DESCRIPTION

Title of Invention: PEPTIDE COMPOUND AND METHOD FOR PRODUCING THE SAME

Technical Field

[0001]
The present invention relates to a method for producing a cyclic peptide compound useful as an active ingredient for a pharmaceutical composition, particularly a pharmaceutical composition for treatment of hepatitis C virus (HCV), which is known as an inhibitor against the RNA replication of hepatitis C virus replicons, an intermediate useful for production of the cyclic peptide compound, and a method for producing the same.

Background Art

[0002]
It is reported that a cyclic peptide compound of the following formula (A) or a salt thereof is useful as an active ingredient of a pharmaceutical composition for treatment of HCV, based on its inhibitory activity against the RNA replication of hepatitis C virus replicons (Patent Citation 1).

[Chem. 1]
[For the symbols in the formula, refer to Patent Citation 1.]

[0003]
Patent Citation 1 discloses that the compound of the formula (A) or a salt thereof can be produced using an FR901459 substance (Patent Citation 2) which is a fermentation product as a starting material via the compound of the formula (I) or a salt thereof. Specifically, it is carried out via the steps <1> to <6> below.
<1> Production of the compound of the formula (I) or a salt thereof by N-0 rearrangement and then ring-opening of the FR901459 substance or a salt thereof.
<2> Production of the compound of the formula (A2-2) or a salt thereof by condensing threonine to a C-terminal of the compound of the formula (I) or a salt thereof.
<3> Production of the compound of the formula (A3) or a salt thereof by carrying out Edman degradation three times on the compound of the formula (A2-2) or a salt thereof.
<4> Production of the compound of the formula (A4-4) or a salt thereof by condensing a diamino acid to the N-terminal of the compound of the formula (A3) or a salt thereof.
<5> Production of the compound of the formula (A) or a salt thereof by cyclizing the compound of the formula (A4-4) or a salt thereof.
<6> Production of the compound of the formula (Ab) or a salt thereof by reducing the compound of the formula (Aa) or a salt thereof.

Each of the steps will be described in detail below.

[0004]
<1> This step is a step of producing the compound of the formula (I) or a salt thereof from an FR901459 substance represented by the formula (Al-1) or a salt thereof. Specifically, the compound of the formula (I) or a salt thereof is produced by subjecting the FR901459 substance to an N-0 rearrangement reaction under weakly acidic conditions, and then hydrolysis of the compound of the formula (A 1-2) or a salt thereof obtained by protection of an amino group to effect ring-opening.


[wherein Prot0 means a protective group. For the other symbols in the formula, refer to Patent Citation 1.]

[0005]
<2> This step is a step of producing the compound of the formula (A2-2) or a salt thereof from the compound of the formula (I) or a salt thereof. The compound of the formula (A2-2) or a salt thereof is produced by condensing the compound of the formula (A2-1) to the compound of the formula (I) or a salt thereof.
[Chem. 3]

[wherein Prot0 means a protective group. For the other symbols, refer to Patent Citation 1.]

[0006]
<3> This step is a step of producing the compound of the formula (A3) or a salt thereof from the compound of the formula (A2-2) or a salt thereof. The compound of the formula (A3) or a salt thereof is produced by subjecting the compound of the formula (A2-2) or a salt thereof to Edman degradation three times, that is, to elimination of amino acids sequentially from the N-terminal of the compound of the formula (A2-2) or a salt thereof.

[For the symbols in the formula, refer to Patent Citation 1.]

[0007]
<4> This step is a step of producing the compound of the formula (A4-4) or a salt thereof from the compound of the formula (A3) or a salt thereof. The compound of the formula (A4-4) or a salt thereof is produced by condensing the protected amino acid of the formula (A4-3) to the compound of the formula (A4-2) or a salt thereof, which has been obtained by subjecting the compound of the formula (A3) or a salt thereof to introduction of an amino acid to the N-terminal and deprotection.

[wherein each of Prot and Prot means a protective group. For the other symbols, refer to Patent Citation 1.]

[0008]
<5> This step is a step of producing the compound of the formula (Aa) or a salt thereof from the compound of the formula (A4-4) or a salt thereof. The compound of the formula (Aa) or a salt thereof is produced by subjecting the compound of the formula (A4-4) or a salt thereof to deprotection and then to macrolactamization.

