109113-72-6

Basic information

• Product Name: 2-(chloromethyl)-4-methylquinazoline
• Synonyms: 2-(chloromethyl)-4-methylquinazoline;Quinazoline,2-(chloroMethyl)-4-Methyl-;Linagliptin interMediate A;2-chloroMethyl-4-Methyl quinaoline;Linagliptin INT3;109113-72-6;Linaint-I;2-(chloromethyl)-4-methylquizoline
• CAS NO: 109113-72-6
• Molecular Formula: C₁₀H₉ClN₂
• Molecular Weight: 192.64486
• EINECS: 1308068-626-2
• Product Categories: Intermediates
• Mol File: 109113-72-6.mol
• Article Data: 8

Chemical Properties

• Melting Point: 61.0 to 65.0 °C
• Boiling Point: 240.039 °C at 760 mmHg
• Flash Point: 122.14 °C
• Appearance: /
• Density: 1.251
• Vapor Pressure: 0Pa at 20℃
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: 1.86±0.50(Predicted)
• Water Solubility: 3.11g/L at 20℃
• CAS DataBase Reference: 2-(chloromethyl)-4-methylquinazoline(CAS DataBase Reference)
• NIST Chemistry Reference: 2-(chloromethyl)-4-methylquinazoline(109113-72-6)
• EPA Substance Registry System: 2-(chloromethyl)-4-methylquinazoline(109113-72-6)

Safety Data

• RIDADR: 3261
• HazardClass: 8
• PackingGroup: III
• Hazardous Substances Data: 109113-72-6(Hazardous Substances Data)

Usage

Chemical Properties

White to yellow powder

Synthesis Reference(s)

Journal of Heterocyclic Chemistry, 23, p. 1263, 1986 DOI: 10.1002/jhet.5570230458

Flammability and Explosibility

Notclassified

Synthetic route

2-aminoacetophenone (551-93-9) + Chloroacetamide (79-07-2) → 2-chloromethyl-4-methylquinazoline (109113-72-6)

Conditions	Yield
Stage #1: 2-aminoacetophenone With phosphoric acid In ethanol at 20℃; Stage #2: Chloroacetamide In ethanol Reagent/catalyst; Solvent; Reflux;	94.26%
With oxygen; triethylamine; copper(l) chloride In tetrahydrofuran for 12h; Reflux;	88%

2-aminoacetophenone (551-93-9) + chloroacetonitrile (107-14-2) → 2-chloromethyl-4-methylquinazoline (109113-72-6)

Conditions	Yield
With hydrogenchloride In 1,4-dioxane at 6℃; for 2h;	85%
With hydrogenchloride; [1-(3-sulfonic acid)]propyl-3-methylimidazolium hydrogen sulfate In 1,4-dioxane; water at 8℃; for 18h; Reagent/catalyst; Temperature;	85.14%
Stage #1: 2-aminoacetophenone With hydrogenchloride In 1,4-dioxane at 10℃; Cooling; Stage #2: chloroacetonitrile In 1,4-dioxane at -10℃; for 1h;	45%

chloroacetonitrile (107-14-2) → 2-chloromethyl-4-methylquinazoline (109113-72-6)

Conditions	Yield
Stage #1: 2-aminoacetophenone With hydrogenchloride In 1,4-dioxane at -10 - 25℃; Stage #2: chloroacetonitrile In 1,4-dioxane at -10 - 2℃; for 3h; Stage #3: With sodium hydroxide In 1,4-dioxane; water at 5 - 11℃;	74%

2-(chloromethyl)-4-methylquinazoline 3-oxide (6640-59-1) → 2-chloromethyl-4-methylquinazoline (109113-72-6)

Conditions	Yield
With phosphorus trichloride In chloroform Heating / reflux;	57%

Ro 5-3663 (70656-87-0) → 2-chloromethyl-4-methylquinazoline (109113-72-6)

Conditions	Yield
With trichlorophosphate for 0.5h; Heating;	52%

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%

(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;

8-[(R)-3-aminopiperidin-1-yl]-3,7-dihydro-3-methyl-7-(2-butynyl)-1H-purine-2,6-dione + 2-chloromethyl-4-methylquinazoline (109113-72-6) → Linagliptin

