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CAS No. : | 20031-21-4 | MDL No. : | MFCD00063295 |
Formula : | C8H14O5 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | JAUQZVBVVJJRKM-XZBKPIIZSA-N |
M.W : | 190.19 | Pubchem ID : | 88338 |
Synonyms : |
Monoacetone-D-xylose;1,2-O-Isopropylidene-alpha-D-xylofuranose
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 41.96 |
TPSA : | 68.15 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) : | -7.75 cm/s |
Log Po/w (iLOGP) : | 1.78 |
Log Po/w (XLOGP3) : | -0.41 |
Log Po/w (WLOGP) : | -0.78 |
Log Po/w (MLOGP) : | -0.85 |
Log Po/w (SILICOS-IT) : | -0.26 |
Consensus Log Po/w : | -0.1 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.69 |
Solubility : | 38.4 mg/ml ; 0.202 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.56 |
Solubility : | 52.8 mg/ml ; 0.277 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.42 |
Solubility : | 499.0 mg/ml ; 2.62 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 4.06 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
92% | In dichloromethane at 20℃; for 2h; | |
91% | With pyridine for 5h; | |
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine at 20℃; for 12h; | |
95% | With pyridine for 16h; | |
95% | With triethylamine In dichloromethane for 3h; Inert atmosphere; |
95% | With pyridine at 0 - 20℃; for 12h; | |
88% | With dmap; triethylamine In N,N-dimethyl-formamide at 20℃; for 18h; Inert atmosphere; | 2 1,2-O-Isopropylidenene-5-O-trityl-α-d-xylofuranose 15 4.2 1,2-O-Isopropylidenene-5-O-trityl-α-d-xylofuranose 15 10 To a solution of the known 14 9 (14.71 g, 77 mmol) in dry DMF (45 mL) were successively added Et3N (12 mL, 85 mmol), trityl chloride (23.7 g, 85 mmol) and DMAP (0.76 g, 6.2 mmol). The resulting mixture was stirred for 18 h at room temperature, then poured into ice-water (140 mL) and extracted with Et2O (2 * 140 mL). The combined organic extracts were dried over Na2SO4, the solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel (n-hexane/ethyl acetate, 5:1) to afford 29.4 g (88%) of compound 15 as a white foam; [α]D22 = +10.9 (c 0.22, CHCl3); {lit 10 [α]DRT = +54.4 (c 1.0, CHCl3)}. IR (neat) νmax 3458, 3058, 2982, 2933, 1448, 1213, 1069 cm-1; 1H NMR (400 MHz, CDCl3): δ 1.33 (s, 3H, CH3), 1.49 (s, 3H, CH3), 3.17 (d, 1H, J4,3 = 2.8 Hz, H-3), 3.47 (dd, 1H, J5,5 = 10.2 Hz, J5,4 = 3.2 Hz, H-5), 3.57 (dd, 1H, J5,5 = 10.2 Hz, J5,4 = 5.2 Hz, H-5), 4.25-4.28 (m, 1H, H-4), 4.53 (d, 1H, J2,1 = 3.7 Hz, H-2), 6.01 (d, 1H, J2,1 = 3.7 Hz, H-1), 7.23-7.26 (m, 3H, Ph), 7.29-7.33 (m, 6H, Ph), 7.43-7.46 (m, 6H, Ph); 13C NMR (100 MHz, CDCl3): δ 26.1 (CH3), 26.8 (CH3), 61.8 (C-5), 76.3 (C-4), 78.4 (C-3), 85.1 (C-2), 87.5 (CqTr), 105.0 (C-1), 111.5 (Cq), 127.3 (3 * CHPh), 128.1 (6 * CHPh), 128.4 (6 * CHPh), 143.2 (3 * Ci). Anal. Calcd for C27H28O5: C, 74.98; H, 6.53. Found: C, 75.02; H, 6.49. |
88% | With pyridine at 60℃; for 16h; | 1.2 [00286] Step 2: Synthesis of 3aR,5R,6S,6aR)-2,2-dimethyl-5- ((trityloxy)methyl)tetrahydrofuro[2,3-d][l,3]dioxol-6-ol To a solution of (3aR,5R,6R)-5-(hydroxymethyl)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3- d][l,3]dioxol-6-ol (125 g, 0.66 mol) in pyridine (600 mL) is added TrCl (219.9 g, 0.79 mol, 1.2 eq.). After 16 h at 60°C, the mixture is cooled down and concentrated. The residue is partitioned between CH2CI2 (400 mL) and aq. NaHCO3 (sat., 800 mL). The aqueous phase is extracted with CH2CI2 (600 mL x 2). The combined organic layers are dried over Na2SO4, filtered, concentrated and purified by column chromatography (S1O2, petroleum ether/ethyl acetate = 10: 1 to 5: 1) to give (3aR,5R,6R)-2,2-dimethyl-5-(trityloxymethyl)-3a,5,6,6a- tetrahydrofuro[2,3-d][l,3]dioxol-6-ol (250 g, 0.58 mol, 88% yield) as white solid. (MS: [M+Na]+ 455.0). |
87% | With pyridine at 60℃; for 16h; | 1 alcohol 56 To a solution ofSS (91.4 g, 481 mmoi) in Py (600 mL) is added trityl chloride (160.7 g, 577 mmoi). After stirring at 60 °C for 16 hours. the mixture is concentrated and coevaporated with toluene for three times. The residue is partitioned between DCM (400 rnL) and saturated sodium bicarbonate aqueous solution (750 mL), The layers are separated and the aqueous phase is extracted with DCM (400 mL x 2). The combined organic layers are dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (EA/PE :r. 1/10 to 1/5) to afford 56 as a white solid (180.5 g, 87% yield). (MS: [M±Na] 455.0) |
78% | With triethylamine In 1,4-dioxane at 100℃; for 3h; | |
68.5% | With pyridine for 20h; | |
60% | With pyridine | |
With pyridine | ||
With dmap; triethylamine In N,N-dimethyl-formamide | ||
With dmap; triethylamine In N,N-dimethyl-formamide for 20h; | ||
With pyridine In dichloromethane at 10 - 25℃; for 5h; | PP1.1 Preparation PP1; 3-Deoxy-1,2-O-(1-methylethylidene)-3-[(phenylmethyl)amino]-5-O-(triphenylmethyl)-α-D-ribofuranose (3 step procedure); Step 1: To a clean and nitrogen purged glass lined reactor, was charged CH2Cl2 (13 gal). To the reactor was added 1,2-O-(1-methylethylidene)-α-D-xylofuranose (7.0 kg, 36.8 mol) followed by pyridine (4.5 L). The reaction was cooled to 10-15° C. and then charged with trityl chloride (10.8 Kg, 38.6 moles; some exotherm noted with this addition). The reaction mixture was then stirred at 20-25° C. for 5 h and judged complete by TLC. The crude reaction mixture was washed with a 5% aqueous acetic acid solution (2×11.5 gal) and with water (22 gal). The organic layer containing 1,2-O-(1-methylethylidene)-5-O-(triphenylmethyl)-α-D-xylofuranose was carried on to Step 2 without drying or isolation. | |
With triethylamine In dichloromethane | ||
With dmap; triethylamine In N,N-dimethyl-formamide for 20h; | ||
Stage #1: 1,2-O-isopropylidene-α-D-xylose With triethylamine In dichloromethane at 20℃; for 1h; Stage #2: trityl chloride at 20℃; for 3h; regioselective reaction; | ||
35.6 g | With dmap; triethylamine In N,N-dimethyl-formamide for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium hydroxide at 80℃; for 2h; | |
With potassium hydroxide | ||
With sodium hydride 1.) THF, reflux, 15 min, 2.) Bu4NBr, reflux, 5 min; Yield given. Multistep reaction; |
With potassium hydroxide at 80℃; for 2h; Yield given; | ||
With potassium hydroxide at 80℃; for 2h; | ||
With sodium hydride In N,N-dimethyl-formamide for 16h; | ||
17.73 g | With potassium hydroxide at 80℃; for 4.5h; | |
With tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran for 3h; Heating; Yield given; | ||
With tetrabutylammomium bromide; sodium hydride 1.) THF, reflux, 15 min; 2.) reflux, 5 min; Yield given. Multistep reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 0℃; | |
95% | Stage #1: 1,2-O-(1-methylethylidene)-α-D-xylofuranose With pyridine; 4-dimethylaminopyridine In dichloromethane at 0℃; for 0.166667h; Stage #2: benzoyl chloride In dichloromethane at 0℃; for 1h; | |
93% | With pyridine In dichloromethane for 12h; Ambient temperature; |
93% | With pyridine In dichloromethane for 24h; Ambient temperature; | |
91% | In pyridine at 0℃; for 1h; | |
90% | With triethylamine In dichloromethane at 0 - 5℃; | |
89% | With pyridine at 0 - 20℃; for 2h; | 19.A Step A. ((3aR,5R,65,6aR)-6-Hydroxy-2,2-dimethyltetrahydrofuro j2,3-dj jl ,3j dioxol-5-yl)methyl benzoate (19a) BzC1 (5.91 g, 42 mmol) was added slowly to a solution of(3aR,5R,65,6aR)-5- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-dj[1,3jdioxol-6-ol (8 g, 42 mmol) in pyridine (80 mL) at 0 °C. The mixture was stirred at rt for 2 h, it was concentrated and the residue was diluted with EtOAc and aq. citric acid. The organic layer was washed (brine), dried and concentrated. The residue was purified by flash column chromatography to provide the title compound (19a) (hg, 89%). mlz (ESI, +ve ion) = 295.4 [M+Hj. |
89% | With pyridine at 0 - 20℃; Inert atmosphere; | 1.1 Step 1 (Compound 1-1) : ((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl benzoate To a solution of 1, 2-O-isopropylidene-alpha-D-xylofuranose (15 g, 78.86 mmol) in pyridine (100 mL) under nitrogen was added benzoyl chloride (11.6 g, 82.8 mmol) at 0°C and stirred at room temperature overnight. After completed, the mixture was concentrated and the residue was dissolved in dichloromethane (100 mL). The resulting mixture was washed with saturated aqueous solution of NaHCO 3 (100 mL) and brine, dried over Na 2SO 4, filtered and concentrated. The residue was purified by silica gel column chromatography (Petroleum ether/ethyl acetate = 50%) to give the title compound (20.7 g, 89%). 1H NMR (400 MHz, DMSO-d6) δ 8.04 -7.94 (m, 2H), 7.68 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.7 Hz, 2H), 5.90 (d, J = 3.7 Hz, 1H), 5.51 (d, J = 5.0 Hz, 1H), 4.49 -4.46 (m, 2H), 4.42 -4.27 (m, 2H), 4.19 -4.09 (m, 1H), 1.40 (s, 3H), 1.25 (s, 3H). LC-MS (M+H) + = 294.9. |
87.3% | With pyridine | |
86.6% | With triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; | 1 Step 1. Synthesis of ((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl benzoate (Int-1-2) To a mixture of compound Int-1-1 (40.00 g, 210.31 mmol, 1 eq.) in DCM (400 mL) was added dropwise TEA (63.84 g, 630.94 mmol, 87.82 mL, 3 eq.) at 0° C. under N2. BzCl (32.52 g, 231.34 mmol, 26.88 mL, 1.1 eq.) was added dropwise to the mixture at 0° C. under N2. The mixture was stirred at 0° C. for 1 h under N2. The mixture was combined another reaction mixture with 10 g of Int-1-1. The combined mixture was quenched by water (600 mL). The organic layer was separated. The aqueous was extracted with DCM (300 mL*3). The combined organic layers were washed with saturated NaHCO3 solution (400 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=50/1 to 2/1) to give compound 2 (67.00 g, 227.66 mmol, 86.60% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=8.12-7.95 (m, 2H), 7.66-7.53 (m, 1H), 7.51-7.41 (m, 2H), 5.97 (d, J=3.7 Hz, 1H), 4.87-4.75 (m, 1H), 4.60 (d, J=3.5 Hz, 1H), 4.47-4.35 (m, 2H), 4.19 (dd, J=2.2, 4.0 Hz, 1H), 3.27 (d, J=4.0 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H). |
86.6% | With triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; | 1 Step 1. Synthesis of ((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3- d][l,3]dioxol-5-yl)methyl benzoate (2) To a mixture of compound 1 (40.00 g, 210.31 mmol, 1 eq.) in DCM (400 mL) was added dropwise TEA (63.84 g, 630.94 mmol, 87.82 mL, 3 eq.) at 0 °C under N2. BzCl (32.52 g, 231.34 mmol, 26.88 mL, 1.1 eq.) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The mixture was combined another reaction mixture with 10 g of 1. The combined mixture was quenched by water (600 mL). The organic layer was separated. The aqueous was extracted with DCM (300 mL x 3). The combined organic layers were washed with saturated NaHCCh solution (400 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 50/1 to 2/1) to give 2 (67.00 g, 227.66 mmol, 86.60% yield) as a yellow solid. NMR (400MHz, CHLOROFORM-d) d = 8.12 - 7.95 (m, 2H), 7.66 - 7.53 (m, 1H), 7.51 - 7.41 (m, 2H), 5.97 (d, J= 3.7 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.60 (d, J= 3.5 Hz, 1H), 4.47 - 4.35 (m, 2H), 4.19 (dd, J= 2.2, 4.0 Hz, 1H), 3.27 (d, J = 4.0 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H). |
86.6% | With triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; | Int-1.1 Step 1. Synthesis of ((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl)methyl benzoate (Int-1-2) [0247] To a mixture of compound Int-1-1 (40.00 g, 210.31 mmol, 1 eq.) in DCM (400 mL) was added dropwise TEA (63.84 g, 630.94 mmol, 87.82 mL, 3 eq.) at 0 °C under N2. BzCl (32.52 g, 231.34 mmol, 26.88 mL, 1.1 eq.) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The mixture was combined another reaction mixture with 10 g of Int-1-1. The combined mixture was quenched by water (600 mL). The organic layer was separated. The aqueous was extracted with DCM (300 mL x 3). The combined organic layers were washed with saturated NaHCO3h solution (400 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 50/1 to 2/1) to give compound 2 (67.00 g, 227.66 mmol, 86.60% yield) as a yellow solid. 1H NMR (400MHz, CHLOROLORM-d) d = 8.12 - 7.95 (m, 2H), 7.66 - 7.53 (m, 1H), 7.51 - 7.41 (m, 2H), 5.97 (d, J= 3.7 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.60 (d, J= 3.5 Hz, 1H), 4.47 - 4.35 (m, 2H), 4.19 (dd, J= 2.2, 4.0 Hz, 1H), 3.27 (d, = 4.0 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H). |
86.6% | With triethylamine In dichloromethane at 0℃; for 1h; Inert atmosphere; | 1 Step 1. Synthesis of ((3aR,5R,6S,6aR)-6-hydroxy-2,2-dimethyltetrahydrofuro[2,3- d][l,3]dioxol-5-yl)methyl benzoate (2) To a mixture of compound 1 (40.00 g, 210.31 mmol, 1 eq.) in DCM (400 mL) was added dropwise TEA (63.84 g, 630.94 mmol, 87.82 mL, 3 eq.) at 0 °C under N2. BzCl (32.52 g, 231.34 mmol, 26.88 mL, 1.1 eq.) was added dropwise to the mixture at 0 °C under N2. The mixture was stirred at 0 °C for 1 h under N2. The mixture was combined another reaction mixture with 10 g of 1. The combined mixture was quenched by water (600 mL). The organic layer was separated. The aqueous was extracted with DCM (300 mL x 3). The combined organic layers were washed with saturated NaHCCh solution (400 mL), dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 50/1 to 2/1) to give 2 (67.00 g, 227.66 mmol, 86.60% yield) as a yellow solid. NMR (400MHz, CHLOROFORM-d) d = 8.12 - 7.95 (m, 2H), 7.66 - 7.53 (m, 1H), 7.51 - 7.41 (m, 2H), 5.97 (d, J= 3.7 Hz, 1H), 4.87 - 4.75 (m, 1H), 4.60 (d, J= 3.5 Hz, 1H), 4.47 - 4.35 (m, 2H), 4.19 (dd, J= 2.2, 4.0 Hz, 1H), 3.27 (d, J = 4.0 Hz, 1H), 1.52 (s, 3H), 1.33 (s, 3H). |
84% | With pyridine In dichloromethane at -30 - -20℃; for 10h; | |
83% | In pyridine at 0℃; | |
83% | With pyridine In toluene at 20℃; for 12h; | |
82% | With triethylamine In dichloromethane at 0℃; for 4h; | 1,2-O-isopropylidene-5-O-benzoyl-a-D-xylofuranose (8) A solution of 7 (21.6 g, 113 mmol) in CH2Cl2 (500 mL) was cooledto 0 C. Et3N (15.8 mL, 113 mmol, 1.0 eq.) was added, followed bydropwise addition (0.2 mL/min) of BzCl (13.4 mL, 116 mmol, 1.02eq.). After 4 h, TLC analysis (petroleum ether/EtOAc 50:50) showedcomplete conversion of the starting material. The mixture wastransferred to a separation funnel and washed with sat. aq. NaHCO3solution (200 mL). the organic phase was dried over Na2SO4 andconcentrated in vacuo. The residue was purified by flash columnchromatography (manual, petroleum ether/EtOAc 90:10 and 60:40)to afford 8 (27.2 g, 92.5 mmol, 82% yield) as a colourless oil. 1H NMR(300 MHz, CDCl3) d 1.33 (3 H, s, CH3), 1.51 (3 H, s CH3), 3.11 (br. s, 1H,OH) 4.20 (1 H, d, J 2.3 Hz, H-3), 4.36e4.44 (2 H, m, H-4, H-5), 4.60(1 H, d, J 3.8 Hz, H-2), 4.80 (1 H, dd, J 12.6, 9.1 Hz, H-5’), 5.97(1 H, d, J 3.5 Hz, H-1), 7.41e7.52 (2 H, m, HPhe), 7.54e7.64 (1 H, m,HPhe), 7.95e8.10 (2 H, m, HPhe) ppm. 13C NMR (75 MHz, CDCl3)d 26.13 (1C, s), 26.79 (1 C, s), 61.32 (1 C, s), 74.38 (1 C, s), 78.52 (1 C,s), 85.02 (1 C, s), 104.73 (1 C, s), 111.86 (1 C, s), 128.48 (1 C, s), 129.21(1 C, s), 129.89 (1 C, s), 133.55 (1 C, s), 167.36 (1 C, s) ppm. HRMS(ESI): calculated for C15H19O6 ([MH]): 295.1182, found: 295.1190. |
78% | In pyridine | |
78% | With pyridine for 0.5h; Ambient temperature; | |
76% | In pyridine at -20 - 0℃; for 0.5h; | |
75% | With pyridine at 20℃; for 4h; chemoselective reaction; | |
74% | With triethylamine In dichloromethane at 20℃; for 2h; | |
70.2% | With pyridine at -20℃; for 2h; | |
60% | With pyridine | |
With pyridine; chloroform | ||
With 4-dimethylaminopyridine; triethylamine In dichloromethane | ||
