Preparation method of sitagliptin intermediate triazolopyrazine derivative

A technology of pyrazine hydrochloride and compound, applied in the direction of organic chemistry and the like, can solve the problems of high odor, high safety hazard, poor reaction selectivity, etc., and achieve the effects of simple process operation, short process flow and high reaction selectivity

Active Publication Date: 2015-11-04
XINFA PHARMA
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0014] This method also has the disadvantage of poor reaction selectivity. At the same time, phosphorus pentasulfide is used to produce thione with strong activity, and then reacted with trifluoroacetylhydrazide to produce highly toxic hydrogen sulfide by-products, which have a strong smell and high safety hazards.
[0015] The above methods are not conducive to the cost reduction and green and safe industrial production of II

Method used

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  • Preparation method of sitagliptin intermediate triazolopyrazine derivative
  • Preparation method of sitagliptin intermediate triazolopyrazine derivative
  • Preparation method of sitagliptin intermediate triazolopyrazine derivative

Examples

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Embodiment 1

[0051] Example 1: Preparation of 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (II)

[0052] In 250 milliliters of four-necked flasks, add successively 50 gram ethanols, 100 gram toluene, 17 gram sodium carbonate powders, 11.6 gram (0.1 moles) 2-chloroethylamine hydrochloride, 14.5 grams (0.10 moles) ethyl trifluoroacetate, After stirring and reacting at 30-35°C for 2 hours, add 14.5 grams (0.10 moles) of glycine ethyl ester hydrochloride, react at 50-55°C for 2 hours, stir and react at 90-95°C for 3 hours, and recover steam at the same time. ethanol out. Cool to 20-25°C, filter, wash the filter cake with 30 grams of toluene; transfer the combined filtrate to a 250 ml four-neck flask with a water separator, add 6.5 grams of 80% hydrazine hydrate dropwise between 20-25°C After about 1 hour, the dripping was completed, then stirred and reacted between 50-55°C for 2 hours, added 15 grams of hydrochloric acid with a concentration of 35%, refluxe...

Embodiment 2

[0057] Example 2: Preparation of 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (II)

[0058] In 250 milliliters of four-necked flasks, add 50 gram methanol successively, 100 gram toluene, 17 gram sodium carbonate powders, 11.6 gram (0.1 mole) 2-chloroethylamine hydrochloride, 13.0 gram (0.1 mole) methyl trifluoroacetate, After stirring and reacting at 30-35°C for 2 hours, add 13.1 grams (0.10 moles) of glycine methyl ester hydrochloride, react at 50-55°C for 2 hours, stir and react at 90-95°C for 3 hours, and recover steam at the same time. Methanol out. Cool to 20-25°C, filter, and wash the filter cake with 30 grams of toluene; transfer the combined filtrate to a 250-ml four-neck flask with a water separator, and add 6.5 grams of 80% hydrated water dropwise between 20-25°C Hydrazine, about 1 hour after the drop, then stirred at 50-55 ° C for 2 hours, added 15 grams of 35% hydrochloric acid, refluxed azeotropic water removal, until the water...

Embodiment 3

[0059] Example 3: Preparation of 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine hydrochloride (II)

[0060] Replace 17 grams of sodium carbonate powder of embodiment 1 with 22 grams of potassium carbonate powder, all the other are the same as embodiment 1, obtain white solid 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4- Triazolo[4,3-a]pyrazine hydrochloride (II) 19.1 g, yield 83.6%.

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Abstract

The invention relates to a preparation method of a sitagliptin intermediate triazolopyrazine derivative. The method comprises the following steps: by using 2-chlorethamin hydrochloride as an initial raw material, reacting the 2-chlorethamin hydrochloride with trifluoroacetate and aminoacetate hydrochloride to generate 1-trifluoroacetyl-2-piperazino ketone (III), and carrying out condensation ring formation on the compound (III), hydrazine hydrate and hydrochloric acid to obtain the sitagliptin intermediate 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazolyl[4,3-a]pyrazine hydrochloride (II). The high-activity triluoroacetyl carbonyl functional group and hydrazine hydrate are dehydrated into hydrazone, and the hydrochloric acid is directly added without separation, thereby performing intramolecular dehydration to generate the triazole ring. The method can avoid using thioketone, has the advantages of cheap and accessible raw materials, high reaction selectivity, short process, simple technical operation, high safety and environment friendliness.

Description

technical field [0001] The invention relates to a preparation method of a sitagliptin intermediate, in particular to a preparation method of a triazolopyrazine derivative. The intermediate is used to prepare sitagliptin, a drug for treating type 2 diabetes, and belongs to the pharmaceutical biochemical industry. field. Background technique [0002] Sitagliptin, the chemical name is (3R)-3-amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4 ,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, the CAS number is 486460-32-6, the English name is sitagliptin, and it is Merck of the United States The dipeptidyl peptidase-1V (DPP-1V) inhibitor developed by the company has the structural formula shown in Formula I. [0003] In October 2006, the US FDA approved sitagliptin for marketing. Sitagliptin is the first dipeptidylase-4 (DPP-4) inhibitor type 2 diabetes treatment drug, and its mechanism of action is different from that of previous oral hypoglycemic drugs. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 戚聿新鞠立柱陈军李新发
Owner XINFA PHARMA
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