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Product Details of [ 24730-88-9 ]

CAS No. :24730-88-9
Formula : C12H20O4
M.W : 228.28
SMILES Code : O=C(C(CC1)(C)CCC21OCCO2)OCC
MDL No. :MFCD16036567
InChI Key :VFWAGFFGWYTECB-UHFFFAOYSA-N
Pubchem ID :19004805

Safety of [ 24730-88-9 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302-H315-H319-H335
Precautionary Statements:P261-P305+P351+P338

Computational Chemistry of [ 24730-88-9 ] Show Less

Physicochemical Properties

Num. heavy atoms 16
Num. arom. heavy atoms 0
Fraction Csp3 0.92
Num. rotatable bonds 3
Num. H-bond acceptors 4.0
Num. H-bond donors 0.0
Molar Refractivity 58.8
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

44.76 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

2.87
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

1.47
Log Po/w (WLOGP)?

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

1.87
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.

1.44
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

2.44
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.02

Water Solubility

Log S (ESOL):?

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

-1.98
Solubility 2.37 mg/ml ; 0.0104 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.

-2.02
Solubility 2.2 mg/ml ; 0.00963 mol/l
Class?

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

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

-2.43
Solubility 0.844 mg/ml ; 0.0037 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.

-6.65 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

0.0
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)

3.08

Application In Synthesis of [ 24730-88-9 ]

* 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 [ 24730-88-9 ]

