[ CAS No. 953039-63-9 ] {[proInfo.proName]}

Name: 953039-63-9|8-Bromo-2-chloro-6-fluoroquinazoline|97%
Brand: Ambeed
SKU: A186965
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Quality Control of [ 953039-63-9 ]

COA NMR CNMR HPLC LC-MS

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SDS Specification

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Product Details of [ 953039-63-9 ]

CAS No. :	953039-63-9	MDL No. :	MFCD18382554
Formula :	C₈H₃BrClFN₂	Boiling Point :	-
Linear Structure Formula :	-	InChI Key :	XTEWVYPXKPYPRE-UHFFFAOYSA-N
M.W :	261.48	Pubchem ID :	59199299
Synonyms :

Calculated chemistry of [ 953039-63-9 ]

Physicochemical Properties

Num. heavy atoms :	13
Num. arom. heavy atoms :	10
Fraction Csp3 :	0.0
Num. rotatable bonds :	0
Num. H-bond acceptors :	3.0
Num. H-bond donors :	0.0
Molar Refractivity :	52.21
TPSA :	25.78 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) :	-5.56 cm/s

Lipophilicity

Log Po/w (iLOGP) :	2.29
Log Po/w (XLOGP3) :	3.29
Log Po/w (WLOGP) :	3.61
Log Po/w (MLOGP) :	2.72
Log Po/w (SILICOS-IT) :	3.65
Consensus Log Po/w :	3.11

Druglikeness

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

Water Solubility

Log S (ESOL) :	-4.1
Solubility :	0.0206 mg/ml ; 0.0000789 mol/l
Class :	Moderately soluble
Log S (Ali) :	-3.51
Solubility :	0.0814 mg/ml ; 0.000311 mol/l
Class :	Soluble
Log S (SILICOS-IT) :	-5.08
Solubility :	0.00218 mg/ml ; 0.00000836 mol/l
Class :	Moderately soluble

Medicinal Chemistry

PAINS :	0.0 alert
Brenk :	0.0 alert
Leadlikeness :	0.0
Synthetic accessibility :	1.68

Safety of [ 953039-63-9 ]

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

Application In Synthesis of [ 953039-63-9 ]

* 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 [ 953039-63-9 ]
Downstream synthetic route of [ 953039-63-9 ]

[ 953039-63-9 ] Synthesis Path-Upstream 1~4

1
[ 953039-62-8 ]
[ 953039-63-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	at 110℃; for 1 h;	Step 5. 8-Bromo-2-chloro-6-fluoroquinazolineA 0.5M suspension of 8-bromo-6-fluoroquinazolin-2-ol in phosphorus oxychloride was heated to 110 ⁰C in an oil bath. The suspension was turned to a brown color solution in 20min. LCMS data showed that the reaction was complete after 1 h. The phosphorus oxychloride was removed by concentration. The residue was mixed with ice water, and adjusted pH to 7 by adding sodium bicarbonate. Reaction mixture was extracted with ethyl acetate. Combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give desired product in 89percent yield. ES/MS m/z 261/263 (MH⁺).

Reference： [1] Patent: WO2007/117607, 2007, A2, . Location in patent: Page/Page column 332
[2] Patent: EP3287463, 2018, A1, . Location in patent: Paragraph 0203; 0212
[3] Patent: US2018/208604, 2018, A1, . Location in patent: Paragraph 0510-0511

2
[ 259269-84-6 ]
[ 953039-63-9 ]

Reference： [1] Patent: EP3287463, 2018, A1,
[2] Patent: US2018/208604, 2018, A1,
[3] Patent: WO2007/117607, 2007, A2,

3
[ 55414-45-4 ]
[ 953039-63-9 ]

Reference： [1] Patent: EP3287463, 2018, A1,
[2] Patent: US2018/208604, 2018, A1,
[3] Patent: WO2007/117607, 2007, A2,

4
[ 446-08-2 ]
[ 953039-63-9 ]

Reference： [1] Patent: EP3287463, 2018, A1,
[2] Patent: US2018/208604, 2018, A1,

[ 953039-63-9 ] Synthesis Path-Downstream 1~21

1
[ 953039-62-8 ]
[ 953039-63-9 ]

