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CAS No. : | 532-32-1 | MDL No. : | MFCD00012463 |
Formula : | C7H5NaO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | WXMKPNITSTVMEF-UHFFFAOYSA-M |
M.W : | 144.10 | Pubchem ID : | 517055 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 31.46 |
TPSA : | 40.13 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.85 cm/s |
Log Po/w (iLOGP) : | -11.15 |
Log Po/w (XLOGP3) : | 1.87 |
Log Po/w (WLOGP) : | 0.05 |
Log Po/w (MLOGP) : | 1.6 |
Log Po/w (SILICOS-IT) : | 1.24 |
Consensus Log Po/w : | -1.28 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.29 |
Solubility : | 0.74 mg/ml ; 0.00513 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.33 |
Solubility : | 0.667 mg/ml ; 0.00463 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -1.72 |
Solubility : | 2.72 mg/ml ; 0.0189 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H319 | 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 |
---|---|---|
48% | at 75 - 135℃; for 26 h; | p-acetamidobenzoic acid Starting Materials Ethyl Acetate 0.75 mol Sodium p-aminobenzoate 0.25 mol Sodium methoxide (catalyst) 0.25 mol Ethylene Glycol 150 g. Operating Conditions Pressure Atmospheric Temperature/time regime 75° C./8 h.; then 90° C./2 h.; then 110° C./9 h.; then 120-125° C./2.5 h.; then 135° C./4.5 h. Reaction Progress Monitored by TLC Work-up The reaction mass was allowed to cool to 40° C., transferred to a beaker, diluted with water to a total volume of 500 mL, pH adjusted to 2-3 by addition of 51.3 g. concentrated hydrochloric acid, cooled to 10° C., stirred during 30 min at that temperature and filtered. The filter cake was later drained, washed with 100 mL cold water, drained thoroughly and dried at 60-68° C. to constant weight. 21.5 g. of crys- tals (m.p. 258-259° C. (dec.))were obtained (literature 252° C.) Yield 48percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate In dichloromethane; water for 3 h; | Preparation of chloromethyl benzoate (5) Sodium benzoate (4.8 g 33.3 mmol), sodium bicarbonate (8.4 g 100.0 mmol) and tetrabutylammonium sulfate (1.1 g, 3.3 mmol) were dissolved in water (70 rtiL). Dichloromethane (70 niL) was added followed by chloromethyl chlorosulfonate (4.2 mL, 40.3 mmol). The resulting mixture (a biphasic solution) was vigorously stirred for 3 hours. The phases were separated. The organic phase was washed with water (2 χ 50 mL) and dried over anliydrous magnesium sulfate. The solution was filtered through a small plug of silica (5 g) and evaporated under reduced pressure at < 30 °C yielding compound 5 as colorless liquid (5.2 g, 92percent). The analytical data for compound 5 were identical to those reported in literature (e.g. , Baudy et al , J. Med. Chem, 2009, 52, 771). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With 1,3-dimethylimidazolinium methanesulfonate at 90℃; for 0.5h; | |
92.7% | In chloroform at 70℃; for 6h; | 1.1; 1.2; 2.1; 2.2; 3.1; 3.2; 4.1; 4.2; 5.1; 5.2; 6.1; 6.2; 7.1; 7.2; 8.1; 8.3; 9.1; 9.2; 10; 1.1; 1.1; 2.1; 2.2; 3 Comparative Example 2 1, The crude benzylate benzoate is synthesized by adding benzyl chloride 100.13g, trichloromethane 100.06g and sodium benzoate 100 g into the reaction kettle flask, 70 °C after the feeding is finished, the reaction 6h. is finished, cooled, discharged, filtered and the filtrate is collected.2, Of Benzyl benzoate: The filtrate was transferred to a reaction kettle, 70 °C under reduced pressure to remove the solvent, and the crude benzylic benzoate obtained in vacuo -0.092 mpa, was distilled off under reduced pressure. The temperature was raised to 170 - 175 °C and vacuum 1.5 Kpa collected fraction 136.5g. |
91% | In dimethyl sulfoxide at 30℃; for 0.583333h; Ionic liquid; |
90% | With polyethylene glycol 400 at 65 - 70℃; for 6.5h; | |
77.5% | With zirconium (benzyldiethylammoniomethylphosphonate chloride) phosphate In water; toluene at 90℃; for 24h; | |
With triethylamine; benzene at 100 - 110℃; | ||
at 170 - 175℃; | ||
With benzoic acid at 200℃; | ||
With copper at 200 - 300℃; | ||
With water at 110 - 115℃; | ||
With tributyl-amine In water at 100℃; for 7h; | ||
87 %Chromat. | With Aliquat 336 In water at 45℃; for 3h; | |
With graphene oxide supported quaternary ammonium salt at 120℃; for 8h; | ||
347.6 kg | With triethylamine In octane at 100℃; for 2h; Large scale; | 1.1-1.2; 2.1-2.2; 3.1-3.2; 4.1-4.2; 5.1-5.2; 6.1-6.2; 7.1-7.2; 8.1-8.2; 9.1-9.2; 1-5 1. Synthesis of crude benzyl benzoate Put 300.02kg of benzyl chloride, 9.01kg of triethylamine, 210.25kg of n-octane (the mass ratio of benzyl chloride to solvent 1:0.7), and 390.07kg of sodium benzoate into the reaction kettle. After the feeding is completed, the reaction is kept at 100C for 2h. After the reaction is over, the temperature is lowered, the material is discharged, filtered, and the filtrate is collected. The obtained filtrate was transferred to the reaction kettle, and the solvent was distilled off under reduced pressure at 60°C, and the vacuum degree was -0.095Mpa, and 461.66 kg of crude benzyl benzoate was obtained by filtration. The calculated theoretical output is 484.38kg. Take 400kg of crude benzyl benzoate and add 400kg of isopropanol and 160kg of purified water (solute-solvent ratio 2:2.8, ratio of isopropanol to water 2:0.8), stir and warm up to completely dissolve, to obtain a crude benzyl benzoate solution. The temperature of the crude benzyl benzoate solution was lowered to 10°C, 400 g of benzyl benzoate seed crystals were added, and after stirring for 30-60 minutes at 8-10°C, the temperature was lowered to 1°C for 30-60 minutes incubation and crystallization to obtain a suspension. The suspension was centrifuged for 5 min, and the rotation speed of the centrifugation was 2000 rpm. After discarding the supernatant, transfer the filter cake to the reactor. After heating and melting at 80 C in a water bath, distill under reduced pressure at 80 C and a vacuum of -0.092Mpa until solvent-free evaporation. Continue distillation for 30 min. Cool down to 20°C. 347.6kg, just filling |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With polyethylene glycol 400 at 65 - 70℃; for 5h; | |
80% | at 150℃; g.l.p.t.c.; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13.9% | In N,N,N,N,N,N-hexamethylphosphoric triamide at 100℃; for 72h; Yield given. Title compound not separated from byproducts; | |
13.9% | In chloroform at 100℃; for 72h; Yields of byproduct given; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With D-Fructose; benzoate dioxygenase from Ralstonia eutropha B9; sodium succinate at 30℃; for 102h; Enzymatic reaction; | |
79% | With D-Fructose; whole cells of Ralstonia eutropha B9 expressing benzoate dioxygenase for 27h; Enzymatic reaction; enantioselective reaction; | (1S,6R)-1,6-dihydroxycyclohexa-2,4-diene-1-carboxylic acid (6).1-6 A 500 mL flask containing 100 mL Hutner’s Mineral Base medium4,5 (HMB medium) wascomplimented with a D-fructose solution (0.33 mL, 3.4 M), inoculated with a 1 mL portion of theovernight LB culture, and grown for 10 h at 30 °C and 200 rpm. An aliquot (40 mL) of thisculture was then used to inoculate a stirred-tank bioreactor containing 3.0 L HMB medium andD-fructose solution (8.82 mL, 3.4 M) to produce a final OD600 = 0.020. The culture was grown at30 °C, pH 7.4, 300 rpm agitation, and 1.0 L/min aeration. The pH was maintained at 7.4 byaddition of concentrated ammonium hydroxide and 30% (v/v) phosphoric acid. When the cellculture reached an OD600 = 2.10 (11 h) it was induced by adding a solution of sodium benzoate(10.5 mL, 2.0 M). The culture was supplemented with D-fructose solution (8.82 mL, 3.4 M).Following complete consumption of the benzoate (3h), as indicated by a rapid spike in pO2,sequential feeding of benzoate (7.5 mL, 2M) and D-fructose (4.5 mL, 3.4 M) was performedevery two hours for 24 h (13 times total, 108 mL benzoate solution total). Over this period,stirring and aeration were adjusted as need to maintain a pO2 >25%. The culture reached a finalOD600 = 5.04 over the same period.The culture broth was centrifuged at 10,000 rpm at 4 °C for 20 min and the supernatant wasconcentrated under reduced pressure to a volume of ~300 mL. The concentrate was filteredthrough a pad of celite. The broth concentrated was chilled in an ice bath and its pH wasadjusted to 3.5 using 6 M HCl. The broth was then extracted with EtOAc (15 x 600 mL). Thecombined organic phases were dried over Na2SO4, filtered, and concentrated to yield 6 as a whitesolid (26.6 g, 79%). |
With ammonium sulfate; manganese(II) sulfate; potassium dihydrogenphosphate; polypropyleneglycol; (per)acetylperoxyboric acid; D-glucose; phosphoric acid; ammonia; oxygen; magnesium sulfate; copper(II) sulfate; iron(II) sulfate; zinc(II) sulfate; citric acid; calcium chloride In water at 30℃; Pseudomonas putida U103 presence; |