[For the symbols in the formula, refer to Patent Citation 1.]

[0009]
<6> This step is a step of producing the compound of the formula (Ab) or a salt thereof from the compound of the formula (Aa) or a salt thereof. The compound of the formula (Ab) or a salt thereof is produced by the usual catalytic reduction.
[Chem. 7]
I1IV Vaf l¥IV IWM N^
[For the symbols in the formula, refer to Patent Citation 1.]

[0010]
This is a process of repeatedly carrying out Edman degradation which may cause a problem when production of the compound of the formula (A) of a salt thereof in the above-described production method is scaled up to an industrial level. Since byproducts obtained by Edman degradation potentially make the next reaction complex, purification is required. It is particularly preferable not to carry out column chromatography requiring complicated operations when scaled up to the industrial level.

In Patent Citation 1 (for example, Prep 3), a step of purifying by means of column chromatography is included between the steps.
Prior Art Citation Patent Citation

[0011]
[Patent Citation 1] WO 2007/049803
[Patent Citation 2] JP-A-5-271267
Summary of Invention

Problem to Be Solved by the Invention

[0012]
An efficient method for producing the compound of the formula (A), which is designed for an industrial production process and is superior in operability, purity, and the like, an intermediate useful for the production, and a method for producing the intermediate, are provided.

Means for Solving the Problem

[0013]
The present inventors have made extensive studies on an efficient production method which is designed for an industrial production process and is superior in operability, purity, and the like. As a result, they have found a reaction with which the number of steps can be reduced, and have thus found a method for producing a compound of the formula (A) with a view to industrial production, in which the compound can be obtained at a high purity even without purification by which requires operations, an intermediate useful for the production, and a method for producing the intermediate, thereby completing the present invention.

[0014]
According to the present invention, Edman degradation may be carried out once, and even without purification by means of column chromatography which follows as a post-treatment, the compound of the formula (A) and an intermediate useful for the production thereof can be provided at a high purity.

[0015]
[1]
A method for producing a compound of the formula (III) or a salt thereof: [Chem. 9]
(wherein Rx means -H or a protective group, iBu means isobutyl, iPr means isopropyl, and Me means methyl),
which comprises eliminating a diamino acid from a compound of the formula (II) or a salt thereof:
[Chem. 8]
[2]
A method for producing a compound of the formula (VI) or a salt thereof:
(wherein R means -H or a protective group, iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot0 and Prot1 mean protective groups), which comprises subjecting a compound of the formula (I) or a salt thereof: [Chem. 10]
to a deprotection reaction to obtain a compound of the formula (U) or a salt thereof, and introducing a protective group to the compound of the formula (UT) or a salt thereof obtained by the step described in [1].

[0016]
[3]
A method for producing a compound of the formula (A) or a salt thereof:
R1 is -H, or lower alkyl;
R is -H, aryl, or lower alkyl,
wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, carbamoyloxy which may be substituted, and amino which may be substituted;

[Chem. 15]
is a nitrogen-containing heterocycle; and
Yis

[Chem. 16]
R3 is cycloalkyl, aryl, a heterocycle which may be substituted, or lower alkyl,
wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, lower alkoxy-lower alkylene-O-, amino which may be substituted, and -OC(0)NR R ,
(wherein R6 and R7 each independently represent -H or lower alkyl, or R6 and R7, together with a nitrogen atom to which they bind, represent a nitrogen-containing heterocycle, which may be substituted with lower alkyl);
R4 and R5 each independently represent -H or lower alkyl;
— represents a single bond or a double bond.
(provided that if R is -H, R is cycloalkyl, aryl, a heterocycle which may be substituted, lower alkoxymethyl, aralkyl, t-butyl, sec-butyl, cycloalkyl, or ethyl,
wherein the ethyl may be substituted with one suitable substituent selected from the group consisting of lower alkyl, or hydroxy, lower alkyl-O-, aryl-lower alkylene-O-, lower alkyl-O-lower alkylene-O-, amino which may be substituted, and -OC(O) NR6R7)), from the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof by the production method of [2].
[4]
A method for producing a compound of the formula (VIII) or a salt thereof:
(wherein Prot means a protective group),
which comprises subjecting the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the production method of [2] to condensation with a protected threonine at the carboxylic acid terminal, and deprotecting the amino terminal.
[5]
A method for producing a compound of the formula (A) or a salt thereof, which comprises subjecting the compound of the formula (VIII) or a salt thereof
obtained from the compound of the formula (I) or a salt thereof according to the method
described in [3] to condensation with a diamino acid at the amino terminal, carrying out
deprotection, and then carrying out cyclization.

