Structure of Methyl 3-Methoxyacrylate
CAS No.: 34846-90-7
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CAS No. : | 34846-90-7 |
Formula : | C5H8O3 |
M.W : | 116.12 |
SMILES Code : | O=C(OC)/C=C/OC |
MDL No. : | MFCD00128206 |
Boiling Point : | No data available |
InChI Key : | AUTCCPQKLPMHDN-ONEGZZNKSA-N |
Pubchem ID : | 5323651 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H227 |
Precautionary Statements: | P501-P210-P264-P280-P302+P352-P370+P378-P337+P313-P305+P351+P338-P362+P364-P332+P313-P403+P235 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.4 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 28.05 |
TPSA ? Topological Polar Surface Area: Calculated from |
35.53 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.86 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.32 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.09 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.16 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.52 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.57 |
Solubility | 31.3 mg/ml ; 0.269 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.64 |
Solubility | 26.6 mg/ml ; 0.229 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.12 |
Solubility | 88.1 mg/ml ; 0.759 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 |
No |
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) |
No |
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 |
-6.77 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 |
1.0 |
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 |
2.0 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) |
2.0 |
* 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 |
---|---|---|
51% | With triethylamine; In dichloromethane; at 20℃; | (Step B-4) Synthesis of methyl 3-(4-chloromethylphenyl)isoxazole-4-carboxylate N-Hydroxy-4-chloromethylbenzenecarboxyimidoyl chloride (15.27 g, 74.82 mmol) was dissolved in dichloromethane (300 ml), methyl 3-methoxyacrylate (10.43 g, 89.82 mmol) was added, and triethylamine (21 ml, 151 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (9.67 g, 51percent). 1H-NMR(300 MHz, CDCl3) delta=3.84(3H, s), 4.63(2H, s), 7.49(2H, d, J=6.9 Hz), 7.70(2H, d, J=6.9 Hz), 9.01(1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | With triethylamine; In dichloromethane; at 20℃; | (Step 4) Synthesis of methyl 3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylate N-Hydroxy-4-(2-chloroethyl)benzenecarboxyimidoyl chloride (2.07 g, 9.48 mmol) was dissolved in dichloromethane (5 ml), methyl 3-methoxyacrylate (1.32 g, 11.37 mmol) was added, and triethylamine (1.92 g, 18.97 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (1.46 g, 58percent). MS(ESI) m/z 266 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With sodium chloride; sodium t-butanolate; In tetrahydrofuran; | Example 3 4-(2-BROMO-PHENYL)-4-CYANO-BUT-3-ENOIC ACID METHYL ESTER A solution of 2-bromo-phenylacetonitrile (6.62 mL, 51.0 mmol) and methyl-3-methoxyacrylate (5.32 mL, 49.5 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium tert-butoxide (5.05 g, 51.0 mmol) in tetrahydrofuran (70 mL) at 0° C. over 10 minutes under a stream of nitrogen. The reaction mixture was warmed to room temperature and after 15 minutes diluted with methyl tert-butyl ether (240 mL). To the mixture was added 0.2 N aqueous citric acid until the aqueous layer had a pH of 2 (80 mL). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (2*80 mL), dried over anhydrous sodium sulfate, filtered through a pad of Celite and silica (4:1) and concentrated in vacuo to provide 4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester as a pale yellow oil (13.8 g, 96percent). Major isomer 1H NMR (400 MHz, CDCl3) delta7.59 (dd, 1H, J =7.6, 1.2), 7.57-719 (m, 3H), 6.71 (t, 1H, J=7.1), 3.71 (s, 3H), 3.61 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) delta169.7, 144.4, 133.7, 131.4, 131.1, 128.3, 122.5, 118.1, 117.3, 115.3, 52.7, 36.6; IR (ATR, neat) 1737, 1434, 1319, 1199, 1171, 1026, 755 cm-1. Minor isomer 1H NMR (400 MHz, CDCl3) delta7.61 (dd, 1H, J=7.6, 1.0), 7.57-7.19 (m, 3H), 6.9 (t,1H, J=7.5), 3.64 (s, 3H), 3.06 (d, 