With sodium succinate In water at 30℃; Microbial dihydroxylation; | 1 A sterile pipette tip was streaked across the surface of a frozen glycerol stock solution to produce small shards (ca. 10 mg). The frozen shards were added to a sterile 125 mL Erlenmeyer flask containing HMB (25 mL) and aqueous sodium succinate solution (140 µL of a 1.5 M solution, 5 mM final concentration). The flask was shaken at 250 rpm for 2 days at 30 °C. An aliquot (10 mL) of the white, heterogeneous solution was transferred using a sterile pipette to a mammalian cell growth jar containing HMB (6 L) and aqueous sodium succinate solution (20 mL of a 1.5 M solution, 5 mM final concentration). The jar was warmed on a hot plate to an internal temperature of 30 °C; cotton-filtered air was sparged through the medium. After 2 days, the white, heterogeneous solution was treated with aqueous sodium benzoate solution (18 mL of a 1.0 M solution) and aqueous sodium succinate solution (10 mL of a 1.5 M solution), inducing dihydroxylation. The resulting mixture was aerated vigorously for 6 hours at an internal temperature of 30 °C. After induction, sufficient aqueous sodium benzoate solution (24 to 48 mL of a 1.0 M solution, depending on the rate of consumption) was added hourly to maintain a concentration of 10-20 mM (determined by UV absorbance at 225 nm). Aqueous sodium succinate solution (10 mL of a 1.5 M solution) was added every fourth hour. These additions proceeded over 18 hours, then the solution was aerated overnight at an internal temperature of 30 °C, to ensure complete conversion. The fermentation broth was centrifuged, in portions, at 6000 rpm (Sorvall GS-3 rotor, model SLA-3000) to remove cellular material. The supernatant was concentrated to a volume of 400 mL using a rotary evaporator (bath temperature <45 °C). The concentrate was cooled to 0 °C and then acidified to pH 3.0 using concentrated aqueous hydrochloric acid. The acidified aqueous solution was extracted repeatedly with ethyl acetate (8 x 500 mL, 4 x 800 mL, 8 x 1 L). The ethyl acetate extracts were dried over sodium sulfate before concentration, using a rotary evaporator (bath temperature <45 °C), providing a pale yellow solid residue. Trituration of the residue with dichloromethane (2 x 200 mL) followed by drying in vacuo afforded pure (1S,2R)-1,2-dihydroxycyclohexa-3,5-diene- 1-carboxylic acid (DRS1) as a white powder mp 95-96 °C dec (38 g, 74%, [α]D -114.8 (c 0.5 in EtOH), lit. , [α]D - 106 (c 0.5 in EtOH) Jenkins, G. N. ; Ribbons, D. W.; Widdowson, D. A.; Slawin, A. M. Z. ; Williams, D. J. J Chem. Soc. Perkin Trans. 1 1995, 2647.). | |
77 g | Stage #1: sodium benzoate With D-fructose In water Microbiological reaction; Stage #2: With hydrogenchloride In water at 0 - 5℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | In N,N-dimethyl-formamide at 100℃; for 5h; | |
93% | In N,N-dimethyl-formamide | |
84% | With caesium carbonate In N,N-dimethyl-formamide at 50 - 65℃; for 24.5h; | 5.c; 12 Crude mesylate 5C (3.75 g, 8.86 mmol) was dissolved in dry DMF (100 mL) under N2 and sodium benzoate (3.83 g, 26.58 mmol) and Cs2CO3 (4.33 g, 13.29 mmol) was added. The suspension was heated to 50°C and stirred at this temperature for 17 hours. The resulting very thick pale yellow slurry was diluted with DMF (100 mL), and more sodium benzoate (2.6 g, 18.04 mmol) was added and the temperature was increased to 65°C. Stirring was continued for 5 hours at this temperature. Then more Cs2CO3 (2.2 g) was added and the mixture was stirred for an additional 2.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (250 mL) and saturated aqueous NaHCO3 (250 mL). The aqueous layer was extracted with CH2Cl2 (2 x 150 mL) and the combined organic layers were washed with brine (100 mL), dried (Na2SO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica: packed in 2 % MeOH in CH2Cl2, v/v, elution with 2 - 4 % MeOH in CH2Cl2, v/v, and gave benzoate 5aC (3.35 g, 84 %) as a pale yellow solid material. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | In dimethyl sulfoxide at 100℃; for 2h; | ((1R,3R,4R,7S)-3-(6-benzamido-9H-purin-9-yl)-7-(benzyloxy)-2,5-dioxabicyclo[2.2.1]heptan-1-yl)methylbenzoate (17) A stirred suspension of sodium benzoate (2.05 g, 14.2 mmol) and ((1R,3R,4R,7S)-3-(6-benzamido-9H-purin-9-yl)-7-(benzyloxy)-2,5-dioxabicyclo[2.2.1]heptan-1-yl)methyl methanesulfonate (3.92 g, 7.11 mmol) in dimethyl sulfoxide(40 mL) was heated at 100 °C for 2 h, then allowed to cool to room temperature. The mixture was diluted with ethyl-acetate (200 mL) and water (200 mL). The layers were separated and the ethyl acetate layer was washed with water(200 mL) and brine (200 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 17 (4.02g, 98%) as a pale brown foam. |
88% | In N,N-dimethyl-formamide at 90℃; for 7h; | |
88% | In N,N-dimethyl-formamide at 90℃; for 7h; | 13 (1S,3R,4R,7S)-7-Benzyloxy-1-methanesulfonyloxymethyl-3-(6-N-benzoyl-adenine-9-yl)-2,5-dioxabicyclo-[2.2.1]heptane (5D) (11.5 g.; 20.8 mmol) was dissolved in anh. DMF (450 mL). Sodium benzoate (5.40 g.; 37.4 mmol) was added and the mixture was heated to 90°C for 7h. The solution was cooled to rt., filtered, evaporated and coevaporated with AcCN. The residue was redissolved in dichloromethane (150 mL) and a saturated aqueous solution of NaHCO3 (150 mL) was added. The phases were separated and the organic phase was washed with a saturated aqueous solution of NaHCO3 (2x100 mL) and brine (100 mL), dried (Na2SO4) and evaporated to give 12.5 g. of a yellowish solid. Recrystallization from EtOH:H2O (1250 mL; 1:1 v/v) gave 28 in 88% yield (10.63 g.). δH (DMSO-d6): 11.2 (1H, br s), 8.72 (1H, s), 8.48 (1H, s), 8.06 (2H, m), 7.94 (2H, m), 7.66 (2H, m), 7.54 (4H, m), 7.36-7.26 (5H, m), 6.11 (1H, s), 4.97 (1H, s), 4.82 (2H, s), 4.77 (1H, s), 4.75 (1H, d, J = 12.4 Hz), 4.69 (1H, d, J = 11.9 Hz), 4.19 (1H, d, J = 8.0 Hz), 4.07 (1H, d, J = 7.9 Hz). δC (DMSO-d6): 165.3, 150.5, 141.9, 137.7, 133.7, 132.5, 129.3, 129.1, 128.9, 128.6, 128.5, 128.3, 127.7, 127.6, 125.7, 85.9, 85.3, 77.9, 77.1, 72.0, 71.3, 60.6. |
88% | In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | Stage #1: sodium benzoate With chloroformic acid ethyl ester In tetrahydrofuran at 20℃; for 0.25h; Stage #2: isopropylzinc iodide In tetrahydrofuran at 70℃; for 14h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | In N,N-dimethyl-formamide at 100℃; for 24h; | |
81% | In DMF (N,N-dimethyl-formamide) at 100℃; for 24h; | (1R,3R,4R,7R)-7-Benzoyloxy-1-benzoyloxymethyl-3-(thymin-1-yl)-2-oxa-5-thiabicyclo[2:2:1]heptane (10) (1R,3R,4R,7R)-7-Benzoyloxy-1-benzoyloxymethyl-3-(thymin-1-yl)-2-oxa-5-thiabicyclo[2:2:1]heptane (10); Nucleoside 9 (1.92 g, 4.1 mmol) was dissolved in DMF (110 cm3). Sodium benzoate (1.2 g, 8.2 mmol) was added and the mixture was heated to 100° C. for 24 h. The reaction mixture was transferred to a separatory funnel with half sat. brine (200 cm3) and extracted with ethyl acetate (3×100 cm3). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo to give a brown liquid. The product was put on a high vacuum pump to remove residual solvent. The resulting brown gum was purified by Dry Column Vacuum Chromatography (id 4 cm; 50 cm3 fractions; 0-100% EtOAc in n-heptane (v/v)-10% increments; 2-10% MeOH in EtOAc (v/v)-2% increments) to give nucleoside 10 (1.64 g, 81%) as a slightly yellow foam. Rf=0.57 (20% n-heptane in EtOAc, v/v); ESI-MS m/z found 495.1 ([MH]+, calcd 495.1); 1H NMR (CDCl3) δ 9.02 (br s, 1H, NH), 8.07-7.99 (m, 4H, Ph), 7.62-7.58 (m, 2H, Ph), 7.47-7.42 (m, 5H, Ph and H6), 5.95 (s, 1H, H1'), 5.46 (d, J=2.2 Hz, 1H, H3'), 4.93 (d, J=12.8 Hz, 1H, H5'a), 4.60 (d, J=12.8 Hz, 1H, H5'b), 4.17 (d, J=2.2 Hz, 1H, H2'), 3.27 (d, J=10.6 Hz, 1H, H1a), 3.16 (d, J=10.6 Hz, 1H, H1b), 1.55 (d, J=1.1 Hz, 3H, CH3); 13C NMR (CDCl3) δ 165.8, 165.1, 163.7 (C4, 2×PhC(O)), 150.0 (C2), 133.9, 133.7, 133.6, 129.8, 129.6, 129.0, 128.8, 128.6, 128.5 (C6, 2×Ph), 110.3 (C5), 91.3 (C1'), 87.5 (C4'), 72.9 (C3'), 61.3 (C5'), 50.6 (C2'), 35.6 (C1), 12.3 (CH3); Elemental anal. calcd for C25H22N2O7S (%): C, 60.72; H, 4.48; N, 5.66. Found: C, 60.34; H, 4.49; N, 5.35. |
81% | In DMF (N,N-dimethyl-formamide) at 100℃; for 24h; | 1 Nucleoside 9 (1.92 g, 4.1 mmol) was dissolved in DMF (110 cm3). Sodium benzoate (1.2 g, 8.2 mmol) was added and the mixture was heated to 100° C for 24 h. The reaction mixture was transferred to a separatory funnel with half sat. brine (200 cm3) and extracted with ethyl acetate (3×100 cm3). The combined organic layers were dried (Na2SO4), filtered and evaporated in vacuo to give a brown liquid. The product was put on a high vacuum pump to remove residual solvent. The resulting brown gum was purified by Dry Column Vacuum Chromatography (id 4 cm; 50 cm3 fractions; 0-100% EtOAc in n-heptane (v/v) -10% increments; 2-10% MeOH in EtOAc (v/v) -2% increments) to give nucleoside 10 (1.64 g, 81%) as a slightly yellow foam. [0243] Rf=0.57 (20% n-heptane in EtOAc, v/v); [0244] ESI-MS m/z found 495.1 ([MH]+, calcd 495.1); [0245] 1H NMR (CDCl3) δ 9.02 (br s, 1H, NH), 8.07-7.99 (m, 4H, Ph), 7.62-7.58 (m, 2H, Ph), 7.47-7.42 (m, 5H, Ph and H6), 5.95 (s, 1H, H1'), 5.46 (d, J=2.2 Hz, 1H, H3'), 4.93 (d, J=12.8 Hz, 1H, H5'a), 4.60 (d, J=12.8 Hz, 1H, H5'b), 4.17 (d, J=2.2 Hz, 1H, H2'), 3.27 (d, J=10.6 Hz, 1H, H1a), 3.16 (d, J=10.6 Hz, 1H, H1b), 1.55 (d, J=1.1 Hz, 3H, CH3); [0246] 13C NMR (CDCl3) δ 165.8, 165.1, 163.7 (C4, 2×PhC(O)), 150.0 (C2), 133.9, 133.7, 133.6, 129.8, 129.6, 129.0, 128.8, 128.6, 128.5 (C6, 2×Ph), 110.3 (C5), 91.3 (C1'), 87.5 (C4'), 72.9 (C3'), 61.3 (C5'), 50.6 (C2'), 35.6 (C1), 12.3 (CH3); [0247] Elemental anal. calcd for C25H22N2O7S (%): C, 60.72; H, 4.48; N, 5.66. Found: C, 60.34; H, 4.49; N, 5.35. |
