[ CAS No. 1226762-74-8 ] {[proInfo.proName]}

Name: 1226762-74-8|Ethyl 7-bromoquinoline-3-carboxylate|98%
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SKU: A593220
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Quality Control of [ 1226762-74-8 ]

COA NMR CNMR HPLC LC-MS

Related Doc. of [ 1226762-74-8 ]

SDS Specification

Alternatived Products of [ 1226762-74-8 ]

Product Details of [ 1226762-74-8 ]

CAS No. :	1226762-74-8	MDL No. :	MFCD16657753
Formula :	C₁₂H₁₀BrNO₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	NCEAPXMAJIWHHN-UHFFFAOYSA-N
M.W :	280.12	Pubchem ID :	46222756
Synonyms :

Calculated chemistry of [ 1226762-74-8 ]

Physicochemical Properties

Num. heavy atoms :	16
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.17
Num. rotatable bonds :	3
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	65.53
TPSA :	39.19 Å²

Pharmacokinetics

GI absorption :	High
BBB permeant :	Yes
P-gp substrate :	No
CYP1A2 inhibitor :	Yes
CYP2C19 inhibitor :	Yes
CYP2C9 inhibitor :	No
CYP2D6 inhibitor :	No
CYP3A4 inhibitor :	No
Log Kp (skin permeation) :	-5.81 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.45
Log Po/w (XLOGP3) :	3.1
Log Po/w (WLOGP) :	3.17
Log Po/w (MLOGP) :	2.59
Log Po/w (SILICOS-IT) :	3.32
Consensus Log Po/w :	2.93

Druglikeness

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

Water Solubility

Log S (ESOL) :	-3.79
Solubility :	0.045 mg/ml ; 0.000161 mol/l
Class :	Soluble
Log S (Ali) :	-3.59
Solubility :	0.0718 mg/ml ; 0.000256 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.03
Solubility :	0.00261 mg/ml ; 0.00000931 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.76

Safety of [ 1226762-74-8 ]

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 [ 1226762-74-8 ]

* 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 [ 1226762-74-8 ]

[ 1226762-74-8 ] Synthesis Path-Downstream 1~50

1
[ 10601-80-6 ]
[ 5551-12-2 ]
[ 1226762-74-8 ]

Yield	Reaction Conditions	Operation in experiment
92%	With tin(II) chloride dihdyrate; In ethanol; at 90℃; for 12h;	To a solution of compound 1 (20 g, 0.087 mol) and ethyl 3,3-diethoxypropionate (33 g, 0.17 mol) in EtOH (500 mE) was added SnCl2-2H20 (87 g, 0.39 mol), the mixture was stirred at 90 C. for 12 hours. TEC monitored completion. Afier cooled, evaporated to obtain the crude product. Then put into EA (600 mE), H20 (300 mE), Na2CO3 (32 g) and stirred for 1 hour. The organic layer was separated, dried, filtered and concentrated to obtain compound 2 (15 g, 92%) as a yellow solid.
21.5%	With tin(II) chloride dihdyrate; In ethanol; at 90℃; for 4h;	Tin (II) chloride dihydrate (9.026 g, 40.0 mmol) was added to a solution of <strong>[5551-12-2]4-bromo-2-nitrobenzaldehyde</strong> (2.3 g, 10.0 mmol) and EtOH (40 ml) followed by 3,3-diethoxypropionic acid ethyl ester (4.75 g, 25.0 mmol ). The reaction was heated to 90 oc for4 hr upon the cooling, the reaction mixture was concentrated and the residue was dissolved inEtOAc and quenched with sat. NaHC03. The resulting emulsion was filtered through a pad ofcelite and rinsed well with EtOAc. The remaining aqueous layer was extracted with EtOAcand the combined organic layer were washed with brine, dried over Na2S04 andconcentrated. The crude product was purified by silica gel column chromatography with 10-30% ofEtOAc in hexanes to give ethyl 7-bromoquinoline-3-carboxylate (0.6 g, 21.5%). OH(400 MHz; CDCh) 1.47 (3H, t, J= 8.0 Hz), 4.50 (2H, q, J= 8.0 Hz), 7.72 (1H, t, J= 4.0 Hz),7.80 (1H, s), 8.36 (1H,s), 8.82 (1H, s), 9.45 (1H, s). 8c (100 MHz; CDCh) 14.3, 61.7, 123.5,125.4,126.3, 130.2, 131.1, 138.5, 150.2, 151.0, 165.0.
	With tin(II) chloride dihdyrate; In ethanol; at 90℃; for 4h;	4-Bromo-2-nitrobenzaldehyde (2.3 g), ethyl 3,3-diethoxypropionate (4.85 ml)Stannous chloride dihydrate (9.05 g),Ethanol (50 ml) was added to a three-necked flask, the oil bath was 90 C,After stirring for 4 hours (thin plate chromatography test), the reaction solution was concentrated to a viscous shape by a rotary evaporator. The viscous substance was dissolved in ethyl acetate, stirred with an excess of sodium carbonate solution,The organic layer was separated by filtration and washed repeatedly with brine, and then dried over anhydrous magnesium sulfate,The organic phase was collected by filtration and evaporated to dryness, recrystallized from ethyl acetate,(7- bromo)quinolinyl-3-carboxylate

