95652-77-0|Methyl 2-chloro-6-methoxynicotinate| Ambeed

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Quality Control of [ 95652-77-0 ] Purity: 97% SDS Specification

COA

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NMR

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CNMR

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Product Details of [ 95652-77-0 ]

CAS No. :	95652-77-0
Formula :	C₈H₈ClNO₃
M.W :	201.61
SMILES Code :	O=C(OC)C1=C(Cl)N=C(OC)C=C1
MDL No. :	MFCD08275100
InChI Key :	WDMMBHZPESWUCL-UHFFFAOYSA-N
Pubchem ID :	10584232

Safety of [ 95652-77-0 ]

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

Computational Chemistry of [ 95652-77-0 ] Show Less

Physicochemical Properties

Num. heavy atoms	13
Num. arom. heavy atoms	6
Fraction Csp3	0.25
Num. rotatable bonds	3
Num. H-bond acceptors	4.0
Num. H-bond donors	0.0
Molar Refractivity	47.02
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	48.42 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.37
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	1.97
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	1.53
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.	1.07
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	1.85
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	1.76

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-2.47
Solubility	0.676 mg/ml ; 0.00335 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.	-2.61
Solubility	0.492 mg/ml ; 0.00244 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	-2.85
Solubility	0.285 mg/ml ; 0.00141 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.	-6.13 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	0.0
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)	2.02

Application In Synthesis of [ 95652-77-0 ]

* 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 [ 95652-77-0 ]

[ 95652-77-0 ] Synthesis Path-Downstream 1~41

1
[ 67-56-1 ]
[ 55366-30-8 ]
[ 95652-77-0 ]

References: [1]Tetrahedron Letters,1984,vol. 25,p. 5693 - 5696.

2
[ 95652-77-0 ]
[ 26218-80-4 ]

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
[ 95652-76-9 ]
[ 95652-77-0 ]

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

5
[ 38496-18-3 ]
[ 95652-77-0 ]

References: [1]Journal of Medicinal Chemistry,2003,vol. 46,p. 702 - 715.
[2]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[3]Chemical and Pharmaceutical Bulletin,2000,vol. 48,p. 1847 - 1853.
[4]Patent: US2012/172391,2012,A1 .
[5]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.
[6]Journal of Medicinal Chemistry,2017,vol. 60,p. 7315 - 7332.
[7]Patent: WO2017/192304,2017,A1 .
[8]Patent: WO2008/76425,2008,A1 .
[9]Patent: CN109810041,2019,A .

6
[ 95652-77-0 ]
[ 503000-90-6 ]

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

7
[ 95652-77-0 ]
[ 503000-89-3 ]

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

8
[ 95652-77-0 ]
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.

9
[ 503000-87-1 ]
[ 95652-77-0 ]

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

10
[ 55366-30-8 ]
[ 95652-77-0 ]

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.

11
[ 95652-77-0 ]
[ 66572-55-2 ]

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

12
[ 97985-23-4 ]
[ 95652-77-0 ]

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

13
[ 911801-63-3 ]
[ 95652-77-0 ]

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

14
[ 74-88-4 ]
[ 853109-24-7 ]
[ 95652-77-0 ]

Yield	Reaction Conditions	Operation in experiment
62%		To a solution of 2-chloro-6-oxo-l,6-dihydro-pyridine-3- carboxylic acid (0.644 g, 3.71 mmol) in DMF (20 mL) was added lithium hydride (95%, EPO <DP n="78"/>0.078 g, 9.28 mmol) and the reaction mixture was stirred for 40 minutes under N2. Methyl iodide (0.508 mL, 1.16 g, 8.16 mmol) was then added and the reaction mixture was stirred for an additional 45 minutes. The reaction mixture was quenched with 2 M HCl until the pH was 6-7. The reaction mixture was diluted with EtOAc and saturated NaCl and the layers separated. The aqueous layer was back extracted with EtOAc (Ix). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield a crude yellow solid. HPLC analysis showed two products in a 4:1 ratio that were separated by flash column chromatography (methylene chloride/EtOAc, 15:1 to 10:1) to give 0.466 g (62%) pure desired product as a white crystalline solid. The minor product was also isolated as a pale yellow crystalline solid and identified as the regioisomer 2-chloro-6-methoxy-nicotinic acid methyl ester; To a solution of 2-chloro-6-oxo-l,6-dihydropyridine-3-carboxylic acid (0.644 g, 3.71 mmol) in DMF (20 mL) was added lithium hydride (95%, 0.078 g, 9.28 mmol) and the reaction mixture was stirred for 40 minutes under N2. Methyl iodide (0.508 mL, 1.16 g, 8.16 mmol) was then added and the reaction mixture was stirred for an additional 45 minutes. The reaction mixture was quenched with 2 M HCl until the pH was 6-7. The reaction mixture was diluted with EtOAc and saturated NaCl and the layers were separated. The aqueous layer was back-extracted with EtOAc (Ix). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to yield a crude yellow solid. HPLC analysis showed two products in a 4:1 ratio that were separated by flash column chromatography (methylene chloride/EtOAc, 15:1 to 10:1) to give 0.466 g (62%) pure desired product as a white crystalline solid. The minor product was also isolated as a pale yellow crystalline solid and identified as the regioisomer methyl 2-chloro-6- methoxynicotinate .

