1154740-48-3|6-Bromo-5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine| Ambeed

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Quality Control of [ 1154740-48-3 ] Purity: 95% SDS Specification

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Product Details of [ 1154740-48-3 ]

CAS No. :	1154740-48-3
Formula :	C₉H₁₀BrNO
M.W :	228.09
SMILES Code :	CC1=C2C(OCCN2)=CC=C1Br
MDL No. :	MFCD20526453

Safety of [ 1154740-48-3 ]

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

Computational Chemistry of [ 1154740-48-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.33
Num. rotatable bonds	0
Num. H-bond acceptors	1.0
Num. H-bond donors	1.0
Molar Refractivity	55.73
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.	2.32
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	2.71
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.99
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.	2.12
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	2.95
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.42

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.33
Solubility	0.106 mg/ml ; 0.000466 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.	-2.81
Solubility	0.353 mg/ml ; 0.00155 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	-3.99
Solubility	0.0235 mg/ml ; 0.000103 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.	-5.77 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	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)	2.16

Application In Synthesis of [ 1154740-48-3 ]

* 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 [ 1154740-48-3 ]

[ 1154740-48-3 ] Synthesis Path-Downstream 1~18

1
[ 1154740-48-3 ]
[ 73183-34-3 ]
[ 1154740-49-4 ]

Yield	Reaction Conditions	Operation in experiment
65%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 90℃; for 5.58333h;	Step 5:A well stirred DMF (15 mL) solution of the arylbromide 5e (0.50 g, 2.19 mmol), potassium acetate (0.728 g, 7.67 mmol) and bis(pinacolato)diborane (0.83 g, 3.3 mmol) is degassed by bubbling Ar through the solution for 20 min. PdCI2(dppf)-DCM (320 mg, 0.44 mmol) is added and degassing is continued for 15 min. The system is sealed (teflon screw cap vessel) under Ar and heated to ~90C for 5 h. The reaction mixture is allowed to cool to RT, dilute with EtOAc (150 mL), washed with brine (3 x 100 mL) and water (2 x 100 mL), dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue is purified by CombiFlash Companion (EtOAc/hexanes) to give the desired boronate 5f (389 mg, 65% yield) as a yellowish waxy solid.
65%	With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; at 90℃; for 5.58h;Sealed vessel;	A well stirred DMF (15 ml.) solution of the arylbromide 5e (0.50 g, 2.19 mmol, 1 eq), potassium acetate (0.728 g, 7.67 mmol, 3.5 eq) and bis(pinacolato)diborane (0.83 g, 3.3 mmol, 1.5 eq) is degassed by bubbling Ar through the solution for about 20 min. PdCI2(dppf)-DCM (320 mg, 0.44 mmol, 0.20 eq) is added and degassing is continued for about 15 min. The system is sealed (teflon screw cap vessel) under Ar and heated to ~90C for about 5 h. The reaction mixture is allowed to cool to RT, dilute with EtOAc (150 ml_), washed with brine (3 x 100 ml_) and water (2 x 100 ml_), dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue is purified by CombiFlash Companion (EtOAc/hexanes) to give the desired boronate 5f (389 mg, 65% yield) as a yellowish waxy solid.
65%		A well stirred DMF (15 mL) solution of the arylbromide 5e (0 50 g, 2 19 mmol), potassium acetate (0 728 g, 7 67 mmol) and biotas(piotanacolato)diotaborane (0 83 g, 3 3 mmol) is degassed by bubbling Ar through the solution for 20 mm PdCI2(dppf)-DCM (320 mg, 0 44 mmol) is added and degassing is continued for 15 mm The system is sealed (teflon screw cap vessel) under Ar and heated to ~90C for 5 h The reaction mixture is allowed to cool to RT, dilute with EtOAc (150 mL), washed with brine (3 x 100 mL) and water (2 x 100 mL), dried over anhydrous MgSO4, filtered and concentrated to dryness The residue is purified by CombiFlash Companion (EtOAc/hexanes) to give the desired boronate 5f (389 mg, 65% yield) as a yellowish waxy solid