With pyridine at -10℃; | ||
With triethylamine In dichloromethane at 0℃; for 3h; | ||
With pyridine at 0℃; for 1.5h; | ||
5.46 g | With pyridine In dichloromethane at 0 - 20℃; Inert atmosphere; | 11-1; 11-2; 11-3; 11-4 Preparation of Intermediate 11 C: To a cooled (0° C.) suspension oflntermediate liB (3.80 g, 20.0 mmol) in CH2Cl2 (32 mL) and pyridine (8 mL) under a nitrogen atmosphere was added a solution of benzoyl chloride (2.3 mL, 20.0 mmol) in CH2Cl2 (3 mL) via addition funnel over 2 hours. The reaction was allowed to stir overnight at room temperature. The reaction was cooled again to oo C. and another portion of benzoyl chloride (0.46 ml, 4.0 mmol) in CH2Cl2 (0.60 mL) was added via addition funnel over 40 min. The mixture was stirred at oo C. for another hour, then the reaction was quenched with H20 (10 mL) and concentrated in vacuo. The residue was partitioned between CH2Cl2 (100 mL) and water (50 mL). The organic phase was washed with saturated aq. sodium bicarbonate (50 mL) and water (3x50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Residual pyridine was removed by co-evaporating a few times with toluene to afford Intermediate liC (5.46 g, 18.55 mmol) as a clear yellow oil. LCMS, [M+H]=295. |
With triethylamine In dichloromethane at 0℃; | ||
With pyridine In dichloromethane for 1h; Inert atmosphere; Large scale; | 1; 19 To a N2 flushed 50 L reactor, CH2Cl2 (5.0 L) was added. Xylofuranose 1 (1.0 kg, LR) and pyridine (0.83 kg, 2.0 eq.) were charged into the reactor. Benzoyl chloride (0.78 kg, 1.05 eq.) was slowly added to the reactor at -10 °C in 1 h and quenched the reaction until the TLC indicated the reaction to finish. To the cold solution, water (1 kg) was added. Layers partitioned and the organic stream was washed with citric acid (3.0 L, 10%wt, aq.), NaHCO3 (3.0 L, 10% wt, aq.), and brine (2.0 L, 15% wt, aq.). The crude will be used in the next step without further purifications. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With triethylamine In dichloromethane at 0 - 20℃; | |
93% | With pyridine | |
82% | With pyridine at 25℃; for 4h; |
76% | With triethylamine In dichloromethane for 1h; Ambient temperature; | |
With pyridine | ||
2.5 g | In dichloromethane; triethylamine at 0℃; for 2h; | |
With pyridine for 0.5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With dmap; triethylamine; 1-amino-3-(dimethylamino)propane In dichloromethane at 20℃; for 2h; | |
92% | With pyridine for 8h; | |
82.3% | With pyridine In dichloromethane at 0 - 20℃; for 24h; | 1.2. 1,2-O-Isopropylidene-3,5-di-O-p-toluenesulfonyl-α-d-xylofuranose (6) A solution of 719 (30.0 g, 158 mmol) and pyridine (38.2 mL, 473 mmol) in CH2Cl2 (300 mL) was cooled to 0 °C, TsCl (75.0 g, 395 mmol) was added to the mixture. After the mixture was stirred for 24 h at 0 °C to room temperature, saturated NaHCO3 solution was added, and the reaction mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and evaporated. Crystallization of the crude product from ethanol gave compound 6 as a white solid (64.7 g, 82.3%) mp 100.4-102.1 °C; -30 (c 1.0, CHCl3); IR (KBr); 2932, 1308, 1191, 1176, 1096, 1065, 1051, 994, 841, 713, 666, 551 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.26 (s, 3H, CH3), 1.42 (s, 3H, CH3), 2.45 (s, 3H, ArCH3), 2.48 (s, 3H, ArCH3), 3.94-4.08 (m, 2H, H-5), 4.33 (td, J = 6.1, 3.0 Hz, 1H, H-4), 4.68 (d, J = 3.6 Hz, 1H, H-2), 4.77 (d, J = 3.0 Hz, 1H, H-3), 5.86 (d, J = 3.6 Hz, 1H, H-1), 7.37 (2d, J = 8.2 Hz, 4H, Ar-H), 7.75 (2d, J = 8.3 Hz, 4H, Ar-H). 13C NMR (101 MHz, CDCl3) δ 21.7 (ArCH3), 21.7 (ArCH3), 26.2 (CMe2), 26.5 (CMe2), 65.9 (CH2), 76.3 (CH), 81.3 (CH), 83.0 (CH), 104.8 (CH), 112.8 (CMe2), 128.0 (ArC), 129.9 (ArC), 130.3 (ArC), 132.2 (ArC), 132.4 (ArC), 145.2 (ArC), 145.9 (ArC). HRMS: calcd for C14H19N3O4Na [M+Na]+ 521.0919, found: 521.0915. |
79% | With pyridine at 25℃; for 4h; | |
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With triethylamine In dichloromethane at 0℃; Inert atmosphere; | |
92% | With triethylamine In tetrahydrofuran at 0 - 20℃; | |
92.1% | With pyridine at 20℃; for 4h; |
91% | With pyridine at 0℃; for 10h; | |
91% | In pyridine at 0℃; for 10h; | |
90% | With pyridine at 20℃; for 3h; | |
88% | With pyridine In chloroform Ambient temperature; | |
84% | With pyridine at 0 - 20℃; for 10h; Inert atmosphere; | |
82% | With pyridine In dichloromethane at 20℃; for 6h; | |
81% | With pyridine at 20℃; for 3h; | |
81% | With triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; | |
80% | With pyridine In dichloromethane | |
79% | With pyridine In chloroform at 0℃; for 12h; | |
77% | With triethylamine In dichloromethane at 20℃; for 15h; | |
72% | With pyridine; dmap for 7h; Ambient temperature; | |
68.7% | With triethylamine In dichloromethane at 0 - 20℃; for 2h; Large scale; | 1 Preparation of Compound of Formula (8a) The compound of formula (7) (33 kg) was added to methylenechloride (330 L) for dissolution, followed by cooling to 0° C. Triethylamine (21.07 kg) was added thereto, with maintaining the temperature of 5° C. or lower. p-Toluenesulfonyl chloride (36.89 kg) was slowly added thereto. The resulting solution was warmed to room temperature, followed by stirring for 2 hours. After the completion of the reaction was confirmed, 15% ammonium chloride aqueous solution (165 L) was added thereto, followed by stirring for 15 minutes. Then, the organic layer was separated, and concentrated under reduced pressure. Toluene (66 L) was added thereto, and warmed to 50° C., followed by cooling to 20° C. Heptane (16.5 L) was added thereto, followed by stirring for 1 hour. The obtained solid was filtered, and washed with heptane:toluene (1:1, 49.5 L), followed by vacuum drying at 20 to 30° C. to give a compound of formula (8a) (40.84 kg, 68.7%). (0201) 1H NMR (300 MHz, CDCl3): δ 7.80 (2H, d, J=8.1 Hz), 7.36 (2H, d, J=8.1 Hz), 5.88 (1H, d, J=3.6 Hz), 4.51 (1H, d, J=3.3 Hz), 4.38-4.30 (3H, m), 4.14 (1H, m), 2.46 (3H, s), 2.40 (1H, brs), 1.46 (3H, s), 1.30 (3H, s). |
67% | With pyridine; dmap at 0℃; for 16h; | 46 1,2-O-Isopropylidene-D-xylofuranose (8.35 g, 43.9 mmol) is dissolved in pyridine (50 mL); the resulting solution is cooled to 0°C and treated with tosyl chloride (10.0 g, 52.5 mmol) and dimethylaminopyridine (0.5 g). After reacting for 16 hours at 0°C, the solution is quenched with water (50 mL) and diluted with toluene (50 mL). The organic phase is separated, dried, filtered and concentrated at reduced pressure <40°C (pyridine is still present in the organic phase). The oil is dissolved in ethyl acetate (100 mL), extracted with 10% acetic acid, washed with water, then extracted with NaHCO3 (saturated). The organic phase is dried, filtered and concentrated at reduced pressure to leave a white solid. The solid is dissolved in ethyl acetate (50 mL) with heating, diluted with hexane (50 mL), filtered through Celite7 filter aid and cooled to 0°C to provide 1,2-O-isopropylidene-5-(p-toluenesulfonyl)-D-xylofuranose as white crystals (10.1 g, 67% yield); m.p. 137-8°C. |
56% | With pyridine for 16h; Ambient temperature; | |
51% | With pyridine at 20℃; Inert atmosphere; Cooling with ice; | |
46% | With triethylamine In dichloromethane at 0 - 5℃; for 13h; | 97 1,2-O-isopropylidene-α-D-xylofuranose (380mg, 2.0 mmol) was dissolved in methylene chloride (20 mL), and under a nitrogen stream, triethylamine (0.56 mL, 4.0 mmol), p-toluenesulfonyl chloride (305 mg, 1.9 mmol) and 4-(dimethylamino)pyridine (24 mg, 0.20 mmol) were added at 0°C with stirring. The mixture was allowed to warm to 5°C, and stirred for 13 hours. The reaction liquor was poured onto ice water, and extracted with methylene chloride. The extract was washed with 1N-hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure, and recrystallization was performed from ethyl acetate/n-hexane, to obtain the title compound (317 mg, 46%) as a solid. NMR(CDCl3)δ:1.30(3H,s),1.47(3H,s),2.28(1H,d,J=3.4Hz), 2.46(3H,s),4.13(1H,dd,J=13.5,8.3Hz),4.30-4.37(3H,m),4.51(1H ,d,J=3.6Hz),5.87(1H,d,J=3.4Hz),7.36(2H,d,J=8.6Hz),7.80(2H,d ,J=8.6Hz). MS(ESI)m/z:363(M++1+H2O) |
With pyridine; chloroform | ||
In pyridine Ambient temperature; Yield given; | ||
With pyridine for 2h; Ambient temperature; | ||
With pyridine | ||
In pyridine | ||
With pyridine In chloroform at 0 - 20℃; | ||
In pyridine; dichloromethane | 2 1,2-O-Isopropylidene-5-O-tosyl-a-D-xylofuranose EXAMPLE 2 1,2-O-Isopropylidene-5-O-tosyl-a-D-xylofuranose In this example a solution containing 68 g of para-toluenesulfonyl chloride dissolved in 124 ml of methylene chloride was slowly added dropwise to an anhydrous solution containing 61.9 g of 1,2-O-isopropylidene-a-D-xylofuranose in 310 ml of pyridine at 0° C. The mixture was stirred for one hour at 0° C. and then allowed to stand overnight at room temperature. The solution was then extracted three times with 200 ml of methylene chloride. The combined organic extracts were washed with cold dilute aqueous sulfuric acid to remove the pyridine, and then washed with water until neutral. The washed extract was then dried over magnesium sulfate and evaporated to dryness under vacuum affording 110 g of solid product. The solid product was then recrystallized twice from ethyl acetate affording the title compound, m.p. 134°-136.5° C. | |
With pyridine | ||
With pyridine at 20℃; for 1.5h; Inert atmosphere; | ||
With pyridine | ||
With pyridine | ||
Stage #1: 1,2-O-isopropylidene-α-D-xylose With triethylamine In dichloromethane at 0℃; for 0.166667h; Stage #2: p-toluenesulfonyl chloride With dmap In dichloromethane at 20℃; for 5h; | 6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-5-yl-methyl-4-methylbenzenesulfonate S7 To a solution of S1 (2.4 g, 12.62 mmol) in dichloromethane (24 mL) at 0 °C was added triethylamine (3.5 mL, 25.24 mmol) and stirred for 10 min. then, p-toluenesulfonyl chloride (2.89 g,15.14 mmol) and DMAP (0.77 g, 6.31 mmol) was added and stirred at room temperature for 5hours. After completion (TLC), reaction was quenched with 1 N HCl and extracted the productin ethyl acetate (3 × 100 mL). Pooled organic layers were dried over Na2SO4, solvent wasremoved under reduced pressure and crude S7 (4 g, 92%) was used for the next step withoutfurther purification. | |
With pyridine at 25℃; | ||
With triethylamine In dichloromethane at 0 - 20℃; | 188.I Step I; Scheme:HO θv TsO OH? .OH/CH, CH3CH, CH,Triethylamine (7.32 mL, 0.053 mol) is added to a solution of 1,2-0-isopropylidene-α-D-xylofiiranose (5.0 g, 0.026 mol) in dichloromethane (50 mL) at room temperature. Reaction mixture is cooled to 0-50C and p- toluenesulfonylchloride ( 8.0 g, 0.042 mol) is added in portions. Reaction mixture is then allowed to stirr at room temperature for 4 hrs. D. M. water (30 mL) is added to the reaction mixture, organic layer is separated and aqueous layer is extracted with dichloromethane (2x50 mL). Combined organic layer is washed with D. M. water (1x50 mL) followed by brine solution (1x50 mL). Removal of dichloromethane under reduced pressure after drying over anhydrous sodium sulphate gives viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 40:60) to get 5-0-tosyl derivative of 1 ,2-O-isopropylidene-α-D-xylofuranose. | |
With pyridine at 10℃; for 14h; Cooling with ice; Inert atmosphere; | 1 Compound I (20.8 g, 0.098 mol) was dissolved in 200 mL of anhydrous pyridine.Under the protection of ice bath and nitrogen, p-toluenesulfonyl chloride (20.9g, 0.108mol) was added in portions, and the temperature was raised to 10°C for 14h after the addition.Water was added to quench the reaction, and the solvent was distilled off under reduced pressure to obtain a yellow solid.Silica gel column chromatography (ethyl acetate: petroleum ether = 1:3 ~ 2:1), concentrated under reduced pressure to obtain a white solid (II). | |
With triethylamine In chloroform at 20℃; for 24h; | ||
15.3 g | With pyridine at 0 - 10℃; for 14h; | 4.2.1. 1,2-O-Diacetyl-4(R)-methyl-3-O-(diethylphosphonomethyl)-L-threose (6) The crude 1 was dissolved in anhydrous pyridine (100 mL) andp-toluenesulfonyl chloride (11 g, 58 mmol)was added in portions at0 C. The reaction mixturewaswarmed to 10 C and stirred for 14 h.The reaction was quenched with saturated NaHCO3 and concentratedin vacuo. The residue was partitioned between H2O (50 mL)and EtOAc (100 mL). The organic layer was dried over Na2SO4, andconcentrated in vacuo. The residue was purified by chromatography on a silica gel column (EtOAc:PE 1:2, Rf 0.2) toafford 5-O-tosyl-1,2-O-isopropylidenyl-D-xylose 2 (15.3 g, 67% fromD-xylose) as a white solid. mp 127.4e127.9 C (literature [21]:134e135 C); 1H NMR (400 MHz, CDCl3) d 7.81 (d, J 8.3 Hz, 2H),7.36 (d, J 8.0 Hz, 2H), 5.88 (d, J 3.6 Hz, 1H), 4.51 (d, J 3.6 Hz,1H), 4.40e4.26 (m, 3H), 4.14 (q, J 9.0 Hz, 1H), 2.46 (s, 3H), 2.40 (d,J 5.1 Hz, 1H), 1.46 (s, 3H), 1.30 (s, 3H). 13C NMR (101 MHz, CDCl3)d 145.3, 132.4, 130.0, 128.0, 112.1, 105.0, 85.0, 76.7, 74.3, 66.2, 26.8,26.2, 21.7 (Identical with NMR data in the literature [21]). |
With pyridine In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 1-hydroxycyclohexyl phenyl ketone; sodium hydroxide In 1,2-dimethoxyethane at 80℃; Sealed tube; chemoselective reaction; | |
64% | With sodium hypochlorite; 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; tetrabutyl-ammonium chloride; sodium hydrogencarbonate; sodium chloride; potassium bromide In dichloromethane; water | |
52% | With potassium carbonate In water at 20℃; electrolysis at 0.4 A; |
With potassium permanganate | ||
42 g | Stage #1: 1,2-O-isopropylidene-α-D-xylose With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; sodium hydrogencarbonate; sodium bromide In water; acetone at 25 - 30℃; for 0.5h; Stage #2: With trichloroisocyanuric acid In water; acetone at 0 - 30℃; for 24h; | 1 Example 1 : Preparation of a compound of formula 29 Sodium bicarbonate (132.5 g), sodium bromide (10.8 g), and (2, 2,6,6- tetramethylpiperidin-1-yl)oxyl (TEMPO, 1.6 g) were added sequentially to 1 ,2-0- isopropylidene-a-D-xylofuranose (compound 30, 100 g) in mixture of acetone (1000 mL) and water (500 mL) at 25-30°C and stirred for 30 minutes. After cooling the reaction mixture to 0-5°C, trichloroisocyanuric acid (122 g) was added lot wise. Thereafter, the reaction mixture temperature was slowly raised to 25- 30°C and the reaction mixture was stirred for 24 hours. After completion of the reaction, the reaction was quenched with methanol (100 ml_) and salts were vacuum filtered out of the reaction mixture. The obtained filtrate was distilled under vacuum to concentrate the mixture, diluted with ethyl acetate (500 ml_) and water (200 ml_), and stirred for 15 minutes at 25-30°C. The organic layer was concentrated by vacuum distillation and dissolved in acetonitrile (200 ml_). N- Methylpiperazine (40.4 g) was added and the resultant reaction mixture was stirred for 15 hours at 25-30°C. The solid was obtained by filtering the reaction mixture, then dried under vacuum to yield a compound of formula 29 as a yellow solid (42 g). 1H-NMR (DMSO-de): 8.21 (bs,1 H), 5.84 (d, 1 H), 4.37 (d, 1 H), 4.21 (d, 1 H), 4.03 (d, 1 H), 2.94 (t, 4H), 2.50 (t, 4H), 2.18 (s, 3H), 1.36 (s, 3H), 1.22 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With phosphotungstic acid; water; In acetonitrile; at 20℃; for 2h; | The substrate (1 mmol) was dissolved in acetonitrile/water mixture (2 mL, 9:1 v/v) and to it was added phosphotungstic acid (5 mol %). The mixture was stirred at room temperature for the appropriate time. After completion of the reaction, the solvent was removed under reduced pressure. The residue was directly purified by using column chromatography on silica gel (60-120 mesh) with 50-100% ethylacetate in hexane as eluent to get the product. |
