486460-32-6

Basic information

• Product Name: Sitagliptin
• Synonyms: (3R)-3-AMino-1-[3-(trifluoroMethyl)-5,6,7,8-tetrahydro-1,2,4-riazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-rifluorophenyl) butan-1-one;(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;Sitagliptin (3R)-3-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;Sitagliptin base;(3R)-3-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;Sitagliptin;1,2,4-Triazolo(4,3-A)pyrazine, 7-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-5,6,7,8-tetrahydor-3-(trifluoromethyl)-;Hsdb 7516
• CAS NO: 486460-32-6
• Molecular Formula: C₁₆H₁₅F₆N₅O
• Molecular Weight: 407.32
• EINECS: 1308068-626-2
• Product Categories: API;Pharmaceutical intermediate;Heterocycles
• Mol File: 486460-32-6.mol
• Article Data: 111

Chemical Properties

• Melting Point: 114.1-115.7 °C
• Boiling Point: 529.9 °C at 760 mmHg
• Flash Point: 274.3 °C
• Appearance: yellow grease
• Density: 1.61 g/cm³
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.59
• PKA: 7.20±0.10(Predicted)
• CAS DataBase Reference: Sitagliptin(CAS DataBase Reference)
• NIST Chemistry Reference: Sitagliptin(486460-32-6)
• EPA Substance Registry System: Sitagliptin(486460-32-6)

Safety Data

• Hazardous Substances Data: 486460-32-6(Hazardous Substances Data)

Usage

Description

Different sources of media describe the Description of 486460-32-6 differently. You can refer to the following data:
1. Sitagliptin is an orally-bioavailable selective DPP4 inhibitor that was discovered through the optimization of a class of β-aminoacid-derived DPP4 inhibitors. It lowers DPP4 activity in a sustained manner following once daily administration, preserves the circulating levels of intact GIP and GLP1 following meals in both acute and chronic studies and reduces blood glucose levels without significant increases in hypoglycaemia. Sitagliptin phosphate (STG) is used to treat DM type 2 because it improves glycemic control by increasing the levels of active incretin hormones, GLP-1 (peptide-1) and GIP (glucose-dependent insulinotropic peptide). The activation of these incretins in β-pancreatic cells causes increased levels of cyclic adenosine monophosphate (cAMP) and intracellular calcium, with subsequent glucose-dependent insulin secretion (2). This hypoglycemic drug belongs to a new class called dipeptidyl peptidase IV inhibitors. STG was approved by the FDA in 2006.
2. Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a first-in-class oral drug launched for the treatment of type 2 diabetes. It acts by slowing the inactivation of incretins, which are endogenous peptides involved in the physiologic regulation of glucose homeostasis. Incretin hormones, including glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. When blood glucose concentrations are normal or elevated,GLP-1 and GIP increase the synthesis and release of insulin from pancreatic b cells via intracellular signaling pathways involving cAMP. GLP-1 also lowers glucagon secretion from pancreatic αcells, which leads to reduced hepatic glucose production.

Mechanism of action

Sitagliptin prolongs the activity of proteins that increase the release of insulin after blood sugar rises, such as after a meal. Sitagliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which metabolizes the naturally occurring incretin hormones glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) resulting in enhanced glucose-dependent insulin secretion from the pancreas and decreased hepatic glucose production. Since GLP-1 enhances insulin secretion in the presence of raised blood glucose levels, inhibiting DPP-IV activity will increase and prolong the action of GLP-1 by reducing its rate of inactivation in plasma. Sitagliptin reduces hemoglobin A1c (HbA1c), fasting and postprandial glucose by glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. GLP-1 has other widespread effects including delaying gastric emptying, significantly reducing glucagons levels and possible central effects on the appetite.

Pharmacokinetics

Bioavailability of sitagliptin is approximately 87%. Halflife is between 8-14 hours. It is 38% bound to plasma proteins. It undergoes limited metabolism via CYP3A4 and CYP2C8. Elimination is mainly through urine.

Indications

Sitagliptin is approved by the FDA as an adjunct to diet and exercise to improve glycaemic control in patients with T2DM, either as a monotherapy, or in combination with metformin or a peroxisome proliferatoractivated receptor-γ agonist (for example, thiazolidinediones) when the single agent does not provide adequate glycaemic control.

