853029-57-9

Usage

Uses

Used in Pharmaceutical Industry:
8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione is used as an intermediate in the synthesis of selective inhibitors of dipeptidyl peptidase 4 (DPP4) for the potential treatment of type 2 diabetes. DPP4 inhibitors are a class of drugs that help regulate blood glucose levels by slowing the degradation of incretin hormones, which in turn stimulate insulin secretion and reduce glucagon release. 8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione's role in the development of DPP4 inhibitors highlights its importance in the pharmaceutical industry for the management of type 2 diabetes.

Synthetic route

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 potassium carbonate In 1-methyl-pyrrolidin-2-one at 75℃; for 6h;	93%
With sodium carbonate In N,N-dimethyl acetamide at 100℃; for 6h; Temperature; Large scale;	89.4%

N-(2-acetylphenyl)-2-[8-bromo-7-(but-2-yn-1-yl)-3-methyl -2,6-dioxo-2,3,6,7-tetrahydro- 1H-purin-1-yl]acetamide → 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 ammonium acetate; acetic acid at 95 - 100℃; Inert atmosphere;	95%

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-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%

C16H13BrN6O2 + 1-Bromo-2-butyne (3355-28-0) → 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 N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 50℃; for 3h;	86.3%

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(1-bromomethyl)-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 7h;	82%
With sodium carbonate In 1-methyl-pyrrolidin-2-one at 100 - 120℃;	72%
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 8h;

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-halogenomethyl-4-methyl-quinazoline → 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 20℃; for 6h;

3-methyl-8-bromoxanthine (93703-24-3) → 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
Multi-step reaction with 2 steps 1.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 - 30 °C 1.2: 25 - 30 °C 2.1: tetrabutylammomium bromide; potassium carbonate / dimethyl sulfoxide / 75 - 80 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 20 °C 2: sodium carbonate / N,N-dimethyl-formamide / 12 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 4 h / 80 °C 2: potassium carbonate / N,N-dimethyl-formamide / 6 h / 65 °C View Scheme

3-methylxanthine (1076-22-8) → 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
Multi-step reaction with 3 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 3.1: tetrabutylammomium bromide; potassium carbonate / dimethyl sulfoxide / 75 - 80 °C View Scheme
Multi-step reaction with 3 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 3: potassium carbonate / N,N-dimethyl-formamide / 6 h / 65 °C View Scheme
Multi-step reaction with 3 steps 1: acetic acid; sodium acetate; bromine / 2 h / 65 °C 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 12 h / 20 °C 3: potassium carbonate / N,N-dimethyl acetamide / 75 - 95 °C View Scheme
Multi-step reaction with 3 steps 1.1: acetic acid; sodium acetate / 25 - 30 °C 1.2: 10 - 65 °C 2.1: N-ethyl-N,N-diisopropylamine / acetone / Reflux 3.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 20 - 80 °C View Scheme
Multi-step reaction with 3 steps 1: sodium acetate; acetic acid; bromine / 3 h / 65 °C 2: triethylamine / N,N-dimethyl-formamide / 10 h / 20 °C 3: potassium carbonate / N,N-dimethyl-formamide / 8 h / 90 °C View Scheme

2-aminoacetophenone (551-93-9) → 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 (853029-57-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: hydrogenchloride / 1,4-dioxane / 10 °C / Cooling 1.2: 1 h / -10 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 65 °C View Scheme
Multi-step reaction with 2 steps 1: hydrogenchloride / 1,4-dioxane / 2 h / 6 °C 2: sodium carbonate / 1-methyl-pyrrolidin-2-one / 2 h / 140 °C View Scheme
Multi-step reaction with 2 steps 1: copper(l) chloride; oxygen; potassium carbonate / tetrahydrofuran / 12 h / Reflux 2: potassium carbonate / N,N-dimethyl-formamide / 6 h / 80 °C View Scheme

8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione (666816-98-4) + 2-(2-bromoethyl)-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 acetamide at 20℃; for 8h;

N-(2-acetylphenyl)-2-chloroacetamide (6140-11-0) → 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
Multi-step reaction with 2 steps 1: potassium iodide; potassium carbonate / dimethyl sulfoxide / 50 - 55 °C / Inert atmosphere 2: ammonium acetate; acetic acid / 95 - 100 °C / Inert atmosphere View Scheme

