1395281-64-7|3-(3,5-Difluorophenyl)oxetan-3-ol| Ambeed

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Quality Control of [ 1395281-64-7 ] Purity: 97% SDS Specification

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Product Details of [ 1395281-64-7 ]

CAS No. :	1395281-64-7
Formula :	C₉H₈F₂O₂
M.W :	186.16
SMILES Code :	OC1(C2=CC(F)=CC(F)=C2)COC1
MDL No. :	MFCD23703311
InChI Key :	NZCUIDNMEKWIBE-UHFFFAOYSA-N
Pubchem ID :	70655206

Safety of [ 1395281-64-7 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 1395281-64-7 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	1
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	40.95
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	29.46 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.83
Log P_o/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry	0.72
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.91
Log P_o/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.	1.71
Log P_o/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	2.85
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.8

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.72
Solubility	3.52 mg/ml ; 0.0189 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.	-0.92
Solubility	22.5 mg/ml ; 0.121 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	-2.94
Solubility	0.213 mg/ml ; 0.00115 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.	-6.92 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)	1.61

Application In Synthesis of [ 1395281-64-7 ]

* 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 [ 1395281-64-7 ]

[ 1395281-64-7 ] Synthesis Path-Downstream 1~10

1
[ 1395281-64-7 ]
[ 74-88-4 ]
[ 1395282-84-4 ]

Yield	Reaction Conditions	Operation in experiment
83%	In N,N-dimethyl-formamide; mineral oil;	Synthesis of 3-(3,5-difluorophenyl)-3-methoxyoxetane A solution of <strong>[1395281-64-7]3-(3,5-difluorophenyl)oxetan-3-ol</strong> (1.0 equiv.) in DMF (0.23 M) was cooled in an ice water bath. NaH, 60% dispersion in mineral oil (1.1 equiv.) was added. The mixture was stirred for 1 hr. iodomethane (1.1 equiv.) was added in a dropwise fashion. The ice bath was removed, and the mixture was stirred for 2 hr at ambient temperature. The reaction mixture was quenched by the addition of water. The mixture was extracted with ether. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (2:1 pentane:ether) to give 3-(3,5-difluorophenyl)-3-methoxyoxetane in 83% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.18 (s, 3H), 4.70 (d, J=7.04 Hz, 2H), 4.92 (d, J=7.43 Hz, 2H), 6.80 (tt, J=8.66, 2.30 Hz, 1H), 6.99-7.08 (m, 2H).
83%		A solution of <strong>[1395281-64-7]3-(3,5-difluorophenyl)oxetan-3-ol</strong> (1.0 equiv.) in DMF (0.23 M) was cooled in an ice water bath. NaH, 60% dispersion in mineral oil (1.1 equiv.) was added. The mixture was stirred for 1 hr. iodomethane (1.1 equiv.) was added in a dropwise fashion. The ice bath was removed, and the mixture was stirred for 2 hr at ambient temperature. The reaction mixture was quenched by the addition of water. The mixture was extracted with ether. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (2:1 pentane:ether) to give 3-(3,5-difluorophenyl)-3-methoxyoxetane in 83% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.18 (s, 3H), 4.70 (d, J=7.04 Hz, 2H), 4.92 (d, J=7.43 Hz, 2H), 6.80 (tt, J=8.66, 2.30 Hz, 1H), 6.99-7.08 (m, 2H).
83%		A solution of <strong>[1395281-64-7]3-(3,5-difluorophenyl)oxetan-3-ol</strong> (1.0 equiv.) in DMF (0.23 M) was cooled in an ice water bath. NaH, 60% dispersion in mineral oil (1.1 equiv.) was added. The mixture was stirred for 1 hr. iodomethane (1.1 equiv.) was added in a dropwise fashion. The ice bath was removed, and the mixture was stirred for 2 hr at ambient temperature. The reaction mixture was quenched by the addition of water. The mixture was extracted with ether. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (2:1 pentane:ether) to give 3-(3,5-difluorophenyl)-3-methoxyoxetane in 83% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 3.18 (s, 3H), 4.70 (d, J=7.04 Hz, 2H), 4.92 (d, J=7.43 Hz, 2H), 6.80 (tt, J=8.66, 2.30 Hz, 1H), 6.99-7.08 (m, 2H).

83%

Synthesis of 3-(3,5-difluorophenyl)-3-methoxyoxetane A solution of <strong>[1395281-64-7]3-(3,5-difluorophenyl)oxetan-3-ol</strong> (1.0 equiv.) in DMF (0.23 M) was cooled in an ice water bath. NaH, 60% dispersion in mineral oil (1.1 equiv.) was added. The mixture was stirred for 1 hr. iodomethane (1.1 equiv.) was added in a dropwise fashion. The ice bath was removed, and the mixture was stirred for 2 hr at ambient temperature. The reaction mixture was quenched by the addition of water. The mixture was extracted with ether. The combined extracts were washed sequentially with water and brine, dried over sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography over silica gel (2:1 pentane:ether) to give 3-(3,5- difluorophenyl)-3-methoxyoxetane in 83% yield. 1H NMR (400 MHz, CHLOROFORM- d) delta ppm 3.18 (s, 3 H), 4.70 (d, J=7.04 Hz, 2 H), 4.92 (d, J=7.43 Hz, 2 H), 6.80 (tt, J=8.66, 2.30 Hz, 1 H), 6.99 - 7.08 (m, 2 H).