Clinical Use

Different sources of media describe the Clinical Use of 486460-32-6 differently. You can refer to the following data:
1. In October 2006, the U.S. Food and Drug Administration (FDA) approved sitagliptin as monotherapy and as add-on therapy to either of two other types of oral diabetes medications, metformin or thiazolidinediones to improve blood glucose control in patients with type 2 diabetes when diet and exercise are not enough. In March, 2007 it was approved in European Union. Sitagliptin is currently approved in 42 countries. The recommended dose of sitagliptin is 100 mg once daily. It may be taken with or without food. In April, 2007 FDA approved the combination product of sitaglibtin and metformin for type 2 diabetes. In clinical trials of 1-year duration, sitagliptin improved glycaemic control by reducing both fasting and postprandial glucose concentrations, leading to clinically meaningful reductions in glycosylated haemoglobin levels. Monotherapy with sitagliptin 100mg daily decreases mean HbA1c by 0.6- 0.79% (mean difference from placebo). When used in combination with metformin or pioglitazone, the mean reduction is HbA1c is 0.7% and 0.9% respectively. Sitagliptin is considered to be weight neutral and lipid neutral.
2. Treatment of type 2 diabetes in combination with metformin or a thiazolidinedione

Side effects

In clinical trials, sitagliptin demonstrated an overall incidence of side effects comparable to placebo. The most common side effects in studies were upper respiratory tract infection, stuffy or running nose, sore throat, headache and diarrhea. The incidence of hypoglycemia with sitagliptin monotherapy was not significantly different than placebo. Pooled data from 2 monotherapy and 2 combination trials show that the incidence of hypoglycemia was 1.2% and 0.9% for sitagliptin 100mg and placebo respectively.

Drug interactions

Different sources of media describe the Drug interactions of 486460-32-6 differently. You can refer to the following data:
1. Sitagliptin plasma concentrations may be increased modestly (approximately 68%), with cyclosporine which is not expected to be clinically important. Digoxin plasma levels may be increased slightly (approximately 18%), no dosage adjustment is recommended. Although sitagliptin is not as likely to cause hypoglycemia as some other oral diabetes medications, be careful while prescribing any other drug that can potentially lower blood sugar, such as: probenecid, nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin or other salicylates, sulfa drugs, a monoamine oxidase inhibitor (MAOI) or beta-blockers.
2. Potentially hazardous interactions with other drugs None known

Uses

Different sources of media describe the Uses of 486460-32-6 differently. You can refer to the following data:
1. Sitagliptin is a useful pharmaceutical drug. Could be useful for treating intestinal inflammation, diabetes, pre-?diabetes, impaired glucose tolerance, hepatitis, and?/or inflammatory liver disease.
2. Labeled Sitagliptin , intended for use as an internal standard for the quantification of Sitagliptin by GC- or LC-mass spectrometry.

Definition

ChEBI: Sitagliptin is a triazolopyrazine that exhibits hypoglycemic activity. It has a role as a serine proteinase inhibitor, a hypoglycemic agent, an EC 3.4.14.5 (dipeptidyl-peptidase IV) inhibitor, an environmental contaminant and a xenobiotic. It is a triazolopyrazine and a trifluorobenzene.

Brand name

Januvia

Metabolism

Sitagliptin undergoes minimal metabolism, mainly by the cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP2C8. Renal excretion of sitagliptin involves active tubular secretion; it is a substrate for organic anion transporter-3 and P-glycoprotein.

InChI:InChI=1/C16H15F6N5O/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/h4,6,9H,1-3,5,7,23H2/t9-/m0/s1

Synthetic route

(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) → sitagliptin (486460-32-6)

Conditions	Yield
With hydrogen; palladium 10% on activated carbon In tetrahydrofuran at 20℃; under 760.051 Torr;	100%
With hydrogen; palladium-on-charcoal In tetrahydrofuran; water at 20℃; under 760.051 Torr;	100%
With hydrogen; palladium 10% on activated carbon In methanol	99%
With methylmagnesium bromide; hydrogen; palladium diacetate; nickel diacetate In water at 45℃; for 20h;	79%

7-(1-oxo-3((R)-amino)-4-(2,4,5-trifluorophenyl)butyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine di-p-tolyl-L-tartarate (1169707-28-1) → sitagliptin (486460-32-6)

