* 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.
With borane-THF In tetrahydrofuran at 0 - 20℃; for 16 h;
4-Bromo-2-fluorobenzonitrile (5.00 mmol) in THF (30 mL)was cooled to 0 °C. A borane tetrahydrofuran complexsolution (1 M in THF, 15.0 mL) was added dropwise. Thesolution was stirred at 0 °C for 20 mm before being broughtup to RT and stirred for 16 h. MeOH was added dropwise (30 mL) and the solution was concentrated under reduced pressure. The residue was partitionedbetween an aqueous solution of NaOH (1 M) and EtOAc. The organic layer was worked up to give the titled compound (5.00 mmol) as a yellow oil. 1H NMR (400 MHz, CDCI3, ): 7.42-7.27 (m, 1H), 7.25-7.16 (m, 2H), 3.65 (t, J = 6.6 Hz, 2H).
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 5, p. 1898 - 1905
[2] Journal of Organic Chemistry, 2009, vol. 74, # 5, p. 1964 - 1970
[3] Patent: WO2017/103611, 2017, A1, . Location in patent: Paragraph 00336
[4] Patent: WO2018/75871, 2018, A1, . Location in patent: Page/Page column 62
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190
[2] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364
4
[ 348-54-9 ]
[ 105942-08-3 ]
Reference：
[1] Molecular Crystals and Liquid Crystals (1969-1991), 1989, vol. 172, p. 165 - 190
5
[ 367-24-8 ]
[ 544-92-3 ]
[ 105942-08-3 ]
Reference：
[1] Journal of Organic Chemistry, 1990, vol. 55, # 16, p. 4817 - 4821
6
[ 105942-08-3 ]
[ 82380-18-5 ]
Yield
Reaction Conditions
Operation in experiment
82%
With formic acid; oxygen; triethylamine; copper(ll) bromide In acetonitrile at 20℃; for 24 h; UV-irradiation
4-Bromo-2-fluorobenzonitrile (0.25 mmol), copper bromide (0.03 mmol), triethylamine (0.25 mmol, 1.0 equiv), HCOOH (0.75 mmol, 3.0 equiv) at room temperature,179mmol of the reaction solvent CH3CN was added to the reaction tube, and the mixture was stirred at room temperature for 24 hours under the oxygen atmosphere.After the completion of the reaction was monitored by thin layer chromatography, 20 mL of water and 10 mL of ethyl acetate were added for extraction, followed by drying over anhydrous sodium sulfate, filtering after 5 minutes, washing the filter cake with ethyl acetate (5 mL×3 times), and then swirling off the solvent.The product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate = 6:1), the product was a yellow liquid, yield 82percent;
Reference：
[1] Organic Letters, 2018, vol. 20, # 3, p. 708 - 711
[2] Patent: CN107915586, 2018, A, . Location in patent: Paragraph 0097-0100
7
[ 593-85-1 ]
[ 105942-08-3 ]
[ 137553-43-6 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1991, vol. 28, # 5, p. 1357 - 1364
8
[ 124-46-9 ]
[ 105942-08-3 ]
[ 137553-43-6 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2011, vol. 21, # 18, p. 5171 - 5176
Stage #1: With potassium <i>tert</i>-butylate In N,N-dimethyl-formamide for 0.5 h; Stage #2: at 20℃; for 2 h;
Step A: 6-Bromobenzo[d]isoxazol-3-amine: N-hydroxyacetamide (1.13 g, 15.0 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.68 g, 15.0 mmol) and the reaction was stirred for 30 minutes before addition of 4-bromo-2-fluorobenzonitrile (2.0 g, 10.0 mmol). The reaction mixture was left at ambient temperature for 2 hours, then diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate The combined organics were washed with water, dried, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with ethyl acetate/hexanes (1:4), ethyl acetate/hexanes (1:3) to give the desired product (1.35 g, 63percent). MS (APCI) m/z 215.2, 217.1 (M+1).
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2925 - 2930
16
[ 105942-08-3 ]
[ 229623-53-4 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2002, vol. 12, # 20, p. 2925 - 2930
17
[ 67-56-1 ]
[ 201230-82-2 ]
[ 105942-08-3 ]
[ 268734-34-5 ]
Yield
Reaction Conditions
Operation in experiment
59%
With triethylamine; triphenylphosphine In acetonitrile at 50℃;
A mixture OF4-BROMO-2-FLUORO-BENZONITRILE (4.00 g, 20.0 mmol), ET3N (3.94 g, 38.9 mmol), palladium (II) acetate (314 mg, 1.40 MMOL), triphenylphosphine (214 mg, 0.816 mmol) in 4: 1 CH3CN/MeOH (50 mL) is purged with a stream of nitrogen for 15 min in a sealed tube equipped with gas inlet/outlet valves. The reaction is flushed with carbon monoxide (3 X 60 psi), releasing the pressure between each addition. The reaction is left under an atmosphere of carbon monoxide (60 psi) and heated to-50 C overnight. The pressure is released and the reaction mixture is filtered through a SINTERED-GLASS FUNNEL containing diatomaceous earth, washing with MEOH (20 mL). The reaction residue is subjected to flash chromatography (silica gel, 9: 1 Hex/EtOAc) to afford the sub-title compound (2.13 g, 59percent) as a white solid. Rf 0.33 (4 : 1 HEX/ETOAC). mp 61-62 C. 'H NMR (300 MHz, CDC13) B 3.97 (s, 3H), 7.72 (DD, J = 6.2, 8.0 HZ, 1H), 7.86 (dd, J= 1.3, 9.2 Hz, 1H), 7.93 (dd, J= 1.3, 8.0 Hz, 1H).
Reference：
[1] Journal of Organic Chemistry, 2008, vol. 73, # 18, p. 7102 - 7107
[2] Patent: WO2004/67529, 2004, A1, . Location in patent: Page 173
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran at -10℃; for 3 h; Inert atmosphere Stage #2: at -10 - 20℃; for 1.5 h;
Synthesis of intermediate Vll-a: 2-Fluoro-4-formyl-benzonitrileA solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) in dry THF (50 mL) at - 10°C under argon was treated with a solution of isopropylmagnesium chloride (2M in THF, 15.0 mL, 30.0 mmol) dropwise before stirring at this temperature for 3 h. A solution of N-formylpiperidine (3.89 g, 35.0 mmol) in dry THF (15 mL) was added dropwise and the mixture allowed to warm to room temperature before stirring for 1.5h. The resultant solution was treated with 4M aq HC1 (250 mL each) and the organics extracted with EtOAc. The combined organics were dried (MgS04), filtered and evaporated before purification of the residue by column chromatography (Si02; eluting with 30percent to 50percent EtOAc in cyclohexane) to afford 2-fluoro-4-formyl-benzonitrile VH-a as a pale yellow solid (2.73 g, 73percent).1H NMR (300 MHz, CDC13) δ 10.07 (d, J = 1.7 Hz, 1H), 7.90 - 7.79 (m, 2H), 7.74 (dd, J= 8.5, 0.8 Hz, 1H).
53.1%
Stage #1: With isopropylmagnesium chloride In tetrahydrofuran; diethyl ether at 0℃; for 2.33333 h; Inert atmosphere Stage #2: at 0℃; for 2 h; Inert atmosphere
General procedure: To a solution of 4-halogen-2-chlorobenzonitrile (23.10mmol) in dry 35 THF under Argon at 0°C was added 36 isopropyl magnesium chloride (30.03mmol, 2M solution in ether) dropwise during 20min, and the reaction mixture was stirred for 2h, keeping the temperature around 0°C. Then 37 1-formyl piperidine (30.03mmol) was added dropwise at 0°C and stirred for additional 2h at 0°C. The reaction mixture was quenched with saturated 38 NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=3:1) to afford 39 compound 10a and 10b.
Stage #1: With 18-crown-6 ether; potassium acetate In acetonitrile for 36 h; Heating / reflux Stage #2: With sodium hydroxide In water; acetonitrile at 20℃;
A mixture of 2-fluoro5-bromobenzonitrile (30 g, 152.3 mmole), potassium acetate (222.4 g, 228.5 mmol), and 18-crown-6 ether (60.4 g, 288.5 mmol) in MeCN (400 mL) was heated at reflux in 36 h. The mixture was cooled, 2.5 N NaOH (200 mL) added, and stirred at RT overnight. The mixture was extracted with ether (discarded). The aqueous layer was acidified with 6N HCl, extracted with EtOAc, dried over MgSO4, concentrated, purified by flash column chromatography (40percent EtOAc/Hex) to give the above titled compound as a light yellow foam (24.45 g, 81percent). NMR(300 MHz, DMSO-d6): 7.13(dd, J=1.7, 8.3 Hz, 1H), 7.17(d, J=1.7 Hz, 1H), 7.61(d, J=8.3 Hz, 1H).
Stage #1: With n-butyllithium In tetrahydrofuran; hexane; toluene at -75 - -74℃; for 2.25 h; Stage #2: With hydrogenchloride; water In tetrahydrofuran; hexane; toluene at -20 - 20℃;
Dissolve 2-Fluoro-4-bromobenzonitrile (200 g, 990 mmol, 1.00 eq.) and triisopropyl borate (228 g, 1188 mmol, 1.2 eq.) in 700 mL of THF and 1400 mL of toluene. Cool the mixture with a dry ice/acetone bath to an internal temperature of -75 0C. Slowly add n-BuLi (396 mL of a 2.5 M solution in hexanes) over a period of 2 hours. After addition is complete, a light-red, thin slurry occurs. Let the solution stir at -74 0C for 15 minutes, allow the solution to warm to -20 0C and then quench with 1500 mL of 2.5 M HCl. Let the solution warm to RT. Separate layers, extract the aqueous layer with EtOAc, dry the combined organic phases with Na2SQ,), filter and concentrate in vacuo to yield a light-brown solid.Triturate the solid with hexane and transfer to a scintered glass funnel. Rinse with hexane one more time to obtain a pale-yellow filtrate. Stir the light-brown solid with cold CH2Cl2 and filter. Rinse with a small volume of CH2Cl2 to yield an off-white solid and a brown filtrate. Dry the solid in a vacuum oven at 40 0C and dried to yield 112g (679 mmol, 69percent) of 3-fluoro-4-cyanophenylboronic acid as an off-white solid.
Stage #1: With sodium hydride In dimethyl sulfoxide at 0 - 20℃; for 0.5 h; Stage #2: at 90℃;
4-Bromo-2-(cyanomethyl)benzonitrile. Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to 0°C in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. 4- Bromo-2-fluorobenzonitrile (118 g, 590 mmol)(commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. <n="191"/>The mixture was heated to an internal temperature of 90°C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 104°C over 3 hours. 2.3 L of water were added, and the mixture was heated at reflux 16 hours. The mixture was cooled to 5°C. HCl (700 mL, 0.2 N) was added, and the mixture was allowed to stir at 5°C for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78 percent). LCMS (API-ES) m/z: 223, 221 (IVH-H+).
78%
Stage #1: With sodium hydride In dimethyl sulfoxide at 0 - 20℃; for 0.5 h; Stage #2: at 90℃;
[00341] 4-Bromo-2-(cyanomethyl)benzonitrile: Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to O0C in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. A- Bromo-2-fluorobenzonitrile (1 18 g, 590 mmol) (commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. The mixture was heated to an internal temperature of 9O0C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 1040C over 3 hours. 2.3 L of water was added and the mixture was heated at reflux 16 hours. The mixture was cooled to 50C and 700 mL of 0.2N HCl was added. The mixture was allowed to stir at 50C for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78 percent). LCMS (API-ES) m/z: 223, 221 (M+I-T).
78%
Stage #1: With sodium hydride In dimethyl sulfoxide at 0 - 30℃; Stage #2: at 20 - 90℃; Stage #3: With water In dimethyl sulfoxide at 104℃; Reflux
4-Bromo-2-(cyanomethyl)benzonitrile: NaH (47.2 g, 1.18 mol, Aldrich) was suspended in DMSO (320 mL) and cooled to O 0C in an ice-water bath. The mixture became viscous as the DMSO froze. Methyl cyanoacetate (104 mL, 1.18 mol, Aldrich) was added slowly causing a slight temperature increase and thus a more easily stirred solution. The internal temperature stayed below 30 0C. The mixture was stirred for 30 minutes at room temperature before 4-bromo-2-fluorobenzonitrile (118.0 g, 590 mmol, 3B Scientific Corporation Product List 3B3-007315) was added via cannula as a solution in DMSO (500 mL). The mixture was heated with a heating mantle to an internal temperature of 90 0C. Upon reaching 90 0C, the reaction was shown to be complete by LCMS. The mixture was allowed to stand at room temperature for 16 hours. Water (1.2 L) was added, and the temperature was then brought up slowly to an internal temperature of 104 0C. Water (2.3 L) was added and the mixture was heated at reflux for 20 hours. The mixture was cooled to 5 0C. HCl (700 mL, 0.2 N) was then added quickly, and the resulting mixture was stirred at 5 0C for about 30 minutes. The resulting precipitate was filtered, washed with water, and dried to afford 4-bromo-2-(cyanomethyl)benzonitrile (102 g, 78 percent).
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 55℃;
A mixture of 4-bromo-2-fluoro-benzonitrile (15.0 g, 75.0 MMOL), methanol (30.4 mL, 350 MMOL) and potassium carbonate (31.1 g, 225 MMOL) in DMF (150 mL) was stirred under argon at 55 °C overnight. At this point TLC (100percent methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over MG2S04, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5percent) OF 4-BROMO-2-METHOXY-BENZONITRILE AS a white SOLID. H-NMR (CDCI3) 8 7.41 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.1, 1,6 Hz, 1H), 7.13 (d, J = 1,6 Hz, 1H), 3.93 (s, 3H); MS GC-MS (M+ = 211; RT= 6.15 min).
95%
With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 20 h;
4-Bromo-2-methoxybenzonitrile4-Bromo-2-fluorobenzonitrile (10 g, 0.05 mol) was mixed with K2CO3 (20 g, 0.15 mol) and MeOH (9.5 mL, 0.23 mol) in DMF (100 mL) and heated to 55 0C under argon for 2Oh. Water was added and the mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give the subtitle compound as a white solid (10 g, 95percent).1H-NMR (400 MHz, CDCl3): δ 7.42 (d, J= 8.1 Hz, IH), 7.20 - 7.13 (m, 2H), 3.95 (s, 3H); GC-MS m/z: 211/213 1:1 [M+].
