767340-03-4

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)but-2-en-2-amine
• Synonyms: （2Z）-2-amine -4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro][1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl] -1-(2,4,5-trifluorophenyl)but-2-en (2-4);(2Z)-3-Amino-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-α]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)-2-buten-1-one;(2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-α]pyrazin -7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine;(2Z)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a];(2Z)-3-Amino-1-[5,6-dihydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazin-7(8H)-yl]-4-(2,4,5-trifluorophenyl)-2-buten-1-one;(2Z)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine;(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)but-2-en-2-amine;3-AMino-1-(3-trifluoroMethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-but-2-en-1-one
• CAS NO: 767340-03-4
• Molecular Formula: C₁₆H₁₃F₆N₅O
• Molecular Weight: 405.3
• EINECS: 1308068-626-2
• Product Categories: All Inhibitors;Heterocycles;Inhibitors;Intermediates;Intermediates & Fine Chemicals;Pharmaceuticals;Pyrazine
• Mol File: 767340-03-4.mol
• Article Data: 17

Chemical Properties

• Melting Point: 178-180°C
• Boiling Point: 555.1 °C at 760 mmHg
• Flash Point: 289.5 °C
• Appearance: /
• Density: 1.6 g/cm³
• Refractive Index: 1.59
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 4.11±0.70(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)but-2-en-2-amine(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)but-2-en-2-amine(767340-03-4)
• 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)but-2-en-2-amine(767340-03-4)

Safety Data

• Hazardous Substances Data: 767340-03-4(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Uses

Sitagliptin intermediate. A dipeptidyl peptidase-4 inhibitor and an anti-hypertensive agent for the treatment of diabetes and hypertension.

InChI:InChI=1/C16H13F6N5O/c17-10-6-12(19)11(18)4-8(10)3-9(23)5-14(28)26-1-2-27-13(7-26)24-25-15(27)16(20,21)22/h4-6H,1-3,7,23H2/b9-5-

Synthetic route

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%

2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide (763105-70-0) → (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
Multi-step reaction with 3 steps 1.1: hydrogenchloride / methanol; water / 0.75 h / 55 °C 2.1: ISOPROPYLAMIDE / 40 - 70 °C 2.2: 20 - 45 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / methanol; water / 0.75 h / 55 °C 2.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 2.2: 3 - 5 h / 20 - 45 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / methanol; water / 0.75 h / 55 °C 2.1: ISOPROPYLAMIDE / 70 °C 2.2: 3 - 5 h / 20 - 30 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / Heating / reflux View Scheme

(2,4,5-trifluorophenyl)acetic acid (209995-38-0) → (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
Multi-step reaction with 3 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 3.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 3 steps 1.1: dmap; N-ethyl-N,N-diisopropylamine / N,N-dimethyl acetamide / 20 - 40 °C 1.2: 2 - 3 h / 0 - 5 °C 2.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 2.2: 3 - 5 h / 20 - 45 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 3 steps 1.1: dmap; pivaloyl chloride; N-ethyl-N,N-diisopropylamine / ISOPROPYLAMIDE / 2 - 3 h / 5 °C 2.1: ISOPROPYLAMIDE / 70 °C 2.2: 3 - 5 h / 20 - 30 °C 3.1: ammonium acetate; ammonia / methanol; water / 2 h / Heating / reflux View Scheme
Multi-step reaction with 3 steps 1: dmap; N-ethyl-N,N-diisopropylamine; pivaloyl chloride / N,N-dimethyl acetamide / 3 h / 5 - 40 °C / Inert atmosphere 2: N,N-dimethyl acetamide / 6 h / 70 °C 3: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 5 h / 50 °C 2: N-ethyl-N,N-diisopropylamine / Isopropyl acetate / 5 h / 75 - 80 °C 3: ammonium acetate; ammonium hydroxide / methanol / 0.5 h / 58 °C View Scheme

5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (764667-64-3) → (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
Multi-step reaction with 2 steps 1.1: ISOPROPYLAMIDE / 40 - 70 °C 1.2: 20 - 45 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 2 steps 1.1: ISOPROPYLAMIDE / 70 °C 1.2: 3 - 5 h / 20 - 30 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / Heating / reflux View Scheme
Multi-step reaction with 2 steps 1: N,N-dimethyl acetamide / 6 h / 70 °C 2: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / Isopropyl acetate / 5 h / 75 - 80 °C 2: ammonium acetate; ammonium hydroxide / methanol / 0.5 h / 58 °C View Scheme

