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Method for manufacturing neuraminic acid derivatives

A compound and alkyl technology, applied in the field of neuraminic acid derivatives, can solve the problems of expensive silyl protecting groups and low efficiency

Active Publication Date: 2010-03-24
DAIICHI SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0028] (3) Including low-efficiency enzyme reaction [production procedure of compound (IVd)];
[0037] (2) Use expensive silyl protecting groups;

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. Under stirring at room temperature, concentrated sulfuric acid (8.63 g) was added to the suspension, 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 (170 ml) and dibutyl ether (510 ml) and dried under reduced pressure to obtain the title compound as a white solid (342.1...

Embodiment 2

[0554] (3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3dioxolane-4-yl]methyl}-2-methyl-3a,7a -Dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylic acid methyl ester (Compound (7) [R 4 , R 5 =oxo group]) synthesis

[0555] Step A-1: ​​N-acetylneuraminic acid methyl ester

[0556] Trimethyl orthoformate (5.14 g) and methanol (120 ml) were added to N-acetylneuraminic acid (1) (15.00 g) and suspended. At room temperature, concentrated sulfuric acid (0.38 g) was added while stirring, and the reaction solution was stirred at 40°C for 3 hours. After the completion of the reaction, 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. After s...

Embodiment 3

[0564] (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

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

[0566] 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.

[0567] 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

[0568] At room temperature, tert-butyl (tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (8.80g) was added to the ethyl acetate solution of the compound o...

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Abstract

The invention provides a method for manufacturing neuraminic acid derivatives, also synthetic intermediates of the neuraminic acid derivatives and methods for their manufacture, and neuraminic acid derivatives having high purity. A synthetic intermediate compound represented by the formula (7) is provided: wherein R3 represents alkyl; R4 and R5 each represents H, alkyl, phenyl, or together represent tetramethylene, pentamethylene, oxo.

Description

[Technical Field] [0001] The present invention relates to a method for preparing neuraminic acid derivatives with neuraminidase inhibitory activity, and relates to synthetic intermediates of neuraminidase derivatives and their preparation methods. In addition, the present invention relates to neuraminic acid derivatives having high purity. [Background technique] [0002] Known compounds represented by formula (I): [0003] [0004] [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 medicine for treating or preventing influenza (Patent Document 1 or 2). [0005] The trifluoroacetate salt of the compound represented by formula (III) is known: [0006] [0007] It has superior neuraminidase inhibitory activity and is therefore used as a medicine for the treatment or prevention of influenza (Non-Patent Document 1 or 2). [0008] A known method W is a method for p...

Claims

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Application Information

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IPC IPC(8): C07D309/28C07D407/06C07D498/04C07C41/00A61K31/351C07C41/60
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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