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[ CAS No. 153556-42-4 ]

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CAS No. :153556-42-4 MDL No. :MFCD00672932
Formula : C7H4BrFO2 Boiling Point : 296.1°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :219.01 g/mol Pubchem ID :2773341
Synonyms :

Safety of [ 153556-42-4 ]

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 [ 153556-42-4 ]

  • Upstream synthesis route of [ 153556-42-4 ]
  • Downstream synthetic route of [ 153556-42-4 ]

[ 153556-42-4 ] Synthesis Path-Upstream   1~18

  • 1
  • [ 153556-42-4 ]
  • [ 57848-46-1 ]
Reference: [1] Patent: WO2011/21209, 2011, A1,
[2] Patent: US2012/101099, 2012, A1,
  • 2
  • [ 153556-42-4 ]
  • [ 222978-03-2 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 10, p. 1257 - 1260
  • 3
  • [ 153556-42-4 ]
  • [ 222978-01-0 ]
YieldReaction ConditionsOperation in experiment
94% With borane-THF In tetrahydrofuran at 25℃; General procedure: BH3.THF (89 mL, 89.49 mmol) was added dropwise to a stirred solution of 4-bromo-3-fluorobenzoic acid (9.8 g, 44.75 mmol) in THF (200 mL) at 25°C, over a period of 10 minutes under nitrogen. The resulting solution was stirred at ambient temperaturefor 2 days. The reaction mixture was cautiously quenched with 2M Na2CO3 (200 mL),extracted with Et2O (2 x 500 mL), the organic extratcts were combined, washed with saturated brine (400 mL), dried over MgSO4, filtered and evaporated to afford a paleyellow oil. The crude product was purified by flash silica chromatography, elution gradient 0 to 70percent EtOAc in heptane. Pure fractions were evaporated to dryness to afford (4-bromo-3-fluorophenyl)methanol (8.65 g, 94 percent) as a white solid.
93%
Stage #1: With borane In tetrahydrofuran at 0 - 70℃;
Stage #2: With hydrogenchloride In methanol; water at 25℃; for 2 h;
To a solution of commercially available 4-bromo-3-fluoro-benzoic acid (SI-2) (11 g, 50 mmol) in THF (250 mL) was added BH3 (1.0 M in THF, 100 mL, 100 mmol) at 0 oC and then the solution was stirred at 70 oC overnight. Then, the mixture was quenched with MeOH and 1 N HCl, and stirred at room temperature for an additional 2 hours. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography to obtainSI-3 (9.5 g, 93percent) as a yellow oil.ESI-MS m/z 205 [M+H]+calc. forC7H6BrFO.This intermediate was used in the next step without further characterization.
91.6% With dimethylsulfide borane complex In tetrahydrofuran; diethyl ether at 0 - 20℃; for 6 h; Step 1 (MT-Si):Boranmethyl sulfide in ether (5.0 M; 38.3 mL, 191.8 mmol) was added to a solution of 4- bromo-3-fluorobenzoic acid (21.0 g, 95.9 mmol) in dry tetrahydrofuran (250 mL) at 0°C and the reaction mixture was stirred at room temperature for 6 h. The reaction was quenched with saturated sodium hydrogen carbonate solution, extracted with ethyl acetate, and the combined organic layers were washed with water, brine; dried over anhydrous sodium sulfate and filtered. The solvent was evaporated under vacuum to afford 18 g (91 .6percent) of MTSi as a colorless liquid, further used without any purification.
87% With borane-THF In tetrahydrofuran at 0 - 20℃; for 72 h; Step A: (4-Bromo-3-fluorophenyl methanolA 0°C solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5 ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1 M solution in THF, 15.75 mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with IN HC1, stirred for 20 minutes, then extracted with DCM. Concentration and silica gel chromatography (10-50percent EtOAc/hexanes) yields the title compound 1.87 g (87 percent yield) as colorless needles. 1H NMR (500 MHz, CDC13) δ 7.55 (m, IH), 7.04 (d, J9.4 Hz, IH), 7.04 (d, J 8.3 Hz, IH), 4.70 (d, 2H).
