762240-92-6

Basic information

• Product Name: 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride
• Synonyms: 3-(TRIFLUOROMETHYL)-5,6,7,8- TETRAHYDRO[1,2,4]TRIAZOLO[4,3-;3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine Hydrochloride;5,6,7,8-Tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazine Monohydrochloride;5,6,7,8-Tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine Monohydrochloride;3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochlorid;3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride;3-(trifluoromethyl)-5,6,7,8-retrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride;5,8-dimethyl-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine
• CAS NO: 762240-92-6
• Molecular Formula: C₆H₇F₃N₄*ClH
• Molecular Weight: 228.6
• EINECS: 1806241-263-5
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Pyrazine
• Mol File: 762240-92-6.mol
• Article Data: 30

Chemical Properties

• Melting Point: 236-246°C
• Boiling Point: 266.2 °C at 760 mmHg
• Flash Point: 114.8 °C
• Appearance: white solid
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride(762240-92-6)
• EPA Substance Registry System: 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride(762240-92-6)

Safety Data

• Hazard Codes: T
• Statements: 25
• Safety Statements: 45
• RIDADR: UN2811
• Hazardous Substances Data: 762240-92-6(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Synthetic route

2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide (763105-70-0) → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
With hydrogenchloride In methanol at 55℃; for 0.5h;	92%
With hydrogenchloride In ethanol; water at 50 - 54℃; for 3.5h; Temperature;	92.6%
With hydrogenchloride In isopropyl alcohol at 60 - 65℃; for 2h; Temperature; Inert atmosphere; Large scale;	91%

piperazinylidene trifluoroacetohydrazide → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
With hydrogenchloride In ethanol at 55 - 60℃; for 1h; Temperature; Solvent; Inert atmosphere;	90.71%

1-trifluoroacetyl-2-piperazinone → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
Stage #1: 1-trifluoroacetyl-2-piperazinone With hydrazine In water at 50 - 55℃; for 3h; Stage #2: With hydrogenchloride In water for 3h; Reflux;	86.2%

3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine (486460-20-2) → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
Stage #1: 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine With palladium on activated carbon; hydrogen In methanol at 40 - 45℃; under 2625.26 - 3375.34 Torr; for 24h; Stage #2: With hydrogenchloride In isopropyl alcohol at 0 - 5℃;	82.9%
Multi-step reaction with 2 steps 1: palladium 10% on activated carbon; hydrogen / ethanol / 45 °C / 3345.86 Torr / Large scale 2: hydrogenchloride / Isopropyl acetate / 1 h / 20 °C / Large scale View Scheme
With palladium 10% on activated carbon; hydrogen In Isopropyl acetate at 40 - 45℃; under 2585.81 Torr;	8 g

3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
With hydrogenchloride In Isopropyl acetate at 20℃; for 1h; Large scale;	51%

(S)-Sitagliptin → sodium (S)-3-amino-4-(2,4,5-trifluorophenyl)butanoate (1253056-11-9) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
Stage #1: (S)-Sitagliptin With water; sodium hydroxide In methanol at 25℃; Reflux; Stage #2: With hydrogenchloride In methanol; water

(1,2)-bis-trifluoroacetyl-1-pyrazinylhydrazide → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
Multi-step reaction with 3 steps 1: phosphoric acid / 5 h / 75 °C / Large scale 2: palladium 10% on activated carbon; hydrogen / ethanol / 45 °C / 3345.86 Torr / Large scale 3: hydrogenchloride / Isopropyl acetate / 1 h / 20 °C / Large scale View Scheme
Multi-step reaction with 2 steps 1: polyphosphoric acid / 5 h / 130 - 135 °C 2: palladium 10% on activated carbon; hydrogen / Isopropyl acetate / 40 - 45 °C / 2585.81 Torr View Scheme

2,2,2-trifluoro-N′-(pyrazin-2-yl)acetohydrazide → 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sulfuric acid / 12 h / 0 - 85 °C 2.1: hydrogen; palladium on activated carbon / methanol / 24 h / 40 - 45 °C / 2625.26 - 3375.34 Torr 2.2: 0 - 5 °C View Scheme

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (R)-tert-butyl 4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-ylcarbamate (486460-23-5)

Conditions	Yield
With 1,1'-carbonyldiimidazole In tetrahydrofuran at 55 - 60℃; for 12h;	99.02%
With triethylamine; 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride In methanol at 20 - 50℃; Reagent/catalyst; Solvent;	96%
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	95%

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3)

Conditions	Yield
With sodium hydroxide In water; ethyl acetate for 0.166667h; Product distribution / selectivity;	99%

