JPS63112565A - N-(n'-protecting-alpha-amino acid)-n-carboxy-alpha,beta-dehydro-alpha-amino acid anhydride, precursor thereof and production of said anhydride and precursor - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I [R1 and R2 are H, properly substituted carboxyl, (substituted)alkyl or (substituted)aryl with the proviso that R1 and R2 are not H at the same time; X1 is alpha-amino group-protecting group of acyl type or urethane type amino acid; AA is alpha-amino acid residue]. EXAMPLE:N-(N'-BOC-L-Alanyl)-N-carboxy-alpha,beta-dehydro-leucine anhydride. USE:A precursor useful for producing physiologically active peptide. PREPARATION:An N-Cbz-alpha,beta-dehydro-alpha-amino acid shown by formula II (Cbz is benzyloxycarbonyl) is reacted with a given acid halogenating agent in a solvent to give an N-carboxy-alpha,beta-dehydro-alpha-amino acid anhydride shown by formula III and the said compound is reacted with an amino acid containing an amino group protected with a given protecting group in a solvent by the use of both a condensation agent and a base to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION "Industrial Application Fields" The present invention provides N-(N".-
protection - α - amino acid) ~N ~ carboyacy α, β -
De11 Dro-α-amino acid anhydride and method for producing the same, and De11 Dro-α-amino acid anhydride and method for producing the same, and de-11 Dro-α-amino acid residue as a constituent element or precursor.
The biologically active peptide 21j or N'-protected-f
[Prior art] Concerning the production method of N-carbogic α, β-dehydro-α-amino acid anhydride and i useful for the production of hydroamino acid amino acids [Prior art] Precursor No. 14 Physiology 1: Beb f de (e.g. Te 1
Bumycin, Kabuj/Opuicin, Cephalosporin C
, homopsin, antrimycin, etc.) are known to have physiological activities such as antibacterial, tumorigenic, phytochemical, and enzyme inhibitory effects. This is because dedroamino acid residues or amino acid residues using them as precursors have a great influence on secondary and tertiary three-dimensional structures, and play an important role in maintaining the three-dimensional structure and expressing physiological activity. This is thought to be because it exhibits anti-proteolytic enzyme activity and plays an important role in improving the sustainability of its activity. Taking peptide-based physiologically active substances as an example, bradykinin, which has antihypertensive and intestinal contracting effects, exhibits an activity that is more than 20 times higher than its original antihypertensive effect when dehydroferalanine is introduced in place of the 5-position phenylalanine. It is known. (Reference; Y, Shimoh
igashi, and N, Izumiya,”T
he peptides, Vt+1. 5″,
ed Academic Press by
E.

Gross and J, Meienhofer,
1983).

Conventionally, there have been roughly two types of 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 them from peptides with leaving groups. For the former,
Examples include the azlactone method, the azide method, the mixed acid anhydride method, and the acid chloride method. However, each method has the following drawbacks: the φ azlactone method. The protection of the amino group of the α-dehydro amino acid and the α-dehydro amino acid residue are limited.

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

・High risk of side reactions in the mixed acid anhydride method. Therefore, the yield is poor, the reaction conditions for the acid chloride method are severe, and other amino acid residues are limited.

・It must have a leaving group by α-1β- or α,β-1 expression, or it must be synthesized using a dehydrogenating agent in the case of an amino acid with an aromatic substituent. Therefore, there are limits to the dehydroamino acid residues that can be produced.

As described above, the above manufacturing method has a problem in terms of weakness. 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 amino components, alcohols, amino acids with phenolic hydroxyl groups, acidic amino acids,
When an amino acid has a functional group in its side chain, such as an amino acid with a mercapto group, conventional production methods require a side chain protecting group. Furthermore, conventional production methods generally have problems in that the reaction conditions are harsh.

Next, methods for producing N-protected dehydroamino acid ester include a method by decomposition of dehydroazlactone,
-Method by desorption of substituent, α-keto acid ester and R-
There was a method by condensation with CONH2, and a method to protect the amide 7 group from a dehydroamino acid ester. However, each method had the following drawbacks.

・Method by decomposition of dehydroazlactone The protecting group at the N-position is limited, and the protecting group is difficult to deprotect and is not weak.

・Method by elimination of β-substituent Depending on the necessity of having or introducing a leaving group at the β-position and the conditions, there are limitations on the protecting groups for amino groups and carboxylic acids. be. -No weaknesses.

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

As described above, all of the above three methods lacked generality and had poor yields.

Method for protecting amino groups from Φ dehydro amino acid esters The nucleophilicity of amino groups decreases due to the influence of double bonds, 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 generality and poor yield.

[Problems to be Solved by the Invention] The present invention solves the above-mentioned drawbacks, and provides for the production of peptides or N-protected dehydroamino acid esters containing dehydroamino acid residues as constituents or precursors. N-(N”-protected-α-aminated-N-
To provide carboxy-α,β-dehydro-α-amino acid anhydride, N-carpoxy α,β-dehydro-α-amino acid anhydride, and a method for producing the above-mentioned substances in high yield etc. purpose.

[Means for Solving the Problems] In order to achieve the above object, the present invention provides the following features: represents the same or different substituents consisting of a group.However, R1 and R2 are not hydrogen atoms at the same time.XI is an α-
The protecting group for the amino group, AA, represents an α-amino acid residue.

) denoted by N-(N'-protected-α-amino wholesale-N-
A carboxy alpha, beta-dehydro-alpha-amino acid anhydride is provided. In particular, in this substance, R1 is a hydrogen atom,
R2 is an inpropyl group, Xl is a t-butoxylcarbonyl group, AA is an L-alanine residue, R1 is a hydrogen atom, R2 is an isopropyl group,
Xl is a t-butoxyl carbonyl group, AA is a glycine residue, R1 is a hydrogen atom, R2 is an isopropyl group,
Xl is t-butoxylcarbonyl group, AA is L-
It is a leucine residue, R1 is a hydrogen atom, R2 is an inpropyl group,
Xl is t-butoxyl carbonyl group, AA is L
7x =) Lyau = 6 points, where R1 is a hydrogen atom, R2 is a phenyl group, and Xl is t-
is a butoxyl carbonyl group, AA is an L-leucine residue, R1 is a hydrogen atom, R2 is a phenyl group, XI
is t-butoxylcarbonyl A is an L-phenylalanine residue, R1 is a hydrogen atom, R2 is a phenyl group, Xl is a t-butoxylcarbonyl group, and AA is an L-proline residue. It has certain characteristics.

The present invention also provides a method for producing the above substance, that is, an N-carboxy-α,β-dehydro-α-amino acid anhydride and an α-amino acid (X2
AAOH) (X2 represents a protecting group for the α-amino group of a urethane-type or alkyl-type amino acid. AA is the same as above) in a predetermined solvent using a predetermined condensing agent and a predetermined base. , N-(N”-protected-α-amino acid)
A method for producing -N-carboxy-α,β-dehydro-α-amino acid anhydride is provided. The manufacturing method is particularly
It is characterized in that the protecting group for the α-amino acid is a t-butoxycarbonyl group, that the predetermined base is pyridine, and that the predetermined base is N-methyl-morpholine.

The present invention also provides another method for producing the above-mentioned substance, namely, N-carboxy-α,β-dehydro-α-amino acid anhydride and α-amino acid (X3 AAOH ) (X3 represents an acyl type or urethane type protecting group that is stable under relatively acidic conditions) is converted into a predetermined halide by a conventional method to produce an N-protected α-amino acid halide (X3AAZ: Z represents a halide). ) in a predetermined solvent in the presence of a predetermined base to form N-(N'-
Provided is a method for producing protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride.

Furthermore, in order to achieve the above object, the present invention provides N-carboxy-α, β-dehydro α-
Provide amino acid anhydride. This substance is unique in that both R1 and R2 are alkyl groups, R1 is a methyl group, and R2
is an ethyl group, R and R2 are both methyl groups, R1 is a hydrogen atom and R2 is the above substituent other than a hydrogen atom, and <R2 is a phenyl group, The same <R2 is an isopropyl group, the same <R2
is a normal propyl group, the same R2 is an ethyl group, the same <R2 is a methyl group, the same <R2
is a para-hydroxyphenyl group, the same <R2 is a para-methoxyphenyl group, and the same <R2 is a para-methoxymethoxyphenyl group.

The present invention also provides a method for producing the above-mentioned substance, that is, N-Cbz-α represented by the general formula % (wherein R,, R2 are the same as above; Cbz represents a benzyloxycarbonyl group), A method for producing an N-carboxy-α, β-dehydro α-amino acid anhydride is provided by reacting a β-dehydro α-amino acid with a predetermined acid halogenating agent in a predetermined solvent. The production method is particularly advantageous in that the predetermined acid halogenating agent is thionyl chloride, that the predetermined solvent is acetyl chloride, and that N-Cbz-α
, R1 of β-dehydro α-amino acid is a hydrogen atom, R2
When is a para-methoxymethoxy-phenyl group, the predetermined solvent is an ether and the ether is diethyl ether.

[Effects of the invention] 1. Regarding membrane properties α,β dehydro The 7-mino group of the α-amino acid takes on a conjugate property with the double bond moiety, so the nucleophilicity of the amino group decreases and the N-protected Conventionally, reactivity with α-amino acids and N-protecting agents has been extremely low.

However, the N-carboxy-α,β-dehydro-α-amino acid anhydride and N-(N′-protected-α
-amino acid) -N-carboxy-α, β-dehydro α
-According to amino acid anhydrides, by adopting the N-carboxy-α,β-dehydro-amino acid anhydride structure, nucleophilicity is improved and it reacts with N-protected-α-amino acids and N-protecting agents. be able to.

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 amino component and carboxy component was easier to control.

Therefore, reactions with various amino acids, alcohols, etc. are facilitated, and dehydroamino acid residues can be freely introduced into the peptide chain.

2. Regarding the yield of N-(N'-protected-α-amino acid)- according to the present invention
Peptides and N-protected dehydroamino acid esters containing dehydroamino acid residues using N-carboxy-α,β-dehydro-α-amino acid anhydride or N-carboxy-α,β-dehydro-α-amino acid anhydride As is clear from the above, the yield was significantly improved compared to the conventional production method.

In addition, in the production itself of N-(N'-protected-α-amino7-N-rupoxy α,β-dehydro-α-amino acid anhydride and N-carboxy-α,β-dehydro-α-amino acid anhydride) Also, according to the method invented by Hato, the desired product can be obtained in high yield.

3. Regarding optical activity, N-(N'-protected-α-amino m)- according to the present invention
If the desired product is synthesized using N-carboxy-α, β-dehydro α-amino acid anhydride and N-carboxy-α, β-dehydro α-amino acid anhydride, the reaction conditions are mild; α, β-dehydro α
- Due to the unique reaction mechanism of 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 ogisazolone. Therefore, there is an effect that there is almost no adverse effect on optically active amino acids.

4. Regarding simplicity, N-(N'-protected-α-amino#)- according to the present invention
Peptides and N-protected dehydroamino acid esters containing dehydroamino acid residues using N-carboxy-α,β-dehydro-α-amino acid anhydride or N-carboxy-α,β-dehydro-α-amino acid anhydride , it is possible to freely introduce dehydroamino acid residues and to produce amino acids of various components using only one reaction system. In addition, the effect of not being complicated to operate is 7.
be.

Regarding amino acids to be reacted as amino components, even amino acids with functional groups in their side chains, such as alcohols, amino acids with phenolic hydroxyl groups, acidic amino acids, and amino acids with mercapto groups, are not necessary in conventional peptide synthesis. There is no problem even if the side chain protecting group is unprotected, and the effect is that steps such as protecting the side chain and cutting off the protecting group can be omitted.

Next, in the production of N-(N'-protected-α-amino-N-carboxy-α,β-dehydro-α-amino acid anhydride and N-carboxy-α,β-dehydro-α-amino acid anhydride itself) According to the method of the present invention, the desired object can be obtained without requiring complicated operations.

5. Regarding reaction conditions, N-(N'-protected-α-amino acid)- according to the present invention
N-protected peptides and N-protected dehydro-amino acid residues are prepared using N-protected amino acid anhydrides or N-carboxy-α,β-dehydro-α-amino acid anhydrides. If amino acid esters are produced, the reaction conditions can be kept at room temperature and pressure, which is advantageous in that it is mild. Excessive cooling is not required even if cooling is required.

N-(N'-protected-α-amino-resistant Q-N-carboxy-
Also in the production of α,β-dehydro α-amino acid anhydride and N-carboxy-α,β-dehydro α-amino acid anhydride, the method of the present invention has the advantage that the reaction conditions are mild. In this case too, even if cooling is required, excessive cooling is not required.

8. Safety According to the method of the present invention, N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro α-amino acid anhydride and N-carboxy-α,β-dehydro- α−
Since phosgene is not used in the production of amino acid anhydride itself, it has the effect of being highly safe.