8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-dione (1005482-51-8) → 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
Multi-step reaction with 4 steps 1.1: potassium hydroxide / N,N-dimethyl-formamide; water / 0.5 h 1.2: 6 h / 20 °C 2.1: acetic acid; dihydrogen peroxide / 0.5 h / Reflux 3.1: sodium ethanolate; ethanol / 1 h / Reflux; Inert atmosphere 4.1: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 50 °C View Scheme

C19H17BrN6O2S → 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
Multi-step reaction with 3 steps 1: acetic acid; dihydrogen peroxide / 0.5 h / Reflux 2: sodium ethanolate; ethanol / 1 h / Reflux; Inert atmosphere 3: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 50 °C View Scheme

C19H17BrN6O4S → 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
Multi-step reaction with 2 steps 1: sodium ethanolate; ethanol / 1 h / Reflux; Inert atmosphere 2: N-ethyl-N,N-diisopropylamine / N,N-dimethyl-formamide / 3 h / 50 °C View Scheme

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) + C40H34Br2N12O4

Conditions	Yield
With potassium carbonate In N,N-dimethyl acetamide at 75 - 85℃;	A n/a B 2 g

6-amino-1-methyluracil (2434-53-9) → 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 (853029-57-9)

Conditions	Yield
Multi-step reaction with 6 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 6.1: potassium carbonate / N,N-dimethyl acetamide / 75 - 95 °C View Scheme
Multi-step reaction with 6 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 6.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 20 - 80 °C View Scheme

6-amino-1-methyl-5-nitrosouracil (6972-78-7) → 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
Multi-step reaction with 5 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 5.1: potassium carbonate / N,N-dimethyl acetamide / 75 - 95 °C View Scheme
Multi-step reaction with 5 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 5.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 20 - 80 °C View Scheme

5,6-diamino-1-methyluracil (6972-82-3) → 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
Multi-step reaction with 4 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 4.1: potassium carbonate / N,N-dimethyl acetamide / 75 - 95 °C View Scheme
Multi-step reaction with 4 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 4.1: potassium carbonate; tetrabutylammomium bromide / dimethyl sulfoxide / 20 - 80 °C View Scheme

4-(N-methylamino)-1H-imidazole-5-carboxamide (90801-87-9) → 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 (853029-57-9)

Conditions	Yield
Multi-step reaction with 4 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 4: potassium carbonate / N,N-dimethyl-formamide / 8 h / 90 °C View Scheme

3-(R)-aminopiperidine dihydrochloride + 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) → Linagliptin

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 60 - 70℃; for 7h; Large scale;	96.7%
With triethyl borane; sodium carbonate; 4-methyl-2-pentanone at 95 - 100℃; for 10h; Concentration;	93.8%
With potassium carbonate; potassium iodide In acetic acid butyl ester; toluene at 40 - 125℃; pH=11 - 12; Solvent;	47%

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) + C13H26N2*C4H6O6 → C31H42N8O2Si2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 80℃;	96%

(R)-piperidin-3-ylcarbamic acid tert-butyl ester (309956-78-3) + 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) → 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
With potassium carbonate In dimethyl sulfoxide; acetonitrile at 84 - 86℃; for 20h;	95.3%
With potassium carbonate In dimethyl sulfoxide; acetonitrile at 20 - 86℃; for 20h; Temperature;	95.3%
With potassium carbonate; potassium iodide In dimethyl sulfoxide at 80 - 85℃; Reagent/catalyst;	91%

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) + C20H20N2O2*C4H6O6 → C40H36N8O4

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃; for 3h;	95%

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) + C7H10N2O2S2*C4H6O6 → C27H26N8O4S2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 80℃; for 3h;	94.3%

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) + ethanolamine (141-43-5) → 7-(but-2-yn-1-yl)-8-((2-hydroxyethyl)amino)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
In toluene for 2h; Reflux;	94.2%

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) + C13H10Cl4N2O2*C4H6O6 → C33H26Cl4N8O4

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 80 - 140℃; for 3h;	94.1%

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)-2-(piperidin-3-yl)isoindoline-1,3-dione D-(-)-tartaric acid salt (886588-62-1) → (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;	94%