95%
With potassium carbonate In N,N-dimethyl-formamide at 55℃; for 16 h; Inert atmosphere
Preparation 16: 2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile; Step I L 4-bromo-2-methoxybenzonitrile; A mixture of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol), methanol (10.0 ml_, 240 mmol), and potassium carbonate (10.6 g, 75.0 mmol) in N,N-dimethylformamide (5OmL) was stirred under nitrogen at 55°C for 16 h. The reaction was diluted with diethyl ether and water. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to the title compound as a white solid (5.03 g, 95percent). 1H NMR (DMSO-d6) δ ppm7.68 (d, 1 H), 7.51 (s, 1 H), 7.32 (d, 1 H), 3.90 (s, 3H).
95.5%
With potassium carbonate In N,N-dimethyl-formamide at 55℃;
Step 1: Preparation of the starting material: 4-bromo-2-methoxy-benzonitrile. A mixture of 4-bromo-2-fluoro-benzonitrile (15.0 g, 75.0 mmol), methanol (30.4 mL, 350 mmol) and potassium carbonate (31. Ig, 225 mmol) in DMF (150 mL) was stirred under argon at 55 0C overnight. At this point TLC (100percent methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over Mg2SO4, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5percent) of 4-bromo-2- methoxy-benzonitrile as a white solid. 1H-NMR (CDCl3) 7.41 (d, J = 8.1 Hz, IH), 7.16 (dd, J = 8.1, 1,6 Hz, IH), 7.13 (d, J = 1,6 Hz, IH), 3.93 (s, 3H); MS GC-MS (M+ = 211; RT= 6.15 min).
With potassium carbonate In DMF (N,N-dimethyl-formamide) at 55℃;
Example 146; Preparation of [(3-Amino-6-bromo-benzofuran-2-yl)-(214-dichloro-phenyl .-methanone; Step 1: Preparation of the starting material : 4-bromo-2-methoxy-benzonitrile; A mixture of 4-bromo-2-fluoro-benzonitrile (15. 0 g, 75.0 mmol), methanol (30.4 mL, 350 mmol) and potassium carbonate (31.1g, 225 mmol) in DMF (150 mL) was stirred under argon at 55 °C overnight. At this point TLC (100percent methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over Mg2SO4, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5percent) of 4-bromo-2-methoxy-benzonitrile as a white solid. 'H-NMR (CDCl3) 8 7.41 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.1, 1,6 Hz, 1H), 7.13 (d, J = 1,6 Hz, 1H), 3.93 (s, 3H); MS GC-MS (M+ = 211 ; RT= 6. 15 min).
In a 1L round-bottomed flask, 53.94 g (270 mmol) of 4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodium methoxide (21.99 g, 407 mmol) was added and the mixture was heated to reflux until TLC (SiO2 : CH2Cl2) showed complete consumption of starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and filtered over a plug of silica gel. The plug was eluted with CH2Cl2 and the filtrate was evaporated in vacuo to afford 45.56 g (80percent) of the product as a white solid. 1HNMR (500 MHz, CDCl3) δ 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).
Stage #1: With potassium carbonate In N,N-dimethyl-formamide; toluene for 4 h; Dean-Stark; Inert atmosphere; Reflux Stage #2: for 4 h; Reflux; Inert atmosphere
In a three-neck flask equipped with a Dean-Stark trap, phenol (12.35 g, 131.25 mmol), K2CO3 (34.55 g, 250 mmol), N,N-dimethylformamide (125 mL) and toluene (125 mL) were charged, and refluxed in a nitrogen atmosphere for 4 hours to perform dehydration until no further water was formed from the reaction system. Thereafter, 100 mL of toluene was removed with the Dean-Stark trap. (0176) After returning to room temperature, 4-bromo-2-fluorobenzonitrile (25.0 g, 125 mmol) was added thereto, and the mixture was refluxed in a nitrogen atmosphere for 4 hours. After completing the reaction, the solution was diluted by adding toluene (200 mL) thereto, and then filtered with Celite. The solution was rinsed twice with water with a separating funnel, dried over anhydrous magnesium sulfate, and filtered. The product was purified by silica gel chromatography (mobile phase: toluene/ethyl acetate=9/1), and a specimen deposited through concentration of the solution was rinsed with 200 mL of hexane under application of ultrasonic wave for 5 minutes, and then filtered. The specimen was dried in vacuum (50° C. for 4 hours) to provide a white solid matter (yield amount: 31.2 g, yield: 91percent). The product was identified by 1H-NMR and ESI-MS. (0177) 1H NMR (500 MHz, CDCl3, δ): 6.97 (s, 1H), 7.11 (d, 2H), 7.25-7.31 (m, 2H), 7.42-7.48 (m, 2H), 7.51 (d, 1H) (0178) ESI-MS (m/z) (M+) calcd. 272.98, found 273.09.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate In dimethyl sulfoxide at 80℃; for 4 h; Inert atmosphere
Under nitrogen, 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol), bis(pinacolato)diboron (3.8 g, 30 mmol) and potassium acetate (6.1 g, 60 mmol) were suspended in DMSO (50 mL), Pd(dppf)Cl2 (1.5 g, 0.2 mmol) was added. The mixture was stirred at 80° C. for 4 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to give compound 56-a (3.6 g, yield: 73percent). (0367) 1H-NMR (400 MHz, CD3OD) δ: 7.62 (m, 3H), 1.35 (s, 12H) ppm
With hydrazine hydrate In butan-1-ol for 4 h; Inert atmosphere; Reflux
Under nitrogen protection, 4-bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in 20 mL of n-butanol,Hydrazine hydrate (1.04 mL, 50.26 mmol) was added,Heated to reflux for 4 h. After cooling to room temperature, a large amount of solid was precipitated.The filter cake was washed with suction and petroleum ether, dried to give 4.759 g of a white solid,Yield 85.7percent.
85.7%
With hydrazine In ethanol for 4 h; Reflux
4-Bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) was dissolvedin absolute ethyl alcohol (20 mL), then followed by the addition ofNH2NH2 (1.0 mL, 50.3 mmol). The reaction mixture was heated toreflux for 4 h, then cooled to rt, filtered, washed with petroleumether and dried to give 3 as white solid (4.8 g, 85.7percent). 1H NMR(400 MHz, DMSO d6) d: 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.37–7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz, 1H), 5.47 (brs, 2H).ESI-MS (m/z): [M+H]+ = 213.0 (Calcd: 213.05).
79.2%
With hydrazine hydrate In butan-1-ol at 100℃; for 14 h;
400 mg of 4-bromo-2-fluorobenzonitrile was dissolved in 6 ml of n-butanol and 0.46 ml of hydrazine hydrate (85percent, w / w)The mixture was heated to 100 ° C and stirred for 14 hours. After heating, the reaction solution was concentrated to 2 ml, filtered, washed with water and a small amount of ethyl acetateThe cake and filter cake were dried in vacuo to give 336 mg of a pale orange solid in a yield of 79.2percent.
76%
With hydrazine hydrate In ethanol at 70℃; for 5 h;
2-Fluoro-4-bromo-benzonitrile (26.9 mmol, 5.38 g) and hydrazine hydrate 50percent (107.6 mmol, 6.7 ml) were dissolved in ethanol (90 ml) and heated at 70°C for 5 hours. After cooling to room temperature the title compound was filtered and isolated as a white solid (4.36 g, 76percent).1HNMR(400 MHz, DMSO-d6)ö 11.51 (s, 1H), 7.63 (dd,J= 8.5, 0.5 Hz, 1H), 7.42 (dd, J= 1.6, 0.5 Hz, 1H), 7.02 (dd, J= 8.5, 1.6 Hz, 1H), 5.47 (s, 2H).13C NMR (101 MHz, DMSO-d6)ö 149.4, 142.1, 122.1, 120.3, 119.8, 113.1, 111.8. (ESI+) MS: mlz 233.1 (MNa+).
653.7 mg
With hydrazine hydrate In butan-1-ol at 120℃; for 4 h;
4-Bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in n-butanol (20mL), followed by the addition of NH2NH2 (1.04 mL, 50.26 mmol). The reaction mixture was heated to reflux for 4 h, then cooled to rt, filtered, washed with n-hexane and dried to give 9 as a white solid (4.76g, 85.7percent).1H NMR (400 MHz, DMSO-d6) δ 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.37–7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz,1H), 5.47 (brs, 2H). ESI-MS (m/z): [M + H]+ = 213.0.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2012, vol. 22, # 14, p. 4579 - 4584
[2] Bioorganic and Medicinal Chemistry Letters, 2010, vol. 20, # 6, p. 1985 - 1989
[3] Patent: CN106032359, 2016, A, . Location in patent: Paragraph 0044; 0045; 0046
[4] Bioorganic and Medicinal Chemistry, 2018, vol. 26, # 3, p. 747 - 757
[5] Patent: CN106146493, 2016, A, . Location in patent: Paragraph 0452; 0453; 0454; 0455
[6] Patent: WO2016/96709, 2016, A1, . Location in patent: Page/Page column 51; 52
[7] Organic Process Research and Development, 2011, vol. 15, # 3, p. 565 - 569
[8] Patent: US2006/106083, 2006, A1, . Location in patent: Page/Page column 23
[9] Patent: US2007/161626, 2007, A1, . Location in patent: Page/Page column 8
[10] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 1, p. 279 - 282
[11] Patent: US2004/14802, 2004, A1, . Location in patent: Page/Page column 17
[12] Patent: WO2011/115725, 2011, A2, . Location in patent: Page/Page column 51
[13] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 16, p. 3782 - 3786
[14] Advanced Synthesis and Catalysis, 2018, vol. 360, # 10, p. 1943 - 1948
Stage #1: With n-butyllithium; diisopropylamine In tetrahydrofuran at -78℃; for 2.5 h; Inert atmosphere Stage #2: at -78 - 20℃; Inert atmosphere
To a solution of diisopropylamine (4.2ml, 30mmol) in dry THF (5ml) was added a solution ofnBuli in THF (2.5M, 11 ml, 27.5mmol) dropwise at -78 °C. Once addition was complete, thereaction was allowed to warm to 0 oc and stirred in an ice-salt bath for 40 mins. The resultingsolution was added dropwise to a solution of 4-bromo-2-fluorobenzonitrile (5g, 25mmol) in dryTHF (50ml) at -78 oc and the mixture stirred for 2.5 hrs. The reaction mixture was then cooled15 to -78 oc and methyl iodide added in one portion and the mixture slowly allowed to warm toroom temperature. The reaction was quenched with aqueous NH4CI and extracted with EtOAc(3x 40ml). The combined organics were washed with water (40ml) and brine (40ml). Theorganics were dried over MgS04, filtered and concentrated. The residue was purified by columnchromatography eluting with 9:1 pet ether : ethyl acetate to afford 4-bromo-2-fluoro-3-methyl-20 benzonitrile as an off white solid (2.40g, 45percent yield).
With sodium carbonate In ethanol; water at 80℃; for 4h;
92%
With sodium hydroxide; sodium carbonate In ethanol; benzene
111.A 3-fluoro-4'-methoxy-1,1'-biphenyl-4-carbonitrile
Example 111A 3-fluoro-4'-methoxy-1,1'-biphenyl-4-carbonitrile A mixture of 4-methoxyphenylboronic acid (4.56 g, 30.0 mmol) in ethanol (20 mL) was added to a solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25.0 mmol) and tetrakis(triphenylphosphine)palladium (578 mg, 0.50 mmol) in benzene (50 mL). The resulting mixture was treated with a 2.0 M aqueous solution of Na2CO3 (25 mL, 50 mmol) and heated briefly at reflux, then at 65° C. overnight. The mixture was cooled to room temperature and treated with 6.0 M aqueous NaOH. The aqueous phase was separated and extracted with ether. First the original organic phase and then the ethereal wash were filtered through diatomaceous earth. The collection flask was changed and the solids remaining atop the diatomaceous earth were washed through with EtOAc. The ethereal wash was concentrated and refiltered as before. The combined EtOAc rinses were combined and concentrated to provide the title compound as a yellow powder (92% yield). 1H-NMR (300 MHz, d6-DMSO) δ 3.82 (s, 3H), 7.07 (d, 2H), 7.72 (dd, 1H), 7.79 (d, 2H), 7.85 (dd, 1H), 7.95 (dd, 1H).
88%
With tetrakis(triphenylphosphine) palladium(0); dihydrogen peroxide; sodium carbonate In ethanol; benzene 1.) 2.5 h, reflux; 2.) 1 h, room temp.;
80%
With tetrakis(triphenylphosphine) palladium(0); potassium carbonate In 1,4-dioxane at 100℃; Inert atmosphere;
90.a a) 3-fluoro-4'-methoxybiphenyl-4-carbonitrile
4-bromo-2-fluorobenzonitrile (1.00 g, 5.00 mmol), 4-methoxyphenylboronic acid (0.84 g, 5.50 mmol), 2M aqueous solution of potassium carbonate (5.00 mL, 10.00 mmol) and dioxane (30 mL). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon and tetrakis(triphenylphosphine)palladium(0) (0.58 g, 0.50 mmol) was added. After three further cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in an oil bath at 100 ºC overnight. The mixture was cooled and filtered. Ethyl acetate and water were added to the mixture and the organic layer was washed with brine, dried (Na2SO4) and evaporated to give the desired compound (0.91 g, 80%) as a white solid. LRMS (m/z): 228 (M+1)+.
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; benzene
Stage #1: 4-methoxyphenylboronic acid; 4-bromo-6-fluorobenzonitrile With potassium carbonate In water at 20℃; for 0.25h;
Stage #2: With palladium dichloride In water
4.3. General procedure for the preparation of compounds 3a-r
General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.
