JPH0426662A - Amino acid acyl derivative and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A basic amino acid acyl derivative of formula I (RICO is 13-20C saturated or unsaturated fatty acid residue; R2 is CH2OH, acyloxycarbonyl, CONH2, lower mono-dialkylaminocarbonyl; R3 is lower alkyl) and an acid adduct thereof. EXAMPLE:N<alpha>-Palmitoyl lysinol. USE:An amino acid cationic surfactant having high safety, excellent bio- decomposability and a high function and particularly useful as a positive charge substance for liposome membranes. PREPARATION:A compound of formula II (R4 is lower aminoalkyl group whose terminal amino group is protected with a protecting group capable of being released under an acidic condition or under a reducing condition) is condensed with a compound of formula III (X is halogen) and a protecting group in the R4 group of the prepared novel compound of formula IV is removed to effectively provide the compound of formula I.

Description

Detailed Description of the Invention (Field of Industrial Application) The present invention relates to an amino acid acyl derivative and a method for producing the same. The present invention relates to a novel amino acid acyl derivative consisting of a basic amino acid and a respiratory fatty acid, which is a compound useful as a pharmaceutical agent, and a method for producing the same.

(Prior Art) A surfactant is an amphiphilic substance having both a hydrophilic group and a hydrophobic group (lipophilic group) in one molecule.

As is well known, synthetic surfactants are widely used in a wide variety of fields, and in recent years, biosurfactants, that is, natural products and natural surfactants derived from natural products, have become more popular than conventional synthetic surfactants. It is attracting attention as it is highly safe and is expected to have new functions and characteristics.

Amino acid surfactants are the most typical natural surfactants, and are already widely used in the cosmetics field, and their types and applications are expanding further.

However, most of the ionic properties of conventional amino acid surfactants are anionic, nonionic, or amphoteric, and only a few examples of cationic surfactants are known.

Regarding cationic amino acid surfactants, which are expected to be used for various special purposes as highly functional substances,
A few reports (N shown in JP-A No. 51-5413)
(2-long chain acyl basic amino acid derivatives, Noda
A., et al., Chem, Phar-m, Bul, 1.
, 19.196199 (1971)), but there are only basic amino acid esters whose carboxyl group is in the lower alcohol type or amide type, which is the subject of the present invention. N(2-
Amino acid acyl derivatives consisting of an acid amide bond with a higher fatty acid via an amino group are rarely found.

On the other hand, stearylamine, a synthetic surfactant, is currently the only positively charged substance (cationic surfactant) used in the membrane material of liposomes (lipid bilayer vesicles with an aqueous inner shell). The current situation is that

However, reports regarding the toxicity of stearylamine (e.g. Tyrell, D. A., et al., Bioc.
himBjo hs, Acta, 457,259 (
1976); Adams, D. A., et al.; J. Ne.
urol, Sci, 31.173~ (1977
), etc.), and when stearylamine is used in biological systems, there is a problem in that it is necessary to pay sufficient attention to safety issues.

Therefore, in order to solve such problems, there is currently a demand for strong cationic surfactants as positively charged substances for liposome membrane materials that are highly safe and exhibit high functionality.

(Problems to be Solved by the Invention) An object of the present invention is to provide an amino acid-based cationic surfactant that is highly safe, has excellent biodegradability, is highly functional, and is particularly useful as a positively charged substance for liposome membrane materials. The object of the present invention is to provide a method that can efficiently manufacture the same.

(Means for Solving the Problems) The present invention achieves the above-mentioned objects by providing that a novel amino acid acyl derivative consisting of a basic amino acid and a higher fatty acid is a compound that satisfies the above-mentioned requirements, and that this compound can be efficiently produced. This was accomplished based on the discovery of a manufacturing method for this method, and its gist will be explained in detail below.

That is, the present invention has the following formula: Represents an aminocarbonyl group. R3 represents a lower aminoalkyl group] Basic amino acid acyl derivatives and acid addition salts thereof, and methods for producing these compounds are featured.

In addition, the general formula [■]: O [wherein RICO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, R2 is hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or a lower mono- or dialkylaminocarbonyl group represents. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amine group that can be removed under acidic conditions or reductively], as well as methods for producing these compounds. This is its characteristic.

Specifically, the compound represented by the above general formula [I] is a basic amino acid such as lysine or ornithine whose carboxyl group is a hydroxymethyl group which is its reduced form, a t-butoxycarbonyl group which is its ester form, or a t-butoxycarbonyl group which is its ester form. Aminocarbonyl group that is amide type or has 1 to 6 carbon atoms
It is a compound that has been converted into a mono- or dicarbonyl group consisting of a linear or branched alkyl group, and its Na-
It is a basic amino acid acyl derivative in which an amine group and a higher fatty acid are bonded through an acid amide bond, or an acid addition salt thereof.

