274901-16-5

Basic information

• Product Name: Vildagliptin
• Synonyms: Vildagliptin (NVP-LAF 237);(-)-(2S)-1-[[(3-Hydroxytricyclo[3.3.1.1[3,7]]dec-1-yl)amino]acetyl]pyrrolidine-2-carbonitrile;Vildagliptin;2-Pyrrolidinecarbonitrile, 1-(((3-hydroxytricyclo(3.3.1.13,7)dec-1-yl)amino)acetyl)-, (2S)-;Galvus;Laf 237;Unii-I6B4B2U96p;Vidagliptin (see vildagliptin)
• CAS NO: 274901-16-5
• Molecular Formula: C₁₇H₂₅N₃O₂
• Molecular Weight: 303.4
• EINECS: 1308068-626-2
• Product Categories: Amines;Chiral Reagents;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labelled Compounds;Metabolites & Impurities;API;Inhibitor;Galvus;Other APIs
• Mol File: 274901-16-5.mol

Chemical Properties

• Melting Point: 153-155?C
• Boiling Point: 531.3 °C at 760 mmHg
• Flash Point: 275.1℃
• Appearance: white crystalline powder
• Density: 1.27
• Storage Temp.: -20°C Freezer
• Solubility: Soluble in DMSO (up to 45 mg/ml), in DMF (up to 20 mg/ml), or in Ethanol (up to 20 mg/ml).
• PKA: 15.05±0.40(Predicted)
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO, DMF, or ethanol may be stored at -20°C for up to 3 months
• CAS DataBase Reference: Vildagliptin(CAS DataBase Reference)
• NIST Chemistry Reference: Vildagliptin(274901-16-5)
• EPA Substance Registry System: Vildagliptin(274901-16-5)

Safety Data

• Statements: 28-38-41-48
• Safety Statements: 24/25-26-28-36/37/39
• RIDADR: 3077
• Hazardous Substances Data: 274901-16-5(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Vildagliptin is used as an antidiabetic agent for the treatment of type 2 diabetes. It helps in regulating blood glucose levels by inhibiting DPP-4, which in turn increases the concentration and duration of active incretins, leading to increased insulin release and decreased glucagon levels.
Used in Cardiovascular Applications:
Vildagliptin is used for its positive cardiovascular effects. As a DPP-4 inhibitor, it can help in managing and reducing the risk of cardiovascular complications associated with type 2 diabetes.
Used in Anti-inflammatory Applications:
Vildagliptin is also used for its anti-inflammatory effects. By inhibiting DPP-4, it can help in reducing inflammation, which is often associated with chronic conditions like type 2 diabetes.
Used in Drug Metabolism Research:
Vildagliptin is used as a research tool to study the major metabolite of the drug and its role in the inhibition of DPP-4 with an IC50 of 2.3 nM. This information can be valuable for understanding the drug's mechanism of action and its potential applications in various therapeutic areas.

Indications and Usage

Vildagliptin (vildagliptin), developed by Novartis (Novartis) Pharmaceutical Co., Ltd, is another oral administrated inhibitor of Dipeptidyl peptidase-IV after sitagliptin (sitagliptin). In 2008, it is approved for marketing in the European Union for the treatment of type 2 diabetes. Diabetes is a chronic metabolic disease with its prevalence being increased year by year. Type 2 diabetes is a complicated diseases caused with the combined action between polygenic genetic factors and environmental factors. Dipeptidyl peptidase IV (DPP-IV) inhibitors are a new class of anti-diabetic drugs which induces and facilitate the biosynthesis and secretion of insulin. It plays a role in lowering the blood carbohydrate concentration through multiple mechanisms such as inhibiting the β cell apoptosis, inhibiting glucagon secretion and reducing food intake. During its lowering effect on reducing blood carbohydrate levels, it can also reverse the situation of deteriorating function of pancreas islet for diabetic patients at the same time. Vildagliptin is the representative of drugs among the dipeptidyl peptidase inhibitor. It exhibited a good anti-diabetic effects and tolerance no matter whether it is being administered alone or in combination with metformin and insulin medication in clinical studies.

