888327-32-0|4-Bromo-1-(difluoromethoxy)-2-methylbenzene| Ambeed

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Quality Control of [ 888327-32-0 ] Purity: 97% SDS Specification

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Product Details of [ 888327-32-0 ]

CAS No. :	888327-32-0
Formula :	C₈H₇BrF₂O
M.W :	237.04
SMILES Code :	CC1=CC(Br)=CC=C1OC(F)F
MDL No. :	MFCD11036069
Boiling Point :	No data available
InChI Key :	KOXSTKLIJNSMIO-UHFFFAOYSA-N
Pubchem ID :	45158710

Safety of [ 888327-32-0 ]

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

Computational Chemistry of [ 888327-32-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	45.7
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	9.23 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.43
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	3.9
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	4.2
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.	3.17
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	3.37
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	3.41

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-4.0
Solubility	0.0235 mg/ml ; 0.0000989 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.	-3.79
Solubility	0.0383 mg/ml ; 0.000161 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	0.0242 mg/ml ; 0.000102 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	Yes
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.	-4.98 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<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)	1.64

Application In Synthesis of [ 888327-32-0 ]

* 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 [ 888327-32-0 ]

[ 888327-32-0 ] Synthesis Path-Downstream 1~28

1
[ 888327-32-0 ]
cis-2,6-dimethylpiperazine [ No CAS ]
1-(4-difluoromethoxy-3-methyl-phenyl)-cis-3,5-dimethyl-piperazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
41%	With potassium tert-butylate;palladium diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; at 80℃; for 4h;	l-(4-Difluoromethoxy-3-methyl-phenyl)-cis-3,5-dimethyl-piperazine:; To 4-bromo-l- (difluoromethoxy)-2-methylbenzene (2.36 g, 10.00 mmol) in toluene (50 mL) was added cis-2,6- dimethylpiperazine (5 g, 58.14 mmol), Pd(OAc)2 (120 mg, 0.53 mmol), BINAP (380 mg, 0.61 mmol), and t-BuOK (2.2 g, 19.64 mmol). The resulting solution was stirred for 4 hours at 80C. The solution was cooled to room temperature and washed with H2O (2 X 50 mL), dried over Na2SCt, concentrated, and purified by silica gel column chromatography (10:1 CH2CWMeOH) to give 1.1 g (41%) of l-(4- (difluoromethoxy)-3-methylphenyl)-3,5-dimethylpiperazine.

References: [1]Patent: WO2006/55187,2006,A1 .Location in patent: Page/Page column 84.

2
[ 83190-02-7 ]
[ 888327-32-0 ]

Yield	Reaction Conditions	Operation in experiment
37%		4-Bromo-l-difluoromethoxy-2-niethyl-benzene:; To a stirred solution of 4-amino-l-difluoromethoxy-2- methyl -benzene (5 g, 28.90 mmol) in HBr (20 mL) and water (20 mL) at 0C was added a solution of sodium nitrite (2.07 g, 30.00 mmol) in H2O (10 ml) dropwise over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 30 minutes at 0C. Copper (I) bromide (4 g, 27.87 mmol) was then added and the mixture was heated at 60C for 30 minutes. The resulting solution was extracted with EtOAc (3 X 50 mL) and the combined organic layers washed with H2O (IX 2OmL), dried over Na2Stheta4 and concentrated to provide 2.5 g (37 %) of 4-bromo-l-(difluoromethoxy)-2- methylbenzene

References: [1]Patent: WO2006/55187,2006,A1 .Location in patent: Page/Page column 83.

3
[ 2362-12-1 ]
[ 1895-39-2 ]
[ 888327-32-0 ]

Yield	Reaction Conditions	Operation in experiment
19%	With potassium carbonate; In water; N,N-dimethyl-formamide; at 120℃; for 12h;	EXAMPLE 101Preparation of: 2-Amino-5-[4-(difluoromethoxy)-3-methylphenyl]-5-(3-ethoxy-4-fluorophenyl)-3- methyl-3,5-dihydro-4H-imidazol-4-oneStep 1 : 4-Bromo-1-(difluoromethoxy)-2-methylbenzene; In a 250 mL round-bottomed flask was placed 4-bromo-2-methylphenol (50 g, 267 mmol) and DMF (241 mL). Water (26.7 mL) was added to give a colorless solution. K2CO3 (148 g, 1069 mmol) was then added. Sodium 2-chloro-2,2-difluoroacetate (61.1 g, 401 mmol) was added and reaction heated to 120 0C for 12 h. The reaction was cooled to room temperature and partitioned between EtOAc (1000 mL) and water (1000 mL). The layers were separated and organic washed with water (2 x 500 mL) and brine (2x 500 mL). The organic layer was dried over Na2SO4 and filtered. The solvent was removed and crude material was passed through a plug of silica eluting with hexanes to provide 12.29 g, 19%, of the title compound as a clear oil.

