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Quality Control of [ 15855-06-8 ] Purity: 95% SDS Specification

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Product Details of [ 15855-06-8 ]

CAS No. :	15855-06-8
Formula :	C₇H₆ClNO₃
M.W :	187.58
SMILES Code :	COC1=CC(=CC(Cl)=N1)C(O)=O
MDL No. :	MFCD00173928
InChI Key :	PJQBTHQTVJMCFX-UHFFFAOYSA-N
Pubchem ID :	2782124

Safety of [ 15855-06-8 ]

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

Computational Chemistry of [ 15855-06-8 ] 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 ?2

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	1.35
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.	-0.36
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	1.09

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)	1.94

Application In Synthesis of [ 15855-06-8 ]

* 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 [ 15855-06-8 ]

[ 15855-06-8 ] Synthesis Path-Downstream 1~30

1
[ 15855-06-8 ]
[ 64-17-5 ]
[ 106719-08-8 ]

Yield	Reaction Conditions	Operation in experiment
		Sulfuric acid (1 ml_) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 ml_). The clear solution is stirred at 700C for 18 h. The mixutre is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3x250 ml_). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give 2-chloro-6-methoxy- isonicotinic acid ethyl ester (4.32 g) as a white solid; LC-MS: tR = 1.00 min, [M+1]+ = 215.89.
		a) Sulfuric acid (1 mL) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 70 C. for 18 h. The mixture is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3*250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> ethyl ester (4.32 g) as a white solid; LC-MS: tR=1.00 min, [M+1]+=215.89.
	With sulfuric acid; at 70℃; for 18h;	a) Sulfuric acid (1 mL) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 70 C. for 18 h. The mixture is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3*250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> ethyl ester (4.32 g) as a white solid; LC-MS: tR=1.00 min, [M+1]+=215.89.

3.205 g	With thionyl chloride; In toluene; at 0 - 20℃; for 24h;	Step 1 : Ethyl 2-chloro-6-methoxyisonicotinate To a previously sonicated suspension of <strong>[15855-06-8]2-chloro-6-methoxyisonicotinic acid</strong> (4.0g, 21 mmol) in ethanol (50 ml.) was added thionyl chloride (4.64 ml_, 64.0 mmol) at 0C. The reaction mixture was stirred at 0C for 2 h and then at room temperature for 18h. Thionyl chloride (4.64 ml_, 64.0 mmol) was slowly added and the mixture was stirred at room temperature for 4 h. The reaction mixture was quenched by slowly pouring into a saturated aqueous solution of sodium bicarbonate (200 ml_). Ice was added to the mixture to lower the temperature. The mixture was extracted with diethyl ether (150 ml_ x2). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a clear syrup as crude product. The crude product was dried for 2 h under high vacuum while heating to 80C. The resulting residue was concentrated from toluene (500 ml.) to afford ethyl 2-chloro-6- methoxyisonicotinate as an off white solid (3.205 g). 1H NMR (400 MHz, CDCI3) delta 1.40 (s, 3H), 3.98 (s, 3H), 4.39 (s, 2H), 7.22 (s, 1 H), 7.44 (s, 1 H).
		Sulfuric acid (1 mL) is added to a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (4.16 g, 22.2 mmol) in ethanol (20 mL). The clear solution is stirred at 700C for 18 h. The mixutre is neutralised by adding sat. aq. NaHCO3 solution and then extracted three times with EA (3x250 mL). The combined org. extracts are dried over MgSO4, filtered, concentrated and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> ethyl ester (4.32 g) as a white solid; LC-MS: tR = 1.00 min, [M+1]+ = 215.89.

References: [1]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1953,vol. 73,p. 845,846, 847.
Chem.Abstr.,1954,p. 10021.
[2]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 88.
[3]Patent: US2011/46170,2011,A1 .Location in patent: Page/Page column 24.
[4]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 32.
[5]Patent: WO2013/150416,2013,A1 .Location in patent: Page/Page column 80.
[6]Patent: WO2009/109907,2009,A1 .Location in patent: Page/Page column 59.

2
[ 15855-06-8 ]
[ 105596-63-2 ]

Yield	Reaction Conditions	Operation in experiment
78%	With hydrogen; triethylamine;palladium 10% on activated carbon; In methanol; at 20℃; under 155.149 Torr;	To a suspension of the title compound of Preparation 22 (1.94 g, 6.49 mmol) in acetonitrile (150 mL), sodium iodide (4.90 g, 32.69 mmol) and trimethylsilyl chloride (4.10 mL, 32.42 mmol) were added. The resulting suspension was stirred under nitrogen atmosphere at 400C for 3 days. The mixture was cooled to O0C and the solid was filtered off, washed with acetonitrile and dried to yield 1.66 g (90%) of the title compound.LRMS: m/z 285(M+1 )+ Retention time: 2.86min (method B)

References: [1]Patent: WO2010/43377,2010,A1 .Location in patent: Page/Page column 64.
[2]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1953,vol. 73,p. 845,846, 847.
Chem.Abstr.,1954,p. 10021.
[3]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1953,vol. 73,p. 845,846, 847.
Chem.Abstr.,1954,p. 10021.

