22620-34-4|(5-Chloro-3-pyridinyl)methanol| Ambeed

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Quality Control of [ 22620-34-4 ] Purity: 95% SDS Specification

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Product Details of [ 22620-34-4 ]

CAS No. :	22620-34-4
Formula :	C₆H₆ClNO
M.W :	143.57
SMILES Code :	ClC1=CN=CC(=C1)CO
MDL No. :	MFCD09743969
InChI Key :	ALUCWNPKIRQBEF-UHFFFAOYSA-N
Pubchem ID :	25067264

Safety of [ 22620-34-4 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302-H315-H319-H332-H335
Precautionary Statements:	P261-P280-P305+P351+P338

Computational Chemistry of [ 22620-34-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.17
Num. rotatable bonds	1
Num. H-bond acceptors	2.0
Num. H-bond donors	1.0
Molar Refractivity	35.37
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	33.12 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.33
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	0.59
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.08
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.	0.49
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	1.85
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.07

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.53
Solubility	4.25 mg/ml ; 0.0296 mol/l
Class? Solubility class: Log S scale Insoluble < -10 < Poorly < -6 < Moderately < -4 < Soluble < -2 Very < 0 < Highly	Very soluble
Log S (Ali)? Ali: Topological method implemented from Ali J. et al. 2012 J. Chem. Inf. Model.	-0.86
Solubility	19.9 mg/ml ; 0.138 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	-2.45
Solubility	0.514 mg/ml ; 0.00358 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.	-6.76 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)	1.34

Application In Synthesis of [ 22620-34-4 ]

* 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 [ 22620-34-4 ]
Downstream synthetic route of [ 22620-34-4 ]

[ 22620-34-4 ] Synthesis Path-Upstream 1~3

1
[ 51269-81-9 ]
[ 22620-34-4 ]

Yield	Reaction Conditions	Operation in experiment
54%	With methanol; sodium tetrahydroborate In dichloromethane at 0 - 20℃; for 18 h;	To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol) in methanol (230 mL) and DCM (230 mL) at 0° C. was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3×300 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5-chloro-pyridin-3-yl)-methanol (7.8 g, 54percent). ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.45-8.52 (m, 2H), 7.83 (s, 1H), 5.45 (t, J=5.8 Hz, 1H), 4.55 (t, J=5.7 Hz, 2H). MS m/z 144.1

References: [1] Patent: US2014/107340, 2014, A1, . Location in patent: Paragraph 0124.
[2] Patent: WO2009/6370, 2009, A1, . Location in patent: Page/Page column 28.

2
[ 22620-27-5 ]
[ 79-22-1 ]
[ 22620-34-4 ]

Yield	Reaction Conditions	Operation in experiment
76%	Stage #1: With triethylamine In tetrahydrofuran at 0 - 20℃; Stage #2: With lithium aluminium tetrahydride In tetrahydrofuran for 0.5 h;	A. (5-Chloro-pyridin-3-yl)-methanol To a solution of 5-chloro-nicotinic acid (2 g, 12.7 mmol) and TEA (1.52 g, 15 mmol) in THF (30 mL) was added slowly methyl chloroformate (1.42 g, 15 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with saturated ammonia chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated to give the crude product (2.8 g, crude), which was dissolved in THF (40 mL) and cooled to -78° C. Lithium aluminium hydride (570 mg, 15 mmol) was added portion-wise. The resulting mixture was stirred for 30 min. The reaction was quenched with aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (30percent ethyl acetate in petroleum ether) to afford the title compound (1.4 g, 9.72 mmol, 76percent yield). MS (ESI) m/z 144.1 [M+H]⁺.

References: [1] Patent: US2015/175557, 2015, A1, . Location in patent: Paragraph 0321.