87% With borane-THF In tetrahydrofuran at 20℃; for 72 h; A ooc solution of 4-bromo-3-fluoro benzoic acid (2.3 g, 10.50 mmol) in dry THF (52.5ml) is treated with borane tetrahydrofuran complex (15.75 ml of a 1M solution in THF, 15.75mmol) and the resulting mixture stirred at RT for 72 hours. The mixture is then quenched with20 IN HCl, stirred for 20 minutes, then extracted with DCM. Concentration and silica gelchromatography (10-50percent EtOAc/hexanes) yields the title compound 1.87 g (87percent yield) ascolorless needles. 1H NMR (500 MHz, CDCh) 8 7.55 (m, IH), 7.04 (d, J9.4 Hz, IH), 7.04 (d, J8.3 Hz, IH), 4.70 (d, 2H).
84%
Stage #1: With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 20℃; for 2 h;
Stage #2: With methanol In tetrahydrofuran
To a suspension of sodium borohydride (10.4 g, 0.27 mol) in tetrahydrofuran (200 mL) was added boron trifluoride etherate (44.3 mL, 0.36 mol) followed by 4-bromo-3- fluoro-benzoic acid (10.0 g, 0.04 mol) in THF (200 mL) at ice temperature. The mixture was allowed to stir at room temperature over a period of 2 h. The resulting reaction mixture was quenched with methanol and methanol was removed under reduced pressure. The residue obtained upon evaporation of methanol was diluted with ethyl acetate (1.0 L), washed with water (700 mL), dried over sodium sulphate and concentrated to give (4- bromo-3-fluoro-phenyl)-methanol as off-white solid (7.9 g, 84percent)
84%
Stage #1: With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 20℃; for 2 h; Cooling with ice
Stage #2: With water In ethyl acetate
To a suspension of sodium borohydride (10.4 g, 0.27 mol) in tetrahydrofuran (200 mL) was added boron trifluoride etherate (44.3 mL, 0.36 mol) followed by 4-bromo-3-fluoro-benzoic acid (10.0 g, 0.04 mol) in THF (200 mL) at ice temperature.
The mixture was allowed to stir at room temperature over a period of 2 h.
The resulting reaction mixture was quenched with methanol and methanol was removed under reduced pressure.
The residue obtained upon evaporation of methanol was diluted with ethyl acetate (1.0 L), washed with water (700 mL), dried over sodium sulphate and concentrated to give (4-bromo-3-fluoro-phenyl)-methanol as off-white solid (7.9 g, 84percent).
73%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran for 0.666667 h; Inert atmosphere
Stage #2: With iodine In tetrahydrofuran at 20℃; for 14.5833 h; Cooling with ice
A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4x 3 mL to rinse) under N2 was added drop- wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous TIIF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2x 3 mL) was added drop- wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10percent HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4x 50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50percent CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73percent) as a white solid: mp (CH2Cl2/petroleum ether) 39-40 °C; 1H NMR (CDCl3) δ 7.52 (dd, J = 8.0, 7.2 Hz, 1 H), 7.16 (dd, J = 9.3, 1.8 Hz, 1 H), 7.02 (dd, J = 8.2, 1.8 Hz, 1 H), 4.67 (d, J = 5.9 Hz, 2 H), 1.75 (t, J = 5.9 Hz, 1 H); HREIMS calcd for C7H6BrFO mlz (M+) 205.9567, 203.9586, found 205.9566, 203.9580.
