Method for preparing 4-substituted chirality oxazolidinone compounds

A technology for oxazolidinones and compounds, applied in the field of preparation of chiral 4-substituted oxazolidinones, can solve problems such as potential safety hazards, and achieve the effects of reducing waste water discharge, reducing production costs, and reducing potential safety hazards

Active Publication Date: 2008-07-30
SUQIAN KEYLAB BIOCHEMICAL CO LTD
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AI-Extracted Technical Summary

Problems solved by technology

[0007] The technical problem to be solved by the present invention is: the use of phosgene in the prior art to carry out acylation ...
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Abstract

The invention relates to a preparation method of chiral 4-substituted oxazolidone, which belongs to the pharmaceutical chemistry technical field. Chiral amino acid ester or chiral amino acid ester salt is added into a solvent, supercarbonate is charged, chloro formate is titrated at the room temperature, and mixed for 5 to 8 hours at the room temperature after titration is completed, filtering is performed, and the solvent is recovered to obtain an intermediate compound a; the intermediate compound a is adopted in an anhydrous chloride solution for accelerating the catalyst of borohydride, reaction is performed for 4 to 10 hours at 0 to 40 DEG C, the solvent is recovered, a citric acid solution is added, extraction is performed by using ethyl acetate, an organic layer is combined, the solvent is recovered, and then an intermediate compound b is obtained; potassium carbonate is added into the intermediate compund b, heating, back flow and water diversion are performed for 2 to 4 hours, pump filtering is performed before cooling down, the filter liquor is cooled and recrystallized, pump filtering and drying are then performed to obtain a white crystalline solid 4-substituted chiral oxazolidone chemical compound. The invention provides the preparation method of a 4-substituted chiral oxazolidone chemical compound, the invention aims at the problem of significant safe hidden danger caused when phosgene is adopted for acidylation and cyclization in the prior art.

Application Domain

Asymmetric syntheses

Technology Topic

SolventBorohydride +20

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  • Method for preparing 4-substituted chirality oxazolidinone compounds
  • Method for preparing 4-substituted chirality oxazolidinone compounds
  • Method for preparing 4-substituted chirality oxazolidinone compounds

Examples

  • Experimental program(4)

Example Embodiment

[0019] Example 1: Preparation of s-(+)-4-benzyl-2-oxazolidinone
[0020] Add 26.1 g (0.12 mol) of L-phenylalanine methyl ester hydrochloride to 100 ml of dichloromethane, 30.2 g (0.36 mol) of sodium bicarbonate, and drop 14.3 g (0.13 mol) of methyl chloroformate at room temperature, After dripping, stir at room temperature for 6 hours, filter, and recover the solvent dichloromethane to obtain an oily substance Add 400ml of absolute ethanol, add 13.3g (0.12mol) of calcium chloride, 12.9g (0.24mol) of potassium borohydride, react at 15~25℃ until reduction is complete, recover the solvent ethanol, add 150ml of 1M citric acid, use ethyl acetate The ester is extracted twice, with the amount of 200ml for each extraction, the organic layers are combined, and the solvent ethyl acetate is recovered to obtain the reduced product Add 160ml of toluene, 33g of potassium carbonate (0.24mol), heat reflux and separate water for 2 hours, filter while hot, and cool the filtrate to crystallize, filter and dry to obtain a white crystalline solid s-(+)-4-benzyl- 19.5 g of 2-oxazolidinone, yield: 91% (calculated as p-L-phenylalanine methyl ester hydrochloride), HPLC purity: ≥ 98.5%, ee value: 99.5% or more.
[0021]
[0022] s-(+)-4-benzyl-2-oxazolidinone

Example Embodiment

[0023] Example 2: Preparation of R-(-)-4-benzyl-2-oxazolidinone
[0024] Add 100ml of dichloromethane and 30.2g (0.36mol) of sodium bicarbonate to 26.1g (0.12mol) of D-phenylalanine methyl ester hydrochloride, and add 14.3g (0.13mol) of ethyl chloroformate dropwise at room temperature, After dripping, stir at room temperature for 6 hours, filter, and recover the solvent dichloromethane to obtain an oily substance , Add 400ml of absolute ethanol, add 13.3g (0.12mol) of anhydrous calcium chloride, 12.9g (0.24mol) of potassium borohydride, react at 15~25℃ until reduction is complete, recover the solvent ethanol, add 150ml of 1M citric acid, Two extractions were carried out with ethyl acetate, the amount of each extraction was 200ml, the organic layers were combined, and the solvent ethyl acetate was recovered to obtain the reduced product. Add 160ml of toluene, 33g of potassium carbonate (0.24mol), heat reflux and separate water for 2 hours, filter while hot, and cool the filtrate to crystallize, filter and dry to obtain a white crystalline solid R-(-)-4-benzyl- 19.7 g of 2-oxazolidinone, yield: 92% (calculated as p-D-phenylalanine methyl ester hydrochloride), HPLC purity: ≥ 98.5%, ee value: 99.5% or more.
[0025]
[0026] R-(-)-4-benzyl-2-oxazolidinone

Example Embodiment

[0027] Example 3: Preparation of s-(+)-4-phenyl-2-oxazolidinone
[0028] To 24.4 g (0.12 mol) of L-phenylglycine methyl ester hydrochloride, 100 ml of dichloromethane and 30.2 g (0.36 mol) of sodium bicarbonate were added, and 14.3 g (0.13 mol) of ethyl chloroformate was added dropwise at room temperature. After stirring at room temperature for 6 hours, filter and recover the solvent dichloromethane to obtain an off-white solid Add 400ml of absolute ethanol, add 13.3g (0.12mol) of anhydrous calcium chloride, 12.9g (0.24mol) of potassium borohydride, react at 15~25℃ until reduction is complete, recover the solvent ethanol, add 150ml of 1M citric acid, use Ethyl acetate was extracted twice, the amount of each extraction was 200ml, the organic layers were combined, and the solvent ethyl acetate was recovered to obtain the reduced product Add 160ml toluene, 33g potassium carbonate (0.24mol), heat and reflux water for 2 hours, filter while hot, cool the filtrate to crystallize, filter with suction, and dry to obtain white crystalline solid s-(+)-4-phenyl-2 -Oxazolidinone 17.8g, yield: 90% (calculated as L-phenylglycine methyl ester hydrochloride), HPLC purity: ≥98.5%, ee value: 99.5% or more.
[0029]
[0030] s-(+)-4-phenyl-2-oxazolidinone

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