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Chemical Structure| 1575-37-7 Chemical Structure| 1575-37-7

Structure of 1575-37-7

Chemical Structure| 1575-37-7

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Product Details of [ 1575-37-7 ]

CAS No. :1575-37-7
Formula : C6H7BrN2
M.W : 187.04
SMILES Code : NC1=CC=C(Br)C=C1N
MDL No. :MFCD02660622
InChI Key :WIHHVKUARKTSBU-UHFFFAOYSA-N
Pubchem ID :323593

Safety of [ 1575-37-7 ]

GHS Pictogram:
Signal Word:Danger
Hazard Statements:H301-H315-H317-H319
Precautionary Statements:P261-P264-P270-P272-P280-P301+P310-P302+P352-P305+P351+P338-P330-P333+P313-P337+P313-P362+P364-P405-P501
Class:6.1
UN#:2811
Packing Group:

Computational Chemistry of [ 1575-37-7 ] Show Less

Physicochemical Properties

Num. heavy atoms 9
Num. arom. heavy atoms 6
Fraction Csp3 0.0
Num. rotatable bonds 0
Num. H-bond acceptors 0.0
Num. H-bond donors 2.0
Molar Refractivity 42.95
TPSA ?

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

52.04 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.36
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

1.34
Log Po/w (WLOGP)?

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

1.63
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.

1.58
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

1.11
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.4

Water Solubility

Log S (ESOL):?

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

-2.34
Solubility 0.861 mg/ml ; 0.0046 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.

-2.03
Solubility 1.73 mg/ml ; 0.00924 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

-2.53
Solubility 0.548 mg/ml ; 0.00293 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

No
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

Yes
Log Kp (skin permeation)?

Skin permeation: QSPR model implemented from
Potts RO and Guy RH. 1992 Pharm. Res.

-6.49 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

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)

1.51

Application In Synthesis of [ 1575-37-7 ]

* 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 [ 1575-37-7 ]