81% | In DMF (N,N-dimethyl-formamide) at 100℃; for 24h; | (1R,3R,4R,7R)-7-Benzoyloxy-1-benzoyloxymethyl-3-(thymin-1-yl)-2-oxa-5-thiabicyclo[2:2:1]heptane (55) Nucleoside 54 (1.92 g, 4.1 mmol) was dissolved in anhydrous DMF (110 ml). Sodium benzoate (1.2 g, 8.2 mmol) was added and the mixture was heated to 100° C for 24 h. The reaction mixture was transferred to a separatory funnel with half sat. brine (200 ml) and extracted with EtOAc (3×100 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a brown liquid. The product was put on a high vacuum pump to remove residual solvent. The resulting brown gum was purified by Dry Column Vacuum Chromatography (Ø 4 cm, 0-100% EtOAc in n-heptane (v/v), 50 ml fractions, 10% increments, followed by 2-10% MeOH in EtOAc (v/v), 50 ml fractions, 2% increments) to afford nucleoside 55 (1.64 g, 81%) as a slightly yellow foam. Rf=0.57 (20% n-heptane in EtOAc, v/v); ESI-MS m/z found 495.1 ([MH]+, calcd 495.1); 1H NMR (CDCl3) δ 9.02 (br s, 1H, NH), 8.07-7.99 (m, 4H, Ph), 7.62-7.58 (m, 2H, Ph), 7.47-7.42 (m, 5H, Ph and H6), 5.95 (s, 1H, H1'), 5.46 (d, J=2.2, 1H, H3'), 4.93 (d, J=12.8, 1H, H5'a), 4.60 (d, J=12.8, 1H, H5'b), 4.17 (d, J=2.2, 1H, H2'), 3.27 (d, J=10.6, 1H, H1a), 3.16 (d, J=10.6, 1H, H1b), 1.55 (d, J=1.1, 3H, CH3); 13C NMR (CDCl3) δ 165.8, 165.1, 163.7 (C4, 2×PhC(O)), 150.0 (C2), 133.9, 133.7, 133.6, 129.8, 129.6, 129.0, 128.8, 128.6, 128.5 (C6, 2×Ph), 110.3 (C5), 91.3 (C1'), 87.5 (C4'), 72.9 (C3'), 61.3 (C5'), 50.6 (C2'), 35.6 (C1), 12.3 (CH3); Anal. calcd for C25H22N2O7S: C, 60.72; H, 4.48; N, 5.66. Found: C, 60.34; H, 4.49; N, 5.35. |
81% | In DMF (N,N-dimethylformamide) at 100℃; for 24h; | (lR, 3R, 4R, 7R)-7-Benzoyloxy-1-benzoyloxymethyl-3-(thymin-1-yl)-2-oxa-5- thiabicyclo [2: 2 : 1] heptane (55) Nucleoside 54 (1.92 g, 4.1 mmol) was dissolved in anhydrous DMF (110 ml). Sodium benzoate (1.2 g, 8.2 mmol) was added and the mixture was heated to 100°C for 24 h. The reaction mixture was transferred to a separatory funnel with half sat. brine (200 ml) and extracted with EtOAc (3 x 100 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a brown liquid. The product was put on a high vacuum pump to remove residual solvent. The resulting brown gum was purified by Dry Column Vacuum Chromatography (0 4 cm, 0-100% EtOAc in n-heptane (v/v), 50 ml fractions, 10% increments, followed by 2-10% MeOH in EtOAc (v/v), 50 ml fractions, 2% increments) to afford nucleoside 55 (1.64 g, 81%) as a slightly yellow foam. Rf = 0.57 (20% n-heptane in EtOAc, v/v); ESI-MS m/z found 495.1 ([MH]+, calcd 495. 1) ; 1H NMR (CDCl3) No. 9. 02 (br s, 1H, NH), 8.07-7. 99 (m, 4H, Ph), 7.62-7. 58 (m, 2H, Ph), 7.47-7. 42 (m, 5H, Ph and H6), 5.95 (s, 1H, H1'), 5.46 (d, J = 2.2, 1H, H3'), 4.93 (d, J = 12.8, 1H, H5'a), 4.60 (d, J = 12.8, 1H, H5'b), 4.17 (d, J = 2.2, 1H, H2'), 3.27 (d, J = 10.6, 1H, H1"a), 3.16 (d, J = 10. 6,1H, H1"b), 1.55 (d, J = 1.1, 3H, CH3) ; ßC NMR (CDCl3) a 165. 8, 165.1, 163.7 (C4,2 x PhC (O) ), 150.0 (C2), 133.9, 133.7, 133.6, 129.8, 129.6, 129.0, 128.8, 128.6, 128.5 (C6,2 x Ph), 110.3 (C5), 91.3 (C1'), 87.5 (C4'), 72.9 (C3'), 61.3 (C5'), 50.6 (C2'), 35.6 (C1"), 12.3 (CH3) ; Anal. calcd for C2sH22N207S : C, 60.72 ; H, 4.48 ; N, 5.66. Found: C, 60.34 ; H, 4.49 ; N, 5.35. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94.4% | In N,N-dimethyl-formamide at 170℃; for 4h; | 2.a Preparation of benzoic acid(2-aldehyde ethyl ester): Dissolve 42.43 g bromoacetaldehyde diethanol200mL DMF,Then it warms up to 170°C.After adding 15.02 grams of sodium benzoate,The reaction was refluxed for 2 h.16.13 g of sodium benzoate was further added to the system and reacted at 170° C. for 2 h.After cooling to room temperature, 500 mL of water and 450 mL of EA were added and the layers were separated. Organic phase with 300 mL saturated NaHCO3 solution and 300 mL saturated saltAfter washing with water, the liquid was separated. Dry the organic phase with anhydrous calcium chloride. Concentrate and spin dry to give 24.2 g of a brown oil.94.4%. TLC purity > 90%. |
83% | With 18-crown-6 ether In N,N-dimethyl-formamide at 160℃; for 6h; | |
72% | In N,N-dimethyl-formamide for 24h; Reflux; | Procedure for the synthesis of 2-oxoethyl benzoate (5) To a stirred solution of 2-bromo-1,1-diethoxyethane (20 mmol, 3 ml) in dry DMF (30 ml), sodium benzoate (22 mmol, 3.17 g) was added. Then the reaction mixture was refluxed for 24 h. The resulting brown solution was cooled and carefully quenched with H2O (40 mL). The product was then repeatedly extracted with EtOAc and the organic layers dried over Na2SO4. Upon solvent removal five portions of toluene (10 ml) were added and subsequently removed. Finally the product 2,2-diethoxyethyl benzoate was purified by flash chromatography eluting with a hexane/ethyl acetate (9:1) solvent system to provide colorless oil (3.43 g, 72%). In a 100 ml round flask a solution of 2,2-diethoxyethyl benzoate (13 mmol, 3.12 g) in H2O (6 ml) and formic acid (25 ml) was stirred 4 h at room temperature. The water and formic acid were removed under vacuum and toluene (20 ml) was added. After the removal of toluene the product was dried 4 h under vacuum obtaining a colorless liquid (2.08 g, 97 %). Spectral data were identical with those reported before.1 |
In N,N-dimethyl-formamide for 5h; Heating; | ||
In N,N-dimethyl-formamide Reflux; | 1 Preparation of 2-(Benzoyloxy)acetaldehyde Diethyl Acetal Example 1 Preparation of 2-(Benzoyloxy)acetaldehyde Diethyl Acetal To a 2-L, three-necked, round-bottomed flask fitted with a mechanical stirrer, a reflux condenser and a glass stopper is added sodium benzoate (0.579 mol, 83.44 g, 1.1 equiv.), bromoacetaldehyde diethyl acetal (0.526 mol, 103.74 g, 1.0 equiv.) and N,N-dimethylformamide (1.0 L). The reaction was heated to reflux and stirred while monitoring progress by thin layer chromatography (TLC). When determined to be complete, the reaction was allowed to cool to ambient temperature and diluted with water (2.0 L). The product was extracted with methyl tert-butyl ether. The organic phase was dried over magnesium sulfate and concentrated by rotary evaporation to give 2-(benzyloxy)acetaldehyde diethyl acetal (111.85 g, 81.1% yield). The crude product was advanced to the next reaction step without further purification. | |
In N,N-dimethyl-formamide Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In N,N-dimethyl-formamide at 20℃; for 3h; | H Benzoic acid 2-fluoro-pyridin-4-ylmethyl ester (36): The mixture of 4-Bromomethyl-2-fluoro-pyridine (35) (4.85 g, 25.5 mmol) and sodium benzoate (5.51 g, 38.25 mmol) in DMF (60 ml) was stirred at room temperature for 3 hr. Ether was then added and the mixture was washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether:hexane (1:4)) to afford 4.68 g (79%) of a colorless oil; 1H NMR (200 MHz, CDCl3) δ: 5.41 (2H, s), 7.11 (1H, m), 7.45-7.66 (3H, m), 8.08-8.12 (2H, m), 8.23 (1H, d, J=5.4 Hz); m/z (EI): 231(M+). |
79% | In N,N-dimethyl-formamide |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | Stage #1: 3-cyano-(<αS)-<α-(3-hydroxytricyclo[3.3.1.137]dec-1-yl)-<β-oxo-(1S,3S,5S)-2-azabicyclo[3.1.0]hexane-2-ethanecarbamic acid 1,1-dimethylethyl ester With hydrogenchloride; water In ethyl acetate at 20℃; for 0.0166667 - 0.0333333h; Stage #2: With sodium hydroxide In water; ethyl acetate at 25℃; Stage #3: sodium benzoate In water; ethyl acetate; isopropyl alcohol at 20℃; for 16 - 24h; | 41 EXAMPLE 41; Deprotection to produce (1S, 3S, 5S)-2- [ (2S)-2-amino-2- (3- hydroxytricyclo [3.3.1.1 3,7] (dec-1-yl)-1-oxoethyl]-2-azabicyclo [3.1.0] hexane-3- carbonitrile, benzoate (1 : 1) (Formula M) (5.0 grams, 12.04 mmoles) was charged to a three-necked flask equipped with a thermometer, a mechanical stirrer, and a gas inlet. EtOAc, approximately 45 to 50 ml, was added to achieve a clear solution. Concentrated HCI (3.00 ml, 37% w/w%, 36.14 mmoles, 3 equivalents) was added at room temperature and the reaction mixture was stirred until a solid was produced. Water (30 ml) was then added and the mixture was stirred for 1 to 2 minutes. This reaction mixture was transferred to a separator funnel and the layers of the reaction mixture were allowed to separate into a clean phase split. The aqueous layer was adjusted to a lower pH of approximately 6 with 25% NAOH while maintaining the temperature below 25C. Salt exchange was then performed by addition of isopropyl alcohol (IPA; 2 to 3 ml) to the aqueous layer followed by addition of sodium benzoate (0.65 ml of a sodium benzoate solution prepared by dissolving 2.6 grams for sodium benzoate in 6.5 ml of water). The remaining sodium benzoate solution was then added in dropwise fashion via an addition funnel. The resulting reaction mixture was stirred at room temperature for 16 to 24 hours. Solids in the reaction mixture were then filtered on a Buchner funnel and washed with water until the solid gave a negative test for Cl- with AGNO3. The solids were then washed with heptane (10 ml) to drive off the water, air dried on the funnel, an dried in a vacuum oven at 35C until KF < 5%. Yield was 79%, 4.1 grams |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In water; at 80℃; for 7h; | Didecyldimethylammonium chloride (0.02 mol) was dissolved in distilled water and 0.015 mol of benzoic acid sodium salt was added. The solution was stirred at 80 C. for 7 h. The reaction mixture was extracted by chloroform. Chloroform phase was removed and washed with distilled, cold water until chloride ions were no longer detected using AgNO3. Then chloroform was removed. Obtainede benzoate in 85% yield was dried in vacuum. 1H NMR and 13C NMR (CDCl3) were obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
