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CAS No. : | 34637-22-4 | MDL No. : | MFCD01321351 |
Formula : | C11H15NO3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WXQCFKYWSKKNKY-UHFFFAOYSA-N |
M.W : | 209.24 | Pubchem ID : | 562256 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.36 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 56.27 |
TPSA : | 58.56 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.79 cm/s |
Log Po/w (iLOGP) : | 2.2 |
Log Po/w (XLOGP3) : | 1.11 |
Log Po/w (WLOGP) : | 1.14 |
Log Po/w (MLOGP) : | 1.25 |
Log Po/w (SILICOS-IT) : | 1.38 |
Consensus Log Po/w : | 1.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.67 |
Solubility : | 4.47 mg/ml ; 0.0214 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.93 |
Solubility : | 2.44 mg/ml ; 0.0117 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -3.19 |
Solubility : | 0.135 mg/ml ; 0.000647 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.06 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.5 μmol | With chloroperoxidase from C. fumago; dihydrogen peroxide In aq. acetate buffer for 24 h; Enzymatic reaction | General procedure: N-Cbz-3-aminopropanol (-OH), N-Cbz-3-aminopropanal (-CHO), and N-Cbz-3-aminopropanoic acid (-COOH) were incu-bated at maximum concentration (38, 17, and 11 mM, respectively)in 5 mL of 100 mM sodium acetate buffer (pH 5.0). The reaction wasallowed to take place under orbital agitation in a MultiThermTMdevice overnight for 19 h. Peroxide was continuously added to thereactor at 3 mM h−1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.1 μmol | With chloroperoxidase from C. fumago In aq. acetate buffer for 7 h; Enzymatic reaction | General procedure: N-Cbz-3-aminopropanol (-OH), N-Cbz-3-aminopropanal (-CHO), and N-Cbz-3-aminopropanoic acid (-COOH) were incu-bated at maximum concentration (38, 17, and 11 mM, respectively)in 5 mL of 100 mM sodium acetate buffer (pH 5.0). The reaction wasallowed to take place under orbital agitation in a MultiThermTMdevice overnight for 19 h. Peroxide was continuously added to thereactor at 3 mM h−1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With pyridinium chlorochromate In dichloromethaneInert atmosphere | PCC (8.75g, 40.6mmol, 1.7 equiv.) and Celite© (9g) were stirred in CH2Cl2 (50mL) for 5min whereupon alcohol 7 (5.0g, 24mmol) dissolved in CH2Cl2 (30mL) was added. After 4h the reaction was diluted with Et2O (100mL) and passed through a short pad of layered silica and Celite©. The remaining solids were suspended in CH2Cl2 (25mL) and precipitated with Et2O (50mL) and this mixture passed through the same pad. This process was repeated a further three times and the filtrate evaporated under reduced pressure to give a yellow oil (5.0g). Column chromatography (40percent EtOAc in PE) gave 8 as a colourless viscous oil (3.0g, 14.5mmol) in 60percent yield. (0012) Rf 0.4 (50percent EtOAc in petrol, PMA); δH 2.75 (2H, t, J 5.7Hz, CH2), 3.49 (2H, apparent q, J 6.0Hz, CH2), 5.09 (2H, s, CH2), 5.15 (1H, br s, HN), 7.30–7.39 (5H, m, Ar), 9.81 (1H, s, CHO); δC 34.6, 44.2, 66.9, 128.2, 128.3, 128.7, 136.5, 165.4, 201.3; vmax 3445, 1704, 1645cm−1. |
20.2% | With triethylamine In dimethyl sulfoxide at 0℃; for 1 h; | To a solution of benzyl (3-hydroxypropyl)carbamate (1.0 g, 4.8 mmol) in DMSO (5 mL) was added Et3N (2.4 g, 24.0 mmol) and sulfur trioxide-pyridine complex (2.3 g, 14.4 mmol) at 0°C and the mixture was stirred at the same temperature for 1 h. The mixture wasthen diluted with DCM (20 mL), which was washed with 10percent Cu504 solution, saturated citric acid solution and brine (30 mL each). The organic layer was dried over Na2504, concentrated and the residue was purified by silica-gel column to give benzyl (3-oxopropyl)carbamate (200 mg, 20.2percent yield) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
11.5 μmol | With chloroperoxidase from C. fumago; dihydrogen peroxide In aq. acetate buffer for 24 h; Enzymatic reaction | General procedure: N-Cbz-3-aminopropanol (-OH), N-Cbz-3-aminopropanal (-CHO), and N-Cbz-3-aminopropanoic acid (-COOH) were incu-bated at maximum concentration (38, 17, and 11 mM, respectively)in 5 mL of 100 mM sodium acetate buffer (pH 5.0). The reaction wasallowed to take place under orbital agitation in a MultiThermTMdevice overnight for 19 h. Peroxide was continuously added to thereactor at 3 mM h−1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16.1 μmol | With chloroperoxidase from C. fumago In aq. acetate buffer for 7 h; Enzymatic reaction | General procedure: N-Cbz-3-aminopropanol (-OH), N-Cbz-3-aminopropanal (-CHO), and N-Cbz-3-aminopropanoic acid (-COOH) were incu-bated at maximum concentration (38, 17, and 11 mM, respectively)in 5 mL of 100 mM sodium acetate buffer (pH 5.0). The reaction wasallowed to take place under orbital agitation in a MultiThermTMdevice overnight for 19 h. Peroxide was continuously added to thereactor at 3 mM h−1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium hydroxide at 0 - 25℃; for 4h; | |
97% | With sodium hydroxide at 0 - 20℃; | |
97% | In dichloromethane | 4.a a a 3-(Benzyloxycarbonylamino)-1-propanol To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylene chloride (40 mL) was slowly added benzyl chloroformate (3.40 g, 20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Additional methylene chloride (50 mL) was added, the solution washed with 10% citric acid (3*50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by filtration through silica gel (1:1 ethyl acetate:hexane) to give the title compound as a white solid (4.05 g, 97%). 1H-NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.17 (bs, 11H), 5.10 (s, 2H), 3.66 (t, 2H, J=5.8 Hz), 3.33 (t, 2H, J=6.1 Hz), 2.63 (bs, 1H), 1.69 (pentet, 2H, J=6.1 Hz). |
97% | In dichloromethane | 1.6 6. 6. 3-(Benzyloxycarbonylamino)-1-propanol To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylene chloride (40 mL) was slowly added benzyl chloroformate (3.4 g, 20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Additional methylene chloride (50 mL) was added, the solution washed with 10% citric acid (3*50 mL) and brine (50 mL), and dried over Na2 SO4. After evaporating the solvent in vacuo, the residue was purified by filtration through silica gel (1:1 ethyl acetate:hexane) to give the title compound as a white solid (4.05 g, 97%). 1 H-NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H), 1.69 (pentet, J=6.1 Hz, 2H). |
97% | In dichloromethane at 0℃; for 3h; | 1.6 6. 3-(Benzyloxycarbonylamino)-1-propanol To a solution of 3-amino-1-propanol (3.75 g, 50 mmol) in methylene chloride (40 mL) was slowly added benzyl chloroformate (3.4 g, 20 mmol) in methylene chloride (10 mL) at 0° C. and the mixture was stirred at 0° C. for 3 h. Additional methylene chloride (50 mL) was added, the solution washed with 10% citric acid (3×50 mL) and brine (50 mL), and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by filtration through silica gel (1:1 ethyl acetate:hexane) to give the title compound as a white solid (4.05 g, 97%). 1H-NMR (300 MHz, CDCl3) δ7.34 (m, 5H), 5.17 (br s, 1H), 5.10 (s, 2H), 3.66 (t, J=5.8 Hz, 2H), 3.33 (t, J=6.1 Hz, 2H), 2.63 (br s, 1H), 1.69 (pentet, J=6.1 Hz, 2H). |
96% | With Sodium hydrogenocarbonate In 1,4-dioxane; lithium hydroxide monohydrate at 0℃; for 1.5h; | 4.1.3. Synthesis of benzyl (3-hydroxypropyl)carbamate (9) 3-amino-1-propanol (1.00 g, 13 mmol) was dissolved in a 1:1mixture of dioxane and water (20 mL). To the resulting suspension,NaHCO3 (1.68 g, 20 mmol) and benzyl chloroformate (2.80 mL, 20mmol) were added at 0 C. The resulting mixture was stirred at thattemperature for 1.5 h. Then, ethyl acetate and water were added, theorganic phase was washed with 10% citric acid (3 × 50 mL) and brine(50 mL), dried over Na2SO4, filtered and the solvent was removed undervacuum. The crude compound was purified by flash chromatography(Hexane:EtOAc 1:1) to obtain compound 9 (2.68 g) in 96% yield.Spectroscopic data were in agreement with those reported in the literature[32]. |
95% | With tetrabutylammonium bromide at 20℃; for 0.333333h; | |
95% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | 17.1 Preparation Example 17: 3-(4-(2,3-dichlorophenyl)piperazin-l-yl)- iV-methylpropan-1-amine dihydrochloride; Step 1 : Benzyl 3-hydroxypropylcarbamate; 3-Aminopropan- l-ol (10 g, 133 mmol) was dissolved in methylene chloride (100 ml) at 0 0C. Triethylamine (9 ml, 65 mmol) and CbzCI (10 ml, 66.8 mmol) were added slowly to the solution at 0 0C and warmed to room temperature. The reaction mixture was stirred for1 hour at room temperature, and then diethyl ether (100 ml) and water(50 ml) were poured into the resulting solution. With diethyl ether normal work-up was taken, dried with magnesium sulfate. After evaporation the volatile material, the residue was purified with normal phase preparative column to produce title compound (15 g, 95%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.27 (brs, IH), 5.09 (s, 2H), 3.71 (t, J = 5.6 Hz, 2H), 3.32 (q, J = 6 Hz, 2H), 1.74- 1.69 (m, 2H).MH+ 210 |
95% | With triethylamine In dichloromethane at 0 - 20℃; for 1h; | 4.1 3-Aminopropan-1-ol (10 g, 133 mmol) was dissolved in methylene chloride (100 ml) at 0° C. Triethylamine (9 ml, 65 mmol) and CbzCl (10 ml, 66.8 mmol) were added slowly to the resulting solution at 0° C. and warmed to room temperature. The reaction mixture thus obtained was stirred for 1 hour at room temperature, and then diethyl ether (100 ml) and water (50 ml) were poured into the resulting solution. With diethyl ether normal work-up was taken, dried with magnesium sulfate. After evaporation the volatile material, the residue was purified with normal phase preparative column to produce the title compound (15 g, 95%) as colorless oil.1H NMR (400 MHz, CDCl3) δ 7.35-7.27 (m, 5H), 5.27 (br.s, 1H), 5.09 (s, 2H), 3.71 (t, J=5.6 Hz, 2H), 3.32 (q, J=6 Hz, 2H), 1.74-1.69 (m, 2H).MH+ 210 |
94% | With anhydrous sodium carbonate In lithium hydroxide monohydrate at 0 - 20℃; for 3h; | |
94% | With lanthanum(III) nitrate at 20℃; for 0.0833333h; | |
94% | With sodium hydroxide In dichloromethane; lithium hydroxide monohydrate at 0 - 20℃; for 10.5h; Inert atmosphere; | |
93% | With tetrapropylammonium L-prolinate at 20℃; for 2h; | |
92% | With anhydrous sodium carbonate In lithium hydroxide monohydrate | |
92% | With 4-dimethylaminopyridine; TEA In 1,4-dioxane; lithium hydroxide monohydrate for 12h; | |
91% | With sulfuric acid; mesoporous silica at 20℃; for 0.166667h; | |
90% | With triethylamine In dichloromethane at 0℃; for 2h; | |
90% | With anhydrous sodium carbonate In lithium hydroxide monohydrate | |
90.5% | With anhydrous sodium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; | 11 Example 11 Preparation of 3-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidopropyl 2-acetoxybenzoate (Ic-1) To a mixture of 3-aminopropan-1-ol (5.0 g, 67 mmol), Na2CO3 (8.8 g, 83 mmol) in THF (40 mL) and H2O (130 mL) at 0° C. was added Cbz-Cl (14.8 g, 87 mmol). The reaction mixture was stirred (RT, 1 h). Water (500 mL) and CH2Cl2 (500 mL) were added, and the layers were separated. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography (PE:EA, 5:1) to afford benzyl 3-hydroxypropylcarbamate as a white solid (12.6 g, 90.5%). |
