JPS63122659A - Production of specific substance containing alpha,beta-dehydro-alpha-amino acid residue - Google Patents

Abstract

PURPOSE:To obtain the titled compound having physiological activity efficiently, by reacting an N-carboxy-alpha,beta-dehydro-alpha-amino acid anhydride with an amino group-protecting agent, etc., and a nucleophilic substance successively. CONSTITUTION:A compound shown by formula I (R1 and R2 are carboxyl, alkyl or aryl which may be replaced, respectively but are not H at the same time) is reacted with (A) a substance consisting of an amino group-protecting agent or an N-protecting-alpha-amino acid (halide) in the presence of a base or a condensation agent and the base and then a prepared compound shown by formula II (X is amino group-protecting group or N-protecting-alpha-amino acid residue) is reacted with (B) a nucleophilic substance in the presence of the base to give the aimed substance. For example, a compound shown by formula III (X1 is acyl type protecting group; Y2 is water) is obtained by using an acyl type protecting agent as the component A and water as the component B and a compound shown by formula IV (Y3 is alkyl; AA1 is alpha-amino acid residue) as the acryl type protecting agent as the component A and an alpha-amino acid alkyl ester as the component B.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a method for producing a specific substance having an α,β-dehydro-α-amino acid residue, and more specifically, it relates to a method for producing a specific substance having an α,β-dehydro-α-amino acid residue, and more specifically, The present invention relates to a novel production method useful for producing physiologically active peptides or N-protected dehydroamino acid esters as precursors.

[Prior Art] Physiologically active peptides (for example, telomycin, cableomycin, cephalosporin C, homopsin, antrimycin, etc.) that have dehydroamino acid residues discovered in nature as constituents or precursors are widely used. It is known to have physiological activities such as antibacterial, antitumor, phytotoxin, and enzyme inhibitory effects. This is because dehydroamino acid residues or amino acid residues using them as precursors have a great effect on the secondary and tertiary three-dimensional structure, and are important sites for maintaining the three-dimensional structure and expressing physiological activity. moreover,
By replacing part of the bioactive peptide consisting of animal-derived protein-constituting amino acids with dehydroamino acid residues, it exhibits anti-proteolytic enzyme activity and is thought to play an important role in improving the sustainability of its activity. For example,
Bradykinin, which has a blood pressure lowering effect and an intestinal constriction effect, has 5
It is known that when dehydroferalanine is introduced in place of phenylalanine, it exhibits an antihypertensive activity more than 20 times higher than the original antihypertensive effect. (jc contribution: Y, Shimo
higashi, and N, Izumiya,
"The peptides, Vol. 5",
ed Acadea+ic Press by E,
Grossand J, Meienhofer, 1
983).

Conventionally, there have been two methods for producing peptides containing dehydroamino acid residues as constituent elements. 1
One method involves direct condensation of dehydroamino acids and amino acids, and the other method involves synthesizing dehydropeptides by removing leaving groups from peptides. The former method includes the azlactone method, the azide method, the mixed acid anhydride method, and the acid chloride method. However, each method had the following drawbacks: Azlactone method Protection of the amino group of α-dehydro amino acid and α-dehydro amino acid residues are limited.

・Azide method There is no adverse effect on other optically active amino acid residues, but the yield rate is poor.

Mixed acid anhydride method The risk of side reactions is high, and therefore the yield is poor.Phi acid chloride method The reaction conditions are harsh and other amino acid residues are limited.

No. α-1β- or α, β-elaboration method The amino acid must have a leaving group, or in the case of an amino acid with an aromatic substituent, it must be synthesized using a dehydrogenating agent, etc. Therefore, the number of dehydroamino acid residues that can be produced is limited.

As described above, the above manufacturing method has a problem in terms of versatility. Additionally, these production methods generally have a drawback of low yields. Furthermore, since some of the optically active amino acid residues are racemized, there is a drawback that other optically active amino acid residues are adversely affected. Furthermore, regarding the amino acids to be reacted as amine components, in the case of amino acids with functional groups in their side chains, such as alcohols, amino acids with phenolic hydroxyl groups, and amino acids with mercapto groups, conventional production methods do not allow side chain protecting groups to be removed. It was necessary. Furthermore, conventional production methods generally had problems in terms of harsh reaction conditions, etc.Next, N-protection-α, β-
As a method for producing dehydro-α-amino acid ester,
Method by decomposition of dehydroazlactone, method by elimination of β-substituent, α-keto acid ester and R-CONH2
There were two methods: condensation with dehydroamino acid ester, and protection of the amine group from dehydroamino acid ester. However, each method had the following drawbacks.

・Method by decomposing dehydroazlactone There are limitations to the protecting group at the N position, and deprotection is difficult with that protecting group, so this method is not versatile.

・Method by elimination of β-substituent Due to the necessity of having or introducing a leaving group at the β-position and the conditions at the time, there are limitations to the protective groups for amine groups and carboxylic acids. be. No versatility.

- Method by condensation of α-keto acid ester and R-CONH2 Protecting groups for amino groups are limited.

In this way, none of the above three methods has versatility.

And the yield was poor.

Method for protecting amine groups from dehydroamino acid esters Due to the influence of double bonds, the nucleophilicity of amine groups decreases, and the desired product may not be obtained or the yield will be poor.

As described above, each of the above production methods has drawbacks such as lack of versatility and poor yield.

As explained in detail above, in the various conventional production methods, in the production of peptides or N-protected dehydroamino acid esters using dehydroamino acid residues as constituents or precursors, it is difficult to achieve versatility, yield, and optically active amino acid residues. eel,
There was no method that satisfied all of the requirements of simplicity and reaction conditions.

[Opening fiber m1 to be solved by the invention The present invention solves the above-mentioned drawbacks, and improves versatility and yield in the production of peptides or N-protected dehydroamino acid esters containing dehydroamino acid residues as constituents or precursors. The purpose is to provide a production method that satisfies all of the requirements such as efficiency, influence on optically active amino acids, simplicity, and reaction conditions.

(Hereinafter in the margin) [Means for solving the problem] In order to achieve the above object, the present invention provides α,β-dehydro-α
- In a method for producing a specific compound having an amino acid residue, in a predetermined solvent, (wherein R, and R2 are each a hydrogen atom, an appropriately substituted carboxyl group, an optionally substituted alkyl group, or an aryl group, represents the same or different substituents consisting of the following groups.However, R1 and R2 are not hydrogen atoms at the same time. A group-protecting agent or a substance consisting of an N-protected α-amino acid or an N-protected α-amino acid halide (a) Engineering process: Add a depot and react with a specified base or a specified condensation scheme 1 in the presence of a specified base. and synthesized by the above reaction (wherein R,, R2 are the same as above, and X is a predetermined α-amine protecting group or N-protected
N-X-N indicated by ), which represents an α-amino acid residue
- Adding a predetermined substance consisting of a substance having nucleophilicity to carboxy-α,β-dehydro-α-amino acid anhydride (two-step substance) and reacting in the presence of a predetermined base,
Particularly, in the production method of the present invention, which provides a method for producing a specific substance having an α,β-dehydro-α-amino acid residue, characterized in that the two steps are carried out in the same system, the specific substance is X+ NHCCOOY+ (In the formula, Rτ and R2 are the same as above, and xl represents an acyl-type protecting group for the α-amino group of the α-amino acid.

Yl represents a lower alkyl group excluding a tertiary alkyl group. and is of the acyl type, and the second step substance is a lower alkyl alcohol excluding tertiary alkyl alcohol. represents. ) When the N-protected α, β-dehydro-α-amino acid shown in At a certain point, a specific X2 NHCCOOY+ (where R,, R2 and Yl are as above, x2 Hα
-Represents a urethane-type protecting group for the α-amine group of an amino acid. ) In the case of the N-protected-α,β-dehydro-α-amino acid ester derivative shown in
The process substance is a lower alkyl alcohol excluding tertiary alkyl alcohol, and the specific substance has the general formula R, R2. /X2 NHCCOOY2 (wherein, R1, R2, X2 and Yl are the same as above.

) In the case of N-protected-α,β-dehydro-α-amino acid shown in In a certain point, a specific substance has the general formula R, R2. ' is an α,β-dehydro-α-amino acid residue, and dehydrodibebutide is protected at both the N and C ends (the N-terminus represents the amine terminal of the peptide, and the C-terminus represents the carboxy terminus of the peptide). In the case of
, R2, In the case of a dipeptide, the first step substance is a protecting agent for the amine 7 group and becomes an acyl type, and the second step substance is an α-amino acid alkyl ester salt compound.
NHCOAAI 0Y3 (wherein R+, R2, X2, Y3 and AA+ are the same as above), the N-terminal amino acid residue
When the dehydrodipeptide is a dehydro-α-amino acid residue and is protected at both N and C ends, the first step substance is an amine group protecting agent and is of urethane type, and the second step substance is is an α-amino acid alkyl ester, and the N-terminal amino acid residue represented by the specific X2 NHCCOAAI 0Y3 (in the formula, R1, R2, When the dehydrodipeptide is an α-amino acid residue and is protected at both N and C ends, the first step substance is an amino group protecting agent and is a urethane type, and the second step substance is an α-amino acid residue. -The specific substance is an amino acid alkyl ester salt compound, and the specific substance has the general formula R, R2. / The C-terminal amino acid residue is α, β-dehydro-α-amino acid residue, and N, CP? When the dehydrodipeptide is a dehydrodipeptide with each end protected, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group, and the second step substance is the third step substance.
The specific substance is a C-terminal amino acid residue represented by the general formula R, R2 X3 AA2 NHCCOOY2 (wherein R1, R2, X3.Y2 and AA2 are the same as above). When the group is an α,β-dehydro-α-amino acid residue and the N-terminus is a protected dehydrodipeptide, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group; The second step substance is water.The specific substance is represented by the general formula R, R2 X2 AA2 NHCCOOY+ (wherein R1, R2, X2, Yl and AA2 are the same as above). When a dehydrodipeptide is a β-dehydro-α-amino acid residue with both N and C ends protected, the first step substance is α
I Yl and AA2 are the same as above. When the C-terminal amino acid residue shown by ) is an α,β-dehydro-α-amino acid residue and the N-terminus is a protected dehydrodipeptide, the first step substance is α -The amine group is an amino acid protected with a urethane-type protecting group, and the second step substance is water, and the specific substance has the general formula R, R2 j X3 AA:I NHCCOOYI (wherein, R1, R2, Yl is the same as above.

AA3 represents an α-amino acid residue. )
When the amino acid residues at the ends are α, β-dehydro-α-amino acid residues, and the N and C ends are each protected dehydrodipeptides, the first step substance is an N-protected α-amino acid halide. The protecting group for the α-amine group is an acyl type, the second step substance is a lower alkyl alcohol excluding tertiary alkyl alcohol, and the specific substance has the general formula R, R2 X3 AA3 NHCCOOY2 Fuchu, R,, R2 , X3, Yl and AA3 are the same as above.

), the C-terminal amino acid residue is an α,β-dehydro-α-amino acid residue, and the N-terminus is a protected dehydrodipeptide, the first step substance is an N-protected-α-amino acid halide. The protecting group for the α-amine group is an acyl type, and the second step substance is water.

X4 AA3 NHCCOOYI (wherein R,, R2, Y, and AA3 are the same as above.X4
represents a urethane-type protecting group for an α-amine group. ), the C-terminal amino acid residue is an α, β-dehydro-α-amino acid residue, and the first step substance is a dehydrodipeptide with both N and C ends protected, respectively.
- It is an amino acid halide, the protecting group for the α-amine group is a urethane type, the second step substance is a lower alkyl alcohol excluding tertiary alkyl alcohol, and the specific substance has the general formula R, R2 X4 AA3 NHCCOOY2 ( In the formula, R1, R2, , the first step material is N-protected-α-amino acid halide, the protecting group for the α-amine group is urethane type, and the second step material is water, X3 AA2 NHCCOAAI 0Y3 (in the formula, R,
, R2, X3. Y3, AA, and AA2 are the same as above. )
The second amino acid residue from the N-terminus is α, β-
When the dehydrotripeptide is a dehydro-α-amino acid residue and is protected at both N and C ends, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group, and the second step The substance is an α-amino acid alkyl ester, X3 AA2 NHCCOAA, oy3(
In the formula, R1, R2, X3, Y3, AA, and AA2 are the same as above, and the second amino acid residue from the N-terminus represented by ) is an α,β-dehydro-α-amino acid residue, and N, C
When the dehydrotripeptide is protected at both ends, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group, and the second step substance is an α-amino acid alkyl ester salt compound; X2 AA2 NHCCOAAI 0Y3 (wherein R,
, R2, X2, Y3. AA and AA2 are the same as above. )
The second amino acid residue from the N-terminus is α, β-
When the dehydro-α-amino acid residue is a dehydrotripeptide with protected N and CTR ends, the first
The process material is an amino acid whose α-amine group is protected with a urethane-type protecting group, and the second process material is an α-amino acid alkyl ester, and the specific substance has the general formula R, R2 ,R,,
R2, X2, Y3, AA, and AA2 are the same as above. ), the second amino acid residue from the N-terminus is α, β-dehydro-α-amino acid residue, and when both the N and C ends are protected dehydrotripeptides, the first step substance is α X3 AA3 NHCCOAAI 0Y3 (in the formula, R,
, R2, X3, Y3, AA, and AA3 are the same as above)
The second amino acid residue from the N-terminus is α, β-
When the dehydrotripeptide is a dehydro-α-amino acid residue and is protected at both N and C ends, the first step substance is an N-protected α-amino acid halide, and the α-
The protecting group for the amino group is acyl type, and the second step substance is α
-It is an amino acid alkyl ester.

X3 AA3 NHCCOAAI 0Y3 (wherein, R1
, R2, X3, Y3, AA blind and AA3 are the same as above. )
The second amino acid residue from the N-terminus is α, β-
When the dehydrotripeptide is a dehydro-α-amic acid residue and is protected at both N and C ends, the first step substance is an N-protected-α-amino acid halide and the protecting group for the α-amino group is It is an acyl type, and the second step substance is α-
Point X4 AA which is an amino acid alkyl ester salt compound
3 NHCCOAAI 0Y3 (wherein R,, R2, X
4, Y3, AA, and AA3 are the same as above. ) The second amino acid residue from the N-terminus is α,β-dehydro-
When the first step substance is an α-amino acid residue and is a dehydrotripeptide protected at both the N and C ends, the N-
Protection - α-amino acid halide, the protecting group for the α-amino group is a urethane type, and the second step substance is an α-amino acid alkyl ester.

X4 AA3 NHCCOAAt 0Y3 (wherein, R1
, R2, X4, Y3, AA, and AA3 are the same as above. )
The second amino acid residue from the N-terminus is α, β-
When the dehydrotripeptide is a dehydro-α-amino acid residue with both N and C ends protected, the first step substance is an N-protected-α-amino acid halide and the protecting group for the α-amine group is urethane. type, and the second process material is α
- It is characterized by being an amino acid alkyl ester salt compound.

[Effects of the Invention] According to the production method of the present invention, versatility, yield, and optical activity can be improved in the production of peptides or N-protected dehydroamino acid esters using dehydroamino acid residues as constituents or precursors. Effect on amino acids, convenience,
All reaction conditions etc. can be satisfied. The details will be explained below.

■About versatility The amine group of α, β dehydro α-amino acid is.

Due to the conjugation with the double bond, the nucleophilicity of the amino group is reduced, and the reactivity with N-protected α-amino acids and N-protecting agents has traditionally been extremely low, unstable and It was causing a side reaction.

However, according to the production method according to the present invention, the 5-alkylidene-2,4-oxacylidinedione structure (N-carboxy-α, β-dehydro-α-amino acid anhydride) and react with amino group protectants or N-protected α-amino acids.

In addition, due to the presence of a double bond between α and β positions,
Compared to N-carboxy-α-amino acid anhydride, which is a similar substance, the stability of the target product was increased, and the reaction of the amine component and carboxy component was easier to control. This facilitates reactions with various amino acids, alcohols, etc., and allows the dehydroamino acid residue to be freely introduced into the peptide chain. Therefore, it has the effect of making it possible to produce various specific substances having α,β-dehydro-α-amino acid residues.

■About the yield If the target product is synthesized by the production method according to the present invention,
As is clear from the above, the yield was significantly improved compared to the conventional production method.

■Influence on optically active amino acids If the target product is synthesized by the production method according to the present invention,
Since the reaction conditions are mild, N-carboxy-α,
Due to the unique reaction mechanism of β-dehydro-α-amino acid anhydride (ΔNCA), there is almost no risk of racemization due to the removal of the hydrogen atom at the α-position of the optically active amino acid or the formation of oxacilone. Therefore, there is an effect that there is almost no adverse effect on optically active amino acids.

■ Regarding simplicity, if the target product is synthesized by the production method according to the present invention,
It is possible to freely introduce dehydroamino acid residues and produce amino acids of various components simply by using side reaction systems. In addition, there is an effect that the operation is not complicated.

In addition, regarding the amino acids to be reacted as amine components, amino acids having a functional group in the side chain (for example, amino acids having an alcoholic hydroxyl group, a phenolic group, a mercapto group, etc.) are reacted with their side chains unprotected. There is no problem in allowing it to be used, and the effect is that steps such as side chain protection and cleavage of the protecting group can be omitted.

■Reaction conditions If the target product is synthesized by the production method according to the present invention,
The reaction conditions are mild, at room temperature and pressure, and even if cooling is required, there is no need for excessive cooling.

