764667-65-4

Basic information

• Product Name: (2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one
• Synonyms: 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;1-(3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophen;rac-Sitagliptin 3-Ketone;1,3-Butanedione,1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)-;-4-(2,4,5-trifluorophenyl);-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H);1-(3-(Trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorop;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-one
• CAS NO: 764667-65-4
• Molecular Formula: C₁₆H₁₂F₆N₄O₂
• Molecular Weight: 406.28
• EINECS: 1806241-263-5
• Product Categories: Aromatics Compounds;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Pyrazine
• Mol File: 764667-65-4.mol
• Article Data: 33

Chemical Properties

• Melting Point: 82-84°C
• Boiling Point: 513.902 °C at 760 mmHg
• Flash Point: 264.598 °C
• Appearance: brown oil
• Density: 1.607 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.58
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 11.44±0.20(Predicted)
• CAS DataBase Reference: (2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one(CAS DataBase Reference)
• NIST Chemistry Reference: (2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one(764667-65-4)
• EPA Substance Registry System: (2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one(764667-65-4)

Safety Data

• Hazardous Substances Data: 764667-65-4(Hazardous Substances Data)

Usage

Chemical Properties

Brown Oil

Uses

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-one is a Sitagliptin intermediate.

InChI:InChI=1/C16H12F6N4O2/c17-10-6-12(19)11(18)4-8(10)3-9(27)5-14(28)25-1-2-26-13(7-25)23-24-15(26)16(20,21)22/h4,6H,1-3,5,7H2

Synthetic route

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%

3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 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
In N,N-dimethyl acetamide at 41.1℃; Kinetics; Further Variations:; Temperatures;	91%

4-(2,4,5-trifluorophenyl)-3-oxobutanoic acid (1256815-03-8) + 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) → 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: 4-(2,4,5-trifluorophenyl)-3-oxobutanoic acid With oxalyl dichloride In dichloromethane at 10 - 35℃; Stage #2: 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine With triethylamine In dichloromethane at 0 - 15℃;	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;

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-one sodium salt → 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 hydrogenchloride In water; ethyl acetate at 25 - 30℃;	90%
With hydrogenchloride In water; ethyl acetate at 25 - 30℃; for 0.5h;	90%

3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]propanenitrile + 2,4,5-trifluorobenzyl bromide (157911-56-3) → 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-trifluorobenzyl bromide With magnesium In tetrahydrofuran at 35 - 45℃; for 2.16667h; Stage #2: 3-oxo-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]propanenitrile In tetrahydrofuran; toluene at 0 - 5℃; for 4h; Temperature;	89.5%

(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;

cycl-isopropylidene malonate (2033-24-1) + 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) + (2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 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 N,N-dimethyl acetamide at 50 - 55℃; Stage #2: 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine With trifluoroacetic acid In N,N-dimethyl acetamide at 55℃; for 6h;	84%

3-oxo-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester (1151240-88-8) + 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) → 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 potassium tert-butylate In tetrahydrofuran at 20℃; for 1h; Reagent/catalyst; Solvent; Temperature;	82%

cycl-isopropylidene malonate (2033-24-1) + 2-(2,3,4-trifluorophenyl)acetic acid + 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-(2,3,4-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In Isopropyl acetate at 45℃; for 0.166667h; Stage #2: cycl-isopropylidene malonate In Isopropyl acetate at 20 - 40℃; for 25.5h; Stage #3: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In Isopropyl acetate at 90℃; for 12h;	71%
Stage #1: 2-(2,3,4-trifluorophenyl)acetic acid With 1,1'-carbonyldiimidazole In ISOPROPYLAMIDE at 45℃; for 0.166667h; Stage #2: cycl-isopropylidene malonate In ISOPROPYLAMIDE at 20 - 50℃; for 25h; Stage #3: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride In ISOPROPYLAMIDE at 90℃; for 12h;	69%

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
Multi-step reaction with 2 steps 1.1: potassium carbonate / toluene / 3 h / 92 - 95 °C 2.1: magnesium / tetrahydrofuran / 2.17 h / 35 - 45 °C 2.2: 4 h / 0 - 5 °C View Scheme

C15H13F3O4 + 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: C15H13F3O4; 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; Stage #2: With sodium hydrogencarbonate In N,N-dimethyl acetamide; water at 20 - 45℃; for 3 - 5h;

sodium 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-2-(2,4,5-trifluorophenyl)ethanolate (1253055-91-2) + 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 methanesulfonic acid In acetonitrile at 25 - 85℃; Product distribution / selectivity;

