JPS58203982A - Vitamin e-amino acid ester and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I or formula II (R1 is mono or diamino-monocarboxylic acid residue or their N-acyl derivative; R2 is mono or diaminodicarboxylic acid residue or their N-acyl derivative; R3 and R4 are H or CH3; R5 is group of formula III or formula IV). EXAMPLE:dl-alpha-Tocopherol-L-methionine ester. USE:It has the physiological and pharmacological activities of both vitamin E and amino acid, and is useful as a hair tonic, antidandruff and antipruritic agent, skin activating agent, etc. having synergistically increased activities and improved physical properties such as the solubility of amino acid in solvents, etc. PROCESS:The compound of formula I or formula II can be prepared by protecting the amino group and the side chain functional group of an amino acid, reacting the product with vitamin E using dicyclohexylcarbodiimide in the presence of pyrrolidinopyridine catalyst, and if necessary, eliminating the protecting groups.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an ester of vitamin E and an N-azil derivative of an amino acid represented by the following general formula (1) or (2), and a method for producing the same.

3.Vsgafu13. R2- represents a monoaminodicarboxylic acid residue, a diaminodicarboxylic acid residue, or an N-acyl derivative thereof. R5 and R+ are each 11 or C113
As for Rq, vitamin E analogues such as tocotrienols can be used similarly. In addition, in consideration of biological activity, ease of obtaining raw materials, etc., the L-form and d-form of the above-mentioned four tocopherols are preferable as raw materials for the present compound.

Vitamin E was originally discovered as an anti-infertility vitamin, but it is now known to be a substance that has a wide range of physiological and invasive effects, and is used in a wide range of fields. For example, the pharmacological effects of vitamin E include antioxidant effects, peripheral vasodilatory effects, biomembrane stabilization, gonadal function regulation effects, liver function enhancement, vascular hardening prevention, hair growth promotion, and abnormal keratin proliferation suppression. There have been many reports on this, and it is widely used in the fields of food, cosmetics, fisheries, livestock, etc. as well as pharmaceuticals.

(Left below) On the other hand, the amino acids constituting the present invention include glycine, alanine, 6-alanine, phosphorus, leucine, isoleucine, phenylalanine, methiotine, cysteine, serine, threonine, tyrosine, thyroxine, proline, oxypro-IJn I N-acyl derivatives of methane, arginine, histidine, cystine, asnowonic acid, glutamic acid, and these amino acids. The above amino acids (well, 0
It can be either L-, DL-, or L-form, but considering biological activity, availability of raw materials, etc., L- and D[.

``゛'' - Paper, margin) Vote - Amino acids are important substances that make up proteins, which are the constituent components of living organisms, and are also used in pharmaceuticals, foods, cosmetics, feed, and other industrial uses. Widely used. This substance is also known as a synergist, which increases and prolongs the antioxidant capacity when used in combination with vitamin E.

Therefore, the vitamin E-amino acid esters obtained by the present invention not only have the physiological and pharmacological actions of both vitamin E and amino acids, but also have the effect of synergistically enhancing each other's actions, and at the same time, the organic solvent It can also improve physical properties such as increasing the solubility of amino acids, which are soluble in food. Therefore, compounds I can be used in a wide variety of fields, such as hair tonics, dandruff and itch suppressants, skin revitalizers, and the like.

To produce this compound, vitamin E1 amino and side chain functional groups are protected with suitable protecting groups and dicyclohexylcarbodiimide are mixed in an organic solvent (e.g. ether, dichloromethane, etc.) as a catalyst. The reaction was carried out at room temperature in the presence of 4-pyrrolidinopyridine, and vitamin E
and an amino acid to form an ester. Thereafter, the protecting group is removed under appropriate conditions to obtain a compound having a free amine 7 group and a side chain functional group. Further, if an acyl group is used as a protecting group for an amino group and is left as it is without being removed after ester formation, an N-acyl derivative can be obtained.

The purpose of the acyl group is to protect and stabilize the amino group, so an acyl group with about 2 to 3 carbon atoms is appropriate.If the acyl group has too many carbon atoms, it will have a molecular weight of about It is inappropriate because it becomes small. Note that the method for producing the present compound is not limited to this method, and other methods (for example, a method involving acid chloride of an amino acid) can be used by selecting the type of amino acid and a protecting group suitable for it.

The method according to the present invention will be specifically explained below with reference to Examples.

