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850649-61-5

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850649-61-5 Usage

Description

Alogliptin, also known as Alogliptine or Alogliptina, is a dipeptidyl-peptidase IV (DPP-4) inhibitor that was approved in Japan in 2010 for the treatment of type 2 diabetes. It is a novel class of insulinotropic agents that help manage insulin resistance and β-cell dysfunction, which are the primary causes of hyperglycemia in type 2 diabetes patients.

Uses

Used in Pharmaceutical Industry:
Alogliptin is used as an oral antihyperglycemic agent for the treatment of type 2 diabetes. It acts as a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which helps in increasing the levels of glucagon-like peptide 1 (GLP-1), an incretin peptide. The insulinotropic effects of GLP-1 depend on glucose concentrations, providing the possibility of glucose normalization without the risk of hypoglycemia.
Additionally, Alogliptin contributes to the treatment of type 2 diabetes through several non-insulinotropic physiological actions. It suppresses glucagon secretion from alpha cells, slows gastric emptying, and contributes to satiety and a slower passage and reabsorption of carbohydrates. Furthermore, GLP-1 also contributes to satiety via a central mechanism as a neurotransmitter with effects on the hypothalamus, making Alogliptin a valuable antidiabetic agent.

Originator

Syrrx Inc. (now Takeda San Diego) (Japan)

Clinical Use

Dipeptidyl peptidase 4 inhibitor: Treatment of type 2 diabetes in combination with other therapies

Drug interactions

Potentially hazardous interactions with other drugs None known

Metabolism

Alogliptin does not undergo extensive metabolism. Two minor metabolites were detected following administration of an oral dose of [14C]-alogliptin, N-demethylated alogliptin, M-I (<1% of the parent compound), and N-acetylated alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is a highly selective inhibitor of DPP-4 similar to alogliptin; M-II does not display any inhibitory activity towards DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 contribute to the limited metabolism of alogliptin.

Check Digit Verification of cas no

The CAS Registry Mumber 850649-61-5 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 8,5,0,6,4 and 9 respectively; the second part has 2 digits, 6 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 850649-61:
(8*8)+(7*5)+(6*0)+(5*6)+(4*4)+(3*9)+(2*6)+(1*1)=185
185 % 10 = 5
So 850649-61-5 is a valid CAS Registry Number.
InChI:InChI:1S/C18H21N5O2/c1-21-17(24)9-16(22-8-4-7-15(20)12-22)23(18(21)25)11-14-6-3-2-5-13(14)10-19/h2-3,5-6,9,15H,4,7-8,11-12,20H2,1H3

850649-61-5SDS

SAFETY DATA SHEETS

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

Version: 1.0

Creation Date: Aug 18, 2017

Revision Date: Aug 18, 2017

1.Identification

1.1 GHS Product identifier

Product name alogliptin

1.2 Other means of identification

Product number -
Other names Alogliptin

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:850649-61-5 SDS

850649-61-5Synthetic route

3-(R)-aminopiperidine dihydrochloride

3-(R)-aminopiperidine dihydrochloride

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile
865758-96-9

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
With potassium hydrogencarbonate In isopropyl alcohol; acetonitrile at 60℃; for 6h;92.7%
With triethylamine In isopropyl alcohol at 65℃; for 17h;85%
With tetra-n-butylphosphonium chloride; sodium hydrogencarbonate In water; toluene at 60 - 70℃; Solvent; Temperature;85.7%
(R)-piperidin-3-ylcarbamic acid tert-butyl ester
309956-78-3

(R)-piperidin-3-ylcarbamic acid tert-butyl ester

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile
865758-96-9

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Stage #1: 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile With (1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate; palladium diacetate In N,N-dimethyl-formamide for 0.0833333h; Schlenk technique; Inert atmosphere;
Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester With triethylamine In N,N-dimethyl-formamide at 23℃; for 2h; Schlenk technique; Inert atmosphere;
Stage #3: With trifluoroacetic acid In dichloromethane; N,N-dimethyl-formamide at 23℃; for 1h; Schlenk technique; Inert atmosphere;
92%
2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile
1246610-74-1

