205444-22-0

Basic information

• Product Name: 2-CHLORO-4-IODO-6-(TRIFLUOROMETHYL)PYRIDINE
• Synonyms: 2-CHLORO-4-IODO-6-(TRIFLUOROMETHYL)PYRIDINE;Pyridine, 2-chloro-4-iodo-6-(trifluoromethyl)-
• CAS NO: 205444-22-0
• Molecular Formula: C₆H₂ClF₃IN
• Molecular Weight: 307.44
• Mol File: 205444-22-0.mol
• Article Data: 5

Chemical Properties

• Melting Point: 94-95℃
• Boiling Point: 231℃
• Flash Point: 93℃
• Appearance: /
• Density: 2.046
• Vapor Pressure: 0.1mmHg at 25°C
• Refractive Index: 1.54
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• PKA: -4.47±0.10(Predicted)
• CAS DataBase Reference: 2-CHLORO-4-IODO-6-(TRIFLUOROMETHYL)PYRIDINE(CAS DataBase Reference)
• NIST Chemistry Reference: 2-CHLORO-4-IODO-6-(TRIFLUOROMETHYL)PYRIDINE(205444-22-0)
• EPA Substance Registry System: 2-CHLORO-4-IODO-6-(TRIFLUOROMETHYL)PYRIDINE(205444-22-0)

Safety Data

• Hazardous Substances Data: 205444-22-0(Hazardous Substances Data)

Usage

Application

2-chloro-4-iodo-6-(trifluoromethyl)pyridine is a useful research chemical.

InChI:InChI=1/C6H2ClF3IN/c7-5-2-3(11)1-4(12-5)6(8,9)10/h1-2H

Synthetic route

2-chloro-6-trifluoromethylpyridine (39890-95-4) → 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0)

Conditions	Yield
With n-butyllithium; iodine; diisopropylamine In tetrahydrofuran; hexane 1.) -100 deg C, 2 h; 2.) -100 -> -80 deg C, 30 min;	92%
Stage #1: 2-chloro-6-trifluoromethylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -100℃; for 2h; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1h; Inert atmosphere; Stage #3: With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -78℃; for 3h; Inert atmosphere;	42%
Multi-step reaction with 2 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere 1.2: -78 - 20 °C 2.1: lithium diisopropyl amide / tetrahydrofuran / 1 h / -78 °C / Inert atmosphere View Scheme

2-chloro-3-iodo-6-(trifluoromethyl)pyridine (205240-59-1) → 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0)

Conditions	Yield
Stage #1: 2-chloro-3-iodo-6-(trifluoromethyl)pyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃; for 0.75h; Stage #2: With hydrogenchloride In tetrahydrofuran; hexane at 25℃; Further stages.;	83%
With lithium diisopropyl amide In tetrahydrofuran at -78℃; for 1h; Inert atmosphere;	81%

6-chloro-3-iodo-2-(trifluoromethyl)pyridine (945717-57-7) → 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0)

Conditions	Yield
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75 - -72℃; for 1.83333h;	69%

4-chloro-2-butanone (6322-49-2) + 2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3-bipyridin]-6-yl)acetamide → 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0)

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere;	11 mg

2-chloro-6-trifluoromethylpyridine (39890-95-4) → 6-chloro-3-iodo-2-(trifluoromethyl)pyridine (945717-57-7) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0)

Conditions	Yield
Stage #1: 2-chloro-6-trifluoromethylpyridine With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -100℃; for 2h; Inert atmosphere; Stage #2: With iodine In tetrahydrofuran; hexane at -78℃; for 1h;

5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (885693-20-9) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → C16H18ClF3N2O2

Conditions	Yield
With potassium phosphate; trans-diacetylpalladium(II) bis(dicyclohexylamine) In ethanol at 20℃; for 18h; Inert atmosphere;	93%
With potassium phosphate; trans-diacetylpalladium(II) bis(dicyclohexylamine) In ethanol at 20℃; for 18h; Suzuki Coupling; Inert atmosphere;	93%