[ 1575-37-7 ] Synthesis Path-Downstream   1~28

  • 1
  • [ 1575-37-7 ]
  • [ 1753-75-9 ]
YieldReaction ConditionsOperation in experiment
86% With thionyl chloride; sulfuric acid; for 1h;Heating / reflux; Example 2 Synthesis of 5-bromo-2,1,3-benzothiadiazole A mixture was prepared by mixing 4.0 g (21 mmol) of 4-bromo-o-phenylenediamine, 14 mL of thionyl chloride and 0.62 mL of concentrated sulfuric acid and was refluxed for one hour. This mixture was cooled and then poured onto ice, and a resulting precipitate was filtered and collected. This precipitate was washed with water till the waste water became neutral and then thoroughly dried to yield 4.5 g of 5-bromo-2,1,3-benzothiadiazole as a crude product (melting point, 48 to 50 C.; yield, 96.5%).
With thionyl chloride; In N,N-dimethyl-formamide; Preparation 1 5-Bromo-benzo[1,2,5]thiadiazole To 4-bromo-benzene-1,2-diamine (17 g, 91 mmol) was added thionyl chloride (200 ml). One drop of DMF was added to the reaction mixture. The reaction mixture was heated at reflux under argon at 80 C. overnight. The reaction mixture was cooled to room temperature and added portionwise to ice in a large beaker and neutralised with solid sodium bicarbonate. The mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was collected and dried (MgSO4). The solvent was removed under reduced pressure. The title compound was isolated by column chromatography on silica gel eluding with 90% ethyl acetate/10% methanol. (12 g, 62%); 1H NMR (250 MHz, CDCl3) delta: 7.61 (1H, dd, J=9, 2 Hz), 7.82 (1H, d, J=9 Hz), 8.16 (1H, s).
  • 2
  • [ 100-52-7 ]
  • [ 1575-37-7 ]
  • [ 1741-50-0 ]
YieldReaction ConditionsOperation in experiment
78% In 1,4-dioxane; at 100℃; Add S1 (1 mmol),Benzaldehyde (1mmol), 8ml 1,4-dioxane, heat to 100C,After the reaction was completed, the solvent was distilled off under reduced pressure,The crude product was purified by column chromatography (dichloromethane/n-hexane/methanol (volume ratio 20:10:1)) to obtain Intermediate 1-1 (yield 78%).
70% With H2SO4 in hydrothermal carbon(II); In ethanol; at 80℃; for 1.5h; General procedure: In an oven-dried 25mL round-bottomed flask equipped with a magnetic stir bar,o-phenylenediamine (1 mmol), benzaldehyde (1 mmol) and 100 mg of H2SO4HTC (II) were mixed and diluted with 5ml of ethanol. The mixture was stirred at reflux for1.5 hr. At the end of the reaction, the catalyst was recovered by filtration and the filtratewas extracted with ethyl acetate (310 mL). The combined organic layers were washedwith 10 ml of water, dried over anhydrous Na2SO4 and filtered. The solvent was evaporated.Pure product was obtained using flash chromatography on silica gel using 20%ethyl acetate in hexane.
To a mixture of 4-bromobenzene-1,2-diamine (0.2 g) in DMF/water (2 mL/50 μL) was added oxone (0.4 g) and benzaldehyde (0.12 g) in DMF (2 mL). After 1 hour, the mixture was diluted with water, treated with K2CO3 and filtered. The filtrate was dissolved in dichloromethane, and this mixture was dried (Na2SO4), filtered and concentrated. The concentrate was chromatographed on silica with an Intelliflash-280 purification system with ethyl acetate/hexanes.
  • 3
  • [ 51293-47-1 ]
  • [ 1575-37-7 ]
  • [ 864296-72-0 ]
  • [ 864296-73-1 ]
YieldReaction ConditionsOperation in experiment
