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Product Details of [ 99548-55-7 ]

CAS No. :99548-55-7
Formula : C9H9BrO2
M.W : 229.07
SMILES Code : BrC1=CC(=C(C(=O)OC)C=C1)C
MDL No. :MFCD09954957
InChI Key :CYEXEOXALMJXDI-UHFFFAOYSA-N
Pubchem ID :22031226

Safety of [ 99548-55-7 ]

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

Computational Chemistry of [ 99548-55-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 12
Num. arom. heavy atoms 6
Fraction Csp3 0.22
Num. rotatable bonds 2
Num. H-bond acceptors 2.0
Num. H-bond donors 0.0
Molar Refractivity 50.39
TPSA ?

Topological Polar Surface Area: Calculated from
Ertl P. et al. 2000 J. Med. Chem.

26.3 Ų

Lipophilicity

Log Po/w (iLOGP)?

iLOGP: in-house physics-based method implemented from
Daina A et al. 2014 J. Chem. Inf. Model.

2.51
Log Po/w (XLOGP3)?

XLOGP3: Atomistic and knowledge-based method calculated by
XLOGP program, version 3.2.2, courtesy of CCBG, Shanghai Institute of Organic Chemistry

3.44
Log Po/w (WLOGP)?

WLOGP: Atomistic method implemented from
Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.

2.54
Log Po/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.

2.97
Log Po/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

2.84
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.86

Water Solubility

Log S (ESOL):?

ESOL: Topological method implemented from
Delaney JS. 2004 J. Chem. Inf. Model.

-3.67
Solubility 0.0495 mg/ml ; 0.000216 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.

-3.67
Solubility 0.0486 mg/ml ; 0.000212 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

-3.72
Solubility 0.0436 mg/ml ; 0.000191 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.

-5.25 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)

1.55

Application In Synthesis of [ 99548-55-7 ]

* 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 [ 99548-55-7 ]

