959992-62-2|6-Bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine| Ambeed

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Quality Control of [ 959992-62-2 ] Purity: 97% SDS Specification

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Product Details of [ 959992-62-2 ]

CAS No. :	959992-62-2
Formula :	C₇H₇BrN₂O
M.W :	215.05
SMILES Code :	BrC1=CC=C2OCCNC2=N1
MDL No. :	MFCD09834129
InChI Key :	OTGDCHNSXQUISE-UHFFFAOYSA-N
Pubchem ID :	20824376

Safety of [ 959992-62-2 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P280-P305+P351+P338-P310

Computational Chemistry of [ 959992-62-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.29
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	48.56
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	34.15 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.89
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	1.94
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.08
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.	1.04
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	2.04
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.6

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.8
Solubility	0.342 mg/ml ; 0.00159 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.	-2.28
Solubility	1.12 mg/ml ; 0.00523 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	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	-3.23
Solubility	0.128 mg/ml ; 0.000593 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	Yes
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.	-6.23 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	0.0
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	1.0 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)	2.41

Application In Synthesis of [ 959992-62-2 ]

* 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 [ 959992-62-2 ]

[ 959992-62-2 ] Synthesis Path-Downstream 1~35

1
[ 959992-61-1 ]
[ 959992-62-2 ]

Yield	Reaction Conditions	Operation in experiment
55%		To a solution of 6-bromo-3-(2-bromoethoxy)-2-nitropyridine (4.5 g, 13.8 mmol) in glacial acetic acid (23 ml) was added iron (powder, 3.08 g, 55.2 mmol) in one portion. The reaction mixture was heated to 90C during 5 hours, then cooled down, diluted in ethyl acetate and filtered through a silica gel plug using ethyl acetate as eluent. After evaporation, the residue was dissolved in DMF (50 ml). Potassium carbonate (5.72 g, 41.4 mmol) was added and the mixture was heated to 90C for 2 hours, then to 70C overnight. After evaporation of solvent, the residue was dissolved in DCM, salts were removed by filtration, and the crude compound was purified by silica gel flash chromatography (30 to 50% ethyl acetate in petroleum ether) to give 6-bromo-3,4-dihydro-2H-pyrido[3,2- b][l,4]oxazine as a pale yellow oil (1.64 g, 55%); Mass Spectrum [M+H]+ = 215; 1H NMR Spectrum (CDC13) 3.54-3.60 (m, 2H), 4.19 (t, 2H), 5.35 (bs, IH), 6.66 (d, IH), 6.82 (d, IH).

References: [1]Patent: WO2007/141473,2007,A1 .Location in patent: Page/Page column 268; 269.
[2]Patent: WO2011/59839,2011,A1 .

3
[ 959992-62-2 ]
[ 544-92-3 ]
[ 928118-39-2 ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 120℃; for 3h;Micrawave irradiation;	A Smith process vial was charged with a stir bar, compound 54B (0.33 g, 1.54 mmol), CuCN (0.276 g, 3.08 mmol) and DMF (3 mL). The reaction vessel was sealed and heated to 120 C. for 3 h under microwave irradiation. After cooling, the reaction mixture was transferred to a round bottom flask and concentrated under vacuum. Compound 55A was obtained quantitatively by continuous extraction with EtOAc in a Soxlet apparatus.

References: [1]Patent: US2007/93477,2007,A1 .Location in patent: Page/Page column 52.

4
[ 959992-62-2 ]
[ 1423-26-3 ]
[ 1303587-79-2 ]

Yield	Reaction Conditions	Operation in experiment
	With caesium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; at 50℃;	6-bromo-3,4-dihydro-2H-pyrido[3,2-b] [l ,4]oxazine (5; 2.0 g, 9.30 mmol), 3-(trifluromethyl)- phenylboronic acid (2.65 g, 1 3.95 mmol), Pd(Ph3)4 (21 5 mg, 0. 186 mmol) and CsCO3 (6.0 g, 18.6 mmol) were all dissolved in dioxane:H20 mixture (45 mL: l mL) and heated to 50 C overnight. Product peak seen by LCMS, but some starting material remained, added more boronic acid and stirred at 50 C overnight. The starting material peak was unchanged, cooled to room temp and some precipitates started to crash out. Diluted with water (40 mL), extracted with EtOAc (3 x 40 mL), washed with brine, dried over MgS04, filtered, concentrated and purified through I SCO silica column (0 to 100% EtOAc/pentanes) to collect mixed fractions of 6-(3-(trifluoromethyl)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][ l ,4]oxazine (6) M S (ESI) calcd for C 14H1 1 F3N2O (m/z) 280.08, found 281 [M+H].

References: [1]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 65.

5
[ 15128-82-2 ]
[ 959992-62-2 ]

References: [1]Patent: WO2011/59839,2011,A1 .
[2]Patent: EP2341052,2011,A1 .

6
[ 443956-08-9 ]
[ 959992-62-2 ]

References: [1]Patent: WO2011/59839,2011,A1 .
[2]Patent: EP2341052,2011,A1 .
[3]Patent: WO2013/169864,2013,A2 .
[4]Patent: WO2007/141473,2007,A1 .
[5]Patent: CN108623615,2018,A .

7
[ 959992-62-2 ]
[ 1303587-91-8 ]

References: [1]Patent: WO2011/59839,2011,A1 .

8
[ 959992-62-2 ]
[ 1303582-20-8 ]

References: [1]Patent: WO2011/59839,2011,A1 .

9
[ 959992-62-2 ]
[ 1303583-13-2 ]

References: [1]Patent: WO2011/59839,2011,A1 .

10
[ 959992-62-2 ]
[ 1303581-80-7 ]

References: [1]Patent: WO2011/59839,2011,A1 .

