503000-87-1|2-Chloro-6-methoxynicotinic acid| Ambeed

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Quality Control of [ 503000-87-1 ] Purity: 95% SDS Specification

COA

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NMR

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CNMR

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Product Details of [ 503000-87-1 ]

CAS No. :	503000-87-1
Formula :	C₇H₆ClNO₃
M.W :	187.58
SMILES Code :	O=C(O)C1=C(Cl)N=C(OC)C=C1
MDL No. :	MFCD08236845
InChI Key :	JPBUYRWPJMVZKX-UHFFFAOYSA-N
Pubchem ID :	11769266

Safety of [ 503000-87-1 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H302
Precautionary Statements:	P280-P305+P351+P338

Computational Chemistry of [ 503000-87-1 ] 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.	1.27
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	1.07

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 [ 503000-87-1 ]

* 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 [ 503000-87-1 ]

[ 503000-87-1 ] Synthesis Path-Downstream 1~36

1
[ 67-56-1 ]
[ 55366-30-8 ]
[ 38496-18-3 ]
[ 65515-33-5 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

2
[ 67-56-1 ]
[ 55366-30-8 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

3
[ 95652-77-0 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

4
[ 67-56-1 ]
[ 38496-18-3 ]
[ 503000-87-1 ]

Yield	Reaction Conditions	Operation in experiment
96.4%	With potassium tert-butylate;	Example 40 Synthesis of (S)-N-(2-(2-cyano-4,4-difluoropyrrolidin-1-yl)-2-oxoethyl)-6-methoxy-2-phenylnicotinamide Compound 86a. To a solution of 2,6-dichloronicotinic acid (2.0 g, 10.41 mmol, 1.0 equiv) in MeOH (50 mL) was added compound potassium tert-butoxide (4.7 g, 41.66 mmol, 4.0 equiv), and resulting reaction mixture was heated at 70 C. for 3 h. Product formation was confirmed by LCMS and TLC. After the completion of reaction, the reaction mixture was concentrated and diluted with water (50 ml). Aqueous layer extracted with ethyl acetate (30 mL*3). Combined organic extracts were washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The crude product obtained was purified by flash chromatography (5% MeOH in DCM as an eluent) to obtain 2-chloro-6-methoxynicotinic acid (1.8 g, 96.4%) as white solid LCMS 188 [M+H]+ 1H NMR 1H NMR (400 MHz, DMSO-d6) delta 13.33 (br. s., 1H), 8.06-8.24 (m, 1H), 6.92 (d, J=8.77 Hz, 1H), 3.91 (s, 3H).
86%	With potassium tert-butylate; for 48h;Reflux;	2,6-Dichloronicotinic acid (10 g, 52.1 mmol, 1.0 eq) was dissolved in methanol (460 mL) and potassium t-butoxide was added.(23.37 g, 208.3 mmol, 4.0 eq), heated to reflux for 48 hours.The reaction was completely detected by LC-MS. The mixture was evaporated to room temperature, and concentrated under reduced pressure.A large amount of white solid precipitated, suction filtration,The filter cake is washed with water (300mL×3),Drying to a white solid product (8.5 g, yield: 86%
84%		2-Chloro-6-methoxypyridine-3-carboxylic acid [00213] A mixture of 2,6-dichloropyndme-3-carboxyhc acid (6 5 g, 33mmol), potassium tert- butoxide (11 4 g, 0 10 mol), and anhydrous methanol (30OmL) was heated to reflux for 4 days and cooled to room temperature After evaporation of the solvent, the residue was diluted with water and acidified with 35% aqueous hydrochloric acid The resulting solid was collected by filtration, washed with water, and dried to give 4 8 g (84%) of 2-chloro-6-methoxypyridine-3-carboxyhc acid as a white solid[00214] 1H NMR (DMSO-(Z5, 400MHz) delta 13 33 (brs, 1H, OH, exchangeable with D2O), 8 19 (d, J=8 5Hz, 1H), 6 92 (d, J=8 5Hz, 1H), 3 92 (s, 3H)

