* 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.
Stage #1: With diisobutylaluminium hydride In n-heptane; dichloromethane at -20 - -15℃; for 0.166667 h; Stage #2: With hydrogenchloride; water In n-heptane; dichloromethane
EXAMPLE 20 Preparation of 1-benzofuran-5-carbaldehyde To a solution of 1-benzofuran-5-carbonitrile (5.0 g, 34.9 mmol) in CH2Cl2 under nitrogen at -15 to -20° C. was added DIBAL-H (41.9 mL, 41.9 mmol, 1 M/heptane) and the temperature was maintained below -15° C. After addition was complete, the reaction mixture was stirred at -15 to -20° C. for an additional 10 min. The reaction mixture was quenched via dropwise addition of aqueous 2N HCl. The organic layer was separated and washed with water, dried over sodium sulfate, and concentrated to give 4.0 g (78percent) of 1-benzofuran-5-carbaldehyde as a yellow oil.
78%
Stage #1: With diisobutylaluminium hydride In n-heptane; dichloromethane at -20 - -15℃; for 0.166667 h; Stage #2: With hydrogenchloride; water In n-heptane; dichloromethane at 20℃;
EXAMPLE 15:PREPARATION OF 5-(5-FORMYL-I -BENZOFURAN-2-YL)-6-METHYL-4-[(4- METHYL-1 H-INDOL-5-YL)AMINO]NICOTINONITRILEStep a): Preparation of 5-formylbenzofuran.To a -150C to -2O0C solution of 1-benzofuran-5-carbonitrile (5 g, 34.9 mmol) in 50 mL of dichloromethane under nitrogen was added DIBAL-H (41.9 mL, 41.9 mmol, 1.0M in heptane) such that the temperature was less than or equal to -150C. The reaction mixture was stirred for an additional 10 min at -150C to -2O0C and quenched by adding 2.0 N HCI dropwise such that the temperature was less than or equal to room temperature. The organic layer was then separated, washed with water, dried over sodium sulfate and concentrated to give 4 g (78percent) of the title compound as a yellow oil, which was used in the next step without further purification.
Reference：
[1] Patent: US2007/287738, 2007, A1, . Location in patent: Page/Page column 25
[2] Patent: WO2009/76571, 2009, A1, . Location in patent: Page/Page column 41
[3] Bioorganic and Medicinal Chemistry Letters, 2009, vol. 19, # 19, p. 5799 - 5802
2
[ 23145-07-5 ]
[ 79002-39-4 ]
Yield
Reaction Conditions
Operation in experiment
85%
for 12 h; Inert atmosphere; Reflux
General procedure: A mixture of 15, 9k or 9m (190 mmol) and CuCN (49.00 g, 570 mmol) in DMF (500 mL) werestirred at 130 °C (for 15 and 9m) or reflux (for 9k) in N2 atmosphere for 12 h, when TLC analysisindicated completion of reaction. On cooling to room temperature, the reaction mixture was dilutedwith CH2Cl2 (1000 mL), and the resulting mixture was further stirred for 1 h and filtered off. Thefiltrate was washed with 5percent brine (500 mL × 5), dried (Na2SO4) and evaporated on a rotaryevaporator, which was purified by column chromatography to afford 16, 10k or 10m.
Reference：
[1] Molecules, 2018, vol. 23, # 2,
[2] Patent: US4341792, 1982, A,
[3] Patent: WO2015/89842, 2015, A1, . Location in patent: Page/Page column 92
[4] Bioorganic and Medicinal Chemistry, 2017, vol. 25, # 1, p. 75 - 83
To benzofura?-5-carbonitrile (500 mg, 3.49 mmol) in THF (9.98 mL) at -78 0C was added nBuLi 1.6M in hexanes (2.401 ml, 3.84 mmol) dropwise. The mixture was stirred for 30min at this temperature, and then trimethyt borate (0.858 mL, 7.68 mmoi) was added dropwise. The mixture was stirred for 20min, and then HC. 2N (11.52 mL, 23.05 mmol) was added. The bath was removed, and stirring continued for 30min. The mixture was diluted with water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated. Crude 5-cyanobenzofuran-2-ylboronic acid (623 mg, 87%) was then dried and used as is for the next step.
