[ CAS No. 145369-94-4 ]

Name: 145369-94-4|6-Bromoquinolin-4-ol|98%
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Quality Control of [ 145369-94-4 ]

COA NMR CNMR HPLC LC-MS

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Product Details of [ 145369-94-4 ]

CAS No. :	145369-94-4	MDL No. :	MFCD00272435
Formula :	C₉H₆BrNO	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	-
M.W :	224.05	Pubchem ID :	-
Synonyms :

Calculated chemistry of [ 145369-94-4 ]

Physicochemical Properties

Num. heavy atoms :	12
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	1.0
Num. H-bond donors :	1.0
Molar Refractivity :	52.27
TPSA :	32.86 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) :	-6.77 cm/s

Lipophilicity

Log Po/w (iLOGP) :	1.79
Log Po/w (XLOGP3) :	1.27
Log Po/w (WLOGP) :	2.29
Log Po/w (MLOGP) :	1.56
Log Po/w (SILICOS-IT) :	3.26
Consensus Log Po/w :	2.03

Druglikeness

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

Water Solubility

Log S (ESOL) :	-2.65
Solubility :	0.506 mg/ml ; 0.00226 mol/l
Class :	Soluble
Log S (Ali) :	-1.56
Solubility :	6.18 mg/ml ; 0.0276 mol/l
Class :	Very soluble
Log S (SILICOS-IT) :	-4.47
Solubility :	0.00764 mg/ml ; 0.0000341 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	1.0
Synthetic accessibility :	1.56

Safety of [ 145369-94-4 ]

Signal Word:	Warning	Class:	N/A
Precautionary Statements:	P261-P280-P305+P351+P338	UN#:	N/A
Hazard Statements:	H302-H315-H319-H332-H335	Packing Group:	N/A
GHS Pictogram:

Application In Synthesis of [ 145369-94-4 ]

* 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 [ 145369-94-4 ]
Downstream synthetic route of [ 145369-94-4 ]

[ 145369-94-4 ] Synthesis Path-Upstream 1~18

1
[ 187278-01-9 ]
[ 145369-94-4 ]

Yield	Reaction Conditions	Operation in experiment
87%	at 0 - 188℃; for 6.5 h;	A mixture of 5-(((4-bromophenyl)amino )methylene)-2,2-dimethyl-1 ,3-dioxane-4, 6-dione (50 g, 154 mmol) in 1,2-dichlorobenzene (500 mL) was stirred at 188°C for 3.5 h. Thereaction was then cooled down to 0°C and stirred further for 3 h. The solid was collected byfiltration, and was then washed with methyl tert-butyl ether (100 mL) to give the title compoundas a brown solid (30.6 g, 87percent). The title compound was characterized by LC-MS and 1H NMRas shown below:LC-MS (ESI, pos. ion) m/z: 224 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 6.32 (d, J= 7.32 Hz, 1H), 7.48 (d, J= 9.08 Hz, 1H), 7.77(dd, J= 8.88 Hz, 2.32 Hz, 1H), 7.95 (d, J = 7.32 Hz, 1H), 8.34 (d, J = 2.28 Hz, 1H).
87%	at 188℃; for 3.5 h;	The 5 - (( (4-bromophenyl) amino) methylene) - 2,2-dimethyl -1,3-dioxane -4,6-dione (50g, 154mmol) in 1,2-dichlorobenzene (500 ml) solution is heated to 188 °C, stirring for 3.5 hours, cooling to 0 °C, continue to stir 3 hours. Filtering, collecting solid, solid after armoruncle ether (100 ml) eluting, to obtain the title compound as brown solid (30.6g, 87percent).
29.9 g	at 190℃; for 0.25 h;	Diphenyl ether (519.9 g, 3.064 mol)Add to a 1000 mL three-necked flask,Preheat to 190 ° C,Compound 2a (50.1 g, 0.153 mol) was added slowly,Reaction for 15 min.TLC detection [V (dichloromethane): V (methanol) = 15:1] reaction junctionbundle,cool down,The reaction solution was poured into 600 mL of petroleum ether and stirred.Precipitating solids,Filtering,dry,Made a grayish yellow solid 29.9g,

Reference： [1] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0144; 0145; 0154
[2] Patent: CN103539777, 2016, B, . Location in patent: Paragraph 0276; 0319; 0320
[3] Archiv der Pharmazie, 2018, vol. 351, # 6,
[4] Molecules, 2018, vol. 23, # 7,
[5] Patent: CN108456165, 2018, A, . Location in patent: Paragraph 0047; 0077-0078

2
[ 98948-95-9 ]
[ 145369-94-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	for 9 h; Heating / reflux	The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. After cooling to room temperature, the mixture was diluted with methanol (20 mL) and diethyl ether (300 mL). Then, the solids were collected by filtration and washed with diethyl ether. After drying in air, 72.43 g (95percent yield) of 6-bromo-quinolin-4-ol was isolated as a white solid: EI-HRMS m/e calcd for C₉H₆BrNO (M⁺) 222.9633, found 222.9630.
90%	for 0.5 h; Reflux	. Deprotection and removal of the carboxylic acid
90%	for 0.5 h; Reflux	10558] The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of the carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5. Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to yield compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in removal of an acetyl group.