(The following is a blank space) [Detailed Description of the Invention] The N-
Carboxy-α,β-dehydro-α-amino acid is used as a starting material. A substance consisting of α-amino acid halide (Step 1 substance) is reacted with a predetermined base or a predetermined condensing agent in the presence of a predetermined base (3+1 step W, by this reaction, as an intermediate substance, N-X- An N-carboxy-α,β-dehydro-α-amino acid tree is synthesized. A predetermined substance (second step substance) consisting of a substance having nucleophilic properties is added to the intermediate substance (i2 process ω).

The first step and the second step are performed continuously in the same system.

Substances synthesized as intermediates are not normally isolated, but may be isolated.

Next, a specific explanation will be given based on the target product to be obtained. In the formula, R,,R2,x+,X2,X3,X4,Y
l * Y2 eY3 and AA, , AA2 , AA3
are as follows: A, R,, R2 R,, R2 are each appropriately selected from the substituents shown below.

hydrogen atom.

Substituted carboxyl group: A carboxyl group substituted with an alkyl group such as a methyl group, ethyl group, or benzyl group.

Alkyl group; methyl group, ethyl group, propyl group, etc.

Substituted alkyl group: Benzyloxycarbonyl 1 (Cbz group, hereinafter the same),
An amine group appropriately substituted with a t-butoxycarbonyl group (BOC group, hereinafter the same), etc., an alkyl group substituted with an alkylmercapto group, etc.

Aryl group: phenyl group, etc.

Substituted aryl group: An aryl group substituted with an alkyl group, a halogen, a hydroxyl group which may be appropriately substituted with a methyl group, a methoxy group, etc.

However, the above substituents R and R2 are not hydrogen atoms at the same time.

X represents a protecting group for a predetermined α-amine group or an N-protected α-amino acid residue, XI, X2, X3, x4 are
Each is as shown below.

xl Represents an acyl-type protecting group for the α-amino group of an α-amino acid, such as a niacetyl group (AC, trifluoroacetyl group (Tfa group), etc.).

X2: represents a urethane-type protecting group for the α-amine group of an α-amino acid, such as a BOC group or a Cbz group.

X3: Represents an acyl-type protecting group for an α-amino group, such as a Pht group.

X4: represents a urethane-type protecting group for an α-amine group such as a Cbz group.

/\, Y Y■ Represents a lower alkyl group excluding a tertiary alkyl group such as an ester group, an ethyl group, an isopropyl group, or a benzyl group.

Y2: represents a hydrogen atom.

Y3 represents a lower alkyl group such as an ester group, an ethyl group, a benzyl group, or a t-butyl group.

2. AA AA represents an α-amino acid residue. AAI, AA2. A
For A3, an appropriate one is selected from the following.

A.A.

α-amino acids without φ side chain functional groups: glycisalanine,
α-aminobutanoic acid, valine, n-valine, leucine,
n-leucine, isoleucine, proline, phenylalanine, etc.

-α-amino acids that have side chain functional groups and require no side chain protection during one reaction; serine, threonine, tyrosine, cysteine, methionine, etc.

- α-amino acids that have a side chain functional group and require appropriate protection of the side chain during reaction: aspartic acid, glutamic acid, ornithine, lysine, arginine, etc.

A2 - α-amino acids without side chain functional groups; glycine, alanine, α-aminobutanoic acid, valine, n-valine, leucine, n-leucine, isoleucine, proline, phenylalanine, etc.

- α-Amino acids whose side chain functional groups require protection as appropriate: serine, threonine, tyrosine, cysteine, methionine, aspartic acid, glutamic acid, ornithine, lysine, arginine, etc.

A3 Alpha-amino acids without side chain functional groups; glycine, alanine, alpha-aminobutanoic acid, valine, n-valine, leucine, n-leucine, inleucine, proline, phenylalanine, etc.

- α-amino acids whose side chain functional groups require appropriate protection with protecting groups that are stable under relatively acidic conditions; serine, threonine, tyrosine, cysteine, methionine, aspartic acid, glutamic acid, ornithine, lysine, arginine, etc.

Moreover, the predetermined solvent, the predetermined base, and the predetermined condensing agent consist of the following substances.

E. Predetermined solvents Examples of aprotic solvents include halogenated hydrocarbons; dichloromethane, chloroform, etc.

Ether type; diethyl ether, tetrahydrofuran (
THF), dioxane, etc.

Ketones: acetone, methyl ethyl ketone, etc.

Ester type; ethyl acetate, etc.

Nitrogen compounds such as niacetonitrile and dimethylformamide (DMF).

Sulfur compound-based dimethyl sulfoxide (DMSO), etc.

Phosphorus compound system; hexamethyl phosphate triamide (HMP
A) etc.

Hydrocarbons: benzene, toluene, etc.

Protic solvent system: tertiary-butanol (t-butanol), etc.

The above solvents can be used alone or in combination of two or more.

to certain basic secondary amine compounds such as diethylamine, dicyclohexylamine, etc.

Tertiary amine compounds: pyridine, N-methylmorpholine (NMM), triethylamine, 1°4-diazabicyclo[2,2,2]octane (DABCO), i,a-diazabicyclo[5,4.

0] undecane-7-ene (DBU), etc.

Alkaline aqueous solution: aqueous aqueous solution of arsenium salt, etc. The above compounds can be used alone or in combination of two or more types, or can be used as a main component.

G, prescribed condensing agent A carbodiimide type condensing agent is used as the predetermined condensing agent.

This includes dicyclohexylcarbodiimide (D, (,
, C), or l-ethyl-3-(3-dimethylaminopropyl)carbodiimide and its hydrochloride (W, S,
C.HCl), etc. The amount used may be about the same amount as the starting material. Preferably, C and C are preferred.

The predetermined base used together with the predetermined condensing agent is appropriately selected from tertiary amine compounds such as pyridine and NMM.

■Synthesis of N-protected α, β-dehydro-α-amino acid derivatives N-carboxy-α, β-dehydro-α-amino acid anhydrous (ΔNCA) is mixed with a specified solvent, and a specified N-protecting agent ( During the first step, in the presence of the specified base, from 1 hour to several tens of hours.
The reaction time is about 5 to 6 hours at room temperature. Next, in the presence of a predetermined base, water or a lower alkyl alcohol such as methyl, ethyl, benzyl, etc. (second step) is reacted for several tens of minutes to several hours (usually about 2 hours), and appropriate treatments such as extraction and washing are carried out. If necessary, purification such as column chromatography or recrystallization was performed to obtain the desired N-protected-α, β-dehydro-α-amino acid and its ester derivative.

In this case, if the object is X, NHCCOOY.

In the case of the N-protected-α,β-dehydro-α-amino acid ester derivative shown in It is a lower alkyl alcohol excluding tertiary alkyl alcohol.

At this time, the solvent is preferably THF, dichloromethane, etc., and the protecting agent is preferably acetyl chloride, trifluoroacetic anhydride, etc. The predetermined base is preferably triethylamine or the like in the first step and pyridine or the like in the second step.

When the target product is an N-protected-α,β-dehydro-α-amino acid represented by , the second step substance is water. At this time, the solvent is preferably THF, dichloromethane, etc., and the protecting agent is preferably acetyl chloride, trifluoroacetic anhydride, etc. The predetermined base is preferably triethylamine or the like in the first step, and preferably an aqueous sodium hydroxide solution, triethylamine or the like in the second step.

When the target product is an N-protected-α,β-dehydro-α-amino acid ester derivative represented by C , second
The process materials are lower alkyl alcohols excluding tertiary alkyl alcohols.

At this time, the solvent is preferably THF, dichloromethane, etc., and the protecting agent is di-t-butyl di-carbonate ((B
OC)20), benzyloxycarbonyl chloride (Cbz-C1), and the like are desirable. The desired base is pyridine or the like in the first step and NMM or the like in the second step. The process substance is the above-mentioned amine group-protecting agent and is of the urethane type, and the second process substance is water. At this time, the solvent is preferably THE or dichloromethane, and Yasuda's drug is (BQC) 20. Cbz-CI etc. are desirable. The predetermined base is preferably pyridine or the like in the first step, and preferably an aqueous sodium hydroxide solution, triethylamine, or the like in the second step.

This method has the effect of improving yield, convenience, and reaction conditions when producing the above-mentioned target products.

■Synthesis of dehydrodipeptide in which the N-terminal amino acid residue is α,β-dehydro-α-amino acid residue and both N- and C-termini are protected N-carboxy-α,β-dehydro-α-amino acid anhydride (ΔN CA) in a specified solvent, mixed with a specified N-protecting agent (in the first step m and in the presence of a specified base, for 1 hour to several tens of hours)
The reaction time is about 5 to 6 hours at room temperature.Next, an amino acid ester or an amino acid ester salt compound (second step material) is added to the above reaction solution, and in the presence of a predetermined base (
In the case of an amino acid ester salt compound, add an amount of a specified base that can neutralize the salt compound), and at about room temperature (there is no need for cooling or heating) for several minutes to several hours (about 1 hour). α, β-dehydro-α-
An N-protected dipeptide ester derivative having an amino acid residue was obtained.

In this case, the target product is X+NHCCOAAt OY3 where the N-terminal amino acid residue is
When the dehydrodipeptide is an α-amino acid radical and has both N and C ends protected (the N end represents the amine end of the peptide, and the C end represents the carboxy end of the peptide), the first step substance is the above-mentioned It is an acyl type protecting agent for amine groups, and the second step substance is an α-amino acid alkyl ester or a salt compound thereof. Above 2
In this case, the solvent is preferably THF, dichloromethane, etc., and the protecting agent is preferably acetyl chloride (AcC1), trifluoroacetic anhydride ((CF3 Co)20), etc. The predetermined base is preferably triethylamine or the like in the first step, and NMM or the like in the second step.

Next, the target product is C X2 NHCCOAAI OY3 where the N-terminal amino acid residue is
When the dehydrodipeptide is an α-amino acid residue and is protected at both N and C ends, the first step substance is a urethane-type protecting agent for the amine group, and the second step substance is a urethane type. α-Amino acid alkyl ester or its salt compound. In the above two cases, the solvent is THF,
Dichloromethane etc. are preferable, and the protective agent is (BOC)2
0, Cbz-CI, etc. are preferable. The predetermined base is preferably pyridine or the like in the first step, and NMM or the like in the second step.

When the above-mentioned target products are produced by such a method, the yield, convenience, and reaction conditions are good, and the optically active amino acids are hardly affected, so it is more advantageous.

Further, in the case of synthesizing a target peptide, when condensing an amino acid serving as the C-terminus, a specific side chain functional group among α-amino acids having a side chain functional group may be unprotected. Therefore, if the next reaction requires a step of removing the protecting group of a specific side chain functional group, this can be carried out without protection.
Alternatively, if protection of a specific side chain functional group is required in the next reaction, an amino acid with a side chain protected can be used.

Therefore, further improvement in yield and convenience can be achieved from this point of view as well.

(Left below) ■Synthesis of dehydrodipeptide derivatives in which the C-terminal amino acid residue is α,β-dehydro-α-amino acid residue and the N-terminus is protected N-carboxy-α,β-dehydro-α-amino acid Anhydride (ΔNCA) and an amino acid having a predetermined N-protecting group (first step m in a predetermined solvent in the presence of a predetermined base, D,
Using a carbodiimide type condensing agent such as C, C, etc., under cooling to 15°C or lower, preferably O to -10°C, for several tens of minutes to several hours (
After that, the reaction is allowed to take place for several hours to several tens of hours (about 10 hours is sufficient) at room temperature. Then,
Water or lower alkyl alcohols (excluding tertiary alcohols such as methyl, ethyl, benzyl, etc. By performing purification such as column chromatography and recrystallization, the desired N-protected dehydrodipeptide and ester derivative having an α,β-dehydro-α-amino acid residue at the C-terminus were obtained.

In this case, the target product is X3 AA2 NHCCOOY+ where the C-terminal amino acid residue is α,β-dehydro-α
- amino acid residue, and when the N and CPf ends are each protected dehydrodipeptide, the first step substance is α-
It is an amino acid whose amino group is protected with an acyl type protecting group, and the second step substance is a lower alkyl alcohol excluding tertiary alkyl alcohol. At this time, the solvent was THF,
Dichloromethane etc. are preferable. N-protected-amino acids are
For example, N-Pht-amino acid. The base is preferably pyridine in the first step, and N in the second step.
MM etc. is desirable. Condensing agents such as C, C, etc. are preferable.

The target product is C X3 AA2 NHCCOOY2, and the C-terminal amino acid residue is
When the dehydrodipeptide is an α-amino acid radical and the N-terminus is protected, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group, and the second step substance is water. At this time, the solvent is preferably THF, dichloromethane, or the like. N-protected-amino acids are, for example, N-Ph
t-amino acids, etc. The base is preferably pyridine or the like in the first step, and preferably an aqueous sodium hydroxide solution, triethylamine or the like in the second step. Condensing agent beam, C
, C etc. are desirable.

When the target product is X 2 A A 2 N HCCOOY 1, the C-terminal amino acid residue is an α, β-dehydro-α-amino acid residue, and both the N and C ends are protected dehydrodipeptides, The first step material is an amino acid whose α-amine group is protected with a urethane type protecting group, and the second step material is a lower alkyl alcohol excluding tertiary alkyl alcohol. At this time, the solvent is preferably THF, dichloromethane, etc., and the N-protected amino acid is, for example, N
-BOC-amino acid, N-Cbz-amino acid, etc.

The base is preferably pyridine or the like in the first step, and NMM or the like is preferable in the second step.
etc. is desirable.

The target product is represented by the general formula RIR2 X2 AA2 NHCCOOY2 where the C-terminal amino acid residue is
When the dehydrodipeptide is an α-amino acid residue with a protected N-terminus, the first step substance is an amino acid whose α-amino group is protected with a urethane-type protecting group, and the second step substance is water. At this time, the solvent is preferably THF, dichloromethane, or the like.

N-protected-amino acids are, for example, N-BOC-amino acids, N-Cbz-amino acids, and the like. The base is preferably pyridine in the first step, preferably an aqueous sodium hydroxide solution, triethylamine, etc. in the second step, and preferably a condensing agent such as C, C, etc.

Other synthesis methods include the following. That is, an N-protected α-amino acid having a protecting group such as a phthalyl group (Pht) or a benzyloxycarbonyl group (Cb z) on the α-amine group of the amino acid that is difficult to remove under relatively acidic conditions is converted into an N-protected α-amino acid using a conventional method. -protection-α-amino acid halide, and the N-protection-α
-Amino acid halide (first step M) and N-carboxy-
α,β-dehydro-α-amino acid anhydride (ΔNCA) is reacted with water or a tertiary compound such as methyl, ethyl, benzyl, etc. in the presence of a specified base for several minutes to several hours (usually about 1 hour) Add lower alkyl alcohol excluding alcohol ■2℃ and react for about 1 hour in the presence of a specified base, then perform appropriate treatments such as extraction and washing, and if necessary, purify by using a silica gel column or recrystallization. By doing so, the desired N-protected dehydropeptide and ester derivative having an α,β-dehydro-α-amino acid residue at the C-terminus were obtained.

In this case, the target product is C-terminal amino acid residue represented by C X3 AA3 NHCCOOYI
When it is an α-amino acid residue and is a dehydrodipeptide with both N and C ends protected, the first step substance is N-
The protected α-amino acid halide has an acyl type protecting group for the α-amine group, and the second step substance is a lower alkyl alcohol other than a tertiary alkyl alcohol. At this time, the solvent is preferably THF or the like. N-protected-amino acid halide is, for example, N-Pht-amino acid chloride. The base is desirably triethylamine or the like in the first step, and triethylamine or the like is desirably the base in the second step.

The target product is X3 AA3 NHCCOOY2 where the C-terminal amino acid residue is α,β-dehydro-
When the dehydrodipeptide is an α-amino acid residue with a protected N-terminus, the first step substance is an N-protected α-amino acid halide in which the protecting group for the α-amino group is an acyl type; The two step material is water. At this time, the solvent is TH
The N-protected amino acid halide, such as F, is preferably, for example, N-Cbz-amino acid chloride. The base is preferably triethylamine etc. in the first step, and the base in the second step is preferably triethylamine.
In the process, sodium hydroxide aqueous solution, triethylamine, etc. are preferable.

The target product is X4 AA3 NHCCOOYI, and the C-terminal amino acid residue is α,β-dehydro-
It is an α-amino acid residue, with both N and C temperatures (when each is a protected dehydrodipeptide, the first step substance is N
-Protection - It is an α-amino acid halide in which the protecting group for the α-amine group is a urethane type, and the second step substance is a lower alkyl alcohol excluding tertiary alkyl alcohol.

At this time, the solvent is preferably THF or the like. N-protected-amino acid halide is, for example, N-Cbz-amino acid chloride. The base is desirably triethylamine or the like in the first step, and triethylamine or the like is desirably the base in the second step.

The C-terminal amino acid residue shown in the target product X4 AA3 NHCCOOY2 is α,β-dehydro-
When the dehydrodipeptide is an α-amino acid residue with a protected N-terminus, the first step substance is an N-protected α-amino acid halide in which the protecting group for the α-amino 7 group is a urethane type; The two step material is water. At this time, the solvent is T
HF etc. are preferable. N-protected-amino acid halide is, for example, N-Cbz-amino acid chloride. The base is desirably triethylamine or the like in the first step, and desirably an aqueous arsenic solution, triethylamine or the like in the second step.