2H, J=7.5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium methylate; sodium hydrogencarbonate; In water; | EXAMPLE 2 The toluene solution of 3-mercapto-2-butanone from the previous step (613 g of ca. 25 wt percent solution) was placed in a clean, dry reactor along with 15 g of methyl-3-methoxyacrylate. The mixture was warmed to 25° C., stirred vigorously, and treated with solid sodium methoxide (8.5 g, ca. 0.1 equiv.) all at once. The remaining methyl-3-methoxyacrylate (151 g) was added in at a rate to keep the temperature at or below 35° C. (2 h). The resulting mixture was allowed to reach room temperature and stir for 21 h. Concentrated hydrochloric acid (88 g) was added to the mixture over 30 min such that the temperature did not exceed 35° C. The resulting mixture was stirred vigorously for 2 h, then treated with 73 g of water, and stirred for 10 min more. The phases were allowed to separate. After standing for 10 min, the aqueous phase was drained from the reactor, and the upper, product phase was washed with 100 g of 5percent sodium bicarbonate solution. After being stirred for 15 min, the phases were allowed to separate. The lower, aqueous phase was drained from the reactor, and the upper, product phase was transferred to a distilling flask. The toluene was distilled through a 5-plate distillation column at 100 mmHg. After a small fraction containing toluene and other low boiling impurities was collected, the product, 3-carbomethoxy-4,5-dimethylthiophene, was distilled through the column at 50 mmHg. | |
With hydrogenchloride; sodium methylate; sodium hydrogencarbonate; In water; | Example 2 The toluene solution of 3-mercapto-2-butanone from the previous step (613 g of ca. 25 wtpercent solution) was placed in a clean, dry reactor along with 15 g of methyl-3-methoxyacrylate. The mixture was warmed to 25°C, stirred vigorously, and treated with solid sodium methoxide (8.5 g, ca. 0.1 equiv.) all at once. The remaining methyl-3-methoxyacrylate (151 g) was added in at a rate to keep the temperature at or below 35°C (2 h). The resulting mixture was allowed to reach room temperature and stir for 21 h. Concentrated hydrochloric acid (88 g) was added to the mixture over 30 min such that the temperature did not exceed 35°C. The resulting mixture was stirred vigorously for 2 h, then treated with 73 g of water, and stirred for 10 min more. The phases were allowed to separate. After standing for 10 min, the aqueous phase was drained from the reactor, and the upper, product phase was washed with 100 g of 5percent sodium bicarbonate solution. After being stirred for 15 min, the phases were allowed to separate. The lower, aqueous phase was drained from the reactor, and the upper. product phase was transferred to a distilling flask. The toluene was distilled through a 5-plate distillation column at 13.3 kPa [100 mmHg]. After a small fraction containing toluene and other low boiling impurities was collected, the product, 3-carbomethoxy-4,5-dimethylthiophene, was distilled through the column at 6.665 kPa [150 mmHg]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-iodo-succinimide; acetic acid; triethylamine; In di-isopropyl ether; | Preparation 1 methyl 2-iodo 3-methoxy 2-propenoate A solution containing 12.95 g of methyl 3-methoxy 2-propenoate and 50 ml ofacetic acid is introduced into a solution containing 37 g of N-iodosuccinimide and 150 ml of acetic acid. The reaction medium is agitated for 4 hours at ambient temperature. It is concentrated under reduced pressure and taken up in isopropyl ether. Filtration and rinsing with isopropyl ether are carried out. After concentrating and taking up inmethylene chloride, a sufficient quantity of triethylamine is added to ensure the conversion to the acrylic derivative. After washing, drying andconcentrating, an oil is obtained which crystallizes spontaneously at ambient temperature. The crystals obtained are recrystallized from isopropanol. 17 g of desired product is obtained melting at 50.9° C. | |