Reference： [1]Patent: US2018/141923,2018,A1 .Location in patent: Paragraph 0344; 0345; 0346
[2]Journal of Organic Chemistry,2010,vol. 75,p. 3488 - 3491
[3]Patent: WO2018/129274,2018,A1 .Location in patent: Paragraph 0051
[4]Patent: CN105419785,2017,B .Location in patent: Paragraph 0027; 0028

2
[ 5941-55-9 ]
[ 59278-65-8 ]
[ 1226762-74-8 ]

Yield	Reaction Conditions	Operation in experiment
51%	With toluene-4-sulfonic acid; In toluene; for 18h;Reflux;	a) ethyl 7-bromoquinoline-3 -carboxylateA mixture of <strong>[59278-65-8]2-amino-4-bromobenzaldehyde</strong> (1 g, 5.00 mmol), ethyl(2E)-3-(ethyloxy)-2-propenoate (0.862 mL, 5.97 mmol) and p-toluenesulfonic acidmonohydrate (0.095 g, 0.500 mmol) in toluene (80 mL) was heated under reflux over inbath for 18 h. The mixture was cooled, evaporated under reduced pressure, and then dissolved in chloroform and washed with sodium hydrogen carbonate solution. The organic solution was dried (Na2504) and evaporated under reduced pressure to a solid thatrecrystallized from ethanol to afford the title compound (720 mg, 51%). MS (ES)+ mle282.1 [M+H] ?H NMR (400MHz, CDC13) oe ppm 9.47 (d, 1 H), 8.84 (d, J= 1.5 Hz, 1 H),8.38 (d, J 1.5 Hz, 1 H), 7.92 - 7.79 (m, 1 H), 7.74 (dd, J= 1.9, 8.7 Hz, 1 H), 4.50 (q, J= 7.1Hz,2H), 1.49(t,J7.2Hz,3H).

Reference： [1]Patent: WO2013/177253,2013,A2 .Location in patent: Page/Page column 58; 59

3
[ 1226762-74-8 ]
7-bromoquinoline-3-carboxylic acid [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
95%	With water; lithium hydroxide In tetrahydrofuran at 20℃;	5; 6; 8; 9 Ethyl 7-bromoquinoline-3-carboxylate (0.526 g, 1.88 mmol), LiOH (0.45 g, 18.8mmol) were added into a 25 mL round bottom flask. A mixed solvent THF/H20 (2:1, 10 mlTHF, 5 mL H20) was added and the reaction mixtre was stirred at rt overnight. Afteracidified by 2M HCl. The precipitate was filtered and dried to afford 7-bromoquinoline-3-carboxylic acid (0.45 g, 95%). OH (400 MHz; d6-DMSO) 7.86, 7.88 (1H, dd, J1= 8Hz, J2=2.0 Hz), 8.18 (1H, d, J= 8.0 Hz), 8.32 (1H, d, J= 2.0 Hz), 9.01 (1H, d, J= 4.0 Hz), 9.31 (1H,d, J= 4.0 Hz). 8c (100 MHz; d6-DMSO) 124.5, 125.9, 131.1, 131.9, 139.1, 150.0, 151.4,166.5.
80%	Stage #1: 7-bromoquinoline-3-carboxylic acid ethyl ester With sodium hydroxide In methanol at 110℃; for 18h; Microwave irradiation; Sealed tube; Stage #2: With hydrogenchloride In methanol; water	19.a a) 7-bromoquinoline-3-carboxylic acid a) 7-bromoquinoline-3-carboxylic acidEthyl 7-bromoquinoline-3-carboxylate (3.3 g, 11.7 mmol) was added to methanol (15 mL) in a microwave vial and 6N sodium hydroxide (13 mL) was added to the mixture. The vial was capped and heated in an oil bath at 110 °C for 18 h. The reaction was cooled and the methanol was evaporated under reduced pressure. Upon evaporation, a solid precipitated outand was collected by filtration. The solid was dissolved in iN HC1 solution and the solution was adjusted to pH = 4.4 with sodium bicarbonate which resulted in the formation of a precipitate. The precipitate was collected by filtration, washed with water, and dried in a vacuum oven at 50 °C over two days to afford the title compound (2.5 g, 80%). MS(ES)+ mle 253 [M+H].

