JPS62201892A - Phosphoric acid ester and production thereof - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {R<1> is R<2> expressed by formula II [R<4> is (F-substituted) 8-36C alkyl; R<5> is H, methyl or ethyl; n is 0-20] or R<3> expressed by formula III [R<6> is R<7> or OR<8>; R<7> and R<8> are (F substituted) 8-36C alkyl]; M<1> and M<2> are H, alkali metal, alkanolamine salt or ammonium salt}. EXAMPLE:2-Amino-2-carboxyethyl-lauric acid. USE:An emulsifying agent and humectant obtainable in high yield at a low cost. PREPARATION:OH groups of a monoalkyl phosphate expressed by formula IV, e.g. monolauryl phosphate, etc., are halogenated and the resultant compound is then reacted with an N-benzyloxycarbonylserine ester expressed by formula V. The protective groups of the carboxyl group and amino group are then removed to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a phosphoric acid ester having a serine or a salt thereof as a substituent.

[Conventional technology]

Conventionally, phosphoric acid esters having polar groups containing nitrogen such as amino groups or ammonium salts in the same molecule include natural phosphatisolcholine, phos-7atisolethanolamine, phosphatisolserine, and sphingolipids. Phospholipids are well known.

These phospholipids have both a hydrophobic group and a hydrophilic group in the same molecule, and have surface activities such as surface activity and emulsifying properties, and are used in a wide variety of fields.

In addition, it has long been known that these phospholipids exist in large amounts within the cells of living organisms and are the main components of biological membranes. It is gradually becoming clear that they do not only exist as components, but also perform various important physiological functions. For example, platelet activating factor (PAF), an ether-type phospholipid with a structure similar to phosphatisolcholine, has been shown to have antihypertensive, hemolytic, and immunostimulatory effects even in very small amounts. There is. In addition, phos-7-atisorserine is involved in various life activities by activating protein kinase C, an adenosine triphosphate (ATP)-independent phosphorylating enzyme, in the presence of diglycerides and calcium ions in vivo. is also becoming clear. Furthermore, phosphatisolserine 2
It is also becoming clear that lysophos 7-atisorserine, which is obtained by hydrolyzing the acyl group at position 1, is involved in allergic reactions and the like.

Therefore, substances similar in structure to these phospholipids that have such biological activity, that is, phosphoric acid esters that have nitrogen-containing polar groups such as amino groups or ammonium groups in the same molecule, also have various activities and functions. It is expected that the use of cheap and easily available raw materials of phospholipid analogues 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 through simple operations.

[Problem that the invention seeks to solve]

However, it is generally extremely difficult to synthesize phospholipids, and the synthesis often requires multi-step reactions, so the desired compound can only be obtained in low yield [for example.

Yi, Ba*r et al., Sharnall Op.
The American Chemical Society (J, Am
er-Chem-8oe, ) 72 r 942 (I
950), “Lipids” edited by Tamio Yamakawa, Kyoritsu Shuppan (I973))
.

In addition, some studies on the synthesis of phosphoric acid esters, which have a structure similar to that of phospholipids, have been reported, but these methods require multi-step reactions and require raw materials that are difficult to synthesize. In many cases, it is difficult to separate the target product after the reaction, the TE yield is low, and the properties of the obtained compound are often not sufficient (for example, Japanese Patent Publication No. 42-23330, Japanese Patent Publication No. 48). -1654, U.S. Pat. No. 3,507,937).

[Means for solving problems]

Under these circumstances, the present inventors conducted intensive studies and found that the present invention is a phosphoric acid ester similar to phosphatisolserine, which is a phospholipid containing serine, an amino acid, and is inexpensive and easily available. He discovered a phosphoric acid ester that could be synthesized with high purity using simple raw materials and a method for producing the same, and completed the present invention.

