3932-97-6

Basic information

• Product Name: 2,4-Dichloro-5-trifluoromethylpyrimidine
• Synonyms: 2,4-DICHLORO-5-(TRIFLUOROMETHYL)PYRIMIDINE;5-TRIFLUOROMETHYL-2,4-DICHLOROPYRIMIDINE;PyriMidine, 2,4-dichloro-5-(trifluoroMethyl)-;4-(broMoMethyl)-3-chlorobenzaMide;2,4-Dichloro-5-(trifluoromethyl)-1,3-diazine;2,4-Dichloro-5-(trifluoroMethyl)pyriMidine 97%;2,4-Dichloro-5-(trifluoroMethyl);2,4-Dichloro-5-trifluoromethylpyrimidine 5-Trifluoromethyl-2,4-dichloropyrimidine
• CAS NO: 3932-97-6
• Molecular Formula: C₅HCl₂F₃N₂
• Molecular Weight: 216.98
• EINECS: 1592732-453-0
• Product Categories: pharmacetical;Pyrimidine;Building Blocks;Halogenated;Halogenated Heterocycles;Heterocyclic Building Blocks;Pyrimidines;Fluorine series;Pyrazoles
• Mol File: 3932-97-6.mol
• Article Data: 22

Chemical Properties

• Boiling Point: 49℃/32mm
• Flash Point: 200 ºF
• Appearance: /
• Density: 1.6087
• Vapor Pressure: 0.101mmHg at 25°C
• Refractive Index: 1.4749
• Storage Temp.: 2-8°C
• Solubility: Chloroform, Methanol
• PKA: -4.89±0.29(Predicted)
• CAS DataBase Reference: 2,4-Dichloro-5-trifluoromethylpyrimidine(CAS DataBase Reference)
• NIST Chemistry Reference: 2,4-Dichloro-5-trifluoromethylpyrimidine(3932-97-6)
• EPA Substance Registry System: 2,4-Dichloro-5-trifluoromethylpyrimidine(3932-97-6)

Safety Data

• Hazard Codes: Xi,C,T
• Statements: 36/37/38-36-25
• Safety Statements: 26-36/37/39-45
• RIDADR: UN 2810
• WGK Germany: 3
• HazardClass: CORROSIVE
• PackingGroup: Ⅲ
• Hazardous Substances Data: 3932-97-6(Hazardous Substances Data)

Usage

Chemical Properties

White liquid or solid

Uses

2,4-Dichloro-5-trifluoromethylpyrimidine is a reactant in the preparation of pyrimidine derivatives as inhibitors of gene ALK protein Kinase phosphorylating kinase and as cell proliferation inhibitors.

InChI:InChI=1/C5HCl2F3N2/c6-3-2(5(8,9)10)1-11-4(7)12-3/h1H

Synthetic route

5-trifluoromethyluracil (54-20-6) → 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6)

Conditions	Yield
With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate at 85 - 100℃; for 20h;	95%
With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate In water at 85 - 100℃; for 20.25h;	95%
With N-ethyl-N,N-diisopropylamine; trichlorophosphate; phosphoric acid at 85 - 100℃; for 20.25h;	95%

trifluoromethyluracil → 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6)

Conditions	Yield
With phosphoric acid; N-ethyl-N,N-diisopropylamine; trichlorophosphate at 85 - 100℃; for 20h;	95%

(trifluoromethyl)trimethylsilane (81290-20-2) + 2,4-dichloro-5-iodopyrimidine (13544-44-0) → 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6)

Conditions	Yield
With potassium fluoride; copper(l) iodide; 1,10-Phenanthroline; Trimethyl borate In dimethyl sulfoxide at 60℃; for 2h; Inert atmosphere;	81%

2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) + 4-(4-aminophenyl)-1-t-butyloxycarbonylpiperazine (170911-92-9) → tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperazine-1-carboxylate (1393900-79-2)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.833333h; Stage #2: 4-(4-aminophenyl)-1-t-butyloxycarbonylpiperazine With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 18h;	98%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.5h; Stage #2: 4-(4-aminophenyl)-1-t-butyloxycarbonylpiperazine With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 18h;	98%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc dibromide In 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.5h; Stage #2: 4-(4-aminophenyl)-1-t-butyloxycarbonylpiperazine With triethylamine In 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 3h;	72.3%

tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate (170011-57-1) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (1383682-52-7)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In cis-1,2-Dichloroethylene; diethyl ether; butan-1-ol at 20℃; for 0.166667h; Stage #2: tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate With triethylamine In cis-1,2-Dichloroethylene; diethyl ether; butan-1-ol at 20℃;	98%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 20℃; for 0.166667h; Stage #2: tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 20℃;	98%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 1h; Inert atmosphere; Stage #2: tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate With triethylamine In 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 24.5h;	88%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 1h; Inert atmosphere; Stage #2: tert-butyl 4-(4-aminophenyl)piperidin-1-carboxylate With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 24.5h;	88%

