Synthesizing process of (S)-2-benzyloxy-pentan-3-one

A benzyloxypentyl, synthesis process technology, applied in the field of chemical synthesis, can solve problems such as not suitable for the preparation of kilogram-scale products, and achieve the effects of short time consumption, increased reaction temperature, and high safety performance

Active Publication Date: 2013-07-10
山东格新精工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Also, dropwise addition of the Grignard reagent ethylmagnesium bromide to the tetrahydrofuran solution of compound 2 brings the danger of transferring the Grignard reagent, especially not suitable for the preparation of kilogram-scale products

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0026] Step (1). Add ethyl lactate (118g, 1mol) and tetrahydropyrrole (142g, 2mol) to a 1L three-necked reaction flask equipped with mechanical stirring, reflux condenser and thermometer, stir at room temperature for 30 minutes, and then heat to After refluxing for 24 hours, the temperature was lowered to 50° C., and excess tetrahydropyrrole and by-product ethanol were evaporated under reduced pressure to obtain 142 g of compound amide with a purity of 98%, which was directly used in the next reaction.

[0027] Step (2). Add the reaction product compound amide (1mol, 143g), potassium hydroxide (1.5mol), benzyl chloride (1.3mol) and 1000 ml of toluene to a 2L three-necked reaction flask equipped with mechanical stirring and a thermometer , stirred vigorously at 80-90°C for 10 hours, followed by GC analysis, and when the reaction reached the end point, add 200ml of water to separate the layers, extract the aqueous layer with 500ml of toluene, combine the organic layers, and wash ...

Embodiment 2

[0031] Step (1). Add (S)-2-hydroxypropionic acid ethyl ester (118g, 1mol) and tetrahydropyrrole (213g, 3mol) to a 1L three-necked reaction flask equipped with mechanical stirring, reflux condenser and thermometer, at room temperature Stir at low temperature for 30 minutes, then heat to reflux for about 12 hours, cool to 60°C, and evaporate excess tetrahydropyrrole and by-product ethanol under reduced pressure to obtain 143 g of crude product with a purity of 98%, which is directly used in the next reaction.

[0032]Step (2). Add compound amide (1mol, 143g), sodium hydroxide (3mol), benzyl chloride (1.3mol) and 1000ml of 2-methyltetrahydrofuran to a 2L three-necked reaction flask equipped with mechanical stirring and a thermometer, Stir vigorously at 60-80°C for 3 hours, follow-up analysis by GC, add 200ml of water to separate layers after the reaction reaches the end point, extract the aqueous layer with 500ml of 2-methyltetrahydrofuran, combine the organic layers, and wash wit...

Embodiment 3

[0036] Step (1). Add ethyl lactate (118g, 1mol) and tetrahydropyrrole (213g, 3mol) to a 1L three-necked reaction flask equipped with mechanical stirring, reflux condenser and thermometer, stir at room temperature for 30 minutes, and then heat to After refluxing for 16 hours, the temperature was lowered to 50°C, and excess tetrahydropyrrole and by-product ethanol were evaporated under reduced pressure to obtain 141 g of compound amide with a purity of 98.5%, which was directly used in the next reaction.

[0037] Step (2). Add the reaction product compound amide (1mol, 143g), sodium carbonate (3mol), benzyl chloride (1.5mol) and 1000ml of 2-methanol to a 2L three-necked reaction flask equipped with mechanical stirring and a thermometer 2-methyltetrahydrofuran, stirred vigorously at 60-75°C for 3 hours, followed by GC analysis. After the reaction reached the end point, 200ml of water was added to treat the layers, and the aqueous layer was extracted with 500ml of 2-methyltetrahydr...

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PUM

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Abstract

The invention discloses a synthesizing process of (S)-2-benzyloxy-pentan-3-one. The synthesizing process comprises the following steps: (1) mixing ethyl lactate with nafoxidine in proportion and performing a reflux reaction for 12 to 48 hours, thereby generating an amide compound; (2) mixing the amide compound with benzyl chloride, alkali and a solvent and reacting, cooling to normal temperature after the reaction, washing an organic layer by using water, concentrating the organic layer under reduced pressure and removing primary distillates, thereby obtaining benzyl-protected amide; and (3) dripping a tetrahydrofuran solution of the benzyl-protected amide into a tetrahydrofuran solution of ethylmagnesium bromide and reacting, adjusting the pH value by using an acid solution after the reaction, extracting a water layer after layering, combining the organic layers, drying, filtering and concentrating filtrate until the filtrate becomes dry, thereby obtaining (S)-2-benzyloxy-pentan-3-one. The synthesizing process is relatively simple to operate, high in safety and low in raw material cost, thereby satisfying the industrial amplification requirement.

Description

technical field [0001] The invention belongs to the field of chemical synthesis and relates to the synthesis of chiral small molecules. The final object is a very useful intermediate for synthesizing antifungal drug Posaconazole. Background technique [0002] Posaconazole is a class of broad-spectrum antifungal drugs. Compared with ketoconazole, fluconazole, and itraconazole, it has higher efficacy and safety, especially in the prevention of fungal infection in leukemia patients undergoing bone marrow transplantation. effect is more pronounced. There are many steps in the synthesis of posaconazole (Posaconazole), which requires more than 20 steps of reaction to complete. The earliest literature reports came from the patent [WO95 / 17407; US005661151A; US005714490A; WO2009 / 141837A2] in the mid-1990s, and the synthesis of related intermediates was reported successively. Wherein, in the preferred synthetic route, (S)-2-benzyloxy-1-(tetrahydropyrrol-1-yl)-propyl-1-one is an impo...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C49/255C07C45/45
Inventor 郭命汇梁建明陈荣伟吕东
Owner 山东格新精工有限公司
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