878207-92-2|Methyl 6-chloro-3-methylpicolinate| Ambeed

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Quality Control of [ 878207-92-2 ] Purity: 98% SDS Specification

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Product Details of [ 878207-92-2 ]

CAS No. :	878207-92-2
Formula :	C₈H₈ClNO₂
M.W :	185.61
SMILES Code :	O=C(OC)C1=NC(Cl)=CC=C1C
MDL No. :	MFCD12756112
InChI Key :	XWPSWOKQWBNRDW-UHFFFAOYSA-N
Pubchem ID :	45489870

Safety of [ 878207-92-2 ]

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

Computational Chemistry of [ 878207-92-2 ] Show Less

Physicochemical Properties

Num. heavy atoms	12
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	2
Num. H-bond acceptors	3.0
Num. H-bond donors	0.0
Molar Refractivity	45.49
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	39.19 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.04
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	2.36
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.83
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.	1.25
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	2.29
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.95

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.72
Solubility	0.357 mg/ml ; 0.00193 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.	-2.82
Solubility	0.279 mg/ml ; 0.0015 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	-3.1
Solubility	0.146 mg/ml ; 0.000785 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	Yes
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.	-5.76 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)	1.89

Application In Synthesis of [ 878207-92-2 ]

* 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 [ 878207-92-2 ]

[ 878207-92-2 ] Synthesis Path-Downstream 1~37

1
[ 878206-29-2 ]
[ 878207-92-2 ]
6-[4-chloro-3-[[(tricyclo[3.3.1.1^3,7]dec-1-ylmethyl)amino]carbonyl]phenyl]-3-methyl-2-pyridinecarboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
		b) 6-Chloro-3-methyl-2-pyridmecarboxylic acid, methyl esterA solution of 3-methyl-2-pyridinecarboxylic acid 1-oxide, methyl ester (Example 71 (a))(300 mg) in phosphorous oxychloride (1 mL) was heated at 60C for 16 hours. Thereaction mixture was then poured into water (10 mL) and extracted with dichloromethane(2x10 mL). The organics were dried over magnesium sulphate, filtered and concentratedto dryness to give the sub-title compound as a colourless oil (300 mg).MS: APCI(+ve) 185/187

References: [1]Patent: WO2006/25783,2006,A1 .Location in patent: Page/Page column 153-154.

2
[ 878207-91-1 ]
[ 878207-92-2 ]

Yield	Reaction Conditions	Operation in experiment
41%	With trichlorophosphate; at 110℃; for 4h;	A solution of 2-(methoxycarbonyl)-3-methylpyridin-1-ium-1-olate (500 mg, 2.99 mmol, 1.00 equiv) in phosphorus oxychloride (2 mL) was stirred for 4 hours at 110 C. The reaction was quenched with water, adjusted pH to 7, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column eluting with ethyl acetate/petroleum ether (1:5) to give the title compound (230 mg, 41%) as a white solid. LC-MS (ES, m/z): 186 [M+H]+.
40%	With trichlorophosphate; In 1,2-dichloro-ethane; for 4h;Reflux;	A solution of 2-(methoxycarbonyl)-3-methylpyridine 1-oxide (500 mg, 2.99 mmol) and phosphorus oxychloride (0.55 mL, 5.98 mmol) in 1,2-dichloroethane (10 ml) was refluxed for 4 h. After completion of reaction, the reaction mixture was combined with 100 ml of ice water and extracted with dichoromethane (50 ml x 2) being washed with water and sodium bicarbonate solution, and then the combined organic layer was dried over anhydrous sodium sulfate, and filtered. The solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (10% EA/Hexnae) to give 223 mg (yield 40%) of the title compound. 1H NMR(300MHz, CDCl3) delta 7.59 (dd, J = 8.1, 0.5 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H), 2.57 (s, 3H).
37%	With trichlorophosphate; at 100℃; for 3h;	A solution of 2-(methoxycarbonyl)-3-methylpyridine 1-oxide (2 g, 6.0 mmol) in POCI3 (5 mL) was stirred at 100C for 3 hours. After being concentrated, the residue was purified by column chromatography (PE : EtOAc = 1 : 1) to give the product of methyl 6-chloro- 3-methylpicolinate (380 mg, yield: 37%). -NMR (CDCI3, 400 MHz) delta 7.59 (d, J= 8.0 Hz, 1H), 7.38 (d, J= 8.0 Hz, 1H), 3.96 (s, 3H), 2.56 (s, 3H). MS (M+H)+: 186 / 188.