2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
With hydrogenchloride In methanol; dichloromethane; water at 0 - 5℃; for 4h;91%
With trifluoroacetic acid In methanol at 65℃; for 7h; Reagent/catalyst; Solvent;83%
With citric acid for 2h; Reagent/catalyst; Reflux;77.82%
(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)piperidine-3-carboxamide

(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)piperidine-3-carboxamide

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
With pyridine; [bis(acetoxy)iodo]benzene In water; isopropyl alcohol at 20℃; for 3h;87%
With pyridine; bis-[(trifluoroacetoxy)iodo]benzene In water; isopropyl alcohol at 20℃; for 3h; Solvent; Hofmann Rearrangement;87.2%
bis(trichloromethyl) carbonate
32315-10-9

bis(trichloromethyl) carbonate

C22H31N5O3

C22H31N5O3

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
In tetrahydrofuran at 45℃; for 5.5h;86.5%
2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile

2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
With benzaldehyde In isopropyl alcohol at 60℃; under 675.068 Torr; for 24h;82%
3-(R)-aminopiperidine dihydrochloride

3-(R)-aminopiperidine dihydrochloride

3-methyl-6-chlorouracil
4318-56-3

3-methyl-6-chlorouracil

2-(bromomethyl)benzonitrile
22115-41-9

2-(bromomethyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Stage #1: 3-methyl-6-chlorouracil; 2-(bromomethyl)benzonitrile With dmap In acetonitrile at 80℃; for 6h; Green chemistry;
Stage #2: 3-(R)-aminopiperidine dihydrochloride In acetonitrile for 8h; Reflux; Green chemistry;
73%
2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile
865758-96-9

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile

(R)-3-piperidinyl phthalimide hydrochloride

(R)-3-piperidinyl phthalimide hydrochloride

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Stage #1: 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile; 3-(R)-piperidinyl phthalimide hydrochloride With sodium hydrogencarbonate In methanol at 100℃; for 0.75h;
Stage #2: With methanol; hydrazine hydrate for 4h; Reagent/catalyst; Temperature; Reflux; Further stages;
70%
2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile
865758-95-8

2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: NaH; LiBr / dimethylformamide; tetrahydrofuran / 0.33 h / 20 °C
1.2: 72 percent / dimethylformamide; tetrahydrofuran / 0 - 35 °C
2.1: 2.7 g / NaHCO3; molecular sieves 4 Angstroem / ethanol / 4 h / 100 °C
View Scheme
Multi-step reaction with 2 steps
1: potassium carbonate / acetone / 50 - 60 °C
2: sodium hydrogencarbonate / methanol / 6 h / 65 - 70 °C / Molecular sieve
View Scheme
Multi-step reaction with 2 steps
1.1: lithium bromide; sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere
1.2: 80 °C / Inert atmosphere
2.1: sodium hydrogencarbonate / isopropyl alcohol / 2 h / 100 °C / Molecular sieve
View Scheme
2-(bromomethyl)benzonitrile
22115-41-9

2-(bromomethyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1.1: NaH / dimethylformamide; dimethylsulfoxide / 0.5 h / 0 °C
1.2: LiBr / dimethylformamide; 1,2-dimethoxy-ethane / 0.25 h / 0 - 20 °C
1.3: 54 percent / dimethylformamide; dimethylsulfoxide / 0 - 20 °C
2.1: NaH; LiBr / dimethylformamide; tetrahydrofuran / 0.33 h / 20 °C
2.2: 72 percent / dimethylformamide; tetrahydrofuran / 0 - 35 °C
3.1: 2.7 g / NaHCO3; molecular sieves 4 Angstroem / ethanol / 4 h / 100 °C
View Scheme
Multi-step reaction with 3 steps
1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one; toluene / 70 - 80 °C
2: potassium carbonate / acetone / 50 - 60 °C
3: sodium hydrogencarbonate / methanol / 6 h / 65 - 70 °C / Molecular sieve
View Scheme
Multi-step reaction with 3 steps
1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C
2.1: lithium bromide; sodium hydride / N,N-dimethyl-formamide / 0.5 h / 0 °C / Inert atmosphere
2.2: 80 °C / Inert atmosphere
3.1: sodium hydrogencarbonate / isopropyl alcohol / 2 h / 100 °C / Molecular sieve
View Scheme
3-methyl-6-chlorouracil
4318-56-3

