Preparation of 6-bromo-2-pyridinemethylamine hydrochloride_Industrial additives

Preparation background and overview of 6-bromo-2-pyridinemethylamine hydrochloride

6-Bromo-2-pyridinemethylamine hydrochloride is the hydrochloride form of 6-bromo-2-pyridinemethylamine. 6-Bromo-2-pyridinemethylamine is an important organic intermediate that can be synthesized from 2 -Bromo-6-hydroxymethylpyridine was prepared.

Preparation of 6-bromo-2-pyridinemethylamine hydrochloride

The synthesis of 6-bromo-2-pyridinemethylamine is as follows. The synthesis of 6-bromo-2-pyridinemethylamine hydrochloride is obtained by stirring 6-bromo-2-pyridinemethylamine with HCl solution.

Step 1

N-(6-Bromopyridin-2-yl)methyl]benzamide: To a flame-dried 125 mL round-bottomed flask equipped with a magnetic stir bar and rubber septum, add 2-bromo-6-hydroxymethyl Pyridine (2.30 g, 12.23 mmol, 1.0 equiv). Dilute the alcohol with sodium perborate tetrahydrate, anhydrous THF (122.3 mL, 0.1 M), then add 1,1′-(azodicarbonyl)dipiperidine (4.012 g, 15.90 mmol, 1.3 equiv). The orange solution was then stirred at room temperature for 2 minutes. Then, triphenylphosphine (4.17g, 1590mmol, 1.3 equivalents) and phthalimide (2.34g, 15.90mmol, 1.3 equivalents) were added in sequence. The reaction was then stirred at room temperature for 24 hours (the solution was clear and orange). The reaction was then cooled to 0°C and a solid precipitated.

The cooled suspension was then filtered on a Buchner filter and the filter cake was washed thoroughly with cold THF. The filtrate was then evaporated to dryness on a rotary evaporator. The residue was then quenched by adding saturated aqueous NaHCO3 solution (30 mL) and the residue was diluted with EtOAc (100 mL). The two-phase layer was then transferred to a 250 mL extraction funnel and the aqueous layer was extracted with EtOAc (3x). Combine the organic layers, dry with anhydrous Na₂SO₄, filter with a sintered funnel, and evaporate to dryness. The residue was then flashed using a 120g Reveleris Grace column using a gradient of 30% EtOAc to 100% deionized EtOAc while using dry packaging to inject the crude mixture. Fractions containing pure product were combined and evaporated to dryness. 2-[(6-Bromopyridin-2-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione is recovered. Crystallized white solid (3.24 g, 84% yield).

Melting point: 118-119°C; Rf: 0.60 (60% EtOAc in hexane);

¹H NMR (CDCl ₃, 500MHz): δ7.92-7.91 (m, 2H), 7.78-7.76 (m, 2H), 7.50 (t , J = 7.5Hz, 1H), 7.38 (d, J = 8.0Hz, 1H), 7.18 (d, J = 7.5Hz, 1H), 5.01 (s, 2H);

¹³CNMR (CDCl₃, 125MHz): δ167.9,156.9,141.9,139.0,134.2,132.1,127.0,123.6,119.9,42.5;

Step 2

Place 2-[(6-bromopyridin-2-yl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione (2.5g, 7.88mmol, 1.0 equivalent) Dissolve in absolute ethanol (78 mL), put into a 250 mL round-bottomed flask equipped with a magnetic stir bar and condenser and heat to reflux until completely dissolved (about 15 minutes). Add hydrazine monohydrate to the homogeneous solution to synthesize fluorphlogopite (1.58g, 1.53mL, 31.53mmol, 4.0 equivalent). Within one minute, the reaction mixture turned yellow. The reaction mixture was heated for 3 hours, during which time the mixture solidified to a white thick suspension. An additional 50 mL of ethanol was added and the mixture was stirred for an additional 2 hours.

The reaction was cooled to room temperature and then to 0°C to precipitate the hydrazine/phthalimide adduct which disintegrated in solution. Filter the precipitate on a Buchner. The precipitate was washed thoroughly with absolute ethanol, and the filtrate was partially concentrated. There is still some solid in the suspension, so filter it through cold EtOH. The filtrate was concentrated to dryness to obtain a solid. The product was clear by NMR and 6-bromo-2-pyridinemethanamine could be carried to the next step without further purification. Yellow colloidal solid (1.30 g, 88% yield).

Rf: 0.25 (3% MeOH in EtOAc solution); ¹H NMR (CDCl₃, 500MHz): δ7.57-7.50 (m, 1H), 7.40-7.35 (m, 1H), 7.31-7.27 (m, 1H), 3.98 (br s, 2H), 1.73 (br s, 2H);

¹³C NMR (CDCl₃, 75MHz): δ163.8, 141.8, 138.9, 126.2, 120.0, 47.4.