[0184] The shampoo compositions illustrated in the following Examples illustrate specific embodiments of the shampoo compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. These exemplified embodiments of the shampoo composition of the present invention provide enhanced conditioning benefits to the hair. [0185] The shampoo compositions illustrated in the following Examples are prepared by conventional formulation and mixing methods, an example of which is set forth hereinbelow. All exemplified amounts are listed as weight percents and exclude minor materials such as diluents, preservatives, color solutions, imagery ingredients, botanicals, and so forth, unless otherwise specified. [0186] The compositions illustrated in the examples were prepared in the following manner (all percentages are based on weight unless otherwise specified). [0187] For each of the compositions, 6-9% of ammonium laureth-3 sulfate, P43 oil, PureSyn6 oil, cationic polymers, 0-1.5% Ammonium Xylene Sulfonate, and 0-5% water was added to a jacketed mix tank and heated to about 74 C. with agitation to form a solution. Citric Acid, Sodium Citrate, Sodium Benzoate, Disodium EDTA, Cocamide MEA and 0.6-0.9% Cetyl alcohol, were added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) was then added to the mixing vessel, and melted. After the EGDS was well dispersed (after about 10 minutes) preservative was added and mixed into the surfactant solution. This mixture was passed through a heat exchanger where it was cooled to about 35 C. and collected in a finishing tank. As a result of this cooling step, the ethylene glycol distearate crystallized to form a crystalline network in the product. [0188] Separately about 20% of the water was heated to about 74 C. and the remainder of the Cetyl Alcohol, Stearyl Alcohol, and the Cationic Surfactant were added to it. After incorporation, this mixture was passed through a heat exchanger where it was cooled to about 35 C. As a result of this cooling step, the Fatty Alcohols and surfactant crystallized to form a crystalline gel network. [0189] These two premixes are the mixed together and the remainder of the surfactants, perfume, Dimethicone, Sodium Chloride or Ammonium Xylene Sulfonate for viscosity adjustment and the remainder of the water were added with ample agitation to insure a homogeneous mixture. [0190] Preferred viscosities range from about 5000 to about 9000 centipoise at 27 C. (as measured by a Wells-Brookfield model RVTDCP viscometer using a CP-41 cone and plate at 2/s at 3 minutes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLES [0184] The shampoo compositions illustrated in the following Examples illustrate specific embodiments of the shampoo compositions of the present invention, but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. These exemplified embodiments of the shampoo composition of the present invention provide enhanced conditioning benefits to the hair. [0185] The shampoo compositions illustrated in the following Examples are prepared by conventional formulation and mixing methods, an example of which is set forth hereinbelow. All exemplified amounts are listed as weight percents and exclude minor materials such as diluents, preservatives, color solutions, imagery ingredients, botanicals, and so forth, unless otherwise specified. [0186] The compositions illustrated in the examples were prepared in the following manner (all percentages are based on weight unless otherwise specified). [0187] For each of the compositions, 6-9% of ammonium laureth-3 sulfate, P43 oil, PureSyn6 oil, cationic polymers, 0-1.5% Ammonium Xylene Sulfonate, and 0-5% water was added to a jacketed mix tank and heated to about 74 C. with agitation to form a solution. Citric Acid, Sodium Citrate, Sodium Benzoate, Disodium EDTA, Cocamide MEA and 0.6-0.9% Cetyl alcohol, were added to the tank and allowed to disperse. Ethylene glycol distearate (EGDS) was then added to the mixing vessel, and melted. After the EGDS was well dispersed (after about 10 minutes) preservative was added and mixed into the surfactant solution. This mixture was passed through a heat exchanger where it was cooled to about 35 C. and collected in a finishing tank. As a result of this cooling step, the ethylene glycol distearate crystallized to form a crystalline network in the product. [0188] Separately about 20% of the water was heated to about 74 C. and the remainder of the Cetyl Alcohol, Stearyl Alcohol, and the Cationic Surfactant were added to it. After incorporation, this mixture was passed through a heat exchanger where it was cooled to about 35 C. As a result of this cooling step, the Fatty Alcohols and surfactant crystallized to form a crystalline gel network. [0189] These two premixes are the mixed together and the remainder of the surfactants, perfume, Dimethicone, Sodium Chloride or Ammonium Xylene Sulfonate for viscosity adjustment and the remainder of the water were added with ample agitation to insure a homogeneous mixture. [0190] Preferred viscosities range from about 5000 to about 9000 centipoise at 27 C. (as measured by a Wells-Brookfield model RVTDCP viscometer using a CP-41 cone and plate at 2/s at 3 minutes). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (S)-[ruthenium(2-methyl-4-(C(CH3)3)-1-(COOCH2CH2P(phenyl)2))cyclopentadienyl)(CH3CN)2]PF6 In tetrahydrofuran at 25℃; for 7h; Inert atmosphere; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With (S)-[ruthenium(2-methyl-4-(C(CH3)3)-1-(COOCH2CH2P(phenyl)2))cyclopentadienyl)(CH3CN)2]PF6 In tetrahydrofuran at 25℃; for 2h; Inert atmosphere; optical yield given as %ee; enantioselective reaction; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dimethyl sulfoxide at 30℃; for 0.333333h; Ionic liquid; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | With water In ethanol for 4h; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
A mixture of TPTZ (0.312 g, 1.00 mmol) and EuCl3·6H2O (0.366 g, 1.00 mmol) in 20 ml of absolute ethanol was stirred under reflux for 1 h. Aqueous C6H5COONa (0.432 g, 3.00 mmol) was added to this mixture. The resulting mixture was stirred under reflux for another 2 h. After the precipitate was filtered off and washed with ethanol and deionized water, the europium complex [Eu(C6H5COO)3(TPTZ)]·4H2O was obtained. The filtrate was collected, from which the crystal of europium complex was obtained at room temperature in two months. Other complexes [Tb(C6H5COO)3(TPTZ)]·4H2O, [Sm(C6H5COO)3(TPTZ)]·4H2O and [Dy(C6H5COO)3(TPTZ)]·4H2O were synthesized with the same method. 1H NMR data of these complexes in DMSO-d6 solution were shown as follows. [Eu(C6H5COO)3(TPTZ)]·4H2O. delta = 8.92 (s, 2H, H6); 8.85 (s, 2H, H5); 8.75 (s, 2H, H4); 8.69 (s, 1H, H6?); 8.14 (s, 1H, H3?); 7.74 (s, 1H, H4?); 7.52 (m, 3H, H5?, H3); 6.94-6.23 (m, 5H, C6H5COO) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: 1-[3-O-benzyl-4-C-hydroxymethyl-2-deoxy-2-acetoxymethyl-3-β-ribo-pentofuranosyl]thymine With pyridine; methanesulfonyl chloride at 20℃; Inert atmosphere; Stage #2: With sodium hydroxide In 1,4-dioxane; water at 20 - 60℃; for 1.33333h; Stage #3: sodium benzoate In N,N-dimethyl-formamide at 130℃; for 5h; | 8 EXAMPLE 8Synthesis of (1 R,3 R,4R, 8S)-i -benzoyloxymethyl-8-benzyloxy-3 -(thymin- 1 -yl)-2 ,6-dioxabicyclo[3 ,2, 1] octane EXAMPLE 8 Synthesis of (lR,3R,4R,8S)-l-benzoyloxymethyl-8-benzyloxy- 3 -(thymin- 1 -yl)-2 ,6-dioxabicyclor3 ,2, 11 octane To a solution of compound 9 (0.64 g, 1.46 mmol) in anhydrous pyridine (15 mL) was added methanesulfonyl chloride (0.25 mL, 3.22 mmol) dropwise at room temperature under nitrogen atmosphere. The mixture was stirred overnight at ambient temperature. Solvent was removed under reduced pressure and the residue taken partitioned between EtOAc (lOOmL) and sat. aHC03 (80mL). The aqueous layer was back extracted with EtOAc (60 mL), and the combined organic phases were washed with water (lOOmL) and brine (lOOmL), dried (Na2S04) and concentrated to a gum. Crude product was co-evaporated from acetonitrile (2 x 50 mL) and used without further purification for the next step. The crude bismesylate was dissolved in a dioxane/water mixture (15 mL) and 2 M sodium hydroxide (15 mL) was added. After 20 min stirring at room temperature the reaction vessel was transferred to an oil bath and heated at 60°C for 1 h. Solvent was removed under reduced pressure and the residue taken between EtOAc (lOOmL) and sat. aHC03 (80mL). The aqueous layer was back extracted with additional EtOAc (2 x 40 mL), after which the combined organic phases were washed with brine (lOOmL), dried over Na2S04, and evaporated to dryness. Crude product was purified with S1O2 chromatography (0-10% MeOH in DCM v/v) to give ring closed bicyclic intermediate (0.59 g, 89%) as a white foam. The bicyclic intermediate (0.715 g, 1.6 mmol) was dissolved in DMF (60 mL) and sodium benzoate added (0.68 g, 4.7 mmol). The solution was heated to 130°C for 5 h and then allowed to cool to room temperature overnight. Solid material was removed by filtration and washed well with DMF. The combined washes were concentrated in vacuo to a brownish solid. The solid material was dissolved in DCM (100 mL) and additional precipitates removed by filtration. The isolated material was purified by silica gel chromatography (2%-5% MeOH in DCM v/v) to give (lR,3R,4R,8S)-l-benzoyloxymethyl-8-benzyloxy-3-(thymin-l-yl)- 2,6-dioxabicyclo[3,2, l] octane 10 (0.70 g, 93%) as a white foam. ES/MS (M-H) m/z: 477. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