Mechanisms of Action

Vildagliptin is a selective, competitive and reversible DPP-4 inhibitor. Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 21 (GLP21) are important hormones that regulate body glucose concentration and have the same functions as intestinal insulin. Type-2 diabetes patients suffer from GIP insulin secretion failure, so only their GLP21 can promote insulin secretion by affecting receptors on islet beta cell membranes. GLP21 can also inhibit glucagon secretion and inhibit gastric clearing to extend the feeling of fullness (control appetite). DPP-4 binds with proteins in many types of tissues, including tissue in the kidney, liver, small intestine brush border, pancreatic duct, lymph cells, and endothelial cells, and it can deactivate GLP21 by hydrolyzing its N-terminal position-2 alanine. Vildagliptin binds with DPP-4 to produce a DPP-4 compound and inhibit its activity. It increases GLP21 concentration and promotes islet beta cells to produce insulin, while also lowering glucagon concentration, thus lowering blood sugar. Vildagliptin has not noticeable effects on weight.

Adverse reactions

Most common adverse reactions include headache, nasopharyngitis, coughing, constipation, dizziness and excess sweating. There have been very rare cases of hypotension, but it is unclear if conditions are related to this drug. Almost all research shows that the hypoglycemia occurrence rate while using Vildagliptin is similar to the rate when using a placebo. Control trials showed that compared to thiazolidinediones, Vildagliptin causes a similar occurrence rate of headaches, rashes, and other adverse reactions, but Vildagliptin has a lower occurrence rate of adverse reactions forcing patients to cease treatment and of severe adverse reactions.

Clinical Use

Dipeptidyl peptidase 4 inhibitor: Treatment of type 2 diabetes mellitus in combination with other antidiabetic drugs

Side effects

The most common adverse events reported in patients receiving vildagliptin included headache, nasopharyngitis, cough, constipation, dizziness, and increased sweating. Vildagliptin is not recommended for patients with liver impairment.

Synthesis

Vildagliptin is chemically derived in three steps starting from L-prolinamide via acylation with chloroacetyl chloride to produce 1-(chloroacetyl)-L-prolinamide, subsequent dehydration of the carboxamide group to the nitrile with trifluoroacetic anhydride, and condensation of the 1-(chloroacetyl)-L-prolinenitrile intermediate with 3-hydroxyadamantan-1-amine.

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

About 69% of a dose of vildagliptin is metabolised, mainly by hydrolysis in the kidney to inactive metabolites. About 85% of a dose is excreted in the urine (23% as unchanged drug), and 15% in the faeces.

References

1) Balas?et al.?(2007),?The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients;? J. Clin. Endocrinol. Metab.,?92?1249 2) Ahren?et al. (2004),?Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels and reduces glucagon levels in type 2 diabetes;? J. Clin. Endocrinol. Metab., 89?2078 3) Kosaraju?et al. (2013),?Vildagliptin: an anti-diabetes agent ameliorates cognitive deficits and pathology observed in streptozotocin-induced Alzheimer’s disease;? J. Pharm. Pharmacol.,?65?1773 4) Shimizu?et al. (2012),?DPP4 inhibitor vildagliptin preserves? β-cell mass through amelioration of endoplasmic reticulum stress in C/EBPB transgenic mice;? J. Mol. Endocrinol.,?49?125

InChI:InChI=1/C18H17F6N3O.H3O4P/c19-13-8-15(21)14(20)6-10(13)5-11(25)7-17(28)26-3-4-27-12(9-26)1-2-16(27)18(22,23)24;1-5(2,3)4/h1-2,6,8,11H,3-5,7,9,25H2;(H3,1,2,3,4)/t11-;/m1./s1

Synthetic route

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride → vildagliptin (274901-16-5)

Conditions	Yield
With sodium carbonate; sodium chloride In dichloromethane at 20 - 40℃; Product distribution / selectivity;	95%
With sodium carbonate In water at 40℃; for 0.0333333h; Product distribution / selectivity;	75%

(2S)‐1‐[[(3-hydroxytricyclo[3.3.1.1[3,7]]decane-1-yl)imino]acetyl]pyrrolidine-2-carbonitrile → vildagliptin (274901-16-5)

Conditions	Yield
With palladium on activated charcoal; ammonium formate In tetrahydrofuran at 20℃; for 8h; Reagent/catalyst; Solvent; Temperature;	91.9%
With palladium on activated charcoal; ammonium formate In tetrahydrofuran at 20℃; for 10h; Solvent; Reagent/catalyst; Temperature;	91.9%

(3-hydroxyadamantan-1-ylamino)acetic acid (1032564-18-3) + (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: C12H14N2O3S With sodium hydroxide In dichloromethane at 0℃; for 1.5h; Stage #2: (3-hydroxyadamantan-1-ylamino)acetic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0℃; Concentration;	90.8%

C16H33NOSi2 + (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (207557-35-5) → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: C16H33NOSi2; (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile With N-ethyl-N,N-diisopropylamine; potassium iodide In acetonitrile at 75 - 80℃; for 3h; Stage #2: With ethanol In acetonitrile for 2h; Reagent/catalyst;	88.3%