[ 24730-88-9 ] Synthesis Path-Downstream   1~2

  • 1
  • [ 24730-88-9 ]
  • [ 147905-77-9 ]
YieldReaction ConditionsOperation in experiment
85% With CAN; In acetonitrile; at 70℃; for 2h; To a solution of ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (7.3 g, 32.0 mmol) in MeCN (50 mL) and water (50 mL) was added CAN (2.11 g, 3.85 mmol). The mixture was heated to 70 C. and stirred for 2 h. The reaction mixture was cooled to room temperature, and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL*2). The combined organic layers were washed with brine (50 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (5 g, 85%) as yellow oil, which was used for next step without further purification.
85% With ammonium cerium (IV) nitrate; In water; acetonitrile; at 70℃; for 2h; To a solution of ethyl 8-methyl-1,4-dioxaspiro [4.5] decane-8-carboxylate (7.3 g, 32.0 mmol) in MeCN (50 mL) and water (50 mL) was added CAN (2.11 g, 3.85 mmol) was added. The mixture was heated to 70 C. and stirred for 2 hours. The reaction mixture was cooled to room temperature and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were washed with brine (50 mL × 2), dried over Na 2 SO 4, filtered and concentrated in vacuo to afford the title compound (5 g, 85%) as a yellow oil, which was obtained without further purification It was used for the next step.
74% With hydrogenchloride; In tetrahydrofuran; water; at 0 - 20℃; for 1h; Ethyl-8-methyl-1,4-dioxa-spiro [4.5] decane-8-carboxylic acid tert-butyl ester (5.00g, 21.9mmol) was dissolved inIn tetrahydrofuran (50mL), was added dropwise at 0C 1N aqueous hydrochloric acid solution (20 mL) was stirred for 1 hour after 20 C. The mixture was cooled to 0 C, was added a solution of sodium bicarbonate (50 mL) to quench the reaction. Mixture of ethyl acetate(100mLx3) extraction. The organic phase was washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate driedAfter drying concentrated under reduced pressure. Was purified by silica gel column chromatograph(1 petroleum ether / ethyl acetate, Rf = 0.4 10) y to give ethyl-1-methyl-4-oxo-cyclohexanecarboxylate (3.00g, colorless oil). Yield: 74%.
67% With toluene-4-sulfonic acid; In water; acetone;Reflux; Ethyl 1-methyl-4-oxocyclohexane-1-carboxylate To a solution of ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8-carboxylate (1 equiv.) in acetone/H2O (0.5 M, 1/1) was added pTSA.H2O (1 equiv.). The mixture was refluxed overnight, then concentrated to remove acetone. The resulting solution was diluted with ethyl acetate, and the layers were separated. The organic phase was washed with saturated NaHCO3, dried over Na2SO4 and filtered. The filtrate was concentrated to afford ethyl 1-methyl-4-oxocyclohexanecarboxylate (67%). 1H NMR (400 MHz, CDCl3) delta ppm: 4.23 (q, J=7.2 Hz, 2H), 2.49-2.39 (m, 4H), 2.37-2.27 (m, 2H), 1.75-1.64 (m, 2H), 1.34-1.28 (m, 6H).
With hydrogenchloride; water; In 1,4-dioxane; ethanol; at 20℃; for 64h;Product distribution / selectivity; Step B - Synthesis of ethyl l-methyl-4-oxocyclohexanecarboxylate (Int-6b) OC2009.701871lnt-6a lnt-6bIn a 50 mL round-bottom flask was mixed with ethyl 8-methyl-l,4- dioxaspiro[4.5]decane-8-carboxylate (Int-6a, 1.99 g, 8.72 mmol), EtOH (10 mL), H2O (5 mL), and 4N HCl in 1,4-dioxane (5 mL). The resulting solution was stirred at room temperature for 64 hours. At this time, the solvent was removed in vacuo and the residue was taken up in DCM. The suspension was washed with saturated NaHCtheta3(aq) and the organic layer was dried over Na2SO^ The resulting product was taken on without further purification. Yield = 1.00 g.
With ammonium cerium (IV) nitrate; water; In acetonitrile; at 70℃; for 1h; The ketal compound (2.09 g, 9.17 mmol) was dissolved in CAN (100 mL) and water (50 mL). H4)2Ce(N03)6 (503 mg, 0.92 mmol) was added in water (50 mL) was added and the mixture was heated up to 70 C and stirred for 1 hour. After cooling down to room temperature, water (100 mL) was added and extracted with Et20 (100 mL x 3) and the organics was dried over Na2S04. After concentration, the crude was purified with column (0-30% EtOAc/Hexane) to give the product (1.72 g).
With ammonium cerium (IV) nitrate; In water; acetonitrile; at 70℃; for 1h; The ketal compound (2.09 g, 9.17 mmol) was dissolved in CAN (100 mL) and water (50 mL). (NH )2Ce N03)6 (503 mg, 0.92 mmol) in water (50 mL) was added and the mixture was heated up to 70 C and stirred for 1 hour. After cooling down to room temperature, water (100 mL) was added and extracted with Et20 (100 mL x 3) and the organics was dried over Na2S04. After concentration, the crude was purified with column (0~30% EtOAc/Hexane) to give the product (1.72 g).
With hydrogenchloride; In water; acetone; at 20℃; for 48h; Intermediate 66: ethyl l-methyl-4-oxocyclohexanecarboxylateTo a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (2.0 g, 8.76 mmol) in aceton (60 ml) was added HC1 (2.5 M, 60 ml, 150 mmol) at romm temperature . After stirring at room temperature over 48 hours, the reaction mixture was poured into DCM , the organic layer was then separated and the aqueous was extracted with DCM, washed with brine, dried over Na2S04 , filtered and concentrated, and purified by MPLC (5-60%> EtOAc in hexane ) to provide ethyl l-methyl-4-oxocyclohexanecarboxylate as colorlee liquid (1.12 g). LC-MS (ES, m/z) CioHi603: 184; Found: 185 [M+H]+. Intermediate 67: ethyl 4-hydroxy-l-methylcyclohexanecarboxylateTo a solution of ethyl l-methyl-4-oxocyclohexanecarboxylate (7.02 g, 38.1 mmol) in methanol (15 ml) at 0C added sodium borohydride (0.721 g, 190.5 mmol) in small portions over 30 min. The reaction mixture aged for 1 hour. Then concentrated under vacuum and applied onto a silica gel column and eluted with ethyl acetate/hexane 10-100%. This resulted in 5.58 g (79%) of ethyl 4-hydroxy-l-methylcyclohexanecarboxylate (cis&trans mixture) as colorless oil. LC-MS (ES, m/z): Ci0Hi8O3: 186; Found: 187 [M+H]+.
8.34 g With hydrogenchloride; In water; acetone; at 20℃; The compound (12.8 g) produced in Example 44 was dissolved in 100 mL of acetone, 50 mL of 2N hydrochloric acid was added while stirring at room temperature, and the mixture was stirred at that temperature overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, 100 mL of tetrabutyl methyl ether was added, and extraction operation was performed. The resulting organic layer was sequentially washed with an aqueous saturated sodium bicarbonate solution and an aqueous saturated sodium chloride solution, and dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 9.7 g of the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/hexane=3%?25%) to obtain the title compound (8.34 g) having the following physical property values.; TLC: Rf 0.41 (hexane:ethyl acetate=4:1); 1H-NMR (CDCl3): delta 1.25-1.32 (m, 6H), 1.58-1.73 (m, 2H), 2.27-2.51 (m, 6H), 4.22 (q, J=7.2 Hz, 2H).
1.12 g With hydrogenchloride; In water; acetone; at 20℃; Intermediate 35 Ethyl 1 -methyl-4-oxocvclohexanecarboxylate To a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (2.0 g, 8.76 mmol) in aceton (60 ml) was added HC1 (2.5 M, 60 ml, 150 mmol) at rt . After stirred at rt over weekend, the reaction mixture was poured into DCM , the organic layer was then separated and the aqueous was extracted with DCM, washed with brine, dried over Na2S04 , filtered and concentrated, and purified by MPLC (5-60% EtOAc in hexane ) to provide ethyl l-methyl-4- oxocyclohexanecarboxylate as colorlee liquid (1.12 g). LC-MS (ES, m/z) C10H16O3: 184; Found: 185 [M+H]+
With sulfuric acid; In acetone; at 20℃; Step 3. Preparation of ethyl 1-methyl-4-oxocyclohexanecarboxylate (i-ld). The mixture of ethyl 8-methyl-l,4-dioxa-spiro[4.5]decane-8-carboxylate (i-lc) (2.0 g, 8.77 mmol) in Acetone (20 mL) and IN H2S04 (20 mL) was stirred at room temperature for overnight. The mixture was diluted with H20 (50 mL). The aqueous layer was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2S04 and concentrated to get the desired product as a pale yellow oil. LCMS (ESI) calc'd for Ci0Hi6O3 [M+H]+: 185, found: 185.
With sulfuric acid; In acetone; at 20℃; Step 3. Preparation of ethyl l-methyl-4-oxocyclohexanecarboxylate (i-ld).A mixture of ethyl 8-methyl-i ,4-dioxa-spiro [4.5] decane-8-carboxylate (i-l c) (2.0 g, 8.77 mmol) in acetone (20 mL) and iN H2504 (20 mL) was stirred at room temperature overnight. The mixture was diluted with H20 (50 mL). The aqueous layer was extracted with DCM (3x30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2504 and concentrated to obtain the desired product as a pale yellow oil. LCMS(ESI) calc?d for C10H1603 [M+H]b: 185, found: 185.
With sulfuric acid; In water; acetone; at 20℃; Step 3. Preparation of ethyl 1-methyl-4-oxocyclohexanecarboxylate (i-1d) [0261] A mixture of ethyl 8-methyl-1,4-dioxa-spiro[4.5]decane-8-carboxylate (i-1c) (2.0 g, 8.77 mmol) in acetone (20 mL) and 1N H2SO4 (20 mL) was stirred at room temperature overnight. The mixture was diluted with H2O (50 mL). The aqueous layer was extracted with DCM (3×30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to obtain the desired product as a pale yellow oil. LCMS (ESI) calc'd for C10H16O3 [M+H]+: 185. found: 185.
With hydrogenchloride; water; In acetone; at 20℃; for 18h; To a solution of compound D2-2 (8.4 g, 36.84 mmol) in acetone (100 mL) was added HCl (3 M in water* 50 mL) dropwise at room temperature, and the whole was stirred at room temperature for 18 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure to provide compound D2-3 (6.3 g) as a light yellow oil. The crude product was used in the next step without purification. 1H NMR (CDC13, 400 MHz): delta 4.22 (q, J = 7.0 Hz, 2H), 2.47-2.38 (m, 4H), 2.34-2.30 (m, 2H), 1.72-1.64 (m, 2H), 1.31- 1.29 (m. 611).
With ammonium cerium (IV) nitrate; In water; acetonitrile; at 70℃; for 2h; Step 3. Preparation of ethyl l-methyl-4-oxocvclohexanecarboxylate (i-23c) [00196] To a solution of ethyl 8-methyl-l,4-dioxaspiro[4.5]decane-8-carboxylate (7.3 g, 32.0 mmol) in MeCN (50 mL) and water (50 mL) was added eerie ammonium nitrate (2.11 g, 3.85 mmol). The mixture was heated to 70 C and stirred for 2 h. The reaction mixture was cooled to room temperature, and partitioned between water (50 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (50 mL* 2). The combined organic layers were washed with brine (50 mL*2), dried over Na2SC>4, filtered and concentrated under reduced pressure to afford the title compound (5 g, 85%) as yellow oil, which was used for next step without further purification.
With sulfuric acid; In acetone; at 20℃; for 14h; Into a 100-mL round-bottom flask, ethyl 8-methyl-1,4-dioxaspiro[4.5]decane-8- carboxylate (2.3 g, 10.08 mmol) was dissolved in acetone (20 mL). Then sulfuric acid (1M, 20 mL) was added. The resulting solution was stirred for 14 h at room temperature. The resulting solution was diluted with 50 ml of water and extracted with 3x50 ml of ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under vacuum. This afforded the title compound (1.8g, crude) as a yellow oil. MS: (ES, m/z): 185 [M+H]+.