3-methyl-6-chlorouracil

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: potassium carbonate / N,N-dimethyl acetamide / 50 - 100 °C
2: potassium carbonate / N,N-dimethyl acetamide / Heating
3: hydrogenchloride; ethanol / dichloromethane / -5 - 25 °C
View Scheme
Multi-step reaction with 3 steps
1: potassium carbonate; potassium iodide / N,N-dimethyl acetamide / 50 - 100 °C
2: potassium carbonate / N,N-dimethyl acetamide / Heating
3: hydrogenchloride; ethanol / dichloromethane / -5 - 25 °C
View Scheme
Multi-step reaction with 2 steps
1: tributyl-amine / toluene / 5 h / 80 °C
2: triethylamine / isopropyl alcohol / 17 h / 65 °C
View Scheme
2-cyanobenzyl chloride
612-13-5

2-cyanobenzyl chloride

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: potassium carbonate; potassium iodide / N,N-dimethyl acetamide / 50 - 100 °C
2: potassium carbonate / N,N-dimethyl acetamide / Heating
3: hydrogenchloride; ethanol / dichloromethane / -5 - 25 °C
View Scheme
Multi-step reaction with 2 steps
1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 1 h / 60 °C
2: triethylamine / isopropyl alcohol; water / 13 h / 60 °C
View Scheme
2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile
865758-96-9

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: potassium carbonate / N,N-dimethyl acetamide / Heating
2: hydrogenchloride; ethanol / dichloromethane / -5 - 25 °C
View Scheme
Multi-step reaction with 2 steps
1: sodium hydrogencarbonate / methanol / 3 h / 100 °C / Molecular sieve
2: hydrazine hydrate / methanol / 2 h / Reflux
View Scheme
Multi-step reaction with 2 steps
1: potassium carbonate / 6 h / 70 - 80 °C
2: hydrogenchloride / dichloromethane; ethanol / -5 - 20 °C
View Scheme
2-({6-[(3R)-3-(5-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile

2-({6-[(3R)-3-(5-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: potassium carbonate / acetone / 0.58 h / 25 - 30 °C
1.2: 25 - 55 °C
2.1: ethanolamine / 60 - 65 °C
View Scheme
2-({3-methyl-6-[(3R)-3-(5-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile

2-({3-methyl-6-[(3R)-3-(5-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)piperidin-1-yl]-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl}methyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
With ethanolamine at 60 - 65℃;
(R)-piperidin-3-ylamine
127294-73-9

(R)-piperidin-3-ylamine

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: acetic acid / toluene / 3 h / Reflux
2: sodium hydrogencarbonate / methanol / 3 h / 100 °C / Molecular sieve
3: hydrazine hydrate / methanol / 2 h / Reflux
View Scheme
((R)-3-piperidinyl)-2,5-pyrrolidinedione

((R)-3-piperidinyl)-2,5-pyrrolidinedione

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: sodium hydrogencarbonate / methanol / 3 h / 100 °C / Molecular sieve
2: hydrazine hydrate / methanol / 2 h / Reflux
View Scheme
C22H23N5O4

C22H23N5O4

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
With hydrazine hydrate In methanol for 2h; Reflux;197.7 g
1,4,5,6-tetrahydropyridine-3-carboxamide
7032-11-3