[ 99548-55-7 ] Synthesis Path-Downstream   1~7

  • 2
  • [ 99548-55-7 ]
  • [ 73183-34-3 ]
  • [ 525362-07-6 ]
YieldReaction ConditionsOperation in experiment
99% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 80℃; for 16h;Inert atmosphere; To a solution of methyl 4-bromo-2-methyl-benzoate (10 g, 44 mmol, 1 eq), KOAc (13 g, 0.13 mol, 3 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2- dioxaborolane (12 g, 48 mmol, 1.1 eq) in dioxane (100 mL) was added Pd(dppf)Ch (1.6 g, 2.2 mmol, 0.05 eq). The reaction mixture was stirred at 80 C for 16 h under N2 atmosphere. The reaction mixture was filtrated. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (S1O2, PE : EA = 1 :0 to 20: 1) to give 1 (12 g, 99% yield) as a yellow solid. LCMS: tR = 1.034 min, (ES+) m/z (M+H)+ = 277.2.
66.4% With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 110℃; for 4h;Inert atmosphere; A mixture of potassium acetate (649.2 mg, 6.55 mmol), 1,1’- bis(diphenylphosphino)ferrocene palladium dichloride (159.7 mg, 0.22 mmol),bis(pinacolato)diboron (1108.5 mg, 4.37 mmol) and methyl 4-bromo-2-methylbenzoate (500.0 mg, 2.18 mmol) in 1,4-dioxane (20 mL) was stirred at 110 C for 4 h under N2 protection, and evaporated to dryness. The residue was taken up in EtOAc (30 mL), washed with water (20 mL x 2) and brine (20 mL), dried over Mg504 and concentrated. The residue was purified by flash column chromatography (10% ethyl acetate in petroleum ether, Rf = 0.6) to afford methyl 2-methyl-4-(4,4,5 ,5-tetramethyl- 1,3 ,2-dioxaborolan-2-yl)benzoate (400 mg, 66.4% yield) as a yellow oil.
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 95℃; for 16h; Preparation 35: 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid methyl ester <n="26"/>4-Bromo-2-methylbenzoic acid methyl ester (0.028 mmol), 4,4,5, 5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (0.028 mmol) and potassium acetate (0.064 mmol) were combined in dioxane (65 mL) and de-gassed with argon. [l,l'-bis(diphenylphosphino)- ferrocene]dichloropalladium (5.62xlO~4 mmol) and l,l'-bis(diphenylphosphino)ferrocene (5.62xlO~4 mmol) were added and the mixture stirred at 950C under argon for 16 h. The mixture was cooled then partitioned between water and ethyl acetate. The water was separated and washed with ethyl acetate. The organic extracts were combined, dried over MgSO4, concentrated and purified by dry-flash chromatography to afford the title compound: RT = 4.07 min; m/z (ES+)=277.24 [M+H]+.
With potassium acetate;1,1'-bis-(diphenylphosphino)ferrocene; (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 95℃; for 16h; Preparation 17: 2-Methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)benzoic acid methyl ester4-Bromo-2-methylbenzoic acid methyl ester (0.028 mmol), ), 4,4,5,5,4',4',5',5'- octamethyl-[2,2']bi[[l,3,2]dioxaborolanyl] (0.028 mmol) and potassium acetate (0.064 mmol) were combined in dioxane (65 mL) and de-gassed with argon. [l,l'-Bis(diphenylphosphino)- ferrocene]dichloropalladium (5.62xlO~4 mmol) and l,l'-bis(diphenylphosphino)ferrocene (5.62xlO~4 mmol) were added and the mixture stirred at 950C under argon for 16 h. The mixture was cooled then partitioned between water and ethyl acetate. The water was separated and washed with ethyl acetate. The organic extracts were combined, dried (MgSO4), concentrated and purified by dry-flash chromatography to afford the title compound: RT = 4.07 min; m/z(ES+) = 277.24 [M+H]+ (LCMS protocol 3).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 2h; Step A. Methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate; A round bottomed flask was charged with methyl 4-bromo-2-methylbenzoate (3.98 g, 17.37 mmol), bis(pinacolato)diboron (4.85 g, 19.11 mmol), potassium acetate (5.12 g, 52.1 mmol), and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.426 g, 0.521 mmol). The flask was purged with nitrogen. Anhydrous DMSO (100 mL) was added, and the resulting suspension was degassed via nitrogen sparge. The mixture was then placed in a pre-heated oil bath (80 C.), and was held at this temperature for 2 h, whereupon it was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with ether, and the organic phase was washed with brine. The organic phase was then separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 277.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 1.35 (s, 12H).