[0017]
[6]
A compound or a salt thereof selected from the group consisting of:

[0018]
The intermediate obtained by the production method of the present invention is useful from the viewpoints shown below.

[0019]
(1) The compound of the formula (VIII) or a salt thereof obtained by the above-described production method [4] is useful as an intermediate for production since by subjecting it to condensation of a diamino acid to the N-terminal, deprotection, and then cyclization, the compound of the formula (A) or a salt thereof can be produced, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment.

[0020]
(2) The compound of the formula (VI) or a salt thereof obtained by the above-described production method [2] is useful as an intermediate for production since by subjecting it to condensation of a protected threonine to the C-terminal and deprotection of the N-terminal, the compound of the formula (VIII) or a salt thereof can be produced, and the compound of the formula (VIII) or a salt thereof thus obtained allows production of the compound of the formula (A) or a salt thereof, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment, by the method as described in (1) above.

(3) The compound of the formula (III) or a salt thereof obtained by the above-described production method [1] is useful as an intermediate for production since by subjecting it to Edman degradation once and then protection of the N-terminal, the compound of the formula (VI) or a salt thereof can be produced, and the compound of the formula (VI) or a salt thereof thus obtained allows production of the compound of the formula (A) or a salt thereof, which is reported to be useful as an active ingredient of an anti-HCV pharmaceutical composition for treatment, by the methods as described in (1) and (2) above.

[0021]
Furthermore, unless specifically described otherwise, in the case where the symbols in any of the formulae in the present specification are also used in other formulae, the same symbols denote the same meanings.

Effects of the Invention

[0022]
The present production method is superior in operability from the viewpoints that a diamino acid can be eliminated in a single step. According to the present production method, for example, since the compound of the formula (III) or a salt thereof of the present invention does not cause by-production of thiohydantoins or the like in a step in which an Edman degradation reaction can be omitted, even without purification by means of chromatography, the compound of the formula (A), an intermediate for producing the same, or a salt of each thereof can be obtained at a high purity by crystallization. Accordingly, it can be scaled up to the industrial level.

Best Mode for Carrying Out the Invention

[0023]
Hereinbelow, the present invention will be described in detail.

In the present specification, the "protective group" is a group which does not have any effect on a functional group even during the deprotection while not interfering with the reaction. Examples thereof include protective groups described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G. M. Wuts and T. W. Greene, and the like, and the protective group may be appropriately selected according the reaction conditions and used.

[0024]
As for the "N-terminal" or the "C-terminal", in the linear peptide, an amino group or a carboxyl group exists on both terminals, but the "N-terminal" means a side on which an amino group exists and the "C-terminal" means a side on which a carboxyl group exists.

[0025]
The expression "which may be substituted" means which is not substituted or which has 1 to 5 substituents. Further, if it has a plurality of substituents, such substituents may be the same as or different from each other.

[0026]
Unless otherwise specifically denoted, the "lower" means a group having 1 to 6 carbon atoms (hereinafter simply referred to as Ci^), and preferably 1 to 4 carbon atoms.

[0027]
The "lower alkyl" is linear or branched Ci-6 alkyl, and it is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or the like, in another embodiment, Ci_4 alkyl, and in a further embodiment, methyl, ethyl, or propyl.

[0028]
The "lower alkylene" is a linear or branched Ci-6 alkylene, and it is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, or the like, and in another embodiment, CM alkylene.

[0029]
The "lower alkoxy" is a linear or branched Ci-e alkylalkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, tert-pentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and the like. In another embodiment, it is methoxy, ethoxy, or propoxy.

[0030]
The "cycloalkyl" is C3-6 alkylcyclic alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0031]
The "aryl" is phenyl, naphthyl, anthryl, or the like.

[0032]
The "aralkyl" is lower alkyl substituted with 1 to 5 aryl groups, such as phenylpropyl, phenethyl, benzyl, and the like.

[0033]
The "aralkoxy" is lower alkoxy substituted with 1 to 5 aryl groups, such as phenylpropoxy, phenethyloxy, benzyloxy, and the like.

