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[ CAS No. 2369-13-3 ] {[proInfo.proName]}

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3d Animation Molecule Structure of 2369-13-3
Chemical Structure| 2369-13-3
Chemical Structure| 2369-13-3
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Product Details of [ 2369-13-3 ]

CAS No. :2369-13-3 MDL No. :MFCD03412239
Formula : C6H5FN2O2 Boiling Point : -
Linear Structure Formula :- InChI Key :KKQPNAPYVIIXFB-UHFFFAOYSA-N
M.W : 156.12 Pubchem ID :75401
Synonyms :

Calculated chemistry of [ 2369-13-3 ]

Physicochemical Properties

Num. heavy atoms : 11
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 1
Num. H-bond acceptors : 3.0
Num. H-bond donors : 1.0
Molar Refractivity : 39.63
TPSA : 71.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : No
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -6.49 cm/s

Lipophilicity

Log Po/w (iLOGP) : 0.76
Log Po/w (XLOGP3) : 1.08
Log Po/w (WLOGP) : 1.74
Log Po/w (MLOGP) : 0.7
Log Po/w (SILICOS-IT) : -0.59
Consensus Log Po/w : 0.74

Druglikeness

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

Water Solubility

Log S (ESOL) : -1.83
Solubility : 2.33 mg/ml ; 0.0149 mol/l
Class : Very soluble
Log S (Ali) : -2.18
Solubility : 1.03 mg/ml ; 0.0066 mol/l
Class : Soluble
Log S (SILICOS-IT) : -1.69
Solubility : 3.22 mg/ml ; 0.0207 mol/l
Class : Soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 3.0 alert
Leadlikeness : 1.0
Synthetic accessibility : 1.75

Safety of [ 2369-13-3 ]

Signal Word:Warning Class:N/A
Precautionary Statements:P261-P280-P305+P351+P338 UN#:N/A
Hazard Statements:H302+H312+H332-H315-H319-H335 Packing Group:N/A
GHS Pictogram:

Application In Synthesis of [ 2369-13-3 ]

* 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 [ 2369-13-3 ]
  • Downstream synthetic route of [ 2369-13-3 ]