When the above-mentioned target products are produced by such a method, the yield, convenience, and reaction conditions are improved, and the optically active amino acids are hardly affected, so that the method is more advantageous.

■Synthesis of dehydrotripeptide derivatives in which the second amino acid residue from the N-terminus is an α,β-kehydro-α-amino acid residue, and both the N and C ends are protected, respectively.N-carboxy-α,β-dehydro-α - Amino acid anhydride (ΔNCA) and an amino acid having a predetermined N-protecting group (first step -D in a predetermined solvent in the presence of a predetermined base,
Using a carbodiimide type condensing agent such as D, C, C, etc., under cooling to 15°C or lower, preferably θ to -10°C, several tens of minutes to several hours (about 1 hour is sufficient), and then several hours to several hours at room temperature. React for 10 hours (about 10 hours is sufficient).Next, add the amino acid ester or amino acid ester salt compound (second step m) to the above reaction solution, and add the amino acid ester or amino acid ester salt compound (second step m) to the above reaction solution, and add the amino acid ester or amino acid ester salt compound (in the case of an amino acid ester salt compound, (further add an amount of the specified base sufficient to neutralize the By purifying the crystals, etc., the desired N-
A protected dehydrotripeptide ester derivative was obtained.

In this case, the target product is x3 AA2 NHCCOAA, the second amino acid residue from the N terminus indicated by OY3 is an α,β-dehydro-α-amino acid residue, and both the N and C ends are protected dehydro-amino acid residues. In the case of tripeptide, the first step substance is α
The second step substance is an α-amino acid alkyl ester or a salt compound thereof. In the above two cases, the solvent is THF
, dichloromethane, etc. are preferable. N-protected-amino acids are, for example, N-Pht-amino acids. The base is the first
In the step, pyridine and the like are preferred, and in the second step, NMM and the like are preferred, and condensing agents such as C, C, etc. are preferred.

Next, the target product is X2 AA2 NHCCOAAI OY3, and the second amino acid residue from the N-terminus is α,β-dehydro-α
- When the amino acid residue is a dehydrotripeptide protected at both N and C ends, the first step substance is an amino acid whose α-amine group is protected with a urethane-type protecting group, and the second step substance is α - Amino acid alkyl ester or its salt compound. In the above two cases, the solvent is THE,
Dichloromethane etc. are preferable. N-protected-amino acids are
For example, N-BOC-amino acid, N-Cbz-amino acid, etc. The base is preferably pyridine or the like in the first step, and preferably NMM or the like in the second step. Condensing agents such as C, C, etc. are preferable.

Other synthesis methods include the following. That is, an N-protected α-amino acid having a protecting group such as a phthalyl group (Pht) or a benzyloxycarbonyl group (Cb z) on the α-amino group of the amino acid that is difficult to remove under relatively acidic conditions is converted into an N-protected α-amino acid using a conventional method. -protection-α-amino acid halide, and the N-protection-α
-Amino acid halides (first step Sec-poD and N-carboxy-α,β-dehydro-α-amino acids (ΔNCA)
in the presence of a predetermined base (from several minutes to several hours to about 1 hour).Next, an amino acid ester or an amino acid ester salt compound (second step substance) is added to the above reaction solution, and in the presence of a predetermined base ( In the case of an amino acid ester salt compound, add an amount of a specified base that can neutralize the salt compound), react at room temperature for several minutes to several hours (about 1 hour is sufficient), and perform extraction, washing, etc. By performing appropriate treatment, if necessary, purification such as column chromatography or reconsolidation, the desired α,β-dehydro-α-
An N-protected dehydrotripeptide ester derivative having an amino acid residue was obtained.

In this case, the target product is represented by the general formula R,R2
- an amino acid residue, N.

When the dehydrotripeptide is protected at both C ends, the first step substance is an N-protected α-amino acid halide, the protecting group for the α-amine group is an acyl type, and the second
The process material is an α-amino acid alkyl ester or a salt compound thereof. In the above two cases, the solvent is preferably THF or the like. N-protected-amino acid halides are, for example, N-P
ht-amino acid chloride, etc. The base is desirably triethylamine or the like in the first step, and triethylamine or the like is desirably the base in the second step.

Next, the target product is X4 AA3 NHCCOAAI OY3, and the second amino acid residue from the N-terminus is α,β-dehydro-α
- When the dehydrotripeptide is an amino acid residue and is protected at both the N and C ends, the first step substance is an N-protected -α-amino acid halide, and the protecting group for the α-amine group is a urethane type. , the second step substance is an α-amino acid alkyl ester or a salt compound of its amine group.

In the above two cases, the solvent is preferably THF, and the N-protected amino acid halide is, for example, N-Cbz-amino acid chloride. The base is preferably triethylamine or the like in the first step and triethylamine or the like in the second step. When producing the above-mentioned target product, the yield, simplicity and reaction conditions are good, and the optical It has an even more advantageous effect because it has almost no effect on active amino acids.

Further, in the case of synthesizing a target peptide, when condensing an amino acid serving as the C-terminus, a specific side chain functional group among α-amino acids having a side chain functional group may be unprotected. Therefore, if the next reaction requires a step of removing the protecting group of a specific side-blocking group, this can be carried out without protection.
Alternatively, if protection of a specific side chain functional group is required in the next reaction, an amino acid with a side chain protected can be used.

Therefore, further improvement in yield and convenience can be achieved from this point of view as well.

In addition, the C-terminal amino acid residue is α,β-dehydro-α-amino acid residue, and the N-terminus is a protected dehydrodipeptide derivative. -dehydro-α-amino acid residue, N, C
In the intermediate material for synthesizing the dehydrotripeptide derivative (Note 2) each protected at both ends, the substituent R
Examples of combinations of 1 and R2 include the following.

That is, R is a hydrogen atom, R2 is an isopropyl group, and X is a t-butoxylcarbonyl group.
is an L-alanine residue, R1 is a hydrogen atom, R2 is an isopropyl group, X is a t-butoxyl carbonyl group, and AA is a glycine residue, R
1 is a hydrogen atom, R2 is an isopropyl group, and
is a t-butoxyl carbonyl group, and AA is an L-leucine residue, R, is a hydrogen atom, R2 is an isopropyl group, X is a t-butoxyl carbonyl group, and AA is a L-leucine residue. - When it is a phenylalanine residue,
R is a hydrogen atom, R2 is a phenyl group, X is a t-butoxylcarbonyl group, and AA is an L-leucine residue, R1 is a hydrogen atom, and R2 is a phenyl group; , when X is a t-butoxyl carbonyl group and AA is an L-phenylalanine residue, or R1
is a hydrogen atom, R2 is a phenyl group, and X is t-
It is a butoxyl carbonyl group, and AA is usually an L-proline residue. However, it may be a geometric isomer that constitutes R1 and R2.

In this case, if R and R2 are both alkyl groups, they cannot become vinyl groups and are stable. Therefore,
It becomes possible to more advantageously induce the synthesis of α,β-dehydro-α-amino acid derivatives and peptides having α,β-dehydro-α-α-amino acid residues in their skeletons.

Similarly, if R is a methyl group and R2 is an ethyl group, then α
, β-dehydro-isoleucine derivatives and peptides having α,β-dehydro-isoleucine residues in their skeletons can be more advantageously induced.

Similarly, if R1 and 2 are both methyl groups, α,
It becomes possible to more advantageously induce the synthesis of β-dehydrovaline derivatives and peptides having α,β-dehydrovaline residues in their skeletons.

Similarly, if R is a hydrogen atom and R2 is the above-mentioned substituent other than a hydrogen atom, it is possible to synthesize α,β-dehydroα-amino acid derivatives and peptides having α,β-dehydroα-amino acid residues in their backbones. It becomes possible to guide the cells more advantageously.

Similarly, if R1 is a hydrogen atom and R2 is a phenyl group,
α,β-dehydro-phenylalanine derivatives and α,β
It becomes possible to more advantageously induce the synthesis of peptides having -dehydro-phenylalanine residues in their backbones.

Similarly, if R1 is a hydrogen atom and R2 is an isopropyl group, it is possible to more advantageously induce the synthesis of α,β-dehydro-leucine derivatives and peptides having α,β-dehydro-leucine residues in their skeletons. becomes.

Similarly, if R1 is a hydrogen atom and R2 is a normal propyl group, the synthesis of α, β-dehydro-normal leucine derivatives and peptides having α, β-dehydro-normal leucine residues in their skeletons can be more advantageously induced. becomes possible.

Similarly, if R is a hydrogen atom and R2 is an ethyl group, then α
, β-dehydro-normal valine derivatives and peptides having α,β-dehydro-normal valine groups in their skeletons can be more advantageously induced.

Similarly, if R1 is a hydrogen atom and R2 is a methyl group, then 2
It becomes possible to more advantageously induce the synthesis of -amino-2-butenoic acid derivatives and peptides having a 2-amino-2-butenoic acid residue in their skeleton.

Similarly, if R is a hydrogen atom and R2 is a para-hydroxyphenyl group, the synthesis of α,β-dehydro-tyrosine derivatives and peptides having α,β-dehydro-tyrosine residues in their backbones is more advantageous. It becomes possible to guide the

Furthermore, if R1 is a hydrogen atom and R2 is a para-methoxyphenol group, it can become a vinyl group and is stable. In addition, when leading to the next reaction, it may be necessary to protect the hydroxyl group, so α and β
-dehydro-O-methyl-tyrosine derivatives and α, β-
It becomes possible to more advantageously induce the synthesis of peptides having a dehydro-0-methyl-tyrosine residue in their backbone.

Similarly, if R1 is a hydrogen atom and R2 is a paramethoxymethoxyphenyl group, α,β-dehydro-0-methoxymethyl-tyrosine derivatives and α,β-dehydro-〇-
It becomes possible to more advantageously induce the synthesis of a peptide having a methoxymethyl-tyrosine residue in its backbone.

(The following is a margin) [Example] Next, an example will be shown. In this case, regarding the geometric isomer of the double bond of the dehydro-amino acid residue, unless otherwise specified, the Z-coordination is shown. In addition, in the following examples, for convenience, XI, X2, X3, and X4 are
and Y for y+, Y2, and Y3, and AA4
, AA2, and AA3 are collectively expressed as AA or AA', and the specific substance is indicated.

The melting point is Yamato (Model Mp-21) micro
The welding-point appatatus is used and is uncorrected. IR is Hitachi, Ltd. EP
I-G2 type was used.

'H-NMR used JEOL JNM-PS-100 model. Solvents CDCl3 or DMSO-d6 were used, and tetramethylsilane was used as an internal standard. Specific rotation is 0
, 5chm tube JASCO DIP-4 was used. The packing material for column chromatography is Kiesel-ge
180 (manufactured by Merck & Co., Ltd., Art-7734) was used.

<Example 1> N-BOC-α, β- represented by XNH-C-COOY (wherein, R+ = C2R5, R2=CH3, Synthesis of dehydro-isoleucine methyl ester (BOC-Δ-inleucine methyl ester) 776 mg (5 mmol) of N-carboxy-α,β-dehydro-isoleucine anhydride was dissolved in 8 ml of THF, and di-t-butyl-dicarbonate ( Below, (BO
C) It is called 20. 1st grade substance) 1,31 g (6
Add 20 ml of pyridine and 60 ml of pyridine at room temperature.
Stir for an hour. After that, methanol (second process material) 5
ml, adjust the pH to 9 with NMM, stir at room temperature for 2 hours, and concentrate the reaction solution under reduced pressure. The residue is dissolved in 40 ml of ethyl acetate, washed with a 10% aqueous citric acid solution, saturated multilayered water and water, and dried over anhydrous sodium sulfate. After filtering off the desiccant, it was concentrated under reduced pressure, and the residue was purified with a silica gel column (benzene: ethyl acetate = 5: IV/V) to obtain the desired N-BOC.
-α,β-dehydro-isoleucine methyl ester was obtained in a yield of 82% of theory.

The physical properties of this substance are as follows.

Melting point ('C): 81-83 IR (KB r , cm'): 1720 (COOH) 1690.1500 (NHCO) 1645 (C=C) 'H-NMR (δ, CDC13): 5.85 (bs , IH, NH) 3.75 (s, 3H, 0CH3) Elemental analysis value 2 Cl2H2, NO4 Calculated value (%): C59,24H8,70N 5.7
6 Actual value (%): C59, 21H8, 80N 5.
73 (E coordination: Z coordination = 3:2) Next, in Examples 2 to 15, the combination of R,, R2, YOH (Y is a hydrogen atom and a tertiary alcohol) during the Kaiun reaction. The yields and physical property values are shown for different cases, such as the alkyl group corresponding to a given alcohol excluding .

<Example 2> Starting material N-carboxy-α-amino-α-butenoic anhydride Step 1 I material: (BOC) 20 Intermediate material N-BOC-α-amino-α-butenoic anhydride Step 2 T material Dihydrate target N-BOC-α-amino-α-butenoic acid, R1=CH
3 R2=H 'H-NMR (δ, DMSO-d6): 6.32 (q,
RC =, J = 7Hz) 1.38 (S, (CH3
)3 C-)7,98 (b s , NH) Elemental analysis value: Cg H+ 5NO4 Calculated value (%): C53,72H7,51N 8.
9B actual measurement value (%): C53.8? H7,57N
B-8? Example 3 Starting material N-carboxy-α,β-dehydro-normal valine anhydride (hereinafter referred to as Δ-n-valine NCA (7)) First step material: (BOC) 20 Intermediate Substance N-BOC-α,β-dehydro-n-valine anhydride (hereinafter referred to as BOC-Δ-n-valine NCA) Second step substance dihydrate target product N-BOC-α,β- Dehydro-normal valine (hereinafter referred to as BOC-Δ-n-valine), where R,=C2H,.

R2=H -NMR (δ, DMSO-dc): 6.24
(t, R-CH=, J=7Hz) 1.38 (s
, (CH3)3C-)8.00 (bs, NH) Elemental analysis value: C1oH1□N04 Calculated value (%): C55,80H7,98N 8.
51 Actual value (%): C55,? I H7,87N
B.80 Example 4> Starting material Δ-n-leucine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-n-leucine NCA 2nd step material Bihydrate target BOC-Δ-n-leucine R1=n-C3H7 R2=H
OOH) 1650 (CONH) 1640 (C=C) 'H-NMR (δ, DMSO-dr, ): 6.3
4 (t, R-C =, J = 7Hz) 1.40 (s
, (CH3)3C-)8.08 (bs, NH) Elemental analysis value: C+ I H+ (INOA calculated value (%)
: C57,82HC35N Ei, 11th measurement value (
%): C57,68H8,21N 8.00 <Example 5> Starting material Δ-Leucine NCA 1st stage substance: (BOC) 20 Intermediate substance BOC-Δ-Leucine NCA 2nd stage substance: Water target BOC- Δ-Leucine However, R+ = i -C3R7 R2=H CONH) 1640 (C=C)'H-NMR (δ, DMSO-d, ): 6.20 (d,
RC =, J = 10Hz) 1-40 (S, (CH3
)3C) 8,04 (b s , NH) Elemental analysis value: C1, H19N04 Calculated value (%): C57,82H8,35N 6.
11 fruit 10 old III (%): C57,57H8
, 23N B, 00 <Example 6> Starting material Δ-phenylalanine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Male 2-step material 2-water objective product BOC-Δ-phenylalanine However, R+ = C6R5 R2=H H-NMR (δ, DMSO-dG) near, 26
Cs, R-CH=)1,40 (s, (C
H3) 3C-)8.52 (bs, NH) Elemental analysis value: C14H17NO4 Calculated value (%): C83,88H8,51N 5.
32 Actual value (%): C83,81H8,85N
5.43 Example 7> Starting material Δ-valine NCA 7Ff, 1TTT Material: (BOC) 20 Intermediate material BOC-Δ-valine NCA 2nd step material: Water target BOC-Δ-valine However, R+: CH :I R2=CH3 IH-NMR (δ, DMSO-dr, ): 1.
38 (s, (CH3) 3 C-)
8.16 (bs, NH) Elemental analysis value: 01oH17NO4 Calculated value (%): C55,80H7,913N B
, 51 lol A Kawa I Nao (%): C55,58H
7,82N 8.80 <Example 8> Starting material Δ-inleucine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-inleucine NCA 2nd step material Biwater objective product BOC-Δ-isoleucine However , R+ =C2R5 R2=CH3 =C) 1H-NMR (δ, DMSO-dG): 1, 40 (
s, (CH3)3C-)8.16(bs,N
H) Elemental analysis value 2C1□H1゜NO4 Calculation 4rM (%): C57,62H8,35N
8.11 Actual value (%): C57,49H8-09
NS, 23 Example 9> Starting material Δ-n-leucine NCA 7A1 material: (BOC) 20 Intermediate material BOC-Δ-n-leucine NCA 2nd step material: methanol Target product BOC-Δ-n- Leucine methyl ester, R1=
n-C3H7 R2=H
OOH) 1700.1500 (CONH) 1655 (C=C) 'H-NMR (δ, CDC13): 6.58 (t, R-C=, J=7, 5Hz
)3.78 (s, -〇CH3) 6.17 (bs, NH) Elemental analysis value: C+ 2 R21NO4 Calculated value (%): C59,24H8,70N 5.
76 Actual value (%): C59,13H8,78N
5.81 <Example 1O> Starting material Δ-leucine NCA 1st step material: (BOC)20 Intermediate material BOC-Δ-leucine NCA 2nd step material: methanol Target product BOC-Δ-leucine methyl ester However, R1= i -C3R7 R2=H
OOH) 1705.1500 (CONH) 1660 (C=C) 'H-NMR (δ, CDCl5): 6.35 (d, R-CH=, J=lOH2) 3.7
6 (s, -0CH3) 6.17 (bs, NH) Elemental analysis value: Cl2H2□NO4 Calculated value (%): C59,24H8,70N 5.
78 actual value (%), C3fl18 H8,88N
5.89 <Example 11> Starting material Δ-phenylalanine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA 2nd step material: methanol Target product BOC-Δ-phenylalanine methyl ester However, R,
=CF, H5 R2=H (C=C)'H-NMR (δ, CDCh) near, 24 (s, R-CH=)3, 85 (
s, -0CH3) 6.27 (bs, NH) Elemental analysis value: C15H19NO4 Calculated value (%): CEf4.96 H6,91N
5.05 Actual value (%): C[34,83H8,8
4N 5-13 <Example 12> Starting material Δ-valine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-valine NCA 2nd step material: methanol Target product BOC-Δ-valine methyl ester However, R ,=CH3 R2=CH3 C=C) 'H-NMR (δ, CDC13): 3,77 (s, -0CH3) 5.95 (bs, NH) Elemental analysis value 2C1□H1°N04 Calculated value (%): C57,82H8, 35N 6.
11 Actual value (%): C57,56H8,29N
S, 05 Example 13> Starting material Δ-phenylalanine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA 2nd step material: ethanol Target product BOC-Δ-phenylalanine ethyl ester However, R2
=CH3 R2=H =C) 'H-NMR (δ, CDC13) near, 20 (S, R-CH=)4.28 (q
, -0CH2-, J=7Hz)6.32 (bs,
NH) Elemental analysis value: C16H2□NO4 Calculated value (%): C85,95H7,27N 4.
81 measurement value (%): C65, 85H7, 19N
4.75 <Example 14> Starting material Δ-phenylalanine NCA 1st step material: (BOC) 20 Intermediate bamboo BOC-Δ-phenylalanine NCA 2nd I9'lh material: benzyl alcohol Target product BOC-Δ-phenylalanine benzyl ester However, R = C6H5 R2 = H CONH) 1640 (C=C) 'H-NMR (δ, CDC13) near, 24 (s, R-CH=) 5.24 (s
, -0CR2) 6.23 (bs, NH) Elemental analysis value: C2□H23N O4 Total 32 [ii (%), C71,37H[3,51
3N 3.98 yen measurement value (%), C71,21H8
,40N 4.10 <Example 15> Starting material Δ-phenylalanine NCA First step material: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Second step material: Isopropanol Target product BOC-Δ-phenylalanine isopropyl ester However, R+ = Ct; H5 R2=H (CONH) 1650 (C=C) 1H-NMR (δ, CDC13) Near, 12 (s, R-C=) 5, 10 (m, -0CR2-) 6.26 (b
s, NH) Elemental analysis value: C17H23N04 Calculated value (%): CEi6.86 H7,59N
4.59 Actual value (%): C8B, 81 H7,70
N 4.80 (blank below) <Example 16> C XNH-C-COAAOY (in the formula, R1= i C3R7, R2=H, X=BQ
Synthesis of (BOC-Δ-leucil-L-serine methyl ester) of N-BOC-α,β-dehydro-leucil-L-serine methyl ester represented by C, Y=CH3, AA=L-serine residue N- Carboxy-α,β-dehydro-leucine anhydride 1
．． Add 5 ml of THF to 55 g (10 mmol) of di-t-butyl-dicarbonate (process material) 2,
Add 62 g (12 mmol) and a few drops of pyridine.

