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CAS No. : | 120686-00-2 |
Formula : | C12H13NO4 |
M.W : | 235.24 |
SMILES Code : | O=C(C1=C(O)CCC2=C1C=CC(OC)=N2)OC |
MDL No. : | MFCD26406741 |
InChI Key : | OPTRBDFGSOAYQF-UHFFFAOYSA-N |
Pubchem ID : | 54696199 |
GHS Pictogram: | ![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 17 |
Num. arom. heavy atoms | 6 |
Fraction Csp3 | 0.33 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 60.95 |
TPSA ? Topological Polar Surface Area: Calculated from | 68.65 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from | 2.14 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by | 1.76 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from | 1.48 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from | 0.49 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by | 1.72 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions | 1.52 |
Log S (ESOL):? ESOL: Topological method implemented from | -2.47 |
Solubility | 0.796 mg/ml ; 0.00339 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (Ali)? Ali: Topological method implemented from | -2.82 |
Solubility | 0.357 mg/ml ; 0.00152 mol/l |
Class? Solubility class: Log S scale | Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by | -2.74 |
Solubility | 0.427 mg/ml ; 0.00182 mol/l |
Class? Solubility class: Log S scale | Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg | High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg | Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) | No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) | Yes |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) | No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) | No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) | No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) | No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from | -6.49 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from | 0.0 |
Ghose? Ghose filter: implemented from | None |
Veber? Veber (GSK) filter: implemented from | 0.0 |
Egan? Egan (Pharmacia) filter: implemented from | 0.0 |
Muegge? Muegge (Bayer) filter: implemented from | 0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat | 0.56 |
PAINS? Pan Assay Interference Structures: implemented from | 0.0 alert |
Brenk? Structural Alert: implemented from | 0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from | No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) | 2.94 |
* 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 |
---|---|---|
With N,N,N',N'-tetramethylguanidine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of beta-ketoester 10a (1 mmol), 1,1,3,3-tetramethylguanidine (26 muL, 0.2 mmol) in dichloromethane (2.5 mL) was added alpha,beta-unsaturated aldehyde 11a (10 mmol). The reaction mixture was stirred at room temperature for 12 h and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to yield the bridged product 12a. To a solution of the alcohol 12a (0.5 mmol) and trimethylamine (690 muL, 5 mmol) in 2.5 mL of dichloromethane was added dropwise mesyl chloride (154 muL, 2 mmol) and a catalytic amount of DMAP at room temperature. The solution was stirred for 12 h at room temperature, and then diluted with dichloromethane, washed with satd aq NH4Cl, dried and concentrated. The above crude product was dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was heated to reflux for 24 h. After concentration in vacuum, the residue was treated with satd aq NaHCO3, and extracted with ethyl acetate. The combined organic extracts was washed with brine and dried. After concentration in vacuum, the residue was purified by silica gel chromatography to give rac-13a. | |
