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[ CAS No. 114897-91-5 ]

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CAS No. :114897-91-5 MDL No. :MFCD07368653
Formula : C8H5BrFN Boiling Point : 281.2°C at 760 mmHg
Linear Structure Formula :- InChI Key :-
M.W :214.03 g/mol Pubchem ID :7172308
Synonyms :

Safety of [ 114897-91-5 ]

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:

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  • Upstream synthesis route of [ 114897-91-5 ]
  • Downstream synthetic route of [ 114897-91-5 ]

[ 114897-91-5 ] Synthesis Path-Upstream   1~19

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YieldReaction ConditionsOperation in experiment
100% at 100℃; for 8.5 h; A solution of 4-bromo-2-fluorobenzyl bromide (26.8 g, 100 mmol) and sodium cyanide (5.4 g, 110 mmol) in ethanol (40 ml) and water (10 ml) was stirred at 100°C for 8.5 h. The reaction mixture was cooled to room temperature, then concentrated under reduced pressure, and extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the title compound (22.6 g, quant.) as a black oily substance. 1H-NMR (400 Hz, CDCl3) δ: 3.73 (2H, s), 7.27-7.38 (3H, m)
99% at 70℃; for 1 h; To a solution of 4-BROMO-1-BROMOMETHYL-2-FLUORO-BENZENE (8.15 G, 30.4 mmol) dissolved in DMF (16 mL) were added sodium cyanide (2.24 g, 45.6 mmol) and water (2 mL). The reaction was stirred for one hour at 70 C. To the reaction was added 130 mL water; 120 mL saturated NAHC03, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3 x 100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over NA2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (6.5 g, 99percent yield). MS (APCI) : 240 (M+H), 242 (M+2+H).
99% at 60℃; for 12 h; Inert atmosphere To a solution of 4-bromo-l-(bromomethyl)-2-fluorobenzene (500 g, 1.87 mol) in EtOH (2.2 L) stirred under nitrogen at 20 °C was added NaCN (93 g, 1.90 mmol) in one charge. The reaction mixture was stirred at 60 °C for 12 h. Then the solution was concentrated and distributed between DCM (2000 inL) and saturated NaHCC>3 solution (1800 mL). Another batch was repeated using the same procedure. Then the two batches were combined. The combined organic extract was washed with brine, dried over MgS04, filtered and concentrated to provide 2-(4-bromo-2- fluorophenyl)acetonitrile (794 g, 99percent yield): lH NMR (400 MHz, CDC13) δ 7.38-7.27 (m, 3H), 3.72 (s, 2H).
99% at 60℃; for 12 h; Inert atmosphere To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (500 g, 1.87 mol) inEtOH (2.2 L) stirred under N2 at 20 °C was added NaCN (93 g, 1.90 mmol) in one charge. The reaction mixture was stirred at 60 °C for 12 h. Then the solution was concentrated and distributed between DCM (2000 mL) and saturated NaHCO3 solution (1800 mL). Anotherbatch was prepared following the same procedure. Then the two batches were combined. The combined organic extract was washed with brine, dried over Mg504, filtered and concentrated to provide 2-(4-bromo-2-fluorophenyl)acetonitrile (794 g, 99percent): ‘H NIVIR (400 IVIFIz, CDC13) 7.3 8-7.27 (m, 3H), 3.72 (s, 2H).
99% at 1260℃; Inert atmosphere Step 4: 2-(4-Bromo-2-fluorophenyl)acetonitrile To a solution of 4-bromo-l-(bromomethyl)-2-fluorobenzene (500 g, 1.87 mol) in EtOH (2.2 L) stirred under N2 at 20 °C was added NaCN (93 g, 1.90 mmol) in one charge. The reaction mixture was stirred at 60 °C for 12 h. Then the solution was concentrated and distributed between DCM (2000 mL) and saturated NaHC03 solution (1800 mL). Another batch was prepared following the same procedure. Then the two batches were combined. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated to provide 2-(4-bromo- 2-fluorophenyl)acetonitrile (794 g, 99percent): lH NMR (400 MHz, CDC13) δ 7.38-7.27 (m, 3H), 3.72 (s, 2H).
