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Structure of 923591-51-9

Chemical Structure| 923591-51-9

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Product Details of [ 923591-51-9 ]

CAS No. :923591-51-9
Formula : C9H11BrClN
M.W : 248.55
SMILES Code : Cl.BrC1=CC=CC2=C1CCNC2
MDL No. :MFCD05861550
InChI Key :SBMVDLGSHBOIOK-UHFFFAOYSA-N
Pubchem ID :45074003

Safety of [ 923591-51-9 ]

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

Computational Chemistry of [ 923591-51-9 ] 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 60.45
TPSA ?

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

12.03 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

0.0
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

2.82
Log Po/w (WLOGP)?

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

2.36
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.

2.8
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

3.12
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

2.22

Water Solubility

Log S (ESOL):?

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

-3.53
Solubility 0.0738 mg/ml ; 0.000297 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.

-2.73
Solubility 0.463 mg/ml ; 0.00186 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

-4.14
Solubility 0.0181 mg/ml ; 0.0000728 mol/l
Class?

Solubility class: Log S scale
Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly

Moderately 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

Yes
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

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.

-5.81 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<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)

1.73

Application In Synthesis of [ 923591-51-9 ]

* 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 [ 923591-51-9 ]

[ 923591-51-9 ] Synthesis Path-Downstream   1~14

  • 1
  • [ 923591-51-9 ]
  • [ 124-63-0 ]
  • [ 1100509-11-2 ]
YieldReaction ConditionsOperation in experiment
91% 5-Bromo-2-(methylsulfonyl)-l,2,3,4-tetrahvdroisoquinoline5-Bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride was suspended in diethyl ether and washed with IN NaOH, dried with Na2SO4 and concentrated to give the free amine as an oil. The amine (405 mg, 1.9 mmol) and DIPEA (0.36 mL, 2.1 mmol) were dissolved in DCM (2 mL) and cooled to 0 0C. Methanesulphonylchloride (0.60 mL, 5.0 mmol) was added dropwise at 0 0C. The reaction mixture was allowed to reach RT and stirred for 1 h. <n="49"/>The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give the product as a white solid (0.5 g, 91%).1H NMR (300 MHz, CDCl3): delta 7.55 - 7.44 (m, IH), 7.16 - 7.00 (m, 2H), 4.46 (s, 2H), 3.60 (t, J = 6.1 Hz, 2H), 2.99 (t, J = 6.1 Hz, 2H), 2.86 (s, 3H); APCI-MS m/z: 290/292 1:1 [MH+].
  • 2
  • [ 923591-51-9 ]
  • [ 109-94-4 ]
  • [ 1100509-09-8 ]
YieldReaction ConditionsOperation in experiment
100% 5-Bromo-3.4-dihvdroisoquinoline-2(lH)-carbaldehyde5-Bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride was suspended in diethyl ether and washed with IN NaOH, dried with Na2SO4 and concentrated to give the free amine as an oil. The amine (405 mg, 1.9 mmol) was mixed with ethyl formate (1 mL) and stirred at 80 0C for 2h. The mixture was concentrated to give the product as a white solid (0.45 g, 100%). <n="48"/>1H NMR (300 MHz, CDCl3): delta 8.26 and 8.21 (s, IH), 7.52 - 7.42 (m, IH), 7.14 - 7.04 (m, 2H), 4.70 and 4.54 (s, 2H), 3.83 and 3.68 (t, J= 6.2 Hz, 2H), 2.98 - 2.85 (m, 2H); APCI-MS m/z: 240/242 1:1 [MH+].
  • 3
  • [ 923591-51-9 ]
  • [ 81237-69-6 ]
YieldReaction ConditionsOperation in experiment
With sodium hydroxide; water; In diethyl ether; 2-Acetyl-5-bromo-l,2,3,4-tetrahydroisoquinoline5-Bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (2.0 g, 8.0 mmol) was taken up in diethyl ether (20 mL) and washed with NaOH (aq, IN), dried (Na2SO4) and concentrated to give the free amine (1.67 g) that was dissolved in pyridine (15 mL) and cooled to 0 0C. Acetic anhydride (0.82 mL, 8.7 mmol) was added dropwise and the reaction was stirred at RT overnight. Azeotropic evaporation with toluene several times gave the product as a white solid (1.9 g, 94%).1H NMR (SOO MHz, DMSO-d6): delta 7.53 - 7.46 (m, IH), 7.27 - 7.11 (m, 2H), 4.66 and 4.61 rotamers 4:6 (s, 2H), 3.73 - 3.66 (m, 2H), 2.83 and 2.71 rotamers 6:4 (t, J= 6.1 Hz, 2H), 2.09 and 2.07 rotamers 6:4 (s, 3H); APCI-MS m/z: 254/256 1:1 [MH+].
