Method for preparing sitagliptin phosphate side chain

A technology of hydrochloride and hydrazine trifluoroacetate, which is applied in the field of preparation of side chains of sitagliptin phosphate, can solve problems such as low yield and explosion of anhydrous hydrazine, and achieve high yield, low cost, and cheap raw materials Effect

Inactive Publication Date: 2011-02-16
ZHEJIANG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The raw material is cheap and easy to get, such as chloropyrazine (150 yuan/kg), but the yield of this route is low, and the first step requires ...

Method used

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  • Method for preparing sitagliptin phosphate side chain
  • Method for preparing sitagliptin phosphate side chain
  • Method for preparing sitagliptin phosphate side chain

Examples

Experimental program
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Effect test

Embodiment 1

[0035] Under nitrogen protection, to P 2 S 5 (4.3g, 10mmol) in THF (150mL) solution was added 2-piperazinone (1g, 10mmol); electric stirring reaction at room temperature for 2h, then the reaction solution was treated with 30mL 3Mol / L NaOH (aq), and then ethyl acetate Extract the ester, concentrate the organic layer, add 60mL toluene to the crude oil, reflux for 4h, let stand to separate layers, pour out the toluene layer while it is hot, and gradually cool down to room temperature; continue to add 60mL toluene to the remaining oil, and reflux for 3h. Stand to separate layers, pour out the toluene layer while hot, and slowly lower to room temperature. The two toluene phases were mixed and cooled at -4°C for 12 hours, then crystallized, collected by filtration, and washed twice with cold toluene to obtain 0.95 g of a yellow solid, with a yield of 81.7%. The obtained product does not need further purification and can be directly used in the next reaction.

[0036] MS (ESI): m / ...

Embodiment 2

[0038] Under nitrogen protection, the P 2 S 5 (5.2g, 12mmol) and 2-piperazinone (1g, 10mmol) were added into 30mL 1,4-dioxane, and the reaction was performed under electric stirring at room temperature for 3h. Then use 30mL 3Mol / L NaOH (aq) to treat the reaction solution, then extract with ethyl acetate, concentrate the organic layer, add 60mL toluene to the crude oil, reflux for 4h, let stand to separate layers, pour out the toluene layer while hot, gradually Cool down to room temperature; continue to add 60mL of toluene to the remaining oil, reflux for 3 hours, let stand to separate layers, pour out the toluene layer while hot, and slowly cool down to room temperature. The two toluene phases were mixed and cooled at -4°C for 12 hours, then crystallized, collected by filtration, and washed twice with cold toluene to obtain 0.91 g of a yellow solid, with a yield of 78.4%. The obtained product does not need further purification and can be directly used in the next reaction. ...

Embodiment 3

[0040]Under nitrogen protection, LR (2.43, 6 mmol) was dissolved in THF (150 mL), and 2-piperazinone (1 g, 10 mmol) was added under vigorous stirring, and reacted at room temperature for 4 h. Then use 30mL 3Mol / L NaOH (aq) to treat the reaction solution, then extract with ethyl acetate, concentrate the organic layer, add 60mL toluene to the crude oil, reflux for 4h, let stand to separate layers, pour out the toluene layer while hot, gradually Cool down to room temperature; continue to add 60mL of toluene to the remaining oil, reflux for 3 hours, let stand to separate layers, pour out the toluene layer while hot, and slowly cool down to room temperature. The two toluene phases were mixed and cooled at -4°C for 12 hours, then crystallized, collected by filtration, and washed twice with cold toluene to obtain 0.97 g of a yellow solid, with a yield of 83.6%. The obtained product does not need further purification and can be directly used in the next reaction.

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Abstract

The invention discloses a method for preparing a sitagliptin phosphate side chain which has a structure shown by a formula 1. The method comprises the following steps of: a) preparing 2-piperazine thioketone with structure shown by a formula 4 by vulcanizing 2-piperazine ketone with structure shown by a formula 2 with a vulcanizing reagent, wherein the vulcanizing reagent is phosphorus pentasulfide or a Lawesson reagent with structure shown by a formula 3; and b) performing cyclization on trifluoro ethyl hydrazine and the 2-piperazine thioketone through Pellizzari reaction and adding hydrochloric acid to form salt so as to obtain 3-trifluoromethyl-[1,2,4] triazole [4,3-a] piperazine hydrochloride serving as a target product. The method of the invention has short route, cheap and readily available raw material, high yield of each step and relatively low cost and is simple to operate.

Description

(1) Technical field [0001] The invention relates to a new route for preparing the side chain of sitagliptin phosphate, namely 3-trifluoromethyl-[1,2,4]triazol[4,3-a]piperazine hydrochloride. (2) Background technology [0002] 3-Trifluoromethyl-[1,2,4]triazol[4,3-a]piperazine hydrochloride is an important intermediate of Sitagliptin Phosphate, a new drug developed by Merck. Sitagliptin phosphate is a new drug approved by the US FDA in 2006 for the treatment of type II diabetes. [0003] When the human blood glucose level rises, sitagliptin phosphate can effectively inhibit dipeptidyl peptidase-4 (DPP-4) to promote two incretins-glucagon-like polypeptide-1 and glucose-dependent Insulin-promoting polypeptide (GIP) activates G protein-coupled receptors on islet cells to promote the release of insulin, which lowers blood sugar. Compared with existing hypoglycemic drugs, sitagliptin phosphate will not produce hypoglycemia. It is also good for blood lipids and blood pressure, ma...

Claims

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Application Information

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IPC IPC(8): C07D487/04
Inventor 杨健夏铃洁余长泉
Owner ZHEJIANG UNIV
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