Conditions	Yield
With sodium hydroxide In ethyl acetate at 10℃; Product distribution / selectivity;	99.5%

(3R)-3-[(benzyIoxy)amino]-l-[3-(trifluoromethyl)-5H,6H,7H,8H [1 ,2,4] triazolo [4,3-a] pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one → sitagliptin (486460-32-6)

Conditions	Yield
With formic acid; Pt/Al2O3; hydrogen In methanol at 20℃; Autoclave; Large scale;	97.8%
Stage #1: (3R)-3-[(benzyIoxy)amino]-l-[3-(trifluoromethyl)-5H,6H,7H,8H [1 ,2,4] triazolo [4,3-a] pyrazin-7-yl]-4-(2,4,5-trifluorophenyl) butan-1-one With hydrogenchloride; palladium 10% on activated carbon In ethanol; water at 30℃; under 2068.65 Torr; for 12 - 14h; Stage #2: With sodium hydroxide In ethanol; water at 12 - 14℃; pH=13; Stage #3: With phosphoric acid In ethanol; water at 45℃;	66%

(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%

C14H13F3N2O4 + 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) → sitagliptin (486460-32-6)

Conditions	Yield
With triethylamine In tetrahydrofuran for 1h; Reflux;	97%

(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) → sitagliptin (486460-32-6)

Conditions	Yield
With hydrogenchloride In isopropyl alcohol at 20 - 25℃;	96.88%
With hydrogenchloride In methanol at 15 - 45℃; for 3h;	95.81%
With hydrogenchloride; methanol In water at 50℃; for 4h;	95%

C23H21F6N5O (1306610-49-0) → sitagliptin (486460-32-6)

Conditions	Yield
With Pt/Al2O3; hydrogen; acetic acid In methanol at 20℃; Autoclave; Large scale;	96.7%

(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%

(R,R)-N-benzyl-N-(α-methylbenzyl)-1-(2',4',5'-trifluorophenyl)-4-oxo-4-{3''-(trifluoromethyl)-5'',6''-dihydro-1'',2'',4''-triazolo[4,3-α]pyrazin-7''(8''H)-yl}butan-2-amine (1380521-88-9) → sitagliptin (486460-32-6)

Conditions	Yield
With 30% w/w Pd(OH)2/C; hydrogen In methanol under 3800.26 Torr; for 24h;	96%
With 5%-palladium/activated carbon; hydrogen; acetic acid In methanol at 50℃; under 19001.3 Torr; for 48h;	95%

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

Conditions	Yield
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With thionyl chloride In ethyl acetate at 26℃; for 2h; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride With triethylamine In ethyl acetate at 25℃; Solvent; Temperature;	96%
Stage #1: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride; (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With 1-methyl-1H-imidazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride at 0 - 20℃; for 16h; Stage #2: With hydrogenchloride In ethanol at 20℃; for 18h; Stage #3: With sodium hydroxide In ethanol; water pH=10 - 12; Time; Solvent;	90%
Stage #1: (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid With pivaloyl chloride; sodium carbonate In toluene Cooling; Stage #2: 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-α]pyrazine hydrochloride In toluene Stage #3: With hydrogenchloride In water; toluene Reagent/catalyst;	4.4 g

Sitagliptin hydrochloride → sitagliptin (486460-32-6)

Conditions	Yield
In water at 20 - 25℃; pH=8 - 9; Alkaline conditions;	96%

(2S)-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 dihydrogenphosphate salt (823817-58-9) → sitagliptin (486460-32-6)

Conditions	Yield
With sodium hydroxide In water at 0 - 5℃; for 1h;	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%

(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) → sitagliptin (486460-32-6)

Conditions	Yield
With 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid In methanol; water at 50℃; under 7500.75 Torr; for 14h;	94%
With palladium 10% on activated carbon; hydrogen; acetic acid In methanol; water at 50℃; under 7500.75 Torr; for 14h;	81.2%
With formic acid; palladium(II) hydroxide/carbon In tetrahydrofuran; methanol; water at 60℃; for 6h;	79.4%

sitagliptin phosphate → sitagliptin (486460-32-6)

Conditions	Yield
In water at 20 - 25℃; pH=8 - 9; Alkaline conditions;	93.5%

sitagliptin sulfate → sitagliptin (486460-32-6)