After stirring at room temperature for 6 hours, 1.31 g (l 1 mmol) of L-serine methyl ester G2 engineering θ-di in 5 ml of THF.
Add the solution dropwise and stir for 1 hour at room temperature. After evaporating the solvent under reduced pressure, the residue was dissolved in 100 ml of ethyl acetate, washed with a 10% aqueous citric acid solution, saturated brine, and water, and dried over anhydrous sodium sulfate. After filtering off the desiccant, it was concentrated under reduced pressure, and the residue was transferred to a silica gel column (benzene: ethyl acetate = 5
:lV/V) to obtain the desired product in the form of a square peak in a yield of 70% of the theoretical amount.

The physical properties of this substance are as follows.

'H-NMR (δ, CDC13): 6.25 (d, R-CH=, J=10Hz) 4.6
6 (d, NHCHCO.

J = 3, 5, 7, 0Hz) [α] PC = 1. Methanol) = -11,9° Elemental analysis value: C15H26N206 Calculated value (%): C54,53H7,93N 8.
48 Actual value (%): C54,39H7,95N
8.44 Next, in Examples 17 to 36, R+, R
2, the yield and physical property values are shown when α,β-dehydropeptide derivatives with different N-protecting groups X, AA, and Y are synthesized by the same method as above.

<Example 17> Starting material α-amino-α-butenoic acid NCA First step material Niacetyl chloride Intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) 'A2. Ili substance: L-L substance: Norleucine methyl ester Target product Mino-α-butenoyl-L-leucine methyl ester However, R+ = CH3 R2=H X=Ac AA=L-leucine residue Y: CH3 Yield (%) )280 Melting point ('C): 148-150 I R (KB r , cm'): 1630.1550 (CONH) 'H-NMR (δ, CDC13): 6.38 (q, R-C =, J=7Hz)4.45
(dt, NHCHCO) [α]24 (C=1.methanol) = -24,3° Elemental analysis value: C13H22N204 Calculated value (%): C57,78H8,20N10.
38 Actual λ11 value (%): C57,63H8,39N
10.42 <Example 18> Starting material α-amino-α-butenoic acid NCA 1st step material: Acetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) 2nd step material: L -Tyrosine methyl ester target product Ac-α-amino-α-butenoyl-L-tyrosine methyl ester However, R,=CH3 R2=H X=Ac AA=L-tyrosine residue Y=CH3 Yield (%) 289 Melting point ('C: Oil IR (KBr, am'): 1660.1520 (CONH) 'H-NMR (δ, DMSO-ds): 5.77
(q, RC =, J = 7Hz) 4.45 (d t
, NHCHCO) [α1D(C=1.82.methanol)=10,2' Elemental analysis value: Cl8H2oN205 Total nim (%): C59,99H13,2
9N 8.75 Actual value (%): C60,08H8
, 17N 8.58 <Example 19> Starting material α-amino-α-butenoic acid NCA 1st step material Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) 2nd step material : L-serine methyl ester Target product Ac-α-amino-α-butenoyl-L-serine methyl ester However, R,=CH3 R2=H X=Ac AA=L-serine residue Y=CH3 Yield: B (% ) Near 4 Melting point (℃): Oil 'H-NMR (δ, CDC13): 6.44 (q, R-CH=, J=7Hz)4,'
56 (m, NHCHCO) [α] D (C = 1. Methanol) = 7.5 @ Elemental analysis value: C1oH16N205 Calculated value (%): C4!9.1? H8,80N1
1.47￥Jll value (%): C49,25H8,4
9N11.58 <Example 20> Starting material α-amino-α-butenoic acid NCA 1st step material Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) 2nd step material: L -Proline methyl ester target product Ac-α-amino-α-butenoyl-proline methyl ester However, R,=CH3 R2=H X=Ac AA=L-proline residue Y=CH3 Yield (%) Near 8 Melting point ('C): 118-120 IR (KB r , cm-1): 1600.15
20 (CONH)'H-NMR (δ, CDC13): 5, 50 (q, R-CH=, J=7Hz)
4.60 (t, NHCHCO) [α]2' (C = 0, 89, methanol) = -2
2.5゜Elemental analysis value: Cl2H18N204 Calculated value (%): C5B, 88 H7,14N11
．． 02 Actual measurement value (%): C58, 51H7, 25N1
1.13 <Example 21> Starting material α-amino-α-butenoic acid NCA First step material Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) Second step material: L-methionine methyl ester Target product Ac-α-amino-α-butenoyl-L-methionine methyl ester However, R,=CH3 R2=H X=Ac AA=L-methionine residue Y=CH3 Yield (%) Near 9 Melting point ('C): 110-112 IR (KB r , cm'): 1630, l 550 (CONH)'H-NMR (
δ, CDC13) , :6.44 (q, R-CH
= , J=7Hz) 4.64 (dd, NHCHCO) [α]D (c=o.22.methanol) = -19,8° Elemental analysis value: Cl2H2oN204S Calculated value (%); C49,! 39 H8-87N
9.89 Actual value (%), C50.05H8.71
N9.5? <Example 22> Starting material α-amino-α-butenoic acid NCA 1st step material Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) 2nd step material: L-)Lypto Fan methyl ester target product Ac-α-amino-α-butenoyl-L-1 ribtophan methyl ester However, R1: CH3 R2=H X=Ac AA=L-) Liptophan residue Y=CH3 Yield (% ) Near 3 Melting point ('C): 183-185 (decomposition) I R (KB
r, cm'): 1620.1500 (CONH)'H-NMR (δ, DMSO-dG): 6.36 (q,
RC =, J = 7Hz) 4.60 (m, NHCHC
O) [α]D (C=0.70.methanol) = -2, 4° Elemental analysis value: Cl8H2, N304 Calculated value (%), C62,98H8,18N12.
24 Actual value (%): C63,13H8,03N1
2-11 <Example 23> Starting material α-amino-α-butene etNCA First step material Niacetyl chloride Intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) Second step material: L-glutamic acid-α-methyl-γ-ethyl ester Target product Ac-α-amino-α-butenoyl-L-glutamic acid-α-methyl-γ-ethyl ester However, R,=CH3 R2=H X=Ac AA= L-glutamic acid-γ-ethyl ester residue Y = CH3 Yield (%): 84 Melting point ('0): 88-90 1H-NMR (δ, CDCh): 6.47 (q, R-C =, J=7Hz)6.54 (
dt, NHCHCO.

J = 7, 5, 6, 0H2) [α]D (c = t, methanol) = -16,5° Elemental analysis value: C14H22N206 Calculated value (%): C53,49H7,05N 8.
91 Actual value (%): C53,61H7,13N 9
．． 00 <Example 24> Starting material α-amino-α-butenoic acid NCA 1st step material Niacetyl chloride intermediate material Ac-α-amino-α-butene #NCA (Ac=acetyl) 2nd step material: L-phenylalanine Methyl ester target product Ac-α-amino-α-butenoyl-L-phenylalanine methyl ester However, R+ = CH3 R2 = H X = Ac AA = L-phenylalanine residue Y = CH3 Yield (%): 94 Melting point (℃ ): 144-145 I R (KB r , cm'): 1620, 15
40 (CONH) IH-NMR (δ, CDCh): 6, 38 (q.R-C =, J = 7Hz) 4, 67 (
dt, NHCHCO) [α]D (C=1, methanol) = -8.5' Elemental analysis value: C18H2oN204 Calculated value (%): C83.14 H 8.82 N
! 9.21 Actual Ill value (%): C83.01
H 8.75 N 9.00 <Example 25> Starting material α-amino-α-butenoic acid NCA i1 step material Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) 2nd step material : L-phenylalanine ethyl ester Target product Ac-α-amino-α-butenoyl-L-phenylalanine ethyl ester However, R,=CH3 R2=H X=Ac AA=L-phenylalanine residue Y=C2H5 Yield (%) :96 Melting point (°C): 138-140'H-NMR (δ, CDC13): 6, 38 (q, R-CH=, J=7, 1
Hz) 4.76 (dt, NHC CO) [α]D (c=t, methanol) = -5,4° Elemental analysis value: C17H22N204 Calculated value (%): C3L13 H8,97N 8.8
0 Actual value (%): C84,30H7,08N 8
．． 133 <Example 26> Starting material Δ-n-valine NCA m1 Step material Niacetyl chloride Intermediate material Ac-Δ-n-barrier NCA (Ac=acetyl) 2nd step material: L-phenylalanine ethyl ester Target product Ac-Δ -n-valyl L-phenylalanine ethyl ester However, R1=C2R5 R2=H δ, CDC13): 6, 38 (t, R-CH=, J=7Hz)
4.87 (dt, NHC DanCo) [α]o (c = 1.methanol) = -6,1" Elemental analysis value: Cl8H24N204 Calculated value (%): Ce5.04 H7,28N 8
．． 43 actual value (%), C84,93H7,38N
8.41 (blank below) <Example 27> Starting material Δ-n-leucine NCA 1st step material Niacetyl chloride intermediate material Ac- Δ-n-leucine NCA (Ac=acetyl) 2nd step n material: L- Phenylalanine ethyl ester Target product Ac-Δ-n-leucyl-phenylalanine ethyl ester However, R1=n C5H7 R2=H X=Ac AA=L-phenylalanine residue Y=C2R5 Mimashi (%) = 93 Melting point ('0): 137-138 1H-NMR (δ, CDC13): 6.26 (t, R-C =, J = 7Hz) 4.82 (d
7. NHCHCO) [α]24 (C=1, methanol) = -7.5゜Elemental analysis value: C1゜H26N204 Calculated value (%), CB5.8? H7,57N 8
．． 09 Actual value (%): C85,91H7,48N
8.20 <Example 28> Starting material Δ-Leucine NCA 1st step material Niacetyl chloride intermediate material Ac-Δ-Leucine NCA (Ac=acetyl) 2nd step material: L-phenylalanine ethyl ester Target product Ac-Δ- Leucyl-L-phenylalanine ethyl ester However, R1=: i C3H fR2=H δ, CDC13): 6.10 (d, R-CH=, J=10Hz) 4.82
(dt, NHCHCO) [α]24 (C=1, methanol) = -6,2° Elemental analysis value: Cl9H26N204 Calculated value (%): C85,87H7,57N 8.
09 actual measurement a (%): C8G, 03 H7,7
2N 8-21 <Example 29> Starting material Δ-phenylalanine NCA 1st step material Niacetyl chloride intermediate material Ac-Δ-phenylalanine NCA (Ac=acetyl) 2nd step material: L-phenylalanine ethyl ester Target product Ac-Δ -Phenylalanyl-L-phenylalanine ethyl ester However, R,=C6HぢR2=H -NMR (δ, CDCl5): 6, 88 (s, R-CH=) 4.79 (dt, NHCHCO) [α]"cc=i, methanol) = -35,8° Elemental analysis value: C22H24N204 Calculated value (%): C89,45H6,38N 7.
38 Actual value (%): C89,53H8,12N 7
．． 19 <Example 30> Starting material Δ-leucine NCA 1st step material: Triple oroacetic anhydride intermediate material Tfa- Δ-leucine NCA (Tfa=trifluoroacetyl) 2nd step material: L-phenylalanine methyl ester target product Tfa- Δ-Leucyl-L-phenylalanine methyl ester However, R1= i -C3R7 R2=H , CDC13): 6.19 (d, R-CH=, J=10H2) 4.83
(dt, NHC Dan CO.

J=8.0.5-7Hz) [α]24(C=1.methanol)=-15-6° Elemental analysis direct: 018H21N2°4 F3 calculated value (%)
: C55-98H5,48N 7.25 actual value (
%): C5G, 18 H5,58N? -42 <Example 31> Starting material Δ-phenylalanine NCA 1st step material: Triple oroacetic anhydride intermediate material Tfa-Δ-phenylalanine NCA (Tfa-4-lifluoroacetyl) 2nd step material: L-threonine methyl ester Target product Tfa-Δ-phenylalanyl-L-threonine methyl ester, R,=CG R5 R2=H X=Tfa AA=L-threonine residue Y=CH3 Yield (%) Near 4 Melting point (℃): Oil H-NMR (δ, CDC13) near, 15-7.29 (m, R-CH=, +C
6Hs ) 4.43 (dd, NHcHco.

J=8-5.3.0H2) [αCoD (C=1.methanol)=29.0@Elemental analysis value: C16H1□N205F3 calculated value (%): C
51,34H4,58N 7.48 Actual value (%):
C51,08H4,89N 7.32 <Example 32> Starting material Δ-Leucine NCA 1st step material: Trifluoroacetic anhydride Intermediate Tfa-Δ-Leucine NCA (Tfa=trifluoroacetyl); 7.2 Step material: δ-Cbz-L-ornithine methyl ester Target product Tfa-Δ-leucyl δ-Cbz-L-ornithine methyl ester However, R1= i -C3R7 R2=H X=Tfa AA=δ-Cbz-L-ornithine residue Y =CH3 Yield (%) Near 9 Melting point (℃) Two oil IH-NMR (δ, CDCh): 6.21 (d
, R-CH=, J=10H2) 4.58 (m, NHC CO) [α] D (c=t, methanol) = -7,5° Elemental analysis value: C22H28N306F3 calculated value (%), C3
L20 H5,79N 12 Measured value (%): C54
,06H5,92N 8.50 <Example 33> Starting material Δ-phenylalanine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA 2nd step material Nigericin methyl ester Target product BOC-Δ-phenyl Alanyl-glycine methyl ester However, RI=C(, R5 R2=H ) near, 14 (S, R-CH=)4.14 (d
, NHCHCO, J=8H2) Elemental analysis value: C1□H2
2N20° Calculated value (%): C81,06H [3,63N 8
．． 38 Actual value (%): C80,89H8,51N
L49 <Example 34> Starting material Δ-phenylalanine NCA First step material: (BOC)20 Intermediate material BOC-Δ-phenylalanine NCA Second step material: L-leucine methyl ester Target product BOC-Δ-phenylalanine L- a Isine methyl ester However, R,=C6R5 R2=H Near, 12 (s, R-CH=)168 (dt
,NHCHCO.