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C6H6F3N4(1-)*Na(1+)

Conditions	Yield
With sodium hydroxide In water; ethyl acetate for 0.166667h; Product distribution / selectivity;	99%

C-(3-chloropyrazin-2-yl)-methylamine hydrochloride salt (939412-86-9) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → N-((3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxamide (1326282-23-8)

Conditions	Yield
Stage #1: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With N-ethyl-N,N-diisopropylamine; trichloromethyl chloroformate In tetrahydrofuran at 0℃; for 1h; Stage #2: C-(3-chloropyrazin-2-yl)-methylamine hydrochloride salt With triethylamine In dichloromethane for 3h;	99%

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (764667-65-4)

Conditions	Yield
With 4-methyl-morpholine In ethyl acetate for 6h; Reflux;	98.1%
With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 85℃; for 4h;	93.3%
With N-ethyl-N,N-diisopropylamine In Isopropyl acetate at 85℃; for 3.5h;	92%

4-Chloro-6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid methyl ester (1215221-92-3) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 6-Ethyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)thieno[2,3-d]pyrimidine-2-carboxylic acid methyl ester (1215221-93-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 0℃; for 16h; Reflux;	98%

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → Sitagliptin hydrochloride

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In N,N-dimethyl-formamide for 0.166667h; Stage #2: With 2-chloro-1,3-dimethylimidazolinium chloride In N,N-dimethyl-formamide at 20 - 25℃; for 5h; Reagent/catalyst;	97%

(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (486460-00-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With triethylamine In dichloromethane for 0.166667h; Stage #2: With benzotriazol-1-ol; dicyclohexyl-carbodiimide In dichloromethane at 25 - 30℃; for 4h; Stage #3: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride Further stages;	96.5%

(S)-2-benzyloxycarbonylamino-succinic acid 1-methyl ester (4668-42-2) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (S)-2-((benzyloxycarbonyl)amino)-4-oxo-4-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine)butanoic acid methyl ester (1404380-70-6)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In dichloromethane for 4h; Reflux;	95%

(4R)-4-(2,4,5-trifluorobenzyl)azetidin-2-one + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → sitagliptin (486460-32-6)

Conditions	Yield
With 2-Ethylhexanoic acid; triethylamine In tetrahydrofuran at 75℃; for 72h;	95%
With 2-Ethylhexanoic acid; triethylamine In tetrahydrofuran at 75℃; for 72h; Solvent; Temperature; Reagent/catalyst; Concentration;	95%

C17H16F3NO2 (1380569-10-7) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C23H21F6N5O (1306610-49-0)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	94%

(3R)-3-azido-4-(2,4,5-trifluorophenyl)-butyric acid (1293293-73-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (R)-3-azido-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one (1253055-98-9)

Conditions	Yield
Stage #1: (3R)-3-azido-4-(2,4,5-trifluorophenyl)-butyric acid; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In water; N,N-dimethyl-formamide for 0.25h; Stage #2: With 4-methyl-morpholine In water; N,N-dimethyl-formamide at 10℃; for 0.166667h; Stage #3: With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In water; N,N-dimethyl-formamide at 0℃; for 1h;	93%
With dmap; dicyclohexyl-carbodiimide In N,N-dimethyl-formamide at 0 - 25℃;

C17H14F3NO3 (1380243-46-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C23H19F6N5O2 (1380243-49-1)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	92%

(4R)-4-(2,4,5-trifluorobenzyl)azetidin-2-one + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → Sitagliptin hydrochloride

Conditions	Yield
In acetonitrile at 100℃; for 2h; Solvent; Temperature; Reagent/catalyst; Concentration;	92%

C17H16F3NO4S (1380243-45-7) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C23H21F6N5O3S (1380243-48-0)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	91%

C30H30F3NO4S2 + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C29H29F6N5O4S

Conditions	Yield
With triethylamine In 1,2-dichloro-ethane at 70℃; for 48h;	91%

2-bromoacetyl chloride (22118-09-8) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C8H8BrF3N4O

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide at 20℃; for 3h;	91%

cycl-isopropylidene malonate (2033-24-1) + (2,4,5-trifluorophenyl)acetic acid (209995-38-0) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (764667-65-4)

