[ CAS No. 63463-15-0 ] {[proInfo.proName]}

Name: 63463-15-0|Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate|98%
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Quality Control of [ 63463-15-0 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

Alternatived Products of [ 63463-15-0 ]

Product Details of [ 63463-15-0 ]

CAS No. :	63463-15-0	MDL No. :	MFCD00085986
Formula :	C₁₃H₁₃NO₄	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	GWLDDWJZROMBRD-UHFFFAOYSA-N
M.W :	247.25	Pubchem ID :	296364
Synonyms :

Calculated chemistry of [ 63463-15-0 ]

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 :	68.65 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	No
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.98 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.72
Log Po/w (XLOGP3) :	2.58
Log Po/w (WLOGP) :	2.13
Log Po/w (MLOGP) :	1.04
Log Po/w (SILICOS-IT) :	2.2
Consensus Log Po/w :	2.13

Druglikeness

Lipinski :	0.0
Ghose :	None
Veber :	0.0
Egan :	0.0
Muegge :	0.0
Bioavailability Score :	0.55

Water Solubility

Log S (ESOL) :	-3.15
Solubility :	0.177 mg/ml ; 0.000715 mol/l
Class :	Soluble
Log S (Ali) :	-3.67
Solubility :	0.0528 mg/ml ; 0.000214 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-3.74
Solubility :	0.045 mg/ml ; 0.000182 mol/l
Class :	Soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.88

Safety of [ 63463-15-0 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 63463-15-0 ]

* 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.

Upstream synthesis route of [ 63463-15-0 ]
Downstream synthetic route of [ 63463-15-0 ]

[ 63463-15-0 ] Synthesis Path-Upstream 1~4

1
[ 63463-15-0 ]
[ 68500-37-8 ]

Reference： [1] Journal of Medicinal Chemistry, 1998, vol. 41, # 25, p. 4918 - 4926
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1268
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3738 - 3748

2
[ 63463-15-0 ]
[ 28027-17-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium hydroxide In water for 1 h; Reflux	4i (4.40 g, 17.80 mmol) was hydrolyzed by refluxing in 2 M NaOH at 110 °C for an hour. The mixture was cooled to room temperature and acidified to pH 3-4 using 2M HCl. The resulting white precipitate was filtered, washed with water and dried to give 5i (2.50 g, 63percent), mp 272 °C (lit. Lauer et al 1946, 257 - 260 °C).³ δ_H (400 MHz; DMSO) 3.90 (3H, s, OCH₃), 7.17 (1H, dd, J 2.4, 9.0 Hz, H-6), 7.29 (1H, d, J 2.3 Hz, H-8), 8.16 (1H, d, J 9.0 Hz, H-5), 8.72 (1H, s, H-2), 13.68 (1H, s, Ar-OH), 15.50 (1H, bs, -COOH). δ_C (100 MHz; DMSO) 56.3 (Ar-OCH₃), 101.1 (C-3), 107.8 (C-8), 116.6 (C-4a), 118.9 (C-6), 127.3 (C-5), 142.0 (C-2), 145.0 (C-8a), 163.8 (C-4), 166.9 (C-7), 178.1 (COOH).
98%	With hydrogenchloride; sodium hydroxide In calcium chloride	(2) Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (24.7 g, 0.1 mol) was hydrolyzed with 2N aqueous solution of sodium hydroxide (250 ml) through boiling for 2 hours. The reaction mixture was allowed to cool to room temperature and adjusted with 2N hydrochloric acid to pH 5. The resulting precipitates were collected by filtration and washed with water. The precipitates were dried at 100°-120° C. for 3 hours in an oven and further dried under reduced pressure overnight over calcium chloride to obtain 21.4 g (98percent) of 4-hydroxy-7-methoxy-3-quinolinecarboxylic acid. NMR:δ 3.92(3H, s), 7.19(1H, d), 7.20(1H, dd), 8.19(1H, d), 8.82(1H, s), 13.15(1H, brs)

Reference： [1] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 13, p. 3738 - 3748
[2] Journal of the American Chemical Society, 1946, vol. 68, p. 1268
[3] Journal of Medicinal Chemistry, 1998, vol. 41, # 25, p. 4918 - 4926
[4] Chemical and Pharmaceutical Bulletin, 2007, vol. 55, # 5, p. 821 - 824
[5] Patent: US6110929, 2000, A,
[6] Patent: US5773449, 1998, A,

