JP2006045113A - Phosphoric acid ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new phosphoric acid ester of a sphingosine derivative, useful as a synthetic raw material such as sphingomyelin, etc. <P>SOLUTION: This phosphoric acid ester is expressed by general formula (I) [wherein, R<SP>1</SP>, R<SP>2</SP>are each an alkyl which may have a substituent; R<SP>3</SP>is a lower alkyl; and Y is a halogen atom]. By using the new phosphoric acid ester, without performing a protection of hydroxy group, etc., it is possible to convert the ester to another phosphoric acid ester, and it becomes possible to produce sphingomyelin which is effective for a drug delivery system, etc., easily in a smaller number of processes as compared with those of the conventional reaction processes. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to phosphate esters of sphingosine derivatives, and more particularly to substances useful as synthetic raw materials such as sphingomyelin effective for drug delivery systems.

Conventionally, as a method for converting a sphingosine derivative into a phosphate ester such as sphingomyelin, a method using chloro-N, N-diisopropylaminomethoxyphosphine (for example, Non-Patent Document 1), a method using ethylene chlorophosphite (for example, Non-Patent Document 2) and methods using cyclic chlorophosphate (for example, Non-Patent Document 3) are known.
AL Weis, Chem. Phys. Lip., 102, 3-12 (1999) HS Byun, RK Erukulla, and RK Bittman, J. Org. Chem., 59, 6495-6498 (1994) Z. Dong and JA Butcher, Tetrahedron Lett., 32, 5291-5294 (1991)

  However, in the method described in Non-Patent Document 1, it is necessary to protect the hydroxyl group. After the reaction, choline tosylate is reacted, further oxidized to a phosphate ester, and further demethylated and desilylated. However, there is a problem that the number of steps is complicated and complicated. In the method described in Non-Patent Document 2, bromine oxidative addition, hydrolysis, and introduction of trimethylammonium ions must be performed after the reaction, and this method also has a problem that it is complicated and requires a large number of steps. In the method described in Non-Patent Document 3, it is necessary to protect and deprotect the hydroxyl group. After the reaction, anhydrous trimethylamine must be reacted to induce phosphocholine, which is also complicated.

  An object of the present invention is to provide novel sphingosine derivative phosphates useful as a raw material for synthesis of sphingomyelin and the like.

  As a result of intensive studies to solve such problems, the present inventors have found novel phosphate esters useful as synthetic intermediates such as sphingomyelin and have completed the present invention.

That is, the novel phosphate esters of the present invention have the following general formula (I)

(Wherein R ¹ and R ² are alkyl groups optionally having substituents, R ³ is a lower alkyl group, and Y represents a halogen atom). To do.

  If the novel phosphate esters of the present invention are used, they can be easily converted to phosphate esters without protecting the hydroxyl group and the like, and sphingomyelin effective for drug delivery systems and the like can be converted into conventional reaction steps. Compared to the number of steps, it can be easily manufactured.

The novel phosphate esters of the present invention have the general formula (I)

Wherein R ¹ and R ² are alkyl groups which may have a substituent, R ³ is a lower alkyl group, and Y represents a halogen atom. .

  Here, the lower alkyl group is an alkyl group having 1 to 8 carbon atoms which may have a branch, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group, t- A butyl group, a pentyl group, etc. can be illustrated.

  The said alkyl group is a C1-C20 alkyl group which may have a substituent and branch which do not participate in reaction. A halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

As shown below, the phosphate esters represented by the general formula (I) of the present invention are known compounds (Toshihiko Shigenari, Toshikazu Hakogi, Naruo Katsumura, The Chemical Society of Japan 84th Spring Annual Meeting 2J2-49. (2004)), for example, can be prepared by deprotection on the N atom followed by acylation.

  The deprotection process is usually preferably performed in the presence of an acid. As the acid that can be used, mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid and trifluoromethanesulfone can be suitably used.

  The acylation process can be suitably performed using a corresponding carboxylic acid anhydride, acid chloride, ester or the like. A base is preferably used in carrying out the acylation process. As the base that can be used, inorganic bases such as potassium carbonate and sodium hydrogen carbonate, and organic bases such as triethylamine, diisopropylethylamine, pyridine, and imidazole can be preferably used.

  The reaction is preferably carried out in a solvent that does not participate in the reaction, hydrocarbon solvents such as benzene, toluene, xylene, hexane and cyclohexane, aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide. , Ester solvents such as ethyl acetate and butyl acetate, ether solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, diglyme and triglyme diethylene glycol monomethyl ether, and ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone Solvent, nitrile solvent such as acetonitrile, halogen solvent such as dichloromethane and 1,2-dichloroethane, aqueous medium and mixed solvent thereof, and the like, preferably tetrahydrofuran, 1,4-dioxane, , 2-dimethoxyethane, diglyme, ether solvents such as triglyme diethylene glycol monomethyl ether is preferred.

