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CAS No. : | 517-23-7 | MDL No. : | MFCD00005394 |
Formula : | C6H8O3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OMQHDIHZSDEIFH-UHFFFAOYSA-N |
M.W : | 128.13 | Pubchem ID : | 10601 |
Synonyms : |
|
Num. heavy atoms : | 9 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 30.33 |
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) : | -6.99 cm/s |
Log Po/w (iLOGP) : | 0.8 |
Log Po/w (XLOGP3) : | 0.13 |
Log Po/w (WLOGP) : | 0.14 |
Log Po/w (MLOGP) : | -0.11 |
Log Po/w (SILICOS-IT) : | 1.11 |
Consensus Log Po/w : | 0.41 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.65 |
Solubility : | 28.7 mg/ml ; 0.224 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.6 |
Solubility : | 32.4 mg/ml ; 0.253 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.68 |
Solubility : | 26.5 mg/ml ; 0.207 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.03 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-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 |
---|---|---|
40.4% | With triethylamine In methanol at 5 - 95℃; for 2.15 - 5 h; | Example 2: At 5 °C, a solution of MAA (46.9 g 0.40 mol) in MeOH (144.0 g) was treated with EO (25.0 g, 1.4 eq.) and then with triethylamine (TEA, 40.7 g, 1.0 eq.). The reaction mixture was heated to 60 °C within 0.5 h and kept at this temperature for 2.5 h. Quantitative GC analysis indicated that 50.8percent of MAA had been transformed into ABL with a selectivity of 72.9percent. Example 4: At 5 °C, a solution of MAA (47.0 g, 0.40 mol) in MeOH (144 g) was treated with EO (35.3 g, 2.0 eq.) and then with triethylamine (TEA) (42.4 g, 1.0 eq.). The reaction mixture was heated to 60 °C within 0.5 h and kept at this temperature for 4.5 h. Quantitative GC analysis indicated that 67.7percent of MAA had been transformed into ABL with a selectivity of 75.0percent. Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1. Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent. Example 28: Example of best mode of a series of reactions with TEA as compound of formula IV: 37 g MeOH were placed in a 250 mL autoclave, pressurized with 2-3 bar nitrogen gas and heated. After reaching 65 °C solution of MMA (39.9 g, 0.34 mol, 1 eq.) and TEA (34.4 g, 0.34 mol, 1 eq.) in methanol (27. g) and EO (30.1 g, 0.68 mol, 2 eq.) were simultaneously fed using two pumps within 11 min. After 2 h additional reaction time ABL was formed (GC analysis) with a selectivity of 77percent, corresponding to 52.3percent based on added MMA. Covered ranges in the series, carried out analogously: Temperature: 65 to 95 °CAddition time: 9 to 13 min.MMA added based on totally added solvent: 1.3 to 2.1 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.7 to 1.3EO/MMA molar ratio added to the reaction mixture: 1.7 to 2.2 Results within the series of Example 28: MMA conversion: 65.6 to 85.0percentSelectivity of ABL formation: 47.5 to 77.4percentABL yield based on MAA: 40.4 to 52.3percent |
