Structure of Ethyl 4,4-difluoroacetoacetate
CAS No.: 352-24-9
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 352-24-9 |
Formula : | C6H8F2O3 |
M.W : | 166.12 |
SMILES Code : | O=C(OCC)CC(C(F)F)=O |
MDL No. : | MFCD00039277 |
InChI Key : | CBDPWKVOPADMJC-UHFFFAOYSA-N |
Pubchem ID : | 67697 |
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 | 11 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.67 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 32.54 |
TPSA ? Topological Polar Surface Area: Calculated from |
43.37 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.31 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.1 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.61 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.64 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.36 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.2 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.23 |
Solubility | 9.72 mg/ml ; 0.0585 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.6 |
Solubility | 4.14 mg/ml ; 0.0249 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.31 |
Solubility | 8.06 mg/ml ; 0.0485 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) |
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 |
-6.53 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 |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
1.0 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) |
1.77 |
* 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 |
---|---|---|
65% | With ammonium acetate; In methanol; | (A) Preparation of: Ethyl 4,4-difluoro 3-amino-2-butenoate STR44 Ammonium acetate (62 g, 805 mM) is added at room temperature to a solution of ethyl 4,4-difluoro acetoacetate (7.400 g, 44.5 mM) in anhydrous methanol (120 ml). Stirring is continued at room temperature for 40 hours; the mixture is then poured into 5% sodium bicarbonate solution (200 ml), and extracted with ether (2*150 ml). The organic layer is dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuo, yielding the expected compound as a yellowish oil. 4.700 g (yield 65%). IR (CHCl3): 3500, 1680, 1640 cm-1. NMR (CDCl3) 1.27 (t,JHH =7 Hz, 3H); 4.14 (q, JHH =7 Hz, 2H); 4.83 (s, broad, 1H); 5.95 (t, JHF =55 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
12%; 57% | In water; at 20℃; for 24h;pH 5.9; | General procedure: To a solution of the appropriate amino ester hydrochloride 2a?g (3.0 mmol) in acetate buffer (pH 5.9) (0.9 mL) ethyl 4,4-difluoro-3-oxobutanoate 4a (1.5 mmol) and formaldehyde 33percent aqueous solution (22.5 mmol) were added. The resulting mixture was stirred for 24 h at room temperature, then it was extracted with CH2Cl2 (3 x 10 mL) and the combined organic layers were dried over Na2SO4 and evaporated in vacuo. The product was purified by column chromatography on Kieselgel 60 (dichloromethane ?ethyl acetate 10:0?7:3 or hexane?ethyl acetate 10:0?7:3). In the case of amino esters hydrochlorides 2a and L-2b only nonfluoratedhexahydropyrimidines 5a and 5b were isolated in yields 71 and 65percent respectively. Their physico-chemical properties coincided with the previously described. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With polyphosphoric acid; at 120℃; for 6.0h; | To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric add (10 mL) was added ethyl 4,4-difiuoroacetoacetate (2.74 ml). The mixture was heated to 120 “C for 6 hours. While hot, the reaction mixture was then slowly added into a stirred saturated NaHCCb solution (200 mL). Once the pH~7, the aqueous layer was extracted with chloroformdPA (4:1). The organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified using aTeledyne SCO Combi-Flash system (liquid loading with DCM, 120G column, 0 - 40% EtOAc/DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1H NMR (400 MHz, CDCb) 6 6.90 (s, 1H), 6.48 (t, J = 54.9 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). E5-MS [M+l]+: 260. |
39% | With polyphosphoric acid; at 120℃; for 6.0h; | To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric add (10 mL) was added ethyl 4,4-difiuoroacetoacetate (2.74 ml). The mixture was heated to 120 “C for 6 hours. While hot, the reaction mixture was then slowly added into a stirred saturated NaHCCb solution (200 mL). Once the pH~7, the aqueous layer was extracted with chloroformdPA (4:1). The organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified using aTeledyne SCO Combi-Flash system (liquid loading with DCM, 120G column, 0 - 40% EtOAc/DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1H NMR (400 MHz, CDCb) 6 6.90 (s, 1H), 6.48 (t, J = 54.9 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). E5-MS [M+l]+: 260. |
39% | With polyphosphoric acid; at 120℃; for 6.0h; | To a solution of 6-choro-3-amino-4,5-dimethylpyridazine (1.65 g) in polyphosphoric add (10 mL) was added ethyl 4,4-difiuoroacetoacetate (2.74 ml). The mixture was heated to 120 “C for 6 hours. While hot, the reaction mixture was then slowly added into a stirred saturated NaHCCb solution (200 mL). Once the pH~7, the aqueous layer was extracted with chloroformdPA (4:1). The organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The crude product was purified using aTeledyne SCO Combi-Flash system (liquid loading with DCM, 120G column, 0 - 40% EtOAc/DCM, 15 min run) to afford the title compound (1.05 g, 39% yield) as a solid. 1H NMR (400 MHz, CDCb) 6 6.90 (s, 1H), 6.48 (t, J = 54.9 Hz, 1H), 2.64 (s, 3H), 2.53 (s, 3H). E5-MS [M+l]+: 260. |
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