3
[ 124-41-4 ]
[ 5398-44-7 ]
[ 15855-06-8 ]

Yield	Reaction Conditions	Operation in experiment
82%	In methanol; for 24h;Heating / reflux;	Freshly prepared sodium methoxide (from 1.5 g sodium in 15 mL dry methanol) was added dropwise to a solution of Example 16 (5.0 g, 26 mmol) in dry methanol (25 mL). The reaction mixture was refluxed for 24 h, allowed to cool to RT and poured in aqueous HCl (10%, 100 mL). A pinkish solid separated and was collected on a filter, washed with water and air-dried (4.0 g, 82%). IH NMR (400 MHz, DMSO-d6) 5 3.89 (s, 3H) 7.17 (s, 1H) 7.39 (s, 1H) 13.96 (br s, OH).
81%	In methanol; for 24h;Reflux;	200 mL of a25% solution of sodium methoxide in methanol was added on a solution of 10.3 g (53.6 mmol) of 2,6-dichloropyridine-4-carboxylic acid (1) in100 mL of methanol and refluxed for 24 h. The mixture was cooled toroom temperature, filtered off and evaporated. The solid was dissolvedin water, acidified with 2 N HCl and extracted with ethyl acetate. Theorganic phase was dried over anhydrous Na2SO4, filtered andevaporated, to obtain 8.1 g (43.2 mmol, 81%) of 2-chloro-6-methoxypyridine-4-carboxylic acid (2) as a brown amorphous solid.1H NMR (200 MHz, CD3OD): 3.87 (3H, s), 7.15 (1H, s), 7.36 (1H, s). 13CNMR (50 MHz, CD3OD): 54.5 (CH3), 109.4 (CH), 115.5 (CH), 144.3 (C),148.1 (C), 164.1 (C), 164.6 (C).

References: [1]Patent: WO2004/63156,2004,A1 .Location in patent: Page 35.
[2]Bioorganic Chemistry,2020,vol. 98.
[3]Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan,1953,vol. 73,p. 845,846, 847.
Chem.Abstr.,1954,p. 10021.
[4]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 1429 - 1433.

6
[ 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.

7
[ 67-56-1 ]
[ 5398-44-7 ]
[ 15855-06-8 ]

Yield	Reaction Conditions	Operation in experiment
		2-(1 -Ethyl -propyl)-6-methoxy-isonicotinic acid; a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34C) and is then heated to 700C for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCI (100 mL) and 25% aq. HCI (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 600C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6- methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR = 0.80 min, [M+1]+ = 187.93.
		a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34 C.) and is then heated to 70 C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60 C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.
183 g	With sodium hydroxide; In water; at 70℃; for 4h;	a) To a solution of 2,6-dichloroisonicotinic acid (200 g, 1.04 mol) in methanol (3 L), 32% aq. NaOH (770 mL) is added. The stirred mixture becomes warm (34 C.) and is then heated to 70 C. for 4 h before it is cooled to rt. The mixture is neutralised by adding 32% aq. HCl (100 mL) and 25% aq. HCl (700 mL). The mixture is stirred at rt overnight. The white precipitate that forms is collected, washed with methanol and dried. The filtrate is evaporated and the residue is suspended in water (200 mL). The resulting mixture is heated to 60 C. Solid material is collected, washed with water and dried. The combined crops give 2-chloro-6-methoxy-isonicotinic acid (183 g) as a white solid; LC-MS: tR=0.80 min, [M+1]+=187.93.

References: [1]Tetrahedron,2002,vol. 58,p. 6951 - 6963.
[2]Organic Letters,2000,vol. 2,p. 3421 - 3423.
[3]ChemMedChem,2020,vol. 15,p. 675 - 679.
[4]Antimicrobial Agents and Chemotherapy,2020,vol. 64.
[5]Patent: WO2011/7324,2011,A1 .Location in patent: Page/Page column 20.
[6]Patent: US2012/108638,2012,A1 .Location in patent: Page/Page column 8.
[7]Patent: US2013/303514,2013,A1 .Location in patent: Paragraph 0192.

8
[ 15855-06-8 ]
[ 74-88-4 ]
[ 42521-10-8 ]

Yield	Reaction Conditions	Operation in experiment
87%	With potassium carbonate; In N,N-dimethyl-formamide;	Example 16.1; 2-Chloro-6-methoxy-isonicotinic acid methyl ester; To <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (16 g, 85.3 mmol) in DMF (220 mL) were added K2CO3 (47 g, 341 mmol) and Mel (6.37 mL, 102.3 mmol). After stirring overnight, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (15 g, 87%).1H NMR (300 MHz, CDCl3): delta 7.45 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H).
87%	With potassium carbonate; In N,N-dimethyl-formamide;	Example 12.1; 2-Chloro-6-methoxy-isonicotinic acid methyl ester; To <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (16 g, 85 mmol) in DMF (220 mL) were added K2CO3 (47 g, 341 mmol) and MeI (6.37 mL, 102 mmol). After stirring for overnight, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (15 g, 87%).1H NMR (300 MHz, CDCl3): delta (ppm) 7.45 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H).
87%	With potassium carbonate; In N,N-dimethyl-formamide;	Example 9.1; 2-Chloro-6-methoxy-isonicotinic acid methyl ester; To <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (16 g, 85.3 mmol) in DMF (220 mL) were added K2CO3 (47 g, 341.2 mmol) and MeI (6.37 mL, 102.3 mmol). After stirring for overnight, the reaction mixture was filtered and then concentrated. The residue was dissolved in ethyl acetate, washed with water (3 times) and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by flash column chromatography eluted with 10-30% ethyl acetate in hexanes gave the title product (15 g, 87%).1H NMR (300 MHz, CDCl3): delta (ppm) 7.45 (s, 1H), 7.23 (s, 1H), 3.98 (s, 3H), 3.95 (s, 3H)