73%
Stage #1: With sodium tetrahydroborate In tetrahydrofuran for 0.666667 h; Inert atmosphere; Cooling with ice
Stage #2: With iodine In tetrahydrofuran at 20℃; for 14.5833 h;
R. Synthesis of (6S)-6-[2-fluoro-4'-(trifluoromethoxy)[1,1'-biphenyl]-4-yl]methoxy}-2-nitro-6,7-dihydro-5H-imidazo[2,1-6][1,3]oxazine (15) by the method of Scheme 11 A suspension of 4-bromo-3-fluorobenzoic acid (84) (1.61 g, 7.35 mmol) in anhydrous THF (10 mL, then 4.x.3 mL to rinse) under N2 was added drop-wise (over 40 min) to a suspension of sodium borohydride (400 mg, 10.6 mmol) in anhydrous THF (15 mL) under N2, and then the mixture was cooled in an ice bath. A solution of iodine (1.008 g, 3.97 mmol) in anhydrous THF (10 mL, then 2.x.3 mL) was added drop-wise (over 35 min) to the stirred solution and then the mixture was stirred at room temperature for 14 h. The mixture was concentrated under reduced pressure and then treated successively with water (20 mL), 10percent HCl (3.4 mL) and water (20 mL), and extracted with CH2Cl2 (4.x.50 mL). The extracts were evaporated to dryness and the residue was chromatographed on silica gel, eluting with 50percent CH2Cl2/petroleum ether, to give (4-bromo-3-fluorophenyl)methanol (85) (1.096 g, 73percent) as a white solid: mp (CH2Cl2/petroleum ether) 39-40° C.; 1H NMR (CDCl3) δ 7.52 (dd, J=8.0, 7.2 Hz, 1H), 7.16 (dd, J=9.3, 1.8 Hz, 1H), 7.02 (dd, J=8.2, 1.8 Hz, 1H), 4.67 (d, J=5.9 Hz, 2H), 1.75 (t, J=5.9 Hz, 1H); HREIMS calcd for C7H6BrFO m/z (M+) 205.9567, 203.9586, found 205.9566, 203.9580.

Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 21, p. 9096 - 9104
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
[3] Synlett, 2014, vol. 25, # 1, p. 123 - 127
[4] European Journal of Medicinal Chemistry, 2018, vol. 150, p. 506 - 524
[5] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 10, p. 1257 - 1260
[6] Patent: WO2014/140279, 2014, A1, . Location in patent: Page/Page column 83; 161; 162
[7] Patent: WO2012/173917, 2012, A1, . Location in patent: Page/Page column 51
[8] Patent: WO2014/52379, 2014, A1, . Location in patent: Page/Page column 48
[9] Patent: WO2011/21209, 2011, A1, . Location in patent: Page/Page column 38
[10] Patent: US2012/101099, 2012, A1, . Location in patent: Page/Page column 13; 14
[11] Patent: WO2011/14774, 2011, A1, . Location in patent: Page/Page column 40; 41
[12] Patent: US2012/28973, 2012, A1, . Location in patent: Page/Page column 16
[13] Patent: US2003/220241, 2003, A1,
[14] Patent: US2002/49217, 2002, A1,
[15] Patent: US2002/99007, 2002, A1,
[16] Patent: US6350755, 2002, B1,
[17] Patent: US6413964, 2002, B1,
[18] Patent: US6358985, 2002, B1,
[19] Patent: US6562823, 2003, B1,
[20] Patent: US6297239, 2001, B1,
[21] Patent: US2016/24060, 2016, A1,
  • 4
  • [ 153556-42-4 ]
  • [ 222978-02-1 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
[2] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 10, p. 1257 - 1260
  • 5
  • [ 452-74-4 ]
  • [ 153556-42-4 ]
YieldReaction ConditionsOperation in experiment
73%
Stage #1: at 90℃; for 3 h;
Stage #2: With sodium hydroxide In water
Stage #3: With hydrogenchloride In water
To a solution of l-bromo-2-fluoro-4-methyl -benzene (20.0 g, 0.10 mol) in 1:1 ratio of pyridine: water (200 mL) was added potassium permanganate (66.0 g, 0.42 mmol) portion wise at 90 °C and the reaction mixture was stirred at 90 °C over a period of 3 h. The resulting reaction mixture was allowed to reach room temperature and filtered trough celite pad. The celite pad was washed with 3N sodium hydroxide (500 mL) and water (400 mL). Then ethanol was removed under reduced pressure and residue was acidified (pH=2) with 6N hydrochloric acid to obtained white precipitate. The precipitate obtained was filtered and dried to give 4-bromo-3 -fluoro-benzoic acid as white solid (17.0 g, 73percent).