77%

at 260℃; for 2 h;

4.1.7
6-Bromoquinolin-4-ol (10)
6-Bromo-4-hydroxyquinoline-3-carboxylic acid (9) (5.0 g, 18.73 mmol) was added to a 100 mL round-bottomed flask in Ph₂O (30 mL) and then stirred at 260 °C for 2 h.
After cooling to 60 °C, 30 mL petroleum ether was added and the suspended solid was filtered, washed with petroleum ether, EtOAc and dried under reduced pressure to give the title compound (3.21 g, 14.39 mmol, 77percent yield) as a brown solid. ESI-MS: m/z = 224 [M+H]⁺.

Reference： [1] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[2] Patent: US2006/63805, 2006, A1, . Location in patent: Page/Page column 9
[3] Patent: WO2012/116237, 2012, A2, . Location in patent: Page/Page column 120
[4] Patent: US2015/320727, 2015, A1, . Location in patent: Paragraph 0557; 0558
[5] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[6] Journal of the Chemical Society, 1950, p. 384,389
[7] Tetrahedron Letters, 2008, vol. 49, # 19, p. 3137 - 3141
[8] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[9] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 77
[10] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 365; 366
[11] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 44-45

3
[ 76228-06-3 ]
[ 145369-94-4 ]

Yield	Reaction Conditions	Operation in experiment
86%	Stage #1: With sulfuric acid In acetonitrile for 0.333333 h; Stage #2: With potassium permanganate In acetonitrile at 85℃; for 5 h;	Add 6-bromo-4-oxo-2,3-dihydroquinoline (0.01 mol) to a 25 ml reaction flask, add 15 ml of acetonitrile, concentrated sulfuric acid (0.02 mol), stir for 20 minutes, and slowly add potassium permanganate. (0.02 mol), the reaction was stirred at 85 ° C, the progress of the reaction was monitored by TLC, and the reaction was stopped after 5 hours. After the reaction solution is cooled to room temperature, it is poured into 50 ml of water, stirred and filtered to obtain a crude product of 6-bromo-4-hydroxyquinoline, which is separated by silica gel column chromatography (column chromatography silica gel 100-200 mesh, eluent oil) Ether: ethyl acetate = 1:4). The eluent was concentrated to give the product. The yield was 86percent, and the purity was 96percent

Reference： [1] Patent: CN108794396, 2018, A, . Location in patent: Paragraph 0019

4
[ 1551219-53-4 ]
[ 145369-94-4 ]

Yield	Reaction Conditions	Operation in experiment
83.5%	at 220℃; for 0.0833333 h;	Compound 1g (47.9 mmol, 10 g) was dissolved in diphenyl oxide and heated to 220 ℃ for 5 min. After cooling, the precipitated solid was filtered and washed with petroleum ether. Yield 83.5percent. HPLC purity: 96.7percent.

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 799 - 807

5
[ 106-40-1 ]
[ 145369-94-4 ]

Reference： [1] Journal of the Chemical Society, 1950, p. 384,389
[2] Patent: WO2012/116237, 2012, A2,
[3] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 799 - 807
[4] Patent: WO2014/22128, 2014, A1,
[5] Patent: WO2014/151147, 2014, A1,
[6] Patent: US2015/30588, 2015, A1,
[7] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[8] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[9] Patent: US2015/320727, 2015, A1,
[10] Patent: US9295673, 2016, B2,
[11] Patent: CN103539777, 2016, B,
[12] Molecules, 2018, vol. 23, # 7,
[13] Patent: WO2006/132739, 2006, A2,

6
[ 10174-70-6 ]
[ 145369-94-4 ]

Reference： [1] Patent: US5153196, 1992, A,

7
[ 2033-24-1 ]
[ 106-40-1 ]
[ 145369-94-4 ]

Reference： [1] Journal of Organic Chemistry, 2007, vol. 72, # 6, p. 2232 - 2235

8
[ 122794-99-4 ]
[ 145369-94-4 ]

Reference： [1] Journal of the Chemical Society, 1950, p. 384,389
[2] Patent: WO2012/116237, 2012, A2,
[3] Patent: WO2014/151147, 2014, A1,
[4] Patent: US2015/30588, 2015, A1,
[5] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[6] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[7] Patent: US2015/320727, 2015, A1,
[8] Patent: US9295673, 2016, B2,
[9] Patent: WO2006/132739, 2006, A2,

9
[ 101937-44-4 ]
[ 145369-94-4 ]

Reference： [1] Journal of the Chemical Society, 1950, p. 384,389
[2] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[3] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50

10
[ 145369-94-4 ]
[ 65340-70-7 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	for 6 h; Heating / reflux	The solid 6-bromo-quinolin-4-ol (52 g, 232.1 mmol) was added to phosphorus oxychloride (213.5 mL) and then the mixture was heated to reflux for 6 h to afford a light brown solution. After cooling to room temperature, the excess phosphorus oxychloride was removed under the vacuum. The remaining residue was poured into an ice-containing beaker (2 L). Then, it was slowly neutralized with solid potassium carbonate and the resulting solids were collected by filtration and washed with water. After drying in air, 55.46 g (98.5percent yield) of 6-bromo-4-chloro-quinoline was isolated as a light yellow solid: EI-HRMS m/e calcd for C₉H₅BrClN (M+) 240.9294, found 240.9297.
93%	for 1.5 h; Reflux	10558] The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of the carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5. Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to yield compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in removal of an acetyl group.
84%	With trichlorophosphate In N,N-dimethyl-formamide at 120℃; for 5 h;	4.1.8 6-Bromo-4-chloroquinoline (11) To a 100 mL round-bottomed flask was added 6-bromoquinolin-4-ol (10) (3.0 g, 13.45 mmol), POCl₃ (20 mL) and DMF (0.5 mL). The mixture was stirred at reflux for 6 h. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL) and stirred for 1 h. Then the pH of the mixture was adjusted to 8 using saturated aqueous NaHCO₃. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (2.75 g, 11.36 mmol, 84percent yield) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.87 (d, J = 4.5 Hz, 1H, Ar-H), 8.32 (d, J = 2.0 Hz, 1H, Ar-H), 8.03 (d, J = 9.0 Hz, 1H, Ar-H), 7.99 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.82 (d, J = 4.5 Hz, 1H, Ar-H). ESI-MS: m/z = 242 [M+H]⁺.

