88912-21-4|6-Chloro-4-methoxypicolinic acid| Ambeed

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Quality Control of [ 88912-21-4 ] Purity: 95% SDS Specification

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Product Details of [ 88912-21-4 ]

CAS No. :	88912-21-4
Formula :	C₇H₆ClNO₃
M.W :	187.58
SMILES Code :	O=C(O)C1=NC(Cl)=CC(OC)=C1
MDL No. :	MFCD03844441
InChI Key :	OIBUWIYWLUXEAM-UHFFFAOYSA-N
Pubchem ID :	23002368

Safety of [ 88912-21-4 ]

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

Computational Chemistry of [ 88912-21-4 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.14
Num. rotatable bonds	2
Num. H-bond acceptors	4.0
Num. H-bond donors	1.0
Molar Refractivity	42.7
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	59.42 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.44
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	1.64
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.44
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.	-0.76
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	1.37
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.03

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.27
Solubility	0.998 mg/ml ; 0.00532 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.	-2.5
Solubility	0.592 mg/ml ; 0.00316 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	-2.14
Solubility	1.35 mg/ml ; 0.00718 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.	-6.28 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.	0.56

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)	1.87

Application In Synthesis of [ 88912-21-4 ]

* 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.

Downstream synthetic route of [ 88912-21-4 ]

[ 88912-21-4 ] Synthesis Path-Downstream 1~12

1
[ 88912-21-4 ]
[ 82967-94-0 ]
[ 204378-21-2 ]

Yield	Reaction Conditions	Operation in experiment
26.5%		Synthesis Example 10 Synthesis of N-[(2,3-Dichlorophenyl)sulfonyl]-6-chloro-4-methoxypyridine-2-carboxamide [Compound (I-345)] Using 2,3-dichlorobenzenesulfonamide [Compound (III-4)] (0.3 g, 1.33 mmol) and 6-chloro-4-methoxypicolinic acid [Compound (II-75)] (0.25 g, 1.33 mmol), the Compound (I-345) was synthesised according to the process of Synthesis Example 3. White solid, yield: 0.14 g, percent yield: 26.5%, m.p.: 132-135 C. IR KBr cm-1: 3358, 1722, 1602, 1560, 1437, 1386, 1167, 1029. 1H-NMR (60 MHz, CDCl3, delta): 3.8 (3H, s, OCH3), 6.9 (1H, d, J=2 Hz, pyridine ring H), 7.4 (1H, d, J=2 Hz, pyridine ring H), 7.3-7.4 (1H, m, aromatic ring H), 7.6 (1H, dd, J=2, 8 Hz, aromatic ring H), 8.16 (1H, dd, J=2, 8 Hz, aromatic ring H), NH indistinctness.

References: [1]Patent: US6610853,2003,B1 .

2
[ 88912-21-4 ]
[ 37526-59-3 ]
[ 204378-29-0 ]

Yield	Reaction Conditions	Operation in experiment
52%		Synthesis Example 16 Synthesis of N-[(2-Trifluoromethoxyphenyl)sulfonyl]-6-chloro-4-methoxy-2-pyridinecarboxamide [Compound (I-795)] Using 2-trifluoromethoxybenzenesulfonamide [Compound (III-12)] (0.23 g, 0.96 mmol) and 6-chloro-4-methoxypicolinic acid [Compound (II-75)] (0.18 g, 0.96 mmol), the Compound (I-795) was synthesised according to the process of Synthesis Example 3. White solid, yield: 0.20 g, percent yield: 52%, m.p.: 135-138 C. IR KBr cm-1: 3372, 1728, 1598, 1440, 1356, 1262, 1192. 1H-NMR (60 MHz, CDCl3, delta): 3.80 (3H, s, OCH3), 6.9 (1H, d, J=2 Hz, pyridine ring H), 7.28-7.65 (3H, m, aromatic ring H), 7.46 (1H, d, J=2 Hz, pyridine ring H), 8.2 (1H, dd, J=2 Hz, 8 Hz, aromatic ring H), NH indistinctness.

References: [1]Patent: US6610853,2003,B1 .

