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Quality Control of [ 452972-11-1 ] Purity: 98% SDS Specification

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Product Details of [ 452972-11-1 ]

CAS No. :	452972-11-1
Formula :	C₁₁H₁₅BClNO₂
M.W :	239.51
SMILES Code :	CC1(C)OB(OC1(C)C)C1=CC=CN=C1Cl
MDL No. :	MFCD04039873
InChI Key :	XFZFMAUUZHBQSS-UHFFFAOYSA-N
Pubchem ID :	12067060

Safety of [ 452972-11-1 ]

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

Computational Chemistry of [ 452972-11-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	16
Num. arom. heavy atoms	6
Fraction Csp3	0.55
Num. rotatable bonds	1
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	65.72
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	31.35 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	0.0
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	2.8
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.03
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.	1.13
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	1.94
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.58

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.3
Solubility	0.12 mg/ml ; 0.000501 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.	-3.12
Solubility	0.184 mg/ml ; 0.000767 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	-4.25
Solubility	0.0136 mg/ml ; 0.0000566 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	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.	-5.77 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	2.0 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)	2.91

Application In Synthesis of [ 452972-11-1 ]

* 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 [ 452972-11-1 ]

[ 452972-11-1 ] Synthesis Path-Downstream 1~33

1
[ 109-09-1 ]
[ 76-09-5 ]
[ 452972-11-1 ]

References: [1]Tetrahedron,2002,vol. 58,p. 3323 - 3328.

2
[ 52200-48-3 ]
[ 76-09-5 ]
[ 452972-11-1 ]

References: [1]Tetrahedron,2002,vol. 58,p. 3323 - 3328.

3
[ 76-09-5 ]
[ 78607-36-0 ]
[ 452972-11-1 ]

References: [1]Tetrahedron,2002,vol. 58,p. 3323 - 3328.

4
[ 452972-11-1 ]
o-CN-C₆H₄-Hal [ No CAS ]
2-(2-chloro-pyridin-3-yl)-benzonitrile [ No CAS ]

References: [1]Tetrahedron,2002,vol. 58,p. 3323 - 3328.

5
[ 452972-11-1 ]
[ 6636-78-8 ]

References: [1]Tetrahedron,2005,vol. 61,p. 1417 - 1421.

6
[ 106-48-9 ]
[ 452972-11-1 ]
2-chloro-3-(4-chlorophenoxy)pyridine [ No CAS ]

References: [1]Tetrahedron,2006,vol. 62,p. 6000 - 6005.

7
[ 452972-11-1 ]
potassium (2-chloropyrid-3-yl)trifluoroborate [ No CAS ]

References: [1]Tetrahedron,2009,vol. 65,p. 9956 - 9960.

8
[ 133038-74-1 ]
[ 452972-11-1 ]
[ 1426414-39-2 ]

References: [1]Organic Letters,2013,vol. 15,p. 1346 - 1349.

9
[ 76-09-5 ]
[ 381248-04-0 ]
[ 452972-11-1 ]

References: [1]Organic Letters,2013,vol. 15,p. 1346 - 1349.

10
[ 452972-11-1 ]
[ 1426414-42-7 ]

References: [1]Organic Letters,2013,vol. 15,p. 1346 - 1349.

11
[ 452972-11-1 ]
[ 1426414-53-0 ]
(S)-2-chloro-3-(1-phenylethyl)pyridine [ No CAS ]

References: [1]Organic Letters,2013,vol. 15,p. 1346 - 1349.

12
[ 3034-55-7 ]
[ 452972-11-1 ]
2-chloro-3-(thiazol-5-yl)-pyridine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
72%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 120℃; for 0.25h;Microwave irradiation;	Svnthesis 32 2-Chlor -3-thiazol-5-yl-pyridine To a degassed suspension of 5-bromothiazole (3 mmol, 0.5 g) and 2-chloro-3-(4, 4,5,5- tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine (3 mmol, 0.73 g) in 1 ,4-dioxane (14 mL) water (6 mL) was added potassium carbonate (9 mmol, 1.25 g) and bis(triphenylphenylphospine) palladium (II) dichloride (0.15 mmol, 0.10 g). The mixture was heated in a microwave reactor at 120 C for 15 minutes. The mixture was purified by flash chromatography using a gradient elution of 0-100% ethyl acetate/cyclohexane. The solvent was removed by evaporation under reduced pressure to yield the title compound as a low-melting point colourless solid. Yield: 0.42 g, 72%. LCMS, analytical method 1 , TR= 3.37 mins, 95%, M+H=197. H NMR (300 MHz, CDCIs) delta: 8.92 (1 H, s), 8.42 (1 H, d), 8.15 (1 H, s), 7.85 (1 H, d), 7.35 (1 H, m).

References: [1]Patent: WO2015/25172,2015,A1 .Location in patent: Page/Page column 114.

13
[ 452972-11-1 ]
3-thiazol-5-yl-2-(2-trifluoromethyl-phenyl)-pyridine [ No CAS ]

References: [1]Patent: WO2015/25172,2015,A1 .

