865758-96-9

Basic information

• Product Name: 2-[(6-Chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2h)-pyriMidinyl)Methyl]benzonitrile
• Synonyms: 2-((6-Chloro-3,4-dihydro-3-methyl-2,4-dioxopyrimidin-1(2H)-yl)methyl)benzonitrile;1:2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile;Alogliptin Related Compound 28;2-((6-Chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H);2-[(6-Chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2h)-pyriMidinyl)Methyl]benzonitrile;Benzonitrile,2-[(6-chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2H)-pyriMidinyl)Methyl]-;2-((6-Chloro-3-Methyl-2,4-dioxo-3,4-dihydropyriMidin-1(2H)-yl)Methyl)benzonitrile;6-chloro-1-(2-isocyanobenzyl)-3-MethylpyriMidine-2,4(1H,3H)-dione
• CAS NO: 865758-96-9
• Molecular Formula: C₁₃H₁₀ClN₃O₂
• Molecular Weight: 275.6904
• EINECS: 1592732-453-0
• Product Categories: Intermediates;INTERMEDIATE;Amines;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 865758-96-9.mol
• Article Data: 32

Chemical Properties

• Boiling Point: 418.0±55.0 °C(Predicted)
• Appearance: White to Off-White Solid
• Density: 1.44
• Storage Temp.: 2-8°C
• Solubility: DMSO (Soluble, Sonicated), Methanol (Slightly, Heated, Sonicated)
• PKA: -3.65±0.40(Predicted)
• CAS DataBase Reference: 2-[(6-Chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2h)-pyriMidinyl)Methyl]benzonitrile(CAS DataBase Reference)
• NIST Chemistry Reference: 2-[(6-Chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2h)-pyriMidinyl)Methyl]benzonitrile(865758-96-9)
• EPA Substance Registry System: 2-[(6-Chloro-3,4-dihydro-3-Methyl-2,4-dioxo-1(2h)-pyriMidinyl)Methyl]benzonitrile(865758-96-9)

Safety Data

• Hazardous Substances Data: 865758-96-9(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Synthetic route

3-methyl-6-chlorouracil (4318-56-3) + 2-(bromomethyl)benzonitrile (22115-41-9) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
Stage #1: 3-methyl-6-chlorouracil With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 23℃; for 0.25h; Schlenk technique; Inert atmosphere; Stage #2: 2-(bromomethyl)benzonitrile In tetrahydrofuran at 65℃; for 2h; Schlenk technique; Inert atmosphere;	96%
With 1-methyl-pyrrolidin-2-one; N-ethyl-N,N-diisopropylamine at 60 - 65℃; for 3h; Large scale;	96.42%
With N-ethyl-N,N-diisopropylamine In dichloromethane at 40 - 45℃; Solvent; Temperature;	95.8%

3-methyl-6-chlorouracil (4318-56-3) + 2-cyanobenzyl chloride (612-13-5) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide at 60℃; for 1h;	85.62%
With potassium carbonate; potassium iodide In N,N-dimethyl acetamide at 50 - 100℃;

2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile (865758-95-8) + dimethyl sulfate (77-78-1) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With potassium carbonate In N,N-dimethyl-formamide at 25℃; for 0.25h; Stage #2: dimethyl sulfate In N,N-dimethyl-formamide for 12h; Solvent; Reagent/catalyst;	84.78%

2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile (865758-95-8) + methyl iodide (74-88-4) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With sodium hydride; lithium bromide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: methyl iodide In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 35℃; Further stages.;	72%
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With sodium hydride; lithium bromide In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; Stage #2: methyl iodide In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 35℃; Inert atmosphere;	72%
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With sodium hydride; lithium bromide In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: methyl iodide In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	70%

methyl iodide (74-88-4) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With sodium hydride; lithium bromide In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 0 - 20℃; for 0.333333h; Stage #2: methyl iodide In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 20 - 35℃;	72%
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With sodium hydride; lithium bromide In tetrahydrofuran; N,N-dimethyl-formamide at 20℃; for 0.333333h; Stage #2: methyl iodide In tetrahydrofuran; N,N-dimethyl-formamide at 20 - 35℃;	72%

1-(2-cyanobenzyl)-3-methylpyrimidine-2,4,6(1H,3H,5H)-trione (1246610-72-9) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
With phosphorus pentachloride; N-benzyl-N,N,N-triethylammonium chloride; trichlorophosphate In acetonitrile for 4 - 5h; Product distribution / selectivity; Reflux;	70.5%

1-(2-cyanobenzyl)-3-methylpyrimidine-2,4,6(1H,3H,5H)-trione (1246610-72-9) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + C13H10ClN3O2

Conditions	Yield
Stage #1: 1-(2-cyanobenzyl)-3-methylpyrimidine-2,4,6(1H,3H,5H)-trione With trichlorophosphate at 0℃; Stage #2: With water at 0 - 110℃;	A 37% B n/a

