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CAS No. : | 13865-20-8 | MDL No. : | MFCD00082184 |
Formula : | C6H10O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XFKYUMYFILZJGG-UHFFFAOYSA-N |
M.W : | 130.14 | Pubchem ID : | 11137194 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 32.18 |
TPSA : | 43.37 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.61 cm/s |
Log Po/w (iLOGP) : | 1.45 |
Log Po/w (XLOGP3) : | 0.68 |
Log Po/w (WLOGP) : | 0.38 |
Log Po/w (MLOGP) : | 0.28 |
Log Po/w (SILICOS-IT) : | 0.56 |
Consensus Log Po/w : | 0.67 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.88 |
Solubility : | 17.3 mg/ml ; 0.133 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 8.85 mg/ml ; 0.068 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.69 |
Solubility : | 26.5 mg/ml ; 0.204 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 2.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.1 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | 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 |
---|---|---|
55% | Stage #1: at 130℃; Stage #2: With hydroxylamine hydrochloride In water at 40 - 130℃; for 12 h; |
Next, an internal volume of 100 ml equipped with a thermometer, cooling tube and receiver Was charged with 30 ml of the above reaction solution. Next, 1000 ppm of sodium hydroxide was added to the mass of the reaction solution, The reaction pressure was adjusted to 13 kPa and the reaction temperature to 130 ° C., The reaction was carried out while distilling off the methanol formed. 1.5 hours after the start of the reaction, the reaction solution in the flask was subjected to gas chromatography As a result of analyzing by analysis, the conversion of methyl 4-hydroxy-2-methylbutyrate was 95.6percent, and the selectivity to α-methyl-γ-butyrolactone was 98percent. At this time, methyl 3-formyl-2-methylpropionate and Methyl 2-formyl-2-methylpropionate The combined concentration was 1.6 wtpercent (0.04 mmol). (Example 1) 20 ml of the reaction solution obtained in the cyclization step (C) of Production Example 1 was charged in a 100 ml three-necked flask equipped with a thermometer, a cooling tube and a receiver, and 9 mg of hydroxylamine hydrochloride dissolved in 5 ml of distilled water ( 0.16 mmol), and the mixture was stirred at 40 ° C. for 12 hours. Distillation was performed on the obtained reaction liquid using a 10-stage distillation column at a heat medium temperature of 130 ° C., a reflux ratio of 30, and a reduced pressure degree of 1.3 kPa. as a result, Α-methyl-γ-butyrolactone having a purity of not less than 99.9percent It can be obtained with a distillation yield of 55percent Methyl 3-formyl-2-methylpropionate and 2- The combined content of methyl formyl-2-methylpropionate is It was 10 ppm or less, which was below the detection limit |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With sulfur trioxide pyridine complex; triethylamine In dichloromethane; dimethyl sulfoxide at 20℃; for 22 h; | To an ice-cooled (0°C) solution of methyl 3-hydroxy-2,2-dimethylpropanoate (1.45 ml, 1 1 .35 mmol) and TEA (4.75 ml, 34.05 mmol) in DCM (45 ml) and DMSO (8 ml, 1 13.5 mmol) was added pyridine sulfur trioxide complex (5.42 g, 34.05 mmol). The resulting mixture was stirred at room temperature for 22 h. The reaction was quenched with saturated NH4CI (30 ml). The layers were separated and the aqueous layer was extracted with DCM (40 ml). The organic layer was washed sequentialy with 2M HCI (2 x 20 ml) and brine (15 ml), dried (MgS04), filtered and evaporated to give the title compound (0.35 g, 99percent) as an orange oil. 1 H-NMR (CDCI3, 250 MHz): d[ppm]= 9.66 (s, 1 H), 5.30 (s, 1 H), 3.75 (s, 3H), 1 .35 (s, 6H) |
88% | Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -78℃; for 0.416667 h; Stage #2: With triethylamine In dichloromethane at 20℃; Reflux |
00319] Synthesis of compound 61[00320] Preparation of compound 61b [00321] A mixture of oxalyl dichloride (11.5 g, 87 mmol) in CH2C12 (180 mL) was cooled down to -78°C, then DMSO (8.9 g, 113 mmol) in CH2C12 (40 mL) was added dropwise over 10 minutes, followed by adding a solution of alcohol 61a (lOg) in 40 mL of CH2C12. After addition, the mixture was stirred for 15 minutes at -78°C. Et3N (52 mL, 378 mmol) was added dropwise and warmed to r.t. The reaction was quenched with water (200mL) and extracted with EA (100 mLx2). Dried and removed the solvent to afford the pure product 61b (8.8 g, 88percent) as an oil |
83% | Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at -60℃; for 0.416667 h; Stage #2: With triethylamine In dichloromethane at -50 - 20℃; for 0.0833333 h; |
[1071] A first intermediate compound, 3-[6-Chloro-2-(2,2-dimethyl-propionylamino)-pyridin-3-yl]-3-hydroxy-2,2-dimethyl-propionic acid methyl ester, was produced as follows: To a stirred solution of oxalyl chloride (11.0 g, 87.0 mmol) in CH2Cl2 (180 mL) at -60° C. was added a solution of DMSO (12.9 mL, 182 mmol) in CH2Cl2 (40 mL), dropwise at a rapid rate. The resulting solution was stirred for 5 min, then a solution of methyl-2,2-dimethyl-3-hydroxypropionate (10.0 g, 75.6 mmol) in CH2Cl2 (10 mL) was added dropwise over 10 min. The cloudy mixture was then stirred for 15 min, at which time triethylamine (52 mL, 380 mmol) was added dropwise, maintaining the temperature at or below -50° C. After stirring for 5 min, the mixture was allowed to warm to room temperature and water (200 mL) was then added. The layers were separated and the aqueous layer extracted with CH2Cl2 (2.x.100 mL). The combined organic layers were washed successively with 1 M HCl (100 mL), water (100 mL), saturated NaHCO3 solution (100 mL), water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated in vacuo until only a small volume of CH2Cl2 remained, to minimize the loss of the volatile product. The crude product was purified by vacuum distillation affording the desired product 2,2-dimethyl-3-oxopropionic acid methyl ester (8.1 g, 83percent, 89° C., ca 80 mmHg). 1H NMR (CDCl3) δ 9.67 (s, 1H), 3.76 (s, 3H), 1.36 (s, 6H). |
83% | With Dess-Martin periodane In dichloromethane at 0 - 20℃; for 18 h; | To a solution of methyl 3-hydroxy-2,2-dimethylpropanoate (8.0 g, 61 mmol) in dryDCM (150 mL) was added Dess-Martin Periodinane (39 g, 91 mmol) at 0 °C and themixture was stirred at rt for 18 hrs. The precipitate was filtered through a celite pad, and the filtrate was concentrated. The resulting residue was dissolved in a minimum amount of Et2O (10 mL) and cooled to 0 °C (to precipitate more benzoic acid) and decanted. The solution was concentrated in vacuo. The crude residue was purified by chromatographythru a SiO2 column using the mobile phase of 11 percent EtOAc in petroleum ether to afford the title compound as a colorless oil (6.5 g, 50 mmol, 83 percent yield). 1HNMR (400 MHz, CDCl3): δ ppm 9.66 (s, 1H), 3.75 (s, 3H), 1.35 (s, 6H). |