Yield	Reaction Conditions	Operation in experiment
89%	With trichlorophosphate; at 110℃; for 1.0h;	Step 5. 8-Bromo-2-chloro-6-fluoroquinazolineA 0.5M suspension of 8-bromo-6-fluoroquinazolin-2-ol in phosphorus oxychloride was heated to 110 0C in an oil bath. The suspension was turned to a brown color solution in 20min. LCMS data showed that the reaction was complete after 1 h. The phosphorus oxychloride was removed by concentration. The residue was mixed with ice water, and adjusted pH to 7 by adding sodium bicarbonate. Reaction mixture was extracted with ethyl acetate. Combined organic phase was washed with water, brine, dried over sodium sulfate and concentrated to give desired product in 89% yield. ES/MS m/z 261/263 (MH+).
	With trichlorophosphate; at 0 - 105℃; for 16.0h;	Compound 21-d (18 g, 74 mmol) was dissolved in phosphorus oxychloride (120 mL, 860 mmol) at 0C, andthe reaction mixture was heated at 105C for 16 hours. The reaction mixture was cooled to room temperature, concentratedto remove phosphorus oxychloride under reduced pressure, and the residue was added to water (100 mL) andstirred. The reaction mixture was filtered and the filter cake was dried in vacuo to deliver a white solid 21-c (5 g, yield:26%), this product was used without further purification.LC-MS (ESI): m/z = 261 [M+H]+.
	With trichlorophosphate; at 0 - 105℃; for 16.0h;	Compound 46-d (18 g, 74 mmol) was dissolved in phosphorus oxychloride (120 mL, 860 mmol) at 0 C. and the reaction was heated at 105 C. for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove phosphorus oxychloride, and the residue was added with water (100 mL) and stirred. The reaction mixture was filtered and the filter cake was dried under vacuum to give 46-c as a white solid (5 g, yield 26%) which was used without further purification. LC-MS (ESI): m/z=261[M+H]+.

Reference： [1]Patent: WO2007/117607,2007,A2 .Location in patent: Page/Page column 332
[2]Patent: EP3287463,2018,A1 .Location in patent: Paragraph 0203; 0212
[3]Patent: US2018/208604,2018,A1 .Location in patent: Paragraph 0510-0511

2
[ 953039-63-9 ]
[ 63-74-1 ]
4-(8-bromo-6-fluoro-quinazolin-2-ylamino)benzensulfonamide [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
81%	In isopropyl alcohol; at 120℃; for 48.0h;	Step 6: 4-(8-Bromo-6-fluoroquinazolin-2-ylamino)benzensulfonamide; To a 0.4M suspension of <strong>[953039-63-9]8-bromo-2-chloro-6-fluoroquinazoline</strong>, 15-3 in isopropanol was added 4-aminobenzensulfonamide (1 eq). The reaction mixture was heated to 120 C. in an oil bath for 2 days. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 min and was filtered. Filter cake was rinsed with hexane and dried in vacuum to give product in 81% yield. ES/MS m/z 397/399 (MH+).
81%	In isopropyl alcohol; at 120℃; for 48.0h;	Step 6. 4-(8-Bromo-6-fluoroqumazolin-2-ylarnino)benzensulfonamide To a 0.4M suspension of <strong>[953039-63-9]8-bromo-2-chloro-6-fluoroquinazoline</strong> in isopropanol was added 4- aminobenzensulfonamide (leq). The reaction mixture was heated to 120 0C in an oil bath for 2days. LCMS showed that reaction was complete under the condition. Ethyl acetate was added to the reaction flask and the suspension was stirred at ambient temperature for 30 min and was filtered. Filter cake was rinsed with hexane and dried in vacuum to give product in 81% yield. ES/MS m/z 397/399 (MH+).

