77156-78-6|Ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate| Ambeed

Structure of 77156-78-6

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Quality Control of [ 77156-78-6 ] Purity: 98% SDS Specification

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Product Details of [ 77156-78-6 ]

CAS No. :	77156-78-6
Formula :	C₁₃H₁₃NO₄
M.W :	247.25
SMILES Code :	CCOC(=O)C1=C(O)C2=C(C=CC(OC)=C2)N=C1
MDL No. :	MFCD00085617
InChI Key :	VNGGYIBIGOOVNP-UHFFFAOYSA-N
Pubchem ID :	228284

Safety of [ 77156-78-6 ]

GHS Pictogram:
Signal Word:	Warning
Hazard Statements:	H319
Precautionary Statements:	P305+P351+P338

Computational Chemistry of [ 77156-78-6 ] Show Less

Physicochemical Properties

Num. heavy atoms	18
Num. arom. heavy atoms	10
Fraction Csp3	0.23
Num. rotatable bonds	4
Num. H-bond acceptors	5.0
Num. H-bond donors	1.0
Molar Refractivity	66.34
TPSA ? Topological Polar Surface Area: Calculated from Ertl P. et al. 2000 J. Med. Chem.	68.65 Å²

Lipophilicity

Log P_o/w (iLOGP)? iLOGP: in-house physics-based method implemented from Daina A et al. 2014 J. Chem. Inf. Model.	2.72
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	2.58
Log P_o/w (WLOGP)? WLOGP: Atomistic method implemented from Wildman SA and Crippen GM. 1999 J. Chem. Inf. Model.	2.13
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.	1.04
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	2.2
Consensus Log P_o/w? Consensus Log P_o/w: Average of all five predictions	2.13

Water Solubility

Log S (ESOL):? ESOL: Topological method implemented from Delaney JS. 2004 J. Chem. Inf. Model.	-3.15
Solubility	0.177 mg/ml ; 0.000715 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.	-3.67
Solubility	0.0528 mg/ml ; 0.000214 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	-3.74
Solubility	0.045 mg/ml ; 0.000182 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.	-5.98 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	0.0 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)	1.9

Application In Synthesis of [ 77156-78-6 ]

* 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 [ 77156-78-6 ]

[ 77156-78-6 ] Synthesis Path-Downstream 1~35

1
[ 77156-78-6 ]
[ 108-24-7 ]
4-acetoxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester [ No CAS ]

References: [1]Journal of the Chemical Society,1946,p. 1035.

2
[ 77156-78-6 ]
[ 28027-16-9 ]

Yield	Reaction Conditions	Operation in experiment
99%	With sodium hydroxide; In water; at 90℃; for 1.5h;	A suspension of <strong>[77156-78-6]ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate</strong> (6, 17.8 g, 72 mmol) in 170 ml of 2 N aqueous sodium hydroxide was heated to 90 C for 1.5 h. Subsequently the reaction mixture was cooled to room temperature, poured on ice-water and acidified to pH 5 by addition of 2 N hydrochloric acid. The precipitated product was filtered, washed with cold water and dried to deliver 4-hydroxy-6-methoxyquinoline-3-carboxylic acid (7, 15.8 g, 72 mmol, 99 %). 1H-NMR (DMSO): delta = 3.91 (s, 3H), 7.53 (dd, 1H), 7.64 (d, 1H), 7.82 (d, 1H), 8.80 (d, 1H), 13.63 (bs, 1H), 15.55 (bs 1H). LC-MS: Rt = 1.20 min; MS: m/z = 220 [M+1]+.

References: [1]Tetrahedron Letters,2017,vol. 58,p. 794 - 796.
[2]Journal of the American Chemical Society,1946,vol. 68,p. 1204,1206.
Organic Syntheses,1955,vol. Coll. Vol. III,p. 272.
[3]Journal of the American Chemical Society,1947,vol. 69,p. 1659,1660.
[4]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824.