Step A: 6-Bromobenzo[d]isoxazol-3-amine: N-hydroxyacetamide (1.13 g, 15.0 mmol) was dissolved in DMF (20 mL). To this was added KOt-Bu (1.68 g, 15.0 mmol) and the reaction was stirred for 30 minutes before addition of 4-bromo-2-fluorobenzonitrile (2.0 g, 10.0 mmol). The reaction mixture was left at ambient temperature for 2 hours, then diluted with ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate The combined organics were washed with water, dried, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with ethyl acetate/hexanes (1:4), ethyl acetate/hexanes (1:3) to give the desired product (1.35 g, 63%). MS (APCI) m/z 215.2, 217.1 (M+1).
A mixture of 2-fluoro5-bromobenzonitrile (30 g, 152.3 mmole), potassium acetate (222.4 g, 228.5 mmol), and 18-crown-6 ether (60.4 g, 288.5 mmol) in MeCN (400 mL) was heated at reflux in 36 h. The mixture was cooled, 2.5 N NaOH (200 mL) added, and stirred at RT overnight. The mixture was extracted with ether (discarded). The aqueous layer was acidified with 6N HCl, extracted with EtOAc, dried over MgSO4, concentrated, purified by flash column chromatography (40% EtOAc/Hex) to give the above titled compound as a light yellow foam (24.45 g, 81%). NMR(300 MHz, DMSO-d6): 7.13(dd, J=1.7, 8.3 Hz, 1H), 7.17(d, J=1.7 Hz, 1H), 7.61(d, J=8.3 Hz, 1H).
With 2-(methylsulfonyl)ethyl alcohol; sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 0 - 20℃;
To a stirred solution of 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol) in DMF (20 mL) was added 2-(methylsulfonyl)ethanol (3.7 g, 30 mmol) and then NaH (2.4 g, 60 % in mineral, 60 mmol) in portions at 0 C. The mixture was then warmed to rt. and quenched with 1N HCl, and extracted by EtOAc. The organic layers were washed with brine and dried over sodium sulfate, concentrated to give 4-bromo-2-hydroxybenzonitrile. 1H-NMR (400 MHz, DMSO) delta 7.55-7.57 (d, J = 8.61 Hz, 1H), 7.16 (s, 1H), 7.11-7.13 (m, 1H).
With sodium hydride; In N,N-dimethyl-formamide; at 0 - 20℃; for 1.0h;
Sodium hydride (4.8 g) was added with ice cooling to a N,N-dimethylformamide solution (150 mL) of 4-bromo-2-fluorobenzonitrile (10.0 g) and ethyl glycolate (12.49 g), stirred for 30 minutes, and then stirred for 30 minutes at room temperature. Water was added to the reaction solution, which was then extracted with diethyl ether. The extract was washed successively with water and saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and recrystallized from the ethyl acetate-hexane to obtain ethyl 3-amino-6-bromo-1-benzofuran-2-carboxylate (3.72 g) as pale yellow crystals. 1H-NMR (300MHz, CDCl3); delta 1.44 (3H, t, J=7.2Hz), 4.44 (2H, q, J=7.2Hz), 4.95 (2H, br s), 7.37 (1H, dd, J=1.5, 8.4Hz), 7.42 (1H, dd, J=0.6, 8.4Hz), 7.63 (1H, dd, J=0.6, 1.5Hz)
Stage #1: tributyl(1-ethoxyvinyl)stannane; 4-bromo-6-fluorobenzonitrile In toluene for 2h; Heating / reflux;
Stage #2: With hydrogenchloride; water In toluene for 0.5h;
4.1
Step 1: 4-Acetyl-2-fluorobenzonitrile A mixture of 4-bromo-2-fluorobenzonitrile (10.6 g, 52.8 mmol), tributyl(1-ethoxyvinyl)tin (21 g, 58.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (371 mg, 0.53 mmol) in 190 mL of dry toluene were refluxed for 2 h and then quenched with 5% HCl and stirred for 30 min. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.5 g of crude product. Purification of the product on silica gel using 5% ethyl acetate:hexane gave 4-acetyl-2-fluorobenzonitrile (1.0 g, 11%), MS (ES) m/z 164 [M+H]+.
11%
Stage #1: tributyl(1-ethoxyvinyl)stannane; 4-bromo-6-fluorobenzonitrile In toluene for 2h; Heating / reflux;
Stage #2: With hydrogenchloride; water In toluene for 0.5h;
81.1
Step 1: 4-Acetyl-2-fluorobenzonitrile A mixture of 4-bromo-2-fluorobenzonitrile (10.6 g, 52.8 mmol), tributyl(1-ethoxyvinyl)tin (21 g, 58.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (371 mg, 0.53 mmol) in 190 mL of dry toluene were refluxed for 2 h and then quenched with 5% HCl and stirred for 30 min. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.5 g of crude product. Purification of the product on silica gel using 5% ethyl acetate:hexane gave 4-acetyl-2-fluorobenzonitrile (1.0 g, 11%), MS (ES) m/z 164 [M+H]+.
11%
Stage #1: tributyl(1-ethoxyvinyl)stannane; 4-bromo-6-fluorobenzonitrile In toluene for 2h; Heating / reflux;
Stage #2: With hydrogenchloride; water In toluene for 0.5h;
6.1 4-Acetyl-2-fluorobenzonitrile
Step 1 4-Acetyl-2-fluorobenzonitrile A mixture of 4-bromo-2-fluorobenzonitrile (10.6 g, 52.8 mmol), tributyl(1-ethoxyvinyl)tin (21 g, 58.1 mmol), and trans-dichlorobis(triphenylphosphine)palladium (II) (371 mg, 0.53 mmol) in 190 mL of dry toluene were refluxed for 2 h and then quenched with 5% HCl and stirred for 30 min. Ethyl acetate was added and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6.5 g of crude product. Purification of the product on silica gel using 5% ethyl acetate:hexane gave 4-acetyl-2-fluorobenzonitrile (1.0 g, 11%), MS (ES) m/z 164 [M+H]+.
4-(2,3-dimethoxyphenyl)-2-fluorobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
With sodium carbonate;bis-triphenylphosphine-palladium(II) chloride; In 1,2-dimethoxyethane; ethanol; water; at 140℃; for 0.222222h;Microwave irradiation;
To a microwave reactor vessel is added 4-bromo-2- fluorobenzonitrile (0.2 g, 1 mmol) , 2 , 3-dimethoxyphenylboronic acid (0.27 g, 1.5 mmol), dichlorobis (triphenylphosphine) palladium (14 mg, 0.02 mmol), sodium carbonate (0.16 g, 1.5 mmol), and 7:3:2 DME :Ethanol : H2O <n="47"/>(5 mL) . The reaction is irradiated at 140 0C for 800 sec. The mixture is extracted with ethyl acetate (100 mL) , washed with brine (2 X 50 mL) , and dried over MgSO4. Solvent is removed in vacuum and the residue is purified by a silica gel column to give 0.23 g of the desired biphenyl 4- (2, 3-Dimethoxyphenyl) -2- fluorobenzonit?le (89%) as a white solid.
With potassium tert-butylate; In dimethyl sulfoxide; at 20℃; for 0.5h;
Example 21 : Scheme G4; Potassium tert-butoxide (2.1 equiv., 104 mmol, 12.0 g) was added to a stirred solution of 4-bromo-2-fluorobenzonitrile (G4.1) (1 equiv., 49 mmol, 10.0 g) and 5-amino-2- methylbenzonitrile (1 equiv., 49 mmol, 6.7 g) in DMSO (60 ml). The reaction mixture was stirred at room temperature for 0.5 h. Water was added, the resulting precipitate was filtered off, washed successively with water, isopropanol and isopropyl ether to give G4.2 (9.9 g, yield = 64%).
4-Bromo-2-(cyanomethyl)benzonitrile. Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to 0C in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. 4- Bromo-2-fluorobenzonitrile (118 g, 590 mmol)(commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. <n="191"/>The mixture was heated to an internal temperature of 90C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 104C over 3 hours. 2.3 L of water were added, and the mixture was heated at reflux 16 hours. The mixture was cooled to 5C. HCl (700 mL, 0.2 N) was added, and the mixture was allowed to stir at 5C for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78 %). LCMS (API-ES) m/z: 223, 221 (IVH-H+).
78%
[00341] 4-Bromo-2-(cyanomethyl)benzonitrile: Sodium hydride (47.2 g, 1.18 mol) was suspended in 320 mL DMSO and cooled to O0C in an ice-water bath. The mixture became viscous as the DMSO began to freeze. Methyl cyanoacetate (104 mL, 1.18 mol) was added slowly causing a slight temperature increase and thus a more easily stirrable solution. The mixture was stirred for 30 minutes at room temperature. A- Bromo-2-fluorobenzonitrile (1 18 g, 590 mmol) (commercially available from Acros Organics (Order Number 29049)) was added via cannula as a solution in 500 mL DMSO. The mixture was heated to an internal temperature of 9O0C. The mixture was cooled and allowed to stand overnight. 1.2 L of water was added to the reaction mixture. The mixture was heated to an internal temperature of 1040C over 3 hours. 2.3 L of water was added and the mixture was heated at reflux 16 hours. The mixture was cooled to 50C and 700 mL of 0.2N HCl was added. The mixture was allowed to stir at 50C for 30 minutes. The resulting precipitate was filtered, washed with water, and dried to provide the product (102 g, 78 %). LCMS (API-ES) m/z: 223, 221 (M+I-T).
78%
4-Bromo-2-(cyanomethyl)benzonitrile: NaH (47.2 g, 1.18 mol, Aldrich) was suspended in DMSO (320 mL) and cooled to O 0C in an ice-water bath. The mixture became viscous as the DMSO froze. Methyl cyanoacetate (104 mL, 1.18 mol, Aldrich) was added slowly causing a slight temperature increase and thus a more easily stirred solution. The internal temperature stayed below 30 0C. The mixture was stirred for 30 minutes at room temperature before 4-bromo-2-fluorobenzonitrile (118.0 g, 590 mmol, 3B Scientific Corporation Product List 3B3-007315) was added via cannula as a solution in DMSO (500 mL). The mixture was heated with a heating mantle to an internal temperature of 90 0C. Upon reaching 90 0C, the reaction was shown to be complete by LCMS. The mixture was allowed to stand at room temperature for 16 hours. Water (1.2 L) was added, and the temperature was then brought up slowly to an internal temperature of 104 0C. Water (2.3 L) was added and the mixture was heated at reflux for 20 hours. The mixture was cooled to 5 0C. HCl (700 mL, 0.2 N) was then added quickly, and the resulting mixture was stirred at 5 0C for about 30 minutes. The resulting precipitate was filtered, washed with water, and dried to afford 4-bromo-2-(cyanomethyl)benzonitrile (102 g, 78 %).
With triethylamine; triphenylphosphine;palladium diacetate; In acetonitrile; at 50℃;
A mixture OF4-BROMO-2-FLUORO-BENZONITRILE (4.00 g, 20.0 mmol), ET3N (3.94 g, 38.9 mmol), palladium (II) acetate (314 mg, 1.40 MMOL), triphenylphosphine (214 mg, 0.816 mmol) in 4: 1 CH3CN/MeOH (50 mL) is purged with a stream of nitrogen for 15 min in a sealed tube equipped with gas inlet/outlet valves. The reaction is flushed with carbon monoxide (3 X 60 psi), releasing the pressure between each addition. The reaction is left under an atmosphere of carbon monoxide (60 psi) and heated to-50 C overnight. The pressure is released and the reaction mixture is filtered through a SINTERED-GLASS FUNNEL containing diatomaceous earth, washing with MEOH (20 mL). The reaction residue is subjected to flash chromatography (silica gel, 9: 1 Hex/EtOAc) to afford the sub-title compound (2.13 g, 59%) as a white solid. Rf 0.33 (4 : 1 HEX/ETOAC). mp 61-62 C. 'H NMR (300 MHz, CDC13) B 3.97 (s, 3H), 7.72 (DD, J = 6.2, 8.0 HZ, 1H), 7.86 (dd, J= 1.3, 9.2 Hz, 1H), 7.93 (dd, J= 1.3, 8.0 Hz, 1H).
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 55℃;
A mixture of 4-bromo-2-fluoro-benzonitrile (15.0 g, 75.0 MMOL), methanol (30.4 mL, 350 MMOL) and potassium carbonate (31.1 g, 225 MMOL) in DMF (150 mL) was stirred under argon at 55 °C overnight. At this point TLC (100percent methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over MG2S04, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5percent) OF 4-BROMO-2-METHOXY-BENZONITRILE AS a white SOLID. H-NMR (CDCI3) 8 7.41 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.1, 1,6 Hz, 1H), 7.13 (d, J = 1,6 Hz, 1H), 3.93 (s, 3H); MS GC-MS (M+ = 211; RT= 6.15 min).
95%
With potassium carbonate; In N,N-dimethyl-formamide; at 55℃; for 20h;
4-Bromo-2-methoxybenzonitrile4-Bromo-2-fluorobenzonitrile (10 g, 0.05 mol) was mixed with K2CO3 (20 g, 0.15 mol) and MeOH (9.5 mL, 0.23 mol) in DMF (100 mL) and heated to 55 0C under argon for 2Oh. Water was added and the mixture was extracted with diethyl ether. The combined organic layers were washed with brine, dried (MgSO4) and concentrated to give the subtitle compound as a white solid (10 g, 95percent).1H-NMR (400 MHz, CDCl3): delta 7.42 (d, J= 8.1 Hz, IH), 7.20 - 7.13 (m, 2H), 3.95 (s, 3H); GC-MS m/z: 211/213 1:1 [M+].
95%
With potassium carbonate; In N,N-dimethyl-formamide; at 55℃; for 16h;Inert atmosphere;
Preparation 16: 2-methoxy-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzonitrile; Step I L 4-bromo-2-methoxybenzonitrile; A mixture of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol), methanol (10.0 ml_, 240 mmol), and potassium carbonate (10.6 g, 75.0 mmol) in N,N-dimethylformamide (5OmL) was stirred under nitrogen at 55°C for 16 h. The reaction was diluted with diethyl ether and water. The layers were separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to the title compound as a white solid (5.03 g, 95percent). 1H NMR (DMSO-d6) delta ppm7.68 (d, 1 H), 7.51 (s, 1 H), 7.32 (d, 1 H), 3.90 (s, 3H).
