Preparation of 2-amino-6-bromothiazolo[5,4-B]pyridine_Industrial additives

Preparation background and overview of 2-amino-6-bromothiazolo[5,4-B]pyridine

2-Amino-6-bromothiazolo[5,4-B]pyridine is an organic intermediate that can be prepared from 5-bromo-2-chloropyridin-3-amine and potassium thiocyanate in one step, or It is prepared in three steps using 3-amino-5-bromo-2-fluoropyridine and benzoyl isothiocyanate as raw materials.

Preparation of 2-amino-6-bromothiazolo[5,4-B]pyridine

Preparation report of 2-amino-6-bromothiazolo[5,4-B]pyridine 1.

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In a 50 ml RB flask, 5-bromo-2-chloropyridin-3-amine (3.11 g, 15 mmol) was put into concentrated HCl (30 mL) and thoroughly sonicated to obtain a light brown solution. Potassium thiocyanate (2.187g, 22.50mmol) was added thereto, and the resulting mixture was heated at 100°C for 6 hours. After refluxing for 30 minutes, the reaction mixture turned into a light yellow suspension. The reaction mixture was evaporated in vacuo; ice-cooled water was added to the residue, sonicated well and neutralized with saturated sodium carbonate under cooling. The precipitated solid was thoroughly treated with ultrasound, filtered and dried under high vacuum to obtain the product 2-amino-6-bromothiazolo[5,4-B]pyridine (2.5 g) as an off-white solid.

Preparation report 2 of sodium percarbonate 2-amino-6-bromothiazolo[5,4-B]pyridine,

Step 1. Preparation of N-(5-bromo-2-fluoropyridin-3-ylthiocarbamoyl(carbamothioyl))benzamide (II):

To a solution of 3-amino-5-bromo-2-fluoropyridine (1.0g, 5.23mmol) in acetone (15.0mL), benzoyl isothiocyanate (0.85mL, 6.25mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. After the reaction was completed (TLC monitoring), the acetone was removed under reduced pressure, the residue was washed with hexane, and filtered to obtain the desired product (1.68 g, 91%). ¹HNMR (MHz, DMSO-d6): δ7.55 (t, J=7.60Hz, 2H), 7.68 (t, J=7.60Hz, 1H), 8.0 (d, J=7.60 Hz, 2H), 8.31 (s, 1H), 8.84 (dd, J=2.0 and 8.40Hz, 1H), 12.03 (brs, 1H) and 12.60 (brs, 1H).

Step 2: Preparation of N-(6-bromothiazole[5,4-b]pyridin-2yl)benzamide (III):

To an ice-cold solution of N-(5-bromo-2-fluoropyridin-3-ylthiocarbamoyl)benzamide II (1.80 g, 5.08 mmol) in THF (20.0 mL) was added NaOH solution ( 1.0g, 22.0mmol, dissolved in 10.0mLH₂O). The reaction mixture was then heated to 60°C for 16 hours. After the reaction was complete (TLC monitoring), the reaction mixture was concentrated, water was added, and extracted with EtOAc (3×150 mL). The combined organic phases were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the desired product (1.60 g, 95%). ¹HNMR (MHz, DMSO-d6): δ7.42 (m, 3H), 7.82 (d, J=2.0Hz, 1H), 8.14 (m, 2H) and 8.18 (d, J =2.0Hz, 1H).

Step 3. Preparation of 2-amino-6-bromothiazolo[5,4-B]pyridine(IV):

Dissolve N-(6-bromothiazol[5,4-b]pyridin-2yl)benzamide III (2.0 g, 5.98 mmol) in 70% H₂SO ₄(10.0 mL) solution was heated to 140°C and maintained for 1 hour. After the reaction was completed (TLC monitoring), the reaction mixture was poured onto crushed ice, basified to pH 8.0 with 30% NaOH aqueous solution, and extracted with EtOAc (3×150 mL). The combined organic phases were washed with brine, dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the desired product (1.34 g, 98%). ¹HNMR (MHz, DMSO-d6): δ7.85 (d, J=2.0Hz, 1H), 8.05 (brs, 2H) and 8.18 (d, J=2.0Hz, 1H).

References

[1][Chinese invention] CN200980121315.9 Thiazolo[5,4-B]pyridine and *azole[5,4-B]pyridine derivatives as antibacterial drugs

[2][China invention, China invention authorization] CN200880126437.2 Antibacterial fused thiazole