(S)-N-Boc-2-Hydroxymethylmorpholine

(S)-2-Benzyloxymethyl-morpholine-4-carboxylic acid tert-butyl ester 4c (5.27 g, 17.2 mmol) was dissolved in 200 mL of ethanol with stirring, and added with 0.527 g of palladium on activated carbon and two drops of 1N hydrochloric acid. The reaction mixture was purged with hydrogen for three times, reacted at 70°C overnight under hydrogen atmosphere and monitored by thin layer chromatography until the disappearance of the starting materials. The resulting mixture was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (200 mL.x.4). The combined organic phase was washed successively with water (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (S)-2-hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester 4d (3.646 g, yield 97.7percent) as a colorless or light yellow liquid. MS m/z (ESI): 240.3 [M+23]. H NMR (CDClStep b) 2S-Hydroxymethyl-morpholine-4-carboxylic acid tert-butyl ester The oil (2.55 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 (2.55 g) was dissolved in 50 ml ethanol and 100 mg palladium on carbon (10percent) was added. The mixture was hydrogenated at 1 atm HTo a solution of (S)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (2.50 g, 10.8 mmol) in THF (25 mL) was added dropwise borane (1 M, 20 mL) at 0 °C over 15 mm. After addition, the reaction mixture was warmed to room temperature and stirred for 2 hrs. The reaction was quenched with MeOH/AcOH (9:1, 10 mL) at 0°C. The mixture was then concentrated and the residue was poured into 35 mL of water and 35 mL of EtOAc. The organic layer was washed with saturated Na2CO3 (30 mL) aqueous solution, dried over Na2SO4 and concentrated to give the title compound D186 (2.6 g, 100percent) as colorless oil.LCMS: 118 [M-1 00-’-Hj. tR =1.96 mins. (LCMS condition 3)1H NMR (300 MHz, CHLOROFORM-d): 53.84-3.91 (m, 3H), 3.49-3.68 (m, 4H), 2.70-2.97 (m, 2H), 2.03 (t, 1H), 1.45 (s, 9H);Di-tert-butyl dicarbonate (0.606 g, 2.77 mmol was added to a solution of (S)-morpholin-2- ylmethanol (0.316 g, 2.69 mmol) and triethylamine (0.54 mL, 3.71 mmol) in dichloromethane (12 mL). The reaction mixture was stirred for 16 h at room temperature. The organic solution was washed with 2M HCI (12 mL), and the aqueous phase was extracted with dichloromethane (2 * 10 mL). The combined organic phases were dried (MgSOTo a vigorously stirred solution of 21 (5.73g, 48.97mmol, leq) in a mixture OfCHTo a solution of (S)-morpholin-2-yl-methanol (1.63 g, 13.9 mmol) in DCM (75 mL) was added a solution of NaOH (0.61 g, 15.3 mmol) in water (2 mL). Di-te/t-butyldicarbonate (3.04 g, 13.9 mmol) was added and the reaction mixture stirred overnight at room temperature. The aqueous phase was separated and further extracted with DCM (2 x 15 mL). The combined organic phases were dried (NaTo a solution of alcohol 22 (2.17g, lO.Ommol, leq) and TEMPO (2, 2, 6, 6-tetramethyl- 1-piperidinyloxy, 16mg, O.lOmmol, lmol percent) in 25ml EtOAc under nitrogen, was added NaHCO3 (2.52g, 30mmol, 3eq). The mixture was cooled at -50C and trichloroisocyanuric acid (2.44g, 10.5mmol, 1.05eq) in 40ml EtOAc was added dropwise over a period of Ih. After stirring Ih at - 5C, 100ml of a IM solution of sodium iodide were added and the mixture extracted three times with EtOAc. The organic layers were combined before addition of 150ml OfNa2SO3 10%. The aqueous layer was washed twice with EtOAc, then the organic layers were combined, dried over Na2SO4 and concentrated under reduced pressure. Filtration