3
[ 63463-15-0 ]
[ 77156-85-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With oxalyl dichloride; N,N-dimethyl-formamide In chloroform at 65℃; for 2.5 h;	Step C. Ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. To a solution of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (2.72 g, 11.0 mmol) in chloroform (100 mL) was added oxalyl chloride (2.93 mL, 33.0 mmol) followed by 5 drops of DMF. The reaction was heated at 65° C. for 2.5 h before cooling to ambient temperature. The reaction mixture was poured into saturated NaHCO₃ (aq.) solution and the organics were extracted with DCM. The combined organics were dried over MgSO₄, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (2.69 g, 92percent). ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.33 (d, J=9.4 Hz, 1H), 7.58 (br. s., 1H), 7.37 (d, J=9.0 Hz, 1H), 4.48 (q, J=6.8 Hz, 2H), 4.01 (s, 3H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=266.2.
91%	With oxalyl dichloride; N,N-dimethyl-formamide In dichloromethane at 35 - 40℃; for 2.5 h;	A mixture of ethyl-4-hydroxy-7-methoxyquinoline-3-carboxylate DK-I-39-1 (37.1 g, 150.0 mmol), N,N- dimethylformamide (0.5 mL, 6.5 mmol), and dichloromethane (150 mL) was heated to 35-40 ^oC. Oxalyl chloride (20.9 g, 165.0 mmol) was added dropwise to the reaction mixture over 30 min. The reaction mixture was then heated for 2 h at reflux (38-40 ^oC). The resulting brown solution was then cooled to 20-25 ^oC. The reaction mixture was diluted with dichloromethane (150 mL) and then neutralized by slowly adding a 25percent solution of potassium carbonate (75 g) in water (300 mL). The layers were then separated and the aqueous layers extracted with dichloromethane (100 mL). The combined organic layers were then washed with a 25percent solution of potassium carbonate (75 g) in water (300 mL). The combined organic layers were then dried over magnesium sulfate. The solvents were then removed by evaporation on a rotovap and the product residue was slurried with hexanes (200 mL). The solid product was then filtered and washed twice with hexanes (50 mL x 2). The solid was dried to afford the product as an off-white solid DK-I-40-1 (36.3 g, 91percent): ¹H NMR (300 MHz, DMSO) δ 9.08 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 7.57– 7.37 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); ¹³C NMR (75 MHz, DMSO) δ 164.32, 162.83, 151.62, 150.81, 142.02, 126.85, 122.12, 121.11, 120.56, 108.36, 62.15, 56.45, 14.49; HRMS m/z calculated for C13H13ClNO3 (M+H)⁺ 266.0584 found 266.15.
68%	at 140℃; for 1 h;	Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (0.68 g, 2.75 mmol) was added tophosphorus oxychloride (2 mL) and heated at 140 oc for an hour. The mixture was thenpoured onto ice, neutralized with 1M NaOH resulting in a solid that was filtered, washed withwater and dried to afforded product (0.50 g, 68percent) as yellowish solid. OH (400 MHz; CDCb)1.46 (3H, t, J =4.0 Hz), 3.99 (3H, s), 4.48 (2H, q, J =8.0 Hz), 7.33(1H, m), 7.44 (1H, d, J=2.8 Hz), 8.30 (1H, d, J= 8.0 Hz), 9.17 (1H, s). 8c (100 MHz; CDCb) 14.2, 55.8, 61.8, 107.6,120.7, 121.5, 126.7, 143.4, 150.9, 151.7.

Reference： [1] Patent: US2014/275548, 2014, A1, . Location in patent: Paragraph 0361
[2] Patent: WO2016/196961, 2016, A1, . Location in patent: Paragraph 00149
[3] Journal of Medicinal Chemistry, 2018, vol. 61, # 6, p. 2422 - 2446
[4] Patent: WO2018/129274, 2018, A1, . Location in patent: Paragraph 0046
[5] Farmaco, 1998, vol. 53, # 8-9, p. 579 - 585
[6] Journal of Medicinal Chemistry, 1993, vol. 36, # 11, p. 1669 - 1673
[7] Patent: WO2006/14618, 2006, A2, . Location in patent: Page/Page column 37-38

4
[ 63463-15-0 ]
[ 659730-27-5 ]

Reference： [1] Patent: US2014/275548, 2014, A1,

[ 63463-15-0 ] Synthesis Path-Downstream 1~49

1
[ 63463-15-0 ]
[ 28027-17-0 ]

