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Structure of 1206487-35-5

Chemical Structure| 1206487-35-5

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Product Details of [ 1206487-35-5 ]

CAS No. :1206487-35-5
Formula : C4H3Br2N3
M.W : 252.90
SMILES Code : NC1=NN=C(Br)C=C1Br
MDL No. :MFCD13689240
InChI Key :ZTXKTTUTGHERSF-UHFFFAOYSA-N
Pubchem ID :46238402

Safety of [ 1206487-35-5 ]

GHS Pictogram:
Signal Word:Warning
Hazard Statements:H302
Precautionary Statements:P280-P305+P351+P338

Computational Chemistry of [ 1206487-35-5 ] 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 2.0
Num. H-bond donors 1.0
Molar Refractivity 41.84
TPSA ?

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

51.8 Ų

Lipophilicity

Log Po/w (iLOGP)?

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

1.64
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

1.21
Log Po/w (WLOGP)?

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

1.59
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.

1.36
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

1.71
Consensus Log Po/w?

Consensus Log Po/w: Average of all five predictions

1.5

Water Solubility

Log S (ESOL):?

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

-2.66
Solubility 0.549 mg/ml ; 0.00217 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.

-1.89
Solubility 3.22 mg/ml ; 0.0127 mol/l
Class?

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

Very 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

-3.0
Solubility 0.251 mg/ml ; 0.000993 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

No
Log Kp (skin permeation)?

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

-6.98 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<0.0
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)

2.1

Application In Synthesis of [ 1206487-35-5 ]

* 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 [ 1206487-35-5 ]