(Space below) [Detailed Description of the Invention] QN-(N'-protected-α-amino-resistant 2)-N-carboxy-α,β-dehydro α-amino acid anhydride represented by the general formula N-( N'-protected-α-amino-N-carboxy-α,β-dehydro-α-amino acid anhydride is
Manufactured by the following method. That is, N-carboxy-α, β-dehydro α- represented by the general formula
An amino acid anhydride and an α-amino acid having a specified amino protecting group are mixed in a specified solvent at a temperature below about 25°C, preferably around 0°C. If the temperature is too high, a side reaction will occur, and if it is too low, the reaction rate will be reduced. falls. ) Add about 1 equivalent of a specified condensing agent, and add the appropriate amount of time from several tens of minutes to several hours in the presence of a specified base.
React at the same temperature, and then at room temperature for an appropriate period of time from about 1 hour to several tens of hours (the reaction time may be longer if the temperature is low).
The desired N-(N'-protected-
α-Amino resistant 2)-N-carboxy-α, β-dehydro α-amino acid mA product is obtained.

B. In the above structural formula, each of R and R2 is selected from the substituents shown below.

Hydrogen atom, substituted carboxyl group; carboxyl group substituted with an alkyl group such as a methyl group, ethyl group, benzyl group, etc.

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

Substituted alkyl group; - Benzyloxycarbonyl group (Cbz group, hereinafter),
An amino group appropriately substituted with a t-butoxycarbonyl group (BOC group, hereinafter referred to as the following), an alkyl group substituted with an alkylmercapto group, or the like.

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.

As a combination of substituents R1 and R2, when R1 is a hydrogen atom, R2 is an isopropyl group, Xl is a t-butoxylcarbonyl group, and AA is an L-alanine residue, R1 is a hydrogen atom. , R2 is an isopropyl group, xI is a 1-butoxylcarbonyl group, and A
When A is a glycine residue, R is a hydrogen atom,
When R2 is an isopropyl group, xl is a t-butoxyl carbonyl group, and AA is an L-leucine residue, R is a hydrogen atom, R2 is an isopropyl group, and xl is a t-butoxyl group. is a carbonyl group, and AA is L
- When it is a phenylalanine residue, R1 is a hydrogen atom, R2 is a phenyl group, Xl is a t-butoxylcarbonyl group, and when AA is an L-leucine residue, R1 is a hydrogen atom; , R2 is a phenyl group,
X! is a t-butoxylcarbonyl group, and AA is L-
Usually, it is a phenylalanine residue, or R1 is a hydrogen atom, R2 is a phenyl group, xl is a t-butoxylcarbonyl group, and AA is an L-broline residue. However, it may be a geometric isomer that constitutes R1 and R2.

In the above structural formula, AA represents an α-amino acid residue.

C. In the above structural formula, xl is a protecting group for the amino group of an amino acid, as shown below.

Acyl-type niacetyl group, trifluoroacetyl group, phthalyl group, etc.

Urethane type; Cbz group, BOC group, etc.

Alkyl type nitrityl group etc.

In the same manufacturing method, B. The prescribed solvent consists of the following substances.

Examples of aprotic solvents include halogenated hydrocarbons such as dichloromethane and chloroform.

Ether Nidiethyl ether, Tetrahydrofuran (
THF), dioxane, etc.

Ketones: acetone, methyl ethyl ketone, etc.

Ester type; ethyl acetate, etc.

Nitrogen compound type; acetonitrile, dimethylformamide (DMF), etc.

Sulfur compound type; dimethyl sulfoxide (DMSO), etc.

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

Hydrocarbons; benzene, toluene, etc.

Protic solvent systems; tertiary-butanol (t-butanol), etc.

The above solvents can be used alone or in combination of two or more. Preferred is dichloromethane or THF.

The predetermined amino protecting group consists of the following substances.

Urethane type; Cbz group, BOC group, etc.

Alkyl type; trityl group, etc.

C. The predetermined condensing agent is a carbodiimide type condensing agent, dicyclohexylcarbodiimide (D, C0C0),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (7), S, C,) or its hydrochloride (W, S
, C, HCl), etc.

2. The predetermined base is a tertiary amino compound such as pyridine or N-methylmorpholine (NMM), or one containing the above-mentioned tertiary amino compound as a main component.

Further, the N-(N'-protected-α-amy4-aryN-poloxy α,β-dehydro-α-amino acid anhydride can also be produced by the following method.

That is, the N-protected N-carboxy-α,β-dehydro α-amino acid anhydride and the α-amino acid having a predetermined 7-mino protecting group were converted into a predetermined halide by a conventional method.
Amino acid and halide are mixed in a predetermined solvent in the presence of a predetermined base, initially in a cooled state, and then at room temperature for several tens of minutes to several yr.
++h for an appropriate time, appropriate treatment, if necessary,
Purification is performed to obtain the desired N-(N'-protected-α-amino4
Button-N-poxy α,β-dehydro-α-amino acid anhydride is obtained.

In the same manufacturing method, B. The prescribed solvent consists of the following substances.

Examples of aprotic solvents include halogenated hydrocarbons such as dichloromethane and chloroform.

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 type; dimethyl sulfoxide (DMSO), etc.

Phosphorus compound system: Hexamethyl phosphate triamide (HMP
A) etc.

Hydrocarbons; benzene, toluene, etc.

Protic solvent systems; tertiary-butanol (t-butanol), etc.

The above solvents can be used alone or in combination of two or more. Preferably it is THF.

The predetermined base consists of the following substances.

Secondary amino compounds didiethylamino, dicyclohexylamino, etc.

Tertiary amino compounds: pyridine, N, M, M, ethylamino, etc.

It is possible to use the above-mentioned compounds alone or in combination of two or more types, or to use them as the main component. Preferably it is triethylamino.

C. The predetermined amino protecting group is a protecting group that is stable under relatively acidic conditions and consists of the following substances.

Acyl-type niacetyl group, trifluoroacetyl group, phthalyl group, etc.

Urethane type; Cbz group, etc.

2. The predetermined halides are those in which the carboxyl group of an amino acid is converted into an acid halide compound such as chloro, bromine, or iodo.

Next, specific effects of the N-(N"-protected-α-amino(2)-N-carboxy-α,β-dehydro α-amino acid anhydride) will be explained.

R, is a hydrogen atom, R2 is an isopropyl group,
xl is t-butoxylcarbonyl group, AA is L-
If it is an alanine residue, it becomes N-(N'-BOC-L-alanyl)-N-carboxy-α,β-dehydroleucine anhydride. Since R1 is a hydrogen atom and R2 is an isopropyl group, this substance cannot become a vinyl group and is stable without polymerization. Therefore, L-alanyl-α, β
-High yield of peptides with dehydroleucine skeleton,
It is easy to operate, requires mild reaction conditions, and has very little adverse effect on optically active amino acids, making it a good precursor for synthesis. The encroaching reduction method normally used for deprotection during peptide synthesis cannot be used because the dehydro moiety is also reduced.

However, if this substance is used, the N-terminus of the peptide becomes BO
Since it is a C group, it can be removed under relatively mild and deleterious conditions without adversely affecting the dehydro structure, and the peptide chain can also be elongated.

R1 is a hydrogen atom, R2 is an isopropyl group,
If xl is a t-butoxylcarbonyl group and AA is a glycine residue, then N-(N''-BOC-L-alanyl)-N-carboxy-α.

Becomes β-dehydro-leucine anhydride. The effects of this substance are the same as above.

R1 is a hydrogen atom, R2 is an isopropyl group,
Xl is t-butoxylcarbonyl group, AA is L-
If it is a leucine residue, it becomes N-(N'-BOC-L-leucyl)-N-carboxy-α,β-dehydroleucine anhydride. The effects of this substance are the same as above.

R1 is a hydrogen atom, R2 is an isopropyl group,
Xl is t-butoxylcarbonyl group, AA is L-
If it is a phenylalanine residue, N-(N'-BOC
-L-phenylalanyl)-N-lupoxy α,β-
It becomes dehydroleucine anhydride. The effects of this substance are the same as above.

R1 is a hydrogen atom, R2 is a phenyl group, xl
If is a t-butoxylcarbonyl group and AA is an L-leucine residue, then N-(N'-BOC-L-leucyl)-N-carboxy-α.

Becomes β-dehydro-phenylalanine anhydride.

The effects of this substance are the same as above.

R1 is a hydrogen atom, R2 is a phenyl group, and Xl
is a t-butoxylcarbonyl group and AA is an L-phenylalanine residue, then N-(N'-BOC-L-
phenylalanyl)-α.

Becomes β-dehydro-phenylalanine anhydride.

The effects of this substance are the same as above.

R1 is a hydrogen atom, R2 is a phenyl group, and XI
is a t-butoxylcarbonyl group and AA is an L-proline residue, then N-(N'-BOC-L-prolyl)-N-carboxy-α.

Becomes β-dehydro-phenylalanine anhydride.

The effects of this substance are the same as above.

Regarding the method for producing N-(N'-protected-α-amino acid)-N-carpoxy α,β-dehydro α-amino acid anhydride, the protecting group of the α-amino acid whose amino group is protected with a predetermined protecting group is t. -Butoxycarbonyl group has the following effects. That is, the catalytic reduction method conventionally used for deprotection during peptide synthesis cannot be used because the dehydro moiety is also reduced. However, B in the method of the present invention
By using an OC group, it can be removed under relatively mild and rapid conditions without adversely affecting the dehydro moiety, and the subsequent elongation of the peptide chain can be made even better.

Further, by using pyridine or N-methyl-morpholine as the predetermined base, side reactions can be suppressed and the yield can be further improved.

(Left below) QN-carboxy-α, β-dehydro-α- represented by the general formula for QN-carboxy-α, β-dehydro-α-amino acid anhydride
Amino acid anhydride is produced by the following method. That is, the general formula % formula % (wherein Cbz represents a benzyloxycarbonyl group.

) The N-Cbz-α, β-dehydro α-amino acid represented by is reacted with a predetermined acid halogenating agent in a predetermined solvent at an appropriate temperature around room temperature for an appropriate time period of several minutes to several io hours. The liquid is subjected to treatments such as concentration and, if necessary, purification such as recrystallization to obtain the desired N-carboxy-α, β-dehydro α-amino acid compound.

Regarding the substituents constituting R,,R2 in the above structural formula and their combinations, the above-mentioned N-(N”-protected-α-amino acid)
-N-carboxy-α,β-dehydroα-amino acid anhydride. However, in this case, regarding the combination of R, The substituents are not necessarily the same. For example, when R1 of the N-Cbz-α,β-dehydro α-amino acid is a hydrogen atom and R2 is a para-methoxymethoxyphenyl group, when diethyl ether is used as a solvent, N-carboxy-α,β-dehydro α−
R1 of the amino acid anhydride is a hydrogen atom, while R2 is a para-methoxymethoxyphenyl group. However, when acetyl chloride, dichloromethane, etc. are used as a solvent, N-
R of the carboxy-α,β-dehydro-α-amino acid anhydride is a hydrogen atom, but R2 is a parahydroxyphenyl group.

In the same manufacturing method, B. The prescribed solvent consists of the following substances.

Examples of aprotic solvents include halogenated hydrocarbons such as dichloromethane and chloroform.

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.

Other solvent systems; thionyl chloride, acetyl chloride, etc.

The above solvents can be used alone or in combination of two or more. Preferred are acetyl chloride and chloroform.

Predetermined acid halogenating agents include thionyl chloride, phosphorus pentachloride, phosphorus trichloride, and the like. Preferably, thionyl chloride is used, and the amount used is 1 equivalent or more, preferably about 3 to 6 equivalents.

Next, the specific effects of N-carboxy-α, β-dehydro α-amino acid anhydride will be explained.

If R1 and R2 are both alkyl groups, they can become vinyl groups and are stable. Therefore, α.

It becomes possible to more advantageously induce the synthesis of peptides having β-dehydro-α-amino acid derivatives and α, β-dehydro-α-α-amino acid residues in their skeletons.

Similarly, if R1 is a methyl group and R2 is an ethyl group, α
, β-dehydro-isoleucine derivatives and peptides having α,β-dehydro-isoleucine residues in their backbones can be more advantageously induced.

Similarly, if R 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 R1 is a hydrogen atom and R2 is the above-mentioned substituent other than a hydrogen atom, the synthesis of α,β-dehydroα-amino acid derivatives and peptides having α,β-dehydroα-amino acid residues in their backbones can be further facilitated. This makes it possible to guide them advantageously.

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

Similarly, if R is a hydrogen atom and R2 is an isopropyl group, the synthesis of α,β-dehydroleucine derivatives and peptides having α,β-dehydroleucine residues in their backbones can be more advantageously induced. It becomes possible.

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

Similarly, if R1 is a hydrogen atom and R2 is an ethyl group, then α
, β-dehydronormalvaline derivatives, and peptides having α,β-dehydronormalvaline residues can be more advantageously synthesized.

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-dehydrotyrosine derivatives and peptides having α,β-dehydrotyrosine residues in the skeleton can be more advantageously induced. It becomes possible to do so.

Furthermore, if R2 is a hydrogen atom and R2 is a methoxyphenyl 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, β-
It becomes possible to more advantageously induce the synthesis of dehydro 〇-methyl-tyrosine derivatives and peptides having α,β-dehydro 〇-methyl-tyrosine residues in their skeletons.

Similarly, if R1 is a hydrogen atom and R2 is a para-methoxymethoxyphenyl group, α,β-dehydro〇-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.

Regarding the method for producing N-carboxy-α,β-dehydro α-amino acid anhydride, if thionyl chloride is used as the predetermined acid halogenating agent, the post-treatment becomes easier.

In addition, if acetyl chloride is used as the specified solvent, it has a high ability to dissolve the raw material N-Cbz-α, β-dehydro α-amino acid, so the yield can be further improved and the reaction time can be shortened. It's simple.

