1228690-37-6|(R)-1-Phenylethyl (5-(4-bromophenyl)-3-methylisoxazol-4-yl)carbamate| Ambeed

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Quality Control of [ 1228690-37-6 ] Purity: 97% SDS Specification

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Product Details of [ 1228690-37-6 ]

CAS No. :	1228690-37-6
Formula :	C₁₉H₁₇BrN₂O₃
M.W :	401.25
SMILES Code :	O=C(O[C@@H](C1=CC=CC=C1)C)NC2=C(C3=CC=C(Br)C=C3)ON=C2C
MDL No. :	MFCD25977339
InChI Key :	YIZLYJGOEIDGMD-CYBMUJFWSA-N
Pubchem ID :	66660383

Safety of [ 1228690-37-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H335
Precautionary Statements:	P261-P305+P351+P338

Computational Chemistry of [ 1228690-37-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	25
Num. arom. heavy atoms	17
Fraction Csp3	0.16
Num. rotatable bonds	6
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	99.69
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	64.36 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	3.46
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	4.6
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	5.21
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.	3.31
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	4.32
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	4.18

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-5.33
Solubility	0.00186 mg/ml ; 0.00000465 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-5.68
Solubility	0.000846 mg/ml ; 0.00000211 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Moderately 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	-7.61
Solubility	0.00000987 mg/ml ; 0.0000000246 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Poorly 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	Yes
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	Yes
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	Yes
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from Potts RO and Guy RH. 1992 Pharm. Res.	-5.48 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<2.0
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)	3.95

Application In Synthesis of [ 1228690-37-6 ]

* 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 [ 1228690-37-6 ]

[ 1228690-37-6 ] Synthesis Path-Downstream 1~25

1
[ 859169-20-3 ]
[ 1228690-37-6 ]
[ 1228690-38-7 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;	Step 3: {4'-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester (39 g, 97.2 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (31 g, 107 mmol), and sodium bicarbonate (32.6 g, 389 mmol) were combined in 3:1 DME:H2O (500 mL), and the mixture was purged with N2 for 15 minutes. (1,1'-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (2.13 g, 2.91 mmol) was added, and the reaction was purged with N2 for an additional 10 minutes and then stirred at 90 C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography (EtOAc/hexane gradient) to give the title compound.
	With sodium hydrogencarbonate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,2-dimethoxyethane; water; at 90℃;Inert atmosphere;Product distribution / selectivity;	Step 3: {4'-[3-Methyl-4-((R)-l-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}- acetic acid ethyl ester[00484] [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)- 1 -phenyl-ethyl ester (39g, 97.2mmol), [4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (31g, 107mmol), and sodium bicarbonate (32.6g, 389mmol) were combined in 3: 1 DME:H20 (500mL), and the mixture was purged with N2 for 15 minutes. (l,l'-Bis(diphenylphosphino)ferrocene)- dichloropalladium(II) (2.13g, 2.91mmol) was added, and the reaction was purged with N2 for an additional 10 minutes and then stirred at 90C overnight. The mixture was partitioned between EtOAc and H20, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with H20, dried over MgS04, filtered, and concentrated, and the residue was purified by silica gel chromatography (EtOAc/hexane gradient) to give the title compound.

References: [1]Patent: US2010/152257,2010,A1 .Location in patent: Page/Page column 25.
[2]Patent: WO2011/159550,2011,A2 .Location in patent: Page/Page column 80.

2
[ 1517-69-7 ]
[ 91182-60-4 ]
[ 1228690-37-6 ]

Yield	Reaction Conditions	Operation in experiment
83%	With diphenyl phosphoryl azide; triethylamine; In toluene; at 80℃; for 3h;	To a solution of compound XLV-1 (8 g, 28.08 mmol) in dry toluene (150 mL) was added compound XLV-2 (1.58 g, 10.1 mmol), triethylamine (8.0 mL) and DPPA (9.2 g, 33.6 mmol). The reaction mixture was heated to 80 C for 3 hours. The mixture was diluted with EtOAc (50 mL), washed with brine, dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (PE/EA = 10 IX) to give compound XLV-3 (9.4 g, yield: 83 %). MS (ESI) m/z (M+H)+ 402.0.
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 75℃; for 2h;	Step 2: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (25 g, 88.7 mmol) in toluene (500 mL) was added triethylamine (18.5 mL, 133 mmol), followed by diphenylphosphoryl azide (22.1 mL, 101.9 mmol). (R)-(+)-1-Phenylethyl alcohol (11.9 mL, 97.5 mmol) was added, and the reaction was stirred at 75 C. for 2 hours. The mixture was partitioned between EtOAc and H2O and filtered through Celite. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give the title compound.
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 80℃; for 4h;	5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (2.Og, 7.09mmol) and triethylamine (0.99mL, 7.09mmol) were dissolved in toluene (5OmL). Diphenylphosphoryl azide (1.5mL, 7.09mmol) was added, followed by (R)-(+)-l- phenylethyl alcohol (0.865g, 7.09mmol; commercially available or prepared using procedures desribed herein or in the literature: e.g. E.J. Corey et al. J. Am. Chem. 1987, 109, 5551-5553), and the reaction was stirred at 8O0C for 4 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.