[0034]
Suitable examples of the "amino which may be substituted" include amino which may be substituted with 1 or 2 suitable substituent(s), such as lower alkyl, an amino protective group (for example, benzyloxycarbonyl, Boc, and the like), etc.

[0035]
Suitable examples of the "carbamoyloxy which may be substituted" include carbamoyloxy which may be substituted with 1 or 2 suitable substituent(s), such as lower alkyl, a protective group for an amino group (for example, benzyloxycarbonyl, Boc, and the like), etc.

[0036]
The "heterocycle" is as follows:

(1) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 to 4 nitrogen atom(s), such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (for example: 4H-l,2,4-triazolyl, lH-l,2,3-triazolyl, 2H-l,2,3-triazolyl, and the like), tetrazolyl (for example 1 H-tetrazolyl, 2H-tetrazolyl, and the like), azepinyl, and the like;

(2) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 to 4 nitrogen atom(s), such as aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl, 2,5-methanopiperazinyl, hexahydroazepinyl, and the like;

(3) an unsaturated condensed heterocycle containing 1 to 4 nitrogen atom(s), such as indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, tetrahydroindolyl, dihydroindazolyl, and the like;

(4) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as oxazolyl, isoxazolyl, oxadiazolyl (for example: 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, and the like), and the like;

(5) saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as morpholinyl, sydnonyl, and the like;

(6) an unsaturated condensed heterocycle containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), such as benzoxazolyl, benzoxadiazolyl, and the like;

(7) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as thiazolyl, isothiazolyl, thiadiazolyl (for example: 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, and the like), dihydrothiazinyl, and the like;

(8) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as thiazolidinyl, and the like;

(9) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 sulfur atom(s), such as thienyl, dihydrodithiinyl, dihydrodithionyl, and the like;

(10) an unsaturated condensed heterocycle containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), such as benzothiazolyl, benzothiadiazolyl, imidazothiadiazolyl, and the like;

(11) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing an oxygen atom, such as furyl and the like;

(12) a saturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing 1 or 2 oxygen atom(s), such as oxiranyl, 1,3-dioxolanyl, tetrahydrofuranyl, tetrahydropyranyl, and the like;

(13) an unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocycle containing an oxygen atom and 1 or 2 sulfur atom(s), such as dihydroxathiinyl, and the like;

(14) an unsaturated condensed heterocycle containing 1 or 2 sulfur atom(s), such as benzothienyl, benzodithiinyl, and the like;

(15) an unsaturated condensed heterocycle containing an oxygen atom and 1 or 2 sulfur atom(s), such as benzoxathiinyl and the like;

(16) a saturated condensed heteromonocycle containing 1 to 3 nitrogen atom(s), such as tetrahydropyridopyrrolidinyl and the like; etc.

[0037]
Suitable examples of the "nitrogen-containing heterocycle" are those in (1) to (7) as described above, and in another embodiment, are heterocycles containing at least one nitrogen atom, such as pyrrolidinyl, piperidyl, morpholinyl, thiazolyl, oxazolyl, and the like.

[0038]
Suitable examples of the "heterocycle" which may be substituted are the above-described heterocycles, which may be substituted with at least one appropriate substituent, such as lower alkyl, lower alkoxy, aryl, amino, lower alkoxycarbonyl, and the like.

[0039]
The "halogen" means fluorine, chlorine, bromine, or iodine.

[0040]
In the present specification, the following abbreviations may be used in some cases.
CPME=cyclopentylmethylether, DIBOC=di-tert-butyl dicarbonate, DME=1,2-dimethoxyethane, DMF=N,N-dimethylformamide, DMI=l,3-dimethyl-2-imidazolidinone, DMSCNdimethylsulfoxdie, DIPEA=diisopropylethylamine, DPPA=diphenylphosphorylazide, EtOAc=ethyl acetate, Ex= Example No., HOBt=l-hydroxybenzotriazole, IPA=isopropyl alcohol, KH2P04=potassium dihydrogen phosphate, NMP=N-methylpyrrolidone, Na2C03=sodium carbonate, Na2HP04=disodium hydrogen phosphate, TEA=triethylamine, TFA=trifiuoroacetic acid, WSC=l-ethyl-3-(3-

dimethylaminopropyl) carbodiimide, tBuOH=tertiary butanol, LR-ESIMS=low-resolution-ESIMS, HR-ESIMS=high-resolution-ESIMS, Me=methyl, iBu=isobutyl, iPr=isopropyl, Boc=tertiary butoxycarbonyl, Ph=phenyl, No.=number.

