4684-94-0

Basic information

• Product Name: 6-Chloropicolinic acid
• Synonyms: OTAVA-BB BB5110090024;2-CHLORO-6-PYRIDINECARBOXYLIC ACID;2-CHLOROPYRIDINE-6-CARBOXYLIC ACID;6-CHLORO-2-PYRIDINECARBOXYLIC ACID;6-CHLORO-2-PICOLINIC ACID;6-CHLOROPICOLINIC ACID;6-CHLOROPYRIDINE-2-CARBOXYLIC ACID;2-Pyridinecarboxylicacid,6-chloro-
• CAS NO: 4684-94-0
• Molecular Formula: C₆H₄ClNO₂
• Molecular Weight: 157.55
• EINECS: -0
• Product Categories: blocks;Carboxes;Pyridines;Pyridine;pyridine derivative;Heterocycles;Pyridines, Pyrimidines, Purines and Pteredines;pharmacetical;Carboxylic Acids;Organic acids;Carboxylic Acids;Picolinic acid series
• Mol File: 4684-94-0.mol
• Article Data: 11

Chemical Properties

• Melting Point: 190-191°C
• Boiling Point: 241.15°C (rough estimate)
• Flash Point: 149.263 °C
• Appearance: White to cream to tan/Crystalline Powder
• Density: 1.3768 (rough estimate)
• Refractive Index: 1.5870 (estimate)
• Storage Temp.: Keep in dark place,Sealed in dry,Room Temperature
• Solubility: DMSO (Slightly), Methanol
• PKA: 3.27±0.10(Predicted)
• Water Solubility: 3.40g/L(temperature not stated)
• BRN: 115849
• CAS DataBase Reference: 6-Chloropicolinic acid(CAS DataBase Reference)
• NIST Chemistry Reference: 6-Chloropicolinic acid(4684-94-0)
• EPA Substance Registry System: 6-Chloropicolinic acid(4684-94-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-37/39
• WGK Germany: 2
• RTECS: TJ7535000
• HazardClass: IRRITANT
• Hazardous Substances Data: 4684-94-0(Hazardous Substances Data)

Usage

Uses

6-Chloropyridine-2-carboxylic Acid is an intermediate of Sorafenib b(S676850), a multiple kinase inhibitor targeting both RAF kinase and receptor tyrosine kinases that promote angiogensis. Antineoplastic.

InChI:InChI=1/C6H4ClNO2/c7-5-3-1-2-4(8-5)6(9)10/h1-3H,(H,9,10)

Synthetic route

6-chloro-2-picoline (18368-63-3) → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
at 30℃; for 16h; with Pseudomonas putida ATCC 33015; other heteroarenes; enzymatical, selective oxidation of methylgroups of heteroarenes;	90%
at 30℃; for 16h; Pseudomonas putida ATCC 33015;	90%
With potassium permanganate In water Heating;	51%
With sodium permanganate; water
With potassium permanganate In water at 70 - 80℃; for 24h; Large scale;

nitrapyrin (1929-82-4) → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
With sulfuric acid; water at 100℃; for 8h;	90%
With sulfuric acid at 100℃; for 6h; Time;	90%

2-bromo-6-chloro-pyridine (5140-72-7) + Acetic formic anhydride (2258-42-6) → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
Stage #1: 2-bromo-6-chloro-pyridine; formyl acetic anhydride With 1,1'-bis-(diphenylphosphino)ferrocene; palladium diacetate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 80 - 90℃; for 3h; Inert atmosphere; Stage #2: With hydrogenchloride In water pH=Ca. 4 - 6;	75%

2-bromo-6-chloro-pyridine (5140-72-7) + carbon dioxide (124-38-9) → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
Stage #1: 2-bromo-6-chloro-pyridine With n-butyllithium In diethyl ether; hexane at -78℃; for 1h; Metallation; Stage #2: carbon dioxide In diethyl ether; hexane at -78℃; for 1h; Carboxylation;	67%

