Purity | Size | Price | VIP Price | USA Stock *0-1 Day | Global Stock *5-7 Days | Quantity | |||||
{[ item.p_purity ]} | {[ item.pr_size ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} |
{[ getRatePrice(item.pr_usd, 1,1) ]} | Inquiry {[ getRatePrice(item.pr_usd,item.pr_rate,item.mem_rate) ]} {[ getRatePrice(item.pr_usd,1,item.mem_rate) ]} | {[ item.pr_usastock ]} | Inquiry - | {[ item.pr_chinastock ]} | Inquiry - |
* Storage: {[proInfo.prStorage]}
CAS No. : | 22323-82-6 | MDL No. : | MFCD00063239 |
Formula : | C6H12O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RNVYQYLELCKWAN-YFKPBYRVSA-N |
M.W : | 132.16 | Pubchem ID : | 736057 |
Synonyms : |
S-(+)-2,3-O-Isopropylideneglycerol
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 32.21 |
TPSA : | 38.69 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.25 cm/s |
Log Po/w (iLOGP) : | 1.87 |
Log Po/w (XLOGP3) : | -0.2 |
Log Po/w (WLOGP) : | 0.13 |
Log Po/w (MLOGP) : | -0.26 |
Log Po/w (SILICOS-IT) : | 0.84 |
Consensus Log Po/w : | 0.48 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.47 |
Solubility : | 45.1 mg/ml ; 0.341 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.16 |
Solubility : | 92.2 mg/ml ; 0.698 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.52 |
Solubility : | 40.1 mg/ml ; 0.303 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 3.09 |
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 |
---|---|---|
99% | at 0 - 20℃; | p-Toluenesulfonyl chloride (6.18 g, 31.7 mmol) was added portionwise over a period of 10 min to a solution of (S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane (19a) (4.0 g, 30.2 mmol) in anhydrous pyridine (50 mL) in an ice bath. The resulting solution was slowly brought to room temperature and stirred overnight. During that time, a white precipitate formed. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 mL), washed subsequently with cold aqueous 1 M HCl (2×150 mL), saturated NaHCO3 (100 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography over silica gel with gradient elution 10–30percent AcOEt/hexanes to afford (R)-(−)-3-tosyloxy-1,2-propanediol acetonide 20a (8.54 g, 99percent yield, 99.9percent ee) as a colourless viscous oil. Rf=0.37 (20percent AcOEt/hexanes). [α]D20 −4.8 (c 1.0, EtOH) (lit. [α]D24 −4.6 (c 13.0, EtOH)).25 FTIR (thin film) ν 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1177, 1096, 1055, 979, 829, 788, 665, 555 cm−1. 1H NMR (600 MHz, CDCl3) δ 1.31 (s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J=5.1 and 8.8 Hz, 1H, one of the CH2-5 group), 3.98 (dd, J=6.0 and 10.2 Hz, 1H, one of the CH2-1′ group), 3.99–4.05 (m, 2H, one of the CH2-1′ group and one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6) ppm. 13C NMR (150 MHz, CDCl3) δ 21.5 (Ar–CH3), 25.1 (CH3-2), 26.5 (CH3-2), 66.1 (C-5), 69.4 (C-1′), 72.8 (C-4), 109.9 (C-2), 127.9 (2C, aromatic C-2 and C-6), 129.8 (2C, aromatic C-3 and C-5), 132.6 (aromatic C-1), 145.0 (aromatic C-4) ppm. HRMS (ESI): calcd for C13H18NaO5S [M+Na]+ 309.07672; found 309.0762. Chiral HPLC: Chiralpak IA, 5 μm, 250×4.6 mm column, hexanes/2-propanol/methanol 97:2:1 (v/v/v), 1.0 mL/min, tR=21.71 min (0.06percent yield of 20b), tR=24.20 min (99.94percent yield of 20a), 99.88percent ee. All physical and spectroscopic data match those reported in the literature. |
98.6% | at 20℃; Cooling with ice | />-Toluenesulfonyl chloride (6.18 g, 31.748 mmol) was added portionwise over a period of 10 min to a solution of (.S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-l ,3-dioxolane (19a) (4.00 g, 30.236 mmol) in anhydrous pyridine (50.0 ml) in an ice bath. The resulting solution was slowly brought to room temperature and stirred overnight. During that time, a white precipitate formed. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml), washed subsequently with cold aqueous 1M HC1 (2 x 150 ml), saturated NaHC03 (100 ml) and brine (200 ml). The organic layer was dried over Na2S04, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography over silica gel with gradient elution 10 - 30percent ethyl acetate/hexanes to afford (i?)-(-)-3-tosyloxy-l ,2-propanediol acetonide 20a (8.54 g, 98.6percent yield, 99.88percent ee) as a colourless viscosous oil. The liquid changes to a white solid at low temperatures, [erg = ^.75° (c 1.0, EtOH) (lit. [a = -4.6° (c 13.0, EtOH))12. FT-IR (thin film) vmax (cm-1): 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1 177, 1096, 1055, 979, 829, 788, 665, 555. NMR (600 MHz, CDC13, 25 °C) δ (ppm): 1.31 (s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J = 5.1 and 8.8 Hz, 1H, one of the CH2-5 group), 3.98 (dd, J = 6.0 and 10.2 Hz, 1H, one of the CH2-1' group), 4.01 (dd, J = 5.6 and 10.3 Hz, 1H, one of the CH2-1' group), 4.03 (dd, J = 6.2 and 8.8 Hz, 1H, one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6). 13C NMR (150 MHz, CDC13, 25 °C) δ (ppm): 21.54 (Ar-CH3), 25.05 (CH3-2), 26.53 (CH3-2), 66.05 (C-5), 69.44 (C-l'), 72.82 (C-4), 109.93 (C- 2), 127.88 (2C, aromatic C-2 and C-6), 129.83 (2C, aromatic C-3 and C-5), 132.55 (aromatic C-l), 144.99 (aromatic C-4). HRMS (ESI): calcd. for C13Hi805NaS [M + Na]+ 309.07672; fund 309.0762. Chiral HPLC: Chiralpak IA, 5 μιη, 250 x 4.6 mm column, hexanes/2-propanol/methanol 97:2: 1 (v/v/v), 1.0 ml/min, Rt = 21.71 min. (0.06percent yield of 20b), Rt = 24.20 (99.94percent yield of 20a), 99.88percent ee. |
98.6% | at 20℃; | p-Toluenesulfonyl chloride (6.18 g, 31.748 mmol) was added portionwise over a period of 10 min to a solution of (S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane (19a) (4.00 g, 30.236 mmol) in anhydrous pyridine (50.0 ml) in an ice bath. The resulting solution was slowly brought to room temperature and stirred overnight. During that time, a white precipitate formed. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml), washed subsequently with cold aqueous 1M HCl (2*150 ml), saturated NaHCO3 (100 ml) and brine (200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography over silica gel with gradient elution 10-30percent ethyl acetate/hexanes to afford (R)-(-)-3-tosyloxy-1,2-propanediol acetonide 20a (8.54 g, 98.6percent yield, 99.88percent ee) as a colourless viscosous oil. The liquid changes to a white solid at low temperatures. [α]D20=-4.75° (c 1.0, EtOH) (lit. [α]D24=-4.6° (c 13.0, EtOH))12. FT-IR (thin film) νmax (cm-1): 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1177, 1096, 1055, 979, 829, 788, 665, 555. 1H NMR (600 MHz, CDCl3, 25° C.) δ (ppm): 1.31 (s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J=5.1 and 8.8 Hz, 1H, one of the CH2-5 group), 3.98 (dd, J=6.0 and 10.2 Hz, 1H, one of the CH2-1' group), 4.01 (dd, J=5.6 and 10.3 Hz, 1H, one of the CH2-1' group), 4.03 (dd, J=6.2 and 8.8 Hz, 1H, one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6). 13C NMR (150 MHz, CDCl3, 25° C.) δ (ppm): 21.54 (Ar-CH3), 25.05 (CH3-2), 26.53 (CH3-2), 66.05 (C-5), 69.44 (C-1'), 72.82 (C-4), 109.93 (C-2), 127.88 (2C, aromatic C-2 and C-6), 129.83 (2C, aromatic C-3 and C-5), 132.55 (aromatic C-1), 144.99 (aromatic C-4). HRMS (ESI): calcd. for C13H18O5NaS [M+Na]+ 309.07672; fund 309.0762. |
90.9% | at 20℃; | p-Toluenesulfonyl chloride (6.5 g, 34.1 mmol) was added portionwise over a period of 10 min to a solution of (£)-(+)- 1 ,2-isopropylideneglycerol (3.0 g, 22.7 mmol) and DMAP (30 mg, 0.25 mmol) in anhydrous pyridine (30 mL) in a water bath. The resulting solution was stirred overnight. The pyridine was removed under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed subsequently with water (2 x 40mL), cold aqueous 1 M HC1 (40 mL), saturated NaHC03 (40 mL) and water (40 mL). The organic layer was dried over Mg2S04, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography (eluent: 10percent ethyl acetate in hexane to 30percent ethyl acetate in hexane) to afford (i?)-2,2-Dimethyl-l,3-dioxolane-4- methanol p-toluenesulfonate i (5.91 g, 90.9percent yield) as a colorless viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In dichloromethane; at 0 - 20℃; | ((S)-2,2-Dimethyl-[1,3]dioxolan-4-yl)-methanol (2.0 g, 15.13 mmol) and triethylamine (2.53 ml, 18.16 mmol) were dissolved in dichloromethane (60 mL) followed by the addition of methanesulfonyl chloride (1.35 ml, 17.40 mmol) at 0 C. The reaction was warmed to ambinet temperature, stirred overnight, and then diluted with water. The organic layer was washed with saturated aqueous sodium bicarbonate solution, brine and dried over sodium sulfate. Removal of solvents gave methanesulfonic acid (R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester as an oil (3.2 g, 100%). |
100% | With triethylamine; In dichloromethane; at 0 - 20℃; for 12h; | To a stirred solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (2.0 g, 15 mmol) in dichloromethane (60 mL) at 0 C. were added triethylamine (2.5 mL, 18 mmol) and methanesulfonyl chloride (1.3 mL, 17 mmol) and stirred at room temperature for 12 hours. The reaction mixture was concentrated, poured into water and made basic with sodium bicarbonate solution. This solution was then extracted with ethyl acetate (3*200 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give an oil. The desired product was obtained by column chromatography on silica gel using 20% ethyl acetate in hexanes as the eluent to give 3.0 g (100%). ?H-NMR (DMSO-d6): oe 4.33-4.23 (m, 2H), 4.16-4.12 (m, 1H), 4.03 (dd, J1=8.8 Hz, J2=6.8 Hz, 1H), 3.71 (dd, J1=8.4 Hz, J2=6.0 Hz, 1H), 3.21 (s, 3H), 1.35 (s, 3H), 1.28 (s, 3H); MS (ES) mle 211 [M+H]. |
77.8% | With triethylamine; In dichloromethane; at 0℃; for 3h; | To a stirred solution of (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (9, 12 g, 0.091 mol) in DCM (100 mL) was added triethylamine (37.76 mL, 0.272 mol) and methane sulfonyl chloride (8.4 mL, 0.109 mol) at 0 C. The reaction mixture was allowed to stir for 3 h at 0 C. The reaction was monitored by TLC and after completion, the reaction mixture was diluted with water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous Na2S04, filtered then concentrated under reduced pressure to afford the title compound as yellow gummy liquid (21.8 g, 77.8%>); LCMS (ESI positive ion) m/z: calculated: 210.06; observed: 211.0 (M+l). |
With triethylamine; In dichloromethane; at 0℃; for 2.5h;Inert atmosphere; | General procedure: To a solution of solketal (1.00 g, 7,56 mmol) in dichloromethane (20 ml) was added methane sulfonyl chloride (1.71 ml, 21,7 mmol) and triethylamine (13.28 ml, 95.2 mmol) at 0C. After 2.5 h the solution was diluted with 5 volume of DCM, washed twice with brine (50 ml), dried over MgSO4. The solvent was removed under vacuum and the product was obtained as a dark red liquid, no further purification was done on thecrude. (2.269 g, Qtv)1HNMR (300MHz, CDCl3):delta 1.32 (s, 3H), 1.39 (s, 3H), 3.02 (s, 3H), 3.78 (dd, 1H, J= 8.6Hz, 5.4Hz), 4.06 (dd, 1H, J= 8.7Hz, 6.5Hz), 4.18 (d, 2H, J= 5Hz), 4.34 (m, 1H) ppm.13CNMR (75MHz, CDCl3):delta 25.19, 26.69, 37.67, 65.81, 69.26, 73.24, 110.25 ppm. | |