Yield	Reaction Conditions	Operation in experiment
63%	With sodium hydroxide; In water; for 1.0h;Reflux;	4i (4.40 g, 17.80 mmol) was hydrolyzed by refluxing in 2 M NaOH at 110 C for an hour. The mixture was cooled to room temperature and acidified to pH 3-4 using 2M HCl. The resulting white precipitate was filtered, washed with water and dried to give 5i (2.50 g, 63%), mp 272 C (lit. Lauer et al 1946, 257 - 260 C).3 deltaH (400 MHz; DMSO) 3.90 (3H, s, OCH3), 7.17 (1H, dd, J 2.4, 9.0 Hz, H-6), 7.29 (1H, d, J 2.3 Hz, H-8), 8.16 (1H, d, J 9.0 Hz, H-5), 8.72 (1H, s, H-2), 13.68 (1H, s, Ar-OH), 15.50 (1H, bs, -COOH). deltaC (100 MHz; DMSO) 56.3 (Ar-OCH3), 101.1 (C-3), 107.8 (C-8), 116.6 (C-4a), 118.9 (C-6), 127.3 (C-5), 142.0 (C-2), 145.0 (C-8a), 163.8 (C-4), 166.9 (C-7), 178.1 (COOH).
	With hydrogenchloride; In sodium hydroxide; water;	Part C A suspension of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (12.0 g, 48 mmol) in 10% sodium hydroxide/water (200 mL) was heated at reflux for 1.5 hr. The reaction mixture was allowed to cool to ambient temperature and then made acidic (pH=3) by the dropwise addition of concentrated hydrochloric acid. The resulting precipitate was isolated by filtration, washed twice with water and then dried overnight in a vacuum oven at 80 C. to provide 10.4 g of 4-hydroxy-7-methoxyquinoline-3-carboxylic acid.
21.4 g (98%)	With hydrogenchloride; sodium hydroxide; In calcium chloride;	(2) Ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate (24.7 g, 0.1 mol) was hydrolyzed with 2N aqueous solution of sodium hydroxide (250 ml) through boiling for 2 hours. The reaction mixture was allowed to cool to room temperature and adjusted with 2N hydrochloric acid to pH 5. The resulting precipitates were collected by filtration and washed with water. The precipitates were dried at 100-120 C. for 3 hours in an oven and further dried under reduced pressure overnight over calcium chloride to obtain 21.4 g (98%) of 4-hydroxy-7-methoxy-3-quinolinecarboxylic acid. NMR:delta 3.92(3H, s), 7.19(1H, d), 7.20(1H, dd), 8.19(1H, d), 8.82(1H, s), 13.15(1H, brs)

Reference： [1]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3738 - 3748
[2]Journal of the American Chemical Society,1946,vol. 68,p. 1268
[3]Journal of Medicinal Chemistry,1998,vol. 41,p. 4918 - 4926
[4]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824
[5]Patent: US6110929,2000,A
[6]Patent: US5773449,1998,A

2
[ 536-90-3 ]
[ 87-13-8 ]
[ 63463-15-0 ]

