Preparation method of alogliptin benzoate

A technology of benzoic acid and acid hydrolysis, applied in carboxylate preparation, organic chemistry, etc., can solve the problems of low purity and low yield of compound 4, and achieve the effects of simple operation, high reaction yield, and easy-to-obtain raw materials

Active Publication Date: 2013-12-25
SUZHOU LANXITE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of this three-step method is about 20-25%, and the yield is relatively low, and the purity of the prepared compound 4 is not high, and it is still necessary to find a higher yield and be more suitable for industrial production to prepare alogliptin or its salt Methods

Method used

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  • Preparation method of alogliptin benzoate
  • Preparation method of alogliptin benzoate
  • Preparation method of alogliptin benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Preparation of Formula 5:

[0032]

[0033] Dissolve (R)-3-amino-piperidine (43g) in 300mL of toluene, add benzaldehyde (45g) dropwise to the above solution at room temperature, continue to stir for 3 hours, distill toluene under reduced pressure to obtain 78g of oil, directly for the next reaction.

[0034] Preparation of Formula 4:

[0035]

[0036] at 0°C, N 2 Under protective conditions, add 6-methyl-3-chlorouracil (200g) into a 10L three-necked flask, dissolve it with DMF / DMSO (4.5L, 5 / 1) solution, add 60% NaH (54.8 g, 1.36mol), stirred for 30 minutes, then added LiBr (87g, 1mol), after continuing to stir for 20 minutes, to which o-cyanobenzyl bromide (244g, 1.25mol) was added dropwise, after reacting for 1 hour, moved to room temperature to continue Reaction, TLC tracked until the raw material reacted completely, and the solvent was evaporated under reduced pressure, and the residue was added with 1.2L water, and the 2 Cl 2 Extraction (1L × 3 times), co...

Embodiment 2

[0053] Preparation of Formula 5:

[0054]

[0055] Dissolve (R)-3-amino-piperidine (50g) in 300mL of toluene, add p-tolualdehyde (66g) dropwise to the above solution at room temperature, continue to stir for 3 hours, evaporate toluene under reduced pressure, and obtain 81g of oil were used directly in the next reaction.

[0056] Preparation of formula 6 and formula 7:

[0057]

[0058] 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2-H-pyrimidin-1-ylmethyl)-benzylcyanide (100g), compound of formula 5 ( 80.7g) and sodium bicarbonate (193g) and 34g activated molecular sieve (4A) in anhydrous MeOH (2L), reflux at 100°C, stir for 3h, spot the plate until the reaction is complete, cool to room temperature (25°C), add 1L HCl (3mol / L) and stir for 2 hours until the compound of formula 6 disappears, evaporate the methanol under reduced pressure, wash the water phase with 300ml of dichloromethane, remove the organic layer, adjust the pH of the water phase to 9 with saturated sodium...

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Abstract

The invention discloses a preparation method of alogliptin benzoate (formula 1). The method is easily available in raw materials, mild in reaction conditions, simple in operation and applicable to large-scale industrial production.

Description

technical field [0001] The present invention relates to a preparation method of medicine, in particular to an improved method for preparing alogliptin benzoate (formula I), alogliptin benzoate is an inhibitor of dipeptidyl peptidase-4 (DPP-4) , for the treatment of type 2 diabetes. Background technique [0002] Due to many factors such as the improvement of living standards, changes in diet structure, increasingly tense pace of life, and less active and more sedentary lifestyle, the incidence of diabetes worldwide is increasing rapidly. Diabetes has become the third serious threat after tumors and cardiovascular diseases. Chronic diseases of human health. At present, there are more than 120 million people with diabetes in the world, and the number of patients in my country ranks second in the world. At present, the incidence of diabetes in China is as high as 9.6%. Diabetes will still be a serious public health problem in China in the next 50 years. According to the survey...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04C07C51/41C07C63/08
Inventor 张健严伟才罗刚
Owner SUZHOU LANXITE BIOTECH
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