1,4,5,6-tetrahydropyridine-3-carboxamide

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 3 steps
1: dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II); hydrogen / methanol / 18 h / 65 °C / 8625.86 Torr / Autoclave
2: potassium carbonate / isopropyl alcohol; water / 23 h / 65 °C
3: pyridine; [bis(acetoxy)iodo]benzene / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
Multi-step reaction with 3 steps
1: ditrifluoroacetato[(S)-(+)-4,12-bis(diphenylphosphino)-[2,2]-paracyclophane]ruthenium(II) complex; hydrogen; lithium bromide monohydrate / methanol / 15 h / 50 °C / 7500.75 Torr / Autoclave
2: potassium carbonate / isopropyl alcohol; water / 23 h / 65 °C
3: pyridine; [bis(acetoxy)iodo]benzene / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
Multi-step reaction with 4 steps
1: ethanol / 20 °C
2: Ru-(CF3CO2)2{(S)-phanephos}; potassium bromide; hydrogen / methanol / 15 h / 50 °C / 7500.75 Torr / Autoclave
3: potassium carbonate / isopropyl alcohol; water / 18 h / 70 °C
4: bis-[(trifluoroacetoxy)iodo]benzene; pyridine / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
nicotinamide
98-92-0

nicotinamide

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1.1: 5%-palladium/activated carbon; hydrogen / methanol / 20 h / 40 °C / 750.08 Torr / Autoclave
1.2: 3.5 h / 10 - 35 °C
2.1: ditrifluoroacetato[(RP,R′P)-1,1′-bis[(S)-α-(dimethylamino)benzyl]-2,2′-bis(diphenylphosphino)ferrocene]ruthenium(II); toluene-4-sulfonic acid; hydrogen; potassium bromide / isopropyl alcohol / 25 h / 5 - 50 °C / 6750.68 Torr / Autoclave
3.1: potassium carbonate / isopropyl alcohol; water / 23 h / 65 °C
4.1: pyridine; [bis(acetoxy)iodo]benzene / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
Multi-step reaction with 4 steps
1: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 45 °C / 750.08 Torr / Autoclave
2: dichloro[(S)-(-)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl]ruthenium(II); hydrogen / methanol / 18 h / 65 °C / 8625.86 Torr / Autoclave
3: potassium carbonate / isopropyl alcohol; water / 23 h / 65 °C
4: pyridine; [bis(acetoxy)iodo]benzene / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
Multi-step reaction with 4 steps
1: 5%-palladium/activated carbon; hydrogen / methanol / 14 h / 45 °C / 750.08 Torr / Autoclave
2: ditrifluoroacetato[(S)-(+)-4,12-bis(diphenylphosphino)-[2,2]-paracyclophane]ruthenium(II) complex; hydrogen; lithium bromide monohydrate / methanol / 15 h / 50 °C / 7500.75 Torr / Autoclave
3: potassium carbonate / isopropyl alcohol; water / 23 h / 65 °C
4: pyridine; [bis(acetoxy)iodo]benzene / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
Multi-step reaction with 5 steps
1: hydrogen; palladium on carbon type-K / methanol / 21 h / 40 °C / 750.08 Torr / Autoclave
2: ethanol / 20 °C
3: Ru-(CF3CO2)2{(S)-phanephos}; potassium bromide; hydrogen / methanol / 15 h / 50 °C / 7500.75 Torr / Autoclave
4: potassium carbonate / isopropyl alcohol; water / 18 h / 70 °C
5: bis-[(trifluoroacetoxy)iodo]benzene; pyridine / isopropyl alcohol; water / 3 h / 20 °C
View Scheme
(R)-piperidin-3-ylcarbamic acid tert-butyl ester
309956-78-3

(R)-piperidin-3-ylcarbamic acid tert-butyl ester

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: potassium carbonate / N,N-dimethyl-formamide / 75 °C
1.2: 75 °C
2.1: trifluoroacetic acid / dichloromethane / 25 °C
View Scheme
Multi-step reaction with 2 steps
1.1: diethyl ether / 10 h / -15 - -10 °C
1.2: 8 h / 35 °C
2.1: tetrahydrofuran / 5.5 h / 45 °C
View Scheme
Multi-step reaction with 3 steps
1.1: diethyl ether / 10 h / -15 - -10 °C
1.2: 8 h / 35 °C
2.1: sodium methylate / N,N-dimethyl-formamide / 0.25 h / 0 - 5 °C
2.2: 2 h / 50 °C
3.1: hydrogenchloride / dichloromethane; methanol; water / 4 h / 0 - 5 °C
View Scheme
3-methyl-6-chlorouracil
4318-56-3

