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Preparation method of sitagliptin intermediate

A technology for sitagliptin and intermediates, applied in the field of pharmaceutical intermediate synthesis, can solve the problems of poor product yield, poor environmental protection, poor reaction selectivity and the like, and achieves the effects of easy operation, easy handling and high selectivity

Active Publication Date: 2021-02-12
江苏八巨药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] In this method, when using ethyl trifluoroacetate and hydrazine hydrate to react, the two amino groups of hydrazine hydrate are easy to react with ethyl trifluoroacetate with strong activity, the reaction selectivity is poor, and a large amount of by-products N,N'- Two (trifluoroacetyl) hydrazine makes product yield relatively poor, and uses phosphorus oxychloride to produce a large amount of phosphorus-containing waste water, and environmental protection is poor

Method used

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  • Preparation method of sitagliptin intermediate
  • Preparation method of sitagliptin intermediate
  • Preparation method of sitagliptin intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0029] Take 30.05g (0.50mol) of 1,2-ethylenediamine and dissolve it in 150ml of ethanol, stir evenly, cool down to 0-5°C, control the temperature and slowly add 61.28g (0.50mol) of ethyl chloroacetate dropwise, and control the temperature at 0 ~5°C, after dropping, stir for 5 hours, then slowly add 20% sodium ethoxide ethanol solution (containing 34.03g sodium ethoxide, 0.50mol) dropwise, temperature control ≤ 25°C, stir at room temperature until complete reaction, After the reaction is finished, filter, collect the filtrate and carry out vacuum distillation to remove the solvent, add acetone to the concentrate and carry out recrystallization treatment, obtain the corresponding product wet product, dry to obtain 2-piperazinone 42.55g (0.425mol ), the yield is 85.0%, and the purity is more than or equal to 98.0%.

Embodiment 2

[0031] Take 50.06 g (0.50 mol) of 2-piperazinone and dissolve it in 500 ml of ethanol, add 31.29 g of hydrazine hydrate with a content of 80% (equivalent to 0.50 mol of hydrazine hydrate), heat up to reflux reaction and keep it overnight, and then add no 10 g of magnesium sulfate in water was dried and stirred for 30 minutes, suction filtered, and the filtrate was collected for distillation and precipitation under reduced pressure to obtain 54.22 g (equivalent to 0.475 mol) of the oily substance of the intermediate product piperazine hydrazone, with a yield of 95.0% and a purity of ≥97.0% .

[0032] Synthesis of (N-[(2Z)-piperazin-2-ylidene]trifluoroacetylhydrazine

[0033] Take 54.22g (0.475mol) of the piperazine hydrazone oil obtained above and dissolve it in 480ml of acetonitrile, cool down to 0-5°C, then slowly add 67.49g (0.475mol) of ethyl trifluoroacetate dropwise, after the dropwise addition, slowly raise the temperature to 25°C, heat preservation reaction overnight, ...

Embodiment 3

[0036] Get 50.06 g (0.50 mol) of 2-piperazinone and dissolve it in 400 ml of ethanol, add 45.9 g of hydrazine hydrate with a content of 80% (equivalent to 0.75 mol of hydrazine hydrate), heat up to reflux reaction and keep it overnight, and then add no 15 g of magnesium sulfate in water was dried and stirred for 45 minutes, suction filtered, and the filtrate was collected for vacuum distillation and precipitation to obtain 54.56 g of the oily substance of the intermediate product piperazine hydrazone, with a yield of 95.3% and a purity of ≥97.8%.

[0037] Synthesis of (N-[(2Z)-piperazin-2-ylidene]trifluoroacetylhydrazine

[0038] Take 54.56g (0.478mol) of the piperazine hydrazone oil obtained above and dissolve it in 500ml of acetonitrile, cool down to 0-5°C, then slowly add 88.29g (0.621mol) of ethyl trifluoroacetate dropwise, after the dropwise addition, slowly raise the temperature to 23°C, heat preservation reaction overnight, then add 15g of sodium sulfate to dry, filter wi...

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Abstract

The invention relates to a preparation method of a sitagliptin intermediate, and belongs to the technical field of drug intermediate synthesis. In order to solve the problems of low product yield andpoor environmental protection property in the prior art, the invention provides a preparation method of a sitagliptin intermediate, and the method comprises the following steps: reacting 2-piperazinone with hydrazine hydrate in an alcohol solvent to generate piperazine hydrazone; in an acetonitrile or ether solvent, reacting the piperazine hydrazone with ethyl trifluoroacetate to obtain a corresponding intermediate N -[(2Z-) piperazine -2-subunit] trifluoroacethydrazide; and performing cyclization and salification reaction on the N -[(2Z-) piperazine -2-subunit] trifluoroacethydrazide in an alcohol solvent under the action of hydrochloric acid to obtain the corresponding sitagliptin intermediate 3-trifluoromethyl 5, 6, 7, 8-tetrahydro-1, 2, 4-triazole [4, 3-a] pyrazine hydrochloride. The reaction has the effects of high selectivity and high product yield.

Description

technical field [0001] The invention relates to a preparation method of a sitagliptin intermediate, belonging to the technical field of synthesis of pharmaceutical intermediates. Background technique [0002] 3-trifluoromethyl-5,6,7,8-tetrahydro-1,2,4-triazol[4,3-a]pyrazine hydrochloride (Ⅱ) is used in the synthesis of sitagliptin The key intermediate of , its structural formula is as follows: [0003] [0004] Regarding the synthesis of this intermediate, in the existing literature, 2-chloropyrazine is first reacted with hydrazine hydrate and trifluoroacetic anhydride, and then undergoes dehydration of phosphoric acid to form a ring, palladium carbon catalytic hydrogenation reduction, and hydrochloric acid to prepare a compound of formula II. , the total yield is 25%, and the route of this synthetic technique is as follows: [0005] [0006] In this method, the price of 2-chloropyrazine, trifluoroacetic anhydride, superphosphoric acid and palladium carbon catalyst i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 程祖福程加铭陈恬胡建涛王建军汪东海
Owner 江苏八巨药业有限公司
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