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CAS No. : | 60702-69-4 | MDL No. : | MFCD00042523 |
Formula : | C7H3ClFN | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | PGKPNNMOFHNZJX-UHFFFAOYSA-N |
M.W : | 155.56 | Pubchem ID : | 109000 |
Synonyms : |
|
Num. heavy atoms : | 10 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.0 |
Num. rotatable bonds : | 0 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 36.13 |
TPSA : | 23.79 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | Yes |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.57 cm/s |
Log Po/w (iLOGP) : | 1.77 |
Log Po/w (XLOGP3) : | 2.37 |
Log Po/w (WLOGP) : | 2.77 |
Log Po/w (MLOGP) : | 2.48 |
Log Po/w (SILICOS-IT) : | 2.86 |
Consensus Log Po/w : | 2.45 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.74 |
Solubility : | 0.282 mg/ml ; 0.00181 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.51 |
Solubility : | 0.481 mg/ml ; 0.00309 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -3.36 |
Solubility : | 0.0673 mg/ml ; 0.000433 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.77 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302+H312+H332-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: With lithium diisopropyl amide In tetrahydrofuran; hexanes at -78 - -65℃; for 6 h; Stage #2: at -65 - -5℃; for 14 h; |
Cool a solution of diisopropylamine (80.6 niL, 0.575 mol) in THF (1 L) to about -5 0C using an ice water/MeOH bath. Add /z-butyllithium (2.5 M in hexanes, 212 mL, 0.530 mol) dropwise over 1 h via a syringe pump (4 mL/min) while maintaining the reaction temperature between -5 to 0 0C during the addition. Stir the lithium diisopropylamide (LDA) solution for 1 h at 0 °C and then transfer it via canula, over 1 h, to a -78 0C solution of 2-chloro-4-fluoro-benzonitrile (68.7 g, 0.442 mol) in THF (1 L). Allow the temperature of the reaction mixture to warm to about -65 0C during the initial addition of the LDA solution; however, keep the internal temperature below -70 0C during the remainder of the LDA addition. Keep the temperature of the resulting dark red-orange reaction mixture below -70 0C for 5 h and add iodomethane (251.2 g, 1.77 mol, ~3 mL/min) at such a rate that the reaction temperature is maintained below -65 0C during the addition. Allow the reaction mixture to slowly warm overnight. After stirring for 14 h, the temperature of the reaction mixture is -5 0C. Quench the reaction with saturated aqueous ammonium chloride (500 mL) and water (750 mL) and dilute with diethyl ether (about 2 L). Separate the layers and extract the aqueous layer with diethyl ether (about 1 L). Dry the combined organic layer (about 5.5 L) over MgSO4, filter, and concentrate to afford the crude title compound as a red-brown oily solid (about 86.7 g). Subject the crude residue (dry loaded on silica gel using methylene chloride) to flash chromatography (silica gel (10 x 30 cm), gradient of 99: 1 to 93:7 hexane/EtOAc) to obtain the title compound (56.7 g, 76percent) as a white solid, m.p. 63 - 65 0C; 1H NMR (300 MHz, CDCl3): δ 7.54 (dd, J= 8.6, 5.6 Hz, IH), 7.08 (dd, J = 8.6, 8.6 Hz , IH), 2.36 (d, / = 2.4 Hz, 3H). |
74% | Stage #1: With n-butyllithium; N-ethyl-N,N-diisopropylamine In tetrahydrofuran; hexane at -70℃; Stage #2: at -70 - -5℃; for 19.5 h; |
Preparation 12-Chloro-4-fluoro-3-methyl-benzonitrileTo a solution of diisopropylamine (474 mL, 3.35 mol) in anhydrous THF (5.8 L) at-5 °C under a nitrogen atmosphere is added dropwise 2.5 M n-butyllithium in hexanes (1.24 L, 3.10 mol) over 3 h and the resulting mixture is stirred at -5 °C for one additional hour. The LDA solution is added dropwise to a solution of 2-chloro-4-fluoro-benzonitrile (400 g, 2.58 mol) in anhydrous THF (5.8 L) at -70 °C over 6 h and then stirred at -70 °C overnight. lodomethane (643 mL, 10.32 mol) is added dropwise over 2.5 h and the temperature is raised to -5 °C for 17 h. Saturated aqueous ammonium chloride (3 L) is added. The solution is diluted with water (3.5 L) and extracted with diethyl ether (2 x 2 L). The organic phases are separated, combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a black solid. The solid is purified through a silica gel pad eluting withEtOAc/hexanes (1/40) to obtain the title compound (323 g, 74percent). 1H NMR (300 MHz, CDCls) δ 7.08 (dd, J= 8.6, 8.6 Hz, 1H), 7.54 (dd, J= 8.6, 5.6 Hz, 1H), 2.36 (d, J= 2.4 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; | (1) The title compound (0.904 g) of Reference Example 10, diisopropylethylamine (1.57 mL) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.467 g) were dissolved in N-methyl-2-pyrrolidone 9 mL), and the mixture was stirred at 80C for 8 hr.The reaction mixture was poured into saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give 3-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl]-1,3-thiazolidine (0.630 g) as a colorless transparent oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium n-butoxide; In tetrahydrofuran; at 20℃; for 72h; | EXAMPLE 28 2-Chloro-4-(4-hydroxy-1-methyl-pentyloxy)-benzonitrile To a solution of 2,5-hexanediol (28 mg, 0.240 mmol) in tetrahydrofuran was added an excess of potassium butoxide. The admixture was stirred, briefly, and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (37 mg, 0.240 mmol) was added. The admixture was stirred at room temperature for 72 hours. Purification by reverse phase high pressure chromatography eluding with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) provided 28.4 mg of 2-chloro-4-(4-hydroxy-1-methyl-pentyloxy)-benzonitrile. 1H NMR (CDCl3) delta 7.50 (d, 1H), 6.95 (m, 1H), 6.79 (br d, 1H), 4.43 (m, 1H), 3.79 (m, 1H), 1.89-1.40 (m, 4H), 1.30 (d, 3H), 1.17 (d, 3H); MS m/z 253. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 29 2-Chloro-4-(3-hydroxy-propoxy)-benzonitrile To 1,3-propanediol (320 mg, 4.2 mmol) was added sodium (21 mg, 0.92 mmol). The mixture is stirred at room temperature for 10 minutes and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (156 mg, 1.0 mmol) was added. The reaction was heated to 105 C. for 24 hours. The reaction was cooled to room temperature, was diluted with water and was extracted with Et2O (3*). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by reverse phase high pressure chromatography eluding with a solvent gradient (15% of 0.1% formic acid/CH3CN in 0.1% formic acid/water to 100% of 0.1% formic acid/water) to provide 107 mg of 2-chloro-4-(3-hydroxy-propoxy)-benzonitrile. 1H NMR (CDCl3) delta 7.54 (d, 1H), 7.00 (m, 1H), 6.85 (dd, 1H), 4.15 (t, 2H), 3.83 (t, 2H), 2.04 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride on basic alumina; In acetonitrile; for 16h;Heating / reflux; | Example 26 2-Chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile 1,3-Cyclohexanediol (116 mg, 1.0 mmole) was added to a flame dried round bottom flask under nitrogen. The flask was then charged with 5 mL of dry acetonitrile, 26 mg of potassium fluoride on alumina (0.1 mmol), and <strong>[60702-69-4]4-fluoro-2-chloro-benzonitrile</strong> (155 mg, 1.0 mmole) and heated at reflux for 16 h. Diethyl ether (15 ml) was added to the reaction mixture, which was then extracted with water (2*), dried (MgSO4) and concentrated. Purification using a chromatotron, eluding with 10% EtOAc/hex (ethylacetate and hexane) provided 22 mg of the title compound. GC/MS: 251 (M/Z for C13H14ClNO2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In N,N-dimethyl-formamide; at 20℃; for 16h;Product distribution / selectivity; | Example 27 2-Chloro-4-(2-ethyl-cyclohexyloxy)-benzonitrile 4-Fluoro-2-chloro-benzonitrile (122 mg, 0.79 mmole) was added to a flame dried round bottom flask under nitrogen containing 2 mL of dry dimethylformamide ("DMF") and 63 mg of 60% sodium hydride as an oil dispersion (1.6 mmol). 