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[ CAS No. 917251-99-1 ] {[proInfo.proName]}

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Chemical Structure| 917251-99-1
Chemical Structure| 917251-99-1
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Product Details of [ 917251-99-1 ]

CAS No. :917251-99-1 MDL No. :MFCD09907839
Formula : C9H5BrFN Boiling Point : -
Linear Structure Formula :- InChI Key :OUZLPGJFGCOKJJ-UHFFFAOYSA-N
M.W : 226.05 Pubchem ID :14548347
Synonyms :

Calculated chemistry of [ 917251-99-1 ]

Physicochemical Properties

Num. heavy atoms : 12
Num. arom. heavy atoms : 10
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 49.4
TPSA : 12.89 Ų

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) : -5.3 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.15
Log Po/w (XLOGP3) : 3.35
Log Po/w (WLOGP) : 3.56
Log Po/w (MLOGP) : 2.98
Log Po/w (SILICOS-IT) : 3.54
Consensus Log Po/w : 3.12

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 1.0
Bioavailability Score : 0.55

Water Solubility

Log S (ESOL) : -3.97
Solubility : 0.0243 mg/ml ; 0.000107 mol/l
Class : Soluble
Log S (Ali) : -3.3
Solubility : 0.114 mg/ml ; 0.000503 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.84
Solubility : 0.00327 mg/ml ; 0.0000145 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.75

Safety of [ 917251-99-1 ]

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 [ 917251-99-1 ]

* 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 [ 917251-99-1 ]
  • Downstream synthetic route of [ 917251-99-1 ]