With 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; triethylamine; In tetrahydrofuran; ethyl acetate; at 0 - 20℃; for 23.0833h; 2.50 g (6.24 mmol) of the dicyclohexylammonium salt of N-Boc-(S)-O-methyl-serine are dissolved in 20 ml 5percent citric acid, the aqueous phase is extracted 2.x. with 20 ml of ethyl acetate, the combined organic phases are dried over sodium sulphate and freed from solvent i. vac. The residue is dissolved together with 1.23 g (6.55 mmol) 4-bromo-1,2-phenylenediamine in 30 ml THF and 1.42 ml (14.0 mmol) triethylamine and 4.97 ml (7.80 mmol) of a 50percent solution of PPA in ethyl acetate are added with stirring in the ice bath. After 5 minutes stirring in the ice bath the mixture is heated to ambient temperature and stirred for 23 hours at ambient temperature. The reaction mixture is poured into 100 ml of water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are extracted with sat. sodium carbonate solution and water, dried over sodium sulphate and evaporated down i. vac. Yield: 2.38 g (98percent) mixture of the two regioisomers C15H22BrN3O4 (388.26) Mass spectrum: (M+H)+=388/390 (bromine isotope) Rf value: 0.63/0.68 (silica gel; dichloromethane/ethanol=9:1)
  • 4
  • [ 182570-26-9 ]
  • [ 1575-37-7 ]
  • C17H17BrN2O3 [ No CAS ]
  • 5
  • [ 57592-42-4 ]
  • [ 1575-37-7 ]
  • [ 1192251-86-7 ]
YieldReaction ConditionsOperation in experiment
toluene-4-sulfonic acid; In N,N-dimethyl-formamide; at 100℃;Microwave irradiation; Step 2: 6-Bromo-2-(2'-fluorobiphenyl-4-yl)-l//-benzimidazole <n="33"/> Into a 5 mL microwave flask, equipped with a magnetic stirbar was added 4- bromobenzene-l,2-diamine (200 mg, 1.07 mmol), />-toluenesulfonic acid monohydrate (20 mg, 0.11 mmol) and <strong>[57592-42-4]2'-fluorobiphenyl-4-carbaldehyde</strong> (214 mg, 1.07 mmol) in DMF (2 mL). The vial was sealed and heated to 100 0C under microwave irradiation. The cooled mixture was poured into a 125 mL separatory funnel containing water (75 mL) and the mixture extracted with ethyl acetate (3 x 30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography on silica gel eluting with 10% MeCN in toluene gave the title compound as a white solid. MS (ESI, Q+) m/z 367, 369 (M+l).
  • 6
  • [ 53911-68-5 ]
  • [ 1575-37-7 ]
  • C17H16BrClN2O3 [ No CAS ]
  • C17H16BrClN2O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
In tetrahydrofuran; at 20℃;Heating; Commercial 4-bromo-l,2-phenylenediamine (561 mg) and 3-(4-chlorophenyl)- glutaric anhydride (674 mg) were dissolved in THF (1 ml) with heating. The dark solution was stirred at rt for 1 h. Then the solution was decolourised with activated carbon and filtered. The filtrate was concentrated and the solid residue dried in vacuo. The solid was dissolved in a mixture of acetic acid (4 ml) and cone. HCI (2 ml) and stirred under reflux for 3 h. All volatiles were removed at the water aspirator and the residue was recrystallised from ethanol/EtOAc 1 : 3 to give a crude (0.47 g). The impure crude was again refluxed with acetic acid/cone. HCI 2: 1 for 1 h to leave after concentration and acetone trituration 4-(5-bromo-2- benzimidazolyl)-3-(4-chlorophenyl)butanoic acid HCI (0.3 g) as light greyish solid.1H-NMR (500 MHz, DMSOd6): delta (ppm) = 2.72 (dd, J = 16.2, 8.6 Hz, IH), 2.83 (dd, J = 16.3, 8.2 Hz, IH), 3.43 (dd, J = 14.9, 9.2 Hz, IH), 3.55 (dd, J = 14.9, 6.9 Hz, IH), 3.85 (m, IH), 7.30 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.5 Hz, IH), 7.60 (dd, J = 8.7, 1.7 Hz, IH), 7.67 (d, J = 8.7 Hz, IH), 7.94 (d, J = 1.7 Hz, IH). 13C-NMR and DEPT (125 MHz, DMSOd6) : delta (ppm) = 32.66 (CH2), 39.19 (CH),39.60 (CH2), 115.57 (CH), 116.42 (CH), 117.34 (C), 128.14 (CH), 128.34 (2 CH), 129.14 (2 CH), 130.26 (C), 131.44 (C), 132.32 (C), 140.69 (C), 153.07 (C), 172.12 (CO). MS ( + ESI) : m/z = 393 (M + H).
  • 7
  • [ 182570-26-9 ]
  • [ 1575-37-7 ]
  • C17H15BrN2O2 [ No CAS ]
  • 8
  • [ 53911-68-5 ]
  • [ 1575-37-7 ]
  • C17H16BrClN2O3 [ No CAS ]
  • 9
  • [ 53911-68-5 ]
  • [ 1575-37-7 ]
  • [ 1221961-88-1 ]
YieldReaction ConditionsOperation in experiment