Yield	Reaction Conditions	Operation in experiment
56%	In diphenylether; ethanol; at 132 - 270℃; for 0.916667h;	A mixture of 3-methoxyaniline (25 g, 204 mmol) 28-A and diethyl (ethoxymethylene) malonate (44 g, 204 mmol) 28-B was heated in an oil bath to 150 C for 40 minutes. EtOH was generated when the temperature reached 132 C and collected. The reaction flask was moved away from oil bath and phenyl ether (70 ml) was added into the reaction mixture. The oil bath was preheated to 270 C. The reaction was heated at 270 C (oil bath temperature) for 15 minutes. The reaction mixture was poured slowly into 800 ml of hexane with stirring. Ethyl 4-hydroxy-7- methoxyquinoline-3-carboxylate 28-C was precipitated, filtrated, washed with hexane and dried (28.4 g, 56% yield).
56%	With diphenylether; at 150 - 270℃; for 0.916667h;	A mixture of 3-methoxyaniline (25 g, 204 MMOL) A and diethyl (ETHOXYMETHYLENE) MALONATE (44 g, 204 MMOL) B were heated in an oil bath to 150C for 40 minutes. EtOH was generated when the temperature reached 132 C and collected. The reaction flask was moved away from oil bath and phenyl ether (70 mL) was added into the reaction mixture. The oil bath was preheated to 270 C. The reaction was heated at 270 C (oil bath temperature) for 15 minutes. The reaction mixture was poured slowly into 800 ml of hexane with stirring. Ethyl 4-hydroxy-7-methoxyquinoline-3- carboxylate C was precipitated, filtrated, washed with hexane and dried (28.4 g, 56% yield). A solution of compound C (4. 2G) and KOH (3 G, 3 eq.) in 40 mL of ETOH/H2O (1: 1) was heated by microwave to 180 C for 50 minutes. The mixture was cooled to room temperature, poured into water (100 mL), neutralized with ACOH to pH 7 and saturated with NACI. The solution was extracted with THF (3 x 300 mL) and concentrated to yield 3.1 G of 7-methoxyquinolin-4-ol D as a solid. Compound D (7.4 G) was dissolved in 20 mL of POCI3. The solution was heated to reflux for 2 hours. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was neutralized with NH40H to pH-7 and extracted with EtOAc. The organic layer was concentrated and purified by chromatography on a silica gel column using hexane/ethylacetate (3: 1) to give 6.5 G of 4-chloro-7-methoxyquinoline as E as a yellow solid.
37%	In diphenylether; at 230℃;	A mixture of 3-methoxyaniline (50.0 g, 406.0 mmol), diethyl ethoxymethylenemalonate (87.8 g, 406.0 mmol) and diphenyl ether (200 mL) was slowly heated to 230 oC. The evolved ethanol was collected in a Dean-Stark trap. Once the ethanol formation ceased, the reaction mixture was heated for an additional 30 min at 230oC. The reaction mixture was then cooled to 80 oC and diluted with ethanol (200 mL). Upon cooling to 20-25 oC the solid product was collected by filtration and washed twice with ethanol (50 mL x 2) and twice with hexanes (50 mL x 2). The solid was dried to afford the product as a light brown solid DK-I-39-1 (37.1 g, 37%): 1H NMR (300 MHz, TFA) delta 11.63 (s, 1H), 9.22 (d, J = 6.3 Hz, 1H), 8.56 (dd, J = 9.1, 6.7 Hz, 1H), 7.66- 7.54 (m, 1H), 7.47 (d, J = 4.2 Hz, 1H), 4.69 (dd, J = 13.8, 6.9 Hz, 2H), 4.13 (d, J = 6.4 Hz, 3H), 1.57 (q, J = 6.8 Hz, 3H); 13C NMR (75 MHz, TFA) delta 171.88, 167.91, 167.62, 144.49, 142.43, 126.28, 121.92, 114.05, 103.81, 99.24, 64.28, 55.45, 12.00; HRMS m/z calculated for C13H14NO4 (M+H)+ 248.0923 found 248.15.

		To a solution of m-anisidine (1.1 Ig, 8.94 mmol) in toluene (5 mL) was added diethylethoxymethylene malonate (1.93 g, 8.94 mmol). After refluxing the reaction for 45 minutes, it was concentrated in vacuo. The residue was dissolved in phenyl ether (5 mL) and added to a solution of refluxing phenyl ether (10 mL). After 1 hour, the reaction was cooled to room temperature. A precipitate crashed out. The reaction was diluted with hexanes and filtered to give a yellow solid. LC-MS: 2.08 min; (M+H)=248.2.
		EXAMPLE 20 Using the procedure of Steps A and B of Example 19, 3-methoxy-aniline and ethyl ethoxymethylenemalonate were reacted to obtain ethyl 4-hydroxy-7-methoxy-3-quinoline-carboxylate melting at >260 C. Analysis: C13 H13 NO4; molecular weight=247.31 Calculated: %C: 63.15; %H: 5.3; %N: 5.66; Found: %C: 63.1; %H: 5.4; %N: 5.7.