3
[ 22620-27-5 ]
[ 22620-34-4 ]

Yield	Reaction Conditions	Operation in experiment
31%	With diborane In tetrahydrofuran at 0 - 20℃; for 72 h; Inert atmosphere	1.3.2 (5-Chloropyridin-3-yl)methanol (AOH-2) 5-Chloronicotinic acid (1 g, 6.35 mmol) was dissolved in dry THF (20 mL) in a N₂flushed flask and 1 M BH₃in THF (25.4 mL, 25.4 mmol) was added via a syringe at 0°C. The mixture was stirred at RT for 72 h. The reaction mixture was cooled in an ice bath and aqueous saturated K₂C0₃(50 mL) was added cautiously. The organic solvent was removed in vacuo and the residue was extracted withEtOAc (2x 50 mL). The combined organic layers were washed with saturated aqueous NaHC0₃(2x 25 mL) and brine (2x 25 mL) before drying on Na₂S0₄and concentration in vacuo to give a colorless oil. The product was purified using column chromatography (silica, heptane/EtOAc, 1 :1 ) to give the desired product (285 mg, 31 percent) as a yellow oil which partially solidified upon standing.

References: [1] Patent: WO2015/90599, 2015, A1, . Location in patent: Page/Page column 53.
[2] Patent: US2014/107340, 2014, A1, .

[ 22620-34-4 ] Synthesis Path-Downstream 1~19

2
[ 51269-81-9 ]
[ 22620-34-4 ]

Yield	Reaction Conditions	Operation in experiment
54%	With methanol; sodium tetrahydroborate; In dichloromethane; at 0 - 20℃; for 18h;	To a solution of 5-chloro-nicotinic acid methyl ester (17.2 g, 101 mmol) in methanol (230 mL) and DCM (230 mL) at 0 C. was added sodium borohydride (16.4 g, 434 mmol). The reaction mixture was stirred at room temperature for 18 hours. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (300 mL) and extracted with AcOEt (3×300 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then purified by silica gel chromatography to afford (5-chloro-pyridin-3-yl)-methanol (7.8 g, 54%). 1H NMR (400 MHz, DMSO-d6) delta ppm 8.45-8.52 (m, 2H), 7.83 (s, 1H), 5.45 (t, J=5.8 Hz, 1H), 4.55 (t, J=5.7 Hz, 2H). MS m/z 144.1
	With methanol; sodium tetrahydroborate; In dichloromethane; at 20℃; for 18h;	Sodium borohydride (790 mg, 20.9 mmol) was added to a solution of crude methyl 5-chloronicotinate (-6.35 mmol) in methanol (10 mL) and CH2CI2 (10 mL). After 18 h at room temperature, the reaction mixture was concentrated in vacuo. Water (50 mL) was added and the mixture was extracted with CH2CI2 (3x50 mL).The organic phase was dried (MgStheta4), filtered and concentrated in vacuo. . Purification of the crude residue by chromatography on 40 g silica gel (hexanes ? EtOAc, gradient) afforded 510 mg (56% over two steps) of(5-chloropyridin-3-yl)methanol.

References: [1]Patent: US2014/107340,2014,A1 .Location in patent: Paragraph 0124.
[2]Patent: WO2009/6370,2009,A1 .Location in patent: Page/Page column 28.

3
[ 22620-34-4 ]
[ 847737-51-3 ]

Yield	Reaction Conditions	Operation in experiment
52%	With methanesulfonyl chloride; triethylamine; In dichloromethane; at 0 - 20℃; for 18h;	Triethylamine (1.75 mL, 12.6 mmol) and methanesulfonyl chloride (0.69 mL, 8.9 mmol) were added to a solution of <strong>[22620-34-4](5-chloropyridin-3-yl)methanol</strong> (510 mg, 3.6 mmol) in CH2CI2 (3.5 mL) at 0 ºC and the reaction was allowed to warm to room temperature. After 18 h at room temperature, the reaction was partitioned between water (50 mL) and CH2CI2 (50 mL). The phases were separated and the organic phase was extracted withCH2CI2 (20 mL). The combined organic phase was dried (MgStheta4), filtered and concentrated in vacuo.Purification of the crude residue by chromatography on 12 g silica gel (hexanes ? EtOAc, gradient) afforded300 mg (52%) of 3-chloro-5-(chloromethyl)pyridine.

References: [1]Patent: WO2009/6370,2009,A1 .Location in patent: Page/Page column 28.

4
[ 22620-27-5 ]
[ 22620-34-4 ]

Yield	Reaction Conditions	Operation in experiment
31%	With diborane; In tetrahydrofuran; at 0 - 20℃; for 72h;Inert atmosphere;	1.3.2 (5-Chloropyridin-3-yl)methanol (AOH-2)5-Chloronicotinic acid (1 g, 6.35 mmol) was dissolved in dry THF (20 mL) in a N2flushed flask and 1 M BH3in THF (25.4 mL, 25.4 mmol) was added via a syringe at 0C. The mixture was stirred at RT for 72 h. The reaction mixture was cooled in an ice bath and aqueous saturated K2C03(50 mL) was added cautiously. The organic solvent was removed in vacuo and the residue was extracted withEtOAc (2x 50 mL). The combined organic layers were washed with saturated aqueous NaHC03(2x 25 mL) and brine (2x 25 mL) before drying on Na2S04and concentration in vacuo to give a colorless oil. The product was purified using column chromatography (silica, heptane/EtOAc, 1 :1 ) to give the desired product (285 mg, 31 %) as a yellow oil which partially solidified upon standing.

References: [1]Patent: WO2015/90599,2015,A1 .Location in patent: Page/Page column 53.
[2]Patent: US2014/107340,2014,A1 .

5
[ 22620-27-5 ]
[ 79-22-1 ]
[ 22620-34-4 ]

Yield	Reaction Conditions	Operation in experiment
76%		A. (5-Chloro-pyridin-3-yl)-methanol To a solution of 5-chloro-nicotinic acid (2 g, 12.7 mmol) and TEA (1.52 g, 15 mmol) in THF (30 mL) was added slowly methyl chloroformate (1.42 g, 15 mmol) at 0 C. The resulting mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed with saturated ammonia chloride and dried over anhydrous sodium sulfate. The organic layer was concentrated to give the crude product (2.8 g, crude), which was dissolved in THF (40 mL) and cooled to -78 C. Lithium aluminium hydride (570 mg, 15 mmol) was added portion-wise. The resulting mixture was stirred for 30 min. The reaction was quenched with aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by silica gel column chromatography (30% ethyl acetate in petroleum ether) to afford the title compound (1.4 g, 9.72 mmol, 76% yield). MS (ESI) m/z 144.1 [M+H]+.

References: [1]Patent: US2015/175557,2015,A1 .Location in patent: Paragraph 0321.

6
[ 22620-34-4 ]
[ 124-63-0 ]
(5-chloropyridin-3-yl)methyl methanesulfonate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With triethylamine; In dichloromethane; at 0 - 20℃; for 1.5h;	B. (5-Chloropyridin-3-yl)methyl methanesulfonate To a mixture of <strong>[22620-34-4](5-chloropyridin-3-yl)MeOH</strong> (1.60 g, 11.3 mmol) and TEA (1.7 g, 16.8 mmol) in dry DCM (30 mL) was added methanesulfonyl chloride (1.53 g, 13.4 mmol) at 0 C. The resulting reaction mixture was stirred at room temperature for 1.5 h. Water was added and the mixture was extracted with DCM (3*100 mL). The combined organic layers were washed with saturated aqueous ammonium chloride, brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated under vacuum to give a crude title compound (2.09 g, crude) as a yellow oil, which was used directly in the next step without further purification. MS (ESI) m/z 222.0 [M+H]+.

References: [1]Patent: US2015/175557,2015,A1 .Location in patent: Paragraph 0322.

7
[ 22620-34-4 ]
[ 39891-07-1 ]