65%	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In N,N-dimethyl-formamide; at 90℃; for 5h;	A well stirred DMF (15 mL) solution of the arylbromide 5e (0.50 g, 2.19 mmol), potassium acetate (0.728 g, 7.67 mmol) and bis(pinacolato)diborane (0.83 g, 3.3 mmol) is degassed by bubbling Ar through the solution for 20 min. PdCI2(dppf)-DCM (320 mg, 0.44 mmol) is added and degassing is continued for 15 min. The system is sealed (teflon screw cap vessel) under Ar and heated to 900C for 5 h. The reaction mixture is allowed to cool to RT, dilute with EtOAc (150 mL), washed with brine (3 x 100 mL) and water (2 x 100 mL), dried over anhydrous MgSO4, filtered and concentrated to dryness. The residue is purified by CombiFlash Companion (EtOAc/hexanes) to give the desired boronate 5f (389 mg, 65% yield) as a yellowish waxy solid.
	With dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; potassium acetate; In N,N-dimethyl-formamide; at 90℃; under 760.051 Torr; for 1h;	A mixture of 6-bromo-5-methyl-3,4-dihydro-2H-benzo[b][1 ,4]oxazine (2.276 g, 9.98 mmol), potassium acetate (2.94 g, 29.9 mmol) and bis(pinacolato)diboron (3.80 g, 14.97 mmol) in Nu,Nu-dimethylformamide (DMF) (10 mL) was degassed with nitrogen. PdCI2(dppf)- CH2CI2 adduct (1 .630 g, 1 .996 mmol) was added and then the flask was immersed in a 90 C oil bath and heated for 1 hour. The mixture was cooled to ambient temperature and allowed to sit for several days. The mixture was filtered over Celite to remove the solids and the filter cake was washed with ethyl acetate. The filtrate was washed twice with water. The water was back extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to afford an off-white solid: 1H NMR (400MHz, CHLOROFORM-d) delta ppm 7.19 (d, J = 8.2 Hz, 1 H), 6.69 (d, J = 8.0 Hz, 1 H), 4.29 - 4.16 (m, 2 H), 3.59 (br. s., 1 H), 3.53 - 3.39 (m, 2 H), 2.35 (s, 3 H), 1.33 (s, 9 H); LC/MS (m/z) ES+ = 276 (M+1 ).

References: [1]Patent: WO2009/62285,2009,A1 .Location in patent: Page/Page column 54; 56.
[2]Patent: WO2009/62308,2009,A1 .Location in patent: Page/Page column 64; 66.
[3]Patent: WO2009/62288,2009,A1 .Location in patent: Page/Page column 61-62.
[4]Patent: WO2009/62289,2009,A1 .Location in patent: Page/Page column 68; 70.
[5]Patent: WO2013/12649,2013,A1 .Location in patent: Paragraph 00322.

2
[ 1154740-47-2 ]
[ 1154740-48-3 ]

Yield	Reaction Conditions	Operation in experiment
86%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 42h;Inert atmosphere;	a) 6-Bromo-5-methyl-3,4-dihydro-2H-benzo[1,4]oxazine A solution of 6-bromo-5-methyl-4H-benzo[1,4]oxazin-3-one (CAS registry 1154740-47-2) (425 mg, 1.56 mmol) in THF (9 ml) was treated under argon at 0 C. with BH3*THF (1M in THF, 4.7 ml, 4.69 mmol) and stirred for 18 h at rt. BH3.THF 1M (2 ml) was added and stirring was continued for another 24 h. The reaction mixture was concentrated and purified by flash chromatography on silica gel (cyclohexane/EtOAc 100:0 to 80:20) to afford the title compound as an orange solid (324 mg, 86% yield) HPLC RtM1=1.04 min; ESIMS: 228, 230 [(M+H)+]. 1H NMR (400 MHz, DMSO-d6): delta 6.68 (d, 1H), 6.48 (d, 1H), 5.54 (br s, 1H), 4.04 (t, 2H), 3.36-3.26 (m, 2H), 2.11 (s, 3H).
81%		Step 4:To an ice cold THF (6 mL) solution of the cyclic amide 5d (280 mg, 1.16 mmol) under nitrogen, a borane-THF solution (1M in THF, 1.74 mL, 1.74 mmol) is added slowly. The reaction mixture is slowly allowed to warm to RT, then is stirred at RT for approximately 1.5 h and then gently heated to reflux for 1 h to complete the conversion. The mixture is cooled in an ice bath and is carefully quenched with aqueous 1 M NaOH (4 mL) over 10 min. The reaction mixture is partitioned between EtOAc (150 mL) and water (25 mL). The organic layer is washed with aqueous 1 N <n="57"/>NaOH (20 ml_), saturated aqueous NaCI, and finally dried over anhydrous MgSO4, filtered and concentrated to give the crude 5e as an amber oil (212 mg, 81% yield). This product is used as such for next transformation.
81%		To an ice cold THF (6 mL) solution of the cyclic amide 5d (280 mg, 1.16 mmol) under nitrogen, a borane-THF solution (1M in THF, 1.74 mL, 1.74 mmol, 1 ,5 eq) is added slowly. The reaction mixture is slowly allowed to warm to RT, then is stirred at RT for approximately 1.5 h and then gently heated to reflux for about 1 h to complete the conversion. The mixture is cooled in an ice bath and is carefully quenched with aqueous 1 M NaOH (4 mL) over about 10 min. The reaction mixture is partitioned between EtOAc (150 mL) and water (25 mL). The organic layer is washed with aqueous 1 N NaOH (20 mL), saturated aqueous NaCI, and finally dried over anhydrous MgSO4, filtered and concentrated to give the crude 5e as an amber oil (212 mg, 81% yield). This product is used as such for next transformation.