(Left below) Example 1 dl! -α-toco7erol-L-methionine ester L-methionine 7.469, triethylamine 7.59
9 in 2B ml of water, and t-butyl-8-4
, 6-dimethylpyrimidin-2-ylthiocarbonate (hereinafter abbreviated as BoC-8DP) 13. A2ti was dissolved in dioxane 28- and added, and the mixture was stirred at room temperature for an hour.

Add 80ml of water, extract twice with 100ml of ethyl acetate,
The aqueous layer was adjusted to pH 2 by adding 4N hydrochloric acid while cooling with water, and extracted three times with 50% of ethyl acetate. The ethyl acetate layer 7 was washed three times with 5% hydrochloric acid (30) and then three times with saturated brine (30), dried over Glauber's salt, and the solvent was distilled off under reduced pressure to obtain 11 q of t-butyloxycarbonyl-L-methionine. was obtained as an oil. (Yield 97%) t-Butyloxycarbonyl-L-methionine crude oil (121) was dissolved in ethyl ether (160), dicyclohexylcarbodiimide (10.9) was dissolved under stirring, and dJ
-α-tocopherol 22.89. Then, 4-pyrodinopyridine α71 was added and stirring was continued for 17 hours. Remove the formed precipitate, wash thoroughly with ethyl ether,
The ethyl ether solution was washed 3 times with water, 3 times with 5% acetic acid, and 3 times with water again, dried over Glauber's salt, and the solvent was distilled off under reduced pressure. 36.5 ml of L-methionine ester was obtained as a yellow oil.

298 g of d/-α-toph7erol-t-butylox, carbonyl-b-methionine ester crude oil was dissolved in 75 g of anhydrous dioxane, and 225 g of a stirred F4N hydrogen chloride/dioxane solution was added dropwise. After stirring for 2 hours, the mixture was neutralized by adding a saturated aqueous solution of sodium bicarbonate under ice cooling, extracted with ethyl ether, washed with water, dried with sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 2599 as a yellow oil. . When this product was purified by column chromatography using silica gel using 8% acetone 2'n-hexane as the eluent, the target product d/-α-tocopherol-L-methionine ester 2o39- was obtained as a yellow oil. . The physical properties of this compound are as follows. (Yield 92%) KBr
-' Infrared absorption spectrum (ν cm) fi1mゝ3582.3364.2916.2852.1738.
1446.1363.1151.11l103130-
N (25,0MH2,pp with TMS internal standard as 0
m value. The same applies to subsequent NMR data) IL8.12.2.130.15, 4.19.7.19
．． 8.2α6.2LOS2Z6.2Z7.239.24
5.24.8.28+), 30.7.31.1.3&
7.3B8.33,9.37.3.374.394.5
34.750,'117.4.1231.1247.1
26.4.1402.1495.1743. (Chloroform) redundancy analysis value 034 HsQOs N S
Calculated value as 0:'[68H:1α58 N149
S: 5.71 actual value 0: '179 H: 10.
73 N=2+45 8:5.78 (blank below) Example 2 at-α-toco7erol-β-alanine ester 15.0 g of β-alanine was dissolved in 80-2N sodium hydroxide solution and stirred under water cooling. while carbobenzoxy chloride 319 and 4N sodium hydroxide solution 46-
were added dropwise at the same time over a period of approximately 1 hour. After further stirring at room temperature for 3 hours, the aqueous layer was extracted with 200% of ethyl ether, the aqueous layer was taken, concentrated hydrochloric acid was gradually added to adjust the PL to 2, and the separated oil was extracted with 70% of ethyl acetate. After washing with water, drying with sodium sulfate and concentrating under reduced pressure, and adding n-hexane, white needle crystals were precipitated. This was collected and recrystallized from chloroform-n-hexane, and carbobenzoxy-β-
Alanine 2a29 was obtained. (Yield 75%) Carbobenzoxy-β-alanine 491 Li was dissolved in ethyl ether 120-, and dicyclohexyl n-lupodiimide 4999 was stirred with the above N and then dl-
α-tocopherol a61 q and 036 g of 4-pyrrolidinopyridine were added and stirring was continued for an hour. The formed precipitate was removed, and the precipitate was washed three times each in the order of water, 5% acetic acid, and water, then dried with Glauber's salt, and the solvent was distilled off under reduced pressure to give dl-α-tocopherol-carbobenzoxy- β-alanine ester 1z69 was obtained as a yellow oil and dissolved in ml of ○QQ, and 10% palladium-carbon 1-
09 was added, and stirring was continued for a specified time while passing hydrogen gas.

