1298031-94-3|8-Bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine| Ambeed

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Quality Control of [ 1298031-94-3 ] Purity: 95% SDS Specification

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Product Details of [ 1298031-94-3 ]

CAS No. :	1298031-94-3
Formula :	C₇H₅BrClN₃
M.W :	246.49
SMILES Code :	CC1=CN2N=C(Cl)C=C(Br)C2=N1
MDL No. :	MFCD29760620
InChI Key :	GHPOTUPEYXAOSM-UHFFFAOYSA-N
Pubchem ID :	57517538

Safety of [ 1298031-94-3 ]

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

Computational Chemistry of [ 1298031-94-3 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	9
Fraction Csp3	0.14
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	0.0
Molar Refractivity	50.66
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	30.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.16
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	2.38
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.45
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.	2.26
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	2.2
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.29

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.42
Solubility	0.0931 mg/ml ; 0.000378 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.	-2.65
Solubility	0.546 mg/ml ; 0.00221 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	-3.57
Solubility	0.0657 mg/ml ; 0.000267 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.	-6.11 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)	2.19

Application In Synthesis of [ 1298031-94-3 ]

* 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.

Upstream synthesis route of [ 1298031-94-3 ]
Downstream synthetic route of [ 1298031-94-3 ]

[ 1298031-94-3 ] Synthesis Path-Upstream 1~2

1
[ 446273-59-2 ]
[ 598-31-2 ]
[ 1298031-94-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium carbonate In isopropyl alcohol at 90℃; for 16 h;	4-Bromo-6-chloropyridazin-3-amine (20 g, 97 mmol), Na₂C0₃ (10.2 g, 97 mmol) and 1- bromopropan-2-one (9.7 mL, 116 mmol) were added into isopropyl alcohol (200 mL). The reaction vessel was degassed and then charged with nitrogen three times. The mixture was stirred at 90 °C for 16 h. The mixture was partitioned between EtOAc and H₂0. The organic layer was washed with brine, dried over Na₂S0₄, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20percent EtOAc in petroleum ether to yield 8-bromo-6- chloro-2-methylimidazo[l,2-b]pyridazine (8.1 g, 34percent). MS m/z 245.9, 247.9 [M+H]⁺.

References: [1] Patent: WO2018/226622, 2018, A1, . Location in patent: Page/Page column 184; 185.

2
[ 446273-59-2 ]
[ 78-95-5 ]
[ 1298031-93-2 ]
[ 1298031-94-3 ]

References: [1] Patent: WO2011/51342, 2011, A1, . Location in patent: Page/Page column 68.
[2] Patent: US2011/269752, 2011, A1, . Location in patent: Page/Page column 28-29.
[3] Patent: WO2016/97347, 2016, A1, . Location in patent: Page/Page column 134.

[ 1298031-94-3 ] Synthesis Path-Downstream 1~23

1
[ 446273-59-2 ]
[ 78-95-5 ]
[ 1298031-93-2 ]
[ 1298031-94-3 ]

Yield	Reaction Conditions	Operation in experiment
	at 90℃; for 16h;Sealed tube;	Example A3Preparation of intermediate 3: Mixture of 6,8-dichloro-2-methyl-imidazo[l,2- ^lpyridazine and 8-bromo-6-chloro-2-methyl-imidazo [ 1 ,2-&"\|pyridazineA mixture of intermediate 1 (28.57 g, 137.1 mmol) and chloroacetone (76.4 ml, 959.4 mmol) was stirred at 90C for 16 h. in a sealed tube protected from light. After cooling to room temperature, diethylether was added and the solid formed was filtered off and washed with further diethylether. The solid was suspended in a saturated solution of sodium carbonate and extracted with dichloromethane. The organic layer was dried (Na2S04), filtered and the solvents evaporated in vacuo. The crude products were purified by open column chromatography (silica; dichloromethane). The desired fractions were collected and concentrated in vacuo to yield intermediate 3 (19.5 g, 66%) as a white solid, in a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[l,2- ¾]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[l,2-¾]pyridazine. C7H5C12N3 requires 201 ; Found 202 [M+H]+; Rt: 1.25 min and C7H5BrClN3 requires 247; Found 248 [M+H]+; Rt: 1.33 min (method 5).
		Example A3 Preparation of intermediate 3: Mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine A mixture of intermediate 1 (28.57 g, 137.1 mmol) and chloroacetone (76.4 ml, 959.4 mmol) was stirred at 90 C. for 16 h. in a sealed tube protected from light. After cooling to room temperature, diethylether was added and the solid formed was filtered off and washed with further diethylether. The solid was suspended in a saturated solution of sodium carbonate and extracted with dichloromethane. The organic layer was dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude products were purified by open column chromatography (silica; dichloromethane). The desired fractions were collected and concentrated in vacuo to yield intermediate 3 (19.5 g, 66%) as a white solid, in a 70/30 mixture of 6,8-dichloro-2-methyl-imidazo[1,2-b]pyridazine and 8-bromo-6-chloro-2-methyl-imidazo[1,2-b]pyridazine. C7H5Cl2N3 requires 201; Found 202 [M+H]+; Rt: 1.25 min and C7H5BrClN3 requires 247; Found 248 [M+H]+; Rt: 1.33 min (method 5).
	at 90℃; for 15h;	3-Amino-4-bromo-6-chloropyridazine (23.65 g; 113.46 mmol) in chloro-2-propanone (70.9 mL; 891 mmol) and the mixture was heated at 90 C for 15 hours. The reaction was cooled to room temperature and Et20 was added. The precipitate was filtered, washed with Et20 and dried. The residue was stirred with DCM. The precipitate was filtered and dried to afford 41.1 g of a mixture intermediate 62 (A/B: 75/25 based on Eta NMR).