3-methyl-6-chlorouracil

2-(bromomethyl)benzonitrile
22115-41-9

2-(bromomethyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: N-ethyl-N,N-diisopropylamine / tetrahydrofuran / 0.25 h / 23 °C / Schlenk technique; Inert atmosphere
1.2: 2 h / 65 °C / Schlenk technique; Inert atmosphere
2.1: palladium diacetate; (1,3,5-triaza-7-phosphaadamantan-1-ium-1-yl)butane-1-sulfonate / N,N-dimethyl-formamide / 0.08 h / Schlenk technique; Inert atmosphere
2.2: 2 h / 23 °C / Schlenk technique; Inert atmosphere
2.3: 1 h / 23 °C / Schlenk technique; Inert atmosphere
View Scheme
ethyl (R)-3-(3-Boc-aminopiperidin-1-yl)-3-oxopropanoate

ethyl (R)-3-(3-Boc-aminopiperidin-1-yl)-3-oxopropanoate

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1: sodium ethanolate / ethanol / 6 h / Inert atmosphere; Reflux
2: trifluoroacetic acid / methanol / 7 h / 65 °C
View Scheme
C22H31N5O3

C22H31N5O3

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: sodium methylate / N,N-dimethyl-formamide / 0.25 h / 0 - 5 °C
1.2: 2 h / 50 °C
2.1: hydrogenchloride / dichloromethane; methanol; water / 4 h / 0 - 5 °C
View Scheme
2-(aminomethyl)benzonitrile
344957-25-1

2-(aminomethyl)benzonitrile

alogliptin
850649-61-5

alogliptin

Conditions
ConditionsYield
Multi-step reaction with 2 steps
1.1: diethyl ether / 10 h / -15 - -10 °C
1.2: 8 h / 35 °C
2.1: tetrahydrofuran / 5.5 h / 45 °C
View Scheme
Multi-step reaction with 3 steps
1.1: diethyl ether / 10 h / -15 - -10 °C
1.2: 8 h / 35 °C
2.1: sodium methylate / N,N-dimethyl-formamide / 0.25 h / 0 - 5 °C
2.2: 2 h / 50 °C
3.1: hydrogenchloride / dichloromethane; methanol; water / 4 h / 0 - 5 °C
View Scheme
nicotinamide
98-92-0

nicotinamide

A

alogliptin
850649-61-5

alogliptin

B

C37H40N10O5

C37H40N10O5

Conditions
ConditionsYield
Multi-step reaction with 5 steps
1: hydrogen; palladium on carbon type-K / methanol / 21 h / 40 °C / 750.08 Torr / Autoclave
2: ethanol / 20 °C
3: Ru-(CF3CO2)2{(S)-phanephos}; potassium bromide; hydrogen / methanol / 15 h / 50 °C / 7500.75 Torr / Autoclave
4: potassium carbonate / isopropyl alcohol; water / 18 h / 70 °C
5: bis-[(trifluoroacetoxy)iodo]benzene; sodium hydroxide / water; acetonitrile / 4 h / 0 - 20 °C
View Scheme
(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)piperidine-3-carboxamide

(R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)piperidine-3-carboxamide

A

alogliptin
850649-61-5

alogliptin

B

C37H40N10O5

C37H40N10O5

Conditions
ConditionsYield
With potassium carbonate; bis-[(trifluoroacetoxy)iodo]benzene In water; acetonitrile at 20℃; for 1h; Reagent/catalyst;
With bis-[(trifluoroacetoxy)iodo]benzene; sodium hydroxide In water; acetonitrile at 0 - 20℃; for 4h;
1,4,5,6-tetrahydropyridine-3-carboxamide
7032-11-3

