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CAS No. : | 613-45-6 | MDL No. : | MFCD00003311 |
Formula : | C9H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LWRSYTXEQUUTKW-UHFFFAOYSA-N |
M.W : | 166.17 | Pubchem ID : | 69175 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 44.81 |
TPSA : | 35.53 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.96 cm/s |
Log Po/w (iLOGP) : | 2.06 |
Log Po/w (XLOGP3) : | 1.91 |
Log Po/w (WLOGP) : | 1.52 |
Log Po/w (MLOGP) : | 0.83 |
Log Po/w (SILICOS-IT) : | 1.98 |
Consensus Log Po/w : | 1.66 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.25 |
Solubility : | 0.944 mg/ml ; 0.00568 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.28 |
Solubility : | 0.873 mg/ml ; 0.00526 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.59 |
Solubility : | 0.424 mg/ml ; 0.00255 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.35 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P273-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335-H412 | 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 |
---|---|---|
94% | With sulfuric acid; dihydrogen peroxide In methanol at 20℃; for 20 h; | To a solution of 2,4-dimethoxybenzaldehyde (54) (5.0g/30mmol) and 5mL of H2O2 30percent in 50mL of methanol, was added dropwise 0.5mL of sulfuric acid. The mixture was stirred for 20h at room temperature. Approximately 45mL of methanol were evaporated by rotary evaporator and the solution was partitioned between dichloromethane and distilled water. The aqueous phase was extracted 3×50mL of dichloromethane. The organic phase was washed with 3×50mL of distilled water, dried over sodium sulfate anhydrous, filtered and the organic solvent evaporated. The crude product was purified by column chromatography (chloroform). 2,4-Dimethoxyphenol (55) was obtained as light yellow oil (4.33g/94percent).2,4-Dimethoxyphenol (55). IR νmax (cm−1) (KBr): 3443, 2997, 2939, 2835, 1610, 1512, 1461, 1433, 1374, 1299, 1263, 1228, 1202, 1151, 1116, 1033, 918, 830, 792. 1H NMR (300.13MHz, CDCl3) δ (ppm): 6.75 (d, J=5.2), 6.42 (d, J=1.7), 6.31 (dd, J=5.2, 1.7), 3.79 (s, OCH3), 3.69 (s, OCH3). EIMS m/z (percent): 156 (4, [M+2]+.), 155 (40, [M+1]+.), 154 (100 [M]+.), 140 (4), 139 (58), 112 (4), 111 (90), 96 (22), 79 (10), 69 (10), 51 (20). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With sulfuric acid; dihydrogen peroxide In methanol | (1) Conc. sulfuric acid (0.4 ml) was added to a mixed solution comprising 3.3 g of 2,4-dimethoxybenzaldehyde and 30 ml of methanol, and under ice-cooling, 2.93 ml of 30percent hydrogen peroxide aqueous solution was added to the mixture. After stirring at room temperature for 4 hours, a 5percent aqueous potassium hydrogen sulfite solution was added to the mixture and the solvent was removed under reduced pressure. The residue was extracted with diethyl ether, the extract was washed and dried and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 2.1 g of 2,4-dimethoxyphenol (yield: 69percent, state: colorless oily product). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With formic acid; water; palladium diacetate; tricyclohexylphosphine In 1,4-dioxane at 90℃; for 18 h; Inert atmosphere; Sealed tube | General procedure: An oven-dried pressure tube containing a Teflon-coated stirring bar was charged with Pd(OAc)2 (11.2 mg, 5 molpercent), PCy3 (21 mg, 7.5 molpercent) and aldehyde(1 mmol).The tube was sealed, evacuated and backfilled with N2. 1 mL of dioxane was subsequently injected. After the mixture was stirred at room temperature for 15 min, H2O (180 mg, 10 equiv) and HCO2H (184 mg, 4 equiv) were injected and the reaction was heated to 90 oC for 18 h. After the reaction was completed, the solvent was removed under vacuo. The residues were purified by flash column chromatography on silica gel to afford 87 mg of benzyl alcohol in 81 percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sodium tris(acetoxy)borohydride In tetrahydrofuran at 20℃; | 2,4-dimethoxybenzaidehyde (Sigma Aldrich; 1.1 g, 661 mmoi) wasdissolved in 20 rnL THF at ambient temperature. To the solution was added 2,4- dimethoxybenzyiamine (Sigma Aldrich; 1.5 rnL, 9.98 mrnol) followed by sodium triacetoxyborohydride (Sigma Aldrich; 1 7 g; 8.4 inmol) and the mixture(increasingly cloudy) was stirred at ambient temperature overnight. The mixturewas then diluted with sat. NaHCO3 and extracted with EtOAc, dried over MgSO4and concentrated. The residue was purified by chromatography on 40 g ISCOcolumn eluting with a gradient of 0 to 100percent EtOAc to deliver bis(2,4-dimethoxybenzyi)amine (2.08 g, 6.55 mrnol, 99percent yield, 96percent purity) |
