JPH064651B2 - Phosphate ester and method for producing the same - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel phosphoric acid ester, and more particularly to a phosphoric acid ester having serine or a salt thereof as a substituent.

[Conventional technology]

Conventionally, phospholipids typified by natural phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and sphingolipids are well known as phosphoric acid esters having a polar group containing nitrogen such as amino group or ammonium group in the same molecule. ing. These phospholipids have both a hydrophobic group and a hydrophilic group in the same molecule and have surface activity such as surface activity and emulsifying property, and are therefore used in various fields.

In addition, it has been known for a long time that these phospholipids are abundant in the cells of living organisms and are the main constituents of biological membranes. In recent years, these phospholipids simply constitute biological membranes in living organisms. It has been gradually elucidated that it does not exist only as a component but has various important physiological actions. For example, it has been clarified that platelet activating factor (PAF), which is one of ether type phospholipids having a structure similar to phosphatidylcholine, exhibits an antihypertensive action, a hemolytic action, an immunoreactive action and the like in an extremely small amount. In addition, phosphatidylserine is also involved in various life activities by activating protein kinase C, which is an adenosine triphosphate (ATP) -independent phosphatase in the presence of diglyceride and calcium ions in vivo. It is becoming clear. Further, it is becoming clear that lysophosphatidylserine obtained by hydrolyzing the 2-acyl group of phosphatidylserine is involved in allergic reaction and the like.

Therefore, substances having a structure similar to those phospholipids having such biological activity, that is, phosphates having a polar group containing nitrogen such as amino group or ammonium group in the same molecule also have various activities and functions. It is expected that, using a cheap and easily available raw materials in analogs of phospholipids containing polar groups containing nitrogen such as amino groups,
It has been desired to develop a phosphoric acid ester that can be synthesized with high purity by a simple operation.

[Problems to be solved by the invention]

However, in general, the synthesis of phospholipids is extremely difficult, and the synthesis often requires multistep reactions, so that the target compound can be obtained only in a low yield [for example, e. .Baer) et al., Journal of the American Chemical Society (J.Amer.Che.
m.Soc.) 72 , 942 (1950), edited by Tamio Yamakawa, "Lipid" Kyoritsu Shuppan (1973)].

In addition, some synthetic studies of phosphoric acid esters having a structure similar to phospholipids have been reported, but those methods require multistep reactions, or require raw materials that are difficult to synthesize, Alternatively, it is often difficult to separate the target product after the reaction, the yield is low, and the properties of the obtained compound are often not sufficient (for example, JP-B-42-23330 and JP-B-48-1654). U.S. Pat.
issue).

[Means for solving problems]

In such an actual situation, as a result of intensive investigations by the present inventors, a phosphoric acid ester similar to phosphatidylserine which is a phospholipid containing serine which is one of amino acids, and a raw material which is inexpensive and easily available The present invention has been completed by discovering a phosphoric acid ester which can be synthesized with high purity by a simple operation and a method for producing the same.

That is, the present invention is the following formula (I) (Wherein, R ¹ is the following formula (II) (In the formula, R ⁴ is a linear or branched alkyl group having 8 to 36 carbon atoms in which a hydrogen atom may be substituted with a fluorine atom, R ⁵ is a hydrogen atom, a methyl group or an ethyl group, and n is Is 0
R ² or the formula represented by 20 the number of) (III) (In the formula, R ⁶ is represented by R ⁷ or OR ⁸ , and R ⁷ and R ⁸ have ⁸ carbon atoms.
~ 36 straight-chain or branched, which represents an alkyl group in which a hydrogen atom may be substituted with a fluorine atom) R ³ is represented by, and M ¹ and M ² are the same or different and each is a hydrogen atom, an alkali. It shows that it is a metal or an alkanolamine salt or an ammonium salt]. Furthermore, the present invention provides a novel production method for producing the phosphoric acid ester represented by the formula (I).