2-Ethylcyclohexanol. (100 mg, 0.79 mmole) dissolved in 1 mL of dry DMF was then added to the reaction vessel via syringe in a dropwise manner. The reaction was stirred at room temperature for 16 h, after which time 5 mL of water was added dropwise. The mixture was extracted twice with diethyl ether, washed with water, dried (MgSO4) and concentrated. Purification using a chromatotron eluding with 5% EtOAc/hex followed by 5% EtOAc/hex gave 155 mg of the title compound. GC/MS: 263 (M/Z for C15H18ClNO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 95℃; for 15h; | a) (2S)-2-[(3-Chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid<strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (2.13 g, 13.8 mmol), (2S)-2-amino-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (2.6 g, 13.8 mmol) and NaHCO3 (3.5 g, 41.4 mmol) in DMSO (70 mL) and H2O (10 mL) were stirred at 95 C. for 15 h. After cooling, the reaction mixture was diluted with H2O (100 mL) and washed with Et2O (100 mL). The H2O layer was acidified to Congo Red midpoint and extracted with Et2O (2×). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to give the titled product (3.59 g, 80%) as a foam. 1H-NMR (CDCl3) delta: 1.45 (9H, s), 2.89 (2H, m), 3.54 (1H, m), 4.42 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.70 (1H, s), 7.43 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 325.4 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 75℃; for 18h;Product distribution / selectivity; | d) 2-Chloro-4-[(3S)-1-methyl-5-oxo-3-pyrrolidinyl]amino}benzonitrile1,1-Dimethylethyl [(3S)-1-methyl-5-oxo-3-pyrrolidinyl]carbamate (0.96 g, 4.5 mmol) was suspended in 4N HCl in dioxane (3 mL) and the mixture was stirred at room temperature for 12 h. Solvent was removed and the residue was dissolved in DMSO (27 mL) and H2O (3 mL). To this solution, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.77 g, 4.90 mmol) and NaHCO3 (1.89 g, 22.5 mmol) were added and the reaction mixture was stirred at 75 C. for 18 h. After cooling to room temperature, the reaction mixture was partitioned between H2O and EtOAc and the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography with 0% MeOH in CH2Cl2 grading to 5% MeOH in CH2Cl2 to give the titled product (0.598 g, 53%) as a white solid. 1H-NMR (CDCl3) delta: 2.350 (1H, m), 2.914 (4H, m), 3.305 (1H, m), 3.825 (1H, m), 4.200 (1H, m), 4.835 (1H, d, J=6.8 Hz), 6.492 (1H, dd, J=8.4 Hz, 2.4 Hz), 6.626 (1H, d, J=2.4 Hz), 7.454 (1H, d, J=8.4 Hz). LC-MS (ES) m/e 250.0 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; | EXAMPLE 345B 4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzonitrile <strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120 C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. | |
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; | Example 345B 4-(8-azabicyclo[3.2.1]oct-8-yl)-2-chlorobenzonitrile <strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (0.97 g, 6.2 mmol), 8-aza-bicyclo[3.2.1]octane hydrochloride (0.92 g, 6.2 mmol), and N,N-diisopropylethylamine (1.6 g, 12 mmol) were combined in DMSO (15 mL) and heated at 120 C. for 16 hours. The mixture was allowed to cool to ambient temperature and partitioned between diethyl ether and saturated NaHCO3 solution. The aqueous phase was separated and extracted with diethyl ether. The organic layers were combined, washed with water, brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure to provide the title compound which was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydride; In dimethyl sulfoxide; at 20℃; for 5h; | 2-CHLORO-4-FLUOROBENZONITRILE (5. 0G) and 3- (1-PIPERIDINYL)-1-PROPANOL (3.4g) were stirred in DMSO (70 ML) at rt under argon. Sodium hydride (60% wt in mineral oil, 1.976g) was then added and the reaction stirred at rt for 5h. The reaction mixture was diluted with ethyl acetate (200MOI), washed with saturated sodium hydrogen carbonate (100ml), water (3X100 ML), brine (100MI), dried (MGSO4) and evaporated. The crude product was then purified by column chromatography [silica gel, step gradient OR10% MEOH (containing 10%. 880 ammonia solution) in DCM) ] and fractions containing pure product were combined and evaporated to give the title compound (D26) as a white solid (6.29g). MS electrospray (+ion) 279/281 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | Anhydrous p-toluene sulfonic acid (41.99 g, 220.76 mmol) was melted at 120 C and 3-amino-4-methoxy benzoic acid methyl ester (20 g, 110.38 mmol) obtained in step 1 of Preparation Example 1 and 2-chloro-4- fluorobenzonitrile (25.76 g, 165.57 mol) were added thereto and stirred at 160 C for 8 hours. The resulting solution was cooled to room temperature and the reaction was stopped by adding NaHCO3 thereto. The resulting mixture was extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (26.70 g, 79.47 mmol) in a yield of 72 %. 1H NMR (CDCl3): delta 7.92-7.75 (4H, m), 7.15-7.02 (3H, m), 3.87-3.81 (6H, d) MW: 336 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With potassium carbonate; In DMF (N,N-dimethyl-formamide); at 110℃; for 1h; | 4-Hydroxy benzaldehyde (I equiv), 2-CHLORO-4-FLUOROBENZONITRILE (1 EQUIV) and K2CO3 (2.5 equiv) in anhydrous DMF (0.2 M) were heated at 0C under nitrogen during 1 hour (the reaction can be monitored by TLC). After cooling down to room temperature, the reaction mixture was poured into water and extracted with ethyl acetate (3X50 mL). The combined organic layer was dried OVER NA2SO4, filtered and concentrated under vacuum (toluene was added to aid DMF evaporation). The crude mixture was purified by flash chromatography using HEXANES/ETHYL acetate (4 : 1) as eluent. 84% yield. H NMR (CDC13, 200 MHz) 8 : 9.99 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.15-7. 13 (m, 2H), 6.99 (dd, J = 8.4, 2.2 Hz, 1H). MS (Electrospray): (M++1) 258.1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