8 g | Stage #1: at 20℃; for 2 h; Stage #2: With sodium tris(acetoxy)borohydride In ethanol at 20℃; for 1 h; |
A) bis(2,4-dimethoxybenzyl)amine A solution of 2,4-dimethoxybenzylamine (8.98 mL) and 2,4-dimethoxybenzaldehyde (9.94 g) in ethanol (200 mL) was stirred at room temperature for 2 hr. To the reaction mixture was added sodium triacetoxyborohydride (20.3 g), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (8 g). 1H NMR (300 MHz, DMSO-d6) δ2.01 (1H, brs) 3.55 (4H, s) 3.74 (6H, s) 3.75 (6H, s) 6.46 (2H, dd, J=8.1, 2.3 Hz) 6.51 (2H, d, J=2.3 Hz) 7.18 (2H, d, J=8.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | Stage #1: at 0 - 20℃; for 1 h; Stage #2: With sodium tetrahydroborate In methanol at 0 - 20℃; for 12 h; |
To a stirred solution of 2,4-dimethoxybenzaldehyde (MM, 20.0 g, 120.48 mmol) in MeOH (200 mL), methanamine (33percent in MeOH, 15.0 g, 481.90 mmol) was added at 0 C and the reaction mixture was stirred at RT for 1H. To the resulting reaction mixture, NaBH4 (5.5 g, 144.57 mmol) was added portion wise at 0 C and the reaction mixture was stirred at RT for 12 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with dilute HC1 (200 mL) and MeOH was distilled out under reduced pressure. The residue was diluted with water and basified with dilute NaOH solution (80 mL). The aqueous layer was extracted with EtOAc (5 x 200 mL). The combined organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (50-80percent EtOAc/hexane) to afford compound MN (20.0 g, 92.0percent) as a light yellow liquid. 1H NMR (400 MHz, DMSO-d6): _ 7.14 (d, J = 8.4 Hz, 1H), 6.51 (brs, 1H), 6.47-6.45 (m, 1H), 3.74 (d, / = 8.0 Hz, 6H), 3.53 (s, 2H), 2.24 (s, 3H); LC-MS: mJz 181.80 [M+H]+. |
81% | Stage #1: at 20℃; for 1 h; Stage #2: With sodium tetrahydroborate In methanol at 0 - 2℃; for 3 h; |
Reference Example 59; 1- (2, 4-dimethoxyphenyl) -N-methylmethanamine; 2, 4-Dimethoxybenzaldehyde (5.0 g) was dissolved in methanol (60 mL) , and a 40percent methanol solution (9.3 mL) of <n="105"/>methylamine was added at room temperature. The mixture was stirred at room temperature for 1 hr, and sodium borohydride (1.37 g) was added by small portions under ice-cooling. The mixture was stirred at room temperature for 3 hr, treated with 1 mol/L hydrochloric acid under ice-cooling, and methanol was evaporated under reduced pressure. The residue was diluted with ethyl acetate, basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane: ethyl acetate=4 : 1-2 : 1) to give the title compound as a colorless oil (yield 4.41 g, 81percent).1H-NMR (CDCl3) δ: 2.40(3H,s), 3.67(2H,s), 3.80(3H,s), 3.81(3H,s), 6.40-6.45(2H,m) , 7.11 (IH, d, J=7.8Hz) , IH not detected. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Stage #1: for 2 h; Reflux; Dean-Stark Stage #2: With sodium tetrahydroborate In methanol; toluene at 0℃; for 18 h; Dean-Stark |
A solution of 1,2,4-thiadiazol-5-amine (1-1, 3.3 g, 32.6 mmol) and 2,4-dimethoxybenzaldehyde(1-2, 5.96 g, 35.9 mmol) in toluene (99 mL) was refluxed under Dean-Stark conditions for 2hours. Upon cooling to ambient temperature (RT, approximately 25 °C), the reaction wasconcentrated under reduced pressure to yield the corresponding imine, which was subsequentlydissolved in methanol (82 mL) and cooled to 0 °C. The reaction mixture was then treated withNaBH4 (1.85 g, 48.9 mmol) portion-wise. After stirring for 18 h, the reaction was concentratedand treated with 100 mL of water and diluted with 100 mL of ethyl acetate. The layers wereseparated and the aqueous layer was back-extracted with EtOAc (2 x 150 mL). The combinedorganic layers were concentrated and purified by normal phase chromatography (20-66percent EtOAcin hexane, 220 g ISCO column) to yield 1-3 as a white solid (5.9 g, 72percent). |
49% | Stage #1: for 2 h; Reflux Stage #2: at 20℃; |