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) + C21H20N2O2*C4H6O6 → C41H36N8O4

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 140℃;	92%

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) + C11H18N2*C4H6O6 → C31H34N8O2

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 100℃;	92%

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)-3-(benzylideneamino)piperidine → (R)-8-(3-(benzylideneamino)piperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With potassium carbonate In toluene at 100℃; Temperature;	91.2%

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%

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)-3-piperidinyl phthalimide hydrochloride → (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: 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; 3-(R)-piperidinyl phthalimide hydrochloride With potassium carbonate In Isopropyl acetate for 0.5h; Stage #2: With benzyltrimethylammonium chloride In Isopropyl acetate for 16h; Solvent; Reflux;	88.7%

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) + dimethyl amine (124-40-3) → 7-(but-2-yn-1-yl)-8-(dimethylamino)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 25 - 55℃; for 24h; Inert atmosphere;	71.66%

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) + (3R)-3-aminopyrrolidine dihydrochloride (103831-11-4, 116183-81-4, 116183-83-6, 122458-34-8) → (R)-8-(3-aminopyrrolidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 6h;	70%

piperidine (110-89-4) + 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) → 7-(but-2-ynyl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-8-(piperidin-1-yl)-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 6h;	67%

piperazine (110-85-0) + 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) → 7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
In DMF (N,N-dimethyl-formamide) at 200℃; for 0.0833333h; Microwave irradiation;	66%
With potassium carbonate In N,N-dimethyl-formamide at 50℃; for 6h;	58%

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) + (S)-3-aminopyrrolidine dihydrochloride (103831-11-4, 116183-81-4, 116183-83-6, 122458-34-8) → (S)-8-(3-aminopyrrolidin-1-yl)-7-(but-2-ynyl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 75℃; for 6h;	65%

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) + tert-butyl (S)-piperidin-3-yl-carbamate (216854-23-8) → 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(S)-tert-butoxycarbonylaminopiperidin-1-yl)xanthine (668273-74-3)

Conditions	Yield
With potassium carbonate In tetrahydrofuran for 16h; Reflux;	65%

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)-1-cyclohexyl-N-(piperidin-3-yl)methanimine → (R)-7-(but-2-yn-1-yl)-8-(3-((cyclohexylmethylen)amino)piperidin-1-yl)-3-methyl-1-((4-methyilquinazolin-2-yl)methyl)-3,7-dihydro-1H-purin-2,6-dione

Conditions	Yield
With potassium phosphate In 1-methyl-pyrrolidin-2-one; toluene at 103℃;	64.2%

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) + (S)-octahydropyrrolo[1,2-a]pyrazine (93643-24-4) → (S)-7-(but-2-ynyl)-8-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
In N,N-dimethyl-formamide at 75℃; for 6h;	60%

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) + 3-phenyl-N-((R)-piperidin-3-yl)prop-2-en-1-imine → 7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-8-((R)-3-(((1E,2E)-3-phenylallylidene)amino)piperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With potassium phosphate In 1-methyl-pyrrolidin-2-one; toluene at 103℃;	56.5%

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)-1-(4-methylphenyl)-N-(piperidin-3-yl)methanimine → (R)-8-(3-(4-methylbenzylideneamino)piperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With potassium phosphate In 1-methyl-pyrrolidin-2-one; toluene at 103℃;	54.7%

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)-1-(4-nitrophenyl)-N-(piperidin-3-yl)methanimine → (R)-8-(3-(4-nitrobenzylideneamino)piperidin-1-yl)-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione

Conditions	Yield
With potassium phosphate In 1-methyl-pyrrolidin-2-one; toluene at 103℃;	54.7%

Upstream product

• 666816-98-4 8-bromo-7-(but2-yn-1-yl)-3-methyl-3,7-dihydro-1H-purine-2,6–dione 
• 6972-78-7 6-amino-1-methyl-5-nitrosouracil 
• 6972-82-3 5,6-diamino-1-methyluracil 
• 90801-87-9 4-(N-methylamino)-1H-imidazole-5-carboxamide 
• 2434-53-9 6-amino-1-methyluracil 
• 109113-72-6 2-chloromethyl-4-methylquinazoline 
• 1005482-51-8 8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-dione 
• 3355-28-0 1-Bromo-2-butyne 
• 6140-11-0 N-(2-acetylphenyl)-2-chloroacetamide 
• 551-93-9 2-aminoacetophenone 
• 1076-22-8 3-methylxanthine 
• 93703-24-3 3-methyl-8-bromoxanthine 