Commercial 4-bromo-1,2-phenylenediamine (561 mg) and 3-(4-chlorophenyl)-glutaric anhydride (674 mg) were dissolved in THF (1 ml) with heating. The dark solution was stirred at rt for 1 h. Then the solution was decolourised with activated carbon and filtered. The filtrate was concentrated and the solid residue dried in vacuo. The solid was dissolved in a mixture of acetic acid (4 ml) and conc. HCl (2 ml) and stirred under reflux for 3 h. All volatiles were removed at the water aspirator and the residue was recrystallised from ethanol /EtOAc 1:3 to give a crude (0.47 g). The impure crude was again refluxed with acetic acid /conc. HCl 2:1 for 1 h to leave after concentration and acetone trituration 4-(5-bromo-2-benzimidazolyl)-3-(4-chlorophenyl)butanoic acid?HCl (0.3 g) as light greyish solid.1H-NMR (500 MHz, DMSO-d6): delta (ppm)=2.72 (dd, J=16.2, 8.6 Hz, 1H), 2.83 (dd, J=16.3, 8.2 Hz, 1H), 3.43 (dd, J=14.9, 9.2 Hz, 1H), 3.55 (dd, J=14.9, 6.9 Hz, 1H), 3.85 (m, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 1H), 7.60 (dd, J=8.7, 1.7 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H), 7.94 (d, J=1.7 Hz, 1H).13C-NMR and DEPT (125 MHz, DMSO-d6): delta (ppm)=32.66 (CH2), 39.19 (CH), 39.60 (CH2), 115.57 (CH), 116.42 (CH), 117.34 (C), 128.14 (CH), 128.34 (2CH), 129.14 (2CH), 130.26 (C), 131.44 (C), 132.32 (C), 140.69 (C), 153.07 (C), 172.12 (CO).MS (+ESI): m/z=393 (M+H).
  • 10
  • [ 1575-37-7 ]
  • [ 4494-26-2 ]
  • [ 1425795-65-8 ]
  • 11
  • [ 53308-95-5 ]
  • [ 1575-37-7 ]
  • [ 1449475-74-4 ]
YieldReaction ConditionsOperation in experiment
78% Preparation 11 (SHe/t-Butyl (1 -(5-bromo-1 H-benzo[d1imidazol-2-yl)butyl Carbamate To a solution of Boc-NVA-OH (4.5 g, 21 mmol) in acetonitrile (68 ml_) and 4- methylmorpholine (2.41 ml_, 21 .9 mmol) cooled to -20°C was added isobutyl chloroformate (2.7 ml_, 21 mmol) dropwise. The mixture was stirred for 120 minutes at -20°C and then 4-bromo-1 ,2-benzenediamine (3.87 g, 20.7 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours. The solvent was evaporated, redissolved in ethyl acetate, washed with water, saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in acetic acid (20 ml_, 400 mmol) and stirred at 70°C for 6 hours. The acetic acid was removed in vacuo and the mixture was redissolved in ethyl acetate, washed with saturated aqueous solution of sodium hydrogen carbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was redissolved in dichloromethane, treated with activated carbon and filtered through a plug of celite. Purification by silica gel column chromatography eluting with a 0-100percent ethyl acetate/hexanes gradient to afford the title compound (5.95 g, 78percent) as a white solid. 1H NMR (400MHz, CDCI3): delta ppm 0.92 (t, 3H), 1 .41 (m, 1 1 H), 1 .90 (m, 1 H), 2.1 1 (m, 1 H), 4.85 (m, 1 H), 5.65 (m,1 H), 7.1 1 (m, 0.5H), 7.25 (m, 0.5H), 7.31 (m, 0.5H), 7.37 (m, 0.5H), 7.52 (m, 0.5H), 7.80 (m, 0.5H), 1 1 .20 (m, 1 H). LCMS Rt = 1 .19 minutes MS m/z 366, 368 [79Br, 81Br M+H]+
  • 12
  • [ 48068-25-3 ]
  • [ 1575-37-7 ]
  • [ 1449473-62-4 ]
  • 13
  • [ 48068-25-3 ]
  • [ 1575-37-7 ]
  • C16H23N3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
Example 77 2-{2-[( 1 R,2R)-1 -Amino-2-methoxypropyl1-1 H-benzimidazol-5-yl)benzonitrile To 4-bromo-1 ,2-benzenediamine (2.3 g, 12.3 mmol) and N-boc-O-methyl-L-threonine (2.9 g, 12.3 mmol) was added DCM (100 ml_) followed by DIEA (3 ml_, 17.5 mmol) and HATU (4.7 g, 12.3 mmol). The reaction was stirred at 30C for 16 hours before concentrating in vacuo. To the residue was added AcOH (120 ml_) and the reaction heated to 50C for 2 hours. The reaction was cooled, concentrated in vacuo and diluted with a 2M solution of LiOH in water (250 ml_). The aqueous layer was extracted with EtOAc (2 x 150 ml_), the organic layers combined, dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dioxane to obtain a 0.075M solution. To an aliquot of this solution (1 ml_) was added cesium carbonate (75 mg, 225 pmol), 2-cyanophenylboronic acid (1 12.5 muomicronIota), water (30 muIota_), and nitrogen was bubbled through for 30 seconds. Pd(dppf)CI2 (6 mg, 7.5 