2-fluoro-4-formylbenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Methylimidazole (15.88 mL, 0.199 mol), dissolved in anhydrous THF (500 mL) in flame-dried glassware under Ar, was cooled to −78° C. and treated with n-butyl lithium (1.6M in hexane)(124 mL, 0.199 mol) via syringe. After stirring for 1 hr chlorotriethylsilane (33.4 mL, 0.199 mol) was added and the reaction mixture was left to warm to ambient temperature overnight. The THF was removed in vacuo with gentle warming, and the residue was redissolved in dry THF (500 mL), cooled to −78° C., and treated with sec-butyl lithium (1.3M in cyclohexane) (153 mL, 0.199 mol) dropwise. After 1 hr this solution was cannulated into a solution of 2-fluoro-4-formylbenzonitrile (27 g, 0.181 mol) in THF (200 mL). After 15 min the cooling bath was removed, the mixture was stirred for 2 hr at ambient temperature, then was quenched with saturated NH4Cl solution. After 15 min 10% HCl was added to pH 3. After 0.5 hr the THF was removed in vacuo, the mixture was made basic with solid Na2CO3 and extracted with EtOAc (3×200 mL). The organics were combined, washed with 10% HCl (3×), the aqueous acidic layers combined, made basic with solid Na2CO3, extracted with EtOAc (3×), the organics combined, washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound. was added the reaction mixture was left to warm to ambient temperature overnight The THF was removed in vacuo with gentle warming the residue was redissolved in dry THF (500 mL) cooled to −78° C. After 15 min the cooling bath was removed was quenched with saturated NH4Cl solution After 15 min 10% HCl was added to pH 3 After 0.5 hr the THF was removed in vacuo extracted with EtOAc (3×200 mL) washed with 10% HCl (3×) extracted with EtOAc (3×) washed with brine dried (MgSO4) Filtration and concentration to dryness

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-4-hydroxymethylbenzonitrile (10 g, 0.066 mol) and triethylamine (32.3 mL, 0.231 mol) were dissolved in CH2Cl2 (100 mL)-DMSO (20 mL) at <5° C. with stirring and treated dropwise with a solution of pyridine.SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL) maintaining the reaction mixture temperature at <10° C. The reaction mixture was stirred at 5° C. for 1 hr after the addition, then at 20° C. for 1 hr, then partitioned between CH2Cl2 and H2O. The organic layer was separated, washed well with H2O, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after purification by chromatography (silica gel, hexane: EtOAc, 3:1). The reaction mixture was stirred at 5° C. for 1 hr after the addition partitioned between CH2Cl2 and H2O The organic layer was separated washed well with H2O, brine dried (Na2SO4) Filtration and concentration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of the product from Step A (970 mg, 6.5 mmol) and (carbethoxymethylene)triphenylphosphorane (2.3 g, 6.5 mmol) was heated at reflux in 50 mL of toluene overnight. The reaction was concentrated in vacuo, triturated with ether, and filtered. The filtrate was concentrated in vacuo, and purified by flash column chromatography on silica gel (15% EtOAc/hexane) to yield the desired product as a white solid. The reaction was concentrated in vacuo triturated with ether filtered The filtrate was concentrated in vacuo purified by flash column chromatography on silica gel (15% EtOAc/hexane)

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 4-iodo-1-trityl-1H-imidazole (5.00 g, 11.5 mmol) in anhydrous CH2Cl2 (30 mL) was added a 3.0M solution of ethylmagnesium bromide (6.58 mL, 19.7 mmol) with stirring under Ar. After 3 h, the reaction mixture was cooled to −78° C. and a solution of 2-fluoro-4-formyl-benzonitrile (1.70 g, 11.5 mmol) dissolved in CH2Cl2 (20 mL) was added dropwise. The reaction was allowed to warm to RT over 2 h, quenched with saturated NH4Cl solution, diluted with satd. NaHCO3 solution to pH=8.5, and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), concentrated and purified using SiO2 chromatography (0-1% MeOH/CH2Cl2) to yield the title compound. was added dropwise to warm to RT over 2 h quenched with saturated NH4Cl solution diluted with satd NaHCO3 solution to pH=8.5, and extracted with CH2Cl2 (3×) The combined organic layers were dried (MgSO4) concentrated purified

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-Fluoro-4-hydroxymethylbenzonitrile (Example 9, Step C) 10 g, 0,066 mol) and triethylamine (32.3 mL, 0.231 mol) were dissolved in CH2Cl2 (100 mL)-DMSO (20 mL) at <5° C. with stirring and treated dropwise with a solution of pyridine.SO3 complex (31.5 g, 0.198 mol) in DMSO (70 mL) maintaining the reaction mixture temperature at <10° C. The reaction mixture was stirred at 5° C. for 1 hr after the addition, then at 20° C. for 1 hr, then partitioned between CH2Cl2 and H2O. The organic layer was separated, washed well with H2O, brine, and dried (Na2SO4). Filtration and concentration gave the title compound after purification by chromatography (silica gel, hexane: EtOAc, 3:1). 1H NMR (CDCl3) δ 10.06 (d, 1H, J=2 Hz), 7.86 (dd, 1H, J=5, 8 Hz), 7.798 (dd, 1H, J=1, 8 Hz), 7.728 (dd, 1H, J=1, 8 Hz). The reaction mixture was stirred at 5° C. for 1 hr after the addition partitioned between CH2Cl2 and H2O The organic layer was separated washed well with H2O, brine dried (Na2SO4) Filtration and concentration