	With diphenyl phosphoryl azide; triethylamine; In toluene; at 75℃; for 2h;Product distribution / selectivity;	Step 2: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-l-phenyl-ethyl ester[00483] 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (25g, 88.7mmol) in toluene (500mL) was added triethylamine (18.5mL, 133mmol), followed by diphenylphosphoryl azide (22.1mL, 101.9mmol). (R)-(+)- 1 -Phenylethyl alcohol (11.9mL, 97.5mmol) was added, and the reaction was stirred at 75C for 2 hours. The mixture was partitioned between EtOAc and H 0 and filtered through Celite. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgS04, filtered, and concentrated to give the title compound.
	With diphenyl phosphoryl azide; triethylamine; In toluene; at 80℃; for 4h;	Step 5: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-l-phenyl-ethyl ester: 5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (2.0g, 7.09mmol) and triethylamine (0.99mL, 7.09mmol) were dissolved in toluene (50mL). Diphenylphosphoryl azide (1.5mL, 7.09mmol) was added, followed by (R)-(+)- 1 -phenylethyl alcohol (0.865g, 7.09mmol; commercially available or prepared using procedures desribed herein or in the literature: e.g. E.J. Corey et al. J. Am. Chem. 1987, 109, 5551-5553), and the reaction was stirred at 80C for 4 hours. The mixture was concentrated, and the residue was purified by silica gel chromatography to give the title compound.

References: [1]Patent: WO2013/25733,2013,A1 .Location in patent: Paragraph 0563.
[2]Organic Process Research and Development,2017,vol. 21,p. 1859 - 1863.
[3]Patent: US2010/152257,2010,A1 .Location in patent: Page/Page column 25.
[4]Patent: WO2010/141761,2010,A2 .Location in patent: Page/Page column 42.
[5]Patent: WO2011/159550,2011,A2 .Location in patent: Page/Page column 80.
[6]Patent: WO2012/78805,2012,A1 .Location in patent: Page/Page column 87-88.

3
[ 1159489-46-9 ]
[ 1228690-37-6 ]
[ 1257213-50-5 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 80℃; for 2h;Inert atmosphere; Sealed tube;	[5-(4-Bromo-phenyl)-3-methyl-isoxazol-4- yl]-carbamic acid (R)-l-phenyl-ethyl ester (0.248g, 0.62mmol), 4-(l'-carboxyl- cyclopropyl)phenylboronic acid (0.16Og, 0.62mmol), and sodium carbonate (0.155g, 1.85mmol) were combined in 2:1 DME:H2theta. The solution was purged with N2 for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.047g, 0.06mmol) was added. The reaction was purged with N2 for an additional 10 minutes, and then stirred in a sealed tube at 8O0C for 2 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
	With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; water; at 80℃; for 2h;Inert atmosphere; Sealed vessel;	Step 6: l-{4'-[3-Methyl-4-((R)-l-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4- yl}-cyclopropanecarboxylic acid: [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)- l- phenyl-ethyl ester (0.248g, 0.62mmol), 4-(l'-carboxyl-cyclopropyl)phenylboronic acid (0.160g, 0.62mmol), and sodium carbonate (0.155g, 1.85mmol) were combined in 2: 1 DME:H20. The solution was purged with N2 for 10 minutes, and then bis(triphenylphosphine)palladium(II) dichloride (0.047g, 0.06mmol) was added. The reaction was purged with N2 for an additional 10 minutes, and then stirred in a sealed tube at 80C for 2 hours. The mixture was partitioned between EtOAc and H20, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO/t, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound. Mass spec, data (M+H) = 483.

References: [1]Patent: WO2010/141761,2010,A2 .Location in patent: Page/Page column 42-43.
[2]Patent: WO2012/78805,2012,A1 .Location in patent: Page/Page column 88.

4
[ 1228690-37-6 ]
[ 1257213-66-3 ]
[ 1257213-67-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,2-dimethoxyethane; water; at 90℃; for 1.5h;Inert atmosphere; Sealed tube;	[5-(4-bromo-phenyl)-3-methyl- isoxazol-4-yl]-carbamic acid (R)-l-phenyl-ethyl ester (0.077g, 0.19mmol), l-[4-(4,4,5,5- tetramethyl-[l,3,2]dioxaborolan-2-yl)-phenyl]-cyclopentanecarboxylic acid ethyl ester (0.079g, 0.23mmol), and potassium carbonate (0.066g, 0.48mmol) were combined in 2:1 DMEiH2O (3mL). The solution was purged with N2 for 5 minutes, and then tetrakis(triphenylphosphine)palladium(0) (0.022g, 0.02mmol) was added. The mixture was purged with N2 for an additional 5 minutes, and then the reaction was stirred at 9O0C in a sealed tube for 1.5 hours. Aqueous work-up, followed by silica gel chromatography, provided the title compound.

References: [1]Patent: WO2010/141761,2010,A2 .Location in patent: Page/Page column 51.

5
[ 98-86-2 ]
[ 1228690-37-6 ]

References: [1]Patent: WO2011/159550,2011,A2 .

6
[ 1228689-61-9 ]
[ 1228690-37-6 ]

References: [1]Patent: WO2011/159550,2011,A2 .
[2]Patent: WO2012/78805,2012,A1 .
[3]Patent: WO2013/25733,2013,A1 .

7
[ 1228690-37-6 ]
[ 1228690-36-5 ]

References: [1]Patent: WO2011/159550,2011,A2 .

8
[ 1228690-37-6 ]
[ 1345614-59-6 ]

References: [1]Patent: WO2011/159550,2011,A2 .

9
C₁₃H₁₄BrNO₃ [ No CAS ]
[ 1228690-37-6 ]

References: [1]Patent: WO2011/159550,2011,A2 .
[2]Patent: WO2012/78805,2012,A1 .

10
[ 1228690-37-6 ]
[ 1380650-53-2 ]

References: [1]Patent: WO2012/78805,2012,A1 .

11
[ 1228690-37-6 ]
[ 1423702-68-4 ]
[ 1423684-87-0 ]