37%	With trichlorophosphate; at 100℃; for 3h;	solution of 2-(methoxycarbonyl)-3-methylpyridine 1-oxide (2 g, 6.0 mmol) in POd3 (5 mL) was stirred at 100C for 3 hours. After being concentrated, the residue was purified by column chromatography (PE : EtOAc = 1: 1) to give the product of methyl 6-chloro-3- methylpicolinate (380 mg, yield: 37%). ?H-NMR (CDC13, 400 MHz) 7.59 (d, J 8.0 Hz, 1H),7.38 (d, J= 8.0 Hz, 1H), 3.96 (s, 3H), 2.56 (s, 3H). MS (M+H): 186 / 188.
20.9%	With trichlorophosphate; at 0 - 20℃; for 16.75h;	POCl3 (30.0 mL) is added slowly to methyl 3 -methyl- 1 -oxido- pyridin- l-ium-2-carboxylate (13.0 g, 0.077 mol) at 0 C over 30 minutes. The reaction mixture is stirred for 15 minutes at 0 C and then gradually warmed to ambient temperature. After 16 hours, the reaction mixture is cooled to 0 C and excess POCl3 is removed under reduced pressure. The crude residue is then quenched by addition of ice and diluted with water and CH2CI2 (50 mL). The organic layer is washed sequentially with saturated NaHC03 solution, water, and brine; dried over sodium sulfate; filtered; and concentrated under reduced pressure. The crude product is purified by silica gel flash chromatography, eluting 5-10% EtOAc in hexanes to afford methyl 6-chloro-3 -methyl - pyridine-2-carboxylate as a white solid (3.00 g, 20.9%). Mass spectrum (m/z): 186.2 (M+H)+.
	With trichlorophosphate; at 60℃; for 16h;Neat (no solvent);	b) 6-Chloro-3-methyl-2-pyridmecarboxylic acid, methyl esterA solution of 3-methyl-2-pyridinecarboxylic acid 1-oxide, methyl ester (Example 71 (a))(300 mg) in phosphorous oxychloride (1 mL) was heated at 60C for 16 hours. Thereaction mixture was then poured into water (10 mL) and extracted with dichloromethane(2x10 mL). The organics were dried over magnesium sulphate, filtered and concentratedto dryness to give the sub-title compound as a colourless oil (300 mg).MS: APCI(+ve) 185/187

References: [1]Patent: US2015/57260,2015,A1 .Location in patent: Paragraph 1234; 1235.
[2]Patent: WO2015/25026,2015,A1 .Location in patent: Page/Page column 268.
[3]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1736 - 1739.
[4]Patent: WO2014/209727,2014,A1 .Location in patent: Page/Page column 69.
[5]Patent: WO2014/205593,2014,A1 .Location in patent: Page/Page column 73.
[6]Patent: WO2015/94912,2015,A1 .Location in patent: Page/Page column 11-12.
[7]Patent: WO2006/25783,2006,A1 .Location in patent: Page/Page column 153.

3
[ 1201924-32-4 ]
[ 18107-18-1 ]
[ 878207-92-2 ]

Yield	Reaction Conditions	Operation in experiment
	With methanol; In tetrahydrofuran; at 20℃; for 2h;	Step 4. Methyl 6-chloro-3 -methylpyridine-2-carbox ylate6-Chloro-3-methylpyridine-2-carboxylic acid (3.69 g, 21.51 mmol) was taken up in THF (100 raL)/MeOH (25 mL). A solution of TMS-diazomethane (21.5 mL, 43.0 mmol) was added and the resulting solution stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid.LRMS (APCI) calc'd for (C8H9ClNO2) [M+Hf: 186, 188, Found: 186, 188.

References: [1]Patent: WO2009/155156,2009,A1 .Location in patent: Page/Page column 63.

4
[ 878207-92-2 ]
[ 1201924-34-6 ]

Yield	Reaction Conditions	Operation in experiment
68%	With N-Bromosuccinimide; acetic acid; dibenzoyl peroxide; In tetrachloromethane; at 100℃; for 1h;	[00486] To a flask containing a magnetic stir bar was added methyl 6-chloro-3- methylpicolinate (750 mg, 4.04 mmol, 1.0 eq.), followed by CC (15.0 mL). To this mixture was added N-bromosuccinimide (1.44 g, 8.08 mmol, 2.0 eq.), benzoyl peroxide (29.4 mg, 0.12 mmol, 0.03 eq.), and acetic acid (231 mu, 4.04 mmol, 1.0 eq.). The reaction mixture was stirred at 100 C for 1 hour. The reaction mixture was cooled to room temperature and quenched with saturated aquesous NH4.CI solution (10 mL). The mixture was extracted with CH2CI2 (3x). The organic layers were combined, dried over Na2SC>4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel to provide the desired compound as a solid (735 mg, 68%). ES-MS [M+l]+: 265.8.
65%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;	A solution of 6-chloro-3-methylpicolinate (100 mg, 0.58 mmol), NBS (104 mg, 0.58 mmol) and AIBN (2 mg, 11 muiotaetaomicron) in CC14 (10 mL) was stirred at 80C overnight. After reaction, the mixture was concentrated and the residue was purified by prep-TLC (PE : EtOAc = 5 : 1) to give the product of methyl 3-(bromomethyl)-6-chloropicolinate (100 mg, yield: 65%). XH-NMR (CDCI3, 400 MHz) delta 7.85 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 1H), 4.81 (s, 2H), 4.01 (s, 3H). MS (M+H)+: 264 / 266 / 268.
65%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃;	A solution of 6-chloro-3-methylpicolinate (100 mg, 0.58 mmol), NBS (104 mg, 0.58 mmol) and AIBN (2 mg, 11 imol) in CC14 (10 mL) was stirred at 80C overnight. After reaction,the mixture was concentrated and the residue was purified by prep-TLC (PE : EtOAc = 5 : 1) to give the product of methyl 3-(bromomethyl)-6-chloropicolinate (100 mg, yield: 65%). ?H-NMR (CDC13, 400 MHz) 7.85 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.0 Hz, 1H), 4.81 (s, 2H), 4.01 (s, 3H). MS (M+H): 264 / 266 / 268.