[ 2369-13-3 ] Synthesis Path-Upstream   1~21

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Reference: [1] Journal of Organic Chemistry, 1960, vol. 25, p. 1342 - 1348
  • 2
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  • [ 2996-31-8 ]
Reference: [1] Journal of Organic Chemistry, 1960, vol. 25, p. 1342 - 1348
[2] Angewandte Chemie - International Edition, 2014, vol. 53, # 43, p. 11625 - 11628[3] Angew. Chem., 2014, vol. 126, # 43, p. 11809 - 11812,4
  • 3
  • [ 372-19-0 ]
  • [ 2369-13-3 ]
YieldReaction ConditionsOperation in experiment
35%
Stage #1: at 80℃; for 1 h;
Stage #2: With sulfuric acid In water at 0 - 20℃;
Stage #3: With sulfuric acid; nitric acid In water at 0℃; for 1 h;
Example 2; Preparation of Compound 7; Compound 7; 58 g of 3-fluoroaniline and 58 mL of benzaldehyde were heated at 80°C during one hour. 200 mL of sulfuric acid were then added to the reaction mixture, cooled with an ice bath. After removing of the ice bath, the reaction mixture was further stirred at room temperature until complete dissolution of the solid. The reaction mixture was next cooled to 0°C with an ice bath and 36 mL of nitric acid in 120 mL of sulfuric acid were added dropwise, maintaining the temperature at 0°C. After one hour of stirring at 0°C, the solid was filtered off and poured into a saturated solution of potassium carbonate in water. Ethyl acetate was then added and the two layers were separated. The aqueous phase was extracted two more times with ethyl acetate. The organic phases were collected, dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 40percent ethyl acetate in hexane, yielding 28.65 g (35percent) of the desired intermediate A-2 3-fluoro-4-nitroaniline. 28.65 g of intermediate A-2 was dissolved in 230 mL of chlorhydric acid 36percent. The reaction mixture was cooled to 0°C with an ice bath and 13.7 g of sodium nitrite was added portion-wise. The reaction was maintained at 0°C during 1.5 hours, then mixed with 145 mL of a S02 saturated acetic acid solution, containing 10.5 mL of water and 9.3 g of CuC12. 2H20. After complete addition, the cooling bath was removed and the reaction mixture was stirred at room temperature during one hour, then poured onto ice. The solid was filtered off yielding 37.7 g of the intermediate B-2 3-fluoro-4-nitro- benzene sulfonyl chloride. To a solution of 53 g of intermediate C-1 (PG = Boc, R4 = isobutyl) in 500 mL of THF containing 42 mL of triethylamine was added portion-wise 37.7 g of intermediate B-2. The reaction mixture was stirred at room temperature overnight then evaporated. The residue was dissolved in ethylacetate and extracted with water, then with a solution of HCI 5percent in water and with a K2CO3 solution in water. The organic layer was then dried over MgSO4 and evaporated. The crude compound was purified on silica gel yielding 53 g (65percent) of the desired intermediate 2-a [(lS, 2R)-3-[[(3-fluoro-4-nitrophenyl)- sulfonyl] (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester. 2 g of intermediate 2-a were dissolved in 50 mL of DMF and 1.85 mL of isopropyl- amine were added. The reaction mixture was stirred at 60°C overnight, then concentrated and the residue treated with a mixture of EtOAc and brine. The organic layer was then dried over MgS04 and evaporated to yield 2 g (91percent) of the desired intermediate 2-b [ (IS, 2R)-2-hydroxy-3- [ (2-methylpropyl) [ [3- (2-methylpropyl) amino-4- nitrophenyl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester, used without other purification in the next step. 2 g of intermediate 2-b were dissolved in 40 mL of methanol, then 1.5 g of ammonium formate and 0.2 g of palladium on charcoal (10percent) were added. The reaction mixture was stirred overnight at 60°C, then 0.5 g of ammonium formate and 0.2 g of palladium on charcoal were added. After three hours, the mixture was filtered on celite and evaporated. The residue was dissolved in 50 mL of DCM, washed with a solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated to yield 1.3 g (68percent) of intermediate 2-c [(1S, 2R)-3-[[4-amino-3-[(2-methylpropyl) amino] phenyl] sulfonyl]- (2-methylpropyl) amino]-2-hydroxy-1-(phenylmethyl) propyl] carbamic acid, 1, 1-dimethylethyl ester, used without other purification in the next step. 1. 3 g of intermediate 2-c was dissolved in 20 mL of ethyl orthoformate. The reaction mixture was stirred at 80°C during 5 hours then concentrated. The residue was dissolved in ethyl acetate and washed with a solution of Na2C03 in water. The organic layer was dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 0 to 2percent methanol in DCM, yielding 0.8 g (70percent) of the desired intermediate 2-d [ S, 2R)-2-hydroxy-3-[(2-methylpropyl) [[l-(2-methylpropyl)- benzimidazol-6-yl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, 1,1-dimethylethyl ester. 2.6 g of intermediate 2-d was dissolved in 100 mL of HCI 5N in isopropanol. The reaction mixture was stirred at room temperature during 2 hours, then concentrated to yield 2.5 g (94percent) of the deprotected amine as an HCI salt, N-[(2R, 3S)-3-amino-2- hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[1-(2-methylpropyl) benzimidazol-6-yl] - sulfonamide, hydrochloride (2-e). 2.5 g of 2-e and 1.5 mL of triethylamine were dissolved in 60 mL of DCM. 3.05 g of 1-[[(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl] oxycarbonyloxy] -2,5- pyrrolidinedione were then added and the reaction mixture was stirred at room temperature during 4 hours. The reaction mixture was then washed with a solution of Na2CO3 in water, then brine, dried over MgS04 and evaporated. The crude compound was purified on silica gel eluting with 5percent methanol in DCM, yielding 1.8 g (60percent) of the desired final compound [ (lS, 2R)-2-hydroxy-3- [ (2-methylpropyl) [ [1- (2-methyl- propyl) benzimidazol-6-yl] sulfonyl] amino]-1-(phenylmethyl) propyl] carbamic acid, [(3R,3aS,6aR)-hexahydrofuro [2,3-b] furan-3-yl] ester (compound 7).
Reference: [1] Patent: WO2003/76413, 2003, A1, . Location in patent: Page/Page column 28-30