84%	Stage #1: Heating / reflux	6-Bromo-4-chloroquinoline. The solution of the compound from Example 17b (2 g, 8.9 mmol) in POCI₃ (10 mL) was refluxed overnight, cooled and quenched by ice water. The precipitate was collected, washed with H₂O and dried in vacuo to afford the title compound as a grey solid (1.8 g, 84percent). 1 H NMR (400 MHz, DMSO-CZ₆) δ ppm 8.90 (d, J=4.80 Hz, 1 H) 8.37 (d, J=2.02 Hz, 1 H) 8.07 (d, J=8.59 Hz, 1 H) 8.03 (dd, J=8.84, 2.02 Hz, 1 H) 7.86 (d, J=4.55 Hz, 1 H).
32%	With trichlorophosphate In toluene at 115℃; for 4 h;	To a suspension of 6-bromo-4-hydroxyquinolin (14.55 g, 64.9 mmol) in toluene (20mL) was added POCh (6.05 mL, 64.9 mmol) slowly. The reaction was stirred at 115°C for 4 h,then cooled down to 0°C and diluted with DCM (400 mL). The mixture was washed with 4MNaOH (70 mL) followed by brine (100 mL), dried over anhydrous Na2S04 and concentrated invacuo. The residue was recrystallized in n-heptane (150 mL) to give the title compound as ayellow solid (5.5 g, 32percent). The title compound was characterized by LC-MS and 1H NMR asshown below:LC-MS (ESI, pos. ion) m/z: 242 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.50 (d, J= 4.72 Hz, 1H), 7.82 (dd, J= 8.96 Hz, 2.16 Hz,1H), 7.98 (d, J= 8.92 Hz, 1H), 7.95 (d, J= 2.16 Hz, 1H), 8.34 (d, J= 4.68 Hz, 1H).
32%	With trichlorophosphate In toluene at 115℃; for 4 h;	To 6-bromo-4-hydroxyquinoline (14.55g, 64 . 9mmol) toluene (20 ml) is slowly added in solution POCl ₃ (6.05 ml, 64 . 9mmol). responds the fluid in 115 °C stirring 4 hours, cooling to 0 °C, and added DCM (400 ml) dilution. The resulting mixed solution for sequentially 4MNaOH aqueous solution (70 ml) and the brine (100 ml) washing, anhydrous Na ₂ SO ₄ drying, and concentrated under reduced pressure. In normal heptane of the residue (150 ml) is recrystallized in, to obtain the title compound as yellow solid (5.5g, 32percent).

Reference： [1] Patent: US2006/63805, 2006, A1, . Location in patent: Page/Page column 9
[2] ChemMedChem, 2015, vol. 10, # 5, p. 836 - 849
[3] Patent: US2015/320727, 2015, A1, . Location in patent: Paragraph 0557; 0558
[4] European Journal of Medicinal Chemistry, 2015, vol. 99, p. 36 - 50
[5] Patent: WO2006/132739, 2006, A2, . Location in patent: Page/Page column 48
[6] Patent: WO2014/22128, 2014, A1, . Location in patent: Paragraph 0144; 0145; 0155
[7] Patent: CN103539777, 2016, B, . Location in patent: Paragraph 0276; 0323; 0324
[8] Journal of the Chemical Society, 1950, p. 384,389
[9] Patent: WO2012/116237, 2012, A2, . Location in patent: Page/Page column 120
[10] Patent: WO2011/84402, 2011, A1, . Location in patent: Page/Page column 144-145
[11] European Journal of Medicinal Chemistry, 2014, vol. 75, p. 96 - 105
[12] Journal of the Brazilian Chemical Society, 2014, vol. 25, # 5, p. 980 - 986
[13] Patent: WO2014/151147, 2014, A1, . Location in patent: Paragraph 00641
[14] Patent: US2015/30588, 2015, A1, . Location in patent: Page/Page column 77; 78
[15] Patent: US9295673, 2016, B2, . Location in patent: Page/Page column 366

11
[ 145369-94-4 ]
[ 65340-70-7 ]

