JPH0120146B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to arginine derivatives or salts thereof useful for producing peptides. guanidino group

In order to produce a peptide using a raw material compound (such as arginine) containing [Formula], it is necessary to protect the guanidino group. Protection of the guanidino group has conventionally been carried out by introducing a nitro group or a tosyl group. In these conventional methods, the yield when removing the protecting group is low, and in order to remove the tosyl group, it must be carried out under strong conditions using liquid ammonia-metallic sodium or anhydrous hydrogen fluoride. As a result, other parts of the peptide are decomposed and by-products are produced, resulting in a reduction in the yield of the desired peptide. The present inventors have proposed a method to overcome these drawbacks by first using p-methoxybenzenesulfonyl, meditylenesulfonyl, etc., which can be easily removed with methanesulfonic acid, as a protecting group for the guanidino group. (Japanese Patent Application Laid-Open No. 51-100030),
It was put into practical use. After that, the present inventors continued research on the protection of guanidino groups, and found that 4-methoxy-2,6
- When using dimethylbenzenesulfonyl group,
After peptide condensation, we found that the protecting group could be removed by mild acid treatment, but further research revealed that pentamethylbenzenesulfonyl group, 2,4,6-trimethoxybenzenesulfonyl group , 4-methoxy-2,3,5,6-tetramethylbenzenesulfonyl group was also found to be able to remove the protecting group by mild acid treatment, and as a result of further research, the present invention was completed. . That is, the present invention provides the guanidino group of arginine with the general formula () [In the formula, R ₁ and R ₅ are methyl or methoxy,
R ₂ and R ₄ represent methyl or hydrogen, and R ₃ represents methyl or methoxy, respectively. However, R ₁ ,
R ₂ , R ₄ and R ₅ are all methyl, and R ₃
represents methyl or methoxy, or
R ₁ , R ₃ and R ₅ are all methoxy, and
Both R ₂ and R ₄ represent hydrogen. ] A compound formed by introducing a substituted benzenesulfonyl group represented by the general formula () Arginine derivatives and salts thereof represented by [wherein R ₁ , R ₂ , R ₃ , R ₄ and R ₅ have the same meanings as above, and R ₆ represents hydrogen or an α-amino group protecting group] , is. In the present invention, when introducing a substituted benzenesulfonyl group represented by the general formula () into the guanidino group of arginine, α
- The amino group can be protected and subjected to the reaction. This α
- The protection of the amino group can be carried out using conventionally known protective groups, such as carbobenzoxy group, p- _{nitrobenzyloxycarbonyl} group, p-methoxybenzyloxycarbonyl group, t -butoxycarbonyl group, t
- amyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, isonicotinyloxycarbonyl group, o-nitrophenylsulfenyl group,
Examples include those in which a 2-(p-biphenyl)isopropyloxycarbonyl group is introduced by a conventional method,
Those protected with a carbobenzoxy group or a t-butoxycarbonyl group are advantageously used. Next, the α-amino group-protected arginine is reacted with a substituted benzenesulfonyl group represented by the general formula (). In this reaction, arginine is preferably reacted with a substituted benzenesulfonic acid group of the general formula () in an amount of about 1 to 5 equivalents, more preferably about 1 to 2 equivalents, per equivalent of arginine. The sulfonic acid group is usually subjected to the reaction in its halide form. Halogenides include chloride, fluoride,
Both bromide and iodide can be used. Usually, it is preferable to carry out the reaction in the presence of a base. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide, etc., and about 1 to 10 equivalents per equivalent of the guanidino group-containing compound,
More preferably, about 1 to 5 equivalents are used. The reaction is usually carried out in a suitable solvent such as water, acetone,
It is preferable to conduct the reaction in dioxane, dimethylformamide, tetrahydrofuran, or a mixed solvent thereof. The reaction is carried out at -10°C to 25°C, preferably -5°C to 10°C. The arginine derivative protected with a substituted benzenesulfonyl group represented by the general formula () obtained in this way is subjected to peptide condensation as a free form or as a salt of cyclohexylamine, dicyclohexylamine, sodium, etc. according to a conventional method. It is offered. The compound thus obtained having a guanidino group protected by a substituted benzenesulfonyl group of the general formula () can be used in a peptide condensation reaction by a conventional method. Conventional methods include, for example, M. Bodansky and MA Ondetti, Peptide Synthesis;
Inter science, New York, 1966; FMFinn
and The Proteins by K.Hormann.