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; dimethyl sulfoxide; at 80℃; for 3h; Methyl 4-bromo-2-methylbenzoate (9.16 g) obtained in Step 2 was dissolved in dimethyl sulfoxide (120 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane(1:1) (1.46 g), potassium acetate (11.8 g) and bis(pinacolato)diboron (11.2 g) were added at 80 C. The mixture was stirred for 3 hrs. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) and the resulting compound was dissolved in toluene (80 ml) and ethanol (80 ml). Thereto was added a solution of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane (1:1) (1.17 g) and (2R)-2-[((1R)-(2-bromophenyl)ethoxy)methyl]oxirane (10.5 g) obtained in Step 1 in ethanol (80 ml) and 2M aqueous sodium carbonate solution (80 ml) was added. The mixture was heated under reflux for 3 hrs. The reaction mixture was allowed to return to room temperature, and extracted with diethyl ether. The organic layer was washed successively with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the title compound (8.93 g). 1H-NMR (300 MHz, δppm, CDCl3) 7.96(1H, d, J=8.6 Hz), 7.60(1H, d, J=6.7 Hz), 7.43-7.28(4H, m), 7.18-7.13(1H, m), 4.55(1H, q, J=6.4 Hz), 3.92(3H, s), 3.44-3.40(1H, m), 3.18-3.12(1H, m), 3.07-3.02(1H, m), 2.73-2.70(1H, m), 2.65(3H, s), 2.47-2.45(1H, m), 1.37(3H, d, J=6.4 Hz
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In dimethyl sulfoxide; at 80℃; for 2h;Inert atmosphere; Example 3; Step A. Methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoateA round bottomed flask was charged with methyl 4-bromo-2-methylbenzoate (3.98 g, 17.37 mmol), bis(pinacolato)diboron (4.85 g, 19.11 mmol), potassium acetate (5.12 g, 52.1 mmol), and dichloro [1,1'-bis(diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (0.426 g, 0.521 mmol). The flask was purged with nitrogen. Anhydrous DMSO (100 mL) was added, and the resulting suspension was degassed via nitrogen sparge. The mixture was then placed in a pre-heated oil bath (80 C.), and was held at this temperature for 2 h, whereupon it was allowed to cool to ambient temperature, then was poured into water. The aqueous phase was extracted with ether, and the organic phase was washed with brine. The organic phase was then separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 277.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.66 (d, J=7.5 Hz, 1H), 3.89 (s, 3H), 2.59 (s, 3H), 1.35 (s, 12H).
With potassium acetate;palladium diacetate; In N,N-dimethyl-formamide; at 20 - 80℃; for 4.5h; As shown in Reaction Scheme 6, a mixture of bis(pinacolato)diboron (0.55 g, 2.2 mmol), methyl 4-bromo-2-methylbenzoate (0.50 g, 2.2 mmol), palladium(II) acetate (0.01 g, 0.07 mmol), and KOAc (0.64 g, 6.6 mmol) in DMF (7.5 mL) was degassed with argon for 30 min at rt. The mixture was then heated at 800C for 4 h. After cooling the mixture to rt, N-(4-bromo-2-fluorophenyl)-6- fluoro-l,3-benzothiazol-2-amine (0.74 g, 2.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.08 g, 0.07 mmol), and saturated aqueous NaHCO3 (5 mL) were added. The mixture was heated at 850C overnight. The mixture was poured into ice water and extracted with EtOAc. The combined organic phases were dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (20% EtOAc in hexanes). This yielded 0.345 g (39%) of the title compound. EPO <DP n="28"/>LC/MS m/z 411.3 (MH+); retention time 4.15 min. 1H NMR (400 MHz, CD2Cl2) δ 2.62 (s, 3H), 3.90 (s, 3H), 7.10 (t, IH), 7.39-7.53 (m, 5H), 7.62-7.70 (m, IH), 7.99 (d, IH), 8.58 (t, IH).
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 85℃; for 6h;Inert atmosphere; Adding the compound 179a (500 mg, 2.18 mmol),Compound 179b (665.1 mg, 2.62 mmol), potassium acetate (427.8 mg, 4.36 mmol) and PdCl2 (dppf) (159.7 mg, 0.22 mmol) were dissolved in 1,4-dioxane (10 mL) and replaced with nitrogen three times. Then, it heated up to 85 C and stirred for 6 hours. Cool to room temperature,The reaction solution was directly used for feeding in the next step.

  • 3
  • [ 99548-55-7 ]
  • [ 35598-05-1 ]
YieldReaction ConditionsOperation in experiment
copper(I) bromide; In N-methyl-acetamide; methanol; diethyl ether; a 4-Methyloxy-2-methylbenzoic acid methyl ester Methyl 4-bromo-2-methylbenzoate (19.0 mmol) was dissolved in dimethylformamide (2.7 mL) and methanol (1.1 mL), and the solution was heated at 80 C. and then added with CuBr (1.09 mmol). After stirring was continued for 2 hours under heating, the mixture was cooled to room temperature. The mixture was added with diethyl ether (25 mL) and filtered. The filtrate was washed four times with water, an aqueous sodium bicarbonate solution, and then with saturated brine, and dried over sodium sulfated. The drying agent was removed by filtration and the filtrate was concentrated to give the title compound. 1H-NMR (CDCl3): delta7.93 (d, J=9.3 Hz, 1H), 6.72-6.76 (m, 2H), 3.86 (s, 3H), 3.84 (s, 3H), 2.60 (s, 3H).
  • 4
  • [ 99548-55-7 ]
  • [ 156001-49-9 ]
  • 7
  • [ 99548-55-7 ]
  • [ 1455091-10-7 ]
 

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