2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) + tert-butyl (4-aminobenzyl)carbamate (94838-55-8) → tert-butyl 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzylcarbamate (1073160-22-1)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 20℃; for 0.333333h; Stage #2: tert-butyl (4-aminobenzyl)carbamate With triethylamine at 20℃;	97%

4-[(tert-butyldimethylsilyl)oxy]aniline (111359-74-1) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → N-(4-((tert-butyldimethylsilyl)oxy)phenyl)-4-chloro-5-(trifluoromethyl)pyrimidin-2-amine

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc dibromide In 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.5h; Stage #2: 4-[(tert-butyldimethylsilyl)oxy]aniline With triethylamine In 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 20h;	97%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc dibromide In 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.5h; Stage #2: 4-[(tert-butyldimethylsilyl)oxy]aniline With triethylamine In 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 20h;	97%

4-nitro-phenol (100-02-7) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → 4-chloro-2-(4-nitrophenoxyl)-5-trifluoromethyl pyrimidine (1265228-21-4)

Conditions	Yield
With 4-methyl-morpholine In isopropyl alcohol at -5 - 20℃; for 4h;	96%
With 4-methyl-morpholine In isopropyl alcohol at -5 - 20℃;	90%
In 1-methyl-pyrrolidin-2-one; isopropyl alcohol at -5 - 20℃; for 4h; Product distribution / selectivity;	90%
With N-(2-(4-tert-butyl-piperazin-1-yl)-4-methoxyl-5-(6-(1-methyl-1H-indol-3-yl)-pyrimidin-4-ylamino)-phenyl)-acrylamide In isopropyl alcohol for 1h; Cooling with ice;

2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) + phenol (108-95-2) → 2-chloro-4-phenoxy-5-(trifluoromethyl)pyrimidine

Conditions	Yield
With potassium carbonate In acetone at 0℃; for 1h;	96%

2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) + sodium thiomethoxide (5188-07-8) → 4-chloro-2-methylsulfany l-5-(trifluoromethyl)pyrimidine (919116-36-2)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether at 0℃; for 2h; Stage #2: sodium thiomethoxide In diethyl ether at 0 - 20℃; for 48h;	95%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether at 0℃; for 2h; Stage #2: sodium thiomethoxide In diethyl ether at 0 - 20℃; for 48h;	95%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether at 0℃; for 2h; Stage #2: sodium thiomethoxide In diethyl ether at 0 - 25℃; for 48h;	95%

4-chloro-aniline (106-47-8) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → (4-chlorophenyl)-(4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-amine (514842-83-2) + C11H6Cl2F3N3 (1448795-01-4)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; Stage #2: 4-chloro-aniline With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 20℃;	A 95% B n/a

2,2,2-trifluoroethanol (75-89-8) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine

Conditions	Yield
Stage #1: 2,2,2-trifluoroethanol With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 0.5h; Inert atmosphere; Stage #2: 2,4-dichloro-5-trifluoromethylpyrimidine In tetrahydrofuran; hexane at -20 - 40℃; for 24.5h; Inert atmosphere;	91%
Stage #1: 2,2,2-trifluoroethanol With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 0.5h; Inert atmosphere; Stage #2: 2,4-dichloro-5-trifluoromethylpyrimidine In tetrahydrofuran; hexane at -20 - 40℃; for 24.5h; Inert atmosphere;	91%
Stage #1: 2,2,2-trifluoroethanol With n-butyllithium In tetrahydrofuran; hexane at -20℃; for 0.5h; Inert atmosphere; Stage #2: 2,4-dichloro-5-trifluoromethylpyrimidine In tetrahydrofuran; hexane at 40℃; for 24h;	91%

2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → 5-trifluoromethyluracil (54-20-6)

Conditions	Yield
With acetic acid In water at 110℃; for 5h;	90.6%

2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) + 4-(4-tert-butoxycarbonyl-piperazino-methyl)-aniline (304897-49-2) → tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (1393901-46-6)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 1h; Stage #2: 4-(4-tert-butoxycarbonyl-piperazino-methyl)-aniline With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 20℃; Cooling with ice;	90%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 1h; Inert atmosphere; Stage #2: 4-(4-tert-butoxycarbonyl-piperazino-methyl)-aniline With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃;	90%