2-(bromomethyl)benzonitrile (22115-41-9) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
Multi-step reaction with 2 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 View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / dimethyl sulfoxide; N,N-dimethyl-formamide; mineral oil / 0.5 h / 0 °C / Inert atmosphere 1.2: 0.25 h / 0 °C / Inert atmosphere 1.3: 0 - 20 °C / Inert atmosphere 2.1: sodium hydride; lithium bromide / tetrahydrofuran; N,N-dimethyl-formamide; mineral oil / 0.33 h / 20 °C / Inert atmosphere 2.2: 20 - 35 °C / Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / 1-methyl-pyrrolidin-2-one; toluene / 70 - 80 °C 2: potassium carbonate / acetone / 50 - 60 °C View Scheme

1-methyl-2,4,6-pyrimidinetrione (2565-47-1) + 2-(bromomethyl)benzonitrile (22115-41-9) → 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9)

Conditions	Yield
Stage #1: 1-methyl-2,4,6-pyrimidinetrione With N,N-dimethyl-aniline; trichlorophosphate In toluene at 90 - 95℃; for 2h; Stage #2: 2-(bromomethyl)benzonitrile With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 60 - 65℃; Temperature; Concentration;	40 g

(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) → 2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile (1246610-74-1)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 6h; Product distribution / selectivity;	96%
With potassium carbonate at 80 - 90℃;	90%
With tetrabutylammomium bromide; potassium carbonate; sodium iodide In acetonitrile for 25h; Reflux;	89.3%

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 hydrochloride (1246610-75-2)

Conditions	Yield
Stage #1: 3-(R)-aminopiperidine dihydrochloride; 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile With potassium carbonate In water; isopropyl alcohol at 75 - 80℃; Large scale; Stage #2: With hydrogenchloride In chloroform; water at -5 - 0℃; for 2h; Reagent/catalyst; Large scale;	95.1%
Stage #1: 3-(R)-aminopiperidine dihydrochloride; 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile In water; isopropyl alcohol at 60 - 65℃; Inert atmosphere; Stage #2: With potassium carbonate In water; isopropyl alcohol at 60 - 65℃; Inert atmosphere; Stage #3: With hydrogenchloride In tetrahydrofuran; water; isopropyl alcohol at 0 - 15℃; Inert atmosphere;

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + (R)-piperidine-3-carboxamide p-toluenesulfonate → (R)-1-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)piperidine-3-carboxamide

Conditions	Yield
With potassium carbonate In water; isopropyl alcohol at 65℃; for 23h;	95%
With potassium carbonate In water; isopropyl alcohol at 70℃; for 18h; Temperature;	93%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + C18H21N5O2 → C31H30N8O4

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 65℃; for 5h; Temperature;	93%

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%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + benzyl N-[(3R)-3-piperidyl]carbamate (478646-32-1) → benzyl N-[(3R)-1-{3-[(2-cyanophenyl)methyl]-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl}piperidin-3-yl]carbamate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h; Solvent;	92.7%
With cetyltrimethylammonim bromide; potassium carbonate In acetone for 24h; Solvent; Reagent/catalyst; Reflux;	87.7%

(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-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + (3R)-3-aminopyrrolidine dihydrochloride (103831-11-4, 116183-81-4, 116183-83-6, 122458-34-8) → (R)-6-(3-aminopyrrolidin-1-yl)-1-(2-cyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione

Conditions	Yield
With sodium hydrogencarbonate In isopropyl alcohol at 100℃; for 2h; Molecular sieve;	84%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + (S)-3-aminopyrrolidine dihydrochloride (103831-11-4, 116183-81-4, 116183-83-6, 122458-34-8) → (S)-6-(3-aminopyrrolidin-1-yl)-1-(2-cyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione

Conditions	Yield
With sodium hydrogencarbonate In isopropyl alcohol at 100℃; for 2h; Molecular sieve;	82%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + (R)-5-azaspiro[2.4]heptan-7-amine dihydrochloride → (R)-6-(7-amino-5-azaspiro[2.4]heptan-5-yl)-1-(2-cyanobenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione

Conditions	Yield
With sodium hydrogencarbonate In isopropyl alcohol at 100℃; for 2h; Molecular sieve;	81%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + ethylenediamine (107-15-3) → C15H17N5O2

Conditions	Yield
With triethylamine In tetrahydrofuran for 4h; Reflux;	80%

tert-butyl (3R)3-aminopiperidine-1-carboxylate (188111-79-7) + 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) → C23H29N5O4

Conditions	Yield
With sodium carbonate In isopropyl alcohol for 13h; Time; Reflux;	78%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + 1-methyl-1-propanethiol (513-53-1) → 2-((6-(sec-butylthio)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile

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: 1-methyl-1-propanethiol With potassium phosphate In N,N-dimethyl-formamide at 50℃; for 2h; Schlenk technique; Inert atmosphere;	76%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + thiophenol (108-98-5) → 2-((3-methyl-2,4-dioxo-6-(phenylthio)-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile

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: thiophenol With potassium phosphate In N,N-dimethyl-formamide at 50℃; for 2h; Schlenk technique; Inert atmosphere;	72%

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-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) → C13H9Cl2N3O2

