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CAS No. : | 135748-35-5 | MDL No. : | MFCD06659464 |
Formula : | C7H2ClF2N | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | OMVDTUXOHXQKML-UHFFFAOYSA-N |
M.W : | 173.55 | Pubchem ID : | 11275302 |
Synonyms : |
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Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302 | 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 |
---|---|---|
With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; N-methyl-acetamide; methanol; water; mineral oil; | EXAMPLE 25 4-Chloro-2-[(1R)-3-(cyclopropylamino)-1-phenylpropyl]oxy}-5-fluorobenzonitrile oxalate (R)-alpha-(2-Chloroethyl)benzenemethanol (341 mg, 2 mmol) was dissolved in tetrahydrofuran (10 ml) and treated with sodium hydride as a 60% suspension in mineral oil (480 mg, 3 mmol) followed after 10 minutes by <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (347 mg, 2 mmol). The mixture was stirred at room temperature for 18 h before being treated with methanol (1 ml) and then water (10 ml). The tetrahydrofuran was then removed via heating the vessel to 80 C. and applying a nitrogen stream. Once the tetrahydrofuran was evaporated the residue was extracted into dichloromethane, dried over magnesium sulphate and concentrated in vacuo. The resultant material was re-dissolved into dimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03 mmol), triethylamine (565 mul, 4.06 mmol) and cyclopropylamine (114 mg, 2 mmol) before being heated to 60 C. for 5 days. The mixture was filtered and purified via RPHPLC on the crude reaction material. The purified compound was then treated with 50% saturated oxalic acid in ether to produce 74 mg of a white powder that was collected via filtration. MS APCI+ve m/z 345/347 [(M+H)+]. 1H NMR 400 MHz (d6-DMSO) 7.97-7.87 (m, 1H), 7.53-7.25 (m, 6H), 5.69 (m, 1H), 3.28-3.07 (m, 2H), 2.80-2.68 (m, 1H), 2.45-2.29 (m, 1H), 2.29-2.12 (m, 1H), 0.85-0.74 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.6% | With oxalic acid; | EXAMPLE 26 4-Chloro-2-[(1R)-3-(cyclopropylamino)-1-(3-furanyl)propyl]oxy}-5-fluorobenzonitrile oxalate Prepared by the method of Example 25 using (R)-alpha-(2-chloroethyl)-3-furanmethanol (321 mg, 2 mmols) and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (347 mg, 2 mmols) initially before converting into the title compound via in situ conversion to the iodo compound and treatment with cyclopropylamine. The free base was treated with a 50% saturated solution of oxalic acid in ether. The resultant white solid was collected via filtration to yield the title compound (14 mg, 1.6%). MS APCI+ve m/z 335/337 [(M+H)+]. 1H NMR 400 MHz (d6-DMSO) 8.01 (d, 1H), 7.70 (s, 1H), 7.70 (s, 1H), 7.59 (d, 1H), 6.53 (s, 1H), 5.72 (t, 1H), 3.15-2.99 (m, 2H), 2.97-2.87 (m, 1H), 2.40-2.26 (m, 1H), 2.24-2.09 (m, 1H), 0.78-0.66 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With oxalic acid; | EXAMPLE 27 4-Chloro-2-[(1R)-3-(cyclopropylamino)-1-(3-thienyl)propyl]oxy}-5-fluorobenzonitrile oxalate Prepared by the method of Example 25 using (R)-alpha-(2-chloroethyl)-3-thiophenemethanol (Example 74(d)) and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> initially before converting into the title compound via i7l situ conversion to the iodo compound and treatment with cyclopropylamine The free base was treated with a 50% saturated solution of oxalic acid in ether. The resultant white solid was collected via filtration to yield the title compound (24 mg, 3%). MS APCI+ve m/z 351 [(M+H)+]. 1H NMR 400 MHz (d6-DMSO) 8.02 (d, 1H), 7.60 (s, 2H), 7.50 (d, 1H), 7.14 (d, 1H), 5.83 (t, 1H), 3.14-2.99 (m, 2H), 2.76-2.62 (m, 1H), 2.42-2.29 (m, 2H), 2.27-2.13 (m,2H), 0.84-0.63 (m, 4H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; water; N,N-dimethyl-formamide; mineral oil; | b 4-Chloro-5-fluoro-2-({(1R)-1-(3-furanyl)-3-[(2-methoxyethyl)amino]propyl}oxy)benzonitrile oxalate (R)-alpha-(2-Chloroethyl)-3-furanmethanol (100 mg, 0.62 mmol) was dissolved in tetrahydrofuran (5 ml) at room temperature. To this solution was added sodium hydride as a 60% suspension in mineral oil (3 7 mg, 0.93 mmol) and the mixture was stirred for 10 minutes before solid <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (107.6 