93% for 3 h; Reflux A solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (1.0 g, 3.73 mmol) in ethanol (5 ml) and water (1 ml) was treated with sodium cyanide (219 mg, 4.48 mmol) and refluxed for 3 hours. The volatiles were evaporated under reduced pressure and the residue was diluted with water and extracted with diethyl ether (.x.2). The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulphate, filtered and evaporated under reduced pressure to afford the desired product as a pale yellow solid (0.748 g, 93percent).1H-NMR (400MHz, CDCl3) δ: 7.37-7.26 (3H, m), 3.72 (2H, s); LC/MS Retention time 2.76 mins/M+H not observed C8H579BrFN requires 213.
88% at 26℃; for 10 h; A suspension of NaCN (2.085 g, 42.5 mmol) in DMF (20 mL) was added to a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.7 g, 21.27 mmol) in DMF (20 mL). The mixture was stirred at 26° C. for 10 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol, 88.0percent yield) was used to next step without further purification. TLC (PE/EA=1/1, Rf 0.5): 1H NMR (400 MHz, CDCl3) δ 7.24-7.37 (m, 3H), 3.70 (s, 2H).
46% at 70℃; for 3 h; To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (100g, 373 mmol) in DMF (190 mL) and water (10 mL) was added sodium cyanide (22g, 448 mmol). The reaction was heated to 70 degrees Celsius for 3 hours, concentrated to a volume of 100 mL, and then the solution was diluted with 100 mL of ethyl acetate. After the solids were removed by filtration, water (250 mL) was added and the layers were separated. The organic layer was further washed with 3 x 100 mL of water. The organic layer was dried over MGS04, filtered to remove solids, and then concentrated. Purification by distillation gave the desired product (37.124g, 46percent). B. P. = 72-75 degrees Celsius.

Reference: [1] Patent: EP2700643, 2014, A1, . Location in patent: Paragraph 0188
[2] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 111-112
[3] Patent: WO2014/141187, 2014, A1, . Location in patent: Page/Page column 54; 44; 56; 57
[4] Patent: WO2016/38519, 2016, A1, . Location in patent: Page/Page column 36
[5] Patent: WO2016/38552, 2016, A1, . Location in patent: Page/Page column 50
[6] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 623 - 628
[7] Patent: US2010/137276, 2010, A1, . Location in patent: Page/Page column 23
[8] Patent: US2014/275111, 2014, A1, . Location in patent: Paragraph 0233; 0234
[9] Organic Process Research and Development, 2006, vol. 10, # 4, p. 814 - 821
[10] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 237
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YieldReaction ConditionsOperation in experiment
94% at 60℃; for 2 h; Potassium cyanide (1.3 g, 20 mmol) was added to a mixed solution of 4-bromo-2-fluorobenzyl bromide (5.00 g, 18.7 mmol) in ethanol-water (3:1, 40 ml), and the mixture was stirred at 60°C for 2 hours. The reaction mixture was poured into water and, after the mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane/ethyl acetate) to obtain to obtain (4-bromo-2-fluorophenyl)acetonitrile as a colorless solid (3.75 g, yield: 94percent). 1H-NMR (400MHz, CDCl3) δ 7.35-7.26 (3H, m) , 3.72 (2H, s).
87% at 40℃; for 3 h; To a solution of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.0 g, 18.7 mmol) in DMF (80 mL) and H2O (8 mL) was added KCN (1.21 g, 18.7 mmol). The mixture was heated to 40° C. for 3 hours before it was cooled down to room temperature. The reaction was diluted with H2O (40 mL) and extracted with Et2O (3.x.100 mL). The combined organic layers were washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by flash column chromatography (0-15percent EtOAc in hexanes) to give the product (3.5 g, 87percent yield). 1H NMR (300 MHz, CDCl3) δ: 3.72 (s, 2H), 7.26-7.35 (m, 3H).