Yield	Reaction Conditions	Operation in experiment
92.6%	With phosphorus trichloride In toluene for 2 h; Reflux	willL0g (44.63 mol) of 6-bromoquinolin-4 (1H) -one, 100 ml of toluene and 12.25 g (89.26 mol) of phosphorus trichloride were added to a 250 ml three-necked flask and heated to reflux for 2 hours. , Dried and dried. The solid was beaten with ether (100 ml), filtered and dried to give a yellow powder (yield 92.6percent).
85%	for 3 h; Heating / reflux	Diphenyl ether (80 ml) was added to 4-bromoaniline (4.5 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxan-4,6-dione (5.4 g), and the mixture was stirred at 80°C for one hr. Biphenyl (24.2 g) was added thereto, and the mixture was stirred at 220°C for 3 hr. The reaction mixture was cooled to room temperature, and diethyl ether was added to the cooled mixture. The precipitated crystal was collected by filtration and was washed with diethyl ether. The residue was purified by column chromatography with a hexane-acetone system to give 6-bromoquinolone (1.57 g, yield 27percent). Thionyl chloride (5 ml) and a minor amount of dimethylformamide were added to 6-bromoquinolone (1.6 g), and the mixture was stirred under reflux for 3 hr. The reaction mixture was added to a saturated aqueous sodium bicarbonate solution under ice cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography with a hexane-ethyl acetate system to give 6-bromo-4-chloroquinoline (1.43 g, yield 85percent).
70%	With trichlorophosphate In N,N-dimethyl-formamide for 2 h; Reflux	A mixture of 4 (17.0 g, 131.5 mmol), POCl₃ (180 mL) and anhydrous DMF (18 mL) was stirred and heated at reflux for 2 h. After removal of POCl₃, the residue was poured into ice water and extracted with EtOAc. The combined organic layers were washed with saturated aqueous NaHCO₃, brine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (4:1 hexanes/EtOAc) to afford 5 (12.8 g, 70percent) as a white solid, mp 111-112 °C (lit³¹ 111-112 °C). ¹H NMR (CDCl₃) δ 8.79 (d, J = 5.0 Hz, 1H, Ar-H), 8.40 (d, J = 2.5 Hz, 1H, Ar-H), 8.00 (d, J = 9.0 Hz, 1H, Ar-H), 7.84 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.52 (d, J = 5.0 Hz, 1H, Ar-H).

Reference： [1] Journal of Medicinal Chemistry, 2015, vol. 58, # 14, p. 5522 - 5537
[2] Patent: CN106432073, 2017, A, . Location in patent: Paragraph 0026; 0027; 0036; 0037; 0045; 0046; 0056; 0057
[3] Patent: EP1724268, 2006, A1, . Location in patent: Page/Page column 41-42
[4] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574

12
[ 145369-94-4 ]
[ 853908-50-6 ]

Yield	Reaction Conditions	Operation in experiment
64.5%	for 2 h;	Synthesis of Compound 3a (29.0 g, 0.130 mol)Add to a 500 mL three-necked flask,Heat and stir until dissolved.Further, a mixture of nitric acid (40.95 g, 0.650 mol) and propionic acid (10 mL) was slowly added dropwise to the reaction flask.After the addition is completed, the reaction is further carried out for 2 hours.TLC detection [V (dichloromethane): V (methanol) = 15:1] The reaction was completed, cooled, filtered,The filter residue is added to the ice saturated sodium bicarbonate solution and stirred.Filtered,The residue is dry,The compound was obtained as a yellow solid (26.0 g, yield: 64.5percent).
50.2%	With nitric acid In propionic acid at 125℃; for 2 h;	The solution of compound 2g (20 mmol, 4.48 g) in propionic acid (30 mL) was heated to 125 ℃ and the mixture of nitric acid (0.89 mL) and propionic acid (6.27 mL) was added dropwise for 1 h. Then the mixture was reacted for 1 h and precipitated by petroleum ether. The solid was filtered and washed with diethyl ether. Yield 50.2percent. HPLC purity: 98.1percent.

Reference： [1] Patent: CN108456165, 2018, A, . Location in patent: Paragraph 0047; 0079-0080
[2] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 799 - 807
[3] Archiv der Pharmazie, 2018, vol. 351, # 6,
[4] Molecules, 2018, vol. 23, # 7,

13
[ 145369-94-4 ]
[ 723281-72-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 3, p. 799 - 807
[2] Molecules, 2018, vol. 23, # 7,
[3] Archiv der Pharmazie, 2018, vol. 351, # 6,
[4] Patent: CN108456165, 2018, A,

14
[ 145369-94-4 ]
[ 874792-20-8 ]

Reference： [1] Patent: WO2011/84402, 2011, A1,

15
[ 145369-94-4 ]
[ 916812-31-2 ]

Reference： [1] Patent: WO2006/132739, 2006, A2,

16
[ 145369-94-4 ]
[ 927801-23-8 ]

Reference： [1] Patent: WO2014/22128, 2014, A1,
[2] Patent: CN103539777, 2016, B,

17
[ 145369-94-4 ]
[ 927801-23-8 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574

18
[ 145369-94-4 ]
[ 1086062-66-9 ]

Reference： [1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 4, p. 1569 - 1574

[ 145369-94-4 ] Synthesis Path-Downstream 1~68

1
[ 145369-94-4 ]
[ 65340-70-7 ]