1,4,5,6-tetrahydropyridine-3-carboxamide

A

alogliptin
850649-61-5

alogliptin

B

C37H40N10O5

C37H40N10O5

Conditions
ConditionsYield
Multi-step reaction with 4 steps
1: ethanol / 20 °C
2: Ru-(CF3CO2)2{(S)-phanephos}; potassium bromide; hydrogen / methanol / 15 h / 50 °C / 7500.75 Torr / Autoclave
3: potassium carbonate / isopropyl alcohol; water / 18 h / 70 °C
4: bis-[(trifluoroacetoxy)iodo]benzene; sodium hydroxide / water; acetonitrile / 4 h / 0 - 20 °C
View Scheme
alogliptin
850649-61-5

alogliptin

benzoic acid
65-85-0

benzoic acid

Alogliptin benzoate

Alogliptin benzoate

Conditions
ConditionsYield
In ethanol at 50 - 80℃;95.7%
In tetrahydrofuran for 1.5h; Reflux; Large scale;94.68%
In ethanol at 60 - 70℃; for 0.166667h;94.3%
alogliptin
850649-61-5

alogliptin

C18H19N7O2

C18H19N7O2

Conditions
ConditionsYield
With fluorosulfonyl azide; potassium hydrogencarbonate In tert-butyl methyl ether; water; N,N-dimethyl-formamide at 20℃; for 0.0833333h;90%
alogliptin
850649-61-5

alogliptin

2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]Methyl]-N-hydroxyamidinobenzene

2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]Methyl]-N-hydroxyamidinobenzene

Conditions
ConditionsYield
With hydroxylamine hydrochloride; sodium carbonate In ethanol; water at 85 - 90℃; for 20h;80.9%
alogliptin
850649-61-5

alogliptin

2(13)CN(1-)*Zn(2+)

2(13)CN(1-)*Zn(2+)

C17(13)CH21N5O2

C17(13)CH21N5O2

Conditions
ConditionsYield
With C10H12O2NiC8H12-1,5-cyclo; triphenylborane; diphenyl(methyl)phosphine In 1-methyl-pyrrolidin-2-one at 100℃; for 18h; Inert atmosphere; Glovebox; Sealed tube;58%
alogliptin
850649-61-5

alogliptin

C18H23N5O3

C18H23N5O3

Conditions
ConditionsYield
With sodium hydroxide In water; isopropyl alcohol for 9h; Reagent/catalyst; Solvent; Reflux;45.7%
alogliptin
850649-61-5

alogliptin

C23H28N2O4

C23H28N2O4

C41H47N7O5

C41H47N7O5

Conditions
ConditionsYield
Stage #1: C23H28N2O4 With N-ethyl-N,N-diisopropylamine; HATU In dichloromethane at 0℃; for 0.666667h;
Stage #2: alogliptin In dichloromethane at 20℃; for 6h;
30%
alogliptin
850649-61-5

alogliptin

2-{6-[3(R)-amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile

2-{6-[3(R)-amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile

Conditions
ConditionsYield
With thionyl chloride In chloroform at 100℃; for 0.5h;
With thionyl chloride In chloroform at 100℃; for 0.5h; Inert atmosphere;
alogliptin
850649-61-5

alogliptin

2-{6-[3(R)-amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile

2-{6-[3(R)-amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile

Conditions
ConditionsYield
With hydrogenchloride In tetrahydrofuran; 1,4-dioxane at 20℃; for 1h;
alogliptin
850649-61-5

alogliptin

toluene-4-sulfonic acid
104-15-4

toluene-4-sulfonic acid

2-{6-[3(R)-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile p-toluenesulfonate
1428858-00-7

2-{6-[3(R)-amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile p-toluenesulfonate

Conditions
ConditionsYield
In 1,4-dioxane at 20℃; for 3h; Product distribution / selectivity; Inert atmosphere;
alogliptin
850649-61-5

alogliptin

Alogliptin hydrochloride
1246610-75-2

Alogliptin hydrochloride

Conditions
ConditionsYield
With hydrogenchloride In tetrahydrofuran; 1,4-dioxane at 20℃; for 1.16667h; Inert atmosphere;
alogliptin
850649-61-5

alogliptin

alogliptin sulfate

alogliptin sulfate

Conditions
ConditionsYield
With sulfuric acid In ethanol for 3h; Solvent; Reflux;1.3 g
alogliptin
850649-61-5

alogliptin

alogliptin nitrate

alogliptin nitrate

Conditions
ConditionsYield
With nitric acid In ethanol for 3h; Solvent; Reflux;1.4 g
alogliptin
850649-61-5