81%	With borane-THF; In tetrahydrofuran; at 0 - 25℃; for 2.5h;Heating / reflux;	To an ice cold THF (6 mL) solution of the cyclic amide 5d (280 mg, 1 16 mmol) under nitrogen, a borane-THF solution (1 M in THF, 1 74 mL, 1 74 mmol) is added slowly The reaction mixture is slowly allowed to warm to RT, then is stirred at RT for approximately 1 5 h and then gently heated to reflux for 1 h to complete the conversion The mixture is cooled in an ice bath and is carefully quenched with aqueous 1 M NaOH (4 mL) over 10 mm The reaction mixture is partitioned between EtOAc (150 mL) and water (25 mL) The organic layer is washed with aqueous 1 N NaOH (20 mL) and brine, dried over anhydrous MgSO4, filtered and concentrated to give the crude 5e as an amber oil (212 mg, 81 % yield) This product is used as such for next transformation
81%	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 2.5h;Heating / reflux;	To an ice cold THF (6 mL) solution of the cyclic amide 5d (280 mg, 1.16 mmol) under nitrogen, a borane-THF solution (1 M in THF, 1.74 mL, 1.74 mmol) is added slowly. The reaction mixture is slowly allowed to warm to RT, then is stirred at RT for 1.5 h and then gently heated to reflux for 1 h to complete the conversion. The mixture is cooled in an ice bath and is carefully quenched with aqueous 1 M NaOH (4 mL) over 10 min. The reaction mixture is partitioned between EtOAc (150 mL) and water (25 mL). The organic layer is washed with aqueous 1 N NaOH (20 mL), saturated aqueous NaCI, and finally dried over anhydrous MgSO4, filtered and concentrated to give the crude 5e as an amber oil (212 mg, 81% yield). This product is used as such for next transformation.
	With borane-THF; In tetrahydrofuran; at 20℃; under 760.051 Torr; for 2.5h;Cooling with ice;	An ice cold mixture of 6-bromo-5-methyl-2H-1 ,4-benzoxazin-3(4H)-one (3.05 g, 12.59 mmol) in tetrahydrofuran (THF) (40 mL) was treated with borane tetrahydrofuran complex (1 .0 M solution in tetrahydrofuran (18.88 mL, 18.88 mmol) and the mixture was stirred at ambient temperature for 150 minutes. The mixture was cooled to 0 C and then quenched slowly with 1 N NaOH (30 mL). The mixture was extracted with ethyl acetate, then washed with 1 N NaOH, dried over sodium sulfate, filtered and then concentrated to a thick dark brown oil. The material was purified on silica gel (95:4:1 dichloromethane/methanol/ammonium hydroxide, gradient) to afford an off-white solid: 1H NMR (400MHz, CHLOROFORM-d) delta ppm 6.87 (d, J = 8.6 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 1 H), 4.31 - 4.15 (m, 2 H), 3.56 - 3.38 (m, 2 H), 2.22 (s, 3 H); LC/MS (m/z) ES+ = 228 (M+1 ).

References: [1]Patent: US2013/165436,2013,A1 .Location in patent: Paragraph 0664; 0665; 0666.
[2]Patent: WO2009/62285,2009,A1 .Location in patent: Page/Page column 54-56.
[3]Patent: WO2009/62308,2009,A1 .Location in patent: Page/Page column 64; 65.
[4]Patent: WO2009/62288,2009,A1 .Location in patent: Page/Page column 61-62.
[5]Patent: WO2009/62289,2009,A1 .Location in patent: Page/Page column 68; 69.
[6]Patent: WO2013/12649,2013,A1 .Location in patent: Paragraph 00321.

3
[ 4920-77-8 ]
[ 1154740-48-3 ]

References: [1]Patent: WO2013/12649,2013,A1 .
[2]Patent: WO2009/62289,2009,A1 .

4
[ 85598-12-5 ]
[ 1154740-48-3 ]

References: [1]Patent: WO2013/12649,2013,A1 .
[2]Patent: WO2009/62289,2009,A1 .

5
[ 1154740-46-1 ]
[ 1154740-48-3 ]

References: [1]Patent: WO2013/12649,2013,A1 .
[2]Patent: WO2009/62289,2009,A1 .

6
[ 1154740-48-3 ]
(2S)-methyl 2-(tert-butoxy)-2-((M)-1-(2,3-difluorobenzyl)-6-methyl-4-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetate [ No CAS ]

References: [1]Patent: WO2013/12649,2013,A1 .

7
[ 1154740-48-3 ]
(2S)(M)-2-(tert-butoxy)-2-(1-(2,3-difluorobenzyl)-6-methyl-4-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)acetic acid [ No CAS ]

References: [1]Patent: WO2013/12649,2013,A1 .

8
[ 1154740-48-3 ]
[ 1418719-85-3 ]