95.5%
With potassium carbonate; In N,N-dimethyl-formamide; at 55℃;
Step 1: Preparation of the starting material: 4-bromo-2-methoxy-benzonitrile. A mixture of 4-bromo-2-fluoro-benzonitrile (15.0 g, 75.0 mmol), methanol (30.4 mL, 350 mmol) and potassium carbonate (31. Ig, 225 mmol) in DMF (150 mL) was stirred under argon at 55 0C overnight. At this point TLC (100percent methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over Mg2SO4, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5percent) of 4-bromo-2- methoxy-benzonitrile as a white solid. 1H-NMR (CDCl3) 7.41 (d, J = 8.1 Hz, IH), 7.16 (dd, J = 8.1, 1,6 Hz, IH), 7.13 (d, J = 1,6 Hz, IH), 3.93 (s, 3H); MS GC-MS (M+ = 211; RT= 6.15 min).
With hydrazine hydrate; In butan-1-ol; for 4h;Inert atmosphere; Reflux;
Under nitrogen protection, 4-bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in 20 mL of n-butanol,Hydrazine hydrate (1.04 mL, 50.26 mmol) was added,Heated to reflux for 4 h. After cooling to room temperature, a large amount of solid was precipitated.The filter cake was washed with suction and petroleum ether, dried to give 4.759 g of a white solid,Yield 85.7%.
85.7%
With hydrazine; In ethanol; for 4h;Reflux;
4-Bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) was dissolvedin absolute ethyl alcohol (20 mL), then followed by the addition ofNH2NH2 (1.0 mL, 50.3 mmol). The reaction mixture was heated toreflux for 4 h, then cooled to rt, filtered, washed with petroleumether and dried to give 3 as white solid (4.8 g, 85.7%). 1H NMR(400 MHz, DMSO d6) d: 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H),7.37-7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz, 1H), 5.47 (brs, 2H).ESI-MS (m/z): [M+H]+ = 213.0 (Calcd: 213.05).
85%
With hydrazine hydrate; In butan-1-ol; for 4h;Reflux;
4-bromo-2-fluorobenzonitrile (5.0 g, 25.1 mmol) was dissolvedin 1-butanol (20 mL), then followed by the addition of hydrazinemonohydrate (1.0 mL, 50.3 mmol). The reaction mixture washeated to reflux for 4 h. Then cooled to room temperture, filtered,washed with n-hexane and dried to give 4 as white solid (4.77 g,85%).
79.2%
With hydrazine hydrate; In butan-1-ol; at 100℃; for 14h;
400 mg of 4-bromo-2-fluorobenzonitrile was dissolved in 6 ml of n-butanol and 0.46 ml of hydrazine hydrate (85%, w / w)The mixture was heated to 100 C and stirred for 14 hours. After heating, the reaction solution was concentrated to 2 ml, filtered, washed with water and a small amount of ethyl acetateThe cake and filter cake were dried in vacuo to give 336 mg of a pale orange solid in a yield of 79.2%.
76%
With hydrazine hydrate; In ethanol; at 70℃; for 5h;
2-Fluoro-4-bromo-benzonitrile (26.9 mmol, 5.38 g) and hydrazine hydrate 50% (107.6 mmol, 6.7 ml) were dissolved in ethanol (90 ml) and heated at 70C for 5 hours. After cooling to room temperature the title compound was filtered and isolated as a white solid (4.36 g, 76%).1HNMR(400 MHz, DMSO-d6)oe 11.51 (s, 1H), 7.63 (dd,J= 8.5, 0.5 Hz, 1H), 7.42 (dd, J= 1.6, 0.5 Hz, 1H), 7.02 (dd, J= 8.5, 1.6 Hz, 1H), 5.47 (s, 2H).13C NMR (101 MHz, DMSO-d6)oe 149.4, 142.1, 122.1, 120.3, 119.8, 113.1, 111.8. (ESI+) MS: mlz 233.1 (MNa+).
With hydrazine; In butan-1-ol; at 112℃; for 5h;
EXAMPLE 1 6-bromo-1H-indazol-3-amine 4-bromo-2-fluorobenzonitrile (67.8 g), hydrazine hydrate (32.8 ml) in n-butanol (410 ml) were heated to 112 C. for five hours. The reaction mixture was allowed to cool down to r.t. The precipitated crystalline solid was filtered off and washed three times with ethylacetate (100 ml each). The product was dried in vacuo at 40 C. mp. 222-225 C. [M+H]+=213; 1H-NMR (300 MHz DMSO-d6): 11.43 (s, 1H); 7.61 (d, 1H); 7.4 (d, 1H); 7.0 (d of d, 1H); 5.4 (s, 2H)
With hydrazine; In ethanol; for 22h;Heating / reflux;
6-Bromo-3-amino-1H-indazole; A solution of 10 g of 4-bromo-2-fluorobenzonitrile in 300 mL of ethanol is admixed with 7.29 mL of hydrazine hydrate. The reaction mixture is stirred for 22 hours at reflux and then concentrated under reduced pressure. The residue obtained is stirred for 30 minutes in 200 mL of distilled water. The suspended solid is isolated by filtration, washed with water and treated with suction. After drying under vacuum, 10 g of 6-bromo-3-amino-1H-indazole are obtained, whose characteristics are as follows: MS spectrum (ES+): m/z=213 [MH+]Melting point: 249 C.
With hydrazine; In ethanol; water; at 78℃; for 12h;Heating / reflux;
7.3 cm3 of hydrazine monohydrate are added to 10 g of 4-bromo-2-fluorobenzonitrile in 100 cm3 of ethanol. The medium is refluxed at about 78 C. for 12 hours. The precipitate formed is then filtered off on a sinter funnel. After drying (90 Pa; 45 C.), 9.7 g of 6-bromo-1H-indazole-3-amine are obtained in the form of a white solid. [0438] 1H NMR spectrum (300 MHz, (CD3)2SO-d6, delta in ppm): 5.45 (broad s: 2H); 7.03 (dd, J=9 and 2 Hz: 1H); 7.43 (d, J=2 Hz: 1H); 7.65 (d, J=9 Hz: 1H); 11.50 (unresolved peak: 1H).
With hydrazine hydrate; In butan-1-ol; at 130℃;
The reaction mixture of 4-bromo-2-fluorobenzonitrile ( 10 g, 50 mmol), hydrazine hydrate (7.85 ml, 250 mmol) in n-butanol (60 mL) was heated at 130 C for overnight. After cooling down to room temperature, the precipitated crystalline solid was filtered off and washed three times with ethyl acetate ( 15 mL each). The product was dried in vacuo ( 10.3 g). NMR 600 MHz (DMSO-d6) delta 1 1 .48 (s, I H); 7.62 (d, 8.4 Hz, I H), 7.40 (d, 1 .2 Hz, I H), 6.99 (dd, 8.4, 1 .2 Hz, I H), 5.43 (s, 2H). MS m/z : 21 1 .97(M + 1 )
653.7 mg
With hydrazine hydrate; In butan-1-ol; at 120℃; for 4h;
4-Bromo-2-fluorobenzonitrile (5 g, 25.13 mmol) was dissolved in n-butanol (20mL), followed by the addition of NH2NH2 (1.04 mL, 50.26 mmol). The reaction mixture was heated to reflux for 4 h, then cooled to rt, filtered, washed with n-hexane and dried to give 9 as a white solid (4.76g, 85.7%).1H NMR (400 MHz, DMSO-d6) delta 11.52 (brs, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.37-7.52 (m, 1H), 7.02 (dd, J = 8.5, 1.6 Hz,1H), 5.47 (brs, 2H). ESI-MS (m/z): [M + H]+ = 213.0.
With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 55℃;
Example 146; Preparation of [(3-Amino-6-bromo-benzofuran-2-yl)-(214-dichloro-phenyl .-methanone; Step 1: Preparation of the starting material : 4-bromo-2-methoxy-benzonitrile; A mixture of 4-bromo-2-fluoro-benzonitrile (15. 0 g, 75.0 mmol), methanol (30.4 mL, 350 mmol) and potassium carbonate (31.1g, 225 mmol) in DMF (150 mL) was stirred under argon at 55 °C overnight. At this point TLC (100percent methylene chloride) revealed no starting material, and the reaction mixture was poured into ether (300 mL) and water (150 mL). The layers were separated, and the organic layer was washed with water (150 mL) and brine (50 mL), dried over Mg2SO4, filtrated, and concentrated under reduced pressure, providing (15.2 g, 95.5percent) of 4-bromo-2-methoxy-benzonitrile as a white solid. 'H-NMR (CDCl3) 8 7.41 (d, J = 8.1 Hz, 1H), 7.16 (dd, J = 8.1, 1,6 Hz, 1H), 7.13 (d, J = 1,6 Hz, 1H), 3.93 (s, 3H); MS GC-MS (M+ = 211 ; RT= 6. 15 min).
In a 1L round-bottomed flask, 53.94 g (270 mmol) of 4-bromo-2-fluorobenzonitrile was dissolved in 500 mL of THF. Sodium methoxide (21.99 g, 407 mmol) was added and the mixture was heated to reflux until TLC (SiO2 : CH2Cl2) showed complete consumption of starting material. The mixture was poured into 1N HCl and the THF was evaporated in vacuo. The remaining mixture was extracted with diethyl ether. The extract was dried (MgSO4) and filtered over a plug of silica gel. The plug was eluted with CH2Cl2 and the filtrate was evaporated in vacuo to afford 45.56 g (80percent) of the product as a white solid. 1HNMR (500 MHz, CDCl3) delta 7.42 (d, 1H), 7.17 (dd, 1H), 7.14 (d, 1H), 3.95 (s, 3H).
In tetrahydrofuran; at 40℃; for 3h;
Description 28; 4-Bromo-2-methoxybenzonitrile (D28); 4-Bromo-2-fluorobenzonitrile (3.5 g, 17.5 mmol) was dissolved in THF (150 ml) and sodium methoxide (4.73 g, 87.5 mmol) was added. The mixture was heated to 40° C. and stirred for 3 h. After this time the mixture was cooled to 25° C. and Amberlyst 15 resin was added. This mixture was stirred for 3 h, the solid residue was filtered off and the solvent removed in vacuo to give the title compound as a white solid (3.36 g). deltaH (CDCl3, 400 MHz) 3.93 (3H, s), 7.16 (1H, s), 7.17 (1H, d), 7.42 (1H, d).
In tetrahydrofuran; at 40℃; for 3h;
Description 28; 4-Bromo-2-methoxybenzonitrile (D28); 4-Bromo-2-fluorobenzonitrile (3.5g, 17.5mmol) was dissolved in THF (150ml) and sodium methoxide (4.73g, 87.5mmol) was added. The mixture was heated to 4O0C and stirred for 3h. After this time the mixture was cooled to 25°C and Amberlyst 15 resin was added. This mixture was stirred for 3h, the solid residue was filtered off and the solvent removed in vacuo to give the title compound as a white solid (3.36g). deltaH (CDCI3, 400MHz) 3.93 (3H, s), 7.16 (1H1 s), 7.17 (1H, d), 7.42 (1H, d).
In tetrahydrofuran; at 0 - 20℃; for 5h;
To a solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 50.0 mmol) in THF (80 mL) at 0 was added CH3ONa (3.36 g, 60.0 mmol) . The mixture was warmed to ambient temperature and stirred for 5 h, then concentrated and partitioned between water (100 mL) and EtOAc (100 mL x 3) . The combined organic layers were washed with brine (100 ml x 2) , dried over anhydrous sodium sulfate, and concentrated to provide the title compound.1H NMR (400 MHz, CDCl3) delta 7.41 (d, J 8.3 Hz, 1H) , 7.11 -7.21 (m, 2H) , 3.93 (s, 3H) . MS : m/z 211 (M + H+) .
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In methanol; for 18h;Heating / reflux;
Example 80 6-Amino-N-{1-[3-(3-amino-benzo[d]isoxazol-6-yl)-phenyl]-2-phenyl-ethyl}-nicotinamide 80A. 4-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluoro-benzonitrile: To 4-bromo-2-fluorobenzonitrile (15 g, 75.0 mmol) in MeOH (250 mL) were added bis(neopentylglycolato)diboron (18.6 g, 82.5 mmol), KOAc (11.0 g, 112.5 mmol), and Pd(dppf)Cl2.CH2Cl2. The reaction was heated at reflux for 18 h. The reaction was cooled, diluted with Et2O, filtered through Celite and the filtrate was concentrated. The residue was re-dissolved in Et2O, washed with water, brine and dried (MgSO4). After filtration and concentration 16.89 g (97%) of an orange solid was obtained and used without further purification. 1H NMR (400 MHz, CDCl3) delta: 7.65-7.58 (m, 3H), 3.78 (s, 4H), 1.02 (s, 6H).
With aluminum oxide; methanesulfonate at 120℃; for 0.5h;
Charge a flask with acidic alumina (Al2O3) (3.03 g, 29.718 mmol) and methanesulfonic acid (10 mL). Heat the resulting solution to 12O0C, and add 4-bromo-2-fluorobenzonitrile (2.00 g, 9.999 mmol) in one portion. Stir the resulting mixture for 30 minutes, then cool the reaction to room temperature and pour it into water (50 mL). Extract the aqueous mixture with dichloromethane (3 x 30 mL). Combine the organic extracts; dry(Na2SO4); remove the solids by filtration; and concentrate the filtrate in vacuo, affording 2.14 g (98%) 4-bromo-2-fluoro-benzamide as a white solid. 1HNMR (DMSO-U5) δ 7.706 (d, 2H, J = 21.1 Hz), 7.598 (dd, IH, J= 1.9, 10.1 Hz), 7.557 (dd, IH, J= 8.0, 8.0 Hz), 7.446 (ddd, IH, J= 0.4, 1.9, 8.1 Hz).
88%
With sodium perborate In 1,4-dioxane; water for 2h; Heating / reflux;
4
4-Bromo-2-fluoro-cyanobenzne (2.Og, 10 mmol) and sodium perborate (3.0g, 20 mmol) were dissolved in dioxane (40ml), water (40ml) and heated at reflux for 1 hour. An extra 2.0 g of sodium perborate was added and the reaction was refluxed for 1 hour. The reaction was cooled, extracted with DCM (2 x 100 ml), dried and the solvent was removed in vacuo to yield a white solid. Ether was added to dissolve any remaining starting material and the solid was stirred for 10 minutes and filtered to give the title compound (1.7g, 88%). NMR (400.132 MHz) 7.74 (brs, IH), 7.68 (brs, IH), 7.64 (d, IH), 7.61 (t, IH), 7.50 (d, IH).
