99.11% |
With sodium hydrogencarbonate; potassium iodide;benzyltri(n-butyl)ammonium chloride; In tetrahydrofuran; at 30 - 55℃; for 5.0h; |
Example 1 Production of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A weight (17.9 g) of sodium salt 2.5 hydrate of (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (purity: 98.05%), potassium iodide (2.08 g), sodium hydrogencarbonate (0.84 g) and BTBAC (1.56 g) were mixed in THF (150 ml); to the mixture, 17.02 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity: 93.3%) was added and agitation was effected at 30C for 2 hours, then at 55C for 3 hours.. After the end of the reaction, the reaction mixture was washed once with 50 ml of water and twice with 50 ml of 20% aqueous sodium chloride adjusted to PH = 8 with sodium hydrogencarbonate; thereafter, the organic layer was concentrated under reduced pressure to give a mixture of the desired product and impurities.. The obtained mixture was subjected to quantitative analysis by liquid chromatography using acetophenone as an internal standard material; the end product was obtained in a yield of 99.11%. |
94.2% |
With sodium hydrogencarbonate; potassium iodide;tetrabutyl-ammonium chloride; In acetone; at 50℃; for 4.0h;Conversion of starting material; |
Example 2 Production of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate A weight (8.95 g) of sodium salt 2.5 hydrate of (5R,6S)-6-((R)-1-hydroxyethyl)-7-oxo-3-((R)-2-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (purity: 98.4%), potassium iodide (0.51 g), sodium hydrogencarbonate (0.21 g) and TBAC (0.40 g) were mixed in acetone (25 ml); to the mixture, 4.13 g of 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (purity: 97.2%) was added and agitation was effected at 50C for 4 hours to perform the reaction.. After filtering the reaction mixture to separate the inorganic salts insoluble in acetone, the solvent was distilled off under reduced pressure to obtain a mixture of the desired product and impurities.. The obtained mixture was subjected to quantitative analysis by liquid chromatography using acetophenone as an internal standard material; the desired product was obtained in a yield of 94.2%. |
70 - 97.4% |
With benzyltri(n-butyl)ammonium chloride; sodium hydrogencarbonate; potassium iodide; In tetrahydrofuran; at 30 - 55℃; for 6.0h;Product distribution / selectivity; |
(Example 1) (5R,6S)-6-(1-(R)-Hydroxyethyl)-7-oxo-3-(2-(R)-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt 2.5-hydrate (111.0 g, purity: 98.4%), potassium iodide (5.15 g), sodium bicarbonate (2.60 g) and BTBAC (3.87 g) were mixed in THF (465 ml). To this mixture, 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (50.48 g, purity: 97.2%) was added and stirred at 30C for 2 hours and then at 55C for 4 hours. After completion of the reaction, the reaction solution was washed once with water (155 ml) and twice with 20% aqueous sodium chloride (155 ml) which had been adjusted to pH 8 with potassium bicarbonate, followed by isolating the organic layer. In this way, a beta-lactam compound solution (534.7 g, hereinafter referred to as 'Solution A') was obtained, which contained a beta-lactam compound of Formula (5) (hereinafter referred to as 'Compound (5)'), iodine compounds, water and THF. By quantitative analysis using high performance liquid column chromatography, Solution A was found to contain the target Compound (5) in an amount of 22.44% by weight (yield: 97.4%). The water content in Solution A was about 4% by weight. Solution A thus obtained was placed in a vacuum of 17.3 to 19.3 kPa and at a temperature of 20C to 32C (bath temperature: 40C) to distill off THF. Whenever about 90 ml of THF was distilled off, Solution A was supplemented with 90 ml fresh THF. This procedure was repeated three times. In this way, a THF solution of Compound (5) was obtained. The resulting solution was a 0.9 L/mol solution of Compound (5). When the water content in Solution A was measured, it was 0.47% by weight. Solution A was then warmed to 75C and THF was distilled off to give a concentrated THF solution of Compound (5) (about 0.25 L/mol in THF), followed by addition of ethanol (95 ml). The resulting solution was stirred to give a homogenous solution and placed in a vacuum of 16 to 20 kPa at 23C to 40C (bath temperature: 23C to 40C) to distill off THF and ethanol. At this time, ethanol was added dropwise at a constant speed to keep the solution volume unchanged, thus obtaining Solution B. The total amount of ethanol added dropwise was 105 ml. Solution B was a 1.2 L/mol solution of Compound (5). Solution B was then cooled to 15C for 30 minutes to crystallize Compound (5). The precipitated crystals were collected by filtration and washed twice with cold ethanol (12 ml). The resulting crystals were dried to give crude crystals of Compound (5) (35.65 g) in 98.9% purity and 88.7% yield. The crude crystals of Compound (5) were suspended in ethanol (180 ml) and heated at 60C for 10 minutes to completely dissolve the crystals. After this solution was filtered under pressure, the resulting filtrate was held at around 30C for 30 minutes and then placed in a vacuum of 10.6 to 13.3 kPa at 30C to 35C to distill off 80 ml ethanol. The resulting solution was then cooled at 15C for 30 minutes to crystallize Compound (5). The crystallized crystals were collected by filtration and washed twice with cold ethanol (13 ml) to give crystals of Compound (5) in 99.5% purity and 85.1% yield. |