The catalyst was removed, the solvent was distilled off under reduced pressure, and a yellow oil was obtained.
α59 was obtained. This was purified by column chromatography using silica gel using % acetone/n-hexane as an eluent to obtain dl-α-tof7erol-β-alanine ester aa4q as a yellow oil. (Yield 82
%), 7.9 Toro Kan' moxibustion ν911 (ν夷, (tube C tsu35
44.3324.287'4,2804. l]54,1
463,1379,1121.8?5゜13C-N M
R L12,111,110,19.7. L9.8. gcL
6,2L0.22-6.2&7.2&9. jZ44゜2
48, 2a0.31. , l, 32+7.3&8.34
2.31L4.37.3.37.4.39.4.4Ql
.

? 5.0.11? ,3.123.0.1!4.7.12
&5.14αa, 149.4.17Q9. (Chloroform) Elemental analysis value Calculated value as '32H5SO3N 0:
'160 H711,05N: 2.79 Actual value 0: 7a62 H: 1L16 N: 2
58 (Remaining examples s a/-α-toco7erol-L-cysteine ester L-cystine salt 25.09 and 140 g of N-hydroxymethylacetamide were dissolved in 40 g of water, cooled with water, and dissolved in concentrated hydrochloric acid 5.5 g. ml was added, the inside of the reaction vessel was replaced with nitrogen (inside) and left for 2 days, and the solution was concentrated under reduced pressure below 40"C. Absolute ethanol was added and distillation was repeated until water disappeared. Methanol was added to the residue. Add a small amount of S-acetamidomethyl-
17.09 g of L-cystine hydrochloride was obtained. (Yield 47%
) S-acetamidomethyl-L-cystine hydrochloride 15.
09 was dissolved in 130 tnl of dimethylformamide,
Tetramethylguanidine 151 was kept at 5°C under a nitrogen stream.
was added dropwise over 15 minutes. Next, 39 g of t-butyloquinyl azide 1α was added dropwise for 2 minutes, and finally 7.7 g of tetramethylguanidine was added dropwise.

The reaction mixture was continued to be stirred overnight and then concentrated under reduced pressure at a temperature below x°C, added with 45% of water, and extracted twice with 45% of ethyl acetate. The aqueous layer was adjusted to pH 3 by adding water-cooled trocitric acid solution, saturated with sodium chloride, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1479 as a yellow oil. This was treated with a small amount of ethyl acetate-benzene to crystallize it, and t-butyloquine-8-7adoamidomethyl-L-
Cystine &79 was obtained as white crystals. (Yield 45%
) t-butyloxycarbonyl-8-acetamidomethyl-L-cysteine 4.009 to ethyl ether 120
d/-α = tocopherol t -Butyloxycarbonyl-8-7adoamidomethyl-L-cysteine ester lαOg was obtained as a yellow oil.
9.95 g of this crude product was dissolved in anhydrous dioxane (36) and treated with a 4N hydrogen chloride/dioxane solution (64) in the same manner as in Example 1 to obtain 9.049 g of a yellow oil.

This was purified by column chromatography using silica gel using ethanol:chloroform:n-he-tsan-5=3°:65 as an elution solvent, and d/-α-tocopherol-8-aceto-amidomethyl-L -Cystine ester 6.18% was obtained as a yellow oil (yield 73%). Infrared absorption spectrum (% cm-1) 3338.
3276.3214, 3023.2902.1743.
1640.1538.1450.1362.1254.
1168.1085% 992130- NMR spectrum 11.8.123.13.1.19.7.19.8.2
0.6.2LO12Z6.227.23.2.23.8
．． 244.248.27.9.3L1.32+7.32
．． 7.37.0.37.3.37.4.39.4.4α
1.42+3.55.2.7&l, 117.5.123
．． 1.1247.1264.1402.149 et al., 17
α0.172+4 (chloroform) elemental analysis value '35
Calculated value as Hao o4N2 S (!: 69.4
9 H: lα00 N: 463 S: 5.30 actual measurement
Value C; 69.3'F) 11.81H:
dl at 4'79 8:5.3! -α-tocopherol-8-acetamidomethyl-L-cysteine ester 4
009 was dissolved in 50% acetic acid 100 resistant, and mercuric acetate 2
After adding 23 g and stirring for 2 hours, hydrogen sulfide gas was passed into the reaction solution to precipitate mercury ions as mercury sulfide.

