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Chemical Structure| 327-51-5
Chemical Structure| 327-51-5
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Product Details of [ 327-51-5 ]

CAS No. :327-51-5 MDL No. :MFCD00000346
Formula : C6H2Br2F2 Boiling Point : -
Linear Structure Formula :- InChI Key :GLVMLJCMUBZVTJ-UHFFFAOYSA-N
M.W : 271.88 Pubchem ID :67596
Synonyms :

Calculated chemistry of [ 327-51-5 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 10
Num. arom. heavy atoms : 6
Fraction Csp3 : 0.0
Num. rotatable bonds : 0
Num. H-bond acceptors : 2.0
Num. H-bond donors : 0.0
Molar Refractivity : 41.76
TPSA : 0.0 Ų

Pharmacokinetics

GI absorption : Low
BBB permeant : No
P-gp substrate : No
CYP1A2 inhibitor : Yes
CYP2C19 inhibitor : No
CYP2C9 inhibitor : No
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.47 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.37
Log Po/w (XLOGP3) : 3.5
Log Po/w (WLOGP) : 4.33
Log Po/w (MLOGP) : 4.63
Log Po/w (SILICOS-IT) : 4.05
Consensus Log Po/w : 3.78

Druglikeness

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

Water Solubility

Log S (ESOL) : -4.17
Solubility : 0.0182 mg/ml ; 0.0000669 mol/l
Class : Moderately soluble
Log S (Ali) : -3.18
Solubility : 0.178 mg/ml ; 0.000656 mol/l
Class : Soluble
Log S (SILICOS-IT) : -4.66
Solubility : 0.00595 mg/ml ; 0.0000219 mol/l
Class : Moderately soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 1.0 alert
Leadlikeness : 0.0
Synthetic accessibility : 1.68

Safety of [ 327-51-5 ]

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 [ 327-51-5 ]

* 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 [ 327-51-5 ]
  • Downstream synthetic route of [ 327-51-5 ]