These compounds are amino acid-based cationic surfactants, and can be said to be novel natural surfactants obtained by recombining and chemically modifying natural product constituents.

In addition, the compound represented by the general formula [IT] is a compound in which a benzyloxycarbonyl group or a t-butoxycarbonyl group, which is a protecting group for the amino group, is attached to the terminal amino group of the amino acid moiety. The above general formula [
A compound represented by I] can be obtained.

Basic amino acids, which are one of the constituent parts of the compounds represented by general formulas [I] and [II], have one amino group and one carboxyl group in the molecule, as well as an amino group, a guanidino group, and an imidazolyl group. Any basic amino acid having one or more basic substituents such as a group may be used, such as naturally occurring lysine, ornithine, arginine, histidine, etc., but other amino acids may also be used as long as they are highly safe. Can be used for

Amino acids with asymmetric carbon atoms have optical isomers, but unless there is a particular safety problem, L-form, D-form, DL-form
Use any part of your body.

Among the basic amino acids used in the present invention, lysine, which has been mass-produced and is available at an extremely low cost, is one of the most suitable amino acids as a raw material amino acid.

Further, higher fatty acids, which are one of the other constituent components of the compounds represented by general formulas [I] and [II], can be used if the fatty acid residue has 14 to 20 carbon atoms and is saturated or unsaturated. Although there are no particular limitations, saturated fatty residues are preferred in order to further enhance biocompatibility and improve storage stability.

The method for producing compounds represented by general formulas [I] and [nl is as follows: represent. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively] and a compound represented by the general formula [TV] , X represents halogen, and RICO has 14 carbon atoms.
By condensing with a higher fatty acid halide represented by ~20 saturated or unsaturated fatty acid residues,
-M The compound represented by the formula [11] can be obtained, and by removing the protecting group attached to the terminal amino group of the lower amino group that is R4 in the compound represented by the general formula [n], the general A compound represented by formula [I] can be produced.

Specifically, the compound represented by the general formula [rl'll is:
The carboxyl group of the basic amino acids lysine and ornithine is a hydroxymethyl group which is its reduced form, a t-butoxycarbonyl group which is its ester form, an aminocarbonyl group which is its amide form, or a carbon number of 1 to 1. It is a compound converted into a mono- or dialkylaminocarbonyl group consisting of a straight-chain or branched-chain alkyl group of 6, and its Na-amine group is unsubstituted and free, but its terminal amino group has a protective group. It is a compound with a benzyloxycarbonyl group or t-butoxycarbonyl group.

Among the basic amino acid derivatives represented by the general formula [m], the compound in which the R2 moiety is converted to its reduced form, hydroxymethyl group, can be prepared by a known method (for example, 5h
unichi Yamada et al; Chem.

Pharm, Bull, Dan (9), 1140-11
45 (1963) and JP-A-52-148036, etc.)
It can be synthesized according to

That is, first, among the basic amino acid derivatives of the compound represented by the general formula [III], an amino acid derivative in which the carboxyl group moiety is in the ester form or an acid addition salt thereof is used as a raw material compound, and this is numerically reduced. Hydroxymethyl whose carboxyl group moiety is the reduced form of the basic amino acid derivative, which is a compound represented by the general formula [ITI], is obtained by applying a method such as contacting with a reducing agent in an appropriate solvent. Compounds substituted with groups can be obtained.

Examples of the reducing agent in this case include metal hydride compounds such as lithium borohydride, sodium borohydride, lithium aluminum hydride, sodium dihydro bis-
Examples include, but are not limited to, hydrogenated organometallic compounds such as (2-methoxyethoxy)aluminate, diborane, and the like. Further, a halogen compound such as calcium chloride can be used together with these reducing agents as an additive.

As a solvent during reduction, for example, when using sodium borohydride, solvents such as alcohols or hydrous alcohols can be used, but other solvents that do not affect the reduction reaction, such as dioxane and tetrahydrohydride, can also be used. Ethers such as furan, ethyl ether, diethylene glycol dimethyl ether, or aromatics such as benzene may also be used. In addition to these solvents, additives such as diethylamine, pyridine, aniline, N-
Amines such as methylamine and γ-collidine may be used in combination.

The reaction temperature during reduction generally proceeds at room temperature, but the reaction may be appropriately cooled or heated to advantageously proceed.

Among basic amino acid derivatives that are compounds represented by the general formula [III], compounds in which the R2 moiety is converted to an alkyloxycarbonyl group, which is the ester type thereof, are represented by the general formula [rlI], as described above. It can be produced in the same manner as when using it as a starting material for synthesizing a basic amino acid derivative compound in which the R2 moiety is converted to its reduced form, hydroxymethyl group.

Among the basic amino acid derivatives of the compound represented by the general formula [m], the compound in which the R2 moiety is converted to an ester-type alkyloxycarbonyl group is the R2' in the compound represented by the general formula [■■']. It can be produced by esterifying the carboxyl group moiety as described above by a conventional method, and the R2 moiety is an amide carbonyl group, or a linear or branched chain having 1 to 6 carbon atoms. A compound converted into a mono- or dialkylaminocarbonyl group consisting of a chain alkyl group has the general formula [■II'
It can be produced by converting the carboxyl group portion, which is R2', of the compound represented by the above into an acid amide type by a known method.

That is, known methods include an active esterification method, a mixed acid anhydride method, an azide method, an acid chloride method, a symmetric anhydride method, and a method using a coupling reagent, which are generally used in peptide bonding reactions.

Examples of this coupling reagent include N.

N'-cyclohexylcarbodiimide, carbonylimidazole, diphenylphosphoryl azide, etc., and N,N
There is a method using '-cyclohexylcarbodiimide and an additive. Examples of the additive in this case include N-hydroxysufushiimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-12,3-dicarboxylic acid imide, and the like.

The compound represented by the general formula [IV] is specifically an acid halide of a higher fatty acid, which can be synthesized by a known method or easily obtained as a commercial product such as palmitic acid chloride or stearic acid chloride. Vine.

-M The halogen represented by X in the compound represented by formula [IV] is not particularly limited, but chlorine is generally used.

In order to obtain the compound represented by the general formula [II] by condensing the compounds represented by the general formula [IIT] and [IV], both of them are combined in a suitable solvent under basic conditions by a conventional method. This can be done by reacting with

Further, as mentioned above, by condensing the compounds represented by the general formulas [rlT] and [lV], the general formula [II
] Apart from the method for obtaining the compound represented by the general formula [II
It can be obtained by condensing the compound represented by I] with a saturated or unsaturated fatty acid having 14 to 20 carbon atoms using a condensing agent under basic conditions.

That is, in this case, among the basic amino acid derivatives of the compound represented by the general formula [ITI], an aminocarbonyl group in which the R2 moiety is an amide type thereof, or a linear or branched alkyl group having 1 to 6 carbon atoms. In order to obtain a compound converted into a mono- or dialkylaminocarbonyl group consisting of a group, R2' of a compound represented by M formula [11T']
The above-mentioned production method and conditions for converting the carboxyl group moiety into an acid amide type can be similarly applied.

Compound [II] can be obtained as described above, but apart from this method, in the compound represented by general formula [II], the carboxyl group of the R2 portion is alkyloxycarbonyl, which is the ester type thereof. A compound converted into a mono- or dialkylaminocarbonyl group consisting of a group, its amide type aminocarbonyl group, or a linear or branched alkyl group having 1 to 6 carbon atoms can also be produced by the following method. .

That is, the general formula [III'] [wherein R2' represents a carboxyl group]. R4 represents a lower aminoalkyl with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively] and a higher fatty acid halide represented by the general formula [IV]. By condensation, the general formula [■'] R2' H○ [wherein RICO represents a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2' represents a carboxyl group. R4
represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively]
After obtaining the compound represented by, R in this general formula [■']
2' carboxyl group is converted to alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group, and the compound is represented by the general formula [n] (However, in this case, R2 is alkyloxycarbonyl, aminocarbonyl, or representing only lower mono- or dialkylaminocarbonyl groups).

Furthermore, by removing the protecting group attached to the terminal amino group of the lower alkyl group R4 in the compound of general formula [nl obtained by this method, general formula [I]
A compound represented by (in this case, R2 represents only an alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group) can be obtained.

That is, specifically, the carboxyl group of the terminal amino group protecting group basic amino acid of R4 in the compound represented by the general formula [111'l is untreated, unsubstituted, and is in a free state as it is. ing.

The compound represented by the general formula [IH'] and the general formula [IV
] is subjected to a condensation reaction in the same manner as above to obtain a compound represented by the general formula [TI'], and then the carboxyl group of this compound is converted into the compound represented by the general formula [I]
By esterification or amidation in the same manner as in the case of the compound represented by ) is manufactured.

In this case, the conditions for the condensation reaction, esterification, amidation reaction, purification step, etc. are based on the general formula [TII] and [IT
The conditions for the preparation of the compound represented by J are similarly applicable.

The benzyloxycarbonyl group or t-butoxycarbonyl group, which is a protecting group attached to the terminal amino group of the compound represented by the general formula [■] obtained as above, is removed under reducing or acidic conditions by a conventional method. By eliminating with , a compound represented by the general formula [nl can be obtained.