EXAMPLE 20 Preparation of 1-benzofuran-5-carbaldehyde To a solution of 1-benzofuran-5-carbonitrile (5.0 g, 34.9 mmol) in CH2Cl2 under nitrogen at -15 to -20 C. was added DIBAL-H (41.9 mL, 41.9 mmol, 1 M/heptane) and the temperature was maintained below -15 C. After addition was complete, the reaction mixture was stirred at -15 to -20 C. for an additional 10 min. The reaction mixture was quenched via dropwise addition of aqueous 2N HCl. The organic layer was separated and washed with water, dried over sodium sulfate, and concentrated to give 4.0 g (78%) of 1-benzofuran-5-carbaldehyde as a yellow oil.
78%
EXAMPLE 15:PREPARATION OF 5-(5-FORMYL-I -BENZOFURAN-2-YL)-6-METHYL-4-[(4- METHYL-1 H-INDOL-5-YL)AMINO]NICOTINONITRILEStep a): Preparation of 5-formylbenzofuran.To a -150C to -2O0C solution of 1-benzofuran-5-carbonitrile (5 g, 34.9 mmol) in 50 mL of dichloromethane under nitrogen was added DIBAL-H (41.9 mL, 41.9 mmol, 1.0M in heptane) such that the temperature was less than or equal to -150C. The reaction mixture was stirred for an additional 10 min at -150C to -2O0C and quenched by adding 2.0 N HCI dropwise such that the temperature was less than or equal to room temperature. The organic layer was then separated, washed with water, dried over sodium sulfate and concentrated to give 4 g (78%) of the title compound as a yellow oil, which was used in the next step without further purification.
methyl magnesium bromide-tetrahydrofuran[ No CAS ]
[ 79002-39-4 ]
[ 190775-71-4 ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran;
Reference Example 42 Ethyl 2-benzofuran-5-yl-propionate STR195 To a solution of <strong>[79002-39-4]5-benzofurancarbonitrile</strong> (Japanese Patent Unexamined Publication No. 9-124,631) (1.30 g) in tetrahydrofuran (5 ml) was added 0.87 M methyl magnesium bromide-tetrahydrofuran solution (21 ml), and the resulting mixture was heated under reflux for 4 hours under a nitrogen atmosphere. The reaction mixture was acidified with conc. sulfuric acid and water was added thereto, after which the resulting mixture was subjected to extraction with diethyl ether. The extract solution was washed with water, dried and then distilled under reduced pressure to remove the solvent. The residue was purified by a silica gel column chromatography to obtain 1-benzofuran-5-yl-ethanone (1.21 g). 1 H-NMR (270 MHz, CDCl3) delta ppm: 2.67(s, 3H), 6.86(d, 1H, J=2.3 Hz), 7.55(d, 1H, J=8.9 Hz), 7.70(d, 1H, J=2.3 Hz), 7.97(dd, 1H, J=8.9, 1.7 Hz), 8.26(d, 1H, J=1.7 Hz)
1-amino-1[5-benzo(b)furanyl]-2-methylsulphinyl-2-methylthio-ethylene[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
In tetrahydrofuran; dichloromethane; water;
B. A solution of dry methyl methylthiomethyl sulphoxide (7.0 g., 0.056 mole) in dry tetrahydrofuran (25 ml.) was added dropwise to a stirred suspension of 50% sodium hydride in oil dispersion (3.0 g., 0.62 mole) in dry tetrahydrofuran (50 ml.) under nitrogen at ambient temperature. This mixture was stirred for 0.5 hours and a solution of <strong>[79002-39-4]5-cyanobenzo(b)furan</strong> (8.0 g., 0.056 mole) in dry tetrahydrofuran (25 ml.) added dropwise. The now reddish suspension was stirred at 50-60 C. overnight, and the resulting thick suspension cooled and treated dropwise with water (5 ml.). Methylene chloride (100 ml.) was next added, followed by magnesium sulphate, and the mixture filtered. Evaporation of the filtrate in vacuo furnished a brown solid (15 g.), which was triturated with ethyl acetate, collected, washed with ethyl acetate and then hexane and dried, in vacuo, to give 1-amino-1[5-benzo(b)furanyl]-2-methylsulphinyl-2-methylthio-ethylene (12.7 g.) as a cream solid, m.p. 157- 159 C. (decomp.). Analysis %: Found: C, 53.9; H, 4.9; N, 5.55; C12 H13 NO2 S2 requires: C, 53.9; H, 4.9; N, 5.2.