14
[ 452972-11-1 ]
3-(2-bromo-thiazol-5-yl)-2-(2-trifluoromethyl-phenyl)-pyridine [ No CAS ]

References: [1]Patent: WO2015/25172,2015,A1 .

15
[ 452972-11-1 ]
5-[2-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazol-2-ylamine [ No CAS ]

References: [1]Patent: WO2015/25172,2015,A1 .

16
[ 452972-11-1 ]
N-{5-[2-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazol-2-yl}-isobutyramide [ No CAS ]

References: [1]Patent: WO2015/25172,2015,A1 .

17
[ 452972-11-1 ]
N-{5-[2-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazol-2-yl}-acetamide [ No CAS ]

References: [1]Patent: WO2015/25172,2015,A1 .

18
[ 452972-11-1 ]
phenyl-{5-[2-(2-trifluoromethyl-phenyl)-pyridin-3-yl]-thiazol-2-yl}-amine [ No CAS ]

References: [1]Patent: WO2015/25172,2015,A1 .

19
[ 1314095-70-9 ]
[ 452972-11-1 ]
[5-(2-chloro-pyridin-3-yl)-thiazol-2-yl]-propyl-amine [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
58%	With bis-triphenylphosphine-palladium(II) chloride; potassium carbonate; In 1,4-dioxane; water; at 150℃; for 0.25h;Microwave irradiation;	Synthesis 41 [5-(2-Chloro- propyl- To a degassed suspension of (5-bromo-thiazol-2-yl)-propyl-carbamic acid tert-butyl ester (2 mmol, 0.64 g) and 2-chloro-3-(4,4,5,5-tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-pyridine (2 mmol, 0.5 g) in 1 ,4-dioxane (10 mL) and water (5 mL) was added potassium carbonate (6 mmol, 0.83 g) and bis(triphenylphenylphospine) palladium (II) dichloride (0.01 mmol, 0.070 g). The mixture was heated in a microwave reactor at 150 C for 15 mins. The solvent was removed by evaporation under reduced pressure. Water was added and the mixture was extracted with dichloromethane. The organic phase was collected, dried over MgS04, filtered and evaporated under reduced pressure to give a gum which was purified by flash chromatography using 2: 1 cyclohexane:ethyl acetate as eluent. Fractions were pooled and evaporated under reduced pressure to give the title compound as a colourless oil which solidified on standing. Yield: 0.3 g, 58%. LCMS, analytical method 2, TR=2.75 mins, 100%, Ml+H=254. H NMR (300 MHz, DMSO-d6): 8.26 (1 H, dd); 8.0 (2H, m); 7.56 (1 H, s); 7.4 (1 H, m); 3.21 (2H, q); 1.56 (2H, m); 0.92 (3H, t).

References: [1]Patent: WO2015/25172,2015,A1 .Location in patent: Page/Page column 119; 120.