3-aminoadamantan-1-ol (702-82-9) + (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (207557-35-5) → vildagliptin (274901-16-5)

Conditions	Yield
With potassium carbonate; potassium iodide In tetrahydrofuran; butanone at 40℃; for 3h;	82%
With potassium carbonate; potassium iodide In tetrahydrofuran; butanone at 40℃; for 3h; Reflux;	82%
With potassium carbonate; potassium iodide In acetone at 50 - 55℃; for 3h; Solvent;	82.2%

3-aminoadamantan-1-ol (702-82-9) + (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate + chloroacetyl chloride (79-04-9) → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate; chloroacetyl chloride With triethylamine In dichloromethane at 0 - 5℃; for 2h; Stage #2: 3-aminoadamantan-1-ol In water for 4h; Temperature; Reflux;	76.9%

(S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carboxylic acid amide → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: (S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carboxylic acid amide With trifluoroacetic acid; trifluoroacetic anhydride In 2-methyltetrahydrofuran Reflux; Stage #2: With potassium carbonate In 2-methyltetrahydrofuran; water at 5 - 10℃; Reagent/catalyst;	75%
With trichlorophosphate In dichloromethane at 10℃; for 4h; Reagent/catalyst; Solvent; Temperature; Time; Reflux;	4.53 g

3-aminoadamantan-1-ol (702-82-9) + (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: (S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide With trifluoroacetic anhydride In tetrahydrofuran at 20℃; for 2h; Cooling with ice; Stage #2: 3-aminoadamantan-1-ol With potassium carbonate; potassium iodide In tetrahydrofuran at 40℃; for 8.5h; Time; Reflux;	71%

(S)-1-{2-[benzyl(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile → vildagliptin (274901-16-5)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol at 20℃;	61.5%
With palladium 10% on activated carbon; hydrogen In methanol for 22h;

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide (214398-99-9) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 2: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1: triethylamine; oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -78 °C 2: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 35 - 48 °C 2.1: potassium carbonate; potassium iodide / butanone / 40 °C 2.2: 3 h / 38 - 75 °C View Scheme
Multi-step reaction with 2 steps 1.1: trichlorophosphate / -5 - 20 °C 2.1: potassium carbonate; potassium iodide / acetone / 0.25 h / 20 °C 2.2: 40 - 65 °C View Scheme

L-prolinamide (7531-52-4) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: 89 percent / K2CO3 / tetrahydrofuran 2: 7.82 g / trifluoroacetic anhydride / tetrahydrofuran / 1 h / 20 °C 3: K2CO3 / tetrahydrofuran / 0 - 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: trifluoroacetic anhydride / tetrahydrofuran / 3 h / 0 - 30 °C 1.2: 1 h / 0 - 5 °C 2.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / tetrahydrofuran / 0.17 h / 0 °C 1.2: 5 h / 0 - 20 °C 2.1: triethylamine; oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -78 °C 3.1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / 60 - 65 °C View Scheme

3-aminoadamantan-1-ol (702-82-9) + (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (207557-35-5) → (2S)-1-{[{2[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}[(3-hydroxytricyclo[3.3.1.1(3,7)]dec-1-yl)amino]]acetyl}pyrrolidine-2-carbonitrile (1036959-23-5) + vildagliptin (274901-16-5)

Conditions	Yield
With potassium carbonate; potassium iodide In tetrahydrofuran at 66℃; for 2 - 14h; Product distribution / selectivity; Heating / reflux;
With potassium carbonate In Isopropyl acetate at 45℃; for 14h; Product distribution / selectivity;
With potassium carbonate In tetrahydrofuran for 14h; Product distribution / selectivity; Heating / reflux;

(3-hydroxyadamantan-1-ylamino)acetic acid (1032564-18-3) + (2S)-pyrrolidine-2-carbonitrile (204387-53-1) → vildagliptin (274901-16-5)

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 6h;

L-proline (147-85-3) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 2.5 h / 65 - 70 °C 2.1: dicyclohexyl-carbodiimide / dichloromethane / 1 h / 0 - 30 °C 2.2: 3 h / 25 - 30 °C 3.1: triethylamine; oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -78 °C 4.1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / 60 - 65 °C View Scheme
Multi-step reaction with 3 steps 1.1: tetrahydrofuran / 3 h / Reflux 2.1: dicyclohexyl-carbodiimide / dichloromethane / 5 h / 20 °C / Cooling with ice 2.2: 6 h / 20 °C 3.1: trifluoroacetic anhydride / tetrahydrofuran / 2 h / 20 °C / Cooling with ice 3.2: 8.5 h / 40 °C / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: tetrahydrofuran / 2.75 h / 90 °C / Cooling with ice 2.1: 1,3,5-trichloro-2,4,6-triazine / dichloromethane / 3 h / 0 °C / Reflux 2.2: 2 h 3.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 35 - 48 °C 4.1: potassium carbonate; potassium iodide / butanone / 40 °C 4.2: 3 h / 38 - 75 °C View Scheme