The reaction temperature can be appropriately selected from a temperature range of −40 ° C. to 80 ° C., but a range of 0 ° C. to room temperature is preferred from the viewpoint of reaction rate and economics.
Hereinafter, the present invention will be described in more detail with reference to Examples and Reference Examples.

Example 1

2-Bromoethyl (2-tert-butyloxycarbonylamino-3-hydroxyoctadec-4-enyl) (2-Bromoethyl (2-tert-butyloxycarbonylamino-3-hydroxyoctadec-4-enyl) ( Methyl chloride (500 mg, 0.833 mmol) in methylene chloride (4.16 ml) was added trifluoroacetic acid (1.67 ml) at 0 ° C. and stirred for 1.5 hours. 1N NaOH aqueous solution was added to the reaction solution for neutralization, followed by extraction with chloroform, and the organic layer was washed with saturated brine. This was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in THF and H ₂ O (8.32 ml, 1: 1), potassium carbonate (575 mg, 4.16 mmol) and palmitoyl chloride (0.28 ml, 0.916 mmol) were sequentially added at 0 ° C., and the mixture was stirred for 15 minutes. The reaction mixture was neutralized with saturated aqueous ammonium chloride and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography (0 to 10% methanol in chloroform), and 2-bromomethyl (2-hexadecanoylamino-3-hydroxyoctadec-4-enyl) methyl phosphate ( 3) (2-Bromoethyl (2-hexadecanoylamino-3-hydroxyoctadec-4-enyl) (methyl) phosphate: 522 mg, 85%) was obtained. IR, ¹ H NMR, and ¹³ C NMR data of 2-bromomethyl (2-hexadecanoylamino-3-hydroxyoctadec-4-enyl) methyl phosphate (above 3) are shown below.

IR (KBr disk): 3291, 2917, 1647, 1547, 1468, 1269, 1047 cm ^-1
1 H NMR (CDCl ₃ , 400 MHz) δ: 6.25 (d, J = 7.3 Hz, 1H), 5.75 (td, J = 6.8, 15.1 Hz, 1H), 5.48 (dd, J = 6.6, 15.4 Hz, 1H ), 4.33 (m, 3H), 4.17 (m, 3H), 3.81 (d, J = 11.2 Hz, 3 / 2H), 3.80 (d, J = 11.2 Hz, 3 / 2H), 3.55 (t, J = 6.1 Hz, 2H), 2.19 (dt, J = 1.7, 7.1 Hz, 2H), 2.03 (td, J = 7.1, 1.7 Hz, 2H), 1.61 (m, 2H), 1.26 (m, 46 H), 0.88 (t, J = 6.6 Hz, 6 H)
¹³ C NMR (CDCl ₃ , 100 MHz) δ: 173.6, 134.8, 128.5, 72.4, 67.2 (m), 66.8 (d, J _CP = 5.0 Hz), 54.77 (d, J _CP = 5.8 Hz, 1/2 C) , 54.74 (d, J _CP = 5.8 Hz, 1/2 C), 53.7 (d, J _CP = 5.8 Hz), 36.7, 32.3, 31.9, 29.7, 29.5, 29.4, 29.3, 29.3, 29.1, 25.7, 22.6, 14.1

(Reference Example 1)

To a solution of 2-bromomethyl (2-hexadecanoylamino-3-hydroxyoctadec-4-enylmethyl phosphate (3: 502 mg, 0.679 mmo) in methanol (8.36 ml) at room temperature with anhydrous trimethylamine (5.40 ml). The reaction mixture was diluted with water, extracted with chloroform and methanol, and the organic layer was concentrated under reduced pressure.The residue was chromatographed on silica gel (methanol: chloroform = 1: 9 to methanol: chloroform: Separation and purification by water = 65: 25: 4) gave sphingomyelin (4) IR and ¹ H NMR data of sphingomyelin are shown below.

IR (KBr disk): 3447, 2919, 1640, 1231, 1090 cm ^-1
1 H NMR (CD3OD), 400MHz) δ: 5.71 (dtd, J = 15.4, 6.6, 0.5Hz, 1H),
5.46 (ddt, J = 15.4, 7.6, 1.5Hz, 1H), 4.28 (m, 2H), 4.14-3.88 (m, 4H),
3.63 (t, J = 4.9Hz, 2H), 3.22 (s, 9H), 2.19 (m, 2H),
2.03 (dt, J = 6.8, 6.8Hz, 2H), 1.59 (m, 2H), 1.29 (s, 46H),
0.90 (t, J = 7.1Hz, 6H)

  As shown in Reference Example 1, by using the novel phosphate esters of the present invention, it is possible to easily produce sphingomyelin that is effective for drug delivery systems and the like with fewer steps than conventional reaction steps. It is.

Claims (1)

The following general formula (I)

(Wherein R ¹ and R ² are alkyl groups optionally having substituents, R ³ is a lower alkyl group, and Y represents a halogen atom). Phosphate esters.