3-(BOC-AMINO)-1-PROPANOL

colorless to yellow or brown liquid

Synthesis of an Aminopropyloxy PBD Scaffold (50) (See FIG. 11)Overall Synthesis Strategy [00165] The on-bead (p-nitrophenyl Wang resin) ring closure (49-50) was carried out using a Dess Martin reagent as in Example 4. The final step (production of the off-bead PBD), was carried out to prove that the on-bead resin was of the desired structure.Synthesis of N-(tert-butoxycarbonyl)-3-hydroxypropylamine 42 [00166] A solution of (Boc)84.2 g (1.2 eq.) sodium carbonate followed by 100 ml water were added in portions to a solution of 50 g (1 eq.) 3-aminopropan-1-ol in 500 ml THF at 0° C. 156.5 ml (1.02 eq.) di-tert-butyl dicarbonate were added dropwise over a period of 30 min to the solution at 0° C. On completion of the addition, the mixture was stirred for 30 min at room temperature. The reaction course was monitored by thin-layer chromatography (10percent MeOH/CHCl3-Aminopropanol (7 g, 92 mmol, 1 equiv.) dissolved in methanol (100 mL) was successively treatd with di-tert-butyl dicarbonate (20.1 g, 92 mmol, 1 equiv.) and di-iso-propylethylamine (32 mL, 184 mmol, 2 equiv.) overnight at room temperature. After removal of the solvent under reduced pressure, the product was dissolved in ethylacetate (150 mL). The organic layer was washed with 10 percent citric acid (X 2). The aqueous layers were extracted with etyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Removal of the solvent under vacuum gave compound 89 as a yellow oil (17.5 g, quant.). TLC: Rf 0.70 (DCM:MeOH 90:10); 1H NMR (CDCl3, 400 MHz): δ 4.76 (bs, 1H, NH), 3.66 (t, J = 5.6, 2H, CH2-O), 3.31-3.27 (m, 2H, CH2-N), 1.69-1.63 (m, 2H, C-CH2-C), 1.45 (s, 9H, tBu).A stirred solution of 3-aminopropanol (250 g, 3334 mmol, 1.0equiv, AlfaAesar)andTEA (505 g, 5000 mmol, 1.5 equiv, AVRA) in CH2Cl2 (3000 ml, 12 vol, MSN 1) was charged with (l3oc)20 (872 g, 4000 mmol, 1.2 equiv, Globe Chemie lot) at 0-5° C., and was stirred at room temperature for 2 h, monitoring the progress of the reaction by TLC (9:1, CH2Cl2:MeOH). Afier the completion of the reaction, water (3000 ml) was added and the mixture was stirred for 10 mm. The layers were separated and the organic layer was washed with 0.2 N HCl (3000 ml) and DI water (1000 ml), dried over anhydrous Na2SO4, and evaporated under vacuum to afford Boc-aminopropanol 23 (588 g, 100percent) as a pale green liquid.5 g (1.0 eq., 66.6 mmol) of the compound 11 was dissolved in 120 mL of DCM, and under ice cooling, it was added with 14.5 g (1.0 eq., 66.6 mmol) of BocStage 1 : tert-Butyl 3-hydroxypropyl(methyl)carbamate; 84.2 g (1.2 eq) sodium carbonate followed by 100 ml water were added in portions to a solution of 50 g (1 eq) 3-aminopropan-1-ol in 500 ml THF at 0Preparation of tert-Butyl 3-hydroxypropylcarbamate (66) Di-tert-butyl dicarbonate (3.046 g, 13.9 mmol) was dissolved in 50 mL of tetrahydrofuran (THF). 3-Aminopropanol (7.0 g, 92 mmol) dissolved in methanol (100 mL) was successively treated with di-tert-butyl dicarbonate (22.0 g, 101.2 mmol) and di-iso-propylethylamine (32 mL, 184 mmol) stir overnight at room temperature. After removal of the solvent under reduced pressure, the product was dissolved in DCM (100 mL). The organic layer was washed with 10percent citric acid (X2). The aqueous layers were extracted with DCM. The combined organic layers were dried over sodium sulfate. Removal of the solvent under vacuum gave Compound 17 as colorless viscous oil (17.5 g, yield: 