3-aminoadamantan-1-ol (702-82-9) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / Reflux 2: potassium hydroxide; water / 12 h / 20 °C 3: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1: tetrahydrofuran / 3 h / Reflux 2: sodium tetrahydroborate; methanol / 0.5 h 3: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: water / 48 h / 20 - 30 °C 2: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / acetonitrile / 3 h / 20 - 30 °C / Inert atmosphere 3: triethylamine / dichloromethane / 5 h / 0 - 10 °C / Inert atmosphere 4: potassium carbonate; methanol / 4 h / 40 °C 5: hydrogenchloride / water / 7 h / 70 °C View Scheme

1-Adamantanamine (768-94-5) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / Reflux 2: potassium hydroxide; potassium permanganate / water / 1.5 h / 60 - 90 °C 3: potassium hydroxide; water / 12 h / 20 °C 4: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sulfuric acid; nitric acid / water / 5 - 25 °C 1.2: 1 h / 0 - 40 °C 2.1: potassium carbonate; potassium iodide / dichloromethane / 0.5 h / Reflux; Inert atmosphere 2.2: 6 h / Reflux 3.1: ammonia / methanol / 10 - 75 °C 4.1: trifluoroacetic anhydride; trifluoroacetic acid / 2-methyltetrahydrofuran / Reflux 4.2: 5 - 10 °C View Scheme
Multi-step reaction with 5 steps 1.1: sulfuric acid; nitric acid / water / 5 - 25 °C 1.2: 1 h / 0 - 40 °C 2.1: potassium carbonate; potassium iodide / ethyl acetate / 75 °C 3.1: sodium hydroxide; water / 65 - 70 °C 4.1: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; N-ethyl-N,N-diisopropylamine / ethyl acetate; acetone 5.1: trifluoroacetic anhydride; trifluoroacetic acid / 2-methyltetrahydrofuran / Reflux 5.2: 5 - 10 °C View Scheme

amantadine hydrochloride (665-66-7) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: nitric acid; sulfuric acid / 2 h / 0 - 12 °C 1.2: Cooling with ice 2.1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / Reflux 3.1: potassium hydroxide; water / 12 h / 20 °C 4.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: nitric acid; sulfuric acid / 2 h / 0 - 12 °C 1.2: Cooling with ice 2.1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / 60 - 65 °C View Scheme
Multi-step reaction with 4 steps 1.1: nitric acid; sulfuric acid / 2 h / 0 - 12 °C 1.2: Cooling with ice 2.1: tetrahydrofuran / 3 h / Reflux 3.1: sodium tetrahydroborate; methanol / 0.5 h 4.1: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme
Multi-step reaction with 2 steps 1: water; sulfuric acid; nitric acid / 14 h / 0 - 20 °C 2: potassium carbonate; tetra-(n-butyl)ammonium iodide / acetonitrile / 60 °C View Scheme

(S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid (23500-10-9) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: dicyclohexyl-carbodiimide / dichloromethane / 1 h / 0 - 30 °C 1.2: 3 h / 25 - 30 °C 2.1: triethylamine; oxalyl dichloride; dimethyl sulfoxide / dichloromethane / 0.5 h / -78 °C 3.1: potassium carbonate; potassium iodide / tetrahydrofuran / 5 h / 60 - 65 °C View Scheme
Multi-step reaction with 2 steps 1.1: dicyclohexyl-carbodiimide / dichloromethane / 5 h / 20 °C / Cooling with ice 1.2: 6 h / 20 °C 2.1: trifluoroacetic anhydride / tetrahydrofuran / 2 h / 20 °C / Cooling with ice 2.2: 8.5 h / 40 °C / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: 1,3,5-trichloro-2,4,6-triazine / dichloromethane / 3 h / 0 °C / Reflux 1.2: 2 h 2.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 35 - 48 °C 3.1: potassium carbonate; potassium iodide / butanone / 40 °C 3.2: 3 h / 38 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: ammonium bicarbonate; pyridine; di-tert-butyl dicarbonate / acetonitrile / 1.5 h / 25 °C 2: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 40 °C 3: potassium carbonate; potassium iodide / tetrahydrofuran; butanone / 3 h / 40 °C View Scheme