mg, 0.62 mmol) was added in one portion. The resultant mixture was stirred for 1 h before water (2 ml) was added and the mixture concentrated in vacuo. The residues were partitioned between dichloromethane and water. The organics were collected, dried over magnesium sulphate, filtered and concentrated to dryness in vacuo. The resultant residue was dissolved in N,N-dimethylformamide (2 ml) and treated with sodium iodide (93 mg, 0.62 mmol), triethylamine (172 mul, 1.24 mmol) and 2-methoxyethanamine (107 mul, 1.24 mmol) before being heated to 60 C. for 72 h. After being allowed to cool the mixture was filtered and purified via reverse phase HPLC to give the title compound as a free base which was treated with a 50% saturated solution of oxalic acid in ether. The resultant white solid was collected via filtration to yield the title compound (61 mg, 28%). MS APCI+ve m/z 353/355 [(M+H)+]. 1H NMR 300 MHz (d6-DMSO) 8.02 (1H, d), 7.82 (1H, s), 7.70 (1H, s), 7.59 (1H, s), 5.72 (2H, t), 3.57 (2H, m), 3.31 (3H, s), 3.16 (2H, m), 3.09-2.98 (2H, b), 2.37 (1H, bm), 2.27 (1H br m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
e 4-Chloro-2-[[(1R)-3-chloro-1-(3-thienyl)-propyl]oxy]-5-fluoro-benzonitrile Using the product of step (d) (322 mg, 1.84 mmol), <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (320 mg, 1.84 mmol) and the procedure described in Example 72(c), the title compound was prepared (540 mg, 89%). 1H NMR 300 MHz (CDCl3) 7.35-7.40 (1H, m), 7.29-7.34 (1H, m), 7.25-7.28 (1H, m), 7.11 (1H, dt), 6.95-6.99 (1H, m), 5.54-5.63 (1H, m), 3.78-3.90 (1H, m), 3.55-3.66 (1H, m), 2.53-2.65 (1H, m), 2.21-2.35 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
b 2-[[(1R)-3-Azido-1-(3-isoxazolyl)propyl]oxy]-4-chloro-5-fluorobenzonitrile The product from step (a) (0.1 g) and 2,5-difluoro-4-chloro-benzonitrile (0.18 g) and sodium hydride (60% dispersion in oil, 0.035 g) were subjected to the procedure described in Example 90(a) to afford the product as a gum (0.15 g). MS APCI+ve m/z 294 [(M-28)+]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium iodide; oxalic acid; triethylamine; In tetrahydrofuran; methanol; water; N,N-dimethyl-formamide; mineral oil; | EXAMPLE 25 4-Chloro-2-[1-ethyl-3-[(2-methoxyethyl)amino]propoxy]-5-fluorobenzonitrile Oxalate 1-Chloro-3-pentanol (1 g, 8.15 mmol) was dissolved in tetrahydrofuran (20 ml) and treated with sodium hydride as a 60% suspension in mineral oil (480 mg, 12.2 mmol) followed after 10 minutes by <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (1.41 g, 8.15 mmol). The mixture was stirred at room temperature for 18 h before being treated with methanol (1 ml) and then water (10 ml). The tetrahydrofuran was then removed via heating the vessel to 80 C. and applying a nitrogen stream. Once the tetrahydrofuran was evaporated off, the residue was extracted into dichloromethane, dried over magnesium sulphate and concentrated in vacuo. The resultant material was re-dissolved into N,N-dimethylformamide (8 ml) and treated with sodium iodide (305 mg, 2.03 mmol), triethylamine (565 mul, 4.06 mmol) and 2-methoxyethanamine (352 mul, 4.06 mmol) before being heated to 60 C. for 5 days. The mixture was filtered and purified via RP-HPLC on the crude reaction material. The purified compound was then treated with 50% saturated oxalic acid in ether to produce a white powder which was collected via filtration. (378 mg, 15%). MS APCI+ve m/z 315 ([M+H]+). 1H NMR 300 MHz (d6-DMSO) 8.03 (1H, d), 7.65 (1H, d), 4.66 (1H, m), 3.56 (2H, m), 3.30 (3H, s), 3.14-3.06 (2H, m), 3.06-2.97 (2H, m), 2.03 (2H, m), 1.65 (2H, m), 0.92 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | In ethyl acetate; N-ethyl-N,N-diisopropylamine; | a 4-Chloro-5-Fluoro-2-[[(1R)-3-Hydroxy-1-Phenylpropyl]Amino]Benzonitrile <strong>[135748-35-5]4-Chloro-2,5-difluorobenzonitrile</strong> (1.0 g, 5.76 mmol) and (gamma1R)-gamma-aminobenzenepropanol (870 mg, 5.76 mmol) were heated in N,N-diisopropylethylamine (740 mg, 5.76 mmol) at 140 C. for 30 h. The reaction mixture was partitioned between ethyl acetate and water and the organic layer separated. The aqueous layer was further extracted with ethyl acetate, and the extracts combined and dried over anhydrous sodium sulphate. The solvent was evaporated and the residue purified by flash chromatography using 10% ethyl acetate/isohexane as eluent to give the title product (260 mg, 15%). MS APCI+vem/z305 ([M+H]+). 