Method for synthesizing novel meropenem chiral side chain
A technology of chiral side chains and synthetic methods, which is applied in the field of synthesis of meropenem intermediates, can solve the problems of difficult production safety, meropenem color difference, and low optical purity, and achieve low price, stable product quality, and optical purity high effect
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Embodiment 1
[0024] The synthesis method of the novel chiral side chain of meropenem adopts the following steps:
[0025] a) Synthesis of compound (Ⅲ):
[0026] Dissolve 22.4 g of sodium hydroxide in 280 mL of water, cool down to 25°C, add 33g of (2S,4R)-4-hydroxyproline, and keep warm at 25°C. Dissolve 33.7mL of allyl chloroformate in 231 mL of dichloromethane, drop into the above solution, and stir at 25°C for 2h. After separation, the aqueous layer was washed with 100 mL of dichloromethane twice. The aqueous layer was adjusted to pH=1, extracted with 200 mL of ethyl acetate, the ethyl acetate layer was dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain an oily substance. Add 280mL of toluene to the oil, stir and crystallize, and filter to obtain 48.9g of solid, yield 90%.
[0027] m.p.=90.8-91.8°C, [α]D25=-81.5° (c=1, MeOH).
[0028] 1H-NMR (300MHz, DMSO-d6)δ: 12.6 (s, 1H, COOH), 5.9 (m, 1H, =CH),5.05-5.35 (m, 2H, =CH2), 5....
Embodiment 2
[0043] The synthesis method of the novel chiral side chain of meropenem adopts the following steps:
[0044] a) Synthesis of compound (Ⅲ):
[0045] Dissolve 22.4g of sodium hydroxide in 280mL of water, cool down to 25°C, add 33g of (2S,4R)-4-hydroxyproline, and keep warm at 25°C. Dissolve 33.7mL of allyl chloroformate in 231mL of dichloromethane, drop into the above solution, and stir at 25°C for 2h. After the layers were separated, the aqueous layer was washed with 100 mL of dichloromethane twice. The aqueous layer was adjusted to about pH=1, extracted with 200 mL of ethyl acetate, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. Filter and concentrate to dryness under reduced pressure to obtain an oil. Add 280mL toluene to the oil, stir and crystallize, filter to obtain 48.9g solid, yield 90%;
[0046] b) Synthesis of compound (IV):
[0047] Add 48.9g of compound (Ⅲ), 1000mL of dichloromethane, and 23.1mL of triethylamine into a 2000mL four-neck f...
Embodiment 3
[0054] The synthesis method of the novel chiral side chain of meropenem adopts the following steps:
[0055] a) Synthesis of compound (Ⅲ):
[0056] Dissolve 31.4g of potassium hydroxide in 280mL of water, cool down to 20°C, add 33g of (2S,4R)-4-hydroxyproline, and keep warm at 20°C. Dissolve 33.7 mL of allyl chloroformate in 231 mL of dichloromethane, drop into the above solution, and react with stirring at 20°C for 2 hours. After separation, the aqueous layer was washed with 100 mL of dichloromethane twice. Adjust the aqueous layer to about pH=1, extract with 200mL butyl acetate, and dry the butyl acetate layer with anhydrous magnesium sulfate. Concentrate under reduced pressure to dryness to obtain an oily substance, add 280mL toluene to the oily substance, stir and crystallize, filter to obtain 49.3g solid, yield 91%;
[0057] b) Synthesis of compound (IV):
[0058] Add 49.3g of compound (Ⅲ), 1000mL of dichloroethane, and 23.2mL of triethylamine into a 2000 mL four-neck...
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