52%	With potassium tert-butylate; at 60℃; for 1h;	[752] Step A: 2-chloro-6-methoxy-nicotinic acid [753] Potassium botoxide (483 mg, 4.31 mmol) and MeOH (8 mL) were added to 2,6-dichloro-nicotinicacid (207 mg, 1.07 mmol), and the mixture was stirred usingmicrowave at 60 for 1 hour.After the termination of the reaction, the reactant was filtered, and 1N HClwas added thereto at 0 to adjust the pH to 3. Thesolid was dried by N2 gas to obtain the title compound (106 mg,52%).[754] 1H-NMR (DMSO-d6) delta 8.17(1H, d), 6.92(1H, d),3.92(3H, s)
3.15 g	With potassium tert-butylate; for 10h;Reflux;	To a solution (250 mL) of 2,6-dichloronicotinic acid (5.00 g) in methanol was added potassium tert-butoxide (8.77 g), and the mixture was heated under reflux for 10 hr. The solvent in the reaction mixture was evaporated under reduced pressure, and the residue was suspended in water and neutralized with 1N HCl. The precipitate was collected by filtration to give the title compound (3.15 g) as a white solid. (1368) MS (ESI+): [M+H]+ 188.0.
	With potassium tert-butylate; at 65℃; for 96h;	Into a 250-mL round-bottom flask, was placed 2,6-dichloropyridine-3-carboxylic acid (5.0 g, 26.04 mmol), methanol (30 mL) and (tert-butoxy)potassium (5.86 g, 52.22 mmol). The resulting solution was stirred for 4 days at 65 C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 30 mL of water and the pH value of the solution adjusted to 3-4 with HC1. The resulting precipitate was collected by filtration resulting in 4.6 g (94%) of 2-chloro-6- methoxypyridine-3-carboxylic acid as a white crude solid.
		Example 11; [0163] (a) I-Chloro--methoxynicotinic acid. A mixture of 2,6- dichloronicotinic acid (50 g, 0.26 mol) and potassium tert-butoxide (87.7 g, 0.783 mol) in MeOH (2300 mL) was heated at reflux for 48 hours. After evaporation of the solvent, the residue was diluted with H2O and acidified with concentrated HCl. The solid precipitate was filtered, washed with water, and dried in vacuo to give the title compound as a white solid.

References: [1]Patent: US2019/185451,2019,A1 .Location in patent: Paragraph 0728-0731; 0798-0801.
[2]Journal of Medicinal Chemistry,2017,vol. 60,p. 7315 - 7332.
[3]Patent: CN109810041,2019,A .Location in patent: Paragraph 0315; 0319-0321.
[4]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.
[5]Patent: WO2009/89263,2009,A2 .Location in patent: Page/Page column 70.
[6]Patent: WO2014/69963,2014,A1 .Location in patent: Paragraph 752-754.
[7]Angewandte Chemie - International Edition,2013,vol. 52,p. 7818 - 7821.
Angew. Chem.,2013,vol. 52,p. 7818 - 7821,4.
[8]Patent: US2016/115128,2016,A1 .Location in patent: Paragraph 1367; 1368.
[9]Patent: WO2017/192304,2017,A1 .Location in patent: Paragraph 0278.
[10]Patent: WO2008/76425,2008,A1 .Location in patent: Page/Page column 41.

5
[ 503000-87-1 ]
2-chloro-6-methoxypyridine-3-carboxylic acid chloride [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With thionyl chloride;Heating / reflux;	(b) Methyl Z-chloro--methoxynicotinate. A mixture of 2- chloro-6-methoxynicotinic acid (300 g, 1.34 mol) in SOCl2 (1400 mL) was heated at reflux overnight. The reaction mixture was left to reach room temperature and was evaporated under reduced pressure. The residue was dissolved in toluene and the solution was concentrated. The residue was re-dissolved in toluene, the solution was evaporated, and the residue was diluted with MeOH (2000 mL), and heated at reflux for 3 hours. The reaction mixture was left to reach room temperature and evaporated under reduced pressure. The solid residue was re- crystallized from EtOH (400 mL) and dried in vacuo to give the title compound.
	With thionyl chloride; for 5h;Heating / reflux;	A mixture of 4.8 g (25.6 mmol) of the compound of Step A and thionyl chloride (25 mL, 343 mmol) was refluxed for 5 h. Excess thionyl chloride was removed under vacuum and the mixture was evaporated twice from toluene to afford the intermediate acid chloride. The acid chloride was refluxed with methanol (30 mL) for 1 h and then stirred at ambient temperature for 12 h. The MeOH was removed under vacuum and the residue extracted with chloroform. The solvent layer was washed with water, sat'd NaCl, dried and evaporated. Trituration with hexanes and filtration gave 2.51 g of the title compound as a white solid: 1H NMR (500 MHz, CDCl3) delta 8.14 (d, IH, J = 8.5 Hz), 6.72 (d, IH, J = 8.7 Hz), 4.02 (s, 3H), 3. 94 (s, 3H).