Furthermore, when R1 of the N-Cbz-α, β-dehydro α-amino acid is a hydrogen atom and R2 is a para-methoxymethoxy-phenyl group, if the predetermined solvent is an ether, convenience is further improved. In other words, the O-methoxymethyl group can be eliminated even under relatively mild acidic conditions, but by using ether as a solvent, the ether acts as a Lewis base and removes excess protons, so it cannot be eliminated. . Therefore, when the next reaction requires protection of the hydroxyl group, a compound in which the hydroxyl group is protected with a methoxymethyl group can be directly used.

Therefore, there is no need to protect it again, making the operation even simpler. When diethyl ether is used as the ether, the above effects are further improved.

(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.

The melting point is Yat (Model Mp-21) micr.
o melting-point appatatus
is used and is uncorrected. IR is Hitachi, Ltd. E
PI-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
, 5 dm tube JASCO DIP-4 was used. The packing material for column chromatography is Kiesel-gel.
60 (manufactured by Merck & Co., Ltd., Art, 7734) was used.

<Example 1> Synthesis of N-(N'-BOC-L-alanyl)-N-carboxy-α,β-dehydroleucine anhydride (BOC-alanyl-Δ-leucine NCA) 0C-L-alanine l , 33 g (7,04 mmo 1) (7) The THF solution was cooled to -io °C and DCCI + 58 g (7
, 68 mmol) and stirred at the same temperature for 20 minutes.
Carboxy-α,β-dehydroleucine anhydride (Δ-
Add 1 g (6,40 mmol) of Leucine NCA). In addition, 2.02 g of pyridine (25.6 mmo
After adding 1) and stirring at the same temperature for 1 hour, the reaction solution was concentrated under reduced pressure. After adding 30 ml of ethyl acetate and stirring for 30 minutes while cooling, insoluble materials were filtered off. Add 300 ml of ethyl acetate to the filtrate.
Add m1, wash with 10% citric acid aqueous solution, and dry with anhydrous sodium sulfate. After filtering off the desiccant, reduce pressure CwI
I. Purify the residue with a silica gel column (chloroform:acetone = 4:IV/V) to obtain the desired BO as a colorless oil.
C-alanyl-Δ-leucine NCA was obtained in a yield of 89% of theory.

The physical properties of this substance are as follows.

I R (KB r , cm-1): 1812 (0
-C=O) 1707.1518 (NHCO) 'H-NMR (δ, CDC13): 4.67 (dt, NHCHCO) 6.51 (d, R-C■=, J=10Hz) [α]D(
C=l, THF)=-35,6@Elemental analysis value: C+5H
22N20s Calculated value (%); C55, 20H8, 80N 8.
58 Actual value (%); C55,1? H8,78N
From 8.57 onwards, almost the same operation was performed by changing the Cbz-Δ-amino acid and N-protected-amino acid as the raw materials. The results are shown in Examples 2 to 7.

<Example 2> N-(N”-BOC-glycyl)-N-carboxy-α
, β-dehydroleucine anhydride (BOC-glycyl-
Synthesis of Δ-leucine NCA) OC-glycyl-Δ-leucine NCA is a combination of BoC-glycine and Δ-leucine
Obtained from A as a colorless oil in a yield of 86% of theory.

The physical properties of this substance are as follows.

I R (KB r , cm'): i a 15 (0-C=0) 1716.1515 (NHCO) IH-NMR (δ, CDC13): 4.45 (m, NHCHCO) 6.68 (d, R -C■=, J=10Hz) Elemental analysis value: Cl4H2・N20G Calculated value (%); C53,84H8,45N 8.
97 Actual value (%); C53,80H8,46N 8
-92 <Example 3> Synthesis of N-(N'-BOC-L-leucyl)-N-carboxy-α,β-dehydroleucine anhydride (BOC-leucyl-Δ-leucine NCA) OC-leucyl-
Δ-Leucine NCA was obtained as a colorless oil from BQC-L-leucine and Δ-Leucine NCA in a yield of 92% of the theoretical amount.The physical properties of this substance are as follows.

I R (KB r , cm-1): 1812 (0
-C=O) 1716 (NHCO) IH-NMR (δ, CDCl:l): 4.71 (m, NHCHCO) 6.50 (d, R-CH=, J=10Hz) [α1 name 5 (C= 1, THF) = -30, 4'' Elemental analysis value: Cl8H211N206 Calculated value (%); C58,88H7,88N 7JO
Actual value (%); C5B, 62 H7, 83N 7.
57 <Example 4>N-(N"-BOC-L-phenylalanyl)-N-carboxy-α,β-dehydroleucine anhydride (BOC
Synthesis of -phenylalanyl-Δ-leucine NCA) OC-phenylalanyl-Δ-leucine NCA is B
Obtained as a colorless oil from OC-L-phenylalanine and Δ-leucine NCA in a yield of 91% of theory.

The physical properties of this substance are as follows.

IR (KBr, cm″″1): 1809 (0-C=O) 1713, 1503 (NHCO) 'H-NMR (δ, CDC13): 4.75 (m, NHCHCO) 6.40 (d, R- CH=, J=10H2) [α]2
5 (Cm 1 , THF) = -37, 8° Elemental analysis value: C2IH2G N206 calculated value (%); C82
,87H8,51N 8.98 Actual value (%): C8
2,64H8,48N B,94 <Example 5>N-(N'-BOC-L-leucyl)-N-carboxy-α,β-dehydrophenylalanine woodless material (BOC
Synthesis of -Leucyl-Δ-phenylalanine NCA) C>C-Leucyl-Δ-phenylalanine NCA is
It was obtained from BOC-L-leucine and Δ-phenylalanine NCA in a yield of 81% of theory.

The physical properties of this substance are as follows.

Melting point ("C): 126-128 IR (KB r , Cm'): 1806 (0-Cm0) 1683.1515 (NHCO) lH-NMR (δ, CDC13): 4.76 (m, NHCHCO) 7. 11 (s, R-C■=) [α] (Cm1.THF)=-45,5" Elemental analysis value: 2002 summer H2G N20G calculated value (%); C62,87H8,51N 8.
96 Actual value (%); C82,81H8,53N
B, 94 <Example 6>N-(N'-BOC-L-phenylalanyl)-N
- Synthesis of carboxy-α,β-dehydrophenylalanine anhydride (BOC-phenylalanyl-Δ-phenylalanine NCA) OC-phenylalanyl-Δ-phenylalanine NC
A was obtained from BOC-L-phenylalanine and Δ-phenylalanine NCA in a yield of 85% of theory.

The physical properties of this substance are as follows.

Melting point (°C): 128-130 IR (KB r , cm'): 1830 (0-CmO) 1695.1524 (NHCO) IH-NMR (δ, CDC13): 4.80 (m, NHCHCO) 7 , 29 (s, R-CH=) [α] (Cm1.THF)=-55,7" Elemental analysis value: C24H24N206 Calculated value (%); C6B, 04 H5,54N 8
．． 42 Actual value (%); C3LOOH5,51N 8
．． 41 <Example 7>N-(N'-BOC-L-prolyl)-N-poxy α,β-dehydrophenylalanine fi hydrate (B
Synthesis of OC-prolyl-Δ-phenylalanine NCA) OC-prolyl-Δ-phenylalanine NCA is
Obtained as a colorless oil from OC-L-7'loline and Δ-phenylalanine NCA in a yield of 80% of theory.

The physical properties of this substance are as follows.

I R (KB r , cm'): 1803 (0-CmO) 1701.1551 (NHCO) 'H-NMR (δ, CDC13): 5.12 (m, NHCHCO) 7 , 12 (S , R-CH= ) [α]D(C=1.THF)=25.5' Elemental analysis value:
C2e H22N20 & calculated value (%): C82,
18H5,74N 7.25 Actual value (%); C8
1,97H5,78N 7.21 (blank below) <Example 8> N-carboxy-α,β-dehydroisoleucine anhydride (Δ-isoleucine NCA, hereinafter [N-Cbz-α in 3 ml of synthetic acetyl chloride) .

To a solution containing 5.27 g (20 mmol) of β-dehydro-isoleucine (Cbz-Δ-isoleucine), 14.28 g (120 mmol) of thionyl chloride is added, and the mixture is stirred at room temperature for 2 hours.

Thereafter, the mixture was concentrated under reduced pressure, 30 ml of carbon tetrachloride was added, and the concentration was repeated three times. The theoretical amount of Δ-isoleucine NCA was obtained by recrystallizing the residue from cyclohexane.
Obtained as 1'af crystals with a yield of 5%. this is,
Contains E-coordination and Z-coordination at a ratio of 3:2,
The physical properties of this substance, which has a melting point of 69 to 101°C and from which E coordination can be extracted by repeated recrystallization, are as follows.

Melting point ("C): 122-123 I R (KB r , cm'): 3200 (NH) 1820.1780 (0-C=C) 'H-NMR (δ, DMSO-d6): E coordination; 1
．． 96 (s, 3H, CH3) 2.70 (q, 2H.

J=7.0Hz.

CH3CH2-) 9.44 (S, IH, NH-) Z coordination; 2, 24 (s, 3H, CH3)2
．． 26 (q, 2H.

J=7.0Hz.

CH3CH2-) 9.44 (s, IH, NH-) Elemental analysis value: C7H, NO3, calculated value (%); C54,19H5,85N 9.
03 Actual value (%); C54,21H5,88N 9
-07 and below, the same operations were carried out by changing the Cbz-Δ-amino acid used as the raw material. The results are shown in Example 9.
This is shown in Example 17.

<Example 9> N-carboxy-α,β-dehydrovaline anhydride (Δ
-Synthesis of Δ-valine NCA) N-Cbz-α,β-dehydro-
The physical properties of this substance obtained as colorless needle crystals from valine (Cbz-Δ-valine) in a yield of 92% of the theoretical amount are as follows.

Melting point (℃): 145-146 IR (KBr, cm'''1): 3200 (NH) 1820.1770 (0 (CO)2) 1680 (C=
C) IH-NMR (δ, CDC13): 1.92, 2.16 (s, CH3-) 11.0 (s,
NH) Elemental analysis value: c,, H7NO3 Calculated value (%); C51,08H5,00N 9.9
3 Actual value (%); C50,94HC97N 9.9
1 <Example 10> Synthesis of N-carboxy-α,β-dehydrophenylalanine anhydride (Δ-phenylalanine NCA)
Obtained from dehydro-phenylalanine (Cbz-Δ-phenylalanine) as colorless needle-like crystals in a yield of 93% of theory.

The physical properties of this substance are as follows.

Melting point ('0): 230-232 IR (KB r , cm'): 3200 (NH
) 1820.1750 (0(Go)2) 1660(C=
C) 'H-NMR (δ, CDC13): 6, 66 (s, R-C)! =)7.38~7.
76 (m, R-CH=)11.62 (s, NH) Elemental analysis value: C+ IH7NO:1 Calculated value (%); C63,49H3,73N 7.
41 Actual value (%); CEf3.51 H3,70N
7.40 Example 11 N-carboxy-α,β-dehydroleucine anhydride (
Synthesis of Δ-Leucine NCA) Δ-Leucine NcA is synthesized from N-CbZ-a, β-dehydro-
94% of the theoretical amount from leucine (Cbz-Δ-leucine)
It was obtained as colorless needle crystals in a yield of .

The physical properties of this substance are as follows.

Melting point (°C): 91-92 I R (KB r , Cm'): 3240 (NH) 1830.1770 (0 (Go) 2) 1680 (C =
C) IH-NMR (δ, CDC13): 5.74 (d, R-CH=, J=lOHz)2,7
0 (m, R-CH=) 11, 26 (s, NH) Elemental analysis value: C7H9NO3 Calculated value (%); C54,19H5,85N 9.
03 Actual measurement value (%): C54,00H5,82N 9.
00 Example 12 Synthesis of N-carboxy-α,β-dehydronormalleucine anhydride (Δ-n-leucine NCA) Δ-n-leucine NCA is N-Cbz-a.

β-dehydro-normal-leucine (Cb z-Δ-n
-Leucine) in a yield of 93% of theory as colorless needle-shaped crystals.

The physical properties of this substance are as follows.

Melting point ('C): 116-117 IR (KB r , cm'): 3210 (NH) 1830.1770 (0 (Co)2) 1690 (C=
C) 'H-NMR (δ, CDC13): 5.82 (t, R-CH=, J=8Hz)2,2
3 ((1, R-CH=) 11.24 (s, NH) Elemental analysis value: C7H, NO3 Calculated value (%); C54,19H5,85N 9.
03 actual value (%): C54, 12H5-88N 8.
99 <Example 13> Synthesis of N-carboxy-α,β-dehydronormal valine anhydride (Δ-n-valine NCA) From luvaline (Cb z-Δ-n-valine) the theoretical amount of 90
% yield as colorless needle crystals.

The physical properties of this substance are as follows.

Melting point ('O): 97-98 I R (KB r , cm'): 3210 (NH) 1820.1780 (0 (Co)2) 1690 (C=
C) 'H-NMR (δ, CDC13): 5.28 (t, R-CH=, J=8Hz) 2.24
(quintet, R-CH=)11.40 (s
, NH) Elemental analysis value: c6H7NO3 Calculated value (%); C51,08H5,00N 9.9
3 Actual value (%); C51,00HC97N 9.9
0 <Example 14> N-carboxy-α-amino-α-butenoic anhydride (α
-Synthesis of amino-α-butenoic acid (NCA) α-amino-α
-Butenoic acid NCA was obtained as colorless needle crystals from Cbz-α-amino-α-butene in a yield of 95% of theory.