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 10h;	94.8%
With sodium hydrogencarbonate In 1-methyl-pyrrolidin-2-one at 90℃; Solvent; Temperature;	1.8 g

2-bromo-3-(2-butyn-1-yl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (705280-62-2) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 2-bromo-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (705280-63-3)

Conditions	Yield
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 1h;	94%
With caesium carbonate In DMF (N,N-dimethyl-formamide) at 80℃; for 1h;	94%
With potassium carbonate In 1-methyl-pyrrolidin-2-one at 80℃; for 3h;	75%

1-methyluracil (615-77-0) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → C15H14N4O2

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one at 80 - 85℃; Reagent/catalyst; Solvent; Temperature;	93.6%
With triethylamine In 1-methyl-pyrrolidin-2-one at 80 - 85℃; for 34h; Solvent; Temperature; Reagent/catalyst;	93.6%

8-iodine-7-(2-butynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 7-but-2-ynyl-8-iodo-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 90℃; for 8h;	93.2%
Stage #1: 8-iodine-7-(2-butynyl)-3-methyl-1H-purine-2,6(3H,7H)-dione; 2-chloromethyl-4-methylquinazoline With sodium carbonate In 1-methyl-pyrrolidin-2-one at 90℃; for 11h; Stage #2: With acetic acid In ethanol at 60℃; for 0.5h;	65%

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%

1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione (1431528-74-3) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 1-(2-butyn-1-yl)-6-chloro-3-[(4-methylquinazolin-2-yl)methyl]pyrimidine-2,4 (1H,3H)-dione

Conditions	Yield
Stage #1: 1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione With sodium hydride; lithium bromide In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloromethyl-4-methylquinazoline In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	88%
Stage #1: 1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione With sodium hydride In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: With lithium bromide In dimethyl sulfoxide; N,N-dimethyl-formamide for 0.25h; Stage #3: 2-chloromethyl-4-methylquinazoline In dimethyl sulfoxide; N,N-dimethyl-formamide at 20℃;	86.5%

1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione (1431528-74-3) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 1-methyl-6-chloro-3-[(4-methylquinazolin-2-yl)methyl]pyrimidine-2,4(1H,3H)-dione

Conditions	Yield
Stage #1: 1-(but-2-yn-1-yl)-6-chloropyrimidine-2,4(1H,3H)-dione With sodium hydride In dimethyl sulfoxide; N,N-dimethyl-formamide at 0℃; for 0.0833333h; Stage #2: With lithium bromide In dimethyl sulfoxide; N,N-dimethyl-formamide for 0.25h; Stage #3: 2-chloromethyl-4-methylquinazoline In dimethyl sulfoxide; N,N-dimethyl-formamide at 20℃;	86.5%

8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-dione (1005482-51-8) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → C19H17BrN6O2S

Conditions	Yield
Stage #1: 8-bromo-3-methyl-7-(thietan-3-yl)-3,7-dihydro-1H-pyrine-2,6-dione With potassium hydroxide In water; N,N-dimethyl-formamide for 0.5h; Stage #2: 2-chloromethyl-4-methylquinazoline In water; N,N-dimethyl-formamide at 20℃; 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%

3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert-butoxycarbonylamino)piperidin-1-yl]xanthine (666816-91-7) + 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
With tetrabutylammomium bromide; potassium carbonate In cyclohexane Reagent/catalyst; Solvent; Reflux;	80.3%

8-bromo-3-methyl-7-(prop-2-ynyl)-1H-purine-2,6(3H,7H)-dione + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 8-bromo-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-7-(prop-2-ynyl)-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;	80%

+ 2-chloromethyl-4-methylquinazoline (109113-72-6) → 1-(3-methyl-2-buten-1-yl)-6-chloro-3-[(4-methylquinazolin-2-yl)methyl]pyrimidine-2,4(1H,3H)-dione

acetaldehyde (75-07-0) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 4,4'-(2-methylpropane-1,3-diyl)bis(2-chloromethylquinazoline)