pmol) was then added and the reaction shaken at 90C for 16 hours before cooling and filtering. MeOH (200muIota_) was then added followed by 4M HCI in dioxane (300 muIota_) and the reaction shaken at 30C for 16 hours. The reaction was concentrated in vacuo and purified using preparative HPLC (Boston Symmetrix ODS-H; 150 x 30 mm x 5 mu; mobile phase A: Acetonitrile, mobile phase B: 0.225% TFA in water; eluting with a gradient of 22-52% organic, over 10 minutes with a flow rate of 30 mL/min) to afford the title compound as the TFA salt. LCMS Rt = 2.42 minutes MS m/z 307 [M+H]+
  • 14
  • [ 48068-25-3 ]
  • [ 1575-37-7 ]
  • [ 1449476-01-0 ]
YieldReaction ConditionsOperation in experiment
96% Preparation 23 tert-Butyl {(1 S,2R)-1 -[(2-amino-4-bromophenyl)carbamoyl1-2- methoxypropyDcarbamate To a solution of N-(fe/t-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51 , 4 g, 17.15 mmol) in anhydrous THF (150 mL) was added NMM (2.43 g, 24.01 mmol) and isobutyl chloroformate (2.58 g, 18.86 mmol) at -78C and the reaction was stirred at this temperature for 1 hour. This solution was then added to a solution of 4- bromophenyl-1 ,2-diamine (3.85 g, 20.58 mmol) in THF ( 50 mL) at -78C and the reaction was stirred warming to room temperature for 18 hours. The reaction was quenched by the addition of water and extracted with EtOAc (3 x 50 mL). The organic layers were combined, dried over Na2SO4 and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with 0-60% acetonitrile in 0.1 % formic acid in water to afford the title compound (6.60 g, 96%). 1H NMR (400MHz, MeOD): delta ppm 0.95-1 .20 (m, 3H), 1 .45 (s, 9H), 3.38 (s, 3H), 3.85 (m, 1 H), 4.20 (m, 1 H), 6.60-7.20 (m, 3H).
  • 15
  • [ 364750-81-2 ]
  • [ 1575-37-7 ]
  • C17H24BrN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of compound 14-1 (2.45 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (30 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 °C. After stirring at 0 °C for 0.5 hr, compound 2-10 (2.22 g, 11.9 mmol) was added in a portionwise manner. At the end of the addition, the mixture was stirred at rt for 4.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL), the THF solvent was removed, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL), and the solution was stirred at 40 °C overnight. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The mixture was washed with Na2C03 aqueous solution (50 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (3.24 g, 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 380.5 [M+H]+; and H NMPv (400 MHz, CDC13) delta (ppm): 7.84 (d, 1H, J= 2.9 Hz), 7.44 (d, 1H, J= 15.0 Hz), 7.33 (dd, 1H, J= 15.0 Hz, 2.9 Hz), 4.88 (t, 1H, J= 16.9 Hz), 4.27 (dd, 1H, J= 24.8 Hz, 17.3 Hz), 3.14 (dd, 1H, J = 24.7 Hz, 17.3 Hz), 2.53 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 2.21-2.03 (m, 1H), 1.81 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 1.41 (s, 9H), 0.95 (d, 3H, J= 12.7 Hz).
  • 16
  • [ 1001353-87-2 ]
  • [ 1575-37-7 ]
  • C18H26BrN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of compound 15-3 (2.6 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (30 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 C. After stirring at 0 C for 0.5 hr, compound 2-10 (2.22 g, 11.9 mmol) was added in a portionwise manner. At the end of the addition, the mixture was stirred at rt for 4.0 hrs. After the reaction was completed, the mixture was quenched with water (50 mL), the THF solvent was removed, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL), and the solution was stirred at 40 C overnight. After the reaction was completed, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL). The mixture was washed with Na2C03 aqueous solution (50 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (2.70 g, 65%). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 395.5 [M+H] ; and NMR (400 MHz, CDC13) δ (ppm): 7.71-7.70 (q, 1H), 7.33, 7.30 (d, d, 1H), 7.20, 7.18 (d, d, 1H), 5.32-5.27 (m, 1H), 3.41-3.34 (m, 1H), 3.30-3.23 (m, 1H), 2.38-2.32 (m, 1H), 2.00-1.94 (m, 1H), 1.41 (s, 9H), 1.01-0.99 (m, 3H), 0.86-0.84 (m, 3H).