Preparation 18N-(2,4-Dimethoxy-benzyl)-[1 ,2,41thiadiazol-5-yl-amine / N-(2,4-dimethoxybenzyl)- -thiadiazol-5-amineA m i x t u r e o f 5-amino-1 ,2,4-thiadiazole (1 g, 9.89 mmol) and 2,4- dimethoxybenzaldehyde (1 .81 g, 1 0.9 mmol) in toluene (30 mL) was refluxed under Dean-Stark cond itions for 2 hou rs . The reaction m ixture was evaporated and the residue taken up in methanol (25 mL), NaBH (600 mg, 15.9 mmol) was added carefully in small portions (vigorous effervescence after each addition), and the reaction was left stirring overnight at ambient temperature. Aqueous HCI (2M, 1 mL) was added followed by aqueous NaOH (2M, 10 mL). The bulk of the methanol was evaporated, water (20 mL) added and extracted with ethyl acetate (2 x 30 mL). The combined organic was washed brine (20 mL), dried, and evaporated. The residue was purified by silica gel column chromatography (ISCO.(TM). column 120 g; 25percent-60percent ethyl acetate in heptane gradient elution) to furnish a semi-solid residue that was re-evaporated from heptane. terf-Butyl methyl ether (2-3 mL) was added, followed by heptane (2-3 mL). The resulting solid was collected by filtration, washed with heptane and dried to afford the title compound (1 .22 g, 49percent).1 HNMR (de-DMSO): δ 3.73 (s, 3 H), 3.78 (s, 3 H), 4.36 (d, 2 H), 6.47 (dd, 2.34 Hz, 1 H), 6.56 (d, 1 H), 7.15 (d, 1 H), 7.88 (s, 1 H), 8.65 (br s, 1 H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
160 g | Stage #1: With triisopropoxytitanium(IV) chloride In dichloromethane for 0.75 h; Stage #2: at 20 - 34℃; for 2 h; |
To a solution of 1,2,4-thiadiazol-5-amine (150 g, 1.48 mol, 1.1 eq) and 2,4-dimethoxybenzaldehyde (224.1 g, 1.35 mol, leq) in anhydrous DCM (6 L) was added chlorotitanium triisopropoxide (771.3 g, 2.96 mol, 2.2 eq) slowly over 15 minutes. The resulting yellow solution was stirred for 30 minutes and then treated with sodium triacetoxyborohydride (715.3 g, 3.38 mol, 2.5 eq.) portionwise (Note: the reaction temperature increased from RT to 34 °C). After 2 hours, LC-MS analysis showed that INTERMEDIATE A was formed as the major product. The reaction mixture was cooled using an ice-water bath and neutralized with saturated aqueous NaHCO3 to a pH of about 7. The resulting thick slurry was passed through a short Celite® (diatomaceous earth) pad and washed with DCM. The white solid left on the pad was collected, put into flask, charged with DCM and water and then stirred well. The resulting slurry was again passed through a short Celite® (diatomaceous earth) pad and washed with DCM. All the filtrates were combined. The organic layer was separated, dried, filtered, and concentrated. The oily residue was purified by column chromatography, affording INTERMEDIATE A (160 g) as a white solid. MS (ESI, positive) m/z: 252.3. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (s, 1 H), 7.89 (s, 1 H), 7.17 (d, J= 8.2 Hz, 1 H), 6.57 (s, 1 H), 6.49 (d, J= 8.3 Hz, 1 H), 4.37 (d, J= 5.2 Hz, 2 H), 3.80 (s, 3 H), 3.75 (s, 3 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium tris(acetoxy)borohydride; acetic acid In acetonitrile at 20℃; Inert atmosphere | General procedure: General Method H General Method A is the procedure used for the synthesis of (R)-4-(2,4-dimethoxybenzyl)-3-methylpiperazin-2-one (R)-C(cf. Scheme 30).In a round-bottom flask, were sequentially introduced (R)-3-methylpiperazin-2-one (R)-A (725 mg, 6.35 mmol, leq.), 2,4-dimethoxybenzaldehydeB (1.16 g, 6.99 mmol, 1.1 eq.), acetic acid (545 μΐ, 9.53 mmol, 1.5 eq.) and sodium triacetoxyborohydride (1.88 g, 8.89 mmol, 1.4 eq.) in commercial anhydrous acetonitrile (65 mL), at RT, under N2 atmosphere. The reaction was stirred at RT overnight. The reaction mixture was quenched carefully at 0 °C with saturated NaHC03 solution (100 mL) until no more bubbling was observed. Aqueous and organic layers were separated. The aqueous layer was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine, dried over MgS04' filtered, and concentrated under reduced pressure to afford the title compound as yellow oil. The crude compound was then purified on silica gel (DCM/MeOH: 98/2 to 95/5) to afford the desired product (R)-C as a viscous pale yellow oil. Yield: 1.65 g, 98 percent. LCMS: P = 100 , retention time = 1.6 min, (M+H)+: 265; chiral HPLC retention time = 41.5 min, ee > 99 ; 1H-NMR (CDC13): δ 7.23 (d, J= 8.9, IH), 6.49 (d, J= 8.9, IH), 6.46 (s, IH), 6.29 (br, IH), 3.81 (s, 3H), 3.80 (s, 3H), 3.78 (d, JAB= 15.0, IH), 3.49 (d, JAB= 15.0, IH), 3.27 (m, 2H), 3.19 (m, IH), 2.95 (m, IH), 2.48 (m, IH), 1.48 (d, J= 6.8, 3H). |
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