1184172-46-0|2-Chloro-3-fluoro-4-hydroxypyridine| Ambeed

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Quality Control of [ 1184172-46-0 ] Purity: 95% SDS Specification

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Product Details of [ 1184172-46-0 ]

CAS No. :	1184172-46-0
Formula :	C₅H₃ClFNO
M.W :	147.54
SMILES Code :	OC1=C(F)C(Cl)=NC=C1
MDL No. :	MFCD13189885
InChI Key :	KMUSIJQLKVODNC-UHFFFAOYSA-N
Pubchem ID :	70700710

Safety of [ 1184172-46-0 ]

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

Computational Chemistry of [ 1184172-46-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	9
Num. arom. heavy atoms	6
Fraction Csp3	0.0
Num. rotatable bonds	0
Num. H-bond acceptors	3.0
Num. H-bond donors	1.0
Molar Refractivity	31.23
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.	1.38
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	1.56
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.0
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.	0.85
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	2.01
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.56

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.23
Solubility	0.867 mg/ml ; 0.00588 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.	-1.87
Solubility	2.01 mg/ml ; 0.0136 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	-2.32
Solubility	0.7 mg/ml ; 0.00474 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.	-6.09 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)	1.77

Application In Synthesis of [ 1184172-46-0 ]

* 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 [ 1184172-46-0 ]

[ 1184172-46-0 ] Synthesis Path-Downstream 1~35

1
[ 1184172-46-0 ]
[ 74-88-4 ]
[ 1184172-10-8 ]

Yield	Reaction Conditions	Operation in experiment
52%	With potassium carbonate; In acetone;Reflux;	2-Chloro-3-fluoro-4-hydroxypyridine (10 mmol), methyl iodide (20 mmol) and potassium carbonate (20 mmol) in acetone (100 ml) was refluxed overnight. The inorganic salt was filtered and the solvent was evaporated. The residue was purified on column (eluent: ethyl acetate: hexane = 1 :5) to afford a colorless liquid (52%).
52%	With potassium carbonate; In acetone;Reflux;	2-Chloro-3-fluoro-4-methoxypyridine (11): 2-Chloro-3-fluoro-4-hydroxypyridine (10 mmol), methyl iodide (20 mmol) and potassiumcarbonate (20 mmol) in acetone (100 ml) was refluxedovernight. The inorganic salt was filtered and the solvent wasevaporated. The residue was purified on column (eluent: ethylacetate:hexane = 1:5) to afford a colorless liquid [19] (52%). 1HNMR (CDCl3): d 8.08 (dd, J = 1.0, 5.8 Hz, 1H, C6-H), 6.88 (t,J = 5.7 Hz, 1H, C5-H), 3.97 (s, 3H, OMe). 19F NMR (CDCl3): d 143.49(s). ESI-MS: 162 (M+1)+.

References: [1]Patent: WO2009/103950,2009,A1 .Location in patent: Page/Page column 22; 23.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 2185 - 2195.
[3]Dalton Transactions,2012,vol. 41,p. 6549 - 6557.
[4]Journal of Fluorine Chemistry,2015,vol. 173,p. 29 - 34.
[5]Tetrahedron Letters,2010,vol. 51,p. 5230 - 5233.

2
[ 1184172-46-0 ]
[ 75-03-6 ]
[ 1184172-58-4 ]

Yield	Reaction Conditions	Operation in experiment
58%	With potassium carbonate; In acetone;Reflux;	2-Chloro-3-fluoro-4-hydroxypyridine (10 mmol), which previously described in the scheme 11, methyl iodide (20 mmol) and potassium carbonate (20 mmol) in acetone (100 ml) was refluxed overnight. The inorganic salt was filtered and the solvent was evaporated. The residue was purified on column eluting with ethyl acetate to afford a white solid (58%).

References: [1]Patent: WO2009/103950,2009,A1 .Location in patent: Page/Page column 29.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 2185 - 2195.