References: [1]Patent: US2007/259916,2007,A1 .Location in patent: Page/Page column 19.
[2]Patent: US2007/259926,2007,A1 .Location in patent: Page/Page column 13.
[3]Patent: US2007/259923,2007,A1 .Location in patent: Page/Page column 11.

9
[ 67-56-1 ]
[ 15855-06-8 ]
[ 42521-10-8 ]

Yield	Reaction Conditions	Operation in experiment
	With sulfuric acid; at 65℃; for 20h;	a) To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (2.00 g, 10.7 mmol) in MeOH (100 mL), H2SO4 (2 mL) is added. The mixture is stirred at 65C for 20 h. The solution is cooled to rt. A precipitate forms. The solid material is collected, washed with MeOH and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (1.66 g) as a white solid; LC- MS: tR = 1.29 min; [M+1]+ = 202.00.
	With sulfuric acid; at 65℃; for 20h;	To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (2.00 g, 10.7 mmol) in methanol (100 mL), H2SO4 (2 mL) is added. The mixture is stirred at 65C for 20 h. The solution is cooled to rt. A precipitate forms. The solid material is collected, <n="49"/>washed with methanol and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (1.66 g) as a white solid; LC-MS: tR = 1.29 min; [IVM]+ = 202.00.
	With sulfuric acid; at 65℃; for 20h;	To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (2.00 g, 10.7 mmol) in MeOH (100 mL), H2SO4 (2 mL) is added. The mixture is stirred at 65 C. for 20 h. The solution is cooled to rt. A precipitate forms. The solid material is collected, washed with MeOH and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (1.66 g) as a white solid; LC-MS: tR=1.29 min; [M+1]+=202.00.

	sulfuric acid; for 24h;Reflux;	b) To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (244 g, 1.30 mol) in methanol (2.5 L), H2SO4 (20 mL) is added. The mixture is stirred at reflux for 24 h before it is cooled to 0C. The solid material is collected, washed with methanol (200 mL) and water (500 mL) and dried under HV to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (165 g) as a white solid; LC-MS: tR = 0.94 min, [M+1]+ = 201.89.
	With sulfuric acid; at 65℃; for 20h;	a) To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (2.00 g, 10.7 mmol) in methanol (100 mL), H2SO4 (2 mL) is added. The mixture is stirred at 65 C. for 20 h. The solution is cooled to rt. A precipitate forms. The solid material is collected, washed with methanol and dried to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (1.66 g) as a white solid; LC-MS: tR=1.29 min; [M+1]+=202.00.
	With sulfuric acid; at 0℃; for 24h;Reflux;	b) To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (244 g, 1.30 mol) in methanol (2.5 L), H2SO4 (20 mL) is added. The mixture is stirred at reflux for 24 h before it is cooled to 0 C. The solid material is collected, washed with methanol (200 mL) and water (500 mL) and dried under HV to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (165 g) as a white solid; LC-MS: tR=0.94 min, [M+1]+=201.89.
165 g	With sulfuric acid; for 24h;Reflux;	b) To a suspension of <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> (244 g, 1.30 mol) in methanol (2.5 L), H2SO4 (20 mL) is added. The mixture is stirred at reflux for 24 h before it is cooled to 0 C. The solid material is collected, washed with methanol (200 mL) and water (500 mL) and dried under HV to give <strong>[15855-06-8]2-chloro-6-methoxy-isonicotinic acid</strong> methyl ester (165 g) as a white solid; LC-MS: tR=0.94 min, [M+1]+=201.89.

References: [1]Organic Process Research and Development,2016,vol. 20,p. 1637 - 1646.
[2]Patent: WO2008/29371,2008,A1 .Location in patent: Page/Page column 47.
[3]Patent: WO2009/24905,2009,A1 .Location in patent: Page/Page column 47-48.
[4]Patent: US2010/63108,2010,A1 .Location in patent: Page/Page column 19.
[5]Patent: WO2011/7324,2011,A1 .Location in patent: Page/Page column 20.
[6]Patent: US2011/212998,2011,A1 .Location in patent: Page/Page column 17.
[7]Patent: US2012/108638,2012,A1 .Location in patent: Page/Page column 8.
[8]Patent: US2013/303514,2013,A1 .Location in patent: Paragraph 0193.

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