Conditions	Yield
With N-chloro-succinimide In 1,2-dichloro-ethane at 80℃; for 8h; Solvent; Temperature;	65.8%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + 3-(R)-aminopiperidine dihydrochloride (943528-10-7) + trifluoroacetic acid (76-05-1) → 2-{6-[3(R)-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}benzonitrile trifluoroacetate

Conditions	Yield
Stage #1: 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile; 3-(R)-aminopiperidine dihydrochloride With sodium hydrogencarbonate In methanol at 100℃; for 2h; Molecular sieve; Stage #2: trifluoroacetic acid	56%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + DL-3-aminohexahydro-1H-azepin (69154-03-6) + trifluoroacetic acid (76-05-1) → 2-{6-[(+/-)-3-aminoazepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}benzonitrile trifluoroacetate + 2-{6-[(+/-)-azepan-3-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}benzonitrile trifluoroacetate

Conditions	Yield
Stage #1: 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile; DL-3-aminohexahydro-1H-azepin With sodium hydrogencarbonate In methanol at 100℃; Molecular sieve; Stage #2: trifluoroacetic acid	A 50% B 11%

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-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile hydrochloride

Conditions	Yield
Stage #1: 3-(R)-aminopiperidine dihydrochloride; 2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile With triethylamine In water; isopropyl alcohol at 65℃; for 48h; Stage #2: With hydrogenchloride In ethanol	47.53%
In water; isopropyl alcohol at 58 - 68℃;
With sodium carbonate; potassium iodide In isopropyl alcohol at 65 - 70℃;	40 g

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + tert-butyl alcohol (75-65-0) → C17H19N3O3

Conditions	Yield
With sodium hydrogencarbonate In water at 70℃; for 12h;	44%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + (5-azaspiro[2.5]oct-8-yl)carbamic acid tert-butyl ester (1232542-24-3) → tert-butyl 5-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)5-azaspiro[2.5]octan-8-ylcarbamate (1232542-25-4)

Conditions	Yield
With sodium hydrogencarbonate In dimethyl sulfoxide at 100℃; for 2h; Inert atmosphere;	40%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + ethanol (64-17-5) → C15H15N3O3

Conditions	Yield
With sodium hydrogencarbonate In water at 73℃; for 8h;	34.5%

2-((6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)methyl)benzonitrile (865758-96-9) + isopropyl alcohol (67-63-0) → C16H17N3O3

Conditions	Yield
With sodium hydrogencarbonate In water at 68℃; for 16h;	23%

Upstream product

• 865758-95-8 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile 
• 74-88-4 methyl iodide 
• 22115-41-9 2-(bromomethyl)benzonitrile 
• 4318-56-3 3-methyl-6-chlorouracil 
• 1246610-72-9 1-(2-cyanobenzyl)-3-methylpyrimidine-2,4,6(1H,3H,5H)-trione 
• 612-13-5 2-cyanobenzyl chloride 
• 2565-47-1 1-methyl-2,4,6-pyrimidinetrione 
• 77-78-1 dimethyl sulfate 

Downstream Products

• 850649-61-5 alogliptin 
• 1246610-76-3 Alogliptin trifluoroacetate 
• 1246610-75-2 Alogliptin hydrochloride 
• 1246610-74-1 2-[[6-[(3R)-3-tert-butoxycarbonylamino-1-piperidinyl]-3,4-dihydro-2,4-dioxo-3-methyl-1(2H)-pyrimidinyl]methyl]benzonitrile 
• 1232542-25-4 tert-butyl 5-(3-(2-cyanobenzyl)-1-methyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)5-azaspiro[2.5]octan-8-ylcarbamate 
• 1638544-64-5 alogliptin benzoate 
• 1638544-64-5 Alogliptin benzoate 
• 2089611-85-6 C₁₈H₂₁N₅O₂ 

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Preparation method of alogliptin benzoate intermediate and preparation method of alogliptin benzoate

The invention provides a reparation method of an alogliptin benzoate intermediate and a preparation method of alogliptin benzoate. The yield of the alogliptin benzoate intermediate prepared by the method is not lower than 88%, and the purity is not lower than 99.5%; and according to the alogliptin benzoate raw material medicine prepared by the method, D90 does not exceed 220 microns, and preferably does not exceed 200 microns. All indexes of the prepared pharmaceutical composition meet medicinal requirements, the quality is stable in the storage process, and the clinical curative effect and medication safety can be guaranteed.

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.

Refining method of alogliptin benzoate

The invention discloses a refining method of alogliptin benzoate, which is characterized in that an alogliptin benzoate crude product (the purity is 99.73%) is used as a starting raw material, the alogliptin benzoate crude product is dissolved by adding an organic solvent, and is cooled to crystallize to obtain a high-purity target product alogliptin benzoate solid, and the purity of the alogliptin benzoate solid can reach 99.99% through HPLC detection. Compared with the prior art, the toxicity of the used solvent is low, the mother liquor solvent can be recycled, and the environmental pollution is small; and the operation is simple and feasible, and industrial large-scale production is facilitated.