Reference： [1]Current Patent Assignee: THE UNITED STATE GOVERNMENT REPRESENTED BY THE DEPARTMENT OF VETERANS AFFAIRS - WO2018/129274, 2018, A1 Location in patent: Paragraph 0052
[2]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/177253, 2013, A2 Location in patent: Page/Page column 60

4
[ 1226762-74-8 ]
[ 1296950-66-7 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: sodium hydroxide / methanol / 18 h / 110 °C / Microwave irradiation; Sealed tube 2: chloroformic acid ethyl ester; triethylamine / tetrahydrofuran / 0.17 h / 0 °C

Reference： [1]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/177253, 2013, A2

5
[ 1226762-74-8 ]
[ 57260-71-6 ]
ethyl 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)quinoline-3-carboxylate [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
100%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; ruphos In toluene at 80 - 145℃; for 1.66667h; Microwave irradiation;	4.2 Step 2: A mixture of compound 2 (560 mg, 2 mmol), N-boc-piperazine (1.3 g, 7 mmol) , Pd2(dba)3 (200 mg, 0.2 mmol), Ruphos(200 mg, 0.4 mmol), and Cs2C03 (1.4 g, 7.3 mmol) in Toluene (20 mL) was microwaved at (80°C 10 min, 110°C 30min, 145°C 60 min). TLC was used to monitor reaction. To the mixture was added EA (30 mL), and H20 (30 mL). The organic layer was separated , washed, dried, filtered and concentrated , petroleum ether (PE) to wash it, get purified compound 3 (620 mg, -100%) as yellow solid.
100%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; caesium carbonate; ruphos In toluene at 80 - 1100℃; for 1.66667h; Microwave irradiation;	23.2 Step 2: A mixture of compound 2 (560 mg, 2 mmol),N-boc-piperazine (1.3 g, 7 mmol), Pd2(dba)3 (200 mg, 0.2mmol), Ruphos (200 mg, 0.4 mmol), Cs2CO3 (1.4 g, 7.3mmol) in toluene (20 mE) using microwave (80° C. 10 mm,1100° C. 30 mm, 145° C. 60 mi. TEC monitored completion. The mixture was added EA (30 mE), and H20 (30 mE).Filtered oil through diatomite. The organic layer was separated, washed, dried, filtered and concentrated to obtain compound 3. Washed with PE to obtain purified compound 3 (620 mg, 100%) as a yellow solid.
21%	With tri-tert-butyl phosphine; palladium diacetate; sodium t-butanolate In toluene at 110℃; for 2.5h; Microwave irradiation; Inert atmosphere; Sealed tube;	18.b b) ethyl 7-(4-(tert-butoxycarbonyl)piperazin- 1 -yl)quinoline-3 -carboxylate b) ethyl 7-(4-(tert-butoxycarbonyl)piperazin- 1 -yl)quinoline-3 -carboxylate In a microwave vial, tert-butyl piperazine-1-carboxylate (160 mg, 0.857 mmol) andethyl 7-bromoquinoline-3-carboxylate (200 mg, 0.7 14 mmol) were dissolved in toluene (8mL). Sodium tert-butoxide (137 mg, 1.428 mmol) and palladium(II) acetate (8 mg, 0.036mmol) were then added. The vial was capped and flushed with nitrogen. Then,tri-tert-butylphosphine (1M in toluene, 428 uL) was injected into the sealed vial by syringe.The reaction was heated in the microwave to 110 °C for 2.5 h. The solvent was evaporated under reduced pressure and the residue was pumped down under high vacuum. The residue was dissolved in dichloromethane, washed with saturated sodium bicarbonate solution, and dried with sodium sulfate. The crude product was dry packed on 1 g of silica and purified bysilica gel chromatography (20-80% ethyl acetate in hexanes) to give the title compound (57 mg, 2 1%). MS(ES)+ mle 386.1 [M+H].

