Structure of 178312-48-6
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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. : | 178312-48-6 |
Formula : | C7H12F2O |
M.W : | 150.17 |
SMILES Code : | OCC1CCC(F)(F)CC1 |
MDL No. : | MFCD11847775 |
InChI Key : | XJZNZSLOHZLFQP-UHFFFAOYSA-N |
Pubchem ID : | 21184133 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 10 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 3.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 34.95 |
TPSA ? Topological Polar Surface Area: Calculated from |
20.23 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.77 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.67 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
2.64 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
1.83 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
2.18 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
2.02 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.76 |
Solubility | 2.63 mg/ml ; 0.0175 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.71 |
Solubility | 2.93 mg/ml ; 0.0195 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-1.68 |
Solubility | 3.17 mg/ml ; 0.0211 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) |
No |
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 |
-6.03 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 |
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) |
1.71 |
* 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 |
---|---|---|
81% | With lithium aluminium tetrahydride; In tetrahydrofuran; diethyl ether; at 0 - 20℃; for 1h;Inert atmosphere; | Under nitrogen atmosphere, at 0 C, to a suspension of LiA1H4 (2.0 M THF solution,11.2 mL, 22.47 mmol) in dry Et20 (55 mL), <strong>[121629-14-9]methyl 4,4-difluorocyclohexane carboxylate</strong> (1.0 g,5.62 mmol) in dry Et20 (10 mL) was added dropwise. The resulting reaction mixture was stirredat r.t. for 1 h, and then cooled to 0 C. H20 (1.0 mL) was slowly and cautiously added, followedby 3.0 M KOH solution (1.0 mL) and additional H20 (4.5 mL). The mixture was stirred at 0 Cfor 1 h and then filtered off. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, affording the title compound (0.68 g, 81%), which was used in the next step without any further purification. ‘H NMR (DMSO-d6): ö 4.51 (t, 1H, J= 5.6 Hz), 3.26 (t, 2H, J= 7.5 Hz), 2.05-1.93 (m, 2H), 1.86-1.66 (m, 4H), 1.55-1.41 (m, 1H), 1.21-1.08 (m, 2H). |
81% | Under nitrogen atmosphere, at 0 C, to a suspension of LiAlH4 (2.0 M THF solution, 11.2 mL, 22.47mmol) in dry Et2O (55 mL), <strong>[121629-14-9]methyl 4,4-difluorocyclohexane carboxylate</strong> (1.0 g, 5.62 mmol) in dryEt2O (10 mL) was added dropwise. The resulting reaction mixture was stirred at room temperature for1 h, and then cooled to 0 C. H2O (1.0 mL) was slowly and cautiously added, followed by 3.0 M KOHsolution (1.0 mL) and additional H2O (4.5 mL). The mixture was stirred at 0 C for 1 h and thenfiltered off. The organic layer was dried over Na2SO4, filtered and concentrated to dryness, affordingthe title compound (0.68 g, 81%), which was used in the next step without any further purification. 1HNMR (DMSO-d6): δ 4.51 (t, 1H, J = 5.6 Hz), 3.26 (t, 2H, J = 7.5 Hz), 2.05-1.93 (m, 2H), 1.86-1.66(m, 4H), 1.55-1.41 (m, 1H), 1.21-1.08 (m, 2H). | |
77% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0℃; for 18h;Inert atmosphere; | 4,4-Difluoro-cyclohexanecarboxylate (500 mg, 2.60 mmol) was dissolved in tetrahydrofuran (15 mL), and lithium aluminum hydride (1.48 g, 3.90 mmol) was added in batches at 0C, and stirred to react for 18 hours under nitrogen atmosphere. The reaction solution was cooled to 0C and water (1.50 mL), 15% sodium hydroxide (1.50 mL) and water (4.50 mL) were added successively slowly. The solution was filtered, and the filtrate was concentrated under reduced pressure to give the product (4,4-difluoro-cyclohexyl)methanol (300 mg, as a colorless liquid) with a yield of 77%. 1H NMR: (400 MHz,CDCl3) δ 3.58-3.44(m, 2H), 2.20-2.05(m, 2H), 1.93-1.42(m, 6H), 1.40-1.20(m, 2H). MS-ESI calcd. [M + H]+ 151, found 151. |