In the phosphate ester of the present invention, examples of the linear or branched alkyl group having 8 to 36 carbon atoms represented by R ⁴ include octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl. , Octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, triacontyl, gentriacontyl, dotriacontyl, tritriacontyl, tetratriacontyl, pentatriacontyl, hexatriacon Tyl, 2-ethylhexyl, 2-butyloctyl, 2-hexyldecyl, 2-hexyldecyl, 2-ethylhexadecyl, 2-octyldodecyl,
2-butylhexadecyl, 2-octyltetradecyl,
2-hexylhexadecyl, 2-butyloctadecyl,
2-ethyl eicosyl, 2-decyl tetradecyl, 2-
Decyl hexadecyl, 2-hexyl eicosyl, 2-ethyl tetraeicosyl, 2-dodecyl hexadecyl, 2
-Tetradecyl octadecyl or 2-hexadecyl eicosyl, tridecafluorooctyl, heptadecafluorodecyl, heneicosafluorododecyl, pentacosafluorotetradecyl, nonacosafluorohexadecyl, tritriacontafluorooctadecyl, 2-pentafluoro Ethyl pentafluorohexyl, 2-tridecafluorohexyl tridecafluorodecyl, 2-heptadecafluorooctyl heptadecafluorododecyl,
2-heneicosafluorodecyl heneicosafluorotetradecyl, 2-pentacosafluorododecyl pentacosafluorohexadecyl, 2-nonacosafluorotetradecyl nonacosafluorooctadecyl group and the like. R ⁵ is a hydrogen atom, a methyl group or an ethyl group. Further, in the formula (III), R ⁶ is represented by R ⁷ or OR ⁸ , and the R ⁷ and R ⁸ include the same substituents as R ^{4 in the} formula (II). Examples of the alkali metal in M ¹ and M ² include sodium and potassium, and examples of the alkanolamine include triethanolamine.

In the present invention, the phosphoric acid ester represented by the formula (I) is produced, for example, according to the reaction formula shown below.

(In the formula, R ¹ is the same as above.) That is, with a halogenating reagent such as thionyl chloride in an amount capable of generating 2 to 10 mol of halogen per 1 mol of the monoalkylphosphoric acid represented by the formula (IV). In an inert solvent such as an ether system such as tetrahydrofuran, a hydrocarbon system such as normal hexane or a halogen system such as chloroform and carbon tetrachloride, or in the absence of a solvent.
The dihalophosphoridate represented by the formula (VI) is obtained by reacting at 0 ° C, preferably 40 to 80 ° C.

Next, with respect to 1 mol of the dihalophosphoridate represented by the formula (VI), 1 to 5 mol, preferably 1 to 2 mol, of the N-benzyloxycarbonyl serine ester represented by the formula (V) is added, for example, chloroform or the like. 0-100 in the presence of an amine such as pyridine or quinoline in an inert solvent or without a solvent
C., preferably 0 to 50.degree. C., and after the reaction is completed, the excess amount of water is added to the halogen of the dihalophosphoridate in the reaction system to cause hydrolysis, whereby the phosphoric ester of the formula (VII) is hydrolyzed. To get

Finally, the obtained phosphate ester represented by (VII)
For example, by debenzylation by heating at a methanol reflux temperature using a metal hydride catalyst such as platinum or palladium in acetic acid / methanol, the phosphoric acid ester represented by the formula (I) can be obtained.

These compounds can be purified by separating and removing impurities by means such as silica gel column chromatography.

〔The invention's effect〕

As described above, the phosphoric acid ester of the present invention has a structure similar to phospholipids and has a polar group containing nitrogen such as an amino group in the same molecule, and therefore has excellent emulsifying ability, moisturizing ability, etc. It is useful as a new emulsifier, moisturizer, etc.

Further, according to the production method of the present invention, a phosphoric acid ester having such excellent properties can be obtained at low cost and in high yield.

〔Example〕

Next, examples will be described. The present invention is not limited to the examples below.