Downstream Products

• 668270-12-0 Linagliptin 
• 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 
• 1673546-62-7 1-[(4-methylquinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-2,2,2-trifluoroacetylaminopiperidin-1-yl)xanthine 
• 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 
• 1646355-34-1 7-(but-2-yn-1-yl)-8-(dimethylamino)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione 

Relevant academic research and scientific papers

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.

Preparation method of linagliptin

The invention relates to a preparation method of linagliptin. The method comprises the following steps: taking a raw material I, namely 2-chloromethyl-4-methylquinazoline, and a raw material II, namely 8-bromo-7-(2-butynyl)-3-methyl-1H-purine-2, 6 (3H, 7H)-diketone as raw materials, performing reaction to obtain an intermediate III, namely 8-bromo-7-(2-butynyl)-3,7-dihydro-3-methyl-1-[(4-methylquinazoline-2-yl)-methyl]-1H-purine-2, 6-diketone, and performing reaction with a raw material IV: (R)-3-aminopiperidine hydrochloride to prepare a target product. In the reaction process, a protecting group does not need to be added, the step of removing the protecting group after the reaction is completed is omitted, and the generation of reaction byproducts in the process of removing the protecting group is reduced. The solvents used in the method are beneficial to recycling, low in price, environment-friendly, green and environmentally friendly, and the obtained product is high in yield, high in purity and suitable for 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.

Industrial preparation method of linagliptin

The invention belongs to the technical field of medicines, and particularly relates to an industrial preparation method of linagliptin. The preparation method comprises the following steps: adding N,N-dimethylacetamide into a reaction kettle, sequentially adding 8-bromo-7-(2-butyne)-3-methylxanthine, 2-chloromethyl-4-methylquinazoline, anhydrous sodium carbonate, anhydrous potassium carbonate andmethyl tert-butyl ether, and sequentially heating, cooling, stirring, filtering, carrying out HPLC monitoring and the like to obtain intermediates I and II, thereby finally obtaining linagliptin. Theindustrial preparation method of linagliptin provided by the invention is simple, high in intermediate purity, low in environmental pollution and low in cost, and meets the requirements of industrialmedicinal products.

Linagliptin intermediate isomer impurity, preparation method and application thereof

The invention relates to a linagliptin intermediate isomer, and provides a preparation method and purification method for obtaining a linagliptin intermediate isomer through a reaction of 4-methyl-2-halogenated methyl quinazoline and 8-bromo-3,7-dihydro-3-methyl-1H-purine-2,6-dione under the action of a silicon ester reagent and an alkali, wherein the preparation method has the advantages that theoperation is simple, the cost is low, and the purity of the obtained linagliptin intermediate isomer is high, and effective synthesis and purification of the linagliptin intermediate isomer lays a good foundation for quality research and control of linagliptin and an intermediate thereof.

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.

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.

Xanthine compound, preparation method and applications thereof

The invention belongs to the technical field of medicinal chemistry, and particularly relates to a new compound I (represented by a formula I), a preparation method and applications thereof. The invention relates to an important application of the new compound I, ie., a method for synthesizing a compound III capable of being used for treating type II diabetes mellitus by taking the compound I as araw material, wherein the method is high in conversion rate, simple in process and mild in reaction condition, provides an economic and environment-friendly route for preparation of the compound III,and has the advantages of being high in yield, good in purity, easy and convenient to operate, low in cost and suitable for industrial production compared with the method for preparing the compound III through linagliptin in the prior art. The compound I of the invention is a solid and is easy to store and purify, and the preparation route of the compound I is mild in reaction condition and simple to operate.

Route for synthesizing diabetes medicine linagliptin

The invention relates to synthesis of a diabetes medicine linagliptin and particularly relates to a new preparation method for 1-[(4-methylquinazoline-2-yl)methyl]-3-methyl-7-(2-butyne-1-yl)-8-bromo-xanthine.