Water → tert-butyl N-hydroxycarbamate

A solution of 2,5-dihydrofuran (3.0 g, 42.8 mmol) was dissolved in 200 mL CH2Cl2 and treated with m-chloroperbenzoic acid (26.0 g, 145 mmol). The reaction was stirred at rt overnight and then extracted from 1 n NaOH with CH2Cl2×3. The combined organic extracts were dried over MgSO4, filtered, and concentrated on a rotary evaporator to give 3.0 g (81% yield) of the furan epoxide 18a which was used without further purification. (18b) A mixture of compound 18a (3.0 g, 34.8 mmol), sodium azide (3.25 g, 50 mmol), and ammonium chloride (2.7 g, 50 mmol) in 15 mL of water and 15 mL of MeOH was refluxed overnight. The reaction mixture was cooled, filtered through a sintered glass funnel and concentrated on a rotary evaporator. The crude residue was carried to the next step without purification. (18c) A solution of 18b and t-butyldicarbonate (7.6 g, 35 mmol) in 50 mL of EtOAc was placed in a Parr bottle with 10% Pd/C (300 mg) and hydrogenated under 50 psi of H2 overnight. The reaction mixture was filtered through Celite in a sintered glass funnel and concentrated on a rotary evaporator. The residue was purified by silica gel chromatography to give 1.5 g (21% yield) of Boc-amino alcohol 18c. (18d) Boc-amino alcohol 18c (1.0 g, 5.0 mmol) was dissolved in 50 mL CH2Cl2, treated with Dess-Martin periodinane (5.0 g, 11.8 mmol) and stirred for 3 hr. The reaction mixture was partitioned between DCM and 1N NaOH, separated, and the organic layer was dried over MgSO4, filtered, and concentrated by rotary evaporator. The residue was taken to the next step without purification. (18e) Ketone 18d was dissolved in 50 mL 2:1 EtOH/water and treated with ammonium carbonate (4.8 g, 50 mmol) and potassium cyanide (657 mg, 10 mmol). The reaction was heated in a 65° C. oil bath for 24 hr. The EtOH was removed by rotary evaporator, the residue was extracted from dil. HCl with 3×EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated to give the crude hydantoin. MS found: (M+H)+=284. (18f) Compound 18e (202 mg, 0.74 mmol) was stirred for 1 hr in TFA/CH2Cl2 (1:1, 5 mL) and concentrated on a rotary evaporator to give 128 mg (100% yield) of the amine 18f which was taken to the next step without purification. (18g) A solution of 18f (128 mg, 0.74 mmol) was dissolved in 10 mL DMSO and treated with triethylamine (0.6 mL, 4.3 mmol), BOP (500 mg, 1.1 mmol), 4-[(2-methyl-4-quinolinyl)methoxy]benzoic acid (322 mg, 1.1 mmol). The reaction was stirred overnight and then extracted from sat KH2PO4 with EtOAc×3. The combined organic extracts were dried over MgSO4, filtered, concentrated on a rotary evaporator and purified by reverse-phase HPLC to give 85 mg of the product as a TFA salt (20% yield). MS found: (M+H)+=447.

1. customwas used without further purification
2. temperaturewas refluxed overnight
3. temperatureThe reaction mixture was cooled
4. filtrationfiltered through a sintered glass funnel
5. concentrationconcentrated on a rotary evaporator
6. customThe crude residue was carried to the next step without purification
7. filtrationThe reaction mixture was filtered through Celite in a sintered glass funnel
8. concentrationconcentrated on a rotary evaporator
9. customThe residue was purified by silica gel chromatography

ORD record

ord-ce5c048a23a84a0d9d8bd84d09f1c0f7

Source dataset

uspto-grants-2009_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07482372B2