99percent). (Boc)General procedure: To a mixture of amine (1.0 mmol) and (Boc)3-Aminopropanol (100 mg, 1.3 mmol) was dissolved in 5 mL tetrahydrofuran. To a solution of 3-aminopropanol (2.0 g, 26.6 mmol) in chloroform (50 mL) was added di-tert-butyl dicarbonate (7.0 g, 31.9 mmol) at 0 °C and stirred for 6 hrs at room temperature. Chloroform was evaporated and the residue was re-dissolved in ethyl acetate and washed with saturated NaHCO3 aqueous solution (100 mL) and brine (2 x 100 mL) The organic solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford N-boc-3-aminopropanol (4.5 g, 97 percent yield). δ1H NMR (400MHz, CDCl3) δ: 3.66 (t, 2H), 3.29 (t, 2H), 1.66 (p, 2H), 1.44 (s, 9H). (Mehlich, et al. 2011 Org. Biomol. Chem. 9, 4108-4115.)A solution of di-tert-butyl dicarbonate (382.8 g, 1.75 mol) in dichloromethane (1.6 L) was added to 3-amino-1-propanol (263.6 g, 3.51 mol) during 2 h. The reaction mixture was stirred for an additional 40 min and water (1 L) was added. The organic phase was washed with water (3.x.500 mL), ), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 3-(tert-butoxycarbonylamino)-1-propanol in 96percent yield.Preparation of tert-Butyl 3-Hydroxypropylcarbamate (67) To the solution of 3-amino-1-propanol (14 mL, 66.6 mmol) in CH2Cl2 (150 mL) were added Et3N (14 mL, 99.9 mmol) and di-tert-butyldicarbonate at 0°C. After stirring for 1 h at rt, the reaction mixture was concentrated under reduced pressure to remove all volatiles. The residuewas diluted with water, and extracted with ethyl acetate.The organic layer was washed twice with brine, dried over MgSO4, filtered, and concentrated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate = 1:1) to give an off-white oil(1.1 g, yield 94 percent).1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.65 (m2H), 3.28 (t, 2H, J = 5.9 Hz), 3.68 (t, 2H, J = 5.4 Hz), 4.86 (s, 1H), MS 175 (M+).3-amino-1-propanol (4 mol, 300 g) was added to 2500 g of dichloromethane, the ice bath was cooled to 0 to 5 ° C, and BOC anhydride (4.4 mol, 958.7 g) was added in six batches, dropwise Add Na2C03 solution (1500ml, 4mol / L), and addition was finished between 3.5h. The reaction was carried out for 2.5 hours. The layers were separated and the aqueous layer was extracted three times with 200 g of dichloromethane. The dichloromethane phase was combined and the dichloromethane was removed by steam to give crude Boc-3-amino-1- propanol. The target product 652.6g was obtained by column chromatography, the yield was 93.17percent and the purity was 95.81percent.10203] 3-amino-1-propanol (3.0 g, 66.569 mmol) was dissolved in dichloromethane (150 mE) at 0° C. under nitrogen atmosphere, and di-tert-butyldicarbonate (16 g, 73.2260 mmol) was added thereto. The obtained mixture was stirred at room temperature for 12 hours. Afier the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography, thereby obtaining Compound la (6.4 g, 92percent).10204] ‘H NMR (400 MHz, CDC13) ö 4.78 (s, 1H), 3.65 (m, 2H), 3.30 (m, 2H), 2.90 (s, 1H), 1.68 (m, 2H), 1.48 (s, 9H); El-MS mlz: 176(M+)3-amino-1-propanol (3.Og, 66.569mmo1) was dissolved in dichloromethane (l5OmL) at 0°C under nitrogen atmosphere, and di-tert-butyldicarbonate (16g, 73.226mmo1) was added thereto. The obtained mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography, thereby obtaining Compound la(6.4g, 92percent).