1-chloroethyl 2,2-dimethylpropanoate

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

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

Procedure: In an operation carried out in a manner similar to that described in Example 1, 42.3 grams (0.2 mole) of methyldopa, 40.3 milliliters (0.24 mole) of 1-chloroethyl pivalate, 14 grams of 4A molecular sieve pellets (1/16") and 85 milliliters of tetramethylurea are mixed together and heated in an atmosphere of nitrogen to 70° C. and maintained at this temperature for about 30 hours. During this time, the methyldopa dissolves with the formation of (R,S)-1-pivaloyloxyethyl ester product. Thereafter, the reaction mixture is cooled to 25° C. and diluted with 380 milliliters of toluene. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution and filtered to clarify the solution. To this solution is added 300 milliliters of isopropanol followed by 16.6 grams (0.14 mole) of 85 percent phosphoric acid and 0.100 gram of methyldopa (R,S)-POE ester phosphoric acid monoisopropanolate seed whereupon the product crystallizes. The crystal-containing slurry is aged for 16 hours at 20°-25° C., then filtered and washed with two 75 milliliter portions of isopropanol and dried in vacuo to obtain (R,S)-1-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate, phosphoric acid, monoisopropanolate salt. are mixed together maintained at this temperature for about 30 hours Thereafter, the reaction mixture is cooled to 25° C. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution filtered To this solution is added 300 milliliters of isopropanol crystallizes filtered washed with two 75 milliliter portions of isopropanol dried 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 an operation carried out in a manner similar to that described in Example 1, 42.3 grams (0.2 mole) of methyldopa, 40.3 milliliters (0.24 mole) of 1-chloroethyl pivalate, 14 grams of 4A molecular sieve pellets (1/16") and 85 milliliters of tetramethylurea are mixed together and heated in an atmosphere of nitrogen to 70° C. and maintained at this temperature for about 30 hours. During this time, the methyldopa dissolves with the formation of (R,S)-1-pivaloyloxyethyl ester product. Thereafter, the reaction mixture is cooled to 25° C. and diluted with 380 milliliters of toluene. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution and filtered to clarify the solution. To this solution is added 300 milliliters of isopropanol followed by 16.6 grams (0.14 mole) of 85 percent phosphoric acid and 0.100 gram of methyldopa (R,S)-POE ester phosphoric acid monoisopropanolate seed whereupon the product crystallizes. The crystal-containing slurry is aged for 16 hours at 20°-25° C., then filtered and washed with two 75 milliliter portions of isopropanol and dried in vacuo to obtain (R,S)-1-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate, phosphoric acid, monoisopropanolate salt. are mixed together maintained at this temperature for about 30 hours Thereafter, the reaction mixture is cooled to 25° C. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution filtered To this solution is added 300 milliliters of isopropanol crystallizes filtered washed with two 75 milliliter portions of isopropanol dried in vacuo

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

Procedure: A solution of (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (70.2 mg, 0.137 mmol), 2,2-Dimethyl-propionic acid 1-chloro-ethyl ester (51 mg, 0.310 mmol), triethylamine (22 mg, 0.217 mmol) and sodium iodide (15 mg, 0.10 mmol) in anhydrous DMF (2.5 mL) was microwaved at 150° C. for 10 min and then concentrated at reduced pressure to remove most of the DMF. The residue was diluted with ethyl acetate (40 mL), washed with water (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (50% to 80% EtOAc in hexanes) to give(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 1-(2,2-dimethyl-propionyloxy)-ethyl ester (25.4 mg, 28.9%) as a yellow solid. MS m/e 641.7 (M+H+). concentrated at reduced pressure to remove most of the DMF The residue was diluted with ethyl acetate (40 mL) washed with water (10 mL), brine (10 mL) dried over MgSO4 filtered concentrated under reduced pressure The resulting crude compound was purified by flash chromatography (50% to 80% EtOAc in hexanes) to give(S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 1-(2,2-dimethyl-propionyloxy)-ethyl ester (25.4 mg, 28.9%) as a yellow solid

Conditions: temp:25.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 10 grams (0.047 mole) of α-methyldopa, 4.7 grams of powdered 4A molecular sieves, 6.1 grams (0.070 mole) of lithium bromide and 47 milliliters of N-methylpyrrolidinone were stirred for about one hour at 25° C. To this mixture, 8.1 grams (0.049 mole) of α-chloroethyl pivalate was added and the mixture was aged at 55° C. for 8 hours. At the end of this time, the mixture was cooled to 25° C., diluted with 100 milliliters of ethyl acetate and washed successively with one 200 milliliter and two 100 milliliter portions of saturated sodium bicarbonate solution. The combined sodium bicarbonate washes were extracted with two 100 milliliter portions of ethyl acetate and the combined ethyl acetate extracts concentrated under vacuum to 150 milliliters. The assay yield of α-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate was found to be 14.4 grams or 90 percent of theoretical. the mixture was aged at 55° C. for 8 hours At the end of this time, the mixture was cooled to 25° C. washed successively with one 200 milliliter and two 100 milliliter portions of saturated sodium bicarbonate solution The combined sodium bicarbonate washes were extracted with two 100 milliliter portions of ethyl acetate the combined ethyl acetate extracts concentrated under vacuum to 150 milliliters

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

Procedure: In an operation carried out in a manner similar to that described in Example 1, 42.3 grams (0.2 mole) of methyldopa, 40.3 milliliters (0.24 mole) of 1-chloroethyl pivalate, 14 grams of 4A molecular sieve pellets (1/16") and 85 milliliters of tetramethylurea are mixed together and heated in an atmosphere of nitrogen to 70° C. and maintained at this temperature for about 30 hours. During this time, the methyldopa dissolves with the formation of (R,S)-1-pivaloyloxyethyl ester product. Thereafter, the reaction mixture is cooled to 25° C. and diluted with 380 milliliters of toluene. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution and filtered to clarify the solution. To this solution is added 300 milliliters of isopropanol followed by 16.6 grams (0.14 mole) of 85 percent phosphoric acid and 0.100 gram of methyldopa (R,S)-POE ester phosphoric acid monoisopropanolate seed whereupon the product crystallizes. The crystal-containing slurry is aged for 16 hours at 20°-25° C., then filtered and washed with two 75 milliliter portions of isopropanol and dried in vacuo to obtain (R,S)-1-pivaloyloxyethyl (S)-3-(3,4-dihydroxyphenyl)-2-methylalaninate, phosphoric acid, monoisopropanolate salt. are mixed together maintained at this temperature for about 30 hours Thereafter, the reaction mixture is cooled to 25° C. The mixture is then washed with three 500 milliliter portions of saturated sodium bicarbonate solution filtered To this solution is added 300 milliliters of isopropanol crystallizes filtered washed with two 75 milliliter portions of isopropanol dried in vacuo