With triethylamine; In dichloromethane; at 0℃; | Step 1. To a solution of ()- (+)-2, 2-dimethyl-1, 3-dioxolane-4-methanol (1.36 g, 10.3 mmol) in dichloromethane (5 mL) was added triethylamine (4.30 mL, 30.9 mmol). The mixture was cooled with an ice/water bath and methanesulfonyl chloride (2.40 mL, 30.9 mmol) was added. The reaction was quenched by addition of saturated NaHCO3 solution (aqueous) after stirring overnight. The aqueous phase was extracted with one portion of dichloromethane; combined organic phase was washed with water, dried with anhydrous sodium sulphate and concentrated. Crude compound 25 was used without purification for next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine; at 0 - 20℃; | p-Toluenesulfonyl chloride (6.18 g, 31.7 mmol) was added portionwise over a period of 10 min to a solution of (S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane (19a) (4.0 g, 30.2 mmol) in anhydrous pyridine (50 mL) in an ice bath. The resulting solution was slowly brought to room temperature and stirred overnight. During that time, a white precipitate formed. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 mL), washed subsequently with cold aqueous 1 M HCl (2×150 mL), saturated NaHCO3 (100 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography over silica gel with gradient elution 10-30% AcOEt/hexanes to afford (R)-(-)-3-tosyloxy-1,2-propanediol acetonide 20a (8.54 g, 99% yield, 99.9% ee) as a colourless viscous oil. Rf=0.37 (20% AcOEt/hexanes). [alpha]D20 -4.8 (c 1.0, EtOH) (lit. [alpha]D24 -4.6 (c 13.0, EtOH)).25 FTIR (thin film) nu 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1177, 1096, 1055, 979, 829, 788, 665, 555 cm-1. 1H NMR (600 MHz, CDCl3) delta 1.31 (s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J=5.1 and 8.8 Hz, 1H, one of the CH2-5 group), 3.98 (dd, J=6.0 and 10.2 Hz, 1H, one of the CH2-1? group), 3.99-4.05 (m, 2H, one of the CH2-1? group and one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6) ppm. 13C NMR (150 MHz, CDCl3) delta 21.5 (Ar-CH3), 25.1 (CH3-2), 26.5 (CH3-2), 66.1 (C-5), 69.4 (C-1?), 72.8 (C-4), 109.9 (C-2), 127.9 (2C, aromatic C-2 and C-6), 129.8 (2C, aromatic C-3 and C-5), 132.6 (aromatic C-1), 145.0 (aromatic C-4) ppm. HRMS (ESI): calcd for C13H18NaO5S [M+Na]+ 309.07672; found 309.0762. Chiral HPLC: Chiralpak IA, 5 mum, 250×4.6 mm column, hexanes/2-propanol/methanol 97:2:1 (v/v/v), 1.0 mL/min, tR=21.71 min (0.06% yield of 20b), tR=24.20 min (99.94% yield of 20a), 99.88% ee. All physical and spectroscopic data match those reported in the literature. |
98.6% | With pyridine; at 20℃;Cooling with ice; | />-Toluenesulfonyl chloride (6.18 g, 31.748 mmol) was added portionwise over a period of 10 min to a solution of (.S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-l ,3-dioxolane (19a) (4.00 g, 30.236 mmol) in anhydrous pyridine (50.0 ml) in an ice bath. The resulting solution was slowly brought to room temperature and stirred overnight. During that time, a white precipitate formed. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml), washed subsequently with cold aqueous 1M HC1 (2 x 150 ml), saturated NaHC03 (100 ml) and brine (200 ml). The organic layer was dried over Na2S04, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography over silica gel with gradient elution 10 - 30% ethyl acetate/hexanes to afford (i?)-(-)-3-tosyloxy-l ,2-propanediol acetonide 20a (8.54 g, 98.6% yield, 99.88% ee) as a colourless viscosous oil. The liquid changes to a white solid at low temperatures, [erg = ^.75 (c 1.0, EtOH) (lit. [a = -4.6 (c 13.0, EtOH))12. FT-IR (thin film) vmax (cm-1): 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1 177, 1096, 1055, 979, 829, 788, 665, 555. NMR (600 MHz, CDC13, 25 C) delta (ppm): 1.31 (s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J = 5.1 and 8.8 Hz, 1H, one of the CH2-5 group), 3.98 (dd, J = 6.0 and 10.2 Hz, 1H, one of the CH2-1' group), 4.01 (dd, J = 5.6 and 10.3 Hz, 1H, one of the CH2-1' group), 4.03 (dd, J = 6.2 and 8.8 Hz, 1H, one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6). 13C NMR (150 MHz, CDC13, 25 C) delta (ppm): 21.54 (Ar-CH3), 25.05 (CH3-2), 26.53 (CH3-2), 66.05 (C-5), 69.44 (C-l'), 72.82 (C-4), 109.93 (C- 2), 127.88 (2C, aromatic C-2 and C-6), 129.83 (2C, aromatic C-3 and C-5), 132.55 (aromatic C-l), 144.99 (aromatic C-4). HRMS (ESI): calcd. for C13Hi805NaS [M + Na]+ 309.07672; fund 309.0762. Chiral HPLC: Chiralpak IA, 5 muiotaeta, 250 x 4.6 mm column, hexanes/2-propanol/methanol 97:2: 1 (v/v/v), 1.0 ml/min, Rt = 21.71 min. (0.06% yield of 20b), Rt = 24.20 (99.94% yield of 20a), 99.88% ee. |
98.6% | With pyridine; at 20℃; | p-Toluenesulfonyl chloride (6.18 g, 31.748 mmol) was added portionwise over a period of 10 min to a solution of (S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-1,3-dioxolane (19a) (4.00 g, 30.236 mmol) in anhydrous pyridine (50.0 ml) in an ice bath. The resulting solution was slowly brought to room temperature and stirred overnight. During that time, a white precipitate formed. The pyridine was removed under reduced pressure and the residue was diluted with ethyl acetate (50 ml), washed subsequently with cold aqueous 1M HCl (2*150 ml), saturated NaHCO3 (100 ml) and brine (200 ml). The organic layer was dried over Na2SO4, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography over silica gel with gradient elution 10-30% ethyl acetate/hexanes to afford (R)-(-)-3-tosyloxy-1,2-propanediol acetonide 20a (8.54 g, 98.6% yield, 99.88% ee) as a colourless viscosous oil. The liquid changes to a white solid at low temperatures. [alpha]D20=-4.75 (c 1.0, EtOH) (lit. [alpha]D24=-4.6 (c 13.0, EtOH))12. FT-IR (thin film) numax (cm-1): 3073, 2987, 2937, 2891, 1598, 1495, 1455, 1368, 1257, 1213, 1190, 1177, 1096, 1055, 979, 829, 788, 665, 555. 1H NMR (600 MHz, CDCl3, 25 C.) delta (ppm): 1.31 (s, 3H, CH3-2), 1.34 (s, 3H, CH3-2), 2.45 (s, 3H, ArCH3), 3.76 (dd, J=5.1 and 8.8 Hz, 1H, one of the CH2-5 group), 3.98 (dd, J=6.0 and 10.2 Hz, 1H, one of the CH2-1' group), 4.01 (dd, J=5.6 and 10.3 Hz, 1H, one of the CH2-1' group), 4.03 (dd, J=6.2 and 8.8 Hz, 1H, one of the CH2-5 group), 4.28 (m, 1H, CH-4), 7.35 (m, 2H, aromatic H-3 and H-5), 7.79 (m, 2H, aromatic H-2 and H-6). 13C NMR (150 MHz, CDCl3, 25 C.) delta (ppm): 21.54 (Ar-CH3), 25.05 (CH3-2), 26.53 (CH3-2), 66.05 (C-5), 69.44 (C-1'), 72.82 (C-4), 109.93 (C-2), 127.88 (2C, aromatic C-2 and C-6), 129.83 (2C, aromatic C-3 and C-5), 132.55 (aromatic C-1), 144.99 (aromatic C-4). HRMS (ESI): calcd. for C13H18O5NaS [M+Na]+ 309.07672; fund 309.0762. |
98.6% | With pyridine; at 20℃; | Toluenesulfonyl chloride (6.18 g, 31.748 mmol) was added dropwise to a solution of acetone carboxy glycerol (4.00 g, 30.236 mmol) in anhydrous pyridine (50.0 ml).The reaction mixture was allowed to warm to room temperature and stirred overnight.Decompression must be removed,Diluted with ethyl acetate (50 ml) using 1M HCl (2 x 150 mL).Wash with saturated NaHCO3 (100ml) and saturated brine (200ml).Dry over anhydrous sodium sulfate,It has a pale yellow oil.Crude product column chromatography (10-30% ethyl acetate / n-hexane),A colorless oil (R)-methanesulfonic acid substituted acetone carboxyglycerol 8.54 g (yield 98.6%) was obtained. |
90.9% | With pyridine; dmap; at 20℃; | p-Toluenesulfonyl chloride (6.5 g, 34.1 mmol) was added portionwise over a period of 10 min to a solution of (£)-(+)- 1 ,2-isopropylideneglycerol (3.0 g, 22.7 mmol) and DMAP (30 mg, 0.25 mmol) in anhydrous pyridine (30 mL) in a water bath. The resulting solution was stirred overnight. The pyridine was removed under reduced pressure, and the residue was diluted with ethyl acetate (50 mL), washed subsequently with water (2 x 40mL), cold aqueous 1 M HC1 (40 mL), saturated NaHC03 (40 mL) and water (40 mL). The organic layer was dried over Mg2S04, filtered and concentrated to give a light yellow oil. The crude product was purified by column chromatography (eluent: 10% ethyl acetate in hexane to 30% ethyl acetate in hexane) to afford (i?)-2,2-Dimethyl-l,3-dioxolane-4- methanol p-toluenesulfonate i (5.91 g, 90.9% yield) as a colorless viscous oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; dmap; In benzene; at 0 - 10℃; for 1h; | General procedure: A solution of RCOCl [2.75 g (10 mmol) in the case of n-C15H31COCl] in dry C6H6 (10 mL) was added dropwise to a stirred and ice-cooled solution of (+/-)-2 (1.00 g, 7.6 mmol) and DMAP (50 mg, 0.4 mmol) in dry pyridine (5 mL) at 5-10 C. Stirring was continued for 1 h at 0-5 C, and the mixture was left to stand overnight in a refrigerator. After dilution with ice and water, the mixture was extracted with Et2O. The extract was washed successively with dil HCl, NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed over SiO2 (35 g). Elution with hexane/EtOAc (20:1) gave 2.60 g (93%) of (+/-)-3a. Preparation of 3a, 3c, and 3d was executed by the above procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With pyridine; dmap; In benzene; at 0 - 10℃; for 1h; | General procedure: A solution of RCOCl [2.75 g (10 mmol) in the case of n-C15H31COCl] in dry C6H6 (10 mL) was added dropwise to a stirred and ice-cooled solution of (+/-)-2 (1.00 g, 7.6 mmol) and DMAP (50 mg, 0.4 mmol) in dry pyridine (5 mL) at 5-10 C. Stirring was continued for 1 h at 0-5 C, and the mixture was left to stand overnight in a refrigerator. After dilution with ice and water, the mixture was extracted with Et2O. The extract was washed successively with dil HCl, NaHCO3 solution and brine, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed over SiO2 (35 g). Elution with hexane/EtOAc (20:1) gave 2.60 g (93%) of (+/-)-3a. Preparation of 3a, 3c, and 3d was executed by the above procedure. |
With pyridine; In dichloromethane; at 0℃; | B-3. Preparation of 1-palmitoyl glycerol using optically active(D or L-form 1. 2-isopropylidene glycerol; [102] 132. 16g of optically active 1, 2-isopropylidene glycerol was dissolved with 660mol of dichloromethane. 237g of pyridine was added thereto, and the reaction mixture was cooled to 0C. Then 274. 9g of palmitoyl chloride was dropwisely added thereto and the reaction was carried out. After completion of the reaction, 1000mol of water was added for an extraction. The organic layer of the reaction mixture was dehydrated with anhydrous MgSO, and filtered, and the solvent was removed by distillation under 4 reduced pressure. Then 1850mol of dichloromethane was added thereto, the reaction mixture was cooled to-50C, and 2L of dichloromethane solution including dimethyl boron bromide of 2. 5M concentration was added thereto. After completion of the reaction, 2.4L of saturated NaHCO3 solution was slowly added with stirring. Then, the organic layer was separated, and was dehydrated with anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure to obtain 277. 9g of the target material (yield : 84. 1%). The obtained 1-palmitoyl glycerol was analyzed with H- NMR, and the results and other property are as follows. [103] (1) (R)-enantiomer : [a] =-8. 92 (c=0. 58, EtOH),'H NMR (250MHz, CDC1) : 8 0. 88 (t, J=7. 5Hz, 3H), 1. 20-1. 35 (m, 24H), 1. 62 (m, 2H), 2. 17 (brs, lH), 2. 35 (t, J=7. 5Hz, 2H), 2. 60 (brs, 1H), 3. 59 (dd, J=3. 75, 11. 5Hz, lH), 3. 72 (dd, J=5. 7, 11. 3Hz, lH), 3. 92 (m, lH), 4. 18 (m, 2H) [104] (2) (S)-enantiomer : [a] =8. 90 (c=0. 58, EtOH),'H NMR (250MHz, CDC1) : 8 0. 88 (t, J=7. 5Hz, 3H), 1. 22-1. 35 (m, 24H), 1. 61 (m, 2H), 2. 18 (brs, lH), 2. 35 (t, J=7. 5Hz, 2H), 2. 60 (brs, 1H), 3. 60 (dd, J=3. 75, 11. 5Hz, lH), 3. 73 (dd, J=5. 7, 11. 3Hz, lH), 3. 94 (m, lH), 4. 19 (m, 2H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With zirconium(IV) tetraisopropoxide 2-propanol; 1,1'-bi-2-naphthol In toluene at 20℃; for 1h; | |
95% | With sodium tetrahydroborate In ethanol; ethyl acetate at 0 - 20℃; for 1h; | |
90% | With zirconium(IV) tetraisopropoxide 2-propanol; 4 Angstroem MS; 1,1'-bi-2-naphthol In isopropyl alcohol; toluene at 20℃; for 8h; |
With nickel; ethyl acetate Hydrogenation; | ||
With disodium hydrogenphosphate; potassium m-borate; ethanol | ||
With hydrogen In ethyl acetate | ||
With lithium aluminium tetrahydride In diethyl ether | ||
With sodium tetrahydroborate | ||
With sodium tetrahydroborate; N-Bromosuccinimide; triphenylbismuthane; potassium carbonate 1.) aqueous acetonitrile, room temperature, 1.25 h, 2.) methanol, 40 deg C, 4 h; Yield given. Multistep reaction; | ||