J = 8.0, 8.0Hz) [α124 (C = 1.methanol) = -41,8° Elemental analysis value: C2□H3oN205 Calculated value (%): C64,59H7,74N 7.1
7 Actual value (%), C84,70H7,87N 7.
01 <Example 35> Starting material Δ-phenylalanine NCA 1st step material = (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA 2nd step material: L-phenylalanine methyl ester Target product BOC-Δ-phenylalanine L- Phenylalanine methyl ester However, R1=C6R5 R2=H ) Near, 04 Cs, R-CH=)4.90 (d
t, NHCHCO.

J = 6.0, 7.0Hz) [αCoD (C = 1, methanol) = -3,6' Elemental analysis value: C24H28N2.05 Calculated value (%); CB7.90 H8,65N f3
．． 80 Actual value (%): C67, 70H8, 72N 6
．． 77 <Example 36> Starting material Δ-n-valine NCA 1st step material: (BOC) 20 Intermediate material BOC-Δ-n-valine NcA 2nd step material: L-tyrosine methyl ester target product BOC-Δ-n - Valyl L-Tyrosine Methyl Ester However, R,=C2B5 R2=H CDC13): 6.39 (t, R-C =, J = 7Hz) 4.80
(dt, NHCHCO.

J=7.0,8.0Hz) [α]24(C=1.methanol)=-11-7' Elemental analysis value: C2oH28N206 Calculated value (%): C81,21H7,19N? =
14 actual value (%), CB1.01 H13i3 N
7.01 (blank below) <Example 37> XAANH-C-COOY (in the formula, R, = C6B5, R2 = H, X = Pht, Y =
CH3, AA = N-P represented by glycine □□□
Synthesis of ht-glycyl-α,β-dehydro-phenylalanine methyl ester N-carboxy-α,β-dehydro-phenylalanine anhydride 1,89 g (10 m
Pht glycyl chloride (2.46 g of Pht glycyl chloride synthesized by a conventional method) (2.46 g
(11 mmol), and add triethylamine at θ° C. under cooling until pH 5-6. Stir at room temperature for 1 hour, add 10 ml of methanol from the second stage, and adjust the pH to 8 to 9 with triethylamine. Stir again at room temperature for 1 hour,
Thereafter, it was concentrated under reduced pressure, and the residue was dissolved in 100 ml of ethyl acetate. IMJ! After washing with A acid and water, drying over anhydrous sodium sulfate, filtering off the desiccant, and concentrating under reduced pressure.
) to obtain the target product in the form of W+ crystals from benzene in a yield of 85% of the theoretical amount.

The physical properties of this substance are as follows.

Melting point ('C): 160-161 1 R (KB r 9cm'): 1680.1530 (CONH) IH-NMR (δ, CDC13) near, 46-7.2 [3 (R-C = , +Cr, H
s) 4.43 (s, NHCHCO) Elemental analysis value 202eH16N20S Calculated value (%), CB5.93 HC43N 7.
89 actual measurement value (%): C8B, 05 H4, 39N
7.73 Next, in Examples 38 to 42, R,,R
2 shows the yield and physical property values when α,β-dehydropeptide derivatives with different X, AA, and Y are synthesized by the same method as above.

<Example 38> Starting material Δ-n-valine NCA Fourth step material: Pht-D, L-phenylalanyl chloride intermediate Pht-D, L-7, Nylalanyl-Δ-n-valine NCA Second step material : Water target Pht-D, L-phenylalanyl-Δ-n-valine However, R blind = C2H5 R2=H x= p h t AA=D, L-phenylalanine residue Y=H Yield (%) 280 Melting point (℃): 148-150'H-NMR (δ, DMSO-dc): 6,7
6 (t, R-CH=, J=7Hz)5.20
(dt, NHCHCO.

J=8.0,5.5Hz) Elemental analysis value: C22H2oN205 Calculation m (%); CB7.33 H5,14N 7.
14 Actual measurement value (%): C87, 15H5, 29N?
, 09 <Example 39> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-L-alanyl chloride intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A Second step substance: Ethanol Target Pht-L-alanyl-α-amino-α-butenoic acid ethyl ester However, R,=CH3 R2=H x= p h t AA=L-alanine residue Y=C2H5 Yield Rate (%) 286 Melting point (°C): 133-135'H-NMR (δ, CDC13): 6.76 ((1, R-CH=, J=7Hz) 5.0
6 (q, NHCHCO, J=7Hz) [α124(C
= 1. Methanol) = 0.9' Elemental analysis value: C, +t
H+5N205 Calculated value (%): CB1.81 H5,49N L
48 actual value (%), C81,89H5,81N 8
．． 41 <Example 40> Starting material α-amino-α-butene fIINCA 1st step product: Cbz-glycyl chloride intermediate material Cbz-glycyl-α-amino-α-butenoic acid CA 2nd step material: ethanol Target product Cbz-glycyl-α-amino-α-butenoic acid ethyl ester, R,=CH3 R2=H X=Cbz AA=glycine residue Y=C2H5 Yield (%)=20 Melting point (°C): Oil 'H -NMR (δ, CDCl5) Near, 02 (q, R-C =, J = 7Hz) 3.87 (
d, NHCHCO, J=6Hz) Elemental analysis value: C16H
2oN205 Calculated value (%): C59,98H8,29N 8.
75 Actual value (%): C80,07H8,35N 8.
63 <Example 41> Starting material Δ-phenylalanine NCA 1st step material: Cbz-glycyl chloride intermediate material Cbz-glycyl Δ-phenylalanine NCgS 2nd step material: methanol Target product Cbz-glycyl-Δ-phenylalanine methyl ester However. R,=C6H= R2=H (m, R-Cdan=, +c
6 N5 ) 3.91 (d, NHCHCO, J=7Hz
) Elemental analysis value: C2oH2oN205 Calculated value (%): C65,21H5-47N 7.8
1 Actual value (%): C85-49H5,40N 7
．． 53 <Example 42> Starting material α-amino-α-butenoic acid NCA 1st step material: Cbz-L-alanyl chloride intermediate material Cbz-L-alanyl-α-amino-α-butenoic acid NC
A 2nd step substance: methanol Target product Cbz-L-alanyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X=Cbz AA=L-alanine residue Y=CH3 Yield ( %): 23 Melting point (°C): 137-138'H-NMR (δ, CDC13): 6.76 (cl, R-CH=, J=7Hz)4.
43 (m, NHCHCO) [α]D (C=0.65.methanol)=-10.5° Elemental analysis value: CIGH2・N20S Calculated value (%): C59,99H8,29N 8.
75 Actual value (%), Cf30.09 HEi, 20
N 8.87 <Example 43> General formula R, R2 XAANH-C-COOY (wherein, R, = C6N5, R2 = H, X = BOC, Y =
Synthesis of N-BOC-L-phenylalanyl-α,β-dehydro-phenylalanine methyl ester represented by CH3, AA=L-phenylalanine residue) N-carboxy-α,β-dehydro-phenylalanine anhydride 1, 89 g (10 mmol) of THF5
ml solution of BOC-L-phenylalanine (1 step material) 2, 92 g (11 mm
Add o l). The mixture was cooled to −10° C., and 2.27 g (llmmol) of dicyclohexylcarbodiimide was added. Stir for 20 minutes at the same temperature, and adjust the pH to 6 with pyridine.

Thereafter, the mixture was stirred at 0° C. for 1 hour and at room temperature for 12 hours. Add 10 ml of methanol (second step material) and add NMM.
After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, and after standing in a cold place for 1 hour, the precipitated dicyclohexylurea was filtered off. This is washed with 50 ml of cold ethyl acetate, both ethyl acetate layers are combined, washed with a 10% aqueous citric acid solution and water, and dried over anhydrous sodium sulfate. After filtering the dry smoke agent, concentrate under reduced pressure,
The residue was filtered onto a silica gel column (chloroform:acetone=2
The desired product in the form of burl yellow needle crystals was obtained from diisopropyl ether in a yield of 90% of the theoretical amount.

The physical properties of this substance are as follows.

Melting point ("0): 116-118 r R (KB r , cm-'): 1640.15
30 (CONH)'H-NMR (δ, CDC13): 6.54 (d, R-CH=, J=lOHz) 4.5
4 (dt, NHCHCO.

J=8.0,7.0Hz) Elemental analysis value: C24H28N205 calculation &(%); C67-90H6,85N 8.
60 Actual value (%): C87,80H8,69N
8J3 Next, in Examples 44 to 55, R,, R2
The yield and physical property values are shown when α,β-dehydropeptide derivatives based on combinations of , X, AA, and Y are synthesized by the same method as above.

<Example 44> Starting material Δ-n-valine NCA 1st step material: Pht-D, L-phenylalanine intermediate Pht D, L 7x Nylalanyl-Δ-n-valine NCA 2nd step material dihydrate Pht- D, L-phenylalanyl-Δ-n-valine However, R, = C2HS R2 = H X = Pht AA = D, L-phenylalanine residue Y = H Yield (%): 85 Melting point ('C): 148-150'H-NMR (δ, DMSOds): 6.76 (t
, R-CH= , J=7Hz)5.20 (dt,
NHCHCO.

J=8.0.5.5Hz) Elemental analysis value: C22H2oN205 Calculated value (%): C87,33H5,14N 7.1
4 Actual value (%): Cf1i7.28 H5,17N
? -20 <Example 45> Starting material Δ-phenylalanine NCA 1st step material: Pht-glycine intermediate Pht-glycyl-Δ-phenylalanine NC 2nd step material: methanol Target product Pht-glycyl-Δ-phenylalanine methyl ester However, R,=C6HS R2=H 28 (m, R-CH=, 106 HS) 4.43 Cs, NHCHCO) Elemental analysis value: C2oH16N20° calculated value (%), CB5.93 H4,43N?,
B9 actual value (%), CBG, 05 H4, 32N
7.81 <Example 46> Starting material α-amino-α-butene @NCA 1st step material: Pht-L-alanine intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A Second step substance: Ethanol Target Pht-L-alanyl-α-amino-α-butenoic acid ethyl ester However, R1=CH3 R2=H X= Pht AA=L-alanine residue Y=C2R5 Yield (%) 287 Melting point ('C:): 133-135'H-NMR (δ, CDC13): 6.76 (q, R-CH=, J=7Hz) 5.06
(q,NHCHCO,J=7Hz)[α]D(c=
t, methanol) = 0.9° Elemental analysis value: C17H18
N205 calculated value (%): C81,81H5,48N 8.4
8 Actual value (%): C81,89H5,58N 8.
30 <Example 47> Starting material α-amino-α-butenoic acid NCA 1st step material: Cbz-glycine intermediate Cbz-glycyl-α-amino-α-butenoic acid CA 2nd step material: ethanol Target product Cbz- Glycyl-α-amino-α-butenoic acid ethyl ester However, R,=CH3 R2=H (δ, CDC13) near, 02 (q, R-CH=, J=7Hz) 3.8
7 (d, NHcHco, J=6Hz) Elemental analysis value: C
16H2・N2O5 Calculated value (%), C5!1199 H6,29N
8.75 Actual value (%), C59,80H8,18N
C92 <Example 48> Starting material Δ-phenylalanine NCA 1st step material: Cbz-glycine intermediate material Cbz-glycyl-Δ-phenylalanine NC'52 step material: methanol Target product Cbz-glycyl-Δ-phenylalanine methyl ester However, R ,=C6R5 R2=H = , +c5
R5) 3.91 (d, NHCHCO, J=7H
z) Elemental analysis value: C2oH2oN20° Calculated value (%); C85-21H5,47N 7.6
1 Actual measurement value (%): C65,03H5,59N? −
77 <Example 49> Starting material α-amino-α-butenoic acid NCA 1st step material: Cbz-L-alanine intermediate Cbz-L-alanyl-α-amino-α-butenoic acid NC
A 2nd step substance: methanol Target product Cbz-L-alanyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X=Cbz AA=L-alanine residue Y=CH3 Yield ( %): 88 Melting point (°C): 137-138 1H-NMR (δ, CDC13): 6-76 (q, R-C temperature =, J = 7Hz) 4.43
(m, NHCHCO) [α]D (c=o, ss, methanol) = -10,5'' Elemental analysis value: C16H2oN205 Calculated value (%): C59,99H8,29N 8.
75 actual value (%), C59,91H8,38N 8
．． 89 <Example 50> Starting material α-amino-α-butenoic acid NCA Fourth step material: BOC-L-alanine intermediate BOC-L-alanyl-α-amino-α-butenoic acid NC
A 2nd step substance: methanol Target product BOC-L-alanyl-α-amino-α-butenoic acid methyl ester However, R1=CH3 R2=H X=BOC AA=L-alanine residue Y=CH3 Yield (% )=65 Melting point (°C): 116-117'H-NMR (δ, CDCl:)): 6.80 (q, R-CH=, J=7Hz) 4.4
0 (m, NHCHCO) [α]24 (c = 1.methanol) = -25,70
Elemental analysis value: C13H22N205 Calculated value (%): C54,53H7,75N 9.
78 Actual value (%); C54,70H7-93N S
, 131 <Example 51> Starting material α-amino-α-butenoic acid NCA 1st step material: BOC-L-valine intermediate BOC-L-valyl-α-amino-α-butenoic acid NCA 2nd step material: Methanol target BOC-L-valyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X=BOC AA=L-valine residue Y=CH3 Yield (%): 69 Melting point ( °C): 110-111'H-NMR (δ, CDC13): 6, 82 (q, R-CH=, J=7Hz)
4.10 (m, NHCHCO) [α]D (C=1.methanol) = -25,4° Elemental analysis value: C15H28N205 Calculated value (%); C57,31H8,34N 8.
91 Actual value (%): C57, 19H8, 49N S,
10 <Example 52> Starting material α-amino-α-butene #NCA 1st step material: BOC-L-leucine intermediate BOC-L-leucyl-α-amino-α-butenoic acid NC
A 2nd step substance: methanol Target product BOC-L-leucyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X=BOC AA=L-leucine residue Y=CH3 Yield ( %): 64 Melting point (℃): Oil 'H-NMR (δ, CDC13): 6.64 (q
, R-CH=, J=7Hz)4.18 (m, NHC
[α]D (C=1.methanol) = -19,2° Elemental analysis value: C16H28N205 Calculated value (%); C58,51H8,59N L53
Actual value (%), C58-70H8,80N 8.3
2 <Example 53> Starting material α-amino-α-butenoic acid NCA 1st step material: BOC-L-phecoalanine intermediate BOC-L-phenylalanyl-α-amino-α-butenoic acid NCA 2nd Process material: methanol Target product BOC-L-phenylalanyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X=BOC AA=L-phenylalanine residue Y=CH3 Yield (% ) = 85 Melting point (℃): 97-98'H-NMR (δ, CDC13): 6.73 (q,
RC =, J = 7Hz) 4.58 (dt, NHC
H.C.O.

J=8.0,7.0Hz) Ea ]o (C=1, ) evening/-ru) =-1
5,0' Elemental analysis value: C19H26N205 Calculated value (%); C82,96H7,23N 7.
73 actual value (%); C83,13H7,10N 7
．． 87 <Example 54> Starting material α-amino-α-butenoic acid NCA 1st step material: BOC-glycine intermediate EOC-glycyl-α-amino-α-butenoic acid CA 2nd step material: methanol Target product BOC- Glycyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X=BOC AA=glycine residue Y=CH3 Yield (%): 60 Melting point ('C): 103-104'H -NMR (δ, CDC13): 6.84 (q, RC =, J = 7H2) 3.98
(d, NHCHCO, J=6Hz) Elemental analysis value: C
l2H2oN205 Calculated value (%): C52,93N7.40 N10.2
9 Actual value (%), C53, 10H7, 26N13
．． 49 <Example 55> Starting material Δ-phenylalanine NCA 1st step material: BOC-L-leucine intermediate BOC-L-leucyl-Δ-phenylalanine CA 2nd step material: methanol Target product BOC-L-leucyl-Δ- Phenylalanine methyl ester However, R,=CG N5 R2=H ) Near, 24-7.50 (m, R-CH=, +C
6N5) 4.28 (m, NHCHCO) [α]D (c=i, methanol) = 41.5° Elemental analysis value: C2□H3oN205 Calculated value (%): C84,59H7,74N 7.
17 Actual value (%): C3L70 H7,86N 7.
13 (blank below) <Example 56>XAANH-C-COAA'OY (in the formula, R1=i C3N7, R2=H, X=BQC
, Y=CH3, AA=L-alanine residue, AA'=L-
Synthesis of N-BOC-L-alanyl-α, β-dehydro-leucil-L-phenylalanine methyl ester (BOC-L-alanyl-Δ-leucil-L-phenylalanine methyl ester) represented by phenylalanine m N-carboxy-α, β-dehydro-leucine anhydride 1
, 55 g (10 mmol) in 5 ml of THF was added with BOC-L-alanine (quaternary
Process material 2.08g (11mm.