[2] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 681 - 690
[3] Journal of the Chemical Society, 1941, p. 766,767
[4] Patent: US2003/216582, 2003, A1, . Location in patent: Page/Page column 6
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  • [ 1152311-98-2 ]
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YieldReaction ConditionsOperation in experiment
99%
Stage #1: With hydrogenchloride In dichloromethane; water for 2 h; Reflux
Stage #2: With potassium carbonate In dichloromethane; water; ethyl acetate
A mixture of N-(3-fluoro-4-nitro-phenyl)-2, 2-dimethyl-propionamide (87.0 g, 0.36 mol) in CH2Cl2 (400 mL) and 6N hydrochloric acid (800 mL) was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature. The reaction mixture was diluted with 1000 mL of ethyl acetate and potassium carbonate (500.0 g) was added portion wise. The aqueous solution was separated and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed by evaporation under reduced pressure; the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 30: 1) to afford 3-fluoro-4-nitroaniline (56.0 g, 99 percent). 1H NMR (300 MHz, CDCl3) δ 8.07 (t, J = 8.7 Hz, 1 H), 7.86 (dd, J= 2.1, 13.2 Hz 1 H), 7.59 (brs, 2 H), 7.22 (s, 1 H).
Reference: [1] Patent: WO2010/53471, 2010, A1, . Location in patent: Page/Page column 56
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  • [ 403-21-4 ]
  • [ 75-65-0 ]
  • [ 658700-15-3 ]
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YieldReaction ConditionsOperation in experiment
32% With diphenyl phosphoryl azide; triethylamine In 1,4-dioxane at 95℃; for 48 h; Diphenylphosphorylazide (5.5 mmol, 1.5 g) was added to a solution of 3-fluoro-4- nitrobenzoic acid (5.4 mmol, [1] g) and triethylamine (5.6 mmol, 0.8 mL) in a 1: 1 mixture of [TERT-BUTYL] alcohol/dioxane (60 mL). The reaction mixture was refluxed for 2 days at 95 [C] and the solvent was evaporated to give an oily residue. The residue was taken up in ethyl acetate (100 mL) and washed with 10percent citric acid, IN NaOH, brine and H20. Evaporation of solvent afforded an orange residue that was subsequently purified by flash chromatography eluting with ethyl acetate/hexane to afford [(TERT-BUTOXY)-N- (3-FLUORO-4-] nitrophenyl) carboxamide (1. [75MMOL,] 0.45g, yield 32percent). 3-Fluoro-4-nitroaniline (0.36 g, 2.3 mmol) was isolated as a byproduct. Treatment of [(TERT-BUTOXY)-N- (3-FLUORO-4-] nitrophenyl) carboxamide with trifluoroacetic acid in methylene chloride afforded additional [3-FLUORO-4-NITROANILINE.]
Reference: [1] Patent: WO2004/14905, 2004, A1, . Location in patent: Page 157-158
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Reference: [1] Patent: WO2004/14905, 2004, A1, . Location in patent: Page 157-158
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 18, p. 5449 - 5453
  • 7
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Reference: [1] Journal of Organic Chemistry, 1992, vol. 57, # 18, p. 4784 - 4785
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Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
  • 9
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Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
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Reference: [1] Journal of Organic Chemistry, 1998, vol. 63, # 15, p. 4878 - 4888
  • 11
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  • [ 2369-11-1 ]
Reference: [1] Journal of Organic Chemistry, 2011, vol. 76, # 9, p. 3286 - 3295
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  • [ 2369-11-1 ]
Reference: [1] Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999), 1988, p. 681 - 690
[2] Helvetica Chimica Acta, 1982, vol. 65, # 2, p. 546 - 550
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Reference: [1] Journal of the Chemical Society, 1941, p. 766,767
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  • [ 372-19-0 ]
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  • [ 2369-11-1 ]
Reference: [1] Journal of the Chemical Society, 1941, p. 766,767
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  • [ 351-28-0 ]
  • [ 7697-37-2 ]
  • [ 108-24-7 ]
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  • [ 2369-11-1 ]
Reference: [1] Journal of the Chemical Society, 1941, p. 766,767
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  • [ 14791-78-7 ]
YieldReaction ConditionsOperation in experiment
100% With ammonium chloride; zinc In ethanol; water at 25℃; for 2 h; Inert atmosphere Zinc powder (4.2 g, 64.1 mmol) was added to ammonium chloride (3.4 g, 64.1 mmol), 3-fluoro-4-nitroaniline (500 mg, 3.2 mmol) and water (4 mL) in ethanol (15 mL) under nitrogen.
The resulting mixture was stirred at 25° C. for 2 hours.
The mixture was filtered, and the filtrate was evaporated to dryness to give a crude residue which was purified by flash silica chromatography, elution gradient 1 to 10percent methanol in DCM (0.1percent DIPEA).
Pure fractions were evaporated to dryness to afford the title compound as a black oil (405 mg, 100percent).
1H NMR (DMSO-d6, 300 MHz) δ 6.27 (1H, dd), 6.39 (1H, dd), 6.58 (1H, dd), 9.74 (2H, s); m/z (ES+), [M+H]+=127; acid. HPLC tR=0.227 min.
Reference: [1] Patent: US2018/312490, 2018, A1, . Location in patent: Paragraph 0287
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  • [ 2369-13-3 ]
  • [ 86156-93-6 ]
YieldReaction ConditionsOperation in experiment
62%
Stage #1: With hydrogenchloride; sodium nitrite In water at 0℃; for 0.5 h;
Stage #2: at 25℃; for 1 h;
To a solution of 3-fluoro-4-nitroaniline (15 g, 96.1 mmol, Combi Blocks) in HC1 (120 ml) was added a C^ (7.9 g, 115.0 mmol, Qualigens) dissolved in water (10 ml) at 0 °C and the mixture was stirred for 30 minutes. Afterward, this diazonium salt was added to an ice-cold solution of CuC^'H^O (14.4 g, 96.1 mmol, Aldrich) in AcOH (80 ml), saturated with SO2 gas. The resulting mixture was stirred at 25 °C) for 1 h. After completion of reaction (monitored by TLC), the mixture was poured into ice-cold water and a solid precipitated. The solid was collected by filtration, washed with water and air dried to provide 14.2 g of 3-fluoro-4- nitrobenzene- 1-sulfonyl chloride as brown solid in 62 percentyield. 1H-NMR (400 MHz, DMSO): δ 8.29 (t, J=7.2 Hz, 1H),8.01 (dd,2H).