72% | With hydrogenchloride; In water; for 1.5h; | To a flask containing 1,2:3,5-di-O-isopropylidene-a-D-xylofuranose(36.3 g,158 mmol)was added 0.2% hydrochloric acid (250 mLwater, 1.5 mL conc. HCl) The oil rapidly started to dissolve and theresulting solutionwas stirred vigorously for 1h30. The mixture wasneutralized with solid NaHCO3 and concentrated under reducedpressure. CHCl3 (200 mL) was added to the residue, and the inorganicsalts were removed by filtration. The solids werewashed withadditional CHCl3 and the combined filtrates dried over Na2SO4 andconcentrated in vacuo to yield 7 (21.6 g, 113 mmol, 72% yield) as ayellow oil. 1H NMR (300 MHz, CDCl3) d 1.33 (3 H, s), 1.50 (3 H, s),4.00e4.21 (3 H, m), 4.34 (1 H, d, J 2.6 Hz), 4.54 (1 H, d, J 3.8 Hz),6.00 (1 H, d, J 3.8 Hz) ppm. Spectral data are in accordance withliterature values |
68.5% | With sulfuric acid; In water; for 0.5h; | 1,2:3,5-Di-O-isopropylidene-D-xylofuranose (70.66 g, 0.30 mol) is treated with H2SO4 (0.1 M, 300 mL). Upon stirring, the xylose slowly dissolves. After 30 minutes, the reaction is quenched with NH4OH (pH 9.0) and half of the water removed at reduced pressure. The aqueous layer is diluted with brine (100 mL) and extracted with ethyl acetate (3x200 mL). A normal work-up provides an oil. Kugelrohr distillation provides 1,2-O-isopropylidene-D-xylofuranose (40 g, 68.5%); b.p. 120-135C/0.4 mm Hg. |
With acetic acid; In water; at 20℃; for 24h; | A solution of 4a1 (3.75 g, 16.29 mmol) in 30% aq AcOH (30 mL) was stirred for 24 h at room temperature. The mixture was neutralized with solid NaHCO3 (pH 6-7) and extracted with CH2Cl2 (4×30 mL). The combined extracts were dried with a mixture of anhydrous Na2SO4 and Na2CO3, filtered and evaporated. The remaining syrup was dried in high vacuum, to afford crude 4b (2.1195 g, 68%) as a colourless oil, Rf=0.11 (3:2 toluene/EtOAc).1H NMR (DMSO-d6): δ 1.24 and 1.39 (2×s, 3 H each, CMe2), 3.52 (dd, 1 H, J4,5a=5.6, J5a,5b=11.1 Hz, H-5a), 3.63 (dd, 1 H, J4,5b=4.9, J5a,5b=11.1 Hz, H-5b), 3.95-4.04 (m, 2 H, H-3 and H-4), 4.39 (d, 1 H, J1,2=3.7 Hz, H-2), 4.60-5.21 (br s, 2 H, 2×OH), 5.82 (d, 1 H, J1,2=3.7 Hz, H-1).13C NMR (DMSO-d6): δ 26.1 and 26.7 (CMe2), 58.9 (C-5), 73.5 (C-3), 81.4 (C-4), 85.1 (C-2), 104.3 (C-1), 110.4 (CMe2). | |
With sulfuric acid; at 20℃; for 3h; | Compound 1 was dissolved in dilute sulfuric acid and stirred at room temperature for 3 hours. After TLC detection of the reaction was completed, solid sodium bicarbonate was added to quench the reaction, the reaction solution was spin-dried, ethyl acetate was dissolved and the insoluble matter was filtered off, and the organic phase was spin-dried to obtain Compound 2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With sulfuric acid at 0 - 20℃; for 30h; | 5-(Hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (S1) To a solution of D-xylose (32.5 g, 0.22 mol) in acetone (780 mL) was added conc. H2SO4 (28.6mL, 0.66 M in acetone) at 0 °C and the mixture was stirred at room temperature for 30 hours. Asolution of Na2CO3 (39.0 g, 0.37 mol) in water (340 mL) was added to neutralize (pH = 6-7) thereaction mixture and stirred for a further 2.5 h. The mixture was filtered and the residue waswashed with acetone. The solvent was removed completely from the filtrate under reducedpressure and the resulting residue was purified by column chromatography to give the desiredproduct S1 (39.3 g, 95%) as pale yellow syrup. |
70% | With sulfuric acid for 3h; Ambient temperature; | |
With sulfuric acid for 2h; Ambient temperature; |
With hydrogenchloride; copper(II) sulfate 1.) H2SO4, 20 deg C, 24 h; 2.) MeOH, 40 deg C, 100 min; Yield given. Multistep reaction; | ||
With sulfuric acid | ||
Stage #1: D-Xylose; acetone With sulfuric acid; copper(II) sulfate Inert atmosphere; Stage #2: With hydrogenchloride In water Inert atmosphere; | ||
Stage #1: D-Xylose; acetone With iodine Stage #2: With hydrogenchloride In water | ||
With sulfuric acid; copper(II) sulfate at 20℃; for 12h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Stage #1: D-xylofuranose; acetone With sulfuric acid; copper(II) sulfate at 20℃; Stage #2: With hydrogenchloride In methanol; water at 40℃; for 2h; | |
95% | With sulfuric acid at 20℃; | |
90% | Stage #1: D-xylofuranose; acetone With sulfuric acid; copper(II) sulfate at 20℃; for 24h; Stage #2: With hydrogenchloride In methanol at 40℃; |
88% | With sulfuric acid at 20℃; | |
87% | Stage #1: D-xylofuranose; acetone With sulfuric acid at 20℃; Stage #2: With sodium carbonate In water at 0℃; | |
85% | Stage #1: D-xylofuranose; acetone With sulfuric acid at 20℃; for 1h; Stage #2: With sodium carbonate In water at 0℃; for 3h; | 1.1 [00285] Stepl: Synthesis of (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[2,3-d][l,3]dioxol-6-ol A solution of (2R,4S,5R)-5-(hydroxymethyl)tetrahydrofuran-2,3,4-triol (100 g, 0.67 mol) in acetone (2.6 L) containing H2SO4 (con., 184.00 g, 1.88 mol, 100 mL, 2.8 eq.) is stirred at 20°C for 1 h. A solution of Na2SO3 (130 g, 1.23 mol, 1.8 eq.) in H2O (600 mL) is carefully added at 0°C. The mixture is stirred for a further 2.5 h before a second batch of Na2CO3 (70 g, 0.66 mol) is added. After 0.5 h, the precipitate is collected by filtration and washed by acetone (0.5 L x 3). The filtrate is concentrated and purified by column chromatography (S1O2, DCM:MeOH = 10: 1 to 5: 1) to give (3aR,5R,6R)-5-(hydroxymethyl)-2,2-dimethyl- 3a,5,6,6a-tetrahydrofuro[2,3-d][l,3]dioxol-6-ol (53.5 g, 0.28 mol, 85% yield) as yellow oil. (MS: [M+Na]+ 213.0). |
79% | Stage #1: D-xylofuranose; acetone With sulfuric acid In water at 20℃; for 0.5h; Stage #2: With sodium carbonate In water at 0 - 20℃; | |
79% | Stage #1: D-xylofuranose; acetone With sulfuric acid at 20℃; for 6.5h; Stage #2: With sodium hydroxide In water | |
75.7% | With sulfuric acid | |
73.1% | With sulfuric acid; sodium carbonate at 20℃; for 3h; | |
73% | With sulfuric acid; sodium carbonate at 20℃; for 3h; | |
68% | Stage #1: D-xylofuranose; acetone With sulfuric acid at 20℃; for 0.5h; Stage #2: With sodium carbonate In water for 3h; | 4.2. 1,2-O-Isopropylidene-α-D-xylofuranoside 26 To the round bottom flask containing acetone (260 mL) and concentrated sulfuric acid (10 mL), D-xylose (10 g, 67 mmol) was added. The mixture was stirred for 30 min and solution of Na2CO3 (13 g, 66 mmol) in water (12 mL) was slowly added. The mixture was further stirred for 3 h, and solid Na2CO3 (7 g, 36 mmol) was added in order to neutralize sulfuric acid. Inorganic salts were filtered off, and the remaining solution was evaporated under vacuum. Crude product was purified by flash chromatography (EtOAc/hexanes 6:4 v/v) to give 1,2-O-isopropylidene-α-D-xylofuranoside 2 as colorless oil (8.46 g, 44.6 mmol, 68% yield) solidifying upon standing in freezer. |
66% | With sulfuric acid | |
50% | 1.) 25 deg C, 6h, 2.) MeOH, 25 deg C, 2h; | |
With sulfuric acid | ||
With sulfuric acid; copper(II) sulfate at 20℃; for 24h; | ||
Stage #1: D-xylofuranose; acetone With sulfuric acid; copper(II) sulfate Stage #2: With hydrogenchloride; water | ||
Stage #1: D-xylofuranose; acetone With sulfuric acid; copper(II) sulfate at 20℃; for 24h; Stage #2: With hydrogenchloride In water at 40℃; for 2h; | 1 According to the reported procedures, (Suhara et al., J. Org. Chem. 2001, 66, 8760-8771) a suspension of D-xylose (50 g), anhydrous CuSO4 (70 g) and cone. U2SO4 (5 mL) in acetone (1 L) was stirred at room temperature for 24 h, followed by partial hydrolysis in aqueous HCl solution (110 mL, 0.1 M) at 40° C for 2 h, to give 1,2-O-isopropylidene-α-D-xylofuranose (4, 61 g) as colorless syrup. Compound 4 (10 g, 52.6 mmol) was treated with pivaloyl chloride (6.6 g, 54.8 mmol) in pyridine (50 mL) at 00C for 8 h to give i,2-O-isopropylidene-5-O- pivaloyl-α-D-xylofuranoside (13 g, 85% yield from D-xylose) as colorless oil. | |
With sulfuric acid at 20℃; for 3h; Inert atmosphere; | ||
Stage #1: D-xylofuranose; acetone With sulfuric acid at 20℃; for 0.833333h; Inert atmosphere; Stage #2: With sodium carbonate In water at 20℃; for 3h; Inert atmosphere; | ||
Stage #1: D-xylofuranose; acetone With sulfuric acid; copper(II) sulfate at 25℃; for 15h; Stage #2: With hydrogenchloride In water at 25℃; for 0.5h; | ||
With sulfuric acid; copper(II) sulfate at 20℃; for 48h; Inert atmosphere; | 1 Step 1: A solution of (3R,4R,5R)-5-(hydroxymethyl)oxolane-2,3,4-triol (750 g, 5 mol) in acetone (7 L), sulfuric acid (75 mL) and dioxo(sulfonylidene)copper (1503 g, 9.42 mol) was placed into a 10-L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen. The resulting solution was stirred for 48 hours at room temperature. The mixture was filtered, and then concentrated NH4OH (25%, 200 mL) was added. The mixture was filtered, dried over Na2SO4, and concentrated under reduced pressure. The residue was diluted with methanol (4.5 L) and HCl 0.1 N, 1.3 L) was added. The reaction was stirred at 40 °C for 2 hours and quenched with NaHCO3(189 g until neutral pH). The mixture was filtered and concentrated under reduced pressure. The residue was co-evaporated with EtOH/toluene, then diluted with DCM, dried over Na2SO4, and concentrated under reduced pressure affording (3aR,5R,6S,6aR)- 5-(hydroxymethyl)-2,2-dimethyl-tetrahydro-2H-furo[2,3-d][1,3]dioxol-6-ol as an oil. The material was used crude without further purification. | |
With sulfuric acid at 20℃; for 1h; Cooling with ice; | 1 Example 1: Preparation of (4R)-methyl-3-O-diethoxyphosphorylmethyl-1,2-di-O-acetyl-L-threose(Compound 2a, represented by Formula 2, acyl is acetyl, R’ is ethyl) D-xylose (10 g, 0.068 mol) and 200 mL of acetone were mixed, and concentrated sulfuric acid (10.8 Ml) was slowly added dropwise under ice bath conditions.After the dropwise addition of concentrated sulfuric acid, the ice bath was removed, and the reaction system was completely clarified after stirring at room temperature for 1 hour.The sodium carbonate aqueous solution (12g/100mL water, 0.110mol) was added dropwise to control the drop acceleration, and the addition was completed in about 40 minutes.Continue stirring at room temperature for 2h, then add sodium carbonate solid (6g, 0.055mol) and 10mL of distilled water to the reaction system,After suction filtration, the filtrate was collected, rotary evaporation, acetone was added to dissolve the organic matter, and the residual salt in the system was filtered off.The solvent was distilled off under reduced pressure, separated by silica gel column chromatography, and concentrated under reduced pressure to obtain a yellow oily liquid (I). | |
With sulfuric acid Cooling with ice; | 4.2.1. 1,2-O-Diacetyl-4(R)-methyl-3-O-(diethylphosphonomethyl)-L-threose (6) To a suspension of D-xylose (10 g, 66.7 mmol) in acetone(100 mL)was slowly added dropwise 98% sulfuric acid (8 mL) undercooling in ice-water bath. Then the cooling bath was removed, themixture was stirred at room temperature until disappearance of Dxyloseby TLC detection. The pH value of the reaction mixture wasadjusted to 1e2 by dropwise addition of 30% aqueous sodium hydroxide.After stirring at ambient temperature for 2 h, solid sodiumhydroxide was added to the solution to adjust pH to 8.0. Theresultant mixture was concentrated under reduced pressure toalmost dryness. The residue was dispersed into acetone (80 mL)and filtrated. The filtrate was dried over Na2SO4, and concentratedin vacuo to give crude 1,2-O-isopropylidenyl-D-xylose 1 as acolorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With tris-(dibenzylideneacetone)dipalladium(0); 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 65℃; for 4h; | |
95% | With 1,4-di(diphenylphosphino)-butane In tetrahydrofuran at 65℃; for 4h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine 0 deg C -> room temperature; | |
96% | With pyridine at 0℃; for 0.5h; Inert atmosphere; | |
86% | With pyridine |
86% | In pyridine at 0℃; for 10h; | |
86% | In pyridine; methanol; diethyl ether | 1.1 (1) (1) Synthesis of 5-O-pivaloyl-1,2-O-isopropylidene-α-D-xylofuranose (Compound 2) 1,2-O-isopropylidene-α-D-xylofuranose (Compound 1, 15.0 g, 78.9 mmol) was dissolved in pyridine (70 mL), cooled to 0°C under argon atmosphere, and trimethylacetyl chloride (9.9 g, 82.2 mmol) was added dropwise over 2 hours. The reaction mixture was stirred for 10 hours at that temperature, then MeOH (5 ml) was added and the mixture was concentrated. The residue was dissolved in diethyl ether (500 mL) and washed with water (100 mL), saturated aqueous copper sulfate solution (100 mL), water (100 mL) and saturated brine (100 mL). The aqueous layer was extracted with 100 mL of diethyl ether three times. The ether layers were combined with the previously obtained diethyl ether layer. The ether layer thus obtained was dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexane 1:4) to give Compound 2 (18.7 g, 86%) as a colorless oil. [α]20D2.69 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1.22 (s, 9H), 1.32 (s, 3H), 1.51 (s, 3H), 4.10 (d, 1H, J = 2.8 Hz), 3.78 (bs, 1H), 4.17 (dd, 1H, J= 5.6, 11.2 Hz), 4.25 (ddd, 1H, J= 2.8, 5.6, 7.2 Hz), 4.50 (dd, 1H, J= 7.2, 11.2 Hz), 4.56 (d, 1H, J= 3.6 Hz), 5.93 (d, 1H, J= 3.6 Hz); HREIMS C12H19O6(M+-CH3) calcd. 259.1182, found 259.1182. |
83% | In pyridine at 0℃; for 0.166667h; | |
81% | With pyridine; dmap at 0 - 20℃; for 1.5h; | 4.3. 1,2-O-Isopropylidene-5-O-pivaloilo-α-D-xylofuranoside 37 Magnetically stirred solution of 2 (8.46 g, 44.6 mmol) in pyridine (40 mL) containing catalytical amount of DMAP (10 mg) was cooled to 0 °C, and pivaloyl chloride (5.51 mL, 44.6 mmol) was added dropwise. The mixture was stirred for 1.5 h at ambient temperature. After TLC showed the disappearance of substrate, the reaction was quenched with water, diluted with Et2O (80 mL), washed several times with diluted solution of CuSO4, and finally with brine. Organic phase was dried over anhydrous MgSO4, filtered, and evaporated under vacuum. Residue was purified by flash chromatography (EtOAc/hexanes 3:7 v/v) to give 3 (9.88 g, 36.1 mmol, 81% yield) as colorless oil. |
With pyridine at 0℃; for 1h; Yield given; | ||
With pyridine Ambient temperature; Yield given; | ||
13 g | With pyridine at 0℃; for 8h; | |
With pyridine at 0℃; for 8h; | 1 According to the reported procedures, (Suhara et al., J. Org. Chem. 2001, 66, 8760-8771) a suspension of D-xylose (50 g), anhydrous CuSO4 (70 g) and cone. U2SO4 (5 mL) in acetone (1 L) was stirred at room temperature for 24 h, followed by partial hydrolysis in aqueous HCl solution (110 mL, 0.1 M) at 40° C for 2 h, to give 1,2-O-isopropylidene-α-D-xylofuranose (4, 61 g) as colorless syrup. Compound 4 (10 g, 52.6 mmol) was treated with pivaloyl chloride (6.6 g, 54.8 mmol) in pyridine (50 mL) at 00C for 8 h to give i,2-O-isopropylidene-5-O- pivaloyl-α-D-xylofuranoside (13 g, 85% yield from D-xylose) as colorless oil. | |
With pyridine at 0℃; for 5h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In pyridine for 5h; Ambient temperature; | |
