1-aminoimidazolidine-2,4-dione;hydrochloride

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

Procedure: The title compound was prepared in 58% yield as a light yellow solid in analogy to the synthesis of example 52 from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.45 (s, 1H), 9.41 (s, 1H), 8.89 (d, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.84 (d, 1H), 7.53 (dd, 1H), 6.23 (s, 2H), 4.56 (s, 2H), 2.49 (s, 3H). LCMS (method B): [MH]+=402, tR=1.81 min.

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

Procedure: The title compound was prepared from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 39% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 8.91 (dd, 1H), 8.40 (d, 1H), 8.24 (d, 1H), 8.04 (d, 1H), 7.94 (m, 2H), 7.82 (d, 1H), 7.55 (q, 1H), 4.64 (s, 2H), 4.50 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+=418, tR=4.62 min.

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

Procedure: The title compound was prepared from 1-aminoimidazolidine-2,4-dione hydrochloride and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 39% yield. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.39 (s, 1H), 8.91 (dd, 1H), 8.40 (d, 1H), 8.24 (d, 1H), 8.04 (d, 1H), 7.94 (m, 2H), 7.82 (d, 1H), 7.55 (q, 1H), 4.64 (s, 2H), 4.50 (s, 2H), 2.40 (s, 3H). LCMS (method A): [MH]+=418, tR=4.62 min.

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 5-azido-2-furaldehyde (240 mg, 1.75 millimole (mmole)) in 20 milliliters (ml) of ethanol was added dropwise over 10-20 minutes to a solution of 1-aminohydantoin hydrochloride (320 mg, 2.1 mmole) in 25 ml of ethanol:water (4:1) and the mixture was chilled in an ice bath. The reaction mixture turned into a yellow-orange suspension within thirty minutes and was gradually heated to about 60° C. to form a complete solution. The heating continued for another 24 hours after which time it was allowed to cool and evaporated to dryness. The dark residue was triturated with 4-5 portions (15 ml each) of acetonitrile to obtain a suspension which was then filtered through a filter paper. The filtrate was evaporated to dryness. The residue was dissolved in 3 ml of acetone and streaked on two preparative silica gel TLC plates (EM Science, Cat # 5717-7) and developed with ethyl acetate: petroleum ether (3:1). The fast moving major band (Rf around 0.51) detected under UV light was stripped, and the silica gel was ground to a fine powder and eluted with acetone. The acetone eluent was evaporated to give a pale yellow solid which showed a homogeneous single spot on TLC (137 mg, 0.67 mmole, 38% yield). Alternatively the crude reaction product can be purified by silica gel column chromatography and further recrystallized from 30% ethyl acetate/hexanes to give the pure desired product (mp 171-173° C.). Elemental analysis supported a molecular formula of C8H6N4O3. 0.15 EtOAc. The structure of compound 1 was established by 1H and 13C NMR analysis as shown in FIGS. 1-4. 1H NMR analysis of 1 revealed that the acrylonitrile moiety has a trans (E)-configuration (coupling constant J=16.5 Hz). MALDI-TOF mass spectral analysis confirmed structure 1 with the M+1 peak of 207.22 the mixture was chilled in an ice bath The reaction mixture turned into a yellow-orange suspension within thirty minutes to form a complete solution to cool evaporated to dryness The dark residue was triturated with 4-5 portions (15 ml each) of acetonitrile to obtain a suspension which was then filtered through a filter paper The filtrate was evaporated to dryness The residue was dissolved in 3 ml of acetone eluted with acetone The acetone eluent was evaporated to give a pale yellow solid which Alternatively the crude reaction product can be purified by silica gel column chromatography further recrystallized from 30% ethyl acetate/hexanes

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

Procedure: An ice-cold suspension of 1-aminohydantoin hydrochloride (457 mg, 3.0 mmol), cyanuric chloride (500 mg, 2.73 mmol) and sodium bicarbonate (505 mg, 6 mmol) in acetonitrile (5 mL) was stirred under an atmosphere of nitrogen for 2 h and then stirred at room temperature for 20 h. The reaction mixture was evaporated to dryness under reduced pressure and the residue was extracted with ethyl acetate and the ethyl acetate was separated and dried (MgSO4). The crude product (770 mg) gave a single spot on thin layer chromatography [silica; CH2Cl2/MeOH (10:1)] and was used in the next step without further purification. NMR (CD3CN): δ=4.11 (s, 2H); 8.71 (s, 1H); 8.85 (s, 1H). stirred at room temperature for 20 h The reaction mixture was evaporated to dryness under reduced pressure the residue was extracted with ethyl acetate the ethyl acetate was separated dried (MgSO4)

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

Procedure: To 99.5 g (0.6 mole) of m-fluorocinnamic acid was added dropwise thionyl chloride (600 ml) followed by heating at reflux for 2 hours. The excess thionyl chloride was removed in vacuo and the residue remaining flushed with dry benzene. The reaction residue was chilled on an ice bath followed by the rapid addition of 1-aminohydantoin hydrochloride (91 g, 0.6 mole). To the cold reaction mixture was added dropwise pyridine (600 ml). After the addition was complete the cold reaction mixture was heated on a steam bath for 3 hours then poured into 6 l. of HCl/ice. Upon standing at room temperature overnight the acidic reaction mixture was filtered and washed with water to give 116 g (73.5%) which after recrystallization from CH3NO2 melted at 294°-296°. by heating at reflux for 2 hours The excess thionyl chloride was removed in vacuo the residue remaining flushed with dry benzene The reaction residue was chilled on an ice bath To the cold reaction mixture After the addition the cold reaction mixture was heated on a steam bath for 3 hours then poured into 6 l the acidic reaction mixture was filtered washed with water to give 116 g (73.5%) which after recrystallization from CH3NO2 melted at 294°-296°

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

Procedure: 3-Chloro-4-ethylcinnamic acid (50 g, 0.24 mole) in SOCl2 (100 ml) was heated under reflux for about 1 hour. The excess SOCl2 was removed in vacuo and the residue flushed with benzene. The acid chloride was treated with 1-aminohydantoin hydrochloride (40 g, 0.26 mole) and pyridine (300 ml) and the reaction mixture heated on a steam bath for 4 hours. The reaction mixture was poured onto HCl/ice to precipitate the product. (40 g, 55%). Several recrystallizations from CH3NO2 provided analytical material which melted at 231°-234°. under reflux for about 1 hour The excess SOCl2 was removed in vacuo the residue flushed with benzene the reaction mixture heated on a steam bath for 4 hours The reaction mixture was poured onto HCl/ice to precipitate the product Several recrystallizations from CH3NO2 provided analytical material which melted at 231°-234°

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

Procedure: A mixture of p-fluorocinnamic acid (36 g, 0.22 mole) in SOCl2 (75 ml) was heated under reflux with stirring for 1 hour. The excess SOCl2 was removed in vacuo and the residue fluxhed with benzene. To the resulting acid chloride was added 1-aminohydantoin hydrochloride (39 g, 0.26 mole) and 250 ml of pyridine and the resulting reaction mixture was heated on the steam bath for 3 hours. The mixture was poured onto HCl/ice and the product allowed to crystallize. was heated under reflux The excess SOCl2 was removed in vacuo the resulting reaction mixture was heated on the steam bath for 3 hours The mixture was poured onto HCl/ice to crystallize

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

Procedure: A stirred mixture of 4-chloro-3-trifluoromethylcinnamic acid (50 g, 0.2 mole) in 200 ml of SOCl2 was heated at reflux for 2 hours. The excess SOCl2 was removed in vacuo and the residue flushed with dry benzene. The residue was treated with a mixture of 1-aminohydantoin hydrochloride (30 g, 0.2 mole) in 400 ml of pyridine. The reaction mixture was heated at reflux for 3 hours; then poured into ice/HCl. The crude residue (74 g, 100%) was recrystallized from CH3NO2 (Darco) to give an analytical sample melting at 270°-273°. was heated at reflux for 2 hours The excess SOCl2 was removed in vacuo the residue flushed with dry benzene The reaction mixture was heated at reflux for 3 hours The crude residue (74 g, 100%) was recrystallized from CH3NO2 (Darco) to give an analytical sample melting at 270°-273°

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

Procedure: To 4-chlorocinnamic acid (46 g, 0.25 mole) was added dropwise SOCl2 (140 ml). The mixture was heated under reflux for 45 minutes after the addition was complete. After stirring at room temperature for 1 hour the SOCl2 was removed in vacuo. Dry benzene was added and then removed in vacuo. The acid chloride residue was treated with 1-aminohydantoin hydrochloride (42 g, 0.275 mole) in 350 ml of pyridine, then heated under reflux for 2 hrs. After cooling slightly, the reaction mixture was poured into a mixture of 200 ml of con HCl and 1500 ml of ice. After standing overnight the product was removed by filtration and washed with H2O. Recrystallization from NaOH/dimethylformamide (H2O) provided analytical material which melted at 230°-235° (25 g, 36%). The mixture was heated under reflux for 45 minutes after the addition was removed in vacuo Dry benzene was added removed in vacuo heated under reflux for 2 hrs After cooling slightly the product was removed by filtration washed with H2O Recrystallization from NaOH/dimethylformamide (H2O) provided analytical material which melted at 230°-235° (25 g, 36%)

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

Procedure: To 3-chloro-4-methylcinnamic acid (50 g, 0.25 mole) was added dropwise SOCl2 (140 ml). The mixture was heated under reflux for 45 min. after the addition was complete. After stirring at room temperature for 1 hour the SOCl2 was removed in vacuo. Dry benzene was added and then removed in vacuo. The acid chloride residue was treated with 1 -aminohydantoin hydrochloride (42 g, 0.275 mole) in 350 ml of pyridine, then heated under reflux for 2 hr. After cooling slightly, the reaction mixture was poured into a mixture of 200 ml of con HCl and 1500 ml of ice. After standing overnight the product was removed by filtration and washed with H2O. Recrystallization from CH3NO2 provided analytical material which melted at 271°-273° (28 g, 38%). The mixture was heated under reflux for 45 min. after the addition was removed in vacuo Dry benzene was added removed in vacuo heated under reflux for 2 hr After cooling slightly the product was removed by filtration washed with H2O Recrystallization from CH3NO2 provided analytical material which melted at 271°-273° (28 g, 38%)

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

Procedure: To a pyridine solution (500 ml) of 1-aminohydantoin hydrochloride (50 g, 0.3 mole) was added cinnamoyl chloride (53 g, 0.3 mole). The stirred mixture was heated on the steam bath for 5 hours, then poured into ice water. After standing overnight, the precipitated product was removed by filtration and washed thoroughly with water. After drying, the crude white product weighed 60 g (74%). Several recrystallizations from methanol provided analytical material which melted at 276°-278°. The stirred mixture was heated on the steam bath for 5 hours the precipitated product was removed by filtration washed thoroughly with water After drying Several recrystallizations from methanol provided analytical material which melted at 276°-278°