3
[ 77156-78-6 ]
[ 22931-71-1 ]

Yield	Reaction Conditions	Operation in experiment
98%	With trichlorophosphate; for 2h;Inert atmosphere; Reflux;	A suspension of <strong>[77156-78-6]ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate</strong> (6, 1.65 g, 6.5 mmol) in 10 ml of phosphorus oxychloride was heated for 2 h to reflux. Subsequently the reaction mixture was cooled to room temperature and freed from the excess phosphorus oxychloride under reduced pressure. The remainder was dissolved in ethyl acetate, to this solution warm water was slowly added under vigorous stirring. The phases were separated, the organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to deliver ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (12, 1.7 g, 6.5 mmol, 98 %) which was pure enough to be directly used in the next step. 1H-NMR (CDCl3): delta = 1.47 (t, 3H), 4.00 (s, 3H), 4.51 (q, 2H), 7.48 (dd, 1H), 7.60 (d, 1H), 8.05 (d, 1H), 9.06 (s, 1H). LC-MS: Rt = 1.81 min; MS: m/z = 266 [M+1]+.
97%	In trichlorophosphate;	Example 1b ethyl 4-chloro-6-methoxyquinoline-3-carboxylate A solution of <strong>[77156-78-6]ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate</strong> (Example 1c, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NMR (400 MHz, DMSO-d6) delta 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
97%	With trichlorophosphate; for 3h;Reflux; Inert atmosphere;	A solution of <strong>[77156-78-6]ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate</strong> (Example Ac, 1.24 g, 5.0 mmol) in POCI3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale -yellow solid (1.29 g, 97%). .H NMR (400 MHz, DMSO-i¾ delta 1.36 (t, J = 7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J = 7.0 Hz, 2H), 7.57 (d, J = 2.8 Hz, 1H), 7.61 (dd, J = 2.8, 8.8 Hz, 1H), 8.05 (d, J = 8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).

97%	With trichlorophosphate; for 3h;Inert atmosphere; Reflux;	Example 1b ethyl 4-chloro-6-methoxyquinoline-3-carboxylate A solution of <strong>[77156-78-6]ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate</strong> (Example 1c, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NMR (400 MHz, DMSO-d6) delta 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
97%	In trichlorophosphate;	Example 1b ethyl 4-chloro-6-methoxyquinoline-3-carboxylate A solution of <strong>[77156-78-6]ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate</strong> (Example 1c, 1.24 g, 5.0 mmol) in POCl3 was refluxed under nitrogen for 3 hrs. The solution was cooled to room temperature and evaporated under reduced pressure. The residue was carefully quenched with ice, and neutralized with 2.0 N NaOH to pH 7. The precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as a pale-yellow solid (1.29 g, 97%). 1H NMR (400 MHz, DMSO-d6) delta 1.36 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.41 (q, J=7.0 Hz, 2H), 7.57 (d, J=2.8 Hz, 1H), 7.61 (dd, J=2.8, 8.8 Hz, 1H), 8.05 (d, J=8.8 Hz, 1H), 8.97 (s, 1H). MS 266, 268 (MH+).
82%	With trichlorophosphate; for 3h;Reflux;	General procedure: To the corresponding intermediate 10 (25 mmol), POCl3 (125 mmol) was added slowly and refluxed for 3 h at 105 C. TLC analysis indicated that the reaction was completed. Excess POCl3 was removed under reduced pressure and the crude reaction mass was quenched with crushed ice then neutralized with saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate(3*100 mL). The organic layer was dried over anhy. Na2SO4, filtered and evaporated under reduced pressure to get corresponding desired chloro intermediate.

References: [1]Tetrahedron Letters,2017,vol. 58,p. 794 - 796.
[2]Patent: US2011/245353,2011,A1 .
[3]Patent: WO2013/25560,2013,A1 .Location in patent: Page/Page column 52; 53.
[4]Patent: US2015/245642,2015,A1 .Location in patent: Paragraph 0287.
[5]Patent: US2012/41078,2012,A1 .
[6]Australian Journal of Chemistry,2009,vol. 62,p. 150 - 156.
[7]European Journal of Medicinal Chemistry,2015,vol. 103,p. 1 - 16.
[8]Journal of Medicinal Chemistry,2012,vol. 55,p. 3578 - 3582.
[9]Il Farmaco,1998,vol. 53,p. 579 - 585.
[10]Journal of the Chemical Society,1951,p. 1389,1391.
[11]Journal of Medicinal Chemistry,1993,vol. 36,p. 1669 - 1673.

4
[ 77156-78-6 ]
4-hydroxy-6-methoxy-quinoline-3-carboxylic acid hydrazide [ No CAS ]

References: [1]Journal Of Scientific and Industrial Research,1955,vol. 14 B,p. 261.

