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274901-16-5

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274901-16-5 Usage

Uses

Different sources of media describe the Uses of 274901-16-5 differently. You can refer to the following data:
1. Glyptins are class of oral anti-hyperglycemic agents that inhibit dipeptidyl peptidase 4 (DPP-4), which can act as a serine exopeptidase. Aside from their use in type 2 diabetes, gliptins have positive cardiovascular and anti-inflammtatory effects. Antidiabetic.
2. Vildagliptin (LAF-237) inhibits DPP?4 with IC50 of 2.3 nM
3. The major metabolite of Vildagliptin

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.

Description

Vildagliptin, a DPP-4 inhibitor, was launched for the oral treatment of type 2 diabetes. Vildagliptin is the second DPP-4 inhibitor to reach the market behind sitagliptin, which was introduced in 2006. DPP-4 inhibitors act by slowing the inactivation of incretins, which are endogenous peptides involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase the synthesis and release of insulin from pancreatic βcells via intracellular signaling pathways involving cAMP. GLP-1 also lowers glucagon secretion from pancreatic α cells, which leads to reduced hepatic glucose production. However, although GLP-1 and GIP effectively lower blood glucose, they are short-lived as a result of rapid inactivation by the ubiquitous serine protease DPP-4. By inhibiting DPP-4, vildagliptin increases the concentration and duration of active incretin levels, which in turn results in increased insulin release and decreased glucagon levels in a glucose-dependent manner. Both vildagliptin and sitagliptin are potent, competitive, reversible inhibitors of DPP- 4 (IC50=3.5 and 18 nM, respectively), and they both show slow, tight-binding inhibition kinetics.

Chemical Properties

White Solid

Brand name

Galvus

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

Check Digit Verification of cas no

The CAS Registry Mumber 274901-16-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 2,7,4,9,0 and 1 respectively; the second part has 2 digits, 1 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 274901-16:
(8*2)+(7*7)+(6*4)+(5*9)+(4*0)+(3*1)+(2*1)+(1*6)=145
145 % 10 = 5
So 274901-16-5 is a valid CAS Registry Number.
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

274901-16-5SDS

SAFETY DATA SHEETS

According to Globally Harmonized System of Classification and Labelling of Chemicals (GHS) - Sixth revised edition

Version: 1.0

Creation Date: Aug 19, 2017

Revision Date: Aug 19, 2017

1.Identification

1.1 GHS Product identifier

Product name Vildagliptin

1.2 Other means of identification

Product number -
Other names Unii-I6B4B2U96p

1.3 Recommended use of the chemical and restrictions on use

Identified uses For industry use only.
Uses advised against no data available

1.4 Supplier's details

1.5 Emergency phone number

Emergency phone number -
Service hours Monday to Friday, 9am-5pm (Standard time zone: UTC/GMT +8 hours).

More Details:274901-16-5 SDS

274901-16-5Synthetic route

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

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

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(3-hydroxyadamantan-1-ylamino)acetic acid

(S)-pyrrolidine-2-carbonitrile p-toluenesulfonate

(S)-pyrrolidine-2-carbonitrile p-toluenesulfonate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

C16H33NOSi2

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
207557-35-5

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

3-aminoadamantan-1-ol

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
207557-35-5

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

3-aminoadamantan-1-ol

(S)-pyrrolidine-2-carbonitrile p-toluenesulfonate

(S)-pyrrolidine-2-carbonitrile p-toluenesulfonate

chloroacetyl chloride
79-04-9

chloroacetyl chloride

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(S)-1-[2-(3-hydroxyadamantan-1-ylamino)acetyl]pyrrolidine-2-carboxylic acid amide

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

3-aminoadamantan-1-ol

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide
214398-99-9

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(S)-1-{2-[benzyl(3-hydroxyadamantan-1-yl)amino]acetyl}pyrrolidine-2-carbonitrile

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(S)-1-(2-chloroacetyl) pyrrolidine-2-carboxamide

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

L-prolinamide

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

3-aminoadamantan-1-ol

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
207557-35-5

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

A

(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

(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

B

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(3-hydroxyadamantan-1-ylamino)acetic acid

(2S)-pyrrolidine-2-carbonitrile
204387-53-1

(2S)-pyrrolidine-2-carbonitrile

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 6h;
L-proline
147-85-3

L-proline

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

3-aminoadamantan-1-ol

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

1-Adamantanamine

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

amantadine hydrochloride

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(S)-1-(2-chloroacetyl)pyrrolidine-2-carboxylic acid

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

[(3-hydroxyadamantan-1-yl)imino]acetic acid

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

t-butyl 2-(adamantan-1-ylamino)acetate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

t-butyl 2-(3-hydroxyadamantan-1-ylamino)acetate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

1-[N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetyl]pyrrolidine-2-nitrile