Example 1 100.0 g (0.38 mol) of monolauryl phosphoric acid and 134.4 g (1.13 mol) of thionyl chloride were placed in a reactor and heated and stirred at 50 ° C. under a nitrogen stream for 4 hours. After completion of the reaction, 100 m of chloroform is added to dissolve the reaction product, and then 103.4 g (0.80 mol) of quinoline is added and stirred. This solution was dissolved in 157.5 g (0.46 mol) of benzyl-N-benzyloxycarbonylserine in 100 m of chloroform and cooled to 0 ° C.
At a nitrogen stream. Stir at 0 ° C. for 4 hours, then raise the reaction temperature to room temperature and stir for 4 hours. After completion of the reaction, 100 m of water is added and the mixture is stirred at 20 ° C. for 1 hour. Then, the solvent is distilled off and the residue is extracted with diethyl ether. The obtained ether layer is washed with a hydrochloric acid aqueous solution, and then the ether is distilled off. The obtained residue is dissolved in methanol, and methanol is heated under reflux under normal pressure with a palladium / carbon catalyst. Hydrogen is blown thereinto for reaction for about 10 hours, then methanol is distilled off, and the obtained residue is purified by silica gel column chromatography. (Developing solvent / chloroform: methanol = 9
0:10). When the obtained 63.5 g of white solid was analyzed, the following results were obtained, and it was confirmed that this compound was 2-amino-2-carboxyethyl-lauryl phosphoric acid (0.18 mol, yield 47.3%).

When the phosphoric acid ester was analyzed, the following results were obtained, and it was confirmed that the target phosphoric acid ester was obtained.

Elemental analysis (% by weight) Calculated value C: 50.99, H: 9.13, N: 3.96, P: 8.76 Actual value C: 50.78, H: 9.02, N: 3.88, P: 8.76 ¹ H-NMR (solvent: CDCl ₃ / CD ₃ OD) Figure 1 δ: 0.87 (broad, s, 3H) 1.27 (broad, s, 21H) 3.30 (m, 4H + MeOH) 3.60〜3.96 (m, 1H) IR (KBr) Figure 2 3420, 2940,1670,1580,1520,1420,1030,990 (cm ^-1 ) Example 2 100.0 g (0.29 mol) of monooctadecylphosphoric acid and 103.5 g (0.87 mol) of thionyl chloride were put into a reactor. React in the same manner as in Example 1. After the reaction was completed, 51.4 g (0.65 mol) of pyridine was added and dissolved in the same manner as in Example 1 to dissolve a solution of benzyl-N-benzyloxycarbonylserine (120.2 g, 0.35 mol) in chloroform. The solution thus prepared was added dropwise in the same manner as in Example 1, and then 67.3 g of 2 was added in the same manner as in Example 1.
A white solid of -amino-2-carboxyethyl-octadecyl phosphate was obtained (0.15 mol, yield 53.0%).

Elemental analysis (% by weight) Calculated value C: 57.64, H: 10.14, N: 3.20, P: 7.08 Actual value C: 57.60, H: 10.19, N: 3.07, P: 6.99 Example 3 Mono (2-octyldodecyl) Phosphoric acid 100.0 g (0.2
6 mol) and thionyl chloride 79.8 g (0.67 mol) were reacted in the same manner as in Example 1 to obtain dichlorophosphoridate. This was mixed with 84.0 g (0.65 mol) of quinoline, and the resulting solution was added dropwise at 0 ° C. to chloroform containing 107.8 g (0.31 mol) of benzyl-N-benzyloxycarbonylserine. By the same method as in Example 1, 58.8 g of the desired white solid of 2-amino-2-carboxyethyl-2-octyldodecylphosphate was obtained (0.12 mol, yield 48.6%).

Elemental analysis (% by weight) Calculated value C: 59.33, H: 10.39, N: 3.01, P: 6.65 Measured value C: 59.27, H: 10.39, N: 2.96, P: 6.43 Example 4 Mono (2-ethyltetraeico) Sil) phosphoric acid 100.0 g
(0.26 mol) and thionyl chloride 99.5 g (0.84 m)
ol) was obtained in the same manner as in Example 1 to obtain dichlorophosphoridate, and then quinoline 72.5 g (0.60 mol) and benzyl-N-benzyloxycarbonylserine 12 were obtained.
Using 0.5 g (0.35 mol) of the same procedure as in Example 1 below, 87.5 g of the desired white solid of 2-amino-2-carboxyethyl-2-ethyltetraeicosylphosphate was obtained ( 0.16 mol, yield 61.2%).

