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Structure of 178312-48-6

Chemical Structure| 178312-48-6

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Product Details of [ 178312-48-6 ]

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

Safety of [ 178312-48-6 ]

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

Computational Chemistry of [ 178312-48-6 ] Show Less

Physicochemical Properties

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

20.23 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.77
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

1.67
Log Po/w (WLOGP)?

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

2.64
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.

1.83
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

2.18
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.

-1.76
Solubility 2.63 mg/ml ; 0.0175 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.

-1.71
Solubility 2.93 mg/ml ; 0.0195 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

-1.68
Solubility 3.17 mg/ml ; 0.0211 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

No
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.

-6.03 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

2.0
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)

1.71

Application In Synthesis of [ 178312-48-6 ]

* 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 [ 178312-48-6 ]

[ 178312-48-6 ] Synthesis Path-Downstream   1~3

  • 1
  • [ 121629-14-9 ]
  • [ 178312-48-6 ]
YieldReaction ConditionsOperation 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

  • 2
  • [ 178312-48-6 ]
  • [ 858121-94-5 ]
YieldReaction ConditionsOperation 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)
  • 3
  • [ 178312-48-6 ]
  • [ 1354961-13-9 ]
  • tert-butyl-5-chloro-4-((4,4-difluoro-cyclohexyl)methoxy)-2-fluorobenzoate [ No CAS ]
 

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