3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester (875798-79-1) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → tert-butyl 3-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (1393900-90-7)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.5h; Stage #2: 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 60h;	90%
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 0.5h; Stage #2: 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester With triethylamine In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 60h;	90%

tert-butyl 4-(4-amino-2-methylphenyl)-piperidine-1-carboxylate (955369-50-3) + 2,4-dichloro-5-trifluoromethylpyrimidine (3932-97-6) → tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)-2-methylphenyl)piperidine-1-carboxylate (1383682-55-0)

Conditions	Yield
Stage #1: 2,4-dichloro-5-trifluoromethylpyrimidine With zinc(II) chloride In diethyl ether; 1,2-dichloro-ethane; tert-butyl alcohol at 0℃; for 1h; Inert atmosphere; Stage #2: tert-butyl 4-(4-amino-2-methylphenyl)-piperidine-1-carboxylate With triethylamine In 1,2-dichloro-ethane; tert-butyl alcohol at 0 - 20℃; for 16.5h;	89%

Upstream product

• 54-20-6 5-trifluoromethyluracil 
• 81290-20-2 (trifluoromethyl)trimethylsilane 
• 13544-44-0 2,4-dichloro-5-iodopyrimidine 
• 24377-95-5 3-chloro-4-methylbenzamide 

Downstream Products

• 869936-77-6 2-(2-methoxy-4-propylcarbamoyl-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
• 869937-03-1 4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzoic acid 
• 874821-72-4 (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine 
• 919116-55-5 benzyl 4-(4-chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-benzoate 
• 1033954-92-5 C₁₄H₉ClF₃N₃O 
• 1033954-22-1 C₂₈H₂₉ClN₆O₂ 
• 1033951-98-2 4-{4-[4-Amino-5-bromo-6-(4-cyano-2,6-dimethyl-phenoxy)-pyrimidin-2-ylamino]-piperidin-1-ylmethyl}-3-chloro-benzamide 
• 1030377-63-9 (5R)-1-[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]-5-methyl-4-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,4-diazepane 
• 919116-35-1 2-chloro-4-methylsulfanyl-5-(trifluoromethyl)pyrimidine 
• 919116-36-2 4-chloro-2-methylsulfany l-5-(trifluoromethyl)pyrimidine 
• 878156-21-9 2-(4-benzyloxycarbonyl-2-methoxy-phenylamino)-4-chloro-5-trifluoromethyl-pyrimidine 
• 903872-59-3 4-chloro-2-methoxy-5-(trifluoromethyl)pyrimidine 
• 1312535-76-4 2-chloro-4-methoxy-5-(trifluoromethyl)pyrimidine 
• 847862-97-9 2-(4-methylphenylamino)-4-chloro-5-(trifluoromethyl)pyrimidine 

Relevant articles and documents

Method for preparing 5-trifluoromethyl uracil

The invention belongs to the field of organic synthesis, and specifically relates to a method for preparing 5-trifluoromethyl uracil. The method comprises the following steps: firstly, carrying out chlorination reaction on 5-iodouracil and phosphorus oxychloride, thus obtaining 2,4-dichloro-5-iodopyrimidine; secondly, carrying out trifluoromethylation reaction on the 2,4-dichloro-5-iodopyrimidineand a trifluoromethylating reagent, thus obtaining 2,4-dichloro-5-trifluoromethylpyrimidine; finally, enabling the 2,4-dichloro-5-trifluoromethylpyrimidine to react with acetic acid, thus obtaining aproduct. According to the method disclosed by the invention, since chlorination reaction, trifluoromethylation reaction and hydrolysis reaction are adopted, a key intermediate-trifluoromethyl uracil of trifluorothymidine is synthesized in high yield, low cost and low pollution.

Trifluoroethoxy group as a leaving group for regioselective sequential substitution reactions of 5-trifluoromethylpyrimidine derivative with heteroatom nucleophiles

Highly regioselective substitution reaction of 2,4-bis(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)pyrimidine (TFEFP) with aniline derivatives smoothly proceeded firstly at the 2-postion. For the subsequent nucleophilic substitution at the 4-position with alkoxides, trifluoroethoxy group at the 4-position serves as a practically efficient leaving group.

SYNTHESIS OF 2,4-DICHLORO-5-TRIFLUOROMETHYL-PYRIMIDINE

This invention relates to a novel method for the synthesis of 2,4-dichloro-5-trifluoromethyl-pyrimidine useful as intermediate in the manufacture of pharmaceutically active ingredients.