30.8% | With N,N,N',N'-tetramethylguanidine In methanol at 5 - 65℃; for 1.15 - 6.18333 h; | Example 1: At 5 °C, a solution of methyl acetoacetate (MAA, 46.7 g, 0.40 mol) in methanol (MeOH, 144.0 g) was treated with ethylene oxide (EO, 17.5 g, 1.0 eq.) and then with 1,1,3,3-tetramethylguanidine (TMG, 46.1 g, 1.0 eq.). The reaction mixture was heated to 40 °C within 0.5 h and kept at this temperature for 4.5 h. Quantitative GC analysis indicated that 53.7percent of MAA had been transformed into α-acetylbutyrolactone (ABL) with a selectivity of 75.2percent. Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1.Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent. Example 29: Example of best mode of a series of reactions with TMG as compound of formula IV: 37 g MeOH were placed in a 250 mL autoclave, pressurized with 2-3 bar nitrogen gas and heated. After reaching 45 °C solution of MMA (35.2 g, 0.30 mol, 1 eq.) and TMG (41.5 g, 0.36 mol, 1.2 eq.) in methanol (27. g) and EO (16.3 g, 0.37 mol, 1.2 eq.) were simultaneously fed using two pumps within 10 min. After 6 h additional reaction time ABL was formed (GC analysis) with a selectivity of 60.4percent, corresponding to 46.0percent total yield based on added MMA. Covered ranges in the series, carried out analogously: Temperature: 45 to 65 °CAddition time: 9 to 11 min.MMA added based on totally added solvent: 1.5 to 1.9 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.8 to 1.2EO/MMA molar ratio added to the reaction mixture: 0.8 to 1.2 Results within the series of Example 29: MMA conversion: 39.5 to 65.0percentSelectivity of ABL formation: 63.8 to 81.2percentABL yield based on MAA: 30.8 to 46.0percent |
30.3% | With trimethylamine In methanol at 60 - 90℃; for 1.3 - 4 h; | Examples 7-27: The process of example 1, by using an EO amount, optionally a catalyst at an amount as described in Table 1, and an additive at an amount as described in Table 1, and a reaction time as described in Table 1. Turnover and selectivity as described in Table 1. Table 1: Examples 7-27: Example EO [eq] Catalyst Catalyst [eq] Additive Additive [eq] t [h] Turnover [percent] Sel. [percent] 7 1 TMG 1 --- --- 1 44.7 76.8 8 1 TMG 1BF3*OEt2 0-1 5 46.3 66 9 1 TMG 1Ti(OiPr)4 0.1 5 36.4 59.1 10 1 TMG 1BF3*OEt2 0.1 3 37 75.1 11 1 TMG 1Ti(OiPr)4 0.1 3 42.4 60.6 12 2 TMG 1BF3*OEt2 0.1 5 82.4 41.9 13 2 TMG 1Ti(OiPr)4 0.1 5 76 38.2 14 1 Mim 1 --- --- 5 39.4 57.7 15 2 Mim 1 --- --- 2 43.9 66.2 16 1 DMAP 0.2 --- --- 3 35 48.9 17 1Dec2MeN 1 --- --- 1 21.9 67.9 18 2Dec2MeN 1 --- -- 2 62.9 71.7 19 1Oct2MeN 1 --- --- 1 18 84.2 20 1 TMA 1 --- --- 4 6.6 39 21 2 TMA 1 --- --- 4 62.8 71.2 22 1 TMA 1 --- --- 2 7 87.5 23 2 TMA 1 --- --- 2 48.7 79.7 24 1 TEA 0.2 --- --- 4 27.4 58.6 25 1 Pyridin 0.99 --- --- 1 42.4 41.4 26 1 NMePip 1 --- --- 4 18.4 65.1 27 1 NMeMorph 1 --- --- 4 27.4 83.0 All reactions of examples 7 to 26 reacting 0.40 eq. MMA with the indicated amount EO have been carried out at 60 °C with 11 1 eq. MeOH as solvent. Examples 27 and 28 have been carried out with 0.10 eq. MMA with 1 eq. EO at 60 °C with 11 eq. MeOH as solvent. Example 30: Example of best mode of a series of reactions with TMA as compound of formula IV using a microreactor: A solution A was prepared consisting of MMA (44.6 g, 0.384 mol, 1.0 eq.), TMA (16.8 g, 0.284 mol, 0.74 eq.) and MeOH (81.3 g). 30.6 g/h EO (0.695 mol/h, 1.495 eq.) and 172.8 g/h of solution A (0.465 mol/h MMA) were simultaneously fed using two pumps to a microreactor adjusted to 90 °C, said microreactor having 9.8 mL internal volume, and is acting as mixing and reaction zone. The residence time of the reaction mixture in the microreactor under the current flows was about 2.5 min. After passing through the microreactor the reaction mixture was collected in an autoclave, containing 250 mL MeOH at 60 °C and 2-3 bar under nitrogen gas. After about 1.3 h additional reaction time in the autoclave ABL was formed (GC analysis) with a selectivity of 74.8percent, corresponding to a total yield of 