The reaction for removing the protecting group can be carried out by a known method for peptide synthesis.

That is, for example, as a method for reductively removing a protecting group, a catalytic reduction method or the like is used.

Examples of catalysts used for catalytic reduction include platinum catalysts such as platinum and platinum oxide, palladium catalysts such as palladium and palladium-carbon, catalysts such as nickel oxide and Raney nickel, and cobalt catalysts such as Raney cobalt. The solvent used in the catalytic reduction usually includes water, methanol, ethanol, propatool, N,N-dimethylformamide, acetic acid, formic acid, or a mixed solvent thereof.

In addition, examples of acids used in the deprotection method under acidic conditions include trifluoroacetic acid, hydrochloric acid, formic acid, hydrogen fluoride, etc., and examples of solvents in this case include dichloromethane, chloroform, dioxane, Examples include, but are not limited to, tetrahydrofuran and acetic acid.

Examples of the acid addition salt of the compound represented by the general formula [I] obtained as above include organic acid salts such as formate, acetate, trifluoroacetate, maleate, tartrate, and oxalate. Examples include addition salts, and inorganic acid addition salts such as hydrochloride, sulfate, hydrobromide, and nitrate, but are not particularly limited thereto.

The acid addition salt of the compound represented by the general formula [I] can be used by removing the addition salt by a conventional method and returning it to a salt-free form, if necessary.

This compound is a natural amino acid acyl derivative obtained by recombining and chemically modifying amino acids and higher fatty acids, which are natural constituents, and is an amino acid-based cationic interface with high safety and excellent biodegradability. It can be said to be an activator.

In addition, the compound represented by the general formula [I] has an acid amide bond between an amino acid and a fatty acid, and the carboxyl group of the amino acid is reduced to a lower alcohol type, or amidated to an amide type. Therefore, it is safe and stable, so it is advantageous when used as a raw material for formulation.

Many reports (for example, JP-A-58-134197, etc.)
As shown in , amino acid higher alkyl ester salts and their N-lower alkyl substituted products have a common drawback of ester salts, as they have an ester bond in their structure, which makes them highly hydrolyzable, making it difficult to stably incorporate them into products. It is said that this is often difficult.

Additionally, there are reports on the use of amino acid derivatives as liposome-forming materials (for example, JP-A No. 63-2921, etc.), but in this report, amino acid-based anionic surfactants, which are N-higher acylamino acids, are used as liposome-forming materials. It is used as a lipid that is easily degradable, has low toxicity, and has the ability to form liposomes.

Furthermore, there are reports of attempts to target cancer cells by modifying liposomes with amino acid lipid derivatives (Proceedings of the 7th Biopharmaceutical Research Society, p. 49-(1989), etc.);
This report describes a commercially available amino acid-based cationic surfactant, Na-cocoyl-arginine ethyl ester (CE).
A), etc., and have begun research on new properties of liposomes whose membranes are modified with amino acids.

Furthermore, there are reports on the surface modification of liposomes with cholesterol derivatives having amino groups (e.g., K, R
, Patel et al., Biochimica et Bio
hsica ~” Yu Post, 256-264 (1
985), etc.), but no reports regarding amino acid acyl-based cationic derivatives such as those of the present invention have been found.

By the way, the constituent parts of liposomes can be roughly divided into 3 parts.
The liposomes are made up of various types of phospholipids as base materials, cholesterol as membrane-strengthening substances, and various cationic or anionic surfactants as membrane-charged substances, and charged substances are added to liposomes to increase surface charge. This prevents aggregation between liposomes, expands the inner aqueous phase due to electrostatic repulsion between the lamellar layers, and increases the amount of water-soluble encapsulated substances encapsulated in the liposomes. It is known that the behavior of liposomes in vivo (for example, tissue migration) is greatly influenced by the type of substance.

On the other hand, when the amino acid acyl-based cationic surfactant of the present invention is used as a liposome membrane material, due to its chemical structure, it is a positively charged substance and also has the characteristic of surface-modifying liposomes with basic amino acids. have.

(Effects of the Invention) As is clear from the above explanation, according to the present invention, as a novel natural amino acid derivative, (1) it is highly safe and has excellent biodegradability, and amino acids and higher fatty acids are Because it has an amide bond and the carboxyl group of the amino acid is in the reduced or amide form, (2) it can be stably incorporated into products (preparations).

In addition, when used as a liposome membrane material, (3) as a safe and novel membrane charged substance, and (4) as a membrane material for amino acid-modified liposomes.
It is possible to provide an amino acid-based cationic surfactant that imparts unprecedented properties to liposomes and can be expected to have benefits such as stiffness.

