Diisopropylethylamine → tert-butyl 1-[[2-bromo-4-[(Z)-N'-hydroxycarbamimidoyl]phenyl]methyl]azetidine-3-carboxylate

Temperature

65 °C

A reaction vial containing a stir bar was charged with 3-bromo-4-(bromomethyl)benzonitrile (100 mg, 0.364 mmol), tert-butyl azetidine-3-carboxylate acetic acid salt, Int.1-C (95 mg, 0.436 mmol), DMF (1 mL), and DIPEA (0.381 mL, 2.182 mmol). The vial was flushed with argon, sealed and placed on a reaction block which was heated to 65° C. After 5 hours, the reaction was cooled to RT and directly purified by preparative HPLC (methanol/water plus 0.1% TFA as eluent). To the product fractions was added a solution of sodium bicarbonate (200 mg) in water (4 mL) and then the volatiles were removed in vacuo to afford a white solid which was slurried in methanol (10 mL). Hydroxylamine hydrochloride (37.6 mg, 0.541 mmol) was added and the reaction was heated overnight in an oil bath set to 50° C. Additional hydroxylamine hydrochloride (30 mg) along with sodium bicarbonate (150 mg) were added and heating continued at 50° C. for 8 hours. The volatiles were removed in vacuo and the residue purified by preparative HPLC (methanol/water plus 0.1% TFA as eluent). The pH of the product containing fractions was adjusted to ˜7 using sodium bicarbonate, the solvents were concentrated and the resulting aqueous solution was extracted with DCM. The organics were dried over anhydrous magnesium sulfate then concentrated to afford (Z)-tert-butyl 1-(2-bromo-4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (12.6 mg, 0.032 mmol). The compound had an HPLC retention time=0.72 min.−Column: BEH C18 2.1×50 mm 1.7 u (gradient: 2% MeCN/water plus 0.05% to 98% MeCN/water plus 0.05% TFA over 1 min.); LC/MS M+1=384/386.

1. additionA reaction vial containing a stir bar
2. customThe vial was flushed with argon
3. customsealed
4. temperaturethe reaction was cooled to RT
5. customdirectly purified by preparative HPLC (methanol/water plus 0.1% TFA as eluent)
6. additionTo the product fractions was added a solution of sodium bicarbonate (200 mg) in water (4 mL)
7. customthe volatiles were removed in vacuo
8. customto afford a white solid which
9. temperaturethe reaction was heated overnight in an oil bath
10. customset to 50° C
11. temperatureheating
12. waitcontinued at 50° C. for 8 hours
13. customThe volatiles were removed in vacuo
14. customthe residue purified by preparative HPLC (methanol/water plus 0.1% TFA as eluent)
15. additionThe pH of the product containing fractions
16. concentrationthe solvents were concentrated
17. extractionthe resulting aqueous solution was extracted with DCM
18. dry with materialThe organics were dried over anhydrous magnesium sulfate
19. concentrationthen concentrated

ORD record

ord-5647dc78f0e74205b977a473f29bdbce

Source dataset

uspto-grants-2013_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08354398B2