71.55% | With lithium aluminium tetrahydride; In tetrahydrofuran; at 0 - 20℃; for 2h;Inert atmosphere; | Under protection of nitrogen gas, LiAlH4 (2.9 g, 76.32 mmol) was added slowly into a solution of methyl 4,4-difluorocyclohexanecarboxylate (3.40 g, 19.08 mmol) in tetrahydrofuran (40 mL) at 0C, and then the reaction solution was stirred at 20C for 2h. The reaction solution was quenched with water (50 mL) and 1 mol/L sodium hydroxide solution (20 mL), and then filtered. The filtrate was extracted with ethyl acetate (50 mL * 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column chromatography to give the title compound (yellow oil, 2.05 g, yield of 71.55%). 1H NMR (400MHz, CHLOROFORM-d) δ = 3.53 (d, J=6.5 Hz, 2H), 2.21 - 2.07 (m, 2H), 1.86 (br d, J=13.6 Hz, 2H), 1.81 - 1.64 (m, 2H), 1.58 (br d, J=3.5 Hz, 1H), 1.43 - 1.27 (m, 3H). |
With sodium tetrahydroborate; lithium chloride; In tetrahydrofuran; ethanol; at 0 - 20℃; | Intermediate 56: 2-(4,4-Difluorocyclohexyl)ethyl 4-methylbenzenesulfonate; 2-(4,4-Difluorocyclohexyl)ethyl 4-methylbenzenesulfonate was prepared by following a six-step sequence of straightforward transformation well known in the art: 1) reduction using NaBH4/LiCl, 2) oxidation using Dess-Martin periodinane, 3) Wittg reaction using methoxytriphenylphosphonium chloride, 4) hydrolysis of the resulting enolether with TsOH, 5) reduction using NaBH4, and 6) tosylation of the resulting alcohol; 1H NMR (CDCl3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.2 Hz, 2H), 4.07 (t, J = 6.0 Hz, 2H), 2.40 (s, 3H), 2.08-1.98 (m, 2H), 1.82-1.42 (m, 7H), 1.27-1.16 (m, 2H); LC-MS [M+Na]+ 341.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With phosphorus tribromide; In dichloromethane; at 0 - 20℃; for 2h; | To a stirred solution of (4,4-difluorocyclohexyl)methanol (2.00 g, 14.372 mmol, 1.0 eq) in DCM (20 mL), PBr3 (1.63 mL, 17.247 mmol, 1.2 eq) was added at 0 C. and the reaction mixture was then stirred at ambient temperature for 2 h. After completion of the reaction (monitored by TLC, TLC system 5% MeOH in DCM, Rf-0.3), the reaction was quenched with NaHCO3 solution (150 mL), extracted with DCM (3×150 mL), dried over Na2SO4 and concentrated to get 4-(bromomethyl)-1,1-difluorocyclohexane (2.80 g, 96%). |
54% | With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 20℃;Inert atmosphere; | (4,4-Difluorocyclohexyl)methanol (7.22 g, 48.08 mmol) and triphenylphosphine (25.2 g, 96.16 mmol) were dissolved in DCM (75 mL) and cooled to 0 C. under nitrogen atmosphere. Carbon tetrabromide (31.9 g, 96.16 mmol) was dissolved in DCM (75 mL) and added to the reaction mixture. The mixture was stirred at room temperature overnight. The solvent was evaporated. Pentane (250 mL) was added to the orange residue, which caused triphenylphosphineoxide to precipitate. The off-white solids were filtered off. The filtrate was evaporated and purified on a ISOLUTE Silica Flash column (50 g). Pentane followed by EtOAc:pentane (1% EtOAc) was used as eluent. 4-(Bromomethyl)-1,1-difluorocyclohexane (5.48 g, 54%) was isolated. 1H NMR (400 MHz, cdcl3) delta 1.32-1.46 (m, 2H), 1.64-1.84 (m, 3H), 1.90-1.99 (m, 2H), 2.05-2.18 (m, 2H), 3.31 (d, 2H). |
With carbon tetrabromide; triphenylphosphine; In dichloromethane; at 26℃; for 16h; | To a solution of (4,4-difluorocyclohexyl)methanol (1 g, 0.0066 mol, commercial source: J&W Pharma) in dichloromethane (5 mL), triphenyl phosphine (3.4 g, 0.0133 mol) was added at 26 C, followed by the addition of a solution of carbon tetrabromide (2.1 g, 0.0066 mol) in dichloromethane (5 mL) slowly in dropwise at 0 C. The reaction mixture was stirred at 26 C for 16 h. On completion, the reaction mixture was concentrated under reduced pressure at 26 C. The crude was stirred with n-pentane (100 mL) at 26 C for 10 min. The n-pentane layer was decanted and concentrated under reduced pressure to afford 4-(bromomethyl)-1 ,1-difluorocyclohexane (1.7 g) as a colorless liquid that was characterized by H-NMR. This crude was used without any purification in the next reaction.1H NMR (400 MHz, CDCI3) 5 3.31 (d, J = 6.4 Hz, 2H), 2.21 -2.06 (m, 2H), 2.00-1 .90 (m, 2H), 1.83-1.63 (m, 3H), 1.47-1.32 (m, 2H) |
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