Conditions	Yield
In water at 20 - 25℃; pH=8 - 9; Alkaline conditions;	93%

sitagliptin sulfate (1169707-31-6) → sitagliptin (486460-32-6)

Conditions	Yield
In water	92%

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

(R)-N-benzyl-1-(2',4',5'-trifluorophenyl)-4-oxo-4-{3''-(trifluoromethyl)-5'',6''-dihydro-1'',2'',4''-triazolo[4,3-α]pyrazin-7''(8''H)-yl}butan-2-amine (1393363-87-5) → sitagliptin (486460-32-6)

Conditions	Yield
With 20 wt.% Pd(OH)2 on activated carbon; hydrogen In methanol under 3800.26 Torr; for 24h;	91%

(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) → sitagliptin (486460-32-6)

Conditions	Yield
With hydrogenchloride; methanol In water at 48℃;	91%
With hydrogenchloride In 1,4-dioxane at 20℃; for 4h; Solvent;	90.7%
With hydrogenchloride; water In methanol at 20℃; for 4h;	89%
With hydrogenchloride In water at 70℃; for 2h;	89%
With hydrogenchloride In methanol; water at 20℃; for 4h;

C17H13F6N5O2 → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: C17H13F6N5O2 With water In ethanol at 80℃; for 2h; Stage #2: With copper In quinoline; ethanol at 140℃; for 3h;	91%

(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) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (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 With triphenylphosphine In tetrahydrofuran at 50℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran; water for 10h;	90%
Stage #1: (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 With triphenylphosphine In tetrahydrofuran at 50℃; for 2h; Stage #2: With ammonium hydroxide In tetrahydrofuran; water for 10h;	86%
With hydrogen; palladium on carbon In methanol for 6h;

sitagliptin succinate → sitagliptin (486460-32-6)

Conditions	Yield
In water at 20 - 25℃; pH=8 - 9; Alkaline conditions;	90%

(R)-3-(((R)-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)butan-1-one hydrochloride → sitagliptin (486460-32-6)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In water; isopropyl alcohol at 65 - 70℃; under 5430.2 Torr; for 8 - 10h; Inert atmosphere;	88%

sitagliptin phosphate → sitagliptin (486460-32-6)

Conditions	Yield
With ammonia In water at 25℃; pH=10; Product distribution / selectivity;	87.3%
With potassium hydroxide In tert-butyl methyl ether; water at 0 - 20℃; pH=11;	85%
With sodium hydroxide In water at 0 - 5℃; for 1h;
With sodium hydrogencarbonate; sodium chloride In water; ethyl acetate at 25 - 42℃; Reagent/catalyst; Temperature;	1.8 g

(R)-3-nitro-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 (1351564-29-8) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (R)-3-nitro-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 With hydrogenchloride; zinc In methanol; water at 20℃; for 0.5h; Stage #2: With sodium hydroxide In methanol; water pH=10;	87%

3(R)-3-[(benzyloxy)amino]-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one (1361389-75-4) → sitagliptin (486460-32-6)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In ethanol; water at 50℃; under 2068.65 Torr; Large scale;	86%
Multi-step reaction with 2 steps 1: phosphoric acid / isopropyl alcohol / 16 h / 30 °C 2: sodium hydroxide / water / 1 h / 0 - 5 °C View Scheme
With palladium 10% on activated carbon; hydrogen In ethanol; water at 50℃; under 2280.15 Torr; for 12h;

(R)-3-amino-4-phenyl(2,4,5-trifluorophenyl)butanoic acid (936630-57-8) + 3-trifluoromethyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (486460-21-3) → sitagliptin (486460-32-6)

Conditions	Yield
With 4-methyl-morpholine; benzotriazol-1-ol In ethanol; dichloromethane at 10 - 25℃; for 3h;	86%

(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) → sitagliptin (486460-32-6)

Conditions	Yield
With 20% palladium hydroxide-activated charcoal; hydrogen; acetic acid In methanol; water at 50℃; under 7500.75 Torr; for 14h;	85%

sitagliptin phosphate + (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) → sitagliptin (486460-32-6)