With sodium tetrahydroborate at 0 - 10℃; Yield given; | ||
With sodium tetrahydroborate In water at 25℃; for 1h; | ||
With sodium tetrahydroborate at 15 - 20℃; for 1h; Yield given; | ||
With sodium tetrahydroborate In water for 3h; Ambient temperature; Yield given; | ||
With hydrogen for 15h; | ||
With sodium tetrahydroborate In water at 0℃; for 1.4h; Yield given; | ||
With sodium tetrahydroborate Yield given; | ||
With sodium tetrahydroborate In ethanol at 0℃; | ||
With sodium tetrahydroborate for 1h; Inert atmosphere; | ||
2.87 g | With sodium tetrahydroborate In methanol at 0 - 20℃; for 1.16667h; | |
7.0 g | With sodium tetrahydroborate In ethanol; water at 0℃; for 2h; | 4.3 General procedure for the synthesis of product 3 In a round-bottom flask, 11.0g of compound 2 (42.1mmol) was added, followed by addition of 100mL of an aqueous solution of NaHCO3 (5% m/v). The reaction mixture was kept under magnetic stirring at 0°C for 10min. Next, 100mL of an aqueous solution containing 18.0g (84.2mmol, 2 equiv.) of sodium periodate was slowly added to the reaction mixture. The reaction was kept under magnetic stirring for 1h, after which 100mL of ethanol was added. The crude reaction mixture was then filtered off to remove the unreacted periodate. The remaining solution was then cooled to 0°C and 3.2g (84.2mmol, 2 equiv.) of sodium borohydride was then added. The reaction mixture was then kept under magnetic stirring for 2h and then filtered off. The solid was diluted in chloroform and submitted to a liquid-liquid extraction employing distilled water. Finally, the organic phase was dried and the compound 3 distilled under reduced pressure (5mmHg). 4.3.1 (S)-(2,2-Dimethyl-1,3-dioxolan-4-yl)methanol (3) (0029) Colorless oil, 7.0g, yield: 63%. [α]20D [α]D20 + 14.7° (pure). IR (ATR) ν (cm-1): 3414, 2990, 2934, 2887, 1641, 1377, 1261, 1211, 1150, 1046.1H NMR (500MHz, CDCl3) δ: 4.23 (tdd, J 6.5Hz, J 5.2Hz, J 3.8Hz, 1H), 4.03 (dd, J 8.2Hz, J 6.6Hz, 1H), 3.78 (dd, J 8.2Hz, J 6.5Hz, 1H), 3.72 (dd, J 11.6Hz, J 3.6Hz, 1H), 3.58 (dd, J 11.6Hz, J 5.1Hz, 1H), 2.10 (br, 1H), 1.43 (s, 3H), 1.36 (s, 3H). 13C {1H} NMR (125MHz, CDCl3) δ: 109.5, 76.3, 65.8, 63.1, 26.8, 25.4. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | To a suspension of N-hydroxyphthalimide (6.6 g, 40.5 mmol) in THF (135 mL) at0 C was added triphenylphosphine (10.6 g, 40.5 mmol) and (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5 mL, 40.5 mmol). Diisopropyl azodicarboxylate (10.3 mL, 52.7 mmol) was added dropwise whilst keeping the internal temperature below 15 C. Upon completion of the addition, the mixture was warmed to room temperature and stirred under N2 for 2 h. The solvent was removed in vacuo and the residue was diluted with DCM (50 mL). The resulting precipitate was filtered and the filtrate was concentrated in vacuo. The crude was purified by flash column chromatography (Silica 340 g, 10-100% EtOAc in hexane) to give the product (11.1 g, 99%) as a white solid. UPLC-MS (Acidic Method, 2 mm): rt 1.06 mi m/z 278.1 [M+H]. ?HNIVIR (400 MHz, CDC13) ppm 7.85-7.82 (m, 2H), 7.76-7.75 (m, 2H), 4.52-4.46 (m, 1H), 4.31 (dd, J= 10.0, 5.5 Hz, 1H), 4.17 (dd, J 8.5, 6.0 Hz, 1H), 4.13 (dd, J 10.0, 6.0 Hz, 1H), 3.96 (dd, J= 8.5, 5.5 Hz, 1H), 1.39 (s, 3H), 1.33 (s, 3H) |
99% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | [0521] To a suspension of TV-hydroxyphthalimide (6.6 g, 40.5 mmol) in THF (135 mL) at 0 C was added triphenylphosphine (10.6 g, 40.5 mmol) and (S)-(2,2-dimethyl-[l,3]dioxolan-4-yl)- methanol (5 mL, 40.5 mmol). Diisopropyl azodicarboxylate (10.3 mL, 52.7 mmol) was added dropwise whilst keeping the internal temperature below 15 C. Upon completion of the addition, the mixture was warmed to room temperature and stirred under N2 for 2 h. The solvent was removed in vacuo and the residue was diluted with DCM (50 mL). The resulting precipitate was filtered and the filtrate was concentrated in vacuo. The crude was purified by flash column chromatography (Silica 340 g, 10-100% EtOAc in hexane) to give the product (1 1.1 g, 99%) as a white solid. UPLC-MS (Acidic Method, 2 min): rt 1.06 min, m/z 278.1 [M+H]+. NMR (400 MHz, CDCb) d ppm 7.85-7.82 (m, 2H), 7.76-7.75 (m, 2H), 4.52-4.46 (m, 1H), 4.31 (dd, J = 10.0, 5.5 Hz, 1H), 4.17 (dd, J= 8.5, 6.0 Hz, 1H), 4.13 (dd, 7 = 10.0, 6.0 Hz, 1H), 3.96 (dd, 7 = 8.5, 5.5 Hz, 1H), 1.39 (s, 3H), 1.33 (s, 3H). |
99% | With di-isopropyl azodicarboxylate; triphenylphosphine; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | To a suspension ofTV-hydroxyphthalimide (6.6 g, 40.5 mmol) in THF (135 mL) at 0 C was added triphenylphosphine (10.6 g, 40.5 mmol) and (S)-(2,2-dimethyl-[l ,3]dioxolan-4-yl)- methanol (5 mL, 40.5 mmol). Diisopropyl azodicarboxylate (10.3 mL, 52.7 mmol) was added dropwise whilst keeping the internal temperature below 15 C. Upon completion of the addition, the mixture was warmed to room temperature and stirred under N2 for 2 h. The solvent was removed in vacuo and the residue was diluted with DCM (50 mL). The resulting precipitate was filtered and the filtrate was concentrated in vacuo. The crude was purified by flash column chromatography (Silica 340 g, 10-100% EtOAc in hexane) to give the product (11.1 g, 99%) as a white solid. UPLC-MS (Acidic Method, 2 min): rt 1.06 min, m/z 278.1 [M+H]+. 'H NMR (400 MHz, CDCb) d ppm 7.85-7.82 (m, 2H), 7.76-7.75 (m, 2H), 4.52-4.46 (m, 1H), 4.31 (dd, 7 = 10.0, 5.5 Hz, 1H), 4.17 (dd, 7 = 8.5, 6.0 Hz, 1H), 4.13 (dd, 7 = 10.0, 6.0 Hz, 1H), 3.96 (dd, 7 = 8.5, 5.5 Hz, 1H), 1.39 (s, 3H), 1.33 (s, 3H). |
97% | With 2,2'-azobis(isobutyronitrile); triphenylphosphine; In tetrahydrofuran; at 3 - 20℃; for 18h; | [0475] A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and the product of Example 31, Step B, (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3 C. to 5 C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15 C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3 C. to 5 C. The white solid was filtered, washed with a small amount of cold EtOH, and dried in vacuum oven at 40 C. to give (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): delta 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1). |
97% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 3 - 20℃; for 18h; | [0158] A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and the product of Preparation 1, Step B, (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3 C. to 5 C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15 C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3 C. to 5 C. The white solid was filtered, washed with a small amount of cold ETOH, and dried in vacuum oven at 40 C. to give (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (1112.5 g, 97%) as a white solid: 1H NMR (CDCl3): delta 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1). |
68.6% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃;Inert atmosphere; | Intermediate 10; (R)-O-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine; Step A: (R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isoindoline-1,3-dione To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (1.00 g, 7.57 mmol), triphenylphosphine (1.99 g, 7.57 mmol), and N-hydroxyphthalimide (1.23 g, 7.57 mmol) in THF (5.2 mL) was added DEAD (2.64 mL, 15.1 mmol) at 0 C. under a N2 atmosphere. After stiffing for 16 h at room temperature, the reaction mixture was concentrated in vacuo. The residue was filtered, washed with chloroform and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex: EtOAc=9:1~1:1) to give (R)-2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)isoindoline-1,3-dione (1.44 g, 68.6%) as a white solid. 1H NMR (CDCl3, Varian 400 MHz) delta 1.35 (3H, s), 1.41 (3H, s), 3.98 (1H, dd, J=8.8, 5.2 Hz), 4.12-4.20 (2H, m), 4.32 (1H, dd, J=10.2, 5.8 Hz), 4.47-4.53 (1H, m), 7.74-7.79 (2H, m), 7.83-7.86 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydride In N,N-dimethyl-formamide; Petroleum ether at 50℃; for 3h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | At first, 1 g of 60% NaH in mineral oil was added to a solution of (S)-3 (1.00 g, 7.6 mmol) in anhydrous THF (10 mL). After 10 min, 1 mL of benzyl bromide (1 mL, 8.4 mmol) was added portion wise. The mixture was stirred for 3 h at room temperature and monitored by TLC (petroleum ether/ethylacetate 9:1). The mixture was cautiously poured in a 10% solution of ammonium chloride into water and extracted with dichloromethane (3 × 10 mL). Evaporation of the solvents under vacuum and purification by chromatography column on silica gel (petroleum ether/ethylacetate 9:1) afforded 1.3 g (5.8 mmol, 76%) of (S)-4 as a colorless oil. inlMMLBox (c 1, CHCl3), {lit.12 inlMMLBox (neat)}. Rf (20% ethyl acetate/hexane) 0.6; 1H NMR (CDCl3) delta 1.39 (3H, s, CH3), 1.45 (3H, s, CH3), 3.50 (1H, dd, J = 5.6, 9.8 Hz, 1-CHHO), 3.59 (1H, dd, J = 5.9, 9.8 Hz, 1-CHHO), 3.77 (1H, dd, J = 6.6, 8.4 Hz, 3-CHHO), 4.09 (1H, dd, J = 6.6, 8.4 Hz, 3-CHHO), 4.33 (1H, dddd, J = 5.6, 5.9, 6.6, 6.6, 2-CHO), 4.59 (1H, d, J = 11.9 Hz, OCHHPh), 4.62 (1H, d, J = 11.9 Hz, OCHHPh), 7.34-7.38 (5H, m, OCH2Ph); 13C NMR delta 25.4 (CH3), 26.8 (CH3), 66.9 (3-C), 71.1 (1-C), 73.5 (OCH2Ph), 74.8 (2-C), 109.4 (C(CH3)2), 127.7 (o-PhCH, p-PhCH), 128.4 (m-PhCH), 137.9 (PhC). | |
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; | 3-O-Benzyl-sn-glycerol: To a solution of S(+) 2,2-dimethyl-l,3-dioxolane-4- methanol (0.48 g, 3.63 mmol) in DMF (5 mL) at 0 0C was added NaH (0.13 g, 5.45 mmol) portion wise, followed by benzyl bromide (0.68 g, 3.99 mmol). The reaction was allowed to reach rt and stirred overnight. It was quenched with addition of a few drops of methanol followed by ethyl acetate (10 mL) and water (10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 x 10 mL). Combined organic layer was dried on anhyd. sodium sulfate and concentrated in vacuo to get crude residue as a colorless oil. 1H NMR (600 MHz, CDCl3), delta 1.36 (s, 3H, CH3), 1.41 (s, 3H, CH3), 3.46 (dd, J= 5.4, 10.4 Hz, IH, CH2), 3.55 (dd, J= 5.4, 10.4 Hz, IH, CH2), 3.73 (dd, J= 8.4, 6.6 Hz, IH, CH2), 4.05 (dd, J= 8.4, 6.6 Hz, IH, CH2), 4.30 (dt, J= 6.0, 12.0 Hz, IH, CH), 4.55, 4.59 (ABq, J = 12.0 Hz, 2H, PhCH2), 7.20-7.40 (m, 5H, ArH); 13C NMR (150 MHz, CDCl3) delta 25.6, 27.0, 67.1, 71.3, 73.8, 75.0, 109.6, 127.87, 127.96, 127.98, 128.0, 128.6, 138.2. | |
Example 55(S)-1-((((2,3-bis(decanoyloxy)propoxy)carbonyl)oxy)methyl)-1-methyl-4-(2-methyl-10H-benzo[b]thieno[2,3-e][1,4]diazepin-4-yl)piperazin-1-ium iodide (Compound 55)Synthesis of (S)-4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolaneTo a suspension of sodium hydride (4.54 g, 113.5 mmol) in tetrahydrofuran (100 mL) and dimethyl formamide (20 mL) at 0 C. was added a solution of (S)-(+)-2,3-O-isopropylideneglycerol (10 g, 75.7 mmol) in tetrahydrofuran (10 mL) and dimethyl formamide (10 mL) dropwise over 30 minutes. Stirring ceased after addition therefore additional tetrahydrofuran (50 mL) and dimethyl formamide (10 mL) was added. After 1 hour, benzyl bromide (10 mL, 83.2 mmol) was added dropwise over 10 minutes. The reaction was then warmed to 25 C. After 4 hours the reaction was quenched with aq satd NH4Cl (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic phases were washed with water (5×100 mL) then brine (100 mL) then dried (MgSO4) and concentrated to give (S)-4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane (23.6 g) which was used without further purification.1H-NMR (300 MHz, CDCl3) delta 7.43-7.26 (5H, m), 4.57 (2H, dd), 4.35-4.27 (1H, m), 4.09-4.01 (1H, m), 3.76-3.69 (1H, m), 3.55 (1H, dd), 3.45 (1H, dd), 1.42 (3H, s), 1.36 (3H, s). |