73%
Stage #1: With potassium permanganate In pyridine; water at 90℃; for 3 h;
Stage #2: With sodium hydroxide In water
Stage #3: With hydrogenchloride In water
To a solution of 1-bromo-2-fluoro-4-methyl-benzene (20.0 g, 0.10 mol) in 1:1 ratio of pyridine: water (200 mL) was added potassium permanganate (66.0 g, 0.42 mmol) portion wise at 90° C. and the reaction mixture was stirred at 90° C. over a period of 3 h.
The resulting reaction mixture was allowed to reach room temperature and filtered trough celite pad.
The celite pad was washed with 3N sodium hydroxide (500 mL) and water (400 mL).
Then ethanol was removed under reduced pressure and residue was acidified (pH=2) with 6N hydrochloric acid to obtained white precipitate.
The precipitate obtained was filtered and dried to give 4-bromo-3-fluoro-benzoic acid as white solid (17.0 g, 73percent).
28%
Stage #1: With potassium permanganate In water at 95℃; for 22 h;
Stage #2: With hydrogenchloride In water
4-Bromo-3-fluorotoluene (24.4 g, 0.128 mol) was added to a mixture of KMnO4 (24g, 0.154 mol) in water (150 ml). The mixture was heated at 95°C for 2 hrs then additional KMnO4 (24 g) was added, after a further 2 hrs at 95 °C additional KMnO4 (24 g) was added and heating was maintained at 950C for 18 hours. The hot mixture was then filtered through a pad of diatomaceous earth and washed with water. The filtrate was acidified to pH 2 with 2N HCl and the white suspension was filtered and dried to give the product (7.33 g). The filtrate was extracted with EtOAc (2 x250 ml), the organic extracts dried and evaporated in vacuo to give additional product. Combined product (7.92g, 28percent). NMR: 7.68 (d, IH), 7.74 (d, IH), 7.82-7.87 (m, IH); M/z (M-Hy 217.
Reference: [1] Bioorganic and Medicinal Chemistry Letters, 2001, vol. 11, # 10, p. 1257 - 1260
[2] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
[3] Patent: WO2011/21209, 2011, A1, . Location in patent: Page/Page column 38
[4] Patent: US2012/101099, 2012, A1, . Location in patent: Page/Page column 13; 14
[5] Patent: WO2006/64251, 2006, A1, . Location in patent: Page/Page column 80
[6] Patent: US5856274, 1999, A,
[7] Patent: US5334753, 1994, A,
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Reference: [1] Patent: US2003/220241, 2003, A1,
[2] Patent: US2003/220241, 2003, A1,
[3] Patent: US2003/220241, 2003, A1,
[4] Patent: US2002/49217, 2002, A1,
[5] Patent: US2002/99007, 2002, A1,
[6] Patent: US6358985, 2002, B1,
[7] Patent: US6350755, 2002, B1,
[8] Patent: US6297239, 2001, B1,
[9] Patent: US6316436, 2001, B1,
[10] Patent: US6284755, 2001, B1,
[11] Patent: US6413964, 2002, B1,
  • 7
  • [ 452-74-4 ]
  • [ 153556-42-4 ]
Reference: [1] Patent: US6562823, 2003, B1,
  • 8
  • [ 153556-42-4 ]
  • [ 101048-76-4 ]
Reference: [1] Journal of Medicinal Chemistry, 2003, vol. 46, # 14, p. 2973 - 2984
  • 9
  • [ 153556-42-4 ]
  • [ 74733-25-8 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
  • 10
  • [ 557-21-1 ]
  • [ 153556-42-4 ]
  • [ 176508-81-9 ]
Reference: [1] Patent: WO2007/70826, 2007, A1, . Location in patent: Page/Page column 121
[2] Patent: WO2005/123050, 2005, A2, . Location in patent: Page/Page column 153
  • 11
  • [ 557-21-1 ]
  • [ 153556-42-4 ]
  • [ 176508-81-9 ]
Reference: [1] Journal of Medicinal Chemistry, 2014, vol. 57, # 23, p. 9915 - 9932
  • 12
  • [ 67-56-1 ]
  • [ 153556-42-4 ]
  • [ 849758-12-9 ]
YieldReaction ConditionsOperation in experiment
100% at 80℃; for 5 h; To a solution of 4-bromo-3-fluoro-benzoic acid (5.0 g, 22.9 mmol) in MeOH (60 mL) was added thionyl chloride (10 mL), This mixture was heated for about 5 h at 80 degrees Celsius until the starting material had been consumed, and then evaporated in vacuo to give white solid product (5.3 g, 100percent).