‘HNMR (400MHz, CDC13) 4.78 (s, 1H), 3.65 (m, 2H), 3.30 (m, 2H), 2.90 (s, 1H), 1.68 (m, 2H), 1.48 (s, 9H); El-MS m/z: 176(M+)Preparation of Compound 45a 3-Amino-l-propanol (3.0 g, 66.57 mmol) was dissolved in DCM (150 mL) at 0 °C under nitrogen, and di-tert-butyl dicarbonate (16 g, 73.23 mmol) was added thereto. The obtained mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography, which produced the compound 45a (6.4 g, 92 percent). 1H-NMR (400 MHz, CDC13-Amino-l-propanol (3.0 g, 66.57 mmol) was dissolved in DCM (150 mL) at 0 °C under nitrogen, and di-tert-butyl dicarbonate (16 g, 73.23 mmol) was added thereto. The obtained mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was concentrated under reduced pressure. The residue was subjected to column chromatography, which produced the compound 45a (6.4 g, 92 percent). 1H-NMR (400 MHz, CDCIIn a round bottom flask, 1.00 g of 3-amino-1-propanol (CAS: 156-87-6, 75.1 g/mol, 13.3 mmol) was dissolved together with 3.17 g of Boctert-butyl 3-hydroxypropylcarbamate 13a: Boc anhydride(319.2g, 1.46 mol) was added drop wise to 3-aminopropan-1-ol (100.0g, 1.33mol) in methanol ( 1000ml )at 0 °C. Reaction mixture was allowed to stir for 4hr. Reaction mixture was concentrated and diluted with water(1000ml) and ethylacetate (1000ml). Layers were separated.Organic layer was washed with water (250ml), dried oversodium sulfate and concentrated. 202.3g of clear liquid was obtained with 87percent yield. General procedure: To a solution of 2a (or 2b–e, 20 mmol) in a mixture of dioxane (15 mL) and H2O (7 mL), wasadded 5N NaOH (4.8 mL) and a solution of Boc2O (5.0 g, 23 mmol) in dioxane at 0 °C. After stirred atrt overnight, the reaction mixture was concentrated in vacuo. The residue was extracted from 10percentcitric acid with AcOEt, and dried over anhydrous Na2SO4. Evaporation of the solvents gave the pureproduct 3a–e. 3a was obtained as a colorless oil (2.67 g, 83percent).A solution of 3-amine-1-propanol (3.22 mL, 40 mmol) in 50 mL of CH2Cl2 and Et3N (5.6 mL, 40 mmol) was stirred for 30 min. A previously prepared solution of Boc2O (9.6 g, 44 mmol) in 50 mL of CH2Cl2 was slowly added and the mixture was stirred for 14 h at rt. To that solution was added aq. NH4Cl (sat., 30 mL) and the resulting mixturewas extracted with CH2Cl2 (3 × 20 mL). The organic fractions were dried and concentrated to give a residue which was directly used for the next reaction (6.00 g, 86percent). A solution of 1H-imidazole (1.4 g, 20.57 mmol) and triphenylphosphine (5.39 g, 20.57 mmol) in 100 mL of CH2Cl2 was cooled to 0 C and I2 (5.22 g, 20.57 mmol) was added in small portions. A solution of the residue obtained in the previous step (3.0 g, 17.14 mmol) in 20 mL of CH2Cl2 was added. The mixture was stirred for 3 h at rt, poured into water (100 mL) and extracted with CH2Cl2 (50 mL). The organic fractions were washed with aq. HCl 10percent solution (12 mL), extracted with CH2Cl2 (3 × 50 mL), dried and concentrated, and the resulting residue purified by flash chromatography (silica gel, 15percent EtOAc) to give the expected iodide (3.78 g, 78percent), as a slightly yellowoil.A-1-Synthesis of N-BOC-1-amino-2-hydroxypropane is (Compound 1); 4.2 g (29.7 mmol) of di-tert-butyl dicarbonate are added at 0° C. to a solution of 2 ml (27 mmol) of 3-amino-1-propanol in a mixture of 60 ml of dioxane, 30 ml of water and 30 ml of 1N NaOH. The reaction mixture is kept stirred at ambient temperature overnight and then it is acidified to pH 1 using concentrated HCl. After several extractions (3 times 50 ml) with ethyl acetate (AcOEt), the organic phases are dried over MgSO4 and then concentrated on a rotary evaporator to give 4 g of the expected product in the form of a yellow oil. Yield: 85percent. 