Yield	Reaction Conditions	Operation in experiment
98.5%	With trichlorophosphate; for 6h;Heating / reflux;	The solid <strong>[145369-94-4]6-bromo-quinolin-4-ol</strong> (52 g, 232.1 mmol) was added to phosphorus oxychloride (213.5 mL) and then the mixture was heated to reflux for 6 h to afford a light brown solution. After cooling to room temperature, the excess phosphorus oxychloride was removed under the vacuum. The remaining residue was poured into an ice-containing beaker (2 L). Then, it was slowly neutralized with solid potassium carbonate and the resulting solids were collected by filtration and washed with water. After drying in air, 55.46 g (98.5% yield) of 6-bromo-4-chloro-quinoline was isolated as a light yellow solid: EI-HRMS m/e calcd for C9H5BrClN (M+) 240.9294, found 240.9297.
93%	With trichlorophosphate; for 1.5h;Reflux;	10558] The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of the carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5. Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to yield compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in removal of an acetyl group.
84%	With trichlorophosphate; In N,N-dimethyl-formamide; at 120℃; for 5h;	4.1.8 6-Bromo-4-chloroquinoline (11) To a 100 mL round-bottomed flask was added <strong>[145369-94-4]6-bromoquinolin-4-ol</strong> (10) (3.0 g, 13.45 mmol), POCl3 (20 mL) and DMF (0.5 mL). The mixture was stirred at reflux for 6 h. After cooling to room temperature, the reaction mixture was poured into ice water (100 mL) and stirred for 1 h. Then the pH of the mixture was adjusted to 8 using saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to give the title compound (2.75 g, 11.36 mmol, 84% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) delta 8.87 (d, J = 4.5 Hz, 1H, Ar-H), 8.32 (d, J = 2.0 Hz, 1H, Ar-H), 8.03 (d, J = 9.0 Hz, 1H, Ar-H), 7.99 (dd, J = 9.0, 2.0 Hz, 1H, Ar-H), 7.82 (d, J = 4.5 Hz, 1H, Ar-H). ESI-MS: m/z = 242 [M+H]+.

84%		6-Bromo-4-chloroquinoline. The solution of the compound from Example 17b (2 g, 8.9 mmol) in POCI3 (10 mL) was refluxed overnight, cooled and quenched by ice water. The precipitate was collected, washed with H2O and dried in vacuo to afford the title compound as a grey solid (1.8 g, 84%). 1 H NMR (400 MHz, DMSO-CZ6) delta ppm 8.90 (d, J=4.80 Hz, 1 H) 8.37 (d, J=2.02 Hz, 1 H) 8.07 (d, J=8.59 Hz, 1 H) 8.03 (dd, J=8.84, 2.02 Hz, 1 H) 7.86 (d, J=4.55 Hz, 1 H).
32%	With trichlorophosphate; In toluene; at 115℃; for 4h;	To a suspension of <strong>[145369-94-4]6-bromo-4-hydroxyquinolin</strong> (14.55 g, 64.9 mmol) in toluene (20mL) was added POCh (6.05 mL, 64.9 mmol) slowly. The reaction was stirred at 115C for 4 h,then cooled down to 0C and diluted with DCM (400 mL). The mixture was washed with 4MNaOH (70 mL) followed by brine (100 mL), dried over anhydrous Na2S04 and concentrated invacuo. The residue was recrystallized in n-heptane (150 mL) to give the title compound as ayellow solid (5.5 g, 32%). The title compound was characterized by LC-MS and 1H NMR asshown below:LC-MS (ESI, pos. ion) m/z: 242 [M+Ht;1H NMR (400 MHz, CDCh) 8 (ppm): 7.50 (d, J= 4.72 Hz, 1H), 7.82 (dd, J= 8.96 Hz, 2.16 Hz,1H), 7.98 (d, J= 8.92 Hz, 1H), 7.95 (d, J= 2.16 Hz, 1H), 8.34 (d, J= 4.68 Hz, 1H).
32%	With trichlorophosphate; In toluene; at 115℃; for 4h;	To <strong>[145369-94-4]<strong>[145369-94-4]6-bromo-4-hydroxyquinolin</strong>e</strong> (14.55g, 64 . 9mmol) toluene (20 ml) is slowly added in solution POCl 3 (6.05 ml, 64 . 9mmol). responds the fluid in 115 C stirring 4 hours, cooling to 0 C, and added DCM (400 ml) dilution. The resulting mixed solution for sequentially 4MNaOH aqueous solution (70 ml) and the brine (100 ml) washing, anhydrous Na 2 SO 4 drying, and concentrated under reduced pressure. In normal heptane of the residue (150 ml) is recrystallized in, to obtain the title compound as yellow solid (5.5g, 32%).
	With trichlorophosphate; for 1.5h;Reflux;	followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5
	With trichlorophosphate; at 20℃; for 19h;	A 20 mL scintillation vial was charged with <strong>[145369-94-4]6-bromoquinolin-4-ol</strong> (0.98 g, 4.4 mmol) and phosphorus (V) oxychloride (10 mL). The reaction mixture was stirred for 19 hours at ambient temperature and carefully poured into a mixture of saturated aqueous sodium bicarbonate solution and ice, extracted into ethyl acetate (3x), washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (MPLC, 0-50% EtOAc-hexanes) to give 4-chloro-5-bromoquinoline.LRMS (ESI) calc'd for C9H6BrClN [M+H : 242, Found: 242.
	With trichlorophosphate; In N,N-dimethyl-formamide; for 6h;Reflux; Inert atmosphere;	General procedure: To a mixture of 6-bromo-4-hydroxyquinazoline (7.9 g,35.1 mmol) in POCl3 (60 ml) was added DMF (1 ml). Then themixture was heated to reflux under N2 for 6 h. The dark clear solutionwas cooled to room temperature and concentrated in vacuumto produce a brown solid. To the mixture of above brown solidin 2-propanol (150 ml) was added morpholine (12.2 ml,140.5 mmol). Then the mixture was heated to reflux under N2 for1 h, concentrated in vacuum to give a residue which was dissolvedin ethyl acetate (200 ml). The ethyl acetate solution was washedwith brine (80 ml 5), dried over Na2SO4 and concentrated to give abrown oil, which was solidified on keeping to produce 6a (8.9 g).