4-fluoroboronic acid (1765-93-1) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-chloro-4-(4-fluorophenyl)-6-(trifluoromethyl)pyridine

Conditions	Yield
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water for 1.5h; Reflux;	90%

chloro-trimethyl-silane (75-77-4) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-Chloro-4-iodo-6-trifluoromethyl-3-trimethylsilanyl-pyridine

Conditions	Yield
With n-butyllithium; diisopropylamine In tetrahydrofuran; hexane at -75℃;	86%

4-methoxy-benzylamine (2393-23-9) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-chloro-N-[(4-methoxyphenyl)methyl]-6-(trifluoromethyl)pyridin-4-amine

Conditions	Yield
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In toluene at 100℃; for 3h; Inert atmosphere;	82.51%

carbon dioxide (124-38-9) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid

Conditions	Yield
Stage #1: 2-chloro-4-iodo-6-(trifluoromethyl)pyridine With n-butyllithium; butyl magnesium bromide In tetrahydrofuran; hexane at 0℃; for 0.0833333h; Stage #2: carbon dioxide In tetrahydrofuran; hexane Stage #3: With hydrogenchloride In tetrahydrofuran; hexane Further stages.;	74%
Stage #1: 2-chloro-4-iodo-6-(trifluoromethyl)pyridine With n-butyllithium In tetrahydrofuran; hexane at -75 - -72℃; for 0.333333h; Stage #2: carbon dioxide In tetrahydrofuran; hexane at 20℃;	56%

C10H18INO2Zn + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → C16H20ClF3N2O2

Conditions	Yield
With bis(tri-t-butylphosphine)palladium(0) In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;	70%

C11H20NO2Zn(1+)*I(1-) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → C17H22ClF3N2O2

Conditions	Yield
With bis(tri-t-butylphosphine)palladium(0) at 20℃; for 1h; Inert atmosphere; Reflux;	69%

acetone (67-64-1) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]propan-2-ol (1379375-72-0)

Conditions	Yield
Stage #1: 2-chloro-4-iodo-6-(trifluoromethyl)pyridine With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.666667h; Inert atmosphere; Stage #2: acetone In tetrahydrofuran at 20℃; for 2h;	65%

C14H23N3O + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → C20H24ClF3N4O

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; DavePhos In 1,4-dioxane at 100℃; Inert atmosphere; Sealed tube;	65%

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-chloro-6-(trifluoromethyl)isonicotinonitrile

Conditions	Yield
With copper(l) cyanide In 1-methyl-pyrrolidin-2-one at 120℃; for 0.166667h; sealed vessel;	64%

3,5-Bis-trimethylsilyl-bromobenzene (81500-92-7) + bis(pinacol)diborane (73183-34-3) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 4-(3,5-bis(trimethylsilyl)phenyl)-2-chloro-6-(trifluoromethyl)pyridine

Conditions	Yield
Stage #1: 3,5-Bis-trimethylsilyl-bromobenzene; bis(pinacol)diborane With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; tricyclohexylphosphine In 1,4-dioxane at 100 - 110℃; for 2h; Inert atmosphere; Stage #2: 2-chloro-4-iodo-6-(trifluoromethyl)pyridine With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,4-dioxane; water for 0.5h; Reflux;	60%

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-Chloro-3,4-diiodo-6-trifluoromethyl-pyridine

Conditions	Yield
With n-butyllithium; iodine; diisopropylamine In tetrahydrofuran; hexane at -75℃;	59%

N-tert-butoxycarbonyl-3-piperidinol (85275-45-2) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → C16H20ClF3N2O3

Conditions	Yield
In N,N-dimethyl-formamide at 20℃; for 16h;	59%
Stage #1: N-tert-butoxycarbonyl-3-piperidinol With sodium hydride In N,N-dimethyl-formamide; mineral oil at -40℃; for 0.5h; Stage #2: 2-chloro-4-iodo-6-(trifluoromethyl)pyridine In N,N-dimethyl-formamide; mineral oil at -40 - 20℃; for 16h;	59%

