3-(1,1-difluoroethyl)aniline

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the general method described in example 293, 3-(1,1-difluoro-ethyl)-aniline [R. O. Neri, J. G. Topliss, Ger. Offen. (1972), DE 2130452 19721221 CAN 78:124310] was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid followed by treatment with triethyl orthoformate, iron and acetic acid and subsequent alkaline hydrolysis. The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex followed by hydrolytic workup and the title compound was obtained as a white crystalline solid. Mp. 104-108° C. (H2O), MS: m/e=238 (M+). The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the general method described in example 293, 3-(1,1-difluoro-ethyl)-aniline [R. O. Neri, J. G. Topliss, Ger. Offen. (1972), DE 2130452 19721221 CAN 78:124310] was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid followed by treatment with triethyl orthoformate, iron and acetic acid and subsequent alkaline hydrolysis. The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex followed by hydrolytic workup and the title compound was obtained as a white crystalline solid. Mp. 104-108° C. (H2O), MS: m/e=238 (M+). The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the general method described in example 293, 3-(1,1-difluoro-ethyl)-aniline [R. O. Neri, J. G. Topliss, Ger. Offen. (1972), DE 2130452 19721221 CAN 78:124310] was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid followed by treatment with triethyl orthoformate, iron and acetic acid and subsequent alkaline hydrolysis. The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex followed by hydrolytic workup and the title compound was obtained as a white crystalline solid. Mp. 104-108° C. (H2O), MS: m/e=238 (M+). The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the general method described in example 293, 3-(1,1-difluoro-ethyl)-aniline [R. O. Neri, J. G. Topliss, Ger. Offen. (1972), DE 2130452 19721221 CAN 78:124310] was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid followed by treatment with triethyl orthoformate, iron and acetic acid and subsequent alkaline hydrolysis. The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex followed by hydrolytic workup and the title compound was obtained as a white crystalline solid. Mp. 104-108° C. (H2O), MS: m/e=238 (M+). The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 2.5 g (15.9 mmol) of 3-(1,1-difluoroethyl)aniline and 2.8 g (15.9 mmol) of bis(2-chloroethyl)amine in 20 mL of chlorobenzene is refluxed overnight. After cooling to room temperature, diethyl ether is added and precipitation occurs. The solid is filtered, washed with diethyl ether and dried under reduced pressure to give 3.8 g (90%) of 1-[3-(1,1-difluoro-ethyl)phenyl]piperazine, hydrochloride as a white solid. is refluxed overnight precipitation The solid is filtered washed with diethyl ether dried under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3.0 g (16 mmol) of 1-(1,1-difluoroethyl)-3-nitrobenzene, 18.0 g (80 mmol) of tin chloride dihydrate and 50 mL of ethanol is refluxed for one hour. The mixture is slowly poured on cooled water. The pH is adjusted to 7 by addition of an aqueous 10N solution of sodium hydroxide, then adjusted to 9 by addition of an aqueous saturated solution of sodium hydrogen carbonate. The product is extracted 4 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue (2.2 g) is purified over 100 g of silica gel (eluant heptane/ethyl acetate 2/1) to give 1.7 g (68%) of 3-(1,1-difluoroethyl)aniline as an oil. is refluxed for one hour The mixture is slowly poured The product is extracted 4 times with ethyl acetate dried over magnesium sulfate filtered concentrated under reduced pressure The oily residue (2.2 g) is purified over 100 g of silica gel (eluant heptane/ethyl acetate 2/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3.0 g (16 mmol) of 1-(1,1-difluoroethyl)-3-nitrobenzene, 18.0 g (80 mmol) of tin chloride dihydrate and 50 mL of ethanol is refluxed for one hour. The mixture is slowly poured on cooled water. The pH is adjusted to 7 by addition of an aqueous 10N solution of sodium hydroxide, then adjusted to 9 by addition of an aqueous saturated solution of sodium hydrogen carbonate. The product is extracted 4 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue (2.2 g) is purified over 100 g of silica gel (eluant heptane/ethyl acetate 2/1) to give 1.7 g (68%) of 3-(1,1-difluoroethyl)aniline as an oil. is refluxed for one hour The mixture is slowly poured The product is extracted 4 times with ethyl acetate dried over magnesium sulfate filtered concentrated under reduced pressure The oily residue (2.2 g) is purified over 100 g of silica gel (eluant heptane/ethyl acetate 2/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Dissolve the nitro compound obtained in Step 1 (870 mg, 4.8 mmol) in ethanol (10 mL), add iron powder (1.3 g, 23.3 mmol), concentrated aqueous HCl (37%, 2.7 mL), stir the reaction at room temperature for 2 hrs. After the reaction, carefully neutralize the mixture with NaOH solution. Filter off the solid, pour the filtrate to ice water (50 mL), extract with EtOAc (15 mL×3), combine the organic layers, wash with brine (100 mL) and dry over anhydrous Na2SO4. Concentrate under reduced pressure to get the crude product (760 mg) which is used without further purification. the reaction at room temperature for 2 hrs After the reaction Filter off the solid pour the filtrate to ice water (50 mL) extract with EtOAc (15 mL×3) wash with brine (100 mL) dry over anhydrous Na2SO4 Concentrate under reduced pressure