3
[ 17282-04-1 ]
[ 1184172-46-0 ]

Yield	Reaction Conditions	Operation in experiment
80%		A solution of 2-chloro-3-fluoropyridine (2 mmol) in anhydrous THF (10ml) was cooled to -780C. To this solution was added a solution of lithium diisopropylamide (LDA; 2.2 mmol) in hexane slowly at same temperature. After 2h at -780C, to the mixture was added trimethoxyborane (0.48ml) and stirred for 2h, followed by an addition of peracetic acid (0.72 ml; 32% in dilute acetic acid). The mixture was allowed to warm to O0C under stirring for Ih, then cooled to -2O0C, sodium dithionite (0.8g in 2ml water) was added dropwise. The mixture was extracted with ethyl acetate and the extract was <n="24"/>dried and concentrated. The residue was purified by chromatography, eluting with 1:19 MeOH:DCM to give the expected product as a white solid (80%).
80%		2-Chloro-3-fluoro-4-hydroxypyridine (10): A solution of 2-chloro-3-fluoropyridine (2 mmol) in anhydrous THF (10 ml) wascooled to 78 8C. To this solution was added a solution of lithiumdiisopropylamide (LDA; 2.2 mmol) in hexane slowly at sametemperature. After 2 h at 78 8C, to the mixture was addedtrimethoxyborane (0.48 ml) and stirred for 2 h, followed by anaddition of peracetic acid (0.72 ml; 32% in dilute acetic acid). Themixture was allowed to warm to 0 8C under stirring for 1 h. Afterthe mixture was cooled to 20 8C, sodium dithionite (0.8 g in 2 mlwater) was added dropwise. The mixture was extracted with ethylacetate and the extract was dried and concentrated. The residuewas purified by chromatography, eluting with 1:19 MeOH:DCM togive the expected product as a white solid [19] (80%). 1H NMR (d6-DMSO): d 11.86 (brs, 1H, OH), 7.89 (d, J = 5.3 Hz, 1H, C6-H), 6.95 (t,J = 5.8 Hz, 1H, C5-H). 19F NMR (d6-DMSO): d 141.29 (s). ESI-MS:148 (M+1)+.
78%		n-BuLi (2 M in cyclohexane, 6 mL, 12.0 mmol) was added to a solution of diisopropylamine (1.8 mL, 12.8 mmol) in dry THF (50 mL) at -78 C. Next, 2-chloro-3-fluoropyridine (1 mL, 10.058 mmol, CAS 17282-04-1) was added dropwise and the reaction mixture was stirred for 2 h at -78 C. Then, trimethylborate (2.4 mL, 21.3 mmol) was added dropwise and the mixture was stirred another 2 h. Then, peracetic acid (39% in acetic acid, 3.0 mL, 17.7 mmol) was added together with water (0.5 mL) and the mixture was allowed to warm to 0 C and stirred for 1 h. The clear solution turned turbid. An aq. saturated Na 2S 2O 3 solution was added, and the org layer was separated. The aq. layer was extracted with EtOAc multiple times, the combined organic layers were dried over MgSO 4, filtered and concentrated. The residue was purified by flash column chromatography (120 g silica, redisep Gold, gradient DCM/MeOH 99:1 to 95:5). After concentration of the product fractions, intermediate 35?? was obtained as white solid (1.16 g, 78%).

References: [1]Patent: WO2009/103950,2009,A1 .Location in patent: Page/Page column 22-23.
[2]Journal of Medicinal Chemistry,2012,vol. 55,p. 2185 - 2195.
[3]Dalton Transactions,2012,vol. 41,p. 6549 - 6557.
[4]Journal of Fluorine Chemistry,2015,vol. 173,p. 29 - 34.
[5]Patent: WO2019/208509,2019,A1 .Location in patent: Paragraph 0138.
[6]Tetrahedron Letters,2010,vol. 51,p. 5230 - 5233.

4
[ 1184172-46-0 ]
[ 1184172-13-1 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 5230 - 5233.

5
[ 1184172-46-0 ]
[ 74-88-4 ]
[ 1184172-30-2 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 5230 - 5233.

6
[ 1184172-46-0 ]
[ 74-88-4 ]
[ 1184172-25-5 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 5230 - 5233.

7
[ 1184172-46-0 ]
[ 74-88-4 ]
[ 1184172-29-9 ]

References: [1]Tetrahedron Letters,2010,vol. 51,p. 5230 - 5233.

8
[ 75-30-9 ]
[ 1184172-46-0 ]
[ 1362857-63-3 ]