[(3-hydroxyadamantan-1-yl)imino]acetic acid (1334337-69-7) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium tetrahydroborate; methanol / 0.5 h 2: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme

t-butyl 2-(adamantan-1-ylamino)acetate (924281-70-9) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium hydroxide; potassium permanganate / water / 1.5 h / 60 - 90 °C 2: potassium hydroxide; water / 12 h / 20 °C 3: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme

t-butyl 2-(3-hydroxyadamantan-1-ylamino)acetate (1334337-68-6) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium hydroxide; water / 12 h / 20 °C 2: dmap; dicyclohexyl-carbodiimide / dichloromethane / 6 h / 20 °C View Scheme

1-[N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetyl]pyrrolidine-2-nitrile (1354835-83-8) → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: 1-[N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetyl]pyrrolidine-2-nitrile With hydrogenchloride In water at 70℃; for 7h; Stage #2: With sodium carbonate In water Product distribution / selectivity;

N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetic acid (1354835-81-6) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / acetonitrile / 3 h / 20 - 30 °C / Inert atmosphere 2: triethylamine / dichloromethane / 5 h / 0 - 10 °C / Inert atmosphere 3: potassium carbonate; methanol / 4 h / 40 °C 4: hydrogenchloride / water / 7 h / 70 °C View Scheme

1-[N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetyl]pyrrolidine-2-amide (1354835-82-7) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 5 h / 0 - 10 °C / Inert atmosphere 2: potassium carbonate; methanol / 4 h / 40 °C 3: hydrogenchloride / water / 7 h / 70 °C View Scheme

t-butyl 2-(3-hydroxyadamantan-1-ylamino)acetate (1334337-68-6) + (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (35150-07-3) → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: (S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate With trifluoroacetic anhydride Stage #2: t-butyl 2-(3-hydroxyadamantan-1-ylamino)acetate

methyl (2S)-pyrrolidine carboxylate (2577-48-2) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ammonium hydroxide 2.1: tetrahydrofuran 3.1: 1,3,5-trichloro-2,4,6-triazine / N,N-dimethyl-formamide / 4 h / 35 - 48 °C 4.1: potassium carbonate; potassium iodide / butanone / 40 °C 4.2: 3 h / 38 - 75 °C View Scheme

(S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate (35150-07-3) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1,3,5-trichloro-2,4,6-triazine; N,N-dimethyl-formamide / dichloromethane / 20 - 40 °C / Inert atmosphere 2: methanesulfonic acid / 40 - 45 °C 3: triethylamine / 20 - 30 °C / Inert atmosphere 4: potassium carbonate / N,N-dimethyl-formamide / 10 h / 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: trifluoroacetic anhydride; triethylamine / dichloromethane / 3 h / -15 °C 2.1: acetonitrile / 10 h / 10 °C 3.1: sodium hydroxide / dichloromethane / 1.5 h / 0 °C 3.2: 0 °C View Scheme

tert-butyl (2S)-2-cyanopyrrolidine-1-carboxylate (228244-04-0) → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 3 steps 1: methanesulfonic acid / 40 - 45 °C 2: triethylamine / 20 - 30 °C / Inert atmosphere 3: potassium carbonate / N,N-dimethyl-formamide / 10 h / 40 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: acetonitrile / 10 h / 10 °C 2.1: sodium hydroxide / dichloromethane / 1.5 h / 0 °C 2.2: 0 °C View Scheme
Multi-step reaction with 3 steps 1: methanesulfonic acid / dichloromethane / 2 h / Reflux 2: triethylamine / dichloromethane / 2 h / Reflux 3: potassium carbonate / dichloromethane / 5 h / Reflux View Scheme

3-aminoadamantan-1-ol (702-82-9) + (2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile → vildagliptin (274901-16-5)

Conditions	Yield
Stage #1: 3-aminoadamantan-1-ol With potassium carbonate; potassium iodide In acetone at 20℃; for 0.25h; Stage #2: (2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile In acetone at 40 - 65℃; Solvent; Temperature;

[benzyl(3-hydroxyadamantan-1-yl)amino]acetic acid ethyl ester → vildagliptin (274901-16-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium hydroxide; water / methanol / 2 h / 65 °C 2: triethylamine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide / N,N-dimethyl-formamide; ethyl acetate / 2 h / 25 °C / Inert atmosphere 3: trifluoroacetic anhydride / 2-methyltetrahydrofuran / Inert atmosphere 4: palladium 10% on activated carbon; hydrogen / methanol / 22 h View Scheme

