1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione

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

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

Procedure: To a solution of 5-chloro-2-methylbenzoic acid (10.0 g, 58.6 mmol) in sulfuric acid (75 mL, 1407 mmol) was added portionwise 1,3-diiodo-5,5-dimethylimidazolidine -2,4-dione (12.0 g, 31.6 mmol). The reaction turned very dark and quickly formed a thick suspension. The reaction was stirred for 2 h, at which time it was poured into ice water (˜500 mL) and stirred for 30 min to break up the solids. The precipitate was filtered off, washed with water, and dried under vacuum to give 5-chloro-3-iodo-2-methylbenzoic acid (17.3 g, 50.2 mmol, 86% yield) as a light beige solid. 1H NMR (400 MHz, DMSO-d6) δ 13.48 (br. s., 1H), 8.11 (d, J=2.27 Hz, 1H), 7.73 (d, J=2.27 Hz, 1H), 2.54 (s, 3H). quickly formed a thick suspension stirred for 30 min The precipitate was filtered off washed with water dried under vacuum

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

Procedure: To a solution of methyl (1S,3S,4R)-2-[(1R)-1-phenylethyl]-2-azabicyclo[2.2.1]hept-5-ene-3-carboxylate obtained in Example 42-2 (1.0 g) in acetic acid (9 mL), was added portionwise 1,3-diiodo-5,5-dimethylhydantoin (782 mg). The mixture was stirred at room temperature for 30 minutes. The solution was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate, and washed successively with sodium hydrogencarbonate solution, sodium thiosulfate solution, sodium hydrogen carbonate solution and brine. The organic layer was dried over MgSO4 and evaporated in vacuo to give the target compound as a solid (1.74 g). The solution was concentrated under reduced pressure The resulting mixture was diluted with ethyl acetate washed successively with sodium hydrogencarbonate solution, sodium thiosulfate solution, sodium hydrogen carbonate solution and brine The organic layer was dried over MgSO4 evaporated in vacuo

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

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500 mL Erlenmeyer flask was added 4.5 g (18 mmol) of 9-phenylanthracene. To the flask was added 200 mL of acetic acid, followed by heating at 70° C. to dissolve 9-phenylanthracene therein. To the resulting solution was added 5.2 g (13 mmol) of 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (DIH), and the solution was stirred under air at 70° C. for 3 hours. After the reaction, ca. 100 mL of water and ca. 200 mL, of chloroform were added to this solution. The resulting mixture was washed with water twice, and the organic layer was separated from the aqueous layer. The aqueous layer was extracted with chloroform. The extract was combined with the organic layer and washed with brine, and then the combined organic layer was dried with magnesium sulfate. This mixture was gravity filtered, and the filtrate obtained was concentrated to give a brown solid. This solid was washed with hexane to give 5.8 g of a yellow solid in a yield of 86%, which was the desired substance. The synthetic scheme is shown in the following (A-2). The resulting mixture was washed with water twice the organic layer was separated from the aqueous layer The aqueous layer was extracted with chloroform washed with brine the combined organic layer was dried with magnesium sulfate filtered the filtrate obtained was concentrated to give a brown solid This solid was washed with hexane

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

Procedure: Prepared by a Method analogous to that as described above for Preparation 87 using 7-cyclopropyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 93) and 1,3-diiodo-5,5-dimethylhydantoin to afford the title compound in 79% yield. Prepared by a Method analogous to

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

Procedure: Concentrated sulphuric acid (10 mL) was carefully added to 7-ethyl-4-(4-fluorophenyl)-7H-imidazo[4,5-c]pyridazine (Preparation 9, 825 mg, 2.4 mmol) surrounded by an ice bath, and the resultant reaction mixture was gently stirred at room temperature until a homogeneous solution was observed. To this was added 1,3-diiodo-5,5-dimethylhydantoin (1.36 g, 3.58 mmol) portion-wise, and stirring was continued for 5 minutes. The viscous mixture was then slowly poured into an aqueous sodium hydroxide solution (1M, 10 mL) at 0° C. with stirring. The black suspension slowly dissolved to give a blue solution. CH2Cl2 (20 mL) was added and the layers were separated. The organic layer was washed with saturated aqueous sodium bisulfite solution (20 mL) then concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with heptane:EtOAc 1:1 to 0:100 to afford the title compound as a white solid in 95% yield, 1.19 g. surrounded by an ice bath the resultant reaction mixture stirring with stirring The black suspension slowly dissolved to give a blue solution the layers were separated The organic layer was washed with saturated aqueous sodium bisulfite solution (20 mL) then concentrated in vacuo The residue was purified eluting with heptane:EtOAc 1:1 to 0:100