With sodium hydride; In N,N-dimethyl-formamide; | First, the free hydroxyl group is reacted with benzylbromide (2) to afford benzyl ether 3. Next, the d ioxolane moiety is cleaved under acidic conditions, yielding diol 4, after which the liberated hydroxyl groups are esterified with stearoic acid to afford 5. Finally, the benzyl ether is cleaved by hydrogenolysis, leading to the desired lipid building block 5. | |
With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 20℃; for 0.25h;Cooling with ice; | To a solution of (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol (1.0 g, 7.6 mmol) in dimethylformamide (10 ml) were added 60% NaH (0.61 g, 15.1 mmol) and benzyl bromide (1.1 ml, 9.1 mmol) under ice-cooling. After stirring at room temperature for 15 min, water was added to the reaction mixture. The aqueous layer was extracted with hexane, and the organic layer was washed with H2O and brine. Then, it was dried over anhydrous MgSO4, and concentrated under reduced pressure to give 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane, which was used for the next step without further purification. To a solution of 4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane in methanol (17.4 ml) was added concentrated HCl (1.93 ml) under ice-cooling. After stirring at 60C for 30 min, a saturated aqueous NaHCO3 solution was added to the reaction mixture under ice-cooling. The aqueous layer was washed with hexane, and then the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure to give (R)-3-benzyloxy-1,2-propanediol (1.22 g, 88%) as an oil. 1H-NMR (400 MHz, CDCl3) : delta 3.53-3.61 (m, 2H), 3.65 (dd, J = 11.4 and 5.5 Hz, 1H), 3.72 (dd, J = 11.4 and 3.6 Hz, 1H), 3.88-3.93 (m, 1H), 4.56 (s, 2H), 7.30-7.39 (m, 5H). | |
To a suspension of NaH (9.08 g, 60 wt% dispersion in mineral oil, 227 mmol, 3.0 equiv.) in THF (189 mL) at 0 C was added (S)-solketal (9.43 mL, 75.7 mmol, 1.0 equiv.) dropwise via syringe. The cooling bath was removed, and the resulting suspension was stirred at room temperature for 1 h before being cooled back to 0 C followed by dropwise addition of benzyl bromide (10.8 mL, 90.8 mmol, 1.2 equiv.). The resulting mixture was brought to reflux and stirred for 4 h after which it was cooled to 0 C, diluted carefully with EtOH (116 mL), followed by addition of a 2.0 M aqueous solution of HCl (114 mL). After stirring at 80 C for 1 h, the resulting mixture was cooled to room temperature and quenched by addition of a saturated aqueous solution of NaHCO3 (250 mL). The organic layer was separated and the aqueous layer further extracted with EtOAc (3 150 mL), the combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified via column chromatography (petroleum ether/EtOAc (50%) / petroleum ether/EtOAc (80%)) to give 3- O-benzyl-sn-glycerol (12.7 g, 69.8 mmol, 92%) as a yellow oil; [a]D 24 5.10 (c 19.6, CHCl3); Rf 0.20 (petroleum ether/EtOAc (70%)); 1 H NMR (400 MHz, CDCl3) dH 7.40e7.27 (5H, m, ArH), 4.56 (2H, s, OCH2Ar), 3.95e3.85 (1H, m, CHOH), 3.77e3.69 (1H, m, CH2OH), 3.67e3.62 (1H, m, CH2?OH), 3.59 (1H, dd, J 9.5 and 4.0 Hz, CH2OBn), 3.55 (1H, dd, J 9.5 and 6.0 Hz, CH2?OBn), 2.57 (1H, d, J 4.5 Hz, OH), 2.06 (1H, app. t, J 6.0 Hz, OH); 13C NMR (100 MHz, CDCl3) dC 137.7, 128.5, 127.9, 127.8, 73.6, 71.8, 70.6, 64.1. | ||
With sodium hydride; | [0188] As illustrated in Scheme 6, commercially available compound 24 is protected as its corresponding benzyl ether on treatment with benzyl bromide and sodium hydride. The acetonide of compound 25 is cleaved under acidic conditions yielding the desired compound 26. Depending upon the number of equivalents of nonadecanoyl chloride used, selective acylation of compound 26 is achieved at either the primary hydroxyl group (compound 28) or at both hydroxyl groups (compound 27). In the case of compound 28, reaction with methyl iodide and silver oxide yields the methyl ether, compound 29. From this point, the benzyl ether of compound 27 or compound 29 is cleaved by catalytic hydrogenation yielding compound 30 or compound 31. Finally, reaction of compound 30 or compound 31 with phosphorodiamidous acid N,N,N',N'-tetrakis(l-methylethyl)-, phenylmethyl ester [Anderson 2010] generates the required phosphate precursor compound 32 or compound 33. These compounds are used in the preparation of compounds A and B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium hydride In dimethyl sulfoxide | |
With potassium hydroxide; acetic acid 1.) DMSO, 2.) 90 deg C; Yield given. Multistep reaction; | ||
With hydrogenchloride 1.), 2.) THF; Yield given. Multistep reaction; |
With sodium hydroxide; sulfuric acid 1.) 110-120 degC, 2 d; 2.) 4 h, reflux; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydride; In tetrahydrofuran; N,N-dimethyl-formamide; at 0 - 20℃; for 4h; | DMF (20 mL) and tetrahydrofuran (THF, 100 mL) were added to sodium hydride (3.44 g), and the mixture was stirred at 0C. The mixture was added dropwise with a solution of (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (10.4 g) in a mixture of DMF (10 mL) and THF (10 mL), and stirred at 0C for 1 hour. The mixture was added with benzyl chloride (9.95 mL), and stirred at room temperature for 3 hours. The mixture was added with a saturated ammonium chloride solution, and extracted twice with ethyl acetate. The resulting organic layer was washed 4 times with water and once with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was removed to obtain a crude product of (S)-(+)-4-benzyloxymethyl-2,2-dimethyl-1,3-dioxolane (17.8 g, quantitative). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.5% | With 15-crown-5; sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 6h; | NaH (60%) (3.4 g; 85.54 mmol) was suspended in dry THF (140 ml) together with S(+) 1,2-Isopropylidenglycerol (5.65 g; 42.75 mmol) and 15-Crown-5 (0.9 g; 4.28 mmol). The mixture was cooled to 0 C. and allyl bromide (7.2 ml; 85.54 mmol) was added dropwise. The suspension was stirred for 6 h at R.T, than NH4Cl saturated solution (100 ml) was added dropwise at 0 C. and then the mixture extracted with Et2O (3*100 ml). The combined organic layers were washed once with brine and concentrated under reduced pressure carefully. The residue was purified by flash chromatography (Biotage SP4 instrument, SNAP 100 column, isocratic elution Et2O/Cyclohexane 1:9), affording 5.8 g, (yield 78.5%) of the title compound. 1H NMR (300 MHz, Chloroform-d) delta 6.00-5.78 (m, 1H), 5.35-5.13 (m, 2H), 4.35-4.21 (m, 1H), 4.11-3.98 (m, 3H), 3.73 (m, 1H), 3.57-3.40 (m, 2H), 1.51-1.32 (m, 6H). |
78.5% | With sodium hydride; In tetrahydrofuran; at 0 - 20℃; for 6h; | NaH (60%) (3.4 g; 85.54 mmol) was suspended in dry THF (140 ml) together with S(+)- l,2-isopropylidenglycerol (5.65 g; 42.75 mmol) and l5-Crown-5 (0.9 g; 4.28 mmol). (0372) The mixture was cooled to 0C and allyl bromide (7.2 ml; 85.54 mmol) was added dropwise. The suspension was stirred for 6h at rt, than NH4CI saturated solution (100 ml) was added dropwise at 0C and then the mixture extracted with Et20 (3 X 100 ml). The combined organic layers were washed once with brine and concentrated under reduced pressure carefully. The residue was purified by flash chromatography (Biotage SP4 instrument, SNAP 100 column, isocratic elution Et20/Cyelohexane 1 :9), affording 5.8 g, (yield 78.5%) of the title compound ((S)-4-(allyloxymethyl)-2, 2-dimethyl- l,3-dioxo lane). NMR (300 MHz, Chloroform-d) d 6.00 - 5.78 (m, 1H), 5.35 - 5.13 (m, 2H), 4.35 - 4.21 (m, 1H), 4.11 - 3.98 (m, 3H), 3.73 (m, 1H), 3.57 - 3.40 (m, 2H), 1.51 - 1.32 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; In dichloromethane; at 25 - 30℃; for 12.5h;Inert atmosphere; | A solution of (S)-(+)-1,2-isopropylidene glycerol (1-1) (4.0 kg, 30.26 mol) in dichloromethane (120.0 L) was charged into a 250 L glass-lined reactor with stirring under an atmosphere of nitrogen. After the reaction mass was cooled to 0 C, pyridine (4.8 kg, 60.53 mol) and p-toluenesulfonyl chloride (11.6 kg, 60.53 mol) were added over a period of 30 min. The resulting reaction mixture was stirred at 25 - 30 C for 12 h, when there was not more than 5.0% of 1-1 remaining in the reaction mixture, as determined by GC-MS analysis. Next, the reaction mass was concentrated to 1/15 of the initial volume (~8 L) at 40 - 45 C under vacuum (500 - 600 mm Hg) and the precipitate was removed. The filtrate was concentrated at 25 - 30 C under vacuum (500 - 600 mm Hg) to give the crude product. The crude product (7.0 kg) was absorbed into 10.0 kg (2.5 w/w based on the input of starting material) of silica gel (60 - 120 mesh) using petroleum ether as solvent. A silica gel column was prepared using 25.0 kg (~6.0 w/w) of silica gel (60 - 120 mesh) in petroleum ether. The adsorbed material was loaded over the silica gel. The column was eluted with 100% petroleum ether, followed by petroleum ether containing 5.0% (v/v) and then 7.0% (v/v) of ethyl acetate to wash out the non-polar impurities. The polarity of the eluent was gradually increased to 10.0% (v/v) and then 20.0% (v/v) of ethyl acetate in petroleum ether and finally to 25.0% (v/v) of ethyl acetate in petroleum ether to elute the product from the column completely. The combined pure fractions were concentrated and the residue was dried in vacuo to give 1-2 (5.0 kg, 58% yield) as a yellow oil, which was contaminated with trace amounts of DCM and EtOAc, and used in the next step without further purification. HPLC purity: 98.8%; GC-MS (ESI): m/z 284 [M-2H]-; 1H NMR (300 MHz, CDCl3): delta 7.77 (dd, J1 = 6.63 Hz, J2 = 1.68 Hz, 2H), 7.34 (d, J = 7.98 Hz, 2H), 4.28 - 4.24 (m, 1H), 4.13 - 3.93 (m, 3H), 3.77 - 3.72 (m, 1H), 2.44 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With dmap; triethylamine; In dichloromethane; at 20℃;Inert atmosphere; | To a solution of (S)-solketal 1 (10.0 g, 75.8 mmol) and 4-dimethylaminopyridine (700 mg, 5.8 mmol) in anhydrous CH2Cl2 (500 mL) was added triethylamine (15.8 mL, 113.2 mmol) in an one portion of syringe under N2 atmosphere. To the colorless clean solution was added t-butyldiphenyl chlorosilane (26.2 mL, 100.6 mmol) rapidly drop-wise (~ 5 minutes) with stirring at room temperature under N2 atmosphere. The reaction mixture was vigorously stirred overnight at room temperature. And then, the slightly pale yellow homogeneous mixture was washed with aqueous, saturated NaHCO3 solution (300 mL) and H2O (300 mL). The organic layer (CH2Cl2) was dried over Na2SO4 and the filtrate was concentrated in vacuo. The yellow sticky gel was purified by silica gel column chromatography (column dimensions ID, 6 cm x length, 35 cm; flow rate, controlled by pressure; loading silica gel, 300 g) using n-hexane: EtOAc (9:1) as eluent to afford 21.2 g (76%) of 8 as syrup. TLC (SiO2), Rf = 0.70, n-hexane:EtOAc = 9:1. 1H NMR (600 MHz, CDCl3): 7.70 - 7.36 (m, 10H), 4.27 - 4.18 (m, 1H, CH), 4.11 (dd, J = 12.0, 1H, CH2), 3.94 (dd, J = 12.0, 9.0 Hz, 1H, CH2), 3.76 (dd, J = 15.6, 6.6 Hz, 1H), 3.68 (dd, J = 15.6, 9.6 Hz, 1H), 1.41 (s, 3H, CH3), 1.38 (s, 3H, CH3), 1.07 (s, 9H, CH3). 13C NMR (150 MHz, CDCl3): 136.00, 135.23, 133.77, 130.15, 130.14, 128.12, 109.61, 67.25, 64.98, 27.22, 27.14, 26.98, 25.90,19.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Adrythree--neckedround--bottomflaskequippedwitharefluxcondenserwaschargedwith(S)--1,2--isopropylideneglycerol(744mg,4mmol)andtetra--n--butylammoniumiodide(10mol%,147mg).SolidsweredegassedinthreecyclesbeforedryTHF(12ml)wasadded.Totheobtainedsolution,KH(50%inparaffin,370mg,1.15equiv)wasaddedinsmallportions.Themixturewasstirredfor10minbefore4--(chloromethyl)--1,2--dimethoxybenzene(Howelletal.,2001)(860mg,1.15equiv)wasaddedinoneportion.Theso--obtainedreactionmixturewasimmersedintoapreheatedoilbath(87C)andrefluxedfor16h.Afterremovalfromtheoilbathandcoolingdowntort,solidNH4Cl(1g)wasadded.Themixturewasstirredfor15min,filteredandthecollectedfiltratewasevaporatedtodryness.Theyellowliquidresiduewasfurtherpurifiedbyflashchromatographyusing50%Et2Oinpentane.FractionswithanRf=0.37(50%Et2Oinpentane)werecollectedandconcentratedtoafford1.04gofthedesiredcompoundascolorlessthickliquid(92%).1HNMR(400MHz,CDCl3)delta6.93-6.70(m,3H),4.54-4.43(m,21HNMR(400MHz,CDCl3)delta6.93-6.70(m,3H),4.54-4.43(m,2H),4.27(m,1H),4.03(dd,J=8.2,6.5Hz,1H),3.71(dd,J=8.2,6.4Hz,1H),3.51(dd,J=9.8,5.8Hz,1H),3.44(dt,J=12.3,4.7Hz,1H),1.40(s,3H),1.34(s,3H).13CNMR(101MHz,CDCl3)delta149.20,148.83,130.66,120.51,111.21,111.02,109.54,74.93,73.56,70.96,67.00,56.06,55.99,26.95,25.54.alphaD=+15.9(c=0.067,CHCl3).ElementalanalysiscalculatedforC15H22O5(C:63.81%,H:7.85%)found(C:63.51%,H:7.88%).Thespectroscopicdatacorrespondtopreviouslypublished(Alcarazetal.,1996) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With pyridine; tetrachloromethane; triphenylphosphine In benzene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; Inert atmosphere; | |