Reference: [1] Patent: WO2006/46593, 2006, A1, . Location in patent: Page/Page column 177
[2] Patent: EP1764075, 2007, A1, . Location in patent: Page/Page column 104
[3] Patent: WO2006/109633, 2006, A1, . Location in patent: Page/Page column 165
[4] Patent: US2005/176701, 2005, A1, . Location in patent: Page/Page column 58
[5] Patent: US2006/160800, 2006, A1, . Location in patent: Page/Page column 76
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YieldReaction ConditionsOperation in experiment
99% at 70℃; for 1 h; To a solution of 4-bromo-1~bromomethyl-2-fluoro-benzene (8.15 g, 30.4 mmol) dissolved in DMF (16 mL) were added sodium cyanide (2.24 g, 45.6 mmol) and water (2 ml_). The reaction was stirred for one hour at 70 °C. To the reaction was added 130 ml water; 120 ml saturated NaHCO3, and 100 mL EtOAc. The layers were separated, and the aqueous layer was extracted with 3 x 100 mL EtOAc. The combined organics were washed with 100 mL water, and then dried over Na2SO4. After filtering off the solids, the mother liquor was concentrated to the desired product by rotary evaporation (6.5 g, 99percent yield). MS (APCI): 240 (M+H), 242 (M+2+H).
96% at 20℃; for 4 h; Preparation of (4-Bromo-2-fluoro-phenyl)-acetonitrile
Sodium cyanide (1.37 g, 28.00 mmol) was added to a stirred solution of 2-fluoro-4-bromo benzyl bromide (5.0 g, 18.66 mmol) in dry DMSO (60 mL) at ambient temperature under nitrogen.
The reaction was stirred for 4 h at ambient temperature then poured into H2O (150 mL) and extracted with EtOAc.
The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the intermediate title compound as a brown oil (3.85 g, 96percent).
Electrospray mass spectrum: M=213, M+2=215
46% at 70℃; for 3 h; To a solution of 4-bromo-1-bromomethyl-2-fluoro-benzene (10 g, 373 mmol) in DMF (190 mL) and water (10 mL) was added sodium cyanide (2 g, 448 mmol). The reaction was heated to 70 degrees Celsius for 3 hours, concentrated to a volume of 100 mL, and then the solution was diluted with 100 mL of ethyl acetate. After the solids were removed by filtration, water (250 mL) was added and the layers were separated. The organic layer was further washed with 3.x.100 mL of water. The organic layer was dried over MgSO4, filtered to remove solids, and then concentrated. Purification by distillation gave the desired product (37.12 g, 46percent). B.P.=72-75 degrees Celsius.
Reference: [1] Patent: WO2006/18725, 2006, A1, . Location in patent: Page/Page column 172
[2] Patent: US7034045, 2006, B1, . Location in patent: Page/Page column 84-85
[3] Patent: US2005/176701, 2005, A1, . Location in patent: Page/Page column 111
[4] Journal of Medicinal Chemistry, 2007, vol. 50, # 17, p. 3969 - 3972
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YieldReaction ConditionsOperation in experiment
87% at 20 - 40℃; for 3 h; To a solution OF 4-BROMO-1-(BROMOMETHYL)-2-FLUOROBENZENE (5.0 g, 18.7 mmol) in DMF (80 mL) and H20 (8 mL) was added KCN (1.21 g, 18.7 mmol). The mixture was heated to 40 C for 3 hours before it was cooled down to room temperature. The reaction was diluted with H20 (40 mL) and extracted with ET20 (3 x 100 mL). The combined organic layers were washed with brine and dried over NA2SO4. The solvent was removed and the residue was purified by flash column chromatography (0-15percent EtOAc in hexanes) to give the product (3.5 g, 87percent YIELD). H NMR (300 MHz, CDC13) 5 : 3.72 (s, 2 H), 7. 26-7.35 (m, 3 H).
