Novel preparation process of alogliptin benzoate

A technology of benzoic acid and methyl, which is applied in the field of drug synthesis and can solve problems such as waste water defects, three waste treatment costs, labor costs, etc.

Inactive Publication Date: 2021-05-07
山东永丞制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] 1) The cost of starting materials and reagents; 2) The cost of equipment, safety, and environmental protection; 3) The cost of three wastes treatment; 4) Labor cost
[0012] After a comprehensive analysis, 2-4 are the key points of cost, and one of the keys is the problem of the three wastes: the generation of the three wastes directly leads to th

Method used

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  • Novel preparation process of alogliptin benzoate
  • Novel preparation process of alogliptin benzoate
  • Novel preparation process of alogliptin benzoate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Step 1: Preparation of 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile

[0040] 100 g of 3-methyl-6-chlorouracil, 184.1 g of 2-cyanobenzyl bromide (1.1 equivalents), 800 ml of toluene, and 117.6 g of sodium carbonate (1.3 equivalents) were added to the reaction flask. The reaction was stirred at 60-70° C., detected by TLC, and the reaction was complete in 3 hours, which was directly used in the next reaction.

[0041] Step 2: Preparation of Alogliptin

[0042] Add 129.7 g of (R)-3-aminopiperidine dihydrochloride (1.05 equivalents) to the reaction flask of the first step above, stir and react at 60-70° C., detect by TLC, and complete the reaction in 7 hours. After filtering, the solvent of the filtrate was evaporated to dryness to obtain Boc-alogliptin.

[0043] Step 3: Preparation of Alogliptin

[0044] Add the above-mentioned Boc-trexagliptin to 400 ml of trifluoroacetic acid, stir and react at 30-40° C., TLC detects that the reacti...

Embodiment 2

[0048] Different from Example 1: the first and second step reaction bases are potassium carbonate (1.1 equivalents), and an off-white solid alogliptin benzoate is obtained. The total yield of the four-step reaction is 68.8%, and the HPLC purity is 99.67%.

Embodiment 3

[0050] Different from Example 1: the first and second reaction bases are sodium carbonate (1.5 equivalents), the total yield of the four-step reaction is 67.1%, and the HPLC purity is 99.69%.

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Abstract

The invention discloses a novel preparation process of alogliptin benzoate. The method comprises the steps: reacting 3-methyl-6-chlorouracil serving as an initial raw material with 2-cyanobenzyl bromide under an alkaline condition by taking toluene as a solvent to obtain 2-[(6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile, then reacting the solvent system with (R)-3-Boc-aminopiperidine under an alkaline condition, dissociating a protecting group by using acid to obtain alogliptin, and carrying out salifying reaction on the alogliptin and benzoic acid to finally prepare the alogliptin benzoate which is an anti-type 2 diabetes medicine. The preparation method adopts a one-pot method, has the advantages of low raw material cost, high yield, reduction of post-treatment operation of each chemical reaction in multi-step reaction, great shortening of the production period, few impurities generated in the reaction, high product quality, relative reduction of the use amount of chemical reagents, relatively environmental protection and the like, and is beneficial to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a new preparation process of alogliptin benzoate, a medicine for treating type 2 diabetes. Background technique [0002] Alogliptin benzoate, also known as alogliptin, is a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Takeda Corporation of Japan. This product can maintain the levels of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) in the body, promote the secretion of insulin, and thus play a hypoglycemic effect. Alogliptin and its pharmaceutical composition are orally effective specific DPP-Ⅳ inhibitors after sitagliptin and vildagliptin came into the market, and provide a new and important treatment option for patients with type 2 diabetes. application prospects. Alogliptin benzoate was officially launched in my country in early 2014. It is the first batch of type 2 diabetes treatment d...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C63/08C07C51/41
CPCC07D401/04C07C63/08C07C51/412Y02P20/55
Inventor 陈胜
Owner 山东永丞制药有限公司
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