Reference： [1]Patent: US2006/63805,2006,A1 .Location in patent: Page/Page column 9
[2]ChemMedChem,2015,vol. 10,p. 836 - 849
[3]Patent: US2015/320727,2015,A1 .Location in patent: Paragraph 0557; 0558
[4]European Journal of Medicinal Chemistry,2015,vol. 99,p. 36 - 50
[5]Patent: WO2006/132739,2006,A2 .Location in patent: Page/Page column 48
[6]Patent: WO2014/22128,2014,A1 .Location in patent: Paragraph 0144; 0145; 0155
[7]Patent: CN103539777,2016,B .Location in patent: Paragraph 0276; 0323; 0324
[8]Journal of the Chemical Society,1950,p. 384,389
[9]Patent: WO2012/116237,2012,A2 .Location in patent: Page/Page column 120
[10]Patent: WO2011/84402,2011,A1 .Location in patent: Page/Page column 144-145
[11]European Journal of Medicinal Chemistry,2014,vol. 75,p. 96 - 105
[12]Journal of the Brazilian Chemical Society,2014,vol. 25,p. 980 - 986
[13]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[14]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 77; 78
[15]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 366

2
[ 145369-94-4 ]
[ 857762-32-4 ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389

3
[ 145369-94-4 ]
[ 857758-88-4 ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389

4
[ 98948-95-9 ]
[ 145369-94-4 ]

Yield	Reaction Conditions	Operation in experiment
95%	In diphenylether; for 9h;Heating / reflux;	The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. After cooling to room temperature, the mixture was diluted with methanol (20 mL) and diethyl ether (300 mL). Then, the solids were collected by filtration and washed with diethyl ether. After drying in air, 72.43 g (95% yield) of 6-bromo-quinolin-4-ol was isolated as a white solid: EI-HRMS m/e calcd for C9H6BrNO (M+) 222.9633, found 222.9630.
90%	for 0.5h;Reflux;	. Deprotection and removal of the carboxylic acid
90%	for 0.5h;Reflux;	10558] The bicyclic compound 3-2 is prepared from bromoaniline 3-1 using diethyl 2-(ethoxymethylene)malonate or a similar reagent. Deprotection and removal of the carboxylic acid, followed by halogenation using a reagent such as phosphorus oxychloride yields compound 3-5. Derivatization with pyridine boronate in Suzuki coupling conditions yields 3-6, which is reacted in a second Suzuki reaction with a benzothiazolyl boronate to yield compound 3-7. Subsequent heating in hydrochloric acid in a solvent such as methanol results in removal of an acetyl group.

77%	In diphenylether; at 260℃; for 2h;	4.1.7 6-Bromoquinolin-4-ol (10) 6-Bromo-4-hydroxyquinoline-3-carboxylic acid (9) (5.0 g, 18.73 mmol) was added to a 100 mL round-bottomed flask in Ph2O (30 mL) and then stirred at 260 C for 2 h. After cooling to 60 C, 30 mL petroleum ether was added and the suspended solid was filtered, washed with petroleum ether, EtOAc and dried under reduced pressure to give the title compound (3.21 g, 14.39 mmol, 77% yield) as a brown solid. ESI-MS: m/z = 224 [M+H]+.
	In diphenylether; for 2h;Heating / reflux;	6-Bromo-4-quinolinol. The mixture of the compound from Example 17a) (2 g, 6.8 mmol) in NaOH ( 6 N, 100 mL) was refluxed overnight, cooled and filtered. The filtrate was acidified. The precipitate was collected and refluxed in phenyl ether EPO <DP n="46"/>for two hours. The product was cooled, then petroleum ether was added until precipitate appeared. The precipitate was collected, washed with petroleum ether and dried over vacuo to afford the title compound as a white solid (1.2 g, 85%). 1 H NMR (400 MHz, DMSOd6) delta ppm 12.06 (br. s., 1 H) 8.16 (d, J=2.27 Hz, 1 H) 7.90 - 8.02 (m, 1 H) 7.79 (dd, J=8.84, 2.53 Hz, 1 H) 7.55 (d, J=8.84 Hz,1 H) 6.08 (d, J=7.33 Hz, 1 H).

Reference： [1]ChemMedChem,2015,vol. 10,p. 836 - 849
[2]Patent: US2006/63805,2006,A1 .Location in patent: Page/Page column 9
[3]Patent: WO2012/116237,2012,A2 .Location in patent: Page/Page column 120
[4]Patent: US2015/320727,2015,A1 .Location in patent: Paragraph 0557; 0558
[5]European Journal of Medicinal Chemistry,2015,vol. 99,p. 36 - 50
[6]Journal of the Chemical Society,1950,p. 384,389
[7]Tetrahedron Letters,2008,vol. 49,p. 3137 - 3141
[8]Patent: WO2014/151147,2014,A1 .Location in patent: Paragraph 00641
[9]Patent: US2015/30588,2015,A1 .Location in patent: Page/Page column 77
[10]Patent: US9295673,2016,B2 .Location in patent: Page/Page column 365; 366
[11]Patent: WO2006/132739,2006,A2 .Location in patent: Page/Page column 44-45