34.8percent based on added MMA, or yield of 61.9percent based on added TMA. 46.6percent MMA has been converted to ABL. Covered ranges in the series, carried out analogously: Temperature of the microreactor: 73 to 107 °CTemperature of the autoclave: 43 to 77 °CDosage rate Solution A: 48.7 to 172 g/hDosage rate EO: 8.6 to 30.6 g/hMMA added based solvent injected to the microreactor: 1.9 mol/LTEA/MMA molar ratio added to the reaction mixture: 0.75EO/MMA molar ratio added to the reaction mixture: 1.5 Results within the series of Example 30: MMA conversion: 38.7 to 66.3percentSelectivity of ABL formation: 50.5 to 78.3percentABL yield based on MAA: 30.3 to 39.7percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | at 75℃; for 10 h; Reflux | (1) The reactor slow heating to 75 °C, adding γ - butyrolactone, ethyl acetate and sodium ethoxide, reflux reaction 10 h after, shall be α - acetyl - γ - butyrolactone sodium salt and the by-product ethanol, wherein γ - butyrolactone and ethyl acetate increase mole ratio of 1:4, γ - butyrolactone and sodium ethoxide in a molar ratio of 1: 1.4;(2) Step (1) the resultant product distillation, to remove the excess of ethanol and ethyl acetate, the residue is dissolved in dilute sulfuric acid to adjust the pH to 4, standing minute fluid minute to the aqueous phase, the organic phase in the pressure is -0.1 mpa, temperature is 70 °C under the condition of reduced pressure distillation shall be α - acetyl γ - butyrolactone. |
83% | Stage #1: at 50 - 100℃; for 5 h; Autoclave Stage #2: at -5 - 5℃; for 5 h; |
100 g of ethyl acetate was added to a 500 ml reaction flask, and after warming to 50 ° C, 80 g of solid sodium methoxide was added simultaneously.The mixture was mixed with 86 g of ethyl acetate and 100 g of γ-butyrolactone, and the temperature of the system was maintained at 50 ° C, and the addition was completed within 2 hours. After the addition of the material, stirring was continued rapidly for 1 h at 60 °C. Discharge, the above liquid material is added to a 500ml autoclave, high pressure reaction at 100 ° C for 2h, the pressure gauge shows a small pressure, the pressure range is 0.1-1MPa, the reaction is completed, cooling, discharge, using 20g ethyl acetate wash reaction The kettle and the washing liquid were combined into the reaction liquid and used. The above materials were transferred to a 500 ml reaction flask, distilled under reduced pressure at 60 ° C (vacuum degree 0.09 MPa - 0.1 MPa), and concentrated to near dryness. The precipitated solid was a solid of α-acetyl-γ-butyrolactone sodium salt.The material was washed with 280 ml of ethyl acetate in a solid of α-acetyl-γ-butyrolactone sodium salt, filtered, and washed twice.Adding 260 ml of ethyl acetate to the above α-acetyl-γ-butyrolactone sodium salt solid.Cooling, temperature control at -5-5 °C, withThe 70percent ethyl acetate solution was adjusted to pH 6-7, stirred for 5 hours, filtered, and the filter cake was washed with 20 ml of ethyl acetate. The filtrate was transferred to a 500 ml single-mouth bottle and distilled under reduced pressure at 70 ° C (vacuum degree 0.09 MPa - 0.1 MPa). After the low-boiling substance was distilled, the concentrated liquid in the bottle was further heated to 95 ° C under reduced pressure (vacuum degree). ≤ 50 Pa), 104.7 g of α-acetyl-γ-butyrolactone was obtained, and the purity was 98.7percent, and the yield was 83.0percent by gas chromatography. |
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