Add 1). Cool to −10° C. and add 27 g (1 mmol) of dicyclohexylcarbodiimide 2. Stir for 20 minutes at the same temperature and adjust the pH to 6 with pyridine. Then, stirred at 0°C for 1 hour and at room temperature for 12 hours,
This is added to L-phenylalaninemethyAy varnish-rAy (
2nd factory fJr￥t) 1,97 g (11 mmol
) in THF, and adjusted the pH with triethylamine.
8-9. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 ml of ethyl acetate, and after standing in a cold place for 1 hour, the precipitated dicyclohexyl urea was filtered off and washed with 50 ml of ethyl acetate. . Both ethyl acetate layers were combined, washed with 10% citric acid solution and water, and dried over anhydrous sodium sulfate. After filtering off the desiccant, concentrate under reduced pressure,
The residual liquid was transferred to a silica gel column (chloroform:acetone = 2
0: IV/V) to obtain a product similar to chloroform and diisopropyl ether in a yield of 90% of the theoretical amount.

The physical properties of this substance are as follows.

Melting point (℃): 121-122'H-NMR (δ, CDC13): 6, 29 (d, R-C temperature = , J = 10Hz)
4,21 (m, NHCHCO) 4,86 (dq, NHCHCO.

J=7.5, 5.0Hz) [α]:? c=t, methanol)=-35.8.

Elemental analysis value: C24H35N306 Calculated value (%): C82.83 H 7.81 N
9.13 Actual value (%); C82.45 H 7.
84 N 9.01 Next, in Examples 57 to 91, the combination of R1 and R2, X. AA, AA', Y (7) Difference α. The yield and physical property values when β-dehydropeptide derivatives were synthesized by the same method as above are shown.

<Example 57> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-glycine intermediate Pht-glycyl-α-amino-α-butylene CA 2nd step material: L-phenylalanine methyl ester Target product Pht -glycyl-α-amino-α-butenoyl-L-
Phenylalanine methyl ester However, R1 = CH3 R2 = H (δ, CDC13): 6, 43 (q, R-CH=, J=7Hz) 4, 7
4 (dt, NHCHCO.

J=7.5.7.0Hz) 4, 28 (s, NHCHCO) [α]:i
! c=t, methanol)=-24.9.

Elemental analysis value: C24H23N306 Calculated value (%); C84.13 H 5.18 N
9.35 Actual value (%): C84.01 H 5.
01 NO. 52 <Example 58> Starting material α-amino-q-butenoic acid NCA 1st step material: Pht-glycine intermediate Pht-glycyl-α-amino-α-butenoic acid CA 2nd step material: L-leucine methyl ester Purpose Pht-glycyl-α-amino-α-butenoyl-L-
Leucine methyl ester, R,=CH.

R2=H 59(q, R-Cdan=, J=7Hz)4.52 (
dt, NHCHCO.

J = 7.0, 7.0Hz) 4.44 (S, NHCHCO) [α] DEC = 1, methanol) = -42,8° Elemental analysis value: C2, H25N306 Calculated value (%): C60,71H6, 07N10.1
2 Actual measurement value C%”); C80, 90H8, 25N10
．． 01 <Example 59> Starting material Δ-leucine NCA 1st step material: Pht-glycine intermediate material pht-glycyl-Δ-leucine NCA 2nd step material:
L-valine methyl ester target product pht-glycyl-Δ-leucyl L-valine methyl ester However, R1= i -C3R7 R2=H Rate (%) 285 Melting point ("C): 204-205'H-NMR (a, CDC13): 6.33 (
d, R-CH=, J=10H2)4.44 (m, NH
CHCO) [α]fi3 (C = 1, methanol) = -24,6
゜Elemental analysis value: C22H27N3o6 calculated value C%); C81,52H8,34N 9.7
9 Actual value (%): C81,37H8,22N 9.
92 <Example 60> Starting material Δ-phenylalanine NCA 1st step material: Pht-glycine intermediate Pht-glycyl-Δ-7 enylalanine NC 2nd step material: L-phenylalanine methyl ester Target product Pht-glycyl-Δ- Phenylalanyl-L-phenylalanine methyl ester However, R word = C6H5 R2 = H x = p h t AA = glycine residue AA' = L-7 enylalanine residue Y = CH3 Yield (%) Near 9 Melting point ('' 0): 175-176'H-NMR (δ, CDC13): 8.92-7.30 (m, R-CH=, +〇&R
5) 4.64 (dt, NHCHCO.

J = 7.5, 7.0Hz) 4.24 (s, NHCHCO) [α]D (C = 0.5.methanol) = -61,8゜Elemental analysis value: C2゜H25N308 Calculated value (%), C60,09H4,93N 8.2
2 Actual measurement value (%); C88,31H4,70N 8.
43 <Example 61> Starting material Δ-leucine NCA 1st step material: Pht-glycine intermediate material Pht-glycyl-Δ-leucine NCA 2nd step material:
L-phenylalanine methyl ester Target product Pht-glycyl-Δ-leucyl L-phenylalanine methyl ester However, R1= i -C3N7 R2=H Yield (%) = 88 Melting point ('0): 193-194'H-NMR (δ, CDC13): 6.25 (d
, R-CH=, J=10Hz)4.80 (dt,
NHC DanCo.

J=15. l0H2) 4.40 (S, NHC CO) [α]33 (C=1.methanol) = -20,2° Elemental analysis value: C26H2°N306 Calculated value (%): C85,39H5,70N 8.
80 Actual value (%): C85,49H5,82N
8.131 <Example 62> Starting material Δ-phenylalanine NCA 1st step material: Pht-glycine intermediate pht-glycyl-Δ-phenylalanine NC 2nd step material: L-valine methyl ester Target product Pht-glycyl-Δ- Phenylalanyl-valine methyl ester However, R,=C6HS R2=H 215-216'H-NMR (δ, CDC13) near, 17 (s, R-CH=)4.26 (d
d, NHC Dan CO.

J = 7.5, 7.0H2) 4.50 (s, NHC CO) [α]23 (c = i, methanol) = -20,5° Elemental analysis value: C25H25N308 Calculated value (%): C84, 78H5-44N 9.0
7 Actual measurement value (%); C84,82H5,32N 9.
16 <Example 63> Starting material Δ-n-valine NCA 1st step material: Pht-glycine intermediate Pht-glycyl-Δ-n-valine NCA7iT12 step material: L-phenylalanine methyl ester Target product Pht-glycyl-Δ- n-valyl L-phenylalanine methyl ester However, R, = C2Hs R2 = H :169-171'H-NMR (δ, CDCl5): 6.36 (t, R-C=, J=7Hz) 4.8
0 (dt, NHCHCO.

J=7.0, 7.0H2) 4.42 (s, NHCHCO) [α]23cc = 1. Methanol) = -18.9° Elemental analysis value: C25H25N306 Calculated value (%); Ce4.78 H5,44N 9.
07 actual measurement value (%), C6t83 H5,82N [
90 <Example 64> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-L-alanine intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A Second step substance: L-phenylalanine methyl ester target product Pht-L-alanyl-α-amino-α-butenoyl-
L-phenylalanine methyl ester However, R,=CH3 R2=H 161l61- 1621H-Nδ, CDC13): 6.48 (q, R-C =, J = 7Hz) 4.92 (
q, NHCHCO, J=7Hz)4.62 (dt
,NHCHCO.

J=7.0,6.5H2) [α]D(C=1.methanol)=12.9゜Elemental analysis value: C25H25N308 Calculated value (%); C84,78H5,44N 9.0
7 Actual measurement value (%); C3L90 H5,29N 9.
18 <Example 65> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-L-leucine intermediate Pht-L-leucyl-α-amino-α-butene #NC
A Second step substance: L-phenylalanine methyl ester target product Pht-L-leucyl-α-amino-α-butenoyl-
L-phenylalanine methyl ester However, R,=CH3 R2=H ~152'H-NMR (δ, CDC13): 6.46 (q, R-C =, J = 7Hz) 5.00 (
dd, NHCHCO.

J=11.0, 5.0Hz) 4.66 (dt, NHCHCO.

J = 7.0, 7.0 Hz) [α 3 (C = 1. methanol) = -4, 5 @ Elemental analysis value: C28H3, N306 Calculated value (%); C68, 52H8, 18N 8.
31 Actual value (%); C88,44H6,24N 8
．． 45 <Example 66> Starting material Δ-n-leucine NCA 1st step product: Pht-L-leucine intermediate product Pht-L-leucyl-Δ-n-leucine NC 2nd step material: L-phenylalanine methyl ester Purpose Pht-L-Leucyl-Δ-i-Leucyl-L-phenylalanine methyl ester However, R1=n C:l H7 R2=H X=Pht AA=L-leucine residue AA'=L-phenylalanine residue Y=CH3 Yield (%): 65 Melting point (C: 53-55'H-NMR (δ, CDC13): 6.46 (t, R-CH=, , J=7Hz)5.
02 (dd, NHCHCO.

J=11.0.5.0H2) 4.72 (dt, NHCHCO.

J=7.5,6.0H2) [α]D(C=1.methanol)=-7,0" Elemental analysis value: C3# H:l s N30s; Calculated value (%)
: C87,52H6,81N 7.88 actual value (%
): C87,39H8,89N 7.79 <Example 67> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-L-phenylalanine intermediate Pht-L-7 enylalanyl-α-ami7-α ~Butenoic acid NCA Second step substance nigericin methyl ester Target product Pht-L-phenylalanyl-α-amino-α-butenoyl-glycine methyl ester However, R,=CH3 R2=H X=Pht AA=L-phenylalanine Residue AA' = Glycine residue Y = CH3 Yield (%) = 87 Melting point ('C): 100-101 1011H-Nδ, CDC13): 6, 56 (q, R-CH=, J=7Hz)
5.20 (dd, NHCHCO.

J=10.5, 5.5Hz) 3+90 (d, NHCHCO, J=6H2) [α]
fi2c=t,ttanol)=-113,4゜Elemental analysis value: C24N23 N30G calculated value (%); C
84,13H5,18N 9.35 Actual value (%);
C84,05H5,31N 9.22 <Example 68> Starting material Δ-leucine NCA 1st step material jJ: Pht-L-phenylalanine intermediate material Pht-L-phenylalanyl-Δ-leucine CA 2nd step material: L -Serine methyl ester target Pht-L-phenylalanyl-Δ-leucyl L-serine methyl ester However, R1= i -C3R7 R2=H X= Pht AA=L-phenylalanine residue AA'=L-serine Residue Y=CH3 Yield (%)=C8 Melting point (''C): 179-180'H-NMR (δ, CDC13): 6.21 (d, R-CH=, J=10Hz) 5.30
(dd, NHCHCO.

J=110.5.0Hz) 4.38 (m, NHCHCO) [α]: 2c=t, methanol) = -59,1° Elemental analysis value: C2□H28N307 Calculated value (%): C63-89H5,78N 8.2
8 Actual value (%): C63,96H5,85N 8.
19 <Example 69> Starting material Δ-phenylalanine NCA 1st step material: Cbz-glycine intermediate Cbz-'l"lysyl-Δ-phenylalanine NC 2nd
Process material: L-serine methyl ester target Cbz-glycyl-Δ-phenylalanyl-L-serine methyl ester However, R,=C6R5 R2=H X=Cbz AA=glycine residue'=L-serine residue Y=CH3 Yield (%) Near 0 Melting point (°C) Two oily substance 1H-NMR (δ, CDC13) Near, 06 Cs, R-(J=) 3.84 (m
, NHCHCO) 4.60 (m, NHCHCO) [α]l1(C=1.16.methanol)=-21,9
” Elemental analysis value: C23H25N307 Calculated value (%): C80,85H5,53N 9.
23 Actual measurement value (%): C80, 80H5, 48N 9
．． 29 <Example 70> Starting material α-amino-α-butenoic acid NCA First step material: BOC-L-alanine intermediate BOC-L-alanyl-α-amino-α-butenoic acid NC
A Second step substance: L-serine methyl ester target product BOC-L-alanyl-α-amino-α-butenoyl-
-Serine methyl ester However, R,=CH3 R2=H X=BOC AA=L-alanine residue AA'=L-serine residue Y=CH3 Yield (%): 61 Melting point (°C): Oil IH -NMR (δ, CDC13): 6.63 (q,
RC =, J = 7Hz) 4.20 (dd, NHC
H.C.O.

J=7.0, 7.0Hz) 4.61 (dt, NHCHCO.

J=8.0, 4.0H2) [α]D (c=i, methanol) = -31,9° Elemental analysis value: C16H2□N30□ Calculated value (%), C51,46H7,29N11.
25 Actual value (%), C51, 37H7, 37N11
29 <Example 71> Starting material α-amino-α-butenoic acid NCA First step material: BOC-L-valine intermediate BOC-L-valyl-α-amino-α-butenoic acid NCA Second step material: L -Serine methyl ester target product BOC-L-valyl-α-amino-α-butenoyl-L
-Serine methyl ester, R,=CH3 R2=H X=BOC AA=L-valine residue AA'=L-serine residue Y=CH3 Yield (%): 63 Melting point (℃): Oil 'H -NMR (δ, CDC13): 6.62 (q, R-CH=, J=7Hz) 4.02
(m, NHCHCO) 4.62 (m, NHCHCO) [α] Ha3 (C = 1. methanol) = -22,9° Elemental analysis value: Cl8H3□N30□ Calculated value (%), C53-85H7 = 78 N1(
L47 actual value (%), C53,75H7,94N1
0.39 <Example 72> Starting material Δ-n-valine NCA 1st step material: BOC-L-alanine intermediate material BOC-L-alanyl-Δ-n-barrier NCA 2nd step material: L-serine methyl ester Target product BOC-L-alanyl-Δ-n-valyl L-serine methyl ester However, R1=C2N5 R2=H X=BOC AA=L-alanine residue AA'=L-serine residue Y=CH3 Yield ( %) = C7 Melting point (°C): Oil'H-NMR (δ, CDC13): 6.57 (t, R-C temperature =, J, = 7Hz) 4.2
0 (dd, NHCHCO.

J=7.0, 7.0H2) 4.60 (dt, NHCHCO.

J = 8.0, 4.0Hz) [Alpha-ization 3 (C = 1. methanol) = -34,5° Elemental analysis value: C17H29N307 Calculated value (%); C52,70H155N10.8
5 Actual measurement value (%): C52, 90H7, 47N10.
89 <Example 73> Starting material Δ-phenylalanine NCA 1st step material: BOC-glycine intermediate BOC-glycyl-Δ-phenylalanine NC 2nd step material: L-methoxyalinine methyl ester Target product BOC-glycyl-Δ- Phenylalanyl-L-methionine methyl ester However, R,=C6HS R2=H 162 1H-NMR (δ, CDC13) Near, 12 (s, R-C Dan=) 3.70 (d, NHCHCO, J=6Hz) 4.5
1 (dt, NHCHCO.

J=8.0,7.0Hz) [α3(C=1.methanol)=-50-9゜Elemental analysis value "22H31N3°6s Calculated value (%): C3L78 H6,71N 9.
03 Actual value (%); C5B, 83 H8, 85N
S, 10 <Example 74> Starting material Δ-phenylalanine NCA Fourth step material: BOC-glycine intermediate BOC-glycyl-Δ-phenylalanine NC Second step M: L-leucine methyl ester Target product BOC-glycyl-Δ- Phenylalanyl-L-leucine methyl ester However, R, = CG H5 R2 = H X = BOC AA = glycine residue = L-leucine residue = CH3 Yield (%) = 85 Melting point (℃) 188-189'H-NMR (δ, CDCl5) near, 16 (s, R-CH=) 3.70 (d,
NHCHCO, J = 5.5 Hz) 4.40 (dt
,NHCHCO.

J=8.0, 4.5Hz) [α]D (c=t, methanol) = -26,2° Elemental analysis value: C23H33N308 Calculated value (%), CB1.72 H7,43N 9.
39 Actual value (%); C81,80H7,38N 9
．． 45 Example 75 Starting material α-amino-α-butenoic acid NCA 11th step Product: BOC-L-phenylalanine intermediate BOC-L-phenylalanyl-α-amino-α-butenoic acid NCA 2nd step material : L-alanine methyl ester target product BOC-L-phenylalanyl-α-amino-α-butenoyl-L-alanine methyl ester However, R,=CH3 R2=H X=BOC AA=L-phenylalanine residue AA' =L-alanine residue Y=CH3 Yield (%): 94 Melting point (°C): 190-191'H-NMR (δ, CDCl: l): 6, 65 (q, R-CH=, J=7 ,5
Hz) 4.36 (dq, NHCHCO.

J=8.0.5.5Hz) 4.59 (m, NHCHCO) [α]D (C=1.methanol)=-26,4° Elemental analysis value: C22H3□N306 Calculated value (%): C80, 95H7, 21N 9.
69 actual value (%), CB1.08 H7,18N
9.73 <Example 76> Starting material Δ-leucine NCA 1st step material: BOC-L-leucine intermediate material BOC-L-leucyl-Δ-leucine NCA 2nd step material: L-alanine methyl ester target product BOC- L-leucyl-Δ-leucyl-L-alanine methyl ester However, RI= i -03R7 R2=H X=BOC AA=L-leucine residue AA'=L-alanine residue Y=CH3 Yield (%) 287 Melting point ("0): 126-127 1H-NMR (δ, CDC13): 6-36 (d, R-CH=, J=lOHz) 4.19
(m, NHCHCO) 4.62 (dq, NHCHCO.