50% | Stage #1: (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; Stage #2: With triethylamine In dichloromethane at -78 - 20℃; | |
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1) CH2Cl2, a) -78 deg C, 10 min, b) -45 deg C, 60 min, 2) to 0 deg C, 20 min; Yield given. Multistep reaction; |
With pyridinium chlorochromate In dichloromethane | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine 1.) CH2Cl2, -78 deg C, 15 min, 2.) CH2Cl2, -78 deg C to room t., 1 h; Multistep reaction; | ||
With Swern oxidn | ||
With molecular sieve; pyridinium chlorochromate In dichloromethane at 20℃; for 5h; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -78 - 20℃; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -60 - 20℃; | ||
With oxalyl dichloride; dimethyl sulfoxide; triethylamine In dichloromethane at -65℃; for 0.25h; | ||
With trichloroisocyanuric acid; sodium acetate In ethyl acetate at 10℃; | 1 (S)-Glycerol acetonide (5.0g, 37.8mmol), sodium acetate (3.7g, 45.4mmol), 4-acetoamino-2,2,6,6-tetramethyl-1-piperidine-1-oxyl radical compound (TEMPO) (81mg, 0.38mmol) and ethyl acetate (50ml) were put in a 200ml-three neck flask. The suspension was cooled to less than 10°C in an ice bath and thereto was added trichloroisocyanuric acid (3.5g, 15.1mmol) divided by five portions. The insoluble salts are removed by filtration and to the filtrate were added 6M aqueous potassium carbonate solution (19ml) and phosphonoacetic acid trimethyl ester (8.3g, 45.4mmol). The mixture was stirred for 12 hours at room temperature. Thereto was added water (30ml). The mixture was separated by a separating funnel and the organic layer was concentrated to give a crude product. The crude product was purified by distillation to give the object ester compound (trans form/cis form=98/2) (5.8g, yield 82%). 1H-NMR (CDCl3/TMS) δ = 1.38 (s, 3H), 1.42 (s, 3H), 3.65 (dd, J=7.1, 8.2Hz, 1H), 3.72 (s, 3H), 4.16 (dd, J=6.6, 8.2Hz, 1H), 4.64 (m, 1H), 6.18 (dd, J=1.4, 15.6Hz, 1H), 6.87 (dd, J=5.6, 15.6Hz, 1H) Optical rotary power [α]D22: + 46.0° (c=3.9, CHCl3) | |
With sodium hypochlorite; sodium hydrogencarbonate In dichloromethane; water at 0 - 15℃; | 4 (S)-Glycerol acetonide (66.1g, 500mmol), TEMPO (0.78g, 5mmol), dichloromethane (170ml) and potassium bromide (5.95g, 50mmol) were dissolved in water (25ml) and the solution was put in a 1-L three neck flask. The solution was cooled to 0°C in an ice bath and therein was dissolved sodium hydrogencarbonate (9.35g, 111mmol). Thereto was dropped 1M aqueous sodium hypochlorite solution (550ml) which were adjusted to around pH 9.5 while the solution was kept at 10 to 15°C. Further sodium carbonate (207g, 1.5mol) and phosphonoacetic acid trimethyl ester (111 g, 600mmol) were added thereto and the mixture was stirred for 12 hours at room temperature. The mixture was separated by a separating funnel and the organic layer was concentrated to give a crude product. The crude product was purified by distillation to give the object ester compound (trans form/cis form=98/2) (74.5g, yield 80%). 1H-NMR (CDCl3/TMS) δ = 1.38 (s, 3H), 1.42 (s, 3H), 3.65 (dd, J=7.1, 8.2Hz, 1H), 3.72 (s, 3H), 4.16 (dd, J=6.6, 8.2Hz, 1H), 4.64 (m, 1H), 6.18 (dd, J=1.4, 15.6Hz, 1H), 6.87 (dd, J=5.6, 15.6Hz, 1H) Optical rotary power [α]D23: + 44.6° (c=3.0, CHCl3) | |
With [bis(acetoxy)iodo]benzene In dichloromethane for 3h; | 2 (S)-Glycerol acetonide (5.0g, 37.8mmol), 4-hydroxy TEMPO (130mg, 0.76mmol) and dichloromethane (50ml) were put in a 200-ml three neck flask. To the suspension was added diacetoxyiodobenzene (13.4g, 41.6mmol) and the mixture was stirred for about 3 hours while confirming disappearance of the starting material. Further sodium carbonate (12.0g, 113mmol) and phosphonoacetic acid triethyl ester (9.1g, 45.4mmol) were added thereto. The mixture was stirred for 16 hours at room temperature and thereto was added water (100ml). The mixture was separated by a separating funnel and the organic layer was concentrated to give a crude product. The crude product was purified by distillation to give the object ester compound (trans form/cis form=98/2) (6.6g, yield 87%). 1H-NMR (CDCl3/TMS) δ = 1.27 (t, J=7.1, 3H), 1.39 (s, 3H), 1.43 (s, 3H), 3.66 (dd, J=7.1, 8.1Hz, 1H), 4.16 (dd, J=6.6, 8.3Hz, 1H), 4.18 (q, J=7.1, 2H), 4.66 (m, 1H), 6.08 (dd, J=1.4, 15.6Hz, 1H), 6.86 (dd, J=5.7, 15.6Hz, 1H) Optical rotary power [α]D20: + 44.0° (c=0.5, CHCl3) | |
11.36 g | With sodium periodate; sodium hydrogencarbonate In dichloromethane; water at 20℃; for 3h; | 4.2 d-(R)-Glyceraldehyde acetonide (19) ZnCl2 (34.04g, 0.25mol) was stirred in AR grade acetone (185mL, 2.52mol) until dissolved. The mixture was cooled to 0°C and d-mannitol 18 (18.28g, 0.10mol) added. The mixture was warmed to rt and stirred for 24h. A 50 w/w% solution of K2CO3 (27.58g) in H2O (27mL) was added at 0°C and the mixture stirred for a further 1h. The acetone layer was then decanted off and the precipitate extracted with EtOAc (3×50mL). The acetone layer was brought to pH 8 by the addition of concentrated NH3 solution (1-2mL) and the resulting mixture was concentrated in vacuo. The residue was diluted with H2O (50mL) and extracted with EtOAc (3×30mL). The combined EtOAc extracts were washed with H2O (60mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was dried under high vacuum overnight to give the acetonide intermediate (18.59g, 71%) as a white powder; mp=108-110°C (lit23 119.5-121°C); [α]D20 +3.5 (c 0.93, CHCl3) (lit24 +2.0 (c 2.38, CHCl3)); δH (400MHz; CDCl3) 1.35 (s, 6H), 1.40 (s, 6H), 2.69 (br s, 1H), 2.70 (br s, 1H), 3.75 (t, J=6.2, 2H), 3.97 (m, 2H), 4.16 (m, 4H); δC (400MHz; CDCl3) 25.2 (2C), 26.7 (2C), 66.8 (2C), 71.2 (2C), 76.2 (2C), 109.2 (2C). NMR data, mp and [α]D closely matched those previously reported.23,24 (0012) The acetonide intermediate (20.00g, 0.076mol) was dissolved in distilled CH2Cl2 (200mL) and satd aqNaHCO3 (8mL) was added. NaIO4 (32.62g, 0.15mmol) was added over 5min keeping the temperature below 25°C using a cool water bath. The reaction mixture was stirred at rt for 3h under a reflux condenser. Anhydrous MgSO4 (9g) was added and the reaction mixture stirred for a further 30min. The reaction mixture was filtered and the residue stirred with distilled CH2Cl2 (50mL) for 10min then filtered again. The solvent was concentrated in vacuo at 40°C keeping the pressure above 150mbar. The residue was vacuum distilled into a chilled receiver at 30mbar (60-65°C) to give the title compound 19 (11.36g, 57%) as a colourless oil; [α]D20 +39.5 (c 1.30, CH2Cl2) (lit25 +53.8 (c 2.00, CHCl3)); δH (400MHz; CDCl3) 1.37 (s, 3H), 1.44 (s, 3H), 4.09 (m, 2H), 4.34 (m, 1H), 9.66 (s, 1H); δC (400MHz; CDCl3) 25.1 (2C), 26.2, 65.5, 79.8, 201.7. NMR data and [α]D matched those previously reported.25 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.4% | Stage #1: 1,2:5,6-di-O-isopropylidene-D-mannitol With lead(IV) acetate In ethyl acetate for 0.583333h; Stage #2: With sodium tetrahydroborate In ethanol Further stages.; | |
72% | Stage #1: 1,2:5,6-di-O-isopropylidene-D-mannitol With lead(IV) acetate In tetrahydrofuran at 0 - 20℃; for 1h; Stage #2: With sodium hydroxide; sodium tetrahydroborate In tetrahydrofuran at 10 - 28℃; for 2h; | |
60% | Stage #1: 1,2:5,6-di-O-isopropylidene-D-mannitol With sodium periodate; sodium hydrogencarbonate In water at 0 - 20℃; for 2h; Stage #2: With sodium tetrahydroborate In water at 0 - 20℃; | 31.B [0472] Step B: Preparation of (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol [0473] To a solution of the product of Example 31, Step A, 1,2:5,6-di-O-isopropylidene-D-mannitol (50 g, 0.191 mol), in water (700 mL), was added solid sodium bicarbonate (20 g). The resultant solution was stirred until all the solid dissolved, and then cooled in an ice-water bath. Solid sodium periodate (81.5 g, 0.381 mol) was slowly added to the solution portionwise. Gas evolution observed. The white mixture was stirred at ambient temperature for 2 hours. Solid sodium chloride (30 g) was added, and the mixture was stirred for 15 minutes. The white solid was filtered. The filtrate was cooled in an ice-water bath. Solid sodium borohydride was added slowly. Gas bubbles evolved. The mixture was warmed to ambient temperature, and stirred overnight. The milky mixture turned to a clear solution. The aqueous solution was extracted with dichloromethane (3×). The organic solution was washed with brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol as a colorless oil, which was dried under high vacuum at ambient temperature overnight, 34.82 g (60%); MS (APCI+)=133 (M++1). |
60% | With sodium periodate; sodium hydrogencarbonate In water at 0 - 20℃; for 2h; | 1.B [0156] To a solution of the product of Preparation 1, Step A, 1,2:5,6-di-O-isopropylidene-D-mannitol (50 g, 0.191 mol), in water (700 mL), was added solid sodium bicarbonate (20 g). The resultant solution was stirred until all the solid dissolved, and then cooled in an ice-water bath. Solid sodium periodate (81.5 g, 0.381 mol) was slowly added to the solution portionwise. Gas evolution observed. The white mixture was stirred at ambient temperature for 2 hours. Solid sodium chloride (30 g) was added, and the mixture was stirred for 15 minutes. The white solid was filtered. The filtrate was cooled in an ice-water bath. Solid sodium borohydride was added slowly. Gas bubble evolved. The mixture was warmed to ambient temperature, and stirred overnight. The milky mixture turned to a clear solution. The aqueous solution was extracted with dichloromethane (3×). The organic solution was washed with brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol as a colorless oil, which was dried under high vacuum at ambient temperature overnight, 34.82 g (60%); MS (APCI+)=133 (M++1). |
45% | ||
With lead(IV) acetate; sodium hydroxide; sodium tetrahydroborate 1.) THF, a) 10 deg C, 30 min, b) RT, 1 h, 2.) a) 10 deg C, 30 min, b) RT, 90 min; Yield given. Multistep reaction; | ||
With sodium periodate | ||
With hydrogenchloride; sodium hydroxide; sodium tetrahydroborate; potassium metaperiodate 1.) water/THF, rt., pH=7-8; 2.) water/THF, rt., 2 h, pH=7-8; Yield given. Multistep reaction; | ||
With sodium tetrahydroborate; sodium periodate Yield given. Multistep reaction; | ||
Yield given. Multistep reaction; | ||
With sodium tetrahydroborate; sodium periodate; disodium hydrogenphosphate; sodium methylate 1.) methanol, RT, 42 h, 2.) 1 h; Yield given. Multistep reaction; | ||