Proteins), Volume 2, edited by H. Nenrath, RL Hill,
Academic Press Inc. New York, 1976; Methods described in "Peptide Synthesis" by Nobuo Izumiya et al., Maruzen Co., Ltd., 1975, such as the azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method. , active ester method, method using Woodward reagent K,
Carboimidazole method, redox method, DCC/
Examples include the HONB method. Next, after peptide condensation, the protecting group of the present invention is removed with an acid. As this desorption method, known acid treatment methods such as anhydrous hydrogen fluoride method, methanesulfonic acid method, and trifluoromethanesulfonic acid method can be applied. Furthermore, in the case of the present peptide production method, trifluoroacetic acid can be advantageously used as a new acid treatment method, and especially when trifluoroacetic acid is used in the presence of thioanisole or anisole, the elimination reaction proceeds very favorably. . The above-mentioned trifluoroacetic acid, thioanisole, and anisole may be used in an amount sufficient to serve as a solvent and remove the protecting group. For example, 1 equivalent of a compound having a protected guanidino group
~ ¹⁰⁵ equivalents, more preferably 1 to ¹⁰³ equivalents are used, and the elimination reaction may be carried out in a solvent such as acetic acid, chloroform, methylene chloride, etc., and the temperature is about -10°C to 300°C, and preferably 10
It is carried out at a temperature of about 100°C to 100°C. This peptide production method can be applied to the production of any peptide having a guanidino group. A specific example is Des−Gly ¹⁰ −[D−Leu ⁶ ]−LH−
RH-ethylamide (see Special Publication No. 53-14072), Des
−Gly ¹⁰ −LH−RH−ethylamide (Special Publication 1977−
24423), Tuftsin [Nature, 228, 672
(1970)], Substance P, Kyotorphin, and other physiologically active peptides can be advantageously produced. Other peptides include MSH, ACTH, Glucagon
−Secretin, Bradykinin, Dynorphin, α−
Neoendorphins and their active fragments can also be advantageously produced. General formula () used in this peptide production method
The substituted benzenesulfonyl group can be easily removed not only by the conventional method of removing the guanidino protecting group by acid treatment but also under milder conditions. For example, mild acid treatment such as trifluoroacetic acid cannot be applied to the removal of conventionally known guanidino protecting groups, but it works well when protected with substituted benzenesulfonyl groups of general formula (). Desorption progresses and can be applied satisfactorily. By the way, when a guanidino group is protected with a p-methoxybenzenesulfonyl group or meditylenesulfonyl group and the protecting group is removed using methanesulfonic acid after peptide condensation by a conventional method,
If the peptide contains asparagine or aspartic acid residues, succinimide-type side reactions may occur, and if serine or threonine residues are present, N→O acyl rearrangement may occur.
In the case of this peptide production method, even peptides containing these amino acid residues can be removed without causing side reactions as described above by using a mild acid such as trifluoroacetic acid. Next, the present invention will be explained in more detail by giving examples, reference examples, and test examples. In addition, in this specification, regarding amino acids, peptides, protective groups, active groups, etc., the IUPAC-IUB commission on
It may be indicated by an abbreviation based on Biological Nomenclature or by an abbreviation commonly used in the field. Illustrate them. pGlu: pyroglutamic acid; His: histidine;
Trp: tryptophan; Ser: serine; Tyr: tyrosine; Leu: leucine; Gly: glycine;
Arg: arginine; Pro: proline; Lys: lysine; Gln: glutamine; Phe: phenylalanine; Met: methionine; Thr: threonine (unless otherwise specified, the amino acid refers to the L-form, and the D-form (Excluding Gly); Z: Carbobenzoxy; Boc: t-butoxycarbonyl; Et: Ethyl; HONB and
ONB: N-hydroxy-5-norbornene-
2,3-dicarboximide and its ester; HOBt: N-hydroxybenztriazole; DCC: N,N'-dicyclohexylcarbodiimide; H ₂ /Pd: catalytic reduction; TFA: trifluoroacetic acid; CHA: cyclohexylamine; OTCP: 2,
4,5-trochlorophenyl ester; OSu:N
-Hydroxysuccinimide ester In addition, in this specification, a substituted benzenesulfonyl group represented by the general formula (), that is, a pentamethylbenzenesulfonyl group, is referred to as Pme, 2,
4,6-trimethoxybenzenesulfonyl group
Tms and 4-methoxy-2,3,5,6-tetramethylbenzenesulfonyl group may be abbreviated as Tmo, respectively. Example 1 (1) Synthesis of Z-Arg(Pme)-OH・CHA Dissolve 10.0 g of Z-Arg-OH in 33 ml of 4N-NaOH and 130 ml of acetone, and cool on ice. An acetone solution (30 ml) containing 14.0 g of pentamethylbenzenesulfonyl chloride was added dropwise to this, and the mixture was stirred for 2 hours. After acidifying with citric acid and distilling off the solvent, the mixture is extracted with ethyl acetate. The target product was extracted from the ethyl acetate layer with NaHCO ₃ water, acidified with citric acid, extracted again with ethyl acetate,
Dry with anhydrous sodium sulfate. After distilling off the solvent, 3.55% of cyclohexylamine was added to the residue.