[0041]
The compound of the present invention may exist in the form of geometric isomers. In the present specification, the compound of the present invention shall be described in only one form of isomer, but the present invention includes such an isomer, isolated forms of the isomers, or a mixture thereof.

In addition, the compound of the present invention has asymmetric carbon atoms, and correspondingly, it exists in the form of optical isomers. The present invention includes both an isolated form of these optical isomers of the compound of the present invention, or a mixture thereof.

[0042]
Furthermore, the compound of the present invention may form a salt with an acid or a base, depending on the kind of substituents, in some cases. Specifically, examples of the salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditolyl tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamic acid, and the like, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and the like or organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, and the like, salts with various amino acids or amino acid derivatives such as acetylleucine and the like, ammonium salts, etc.

[0043]
In addition, the present invention also includes various hydrates or solvates, and polymorphic crystal substances of the compound of the present invention and a salt thereof. Also, the present invention includes compounds labeled with various radioactive or non-radioactive isotopes.

[0044]
(Production Methods)

Hereinbelow, representative production methods for the compounds of the formula (I) to (VIII) will be described. (First Step) [Chem. 19]

[0045]
The present step is a step in which the N-terminal is deprotected, and then a diamino acid is eliminated in a single step under the heating condition.
When Rx is a protective group, examples thereof include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like. In another embodiment, examples thereof include lower alkyl, benzyl, and tert-butyl.
Examples of Prot0 include carbamate, toluenesulfonyl, nitrobenzenesulfonyl, and the like. In another embodiment, examples thereof include Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and allyloxycarbonyl.
For deprotection, reference may be made to, for example, a deprotection reaction for each protective group as described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G. M. Wuts and T. W. Greene, and the deprotection may be appropriately selected and used according to these reaction conditions.

By warming the starting material intermediate in a solvent, the diamino acid is eliminated. As a reaction temperature, conditions from heating to reflux are preferable. The solvent is not limited as long as it does not disturb the reaction. As the solvent, for example, CPME, dioxane, THF, DMSO, DMF, IPA, tBuOH, NMP, DMI, DME, water, or the like is used, ether-based solvents or water is preferable, and CPME-aqueous solvents are particularly preferable. The reaction may be either homogeneous or biphase, but biphase is particularly preferred. It may be advantageous to carry out the reaction in the presence of an acid or a base, or salts. Usually, to the reaction liquid is added a buffer solution, and thus, the reaction is carried out in the water-containing system. Examples of the buffer solution include phosphate buffers, Tris buffers, and the like, but phosphate buffers are preferred. The temperature varies depending on the solvent, and the reaction is carried out at a temperature of from 30°C to a refluxing temperature of the solvent, for example, from 30°C to 180°C. A temperature from 50°C to 120°C is preferred, and a temperature from 60°C to 85°C is particularly preferred. As in the description in Examples as described later, the product can be obtained as a crystal even without a seed crystal, but when the seed crystal is added to precipitate the crystal, the crystal may be easily precipitated in some cases.

[0046]

[0047]
The present step is Edman degradation, which is a step of eliminating an amino acid of the peptide from the N-terminal.

It includes two steps of subjecting phenyl isothiocyanate at the N-terminal under weakly basic conditions, and eliminating the amino acid under acidic conditions as 3-phenyl-2-thiohydantoin. As for the solvent, the reaction is usually carried out in a common solvent such as an organic solvent not giving an adverse effect on the reaction, such as acetonitrile, acetone, alcohols such as MeOH, EtOH, and the like, THF, dioxane, toluene, methylene chloride, chloroform, EtOAc, DMF, and the like, or a mixed solvent thereof, and the like. The reaction temperature is not limited, and the reaction is usually carried out under conditions from cooling to heating. The present reaction can be carried out by, for example, the method disclosed in M. K. Eberle et al., J. Org. Chem. 59, 7249-7258 (1994) or the like, or an equivalent method.

[0048]

[0049]
The present step is a step in which the N-terminal of a chained peptide as an intermediate is protected, a protected threonine is condensed to a C-terminal, and then the N-terminal is deprotected.