The physical properties of this substance are as follows.

Melting point ("C): 136-138 IR (KB r , cm-1): 3150 (NH
) 1820.1780 (0(Co)2) 1695(C=
C) 'H-NMR (δ, CDC13): 5.80 (ci, R-CH=, J=7.5Hz)1.
82 (d, Dan-CH=) 11, 20 (s, NH) Elemental analysis value: Cs N5 NO3 Calculated value (%); C47,25H3,97N11.0
2 Actual measurement value (%); C47, 19H3, 95N11
．． 08 <Example 15> N-carboxy-α,β-dehydrotyrosine anhydride (
Synthesis of Δ-tyrosine NCA)
-α,β-dehydro-tyrosine (cb2-Δ-tyrosine) was obtained with a yield of 86% of the theoretical amount, and N-Cbz-
0-methoxymethyl-α,β-dehydro-tyrosine (C
bz-0-methoxymethyl-Δ-tyrosine) in a yield of 85% of the theoretical amount.

The physical properties of this substance are as follows.

Melting point (°C): 196 (decomposed) I R (KB r , cm'): 1765 (C=C) 1662 (C=C)' H-NMR (δ, DMSO-d6): 3, 59 (
s, R-CH=) 10.05, 11.30 (bs, NH) elemental analysis value:
C, @H, NO4 Calculated value (%); C58,54H3,44N 8.
83 actual value (%); C58,48H3,41N 8
．． 80 Example 16 Synthesis of N-carboxy-〇-methyl-α,β-dehydrotyrosine anhydride (0-methyl-Δ-tyrosine NCA) O-methyl-Δ-tyrosine NCA is N-Cbz-0-
Obtained from methyl-α,β-dehydro-tyrosine (Cbz-0-methyl-Δ-tyrosine) in a yield of 80% of theory.

The physical properties of this substance are as follows.

Melting point ("C): 197-198 IR (KB r , cm'): 1770 (C=C) 1670 (C=C) 'H-NMR (δ, DMSO-d6): 3.59 (s,
RC tan =) 11.39 (bs, NE () Elemental analysis value: Cr IHg NO4 Calculated value (%); C80,27H4,14N B-3
9 Actual value (%); C80, 13H4, 11N 8.
38 <Example 17> Synthesis of N-carboxy-O-methoxymethyl-α,β-dehydrotyrosine anhydride (0-methoxymethyl-Δ-tyrosine NCA) 0-methoxymethyl-Δ-tyrosine NCA is N- Cb
Obtained from z-0-methoxymethyl-α,β-dehydro-tyrosine (Cbz-0-methoxymethyl-Δ-tyrosine) in a yield of 90% of theory.

The physical properties of this substance are as follows.

Melting point ('C): 148-149 IR (KB r , cm-1): 1760 (C=
C) 1660 (C=C) 1H-NMR (δ, DMSO-d6): 6, 68
(5, R-CH=) 1130 (bs, NH) Elemental analysis value: Cl2H NO5 Calculated value (%); C57,83Ht, 45 N5
．． 62 Actual value (%); C57,95HC42N 5.
85 (blank below) <Example is> General formula % Formula % (In the formula, R, = C2R5, R2 = CH3, X, =t-
Synthesis of N-BOC-α,β-dehydro-isoleucine methyl ester (BOC-Δ-isoleucine methyl ester) represented by N-carboxy-α,β-dehydro-inleucine anhydride 776 mg (5 mmol) was dissolved in 8 ml of THF, di-t-butyl-dicarbonate (hereinafter, (BO
C) It is called 20. Additive ■)1.

31 g (6 mmol) and 20 m of pyridine
1 and stirred at room temperature for 6 hours. Then, 5 ml of methanol (additive ■) was added, and N - M, M,
The pH was adjusted to 9, and the mixture was stirred at room temperature for 2 hours, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in 40 ml of ethyl acetate and diluted with 10%
Wash with an aqueous citric acid solution, saturated multilayered water, and water, and dry with anhydrous sodium sulfate. The dry smoke agent was filtered and concentrated under reduced pressure, and the residue was purified with a silica gel column (benzene: ethyl acetate = 5:1V/V) to obtain the desired N-BOC-α,β.
-dehydro-isoleucine methyl ester in a theoretical amount of 8
Obtained with a yield of 2%.

The physical properties of this substance are as follows.

Melting point ('C: 81-83 IR (KBr, cm"1): 1720 (COOH) 1690, 1500 (NHCO) 1645 (C=C) 'H-NMR (δ, CDC13): 5, 85 (bs, LH, NH) 3,75 (s, 3H, OCH3) Elemental analysis value: C12H2□N04 Calculated value (%); C59,24H8,70N 5.
713 actual value (%); C59,21H8,80N
5.73 (E coordination body: Z coordination body = 3:2) Next, in Examples 19 to 32, the combination of R1, R2, YOH (Y is a hydrogen atom and a third The yield and physical property values are shown for different cases, such as alkyl groups corresponding to predetermined alcohols (excluding alcohols).

<Example 19> Starting material N-carboxy-α-amino-α-butenoic anhydride additive material ■: (BOC) 20 Intermediate material N-BOC-α-amino-α-butenoic anhydride additive material ■: Water Target product N-BOC-α-amino-α-butenoic acid However, R,=CH3 R2=H X,=BOC Y=H Yield (%)=73 Melting point (℃): 135-137 IR (KBr, cm ″″1): 1700 (COOH) 1680 (CONH) 1655 (C=C) 'H-NMR (δ, DMSO-ds): 6, 3
2 (q, R-CH=, J=7Hz) 1.38
(s, (CH3)3G-)7.98(bs,NH
) Elemental analysis value: C3H15NO4 Calculated value (%): C53,72H7,51N 6.9
8 Actual value (%); C53,E (7H7,57N
8.87 <Example 20> Starting material N-carboxy-α,β-dehydrofurmalvaline anhydride (hereinafter referred to as Δ-n-valine NCA) Additive material ■: (BOC) 20 Intermediate material N-BOC-α, β-dehydronormalvaline anhydride (hereinafter referred to as BOC-Δ-n-valine NCA) Additive substance ■: Water target N-BOC-α, β-dehydro- Normal-valine (hereinafter expressed as BOC-Δ-n-valine) However, R,=C2R5 R2=H x,=BOC Y=H Yield (%) Near 0 Melting point ('C): ill ~113 I R (KB r , cm'): 1700 (COOH) 1670 (CONH) 1650 (C=C) 'H-NMR (δ, DMSO-d6): 6.24 (t
, R-C =, J = 7Hz) 1, 38 (s,
(CH3) 3 C-)8.00 (bs, NH) Elemental analysis value: C1oH1□NO4 Calculated value (%); C55,80H7,96N 13
．． 51 Actual value (%): C55,71H7,87N S
, 80 <Example 21> Starting material Δ-n-leucine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-n-leucine NCA Additive material ■: Water object BOC-Δ-n-leucine However, R1 = n-C5R7 R2=H
OOH) 1650 (CONH) 1640 (C=C) 'H-NMR (δ, DMSO-d6): 6.34 (t
, R-CH=, J=7Hz)1.40 C5,(CH
3) 3C) 8.08 (bs, NH) Elemental analysis value: C1, Hl. No.4 Calculated value (%): C57,62H8,35N 6.11
Actual value (%), C57,68H8,21N 13
．． 00 <Example 22> Starting material Δ-Leucine NCA Additive substance ■: (BOC) 20 Intermediate substance BOC-Δ-Leucine NCA Additive substance ■: Water object BOC-Δ-Leucine However, R1= i -C3R7 R2=H X, =BOC Y=H Yield (%) Near 0 Melting point ('0): 141-142 I R (KB r , cm'): 1710 (COOH) 1690 (CONH) 1640 (C=C) 'H- NMR (δ, DMSO-dG): 6.20 (d
, R-CH=, J=10H2)1.40 (s, (C
H3)3 C-)8.04 (bs, NH) Elemental analysis value 2C1□H1°NO4 Calculated value (%): C57,82H8,35N 6.
11 Actual value (%); C57,57H8,23N
G, 00 <Example 23> Starting material Δ-phenylalanine NCA Additive substance ■: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Additive substance ■: Water object BOC-Δ-phenylalanine However, R,=C6R5 R2= H xt =BOC Y=H Yield (%) Near 2 Melting point (°C): 169-172 I R (KB r , cm-1): 1710 (C
OOH) 1690 (CONH) 1630 (C=C) 'H-NMR (δ, DMSO-d6) near, 26
(s, R-CH=)1.40 (S, (CH3)3
C) 8.52 (bs, NH) Elemental analysis value: C14H17N04 Calculated value (%); CEI3.88 H8,51N
5.32 Actual value (%); C83,81HEi, 8
5 N 5.43 <Example 24> Starting material Δ-valine NCA Additive substance ■: (BOC) 20 Intermediate material BOC-Δ-valine NCA Additive substance ■: Water target BOC-Δ-valine However, R,=CH3 R2=CH3 'H-NMR (δ, DMSO-dc): 1.38
(S , (CH3) 3 C) 8.16 (bs,
NH) Elemental analysis value: C1oH17NO4 calculated value (%), C55,80H7,96N 6.
51 Actual value (%); C55,58H7,82N 8
．． 80 <Example 25> Starting material Δ-isoleucine NCA Additive substance ■: (BOC) 20 Intermediate material BOC-Δ-isoleucine NCA Additive substance ■: Water object BOC-Δ-isoleucine However, R,=C2R5 R2=CH3 X , =BOC Y=H Yield (%): 82 Melting point (°C): 138-140 I R (KB r , Cm-1): 1700 (C
OOH) 1670 (CONH) 1640 (C=C) 'H-NMR (δ, DMSOds): 1.40 (S
, (CH3)3C-)8.16(bs,NH
) Elemental analysis value 2C1□H1°N04 Calculated value (%); C57,62H8,35N 6.
11 Actual value (%); C57,49H8,09N
6.23 <Example 26> Starting material Δ-n-leucine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-n-leucine NCA Additive material ■: Methanol Target product BOC-Δ-n-leucine methyl ester However, R1=n-C3H7 R2=H ) 1655 (C=C)'H-NMR (δ, CDC13): 6, 58 (t, R-CH=, J=7, 5
Hz) 3.78 (s, -0CH3) 6.17 (bs, NH) Elemental analysis value 12H2□NO4 Calculated value (%); C59,24H8,70N 5.
7f3 actual value (%); C59,13H8,78N
5.81 <Example 27> Starting material Δ-leucine NCA Additive substance ■: (BOC) 20 Intermediate material BOC-Δ-leucine NCA Additive substance ■: Methanol Target product BOC-Δ-leucine methyl ester However, R1= i − C3R7 R2=H x+ =BOC Y=CH3 Yield (%) Near 1 Melting point (°C) Near 4-75 I R (KB r , cm'): 1705 (COOH) 1705.1500 (CONH) 1660 (C=C ) 1H-NMR (δ, CDC13): 6.35 (d, R-CH=, J=10Hz) 3.7
6 (s, -0CH3) 6.17 (bs, NH) Elemental analysis value: Cl2H2□NO4 Calculated value (%); C59,24H8,70N 5.
713 actual value (%); C5!3.18 H8,8
6N 5.89 <Example 28> Starting material Δ-phenylalanine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Additive material ■: Methanol Target product BOC-Δ-phenylalanine methyl ester However, R, = C6R5 R2=H =C) 'H-NMR (δ, CDC13) near, 24 (s, R-C■=) 3.85 t':s, -0CH3) 6.27 (bs, NH) Elemental analysis value: C15H18N04 Calculated value (%) , Ce4.96 H8,91N 5
．． 05 Actual value (%); C64,83H8,84N
5.13 <Example 29> Starting material Δ-valine NCA Additive material ■: (BOC)20 Intermediate material BOC-' et al. NCA Additive material ■: Methanol Target product BOC-Δ-valine methyl ester However, R,= CH3 R2=CH3 =C) IH-NMR (δ, CDC13): 3.77 (s, -0CH3) 5.95 (bs, NH) Elemental analysis value 201, H19N04 Calculated value (%); C57,62H8,35N f3
．． 11 Actual value (%); C57, 5θH8, 29N
S, 05 <Example 30> Starting material Δ-phenylalanine NCA Additive material ■: (BOC)20 Intermediate material BOC-Δ-phenylalanine NCA Additive material ■: Ethanol Target product BOC-Δ-phenylalanine ethyl ester However, R,=C6R5 R2=H x, =BOC Y=C2R5 Yield (%) Near 1 Melting point ('0) : Oil I R (KB r , cm') : 1720 (COOH) 1705.1480 (CONH) 1640 (C=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 (%); Ce5.95 H7,27N 4
．． 81 Actual value (%); C65,85H7,19N
4.75 <Example 31> Starting material Δ-phenylalanine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Additive material ■: Benzyl alcohol Target product BOC-Δ-phenylalanine benzyl ester However, R, = C6R5 R2=H
COOH) 1700.1490 (CONH) 1640 (C=C) 'H-NMR (δ, CDC13) near, 24 (s, R-CH=)5, 24 C
s, -0CH2-)6.23 (bs, NH) Elemental analysis value 2C2□H23NO4 Calculated value (%); C71,3? H8,56N:
119B actual value (%); C71,21H6,40N
4.10 Example 32 Starting material Δ-phenylalanine NCA Additive ■: (BOC) 20 Intermediate BOC-Δ-phenylalanine NCA Additive ■: Isopropanol Target product BOC-Δ-phenylalanine impropyl ester However, R, =C6Hs R2=H
OOH) 1710.1490 (CONH) 1650 (C=C) IH-NMR (δ, CDC13) near, 12 (s, R-CH=)5, 10 (
m, -0CH2-)6.26 (bs, NH) Elemental analysis value 2C17H23N04 Calculated value (%), COO,88H7,59N 4.
59 Actual Jlll value (%); C8B, 81 H7,7
0N 4.80 (blank below) <Example 33> General formula % formula % (In the formula, R1=i C3H7, R2=H, X, =B
Synthesis of (BOC-Δ-leucyl-L-serine methyl ester) of N-BOC-α, β-dehydro-leucyl-monoserine methyl ester represented by OC, Y=CH3, AA=L-serine with 0 residues N-carboxy-α,β-dehydroleucine anhydride 1
, 55 g (l Ommol) was added with 5 ml of THF, and di-7-butyl dicarbonate (additive ■) 2
．． Add 62 g (12 mmol) and a few drops of pyridine. After stirring for 6 hours at room temperature, 1.31 g (11 mm01) of L-serine methyl ester (additive @) 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 removing the desiccant for 11 minutes, it was concentrated under reduced pressure, and the residue was transferred to a silica gel column (benzene: ethyl acetate = 5: l
V/V) to obtain the desired product as a colorless oil at 70% of the theoretical amount.
It was obtained in a yield of .

