4-Pyridinecarboxylic acid, 2,6-dichloro-, methyl ester

Step I. To a stirred solution of 2, 6-dichloropyridine-4-carboxylic acid (CAS Number 5398-44-7, available from Ark Pharma) (20.00 g, 104.700 mmol) in methanol (400 ml) was added concentrated sulphuric acid (20 ml) at ambient temperature. The reaction mixture was refluxed for 3 h. The resulting reaction mixture was cooled to ambient temperature, concentrated under reduced pressure and poured into saturated solution of NaHCC>3 (100 ml). The resulting reaction mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was dried over Na2S0Reagents and conditions: a) n-BuLi, ArBr; ZINC12 ; then 2, 6- dibromopyridine and cat. Pd (PPH3) 4 (95%); b) LiOH, THF/H2O (100%); C) (COCI) 2; NaN3 ; TFA; d) K2CO3, CH30H (78%); e) HCI, CH3CN, NAN02 ; KI (52%); f) n-BuLi, ArBr; ZINC12 ; then 13 and cat. Pd (PPh3) 4 (98%); g) ArB (OH} 2, cat. Pd2 (dba) 3, cat. P (T-BU) 3, CS2CO3, (82%); h) as (F) (71%) ; i) as (g) (31%) ; j) n-BuLi, ArBr; ZINC12 ; then 12 (80%) ; k) 2- aminophenol, EDCI (97%); 1) 230C (87%); m) ArB (OH) 2, cat. Pd2 (dba) 3, cat. [HP (T-BU) 3] BF4, CS2CO3 (78%).Reagents and conditions: a) n-BuLi, ArBr; ZINC12 ; then 2, 6- dibromopyridine and cat. Pd (PPH3) 4 (95%); b) LiOH, THF/H2O (100%); C) (COCI) 2; NaN3 ; TFA; d) K2CO3, CH30H (78%); e) HCI, CH3CN, NAN02 ; KI (52%); f) n-BuLi, ArBr; ZINC12 ; then 13 and cat. Pd (PPh3) 4 (98%); g) ArB (OH} 2, cat. Pd2 (dba) 3, cat. P (T-BU) 3, CS2CO3, (82%); h) as (F) (71%) ; i) as (g) (31%) ; j) n-BuLi, ArBr; ZINC12 ; then 12 (80%) ; k) 2- aminophenol, EDCI (97%); 1) 230C (87%); m) ArB (OH) 2, cat. Pd2 (dba) 3, cat. [HP (T-BU) 3] BF4, CS2CO3 (78%). Synthesis of 4 begins with pyridine derivative citrazinic acid. Treatment with POC13 at elevated temperature afforded the corresponding 2-6, dichloroisonicotinoyl chloride. To facilitate purification, the reaction was quenched with methanol; methyl ester 1 was isolated in 76% yield after passage through a plug of silica gel to remove colored impurities. Saponification then provided acid 2 in quantitative yield without purification. Transformation to 3 was effected by conversion to the acyl azide, thermal Curtius rearrangement, and hydrolysis of the resulting trifluoroacetamide to provide 2, 6-DICHLORO-4-AMINOPYRIDINE (3), (Pfister, J. R. , Wymann, W. E. Synthesis 1983, 38). While this method for converting 2 to 3 is nominally 3 steps, it requires only a single extractive workup and the steps can thus be carried out in rapid succession. 3 was converted directly to 4 by diazotization and reaction with potassium iodide (it is necessary to stir 3 in cold hydrochloric acid for several hours prior to diazotization in order to obtain an acceptable yield) providing 4 in reasonable yield and excellent purity after trituration with acetone. This short sequence of reactions allows preparation of 4 IN-35% overall yield, requires no chromatography beyond a single filtration through a plug of silica gel, and has allowed the routine preparation of 5-10 g quantities of this intermediate. Unlike many 4-halopyridines, 4 is stable for several months at room temperature if protected from light. 4 can be ready transformation to fluorophores of the present invention.2, 6-Dichloroisonicotinic acid was (5 g, 26.04 mmol) was suspended in anhydrous toluene (75 ml). Thionyl chloride (19 ml, 260.4 mmol) was added and the mixture was heated to reflux for 4 h. The excess thionyl chloride was removed and solvent was removed in vacuo. Anhydrous MeOH (25 ml) was added and reaction was stirred for a further 4 h. Solvents were removed in vacuo to give a white coloured solid which was dried under vacuum (4.8 g). MS (APCL M+H): 206 for C7H5C12NO2 1 H NMR 5 : 4.10 (s, 3H) ; 8.15 (s, 2H).EXAMPLE 145; 3-(4-{[2, -Piperazin-1-yl-6-(pyrazin-2-y.amino)-2, 4, -bipyridin-4- yl]methoxy}phenyl)propanoic acid; a) Methyl 2, 6-dichloroisonicotinate; Sulfuric acid (3 mL, 56.28 mmol) was added dropwise to a stirred solution of 2, 6- dichloroisonicotinic acid (6.60 g, 34.38 mmol) in methanol (100 mL), the reaction mixture was heated under reflux. After 16 hours, the reaction mixture was slow cooled, and the solvent was removed in vacuo. Ethyl acetate and satured aqueous sodium carbonate solution were added to the crude. The organic layer was washed with brine, dried (Na2S04), concentrated in vacuo and the resulting oil was used without further purification. LRMS (m/z): 207 (M+1 )+.Sulfuric acid (3 mL, 56.28 mmol) was added dropwise to a stirred solution of 2, 6-dichloroisonicotinic acid (6.60 g, 34.38 mmol) in methanol (100 mL), the reaction mixture was heated under reflux. After 16 hours, the reaction mixture was slow cooled, and the solvent was removed in vacuo. Ethyl acetate and satured aqueous sodium carbonate solution were added to the crude. The organic layer was washed with brine, dried (Na2SO4), concentrated in vacuo and the resulting oil was used without further purification.LRMS (m/z): 207 (M+1)+.To a round bottom flask (rbf) was added carboxylic acid (15.0 g, 78.9 mmol) in MeOH (250 mE, 0.32M) at it. To the vessel was added concentrated sulfuric acid (10.0 mE, 189.4 mmol, 2.4 equiv.), and the mixture was refluxed for 2 hours. Upon completion by ECMS, the contents of the flask were cooled to it and concentrated under vacuum. The residue was added to a separatory funnel containing saturated sodium bicarbonate. The mixture was then extracted x3 with ethyl acetate. The combined organics were washed xi with brine, dried over magnesium sulfate, filtered, and concentrated. The oil-white solid was used without further purification.To a stirred solution of 2, 6-dichloropyridine-4-carboxylic acid (CAS Number 5398-44-7, available from Ark Pharma) (20.00 g, 104.700 mmol) in methanol (400 ml) was added concentrated sulphuric acid (20 ml) at ambient temperature. The reaction mixture was refluxed for 3 h. The resulting reaction mixture was cooled to ambient temperature, concentrated under reduced pressure and poured into saturated solution of NaHCC>3 (100 ml). The resulting reaction mixture was extracted with ethyl acetate (3 x 50 ml). The combined organic phase was dried over Na2S04, filtered and concentrated under reduced pressure yielding methyl 2, 6-dichloropyridine-4-carboxylate (21 .00 g, 102.450 mmol), which was used in the next step without further purification.

Molecular Weight:206.02
XLogP3:2.6
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:2
Exact Mass:204.9697338
Monoisotopic Mass:204.9697338
Topological Polar Surface Area:39.2
Heavy Atom Count:12
Complexity:167
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes