Preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one

A kind of technology of phenyl oxazolidinone and dioxopentyl, which is applied in the field of organic synthesis and can solve the problems such as affecting yield and being difficult to separate

Inactive Publication Date: 2012-11-14
SHANGHAI INST OF PHARMA IND CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] This impurity (structural formula V) is quite polar with the compound of structural formula I, is difficult to separate, so has influenced this step yield
The total yield of formula I compound is only 72%

Method used

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  • Preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one
  • Preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one
  • Preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one

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preparation example Construction

[0043] Specifically, the present invention provides a preparation of 3-(5-methoxy-1,5-dioxopentyl)-(4S)-phenyloxazolidin-2-one with significantly higher yield method comprising the steps of:

[0044] In the first step, glutaric anhydride and methanol are mixed in an organic solvent, and the reaction is complete at the reflux temperature of the organic solvent to obtain a mixture 1, which contains monomethyl glutarate and glutaric acid;

[0045] In the second step, remove the organic solvent in Compound 1, mix the residue with methylene chloride, the weight-to-volume ratio of the residue to methylene chloride is 1: 16-18, add saturated sodium chloride solution to this solution, and the volume is 1 / 10-1 / 6 of the volume of dichloromethane, washed 3 times until the amount of glutaric acid is very small, separated, the dichloromethane layer was dried with anhydrous magnesium sulfate, concentrated to obtain monomethyl glutarate.

[0046] The third step is to mix monomethyl glutarat...

Embodiment 1

[0067] Preparation of monomethyl glutarate (II)

[0068] Add 125.0g of glutaric anhydride (90% purity) and 35.0g of methanol to 375ml of chloroform, and heat to 60°C for 5h. TLC (thin layer chromatography) showed that after the reaction was complete (see figure 1 ), the solvent was evaporated under reduced pressure, dichloromethane (2L) was added to the residue, and washed with saturated sodium chloride solution (250ml×3) (see figure 2 ), dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain 145.0 g of II with a yield of 90% (the yield of the crude product in literature was 99%).

Embodiment 2

[0070] Preparation of methyl 4-chloroformyl butyrate (III)

[0071] Add 145.0g II to 236.0g thionyl chloride, and heat to 80°C for 3h. After removing the remaining thionyl chloride by distillation under reduced pressure, continue the distillation under reduced pressure to collect the fraction at 60°C / 200Pa to obtain 158.0g III of colorless transparent liquid with a yield of 97%, (97% yield in literature, bp 96-98°C / 10mmHg).

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Abstract

The invention discloses a preparation method for 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one. The method comprises the following steps: (1) mixing and reacting glutaric anhydride and methanol to obtain mixture 1 which contains monomethyl glutarate and glutaric acid; (2) mixing the mixture 1 with dichloromethane and rinsing an obtained mixture with an saturated sodium chloride solution to obtain monomethyl glutarate; (3) mixing and reacting monomethyl glutarate with thionyl chloride to obtain methyl 4-(chlorofomyl)butyrate; and (4) mixing methyl 4-(chlorofomyl)butyrate with (S)-4-phenyloxazolidinone at a temperature of 0 to 5 DEG C within 3 to 3.5 h and carrying out condensation to obtain 3-(5-methoxy-1,5-dioxopenyl)-(4S)-phenyloxazolidin-2-one.

Description

technical field [0001] The invention relates to the field of organic synthesis, in particular to a preparation method of 3-(5-methoxy-1,5-dioxopentyl)-(4S)-phenyloxazolidin-2-one. Background technique [0002] 3-(5-Methoxy-1,5-dioxopentyl)-(4S)-phenyloxazolidin-2-one is an important intermediate in the synthesis of lipid-lowering drug ezetimibe body, its structure is shown in the following formula (I). [0003] [0004] US5846966 reports the synthetic method of formula I compound, and this method takes glutaric anhydride as raw material, and alcoholysis with methanol, sulfur oxychloride chlorination, obtains again with (S)-4-phenyl oxazolidinone condensation, following reaction The formula shows: [0005] [0006] In the preparation method provided by this synthetic route, since the raw material glutaric anhydride contains glutaric acid (imported glutaric acid purity 90%-95%), glutaric acid reacts with thionyl chloride to generate glutaryl chloride, glutaryl chloride...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D263/26C07D205/08
Inventor 王淑静王俊芳单晓燕时惠麟
Owner SHANGHAI INST OF PHARMA IND CO LTD
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