J=7.5. ．． 5.0Hz) [61g3cc = 1. methanol) = -60,8'
Elemental analysis value: 02, H3□N308 Calculated value (%); C58,99H8,72N 9-8
3 Actual measurement value (%): C59, 10H8, 85N 9.
92 <Example 77> Starting material Δ-inleucine NCA First step material: BOC-L-alanine intermediate BOC-L-7 Ranil-Δ-inleucine NC Second step material: L-serine methyl ester Target product BOC- L-alanyl-Δ-inleucyl-L-serine methyl ester However, R1=C2R5 R2=CH3 X=BOC AA=L-alanine residue AA'=L-serine residue Y=CH3 E and Z coordinations Mixture yield (%) = 94 Melting point (°C): 159-161 1R (KB r , cm'''1): 1650.1520 (CONH) 'H-NMR (δ, CDC13): 4.16 (dq, NHCHCO.

J = 7.0, 7.0 Hz) 4.60 (m, NHCHCO) E coordination: 2, 40 (q, CH3CH2, J = 7.5 Hz
) 1.72 (S, CH3) Z coordination: 2, 10 (q, CH3CH2, J=7.5 Hz
) 2.04 (s, CH3) [α]D (C=1.methanol) = -31,6° Elemental analysis value: Cl8H31N307 Calculated value (%): C53,85H7,78NIo, 4
7 Actual value (%): C53-92H7,90Nl(
140 Example 78 Starting material Δ-inleucine NCA Fourth step material: BOC-L-α-aminobutanoic acid intermediate BOC-L-α-aminobutyryl-Δ-inleucine N
CA 2nd step substance: L-serine methyl ester target 'BOC-L-α-aminobutyryl-Δ-inroin-L-serine methyl ester However, R,=C2R5 R2=CH3 X=BOC AA=L-α-aminobutanoic acid Residue AA' = L-serine residue Y = CH3 Mixture yield (%) of E and Z ligands 281 Melting point ('C): 175-176 I R (KB r , cm'): 1650.1520 (CONH) 'H-NMR (δ, CDC13): 4.08.4.68 (m, NHCHCO)E coordination: 2.44 (Q, CH: ICC20, J = 7.5 Hz
)1,76 (S, CH:s) Z coordination; 2,08 (q, CH3CH2, J=7.5)1
z) 2.04 (S, CH: l) [α] D (C = 1. Methanol) = -26,2° Elemental analysis value: C1° R33N307 Calculated value (%); C54,92H8,01N10.1
1 Actual value (%): C55-03H7, 90N10.
00 Example 79 Starting material Δ-inleucine NCA 1st step material: BOC-Ln-valine intermediate BOC-Ln-valyl-Δ-inleucine NA 2nd step material: L-serine methyl ester Target object BOC-L-n-valyl-Δ-inleucyl-L-serine methyl ester However, R,=C2R5 R2=CH3 X=BOC AA=L-n-valine residue AA'=L-serine residue Y=CH3 Mixture yield (%) of E-coordination and Z-coordination Near 3 Melting point (°C): 178-179 I R (KB r , cm'): 1650.1520 (CONH) IH-NMR (δ, CDC13) : 4.12, 4.64 (m, NHCHCO)E coordination; 2.40 ((1, CH3C dan 2. J = 7.5 7) 1.7
6 (s, CH3) Z coordination; 2,08 ((1, CH3CH2, J=7.5 Hz
) 2.04 (s, CH3) [α詔3(C=1.methanol)=-27,0' Elemental analysis value: C2・R3t, N30? Calculated value (%): C55, 93H8, 21N 9.7
8 Actual measurement value (%); C5B, 08 H8, 29N!
3.87 <Example 80> Starting material Δ-isoleucine NCA 1st step material: BOC-L-leucine intermediate material BOC-L-leucyl-Δ-isoleucine NC 2nd step material: L-serine methyl ester target product BOC- L-Leucyl-Δ-isoleucilyl-L-serine methyl ester However, R,=C2R5 R2=CH3 X=BOC AA=L-leucine residue AA'=L-serine residue Y=CH3 E coordination and Z coordination Mixture yield (%) near 8 Melting point ('0): 186-187 1H-NMR (δ, CDC13): 4.14.4.60 (m, NHCHCO)E coordination: 2, 42 (q , CH3CH2, J=7.5H
z) 1,76 (s, CH3) Z coordination: 2,08 (q, CH3CH2, J=7.5Hz
)2+04 (s, CH3) [α]D (C=1.methanol)=-29,0° Elemental analysis value: 02, H3□N30□ Calculated value (%); C5G, 88 H8,41N 9
．． 47 Actual value (%); C57, OOH8, 32N
9.59 <Example 81> Starting material Δ-valine NCA 1st step material: BOC-L-alanine intermediate material BOC-L-alanyl-Δ-valine NCA 2nd step material: L-serine methyl ester Target product BOC- L-alanyl-Δ-valyl L-serif methyl ester However, R1=CH3 R2=CH3 X=BOC AA=L-alanine residue AA'=L-serine residue Y=CH3 E-ligand and di-coord Mixture yield (%): 92 Melting point ('C): 149-150 I R (KBr, cm'): 1660.1520 (CONH)'H-NMR (δ, CDC13): 4.16 (dq, NHCHCO.

J=7.0,7.0H2) 4.58 (m, NHCHCO) E coordination: 2.04 (s, CH3) Z coordination; 1.72 (s, CH3) [α]D(C = 1. Methanol) = -26-8° Elemental analysis value: Cl7H29N30 Calculated value (%): C52,70H7,55N10.8
5 Actual measurement value (%): C52, 83H7, 59N10.
97 <Example 82> Starting material Δ-valine NCA 1st step material: BOC-L-α-aminobutanoic acid intermediate BOC-L-α-aminobutyryl-Δ-valine CA 2nd step material ff: L-serine methyl ester Target object BOC-L-α-aminobutyryl-Δ-valyl L-serine methyl ester However, R1=CH3 R2=CH3 X=BOC AA=L-α-aminobutanoic acid residue AA'=L-serine residue Y=CH3 Mixture yield (%) of E-coordination and Z-coordination 281 Melting point (C°C): 156-157 I R (KB r , cm-1): 1660.15
20 (CONH) IH-NMR (δ, CDC13): 4.08.4.68 (m, NHCHCO) E coordination: 2.06 (S, CH3) Z coordination: 1. 76 (s, CH3) [α]D (C=1.methanol) = -26,4° Elemental analysis value: C+5H3IN30 calculated value (%), C53-85H7-78NIQ, 4
7 Actual measurement value (%): C53,? 7 H7,80NIO
, 35 <Example 83> Starting material Δ-valine NCA 1st step material: BOC-L-n-valine intermediate material BOC-L-n-valyl-Δ-barrier NCA 2nd step material: L-serine methyl ester Purpose Product BOC-L-n-valyl-Δ-valyl L-serine methyl ester However, R,=CH3 R2=CH3 CH3 Mixture yield (%) of E and Z coordinations Near 9 Melting point ("0): 170-171 1R (KBr, cm'): '1640.15
20 (CONH) 'H-NMR (δ, CDC13): 4.12.4.64 (m, NHCHCO) E coordination: 2.04 (S, CH3) Z coordination: 1.76 (s, CH3) [α]23 (C= 1.methanol) = -24,7° Elemental analysis: 01SH33N307 Calculated value C%): C54,92H8,01N10.11
Actual value (%); C55,08H7,90N10.2
2 <Example 84> Starting material Δ-valine NCA 1st step material: BOC-L-coicin intermediate BOC-L-coicyl-Δ-valine NCA 2nd step material: L-serine methyl ester target product BOC-L -Leucyl-Δ-valyl L-serine methyl ester However, R,=CH3 R2=CH3 X=BOC AA=L-leucine residue AA'=L-serine residue Y=CH3 E and Z coordination Mixture yield (%) near 3 Melting point (''C): 185-186 I R (KB r , cm-1): 1650.15
20 (CONH)'H-NMR (δ, CDC13).

4.20.4.64 (m, NHCHCO)E coordination; 2.04 (s, CH3) Z coordination: 1.74 (S, CH3) [α]23(C= t, methanol)= -27,4゜Elemental analysis value: C2oH35N30□ Calculated value (%): C55,93H13,21N 9
．． 78 Actual value (%); C55,88H8,14N
9.87 Example 85 Starting material Δ-inleucine NCA 1st step material: BOC-L-alanine intermediate BOC-L-alanyl-Δ-inleucine NC 2nd step product J: L-serine benzyl ester Purpose BOC-L-alanyl-Δ-isoleucilyl-L-serine benzyl ester However, R,=C2HS R2=CH3 X=BOC AA=L-alanine residue AA'=L-serine residue Y=CH2c6H5 E coordination and Z-coordination mixture yield (%): 63 Melting point (°C): 107-108 I R (KB r , Cm-1): 1650.15
20 (CONH)'H-NMR (δ, CDC13): 4.16.4.64 (m, NHCHCO) E coordination: 2, 34 ((L, CH3CH2) 1.70 (
s, CH3) Z coordination: 2.06 (q, CH3Cdan2) 1.98 (S, CH3) [α]D (Cm1.methanol) = -37,9° Elemental analysis value: C24R3S N30 calculation Value (%); C8
0,38H7,3!3 N 8.80 Actual value (%)
; C3L50 H7,31N 8.59〈Example 86
> Starting material Δ-inleucine NCA 1st step material: BOC-L-n-valine intermediate BOC-L-n-valyl-Δ-inleucine NA 2nd step M: L-serine benzyl ester target product BOC-L -n-valyl-Δ-isoleucilyl-L-serine benzyl ester However, R,=C2R5 R2=CH3 X=BOC AA=L-n-valine residue AA'=L-serine residue Y=CH2C6R5 E coordination and Mixture yield (%) of Z-coordinator = 50 Melting point (°C): 136-138 IR (KB r , cm'): 1650.1530 (CONH) 'H-NMR (δ, CDC13): 4.08 .4.64 (m, NHCHCO) E coordination: 2.34 (q, CH3C dan 2) 1.68 (s, CH3) Z coordination: 2.06 ((1, CH3C dan 2) 1. 92 (5, CH3) [α] Ba5 (Cm1.methanol) = -22,5° Elemental analysis value: C26H38N307 Calculated value (%); C8178H7,76N L31
Actual value (%): C81,75H7,71N 8.3
4 <Example 87> Starting material Δ-inleucine NCA 1st step material: BOC-L-leucine intermediate BOC-L-leucyl-Δ-isoleucine NC 2nd step material m: L-serine benzyl ester target product BOC- L-leucyl-Δ-inleucyl-L-serine benzyl ester R,=02 R5 R2=CH3 X=BOC AA=L-leucine residue AA'=L-serine residue Y=CH2c,, R5 E ligand Mixture yield (%) of
30 (CONH) 1H-NMR (δ, CDC13): 4.10.4.70 (m, NHCHCO)E coordination; 2.40 (q, CH3Cdan2) 1.72 (s, CH3) Z coordination Topic structure: 2.12 (q, CH3Cdan2) 2.00 (S, CH3) [α]D (Cm1.methanol) = -23,9° Elemental analysis value 2C2□H4□N307 Calculated value (%) :C82,41H7,95N 8.0
9 Actual value (%); C82,35H7,90N 8.
15 <Example 88> Starting material Δ-valine NCA 1st step product: BOC-L-alanine intermediate BOC-L-alanyl-Δ-valine NCA 2nd step product W
: L-serine benzyl ester target product BOC-L-alanyl-Δ-valyl L-serine benzyl ester However, R,=CH3 R2=CH3 X=BOC AA=L-alanine residue AA'=L-serine residue Y =CH2C6R5 Mixture yield (%) of E and Z coordinations = 61 Melting point (°C): 97-98 I R (KB r , cm-1): 1660.15
20 (CONH) IH-NMR (δ, CDC13): 4.08.4.60 (m, NHCHCO) E coordination; 2.04 (S, CH3) Z coordination: 1.76 (s, CH3) ) [α]25 (C=1, methanol) = -32.5° Elemental analysis value: C23H33N307 Calculated value (%), C5! J, 80 H7, 18N
9.07 Actual value (%); C59,23H8,83N
9.09 Example 89 Starting material Δ-valine NCA 1st step product: BOC-Ln-valine intermediate BOC-Ln-valyl-Δ-barrier NCA 2nd step material: L-serine benzyl Ester target BOC-L-n-valyl-Δ-valyl L-serine benzyl ester where R,=CH3 R2=CH3 X=BOC AA=L-n-valine residue AA'=L-serine residue Y= CH2c6H5 Mixture yield (%) of E and Z coordinations: 41 Melting point (°C): 145-147 I R (KB r , cm'): 1650, 1530 (CONH) 'H-NMR (δ, CDC13): 4.08, 4.60 (m, NHCHCO) E coordination; 1.90' (S, CH3) Z coordination: 1.64 (S, CH3) [α]25 (C= 1 , methanol) = -20.8° Elemental analysis value 2C25H3□N30□ Calculated value (%), CG1.08 H7,59N 8
．． 55 Actual value (%); C80,71H8,05N
8.48 <Example 90> Starting material Δ-valine NCA 1st step material: BOC-L-leucine intermediate BOC-L-leucyl-Δ-valine NCA 2nd step material: L-serine benzyl ester target product BOC- L-Leucyl-Δ-valyl L-serine benzyl ester However, R,=CH3 R2=CH3 X=BOC AA=L-leucine residue AA'=L-serine residue Y: CH2C6R5 E coordination and Z coordination Mixture yield (%) = 47 Melting point (°C): 158-159 IR (KB r , cm'): 1650.1530 (CONH) 'H-NMR (δ, CDC13): 4.08.4. 60 (m, NHCHCO)E coordination; 1.98 (s, CH3) Z coordination: 1.70 (s, CH3) [α]D (C=1.methanol)=-22,6° element Analysis value: C26H39N307 Calculated value (%), CB1.78 H7,78N 8
．． 31 Actual value (%); C81,88H7,74N 8
．． 39 <Example 91> Starting material Δ-inleucine NCA 1st step material: BOC-L-alanine intermediate material BOC-L-alanyl-Δ-inleucine NC 2nd step material: L-serine-t-butyl ester Purpose BOC-L-alanyl-Δ-ynleucyl-L-serine-t-butyl ester However, R,=C2Hs R2=CH3 X=BOC AA=L-alanine residue AA'=L-serine residue Y=t C4H9 E configuration Mixture yield (%) of phase and Z coordination body = 80 Melting point ('0): 62-63 I R (KB r , cm-1): 1660, 1
510 (CONH)'H-NMR (δ, CDCl5): 4.26 (dq, NHCHCO.

J=7.0, 7.0Hz) 4.58 (m, NHCHCO) E coordination body; 2.40 (q, CH:Icdan2) 1.72 (S, CH3) Z coordination body: 2. 10 ((1, CH3CH2) 2.00 (s, CH3) [α]25(C=t, methanol) = -9,5° Elemental analysis value: C25H45N30□ Calculated value (%): C3 (110H9-08N 8 .4
1 Actual value (%): C80,52H9,57N 7.
92 (blank below) <Example 92> General formula R, R2 XAANH-C-COAA'OY (in the formula, R1=iC3R7, R2=H, X=Pht, Y
=CH3, AA=glycine residue, AA''=L-valine residue) Synthesis of N-carboxy-α,β-dehydro-leucine anhydride 1
．． In a solution of 55 g (lommol) in 5 ml of THF,
Pht glycyl chloride (2.46 g (11 mm) of the first step) synthesized by a conventional method was added, and the mixture was cooled to 0.
The pH is adjusted to 5-6 with triethylamine at around .degree. Stir at room temperature for 1 hour, add a solution of 44 g (11 ml) of L-valine methyl ester (second step material) in 5 ml of THF, and adjust the pH to 8 to 9 with triethylamine. After stirring at room temperature for 1 hour, the reaction solution was concentrated, the residue was dissolved in 100 ml of ethyl acetate, and IM-hydrochloric acid,
Wash twice with water and dry with anhydrous sodium sulfate. After removing the desiccant by ultra-IJ, it was concentrated under reduced pressure, and the residue was transferred to a silica gel column (
The product was purified with benzene:ethyl acetate (lO:IV/V), and the desired product in the form of colorless needle crystals was obtained from chloroform and n-hexane in a yield of 77% of the theoretical amount.

The physical properties of this substance are as follows.

Melting point (0C: 204-205'H-NMR (δ, CDC13): 6.33 (d, R-CH=, J=10Hz) 4.44
(m, NHCHCO) [α] 23 (C = t, methanol) = -24,6° Elemental analysis value: C22R27N: 106 calculated value (%)
; C61-52H6,34N 9.79 actual value (%)
; C61,63H8,17N 9.63 Next, in Examples 93 to 103, the combination of R,, R2,
, AA, AA', and Y are different, yields and physical property values are shown when α,β-dehydropeptide derivatives are synthesized by the same method as above.

<Example 93> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-glycyl chloride intermediate Pht-glycyl-α-amino-α-butenoic acid CA 2nd step material: L-phenylalanine methyl Ester target Pht-glycyl-α-amino-α-butenoyl-L-
Phenylalanine methyl ester However, R, = CH3 R2 = H x =: Ph t AA = Glycine residue' = L-phenylalanine residue Y = CH3 Yield (%): 62 Melting point (°C) :175-176 1H-NMR (δ, CDCl5): 6.43 (q, R-C =, J = 7Hz) 4.74 (
dt, NHC DanCo.