Add 100 ml of ethyl ether and remove the precipitate LSP
The solution was neutralized by adding an aqueous sodium bicarbonate solution, and then extracted by adding 100 ml of ethyl ether.

The ether layer was washed with water, dried over Glauber's salt, and the solvent was distilled off under reduced pressure to obtain d/-α-toco-7-rol-L-7 stain ester L519 as a yellow oil.

This product contains a small amount of impurities and, like cysteine, is susceptible to oxidation, making it difficult to purify, but its structure was confirmed by the spectrum shown below. (Crude yield 41%) Infrared absorption spectrum (l m, cm-1) 3580.3351.29
17.2850, 2557.1745.1461°13
81S 1149.1103, ``'c-NMR spectrum 11.8.122, 13.1.19.'7.198.2
α6.21.0122=6.22? , 238.244.
248.25.0.27.9.31.0.32.7.3
27.37.3.37.4.394.4α1.55.1
．． 75.1.1174.123.1124.7.126
4.1402.1495.17Lo (Rioophor A) Example 4dt-α-tocopherol-L-cystine ester L-cystine e>ao9 and triethylamine 7.599
BoC-8DP 13 was dissolved in tt water gme.
．． 22 was dissolved in dioxane i mt' and treated in the same manner as in Example 1 to obtain 11.1 g of pale yellow powder. This was crystallized from ethyl acetate to obtain 9.249 di-t-butyloxycarbonyl-L-cystine as white crystals.

(Yield 90%) Di-t-butyloxycarbonyl-L-cystine a25
g was dissolved in 15 oml of ethyl ether, and with stirring, tocopherol 1a95 and 4-pyrodinopyrine 0599 were added, and the mixture was treated in the same manner as in Example 1 to give a yellow i.
/, I got Kuss 2 & 41. This was purified by column chromatography using silica gel using 2% ethyl ether/beshizene as the elution solvent, and the resultant mixture was purified by column chromatography using silica gel using 2% ethyl ether/beshizene as the elution solvent. obtained as.

This ester 6199 was dissolved in 24 ml of anhydrous dioxane and treated with 4N hydrogen chloride 7/dioxane solution p 50 mt in the same manner as in Example 1' to obtain di-cl/-α-toffeum-L-cystine ester 5.169 total. Obtained as a yellow oil. (Yield 65%) Infrared absorption spectrum "'>il'm, cm-') 3 35 School, 3344.2922.2866.1747.
1463.1380,1151, 2 characters 11104°
ONMR spectrum 11.8.12+2.130.19.7.197.2α
6.208.21.0.226.22+7.239.2
44.248.27.9.311.327.327.3
73.374.394.401.439.44], 54
0.750.1174.123.1.1247.126
4.1402.1495, I'110 (ri00 Hol A
) (hereinafter blank) Example 5 dl-α-tocopherol-N-acetyl-
L-methionine ester L-methionine 2,509 g was suspended in 50 g of water and 35.7 g of acetic anhydride was added with vigorous stirring. After continued stirring for 3 hours, excess reagent and solvent were distilled off at 30°C under reduced pressure. Ethyl acetate was added to the oily residue and dissolved by heating. After removing insoluble matter, the p solution was concentrated and left in the refrigerator for 2 days to crystallize. Recrystallized from ethyl acetate to N-acetyl-L
- 24.89 g of white crystals of methionine were obtained. m, p, 1
04~105°, [α] C0213 040. water),(
Yield 78%) N-acetyl to L-methionine 9.56i; l! Dissolve in 170 ml of ethyl ether and add 113.7 g of dicyclohexylcarbodiimide, 237 g of dl-α-tocopherol, and 0.74+7 of 4-pyro-di)bitocopherol under stirring.
Stirring was continued for days. The following treatment was carried out in the same manner as in Example 1 to obtain 30.0% of a pale yellow oil. This was purified by column chromatography using silica gel using 15% acetone/n-hexane as the elution solvent to obtain a colorless oil.
I got no. This was crystallized from methanol to give aZ-α-
White crystals 1a6 of Toco7 Erol-N-acetyl-L-methionine ester were obtained. tn, p.