88%
Stage #1: 4-bromo-6-fluorobenzonitrile With sulfuric acid; trifluoroacetic acid at 20 - 50℃; for 25h;
Stage #2: With water at 0℃; for 1.5h;
6.1
A solution of 4-bromo-2-fluorobenzonitrile (1.00 g, 5.00 mmol), trifluoroacetic acid (3.5 mL, 45 mmol), and sulfuric acid (3.5 mL, 66 mmol) was stirred at ambient temperature for 4 hours, at 30 °C for 15 hours, and at 50 °C for 6 hours. After cooling to 0 °C, water (20 mL) was added, and the resulting suspension was stirred at 0 °C for 1.5 hours. The solids were collected by vacuum filtration, rinsed with excess water, and dried to afford 4-bromo-2-fluorobenzamide (0.956 g, 88%) as an off-white solid which was carried on without further purification.
87%
With sulfuric acid; trifluoroacetic acid at 40℃; for 16h;
A
A solution of 4-bromo-2- fluorobenzonitrile (10.0 g, 50.0 mmol) in a 70 mL mixture of TFA (56.0 mL, 727 mmol)- sulfuric acid (14.0 mL, 263 mmol) (4:1 V/V) was stirred at 40 0C for 16 h. The reaction was poured while still warm over ice water. The product precipitated and the solid was filtered and dried to give 4-bromo-2-fTuorobenzamide (9.53 g, 43.7 mmol, 87 % yield) as a white solid. MS (ESI) m/z 218.1 [M]+, 220.1 [M+2]+.
73%
In Petroleum ether
300.1 Step 1:
Step 1: 4-Bromo-2-fluorobenzamide A mixture of 4-bromo-2-fluorobenzonitrile (50.0 g, 249 mmol) and aluminum oxide (76.5 g, 750 mmol) in methanesulfonic acid (650 mL) was stirred at 120° C. for 1 h. The resultant mixture was quenched with water and extracted with DCM. The organic extracts were dried over sodium sulfate and evaporated in vacuo. The residue was purified via flash chromatography on silica gel (solvent gradient: 0-50% ethyl acetate in petroleum ether) to yield 40 g (73%) of the title compound as a gray solid. LCMS (ESI): [M+H]+=218/220.
1284 mg
With dihydrogen peroxide; potassium carbonate In water; dimethyl sulfoxide at 20℃; Cooling with ice;
78.1
To a solution of Compound 1 (3.00 g) and potassium carbonate (311 mg) in dimethylsulfoxide (45 mL) wasadded an aqueous 30% hydrogen peroxide solution (1.7 mL) under ice cooling, and the mixture was stirred at roomtemperature overnight. To this was added an additional aqueous 30% hydrogen peroxide solution (0.5 mL), and themixture was further stirred at room temperature for 4 days. Water was slowly added dropwise, and the obtained crystalswere collected by filtration, washed with diethyl ether and subsequently vacuum-dried to obtain Compound 2 (1284 mg)as a colorless solid.MS (m/z): 218/220 [M+H]+
With Rhodococcus rhodochrous ATCC BAA 870 cobalt nitrile hydratase In aq. buffer at 30℃; Enzymatic reaction;
Composition of the reaction mixture
General procedure: 1800 μL (90%) Tris buffer (50 mM, pH 7.6) and 200 μL(10%) of methanol or acetone. In a 2 mL Eppendorf, NHase (10 mg) was added followed by Trisbuffer. Nitrile substrate (10 mg dissolved in 200 μL methanol or acetone) was added to the 2 mLEppendorf tube. (If an amine group was present on the nitrile substrate a Tris buffer of pH 9 wasused). The reaction mixture was incubated at 30 °C on an ESCO Provocell microplateshaker/incubator (Esco Technologies, Halfway House, South Africa) (199 rpm). The reaction wasallowed to proceed for 24 h, 48 h or 5 d, depending on conversion, as monitored by TLC analysis.Ethyl acetate and water were added to the reaction mixture, and after separation, the organic layerwas concentrated under reduced pressure, and the resulting mixture was then purified by silica gelcolumn chromatography eluting with 20% to 90% ethyl acetate/ hexane.
potassium acetate, bispinacolatoboronate[ No CAS ]
[ 15366-62-8 ]
[ 105942-08-3 ]
[ 393813-57-5 ]
Yield
Reaction Conditions
Operation in experiment
With hydrogenchloride; sodium carbonate; In 1,4-dioxane; ethanol; ethyl acetate; N,N-dimethyl-formamide;
a 5-(4-Cyano-3-fluoro-phenyl)-nicotinic acid ethyl ester A solution of 2-fluoro-4-bromobenzonitrile in DMF is treated with potassium acetate, bispinacolatoboronate (1.1 equiv.) and catalytic PdCl2(dppf) and heated for 2 h at 80 C. The reaction mixture is cooled to room temperature and <strong>[15366-62-8]4-bromonicotinic acid</strong> (1 equiv.) is added along with fresh catalyst and 2 M Na2CO3 and the resulting mixture is stirred at 80 C. for 18 h. Solvent is removed and the residue is treated with 4N HCl/dioxane in refluxing ethanol for 18 h. The reaction is evaporated and the residue in ethyl acetate is washed with NaHCO3 (aqueous), dried over MgSO4 and evaporated to give 5-(4-cyano-3-fluoro-phenyl)-nicotinic acid ethyl ester.
EXAMPLE 52A methyl 4-cyano-3-fluorobenzoate A solution of 4-bromo-2-fluorobenzonitrile (10.0 g, 0.05 mol) in methanol (150 mL) was treated with (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(II) complex with dichloromethane (1:1) (0.408 g, 0.5 mmol) and triethylamine (13.9 mL), heated to 115 C. under 450 psi CO pressure for 24 hours, cooled to room temperature, filtered, and concentrated to provide the desired product of sufficient purity for subsequent use without further purification.
a 4-Bromo-2-methoxybenzonitrile A suspension of potassium methoxide (4.24 g, 60.0 mmol) in tetrahydrofuran (40 mL) was added in portions to a solution of 4-Bromo-2-fluorobenzonitrile (8.0 g, 40.0 mmol) in tetrahydrofuran (50 mL) at -50° C. After one hour, the dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 6 hours. The reaction mixture was poured onto water (250 mL) and the solid was collected by filtration to give 4-bromo-2-methoxybenzonitrile (7.85 g, 92percent). 1H NMR (DMSO-d6) delta 3.94(s, 3H), 7.32 (d, J=8.23 Hz, 1H), 7.15 (s, 1H), 7.69 (d, J=8.23 Hz, 1H).
92%
In tetrahydrofuran;
a) 4-Bromo-2-methoxybenzonitrile A suspension of potassium methoxide (4.24 g, 60.0 mmol) in tetrahydrofuran (40 mL) was added in portions to a solution of 4-Bromo-2-fluorobenzonitrile (8.0 g, 40.0 mmol) in tetrahydrofuran (50 mL) at -50° C. After one hour, the dry ice bath was removed and the reaction mixture was allowed to warm up to room temperature and stirred at room temperature for 6 hours. The reaction mixture was poured onto water (250 mL) and the solid was collected by filtration to give 4-bromo-2-methoxybenzonitrile (7.85 g, 92percent). 1H NMR (DMSO-d6) delta 3.94(s, 3H), 7.32 (d, J=8.23 Hz, 1H), 7.15 (s, 1H), 7.69 (d, J=8.23 Hz, 1H).
R.10 Preparation of 2-Fluoro-4-(2,4-dichlorophenyl)benzonitrile (Compound XVI)
Reference Example 10 Preparation of 2-Fluoro-4-(2,4-dichlorophenyl)benzonitrile (Compound XVI) 1.0 g (5.2 mmol) of 2,4-dichlorophenylboronic acid, 1.1 g (5.5 mmol) of 4-bromo-2-fluorobenzonitrile, 1.6 g (15.0 mmol) of sodium carbonate and 0.8 g (0.7 mmol) of tetrakis(triphenylphosphine) palladium were added to a solvent mixture of 50 ml of toluene, 25 ml of ethanol and 25 ml of water, and the reaction was carried out under reflux with heating for 2 hours. The reaction mixture was poured into ice-cold water and extracted with toluene. The toluene layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3 g of 2-fluoro-4-(2,4-dichlorophenyl)benzonitrile (yield 93.0%), which was used in Example 8 (1) as the starting material.
tetrakis(triphenylphosphine) palladium(0); In ethyl acetate; N,N-dimethyl-formamide; toluene;
B) Preparation of 2-fluoroterephthalonitrile A solution of 4-bromo-2-fluorobenzonitrile (20 g, 100 mmol), zinc cyanide (7 g, 60 mmol) and tetrakis(triphenylphosphine)palladium (4.6 g, 4 mmol) in DMF (100 mL) was heated at 80 C. for 4 hr. Toluene (300 mL) and saturated aqueous ammonium chloride (300 mL) were added and the layers were separated. The organic layer was washed once with saturated aqueous ammonium chloride and twice with brine. The organic phase was dried (MgSO4), filtered and concentrated. The product was purified by silica gel chromatography, eluding with a gradient of hexanes to 30% EtOAc/hexanes (11 g, 75%).
With trifluoroacetic acid; for 15.0h;Heating / reflux;
To a solution of 4-bromo-2-fluoro-benzonitrile (2 g) in trifluoroacetic acid (25 mL) was added thiosemicarbazide (0.91 g) and refluxed for 15 hours. The solvent was evaporated, the compound was taken in ethyl acetate and neutralized with sodium bicarbonate solution. The aqueous layer separated out and was dried with anhydrous sodium sulfate and concentrated to yield the title compound (1.35 g).
With N-ethyl-N,N-diisopropylamine; In butan-1-ol; at 140℃; for 72h;
To a dried flask charged with 4-bromo-2-fluorobenzonitrile (5.0 g, 22.5 mmol) in n-butanol (60 mL) was added a solution of <strong>[1073-62-7]benzylhydrazine hydrochloride</strong> (17.56 g, 90 mmol, 4.0 eq) and diisopropylethylamine (32.1 mL, 184.48 mmol, 8.2 eq). The reaction mixture was stirred at 140 0C under N2 for 3 days. The mixture was cooled to rt and partitioned between EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3, water, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified using an ISCO instrument (gradient 5 to 60% EtOH/ DCM) and the product containing fractions were concentrated to give 3.4 g (50 %) of the title compound as beige solid. 1H NMR (300 MHz, CD2CI2) delta 7.63 (dd, 1H), 7.37 to 7.30 (m, 4H), 7.20 to 7.16 (m, 2H), 6.94 (dd, 1 H), 5.44 (s, 2H), 4.02 (broad s, 2H); ES-MS m/z 302.3/304.3 [M+H]+, RT (min) 2.34.
With potassium <i>tert</i>-butylate In 1-methyl-pyrrolidin-2-one at 10 - 20℃;
XXIII
Example XXIII; 1-Bromo-4-cvano-3-(4-methoxy-benzyl)-benzene; A mixture of 25 g of ethyl (4-methoxy-phenyl)-acetate, 27.4 g of 1-bromo-4-cyano-3-fluoro- benzene and 20 mL of N-methyl-pyrrolidin-2-one is slowly added to 31.4 g of potassium tert butoxide in 130 mL of N-methyl-pyrrolidin-2-one keeping the temperature below 10°C. After stirring for 1 hour at room temperature, 100 mL of methanol and 137 mL of 1 M aqueous sodium hydroxide are added and the mixture is stirred overnight at room temperature. The methanol fraction is evaporated, the residue is basified with 1 M aqueous sodium hydroxide and extracted with tert butyl-methyl ether. The aqueous phase is acidified with 4 M hydrochloric acid and extracted with ethyl acetate several times. The combined ethyl acetate extracts are evaporated and the residue together with 120 mL of N,N-dimethyl formamide and 24.9 g of potassium carbonate heated at 100°C for 1 hour. The reaction mixture is diluted with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The combined extracts are evaporated and the residue crystallized from methanol.Yield: 13 g (33% of theory)Mass spectrum (ESI+): m/z = 319/321 (Br) [IVH-NH4] +
Stage #1: 4-bromo-6-fluorobenzonitrile; phenylboronic acid With sodium methylate In ethanol Inert atmosphere;
Stage #2: In ethanol at 60℃; for 1h; Inert atmosphere;
4.5.1. Catalytic studies for Suzuki-Miyaura reactions
General procedure: In glass tubes of a Radleys Carousel 12 Plus StationTM fitted witha water-cooled aluminum reflux head and septa, 16 mL of an absoluteEtOH solution containing p-halogenoacetophenone (0.05 M,1 eq), phenylboronic acid (0.06 M, 1.2 eq) and MeONa (0.075 M,1.5 eq) were added. The reaction mixtures were stirred and heatedat 25 C or 60 C under nitrogen atmosphere for 30 min. Then, thepalladium catalyst (8 10-4 mmol Pd, 5 10-5 M, 0.001 eq) wasadded. The mixture was vigorously stirred and kept at 60 C for1 h under nitrogen. Then, an aliquot (ca. 0.5 mL) of the reactioncrude was taken at different reaction times and quenched in a vial filled with water/ethyl acetate mixture (2:1.5, 3.5 mL) and withnaphthalene (0.09 mmol) as standard
98%
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In 1,2-dimethoxyethane Reflux; Inert atmosphere;
Suzuki coupling reaction: general procedure
General procedure: A benzonitrile derivative was reacted with theboronic acid (1.2 eq) in the presence of Pd(PPh) (5 mol%) and 2M NaCO in DME, and the reactionmixture was refluxed overnight under a nitrogen atmosphere. After completion, the reaction wascooled and ethyl acetate and water were added. After separation, the organic layer was dried over Na2SO4 and the solvent removed under reduced pressure. The mixture was then purified using flashsilica gel column chromatography using 5% ethyl acetate/hexane.