That is, the present invention provides the following formula 〇) [wherein R1 is the following formula (ill 埜"R": -(CH,CHO-) nR' (I)(
In the formula, 14 is a linear or branched chain alkyl group having 8 to 36 carbon atoms in which the hydrogen atom may be substituted with a fluorine atom, R1 is a hydrogen atom, a methyl group or an ethyl group, and n is O
~20) or the following formula (II) H number xtj: -CH,C)IcH,R'
(In the ship C formula, s R' is R' or OR'. R' and Ha are straight or branched chains having 8 to 36 carbon atoms.
Indicates 18 represented by The present invention provides a phosphoric acid ester represented by the following. Furthermore, the present invention provides a novel method for producing a phosphoric acid ester represented by formula (I).

In the phosphoric acid ester of the present invention, the branched alkyl group having 8 to 36 carbon atoms represented by % R4 includes, for example, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, Heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, tocosyl, trickle, tetradecyl, bentacyl, hexadecyl, heptadecyl, octacosyl, nonacosyl, triacontyl,
hentriacontyl, todriacontyl, tritriacontyl, tetratriacontyl% pentatriacontyl, hexatriacontyl, 2-ethylhexyl, 2-
Butyloctyl, 2-hexyldecyl, 2-hexyldodecyl, 2-ethylhexadecyl% 2-octyldodecyl, 2-butylhexadecyl, 2-octyltetradecyl, 2-hexylhexadecyl, 2-butyloctadecyl, 2 -Ethyl eicosyl, 2-decyltetradecyl, 2-decylhexadecyl% 2-hexyleicosyl, 2-ethyltetraeicosyl, 2-dodecylhexadecyl, 2-tetradecyloctadecyl or 2-hexadecyleicosyl, tridecafluorooctyl, heptadecafluorodecyl, heneicosafluorododecyl,
Pentacosafluorotetradecyl, nonacosafluorohexadecyl, tritriacontafluorooctadecyl,
2-Pentafluoroethylpentafluorohexyl%2
−)! 7decafluorohexyl tridecafluorodecyl, 2-hebutadecafluorooctyl hebutadecafluorodobucul, 2-heneicosafluorodecylheneicosafluorotetratecyl, 2-pentacosafluorododecylpentacosafluorohexadecyl, 2 -Nonaphthafluorotetradecylnonacosafluorooctadecyl group and the like. Further, R8 is a hydrogen atom, and the methyl group is an ethyl group. Also, in formula (m), R@ is represented by R7 or OR'', but H? and R6 are represented by 1 formula (
The same substituents as R' in N) can be mentioned. Ma7jM", M
Examples of alkali metals in "X" include sodium and potassium, and examples of alkanolamines include triethanolamine.
Examples include an amino group or an ammonium group.

In the present invention, the ester phosphate represented by formula 0) is produced, for example, according to the reaction formula shown below.

(■) m-(I1 (in the formula, R1 is the same as above) That is, monoalkyl phosphoric acid 1 represented by formula (IV)
In an amount capable of generating 2 to 10 moles of halogen per mole,
For example, a halogenating reagent such as thionyl chloride is dissolved in an inert solvent such as an ether type such as tetrahydrofuran, a hydrocarbon type such as n-hexane, or a halogen type such as chloroform or carbon tetrachloride, or in the absence of a solvent.
By reacting at 100°C, preferably 40 to 80°C, a zohalophosphorylate represented by formula (Vl) is obtained.

Next, per 1 mol of zohalophosphorite represented by the formula (crane), 1 to 5 mol, preferably 1 to 2 mol, of an N-benzyloxycarbonylserine ester represented by the formula (■) is added to an inert compound such as chloroform, etc. In a solvent, the temperature is 0 to 100°C in the presence of an amine such as pyricine or quinoline without a solvent.
, preferably at 0 to 50°C, and after the completion of the reaction, water in excess of the halogen of the zohalophosphorite is added to the reaction system for hydrolysis, thereby producing a phosphoric acid ester represented by formula (Vl). obtain.

