666816-98-4

Basic information

• Product Name: 8-bromo-7-(but-2-ynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione
• Synonyms: 8-bromo-7-(but-2-ynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione;8-broMo-7-(but-2-ynyl)-3-Methyl-3,7-dihydropurine-2,6-dione;3-Methyl-7-(2-butyn-1-yl)-8-bromoxanthine;8-Bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1H-purine-2,6-dione;8-broMo-7-(but-2-yn-1-yl)-3-Methyl-1H-purine-2,6(3H,7H)-dione;8-broMo-7-but-2-yn-1-yl-3-Methyl-3,7-dihydro-1H-purine-2,6-dione;8-BroMo-7-(2-butyn-a-yl)-3,7-dihydro-3-Methyl-1-1H-purine-2,6-dione;Linagliptin interMediateC
• CAS NO: 666816-98-4
• Molecular Formula: C₁₀H₉BrN₄O₂
• Molecular Weight: 297
• EINECS: 1308068-626-2
• Mol File: 666816-98-4.mol

Chemical Properties

• Melting Point: 285 °C
• Appearance: /
• Density: 1.71
• Refractive Index: 1.694
• Storage Temp.: 2-8°C
• PKA: 8.91±0.70(Predicted)
• CAS DataBase Reference: 8-bromo-7-(but-2-ynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 8-bromo-7-(but-2-ynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(666816-98-4)
• EPA Substance Registry System: 8-bromo-7-(but-2-ynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(666816-98-4)

Safety Data

• Hazardous Substances Data: 666816-98-4(Hazardous Substances Data)

Usage

Chemical Properties

White powder

InChI:InChI=1/C10H9BrN4O2/c1-3-4-5-15-6-7(12-9(15)11)14(2)10(17)13-8(6)16/h5H2,1-2H3,(H,13,16,17)

Synthetic route

3-methyl-8-bromoxanthine (93703-24-3) + 1-Bromo-2-butyne (3355-28-0) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
With sodium carbonate In acetone at 40℃; for 4h; Temperature; Reagent/catalyst; Solvent;	98%
With N-ethyl-N,N-diisopropylamine In acetone Solvent; Reflux; Further stages;	97.4%
With triethylamine In N,N-dimethyl-formamide at 20℃; for 10h;	95.68%

8-bromo-3-methylxanthine + 1-Bromo-2-butyne (3355-28-0) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃;	85%

3-methylxanthine (1076-22-8) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium acetate / acetic acid / 25 - 30 °C 1.2: 10 - 65 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 - 30 °C 2.2: 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1: sodium acetate; acetic acid; bromine / 2 h / 65 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium acetate; bromine; acetic acid / water / 2 h / 65 °C 2.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C 2.2: 5 h / 80 °C View Scheme

5,6-diamino-1-methyluracil (6972-82-3) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: water / 3 h / 105 °C 1.2: 1 h / 105 °C 2.1: sodium acetate; bromine; acetic acid / water / 2 h / 65 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C 3.2: 5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: water / 3 h / Reflux; Inert atmosphere 1.2: 1 h / Reflux; Inert atmosphere 2.1: acetic acid; sodium acetate; bromine / water / 2 h / 65 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: water / 3 h / 105 °C 1.2: 1 h / 105 °C 2.1: acetic acid; sodium acetate; bromine / 2 h / 65 °C 3.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: water / 3 h / Reflux; Inert atmosphere 2.1: acetic acid; sodium acetate / 25 - 30 °C 2.2: 10 - 65 °C 3.1: N-ethyl-N,N-diisopropylamine / acetone / Reflux View Scheme