92%
With sodium carbonate In ethanol; water at 80℃; for 10h;
88%
With potassium carbonate In 1,4-dioxane; water at 140℃; for 0.5h; Microwave irradiation;
20
To a mixture of 4-bromo-2-fluorobenzonitrile (500 mg, 2.500 mmol), phenyl boronic acid (305 mg, 2.500 mmol), and K2CO3 (691 mg, 5.00 mmol) in 1,4-dioxane (6.0 mL) and water (2.0 mL) was added PdCl2(dppf) (10 mg, 0.014 mmol). The vial was capped and the reaction mixture was heated in a Biotage Initiator microwave reactor to 140 0C for 30 min. Water (5 mL) and EtOAc (10 mL) were added to the reaction mixture. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (3 x 5 mL), dried over Na2SO4, filtered, concentrated under a stream of nitrogen at 50 0C, and dried under high vacuum to afford the title compound (490 mg, 88%). LC-MS m/z 198 (M+H)+, 1.10 min (ret time).
74%
With cesium fluoride In 1,2-dimethoxyethane; ethyl acetate
9.A A.
A. 3-Fluoro-biphenyl-4-carbonitrile To a solution of 4-bromo-2-fluorobenzonitrile (1.12 g, 5.6 mmol) in 1,2-dimethoxyethane (10 mL) were added Phenyl boronic acid (750 mg, 6.16 mmol), tetrakis(triphenylphosphine)palladium (0) (194 mg, 0.17 mmol) and Cesium fluoride (1.8 g, 12.3 mmol). The mixture of reaction was stirred at 100° C. under nitrogen for 3 h. Then, the mixture is cooled and filter through celite. Then added ethyl acetate and water and extracted (3*). The crude was purified by chromatography (silica gel, hexane-ethyl acetate 10:1) affordind 818 mg (74% yield)n of the title compound.
With potassium carbonate; palladium In N,N-dimethyl-formamide
tetrakis(triphenylphosphine) palladium(0); In N,N-dimethyl-formamide; at 90℃;
To a solution of 4-bromo-6-fluorobenzonitrile (5 g, 25 mmol) in anhydrous DMF (20 mL) was added Zinc cyanide (1.75 g, 14.9 mmol) and tetrakis(triphenylphosphine)-palladium(0) (0.6 g, 0.519 mmol). The reaction mixture was heated overnight under argon at 90 C. After cooling to room temperature, the reaction mixture was poured into ethyl acetate (150 mL) and extracted with water 50 mL, 2×30 mL, brine (30 mL), then dried over anhydrous sodium sulfate. After rotary evaporation of most solvent, the concentrated solution was loaded onto a silica column and eluted with EtOAc/Hexane (1:6). A white solid was obtained (3.73 g). 1H-NMR (300 MHz, CDCl3) delta 7.80 (m, 1H), 7.58 (m, 2H).
With borane-THF; In tetrahydrofuran; at 0 - 20℃; for 16h;
4-Bromo-2-fluorobenzonitrile (5.00 mmol) in THF (30 mL)was cooled to 0 °C. A borane tetrahydrofuran complexsolution (1 M in THF, 15.0 mL) was added dropwise. Thesolution was stirred at 0 °C for 20 mm before being broughtup to RT and stirred for 16 h. MeOH was added dropwise (30 mL) and the solution was concentrated under reduced pressure. The residue was partitionedbetween an aqueous solution of NaOH (1 M) and EtOAc. The organic layer was worked up to give the titled compound (5.00 mmol) as a yellow oil. 1H NMR (400 MHz, CDCI3, ): 7.42-7.27 (m, 1H), 7.25-7.16 (m, 2H), 3.65 (t, J = 6.6 Hz, 2H).
With borane-THF; In tetrahydrofuran; at 0 - 60℃; for 0.5h;
A solution of 100.00 mg Compound BD2-1 (i.e., 4-bromo-2-fluorobenzonitrile) in THF (2.00 mL) was cooled to 0°C. Then BH3-THF (1 M, 1.50 mL) was added and stirred at 60°C for 0.5 hour. LCMS showed the reaction was completed. The reaction mixture was diluted by addition of MeOH (3 mL) and then concentrated under reduced pressure to afford Compound BD2-2 (100.00 mg, crude) as a red oil.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 20℃;
4-Bromo-2-fluoro-bezonitrile (1.25 g), (S)-tetrahydro-furan-3-ylamine hydrochloride (0.785 g), and DIPEA (2.4 mL) are dissolved in DMSO (20 mL) and stirred at room temperature overnight. The reaction mixture is poured into saturated aqueous NH4Cl (150 mL), extracted with EtOAc (3×100 mL), dried over Na2SO4, filtered, and concentrated to give (S)-4-bromo-2-(tetrahydrofuran-3-ylamino)benzonitrile (1.6 g, 96% yield). LCMS: m/z=267, 269 [M+H]+.
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 0.333333h;microwave irradiation;
2-Fluoro-4-Bromobenzonitrile (1.0 g, 5.0 mmol), (S,S)-<strong>[930-45-0]trans-2-aminocyclopentanol</strong> (708 mg, 5.2 mmol), and N,N-diisopropylethylamine (2.18 mL, 7.5 mmol) are dissolved in DMSO (16 mL) in a ?personal chemistry? microwave vial. This vial is placed in a microwave reactor and heated with microwave irradiation at 100 C. for 20 minutes. Analysis by LCMS showed complete conversion to product. The reaction is poured into H2O and a white precipitate formed. The solids are isolated by vacuum filtration to give 4-bromo-2-((1S,2S)-2-hydroxycyclopentylamino)benzonitrile (660 mg, 47% yield). LC/MS: m/z=281 [M+H]+.
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In 1,4-dioxane; dimethyl sulfoxide; at 105℃; for 3.0h;Inert atmosphere;
A mixture of 4-bromo-2-fluorobenzonitrile (1.0 g, 5.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.3 g, 5.0 mmol), potassium acetate (5.9 g, 20.0 mmol) and Pd(dppf)Cl2 (2.0 g, 1.0 mmol) in DMSO (50 ml.) and 1,4-dioxane (10 ml.) was heated at 105 C under N2 for 3 h. [82] The mixture was diluted with EtOAc (200 ml.) and washed with water (100 ml. x 3). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by column chromatography (Pet. ether/EtOAc= 100/0 to 50/1) to give the title compound (1.1 g, 89%) as a white solid, which was used directly in the next step.
73%
With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate; In dimethyl sulfoxide; at 80℃; for 4.0h;Inert atmosphere;
Under nitrogen, 4-bromo-2-fluorobenzonitrile (4.0 g, 20 mmol), bis(pinacolato)diboron (3.8 g, 30 mmol) and potassium acetate (6.1 g, 60 mmol) were suspended in DMSO (50 mL), Pd(dppf)Cl2 (1.5 g, 0.2 mmol) was added. The mixture was stirred at 80 C. for 4 hours. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3). The organic layers were combined, washed with water (50 mL×3) and saturated brine (50 mL) in sequence, dried over anhydrous sodium sulfate, then filtrated, the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography (petroleum ether:ethyl acetate=50:1 to 10:1) to give compound 56-a (3.6 g, yield: 73%). (0367) 1H-NMR (400 MHz, CD3OD) delta: 7.62 (m, 3H), 1.35 (s, 12H) ppm
With potassium acetate;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; In dichloromethane; dimethyl sulfoxide; at 100℃;in a sealed tube;
Example 12-Fluoro-4-(2-(4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)pyrimidin-4-yl)benzonitrilePart I: 2-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile <n="47"/>General procedure A: Preparation of arylboronate ester from aryl halide.[0113] A mixture of 4-bromo-2-fluorobenzonitrile (4.00 g, 20 mmol), bis(pinacolato)diboron (6.60 g, 26 mmol), Pd(dppf)Cl2(CH2Cl2) (0.82 g, 1.0 mmol), KOAc (5.89 g, 60 mmol) and DMSO (20 mL) was heated in a sealed tube at 100C overnight. The reaction mixture was cooled down to room temperature, diluted with water and extracted with ethyl acetate (2x). The combined organic solution was dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purification of this material by column chromatography on silica gel (5% EtOAc / hexane) provided the desired product as a yellow solid. 1H NMR (CDCl3, 400 MHz) delta 7.68 (d, 1H), 7.64 (d, 1H), 7.62 (d, 1H), 1.37 (s, 12H).
With potassium acetate;dichloro(1,1'-bis(diphenylphosphanyl)ferrocene)palladium(II)*CH2Cl2; In 1,4-dioxane; dimethyl sulfoxide; at 110℃;Inert atmosphere;
Intermediate 68; 2-Fluoro-4-(4A5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzonitrile; A mixture of 4-bromo-2-fluorobenzonitrile (30 g, 150 mmol), bis(pinacolato)diboron (49.5 g, 195 mmol), potassium acetate (29.4 g, 300 mmol), and Pd(dppf)CI2«CH2CI2 (12.2 g,15.0 mmol) in DMSO and 1 ,4-dioxane (65 ml.) was heated overnight at 1 10 0C under nitrogen. The reaction mixture was cooled to room temperature, filtered throughKieselguhr, and concentrated. The resilting residue was purified by SiO2 chromatography(100:1 petroleum ethe?EtOAc) to afford the title compound (35 g) as a white solid. LC-MS (ES) m/z = 247 [M+H]+.
Example 68: 4-(7-(8-Ethyl-8-azabicyclo[3.2.1]octan-3-yl)-2-(pyridin-4- yl)pyrazolo[1 ,5-a]pyrimidin-3-yl)-2-hydroxybenzonitrile; Step 1 : To a solution of 4-bromo-2-fluorobenzonitrile (5 g, 25 mmol) in tetrahydrofuran was added sodium methoxide (125 mmol) in methanol (20 mL) and the reaction was stirred at 40° C for 3 hours. The reaction was then cooled to room temperature and Amberlyst.(TM). 15 was added and the mixture was stirred for 2 hours. The reaction was filtered and the organics were concentrated in-vacuo to give 4-bromo-2-methoxybenzonitrile as a white solid that was used directly in the next reaction. MS 212.1 [M+H].
To a solution of diisopropylamine (4.2ml, 30mmol) in dry THF (5ml) was added a solution ofnBuli in THF (2.5M, 11 ml, 27.5mmol) dropwise at -78 C. Once addition was complete, thereaction was allowed to warm to 0 oc and stirred in an ice-salt bath for 40 mins. The resultingsolution was added dropwise to a solution of 4-bromo-2-fluorobenzonitrile (5g, 25mmol) in dryTHF (50ml) at -78 oc and the mixture stirred for 2.5 hrs. The reaction mixture was then cooled15 to -78 oc and methyl iodide added in one portion and the mixture slowly allowed to warm toroom temperature. The reaction was quenched with aqueous NH4CI and extracted with EtOAc(3x 40ml). The combined organics were washed with water (40ml) and brine (40ml). Theorganics were dried over MgS04, filtered and concentrated. The residue was purified by columnchromatography eluting with 9:1 pet ether : ethyl acetate to afford 4-bromo-2-fluoro-3-methyl-20 benzonitrile as an off white solid (2.40g, 45% yield).
To a solution of DIPA (12.1 g, 0.120 mmol) in 20 mL of dry THF was added 2.5M of n-BuLi (44 mL, 0.11 mmol) dropwise under Ar at -78 0C, and then the reaction was allowed to warm to 0 0C. After stirring for 1 hour, the solution was added to a solution of 4-bromo-2-fluorobenzonitrile (20 g, 0.1 mmol) in 200 mL of dry THF dropwise at -78 0C under Ar and the mixture was stirred for 3 hours, then MeI (15.6 g, 0.110 mmol) was added at one portion and the mixture was stirred for another 30 minutes. Then the reaction was quenched with aq. NH4Cl and extracted with EtOAc (200 mL X 3). The combined organic layers were washed with water, brine, dried and concentrated to brown oil, which was purified by silica gel column to give 4-bromo-2-fluoro-3- methylbenzonitrile.
With potassium carbonate; In N,N-dimethyl-formamide; at 60.0℃;
A mixture of 4-Bfomo-2-flupsilonoro-benzonitrile (5 g, 25.00 mmol), potassium carbonate (10.37 g. 75.0 mmol), ethanol (6.86 mL, 117 mmol) in DMF (50 ml) was heated at 60 betaC for overynight. After filtration and concentration, the redisue was dissolved in ethyl acetate (150 mL), and the solution was washed with water (30 mL) and brine (50 mL). After drying over Na2SO4, filtration and concentration, a light brown solid (5.7 g) was obtained without further purification. 1H NMR (400 MHz, CDCI3): 5 1.49 (t, J 7 Hz, 3H), 4.14 (q, J = 7 Hz, 2H), 7.11 (d, J « 1.7 Hz1 1H), 7.14 (dd, J * 8.1, 1.7 Hz, 1H), 7.40 (d, J « 8.1 Hz, 1H).
Stage #1: methylmagnesium bromide; 4-bromo-6-fluorobenzonitrile In tetrahydrofuran; diethyl ether at 0℃; for 6h;
Stage #2: With sodium tetrahydroborate In tetrahydrofuran; methanol; diethyl ether at 20℃; for 16h;
18.1
To a solution of 12 g of 4-bromo-2-fluorobenzonitrile (60 mM) in THF (120 ml) were added 75 ml (150 mM) of a 2 M solution of methylmagnesium bromide in diethyl ether at 0° C. The reaction mixture was stirred at 0° C. for 6 h. Then 200 ml of methanol were added gradually to the reaction mixture. Subsequently, 5.7 g (150 mM) of sodium borohydride were added in portions, and the mixture was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added. The pH was adjusted to pH=1 with 2 M HCl, and the aqueous solution was extracted with chloroform. Subsequently, the pH was adjusted to pH=9 with 2M NaOH, and extraction was effected with chloroform (2×100 ml). The combined chloroform extracts were dried, and the solvent was removed under reduced pressure. 7.3 g (44%) of 1-(4-bromo-2-fluorophenyl)ethanamine were obtained as a yellow oil.1H NMR (400 MHz, CDCl3): δ=1.39 (d, 3H), 1.61 (s, 2H, br), 4.34 (m, 1H), 7.18 (m, 3H).