Finally, the obtained phosphoric acid ester represented by (Vl) is debensylated by heating at methanol reflux temperature using a hydrogenation metal catalyst such as platinum or no-9-razoum in acetic acid/methanol. The phosphoric acid ester shown in (summer) can be obtained.

These compounds can be purified by separating and removing cine-retardants by means such as silica column chromatography.

〔Effect of the invention〕

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

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

〔Example〕

Next, an example will be given and explained. Note that the present invention is not limited to the following examples.

Example 1 Monolauryl phosphoric acid 100.0f (0,38tool
) and thionyl chloride 134.4f (I, 13 mol
) was placed in a reactor and heated and stirred at 50°C under a nitrogen stream for 4 hours. After the reaction was completed, 100% of chloroform was added to dissolve the reactants, and then 103.49% of quinoline (0.80%) was added.
moi) and stir. Add this solution to benzo-N
-Penzoloxycarbonylserine 157.5f (0
, 46 mol) in 100-chloroform and cooled to 0°C, added dropwise under a nitrogen stream at 0°C. Stir at 00°C for 4 hours, then raise the reaction temperature to room temperature and stir for 4 hours. . After the reaction is completed, water of IQ□j is added and stirred at 20°C for 1 hour. Thereafter, the solvent was distilled off and the mixture was extracted with diethyl ether. The obtained ether layer was washed with an aqueous hydrochloric acid solution, and then the ether was distilled off. The obtained residue was dissolved in methanol, and hydrogen was blown into the methanol under normal pressure using a carbon catalyst and heated under reflux for about 10 hours. Methanol was distilled off, and the obtained residue was subjected to silica gel column chromatography. The product was purified by graphy (developing solvent/chloroform:methanol=90:10). When the obtained white solid of 63.5f was analyzed, the following results were obtained, and it was confirmed that this compound was 2-amino-2-carboxyethyl-lauryl phosphoric acid (0.1
8 mol, yield 47.3%) 0 When the phosphoric acid ester was analyzed, the following results were obtained, confirming that it was the desired phosphoric ester. Elemental analysis (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'
H-NMR (solvent: CDCt, /CD, OD) Figure 1 δ: 0.87 (broad, s +3H
) 1.27 (broadl, 21H) 3.30 (m, 4H+MeOH) 3.60-3.
96 (m, IH) I R (KBr) Fig. 2 3420.2940.1670.1580,1520,
1420°103Q, 990 (am-') Example 2 Monooctadecyl phosphoric acid 100.0f (0.29 mol
) and thionyl chloride 103.5 f (0.87 m
ol) was placed in a reactor and reacted in the same manner as in Example 1. After the reaction, 51.4F was added in the same manner as in Example 1.
(0.65 mol) of bilicin was added and dissolved in a solution of benzo-N-benzyloxycarbonylserine 1
20.2F (0.35 mol) i was added dropwise to a solution dissolved in chloroform in the same manner as in Example 1, and then 67.3 f of 2-amino-2 was added in the same manner as in Example 1.
- A white solid of carmexyethyl-octadecyl phosphoric acid was obtained (0.15 mol.

yield 53.0%).

Elemental analysis (weight%) Calculated value C: 57.64% H: 10.14. N:
3.20, P: 7.08 Actual value C: 57.60
．． H: 10.19. N: 3.0? ,P:6.99
Example 3 Mono(2-octyldodecyl)phosphoric acid 100, Of (0.26 mol) and thionyl chloride? 9.8f (0.67 mol) was reacted in the same manner as in Example 1 to obtain zochlorophosphorite.