Reference: [1] Patent: WO2013/122897, 2013, A1, . Location in patent: Page/Page column 175; 176
[2] Helvetica Chimica Acta, 1983, vol. 66, # 1, p. 68 - 75
[3] Patent: WO2003/76413, 2003, A1, . Location in patent: Page/Page column 28-30
[4] Patent: WO2017/156181, 2017, A1, . Location in patent: Paragraph 00359
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Reference: [1] Journal of Organic Chemistry, 2014, vol. 79, # 5, p. 1979 - 1988
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YieldReaction ConditionsOperation in experiment
90%
Stage #1: With bromine; acetic acid In chloroform at 0 - 20℃; for 2 h;
Stage #2: With sodium hydroxide In chloroform; water at 0℃;
To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C. After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water. The mixture was basified with aqueous NaOH (10percent) to pH 8.0-9.0 under cooling and then extracted with EtOAc (50 mL.x.3). The combined organic layers were washed with water (80 mL.x.2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent). 1H-NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
90% With bromine In chloroform; acetic acid 2-Bromo-5-fluoro-4-nitroaniline
To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C.
After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water.
The mixture was basified with aqueous NaOH (10percent) to pH ~8.0-9.0 under cooling and then extracted with EtOAc (50 mL*3).
The combined organic layers were washed with water (80 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent).
1H-NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
90% With bromine; acetic acid In chloroform at 0 - 20℃; for 2 h; To a mixture of 3-fluoro-4-nitroaniline (6.5 g, 42.2 mmol) in AcOH (80 mL) and chloroform (25 mL) was added dropwise Br2 (2.15 mL, 42.2 mmol) at 0° C.
After addition, the resulting mixture was stirred at room temperature for 2 h and then poured into ice water.
The mixture was basified with aqueous NaOH (10percent) to pH˜8.0-9.0 under cooling and then extracted with EtOAc (50 mL*3).
The combined organic layers were washed with water (80 mL*2) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure to give 2-bromo-5-fluoro-4-nitroaniline (9 g, 90percent).
1H-NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=8.0, Hz, 1H), 7.07 (brs, 2H), 6.62 (d, J=9.6 Hz, 1H).
84%
Stage #1: With bromine In acetic acid at 0 - 5℃; for 2 h;
Stage #2: With sodium carbonate In water; acetic acid
To a solution of 3-fluoro-4-nitroaniline (56 g, 0.36 mol) in acetic acid (500 mL) was added drop-wise bromine (17.7 mL, 0.36 mol) over 1 hour. The reaction mixture was stirred for 1 hour at 0-5 °C in an ice bath. The reaction mixture was basified with saturated Na2CO3 and extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield a residue that was purified by column chromatography on silica gel (petroleum ether / ethyl acetate 10 : 1) to give the 2-bromo-5-fluoro-4-nitroaniline ( 45.6 g, 84 percent ) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J = 7.6 Hz, 1 H), 653 (d, J = 12.4 Hz, 1 H), 4.94 (br s, 2 H).
61% With bromine; acetic acid In chloroform at 0℃; for 2.33 h; Step 1214 15[00168] methyl 2.2-difluorobenzo[d1[1.31dioxole-5-carboxylate: To a solution of 3- fluoro-4-nitroaniline (6.5 g, 41.64 mmol, 1.00 equiv) in chloroform (25 mL) and AcOH (80 mL) was added Bn (6.58 g, 41.17 mmol, 1.00 equiv.) dropwise with stirring at 0 °C in 20 min. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 150 mL of water/ice. The pH value of the solution was adjusted to 9 with sodium hydroxide (10 percent). The resulting solution was extracted with 3 x 50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 50 mL of water and 2 x 50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from PE/EA (10: 1) to afford 6 g (61percent) of 2-bromo-5-fluoro-4-nitroaniline as a yellow solid.
50% With N-Bromosuccinimide In ethyl acetate at 22℃; Synthesis of 2-bromo-5-fluoro-4-nitroaniline
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C.
At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap.
The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight.
The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved.
A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
50% With N-Bromosuccinimide In ethyl acetate at 22℃; Synthesis of 2-bromo-5-fluoro-4-nitroaniline
A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22° C.
At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap.
The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight.
The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50° C. overnight with N2 bleed until constant weight was achieved.
A yellowish tan solid was isolated (50percent yield, 97.5percent AUC).Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). 1H NMR (500 MHz, DMSO) δ 8.19 (1H, d, J=8.1 Hz), 7.06 (br. s, 2H), 6.64 (d, 1H, J=14.3 Hz).
50% With N-Bromosuccinimide In ethyl acetate at 22℃; A flask was charged with 3-fluoro-4-nitroaniline (1.0 equiv) followed by ethyl acetate (10 vol) and stirred to dissolve all solids. N-Bromosuccinimide (1.0 equiv) was added as a portion-wise as to maintain internal temperature of 22 °C. At the end of the reaction, the reaction mixture was concentrated in vacuo on a rotavap. The residue was slurried in distilled water (5 vol) to dissolve and remove succinimide. (The succinimide can also be removed by water workup procedure.) The water was decanted and the solid was slurried in 2-propanol (5 vol) overnight. The resulting slurry was filtered and the wetcake was washed with 2-propanol, dried in vacuum oven at 50 °C overnight with N2 bleed until constant weight was achieved. A yellowish tan solid was isolated (50percent yield, 97.5percent AUC). Other impurities were a bromo-regioisomer (1.4percent AUC) and a di-bromo adduct (1.1percent AUC). 1H NMR (500 MHz, DMSO) δ 8.19 (1 H, d, J= 8.1 Hz), 7.06 (br. s, 2 H), 6.64 (d, 1 H, J= 14.3 Hz).