ml and filter the crystals from ethyl acetate. Yield 13.3g (66.4%), melting point 173-175℃,
[α] ²³ _D +5.8゜ (c=1.27, MeOH) Elemental analysis C ₃₁ H ₄₇ O ₆ N ₅ Calculated value: C, 60.26; H, 7.67; N, 11.34; S, 5.19 Experimental value: C , 60.15; H, 7.84; N, 11.25; S, 5.30 (2) Synthesis of H-Arg(Pme)-OH Z-Arg(Pme)-OH・CHA1.24g to 1N-
After adding 3 ml of H ₂ SO ₄ and extracting with ethyl acetate, the solvent was distilled off. Pour the residue into 30ml of methanol
and then catalytically reduced using palladium black as a catalyst. After the catalyst is filtered off and the solvent is distilled off, ether is added and the crystals are collected by filtration. Yield 0.77
g (97.8%), melting point 153-156℃, [α] ²³ _D −5.5゜ (c = 0.91, MeOH) Elemental analysis C ₁₇ H ₂₈ O ₄ N ₄ S・1/2H ₂ O Calculated value: C, 51.89; H, 7.43; N, 14.24; S, 8.15 Experimental value: C, 51.60; H, 7.74; N, 13.80; S, 8.12 Example 2 (1) Synthesis of Z-Arg(Tms)OH Z-Arg- Dissolve 0.77 g of OH in a mixture of 2.5 ml of 4N-NaOH and 10 ml of acetone and cool on ice. An acetone solution (3 ml) containing 1.0 g of 2,4,6-trimethoxybenzenesulfonyl chloride was added dropwise to the mixture, and the mixture was stirred for 2 hours. The mixture is acidified with citric acid, the solvent is distilled off, the mixture is saturated with sodium chloride, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. After distilling off the solvent, ether is added and the powder is collected by filtration. Dissolve this in 10 ml of chloroform and apply to silica gel column (4 x 10 cm) chromatograph. Chloroform: Methanol:
Elute with acetic acid (9:0.7:0.35) system, 110ml~
Take a 210 ml fraction, concentrate it, and filter it as a powder from ether. Yield 250mg (18.0%), melting point 89
~93℃, [α] ²³ _D +0.8゜ (c=0.50, MeOH) Elemental analysis C ₂₃ H ₃₀ O ₉ N ₄ S・H ₂ O Calculated value: C, 49.63; H, 5.80; N, 10.07 ; S, 5.76 Experimental value: C, 49.67; H, 5.57; N, 9.87; S, 5.81 (2) Synthesis of H-Arg(Tms)OH 150 mg of Z-Arg(Tms)OH in methanol,
Catalytic reduction using palladium black as a catalyst. After the catalyst is filtered off and the solvent is distilled off, ether is added and the powder is collected by filtration. Yield 105mg (89.1
%), melting point 115-120℃, [α] ²³ _D -8.9゜(c=0.60,
MeOH) Elemental analysis C ₁₅ H ₂₄ O ₇ N ₄ S・CH ₃ OH Calculated value: C, 44.02; H, 6.47; N, 12.84; S, 7.35 Experimental value: C, 43.55; H, 6.33; N, 12.84 ; S, 6.99 Example 3 (1) Synthesis of 2,3,5,6-tetramethylanisole 2,3,5,6-tetramethylphenol
Dissolve 15.0 g and 28 ml of methyl iodide in 150 ml of DMSO and add 6.3 ml of 60% oily sodium hydride under ice cooling.
Add g, return to room temperature and stir for 1 hour.
After adding MeOH to decompose excess sodium hydride, add water, extract with ether, and dry with sodium sulfate. When the solvent is distilled off, crystals will precipitate, so recrystallize from MeOH. Yield 10.2g (62.1%), melting point 45-47℃ (2) Synthesis of 4-methoxy-2,3,5,6-tetramethylbenzenesulfonyl chloride 2,3,5,6-tetramethylanisole
Dissolve 10.0g in 600ml of dichloromethane and cool to -5℃.
Add a solution of 12 ml of chlorosulfonic acid in dichloromethane (400 ml) at ~-10°C. After stirring for 2 hours, the reaction solution was poured onto ice containing 5% NaHCO ₃ water, the organic layer was washed with water, and then dried over magnesium sulfate. The solvent was distilled off and n-
Filter the crystals from hexane. Yield 10.0g
(62.5%), melting point 58-59℃ Elemental analysis as C ₁₁ H ₁₅ O ₃ SCl Calculated value: C, 50.28; H, 5.75; S, 12.21; Cl, 13.50 Experimental value: C, 50.52; H, 5.56; , 11.92; Cl, 13.42 (3) Synthesis of Z-Arg(Tmo)-OH・CHA Dissolve 1.85 g of Z-ArgOH in 6 ml of 4N-NaOH and 25 ml of acetone and cool on ice. To this was added an acetone solution of 2.50 g of 4-methoxy-2,3,5,6-tetramethylbenzenesulfonyl chloride (10
ml) and stir for 1 hour. After adding citric acid water and distilling off the solvent, the desired product is extracted with ethyl acetate and dried over anhydrous sodium sulfate.
After distilling off the solvent, cyclohexylamine
Add 0.58 ml, filter the crystals from ether, and dry. Yield 2.40g (63.1%), melting point 127
~129℃, [α] ²³ _D +5.9゜ (c=0.84, MeOH) Elemental analysis As C ₃₁ H ₄₇ O ₇ N ₅ S Calculated value: C, 58.74; H, 7.48; N, 11.05; S, 5.06 Experimental values: C, 58.84; H, 7.30; N, 11.25; S, 5.06 (4) Synthesis of H・Arg(Tmo)-OH Suspend 2.0 g of Z・Arg(Tmo)OH・CHA in 40 ml of ethyl acetate, After adding 4 ml of 1N sulfuric acid, shaking well and washing with water, the solvent was distilled off. Dissolve this in 40 ml of methanol and perform catalytic reduction using palladium black as a catalyst. After the catalyst is filtered off and the solvent is distilled off, ether is added and the powder is collected by filtration and dried. Yield 1.20g (92.7%), melting point 150
~153℃, [α] ²³ _D −4.5゜ (c=0.92, MeOH) Elemental analysis C ₁₇ H ₂₈ O ₅ N 4 S・₁ /2H ₂ O Calculated value: C, 49.86; H, 7.14; N, 13.68; S, 7.83 Experimental value: C, 50.38; H, 7.57; N, 13.48; S, 7.60 Test example Approximately 20 mg of N ⁰ -protected arginine obtained above was mixed with trifluoroacetic acid-thioanisole (9:1) 2
ml and left at 50℃ for 1 hour and 4 hours, then take 100μ of it and weigh the whole to 10ml.
Amino acid analysis was performed to measure the amount of arginine produced. The results are shown in Table 1.

【table】

[Table] Reference example 1 Synthesis of pentamethylbenzenesulfonyl chloride 17.8g of pentamethylbenzene was dissolved in dichloromethane
Dissolve to 500 ml and cool to -5°C to -10°C. Add 24ml of chlorsulfonic acid to 400ml of dichloromethane.
