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The preparation method of tiagliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine

A technology for ticagliptin and an intermediate, which is applied in the field of pharmaceutical preparation and can solve the problems of easily causing human body burns, low reaction yield, instability and the like

Active Publication Date: 2016-08-17
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Methanesulfonic acid needs to be used in the reaction process. Methanesulfonic acid is flammable, easy to absorb water and deliquescence, and is highly corrosive and irritating, and can easily cause burns to the human body; Smoke, which is hydrolyzed into phosphoric acid and hydrogen chloride, is very unstable and brings a lot of trouble to the operation; trifluoroacetic acid is highly corrosive and irritating, and can cause burns to the human body; the reaction yield is low (10%)

Method used

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  • The preparation method of tiagliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine
  • The preparation method of tiagliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine
  • The preparation method of tiagliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine

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Experimental program
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Effect test

Embodiment 1

[0028] The preparation of embodiment 11-(3-methyl-1-phenyl-5--pyrazolyl)-4-tert-butoxycarbonylpiperazine

[0029] N-Boc-N acetoacetylpiperazine (200g, 0.7mol), phenylhydrazine (87.2g, 0.8mol), and 2400mL tetrahydrofuran were respectively added to a 3000mL four-neck flask, stirred and reacted at 30°C for 2h, and then 120mL of pyridine was added. After stirring for a while, Lawesson's reagent (329.2 g, 0.8 mol) was added and reacted overnight at 60° C., and the reaction was stopped after the completion of the reaction detected by TLC. Concentrate under reduced pressure, wash the oil in batches with ethyl acetate, combine several layers, wash with saturated sodium bicarbonate, dry and concentrate to give a yellow oil (228 g, 90%).

[0030] LC-MS(ESI)m / z343[M+H] + .

Embodiment 2

[0031] The preparation of embodiment 21-(3-methyl-1-phenyl-5--pyrazolyl)piperazine

[0032] The oil obtained above was fully dissolved with methanol until clear, and 400 mL of concentrated hydrochloric acid was added at 35° C., and the reaction was stopped after the completion of the reaction detected by TLC. Concentrate under reduced pressure, add 1000mL ethyl acetate to dissolve, wash with dilute hydrochloric acid, adjust the pH of the system until a large amount of solid precipitates, then wash the solid with DCM several times, dry and evaporate to dryness to obtain a gray solid (157.8g, 88%).

[0033] LC-MS(ESI)m / z243[M+H] + .

[0034] 1H NMR (500MHz, CDCl 3 ): δ2.26(3H, s), 2.8-3.4(8H, m), 5.67(1H, s), 7.21-7.24(1H, t), 7.27-7.42(2H, t), 7.74~7.77(2H , d).

Embodiment 3

[0035] Example 3 Preparation of 1-(3-methyl-1-phenyl-5--pyrazolyl)-4-tert-butoxycarbonylpiperazine

[0036] According to the operation of Example 1, the tetrahydrofuran solution was replaced with toluene solution, dried and concentrated to obtain a yellow oil with a yield of 75%.

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Abstract

The invention provides a teneligliptin key intermediate 1-(3-methyl-1-phenyl-5-pyrazolyl) piperazine preparation method which is as follows: reacting N-Boc-N-acetyl acetyl piperazine with phenylhydrazine in an organic solvent with Lawesson reagent, and then removing the protection base in the presence of concentrated hydrochloric acid to obtain an teneligliptin key intermediate. The preparation method has the advantages of being high in yield, low in cost, friendly to the environment and the human body, and more suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of medicine preparation, and in particular relates to an improved preparation method of 1-(3-methyl-1-phenyl-5-pyrazolyl)piperazine, a key intermediate of tiagliptin. Background technique [0002] Diabetes is a chronic disease that has attracted worldwide attention. It is currently the third major non-communicable disease that threatens human health after tumors and cardiovascular and cerebrovascular diseases. At present, it is estimated that there are about 200 million diabetic patients in the world, and it is estimated that the total number of diabetic patients in the world will reach 324 million in 2025. At present, according to the classification of diabetes, it can be divided into four categories: (1) type 1 diabetes; (2) type 2 diabetes; (3) gestational diabetes; (4) special type of diabetes. Among them, type 2 diabetes accounts for more than 90% of the entire diabetic population, and is currently the most impo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D231/38
CPCC07D231/38
Inventor 宋志春胡丹丹蒋玉伟张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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