26%; 26% | With sulfuric acid; potassium nitrate; at 5 - 20℃; | 2 g (12.86 mmol) <strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> in 20 ml H2SO4 are treated with 1. 7 g (16.81 mmol) KNO3 in small portions at 5-10 C. The reaction mixture is allowed to warm up to room temperature overnight, then poured onto ice. The obtained precipitate is removed by filtration and rinsed neutral with water. The solid is digested with dichloromethane, filtered and dried. Yield : 780 mg (26 %) 93, colourless solid The filtrate is evaporated and the residue is purified by chromatography (110 g silica gel, n-heptane/DCM (50-100%)). Yield : 680 mg (26 %) 92, colourless solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | To a freshly-prepared solution of LDA (33.7 mmol) in anhydrous THF (30 mL) at -78Cwas added a solution of commercially available <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (5.00 g,32.1 mmol) in THF (10 mL), dropwise at such a rate that the internal temperature remained < -70 C. The mixture was stirred for 2 h and a solution of iodine (8.97 g, 35.4 mmol) in THE (20 mL) was added dropwise (temp < -70 C). The mixture was stirred 30 min, removed from the cooling bath and quenched by addition of 10% Na2S2O3. Themixture was poured into water and extracted with EtOAc (x3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in a small amount of CH2Cl2 and filtered through a pad of silica (25% EtOAc/hexanes eluent). Fractions containing the major product were concentrated in vacuo and the residue was recrystallized from heptane affording 3.24 g tan solid. Themother liquor was concentrated and the residue was purified by flash chromatography (EtOAc / hexanes, gradient elution) affording 2.85 g of a pale yellow solid. Solids were combined to give 2-chloro-4-fluoro-3-iodobenzonitrile (6.09 g, 67 % yield): 1H NMR (400MHz, CDCl3) delta 7.70 (dd, J = 8.6, 5.5 Hz, 1 H), 7.08 (dd, J = 8.6, 6.8 Hz, 1 H); MS (GCMS EI) m/z 281 ([M]+, 100%). | |
Example 11 2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)-3-iodobenzonitrile (195JP18) Adapting a protocol by Uchiyama et al (J. Am. Chem. Soc., 2002, 124, 8514-8515), which reference is incorporated herein by reference in its entirety, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (311 mg, 2.0 mmol) in dry THF (1.0 mL) was added dropwise to lithium di-t-butyl(2,2,6,6-tetramethylpiperidino)zinncate (4.0 mmol in 10 mL THF, Uchiyama et al J. Am. Chem. Soc., 1999, 121, 3539-3540, which is incorporated herein by reference in its entirety) at 0 C. and stirred at 0 C. for 3.5 h. Iodine (5.08 g, 20.0 mmol) was then added and the reaction was stirred at r.t. overnight. Na2S2O3 (1.0 M, 50 mL) and saturated aqueous NH4Cl (100 mL) were added, followed by extraction with dichloromethane (3*100 mL), drying of the combined organic layers over Na2SO4, filtering, and removal of the solvents in vacuo. The residue was passed through a pad of silica gel eluding with EtOAc/n-heptane (1:40), affording 112 mg (0.40 mmol) of 2-chloro-4-fluoro-3-iodobenzonitrile. This material was combined with nortropine (114 mg, 0.90 mmol), K2CO3 (186 mg, 0.134 mol) and DMSO (2.0 mL), and stirred at 130 C. for 1.5 h. The crude mixture thus obtained was diluted with n-heptane (10 mL), passed through a pad of silica gel using EtOAc/n-heptane (1:2), concentrated and purified by preparative TLC (EtOAC/n-heptane, 1:1) to give 1.5 mg (1.7%) of 195JP18 as an off-white solid. Rf=0.21 (EtOAc/n-heptane 1:1). LC/MS m/z 389 [M+H]+. 1H-NMR (CDCl3) delta 7.42 (d, 1H, J=8.6), 6.70 (d, 1H, J=8.6), 4.16 (br s, 1H), 3.95 (br s, 2H), 2.50-2.22 (m, 4H) 1.93-1.78 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
63% | With pyridine; at 110℃; for 20h; | Example 20 2-Chloro-4-(3-endo-hydroxy-8-azabicyclo[3.2.1]oct-8-yl)benzonitrile (196MBT8-B) Nortropine (269 mg, 2.12 mmol) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (100 mg, 0.643 mmol) were dissolved in pyridine (2 mL). The mixture was heated to 110 C. in a sealed flask for 20 hours and then concentrated. The residue was dissolved in 2 M HCl (20 mL) and extracted with dichloromethane (2×20 mL). The combined organic phases were dried over Na2SO4, filtered and evaporated, and the resulting oil was purified by preparative TLC (eluting with dichloromethane) to afford 107 mg (63%) of the title compound as a colorless solid. LC/MS m/z 263 [M+H]+. 1H-NMR (CDCl3) delta 7.46-6.51 (m, 3H), 4.29-4.16 (m, 2H), 4.16-4.00 (m, 1H), 2.45-2.27 (m, 2H), 2.18-1.96 (m, 4H), 1.79-1.65 (m, 2H), 1.56 (s, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 32 2-Chloro-4-(2-methyl-4-pyrrolidin-1-yl-quinolin-7-ylmethoxy)-benzonitrile The title compound was produced in accordance with the general method of example 6 from (2-methyl-4-pyrrolidin-1-yl-quinolin-7-yl)-methanol (example 2) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong>. Light yellow solid, ISP-MS: m/e=378.3 ([M+H]+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example A20 Synthesis of N-(3-chloro-4-cyanophenyl)alanine Iso-butyl Ester Following General Procedure AP above and using <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant. NMR data was as follows: 1H-nmr (CDCl3): delta=7.40 (d, J=8.5 Hz,1H), 6.62 (d, J=2.3 Hz, 1H), 6.48 (dd, J=2.4, 8.6 Hz, 1H), 4.90 (d, J=7.6 Hz, 1H), 4.16 (quintet, J=7.1 Hz, 1H), 3.96 (dd, J=2.2, 6.7 Hz, 2H), 1.97 (m, 1H), 1.51 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H). 13C-nmr (CDCl3): delta=173.0, 150.4, 138.3, 134.9, 117.3, 112.8, 111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18.4. | ||
Example A20 Synthesis of N-(3-Chloro-4-cyanophenyl)alanine iso-Butyl Ester Following General Procedure AP above and using <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example AA above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant. NMR data was as follows: 1H-nmr (CDCl3): delta=7.40 (d, J=8.5 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.48 (dd, J=2.4, 8.6 Hz, 1H), 4.90 (d, J=7.6 Hz, 1H), 4.16 (quintet, J=7.1 Hz, 1H), 3.96 (dd, J=2.2, 6.7 Hz, 2H), 1.97 (m, 1H), 1.51 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H). 13C-nmr (CDCl3): delta=173.0, 150.4, 138.3, 134.9, 117.3, 112.8, 111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18.4. C14H17N2O2Cl MW=280.76; mass spectroscopy (MH+) 281. | ||
EXAMPLE 20 Synthesis of N-(3-chloro-4-cyanophenyl)alanine Iso-butyl Ester Following General Procedure P above and using <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (Aldrich) and D,L-alanine iso-butyl ester hydrochloride (from Example A above), the title compound was prepared. The product was recovered by column chromatography on silica gel using 1:5 EtOAc/hexanes as the eluant. NMR data was as follows: 1 H-nmr (CDCl3): delta=7.40 (d, J=8.5 Hz, 1H), 6.62 (d, J=2.3 Hz, 1H), 6.48 (dd, J=2.4, 8.6 Hz, 1H), 4.90 (d, J=7.6 Hz, 1H), 4.16 (quintet, J=7.1 Hz, 1H), 3.96 (dd, J=2.2, 6.7 Hz, 2H), 1.97 (m, 1H), 1.51 (d, J=7.0 Hz, 3H), 0.93 (d, J=6.7 Hz, 6H). 13 C-nmr (CDCl3): delta=173.0, 150.4, 138.3, 134.9, 117.3, 112.8, 111.3, 100.6, 71.7, 51.1, 27.7, 18.9, 18.4. |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 3 Using the same conditions as in Example 1,2-chloro-4-nitrobenzonitrile reacted to give 2-chloro-4-fluorobenzonitrile in 95% yields by g.c. after 1.5 h. The product, isolated as a solid, showed the following data: |
Yield | Reaction Conditions | Operation in experiment |