3-hydroxy-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8E)-yl)-4-(2,4,5-trifluorophenyl)butan-1-one → 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 potassium dichromate; sulfuric acid; acetic acid at 25 - 30℃; for 24h;

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 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 N-ethyl-N,N-diisopropylamine In toluene at 25 - 30℃; Reflux;
With N-ethyl-N,N-diisopropylamine In toluene at 25 - 30℃; for 8h; Product distribution / selectivity; Reflux;
Stage #1: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride With 4-methyl-morpholine In ethyl acetate at 10℃; for 20h; Stage #2: 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione In ethyl acetate for 6h; Reflux;	115 g

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → 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
Multi-step reaction with 2 steps 1.1: dmap / acetonitrile / 25 - 30 °C 1.2: 30 - 50 °C 2.1: hydrogenchloride / ethyl acetate; water / 0.5 h / 25 - 30 °C View Scheme
Multi-step reaction with 3 steps 1.1: oxalyl dichloride / dichloromethane; N,N-dimethyl-formamide / 4 h / 20 - 25 °C 2.1: dichloromethane / 4 h / -5 - 30 °C / Inert atmosphere 2.2: 0 - 5 °C 3.1: N-ethyl-N,N-diisopropylamine / toluene / 8 h / 25 - 30 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine / ISOPROPYLAMIDE / 2 - 3 h / 0 - 40 °C 2.1: ISOPROPYLAMIDE / 40 - 70 °C 2.2: 20 - 45 °C View Scheme

2-(2,4,5-trifluorophenyl)acetyl chloride (1176895-65-0) → 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
Multi-step reaction with 2 steps 1.1: dichloromethane / 4 h / -5 - 30 °C / Inert atmosphere 1.2: 0 - 5 °C 2.1: N-ethyl-N,N-diisopropylamine / toluene / 8 h / 25 - 30 °C / Reflux View Scheme

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride → 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
Multi-step reaction with 2 steps 1.1: dmap / acetonitrile / 25 - 30 °C 1.2: 30 - 50 °C 2.1: hydrogenchloride / ethyl acetate; water / 0.5 h / 25 - 30 °C View Scheme

sitagliptin (486460-32-6) → 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: sitagliptin With sulfuric acid; sodium nitrite Stage #2: With potassium dichromate
Stage #1: sitagliptin With sulfuric acid; sodium nitrite Stage #2: With potassium dichromate

1-bromo-2,4,5-trifluorobenzene (327-52-6) → 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
Multi-step reaction with 2 steps 1: copper(l) iodide; L-valine; potassium phosphate / dimethyl sulfoxide / 24 h / 90 °C / Inert atmosphere 2: potassium tert-butylate / tetrahydrofuran / 1 h / 20 °C View Scheme

1-t-Butoxycarbonylpiperazine (57260-71-6) → 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
Multi-step reaction with 2 steps 1.1: 1,4-dioxane / 1 h / 20 °C 1.2: 7 h / 70 °C 2.1: potassium tert-butylate / tetrahydrofuran / 1 h / 20 °C View Scheme

2-oxo-2-(2,4,5-trifluorophenyl)acetamide → 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
Multi-step reaction with 4 steps 1: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 2: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 3: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 4: N,N-dimethyl acetamide / 6 h / 70 °C View Scheme

(2,4,5-trifluorophenyl)oxoacetic acid → 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
Multi-step reaction with 3 steps 1: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 2: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 3: N,N-dimethyl acetamide / 6 h / 70 °C View Scheme

triazale + 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → 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
In N,N-dimethyl acetamide at 70℃; for 6h;

2,4-dichloro-5-fluorobenzoyl chloride (86393-34-2) → 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

Multi-step reaction with 8 steps 1: potassium fluoride; tetraphenylphosphonium bromide; 18-crown-6 ether / 1,2-dichloro-benzene / 15 h / 120 - 130 °C / Inert atmosphere 2: 1,2-dichloro-benzene / 140 °C 3: potassium fluoride / 1,2-dichloro-benzene / 7 h / 110 °C / Inert atmosphere 4: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 5: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 6: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 7: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 8: N,N-dimethyl acetamide / 6 h / 70 °C View Scheme

2-chloro-4,5-difluorobenzoyl fluoride → 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

Multi-step reaction with 7 steps 1: 1,2-dichloro-benzene / 140 °C 2: potassium fluoride / 1,2-dichloro-benzene / 7 h / 110 °C / Inert atmosphere 3: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 4: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 5: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 6: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 7: N,N-dimethyl acetamide / 6 h / 70 °C View Scheme