29% | With dmap; triethylamine In dichloromethane | B.2 1,2-O-Isopropylidene-3,5-di-O-pivaloyl-α-D-xylofuranose EXAMPLE B2 1,2-O-Isopropylidene-3,5-di-O-pivaloyl-α-D-xylofuranose A dry 250 ml round-bottomed flask was equipped with an internal thermometer and magnetic stirring bar and maintained under a nitrogen atmosphere. The flask was charged with 1,2-O-isopropylidene-α-D-xylofuranose (9.5 g, 49.95 mmol) from Example B1, methylene chloride (70 mL), and triethylamine (8.7 mL, 62.4 mmol). The solution was cooled to an internal temperature of 3° C. using a brine/ice bath. Trimethylacetyl chloride (7.69 ml, 62.4 mmol) was added dropwise, via syringe, over a ten minute period. Finally, 4-dimethylaminopyridine (1.83 g, 14.99 mmol) was added and stirring continued for 75 minutes. The mixture was brought to room temperature and diluted with methylene chloride (70 mL). It was then extracted with water (40 mL) and brine (40 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified on a preparatory silica gel column eluted with 80:20 (v/v) hexane/ethyl acetate. The product was obtained as a clear colourless oil. Yield 29%. TLC (silica gel): Rf 0.63 (80:20 hexane/ethyl acetate) Calc: C 60.32, H 8.43 Found: C 60.25, H 8.45 |
29% | With dmap; triethylamine In dichloromethane | B.2 1,2-0-Isopropylidene-3,5-di-0-pivaloyl-α-D-xylofuranose Example B2 1,2-0-Isopropylidene-3,5-di-0-pivaloyl-α-D-xylofuranose A dry 250mL round-bottomed flask was equipped with an internal thermometer and magnetic stirring bar and maintained under a nitrogen atmosphere. The flask was charged with 1,2-0-isopropylidene-α-D-xylofuranose (9.5g, 49.95 mmol) from Example B1, methylene chloride (70mL), and triethylamine (8.7mL, 62.4 mmol). The solution was cooled to an internal temperature of 3°C using a brine/ice bath. Trimethylacetyl chloride (7.69ml, 62.4 mmol) was added dropwise, via syringe, over a ten minute period. Finally, 4-dimethylaminopyridine (1.83g, 14.99 mmol) was added and stirring continued for 75 minutes. The mixture was brought to room temperature and diluted with methylene chloride (70mL). It was then extracted with water (40mL) and brine (40mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo . The product was purified on a preparatory silica gel column eluted with 80:20 (v/v) hexane/ethyl acetate. The product was obtained as a clear colourless oil. Yield 29%. TLC (silica gel): Rf 0.63 (80:20 hexane/ethyl acetate) Calc: C 60.32, H 8.43 Found: C 60.25, H 8.45 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With di(n-butyl)tin oxide In toluene at 130℃; Dean-Stark; Stage #2: benzyl bromide With tetrabutylammomium bromide In toluene at 20 - 110℃; for 8h; | 23 (3aR,5R,6S,6aR)-5-((Benzyloxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (I37A) A solution of (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (200 g, 10.5 mol) in toluene (2 L) was treated with Bu2SnO (290 g, 11.6 mol). The mixture was refluxed at 130° C. with a Dean-Stark apparatus overnight. After the reaction mixture was cooled to RT, benzyl bromide (190 mL, 15.8 mol) and tetra-n-butylammonium bromide (170 g, 5.3 mol) were added and the mixture was stirred at 110° C. for 8 hrs. The resulting mixture was extracted with EtOAc (3*1 L), the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica column chromatography (20%-25% EtOAc/PE) to give I37 Å as a yellow oil (240 g, 81%). 1H NMR (400 MHz, CDCl3): δ 7.30-7.21 (m, 1H), 5.91 (d, J=4.0 Hz, 1H), 4.59-4.49 (m, 2H), 4.44 (d, J=4.0 Hz, 1H), 4.22-4.16 (m, 2H), 3.90-3.82 (m, 2H), 1.41 (s, 3H), 1.25 (s, 3H). |
80.9% | With sodium hydride In N,N-dimethyl-formamide at 20℃; for 5h; | |
70% | With tetrabutylammomium bromide; bis(tri-n-butyltin)oxide In toluene at 90℃; for 72h; |
62% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With sodium hydride In tetrahydrofuran; mineral oil at -78℃; for 0.5h; Inert atmosphere; Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide at 20℃; | |
61% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With sodium hydride In tetrahydrofuran at -78℃; for 0.166667h; Stage #2: benzyl bromide With tetra-(n-butyl)ammonium iodide In tetrahydrofuran at 20℃; for 2.5h; Further stages.; | |
60% | With sodium hydride | |
53.2% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With di(n-butyl)tin oxide In toluene Heating / reflux; Stage #2: benzyl bromide With tetrabutylammomium bromide In toluene at 110℃; for 6h; | 5-benzyl-1,2-O-isopropylidene-α-D-xylofuranose (21) To a solution of the furanose (3.000 g, 15.77 mmole) in dry toluene (85 mL) was added Bu2SnO (4.124 g, 16, 57 mmole). The reaction flask was equipped with a Dean-Stark apparatus, and the reaction mixture heated to reflux and maintained at reflux with removal of water overnight. The temperature was lowered to about 110° C., and benzyl bromide (3.11 mL, 23.7 mmole) and Bu4NBr (1.526 g, 4.734 mmole) were added. The resulting reaction mixture was stirred for 6 h. After cooling to room temperature, the reaction mixture was diluted with EtOAc and NaHCO3, filtered through Celite, and washed. The combined filtrates were portioned between NaHCO3, and the organic layer washed with brine, dried, and concentrated under reduced pressure to afford the crude product. The crude product was purified via chromatography (silica gel, 3:2 hexanes/EtOAc) to afford 2.350 g (53.2% yield) of 5-benzyl-1,2-O-isopropylidne-α-D-xylofuranose. The reaction was analyzed by TLC (4:4:1 hexanes/EtOAc/MeOH). |
With sodium hydride In tetrahydrofuran | ||
With tetra-(n-butyl)ammonium iodide; di(n-butyl)tin oxide 1.) toluene, reflux, overnight, 2.) toluene, 110 deg C, 7 h; Yield given. Multistep reaction; | ||
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 15h; | ||
With 3 A molecular sieve; tetrabutylammomium bromide; di(n-butyl)tin oxide In acetonitrile for 48h; Heating; | ||
With tetra-(n-butyl)ammonium iodide; di(n-butyl)tin oxide In toluene Heating; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydride In tetrahydrofuran | |
98% | With sodium hydride In tetrahydrofuran at 0 - 20℃; for 16h; | |
97% | With 18-crown-6 ether; tetra-(n-butyl)ammonium iodide; sodium hydride In tetrahydrofuran |
97% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1.5h; Inert atmosphere; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 12h; Inert atmosphere; | 5.A (3aR,5R,6aR)-6-(Benzyloxy)-5-((benzyloxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d] [1,3]dioxole (3)ref 1 Method A: To a solution of 1,2-isopropylidenyl xylose (14.0 g, 73.57 mmol) in 200 mL of DMF was added NaH (6.62 g, 0.166 mol, 60% dispersion in mineral oil) over 30 min at 0 °C under N2 atmosphere. After being stirred for lh, benzyl bromide (31.25 g, 0.19 mol) was added dropwise to the solution at 0 °C under N2 atmosphere. The resulting solution was stirred for 12h at room temperature and treated with 10 mL of saturated H4CI (aq) at 0 °C and additionally stirred for 10 min then poured into a mixture of EtO Ac-water (300 mL, 2: 1 v/v). The organic layer was separated and aqueous layer was washed with EtO Ac (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over Na2S04 and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel (hexanes:EtOAc = 10: 1 v/v) to give compound 23 (26.44g, 71.36 mmol) in 97% yield.1H MR (400 MHz, CDC1 ) δ 7.37- 7.28 (m, 10H), 5.98 (d, J= 3.8 Hz, 1H), 4.71-4.63 (m, 3H), 4.56 (d, J= 4.5 Hz, 1H), 4.53 (d, J = 4.6 Hz, 1H), 4.44 (m, 1H), 4.01 (d, J = 3.2, 1H), 3.84-3.78 (m, 2H), 1.52 (s, 3H), 1.5 (s, 3H); 1 C MR (100 MHz, CDC1 ) δ 138.1, 137.6, 128.5, 128.4, 127.9, 127.8, 127.7, 127.6, 111.7, 105.1, 82.4, 81.7, 79.3, 73.6, 72.0, 67.6, 26.8, 26.3. |
93% | With sodium hydride In tetrahydrofuran | |
89% | With sodium hydride In N,N-dimethyl-formamide | |
88% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With sodium hydride In N,N-dimethyl-formamide at 20℃; for 2.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide for 2.5h; | |
87% | With sodium hydride | |
85% | With potassium hydroxide In tetrahydrofuran for 24h; Heating; | |
85% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With sodium hydride In tetrahydrofuran at 20℃; for 1h; Inert atmosphere; Stage #2: benzyl bromide In tetrahydrofuran at 20℃; Inert atmosphere; | |
With sodium hydride 1) DMF, RT, 45 min, 2) 2 h; Yield given. Multistep reaction; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride 1.) THF, 1 h, 2.) THF, 6 h; Yield given. Multistep reaction; | ||
With tetra-(n-butyl)ammonium iodide; sodium hydride 1) THF, 0 deg C, 20 min, rt, 30 min; 2) THF, rt, 19 h; Multistep reaction; | ||
20.4 g | Stage #1: 1,2-O-isopropylidene-α-D-xylose With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 1.5h; Stage #2: benzyl bromide In N,N-dimethyl-formamide; mineral oil at 0 - 20℃; for 5h; | |
With sodium hydride In N,N-dimethyl-formamide at 20℃; for 3h; | ||
With sodium hydride In N,N-dimethyl-formamide Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With pyridine at 0℃; for 1h; | |
95% | With pyridine | |
80% | With triethylamine In dichloromethane at 20℃; for 2h; |
66% | In pyridine at 0℃; for 1h; | |
With pyridine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With pyridine for 1.5h; Ambient temperature; | |
99.8% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 16h; | |
98% | With 1H-imidazole In N,N-dimethyl-formamide |
98.6% | With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 0.75h; | |
98% | With 1H-imidazole In N,N-dimethyl-formamide at 0℃; for 1h; | |
97% | Stage #1: 1,2-O-isopropylidene-α-D-xylose; tert-butyldimethylsilyl chloride With pyridine at 20℃; for 2h; Inert atmosphere; Stage #2: Inert atmosphere; | |
96% | With silver nitrate In tetrahydrofuran at 25℃; for 10h; | |
96% | With 1H-imidazole In dichloromethane at 20℃; for 1h; | 4.13. 1,2-O-Isopropylidene-5-O-tert-butyldimethylsilyl-α-D-lyxofuranoside 1116 To the solution of 2 (2.0 g, 10.58 mmol) and imidazole (1.0 g, 14.81 mmol) in CH2Cl2 (30 mL) TBDMSCl (0.17 g, 1.10 mmol) was added and the mixture was stirred for 1 h at room temperature. Water (30 mL) was added and the solutionwas extracted with Et2O (3x30 mL). Combined extracts were washed with brine and dried over anhydrous MgSO4, filtered, and evaporated under vacuum. Residue was purified by flash chromatography (EtOAc/hexanes 2:8 v/v) to give 11 (3.07 g, 10.1 mmol, 96% yield) as a pale yellow oil. |
94% | With dmap In dichloromethane at 0 - 20℃; | 4.2. 5-O-tert-Butyldimethylsilyl-1,2-O-isopropylidene-α-d-xylofuranoside (1a) 1,2-O-isopropylidene-α-d-xylofuranoside (5.60 g, 29.5 mmol) dissolved in dry pyridine/dry DCM (40 mL/40 mL) was added dropwise to a solution of TBDMSCl (4.90 g, 32.5 mmol) and DMAP (0.38 g, 3.00 mmol) in dry DCM (50 mL) at 0 °C. The resulting solution was allowed to warm up to room temperature and was stirred overnight. The solvent was then removed under vacuum. The white residue was dissolved in CHCl3 (100 mL), washed with a saturated solution of NaHCO3 (2×50 mL). The aqueous layer was then extracted with CHCl3 (3×50 mL). The combined organic layers were washed with water and brine, dried, filtered and evaporated. Purification by flash chromatography on silica gel (gradient from 8/2 to 6/4, v/v, hexane/EtOAc) gave the title compound 1a (8.45 g, 94%) as a colourless oil. Rf (25% EtOAc/hexane) 0.74; -8.7 (c 0.4, CHCl3); νmax (CHCl3) 3411, 2932, 2859, 1257, 1120, 1074, 840 cm-1; δH (400 MHz, CDCl3) 5.96 (1H, d, J 3.7 Hz, H-1), 4.51 (1H, d, J 3.7 Hz, H-2), 4.32 (1H, br s, H-3), 4.14-4.10 (3H, m, H-4, H-5a, H-5b), 1.49 (3H, s, C(CH3)2), 1.32 (3H, s, C(CH3)2), 0.89 (9H, s, SiC(CH3)3), 0.11 (3H, s, SiCH3), 0.11 (3H, s, SiCH3); δC (100 MHz, CDCl3) 111.5 (C(CH3)2), 105.0 (C-1), 85.6 (C-2), 78.3 (C-4), 77.1 (C-3), 62.3 (C-5), 26.8 (C(CH3)2), 26.2 (C(CH3)2), 25.7 (SiC(CH3)3), 18.1 (SiC(CH3)3), -5.5 (SiCH3), -5.6 (SiCH3); HRMS (ESI): MNa+, found 327.15986. C14H28NaO5Si requires 327.15982. |
90% | With 1H-imidazole In N,N-dimethyl-formamide for 8h; | |
88% | With triethylamine In dichloromethane 1) 0 deg C, 30 min; 2) rt, 23 h; | |
88% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With triethylamine In N,N-dimethyl-formamide at 0℃; for 0.166667h; Stage #2: tert-butyldimethylsilyl chloride With dmap In N,N-dimethyl-formamide at 0℃; for 0.25h; | 5-(((tert-Butyldimethylsilyl)oxy)methyl)-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol(S2) To a solution of S1 (15.5 g, 81.58 mmol) in anhydrous DMF (50 mL) at 0 °C was added Triethylamine (20.60 g, 203.95 mmol). The resulting mixture was stirred at 0 °C for 10 min and wasadded TBDMSCl (13.46 g, 89.74 mmol) and catalytic amount of DMAP (0.99 g, 8.16 mmol).The resulting mixture was stirred at 0 °C for 15 min. A white precipitate was formed which wasfiltered off, filtrate was diluted with water (100 mL) and extracted in ethyl acetate (3 × 200 mL).Pooled organic layers are washed with brine (200 mL), dried over Na2SO4 and solvent wasremoved under reduced pressure to obtain the crude product which was purified by silica gelcolumn chromatography to afford S2 as colourless oil (22.0 g, 88%). |
84% | With 1H-imidazole In dichloromethane | |
81% | With dmap; triethylamine In dichloromethane for 3h; Ambient temperature; | |
80% | With 1H-imidazole In N,N-dimethyl-formamide for 6h; Ambient temperature; | |
76% | With triethylamine In dichloromethane at 20℃; | |
With pyridine | ||
With 1H-imidazole In DMF (N,N-dimethyl-formamide) at -20℃; | ||
In pyridine | 7 To a solution of 1,2-O-isopropylidene-α-D-xylose (10.5 g, 55 mmol) in pyridine (150 mL) was added TBDMSCl (10 g, 66 mmol). After stirring for 3 h, the solvent was removed under vacuo and the residue extracted with CH2Cl2 and H2O. The organic layer was dried over Na2SO4, filtered and evaporated to afford compound 3 (15 g, 88%) as a syrup, which was used in the next step without further purification. | |
With dmap; triethylamine In N,N-dimethyl-formamide | 27.1 Example 27 Synthesis of Ribofuranosyl Derivative In step 1, 1,2-O-isopropylidene-α-D-xylofuranose is treated with tert-butyldimethylsilyl chloride in an organic solvent such as N,N-dimethylformamide (DMF), and organic bases such as triethylamine and 4-dimethylaminopyridine. In step 2, the alcohol is treated with 3,4-dimethoxybenzyl bromide in the presence of a base such as sodium hydride and an organic solvent such as DMF. In step 3, the furanose derivative is treated with tetra-n-butylammonium fluoride in an organic solvent such as acetonitrile. In step 4, the furanose derivative is treated with an oxidizing agent such as potassium permanganate. The carboxylic acid is treated with diazomethane to afford the methyl ester. In step 5, the methyl ester is treated with sodium borodeuteride in a protic solvent such as deuterated ethanol optionally at a lowered temperature to afford the deuterated alcohol. In step 6, the primary alcohol is treated with tert-butyldimethylsilyl chloride in an organic solvent such as (DMF), and organic bases such as triethylamine and 4-dimethylaminopyridine. In step 7, the 3,4-dimethoxybenzyl protecting group is removed by treating the xylose derivative with 2,3-dichloro-5,5-dicyano-1,4-benzoquinone. In step 8, the alcohol is treated with an oxidizing agent such as pyridinium dichromate (PDC) in an organic solvent such as dichloromethane and an anhydride such as acetic anhydride. The reaction can optionally be carried out at an elevated temperature. The ketone is treated with a reducing agent such as sodium borohydride in a protic solvent such as ethanol optionally at a lowered temperature. The alcohol is treated with 3,4-dimethoxybenzyl bromide in the presence of a base such as sodium hydride and an organic solvent such as DMF. In step 9, the acetonide is treated with an acid such as hydrochloric acid in a protic solvent to afford the 1-O-methyl compound. In step 10, the alcohol is treated with an oxidizing agent such as pyridinium dichromate (PDC) in an organic solvent such as dichloromethane and an anhydride such as acetic anhydride. The reaction can optionally be carried out at an elevated temperature. In step 11, the ketone is treated with methylmagnesium bromide to afford alcohol. The alcohol is treated with an anhydride such as acetic anhydride in an organic solvent such as pyridine to afford the acetate derivative. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With 2,4,6-trimethyl-pyridine In dichloromethane at -78℃; | |