Conditions	Yield
Stage #1: (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 With formic acid; 10 wt% Pd(OH)2 on carbon In tetrahydrofuran; methanol for 6h; Reflux; Stage #2: With phosphoric acid In ethanol; water; ethyl acetate at 50 - 74℃; for 1.5h; Stage #3: sitagliptin phosphate In ethanol; water at 65℃; for 1h;	67.1%

orotic acid (65-86-1) + sitagliptin (486460-32-6) → sitagliptin orotate (1246343-77-0)

Conditions	Yield
In acetonitrile at 25 - 75℃; Product distribution / selectivity;	99%
In water at 35 - 37℃; for 0.166667h;

sitagliptin (486460-32-6) → sitagliptin phosphate monohydrate (654671-77-9)

Conditions	Yield
With phosphoric acid In water; isopropyl alcohol at 70 - 80℃; for 2h; Temperature;	97.7%
With phosphoric acid; water In isopropyl alcohol at 20 - 75℃;	95%
With phosphoric acid; water In isopropyl alcohol at 75℃;

(R)-Mandelic Acid (611-71-2) + sitagliptin (486460-32-6) → sitagliptin (R)-(-)mandelate (1240038-86-1)

Conditions	Yield
In ethyl acetate at 25 - 50℃; Product distribution / selectivity;	97%

sitagliptin (486460-32-6) → sitagliptin phosphate

Conditions	Yield
With phosphoric acid In ethanol at 80℃; optical yield given as %ee;	96%
With phosphoric acid In ethanol at 80℃; for 0.5h;	96%
With phosphoric acid; water In isopropyl alcohol at 70 - 80℃;	96%

sitagliptin (486460-32-6) → (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
With fluorosulfonyl azide; potassium hydrogencarbonate In tert-butyl methyl ether; water; N,N-dimethyl-formamide at 20℃; for 0.0833333h;	96%

Adipic acid (124-04-9) + sitagliptin (486460-32-6) → (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 adipic acid (1417158-34-9)

Conditions	Yield
In isopropyl alcohol at 25 - 50℃; for 0.5h;	95.9%
In isopropyl alcohol at 25 - 50℃;	95.9%
In ethanol at 25 - 80℃;	56.8%

(2E)-but-2-enedioic acid (110-17-8) + sitagliptin (486460-32-6) → Sitagliptin fumarate (837430-24-7)

Conditions	Yield
In methanol at 25 - 32℃; for 1h;	95%
In ethyl acetate; isopropyl alcohol at 25.5 - 26.7℃; for 0.683333h;	91%
In isopropyl alcohol at 30℃; Reflux;
In acetonitrile at 25 - 50℃; Product distribution / selectivity;
In butanone at 20℃; for 1h; Product distribution / selectivity;

(S)-Mandelic acid (17199-29-0) + sitagliptin (486460-32-6) → sitagliptin L-mandelate

Conditions	Yield
In ethanol	95%

sitagliptin (486460-32-6) → sitagliptin hydrogensulfate

Conditions	Yield
With sulfuric acid In tert-butyl methyl ether; acetonitrile at 20℃;	95%
With sulfuric acid In acetonitrile at 25 - 50℃; Product distribution / selectivity;

sitagliptin (486460-32-6) → sitagliptin sulfate

Conditions	Yield
With sulfuric acid In ethanol for 0.766667h;	94.8%

benzenesulfonic acid (98-11-3) + sitagliptin (486460-32-6) → (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 besylate

Conditions	Yield
In methanol at 25 - 32℃; for 1h;	93%
In Isopropyl acetate at 50℃; for 1h;
In Isopropyl acetate at 45 - 50℃;	0.63 g

sitagliptin (486460-32-6) → (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 phosphate

Conditions	Yield
With phosphoric acid In water; isopropyl alcohol at 20 - 60℃; for 1.5h;	92.6%
With phosphoric acid In methanol
With phosphoric acid In water; isopropyl alcohol at 25 - 78℃;	6.7 g

sitagliptin (486460-32-6) → Sitagliptin hydrochloride

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 20℃; for 0.75h;	92.4%
With hydrogenchloride In isopropyl alcohol at 30℃; for 3h;
With isopropyl alcohol hydrogen chloride In methanol; diethyl ether at 25 - 45℃; for 1h;	1.1 g
With hydrogenchloride In water; ethyl acetate at 0 - 65℃; Solvent; Temperature;	102 g
With hydrogenchloride In isopropyl alcohol at 50℃; Temperature; Solvent;	10.3 g