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The compounds of the formula XXX which are listed in Table 7 are prepared analogously to Example 87. 2-Chloro-4-fluoropropiophenone is obtained as an oil by analogous reaction of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> with ethylmagnesium bromide; b.p. 44 C./0.07 torr (Example 96). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hexamethyldisilazane; In toluene; for 8h;Heating / reflux; | To an anhydrous toluene solution containing 3 (S)- [(3- chloro-4-fluorophenyl) amino] pyrrolidine-1-carboxylic acid tert- butyl ester (0.50 g, 1.6 mmol) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.30 g, 1.9 mmol) was added a 1.45 ml tetrahydrofuran solution containing sodium bis (trimethylsilyl) amide (1.1 M) using a syringe. The mixture was heated under reflux under a nitrogen atmosphere for 8 hours and cooled to room temperature. Water was added to the reaction solution, and extraction with diethyl ether was conducted. After drying over sodium sulfate and concentration under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane : ethyl acetate = 4 : 1) . The purified product was concentrated to dryness under reduced EPO <DP n="78"/>pressure to thereby obtain 0.56 g of white amorphous solid 3(S)- [ (3-chloro-4-cyanophenyl) - (3-chloro-4-fluorophenyl) amino]pyrrolidine-1-carboxylic acid tert-butyl ester. 1H-NMR(CDCl3) deltappm: 1.43{9H,s), 1.76-1.93 (lH,m), 2.11-2.27 (IH,m) , 3.15-3.39 (3H,m) , 3.66-3.87 (IH,m) , 4.39-4.55 (lH,m) , 6.42 (IH, dd, J=2.5Hz, J=9. OHz) , 6.57 (IH, d, J=2.5Hz) , 6.98-7.04 (IH,m) , 7.20 (IH, dd, J=2.5Hz, J=6.5Hz) , 7.23-7.32 (IH,m) , 7.40 (IH, d, J=8.5Hz) . |
Yield | Reaction Conditions | Operation in experiment |
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EXAMPLE 15 Preparation of 1-methyl-3-(2-chloro-4-fluorophenacyl)piperidine and maleate salt thereof The procedure of Example 6 was repeated, except that the concentration of Grignard reagent was 79 mg/ml (calculated), the volume of Grignard reagent employed was 77 ml, the 4-chlorobenzonitrile was replaced with 5.3 g of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong>, the amount of ammonium chloride employed in the work-up procedure was reduced to 2.5 g, and the pure piperidine compound was isolated prior to the preparation of the maleate salt thereof. The yield of 1-methyl-3-(2-chloro-4-fluorophenacyl)piperidine was 4.8 g, bp 117.5-120/0.2 mm. The following elemental analysis was obtained: Calculated for C14 H17 ClFNO: |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; water; | (1) The title compound (0.924 g) of Reference Example 3, diisopropylethylamine (1.7 mL) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.78 g) were dissolved in N-methyl-2-pyrrolidone (10 mL), and the mixture was stirred at 80C for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give (S)-1-[(2S,4S)-1-tert-butoxycarbonyl-4-(3-chloro-4-cyanophenyl)amino-2-pyrrolidinylcarbonyl] -2-cyanopyrrolidine (0.94 g) as amorphous. |
Yield | Reaction Conditions | Operation in experiment |
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36% | With 4-methyl-morpholine; at 100℃; for 1h;microwave; | Combine 2-(l,3-benzodioxol-5-yl)-4,4-dimethylpyrrolidine (338 mg, 1.54 mmol) with <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (216 mg, 1.39 mmol) and N- methylmorpholine (0.169 mL, 1.54 mmol) and then heat to 100 0C in a microwave for 1 h. Purify by flash chromatography (12 g RediSep silica gel columns, 0:100 to 90:10 gradient of [cyclohexane : ethylacetate] then repeat using (12 g RediSep silica gel columns, 0:100 to 97:3 gradient of [cyclohexane : ethylacetate] to provide 179 mg (36%) of the title compound. MS: 355 [M C135+H]+ and 377 [M Cl35+Na]+; 1H NMR (300 MHz, CDCl3): delta 7.28-7.30 (m, IH), 6.72-6.76 (m, IH), 6.61-6.67 (m, . IH), 6.58 (s, IH), 6.51 (s, IH), 6.28-6.31 (m, IH), 5.92-5.95 (m, 2H), 4.68-4.72 (m, IH), 3.48-3.50 (m, IH), 3.30-3.35 (m, IH), 2.20-2.30 (IH, m), 1.75-1.81 (IH, m), 1.18 (s, 3H) and 1.09 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
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74% | To a solution of (4S,5S)-4-hydroxy-5-methylpyrrolidin-2-one 7 33 (7.00 g, 60.8 mmol) in THF (120 mL) was added sodium bis(2-methoxyethoxy)aluminium dihydride (70% in toluene, 59.7 mL, 215 mmol) slowly at 5 C. After stirring at 70 C for 3 h, the reaction mixture was cooled to 5 C followed by addition of sodium carbonate decahydrate (26.1 g, 91.2 mmol). The mixture was stirred at room temperature for 16 h, diluted with THF, and the precipitate was filtered off. The filtrate was concentrated in vacuo, and the residue was dissolved in DMSO (80 mL). To the solution was added lithium carbonate (8.99 g, 122 mmol) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (9.46 g, 60.9 mmol), and the mixture was stirred at 100 C for 1 h. The mixture was diluted with EtOAc and H2O, and the organic layer was dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 10 (10.7 g, 74%) as a colorless solid. 1H NMR (300 MHz, CDCl3) delta: 1.18 (3H, d, J = 6.6 Hz), 1.82 (1H, d, J = 5.5 Hz), 2.01-2.14 (1H, m), 2.25-2.35 (1H, m), 3.19-3.28 (1H, m), 3.43-3.51 (1H, m), 3.89-3.98 (1H, m), 4.43-4.52 (1H, m), 6.43 (1H, dd, J = 8.9 and 2.4 Hz), 6.56 (1H, d, J = 2.4 Hz), 7.42 (1H, d, J = 8.9 Hz). MS (ESI) m/z 237 [(M+H)+]. |
Yield | Reaction Conditions | Operation in experiment |
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78% | With sodium hydrogencarbonate; In water; dimethyl sulfoxide; at 86 - 96℃; for 22h; | A mixture of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (4.26 g, 27.5 mmol), 1,1-dimethylethyl (36)-3-amino-l- pyrrolidinecarboxylate (5.11 g, 27.5 mmol) and NaHCO3 (4.62 g, 55 mmol) in 45 mL of DMSO and 5 mL OfH2O was heated with stirring at 96 0C for 6 h and 86 0C for 16 h. The reaction was diluted with 200 mL OfH2O and extracted with Et2O (3x). The extracts were washed with H2O (2x), dried over Na2SO4, filtered, and concentrated. The residue was crystallized from Et2O/hexane to |
Yield | Reaction Conditions | Operation in experiment |
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1.44 g [4-(3-Benzyloxy-propyl)-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-yl]-methanol were dissolved in 15 ml dimethylformamide. 231 mg sodium hydride (95%) were added and the reaction mixture stirred at room temperature. After thirty minutes 549 mg <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> were added and the reaction mixture stirred at room temperature for one hour. Then the reaction was quenched by the addition of 20 ml water and extracted three times with portions of 50 ml methyltertbutylether. The combined organic phases were dried over MgSO4. The solvent was removed in vacuo. The resulting residue was purified by reversed phase HPLC to obtain 641 mg 4-[4-(3-Benzyloxy-propyl)-2-(6-trifluoromethyl-pyridin-3-yl)-thiazol-5-ylmethoxy]-2-chloro-benzonitrile as yellow lyophilisate.C27H21ClF3N3O2S (544.0), MS (ESI): 544.2 (M+H+), Rf (n-heptane:ethyl acetate=1:1) 0.66. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.2% | To a 100L reaction vessel were added ethanol (40L) and <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (7kg). Then hydrazine hydrate (4 L) was added. The resulting mixture was heated to reflux for 5 hours, then cooled, and subjected to centrifugal filtration. The resulting solid was introduced into a 100L reaction vessel. Anhydrous ethanol (40L) was added, and then concentrated hydrochloric acid (7.5L) was slowly added. The resulting mixture was heated to reflux for 2 hours, subjected to centrifugal filtration, and dried to produce 2-chloro-4-hydrazinobenzonitrile hydrochloride (7kg), yield: 76.2%. | |