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into the same reactor as in Example 1 were charged 1.32 mg of palladium acetate, 0.78 g of 1,3-diiodo-5,5-dimethylhydantoin, n-butyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)benzoate and 5 ml of N,N-dimethylacetamide. After stirring the mixture at 90° C. for 30 minutes, 0.56 g of 1,3-diiodo-5,5-dimethylhydantoin was added, and the mixture thus obtained was stirred at 90° C. for 3.5 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, an aqueous solution of sodium thiosulfate was added, and the mixture thus obtained was extracted twice with toluene. The organic layer was washed successively with 0.5N aqueous hydrochloric acid, an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The crude product thus obtained was washed with hexane-ether mixture to obtain 2.26 g of n-butyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)-3-iodobenzoate (yield 82%, melting point 57.5–66.3° C.). Regioselectivity of iodination into the 3-position was 100%. the mixture thus obtained was stirred at 90° C. for 3.5 hours After completion of the reaction the solvent was distilled off under reduced pressure an aqueous solution of sodium thiosulfate was added the mixture thus obtained was extracted twice with toluene The organic layer was washed successively with 0.5N aqueous hydrochloric acid The organic layer was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The crude product thus obtained was washed with hexane-ether mixture

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into the same reactor as in Example 1 were charged 0.10 g of palladium acetate, 0.40 g of 2-methyl-2′-methylsulfinylbenzanilide, 0.33 g of 1,3-diiodo-5,5-dimethylhydantoin and 5 ml of N,N-dimethylacetamide. The mixture thus obtained was stirred at 90° C. for 2 hours. After cooling to room temperature, the reaction mixture was filtered with Celite, and the filtrate was poured into saturated aqueous solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with 0.1N-aqueous hydrochloric acid and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrate thus obtained was purified by silica gel dry column chromatography (hexane/ethyl acetate=1/2). Thus, 0.43 g (yield 72%) of 2-iodo-6-methyl-2′-methylsulfinylbenzanilide was obtained. Regioselectivity of iodination into the 2-position was 100%. The mixture thus obtained After cooling to room temperature the reaction mixture was filtered with Celite the filtrate was poured into saturated aqueous solution of sodium thiosulfate extracted with ethyl acetate The organic layer was washed with 0.1N-aqueous hydrochloric acid dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The concentrate thus obtained was purified by silica gel dry column chromatography (hexane/ethyl acetate=1/2)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into the same reactor as in Example 1 were charged 1.5 mg of palladium acetate, 0.83 g of 1,3-diiodo-5,5-dimethylhydantoin, 1.0 g of methyl 2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)benzoate and 5 ml of N-methylpyrrolidone. The mixture thus obtained was heated with stirring at 90° C. for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into water, and the objective product was extracted with ethyl acetate. The organic layer was washed successively with aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, a crude product was obtained. Purification of the crude product by silica gel column chromatography (ethyl acetate/n-hexane=1/3) gave 1.27 g of methyl 3-iodo-2-(1,1-dimethyl-2-methylsulfinylethylaminocarbonyl)-benzoate (yield 89.1%, melting point 150.7–151.8° C.). The mixture thus obtained was heated After completion of the reaction the reaction mixture was cooled to room temperature the objective product was extracted with ethyl acetate The organic layer was washed successively with aqueous solution of sodium thiosulfate and saturated aqueous solution of sodium chloride dried over anhydrous magnesium sulfate By distilling off the solvent under reduced pressure a crude product was obtained Purification of the crude product by silica gel column chromatography (ethyl acetate/n-hexane=1/3)

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

Procedure: To 0.1 g (0.00025 mole) of tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate in acetonitrile (2 mL) was added 1,3-Diiodo-5,5-dimethylhydantoin (95 mg, 1 eq), and solid NaHCO3 (63 mg, 3 eq). Stir at room temperature for 16 hrs. Filter, concentrate and then column with hexane/ethylacetate (0-50%) to afford tert-butyl N-[2-[2-chloro-6-(diethoxymethyl)-5-iodo-pyrrolo[2,3-d]pyrimidin-7-yl]ethyl]carbamate as a pale yellow solid 0.03 g. LCMS (ESI) 525 (M+H). Filter concentrate

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 500 mL Erlenmeyer flask was put 4.5 g (18 mmol) of 9-phenylanthracene. Then 200 mL of acetic acid was added to the flask, followed by heating to 70° C., and 9-phenylanthracene was dissolved therein. Into this solution, 5.2 g (13 mmol) of 1,3-diiodo-5,5-dimethylimidazolidine-2,4-dione (abbreviation: DIH) was added. This solution was stirred in air at 70° C. for 3 hours. After the stirring, about 100 mL of water and about 200 mL of chloroform were added to this solution. This mixture was washed with water twice, and the aqueous layer was extracted with chloroform. The extracted solution was combined with the organic layer and washed with a saturated saline, and then the organic layer was dried with magnesium sulfate. This mixture was gravity filtered, and the obtained filtrate was concentrated to give a brown solid. This solid was washed with hexane to give 5.8 g of a yellow solid, which was the object of the synthesis, in a yield of 86%. This mixture was washed with water twice the aqueous layer was extracted with chloroform washed with a saturated saline the organic layer was dried with magnesium sulfate filtered the obtained filtrate was concentrated to give a brown solid This solid was washed with hexane