2,4,5-trifluorobenzoyl fluoride → 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

Multi-step reaction with 6 steps 1: potassium fluoride / 1,2-dichloro-benzene / 7 h / 110 °C / Inert atmosphere 2: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 3: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 4: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 5: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 6: N,N-dimethyl acetamide / 6 h / 70 °C View Scheme

2,4,5-trifluorobenzene-1-carbonyl cyanide → 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

Multi-step reaction with 5 steps 1: sulfuric acid; sodium chloride / water / 8 h / 20 °C / Inert atmosphere 2: hydrogenchloride / water / 5 h / 70 °C / Inert atmosphere 3: phosphonic Acid; iodine; methanesulfonic acid / 24 h / 110 °C 4: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 5: N,N-dimethyl acetamide / 6 h / 70 °C View Scheme

2-(2,4,5-trifluorophenyl)acetonitrile (220141-74-2) → 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
Multi-step reaction with 3 steps 1.1: 40 - 45 °C / Inert atmosphere 2.1: trifluoroacetic acid / dichloromethane / 10 - 30 °C 3.1: oxalyl dichloride / dichloromethane / 10 - 35 °C 3.2: 0 - 15 °C View Scheme

tert-butyl 3-oxo-4-(2,4,5-trifluorophenyl)butanoate → 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
Multi-step reaction with 2 steps 1.1: trifluoroacetic acid / dichloromethane / 10 - 30 °C 2.1: oxalyl dichloride / dichloromethane / 10 - 35 °C 2.2: 0 - 15 °C View Scheme

(R)-1-phenyl-ethyl-amine (3886-69-9) + 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) → (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 (1169707-29-2)

Conditions	Yield
With acetic acid In toluene at 110℃; Reflux;	100%
With acetic acid In isopropyl alcohol at 40℃;	99.7%
In acetic acid; isopropyl alcohol at 50℃; for 18h;	95.2%
With acetic acid for 5h; Product distribution / selectivity; Reflux;	92.07%

(R)-1-phenyl-ethyl-amine (3886-69-9) + 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) → (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 (1169707-30-5)

Conditions	Yield
With sodium tris(acetoxy)borohydride; trifluoroacetic acid In 1,2-dichloro-ethane at 20℃; for 5h; Reagent/catalyst; Solvent; stereoselective reaction;	95%

(R)-2-methylpropane-2-sulfinamide (196929-78-9) + 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) → (R)-2-methyl-N-((R)-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)propane-2-sulfinamide (1349649-83-7)

Conditions	Yield
With platinum(IV) oxide; hydrogen In tetrahydrofuran at 0℃; under 4500.45 Torr; for 5h; Catalytic behavior; Temperature; Pressure; Solvent;	93%

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) → (Z)-3-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 (767340-03-4)

Conditions	Yield
With ammonium hydroxide; ammonium acetate In methanol at 58℃; for 0.5h;	92%
With ammonium acetate In methanol at 40 - 45℃; Large scale reaction;	82%
With ammonia In methanol at 25 - 65℃;	79.8%

L-phenylglycine amide (6485-52-5) + 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) → (2S)-2({(1Z)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-]pyrazin-7(8H)-yl]prop-1-enyl}amino-2-phenylethanamide) (769195-19-9)

Conditions	Yield
With acetic acid In isopropyl alcohol at 45℃; for 10h;	91.3%
In acetic acid; isopropyl alcohol at 50℃; for 18h;

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) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: 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 With ammonium formate; chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-2-methylphenylphosphine In methanol at 55℃; for 5h; Stage #2: With hydrogen In methanol at 55℃; under 12929 Torr; for 20h; Product distribution / selectivity;	91%
Multi-step reaction with 3 steps 1: isopropyl alcohol; acetic acid / 18 h / 50 °C 2: sodium tetrahydroborate; acetic acid / tetrahydrofuran / 3 h / 20 °C 3: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr View Scheme
Multi-step reaction with 3 steps 1: isopropyl alcohol; acetic acid / 18 h / 50 °C 2: sodium tetrahydroborate; formic acid / tetrahydrofuran / -30 °C 3: 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid / methanol; water / 14 h / 50 °C / 7500.75 Torr View Scheme

L-phenylglycine amide (6485-52-5) + 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) → (2S)-2({(1R)-3-oxo-1-(2,4,5-trifluorobenzyl)-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-α]pyrazin-7(8H)-yl]propyl}amino)-2-phenylethanamide (769195-20-2)

