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Structure of 886501-33-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 886501-33-3 |
Formula : | C7H2ClF2N |
M.W : | 173.55 |
SMILES Code : | N#CC1=C(F)C=CC(F)=C1Cl |
MDL No. : | MFCD06660175 |
InChI Key : | AREWFYUZFHLWNH-UHFFFAOYSA-N |
Pubchem ID : | 17750746 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H301-H311-H331 |
Precautionary Statements: | P261-P264-P270-P271-P280-P302+P352-P304+P340-P310-P330-P361-P403+P233-P405-P501 |
Class: | 6.1 |
UN#: | 3276 |
Packing Group: | Ⅲ |
* 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 acetic anhydride; for 16.0h;Heating / reflux; | EXAMPLE 54 4-Chloro-3-fluoro-10-methyl-9H-imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepine hydrochloride (1:1); a) 2-Chloro-3-fluoro-6-(4-methyl-imidazol-1-yl)-benzonitrile; A solution of 2-chloro-3,6-difluoro-benzaldehyde (16.5 g, 93 mmol) in ethanol (80 ml) was treated with hydroxylamine HCl (7.80 g, 112 mmol) and sodium acetate (9.20 g, 112 mmol). The mixture was heated under reflux for 16 h, then the solvent was evaporated, and the residue stirred with water. The precipitate was filtered and dried to afford 2-chloro-3,6-difluoro-benzaldehyde oxime. It was dissolved in acetic anhydride (140 ml) and refluxed for 16 h, then the mixture was evaporated to afford 2-chloro-3,6-difluoro-benzonitrile as a light brown liquid (10.6 g, 65%). In analogy to example 5a, this compound was reacted with 4-methylimidazole and potassium carbonate for 20 h at 90 C. Aqueous workup, extraction with Ethyl acetate followed by chromatography (SiO2, dichloromethane:methanol=100:0 to 97:3) afforded the title compound as a white solid (yield: 6%). MS: m/e=336.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2,3-dichIoro-iV-hydroxybenzamidineTo <strong>[886501-33-3]2-chloro-3,6-difluorobenzonitrile</strong> (0.36 g, 2.08 mmol) in 95 % EtOH (4 mL) was added H2NOH-HCl (0.32 g, 4.56 mmol) and Et3N (0.66 mL, 4.77 mmol). The mixture was stirred at 75 0C for 18 h. After cooling to rt, the mixture was filtered. The filtrate was diluted with water (3 mL), and neutralized to pH 7 with aq. cone. HCl. The solvents were partially evaporated under reduced pressure, and the residue was filtered, washed with water, and dried under vacuum. The residue (0.4Ig) was used in the next step without further purification. LC-MS: Rt = 0.34 min, ES+=207.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To <strong>[886501-33-3]2-chloro-3,6-difluorobenzonitrile</strong> (0.36 g, 2.08 mmol) in 95 % EtOH (4 mL) was added H2NOH-HCl (0.32 g, 4.56 mmol) and Et3N (0.66 mL, 4.77 mmol). The mixture was stirred at 75 0C for 18 h. After cooling to rt, the mixture was filtered. The filtrate was diluted with water (3 mL), and neutralized to pH 7 with aq. cone. HCl. The solvents were partially evaporated under reduced pressure, and the residue was filtered, washed with water, and dried under vacuum. The residue (0.41 g) was used in the next step without further purification. LC-MS: tR = 0.34 min, ES+ = 207.02. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | at 130℃; for 24.0h; | A mixture of 2-chloro-3,6-difluorobenzamide and 1,3-dichloroacetone was stirred for 24 h at 130 0C. Purification of the residue by FC (EtOAc/heptane 10:90) yielded the title compound (0.30 g, 43%). LC-MS: tR = 0.97 min; ES+: 264.07. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2-ChIoro-3,6-difluorobenzoαitriIe2-Chloro-3,6-difluorobenzamide (0.80 g, 4.18 mmol) in POCl3 (12 mL) was heated for 2 h at 95 0C. The sol. was cooled and the excess of POCl3 was removed by distillation under reduced pressure. The residue was diluted with EtOAc and aq. 10% K2CO3 was cautiously added. The layers were separated and the org. phase was washed with water (2x), and brine. The org. extracts were dried over MgSO4, filtered, and the solvent were removed under reduced pressure to yield the title compound (0.46 g) that was not further purified. | ||
2-Chloro-3,6-difluorobenzamide (0.80 g, 4.18 mmol) in POCl3 (12 mL) was heated for 2 h at 95 0C. The sol. was cooled and the excess of POCl3 was removed by distillation under reduced pressure. The residue was diluted with EtOAc and aq. 10% K2CO3 was cautiously added. The layers were separated and the org. phase was washed with water (2x), and brine. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to yield the title compound (0.46 g) that was not further purified. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With sodiosulfanylsodium; In N,N-dimethyl-formamide; at 20℃; for 0.75h;Inert atmosphere; Cooling with ice; | A flask containing a solution of 2-chloro-3,6-difluoro-benzonitrile (2.0 g, 1 1.5 mmol) in DMF (10 mL) was sparged with nitrogen, cooled in ice, and treated with sodiosulfanylsodium (944 mg, 12.1 mmol). The yellow suspension was stirred and slowly allowed to warm to ambient temperature. After 45 min, the reaction mixture was diluted with 1 M NaOH, washed with 2 portions of dichloromethane, acidified to pH 2 with cone. HC1, and extracted with 2 portions of dichloromethane. The dichloromethane was washed with two portions of brine, dried over MgS04, filtered, and evaporated to yield 2-chloro-3-fluoro-6-sulfanyl-benzonitrile (1 .44 g, 7.7 mmol, 67% yield) as a waxy pale yellow solid, m/z (ES-API-neg) [M-H] = 186. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.32 g | With hydrazine hydrate; In ethanol; for 4.0h;Reflux; | Example 154A 4-Chloro-5-fluoro-1H-indazol-3-amine <strong>[886501-33-3]2-chloro-3,6-difluorobenzonitrile</strong> (purity 60%, 0.42 g, 1.45 mmol) was dissolved in ethanol (12 mL) and treated with hydrazine hydrate (0.49 g, 9.68 mmol). After stirring at reflux for 4 h, the mixture was cooled to RT and concentrated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, concentrated in vacuo and dried to yield the title compound (0.32 g, 99% of theory) in a purity of 85%. LC-MS (Method 1B): Rt=0.63 min, MS (ESIPos): m/z=186 [M+H]+ |
With hydrazine hydrate; In ethanol; for 4.0h;Reflux; | <strong>[886501-33-3]2-chloro-3,6-difluorobenzonitrile</strong> (purity 60%, 0.42 g, 1.45 mmol) was dissolved in ethanol (12 mL) and treated with hydrazine hydrate (0.49 g, 9.68 mmol). After stirring at reflux for 4 h, the mixture was cooled to RT and concentrated in vacuo. The residue was dissolved in a mixture of water and ethyl acetate. The aqueous layer was extracted once more with ethyl acetate. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, concentrated in vacuo and dried to yield the title compound (0.32 g, 99% of theory) in a purity of 85%. LC-MS (Method IB): Rt = 0.63 min, MS (ESIPos): m/z = 186 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.42 g | With [bis(acetoxy)iodo]benzene; ammonium acetate; sodium dodecyl-sulfate; In water; at 70℃; for 0.5h; | Example 153A 2-Chloro-3,6-difluorobenzonitrile A mixture of 2-chloro-3,6-difluorobenzaldehyde (1.51 g, 8.5 mmol), sodium lauryl sulfate (0.49 g, 1.71 mmol), (Diacetoxyiodo)benzene (4.12 g, 12.8 mmol) and ammonium acetate (3.29 g, 42.7 mmol) in water (9 mL) was stirred at 70 C. for 30 min After extraction with dichloromethane, the organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification via preparative HPLC (Method 1A) afforded the title compound (0.42 g, 28% of theory) in a purity of 60%. GC-MS (Method 1G): Rt=2.80 min, MS (ESIPos): m/z=175 [M+H]+ |
With [bis(acetoxy)iodo]benzene; ammonium acetate; sodium dodecyl-sulfate; In water; at 70℃; for 0.5h; | A mixture of 2-chloro-3,6-difluorobenzaldehyde (1.51 g, 8.5 mmol), sodium lauryl sulfate (0.49 g, 1.71 mmol), (Diacetoxyiodo)benzene (4.12 g, 12.8 mmol) and ammonium acetate (3.29 g, 42.7 mmol) in water (9 mL) was stirred at 70 C for 30 min. After extraction with dichloromethane, the organic phase was dried over magnesium sulfate and concentrated in vacuo. Purification via preparative HPLC (Method 1A) afforded the title compound (0.42 g, 28% of theory) in a purity of 60%. GC-MS (Method 1G): Rt = 2.80 min, MS (ESIPos): m/z = 175 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With sodium sulfide; In N,N-dimethyl-formamide; at 20℃; for 3.0h;Inert atmosphere; Cooling with ice; | A vial containing a clear solution of 2-chloro-3,6-difluoro-benzonitrile (1.00 g, 5.8 mmol) in]V Ndimethylformamide (DMF, 5 mL) was flushed with nitrogen, cooled in ice, and treated with sodium sulfide (472 mg, 6.1 mmol). The stirred yellow suspension was allowed to slowly warm to ambient temperature. After 3 hours, the reaction mixture was treated with dimethyl sulfate (0.60 rnL, 6.3 mmol). The yellow suspension turned milky white. The reaction mixture was partitioned between EtOAc and water. The EtOAc was washed with brine, dried over MgSO4, filtered, and evaporated. The residue was chroniatographed on a Biotage 50 g SNAP column with a 10% to 40% EtOAc/hexane gradient to afford 2-chloro-3-fluoro-6- (rnethylthio)benzonitrile (430 mg, 2.13 rnmol, 37% yield) as a fluffy white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | A vial containing a clear solution of 2-chloro-3,6-difluoro-benzonitrile (1.00 g, 5.8 mmol) in N, N- dimethylformamide (DMF, 5 mL) was flushed with nitrogen, cooled in ice, and treated with sodium sulfide (472 mg, 6.1 mmol). The stirred yellow suspension was allowed to slowly warm to ambient temperature. After 3 hours, the reaction mixture was treated with dimethyl sulfate (0.60 mL, 6.3 mmol). The yellow suspension turned milky white. The reaction mixture was partitioned between EtOAc and water. The EtOAc was washed with brine, dried over MgS04, filtered, and evaporated. The residue was chromatographed on a Biotage 50 g SNAP column with a 10% to 40% EtOAc/hexane gradient to afford 2-chloro-3-fluoro-6- (methylthio)benzonitrile (430 mg, 2.13 mmol, 37% yield) as a fluffy white solid |
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