5
[ 83507-70-4 ]
[ 77156-78-6 ]

Yield	Reaction Conditions	Operation in experiment
71%	In diphenyl ether-biphenyl eutectic; at 250℃; for 1.5h;Product distribution / selectivity;	b) Ethyl 4-hydroxy-6-(methyloxy)-3-quinolinecarboxylate; Diethyl ([4-(methyloxy)phenyl]amino}methylidene)propanedioate (100 g, 0.34 mol) was taken up in Dowtherm (500 mL) and heated at 250 0C for 1.5 h; 75% conversion. The reaction solution was cooled, treated with hexanes (750 mL) and cooled to 0 0C in ice bath. The brown solid was filtered off and washed with hexanes (2X) and dried under vacuum to give 60 g (71%).
66%	With trichlorophosphate; at 75℃; for 8h;	General procedure: Polyphosphoric acid (PPA) (2 equiv by weight) was added to corresponding intermediate 1 (40 mmol) to this phosphorousoxychloride (POCl3) (10 mmol) was added. The reaction mixture was heated to 75 C for 8 h, monitored by TLC, after completion of the reaction. The reaction mixture was quenched slowly with 10% sodium hydroxide solution by keeping it in an ice bath and the PH was adjusted to a pH ~ 7, the solid separated was filtered, dried and washed with diethyl ether (3*20 mL) to afford desired compound in good yield.
41%	In diphenylether; at 243 - 250℃; for 3h;Inert atmosphere;	A solution of diethyl 2-[(4-methoxyanilino)methylene]propanedioate (5, 71.4 g, 0.24 mol) in 150 ml of diphenyl ether was slowly heated in a metal bath to 243 C. During 3 h at this temperature 15 ml liquid were distilled off. The reaction mixture was cooled to room temperature and taken up in 250 ml hexane. This mixture was stirred for 3 h, then filtered. The solid was washed with hexane and dried to deliver ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate (6, 25.0 g, 0.10 mol, 41 %) which was pure enough to be directly used in the next step. 1H-NMR (CDCl3): delta = 1.28 (t, 3H), 3.85 (s, 3H), 4.21 (q, 2H), 7.34 (dd, 1H), 7.55 - 7.62 (m, 2H), 8.49 (s, 1H). LC-MS: Rt = 1.17 min; MS: m/z = 248 [M+1]+.

23 g

With Dowtherm A; at 250℃; for 3h;

Compound 2 (61 g) was taken up in dowtherm( 400ml) and heated at 250C for 3h. The reaction mixture was cooled to (RT) and treated with pentane (300 mL) and filtered under suction. The resulting solids were washed thoroughly with excess of pentane and dried under vacuum to give 3 (23 g).

References: [1]Patent: WO2006/2047,2006,A2 .Location in patent: Page/Page column 60.
[2]European Journal of Medicinal Chemistry,2015,vol. 103,p. 1 - 16.
[3]Organic Process Research and Development,2014,vol. 18,p. 1482 - 1491.
[4]Tetrahedron Letters,2017,vol. 58,p. 794 - 796.
[5]Journal of the American Chemical Society,1946,vol. 68,p. 1204,1206.
Organic Syntheses,1955,vol. Coll. Vol. III,p. 272.
[6]Journal of the Chemical Society,1946,p. 1033,1035.
[7]Il Farmaco,1998,vol. 53,p. 579 - 585.
[8]Australian Journal of Chemistry,2009,vol. 62,p. 150 - 156.
[9]Patent: WO2014/57415,2014,A2 .Location in patent: Page/Page column 9.

6
[ 77156-78-6 ]
[ 64-04-0 ]
[ 104406-72-6 ]

References: [1]Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry,1985,vol. 24,p. 737 - 746.

7
[ 104-94-9 ]
[ 87-13-8 ]
[ 77156-78-6 ]

Yield	Reaction Conditions	Operation in experiment
78%	With diphenyl ether-biphenyl eutectic; In ethanol; for 0.5h;Heating / reflux;	A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A).
78%	In diphenyl ether-biphenyl eutectic; for 0.5h;Heating / reflux;Product distribution / selectivity;	Preparation 10; Preparation of 4-ethenyl-3-fluoro-6-(methyloxy)quinoline; a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester; A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A).
78%	In diphenyl ether-biphenyl eutectic; for 0.5h;Heating / reflux;	Preparation 8; Preparation of 4-ethenvl-3-fluoro-6-(methvloxv)quinoline; a) 4-Hydroxy-6-methoxy-quinoline-3-carboxylic acid ethyl ester; A solution of 4-methoxyaniline (40g, 0.32 mole) and diethylethoxymethylenemalonate (65 ml, 0.32 mole) in Dowtherm A (500 ml_) was heated atreflux in a flask fitted with side-arm and condenser, and heating was continued until all theethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added togive a sticky precipitate. The solvents were decanted off and the residue was treated withmore pentane and allowed to stand overnight. The solid was filtered off and washed wellwith pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A).