With Amberlite A27 borohydride form; Amberlite A27 periodate form In methanol; water for 2h; | ||
With lead(IV) acetate; lithium aluminium tetrahydride Yield given. Multistep reaction; | ||
With lithium hydroxide; sodium tetrahydroborate; sodium periodate 1.) methanol, 20 degC, 15 min; 2.) 20 min, ice cooling; Yield given. Multistep reaction; | ||
With BH4- resin; IO4- resin Multistep reaction; | ||
Multi-step reaction with 2 steps 1: NaIO3, Na2HPO4*2H2O / H2O / 0.25 h / Ambient temperature 2: NaBH4 / H2O / 3 h / Ambient temperature | ||
Multi-step reaction with 2 steps 1: NaIO4 / H2O / 1.5 h / Ambient temperature; pH 6-7 2: NaBH4 / 1 h / 15 - 20 °C | ||
Multi-step reaction with 2 steps 1: NaIO4, NaHCO3 / methanol; H2O / 1 h / 0 °C 2: NaBH4 / 0 - 10 °C | ||
Multi-step reaction with 2 steps 1: NaIO4, NaHCO3 / H2O / 0.5 h / 25 °C 2: NaBH4 / H2O / 1 h / 25 °C | ||
Multi-step reaction with 2 steps 1: Pb(OAc)4 / ethyl acetate / Ambient temperature 2: NaBH4 | ||
Multi-step reaction with 2 steps 1: NaIO4 / H2O / 0.17 h / ice-cooling 2: NaBH4 / H2O / 1.4 h / 0 °C | ||
Multi-step reaction with 2 steps 1: 52 percent / triphenylbismuth, N-bromosuccinimide, K2CO3 / H2O; acetonitrile / 6 h / Ambient temperature 2: 1.) triphenylbismuth, N-bromosuccinimide, K2CO3, 2.) NaBH4 / 1.) aqueous acetonitrile, room temperature, 1.25 h, 2.) methanol, 40 deg C, 4 h | ||
Multi-step reaction with 2 steps 1: 72 percent / NaHCO3, NaIO4 / CH2Cl2 / 2 h 2: NaBH4 | ||
Multi-step reaction with 2 steps 1: lead (IV)-acetate; benzene 2: Raney nickel; aqueous ethyl acetate / Hydrogenation | ||
Multi-step reaction with 2 steps 1.1: sodium hydrogencarbonate / water / 0.17 h / 0 °C 1.2: 1 h / 0 °C 2.1: sodium tetrahydroborate / ethanol; water / 2 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride 1.) DMF, 45 min, 2.) DMF, 25 deg C, 14 h; Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With 1H-imidazole; iodine; triphenylphosphine; In toluene; at 90℃; for 2h; | In a round-bottom flask, 3.0g of product 3 (22.7mmol) was added, followed by addition of 100mL of toluene. Next, 7.2g of triphenylphosphine (27.3mmol, 1.2 equiv.), 2.3g (34.1mmol, 1.5 equiv.) of imidazole and 7.5g of I2 (29.6mmol, 1.3 equiv.) were added. The reaction mixture was kept under reflux at 90C for 2h. Next, the solvent was dried under reduced pressure and the crude reaction mixture diluted in chloroform. A liquid-liquid extraction employing a saturated aqueous solution of Na2S2O3 (two aliquots of 100.0mL) was then carried out. The organic phase was then dried under reduced pressure and further purification by column chromatography (silica gel) employing isocratic eluent 2:8 ethyl acetate/hexane was carried out. 4.4.1 (R)-4-(iodomethyl)-2,2-dimethyl-1,3-dioxolane (4) (0031) Colorless oil, 4.0g, yield: 73%. [alpha]20D [alpha]D20 + 33.3 (c 1.8, ethanol). IR (ATR) nu (cm-1): 2984, 2929, 2873, 1371, 1211, 1144, 1040.1H NMR (500MHz, CDCl3) delta: 4.30-4.25 (m, 1H), 4.14 (dd, J 8.6Hz, J 6.1Hz, 1H), 3.78 (dd, J 8.6Hz, J 5.5Hz, 1H), 3.25 (dd, J 9.8Hz, J 4.6Hz, 1H), 3.14 (dd, J 9.8Hz, J 8.5Hz, 1H), 1.45 (s, 3H), 1.34 (s, 3H). 13C {1H} NMR (125MHz, CDCl3) delta: 110.7, 75.8, 69.8, 27.3, 25.7, 6.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 0 - 20℃; | 4.2.2. Acylation of 2 with acid and DCC General procedure: A solution of DCC (824 mg, 4 mmol) in dry CH2Cl2 (7 mL) was added dropwise to a stirred and ice-cooled solution of (9Z,12Z)-n-C5H11CHCHCH2CHCH(CH2)7CO2H (linoleic acid, 560 mg, 2 mmol), (+/-)-2 (264 mg, 2 mmol), and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (10 mL) over 30 min at 0-5 °C. Stirring was continued for 1 h at 0-5 °C, and the mixture was left to stand overnight at room temperature. It was then diluted with hexane and filtered through Celite. The Celite layer was washed with hexane. The combined filtrate and washings were concentrated in vacuo. The residue was chromatographed over SiO2 (15 g). Elution with hexane/EtOAc (20:1) gave 836.5 mg (quant.) of (+/-)-3e contaminated with DCC, which could be removed in the next step. Preparation of 3b and 3e was executed by the above procedure. |
With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In tetrahydrofuran at 0℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: To a solution of <strong>[2265-94-3]3,5-difluoronitrobenzene</strong> (6.0 mmol) and (S)-(+)-2,2-dimethyl-1,3-dioxolan-4-methanol (7.5 mmol) in DMF (10 mL) is added NaH (2.3 equiv.) at room temperature. After stirring for 2 hours, saturated NH4Cl is added and the reaction is extracted with EtOAc. The organic layer is separated, washed with brine, dried and concentrated to give a residue that was purified by preparative TLC (30% EtOAC in hexanes). The corresponding nitro compound thus obtained (1.0 mmol) is stirred at room temperature for 12 hours under a hydrogen atmosphere over 10% Pd/C (30 mg) in MeOH/EtOAc (15 mL). The reaction is filtered through a Celite pad and concentrated to dryness to provide 3-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-5-fluoro-phenylamine (compound 70.1) of sufficient purity to be used in the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | (R)-1-O-(1-naphthylmethyl)glycerol (compound 3) Under an argon atmosphere, 4.64 ml (31.0 mmol) of 1-(chloromethyl)naphthalene (compound 1) and 3.71 ml (30.0 mmol) of (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol (compound 2) were dissolved in 150 ml of a mixed solution (2:1) of toluene and dioxane. 9.0 g of pulverized potassium hydroxide was added to the solution, followed by 2 hours of heating and agitation at 120 C. The reaction solution was cooled to room temperature and then 350 ml of ethyl acetate was added to the solution. The resultant was washed 4 times with 100 ml of water and then washed once with 100 ml of saturated saline. The organic layer was dried using sodium sulfate. The solution was concentrated under reduced pressure. 150 ml of a 80% acetic acid aqueous solution was added to the thus obtained yellow oily substance and then the substance was dissolved therein, followed by 6 hours of agitation at room temperature. The reaction solution was concentrated under reduced pressure and then subjected to azeotrophy with toluene, thereby removing acetic acid. The residue was purified by silica gel column chromatography (elution solvent: ethanol-chloroform). Thus, 6.82 g (yield 98%) of the subject compound (compound 3) was obtained as a white solid substance. 1H NMR (270 MHz, DMSO-d6)delta: 8.12-8.09 (m, 1H), 7.95-7.86 (m, 2H), 7.59-7.44 (m, 4H), 4.93 (s, 2H), 4.67 (d, 1H, J=5.3 Hz), 4.48 (t, 1H, J=5.5 Hz), 3.66 (ddddd, 1H, J=3.5, 4.8, 5.2, 5.3, 5.9 Hz), 3.56 (dd, 1H, J=4.8, 9.7 Hz), 3.45 (dd, 1H, J=3.5, 9.7 Hz), 3.39 (ddd, 1H, J=5.2, 5.5, 10.9 Hz), 3.34 (ddd, 1H, J=5.5, 5.9, 10.9 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With potassium hydroxide; In methanol; dimethyl sulfoxide; at 20℃; for 18h;Inert atmosphere; | Under a nitrogen atmosphere, under water cooling, (S)-(+)-2, 2-dimethyl -1, 3-dioxolan-4-dimethyl sulfoxide (1 equiv.) methanol solution of potassium hydroxide (10 equiv.), p-methoxybenzylhydroxyurea diazidosulfochloride (1. 1-1. 2 equiv.) is added, 18 hours at room temperature. The reaction solution is poured on ice, diethyl ether is extracted. The extracted liquid diethyl ether, saturated saline solution after cleaning, anhydrous magnesium sulfate and dried. After filtering, the solvent by distillation under reduced pressure, residue through the silica gel column chromatography (20% ethyl acetate/Phenylbicyclohexane) of purified methanol soln. obtd. compd. p-toluenesulfonic acid hydrate (catalyst amount) is added, with stirring at room temperature between 2 January. The solvent by distillation under reduced pressure, residue through the silica gel column chromatography (50-100% ethyl acetate/Phenylbicyclohexane), purifying, compd. (74-94%, 2steps) 1 is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | To a solution of (S)-(2,2-dimethyl- 1 ,3-dioxolan-4-y l)methanol (19.5 g, 150 mmol) in dioxane (250 mL) was added NaH (6.0 g, 60%) at room temperature and stirred for 30 min. then 2- amino-6-chloropyridine (29; 6.43 g, 50 mmol) was added and the mixture was stirred under reflux for48h. Water was added and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with water (6 x 50 mL), dried over Na2SC , concentrated in vacuo and purified by silica gel chromatography (20:1 dichloromethane : methanol) to afford (S)-6- ((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridin-2-amine as an oil (30; 5.7 g, 25.4 mmol, 51%). MS (ESI) calcd for CH^Os (m/z) 224.12, found 225 [M+H]. | |
20.92% | To a stirred suspension of NaH (62.2 g, 1556 mmol) in N-Methyl-2-pyrrolidone (NMP) (800 mL), under nitrogen at 0C, was added a solution of (S)-(2,2-dimethyl-l,3-dioxolan- 4-yl)methanol (206 g, 1556 mmol) in N-Methyl-2-pyrrolidone (NMP) (300 mL) dropwise during 2 h. After stirring for another 10 min added a solution of <strong>[45644-21-1]6-chloropyridin-2-amine</strong> (200 g, 1556 mmol) in N-Methyl-2-pyrrolidone (NMP) (300 mL) dropwise during 30 min at 0C. The reaction mixture was stirred at 120 C for 48 hr. TLC indicated that starting material was. Reaction mixture was poured into ice cold water (2000 mL), aqueous layer was extracted with EtOAc (3 x 1000 mL). The combined organic layer was washed with water (3 x 1000 mL) to remove excess NMP. The organic layer was dried over Na2SC" , filtered and concentrated under reduced pressure to obtain crude product. Crude product was purified by column chromatography using 100-200 silica gel (eluent 12-15% EtOAc in pet ether) to obtain the desired pure product (S)-6-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)pyridin-2-amine (75 g, 325 mmol, 20.92 % yield) as a yellow viscous liquid. LCMS (m/z): 225 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol With potassium hydride In toluene at 20℃; for 18h; Stage #2: 17-bromoheptadec-1-ene In toluene for 10h; Reflux; | |
72% | Stage #1: (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)methanol With potassium hydride In toluene; paraffin oil at 20℃; for 18h; Inert atmosphere; Stage #2: 17-bromoheptadec-1-ene In toluene; paraffin oil for 10h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap; dicyclohexyl-carbodiimide; In dichloromethane; at 0 - 20℃; | General procedure: A solution of DCC (824 mg, 4 mmol) in dry CH2Cl2 (7 mL) was added dropwise to a stirred and ice-cooled solution of (9Z,12Z)-n-C5H11CHCHCH2CHCH(CH2)7CO2H (linoleic acid, 560 mg, 2 mmol), (+/-)-2 (264 mg, 2 mmol), and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (10 mL) over 30 min at 0-5 C. Stirring was continued for 1 h at 0-5 C, and the mixture was left to stand overnight at room temperature. It was then diluted with hexane and filtered through Celite. The Celite layer was washed with hexane. The combined filtrate and washings were concentrated in vacuo. The residue was chromatographed over SiO2 (15 g). Elution with hexane/EtOAc (20:1) gave 836.5 mg (quant.) of (+/-)-3e contaminated with DCC, which could be removed in the next step. Preparation of 3b and 3e was executed by the above procedure. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | (5 -(2,2-dimethyl-l ,3-dioxolan-4-yl)methanol (4.98 g, 37.72 mmol) was added to a room temperature suspension of NaH 60 wt% (1.7 g, 41.5 mmol) in THF. The reaction mixture was stirred at room temp for 30 min and a solution of <strong>[21190-89-6]ethyl 6-chloropicolinate</strong> (1.40 g, 7.54 mmol) in THF was added. The reaction mixture was heated at reflux for 16 h. After cooling to room temp, the pH was adjusted to 4 by the addition of 3 N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were dried and concentrated. The crude product was recrystallized from pentane/EtOAc to give (5)-6-((2,2-dimethyl-l ,3-dioxolan-4-yl)methoxy)pyrazine-2-carboxylic acid (1.30 g, 68% yield). MS (ESI) calcd for Ci2Hi5N05 (m/z): 253.10. | |