Stage #1: 2-pentylfuran With n-butyllithium In tetrahydrofuran; hexane at 20℃; for 0.0166667h; Inert atmosphere;
Stage #2: With Triisopropyl borate In tetrahydrofuran; hexane at 20℃; for 0.00166667h; Inert atmosphere;
Stage #3: 4-bromo-6-fluorobenzonitrile With chloro-(2-dicyclohexylphosphino-2,4,6-triisopropyl-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II); potassium hydroxide In tetrahydrofuran; hexane; water at 60℃; for 0.166667h; Inert atmosphere; Sonication;
With potassium phosphate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In toluene; at 110℃; for 20h;Inert atmosphere;
<strong>[53903-49-4]2-Amino-5-methoxy-benzotrifluoride</strong> (10.46 mmol), K3PO4 (15.7 mmol), Xphos (1.05 mmol) and Pd4(dba)3 (0.314 mmol) were added under nitrogen to a solution of 4-bromo-2-fluoro-benzonitrile (10.46 mmol) in 50 mL toluene and the mixture was stirred for 20 hours at a bath temperature of 110 C. Then the mixture was filtered through a glass fibre filter, then the filtrate was extracted with 150 mL water. The organic phase was dried on sodium sulphate and evaporated down. In this way the product was obtained in a yield of 87% of theory. C15H10F4N2O (310.2) Mass spectrum (ESI): [M+H]+=311 [M-H]-=309 Thin layer chromatograph (silica gel; petroleum ether/ethyl acetate 7:3): Rf=0.48
Stage #1: 4-bromo-6-fluorobenzonitrile With hydrogenchloride In ethanol; chloroform at 20℃; Cooling;
Stage #2: With ammonium carbonate In ethanol at 20℃;
5.7. 4-Chlorobenzamidine hydrochloride (12b)
General procedure: Hydrogen chloride gas was passed through a solution of 4-chlorobenzonitrile (9b, 25.0 g) in chloroform (350 mL) and ethanol (100 mL) at -78 °C for 0.5 h. Then the solution was warmed up to room temperature, and stirred at room temperature overnight. The solution was evaporated in vacuo, and the resulting residue was dissolved with ethanol (500 mL). To the solution was added ammonium carbonate (90.0 g), and the reaction mixture was stirred at room temperature for 3 days. To the mixture was added water (300 mL), and ethanol was removed by concentration in vacuo. The resulting solid was collected by filtration, washed with water and dried in vacuo to give 12b (25.4 g, 71%) as a white solid.
With potassium hexamethylsilazane In tetrahydrofuran at 20℃; for 6h; Inert atmosphere;
2 Methyl 3-(1H-imidazol-2-yl) propanoate
4.2.2 tert-Butyl 3-(5-bromo-2-cyanophenoxy)propylcarbamate (1a) To a 0 °C stirring solution of 100 mL tetrahydrofuran, 3 g (1 equiv, 15 mol) 4-bromo-2-fluorobenzonitrile, 2.63 g (1 equiv, 15 mol) tert-butyl 3-hydroxypropylcarbamate was added 30 mL (1 equiv, 15 mol) of 0.5 M potassium hexamethyldisilane solution in toluene. The reaction mixture was allowed to warm to room temperature over the course of 6 h. Upon completion the reaction was reduced, then diluted with dichloromethane and washed repeatedly with 0.1 M HCl. The organic portions were collected, dried with sodium sulfate, filtered, and reduced to produce tert-butyl 3-(5-bromo-2-cyanophenoxy) propylcarbamate as an off white powder in quantitative yield (5.31 g, 99%).δH (500 MHz, DMSO-d6) 1.37 (s, 9H, C(CH3)3), 1.84-1.86 (m, 2H, CH2CH2CH2), 3.09-3.11 (m, 2H, NCH2), 4.17 (t, J=6.75 Hz, 2H, CH2O), 6.90 (br s, 1H, NH), 7.30 (d, J=8.25 Hz, 1H, Ar), 7.49 (s, 1H, Ar), 7.68 (d, J=8.25 Hz, 1H, Ar); δC (125 MHz, DMSO-d6) 27.77, 28.35, 36.03, 54.43, 66.67, 77.07, 99.58, 116.04, 123.65, 128.05, 134.39, 155.14, 160.26; HRMS (ES+) calcd for [C15H19BrN2O3+H] 355.06573, found 355.06533.
68%
With potassium <i>tert</i>-butylate In tetrahydrofuran at 0 - 25℃; for 16h;
Synthesis of intermediate Vll-a: 2-Fluoro-4-formyl-benzonitrileA solution of 4-bromo-2-fluorobenzonitrile (5.00 g, 25 mmol) in dry THF (50 mL) at - 10C under argon was treated with a solution of isopropylmagnesium chloride (2M in THF, 15.0 mL, 30.0 mmol) dropwise before stirring at this temperature for 3 h. A solution of N-formylpiperidine (3.89 g, 35.0 mmol) in dry THF (15 mL) was added dropwise and the mixture allowed to warm to room temperature before stirring for 1.5h. The resultant solution was treated with 4M aq HC1 (250 mL each) and the organics extracted with EtOAc. The combined organics were dried (MgS04), filtered and evaporated before purification of the residue by column chromatography (Si02; eluting with 30% to 50% EtOAc in cyclohexane) to afford 2-fluoro-4-formyl-benzonitrile VH-a as a pale yellow solid (2.73 g, 73%).1H NMR (300 MHz, CDC13) delta 10.07 (d, J = 1.7 Hz, 1H), 7.90 - 7.79 (m, 2H), 7.74 (dd, J= 8.5, 0.8 Hz, 1H).
53.1%
General procedure: To a solution of 4-halogen-2-chlorobenzonitrile (23.10mmol) in dry 35 THF under Argon at 0C was added 36 isopropyl magnesium chloride (30.03mmol, 2M solution in ether) dropwise during 20min, and the reaction mixture was stirred for 2h, keeping the temperature around 0C. Then 37 1-formyl piperidine (30.03mmol) was added dropwise at 0C and stirred for additional 2h at 0C. The reaction mixture was quenched with saturated 38 NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel flash column chromatography (PE/EtOAc=3:1) to afford 39 compound 10a and 10b.
53.1%
2-Fluoro-4-bromobenzonitrile (8.00 g, 40.00 mmol) was dissolved in 120 mL of anhydrous tetrahydrofuran, and a solution of 2N isopropylmagnesium chloride in tetrahydrofuran (26.00 ml, 52.00 mmol) was added dropwise at 0 C.The reaction mixture was reacted under argon at 0 C for 2 hours.Thereafter, N-formylpiperidine (5.77 ml, 52.00 mmol) was added at 0 C and the reaction was continued at 0 C for 2 hours.Saturating the reaction with a saturated ammonium chloride solution,It was extracted three times with ethyl acetate (3 × 50 mL), and the organic layer was combined, washed twice with distilled water, and washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Concentrated and separated by column chromatography. The eluent was petroleum ether: ethyl acetate = 3:1.A white solid was obtained in 3.17 g, yield 53.1%.
With triethylamine; In dimethyl sulfoxide; at 120℃; for 20h;
To a solution of 4-bromo-2-fluoro-benzonitrile (2.0 g, 10.0 mmol) and (LR)-l- (2,4-dichlorophenyl)ethanamine (1.9 g, 10.0 mmol) in dimethyl sulfoxide (DMSO) (4 mL) was added triethylamine (1.45 g, 14.3 mmol). The reaction mixture was heated at 120 C for 20 h. After cooling to room temperature, the mixture was diluted with deionized water and a brown gummy material was obtained. The aqueous layer was decanted off, and the gum was dissolved in ethyl acetate, washed with deionized water, and brine. The organic layer was dried (Na2S04), filtered, and concentrated in vacuo. The crude product was used without further purification ((3.4 g, 9.2 mmol, 92%).
4-bromo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
77%
With triethylamine In water; dimethyl sulfoxide at 140℃; for 2.33333h;
156.1 Step 14-bromo-2-14-(2,2,2-trifluoroethyl)piperazin-1-yljbenzonitrile
Step 14-bromo-2-14-(2,2,2-trifluoroethyl)piperazin-1-yljbenzonitrileA mixture of 1-(2,2,2-trifluoroethyl)piperazine (270 mg, 1.606 mmol), 4-bromo-2-fluorobenzonitrile (321 mg, 1.61 mmol) and triethylamine (0.45 mL, 3.21 mmol) in dimethyl sulfoxide (1 mL) was heated in a capped vial at 120 °C for 2 hours, then cooled to room temperature, and added dropwise over 2 minutes to rapidly stirring water (30 mL). The resulting slurry was stirred at room temperature for 20 minutes, and the solid was collected by filtration, washed with water (20 mL) and dried under vacuum to provide the titled compound (431 mg, 77%). . ‘H NMR (300 MHz, methanol-d4) 5 ppm 2.84-2.91 (m, 4H), 3.15 (q, J = 9.8 Hz, 2H), 3.21 - 3.28 (m, 4H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H);MS (ESI) m/z 348/350 (M+H).
77%
With triethylamine In dimethyl sulfoxide at 120℃; for 2h;
156.1 Step 1 4-bromo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]benzonitrile
Step 1 4-bromo-2-[4-(2,2,2-trifluoroethyl)piperazin-1-yl]benzonitrile A mixture of 1-(2,2,2-trifluoroethyl)piperazine (270 mg, 1.606 mmol), 4-bromo-2-fluorobenzonitrile (321 mg, 1.61 mmol) and triethylamine (0.45 mL, 3.21 mmol) in dimethyl sulfoxide (1 mL) was heated in a capped vial at 120° C. for 2 hours, then cooled to room temperature, and added dropwise over 2 minutes to rapidly stirring water (30 mL). The resulting slurry was stirred at room temperature for 20 minutes, and the solid was collected by filtration, washed with water (20 mL) and dried under vacuum to provide the titled compound (431 mg, 77%). 1H NMR (300 MHz, methanol-d4) δ ppm 2.84-2.91 (m, 4H), 3.15 (q, J=9.8 Hz, 2H), 3.21-3.28 (m, 4H), 7.24 (dd, J=8.1, 1.7 Hz, 1H), 7.30 (d, J=1.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H); MS (ESI) m/z 348/350 (M+H)+.
With potassium carbonate In dimethyl sulfoxide at 140℃; for 2h; Microwave irradiation;
95.1 Step 1: 4-Bromo-2-(mesityloxy)benzonitrile
A mixture of 4-bromo-2-fluoro-benzonitrile (1.2 g, 6.0 mmol), 2,4,6-trimethylphenol (780 mg, 6.1 mmol), potassium carbonate (2.50 g, 18.1 mmol), and dimethylsulfoxide (9.0 mL) were microwave irradiated at 140° C. for 2 hours. Water (20 mL) was added and the resulting mixture was stirred for 5 minutes. The resulting suspension was filtered and the solid was washed with water and dried under vacuum at 50° C. for 16 hours to yield 4-bromo-2-(mesityloxy)benzonitrile (1.8 g, 95%) as a brown solid. 1H NMR (CDCl3, 250 MHz): 7.50 (d, J=8.2 Hz, 1H), 7.20 (d, J=8.2 Hz, 1H), 6.94 (s, 2H), 6.61 (s, 1H), 2.33 (s, 3H), 2.10 (s, 6H) ppm.
95%
With potassium carbonate In dimethyl sulfoxide at 140℃; for 2h; Microwave irradiation;
95.1 Step 1: 4-Bromo-2-(mesityloxy)benzonitrile
Combine 4-bromo-2-fluoro-benzonitrile (1.2g, 6.0mmol), 2,4,6-trimethylphenol (780mg, 6.1mmol), potassium carbonate (2.50g, 18.1mmol) and dimethylsulfoxide(9.0 ml) The mixture was irradiated with microwave at 140°C for 2 hours. Water (20 mL) was added and the resulting mixture was stirred for 5 minutes. The resulting suspension was filtered and the solid was washed with water and dried under vacuum at 50°C for 16 hours to obtain 4-bromo-2-(mesityloxy)benzonitrile (1.8 g, 95%) as a brown solid.
2-fluoro-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
74%
With tris-(dibenzylideneacetone)dipalladium(0); sodium t-butanolate; ruphos In <i>tert</i>-butyl alcohol at 100℃; for 3h; Inert atmosphere;
5.1.3.1. 2-Fluoro-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzonitrile (18).
To a solution of tert-butyl (3-aminopyridin-2-yl)carbamate (500 mg, 2.39 mmol) in tBuOH (5 mL) was added Pd2(dba)3 (182 mg, 0.20 mmol), 4-bromo-2-fluorobenzonitrile (15) (398 mg, 1.99 mmol), tBuONa (383 mg,3.98 mmol) and RuPhos (372 mg, 0.80 mmol). The mixture was stirred at 100° C for 3 h under an Ar atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted withMeOH in EtOAc). The resultant solid was recrystallized from EtOH-EtOAc-hexane to give 2-fluoro-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)benzonitrile (373 mg, 74%) as a pale yellow solid. 1H NMR (DMSO-d6) d: 7.07 (1H, dd, J = 7.9, 5.3 Hz), 7.59(1H, d, J = 7.9 Hz), 7.68-7.74 (1H, m), 7.87 (1H, dd, J = 11.0,1.9 Hz), 8.04 (1H, d, J = 4.9 Hz), 8.08-8.15 (1H, m), 12.08 (1H, brs). LC-MS (ESI) m/z = 253.0 [M-H]-
With tetrakis(triphenylphosphine) palladium(0); sodium carbonate In ethanol; toluene for 3h; Reflux; Inert atmosphere;
General Method D - Formation of biaryl group
General procedure: N-(4-Bromobenzyl)-1H-indole-2-sulfonamide (1 g) was dissolved in a mixture of toluene (15 ml) and ethanol (15 ml). The required benzeneboronic acid (1 g) was added followed by (PPh3)4Pd (0.20 g). The mixture was stirred vigorously under N2 and 2 M Na2CO3 (15 ml) added. The mixture was refluxed with stirring for 3 hrs under an atmosphere of N2. The solvent was removed under vacuum, the residue dissolved in ethyl acetate washed with water and saturated NaCl solution. After drying (Na2SO4) the solvent was evaporated and the resultant oil purified by column chromatography to give a clear oil, which solidified on standing. Recrystallisation from diethyl ether / petroleum spirit gave white crystals.