58-6CPo (yield 62%) to 8r infrared absorption spectrum (epiversion, cm-') 3223,
3030. 2881. 2814. 1?55. 1
6411. 1552. 1462. 1380°12
62, 1153. 1109°+30-NMR spectrum 118, 12J, 130.154. 19.7.
198. 206. 210.226. 2Z Su 2
39°239, 244. 248. 27.9. 3
04. 31↓ 31.9. 32.7. 32.7.
373. 374°394, 40.1.51Jl]
, ? 5.1. 11?4 1231. 124.7
．． 1264. 14CL% 14'l et al. 1703,
170B, (chloroform) elemental analysis value 036-04
JL calculation value as NS 0: 7160 H: 1 (118N:
232 S: 531 actual measurement value 0: 7155 H
: 10.1!4 N : 224 S : 533 Other examples are briefly described below. The manufacturing method and confirmation of the composite were carried out in the same manner as in Examples 1 to 5.

[ Summer - Abbreviations ToC: Tocopherol, Boa: t-
Butyloxycarbonyl group.

OBZ: carhopenzoxy group, Bzl: benzyl group * d-α-topherol, d-ni-tocopherol,
a-'6-) Copherol was obtained by fractionation using high performance liquid chromatography using Emix Shui and Emix D (manufactured by Eisai) as a packing material and 8% chloroform/rl-hexane. .

Procedural amendment (spontaneous) September 1, 1980 Kazuo Wakasugi, Commissioner of the Japan Patent Office1, Indication of the case Patent Application No. 87580 of 19872 Name of the invention Vitamin E-amino acid esters and their manufacturing method 3
, Claims and Detailed Description of the Invention column 5 of the amended person's specification
Contents of amendment (2) The statement on page 3, line 10 of the specification will be corrected.

(3) "1 methiotine" on page 5, line 2 of the specification
methionine”.

(4) [t-Butyl-m-4,6-dimethylpyrimidin-2-ylthiocarbonate] in lines 4 to 6 on page 8 of the specification was replaced with methylpyrimidin-2-ylthiocarbonate”.

(5) “Vitamin E” in the first row of the table on page 1 of the specification
`` is corrected to ``1 bottle of vitamin E.'' (6) ``1 yield'' in the first row of the table on page η of the detailed accounting is corrected to 1.
Correct "yield main tree".

(7) 4th row of the table of detailed count (row of Example 8) [d-α-TocJ of rd-1-TOqJ
I will correct it.

(8) "A protective group was attached" on page 3, line 19 of the specification will be corrected to "A protective group was attached."

Esters 3 of vitamin E homologs and amino acids represented by general formula [I] or (II) (111') (wherein R1 is a monoaminomonocarboxylic acid residue or a diaminomonocarboxylic acid residue, or their N-acyl derivatives; R2 represents a monoaminodicarboxylic acid residue, a diaminodicarboxylic acid residue, or an N-acyl derivative thereof; R3 and R6 each represent H or;

(2) The amino acid residues of R are glycine, alanine,
β-alanine, valine, leucine, isoleucine, phenylalanine, methionine, cysteine, heptaline, threonine, tyrosine, thyroxine, proline, oxyproline, lysine, arginine, hif, tobi7. ＋ゎ、.

The vitamin E-amino acid esters (3 ) The amine 7 group and side chain functional group of the amino acid are protected with a suitable protecting group, and reacted with vitamin E using dicyclohexylcarbodiimide in the presence of a 4-pyrrolidinopyridine catalyst to form an ester. A manufacturing method for obtaining a compound represented by the general formula (1) or (It) with or without removing the protecting group.

Claims (3)

[Claims] (1) Esters 3 of vitamin E analogs and amino acids represented by the following general formula (1) or (fl) H30H3 (wherein R1 is a monoaminomonocarboxylic acid residue, a diaminomonocarboxylic acid residue, or R2 represents a monoaminodicarboxylic acid residue, a diaminodicarboxylic acid residue, or their N-acyl derivative. R3 and R4 each represent H or L+l(,, h, the law of nature (2)) The 11 amino acid residues are glycine, alanine, β-alanine, valine, leucine, inleucine, phenylalanine, methionine, cysteine, serine, threonine, tyrosine, thyroxy>, proline, oxyproline, lysine, and albocon. , histidine and their N-acyl derivatives, and the amino acid residue of R2 is cystine, aspartic acid, glutamic acid and their N-acyl derivatives. (3) Protect the amide 7 group and the side chain functional group of the amino acid with an appropriate protecting group, react with vitamin E using dicyclohexylcarbodiimide in the presence of a 4-pyrofudi-1-pyridine catalyst, and form an ester. Production method for obtaining a compound represented by the general formula (1) where K is 1 by removing or not removing the post-protecting group〇