Therefore, the compound of the present invention is an amino acid derivative suitable for use in fields such as medical liposomes, which require consideration of safety, biocompatibility, and various compatibility with biological membranes, and is also suitable for use in biomedical applications. Materials, cosmetic applications, etc.
Furthermore, it is expected to be used in a wide range of fields such as biochemistry, medicine, pharmacy, and engineering, and its industrial value is great.

(Example) Next, the present invention will be explained in more detail with reference to Examples.
It is not limited to these.

Reference example, Synthesis of N E-amine group protected ricinol N8
-Dissolve 3.31 g (10 m moβ) of benzyloxycarbonyl lysine methyl ester (Sigma) in 100 mJ2 of ethanol, and add 20 m of ethanol under cooling with water.
It was suspended in fl. Sodium borohydride 2.66g
(70 m'moβ) was added dropwise. After dripping, in an oil bath,
It was refluxed for 1 day. The reaction solution was filtered, the solvent was distilled off under reduced pressure, and the concentrate was redissolved in chloroform and washed with water. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting crude product was crystallized in acetonitrile to yield 2.05 g of the target product, ε N -penzyloxytriponylridinol.
was obtained (yield 77%).

Example l Synthesis of N8-benzyloxycarbonyl-N(Z-balmitoyllisinol) 1.49 g of N8-benzyloxycarbonyl-N(Z-balmitoyllisinol)
(5,6 mmon) in chloroform70 +++j2
1.55 g of balmitoyl chloride (5,
6 mmoρ) and sodium hydroxide aqueous solution 5.6n+j2
was added in three portions, and the mixture was stirred at room temperature for 4 hours. The reaction solution was washed with saturated brine and water, and the organic layer was dried over anhydrous magnesium sulfate and then concentrated to dryness under reduced pressure to obtain 2.79 g (yield: 98%) of a solid crude product.

The obtained crude product was crystallized in a methanol-water mixed solvent to obtain the target product N8-benzyloxycarbonyl-N(
Z-balmitoyl ricinol 1.75 g (yield 62%)
I got it.

Example 2 Synthesis of N8-benzyloxycarbonyl, No-valmitoyllysine-tert-butyl ester (I) N8-benzyloxycarbonyllysine-tert-butyl ester (hydrochloride) (Tokyo Kasei Co., Ltd.) 599 mg (1
, 60m moρ) and stearic acid 600mg (2,
1,1m moβ) was dissolved in 20 mj2 of dichloromethane, and while stirring under water cooling, 540 mj2 of triethylamine was added.
(3.9 mmo℃) and 494 mg (2.40 mmof2.) of N,N-dichlorohexylcarbodiimide were added, and the mixture was stirred for 2 hours under water cooling, and then stirred for 1 hour at room temperature.
Stir for days. After filtering the reaction solution, the filtrate was washed with water. After drying the organic layer over anhydrous magnesium sulfate, it was concentrated to dryness under reduced pressure, and the resulting residue was applied to a silica gel column and sequentially eluted with a mixed solvent of n-hexane and ethyl acetate (5:l). The obtained elution fractions were subjected to thin layer chromatography (hereinafter abbreviated as TLC) to collect the desired fractions, and after concentration under reduced pressure to dryness, 392 mg (yield: 40%) of a solid was obtained. This solid matter is n
- By crystallizing in hexane, the target substance N
8-benzyloxyoxycarbonyl, N(Z-balmitoyllysine-tert-butyl ester was obtained.

Example 3 Synthesis of N8-benzyloxycarbonyl, Na-balmitoyllysine-tert-butyl ester (II) N8-benzyloxycarbonyllysine-tert-butyl ester 1.074 g (2,88 m mog)
was dissolved in 40 m of chloroform (2, and 750 mg of sodium bicarbonate dissolved in 3 mρ of water: 821 mg of balmitoyl chloride (2,98 mmoff) was added in three portions, and the mixture was stirred at room temperature for 5 hours. Add 20 mj2, extract the organic layer, and add 40 mj2 of water.
I washed it with water. After drying the organic layer with anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the resulting crude product was crystallized in n-hexane to yield 1.376 g of the target product, N8-benzyloxycarbonyl, No-valmitoyllysine-tert-butyl ester. 83%).

Example 4 Synthesis of Na-balmitoyl ricinol A 20 Erlenmeyer flask (with a Tetron stirring bar) was filled with argon gas, 180 mg of 10% palladium activated carbon (Kojima Chemical Co., Ltd.) was poured into the flask, and the argon gas was replaced again. Inject 100 mj2 of ethanol while stirring,
suspended. This suspension was added to N8 benzyloxycarbonyl-N (1-balmitoyl ricinol 1.744 g (
The flask was connected to a catalytic reduction apparatus (Skeeter-Pearl improved type; manufactured by Ishii Shokai) and stirred at room temperature for 5 hours. Methanol was added to the reaction solution, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain crude product 1.
249 g (yield 98%) was obtained. This crude product was crystallized in ethanol to obtain 1.185 g (yield: 92%) of Na-valmitoyl-ricinol, the target product.

Example 5 Synthesis of No-valmitoyl-lysine-tert-butyl ester In the same manner as in Example 4, 20 Erlenmeyer flasks (with Tetron stirring bar) were filled with argon gas, and 120 mg of 10% palladium activated carbon (Kojima Chemical) was added. Slowly add 10% of ethanol while replacing the argon gas again.
0 mj2 was injected and suspended under stirring. To this suspension was added 1.185 g of N8-benzyloxycarbonyl-N (Z-balmitoyl-lysine-tert-butyl ester).
(2.06 mmof2.) was added, the flask was connected to a catalytic reduction apparatus, and the mixture was stirred at room temperature for 5.5 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product of 90%
3 mg (yield 99%) was obtained. This crude product was crystallized in acetonitrile-〇-hexane, and the target product N
181 mg of CE-valmitoyl-lysine-tert-butyl ester was obtained.

The analysis results are shown below.

+ II (CH2), 4C:H1lCH20H (CH2) 18CH3CH20H (CH2)14CH3CH20H (GHz) I 4C+(3Coot-Bu(CH2)
+6c: H3C00t-Bu (CH2), 4C88C
Physicochemical data of 0NH2 (CH2)14c83 C0NEt 2 compound mp: (℃) IR: (cm-') 'H-NMR: (ppm) (CH2)4NH2 (CH2), Nl2 (CH2)3NH2 (CH2)4NH2 (CH2)4NH2 (CH2)4NH2 (CH2), Nl2 No, 1 mp: 1] 7 ~ 120 IR: 3300, 1645, 1550.147 ON
MR (CD, OD): 0.97 (3H, t), 1.1
7-1.80 (8H, m), 1.30 (24H, s
), 2.20(2H,t).

2.64 (2H, t), 3.47 (2H, dd)
, 3.74 (IH, br) No, 2 mp: 120 ~ 123 IR: 3300, 1645, 1550.147 ON
MR (CD30D): 0.90(3)(,t), 1.
20-1.70 (8H, m), 1.28 (28
H,s), 2.20 (2H,t).

2.72 (2H, t), 3.48 (2H, dd)
, 3.85 (IH, br) No, 3 mp: 107-110 IR: 3320, 1640, 1560.147ONM
R(CD30D): 0.88(3H,t), 1
．． 27 (24H, s).

1.40-1.77 (6H, m), 2.20 (2H
,t) ,2.93(2H,t) ,3.50(2
H, dd), 3.86 (LH, br) No, 4 mp: 43-46 IR: 3330.1730.1645, 1530.1
47ONMR (CDCLi): 0.87 (3H, t)
, 1.09-1.88 (8H, m), 1.26 (2
4H, s), 1.46 (9H, s) 2.19 (2H
, t), 2.70 (3H, br).

4.46 (LH, br), 6.11. (LH,br
) No, 5 mp: 49-52 IR: 3330, 1730, 1645, 1530.
147ONMR (CDCl2): 0.85 (3H, t
), 1.08-1.90 (8H, m), 1.23 (
28H,s), 1.44(9H,s) 2.18(2
H,t), 2.66(2H,t).

4.48 (IH, br), 5.98 (IH, br) No.
, 6 mp: 133 ~ 135 IR: 3390, 3295, 3320, 1675, 16
20,155ONMR (CD30D): 0.87(3
H, t), 1.18-1.89 (8H, m), 1
．． 26 (24H, s), 2.22 (2H, t
) 2.63 (2H, t), 4.60 (LH, dd)
47O No, 7 mp: 38-40 IR: 3295, 1635, 1540.147ON
MR(CD(1,L3): 0.85(3H,t)
, 1.00-1.79 (8H, m) , 1.09 (
3H, t) , 1.20 (3H, t) , 1.22
(24H, s), 2.18 (2H, t), 2.49 (2
H, br).

2.70 (2H, t), 3.13-3.58 (4H
, m).

4.86 (IH, br), 6.50 (LH, br)N.

(CH2)14CH3 (CH2) l 5CHa (CH2) 14cH3 (CH□)14CH3 (CH2) 14CH3 (CH2116cH3 (CH2), 4CI(.