Reference： [1]Patent: US2010/216767,2010,A1 .Location in patent: Page/Page column 82
[2]Patent: WO2007/117607,2007,A2 .Location in patent: Page/Page column 332

3
[ 953039-63-9 ]
[ 873-74-5 ]
(E)-4-((8-(4-(2-cyanovinyl)-2,6-dimethylphenyl)-6-fluoroquinazolin-2-yl)amino)benzonitrile [ No CAS ]

Reference： [1]Patent: WO2016/105564,2016,A1

4
[ 953039-63-9 ]
[ 873-74-5 ]
4-((8-bromo-6-fluoroquinazolin-2-yl)amino)benzonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	In 1-methyl-pyrrolidin-2-one; at 200℃; for 5.0h;Microwave irradiation;	Step 1: Synthesis of 4-((8-bromo-6-fluoroquinazolin-2-yl)amino)benzonitrile (Compound 4a) Compound 4a [0257] A mixture of <strong>[953039-63-9]8-bromo-2-chloro-6-fluoroquinazoline</strong> (500 mg, 1.91 mmol, Ark Pharm Inc, AK-93358) and 4-aminobenzonitrile (250 mg, 2.12 mmol, Sigma-Aldrich) in dry N-methylpyrrolidone was heated in microwave at 200 C for 5 hours. The reaction mixture was cooled down to room temperature and subjected to silica gel chromatography (gradient from 5-50% ethyl acetate in wo-hexanes).to afford the title compound 4a. NMR (400 MHz, DMSO-i ) delta 10.69 (s, 1H), 9.37 (s, 1H), 8.32 (d, J= 8.7 Hz, 2H), 8.26 (dd, J= 8.5, 2.7 Hz, 1 H), 7.86 (dd, J= 8.5, 2.7 Hz, 1 H), 7.78 (d, J = 8.7 Hz, 2H). LCMS (m/z) 343.0 [M+H], Tr = 4.72 min (LCMS method 1 ).

Reference： [1]Patent: WO2016/105564,2016,A1 .Location in patent: Paragraph 0257

5
[ 953039-63-9 ]
(E)-3-(3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylonitrile [ No CAS ]
(E)-3-(4-(2-chloro-6-fluoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
	With potassium phosphate monohydrate; dichloro[1,1'-bis(di-t-butylphosphino)ferrocene]palladium(II); In N,N-dimethyl-formamide; at 80℃; for 0.5h;Inert atmosphere;	Step 1 : (E)-3-(4-(2-chloro-6-fIuoroquinazolin-8-yl)-3,5-dimethylphenyl)acrylonitrile (Compound 14a) Compound 14a [0277] A mixture of compound lc (100 mg, 0.35 mmol), 8-bromo-2-chloro-6- fluoroquinazoline (100 mg, 0.38 mmol, Ark Pharm Inc, AK-93358), l ,l '-bis(di-/ert- butylphosphino)ferrocene palladium dichloride (50 mg, 0.08 mmol) and potassium phosphate tribasic monohydrate (200 mg, 0.77 mmol) in N,N-dimethylformamide (3 mL) and water (0.3 mL) was heated under argon at 80C for 30 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel chromatography This was subjected to silica gel chromatography (gradient from 0- 100% ethyl acetate in wo-hexanes) to afford compound 14a. LCMS (m/z) 337.9 [M+H], Tr = 4.52 min (LCMS method 1 ).