ml of the solution was added dropwise, and then allowed to warm to room temperature. The reaction solution was poured onto ice containing 5% aqueous sodium hydrogen carbonate, and the organic layer was washed with water and then dried over magnesium sulfate. When the solvent is distilled off, crystals precipitate, which are collected by filtration and recrystallized from n-hexane. Yield 27.7g (93.5%), melting point 80-81℃ Elemental analysis as C ₁₁ H ₁₅ O ₂ SCl Calculated value: C, 53.54; H, 6.13; N, 13.00; Cl, 14.37 Experimental value: C, 53.78; H, 6.09; N, 13.00; Cl, 14.39 Reference example 2 Synthesis of 2,4,6-trimethoxybenzenesulfonyl chloride Dissolve 5.05 g of 1,3,5-trimethoxybenzene in 500 ml of dichloromethane and heat at -5°C to -10°C. Cool to ℃. A solution of 6 ml of chlorosulfonic acid dissolved in 400 ml of dichloromethane was added dropwise to this, and then
Bring to room temperature. Thereafter, it was treated in the same manner as in Reference Example 1, and the crystals were collected by filtration from carbon tetrachloride. yield
610 mg (6.3%), melting point 126-129°C Elemental analysis as C ₉ H ₁₁ O ₅ SCl Calculated value: C, 40.53; H, 4.16; S, 12.02; Cl, 13.30 Experimental value: C, 40.79; H, 4.16; S, 11.84; Cl, 13.28 Reference example 3 (1) Synthesis of Boc-Tyr-Arg(Pme)-OH Dissolve 790 mg of H-Arg(Pme)-OH in 20 ml of tetrahydrofuran, add triethylamine while cold.
0.34ml, Boc-Tyr-ONB (Boc-Tyr-
(Prepared from 0.57 g of OH, 0.40 g of HONB, and 0.50 g of DCC) and stirred at room temperature for 15 hours. After evaporating the solvent, the mixture is acidified with citric acid and extracted with ethyl acetate. After washing the ethyl acetate layer with water, the solvent was distilled off, dissolved in chloroform, and applied to a silica gel column (4 x 6 cm). 5%
Elute with MeOH/CHCl ₃ , collect fractions of the desired product, concentrate and filter off as a powder from ether.
Yield 690 mg (51.8%), melting point 136-139℃, [α] ²³ _D
-15.0゜ (c=0.5, dimethylformamide) Elemental analysis C ₃₁ H ₄₅ O ₈ N ₅ S・H ₂ O Calculated value: C, 55.92; H, 7.12; N, 10.52; S, 4.82 Experimental value: C, 55.95 ; H, 7.02; N, 10.58; S, 4.62 (2) Synthesis of H-Tyr-Arg-OH (Kyotorphin) 300 mg of Boc-Tyr-Arg (Pme) OH was added to 5 ml of trifluoroacetic acid-thioanisole (9:1). Comb and leave at 50℃ for 4 hours. After the trifluoroacetic acid is distilled off under reduced pressure, ether is added to the residue and the resulting precipitate is filtered. This is dissolved in a small amount of water, passed through a column (1 x 10 cm) of Amberlite IRA-410 (acetic acid type), and then freeze-dried. This was dissolved in a small amount of water and applied to a carboxymethyl cellulose column (2.2 x 8 cm), followed by elution using a linear gradient between water (300 ml) and 0.1M ammonium acetate (300 ml). Collect fractions of 110-155 ml and freeze-dry them. Yield 135 mg, [α] ²¹ _D −17.8° (c=0.5, H ₂ O) Amino acid decomposition (acid decomposition): Arg1.00(1), Tyr0.92
(1), average recovery rate 88.7%. Also, instead of Arg(Pme), Arg(Tms),
The desired product can be obtained similarly using Arg(Tmo). However, in the trifluoroacetic acid-thioanisole (9:1) treatment when removing the final protecting group, Arg (Tms) was
Preferably, Arg(Tmo) is treated at 50° C. for 5 hours for 90 minutes. Reference example 4 (1) Z−Arg(Pme)−Pro−Lys(Boc)−Pro−
Synthesis of OH H-Pro-OMe, Z-Lys(Boc)-ONB and Z
-Oily Z-Pro-Lys(Boc)-Pro- synthesized by sequential condensation of -Pro-ONB
Dissolve 0.59 g of OMe in 30 ml of methanol and perform catalytic reduction using palladium black as a catalyst. After filtering off the catalyst and concentrating the filtrate, the residue was dissolved in 10 ml of dimethylformamide, and Z-
Arg(Pme)OH・(Z−Arg(Pme)・OH・
Prepared from CHA0.56g), HOBt0.15g,
Add 0.23 g of DCC and stir at room temperature for 15 hours. After filtering off the generated DCU and distilling off the solvent, the residue was dissolved in ethyl acetate and diluted with sodium bicarbonate solution, 0.2N.