6-amino-1-methyluracil (2434-53-9) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: acetic acid; sodium nitrite / water / 1.5 h / 20 - 50 °C 2.1: ammonium hydroxide; sodium dithionite / 7 h / 25 - 60 °C 3.1: water / 3 h / 105 °C 3.2: 1 h / 105 °C 4.1: sodium acetate; bromine; acetic acid / water / 2 h / 65 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C 5.2: 5 h / 80 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium dithionite; ammonium hydroxide / 1 h / 50 °C 2.1: water / 3 h / Reflux; Inert atmosphere 2.2: 1 h / Reflux; Inert atmosphere 3.1: acetic acid; sodium acetate; bromine / water / 2 h / 65 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: acetic acid; sodium nitrite / water / 1 h / 50 °C 2.1: ammonium hydroxide; sodium dithionite / 1 h / 35 - 60 °C 3.1: water / 3 h / 105 °C 3.2: 1 h / 105 °C 4.1: acetic acid; sodium acetate; bromine / 2 h / 65 °C 5.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: acetic acid; sodium nitrite / water / 1 h / 50 °C 2.1: sodium dithionite; ammonia / 1 h / 50 °C 3.1: water / 3 h / Reflux; Inert atmosphere 4.1: acetic acid; sodium acetate / 25 - 30 °C 4.2: 10 - 65 °C 5.1: N-ethyl-N,N-diisopropylamine / acetone / Reflux View Scheme

6-amino-1-methyl-5-nitrosouracil (6972-78-7) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: ammonium hydroxide; sodium dithionite / 7 h / 25 - 60 °C 2.1: water / 3 h / 105 °C 2.2: 1 h / 105 °C 3.1: sodium acetate; bromine; acetic acid / water / 2 h / 65 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 0.5 h / 25 °C 4.2: 5 h / 80 °C View Scheme
Multi-step reaction with 4 steps 1.1: ammonium hydroxide; sodium dithionite / 1 h / 35 - 60 °C 2.1: water / 3 h / 105 °C 2.2: 1 h / 105 °C 3.1: acetic acid; sodium acetate; bromine / 2 h / 65 °C 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium dithionite; ammonia / 1 h / 50 °C 2.1: water / 3 h / Reflux; Inert atmosphere 3.1: acetic acid; sodium acetate / 25 - 30 °C 3.2: 10 - 65 °C 4.1: N-ethyl-N,N-diisopropylamine / acetone / Reflux View Scheme

4-(N-methylamino)-1H-imidazole-5-carboxamide (90801-87-9) → 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: perchloric acid adsorbed on silica gel; formic acid / ethanol / 0.33 h / 20 °C 2: sodium acetate; acetic acid; bromine / 3 h / 65 °C 3: triethylamine / N,N-dimethyl-formamide / 10 h / 20 °C View Scheme

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) → 7-butyl-3-methyl-1H-purine-2,6(3H,7H)-dione (55242-69-8)

Conditions	Yield
With palladium 10% on activated carbon; hydrogen In methanol under 3800.26 Torr; for 16h;	100%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-bromomethyl-5-fluorobenzothiazole (143163-70-6) → 1-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃; Inert atmosphere;	99%
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃;	99%
With potassium carbonate In N,N-dimethyl-formamide at 20℃;	99%
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃;	97%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(bromomethyl)-5-chloro-1,3-benzothiazole (143163-72-8) → 1-[(5-chloro-1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃; Inert atmosphere;	96%
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃;	96%
With potassium carbonate In N,N-dimethyl-formamide	96%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (853029-57-9)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 8h;	95.77%
With sodium hydroxide In water; acetonitrile at 70℃; for 5h; Solvent; Reagent/catalyst;	94.9%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 75℃; for 6h;	93%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)-piperidin-1-yl]-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; 2-chloromethyl-4-methylquinazoline With potassium carbonate In 1-methyl-pyrrolidin-2-one; acetonitrile at 50℃; for 6h; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In 1-methyl-pyrrolidin-2-one; acetonitrile at 60℃; for 8h; Solvent; Temperature;	95.1%
With sodium carbonate at 55 - 60℃; for 6h; Concentration; Reagent/catalyst;	91.8%
Stage #1: (R)-piperidin-3-ylcarbamic acid tert-butyl ester; 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione With 1-methyl-pyrrolidin-2-one; potassium carbonate; potassium iodide for 10h; Stage #2: 2-chloromethyl-4-methylquinazoline for 12h; Time;	90%
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; 2-chloromethyl-4-methylquinazoline With potassium carbonate; potassium iodide In 1-methyl-pyrrolidin-2-one at 40 - 50℃; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester Reagent/catalyst; Solvent; Temperature;	86.7%
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; 2-chloromethyl-4-methylquinazoline With potassium carbonate; potassium iodide In 1-methyl-pyrrolidin-2-one at 40 - 50℃; Stage #2: (R)-piperidin-3-ylcarbamic acid tert-butyl ester In 1-methyl-pyrrolidin-2-one Reagent/catalyst; Solvent; Temperature;