3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (762240-92-6) → (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
Multi-step reaction with 2 steps 1.1: ISOPROPYLAMIDE / 40 - 70 °C 1.2: 20 - 45 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 2 steps 1.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 1.2: 3 - 5 h / 20 - 45 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme
Multi-step reaction with 2 steps 1.1: ISOPROPYLAMIDE / 70 °C 1.2: 3 - 5 h / 20 - 30 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / Heating / reflux View Scheme

C15H13F3O4 → (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
Multi-step reaction with 2 steps 1.1: N,N-dimethyl acetamide / 1 h / 40 - 70 °C 1.2: 3 - 5 h / 20 - 45 °C 2.1: ammonium acetate; ammonia / methanol; water / 2 h / 30 °C / Heating / reflux View Scheme

2-oxo-2-(2,4,5-trifluorophenyl)acetamide → (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

Multi-step reaction with 5 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 5: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme

(2,4,5-trifluorophenyl)oxoacetic acid → (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
Multi-step reaction with 4 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 4: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme

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

Multi-step reaction with 9 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 9: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme

2-chloro-4,5-difluorobenzoyl fluoride → (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

Multi-step reaction with 8 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 8: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme

2,4,5-trifluorobenzoyl fluoride → (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

Multi-step reaction with 7 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 7: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme

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

Multi-step reaction with 6 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 6: ammonium acetate; ammonium hydroxide / water; methanol / 2 h / 30 °C / Reflux View Scheme

(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) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (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 With ammonium chloride; chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-1-[(S)-2-(di-tert-butylphosphino)ferrocenyl]ethyl-di-2-methylphenylphosphine In methanol at 20℃; for 1h; Stage #2: With hydrogen In methanol at 50℃; under 5171.62 Torr; for 18h; Product distribution / selectivity;	97%
With di-μ-chloro-bis(1,5-cyclooctadiene)dirhodium; hydrogen; (R,S)-t-bu Josiphos In methanol at 20 - 50℃; under 10343.2 Torr; for 14h;	93%
With chloro(1,5-cyclooctadiene)rhodium(I) dimer; (2S)-1-[(1S)-1-[bis(1,1-dimethylethyl)phosphino]ethyl]-2-(diphenylphosphino)ferrocene; hydrogen; ammonium chloride In methanol at 50℃; under 13689.1 Torr; Inert atmosphere; enantioselective reaction;	82%

(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) → (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 (823817-56-7)

Conditions	Yield
With sodium tetrahydroborate; methanesulfonic acid In tetrahydrofuran; isopropyl alcohol at -15 - -5℃; for 4.5h; Reagent/catalyst;	60%
With sodium tetrahydroborate; acetic acid In toluene at 5 - 10℃; for 3h; Product distribution / selectivity;
With sodium tetrahydroborate; formic acid In chlorobenzene at 0 - 5℃; Temperature;

(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) + di-tert-butyl dicarbonate (24424-99-5) → (Z)-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)-but-2-en-2-ylcarbamate (1234321-84-6)

Conditions	Yield
With triethylamine In dichloromethane for 40h; Reflux;	49.8%

(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) → (S)-Sitagliptin + sitagliptin (486460-32-6)

Conditions	Yield
With hydrogen; bis(1,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate; (S)-Cy2-p-Tol-Biphemp In 2,2,2-trifluoroethanol at 20℃; under 5931.67 Torr; for 20h; Product distribution / selectivity;	A n/a B 94 %Chromat.
With hydrogen; chloro(1,5-cyclooctadiene)rhodium(I) dimer; 4,12-bis(diphenylphosphino)-[2.2]-paracyclophane In 2,2,2-trifluoroethanol at 50℃; under 5414.51 Torr; for 18h; Product distribution / selectivity;	A n/a B 58 %Chromat.
With hydrogen; chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R)-(-)-tetraMe-BITIOP In 2,2,2-trifluoroethanol at 50℃; under 5414.51 Torr; for 18h; Product distribution / selectivity;	A 15 %Chromat. B n/a
With hydrogen; chloro(1,5-cyclooctadiene)rhodium(I) dimer; (R,R)-1-[1-(di(t-butyl)phosphino)ethyl]-2-(diphenylphosphino)ferrocene In 2,2,2-trifluoroethanol at 20 - 55℃; under 3750.38 Torr; for 26h;