68% | (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (4.98 g, 37.72 mmol) was added to a room temperature suspension of NaH 60 wt% (1.7 g, 41.5 mmol) in THF. The reaction mixture was stirred at room temp for 30 min and a solution of <strong>[21190-89-6]ethyl 6-chloropicolinate</strong> (1.40 g, 7.54 mmol) in THF was added. The reaction mixture was heated at reflux for 16 h. After cooling to room temp, the pH was adjusted to 4 by the addition of 3 N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were dried and concentrated. The crude product was recrystallized from pentane/EtOAc to give (S)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-carboxylic acid (1.30g, 68% yield). MS (ESI) calcd for C12H15NO5 (m/z): 253.10 | |
(S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (4.98 g, 37.72 mmol) was added to a room temperature suspension of NaH 60 wt% (1.7 g, 41.5 mmol) in THF. The reaction mixture was stirred at room temp for 30 min and a solution of <strong>[21190-89-6]ethyl 6-chloropicolinate</strong> (1.40 g, 7.54 mmol) in THF was added. The reaction mixture was heated at reflux for 16 h. After cooling to room temp, the pH was adjusted to 4 by the addition of 3 N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were dried and concentrated. The crude product was recrystallized from pentane/EtOAc to give (S)-6-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazine-2-carboxylic acid (1.30g, 68% yield). MS (ESI) calcd for C11H15NO5 (m/z): 253.10. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 8 h 2: sodium azide / N,N-dimethyl-formamide / 20 h / 65 °C 3: triphenylphosphine / water; tetrahydrofuran | ||
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 0 °C 2: sodium azide / water; N,N-dimethyl-formamide / 18 h / 80 °C 3: triphenylphosphine / tetrahydrofuran; water / 20 °C | ||
Multi-step reaction with 3 steps 1: triphenylphosphine; 1H-imidazole; iodine / toluene / 2 h / 90 °C 2: sodium azide / N,N-dimethyl-formamide / 6 h / 60 °C 3: hydrogen; 15% palladium on carbon / methanol / 24 h / 20 °C |
Multi-step reaction with 2 steps 1: triphenylphosphine; diethylazodicarboxylate / tetrahydrofuran / 20 h / 20 °C 2: water; hydrazine / methanol / Reflux |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.46% | With di-isopropyl azodicarboxylate; triphenylphosphine In toluene at 90 - 100℃; for 1.5h; | 1.B Method B. A solution of (>S)-(+)-2,2-dimethyl-4-(hydroxymethyl)-l,3-dioxolane (19a) (3.56 g, 26.952 mmol) and DIAD (6.98 ml, 33.69 mmol) in toluene (10 ml) was slowly added to a mixture of 3-trifluoromethylphenol (2.75 ml, 22.46 mmol) and PPh3 (8.925 g, 33.69 mmol) in toluene (50 ml) at 90 °C over 30 min. After heating at 100 °C for another 1 h, TLC analysis (CH2Cl2/MeOH 20: 1) indicated disappearance of the starting solketal 19a. The excess of toluene (30 ml) was evaporated and the residue was put into refrigerator for several hours. Triphenylphosphine oxide was removed by filtration on a Buchner funnel and washed with cold toluene (3 x 15 ml). The filtrate and washings were combined and concentrated under reduced pressure to give the crude product 21a (9.6 g) as an orange- yellow oil. The crude product was distilled to afforded the acetonide (5)-(+)-21a (5.98 g, 96.46% yield, 89.50% ee) as a colourless oil. bp 80 - 94 °C (0.2 mmHg). The characterization data from IR and NMR spectra were identical in all aspects with those of (5}-(+)-21a obtained according to the Method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30.7% | With sodium hydride; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere; | To suspension of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (10.20 g, 77 mmol), and NaH (4.63 g, 116 mmol) in tetrahydrofuran (THF) (50 mL) stirred under nitrogen at room temperature was added <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (5 g, 38.6 mmol) portion wise over 15 min. The reaction mixture was stirred at 70 C. for 16 hr. Next, the reaction mixture was quenched with solution of aq. NaHCO3 and then extracted with EtOAc, dried Na2SO4 and evaporated. The crude product was added to a silica gel column and was eluted with 50% Hex/EtOAc. Collected fractions were evaporated to give the desired product (3 g, 11.84 mmol, 30.7% yield) as off white solid, LCMS (m/z) 226.2 [M+H]+. |
30.7% | With sodium hydride; In tetrahydrofuran; at 70℃; for 16h;Inert atmosphere; | To suspension of (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (10.20 g, 77 mmol), and NaH (4.63 g, 1 16 mmol) in tetrahydrofuran (THF) (50 mL)stirred under nitrogen at room temperature was added <strong>[7461-50-9]2-chloropyrimidin-4-amine</strong> (5 g, 38.6 mmol) portion wise over 15 min. The reaction mixture was stirred at 70 C for 16 hr. Next, the reaction mixture was quenched with solution of aq. NaHC03 and then extracted with EtOAc, dried Na2S04 and evaporated. The crude product was added to a silica gel column and was eluted with 50% Hex/EtOAc. Collected fractions were evaporated to give the desired product (3 g, 1 1.84 mmol, 30.7 % yield) as off white solid, LCMS (m/z) 226.2 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.2% | With sodium; at 130℃; for 16h;Sealed tube; | 6-chloropyrazin-2-amine (0.980 g, 7.57 mmol), (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (2 g, 15.13 mmol) and sodium (0.348 g, 15.13 mmol) were taken in a seal tube and heated at 130 C. for 16 hr and then the reaction mixture was quenched with methanol and ice cold water (100 mL) and extracted with ethyl acetate (5×50 mL). The combined organic layers were washed with water, saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the product (1 g, 4.26 mmol, 28.2% yield), LCMS (m/z) 265.1 [M+H]+. |
28.2% | With sodium; at 130℃; for 16h;Sealed tube; | 6-chloropyrazin-2-amine (0.980 g, 7.57 mmol),(S)-(2,2-dimethyl-l,3-dioxolan-4- yl)methanol (2 g, 15.13 mmol) and sodium (0.348 g, 15.13 mmol) were taken in a seal tube and heated at 130 C for 16 hr and then the reaction mixture was quenched with methanol and ice cold water (100 mL) and extracted with ethyl acetate (5 x 50 mL). The combined organic layers were washed with water, saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated to give the product (1 g, 4.26 mmol, 28.2 % yield), LCMS (m/z) 265.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With zinc(II) chloride at 0 - 20℃; for 24h; | 4.2 d-(R)-Glyceraldehyde acetonide (19) ZnCl2 (34.04g, 0.25mol) was stirred in AR grade acetone (185mL, 2.52mol) until dissolved. The mixture was cooled to 0°C and d-mannitol 18 (18.28g, 0.10mol) added. The mixture was warmed to rt and stirred for 24h. A 50 w/w% solution of K2CO3 (27.58g) in H2O (27mL) was added at 0°C and the mixture stirred for a further 1h. The acetone layer was then decanted off and the precipitate extracted with EtOAc (3×50mL). The acetone layer was brought to pH 8 by the addition of concentrated NH3 solution (1-2mL) and the resulting mixture was concentrated in vacuo. The residue was diluted with H2O (50mL) and extracted with EtOAc (3×30mL). The combined EtOAc extracts were washed with H2O (60mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting solid was dried under high vacuum overnight to give the acetonide intermediate (18.59g, 71%) as a white powder; mp=108-110°C (lit23 119.5-121°C); [α]D20 +3.5 (c 0.93, CHCl3) (lit24 +2.0 (c 2.38, CHCl3)); δH (400MHz; CDCl3) 1.35 (s, 6H), 1.40 (s, 6H), 2.69 (br s, 1H), 2.70 (br s, 1H), 3.75 (t, J=6.2, 2H), 3.97 (m, 2H), 4.16 (m, 4H); δC (400MHz; CDCl3) 25.2 (2C), 26.7 (2C), 66.8 (2C), 71.2 (2C), 76.2 (2C), 109.2 (2C). NMR data, mp and [α]D closely matched those previously reported.23,24 (0012) The acetonide intermediate (20.00g, 0.076mol) was dissolved in distilled CH2Cl2 (200mL) and satd aqNaHCO3 (8mL) was added. NaIO4 (32.62g, 0.15mmol) was added over 5min keeping the temperature below 25°C using a cool water bath. The reaction mixture was stirred at rt for 3h under a reflux condenser. Anhydrous MgSO4 (9g) was added and the reaction mixture stirred for a further 30min. The reaction mixture was filtered and the residue stirred with distilled CH2Cl2 (50mL) for 10min then filtered again. The solvent was concentrated in vacuo at 40°C keeping the pressure above 150mbar. The residue was vacuum distilled into a chilled receiver at 30mbar (60-65°C) to give the title compound 19 (11.36g, 57%) as a colourless oil; [α]D20 +39.5 (c 1.30, CH2Cl2) (lit25 +53.8 (c 2.00, CHCl3)); δH (400MHz; CDCl3) 1.37 (s, 3H), 1.44 (s, 3H), 4.09 (m, 2H), 4.34 (m, 1H), 9.66 (s, 1H); δC (400MHz; CDCl3) 25.1 (2C), 26.2, 65.5, 79.8, 201.7. NMR data and [α]D matched those previously reported.25 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.58% | With dmap; dicyclohexyl-carbodiimide In dichloromethane at 25℃; for 2h; | 1 Compound 17: (R)-2,3-bis(propionyloxy)propy methyl fumarate To a solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (5 g, 37.83 mmol, 4.67 mL, 1 equiv.) in DCM (50 mL) was added (E)-4-methoxy-4-oxo-but-2-enoic acid (7.38 g, 56.75 mmol, 1.5 equiv.), DCC (11.71 g, 56.75 mmol, 1 1.48 mL, 1.5 equiv.) and DMAP (2.31 g, 18.92 mmol, 0.5 equiv.) at 25 °C. The mixture was stirred at 25 °C for 2 h. Spots on a thin layer chromatogram (TLC) indicated formation of a new compound. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 10/1 ). Compound (R)-(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl methyl fumarate (8 g, 32.75 mmol, 86.58% yield) was obtained as a white solid. |
With dmap; 1-ethyl-3-(3-methylaminopropyl)-carbodiimide hydrochloride In dichloromethane at 20℃; for 5h; Inert atmosphere; | 3.1 Step 1 : R-(E)-But-2-enedioic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester methyl ester Step 1 : R-(E)-But-2-enedioic acid 2,2-dimethyl-[l,3]dioxolan-4-ylmethyl ester methyl ester : Monomethylfumarate (1.65 g; 12.7 mmol), S-(2,2-Dimethyl-[l,3]dioxolan-4-yl)- methanol (1 g; 8 mmol), N-ethyl-N'-(3-methylaminopropyl)carbodiimide hydrochloride (1.62 g, 8.5 mmol) and 4-(dimethylamino)pyridine (0.05 g, 0.4 mmol) are dissolved in dry dichloromethane (22 ml). The reaction mixture is kept under continuous stirring at room temperature under nitrogen for 5 h. The organic layer is washed with water (20 ml), the aqueous layer is washed with dichloromethane (3x50 ml) and the combined organic layers are dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The black oily product is subjected to column chromatography (flash chromatographie; eluent: EtOAc/n-heptane 1/1). The obtained product is subjected once more to column chromatography (EE/n-heptane 1/2) to yield the product as colourless oil. After drying the oil on the rotary evaporator at 50°C for 3 hours, the colourless oil is slowly solidifying to a white solid at room temperature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.56 g | To a stirred solution of diacetonoid (11) (6 g) in DCM (60 mL),sat. NaHCO3 solution (2 mL) and NaIO4 (3.3 g) was added portionwise in 2e3 min. The reaction mixture was stirred for 2 h at RT.After 2 h, anhydrous sodium sulphate (2 g) was added and thereaction mixture was stirred for 1 h at RT. After completion of reaction time, the reaction mixture was filtered through vacuum filterand filtrate was concentrated on rotary evaporator at 28 C withcool water circulation. The crude (S)-()-glyceraldehyde was dissolved in ethyl acetate (40 mL) and ethanol (5 mL) followed bygradual addition of NaBH4 (0.65 g) at 0 C. This reaction mixturewas stirred at RT for 3 h. At that stage, acetone was added (5 mL) at0 C and allowed to stir at RT for 15 min. Then the reaction mixturewas cooled to 0 C and saturated NH4Cl solution was added dropwise with the dropper until there was no more evolution ofhydrogen gas. After this quenching process, the reaction mixturewas transferred to a separating funnel. The two layers were separated, from this the organic layer was separated and the aqueouslayer was extracted with diethyl ether twice. The combined organiclayers were washed with brine solution and dried over anhydrousNa2SO4 and concentrated under vaccum at 45 C to obtain a crudeproduct. The crude product was purified by silica gel columnchromatography using a solvent mixture of hexane: EtOAc (4: 1, v/v) to obtain a title compound (2.56 g, 85percent) with oil like characteristics. 