[ 327-51-5 ] Synthesis Path-Upstream   1~13

  • 1
  • [ 540-36-3 ]
  • [ 399-94-0 ]
  • [ 327-51-5 ]
Reference: [1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 1593; engl. Ausg. S. 1566
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 153[3] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
[4] Green Chemistry, 2012, vol. 14, # 9, p. 2380 - 2383
  • 2
  • [ 540-36-3 ]
  • [ 399-94-0 ]
  • [ 327-51-5 ]
  • [ 128259-70-1 ]
  • [ 128259-69-8 ]
Reference: [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406
  • 3
  • [ 124-38-9 ]
  • [ 327-51-5 ]
  • [ 28314-82-1 ]
YieldReaction ConditionsOperation in experiment
97%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h; Inert atmosphere
Stage #2: at 20℃; for 1 h;
(a) 4-bromo-2,5-difluorobenzoic acid To a 780C solution of 1,4-dibromo-2,5-difluorobenzene (2.72 g, 9.99 mmol) in dry Et20 (30 mL) under an inert atmosphere was added 2.5 M n-butyllithium solution in hexanes (4 mL, 9.99 mmol) drop-wise and the mixture left stirring for 2 h. Crushed CO2 pellets were added slowly and the mixture was allowed to warm to ambient temperature and left stirring for 1 h. After quenching with 1M aqueous HCI (10 mL) the mixture was basified with 1M aqueous NaOH (70 mL) and then washed with Et20 (2 x 50 mL). The aqueous layer was acidified with 1M aqueous HCI (80 mL) and extracted with Et20 (3 x 100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and solvent was removed in vacuo to give 4-bromo-2,5-difluoro benzoic acid (2.3 g, 97 percent) as an off-white solid, which was used without further purification.1H NMR (Method B) (CDCI3): O ppm 9.50 (brs, 1H), 7.78 (dd, J= 8.2, 6.1 Hz, 1H), 7.46 (dd, J= 9.3, 5.4 Hz, 1H); LC-MS (Method C) 234.9/236.9 [M-H] RT 3.43 mm
97%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 2 h; Inert atmosphere
Stage #2: at 20℃; for 1 h;
To a -78°C solution of 1 ,4-dibromo-2,5-difluorobenzene (2.72 g, 9.99 mmol) in dry Et20 (30 mL) under an inert atmosphere was added 2.5 M n-butyllithium solution in hexanes (4 mL, 9.99 mmol) drop-wise and the mixture left stirring for 2 h. Crushed CO2 pellets were added slowly and the mixture was allowed to warm to ambient temperature and left stirring for 1 h. After quenching with 1 M aqueous HCI (10 mL) the mixture was basified with 1 M aqueous NaOH (70 mL) and then washed with Et20 (2 χ 50 mL). The aqueous layer was acidified with 1 M aqueous HCI (80 mL) and extracted with Et20 (3 χ 100 mL). The organic layer was washed with brine (50 mL), dried over Na2S04, filtered and solvent was removed in vacuo to give 4-bromo-2,5-difluoro benzoic acid (2.3 g, 97 percent) as an off-white solid, which was used without further purification. 1 H NMR (Method B) (CDC ): δ ppm 9.50 (br s, 1 H), 7.78 (dd, J = 8.2, 6.1 Hz, 1 H), 7.46 (dd, J = 9.3, 5.4 Hz, 1 H); LC-MS (Method C) 234.9/236.9 [M-H]+; RT 3.43 min
85%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; Inert atmosphere
Stage #2: at -78 - 20℃;
Stage #3: With hydrogenchloride In water
Under an argon atmosphere, to a solution of 1,4-dibromo-2,5-difluorobenzene (1) (20.00 g, 73.6mmol) in diethyl ether (160 mL) was added dropwise 1.6 M n-butyl lithium solution in hexane(1.05 eq, 49 mL) at -78 °C, and the mixture was stirred at same temperature for 2 min. Themixture was added quickly to the mixture of dry ice (about 100 g) and diethyl ether (200 mL),and the mixture was warmed up to room temperature. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was treated with water (50 mL) and 1 M hydrochloric acid (150 mL), and extracted with diethyl ether. The organic layer was washed with brine and dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo. The resulting residue was washed with hexane, dried in vacuo to obtain 4-bromo-2,5-difluorobenzoic acid ( 14.8 g, 85 percent) as a pale yellow solid: 1H NMR (DMSO-d6) δ 7.78(1H, dd, J = 6.4, 8.3 Hz), 7.89 (1H, dd, J = 5.9, 9.8 Hz).
84.4%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78 - 20℃; Inert atmosphere
Stage #3: With hydrogenchloride In water
To the solution of XLVII-1 (13.55 g, 50 mmol), in Et2O (150 mL) was added n-BuLi (2.5 N, 20 mL) at −78° C. The reaction mixture was stirred at −78° C. under Ar for 30 min and CO2 was bubbled into the solution. The mixture was warmed up to rt. The precipitate was collected by filtration and washed with Et2O. The obtained solid was treated with water and HCl (1N) to pH=2. The mixture was extracted with t-BuOMe. The combined organic layers were washed with brine, dried over MgSO4, and concentrated to afford XLVII-2 (10.0 g, yield 84.4percent), which was used next step without purification.