[ 917251-99-1 ] Synthesis Path-Upstream   1~3

  • 1
  • [ 1003-99-2 ]
  • [ 56-81-5 ]
  • [ 917251-99-1 ]
YieldReaction ConditionsOperation in experiment
89.8%
Stage #1: With sulfuric acid; sodium 3-nitrobenzenesulfonate In water at 60 - 130℃; for 3 h;
Stage #2: With sodium hydroxide In tert-butyl methyl ether; water
1-(5-fluoroquinolin-8-yl)piperidin-4-one (Example P, Step 3) is also prepared as shown in the reaction scheme above. To a 500 ml flask equipped with a stirrer, a thermocouple, a condenser and nitrogen inlet were charged 50 g 2-bromo-5-fluoroaniline and 60 g glycerol. The mixture was heated to 60° C. and 55 g nitrobenzene sulfonic acid was charged in portion. The mixture was then heated to 100-110° C., started charge 200 ml 70percent sulfuric acid. After sulfuric acid addition, the mixture was heat to 130° C. and stirred for 3 hours before cooled to room temperature. Water (300 g) was added and a grayish by product was filtered off. The filtrate was slowly added into a 2-L reactor containing a mix of 420 g 50percent NaOH, 420 g of water, 352 g methyl tert-butyl ether. After filtering off small amount solid, the aqueous layer was split off and the organic layer was washed with 10percent NaOH (2.x.100 ml), 20percent NaCl (2.x.200 ml), the solvent was removed, weight 56 g, 89.8percent.
87.5% With 4-nitro-phenol; sulfuric acid In water at 140 - 150℃; for 1.5 h; Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (100 g, 1.0 eq), 4-nitrophenol (40 g, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 mL) and water (114 mL) at 140-150° C. The initial mixture showed 37.8percent 4-nitrophenol by relative HPLC area percent. Samples showed 4.7percent 4-nitrophenol immediately after adding 50percent of mixed starting materials and 5.0percent immediately after adding all of the materials. The yield upon workup was 87.5percent, with total impurities 0.29percent. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.
87.5%
Stage #1: With 4-nitro-phenol; sulfuric acid In water at 135 - 150℃; for 2.5 h;
Stage #2: With ammonia In water; toluene at 20 - 40℃; for 0.25 h;
Stage #3: With potassium hydroxide In water; toluene for 0.666667 h;
To a 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet were charged with an aqueous solution of sulfuric acid made from 267 ml concentrated sulfuric acid and 114 mL of water. The sulfuric acid was heated to 140-150 0C. Prior to addition to the hot sulfuric acid, 228 g of water, 200 g of 2-bromo-5-fluoroaniline, 97 g of glycerol, and 80 g of 4-nitrophenol were mixed at between 25-50 0C. The 2-bromo-5-fluoroaniline mixture was added slowly over 1.5 hours to the diluted, hot (140-150 0C) sulfuric acid. The mixture was incubated at 135-145 0C for 1 hour after the addition. The reaction mixture was cooled to below 20-50 0C, and the reaction mixture was transferred slowly to a 5-L reactor containing 1100 g of water and 121O g of toluene.[0263] The 2-L reactor was washed with 300 g of water and the wash was combined into the 5-L reactor. The pH of the contents in the 5-L reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL) ammonium hydroxide (28-30 percent NH3) at 20-40 0C. The mixture was stirred at room temperature for 15 min and the solid by-product was filtered off while the filtrate was retained. The filter cake was washed with 400 ml of <n="75"/>toluene and the all the filtrate was combined and charged a 3-L reactor. About 500 ml of 8.5percent KOH solution was charged into the 3-L reactor and stirred for 10 min and bottom aqueous layer was split off. A second portion of 500 ml of 8.5percent KOH solution was added and the mixture was stirred for 15 min and the bottom aqueous layer was split off. Water, at a volume of 500 ml, was added and stirred for 15 min before the bottom aqueous layer was split off. The aqueous layers were subsequently discarded. The organic layer was heated to distill off about 100-200 ml of toluene to azeotropically remove water. A clear solution was obtained . This solution was used directly in the following step.[0264] During the typical reaction scheme, the yield is 178 g real 8-bromo-5- fluoroquinoline, ~75percent. The yield for the above reaction scheme was 87.5percent at a product purity of over 99percent.