7 g With tetrabutylammomium bromide In dichloromethane; water at 20℃; for 15 h; To a solution of 4-bromo- l -(bromomethyl)-2-fluorobenzene (9 g, crude) in DCM (50 mL) and H20 (50 mL) was added CN (6.56 g, 100.74 mmol) and TBAB (1 g) and stirred at r.t. for 15 h. The mixture was washed with water, extracted with DCM (2 x 50 mL). The combined layers were washed with brine (100 mL), dried over Na2SC>4 and concentrated to afford 75c (7 g) which was used in the next step without further purification. LCMS m/z 214 (M+l)+.
Reference: [1] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 130
[2] Patent: WO2013/43232, 2013, A2, . Location in patent: Paragraph 00603; 00650
[3] Patent: WO2013/40863, 2013, A1, . Location in patent: Page/Page column 100
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YieldReaction ConditionsOperation in experiment
84% With potassium cyanide In ethanol; water; ethyl acetate REFERENCE EXAMPLE 60
(4-Bromo-2-fluorophenyl)acetonitrile
To a solution of 4-bromo-2-fluorobenzylbromide (44.5 g, 166 mmol) in EtOH (118 mL) was added KCN (13.13 g, 182 mmol) and the mixture was stirred at reflux under an argon atmosphere for 18 h.
The mixture was allowed to cool and the solvent was concentrated.
The residue thus obtained was dissolved in a mixture of EtOAc and H2 O and the two phases were separated.
The aqueous phase was extracted with EtOAc and the combined organic phases dried and concentrated to a crude product.
Purification by chromatography on silica gel (hexane-EtOAc, 10percent) afforded the title compound as a reddish oil (30.0 g, 84percent).
1 H-NMR-(CDCl3) δ (TMS): 3.71 (s 2H), 7.30 (m, 3H).
60% With potassium cyanide In ethanol Step (1)
Preparation of 4-Bromo-2-fluorophenylacetonitrile
KCN (2.91 g, 44.8 mmol) was added to a solution of 4-bromo-2-fluorobenzyl bromide (10.0 g, 37.3 mmol) in absolute ethanol (150 mL), and the resulting mixture heated to reflux for 18 hours.
The mixture was cooled to room temperature and partitioned between water (100 mL) and ether (250 mL).
The layers were separated and the aqueous layer reextracted with ether (150 mL).
The combined organic layers were washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a light yellow oil.
The oil was triturated with hexanes to give a white crystalline solid which was collected by filtration and dried in vacuo (3.93 g).
The filtrate was concentrated and the residue purified by chromatography on silica gel with elution by EtOAc/hexanes (5:95) to give additional product (0.9 g).
The solids were combined to give the desired product (total 4.83 g, 60percent) of sufficient purity for use in the subsequent reaction.
NMR (DMSO-d6): δ 7.63 (dd, J1 =9.2 Hz, J2 =1.3 Hz, 1H), 7.42 (m, 2H).
4.05 (s, 2H).
Reference: [1] Patent: US2004/63680, 2004, A1,
[2] Patent: US5827863, 1998, A,
[3] Patent: US4895862, 1990, A,
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YieldReaction ConditionsOperation in experiment
93% at 20 - 25℃; for 18 h; Inert atmosphere Step A: (4-Bromo-2-fluoro-phenyl)-acetonitrile2-Fluoro-4-bromo-chloromethylbenzene (25.0 g, 1 12 mmol) and NaCN (6.32 g, 129 mmol) were dissolved in DMF (70 ml.) and the solution was stirred under a N2 atmosphere for 18 hrs at ambient temperature. The solution was poured into water (300 ml_), and was extracted with EtOAc (1x 1 L, 4x 300 ml_). The combined organic layers were dried (Na2S04), filtered and concentrated under reduced pressure, yielding the title compound (22.5 g, 105 mmol, 93percent) as a yellow oil that contained some traces of DMF. 1 H-NMR (CDCI3, 300 MHz) : 3.75 (s, 2H); 7.20-7.4 (m, 3H)
Reference: [1] Patent: WO2011/45703, 2011, A2, . Location in patent: Page/Page column 44
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YieldReaction ConditionsOperation in experiment
53% at 20℃; for 19.5 h; (1)
Production of (4-bromo-2-fluorophenyl)acetonitrile:
Tetraethylammonium cyanide (3.8 g, 24.3 mmol) was added to a DMF solution (50 mL) of 4-bromo-1-(bromomethyl)-2-fluorobenzene (5.0 g, 18.7 mmol), and stirred at room temperature for 19.5 hours.