2,6-dichloropyridine (2402-78-0) + carbon dioxide (124-38-9) → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
Stage #1: carbon dioxide With o-phenylenebis(diphenylphosphine); copper(II) acetate monohydrate In 1,4-dioxane at 65℃; for 0.333333h; Schlenk technique; Stage #2: 2,6-dichloropyridine With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane; toluene at 100℃; for 10h; Schlenk technique; Sealed tube;	45%
Stage #1: carbon dioxide With o-phenylenebis(diphenylphosphine); copper(II) acetate monohydrate In 1,4-dioxane at 65℃; for 0.416667h; Schlenk technique; Stage #2: 2,6-dichloropyridine With palladium diacetate; triethylamine; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene In 1,4-dioxane; toluene at 100℃; for 10h; Schlenk technique;	45%

6-oxy-pyridine-carboxylic acid-(2) → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
With phosphorus pentachloride; trichlorophosphate at 100℃; Zerlegen des Reaktionsprodukts mit Eis;

C6H3Cl2NO2 → 6-chloropicolinic acid (4684-94-0)

Conditions	Yield
With water; potassium carbonate

methanol (67-56-1) + 6-chloropicolinic acid (4684-94-0) → methyl 6-chloropicolinate (6636-55-1)

Conditions	Yield
With thionyl chloride at 0 - 50℃; for 6.75h;	100%
Stage #1: methanol; 6-chloropicolinic acid With hydrogenchloride for 15h; Heating / reflux; Stage #2: With sodium hydroxide In water	95%
With hydrogenchloride In water at 80℃; for 48h;
With hydrogenchloride In water at 80℃; for 48h;

6-chloropicolinic acid (4684-94-0) + 4-((2-aminobenzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide → 6-chloro-N-(6-((2-(methylcarbamoyl)pyridin-4-yl)oxy)benzo[d]thiazol-2-yl)picolinamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;	100%

6-chloropicolinic acid (4684-94-0) + [5-(6-methylpyrazin-2-yl)pyrazin-2-yl]methanamine dihydrochloride → 6-chloro-N-[[5-(6-methylpyrazin-2-yl)pyrazin-2-yl]methyl]pyridine-2-carboxamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 1h;	97%

6-chloropicolinic acid (4684-94-0) + tert-butyl alcohol (75-65-0) → tert-butyl 6-chloropyridine-2-carboxylate (1280786-59-5)

Conditions	Yield
With pyridine; p-toluenesulfonyl chloride at 20℃;	96%

6-chloropicolinic acid (4684-94-0) + 4-(2-fluorophenyl)piperidine (180161-17-5) → (6-chloro-pyridin-2-yl)-[4-(2-fluoro-phenyl)-piperidin-1-yl]-methanone (1175689-41-4)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 18h;	95%

6-chloropicolinic acid (4684-94-0) → 2-chloro-6-pyridinecarboxamide (70593-61-2)

Conditions	Yield
With endo-N-hydroxy-5-norbornene-2,3-dicarboxyimide; ammonium chloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	94%
With endo-N-hydroxy-5-norbornene-2,3-dicarboxyimide; ammonium chloride; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 1h;	94%

6-chloropicolinic acid (4684-94-0) + ethanol (64-17-5) → 6-chloropyridine-2-carboxylic acid ethyl ester (21190-89-6)

Conditions	Yield
Stage #1: 6-chloropicolinic acid; ethanol With sulfuric acid In toluene for 3h; Reflux; Stage #2: With potassium carbonate In water; ethyl acetate	94%
With sulfuric acid for 16h; Inert atmosphere; Reflux;	85%
Stage #1: 6-chloropicolinic acid; ethanol With thionyl chloride at 0℃; Reflux; Inert atmosphere; Stage #2: With water; potassium carbonate In ethanol

2-(2'-anilinyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (63478-10-4) + 6-chloropicolinic acid (4684-94-0) → 6-chloro-N-(2-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)phenyl)picolinamide