75% With 4-nitro-phenol; sulfuric acid In water at 20 - 150℃; for 3.16667 - 3.5 h; 00299] To a 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet were charged 228 g of water, 200 g of 2-bromo- 5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-1200C. The mixture was heated to 135-1400C and 194 g of glycerol was charged into the reactor over two hours at 135-145°C. The mixture was held at 135- 145°C for 1 hour after the addition. The reaction mixture was cooled to below 20-500C and slowly transferred to a 5-L reactor containing 1 100 g of water and 121O g of toluene. The 2-L reactor was washed with 300 g of water and the wash was combined into the 5-L- 101 -USlDOCS 6425925V I <n="104"/>Docket No. AM 102651 (361 19.379WO1)reactor. The pH of the contents in the 5-L reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL) ammonium hydroxide (28-30 percent NH3) at 20-400C. The mixture was stirred at room temperature for 15 min and the solid by-product was filtered off while the filtrate was retained. The filter cake was washed with 400 ml of toluene and the all the filtrate was combined and charged a 3-L reactor. About 500 ml of 8.5percent KOH solution was charged into the 3-L reactor and stirred for 10 min and bottom aqueous layer was spit off. A second portion of 500 ml of 8.5percent KOH solution was added and the mixture was stirred for 15 min and the bottom aqueous layer was split off. Water 500 ml was added and stirred for 15 min before the bottom aqueous layer was split off. The organic layer was heated to distill off about 100-200 ml of toluene to azeo tropically remove water. A clear solution will be obtained. Typical yield 178g real 8-bromo~5- fluoroquinoline, -75percent.[00300] Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (10Og, 1.0 eq), 4-nitrophenol (4Og, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 ml) and water (1 14 mL) at 140-1500C. The initial mixture showed 37.8percent 4-nitrophenol by relative HPLC areapercent. Samples showed 4.7percent 4-nitrophenol immediately after adding 50percent of mixed starting materials and 5.0percent immediately after adding all of the materials. The yield upon workup was 87.5percent, with total impurities 0.29percent. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.
75%
Stage #1: With 4-nitro-phenol; sulfuric acid In water at 20 - 150℃; for 1.5 - 3.5 h;
Stage #2: With ammonia; water In toluene at 20 - 40℃; for 0.25 h;
To a 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet were charged 228 g of water, 200 g of 2-bromo-5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-120° C. The mixture was heated to 135-140° C. and 194 g of glycerol was charged into the reactor over two hours at 135-145° C. The mixture was held at 135-145° C. for 1 hour after the addition. The reaction mixture was cooled to below 20-50° C. and slowly transferred to a 5-L reactor containing 1100 g of water and 1210 g of toluene. The 2-L reactor was washed with 300 g of water and the wash was combined into the 5-L reactor. The pH of the contents in the 5-L reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL) ammonium hydroxide (28-30percent NH3) at 20-40° C. The mixture was stirred at room temperature for 15 min and the solid by-product was filtered off while the filtrate was retained. The filter cake was washed with 400 ml of toluene and the all the filtrate was combined and charged a 3-L reactor. About 500 ml of 8.5percent KOH solution was charged into the 3-L reactor and stirred for 10 min and bottom aqueous layer was spit off. A second portion of 500 ml of 8.5percent KOH solution was added and the mixture was stirred for 15 min and the bottom aqueous layer was split off. Water 500 ml was added and stirred for 15 min before the bottom aqueous layer was split off. The organic layer was heated to distill off about 100-200 ml of toluene to azeotropically remove water. A clear solution will be obtained. Typical yield 178 g real 8-bromo-5-fluoroquinoline, 75percent.Alternatively, 8-bromo-5-fluoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (100 g, 1.0 eq), 4-nitrophenol (40 g, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 ml) and water (114 mL) at 140-150° C. The initial mixture showed 37.8percent 4-nitrophenol by relative HPLC area percent. Samples showed 4.7percent 4-nitrophenol immediately after adding 50percent of mixed starting materials and 5.0percent immediately after adding all of the materials. The yield upon workup was 87.5percent, with total impurities 0.29percent. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.