References: [1]Patent: WO2007/44084,2007,A2 .Location in patent: Page/Page column 76; 77.

15
[ 3300-51-4 ]
[ 95652-77-0 ]
[ 1073230-29-1 ]

Yield	Reaction Conditions	Operation in experiment
	In 1,2-dimethoxyethane; for 48h;Heating / reflux;	A mixture of 1.0 g (5.0 mmol) of the compound of Step B and 4-(trifluoromethyl)- benzylamine (1.82 g, 10.4 mmol) in DME (25 mL) was refluxed for 48 h. The resulting mixture was filtered and washed with DME. The combined filtrate was evaporated followed by the purification silica column (combiflash, ISCO) and eluted with hexane + EtOAc (0 to 10% gradient) to give 1.49 g of the title compound as an off white solid: 1H NMR (500 MHz, CDCl3) delta 8.63 (br s, IH), 8.04 (d, IH, J = 8.5 Hz), 7.59 (d, 2H, J = 7.3 Hz), 7.48 (d, 2H, J = 7.2 Hz), 6.02 (d, IH, J = 8.5 Hz), 4.81 (d, 2H, J = 5.5 Hz), 3.86 (s, 3H), 3.81 (s, 3H); MS: m/z 341 (M+H).

References: [1]Patent: WO2008/130527,2008,A1 .Location in patent: Page/Page column 26.

16
[ 95652-77-0 ]
[ 1226898-93-6 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

17
[ 95652-77-0 ]
[ 1228600-91-6 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

18
[ 95652-77-0 ]
[ 1251033-14-3 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

19
[ 95652-77-0 ]
[ 1384262-74-1 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

20
[ 95652-77-0 ]
[ 1384262-35-4 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

21
[ 95652-77-0 ]
[ 1384262-36-5 ]

References: [1]Patent: US2012/172391,2012,A1 .

22
[ 95652-77-0 ]
[ 1384262-39-8 ]

References: [1]Patent: US2012/172391,2012,A1 .

23
[ 95652-77-0 ]
[ 1384262-77-4 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

24
[ 95652-77-0 ]
[ 1384262-78-5 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

25
[ 95652-77-0 ]
[ 1384262-79-6 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

26
[ 1384262-66-1 ]
[ 95652-77-0 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

27
[ 7486-35-3 ]
[ 95652-77-0 ]
[ 1384262-70-7 ]

Yield	Reaction Conditions	Operation in experiment
71%	With bis-triphenylphosphine-palladium(II) chloride; 2,6-di-tert-butyl-4-methyl-phenol; In N,N-dimethyl-formamide; at 80℃; for 12h;Inert atmosphere;	Under the protection of nitrogen,The intermediate <strong>[95652-77-0]2-chloro-6-methoxynicotinate methyl ester</strong> (4.0 g, 19.88 mmol, 1.0 eq), tributylvinyltin (7.57 g, 23.86 mmol, 1.2 eq), 2,6-di-tert Butyl-4-methylphenol (219 mg, 0.99 mmol, 0.05Eq) and Pd(PPh3)2Cl2 (700 mg, 0.99 mmol, 0.05 eq) were sequentially added to DMF (45 mL) and heated to 80 C for 12 hours. LC-MS detected that a small amount of raw materials were not completely reacted, the system was cooled to room temperature, and the reaction solution was concentrated under reduced pressure.The crude product was purified by silica gel column chromatography.Yellow oily product (2.7 g, yield: 71%).
54%	bis-triphenylphosphine-palladium(II) chloride; 2,6-di-tert-butyl-4-methyl-phenol; In N,N-dimethyl-formamide; at 80℃; for 16h;Inert atmosphere;	A mixture of <strong>[95652-77-0]2-chloro-6-methoxy-nicotinic acid methyl ester</strong> (10 g, 49.8 mmol), tributyl(vinyl)tin (15.8 g, 49.8 mmol), 2,6-di-tert-butyl-4-methylphenol (0.3 g, 1.36 mmol) and trans-bis(triphenylphosphine)palladium(II) chloride (0.5 g, 0.71 mmol) was added to DMF (50 mL) under nitrogen. The mixture was stirred at 80 C. for 16 h. The solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; petroleum ether/EtOAc 50/1). The desired fractions were collected and the solvents evaporated in vacuo to yield 6-methoxy-2-vinyl-nicotinic acid methyl ester (5.12 g, 54%) as an oil.

References: [1]Patent: CN109810041,2019,A .Location in patent: Paragraph 0315; 0325-0327.
[2]Patent: US2012/172391,2012,A1 .Location in patent: Page/Page column 78.
[3]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

28
[ 95652-77-0 ]
[ 1384262-40-1 ]

References: [1]Patent: US2012/172391,2012,A1 .

29
[ 95652-77-0 ]
[ 1384262-80-9 ]

References: [1]Patent: US2012/172391,2012,A1 .
[2]Journal of Medicinal Chemistry,2014,vol. 57,p. 5620 - 5637.

30
[ 95652-77-0 ]
[ 1384262-38-7 ]

References: [1]Patent: US2012/172391,2012,A1 .

31
[ 1338605-42-7 ]
[ 95652-77-0 ]
methyl (S)-2-{2'-[N-(tert-butoxycarbonyl)pyrrolidin-2-yl]-2,4'-bithiazol-4-yl}-6-methoxynicotinate [ No CAS ]