through a Whatman 0.45mum PFTE filter and evaporation of the solvent provided the aldehyde 23 as a yellow oil (1.92g, 89%).NMR 1H (CDCl3), 5=9.62 (s, IH, HCO); 4.15-3.71 (m, 4H); 3.68-3.52 (m, IH); 3.12- 2.79 (m, 2H); 1.45 (s, 9H, 3CH3). NMR 13C (CDCl3), 5=200.1 (HCO); 154.5 (NCO); 80.6 (C(CH3)3); 79.0 (CH); 66.3 (CH2O); 43.7 (br, NCH2CH); 42.9 (br, NCH2CH2); 28.4 (CH3).Intermediate 250 (500 mg, 2.30 mmol) and IBX (1.29 g, 4.60 mmol) were dissolved in DCE (20 mL) and heated at 70 C. for 18 h. The reaction mixture was filtered, washed with sat aq Na2CO3 (10 mL), dried (MgSO4) and concentrated in vacuo to give the crude title compound (684 mg) as a pale yellow oil.(S)-tert-Butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5 g, 23.01 mmol, commercially available from, for example, AOK Chem) was dissolved in DCM (10 mL) and Dess-Martin periodinane (11.71 g, 27.6 mmol) was added, then the solution was stirred at rt for 2 h. The mixture was washed with NaHCO3 solution (20 mL) and the organic layer dried and evaporated to give a colourless solid. NMR shows the presence of the desired aldehyde. The crude intermediate was dissolved in toluene (20mL) and ethyl 2-(triphenylphosphoranylidene)acetate (10.42 g, 29.9 mmol) was added, then the mixture was heated at 90 C overnight. The resulting suspension was filtered and the filtrate washed with water, then the organic layer was dried and evaporated in vacuo. The residue was purified by chromatography on a 25 g silica column eluting with O-5O% EtOAc/cyclohexane and the productcontaining fractions were evaporated in vacuo to give (R, E)-tert-butyl 2-(3-ethoxy-3-oxoprop-1-en-1-yl)morpholine-4-carboxylate (1.9 g, 6.66 mmol, 28.9 % yield) as a colourless gum.1H NMR (400 MHz, CDCI3) O ppm 6.84 (dd, J=15.9, 4.2 Hz, 1 H) 6.02 - 6.24 (m, 1 H) 4.15 -4.34 (m, 2 H) 4.02 - 4.12 (m, 1 H) 3.80 - 3.99 (m, 2 H) 3.49 - 3.67 (m, 1 H) 2.98 (t, J=10.6 Hz, 1H) 2.70 (br. s., 1 H) 1.49 (5, 9 H) 1.26 - 1.36 (m, 4 H)(5)-ter1Butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.0 g, 23 minol, cominercially available from, for example, AOK Chem) was dissolved in DCM (10 mL) and Dess-Martin periodinane (11.7 g, 27.6 minol) was added, then the solution was stirred at room temperature for 2 h. Theminxture was washed with a saturated sodium bicarbonate aqueous solution (20 mL) and the organic layer dried and evaporated to give a colourless solid. NMR shows the presence of the desired aldehyde.The crude intermediate was dissolved in toluene (20 mL) and ethyl 2-(triphenylphosphoranylidene)acetate (10.4 g, 29.9 minol) was added, then the minxture was heated at90C for 16 h and then was cooled to room temperature. The resulting suspension was filtered andthe filtrate washed with water, then the organic layer was dried and evaporated in vacuo. The residue was purified by chomatography on a 25 g silica column eluting with 0-50% EtOAc/cyclohexane and product-containing fractions were evaporated in vacuoto give (R, E)-tertbutyl 2-(3-ethoxy-3-oxoprop- 1-en-1-yl)morpholine-4-carboxylate (1.9 g, 29%) as a colourless gum.1H NMR (400 MHz, CDCI3) O ppm 6.84 (dd, J= 15.9, 4.2 Hz, 1 H) 6.02 - 6.24 (m, 1 H) 4.15 -4.34 (m, 2 H) 4.02 - 4.12 (m, 1 H) 3.80 - 3.99 (m, 2 H) 3.49 - 3.67 (m, 1 H) 2.98 (t, J= 10.6 Hz, 1 H) 2.70 (br. s., 1 H) 1.49 (5, 9 H) 1.26 - 1.36 (m, 4 H)Under cooling in an ice bath,

(S)-N-Boc-2-hydroxymethylmorpholine is used as a pharmaceutical intermediate.

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