Pregabalin Impurity 12 synthesis

Yield:930280-44-7 97%

Reaction Conditions:

with bromine;sodium methylate at -25 - 65; for 2 - 4 h;Product distribution / selectivity;Hofmann Rearrangement;

Steps:

7; 10; 13; 16; 20

three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methanol (2000 ml), (R)-3- isobutylpentanedioic acid amide-((S)-l-phenylmethyl) amide, compound of formula 1 (20Og, 0.689 mole) and cooled to 0° to 5°C followed by addition of sodium methoxide (149 g, 2.758 mole). The reaction mass was cooled to -15 to -25°C followed by addition of bromine (165.5 g, 1.034 mole) and stirred for 1-2 h at -15 to -25°C. The mixture was gradually warmed to a temperature of 0°C and then to 55-65°C, followed by stirring for 1 to 2 hours. The solvent was then stripped off and water was added to the mass. The resulted slurry was further extracted with toluene, toluene layer washed with brine followed by stripping off the solvent results in 215 g (97% yield) of {(S)-4-methyl-2-[((S)- 1 -phenylethylcarbamoyl)- methyl]pentyl}carbamic acid methyl ester (4) with a purity of 90.9% area, as measured by HPLC; Example 10: Preparation of (S)-PregabalinA three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methanol (2000 ml), (R)-3- isobutylpentanedioic acid amide-((S)-l-phenylmethyl) amide, compound of formula 1 (20Og, 0.689 mole) and cooled to 0° to 5°C followed by addition of sodium methoxide (149 g,2.758 mole). The reaction mass was cooled to -15 to -25°C followed by addition of bromine (165.5 g, 1.034 mole) and stirred for 1-2 h at -15 to -25°C. The mixture was gradually warmed to a temperature of 0°C and then to 55-65°C, followed by stirring for 1 to 2 hours. The solvent was then stripped off and water was added to the mass. The resulted slurry was further extracted with toluene, toluene layer washed with brine followed by stripping off the solvent. 4N hydrochloric acid (2580 ml), phenol (10.72 g, 0.114 mole) , sodium chloride (78.15 g, 1.342 mole) was added to the mass and was heated to 105°-l 10⁰C for 15-24 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 600ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 100ml of iso-butanol which on crystallization from isobutanol water mixture results in (S)-Pregabalin as white crystals in a 56% yield. Purity: 99.85% area by HPLC. N-benzylated pregabalin: 0.01% area by HPLC.; Example 13: Preparation of (SVPregabalinA three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methanol (2000 ml), (R)-3- isobutylpentanedioic acid amide-((S)-l-phenylmethyl) amide, compound of formula 1 (20Og, 0.689 mole) and cooled to 0° to 5°C, followed by addition of sodium methoxide (149 g, 2.758 mole). The reaction mass was cooled to -15 to -25°C, followed by addition of bromine (165.5 g, 1.034 mole) and was stirred for 1-2 h at -15 to -25°C. The mixture was gradually warmed to a temperature of 0°C and then to 55-65°C, followed by stirring for 1 to 2 hours. The solvent was stripped off and then 4N hydrochloric acid (2580 ml), phenol (10.72 g,0.114 mole) , and sodium chloride (78.15 g, 1.342 mole) were added to the mass, followed by heating to 105°-l 10°C for 15-24 hours, and then cooling to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 600ml of iso-butanol, and the organic layer was separated. Bu3N was added in an amount sufficient to provide a pH of 4. The crude (S)-Pregabalin was precipitated, filtered, and washed with 100ml of iso- butanol providing (S)-Pregabalin with purity of 95.87% area by HPLC.; Example 16: One pot Preparation of (S)-Pregabalin from (R)-3-isobutylpentanedioic acid amide-((SVl-phenylmethyl) amideA three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methanol (2000 ml), (R)-3- isobutylpentanedioic acid amide-((S)-l-phenylmethyl) amide, compound of formula 1 (50g, 0.172 mole) and cooled to 0° to 5°C followed by addition of sodium methoxide (37.25 g, 0.689 mole). The reaction mass was cooled to -15 to -25°C followed by addition of bromine (41.4 g, 0.258 mole) and stirred for 1-2 h at -15 to -25°C. The mixture was gradually warmed to a temperature of 0°C and then to 55-65°C, followed by stirring for 1 to 2 hours. The reaction was cooled to 25-30°C followed by addition of 4N hydrochloric acid (600 ml), phenol (2.42 g, 0.026 mole) , sodium chloride (10. Ig, 0.1724 mole). The mass was heated to 105°-l 10°C for 15-24 hours, and then cooled to room temperature, i.e., about 20° to about 25 °C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 300 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of -4-5. The (S)-Pregabalin was precipitated, filtered, and washed with 100ml of iso-butanol which on crystallization from isobutanol water mixture results in (S)-Pregabalin as white crystals in a 46% yield. Purity: 100% area by HPLC.; Example 20: Preparation of (S)-PregabalinA three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with methanol (2000 ml), (R)-3- isobutylpentanedioic acid amide-((S)-l-phenylmethyl) amide, compound of formula 1 (20Og, 0.689 mole) and cooled to 0° to 5°C, followed by addition of sodium methoxide (149 g,2.758 mole). The reaction mass was cooled to -15 to -25°C, followed by addition of bromine (165.5 g, 1.034 mole) and was stirred for 1-2 h at -15 to -25°C. The mixture was gradually warmed to a temperature of 0°C and then to 55-65°C, followed by stirring for 1 to 2 hours. The solvent was stripped off and then 4N hydrochloric acid (2580 ml), and sodium chloride (78.15 g, 1.342 mole) were added to the mass, followed by heating to 105°- 110°C for 15-24 hours, and then cooling to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 600ml of iso-butanol, which on crystallization from isobutanol water mixture resulted in (S)-Pregabalin as white crystals in a 64.9% yield; Purity 99.68% area by HPLC, N-benzylated pregabalin: 0.13% area by HPLC.

References:

WO2008/118427,2008,A2 Location in patent:Page/Page column 16-17; 19; 21; 23