With N,N,N',N'-tetramethylguanidine; In dichloromethane; at 20℃; for 12h; | rac-4 To a solution of beta-keto ester 2 (0.5 mmol),1,1,3,3-tetramethyl guanidine (13 mL, 0.1 mmol) in dryDCM (2 mL) was added methacrolein 3 (5 mmol). Thereaction mixture was stirred at room temperature for 12 hand then the solvent was removed under vacuum. Theresidue was purified by silica gel chromatography to yieldthe rac-9. To a solution of the alcohol rac-9 (0.25 mmol)and triethylamine (340 muL, 2.5 mmol) in 2 mL of DCMwas added dropwise mesyl chloride (77 muL, 1 mmol) and DMAP (3 mg, 0.025 mmol) at room temperature. Thesolution was stirred for 12 h at room temperature, andthen diluted with DCM, washed with saturated aq NH4Cl,dried and concentrated. The above crude product was dissolvedin HOAc (5 mL), and NaOAc (24 mg, 0.3 mmol)was added. The solution was heated to reflux for 24 h.After concentration in vacuum, the residue was dissolvedin ethyl acetate, was washed with saturated Na2CO3 andbrine, dried over Na2SO4. Evaporation of the ethyl acetateand flash chromatography of the residue (20 % and then40 % ethyl acetate in hexanes) gave 79 mg of rac-4 in 55 %yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; at 85 - 90℃; for 2h;Inert atmosphere; | Sodium hydride (50%, 27.7 g, 1.2 equivalents) and dimethyl carbonate (1,275 ml) were heated to 85-90 C. under nitrogen atmosphere, and the ketone of Formula (4) (85 g, 1.0 equivalent) diluted with dimethyl carbonate (1,275 ml) was added drop wise over a period of 1.5 hours. After addition, the reaction mixture was maintained at the same temperature for approximately 30 minutes. A sample for HPLC showed <1% of the ketone starting material remained. Dimethyl carbonate was then distilled off completely under vacuum at 40-45 C., and the residue was cooled to 10-15 C. Chilled water was added and dissolved completely. The pH was adjusted to 2-3 by adding 5 N HCl (160 ml) and extraction was performed with ethyl acetate (1 time with 340 ml and 2 times with 170 ml). The solvent was distilled off completely to get the crude beta-keto ester of Formula (5). The crude ester was dissolved in 800 ml 5% ethyl acetate:hexane mixture by heating at 60-65 C. The resulting mixture was allowed to cool to ambient temperature (20-25 C.) and filtered through filter paper. The solvent was distilled off completely under vacuum at 40-45 C. The resulting residue was stirred with hexane for 30 minutes at 20-25 C. The product was then collected by filtration and bed washed with portions of hexane. The product was dried under vacuum (740-750 mm/Hg) at 25-30 C. for 2 hours to yield pure product (80.2 g, 71% yield, HPLC purity-98%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a suspension of (2R)-catalyst 8b(18 mg, 0.03 mmol) and benzoic acid (12 mg, 0.1 mmol)and the beta-keto ester 2 (47 mg, 0.2 mmol) in dry DCM(2 mL) was added methacrolein 3 (84 mg, 1.2 mmol) at0 C. The reaction mixture was refluxed for 4 days, then thesolvent was removed under vacuum, the residue was dissolvedin DCM (2 mL), and then DBU (42 muL, 0.3 mmol)was added. The reaction mixture was stirred at room temperaturefor 2 h, and the solvent was removed under vacuum,then ethyl acetate and saturated NaCl were added. Theorganic phase was separated and the aqueous phase wasextracted with ethyl acetate. The combined organic layerswere dried over Na2SO4 and concentrated to give the crudeproduct. Purification of the residue by flash column chromatography(silica gel) eluting with 20 % ethyl acetate in hexanesgave 50 mg of 9 (82 %) as a mixture of diastereomers.1H NMR (400 MHz, CDCl3) (main diastereomer): delta 7.07 (d,J = 8.8 Hz, 1H), 6.62 (d, J = 8.4 Hz, 1H), 3.89 (s, 3 H),3.73 (s, 3 H), 3.70-3.78 (m, 1H), 3.43 (dd, J = 5.2, 17.6 Hz,1H), 3.43 (dd, J = 2.0, 18.0 Hz, 1H), 3.17 (dd, J = 6.8,13.2 Hz, 1H), 2.77-2.80 (m, 1H), 2.18 (brs, 1H), 1.71-1.78(m, 1H), 1.61-1.66 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H); 13CNMR (100 Hz, CDCl3): delta 207.01, 171.77, 163.26, 149.88,138.74, 128.39, 110.45, 80.28, 60.28, 54.66, 53.70, 53.01,41.85, 39.20, 34.56, 17.58; ESI-MS m/z: 306.1 [M + H]+;ESI-HRMS calcd for C16H20NO5+ [M + H]+ 306.1339,found 306.1336 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | A chiral ligand according to Formula (13) (2.13 g, 2 mol %), allyl palladiumchloride dimer (0.56 g, 1 mol %), and acetone (140 ml) were combined and stirred at 20-25 C. for 1 hour under a nitrogen atmosphere. To the mixture was added 2-methylene-1,3-propanediol diacetate (26.2 ml, 1.0 equivalent) and 35 ml of acetone and the new mixture was maintained at the same temperature for 1 