47.9% | With 15-crown-5 In N,N-dimethyl-formamide at 60 - 70℃; for 3h; | 22 Preparation of (P22-3): P22-2 (4.9 g, 10.0 mmol), BzONa (14.4 g, 100 mmol) and 15-crown-5 (22.0 g, 100 mmol) were suspended in DMF (200 mL). The mixture was stirred at 60-70° C. for 3 days. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solvent was washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified on a silica gel column (20-60% EA in PE) to afford P22-3 as a white foam (2.3 g, 47.9%). |
47.9% | With 15-crown-5 In N,N-dimethyl-formamide at 60 - 70℃; for 72h; | 22 EXAMPLE 22 j0283j Compound P22-2 (4.9 g, 10.0 mmol), BzONa (14.4 g, 100 mmol) and 15- crown-S (22.0 g, 100 mmol) were suspended in DMF (200 mL). The mixture was stirred at 60-70°C for 3 days. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solvent was washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified on a silica gel column (2060% EA in PE) to afford P22-3 as a white foam (2.3 g, 47.9%). |
35% | With 15-crown-5 In N,N-dimethyl-formamide at 60 - 70℃; for 72h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium dihydrogenphosphate; tetra-(n-butyl)ammonium iodide In water; acetonitrile at 80℃; for 36h; Schlenk technique; | General procedure for the aerobic oxidative esterification reactions General procedure: Alcohol (0.50 mmol), hydrocarbon (10 mmol, 20 equiv), NaH2PO4 (74 mg, 97%, anhydrous, 0.6mmol, 1.2 equiv), Bu4NI (36.9 mg, 0.10mmol, 20 mol %), TBHP (70% aqueous solution, 0.42 mL,3.0 mmol, 6 equiv) and MeCN (2 mL) were added into a Schlenk flask with a high vacuum valve (V = 45 mL) fitting in a Radleys parallel synthesis station.1 The solution was stirred vigorously and heated at 80 oC for 36 hours. After it was cooled down to room temperature, 5 mL of water was added and the products were extracted by 15 mL of chloroform for three times. After dried by anhydrous MgSO4,the solution was diluted with methanol to 25.00 mL for GC test. The ester products for GC standard curves were synthesized independently following the reported procedures.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.5% | With 15-crown-5 In N,N-dimethyl-formamide at 130℃; for 6h; | 1 Example 1 To a solution of 1-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) were added NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol). The reaction mixture was stirred at 130° C. for 6 h. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel column (10-30% EA in PE) to give 1-5 (2.8 g, 40.5%). 1H NMR: (CDCl3, 400 MHz) 8.84 (s, 1H), 8.04-8.06 (m, 2H), 7.59 (t, J=7.2 Hz, 1H), 7.44-7.47 (m, 2H), 7.21-7.26 (m, 1H), 6.21 (s, 1H), 5.85 (d, J=18 Hz, 1H), 5.67 (d, J=8.0 Hz, 1H), 4.59-4.72 (m, 2H), 2.14 (s, 6H), 1.64 (d, J=6.0 Hz, 3H). ESI-MS: m/z 444.9 [M-F+H]+. |
40.5% | With 15-crown-5 In N,N-dimethyl-formamide at 130℃; for 6h; | 77 Compound 108 To a solution of 108-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) were added NaOBz (21.44 g, 148.9mmol) and 15-crown-5 (32.75 g, 148.9 mmol). The reaction mixture was stirred at 130° C. for 6 h. Thesolvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporatedand purified on a silica gel column (10-30% EA in PE) to give 108-5 (2.8 g, 40.5%). ESI-MS: m/z 444.9[M-F+H]+ |
40.5% | With 15-crown-5 In N,N-dimethyl-formamide at 130℃; for 6h; | 77 To a solution of 108-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mE) were added NaOl3z (21.44 g, 148.9 mmol) and 15-crown-S (32.75 g, 148.9 mmol). The reaction mixture was stirred at 130° C. for 6 h. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel colunm (10-30% EA in PE) to give 108-5 (2.8 g, 40.5%). ESI-MS: mlz 444.9 [M-F+H]. |
40.5% | With 15-crown-5 In N,N-dimethyl-formamide at 130℃; for 6h; | 77 Example 77 Compound 108 To a solution of 108-4 (7.0 g, 14.89 mmol) in anhydrous DMF (400 mL) were added NaOBz (21.44 g, 148.9 mmol) and 15-crown-5 (32.75 g, 148.9 mmol). The reaction mixture was stirred at 130° C. for 6 h. The solvent was removed, diluted with EA and washed with water and brine. The organic layer was evaporated and purified on a silica gel column (10-30% EA in PE) to give 108-5 (2.8 g, 40.5%). ESI-MS: m/z 444.9 [M-F+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | With N,N,N,N,N,N-hexamethylphosphoric triamide; 15-crown-5 at 60℃; for 48h; | 3 To a solution of crude 4-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mE) was added NaOBz (1.2 g, 8.3 mmol) and iS-crown-S (1.8 g, 8.3 mmol). The mixture was stirred at 60°C. for 2 d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA=1 :1) to give crude 4-10 (550 mg, 73%) as a white solid. |
73% | With 15-crown-5 In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 48h; | 3 Example 3 Compound 4 To a solution of crude 4-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL) was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). The mixture was stirred at 60° C. for 2 d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA=1:1) to give crude 4-10 (550 mg, 73%) as a white solid. |
With 15-crown-5 In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 48h; | 10 Example 10 To a solution of crude 8-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL) was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). The mixture was stirred at 60° C. for 2 d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA=1:1) to give crude 8-10 (550 mg, 73%) as a white solid. |
With 15-crown-5 In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 48h; | 3 Compound 4 To a solution of crude 4-9 (750 mg, 0.82 mmol) in anhydrous HMPA (20 mL) was added NaOBz (1.2 g, 8.3 mmol) and 15-crown-5 (1.8 g, 8.3 mmol). The mixture was stirred at 60° C. for 2 d. The mixture was diluted with EA, and the solution was washed with brine. The organic layer was dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by prep-TLC (PE/EA=1:1) to give crude 4-10 (550 mg, 73%) as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78.5% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 11 Example 11 To a solution of 34-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) was added NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). The mixture was stirred at 90-100° C. for 48 h. The mixture was diluted with EA, and washed with water and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 34-9 (3.9 g, 78.5%) as a white solid. |
78.5% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 22 Compound 27 and 28 To a solution of 27-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) was added NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). The mixture was stirred at 90-100° C. for 48 h. The mixture was diluted with EA, and washed with water and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 27-9 (3.9 g, 78.5%) as a white solid |
78.5% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 22 To a solution of 27-8 (5.0 g, 5.3 mmol) in anhydrous DMF (150 mL) was added NaOBz (7.64 g, 53 mmol) and 15-crown-5 (14 g, 68 mmol). The mixture was stirred at 90-100° C. for 48 h. The mixture was diluted with EA, and washed with water and brine. The organic layer was concentrated, and the residue was purified by silica gel column (PE/EA=5/1) to give 27-9 (3.9 g, 78.5%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With 15-crown-5 In N,N-dimethyl-formamide at 100℃; for 48h; | 15 Example 15 To a solution of 29-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was added NaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture was stirred at 100° C. for 48 h. The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 mL), and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 29-10 (500 mg, 78%) as a white solid |
78% | With 15-crown-5 In N,N-dimethyl-formamide at 100℃; for 48h; | 16 Compound 20 To a solution of 20-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was added NaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture was stirred at 100° C. for 48 h. The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 mL), and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 20-10 (500 mg, 78%) as a white solid |
78% | With 15-crown-5 In N,N-dimethyl-formamide at 100℃; for 48h; | 16 To a solution of 20-9 (0.65 g, 0.8 mmol) in dry DMF (40 mE) was added NaOl3z (1.15 g, 8 mmol) and 15-crown-S (1.77 g, 8 mmol). The mixture was stirred at 100° C. for 48 h. The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 mE), and washed with water and brine. The organic layer was dried over Na2 SO4 and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 20-10 (500 mg, 78%) as a white solid. |
78% | With 15-crown-5 In N,N-dimethyl-formamide at 100℃; for 48h; | 16 Example 16 Compound 20 To a solution of 20-9 (0.65 g, 0.8 mmol) in dry DMF (40 mL) was added NaOBz (1.15 g, 8 mmol) and 15-crown-5 (1.77 g, 8 mmol). The mixture was stirred at 100° C. for 48 h. The solvent was evaporated at low pressure, and the residue was dissolved in EA (30 mL), and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated at low pressure. The residue was purified by silica gel column (20% EA in PE) to give 20-10 (500 mg, 78%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 16 Example 16 To a solution of 42-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz (3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at 95° C. for 72 h. The mixture was then diluted with EA (100 mL), and washed with water and brine. The organic phase was dried over MgSO4, and concentrated at low pressure. The residue was purified by silica gel column (15% EA in PE) to give 42-6 (1.5 g, 75%) as a white solid. |
75% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 66 To a solution of 86-5 (2 g, 2.4 mmol) in dry DMF (40 mE) was added NaOl3z (3.46 g, 24 mmol) and 15-crown-S (4.5 mE). The mixture was stirred at 95° C. for 72 h. The mixture was then diluted with EA (100 mE), and washed with water and brine. The organic phase was dried over MgSO4, and concentrated at low pressure. The residue was purified by silica gel colunm (15% EA in PE) to give 86-6(1.5 g, 75%) as a white solid. |
75% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 66 Example 66 Compounds 86 and 87 To a solution of 86-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz (3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at 95° C. for 72 h. The mixture was then diluted with EA (100 mL), and washed with water and brine. The organic phase was dried over MgSO4, and concentrated at low pressure. The residue was purified by silica gel column (15% EA in PE) to give 86-6 (1.5 g, 75%) as a white solid. |
42% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 66 Compound 86 and 87 To a solution of 86-5 (2 g, 2.4 mmol) in dry DMF (40 mL) was added NaOBz (3.46 g, 24 mmol) and 15-crown-5 (4.5 mL). The mixture was stirred at 95° C. for 72 h. The mixture was then diluted with EA (100mL), and washed with water and brine. The organic phase was dried over MgSO4, and concentrated at lowpressure. The residue was purified by silica gel column (15% EA in PE) to give 86-6 (1.5 g, 75%) as a whitesolid |
1.1 g | With 15-crown-5 In N,N-dimethyl-formamide at 100℃; for 48h; | 1 9-(3,5-di-O-Benzoyl-2-deoxy-2,4-difluoro-2-C-methyl-β-D-ribofuranosyl)-6-ethoxy-2- (monomethoxytritylamino)purine (32). To Nucleoside 31 (2.1 g, 3 mmol) dissolved in 40 ml_ of pyridine, BzCI (464 mg, 3.3 mmol) was added and reaction mixture was left at rt overnight. After usual work-up and chromatography on silica gel with 20% EtOAc in hexane 2g of 3’-benzoylated product was obtained. It was dissolved in DMF (60 ml_), NaOBz (3.45 g, 24 mmol) and 15-crown-5 (5.31 mg, 24 mmol) were added and reaction mixture was stirred at 100°C for 48h. Solvent was evaporated. After usual work-up the crude product was purified by column chromatography in 20% EtOH in hexane to get 1.1 g (45% for 2 steps) of nucleoside 32. MS, m/z (M+H)+ 826. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68.8% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 1 To a solution of 66-17 (22 g, 22 mmol) in dry DMF (500 mL) was added NaOBz (31.9 g, 220 mmol) and 15-crown-5 (48.4 g, 220 mmol), and the mixture was stirred for 72 h. at 95°C. The mixture was diluted with EA, washed with water and brine, and dried over MgSCL . The organic layer was evaporated at low pressure, and the residue was purified using a silica gel column chromatography to give 66-18 (15 g, 68.8%) as a white solid. |
60% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 17 Example 17 To a solution of 32-1 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was added NaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirred at 95° C. for 72 h. The mixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO4 and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 32-2 (0.3 g, 60%) as a white solid. |
60% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 21; 114 Compound 25 and 26 To a solution of 25-2 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was added NaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirred at 95° C. for 72 h. The mixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO4 and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 25-3 (0.3 g, 60%) as a white solid |
60% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 21 To a solution of 25-2 (0.5 g, 0.5 mmol) in dry DMF(10 mL) was added NaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirred at 95° C. for 72 h. Themixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO4 and concentrated at low pressure. The residue was purified by silica gel colunm (10% EA in PE) to give 25-3 (0.3 g, 60%) as a white solid. |
60% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 72h; | 21 Example 21 Compounds 25 and 26 To a solution of 25-2 (0.5 g, 0.5 mmol) in dry DMF (10 mL) was added NaOBz (0.72 g, 5 mmol) and 15-crown-5 (0.9 mL). The mixture was stirred at 95° C. for 72 h. The mixture was diluted with EA, and washed with water and brine. The organic phase was dried over MgSO4 and concentrated at low pressure. The residue was purified by silica gel column (10% EA in PE) to give 25-3 (0.3 g, 60%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 36h; | 9 Example 9 Compound 10 To a solution of 10-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H2O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 10-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]+. |
With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 36h; | 24; 26 Example 24 To a solution of 16-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H2O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 16-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]+. | |
With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 36h; | 9; 58 Compound 10 To a solution of 10-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90° C. The mixture was diluted with H2O (100 mL), and extracted with EA (3×150 mL). The organic layer was dried over anhydrous Na2SO4, and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 10-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]+ |
With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 36h; | 9 To a solution of 10-8 (7.5 g, 8.0 mmol) in dry DMF(100 mE) was added NaOl3z (11.5 g, 80.0 mmol) and15-crown-S (15.6 mE). The mixture was stirred for 36 h. at90° C. The mixture was diluted with H20 (100 mE), andextracted with EA (3x1 50 mE). The organic layer was driedover anhydrous Na2SO4, and evaporated at low pressure. Theresidue was purified by silica gel column chromatography(EA in PE from 10% to 30%) to give crude 10-9 (6.0 g,80.0%) as a solid. ESI-MS: mlz 928 [M+H]. | |
With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 36h; | 1 To a solution of 128-8 (7.5 g, 8.0 mmol) in dry DMF (100 mL) was added NaOBz (11.5 g, 80.0 mmol) and 15-crown-5 (15.6 mL). The mixture was stirred for 36 h. at 90°C. The mixture was diluted with H2O (100 mL), and extracted with EA (3 x 150 mL). The organic layer was dried over anhydrous Na2SC>4 , and evaporated at low pressure. The residue was purified by silica gel column chromatography (EA in PE from 10% to 30%) to give crude 128-9 (6.0 g, 80.0%) as a solid. ESI-MS: m/z 928 [M+H]+ . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32.4% | With 15-crown-5 In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 48h; | 28 Example 28 To a solution of crude 10-6 (650 mg, 0.72 mmol) in dry HMPA (20 mL) was added NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). The reaction was stirred for 2 d at 60° C. The mixture was diluted with H2O, and extracted with EA. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give 10-7 (210 mg, 32.4%). ESI-MS: m/z: 900.4 [M+H]+. |
32.4% | With 15-crown-5 In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 48h; | 5 Example 5 Compound 6 To a solution of crude 6-5 (650 mg, 0.72 mmol) in dry HMPA (20 mL) was added NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). The reaction was stirred for 2 d at 60° C. The mixture was diluted with H2O, and extracted with EA. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give 6-6 (210 mg, 32.4%). ESI-MS: m/z: 900.4 [M+H]+. |
210 mg | With 15-crown-5 In N,N,N,N,N,N-hexamethylphosphoric triamide at 60℃; for 48h; | 5 Compound 6 To a solution of crude 6-5 (650 mg, 0.72 mmol) in dry HMPA (20 mL) was added NaOBz (1.03 g, 7.2 mmol) and 15-crown-5 (1.59 g, 7.2 mmol). The reaction was stirred for 2 d at 60° C. The mixture was diluted with H2O, and extracted with EA. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give 6-6 (210 mg, 32.4%). ESI-MS: m/z: 900.4 [M+H]+ |
210 mg | With N,N,N,N,N,N-hexamethylphosphoric triamide; 15-crown-5 at 60℃; for 48h; | 5 To a solution of crude 6-5 (650 mg, 0.72 mmol) in dry HMPA (20 mE) was added NaOl3z (1.03 g, 7.2 mmol) and 15-crown-S (1.59 g, 7.2 mmol). The reaction was stirred for 2 dat 600 C. The mixture was diluted with H20, and extracted with EA. The organic layer was evaporated at low pressure. The residue was purified by prep-TLC to give 6-6 (210 mg, 32.4%). ESI-MS: mlz: 900.4 [M+H]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With 15-crown-5 In dimethyl sulfoxide at 100℃; for 47h; | Synthesis of (2S,3S,4R,5R)-2-((benzoyloxy)methyl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-fluoro-4-methyltetrahydrofuran-3,4-diyl dibenzoate. To a solution of (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-fluoro-2-(iodomethyl)-4-methyltetrahydrofuran-3,4-diyl dibenzoate (349 mg, 0.59 mmol) in DMSO (3 mL) was added NaOBz (670 mg, 5.87 mmol) followed by 15-crown-5 (1.17 mL, 5.87 mmol). The reaction mixture was stirred at 100 °C for 47 h. After dilution with EtOAc, the mixture was washed with sat aq. NaHCO3 (x2), water, aq. KHSO4, water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography to give the title compound (170 mg, 0.29 mmol, 49 % yield). LC-MS: m/z 611.3 (M+Na)+. |
46.1% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 48h; | 90 Example 90 Compound 150 To a solution of 150-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) was added NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at 95° C. for 48 h. The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200 mL), and the solution was washed with sat. NaHCO3 solution, and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 150-4 (3 g crude, 46.1%) as an oil. |