In N,N-dimethyl-formamide; for 12h;Inert atmosphere; Reflux;
General procedure: A mixture of 15, 9k or 9m (190 mmol) and CuCN (49.00 g, 570 mmol) in DMF (500 mL) werestirred at 130 C (for 15 and 9m) or reflux (for 9k) in N2 atmosphere for 12 h, when TLC analysisindicated completion of reaction. On cooling to room temperature, the reaction mixture was dilutedwith CH2Cl2 (1000 mL), and the resulting mixture was further stirred for 1 h and filtered off. Thefiltrate was washed with 5% brine (500 mL × 5), dried (Na2SO4) and evaporated on a rotaryevaporator, which was purified by column chromatography to afford 16, 10k or 10m.
With pyridine; hydrogenchloride; In ammonium hydroxide; water; toluene;
A. Preparation of 5-Cyanobenzo(b)furan: 5-Bromobenzo(b)-furan (19.3 g., 0.098 mole) was added dropwise to a stirred mixture of cuprous cyanide (0.14 mole) and pyridine at 165 C. Heating at 165 C. was continued for 26 hours and the cool reaction mixture was then added to 10% (by weight) aqueous ammonia solution. Toluene (100 ml.) was added and the resulting mixture stirred for 0.5 hours and then filtered. Ether (250 ml.) was added to the filtrate and the organic phase separated and combined with the ether extracts (2*100 ml.) of the aqueous phase. The combined organic solutions were washed in turn with 5% aqueous ammonia (4*100 ml.), water (100 ml.), dilute hydrochloric acid (3*100 ml.) and finally water (100 ml.). Evaporation in vacuo of the dried (MgSO4) organic solution gave an oil which readily solidified. Purification was effected by column chromatography on silica gel using methylene chloride as eluent. Trituration of the product with hexane provided pure 5-cyanobenzo(b)furan as a white solid (8.2 g), m.p. 85-87 C. Analysis %: Found: C, 75.2; H, 3.5; N, 9.7; C9 H5 NO requires: C, 75.5; H, 3.5; N, 9.8.
With copper(l) iodide; In N,N-dimethyl-formamide; at 150℃; for 4h;
Step 1 : A mixture of S21-SM (19.6 g, 0.1 mol), CuCN (27.3 g, 0.3 mol) and Cul (38.3 g, 0.2 mol) in DMF (200 mL) was stirred at 150 C for 4hs. Cooled, the mixture was diluted with ethyl acetate and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S21-1.
With cerium(III) chloride; In tetrahydrofuran; diethyl ether; at -78 - 20℃; for 25h;Inert atmosphere;
A flask containing anhydrous cerium (III) chloride (5.17 g, 21.0 mmol) was flushed with nitrogen several times and placed under high vacuum. The solid was heated with a heat gun for several minutes to remove any excess water. The flask was re-filled with nitrogen and allowed to cool. THF (80 mL) was added and the suspension was stirred at room temperature for 3 h. The suspension was cooled to -78 0C and methyllithium, 3.0 M solution in Et2O (6.99 mL, 21.0 mmol) was added. After stirring for 1 h, <strong>[79002-39-4]benzofuran-5-carbonitrile</strong> (1.00 g, 6.99 mmol) was added. The mixture was stirred for 5 h at -78 0C, then allowed to slowly warm to room temperature over 16 h. The mixture was cooled back to -78 0C, then treated with cone. NH4OH (30 mL). After warming to room temperature, the mixture was diluted with H2O and extracted with CH2Cl2. The combined organics were dried over Na2SO4, filtered and <n="94"/>concentrated. The residue was then dissolved in CH2CI2 and extracted with 2 N HCl. The combined aqueous layers were basified with 5 N NaOH, and extracted with CH2CI2. The combined organics were dried over Na2SO4, filtered and concentrated to yield 2-(benzofuran- 5-yl)propan-2-amine. MS (ESI, pos. ion) m/z: 159 (M- 16).