hour. A mixture of the purified keto ester of Formula (5) (35 g, 1.0 equivalent), 1,1,3,3-tetramethyl guanidine (42 ml, 2.2 equivalents), and acetone (175 ml) was added to the above solution in lots over a period of 30 minutes at 20-25 C. The resulting mixture was then stirred at the same temperature for 1 hour under a nitrogen atmosphere. A sample for chiral HPLC indicated <1% starting material (keto ester) remained. Acetone was then distilled off under vacuum at 40-45 C. to obtain a crude material. The Crude material was passed through silica gel column and eluted with hexane and ethyl acetate mixtures to remove catalyst and ligand. The fractions containing product were collected and the solvent was distilled completely to yield pure product of the compound of Formula (6) (35 g, 82% yield, HPLC purity of 78%). This crude product (35 g) was stirred with isopropyl alcohol (140 ml) at 20-25 C. for 30 minutes. The obtained solid was filtered and washed with isopropyl alcohol (17.5 ml), and the material was dried under vacuum for 2-3 hours at 35-40 C. to get pure product as a white solid (21 g, 50% yield, HPLC purity of 97.5%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N,N',N'-tetramethylguanidine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of beta-ketoester 10a (1 mmol), 1,1,3,3-tetramethylguanidine (26 muL, 0.2 mmol) in dichloromethane (2.5 mL) was added alpha,beta-unsaturated aldehyde 11a (10 mmol). The reaction mixture was stirred at room temperature for 12 h and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to yield the bridged product 12a. To a solution of the alcohol 12a (0.5 mmol) and trimethylamine (690 muL, 5 mmol) in 2.5 mL of dichloromethane was added dropwise mesyl chloride (154 muL, 2 mmol) and a catalytic amount of DMAP at room temperature. The solution was stirred for 12 h at room temperature, and then diluted with dichloromethane, washed with satd aq NH4Cl, dried and concentrated. The above crude product was dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was heated to reflux for 24 h. After concentration in vacuum, the residue was treated with satd aq NaHCO3, and extracted with ethyl acetate. The combined organic extracts was washed with brine and dried. After concentration in vacuum, the residue was purified by silica gel chromatography to give rac-13a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of beta-ketoester 10a (0.5 mmol), catalyst 8 (0.05 mmol) and PhCOOH (0.05 mmol) in toluene/dichloromethane (1:1, 0.2 M) was added alpha,beta-unsaturated aldehyde 11a (5 mmol). The reaction mixture was stirred at room temperature for the time indicated in tables. The solvent was then removed under vacuum. The residue was dissolved in dichloromethane (2.5 mL), and tetramethylguanidine (20 muL, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 12 h, and the solvent was then removed under vacuum. The residue was submitted to a short silica gel column to remove the catalyst from the bridged product 12a quickly. To a solution of the alcohol 12a, trimethylamine (690 muL, 5 mmol) and a catalytic amount of DMAP in 5 mL of dichloromethane was added dropwise mesyl chloride (154 muL, 2 mmol) at room temperature. The solution was stirred for 12 h at room temperature, and then diluted with dichloromethane. The mixture was washed with satd aq NH4Cl, dried and concentrated. The resulting crude product was dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was heated to reflux for 24 h. After concentration in vacuum, the residue was diluted with satd aq NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried. After concentration in vacuum, the residue was purified by silica gel chromatography to give 13a. The procedure for the gram-scale synthesis was enlarged accordingly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of beta-ketoester 10a (0.5 mmol), catalyst 8 (0.05 mmol) and PhCOOH (0.05 mmol) in toluene/dichloromethane (1:1, 0.2 M) was added alpha,beta-unsaturated aldehyde 11a (5 mmol). The reaction mixture was stirred at room temperature for the time indicated in tables. The solvent was then removed under vacuum. The residue was dissolved in