Conditions	Yield
With sodium tris(acetoxy)borohydride; acetic acid In acetonitrile at 20℃; for 5h; Reagent/catalyst; stereoselective reaction;	87%

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) → dehydrositagliptin (847445-81-2)

Conditions	Yield
With ammonium acetate; ammonia In methanol; water at 55℃; for 6h;	75%
With ammonium acetate; ammonia In methanol; water at 0 - 45℃;
With ammonium acetate

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) → (3E)-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-3-en-1-one

Conditions	Yield
Stage #1: 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 With dimethylsulfide borane complex In methanol at 20℃; for 0.416667h; Stage #2: With methanesulfonyl chloride; triethylamine In tetrahydrofuran at 0 - 40℃; for 20h; Temperature; Reagent/catalyst; Solvent;	65.5%

N-methoxylamine hydrochloride (593-56-6) + 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) → 3-(methoxyimino)-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 (1376615-90-5)

Conditions	Yield
With pyridine In ethanol at 20℃; for 4h;	20%
With pyridine In ethanol at 20℃; for 4h;	20%

ammonia (7664-41-7) + 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) → dehydrositagliptin (847445-81-2)

Conditions	Yield
With ammonium acetate In methanol; water at 0 - 45℃; for 0.25 - 0.5h;

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) → 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-one calcium salt

Conditions	Yield
Stage #1: 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 With sodium hydroxide In methanol; water at 25 - 30℃; Stage #2: With calcium acetate In methanol; water at 25 - 60℃;

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) → (R/S)-3-hydroxy-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 (1253056-01-7)

Conditions	Yield
With sodium tetrahydroborate; acetic acid at 15℃; for 2h; Product distribution / selectivity;
With methanol; sodium tetrahydroborate at 0℃; for 1.5h;

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) → (R)-3-hydroxy-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 (1253055-99-0)

Conditions	Yield
Stage #1: 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 With dimethylsulfide borane complex; (3aR)-1-methyl-3,3-diphenyl-tetrahydro-pyrrolo[1,2-c][1,3,2]oxazaborole In toluene at 0 - 5℃; for 3h; Inert atmosphere; Stage #2: With methanol In toluene
With β-nicotinamide adenine dinucleotide phosphate disodium salt In aq. phosphate buffer; isopropyl alcohol at 37℃; Enzymatic reaction;	n/a

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) → (Z)-3-(hydroxyimino)-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 (1253056-15-3)

Conditions	Yield
With pyridine; hydroxylamine hydrochloride In ethanol at 25 - 30℃; for 2h;

Upstream product

• 762240-92-6 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 
• 2033-24-1 cycl-isopropylidene malonate 
• 243666-12-8 2-(2,3,4-trifluorophenyl)acetic acid 
• 486460-32-6 sitagliptin 
• 1152439-73-0 2,2-dimethyl-5-[2-(2,4,5-trifluorophenyl)acetyl]-[1,3]dioxane-4,6-dione 
• 220141-74-2 2-(2,4,5-trifluorophenyl)acetonitrile 
• 1256815-03-8 4-(2,4,5-trifluorophenyl)-3-oxobutanoic acid 
• 486460-21-3 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine 
• 101513-67-1 2,4,5-trifluorobenzoyl fluoride 
• 86393-34-2 2,4-dichloro-5-fluorobenzoyl chloride 
• 764667-64-3 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 57260-71-6 1-t-Butoxycarbonylpiperazine 
• 327-52-6 1-bromo-2,4,5-trifluorobenzene 
• 1151240-88-8 3-oxo-4-(2,4,5-trifluorophenyl)-butyric acid ethyl ester 

Downstream Products

• 767340-03-4 (Z)-3-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 
• 486460-32-6 sitagliptin 
• 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 
• 847445-81-2 dehydrositagliptin 
• 1253056-01-7 (R/S)-3-hydroxy-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 
• 1253055-99-0 (R)-3-hydroxy-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 
• 1253056-15-3 (Z)-3-(hydroxyimino)-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 
• 1376615-90-5 3-(methoxyimino)-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 
• 823817-55-6 (S)-Sitagliptin 
• 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 
• 769195-20-2 (3R)-3-[[(1S)-1-carboxamidophenylmethyl]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 
• 1675201-14-5 (3E)-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)but-3-en-1-one 
• 823817-56-7 (R/S)-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 
• 1253056-18-6 C₁₆H₁₂F₆N₄O 

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