With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 48h; | 37 Example 37 To a solution of 54-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) was added NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at 95° C. for 48 h. The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200 mL), and the solution was washed with sat. NaHCO3 solution, and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 54-4 (3 g crude, 46.1%) as an oil. |
With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 48h; | 218 EXAMPLE 218 j1023j To a solution of 300-3 (6.5 g, 11 mmol) in arthydrous DMF (270 mL) was added NaOBz (15.8 g, 110 mmol) and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at 95°C for 48 h. The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200 mL), and the solution was washed with sat. NaHCO3 solution, and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 300-4 (3 g crude, 46.1%) as an oil. | |
With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 48h; | 90 Compound 150 To a solution of 150-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mL) was added NaOBz (15.8 g, 110 mmol)and 15-crown-5 (29 g, 132 mmol). The mixture was stirred at 95° C. for 48 h. The precipitate was removedby filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200mL), and the solution was washed with sat. NaHCO3 solution, and brine. The organic layer was dried overanhydrous Na2SO4 and filtered. The filtrate was concentrated at low pressure. The residue was purified bysilica gel column chromatography (20% EA in PE) to give 150-4 (3 g crude, 46.1%) as an oil | |
With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 48h; | 90 To a solution of 150-3 (6.5 g, 11 mmol) in anhydrous DMF (270 mE) was added NaOl3z (15.8 g, 110 mmol) and 15-crown-S (29 g, 132 mmol). The mixture was stirred at 95° C. for 48 h. The precipitate was removed by filtration, and the organic solvent was removed at low pressure. The residue was dissolved in EA (200 mE), and the solution was washed with sat. NaHCO3 solution, and brine. The organic layer was dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated at low pressure. The residue was purified by silica gel column chromatography (20% EA in PE) to give 150-4 (3 g crude, 46.1%) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 24h; | 135 Compound 250 A mixture of 250-15 (600 mg, 1 mmol), BzONa (1.45 g, 10 mmol), and 15-crown-5 (2.2 g, 10 mmol) inDMF (25 mL) was stirred at 90-100° C. for 24 h. The mixture was diluted with EA (20 mL). The solutionwas washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue waspurified by column chromatography (30% EA in PE) to give 250-16 (275 mg, 37%) as a light yellow foam |
37% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 24h; | 135 A mixture of 250-15 (600 mg, 1 mmol), l3zONa (1.45 g, lOmmol), and 15-crown-S (2.2 g, lOmmol)inDMF (25 mE) was stirred at 90-100° C. for 24 h. The mixture was diluted with EA (20 mE). The solution was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (30% EA in PE) to give 25 0-16 (275 mg, 37%) as a light yellow foam. |
37% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 24h; | 135 Example 135 Compound 250 A mixture of 250-15 (600 mg, 1 mmol), BzONa (1.45 g, 10 mmol), and 15-crown-5 (2.2 g, 10 mmol) in DMF (25 mL) was stirred at 90-100° C. for 24 h. The mixture was diluted with EA (20 mL). The solution was washed with brine, dried over anhydrous Na2SO4, and concentrated at low pressure. The residue was purified by column chromatography (30% EA in PE) to give 250-16 (275 mg, 37%) as a light yellow foam. |
275 mg | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 24h; | 46 Example 46 To a solution of 75-15 (600 mg, 1 mmol) in DMF (25 mL) was added BzONa (1.45 g, 10 mmol), 15-crown-5 (2.2 g, 10 mmol), and the mixture was stirred at 90-100° C. for 24 h. The mixture was concentrated at low pressure, and the residue was dissolved in EA (20 mL), and washed with brine. The organic phase was dried over anhydrous MgSO4, and then concentrated at low pressure. The residue was purified by chromatography using 15% EA in PE to give 75-16 (275 mg, 37%) as a light yellow foam. |
275 mg | With 15-crown-5 In N,N-dimethyl-formamide at 130℃; for 6h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 53 Example 53 To a solution of 47-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (4.5 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100° C. The mixture was diluted with EA (100 mL), and washed with brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 47-7 (500 mg, 56%) as a solid. |
56% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 216 EXAMPLE 215 jlOl6j To a solution of 296-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (2.5 g, 17.4 mmol) and 15-crown-S (4.5 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100°C. The mixture was diluted with EA (100 mL), and washed with brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 296-7 (500 mg, 56 %) as a solid. |
56% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 111 Compound 206 To a solution of 206-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (2.5 g, 17.4 mmol) and15-crown-5 (4.5 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100° C. The mixture was diluted withEA (100 mL), and washed with brine. The organic layer was evaporated at low pressure, and the residue waspurified by silica gel column chromatography (20% EA in PE) to give 206-7 (500 mg, 56%) as a solid |
56% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 111 To a solution of 206-6 (900 mg, 1.74 mmol) in dry DMF (45 mE) was added NaOl3z (2.5 g, 17.4 mmol) and 15-crown-S (4.5 g, 20.9 mmol). The mixture was stirred for48 h at 90-100° C. The mixture was diluted with EA (100 mE), and washed with brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 206-7 (500 mg, 56%) as a solid. |
56% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 48h; | 111 Example 111 Compound 206 To a solution of 206-6 (900 mg, 1.74 mmol) in dry DMF (45 mL) was added NaOBz (2.5 g, 17.4 mmol) and 15-crown-5 (4.5 g, 20.9 mmol). The mixture was stirred for 48 h at 90-100° C. The mixture was diluted with EA (100 mL), and washed with brine. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (20% EA in PE) to give 206-7 (500 mg, 56%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With tetra(n-butyl)ammonium hydrogensulfate; sodium hydrogencarbonate; In dichloromethane; water; for 3h; | Preparation of chloromethyl benzoate (5) Sodium benzoate (4.8 g 33.3 mmol), sodium bicarbonate (8.4 g 100.0 mmol) and tetrabutylammonium sulfate (1.1 g, 3.3 mmol) were dissolved in water (70 rtiL). Dichloromethane (70 niL) was added followed by chloromethyl chlorosulfonate (4.2 mL, 40.3 mmol). The resulting mixture (a biphasic solution) was vigorously stirred for 3 hours. The phases were separated. The organic phase was washed with water (2 chi 50 mL) and dried over anliydrous magnesium sulfate. The solution was filtered through a small plug of silica (5 g) and evaporated under reduced pressure at < 30 C yielding compound 5 as colorless liquid (5.2 g, 92%). The analytical data for compound 5 were identical to those reported in literature (e.g. , Baudy et al , J. Med. Chem, 2009, 52, 771). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 48h; | 14 Compound 16 To a solution of 16-4 (10.0 g, 13.7 mmol) in dry DMF (100 mL) was added NaOBz (19.8 g, 137 mmol) and 15-crown-5 (30.2 g, 137 mmol). The reaction was stirred for 48 h at 90° C., and diluted with EA. The solution was washed with water and brine, and dried over MgSO4. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (EA in PE from 12% to 50%) to give 16-5 (8.0 g, 80.0%). |
80% | With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 48h; | 14 To a solution of 16-4 (10.0 g, 13.7 mmol) in dry DMF (100 mE) was added NaOl3z (19.8 g, 137 mmol) and 15-crown-S (30.2 g, 137 mmol). The reaction was stirred for48 hat 90° C., and diluted with EA. The solution was washed with water and brine, and dried over Mg504. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (EA in PE from 12% to 50%) to give 16-5 (8.0 g, 80.0%). |
80% | With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 48h; | 14 Example 14 Compound 16 To a solution of 16-4 (10.0 g, 13.7 mmol) in dry DMF (100 mL) was added NaOBz (19.8 g, 137 mmol) and 15-crown-5 (30.2 g, 137 mmol). The reaction was stirred for 48 h at 90° C., and diluted with EA. The solution was washed with water and brine, and dried over MgSO4. The organic layer was evaporated at low pressure, and the residue was purified by silica gel column chromatography (EA in PE from 12% to 50%) to give 16-5 (8.0 g, 80.0%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87.2% | With 15-crown-5 In N,N-dimethyl-formamide at 90 - 100℃; for 24h; | 196 Example 196 Compound 362 To a solution of 362-6 (573 mg, 1.16 mmol) in dry DMF (30 mL) was added NaOBz (1.68 g, 11.64 mmol) and 15-crown-5 (3.08 g, 13.97 mmol), and the mixture was stirred at 90-110° C. for 24 h. The mixture was filtered and extracted with EA (3×20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated at low pressure. The residue was purified by column chromatography (30% EA in PE) to give 362-7 (492 mg, 87.20%) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