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.200 g, 0.537 mmol), thionyl chloride (2.0 mL), 3-(1,1-difluoroethyl)aniline (Intermediate-39, 0.088 g, 0.537 mmol), THF (5.0 mL) and DIPEA (3.0 mL), benzene (2 mL). The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 1.97 (s, 3H), 2.24 (s, 3H), 3.11 (s, 2H), 7.25-7.32 (m, 3H), 7.41-7.49 (m, 3H), 7.61 (d, J=7.8 Hz, 1H), 8.07 (s, 1H), 9.05 (m, 1H), 9.87 (s, 1H), 10.95 (s, 1H); MS [M−H]−: 513.42. The title compound was prepared The obtained crude product was purified by column chromatography on neutral alumina eluting with 0.7-1.0% MeOH

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.273 g, 0.736 mmol), thionyl chloride (2.0 mL), 3-(1,1-difluoroethyl)aniline (Intermediate-39, 0.120 g, 0.736 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.025 g of the desired product. 1HNMR (DMSO d6): δ 1.57 (s, 6H), 1.97 (t, J=19.2 Hz, 3H), 3.10 (s, 2H), 7.26-7.32 (m, 3H), 7.35-7.48 (m, 3H), 7.62 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 9.85 (s, 1H), 11.00 (s, 2H); MS [M−H]−: 513.14. The title compound was prepared The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a solution of 1-(1,1-difluoroethyl)-3-nitrobenzene (1.00 g, 5.34 mmol) in methanol (5.0 mL) was added Pd/C (catalytic amount) and ethylene diamine (catalytic amount). The reaction mixture was subjected for hydrogenation in Parr apparatus under 30 psi for 5-6 h. The excess of solvent was removed under vacuum to afford 0.800 g of the desired product. 1HNMR (DMSO-d6): δ 1.88 (d, J=18.0 Hz, 3H), 3.74 (s, 1H), 7.72 (t, J=8.4 Hz, 1H), 6.81 (s, 1H), 6.87 (d, J=7.8 Hz, 1H), 7.19 (t, J=7.8 Hz, 1H). The excess of solvent was removed under vacuum

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: Following the general method described in example 293, 3-(1,1-difluoro-ethyl)-aniline [R. O. Neri, J. G. Topliss, Ger. Offen. (1972), DE 2130452 19721221 CAN 78:124310]was reacted with triethyl orthoformate, ethyl nitroacetate and acetic acid followed by treatment with triethyl orthoformate, iron and acetic acid and subsequent alkaline hydrolysis. The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex followed by hydrolytic workup and the title compound was obtained as a white crystalline solid. Mp. 104-108° C. (H2O), MS: m/e=238 (M+). The isolated acid was directly reduced according to example 264, by reaction with BH3 THF complex