(±)-tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → tert-Butyl 7-(2-Chloro-6-(trifluoromethyl)pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Conditions	Yield
With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; caesium carbonate In toluene at 100℃; for 16h; Sealed tube; Inert atmosphere;	53%

1-iodo-2,2,3,3,4,4,5,5,5-nonafluorobutane (423-39-2) + allyl 1-methyl-1H-indole-3-carboxylate + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → (S)-2-(2-chloro-6-(trifluoromethyl)pyridin-4-yl)-4,4,5,5,6,6,7,7,7-nonafluoroheptyl 1-methyl-1H-indole-3-carboxylate

Conditions

Yield

Stage #1: allyl 1-methyl-1H-indole-3-carboxylate; 2-chloro-4-iodo-6-(trifluoromethyl)pyridine With manganese; (1,2-dimethoxyethane)dichloronickel(II); (4R,4'R)-4,4'-di(heptan-4-yl)-4,4',5,5'-tetrahydro-2,2'-bioxazole In 1,2-dimethoxyethane for 0.5h; Inert atmosphere; Stage #2: 1-iodo-2,2,3,3,4,4,5,5,5-nonafluorobutane With chloro-trimethyl-silane In 1,2-dimethoxyethane at -10℃; for 24h; Inert atmosphere; enantioselective reaction;

50%

C10H18INO2Zn + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → C16H20ClF3N2O2

Conditions	Yield
With bis(tri-t-butylphosphine)palladium(0) In tetrahydrofuran at 20℃; for 1h; Inert atmosphere;	39%

oxetan-3-one (6704-31-0) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 3-[2-chloro-6-(trifluoromethyl)pyridin-4-yl]oxetan-3-ol

Conditions	Yield
Stage #1: 2-chloro-4-iodo-6-(trifluoromethyl)pyridine With isopropylmagnesium chloride In tetrahydrofuran at 0℃; for 0.5h; Stage #2: oxetan-3-one In tetrahydrofuran for 1h;	38%

(S)-N-(4-cyanophenethyl)pyrrolidine-2-carboxamide hydrochloride + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → (S)-N-(4-cyanophenethyl)-1-(4-iodo-6-(trifluoromethyl)pyridin-2-yl)pyrrolidine-2-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 95℃; for 96h;	30%

3,4-dimethoxybenzylamine (5763-61-1) + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → N-(3,4-dimethoxybenzyl)-4-iodo-6-(trifluoromethyl)pyridin-2-amine

Conditions	Yield
With triethylamine In 1-methyl-pyrrolidin-2-one at 100℃; for 0.333333h; Inert atmosphere; Microwave irradiation;	28%

copper(l) cyanide + 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-chloro-6-(trifluoromethyl)isonicotinamide

Conditions	Yield
In 1-methyl-pyrrolidin-2-one at 120℃; for 3h; Inert atmosphere;	7%

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → tert-butyl 4-{[4-(aminocarbonyl)-6-(trifluoromethyl)pyridin-2-yl]oxy}piperidine-1-carboxylate (1379376-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: copper(l) cyanide / 1-methyl-pyrrolidin-2-one / 0.17 h / 120 °C / sealed vessel 2: sodium hydride / tetrahydrofuran; mineral oil / 0.75 h View Scheme

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-(piperidin-4-yloxy)-6-(trifluoromethyl)isonicotinamide (1379376-04-1)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: copper(l) cyanide / 1-methyl-pyrrolidin-2-one / 0.17 h / 120 °C / sealed vessel 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.75 h 3.1: hydrogenchloride / 1,4-dioxane / 2.5 h 3.2: pH 11 View Scheme

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-[(1-{cis-3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinamide + 2-[(1-{trans-3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinamide

Conditions	Yield
Multi-step reaction with 4 steps 1.1: copper(l) cyanide / 1-methyl-pyrrolidin-2-one / 0.17 h / 120 °C / sealed vessel 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.75 h 3.1: hydrogenchloride / 1,4-dioxane / 2.5 h 3.2: pH 11 4.1: sodium cyanoborohydride; zinc(II) chloride / methanol View Scheme