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α,α-dibromo-4-cyano-3-fluorotoluene, as described above in Step B, (5.60 g, 19.1 mmol) in EtOH (255 mL) and water (45 mL) was added AgNO3. The mixture was heated to reflux for 3 hrs, then stood at ambient temperature for 18 hrs, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL. Water (30 mL) was added, and the mixture was concentrated to dryness in vacuo. The residue was partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dried for several days at ca. 0.5 mm Hg to yield the desired aldehyde as a pale solid. The mixture was heated to reflux for 3 hrs the solid was removed by filtration the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL Water (30 mL) was added the mixture was concentrated to dryness in vacuo The residue was partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (50 mL) The aqueous layer was extracted further with CH2Cl2 (2×50 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo The residue was dried for several days at ca. 0.5 mm Hg

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of α,α-dibromo-4-cyano-3-fluorotoluene, as described above in Step B, (5.60 g, 19.1 mmol) in EtOH (255 mL) and water (45 mL) was added AgNO3. The mixture was heated to reflux for 3 hrs, then stood at ambient temperature for 18 hrs, then the solid was removed by filtration and the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL. Water (30 mL) was added, and the mixture was concentrated to dryness in vacuo. The residue was partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (50 mL). The aqueous layer was extracted further with CH2Cl2 (2×50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dried for several days at ca. 0.5 mm Hg to yield the desired aldehyde as a pale solid. The mixture was heated to reflux for 3 hrs the solid was removed by filtration the filtrate was concentrated under reduced pressure to a volume of approximately 20 mL Water (30 mL) was added the mixture was concentrated to dryness in vacuo The residue was partitioned between sat. aq. NaHCO3 (20 mL) and CH2Cl2 (50 mL) The aqueous layer was extracted further with CH2Cl2 (2×50 mL) The combined organic extracts were dried over Na2SO4 filtered concentrated in vacuo The residue was dried for several days at ca. 0.5 mm Hg

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde and 4.0 g of 2-(trans-4-n-propylcyclohexyl)-propane-1,3-diol is reacted analogously to Example 5. 2-(4-Cyano-3-fluorophenyl)-5-(trans-4-n-propylcyclohexyl)-1,3-dioxane is obtained. The following compounds are prepared analogously: is reacted analogously to Example 5

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde and 4.0 g of 2-(trans-4-n-propylcyclohexyl)-propane-1,3-diol is reacted analogously to Example 5. 2-(4-Cyano-3-fluorophenyl)-5-(trans-4-n-propylcyclohexyl)-1,3-dioxane is obtained. The following compounds are prepared analogously: is reacted analogously to Example 5

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde obtainable from 2-fluoro-4-nitrotoluene by oxidation to the corresponding benzoic acid, conversion into the corresponding nitrile, reduction to 2-fluoro-4-aminobenzonitrile and conversion of the corresponding diazonium salt with formaldoxime into the aldehyde in accordance with the method of Beech (J. Chem. Soc. 1297 (1954)); the target product is also obtainable from 2-fluoro-4-aminotoluene by conversion into 3-fluoro-4-methylbenzonitrile by the Sandmeyer method, hydrolysis of the nitrile, bromination of the side chain of the ethyl 3-fluoro-4-methylbenzoate obtainable, conversion into the aldehyde by the Sommelet method, conversion of the resulting oxime into ethyl 3-fluoro-4-cyanobenzoate, reduction to 3-fluoro-4-cyanobenzyl alcohol and subsequent oxidation to the target product) and 3.5 g of 2-n-heptylpropane-1,3-diol is heated together with 1 g of strongly acid cation exchanger in 100 ml of toluene for 8 hours using a water separator. The catalyst is then filtered off and the toluene is removed. After customary working-up, 2-(4-cyano-3-fluorophenyl)-5-n-heptyl-1,3-dioxane is obtained. The catalyst is then filtered off the toluene is removed

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 3.0 g of 4-cyano-3-fluorobenzaldehyde obtainable from 2-fluoro-4-nitrotoluene by oxidation to the corresponding benzoic acid, conversion into the corresponding nitrile, reduction to 2-fluoro-4-aminobenzonitrile and conversion of the corresponding diazonium salt with formaldoxime into the aldehyde in accordance with the method of Beech (J. Chem. Soc. 1297 (1954)); the target product is also obtainable from 2-fluoro-4-aminotoluene by conversion into 3-fluoro-4-methylbenzonitrile by the Sandmeyer method, hydrolysis of the nitrile, bromination of the side chain of the ethyl 3-fluoro-4-methylbenzoate obtainable, conversion into the aldehyde by the Sommelet method, conversion of the resulting oxime into ethyl 3-fluoro-4-cyanobenzoate, reduction to 3-fluoro-4-cyanobenzyl alcohol and subsequent oxidation to the target product) and 3.5 g of 2-n-heptylpropane-1,3-diol is heated together with 1 g of strongly acid cation exchanger in 100 ml of toluene for 8 hours using a water separator. The catalyst is then filtered off and the toluene is removed. After customary working-up, 2-(4-cyano-3-fluorophenyl)-5-n-heptyl-1,3-dioxane is obtained. The catalyst is then filtered off the toluene is removed