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetic acid

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

1-[N-formyl-N-(3-hydroxy-1-adamantyl)aminoacetyl]pyrrolidine-2-amide

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

t-butyl 2-(3-hydroxyadamantan-1-ylamino)acetate

(S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate
35150-07-3

(S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

methyl (2S)-pyrrolidine carboxylate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(S)-tert-butyl 2-carbamoylpyrrolidine-1-carboxylate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

tert-butyl (2S)-2-cyanopyrrolidine-1-carboxylate

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

3-aminoadamantan-1-ol

(2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

(2S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

[benzyl(3-hydroxyadamantan-1-yl)amino]acetic acid ethyl ester

vildagliptin
274901-16-5

vildagliptin

Conditions
ConditionsYield
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

(2E)-but-2-enedioic acid

vildagliptin
274901-16-5

vildagliptin

vildagliptin hydrogen fumarate
924667-20-9

vildagliptin hydrogen fumarate

Conditions
ConditionsYield
In ethanol at 3 - 50℃; for 5h;97.1%
copper dichloride

copper dichloride

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile copper(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile copper(II)-chloride

Conditions
ConditionsYield
In ethanol at 20 - 50℃;97%
In ethanol at 20℃; for 2h;97%
calcium(II) chloride dihydrate

calcium(II) chloride dihydrate

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

Conditions
ConditionsYield
In ethanol; water; isopropyl alcohol at 35 - 40℃; Product distribution / selectivity;97%
vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile calcium(II)-chloride

Conditions
ConditionsYield
With calcium(II) chloride dihydrate In ethanol; water at 35 - 40℃; for 1.5h; Product distribution / selectivity;97%
vildagliptin
274901-16-5

vildagliptin

Vildagliptin hydrochloride
924914-75-0

Vildagliptin hydrochloride

Conditions
ConditionsYield
With hydrogenchloride In water; isopropyl alcohol at 30 - 70℃; for 0.0833333h;93.8%
zinc diacetate
557-34-6

zinc diacetate

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-acetate

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-acetate

Conditions
ConditionsYield
In ethanol at 20 - 50℃;92%
zinc(II) acetate dihydrate
5970-45-6

zinc(II) acetate dihydrate

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-acetate

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-acetate

Conditions
ConditionsYield
In ethanol at 20℃; for 2h;92%
zinc(II) chloride
7646-85-7

zinc(II) chloride

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-chloride

Conditions
ConditionsYield
In ethanol at 20 - 50℃;90%
zinc(II) chloride
7646-85-7

zinc(II) chloride

vildagliptin
274901-16-5

vildagliptin

vildagliptin zinc(II) chloride complex

vildagliptin zinc(II) chloride complex

Conditions
ConditionsYield
In ethanol at 20℃; for 2h;90%
vildagliptin
274901-16-5

vildagliptin

N-(3-hydroxyadamantan-1-yl)-1-imino-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

N-(3-hydroxyadamantan-1-yl)-1-imino-hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one

Conditions
ConditionsYield
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

malonic acid

vildagliptin
274901-16-5

vildagliptin

vildagliptin hydrogen malonate
924667-41-4

vildagliptin hydrogen malonate

Conditions
ConditionsYield
In ethanol at 3 - 45℃; for 5h;88%
(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile
207557-35-5

(S)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile

vildagliptin
274901-16-5

vildagliptin

(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

(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

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

zinc dibromide

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-bromide

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-bromide

Conditions
ConditionsYield
In ethanol at 20 - 50℃;85%
In ethanol at 20℃; for 2h;85%
zinc(II) chloride
7646-85-7

zinc(II) chloride

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile zinc(II)-chloride

Conditions
ConditionsYield
In ethanol at 20 - 50℃;82%
In ethanol at 20℃; for 2h;82%
vildagliptin
274901-16-5

vildagliptin

vildagliptin hydrogen sulfate form II
924667-83-4

vildagliptin hydrogen sulfate form II

Conditions
ConditionsYield
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

magnesium(II) chloride hexahydrate

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile magnesium(II)-chloride

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile magnesium(II)-chloride

Conditions
ConditionsYield
In isopropyl alcohol at 20 - 50℃;78%
vildagliptin
274901-16-5

vildagliptin

vildagliptin magnesium(II) chloride complex

vildagliptin magnesium(II) chloride complex

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

strontium nitrate

vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile stroncium(II)-nitrate

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile stroncium(II)-nitrate

Conditions
ConditionsYield
In ethanol at 20 - 50℃;77%
vildagliptin
274901-16-5

vildagliptin

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile stroncium(II)-nitrate

1-[2-(3-hydroxyadamant-1-yl-amino)acetyl]pyrrolidin-(2S)-carbonitrile stroncium(II)-nitrate

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

274901-16-5Relevant articles and documents

Continuous preparation method of vildagliptin

-

Paragraph 0034-0046, (2021/04/21)

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.

PROCESS FOR THE PREPARATION OF VILDAGLIPTIN

-

Page/Page column 8, (2021/06/22)

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.

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

An, Qing,Chen, Yuegang,Liu, Weimin,Pan, Hui,Wang, Xin,Wang, Ziyu,Zhang, Kaining,Zuo, Zhiwei

, p. 6216 - 6226 (2020/04/27)

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.

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