Conditions	Yield
With dmap; dicyclohexyl-carbodiimide In dichloromethane at 20℃;	93%

6-chloropicolinic acid (4684-94-0) + 4-((2-aminoquinolin-5-yl)oxy)-N-methylpicolinamide

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 24h; Inert atmosphere;	91.7%

Conditions	Yield
at 30℃; for 16h; with Pseudomonas putida ATCC 33015; other heteroarenes; enzymatical, selective oxidation of methylgroups of heteroarenes;	90%
at 30℃; for 16h; Pseudomonas putida ATCC 33015;	90%
With potassium permanganate In water Heating;	51%
With sodium permanganate; water
With potassium permanganate In water at 70 - 80℃; for 24h; Large scale;

6-chloropicolinic acid + tert-butyl 3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (960535-17-5) → tert-butyl 4-(6-chloropicolinoyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (960535-98-2)

Conditions	Yield
Stage #1: 6-chloropicolinic acid; tert-butyl 3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine In N,N-dimethyl-formamide Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide for 1h;	90%

4-methylpiperidin (626-58-4) + 6-chloropicolinic acid (4684-94-0) → C12H15ClN2O (912934-67-9)

Conditions	Yield
With dmap; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃;	88%
With dmap; 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In hexane; dichloromethane; ethyl acetate; N,N-dimethyl-formamide at 20℃; for 18h;	88%

6-chloropicolinic acid (4684-94-0) + 1,1-dimethylethyl (2S)-4-{[5'-(aminomethyl)-2'-fluoro-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate (865314-22-3) → 6-chloro-N-({3'-[((3S)-4-{[(1,1-dimethylethyl)-oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]-6-fluoro-3-biphenylyl}methyl)-2-pyridinecarboxamide (1179343-96-4)

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In dichloromethane at 20℃; for 19h;	84%

6-chloropicolinic acid (4684-94-0) + (cis-3,5-dimethylpiperazin-1-yl)-1-phenyl-1H-thieno[3,2-c]pyrazole hydrochloride → cis-(6-chloropyridin-2-yl)-(2,6-dimethyl-4-(1-phenyl-1H-thieno[3,2-c]pyrazol-3-yl)piperazin-1-yl)methanone

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 0℃; for 1h;	84%

6-chloropicolinic acid (4684-94-0) + Methyl trichloroacetate (598-99-2) → methyl 6-chloropicolinate (6636-55-1)

Conditions	Yield
With 18-crown-6 ether; potassium carbonate at 90 - 150℃; for 2h;	83%

2-Picolinic acid (98-98-6) + 6-chloropicolinic acid (4684-94-0) + water (7732-18-5) + zinc(II) acetate dihydrate (5970-45-6) → [Zn(6-chloropicolinic acid)(2-picolinic acid)(H2O)2]

Conditions	Yield
In ethanol at 60℃; for 3h; Sealed tube;	82.8%

6-chloropicolinic acid (4684-94-0) + 6-chloropicolinoyl chloride (80099-98-5) + 4-fluoroaniline (371-40-4) → 6-chloro-N-(4-fluorophenyl)pyridin-2-amide (137640-94-9)

Conditions	Yield
In thionyl chloride; diethyl ether; water	82%
In thionyl chloride; diethyl ether; water	75%

4-aminopyridine (504-24-5) + 6-chloropicolinic acid (4684-94-0) → 6-chloro-N-(pyridin-4-yl)pyridine-2-carboxamide (1026136-67-3)

Conditions	Yield
Stage #1: 6-chloropicolinic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 20℃; for 0.5h; Stage #2: 4-aminopyridine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃;	81.7%
Stage #1: 6-chloropicolinic acid With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane for 0.5h; Stage #2: 4-aminopyridine With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 0.5h;	81.7%
Stage #1: 6-chloropicolinic acid With thionyl chloride at 25℃; for 1h; Stage #2: 4-aminopyridine With triethylamine In dichloromethane at 25℃; for 18h;
Stage #1: 6-chloropicolinic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 15 - 25℃; for 1h; Stage #2: 4-aminopyridine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 25℃; for 3h;
Stage #1: 6-chloropicolinic acid With oxalyl dichloride In dichloromethane; N,N-dimethyl-formamide at 15 - 25℃; for 1h; Stage #2: 4-aminopyridine With triethylamine In dichloromethane; N,N-dimethyl-formamide at 15 - 25℃; for 3h;