This was mixed with 84.0 F (0.65 mol) of quinoline, and the resulting solution was added dropwise at 0° C. to chloroform in which 107.8 F (0.31 mol) of benzol-N-pencyloxycarbonylserine was dissolved. In the same manner as above, the desired white solid 58.8F of 2-amino-2-carboxyethyl-2-octyldodecyl phosphoric acid was obtained (
0-12 mol, yield 48.6%) 0 Elemental analysis (weight %) Calculated value C: 59.33%H: 10.39, N: 3.
01. P: 6.65 Actual value c: 59.27, H
: 10.39% N: 2.96, p: 6.43
Example 4 %/(2-ethyltetraeicosyl)phosphorus fil OO
, Of (0,26 mol) and thionyl chloride 9
After obtaining zochlorophosphorite from 9.5 t (0.84 mol) in the same manner as in Example 1, quinoline 72.5F (0.60rIIIol) and hibenzo-N-pencyloxycal? Nilserine 120.9F
(0.35 mol) and the same method as in Example 1 to obtain the desired white solid of 87.5F 2-amino-2-carboxyethyl-2-ethyltetraeicosyl phosphoric acid (0.16 rnol, yield 61.2%)
0 The results of elemental analysis were as follows.

Elemental analysis C3i amount%] Calculated value c: 6336. H:11. OO%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)
Rin! 100. Of (0,29 mol) and 105.
After obtaining dichlorophosphorib-tra using 0f(0,88rnol) of thioni/L+chloride, 55.4
f (0.70 mol) of bilicin and pencil-N-
Pencyloxycarbonylserine 179.61 (0,
Dissolve 52 mol) in 100 m chloroform and
Stir at ℃ for 4 hours.

Thereafter, the reaction temperature was raised to room temperature and stirred for 4 hours. After the reaction is complete, 100 MI of water is added and stirred at 20°C for 1 hour. Thereafter, the solvent was distilled off and the mixture was extracted with diethyl ether. The obtained residue is dissolved in methanol, and hydrogen is bubbled in while heating the methanol under normal pressure under reflux using a norazoum/carbon catalyst, and the mixture is reacted for about 10 hours. After the reaction, all methanol was distilled off and the resulting residue was subjected to silica gel column chromatography (
The desired white solid of 2-amino-2-carboxyethyl-(2-hydroxy-3-lauryloxypropyl) phosphoric acid is obtained by purification with developing solvent/chloroform:methanol=90:10). :39.7f Toku9 (o, o
9 mol, yield 32.0%).

The results of elemental analysis were as follows.

Elemental analysis (weight%) Calculated value C: 50.58. H: 8.96, N: 3.2
8, P: 7.24 actual measurement value C: 50.55, yt
: 8,92, N: 3.25, Pnia, 18 Example 6 monotetraoxyethylene monolauryl ether phosphoric acid 100. Of (0.25 mol) and thionyl chloride 90.5 f (0.76 mol) were obtained in zochlorophosphoride. Thereafter, 103.6 t (0.30 m
ol) and Kinori y90.4f (0.70mol)
2- of 43.6 f in the same manner as in Example 1 using
A white solid of amino-2-carboxyethyl-tetraoxyethylene monolauryl ether phosphoric acid was obtained (0.08 mol, yield 32.9%). The results of elemental analysis were as follows.

Elemental analysis (weight%) Calculated values C: 52.16, H: 9.14, N: 2.6
4. P: 5.85 Actual value C: 52.01% H: 9.
13% N: 2.61% P: 5.73 Example 7 Octadecyloxyethylene monolauryl ether phosphoric acid 100. Of (0,094 mol) and thionyl chloride 33.7 F (0,28 mol) to obtain zochlorophosphoride. Nylserine 46.6 t (0,14
Using pyridine 22.4F (0.28 mol) and 22.4F (0.28 mol), a white solid of 17.3F of 2-amino-2-carmexyethyl-octadecyloxyethylene monolauryl ether phosphorus was obtained in the same manner as in Example 1. ( 0
．． 015 mol, yield 16.0%).

The results of elemental analysis were as follows.