Next, aqueous saturated ammonium chloride solution was added to the reaction liquid, and extracted with ethyl acetate.
The obtained organic layer was washed with saturated saline, then dried with anhydrous sodium sulfate, and filtered.
The obtained filtrate was concentrated under reduced pressure, then the residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 to 9:1) to obtain the entitled compound (2.11 g, 53 percent).
Mass Spectrum (APCI): 214.0 (M+H).
Reference: [1] Patent: EP1916239, 2008, A1, . Location in patent: Page/Page column 33
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Reference: [1] Patent: WO2007/69986, 2007, A1, . Location in patent: Page/Page column 95
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Reference: [1] Patent: WO2013/28447, 2013, A1, . Location in patent: Page/Page column 93
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Reference: [1] Patent: EP1806332, 2007, A1,
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Reference: [1] Patent: WO2013/43232, 2013, A2,
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  • [ 114897-92-6 ]
YieldReaction ConditionsOperation in experiment
98% With potassium hydroxide In ethanol; water; ethyl acetate REFERENCE EXAMPLE 61
4-Bromo-2-fluorophenylacetic acid
To a solution of the compound obtained in reference example 60 (28.0 g, 131 mmol) in EtOH (165 mL) was added KOH (46 g, 710 mmol) in H2 O (62 mL) and the mixture was stirred at reflux under an argon atmosphere for 18 h.
The mixture was allowed to cool and the solvent was concentrated.
The residue thus obtained was dissolved in a mixture of EtOAc and H2 O and the two phases were separated.
The aqueous phase was extracted with EtOAc and the combined organic phases dried and concentrated to a crude product.
Purification by chromatography on silica gel (hexane-EtOAc, 10percent) afforded the title compound as a white solid (30.0 g, 98percent).
mp 121°-122° C.;
1 H-NMR-(CDCl3) δ (TMS): 3.65 (s, 2H), 7.30 (m, 3H), 9.03 (s, 1H).
Analysis calculated for C8 H6 BrFO2: C 41.23percent; H 2.60percent. Found: C 41.43percent; H 2.59percent.
95% With sodium hydroxide In methanol at 100℃; for 12 h; NaOH (56.2 mL, 112 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol) in MeOH (30 mL).The mixture was stirred at 100° C. for 12 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetic acid (4.13 g, 17.72 mmol, 95.0percent yield) was used to next step without further purification. TLC (PE/EA=1/1, Rf=0.4): 1H NMR (400 MHz, CDCl3) δ 7.22-7.31 (m, 2H), 7.13 (t, J=8.05 Hz, 1H), 3.67 (s, 2H); ES-LCMS m/z 232.9 (M+H).
95% at 100℃; for 12 h; NaOH (56.2 mL, 112 mmol) was added to a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (4.01 g, 18.74 mmol) in Me OH (30 mL). The mixture was stirred at 100 °C for 12 h. The mixture was cooled to rt. Then the solution was concentrated and distributed between EA and saturated NaHC03 solution. The combined organic extract was washed with brine, dried over MgSO/i, filtered and concentrated. The resulting 2-(4-bromo-2-fluorophenyl)acetic acid (4.13 g, 17.72 mmol, 95.0percent yield) was used to next step without further purification. TLC (PE/EA = 1/1, Rf = 0.4): lH NMR (400 MHz, CDC13) δ 7.22-7.31 (m, 2H), 7.13 (t, J = 8.05 Hz, 1H), 3.67 (s, 2H); ES-LCMS m/z 232.9 (M+H).