5
[ 2033-24-1 ]
[ 106-40-1 ]
[ 145369-94-4 ]

Reference： [1]Journal of Organic Chemistry,2007,vol. 72,p. 2232 - 2235

6
[ 145369-94-4 ]
6-bromo-3,4-dichloroquinoline [ No CAS ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389

7
[ 145369-94-4 ]
3,6-dibromo-4-chloro-quinoline [ No CAS ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389

8
[ 122794-99-4 ]
[ 145369-94-4 ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389
[2]Patent: WO2012/116237,2012,A2
[3]Patent: WO2014/151147,2014,A1
[4]Patent: US2015/30588,2015,A1
[5]ChemMedChem,2015,vol. 10,p. 836 - 849
[6]European Journal of Medicinal Chemistry,2015,vol. 99,p. 36 - 50
[7]Patent: US2015/320727,2015,A1
[8]Patent: US9295673,2016,B2
[9]Patent: WO2006/132739,2006,A2

9
[ 101937-44-4 ]
[ 145369-94-4 ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389
[2]ChemMedChem,2015,vol. 10,p. 836 - 849
[3]European Journal of Medicinal Chemistry,2015,vol. 99,p. 36 - 50

10
[ 106-40-1 ]
[ 145369-94-4 ]

Reference： [1]Journal of the Chemical Society,1950,p. 384,389
[2]Patent: WO2012/116237,2012,A2
[3]Bioorganic and Medicinal Chemistry Letters,2014,vol. 24,p. 799 - 807
[4]Patent: WO2014/22128,2014,A1
[5]Patent: WO2014/151147,2014,A1
[6]Patent: US2015/30588,2015,A1
[7]ChemMedChem,2015,vol. 10,p. 836 - 849
[8]European Journal of Medicinal Chemistry,2015,vol. 99,p. 36 - 50
[9]Patent: US2015/320727,2015,A1
[10]Patent: US9295673,2016,B2
[11]Patent: CN103539777,2016,B
[12]Molecules,2018,vol. 23
[13]Patent: WO2006/132739,2006,A2
[14]Patent: WO2019/229765,2019,A1

11
[ 474706-57-5 ]
[ 145369-94-4 ]
[ 474707-37-4 ]

Yield	Reaction Conditions	Operation in experiment
	With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In ethanol; toluene; for 6h;Heating / reflux;	Production Example 90 6-(3-Methyl-1-trityl-1H-4-pyrazolyl)-4-quinolinol While a mixture of 1.79 g <strong>[145369-94-4]6-bromo-4-quinolinol</strong>, 3.83 g 3-methyl-1H-4-pyrazolylboronic acid, 4.8 g sodium carbonate, 30 ML toluene and 60 ML ethanol was stirred in a stream of nitrogen, 280 mg tetrakis (triphenylphosphine) palladium was added thereto, and then this mixture was heated for 6 hours under reflux in a stream of nitrogen.. The reaction solution was cooled to room temperature, then ethyl acetate and water were added, and the organic layer was separated.. The organic layer was evaporated, and methanol and toluene were added to the residues which were then subjected to azeotropic distillation, ethyl acetate was added thereto, and the resulting crystals were collected.. The crystals were dried in hot air at 60C for 20 hours, whereby 3.14 g of the title compound was obtained as pale reddish brown crystals.1H-NMR (CDCl3) delta: 2.40(s, 3H), 6.26(d, J=7.2Hz, 1H), 7.20(m, 7H), 7.30(m, 9H), 7.49(m, 2H), 7.59(dd, J=8.8, 2.0Hz, 1H), 8.30(d, J=2.0Hz, 1H), 9.95(brs, 1H)

Reference： [1]Patent: EP1382603,2004,A1 .Location in patent: Page 74

12
[ 145369-94-4 ]
[ 126747-14-6 ]
C₁₆H₁₀N₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
75%	With potassium carbonate;tetrakis(triphenylphosphine) palladium(0); In acetonitrile; at 160℃; for 0.1h;Microwave irradiation;	Example 2; Synthesis of (104); Step A; Synthesis of (105); [0180] A mixture of <strong>[145369-94-4]<strong>[145369-94-4]6-bromo-4-hydroxyquinolin</strong>e</strong> (224 mg, 1 mmol) and 4- cyanophenylboronic acid (282 mg, 2 mmol) were dissolved in acetonitrile (8 mL), followed by addition of 1M aqueous K2C03 (4 mL) and tetrakis(triphenylphosphine) palladium(0) (10 mg, 0.009 mmol). The reaction mixture was irradiated in a microwave oven (max. power 250W, 160 C) for 6 min, cooled to room temperature, and then concentrated in vacuo. Water was added to the resulting residue and the mixture was extracted with EtOAc. The aqueous layer was adjusted to pH 7 with 0.5M aqueous HCI, at which time the product precipitated from the mixture. The resulting solid was filtered, washed with water, and dried in vacuo to provide 105 (185 mg, 75%) as a grey powder.

Reference： [1]Patent: WO2005/120509,2005,A1 .Location in patent: Page/Page column 56-57

13
[ 10174-70-6 ]
[ 145369-94-4 ]

Yield	Reaction Conditions	Operation in experiment
	In mineral oil;	The 2-carboxy-4-hydroxy-6-bromoquinoline (5.42 g, 20 mmol) was slurried in 250 ml of light mineral oil and heated to 270-295 C. for 10-15 minutes. The mixture was allowed to cool overnight, diluted with chloroform and filtered, and then washed with adequate amounts of chloroform, yielding 6-bromo-4-hydroxyquinoline.