90% | With sodium hydroxide In lithium hydroxide monohydrate at 0 - 20℃; | |
90.5% | With anhydrous sodium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; | 1 Preparation of benzyl 3-hydroxypropylcarbamate. To a mixture of 3-aminopropan-1-ol (5.0 g, 67 mmol), Na2CO3 (8.8 g, 83 mmol) in tetrahydrofuran (THF, 40 mL) and H20 (130 mL) at 00 C was added benzyl chloroformate (14.8g, 87 mmol). The reaction mixture was stirred overnight at ambient temperature. THF was removed under reduced pressure and the aqueous phase was extracted with DCM (3 x 100 mL). The combined organic extracts were loaded onto a flash silica gel column, and eluted with 3-5 % MeOH in DCM to afford benzyl 3-hydroxypropylcarbamate as a white solid (12.6 g, 90.5%).j00190J 1H NMR (400 MHz, CDC13): 7.35-7.27 (m, 5H), 5.27 (br.s, 1H), 5.09 (s, 2H), 3.71(t, J = 5.6 Hz, 2H), 3.32 (q, J = 6 Hz, 2H), 1.74-1.69 (m, 2H). |
88% | With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one | |
88% | Stage #1: benzyl carbonochloridate; propan-1-ol-3-amine With sodium hydroxide In lithium hydroxide monohydrate at 0 - 20℃; for 1.16667h; Stage #2: In dichloromethane; lithium hydroxide monohydrate at 20℃; for 16h; | 5.1 Benzyl (3-hydroxypropyl)carbamate 7 A stirred solution of 1-aminopropan-3-ol 6 (12.0g, 133mmol) and NaOH (aqueous, 1M) (40mL, 3.0 equiv.) was cooled (0°C) and benzyl chloroformate (22.5g, 133mmol, 1 equiv.) was added drop-wise over 10min. After warming to rt the mixture was stirred for 1h and CH2Cl2 (100mL) was added and stirring continued for 16h. The layers were separated and the aqueous layer extracted with CH2Cl2 (2×50mL) and EtOAc (2×50mL). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure to yield the crude product as a pale yellow solid. The solid was dissolved in warm EtOAc (ca. 50mL) and cooled (-20°C) overnight to give crystals which were filtered and washed with petrol to give 7 as white crystals (22.5g, 117mmol) 88% yield. (0010) Mp. 49-50°C (Lit 50-51°C); Rf 0.13 (50% EtOAc in PE, PMA); δH 1.68-1.74 (2H, m, CH2), 2.59 (1H, br. s, OH), 3.34 (2H, apparent q, J 6.2, CH2), 3.67 (2H, t, J 5.8Hz, CH2), 5.08 (1H, br. s, 1H, NH), 5.11 (2H, s, CH2), 7.30-7.39 (5H, m, Ph); δC 32.6, 37.7, 59.6, 66.9, 128.1, 128.2, 128.6, 136.5, 157.3. |
86% | With Sodium hydrogenocarbonate In lithium hydroxide monohydrate at 20℃; for 1.5h; | |
86% | With triethylamine In dichloromethane; lithium hydroxide monohydrate | 7.1 Production of STR48 (1) In 300 ml of methylene chloride was dissolved 50 g of 3-aminopropanol, and thereto were successively added dropwise 33 g of triethylamine and 57 g of benzyloxycarbonyl chloride at -10° C. to -5° C. At the same temperature, the resulting mixture was stirred for 1 hour and then further stirred at room temperature for 1 hour. Subsequently, the reaction mixture was washed successively with 100 ml of diluted hydrochloric acid and 100 ml of water, and thereafter dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 60 g (yield 86%) of 3-(benzyloxycarbonylamino)propanol having a melting point of 55°-56° C. |
85% | With anhydrous sodium carbonate In lithium hydroxide monohydrate; propan-2-one at 0℃; for 2.5h; | |
81% | With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | |
78% | With sodium hydroxide In toluene at 25℃; for 48h; | |
77% | With Sodium hydrogenocarbonate In tetrahydrofuran; lithium hydroxide monohydrate for 12.5h; | |
72% | With triethylamine In dichloromethane at 0 - 25℃; for 12h; | 4.1 Step 1: Synthesis of compound 5A To a solution of 3-aminopropan-1-ol (30 g, 399.41 mmol) and TEA (66.44 mL, 479.29 mmol) in DCM (400 mL) was added the solution of CbzCl (62.5 mL, 439.35 mmol) in DCM (500 mL). The solution was stirred slowly from 0 °C to 25 °C for 12 hours. The mixture was extracted with DCM (200 mL) and washed by brine (100 mL x 3). The organics was collected, dried with Na2SO4, filtered and concentrated. The mixture was washed by PE (200 mL) and EA (20 mL) to give compound 5A (60 g, yield 72%) as a white solid. |
71% | With sodium hydroxide In lithium hydroxide monohydrate | |
68% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 6h; | Cbz-aminopropanol (S2, n=3): To a cooled solution (0 °C ) of 3-amino-l- propanol (Sl) (2 g, 26.6 mmol, 1.0 equiv.) in DCM (30 mL) were slowly added Cbz-Cl (3.6 mL, 31.9 mmol, 1.2 equiv.) and DIEA (2.9 mL, 31.9 mmol, 1.2 equiv.). The mixture was allowed to warm to room temperature over 6 h before quenching with aqueous 5% AcOH (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL), the combined organic extracts washed with aqueous NaHCO3 (20 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica gel; EA-hexane, 3 : 1, R/ 0.37) gave 3.8 g (68%) of S2 as a white solid. 1H NMR: (300 MHz, CDCl3) δ 7.37-7.31 (m, 5H), 5.11 (s, 2H), 5.08 (br s, IH), 3.44-3.41 (m, 2H), 3.36-3.31 (m, 2H), 2.54 (br s, IH), 1.74-1.66 (m, 2H); 13C NMR: (75 MHz, CDCl3) δ 157.46, 136.59, 128.65, 128.27, 128.19, 66.93, 59.67, 37.93, 32.56; ESI-MS, m/z 2lOλ for [M + H]+ (calcd for CnH16N2O3 210.2). |
61% | In dichloromethane at 0 - 20℃; for 2h; | 3 Synthesis of Compound 3.1 3-aminopropan-1-ol (7.01 g, 93 mmol) was dissolved in DCM (70 mL) and cooled to 0° C. Benzyl chloroformate (5.40 mL, 32 mmol) was dissolved in DCM (20 mL) and added dropwise keeping the internal reaction temp below 10° C. Once complete, the flask was stirred at room temperature for 2 h. A sample removed for NMR analysis (IPC: 20 μL+0.6 mL d6-DMSO) indicated that the benzyl chloroformate reagent had been consumed. The product mixture was then washed with citric acid (10% w/w, 2×90 mL), water (90 mL) and brine (90 mL). The DCM (lower) layer was then evaporated in a rotary evaporator at 40° C. bath temperature to give a slightly cloudy oil/liquid (6.455 g). This oil was dissolved in ethyl acetate (7 mL), warming to 40° C. if necessary to dissolve any precipitated solid, and then allowed to cool to room temperature. Petroleum ether (4 mL) was added slowly to the stirring solution along with a seed crystal, at which point the product started crystallizing slowly. Once the majority of the product had precipitated, the final portion of petroleum ether (17 mL) was then added slowly (total solvent added: ethyl acetate:petroleum ether 1:3, 21 mL). The product was then filtered under vacuum and washed with petroleum ether (5 mL) to give the product as a fine white powder (4.72 g). Expected Yield: 4.7 g (61%). |
61% | In dichloromethane at 0 - 20℃; for 2h; | 3 Synthesis of Compound 3.1 [0093] 3-aminopropan-l-ol (7.01 g, 93 mmol) was dissolved in DCM (70 mL) and cooled to 0°C. Benzyl chloroformate (5.40 mL, 32 mmol) was dissolved in DCM (20 mL) and added dropwise keeping the internal reaction temp below 10°C. Once complete, the flask was stirred at room temperature for 2 h. A sample removed for NMR analysis (IPC: 20 HL + 0.6 mL d6-DMSO) indicated that the benzyl chloroformate reagent had been consumed. The product mixture was then washed with citric acid (10% w/w, 2 x 90 mL), water (90 mL) and brine (90 mL). The DCM (lower) layer was then evaporated in a rotary evaporator at 40 °C bath temperature to give a slightly cloudy oil/liquid (6.455 g). This oil was dissolved in ethyl acetate (7 mL), warming to 40 °C if necessary to dissolve any precipitated solid, and then allowed to cool to room temperature. Petroleum ether (4 mL) was added slowly to the stirring solution along with a seed crystal, at which point the product started crystallizing slowly. Once the majority of the product had precipitated, the final portion of petroleum ether (17 mL) was then added slowly (total solvent added: ethyl acetate:petroleum ether 1:3, 21 mL). The product was then filtered under vacuum and washed with petroleum ether (5 mL) to give the product as a fine white powder (4.72 g). Expected Yield: ~4.7 g (61 %). |
60% | With sodium hydroxide In dichloromethane at 0 - 25℃; for 4h; | |
52% | With potassium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 0 - 20℃; | 1.B.14.2 Step 2: Preparation of benzyl 3-hydroxypropylcarbamate To a stirred solution of 3-aminopropan-1-ol (20 g, 266mmol) and potassium carbonate (73 g, 529 mmol) in a mixture of water (50 mL) and tetrahydrofuran (100 mL) was added benzylchloroformate (68 g, 398 mmol) at 0°C. The mixture was allowed to warm up to room temperature and stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (200 mL) and water (100 mL). The organic layer was collected, washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with 20-50 % ethyl acetate in hexane) to afford benzyl 3- hydroxypropylcarbamate (26.9 g, yield 52%) as a colorless oil. LC/MS (ES+): m/z 232.1 [M+Na+]; tR = 1.697 min; 1HNMR (400MHz, CDCl3): δ 1.67-1.73 (m, 2H), 2.56 (t, J = 5.8 Hz, 1H), 3.33-3.38 (m, 2H), 3.65-3.70 (m, 2H), 5.06 (br, 1H), 5.11 (s, 2H), 7.29-7.36 (m, 5H); chemical formula: C11H15NO3; molecular weight: 209.24 |
With anhydrous sodium carbonate | ||
With sodium hydroxide In lithium hydroxide monohydrate; toluene | ||
In chloroform | ||
With sodium hydroxide In lithium hydroxide monohydrate | ||
With triethylamine In chloroform for 3h; | ||
With TEA In methanol | ||
With triethylamine In dichloromethane at 0℃; | ||
With sodium hydroxide In dichloromethane; lithium hydroxide monohydrate at 20℃; for 3h; Cooling with ice; | ||
With sodium hydroxide at 0 - 20℃; for 24h; | ||
With triethylamine at 0℃; for 12h; | ||
35.26 g | With anhydrous sodium carbonate In tetrahydrofuran; lithium hydroxide monohydrate at 10 - 20℃; | 7 Synthesis of benzyl(3-hydroxypropyl)carbamate (35) Example 7 Synthesis of benzyl(3-hydroxypropyl)carbamate (35) To a solution of sodium carbonate (26.50 g) in water (150.22 g), 3-aminopropan-1-ol (2) (15.22 g) was added at room temperature, and then a solution of benzyl chloroformate (23) (37.53 g) in tetrahydrofuran (60.09 g) was added at not more than 10° C., followed by stirring at room temperature overnight. After the pH was adjusted to 7.0 with concentrated hydrochloric acid at not more than 10° C., tetrahydrofuran was distilled off by vacuum concentration, methyl tert-butyl ether (150.12 g) was added, and the solution was phase separated. Next, ethyl acetate (60.01 g) and sodium sulfate (15.01 g) were added, followed by stirring, filtration, washing with ethyl acetate (30.03 g), and concentration. After crystallization with methyl tert-butyl ether (150.01 g) and heptane (37.51 g), the product was filtrated and washed with a mixed solvent of methyl tert-butyl ether (25.00 g) and heptane (5.00 g) to thereby obtain benzyl(3-hydroxypropyl)carbamate (35) (35.26 g). MS (ESI/APCI Dual) m/z: 210 [(M+H)+], 232 [(M+Na)+]. IR (KBr) cm-1: 3326, 1684, 1534, 1262, 697. Anal. Calcd for C11H15NO3: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.02; H, 7.18; N, 6.64. The HPLC retention time for (35) was about 12.2 min. The HPLC analysis was done under the following conditions: column: YMC Triart C18 (3.0 mmφ*100 mm, 3 μm); column temperature: 40° C.; flow rate: 0.7 mL/min.; detection wavelength: 230 nm (UV); mobile phase: solution A: 0.1% v/v phosphoric acid aqueous solution, solution B: methanol:acetonitrile=3:1 (v/v); and gradient conditions: changed from 90:10 A:B to 10:90 A:B over 20 min., held at 10:90 A:B for 5 min., reverted back to 90:10 A:B over 0.1 min., and held at 90:10 A:B for 9.9 min. |