Reference： [1]Patent: WO2005/63739,2005,A1 .Location in patent: Page/Page column 69
[2]Patent: WO2005/21554,2005,A1 .Location in patent: Page/Page column 94-95
[3]Patent: WO2016/196961,2016,A1 .Location in patent: Paragraph 00142
[4]Journal of Medicinal Chemistry,2018,vol. 61,p. 2422 - 2446
[5]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824
[6]Journal of the American Chemical Society,1946,vol. 68,p. 1268
[7]Journal of Medicinal Chemistry,1993,vol. 36,p. 1669 - 1673
[8]Patent: WO2006/14618,2006,A2 .Location in patent: Page/Page column 37
[9]Patent: US4450167,1984,A

3
[ 63463-15-0 ]
[ 64-04-0 ]
[ 104386-03-0 ]

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

4
[ 63463-15-0 ]
[ 77156-85-5 ]

Yield	Reaction Conditions	Operation in experiment
92%	With oxalyl dichloride; N,N-dimethyl-formamide; In chloroform; at 65℃; for 2.5h;	Step C. Ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. To a solution of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (2.72 g, 11.0 mmol) in chloroform (100 mL) was added oxalyl chloride (2.93 mL, 33.0 mmol) followed by 5 drops of DMF. The reaction was heated at 65 C. for 2.5 h before cooling to ambient temperature. The reaction mixture was poured into saturated NaHCO3 (aq.) solution and the organics were extracted with DCM. The combined organics were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (2.69 g, 92%). 1H NMR (400 MHz, CDCl3) delta 9.20 (s, 1H), 8.33 (d, J=9.4 Hz, 1H), 7.58 (br. s., 1H), 7.37 (d, J=9.0 Hz, 1H), 4.48 (q, J=6.8 Hz, 2H), 4.01 (s, 3H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=266.2.
91%	With oxalyl dichloride; N,N-dimethyl-formamide; In dichloromethane; at 35 - 40℃; for 2.5h;	A mixture of ethyl-4-hydroxy-7-methoxyquinoline-3-carboxylate DK-I-39-1 (37.1 g, 150.0 mmol), N,N- dimethylformamide (0.5 mL, 6.5 mmol), and dichloromethane (150 mL) was heated to 35-40 oC. Oxalyl chloride (20.9 g, 165.0 mmol) was added dropwise to the reaction mixture over 30 min. The reaction mixture was then heated for 2 h at reflux (38-40 oC). The resulting brown solution was then cooled to 20-25 oC. The reaction mixture was diluted with dichloromethane (150 mL) and then neutralized by slowly adding a 25% solution of potassium carbonate (75 g) in water (300 mL). The layers were then separated and the aqueous layers extracted with dichloromethane (100 mL). The combined organic layers were then washed with a 25% solution of potassium carbonate (75 g) in water (300 mL). The combined organic layers were then dried over magnesium sulfate. The solvents were then removed by evaporation on a rotovap and the product residue was slurried with hexanes (200 mL). The solid product was then filtered and washed twice with hexanes (50 mL x 2). The solid was dried to afford the product as an off-white solid DK-I-40-1 (36.3 g, 91%): 1H NMR (300 MHz, DMSO) delta 9.08 (s, 1H), 8.25 (d, J = 9.2 Hz, 1H), 7.57- 7.37 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, DMSO) delta 164.32, 162.83, 151.62, 150.81, 142.02, 126.85, 122.12, 121.11, 120.56, 108.36, 62.15, 56.45, 14.49; HRMS m/z calculated for C13H13ClNO3 (M+H)+ 266.0584 found 266.15.
68%	With trichlorophosphate; at 140℃; for 1.0h;	Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (0.68 g, 2.75 mmol) was added tophosphorus oxychloride (2 mL) and heated at 140 oc for an hour. The mixture was thenpoured onto ice, neutralized with 1M NaOH resulting in a solid that was filtered, washed withwater and dried to afforded product (0.50 g, 68%) as yellowish solid. OH (400 MHz; CDCb)1.46 (3H, t, J =4.0 Hz), 3.99 (3H, s), 4.48 (2H, q, J =8.0 Hz), 7.33(1H, m), 7.44 (1H, d, J=2.8 Hz), 8.30 (1H, d, J= 8.0 Hz), 9.17 (1H, s). 8c (100 MHz; CDCb) 14.2, 55.8, 61.8, 107.6,120.7, 121.5, 126.7, 143.4, 150.9, 151.7.