(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) → sitagliptin phosphate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium tetrahydroborate; formic acid / chlorobenzene / 0 - 5 °C 2.1: ethyl acetate / Reflux 3.1: hydrogenchloride / water 3.2: 0.25 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: (R,S) t-butyl Josiphos; hydrogen / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 13 h / 50 °C / 10343.2 Torr 2: phosphoric acid / water; isopropyl alcohol / 75 °C View Scheme
Multi-step reaction with 3 steps 1.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 1.2: 13 h / 50 °C / 10343.2 Torr 2.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C 3.1: 1 - 8 h / 58 - 140 °C View Scheme
Multi-step reaction with 3 steps 1: sodium tetrahydroborate; methanesulfonic acid / tetrahydrofuran; isopropyl alcohol / 4.5 h / -15 - -5 °C 2: methanol; isopropyl alcohol / 1 h / 65 °C 3: phosphoric acid / isopropyl alcohol / 1 h / 78 °C View Scheme

(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) → (R)-3-amino-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 (S)-3-(2-amino-2-oxoethyl)-5-methylhexanoate

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; formic acid / chlorobenzene / 0 - 5 °C 2: ethyl acetate / Reflux View Scheme

(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) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: (R, S) t-butyl Josiphos / chloro(1,5-cyclooctadiene)rhodium(I) dimer / methanol / 1 h / 20 °C 1.2: 13 h / 50 °C / 10343.2 Torr 2.1: phosphoric acid; water / isopropyl alcohol / 2 h / 68 - 75 °C View Scheme

(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) → sitagliptin tartrate + C16H15F6N5O*C4H6O6

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanesulfonic acid / tetrahydrofuran; isopropyl alcohol / 4.5 h / -15 - -5 °C 2: methanol / 1 h / 65 °C View Scheme

(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) → C16H15F6N5O*C20H18O8

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanesulfonic acid / tetrahydrofuran; isopropyl alcohol / 4.5 h / -15 - -5 °C 2: methanol; isopropyl alcohol / 1 h / 65 °C View Scheme

Upstream product

• 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 
• 763105-70-0 2,2,2-trifluoro-N’-[(2Z)-piperazin-2-ylidene]acetohydrazide 
• 209995-38-0 (2,4,5-trifluorophenyl)acetic acid 
• 764667-64-3 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 762240-92-6 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride 
• 86393-34-2 2,4-dichloro-5-fluorobenzoyl chloride 
• 101513-67-1 2,4,5-trifluorobenzoyl fluoride 

Downstream Products

• 486460-32-6 sitagliptin 
• 823817-55-6 (S)-Sitagliptin 
• 1234321-84-6 (Z)-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)-but-2-en-2-ylcarbamate 
• 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 
• 654671-78-0 sitagliptin phosphate 
• 654671-77-9 sitagliptin phosphate monohydrate 

Relevant articles and documents

Two methods for the preparation of sitagliptin phosphate: Via chemical resolution and asymmetric hydrogenation

Two effective processes have been developed for the preparation of sitagliptin phosphate. The approach of chemical resolution obtained R-sitagliptin in five steps from commercially available starting materials using the inexpensive NaBH4 to reduce the enamine and then using (-)-di-p-toluoyl-l-tartaric acid to resolve racemates in 11% yield overall. The route successfully avoids the use of expensive noble metal as catalysts compared with traditional synthesis methods, resulting in greatly reduced costs and simplified synthetic routes. Other alternative asymmetric hydrogenation of β-ketomide routes for the synthesis of sitagliptin were found, two of the intermediates were synthesized for the first time. This journal is

NOVEL PROCESS FOR THE PREPARATION OF DIPEPTIDYL PEPTIDASE-4 (DPP-4) ENZYME INHIBITOR

The present invention relates to a novel and improved process for the preparation of Sitagliptin of Formula (I) and its pharmaceutically acceptable salts. The present invention also relates to novel intermediates and process for the preparation of intermediates used in the preparation of Sitagliptin.

Highly efficient asymmetric synthesis of sitagliptin

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/tBu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.