Structure of Methyl potassium malonate
CAS No.: 38330-80-2
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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. : | 38330-80-2 |
Formula : | C4H5KO4 |
M.W : | 156.18 |
SMILES Code : | O=C([O-])CC(OC)=O.[K+] |
MDL No. : | MFCD00014021 |
InChI Key : | WWTULTKUWBKVGV-UHFFFAOYSA-M |
Pubchem ID : | 2724687 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H319 |
Precautionary Statements: | P305+P351+P338 |
Num. heavy atoms | 9 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.5 |
Num. rotatable bonds | 3 |
Num. H-bond acceptors | 4.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 22.46 |
TPSA ? Topological Polar Surface Area: Calculated from |
66.43 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
-9.2 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.38 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.7 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.54 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.48 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-2.46 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.37 |
Solubility | 66.5 mg/ml ; 0.426 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.55 |
Solubility | 43.8 mg/ml ; 0.281 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
0.32 |
Solubility | 324.0 mg/ml ; 2.07 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) |
Yes |
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 |
-7.52 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 |
2.0 |
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) |
1.57 |
* 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 |
---|---|---|
59 g | 10300] Under argon 64.1 g cabonyldiimidazol (396 mmol) was added to 31.5 mL cyclobutanecarboxylic acid (330 mmol) in 300 mL THF within 10 minutes at tt. After 25 minutes 226 mL DCM, 77 g potassium 3-methoxy-3-oxopro- panoate (494 mmol) and 37.7 g magnesium chloride (396 mmol) were added subsequently, heated up to 56 C. within 2.5 hours, and stirred for another 3.5 hours. The resulting suspension was cooled to tt., 600 mL 2N aqueous hydrochloric acid was added to reach pH 2, another 800 mL water was added and the resulting biphasic solution was separated. The aqueous phase was extracted twice with 250 mL DCM, the combined organic phases were washed with half concentrated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The resulting methyl 3-cy- clobutyl-3-oxopropanoate (59 g, used for the next step without purification) was dissolved in 10 mL methanol, 378 mL 2M aqueous sodium hydroxide solution was added and the mixture was stirred for one hour. 100 mL TI3ME was added, the aqueous phase twice extracted with 50 mL TEME, combined aqueous phases filtered and cooled to 5 C. To that solution 65.1 mL concentrated aqueous hydrochloric acid was added to reach pH <1. 167 g solid sodium chloride was added and the mixture was four times extracted with 100 mLethyl acetate, organic phases washed with water, dried over sodium sulfate, and evaporated to yield 3-cyclobutyl-3-oxo- propanoic acid (43 g, used for the next step without purification) as a slightly yellow oil. This oil was dissolved in 508 mL THF and 53.1 g carbonyldiimidazol (328 mmol) were added carefully and stirred for 6 hours. To the resulting solution 50 mL water was added, the THF evaporated under reduced pressure, 200 mL DCM added and washed with 400 mL 2M aqueous hydrochloric acid, 200 mL 0.5M aqueous hydrochloric acid, 200 mL water. Aqueous phases were extracted with 100 mL DCM and combined organic phases were dried over sodium sulfate, filtered and evaporated. The suiting orange oil was purified by liquid chromatography over silica gel with DCM/methanol as eluent. Target fractions were combined and evaporated to yield 22 g 3-(cyclobutanecarbonyl)- 6-cyclobutyl-4-hydroxy-2H-pyran-2-one (89 mmol, 53%) as a slowly crystallizing oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | 52d) 3-Oxo-3-(2-pyridin-2-yl-cyclopropyl)-propionic acid methyl ester 1 ,10-carbonyldiimidazole (0.33 g, 2.02 mmol) was added portionwise over 5 min to a stirred solution of 2-pyridin-3-yl-cyclopropanecarboxylic acid (0.30 g, 1 .84 mmol) in anhydrous THF (5 mL) under argon. After 1 h, a mixture of MgCI2 (0.35 g, 3.68 mmol) and potassium hydrogen methyl malonate (0.86 g, 5.52 mmol) was added. After 7 h the mixture was concentrated under vacuum and diluted with ethyl acetate. The mixture was then washed with aqueous NaHS04 (1 M) and brine, and the organic phase dried over Na2S04, filtered, and concentrated to dryness to give the product, used without further purification (0.335 g, 83%). LC-MS m/z 220 (M + H) +, 0.99 (ret. time). |
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