80% | With 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical; trichloroisocyanuric acid In dichloromethane at 0 - 20℃; for 1.25 h; Cooling with ice | Preparation 8Methyl 2,2-dimeth l-3-oxo-propanoateMethyl 3-hydroxy-2,2-dimethyl-propanoate (52.4 g, 396.49 mmol) is dissolved in dichloromethane (495 mL) and the mixture is cooled in an ice-water bath. Trichloroisocyanuric acid (101.36 g, 436.14 mmol) is added portionwise, followed by 2,2,6,6-tetramethylpiperidine-N-oxide (6.20 g, 39.65 mmol). The mixture is stirred at 0 °C for 15 min and then allowed to warm to RT and stirred for an additional 60 min. The solid is then filtered through CELITE.(R). and rinsed with dichloromethane (300 mL). The filtrate is washed with a saturated solution of a2C03 in water. The organic phase is dried over Na2S04, filtered, and concentrated under reduced pressure to afford the title compound (41.24 g, 80percent) as a greenish oil. The product is used without further purification in the next reaction step. XH NMR(400 MHz, CDC13); δ 1.34 (6H, s), 1.34 (6H, s), 3.74 (3H, s), 9.64 (1H, s). |
66% | With sulfur trioxide pyridine complex; dimethyl sulfoxide; triethylamine In dichloromethane for 1.5 h; Cooling with ice | Example 11 3-{4-[4-(5-acetylamino-2-methoxypyridin-4-ylamino)phenyl]piperazin-1-yl}-2,2-dimethylpropionic acid (11a) methyl 2,2-dimethyl-3-oxopropionate Methyl 3-hydroxy-2,2-dimethylpropionate (10.0 g, 75.7 mmol) was dissolved in methylene chloride (100 mL) and, under ice-cooling, dimethyl sulfoxide (16.1 mL, 227 mmol), triethylamine (15.8 mL, 114 mmol) and sulfur trioxide-pyridine complex (18.1 g, 114 mmol) were added and the mixture was stirred at the same temperature for 1.5 hr. The reaction mixture was washed with 5percent citric acid water and water, and dried over anhydrous sodium sulfate. Under reduced pressure (400 mmHg), the solvent was evaporated to give the title object compound as a colorless oil (10.1 g, P=64percent, yield 66percent). |
48% | With pyridinium chlorochromate In dichloromethane at 0 - 20℃; for 24 h; | Example 2; Preparation of 2,2-Dimethyl-3-oxo-propionic Acid Methyl Ester; 3-Hydroxy-2,2- dimethyl-propionic acid methyl ester (15 g, 113 mmol) in 200 mL dichloromethane was cooled to 0°C. Pyridinium chlorochromate (43 g, 200 mmol) was added. The mixture was slowly warmed to room temperature and stirred 24 h. The crude in dichloromethane was filtered through silica gel. Celite was added to the remaining black viscous oil from the reaction mixture until the viscous oil is all absorbed to the celite. Dichloromethane was added to this slurry and the dichloromethane solution was filtered through silica gel. Dichloromethane was removed at reduced pressure (80 Torr) to give a pale yellow crude. Distillation removed residue dichloromethane and obtained 2,2-dimethyl- 3-oxo-propionic acid methyl ester as a colorless oil (7 g, 48percent yield). 1H NMR (300 MHz, CDCl3, δ): 9.60 (s5 IH); 3.70 (s> 3H); 1.29 (s, 6H). 13C NMR (75 MHz, CDCl3, δ): 199.1, 173.2, 53.9, 52.6, 19.7. IR (NaCl, thin film): 2988, 2958, 1726, 1468, 1278, 1151, 866. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81 %Chromat. | With dicarbonylacetylacetonato rhodium(I); 3,3'-(methoxyphosphanediyl)bis(N,N-diethylaniline); hydrogen In toluene at 100℃; for 16 h; Autoclave; Glovebox; Inert atmosphere | General procedure: In a typical hydroformylation experiment a stainless steelautoclave (450 mL) equipped with pressure regulator and asafety valve was used. Individual vials were charged withmetal precursor [Rh(acac)(CO)2] (2 mg)}, ligand (as inTables 1 and 2), solvent (1 mL), substrate (100 equiv.) andstirring bars in a glove box. The vials were transferred to autoclaveand the autoclave was purged three times with syngas(CO: H2 = 1:1) before pressurizing it to the desired pressure.Suitable temperature and pressure were maintained duringthe reaction. After completion of the reaction, the autoclavewas cooled to 0C, and excess gas was vented off in a wellventilatedfume-hood. The conversion and regio-selectivitieswere determined by proton NMR spectroscopy and gas chromatography. |
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