Elemental analysis (weight%) Calculated values C: 53.44, H: 9.14, N: 1.22
, P: 2.70 Actual value c: s 3.2 s, H:
9.02. N: 1.19, P: 2.73 Example 8 2-hydroxyhexadecyl phosphate 100.0f (0,
30m01) and thionyl chloride 105.5f (0,
0
Then benzol-N-benzoloxy cartilage Nylserine 146. Of(0.44mol) and bilicin? 0.1
Using r (0.89 mol), 2-amino-2-casimexyethyl-24,6f was prepared in the same manner as in Example 1.
Obtained a white solid of 2-hydroxyhexadecyl phosphate (9)
o, o 58 mol, yield 19.6%) The results of elemental analysis were as follows.

Elemental analysis (weight%) Calculated values C: 53.63, H: 9.48, N: 3.2
9, P near, 28%m 1st shift C: 53.48.
H:9.45. N: 3.35% P near, 1
9 Example 9 Dichlorochloridate was obtained from monohebutadecafluorodecyl phosphoric acid 100, Of (0,18 mol) and thionyl chloride 64.3 f (0,54 mol). 2-amino-2- of 17,6f was prepared in the same manner as in Example 1 using (0.26 mol) and pyridiy42.4t (0.54 mol).
A white solid of cargoxyethyl hedetadecafluorodecyl phosphoric acid was obtained (0,028 mo11 yield 15.4%).
).

The results of elemental analysis are as follows.

Elemental analysis (weight%) Calculated values C: 24.72, H: 1.74, N: 222
, 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 mono-4° sodium salt of 2-amino-2-carboxyethyl-lauryl phosphate synthesized in Example 1. Prepared. It is a neutral or slightly acidic cream with good emulsification and is not sticky and blends well.

Skin cream: Glyceryl monostearate 2.4 cetanol 4.0 solid noq.
Rough In 5.0 Squalane
10.0 Octyldodecyl myristate 6.0 Glycerin
6.0 Fragrances, pigments, preservatives Appropriate amount of ion exchange water Balance

[Brief explanation of drawings]

FIG. 1 is a drawing showing the 'H-NMR spectrum of 2-amino-2-carmexiethyl lauryl phosphoric acid obtained in Example 1. FIG. 2 is a drawing showing the IB spectrum of the same compound. Above-Written 1,000 Procedural Amendment (Voluntary) September 3, 1986

Claims (1)

[Claims] 1. The following formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R^1 is the following formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼( II) (In the formula, R^4 is a linear or branched alkyl group having 8 to 36 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom, and R^5 is a hydrogen atom, methyl group, or ethyl group. group, n represents a number from 0 to 20) or the following formula (III) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (III) (In the formula, R^6 is R^7 Or indicated by OR^8, R^
7, R^8 represents a linear or branched alkyl group having 8 to 36 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom), and M^1 and M ^2 are the same or different and represent a hydrogen atom, an alkali metal, an alkanolamine group, or an ammonium salt] A phosphoric acid ester represented by the following. 2. The following formula (IV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (IV) [In the formula, R^1 is the following formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the formula, R^4 is a linear or branched alkyl group having 8 to 36 carbon atoms, the hydrogen atom of which may be substituted with a fluorine atom, R^5 is a hydrogen atom, methyl group or ethyl group, n is 0 ~20) or the following formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) (In the formula, R^6 is represented by R^7 or OR^8 It is R^
7, R^8 represents a linear or branched alkyl group having 8 to 36 carbon atoms, in which the hydrogen atom may be substituted with a fluorine atom) R^3 is represented by] monoalkyl represented by After halogenating the hydroxyl group of phosphoric acid, it is reacted with N-benzyloxycarbonylserine ester represented by the following formula (V) ▲Mathematical formula, chemical formula, table, etc.▼ (V), and then the carboxyl group and amino group are protected. The following formula (I), which is characterized by the removal of a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, M^1 and M^2 are the same or different and represent a hydrogen atom, an alkali metal, or an alkanolamine salt or an ammonium salt, and R^1 is the same as above].