The physical properties of this substance are as follows.

'H-NMR (δ, CDC13): 6.25 (d, R-CH=, J=10Hz)4.
66 (d, NHCHCO.

J=3.5,7.0Hz) [α]32c=t, methanol)=-11,9° Elemental analysis value: C15H26N206 Calculated value (%); C54,53H7,93N 8.4
8 Actual value (%); C54,39H7,95N 8
．． 44 Next, in Examples 34 to 53, R,, R2
α due to the combination of N-protecting groups xt, AA, and Y
, shows the yield and physical property values when a β-dehydropeptide derivative was synthesized by the same method as above.

<Example 34> Starting material α-amino-α-butenoic acid NCA Additive ■ Niacetyl chloride Intermediate Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) Additive 'It■: L-leucine methyl Ester target product Ac-α-amino-α-butenoic acid-L-leucine methyl ester However, R,=CH3 R2=H X1=Ac AA=L-leucine residue Y=CH3 Yield (%)=80 Melting point ( °C): 148-150 I R (KB r , am-1): 1630.15
50 (CONH) IH-NMR (δ, CDC13): 6.38 (q, R-CH=, J=7Hz) 4.45
(dt, NHCHCO) [α]D (c=t, methanol) = -24,3' Elemental analysis value: C13H22N204 Calculated value (%); C57,78H8,20N10.38
Actual value (%): C57, 63H8, 39N10.42
<Example 35> Starting material α-amino-α-butenoic acid NCA Additive material ■ Niacetyl chloride Intermediate material Ac-α-amino-α-butenoic acid NCA (Ac = acetyl) Additive material ■: L-tyrosine methyl ester Purpose Product Ac-α-Amino-α-Butene M-L-Tyrosine Methyl Ester However, R,=CH3 R2=H xl・=Ac AA=L-Tyrosine Residue Y=CH3 Yield (%)=89 Melting Point (℃ ): Oil I R (KB r , cm'): 1660.1520 (CONH) 'H-NMR (δ, DMSOd6): 5, 77 (
q, R-CH=, J=7Hz)4,45 (
d t , NHCHCO)[α]D(C=1.82.
Methanol) = 10.2° Elemental analysis value: Cl8H2oN205 Calculated value (%); C59,99H6,29N 11
75 Actual value (%); C80,08H[7N L58
<Example 36> Starting material α-amino-α-butenoic acid NCA Additive material ■ Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac = acetyl) Additive material ■: L-serine methyl ester Purpose Product Ac-α-amino-α-butenoic acid-L-serine methyl ester However, R,=CH3 R2=H X1=Ac AA=L-serine residue Y=CH3 Yield (%) Near 4 Melting point (°C) : Oil 1H-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 (%); C49,17H6,60N11.47
Actual Jlll value (%); C49,25H6,49N
11.56 <Example 37> Starting material α-amino-α-butenoic acid NCA Additive material ■ Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac = acetyl) Additive material ■: L-proline Methyl ester target product Ac-α-amino-α-butenoic acid-L-7'loline methyl ester However, R,=CH3 R2=H X1=Ac AA=L-proline residue Y=CH3 Yield (%) Near 8 Melting point ('C): 118-120 IR (KBr, cm''): 1600.1520 (CONH) 'H-NMR (δ, CDC13): 5, 50 (q, R-CH=, J=7Hz)
4,80 (t,NHCHCO)[α]D(C=
0.89. Methanol) = -215° Elemental analysis value: Cl2H18N204 Calculated value (%); C58,68H7,14N11.0
2 Actual measurement value (%); C5B, 51 H7, 25N1
1.13 <Example 38> Starting material α-amino-α-butenoic acid NCA Additive material ■ Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac = acetyl) Additive material ■: L-methionine Methyl ester target product Ac-α-amino-α-butenoic acid-L-methionine methyl ester However, R,=CH3 R2=H X1=Ac AA=L-methionine residue Y=CH3 Yield (%) Near 9 Melting point (°C): 110 N112 I R (KBr, cm'): 1630.1550 (CONH) IH-NMR (δ, CDC13): 6.44 (q, R-CH=, J=7Hz) 4.64
(dd, NHCHCO) [α]24(C=0.22.methanol)=-19,8
゜Elemental analysis value: Cl2H2oN204S Calculated value (%); C49,83H[3,87N 9
．． 69 Actual value (%); C50,05HL71 N
9.57 <Example 39> Starting material α-amino-α-butenoic acid NCA Additive material ■ Niacetyl chloride intermediate material Ac-α-amino-α-butenoic acid NCA (Ac = acetyl) Additive material ■: L-) Liptophan methyl ester Target product Ac-α-amino-α-butenoic acid-L-4 Liptophan methyl ester However, R,=CH3 R2=H X1=Ac AA=L-)Lyptophan residue Y=CH3 Yield (%) Near 3 Melting point (℃): 183-185 (decomposed) IR (KB r, cm'): 1620.1500 (CONH) IH-NMR (δ, DMSO-db): 6.36
(q, R-CH= , J=7Hz)4.60 (m
, NHCHCO) [α]D (C=0-70.methanol) = -2, 4° Elemental analysis value: Cl8H2□N304 Calculated value (%); C82,98H6,16N12.
24 Actual value (%); C83,13H8,03N12
．． 11 <Example 40> Starting material α-amino-α-butenoic acid NCA Additive material ■ Niacetyl chloride Intermediate material Ac-α-amino-α-butenoic acid NCA methyl Target product Ac-α-amino-α-butenoic acid- L-Gurta telephone pole? Mic acid thyl ester However, R,=CH3 R2=H (δ, CDCl:?): 6.47 (q, R-CH=, J=7Hz) 6.54
(dt, NHCHCO.

J=7.5,6.0H2) Uα]D(C=1.methanol)=-16.5° Elemental analysis value: C14H22N206 Calculated value (%), C53,49H7,05N 8.
91 Actual value (%): C53,61H7,13N O,
00〈Example 41〉 Starting material α-amino-α-butenoic acid NCA Additive substance ■: Niacetyl fluoride interdehyde Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) Additive substance ■: L-phenylalanine Methyl ester target product Ac-α-amino-α-butenoic acid-L-phenylalanine methyl ester However, R,=CH3 R2=H X(=Ac AA=L-phenylalanine residue Y=CH3 Yield (%): 94 Melting point ('0): 144-145 IR (KB r , cm'): 1620.1540 (CONH) IH-NMR (δ, CDC13): 6.38 (q, R-CH= , J=7Hz) 4 .6
7 (dt, NHCHCO) [α]D (C=1.methanol)=-8,5' Elemental analysis value: C16H2oN204 Calculated value (%); Ce3.14 HEi, 82 N
9.21 actual value (%), Cf33.01 Hf
3.75 N 9. OQ <Example 42> Starting material α-amino-α-butenoic acid NCA Additive material Niacetyl chloride Intermediate Ac-α-amino-α-butenoic acid NCA (Ac=acetyl) Mt■: L-phenylalanine ethyl Ester target product Ac-α-amino-α-butenoic acid-L-phenylalanine ethyl ester However, R,=CH3 R2=H X1=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)
1z) 4.76 (dt, NHC ■ coo) [α] 2
4 (C= , , methanol) = -5,4° Elemental analysis value: C17H22N204 Calculated value (%); C64,13H6,97N 8.8
0 Actual value (%); C84,30H7,08N 8.
83 <Example 43> Starting material Δ-n-valine NCA Additive material ■ Niacetyl chloride intermediate material Ac-Δ-n-valine NCA (Ac = acetyl) Additive material ■: L-phenylalanine ethyl ester target product Ac-Δ- n-valyl L-phenylalanine ethyl ester However, R,=C2H5 R2=H δ, CDC13): 6.38 (j, R-C■=, J=7Hz) 4.87
(dt, NHC■CO) [α]'A4 (c = t, methanol) = -6,1
'Elemental analysis value: Cl8H24N204 Calculated value (%); C85,04H? -28N 8.4
3 Actual measurement value (%); C84,93H7,38N 8.
41 (blank below) <Example 44> Starting material Δ-n-leucine NCA Additive material ■ Niacetyl chloride intermediate material Ac-Δ-n-leucine NCA (Ac=acetyl) Additive material ■: L-phenylalanine ethyl ester target product Ac-Δ-n-leucyl-L-phenylalanine ethyl ester However, R1=n C3R7 R2=H H-NMR (δ, CDC13): 6, 26 (t, R-CH=, J=7Hz)
4.82 (dt, NHCHCO) [α]D (C=1.methanol) = -7,5° Elemental analysis fIM: 019H26N2°4 Calculated value (%); C8
5-87H7,57N 8.09 Actual value (%); C
85,91H7,48N 8.20 <Example 45> Starting material Δ-leucine NCA Additive material ■ Niacetyl chloride intermediate material Ac - Δ-leucine NCA (Ac = acetyl) l Substance ■: L-phenylalanine ethyl ester target product Ac -Δ-Leucyl-L-phenylalanine ethyl ester However, R1= i -C3R7 R2=H NMR (δ, CDC13): 6.10 (d, R-CH=, J=lOHz) 4.8
2 (d t , NHCHCO) [α124(C=
1. Methanol) = -6-2゜Elemental analysis value: Cl8H2
8N204 Calculated value (%); C135,87H7,57N 8
．． 09 Actual value (%); C88,03H7,72N
8.21 <Example 46> Starting material Δ-phenylalanine NCA Additive material ■ Niacetyl chloride intermediate material Ac-Δ-phenylalanine NCA (Ac=acetyl) m Additive W ■: L-phenylalanine ethyl ester target product Ac-Δ- Phenylalanyl-L-phenylalanine ethyl ester However, R,=C6R5 R2=H , CDC13): 6,88 (s, R-CH=) 4.79 (dt, NHCHCO) [α]D (C=1.methanol)=-35,8° Elemental analysis value: C22H24N204 Calculated value (%) , C60,45Hf3.36N 7
．． 36 Actual value (%); C69,53HS, 12N
7.19 <Example 47> Starting material Δ-Leucine NCA Additive material ■: Water trifluoroacetic acid intermediate Tfa-Δ-Leucine NcA (Tfa=trifluoroacetyl) Additive material ■: L-phenylalanine methyl ester target product Tfa -Δ-Leucyl-L-phenylalanine methyl ester However, R1=i C5H7 R2=H CDC13): 6.19 (d, R-CH=, J=10Hz) 4.83
(dt, NHCHCO.

J=8.0,5.7H2) [α]24(C=1.methanol)=-15,66 Elemental analysis value 2 Cl8H2□N204F3 calculated value (%)
; C55,9B H5,48N 7.25 actual value (%
); C5B, 18 H5,58N 7.42 <Example 48> Starting material Δ-phenylalanine NCA Additive material ■: Anhydrous triple coloacetic acid intermediate fa-Δ-phenylalanine NCA (Tfa = trifluoroacetyl) Additive W ■ : L-threonine methyl ester Target product Tfa-Δ-phenylalanyl-L-threochone methyl ester However, RI=C6Hs R2=H X1=Tfa AA=L-threonine residue Y=CH3 Yield (%) Near 4 Melting point (°C) 2 Oil IH-NMR (δ, CDC13) Near, 15-7.29 (m, +C6Hs) 4.43 (
dd, NHCHCO.