With triethylamine In dichloromethane at 0 - 20℃; Inert atmosphere; | ||
4.72 g | In dichloromethane at 0 - 20℃; for 2h; | 3 Synthesis of Compound 3.1 3-aminopropan-l-ol (7.01 g, 93 mmol) was dissolved in DCM (70 mL) and cooled to 0°C. Benzyl chloroformate (5.40 mL, 32 mmol) was dissolved in DCM (20 mL) and added dropwise keeping the internal reaction temp below 10°C. Once complete, the flask was stirred at room temperature for 2 h. A sample removed for NMR analysis (IPC: 20 L + 0.6 mL d6-DMSO) indicated that the benzyl chloroformate reagent had been consumed. The product mixture was then washed with citric acid (10% w/w, 2 x 90 mL), water (90 mL) and brine (90 mL). The DCM (lower) layer was then evaporated in a rotary evaporator at 40 °C bath temperature to give a slightly cloudy oil/liquid (6.455 g). This oil was dissolved in ethyl acetate (7 mL), warming to 40 °C if necessary to dissolve any precipitated solid, and then allowed to cool to room temperature. Petroleum ether (4 mL) was added slowly to the stirring solution along with a seed crystal, at which point the product started crystallizing slowly. Once the majority of the product had precipitated, the final portion of petroleum ether (17 mL) was then added slowly (total solvent added: ethyl acetate:petroleum ether 1:3, 21 mL). The product was then filtered under vacuum and washed with petroleum ether (5 mL) to give the product as a fine white powder (4.72 g). Expected Yield: ~4.7 g (61 %). |
With triethylamine In dichloromethane at 0℃; for 12h; | ||
In dichloromethane at 0℃; for 12h; Alkaline conditions; | ||
4.72 g | In dichloromethane at 0 - 20℃; for 2h; | 3 Synthesis of Compound 3.1 3-aminopropan-1-ol (7.01 g, 93 mmol) was dissolved in DCM (70 mL) and cooled to 0°C. Benzyl chloroformate (5.40 mL, 32 mmol) was dissolved in DCM (20 mL) and added dropwise keeping the internal reaction temp below 10°C. Once complete, the flask was stirred at room temperature for 2 h. A sample removed for NMR analysis (IPC: 20 + 0.6 mL d6-DMSO) indicated that the benzyl chloroformate reagent had been consumed. The product mixture was then washed with citric acid (10% w/w, 2 x 90 mL), water (90 mL) and brine (90 mL). The DCM (lower) layer was then evaporated in a rotary evaporator at 40 °C bath temperature to give a slightly cloudy oil/liquid (6.455 g). This oil was dissolved in ethyl acetate (7 mL), warming to 40 °C if necessary to dissolve any precipitated solid, and then allowed to cool to room temperature. Petroleum ether (4 mL) was added slowly to the stirring solution along with a seed crystal, at which point the product started crystallizing slowly. Once the majority of the product had precipitated, the final portion of petroleum ether (17 mL) was then added slowly (total solvent added: ethyl acetate:petroleum ether 1:3, 21 mL). The product was then filtered under vacuum and washed with petroleum ether (5 mL) to give the product as a fine white powder (4.72 g). Expected Yield: ~4.7 g (61 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 4 A molecular sieve; silver silicate-aluminate In dichloromethane; toluene at -45℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With N-iodo-succinimide; trifluorormethanesulfonic acid In diethyl ether; 1,2-dichloro-ethane at -25℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-iodo-succinimide; 4 A molecular sieve In diethyl ether; 1,2-dichloro-ethane at 0℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With mercury(II) cyanide; mercury dibromide In acetonitrile at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With mercury(II) cyanide; mercury dibromide In acetonitrile at 20℃; for 1h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With Dess-Martin periodane In dichloromethane at 20℃; | |
87% | With sodium periodate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium bromide In dichloromethane; water at 20℃; for 12h; | |
86% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -50℃; for 0.666667h; Stage #2: With triethylamine In dichloromethane at -50 - 20℃; for 0.166667h; |
85% | With Pyr*CrO3*HCl In dichloromethane for 1.5h; further oxidizing agents; | |
85% | With tert.-butylnitrite; 2-azatricyclo[3.3.1.13,7]dec-2-yloxidanyl In acetonitrile at 20℃; for 10h; chemoselective reaction; | |
84% | With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -65℃; for 0.25h; | |
84% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -65℃; for 1.08333h; | |
83% | With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60℃; | |
82% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 25℃; | |
81% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 25℃; Inert atmosphere; | |
68% | With pyridinium chlorochromate In dichloromethane at 0℃; for 2h; | |
60% | With pyridinium chlorochromate In dichloromethane Inert atmosphere; | 5.2 Benzyl (3-oxopropyl)carbamate 8 PCC (8.75g, 40.6mmol, 1.7 equiv.) and Celite (9g) were stirred in CH2Cl2 (50mL) for 5min whereupon alcohol 7 (5.0g, 24mmol) dissolved in CH2Cl2 (30mL) was added. After 4h the reaction was diluted with Et2O (100mL) and passed through a short pad of layered silica and Celite. The remaining solids were suspended in CH2Cl2 (25mL) and precipitated with Et2O (50mL) and this mixture passed through the same pad. This process was repeated a further three times and the filtrate evaporated under reduced pressure to give a yellow oil (5.0g). Column chromatography (40% EtOAc in PE) gave 8 as a colourless viscous oil (3.0g, 14.5mmol) in 60% yield. (0012) Rf 0.4 (50% EtOAc in petrol, PMA); δH 2.75 (2H, t, J 5.7Hz, CH2), 3.49 (2H, apparent q, J 6.0Hz, CH2), 5.09 (2H, s, CH2), 5.15 (1H, br s, HN), 7.30-7.39 (5H, m, Ar), 9.81 (1H, s, CHO); δC 34.6, 44.2, 66.9, 128.2, 128.3, 128.7, 136.5, 165.4, 201.3; vmax 3445, 1704, 1645cm-1. |
54% | With pyridinium chlorochromate | |
50% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; | |
50% | With Dess-Martin periodane In dichloromethane at 25℃; for 2h; Inert atmosphere; | 1 Step 1 - Benzyl N-(3-oxopropyl)carbamate To a mixture of benzyl N-(3-hydroxypropyl)carbamate (2.00 g, 9.56 mmol, CAS 17996-13-3) in DCM (20 mL) was added DMP (6.08 g, 14.3 mmol). The reaction mixture was stirred at 25 °C for 2 hours. On completion, the reaction mixture was quenched by saturated Na2S2O3 (10 mL) and saturated NaHCO3 (10 mL) at 25 °C, and stirred for 30 minutes. The mixture was extracted with DCM (3 X 20 mL), the combined organic phase was dried over Na2SO4, filtered and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography to give the title compound (1.00 g, 50% yield) as white solid.1H NMR (400 MHz, CDCl3) d 9.80 (s, 1H), 7.38 - 7.30 (m, 5H), 5.22 (s, 1H), 5.09 (s, 2H), 3.54 - 3.42 (m, 2H), 2.74 (t, J = 5.6 Hz, 2H). |
20.2% | With triethylamine In dimethyl sulfoxide at 0℃; for 1h; | 423.1 To a solution of benzyl (3-hydroxypropyl)carbamate (1.0 g, 4.8 mmol) in DMSO (5 mL) was added Et3N (2.4 g, 24.0 mmol) and sulfur trioxide-pyridine complex (2.3 g, 14.4 mmol) at 0°C and the mixture was stirred at the same temperature for 1 h. The mixture wasthen diluted with DCM (20 mL), which was washed with 10% Cu504 solution, saturated citric acid solution and brine (30 mL each). The organic layer was dried over Na2504, concentrated and the residue was purified by silica-gel column to give benzyl (3-oxopropyl)carbamate (200 mg, 20.2% yield) as a white solid. |
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, -50 deg C, 15 min, 2.) 5 min; Yield given. Multistep reaction; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) -70 deg C; 2.) -70 deg C to 0 deg C; Multistep reaction; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78℃; to RT; | ||
With Swern oxidation | ||
With pyridinium chlorochromate In dichloromethane for 4h; Ambient temperature; Yield given; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1) CH2Cl2, -78 deg C, 2) CH2Cl2, -78 to 0 deg C; Yield given. Multistep reaction; | ||
With chromium(VI) oxide In pyridine for 1.5h; | ||
With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.25h; | ||
With pyridine-SO3 complex; dimethyl sulfoxide; triethylamine In dichloromethane for 1h; cooling; | ||
With Dess-Martin periodane In dichloromethane for 1.5h; | ||
With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; [bis(acetoxy)iodo]benzene In dichloromethane at 20℃; for 18h; | 1 Example 1 (3-Oxo-propyl)-carbamic acid benzyl ester A solution of (3-hydroxy-propyl)-carbamic acid benzyl ester (100 g, 478 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (TEMPO; 7.5 g, 48 mmol) in DCM (1 L) was treated with (diacetoxyiodo)benzene, PhI(OAc)2, (170 g, 528 mmol) in three portions. After 18 h at rt, the mixture was slowly quenched with saturated aqueous (satd. aq.) NaHCO3. The organic layer was separated, washed with satd. aq. NaCl (500 mL), dried (Na2SO4), and concentrated. The residue was purified by FCC to give a solid, which was stirred in 1:1 Et2O/hexanes for 2 h. The solid was collected by filtration. Successive iterations were combined to provide the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 9.81 (s, 1H), 7.36-7.31 (m, 5H), 5.14 (br s, 1H), 5.08 (s, 2H), 3.49 (q, J=6.0, 2H), 2.75 (t, J=5.7, 2H). | |
With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrabutylammomium bromide; sodium hydrogencarbonate; potassium bromide In dichloromethane; water at 0℃; for 0.5h; Inert atmosphere; | ||
With sodium periodate; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium bromide In dichloromethane; water at 20℃; for 12h; | 1 Preparation of 3-(Benzyloxycarbonylamino)propanal (1-5). Benzyl 3-hydroxypropylcarbamate (8.37 g, 40 mmol) and 2,2,6,6-tetramethylpiperidine1-oxyl (TEMPO, 0.19 g, 1.2 mmol) in dichloromethane (80 mL) were added to a solution ofNaTO4 (10.27 g, 48 mmol) and NaBr (0.41 g, 4.0 mmol) in water (100 mL). After stirring for 12hrs at ambient temperature, the organic layer was separated, washed with 10% Na2 S203 anddried over MgSO4. The solvent was removed in vacuo and the residue was recrystallized from Et20/n-hexane providing the aldehyde 1-5 (7.23 g, 87%) as a colorless solid. M.p. 52-54 °C. Rf = 0.36 (n-hexane/ethyl acetate 1:1). FTMS +pESI: calculated for C,,H,4N03 [M+H], 208.0974, found, 208.0967. ‘H NIVIR (300 IVIHz, CDC13): = 2.72 (t, J= 5.7 Hz, 2H, CH2CH2CHO), 3.48 (dt, J6.0, 6.0 Hz, 2H, CH2CH2CHO), 5.08 (s, 2H, OCH2Ph), 5.21 (s, 1H, NI]), 7.27-7.40 (m, 5H, Ph), 9.78 (s, 1H, CHO). ‘3C NIVIR (75 MHz, CDC13): = 34.5, 44.0, 66.7, 128.0, 128.1, 128.5, 136.4, 156.3,201.0 ppm. | |
With Dess-Martin periodane In dichloromethane at 25℃; for 24h; | 4.2 Step 2: Synthesis of compound 5B To a solution of compound 5A (20 g, 95.58 mmol) in DCM (500 mL) was added DMP (81.1 g, 191.16 mmol). The solution was stirred at 25 °C for 24 hours. The mixture was diluted with DCM (300 mL), quenched with a solution of 10% aq. Na2S2O3 and 10% aq. NaHCO3 (300 mL) (v/v : 1/1). The organic phase were collected and concentrated to give compound 5B (56.8 g, cmde) as green oil. 1H NMR (DMSO-d6 400 MHz) 5 9.66 (s, 1H), 7.37-7.31 (m, 6H), 5.06-5.03 (m, 2H), 3.34-3.32 (m, 2H), 2.61 -2.58 (m, 2H). | |
With 1-hydroxy-3H-benz[d][1,2]iodoxole-1,3-dione | ||