Conditions	Yield
Stage #1: cycl-isopropylidene malonate; (2,4,5-trifluorophenyl)acetic acid With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 45 - 55℃; Large scale reaction; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With trifluoroacetic acid In acetonitrile at 50 - 55℃; for 6h; Large scale reaction;	90%
Stage #1: cycl-isopropylidene malonate; (2,4,5-trifluorophenyl)acetic acid With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 20 - 50℃; for 2 - 3h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In N,N-dimethyl acetamide at 40 - 70℃; Stage #3: With sodium hydrogencarbonate In N,N-dimethyl acetamide; water at 20 - 45℃;	89%
Stage #1: cycl-isopropylidene malonate; (2,4,5-trifluorophenyl)acetic acid With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In acetonitrile at 20 - 50℃; for 2 - 3h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With trifluoroacetic acid In acetonitrile at 40 - 55℃; for 6h;
Stage #1: cycl-isopropylidene malonate; (2,4,5-trifluorophenyl)acetic acid With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In ISOPROPYLAMIDE at 0 - 40℃; for 2 - 3h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In ISOPROPYLAMIDE at 40 - 70℃;
Stage #1: cycl-isopropylidene malonate; (2,4,5-trifluorophenyl)acetic acid With dmap; N-ethyl-N,N-diisopropylamine In acetonitrile at 50℃; Stage #2: With pivaloyl chloride In acetonitrile at 50℃; for 3.75h; Stage #3: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With trifluoroacetic acid In acetonitrile at 55℃; for 6h;

(R)-3-(((benzyloxy)carbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid (1246960-25-7) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (R)-benzyl (4-oxo-4-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-1-(2,4,5-trifluorophenyl)butan-2-yl)carbamate (1242069-63-1)

Conditions	Yield
Stage #1: (R)-3-(((benzyloxy)carbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid With 4-methyl-morpholine; 2-chloro-4,6-dimethoxy-1 ,3,5-triazine In tetrahydrofuran at 0 - 5℃; for 1h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In tetrahydrofuran at 25℃; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water	90%
Stage #1: (R)-3-(((benzyloxy)carbonyl)amino)-4-(2,4,5-trifluorophenyl)butanoic acid With 1,1'-carbonyldiimidazole In tetrahydrofuran at 0℃; for 0.166667h; Inert atmosphere; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With triethylamine In tetrahydrofuran Reflux;
With triethylamine; 1,1'-carbonyldiimidazole In tetrahydrofuran at 0℃; Reflux; Inert atmosphere;

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione (764667-65-4)

Conditions	Yield
Stage #1: (2,4,5-trifluorophenyl)acetic acid With cycl-isopropylidene malonate; N-ethyl-N,N-diisopropylamine; dmap In ISOPROPYLAMIDE at 20 - 40℃; Stage #2: With pivaloyl chloride In ISOPROPYLAMIDE at 0 - 5℃; for 1 - 3h; Stage #3: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In ISOPROPYLAMIDE at 40 - 70℃;	89%
Stage #1: cycl-isopropylidene malonate; (2,4,5-trifluorophenyl)acetic acid With dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl acetamide at 0 - 40℃; for 2 - 3h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In N,N-dimethyl acetamide at 40 - 70℃; for 1h;

para-fluorophenyl isocyanate (1195-45-5) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → N-(4-Fluorophenyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1, 2, 4]triazolo [4,3-a]pyrazine-7-carboxamide

Conditions	Yield
With triethylamine In toluene at 75 - 80℃; for 4h;	88.2%

C10H7F3O2 + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (Z/E)-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-3-en-1-one

Conditions	Yield
Stage #1: C10H7F3O2 With 1,1'-carbonyldiimidazole In ethyl acetate at 20℃; for 0.5h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With triethylamine In ethyl acetate at 20℃; Concentration;	87.2%

3-nitropropionic acid (504-88-1) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 3-nitro-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propan-1-one

Conditions	Yield
Stage #1: 3-nitropropionic acid; 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0 - 20℃; Stage #2: With sodium hydrogencarbonate In water; ethyl acetate; acetonitrile	85%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0 - 20℃; for 20h;	79%
With 4-methyl-morpholine; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In acetonitrile at 0 - 20℃; for 20h;	79%

Acetic acid 2-acetoxy-3-(4-chloro-6-ethyl-thieno[2,3-d]pyrimidin-2-yloxy)-propyl ester (1215221-53-6) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → acetic acid 2-acetoxy-3-[6-ethyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-thieno[2,3-d]pyrimidin-2-yloxy]-propyl ester (1215221-54-7)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine at 80℃; for 16h;	85%

C16H14F3NO4S (1380243-47-9) + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → C22H19F6N5O3S (1380243-50-4)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In acetonitrile at 0 - 20℃; for 24h;	85%

5-(2-(3-fluorophenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 4-(3-fluorophenyl)-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)butane-1,3-dione

Conditions	Yield
Stage #1: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride With 4-methyl-morpholine In ethyl acetate at 40℃; Stage #2: 5-(2-(3-fluorophenyl)-1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione In ethyl acetate Reflux;	85%