83%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.0333333 h; Inert atmosphere
Stage #2: at -78 - 20℃; Inert atmosphere
Stage #3: With hydrogenchloride In diethyl ether; hexane; waterInert atmosphere
Under an argon atmosphere, to a solution of 1,4-dibromo-2,5-difluorobenzene (10, 70.00 g) in diethyl ether (500 mL) was added dropwise 1.58 M n-butyl lithium solution in hexane (171 mL) at -78 °C, and the mixture was stirred at same temperature for 2 min. The mixture was added quickly to the mixture of dry ice (about 300 g) and diethyl ether (600 mL), and the mixture was warmed up to room temperature. The precipitate was collected by filtration, and washed with diethyl ether. The obtained solid was treated with water (100 mL) and 1 M hydrochloric acid (500 mL), and extracted with diethyl ether. The organic layer was washed with brine and dried. The desiccant was removed by filtration and the filtrate was evaporated in vacuo. The resulting residue was washed with hexane, dried in vacuo to obtain 11a (53.29 g, 83percent) as a pale yellow solid: 1H NMR (DMSO-d6) δ 7.78 (1H, dd, J = 6.4, 8.3 Hz), 7.89 (1H, dd, J = 5.9, 9.8 Hz); FAB-MS m/z 235, 237 [(M-H)-].
76%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 3 h; Inert atmosphere
Stage #2: for 0.5 h;
To the solution of 1,4- dibromo-2,5-difluorobenzene (i-6a) (27.0 g, 100 mmol) in THF(500 ml) was added n-BuLi (60 ml, 2M) dropwise at -78°C and stirred for 3 h which was protected by N2 .Then the solution was poured to excess dry ice over 0.5 h. Added 300 ml water to the solution, washed with EA (100 mix 3). The aqueous solution was acidified with HC1 (2M), extracted with EA (150 ml><3) and the organic layer was dried and concentrated. The crude material was purified by chromatography column (EA:PE = 1 : 10) to afford 18.24 g product (76percent). LCMS (ESI) calc'd [M+H]+: 237.00, found: 237.1.
76%
Stage #1: With n-butyllithium In tetrahydrofuran at -78℃; for 3 h;
Stage #2: With water In tetrahydrofuran for 0.5 h;
To a solution of 1,4-dibromo-2,5-difluorobenzene (i-6a) (27.0 g, 100 mmol) in THF(500 ml) was added n-BuLi (60 ml, 2M) dropwise at -78°C and the reaction mixture was kept stirring for 3h. Then excess dry ice was added into the reaction mixure portwise over 0.5 h. The reaction mixture wasquenched with 300 ml water and extracted with EA (100 mlx 3). The aqueous solution was acidified with HC1 (2M), extracted with EA (150 mlx3), and the organic layer was dried and concentrated. The crude material was purified by chromatography column (EA:PE = 1:10) to afford 18.24 g product (76percent). LCMS (ESI) calc’d [M+H]: 237.00, found: 237.1.
67%
Stage #1: With n-butyllithium In hexane; monoethylene glycol diethyl ether at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at -78 - 20℃;
1,4-Dibromo-2,5-difluorobenzene (51.2 g, 188 mmol) was dissolved in 1,2-diethoxyethane (400 ml), and a 2.5 M n-butyllithium/ hexane solution (76.0 ml, 190 mmol) was slowly added dropwise thereto at −78° C. in the presence of nitrogen gas. [0674] After the reaction solution was stirred at −78° C. for 30 minutes, dry ice was added thereto, followed by stirring for further 30 minutes. After the temperature was gradually raised to room temperature, water (200 ml) was added to the reaction liquid. The reaction liquid was diluted with ethyl acetate, and washed with a 10percent aqueous sodium carbonate solution (200 ml×2). Then, the obtained aqueous layers were combined, and made acidic by adjustment with 1 N hydrochloric acid. The precipitated yellow solid was filtered and dried to obtain the title compound (30.0 g, 67percent). [0675] 1H NMR (DMSO-d6, 400 MHz): δ 7.90-7.87 (m, 1H), 7.79-7.75 (m, 1H).; MS (ESI) m/z 191 (M+H-44)+