62% | Preparation 1; 2-chloro-4-hydrazinylbenzonitrile hydrochloride; A mixture of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (20.0 g, 129 mmol), hydrazine monohydrate (9.4 m._, 193 mmol), and ethanol (80 ml_) was refluxed for 4 hours (Method H and Scheme 3a). The mixture was diluted with water (200 ml_). The precipitate was filtered, washed with water, and dried to give an off-white solid (16.8 g). The solid was suspended in diethyl ether (400 mL) and treated with 2N hydrogen chloride/ether (50 mL, 100 mmol). The precipitate was filtered, washed with diethyl ether, and dried to give 2-chloro-4-hydrazinylbenzonitrile hydrochloride as a white solid (16.3 g, 79.9 mmol, 62% yield). 1H NMR (400 MHz, DMSO-d6) delta ppm 9.63 (br. s., 3 H), 9.17 (br. s., 1 H), 7.74 (d, J=8.9 Hz, 1 H), 7.13 (d, J=2.1 Hz, 1 H), 6.92 (dd, J=8.6, 2.1 Hz, 1 H). ES-MS m/z 168 (M+H). | |
Reference Example 402-chloro-4-hydrazinylbenzonitrile hydrochloride [0320] <strong>[60702-69-4]2-Chloro-4-fluorobenzonitrile</strong> (16.27 g) was dissolved in ethanol (65 ?iL) , hydrazine monohydrate (7.65 mL) was added, and the mixture was stirred at 80C for 4 hr. Water (160 mL) was added, and the precipitate was collected by filtration. The precipitate was suspended in diethyl ether (325 mL) , and hydrogen chloride-diethyl ether solution (1 mol/L, «81 mL) was added. After stirring for 30 min, insoluble material was collected by filtration to give the title compound (15.66 g) as a pale-yellow powder.1H-NMR (DMSOd6) delta:6.95 (IH, dd) , 7.17 (IH, d) , 7.78 (IH, d) , 9.29 (IH, s), 10.03 (3H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step C: 2-Chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile To a solution of the regioisomer mixture above, Example 31, Step B, (1.67 g, 4.95 mmol) in THF (15 mL) was added tert-butyl ammonium fluoride (1.0 M in THF, 5.44 mL, 5.44 mmol). The reaction was stirred at room temperature for 15 minutes, was diluted with aqueous NH4Cl and extracted with EtOAc (3*). The organic solution was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluding with a solvent gradient (hexanes to 100% EtOAc in hexanes over 70 minutes) to provide 112 mg of 2-chloro-4-(1-hydroxymethyl-allyloxy)-benzonitrile. 1H NMR (CDCl3) delta 7.55 (d, 1H), 7.04 (d, 1H), 6.89 (dd, 1H), 5.85-5.76 (m, 1H), 5.38 (m, 2H), 4.80 (m, 1H), 3.80 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
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Step B: 4-[1-(tert-Butyl-dimethyl-silanyloxymethyl)-allyloxy]-2-chloro-benzonitrile To a solution of 1-(tert-butyl-dimethyl-silanyloxy)-but-3-en-2-ol (1.102 g, 5.45 mmol) in THF (26 mL) at -78 C. was added potassium tert-butoxide (1.0 M in THF, 5.99 mL, 5.99 mmol). The solution was stirred for 15 minutes and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (847 mg, 5.45 mmol) was added at -78 C. The reaction was stirred at room temperature for 24 hours, quenched with water and extracted with EtOAc (3×). The organic solution was washed with water and brine, dried (MgSO4), filtered and concentrated to provide 1.67 9 of a 1:1 mixture of 4-[1-(tert -butyl-dimethyl-silanyloxymethyl)-allyloxy]-2-chloro-benzonitrile and 4-[2-(tert -butyl-dimethyl-silanyloxy)-but-3-enyloxy]-2-chloro-benzonitrile. 1H NMR (CDCl3) delta 7.55 (m, 2H), 7.02 (m, 2H), 5.91-5.78 (m, 2H), 5.42-5.22 (m, 4H), 4.75 (m, 1H), 4.51 (m, 1H), 3.90 (m, 2H), 3.79 (m, 2H), 0.89 (s, 9H), 0.87 (s, 9H), 0.07 (s, 6H), 0.04 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With caesium carbonate; In dimethyl sulfoxide; at 90℃; | Reference Example 116 N-(3-chloro-4-cyanophenyl)-4-cyanophenylalanine To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (0.90 g) in dimethyl sulfoxide (20 mL) were added 4-cyanophenylalanine (1.00 g) and cesium carbonate (2.23 g), and the mixture was stirred at 90 C. overnight. After warming to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 1.57 g, 92%). 1H-NMR(CDCl3)delta:3.17-3.38(2H,m), 4.41-4.51(1H,m), 4.78(1H,d,J=7.7 Hz), 6.49(1H,dd,J=8.6,2.4 Hz), 6.63(1H,d,J=2.5 Hz), 7.24-7.30(2H,m), 7.44(1H,d,J=8.5 Hz), 7.56-7.64(2H,m). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With caesium carbonate; In dimethyl sulfoxide; at 90℃; | Reference Example 114 N-(3-chloro-4-cyanophenyl)valine To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (3.50 g) in dimethyl sulfoxide (60 mL) were added L-valine (3.16 g) and cesium carbonate (9.53 g), and the mixture was stirred at 90 C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 5.69 g, 100%). 1H-NMR(CDCl3)delta:1.07(6H,t,J=6.7 Hz), 2.16-2.31(1H,m), 3.91-3.99(1H,m), 4.71(1H,d,J=8.9 Hz), 6.51(1H,dd,J=8.7,2.3 Hz), 6.67(1H,d,J=2.5 Hz), 7.42(1H,d,J=8.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With caesium carbonate; In dimethyl sulfoxide; at 90℃; | Reference Example 108 N-(3-chloro-4-cyanophenyl)phenylalanine To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (5.0 g) in dimethyl sulfoxide (100 mL) were added phenylalanine (6.37 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90 C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted 3 times with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 9.67 g, 100%). 1H-NMR(CDCl3)delta:3.09-3.19(1H,m), 3.24-3.32(1H,m), 4.37-4.47(1H,m), 4.67-4.76(1H,m), 6.44(1H,dd,J=8.6,2.4 Hz), 6.59(1H,d,J=2.3 Hz), 7.12-7.19(2H,m), 7.27-7.35(3H,m), 7.40(1H,d,J=8.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With caesium carbonate; In dimethyl sulfoxide; at 90℃; | Reference Example 112 N-(3-chloro-4-cyanophenyl)-4-fluorophenylalanine To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (1.8 g) in dimethyl sulfoxide (30 mL) were added 4-fluorophenylalanine (2.54 g) and cesium carbonate (4.90 g), and the mixture was stirred at 90 C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 3.69 g, 100%). 1H-NMR(CDCl3)delta:3.07-3.30(2H,m), 4.40(1H,q,J=5.9 Hz), 4.72(1H,d,J=6.6 Hz), 6.46(1H,dd,J=8.7,2.3 Hz), 6.60(1H,d,J=2.3 Hz), 6.94-7.05(2H,m), 7.07-7.16(2H,m), 7.41(1H,d,J=8.7 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With caesium carbonate; In dimethyl sulfoxide; at 90℃; | Reference Example 118 N-(3-chloro-4-cyanophenyl)-3-cyclopropylalanine To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (1.33 g) in dimethyl sulfoxide (20 mL) were added 3-cyclopropyl-L-alanine (1.00 g) and cesium carbonate (3.28 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 2.05 g, 100percent). 1H-NMR(CDCl3)delta:0.10-0.21(2H,m), 0.47-0.58(2H,m), 0.72-0.87(1H,m), 1.71-1.92(2H,m), 4.14-4.24(1H,m), 4.95(1H,d,J=7.9 Hz), 6.51(1H,dd,J=8.7,2.5 Hz), 6.66(1H,d,J=2.3 Hz), 7.41(1H,d,J=8.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