64%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In 1,2-dichloro-ethane; at 85℃; for 72h;Inert atmosphere;	<strong>[878207-92-2]methyl 6-chloro-3-methylpicolinate</strong> (100 mg, 539 muiotaetaomicron, Eq: 1) and N-bromosuccinimide (95.9 mg, 539 muiotaetaomicron, Eq: 1) were dissolved in 1,2-dichloroethane (1.1 ml) under argon atmosphere. Azobisisobutyronitrile (8.85 mg, 53.9 muiotaetaomicron, Eq: 0.1) was then added. The reaction mixture was stirred at 85 C for 3 days, after 2 more additions of N-bromosuccinimide and azobisisobutyronitrile. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel to afford the desired product as a white solid (92 mg, 64 %). MS (m/z) = 266.0 [M + H]+.
59%	With N-Bromosuccinimide; dibenzoyl peroxide; In tetrachloromethane; for 3h;Reflux;	A carbon tetrachloride (10 ml) solution of 6-chloro-3-methyl methyl picolinate (500 mg, 2.69 mmol), N-bromosuccinimide (719 mg, 4.04 mmol), and benzoyl peroxide (124 mg, 0.23 mmol) was refluxed for 3 h. After completion of reaction, the reaction mixture was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (2% EA/Hexnae) to give 422 mg (yield 59%) of the title compound. 1H NMR(300 MHz, CDCl3) delta 8.50 (d, J = 8.2 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 3H).
37%	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; at 80℃; for 16h;Inert atmosphere;	To a solution of <strong>[878207-92-2]methyl 6-chloro-3-methyl-pyridine-2-carboxylate</strong> (5.0 g, 26.94 mmol) and 1- bromo-2,5-pyrrolidinedione (4.8 g, 26.94 mmol) in carbon tetrachloride (10 ml) under nitrogen atmosphere was added azobisisobutyronitrile (0.44 g, 2.69 mmol). The mixture was stirred at 80 C for 16h, diluted with water (50 ml) and extracted with ethyl acetate (100 ml x 3). The combined organic phases were washed with brine (100 ml x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column (0381) chromatography (eluent: 20% ethyl acetate: petroleum ether) to afford methyl 3- (bromomethyl)-6-chloro-pyridine-2-carboxylate (5.3 g, 37%) as a white solid. 1H NMR (400 MHz, CDC13): delta 7.86 (d, / = 8.0 Hz, 1H), 7.50 (d, / = 8.0 Hz, 1H), 4.89 (s, 2H), 4.03 (s, 3H).
	With N-Bromosuccinimide; 2,2'-azobis(isobutyronitrile); In tetrachloromethane; for 6h;Reflux;	Step 5. Methyl 3 -(bromomethyl)-6-chloropyridine-2-carboxylateMethyl 6-chloro-3-methylpyridine-2-carboxylate (3.46 g, 18.6 mmol), NBS (3.32 g, 18.6 mmol) and AIBN (61 mg, 0.37 mmol) were stirred in refluxing CCl4 (40 mL) for 6 hours. The mixture was then cooled to room temperature and purified directly by silica gel chromatography (2-20% EtOAc/hexanes) to give the title compound as a white solid. LRMS (APCI) calc'd for (C8H8BrClNO2) [M+Hf, 266; found 266.

References: [1]Patent: WO2016/172547,2016,A1 .Location in patent: Paragraph 00486.
[2]Patent: WO2014/209727,2014,A1 .Location in patent: Page/Page column 69.
[3]Patent: WO2014/205593,2014,A1 .Location in patent: Page/Page column 73.
[4]Patent: WO2017/76852,2017,A1 .Location in patent: Page/Page column 47.
[5]Bioorganic and Medicinal Chemistry Letters,2013,vol. 23,p. 1736 - 1739.
[6]ACS Chemical Neuroscience,2019,vol. 10,p. 1035 - 1042.
[7]Patent: WO2018/83085,2018,A1 .Location in patent: Page/Page column 62-63.
[8]Patent: WO2009/155156,2009,A1 .Location in patent: Page/Page column 63-64.

5
[ 20970-75-6 ]
[ 878207-92-2 ]

References: [1]Patent: WO2009/155156,2009,A1 .

6
[ 159727-88-5 ]
[ 878207-92-2 ]

References: [1]Patent: WO2009/155156,2009,A1 .

7
[ 1201924-31-3 ]
[ 878207-92-2 ]