67% With n-butyllithium In hexane at -78℃; for 1 h; Inert atmosphere (Step 2) 4-Bromo-2,5-difluorobenzoic acid (0236) (0237) 1,4-Dibromo-2,5-difluorobenzene (51.2 g, 188 mmol) was dissolved in 1,2-diethoxyethane (400 ml), and a 2.5 M n-butyllithium/hexane solution (76.0 ml, 190 mmol) was slowly added thereto dropwise at −78° C. in the presence of nitrogen gas. The reaction solution was stirred at −78° C. for 30 minutes, then dry ice was added, and the resulting mixture was further stirred for 30 minutes. The temperature was gradually raised to room temperature, and then water (200 ml) was added to the reaction liquid. The reaction liquid was diluted with ethyl acetate, the resulting solution was washed with a 10percent aqueous solution of sodium carbonate (200 ml×2), then the obtained aqueous layers were combined, 1 N hydrochloric acid was added for adjustment to acidic pH, and the precipitated yellow solid was filtered and dried to obtain the title compound (30.0 g, 67percent). (0238) 1H NMR (DMSO-d6, 400 MHz): δ 7.90-7.87 (m, 1H), 7.79-7.75 (m, 1H); MS (ESI) m/z 191 (M+H−44)+
58.5%
Stage #1: With n-butyllithium In diethyl ether at -78℃; for 2.5 h;
Stage #2: at -78℃; for 0.5 h;
STEP 1 : SYNTHESIS OF 4-BROMO-2,5-DIFLUOROBENZOIC ACID
[00316] To a solution of l,4-dibromo-2,5-difluorobenzene (30.0 g, 110 mmol) in diethyl ether (300 mL), n-BuLi (1.6 M in hexanes, 44.1 mL, 110 mmol) was added dropwise at -78 °C over a period of 30 min. The reaction mixture was stirred at -78 °C for 2 h. Carbon dioxide gas was bubbled through the reaction mixture at the same temperature for 30 min. The reaction mixture was quenched with 1 N aqueous HC1 (200 mL) and extracted with ethyl acetate (2 x 400 mL). The combined organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 4-bromo-2,5-difluorobenzoic acid (15.3 g, 58.5percent) as off white solid. TLC solvent system: 30percent> EtOAc in hexanes. Product's Rf: 0.1. MS (ESI, positive ion) m/z; No ionization. 1H NMR (400 MHz, DMSO) δ 13.79 (s, 1H), 7.88 (dd, J= 9.7, 5.6 Hz, 1H), 7.77 (dd, J= 8.6, 6.3 Hz, 1H).
53%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h; Cooling with acetone-dry ice
Stage #2: at -78 - 20℃; for 0.583333 h; Cooling with acetone-dry ice
Intermediate 24A: 4-Bromo-2,5-difluorobenzoic acid
A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol).
The solution was stirred at -78° C. for 30 min, then was treated with a piece of dry ice.
The cooling bath was removed after 5 min and the mixture was stirred for another 30 min while warming to room temperature.
The mixture was diluted with EtOAc and water.
The organic phase was separated and washed twice with saturated aqueous NaHCO3.
The combined aqueous phases were acidified with 1M aqueous HCl, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53percent yield).
53%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at 20℃; for 0.583333 h; Cooling with acetone-dry ice
A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n20 butyllithium in hexanes (1.04 mL, 2.59 mmol). The solution was stirred at -78 °C for 30mm, then was treated with a piece of dry ice. The cooling bath was removed after 5 mm and the mixture was stirred for another 30 mm while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCO3. The combined aqueous phases were acidified with 1 M aqueous HC1, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53percent yield).
53%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 0.583333 h;
A solution of 1,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n-butyllithium in hexanes (1.04 mL, 2.59 mmol).
The resulting solution was stirred at -78° C. for 30 min, then was treated with a piece of dry ice.
The cooling bath was removed after 5 min and the mixture was stirred for another 30 min while warming to room temperature.
The mixture was diluted with EtOAc and water.
The organic phase was separated and washed twice with saturated aqueous NaHCO3.
The combined aqueous phases were acidified with 1 M aqueous HCl, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53percent yield).
53%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 0.583333 h;
A solution of l,4-dibromo-2,5-difluorobenzene (640 mg, 2.35 mmol) in dry diethyl ether (10 mL) cooled in a dry ice-acetone bath was treated dropwise with 2.5 M n- butyllithium in hexanes (1.04 mL, 2.59 mmol). The solution was stirred at -78 °C for 30 min, then was treated with a piece of dry ice. The cooling bath was removed after 5 min and the mixture was stirred for another 30 min while warming to room temperature. The mixture was diluted with EtOAc and water. The organic phase was separated and washed twice with saturated aqueous NaHCC . The combined aqueous phases were acidified with 1 M aqueous HCI, extracted twice with DCM, and the combined organic phases were dried and concentrated to give 4-bromo-2,5-difluorobenzoic acid as a white solid (297 mg, 53percent yield).