With oxalyl dichloride; dimethyl sulfoxide at -78℃; for 1h; | Diethyl 3-amino-1-hydroxypropanephosphonate 11 [19] General procedure: A mixture of 2.02 g of the protected aldehyde 16 (9.76 mmol),1.13 cm3 diethyl phosphite (8.78 mmol), and 0.136 cm3 triethylamine(0.976 mmol) was stirred at room temperaturefor 24 h. After the solution was concentrated in vacuo, theresidue was chromatographed on a silica gel column witha chloroform-methanol mixture (200:1, 100:1 v/v) to givethe phosphonate 17 (2.27 g, 67%) as a white powder. Inthe next step, a solution of 0.750 g of the phosphonate 17(2.17 mmol) in 6 cm3 ethanol was hydrogenated over 30 mgPd-C (10%) at room temperature for 72 h. The suspensionwas filtered through a pad of Celite and washed with ethanol.The solution was concentrated in vacuo to afford pure3-amino-1-hydroxypropanephosphonate 11 (0.460 g, 100%)as a yellowish oil. | |
Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.75h; Inert atmosphere; Stage #2: With triethylamine In dichloromethane at -78 - 25℃; for 0.166667h; Inert atmosphere; | 27.1 Step 1. Benzyl N-(3-oxopropyl)carbamate. To a solution of oxalyl chloride (1.63 ml, 18.6 mmol) in DCM (40 ml) was added DMSO (2.91 ml, 37.3 mmol) dropwise under N2 at -78° C and stirred for 5 min. Benzyl N-(3-hydroxypropyl)carbamate (3.0 g, 14.3 mmol) was added dropwise and stirred at -78° C for 45 min. TEA (10.4 ml, 74.6 mmol) was added and the RM stirred at -78° C for 5 min and 25° C for 5 min. The RM was diluted with water (30 ml) and extracted (DCM, 40 ml x 3). The combined organic layers were washed (brine, 30 ml), dried (Na2SO4) and concentrated in vacuo to give crude benzyl N-(3-oxopropyl)carbamate as pale yellow oil. NMR (400 MHz, DMSO-d6) d 9.63 (s, 1H), 7.38 - 7.29 (m, 5H), 5.10- 5.00 (m, 2H), 3.33 - 3.27 (m, 2H), 2.61 - 2.55 (m, 2H). | |
1.98 g | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine In tetrahydrofuran at 0 - 5℃; for 0.75h; Inert atmosphere; | |
96% | With triethylamine In dichloromethane at 20℃; for 2h; Cooling; | 1 Methanesulfonic acid 3-benzyloxycarbonylamino-propyl esterCbzHNsLyOMsVfn 3[0664] MsCl (2.03 niL, 26.3 mmol) was added slowly to a solution OfEt3N (4.9 niL, 36 mmol) and 4-benzyloxy-butan-l-ol (5.0 g, 24 mmol) in CH2Cl2 (100 mL) at 0 0C (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The mixture was extracted with CH2Cl2 and the organic layer was dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid: yield 6.58 g (96%).[0665] 1H NMR (400 MHz, CDCl3) δ (ppm): 7.43-7.24 (m, 5H), 5.36 (bs, IH), 5.09 (s, 2H), 4.29 (t, J= 5.9 Hz, 2H), 3.39-3.26 (m, 2H), 3.01 (s, 3H), 2.01-1.89 (m, 2H). |
92% | With triethylamine In dichloromethane at 20℃; for 1h; |
77% | With triethylamine In benzene | |
With pyridine at 15 - 20℃; for 1h; | ||
With triethylamine In dichloromethane at 0 - 20℃; for 2h; | ||
With triethylamine In dichloromethane at 20℃; for 1.08333h; | ||
With triethylamine In dichloromethane at 0℃; | ||
With triethylamine In dichloromethane at 0℃; for 3h; | ||
With triethylamine at 0℃; for 4h; | ||
With triethylamine In dichloromethane at 0℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane | |
82% | With pyridine at 0 - 20℃; for 2h; | 1.B.14.3 Step 3: Preparation of 3-(benzyloxycarbonylamino)propyl 4-methylbenzenesulfonate To a stirred solution of benzyl 3-hydroxypropylcarbamate (26.9 g, 128.6 mmol) in pyridine (40 mL) was added 4-toluenesulfonyl chloride(73 g, 384 mmol) at 0°C. The mixture was allowed to warm up to room temperature and stirred at room temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate (120 mL) and water (80 mL). The organic layer was collected, washed with hydrochloric acid (1N, 480 mL) and brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude residue which was purified by silica gel flash column chromatography (eluted with10- 20 % ethyl acetate in hexane) to afford 3-(benzyloxycarbonylamino)propyl 4- methylbenzenesulfonate (38.5 g, yield 82%) as a yellow oil. LC/MS (ES+): m/z 386.2 [M+Na+]; tR = 2.582 min; 1HNMR (400MHz, CDCl3): δ 1.85-1.91 (m, 2H), 2.43 (s, 3H), 3.25 (m, 2H), 4.09 (t, J = 6.0 Hz, 2H), 4.83 (br, 1H), 5.07 (s, 2H), 7.26-7.39 (m, 7H), 7.78 (d, J = 8.4 Hz, 2H); chemical formula: C18H21NO5S; molecular weight: 363.43 |
76% | With triethylamine In tetrahydrofuran at 0℃; for 2h; Inert atmosphere; Schlenk technique; |
72% | In pyridine; chloroform for 10h; | |
With pyridine | ||
With triethylamine In dichloromethane at 0 - 20℃; | Benzyl N-(3-hydroxypropyl)carbamate (ALDRICH, 500 mg, 2.39 mmol) was dissolved in 12 mL of dry DCM under nitrogen atmosphere and cooled at 0°C in an ice bath. Triethylamine (FLUKA, 0.5 mL, 3.58 mmol) and toluene-4-sulfonyl chloride (ALDRICH, 528 mg, 2.77 mmol) were added and the resultant solution was stirred at room temperature overnight. Reaction was diluted with more DCM and washed with water. Organic phase was dried with MgS04, filtered and evaporated. Residue was immediately dissolved in 10 mL of anhydrous acetonitrile and sodium bicarbonate (PANREAC, 507 mg, 6.04 mmol) and terf-butylamine (ALDRICH, 367 mg, 5.02 mmol) were added. The suspension was heated at 50-55°C for 3 hours and more sodium bicarbonate (PANREAC, 507 mg, 6.04 mmol) and terf-butylamine (ALDRICH, 367 mg, 5.02 mmol) were added. Reaction was heated at 50-55°C overnight, then cooled down to room temperature, filtered over Celite and evaporated to dryness. The residue was purified in silica using mixtures of DCM/Methanol. 1H NMR (300 MHz, DMSO) 8 ppm: 8.19 (br s, 2H), 7.30-7.43 (m, 5H), 5.02 (s, 2H), 3.09 (q, 2H, J = 6.1 Hz), 2.85 (m, 2H), 1.70 (m, 2H), 1.23 (s, 9H). [ES+ MS] m/z 265 (MH)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With N-iodo-succinimide; trifluorormethanesulfonic acid; 4 A molecular sieve In diethyl ether; 1,2-dichloro-ethane at 0℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With dmap In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | With dmap In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With N-iodo-succinimide; trimethylsilyl trifluoromethanesulfonate In dichloromethane at 20℃; for 0.05h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With N-iodo-succinimide; trimethylsilyl trifluoromethanesulfonate; 4 A molecular sieve In acetonitrile at -40℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate In tetrahydrofuran at 0℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With 4 A molecular sieve; tin(IV) chloride In 1,2-dichloro-ethane at 20℃; for 16h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With camphor-10-sulfonic acid In 1,1,2,2-tetrachloroethane at 110℃; for 22h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With tetrafluoroboric acid diethyl ether In diethyl ether; dichloromethane at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In methanol; ethyl acetate for 0.5h; | |
82% | In 1,4-dioxane; water for 12h; | |
In ethyl acetate |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: potassium phenyltrifluoborate With dmap; copper diacetate; 4 A molecular sieve In dichloromethane at 20℃; for 0.0833333h; Stage #2: 3-[(N-benzyloxycarbonyl)amino]propanol With oxygen In dichloromethane at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 8h; | |
43% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With iodine In acetonitrile at 20℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0 - 10℃; for 1.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at -10℃; for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With molecular sieve; boron trifluoride diethyl etherate In dichloromethane at 20℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-iodo-succinimide; trifluorormethanesulfonic acid; 4 A molecular sieve In dichloromethane at 0℃; | |
72% | With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane Molecular sieve; | 16 3-[(N-benzyloxycarbonyl)amino]propyl 2-O-benzoyl-4-O-benzyl-α-L-rhamnopyranoside (16) Glycosyl donor 14 (3.79 g, 9.42 mmol), 3-(N-benzyloxycarbonyl)aminopropanol (3.94 g, 18.83 mmol) and 4 powdered molecular sieves (7.73 g) in DCM (150 mL) in the presence of NIS (2.33 g, 10.36 mmol) and TfOH (0.166 mL, 1.88 mmol) were reacted according to the general procedure for NIS glycosylation to give compound 16 as white solid (3.73 g, 72%). Rf=0.26 (Hexane/EtOAc, 2:1, v:v). [α]27D=+11.3 (CHCl3, c=18.0 mg/mL). 1H NMR (300 MHz, CDCl3): δ 1.32 (d, 3H, J5,6=6.0 Hz, H-6), 1.73 (m, 2H, OCH2CH2CH2NHZ), 2.11 (d, 1H, J=4.5 Hz, OH), 3.24 (dd, 2H, J=6.3, 12.6 Hz, OCH2CH2CH2NHZ), 3.36-3.45 (m, 2H, OCH2CH2CH2NHZ, H-4), 3.65-3.75 (m, 2H, OCH′2CH2CH2NHZ, H-5), 4.12 (dd, 1H, J2,3=3.3, J3,4=8.4 Hz, H-3), 4.69 (d, 1H, J=11.1 Hz, PhCH2), 4.76 (s, 1H, H-1), 4.79 (d, 1H, J=11.1 Hz, PhCH′2), 4.85 (broad, 1H, NH), 5.02 (s, 2H, PhCH2OC(O)), 5.25 (dd, 1H, J1,2=1.5, J2,3=3.3 Hz, H-2), 7.18-7.99 (m, 15H, Harom); 13C NMR (75 MHz, CDCl3): δ 18.2 (C-6), 29.6 (OCH2CH2CH2NHZ), 38.6 (OCH2CH2CH2NHZ), 65.6 (OCH2CH2CH2NHZ), 66.6 (C-5), 67.6 (PhCH2OC(O)), 70.5 (C-3), 73.2 (C-2), 75.2 (PhCH2), 81.6 (C-4), 97.5 (C-11), [127.9, 128.1, 128.4, 129.7, 129.9, 130.4, 133.3, 136.6, 138.1 (Carom)], 156.3 (PhCH2OC(O)), 166.3 (PhC(O)O); MALDI-TOF/MS: m/z: found [M+Na]+ 572.9, MALDI-FTICR/MS: m/z: found [M+Na]+ 572.2259, C31H35NO8 calcd for [M+Na]+ 572.2260. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With N-iodo-succinimide; molecular sieve; triethylsilyl trifluoromethyl sulfonate In dichloromethane at 0℃; for 0.166667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 3,4,6-tri-O-benzyl-1,2-O-(1-methoxyethylidene)-α-D-glucopyranose; 3-[(N-benzyloxycarbonyl)amino]propanol In dichloromethane at 0℃; for 2.5h; Stage #2: With sodium methylate In methanol at 20℃; for 4h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triphenylphosphine In tetrahydrofuran; dichloromethane; ethyl acetate | 1.7 7. 7. N-[3-(Benzyloxycarbonylamino)-1-propoxy]phthalimide To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2*100 mL) and brine (100 mL), and dried over Na2 SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (6.85 g, 100%). 1 H-NMR (300MHz, CDCl3) δ7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H). |
100% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 20℃; | 1.7 7. N-[3-(Benzyloxycarbonylamino)-1-propoxy]phthalimide To a solution of 3-(benzyloxycarbonylamino)-1-propanol (4.0 g, 19 mmol), as prepared in the preceding step, N-hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g, 20 mmol) in tetrahydrofuran (80 mL) was added diethyl azodicaroxylate (3.5 g, 20 mmol). The reaction mixture was stirred at room temperature overnight. Ethyl acetate (200 mL) was added, the solution washed with saturated NaHCO3 (2?100 mL) and brine (100 mL), and dried over Na2SO4. After evaporating the solvent, the residue was purified by flash column chromatography (methylene chloride to 4% ethyl acetate in methylene chloride) to give the title compound as a white solid (6.85 g, 100%). 1H-NMR (300 MHz, CDCl3) ?7.83 (m, 2H), 7.77 (m, 2H), 7.36 (m, 5H), 5.67 (br s, 1H), 5.12 (s, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.51 (q, J=6.1 Hz, 2H), 1.99 (pentet, J=6.0 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In toluene | A.2.b Preparation of (3-benzyloxycarbonylamino)-propyl 6-O-benzyl-2deoxy-2-tetrachlorophthalimido-β-D-glucopyranoside 14 (b) 3-Benzyloxycarbonylamino-1-propanol (8.61 g, 41.3 mmol) and mercuric cyanide (10.45 g, 41.3 mmol) are added to a solution of crude 10 (13.15 g) in 165 ml of dry toluene. The suspension is stirred for 18 h, filtered through a cotton plug, and solvent is evaporated under reduced pressure. Chromatography of the residue on silica gel (1.3 kg) with hexane/ethyl acetate (2:1) as eluent gives (3-benzyloxycarbonylamino)-propyl 3,4,6-tri-O-acetyl-2-deoxy-2-tetrachlorophthalimido-β-D-glucopyranoside 11. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With phosphorus pentachloride; acetic acid In tetrahydrofuran; methanol; conc. H2 SO4; ethyl acetate; benzene | 4 Preparation of 3-(3-Aminopropoxy)isocoumarin Hydrochloride EXAMPLE 4 Preparation of 3-(3-Aminopropoxy)isocoumarin Hydrochloride Homophthalic acid (18 g, 0.1 mole) and 3-(benzyloxycarbonylamino)-1-propanol (41 g, 0.2 mole) were heated in 150 ml of benzene at 120°-130° C. for 2 hrs in the presence of a few drops of conc. H2 SO4. Benzene was evaporated, and 200 ml of ethylacetate was added. The organic solution was washed with 4% NaHCO3 twice (150 ml*2). The aqueous layer which contained the monoester salt was acidified with 5N HCl and extracted with ethylacetate. 33 g of 3-(benzyloxycarbonylamino)propyl 2-carboxyphenylacetate (yield, 89%) was obtained after the solvent was evaporated. Hydrogenation of this monoester (1.86 g, 5 mmole) was performed in methanol containing 0.3 ml of acetic acid and 10% palladium on carbon to give 1 g of 3-aminopropyl 2-carboxphenylacetate.HAc (yield, 67%). This compound was identified by its NMR spectrum and TLC (Butanol:acetic acid:pyridine:water=4:1:1:2). 1 g of 3-aminopropyl 2-carboxyphenylacetate.HAc (3 mmole) was heated with 1.6 g of PCl5 (7.5 mmole) in 50 ml of anhydrous THF at 70°-80° C. for 2 hrs, a white precipitate formed. This white solid was purified by column chromatography (methylene chloride:methanol=5:1) and crystallized from MeOH-ether to give 0.2 g of 3-(3-aminopropoxy)isocoumarin.HCl (yield, 26%), m.p. 173°-174° C.; mass spectrum, m/e=220 (M+ -Cl). Anal. Calc. for C12 H14 N1 O3 Cl1: C, 56.37; H, 5.52; N, 5.48; Cl, 13.87. Found: C, 56.15; H, 5.49; N, 5.44; Cl 13.95. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane; water | 7.2 Production of STR48 (2) In 200 ml of methylene chloride was dissolved 21 g of the 3-(benzyloxycarbonylamino)propanol, and 11 g of triethylamine was added thereto, after which 8.6 g of acetyl chloride was added thereto dropwise at -10° C. to -5° C. The resulting mixture was subjected to reaction at the same temperature for 1 hour. Subsequently, at room temperature, the reaction mixture was washed successively with 50 ml of diluted hydrochloric acid, 50 ml of a saturated aqueous sodium hydrogencarbonate solution and 50 ml of water, and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure to obtain 28 g of oily 1-acetoxy-3-(benzyloxycarbonylamino)propane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With triethylamine In dichloromethane; water; ethyl acetate | 15.2 (2) (2) Synthesis of 3-benzyloxycarbonylamino-1-propanol t-butyldimethylsilyl ether 3-Benzyloxycarbonylamino-1-propanol (8.1 g) was dissolved in methylene chloride (200 ml), and to the resulting solution were added triethylamine (4.1 g) and t-butyldimethylsilyl chloride (7.1 g). The resultant mixture was stirred at room temperature for 1 day. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the titled compound (10.1 g; 82%). NMR(CDCl3): δ=0.12(6H,s), 0.96(9H,s), 1.79(2H,m), 3.39(2H,q), 3.78(2H,t), 5.16(2H,s), 7.38-7.42(5H,m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With sodium bicarbonate In 1,4-dioxane; water; ethyl acetate | 15.1 (1) (1) Synthesis of 3-benzyloxycarbonylamino-1-propanol 3-Amino-l-propanol (5.0 g) was dissolved in a mixture of dioxane (50 ml) and water (50 ml), and to the resulting solution were added under ice-cooling sodium hydrogen carbonate (4.3 mg) and benzyloxychloride (15.6 ml). The resultant mixture was stirred at that temperature for 1.5 hours. Ethyl acetate and water were added to the reaction solution obtained. The organic layer so separated was dried over magnesium sulfate. The solvent was evaporated off from the solution, and the residue was purified by a silica gel chromatography, thus affording the title compound (8.5 g; 62%). NMR(CDCl3): δ=1.70(2H,m), 2.55(1H,t), 3.36(2H,q), 3.68(2H,q), 5.11(2H,s), 7.32-7.37(5H,m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 4-tertbutyloxycarbonylaminomethyl-biphenyl-2-ol; 3-[(N-benzyloxycarbonyl)amino]propanol With triphenylphosphine In tetrahydrofuran at 50℃; for 0.5h; Stage #2: With di-isopropyl azodicarboxylate In tetrahydrofuran; toluene at 50℃; for 3h; | 101 A solution of tert-butyl N-(2-hydroxybiphenyl-4-yl-methyl)carbamate (0.30 g), benzyl N-(3-hydroxypropyl)-carbamate (0.273 g) and triphenylphosphine (0.342 g) in tetrahydrofuran (4.0 mL) was stirred at 50° C. for 30 minutes. Then diisopropyl azodicarboxylate (40% toluene solution, 0.701 mL) was added dropwise, and the resulting mixture was stirred at50° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethylacetate=3/1) to give the title compound (0.750 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | In dichloromethane at 20℃; for 0.0833333h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With triphenylphosphine; diethylazodicarboxylate In tetrahydrofuran at 0 - 20℃; | 61 Benzyl [3-(3-formylphenoxy)propyl]carbamate Reference Example 61 Benzyl [3-(3-formylphenoxy)propyl]carbamate Diethyl azodicarboxylate (2.5 mL, 16.0 mmol) was added to a solution of 3-hydroxybenzaldehyde (2.0 g, 16.0 mmol), benzyl (3-hydroxypropyl)carbamate (3.4 g, 16.0 mmol) and triphenylphosphine (1.2 g, 16.0 mmol) in THF (40 mL) with ice-cooling, and stirred at room temperature overnight. The solvent was filtered out under reduced pressure. Then, the residue was diluted with ethyl acetate, washed with water and then with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluding solution: ethyl acetate/hexane = 3/7) to give the title compound (3.7 g, 73%) as an oily substance. 1H-NMR (300MHz, CDCl3) δ: 1.95-2.15 (2H, m), 3.43 (2H, td, J = 6.3, 6.0 Hz), 4.09 (2H, t, J = 6.0 Hz), 4.95 (1H, br s), 5.11 (2H, s), 7.17 (1H, m), 7.28-7.40 (6H, m), 7.41-7.49 (2H, m), 9.97 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 5h; | N-Cbz-O-trityl-propanolamine (S3, n=3): To a cooled solution (0 °C ) of S2 (2 g, 9.6 mmol, 1.0 equiv.) in DCM (30 mL) were slowly added Trt-Cl (3.2 g, 11.5 mmol, 1.2 equiv.) and DIEA (2.0 mL, 11.5 mmol, 1.2 equiv.). The mixture was allowed to warm to room temperature over 5 h before being quenched with aqueous 5% AcOH (20 mL). The aqueous phase was extracted with DCM (2 x 20 mL), the combined organic extracts washed with aqueous NaHCO3 (20 mL) and brine (30 mL), dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (silica gel; EA-hexane, 1 : 7, R/ 0.29) gave 3.2 g (75%) of S3 as a white solid. 1H NMR: (300 MHz, CDCl3) δ 7.43-7.21 (m, 20H), 5.07 (s, 2H), 3.33-3.30 (m, 2H), 3.20-3.16 (m, 2H), 1.81-1.77 (m, 2H); 13C NMR: (75 MHz, CDCl3) δ 156.50, 144.21, 128.76, 128.64, 128.16, 128.11, 128.09, 128.03, 127.41, 127.20, 66.63, 62.02, 39.42, 29.92; ESI-MS, m/z 452.1 for [M + H]+ (calcd for C30H30N2O3 452.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With toluene-4-sulfonic acid In dichloromethane; water at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With amberlyst-15 In dichloromethane at 20℃; for 2h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine In dichloromethane at 20℃; for 4h; | 11 To a solution of 2-acetoxybenzoic acid (2.0 g, 11.1 mmol) and triethylamine (1.8 mL, 11.1 mmol) in CH2Cl2 (40 mL) at 0° C. was slowly added ClCO2Et (1.1 mL, 167 mmol). The reaction mixture was stirred (0° C., 2 h) and filtered. The filtrate was added to a solution of benzyl 3-hydroxypropylcarbamate (2.1 g, 10.0 mmol) and triethylamine (15 mL) in CH2Cl2 (40 mL). The reaction mixture was stirred (RT, 4 h) and quenched with H2O (50 mL). The organic layer was washed with 1M HCl, saturated Na2CO3 (30 mL) and H2O (50 mL). The organic solution was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica chromatography, (PE-EtOAc, 5:1) to afford 3-(benzyloxycarbonylamino)propyl 2-acetoxybenzoate (2.0 g, 54%) as a colorless oil. Mass calculated for C20H21NO64=371.38; found: [M+H]+=372.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; Inert atmosphere; | 17.2 Step 2: Benzyl 3-(tert-butyIdimethylsilyloxy)propylcarbamate; Benzyl 3-hydroxypropylcarbamate (15 g, 72 mmol) was treated with imidazole (10 g, 146.9 mmol) and TBSCl (12 g, 79.6 mmol) in DMF ( 10 ml) at 0 0C. After warming up the reaction mixture to room temperature, it was stirred for 30 minutes. The resulting solution was quenched with water (50 ml), and then extracted with diethyl ether (50 ml x2) twice. After evaporation of volatile material under reduced pressure, the residue was purified with silica gel column chromatography (EtOAc:Hx = 1 : 10) to afford title compound (23 g, 98%) as colorless oil. MH+ 324 |
98% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol; tert-butyldimethylsilyl chloride With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: With water In N,N-dimethyl-formamide at 20℃; | 4.2 Benzyl 3-hydroxypropylcarbamate obtained in step 1 (15 g, 72 mmol) was treated with imidazole (10 g, 146.9 mmol) and TBSCl (12 g, 79.6 mmol) in DMF (10 ml) at 0° C. After warming up the resulting reaction mixture to room temperature, it was stirred for 30 minutes. The resulting solution was quenched with water (50 ml), and then extracted with diethyl ether twice (50 ml×2). After evaporation of volatile material under reduced pressure, the residue was purified with silica gel column chromatography (EtOAc:Hx=1:10) to afford the title compound (23 g, 98%) as colorless oil.MH+ 324 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol; di-tert-butyl diisopropylphosphoramide With 1H-tetrazole In tetrahydrofuran; acetonitrile at 25℃; for 16h; Stage #2: With dihydrogen peroxide In tetrahydrofuran; water; acetonitrile at 0 - 25℃; for 6.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -10 - 20℃; Inert atmosphere; | |
43% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -10 - 20℃; Inert atmosphere; | 3-(Benzyloxycarbonyl)aminopropyl 2,3,4,6-tetra-O-acetyl-α- D -mannopyranoside 11 3-(Benzyloxycarbonyl)aminopropyl 2,3,4,6-tetra-O-acetyl-α- D -mannopyranoside 11 Trichloroacedimidate donor 10 (31.00 g, 61 mmol) and 3(benzyloxycarbonyl)aminopropanol (16.00 g, 73 mmol) were dissolved in dry dichloromethane (150 ml), under nitrogen atmosphere, then the mixture was cooled to -10° C. and TMSOTf (105 μl, 0.6 mmol) was slowly added. The mixture was stirred overnight allowing it to warm to room temperature, when TLC showed the reaction was complete (1:1 cyclohexane-EtOAc). The mixture was neutralized with triethylamine and concentrated. Chromatography of the crude mixture (9:1→1:1 toluene-EtOAc) gave 14.50 g of foamy product 11 (43%). [α]D24=+17.6 (c 0.55, CHCl3). 1H NMR (CDCl3, 400 MHz): δ=7.39-7.27 (m, 5H, Ph), 5.32 (dd, J2,3=3.5, J3,4=9.9 Hz, 1H, H-3), 5.30-5.20 (m, 2H, H-2, 4), 5.11 (br t, J=5.5 Hz, 1H, NH), 5.09 (s, 2H, CH2Cbz), 4.76 (s, 1H, H-1), 4.28 (dd, J5,6a=5.3, J6a,6b=12.2 Hz, 1H, H-6a), 4.11 (dd, J5,6b=2.7 Hz, 1H, H-6b), 4.00 (m, 1H, H-5), 3.80 (m, 1H, H-1'a), 3.47 (m, 1H, H-1'b), 3.26 (m, 2H, H-3'), 2.5, 2.08, 2.04, 1.99 (4 s, 12H, 4*CH3CO), 1.80 (m, 2H, H-2'). 13C NMR (CDCl3, 100 MHz): δ=170.65, 169.83, 169.76, 169.69 (4*CO), 156.42 (CONH), 136.51-127.71 (Ar), 97.60 (C-1), 69.46 (C-2), 69.01 (C-3), 68.46 (C-5), 66.55 (CH2Cbz), 66.09 (C-4), 65.86 (C-1'), 62.52 (C-6), 38.13 (C-3'), 29.55 (C-2'), 20.97, 20.81, 20.72, 20.65 (CH3CO). ESI HR-MS (C25H33NO12): m/z=([M+H]+ found 540.2088. calcd 540.2081). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at -20℃; for 0.5h; Molecular sieve; Inert atmosphere; | 3.3. General procedure for NIS-TfOH-catalyzed glycosylation General procedure: A solution of an ethyl thioglycoside (0.1 mmol) and a glycosyl acceptor (0.09 mmol) in freshly distilled anhydrous CH2Cl2 (1 mL) containing 4 Å MS (130 mg) was stirred at rt under argon for 1 h and then cooled to -20 °C. NIS (0.2 mmol) and TfOH (0.04 mmol) were successively added and the resulting mixture was stirred for an additional 30 min at -20 °C. The reaction was quenched with a drop of pyridine, allowed to attain rt, diluted with CH2Cl2, and filtered through Celite. The filtrate was washed with 1 M Na2S2O3, then with water, dried with Na2SO4, and concentrated. The residue was purified by gel chromatography either on the Bio-Beads SX-1 (hexa- and nonasaccharides) or on the Bio-Beads SX-3 (lower oligosaccharides) column in toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at -20℃; for 0.5h; Molecular sieve; Inert atmosphere; | 3.3. General procedure for NIS-TfOH-catalyzed glycosylation General procedure: A solution of an ethyl thioglycoside (0.1 mmol) and a glycosyl acceptor (0.09 mmol) in freshly distilled anhydrous CH2Cl2 (1 mL) containing 4 Å MS (130 mg) was stirred at rt under argon for 1 h and then cooled to -20 °C. NIS (0.2 mmol) and TfOH (0.04 mmol) were successively added and the resulting mixture was stirred for an additional 30 min at -20 °C. The reaction was quenched with a drop of pyridine, allowed to attain rt, diluted with CH2Cl2, and filtered through Celite. The filtrate was washed with 1 M Na2S2O3, then with water, dried with Na2SO4, and concentrated. The residue was purified by gel chromatography either on the Bio-Beads SX-1 (hexa- and nonasaccharides) or on the Bio-Beads SX-3 (lower oligosaccharides) column in toluene. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With silver carbonate In dichloromethane at 20℃; for 16h; Molecular sieve; Darkness; | |
With silver trifluoromethanesulfonate In dichloromethane at 20℃; Molecular sieve; Cooling with ice; Inert atmosphere; | 3.A Synthesis of Neu5AcaProNHCbz (SI). Peracetylated Neu5Ac methyl ester (3, 6.0 g, 11.3 mmol) was dissolved in anhydrous dichloromethane (20 mL) in a round bottom flask (200 mL) and the reaction was placed in an ice-water bath. Acetyl chloride (80 mL) was added followed by the addition of anhydrous methanol (2 mL) under Argon and the reaction mixture was stirred for 20 minutes. The reaction flask was then sealed and the mixture was stirred at room temperature for 2 days. The reaction progress was monitored by TLC analysis (hexane:EtOAc = 1 :4, by volume). Upon completion, the reaction mixture was concentrated, co-evaporated with toluene for three times, and dried under vacuum. Without further purification of the crude product, molecular sieves 4 A (6.0 g), anhydrous dichloromethane (50 mL), and benzyl A-(3-hydroxypropyl) carbamate (4.78 g, 22.8 mmol) were added under argon. The mixture was placed in an ice-water bath and silver triflate (2.90 g, 11.3 mmol) was added. The reaction flask was covered with an aluminum foil and the mixture was stirred at room temperature for overnight. The reaction progress was monitored by TLC analysis (hexane:EtOAc = 1 :4, by volume). Upon completion, the reaction mixture was filtered over Celite and washed with DCM. The filtrate was concentrated for purification by silica gel column chromatography (hexane:EtOAc = 1 : 1 to 1 :4, by volume). Fractions were collected, concentrated, and dried under vacuum. (Note, when silver carbonate was used as a promoter instead of silver triflate, the glycosylation yield was much lower and glycal was formed as a major byproduct.) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With dmap; triethylamine In dichloromethane at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With iodoform; tris(2,2'-bipyridyl)ruthenium(II) chloride hexahydrate; N,N-dimethyl-formamide; sodium iodide at 25 - 30℃; Inert atmosphere; visible-light irradiation; | |
79% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane at 22℃; for 5h; Inert atmosphere; | |
With 1H-imidazole; iodine; triphenylphosphine In dichloromethane for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | Synthetic Example 4. Synthesis of Th56 (ll-E):3'-(Benzyloxycarbonylamino)propyl (1 ,3-dimethyl-2,6-dioxo-2,3-dihydro-1 H-purin- 7(6H)-yl)acetate was synthesized as follows:; The carboxyl function of theophylline-7-acetic acid (119 mg, 0.5 mmol) was activated by the addition of N-hydroxysuccinimide (57.5 mg, 0.5 mM) and EEDQ (127 mg, 0.5 mmol) in 4 ml dry DMF for 1 hour at room temperature. To this solution was added dropwise 107 mg (0.5 mmol) benzyl N-(3-hydroxypropyl) carbamate and the reaction mixture was stirred for 24 hours. The solvent was removed under vacuum; the product was dissolved in chloroform and purified by flash chromatography on Silicagel-60A with ethyl acetate/petroleum ether used as eluents. The fractions from the third spot (Rf=0.32, ethyl acetate) were pooled, concentrated and washed with 1 N sodium bicarbonate. After evaporation of the organic solvent, 54 mg (25%) from Th56 were isolated. The observed mass by LC/MS was 430 for [M+H]+, corresponding to the expected mass of 429. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol With pyridine; 2-Chloro-4H-1,3,2-benzodioxaphosphorin-4-one In acetonitrile at 20℃; for 0.75h; Inert atmosphere; Stage #2: triethylamine In methanol; dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With silver trifluoromethanesulfonate In dichloromethane at -20℃; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.5h; Molecular sieve; | 3-(Benzyloxycarbonyl)aminopropyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-galactopyranoside 40. To a solution of imidate 39 (2.75 g, 4.7 mmol) and benzyl N-(3-hydroxypropyl)carbamate (1.46 g, 7 mmol) in CH2Cl2 (100 ml) containing pre activated molecular sieves (2.5 g), TMSOTf (167 l, 0.93 mmol) was added at 0°C. The mixture was stirred at that temperature for 30 min, when TLC (3:2 toluene-EtOAc) showed the reaction was complete. Triethylamine (170 µl) was added and the mixture was filtered through celite. The filtrate was concentrated and chromatography of the residue (cyclohexane-EtOAc) gave 2.7 g of product 40 (91%). [α]D23= -29.9 (c 2.00, CHCl3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 2h; | 16 4.1.16 3-(Benzyloxycarbonyl)aminopropyl 2,3,4-tri-O-acetyl-β-d-fucopyranoside 29 _ To a solution of fucose peracetate 28 (24 g, 72 mmol) and benzyl N-(3-hydroxypropyl)carbamate (22.5 g, 108 mmol) in CH2Cl2 (100 ml), BF3·Et2O (13.3 ml, 108 mmol) was added at 0 °C. The mixture was stirred at room temperature for 2 h, when TLC (3:2 cyclohexane/EtOAc) showed that the reaction was complete. After neutralization with triethylamine (13.3 ml), the crude mixture was concentrated and purified on silica gel (6:1 → 1:1 cyclohexane/EtOAc) to give 26.1 g of 29 (72%). = -31.9 (c 3.90, CHCl3). 1H NMR (CD3OD, 400 MHz): δ = 7.40-7.29 (m, 5H, Ph), 5.22 (d, 1H, J3,4 = J4,5 = 3.5 Hz, H-4), 5.18 (dd, 1H, J1,2 = 7.9, J2,3 = 10.5 Hz, H-2), 5.13-5.08 (m, 3H, NH, CH2Ph), 5.00, (dd, 1H, H-3), 4.42 (d, 1H, J1,2 = 7.9 Hz, H-1), 3.98-3.92 (m, 1H, H-1'a), 3.82-3.73 (m, 1H, H-5), 3.59-3.54 (m, 1H, H-1'b), 3.38-3.20 (m, 2H, H-3'), 2.16, 2.02, 1.98 (3 s, 3H each, 3 CH3), 1.86-1.74 (m, 2H, H-2'), 1.22 (d, 3H, J5,6 = 6.7 Hz, H-6). 13C NMR (CD3OD, 100 MHz): δ = 170.69, 170.22, 169.69, 156.58 (4 CO), 136.66, 128.47, 128.03 (Ph), 100.97 (C-1), 71.27 (C-3), 70.18 (C-4), 69.20 (C-2), 68.87 (C-5), 67.46 (C-1'), 66.52 (CH2), 38.29 (C-3'), 29.44 (C-2'), 20.67, 20.62 (3 CH3), 16.00 (C-6). ESI HR-MS (C23H31NO10): m/z = found ([M+Na]+ 504.1874; calcd 504.1846). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With pyridine; thionyl chloride In acetonitrile at -10℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol With 1H-imidazole; iodine; triphenylphosphine In acetonitrile at 0 - 20℃; Inert atmosphere; Stage #2: With tris[2-phenylpyridinato-C2,N]iridium(III); N-ethyl-N,N-diisopropylamine In methanol; acetonitrile for 0.3h; Inert atmosphere; Irradiation; Flow reactor; | |
80% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol With carbon tetrabromide In N,N-dimethyl-formamide UV-irradiation; Stage #2: With {Au(dppm)}2Cl2; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide; isopropyl alcohol |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane at 20℃; for 6h; | 3-(Benzyloxycarbonylamino)propyl 2,3-di-O-benzyl-β-D-arabinofuranoside (5) Compound 10 (8 g, 19.32 mmol) was dissolved in dry dichloromethane (30 ml) and HCI gas was bubbled through the solution for 30 min. The reaction mixture was further stirred for an additional 10 min. After completion of reaction, the reaction mixture was concentrated to yield 5-O-acetyl-2,3-di-O-benzyl-α-D-arabinofuranosylchloride 11 as a light yellow syrup. The concentrated crude product 11 was dissolved in dry CH2CI2 (50 mL) without any purification and benzyl N-(3-hydroxypropyl)carbamate (6.1 g, 28.98 mmol) was added to it. After 6 h of stirring, the reaction mixture was diluted with CH2C12 (80 mL) and washed with water (30 mL) and then saturated NaHCO3 solution (250 mL) and water (50 mL). The organic layers were collected and dried over anhydrous Na2SO4, then filtered and concentrated as light yellow syrup. De-acetylation was done by adding few drops of 0.1 M NaOMe to a solution of crude product in methanol (90 mL). The reaction was stirred for 1 h. The reaction mixture was concentrated and the light yellow oil obtained was purified by chromatography (2:1 hexane: EtOAc) to give 5 (4.5 g, 42%) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 77% 2: 11% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0℃; for 0.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With t-butyl bromide In acetonitrile for 1.5h; Reflux; chemoselective reaction; | Representative procedure for the deprotection of the PMB ethers by t-BuBr General procedure: To asolution of the PMB ether (1 mmol) in acetonitrile (10 mL), t-BuBr (1.1 equiv)was added and stirred at reflux. After completion of the reaction (monitored byTLC), it was concentrated under reduced pressure and the resulting crude wasdissolved in ethyl acetate (50 mL) and washed with saturated sodiumhydrogenocarbonate (25 mL). The aqueous layer was extracted with ethylacetate (2 5 mL) and the combine organic layer was washed with brinesolution, dried (MgSO4), concentrated under reduced pressure and the residuewas purified by column chromatography (silica gel, EtOAc, cyclohexane) toafford the corresponding alcohol. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With (carbonyl)(chloro)(hydrido)tris(triphenylphosphine)ruthenium(II); diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate In toluene at 160℃; for 16h; Inert atmosphere; Sealed tube; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol; phenyl N-(2,2,2-trichloroethoxy)carbonyl-2-amino-4,6-O-benzylidene-2-deoxy-1-thio-β-D-glucopyranoside With N-iodo-succinimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol; phenyl 3-O-benzoyl-4-O-benzyl-2,6-dideoxy-2-trichloroacetamido-1-thio-β-L-glucopyranoside With N-iodo-succinimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; Inert atmosphere; | 2 General procedure: Glycosylation reactions were performed using standard methods by combining a donor saccharide and receptorsaccharide. Briefly, donor and acceptor compounds were dissolved in anhydrous DCM under dry nitrogen in the presenceof heat-activated 4A molecular sieves unless indicated otherwise. The solution was cooled and held at 0 °C for ~30mins, followed by the slow addition of TMSOTf (1 eq). Reactions were checked by TLC (silica gel) using hexanes/EtOAcand quenched with TEA or Hünig’s base (1.05 eq). The mixtures were filtered and concentrated to syrups and purifiedby flash column chromatography using hexanes/EtOAc gradients unless indicated Trichloroacetonitrile (1.75 mL, 17.4 mmol) and DBU (0.05 mL, 0.35 mmol) were added to a solution of 3 (1.0g 1.74 mmol) in dry DCM (1 mL). After ~ 75 min, the solution was directly purified by silica gel flash column chromatographyusing EtOAc in hexanes (0 to 30%), affording 2-O-acetyl-6-O-t-butyldiphenylsilyl-3-O,4-O [dimethoxybutan-2’,3’-diyl]-α-D-mannose trichloroacetimidate 4 as a white foam (0.98 g, 78.2 %). Donor 4 (0.98 g, 1.36 mmol) and acceptor 3-N-benzyloxycarbonylaminopropanol (0.284 g, 1.36 mmol) were converted according to the general glycosylation procedureof Example 1, affording N-benzyloxycarbonylaminopropyl 2-O-acetyl-6-O-t-butyldiphenylsilyl-3-O,4-O [dimethoxybutan-2’,3’-diyl]-α-D-mannoside 5 as a white foam (0.66 g, 64 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide In acetonitrile at 50℃; for 1.25h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | With iron(III) chloride; N-iodo-succinimide In dichloromethane at -5 - 20℃; for 0.666667h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With iron(III) chloride; N-iodo-succinimide In dichloromethane at -5 - 20℃; for 0.666667h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With boron trifluoride diethyl etherate In dichloromethane at 20℃; for 0.166667h; | 3.2. 3-Benzyloxycarbonylaminopropyl 6-O-acetyl-2,3,4-tri-Obenzoyl-b-D-glucopyranoside (3) BF3Et2O (0.4 mL, 3.15 mmol, 1.92 equiv.) was added to a stirredmixture of trichloroacetimidate 1 (1.1 g, 1.64 mmol) and 3-benzyloxycarbonylaminopropanol 2 (754 mg, 3.61 mmol, 2.2equiv.) in CH2Cl2 (10 mL) at rt. The mixture was stirred at rt for10 min, diluted with CH2Cl2, washed with satd aq NaHCO3 and theorganic layer was separated, dried and concentrated. Columnchromatography of the residue (6:1 toluene e EtOAc) providedglucoside 3 (950 mg, 74%): amorphous solid, [a]D e4 (c 1, CHCl3). 1HNMR (CDCl3, 600 MHz): d 1.70e1.85 (m, 2 H, NHCH2CH2CH2O), 2.03(s, 3 , ), 3.15e3.30 (m, 2 H, NHCH2CH2CH2O), 3.52e3.59 (m, 1 ,NHCH2CH2CaHbO), 3.94e4.03 (m, 2 , -5, NHCH2CH2CaHbO),4.31 (s, 2 , -6a, -6b), 4.80 (d, 1 , J1,2 7.8, -1), 5.02e5.12 (m, 3, PhCH2O, NH), 5.49 (dd, 1 , J1,2 7.8, J2,3 9.6, -2), 5.59 (t, 1 ,J 9.7, -4), 5.87 (t, 1 , J 9.7, -3), 7.25e7.96 (m, 20 , 4 Ph). 13CNMR (CDCl3, 150 MHz): d 20.6 (CH3CO), 29.5 (NHCH2CH2CH2O),38.0 (NHCH2CH2CH2O), 62.4 (-6), 66.4 (PhCH2O), 67.7(NHCH2CH2CH2O), 69.4 (-4), 71.8 (-2), 72.2 (-5), 72.8 (-3),101.2 (-1), 128.0, 128.3, 128.4, 128.8, 129.2, 129.7, 129.8, 129.9133.2, 133.3 and 133.5 (h), 156.4 (OCONH), 165.2, 165.8 (3 PhCO),170.6 (CH3CO). HRMS (ESI): calcd. for C40H39NO12 [MNa]748.2364; found 748.2361. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With AlkJ and Fsa1-A129S In acetonitrile at 25℃; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With AlkJ and Fsa1-A129S In acetonitrile at 25℃; Enzymatic reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol; phenyl 3-O-benzyl-4,6-O-benzylidene-2-deoxy-2-trichloroacetamido-1-thio-β-D-glucopyranoside With N-iodo-succinimide In dichloromethane at 20℃; for 0.5h; Molecular sieve; Inert atmosphere; Stage #2: With silver trifluoromethanesulfonate In dichloromethane at -15℃; for 1h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With boron trifluoride diethyl etherate In dichloromethane at 0 - 20℃; for 12h; Inert atmosphere; | Synthesis of N-(benzyloxycarbonyl)aminopropyl 2,3,4-tri-O-acetyl-α-L-rhamnopyranoside (5) BF3Et2O (5.0mL, 39.45mmol) was slowly added through a dropping funnel to a solution at 0°C under argon of compound 4 (2.28g, 6.86 mmol) and N-CBz-aminopropanol (3.59g, 17.15mmol) in dry CH2Cl2 (70mL). The reaction was stirred at room temperature, monitored by TLC (hexane/ethyl acetate, 1:1) and appeared to be complete after 12h. The reaction was washed with saturated NaHCO3 solution (2×100mL), and the combined aqueous phases extracted with AcOEt (2×100mL). The combined organic layers were dried over Na2SO4 and concentrated. Purification by flash chromatography (hexane/AcOEt, 6:4) gave pure 5 (2.48g, 75%) as a colorless oil. [α]D20=-43.6 (c=0.5 in chloroform). 1H NMR (CDCl3): δ=7.40-7.30 (m, 5H, arom.), 5.29 (dd, 1H, J2,3=3.5Hz, J3,4=10.0Hz, H-3), 5.25 (dd, 1H, J1,2=1.7Hz, J2,3=3.5Hz, H-2), 5.13 (s, 2H, CH2Ph), 5.08 (t, 1H, J3,4=J4,5=10.0Hz, H-4), 4.95-4.88 (m, 1H, NH), 4.73 (br s, 1H, H-1), 3.91-3.83 (m, 1H, H-5), 3.81-3.74 (m, 1H, H-a), 3.54-3.47 (m, 1H, H-a′), 3.37-3.29 (m, 2H, 2H-c), 2.17 (s ,3H, CH3CO), 2.06 (s, 3H, CH3CO), 2.01(s, 3H, CH3CO), 1.92-1.80 (m, 2H, 2H-b), 1.24 (d, 3H, J5,6=6.3Hz, 3H-6); 13C NMR (CDCl3): δ=170.2 (C=O), 170.0 (C=O), 169.9 (C=O), 156.4 (C=O, Cbz), 136.6 (arom), 128.5-128.1 (5C arom), 97.5 (C-1), 71.1 (C-4), 69.8 (C-2), 69.1 (C-3), 66.7 (CH2Ph), 66.5 (C-5), 65.8 (C-a), 38.4 (C-c), 29.6 (C-b), 20.9 (CH3), 20.8 (CH3), 20.7 (CH3), 17.4 (C-6). MS (ESI) m/z (%): 504.1 (100) [M+Na]+. HRMS (ESI): m/z calcd for C23H31NO10Na 504.1846 [M+Na]+, found 504.1836. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 0.48 g 2: 0.63 g | With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0 - 20℃; for 0.25h; Molecular sieve; Inert atmosphere; Overall yield = 96 percent; | 4.1.9 N-(tertbutoxycarbonyl)-3-amminopropyl (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-mannopyranosyl)-(1→4)-(2,3,6-tri-O-acetyl-α-d-glucopyranosyl)-(1→2)-3,4-di-O-acetyl-L-rhamnopyranoside (15) Compound 16 [37] (0.19g, 0.147mmol) and N-(benzyloxycarbonyl)-3-amminopropyl (0.12g, 0.586mmol), as previously described [38], were dissolved in dry CH2Cl2 (3mL) and activated powder molecular sieves 4Å (0.10g) were added. The suspension was stirred under Ar atmosphere at room temperature for 15min, then it was cooled to 0°C and TMSOTf 0.1M in dry CH2Cl2 (0.29mL, 0.029mmol) was added. After 15min, the reaction was quenched by the addition of TEA, filtered over a Celite pad and the solvent evaporated under reduced pressure. Purification of the crude through flash chromatography (Hexane/Ethyl Acetate 6:4) afforded 0.48g of the less polar α-anomer, 0.80g of a mixture of the two anomers, and 0.63g of the β-anomer (17 overall yield: 96%). 17α and 17β were reacted separately in the next step. To a solution under Argon of compound SP3 in MeOH (0.01M), Boc2O (3.5eq.) and then Pd(OH)2/C (1/1, w/wsubstrate) were added. The mixture was stirred under hydrogen atmosphere for 3h, and checked by TLC (hexane/AcOEt, 1/1) to confirm that the Z-amino protecting group has been exchanged with BOC. Then, one drop of HCl 1N was added, and the reaction was stirred again under hydrogen atmosphere overnight. TLC (DCM/MeOH, 75/25) control showed that the reaction was completed, then few drops of dry Py were added, and the reaction was filtered over filter paper. After evaporation of the solvent, the crude was dissolved in dry Py (0.03M), and acetic anhydride was added (Ac2O/Py, 1/2) together with a catalytic amount of DMAP. The reaction was stirred at room temperature for 19h, diluted with MeOH, and then the solvent evaporated. Purification of the crude by flash chromatography (hexane/EtOAc, 1:9) gave compound 15 as an amorphous white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-iodo-succinimide; trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 0.5h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine / 4 h / 0 °C 2: sodium azide / dimethyl sulfoxide / 2 h / 70 °C 3: triphenylphosphine / methanol / 2 h / Reflux | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 4 h / 0 °C 2: sodium azide / dimethylsulfoxide-d6 / 2 h / 70 °C 3: triphenylphosphine; methanol / 2 h / Reflux | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 4 h / 0 °C 2: sodium azide / dimethyl sulfoxide / 2 h / 70 °C 3: methanol; triphenylphosphine / 2 h / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With di-n-butyltin maleate In toluene for 3h; Reflux; | Tin-Catalyzed Transcarbamoylation Using Methyl Carbamate; Typical Procedure. Dodecyl Carbamate (13b) General procedure: A solution of dodecanol (13a; 300 mg, 1.6 mmol), methyl carbamate (480 mg, 6.4 mmol) and dibutyltin maleate (35 mg, 0.1 mmol) in toluene (13 mL) was heated at reflux for 3 h. The reaction mixture was cooled to r.t. and diluted with H2O and EtOAc. The separated aqueous layer was extracted with EtOAc and the combined organic layers were washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product (422 mg) was purified by silica gel chromatography (1:5 EtOAc/n-hexane) to afford dodecyl carbamate (13b; 357 mg, 97%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethyl 6-O-acetyl-3,4-di-O-benzoyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside; 3-[(N-benzyloxycarbonyl)amino]propanol With N-iodo-succinimide In dichloromethane at 20℃; for 0.5h; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 22 - 27℃; | 3 Synthesis of Compound 7 Compound 4 (500 mg) and intermediate 3.1 (211 mg, 1.2 eq.) were weighed into a dry flask, toluene (5 mL) was added and the solution concentrated on a rotary evaporator (45° C. bath temperature). This was repeated once more before the starting materials were concentrated from anhydrous DCM (5 mL). Once all of the solvent was removed, the residual solid was dried under vacuum for 10 minutes. Following drying, the starting materials were placed under argon, dissolved in anhydrous DCM (5.0 mL) and activated 4 molecular sieves (450 mg, pellet form) were added. At this point, the NIS reagent was placed under high-vacuum to dry. After 10 minutes, the dried NIS (400 mg, 2.0 equivalents) was added and the solution stirred at room temperature for 30 minutes. TMSOTf (8 μL, 5 mol %) was then added quickly, which results in the solution changing from red/orange to a deep red/brown color. The reaction temperature also rose from 22 to 27° C. As soon as the TMSOTf was added an IPC was run for information only (HPLC; 10 μL into 1 mL MeCN-H2O (8:2)). The reaction was then quenched by the addition of pyridine (20 μL, 0.245 mmol) and stirred at ambient temperature for 5 minutes. The DCM solution was filtered to remove the molecular sieves and then washed with 10% Na2S2O3 (3×5 mL), brine (5 mL) and then concentrated on a rotary evaporator (40° C. bath temperature) to give crude compound 7 as a foamy yellow oil (616 mg). Expected Yield: 616 mg, (99%). | |
