HCID 68824869, compound → HCID 131725235, compound

A solution of crude aldehyde from part 3 above (6.6 g, 28 mmol) in CH2Cl2 (100 ml) was treated with R-α-methylbenzyl amine (3.4 g, 28 mmol) and Na(OAc)3BH (8.9 g, 42 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was quenched with 1 N NaOH (50 ml) and stirred for 30 minutes. The organic layer separated and washed with water, and brine. The extract was dried over MgSO4, filtered and concentrated on a rotary evaporator to give a thick oil. This was chromatographed on silica gel (50% EtOAc/Hexane) to give 3.38 g grams of one amine diastereomer and 2.65 g of a second amine diastereomer. An additional 0.5 g of a mixture of diastereomers was also obtained. Part 5. {((1R)-1-Phenyl-ethyl)-[3-phenyl-(2S)-2-(tetrahydro-pyran-2-yloxy)-propyl]-amino}-acetic acid methyl ester A solution of the amine from part 4 above (3.38 g, 10 mmol) in DMF (20 ml) was treated with methyl bromoacetate (2.29 g, 15 mmol) and K2CO3 (2.0 g, 15 mmol). The resulting mixture stirred overnight at room temperature. The reaction mixture was diluted with 300 ml of water and extracted into EtOAc. The organic extracts were washed with water, and brine. The extract was dried over MgSO4, filtered and concentrated on a rotary evaporator to give 4.1 g of the amine ester as a thick oil and was used without further purification. Part 6. (6S)-6-Benzyl-4-((1S)-1-phenyl-ethyl)-morpholin-2-one The crude amine ester (4.1 g, 10 mmol) from Part 5 was dissolved in methanol and treated with 1 ml of H2SO4 and heated to reflux for 2 hours. Most of the methanol was then removed under vacuum on a rotary evaporator and the resulting residue neutralized with 1 N NaOH and extracted into EtOAc. The organic extract was washed with water and brine. The organic solvent was removed on a rotary evaporator and the resulting residue chromatographed on silica gel (15% EtOAc/hexane) to give 1.8 grams of morpholinone as an oil. Part 7. (6S)-6-Benzyl-morpholin-2-one A solution of N-benzyl morpholin-2-one from part 6 (1.8 g, 6.1 mmol) in methanol (100 ml) was treated with 0.5 g of 10% Pd(OH)2/C and hydrogenated at 60 psi of hydrogen for 15 hours. The mixture is filtered and the solvent removed under vacuum on a rotary evaporator to give 1.16 grams of the morpholin-2-one as an oil. Part 8. [(1R,2S)-2-(2-Benzyl-6-oxo-morpholin-4-ylmethyl)-cyclohexyl]-carbamic acid benzyl ester A solution of cyclohexyl aldehyde from EXAMPLE 2 above (1.6 g, 6.1 mmol) and morpholin-2-one from Part 7 above (1.16 g, 6.0 mmol) in CH2Cl2 (50 ml) was treated with Na(OAc)3BH (1.93 g, 9.1 mmol). The resulting mixture was stirred at room temperature for 4 hours (until reaction was judged to be complete by TLC). The mixture was quenched with 1N NaOH (50 ml) and stirred for 30 minutes. The organic layer separated and washed with water, and brine. The extract was dried over MgSO4, filtered and concentrated on a rotary evaporator to give a thick oil. This was chromatographed on silica gel (25% EtOAc/Hexane) to give 1.2 grams of product as a white solid. Part 9. 4-((1R,2R)-2-Amino-cyclohexylmethyl)-(6S)-6-benzyl-morpholin-2-one A solution of N-CBZ cyclohexyl morpholin-2-one from part 8 above (1.2 g, 2.7 mmol) in methanol (100 ml) was treated with 0.5 g of 10% Pd/C and hydrogenated at 60 psi of hydrogen for 15 hours. The mixture is filtered and the solvent removed on a rotary evaporator to give 0.83 grams of the free amino cyclohexyl morpholin-2-one as a white solid. Part 10. N-[(1R,2S)-2-[(2S)-2-Benzyl-6-oxo-morpholin-4-ylmethyl]-cyclohexyl]-N′-phenyl-urea A solution of crude amine from part 9 above (75 mg, 0.25 mmol) in THF was treated with phenylisocyanate (30 mg, 0.25 mmol) and stirred at room temperature for 30 minutes. The solvents were removed under vacuum on a rotary evaporator and the residue chromatographed on silica gel (25%-50% EtOAc/Hexane) to give 30 mg of desired urea as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.33-7.19 (m, 7H), 7.05-7.00 (m, 3H), 6.92 (bs, 1H), 5.69 (d, J=8 Hz, 1H), 4.40 (m, 1H), 3.50 (d, J=18 Hz, 1H), 3.43 (, 1H), 2.93 (d, J=18 Hz, 1H), 2.90(abx m, 2H), 2.62 (m, 2H), 2.31-2.03 (m, 3H), 1.66 (m, 2H), 1.34-0.81 (m, 5H). ESI MS: (M+H)+=422.2.

1. filtrationThe mixture is filtered
2. customthe solvent removed on a rotary evaporator

ORD record

ord-efe3ebdb11154e9b804b0e1d6971d4be

Source dataset

uspto-grants-2005_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06974869B2