Reference: [1] Patent: WO2015/155549, 2015, A1, . Location in patent: Page/Page column 105; 106
[2] Patent: WO2017/46603, 2017, A1, . Location in patent: Page/Page column 97; 98
[3] Molecular Pharmacology, 2016, vol. 89, # 2, p. 303 - 312
[4] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 1321; 1322
[5] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5235 - 5246
[6] Patent: WO2014/26327, 2014, A1, . Location in patent: Page/Page column 57
[7] Patent: WO2014/28589, 2014, A2, . Location in patent: Page/Page column 59; 60
[8] Patent: US2015/51395, 2015, A1, . Location in patent: Paragraph 0673-0675
[9] Patent: US2016/244451, 2016, A1, . Location in patent: Paragraph 0236; 0237; 0238
[10] Patent: WO2015/51043, 2015, A1, . Location in patent: Paragraph 00316
[11] Patent: US2014/378475, 2014, A1, . Location in patent: Paragraph 0430; 0431
[12] Patent: WO2016/65236, 2016, A1, . Location in patent: Page/Page column 72; 73
[13] Patent: US2016/115126, 2016, A1, . Location in patent: Paragraph 0297-0298
[14] Patent: WO2016/65222, 2016, A1, . Location in patent: Page/Page column 49-50
[15] Patent: WO2005/19228, 2005, A1, . Location in patent: Page/Page column 49-50
[16] Patent: WO2012/106995, 2012, A1, . Location in patent: Page/Page column 50-51
[17] Patent: WO2017/46605, 2017, A1, . Location in patent: Page/Page column 66-67
[18] Patent: WO2009/133110, 2009, A1, . Location in patent: Page/Page column 45
  • 4
  • [ 327-51-5 ]
  • [ 28314-82-1 ]
Reference: [1] Patent: WO2014/117274, 2014, A1,
  • 5
  • [ 124-38-9 ]
  • [ 540-36-3 ]
  • [ 327-51-5 ]
Reference: [1] Patent: US5075319, 1991, A,
  • 6
  • [ 540-36-3 ]
  • [ 399-94-0 ]
  • [ 327-51-5 ]
Reference: [1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. 1593; engl. Ausg. S. 1566
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 153[3] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
[4] Green Chemistry, 2012, vol. 14, # 9, p. 2380 - 2383
  • 7
  • [ 540-36-3 ]
  • [ 327-51-5 ]
Reference: [1] Zhurnal Obshchei Khimii, 1959, vol. 29, p. engl. Ausg. S. 1566
[2] Journal of the American Chemical Society, 1951, vol. 73, p. 153[3] Journal of the American Chemical Society, 1959, vol. 81, p. 94,98
  • 8
  • [ 540-36-3 ]
  • [ 399-94-0 ]
  • [ 327-51-5 ]
  • [ 128259-70-1 ]
  • [ 128259-69-8 ]
Reference: [1] Journal of Fluorine Chemistry, 1990, vol. 46, # 3, p. 393 - 406
  • 9
  • [ 327-51-5 ]
  • [ 133541-45-4 ]
Reference: [1] Bioorganic and Medicinal Chemistry, 2012, vol. 20, # 17, p. 5235 - 5246
[2] Patent: US2014/274696, 2014, A1,
  • 10
  • [ 327-51-5 ]
  • [ 68-12-2 ]
  • [ 357405-75-5 ]
YieldReaction ConditionsOperation in experiment
86%
Stage #1: With n-butyllithium In diethyl ether; hexane at -78℃; for 0.5 h; Inert atmosphere
Stage #2: at 20℃; for 2 h;
Example 31 Preparation of 4-bromo-2,5-difluorobenzaldehyde [0289] 2,5-dibromo-1,4-difluorobenzene (10.0 g, 36.77 mmol) in diethyl ether (150 mL) at −78° C. was added n-butyl lithium (2.5 M in Hexanes, 14.86 mL, 37.15 mmol) dropwise under nitrogen. The reaction mixture was stirred at −78° C. for 30 min. Dry DMF (3.13 mL, 40.46 mmol) in diethyl ether (10 mL) was added dropwise and reaction was slowly warmed to room temperature over 2 h. The reaction was quenched with aqueous saturated ammonium chloride solution (25 mL) and extracted with diethyl ether. The organic phase was washed with saturated brine solution, dried (Na2SO4), filtered, and concentrated under reduced pressure (Note: Product is highly volatile). The crude product was purified by flash chromatography (SiO2, eluting with 2-20percent ethyl acetate in hexanes) to provide the title compound as a pale yellow solid (7.0 g, 86percent): 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J=5.08, 8.92 Hz, 1H), 7.62 (dd, J=5.80, 7.68 Hz, 1H), 10.30 (d, J=2.76 Hz, 1H).
66.7%
Stage #1: With isopropylmagnesium chloride; lithium chloride In tetrahydrofuran at -40℃; for 1 h;
To a stirred solution of XXXII-1 (12 g, 44.1 mmol) in THF (150 mL) was added dropwise of XXXII-1A (44.1 mmol, 34 mL, 1.3 M) at −40° C. After stirred 1 h at −40° C., DMF (64 g, 882 mmol) was added and the mixture was stirred overnight. NH4Cl (aq., 2M) was added and the mixture was extracted with EtOAc. The organic phase was dried with Na2SO4. The solvent was removed in vacuo and the residue was purified by column chromatography (PE/EA=10/1) to afford XXXII-2 (6.5 g, yield: 66.7percent).
55.8%
Stage #1: With n-butyllithium In toluene at -78℃; for 0.5 h;
Stage #2: at -78 - 20℃; for 2 h;
To a solution of l,4-dibromo-2,5-difluorobenzene (15 g, 55 mmol) in toluene (600 mL) cooled to -78 °C was added butyllithium (22 mL, 55 mmol) and the reaction was kept at -78 °C for 30 minutes. N,N-dimethylformamide (4.4 g, 61 mmol) was added and the reaction was stirred for 2 hours while warming to ambient temperature. To the reaction was added water (200 mL) and EtOAc (400 mL) and the organic layers were separated. The organic layer was washed with brine (200 mL), dried over MgS04, filtered and concentrated in vacuo. The crude material was chromatographed eluting with 5percent EtOAc/Hexane to yield 4-bromo-2,5-difluorobenzaldehyde (6.7 g, 55.8percent).
37%
Stage #1: With n-butyllithium In diethyl ether at -78℃; Inert atmosphere
Stage #2: at 20℃; for 1 h;
n-Butyl lithium (3.6 ml,7.7 mmol) was added drop wise to a solution of 1,4- dibromo-2,5-difluoro-benzene (2g, 7.35mmol) in dry ether at -78°C under nitrogen atmosphere and the resulting mixture was stirred at -78°C for 30 minutes. This was followed by the addition of DMF (0.85ml, 11.03mmol) in dry THF. The resultant was stirred at room temperature for 1 hour. The reaction was monitored by TLC (5percent ethyl acetate in hexane). The reaction mixture was partitioned between ethyl acetate and saturated ammonium chloride. The organic layer was concentrated and purified by column chromatography on silica gel (2percent ethyl acetate in hexane) to afford 600mg of the product (37percent yield).1H NM (CDC13, 300 MHZ): δ 10.27-10.26 (d, 1H), 7.61-7.57 (t, 1H), 7.49- 7.44 (q, 1H)