4-Bromo-2-(4-bromophenylthio)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
Stage #1: para-bromobenzenethiol With sodium hydride; zinc In N,N-dimethyl-formamide; mineral oil at 20℃; for 0.166667h; Inert atmosphere;
Stage #2: 4-bromo-6-fluorobenzonitrile In N,N-dimethyl-formamide; mineral oil at 20℃; Inert atmosphere;
4.1.3 4-Bromo-2-(4-bromophenylthio)benzonitrile (7)
A 250mL round-bottom flask equipped with a stir bar was charged with NaH (360mg, 60% NaH in mineral oil, 9.0mmol). A solution of 4-bromothiophenol 5 (1.42g, 7.50mmol) in DMF (50mL) was added, followed by addition of Zn dust (100mg, 1.5mmol). A light yellow solution was obtained. After stirring the mixture for 10minat rt, 4-bromo-2-fluorobenzonitrile 6 (1.50g, 7.50mmol) was added as a solution in DMF (40mL). After the mixture turned into a white suspension (∼10min), it was stirred overnight at rt. Water (100mL) was added and the product was extracted with Et2O (30mL×3). The combined organic phase was washed with water (50mL×5). After layer separation the organic fraction was dried over anhydrous MgSO4 and the solvent was removed under vacuum. The crude product was purified using flash column chromatography (silica gel, 25% CH2Cl2 in hexanes) to give 7 as a white solid (1.88g, 68%): m.p. 130-131°C; FTIR (neat) 3062, 2934, 2850, 2218, 1738, 1716, 1572, 1540, 1454, 1376, 1086, 1066cm-1; 1H NMR (400MHz, CDCl3) δ 7.59-7.55 (m, 2H), 7.49 (d, J=8.3Hz, 1H), 7.41 (dd, J1=8.3Hz, J2=1.8Hz, 1H), 7.39-7.34 (m, 2H), 7.21 (d, J=1.8Hz); 13C NMR (100MHz, CDCl3) δ 143.83, 135.38, 134.59, 133.28, 132.17, 130.08, 129.74, 128.34, 124.19, 116.13, 111.34; HRMS (APCI) m/z calcd for [M] + C13H7Br2NS 366.8660, found 366.8669.
5.2 g
With sodium hydride In N,N-dimethyl-formamide for 20h; Inert atmosphere; Reflux;
11 Step 11. The reaction of p-bromothiophenol with 2-fluoro-4-bromobenzonitrile to obtain (b1)
The specific steps of the step 11 are: 0.73 g (30 mmol) of NaH was slowly added to 20 ml of dry dimethylformamide (DMF) in which 4.7 g (25 mmol) of p-bromothiophenol was dissolved in a 250 ml three-necked flask. Was then added dropwise dissolved 5 g (25 mmol) 2-fluoro-4-bromobenzonitrile in 20 ml of dry dimethylformamide. Under nitrogen protection, heating reflux reaction 20h. After completion of the reaction, the temperature was lowered to room temperature. The reaction solution was poured into 50 ml of a 1 M NaOH solution. Dichloromethane (DCM) was extracted. Decompression out solvent. Over silica gel column afforded 5.2 g of a white solid compound b1.
5.2 g
With sodium hydride In N,N-dimethyl-formamide; mineral oil for 20h; Inert atmosphere; Reflux;
11 The specific steps of the step 11 are
To a 250 ml three-necked flask, 0.73 g (30 mmol) of NaH was slowly added to a solution of 4.7 g (25 mmol) of p-bromobenzeneThiol in 20 ml of dry dimethylformamide (DMF), and then a solution of 5 g (25 mmol)2-fluoro-4-bromobenzonitrile in 20 ml of dry dimethylformamide.Under nitrogen protection, the reaction was heated under reflux for 20 h,After the reaction was allowed to drop to room temperature, the reaction solution was poured into 50 ml of a 1 M NaOH solution,Dichloromethane (DCM), the solvent was removed under reduced pressure,Afforded 5.2 g of a white solid,Is compound b1.
4-bromo-1-(5-bromo-2-cyanophenyl)-1H-pyrrole-2-carboxylic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
72%
With caesium carbonate; In N,N-dimethyl-formamide; at 130℃; for 0.166667h;Inert atmosphere; Microwave irradiation;
General procedure: Method (ii): under microwave irradiation: Under inert atmosphere, a mixture of fluorobenzonitrile A (1.0 equiv.), methyl ester B, B? or B?? (1.0 equiv.) and cesium carbonate (2.5 equiv.) in DMF (0.20 mol.L-1) was submitted to microwave irradiation at 130C for 10 minutes. The reaction mixture was neutralized with aqueous HCl (1N), and then extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over MgSO4, concentrated and purified by flash column chromatography on silica gel (using a gradient of EtOAc in cyclohexane as eluent) to afford the product. Compound 2: 4-Bromo-1-(5-bromo-2-cyano-phenyl)-1H-pyrrole-2-carboxylic acid methyl ester. Compound 2 was obtained according to general procedure I(ii), starting from 4-bromo-2- fluorobenzonitrile and 4-Bromo-1H-pyrrole-2-carboxylic acid methyl ester. It was isolated as a white solid in 72% yield.1H-NMR (400 MHz, DMSO-D6): 8.02 (d, J 1.6 Hz, 1H, Ar); 7.96 (d, J 8.2 Hz, 1H, Ar); 7.93 (dd, J 8.2, 1.6 Hz, 1H, Ar); 7.65 (d, J 1.9 Hz, 1H, Ar); 7.18 (d, J 1.9 Hz, 1H, Ar); 3.67 (s, 3H, CH3). M/Z (M[79Br] [80Br]+H)+ = 385.
2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-bromobenzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
6.7 g
With sodium t-butanolate; In N,N-dimethyl-formamide; at 2 - 30℃; for 4.25h;Inert atmosphere;
A mixture of 2-fluoro 4-bromo benzonitrile (5 g) and 5-hydroxy pyrrolo[2,3-b]pyridine(3.35 g) in dimethylformamide (20 mL) was cooled to 2C under nitrogen atmosphere.Sodium tert.butoxide (2.52 g) in dimethylformamide (10 mL) was added to reactionmixture in 15 minutes and allowed to attain 30C. The reaction mixture is stirred at the same temperature for 2 hours. Cooled the reaction mixture to 5C and 0.1 equivalent ofsodium tert.butoxide was added. Allowed the reaction mixture to attain 30C and stirredat the same temperature for 2 hours. Quenched the reaction mixture with water (200 mL)and stirred for 30 minutes. Filtered the reaction mixture and washed with water (50 mL)and n-hexane (50 mL) and evaporated the solvent under reduced pressure to obtain crudeproduct. The crude product suspended in ethyl acetate (76 mL) and heated to reflux andevaporated the solvent completely. The product was stirred with 20% ethyl acetate/hexane(76 mL) for 30 minutes and filtered the solid and dried under vacuum to obtain the titlecompound as light brown solid. Yield: 6.7 g; Purity by HPLC: 98.44%
With formic acid; oxygen; triethylamine; copper(ll) bromide; In acetonitrile; at 20℃; for 24h;UV-irradiation;
4-Bromo-2-fluorobenzonitrile (0.25 mmol), copper bromide (0.03 mmol), triethylamine (0.25 mmol, 1.0 equiv), HCOOH (0.75 mmol, 3.0 equiv) at room temperature,179mmol of the reaction solvent CH3CN was added to the reaction tube, and the mixture was stirred at room temperature for 24 hours under the oxygen atmosphere.After the completion of the reaction was monitored by thin layer chromatography, 20 mL of water and 10 mL of ethyl acetate were added for extraction, followed by drying over anhydrous sodium sulfate, filtering after 5 minutes, washing the filter cake with ethyl acetate (5 mL×3 times), and then swirling off the solvent.The product was isolated by column chromatography (eluent: petroleum ether: ethyl acetate = 6:1), the product was a yellow liquid, yield 82%;
4-bromo-2-(2-(2-oxoimidazolidin-1-yl)ethoxy)benzonitrile[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
71%
With potassium hexamethylsilazane; In toluene; at 20℃; for 18h;
General procedure: General procedure. 4-bromo-2-fluorobenzonitrile (3.25 mmol) was reacted with the corresponding alcohol (3.5 mmol) in the presence of a 0.5 M solution of KHMDS (3.75 mmol) in toluene (40mL). The resulting mixture was stirred at room temperature until complete dissapareance of starting material and the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (50 mL) and was successively washed with HCl aq (3 x 10 mL) and brine (3 x 10 mL). The organic phase was dried (MgSO4), filtered and evaporated to dryness. The final residue was purified by flash column chromatography in silica gel (CH2Cl2/MeOH, 9.75:0.25 for 1a, Hexane/AcOEt, 8:2 for 1b) to give intermediate 1a,b as a yellow solid and colorless oil in 71% and 94% yields, respectively. 4-Bromo-2-(2-(2-oxoimidazolidin-1-yl)ethoxy)benzonitrile (1a) M.p: 165-171 C; IR (KBr), v (cm-1): 3250 (NH-st), 3097 (Csp-H st), 2227 (C=N st), 1685 (C=O st); 1H-NMR (DMSO-d6, 400 MHz) delta (ppm): 7.69 (d, J = 8.2 Hz, 1H, Ar), 7.56 (d, J = 1.8 Hz, 1H, Ar), 7.32 (dd, J = 8.2, 1.7 Hz, 1H, Ar), 6.42 (bs, 1H, NH), 4.26 (t, J = 5.2 Hz, 2H, OCH2), 3.51 (m, 2H, CH2CH2NHCON), 3.44 (t, J = 5.2 Hz, 2H, OCH2CH2), 3.23 (t, J = 7.8 Hz, 2H, CH2CH2NHCON); 13C-NMR (DMSO-d6, 75 MHz) delta (ppm): 162.1 (NHCON), 160.5 (OCAr), 134.9 (CHAr), 128.6 (CAr), 124.4 (CHAr), 116.5 (CHAr), 115.7 (CN), 100.0 (CAr), 68.7 (OCH2), 45.9 (CH2CH2NHCON), 42.4 (OCH2CH2), 37.5 (CH2CH2NHCON); MS (ESI, positive mode) m/z: 332.0 [M+Na]+, 310.0 [M+H]+, with a Br isotopic pattern
General procedure: In 6.6 g of intermediate 17, 8 g of intermediate 18 (Hal = F, X = I) were dissolved in 28.5 g tetrahydrofuran and 6.2 g dimethylformamide, and a solution of 8 g potassium tert-butoxide in 59 g tetrahydrofuran was added to the mixture at -20C and stirred for 1 h . The reaction was quenched by addition of 27.2 g water and 13.2 g 30% aqueous sodium hydroxide solution. The resulting mixture was then stirred at 55c for 16 h and cooled to 22C. 10 g acetic acid and 25 g water were added, the phases separated and 67.5 g isopropyl acetate added to the organic phase. The organic phases was washed with 67 g 5% aqueous sodium chloride solution, and the solvent swapped to 2-propanol. The product was crystallized from 2-propanol by seeding and cooling to 15C. The product was filtered and washed with 2-propanol to yield intermediate II in 97% purity and 50% yield.
General procedure: A reaction mixture of 2a-e (5.0 mmol, 1.0 equiv.), differentsubstituted 4-bromobenzonitrile (6.0 mmol, 1.2 equiv.) and potassiumcarbonate (12.5 mmol, 2.5 equiv.) in PEG400/H20 (10 mL/10 mL) was stirred at room temperature for 15 min, and PdCl2(0.05 mmol, 0.01 equiv.) was subsequently added. Stirring wascontinued for an additional 15 h until complete consumption ofstarting material as judged by TLC. Then the reaction mixture waspoured into water (80 mL) and extracted with ethyl acetate(30 mL*3). The organic layers were washed with brine, dried overanhydrous Na2SO4, filtered and condensed under reduced pressure.The residuewas then purified via column chromatography on silicagel, eluting with EtOAc/petroleum ether to 3a-r as white solid.
Stage #1: 4-Phenylphenol With potassium carbonate In N,N-dimethyl-formamide; toluene for 4h; Dean-Stark; Reflux;
Stage #2: 4-bromo-6-fluorobenzonitrile In N,N-dimethyl-formamide for 24h; Inert atmosphere; Reflux;
11.1
(1) In a 500 mL three-necked bottle equipped with a Dean-Stark separator, pass nitrogen gas, add 0.1 mol of raw material J, 0.2 mol potassium carbonate, 125 ml of toluene, 125 ml of DMF, stir, and reflux for 4 hours to perform dehydration. Until no more water is generated in the system, about 100 mL of toluene is removed using a Dean-Stark separator. It was left to cool to room temperature, 0.12 mol of raw material K was added, and the reaction was refluxed under a nitrogen atmosphere for 24 hours. After the reaction was completed, 200 ml of toluene was added to dilute the system, and the organic phase was washed with water (200 mL) three times with a separating funnel, and the layers were separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was subjected to spin evaporation and purified through a silica gel column.Intermediate O was obtained with a purity of 99.4% by HPLC and a yield of 87.5%.
85.8%
Stage #1: 4-Phenylphenol With potassium carbonate In N,N-dimethyl-formamide; toluene at 24℃; Inert atmosphere; Reflux; Dean-Stark;
Stage #2: 4-bromo-6-fluorobenzonitrile In N,N-dimethyl-formamide for 24h; Inert atmosphere; Reflux;
14.1
In a 500 mL three-necked bottle equipped with a Dean-Stark separator, pass nitrogen gas, add 0.1 mol of raw material J1, 0.2 mol potassium carbonate, 125 ml of toluene, 125 ml of DMF, stir, reflux for 4 hours, and dehydrate. Until no more water is generated in the system, about 100 mL of toluene is removed using a Dean-Stark separator. It was left to cool to room temperature, 0.12 mol of raw material K was added, and the reaction was refluxed under a nitrogen atmosphere for 24 hours. After the reaction was completed, 200 ml of toluene was added to dilute the system, and the organic phase was washed with water (200 mL of water) three times with a separating funnel. The target product intermediate O1 had a purity of 99.2% by HPLC and a yield of 85.8%.
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