis method of teneligliptin-related impurity

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Embodiment 1

[0057] A method for synthesizing related impurities of teneligliptin, comprising the following steps:

[0058] (1) Dissolve 22.50g of Boc-L-hydroxyproline in 250mL of tetrahydrofuran, and add 42.43g of O-tert-butyl-N,N'-diisopropylisourea dropwise at room temperature. After stirring for 12 hours, a white turbid liquid was obtained. The completion of the reaction was monitored by pointing a plate; the reaction liquid was filtered to remove solid insoluble matter, and the filtrate was evaporated to dryness and purified by column chromatography to obtain 21.70 g of yellow oily compound II, with a reaction yield of 82.73%.

[0059] (2) Dissolve 17.36g of compound II in dichloromethane, add 9.45g of N-methyl-N-morpholine oxide and stir at room temperature for 1.5 hours, the reaction is complete to obtain a black turbid liquid, and the reaction liquid is filtered out to remove insoluble matter , the filtrate was evaporated to dryness and purified by column chromatography to obtain 1...

Embodiment 2

[0067] A method for synthesizing related impurities of teneligliptin, comprising the following steps:

[0068] (1) Dissolve 30g of Boc-L-hydroxyproline in 300mL of tetrahydrofuran, add 62.92g of O-tert-butyl-N,N'-diisopropylisourea dropwise at room temperature, and stir at 60°C After 12 hours, a white turbid solution was obtained, and the reaction was monitored by pointing a plate; the reaction solution was filtered to remove solid insoluble matter, and the filtrate was evaporated to dryness and purified by column chromatography to obtain 30.11 g of yellow oily compound II, with a reaction yield of 80.77%.

[0069] (2) Dissolve 30.11g of compound II in dichloromethane, add 5.84g of tetrapropyl ammonium perruthenate and stir at room temperature for 3.5 hours, the reaction is complete to obtain a black turbid solution, the reaction solution is suction filtered to remove insoluble matter, and the filtrate is evaporated After drying, it was purified by column chromatography to obt...

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Abstract

The invention discloses a synthesis method of a teneligliptin-related impurity, optimal reaction steps and reaction conditions are screened out through a large number of experiments, the whole processis reasonable in design, high in operability, mild in reaction condition and high in yield, and industrial production can be realized. According to the invention, Boc-L-hydroxyproline and 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine are taken as raw materials, and the raw materials are subjected to seven-step reaction to synthesize the teneligliptin-related impurity, and the prepared teneligliptin-related impurity is high in purity, can provide a basis for quality control, safety and efficiency evaluation of teneligliptin, and has important application values.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a method for synthesizing impurities related to teneligliptin. Background technique [0002] Diabetes mellitus is a metabolic disease caused by relative lack of insulin secretion and insulin-resistant β-cell dysfunction, and its main feature is hyperglycemia. Clinically, it is mainly divided into two types: insulin-dependent diabetes (Type I) and non-insulin-dependent diabetes (Type II). Among the sick population in my country, type Ⅱ diabetes is the main one. [0003] Type 1 diabetes is caused by the lack of insulin secretion caused by the damage of pancreatic beta cells. The main reason is that the pancreatic beta cells are attacked and destroyed, causing inflammation and leading to absolute insufficient insulin secretion. It is an autoimmune disease, which is more common in children and adults juvenile. Patients with type Ⅰ diabetes have three more and one less sym...

Claims

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Application Information

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IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 何旭王加燕张池刘春崔希林
Owner TLC NANJING PHARMA RANDD CO LTD
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