94% for 20 h; Reflux Step B: 4-Bromo-2-fluoro-phenyl-acetic acid(4-Bromo-2-fluoro-phenyl)-acetonitrile (41.4 g, 174 mmol) (21.2 g, 99.1 mmol) was suspended in 30percent aq. HCI (200 ml.) and heated to reflux for 20 hours. After cooling to room temperature, the solids were collected by filtration, washed with water and allowed to dry in open air. The solids were azeotroped with toluene under reduced pressure to remove the final traces of water, yielding the title compound as a solid (21 .7 g, 89 mmol, 94percent).1 H-NMR (CD3OD, 300 MHz): 3.68 (s, 2H); 7.20-7.4 (m, 3H)
92% at 20 - 80℃; Inert atmosphere To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (397 g, 1.82 mol) in MeOH (500 mL) stirred under N2 at 20 °C was added NaOH (2.22 L, 2.5M, 5.56 mol) solution in one charge. The reaction mixture was stirred at 80 °C for 5 h. Then the solution wasconcentrated and neutralized with cone. HC1 to pH = 5 with stirring. Then the solution was extracted with EA (1.5 L x 2). Another two batches were prepared following the same procedure. Then the three batches were combined. The combined organic extract was washed with brine, dried over Na2504, filtered and concentrated in vacuo to give the pure 2-(4-bromo-2-fluorophenyl)acetic acid (1200 g, 92percent): TLC (PE/EA = 5:1, Rf = 0.2); ‘HNIVIR (400 IVIFIz, CDC13) 7.24 (br. s., 1H), 7.12 (t, J 7.9 Hz, 1H), 3.65 (s, 2H).
92% With water; sodium hydroxide In methanol at 80℃; for 5 h; Step 5 : 2-(4-Bromo-2-fluorophenyl)acetic acid To a solution of 2-(4-bromo-2-fluorophenyl)acetonitrile (397 g, 1.82 mol) in MeOH (500 mL) stirred under N2 at 20 °C was added NaOH (2.22 L, 2.5M, 5.56 mol) solution in one charge. The reaction mixture was stirred at 80 °C for 5 h. Then the solution was concentrated and neutralized with cone. HC1 to pH = 5 with stirring. Then the solution was extracted with EA (1.5 L x 2). Another two batches were prepared following the same procedure. Then the three batches were combined. The combined organic extract was washed with brine, dried over NaaSOzi, filtered and concentrated in vacuo to give the pure 2-(4-bromo-2-fluorophenyl)acetic acid (1200 g, 92percent): TLC (PE/EA = 5: 1, Rf = 0.2); lH NMR (400 MHz, CDC13) δ 7.24 (br. s., 1H), 7.12 (t, J = 7.9 Hz, 1H), 3.65 (s, 2H).
89%
Stage #1: With potassium hydroxide; water In ethanol for 5 h; Heating / reflux
Stage #2: With hydrogenchloride In water
A solution of (4-bromo-2-fluorophenyl)acetonitrile (2.345g, 10.96mmol) in ethanol (60ml) and water (18ml) was treated with potassium hydroxide (5.2Og, 93mmol, 8.5 equiv) and refluxed for 5 hours. The volatiles were distilled off, the residue was diluted with water and poured into diluted cold hydrochloric acid and the precipitated solid was filtered. The desired product was dried under high vacuum at 370C for 48 hours to afford the title compound (2.283g, 89percent). <n="35"/>1H-NMR (400MHz, DMSO-d6): 3.6 (2H, s), 7.30 (1 H, m), 7.39 (1 H, m), 7.53 (1 H, m) 12.57 (1 H, br s).
