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Composition containing chloromethyl phosphate derivative with improved stability and method for producing the same

A composition and compound technology, which can be applied to phosphorus organic compounds, compounds of Group 5/15 elements of the periodic table, chemical instruments and methods, etc. The problems of unrealistic industrial preparation methods, etc., to achieve the effect of stabilization and energy saving

Inactive Publication Date: 2010-01-06
EISIA R&D MANAGEMENT CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] However, in the production method of Non-Patent Document 1, since a halogen-based solvent must be used, the load on the environment is large during industrial production, and waste liquid treatment is cumbersome.
Therefore, the preparation method disclosed in Non-Patent Document 1 cannot be said to be an excellent preparation method in terms of workability, operability, and energy saving. As an industrial preparation method of chloromethyl phosphate derivatives is unrealistic

Method used

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  • Composition containing chloromethyl phosphate derivative with improved stability and method for producing the same
  • Composition containing chloromethyl phosphate derivative with improved stability and method for producing the same
  • Composition containing chloromethyl phosphate derivative with improved stability and method for producing the same

Examples

Experimental program
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Effect test

preparation example 1

[0093] Synthesis of Chloromethyl Chlorosulfonate

[0094]

[0095] Add paraformaldehyde (10 g) into a 100 mL four-necked flask, and stir in an ice-water bath. Chlorosulfonic acid (24 mL) was added dropwise at an internal temperature of below 80°C, and after stirring at room temperature for 1 hour, thionyl chloride (22 mL) was added dropwise. After completion of the dropping, heating was performed at 60° C. for 3 hours, followed by cooling. The reaction solution was dropped into ice water (400 mL), followed by liquid separation. After washing with water, MgSO was added to the organic layer 4 , diluted with hexane equivalent to the organic layer, filtered to remove MgSO 4 . The filtrate was concentrated under reduced pressure, and the resulting residue was distilled under reduced pressure to obtain 15 g of the title compound as a colorless and transparent liquid. (BP50~60°C / 18~20mmHg) (30% yield).

preparation example 2

[0097] Synthesis of Chloromethyl Chlorosulfonate

[0098]

[0099] Add paraformaldehyde (10 g) into a 200 mL four-necked flask, and stir in an ice-water bath. Thionyl chloride (22 mL) was added dropwise, followed by chlorosulfonic acid (24 mL). After stirring at room temperature for 4 hours, it was heated at 60°C for 14 hours and cooled. The reaction solution was dropped into ice water (400 mL) for liquid separation. After washing with water, MgSO was added to the organic layer 4 , diluted with an equal amount of hexane to the organic layer, and filtered. After concentration under reduced pressure, the resulting residue was distilled under reduced pressure to obtain 7.9 g of the title compound as a colorless and transparent liquid. (BP 54°C / 15mmHg) (Yield 16%)

Embodiment 1

[0101] Synthesis of Di-tert-butyl Chloromethyl Phosphate

[0102]

[0103] Install a mechanical stirrer and a thermometer on a 2L four-neck round bottom flask, add di-tert-butyl potassium phosphate (100g), dipotassium hydrogen phosphate (561.2g), tetrabutyl ammonium hydrogen sulfate (13.7g), tert-butyl methyl ether (400mL) and water (700mL), stirring while cooling in a water bath. At an internal temperature of 28°C or lower, chloromethyl sulfonate (99.7 g) having an internal temperature of 23°C was added dropwise over 2 hours. After the dropwise addition, the mixture was stirred for 2 hours, water (300 mL) was added, the lower layer was separated, and the organic layer was washed with 5N aqueous sodium hydroxide solution (600 mL) and 2M aqueous solution of potassium hydrogen phosphate (600 mL). N,N-Diisopropylethylamine (10.4 g) was added to the organic layer, followed by washing with water (200 mL). N,N-diisopropylethylamine (10.4 g) was added, and after washing with wat...

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Abstract

Disclosed is a method for producing a chloromethyl phosphate derivative which is useful for producing a water-soluble prodrug. This method is excellent from the viewpoints of workability, operability and energy saving. Specifically disclosed is a method for producing a composition containing a compound represented by the following formula (I) below and a tertiary amine having a boiling point not less than 150 DEG C. at a pressure of 1 atm, which comprises a step for adding the tertiary amine to the compound represented by the formula (I) below. In the formula, R<1> and R<2> may be the same or different and represent a C1-C6 alkyl group, a C2-C6 alkenyl group or an optionally substituted C6-C14 aryl C1-C6 alkyl group; or R<1> and R<2> may combine together to form a ring.

Description

technical field [0001] The present invention relates to chloromethyl phosphate derivatives for the preparation of water-soluble prodrugs, and more specifically, to a composition containing at least one tertiary amine and chloromethyl phosphate derivatives with improved storage stability and a preparation method thereof , and methods for stabilization of chloromethyl phosphate derivatives. Background technique [0002] As an example of a water-soluble prodrug, a compound represented by the following formula is known (for example, see Patent Document 1). The compound is a water-soluble azole compound useful for the treatment of severe systemic fungal infections. [0003] [0004] In addition, it is also known that this water-soluble azole compound can be produced by the following scheme (see Patent Document 1 mentioned above). [0005] [0006] As shown in the above scheme, in order to prepare a water-soluble prodrug, it is necessary to react chloromethyl phosphates (c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/09
CPCC07F9/091C07F9/025
Inventor 佐藤圭三阿部信也吉泽一洋若杉和纪根木茂人宫泽守
Owner EISIA R&D MANAGEMENT CO LTD
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