(2S)-2-[(t-butoxycarbonyl)amino]-3-{4-[(3-cyano pyridin-2-yl)oxy]phenyl}propanoic acid + 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → 2-{4-[(2S)-2-(t-butoxycarbonyl)amino-3-oxo-3-(3-(trifluoro methyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)propyl]phenoxy}nicotinonitrile

Conditions	Yield
With (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide for 5h;	84.5%

Upstream product

• 486460-21-3 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 
• 486460-20-2 3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyrazine 
• 823817-55-6 (S)-Sitagliptin 
• 763105-70-0 2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide 

Downstream Products

• 764667-65-4 1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl)butane-1,3-dione 
• 1253055-98-9 (R)-3-azido-1-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 1215222-17-5 benzoic acid 6-propyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)thieno[2,3-d]pyrimidin-2-ylmethyl ester 
• 1215221-61-6 7-(2-Benzylsulfanyl-6-propyl-thieno[2,3-d]pyrimidin-4-yl)-3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 
• 1215221-41-2 4-{3-[6-propyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-yl)-thieno[2,3-d]pyrimidin-2-yloxy]-phenyl}-piperazine-1-carboxylic acid t-butyl ester 
• 1215221-39-8 7-[2-(3-piperazin-1-yl-phenoxy)-6-propyl-thieno[2,3-d]pyrimidin-4-yl]-3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 
• 1215167-66-0 Phenyl-[6-propyl-4-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-thieno[2,3-d]pyrimidin-2-yl]-amine 
• 486459-71-6 (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine hydrochloride 
• 1169707-30-5 (3R)-3-[[(1R)-1-phenylethyl]amino]-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one 
• 1169707-29-2 (R,Z)-3-[(1-phenylethyl)amino]-1-{3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl}-4-(2,4,5-trifluorophenyl)but-2-en-1-one 
• 654671-78-0 sitagliptin phosphate 
• 486460-21-3 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 
• 959839-50-0 4-[(4,5-dimethyl-6-oxo-1,6-dihydropyridazin-3-yl)methyl]-N,N-dimethyl-2-{[3-(trifluoromethyl)-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]carbonyl}benzenamine 
• 959839-54-4 6-(4-Fluoro-3-{[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]carbonyl}benzyl)-4,5-dimethylpyridazin-3(2H)-one 

Relevant articles and documents

Green synthesis method of sitagliptin intermediate

The invention relates to a green synthesis method of sitagliptin intermediate, and belongs to the technical field of drug intermediate synthesis. In order to solve the problems that an existing pollution is large and unstable, a green synthesis method of sitagliptin intermediate is provided, and the method comprises the following steps: in an ether solvent, reacting trifluoroacetic acid ethyl ester with ethylenediamine to generate 2 - trifluoroacetamide ethyl ethylamine. Under the presence of an acid binding agent, 2 - trifluoroacetamide ethyl ethylamine and halogenated ethyl acetate are condensed and reacted under the conditions of 45 °C - 65 °C DEG C to form an intermediate, and then, the temperature is raised to 90 - 110 °C for cyclization reaction to generate N - trifluoroacetyl piperidine. The N -trifluoroacetyl piperidine ketone is reacted with hydrazine hydrate to generate 1 -trifluoroacetylamino -2 -piperazinone. The product is reacted with hydrochloric acid to form a ring-forming reaction, and a product sitagliptin intermediate is obtained. The method provided by the invention has the advantages of high product yield and purity on the whole, and has the advantage of environmental friendliness.

Preparation method of sitagliptin intermediate

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.

Microwave-Assisted Synthesis and Antituberculosis Screening of Some 4-((3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-l)methyl)benzenamine Hybrids

In the present investigation, a series of 4-((3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methyl)benzenamine analogs 6a–o were synthesized and characterized by IR, NMR (1H and 13C), and mass spectra. All newly synthesized compounds 6a–o were prepared under conventional and microwave irradiation methods. These compounds obtained in higher yields and in shorter reaction times in the microwave irradiation method when compared with the conventional method. Synthesized compounds 6a–o were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Ra using an established XTT reduction menadione assay. Among the screened compounds, 6i (IC50: 1.82?μg/mL), 6j (IC50: 1.02?μg/mL), and 6k (IC50: 1.59?μg/mL) showed excellent activity. Furthermore, compound 6i showed MIC90 value of 16.02?μg/mL. In summary, the results indicate the identification of some novel, selective, and specific inhibitors against M.?tuberculosis that can be explored further for the potential antitubercular drug.