3-(3-hydroxypropylamino)propan-1-ol

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(γ-hydroxypropyl)tetrahydro-1,3-oxazine. To a glass reaction vessel equipped with stirrer thermometer, and condenser fitted with a water trap The reaction is heated to reflux the water separated of water is removed Toluene is removed at reduced pressure The residue is distilled at high vacuum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(γ-hydroxypropyl)tetrahydro-1,3-oxazine. To a glass reaction vessel equipped with stirrer thermometer, and condenser fitted with a water trap The reaction is heated to reflux the water separated of water is removed Toluene is removed at reduced pressure The residue is distilled at high vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Dissolve bis(3-hydroxypropyl)amine (1.33 g, 10 mmol) in 50/50 dioxane/water (25 mL) and buffer to pH 10 with 1N sodium hydroxide. Add, by dropwise addition, an ether solution of t-butyl azidoformate (1.58 g, 11 mmol) at 10° C. Allow to warm to room temperature and buffer occasionally to retain pH 10. Acidify with a sodium citrate/citric acid buffer to pH 5, extract with ether (3X), dry (MgSO4) and evaporate the solvent in vacuo. Purify the residue by silica gel chromatography to give bis(3-hydroxypropyl)-t-butylcarboxamide. Dissolve 3,5-di-t-butyl-4-hydroxy-N-[(4-methylphenyl)sulfonyl]-aniline (142 mg, 0.43 mmol) in anhydrous tetrahydrofuran (3 mL) and add triphenylphosphine (168 mg, 0.645 mmol). Stir under a nitrogen atmosphere and add bis(3-hydroxypropyl)-t-butylcarboxamide (83.6 mg, 0.215 mmol) followed by diethyl azodicarboxylate (0.083 mL, 0.530 mmol). Stir at room temperature for several hours and evaporate the solvent in vacuo. Purify by silica gel chromatography to give the title compound. Add, by dropwise addition at 10° C extract with ether (3X) dry (MgSO4) evaporate the solvent in vacuo Purify the residue by silica gel chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 3,3′-azanediylbis(propan-1-ol) (1000 mg, 7.51 mmol, 1.0 eq) was in DMF (10 ml), was added benzyl (2,5-dioxopyrrolidin-1-yl) adipate (2503 mg, 7.51 mmol, 1.0 eq) followed by TEA (1.046 ml, 7.51 mmol, 1.0 eq). The reaction was stirred at 25 deg for 18 hr. UPLC indicated formation of desired product. DMF was removed under reduced pressure. The crude was purified by C18 Reverse phase chromatograph (eluted with 0-40% ACN/water in 16 CV). Fractions containing desired product were combined and concentrated to give the titled compound as colorless oil (1.55 g, 4.41 mmol, 58.7%). UPLC Method B: m/e=352.2171 [M+1]; Rt=3.47 min. 1H NMR (CDCl3, 500 MHz) δ 7.3-7.5 (m, 5H), 5.15 (m, 2H), 3.65 (m, 2H), 3.40 (m, 5H), 2.66 (s, 3H), 2.45 (m, 3H), 2.29 (s, 1H), 1.84 (s, 1H), 1.70 (m, 7H).

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(β-hydroxypropyl)tetrahydro-1,3-oxazine. To a glass reaction vessel equipped with stirrer thermometer, and condenser fitted with a water trap The reaction is heated to reflux the water separated of water is removed Toluene is removed at reduced pressure The residue is distilled at high vacuum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(β-hydroxypropyl)tetrahydro-1,3-oxazine. To a glass reaction vessel equipped with stirrer thermometer, and condenser fitted with a water trap The reaction is heated to reflux the water separated of water is removed Toluene is removed at reduced pressure The residue is distilled at high vacuum

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a glass reaction vessel equipped with stirrer, thermometer, and condenser fitted with a water trap is added di-(3-hydroxypropyl) amine (3.0 mole, 399 g.) and toluene (500 g.). Paraformaldehyde (3.15 mole, 90% pure, 105 g.) is weighed out and about 1/3 is added to the amine solution. The resulting mixture is stirred and heated to 90° C. while slowly adding the remaining paraformaldehyde in about 70 minutes. The reaction is heated to reflux and the water separated. After 4 hours, a total of 63 ml. of water is removed. Toluene is removed at reduced pressure. The residue is distilled at high vacuum to yield 3-(γ-hydroxypropyl)tetrahydro-1,3-oxazine. To a glass reaction vessel equipped with stirrer thermometer, and condenser fitted with a water trap The reaction is heated to reflux the water separated of water is removed Toluene is removed at reduced pressure The residue is distilled at high vacuum