(R)-N-Boc-2-Hydroxymethylmorpholine

Intermediate 111 (19.8 g, 64.4 mmol) was stirred under an atmosphere of hydrogenin the presence of 10percent Pd/C (1.98 g, 1.86 mmol) for 16 h. The catalyst wasremoved by vacuum filtration and the filtrate concentrated at reduced pressure to give 13.98 g (100percent yield) of the title compound as a colourless viscous oil, which crystallised on standing.1H NMR (250 MHz, chloroform-d): 6 [ppm] 3.98 - 3.75 (m, 3H), 3.73 - 3.41 (m, 4H), 3.03- 2.83 (m, 1H), 2.82-2.65 (m, 1H), 2.12 (t, J = 5.9 Hz, 1H), 1.45 (5, 9H).To a solution of (R)-tert-buty{ 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a HStep 3. To a solution of (K)-tert-butyl 2-(benzyloxymethyl)rnorpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a HTo a solution of (R)-tert-butyl 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a HStep 3. (R)-tert-Buty\ 2-(hydroxymethyl)morpholine-4-carboxylate: To a solution of (R)-tert-buty\ 2-(benzyloxymethyl)morpholine-4-carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a HTo a solution of (K)-lert-buy\ 2-(benzyloxymethyl)morpholine-4- carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a HStep 3. (R)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate. To a solution of (R)-ter/-butyl 2-(benzyloxymethyl)morpholine-4- carboxylate (8.33 g, 27.1 mmol) in EtOH was added Pd-C (wet, 3.6 g), and the resulting mixture was stirred at rt under a HStep b) 2R-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester The oil (1.80 g) was dissolved in 50 ml ethanol and 100 mg palladium on carbon (10percent) was added. The mixture was hydrogenated at 1 atm HThe oil (1.80 g) was dissolved in 50 ml ethanol and 100 mg palladium on carbon (10percent) was added. The mixture was hydrogenated at 1 atm H(R)-2-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1c (1.02 g, 3.32 mmol) and 0.45 g of palladium on activated carbon were added to a reaction flask. The reaction flask was purged with hydrogen for three times. 10 mL of ethanol was added under hydrogen atmosphere. The reaction mixture was stirred overnight at 70°C and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was purified by silica gel column chromatography to obtain the title compound (R)-2-hydroxymethyl-morpholine-4-carboxylate acid tert-butyl ester 1d (0.428 g, yield 59percent) as a colorless oil. MS m/z (ESI): 240.3 [M+1]. (R)-2-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 1c (1.02 g, 3.32 mmol) and 0.45 g of palladium on activated carbon were added to a reaction flask. The reaction flask was purged with hydrogen for three times. 10 mL of ethanol was added under hydrogen atmosphere. The reaction mixture was stirred overnight at 70° C. and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was purified by silica gel column chromatography to obtain the title compound (R)-2-hydroxymethyl-morpholine-4-carboxylate acid tert-butyl ester 1d (0.428 g, yield 59percent) as a colorless oil.MS m/z (ESI): 240.3 [M+1].Di-tert-butyl dicarbonate (0.558 g, 2.55 mmol) was added to a solution of (f?)-morpholin-2- ylmethanol (0.291 g, 2.48 mmol) and triethylamine (0.47 mL, 3.42 mmol) in dichloromethane (11 mL). The reaction mixture was stirred for 16 h at room temperature. The organic solution was washed with 2M HCI (10 mL), and the aqueous phase was extracted with dichloromethane (2 * 10 mL). The combined organic extracts were dried (MgSOSodium metal (2.78 g, 121 mmol) was placed in a flask with naphthalene (17.0 g, 133 mmol) in tetrahydrofuran (140 ml_) and sonicated for 2.5 h to give a dark green solution. In a separate flask {(2/t)-4-[(4-methylphenyl)sulfonyl]- 2-morpholinyl}methanol (1.64 g, 6.04 mmol) was dissolved in tetrahydrofuran (40 ml_) and cooled to 0 A mixture of the (R) -tert-butyl 2- (hydroxymethyl) morpholine-4-carboxylate (2.0 g, 9.21 mmol) , DMAP (114 mg, 0.92 mmol) , Tosyl chloride (TsCl, 1.93 g, 10.13 mmol) and EtTo a solution of 11A (3.0 g, 13.8 mmol) in THF (30 mL) at -20 C under argon, LiAlH4 (1.5 g, 41.4 mmol) was added and the resulting mixture was stirred at -20 C for 20 min and then stirred at reflux for 3h. The mixture was cooled to -20 C, water (1 mL) was added slowly, NaOH (15%, 1 mL) was added slowly, water (3 mL) was added slowly and stirring was continued for 15 min. The mixture was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the desired product 11B. ESI-MS m/z: 131.17 [M+H]+. The crude product 11B was used in the next step without further purification.

Molecular Weight:217.26
XLogP3:0.1
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:3
Exact Mass:217.13140809
Monoisotopic Mass:217.13140809
Topological Polar Surface Area:59
Heavy Atom Count:15
Complexity:224
Defined Atom Stereocenter Count:1
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes