5,5-dibromo-1,3-diazinane-2,4,6-trione

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

Procedure: To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in mL of ethyl ether was added 1.02 g (3.52 mmol, 0.5 equiv) of dibromobarbituric acid. The mixture was allowed to stir at room temperature overnight. The resultant white slurry was filtered and the tiltrate was concentrated. Purification by flash chromotography (silica gel, ethyl acetate/hexane) gave 1.28 g (81%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.26 (t, 1H, J=1.4 Hz), 8.20 (td, 1H, J=1.5, 8.0 Hz), 7.87 (dd, 1H, J=1.3, 7.8 Hz), 7.64 (t, 1H, J=7.9 Hz), 4.40 (s, 2H). The resultant white slurry was filtered the tiltrate was concentrated Purification by flash chromotography (silica gel, ethyl acetate/hexane)

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

Procedure: To a solution of 1.02 g (7.04 mmol) of 3-acetylbenzonitrile in mL of ethyl ether was added 1.02 g (3.52 mmol, 0.5 equiv) of dibromobarbituric acid. The mixture was allowed to stir at room temperature overnight. The resultant white slurry was filtered and the tiltrate was concentrated. Purification by flash chromotography (silica gel, ethyl acetate/hexane) gave 1.28 g (81%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.26 (t, 1H, J=1.4 Hz), 8.20 (td, 1H, J=1.5, 8.0 Hz), 7.87 (dd, 1H, J=1.3, 7.8 Hz), 7.64 (t, 1H, J=7.9 Hz), 4.40 (s, 2H). The resultant white slurry was filtered the tiltrate was concentrated Purification by flash chromotography (silica gel, ethyl acetate/hexane)

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

Procedure: A solution of 784 mg of 2-chloro-5-acetylpyridine in 10 mL of THF was added via canula to a solution of 1.44 g of dibromobarbituric acid (DBBA) in 10 mL of THF. The resultant solution was heated at 50°-55° C. for 12 h, and then an additional 0.72 g DBBA was added. After stirring at 50°-55° C. for 2.5 more hours, 0.36 g DBBA was added. The mixture was allowed to stir for 2 h at which point NMR analysis of an aliquot indicated 87% conversion. The reaction mixture was cooled, diluted with ethyl acetate, washed with two portions of saturated aqueous sodium bicarbonate, water, and brine, dried over magnesium sulfate and concentrated. Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane) provided 0.86 g (73%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ8.96 (d, 1H, J=2.6 Hz), 8.21 (dd, 1H, J=2.5, 8.3 Hz), 7.46 (d, 1H, J=8.4 Hz), 4.37 (s, 2H). The NMR also indicated the presence of the corresponding 2-bromo derivative. The ~4:1 mixture was carried on through the synthesis. was added The reaction mixture was cooled washed with two portions of saturated aqueous sodium bicarbonate, water, and brine dried over magnesium sulfate concentrated Purification by flash chromatography (silica gel, 15% ethyl acetate/hexane)

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

Procedure: A solution of 0.43 g (3.43 mmol) of 5-acetyl-3-methylisoxazole (for synthesis see S. Chimichi, B. Cosimelli, Synth. Comm. 1992, 22, 2909-2920) in 10 mL of THF was added to a solution of 688 mg (2.41 mmol) of dibromobarbituric acid in 10 mL of THF. The colorless solution was heated at reflux for 20 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phase was washed with water, brine, dried(MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 40-50% dichloromethane-hexanes) afforded 337 mg (48%) of the title compound: 1H NMR (400 MHz, CDCl3) 6.87 (s, 1H), 4.39 (s, 2H), 2.38 (s, 3H). The colorless solution was heated at reflux for 20 h partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution The organic phase was separated the aqueous phase re-extracted with ethyl acetate The combined organic phase was washed with water, brine, dried(MgSO4) the solvent removed in vacuo

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 0.17 g (0.285 mmol) [(3S,4R)-1-(5′-Acetyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid 4-fluoro-phenyl ester (example 38) and 84.3 mg (0.295 mmol) 5,5-dibromobarbituric acid in 10 mL dioxane was heated to 85° C. for 40 h. At room temperature 0.216 g (2.95 mmol) diethylamine was added and heated to 45° C. for 2 h and evaporated. the residue was taken up in methanol and subjected to preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 49 mg (26%) of the title compound as light brown solid. MS m/e: 648.3 [M+H]+. heated to 45° C. for 2 h evaporated eluting with a gradient formed from acetonitrile, water and NEt3 The product containing fractions were evaporated

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

Procedure: To a solution of tert-butyl 4-(3-oxopropyl)piperidine-1-carboxylate (Wityak J., et al., J. Med. Chem., 40, p. 50 (1997): 27.6 g) in diethyl ether was added dibromobarbituric acid (17.0 g), and the mixture was mixed for 12 hours. The insolubles were filtered off, and the filtrate was diluted with diethyl ether, sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off to give the title compound (31.8 g) as a pale yellow viscous oily matter. the mixture was mixed for 12 hours The insolubles were filtered off the filtrate was diluted with diethyl ether sequentially washed with a saturated aqueous sodium bicarbonate solution and saturated brine dried over anhydrous sodium sulfate The solvent was distilled off

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

Procedure: The mixture of 2-acetyl-6-nitro-benzoic acid methyl ester (8.20 g, 36.7 mmol, Step C) and 5,5-dibromobarbituric acid (7.35 g, 25.7 mmol) in 200 mL of THF was heated to reflux under N2 for 64 h. The solvents were removed, and the residue was partitioned between EtOAc and Na2CO3(aq). The organic portion was dried over MgSO4, filtered, condensed, and the titled compound was obtained as a white solid after flash column chromatography (5 to 20% of EtOAc in hexanes). was heated to reflux under N2 for 64 h The solvents were removed the residue was partitioned between EtOAc and Na2CO3(aq) The organic portion was dried over MgSO4 filtered condensed

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

Procedure: The mixture of 2-acetyl-6-nitro-benzoic acid methyl ester (8.20 g, 36.7 mmol, Step C) and 5,5-dibromobarbituric acid (7.35 g, 25.7 mmol) in 200 mL of THF was heated to reflux under N2 for 64 h. The solvents were removed, and the residue was partitioned between EtOAc and Na2CO3(aq). The organic portion was dried over MgSO4, filtered, condensed, and the titled compound was obtained as a white solid after flash column chromatography (5 to 20% of EtOAc in hexanes). was heated to reflux under N2 for 64 h The solvents were removed the residue was partitioned between EtOAc and Na2CO3(aq) The organic portion was dried over MgSO4 filtered condensed

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

Procedure: To a tetrahydrofuran (5.0 mL) solution of 3-(acetyl)-6-tert-butylpyridin-2(1H)-one (0.50 g), 5,5-dibromobarbituric acid (0.41 g) was added, and the resultant was heated to reflux for 2 hours. A deposit formed during the course of concentration of the reaction solution under reduced pressure was filtered to obtain the title compound (0.28 g) as a light brown solid. the resultant was heated to reflux for 2 hours A deposit formed during the course of concentration of the reaction solution under reduced pressure was filtered

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

Procedure: Preparation of 2-bromo-3-phenylpropanal: dibromobarbituric acid (1.43 g, 5 mmol) was dissolved in diethylether (40 mL) and phenylpropionaldehyde (1.34 g, 1.33 mL, 10 mmol) was added. After stirring at room temperature for 5 days, precipitation of barbituric acid was observed. The reaction mixture was filtered and washed with sat. aq. NaHCO3 (1×40 mL), and brine (2×40 mL). The mixture was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. GC-MS analysis of the concentrate showed 2-bromo-3-phenylpropanal as the sole product. (2) Preparation of (61): N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (100 mg, 0.321 mmol) was suspended in EtOH (1 mL) and 2-bromo-3-phenylpropanal (82 mg, 0.385 mmol, 1.2 eq) in EtOH (0.6 mL) was added. The reaction was stirred at r.t. for 1 h, and then heated to reflux for 30 min. The solvent was removed under reduced pressure and the residue purified by preparative reverse-phase column chromatography (water/acetonitrile). 5-{1-[(5-benzyl-1,3-thiazol-2-yl)(methyl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (61) was obtained in form of a yellowish oil (26 mg, 0.061 mmol, 19%) as a racemate and 1:1 mixture of diastereomers. 1H-NMR (CDCl3, 400 MHz): δ=1.89 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 1); 1.92 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 2); 3.09 (s, 1.5H, S—CH3, diastereomer 1); 3.20 (s, 1.5H, S—CH3, diastereomer 2); 3.94 (s, 1H, CH2Ph, diastereomer 1), 3.97 (s, 1H, CH2Ph, diastereomer 2); 5.14 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 1); 5.21 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 2); 6.90 (s, 0.5H, thiazole, diastereomer 1); 6.92 (s, 0.5H, thiazole, diastereomer 2); 7.15-7.37 (m, 5H, Ph); 7.71 (d, J=8.2 Hz, 0.5H, pyr-C3-H, diastereomer 1), 7.72 (d, J=8.2 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.09 (dd, 3J=8.2 Hz, 4J=1.8 Hz, 0.5H, pyr-C4-H, diastereomer 1); 8.12 (dd, 3J=8.2 Hz, 4J=1.7 Hz, 0.5H, pyr-C4-H, diastereomer 2); 8.75 (d, 4J=1.8 Hz, 0.5H, pyr-C6-H, diastereomer 1); 8.79 (d, 4J=1.8 Hz, 0.5H, pyr-C6-H, diastereomer 2); 13C-NMR (CDCl3, 100 MHz): δ=13.8, 14.2 (CHCH3, two diastereomers); 33.2. 33.3 (CH2Ph, two diastereomers); 36.5, 36.8 (S—CH3, two diastereomers); 60.8, 61.6 (CHCH3, two diastereomers); 119.5, 119.6 (pyr-C, 2 diastereomers); 125.6, 125.7 (Ph, two diastereomers), 127.2, 127.3 (Ph, two diastereomers, 127.5 (Ph, two diastereomers), 130.1, 130.2 (pyr-C, two diastereomers), 131.1, 131.5, (pyr-C, two diastereomers), 132.7, 133.2 (thiazole, two diastereomers), 137.3, 137.6 (pyr-C, 2-diastereomers); 137.9, 138.0 (thiazole, two diastereomers); 149.2, 149.4 (pyr-C, 2-diastereomers); 165.6, 165.8 (thiazole, two diastereomers); CF3, not detected. UPLC-MS (ESI+): mass calc'd for C19H19F3N3OS2 (M+H+): 426.1. Found 426.1, UPLC-MS (ESI−) mass calc'd for C19H17F3N3OS2 (M−H+): 424.1. Found 424.1. precipitation of barbituric acid The reaction mixture was filtered washed with sat. aq. NaHCO3 (1×40 mL), and brine (2×40 mL) The mixture was dried over Na2SO4 filtered the solvent was removed under reduced pressure (2) Preparation of (61) The reaction was stirred at r.t. for 1 h heated to reflux for 30 min The solvent was removed under reduced pressure the residue purified by preparative reverse-phase column chromatography (water/acetonitrile)

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

Procedure: Preparation of 2-bromo-3-phenylpropanal: dibromobarbituric acid (1.43 g, 5 mmol) was dissolved in diethylether (40 mL) and phenylpropionaldehyde (1.34 g, 1.33 mL, 10 mmol) was added. After stirring at room temperature for 5 days, precipitation of barbituric acid was observed. The reaction mixture was filtered and washed with sat. aq. NaHCO3 (1×40 mL), and brine (2×40 mL). The mixture was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. GC-MS analysis of the concentrate showed 2-bromo-3-phenylpropanal as the sole product. (2) Preparation of (61): N-(methyl(oxo){1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}-λ6-sulfanylidene)thiourea (J) (100 mg, 0.321 mmol) was suspended in EtOH (1 mL) and 2-bromo-3-phenylpropanal (82 mg, 0.385 mmol, 1.2 eq) in EtOH (0.6 mL) was added. The reaction was stirred at r.t. for 1 h, and then heated to reflux for 30 min. The solvent was removed under reduced pressure and the residue purified by preparative reverse-phase column chromatography (water/acetonitrile). 5-{1-[(5-benzyl-1,3-thiazol-2-yl)(methyl)sulfonimidoyl]ethyl}-2-(trifluoromethyl)pyridine (61) was obtained in form of a yellowish oil (26 mg, 0.061 mmol, 19%) as a racemate and 1:1 mixture of diastereomers. 1H-NMR (CDCl3, 400 MHz): δ=1.89 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 1); 1.92 (d, J=7.2 Hz, 1.5H, CHCH3, diastereomer 2); 3.09 (s, 1.5H, S—CH3, diastereomer 1); 3.20 (s, 1.5H, S—CH3, diastereomer 2); 3.94 (s, 1H, CH2Ph, diasteromer 1), 3.97 (s, 1H, CH2Ph, diasteromer 2); 5.14 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 1); 5.21 (q, J=7.2 Hz, 0.5H, CHCH3, diastereomer 2); 6.90 (s, 0.5H, thiazole, diastereomer 1); 6.92 (s, 0.5H, thiazole, diastereomer 2); 7.15-7.37 (m, 5H, Ph); 7.71 (d, J=8.2 Hz, 0.5H, pyr-C3-H, diastereomer 1), 7.72 (d, J=8.2 Hz, 0.5H, pyr-C3-H, diastereomer 2); 8.09 (dd, 3J=8.2 Hz, 4J=1.8 Hz, 0.5H, pyr-C4-H, diastereomer 1); 8.12 (dd, 3J=8.2 Hz, 4J=1.7 Hz, 0.5H, pyr-C4-H, diastereomer 2); 8.75 (d, 4J=1.8 Hz, 0.5H, pyr-C6-H, diastereomer 1); 8.79 (d, 4J=1.8 Hz, 0.5H, pyr-C6-H, diastereomer 2); 13C-NMR (CDCl3, 100 MHz): δ=13.8, 14.2 (CHCH3, two diastereomers); 33.2. 33.3 (CH2Ph, two diastereomers); 36.5, 36.8 (S—CH3, two diastereomers); 60.8, 61.6 (CHCH3, two diastereomers); 119.5, 119.6 (pyr-C, 2 diastereomers); 125.6, 125.7 (Ph, two diastereomers), 127.2, 127.3 (Ph, two diastereomers, 127.5 (Ph, two diastereomers), 130.1, 130.2 (pyr-C, two diastereomers), 131.1, 131.5, (pyr-C, two diastereomers), 132.7, 133.2 (thiazole, two diastereomers), 137.3, 137.6 (pyr-C, 2-diastereomers); 137.9, 138.0 (thiazole, two diastaereomers); 149.2, 149.4 (pyr-C, 2-diastereomers); 165.6, 165.8 (thiazole, two diastereomers); CF3, not detected. UPLC-MS (ESI+): mass calc'd for C19H19F3N3OS2 (M+H+): 426.1, found 426.1, UPLC-MS (EST) mass calc'd for C19H17F3N3OS2 (M−H+): 424.1, found 424.1. precipitation of barbituric acid The reaction mixture was filtered washed with sat. aq. NaHCO3 (1×40 mL), and brine (2×40 mL) The mixture was dried over Na2SO4 filtered the solvent was removed under reduced pressure (2) Preparation of (61) The reaction was stirred at r.t. for 1 h heated to reflux for 30 min The solvent was removed under reduced pressure the residue purified by preparative reverse-phase column chromatography (water/acetonitrile)

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

Procedure: Dissolve 16-dehydropregnenolone (5.00 g, 15.90 mmol) and 5,5-dibromobarbituric acid (4.55 g, 15.90 mmol) in tetrahydrofuran (60 mL). Add concentrated aqueous hydrogen bromide (100 μL of a 48% solution) to the stirring solution and heat the reaction at reflux for 1 hour. Cool slightly and then concentrate under vacuum to produce a brown oily foam. Dissolve the residue in methylene chloride (350 mL), rinse with 50% saturated sodium bicarbonate (2×200 mL, brine (125 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide 21-bromo-3β-hydroxypregna-5,16-dien-20-one (6.53 g) as an orange-brown solid, slightly contaminated with starting material. heat the reaction at reflux for 1 hour Cool slightly concentrate under vacuum to produce a brown oily foam rinse with 50% saturated sodium bicarbonate (2×200 mL, brine (125 mL) dry over anhydrous magnesium sulfate filter concentrate under vacuum