Reference: [1] Patent: US2014/274696, 2014, A1, . Location in patent: Paragraph 0289; 0290
[2] Patent: US2014/200215, 2014, A1, . Location in patent: Paragraph 1205; 1206
[3] Patent: WO2013/74641, 2013, A1, . Location in patent: Paragraph 00350
[4] Patent: WO2012/149413, 2012, A1, . Location in patent: Page/Page column 63
[5] Patent: US2010/222345, 2010, A1, . Location in patent: Page/Page column 97
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YieldReaction ConditionsOperation in experiment
74% With ammonium chloride In tetrahydrofuran; N,N-dimethyl-formamide Method 6
4-Bromo-2,5-difluorobenzaldehyde
To 1,4-dibromo-2,5-difluorobenzene (10.28 g, 37.81 mmol) in tetrahydrofuran (80 mL) at -40° C. was isopropylmagnesium chloride lithium chloride complex (29.1 mL, 37.81 mmol) added dropwise.
After 1 h at -40° C. was N,N-dimethylformamide (58 mL, 756 mmol) added and the mixture was stirred for 30 minutes at -40° C. NH4Cl (2M, aq, 100 mL) was added and the mixture was extracted with ethyl acetate.
The organic phase was dried with MgSO4 and concentrated to give 4-bromo-2,5-difluorobenzaldehyde (6.20 g, 74percent) as a solid.
1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.28 (d, 1H) 7.61 (dd, 1H) 7.48 (dd, 1 H).
Reference: [1] Patent: US2010/267723, 2010, A1,
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  • [ 109-72-8 ]
  • [ 327-51-5 ]
  • [ 357405-75-5 ]
Reference: [1] Patent: US2003/158185, 2003, A1,
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  • [ 327-51-5 ]
  • [ 952285-52-8 ]
Reference: [1] Patent: US2015/51395, 2015, A1,
[2] Patent: US2016/244451, 2016, A1,
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