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.
[2]European Journal of Organic Chemistry,2013,p. 6404 - 6419.
[3]Patent: WO2008/76425,2008,A1 .Location in patent: Page/Page column 41-42.
[4]Patent: WO2008/130527,2008,A1 .Location in patent: Page/Page column 26.

6
[ 503000-87-1 ]
[ 530-62-1 ]
C₁₀H₈ClN₃O₂ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In N,N-dimethyl-formamide; at 50℃; for 1h;	2-Chloro-6-methoxy nicotinic acid (0.23 g, 1.1 eq) was combined with CDI (0.20 g, 1.1 eq) in DMF (5 mL) and heated at 50 C. for 1 h. The reaction was cooled to -10 C. and a solution of 114 (0.45 g, 1.13 mmol) and DMF (5mL) and was added followed by NaH (0.14 g, 3.2 eq). After addition the reaction stirred at RT for 3 h. The reaction mixture was poured into saturated aqueous NH4Cl, extracted with EtOAc/hexanes (1:1, 50 mL), washed with H2O and brine, dried (MgSO4) and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (0-15% EtOAc) to afford 0.35 g (54%) of 112a as a white solid.

References: [1]Patent: US2008/45511,2008,A1 .Location in patent: Page/Page column 35.

7
[ 503000-87-1 ]
[ 95652-77-0 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.
[2]Patent: WO2008/76425,2008,A1 .

8
[ 503000-87-1 ]
[ 503000-88-2 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.
[2]Patent: WO2008/76425,2008,A1 .

9
[ 503000-87-1 ]
[ 503000-90-6 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.

10
[ 503000-87-1 ]
[ 503000-89-3 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.

11
[ 503000-87-1 ]
5-chloro-<i>N</i>-(1-ethyl-4-methyl-[1,4]diazepan-6-yl)-6-methoxy-2-methylamino-nicotinamide [ No CAS ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.

12
[ 55366-30-8 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.
[2]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.
[3]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

13
[ 95652-76-9 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

14
[ 97985-23-4 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

15
[ 911801-63-3 ]
[ 503000-87-1 ]

References: [1]Journal of the Chemical Society. Perkin transactions I,1988,p. 227 - 234.

17
[ 503000-87-1 ]
[ 1171823-22-5 ]

Yield	Reaction Conditions	Operation in experiment
78%	With bromine; sodium acetate; In acetic acid; at 80℃;	To a suspension of 2-crdoro-6-methoxypyndine-3-carboxylic acid (469g, 25mmol) and sodium acetate (4 1Og, 50mmol) in 200 ml of glacial acetic acid was added bromine (160, lOOmmol) at room temperature The mixture was wanned to 80C overnight, cooled to room temperature and poured into 500 ml of ice-water with strong stirring The solid was filtered and washed with water to give 5 2 g (78%) of pure product as a white solid [00216] 1H NMR (DMSO-^, 400MHz) delta 8 51 (s, 1H), 3 93 (s, 3H) [00217] MS 266 (M-I)

References: [1]Patent: WO2009/89263,2009,A2 .Location in patent: Page/Page column 71.
[2]Bioorganic and Medicinal Chemistry Letters,2011,vol. 21,p. 760 - 763.

18
[ 503000-87-1 ]
[ 1171823-27-0 ]