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Method for preparing Landiolol oxalate

A technology of devolol oxalate and alkali metal carbonate, applied in the directions of carboxylate preparation, organic chemistry, etc., can solve the problems of difficult to use pharmaceutical injection preparations, low product yield, poor quality, etc., and avoid alcohol Solution, simple operation, improved productivity and product quality effect

Active Publication Date: 2014-08-27
ZEIN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the above patents and related literature reports, isopropanol / water is used as the solvent, and the target object is very easy to undergo transesterification or alcoholysis with alcohol in an alkaline environment, resulting in low product yield and poor quality, which is difficult to use Drug Injection Preparations

Method used

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  • Method for preparing Landiolol oxalate
  • Method for preparing Landiolol oxalate
  • Method for preparing Landiolol oxalate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Embodiment 1, the preparation of compound I

[0031] Add 1565.5g of compound III and 3000g of water into the reaction flask, stir and heat up to t 内 =45°C, dissolve clear, use 1190g of 40% sodium hydroxide (475g of sodium hydroxide dissolved in 715g of water) to adjust the pH to 10-11, control the temperature below 50°C, a large amount of yellow solid precipitates, cool down to 30-35°C in an ice bath , add 500g of compound Ⅱ, 3000g of N,N-dimethylformamide, keep the reaction at 30~35℃ for 3~4h, after TLC confirms that the reaction of compound Ⅱ is complete, filter, extract the filtrate with 800mL×3 isopropyl ether, collect water layer, extracted with 3000 mL×4 ethyl acetate, combined the organic layers, and washed with 5000 mL×3 saturated brine. Collect the organic layer, add 2000g of anhydrous sodium sulfate and 100g of activated carbon, stir and dry for 2-3 hours to decolorize. Filtrate, evaporate the filtrate to dryness at 60°C under reduced pressure, add 5.0kg o...

Embodiment 2

[0032] Embodiment 2, the preparation of compound I

[0033] Add 1956.9g of compound III and 5000g of water into the reaction flask, stir and heat up to t内 =45°C, dissolve clear, use 1313g of 40% sodium hydroxide (525g of sodium hydroxide dissolved in 788g of water) to adjust the pH to 10-11, control the temperature below 50°C, a large amount of yellow solid precipitates, cool down to 40-45°C in an ice bath , add 500g of compound II, 5000g of dimethyl sulfoxide, and incubate at 40-45°C for 3-4h. After TLC confirms that the reaction of compound II is complete, filter and extract the filtrate with 800mL×3 isopropyl ether, collect the aqueous layer, and wash with 3000mL× 4 Extract with ethyl acetate, combine the organic layers, and wash with 5000 mL×3 saturated brine. Collect the organic layer, add 2000g of anhydrous sodium sulfate and 100g of activated carbon, stir and dry for 2-3 hours to decolorize. Filtrate, evaporate the filtrate to dryness under reduced pressure at 60°C, ...

Embodiment 3

[0034] Embodiment 3, the preparation of compound I

[0035] Add 1174.2g of compound III and 1500g of water into the reaction flask, stir and heat up to t 内 =45°C, dissolve clear, use 40% sodium hydroxide 1063g (425g sodium hydroxide dissolved in 638g water) to adjust the pH to 10-11, control the temperature below 50°C, a large amount of yellow solid precipitates, at 45-50°C, add the compound Ⅱ 500g, N,N-dimethylacetamide 1500g, keep the reaction at 45~50℃ for 3~4h, TLC confirms that the reaction of compound Ⅱ is complete, filter, and extract the filtrate with 800mL×3 isopropyl ether, collect the water layer, and use Extract with 3000 mL×4 ethyl acetate, combine the organic layers, and wash with 5000 mL×3 saturated brine. Collect the organic layer, add 2000g of anhydrous sodium sulfate and 100g of activated carbon, stir and dry for 2-3 hours to decolorize. Filtrate, evaporate the filtrate to dryness under reduced pressure at 60°C, add 6.5kg of absolute ethanol to the residu...

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Abstract

The invention discloses a method for preparing Landiolol oxalate. The method comprises the steps of enabling (2,2-dimethyl-1,3-dioxolane-4S-yl)methyl-3-[4-(2(S),3-epoxypropyl)phenyl] propionate (a compound represented by a formula II) and N-(2-aminoethyl)-4-morpholino-carboxamide oxalate (a compound represented by a formula III), which serve as raw materials, to be subjected to carrying out ring cleavage reaction (2,2-dimethyl-1,3-dioxolane-4S-yl)methyl-3-[4-(2(S),3-epoxypropyl)phenyl] propionate (a compound represented by a formula II) and N-(2-aminoethyl)-4-morpholino-carboxamide oxalate (a compound represented by a formula III) serving as raw materials in an appropriate solvent, thereby preparing [(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl-3-[4-[(2S)-2-hydroxy-3-[2(morpholino-4-formylamino)ethylamino]propoxy]phenyl]propionate oxalate (a compound represented by a formula I). The method disclosed by the invention has the advantages of mild synthesis process reaction conditions, low cost, high product yield good quality and the like, and is simple to operate and applicable to industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a preparation process of landisolol oxalate, which is an important intermediate product for preparing landisolol hydrochloride. Background technique [0002] During surgery, various stimuli to the body due to endotracheal intubation, extubation, skin incision, and surgical operations cause sympathetic nerve excitement, release excess catecholamines, increase heart rate, and easily lead to tachycardia. out of order. Especially in patients with ischemic heart disease and high blood pressure, the load on the heart will be increased just because of the increase in the heart rate, thereby causing coronary ischemia. Therefore, anesthesia surgery, especially in patients with ischemic heart disease or hypertension, has great risks. According to literature reports, even in countries with advanced medical facilities and technologies such as Europe and the United States, the inc...

Claims

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Application Information

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IPC IPC(8): C07D317/24C07C55/07C07C51/41
CPCC07D317/24
Inventor 邓祥林陈磊肖玉梅罗礼平王晓琳吴晶张竞李宏伟黄超民谭瑶余佳
Owner ZEIN BIOTECHNOLOGY CO LTD
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