(2E)-but-2-enedioic acid (110-17-8) + vildagliptin (274901-16-5) → vildagliptin hydrogen fumarate (924667-20-9)

Conditions	Yield
In ethanol at 3 - 50℃; for 5h;	97.1%

copper dichloride + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile copper(II)-chloride

Conditions	Yield
In ethanol at 20 - 50℃;	97%
In ethanol at 20℃; for 2h;	97%

calcium(II) chloride dihydrate + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

Conditions	Yield
In ethanol; water; isopropyl alcohol at 35 - 40℃; Product distribution / selectivity;	97%

vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

Conditions	Yield
With calcium(II) chloride dihydrate In ethanol; water at 35 - 40℃; for 1.5h; Product distribution / selectivity;	97%

vildagliptin (274901-16-5) → Vildagliptin hydrochloride (924914-75-0)

Conditions	Yield
With hydrogenchloride In water; isopropyl alcohol at 30 - 70℃; for 0.0833333h;	93.8%

zinc diacetate (557-34-6) + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-acetate

Conditions	Yield
In ethanol at 20 - 50℃;	92%

zinc(II) acetate dihydrate (5970-45-6) + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-acetate

Conditions	Yield
In ethanol at 20℃; for 2h;	92%

zinc(II) chloride (7646-85-7) + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-chloride

Conditions	Yield
In ethanol at 20 - 50℃;	90%

zinc(II) chloride (7646-85-7) + vildagliptin (274901-16-5) → vildagliptin zinc(II) chloride complex

Conditions	Yield
In ethanol at 20℃; for 2h;	90%

vildagliptin (274901-16-5) → N-(3-hydroxyadamantan-1-yl)-1-imino-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

Conditions	Yield
With potassium hydroxide In water; N,N-dimethyl-formamide at 70℃; for 5h; Solvent; Reagent/catalyst; Temperature;	90%
With triethylamine In ethyl acetate at 90℃; for 168h; Temperature; Reagent/catalyst; Solvent;	21%
In 5,5-dimethyl-1,3-cyclohexadiene at 135 - 140℃; Concentration; Temperature; Solvent;	10%

malonic acid (141-82-2) + vildagliptin (274901-16-5) → vildagliptin hydrogen malonate (924667-41-4)

Conditions	Yield
In ethanol at 3 - 45℃; for 5h;	88%

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile (207557-35-5) + vildagliptin (274901-16-5) → (2S)-1-{[{2[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}[(3-hydroxytricyclo[3.3.1.1(3,7)]dec-1-yl)amino]]acetyl}pyrrolidine-2-carbonitrile (1036959-23-5)

Conditions	Yield
With potassium carbonate; potassium iodide In tetrahydrofuran at 20℃; for 24h; Time; Reflux;	87%

zinc dibromide + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-bromide

Conditions	Yield
In ethanol at 20 - 50℃;	85%
In ethanol at 20℃; for 2h;	85%

zinc(II) chloride (7646-85-7) + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-chloride

Conditions	Yield
In ethanol at 20 - 50℃;	82%
In ethanol at 20℃; for 2h;	82%

vildagliptin (274901-16-5) → vildagliptin hydrogen sulfate form II (924667-83-4)

Conditions	Yield
With sulfuric acid In butan-1-ol at 0 - 60℃; for 22.08h;	81.3%
With sulfuric acid In methanol at 20 - 40℃;

magnesium(II) chloride hexahydrate + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile magnesium(II)-chloride

Conditions	Yield
In isopropyl alcohol at 20 - 50℃;	78%

vildagliptin (274901-16-5) → vildagliptin magnesium(II) chloride complex

Conditions	Yield
With magnesium(II) chloride hexahydrate In isopropyl alcohol at 20℃; for 2h;	78%

strontium nitrate + vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile stroncium(II)-nitrate

Conditions	Yield
In ethanol at 20 - 50℃;	77%

vildagliptin (274901-16-5) → 1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile stroncium(II)-nitrate

Conditions	Yield
With strontium nitrate In ethanol at 20℃; for 2h;	77%

Upstream product

• 702-82-9 3-aminoadamantan-1-ol 
• 207557-35-5 (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile 
• 56-86-0 L-glutamic acid 
• 1119-33-1 (S)-2-Amino-pentanedioic acid 5-ethyl ester 
• 79-04-9 chloroacetyl chloride 
• 768-95-6 1-adamanthanol 
• 1032564-18-3 [(3‐hydroxytricyclo[3.3.1.13,7]decan‐1‐yl)amino]acetic acid 
• 204387-53-1 (2S)-pyrrolidine-2-carbonitrile 
• 23500-10-9 (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid 
• 147-85-3 L-proline 