J = 8.5.3-OHz) [α] rJ (C = 1. methanol) = 29.0' Elemental analysis value: C16H1□N205F3 calculated value (%)
; C51,34H4,58N 7.48 Actual value (%)
; C51,06H4,89N 7.32〈Example 4
9> Starting material Δ-leucine NCA Additive material ■: Triple coloacetic anhydride intermediate material fa-Δ-leucine NCA (Tfa=trifluoroacetyl) Additive material ■: δ-Cbz-L-ornithine methyl ester target product Tfa-Δ -Leucyl δ-cbz-L-ornithine methyl ester However, R1= i -C3R7 R2=H X1==Tfa AA=δ-Cbz-L-ornithine residue Y=CH3 Yield (%)=79 Melting point (℃) : Oil "H-NMR (δ, CDCl5): 6.21 (d, R-CH=, J=10Hz) 4.58
(m, NHCHCO) [α]D (C=1.methanol) = -7,5' Elemental analysis value: 022H28N3°6 F3 calculated value (%);
C54,20H5,79N 8.132 Actual value (%)
; C54, OEf H5,! 32 N 8.50
Example 50> Starting material Δ-phenylalanine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Additive material ■ Nigericin methyl ester Target product BOC-Δ-phenylalanyl Rougesin methyl ester However, R, =C6R5 R2=H =)4.14 (d
, NHCHCO, J=8Hz) Elemental analysis value: C17H
22N205 Calculated value (%); C81,08H6,83N 8.
38 Actual value (%); Cf30.89 H8,51
N 8.49 <Example 51> Starting material Δ-phenylalanine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA iUtnh quality ■: L-leucine methyl ester Target product BOC-Δ-phenylalanine L -Leucine methyl ester However, RI=C6H5 R2=H ) near, 12 (S, R-CH=)4.68 (d
t, NHCHCO.

J=8.0,8.0Hz) [α]D(C=1.methanol)=-41,8@Elemental analysis value: C2□H3oN205 Calculated value (%); C84,59H7,74N 7.17
Actual value (%); C84,70H7,87N 7.
01 <Example 52> Starting material Δ-phenylalanine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-phenylalanine NCA Addition 'thfl■: L-phenylalanine methyl ester Target product BOC-Δ-phenylalanine-L-phenylalanine Methyl ester, R,=C6H5 R2=H Near, 04 (s, R-CH=)4.90 (d
t, NHCHCO.

J = 6.0, 7.0 Hz) [α] D (C = 1. methanol) = -3, 6° Elemental analysis value: C24H28N205 Calculated value (%); C8? -90H8,85N 8.
60 actual value (%); C67,70H8,72N
8.77 <Example 53> Starting material Δ-n-valine NCA Additive material ■: (BOC) 20 Intermediate material BOC-Δ-n-valine NCA Additive material ■: L-tyrosine methyl ester target product BOC-Δ-n -Varylu L-thousandrosycin methyl ester R,=C2Hs R2=H CDC13): 6, 39 (t, R-CH=, J=7Hz)
4.80 (dt, NHCHCO.

J=7.0,8. OH2) [α]D (C=1.methanol) = -11,7° Elemental analysis value: C2oH28N206 Calculated value (%); C8121H7,19N 7.14
Actual value (%); C81,01H7,39N 7.
01 (blank below) <Example 54> General formula % formula % (in the formula, R, = C6R5, uz :H, X2 = Pht
, Y=CH3, AA=N- represented by glycine Masakazu
Synthesis of Pht-glycyl-α,β-dehydro-phenylalanine methyl ester N-carboxy-α,β-dehydrophenylalanine anhydride 1,89 g (10
Add 10 ml of T3 (mmol) and adjust the pH to 8-9 with triethylamino. The mixture was stirred again at room temperature for 1 hour, then concentrated under reduced pressure 'ff2, and the residue was dissolved in 100 ml of ethyl acetate. After washing with 1M hydrochloric acid and water, drying over anhydrous sodium sulfate, filtering the desiccant, concentrating under reduced pressure, and applying the residue to a silica gel column (benzene: ethyl acetate = 1O:IV/V
) to obtain the desired product in the form of colorless needle 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 1R (KBr, cm-1): 1680, 1530 (CONH) IH-NMR (δ, CDC13) near, 46-7.28 (R-C■= , +c6 H
s) 4.43 (s, NHCHCO) Elemental analysis value: C2oH16N205 Calculated value (%); C65,93H4,43N 7.
69 Actual value (%); C8B, 05 H4, 39N
7.73 Next, in Examples 55 to 59, R1, R
2, the yield and physical property values are shown when α,β-dehydropeptide derivatives with different X2, AA, and Y are synthesized by the same method as above.

<Example 55> Starting material Δ-n-valine NCA Additive material ■: Pht-D, L-phenylalanyl chloride intermediate Pht-D, L-phenylalanyl-Δ-n-valine N
CA Additive substance ■: Water target P h t -D, L-7, Nylalanyl-Δ-n
-valine, R,=(:2 R5 R2=H δ, DMSO-d6): 6.76
(t, R-CH=, J=7H2)5.20 (dt
,NHCHCO.

J=8.0, 5.5Hz) Elemental analysis value: C22H2oN205 Calculated value (%); C87,33H5,14N 7.
14 Actual value (%), C87-15H5,29N?
, 09 <Example 56> Starting material α-amino-α-butenoic acid NCA Additive material ■: Pht-L-alanyl chloride intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A Additive substance ■: Ethanol target Pht-L-alanyl-α-amino-α-butenoic acid ethyl ester However, R,=CH3 R2=H XI=Pht AA=L-alanine residue Y=C2R5 Yield (% )286 Melting point ('C): 133-135 1H-NMR (δ, CDC13): 6, 76 (ci, R-CH=, J=7Hz
)5.06 ((1,NHCHCO,J=7Hz)[α
: +g4 (c = i, methanol) = 0.9° Elemental analysis value: 017H18N2°5 Calculated value (%); C61,81H5,49N 8.
48 Actual value (%); C81,139H5,81N
B, 41 <Example 57> Starting material α-amino-α-butenoic acid NCA Additive material ■: Cbz-glycyl chloride intermediate Cbz-glycyl-α-amino-α-butenoic acid CA Additive material ■: Ethanol Target product Cbz-glycyl-α-amino-α-butenoic acid ethyl ester R,=CH3 R2=H X1=Cbz AA=glycine residue C2R5 Yield (%): 20 Melting point (°C): Oil 'H -NMR (δ, CDC13) near, 02 (q, R-CH=, J=7Hz
) 3.87 (d, NHCHCO, J=6Hz) Elemental analysis value: C16H2oN205 Calculated value (%); C59, f39 H6,29N
8.75 Actual value (%); C80,0? H6,35
N 8.83 <Example 58> Starting material Δ-phenylalanine NCA Additive ■: Cbz-glycyl chloride intermediate Cbz-glycyl-Δ-phenylalanine NC Additive ■: methanol Target object Cbz-glycyl-Δ-phenylalanine methyl Ester, R,=C6R5 R2=H 53 (m, +C6R5)3.
91 (d, NHCHCO, J=7Hz) Elemental analysis value: C2oH2oN205 Calculated value (%); Ce5.21 H5,47N 7
-Eft actual value (%): C85,4f3 H5,40
N 7.53 <Example 59> Starting material α-amino-α-butenoic acid NCA Additive material ■: Cbz-L-alanyl chloride intermediate Cbz-L-alanyl-α-amino-α-butenoic acid NC
A Additive substance ■: Methanol target Cbz-L-alanyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X1=Cbz AA=L-alanine residue Y=CH3 Yield (% ): 23 Melting point (°C): 137-138 1H-NMR (δ, CDC13): 6.76 (q, R-CH=, J=7Hz) 4.43
(m, NHCHCO) [α]D (C=0.65.methanol) = -10,5° Elemental analysis value: Cl8H2oN205 Calculated value (%); C5!199 H[3,29N
8.75 Actual value (%); C[30,09H8-2
0N 8.87 (blank below) <Example 60> General formula % formula % (In the formula, R, = C6Hs, R2 = H, X3 = BOC,
N-BOC-L-phenylalanyl-α, β- represented by Y=CH3, AA=L-phenylalanine residue)
Synthesis of dehydro-phenylalanine methyl ester N-carboxy-α,β-dehydrophenylalanine anhydride 1.89 g (10 mmol) C7) THF5
ml solution, BOC-L-y, =
Luara =, y2.92g (11mm.

Add l). The mixture was cooled to −10° C., and 2.27 g (1 mmol) 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 1 ml of methanol, adjust the pH to 9 with NMM, stir at room temperature for 1 hour, concentrate the reaction solution under reduced pressure, dissolve the residue in 50 ml of ethyl acetate, leave it in a cool place for 1 hour, and then filter out the precipitated dicyclohexyl urea. do. This was washed with 50ml of cold ethyl acetate, and both ethyl acetate layers were combined and 10%
Wash with a citric acid aqueous solution and water, and dry smoke with anhydrous sodium sulfate. After removing the desiccant, it was concentrated under reduced pressure, and the residue was transferred to a silica gel column (chloroform:acetone=20:IV/V
) to obtain the desired product in the form of pearl yellow needle crystals from diisopropyl ether in a yield of 90% of the theoretical amount.

The physical properties of this substance are as follows.

Melting point (°C): 116-118 I R (KB r , cm'): 1640.1530 (CONH) 'H-NMR (δ, CDC13): 6.54 (d, R-CH=, J=10Hz) 4 .5
4 (dt, NHC CO.

J=8.0,7.0Hz) Elemental analysis value: C24H28N205 Calculated value (%): C87,90H8,85N 8.6
0 Actual value (%); C87°80 H8,89N 6.6
3 Next, in Examples 61 to 72, the yield and physical property values when α,β-dehydropeptide derivatives with different combinations of R1, R2, x3, AA, and Y were synthesized by the same method as above. shows.

<Example 61> Starting material Δ-n-valine NCA Additive 'fl■: Pht-D, L-phenylalanine intermediate substance Pht D, L Phenylalanyl-Δ-n-valine NCA Additive substance ■: Water target Pht -D, L-phenylalanyl-Δ-n-valine However, R,=(:2 R5 R2=H X,=Pht AA=D, L-phenylalanine residue Y=H Yield (%) 285 Melting point ('C): 148-150 1H-NMR (δ, DMSO-ci=): 6.76 (
t, R-CH= , J=7Hz)5.20 (dt
,NHC■CO.

J=8.0, 5.5Hz) Elemental analysis value: C22H2oN205 Calculated value (%); C87,33H5,14N 7.1
4 Actual value (%); C67,28H5,17N 7.
20 <Example 62> Starting material Δ-phenylalanine NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-Δ-phenylalanine NC Additive material ■: methanol Target product Pht-glycyl-Δ-phenylalanine methyl ester However, R,= C6Hs R2=H +C6H3)4,43
(S, NHCHCO) Elemental analysis value: C2oH16
N205 calculated value (%); C65,93H4,43N 7.
69 Actual value (%); C3B-05HC32N? ,
81 <Example 63> Starting material α-amino-α-butenoic acid NCA Additive material ■: Pht-L-alanine intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A Additive substance ■: Ethanol target Pht-L-alanyl-α-amino-α-butenoic acid ethyl ester However, R,=CH3 R2=H X3=Pht AA=L-alanine residue Y=C2R5 Yield (% )287 Melting point ('0): 133-135'H-NMR (δ, CDC13): 6.76 (q, R-CH=, J=7Hz) 5.06
(q, NHCHCO, J=7Hz) [α]D(C=1.
Methanol) = 0.9゜Elemental analysis value: C1□H18N2
05 Calculated value (%); C81,81H5t49 N 8
．． 48 Actual value (%); C81,69H5,58N
8.30 <Example 64> Starting material α-amino-α-butenoic acid NCA Additive material ■: Cbz-glycine intermediate Cbz-glycyl-α-amino-α-butenoic acid CA Additive material ■: Ethanol Target product Cbz- Glycyl-α-amino-α-butenoic acid ethyl ester However, R,=CH3 R2=H x3=cbz AA=glycine residue Y=C2Hs Yield (%) Near 9 Melting point (℃): Oil IH-NMR ( δ, CDC13) Near, 02 (q, R-CH=, J=7Hz
) 3.87 (d, NHCHCO, J=6Hz) Elemental analysis value: C16H2oN205 Calculated value (%); C59,99H8,29N 8.7
5 Actual value (%); C59,80H6,16N 8
．． 92 <Example 65> Starting material Δ-phenylalanine NCA Additive material ■: Cbz-glycine intermediate Cbz-glycyl-Δ-phenylalanine NC additive material ■ Nimethanol Target product Cbz-glycyl-Δ-phenylalanine methyl ester However, R, = C6Hs R2=H Hs) 3.91(
cl, NHCHCO, J=7Hz) Elemental analysis value: C2o
H2oN20°calculated value (%); C85,21H5,47N 7.8
1 Actual value (%): C85,03H5,59N 7.7
7 <Example 66> Starting material α-amino-α-butenoic acid NCA Additive material ■: Cbz-L-alanine intermediate Cbz-L-alanyl-α-amino-α-butenoic acid NC
A Additive substance ■: Methanol target Cbz-L-alanyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X3=Cbz AA=L-alanine residue Y=CH3 Yield (% ): 88 Melting point (°C): 137-138'H-NMR (δ, CDC13): 6, 76 (q, R-CH=, J=7H
z) 4.43 (m, NHCHCO) [α]: 4 (C = 0, 65, methanol) = -1
0.5° Elemental analysis value: C16H2oN205 Calculated value (%); C59,99HL29 N L7
5 Actual value (%); C59,91H13,38N 8
．． 89 <Example 67> Starting material α-amino-α-butenoic acid NCA Additive material ■: BOC-L-alanine intermediate BOC-L-alanyl-α-amino to α-butenoic acid NC
A Additive substance ■: methanol Target product BOC-L-alanyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X3=BOC AA=L-alanine residue Y=CH3 Yield (talo ): 65 Melting point (°C): 116-117'H-NMR (δ, CDCh): 6, 80 (q, R-CH=, J=7Hz)
4.40 (m, NHCHCO) [α]D (c=t, methanol) = -25,7° Elemental analysis value: C13H22N205 Calculated value (%); C54,53H7,75N 9.
78 Actual value (%): C3L70 H7,93N 9.
81 <Example 68> Starting material α-amino-α-butenoic acid NCA Additive material ■: BOC-L-valine intermediate BOC-L-valyl-α-amino-α-butenoic acid NCA Additive material ■: Methanol Target object BOC-L-valyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H X3 =BOC AA=L-valine residue Y=CH3 Yield (%)=69 Melting point (°C): 110-111'H-NMR (δ, CDC13): 6.82 ((1, R-CH=, J=7Hz)4,
IO (m, NHCHCO) [α]D (c=t, methanol) = -25,4 @ elemental analysis value: C15H26N205 Calculated value (%); C57-31H8,34N 8.
91 Actual value (%); C57,19H8,49N
9.10 <Example 69> Starting material α-amino-α-butene @NCA Additive material ■: BOC-L-leucine intermediate BOC-L-leucyl-α-amino-α-butenoic acid NC
A Additive substance ■: Methanol target BOC-L-leucyl-α-amino-α-butenoic acid methyl ester R,=CH3 R2=H X3=BOC AA=L-leucine residue Y=CH3 Yield (% )=64 Melting point (°C): Oil IH-NMR (δ, CDC13): 6 + 64 (q, R-CH=, J=7Hz)4.
18 (m, NHCHCO) [α]D (C=1.methanol) = -19,2° Elemental analysis value: C16H28N205 Calculated value (%): C58,51H8,59N 8.5
3 actual value C%), C58,70H [80N L32
<Example 70> Starting material α-amino-α-butenoic acid NCA 1 Additive substance ■: BOC-L-phenylalanine intermediate BOC-L-phenylalanyl-α-amino-α-butenoic acid NCA Additive substance ■: Methanol Target object BOC-L-phenylalanyl-α-amino-α-butenoic acid methyl ester However, R+ = CN3 R2=H X3=BOC AA=L-phenylalanine residue Y=CH3 Yield (%) = 85 Melting point ( 'C): 97-98 1H-NMR (δ, cnci3): 6, 73 (q, R-CH=, J=7Hz)
4.58 (dt, NHCHCO.

