methyl 2-isocyanato-2-methylpropanoate

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

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

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

Procedure: (R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (50 mg, enantiomer B, preparation as described in WO2004085404) was dissolved in absolute dichloromethane (5 ml), and methyl 2-isocyanato-2-methylpropionate was added dropwise with stirring. After being stirred for 3 h and left to stand overnight, the mixture was admixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were purified, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in acetonitrile (1 ml) and admixed with 10% hydrochloric acid. After stirring for 2 h, the mixture was diluted with water (3 ml) and freeze-dried. 68 mg of the title compound were obtained. After being stirred for 3 h left the phases were separated the aqueous phase was extracted twice with dichloromethane The combined organic phases were dried over magnesium sulfate filtered concentrated The residue was purified by means of preparative HPLC were purified the acetonitrile was removed on a rotary evaporator extracted three times with ethyl acetate After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered concentrated to dryness The residue was dissolved in acetonitrile (1 ml) After stirring for 2 h the mixture was diluted with water (3 ml) freeze-dried

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

Procedure: (R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (50 mg, enantiomer B, preparation as described in WO2004085404) was dissolved in absolute dichloromethane (5 ml), and methyl 2-isocyanato-2-methylpropionate was added dropwise with stirring. After being stirred for 3 h and left to stand overnight, the mixture was admixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were purified, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in acetonitrile (1 ml) and admixed with 10% hydrochloric acid. After stirring for 2 h, the mixture was diluted with water (3 ml) and freeze-dried. 68 mg of the title compound were obtained. After being stirred for 3 h left the phases were separated the aqueous phase was extracted twice with dichloromethane The combined organic phases were dried over magnesium sulfate filtered concentrated The residue was purified by means of preparative HPLC were purified the acetonitrile was removed on a rotary evaporator extracted three times with ethyl acetate After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered concentrated to dryness The residue was dissolved in acetonitrile (1 ml) After stirring for 2 h the mixture was diluted with water (3 ml) freeze-dried

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

Procedure: To a solution of 4-(3-amino-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (4) (50 mg, 0.195 mmol) in dry DCM (10 ml) was added 2-isocyanato-2-methyl-propionic acid methyl ester (60 mg, 0.428 mmol). The resulting solution was stirred for 2 days, washed with water (3×10 ml), dried over sodium sulphate and concentrated in vacuo to yield a semi-crystalline solid (44 mg). washed with water (3×10 ml) dried over sodium sulphate concentrated in vacuo

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

Procedure: To a solution of 4-(3-amino-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (4) (50 mg, 0.195 mmol) in dry DCM (10 ml) was added 2-isocyanato-2-methyl-propionic acid methyl ester (60 mg, 0.428 mmol). The resulting solution was stirred for 2 days, washed with water (3×10 ml), dried over sodium sulphate and concentrated in vacuo to yield a semi-crystalline solid (44 mg). washed with water (3×10 ml) dried over sodium sulphate concentrated in vacuo

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

Procedure: 9.75 g. of 5-amino-2-chlorobenzotrifluoride and 7.15 g. of 2-isocyanato-2-methylpropionic acid methyl ester are melted at 80° and the melt is kept at this temperature for 30 minutes. The product which has crystallized out during this process is recrystallized from isopropanol/methylene chloride and dried under greatly reduced pressure at 50° for 20 hours. N-[(3-trifluoromethyl-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, which melts at 141°-142° is obtained. The product which has crystallized out during this process is recrystallized from isopropanol/methylene chloride dried under greatly reduced pressure at 50° for 20 hours

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

Procedure: 3-(3,5-dichloro-4-phenyl)-5,5-dimethylhydantoin, which melts at 175°-176°, is obtained in the manner indicated in Example 1 from 3,5-dichloro-4-fluoro-aniline and 2-isocyanato-2-methylpropionic acid methyl ester and after crystallizing from ether/petroleum ether. The N-[(3,5-dichloro-4-fluorophenyl)-carbamoyl]-2-methylalanine methyl ester intermediately formed is not isolated. after crystallizing from ether/petroleum ether

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

Procedure: (R)-2-(6,8-Dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylamine (50 mg, enantiomer B, preparation as described in WO2004085404) was dissolved in absolute dichloromethane (5 ml), and methyl 2-isocyanato-2-methylpropionate was added dropwise with stirring. After being stirred for 3 h and left to stand overnight, the mixture was admixed with water, the phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The fractions comprising product were purified, the acetonitrile was removed on a rotary evaporator, and the aqueous residue was neutralized with saturated potassium carbonate solution and extracted three times with ethyl acetate. After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered and concentrated to dryness. The residue was dissolved in acetonitrile (1 ml) and admixed with 10% hydrochloric acid. After stirring for 2 h, the mixture was diluted with water (3 ml) and freeze-dried. 68 mg of the title compound were obtained. After being stirred for 3 h left the phases were separated the aqueous phase was extracted twice with dichloromethane The combined organic phases were dried over magnesium sulfate filtered concentrated The residue was purified by means of preparative HPLC were purified the acetonitrile was removed on a rotary evaporator extracted three times with ethyl acetate After the combined ethyl acetate phases had been dried over magnesium sulfate, they were filtered concentrated to dryness The residue was dissolved in acetonitrile (1 ml) After stirring for 2 h the mixture was diluted with water (3 ml) freeze-dried

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.75 g (50 mmol) of 5-amino-2-chlorobenzotrifluoride and 7.15 g (50 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester were admixed and melted at 80° C. The melt was maintained at 80° C. for 30 minutes. The resulting product which was crystallized during the process, was recrystallized from isopropanol/methylene chloride and dried at 50° C. for 20 hours, under greatly reduced pressure, to yield N-[(3-Trifluoromethyl-4-chloro-phenyl)-carbamoyl]-2-methylalanine methyl ester, m.p. 141°-142° C. The resulting product which was crystallized during the process was recrystallized from isopropanol/methylene chloride dried at 50° C. for 20 hours, under greatly reduced pressure

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

Procedure: A solution of 17.0 g (119 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester in 150 ml of absolute tetrahydrofuran was added, over a 15 minute period to 15.1 g (119 mmol) of p-chloroaniline in 300 ml of absolute tetrahydrofuran. After refluxing the mixture for three days, the solution was evaporated to dryness. The product, after two recrystallizations from methylene chloride, was dried for 6 hours at 40° C., under greatly reduced pressure, to yield N-[(4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, m.p. 147°-148° C. After refluxing the mixture for three days the solution was evaporated to dryness The product, after two recrystallizations from methylene chloride was dried for 6 hours at 40° C., under greatly reduced pressure

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 9.75 g (50 mmol) of 5-amino-2-chlorobenzotrifluoride and 7.15 g (50 mmol) of 2-isocyanato-2-methylpropionic acid methyl ester were admixed and melted at 80° C. The melt was maintained at 80° C. for 30 minutes. The resulting product which was crystallized during the process, was recrystallized from isopropanol/methylene chloride and dried at 50° C. for 20 hours, under greatly reduced pressure, to yield N-[(3-Trifluoromethyl-4-chloro-phenyl)-carbamoyl]-2-methylalanine methyl ester, m.p. 141°-142° C. The resulting product which was crystallized during the process was recrystallized from isopropanol/methylene chloride dried at 50° C. for 20 hours, under greatly reduced pressure