Downstream Products

• 565453-40-9 vildagliptin carboxylic acid 
• 1789703-37-2 2-(3-hydroxyadamantan-1-yl)-1-imino-hexahydropyrrolo[1,2-a]pyrazin-4-one 

Relevant articles and documents

PROCESS FOR THE PREPARATION OF VILDAGLIPTIN

The present invention relates to process for the preparation of Vildagliptin. The present invention involves an ecologically friendly process by avoiding the dehydrating agent and use of reagents that are less expensive, easier to handle and its cost effective industrial applicable process.

Continuous preparation method of vildagliptin

The invention discloses a continuous preparation method of vildagliptin, which comprises the following steps: 1, preparing (S)-1-(2-chloracetyl) pyrrolidine-2-carbonitrile from (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate, chloroacetyl chloride, triethylamine and dichloromethane, washing, separating the liquid, and keeping the organic phase; 2, adding water and 3-amino-1-adamantanol into the organic phase, refluxing, evaporating to remove the organic solvent, heating, and reacting to obtain a feed liquid; 3, washing the feed liquid, cooling, adjusting to be acidic, and washing to obtain feed liquid; and 4, carrying out aqueous phase extraction, cooling, adjusting to alkalinity, carrying out liquid separation to reserve an organic phase, carrying out aqueous phase re-extraction, carrying out liquid separation, merging the organic phases, evaporating to remove the solvent, and adding a crystallization solvent to obtain vildagliptin with HPLC purity of 99.5% or more. The raw material provided by the invention is low in water absorption and convenient to prepare, store and feed; through continuous process operation, the operation steps are reduced, and the overall yield is improved; finally, water is used as a reaction solvent, so that the production cost is reduced, the environmental pollution pressure is reduced, and the method is suitable for preparing vildagliptin.

A facile method to synthesize vildagliptin

An efficient and high-yielding synthetic method for the preparation of vildagliptin via four steps is reported. The process starts from L-proline and involves a successful reaction with chloroacetyl chloride in tetrahydrofuran to afford (S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid, followed by a reaction with acetonitrile in the presence of sulfuric acid to give (S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile. This is then reacted with 3-aminoadamantanol to give vildagliptin. 3-Aminoadamantanol is prepared from 1-aminoadamantane hydrochloride via oxidation with sulfuric acid/nitric acid and boric acid as the catalyst followed by ethanol extraction. The overall yield is 95%.

Synthesis method of vildagliptin

The invention discloses a synthesis method of vildagliptin. The method comprises the following steps: performing esterification reaction on L-glutamic acid and ethanol to obtain L-glutamic acid-gamma-ethyl ester; reducing the L-glutamic acid-gamma-ethyl ester under the action of potassium borohydride to obtain L-proline; mixing L-proline with ethyl chloroformate for reaction to obtain acid anhydride; further reacting the acid anhydride with amine to obtain amide; dehydrating the amide under the action of phosphorus pentoxide to obtain an intermediate 1; performing substitution reaction on theintermediate 1 and chloroacetyl chloride to obtain an intermediate 2; and further reacting the intermediate 2 with 3-amino-1-adamantanol to obtain vildagliptin. The method has the advantages that fewimpurities are generated in the vildagliptin preparation process, the yield of the prepared vildagliptin is high, and compared with the prior art, the process is simpler, and the vildagliptin preparation cost is greatly reduced.

Cerium-Catalyzed C-H Functionalizations of Alkanes Utilizing Alcohols as Hydrogen Atom Transfer Agents

Modern photoredox catalysis has traditionally relied upon metal-to-ligand charge-transfer (MLCT) excitation of metal polypyridyl complexes for the utilization of light energy for the activation of organic substrates. Here, we demonstrate the catalytic application of ligand-to-metal charge-transfer (LMCT) excitation of cerium alkoxide complexes for the facile activation of alkanes utilizing abundant and inexpensive cerium trichloride as the catalyst. As demonstrated by cerium-catalyzed C-H amination and the alkylation of hydrocarbons, this reaction manifold has enabled the facile use of abundant alcohols as practical and selective hydrogen atom transfer (HAT) agents via the direct access of energetically challenging alkoxy radicals. Furthermore, the LMCT excitation event has been investigated through a series of spectroscopic experiments, revealing a rapid bond homolysis process and an effective production of alkoxy radicals, collectively ruling out the LMCT/homolysis event as the rate-determining step of this C-H functionalization.