97% at 80℃; for 18 h; STEP 2: To 1 -methylpiperazine (980 μl, 8.80 mmol) in toluene (15 ml) was added tris(dibenzylidene acetone)dipalladium (201 mg, 0.22 mmol), BINAP (550 mg, 0.88 mmol), and cesium carbonate (4.30 g, 13.2 mmol). The mixture was stirred for 30 minutes before the addition of methyl 4-bromo-3-fluorobenzoate (2.05 g, 8.80 mmol), after which, the temperature was increased to 1050C and stirred for an additional 18 h. The mixture was cooled and filtered through Celite, washed with ethyl acetate, and the resultant filtrate concentrated in vacuo to afford an orange oil. The residue was purified by column chromatography eluting with 5percent methanol in <n="372"/>dichloromethane. Pure fractions were concentrated to afford (1.80 g, 81percent) of methyl 3-fluoro-4-(4-methylpiperazin-l-yl)benzoate as a colorless oil. 1H NMR (400 MHz, CD3OD): 7.78-7.73 (d, IH), 7.64-7.59 (d, IH), 7.09-7.03 (m, IH), 3.86 (s, 3H), 3.26- 3.20 (m, 4H), 2.65-2.59 (m, 4H), 2.35 (s, 3H). MS (EI) for Ci3H17FN2O2: 253 (MH+).
95% With diazomethyl-trimethyl-silane In hexanes; toluene at 0 - 20℃; for 0.666667 h; Step a) Methyl 4-bromo-3-fluorobenzoate (9a)
3-Fluoro-4-[2-(4-methylpiperazin-1-yl)-thiazol-4-yl]benzoic acid HCl salt
4-Bromo-3-fluorobenzoic acid (2.46 g, 11.2 mmol) was dissolved in MeOH (9 mL) and toluene (4 mL) and cooled in an ice bath. (Trimethylsilyl)diazomethane (11 mL, 2.0 M in hexanes, 22 mmol) was added dropwise until the yellow color persisted.
The solution was stirred at room temperature for 40 mins and then concentrated in vacuo.
A second batch of carboxylic acid (2.43 g) was treated similarly.
The crude product from both batches were combined and subjected to flash chromatography (silica, 5/1 pentane-EtOAc) to give the methyl ester as white solids (4.92 g, 95percent yield).
1H NMR (400 MHz, CDCl3) delta ppm 7.77 (m, 1H), 7.71 (m, 1H), 7.64 (m, 1H), 3.93 (s, 3H).
95% With diazomethyl-trimethyl-silane In hexane; toluene at 0 - 20℃; for 0.666667 h; Example 35
{(2S,5S)-2-[5-(2-Fluoro-4'-{2-[(S)-1-((S)-2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-1H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-1,2,4,5,6,7-hexahydro-azepino[3,2,1-hi]indol-5-yl}-carbamic acid methyl ester
4-Bromo-3-fluorobenzoic acid (2.46 g, 11.2 mmol) was dissolved in MeOH (9 ml) and toluene (4 ml) and then was cooled in an ice-water bath to 0° C. (Trimethylsilyl)-diazamethane (11 ml, 2 M in hexane, 22 mmol) was added dropwise to the reaction mixture at 0° C.
The reaction mixture was raised to room temperature and stirred for 40 min at RT and was concentrated in vacuo.
The resulting residue was added toluene and further concentrated under high vacuum to obtain 2.5 g (95percent yield) of Methyl 4-bromo-3-fluorobenzoate as white solid. 1H NMR (DMSO-d6) δ: 7.75-7.83 (m, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.61 (d, J=8.3 Hz, 1H), 3.20 (s, 1H).