3
[ 88912-21-4 ]
[ 6961-82-6 ]
[ 204378-27-8 ]

Yield	Reaction Conditions	Operation in experiment
66.3%		Synthesis Example 14 Synthesis of N-[(2-Chlorophenyl)sulfonyl]-6-chloro-4-methoxypyridine-2-carboxamide [Compound (I-705)] Using 2-chlorobenzenesulfonamide [Compound (III-11)] (0.255 g, 1.33 mmol) and 6-chloro-4-methoxypicolinic acid [Compound (II-75)] (0.25 g, 1.33 mmol), the Compound (I-705) was synthesised according to the process of Synthesis Example 3. White solid, yield: 0.27 g, percent yield: 66.3%, m.p.: 175-177 C. IR KBr cm-1: 3472, 3292, 1728, 1605, 1434, 1392, 1170, 1035. 1H-NMR (60 MHz, CDCl3, delta): 3.8 (3H, s, OCH3), 6.9 (1H, d, J=2 Hz, pyridine ring H), 7.3-7.6 (4H, m, pyridine ring H1, aromatic ring H3), 8.0-8.4 (1H, m, aromatic ring H), NH indistinctness.

References: [1]Patent: US6610853,2003,B1 .

4
[ 88912-21-4 ]
[ 60230-37-7 ]
[ 204378-33-6 ]

Yield	Reaction Conditions	Operation in experiment
54.0%		Synthesis Example 19 Synthesis of N-[(2,6-Difluorophenyl)sulfonyl]-6-chloro-4-methoxy-2-pyridinecarboxamide [Compound (I-975)] Using 2,6-difluorobenzenesulfonamide [Compound (III-14)] (0.309 g, 1.6 mmol) and 6-chloro-4-methoxypicolinic acid [Compound (II-75)] (0.3 g, 1.6 mmol), the Compound (I-975) was synthesised according to the process of Synthesis Example 3. White solid, yield: 0.3129 g, percent yield: 54.0%, m.p.: 160-163 C. IR KBr cm-1: 3262, 1725, 1620, 1434, 1398, 1317, 1188, 1029, 891, 642. 1H-NMR (60 MHz, CDCl3, 6): 3.8 (3H, s, OCH3), 6.7-7.5 (4H, m, aromatic ring H*3, pyridine ring H), 7.43 (1H, d, J=2 Hz, pyridine ring H), NH indistinctness.

References: [1]Patent: US6610853,2003,B1 .

5
[ 204378-41-6 ]
[ 88912-21-4 ]

Yield	Reaction Conditions	Operation in experiment
97.0%		(2) Synthesis of 6-chloro-4-methoxypicolinic Acid [Compound (II-75)] Using 6-chloro-4-methoxypicolinic acid methyl ester [Compound (V-75)] (0.5 g, 2.48 mmol), the Compound (II-75) was synthesised according to the process of Synthesis Example 20 (3). White solid, yield: 0.45 g, percent yield: 97.0%, m.p.: 183-185 C. IR KBr cm-1: 1707, 1599, 1473, 1320, 1284, 1107, 1038, 921, 870, 723. 1H-NMR (60 MHz, d6-DMSO, delta): 3.84 (3H, s, OCH3), 6.94 (1H, d, J=2 Hz, pyridine ring H), 7.45 (1H, d, J=2 Hz, pyridine ring H), COOH indistinctness.

References: [1]Patent: US6610853,2003,B1 .

6
[ 88912-21-4 ]
[ 64-17-5 ]
[ 1122090-80-5 ]