[ 1206487-35-5 ] Synthesis Path-Downstream   1~8

  • 1
  • [ 1355999-71-1 ]
  • [ 1206487-35-5 ]
  • [ 1402608-82-5 ]
YieldReaction ConditionsOperation in experiment
78% With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; for 8.0h;Reflux; A mixture of crude tert-butyl (1 -{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example lnt-1 -A (5.80 g, 13.1 mmol), <strong>[1206487-35-5]3-amino-4,6-dibromopyridazine</strong> (CAS Registry No. 1206487-35-5, 3.96 g, 15.7 mmol, 1 .2 eq), N,N-diisopropylethylamine (2.3 mL, 13.0 mmol, 1 .0 eq) and powdered activated 3A molecular sieves (1 0 g) in isopropanol (70 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure. The remaining material was purified using MPLC (Biotage Isolera; 1 00 g SNAP cartridge: 100% hexane 2.0 min., gradient to 75% hexane /25% EtOAc 2.5 min., 75% hexane /25% EtOAc 4.5 min., gradient to 50% hexane /50% EtOAc 2 min., 50% hexane /50% EtOAc 4.5 min., gradient to 100% EtOAc 2.5 min., 100% EtOAc 5.7 min.) to give partially purified tert-butyl (1 -{4-[3-phenyl-6,8-dibromoimidazo[1 ,2-b]pyridazin-2- yl]phenyl}cyclobutyl)carbamate (2.65 g, -82% pure, 28% yield):UPLC-MS (Method 3): RT = 1 .67 min; m/z (rel intensity) 597 (50, (M+H)+). 1 H-NMR (d6-DMSO): delta 1 .00-1 .20 (br s, 3H), 1 .20-1 .37 (br s, 6H), 1 .65-1 .81 (m, 1 H), 1 .85-2.00 (m, 1 H), 2.25-2.38 m, 4H), 3.80 (s, 3H), 6.92 (d, J=9.6 Hz, 1 H), 7.28 (d, J=8.5 Hz, 2H), 7.37-7.59 (m, 8H), 8.50 (d, J=9.6 Hz, 1 H).
  • 2
  • [ 1206487-35-5 ]
  • [ 2032-35-1 ]
  • [ 1206487-36-6 ]
YieldReaction ConditionsOperation in experiment
80% In tetrahydrofuran; at 20 - 125℃;Inert atmosphere; A mixture comprising 235 g (931 mmol) <strong>[1206487-35-5]4,6-dibromopyridazin-3-amine</strong> which was prepared according to intermediate example 30g, 421 mL (2792 mmol) 2- bromo-1 ,1 -diethoxyethane, 2.93 L water and 227 mL THF was heated at 125C for for h and at rt overnight. The solution was neutralized by addition of solid NaHC03, the precipitate was filtered off, washed with water and dried to give 156 g (80%) of the title compound as a brownish solid. 1 H-NMR (DMSO-d6): delta= 7.81 (1 H), 8.40 (1 H) ppm.
80% In tetrahydrofuran; water; at 20 - 125℃; A mixture comprising 235 g (931 mmol) <strong>[1206487-35-5]4,6-dibromopyridazin-3-amine</strong> which was prepared according to intermediate example 1g, 421 mL (2792 mmol) 2-bromo-1 ,1 - diethoxyethane, 2.93 L water and 227 mL THF was heated at 125 C for for h and at rt overnight. The solution was neutralized by addition of solid NaHC03, the precipitate was filtered off, washed with water and dried to give 156 g (80%) of the title compound as a brownish solid. 1 H-NMR (DMSO-d6): delta= 7.81 (1 H), 8.40 (1 H) ppm.
80% In tetrahydrofuran; water; at 20 - 125℃;Inert atmosphere; Intermediate Example 26f 6,8-dibromoimidazo[1 ,2-b]pyridazine A mixture comprising 235 g (931 mmol) <strong>[1206487-35-5]4,6-dibromopyridazin-3-amine</strong> which was prepared according to intermediate example 26g, 421 mL (2792 mmol) 2- bromo-1 , 1 -diethoxyethane, 2.93 L water and 227 mL THF was heated at 125C for for h and at rt overnight. The solution was neutralized by addition of solid NaHC03, the precipitate was filtered off, washed with water and dried to give 156 g (80%) of the title compound as a brownish solid. 1 H-NMR (DMSO-d6): delta= 7.81 (1 H), 8.40 (1 H) ppm.
  • 3
  • [ 88497-27-2 ]
  • [ 1206487-35-5 ]
YieldReaction ConditionsOperation in experiment
99% With bromine; sodium hydrogencarbonate; In methanol; at 20℃;Inert atmosphere; To a mixture comprising 285 g (1638 mmol) 6-bromopyridazin-3-amine which was prepared according to intermediate example 30h,275 g (3276 mmol) NaHCCb and 2815 mL MeOH was dropwise added 85 mL (1638 mmol) bromine at rt and it was stirred at rt overnight. After further addition of 34 mL (655 mmol) bromine and 55 g (655 mmol) NaHC03,the mixture was stirred overnight again. The solvent was reduced to about 1000 mL and the mixture was poured on 5 L of water. The precipitate was filtered off, washed with water and dried give 41 1 g (99%) of the title compound. 1 H-NMR (CDCla): delta= 6.14 (1 H), 9.92 (2H) ppm.
99% With bromine; sodium hydrogencarbonate; In methanol; at 20℃; To a mixture comprising 285 g (1638 mmol) 6-bromopyridazin-3-amine which was prepared according to intermediate example 1 h,275 g (3276 mmol) NaHC03 and 2815 mL MeOH was dropwise added 85 mL (1638 mmol) bromine at rt and it was stirred at rt overnight. After further addition of 34 mL (655 mmol) bromine and 55 g (655 mmol) NaHC03,the mixture was stirred overnight again. The solvent was reduced to about 1000 mL and the mixture was poured on 5 L of water. The precipitate was filtered off, washed with water and dried give 411 g (99%) of the title compound. 1 H-NMR (CDCls): delta= 6.14 (1 H), 9.92 (2H) ppm.