The results of elemental analysis were as follows.

Elemental analysis (% by weight) Calculated value C: 63.36, H: 11.00, N: 2.55, P: 5.63 Actual value C: 63.26, H: 10.89, N: 2.53, P: 5.52 Example 5 Mono (2-hydroxy-3) -Lauryloxypropyl)
Phosphoric acid 100.0 g (0.29 mol) and 105.0 g (0.88 m)
ol) thionyl chloride to obtain dichlorophosphoridate, and then 55.4 g (0.70 mol) of pyridine and benzyl-N-benzyloxycarbonylserine 179.6
g (0.52 mol) is dissolved in 100 m of chloroform and stirred at 0 ° C. for 4 hours, then the reaction temperature is raised to room temperature and stirred for 4 hours. After completion of the reaction, 100 m of water is added and the mixture is stirred at 20 ° C. for 1 hour. After that, the solvent is distilled off and the residue is extracted with diethyl ether. The obtained residue is dissolved in methanol, and hydrogen is bubbled in while heating and refluxing methanol under atmospheric pressure using a palladium / carbon catalyst and reacted for about 10 hours. After completion of the reaction, methanol was distilled off, and the obtained residue was purified by silica gel column chromatography (developing solvent / chloroform: methanol = 90: 10) to obtain the target 2
-Amino-2-carboxyethyl- (2-hydroxy-
The white solid of 3-lauryloxypropyl) phosphoric acid 39.
7 g was obtained (0.09 mol, yield 32.0%).

The results of elemental analysis were as follows.

Elemental analysis (wt%) Calculated value C: 50.58, H: 8.96, N: 3.28, P: 7.24 Actual value C: 50.55, H: 8.92, N: 3.25, P: 7.18 Example 6 monotetraoxyethylene monolauryl ether Phosphoric acid 100.0 g (0.25 mol) and thionyl chloride 90.5
Dichlorophosphoridate was obtained from g (0.76 mol).
Thereafter, 103.6 g (0.30 mol) of benzyl-N-benzyloxycarbonylserine and 90.4 g (0.70 m) of quinoline.
in the same manner as in Example 1, except that 43.6 g of 2-
A white solid of amino-2-carboxylethyl-tetraoxyethylene monolauryl ether phosphoric acid was obtained (0.0.
8 mol, yield 32.9%).

The results of elemental analysis were as follows.

Elemental analysis (% by weight) Calculated value C: 52.16, H: 9.14, N: 2.64, P: 5.85 Measured value C: 52.01, H: 9.13, N: 2.61, P: 5.73 Example 7 Octadecyloxyethylene monolauryl ether phosphorus Acid 100.0 g (0.094 mol) and thionyl chloride 3
Dichlorophosphoridate was obtained from 3.7 g (0.28 mol). After that, benzyl-N-benzyloxycarbonylserine 46.6 g (0.14 mol) and pyridine 22.4 g (0.2
8 mol) was used in the same manner as in Example 1 below to obtain 17.3 g of 2-amino-2-carboxylethyl-octadecyloxyethylene monolauryl ether phosphoric acid white solid (0.015 mol, yield 16.0). %).

The results of elemental analysis were as follows.

Elemental analysis (% by weight) Calculated value C: 53.44, H: 9.14, N: 1.22, P: 2.70 Actual value C: 53.28, H: 9.02, N: 1.19, P: 2.73 Example 8 2-hydroxyhexadecylphosphate 100.0 g (0.30
mol) and 105.5 g (0.89 mol) of thionyl chloride to obtain dichlorophosphoridate. Then benzyl-N
-Benzyloxycarbonylserine 146.0 g (0.44
mol) and 70.1 g (0.89 mol) of pyridine and in the same manner as in Example 1 below, 24.6 g of 2-amino-2-carboxyethyl-2-hydroxyhexadecylphosphate white solid was obtained ( (0.058 mol, yield 19.6%).

