850649-61-5

Basic information

• Product Name: ALOGLIPTIN(ALOGLIPTINE, ALOGLIPTINA)
• Synonyms: Alogliptin(free base);Benzonitrile, 2-[[6-[(3R)-3-aMino-1-piperidinyl]-3,4-dihydro-3-Methyl-2,4-dioxo-1(2H)-pyriMidinyl]Methyl]-;Alogliptin (SYR-322);Axagliptin hydrate;(R)-2-[6-(3-aMino-piperidin-1-yl)-3-Methyl-2,4-dioxo-3,4-dihydropyriMidin-1(2H)-yl)Methyl]-benzonitrile;Alogliptin Benzoate API;Alogliptin 2-[[6-[(3R)-3-Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile;Trajenta
• CAS NO: 850649-61-5
• Molecular Formula: C18H21N5O2
• Molecular Weight: 339.39164
• EINECS: 1592732-453-0
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;intermediat;Inhibitor;Inhibitors;Amines;Aromatics;Chiral Reagents;Heterocycles
• Mol File: 850649-61-5.mol
• Article Data: 28

Chemical Properties

• Boiling Point: 519.238 °C at 760 mmHg
• Flash Point: 267.8℃
• Appearance: White powder
• Density: 1.342
• Storage Temp.: Refrigerator
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)
• PKA: 9.89±0.20(Predicted)
• CAS DataBase Reference: ALOGLIPTIN(ALOGLIPTINE, ALOGLIPTINA)(CAS DataBase Reference)
• NIST Chemistry Reference: ALOGLIPTIN(ALOGLIPTINE, ALOGLIPTINA)(850649-61-5)
• EPA Substance Registry System: ALOGLIPTIN(ALOGLIPTINE, ALOGLIPTINA)(850649-61-5)

Safety Data

• Safety Statements: 24/25
• RIDADR: 3077
• Hazardous Substances Data: 850649-61-5(Hazardous Substances Data)

Usage

Description

Alogliptin is a dipeptidyl-peptidase IV (DPP-4) inhibitor that was approved in Japan in 2010 for treatment of type 2 diabetes, a disease in which insulin resistance and β-cell dysfunction lead to hyperglycemia. As islet function is lost, the severity of insulin resistance increases. The introduction of DPP-4 inhibitors has brought a novel class of insulinotropic agents for the treatment options available to type 2 diabetic patients. The therapeutic potential of glucagon-like peptide 1 (GLP-1), an incretin peptide, for the treatment of type 2 diabetes was realized in the 1990s. The insulinotropic effects of GLP-1 depend closely on glucose concentrations providing the possibility of glucose normalization without the risk of hypoglycemia. GLP-1 has other non-insulinotropic physiological actions that are advantageous. It suppresses glucagon secretion from a cells and slows gastric emptying, which contributes to satiety and to a slower passage and reabsorption of carbohydrates. GLP-1 also contributes to satiety via a central mechanism as a neurotransmitter with effects on the hypothalamus.

Chemical Properties

White Solid

Originator

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

Uses

Alogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). Antidiabetic agent.

Definition

ChEBI: A piperidine that is 3-methyl-2,4-dioxo-3,4-dihydropyrimidine carrying additional 2-cyanobenzyl and 3-aminopiperidin-1-yl groups at positions 1 and 2 respectively (the R-enantiomer). Used in the form of its benzoate salt for treatment of t pe 2 diabetes.

Brand name

Nesina

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.

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

Synthetic route

3-(R)-aminopiperidine dihydrochloride + 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) → alogliptin (850649-61-5)

Conditions	Yield
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) + 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) → alogliptin (850649-61-5)

Conditions

Yield

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) → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
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) + C22H31N5O3 → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
With benzaldehyde In isopropyl alcohol at 60℃; under 675.068 Torr; for 24h;	82%

3-(R)-aminopiperidine dihydrochloride + 3-methyl-6-chlorouracil (4318-56-3) + 2-(bromomethyl)benzonitrile (22115-41-9) → alogliptin (850649-61-5)

Conditions	Yield
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) + (R)-3-piperidinyl phthalimide hydrochloride → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
With ethanolamine at 60 - 65℃;

(R)-piperidin-3-ylamine (127294-73-9) → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
With hydrazine hydrate In methanol for 2h; Reflux;	197.7 g

1,4,5,6-tetrahydropyridine-3-carboxamide (7032-11-3) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) + 2-(bromomethyl)benzonitrile (22115-41-9) → alogliptin (850649-61-5)

Conditions

Yield

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 → alogliptin (850649-61-5)

Conditions	Yield
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 → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5)

Conditions	Yield
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) → alogliptin (850649-61-5) + C37H40N10O5

Conditions

Yield

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 → alogliptin (850649-61-5) + C37H40N10O5

Conditions	Yield
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) → alogliptin (850649-61-5) + C37H40N10O5

Conditions	Yield
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) + benzoic acid (65-85-0) → Alogliptin benzoate

Conditions	Yield
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) → C18H19N7O2