99% With bromine; sodium hydrogencarbonate; In methanol; at 20℃;Inert atmosphere; Intermediate Example 26 6,8-dibromoimidazo[1 ,2-b]pyridazine To a mixture comprising 285 g (1638 mmol) 6-bromopyridazin-3-amine which was prepared according to intermediate example 26h,275 g (3276 mmol) NaHC03 and 2815 mL MeOH was dropwise added 85 mL (1638 mmol) bromine at rt and it was stirred at rt overnight. After further addition of 34 mL (655 mmol) bromine and 55 g (655 mmol) NaHC03,the mixture was stirred overnight again. The solvent was reduced to about 1000 mL and the mixture was poured on 5 L of water. The precipitate was filtered off, washed with water and dried give 411 g (99%) of the title compound. 1 H-NMR (CDCb): delta= 6.14 (1 H), 9.92 (2H) ppm.
  • 4
  • [ 187973-60-0 ]
  • [ 1206487-35-5 ]
  • 4-bromo-6-iodopyridazin-3-amine [ No CAS ]
YieldReaction ConditionsOperation in experiment
With bromine; sodium hydrogencarbonate; In methanol; at 20℃; for 16.0h; Toa mixture of 6-iodopyridazin-3-amine (500 mg, 2.26 mmol), NaHC03(230 mg, 2.71 mmol) in MeOH (5 mL) was added bromine (117 mu, 2.26 mmol)dropwise. The resulting mixture was stirred at room temperature for 16 hrs. Thesolution was filtered and the filtrate concentrated in vacuo. The residue wasdissolved in water, and the product extracted with EtOAc (3 times). The organiclayers were combined, dried ( a2S04) and concentrated invacuo to give a dark red solid which was purified by flash silicachromatography (eluent: 20% EtOAc :Hexane) to give a 60:40 mixture of the titlecompounds as an off white solid (250 mg); H NMR (400 MHz, CDC13) delta5.49 (s, 4H), 7.66 (s, 1H), 7.81 (s, 1H)
  • 5
  • [ 1206487-35-5 ]
  • (1r,3r)-2-bromo-1-(3-(quinolin-2-yl)cyclobutyl)ethanone [ No CAS ]
  • 2-((1r,3r)-3-(6,8-dibromoimidazo[1,2-b]pyridazin-2-yl)cyclobutyl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
In N,N-dimethyl-formamide; at 20℃; for 72.0h; A solution of 2-bromo- 1 -((lr,3 r)-3- (quinolin-2-yl)cyclobutyl)ethanone (1.56 g, 4.62 mmol, prepared using themethod described in Example 1, step C) and 4,6-dibromopy-ridazin-3-amine (1.17 g, 4.62 mmol) in DMF (10 mE) wasstirred at rt for 3 days. The reaction mixture was poured intowater (200 mE), and extracted with EtOAc (2x200 mE). The combined organic layers were washed with saturated NaHCO3 and brine, dried over Na2 SO4, filtered, and concentrated. The residue obtained was purified by flash chromatography on silica gel (0-40% EtOAc/heptane) to obtain 2-((lr, 3r)-3-(6,8-dibromoimidazo[ 1 ,2-b]pyridazin-2-yl)cyclobutyl)quinoline as a yellow oil. ?H-NMR (400 MHz, CDC13) oe (ppm): 8.10 (dd, J=8.3, 4.8 Hz, 2H), 7.98 (s, 1H), 7.79 (d, J=8.1 Hz, 1H), 7.70 (t, J=7.8 Hz, 1H), 7.47-7.53 (m, 1H), 7.44 (s, 1H), 7.38 (d, J=8.6 Hz, 1H), 4.01-4.10 (m, 1H),3.89-3.99 (m, 1H), 2.96-3.08 (m, 2H), 2.75-2.86 (m, 2H).
  • 6
  • [ 1206487-35-5 ]
  • C15H14BrNO [ No CAS ]
  • 2-((1r,3r)-3-(6,8-dibromoimidazo[1,2-b]pyridazin-2-yl)cyclobutyl)quinoline [ No CAS ]
YieldReaction ConditionsOperation in experiment
40% With bromine; sodium hydrogencarbonate; In methanol; at 0 - 20℃; for 16.0h; General procedure: To a stirred solution of 6-chloropyridazin-3-amine (20.0 g, 155.02 mmol) in MeOH (100 mL) was added NaHC03 (19.53 g, 232.00 mmol) at RT and stirred for 15 min and then bromine (8.74 mL, 170.52 mmol) was added drop wise to the reaction mixture over period of 1 h at 0 C and stirred for 16 h at RT. After completion of the reaction (monitored by TLC), reaction mixture was quenched with water (100 mL). Dark brown colored solid was precipitated which was filtered and washed with water (50 mL) and dried under vacuum to afford crude title compound. The solid was washed with 20% EtOAc in hexane and diethyl ether to afford pure title compound (15.0 g, 46 %). 1H NMR (400 MHz, DMSO-d6) d 7.99 (s, 1H), 6.97 (bs, 2H); LC-MS: m/z 208.0 (M+l)+.
  • 8
  • [ 1206487-35-5 ]
  • tert-butyl 8-(2-ethoxy-2-oxoethyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate [ No CAS ]
  • ethyl 2-(3-(3-amino-6-bromopyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)acetate [ No CAS ]
YieldReaction ConditionsOperation in experiment
55% With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 90℃; for 16.0h;Inert atmosphere; To a stirred solution of 4-bromo-6-bromopyridazin-3-amine (3a), (0.20 g, 0.79 mmol) in DML (5 mL) were ethyl 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)acetate hydrochloride (0.278 g, 1.11 mmol ) and DIPEA (0.7 mL, 3.95 mmol) at RT and stirred for 16 h at 90 C under nitrogen atmosphere. Then the reaction mixture was quenched with cold water (20 mL) and the brown solid obtained was washed with diethyl ether, filtered and dried under vacuum. The same procedure was repeated four times to afford pure title compound (0.155 g, Yield : 55 %). 1H NMR (400 MHz, DMSO-d6): d 6.96 (s, 1H), 5.76 (s, 2H), 4.15-4.03 (m, 2H), 3.37-3.29 (m, 2H), 3.19 (s, 2H), 3.16-3.14 (m, 2H), 2.83-2.80 (m, 2H), 1.85 (s, 4H), 1.23-1.13 (m, 3H); LC-MS: m/z 371.1 (M+l)+.
 

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Technical Information

Categories

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