Structure of 24730-88-9
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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 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
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 |
44.76 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
2.87 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.47 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.87 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.44 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.44 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.02 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.98 |
Solubility | 2.37 mg/ml ; 0.0104 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.02 |
Solubility | 2.2 mg/ml ; 0.00963 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.43 |
Solubility | 0.844 mg/ml ; 0.0037 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 |
-6.65 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 |
0.0 |
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) |
3.08 |
* 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 |
---|---|---|
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]+. |
Yield | Reaction Conditions | Operation 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 |
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