Reference: [1] Patent: US2010/216806, 2010, A1, . Location in patent: Page/Page column 103
[2] Patent: WO2009/55077, 2009, A1, . Location in patent: Page/Page column 369
[3] Patent: US2009/23748, 2009, A1, . Location in patent: Page/Page column 21
[4] Patent: US2012/230951, 2012, A1, . Location in patent: Page/Page column 97-98
[5] Patent: WO2016/20836, 2016, A1, . Location in patent: Page/Page column 101; 102
[6] Patent: WO2016/201096, 2016, A1, . Location in patent: Paragraph 00357
  • 13
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  • [ 18107-18-1 ]
  • [ 849758-12-9 ]
YieldReaction ConditionsOperation in experiment
95% at 0 - 20℃; for 0.666667 h; 4-Bromo-3-fluorobenzoic acid (2.46 g, 11.2 mmol) was dissolved in MeOH (9 ml_) and toluene (4 ml_) and cooled in an ice bath. (Trimethylsilyl)diazomethane (11 ml_, 2.0 M in hexanes, 22 mmol) was added dropwise until the yellow color persisted. The solution was stirred at room temperature for 40 mins and then concentrated in vacuo. A second batch of carboxylic acid (2.43 g) was treated similarly. The crude product from both batches were combined and subjected to flash chromatography (silica, 5/1 pentane - EtOAc) to give the methyl ester as white solids (4.92 g, 95percent yield).1H NMR (400 MHz, CDCI3) delta ppm 7.77 (m, 1 H), 7.71 (m, 1 H), 7.64 (m, 1 H), 3.93 (s, 3H).
95% at 20℃; Cooling in ice 4-Bromo-3-fluorobenzoic acid (2.46 g, 1 1.2 mmol) was dissolved in MeOH (9 ml.) and toluene (4 ml.) and cooled in an ice bath. (Trimethylsilyl)diazomethane (11 ml_, 2.0 M in hexanes, 22 mmol) was added dropwise until the yellow color persisted. The solution was stirred at room temperature for 40 mins and then concentrated in vacuo. A second batch of carboxylic acid (2.43 g) was treated similarly. The crude product from both batches were combined and subjected to flash chromatography (silica, 5/1 pentane - EtOAc) to give the methyl ester as white solids (4.92 g, 95percent yield).1H NMR (400 MHz, CDCI3) delta ppm 7.77 (m, 1 H), 7.71 (m, 1 H), 7.64 (m, 1 H), 3.93 (s, 3H).
95% at 20℃; Cooling in ice 4-Bromo-3-fluorobenzoic acid (2.46 g, 11.2 mmol) was dissolved in MeOH (9 ml.) and toluene (4 ml.) and cooled in an ice bath. (Trimethylsilyl)diazomethane (11 ml_, 2.0 M in hexanes, 22 mmol) was added dropwise until the yellow color persisted. The solution was stirred at room temperature for 40 mins and then concentrated in vacuo. A second batch of carboxylic acid (2.43 g) was treated similarly. The crude product from both batches were combined and subjected to flash chromatography (silica, 5/1 pentane - EtOAc) to give the methyl ester as white solids (4.92 g, 95percent yield).1H NMR (400 MHz, CDCI3) delta ppm 7.77 (m, 1 H), 7.71 (m, 1 H), 7.64 (m, 1 H), 3.93 (s, 3H).
Reference: [1] Patent: WO2008/114054, 2008, A1, . Location in patent: Page/Page column 46
[2] Patent: WO2010/34788, 2010, A1, . Location in patent: Page/Page column 29
[3] Patent: WO2010/34789, 2010, A1, . Location in patent: Page/Page column 24
[4] Journal of Medicinal Chemistry, 2014, vol. 57, # 6, p. 2334 - 2356
[5] Patent: US2002/55631, 2002, A1,
[6] Patent: US2002/86887, 2002, A1,
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  • [ 74-88-4 ]
  • [ 849758-12-9 ]
YieldReaction ConditionsOperation in experiment
100% With potassium carbonate In N,N-dimethyl-formamide at 20℃; for 2.5 h; (32c) methyl 4-bromo-3-fluorobenzoate 4-Bromo-3-fluorobenzoic acid (5.0 g, 23 mmol) was suspended in dimethylformamide (20 mL), potassium carbonate (6.30 g, 45.6 mmol) and methyl iodide (1.71 mL, 27.4 mmol) were added, and the mixture was stirred at room temperature for 2.5 hr. Ethyl acetate was added and the mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title object compound as a pale-yellow powder (5.7 g, yield 100percent). 1H-NMR (CDCl3, 400 MH) δ: 3.93 (3H, s), 7.60-7.80 (3H, m).