Synthetic method of vildagliptin

The invention discloses a synthetic method of vildagliptin. Glycolic acid and (S)-pyrrolidine-2-carbonitrile are used as raw materials; a condensation reaction is carried out under the action of a condensing agent, so that (S)-1-(2-hydroxyacetyl) pyrrolidine-2-formonitrile is prepared; and then the (S)-1-(2-hydroxyacetyl) pyrrolidine-2-carbonitrile and thionyl chloride are subjected to a substitution reaction, wherein only reduced pressure distillation is needed to remove small molecular compounds to obtain a relatively pure carbon tetrachloride solution containing (S)-1-(2-chloracetyl) pyrrolidine-2-carbonitrile; finally, 3-amino-1-adamantanol hydrate and cesium carbonate are added into the solution, and a substitution reaction is carried out just in 4-5 h, finally, the purity of a crudeproduct reaches up to 99.85% after ethyl alcohol recrystallization. According to the present invention, a high-efficiency synthesis route is provided for synthesis of high-purity vildagliptin, and good practicability is achieved.

Preparation method of vildagliptin

The invention relates to a preparation method of vildagliptin. The preparation method comprises the following steps: (1) adding 1,1,1,3,3,3-hexamethyldisilazane, 3-aminoadamantanol, a catalyst and dichloromethane into a reactor, carrying out heating, carrying out a heat-preserved reaction, and after the reaction is completed, evaporating out 1,1,1,3,3,3-hexamethyldisilazane and the solvent to obtain a silicyl-protected 3-aminoadamantanol crude product; and (2) adding potassium iodide, organic alkali and acetonitrile into the reactor filled with the silicyl-protected 3-aminoadamantanol crude product, carrying out heating, dropwise adding (S)-1-(2-chloroacetyl chloride)pyrrolidine-2-carbonitrile dissolved in acetonitrile, carrying out a reaction for 1-6 h, adding ethanol with a concentrationof 95%, continuing stirring for 0.5-2 h, and successively performing cooling, filtering, desolventizing and recrystallizing after the stirring reaction is finished so as to obtain vildagliptin. The preparation method can significantly reduce the generation of the impurity Ia, improve yield and reduce the cost, and is beneficial for industrial production.

Preparation method for vildagliptin

The invention provides a preparation method for vildagliptin. Through the presence of imidazo thiazole as a chiral ligand and a palladium catalyst, a vildagliptin product with high yield and high purity can be obtained by taking diethyl fumarate and amino protected (S)-3-amino-cyano-ethyl propanoate as initial raw materials through steps such as cyclization, deprotection and coupling; and the preparation method is short in reaction route, high in yield and less in by-product, so that production costs can be reduced, and industrial production can be realized.

Synthesizing method of vildagliptin

The invention discloses a synthesizing method of vildagliptin, and belongs to the field of medicine intermediate synthesis. The method includes the steps of conducting an imidization with 3-amino-1-adamantanol and monohydrated glyoxylic acid as the raw materials to obtain (3-hydroxyl adamantly imino)acetic acid, conducting acylation condensation on the (3-hydroxyl adamantly imino)acetic acid and (S)-pyrrolidine-2-formonitrile under the catalysis of electron-withdrawing phenylboric acid to obtain (2S)-1-[[(3-hydroxyl tricyclic[3,3,1,1[3,7]]decane-1-yl)imino]acetyl]pyrrolidine-2-formonitrile, and then conducting hydrazine hydrate reduction to obtain vildagliptin. A one-pot method is adopted, operation is simple, impurities are few, the product is easy to purify, the purifying steps are reduced, cost is reduced, and the method is suitable for industrial production.

Method for preparing vitaletine

The invention discloses a method for preparing vitaletine, and belongs to the field of synthesizing of medicine intermediates. The method comprises the following steps of using 3-amino-1-amantadol andmonohydrated acetaldehyde acid as raw materials, and performing imidization reaction, so as to obtain (3-hdyroxyl amantadine)acetic acid; under the catalyzing function of tris(2,2,2-trifluoroethyl)borate, acylating and condensing with (S)-pyrrolidine-2-formonitrile, so as to obtain (2S)-1-[[(3-hydroxyl tricyclic[3.3.1.1[3,7]]decane-1-yl)imino]acetyl]pyrrolidine-2-formonitrile; reducing by palladium carbon/ammonium formate, so as to obtain the vitaletine. The method has the advantages that one-pot process is adopted, the operation is simple, fewer impurities are contained, the product is easyto purify, the purifying step is not needed, the cost is reduced, and the method is suitable for industrialized production.