  • 4
  • [ 4005-51-0 ]
  • [ 923591-51-9 ]
  • [ 1454667-90-3 ]
YieldReaction ConditionsOperation in experiment
46.7% Example 62 : 5 -(3 ',4'-difluoro-3 -methoxy- [1, 1 '-biphenyl] -4-yl)-N-( 1 ,3 ,4-thiadiazol-2-yl)-3 ,4- dihydroisoquinoline-2( 1 H)-sulfonamide Step 1 : 5-bromo-N-(l,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide A solution of l, l"-sulfonyldiimidazole (0.588 g, 2.97 mmol) and l,3,4-thiadiazol-2- amine (0.300 g, 2.97 mmol) in 6 mL of DMF was cooled to 0C. NaH (60% in mineral oil) (0.238 g, 9.91 mmol) was added. After 30 minutes, the reaction mixture was heated to 80C for one hour. 5-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (0.737 g, 2.97 mmol) and n,n-diisopropylethylamine (2.59 ml, 14.83 mmol) were added, and the reaction mixture was heated to 110C for an additional 3 hours. The reaction mixture was then diluted with DCM and washed with IN citric acid solution. The organics were dried over MgSC^ and concentrated. Purification of the crude residue by reverse phase column chromatography [Redisep Gold C18, 10-100% (0.1%NH4OH in MeOH)/(0.1%NH4OH in water)] gave 5- bromo-N-(l,3,4-thiadiazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide (0.520 g, 1.386 mmol, 46.7 % yield). (M+H)+= 375.0.
  • 5
  • [ 923591-51-9 ]
  • [ 1086118-52-6 ]
  • [ 1454667-56-1 ]
YieldReaction ConditionsOperation in experiment
Intermediate AA: 5-Bromo-N-(l,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(lH)- sulfonamide To a 50 mL flask containing sodium l,2,4-thiadiazol-5-ylsulfamate (Intermediate A, 96 mg, 0.472 mmol) and 10 mL of DCM was added PC15 (Aldrich, St. Louis, MO, 245 mg, 1.179 mmol). The resutling slurry was heated at 50 C for 1.5 hours. LCMS showed conversion to the methyl sulfamate (following quench into methanol). The reaction was cooled to rt and was quenched with the addition of 5 drops of brine. The resulting slurry was stirred vigorously for 5 minutes before being filtered through a plug of diatomaceous earth, washing well with DCM. The mixture was concentrated under reduced pressure. The derived oil was taken up in 1 mL of DCM and was added to a solution of 5-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, 50 mg, 0.236 mmol) and TEA (164 mu, 1.179 mmol) in 2 mL of DCM at 0 C. Another 0.164 mL of TEA was added and the reaction allowed to warm to room temeprature where it was maintained for 2 hours. LCMS showed clean conversion to sulfonamide. The reaction was allowed to stir overnight before being diluted with saturated sodium bicarbonate (10 mL) and poured into a separatory funnel containing methylenechloride (10 mL). The layers were separated and the aqueous layer was extracted with methylenechloride (2 x 25 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under a vacuum to provide a yellow oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride) to provide 5-bromo-N-(l,2,4-thiadiazol-5-yl)-3,4- dihydroisoquinoline-2(lH)-sulfonamide as an off white solid. [M+H]+ = 375.0 XH NMR (400 MHz, Acetone)8 ppm 8.28 (s, 1H), 7.96 (s, 1H), 7.45 - 7.50 (m, 1H), 7.09 - 7.20 (m, 2H), 4.32 (s, 2H), 3.48 (t, J = 6.1 Hz, 2H), 2.86 - 2.92 (m, 2H)
  • 6
  • [ 745053-64-9 ]
  • [ 923591-51-9 ]
  • [ 1454667-20-9 ]
YieldReaction ConditionsOperation in experiment
