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Structure of 66336-42-3

Chemical Structure| 66336-42-3

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Product Details of [ 66336-42-3 ]

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

Safety of [ 66336-42-3 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 66336-42-3 ] Show Less

Physicochemical Properties

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
Ertl P. et al. 2000 J. Med. Chem.

38.69 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.15
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

0.46
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

1.05
Log Po/w (MLOGP)?

MLOGP: Topological method implemented from
Moriguchi I. et al. 1992 Chem. Pharm. Bull.
Moriguchi I. et al. 1994 Chem. Pharm. Bull.
Lipinski PA. et al. 2001 Adv. Drug. Deliv. Rev.

0.74
Log Po/w (SILICOS-IT)?

SILICOS-IT: Hybrid fragmental/topological method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

1.76
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.23

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-1.2
Solubility 10.9 mg/ml ; 0.0634 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (Ali)?

Ali: Topological method implemented from
Ali J. et al. 2012 J. Chem. Inf. Model.

-0.84
Solubility 24.8 mg/ml ; 0.144 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Very soluble
Log S (SILICOS-IT)?

SILICOS-IT: Fragmental method calculated by
FILTER-IT program, version 1.0.2, courtesy of SILICOS-IT, http://www.silicos-it.com

-1.36
Solubility 7.45 mg/ml ; 0.0433 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Soluble

Pharmacokinetics

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)
and tested on 415 molecules (test set)
10-fold CV: ACC=0.72 / AUC=0.77
External: ACC=0.88 / AUC=0.94

Yes
CYP1A2 inhibitor?

Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.83 / AUC=0.90
External: ACC=0.84 / AUC=0.91

No
CYP2C19 inhibitor?

Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set)
and tested on 3000 molecules (test set)
10-fold CV: ACC=0.80 / AUC=0.86
External: ACC=0.80 / AUC=0.87

No
CYP2C9 inhibitor?

Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set)
and tested on 2075 molecules (test set)
10-fold CV: ACC=0.78 / AUC=0.85
External: ACC=0.71 / AUC=0.81

No
CYP2D6 inhibitor?

Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set)
and tested on 1068 molecules (test set)
10-fold CV: ACC=0.79 / AUC=0.85
External: ACC=0.81 / AUC=0.87

No
CYP3A4 inhibitor?

Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set)
and tested on 2579 molecules (test set)
10-fold CV: ACC=0.77 / AUC=0.85
External: ACC=0.78 / AUC=0.86

No
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-7.02 cm/s

Druglikeness

Lipinski?

Lipinski (Pfizer) filter: implemented from
Lipinski CA. et al. 2001 Adv. Drug Deliv. Rev.
MW ≤ 500
MLOGP ≤ 4.15
N or O ≤ 10
NH or OH ≤ 5

0.0
Ghose?

Ghose filter: implemented from
Ghose AK. et al. 1999 J. Comb. Chem.
160 ≤ MW ≤ 480
-0.4 ≤ WLOGP ≤ 5.6
40 ≤ MR ≤ 130
20 ≤ atoms ≤ 70

None
Veber?

Veber (GSK) filter: implemented from
Veber DF. et al. 2002 J. Med. Chem.
Rotatable bonds ≤ 10
TPSA ≤ 140

0.0
Egan?

Egan (Pharmacia) filter: implemented from
Egan WJ. et al. 2000 J. Med. Chem.
WLOGP ≤ 5.88
TPSA ≤ 131.6

0.0
Muegge?

Muegge (Bayer) filter: implemented from
Muegge I. et al. 2001 J. Med. Chem.
200 ≤ MW ≤ 600
-2 ≤ XLOGP ≤ 5
TPSA ≤ 150
Num. rings ≤ 7
Num. carbon > 4
Num. heteroatoms > 1
Num. rotatable bonds ≤ 15
H-bond acc. ≤ 10
H-bond don. ≤ 5

1.0
Bioavailability Score?

Abbott Bioavailability Score: Probability of F > 10% in rat
implemented from
Martin YC. 2005 J. Med. Chem.

0.55

Medicinal Chemistry

PAINS?

Pan Assay Interference Structures: implemented from
Baell JB. & Holloway GA. 2010 J. Med. Chem.

0.0 alert
Brenk?

Structural Alert: implemented from
Brenk R. et al. 2008 ChemMedChem

0.0 alert: heavy_metal
Leadlikeness?

Leadlikeness: implemented from
Teague SJ. 1999 Angew. Chem. Int. Ed.
250 ≤ MW ≤ 350
XLOGP ≤ 3.5
Num. rotatable bonds ≤ 7

No; 1 violation:MW<1.0
Synthetic accessibility?

Synthetic accessibility score: from 1 (very easy) to 10 (very difficult)
based on 1024 fragmental contributions (FP2) modulated by size and complexity penaties,
trained on 12'782'590 molecules and tested on 40 external molecules (r2 = 0.94)

3.11

Application In Synthesis of [ 66336-42-3 ]

* 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.

  • Downstream synthetic route of [ 66336-42-3 ]

[ 66336-42-3 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 66336-42-3 ]
  • [ 17429-02-6 ]
YieldReaction ConditionsOperation 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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Technical Information

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