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) → 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthine (666816-91-7)

Conditions	Yield
With potassium carbonate In dimethyl sulfoxide at 114℃; for 6h;	94%
With potassium carbonate In dimethyl sulfoxide at 114℃; for 6h;	94%
With potassium carbonate In dimethyl sulfoxide at 114℃; for 6h;	94%

3-(R)-aminopiperidine dihydrochloride + 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) → 8-[(R)-3-aminopiperidin-1-yl]-3,7-dihydro-3-methyl-7-(2-butynyl)-1H-purine-2,6-dione

Conditions	Yield
With potassium hydrogencarbonate In ethanol at 70℃; for 5h;	93.9%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + methyl 3-(bromomethyl)-4-fluorobenzoate (878744-25-3) → Methyl 2-((8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl) benzoate

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 10h;	93.9%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-p-toluenesulfonylmethyl-4-methylquinazoline → 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (853029-57-9)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 6h;	93%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (114772-54-2) → 4'-((8-bromo-7-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)biphenyl-2-carbonitrile

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 6h;	92%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(chloromethyl)nicotinenitrile (848774-96-9) → 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromo-xanthine

Conditions	Yield
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 70℃; for 19h;	91%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 70℃; for 19h;	91%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + C13H14N2O2 (886588-61-0) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → (R)-7-(but-2-yn-1-yl)-8-(3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine2,6-dione (886588-63-2)

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; C13H14N2O2 With 1-methyl-pyrrolidin-2-one; potassium carbonate; potassium iodide at 50 - 60℃; Stage #2: 2-chloromethyl-4-methylquinazoline	91%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + C13H14BrFN2O2 → C23H22BrFN6O4

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃;	90.5%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (853029-57-9) → (R)-7-(but-2-yn-1-yl)-8-(3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine2,6-dione (886588-63-2)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 2h;	90%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(bromomethyl)-1,3-benzothiazole (106086-78-6) → 1-[(1,3-benzothiazol-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-bromoxanthine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃; Inert atmosphere;	90%
With potassium carbonate In N,N-dimethyl-formamide at 10 - 25℃;	90%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 4-chloromethyl-2-methylquinazoline → 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione (853029-57-9)

Conditions	Yield
With potassium carbonate; potassium iodide In 1-methyl-pyrrolidin-2-one at 75℃; for 3h; Temperature; Large scale;	90%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) → (Z)-8-bromo-7-(2-buten-1-yl)-3-methylxanthine

Conditions	Yield
With hydrogen In methanol under 3800.26 Torr; for 16h; Reagent/catalyst; Solvent; Green chemistry; stereoselective reaction;	90%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + tert-butyl 2-(bromomethyl)-6-fluoro-1H-indole-1-carboxylate (912959-91-2) → C24H23BrFN5O4

Conditions	Yield
With 1,8-diazabicyclo[5.4.0]undec-7-ene In N,N-dimethyl-formamide at 20℃;	89%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-bromomethyl-3-cyanopyrazine → 1-[(3-cyanopyrazine-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;	89%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(chloromethyl)-4-methylquinazoline 3-oxide (6640-59-1) → C20H17BrN6O3