Conditions	Yield
With sodium hydroxide In 1,4-dioxane; water at 10 - 25℃; for 17.5h;	77.78%

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) → C20H17BrN6O2

Conditions	Yield
Stage #1: 8-bromo-7-(but-2-yn-1-yl)-3-methyl-2,,6-dihydro-1H-purine-2,6-dione With chloro-trimethyl-silane; trimethylsilyl trifluoromethanesulfonate In toluene for 24h; Reflux; Stage #2: 2-chloromethyl-4-methylquinazoline With sodium hydride In N,N-dimethyl-formamide at 0 - 10℃; for 5h;	72.5%

7-allyl-8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 7-allyl-8-bromo-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine-2,6(3H,7H)-dione

Conditions	Yield
With sodium carbonate In N,N-dimethyl-formamide at 80℃; for 12h;	72%

C23H22N6O4 + 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
With potassium carbonate In tetrahydrofuran for 25h; Reflux;	69.8%

1-allyl-6-chloropyrimidine-2,4(1H,3H)-dione + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 1-allyl-6-chloro-3-[(4-methylquinazolin-2-yl)methyl]pyrimidine-2,4(1H,3H)-dione

Conditions	Yield
Stage #1: 1-allyl-6-chloropyrimidine-2,4(1H,3H)-dione With sodium hydride; lithium bromide In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloromethyl-4-methylquinazoline In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	65%

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) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → Linagliptin

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 N,N-dimethyl-formamide at 90℃; for 6h; Stage #2: 3-(R)-aminopiperidine dihydrochloride With potassium carbonate In N,N-dimethyl-formamide at 80℃; for 8h;	57%
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 N,N-dimethyl-formamide at 90℃; for 6h; Stage #2: 3-(R)-aminopiperidine dihydrochloride With potassium carbonate In N,N-dimethyl-formamide at 20 - 80℃; for 8h; Stage #3: pH=8;	57%

2,2,2-trifluoroacetamide (354-38-1) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 2,2,2-trifluoro-N-((4-methylquinazolin-2-yl)methyl)acetamide

Conditions	Yield
Stage #1: 2,2,2-trifluoroacetamide With caesium carbonate In tetrahydrofuran at 20℃; for 0.0833333h; Inert atmosphere; Stage #2: 2-chloromethyl-4-methylquinazoline In tetrahydrofuran at 65℃; for 16h; Inert atmosphere;	55%

2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile (865758-95-8) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 6-chloro-1-(2-cyanobenzyl)-3-[(4-methylquinazolin-2-yl)methyl]pyrimidine-2,4(1H,3H)-dione

Conditions	Yield
Stage #1: 2-[(6-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-yl)methyl]benzonitrile With sodium hydride; lithium bromide In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloromethyl-4-methylquinazoline In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	50%

2,5-dimethoxyphenylboronic acid (107099-99-0) + 2-chloromethyl-4-methylquinazoline (109113-72-6) → C18H18N2O2 (1416422-98-4)

Conditions	Yield
With potassium phosphate; C12H10ClNPd*C16H21O3P In tetrahydrofuran; water at 60℃; for 20h;	24%

6-chloro-1-(prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione + 2-chloromethyl-4-methylquinazoline (109113-72-6) → 6-chloro-3-[(4-methylquinazolin-2-yl)methyl]-1-(prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione

Conditions	Yield
Stage #1: 6-chloro-1-(prop-2-ynyl)pyrimidine-2,4(1H,3H)-dione With sodium hydride; lithium bromide In N,N-dimethyl-formamide at 0℃; for 0.5h; Inert atmosphere; Stage #2: 2-chloromethyl-4-methylquinazoline In N,N-dimethyl-formamide at 80℃; Inert atmosphere;	22%

Upstream product

• 551-93-9 2-aminoacetophenone 
• 79-07-2 Chloroacetamide 
• 107-14-2 chloroacetonitrile 
• 6640-59-1 2-(chloromethyl)-4-methylquinazoline 3-oxide 
• 70656-87-0 Ro 5-3663 

Downstream Products

• 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 
• 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 
• 1416422-98-4 C₁₈H₁₈N₂O₂ 

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