dichloromethane (2.5 mL), and tetramethylguanidine (20 muL, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 12 h, and the solvent was then removed under vacuum. The residue was submitted to a short silica gel column to remove the catalyst from the bridged product 12a quickly. To a solution of the alcohol 12a, trimethylamine (690 muL, 5 mmol) and a catalytic amount of DMAP in 5 mL of dichloromethane was added dropwise mesyl chloride (154 muL, 2 mmol) at room temperature. The solution was stirred for 12 h at room temperature, and then diluted with dichloromethane. The mixture was washed with satd aq NH4Cl, dried and concentrated. The resulting crude product was dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was heated to reflux for 24 h. After concentration in vacuum, the residue was diluted with satd aq NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried. After concentration in vacuum, the residue was purified by silica gel chromatography to give 13a. The procedure for the gram-scale synthesis was enlarged accordingly. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N,N,N',N'-tetramethylguanidine; In dichloromethane; at 20℃; for 12h; | General procedure: To a solution of beta-ketoester 10a (1 mmol), 1,1,3,3-tetramethylguanidine (26 muL, 0.2 mmol) in dichloromethane (2.5 mL) was added alpha,beta-unsaturated aldehyde 11a (10 mmol). The reaction mixture was stirred at room temperature for 12 h and then the solvent was removed under vacuum. The residue was purified by silica gel chromatography to yield the bridged product 12a. To a solution of the alcohol 12a (0.5 mmol) and trimethylamine (690 muL, 5 mmol) in 2.5 mL of dichloromethane was added dropwise mesyl chloride (154 muL, 2 mmol) and a catalytic amount of DMAP at room temperature. The solution was stirred for 12 h at room temperature, and then diluted with dichloromethane, washed with satd aq NH4Cl, dried and concentrated. The above crude product was dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was heated to reflux for 24 h. After concentration in vacuum, the residue was treated with satd aq NaHCO3, and extracted with ethyl acetate. The combined organic extracts was washed with brine and dried. After concentration in vacuum, the residue was purified by silica gel chromatography to give rac-13a. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: To a solution of beta-ketoester 10a (0.5 mmol), catalyst 8 (0.05 mmol) and PhCOOH (0.05 mmol) in toluene/dichloromethane (1:1, 0.2 M) was added alpha,beta-unsaturated aldehyde 11a (5 mmol). The reaction mixture was stirred at room temperature for the time indicated in tables. The solvent was then removed under vacuum. The residue was dissolved in dichloromethane (2.5 mL), and tetramethylguanidine (20 muL, 0.15 mmol) was added. The reaction mixture was stirred at room temperature for 12 h, and the solvent was then removed under vacuum. The residue was submitted to a short silica gel column to remove the catalyst from the bridged product 12a quickly. To a solution of the alcohol 12a, trimethylamine (690 muL, 5 mmol) and a catalytic amount of DMAP in 5 mL of dichloromethane was added dropwise mesyl chloride (154 muL, 2 mmol) at room temperature. The solution was stirred for 12 h at room temperature, and then diluted with dichloromethane. The mixture was washed with satd aq NH4Cl, dried and concentrated. The resulting crude product was dissolved in HOAc (10 mL), and NaOAc (48 mg, 0.6 mmol) was added. The solution was heated to reflux for 24 h. After concentration in vacuum, the residue was diluted with satd aq NaHCO3 and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried. After concentration in vacuum, the residue was purified by silica gel chromatography to give 13a. The procedure for the gram-scale synthesis was enlarged accordingly. |
Tags: 120686-00-2 synthesis path| 120686-00-2 SDS| 120686-00-2 COA| 120686-00-2 purity| 120686-00-2 application| 120686-00-2 NMR| 120686-00-2 COA| 120686-00-2 structure
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P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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