Reference： [1]Patent: WO2016/105564,2016,A1 .Location in patent: Paragraph 0277

Yield	Reaction Conditions	Operation in experiment
84%	With trichlorophosphate; at 120℃; for 1.0h;	General procedure: Phosphoryl trichloride (135 mL) was added over 6-(trifluoromethyl)-l,2- dihydroquinolin-2-one (27 g, 126.67 mmol, 1.00 equiv). The reaction mixture was stirred for 1 h at 120 C and concentrated under vacuum. Water (100 mL) was added and the resulting solid was collected by filtration to afford the desired final product in 68% yield.
84%	With trichlorophosphate; at 120℃; for 1.0h;	General procedure: Phosphoryl trichloride (135 mL) was added over 6-(trifluorom ethyl)- 1,2- dihydroquinolin-2-one (27 g, 126.67 mmol, 1.00 equiv). The reaction mixture was stirred for 1 h at 120 C and concentrated under vacuum. Water (100 mL) was added and the resulting solid was collected by filtration to afford the desired final product in 68% yield.
45.5%	With ammonium hydroxide; zinc; In dichloromethane; for 4.0h;Reflux;	General procedure: 2,4-dichloro-6-fluoro-quinazoline (700mg, 3.2mmol) was dissolved in dichloromethane (10 mL), washed with 9% aqueous ammonia was added saturated brine (10 mL) and activated zinc dust (1.50 g of , 22.90mmol), The reaction was refluxed for 4 hours at elevated temperatures. The reaction is stopped, cooled to room temperature, evaporated to dryness under reduced pressure dichloromethane. (20mLx3) and the combined organic phase was washed with ethyl acetate. The organic phase was washed with saturated brine (20mLx3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate (v / v) = 20/1) to give the title compound as as a white solid (315mg, 53.4%).

7
[ 953039-63-9 ]
[ 5720-06-9 ]
C₁₅H₁₀ClFN₂O [ No CAS ]

Yield	Reaction Conditions	Operation in experiment
43%	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In 1,4-dioxane; water; at 120℃; for 16.0h;Inert atmosphere;	Compound 21-c (1.03 g, 3.93 mmol), o-methoxyphenylboronic acid (600 mg, 3.95 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (150 mg, 0.2 mmol) and sodium carbonate (1.2 g, 11.3 mmol) were dissolvedin 1,4-dioxane (30 mL) and water (10 mL). The reaction mixture was replaced with nitrogen three times to remove theoxygen inside the system and then heated at 120C for 16 hours. The reaction mixture was cooled to room temperature,diluted with ice water (10 mL) and extracted with dichloromethane (50 mL 3 3). The combined organic phases werewashed successively with water (20 mL 3 3) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleumether: ethyl acetate = 5: 1) to deliver a white solid 21-b (0.49 g, yield: 43%). LC-MS (ESI): m/z = 599 [M+H]+.
0.49 g	With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate; In 1,4-dioxane; water; at 120℃; for 16.0h;Inert atmosphere;	Compound 46-c (1.03 g, 3.93 mmol), o-methoxyphenylboronic acid (600 mg, 3.95 mmol), [1,1?-bis(diphenylphosphino)ferrocene]dichloropalladium (150 mg, 0.2 mmol) and sodium carbonate (1.2 g, 11.3 mmol) were dissolved in 1,4-dioxane (30 mL) and water (10 mL). The reaction solution was purged with nitrogen gas for three times to remove the oxygen contained in the system, and then heated at 120 C. for 16 hours. The reaction was cooled to room temperature, diluted with ice water (10 mL) and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with water (20 mL×3) and brine (20 mL) sequentially, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate=5:1) to give 46-b as a white solid (0.49 g, yield 43%). LC-MS (ESI): m/z=599[M+H]+.

Reference： [1]Patent: EP3287463,2018,A1 .Location in patent: Paragraph 0203; 0213
[2]Patent: US2018/208604,2018,A1 .Location in patent: Paragraph 0512-0513

8
[ 259269-84-6 ]
[ 953039-63-9 ]

Reference： [1]Patent: EP3287463,2018,A1
[2]Patent: US2018/208604,2018,A1
[3]Patent: WO2007/117607,2007,A2

9
[ 55414-45-4 ]
[ 953039-63-9 ]

Reference： [1]Patent: EP3287463,2018,A1
[2]Patent: US2018/208604,2018,A1
[3]Patent: WO2007/117607,2007,A2

10
2-amino-3-bromo-5-fluorobenzaldehyde [ No CAS ]
[ 953039-63-9 ]

Reference： [1]Patent: EP3287463,2018,A1
[2]Patent: WO2007/117607,2007,A2

11
[ 953039-63-9 ]
N-[2,2-dimethyl-4-(piperidin-4-yl)-2,3-dihydro-1-benzofuran-7-yl]-6-fluoro-8-(2-methoxyphenyl)quinazolin-2-amine [ No CAS ]