Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same

a technology sodium salt, which is applied in the field of crystallization of cyclic phosphonic acid sodium salt, can solve the problems of strong acidity of the reaction system, inability to synthesis on a large scale, and product prone to decomposition, and achieves excellent storage stability, high yield, and simple manner

Active Publication Date: 2018-07-26
SANSHO CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a high-purity crystal of 2ccPA that has excellent storage stability and does not significantly decompose even after long-term storage. The production method of the present invention involves a novel process and is simple and efficient, resulting in a high yield of 2ccPA. Additionally, this method reduces the risk of decreased purity without using strong acids or bases and produces a stable crystal of 2ccPA from a cyclic phosphonic acid ester.

Problems solved by technology

This indicates that the method is not suitable for synthesis on a large scale.
In addition, the use of bromotrimethylsilane (TMSBr) in the demethylation step generates hydrogen bromide as a by-product, which makes the reaction system strongly acidic, making the product prone to decomposition.
Thus, decomposition of 2ccPA by sodium hydroxide is unavoidable, causing a storage stability problem.

Method used

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  • Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same
  • Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same
  • Crystal of cyclic phosphonic acid sodium salt and method for manufacturing same

Examples

Experimental program
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Effect test

examples

[0255]The present invention is described in further detail with reference to Synthesis Examples, Examples, and Comparative Examples. However, the present invention is not limited to the following Examples.

Step (A)

Synthesis Example A1: (Step A: R2=n-Propyl)

Synthesis of 2,2-di-n-propyl-5-(hydroxymethyl)-1,3-dioxane (3b)

[0256]

[0257]2-Hydroxymethyl-1,3-propanediol (2) (3.0 g) was dissolved in 30 mL of tetrahydrofuran, and 4.74 mL of 4-heptanone and 53.8 mg of p-toluenesulfonic acid monohydrate were added thereto, followed by heating under reflux for 3.5 hours using a Dean-Stark trap. During the reaction, distilled tetrahydrofuran was discarded, and new tetrahydrofuran was added to the reaction mixture. Thereafter, 0.39 mL of triethylamine was added to the reaction mixture to stop the reaction, and tetrahydrofuran was distilled off under reduced pressure. Then, 30 mL of ethyl acetate and 30 mL of water were added to the residue, and the layers were separated. After the organic layer was ...

synthesis example c2-1 (

Step C: Solvent=Acetone+Methyl Isobutyl Ketone)

Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

[0289]

[0290]The compound (4a) obtained in Synthesis Example B1 (300 mg) was dissolved in 3 mL of acetone and 3 mL of methyl isobutyl ketone in an argon atmosphere, and 9.3 μL of triethylamine and 301 mg of sodium iodide were further added thereto, followed by heating under reflux for 2 hours. Acetone and methyl isobutyl ketone in the reaction solution were distilled off under reduced pressure, 6 mL of CH2Cl2 and 6 mL of water were added thereto, and the layers were separated. The water layer was extracted twice with 6 mL of CH2Cl2, the organic layers were washed with 3 mL of 5% sodium thiosulfate and 3 mL of 1% sodium hydrogen carbonate water. After the organic layers were further washed with 6 mL of saturated brine and dried over magnesium sulfate, CH2Cl2 was distilled off under reduced pressure. The resulting residue was purified with silica gel chromatography (n-hexane:ethyl acet...

synthesis example c2-2 (

Step C: Solvent=Acetone)

Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

[0291]

[0292]The compound (4a) obtained in Synthesis Example B1 (300 mg) was dissolved in 6 mL of acetone in an argon atmosphere. Then, 9.3 μL of triethylamine and 301 mg of sodium iodide were further added thereto, and the mixture was heated under reflux for 2 hours. Acetone in the reaction solution was distilled off under reduced pressure, 6 mL of CH2Cl2 and 6 mL of water were added thereto, and the layers were separated. The water layer was extracted twice with 6 mL of CH2Cl2, and the organic layers were washed with 3 mL of 5% sodium thiosulfate and 3 mL of 1% sodium hydrogen carbonate water. After the organic layers were further washed with 6 mL of saturated brine and dried over magnesium sulfate, CH2Cl2 was distilled off under reduced pressure. The resulting residue was purified with silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 204 mg of compound (5a) (yield: 59%).

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Abstract

An object of the present invention is to provide a crystal of a cyclic phosphonic acid sodium salt (2ccPA) with high purity and excellent storage stability and a method for producing the crystal. The present invention provides a crystal of a cyclic phosphonic acid sodium salt (2ccPA) represented by formula (1):

Description

TECHNICAL FIELD[0001]The present invention relates to a crystal of a cyclic phosphonic acid sodium salt and a method for producing the crystal.BACKGROUND ART[0002]The cyclic phosphonic acid sodium salt (a sodium salt of 9-octadecenoic acid(9Z)-(2-hydroxy-2-oxo-2λ5-1,2-oxaphosphoran-4-yl)methyl ester) represented by the following formula (1) is a compound, typically referred to as 2ccPA.[0003]2ccPA is known to have a potent analgesic action (Patent Literature 1) and is also expected to serve as an anti-cancer agent because of its infiltration-inhibitory activity on cancer cells (Patent Literature 2), an osteoarthritis therapeutic agent because of its accelerated production of hyaluronic acid (Patent Literature 3), or other agents.[0004]2ccPA has traditionally been produced by the production method shown in the following reaction scheme-1 (Patent Literature 2 and 4 and Non-patent Literature 1 and 2).[0005]Specifically, iodine compound (5a), which is obtained by the production method d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07F9/6571
CPCC07F9/657163C07B2200/13A61K31/665C07F9/657181C07F9/65742A61P19/00A61P29/00A61P35/00C07F9/65748
Inventor YUASA, HIROAKIOKAZAKI, HIROKI
Owner SANSHO CO LTD
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