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Process for the preparation of triazole and salt thereof

a triazole and salt technology, applied in the field of triazole and salt thereof, can solve the problems of long cycle time, complex recovery of solvents, and relatively low productivity of triazole, and achieve the effect of increasing productivity

Active Publication Date: 2018-08-16
F I S FAB ILTALIANA SINTETICI SPA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides an improved process for the preparation of Triazole and salts thereof that increases productivity and avoids the need for different solvents for both the conversion reaction and product isolation.

Problems solved by technology

The prior art methods this suffers of the drawbacks that the productivity of triazole is relatively low, especially considering the large volumes of solvents used, thus effecting the overall production capacity.
Moreover, considering large productions, the recovery of the solvents is quite complex and require long cycling time.

Method used

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  • Process for the preparation of triazole and salt thereof
  • Process for the preparation of triazole and salt thereof
  • Process for the preparation of triazole and salt thereof

Examples

Experimental program
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Effect test

example 1

[0088]Preparation of Triazole of formula (II) as HCl salt in 5 volumes of ethanol with the presence catalytic amount of water.

[0089]Into a three necked round bottom flask, under nitrogen atmosphere, 250 g of Amidine of formula (III), 1000 mL of denatured ethanol (4V) and 12.5 mL of water (0.05V). The obtained suspension is heated at temperature 60° C. and stirring at the same temperature at least 15 min. Then a solution of 45 g HCl (gas) in 250 mL denatured ethanol (1V) was dosed in 20 min., keeping the temperature at temperature range from 55° C. to 60° C. The resulting mixture was stirred for 1 hour at the same temperature. The slurry was cooled at room temperature and was stirred for least 30 min. at the same temperature. The obtained slurry was filtered and the solid was washed with 250 mL of denatured ethanol. Drying the solid under vacuum at T=45° C., 246.25 g of Triazole of formula (II) as HCl salt were obtained with 90.53% of molar yield.

example 2

[0090]Preparation of Triazole of formula (II) as HCl salt in 1.7 volumes of ethanol.

[0091]Into a three necked round bottom flask, under nitrogen atmosphere, 500 g of Amidine of formula (III), 450 mL of denatured ethanol (0.9V). The obtained suspension is heated at temperature 60° C. and stirring at the same temperature at least 15 min. Then a solution of 90 g HCl (gas) in 315 mL denatured ethanol (0.8V) was dosed in 20 min., keeping the temperature at temperature range from 55° C. to 60° C. The resulting mixture was stirred for 1 hour at the same temperature. The slurry was cooled at room temperature and was stirred for least 30 min. at the same temperature. The obtained slurry was filtered and the solid was washed with 500 mL of denatured ethanol. Drying the solid under vacuum at T=45° C., 493.5 g of Triazole of formula (II) as HCl salt were obtained with 90.71% of molar yield.

example 3

[0092]Preparation of Triazole of formula (II) as HCl salt in 1.7 volumes of ethanol.

[0093]Into a three necked round bottom flask, under nitrogen atmosphere, 180 g of Amidine of formula (III) and 180 mL of denatured ethanol (1V). The obtained suspension is heated at temperature 60° C. and stirring at the same temperature at least 15 min. 122,1 g of a solution of HCl (gas) on denatured ethanol (0.7V) were dosed for 20 min., keeping the temperature at temperature range from 60° C. to 70° C. The resulting mixture was heated a reflux (T=79° C.) for 30 min. The slurry was cooled at room temperature and was stirred for least 30 min. at the same temperature. The obtained slurry was filtered washing the solid with 180 mL of denatured ethanol. Drying the solid under vacuum at T=50° C., 175,7 g of Triazole of formula (II) as HCl salt were obtained with 89,94% of molar yield and HPLC purity of 99.8% A / A%.

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Abstract

An improved process for the preparation of Triazole and salts thereof, a key intermediate for the synthesis of Sitagliptine is disclosed.

Description

TECHNICAL FIELD[0001]The present invention relates to an improved process for the preparation of Triazole and salts thereof, a key intermediate for the synthesis of Sitagliptin.BACKGROUND OF THE INVENTION[0002]The compound Triazole, having the following chemical formula (II):[0003]has the chemical name 3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine and CAS RN 486460-21-3.[0004]Triazole is a key intermediate for the synthesis of Sitagliptin of formula (I):a substance also known as MK-0431 and having chemical name 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-5,6,7,8-tetrahydro-3-(tri-fluoromethyl)-1,2,4-triazolo[4,3-a] pyrazine. Sitagliptin is commercially available as the phosphate salt monohydrate under the trade name Januvia.[0005]This active pharmaceutical ingredient is an oral antihyperglycemic (antidiabetic drug) of the dipeptidyl peptidase-4 (DPP-4) inhibitor. This enzyme-inhibiting drug is used alone or in combination with other oral antihypergly...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04A61K31/4985C12P7/26
CPCC07D487/04C12P7/26A61K31/4985C12P17/182
Inventor GALVAGNI, MARCOGRENDELE, ENNIOLORA, GIOVANNI
Owner F I S FAB ILTALIANA SINTETICI SPA
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