Yield	Reaction Conditions	Operation in experiment
	With chloro-trimethyl-silane; at 20℃; for 16h;	To a stirred solution of <strong>[88912-21-4]6-chloro-4-methoxypyridine-2-carboxylic acid</strong> (5.00 g, 26.7 mmol) in ethanol (75 ml_), chlorotrimethylsilane (15 ml_) is added. The reaction mixture is stirred at rt for 16 h before the solvent is evaporated. The remaining residue is dried under vacuum to give 6-chloro-4-methoxy-2-carboxylic acid ethyl ester (5.95 g) as a pale yellow oil; LC-MS: tR = 0.85 min; [IVM]+ = 215.97; 1H NMR (CDCI3): delta lambda AA (t, J = 7.0 Hz, 3 H), 3.94 (s, 3 H), 4.48 (q, J = 7.0 Hz, 2 H), 7.01 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H).
	With chloro-trimethyl-silane; at 20℃; for 16h;	a) To a stirred solution of <strong>[88912-21-4]6-chloro-4-methoxypyridine-2-carboxylic acid</strong> (5.00 g, 26.7 mmol) in ethanol (75 mL), chlorotrimethylsilane (15 mL) is added. The reaction mixture is stirred at rt for 16 h before the solvent is evaporated. The remaining residue is dried under vacuum to give 6-chloro-4-methoxy-2-carboxylic acid ethyl ester (5.95 g) as a pale yellow oil; LC-MS: tR=0.85 min; [M+1]+=215.97; 1H NMR (CDCl3): delta 1.44 (t, J=7.0 Hz, 3H), 3.94 (s, 3H), 4.48 (q, J=7.0 Hz, 2H), 7.01 (d, J=2.0 Hz, 1H), 7.61 (d, J=2.0 Hz, 1H).
	With chloro-trimethyl-silane; at 20℃; for 16h;	To a stirred solution of <strong>[88912-21-4]6-chloro-4-methoxypyridine-2-carboxylic acid</strong> (5.00 g, 26.7 mmol) in ethanol (75 mL), chlorotrimethylsilane (15 mL) is added. The reaction mixture is stirred at rt for 16 h before the solvent is evaporated. The remaining residue is dried under vacuum to give 6-chloro-4-methoxy-2-carboxylic acid ethyl ester (5.95 g) as a pale yellow oil; LC- MS: tR = 0.85 min; [M+1]+ = 215.97; 1H NMR (CDCI3): delta 1.44 (t, J = 7.0 Hz, 3 H), 3.94 (s, 3 H), 4.48 (q, J = 7.0 Hz, 2 H), 7.01 (d, J = 2.0 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H).

References: [1]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 77.
[2]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 28.
[3]Patent: WO2009/109872,2009,A1 .Location in patent: Page/Page column 30.

7
[ 88912-21-4 ]
[ 1393486-28-6 ]

Yield	Reaction Conditions	Operation in experiment
61%	With ammonium hydroxide; CDI; In N,N-dimethyl-formamide;	To a solution of <strong>[88912-21-4]4-methoxy-6-chloro picolinic acid</strong> (25 mmol) in anhydrous DMF (48 mL) was added CDI (27.5 mmol) at 0 C. The reaction mixture was stirred for 5 min in an ice-bath and then stirred at room temperature. After the reaction was completed, NH4OH (190 mL) was added and the reaction mixture was stirred at room temperature for 6 hrs. The mixture was partioned between H2O (200 mL) and DCM (300 mL). The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel chromatography (eluent: DCM/CH3OH) to give compound 18 as a beige solid in 61% yield. MS (ESI, EI+): m/z=187.14 (MH+).
61%		To a solution of <strong>[88912-21-4]4-methoxy-6-chloro picolinic acid</strong> (25 mmol) in anhydrous DMF (48 mL) was added CDI (27.5 mmol) at 0 C. The reaction mixture was stirred for 5 min in an ice-bath and then stirred at room temperature. After the reaction was completed, NH4OH (190 mL) was added and the reaction mixture was stirred at room temperature for 6 hrs. The mixture was partioned between H2O (200 mL) and DCM (300 mL). The organic layer was washed with H2O and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude was purified by silica gel chromatography (eluent: DCM/CH3OH) to give compound 18 as a beige solid in 61% yield. MS (ESI, EI+): m/z=187.14 (MH+).

References: [1]Patent: US2012/207703,2012,A1 .
[2]Patent: US9353100,2016,B2 .Location in patent: Page/Page column 144.

8
[ 88912-21-4 ]
[ 1393486-27-5 ]