Example 7: Synthesis of 2-(5-fluoro-4-(1-hydroxyethyl)pyridin-3-yl)benzofuran-5- carbonitrile (17)Step 1: 5-cyanobenzofuran-2-ylboronic acid (7a) To <strong>[79002-39-4]benzofuran-5-carbonitrile</strong> (500 mg, 3.49 mmol) in THF (9.98 mL) at -78 C was added n- BuLi 1 6M in hexanes (2.401 mL, 3.84 mmol) dropwise. The mixture was stirred for 30min at this temperature, and then trimethy. borate (0.858 mL, 7.68 mmol) was added dropwise. The mixture was stirred for 20 min, and then HCI (2M, 1 1.52 mL, 23.05 mmol) was added. The bath was removed, and then stirred for 30min. To the mixture was added more water and extracted with EtOAc three times, dried over magnesium sulfate, filtered, concentrated, crude 7a (623 mg, 87%) was then dried and used as is for next step.
With hydroxylamine hydrochloride; sodium carbonate; In ethanol; at 75℃;
[0494] N-hydroxybenzofuran-5-carboximidamide (INT-68)[0495] Prepared using General Procedure 1. To a flask containing <strong>[79002-39-4]benzofuran-5-carbonitrile</strong>(200 mg, 0.73 mmol) was added EtOH (6 mL), hydroxylamine hydrochloride (176.7 mg, 2.54 mmol) and Na2C03 (154 mg, 1.42 mmol). The mixture was stirred at 75C overnight then concentrated, re-dissolved in DCM and washed with NaHC03. The combined organic layers were dried over Na2S04, and concentrated to provide 222 mg of crude N- hydroxybenzofuran-5-carboximidamide INT-68 as a white solid which was used directly in the next step without purification. LCMS-ESI (m/z) calculated for C9H8N202: 176.2; found 177.1 [M+H]+, tR = 0.83 min.
With (1,5-cyclooctadiene)(methoxy)iridium(I) dimer; 4,4'-di-tert-butyl-2,2'-bipyridine; In hexane; at 20℃; for 2.5h;Inert atmosphere;
A solution of <strong>[79002-39-4]benzofuran-5-carbonitrile</strong> (23) (11.0 g, 76.8 mmol) in hexane (250 mL) was sparged with Ar for 15 min, then Bis(pinacolato)diboron (12.3mL, 85 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (764mg, 1.15 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (618 mg, 2.3 mmol) were added. The mixture was stirred at room temperature for 2.5 h, and the resulting solid was filtered, washed with hexane (200 mL), and dried to obtain 17g (83%) of product as pale yellow solid.
With copper(l) iodide; In N,N-dimethyl-formamide; at 150℃; for 4h;
Step 1: A mixture of S21-SM (19.6 g, 0.1 mol), CuCN (27.3 g, 0.3 mol) and CuT (38.3 g, 0.2mol) in DMF (200 mL) was stirred at 150 C for 4hs. Cooled, the mixture was diluted with ethylacetate and washed with brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S2 1-1.
5-(1-((R)-2-hydroxy-3-((2-methyl-1-(naphthalen-2-yl)propan-2-yl)amino)propoxy)ethyl)-1a,6b-dihydro-1H-cyclopropa[b]benzofuran-1-carboxylic acid[ No CAS ]
Step 2: To a mixture of S21-1 (20.0 g, 0.14 mol) in toluene (150 mL) was added dropwise methylmagnesium bromide (140 mL, 3.0 M, 0.42 mol) at RT under N2. The solution was stirredat 60 C for lh. NH4C1 (aq.) was added to the solution and the mixture was acidified with iN HC1. The resulting mixture was refluxed for 1 h, and it was extracted with ether, washed with NaHCO3 and brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S21-2.