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100% | With caesium carbonate; In dimethyl sulfoxide; at 90℃; | Reference Example 110 N-(3-chloro-4-cyanophenyl)norvaline To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (5.0 g) in dimethyl sulfoxide (80 mL) were added L-norvaline (4.52 g) and cesium carbonate (13.6 g), and the mixture was stirred at 90 C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 8.12 g, 100%). 1H-NMR(CDCl3)delta:0.97(3H,t,J=7.3 Hz), 1.40-1.54(2H,m), 1.71-2.00(2H,m), 4.08-4.16(1H,m), 4.71(1H,br.s.),6.50(1H,dd,J=8.7,2.5 Hz), 6.64(1H,d,J=2.5 Hz), 7.42(1H,d,J=8.5 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Combine the compound from Example 218 step 2 (692 mg, 2.12 mmol) and K2CO3 (323 mg, 2.33 mmol) in DMF (9 mL), stir the mixture at room temperature for 30 min and then add <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (330 mg, 2.12 mmol), and heat at 100 C overnight. Cool to ambient temperature and pour into water. Extract the aqueous layer with EtOAc. Dry the organic layer over NA2SO4 and eliminate the solvent. Purify by flash chromatography on silica gel (eluent: ETOAC/HEXANE 15/85) to obtain the title compound (940 mg, 95%). Electrospray MS M-1 ion = 461, H-NMR (CDC13, 400 MHz): 7.57 (d, 1H, J= 7.8 Hz), 7.36-7. 13 (m, 7H), 7. 00-6. 85 (m, 4H), 4.44-4. 36 (M, 2LI) 3.49-3. 32 (m, 2H), 2.83-2. 73 (m, 2H), 1.51-1. 43 (m, 9H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | Example 44 2-Chloro-4-(1-phenyl-propoxy)-benzonitrile) To a solution of 21 mg of 1-phenyl-propan-1-ol in 150 uL of THF at room temperature, 150 uL of a 1.0 M solution of tert-butoxide in THF was added. This mixture was stirred for 15 minutes, then transferred via syringe to a solution of 23 mg of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> in 150 uL of THF. The reaction was shaken at room temperature for 16 h, concentrated, diluted with 250 uL of DMF, filtered and then purified by reverse phase chromatography (Shimadzu semi prep HPLC) to give 7 mg (17% of the title compound) as a colorless oil. GC/MS M/Z 271 (calc 271.1). |
Yield | Reaction Conditions | Operation in experiment |
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20% | Example 43 2-Chloro-4-(cyclopropyl-phenyl-methoxy)-benzonitrile To a solution of 24 mg of cyclopropyl-phenyl-methanol in 150 uL of THF at room temperature, 150 uL of a 1.0 M solution of tert-butoxide in THF was added. This mixture was stirred for 15 minutes, then transferred via syringe to a solution of 23 mg of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> in 150 uL of THF. The reaction was shaken at room temperature for 16 h, concentrated, diluted with 250 uL of DMF, filtered and then purified by reverse phase chromatography (Shimadzu semi prep HPLC) to give 9 mg (20%) of the title compound as a colorless oil. GC/MS MIZ 283 (calc 283.1). |
Yield | Reaction Conditions | Operation in experiment |
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42% | Example 11; 2-chloro-3-ethyl-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzonitrile; Intermediate 11a; 2-Chloro-3-ethyl-4-fluorobenzonitrile; A 500 mL round bottomed flask was charged with di-isopropylamine (11.81 mL, 83.60 mmol), anhydrous THF (30 mL) and a magnetic stir bar while being maintained under at atmosphere of N2. The mixture was stirred and cooled to -5 C. with the aid of an ice/methanol bath whereupon a 2.5M solution of n-BuLi (30.87 mL, 77.17 mmol) was added dropwise and the mixture stirred for a further hour. The LDA was then added via cannula to a 500 mL three-necked round bottomed flask containing a pre-cooled solution of <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (10.0 g, 64.31 mmol) in anhydrous THF at -78 C. The reaction mixture was stirred and maintained at this temperature for 4.5 h whereupon iodoethane was added slowly. When the addition was complete the mixture was stirred overnight and allowed to gradually warm to room temperature. After 18 h a saturated aqueous solution of ammonium chloride (60 mL) was added to the mixture, followed by EtOAc (50 mL). The phases were partitioned and the aqueous phase was extracted with EtOAc. The combined organics were dried (Na2SO4) and concentrated to furnish a yellow solid (12g). A sample of the mixture was taken and 1H NMR analysis revealed that a trace of starting material remained. The crude mixture was then subjected to flash column chromatography on silica gel [hexanes-EtOAc (95:5) as eluent] to furnish the title compound (5g, 42%). 1H NMR (500 MHz, CDCl3, delta in ppm) 7.56 (dd, J=1.0, 8.0 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 2.82 (q, J=7 Hz, 2H), 1.19 (t, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 46; 2-Chloro-4-((1R,2R)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-benzonitrile; Intermediate 46a; (2R,3R)-2-(3-Chloro-4-cyanophenylamino)-3-hydroxybutanoic acid; To a suspension of D-allo-threonine (5.08 g, 42.7 mmol) and K2CO3 (10.32 g, 74.7 mmol) in DMSO (50 mL) was added <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (5.53 g, 35.5 mmol) at room temperature. The reaction mixture was heated to 75 C. and stirred for 39 h. The reaction mixture was allowed to cool to room temperature and quenched with H2O (400 mL) and extracted with EtOAc (3×200 mL). The aqueous layer was then acidified with solid citric acid and extracted with EtOAc (2×100 mL). The later organic extracts were combined, washed with H2O (3×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provided the title compound as a brown solid (9.04 g, 100%): 1H NMR (400 MHz, acetone-d6, delta in ppm) 7.51 (d, J=8.8 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.83 (dd, J=2.4, 8.8 Hz, 1H), 6.31 (br d, J=7.6 Hz, 1H), 4.28-4.20 (m, 2H), 1.31 (d, J=6.5 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | Example 80; 2-chloro-4-((1R,2S)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-vinylbenzonitrile; Intermediate 80a; 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile; To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (20.0 g, 128.6 mmol) in THF (200 mL) was added LDA (28% wt in THF, 71.0 mL, 142.0 mmol) at -78 C. After addition, the mixture was stirred at the same temperature for 5 h, then ethylene oxide (9.7 ml, 194.2 mmol) was added. The reaction mixture was allowed to warm to R. T. gradually and stirred overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by SiO2 column to give 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (17.0 g, 66%). 1H NMR (400 MHz, CDCl3, delta in ppm) 7.5 8 (dd, J=5.5, 8.6 Hz, 1H), 7.10 (t, J=8.6 Hz, 1H), 3.8 8 (m, 2H), 3.13 (t, J=6.8 Hz, 2H). | |