3.25 g Intermediate I: 5-Bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(lH)- sulfonamide A solution of 5-fluorothiazol-2-amine hydrochloride (Milestone Pharmatech, Brunswick, NJ, 6.22 g, 40.2 mmol) and IH-imidazole (10.96 g, 161 mmol) in 200 mL DCM was cooled to -78 C and was treated with sulfuryl chloride (3.27 ml, 40.2 mmol). After stirring for 10 minutes, the reaction mixture was placed into a 0 C bath and was allowed to stir for an additional hour. To this mixture was added 30 mL of heptane and the solvent was decanted. The remaining solid was treated with 5-bromo- 1,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, Brunswick, NJ, 5.00 g, 20.12 mmol) then treated sequentially with 100 mL THF and DIPEA (42.2 ml, 241 mmol). The reaction mixture was heated to reflux for one hour before being cooled and poured into IN citric acid. The desired product was extracted with ethyl acetate. The organics were concentrated and the resulting residue was purified directly by silioca gel column chromatography (0 to 100% EtO Ac/heptane, 2% MeOH) yielding 5-bromo-N-(5-fluorothiazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide (3.25 g, 8.29 mmol). [M+H]+ = 393.9
  • 7
  • [ 923591-51-9 ]
  • [ 1454666-53-5 ]
  • 8
  • [ 923591-51-9 ]
  • [ 1454667-60-7 ]
  • 9
  • [ 923591-51-9 ]
  • [ 1454666-86-4 ]
  • 10
  • [ 923591-51-9 ]
  • [ 1454666-23-9 ]
  • 11
  • [ 923591-51-9 ]
  • [ 1423161-92-5 ]
  • [ 1454667-32-3 ]
YieldReaction ConditionsOperation in experiment
With potassium phosphate; bis(di-tert-?butyl(4-?dimethylaminophenyl)?phosphine)?dichloropalladium(II); In 1,4-dioxane; water; at 90℃; for 0.5h;Inert atmosphere; Microwave irradiation; Intermediate O: 5-(2-(l-Methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-l,2,3,4- tetrahydroisoquinoline A vial was charged with 5-bromo-l,2,3,4-tetrahydroisoquinoline hydrochloride (ASW Medchem, Brunswick, NJ, 400.42 mg, 1.367 mmol), (2-(l- methyl-lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid (Intermediate B, 443 mg, 1.640 mmol), potassium phosphate (1 160 mg, 5.47 mmol), and Pd(AmPhos)2Ci2 (Sigma- Aldrich, St. Louis, MO, 48.4 mg, 0.068 mmol). The vial was flushed with Ar (g), then dioxane (2928 mu) and water (976 mu) were added in sequence. The mixture was heated in a microwave reactor for 30 min at 90 C. After cooling to room temperature, the mixture was diluted with EtOAc, washed with water (and a small amount of brine to break up emulsions, 2x), washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was taken up in MeOH, then loaded onto a 10 g SCX-2 ion exchange column. The column was eluted with MeOH, then with 2M ammonia in MeOH. The basic filtrate was concentrated, and the residue was chromatographed on a 40 g silica gel column with 0 to 10% MeOH/DCM to provide 5-(2-(l -methyl- lH-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-l ,2,3,4- tetrahydroisoquinoline as a pale yellow solid. [M+H]+ = 358.1. XH NMR (400 MHz, DMSO-d6) delta ppm = 7.91 - 7.80 (m, 2 H), 7.56 (d, J= 8.0 Hz, 1 H), 7.28 (d, J= 2.0 Hz, 1 H), 7.09 - 6.95 (m, 2 H), 6.84 (dd, J= 1.3, 7.4 Hz, 1 H), 5.96 (d, J= 1.9 Hz, 1 H), 3.85 (s, 2 H), 3.52 (br. s., 3 H), 2.93 - 2.84 (m, 1 H), 2.79 - 2.67 (m, 1 H), 2.48 - 2.39 (m, 1 H), 2.09 (td, J= 5.3, 16.7 Hz, 1 H).
  • 12
  • [ 96-50-4 ]
  • [ 923591-51-9 ]
  • [ 1454667-58-3 ]
YieldReaction ConditionsOperation in experiment
1.092 g Step 1 : 5-Bromo-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide A solution of imidazole (1.530 g, 22.47 mmol) and thiazol-2 -amine (0.750 g, 7.49 mmol) in 8 mL DCM was cooled to -78 C and was treated with sulfuryl chloride (0.609 ml, 7.49 mmol). After stirring for 20 minutes, the cooling bath was removed and the reaction mixture was allowed to stir for an additional 30 minutes. 5-Bromo-l,2,3,4- tetrahydroisoquinoline hydrochloride (ASW Medchem, Brunswick, NJ, 1.396 g, 5.62 mmol) was added, followed by triethylamine (7.31 ml, 52.4 mmol). The reaction mixture was then heated to 80 C for 30 minutes. The mixture was cooled to rt and poured into IN citric acid solution before being extracted into EtO Ac. The organics were dried over MgS04 and concentrated. Purification of the residue by silica gel column chromatography (0 to 100% EtO Ac/heptane) gave 5-bromo-N-(thiazol-2-yl)-3,4-dihydroisoquinoline-2(lH)-sulfonamide (1.092 g, 2.92 mmol). [M+H]+ = 375.6.
  • 13
  • [ 24424-99-5 ]
  • [ 923591-51-9 ]
  • [ 215184-78-4 ]
  • 14
  • [ 24424-99-5 ]
  • [ 923591-51-9 ]
  • tert-butyl 9-bromo-1,2-dihydro-3H-benzo[d]azepine-3-carboxylate [ No CAS ]
 

Historical Records

Technical Information

Categories

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[ 923591-51-9 ]

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