Reference: [1] Patent: US2016/207883, 2016, A1, . Location in patent: Paragraph 0799-0801
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  • [ 304445-49-6 ]
Reference: [1] Patent: US2011/212967, 2011, A1,
[2] Patent: US2017/253614, 2017, A1,
  • 16
  • [ 64-17-5 ]
  • [ 153556-42-4 ]
  • [ 1130165-74-0 ]
YieldReaction ConditionsOperation in experiment
100% at 60℃; for 66 h; To a suspension of 4-bromo-3-fluorobenzoic acid (15.0 g) in EtOH (230 mL), concentrated sulphuric acid (8.0 mL) was added. Reaction mixture was warmed at 60°C for 66 Hrs. After cooling to room temperature, solvent was removed under reduced pressure. The residue was tretaed with NaOH 1N solution (70 mL), then extracted with EtOAc (500 mL). Organic layer was washed with water (250 mL), brine (250 mL), dried over MgSO4 and then concentrated under reduced pressure. Product was obtained as a light yellow solid (17.0 g) in quantitative yield. M/Z (M[79Br]+H)+ = 247.
Reference: [1] Patent: EP2210891, 2010, A1, . Location in patent: Page/Page column 17-18
[2] Journal of Medicinal Chemistry, 2009, vol. 52, # 6, p. 1540 - 1545
  • 17
  • [ 153556-42-4 ]
  • [ 1220886-29-2 ]
Reference: [1] Patent: WO2014/128655, 2014, A1,
[2] Patent: WO2015/17589, 2015, A1,
[3] Patent: US2015/183802, 2015, A1,
[4] Patent: WO2015/102929, 2015, A1,
[5] Patent: WO2016/20836, 2016, A1,
[6] Patent: WO2010/37210, 2010, A1,
  • 18
  • [ 153556-42-4 ]
  • [ 1020717-99-0 ]
YieldReaction ConditionsOperation in experiment
99.5% at 20℃; for 18 h; Compound 1 (75 g, 342.5 mmol) was dissolved in sulfuric acid (500 ml) at room temperature, and nitric acid (103.8 g, 1027 mmol) was added slowly. After stirring for 18 h, the mixture was slowly poured over 3 kg of ice, stirred, filtered, washed with water and dried at 45 ° C under reduced pressure to give compound 2 (90 g, 99.5percent).
75% at 20℃; for 3 h; Inert atmosphere To a solution of 4-bromo-3-fluorobenzoic acid (20 g, 91 mmol) in concentrated H2S04 (70 mL) at room temperature was added potassium nitrate (9.69 g, 96 mmol) portionwise and the reaction mixture was stirred at 20 °C for 3 hr. The reaction solution was combined with other batches and the mixture was poured onto ice. The solid was collected by filtration and dried to give 4-bromo-5-fluoro-2-nitrobenzoic acid (45 g, 153 mmol, 75 percent yield) as a white solid.
Reference: [1] Patent: CN106146482, 2016, A, . Location in patent: Paragraph 0124; 0125; 0126
[2] Patent: WO2017/98440, 2017, A1, . Location in patent: Page/Page column 113
[3] Patent: WO2014/128655, 2014, A1, . Location in patent: Page/Page column 20
[4] Patent: WO2015/17589, 2015, A1, . Location in patent: Page/Page column 42
[5] Patent: US2015/183802, 2015, A1, . Location in patent: Paragraph 1175-177
[6] Patent: WO2015/102929, 2015, A1, . Location in patent: Page/Page column 139
[7] Patent: WO2010/37210, 2010, A1, . Location in patent: Page/Page column 79-80
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