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Method for manufacturing neuraminic acid derivatives

A compound, alkyl technology, applied in the field of neuraminic acid derivatives, can solve problems such as low efficiency

Active Publication Date: 2012-07-25
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0029] (3) Including low-efficiency enzyme reaction [production procedure of compound (IVd)];

Method used

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  • Method for manufacturing neuraminic acid derivatives
  • Method for manufacturing neuraminic acid derivatives
  • Method for manufacturing neuraminic acid derivatives

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0498] (4S, 5R, 6R)-5-acetamide-4-guanidino-6-[(1R, 2R)-2-hydroxy-1-methoxy-2-(octanoyloxy)propyl]-5 , Synthesis of 6-dihydro-4H-pyran-2-carboxylic acid [compound (Ib)]

[0499] Step A-1: ​​N-acetylneuramate methyl ester

[0500] Trimethyl orthoformate (116.67 g) and methanol (2720 ml) were added to N-acetylneuraminic acid (340.00 g) and suspended. Concentrated sulfuric acid (8.63 g) was added to the suspension with stirring at room temperature, and the mixture was stirred at 40°C for 3 hours. The solvent was distilled off under reduced pressure until the amount of the solution became about 1530 ml, dibutyl ether (4420 ml) was added to the reaction solution at 30°C, and the reaction solution was stirred at the same temperature for 1 hour. After stirring it for another 1 hour at 0°C, the crystals were filtered. The crystals were washed with a mixture of methanol (170ml) and dibutyl ether (510ml) and dried under reduced pressure to afford the title compound as a white solid (...

Embodiment 2

[0552] (3aS,4R,7aR)-4-{(S)-Hydroxy[(4R)-2-oxo-1,3dioxolan-4-yl]methyl}-2-methyl-3a,7a -Dihydro-4H-pyrano[3,4-d][1,3] Azole-6-carboxylic acid methyl ester (compound (7) [R 4 , R 5 =Oxo group]) synthesis

[0553] Step A-1: ​​N-acetylneuraminic acid methyl ester

[0554] Trimethyl orthoformate (5.14 g) and methanol (120 ml) were added to N-acetylneuraminic acid (1) (15.00 g) and suspended. Concentrated sulfuric acid (0.38 g) was added with stirring at room temperature, and the reaction solution was stirred at 40° C. for 3 hours. After the reaction was completed, N,N-dimethylacetamide (15 ml) was added to the reaction solution, and then the solvent was distilled off under reduced pressure until the amount of the solution became about 40 ml. At 20°C, water (7.5ml) and ethyl acetate (150ml) were added to the concentrated solution, the mixture was stirred at 30°C for 0.5 hours, then ethyl acetate (150ml) was added and stirred at the same temperature for another 0.5 Hour. Afte...

Embodiment 3

[0562] (4S, 5R, 6R)-5-acetamide-4-guanidino-6-[(1R, 2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro- 4H-pyran-2-carboxylic acid (compound (13) [R 2 = methyl]) synthesis

[0563] Step B-1: (4S,5R,6R)-5-acetamide-4-amino-6-{(S)-methoxy[(4R)-2-oxo-1,3dioxolane- 4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylic acid methyl ester

[0564] At room temperature, ethyl acetate (40ml), triphenylphosphine (7.79g) and water (1.94g) were added to the compound (10.00g) obtained in Step A-6 of Example 1, followed by stirring at 72°C for 2.5 Hour. The reaction solution was cooled to room temperature to obtain an ethyl acetate solution of the title compound.

[0565] Step B-2: (4S, 5R, 6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-{(S)-methoxy[(4R )-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylic acid methyl ester

[0566] At room temperature, tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (8.80 g) was added to the ethyl acetate solution of ...

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Abstract

The invention provides a method, which is embraced in a compound represented by the formula (9), wherein, R<2> represents a Ci-C4 alkyl group, R<3> represents a Ci-C6 alkyl group, R<4> and R<5> mutually independanly represent hydrogen atom, C1-C6 alkyl group or phenyl group, or R<4> and R<5> form to a tetramethylene, a pentamethylene, oxo, and Ac represents an ethanoyl.

Description

[0001] This application is a divisional application of the following applications: filing date: April 11, 2008; application number: 200880019205.7; invention title: same as above. [technical field] [0002] The present invention relates to a method for preparing neuraminic acid derivatives having neuraminidase inhibitory activity, and to synthetic intermediates of neuraminic acid derivatives and their preparation methods. Furthermore, the present invention relates to neuraminic acid derivatives with high purity. [Background technique] [0003] Compounds represented by known formula (I): [0004] [0005] [where R 1 means C 1 -C 19 Alkyl and R 2 means C 1 -C 4 Alkyl] or a pharmaceutically acceptable salt thereof has superior neuraminidase inhibitory activity, and thus is used as a drug for treating or preventing influenza (Patent Document 1 or 2). [0006] Known trifluoroacetate salts of compounds represented by formula (III): [0007] [0008] It has superior n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/06C07D309/28
CPCC07C41/60C07D309/28C07D407/06C07D498/04C07D231/14A61K31/351A61P31/16A61P43/00C07C43/32
Inventor 中村嘉孝村上正行山冈诚若山雅一梅尾和宽
Owner DAIICHI SANKYO CO LTD
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