6-chloropicolinic acid (4684-94-0) + 1-(2-amino-4-ethynylphenyl)propan-1-one → 6-chloro-N-(5-ethynyl-2-propionylphenyl)picolinamide

Conditions	Yield
Stage #1: 6-chloropicolinic acid With N-ethyl-N,N-diisopropylamine; O‐(1H‐benzotriazol‐1‐yl)‐N,N,N′,N′‐tetramethyluronium tetrafluoroborate In N,N-dimethyl-formamide at 20℃; for 0.0833333h; Stage #2: 1-(2-amino-4-ethynylphenyl)propan-1-one In N,N-dimethyl-formamide at 150 - 154℃; for 0.5h; Microwave irradiation;	81%

pyridin-3-ylamine (462-08-8) + 6-chloropicolinic acid (4684-94-0) → 6-chloro-N-(pyridin-3-yl)picolinamide

Conditions	Yield
With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; triethylamine In N,N-dimethyl-formamide at 20℃; for 13h;	78%

6-chloropicolinic acid (4684-94-0) + 4-heptafluoroisopropyl-2,6-dimethylaniline (273735-43-6) → N-(2,6-dimethyl-4-heptafluoroisopropyl)phenyl 6-chloropyridine-2-carboxylic acid amide (847622-55-3)

Conditions	Yield
Stage #1: 6-chloropicolinic acid With thionyl chloride; N,N-dimethyl-formamide In toluene at 80℃; for 3h; Heating / reflux; Stage #2: 4-heptafluoroisopropyl-2,6-dimethylaniline With pyridine In tetrahydrofuran at 20℃; for 2h; Stage #3: With sodium hydrogencarbonate In tetrahydrofuran; water; ethyl acetate	77%

6-chloropicolinic acid (4684-94-0) + Cyclopropylamine (765-30-0) → C9H9ClN2O (149527-07-1)

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 12h;	77%

6-chloropicolinic acid (4684-94-0) + 3-Trifluoromethylphenol (98-17-9) → 6-(3-α,α,α-trifluoromethylphenoxy)picolinic acid (137640-84-7)

Conditions	Yield
With potassium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 140℃; for 6h;	75%
With potassium carbonate; copper(l) chloride In N,N-dimethyl-formamide at 140℃; for 8h; Solvent; Temperature; Reagent/catalyst;	75%

6-chloropicolinic acid (4684-94-0) + methyl 2-(2-aminophenyl)acetate hydrochloride (49851-36-7) → methyl 2-(2-(6-chloropicolinamido)phenyl)acetate

Conditions	Yield
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 2.5h;	71%
With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; for 2.5h; Inert atmosphere;

6-chloropicolinic acid (4684-94-0) + 1,2-diamino-benzene (95-54-5) → 2-(6-Chloro-pyridin-2-yl)-1H-benzoimidazole

Conditions	Yield
With PPA at 160℃; for 4h;	70%

6-chloropicolinic acid (4684-94-0) + (3S,6S)-3-((1H-indol-3-yl)methyl)-6-(3-aminopropyl)piperazine-2,5-dione → N-(3-((2S,5S)-5-((1H-indol-3-yl)methyl)-3,6-dioxopiperazin-2-yl)propyl)-6-chloropicolinamide

Conditions	Yield
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane; N,N-dimethyl-formamide at 0 - 20℃;	69%

Upstream product

• 18368-63-3 6-chloro-2-picoline 
• 5140-72-7 2-bromo-6-chloro-pyridine 
• 124-38-9 carbon dioxide 
• 2402-78-0 2,6-dichloropyridine 
• 1929-82-4 nitrapyrin 
• 2258-42-6 formyl acetic anhydride 