85.1% | With pyridine In dichloromethane Ambient temperature; | |
With pyridine In dichloromethane |
With dmap; triethylamine In tetrahydrofuran at 0 - 5℃; | 183.I Step l; Scheme: Triethylamine (4.38 mL, 0.032 mot) is added to a solution of 1,2-0-isopropylidene-α-D-xylofuranose (5.0 g, 0 026 mol) in tetrahydrofuran (50 mL) at room temperature. Reaction mixture is cooled to 0-50C, acetyl chloride (1.68 mL, 0.024 mol) is added slowly to the reaction mixture. 4-Dimethyl aminopyridine (0.5 g, 0.004 mol) is added and reaction mixture is stirred at 0-50C for 45 minutes. D.M. water (10 mL) is added to the reaction mixture and concentrated under reduced pressure. Again, D.M. water (10 mL) is added to the residue and aqueous layer is extracted with ethyl aceate (3x20 mL). Combined organic layer is washed with saturated aqueous sodium bicarbonate solution (1x20 mL) followed by D. M. water (1x20 mL) and brine solution (1 x20 mL) respectively. Removal of ethyl acetate under reduced pressure after drying over anhydrous sodium sulphate gives viscous liquid, which is purified by column chromatography (silica gel 230-400 mesh, ethyl acetate:n-hexane, 50:50) to get l,2-O-isopropylidene-5-acetyl-α-D-xylofuranose. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 1.16667h; Inert atmosphere; | |
100% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 1h; | 25 1,2-O-isopropylidene-5-O-t-butyldiphenylsilyl-α-D-xylofuranose (31) A mixture of 1,2-O-isopropylidene-α-D-xylofuranose (38.0 g, 0.2 mol), t-butyl-diphenylchlorosilane (70 g, 0.25 mol) and imidazole (21.5 g, 0.4 mol) in N,N-dimethyl-formamide (50 mL) is stirred at room temperature for 1 hour. The solvent is removed in vacuo, and the residue is dissolved in ethyl acetate (1 L), and extracted with water (300 mL*2) and brine (300 mL), dried over sodium sulfate, and concentrated to dryness in vacuo to give crude 31 (86 g, 100%), which is used directly in the next step without further purification. |
99% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With 1H-imidazole In N,N-dimethyl-formamide for 0.25h; Inert atmosphere; Cooling with ice; Stage #2: tert-butylchlorodiphenylsilane In N,N-dimethyl-formamide for 1h; Inert atmosphere; | Synthesis of 1,2-O-isopropylidene-5-O-TBDPS-α-D-xylofuranose (I)2 1,2-O-isopropylidene-α-D-xylofuranose (11.41 g, 60 mmol) was dissolved in anhydrous DMF (300 mL) under Argon. Next imidazole (10.21 g, 150 mmol) was added and the mixture was cooled in an ice bath. After 15 min, TBDPSiCl (20.30 mL, 78 mmol) was added and the ice bath removed. TLC analysis (25 % EA / Hex; Rf = 0.33) showed full conversion after 1 hour. Water was added and the mixture evaporated till dryness. The residue was taken up in EA (300 mL) and water (150 mL). The layers were separated and the organic layer was sequentially washed with sat. NH4Cl sol. (150 mL), sat. NaHCO3 sol. (150 mL) and brine (150 mL). The organic layer was dried over Na2SO4, filtered and evaporated till dry. The mixture was purified by column chromatography (10 % → 30 % EA / Hex). The product (25.5 g, 59.5 mmol) was isolated as white waxy solid (99% yield). |
98% | With pyridine for 18h; Ambient temperature; | |
98% | With TEA In N,N-dimethyl-formamide at 20℃; | |
96% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 25℃; for 2h; | |
95% | With pyridine for 3h; | |
95% | ||
95% | With pyridine; 1H-imidazole for 3h; | 1 alcohol 21 To a solution of 20 (12.8 g, 67.0 mrnol) in Py (300 mL) is added TBDPSC1 (21.0 mL, 80.4 rnmoi). After stirring for 3 h, MeOH (25 mL) is added and the mixture is concentrated. The residue is dissolved in diethyl ether (200 mL), washes with sodium bicarbonate aqueous solution (10%, 100 mL) and water (100 mL), dried, over anhvdrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (diethy”l ether/PE = 1/2)to give 21 as awhite solid (27.2 g, 95%yield). (MS: M+Na 451.2) |
94% | With 1H-imidazole In N,N-dimethyl-formamide for 1h; Ambient temperature; | |
94.7% | With 1H-imidazole In N,N-dimethyl-formamide at 25℃; for 1h; | |
88% | With dmap; TEA In dichloromethane | |
88.7% | With 1H-imidazole In N,N-dimethyl-formamide at 0 - 25℃; for 5h; Inert atmosphere; | 100.1 Step 1: To a solution of 1,2-0-(1-Methylethylidene-a-D-xylofuranose (40 g, 210.31 mmol, 1eq.) in DMF (300 mL) was added imidazole (35.80 g, 525.78 mmol, 2.5 eq.) and TBDPSCl(69.37 g, 252.37 mmol, 64.83 mL, 1.2 eq.) at 0°C underN2 atomsphere. The mixture wasstirred at 25°C for 5 h before it was quenched with H20 (1000 mL). The aqueous phase wasextracted with EtOAc (3 x 250 mL). The combined organic layer was washed with brine(500 mL), dried over Na2S04 and filtered. The filtrate was concentrated to dryness. Thecrude product was purified by flash silica gel chromatography to provide the product( 3aR, 5R, 6S, 6aR)-5-( ( (tert-butyldi phenylsilyl )oxy )methyl )-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-ol (80 g, 88.7% yield) as a colorless syrup. |
83% | With pyridine; dmap at 20℃; for 16h; | |
75% | With 1H-imidazole In dichloromethane at 0 - 20℃; Inert atmosphere; | |
75% | With 1H-imidazole In N,N-dimethyl-formamide | |
60% | With 1H-imidazole In pentane for 3h; Ambient temperature; | |
With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 12h; | ||
With pyridine at 20℃; Inert atmosphere; | 2 Step 2: Into a 10L 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added a solution of (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyl- tetrahydro-2H-furo[2,3-d][1,3]dioxol-6-ol (951 g, 5 mol) in pyridine (7 L) and tert- butyl(chloro)diphenylsilane (1404 g, 5.1 mol). The resulting solution was stirred overnight at room temperature. To the solution was added 600 mL of MeOH. The resulting mixture was concentrated under reduced pressure. The residue was solubilized in EtOAc, washed with HCl (0.5 M), saturated NaHCO3and brine. The organic layer was dried over Na2SO4, andconcentrated under reduced pressure to give (3aR,5R,6S,6aR)-5-[[(tert- butyldiphenylsilyl)oxy]methyl]-2,2-dimethyl-tetrahydro-2H-furo[2,3-d][1,3]dioxol-6-ol as an oil. MS: 451 [M+Na]+. | |
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 4h; | 1 first step Add 1,2-O-isopropylidene-α-D-xylofuranose (5.70 g, 29.99 mmol) into a 150mL two-neck bottle,Imidazole (5.76 g, 84.65 mmol) and 30 mL of ultra-dry N,N-dimethylformamide. Place the reaction flask in an ice bath at 0°C, and then add tert-butyldiphenylchlorosilane (10mL, 38.46 mmol) dropwise. The addition is complete. The reaction is stirred at room temperature for 4 h, and water (100 mL ) And ethyl acetate (50 mL), extracted with ethyl acetate (50 mL×2), the combined organic phase was washed with saturated brine (50 mL×2), dried by adding anhydrous Na2SO4, filtered, and separated by column chromatography ( PE:EA = 30:1 to 6:1), a colorless liquid is obtained, which is indeed the target product after NMR identification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Yield given. Multistep reaction; | ||
With 1H-imidazole In N,N-dimethyl-formamide at 0 - 20℃; for 24h; | 7 [0440] General procedure for the synthesis of compound 2f : To a stirred solution of (3aR,5R,6S,6aR)-5-(hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-d][l,3]dioxol-6-ol (prepared according to the reported method in Nucleosides, Nucleotides and Nucleic Acids, 2013, 32, 646-659)(1.0 eq) in DMF (24 mL) was added the Imidazole (2 eq) and TBDPSC1 (1.1 eq) at 0 °C. The reaction mixture was allowed to warm to room temperature. After stirring at this temperature for 24 hours, the reaction mixture was diluted with EtOAc (100 mL), and the organic phase was washed with water (5X50 mL), dried over anhydrous Na2S04, filtered and concentrated to give a residue. The residue was purified by a flash column chromatography on silica gel to afford the desired product. The product was oxidized by Swern-Oxidation according to the standard procedure to offer the compound 2f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | With 1H-imidazole; iodine; triphenylphosphine In dichloromethane for 8h; Heating; | |
94% | With 1H-imidazole; iodine; triphenylphosphine In toluene; acetonitrile for 1h; Heating; | |
91% | With pyridine; carbon tetraiodide; triphenylphosphine at 60℃; for 1.5h; |
74% | With 1H-imidazole; iodine; triphenylphosphine In toluene at 70 - 100℃; for 5h; | |
53% | With 1H-imidazole; iodine; triphenylphosphine In tetrahydrofuran for 4.5h; Inert atmosphere; | |
With 1H-imidazole; iodine; triphenylphosphine In benzene | ||
Multi-step reaction with 2 steps 1: pyridine / Ambient temperature 2: 16.7 g / NaI / butan-2-one / 12 h / 110 °C | ||
Multi-step reaction with 3 steps 1: 93 percent / 1,2-dichloro-ethane / 18 h / Ambient temperature 2: 99 percent / 1,2-dichloro-ethane / 18 h / Heating 3: 99 percent / DIBAL-H / CH2Cl2 / 1 h / -78 °C | ||
Multi-step reaction with 2 steps 1: chloroform; pyridine 2: acetone; sodium iodide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 0℃; | |
In Isopropyl acetate at 3 - 10℃; Inert atmosphere; | 1.a A 4 liter 4 necked flask equipped with a nitrogen inlet, addition funnel, thermometer, and mechanical stirrer was charged with mono acetonexy lose (152.16 grams, 800 mmol) and isopropylacetate (1200 ml) and stirred until the solids dissolved, yielding a slightly cloudy solution. Ketenedimethylacetal (3.36 ml, 35.5 mmol) was added and the reaction cooled to 3 0C using an ice bath. Methanesulfonic acid (0.52 ml, 8 mmol) was added followed by the dropwise addition of ketenedimethylacetal (80 ml, 844.5 mmol) over 45 minutes. The reaction temperature reached 10 0C during the addition. When the addition was complete TLC, using 80% MTBE in hexane, indicated a complete, clean conversion to the much faster running tricycle 5 A. The ice bath was removed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With pyridine In toluene at 0 - 20℃; Inert atmosphere; | |
73.6% | With pyridine In toluene Ambient temperature; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In 1,2-dichloro-ethane for 18h; Ambient temperature; | |
70% | With dmap In acetonitrile at 20℃; for 24h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.7% | With sodium hydride In tetrahydrofuran; paraffin at 20℃; | |
Stage #1: 1,2-O-isopropylidene-α-D-xylose With potassium <i>tert</i>-butylate In tetrahydrofuran at 20℃; Stage #2: benzyl bromide In tetrahydrofuran at 20℃; | 176.I Step I; Scheme: Potassium tert-butoxide (1.473 g, 0.016 mol) is added to a stirred solution of 1 ,2-O-isopropylidene-α-D- xylofuranose (3.0 g, 0.016 mol) in tetrahydorfuran (20 mL) at room temperature. Benzyl bromide (1.86 mL, 0.016 mol) is dissolved in tetrahydorfuran (5 mL) and the solution was added slowly to the reaction mixture at room temperature. Reaction mixture is stirred at room temperature for 1 hr, concentrated under reduced pressure, D.M.water (20 mL) is added to the residue and exctracted with ethyl acetated (3x20 mL). Combined organic layer is washed with D.M.water (1x10 mL) followed by brine solution (1x10 mL) and then dried over anhydrous sodium sulphate. Removal of ethyl acetate under reduced pressure gives viscous liquid which is purified by column chromatography (silica 230-400 mesh, n-hexane:ethyl acetate, 70:30) to get 1 ,2-O-isopropylidene-3-O-benzyl-α-D-xylofuranose. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With pyridine In dichloromethane at 20℃; for 44h; | |
98% | With dmap; triethylamine; 1-amino-3-(dimethylamino)propane In dichloromethane at 20℃; for 2h; | |
With pyridine In dichloromethane at 0℃; |
3.28 g | With pyridine In dichloromethane at 0 - 20℃; for 44h; | 3,5-Di-O-benzoyl-1,2-O-isopropylidene-α-D-xylofuranose (5) A solution of 4a1 (3.75 g, 16.29 mmol) in 30% aq AcOH (30 mL) was stirred for 24 h at room temperature. The mixture was neutralized with solid NaHCO3 (pH 6-7) and extracted with CH2Cl2 (4×30 mL). The combined extracts were dried with a mixture of anhydrous Na2SO4 and Na2CO3, filtered and evaporated. The remaining syrup was dried in high vacuum, to afford crude 4b (2.1195 g, 68%) as a colourless oil, Rf=0.11 (3:2 toluene/EtOAc).1H NMR (DMSO-d6): δ 1.24 and 1.39 (2×s, 3 H each, CMe2), 3.52 (dd, 1 H, J4,5a=5.6, J5a,5b=11.1 Hz, H-5a), 3.63 (dd, 1 H, J4,5b=4.9, J5a,5b=11.1 Hz, H-5b), 3.95-4.04 (m, 2 H, H-3 and H-4), 4.39 (d, 1 H, J1,2=3.7 Hz, H-2), 4.60-5.21 (br s, 2 H, 2×OH), 5.82 (d, 1 H, J1,2=3.7 Hz, H-1).13C NMR (DMSO-d6): δ 26.1 and 26.7 (CMe2), 58.9 (C-5), 73.5 (C-3), 81.4 (C-4), 85.1 (C-2), 104.3 (C-1), 110.4 (CMe2).This material was used for further work without purification.To a cooled (0 °C) and stirred solution of crude 4b (1.5732 g, 8.27 mmol) in dry Py (6 mL) and CH2Cl2 (17 mL) was added BzCl (3.84 mL, 33.08 mmol). The mixture was left at room temperature for 44 h, then poured into 6 M HCl (pH 1-2) and extracted with CH2Cl2 (4×20 mL). The combined extracts were washed successively with water (1×25 mL), saturated aq NaHCO3 (1×25 mL) and again with water (1×25 mL). The organic solution was dried and evaporated to give crude 5 (5.3118 g), which was purified by flash column chromatography (19:1 toluene/EtOAc), to give pure 5 (3.28 g, 99%) as a colourless syrup, [α]D=-54.7 (c 0.4, CHCl3); lit.2 [α]D=-50.0 (c 0.7, CHCl3); Rf=0.34 (19:1 toluene/ EtOAc).IR (film): νmax 1724 (C=O, Bz).1H NMR (CDCl3): δ 1.35 and 1.58 (2×s, 3 H each, CMe2), 4.59 (dd, 1 H, J4,5a=6.1, J5a,5b=11.6 Hz, H-5a), 4.66 (dd, 1 H, J4,5b=6.0, J5a,5b=11.8 Hz, H-5b), 4.70 (d, 1 H, J1,2=3.7 Hz, H-2), 4.77 (td, 1 H, J4,5=5.9, J3,4=2.9 Hz, H-4), 5.60 (d, 1 H, J3,4=3.0 Hz, H-3), 6.07 (d, 1 H, J1,2=3.7 Hz, H-1), 7.34-8.15 (m, 10 H, 2×Ph),13C NMR (CDCl3): δ 26.1 and 26.6 (CMe2), 61.8 (C-5), 76.6 (C-3), 77.0 (C-4), 83.4 (C-2), 105.9 (C-1), 112.3 (CMe2), 128.2, 128.5, 129.6, 129. 7, 133.0, 133.6 (2×Ph), 165.1 and 166.0 (2×PhC=O). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With Zn(N3)2/bis-pyridine complex; triphenylphosphine; diethylazodicarboxylate In pyridine at 80℃; for 0.5h; | |
85% | With triphenylphosphine; diethylazodicarboxylate In pyridine at 80℃; for 0.5h; | |
Multi-step reaction with 2 steps 1: pyridine / CHCl3 / 0 - 20 °C 2: sodium hydride / tetrahydrofuran / 0 - 20 °C |
Multi-step reaction with 2 steps 1: pyridine / CHCl3 / 0 - 20 °C 2: 86 percent / sodium hydride / tetrahydrofuran | ||
Multi-step reaction with 2 steps 1: pyridine 2: ethanolic KOH-solution | ||
Multi-step reaction with 2 steps 1: chloroform; pyridine 2: sodium methylate; methanol | ||
Multi-step reaction with 2 steps 1: pyridine / 1.5 h / 20 °C / Inert atmosphere 2: sodium methylate / methanol / 24 h / 20 °C / Inert atmosphere | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 2 h / 0 - 20 °C / Large scale 2: potassium carbonate / methanol / 3 h / 45 - 50 °C / Large scale | ||
