853029-57-9

Basic information

• Product Name: 8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione
• Synonyms: 8-BroMo-7-(2-butyn-a-yl)-3,7-dihydro-3-Methyl-1-[(4-Methyl-2-quinazolinyl)Methyl]-1H-purine-2,6-dione;8-Bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquin-azolin-2-yl)methyl)-1H-purine-2,6(3H,7H)-dion;8-BroMo-7-(but-2-yn-1-yl)-3-Methyl-1-((4-Methylquinazolin-2-yl)Methyl)-1H-purine-2,6(3H,7H)-dione;1H-Purine-2,6-dione,8-broMo-7-(2-butynyl)-3,7-dihydro-3-Methyl-1-[(4-Methyl-2-quinazolinyl)Methyl]-;Linagliptin interMediate F;1-[(4-Methylquinazolin-2-yl)Methyl]-3-Methyl-7-(2-butin-1-yl)-8-broMoxanthine;Iinagliptin Intermediate3;8-bromo-7-(but-2-yn-1-yl)-3-methyl-1-((4-methylquinazolin-2-yl)methyl)-3,7-dihydro-1H-purine-2,6-dione
• CAS NO: 853029-57-9
• Molecular Formula: C₂₀H₁₇BrN₆O₂
• Molecular Weight: 453
• EINECS: 1308068-626-2
• Product Categories: Intermediates
• Mol File: 853029-57-9.mol
• Article Data: 37

Chemical Properties

• Boiling Point: 558.8±60.0 °C at 760 mmHg
• Flash Point: 291.8±32.9 °C
• Appearance: /
• Density: 1.55
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly, Heated, Sonicated), Methanol (Very Slightly, Heated, Sonicated)
• PKA: 2.34±0.50(Predicted)
• CAS DataBase Reference: 8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione(853029-57-9)
• EPA Substance Registry System: 8-Bromo-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione(853029-57-9)

Safety Data

• Hazardous Substances Data: 853029-57-9(Hazardous Substances Data)

Usage

Uses

8-Bromo-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-1H-purine-2,6-dione is an intermediate used to prepare selective inhibitors of dipeptidyl peptidase 4 (DPP4) for potential use in the treatment 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 
• 93703-24-3 3-methyl-8-bromoxanthine 
• 551-93-9 2-aminoacetophenone 
• 2434-53-9 6-amino-1-methyluracil 
• 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 
• 109113-72-6 2-chloromethyl-4-methylquinazoline 
• 1076-22-8 3-methylxanthine 
• 6140-11-0 N-(2-acetylphenyl)-2-chloroacetamide 
• 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 

Downstream Products

• 668270-12-0 Linagliptin 
• 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 
• 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 
• 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 articles and documents

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.

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.