2,6-dichloro-4-iodopyridine

2587-02-2

98027-84-0

The general procedure for the synthesis of 2,6-dichloro-4-iodopyridine from 4-amino-2,6-dichloropyridine is as follows: Reagents and conditions: a) n-BuLi, ArBr; ZnCl2; followed by addition of 2,6-dibromopyridine and catalyst Pd(PPh3)4 (95% yield). b) LiOH, THF/H2O (100% yield). c) (COCl)2; NaN3; TFA. d) K2CO3, CH3OH (78% yield). e) HCl, CH3CN, NaNO2; KI (52% yield). f) n-BuLi, ArBr; ZnCl2; followed by the addition of 13 and catalyst Pd(PPh3)4 (98% yield). g) ArB(OH)2, catalyst Pd2(dba)3, catalyst P(t-Bu)3, Cs2CO3 (82% yield);. h) Same as step f (71% yield). i) Same as step g (31% yield). j) n-BuLi, ArBr; ZnCl2; followed by addition of 12 (80% yield); and k) 2-aminophenol, EDCI (97% yield); l) 230°C (87% yield); n-BuLi, ArBr; ZnCl2; followed by 12 (80% yield) l) 230°C (87% yield). m) ArB(OH)2, catalyst Pd2(dba)3, catalyst [HP(t-Bu)3]BF4, Cs2CO3 (78% yield). The synthesis of 4 began with the pyridine derivative citric acid. Treatment with POCl3 at elevated temperatures afforded the corresponding 2,6-dichloroisonicotinoyl chloride. To facilitate purification, the reaction was quenched with methanol; after passing a silica plug to remove colored impurities, the methyl ester 1 was isolated in 76% yield. Saponification then provided acid 2 in quantitative yield without purification. Conversion to 3 was achieved by conversion to acyl azides, thermal Curtius rearrangement and hydrolysis of the resulting trifluoroacetamide to give 2,6-dichloro-4-aminopyridine (3) (Pfister, JR, Wymann, WE Synthesis 1983,38). Although this method for converting 2 to 3 is nominally a 3-step process, it requires only a single post-extraction treatment so that these steps can be performed in rapid succession. Direct conversion of 3 to 4 by diazotization and reaction with potassium iodide (which must be stirred in cold hydrochloric acid for 3 h prior to diazotization to obtain acceptable yields) provides 4 in reasonable yields and with excellent purity after grinding with acetone. This short reaction sequence permits the preparation of 4 in 35% overall yield, does not require chromatography except for a single filtration through a silicone plug, and permits the routine preparation of 5-10 g amounts of this intermediate. Unlike many 4-halopyridines, 4 is stable at room temperature for several months if protected from light.4 can be readily converted to the fluorophore of this invention.