References: [1]Patent: WO2011/51342,2011,A1 .Location in patent: Page/Page column 68.
[2]Patent: US2011/269752,2011,A1 .Location in patent: Page/Page column 28-29.
[3]Patent: WO2016/97347,2016,A1 .Location in patent: Page/Page column 134.

2
[ 110-91-8 ]
[ 1298031-94-3 ]
[ 1298032-21-9 ]

Yield	Reaction Conditions	Operation in experiment
		Preparation of intermediate 31 : 6-Chloro-3-iodo-2-methyl-8-morpholin-l-yl- imidazo [ 1 ,2-&"\|pyridazineN-Iodosuccinimide (0.95 g, 4.36 mmol) was added to a stirred solution of a mixture 70/30 of intermediate 3 (0.95 g, 3.36 mmol) in a mixture of dichloromethane (9 ml) and acetic acid (1 ml). The mixture was stirred at room temperature for 16 h. and then washed with a saturated solution of sodium carbonate. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield 1.33 g of crude product. A portion of this crude product (0.5 g) was dissolved in acetonitrile (8 ml) and morpholine (0.140 ml, 1.6 mmol) and N,N-diisopropylethylamine (0.393 ml, 2.29 mmol) were added. The mixture was stirred at 150 C for 10 min in a sealed tube, under microwave irradiation. The mixture was diluted with ethyl acetate and washed with a saturated solution of ammonium chloride. The organic layer was separated, dried (Na2S04), filtered and the solvents evaporated in vacuo to yield intermediate 31 (0.53 g, 69%).

References: [1]Patent: WO2011/51342,2011,A1 .Location in patent: Page/Page column 80.

3
[ 67-56-1 ]
[ 1298031-94-3 ]
6-chloro-8-methoxy-2-methylimidazo[1,2-b]pyridazine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
90%	With caesium carbonate; In acetonitrile; at 20℃; for 4h;	8-Bromo-6-chloro-2-methyl-imidazo[l,2-b]pyridazine (250 mg, 1.01 mmol) was combined with CS2CO3 (700 mg, 2.15 mmol) in CH3CN (5 mL). To the mixture was added MeOH (0.2 mL). The mixture was stirred at room temperature for 4 h. The volatiles were removed from the reaction mixture. The residue was partitioned between EtOAc and H20. The organic layer was collected, concentrated and chromatographed on silica gel, eluting with 20- 100% EtOAc in hexanes to yield 6-chloro-8-methoxy-2-methyl-imidazo[l,2-b]pyridazine (180 mg, 90%). MS m/z 198.2, 202.2 [M+H]+.

References: [1]Patent: WO2018/226622,2018,A1 .Location in patent: Page/Page column 145; 146.

4
[ 446273-59-2 ]
[ 598-31-2 ]
[ 1298031-94-3 ]

Yield	Reaction Conditions	Operation in experiment
34%	With sodium carbonate; In isopropyl alcohol; at 90℃; for 16h;	4-Bromo-6-chloropyridazin-3-amine (20 g, 97 mmol), Na2C03 (10.2 g, 97 mmol) and 1- bromopropan-2-one (9.7 mL, 116 mmol) were added into isopropyl alcohol (200 mL). The reaction vessel was degassed and then charged with nitrogen three times. The mixture was stirred at 90 C for 16 h. The mixture was partitioned between EtOAc and H20. The organic layer was washed with brine, dried over Na2S04, filtered and concentrated. The residue was chromatographed on silica gel, eluting with 0-20% EtOAc in petroleum ether to yield 8-bromo-6- chloro-2-methylimidazo[l,2-b]pyridazine (8.1 g, 34%). MS m/z 245.9, 247.9 [M+H]+.

References: [1]Patent: WO2018/226622,2018,A1 .Location in patent: Page/Page column 184; 185.

5
[ 1298031-94-3 ]
8-fluoro-6-(8-methoxy-2-methylimidazo[1,2-b]pyridazin-6-yl)-2-(piperidin-4-yl)quinoline hydrochloride [ No CAS ]