Structure of 66336-42-3
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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. : | 66336-42-3 |
Formula : | C9H16O3 |
M.W : | 172.22 |
SMILES Code : | OC(CC1)(C)CCC21OCCO2 |
MDL No. : | MFCD11108667 |
InChI Key : | AAYZDXMYYIJKLR-UHFFFAOYSA-N |
Pubchem ID : | 18713075 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 12 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 44.56 |
TPSA ? Topological Polar Surface Area: Calculated from |
38.69 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.15 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.46 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.05 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.74 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
1.76 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.23 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.2 |
Solubility | 10.9 mg/ml ; 0.0634 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.84 |
Solubility | 24.8 mg/ml ; 0.144 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.36 |
Solubility | 7.45 mg/ml ; 0.0433 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) |
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 |
-7.02 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 |
0.0 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) |
3.11 |
* 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 |
---|---|---|
92% | With hydrogenchloride; water; In tetrahydrofuran; at 20℃; for 6h; | Step 2: Synthesis of 4-hydroxy-4-methylcyclohexanone [567] 8-Methyl-1,4-dioxaspiro[4.5]decane-8-ol (650 mg, 3.77 mmol) was dissolved in THF (10 ml), followed by addition of 1N aqueous HCl solution (5 ml), and then the resulting mixture was stirred at room temperature for 6 hours. The resulting reaction liquid was concentrated under reduced pressure, and then extracted with 10% MeOH/MC (20 ml x 5). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (50% EtOAc/Hexanes), to obtain 443 mg of yellow oil (92%). |
86.7% | With hydrogenchloride; In tetrahydrofuran; water; at 20℃; | Step 2: synthesis of 4-hydroxy-4-methylcyclohexanone To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (6.1 g, 35.5 mmol) in THF (200 mL) was added 2 N HC1 (32 mL). The resulting mixture was stuffed at RT overnight, and then was basified to pH 8.0 by saturated K2C03 solution. The separated organic layer was concentrated invacuo and the residue was purified by column chromatography on silica gel (EA: PE= 3:20 to2:3) to afford the title compound as yellow oil (4.1 g, yield: 86.7%). |
86% | With pyridinium p-toluenesulfonate; In water; acetone; for 8h;Reflux; | To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (1 equiv) in a 2:1 mixture of acetone and water (0.38 M) was added pyridinium p-toluenesulfonate (0.2 equiv). The resulting mixture was refluxed for 8 h. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the title compound (86% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d1) delta ppm 3.96-3.93 (m, 2H), 2.27-2.25 (m, 1H), 2.25-2.22 (m, 1H), 2.01-1.94 (m, 2H), 1.90-1.82 (m, 2H), 1.38 (s, 3H). |
86.7% | With hydrogenchloride; In tetrahydrofuran; water; at 20℃; | Step 2: synthesis of 4-hydroxy-4-methylcyclohexanone To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (6.1 g, 35.5 mmol) in THF (200 mL) was added 2 N HCl (32 mL). The resulting mixture was stirred at RT overnight, and then was basified to pH 8.0 by saturated K2CO3 solution. The separated organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EA:PE=3:20 to 2:3) to afford the title compound as yellow oil (4.1 g, yield: 86.7%). |
86.7% | With hydrogenchloride; In tetrahydrofuran; water; at 20℃; | To a solution of 8-methyl-1,4-dioxaspiro[4.5]decan-8-ol (6.1 g, 35.5 mmol) in THF (200 mL) was added 2 N HCl (32 mL). The resulting mixture was stirred at RT overnight, and then was basified to pH 8.0 by saturated K2CO3 solution. The separated organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EA:PE=3:20 to 2:3) to afford the title compound as yellow oil (4.1 g, yield: 86.7%). |