alogliptin

benzoic acid
65-85-0

benzoic acid

alogliptin benzoate

alogliptin benzoate

Conditions
ConditionsYield
In ethanol at 75 - 80℃; for 2h;12 g
alogliptin
850649-61-5

alogliptin

(2E)-but-2-enedioic acid
110-17-8

(2E)-but-2-enedioic acid

alogliptin fumarate

alogliptin fumarate

Conditions
ConditionsYield
In ethanol for 3h; Solvent; Reflux;1.7 g
alogliptin
850649-61-5

alogliptin

malic acid
617-48-1

malic acid

alogliptin malate

alogliptin malate

Conditions
ConditionsYield
In ethanol for 3h; Solvent; Reflux;1.8 g
alogliptin
850649-61-5

alogliptin

toluene-4-sulfonic acid
104-15-4

toluene-4-sulfonic acid

alogliptin tosylate

alogliptin tosylate

Conditions
ConditionsYield
In ethanol for 3h; Solvent; Reflux;1.6 g
alogliptin
850649-61-5

alogliptin

oxalic acid
144-62-7

oxalic acid

alogliptin oxalate

alogliptin oxalate

Conditions
ConditionsYield
In ethanol for 3h; Solvent; Reflux;1.8 g

850649-61-5Relevant articles and documents

Development and Scale-Up of an Asymmetric Synthesis Process for Alogliptin

Yamada, Masatoshi,Hirano, Sayuri,Tsuruoka, Ryoji,Takasuga, Masahiro,Uno, Kenichi,Yamaguchi, Kotaro,Yamano, Mitsuhisa

, p. 327 - 336 (2021/03/01)

Alogliptin (1) benzoate is a potent, highly selective inhibitor of serine protease dipeptidyl-peptidase IV, approved by US FDA for the treatment of type 2 diabetes. Herein, we report a more cost-effective process that includes ruthenium-catalyzed asymmetric hydrogenation followed by Hofmann rearrangement of 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile (10) to introduce a chiral amino moiety at a late stage. Use of an inexpensive and readily available nicotinamide (6) for a chiral aminopiperidine core and iodobenzene diacetate (PIDA) under mild and specific conditions allowed us to access 1 with excellent total yield and comparable quality to that manufactured by the original process.

Synthesis process of alogliptin benzoate

-

, (2021/02/10)

The invention discloses a synthesis process of alogliptin benzoate. The synthesis process comprises the following steps: 1, preparing an initial raw material 6-chlorouracil; 2, preparing 2-((6-chlorine-2, 4-dioxo-3, 4-dihydro-2H-pyrimidine-1-radical)methyl)cyanophenyl; 3, preparing 2-[(6-chlorine-3, 4-dihydro-3-methyl-2, 4-dioxo-1(2H)-pyrimidinyl)methyl]benzonitrile; 4, preparing alogliptin; 5, preparing alogliptin benzoate. According to the invention, the alogliptin benzoate is synthesized by taking cheap and easily available 6-chlorouracil, alpha bromo-o-methylbenzonitrile and (R)-3-aminopiperidine as raw materials through reactions such as alkylation, methylation, affinity substitution, salification and the like; according to the synthetic route, raw materials are cheap and easy to obtain, the synthetic cost is reduced, all steps are classic reactions, and synthesis improvement is easy; the improved process is low in raw material cost, simple to operate, mild in reaction condition,simple in post-treatment and suitable for industrial production.

Simple preparation method of alogliptin benzoate

-

, (2019/10/01)

The invention relates to an alogliptin benzoate preparation method, which comprises that 3,3-dihalogenated-N-methyl acrylamide sequentially reacts with (R)-3-Boc-aminopiperidine and 2-cyano benzylamine to prepare (R)-3-(3-Bocamino)piperidine-1-yl-3-(2-cyano)benzylamino-N-methacrylamide, the obtained material reacts with a carbonylation reagent to prepare alogliptin, and the alogliptin and benzoicacid are subjected to salt forming to prepare alogliptin benzoate. According to the present invention, the method has advantages of inexpensive and easily available raw materials, simple operation andless wastewater, and is suitable for the industrial production of alogliptin benzoate.

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