Reference: [1] Patent: US2007/244159, 2007, A1, . Location in patent: Page/Page column 112-113
[2] Patent: US2011/98311, 2011, A1,
[3] Patent: US2015/231142, 2015, A1, . Location in patent: Paragraph 1640; 1979
[4] Patent: WO2010/53471, 2010, A1, . Location in patent: Page/Page column 56-57
[5] Patent: WO2016/109362, 2016, A1, . Location in patent: Paragraph 00168
[6] Patent: US2013/143918, 2013, A1, . Location in patent: Paragraph 0201
[7] Patent: US2013/116238, 2013, A1, . Location in patent: Paragraph 0288; 0289
[8] Patent: WO2014/14841, 2014, A1, . Location in patent: Paragraph 00327
[9] Patent: WO2011/119984, 2011, A1, . Location in patent: Page/Page column 50
[10] Patent: WO2013/185112, 2013, A1, . Location in patent: Paragraph 00580
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  • [ 128-08-5 ]
  • [ 2369-13-3 ]
  • [ 952664-69-6 ]
Reference: [1] Patent: US2012/15999, 2012, A1,
  • 21
  • [ 2369-13-3 ]
  • [ 1152311-62-0 ]
Reference: [1] Patent: WO2011/119984, 2011, A1,
[2] Patent: US2013/143918, 2013, A1,
[3] Patent: WO2013/185112, 2013, A1,
[4] Patent: WO2014/14841, 2014, A1,
[5] Patent: US2015/231142, 2015, A1,
[6] Patent: US2013/116238, 2013, A1,
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