30.5 g | A mixture of methyl-3-methoxypropenoate, 37-f, (13.92 g, 120 mmol), N- iodosuccinimid (32g, 140mmol), glacial acetic acid (18 mL, 240 mmol), and dichloromethane(150 mL) was stirred at room temperature for 24h. Triethylamine (50 mL, 36 mmol) was added, and the reaction mixture was stirred at room temperature for 12h before water was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and water, and were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (PE:EA=1 :5) to afford compound, 37-g (30.5 g, crude) . 1H NMR (300 MHz, CDCI3) delta 7.69 (s, 1H), 4.01 (s, 3H), 3.80 (s, 3H); LC-MS (ESI): 243 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | In methanol; at 0℃; for 4.66667h;Heating / reflux; | 3-Methoxyacrylic acid methyl ester (4 g, 34.45 mmol) was dissolved in methanol (50 ml) and cooled to O0C. Methyl hydrazine (1.75 g, 37.9 mmol) in methanol (20ml) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 10 minutes then heated to reflux for 4 hours. The reaction was then concentrated and purified by silica gel column chromatography eluted with ethyl acetate/methanol = 100/0 to 80/20 to recover the title product as a white solid (2.5 g, 73% yield). 1H NMR (400 MHz, DMSO-de) delta 3.463.47(3H s) 5.28-5.29(1H d) 7.06-7.08(1 H d) 10.75-10.81(1H bs) |
In methanol; for 8h;Reflux; Inert atmosphere; | A magnetically stirred solution of methyl 3-methoxyacrylate (20.0g, 172.2mmol) in methanol (100mL) was treated slowly with N-methylhydrazine (10.0mL, 189.4mmol) then heated at reflux for 8h. The resulting mixture was cooled to room temperature then concentrated under a stream of nitrogen followed by high vacuum pump to afford an orange solid that was dissolved in DMF (19.9mL, 258.4mmol) and cooled to 0C. The resulting mixture was treated dropwise with phosphoryl chloride (48.1mL, 516.6mmol) then heated at 80C for 12h before being cooled and neutralised via the slow addition of ice cold NaOH (10M, 300mL). The aqueous solution was then extracted with a dichloromethane/isopropanol mixture (9:1, 5×100mL) and the combined organic phases were washed with chilled water (3x100mL), brine (1×100mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to afford an orange solid. Recrystallisation (dichloromethane/hexane) afforded the title pyrazole 8 (16.31g, 66%) as yellow crystals | |
In methanol; water; for 2h;Cooling with ice; | To a 1000 mL four-necked flask was placed 170 g of methanol under ice-water bath.At the same time, 116 g of methyl 3-methoxyacrylate and 262.8 g (35%) of an aqueous methylhydrazine solution were added dropwise to the flask.After the addition was completed, the reaction was continued for 2 hours.After the reaction was completed, methanol, water and methylhydrazine were distilled off under reduced pressure.That is, the product 1-methyl-5-hydroxypyrazole. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Montmorillonite K10; at 0℃;Product distribution / selectivity; | Example 1: Preparation of methyl 3,3-dimethoxypropionate Simultaneously, but separately, 150 kg/h (1.413 kmol/h) of trimethyl ortho formate (Fluka), comprising 1.5percent by weight of montmorillonite KlO (Sd-Chemie), and 84 kg/h of ketene (ketene content about 70percent, remainder inert gases, such as N2, CO and CO2, i.e. neat ketene about 59 kg/h, that is about 1.4 kmol/h) were fed into a 620 L jet reactor (see figure 1), which had been inertized and cooled to an internal temperature of 0 0C. Under an atmosphere of nitrogen, the reaction mixture was kept at a temperature of about 0 °C and circulated in the loop via a circulating pump. Corresponding to the amount of starting materials added, and also continuously, a corresponding part of the reaction mixture flowed over into a collecting tank. After filtration, the purity of the filtrate was determined by GC as 80percent methyl 3,3-dimethoxypropionate, 8percent unreacted trimethyl orthoformate, 4percent methyl 3-methoxyprop-2-enoate and 4percent methyl acetate.By virtue of its low boiling point, it was easy to remove trimethyl orthoformate by distillation. The recovered starting material was subsequently re-cycled into the reaction mixture. <n="9"/>The yield of methyl 3,3-dimethoxypropionate was 82percent (based on conversion). |
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