1H NMR (300 MHz, CDCl3) d 4.19e4.27 (m, 1H), 4.04 (t,J 8.1 Hz, 1H), 3.78 (t, J 8.1 Hz, 1H), 3.69 (d, J 11.3 Hz, 1H), 3.59(dd, J 4.9, 11.1 Hz, 1H), 2.9(Bs, OH), 1.43 (s, 3H), 1.37 (s, 3H); 13CNMR (125 MHz, CDCl3) d 109.2, 76.1, 65.6, 62.8, 26.5, 25.1; IR (CHCl3)3420, 2987, 2936, 2884, 1457, 1372, 1214, 1157, 1051, 845 cm1;Specific rotation: [a ]D 20 ()10.28, (C 5, MeOH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44.9% | Cesium carbonate (37.0 g, 1 14 mmol) was taken into multi-neck RB. Then flask was cooled to 0 C and N-Methyl-2-pyrrolidone ( MP) (100 mL) was added slowly over a period of 3 minutes. The resulting reaction mixture was stirred under nitrogen for 15 min. Then (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (10 g, 76 mmol) was added dropwise over a period of 5 min at 0 C. This suspension was stirred at room temperature C for 1 h. Suspension became pale yellow solution after added <strong>[407-20-5]3-bromo-5-fluoropyridine</strong> (7.62 mL, 73.9 mmol). The resulting solution was stirred at 75 C for 24 hr. Reaction progress was monitored by TLC 40% EtOAc in Hexane. TLC indicated consumption of SM and formation of new spot after 24 h. The reaction mass was cooled to room temperature, diluted with water (500 mL). The aqueous layer was extracted with ethyl acetate (2X300 mL). The organic layer was washed with brine (250 mL), dried over Na2S04 filtered, concentrated under reduced pressure to afford brown oil. The crude product was purified by column chromatography over 100-200 mesh size silica gel. Column was eluted with a gradient of EtOAc/Hexane. Desired compound was eluted with 20% EtOAc in Hexane. Compound fractions containing pure compound were concentrated under reduced pressure to afford (S)-3-bromo-5-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridine (10 g, 34.0 mmol, 44.9 % yield) as pale yellow viscous oil, LCMS (m/z): 289.99 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.8% | To a suspension of NaH (8.25 g, 189 mmol) in 1,4-Dioxane (200 mL) was added dropwise a solution of (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (10 g, 76 mmol) in 1,4- Dioxane (50 mL) under Nitrogen at 0C. The resulting suspension was stirred at rt for lh. 4-chloropyrimidin-2-amine (7.84 g, 60.5 mmol) was added to the reaction mixture portion wise at rt and the resulting suspension was heated to 90 C for 48 hr. The reaction mixture was cooled to 28 C and was partitioned between water (200 mL) and EtOAc (200 mL). Organic layer was separated and was dried over anhydrous Na2S04, filtered and filtrate was evaporated to get crude (TLC eluent: Neat ethyl acetate R/0.3; UV active). The crude compound was purified by column chromatography (100-200 mesh silica gel, eluted at 60% Ethyl acetate in hexane) to afford (S)-4-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)pyrimidin-2-amine (8.0 g, 35.4 mmol, 46.8 % yield) as pale yellow solid LCMS (m/z) 226.30 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25.6% | To a suspension of NaH (6.17 g, 154 mmol) in THF (100 ml) was added (S)-(2,2- dimethyl-l,3-dioxolan-4-yl)methanol (13.26 g, 100 mmol) in THF (50 ml) was added to the reaction mixture at 0 C, and the reaction mixture was stirred for lh at 25C.to this 2- chloropyrimidin-5-amine (10 g, 77 mmol) in THF (50 ml) and was added at 0C and slowly heated to 80 C and stirred for 16 hr at 80 C. After completion of the reaction, reaction mixture was quenched with the ammonium chloride (10 ml) and extracted with the ethyl acetate (3x20 ml). The organic layer was separated and washed with the brine and dried over Na2S04,filtered it and concentrated under reduced pressure to get the crude. This crude was triturated with the diethyl ether to get (S)-2-((2,2-dimethyl-l,3-dioxolan-4- yl)methoxy)pyrimidin-5 -amine (5.0 g, 19.77 mmol, 25.6 % yield) as a brown solid, LCMS (/// r): 226.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | To a stirred solution of cesium carbonate (492 g, 1510 mmol) in DMF (1000 mL) was added (S)-(2, 2-dimethyl-l, 3-dioxolan-4-yl) methanol (133 g, 1007 mmol) at 0 C. The resulting reaction mixture was stirred at room temperature for 30 min. Then a solution of 2, 5-dichloropyrazine (150 g, 1007 mmol) in DMF (500 mL) was added at 0 C and the resulted reaction mixture was stirred at 100 C for 4 h. (TLC System: 20% Ethyl acetate in Petether, R 0.5, UV active). The reaction mixture was diluted with ice cold water (500 mL), extracted with EtOAc (3 x 300 mL). The combined organic layer was washed with water (2 x 200 mL) and brine solution (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to obtain crude compound. The crude compound was purified by flash column chromatography (silica gel: 100-200 mesh, eluent: 10 % EtOAc in Hexane) to afford the desired product (,S)-2-chloro-5-((2, 2-dimethyl-l, 3- dioxolan-4-yl) methoxy) pyrazine (200 g, 768 mmol, 76 % yield) as a yellow liquid. LCMS (m/z): 245.1 [M+H]+. | |
71% | To a suspension of (S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (8.87 g, 67.1 mmol), in Nu,Nu-Dimethylformamide (DMF) (50 mL) stirred under nitrogen at 0C was added cesium carbonate (32.8 g, 101 mmol), the resulting reaction mixture was stirred at 0 C for 1 hr. To this added <strong>[19745-07-4]2,5-dichloropyrazine</strong> (10 g, 67.1 mmol). The resulting reaction mixture was stirred at 100 C for 6 hr. Progress of the reaction was monitored by TLC. TLC indicated starting material was consumed to form new polar spot with 0.3 Rf. The reaction mass was cooled to rt, added water(lOOmL) and extracted with Ethyl acetate(lOOmL). The organic layer was washed with water(100mLX2). The organic layer was dried over Na2S04 and filtered and concentrated to get crude as light brown liquid. The crude product was added to a silica gel (60-120) column and was eluted with Hex/EtOAc. Collected fractions: 30%EtOAc in Hexane the product was eluted. Concentrated the product fractions to afford (S)-2-chloro-5-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyrazine (12 g, 47.7 mmol, 71.0 % yield) as light brown liquid, LCMS (m/z): 244.90 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | With triphenylphosphine; diethylazodicarboxylate; In tetrahydrofuran; at 0 - 20℃; for 4h; | To a stirred solution of <strong>[4983-28-2]2-chloropyrimidin-5-ol</strong> (13 g, 100 mmol) in THF (100 mL) at 0 C was added (,S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (13.16 g, 100 mmol), triphenylphosphine (32.7 g, 124 mmol) followed by DEAD (19.71 mL, 124 mmol) and reaction was stirred at RT for 4 h. (TLC eluting system: 30% EtOAc in pet ether; R/-0.5; UV active). The reaction mixture was quenched with water (50 mL) and extracted into EtOAc (2x75 mL). Organic layer was separated and dried over anhydrous Na2S04, filtered and filtrate was evaporated to give crude product. The crude was purified by chromatography (Silicagel, eluent: 20% EtOAc in hexane) to afford (,S)-2-chloro-5-((2,2- dimethyl-l,3-dioxolan-4-yl)methoxy)pyrimidine (20g, 79 mmol, 79 % yield) as an off white solid. LCMS (m/z): 245.10; [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | To a stirred suspension of potassium tert-butoxide (3.90 g, 34.7 mmol) in 1,4-Dioxane (50 mL) was added a mixture of (,S)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (2.75 g, 20.84 mmol) at 0 C and the reaction mixture was stirred at 25 C for 1 h. under Nitrogen atmosphere, then <strong>[29049-45-4]6-chloropyridazin-4-amine</strong> (1.5 g, 1 1.58 mmol) was added to the reaction mixture and the resulted reaction mixture was stirred at 1 10 C for 16 h. (TLC System: Neat Ethyl acetate, Rf: 0.3). The reaction mixture was poured in to ice cold water (40 ml) and extracted with EtOAc (2x80 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to get crude compound. The crude material was purified by flash column chromatography (Neutral alumina, Eluent: 65% Ethyl acetate in Pet ether) to afford the desired product (,S)-6-((2,2-dimethyl-l,3-dioxolan-4-yl)methoxy)pyridazin-4-amine (1.0 g, 4.28 mmol, 37.0 % yield) as a white solid. LCMS (m/z): 226.20 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In tetrahydrofuran; mineral oil; at 0 - 60℃; for 4h; | To a solution of <strong>[327056-62-2]5-fluoropicolinonitrile</strong> (366mg, 3 mmol) and (S)-(2,2-dimethyl- 1 ,3-dioxolan-4-yl)methanol (528 mg, 4 mmol) in THF (15 mL) was added NaH (60% in mineral oil, 160 mg, 4 mmol) at 0 C. The reaction was heated to 60 C and stirred for 4 h. The reaction mixture was diluted with water (50ml_) and filtered to afford Compound 2 (700 mg) without purification. |
[ 5754-34-7 ]
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol
Similarity: 0.88
[ 4728-12-5 ]
(2,2-Dimethyl-1,3-dioxan-5-yl)methanol
Similarity: 0.77
[ 5754-34-7 ]
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol
Similarity: 0.88
[ 57280-22-5 ]
4,4-Dimethyl-3,5,8-trioxabicyclo[5.1.0]octane
Similarity: 0.81
[ 4728-12-5 ]
(2,2-Dimethyl-1,3-dioxan-5-yl)methanol
Similarity: 0.77
[ 1607-37-0 ]
4-[(2,3-Epoxypropoxy)methyl]-2,2-dimethyl-1,3-dioxolane
Similarity: 0.96
[ 5754-34-7 ]
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)ethanol
Similarity: 0.88
[ 23735-39-9 ]
(R)-4-(Iodomethyl)-2,2-dimethyl-1,3-dioxolane
Similarity: 0.73
Precautionary Statements-General | |
Code | Phrase |
P101 | If medical advice is needed,have product container or label at hand. |
P102 | Keep out of reach of children. |
P103 | Read label before use |
Prevention | |
Code | Phrase |
P201 | Obtain special instructions before use. |
P202 | Do not handle until all safety precautions have been read and understood. |
P210 | Keep away from heat/sparks/open flames/hot surfaces. - No smoking. |
P211 | Do not spray on an open flame or other ignition source. |
P220 | Keep/Store away from clothing/combustible materials. |
P221 | Take any precaution to avoid mixing with combustibles |
P222 | Do not allow contact with air. |
P223 | Keep away from any possible contact with water, because of violent reaction and possible flash fire. |
P230 | Keep wetted |
P231 | Handle under inert gas. |
P232 | Protect from moisture. |
P233 | Keep container tightly closed. |
P234 | Keep only in original container. |
P235 | Keep cool |
P240 | Ground/bond container and receiving equipment. |
P241 | Use explosion-proof electrical/ventilating/lighting/equipment. |
P242 | Use only non-sparking tools. |
P243 | Take precautionary measures against static discharge. |
P244 | Keep reduction valves free from grease and oil. |
P250 | Do not subject to grinding/shock/friction. |
P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
Home
* Country/Region
* Quantity Required :
* Cat. No.:
* CAS No :
* Product Name :
* Additional Information :