Downstream Products

• 6636-55-1 methyl 6-chloropicolinate 
• 192699-04-0 N,N'-bis[(6-chloropicolinyl)-L-Ser(t-Bu)-β-Ala]-1,4-phenylenediamine 
• 596825-40-0 6-chloro-N'-{6-[methyl(phenyl)amino]pyridazin-3-yl}pyridine-2-carbohydrazide 
• 21190-89-6 6-chloropyridine-2-carboxylic acid ethyl ester 
• 55676-22-7 3-acetyl-6-chloropyridine 
• 137640-93-8 N-(2,4-difluorophenyl)-2-chloro-6-pyridinecarboxamide 
• 137640-94-9 6-chloro-N-(4-fluorophenyl)pyridin-2-amide 
• 142832-29-9 2-chloro-6-pyridinecarboxylic acid N-oxide 
• 109-09-1 2-chloropyridine 
• 1373272-10-6 6-[4-(4-tert-butylcyclohexyl)-1,4-diazepan-1-yl]pyridine-2-carboxylic acid 
• 1373272-65-1 6-[(1-benzylpiperidin-4-yl)oxy]pyridine-2-carboxylic acid 
• 1373272-66-2 6-[(1-benzylpiperidin-4-yl)oxy]-N-(pyridin-4-yl)pyridine-2-carboxamide 
• 1373270-61-1 2-phenyl-1-(6-{4-[1-(propan-2-yl)piperidin-4-yl]-1,4-diazepan-1-yl}pyridin-2-yl)ethan-1-one 
• 1373270-97-3 6-[4-(4-tert-butylcyclohexyl)-1,4-diazepan-1-yl]-N-(pyridin-3-ylmethyl)pyridine-2-carboxamide 

Relevant articles and documents

-

-

Method for preparing aromatic carboxylic acid compound

The invention discloses a method for preparing an aromatic carboxylic acid compound. The method comprises the following steps: 1) heating carbon dioxide and hydrosilane in the presence of a copper catalyst in a reaction medium A; and 2) adding a reaction medium B, aryl halide, a palladium catalyst and a base to the reaction mixture in the step 1), sealing the reaction system, and performing a heating reaction. The method has the advantages that raw materials are simple and easy to obtain, the raw materials are cheap and stable, the catalyst is common, easy to obtain and stable, the reaction conditionsaremild, the aftertreatment is simple, the yield is high, and the like.

Method for preparing picolinafen

The invention discloses a method for preparing picolinafen, and belongs to the field of pesticide original medicine technology. The method comprises the following steps that (1) 2-chlorine-6-nitrapyrin serves as a raw material, and acid catalysis hydrolysis is carried out to synthesize 2-chlorine-6-pyridine carboxylic acid; (2) under conditions of alkali 1, catalyst and organic solvent 1, etherification reaction is carried out on 2-chlorine-6-pyridine carboxylic acid and m-trifluoromethylphenol to obtain 2-(3-trifluoromethylphenoxy pendant)-6-picolinic acid; (3) the 2-(3-trifluoromethylphenoxypendant)-6-picolinic acid and di(trichloromethyl) dimethyl carboxylate are reacted in alkali 2 and organic solvent 2 to synthesize intermediate 2-(3-trifluoromethylphenoxy pendant)-6-pyridinecarbonylchloride; (4) the intermediate 2-(3-trifluoromethylphenoxy pendant)-6-pyridinecarbonyl chloride and 4-fluoroaniline are reacted in alkali 3 and organic solvent 2 to prepare the picolinafen. The method for preparing the picolinafen has the advantages that the content of the prepared picolinafen product is 98.1%, the yield of the prepared picolinafen product is 83%, synthesis conditions are mild and safe, the operation process is controlled easily, aftertreatment is simple and convenient, the wastewater quantity is less, and the method is a green synthetic method for preparing the picolinafen.