17%		A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120 C under nitrogen for 4 hrs. The solution was cooled to room temperature and Ph20 (100 mL) was added. The reaction mixture was refluxed at 260 C under nitrogen for 8 hrs. The solution was cooled to room temperature and diluted with hexanes. The resultant precipitate was collected by filtration, washed with 25% ethyl acetate in hexanes, and dried under vacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale- yellow solid (4.21 g, 17%). 1H NMR (400 MHz, DMSO-i¾ delta 1.26 (t, J = 7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J = 7.0 Hz, 2H), 7.32 (dd, J = 3.2, 9.6 Hz, 1H), 7.55 (d, J = 3.2 Hz, 1H), 7.56 (d, J = 9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH+).
17%		Example 1c ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate A mixture of 4-methoxyaniline (12.3 g, 100 mmol) and diethyl 2-(ethoxymethylene)malonate (21.6 g, 100 mmol) was stirred at 120 C. under nitrogen for 4 hrs. The solution was cooled to room temperature and Ph2O (100 mL) was added. The reaction mixture was refluxed at 260 C. under nitrogen for 8 hrs. The solution was cooled to room temperature and diluted with hexanes. The resultant precipitate was collected by filtration, washed with 25% ethyl acetate in hexanes, and dried under vacuum to give ethyl 4-hydroxy-6-methoxyquinoline-3-carboxylate as a pale-yellow solid (4.21 g, 17%). 1H NMR (400 MHz, DMSO-d6) delta 1.26 (t, J=7.0 Hz, 3H), 3.83 (s, 3H), 4.19 (q, J=7.0 Hz, 2H), 7.32 (dd, J=3.2, 9.6 Hz, 1H), 7.55 (d, J=3.2 Hz, 1H), 7.56 (d, J=9.6 Hz, 1H), 8.47 (s, 1H), 12.27 (s, 1H). MS 248 (MH+).
	In diphenyl ether-biphenyl eutectic; for 0.5h;Heating / reflux;	A solution of 4-methoxyaniline (4Og, 0.32 mole) and diethyl ethoxymethylenemalonate (65 mL, 0.32 mole) in Dowtherm A (500 mL) was heated at reflux in a flask fitted with side-arm and condenser, and heating was continued until all the ethanol had distilled off (ca. 0.5 hr). The solution was cooled and pentane was added to give a sticky precipitate. The solvents were decanted off and the residue was treated with more pentane and allowed to stand overnight. The solid was filtered off and washed well with pentane to give the title compound (62.4 g; 78%, contains traces of Dowtherm A)

References: [1]Patent: WO2006/81289,2006,A2 .Location in patent: Page/Page column 19.
[2]Patent: WO2006/2047,2006,A2 .Location in patent: Page/Page column 74.
[3]Patent: WO2006/14580,2006,A1 .Location in patent: Page/Page column 38.
[4]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824.
[5]Patent: WO2013/25560,2013,A1 .Location in patent: Page/Page column 53.
[6]Patent: US2015/245642,2015,A1 .Location in patent: Paragraph 0288; 0289.
[7]Journal of Medicinal Chemistry,2012,vol. 55,p. 3578 - 3582.
[8]Journal of Medicinal Chemistry,1993,vol. 36,p. 1669 - 1673.
[9]Patent: WO2007/16610,2007,A2 .Location in patent: Page/Page column 28.

8
[ 77156-78-6 ]
[ 931127-28-5 ]

References: [1]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824.

9
[ 77156-78-6 ]
4-(β-D-glucosyloxy)-6-methoxyquinoline [ No CAS ]

References: [1]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824.

10
[ 77156-78-6 ]
[ 23432-39-5 ]

References: [1]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824.
[2]Journal of the American Chemical Society,1946,vol. 68,p. 1204,1206.
Organic Syntheses,1955,vol. Coll. Vol. III,p. 272.
[3]Journal of the American Chemical Society,1947,vol. 69,p. 1659,1660.
[4]Tetrahedron Letters,2017,vol. 58,p. 794 - 796.

11
[ 77156-78-6 ]
PW 007A [ No CAS ]

References: [1]Il Farmaco,1998,vol. 53,p. 579 - 585.
[2]Journal of Medicinal Chemistry,1993,vol. 36,p. 1669 - 1673.

12
[ 104-94-9 ]
Tulsion A-27 supported Meldrum's acid [ No CAS ]
[ 77156-78-6 ]

References: [1]Il Farmaco,1998,vol. 53,p. 579 - 585.

13
[ 87-13-8 ]
[ 77156-78-6 ]

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[ 148018-29-5 ]