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Quality Control of [ 201227-39-6 ] Purity: 97% SDS Specification

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Product Details of [ 201227-39-6 ]

CAS No. :	201227-39-6
Formula :	C₈H₄BrN₃
M.W :	222.04
SMILES Code :	N#CC1=NNC2=C1C=C(Br)C=C2
MDL No. :	MFCD07371567
InChI Key :	QIULWQLXNFSZJG-UHFFFAOYSA-N
Pubchem ID :	24728911

Safety of [ 201227-39-6 ]

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

Computational Chemistry of [ 201227-39-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	9
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	48.51
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	52.47 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.19
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	2.3
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.2
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.	1.23
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	2.64
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.91

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.22
Solubility	0.134 mg/ml ; 0.000602 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.	-3.04
Solubility	0.203 mg/ml ; 0.000912 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	-3.86
Solubility	0.0309 mg/ml ; 0.000139 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.	-6.02 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)	1.81

Application In Synthesis of [ 201227-39-6 ]

* 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 [ 201227-39-6 ]

[ 201227-39-6 ] Synthesis Path-Downstream 1~32

1
[ 2973-50-4 ]
[ 201227-39-6 ]

References: [1]Patent: US2011/111046,2011,A1 .
[2]Patent: WO2011/58473,2011,A1 .

2
[ 882855-95-0 ]
[ 201227-39-6 ]

Yield	Reaction Conditions	Operation in experiment
60%		To a cooled solution of (2-amino-5-bromophenyl)acetonitrile (11 g, 52 mmol) in concentrated hydrochloric acid (110 mL) at -50 C., a solution of sodium nitrite (3.9 g, 57 mmol) in water (20 mL) was added slowly. After the addition, the mixture was stirred at -50 C. for 2 h. The mixture was neutralized with 33% ammonium hydroxide at 0 C. and extracted with ethyl acetate (3*100 mL). The combined organic layers were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford 5-bromo-3-cyanoindazole (7 g, 60%) as a solid. 1HNMR (CDCl3) δ ppm 10.7 (br, 1H), 8.1 (s, 1H), 7.64 (d, 1H), 7.5 (d, 1H).
60%	With hydrogenchloride; sodium nitrite; In water; at -50℃; for 2h;	To a cooled solution of (2-amino-5-bromophenyl)acetonitrile (11 g, 52 mmol) in concentrated hydrochloric acid (110 mL) at -50 C, a solution of sodium nitrite (3.9 g, 57 mmol) in water (20 mL) was added slowly. After the addition, the mixture was stirred at-50 C for 2h. The mixture was neutralized with 33% ammonium hydroxide at 0 C and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with saturated sodium chloride (100 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in petroleum ether as eluent to afford 5-bromo-3-cyanoindazole (7 g, 60%) as a solid. 1HNMR (CDCIs) ppm 10.7 (br, 1 H), 8.1 (s, 1 H), 7.64 (d, 1 H), 7.5 (d, 1 H).

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3611 - 3625.
[2]Patent: US2011/111046,2011,A1 .Location in patent: Page/Page column 17.
[3]Patent: WO2011/58473,2011,A1 .Location in patent: Page/Page column 35; 36.

3
[ 610-66-2 ]
[ 201227-39-6 ]

References: [1]Patent: US2011/111046,2011,A1 .
[2]Patent: WO2011/58473,2011,A1 .

4
[ 67-56-1 ]
[ 201230-82-2 ]
[ 201227-39-6 ]
[ 1190319-99-3 ]