Conditions	Yield
With potassium carbonate In N,N-dimethyl-d6-formamide at 35 - 75℃; Reagent/catalyst; Temperature;	88.6%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-bromomethyl-5-fluorobenzoxazole (1263413-87-1) → C18H13BrFN5O3

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃;	88.2%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + alpha-bromo-3,4-difluorotoluene (85118-01-0) → 8-bromo-7-(but-2-yn-1-yl)-1-(3,4-difluorobenzyl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With potassium carbonate In N,N-dimethyl acetamide at 100℃; for 16h;	87%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 4-(3-chloropropyl)-1-[(5-methylpyrimidin-2-yl)]piperazine → C22H27BrN8O2

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione With potassium carbonate In 1-methyl-pyrrolidin-2-one at 70℃; for 0.25h; Stage #2: 4-(3-chloropropyl)-1-[(5-methylpyrimidin-2-yl)]piperazine In 1-methyl-pyrrolidin-2-one at 70℃; for 6h;	86.9%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 3-methylisoquinolin-1-ylmethylene chloride (91348-82-2) → 8-bromo-7-(but-2-ynyl)-3-methyl-1-(3-methyl-isoquinolin-1-ylmethyl)-3,7-dihydro-purine-2,6-dione (853029-58-0)

Conditions	Yield
With 1-methyl-pyrrolidin-2-one; potassium carbonate at 75℃; for 3.5h;	86%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-bromomethyl-4,5-difluorobenzonitrile → 1-[(4,5-difluoro-benzonitrile-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;	86%

4-(3-chloropropyl)piperazine-1-carboxylic acid tert-butyl ester (165530-45-0) + 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) → C22H31BrN6O4

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione With potassium carbonate In 1-methyl-pyrrolidin-2-one at 70℃; for 0.25h; Stage #2: 4-(3-chloropropyl)piperazine-1-carboxylic acid tert-butyl ester In 1-methyl-pyrrolidin-2-one at 70℃; for 6h;	86%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + (R)-ethyl nipecotate (25137-01-3) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → C28H31N7O4

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6-dione; (R)-ethyl nipecotate With 1-methyl-pyrrolidin-2-one; potassium carbonate; potassium iodide at 60 - 70℃; Stage #2: 2-chloromethyl-4-methylquinazoline	85%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(bromomethyl)-6-fluoro-benzonitrile → 1-[(6-fluorobenzonitrile-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromoxanthine

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 5h;	84%

Upstream product

• 93703-24-3 3-methyl-8-bromoxanthine 
• 3355-28-0 1-Bromo-2-butyne 
• 1076-22-8 3-methylxanthine 
• 6972-82-3 5,6-diamino-1-methyluracil 
• 2434-53-9 6-amino-1-methyluracil 
• 6972-78-7 6-amino-1-methyl-5-nitrosouracil 
• 90801-87-9 4-(N-methylamino)-1H-imidazole-5-carboxamide 

Downstream Products

• 668271-94-1 8-bromo-7-(but-2-ynyl)-3-methyl-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione 
• 853029-57-9 2-bromo-1-(but-2-ynyl)-4-methyl-6-((4-methylquinazolin-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-5,7-(4H,6H)-dione 
• 666816-91-7 3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthine 
• 886588-63-2 (R)-7-(but-2-yn-1-yl)-8-(3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine2,6-dione 
• 668270-12-0 Linagliptin 
• 668273-74-3 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(S)-tert-butoxycarbonylaminopiperidin-1-yl)xanthine 

Relevant articles and documents

Design and synthesis of purine connected piperazine derivatives as novel inhibitors of Mycobacterium tuberculosis