  • 2
  • [ 144-55-8 ]
  • [ 24730-88-9 ]
  • [ 147905-77-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; In methanol; EXAMPLE 3 Hydrolysis 5.81 g of ethyl 8-methyl-1,4-dioxaspiro[4.5]-decane-8-carboxylate (Example 2) was dissolved in 200 ml of methanol. Then, 30 ml of concentrated hydrochloric acid was added to the solution under ice-cooling, and was stirred at room temperature for one hour. After reaction, 300 ml of an aqueous sodium hydrogencarbonate solution was added to the reaction solution. The resultant solution was extracted three times with 70 ml of ethyl acetate. The resultant organic layer was washed once with each of an aqueous sodium chloride solution and an aqueous sodium hydrogen-carbonate solution, and was then dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was refined by vacuum distillation (Kugelrohl), yielding 3.4 g of ethyl 1-methyl-4-oxo-1-cyclohexanecarboxylate as a colorless oil, which had the following physiochemical properties: Boiling point: 170 C./0.4 mmHg (Kugelrohl) Proton nuclear magnetic resonance spectrum (delta ppm in CDCl3): 0.8-2.5 (9H,m), 1.26 (3H, t, J=7Hz), 1.30 (3H, s), 4.17 (2H, q, J=7Hz) IRmax (neat, cm-1): 2964, 1724 MS (M+): 184
 

Historical Records

Technical Information

Categories

Related Functional Groups of
[ 24730-88-9 ]

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