With trichlorophosphate; for 1.0h;Heating / reflux;

The intermediate from step A (890 mg, mmol) was suspended in POCl3 (5 mL) and refluxed for 1 hour. The reaction was cooled to room temperature and poured into an erlenmeyer flask containing ice and 5 N NaOH (30 mL). The resulting mixture was extracted with ethyl acetate (3X). The organic layer was washed with saturated NaHCO3, saturated NaCl solution dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using 30% ethyl acetate- hexanes to afford the product as a white solid. 1H NMR (500 MHz, CDCl3): 9.19 (s, IH), 8.33 (s, 7=9.2 Hz, IH), 7.46 (d, 7=2.5 Hz, IH), 7.36 (dd, 7=2.5, 9.1 Hz, IH), 4.53 (q, 7=7.1 Hz, 2H), 4.01 (s, 3H), 1.5 (t, 7=7.4 Hz, 3H). LC-MS: 3.22 min; (M+H)=266.1

Reference： [1]Patent: US2014/275548,2014,A1 .Location in patent: Paragraph 0361
[2]Patent: WO2016/196961,2016,A1 .Location in patent: Paragraph 00149
[3]Journal of Medicinal Chemistry,2018,vol. 61,p. 2422 - 2446
[4]Patent: WO2018/129274,2018,A1 .Location in patent: Paragraph 0046
[5]Il Farmaco,1998,vol. 53,p. 579 - 585
[6]Journal of Medicinal Chemistry,1993,vol. 36,p. 1669 - 1673
[7]Patent: WO2006/14618,2006,A2 .Location in patent: Page/Page column 37-38

5
[ 56881-19-7 ]
[ 63463-15-0 ]

Yield	Reaction Conditions	Operation in experiment
90%	In diphenylether; biphenyl; for 0.25h;Heating;	Step B. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate. To a solution of boiling Dowtherm (100 mL) was added diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate (20.0 g, 68.3 mmol). After 15 minutes the reaction was cooled to ambient temperature and poured into hexanes (500 mL). The precipitate was collected by filtration and dried under high vacuum to yield the title compound as a brown solid (15.2 g, 90%). 1H NMR (400 MHz, DMSO-d6) delta 12.09 (d, J=5.9 Hz, 1H), 8.47 (d, J=6.7 Hz, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.04-6.97 (m, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.85 (s, 3H), 1.25 (t, J=7.2 Hz, 4H).
86%	In diphenylether; for 1h;Reflux;	3i (6.30 g, 30.00 mmol) was suspended in boiling phenyl ether (100 mL) and refluxed at 260 C for an hour. The resulting quinoline ester was cooled to room temperature, diluted with petroleum ether and filtered. The solid was washed with large volume of petroleum ether and dried to yield 4i (4.40 g, 86%), mp 273-274 C (lit. Lauer et al 1946, 275 C).3 deltaH (400 MHz; DMSO) 1.28 (3H, t, J 7.1, CH3), 3.87 (3H, s, OCH3), 4.21 (2H, q, J 7.1Hz, CH2), 7.13 (2H, m, Ar-H), 8.06 (1H, d, J 8.5 Hz, H-5), 8.42 (1H, s, H-2), 11.88 (1H, s, OH). deltaC (100 MHz; DMSO) 14.7 (-CH2CH3), 55.9 (-OCH3), 59.9 (-CH2CH3), 100.8 (C-3), 109.1 (C-8), 113.4 (C-4a), 114.5 (C-6), 127.3 (C-5), 128.0 (C-2), 139.3 (C-8a), 145.0 (C-4), 162.4 (C-7), 162.9 (COO).
57%	In diphenylether; at 265℃; for 1h;	Diethyl2-(((3-methoxyphenyl)amino)methylene)malonate (1.48 g, 5.05 mmol) was added toalready refluxing (265 C) phenyl ether (10 mL). The mixture was left to reflux for 1 hr. and then cooled to room temperature. The solid that formed was filtered and washed thoroughlywith hexane to give product (0. 7 g, 57%) as a white powder. OH ( 400 MHz; d-DMSO) 1.29(3H, t, J=8.0 Hz), 3.86 (3H, s) 4.20 (2H, q, J= 8.0 Hz), 7.01 (2H, m), 8.05 (1H, d, J= 8.0Hz), 8.49 (1H, s), 12.11 (1H, br, s).