A series of novel purine linked piperazine derivatives were synthesized to identify new, potent inhibitors of Mycobacterium tuberculosis. The compounds were designed to target MurB disrupting the biosynthesis of the peptidoglycan and exert antiproliferative effects. The first series of purine-2,6-dione linked piperazine derivatives were synthesized using an advanced intermediate 1-(3,4-difluorobenzyl)-7-(but-2-ynyl)-3-methyl-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione hydrochloride (6) which was coupled with varied carboxylic acid chloride derivatives. Following this piperazine linked derivatives were also synthesized from 6 using diverse isocyanate partners. The anti-mycobacterial activity of the analogues was tested against Mycobacterium tuberculosis H37Rv which revealed a cluster of six analogues (11, 24, 27, 32, 33 and 34), possessed promising activity. In comparison, a set of these new compounds possessed greater potencies relative to current drugs used in the clinic such as Ethambutol. These results were also correlated with computational molecular docking analysis, providing models for strong interactions of the inhibitors with MurB providing a template for the future development of preclinical agents against Mycobacterium tuberculosis.

Design, synthesis and biological evaluation of novel 1,2,3-triazole-based xanthine derivatives as DPP-4 inhibitors

Abstract: Inhibitors of dipeptidyl peptidase-4 (DPP4) have been shown to be effective treatments for type 2 diabetes. A series of novel 1,2,3-triazole based xanthine derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) activity. Among them, the representative compounds 7b, 7e, 7g and 6e showed excellent inhibitory activity of DPP-4 with IC50 values ranging from 87.41 to 16.34 nM, respectively. The SAR of these xanthine derivatives have been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes. Graphic Abstract: 1,2,3-triazole based xanthine derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) activity. The SAR of these xanthine derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.[Figure not available: see fulltext.].

Preparation method of hypoglycemic drug linagliptin intermediate

The invention provides a preparation method of a hypoglycemic drug linagliptin intermediate, wherein the method comprises the steps: in the presence of a catalyst and an organic solvent, carrying out condensation reaction on o-aminoacetophenone (1) and 2-chloroacetamide (2) to obtain an intermediate II; carrying out condensation, bromination, substitution and other reactions on 4-(methylamino)-1H-imidazol-5-carboxamide (3) to generate an intermediate III; and finally, carrying out alkylation reaction on the intermediate II and the intermediate III to generate an intermediate I. According to the preparation method, generation of side reactions are avoided. Moreover, the reaction cost is saved, the operation conditions are mild, the yield is high, the post-treatment is simple, and the method is suitable for industrial large-scale production.

Novel preparation process of linagliptin

The invention discloses a novel preparation process of linagliptin. 8-bromo-3-methyl xanthine (SM1) is used as an initial raw material, DMF is used as a solvent and reacts with 1-bromo-2-butyne (SM2)under the alkaline condition to obtain an intermediate I, then the intermediate I reacts with 2-chloromethyl-4-methyl quinazol (SM3) under the solvent system to obtain an intermediate II, the intermediate II and (R) 3-aminopiperidine dihydrochloride (SM4) are subjected to a substitution reaction, and finally anti-type 2 diabetes drug linagliptin (I) is prepared. By adopting a one-pot method, the method has the advantages that the raw material cost is low, the yield is high, the post-treatment operation of each step of chemical reaction in multi-step reaction is reduced, the production period is greatly shortened, few impurities are generated in the reaction, the product quality is high, the use amount of chemical reagents is relatively reduced, and the method is relatively green and environment-friendly, and is beneficial to industrial production.

Novel preparation process of linagliptin

The invention discloses a novel preparation process of linagliptin. 8-bromine-3-methyl xanthine (SM1) is used as an initial raw material, DMF is used as a solvent to react with 1-bromine-2-butyne (SM2) under an alkaline condition to obtain an intermediate I, then the intermediate I reacts with 2-chloromethyl-4-methyl quinazol (SM3) under the solvent system to obtain an intermediate II, and the solvent system reacts with (R)-3-Boc-aminopiperidine (SM4) under the alkaline condition to obtain an intermediate III; and the protecting group is dissociated by using acid to obtain the linagliptin (I) for resisting type 2 diabetes mellitus. By adopting a one-pot method, the method has the advantages that the raw material cost is low, the yield is high, the post-treatment operation of each step of chemical reaction in multi-step reaction is reduced, the production period is greatly shortened, few impurities are generated in the reaction, the product quality is high, the use amount of chemical reagents is relatively reduced, and the method is relatively green and environment-friendly, and is beneficial to industrial production.