89.7%
Stage #1: With water; potassium hydroxide In ethanol for 5 h; Reflux
Stage #2: With hydrogenchloride In water
A solution of (4-bromo-2-fluorophenyl)acetonitrile (D29, 2.354 g, 10.9 mmol) in ethanol (60 ml) and water (18 ml) was treated with potassium hydroxide (5.2 g, 93.09 mmol) and refluxed for 5 hours. The volatiles were evaporated off under reduced pressure and the residue was diluted with water and poured into cold, dilute hydrochloric acid and the precipitated solid was filtered. The solid was dried under high vacuum at 37° C. for 48 hours (2.283 g, 89.7percent).1H-NMR (400 MHz, DMSO-d6) δ: 12.57 (1H, br s), 7.52 (1H, m), 7.38 (1H, m), 4.32 (1H, m), 3.62 (2H, s); LC/MS Retention time 2.34 mins/M+H not observed C8H679BrFO2 requires 232.
48%
Stage #1: With potassium hydroxide; water In ethanol at 70℃; for 24 h;
Stage #2: With sulfuric acid In water
A mixture of (4-BROMO-2-FLUOROPHENYL) ACETONITRILE (8.55 g, 40 mmol) from step 1 in Example A (97); Potassium hydroxide (11.52 g, 320 mmol) ; Ethanol (80 ml) and water (16 ml) was heated at 70 C for 24 hours. The mixture was then diluted with water (50 ML), and subsequently extracted with ether (3x 75 ML). The pH of the aqueous layer was adjusted to approximately 3 with dropwise addition of 1 N H2SO4. After the aqueous layer was extracted with ether (3X125 ml), the combined organic layers were washed with brine and dried over MgSO4. The solvent was removed to give product (4.50 g, 48percent YIELD). H NMR (CDCl3) No. : 3.60 (s, 2H), 7.07-7. 22 (m, 3H).

Reference: [1] Patent: US5827863, 1998, A,
[2] Patent: US2014/275111, 2014, A1, . Location in patent: Paragraph 0232; 0235; 0236
[3] Patent: WO2014/141187, 2014, A1, . Location in patent: Page/Page column 44; 54; 57
[4] Patent: WO2011/45703, 2011, A2, . Location in patent: Page/Page column 44-45
[5] Patent: WO2016/38519, 2016, A1, . Location in patent: Page/Page column 36
[6] Patent: WO2016/38552, 2016, A1, . Location in patent: Page/Page column 50-51
[7] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 623 - 628
[8] Patent: WO2008/110566, 2008, A1, . Location in patent: Page/Page column 33-34
[9] Patent: US2010/137276, 2010, A1, . Location in patent: Page/Page column 23
[10] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 150
[11] Patent: WO2007/69986, 2007, A1, . Location in patent: Page/Page column 95
  • 13
  • [ 67-56-1 ]
  • [ 75-77-4 ]
  • [ 114897-91-5 ]
  • [ 193290-19-6 ]
YieldReaction ConditionsOperation in experiment
35%
Stage #1: at 20 - 50℃; for 4 h;
Stage #2: With water; sodium carbonate In dichloromethane
MeOH (16MMOL, 0.81 ml), TMSCI (20mmol, 2. 13g) and (4-bromo-2-fluorophenyl) acetonitrile (10MMOL, 2. 13g) were sequentially added to a dry flask under a nitrogen atmosphere at room temperature. The reaction mixture was heated at 50 C for 4 hours. After being cooled to room temperature, water (20MMOL, 0. 36MOI) was added to the mixture, followed by the addition of NA2CO3 (10mmol, 1. 06g) and CH2Cl2 (10ml). Drying over MGSO4 and concentrating at low pressure afforded product (0.85 g, 35percent YIELD). H NMR (300 MHz, CDC13) No. : 3.57 (s, 2 H), 3.65 (s, 3H), 7.08 (t, J=8.3 Hz, 1H), 7.16-7. 21 (m, 2H).