Reference： [1]Patent: US2014/275548,2014,A1 .Location in patent: Paragraph 0360
[2]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3738 - 3748
[3]Patent: WO2018/129274,2018,A1 .Location in patent: Paragraph 0045
[4]Journal of Medicinal Chemistry,1998,vol. 41,p. 4918 - 4926
[5]Il Farmaco,1998,vol. 53,p. 579 - 585
[6]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2980 - 2985

Yield	Reaction Conditions	Operation in experiment
		Part B Dowtherm A (~200 mL) was charged into a flask equipped with a stir bar, nitrogen inlet, Dean-Stark trap and condenser. The solvent was heated to a vigorous reflux and then 2-[3-(methoxyanilino)methylene]malonate (20.0 g, 68 mmol) was added. The reaction mixture was heated for 0.5 hr. and the brown solution was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, washed with acetone and then air dried to provide 12.5 g of ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate as a yellow powder.
		STEP A Ethyl 7-methoxy-4-hydroxy-3-quinoline-carboxylate Using the procedure of Example 2, ethyl ethoxymethylene malonate and 3-methoxy-aniline were reacted and treated with phenyl oxide to obtain ethyl 7-methoxy-4-hydroxy-3-quinoline-carboxylate melting at >260 C. Analysis: C13 H13 NO4; molecular weight=247.31. Calculated:%C 63.15; %H 5.3; %N 5.66. Found: %C 63.1; %H 5.4; %N 5.7.

7
[ 53369-71-4 ]
[ 63463-15-0 ]
4-hydroxy-7-methoxy-quinoline-3-carboxylic acid (3-dimethylamino-2,2-dimethyl-propyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2980 - 2985

8
[ 63463-15-0 ]
[ 108-00-9 ]
4-hydroxy-7-methoxy-quinoline-3-carboxylic acid (2-dimethylamino-ethyl)-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2980 - 2985

9
[ 63463-15-0 ]
[ 100-61-8 ]
4-hydroxy-7-methoxy-quinoline-3-carboxylic acid methyl-phenyl-amide [ No CAS ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2980 - 2985

10
[ 63463-15-0 ]
[ 931127-29-6 ]

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

11
[ 63463-15-0 ]
4-(β-D-glucosyloxy)-7-methoxyquinoline [ No CAS ]

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

12
[ 63463-15-0 ]
[ 82121-05-9 ]

Yield	Reaction Conditions	Operation in experiment
> 80%		Method 1: A solution of <strong>[63463-15-0]ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate</strong> D (5 G) and KOH (3 eq) in 60 mL of H20/HO (CH2) 20H (1: 1) was placed in a sealed vessel (XP-500 Plus vessel). The reaction was heated by microwave (MARS 5 Microwave System) at 200C, under 220-240 psi pressure for 30 minutes. The reaction mixture was cooled to room temperature and poured into H20 (100 mL). The solution was acidified with 2 N HCI to PH-6, saturated with NACI and extracted with THF (3X200 mL). The combined oil layer was washed with brine and concentrated to give compound E (>80% yield). Compound E : H NMR (300 MHz, DMSO-D6) d 11.55 (s, 1H), 7.81 (dd, J = 7.25, 5.93 Hz, 1 H), 6.91 (m, 2H), 5.94 (d, J = 7.54 Hz, 1 H), 3.85 (m, 3H)
> 80%		Method 2: A solution <strong>[63463-15-0]ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate</strong> D (5 G) and KOH (3 eq) in 60 mL of H2O/ETOH (1: 1) was placed in a sealed vessel (XP-500 Plus vessel) and heated by microwave (MARS 5 Microwave System) at 180C, under 260-280 psi pressure for 50 minutes. The reaction mixture was cooled to room temperature and poured into H20 (100 mL). The solution was acidified with 2 N HCI to PH-6, saturated with NACI and extracted with THF (3X200 mL). The combined oil layers were washed with brine and concentrated to give compound E (>80% yield)
	With potassium hydroxide; In ethanol; water; at 180℃; for 0.833333h;Microwave irradiation;	A solution of compound 28-C (4.2 g) and KOH (3 g, 3 eq. ) in 40 ml of EtOH/H2O (1: 1) was heated by microwave to 180 C for 50 minutes. The mixture was cooled to room temperature, poured into water (100 ml), neutralized with AcOH to pH 7 and saturated with NaCI. The solution was extracted with THF (3 x 300 ml) and concentrated to yield 3.1 g of 7- methoxyquinolin-4-ol 28-D as a solid.