1H NMR 300 MHz (CDCl3) 7.33 (5H, m), 7.15 (1H, d), 6.43 (1H, d), 5.98 (1H, d), 4.61 (1H, d), 3.79 (2H, m), 2.11 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | a [3-(5-Chloro-2-cyano-4-fluorophenoxy)hexyl]methylcarbamic Acid, 1,1-dimethylethyl Ester The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxyhexyl)methylcarbamic acid, 1,1-dimethylethyl ester and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> in N,N-dimethylformamide. 1H NMR 300 MHz (CDCl3) 7.33 (1H, d), 6.99 (1H, bs), 4.33 (1H, m), 3.34 (2H, m), 2.85 (3H, s), 1.95 (2H, m), 1.70 (2H, m), 1.41 (11H, m), 0.95 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | a [3-(5-Chloro-2-cyano-4-fluorophenoxy)pentyl]methylcarbamic acid, 1,1-dimethylethyl Ester The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> in N,N-dimethylformamide. 1H NMR 300 MHz (CDCl3) 7.33 (1H, d), 6.99 (1H, s), 4.26 (1H, m), 3.34 (2H, m), 2.85 (3H, s), 1.96 (2H, m), 1.74 (2H, m), 1.41 (9H, s), 0.99 (3H, t). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | a [3-(5-Chloro-2-cyano-4-fluorophenoxy)-4,4,4-trifluorobutyl]methylcarbamic acid, 1,1-dimethylethyl Ester The subtitle compound was prepared according to the method of Example 3 step (b) using methyl-(4,4,4-trifluoro-3-hydroxybutyl)carbamic acid, 1,1-dimethylethyl ester and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> in N,N-dimethylformamide. 1H NMR 300 MHz (CDCl3) 7.37 (1H, d), 7.30 (1H, bm), 4.62 (1H, m), 3.80 (1H, bm), 3.20 (1H, bm), 2.86 (3H, s), 2.16 (2H, m), 1.40 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | b [3-(5-Chloro-2-cyano-4-fluorophenoxy)-4-pentenyl]methylcarbamic Acid, 1,1-dimethylethyl Ester The subtitle compound was prepared according to the method of Example 3 step (b) using (3-hydroxy-4-pentenyl)methylcarbamic acid, 1,1-dimethylethyl ester and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> in N,N-dimethylformamide. 1H NMR 300 MHz (CDCl3) 7.33 (1H, d), 7.00 (1H, d), 5.85 (1H, m), 5.30 (2H, m), 4.65 (1H, m), 3.35-3.51 (2H, m), 2.87 (3H, s), 1.97-2.10 (2H, m), 1.41 (9H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | b [3-(5-Chloro-2-cyano-4-fluorophenoxy)-3-cyclopentylpropyl]methylcarbamic Acid, 1,1-dimethylethyl Ester The subtitle compound was prepared according to the method of Example 3 step (b) using (3-cyclopentyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> in N,N-dimethylformamide. 1H NMR 300 MHz (CDCl3) 7.32 (1H, d), 7.04 (1H, bm), 4.28 (1H, m), 3.35 (2H, bm), 2.83 (3H, s), 2.28 (1H, m), 1.95 (2H, q), 1.50-1.80 (6H, m), 1.42 (9H, s), 1.26-1.45 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | 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. | |
Reference Example 1 A chloroform-EtOH solution of <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> was saturated with hydrogen chloride by bubbling, stirred at ambient temperature for 16 hours, and then concentrated to yield an imidate, which was stirred together with ammonium carbonate in EtOH at ambient temperature for 3 days to yield 4-chloro-2,5-difluorobenzenecarboxamidine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | With sodium hydride; In N,N-dimethyl-formamide; mineral oil; at 60℃; for 2h;Inert atmosphere; | A mixture of the (R)-alpha-(2-azidoethyl) benzenemethanol (8 g, 0.045 mol) and <strong>[135748-35-5]4-chloro-2,5-difluorobenzonitrile</strong> (7.83 g, 0.045 mol) in dry dimethylformamide (70 ml) under nitrogen atmosphere was treated with sodium hydride (60% dispersion in oil, 1.81 g, 0.045 mol). The mixture was stirred and heated to 60 C for 2 h, then quenched with water (500 ml). The products were extracted into diethyl ether (2 x 300 ml). The combined extracts were dried over magnesium sulphate, filtered and concentrated to give an oil. The crude material was purified on silica using 20% ether in isohexane to afford the title compound as a colourless oil (9.4 g, 80%). 1H NMR 300MHz (CDCl3) 7.43-7.3 (6H, m), 6.84 (1H, dd), 5.29 (1H, dd), 3.7-3.42 (2H, m), 2.4-2.04 (2H, m). |
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