Reference: [1] Patent: WO2004/74270, 2004, A2, . Location in patent: Page 147
  • 14
  • [ 67-56-1 ]
  • [ 114897-91-5 ]
  • [ 193290-19-6 ]
YieldReaction ConditionsOperation in experiment
5 g at 0 - 20℃; for 15 h; To a solution of 2-(4-bromo-2-fluorophenyl) acetonitrile (7 g, crude) in MeOH (50 mL) was added dropwise SOCl2 (35 mL) at 0 °C. The mixture was stirred at r.t. for 15h. The solvent was removed. The residue was washed with water and extracted with EtOAc (3 x 50 mL). The combined layers were washed with brine (50 mL), dried over Na2S04 and concentrated. The residue was purified by column chromatography on silica gel eluted with 0- 10percent EtOAc in petroleum ether to afford the desired product (5 g, 68percent). LCMS m/z 247 (M+l )+.
Reference: [1] Patent: WO2008/51404, 2008, A2, . Location in patent: Page/Page column 66
[2] Patent: WO2013/43232, 2013, A2, . Location in patent: Paragraph 00604; 00651
  • 15
  • [ 67-56-1 ]
  • [ 1000668-71-2 ]
  • [ 114897-91-5 ]
  • [ 193290-19-6 ]
Reference: [1] Patent: WO2013/28447, 2013, A1, . Location in patent: Page/Page column 93-94
  • 16
  • [ 114897-91-5 ]
  • [ 74-88-4 ]
  • [ 193290-19-6 ]
Reference: [1] Patent: WO2006/109633, 2006, A1, . Location in patent: Page/Page column 165-166
  • 17
  • [ 114897-91-5 ]
  • [ 193290-19-6 ]
Reference: [1] Patent: WO2014/141187, 2014, A1,
[2] Patent: WO2016/38519, 2016, A1,
[3] Patent: WO2016/38552, 2016, A1,
[4] ACS Medicinal Chemistry Letters, 2018, vol. 9, # 7, p. 623 - 628
  • 18
  • [ 114897-91-5 ]
  • [ 107-04-0 ]
  • [ 872422-15-6 ]
YieldReaction ConditionsOperation in experiment
70%
Stage #1: With sodium hydroxide; N-benzyl-N,N,N-triethylammonium chloride In water at 50℃; for 10 h;
Stage #2: With sodium hydroxide In water; ethylene glycol at 100℃;
Step 1.
1-(4-Bromo-2-fluorophenyl)cyclopropanecarboxylic acid
Sodium hydroxide, 50percent aqueous solution (5.71 mL, 0.149 mol), was added to a mixture of (4-bromo-2-fluorophenyl)acetonitrile (3.16 g, 0.0145 mol), benzyltriethylammonium chloride (0.26 g, 0.0011 mol), and 1-bromo-2-chloro-ethane (2.51 mL, 0.0302 mol) at 50° C. for 10 h.
The mixture was poured into ice-water (50 mL) and was extracted with ethyl ether (2*50 mL).
The combined organic phase was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give 2.88 g of brown solid.
1H-NMR confirmed that desired nitrile intermediate was isolated.
To the resulting residue was added 50percent NaOH aqueous solution (3.8 mL) and ethylene glycol (20 mL) and the solution was heated to 100° C. and stirred overnight.
The reaction mixture was poured into 50 mL of water and washed with ether (2*50 mL).
The aqueous layer was cooled with an ice bath and then acidified by the slow addition of 6 N HCl. to pH=2.
The product was extracted with EtOAc (2*100 mL), dried over MgSO4 and concentrated to give 1.634 g. (70percent) of the desired product.
1H NMR confirmed that the desired product was isolated.
Reference: [1] Patent: US2005/288338, 2005, A1, . Location in patent: Page/Page column 34
[2] Patent: WO2006/20598, 2006, A2, . Location in patent: Example 145.1
  • 19
  • [ 114897-91-5 ]
  • [ 872422-15-6 ]
Reference: [1] Patent: WO2013/189865, 2013, A1,
[2] Patent: EP2700643, 2014, A1,
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