56346-41-9|7-Fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine| Ambeed

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Quality Control of [ 56346-41-9 ] Purity: 97% SDS Specification

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Product Details of [ 56346-41-9 ]

CAS No. :	56346-41-9
Formula :	C₈H₈FNO
M.W :	153.15
SMILES Code :	FC1=CC=C2NCCOC2=C1
MDL No. :	MFCD11848177
InChI Key :	VRBQMPCMLZNPSK-UHFFFAOYSA-N
Pubchem ID :	14422953

Safety of [ 56346-41-9 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H320-H335
Precautionary Statements:	P264-P270-P301+P312-P330

Computational Chemistry of [ 56346-41-9 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	43.02
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	21.26 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.81
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	1.75
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.48
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.	1.52
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	2.28
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.77

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.3
Solubility	0.775 mg/ml ; 0.00506 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-1.81
Solubility	2.35 mg/ml ; 0.0154 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	-3.0
Solubility	0.152 mg/ml ; 0.000993 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.	-5.99 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)	1.95

Application In Synthesis of [ 56346-41-9 ]

* 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 [ 56346-41-9 ]

[ 56346-41-9 ] Synthesis Path-Downstream 1~24

1
[ 103361-99-5 ]
[ 56346-41-9 ]

Yield	Reaction Conditions	Operation in experiment
55.01%	With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 16h;Inert atmosphere;	To lithium tetrahydroaluminum (284mg, 7.48mmol)Tetrahydrofuran (5mL)To the suspension was added compound 2 (500 mg, 2.99 mmol).The mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours.The reaction system is water,15% sodium hydroxide aqueous solution was quenched, suction filtered, and the filtrate was extracted with ethyl acetate.Concentration and purification by column chromatography gave Compound 3 (252 mg, yield: 55.01%) as a yellow oil.

References: [1]Patent: CN110511220,2019,A .Location in patent: Paragraph 0496; 0497; 0501-0503.
[2]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4700 - 4704.

2
[ 56346-41-9 ]
[ 6160-65-2 ]
C₉H₉FN₂OS [ No CAS ]

References: [1]Bioorganic and Medicinal Chemistry Letters,2008,vol. 18,p. 4700 - 4704.

3
[ 53981-24-1 ]
[ 106-93-4 ]
[ 56346-41-9 ]

Yield	Reaction Conditions	Operation in experiment
43%	With potassium carbonate; In N,N-dimethyl-formamide; at 100℃; for 6h;	A suspension of 2-amino-5-fluorophenol (5.0 g, 39.37 mmol), 1,2-dibromoethane (21.9 g, 118.15 mmol), and potassium carbonate (27.16 g, 196.8 mmol) in DMF (50 mL) was stirred at 100C for 6 h. The reaction was diluted with water and extracted the product into ethyl acetate. The combined organic layer was washed with water, brine, dried over anhyd. Na2S04 and concentrated in vacuo. The residue was purified by column chromatography over silica gel (100-200 mesh) with 10% ethyl acetate in pet-ether as eluant gave 2.6 g (43%) of 7-fluoro-3,4- dihydro-2H-benzo[b][1,4]oxazine I-73 as a brown solid. 1H NMR (400 MHz, CDCI3): 6.46-6.55 (m, 3H), 4.24 (t, J = 4.4 Hz, 2H), 3.61 (br. s, 1H), 3.38 (t, J = 4.4 Hz, 2H).
	With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 125℃;	To a solution of 5-fluoro-2-nitrophenol (9.50 g) in methanol (10 ml), 5% palladium on activated carbon (1.90 g) was added and stirred overnight under a hydrogen atmosphere at room temperature. The catalyst was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was converted into a powder form by addition of chloroform, and then collected by filtration to give 2-amino-5-fluorophenol (6.81 g) as a brown powder. To a solution of 2-amino-5-fluorophenol thus obtained (3.00 g) in N,N-dimethylformamide (20 ml), potassium carbonate (16.31 g) and 1,2-dibromoethane (3.05 ml) were added and stirred at 125C for 10 hours. The reaction mixture was allowed to stand overnight at room temperature, to which additional 1,2-dibromoethane (1.52 ml) was then added and stirred at 125C for 7 hours. After cooling at room temperature, the reaction mixture was diluted with water under ice cooling and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by NH silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate = 9:1 to 7:3) to give the titled compound, i.e., 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine (1.15 g) as a red-brown oil. 1H NMR (300 MHz, CHLOROFORM-D) δ 3.35-3.42 (m, 2 H), 3.60 (brs, 1 H), 4.22-4.26 (m, 2 H), 6.44-6.56 (m, 3 H).

References: [1]Patent: WO2014/78813,2014,A1 .Location in patent: Page/Page column 143; 144.
[2]Patent: EP2172453,2010,A1 .Location in patent: Page/Page column 14-15.

4
[ 32315-10-9 ]
[ 56346-41-9 ]
E-4-aminoadamantan-1-ol [ No CAS ]
7-fluoro-N-(E-5-hydroxyadamantan-2-yl)-2,3-dihydro-4H-1,4-benzoxazine-4-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		To a solution of triphosgene (138 mg) in chloroform (3 ml), a solution of triethylamine (0.19 ml) and 7-fluoro-3,4-dihydro-2H-1,4-benzoxazine obtained in Reference Example 19 (142 mg) in chloroform (1 ml) was added under ice cooling and stirred at the same temperature for 10 minutes. To the reaction mixture, E-4-aminoadamantan-1-ol obtained in Reference Example 2 (153 mg), triethylamine (0.19 ml) and N,N-dimethylformamide (3 ml) were then added and stirred at room temperature for 20 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine. After drying over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluding solvent: chloroform alone → chloroform:methanol = 47:3). The residue was converted into a powder form by addition of a mixed solvent of diethyl ether and n-hexane, and then collected by filtration to give the titled compound (Compound 24, 190 mg) as a colorless powder. 1H NMR (300 MHz, CHLOROFORM-D) δ 1.38 (s, 1 H), 1.46-1.60 (m, 4 H), 1.71-1.81 (m, 4 H), 1.85-1.94 (m, 2 H), 2.09-2.18 (m, 3 H), 3.86 (dd, J=5.2, 4.2 Hz, 2 H), 3.92-3.99 (m, 1 H), 4.24 (dd, J=5.2, 4.2 Hz, 2 H), 5.46-5.53 (m, 1 H), 6.64-6.73 (m, 2 H), 7.20-7.25 (m, 1 H).

References: [1]Patent: EP2172453,2010,A1 .Location in patent: Page/Page column 30.

5
[ 56346-41-9 ]
C₁₁H₁₂FNO₃ [ No CAS ]