J = 8.0, 7.0Hz) [α ko (c = 1-methanol) = -15,0'
Elemental analysis value: 018H26N2°5 Calculated value (%); (J2.f36t H7,23N
7.73 Actual value (%); C83,13H7,1
0N 7.87 <Example 71> Starting material α-amino-α-butenoic acid NCA Additive material ■: BOC-Glycine intermediate BOC-glycyl-α-amino-α-butenoic acid CA Additive material ■: Methanol Target object BOC -Glycyl-α-amino-α-butenoic acid methyl ester However, R,=CH3 R2=H Nδ, CDC13): 6.84 (q, R-C■=, J=7Hz) 3.98 (
d, NHCHCO, J=6Hz) Elemental analysis value: 012H
2ON2°5 Calculated value (%); C52,93H7,40NlO,2
9 Actual value (%); C53, 10H7, 26N10
．． 49 <Example 72> Starting material Δ-phenylalanine NCA Additive material ■: BOC-L-leucine intermediate BOC-L-leucyl-Δ-phenylalanine CA Additive material ■: Methanol Target product BOC-L-leucyl-Δ-phenylalanine methyl Ester, R,=C6Hs R2=H ~7.50 (m, +C6R5)4.28
(m, NHCHCO) [α]24 (C=t, methanol) = 41.56 Elemental analysis value: C2□H3oN205 Calculated value (%); C84,59H7,74N 7.
17 Actual value (%); C84,70H7,88N 7
．． 13 (blank below) <Example 73> N3 AANH-C-COAA'OY (wherein, R1=i-C3R7, R2=H, N3=BO
C, Y=CH3, AA=L-alanine residue, AA'=L
-N-BOC-L expressed as phenylalanine Masakazu
-alanyl-α,β-dehydroloucyl-L-phenylalanine methyl ester (BOC-L-alanyl-Δ
Synthesis of N-carboxy-α,β-dehydroleucine anhydride 1, 55 g (10 mmol) in 5 ml of THF
Into the solution, BOC-L-alanine (
Add 0.8 g (11 mmo 1) of additive material ■) 2. The mixture was cooled to −10° C. and 2.27 g (11 mmol) of dicyclohexylcarbodiimide was added. Stir for 20 minutes at the same temperature and adjust the pH to 6 with pyridine. Thereafter, it was stirred at 0°C for 1 hour and at room temperature for 12 hours, and 1.97 g of L-phenylalanine methyl ester (additional substance ■) was added to this.
Add a solution of g (11 mmol) in 5 ml of THF and adjust the pH to 8-9 with triethylamino. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate.
After leaving 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, dried over anhydrous M sodium. ff desiccant
1 l@, concentrated under reduced pressure, and the residue was purified with a silica gel column (chloroform:acetone = 20:IV/V) to obtain the target product in the form of sintered ↑-shaped crystals from chloroform and diisopropyl ether in a yield of 90% of the theoretical amount. Obtained.

The physical properties of this substance are as follows.

Melting point ('0): 121-122 1H-NMR (δ, CDC13): 6.29 (d, R-CH=, J=10Hz) 4.21
(m, NHCHCO) 4.86 (dq, NHcHco.

J = 7.5, 5.0Hz) [α]: 2c = t, methanol) = -35, 8° Elemental analysis value: C24H3, N306 Calculated value (%); C82, C3H7, 81N 9.1
3 Actual value (%); C82,45H7,84N 9
．． 01 Next, in Examples 74 to 93, R,, R2
α due to the combination of N3, AA, AA', Y (7) difference
, shows the yield and physical property values when a β-dehydropeptide derivative was synthesized by the same method as above.

<Example 74> Starting material α-amino-α-butenoic acid NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-α-amino-α-butenoic acid CA Additive material ■: L-phenylalanine methyl ester Target product Pht-glycyl-α-amino-α-butenoic acid L-phenylalanine methyl ester However, R,=CH3 R2=H )=68 Melting point ("C): 175-176'H-NMR (δ, CDC13): 6.43 (q, R-CH=, J=7Hz) 4.74
(dt, NHCHCO.

J = 7.5, 7.0Hz) 4.28 (S, NHCHCO) [α] p2 c = i, methanol) = -24,
9゜Elemental analysis value: C24H23N306 Calculated value (%); C64,13H5,IB N 9
．． 35 Actual value (%): C84,01H5,01N
S, 52 <Example 75> Starting material α-amino-α-butenoic acid NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-α-amino-α-butenoic acid CA! Addition W■: L-leucine methyl ester Target product Pht-glycyl-α-amino-α-butenoic acid monoleucine methyl ester However, R,=CH3 R2=H X3=Pht AA=glycine residue'= L-leucine residue Y=CH3 Yield (%): 85 Melting point (°C): 161-162'H-NMR (δ, CDC13): 6, 59 (q, R-CH=, J=7H2)
4.52 (dt, NHCHCO.

J=7.0, 7.0Hz) 4.44 (s, NHCHCO) [α] Qc=t, methanol) = -42,8° Elemental analysis value: C2□H25N308 Calculated value (%), CBo, 71 H6,07NlO,
12 Actual value (%); C80,90HEi, 25N
10.01 <Example 76> Starting material Δ-leucine NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-Δ-leucine NCA additive W ■: L
-valine methyl ester target productpht-glycyl-Δ-leucyl L-valine methyl ester However, R1=: i C3R7 R2=H X3=Pht AA=glycine residue AA'=L-valine residue Y=CH3 Yield ( %): 85 Melting point (°C): 204-205 1H-NMR (δ, CDCl5): 6.33 (d, R-CH=, J=10Hz)4.
44 (m, NHCHCO) [α]D (C=1.methanol) = -24,6° Elemental analysis value: C22H27N306 Calculated value (%); Cf31.52 H8,34N!
9.79 Actual value (%): C81,37H8,22N
9.92 <Example 77> Starting material Δ-phenylalanine NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-Δ-phenylalanine NC Additive material ■: L-phenylalanine methyl ester Target product Pht-glycyl-Δ-phenylalanine -L-phenylalanine methyl ester However, R, = (: 6 R5 R2 = H x3 = pht AA = glycine residue AA' = L-phenylalanine residue Y = CH3 Yield (%) Near 9 Melting point (°C): 175 ~176 4.64 (dt, NHCHCO.

J=7.5, 7.0Hz) 4.24 (s, NHCHCO) [α]D (C=0.5.methanol) = -64,6゜Elemental analysis value 29H25N30B Calculated value (%); C68, 09H4,93N 8.
22 Actual value (%); C88,31H4,70N
B, 43 <Example 78> Starting material Δ-leucine NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-Δ-leucine NCA addition MJ ■: L
-Phenylalanine methyl ester target product Pht-glycyl-Δ-leucyl L-phenylalanine methyl ester However, R1= i -C3R7 R2=H (%) 288 Melting point (℃): 193-194'H-NMR (δ, CDC13): 6.25 (d, R-CH=, J=10Hz) 4.8
0 (dt, NHCHCO.

J = 7.5, 7.0H2) 4.40 (S, NHCHCO) [α]23 (C = t, methanol) = -20,29 Elemental analysis value: 026H27N3°6 Calculated value (%); CEi5.39 H5,70N 8
．． 80 Actual value (%); C65,49H5-82N
8.81 <Example 79> Starting material Δ-phenylalanine NCA Additive substance ■: Pht-glycine intermediate substance Pht-glycine Δ-phenylalanine NCUo product W
■: L-valine methyl ester target product pht-glycyl-Δ-phenylalanyl-L-valine methyl ester However, R, = C6) (5 R2 = H X3 = Pht AA = glycine residue AA" = L-valine residue Residue = CH3 Yield (%) = 87 Melting point ('0): 215-216' H-NMR (δ, CDC13) near, 17 (s, R-CH=) 4.26 (
dd, NHCHCO.

J = 7.5, 7.0 Hz) 4.50 (S, NHCHCO) [α] D (C = 1. methanol) = -20,5° Elemental analysis value: 025H25N306 Calculated value (%); C[34, 78H5,44N 9
．． 07 Actual AIII value (%); C[34,82H5,
32N 9.1B <Example 80> Starting material Δ-n-valine NCA Additive material ■: Pht-glycine intermediate Pht-glycyl-Δ-n-valine NCAm Additive material ■:
L-phenylalanine methyl ester Target product Pht-glycyl-Δ-n-valyl L-phenylalanine methyl ester However, R,=C2R5 R2=H X3=Pht AA=glycine residue AA'=L-phenylalanine residue Y=CH3 Yield Rate (%) 283 Melting point ('0): 169-171'H-NMR (δ, CDC13): 6, 36 (t, R-CH=, J=7Hz)
4.80 (dt, NHCHCO.

J = 7.0, 7.0Hz) 4.42 (s, NHCHCO) [α]D (C = 1. methanol) = -18,9° Elemental analysis value: C25H25N306 Calculated value (%); C84,78H5, 44N 9.0
7 Actual measurement value (%); C84,83H5,82N 8.
90 <Example 81> Starting material α-amino-α-butenoic acid NCA Additive material ■: Pht-L-alanine intermediate Pht-L-alanyl-α-amino-α-butenoic acid NC
A m addition 'fl■: L-phenylalanine methyl ester target product Pht-L-alanyl-α-amino-α-butenoic acid-L
-Phenylalanine methyl esterification, R,=CH3 R2=H -NMR (δ, CDC13): 6.48 (q, R-CH=, J=7Hz) 4.92
(q,NHCHCO,J=7Hz)4.62 (d
t, NHCHCO.

J = 7.0, 6.5Hz) [α]D (c = t, methanol) = 12.9° Elemental analysis value: C2, H25N306 Calculated value (%); C134,78H5,44N 9
．． 0? Actual value (%); (J4.90 H5,29
N 9.18 <Example 82> Starting material α-amino-α-butenoic acid NCA Additive material ■: Pht-L-leucine intermediate Pht-L-leucyl-α-amino-α-butenoic acid NC
A Additive 'A■: L-phenylalanine methyl ester target product Pht-L-leucyl-α-amino-α-butenoic acid-L
-Phenylalanine methyl esterification, R,=CH3 R2=H H-NMR (δ, CDC13): 6, 46 (q, R-CH=, J=7Hz)
5.00 (dd, NHCHCO.

J = 11.0, 5.0H2) 4.66 (dt, NHC■C02 J = 7.0, 7.0Hz) [α] 23 (C = 1. methanol) = -4-5° Elemental analysis value 2 C28H3□N306 Calculated value (%); C8B, 52 H8,18N 8
．． 31 Actual value (%); C8B, 44 HG, 24
N 8-45 <Example 83> Starting material Δ-n-leucine NCA Additive substance ■: Pht-L-leucine intermediate substance Pht-L-leucyl-Δ-n-leucine NCUn substance ■: L-phenylalanine methyl ester Target object Pht-L-leucyl-Δ-n-leucyl-L-phenylalanine methyl ester However, R1=n-C3H7 R2=H X3=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, 5.0Hz) 4.72 (dt, NHCHCO.