Yield	Reaction Conditions	Operation in experiment
68%	With sodium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In water; N,N-dimethyl-formamide; at 80℃; under 4137.29 Torr; for 16h;autoclave;	A suspension of 5-bromo-3-cyanoindazole (3 g, 13.51 mmol), palladium dichloride 1,1'-bis(diphenylphosphino)ferrocene (1.76 g, 2.16 mmol), sodium acetate (3.32 g, 40.5 mmol), dimethylformamide (1 mL) in methanol (100 mL) was degassed, and kept under carbon monoxide (80 psi) pressure at 80 C. in a autoclave for 16 hours. The mixture was diluted with water (50 mL), filtered through Celite bed and the filtrate was concentrated. The obtained residue was acidified with 10% citric acid solution and extracted with ethyl acetate (2*100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in chloroform as eluent to afford methyl 3-cyano-1H-indazole-5-carboxylate (1.8 g, 68%) as a solid. 1HNMR (CDCl3) δ ppm 10.8 (s, 1H), 8.7 (s, 1H), 8.22 (d, 1H), 7.64 (d, 1H), 4.0 (s, 3H).
68%	With sodium acetate;1,1'-bis-(diphenylphosphino)ferrocene; palladium dichloride; In N,N-dimethyl-formamide; at 80℃; under 4137.29 Torr; for 16h;Autoclave;	A suspension of 5-bromo-3-cyanoindazole (3 g, 13.51 mmol), palladium dichloride 1,1'-bis(diphenylphosphino)ferrocene (1.76 g, 2.16 mmol), sodium acetate (3.32 g, 40.5 mmol), dimethylformamide (1 mL) in methanol (100 mL) was degassed, and kept under carbon monoxide (80 psi) pressure at 80 C in a autoclave for 16 hours. The mixture was diluted with water (50 mL), filtered through Celite bed and the filtrate was concentrated. The obtained residue was acidified with 10% citric acid solution and extracted with ethyl acetate (2 x 100mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate andconcentrated. The obtained crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in chloroform as eluent to afford methyl 3-cyano-1H-indazole-5-carboxylate (1 .8 g, 68%) as a solid. 1 HNMR (CDCI3) ppm 10.8 (s, 1 H), 8.7 (s, 1 H), 8.22 (d, 1 H), 7.64 (d, 1 H), 4.0 (s, 3H).

References: [1]Patent: US2011/111046,2011,A1 .Location in patent: Page/Page column 17.
[2]Patent: WO2011/58473,2011,A1 .Location in patent: Page/Page column 36.

5
[ 201227-39-6 ]
[ 1301214-73-2 ]

References: [1]Patent: US2011/111046,2011,A1 .
[2]Patent: WO2011/58473,2011,A1 .

6
[ 201227-39-6 ]
[ 73183-34-3 ]
[ 1463055-84-6 ]

Yield	Reaction Conditions	Operation in experiment
20.8%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; at 90℃; for 16h;Inert atmosphere;	Step A: 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indazole-3-carbonitrile [0449] To a mixture of 5-bromo-lH-indazole-3-carbonitrile (475 mg, 2.139 mmol), 1,4- dioxane (15 mL), potassium acetate (735 mg, 7.49 mmol), and bis(pinacolato)diboron (652 mg, 2.57 mmol), was added PdCl2(dppf) (78 mg, 0.107 mmol). The mixture was purged with N2 and then heated at 90C for 16 hours. The mixture was subsequently cooled and purified by column chromatography, eluting with a gradient of MeOH (0-10%) in DCM. The relevant fractions were collected and concentrated to give the title compound as an off-white solid (120 mg, 20.8%).

References: [1]Patent: WO2013/148603,2013,A1 .Location in patent: Paragraph 0448-0449.

7
[ 201227-39-6 ]
[ 76513-69-4 ]
5-bromo-1-(2-trimethylsilylethoxymethyl)indazole-3-carbonitrile [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2015,vol. 58,p. 3611 - 3625.

8
[ 201227-39-6 ]
5-bromo-1H-indazole-3-carboxamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; trifluoroacetic acid; at 20℃; for 4h;	A mixture of 5-Bromo-1H-indazole-3-carbonitrile 110 (10 g) in trifluoroacetic acid (160 mL) and sulfuric acid (40 mL) was stirred at rt for 4 h. The reaction mixture was then poured into ice, and the precipitated solid was filtered, washed with water, and dried under high vacuum to give 5-bromo-1H-indole-3-carboxamide (111).

References: [1]Patent: WO2017/35351,2017,A1 .Location in patent: Paragraph 0526; 0527.

9
[ 201227-39-6 ]
tert-butyl 2-(3-acetyl-5-bromo-1H-indazol-1-yl)acetate [ No CAS ]

References: [1]Patent: WO2017/35355,2017,A1 .
[2]Patent: WO2017/35353,2017,A1 .
[3]Patent: WO2017/35409,2017,A1 .

10
[ 201227-39-6 ]
tert-butyl 2-(3-acetyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)acetate [ No CAS ]

References: [1]Patent: WO2017/35355,2017,A1 .
[2]Patent: WO2017/35353,2017,A1 .
[3]Patent: WO2017/35409,2017,A1 .

11
[ 201227-39-6 ]
[ 75-16-1 ]
1-(5-bromo-1H-indazol-3-yl)ethan-1-one [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
37.1%	In tetrahydrofuran; at 0 - 20℃; for 16h;Inert atmosphere;	To a stirred solution of scheme 6-6 compound S1 (10 g, 57.5 mmol) in THF (150 mL) under nitrogen was added methyl magnesium bromide solution (63.2 mL, 126.5 mmol) dropwise at 0 oC under N2 atmosphere. The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with saturated aqeuous NH4Cl solution and extracted with EtOAc (200 mL). The organic phase was washed with brine, dried with anhydrous Na2SO4 and concentrated. The residue was purified by silica gel cloumn chromatography (eluted with petroleum ether: ethyl acetate =10:1 to 5:1) to afford the title compound (5.1 g, 37.1 % yield) as a white solid.
100 g	In tetrahydrofuran; diethyl ether; at 20℃; for 3h;Cooling with ice;	Step 1 : l-(5-Bromo-lH-indazol-3-yl)ethan-l-one (223) [0711] To an ice cold solution of 5-bromo-lH-indazole-3-carbonitrile (110 g) in a mixture of 1.1 L THF and 3.3 I, diethyl ether, methyl magnesium bromide (1 M in THF, 1.48 L, 3 equiv) was added dropwise. After completion of addition, the reaction mixture was brought to rt and stirred for 3 h (monitored by UPLC). Then the reaction was cooled to 0 nC and the pH was adjusted to 5 using 1 ,5 N HC1 (pH ~ 5). Then the reaction mass was stirred at rt for another 30 min. The reaction mixture was diluted with EtOAc and the layers were separated. The aqueous layer was again extracted with EtOAc. The combined organic layer was washed with water, washed with brine, dried over Na?.SQ4, and concentrated. The crude residue was recrystallized with a mixture of DCM:hexane (1 :2, total 10 volume based on crude weight) to afford brown solid (100 g).
100 g	In tetrahydrofuran; diethyl ether; at 20℃; for 3h;Cooling with ice;	To an ice-cold solution of <strong>[201227-39-6]5-bromo-1H-indazole-3-carbonitrile</strong> (110 g) in a mixture of 1.1 L THF and 3.3 L diethyl ether, methyl magnesium bromide (1 M in THF, 1.48 L, 3 equiv) was added dropwise. After completion of addition, the reaction mixture was brought to room temperature and stirred for 3 h. Then the reaction was cooled to 0 C. and the pH was adjusted to 5 using 1.5 N HCl (pH≈5). Then the reaction mass was stirred at room temperature for another 30 min. The reaction mixture was diluted with EtOAc and the layers were separated. The aqueous layer was again extracted with EtOAc. The combined organic layer was washed with water, washed with brine, dried over Na2SO4, and concentrated. The crude residue was recrystallized with a mixture of DCM:hexane (1:2, total 10 volume based on crude weight) to afford brown solid (100 g).

References: [1]Patent: WO2017/35409,2017,A1 .Location in patent: Paragraph 0648; 0788.
[2]Patent: WO2017/35355,2017,A1 .Location in patent: Paragraph 0711.
[3]Patent: WO2017/35353,2017,A1 .Location in patent: Paragraph 1199.

12
[ 201227-39-6 ]
2-(3-acetyl-5-(2-methylpyrimidin-5-yl)-1H-indazol-1-yl)-1-((2S,4R)-2-(4-(6-bromopyridin-2-yl)-1H-imidazol-2-yl)-4-fluoropyrrolidin-1-yl)ethan-1-one [ No CAS ]