(CH2) l-CH5 CH,0H CH20)I H20H H20H COOt-Bu COOt-Bu 0NH2 0NEt2 (CH2) 4NH-CBZ (CH2)4NH-(:BZ (CH2)4NH-BOC (C:H,), NH -CBZ (CH2)4NH-CBZ (CH2) 4NH-CBZ (CH2) 4NH-CBZ (CH2), NH-CBZ Physical and chemical data of the compound mp: ('C) IR: (cm-') 'H-NMR : (ppm, CDCLa)No,
8mp: 102.5 ~ 103.5IR:
3415, 3325, 1685, 1615, 1560,
1550, 1470°27O MR + 0.86 (3H, t), 1.08~1.70 (
88, m), 1.22 (24H, s), 2.
17 (2H, t), 2.90 (LH, br)
3.1.9 (2H, br), 3.58 (2H, br
).

3.87 (IH, br), 4.82 (LH, br).

5.08 (2H, s), 5.82 (LH, br), 7.
34(5t(,5)No, 9mp IR MR: 106-107: 3410,3330,1685,1615,15
60,1470.1280+ 0.87(3H,t)
, 1.08-1.69 (8H, m) , 1.23 (
24H,s), 2.17(2H,t), 2.77(LH
,br).

3.18 (2H, br), 3.58 (2H,
br), 3.87 (IH, br), 4.81
．． (LH, br), 5.08 (:28.s).

5.82(1)! ,br) ,7.34(5H,5)
No, 10:96.5~97.5 3410.3360.16g5,1615,1560,
1540.1470MR + 0.86(3H,t), 1.02~1.70(
8H, m), 1.23 (24H, s), 1.4
2(9H,s), 2.18(2H,t).

2.92-3.28 (3H, m), 3.60 (2t
(, br) , 3.89 (18, br) , 4.5
8 (LH, br), 5.85 (IH, br) No,
1. 1 87-88 MR 3360, 1,690, 1640, 1560, 1540
, 1470, 1,275: 0.85 (3H, t)
, 1.23 (24H, s) , 1.40-1.80 (
6H, m), 2.82 (IH, br), 3.2
0(2H,br).

3.59 (2H, br), 3.91 (LH, br), 4
．． 97 (LH,brl, 5.07 (2H,s)
, 5.90 (LH,br).

7.32 (5H, 5) No, 1 2 MR 2 68-69 2 3340.1735.1685.1650.154
0.1265: 0.88(3H,t), 1.11
~1.92 (8H, m), 1.25 (24H, sl
, 1.45 (9H, s); 2.20 (2H, t
).

3.18 (2H, dd), 4.48 (LH, br)
, 4.81 (LH, br) , 5.08 (2H,
s), 6.01 (IH, br).

7, 35 (5H, 5) No, 1 3 MR Near 0.5-71.5: 3340.1735, 1685, 1650, 154
0.1265+ 0.86(3H,t), 1.1(
1 to 1.88 (8H, m), 1.24 (28H, s
), 1.44(9t(,sl, 2.17(28
, t) 3, 16 (2H, dd) , 4.46 (
IH, br), 4.79 (IH, br), 5
．． 07(2H,s), 5.98(],t(,br)
.

7, 34 (5H, s) No, 1 4 = 167-170: 3390, 3300, 3200, 1695, 16
75,1,620,154OMR 1470,1275 + 0.88(3H,t), 1.01~1.98(
8H, m), 1.25 (24H, s), 2.
21 (2H, t), 3.21 (2H, br)
4.42 (LH, br), 4.86 (LH, br)
, 5.09 (2H, s) , 5゜30 (LH, b
r), 6.17 (2H, br).

7.34 (5H5) No. 1 5 mp: Syrup IR: 3305.1725.1630.1535.1
455.126ONMR: 0.85(3)1. t)
, 1.00-1.96 (8H, m), 1.07 (3H
,t) ,1.14(3H,t) ,1.21(24H
, sr).

2.15 (2H, t), 3.07-3.57 (6H,
m).

Claims (1)