Linagliptin intermediate compound V

The invention belongs to the field of pharmaceutical chemicals, and provides a linagliptin intermediate compound V and an important intermediate for synthesizing linagliptin by using the intermediateV. The method solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art, and the synthesized novel intermediate compound V has the advantages of high yield, simple operation, significantly reduced production cost, and suitableness for industrial production.

Linagliptin intermediate compound IV

The invention belongs to the field of pharmaceutical chemicals, and discloses a linagliptin intermediate IV and a novel route for synthesizing an important linagliptin intermediate from the linagliptin intermediate IV. The linagliptin intermediate IV synthesized in the invention has the advantages of high yield, simple operation, substantial reduction of production cost, suitableness for industrial production; and the synthesis route solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art.

Preparation method of linagliptin intermediate

The invention provides a preparation method of a linagliptin intermediate. The preparation method comprises the following steps: (1) reacting 2-bromo-4-methylimidazole, N-methylurea and an oxidizing agent to obtain a compound II; (2) reacting the compound II with a bromine source in the presence of an alkali to obtain a compound III; and (3) reacting the compound III with 1-bromo-2-butyne in the presence of alkali to obtain a compound IV that is the key linagliptin intermediate. The method has the advantages of cheap and easily available initial raw materials, simplified steps, high atom utilization rate, mild reaction conditions, high yield, suitability for industrial production and the like.

Rapid generation of novel benzoic acid–based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study

A series of novel xanthine derivatives 2a-l incorporating benzoic acid moieties were rapidly generated by using strategy of scaffold-hopping from our previously reported scaffold uracil to xanthine, a scaffold of approved drug linagliptin. After systematic structure-activity relationship (SAR) study around benzoic acid moieties, 5 novel DPP-4 inhibitors with low picomolar potency range (IC50 50 value of 0.1 nM for DPP-4, showed 22-fold improvement in inhibitory activity compared to lead compound uracil 1, its activity was 45-fold more potent than alogliptin. 2e, 2f, 2i and 2k were selected for pharmacokinetic evaluation, and 2f and 2i showed the better pharmacokinetic profiles after iv administration, but poor oral bioavailability. To improve the oral pharmacokinetic profile, prodrug design approach was performed around 2f and 2i. Esters of 2f and 2i were synthesized and evaluated for stability, toxicity and pharmacokinetics. Compound 3e, the methyl ester of compound 2f, was identified to demonstrate good stability, low toxicity and improved oral bioavailability, with 3-fold higher blood concentration compared to 2f in rats. The following in vivo evaluations revealed 3e provided a sustained pharmacodynamics effect for 48h, and robustly improved glucose tolerance in normal ICR and db/db mice in dose-dependent manner. Chronic treatments investigations demonstrated that 3e achieved more beneficial effects on fasting blood glucose levels and glucose tolerance than alogliptin in type 2 diabetic db/db mice. The overall results have shown that compound 3e has the potential to efficacious, safety and long-acting treatment for T2DM.

Substituted xanthine compound and its preparation and use (by machine translation)

The invention discloses substituted xanthine compounds, a preparation method and applications thereof, and specifically relates to compounds represented by the formula (I), stereo isomers and pharmaceutically acceptable salts thereof, wherein the R1 and R2 are defined in the description. The invention also relates to a pharmaceutical composition containing the compounds, an application of the pharmaceutical composition in preparation of drugs for treating diseases or symptoms caused by high activity of DPP-IV or overexpression of DPP-IV, and a method using the pharmaceutical composition to treat related diseases. The provided compounds can effectively inhibit the activity of DPP-IV.