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
• Article Data: 41

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

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

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 
• 668270-12-0 Linagliptin 

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.

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-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 IV

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