  • 17
  • [ 364750-81-2 ]
  • [ 1575-37-7 ]
  • [ 1326303-53-0 ]
YieldReaction ConditionsOperation in experiment
85% [001811 To a cooled 0°C solution of compound 2-1(13.3 g, 47.1 mmol), HATU (26.5 g, 69 mmol)in 150 mL of THF was added DIPEA (9 mL, 51.1 mmol) dropwise. After the addition, the mixture was stirred at 0 °C for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (10 g, 53.5 mmol) in THF (20 mL) After the addition, the mixture was stirred at 25 °C for 4.0 hours, quenched with little water, removed the THF and then to the mixture was added water (50 mL). To the residue was added water (50 mL), and the resulting mixture was extracted with EtOAc (60 mLx3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2504 and concentrated in vacuo.The residue was diossloved in 100 mL of acetic acid, and the resulting mixture was stirred at 40 °C for 12 hours. Then the mixture was concentrated in vacuo to remove the acetic acid. To the residue was added saturate aqueous NaHCO3 solution (100 mL), and the resulting mixture was extracted with EtOAc (100 mLx3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2504 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 2/1) to give the title compound as a light yellow solid (17.32 g, 85percent). The compound was characterized by the following spectroscopic data:?H NMR (400 MHz, CDC13): oe 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H) ppm.
85% Step 1) the Preparation of Compound 2-2 (0278) To a cooled 0° C. solution of compound 2-1 (13.3 g, 47.1 mmol), HATU (26.5 g, 69 mmol) in 150 mL of THF was added DIPEA (9 mL, 51.1 mmol) dropwise. After the addition, the mixture was stirred at 0° C. for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (10 g, 53.5 mmol) in THF (20 mL) After the addition, the mixture was stirred at 25° C. for 4.0 hours, quenched with little water, removed the THF and then to the mixture was added water (50 mL). To the residue was added water (50 mL), and the resulting mixture was extracted with EtOAc (60 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was dissolved in 100 mL of acetic acid, and the resulting mixture was stirred at 40° C. for 12 hours. Then the mixture was concentrated in vacuo to remove the acetic acid. To the residue was added saturate aqueous NaHCO3 solution (100 mL), and the resulting mixture was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=2/1) to give the title compound as a light yellow solid (17.32 g, 85percent). The compound was characterized by the following spectroscopic data: (0279) 1H NMR (400 MHz, CDCl3): delta 7.68 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 2H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H) ppm.
80% To a solution of compound 10-1 (2.45 g, 10.7 mmol) and HATU (4.88 g, 12.84 mmol) in THF (30 mL) was added DIPEA (1.95 mL, 11.8 mmol) at 0 °C. The mixture was stirred at this temperature for 0.5 hour and compound 3-16-0 (2.21 g, 11.9 mmol) was added in portions. Then the mixture was stirred at rt for 4 hours. After the reaction was completed, the reaction was quenched with water (50 mL). The THF was removed in vacuo and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo. The residue was dissolved in glacial acetic acid (20 mL) and the solution was stirred at 40 °C overnight. After the reaction was completed, the reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL). The resulting solution was washed with an aqueous solution of sodium carbonate (50 mL x 3), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 1/2) to give the title compound (3.24 g, 80percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 381.3 [M+H]+; and *H NMR (400 MHz, CDC13): delta 7.84 (d, 1H, J= 2.9 Hz), 7.44 (d, 1H, J= 15.0 Hz), 7.33 (dd, 1H, J= 15.0 Hz, 2.9 Hz), 4.88 (t, 1H, J= 16.9 Hz), 4.27 (dd, 1H, J= 24.8 Hz, 17.3 Hz), 3.14 (dd, 1H, J = 24.7 Hz, 17.3 Hz), 2.53 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 2.21-2.03 (m, 1H), 1.81 (dt, 1H, J= 24.4 Hz, 17.2 Hz), 1.41 (s, 9H), 0.95 (d, 3H, J= 12.7 Hz) ppm.