Reference： [1]Current Patent Assignee: REGENACY PHARMACEUTICALS LLC - WO2014/121062, 2014, A1 Location in patent: Page/Page column 31
[2]Current Patent Assignee: REGENACY PHARMACEUTICALS LLC - US2018/141923, 2018, A1 Location in patent: Paragraph 0344; 0347; 0348
[3]Current Patent Assignee: GLAXOSMITHKLINE PLC - WO2013/177253, 2013, A2 Location in patent: Page/Page column 58

6
[ 1226762-74-8 ]
[ 109-85-3 ]
[ 1609390-93-3 ]

Yield	Reaction Conditions	Operation in experiment
70%	With N-ethyl-N,N-diisopropylamine In 1,4-dioxane at 100℃; for 6h;	37.1 To a solution of compound 1 (2 g, 7.17 mmol) in Dioxane (20 ml) was added 2-methoxyethanamine (806 mg, 10.75 mmol) and DIPEA (1.85 g, 14.34 mmol). The reaction mixture was stirred 100° C. for 6 hours, poured into H2O, filtered, and dried to give compound 2 (1.37 g, 70%)
47%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; 2-dicyclohexylphosphino-2,6-di-i-propoxy-1,1-biphenyl; caesium carbonate In toluene at 100℃; for 18h; Inert atmosphere;	25.1 Step 1 : Under N2, ethyl 7-bromoquinoline-3-carboxylate (500 mg, 1.78 mmol), 2-methoxy- ethanamine (134 mg, 1.78 mmol), tris(dibenzylideneacetone) dipalladium (41 mg, 0.045 mmol), Ruphos (42 mg, 0.089 mmol) and Cs2C03 (1 .16 g, 3.57 mmol) were combined in toluene (15 ml_). The reaction was heated to 100 °C and stirred for 18 h. The reaction was then cooled to rt. and filtered. The filtrate was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 2 (288 mg, 47%).

Reference： [1]Current Patent Assignee: REGENACY PHARMACEUTICALS LLC - US2014/128391, 2014, A1 Location in patent: Paragraph 0523; 0524; 0525
[2]Current Patent Assignee: REGENACY PHARMACEUTICALS LLC - WO2020/68950, 2020, A1 Location in patent: Page/Page column 49-50

7
[ 1226762-74-8 ]
[ 100-46-9 ]
[ 1609390-29-5 ]

Yield	Reaction Conditions	Operation in experiment
70%	With tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; ruphos In toluene at 100℃; Inert atmosphere;	36.1 To a solution of compound 1 (5.52 g, 20 mmol) in toluene (40 ml) was added compound 2 (4.3 g. 40 mmol), RuPhos (930 mg, 2 mmol), Pd2(dba)3 (575 mg, 1 mmol), under N2. The reaction mixture was heated to 100° C. and stirred overnight. Then, the reaction mixture was extracted with EA (2×50 ml), and the combined organic layers were washed with aqueous NaCl, dried by Na2SO4, and concentrated to give compound 3 (4.28 g, 70%)

Reference： [1]Current Patent Assignee: REGENACY PHARMACEUTICALS LLC - US2014/128391, 2014, A1 Location in patent: Paragraph 0510; 0511; 0512

8
[ 1226762-74-8 ]
[ 1609389-77-6 ]

Yield	Reaction Conditions	Operation in experiment
	Multi-step reaction with 2 steps 1: tris-(dibenzylideneacetone)dipalladium⁽⁰⁾; ruphos; caesium carbonate / toluene / 1.67 h / 80 - 145 °C / Microwave irradiation 2: N-Bromosuccinimide / dichloromethane / 3 h / 20 °C