Reference: [1] Patent: US2007/27160, 2007, A1, . Location in patent: Page/Page column 66
[2] Patent: US2007/299083, 2007, A1, . Location in patent: Page/Page column 9
[3] Patent: WO2007/146072, 2007, A2, . Location in patent: Page/Page column 73-74
[4] Patent: WO2008/67390, 2008, A2, . Location in patent: Page/Page column 101-102
[5] Patent: US2007/27160, 2007, A1, . Location in patent: Page/Page column 63-65
  • 2
  • [ 100-02-7 ]
  • [ 1003-99-2 ]
  • [ 917251-99-1 ]
YieldReaction ConditionsOperation in experiment
87.5% With sulfuric acid In water; glycerol at 140 - 150℃; for 1.5 h; Alternatively, 8-bromo-5-fiuoroquinoline was prepared by adding a warm mixture containing 2-bromo-5-fluoroaniline (10Og, 1.0 eq), 4-nitrophenol (4Og, 0.54 eq), and glycerol (97 g, 2.0 eq) over 1.5 hours to sulfuric acid (267 mL) and water (114 mL) at 140-1500C. O The initial mixture showed 37.8percent 4-nitrophenol by relative HPLC areapercent. Samples showed 4.7percent 4-πitrophenol immediately after adding 50percent of mixed starting materials and 5.0percent immediately after adding all of the materials. The yield upon workup was 87.5percent, with total impurities 0.29percent. Addition of less (0.46 eq, 34 g) 4-nitrophenol also successfully produced the intermediate of interest at acceptable yield.
75%
Stage #1: With sulfuric acid In water; glycerol at 20 - 145℃; for 1.16667 - 1.5 h;
Stage #2: With ammonia In water; glycerol; toluene at 20℃; for 0.25 h;
Step 2: 8-Bromo-5-fluoroquinolineA 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet was charged with 228 g of water, 200 g of 2-bromo-5-fluoroaniline and 80 g of 4-nitrophenol. To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-1200C. The mixture was heated to 135-1400C and 194 g of glycerol was charged into the reactor over two hours at 135-145°C. The mixture was held at 135-145°C for 1 hour after the addition. The reaction mixture was cooled to below 20-500C and slowly transferred to a 5-L reactor containing 1100 g of water and 1210 g of toluene. The 2-L reactor was washed with 300 g of water and the wash was combined into the 5-L reactor. The pH of the contents in the 5-L reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL) ammonium hydroxide (28-30 percent NH3) at 20-400C. The mixture was stirred at room temperature for 15 min and the solid by-product was filtered off while the filtrate was retained. The filter cake was washed with 400 mL of toluene and the all the filtrate was combined and charged a 3-L reactor. About 500 ml of 8.5percent KOH solution was charged into <n="32"/>the 3-L reactor and stirred for 10 min and bottom aqueous layer was spit off. A second portion of 500 ml of 8.5percent KOH solution was added and the mixture was stirred for 15 min and the bottom aqueous layer was split off. Water 500 mL was added and stirred for 15 min before the bottom aqueous layer was split off. The organic layer was heated to distill off5 about 100-200 mL of toluene to azeotropically remove water. A clear solution was obtained. Yield: about 178 g 8-bromo-5-fluoroquinoline, -75percent.
Reference: [1] Patent: WO2007/146202, 2007, A2, . Location in patent: Page/Page column 31
[2] Patent: WO2007/146202, 2007, A2, . Location in patent: Page/Page column 30-31
  • 3
  • [ 56-81-5 ]
  • [ 917251-99-1 ]
YieldReaction ConditionsOperation in experiment
75%
Stage #1: With 4-nitro-phenol; sulfuric acid In water at 20 - 120℃; for 0.166667 - 0.5 h;
Stage #2: at 135 - 145℃; for 3 h;
Step 2:
8-Bromo-5-fluoroquinoline
A 2-L reactor equipped with a mechanic agitator, a condenser, a thermocouple, a baffle, and nitrogen inlet was charged with 228 g of water, 200 g of 2-bromo-5-fluoroaniline and 80 g of 4-nitrophenol.
To this mixture was charged 96percent sulfuric acid in 10-30 min at 20-120° C.
The mixture was heated to 135-140° C. and 194 g of glycerol was charged into the reactor over two hours at 135-145° C.
The mixture was held at 135-145° C. for 1 hour after the addition.
The reaction mixture was cooled to below 20-50° C. and slowly transferred to a 5-L reactor containing 1100 g of water and 1210 g of toluene.
The 2-L reactor was washed with 300 g of water and the wash was combined into the 5-L reactor.
The pH of the contents in the 5-L reactor was adjusted to pH 8-10 by adding approximately 1233 g (1370 mL) ammonium hydroxide (28-30percent NH3) at 20-40° C.
The mixture was stirred at room temperature for 15 min and the solid by-product was filtered off while the filtrate was retained.
The filter cake was washed with 400 mL of toluene and the all the filtrate was combined and charged a 3-L reactor.
About 500 ml of 8.5percent KOH solution was charged into the 3-L reactor and stirred for 10 min and bottom aqueous layer was spit off.
A second portion of 500 ml of 8.5percent KOH solution was added and the mixture was stirred for 15 min and the bottom aqueous layer was split off.
Water 500 mL was added and stirred for 15 min before the bottom aqueous layer was split off.
The organic layer was heated to distill off about 100-200 mL of toluene to azeotropically remove water.
A clear solution was obtained. Yield: about 178 g 8-bromo-5-fluoroquinoline, ~75percent.
Reference: [1] Patent: US2007/299083, 2007, A1, . Location in patent: Page/Page column 9
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