66% | To a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (20.0 g, 128.6 mmol) in THF (200 mL) was added LDA (28% wt in THF, 71.0 mL, 142.0 mmol) at -78 0C. After addition, the mixture was stirred at the same temperature for 5 h, and then ethylene oxide (9.7 ml, 194.2 mmol) was added. The reaction mixture was allowed to warm to R. T. gradually and stirred overnight. The reaction was quenched by adding saturated aqueous NH4Cl solution and extracted with EtOAc (400 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. After the solvent was removed, the residue was purified by SiO2 column to give 2-chloro-4-fluoro-3-(2- hydroxyethyl)benzonitrile (17.0 g, 66%). 1H NMR (400 MHz, CDCl3, delta in ppm) 7.58 (dd, J = 5.5, 8.6 Hz, IH), 7.10 (t, J= 8.6 Hz, IH), 3.88 (m, 2H), 3.13 (t, J= 6.8 Hz, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 12; 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)benzonitrile; Intermediate 12a; (2R,3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid; <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (60702-69-4) (2.0 g, 12.86 mmol) was mixed together with H-D-Thr-OH (1.84 g, 15.43 mmol) in DMSO (30 mL). K2CO3 (3.73 g, 27.0 mmol) was added to the reaction mixture and stirred at 75 C. for 24 h. The reaction mixture was cooled down to room temperature and poured slowly into a 10% citric acid solution and stirred for 10 min at room temperature. The solution was extracted with EtOAc several times to get the crude product. The crude product was chromatographed with a gradient of hexane EtOAc and then with EtOAc, 100% to get the pure final product 1.8 g): 1H NMR (500 MHz, acetone-d6, delta in ppm) 7.51 (d, J=9 Hz, 1H), 6.95 (s, 1H), 6.82 (d, J=9 Hz, 1H), 5.17 (d, J=9 Hz, 1H), 4.42 (m, 1H), 4.22 (d, J=6 Hz, 1H), 2.34 (s, 3H), 1.28 (d, J=6 Hz, 3H). | ||
Examples 21 and 2221 a 21 b 21 c 2igExample 21 Example 2221a to 21b(2R, 3S)-2-(3-chloro-4-cyanophenylamino)-3-hydroxybutanoic acid21a 21 bTo a solution of D-Threonine (1.7 g, 14.2 mmol) in DMSO (10 mL), K2C03 (1.77 g, 12.8 mmol) followed by <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (21a) (1.0 g, 6.43 mmol) was added at room temperature. The resulting reaction mixture was heated up to 90C and stirred for 16 h. After completion of reaction (by TLC), the reaction mixture was brought to room temperature, diluted with water (10 mL) and extracted with EtOAc (2 20 mL). The combined aqueous layer was acidified by citric acid(pH 3) and extracted with EtOAc (3 chi 20 mL). The combined organic extracts were dried over Na2S04 and concentrated under reduced pressure to afford the acid 21b (0.8 g, crude) as a syrup. The crude material was taken for the next step without purification.TLC: 30% EtOAc/Hexane (Rf: 0.3).1H NMR (500MHz, DMSO-t¾, delta in ppm): 7.52 (d, J= 8.5 Hz, 1H), 6.92 (s, 1H), 6.88 (d, J= 9.0 Hz, 1H), 6.73 (d, J= 7.5 Hz, 1H), 4.21-4.17 (m, 1H), 4.07-4.05 (m, 1H), 3.35 (br s, 1H), 1.14 (d, J= 6.5 Hz, 3H).Mass (ESI): 253 [M+-l] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 33a; (2R,3S)-2-(2,3-Dichloro-4-cyanophenylamino)-3-hydroxybutanoic acid; A 500 mL round bottomed flask was charged with diisopropylamine (11.81 mL, 83.60 mmol) and dry THF (100 mL) then the flask was cooled to -5 C. A 2.5M hexane solution of n-butyllithium (30.87 mL, 77.17 mmol) was then added and the mixture was stirred for 1 h at 0 C. This pre-formed LDA solution was then added via cannula to a -78 C. solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (10 g, 64.31 mmol) in THF (100 mL) and the mixture was stirred for 2 h. To this was added a solution of hexachloroethane (16 g, 67.58 mmol) in dry THF (50 mL), and the mixture was allowed to warm to room temperature and stirred for 17 h before being concentrated to furnish a yellow solid (12.15 g) which was used directly in the next step without further purification. K2CO3 (17.8 g, 128.62 mol) was added to a solution of 2,3-dichloro-4-fluorobenzonitrile (12.15 g, 64.31 mol) and (2R,3S)-2-amino-3-hydroxybutanoic acid (11.43 g, 0.096 mol) in DMSO (150 mL) at room temperature. The reaction mixture was heated to 75 C. and stirred for 16.5 h, then was allowed to cool to room temperature whereupon water (150 mL) and ethyl acetate (150 mL) was added to the mixture which was then partitioned. The aqueous phase was then washed with EtOAc (70 mL) and the acidified with citric acid monohydrate (19g). The aqueous phase was then extracted with EtOAc (180 mL) (×2) and the combined organics were washed with water (80 mL), dried (Na2SO4), filtered and concentrated to furnish the title compound as a brown solid (9g, 48%). 1H NMR (500 MHz, acetone d6, delta in ppm) 7.61 (d, J=8 Hz, 1H), 6.84 (d, J=8 Hz, 1H), 6.02 (d, J=7 Hz, 1H), 4.60-4.57 (m, 1H), 4.39-4.37 (m, 1H) and 1.38 (d, J=7 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | a) 2-Chloro-4-(3,5-dimethyl-1H-pyrazol-1-yl) benzonitrile I58 A mixture of 3,5-dimethyl-1H-pyrazole (5 g, 0.052 mol), NaH (60% dispersion in oil, 2.6 g, 0.065 mol) in DMF (50 ml.) was stirred at RT for 1 h. A solution of 2-chloro-4- fluorobenzonitrile (6.74 g, 0.043 mol) in DMF (50 ml.) was then added and stirring was continued at RT for 1 h. The reaction was quenched with water and the mixture was extracted with EtOAc. The organic extract was concentrated under reduced pressure to give the title compound (11.0 g, 92%) as a yellow solid. LCMS-D: Rt2.58 min; m/z 232.1 [M+H]+. | |
58% | To a cooled suspension of NaH (60% in mineral oil, 6.24 g, 156 mmol) in DMF (100 mL) at 5 C was added 3,5-dimethylpyrazole 30 (15.0 g, 156 mmol) dropwise. After stirring at 5 C for 30 min, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (24.3 g, 156 mmol) was added dropwise, and the whole was stirred at 0 C for 1 h. The mixture was diluted with water. The resulting precipitates were collected by filtration, washed with water and hexane, and dried in air. The resulting solid was purified by silica gel column chromatography (NH silica gel, hexane-EtOAc). The product was recrystallized from hexane-EtOAc to afford 31 (21.0 g, 58%) as a colorless powder. 1H NMR (300 MHz, CDCl3) delta: 2.29 (3H, s), 2.42 (3H, s), 6.07 (1H, s), 7.51 (1H, dd, J = 8.5 and 2.1 Hz), 7.70-7.76 (2H, m). | |
Reference Example 292-chlor?-4- (3, 5-dimethyl-lH-pyrazol-l-yl) benzonitrile [0287] [0288] 3, 5-Dimethylpyrazole (15.0 g) was dissolved in DMF (100 mL) , 60% sodium hydride (6.24 g) was added at 0C under ice- <n="171"/>cooling, and the mixture was stirred for 30 iriin. 2-Chloro-4- fluorobenzonitrile (24.3 g) was added to the mixture, and the mixture was stirred at O0C for 1.5 hr. Water was added to the reaction mixture, and the obtained white precipitate was collected by filtration. The obtained solid was washed with water and hexane, and dried under reduced pressure to give the title compound (33.3 g) . 1H-NMR (CDCl3) delta:2.29 (3H, s), 2.42 (3H, s) , 6.07 (IH, s) , 7.51(IH, dd) , 7.73 (2H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
14.5 g | To a solution of 24 (7.18 g, 29.2 mmol) in DMF (75 mL) was added NaH (60% in mineral oil, 1.40 g, 35.0 mmol) at 0 C. After stirring at 0 C for 30 min, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (9.07 g, 58.3 mmol) was added. The mixture was stirred at 0 C for 2 h, neutralized with saturated aqueous solution of NH4Cl, and extracted twice with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give methyl 4-[1-(3-chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazol-4-yl]oxy}benzoate 26 (14.5 g) as a white solid. | |