Wash with hydrochloric acid. After drying, the solvent was distilled off and the remaining oil [Z-Arg(Pme)-Pro-Lys
(Boc)-Pro OMe] in 10 ml of methanol. When cool, add 2 ml of 1N sodium hydroxide solution and saponify at room temperature for 2 hours. 1N−
After cold addition of 2 ml of hydrochloric acid to neutralize and distill off methanol, the precipitated oil was extracted with ethyl acetate. After distilling off the solvent, petroleum benzine was added and the powder was collected by filtration and reprecipitated from ethyl acetate-ether. Yield 0.49g (53.2%),
Melting point 92-96℃, [α] ²³ _D -34.4゜ (c = 0.5, dimethylformamide) Elemental analysis as C ₄₄ H ₇₂ O ₁₁ N ₈ S Calculated value: C, 57.37; H, 7.88; N, 12.17; S , 3.48 Experimental value: C, 57.09; H, 7.79; N, 11.86; S, 3.15 (2) Z−Arg(Pme)−Pro−Lys(Boc)−Pro−
Gln−Gln−Phe−Phe−Gly−Leu−Met−
Synthesis of NH ₂ Boc−Gln−Gln−Phe−Phe−Gly−Leu−
Met-NH ₂ 0.49g in trifluoroacetic acid (4.5ml)
-Dissolve in a mixture of water (0.5 ml) and stir at 10°C for 20 minutes. Add 0.5 ml of 1N hydrochloric acid and evaporate, add ether to the residue, filter it as a powder, and dry. Add this to 15ml of dimethylformamide
Stir, add 0.1ml of triethylamine when cold,
Furthermore, Z−Arg(Pme)−Pro−Lys(Boc)−Pro
-Add 0.45g of OH, 0.18g of HONB, and 0.20g of DCC and stir for 24 hours. generated
Filter off the DCU and concentrate the filtrate. Add water to the residue and filter the resulting precipitate. Reprecipitate from ethanol water. Yield 0.52g (55.2%),
Melting point 245-250°C (decomposition), [α] ²³ _D -32.8° (c=
0.5, dimethylformamide) Elemental analysis C ₈₅ H ₁₃₀ O ₁₉ N ₁₈ S as ₂ Calculated value: C, 57.60; H, 7.39; N, 14.23; S, 3.62 Experimental value: C, 57.35; H, 7.48; N, 14.02 ; S, 3.39 (3) H-Arg-Pro-Lys-Pro-Gln-Gln-Phe
−Phe−Gly−Leu−Met−NH ₂ (Substance
Synthesis of P) Z-Arg(Pme)-Pro-Lys(Boc)-Pro-
Gln−Gln−Phe−Phe−Gly−Leu−Met−
Dissolve 100 mg of NH ₂ in 5 ml of trifluoroacetic acid-thioanisole (9:1) and shake at 50° C. for 4 hours. Trifluoroacetic acid is distilled off under reduced pressure, ether is added to the residue, and the resulting precipitate is filtered and dried. Dissolve this in a small amount of water and use a column of Amberlite IRA-410 (acetic acid type) (1×
10cm) and then freeze-dried. This was applied to a Sephadex G-25 column (2.5 x 120 cm) and eluted with 30% aqueous acetic acid. The main elution fraction (235-270 ml) is collected and lyophilized. Yield 62
mg, [α] ²³ _D -79.6° (c = 0.5, 5% acetic acid) Amino acid analysis (acid analysis): Lys1.00(1), Arg1.03
(1), Gln2.21(2), Pro2.15(2), Gly0.95(1),
Met0.91(1), Leu1.02(1), Phe1.95(2), average recovery rate 85.6%. Also, instead of Arg(Pme), Arg(Tms), Arg
The desired product can be obtained similarly using (Tmo). However, when removing the final protecting group, trifluoroacetic acid-thioanisole (9:
1) In the treatment, Arg (Tms) was set at 50℃ and 90℃.
Arg(Tmo) is preferably treated at 50°C for 5 hours.

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ and R ₅ are methyl or methoxy,
R ₂ and R ₄ represent methyl or hydrogen, R ₃ represents methyl or methoxy, and R ₆ represents hydrogen or an α-amino group protecting group, respectively. However, R ₁ , R ₂ ,
R ₄ and R ₅ are both methyl, and R ₃ represents methyl or methoxy, or R ₁ ,
R ₃ and R ₅ are both methoxy, and R ₂
Both R ₄ represent hydrogen. ] Arginine derivatives and salts thereof.