(2S)-1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 23.3 g of pure levobupivacaine free base were dissolved in 125 mL of hot isopropanol. To this solution was added 8.8 mL of concentrated hydrochloric acid. The solution was cooled to room temperature and kept at a temperature between 4° C. to 6° C. for two hours. The mixture was vacuum filtered and the solids were stirred with 20 mL of acetone. The mixture was filtered and the solid was allowed to dry in an oven yielding 24.2 g of levobupivacaine hydrochloride ee>99.5%, MP=246-250° C., [α]D25=−12 (c=2, H2O). filtered The mixture was filtered to dry in an oven

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 45 g of levobupivacaine tartrate were dissolved in 222 mL of water under stirring. Concentrated ammonium hydroxide was added under stirring until the pH adjusted at 9-10. The solids were filtered and washed with 222 mL of water. The solids were dried in an oven with temperature around 45° C. until constant weight. Yield 27.6 g of enriched levobupivacaine free base (70%≦ee≦80%), MP=125-132° C. under stirring until the pH The solids were filtered washed with 222 mL of water The solids were dried in an oven with temperature around 45° C. until constant weight

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 45 g of levobupivacaine tartrate were dissolved in 222 mL of water under stirring. Concentrated ammonium hydroxide was added under stirring until the pH adjusted at 9-10. The solids were filtered and washed with 222 mL of water. The solids were dried in an oven with temperature around 45° C. until constant weight. Yield 27.6 g of enriched levobupivacaine free base (70%≦ee≦80%), MP=125-132° C. under stirring until the pH The solids were filtered washed with 222 mL of water The solids were dried in an oven with temperature around 45° C. until constant weight

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a first vial, levobupivacaine-HCl (6, 12.5 or 25 mg), tetrafunctional PEG, pentaerythritol poly(ethylene glycol) ether tetra-N-hydroxy-succinimidyl glutarate (10,000 g/mol) (SG-PEG) (50 mg) and tetrafunctional PEG, pentaerythritol poly(ethylene glycol) ether tetra-sulfhydryl (10,000 g/mol) (PEG-SH) (50 mg) were dissolved in 250 μL of pH 2.2 buffer. This solution was combined with an equal volume of carbonate buffer (pH 9.7) using a spray kit. Levobupivacaine precipitated within the gel upon mixing. All levobupivacaine-loaded gels swelled 1.5-2 times their original volume except for the gel containing the highest amount of levobupivacaine, which swelled about 4 times its initial volume. In vitro release studies showed a steady release of levobupivacaine from the gel. At 9 days, 30% of the drug was released. Levobupivacaine precipitated within the gel upon mixing containing the highest amount of levobupivacaine, which

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a first vial, levobupivacaine-HCl (25 mg), 4-arm PEG succinimidyl carbonate (60 mg) and 4-arm PEG-SH (60 mg) were dissolved in 250 μL of pH 2.2 buffer. This solution was combined with an equal volume of carbonate buffer (pH 9.7) through a spray kit. Levobupivacaine precipitated within the gel upon mixing. The levobupivacaine-loaded TC gel swelled 2-2.5 times its original volume. Levobupivacaine precipitated within the gel upon mixing

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: In a first vial, levobupivacaine-HCl (25 mg), 4-arm PEG succinimidyl carbonate (60 mg) and 4-arm PEG-SH (60 mg) were dissolved in 250 μL of pH 2.2 buffer. This solution was combined with an equal volume of carbonate buffer (pH 9.7) through a spray kit. Levobupivacaine precipitated within the gel upon mixing. The levobupivacaine-loaded TC gel swelled 2-2.5 times its original volume. Levobupivacaine precipitated within the gel upon mixing

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A stirred mixture of (S)-bupivacaine (0.140 g, 0.49 mmol) and propanoic acid (3.5 ml) was heated to reflux under a nitrogen atmosphere for 7 hours. The resulting solution was cooled and then poured into a mixture of distilled water (20 ml) and ethyl acetate (20 ml). Aqueous ammonia (28% w/v) was added until the pH of the aqueous layer was 10. The organic layer was separated and the aqueous layer extracted with ethyl acetate (20 ml). The combined organic extracts were washed with distilled water (20 ml), dried (MgSO4) and concentrated under reduced pressure to give racemic bupivacaine (0.137 g, 98%). ##STR1## was heated to reflux under a nitrogen atmosphere for 7 hours The resulting solution was cooled The organic layer was separated the aqueous layer extracted with ethyl acetate (20 ml) The combined organic extracts were washed with distilled water (20 ml) dried (MgSO4) concentrated under reduced pressure

反応条件: temp:138.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of (S)-bupivacaine (>99% ee, 1.5 g mmol), ethylene glycol (13.5 ml) and water (1.5 ml) was heated at 138° C. for 9 hours. On cooling to ambient temperature crystallisation of a solid occurred. The solid was filtered to give a quantitative yield of bupivacaine which was shown by chiral HPLC analysis to be a 52:48 mixture of (S)-bupivacaine and (R)-bupivacaine. On cooling to ambient temperature crystallisation of a solid The solid was filtered

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 23.3 g of pure levobupivacaine free base were dissolved in 125 mL of hot isopropanol. To this solution was added 8.8 mL of concentrated hydrochloric acid. The solution was cooled to room temperature and kept at a temperature between 4° C. to 6° C. for two hours. The mixture was vacuum filtered and the solids were stirred with 20 mL of acetone. The mixture was filtered and the solid was allowed to dry in an oven yielding 24.2 g of levobupivacaine hydrochloride ee>99.5%, MP=246-250° C., [α]D25=−12 (c=2, H2O). filtered The mixture was filtered to dry in an oven

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 45 g of levobupivacaine tartrate were dissolved in 222 mL of water under stirring. Concentrated ammonium hydroxide was added under stirring until the pH adjusted at 9-10. The solids were filtered and washed with 222 mL of water. The solids were dried in an oven with temperature around 45° C. until constant weight. Yield 27.6 g of enriched levobupivacaine free base (70%≦ee≦80%), MP=125-132° C. under stirring until the pH The solids were filtered washed with 222 mL of water The solids were dried in an oven with temperature around 45° C. until constant weight