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Preparation method of alpha-configuration aroyl bromo-sugar

A technology of aroyl bromosugar and configuration, which is applied in the field of preparation of aroyl bromosugar, and can solve problems such as unguaranteed yield of aroyl bromosugar and unfavorable α-configuration aroyl bromosugar yield, etc.

Active Publication Date: 2022-02-11
JIANGSU COBEN PHARMA CO LTD +2
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  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

During the repetition of the above process, the applicant found that: if the S N 2 configuration reverse feed solution for purification, will lead to S N 2 Configuration inversion The α-configuration aroyl bromosugar in the feed solution is converted into the β-configuration aroyl bromosugar. The longer the storage time, the more conversion, which is not conducive to the α-configuration of the aroyl bromosugar. yield
Especially in the industrial production of α-configured aroyl bromosugars, there is the transfer of feed liquid between the production workshop and the purification workshop, which makes the yield of α-configured aroyl bromosugars even less guaranteed

Method used

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  • Preparation method of alpha-configuration aroyl bromo-sugar
  • Preparation method of alpha-configuration aroyl bromo-sugar
  • Preparation method of alpha-configuration aroyl bromo-sugar

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preparation example Construction

[0032] The invention provides a method for preparing an aroyl bromosugar of α configuration, comprising the following steps:

[0033] Under the condition of acid-binding agent, (2R)-3,5-bis(4-chlorobenzoate)-2-deoxy-2-fluoro-2-methyl -β-D-erythro-pentofuranose is mesylated to obtain a mixture containing α-sulfonylated sugars and β-sulfonylated sugars;

[0034] Transforming the mixture containing α-sulfonylated sugars and β-sulfonylated sugars to obtain a mixture mainly containing β-sulfonylated sugars;

[0035] The mixture mainly composed of β-sulfonylated sugars is subjected to S N The configuration of 2 is inverted to give the aroyl bromosugar in the alpha configuration.

[0036] In the present invention, unless otherwise specified, the raw materials used in the present invention are preferably commercially available products.

[0037] In the present invention, under the condition of an acid-binding agent, (2R)-3,5-bis(4-chlorobenzoate)-2-deoxy-2-fluoro-2- Methyl-β-D-ery...

Embodiment 1

[0070] The preparation of the pure product of embodiment 1β-sulfonylated sugar

[0071] (2R)-3,5-bis(4-chlorobenzoate)-2-deoxy-2-fluoro-2-methyl-β-D-erythro-pentofuranose (44.3g , 100mmol) was dissolved in dichloromethane (222g), and triethylamine (11.1g, 110mmol) was added to cool down to -50°C, and the methanesulfonyl chloride solution was added dropwise in 1.5h (the methanesulfonyl chloride solution included methanesulfonyl chloride (12.0 g, 105mmol), dichloromethane (88.6g)), the dropwise temperature is not higher than -50°C. Incubate after dropping, and monitor the β-configuration (2R)-3,5-bis(4-chlorobenzoate)-2-deoxy-2-fluoro-2-methyl-β-D-erythro- The mass content of pentofuranose is less than 1%, and the mesylation reaction is completed; at this time, HPLC monitors that the mass proportion of β-sulfonylated sugar in the reaction solution is 85%, and the mass proportion of α-sulfonylated sugar is 15%. Add 200g of water and 10g of sodium bicarbonate to the mesylation ...

Embodiment 2

[0079] Preparation of pure aroyl bromosugar of embodiment 2α configuration

[0080]Dissolve the pure β-sulfonylated sugar obtained in Example 1 (52.1 g, 100 mmol) in acetonitrile, cool down to 8°C, add anhydrous lithium bromide (13.1 g, 150 mmol) to react for 12 hours, and detect the β-sulfonylated sugar by HPLC The content of sugar is less than 1%, the solvent is evaporated to dryness, and dichloromethane 300g and water 200g are added, and the first extraction is carried out to obtain the first aqueous phase and the first organic phase; the first organic phase is mixed with 200g water, and the The second extraction obtains the second aqueous phase and the second organic phase; the second organic phase is mixed with 200g water, and the third extraction is carried out to obtain the third aqueous phase and the third organic phase; the third organic phase As the organic phase obtained by extraction, dichloromethane in the organic phase was evaporated to dryness; the sticky substa...

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Abstract

The invention belongs to the technical field of organic synthesis, and provides a preparation method of alpha-configuration aroyl bromo-sugar. Beta-configuration (2R)-3, 5-bis(4-chlorobenzoate)-2-deoxy-2-fluoro-2-methyl-beta-D-erythro-furanpentose is used as a raw material, and is subjected to methylsulfonylation to prepare a mixture containing alpha-sulfonylated sugar and beta-sulfonylated sugar, the proportion of the beta-sulfonylated sugar is increased through transformation, the property of the obtained SN2 configuration inversion feed liquid obtained through SN2-configuration inversion under the action of lithium bromide is stable, the configuration of the alpha-configuration aroyl bromo-sugar is not converted any more, and the yield of the alpha-configuration aroyl bromo-sugar is improved. In addition, the preparation method provided by the invention is more suitable for industrial application.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing an alpha-configuration aroyl bromosugar. Background technique [0002] It is currently reported that AT-527, which has a good therapeutic effect on the new coronavirus, has a structure as shown in Formula 1: [0003] [0004] Good, Stevens et al (Good, Stevens et al, "AT-527, A double prodrug of aguanosine nucleotide analog, is a potent inhibitor of SARS-CoV-2 in vitro and promising oral antiviral fortreatment of COVID-19", Antimicrobial Agents and Chemotherapy, 65( 4), e02479, (2021)) disclosed the synthesis route of AT-527 as shown in formula 2: [0005] [0006] Specifically: aroyl bromosugar (2R)-3,5-bis(4-chlorobenzoate)-2-deoxy-2-fluoro-2-methyl-α-D-erythro Formula-bromopentofuranose (compound 1a in formula 2), through condensation with 6-chloroguanine (compound 3 in formula 2), by S N 2 The inversion of the α configuration in the r...

Claims

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Application Information

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IPC IPC(8): C07H5/02C07H1/00
CPCC07H5/02C07H1/00Y02P20/55
Inventor 游金宗郑力史磊蔡金元胡建隆郭红强邓飞
Owner JIANGSU COBEN PHARMA CO LTD
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