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-[(1-{cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}piperidin-4-yl)oxy]-6-(trifluoromethyl)isonicotinonitrile

Conditions	Yield
Multi-step reaction with 5 steps 1.1: copper(l) cyanide / 1-methyl-pyrrolidin-2-one / 0.17 h / 120 °C / sealed vessel 2.1: sodium hydride / tetrahydrofuran; mineral oil / 0.75 h 3.1: hydrogenchloride / 1,4-dioxane / 2.5 h 3.2: pH 11 4.1: sodium cyanoborohydride; zinc(II) chloride / methanol 5.1: triethylamine; trichloroacetic acid anhydride / dichloromethane / 0.42 h / 0 °C 5.2: 1 h View Scheme

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → {cis-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 1.2: 1.5 h / -78 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3.33 h / 100 - 140 °C / Microwave irradiation 3.1: sodium cyanoborohydride; zinc(II) chloride / methanol / 1.33 h 4.1: trifluoroacetic acid / dichloromethane / 1 h View Scheme

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → {trans-3-(4-{[4-(2-hydroxyethyl)-6-(trifluoromethyl)pyridin-2-yl]amino}piperidin-1-yl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutyl}acetonitrile

Conditions	Yield
Multi-step reaction with 4 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 1.2: 1.5 h / -78 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3.33 h / 100 - 140 °C / Microwave irradiation 3.1: sodium cyanoborohydride; zinc(II) chloride / methanol / 1.33 h 4.1: trifluoroacetic acid / dichloromethane / 1 h View Scheme

2-chloro-4-iodo-6-(trifluoromethyl)pyridine (205444-22-0) → 2-[2-(piperidin-4-ylamino)-6-(trifluoromethyl)pyridin-4-yl]ethanol

Conditions	Yield
Multi-step reaction with 2 steps 1.1: n-butyllithium / tetrahydrofuran; hexane / 0.75 h / -78 °C 1.2: 1.5 h / -78 - 20 °C 2.1: N-ethyl-N,N-diisopropylamine / dimethyl sulfoxide / 3.33 h / 100 - 140 °C / Microwave irradiation View Scheme

Upstream product

• 39890-95-4 2-chloro-6-trifluoromethylpyridine 
• 6322-49-2 4-chloro-2-butanone 
• 945717-57-7 6-chloro-3-iodo-2-(trifluoromethyl)pyridine 
• 205240-59-1 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 

Downstream Products

• 796090-23-8 2-chloro-6-(trifluoromethyl)pyridine-4-carboxylic acid 

Relevant articles and documents

NOVEL NON-SYSTEMIC TGR5 AGONISTS

The present invention relates to tricyclic compounds of formula (I) and formula (II), or a pharmaceutically acceptable salt thereof. The present tricyclic compounds are useful non-sytemic TGR5 agonists that can be used to treat diabetic diseases in human. The present invention provides a pharmaceutical composition containing tricyclic compounds of formula (I) and formula (II) and a method of making as well as a method of using same in treating patients inflicted with metabolic disorders by administering same. The compounds of the present invention may be used in combination with additional anti-diabetic drugs.

Heteroaryl and benzyl amide compounds

Compounds of formula I wherein R1, R2, R4, R5, A, B, D and n are as defined, and pharmaceutically acceptable salts thereof, processes for their preparation, their use as pharmaceuticals and pharmaceutical compositions comprising them.

Halogen shuffling in pyridines: Site selective electrophilic substitutions of 2-chloro-6-(trifluoromethyl)pyridine

When treated with lithium diisopropylamide in tetrahydrofuran at -85 °C and subsequently with iodine, 2-chloro-6-(trifluoromethyl)pyridine is neatly converted into its 3-iodo derivative. The latter can be quantitatively isomerized to afford 2-chloro-4-iodo-6-(trifluoromethyl)pyridine. Either iodo compound can serve as the starting material for further manipulation in reaction sequences consisting of halogen/metal exchange and electrophilic trapping.