72% With N-ethyl-N,N-diisopropylamine; HATU; In tetrahydrofuran; at 20℃; for 2.5h;Inert atmosphere; To a mixture of compound N-2 (2 g, 8.7 mmol) and HATU (3.5 g, 9.2 mmol) in THF (30 mL) was added DIPEA (6 mL) at 0 °C under N2. The mixture was stirred at rt for 0.5 hour, and compound N-1 (1.8 g, 9.6 mmol) was added. The mixture was stirred at rt for another 2 hours and quenched with water (10 mL). THF was removed in vacuo, and the aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine and concentrated in vacuo. To the above residue was added acetic acid (35 mL) and the mixture was stirred at 40 °C overnight. The mixture was then neutralized with NaHCO3 saturated solution and extracted with EtOAc (50 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound N-3 as a reddish brown solid (2.4 g, 72percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.87 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H). [0527] To a mixture of compound N-3 (2.4 g, 6.3 mmol), bis(pinacolato)diboron (1.8 g, 7 mmol), Pd(dppf)Cl2·CH2Cl2 (0.1 g, 0.12 mmol) and KOAc (1.6 g, 16 mmol) was added DME (30 mL) under N2 via syringe. The mixture was stirred at 90 °C in an oil bath for 3 hours and concentrated in vacuo. To the residue was added water (5 mL), and the mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound N-4 (2.1 g, 78percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.87 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m, 2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H). [0528] To a mixture of compound 11-1 (54 mg, 0.12 mmol), compound N-4 (50 mg, 0.11 mmol), Pd(PPh3)4 (12.7 mg, 0.01 mmol) and potassium carbonate (46 mg, 0.33 mmol) was added DME (5 mL) under N2 via syringe followed by pure water (1 mL). The mixture was stirred at 90 °C overnight and concentrated in vacuo. To the residue was added water (3 mL) and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc (v/v) = 2/1) to give the title compound 28-2 as a yellow solid (32 mg, 46.9percent). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3): delta 7.82 (s, 2H), 7.52 (s, 2H), 7.39 (d, J = 8.24 Hz, 2H), 7.11 (d, J = 8.24 Hz, 2H), 4.94 (m, H), 3.78 (m, H), 3.44 (m, 1H), 3.19 (m, 1H), 2.83 (s, 4H), 1.82 (m, 2H), 1.76 (m, 1H), 1.55 (m, 17H), 0.96 (d, 3H).
72% To a mixture of compound N-2 (2 g, 8.7 mmol) and HATU (3.5 g, 9.2 mmol) in THF (30 mL) was added DIPEA(6 mL) at 0 °C under N2. The mixture was stirred at rt for 0.5 hour, and compound N-1 (1.8 g, 9.6 mmol) was added.The mixture was stirred at rt for another 2 hours and quenched with water (10 mL). THF was removed in vacuo, and theaqueous layer was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine andconcentrated in vacuo. To the above residue was added acetic acid (35 mL) and the mixture was stirred at 40 °Covernight. The mixture was then neutralized with NaHCO3 saturated solution and extracted with EtOAc (50 mL x 3). Thecombined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified bysilica gel column chromatography (hexane/EtOAc (v/v) = 4/1) to give compound N-3 as a reddish brown solid (2.4 g,72percent). The compound was characterized by the following spectroscopic data:1H NMR (400 MHz, CDCl3): delta 7.87 (s, 1H), 7.42-7.40 (m, 1H), 7.30-7.28 (m, 1H), 5.11-5.09 (m, 1H), 3.45-3.43 (m,2H), 2.94-2.93 (m, 1H), 2.21-2.18 (m, 1H), 2.01-1.91 (m, 1H), 1.49 (s, 9H), 1.23 (d, 3H).