Example 305 methyl 4-{ [1- (3-chloro-4-cyanophenyl) -3, 5-dimethyl-lH-pyrazol-4-yl] oxy}benzoate[1246] [1247]To a solution of methyl 4- [ (3, 5-dimethyl-lH-pyrazol-4- yl) oxy]benzoate (3.00 g) synthesized in Reference Example 16 in DMF (25 mL) was added sodium hydride (0.580 g) at 0C, and the mixture was stirred for 30 min. 2-Chloro-4- fluorobenzonitrile (3.79 g) was added to the reaction mixture, and the mixture was stirred for 1 hr. The mixture was mixed with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (hexane-ethyl acetate) to give the title compound (4.08 g) as a white solid. <n="363"/>1H-NMR (CDCl3) delta:2.14 (3H, s) , 2.32 (3H, s) , 3.90 (3H, s) , 6.92 - 6.99 (2H, m) , 7.57 (IH, dd) , 7.77 (IH, d) , 7.80 (IH, d) , 7.98 - 8.06 (2H, m) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 10; [2-Chloro-4-(3-methyl-pyrazol-1-yl)-phenyl]-(5H,11H)-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone; Step a) 2-chloro-4-(3-methylpyrazol-1-yl)benzonitrile: To a cooled (0 C) suspension of sodium hydride (60%in oil; 2.0 g) in dimethylformamide (50 ml) was added 3-methylpyrazole (3.39 g) in portions. After hydrogen gas evolution ceased, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (5.17 g) was added and the mixture was stirred at room temperature for 18 hours.The mixture was poured onto ice, diluted with brine, and the resulting precipitate was collected by filtration. The crude product was dissolved in dichloromethane, filtered through a column of anhydrous sodium magnesium silicate, and crystallized by the addition of hexane. Recrystallization from ethanol gave 4.42 g of product, m.p. 148-150 C. | ||
Step a) 2-Chloro-4-(3-methylpyrazol-1-yl)benzonitrile: To a cooled (0 C.) suspension of sodium hydride (60% in oil; 2.0 g) in dimethylformamide (50 ml) was added 3-methylpyrazole (3.39 g) in portions. After hydrogen gas evolution ceased, <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (5.17 g) was added and the mixture was stirred at room temperature for 18 hours. The mixture was poured onto ice, diluted with brine, and the resulting precipitate was collected by filtration. The crude product was dissolved in dichloromethane, filtered through a column of anhydrous sodium magnesium silicate, and crystallized by the addition of hexane. Recrystallization from ethanol gave 4.42 g of product, m.p. 148-150 C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
4-Piperidinol (6.5 g) was added to a solution of potassium tert-butoxide (7.2 g) in N-methyl-2-pyrrolidinone (25 mL) and stirred at room temperature for 30 min. The reaction mixture was cooled to 0 C and <strong>[60702-69-4]2-chloro-4-fluoro-benzonitrile</strong> (10 g) was added portionwise. The reaction mixture was allowed to reach room temperature and was stirred overnight. LC/MS showed a major peak with the required product mass. The reaction was quenched by addition of ammonium chloride solution and the mixture was partitioned partitioned between ethyl acetate and water. The ethyl acetate was washed with water then brine, dried (MgSO4), filtered and concentrated in vacuo. Crude material was purified by flash chromatography, eluting with 2-5% methanol, 0. 1% triethylamine in dichloromethane to give the title compound (6.6 g). MS (APCI+ve) 236/238; 1H NMR delta (CD3OD) 2.00-2. 29 (4H, m), 3.22-3. 47 (4H, m), 4.85-4. 92 (1H, M), 7.14 (1H, dd), 7.33 (1H, d), 7.76 (1H, d) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 74 (1R,3R)-2-Chloro-4-(3-hydroxy-cyclohexyloxy)-benzonitrile A commercial mixture of cis/trans 1,3-cyclohexanediol (7.77 g, 66.9 mmol) was dissolved in 50 mL anhydrous THF (tetrahydrofuran), under a nitrogen atmosphere, and cooled in an ice/acetone bath. NaH (60% suspension in oil, 2.69 g, 6.725 mmol) was then added and the solution stirred approximately 10 min. Then a solution of <strong>[60702-69-4]2-chloro-4-fluorobenzonitrile</strong> (1.06 gms, 6.79 mmol)(in 20 mL anhydrous THF was added in a slow, steady stream (not dropwise). The cold bath was removed, and allowed to stir at room temperature overnight. The reaction was quenched with approximately 10 mL 5% citric acid and the THF was removed by rotovap. off. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the organic layers were combined. The combined organic layers were washed twice with brine, then dried over magnesium sulfate, filtered and rotovapped. The resulting product was triturated with hexane, and the hexane decanted off. The crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate), and the desired fractions were combined, and the solvent removed. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | Example 23 2-Chloro-4-(3-methyl-cyclopentyloxy)-benzonitrile A 1.0 M solution of potassium t-butoxide in t-butanol (0.3 mL) was added to a 8 mL vial fitted with a septa cap containing 0.3 mL of dry THF and 30 mg (0.3 mmoles) of 3-hydroxy cylcopentanol at 5 C. The mixture was stirred for 0.5 h at 5 C., after which time 0.3 mL of a 1.0 M THF solution of <strong>[60702-69-4]4-fluoro-2-chloro-benzonitrile</strong> was added. The reaction was stirred at 5 C. for 3 h and then allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to 0 C., and quenched with 2 mL of water, diluted with 2 mL of methyl tert-butyl ether. The vial was shaken vigourously and the phases allowed to separate. The aqueous layer was removed with a pipette, and the organic layer washed with another 2 mL of water. The organic phase was dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 36 mg (52%) of the title compound. GC/MS: 235 (M/Z for C13H14ClNO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step A: 2-Chloro-4-(cis-2-hydroxy-cyclopentyloxy)-benzonitrile A 1.0 M solution of potassium t-butoxide in t-butanol (3.2 mL) was added to a 16 mL vial fitted with a septa cap containing 3 mL of dry THF and 300 mg (3 mmoles) of cis-1,2-dihydroxy cylcopentanol at 5 C. The mixture was stirred for 0.5 h at 5 C., after which time 3 mL of a 1.0 M THF solution of <strong>[60702-69-4]4-fluoro-2-chloro-benzonitrile</strong> was added. The reaction was stirred at 5 C. for 3 h and then allowed to warm to room temperature and stirred overnight at room temperature. The reaction mixture was cooled to 0 C., poured into a seperatory funnel containing 15 mL of water, and extracted with 20 mL of methyl tert-butyl ether. The organic phase was washed with water, brine, dried (MgSO4), concentrated in vacuo, and the residue purified by reverse phase HPLC (Shimadzu) to give 185 mg 2-Chloro-4-(cis-2-hydroxy-cyclopentyloxy)-benzonitrile. GC/MS: 237 (M/Z for C13H14ClNO). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 125℃; | Intermediate 10Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (100 mg, 0.47 mmol), 2-chloro-4- fluoro-benzonitrile (72.5 mg, 0.47 mmol) and N,N-diisopropylethylamine (0.160 ml, 1.23 mmol) were dissolved in 10 ml of DMF and the reaction mixture was stirred at 125 0C overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography (Isolute silica gel cartride: 5g; eluent: ethyl acetate). 125 m£ (0.36 mmol) of the desired compound were obtained. |
Tags: 60702-69-4 synthesis path| 60702-69-4 SDS| 60702-69-4 COA| 60702-69-4 purity| 60702-69-4 application| 60702-69-4 NMR| 60702-69-4 COA| 60702-69-4 structure
[ 796600-15-2 ]
2-Chloro-4-fluoro-3-methylbenzonitrile
Similarity: 0.88
[ 796600-15-2 ]
2-Chloro-4-fluoro-3-methylbenzonitrile
Similarity: 0.88
[ 796600-15-2 ]
2-Chloro-4-fluoro-3-methylbenzonitrile
Similarity: 0.88
[ 796600-15-2 ]
2-Chloro-4-fluoro-3-methylbenzonitrile
Similarity: 0.88
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P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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