J=7.5, 6.0H2) [α]D (C=1.methanol)=-7.0° Elemental analysis value: C3oH35N306 Calculated value (%); C87,52H8,61N 7.
88 actual value (%); C87,39H6,89N 7
．． 79 (blank below) <Example 84> Starting material α-amino-α-butenoic acid NCA Additive 'M■: Pht-L-phenylalanine intermediate Pht-L-phenylalanyl-α-amino-α-butenoic acid NCA Additive substance ■ Nigericin methyl ester target Pht-L-phenylalanyl-α-amino-α-butenoic acid-glycine methyl esterification, R,=CH3 R2=H X3=Pht AA=L-phenylalanine residue AA '=glycine residue Y=CH3 Yield (%) 287 Melting point (°C): 100-101 'H-NMR (δ, CDC13): 6.56 (q, R-CH=, J=7Hz)5. 20
(dd, NHCHCO.

J=10.5, 5.5Hz) 3.90 (d, NHCHCO, J=6Hz) [α]
:2c=t, methanol)=-113,4° Elemental analysis value: C24H23N306 Calculated value (%); C84,13H5,16N 9.
35 actual Δ11 value (%): C84,05H5,31N
S, 22 <Example 85> Starting material Δ-leucine NCA Additive material ■: Pht-L-phenylalanine intermediate Pht-L-phenylalanyl-Δ-leucine CA Yf-Additional material ■: L-serine methyl ester Target product Pht-L-phenylalanyl-Δ-leucyl L-serine methyl ester However, R1= i C3R7 R2=H X3=Pht AA=L-phenylalanine residue AA'=L-serine residue Y=CH3 Yield (% )268 Melting point (°C): 179-180'H-NMR (δ, CDC13): 6.21 (d, R-CH=, J=10Hz)5.
30 (dd, NHCHCO.

J=11.0, 5.0Hz) 4.38 (m, NHCHCO) [α]32c=t, methanol) = -59,1° Elemental analysis value: C27H2°N5o7 Calculated value (%); C83,89H5, 78N 8.
28 Actual value (%); C63,96H5,85N 8
．． 19 <Example 86> Starting material Δ-phenylalanine NCA Additive material ■: Cbz-glycine intermediate Cbz-glycyl-Δ-phenylalanine NC Additive material ■: L-serine methyl ester Target product Cbz-glycyl-Δ-phenylalanine L -Serine methyl ester However, RI=C6H5 R2=H (δ, CDC13) near, 06 (s, R-CH=)3.84 (m
, NHCHCO) 4.60 (m, NHCHCO) [α]D (C=1.16.methanol) = -21, 9° Elemental analysis value: C23H25N307 Calculated value (%); C80,85H5,53N 9.
23 Actual value (%); C80,80H5,48N 9
．． 29 <Example 87> Starting material α-amino-α-butenoic acid NCA Additive material ■: BOC-L-alanine intermediate BOC-L-alanyl-α-amino-α-butenoic acid NC
A Additive substance ■: L-serine methyl ester target product BOC-L-alanyl-α-amino-α-butenoic acid-L
-Serine methyl ester However, R,=CH3 R2=H -NMR (δ, CDC13): 6.63 (q, R-CH=, J=7H2) 4.20
(dd, NHCHCO.

J=7.0, 7.0H2) 4.61 (dt, NHCHCO.

J = 8.0, 4.0H2) [α]D (c = t, methanol) = -31-9° Elemental analysis value: Cl8H2□N307 Calculated value (%); C51,48H7,29N11.
25 Actual value (%); C51,37H7,37N1
1.29 <Example 88> Starting material α-amino-α-butenoic acid NCA Additive substance ■: BOC-L-valine intermediate BOC-L-valyl-α-amino-α-butenoic acid NCA Additive substance ■: L -Serine methyl ester target product BOC-L-valyl-α-amino-α-butenoic acid-L-
Serine methyl ester, R,=CH3 R2=H X3=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=7H2) 4.02
(m, NHCHCO) 4+ 62 (m, NHCHCO) [α]D (C=1.methanol)=-22,9゜Elemental analysis value 018H31N30□ Calculated value (%); C5:1185 H7,78N10
．． 47 Actual value (%); C53,75H7,94N1
0.39 <Example 89> Starting material Δ-n-valine NCA Additive material ■: BOC-L-alanine intermediate BOC-L-alanyl-Δ-n-valine NcA Additive ■: L-serine methyl ester Purpose Product BOC-L-alanyl-Δ-n-valyl L-serine methyl ester However, R,=C2N5 R2=H X3=BOC AA=L-alanine residue AA'=L-serine residue Y=CH3 Yield ( %) 267 Melting point (℃): Oil IH-NMR (δ, CDC13): 6, 57 (t, R-CH=, J=7Hz)
4.20 (dd, NHCHCO.

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

J=8.0, 4.0Hz) [α]D (c=1, methanol) = -34,5° Elemental analysis value: C17H2°N30□ Calculated value (%); C52-70H7,55N10.
85 Actual value (%); C52,90H7,47N1
0.69 <Example 90> Starting material Δ-phenylalanine NCA Additive material ■: BOC-glycine intermediate BOC-glycyl-Δ-phenylalanine NG Additive material ■: L-methionine methyl ester Target product BOC-glycyl-Δ-phenylalanine Ru L-methionine methyl ester However, R,=C6N5 R2=H H-NMR (δ, CDC13) near, 12 (5, R-CH=) 3.70 (d, NHCHCO, J=6Hz) 4.51
(dt, NHCHCO.

J = 8.0, 7.0Hz) [α]D (c = t, methanol) = -50,9° Elemental analysis value: C22H3□N306S Calculated value (%); C5B, 78 H8, 71N 9
．． 03 actual value (%); C3f3.83 H8,85
N 9.10 <Example 91> Starting material Δ-phenylalanine NCA Additive material ■: BOC-glycine intermediate BOC-glycyl-Δ-phenylalanine NCUn substance ■: L-leucine methyl ester Target product BOC-glycyl-Δ-phenylalanine Leu L-leucine methyl ester However, R,=C6R5 R2=H 1H-NMR (δ, CDC13) near, 16 (s, R-C =) 3, 70 (d, NHCHCO, J = 5.5
Hz) 4.40 (dt, NHCHCO.

J=8.0, 4.5Hz) [α]D (C=1.methanol)=-26,2° Elemental analysis value: C23H33N306 Calculated value (%); C81,72H7,43N 9.
38 Actual value (%); C81,80H7,38N
L45 <Example 92> Starting material α-amino-α-butenoic acid NCA Additive material ■: BOC-L-phenylalanine intermediate BOC-L-phenylalanyl-α-amino-α-butenoic acid NCA 1 Additive J■ : L-alanine methyl ester target product BOC-L-phenylalanyl-α-amino-α-butene 1-L-alanine methyl ester However, R,=CH3 R2=H X3=BOC AA=L-phenylalanine residue AA '=L-alanine residue Y=CH3 Yield (%)=94 Melting point (°C): 190-191 1H-NMR (δ, CDC13): 6, 65 (q, R-CH=, J=7, 5
Hz) 4.36 (dq, NHCHCO.

J = 8.0, 5.5 Hz) 4.59 (m, NHCHCO) [α] D (c = t, methanol) = -26, 4° Elemental analysis value 022H31N3°6 Calculated value (%); C80, 95H7, 21N 9.
89 actual value (%); C81,08H7,18N 9
．． 73 <Example 93> Starting material Δ-leucine NCA Additive material ■: BOC-L-leucine intermediate BOC-L-leucyl-Δ-leucine NCA1 additive W■
: L-alanine methyl ester Target object BOC-L-leucyl-Δ-leucyl-L-alanine methyl ester However, R1= i -C3R7 R2=H X3=BOC AA=L-leucine residue AA"=L-alanine residue Y=CH3 Yield (%)=87 Melting point (C: 126-127'H-NMR (δ, CDC13): 6.36 (d, R-C■=, J=10Hz) 4.19
(m, NHCHCO) 4.62 (dq, NHCHCO.

J=7.5, 5.0Hz)

Claims (31)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. represents a substituent.However, R_1 and R_2 are not hydrogen atoms at the same time.X_1 represents a protecting group for the α-amino group of an acyl or urethane amino acid, and AA represents an α-amino acid residue N-(N'-protected-α-amino acid)-N-
Carboxy-α,β-dehydro-α-amino acid anhydride. (2) N-(N '-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride. (3) N-(N'- protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride. (4) N-(N '-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride. (5) N-(N '-protected-α-amino acid)-N
-Carboxy-α,β-dehydro-α-amino acid anhydride. (6) R_1 is a hydrogen atom, R_2 is a phenyl group, X_1 is a t-butoxylcarbonyl group, and A
N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 1, wherein A is an L-leucine residue. (7) R_1 is a hydrogen atom, R_2 is a phenyl group, X_1 is a t-butoxylcarbonyl group, and A
N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 1, wherein A is an L-phenylalanine residue. (8) R_1 is a hydrogen atom, R_2 is a phenyl group, X_1 is a t-butoxylcarbonyl group, and A
N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 1, wherein A is an L-proline residue. (9) N-carboxy-α,β-dehydro-α-amino acid anhydride and α-carboxy-α,β-dehydro-α-amino acid anhydride and α-
An amino acid (X_2AAOH) (X_2 represents a protecting group for the α-amino group of a urethane-type or alkyl-type amino acid. AA is the same as above) in a predetermined solvent using a predetermined condensing agent and a predetermined base. A method for producing N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride by reaction. (10) The N-(N'
-Protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride. (11) N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 9 or 10, wherein the predetermined base is pyridine. A manufacturing method to obtain something. (12) N-(N'-protected-α-amino acid)-N-carboxy-α,β-dehydro- according to claim 9 or 10, wherein the predetermined base is N-methyl-morpholine. A manufacturing method for obtaining α-amino acid anhydride. (13) N-carboxy-α,β-dehydro-α-amino acid anhydride and α whose amino group is protected with a specified protecting group.
-Amino acid (X_3AAOH) (X_3 represents an acyl type or urethane type protecting group that is stable under relatively acidic conditions) is converted into an N-protected α-amino acid halide (X_3AAZ:Z is (representing a halide) in a predetermined solvent in the presence of a predetermined base,
N-(N'-protected-α-amino acid)-N-carboxy-
A manufacturing method for obtaining α,β-dehydro-α-amino acid anhydride. (14) General formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are the same as above.) N-carboxy-α,β-dehydro-α-
Amino acid anhydride. (15) N-carboxy-α,β- according to claim 14, wherein R_1 and R_2 are both alkyl groups.
Dehydro-α-amino acid anhydride. (16) N-carboxy-α according to claim 15, wherein R_1 is a methyl group and R_2 is an ethyl group
, β-dehydro-α-amino acid anhydride. (17) N-carboxy-α,β- according to claim 15, wherein R_1 and R_2 are both methyl groups.
Dehydro-α-amino acid anhydride. (18) N according to claim 14, wherein R_1 is a hydrogen atom and R_2 is the above-mentioned substituent other than a hydrogen atom.
-Carboxy-α,β-dehydro-α-amino acid anhydride. (19) Claim 1 in which R_2 is a phenyl group
N-carboxy-α,β-dehydro-α-amino acid anhydride according to item 8. (20) N-carboxy-α,β-dehydro-α according to claim 18, wherein R_2 is an isopropyl group
- Amino acid anhydrides. (21) The N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 18, wherein R_2 is a normal propyl group. (22) Claim 18 in which R_2 is an ethyl group
N-carboxy-α,β-dehydro-α-amino acid anhydride as described in 2. (23) Claim 18 in which R_2 is a methyl group
N-carboxy-α,β-dehydro-α-amino acid anhydride as described in 2. (24) N-carboxy-α,β- according to claim 18, wherein R_2 is a para-hydroxyphenyl group
Dehydro-α-amino acid anhydride. (25) The N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 18, wherein R_2 is a para-methoxyphenyl group. (26) N-carboxy-α according to claim 18, wherein R_2 is a para-methoxymethoxyphenyl group
, β-dehydro-α-amino acid anhydride. (27) N-Cbz-α, β-dehydro-α shown by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (In the formula, R_1 and R_2 are the same as above. Cbz represents a benzyloxycarbonyl group.) - A production method for producing N-carboxy-α,β-dehydro-α-amino acid anhydride by reacting an amino acid with a predetermined acid halogenating agent in a predetermined solvent. (28) N-carboxy-α,β- according to claim 27, wherein the predetermined acid halogenating agent is thionyl chloride.
A manufacturing method for obtaining dehydro-α-amino acid anhydride. (29) N-carboxy-acid according to claim 27 or 28, wherein the predetermined solvent is acetyl chloride.
A manufacturing method for obtaining α,β-dehydro-α-amino acid anhydride. (30) When R_1 of the N-Cbz-α,β-dehydro-α-amino acid is a hydrogen atom and R_2 is a para-methoxymethoxy-phenyl group, the predetermined solvent is an ether. A manufacturing method for obtaining N-carboxy-α,β-dehydro-α-amino acid anhydride according to item 28. (31) The method for producing N-carboxy-α,β-dehydro-α-amino acid anhydride according to claim 30, wherein the ether is diethyl ether.