1H NMR (CDCl3): 1.25 (s, 9H); 2.50 (m, 2H); 3.05 (m, 2H); 3.45 (m, 2H); 5.40 (broad s, 1H).To a stirring solution of 3-amino-1-propanol (7.5 g, 100 mmol) and triethylamine (12.1 g, 120 mmol) in methanol (150 ml) at room temperature was added di-tert-butyl-dicarbonate (24.4 g, 112 mmol). 3-Aminopropan-1-ol (1.0 g, 13.3 mmol) was suspended in 1, 4-dioxane (20 ml). Water(10 ml) and aq. NaOH (1 M, 10 ml) were added, and the mixture was cooled to 0 °C in an ice-water bath. Di-tert-butyl dicarbonate (3.2 g, 14.6 mmol) was added, the cooling bath removed and the mixture stirred at ambient temperature. After 5 h additional di-tert-butyl dicarbonate (1.2 g, 5.3 mmol) was added. After 18 h the reaction mixture was transferred to a separatory funnel with sulfate buffer (40 ml) and extracted with EtOAc (3 × 30 ml). The combined organic phases were washed with saturated aq. NaHCO3 (90 ml), brine (90 ml), dried (Na2SO4) and concentrated in vacuo. Purification by flash column chromatography (40percent EtOAc in n-heptane, v/v) gave the carbamate 3 (1.86 g, 80percent) as a colourless oil.A mixture of 1.0 mmol of the amine salt, 1 mmol (Boc)To a solution of 3-aminopropan-l-ol (10 g, 133.3 mmol) in dichloromethane (500 mL) was added triethylamine (26.9 g, 266.6 mmol) followed by Boc-anhydride (31.82 g, 146.6 mmol) dropwise over fifteen minutes at 0 °C. The reaction mixture was stirred at room temperature for 18 h while monitoring by TLC. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (400 mL), washed with saturated ammonium chloride solution (2 x 250 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo to give tert-.pound.w y/-3-hydroxypropylcarbamate (9.8 g, 42.06percent) as a colorless liquid. 1Η NMR (400 MHz, DMSO-i/6) δ ppm 6.72 (1H, s), 4.36 (1H, t, J=5.2 Hz), 3.41-3.37 (2H, q, J=6.4 Hz), 2.99-2.94 (2H, q, J= 6.4 Hz), 1.55-1.50 (2H, m), 1.38 (9H, s).Compound 1-1 (24.6 g, 328.0 mmol)Was dissolved in a mixed solvent of 2.0 L of 1, 4-dioxane and water (1, 4-dioxane: water = 10: 1)Sodium hydroxide (20.0 g, 328.0 mmol) was added, Was added dropwise in an ice-water bath and di-tert-butyl carbonate (77.0 g, 354.0 mmol)The reaction was stirred at 0 ° C for 2 hours. After completion of the reaction, 2.0 L of saturated sodium bisulfate solution was added to the system, Extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column.Compound 1-2 (50.5 g, 88.0percent) was obtained.To a suspension of 3-bromopropylamine hydrobromide (50 g, 0.228 mol) in DCM (1000mL) were added (Boc)zO (52 g, 0.238 mol) and triethylamine (100 mL, 0.722 mol). Then thereaction was stirred at room temperature for another 3 hours. The solvent was removed in vacuo15 and the residue was washed with petroleum ether (500 mL). The mixture was filtered and thefiltrate was evaporated to give the title compound (54 g, 99.2 percent) as a colorless oil. 1H NMR(300 MHz, CDC13): 8 4.69 (brs, 1H), 3.43 (t, 2H, J = 6.6 Hz), 3.27- 3.23 (m, 2H), 2.10- 2.03 (m, 2H), 1.27 (s, 9H).

Amino-protected bifunctional reagent for the synthesis of phosphatidylethanolamine and ornithine.

Molecular Weight:175.23
XLogP3:0.6
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:5
Exact Mass:175.12084340
Monoisotopic Mass:175.12084340
Topological Polar Surface Area:58.6
Heavy Atom Count:12
Complexity:140
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes