193001-91-1|(2-Chloro-6-methoxypyridin-4-yl)methanol| Ambeed

CAS No. :	193001-91-1
Formula :	C₇H₈ClNO₂
M.W :	173.60
SMILES Code :	OCC1=CC(Cl)=NC(OC)=C1
MDL No. :	MFCD09029989
InChI Key :	LGAAPDVGNCACDI-UHFFFAOYSA-N
Pubchem ID :	11457961

Safety of [ 193001-91-1 ]

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

Computational Chemistry of [ 193001-91-1 ] Show Less

Physicochemical Properties

Num. heavy atoms	11
Num. arom. heavy atoms	6
Fraction Csp3	0.29
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	41.87
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	42.35 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.74
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	1.23
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.	0.61
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	1.81
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.3

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-1.96
Solubility	1.89 mg/ml ; 0.0109 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.	-1.72
Solubility	3.33 mg/ml ; 0.0192 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	-2.59
Solubility	0.442 mg/ml ; 0.00255 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.	-6.49 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	1.0 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)	1.94

Application In Synthesis of [ 193001-91-1 ]

* 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 [ 193001-91-1 ]

[ 193001-91-1 ] Synthesis Path-Downstream 1~56

1
[ 71-23-8 ]
[ 201230-82-2 ]
[ 193001-91-1 ]
[ 308357-96-2 ]

References: [1]Tetrahedron,2002,vol. 58,p. 6951 - 6963.
[2]Organic Letters,2000,vol. 2,p. 3421 - 3423.

2
[ 15855-06-8 ]
[ 193001-91-1 ]

Yield	Reaction Conditions	Operation in experiment
42%		BH3. DMS (1.0 mL, 10.66 mmol) was refluxed in THF (20 mL) for 30 min (formation of BH3. THF). At RT, Example 17 (2.0 g, 10.66 mmol in 10 mL THF) was added dropwise, and then the reaction mixture was heated to reflux for 3 h. The solution was allowed to cool to ambient temperature, solid sodium carbonate (0.5 g) and water (5 mL). The resulting mixture was heated for a short while and poored in water (50 mL). Extraction with ethyl acetate (3 x 50 mL), drying of the combined organic layers (Na2SO4) and evaporation in vacuo gave a 1: 1 mixture of starting material and product. Purification by flash column chromatography over silica gel eluting with ethyl acetate gave 780 mg (42 %) of an off-white solid. IH NMR (400 MHz, CDC13) 8 3.92 (s, 3H) 4.66 (s, 2H) 6.64 (s, 1H) 6.89 (s, 1H).
2 g	With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 20.5h;Inert atmosphere;	To a solution of 2-chloro-6-methoxyisonicotinic acid (2.5 g) in dry tetrahydrofuran (50 ml) at 0C under nitrogen was added dropwise a solution of borane- tetrahydrofuran complex (1.0M solution in tetrahydrofuran; 40 ml) over fifteen minutes. After the addition was complete, the cooling bath was removed and the mixture allowed to warm to room temperature. After three hours, the mixture was cooled to 0C and borane-tetrahydrofuran complex (1.0M solution in tetrahydrofuran; 40 ml) was addedover fifteen minutes. After the addition was complete, the cooling bath was removed and the mixture allowed to warm to room temperature and stirred for seventeen hours. The reaction mixture was cooled to 0C, quenched with 1.0M aqueous sodium hydroxide solution (30 ml), diluted with saturated aqueous ammonium chloride solution (50 ml) and extracted with diethyl ether (2 x 100 ml), the combined organic layer washed with brine then dried (Na2SC"4) and evaporated. The residue was triturated with hexane and filtered to afford (2-chloro-6-methoxypyridin-4-yl)methanol (2.0 g) as a white solid. LCMS: Rt 1.16 min, m/z 174/176 [M+H]+. 1H-NMR (400 MHz, CDC13) delta (ppm): 1.96 (t, 1 H) 3.94 (s, 3 H) 4.67 (d, J=3.67 Hz, 2 H) 6.65 (d, J=0.86 Hz, 1 H) 6.91 (s, 1 H)

References: [1]ChemMedChem,2020,vol. 15,p. 675 - 679.
[2]European Journal of Organic Chemistry,2003,p. 4445 - 4449.
[3]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676.
[4]Organic Letters,2000,vol. 2,p. 3421 - 3423.
[5]Patent: WO2004/63156,2004,A1 .Location in patent: Page 36.
[6]Tetrahedron,2002,vol. 58,p. 6951 - 6963.
[7]Patent: WO2014/13076,2014,A1 .Location in patent: Page/Page column 62; 63.

3
[ 193001-91-1 ]
[ 478946-80-4 ]

References: [1]European Journal of Organic Chemistry,2003,p. 4445 - 4449.
[2]Tetrahedron,2002,vol. 58,p. 6951 - 6963.

4
[ 109-87-5 ]
[ 193001-91-1 ]
[ 888729-53-1 ]

Yield	Reaction Conditions	Operation in experiment
95%	With boron trifluoride diethyl etherate; In dichloromethane; at 0 - 20℃; for 4.25h;Inert atmosphere;	2-Chloro-6-methoxy-4-[(methoxymethoxy)methyl]pyridine (10). Boron trifluoride etherate (9.32 mL, 75.81 mmol) was added dropwise under argon during 15 min at 0 C. to a solution of dimethoxymethane (38.22 mL, 431.5 mmol) and <strong>[193001-91-1](2-chloro-6-methoxy-pyridin-4-yl)-methanol</strong> (9), (10.700 g, 61.64 mmol) in dry dichloromethane (80 mL). After the addition, the reaction mixture was stirred at room temperature for 4 h, cooled to 0 C. and quenched by dropwise addition of water. Diluted with dichloromethane and the organic layer was washed with saturated sodium bicarbonate and brine, dried over anhydrous sodium sulfate and evaporated. The crude product was purified using silica gel column chromatography (10% EtOAc/Hexane) to afford 12.820 g, (95%) of the protected alcohol 10. 1H NMR (CDCl3, 400 MHz): delta 6.91 (s, 1H), 6.65 (d, 1H, J=0.7 Hz), 4.72 (s, 2H), 4.54 (s, 2H), 3.95 (s, 3H), 3.42 (s, 3H). 13C NMR (CDCl3, 100 MHz): 163.7, 152.3, 148.1, 114.1, 106.5, 95.7, 66.5, 55.2, 53.7.

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676.
[2]Patent: US2010/48606,2010,A1 .Location in patent: Page/Page column 34.

5
[ 18162-48-6 ]
[ 193001-91-1 ]
[ 944407-72-1 ]

Yield	Reaction Conditions	Operation in experiment
93%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;	(a) 2-Chloro-4-([(l,l-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)pyridineA solution of <strong>[193001-91-1][2-chloro-6-(methyloxy)-4-pyridinyl]methanol</strong> (for a synthesis see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry DMF (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at rt for 2h. The reaction mixture was treated with water extracted three times with dichloromethane, <n="75"/>dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluting with 1 :4 ethyl acetate-hexane to give the desired product (12.38g, 93%). MS (+ve ion electrospray) m/z 288/290 (MH+).
93%	With 1H-imidazole; In N,N-dimethyl-formamide; at 20℃; for 2h;	(a) 2-Chloro-4-([(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)-6-(methyloxy)pyridine A solution of <strong>[193001-91-1][2-chloro-6-(methyloxy)-4-pyridinyl]methanol</strong> (for a synthesis, see Adamczyk, M.; Akireddy, S. R.; Reddy, Rajarathnam E. Tetrahedron 2002, 58(34), 6951)(8.02 g, 46.22 mmol) in dry dimethylformamide (100 ml) was treated with tert-butyldimethylsilyl chloride (8.36 g, 55.46 mmol) and imidazole (3.77 g, 55.46 mmol) and stirred at room temperature for 2 hours. The reaction mixture was treated with water extracted 3* with dichloromethane, dried (magnesium sulphate), evaporated and chromatographed on silica gel (100 g), eluding with 1:4 ethyl acetate-hexane to give the desired product (12.38 g, 93%). MS (+ve ion electrospray) m/z 288/290 (MH+).

References: [1]Patent: WO2007/122258,2007,A1 .Location in patent: Page/Page column 73-74.
[2]Patent: US2008/221110,2008,A1 .Location in patent: Page/Page column 30.

6
[ 193001-91-1 ]
SKC-2-150 [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676.
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676.

7
[ 193001-91-1 ]
SKC-2-203 [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676.
[2]Journal of Medicinal Chemistry,2006,vol. 49,p. 2673 - 2676.

8
[ 193001-91-1 ]
[ 888729-64-4 ]