Stage #1: ethyl 6-O-acetyl-3,4-di-O-benzoyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside; 3-[(N-benzyloxycarbonyl)amino]propanol With N-iodo-succinimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 22 - 27℃; Inert atmosphere; Molecular sieve; | 3 Synthesis of Compound 7 [0095] Compound 4 (500 mg) and intermediate 3.1 (211 mg, 1.2 eq.) were weighed into a dry flask, toluene (5 mL) was added and the solution concentrated on a rotary evaporator (45°C bath temperature). This was repeated once more before the starting materials were concentrated from anhydrous DCM (5 mL). Once all of the solvent was removed, the residual solid was dried under vacuum for 10 minutes. Following drying, the starting materials were placed under argon, dissolved in anhydrous DCM (5.0 mL) and activated 4Å molecular sieves (450 mg, pellet form) were added. At this point, the NIS reagent was placed under high-vacuum to dry. After 10 minutes, the dried NIS (400 mg, 2.0 equivalents) was added and the solution stirred at room temperature for 30 minutes. TMSOTf (8 mL, 5 mol%) was then added quickly, which results in the solution changing from red/orange to a deep red/brown color. The reaction temperature also rose from 22 to 27 °C. As soon as the TMSOTf was added an IPC was run for information only (HPLC; 10 mL into 1 mL MeCN-H2O (8:2)). The reaction was then quenched by the addition of pyridine (20 mL, 0.245 mmol) and stirred at ambient temperature for 5 minutes. The DCM solution was filtered to remove the molecular sieves and then washed with 10% Na2S203 (3 x 5 mL), brine (5 mL) and then concentrated on a rotary evaporator (40°C bath temperature) to give crude compound 7 as a foamy yellow oil (616 mg). Expected Yield: ~616 mg, (99 %). | |
Stage #1: ethyl 6-O-acetyl-3,4-di-O-benzoyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside; 3-[(N-benzyloxycarbonyl)amino]propanol With N-iodo-succinimide In dichloromethane at 20℃; for 0.666667h; Inert atmosphere; Molecular sieve; Stage #2: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 22 - 27℃; Inert atmosphere; | 3 Synthesis of Compound 7 Compound 4 (500 mg) and intermediate 3.1 (211 mg, 1.2 eq.) were weighed into a dry flask, toluene (5 mL) was added and the solution concentrated on a rotary evaporator (45°C bath temperature). This was repeated once more before the starting materials were concentrated from anhydrous DCM (5 mL). Once all of the solvent was removed, the residual solid was dried under vacuum for 10 minutes. Following drying, the starting materials were placed under argon, dissolved in anhydrous DCM (5.0 mL) and activated 4Å molecular sieves (450 mg, pellet form) were added. At this point, the NIS reagent was placed under high-vacuum to dry. After 10 minutes, the dried NIS (400 mg, 2.0 equivalents) was added and the solution stirred at room temperature for 30 minutes. TMSOTf (8 μL, 5 mol%) was then added quickly, which results in the solution changing from red/orange to a deep red/brown color. The reaction temperature also rose from 22 to 27 °C. As soon as the TMSOTf was added an IPC was run for information only (HPLC; 10 μL into 1 mL MeCN-H2O (8:2)). The reaction was then quenched by the addition of pyridine (20 μL, 0.245 mmol) and stirred at ambient temperature for 5 minutes. The DCM solution was filtered to remove the molecular sieves and then washed with 10% Na2S2O3 (3 x 5 mL), brine (5 mL) and then concentrated on a rotary evaporator (40°C bath temperature) to give crude compound 7 as a foamy yellow oil (616 mg). Expected Yield: ~616 mg, (99 %). |
Stage #1: ethyl 6-O-acetyl-3,4-di-O-benzoyl-2-deoxy-2-phthalimido-1-thio-β-D-glucopyranoside; 3-[(N-benzyloxycarbonyl)amino]propanol In dichloromethane for 0.166667h; Inert atmosphere; Molecular sieve; Stage #2: With N-iodo-succinimide In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Stage #3: With trimethylsilyl trifluoromethanesulfonate In dichloromethane at 22 - 27℃; Inert atmosphere; | 3 Synthesis of Compound 7 Compound 4 (500 mg) and intermediate 3.1 (211 mg, 1.2 eq.) were weighed into a dry flask, toluene (5 mL) was added and the solution concentrated on a rotary evaporator (45°C bath temperature). This was repeated once more before the starting materials were concentrated from anhydrous DCM (5 mL). Once all of the solvent was removed, the residual solid was dried under vacuum for 10 minutes. Following drying, the starting materials were placed under argon, dissolved in anhydrous DCM (5.0 mL) and activated 4Å molecular sieves (450 mg, pellet form) were added. At this point, the NIS reagent was placed under high-vacuum to dry. After 10 minutes, the dried NIS (400 mg, 2.0 equivalents) was added and the solution stirred at room temperature for 30 minutes. TMSOTf (8 μL, 5 mol%) was then added quickly, which results in the solution changing from red/orange to a deep red/brown color. The reaction temperature also rose from 22 to 27 °C. As soon as the TMSOTf was added an IPC was run for information only (HPLC; 10 μL into 1 mL MeCN-H2O (8:2)). The reaction was then quenched by the addition of pyridine (20 μL, 0.245 mmol) and stirred at ambient temperature for 5 minutes. The DCM solution was filtered to remove the molecular sieves and then washed with 10% Na2S2O3 (3 x 5 mL), brine (5 mL) and then concentrated on a rotary evaporator (40°C bath temperature) to give crude compound 7 as a foamy yellow oil (616 mg). Expected Yield: ~616 mg, (99 %). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-iodo-succinimide; trifluorormethanesulfonic acid In dichloromethane at 20℃; for 0.5h; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.78 g | With acetic acid In water at 60℃; for 17h; | 8 Synthesis of 3-[(benzyloxy)carbonyl]-1,3-oxazinane-2-carboxylic acid (24) Example 8 Synthesis of 3-[(benzyloxy)carbonyl]-1,3-oxazinane-2-carboxylic acid (24) To a 50% glyoxylic acid aqueous solution (2.960 g), acetic acid (7.41 g) and compound (35) (4.18 g) were added, and stirring was continued at 60° C. for 17 hours. After the solution was concentrated, a 1 mol/L NaOH aqueous solution (70 mL) and methyl tert-butyl ether (50 mL) were added, and the solution was phase separated. Then, concentrated hydrochloric acid was added to the aqueous phase at not more than 10° C. to adjust the pH to 2.00, and the solution was phase separated with ethyl acetate (50 mL). Column purification was done with chloroform and methanol, whereby 3-[(benzyloxy)carbonyl]-1,3-oxazinane-2-carboxylic acid (24) (2.78 g) was obtained. MS (ESI/APCI Dual) m/z: 266 [(M+H)+], 288 [(M+Na)+], 264 [(M-H)-]. IR (KBr) cm-1: 2960, 1751, 1636, 1458, 1450, 1147, 1091, 968. Anal. Calcd for C13H15NO5: C, 58.86; H, 5.70; N, 5.28. Found: C, 58.83; H, 5.73; N, 5.32. The HPLC retention time for (24) was about 14.5 min. The HPLC analysis was done under the following conditions: column: YMC Triart C18 (3.0 mmφ*100 mm, 3 μm); column temperature: 40° C.; flow rate: 0.7 mL/min.; detection wavelength: 230 nm (UV); mobile phase: solution A: 0.1% v/v phosphoric acid aqueous solution, solution B: methanol:acetonitrile=3:1 (v/v); and gradient conditions: changed from 90:10 A:B to 10:90 A:B over 20 min., held at 10:90 A:B for 5 min., reverted back to 90:10 A:B over 0.1 min., and held at 90:10 A:B for 9.9 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50 % de | Stage #1: C33H32N4O4S; p-methoxybenzyl chloride With potassium carbonate; potassium iodide In N,N-dimethyl-formamide for 16h; Inert atmosphere; Stage #2: 3-[(N-benzyloxycarbonyl)amino]propanol In dichloromethane for 1h; Molecular sieve; Inert atmosphere; Stage #3: With N-iodo-succinimide; silver trifluoromethanesulfonate In dichloromethane at -40 - 0℃; for 3h; Molecular sieve; Inert atmosphere; Overall yield = 34 percent; Overall yield = 110 mg; | S2.12. PMB-protected C-6 tetrazole thioglycosides 18 and 19 To a stirred solution of 17 (920 mg, 1.37 mmol, 1.0 equiv) in DMF (10 mL) wasadded successively, KI (341 mg, 2.06 mmol, 1.5 equiv), K2CO3 (227 mg, 1.65 mmol, 1.2equiv) and PMBCl (279 μL, d = 1.155, 2.06 mmol, 1.5 equiv). The reaction was left stirringfor 16 h and was diluted with CH2Cl2 (30 mL). The organic layer was washed with 10%aq. Na2S2O3 solution (30 mL) and brine (30 mL), dried over MgSO4, filtered andconcentrated under reduced pressure. The crude product was purified using silica gelflash column chromatography, eluting with EtOAc/petroleum ether (5/95, 10/90, 15/85) tofurnish isomers 18 and 19 (732 mg, 1.04 mmol, 76%) as colourless oils. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol; C21H19Cl3N4O4S In dichloromethane at 20℃; for 0.5h; Inert atmosphere; Molecular sieve; Stage #2: With N-iodo-succinimide; trimethylsilyl trifluoromethanesulfonate In dichloromethane at 0℃; for 1h; Inert atmosphere; Molecular sieve; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine In 2-methoxy-2-methylpropane at 23℃; for 0.25h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | Stage #1: 3-[(N-benzyloxycarbonyl)amino]propanol With di-isopropyl azodicarboxylate; triphenylphosphine In tetrahydrofuran at -20℃; for 0.5h; Inert atmosphere; Stage #2: (S)-tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate In tetrahydrofuran at -20 - 20℃; for 16h; Inert atmosphere; | 4.1.4. Synthesis of (S)-tert-butyl 3-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-(4-(3-(((benzyloxy)carbonyl)amino)-propoxy)phenyl)propanoate (10) To a solution of benzyl (3-hydroxypropyl)carbamate 9 (427 mg,2.046 mmol) in freshly distilled THF (10 mL) under a nitrogen atmosphere,PPh3 (584 mg, 2.232 mmol) was added. Then, the mixture wascooled to 20 C and DIAD (437 μL, 2.232 mmol) was slowly added over30 min, finally a solution of 8 (854 mg, 1.86 mmol) in dry THF (9 mL)was added dropwise. The reaction was left reaching room temperatureand stirred for 16 h. Then, the reaction was quenched with 1 M HCl (60mL), the aqueous phase was extracted with EtOAc (3 × 50 mL) and thecombined organic phases were washed with a saturated solution ofNaHCO3 (3 × 40 mL) and Brine (40 mL), dried over Na2SO4, filtered andconcentrated under vacuum. The crude compound was purified by flashchromatography (hexane:EtOAc 2:1) to obtain compound 10 (725 mg)in 60% yield. [α]17D = 9.06 (c 0.70, CHCl3). 1H NMR (400 MHz, CDCl3)δ ppm = 7.76 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 6.7 Hz, 2H), 7.44-7.26 (m,9H), 7.21 (d, J = 8.0 Hz, 2H), 6.81 (dd, J = 19.6, 8.6 Hz, 3H), 5.77 (d, J= 8.0 Hz, 1H), 5.19-5.01 (m, 3H), 4.48-4.29 (m, 2H), 4.23-4.14 (m,1H), 4.00 (t, J = 5.8 Hz, 2H), 3.40 (dd, J = 12.5, 6.3 Hz, 2H), 2.81-2.69(m, 2H), 2.12-1.88 (m, 2H), 1.36 (s, 9H). 13C NMR (50 MHz, CDCl3) δppm = 170.2, 158.0, 156.5, 155., 143.9, 141.3, 136.5, 133.3, 128.5,128.1, 127.7, 127.4, 127.0, 125.1, 119.9, 114.5, 81.3, 66.7, 65.7, 51.3,47.2, 41.9, 38.6, 29.4, 27.9. MS(ESI) m/z (%): 673.10 (100, [M+Na]+). |
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