References: [1]Patent: WO2008/115552,2008,A1 .Location in patent: Page/Page column 72.

4
[ 888327-32-0 ]
[ 1066-54-2 ]
[ 1062613-93-7 ]

Yield	Reaction Conditions	Operation in experiment
73%	With pyrrolidine;tetrakis(triphenylphosphine) palladium(0); at 80℃; for 0.5h;Microwave irradiation;	EXAMPLE 71 Preparation of 2-Amino-5,5-bis-[4-(difluoromethoxy)-3-methylphenyl]-3-methyl-3,5-dihydro-4H- imidazol-4-one; Step 1 : bis(4-difluoromethoxy-3-methyl-phenyl)acetyleneIn a CEM snap top microwave vial were combined trimethylsilylacetylene (0.207 g, 2.11 mmol), 4-Bromo-1-difluoromethoxy-2-methyl-benzene (1.00 g, 4.22 mmol), tetrakis(triphenylphosphine)palladium (56 mg, 0.0485 mmol) and pyrrolidine (1 ml_, 12 mmol).The reaction vial was placed in a CEM Explorer microwave and irradiated for 30 minutes at 8O0C. The crude reaction mixture was poured directly onto silica gel and purified by column chromatography (hexanes) to yield 0.519 g of 1 ,1'-(1.2-ethynediyl)bis[4-difluoromethoxy-3- methylbenzene] as a clear oil (73%). 1H NMR (400 MHz, DMSO-cfe) delta ppm 2.24 (s, 6 H) 7.19 (d, 2 H) 7.26 (t, J=73.7 Hz, 2H) 7.44 (q,J=8.6, 2.1 Hz, 2 H) 7.51 (d, J=1.4 Hz, 2 H); MS (El) m/z 338 [M+.]

References: [1]Patent: WO2008/115552,2008,A1 .Location in patent: Page/Page column 51.

5
[ 888327-32-0 ]
[ 1066-54-2 ]
[ 1062613-73-3 ]

Yield	Reaction Conditions	Operation in experiment
97%	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 65℃; for 12h;Product distribution / selectivity;	EXAMPLE 3Preparation of 2-Amino-4-(4-(difluoromethoxy)-3-methylphenyl)-4-(4-fluorophenyl)-1 -methyl-1 H- imidazol-5(4H)-oneStep 1 : (f4-(difluoromethoxy)-3-methylphenvnethvnyl)trimethylsilane; A solutionof <strong>[888327-32-0]4-bromo-1-(difluoromethoxy)-2-methylbenzene</strong> (5.3 g, 22.36 mmol), ethynyltrimethylsilane (4.74 ml_, 33.5 mmol), and triethylamine (15.58 ml_, 112 mmol) in DMF was degassed by bubbling with N2 for 30 min, treated with bis(triphen- ylphosphine)dichloropalladium (0.785 g, 1.118 mmol) with continued N2 bubbling, treated with copper(l) iodide (0.426 g, 2.236 mmol), warmed to 65 C for 12h, cooled toroom temperature, partitioned between ether and 2M HCI and filtered through Celite. The filtrate was separated and the organic phse was washed sequentially with 2M HCI and brine, dried over Na2SO4 and concentrated in vacuo. The resultant residue was purified by flash chromatography(100%hexanes) to provide ((4-(difluoromethoxy)-3-methylphenyl)ethynyl)trimethylsilane (5.49 g, 21.58 mmol, 97% yield). 1H NMR (400 MHz, DMSO-d6) § 7.39 (d, J = 1.5 Hz, 1 H), 7.32 (dd, J = 8.47 and 1.5 Hz, 1 H)1 7.20 (t, JH.F = 74 Hz, 1 H), 7.08 (d, J = 8.47 Hz, 1H), 2.15 (s, 3H), 0.18 (s, 9H).
83%	With pyrrolidine; copper(l) iodide;bis-triphenylphosphine-palladium(II) chloride; In acetonitrile; at 65℃; for 4h;Product distribution / selectivity;	Step 2: ((4-(Difluoromethoxy)-3-methylphenyl)ethvnyl)trimethylsilane; In a 250 mL round-bottomed flask was placed 4-bromo-1-(difluoromethoxy)-2- methylbenzene (14 g, 59.1 mmol) from the previous step. Pyrrolidine (23.6 mL) and acetonitrile (35.4 mL) were added to give a colorless solution. The reaction was degassed by bubbling with N2. Ethynyltrimethylsilane (7.0 g, 10 mL, 70.9 mmol) was added followed by bis(triphenylphosphine)dichloropalladium (2.07 g, 2.95 mmol) and copper(l) iodide (0.56 g, 2.95 <n="75"/>mmol) was added. The reaction was warmed to 65 0C for 4h. The reaction was cooled. The solution was partitioned between EtOAc (200 mL) and 1 M HCI (200 ml_). The organic was washed with 1M HCI (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4 and filtered. The solvent was removed and the resulting crude material was purified by flash chromatography (SiO2, 100% hexanes) to provide 12.4 g, 83%, of the title compound as a light yellow oil.
49.4%	With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; In N,N-dimethyl-formamide; at 60℃;	Dissolve <strong>[888327-32-0]4-bromo-1-(difluoromethoxy)-2-methylbenzene</strong> (18) (10 g, 42.2 mmol) in dry DMF (100 mL). Trimethylsilylacetylene (7.01 mL, 50.6 mmol), and triethylamine (17.6 mL, 127 mmol) were added and the mixture was bubbled with argon gas for about 5 minutes. Copper(I)iodide (8.3 mg, 4.22 mmol) and bis(tpp)PdCl2 (1.48 g, 2.11 mmol) were added and the mixture was stirred at 60 C overnight. The reaction mixture was diluted with ether and washed with brine. The organic layer was separated, washed with water and dried using sodium sulfate, filtered and concentrated under reduced pressure. The crude mixture was purified using flash chromatography using hexane and ethyl acetate to yield light brown solid ((4-(difluoromethoxy)-3-methylphenyl)ethynyl)trimethylsilane (19) (5.3 g, 49.4% yield).