D-glucuronic acid (6556-12-3, 489-91-8, 528-16-5, 552-12-5, 577-46-8, 643-33-4, 2240-07-5, 6294-16-2, 10133-02-5, 18402-78-3, 18968-14-4, 21179-08-8, 23018-83-9, 33599-45-0, 33599-46-1, 46171-67-9, 46171-69-1, 46172-26-3, 70021-34-0, 71031-08-8, 104195-06-4, 106499-29-0, 124817-72-7) + sitagliptin (486460-32-6) → sitagliptin D-glucuronate

Conditions	Yield
In methanol; water; isopropyl alcohol at 20℃;	92%

Upstream product

• 1190094-97-3 (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 (-)dibenzolyl-L-tartaric acid salt 
• 144284-25-3 (2,4,5-trifluorophenyl)methanol 
• 1306610-49-0 C₂₃H₂₁F₆N₅O 
• 1352613-31-0 (S)-3-(methanesulfonyloxy)-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 
• 1352613-30-9 (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 
• 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 
• 764667-64-3 5-(1-hydroxy-2-(2,4,5-trifluorophenyl)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione 
• 486459-71-6 Sitagliptin hydrochloride 

Downstream Products

• 654671-78-0 sitagliptin phosphate 
• 486460-23-5 (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 
• 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 
• 1675201-14-5 (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 

Relevant articles and documents

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.

Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a new class of anti-diabetic agents that are widely used in clinical practice to improve glycemic control in patients with type 2 diabetes. DPP-4 is also known as lymphocyte cell surface protein, CD26, and plays an important role in T-cell immunity. Recent studies suggest that DPP-4 inhibitors improve beta-cell function and attenuate autoimmunity in type 1 diabetic mouse models. To investigate the direct effect of DPP4 in immune response, human peripheral blood mononuclear cells (PBMC) from healthy volunteers were obtained by Ficoll gradient and cultivated in the absence (control) or presence of phytohemagglutinin (PHA), or stimulated with PHA and treated with sitagliptin. The immune modulation mechanisms analyzed were: cell proliferation, by MTT assay; cytokine quantification by ELISA or cytometric bead array (CBA), Th1/Th2/Th17 phenotyping by flow cytometric analysis and CD26 gene expression by real time PCR. The results showed that sitagliptin treatment inhibited the proliferation of PBMC-PHA stimulated cells in a dose dependent manner and decreased CD26 expression by these cells, suggesting that sitagliptin may interfere in CD26 expression, dimerization and cell signaling. Sitagliptin treatment not only inhibited IL-10 (p?A statistically significant increase (p?a significantly (p?+?IL-17+, T CD4+?IFNgamma+ and T CD4+?IL-4+ cells were significantly reduced (p??0.05) by sitagliptin. Our data demonstrated an immunosuppressive effect of sitagliptin on Th1, Th17 and Th2 lymphocytes differentiation that leads to the generation of regulatory TGF-beta1 secreting cells with low CD26 gene expression that may influence the state of pancreatic beta-cells and controlling DM1 patients.

Preparation method of chiral 4 - aryl - β β-amino acid derivative

Provided is a method for preparing a chiral 4-aryl-β-amino acid derivative. The preparation method comprises hydrogenating an enamine compound having a structure as shown in Formula III in an organic solvent in the presence of a catalyst containing a transition metal and BIBOPs. The preparation method of the present invention uses a small amount of a selected asymmetric catalyst, and has a simple operation, mild reaction conditions, a high yield, a high stereoselectivity, and better industrial application and economic values.

Process method for improving yield and purity of sitagliptin

The invention provides a process method for improving yield and purity of sitagliptin, which comprises the following steps: mixing Boc sitagliptin as shown in a formula iii with solvent ester and acid, carrying out hydrolysis reaction at 0-50 DEG C, neutralizing with acid and alkali after the reaction is finished, and removing a water layer to obtain an organic layer containing sitagliptin as shown in a formula iv. The process method disclosed by the invention has the advantages that degradation of sitagliptin iv in reaction and post-treatment processes can be avoided, so that the yield and quality of sitagliptin iv are effectively improved.