Reference： [1]Patent: US5153196,1992,A

14
[ 145369-94-4 ]
C₉H₅BrNO^(1-)*Na⁽¹⁺⁾ [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With sodium hydride; In tetrahydrofuran; at 0℃; for 0.5h;	c) 4-Hydroxy-6-quinolinecarbaldehyde. Sodium hydride (60% dispersion in mineral oil, 36 mg, 0.89 mmol) was added to the solution of the compound from Example 17b) (200 mg, 0.89 mmol) in THF (5 mL) at 0 0C. The mixture was kept stirring at O0C for half hour and then cooled to -780C. N-butyl lithium (1.6 M in hexane, 0.55 mL, 0.89 mmol) was added dropwise. After half hour, DMF (69 mul_, 0.89 mmol) was added. The product was let to raise the ambient temperature, quenched by saturated NH4CI solution and extracted with ethyl acetate. The extract was dried over magnesium sulfate, concentrated in vacuo and purified via flash column chromatography (0-100% ethyl acetate in hexanes) to give the title compound as a white solid (40 mg, 28%). MS(ES+) m/e 174 [M+H]+.

Reference： [1]Patent: WO2006/132739,2006,A2 .Location in patent: Page/Page column 45

15
[ 145369-94-4 ]
6-bromo-3-iodoquinolin-4-ol [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
45%	With iodine; potassium iodide; sodium hydroxide; In water; at 20℃; for 3h;	Compound 64 (0.5g, 2.23mmol) was dissolved in 2(N) NaOH solution (lOmL). I2 (0.34g, 2.7mmol) in 20% KI solution in H20 (lOmL) was added dropwise to the mixture and allowed to stir for 3 hours at room temperature. The reaction mixture was acidified with AcOH. The solid obtained was filtered and washed several times with water to give compound 65 (0.35g, 45%) as a grey solid. NMR (300 MHz, CDCl3) d ppm 7.76 (d, / = 8.7 Hz, 1H), 7.62 (d, / = 9 Hz, 1H), 7.51 (s, 1H), 7.41 (d, / = 5.4 Hz, 1H). ESI-MS m/z 371.89 (M+H+).
	With N-iodo-succinimide; In acetic acid; at 50℃; for 1h;	6-Bromoquinolin-4-ol (2.15 g, 9.6 mmol)And N-iodosuccinimide (2.6 g, 11.6 mmol, 1.2 eq)In glacial acetic acid (25 mL) 50 C for 1 hour. The reaction mixture was poured into water (100 mL) and the resulting yellow solid was collected by suction filtration, washed with methanol and dried at 50 C to give a pale yellow solid (2.7 g, yield 81%). The crude product was used directly in the next step without further purification.

Reference： [1]Patent: WO2019/229765,2019,A1 .Location in patent: Page/Page column 35; 64
[2]Tetrahedron Letters,2008,vol. 49,p. 3137 - 3141
[3]Patent: CN105859684,2016,A .Location in patent: Paragraph 0165; 0166; 0167

16
[ 145369-94-4 ]
[ 73183-34-3 ]
[ 1201844-89-4 ]

Yield	Reaction Conditions	Operation in experiment
	With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; at 90℃; for 3h;Inert atmosphere;	EXAMPLE 23; N-(2-chloro-5-(4-hydroxy-6-quinolinyl)-3-pyridinyl)-4- fluorobenzenesulfonamide; (1) 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-4-ol.; (Some starting materials may be obtained from BioBlocks, San Diego, CA and Small Molecule, Inc., Hoboken, NJ) To a suspension of <strong>[145369-94-4]6-bromoquinolin-4-ol</strong> (0.2 g, 0.9 mmol) in dioxane (10 mL) was added bis(pinacolato)diboron (0.3 g, 1 mmol), potassium acetate (0.4 g, 4 mmol), and 1,1'- bis(diphenylphosphino)ferrocene]dichloride palladium(II) (0.05 g, 0.07 mmol) in order. The reaction mixture was then heated at 90 0C under N2 for 3 h. LC/MS showed no sign of starting material mass. Reaction mixture was cooled to rt. The solvent was separated from the inorganic solid by filtration. The filtrate was concentrated to driness. The crude product was purified using SiO2 (12 g) chromatography with DCM:MeOH=95%:5% as the solvent system to afford the product as brownish solid.(50 mg) MS (ESI pos. ion) m/z: calc'd for C15H18BNO3: 271.1; found: 272.3 (M+l). 1H NMR (300 MHz, CHLOROFORM-d) delta ppm 1.34 (s, 12 H) 6.34 (d, J=7.31 Hz, 1 H) 7.53 (d, J=8.33 Hz, 1 H) 7.69 - 7.85 (m, 1 H) 7.99 (d, J=9.50 Hz, 1 H) 8.89 (s, 1 H) 10.78 (br. s., 1 H).

Reference： [1]Patent: WO2009/155121,2009,A2 .Location in patent: Page/Page column 88-89

17
[ 145369-94-4 ]
[ 116133-09-6 ]
[ 1375077-25-0 ]

Reference： [1]Journal of Enzyme Inhibition and Medicinal Chemistry,2012,vol. 27,p. 370 - 379

18
[ 145369-94-4 ]
[ 1384419-79-7 ]