20
[ 651780-02-8 ]
[ 452972-11-1 ]
5-(2-chloropyridin-3-yl)-1H-indazole [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
47%	With tetrakis(triphenylphosphine) palladium(0); water; sodium carbonate; In 1,4-dioxane; at 100℃; for 18h;Inert atmosphere;	[0150j A single necked round bottom flask (250 mL) equipped with a magnetic stir bar was charged with tert-butyl 5-bromo-1H-indazole-carboxylate (4.0 g, 13.4 mmol) dissolved in 1,4- dioxane (130 mL), 2-chloro-3-pyridine boronic acid pinacol ester (4 g, 16.7 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol) and 2M aq. Na2CO3 (20 mL, 40 mmol) under nitrogen atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100 C (oil-bath) under argon. Inflated argon balloon was emptied, refilled with argon and remounted in the course of reaction. The initial pale yellow heterogeneous reaction mixture turned to clear biphasic off-brown solution. After 18 h with no additional change in the proportion of the product (62%) as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL / 75 mL) was transferred to the concentrate and stirred for 30 mm. The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL X 2). Mg504 (20 g) and Celite (20 g) were added to combined organic layers and the contents suction filtered after stirring for 1 h. The filter cake was washed with EtOAc (300 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in in 1% MeOH/CH2C12 and absorbed on silica gel (20 g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel columnpurification of the dry powder (Combiflash companion system with RediSep silica gel column 120 g, 30-70%EtOAC/hexanes eluting solvent) provided 5-(2-chloropyridin-3-yl)-1H-indazole (1.5 g, 47%) as a white crystalline solid after concentration of the desired product fractions. 1H NMR (DMSO-d6): 13.2 (s, 1H), 8.41 (dd, 1H, J = 1.8 and 4.7 Hz), 8.13 (s, 1H), 7.90 (dd, 1H, J = 1.7 and 4.7 Hz), 7.84 (s, 1H), 7.62 (d, 1H, J = 8.8 Hz), 7.51 (dd, 1H, J = 4.7 and 7.3 Hz), 7.42 (dd, 1H, J = 1.4 and 8.5 Hz). LCMS: 95 %, MS (mle) 230 (MH+).
47%	With tetrakis(triphenylphosphine) palladium(0); sodium carbonate; In 1,4-dioxane; water; at 100℃; for 18h;Inert atmosphere;	A single necked round bottom flask containing a with a magnetic stir bar was charged with 5-bromo-1H-indazole (3.0 g, 15.2 mmol), di-tert-butyl dicarbonate (4.2 g, 19.2 mmol) and acetonitrile (30 mL) under mild stream of nitrogen at room temperature. Triethylamine (1.8 g, 2.5 mL, 17.7 mmol) was added in one portion to above stirred homogeneous solution followed by 4-(dimethylamino)pyridine (2.2 g, 18 mmol) over a period of 15 mm in portions. The homogenous off-brown clear reaction mixture was stirred at room temperature under nitrogen and the progress of reaction monitored by TLC (50% EtOAc/hexanes). Stirring was discontinued after 3h and the reaction mixture concentrated by rotary evaporator under vacuum. A clear viscous liquid was obtained and dissolved in EtOAc/hexanes (7:3, 200 mL), and diluted with water (75 mL). Organic layer was separated and the aqueous layer extracted with EtOAc/hexanes (1:1, 125 mL). The combined organic layers were washed with water (100 mL) followed by iN aq. HC1 (2 x 75mL) to remove 4-(dimethylamino)pyridine. The combined organic layers were washed with water (2 X 75 mL), saturated aq. NaHCO3 (2 X 75 mL) and saturated aqueous NaC1. Separated organic layers were dried over anhydrous Mg504, filtered, concentrated and dried under vacuum to provide tert-butyl 5-bromo-1H-indazole-carboxylate (4.5 g, purity 97%) as a pale yellow viscous liquid which was used without further purification. ?H NMR (DMSOd6): oe 8.36 (d, J 0.8 Hz, 1H), 8.11 (app d, J= 0.8 Hz, 1H), 8.00 (d, J= 8.8 Hz, 1H), 7.71 (app dd, J= 8.8, 0.8 Hz, 1H), 1.62 (s, 9H). LCMS: 97 %, MS (m/e) 241 (MHttBu). A single necked round bottom flask (250 mL) equipped with a magnetic stir bar was charged with tertbutyl 5-bromo-1H-indazole-carboxylate (4.0 g, 13.4 mmol) dissolved in 1,4-dioxane (130 mL), 2-chloro-3-pyridine boronic acid pinacol ester (4 g, 16.7 mmol), Pd(PPh3)4 (1.5 g, 1.3 mmol) and 2M aq.Na2CO3 (20 mL, 40 mmol) under nitrogen atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock equipped with argon filled balloon. The reaction contents were stirred and air was removed from the closed reaction system by vacuum and back filled with argon. Following three cycles of degassing, the reaction mixture was heated at 100 C (oil-bath) under argon. Inflated argon balloon was emptied, refilled with argon and remounted in the course of reaction. The initial pale yellow heterogeneous reaction mixture turned to clear biphasic off-brown solution. After 18 h with no additional change in the proportion of the product (62%) as analyzed by LC/MS, the reaction mixture was cooled to room temperature. Upon concentration of the reaction mixture, EtOAc/water (200 mL / 75 mL) was transferred to the concentrate and stirred for 30 mm. The organic layer was separated and the aqueous layer extracted with EtOAc (100 mL X 2). Mg504 (20 g) and Celite (20 g) were added to combined organic layers and the contents suction filtered after stirring for 1 h. The filter cake was washed with EtOAc (300 mL) and the combined filtrates concentrated by rotary evaporator under vacuum. The crude concentrate was dissolved in in 1% MeOH/CH2C12 and absorbed on silica gel (20 g) by evaporating the solvent followed by drying. Subsequent purification by flash silica gel column purification of the dry powder (Combiflash companion system with RediSep silica gel column 120 g, 30-70% EtOAc/hexanes eluting solvent) provided 5-(2- chloropyridin-3-yl)-1H-indazole (1.5 g, 47%) as a white crystalline solid after concentration of the desired product fractions. ?H NMR (DMSO-d6): oe 13.2 (s, 1H), 8.41 (dd, J= 1.8 and 4.7 Hz, 1H), 8.13 (s, 1H), 7.90 (dd, J 4.7, 1.7 Hz, 1H), 7.84 (s, 1H), 7.62 (d, J= 8.8 Hz, 1H), 7.51 (dd, J= 7.3, 4.7 Hz, 1H), 7.42 (dd, J= 8.5, 1.4 Hz, 1H). LCMS: 95 %, MS (m/e)230 (MI-i?).

References: [1]Patent: WO2015/157093,2015,A1 .Location in patent: Paragraph 0150.
[2]Patent: WO2016/133838,2016,A1 .Location in patent: Paragraph 0164; 0165.

21
[ 452972-11-1 ]
2'-(4-fluoro-3-methylphenyl)-[3,3'-bipyridine]-6-carbonitrile [ No CAS ]