  • 18
  • [ 334769-80-1 ]
  • [ 1575-37-7 ]
  • [ 1241377-87-6 ]
YieldReaction ConditionsOperation in experiment
66% [001861 To a cooled 0 °C solution of compound 1-6 (3.8 g, 16.57 mmol) in 50 mL of DCM was added C1COOEt (1.58 mL, 16.57 mmol) and TEA (2.4 mL, 17.36 mmol) dropwise. After the addition, the mixture was stirred at 0 °C for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (2.96 g, 15.78 mmol) in DCM (30 mL). Then the mixture was stirred at 25 °C for 4 hours. To the mixture was added water (20 mL). The resulting mixture was extracted with DCM (100 mLx3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (4.2 g, 10.57 mmol) was dossloved in 50 mL of acetic acid, and the resulting mixture was stirred at 50 °C for 10 h. After the reaction was completed, the mixture was concentrated in vacuo to remove acetic acid. The residue was dissolved in EtOAc (100 mL), and the resulting mixture was washed with aquous NaHCO3 solution (50 mLx 2).The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 4/1) to give the title compound as a light red solid (3.98 g, 66percent). The compound was characterized by the following spectroscopic data:MS (ESI, pos.ion) m/z: 381.3 [M+Hfb; and?HNMR (400 MHz, CDC13): 7.71 (br, 1H), 7.43 (br, 1H), 7.30-7.32 (d,J= 8.0 Hz, 1H), 5.07-5.10 (m, 1H), 3.95-3.97 (m, 1H), 2.94 (br, 1H), 2.12-2.26 (m, 2H), 1.86 (br, 1H), 1.49 (s, 9H), 1.14 (d,J= 6.4 Hz, 3H) ppm.
66% Step 1) the Preparation of Compound 3-1 (0293) To a cooled 0° C. solution of compound 1-6 (3.8 g, 16.57 mmol) in 50 mL of DCM was added ClCOOEt (1.58 mL, 16.57 mmol) and TEA (2.4 mL, 17.36 mmol) dropwise. After the addition, the mixture was stirred at 0° C. for 0.5 hour, and then to the mixture was added a solution of compound 2-1-2 (2.96 g, 15.78 mmol) in DCM (30 mL). Then the mixture was stirred at 25° C. for 4 hours. To the mixture was added water (20 mL). The resulting mixture was extracted with DCM (100 mL×3), the combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (4.2 g, 10.57 mmol) was dissolved in 50 mL of acetic acid, and the resulting mixture was stirred at 50° C. for 10 h. After the reaction was completed, the mixture was concentrated in vacuo to remove acetic acid. The residue was dissolved in EtOAc (100 mL), and the resulting mixture was washed with aqueous NaHCO3 solution (50 mL×2). The separated organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EtOAc (v/v)=4/1) to give the title compound as a light red solid (3.98 g, 66percent). The compound was characterized by the following spectroscopic data: (0294) MS (ESI, pos. ion) m/z: 381.3 [M+H]+; and (0295) 1H NMR (400 MHz, CDCl3): delta 7.71 (br, 1H), 7.43 (br, 1H), 7.30-7.32 (d, J=8.0 Hz, 1H), 5.07-5.10 (m, 1H), 3.95-3.97 (m, 1H), 2.94 (br, 1H), 2.12-2.26 (m, 2H), 1.86 (br, 1H), 1.49 (s, 9H), 1.14 (d, J=6.4 Hz, 3H) ppm.
  • 19
  • [ 79-14-1 ]
  • [ 1575-37-7 ]
  • [ 540516-28-7 ]
  • 22
  • [ 93-97-0 ]
  • [ 1575-37-7 ]
  • [ 1741-50-0 ]
  • 23
  • [ 611-73-4 ]
  • [ 1575-37-7 ]
  • [ 1741-50-0 ]
  • 24
  • [ 5417-17-4 ]
  • [ 1575-37-7 ]
  • 5-bromo-2-(2-chloro-3,4-dimethoxyphenyl)-1H-benzo[d]imidazole [ No CAS ]
YieldReaction ConditionsOperation in experiment
56% With sodium metabisulfite; In N,N-dimethyl-formamide; for 4h;Reflux; General procedure: 4-Bromo-1,2-diaminobenzene (1 mmol) and different substitutedaromatic aldehydes (1 mmol) in N,N-dimethylformamide(10 mL) were taken into a 100 mL round-bottomedflask. Catalytic amount of sodium metabisulfite (Na2S2O5)was added into the reaction mixture and refluxed for 4 h.Reaction progress was carefully monitored by thin layerchromatography. After completion of reaction, it was addedinto chilled distilled water (100 mL). Precipitates wereformed and filtered to afford products. Crude products werecrystallized from ethanol to get pure products in high yields.
  • 25
  • [ 364750-81-2 ]
  • [ 1575-37-7 ]
  • C17H24BrN3O3 [ No CAS ]
YieldReaction ConditionsOperation in experiment
To a solution of compound 8-1 (2.45 g, 10.7 mmol) and compound HATU (4.88 g,12.84 mmol) in THF (30 mL) at 0 ° C was added DIPEA (1.95 mL, 11.8 mmol) Compound 1-9-2(2.21 g, 11.9 mmol) was added in portions, and after the addition was complete, thereaction was carried out at room temperature for 4.0 hours. After the reaction wascompleted, the reaction was quenched by the addition of water (50 mL), the THF wasremoved, extracted with EtOAc (50 mL x 3), and the organic phases were combined, washedwith brine, dried over anhydrous sodium sulfate and concentrated. The residue wasdissolved in glacial acetic acid (20 mL) at 40 ° C overnight. After completion of thereaction, glacial acetic acid was removed and the residue was dissolved in EtOAc (100 mL), washed with sodium carbonate solution (50 mL x 3), dried over anhydrous sodiumsulfate, concentrated and purified by column chromatography (eluent: PE / EtOAc (v / v)= 1/2) to give the product 3.24 g, yield: 80percent.
  • 27
  • [ 721-04-0 ]
  • [ 1575-37-7 ]
  • [ 1741-50-0 ]
  • [ 4887-88-1 ]
  • [ 108-95-2 ]
YieldReaction ConditionsOperation in experiment
With 2,3-dicyano-5,6-dichloro-p-benzoquinone; In 2-methoxy-ethanol; at 120℃; for 24.0h;Sealed tube; Put 0.1mmol oxidized lignin model substrate 1 in a 10mL pressure tube, add 0.01mmol HNO3, 1mL DMSO and 0.2mmol o-phenylenediamine 2,After tightening the cap, heat the resulting reaction solution (the concentration of oxidized lignin in the reaction solution is 0.1 mmol/mL) in an oil bath at 100C for 12 hours,The decomposition reaction is carried out. After the reaction is completed, the obtained product is taken out and the solvent is drained and separated by a column to obtain two nitrogen-containing heterocyclic products.
  • 28
  • 1-phenyl-3-hydroxy-2-phenoxy propan-1-one [ No CAS ]
  • [ 1575-37-7 ]
  • [ 1741-50-0 ]
  • [ 4887-88-1 ]
  • [ 108-95-2 ]
 

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