4-fluorobenzohydrazide

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

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

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-[4-((1R,2S,3R)-1,2,3,4-Tetrahydroxy-butyl)-1H-imidazol-2-yl]-ethanone (172 mg, 0.74 mmol) was suspended in ethanol (4 ml) and water (1 ml). 4-fluorobenzoic acid hydrazide (131 mg, 0.85 mmol, 1.1 eq.) and hydrochloric acid (one drop, 12 N) were added, and the suspension was stirred at 55° C. for 48 hours. LCMS analysis indicated the formation of the product and the absence of starting material. The reaction mixture was cooled to room temperature, and partially concentrated in vacuo. The resulting white precipitate was collected and washed with ethanol to yield the product, as one apparent isomer, as a white solid: 97 mg (35%). The reaction mixture was cooled to room temperature partially concentrated in vacuo The resulting white precipitate was collected washed with ethanol to yield the product

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

Procedure: 4 g 4-fluoro-benzamidine was added to 4.5 g 4-fluoro-benzoic acid hydrazide and this mixture was melted. This mixture was crystallized with ethyl acetate to give 5.3 g of the desired compound. Rt: 1.55 min (method A), (M+H)+: 258 This mixture was crystallized with ethyl acetate

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

Procedure: 4 g 4-fluoro-benzamidine was mixed with 4.5 g 4-fluoro-benzoic acid hydrazide and the mixture was melted. Then the mixture was crystallized from ethyl acetate to yield 5.3 g of the desired compound. Rt: 1.55 min (method A), (M+H)+: 258 Then the mixture was crystallized from ethyl acetate

Conditions: temp:-20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoic acid (4.0 g, 14.2 mmol) in THF (100 mL) were added 4-fluorobenzoic hydrazide (2.40 g, 15.6 mmol), HOBt (1.91 g, 14.1 mmol), EDC (4.07 g, 21.2 mmol) and Et3N (3.0 mL, 21.5 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (300 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound (R)—N′-(2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxy-3-methylbutanoyl)-4-fluorobenzohydrazide (4.28 g, 72%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.61 (b, 2H), 8.00 (dd, J=5.5, 9.0 Hz, 2H), 7.51 (d, J=8.6 Hz, 1H), 7.25 (t, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H), 5.53 (d, J=7.4 Hz, 1H), 4.06 (d, J=7.4 Hz, 1H), 2.35 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H). After addition room temperature overnight The reaction was quenched by adding ice-water After removal of the THF the residue was extracted with EtOAc (300 mL) The EtOAc extracts were washed with water, brine dried over Na2SO4 The filtrate was concentrated purified by flash chromatography

Conditions: temp:-15.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (R)-2-(4-cyano-2-methyl-3-(trifluoromethyl)phenylamino)-3-hydroxy-3-methylbutanoic acid (500 mg, 1.58 mmol) and 4-fluorobenzohydrazide (244 mg, 1.58 mmol) were mixed together in THF (20 mL) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (214 mg, 1.58 mmol), TEA (0.33 mL, 2.37 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (454 mg, 2.37 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete, ethyl acetate (50 mL) was added and the solution was washed with 5% citric acid (2×40 mL), 5% NaHCO3 (2×40 mL) followed by water (40 mL) and then dried (Na2SO4) to provide the crude product as a yellow solid (660 mg, 92%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.81 (br s, 1H), 8.02-7.95 (m, 2H), 7.69-7.63 (m, 1H), 7.27-7.21 (m, 2H), 7.01-6.95 (m, 1H), 5.54 (d, J=7 Hz, 1H), 4.14 (d, J=8 Hz, 1H), 2.38 (s, 3H), 1.47 (s, 3H) and 1.43 (s, 3H). To the pre-cooled reaction mixture at room temperature overnight the solution was washed with 5% citric acid (2×40 mL), 5% NaHCO3 (2×40 mL) dried (Na2SO4)

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

Procedure: The p-fluorobenzoic acid hydrazide is prepared as follows. Ethyl p-fluorobenzoate (8.4 g) is refluxed with hydrazine hydrate (3.75 g) for 3 hours. The mixture is then cooled, ether is added and the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration, washed with ether and desiccated, m.p. 149°-151° C. The mixture is then cooled the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration washed with ether

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

Procedure: The p-fluorobenzoic acid hydrazide is prepared as follows. Ethyl p-fluorobenzoate (8.4 g) is refluxed with hydrazine hydrate (3.75 g) for 3 hours. The mixture is then cooled, ether is added and the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration, washed with ether and desiccated, m.p. 149°-151° C. The mixture is then cooled the precipitate of p-fluorobenzoic acid hydrazide (3.2 g) is removed by filtration washed with ether

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

Procedure: This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone, 4-fluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol instead of (2-methyl-2H-[1,2,4]triazol-3-yl)methanol in step f). Data for the title compound: mp=179° C.; 1H NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J=7.4 Hz), 4.23 (2H, m), 5.67 (2H, s), 7.22-7.32 (4H, m), 7.39-7.44 (1H, m), 7.57 (1H, m), 7.92 (1H, s), 8.54-8.58 (2H, m), 9.21 (1H, s); MS (ES+) m/e 434 [MH]+; Anal. Found: C, 60.86; H, 3.83; N, 22.30%. C22H17F2N7O requires: C, 60.97; H, 3.95; N, 22.62%. This compound was prepared

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

Procedure: This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone, 4-fluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e) and (2-ethyl-2H-[1,2,4]triazol-3-yl)methanol instead of (2-methyl-2H-[1,2,4]triazol-3-yl)methanol in step f). Data for the title compound: mp=179° C.; 1H NMR (400 MHz, CDCl3) δ 1.38 (3H, t, J=7.4 Hz), 4.23 (2H, m), 5.67 (2H, s), 7.22-7.32 (4H, m), 7.39-7.44 (1H, m), 7.57 (1H, m), 7.92 (1H, s), 8.54-8.58 (2H, m), 9.21 (1H, s); MS (ES+) m/e 434 [MH]+; Anal. Found: C, 60.86; H, 3.83; N, 22.30%. C22H17F2N7O requires: C, 60.97; H, 3.95; N, 22.62%. This compound was prepared

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

Procedure: This compound was prepared using the procedure described in Example 21, steps b) to f), using 3-(2-fluorophenyl)-4-hydroxy-2-furanone (cf. Example 2) instead of 3-tert-butyl-4-hydroxy-2-furanone and 4-fluorobenzoic hydrazide instead of 2,5-difluorobenzoic hydrazide in step e). Data for the title compound: mp=191° C.; 1H NMR (400 MHz, CDCl3) δ 3.92 (3H, s), 5.66 (2H, s), 7.22-7.32 (4H, m), 7.39-7.44 (1H, m), 7.58 (1H, m), 7.90 (1H, s), 8.51-8.55 (2H, m), 9.21 (1H, s); MS (ES+) m/e 420 [MH]+; Anal. Found: C, 60.11; H, 3.52; N, 23.37%. C21H15F2N7O requires: C, 60.14; H, 3.61; N, 23.38%. This compound was prepared