88.1% | With 15-crown-5 In N,N-dimethyl-formamide at 95℃; for 24h; | 38.5 Compound 5 (100 mg, 0.194 mmol), BzONa (279 mg, 1.94 mmol) and 15-crown-5 (427 mg, 1.94 mmol) were suspended in DMF (20 mL). The mixture was stirred at 95° C. for 1 day. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solution was washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified on a silica gel column (PE/EA=4/1 to 2/1) to afford compound 10-6 (87 mg, 88.1%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.3% | With 15-crown-5 In N,N-dimethyl-formamide at 90℃; for 24h; | 50.7 Compound 37-6 (1.80 g, 2.91 mmol), BzONa (4.20 g, 29.10 mmol) and 15-crown-5 (6.40 g, 29.10 mmol) were suspended in DMF (100 mL). The mixture was stirred at 90° C. for 1 day. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solution was washed with brine and dried over Na2SO4. The solvent was removed, and the residue was purified on a silica gel column (PE:EA=10:1 to 2:1) to afford compound 37-7 (1.52 g, 85.3%) as a white solid. 1H NMR (CD3OD, 400 MHz) δ 7.83-7.95 (m, 5H), 7.82 (d, J=1.2 Hz, 2H), 7.54-7.64 (m, 3H), 7.40-7.47 (m, 5H), 7.31-7.35 (m, 2H), 6.60 (d, J=5.6 Hz, 1H), 6.10 (d, J=6.0 Hz, 1H), 5.53 (d, J=8.4 Hz, 1H), 4.59 (d, J=12 Hz, 1H), 1.98 (s, 3H); |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | General procedure: Erbium(III) nitrate pentahydrate (0.125mmol), the sodium carboxylate salt (4 mmol; 1: trimethylacetate hydrate based on an assumption of three waters of hydration; 2: sodium benzoate; 3: sodium salicylate), and <strong>[89-73-6]salicylhydroxamic acid</strong> (2mmol) were mixed in 10 mL of DMF resulting in a cloudy, white mixture for 1 and 2 or a clear, colorless solution for 3. In a separate beaker, manganese(II) acetate tetrahydrate (2 mmol) was dissolved in 10mL of DMF resulting in an orange/red solution. The two solutions were mixed resulting in a dark brown solution and then allowed to stir overnight. The solution was then filtered to remove a dark brown precipitate, which was discarded. The filtrate was then prepared for crystal growth (details below). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; at 80℃; | (R) -1-tert-butoxycarbonyl-3-methanesulfonylpiperidine (27.9 g, 0.1 mol) prepared in (1) or (2) in Example 7 was added to a 500 ml three-necked flask DMF 100ml, sodium benzoate (28.8g; 0.2mol), 80 C reaction overnight, the reaction solution cooling, add Water quenched, extracted with dichloromethane, washed with organic phase and concentrated to give crude (S) -1-tert-butoxycarbonyl-3-benzoyloxypiperidine.. (Yield: ~ 100%; LC-MS: m / e= 243.3) (theory: 24.3 g). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: sodium benzoate; N,N'-propane-1,3-diylbis(salicylideneimine); cobalt(II) perchlorate hexahydrate In methanol; water for 1h; Stage #2: acetonitrile | 2.4 Synthesis of the complex [Co3L2(μ2-C6H5CO2-)2(CH3CN)2](ClO4-)2·(CH3CN)3 (1) The yellow colored methanolic solution (12mL) of the di-Schiff base (H2L) ligand (2mmol) was taken in a beaker. To this methanolic solution, a water solution (2mL) of Co(ClO4)2·6H2O (1.098g, 3mmol) followed by an aqueous solution (2mL) of sodium benzoate (0.576g, 4mmol) was added. The mixture was stirred for 1h and then filtered. The filtrate was allowed to stand overnight till brown colored microcrystalline product of 1 appeared at the bottom of the beaker. The crystalline product was recrystallized from acetonitrile solution. The crystals were washed with an acetonitrile-water mixture and dried in a desiccator containing anhydrous CaCl2 and then characterized by elemental analysis, spectroscopic methods, and X-ray diffraction. Complex 1. Yield: 0.917g, 67%. Anal. Calc. for C58H57Co3Cl2N9O16: C, 50.34; H, 4.15; N, 9.11. Found: C, 50.52; H, 4.35; N, 9.31%; UV/vis: [λmax in nm (εmax in M-1cm-1)] (MeCN)=621(223), 362(2908). IR (KBr) in cm-1: ν(C=N) 1633; ν(C=O) 1597; ν(C=O) 1558. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.63% | With tetrabutylammomium bromide In toluene at 40 - 70℃; for 1h; Autoclave; Inert atmosphere; | 2 Example 2 100 g of sodium benzoate, 400 g of toluene recovered in Example 1, and 3 g of tetrabutylammonium bromide were placed in an autoclave, and the autoclave was sealed, stirred, and the air in the autoclave was replaced with nitrogen, and the temperature was raised to 40 ° C.Slowly pass the reaction after preheating (preheating temperature is 50 ° C, gasification pressure is 0.5 Mpa), and control the reaction temperature to be 50 ° C ~ 70 ° C by controlling the amount of ethyl chloride.The pressure is 0.4Mpa-0.6Mpa, and the reaction temperature is maintained by jacket heating at the end of the reaction.When the kettle pressure was no longer lowered, the chlorine gas was stopped, and the pressure was maintained at 0.6 Mpa for 1 hour to terminate the reaction.The temperature is lowered to 30 ° C to 40 ° C, the pressure is released, the nitrogen is replaced, and the catalyst and the sodium chloride produced by the reaction are filtered off to obtain a crude solvent containing toluene.The crude product was subjected to atmospheric distillation to recover a toluene solvent, and then subjected to vacuum distillation to obtain a finished ethyl benzoate product. The effective amount of the product was 101.7 g, and the yield was 97.63%.The recovered toluene collection is to be reused. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: sodium benzoate; copper(II) acetate dihydrate In ethanol; water at 20℃; for 0.0833333h; Stage #2: salicylamide In ethanol; water for 4h; | Compound 1 A solution of sodium benzoate (0.122g, 1.0mmol) in 5mL of ethanol was added to a solution of copper(II)acetate dihydrate (0.199g, 2.0mmol) in 10mL of water. The mixture was stirring gently at room temperature for 5min, then a solution of salicylamide (0.122g, 1.0mmol) in 5mL of ethanol was added. After continuous stirring for four hours, the clear blue solution at pH 5 was filtered and allowed to evaporate slowly at room temperature. The good quality blue-green prism crystals of compound 1 appeared within a week. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With polysorbate 80; In water;Sonication; | The benzoate salt of amlodipine was prepared in stainless steel containers in the absence and presence of varying amount of polysorbate 80. <strong>[111470-99-6]Amlodipine besylate</strong> has been reported to adsorb/adhere to stainless steel surfaces with one report indicating that 0.1% polysorbate 80 inhibits this adsorption/adherence in solution. The batches were prepared using the ingredients as specified in Table 4. The batch with no polysorbate (2A) was prepared by adding the purified water to a stainless steel vessel and initiating mixing with an overhead mixer and stainless steel stirrer shaft and blade. Citric acid was added and dissolved, then <strong>[111470-99-6]amlodipine besylate</strong> was added. The suspension was mixed for 5 minutes then sodium benzoate was added. (0333) Large crystals promptly formed in the suspension and solid material was observed to stick to, and coat, the stir-shaft and impeller as well as the inner surface of the stainless steel vessel. No further processing or sampling was undertaken. (0334) The polysorbate containing batches (2B-2F) were prepared as 7.5% concentrates by adding 4.50 liters of purified water to a stainless steel sonication tank with an overhead mixer and stainless steel stirrer shaft and blade. Mixing was initiated and the polysorbate 80 was added. The polysorbate container was rinsed with 0.25 L purified water and the rinse was added to the tank. The solution was stirred for 10 minutes and the <strong>[111470-99-6]amlodipine besylate</strong> was added to the tank. The <strong>[111470-99-6]amlodipine besylate</strong> container was rinsed with 0.25 L purified water and the rinse was added to the tank. The solution/suspension was stirred for 10 minutes then sonication was initiated (40 kHz frequency, 280 watts) and sodium benzoate was added to the tank. The sonication was discontinued after 10 minutes and the mixing continued for an additional 20 minutes. No solid material was observed to adhere to the container or the mixing shaft and blade. Samples of the suspension were taken periodically, filtered through a 0.45 micron nylon filter and the supernatant analyzed by the HPLC method in Example 1 for amlodipine content. Additional samples of the suspension were taken after the sonication and subsequent 20 minute stirring were completed. The samples were evaluated for particle size with a Malvern Mastersizer S using a 5 mg/mL sodium benzoate in water dispersant. [table-us-00004-en] TABLE 4 Amlodipine Salt Batches Evaluating Polysorbate Content Batch Components (grams) 2A 2B 2C 2D 2E 2F Purified water 1350 5000 5000 5000 5000 5000 Citric acid, anhydrous 0.825 - - - - - Polysorbate 80 0 5.00 15.0 25.0 30.0 66.7 <strong>[111470-99-6]Amlodipine besylate</strong> 2.08 92.6 92.6 92.6 92.6 92.6 Sodium benzoateResultsParticle size (mum) 7.50 333.6 333.6 333.6 333.6 333.6 D10 - 5 3 3 3 3 D50 - 29 13 14 13 14 D90 - 56 32 43 34 33 (0335) The concentration of amlodipine in solution over time for batches 2B-2F are given in FIG. 1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With lithium perchlorate In water; acetonitrile for 1h; Electrochemical reaction; |
Tags: 532-32-1 synthesis path| 532-32-1 SDS| 532-32-1 COA| 532-32-1 purity| 532-32-1 application| 532-32-1 NMR| 532-32-1 COA| 532-32-1 structure
[ 99-04-7 ]
3-Methylbenzoic acid(Flakes or Chunks or Granular)
Similarity: 0.97
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H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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