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 15 h / 20 °C 2: potassium methanolate / acetonitrile / 0.25 h / 20 °C / Schlenk technique |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With 1,2,3-Benzotriazole; thionyl chloride In dichloromethane at 20℃; | |
83% | With thionyl chloride; triethylamine at 20℃; Inert atmosphere; Ionic liquid; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In methanol; N,N-dimethyl-formamide at 70℃; for 2h; | |
89% | With toluene-4-sulfonic acid In N,N-dimethyl-formamide at 70℃; for 2h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With triethylamine In dichloromethane at 0℃; for 2h; | |
74.6% | With triethylamine In dichloromethane at 0℃; | 2 The synthesis of compound c: The compound b (154g, 0.81mol) and triethylamine (339ml, 2.43mol) were dissolved in dichloromethane (1.50L). The solution was cooled to 0 °C in an ice salt bath, slowly added dropwise with parachlorobenzoyl chloride (113ml, 0.891mol) and mechanically stirred for reaction at a temperature below 0 °C for 4 hours. After completion of the reaction, the solution was added with a saturated NaHCO3 solution (500ml). The dichloromethane layer was washed with water and saturated salt water, dried over anhydrous MgSO4, filtered, and evaporated under a reduced pressure to remove the solvent. The residue was recrystallized to obtain white crystalline compound c (196g, yield=74.6%), ESI-MS: 330[M+H]. |
With TEA In dichloromethane |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium hydrogen sulfate; silica gel In methanol; dichloromethane at 20℃; for 2h; | |
90% | With antimony(III) chloride In water; acetonitrile at 20℃; for 0.666667h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With pyridine In toluene at -10 - 20℃; for 0.5h; | 1.1; 1.a EXAMPLE 1 Step 1) Preparation of 1,2-Isopropylidene-5-O-isopropyloxycarbonyl-D-xylofuranose (1) To a solution of commercially available 1,2-isopropylidene-D-xylofuranose (5.00 g, 26.3 mmol) in pyridine (104 mL) at -10° C. was added 1 M isopropyl chloroformate in toluene (27.6 mL, 27.6 mmol). The resultant pink reaction mixture was kept at -10° C. for 30 min, then slowly warmed to rt whereupon the pink color faded. The reaction was quenched with a few drops of IPA, concentrated via rotary evaporation at 40° C., and further dried under high vacuum overnight. The residue was taken up in ether (100 mL), filtered, and then submitted to flash chromatography (SiO2, 10-50% EtOAc-hexanes) to afford 5.6 g (77%) of carbonate 1 as a clear, colorless oil. Subsequent preparations utilized a step involving aqueous extraction of the ether phase with 1 M HCl followed by water and then NaHCO3. 1H NMR (400 MHz, DMSO-d6) δ 5.84 (1H, d, J=3.1 Hz), 5.41 (1H, d, J=4.4 Hz), 4.75 (1H, septet, J=6.2 Hz), 4.40 (1H, d, J=4.1 Hz), 4.24 (1H, dd, J1=2.9 Hz, J2=10.1 Hz), 4.09-4.17 (2H, m), 4.02 (1H, dd, J1=2.3 Hz, J2=4.6 Hz), 1.37 (3H, s), 1.23 (3H, s), 1.22 (6H, d, J=6.2 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With pyridine at 20 - 50℃; for 192h; | 14.1 Step 1) Preparation of 5-O-Diethylcarbamoyl-1,2-isopropylidene-β-D-xylofuranose EXAMPLE 14 Preparation of 5-Amino-3-(5'-O-diethylcarbamoyl-β-D-xylofuranosyl)-3H-thiazolo[4,5-d]pyrimidin-2-one (57) Step 1) Preparation of 5-O-Diethylcarbamoyl-1,2-isopropylidene-β-D-xylofuranose To a solution of D-xylofuranose-1,2-isopropylidene ketal (8.0 g, 42 mmol) in pyridine (20 mL) was added diethylcarbamoyl chloride (5.8 mL, 46 mmol) at rt. The resultant mixture was heated to 50° C., then stirred for 8 days whereupon it was cooled to rt, concentrated, and partitioned between EtOAc (100 mL) and 1 N HCl (100 mL). The organic phase was diluted with hexanes (50 mL) and then extracted successively with 1 N HCl (100 mL) and water (100 mL). The organic phase was dried over MgSO4, filtered, concentrated and submitted to chromatography (SiO2, 10-80% EtOAc-hexanes), providing 54 (6.17 g) in a 50% yield: 1H NMR (400 MHz, DMSO-d6) δ: 5.83 (1H, d, J=4.2 Hz), 5.35 (1H, d, J=5.6 Hz), 4.39 (1H, d, J=3.4 Hz), 4.12-4.20 (2H, m), 3.98-4.06 (2H, m), 3.20 (4H, quartet, J=7.0 Hz), 1.37 (3H, s), 1.23 (3H, s), 1.04 (6H, t, J=7.0 Hz); [M+H]+ m/z 290. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With 2,4-dichlorophenoxyacetic acid dimethylamine; sodium hydride In various solvent(s) at 20℃; for 0.5h; Stage #2: polymer, 33% reactive sites, 2.8 mmol/g; monomer(s): styrene, 4-vinylbenzylchloride With sodium hydride In various solvent(s) for 10h; Further stages.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77% | With tributylphosphine; 4 A molecular sieve In toluene at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With 1H-imidazole; iodine; triphenylphosphine In acetonitrile at 50℃; Inert atmosphere; Stage #2: With tris[2-phenylpyridinato-C2,N]iridium(III); N-ethyl-N,N-diisopropylamine In methanol; acetonitrile for 0.3h; Inert atmosphere; Irradiation; Flow reactor; | |
Multi-step reaction with 2 steps 1: 70 percent / DMAP / acetonitrile / 24 h / 20 °C 2: 75 percent / (Bu4N)2S2O8; HCO2Na; Et3N / dimethylformamide / 0.25 h / 65 °C | ||
Multi-step reaction with 2 steps 1: Ph3P, N-bromosuccinimide 2: H2 / Raney-Ni |
Multi-step reaction with 3 steps 1: pyridine / Ambient temperature 2: 16.7 g / NaI / butan-2-one / 12 h / 110 °C 3: 5.6 g / Et3N, H2 / Raney nickel / methanol / 48 °C | ||
Multi-step reaction with 2 steps 1: 80 percent / Pyr / CH2Cl2 2: 80 percent / LAH / tetrahydrofuran | ||
Multi-step reaction with 2 steps 2: LiAlH4 / diethyl ether; CHCl3 / 18 h / Heating | ||
Multi-step reaction with 2 steps 1: 79 percent / pyridine / CHCl3 / 12 h / 0 °C 2: 99 percent / LiAlH4 / tetrahydrofuran / 12 h / Heating | ||
Multi-step reaction with 2 steps 1: 91 percent / PPh3, pyridine, CI4 / 1.5 h / 60 °C 2: 24 percent / azoisobutyronitrile / toluene / 80 °C | ||
Multi-step reaction with 2 steps 1: 91 percent / PPh3, pyridine, CI4 / 1.5 h / 60 °C 2: 24 percent / allyltributylstannane, azoisobutyronitrile / toluene / 80 °C | ||
Multi-step reaction with 2 steps 1: pyridine 2: lithium alanate; diethyl ether | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0 - 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 6 h / Reflux | ||
Multi-step reaction with 2 steps 1: triethylamine / tetrahydrofuran / 0.5 h / 0 - 20 °C 2: lithium aluminium tetrahydride / tetrahydrofuran / 2 h / 0 °C | ||
Multi-step reaction with 2 steps 1.1: triethylamine / dichloromethane / 0 - 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 20 - 80 °C 2.2: 0 - 5 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 14 h / 10 °C / Cooling with ice; Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 20 °C / Cooling with ice; Inert atmosphere | ||
Multi-step reaction with 2 steps 1: pyridine / 10 h / 0 - 20 °C / Inert atmosphere 2: lithium aluminium tetrahydride / tetrahydrofuran / 6 h / 0 - 20 °C | ||
Multi-step reaction with 2 steps 1: pyridine / 14 h / 0 - 10 °C 2: aluminium hydride / 0 °C / Inert atmosphere |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 2 steps 1: 70 percent / (Bu3Sn)2O; TBAB / toluene / 72 h / 90 °C 2: (COCl)2; DMSO; TEA | ||
Multi-step reaction with 2 steps 1: Bu2SnO; Bu4NBr; 3A molecular sieves / acetonitrile / 48 h / Heating 2: Ac2O / dimethylsulfoxide / 18 h | ||
Multi-step reaction with 3 steps 1: 89 percent / p-TsOH / dimethylformamide / 2 h / 70 °C 2: 68 percent / NaCNBH3; aq,. HCl; 3A molecular sieves / tetrahydrofuran; diethyl ether / 0.08 h / 20 °C 3: Ac2O / dimethylsulfoxide / 18 h |
Multi-step reaction with 3 steps 1: 89 percent / TsOH / dimethylformamide; methanol / 2 h / 70 °C 2: 68 percent / NaCNBH3; HCl; 3 Angstroem molecular sieves / tetrahydrofuran; diethyl ether / 0.08 h / 20 °C 3: DMSO; Ac2O / 18 h / 20 °C | ||
Multi-step reaction with 2 steps 1: 1.) Bu2SnO, 2.) TBAI / 1.) toluene, reflux, overnight, 2.) toluene, 110 deg C, 7 h 2: 1.) (COCl)2, DMSO, 2.) Et3N / 1.) CH2Cl2, -35 deg C, 15 min, 2.) CH2Cl2, from -35 deg C to RT | ||
Multi-step reaction with 3 steps 1: 88 percent / pyridine / CHCl3 / Ambient temperature 2: 81 percent / Na / 15 h / 100 °C 3: CrO3, pyridine, Celite / CH2Cl2 / 2 h | ||
Multi-step reaction with 3 steps 1: camphor-10-sulfonic acid / dichloromethane / 0 - 20 °C 2: triethylsilane; trifluoroacetic acid / dichloromethane / 12 h 3: oxalyl dichloride; dimethyl sulfoxide; triethylamine / dichloromethane / 5 h / -78 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Multi-step reaction with 3 steps 1: 94 percent / imidazole / dimethylformamide / 1 h / Ambient temperature 2: 1.) pyridine, (CF3SO2)2O; 2.) n-Bu4NI / 1.) CH2Cl2, -10 deg C, 15 min; 2.) benzene, reflux, 12 h 3: 95 percent / LiEt3BH / tetrahydrofuran / 12 h / Heating | ||
Multi-step reaction with 3 steps 1: 94 percent / imidazole / dimethylformamide / 1 h / Ambient temperature 2: 94 percent / pyridine / DMAP / CH2Cl2 / 15 h / 0 °C 3: 77 percent / n-BuSnH / AIBN / toluene / 1 h / 80 °C | ||
Multi-step reaction with 3 steps 1: 96 percent / imidazole / dimethylformamide / 2 h / 0 - 25 °C 2: 94 percent / pyr / DMAP / CH2Cl2 / 15 h / 0 - 25 °C 3: 77 percent / n-Bu3SnH / AlBN / toluene / 1 h / 80 °C |
Multi-step reaction with 3 steps 1: pyridine; dmap / 16 h / 20 °C 2: 1,2-dichloro-ethane / 2 h / 85 °C 3: tri-n-butyl-tin hydride; 2,2'-azobis(isobutyronitrile) / toluene / 3 h / 116 °C / Inert atmosphere | ||
Multi-step reaction with 4 steps 1: 1H-imidazole / N,N-dimethyl-formamide 2: pyridine / dichloromethane 3: tetra-(n-butyl)ammonium iodide / toluene 4: lithium triethylborohydride / tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With dmap; triethylamine; p-toluenesulfonyl chloride In dichloromethane at 0 - 20℃; Stage #2: In dichloromethane | 19 1,2-Isopropylidene-5-p-toluenesulfonyl-α-D-xylofuranose Example 19 1,2-Isopropylidene-5-p-toluenesulfonyl-α-D-xylofuranose To a stirred solution of 1,2-O-isopropylidene-D-xylofuranose (1.978 g, 10.30 mmol) in dichloromethane (15 mL) was added DMAP (63 mg, 0.52 mmol), Et3N (2.87 ml, 20.59 mmol), the solution was then cooled to 0° C. TsCl (2.022 g, 10.50 mmol) in dichloromethane (5 mL) was cannulated to the above solution. Reaction mixture was slowly warmed to room temperature overnight. Reaction mixture was diluted with EtOAc, washed with 2N HCl, saturated NaHCO3, and saturated NaCl. The organic layer was dried over MgSO4. After the removal of volatiles, the residue was chromatographed on silicagel using hexanes-ethylacetate (7:3), then hexanes-ethylacetate (55:45) to yield pure product as white solid (2.629 g, 74% yield). 1H NMR (360 MHz, CDCl3) δ 7.76 (d, J=8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 5.88 (d, J=3.8 Hz, 1H), 4.51 (d, J=3.8 Hz, 1H), 4.38-4.28 (m, 3H), 4.14 (td, J=9.4, 6.8 Hz, 1H), 2.46 (s, 3H), 1.46 (s, 3H), 1.30 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Concentrated HCl (1 ml), water (1 ml) and methanol (20 ml) were mixed together. One hundred mg of a 1:1 acetal mixture was dissolved in 2 ml of the acidic methanol. After 25 mins 20 microliters of a 20% solution of sodium hydroxide was added to neutralize the solution. Hexane (4 ml) was then added. After brief mixing the layers were separated and the upper hexane layer was dried with sodium sulfate and analyzed by GC (Figure 10) which indicated that all of the 1,2-3,5-di-O-isopropylidene-D-xylofuranose had been converted to the 1,2-monoacetal as a result of the selective hydrolysis. | ||
Concentrated HCl (5 ml), water (5 ml) and methanol (100 ml) were mixed together. 24 grams of a 1:1 acetal mixture was dissolved in the acidic methanol solution. After 30 mins 20 ml of a 25% solution of sodium hydroxide was added to neutralize the solution. Hexane (400 ml) was then added. After brief mixing the layers were separated and the upper hexane layer was dried with sodium sulfate, concentrated and analyzed by GC (Figure 11) and 1H (Figure 12) and 13C (Figure 13) NMR spectroscopy. GC analyses indicated that all of the 1,2-3,5-di-O-isopropylidene-D-xylofuranose had been converted to the 1,2-monoacetal and the layer was 99% arabino di-acetal. NMR analyses also indicated that exclusively arabino di-acetal was present in the hexane layer. The yield was 12.1 grams (- 100%). The lower layer was concentrated to give a crude yield of 29.30 grams. This was taken up in tetrahydrofuran and the THF solution dried (sodium sulfate) and concentrated to give 9.7 grams (98%) of the mono acetal. 1H (Figure 14) and 13C (Figure 15) NMR spectra indicated that this layer contained only the 1,2-monoacetal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With pyridine; copper(II) sulfate In dichloromethane; water | 1 Synthesis of (3aR,4S,6aR)-Hexahydro-2-oxofuro-[3,4-b]furan-4-carboxaldehyde (11) EXAMPLE 1 Synthesis of (3aR,4S,6aR)-Hexahydro-2-oxofuro-[3,4-b]furan-4-carboxaldehyde (11) The compounds of this invention (both the PGD2 -type and the PGF2α -type analogs) may be prepared from the same intermediate compound, (3aR,4S,6aR)-hexahydro-2-oxofuro[3,4-b]furan-4-carboxaldehyde (11) which is prepared from the readily available 1,2-O-isopropylidene-α-D-xylofuranose (1) according to published methodology (Arndt, et al. S. Afr. J. Chem., 34:121-127 (1981); U.S. Pat. No. 4,133,948). The following Scheme 1 outlines the synthetic route to (11). STR12 A:5-O-Benzoyl-1,2-O-isopropylidene-α-D-xylofuranose (2): A solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (30 g, 0.15 mol) in 360 mL of CH2 Cl2 was cooled to 0° C. and to it was added 20 mL (0.23 mol) of pyridine and a catalytic amount (1.0 g) of N,N-dimethylaminopyridine. The resulting mixture was stirred at 0° C. for 10 min, at which time 20 mL (0.17 mol) benzoyl chloride was added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0° C. for an additional 30 min and then quenched by the addition of 200 mL a saturated solution of NH4 Cl. The reaction was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with 3*50 mL of CH2 Cl2. The combined organic extracts were washed with 3*50 mL of a 10% aqueous solution of CuSO4, 2*50 mL of water and brine. The organic solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product mixture was purified by chromatography on silica gel to afford 44.3 g (95% yield) of 2 as a colorless liquid: Rf 0.54 (60% EtOAc/hexane); 1 H-NMR (CDCl3) δ 8.03 (m, 2H), 7.40-7.68 (m, 3H), 5.97 (d, 1H, J=3.6 Hz), 4.80 (m, 1H), 4.61 (d, 1H, J=3.4 Hz), 4.37 (m, 2H), 4.20 (s, broad, 1H), 3.35 (broad, 1H), 1.50 (s, 3H), 1.32 (s, 3H). |
95% | With pyridine; copper(II) sulfate In dichloromethane; water | 1 Synthesis of (3aR,4S,6aR)-Hexahydro-2-oxofuro[3,4-b]furan-4-carboxaldehyde (11) EXAMPLE 1 Synthesis of (3aR,4S,6aR)-Hexahydro-2-oxofuro[3,4-b]furan-4-carboxaldehyde (11) The compounds of this invention may be prepared from the compound (3aR,4S,6aR)-hexahydro-2-oxofuro[3,4-b]furan-4-carboxaldehyde (11), which is prepared from the readily available 1,2-O-isopropylidene-α-D-xylofuranose (1) according to published methodology (Arndt, et al. S. Afr. J. Chem., 34:121-127 (1981); U.S. Pat. No. 4,133,948). The following Scheme 1 outlines the synthetic route to (11). STR7 A:5-O-Benzoyl-1,2-O-isopropylidene-α-D-xylofuranose (2) A solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (30 g, 0.15 mol) in 360 mL of CH2 Cl2 was cooled to 0° C. and to it was added 20 mL (0.23 mol) of pyridine and a catalytic amount (1.0 g) of N,N-dimethylaminopyridine. The resulting mixture was stirred at 0° C. for 10 min, at which time 20 mL (0.17 mol) benzoyl chloride was added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0° C. for an additional 30 min and then quenched by the addition of 200 mL a saturated solution of NH4 Cl. The reaction was allowed to warm to room temperature, the layers were separated, and the aqueous layer was extracted with 3*50 mL of CH2 Cl2. The combined organic extracts were washed with 3*50 mL of a 10% aqueous solution of CuSO4, 2*50 mL of water and brine. The organic solution was dried over anhydrous MgSO4, filtered and concentrated. The crude product mixture was purified by chromatography on silica gel to afford 44.3 g (95% yield) of 2 as a colorless liquid: Rf 0.54 (60% EtOAc/hexane); 1 H-NMR (CDCl3) δ8.03 (m, 2H), 7.40-7.68 (m, 3H), 5.97 (d, 1H, J=3.6 Hz), 4.80 (m, 1H), 4.61 (d, 1H, J=3.4 Hz), 4.37 (m, 2H), 4.20 (s, broad, 1H), 3.35 (broad, 1H), 1.50 (s, 3H), 1.32 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With pyridine In toluene at 0 - 20℃; Inert atmosphere; | |