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

Conditions	Yield
With hydroxylamine hydrochloride; sodium carbonate In ethanol; water at 85 - 90℃; for 20h;	80.9%

alogliptin (850649-61-5) + 2(13)CN(1-)*Zn(2+) → C17(13)CH21N5O2

Conditions	Yield
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) → C18H23N5O3

Conditions	Yield
With sodium hydroxide In water; isopropyl alcohol for 9h; Reagent/catalyst; Solvent; Reflux;	45.7%

alogliptin (850649-61-5) + C23H28N2O4 → C41H47N7O5

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

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

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; 1,4-dioxane at 20℃; for 1h;

alogliptin (850649-61-5) + toluene-4-sulfonic acid (104-15-4) → 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)

Conditions	Yield
In 1,4-dioxane at 20℃; for 3h; Product distribution / selectivity; Inert atmosphere;

alogliptin (850649-61-5) → Alogliptin hydrochloride (1246610-75-2)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; 1,4-dioxane at 20℃; for 1.16667h; Inert atmosphere;

alogliptin (850649-61-5) → alogliptin sulfate

Conditions	Yield
With sulfuric acid In ethanol for 3h; Solvent; Reflux;	1.3 g

alogliptin (850649-61-5) → alogliptin nitrate

Conditions	Yield
With nitric acid In ethanol for 3h; Solvent; Reflux;	1.4 g

alogliptin (850649-61-5) + benzoic acid (65-85-0) → alogliptin benzoate

Conditions	Yield
In ethanol at 75 - 80℃; for 2h;	12 g

alogliptin (850649-61-5) + (2E)-but-2-enedioic acid (110-17-8) → alogliptin fumarate

Conditions	Yield
In ethanol for 3h; Solvent; Reflux;	1.7 g

alogliptin (850649-61-5) + malic acid (617-48-1) → alogliptin malate

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

alogliptin (850649-61-5) + toluene-4-sulfonic acid (104-15-4) → alogliptin tosylate

Conditions	Yield
In ethanol for 3h; Solvent; Reflux;	1.6 g

alogliptin (850649-61-5) + oxalic acid (144-62-7) → alogliptin oxalate

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

Upstream product

• 127294-73-9 (R)-piperidin-3-ylamine 
• 309956-78-3 (R)-piperidin-3-ylcarbamic acid tert-butyl ester 
• 334618-23-4 3-(R)-aminopiperidine dihydrochloride 
• 865758-96-9 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile 
• 7032-11-3 1,4,5,6-tetrahydropyridine-3-carboxamide 
• 98-92-0 nicotinamide 
• 1381795-31-8 3-(R)-piperidinyl phthalimide hydrochloride 
• 1108732-05-3 2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile 
• 344957-25-1 2-(aminomethyl)benzonitrile 
• 32315-10-9 bis(trichloromethyl) carbonate 
• 4318-56-3 3-methyl-6-chlorouracil 
• 22115-41-9 2-(bromomethyl)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 
• 612-13-5 2-cyanobenzyl chloride 

Downstream Products

• 1638544-64-5 Alogliptin benzoate 
• 1820685-30-0 C₁₈H₂₃N₅O₃ 
• 1638544-64-5 alogliptin benzoate 
• 1246610-75-2 Alogliptin hydrochloride 

Relevant articles and documents

Preparation method of alogliptin benzoate

The invention discloses a preparation method of alogliptin benzoate. Main starting materials of the preparation method are 6-chloro-3-methyluracil, o-cyanobenzyl bromide, (R)-3-Boc-aminopiperidine andbenzoic acid. According to the method, all indexes meet the specification, meanwhile, dangerous reagents such as sodium hydride and highly toxic methyl iodide are prevented from being used in the reaction process, the requirement for the operation process is not strict, and water-free and oxygen-free conditions are not needed; a high-boiling-point mixed solvent is not used in the reaction, and the solvent is easy to recycle; the selected starting materials are available in the market and easy to obtain, and large-scale production is facilitated; in addition, starting materials or intermediates in the synthetic route are good in stability and convenient to store and control, and genotoxic impurities are avoided in the reaction process; and the synthesis process is environment-friendly.

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

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.

Industrial production method of Alogliptin benzoate

The invention relates to an industrial production method of Alogliptin benzoate, and belongs to the technical field of industrial pharmacy. The method comprises three steps of 1, preparing an Alogliptin intermediate AG I; 2, preparing an Alogliptin intermediate AG II; 3, preparing the Alogliptin benzoate. The industrial production method has the beneficial effects that the reaction conditions areproper; the operation is simple and convenient; the realization is easy; only the Alogliptin intermediate AG II is prepared; then, the AG II and benzoic acid are subjected to tetrahydrofuran synthesis; the Alogliptin benzoate can be obtained; the process is saved; the cost is reduced; used solvents have small environment pollution; the operation is safe; under the large-scale industrial productioncondition, the existing average yield is only about 30 percent; under the condition that the final yield reaches 19.32kg, the finial product yield reaches 94.77 percent; the total yield reaches 60.11percent; high quality and purity can be maintained; the production efficiency is greatly improved.