The results of elemental analysis were as follows.

Elemental analysis (% by weight) Calculated value C: 53.63, H: 9.48, N: 3.29, P: 7.28 Measured value C: 53.48, H: 9.45, N: 3.35, P: 7.19 Example 9 Monoheptadecafluorodecylphosphate 100.0 g (0.1
Dichlorophosphoridate was obtained from 8 mol) and 64.3 g (0.54 mol) of thionyl chloride. Then benzyl-N
-Benzyloxycarbonyl serine 86.3g (0.26mo
l) and pyridine 42.4 g (0.54 mol) were used in the same manner as in Example 1 to obtain 17.6 g of 2-amino-2-carboxyethyl-heptadecafluorodecylphosphoric acid white solid (0 0.028 mol, yield 15.4%).

The results of elemental analysis were as follows.

Elemental analysis (wt%) Calculated value C: 24.72, H: 1.74, N: 2.22, P: 4.91, F: 51.19 Actual value C: 24.65, H: 1.77, N: 2.29, P: 4.95, F: 51.10 Test example 1 A skin cream having the following composition was prepared using the monosodium salt of 2-amino-2-carboxyethyl-lauryl phosphoric acid synthesized in Example 1. It was a neutral or weakly acidic cream, and had a good emulsified state and was not sticky and had good compatibility.

Skin cream: 2-amino-2-carboxyethyl-lauryl phosphate 1.2 (% by weight) Glycerin monostearate 2.4 Cetanol 4.0 Solid paraffin 5.0 Squalane 10.0 Octyldodecyl myristate 6.0 Glycerin 6.0 Fragrance, dye, preservative A suitable amount of ion-exchanged water balance

[Brief description of drawings]

FIG. 1 is a drawing showing the ¹ H-NMR spectrum of 2-amino-2-carboxyethyl-lauryl phosphate obtained in Example 1. FIG. 2 is a drawing showing the IR spectrum of the same compound.

Claims (2)

[Claims] 1. The following formula (I) (Wherein, R ¹ is the following formula (II) (In the formula, R ⁴ is a linear or branched alkyl group having 8 to 36 carbon atoms in which a hydrogen atom may be substituted with a fluorine atom, R ⁵ is a hydrogen atom, a methyl group or an ethyl group, and n is Is 0
R ² or the formula represented by 20 the number of) (III) (In the formula, R ⁶ is represented by R ⁷ or OR ⁸ , and R ⁷ and R ⁸ have ⁸ carbon atoms.
~ 36 straight-chain or branched, which represents an alkyl group in which a hydrogen atom may be substituted with a fluorine atom) R ³ is represented by, and M ¹ and M ² are the same or different and each is a hydrogen atom, an alkali. A metal, or an alkanolamine salt or an ammonium salt]. 2. The following formula (IV) (Wherein, R ¹ is the following formula (II) (In the formula, R ⁴ is a linear or branched alkyl group having 8 to 36 carbon atoms in which a hydrogen atom may be substituted with a fluorine atom, R ⁵ is a hydrogen atom, a methyl group or an ethyl group, and n is Is 0
R ² or the formula represented by 20 the number of) (III) (In the formula, R ⁶ is represented by R ⁷ or OR ⁸ , and R ⁷ and R ⁸ have ⁸ carbon atoms.
To 36 of a linear or branched, hydrogen atom of the monoalkyl phosphoric acid represented by the formula ( ³ ), which represents an alkyl group in which a hydrogen atom may be substituted with a fluorine atom). Formula (V) The following formula (I) is characterized by reacting with N-benzyloxycarbonylserine ester represented by the following formula, and then removing protecting groups for carboxyl group and amino group. [Wherein, M ¹ and M ² are the same or different and each represents a hydrogen atom, an alkali metal, or an alkanolamine salt or an ammonium salt, and R ¹ is the same as the above]. .