65% | With pyridine In toluene at 0 - 20℃; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; sulfuryl dichloride In ethyl acetate at 0 - 5℃; Inert atmosphere; | 165.I Step l; Scheme: A solution of pyridine (0.64 mL, 0.008 mol) and 1,2-O-isopropylidene-α-D-xylofiiranose (1.5 g, 0.008 tnol) in ethyl acetate (15 mL) is added drop wise to a stirred solution of sulfuryl chloride (0.64 mL, 0.008 mol) in ethyl acetate (15 mL) at 0-50C under an atmosphere of nitrogen. Reaction mixture is stirred at 0-50C for 1 hr and then diluted with ethyl acetate (30 mL). D. M. water (40 mL) is added, organic layer is separated and aqueous layer is extracted with ethyl acetate (2x30 mL). Combined organic layer is washed with saturated aqueous sodium bicarbonate solution (1x30 mL) followed by D. M. water (1x30 mL) and brine solution ( 1 x30 mL) respectively. Ethyl acetate layer is concentrated under reduced pressure at room temperature after drying over anhydrous sodium sulphate to get l,2-0-isopropylidene-5-chlorosulphate-α- D-xylofuranose, which is directly used for the next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride In water | ||
3.83 g | With ammonium cerium (IV) nitrate In water; acetonitrile at 20℃; for 6h; | 11-1; 11-2; 11-3; 11-4 Preparation of Intermediate liB: To a stirred solution of Intermediate liA (4.61 g, 20.0 mmol) in acetonitrile (17.4 mL) and water (18.5 mL) was added CAN (0.33 g, 0.60 mmol) as a solid. The resulting mixture was stirred at room temperature. After 6 hours, the reaction was quenched with ammonium hydroxide (1.4 mL, 10.00 mmol) and the resulting suspension was filtered over a pad of Celigel (9: 1 w/w Celite/silica gel), rinsing with MeOH (3x10 mL). The filtrate was concentrated in vacuo and the residue was co-evaporated with MeOH several times then dried overnight under high vacuum to afford Intermediate liB (3.83 g, 20.14 mmol) as a clear yellow oil. 1H NMR (499 MHz, CHLOROFORM-d) ll 5.99 (d, 1=3.7 Hz, lH), 4.53 (d, 1=3.7 Hz, lH), 4.33 (d, 1=2.7 Hz, lH), 4.20-4.li (m, 2H), 4.08-4.03 (m, lH), 3.86 (br s, lH), 2.51 (br s, lH), 1.49 (s, 3H), 1.33 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sulfuric acid for 0.5h; | 5-O-(o-Toluoyl)-1,2-isopropylidene-α-D-xylofuranose (27). D-xylose (10.0 g, 0.067 mol) was dissolvedin acetone (260 mL) containing H2SO4 (0.66 M, 10.0 mL) and the solution was stirred for 30 min.A solution of Na2CO3 (13.0 g, 0.123 mol) in water (112 mL) was carefully added to the above cooledmixture, which was then stirred for further 2.5 h at 20 °C. Then, solid Na2CO3 (7.00 g, 0.066 mol) wasadded, Na2SO4 (22.3 g) was filtered off and washed with acetone, and the filtrate was evaporatedin vacuo to afford a crude residue (14 g). This residue was resolubilized in a 9:1 mixture of EtOAc(270 mL) and methanol (30 mL), filtered, and evaporated in vacuo to give a yellow oil (12 g, 96%).This residue was dissolved in dry DMF (150 mL) under an inert atmosphere, cooled in an ice bath,and then o-toluoyl chloride (9.85 g, 8.31 mL, 0.064 mol) was added, followed by imidazole (4.35 g,0.064 mol). The reaction mixture was allowed to warm to room temperature and stirred for 5 h. It wasthen diluted with EtOAc (300 mL) and washed with water (300 mL) and brine (100 mL). The organiclayer was dried over Na2SO4, filtered, and evaporated in vacuo to give a crude residue, which waspurified by column chromatography (hexane:EtOAc 7:3) to afford compound 27 (16.5 g, 84%) asa colorless oil. 1H-NMR (300 MHz, CDCl3):δ 7.92 (dd, 1H, J = 8.2, 1.6 Hz, ArH), 7.41-7.20 (m, 3H,ArH), 5.97 (d, J = 3.6 Hz, 1H, H-1'), 4.69 (dd, 1H, J = 13.4, 8.4 Hz, H-5'), 4.57 (d, 1H, J = 3.6 Hz, H-2'),4.43 (dd, 1H, J = 13.4, 6.0 Hz, H-5”), 4.42 (ddd, 1H, J = 8.4, 6.0, 2.1 Hz, H-4'), 4.24 (d, 1H, J = 2.1, H-30),3.73 (s, 1H, OH), 2.57 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C-NMR (75 MHz, CDCl3): δ168.2 (CO), 140.7 (ArC), 132.7 (ArC), 132.0 (ArC), 131.1 (ArC), 129.0 (ArC), 126.0 (ArC), 112.0 (OCO)105.1 (1'-C), 85.4 (4'-C), 78.8 (3'-CH), 74.8 (2'-CH), 62.0 (5'-CH2), 27.0 (CH3), 26.4 (CH3), 22.0 (CH3);HRMS for C16H20O6 [M + Na+]+ Calc.: 331.1152, found: 331.1156. |
95% | With sulfuric acid at 20℃; | 2 The synthesis of compound b: Compound a (60g) was added in acetone (2L) and the concentrated sulfuric acid (40ml) was slowly added while stirring. The solution was stirred for reaction at a room temperature for 40 minutes. After the reaction was detected by TLC as complete, the solution was added with the concentrated ammonia to adjust pH=7-8, filtered, and evaporated under a reduced pressure to remove most of the acetone. The remaining acetone and water were about 150 ml. Then the solution was added with 0.4% dilute hydrochloric acid (150m1) while being stirred, and the reaction was completed under the acetone reflux condition for 20 minutes until the compound a has been completely hydrolyzed into the compound b. After completion of the reaction, the reaction solution was neutralized to pH=7-8 by solid NaHCO3, filtered, and evaporated to remove the solvent under a reduced pressure. The residue was dissolved with dichloromethane (200ml), dried over anhydrous Na2SO4 overnight and then filtered. Finally the solvent was removed through evaporation to obtain the yellow viscous oily b (73g, 95%), ESI-MS: 191 [M+H]. |
65% | With sulfuric acid; copper(II) sulfate at 20℃; for 48h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
53% | With pyridine In dichloromethane at -78 - 20℃; for 2h; Inert atmosphere; | 4 Example 4; Synthesis of 1,2-O-isopropylidene-3,5-O-dioxan-6-one-D-xylofuranose (ICXF) 1,2-O-isopropylidene-D-xylofuranose (IPXF) (5.0 g, 26.3 mmol) was dissolved in 80 ml of CH2Cl2 and pyridine (13 ml, 0.16 mol) and the solution was chilled at -78° C. under N2. A solution of triphosgene (3.9 g, 13.1 mmol) in CH2Cl2 was added dropwise under stirring. The addition completed, the mixture was allowed to warm up to room temperature for 2 hours. The reaction was quenched by addition of saturated aqueous NH4Cl (40 ml), after which the organic layer was successively washed with 1 M aqueous HCl (3×50 ml) and saturated NaHCO3 (1×50 ml), then dried over MgSO4, filtered and concentrated under vacuum. The crude product was recrystallized in toluene to give a yellowish crystalline solid. Yield: 3.0 g (53%). Characterization matched the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of chiral aryl boronate ester (3a-3j): General procedure: A mixture of selected aryl boronic acid 2 (3 mmol) and 1,2-O-isopropylidene-α-D-xylofuranose 1 (3mmol) were dissolved in anhydrous Et2O; the mixture was stirred at room temperature for 2h and concentrated under reduced pressure. The crude product was purified by column chromatography onsilica gel (10%EtOAc/hexane) to afford a white crystalline solid. |
In diethyl ether at 20℃; for 2h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With ethanol; potassium hydroxide for 3h; Inert atmosphere; Reflux; | 4.2. Base-induced removal of PSE acetals Typical procedure. PSE acetals (0.18 mmol) were dissolved in a KOH/EtOH solution [0.6 M/3 mL]. The mixture was refluxed for 5 h, then cooled to rt, evaporated and directly purified by silica gel column chromatography (petroleum ether/EtOAc 1:1). The analytical data obtained for the resulting diols are in agreement with the literature. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 73% 2: 25% | With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 0.166667h; | 4.5. General procedure for TBDMS group removal with TBAF General procedure: TBAF (1×n, 1 M in THF) was added to a stirred solution of furanoside 1b-d and 2b-d (1×n), respectively, in dry THF at room temperature. After stirring for 10 min or 12 h (when stated), the reaction mixture was diluted with CHCl3 and washed with a saturated solution of NH4Cl (15 mL). The aqueous layer was extracted (3×15 mL) with CHCl3, then evaporated and extracted with CHCl3 (5×5 mL) as solid. The combined organic layers were dried and evaporated. The longer reaction time was used for the successful isolation and identification of minor products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 76% 2: 23% | With tetrabutyl ammonium fluoride In tetrahydrofuran; methanol at 20℃; for 0.166667h; | 4.5. General procedure for TBDMS group removal with TBAF General procedure: TBAF (1×n, 1 M in THF) was added to a stirred solution of furanoside 1b-d and 2b-d (1×n), respectively, in dry THF at room temperature. After stirring for 10 min or 12 h (when stated), the reaction mixture was diluted with CHCl3 and washed with a saturated solution of NH4Cl (15 mL). The aqueous layer was extracted (3×15 mL) with CHCl3, then evaporated and extracted with CHCl3 (5×5 mL) as solid. The combined organic layers were dried and evaporated. The longer reaction time was used for the successful isolation and identification of minor products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1: 92% 2: 4% | With tetrabutyl ammonium fluoride In tetrahydrofuran at 20℃; for 0.166667h; | 4.5. General procedure for TBDMS group removal with TBAF General procedure: TBAF (1×n, 1 M in THF) was added to a stirred solution of furanoside 1b-d and 2b-d (1×n), respectively, in dry THF at room temperature. After stirring for 10 min or 12 h (when stated), the reaction mixture was diluted with CHCl3 and washed with a saturated solution of NH4Cl (15 mL). The aqueous layer was extracted (3×15 mL) with CHCl3, then evaporated and extracted with CHCl3 (5×5 mL) as solid. The combined organic layers were dried and evaporated. The longer reaction time was used for the successful isolation and identification of minor products. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With sulfuric acid In acetone for 0.5h; | 1,2-O-Isopropylidene-α-D-xylofuranoside (20) D-Xylose 19 (10.0 g, 67 mmol) was dissolved in acetone(260 mL) containing H2SO4 (10 mL, 96 %) by stirring over 30 min. A solution of Na2CO3 (13.0 g, 123.0 mmol)in water (112 mL) was added dropwise applying externalcooling to keep the internal temperature below 20 C. Themixture was stirred for 2.5 h, then solid Na2CO3 (7.0 g,66 mmol) was added. The mixture was filtered, the filtercake was washed with acetone and the combined filtrates were concentrated in vacuum. The crude product was purified by column chromatography (silica gel, CHCl3-CH3OH 100:0 →100:3) to afford compound 20 (10.81 g,85 %); a22D = -19.4 (c = 1, CHCl3); 1H NMR(300 MHz, CDCl3), d (ppm): 5.98 (d, J = 3.3 Hz, 1H,H-1), 4.52 (d, J = 3.3 Hz, 1H, H-2), 4.30-4.26 (m, 1H,H-4), 4.20-4.17 (m, 1H, H-3), 4.10 (m, 2H, H-5a, H-5b),1.48 (s, 3H, CCH3), 1.32 (s, 3H, CCH3); 13C NMR(75 MHz, CDCl3), d (ppm): 111.64, 105.26, 82.73, 82.30,79.37, 70.36, 26.77, 26.29; HRMS calcd for C8H14O5190.0841, found 190.0840. |
Multi-step reaction with 2 steps 1: iodine / 7 h / 20 °C 2: ammonium cerium (IV) nitrate / water; acetonitrile / 6 h / 20 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydroxide In water at 20℃; for 14h; | General procedure for preparation of bis-chlorocompounds (6, 7, 16 and 21) General procedure: To a mechanically stirred solution of carbohydrated erivative having two free OH groups (4, 5, 15 and 20) in bis(2-chloroethyl)ether, 50 % aq. NaOH solution and Bu4NHSO4 were added. The mixture was stirred for 14 h at rt then poured into a 1:1 mixture of CH2Cl2 and water(used in a threefold volume of volume of the reaction mixture). The phases were separated, and the aqueous layer was extracted with CH2Cl2 twice. The combined organic layers were washed with water, dried (Na2SO4), and concentrated under reduced pressure. The excess of the bis(2-chloroethyl)ether was removed by vacuum distillation. The crude product was purified by column chromatography(silica gel, CHCl3-CH3OH 100:0→100:5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of formyl phenyl boronate ester (2b-c) A mixture of 1,2-O-isopropylidene-α-D-xylofuranose 1 (3 mmol) and selected formyl phenylboronic acid (3 mmol) were dissolved in anhydrous Et2O, the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10%EtOAc/hexane) to afford a white crystalline solid of corresponding formyl phenyl boronate ester 2b-c. 1,2-O-isoropylidene-α-D-xylofuranose-3,5-(3’-formyl)phenyl boronate (2b)According to the general procedure, 3-formylphenylboronic acid (0.45 g, 3 mmol), yields the corresponding boronate ester as a white crystalline solid. Yield: 0.81 g (89%). M.p. 84-86 °C. 1H NMR (400 MHz, CDCl3): δ 10.04 (s, 1H), 8.28 (s, 1H), 8.05 - 8.02 (m, 1H), 7.95 (dt, J = 7.7, 1.5 Hz, 1H), 7.51 (t, J = 7.5 Hz, 1H), 5.94 (d, J = 3.7 Hz, 1H), 4.76 (d, J = 3.7 Hz, 1H), 4.55 (dd, J = 8.0, 1.9 Hz, 2H), 4.46 - 4.41 (m, 1H), 4.29 (dd, J = 13.2, 2.0 Hz, 1H), 1.54 (s, 3H), 1.36 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 192.75, 139.90, 136.06, 135.70, 131.50, 128.31, 112.18, 104.99, 84.90, 76.27, 74.86, 74.28, 60.79, 26.71, 26.19. 11B NMR (128 MHz, CDCl3): δ 26.38 (brs). IR (KBr): ν 3023(w), 2986 (w), 2961 (m), 2825 (m), 2727 (m), 1704 (s), 1597 (m), 1468 (m), 1435 (m), 1379 (m), 1323 (s), 1261 (m), 1195 (w), 1163 (m), 1136 (m), 1086 (m), 1023 (m), 908 (w), 886 (w), 836 (m), 700 (m), 648 (w) cm-1. Anal. Calc. for C15H17BO6 (304.10): C 59.24, H 5.63%. Found: C 59.57, H 5.41%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | General procedure for the synthesis of formyl phenyl boronate ester (2b-c) General procedure: A mixture of 1,2-O-isopropylidene-α-D-xylofuranose 1 (3 mmol) and selected formyl phenylboronic acid (3 mmol) were dissolved in anhydrous Et2O, the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10%EtOAc/hexane) to afford a white crystalline solid of corresponding formyl phenyl boronate ester 2b-c. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | Stage #1: terephthalaldehyde,; 1,2-O-isopropylidene-α-D-xylose With toluene-4-sulfonic acid In toluene for 5h; Inert atmosphere; Dean-Stark; Reflux; Stage #2: With triethylamine In toluene Inert atmosphere; Dean-Stark; | 3,5-O-(4-formylbenzylidene)-1,2-O-isopropylidene-α-D-xylofuranose (8d) To a toluene (30 mL) solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (0.57 g, 3 mmol),terephthalaldehyde (0.41 g, 3 mmol) was added p-toluene sulfonic acid monohydrate, pTSA (9 mg) andthe solution was refluxed for 5 h using a Dean-Stark condenser. After this time, Et3N (0.15 mL) wasadded and the reaction mixture was cooled and extracted with EtOAc. The extract was washed withwater; combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure.The crude product was purified by column chromatography on silica gel (10%EtOAc/hexane) to afford awhite crystalline solid of corresponding 3,5-O-(4-formylbenzylidene)-1,2-O-isopropylidene-α-Dxylofuranose8d. Yield: 0.38 g (41%). M.p. 134-136 °C. 1H NMR (400 MHz, CDCl3): δ 10.03 (s, 1H),7.91 - 7.86 (m, 2H), 7.66 (d, J = 8.2 Hz, 2H), 6.07 (d, J = 3.7 Hz, 1H), 5.53 (s, 1H), 4.66 (d, J = 3.7 Hz,1H), 4.49 (d, J = 13.6 Hz, 1H), 4.46 (d, J = 1.7 Hz, 1H), 4.19 (dd, J = 11.5, 2.0 Hz, 2H), 1.53 (s, 3H),1.35 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 191.98, 143.42, 136.81, 129.67, 126.90, 111.97, 105.68,98.39, 83.82, 79.16, 72.14, 66.86, 26.74, 26.19. IR (KBr): ν 3030 (w), 2990 (w), 2914 (w), 2858 (m), 1698(s), 1613 (m), 1447 (w), 1378 (m), 1328 (w), 1257 (w), 1211 (s), 1164 (m), 1143 (s), 1096 (s), 1018 (s), 991 (w), 848 (w), 830 (m), 656 (w) cm-1. Anal. Calc. for C16H18O6 (306.30): C 62.74, H 5.92%. Found: C 62.56, H 5.80%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | Stage #1: Isophthalaldehyde; 1,2-O-isopropylidene-α-D-xylose With toluene-4-sulfonic acid In toluene for 5h; Inert atmosphere; Dean-Stark; Reflux; Stage #2: With triethylamine In toluene Inert atmosphere; Dean-Stark; Reflux; | 3,5-O-(3-formylbenzylidene)-1,2-O-isopropylidene-α-D-xylofuranose (8e) To a toluene (30 mL) solution of 1,2-O-isopropylidene-α-D-xylofuranose 1 (0.57 g, 3 mmol), isophthalaldehyde (0.41 g, 3 mmol) was added p-toluene sulfonic acid monohydrate, pTSA (9 mg) and the solution was refluxed for 5 h using a Dean-Stark condenser. After this time, Et3N (0.15 mL) was added and the reaction mixture was cooled and extracted with EtOAc. The extract was washed with water; combined extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10%EtOAc/hexane) to afford a white crystalline solid of corresponding 3,5-O-(3-formylbenzylidene)-1,2-O-isopropylidene-α-D-xylofuranose 8e. Yield: 0.39 g (43%). M.p. 92-94 °C. 1H NMR (500 MHz, CDCl3): δ 10.03 (s, 1H), 8.01 (t, J = 1.6 Hz, 1H), 7.88 (dt, J = 7.6, 1.4 Hz, 1H), 7.77 - 7.74 (m, 1H), 7.54 (dd, J = 9.5, 5.9 Hz, 1H), 6.08 (d, J = 3.7 Hz, 1H), 5.55 (s, 1H), 4.67 (d, J = 3.7 Hz, 1H), 4.49 (t, J = 7.6 Hz, 1H), 4.46 (d, J = 1.6 Hz, 1H), 4.21 - 4.16 (m, 2H), 1.53 (s, 3H), 1.35 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 191.98, 138.63, 136.39, 132.19, 130.08, 129.02, 127.78, 111.95, 105.68, 98.33, 83.81, 79.12, 72.12, 66.82, 26.73, 26.18. IR (KBr): ν 3031(w), 2976 (w), 2924 (m), 2898 (m), 2725 (m), 1701 (s), 1590 (m), 1445 (m), 1408 (m), 1380 (m), 1335 (w), 1268(m), 1211 (m), 1152 (m), 1104 (s), 1069 (m), 1002 (m), 927 (w), 900 (w), 879 (m), 807 (m), 699 (w) cm-1. Anal. Calc. for C16H18O6 (306.30): C 62.74, H 5.92%. Found: C 62.67, H 5.98%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | 1,2-O-isoropylidene-α-D-xylofuranose-3,5-(2’-fluoro)phenyl boronate (9a) According to Scheme S2, a mixture of 1,2-O-isopropylidene-α-D-xylofuranose 1 (1 mmol) and 2-fluorophenylboronic acid (0.14 g, 1 mmol) were dissolved in anhydrous Et2O, the mixture was stirred atroom temperature for 2 h and concentrated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (10%EtOAc/hexane) to afford a white crystalline solid ofcorresponding 2-fluorophenyl boronate ester 9a. Yield: 0.27 g (91%). M.p. 135-137 °C. 1H NMR (400MHz, CDCl3): δ 7.72 - 7.67 (m, 1H), 7.40 (m, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.99 (t, J = 9.1 Hz, 1H),5.96 (d, J = 3.7 Hz, 1H), 4.73 (d, J = 3.7 Hz, 1H), 4.53 (dt, J = 3.9, 2.5 Hz, 2H), 4.43 (d, J = 13.3 Hz,1H), 4.28 (dd, J = 13.2, 2.0 Hz, 1H), 1.53 (s, 3H), 1.35 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 167.21 (d, J = 250.9 Hz), 136.13 (d, J = 7.6 Hz), 132.92 (d, J = 8.8 Hz), 123.47 (d, J = 2.7 Hz), 115.53, 115.29, 112.13, 105.05, 84.96, 74.84, 74.28, 60.79, 26.74, 26.20. 11B NMR (160 MHz, CDCl3): δ 26.30 (brs). IR (KBr): ν 3062 (w), 2991 (m), 2955 (w), 1615 (m), 1574 (m), 1483 (m), 1453 (m), 1379 (m), 1327 (s), 1267 (m), 1210 (m), 1160 (s), 1080 (m), 1039 (m), 904(w), 886 (m), 763 (m), 640 (w) cm-1. Anal. Calc. for C14H16BFO5 (294.00): C 57.18, H 5.48%. Found: C 57.23, H 5.45%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In diethyl ether at 20℃; for 2h; Inert atmosphere; | 1,2-O-isoropylidene-α-D-xylofuranose-3,5-(2’-methyl)phenyl boronate (9b) According to Scheme S2, a mixture of 1,2-O-isopropylidene-α-D-xylofuranose 1 (1 mmol) and 2-methylphenylboronic acid (0.14 g, 1 mmol) were dissolved in anhydrous Et2O, the mixture was stirred at room temperature for 2 h and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (10%EtOAc/hexane) to afford a white crystalline solid of corresponding 2-methylphenyl boronate ester 9b. Yield: 0.26 g (90%). M.p. 80-82 °C. 1H NMR (400 MHz, CDCl3): δ 7.74 - 7.70 (m, 1H), 7.28 (td, J = 7.5, 1.5 Hz, 1H), 7.14 (dd, J = 11.8, 4.2 Hz, 2H), 5.95 (d, J = 3.7 Hz, 1H), 4.70 (d, J = 3.7 Hz, 1H), 4.53 (d, J = 2.6 Hz, 1H), 4.51 - 4.49 (m, 1H), 4.41 (d, J = 13.2 Hz, 1H), 4.26 (dd, J = 13.2, 2.0 Hz, 1H), 2.49 (s, 3H), 1.54 (s, 3H), 1.35 (s, 3H). 13C NMR (101 MHz, CDCl3): δ 144.20, 134.97, 130.48, 130.11, 124.72, 112.12, 105.10, 85.08, 74.75, 74.27, 60.56, 26.78, 26.24, 22.55. 11B NMR (160 MHz, CDCl3): δ 27.58 (brs). IR (KBr): ν 3060 (w), 2981 (w), 2945 (m), 1600 (m), 1568 (m), 1463 (m), 1417 (m), 1377 (m), 1321 (s), 1264 (m), 1209 (m), 1160 (m), 1081 (m), 1012 (m), 903 (w), 884 (m), 824(w), 762 (m), 647 (w) cm-1. Anal. Calc. for C15H19BO5 (290.10): C 62.10, H 6.60%. Found: C 62.02, H 6.37%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetrabutyl-ammonium chloride; sodium hydroxide In water at 25℃; for 4.5h; Cooling with ice; | 12.B 500 mL of toluene, 500 mL of a 20% sodium hydroxide aqueous solution, and 10 g of tetrabutyl ammonium chloride were added to 100 g of 1,2-O-isopropylidene-α-D-xylofuranose, then, 150 mL of 4-methylbenzoyl chloride was added dropwise thereto at 25° C. or lower under ice-cooling, and the resultant product was stirred at 25° C. for 4.5 hours. After the aqueous layer was removed, the organic layer was washed sequentially with 500 mL of water and 200 mL of a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, whereby 370 g of a crude product of (3 aR,5R,6S,6aR)-2,2-dimethyl-5-((4-methylbenzoyloxy)methyl)-tetrahydro-2H-furo[2,3-d][1, 3]dioxol-6-yl 4-methylbenzoate was obtained as a colorless oily material. The crude product was used in the next step without purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 g | Stage #1: D-xylose; acetone With sulfuric acid; copper(II) sulfate at 0 - 20℃; Inert atmosphere; Stage #2: With hydrogenchloride In water at 20℃; for 12h; | 5 To a solution of D-xylose (30.0 g, 0.20 mol) in 800 mL of acetone was treated with CuS04 (60.0g, 0.38 mol) and H2S04 (2.0 mL) at 0 °C under N2 atmosphere. After being stirred for 12h at room temperature, the solution was neutralized with Na2C03 at 0 °C, and filtered out all white solid by using a celite pad. The filtrate was concentrated under reduced pressure to provide 1,2,3,5-diisopropylidenyl xylose. The xylose derivative was dissolved in 300 mL of aqueous 0.1% hydrochloric acid at room temperature and stirred for 12h. The resulting solution was neutralized with NaHC0 at 0 °C to reach pH 7 and the solid was removed by using a celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel pad (EtOAc) to give a 1,2-isopropylidenyl xylose (31.0 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With 1H-imidazole In N,N-dimethyl-formamide at 20℃; for 5h; Inert atmosphere; Cooling with ice; | 5-O-(o-Toluoyl)-1,2-isopropylidene-α-D-xylofuranose (27). D-xylose (10.0 g, 0.067 mol) was dissolvedin acetone (260 mL) containing H2SO4 (0.66 M, 10.0 mL) and the solution was stirred for 30 min.A solution of Na2CO3 (13.0 g, 0.123 mol) in water (112 mL) was carefully added to the above cooledmixture, which was then stirred for further 2.5 h at 20 °C. Then, solid Na2CO3 (7.00 g, 0.066 mol) wasadded, Na2SO4 (22.3 g) was filtered off and washed with acetone, and the filtrate was evaporatedin vacuo to afford a crude residue (14 g). This residue was resolubilized in a 9:1 mixture of EtOAc(270 mL) and methanol (30 mL), filtered, and evaporated in vacuo to give a yellow oil (12 g, 96%).This residue was dissolved in dry DMF (150 mL) under an inert atmosphere, cooled in an ice bath,and then o-toluoyl chloride (9.85 g, 8.31 mL, 0.064 mol) was added, followed by imidazole (4.35 g,0.064 mol). The reaction mixture was allowed to warm to room temperature and stirred for 5 h. It wasthen diluted with EtOAc (300 mL) and washed with water (300 mL) and brine (100 mL). The organiclayer was dried over Na2SO4, filtered, and evaporated in vacuo to give a crude residue, which waspurified by column chromatography (hexane:EtOAc 7:3) to afford compound 27 (16.5 g, 84%) asa colorless oil. 1H-NMR (300 MHz, CDCl3):δ 7.92 (dd, 1H, J = 8.2, 1.6 Hz, ArH), 7.41-7.20 (m, 3H,ArH), 5.97 (d, J = 3.6 Hz, 1H, H-1'), 4.69 (dd, 1H, J = 13.4, 8.4 Hz, H-5'), 4.57 (d, 1H, J = 3.6 Hz, H-2'),4.43 (dd, 1H, J = 13.4, 6.0 Hz, H-5”), 4.42 (ddd, 1H, J = 8.4, 6.0, 2.1 Hz, H-4'), 4.24 (d, 1H, J = 2.1, H-30),3.73 (s, 1H, OH), 2.57 (s, 3H, CH3), 1.49 (s, 3H, CH3), 1.30 (s, 3H, CH3); 13C-NMR (75 MHz, CDCl3): δ168.2 (CO), 140.7 (ArC), 132.7 (ArC), 132.0 (ArC), 131.1 (ArC), 129.0 (ArC), 126.0 (ArC), 112.0 (OCO)105.1 (1'-C), 85.4 (4'-C), 78.8 (3'-CH), 74.8 (2'-CH), 62.0 (5'-CH2), 27.0 (CH3), 26.4 (CH3), 22.0 (CH3);HRMS for C16H20O6 [M + Na+]+ Calc.: 331.1152, found: 331.1156. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Stage #1: 1,2-O-isopropylidene-α-D-xylose With pyridine; dmap In dichloromethane at 0℃; for 0.166667h; Inert atmosphere; Stage #2: benzoyl chloride In dichloromethane at 0℃; for 1h; Inert atmosphere; | 1 ((3aR,5R,6aR)-6-Hydroxy-2,2-dimethyltetrahydrofuro[2,3- d][1,3]dioxol-5-yl)methyl benzoate (3). A solution of commercially available 1,2-O-Isopropylidene-^-D-xylofuranose 2 (3.00 g, 15.77 mmol) in dry dichloromethane (DCM) (40 mL) was cooled to 0 C and to it were added 1.90 mL (23.65 mmol) pyridine and a catalytic amount (192 mg) of N,N- dimethylaminopyridine. The resulting mixture was stirred at 0 C for 10 min, at which time 2.00 mL (17.34 mmol) benzoyl chloride were added to it dropwise over a period of 30 min. The reaction mixture was stirred at 0 C for an additional 30 min and then quenched by the addition of 20 mL of a saturated solution of NH4Cl. The reaction was allowed to warm to room temperature, the layers were separated and the aqueous layer was extracted with 3x10 mL of DCM. The combined organic extracts were washed with 3x10 mL of aqueous solution of CuSO4, 2x10 mL of water and brine. The organic solution was dried over anhydrous NaSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (50% ethyl acetate (EtOAc) in hexane) to afford 3 (4.43 g, 95%). ^ +15.5 (c = 0.15, CHCl3 1 ). H NMR (400 MHz, CDCl3) ^ 8.08 - 8.01 (m, 2H), 7.62 - 7.54 (m, 1H), 7.49 - 7.40 (m, 2H), 5.95 (d, J = 3.6 Hz, 1H), 4.83 - 4.73 (m, 1H), 4.59 (d, J = 3.6 Hz, 1H), 4.43 - 4.34 (m, 2H), 4.18 (dd, J = 4.2, 2.3 Hz, 1H), 3.36 - 3.31 (m, 1H), 1.50 (s, 3H), 1.32 (s, 3H).13C NMR (100 MHz, CDCl3) ^ 167.3, 133.5, 129.8 (2C), 129.1, 128.4 (2C), 111.8, 104.6, 84.9, 78.4, 74.3, 61.2, 26.7, 26.0. LRMS (ESI) m/z: [M + H]+ 295.1. HRMS (ESI) m/z: [M + Na]+ calcd C15H18O6Na 317.0996; found 317.0998. |
89% | With pyridine at 0 - 20℃; for 2h; | 40.A Step A: ((3aR,5R,65,6aR)-6-Hydroxy-2,2-dimethyltetrahydrofuro j2,3-dj 11 ,3j dioxol-5-yl)methyl benzoate (40a) BzC1 (5.91 g, 42 mmol) was added slowly to a solution of(3aR,5R,6S,6aR)-5- (hydroxymethyl)-2,2-dimethyltetrahydrofuro[2,3-dj[1,3jdioxol-6-ol (8 g, 42 mmol) in pyridine (80 mL) at 0°C. The mixture was stirred at rt for 2 h, it was concentrated and the residue was diluted with EtOAc and aq. citric acid. The organic layer was washed (brine), dried and concentrated. The residue was purified by flash column chromatography on silica gel to provide the title compound (40a) (hg, 89%). mlz (ESI, +ve ion) = 295.4 [M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: ethylene glycol With triethylamine; trichlorophosphate In diethyl ether at -20℃; for 1h; Stage #2: 1,2-O-isopropylidene-α-D-xylose In diethyl ether at 60℃; | 9 Example 9 Dissolve ethylene glycol in ether, add triethylamine, slowly add 2eq of phosphorous oxychloride at -20°C to react for 1 hour, add 2 times the equivalent of compound 2, and move to 60°C oil bath for reaction. After the reaction is completed, quench with water, spin-dry the solvent, extract with dichloromethane, wash with water, and wash with saturated brine, and concentrate the organic phase to obtain compound 9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: hydroquinone With triethylamine; trichlorophosphate In diethyl ether at -20℃; for 1h; Stage #2: 1,2-O-isopropylidene-α-D-xylose In diethyl ether at 60℃; | 11 Example 11 Dissolve hydroquinone in ether, add triethylamine, slowly add 2 times equivalent of phosphorus oxychloride to react for 1 hour at -20°C, add 2eq of compound 2, and move to 60°C oil bath for reaction. After the reaction, the reaction was quenched with water, the solvent was spin-dried, extracted with dichloromethane, washed with water, washed with saturated brine, and the organic phase was concentrated to obtain compound 11 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,2-O-isopropylidene-α-D-xylose With triethylamine; trichlorophosphate In dichloromethane at -20 - 60℃; for 3.16667h; Stage #2: methanol In dichloromethane at -20 - 60℃; | 3 Example 3 Dissolve compound 2 in dichloromethane, add triethylamine, slowly add phosphorus oxychloride at -20°C, move to 60°C oil bath for 10 minutes and react for 3 hours, check with TLC silica gel plate to judge that the reaction is complete Then, slowly add excess methanol at -20°C, continue the reaction at 60°C, check with TLC silica gel plate to determine that the reaction is complete, quench with water, extract with dichloromethane, wash with water, wash with saturated brine, and concentrate the organic phase. Compound 3 is obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,2-O-isopropylidene-α-D-xylose With triethylamine; trichlorophosphate In dichloromethane at -20 - 60℃; for 3.16667h; Stage #2: ethanol In dichloromethane at -20 - 60℃; | 5 Example 5 Dissolve compound 2 in dichloromethane, add triethylamine, slowly add phosphorus oxychloride at -20°C, move to 60°C oil bath after 10 minutes and react for 3 hours, check with TLC silica gel plate to judge that the reaction is complete Then, slowly add excess ethanol at -20°C, continue the reaction at 60°C, check with TLC silica gel plate to determine that the reaction is complete, quench with water, extract with dichloromethane, wash with water, wash with saturated brine, and concentrate the organic phase. Compound 5 was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Stage #1: 1,2-O-isopropylidene-α-D-xylose With triethylamine; trichlorophosphate In dichloromethane at -20 - 60℃; for 3.16667h; Stage #2: With water In dichloromethane at 60℃; | 7 Example 7 Dissolve compound 2 in dichloromethane, add triethylamine, slowly add phosphorus oxychloride at -20°C, move to 60°C oil bath after 10 minutes and react for 3 hours, then slowly add at 20°C With 0.5 eq H2O, the reaction was continued at 60°C. After the reaction, the reaction was quenched with water, extracted with dichloromethane, washed with water, and washed with saturated brine, and the organic phase was concentrated to obtain compound 7. |
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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 |
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