Step 2: To a mixture of S21-1 (20.0 g, 0.14 mol) in toluene (150 mL) was added dropwise methylmagnesium bromide (140 mL, 3.0 M, 0.42 mol) at RT under N2. The solution was stirred at 60 C for lh. NH4C1 (aq.) was added to the solution and the mixture was acidified with IN HCl. The resulting mixture was refluxed for 1 h, and it was extracted with ether, washed with NaHC03 and brine, dried over anhydrous sodium sulfate, filtrated and concentrated to provide a residue, which was purified by column chromatography to afford S21-2.
With lithium aluminium tetrahydride; In tetrahydrofuran; at 20℃; for 6h;Reflux;
General procedure: To a stirred solution of 13, 10k or 10m (130 mmol) in dried THF (150 mL) cooled in an ice-waterbath was added portionwise LiAlH4 (6.41 g, 169 mmol). Thereafter the reaction mixture was stirredat room temperature for 1 h and then at reflux for another 5 h, when the reaction completed asindicated by TLC analysis. On cooling to room temperature, the reaction mixture was carefullypoured into ice-water (500 mL) while stirring, and the resulting mixture was diluted with CH2Cl2(300 mL), stirred for 0.5 h and filtered off through Celite. The organic phase was separated from thefiltrate, and the aqueous phase was back-extracted with CH2Cl2 (200 mL × 2). The combined organicphases were washed with saturated brine (200 mL), dried (Na2SO4) and evaporated on a rotaryevaporator to give a residue, which was purified by column chromatography through a short silicagel column to afford 2d, 2k or 2m. These amines were used directly in the next step without furtherpurification and characterization.
With palladium 10% on activated carbon; hydrogen; water-d2; hydrogen chloride; In d(4)-methanol; at 20℃;Sealed tube;
10% Pd/C (29 mg, 20% wt of <strong>[79002-39-4]benzofuran-5-carbonitrile</strong>) and 5 mL of D2O were placed in a 100 mL round- bottom flask. The system was sealed with a rubber septum and filled with using five vacuum/th cycles. The mixture was stirred at room temperature for 24h, then the solution of <strong>[79002-39-4]benzofuran-5-carbonitrile</strong> (1 mmol, 143 mg) in 3 mL of CD3OD was added followed by 1.5 mmol (160 pL) deuterium chloride (D, 99.5%, DC1 35% in D2O). The mixture was stirred at room temperature overnight and then filtered to remove the catalyst. The residue was concentrated under reduced pressure to give RL-II-200-a as a white solid in 78% yield (148 mg, 0.78 mmol) used for the next step without further purification. ' H NMR (400 MHz, DMSO- d6) d 3.13-3.19 (m, 1.32H), 3.86-3.90 (m, 0.4H), 4.50-4.56 (m, 1.16H), 6.77 (d, 1H, J = 8.0 Hz), 7.19 (d, 1H, / = 8.0 Hz), 7.35 (s, 1H), 8.28(s, 2H).
2,2‐difluoro‐2‐(triphenylphosphonio)acetate[ No CAS ]
[ 79002-39-4 ]
Yield
Reaction Conditions
Operation in experiment
50%
With copper nitrate hemi(pentahydrate); 4,4'-bis(carbomethoxy)-2,2'-bipyridine; sodium amide; In N,N-dimethyl-formamide; at 130℃; for 20h;
General procedure: Under air atmosphere, a reaction tube was charged with aryl iodides (0.5 mmol), Ph3P+CF2CO2- (268 mg, 0.75 mmol, 1.5equiv), L4 (6.3 mg, 5 mol %), Cu (NO3)2·2.5H2O (143 mg, 0.65 mmol, 1.3 equiv), NaNH2 (39 mg, 1.0 mmol, 2.0 equiv) and dry DMF (4 mL). The resulting mixture was stirred at 130C for 15 h. After being cooled to room temperature, the mixture was filtered through a pad of Celite. The solid was washed with DCM, and the combined organic phase was washed with water (15 mL × 3). The organic layer was further washed with saturated sodium sulfite and saturated brine, and then dried with sodium sulfate. After the solvent was removed by concentration under vacuum, the residue was subjected to flash column chromatography to afford the final product.
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