With potassium hydroxide; ethanol; water; at 180℃; for 0.833333h;Irradiation;

A mixture of 3-methoxyaniline (25 g, 204 MMOL) A and diethyl (ETHOXYMETHYLENE) MALONATE (44 g, 204 MMOL) B were heated in an oil bath to 150C for 40 minutes. EtOH was generated when the temperature reached 132 C and collected. The reaction flask was moved away from oil bath and phenyl ether (70 mL) was added into the reaction mixture. The oil bath was preheated to 270 C. The reaction was heated at 270 C (oil bath temperature) for 15 minutes. The reaction mixture was poured slowly into 800 ml of hexane with stirring. Ethyl 4-hydroxy-7-methoxyquinoline-3- carboxylate C was precipitated, filtrated, washed with hexane and dried (28.4 g, 56% yield). A solution of compound C (4. 2G) and KOH (3 G, 3 eq.) in 40 mL of ETOH/H2O (1: 1) was heated by microwave to 180 C for 50 minutes. The mixture was cooled to room temperature, poured into water (100 mL), neutralized with ACOH to pH 7 and saturated with NACI. The solution was extracted with THF (3 x 300 mL) and concentrated to yield 3.1 G of 7-methoxyquinolin-4-ol D as a solid. Compound D (7.4 G) was dissolved in 20 mL of POCI3. The solution was heated to reflux for 2 hours. The excess amount of POCI3 was removed by evaporation under vacuum. The residue was neutralized with NH40H to pH-7 and extracted with EtOAc. The organic layer was concentrated and purified by chromatography on a silica gel column using hexane/ethylacetate (3: 1) to give 6.5 G of 4-chloro-7-methoxyquinoline as E as a yellow solid.

Reference： [1]Patent: WO2005/21553,2005,A1 .Location in patent: Page/Page column 77
[2]Patent: WO2005/21553,2005,A1 .Location in patent: Page/Page column 77
[3]Chemical and Pharmaceutical Bulletin,2007,vol. 55,p. 821 - 824
[4]Journal of Medicinal Chemistry,1998,vol. 41,p. 4918 - 4926
[5]Journal of the American Chemical Society,1946,vol. 68,p. 1268
[6]Patent: WO2005/63739,2005,A1 .Location in patent: Page/Page column 70
[7]Patent: WO2005/21554,2005,A1 .Location in patent: Page/Page column 94-95
[8]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3738 - 3748

13
[ 536-90-3 ]
[ 63463-15-0 ]

Reference： [1]Bioorganic and Medicinal Chemistry Letters,2005,vol. 15,p. 2980 - 2985
[2]Il Farmaco,1998,vol. 53,p. 579 - 585
[3]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3738 - 3748
[4]Patent: US2014/275548,2014,A1
[5]Patent: WO2018/129274,2018,A1

14
[ 87-13-8 ]
[ 63463-15-0 ]

Yield	Reaction Conditions	Operation in experiment
12.4 g (50%)	In diphenylether; ethyl acetate;	?Preparations and[Examples] The present invention is more specifically illustrated with reference to the following preparations and examples. It is to be, however, noted that the present invention is not limited to the preparations and examples. Preparation 1 Preparation of 4-hydroxy-7-methoxyquinoline (1) m-Anisidine (12.3 g, 0.1 mol) is mixed with diethyl ethoxymethylenemalonate (21.6g, 0.1 mol) without solvent and stirred at 110-120 C. for an hour with resulting ethanol being removed. The reactant was dissolved in diphenyl ether (150 ml) and further stirred at 230 C. for 4 hours with resulting ethanol being removed. The reaction mixture was allowed to cool to room temperature and was added with ethyl acetate (300 ml). The resulting precipitates were collected by filtration to obtain 12.4 g (50%) of ethyl 4-hydroxy-7-methoxy-3-quinolinecarboxylate. NMR:delta 1.28(3H, t), 3.87(3H, s), 4.20(2H, q), 7.00(2H, m), 8.05(1H, d), 8.48(1H, s), 12.09(1H, brs)

15
[ 63463-15-0 ]
2-phenyl-7-methoxypyrazoloquinolin-3-one [ No CAS ]

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

16
[ 63463-15-0 ]
2-(4-chloro-phenyl)-7-methoxy-2,5-dihydro-pyrazolo[4,3-<i>c</i>]quinolin-3-one [ No CAS ]

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

17
[ 63463-15-0 ]
[ 68500-37-8 ]

Reference： [1]Journal of Medicinal Chemistry,1998,vol. 41,p. 4918 - 4926
[2]Journal of the American Chemical Society,1946,vol. 68,p. 1268
[3]Bioorganic and Medicinal Chemistry,2013,vol. 21,p. 3738 - 3748
[4]Patent: US5773449,1998,A

18
[ 63463-15-0 ]
[ 7597-09-3 ]