J = 7.5, 7.0Hz) 4.28 (s, NHCHCO) [α]D (C = 1. Methanol) Density -24,9° Elemental analysis value: C2, s R23N30ts calculated value (%)
:C84,13H5,18N 9.35 Actual J1 value (%)
CF34.20 H5,24N 9.2f3 <Example 94> Starting material α-amino to α-butenoic acid NCA 1st step material: Pht-glycyl chloride intermediate Pht-glycyl-α-amino-α-butenoic acid CA 2nd step substance: L-leucine methyl ester target product Pht-glycyl-α-amino-α-butenoyl-L-
Leucine methyl ester However, R1=CH3 R2=H -NMR (δ, CDC13): 6, 59 (q, R-CH=, J=7Hz)
4.52 (dt, NHCHCO.

J = 7.0, 7.0Hz) 4.44 (s, NHCHCO) [α]D (C = 1. methanol) = -42,8° Elemental analysis value: C2□H25N306 Calculated value (%); C80, 71H8, 07N10.
12 Actual value (%); C60, 83H8, 19N1
0.18 <Example 95> Starting material Δ-phenylalanine NCA 1st step material: Pht-glycyl chloride intermediate material Pht-glycyl-Δ-phenylalanine NC 2nd step material: L-phenylalanine methyl ester Target product Pht-glycyl- Δ-phenylalanyl-L-phenylalanine methyl ester However, R+ = C6H5 R2 = H C): 175-176 1H-NMR (δ, CDC13): 6, 92-7, 30 (m, R-CH=) 4.6
4 (dt, NHCHCO.

J = 7.5, 7.0Hz) 4.24 (s, NHCHCO) [αco (c = o-5, methanol) = -64,
6゜Elemental analysis value: C28H25N306 Calculated value (%), CBB, 09 H4,93N 8
．． 22 Actual value (%); C68,27H5,05N
8.13 <Example 96> Starting material Δ-leucine NCA 1st step material: Pht-glycyl chloride intermediate material pht-glycyl-Δ-leucine NCA 2nd step material:
L-phenylalanine methyl ester Target product Pht-glycyl-Δ-leucyl L-phenylalanine methyl ester However, R1=iC3H7 R2=H X= Pht AA=glycine residue AA'=L-phenylalanine residue Y=CH3 Yield (%) ~ 82 Melting point ('0): 193 ~ 194 1H-NMR (δ, CDC13): 6.25 (d, R-C =, J = 10Hz) 4.80
(dt, NHCHCO.

J = 7.5, 7.0Hz) 4, 40 (s, NHCHCO) [α] 23 (C
= 1, methanol) = -20,2゜Elemental analysis value: C
26H27N306 Calculated value (%), CG5.39 H5,70N F
L80 actual value (%); C85,45H5,82N
8.99 <Example 97> Starting material Δ-phenylalanine NCA 1st step material: Pht-glycyl chloride intermediate Pht-glycyl-Δ-phenylalanine NC 2nd step material: L-valine methyl ester Target product Pht-glycyl -Δ-phenylalanyl-L-herine methyl ester However, R, = C6H5 R2 = H X = Ph t AA = Glycine residue AA' = L-valine residue Y = CH3 Yield (%) = 85 Melting point (℃) +215~216'H-NMR (δ, CDC13) near, 17 (s, R-CH=)4.26 (d
d.NHCHCO.

J = 7.5, 7.0H2) 4.50 (s, NHCHCO) [α]D (C = 1. methanol) = -20,5° Elemental analysis value: C2, H25N306 Calculated value (%); C64, 78H5,44N 9.
07 Actual value (%), Cf34.83 H5,59N
9.15 <Example 98> Starting material Δ-n-valine NCA 1st step material: Pht-glycyl chloride intermediate material Pht-glycyl-Δ-n-valine NcA 2nd step material: L-phenylalanine methyl ester Target product Pht-glycyl-Δ-n-valyl L-phenylalanine methyl ester However, R,=C2H5 R2=H ) Near 5 Melting point ('C): 169-171'H-NMR (δ, CDC13): 6.36 (t, R-CH=, J=7Hz) 4.8
0 (dt, NHCHCO.

J = 7.0, 7.0Hz) 4.42 (s, NHCHCO) [α]23 (C = t, methanol) = -18,9° Elemental analysis value: C25H25N308 Calculated value (%): C84,78H5, 44N 9.
07 actual measurement value (%): C84,88H5,57N
8.98 <Example 99> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-L-alanyl chloride intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A Second step substance: L-phenylalanine methyl ester target product Pht-L-alanyl-α-amino-α-butenoyl-
L-phenylalanine methyl ester However, R,=CH3 R2=H 161-162'H-NMR (δ, CDC13): 6.48 (q, R-C =, J = 7Hz) 4.92 (q
,NHCHCO,J=7Hz)4.62(dt,N
HCHCO.

J=10,8.5H2) [α]23(C=1.methanol)=12.9° Elemental analysis value: C2, N2. N306 Calculated value (%): (J4.78 H5-44N 9
．． 07 Actual value (%); C84,85H! 5.31
N 9.23 <Example 100> Starting material α-amino-α-butenoic acid NCA 1st step Product: Pht-L-leucyl chloride intermediate Pht-L-leucyl-α-amino-α-butenoic acid NC
A Second step substance: L-7 enylalanine methyl ester target product Pht-L-leucyl-α-amino-α-butenoyl-
L-phenylalanine methyl ester However, R,=CH3 R2=H 151-152'H-NMR (δ, CDC13): 6.46 (q, R-C = , J = 7Hz) 5.00
(dd, NHCHCO.

J=11.0, 5.0Hz) 4.66 (dt, NHCHCO.

J=7.0, 7.0Hz) [αko23CC=1. Methanol) = -4,5° Elemental analysis value: C28H3, N306 Calculated value (%); C3B-52H8,18N 8.3
1 Actual value (%); C6B, 87 HB, (19N
8.40 <Example 101> Starting material Δ-n-leucine NCA 1st step material: Pht-L-leucyl chloride intermediate material Pht-ly-leucyl-Δ-n-leucine NC 2nd step material: L-phenylalanine Methyl ester target Pht-L-leucyl-Δ-n-leucyl L-7 enylalanine methyl ester However, R1= nC3N7 R2=H X= Pht AA=L-leucine residue AA'=L-7 enylalanine Residue Y=CH3 Yield (%)=71 Melting point (°C): 53-55'H-NMR (δ, CDCl5): 6.46 (t, R-CH=, J=7Hz) 5.0
2 (dd, NHCHCO.

J=11.0, 5.0H2) 4.72 (dt, NHCHCO.

J=7.5,6.0Hz) 23゛[α]D(C=1.methanol)=-7.0゜Elemental analysis value: C3o N3 r, N:l O(.

Estimated value (%); C8? , 52 H8JI N 7
．． 88 actual measurement value (%); C87.6! JH8,42
N 8.01 <Example 102> Starting material α-amino-α-butenoic acid NCA 1st step material: Pht-L-phenylalanyl chloride intermediate Pht-L-phenylalanyl-α-amino-α-butene Acid NCA Second step substance Nigericin methyl ester Target product Pht-L-phenylalanyl-α-amino-α-butenoyl-glycine methyl ester However, R1: CH3 R2=H X= Pht AA=L-phenylalanine residue Group AA' = Glycine residue Y = CH3 Yield (%) Near 9 Melting point (°C): 100-101'H-NMR (δ, CDC13): 6.56 (q, R-C =, J = 7Hz )5.20(d
d.NHCHCO.

J=10.5, 5.5Hz) 3.90 (d, NHCHCO, J=6Hz) [α]
(C=1.methanol)=-113,4゜Elemental analysis value:
C24H23N306 Calculated value (%): C64,13H5,18N 9.3
5 Actual measurement value (%), C60,30H5-01N 9
．． 09 <Example 103> Starting material Δ-leucine NCA 1st step material: Pht-L-phenylalanyl chloride intermediate material Pht-L-phenylalanyl-Δ-leucine CA 2nd step material: L-serine methyl ester Purpose Pht-L-phenylalanyl-Δ-leucyl-L-serine methyl ester However, R1= i C3N7 R2=H X= Pht AA=L-phenylalanine residue AA'=L-serine residue Y=CH3 Yield Rate (%) = 70 Melting point (°C): 179-180'H-NMR (δ, CDCl:l): 6.21 (d, R-C temperature =, J = 10Hz) 5.3
0 (dd, NHCHCO.

J=11.0, 5.0Hz)

Claims (1)

[Claims] (1) In a method for producing a specific compound having an α,β-dehydro-α-amino acid residue, in a predetermined solvent, the general formula ▲ includes a mathematical formula, a chemical formula, a table, etc. , R^1, and R^2 each represent the same or different substituents consisting of a hydrogen atom, an appropriately substituted carboxyl group, or an optionally substituted alkyl group or aryl group.However, R^1 and R^ 2 are not hydrogen atoms at the same time.) N-carboxy-α,
β-dehydro-α-amino acid anhydride, amino group protecting agent or N-protected-α-amino acid or N-protected-α
- A substance consisting of an amino acid halide (hereinafter referred to as the first step substance) is added and reacted with a predetermined base or a predetermined condensing agent in the presence of a predetermined base, and the general formula ▲ mathematical formula, chemical formula, synthesized by the above reaction, There are tables, etc. ▼ (In the formula, R_1 and R_2 are the same as above. -carboxy-α,β-
It consists of a step of adding a predetermined substance (hereinafter referred to as the second step material) consisting of a substance having nucleophilicity to dehydro-α-amino acid anhydride and reacting it in the presence of a predetermined base;
α, characterized in that two steps are performed in the same system,
A method for producing a specific substance having a β-dehydro-α-amino acid residue. (2) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. Represents a lower alkyl group excluding a tertiary alkyl group.) N-protected -α,β-dehydro-α-
In the case of amino acid ester derivatives, the first step substance is an amino group protecting agent and is in the acyl type, and the second step substance is an acyl type protecting agent.
α, β according to claim 1, wherein the process material is a lower alkyl alcohol excluding tertiary alkyl alcohol
-Dehydro-α-Amino acid residue manufacturing method (3) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2 and X_1 are the same as above, Y_2
represents a hydrogen atom. ) denoted by N-protection-α, β
-dehydro-α-amino acid, the first step substance is an amino group protecting agent that becomes an acyl type, and the second step substance is water.
A method for producing a specific substance having a β-dehydro-α-amino acid residue. (4) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2 and Y_1 are the same as above, X_2
represents a urethane-type protecting group for the α-amino group of the α-amino acid. ) N-protected-α,β-dehydro-α
- In the case of an amino acid ester derivative, the first step substance is an amino group protecting agent and is a urethane type;
α according to claim 1, wherein the second step substance is a lower alkyl alcohol excluding tertiary alkyl alcohol.
, a method for producing a specific substance having a β-dehydro-α-amino acid residue. (5) The specific substance is N-protected-α,β-dehydro-α- represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, X_2 and Y_2 are the same as above.) In the case of an amino acid, the first step substance is an amino group protecting agent of urethane type, and the second step substance is water, α,β-dehydro-α according to claim 1. −
A method for producing a specific substance having an amino acid residue. (6) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2 and X_1 are the same as above, Y_3
represents a lower alkyl group. AA_1 represents an α-amino acid residue. ) the N-terminal amino acid residue is α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue and has both N and C ends protected (the N-terminus represents the amino-terminus of the peptide, and the C-terminus represents the carboxy-terminus of the peptide), the first The α,β-dehydro-α-amino acid according to claim 1, wherein the process substance is an amino group protecting agent and becomes an acyl type, and the second process substance is an α-amino acid alkyl ester. A method for producing a specific substance having a residue. (7) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_1, Y_3 and AA_1
is the same as above. ) the N-terminal amino acid residue is α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue and is protected at both the N and C ends, the first step substance is an amino group-protecting agent and is in the acyl type, and the second α,β- according to claim 1, wherein the process material is an α-amino acid alkyl ester salt compound.
A method for producing a specific substance having a dehydro-α-amino acid residue. (8) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_2, Y_3 and AA_1
is the same as above. ) the N-terminal amino acid residue is α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue and is protected at both the N and C ends, the first step substance is an amino group-protecting agent and is of the urethane type, and the second The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the process material is an α-amino acid alkyl ester. (9) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_2, Y_3 and AA_1
is the same as above. ) the N-terminal amino acid residue is α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue and is protected at both the N and C ends, the first step substance is an amino group-protecting agent and is of the urethane type, and the second α, β according to claim 1, wherein the process material is an α-amino acid alkyl ester salt compound
- A method for producing a specific substance having a dehydro-α-amino acid residue. (10) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1 and R_2 are the same as above. . Y_1 is the same as above.)
When the terminal amino acid residue is an α,β-dehydro-α-amino acid residue, and the N and C ends are each protected, the first step substance is a dehydrodipeptide in which the α-amino group is protected with an acyl-type protecting group. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is a lower alkyl alcohol excluding a tertiary alkyl alcohol. . (11) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_3, Y_2 and AA_2
is the same as above. ) is the C-terminal amino acid residue α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue and the N-terminus is protected, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group,
α according to claim 1, wherein the second step substance is water
, a method for producing a specific substance having a β-dehydro-α-amino acid residue. (12) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_2, Y_1 and AA_2
is the same as above. ) is the C-terminal amino acid residue α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue with both N and C ends protected, the first step substance is an amino acid whose α-amino group is protected with a urethane-type protecting group, and the second 2. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the process material is a lower alkyl alcohol excluding tertiary alkyl alcohol. (13) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_2, Y_2 and AA_2
is the same as above. ) is the C-terminal amino acid residue α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue with a protected N-terminus, the first step substance is an amino acid whose α-amino group is protected with a urethane-type protecting group, and the second step substance is A method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, which is water. (14) The specific substance is the C-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_3 and Y_1 are the same as above. AA_3 represents an α-amino acid residue.) When the amino acid residue is an α,β-dehydro-α-amino acid residue and is a dehydrodipeptide protected at both the N and C ends, the first step substance is an N-protected-α-amino acid halide and α - The α,β-dehydro-α-amino acid residue according to claim 1, wherein the protecting group for the amino group is an acyl type, and the second step substance is a lower alkyl alcohol other than a tertiary alkyl alcohol. A manufacturing method for a specific substance that has (15) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_3, Y_2 and AA_3
is the same as above. ) is the C-terminal amino acid residue α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue with a protected N-terminus, the first step substance is an N-protected-α-amino acid halide and the protecting group for the α-amino group is an acyl type. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is water. (16) The specific substance has a general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, Y_1 and AA_3 are the same as above. X_4 represents a urethane type protecting group for the α-amino group.) When the C-terminal amino acid residue shown is an α,β-dehydro-α-amino acid residue, and both the N and C ends are protected dehydrodipeptides, the first step substance is N
-Protection-α-amino acid halide according to claim 1, wherein the protecting group for the α-amino group is a urethane type, and the second step substance is a lower alkyl alcohol other than a tertiary alkyl alcohol. , a method for producing a specific substance having a β-dehydro-α-amino acid residue. (17) The specific substance has a general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_4, Y_2 and AA_3
is the same as above. ) is the C-terminal amino acid residue α,
When the dehydrodipeptide is a β-dehydro-α-amino acid residue with a protected N-terminus, the first step substance is an N-protected-α-amino acid halide and the protecting group for the α-amino group is a urethane type. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is water. (18) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide protected at both the N and C ends, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is an α-amino acid alkyl ester. (19) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_3, Y_3, AA_1 and AA_2 are the same as above. When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide protected at both the N and C ends, the first step substance is an amino acid whose α-amino group is protected with an acyl-type protecting group. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is an α-amino acid alkyl ester salt compound. (20) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_2, Y_3, AA_1 and AA_2 are the same as above. When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide protected at both the N and C ends, the first step substance is an amino acid whose α-amino group is protected with a urethane-type protecting group. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is an α-amino acid alkyl ester. (21) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_2, Y_3, AA_1 and AA_2 are the same as above. When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide protected at both the N and C ends, the first step substance is an amino acid whose α-amino group is protected with a urethane-type protecting group. The method for producing a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the second step substance is an α-amino acid alkyl ester salt compound. (22) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_3, Y_3, AA_1 and AA_3 are the same as above.) When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide protected at both the N and C ends, the first step substance is an N-protected-α-amino acid halide, and the α- The α,β-dehydro-according to claim 1, wherein the protecting group for the amino group is an acyl type, and the second step substance is an α-amino acid alkyl ester.
A method for producing a specific substance having an α-amino acid residue. (23) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_3, Y_3, AA_1 and AA_3 are the same as above. When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide with both N and C ends protected, the first step substance is an N-protected-α-amino acid halide and an α-amino acid residue. Production of a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the protecting group is an acyl type, and the second step substance is an α-amino acid alkyl ester salt compound. Method. (24) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1, R_2, When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide with both N and C ends protected, the first step substance is an N-protected-α-amino acid halide and an α-amino acid residue. α,β-dehydro- as claimed in claim 1, wherein the protective group for the group is a urethane type, and the second step substance is an α-amino acid alkyl ester.
A method for producing a specific substance having an α-amino acid residue. (25) The specific substance is the second amino acid residue from the N-terminus represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, R_1, R_2, X_4, Y_3, AA_1 and AA_3 are the same as above.) When the group is an α,β-dehydro-α-amino acid residue and is a dehydrotripeptide with both N and C ends protected, the first step substance is an N-protected-α-amino acid halide and an α-amino acid residue. Production of a specific substance having an α,β-dehydro-α-amino acid residue according to claim 1, wherein the protecting group is a urethane type, and the second step substance is an α-amino acid alkyl ester salt compound. Method.