84% | With hydrogenchloride; water; In acetone; at 40℃; for 14h;Inert atmosphere; | Step 2. Preparation of 4-hydroxy-4-methylcyclohexanone To a solution of 8-methyl-l,4-dioxaspiro[4.5]decan-8-ol (5.26 g, 30.5 mmol) in acetone (40 mL) and water (60 mL) at room temperature was added 4 M HC1 (22.91 mL, 92 mmol). The reaction mixture was heated at 40 C for 14 h. The mixture was cooled to room temperature and was neutralized by the addition of solid sodium carbonate. The acetone was removed on the rotovapor and the aqueous layer was extracted with ethyl acetate (7 x 150 mL). The combined organic layers were dried over MgS04, filtered, and concentrated. The product was purified by column chromatography on silica gel (70% ethyl acetate in hexanes) to afford 4-hydroxy-4-methylcyclohexanone (3.27 g, 25.5 mmol, 84% yield) as a white solid: 1H NMR (400MHz, CHLOROFORM-d) delta 2.80 - 2.68 (m, 2H), 2.30 - 2.20 (m, 2H), 2.04 - 1.94 (m, 2H), 1.92 - 1.80 (m, 2H), 1.56 (s, 1H), 1.39 (s, 3H); 13C MR (100MHz, CHLOROFORM-d) delta 21 1.55, 68.14, 38.40, 36.80, 29.51. |
82% | With hydrogenchloride; In tetrahydrofuran; water; at 20℃; for 16h; | Compound 1A (5.1 g, 29.6 mmol) was dissolved in THF (100 mL), followed by addition of 1N aqueous HCl (44.4 mL, 44.4 mmol) at room temperature. The resulting mixture was stirred at room temperature for 16 h. The resulting reaction liquid was concentrated under reduced pressure and then extracted with 10% MeOH/DCM (2*200 mL). The combined organic layer were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1B (yellow liquid, 3.1 g, 24.19 mmol, 82% yield) which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) delta 2.81-2.65 (m, 2H), 2.32-2.15 (m, 2H), 2.01-1.75 (m, 4H), 1.36 (s, 3H). |
With hydrogenchloride; water; at 20℃; for 48h; | A mixture of 8-methyl-1 ,4-dioxa-spiro[4.5]decan-8-o. (Step BB.7, 9.35 g, 54.3 mmol), water (400 ml) and hydrochloric acid (0.3 ml) was stirred at room temperature for 48 hours and then extracted 3X with ethyl acetate. The combined organic layers were dried over magnesium sulphate and evaporated at 40 C under a vacuum of 170 mbar to give the title compound as a pale yellow oil. 1H NMR (400 MHz, CDCI3) delta ppm 1.29-1.40 (m, 1 H), 1.58 (s, 1 H), 1.85 (td, 1 H), 1.97 (qd, 1 H), 2.24 (d, J = 14.8 Hz, 1 H), 2.72 (td, J = 13.7, 6.3 Hz, 1 H). | |
With hydrogenchloride; In tetrahydrofuran; water; at 20℃; | To a solution of 8-methyl-1 ,4-dioxaspiro[4.5]decan-8-ol (1 1 .78 g, 68.4 mmol) in THF (50 mL) was added aqueous HCI (1 M, 205 mL, 205.2 mmol). The reaction mixture was allowed to stir overnight at room temperature. Then, a saturated solution of Na2C03 was added and the mixture extracted with DCM. The combined organic extracts were dried over Na2S04, filtered and concentrated under reduced pressure to afford crude 4-hydroxy-4-methyl-cyclohexanone (6.18 g, 48.2 mmol, 71 % yield). NMR (400 MHz, CDCI3, delta): 2.70-2.61 (m, 2H), 2.21 -2.14 (m, 2H), 1 .94-1 .87 (m, 2H), 1 .83-1 .75 (m, 2H), 1 .31 (s, 3H), 1 .23 (s, 1 H). | |
With hydrogenchloride; In tetrahydrofuran; at 0 - 20℃; for 14h; | General procedure: Hydrochloric acid (1 M, 3.0 eq.) was added to a suspension of 1 ,3-dioxolane derivative (1.0 eq.) in THF (1 M), cooled at 0 C. The reaction mixture was allowed to return to RT and stirred for 14 h. The mixture was then carefully basified with a saturated solution of sodium carbonate and the aqueous layer was extracted with DCM (x 3). The combined organic extracts were filtered over a phase separator and concentrated under reduced pressure to afford crude carbonyl; Following general procedure J, 8-methyl-i ,4-dioxaspiro[4.5]decan-8-ol (2.50 mmol) in THF (2.5 mL)afforded the titled compound crude (2.50 mmol) as a brown oil. 1H NMR (400 MHz, CDCI3, ): 2.71 -2.59(m, 2H), 2.23-2.12 (m, 2H), 1.96-i .86 (m, 2H), 1.85-i .73 (m, 2H), 1.31 (5, 3H), 1.23 (5, 1H) | |
With hydrogenchloride; In water; at 70℃; for 2.5h; | To a stirred solution of 0.05 N HCl (1800 mL) was added 8-methyl-1,4- dioxaspiro [4.5] decan-8-ol (140.0 g, 0.814 mol). The mixture was stirred at 70 C for 2.5 hours. The resulting mixture was cooled to room temperature and added NaCl solid to saturation, then extracted with EtOAc (5 700 mL). The combined organic phase was dried over Na 2SO 4 and concentrated to give the 4-hydroxy-4-methylcyclohexan-1-one (105.0 g, crude) as a yellow oil. |
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