[Claims] 1. General formula [I]: ▲Mathematical formula, chemical formula, table, etc.▼[I] [In the formula, R1CO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2 is Represents hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group. R3 represents a lower aminoalkyl group] Basic amino acid acyl derivatives and acid addition salts thereof. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R1CO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2 is hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or lower mono- or Represents a dialkylaminocarbonyl group. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively]. 3. In claim 1, R2 is a hydroxymethyl group, R
A basic amino acid acyl derivative in which 3 is a 4-aminobutyl or 3-aminopropyl group, and an acid addition salt thereof. 4. The basic amino acid acyl derivative and acid addition salt thereof according to claim 1, wherein R2 is a t-butoxycarbonyl group, and R3 is a 4-aminobutyl or 3-aminopropyl group. 5. The base according to claim 1, wherein R2 is an aminocarbonyl group, or a linear or branched mono- or dialkylcarbonyl group having 1 to 6 carbon atoms, and R3 is a 4-aminobutyl or 3-aminopropyl group. amino acid acyl derivatives and their acid addition salts. 6. In claim 2, R2 is a hydroxymethyl group, R
A basic amino acid acyl derivative in which 4 is 4-aminobutyl or a 3-aminopropyl group with a protecting group attached to the terminal amino group that can be removed under acidic conditions or reductively. 7. In claim 2, R2 is a t-butoxycarbonyl group, R4 is 4-aminobutyl, or a 3-aminopropyl group with a protecting group attached to the terminal amino group that can be removed under acidic conditions or reductively. A basic amino acid acyl derivative that is 8. In claim 2, R2 is an aminocarbonyl group, or a mono- or dialkylcarbonyl group consisting of a linear or branched alkyl group having 1 to 6 carbon atoms, and R4 is the terminal of a 4-aminobutyl or 3-aminopropyl group. A basic amino acid acyl derivative that has an amino group attached with a protecting group that can be removed under reductive or acidic conditions. 9. The basic amino acid acyl derivative according to any one of claims 2 and 6 to 8, wherein the protecting group for the terminal amino group of the lower aminoalkyl group represented by R4 is a benzyloxycarbonyl group or a t-butoxycarbonyl group. 10. General formula [III]: ▲Mathematical formulas, chemical formulas, tables, etc.▼[III] [In the formula, R2 represents hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or a lower mono- or dialkylaminocarbonyl group. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively] and the general formula [IV]: ▲ Numerical formula, chemical formula, table, etc. ▼ [IV] [In the formula, X represents halogen, and R1CO has 14 carbon atoms.
~20 saturated or unsaturated fatty acid residues] is condensed with a higher fatty acid halide represented by General formula [II]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [II] [In the formula, R1CO represents a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R2 represents hydroxymethyl, alkyloxycarbonyl, aminocarbonyl, or a lower mono- or dialkylaminocarbonyl group. R4 represents a lower aminoalkyl group with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively. Method. 11, characterized by removing the protecting group attached to the terminal amino group of the lower alkyl group R4 in the compound represented by the general formula [II] produced by the method of claim 10,
The following general formula [I]: ▲Mathematical formulas, chemical formulas, tables, etc.▼[I] [In the formula, R1CO is a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, R2 is hydroxymethyl, alkyloxycarbonyl, Represents aminocarbonyl or a lower mono- or dialkylaminocarbonyl group. 2. The method for producing a compound according to claim 1, characterized in that R3 represents a lower aminoalkyl group. 12. A compound represented by the general formula [III] and a compound having 1 carbon number
4 to 20 saturated or unsaturated fatty acids under basic conditions,
By condensing using a condensing agent, the general formula [II]
Claim 2 characterized in that the compound represented by is produced.
A method for producing a compound. 13, characterized by removing the protecting group attached to the terminal amino group of the lower alkyl group R4 in the compound represented by the general formula [II] produced by the method of claim 12,
A method for producing the compound according to claim 1 represented by the general formula [I]. 14. General formula [III'] ▲Mathematical formulas, chemical formulas, tables, etc.▼[III'] [In the formula, R2' is a carboxyl group, and R4 is a lower aminoalkyl group whose terminal amino group is attached under acidic conditions or reductively. Represents a compound with a removable protecting group] and the general formula [IV]: ▲There are mathematical formulas, chemical formulas, tables, etc.▼[IV] [In the formula, X represents a halogen, and R1CO is Number of carbons is 1
4 to 20 saturated or unsaturated fatty acid residues] is condensed with a higher fatty acid halide represented by the general formula [II'] ▲There are mathematical formulas, chemical formulas, tables, etc.▼[II'] [Formula where R1CO represents a saturated or unsaturated fatty acid residue having 14 to 20 carbon atoms, and R4 represents a lower aminoalkyl with a protective group attached to the terminal amino group that can be removed under acidic conditions or reductively. After obtaining the shown amino acid derivative, the carboxyl group of R2' in this general formula [II'] is converted to an alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group to obtain the general formula [II]. Claim 2, characterized in that the compound shown in FIG.
A method for producing a compound. 15. General formula [I] characterized by removing the protecting group attached to the terminal amino group of the lower alkyl group that is R4 in the compound represented by general formula [II] produced by the method of claim 14. ] (However, in this case, R2 represents only an alkyloxycarbonyl, aminocarbonyl, or lower mono- or dialkylaminocarbonyl group). 16. The manufacturing method according to claim 10 or 12, wherein the halogen of X in general formula [IV] is chlorine or bromine.