11
[ 1303588-62-6 ]
[ 959992-62-2 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate; In N,N-dimethyl-formamide; at 90℃;	To a solution of 6-bromo-3-(2-bromoethoxy)-2-nitropyridine (3; 560 mg, 1 .73 mmol) in glacial acetic acid (6 mL) was added Fe (387 mg, 6.91 mmol) in one portion. The reaction mixture was heated at 90 C for 5 h, then cooled down, di luted in EtOAc and filtered through a silica plug using EtOAc as the eluent. After evaporation of the AcOH, the residue 4 was dissolved in DMF (5 mL), 2CO3 (716 mg, 5. 19 mmol) was added and the mixture was heated to 90 C overnight. In general, the solvent was concentrated and the mixture was purified by silica gel chromatography to afford 6-bromo-3,4-dihydro-2H-pyrido[3,2- b][l ,4]oxazine (5; 185 mg, 50%). MS (ESI) calcd for C7H7BrN20 (m/z): 21 3.97.

References: [1]Patent: WO2011/59839,2011,A1 .Location in patent: Page/Page column 65.

12
[ 959992-62-2 ]
[ 103-71-9 ]
[ 1214927-90-8 ]

Yield	Reaction Conditions	Operation in experiment
85%	With triethylamine; In N,N-dimethyl-formamide; at 25℃; for 24h;	Step 5 To a solution of Compound (10) (2.50 g, 11.6 mmol) in dimethylformamide (20 mL), triethylamine (4.8 mL), 34.9 mmol) and phenylisocyanate (1.6 mL, 15.1 mmol) were added. The solution was then stirred at 25 C for 24 hours. Water (3.0 mL) was then added to the reaction solution. The precipitated powder was filtered, washed with water, and then dried to yield subject compound I-113 (3.4 g, 85%) as a pale brown powder.1H-NMR (DMSO-d6) delta11.92 (1H, s), 7.52-7.55 (2H, m), 7.34-7.40 (3H, m), 7.28 (1H, dd, J = 8.4 Hz, J = 1.5 Hz), 4.30 (2H, t, J = 4.8 Hz), 4.04 (2H, t, J = 4.8 Hz) LC/MS (Method A): 2.45 min, [M+H]+ = 334.0.

References: [1]Patent: EP2341052,2011,A1 .Location in patent: Page/Page column 35; 36.

13
[ 443956-09-0 ]
[ 959992-62-2 ]

References: [1]Patent: EP2341052,2011,A1 .
[2]Patent: CN108623615,2018,A .

14
[ 337463-88-4 ]
[ 959992-62-2 ]

Yield	Reaction Conditions	Operation in experiment
100%		Step 4 To a solution of Compound (9) (3.12 g, 13.7 mmol) in tetrahydrofuran (50 mL), borane-tetrahydrofuran complex (33 mL, 33.0 mmol) was added at room temperature. The solution was then stirred at 90C for 1.5 hours. Methanol (2.0 mL) was added to the reaction solution, and then the mixture was stirred at 90C for 20 minutes. The reaction solution was concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate, dried with anhydrous magnesium sulfate, and then concentrated in vacuo to yield subject compound (10) (3.17 g, 100%) as a yellow powder.1H-NMR (DMSO-d6) 57.04 (1H, br s), 6.69 (1H, d, J = 7.8 Hz), 6.40 (1H, d, J = 7.8 Hz), 3.91 (2H, t, J = 4.2Hz), 3.19-3.23 (2H, m) LC/MS (Method A): 1.44 min, [M+H]+ = 215.2.
99%	With diborane; In tetrahydrofuran; for 1h;Cooling with ice; Reflux;	Under ice bath conditions, Borane in tetrahydrofuran (5.5 mL, 5.5 mmol, 1.0 M) Add dropwise to compound 3.2 (500 mg, 2.19 mmol) In a solution of tetrahydrofuran (25 mL), The reaction system was stirred under reflux with heating for 1 hour. The reaction was then carefully quenched with methanol (10 drops) under reflux. The mixture was cooled to room temperature and concentrated under reduced pressure to remove solvent. The residue was chromatographed on silica gel ( petroleum ether / ethyl acetate = 5/1) Purification afforded compound 23.1 (470 mg, yield: 99%) It is a white solid.
87%	With dimethylsulfide borane complex; potassium carbonate; In tetrahydrofuran; at 70℃; for 0.25h;Inert atmosphere;	Part IV- Synthesis of 6-Bromo-3,4-dihydro-2H-pyrido[3,2-b] [1,4]oxazine; 6-Bromo-4H-pyrido[3,2-b][1,4]oxazin-3-one (1.35 g, 5.89 mmol) was dissolved inTHF (40 mL). Boranedimethylsulphide complex (2.0 Min THF, 5.89 mL, 11.79 mmol) wasadded and the resulting mixture heated to 70 C under nitrogen for 15 minutes. Next, thereaction mixture was cooled to room temperature, quenched with methanol ( ~5 mL ), and then dried under vacuum to obtain a white solid. The crude material was dissolved indichloromethane and washed with H20. The aqueous phase was discarded and the organicphase was dried under vacuum to give 6-bromo-3,4-dihydro-2H-pyrido[3,2-b ][1,4]oxazine.Yield: 1.1 g (87%). LCMS (ESI): calc. C7H7BrN20 = 214, 216; obs. M+H = 215, 217.

References: [1]Patent: EP2341052,2011,A1 .Location in patent: Page/Page column 35; 36.
[2]Patent: CN108623615,2018,A .Location in patent: Paragraph 0388; 0389; 0390.
[3]Patent: WO2013/169864,2013,A2 .Location in patent: Paragraph 00205.

15
[ 959992-62-2 ]
[ 1214928-52-5 ]