References: [1]Patent: WO2008/115552,2008,A1 .Location in patent: Page/Page column 35.
[2]Patent: WO2008/115552,2008,A1 .Location in patent: Page/Page column 72-73.
[3]Patent: WO2019/169183,2019,A1 .Location in patent: Page/Page column 44; 45.

6
[ 888327-32-0 ]
[ 766-82-5 ]
[ 1062614-14-5 ]

Yield	Reaction Conditions	Operation in experiment
96%	With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; In N,N-dimethyl-formamide; at 60℃; for 12h;	EXAMPLE 77 Preparation of: 2-amino-5-[4-(difluoromethoxy)-3-methylphenyl]-3-methyl-5-(3-methylphenyl)- 3,5-dihydro-4H-imidazol-4-oneStep 1 : 1-(difluoromethoxy)-2-(2-fluoroethyl)-4-(phenylethvnyl)benzene; In a 50 mL round-bottomed flask was placed 4-bromo-1-(difluoromethoxy)-2- methylbenzene (0.8 g, 3.37 mmol) and DMF (6.75 mL) was added to give a colorless solution.1-Ethynyl-3-methylbenzene (0.436 mL, 3.37 mmol) and triethylamine (2.352 mL, 16.87 mmol) were added. The reaction was degassed by bubbling with N2.Bis(triphenylphosphine)palladium(ll) chloride (0.118 g, 0.169 mmol) was added and N2 bubbling was continued. Copper iodide (0.032 g, 0.169 mmol) was added. The reaction was heated to 60 C for 12h. The reaction was cooled and partitioned between ether (70 mL) and 1MHCI (50 mL). The organic was washed with 1 M HCI (50 mL) and brine (2 x 50 mL). The organic layer was dried over Na2SO4. The crude was purified by flash chromatography (100% hexanes) to <n="59"/>provide 1-(difluoromethoxy)-2-methyl-4-(m-tolylethynyl)benzene (0.88 g, 3.23 mmol, 96% yield) as a yellow oil with minor impurities.1H NMR (400 MHz, DMSO-d6) § 7.05-7.70 (m, 7H), 7.18 (t, JH.F = 74 Hz, 1H), 2.30 (s, 3H), 2.20(s, 3H)

References: [1]Patent: WO2008/115552,2008,A1 .Location in patent: Page/Page column 56-57.

7
[ 83190-00-5 ]
[ 888327-32-0 ]

References: [1]Patent: WO2006/55187,2006,A1 .

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[ 99-53-6 ]
[ 888327-32-0 ]

References: [1]Patent: WO2006/55187,2006,A1 .

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[ 888327-32-0 ]
[ 1062613-75-5 ]

References: [1]Patent: WO2008/115552,2008,A1 .
[2]Patent: WO2019/169183,2019,A1 .

10
[ 888327-32-0 ]
[ 1062613-78-8 ]

References: [1]Patent: WO2008/115552,2008,A1 .

11
[ 888327-32-0 ]
[ 1062614-17-8 ]

References: [1]Patent: WO2008/115552,2008,A1 .

12
[ 888327-32-0 ]
[ 1062614-64-5 ]

References: [1]Patent: WO2008/115552,2008,A1 .

13
[ 888327-32-0 ]
[ 1062613-95-9 ]

References: [1]Patent: WO2008/115552,2008,A1 .

14
[ 888327-32-0 ]
[ 1062614-72-5 ]

References: [1]Patent: WO2008/115552,2008,A1 .
[2]Patent: WO2008/115552,2008,A1 .

15
[ 888327-32-0 ]
[ 1062605-56-4 ]

References: [1]Patent: WO2008/115552,2008,A1 .

16
[ 888327-32-0 ]
5-(3-((4-(difluoromethoxy)-3-methylphenyl)ethynyl)phenyl)pyrimidine [ No CAS ]