References: [1]Patent: US2012/225061,2012,A1 .
[2]Patent: US2012/225062,2012,A1 .Location in patent: Page/Page column 63.
[3]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 48.
[4]Patent: WO2014/99880,2014,A1 .Location in patent: Page/Page column 162.

2
[ 6704-31-0 ]
[ 461-96-1 ]
[ 1395281-64-7 ]

Yield	Reaction Conditions	Operation in experiment
56%	In tetrahydrofuran; ethyl acetate;	Synthesis of 3-(3,5-difluorophenyl)oxetan-3-ol To a solution of 1-bromo-3,5-difluorobenzene in THF (0.27 M) under Ar was added Mg turnings (1.6 M). A reflux condenser was attached and the solution was submerged in a 90 C. oil bath and refluxed for two hours. The oxetan-3-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar overnight. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 3-(3,5-difluorophenyl)oxetan-3-ol in 56% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.82 (d, J=7.63 Hz, 2H), 4.91 (d, J=7.63 Hz, 2 H), 7.16-7.23 (m, 2H).
56%		To a solution of 1-bromo-3,5-difluorobenzene in THF (0.27 M) under Ar was added Mg turnings (1.6 M). A reflux condenser was attached and the solution was submerged in a 90 C. oil bath and refluxed for two hours. The oxetan-3-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar overnight. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 3-(3,5-difluorophenyl)oxetan-3-ol in 56% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.82 (d, J=7.63 Hz, 2H), 4.91 (d, J=7.63 Hz, 2 H), 7.16-7.23 (m, 2H).
56%		To a solution of 1-bromo-3,5-difluorobenzene in THF (0.27 M) under Ar was added Mg turnings (1.6 M). A reflux condenser was attached and the solution was submerged in a 90 C. oil bath and refluxed for two hours. The oxetan-3-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar overnight. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 3-(3,5-difluorophenyl)oxetan-3-ol in 56% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.82 (d, J=7.63 Hz, 2H), 4.91 (d, J=7.63 Hz, 2 H), 7.16-7.23 (m, 2H).

56%		Synthesis of 3-(3,5-difluorophenyl)oxetan-3-ol To a solution of l-bromo-3,5-difluorobenzene in THF (0.27 M) under Ar was added Mg turnings (1.6 M). A reflux condenser was attached and the solution was submerged in a 90 C oil bath and refluxed for two hours. The oxetan-3-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar overnight. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography (0-100%) EtOAc/n-heptanes gradient) to yield 3-(3,5-difluorophenyl)oxetan-3-ol in 56% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.82 (d, J=7.63 Hz, 2 H), 4.91 (d, J=7.63 Hz, 2 H), 7.16 - 7.23 (m, 2 H).
56%		To a solution of l-bromo-3,5-difluorobenzene in THF (0.27 M) under Ar was added Mg turnings (1.6 M). A reflux condenser was attached and the solution was submerged in a 90 C oil bath and refluxed for two hours. The oxetan-3-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar overnight. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sat.), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography (0-100% EtOAc/n-heptanes gradient) to yield 3-(3,5- difhiorophenyl)oxetan-3-ol in 56% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.82 (d, J=7.63 Hz, 2 H), 4.91 (d, J=7.63 Hz, 2 H), 7.16 - 7.23 (m, 2 H).
56%		Synthesis of 3-(3,5-difluorophenyl)oxetan-3-ol To a solution of l-bromo-3,5-difluorobenzene in THF (0.27 M) under Ar was added Mg turnings (1.6 M). A reflux condenser was attached and the solution was submerged in a 90 C oil bath and refluxed for two hours. The oxetan-3-one (1.0 equiv.) was added in THF via syringe. The solution was left stirring at rt under Ar overnight. The reaction solution was quenched by addition of NH4Cl(sat) and the solution was extracted with EtOAc, washed with NaCl(sa ), dried over MgS04, filtered, concentrated and purified by ISCO Si02 chromatography (0-100%) EtOAc/n-heptanes gradient) to yield 3-(3,5-difluorophenyl)oxetan-3-ol in 56% yield. 1H NMR (400 MHz, CHLOROFORM-d) delta ppm 4.82 (d, J=7.63 Hz, 2 H), 4.91 (d, J=7.63 Hz, 2 H), 7.16 - 7.23 (m, 2 H).

References: [1]Patent: US2012/225061,2012,A1 .
[2]Patent: US2012/225062,2012,A1 .Location in patent: Page/Page column 39.
[3]Patent: US2012/225061,2012,A1 .Location in patent: Page/Page column 38.
[4]Patent: WO2014/33631,2014,A1 .Location in patent: Page/Page column 52.
[5]Patent: WO2014/33630,2014,A1 .Location in patent: Page/Page column 64.
[6]Patent: WO2014/99880,2014,A1 .Location in patent: Page/Page column 161.

3
[ 61676-62-8 ]
[ 1395281-64-7 ]
[ 1395281-67-0 ]