Examples of Prot2 include lower alkyl which may be substituted with phenyl, lower alkyl which may be substituted with aryl, and the like. In another embodiment, examples thereof include lower alkyl, benzyl, and tert-butyl.

Examples of Prot1 include carbamate, toluenesulfonyl, nitrobenzenesulfonyl, and the like. In another embodiment, examples thereof include Boc, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl.
In order to condense a protected threonine to the C-terminal of the chained peptide of the substrate, the condensation can be carried out in the same manner as a so-called amidation reaction. Specifically, the compound of the formula (VII) or a salt thereof can be obtained by reacting the compound of the formula (VI) or a salt thereof with the protected threonine of the formula (B2). In this reaction, the compound of the formula (VI) or a salt thereof and the protected threonine of the formula (B2) are used in equal amounts or with an excess amount of either, and the mixture is stirred under any temperature condition from cooling to heating in a solvent which is inert to the reaction, preferably at -20°C to 60°C, usually for 0.1 hours to 5 days. Examples of the solvent used herein are not particularly limited, but the examples include aromatic hydrocarbons such as toluene, xylene, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, ethers such as diethyl ether, THF, dioxane, dimethoxyethane, and the like, DMF, DMSO, EtOAc, MeCN, water, and a mixture thereof. Examples of the condensing agent include, but are not limited to, WSC, DPPA, and phosphorous oxychloride. It may be preferable for the reaction to use an additive (for example, HOBt) in some cases. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction in the presence of organic bases such as TEA, DIPEA, N-methylmorpholine, and the like, or inorganic bases such as K2C03, Na2C03, KOH, and the like.

Furthermore, a method in which the compound of the formula (VII) or a salt thereof is converted to its reactive derivative, followed by performing a reaction with the protected threonine of the formula (B2) may be used. Examples of the reactive derivative of the carboxylic acid include acid halides that can be obtained by the reaction of a halogenating agent such as phosphorus oxychloride, thionyl chloride, and the like, mixed acid anhydrides obtained by the reaction of isobutyl chloroformate or the like, active esters obtained by the condensation with HOBt or the like, etc. The reaction of the reactive derivative and the protected threonine of the formula (B2) can be carried out at a temperature from under cooling to heating, preferably at -20°C to 60°C, in a solvent which is inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, and the like.

[Citation] "Organic Functional Group Preparations", S. R. Sandler and W. Karo, 2nd edition, Vol. 1, Academic Press Inc., 1991
"Courses in Experimental Chemistry (5th edition)", edited by The Chemical Society of Japan, vol. 16 (2005) (Maruzen Company, Limited)

[0050]
(Fourth Step)
The compound of the formula (III) or a salt thereof, the compound of the formula (V) or a salt thereof, or the compound of the formula (VIII) or a salt thereof can be protected or deprotected using a suitable protective group in a suitable process, and condensed with an amino acid or peptide, thereby producing the compound of the formula (A) or a salt thereof. The cyclization reaction is amidation, and thus, it can be carried out according to the method as in the above-described third step, and accordingly, reference may be made to the third step for the reagent and reaction conditions used (for example, a solvent, a reaction temperature, and the like).

[0051]
(Starting Material Synthesis)

As described above, the compound of the formula (I) or a salt thereof can be produced using an FR901459 substance as a starting material in accordance with Patent Citation 1.
The FR901459 substance can be obtained by, for example, the method described in Patent Citation 2 from a culture of a Stachybotrys spp. microorganism {Stachybotrys chartarwn No. 19292), deposited at International Patent Organism Depositary National Institute of Advanced Industrial Science and Technology, Tsukuba Central 6, 1-1-1, Higashi, Tsukuba-shi, Ibaraki-ken, (Postal Code) 305-8566, JAPAN on April 16, 1991 with deposit No. FERM BP-3364.

[0052]
Example Compounds are isolated and purified as free compounds, salts thereof, hydrates, solvates, or polymorphic crystal substances thereof.

The salt of Example

Compounds can also be produced in accordance with a conventional method for a salt formation reaction. Isolation and purification are carried out by employing extraction or fractional crystallization.

Examples

[0053]
Hereinbelow, the methods for producing the compounds of the formulae (I) to (VIII) will be described in detail with reference to Examples. The structures of Example Compounds are shown in Table 4.

[0054]
Example 1 (Production of the compound of the formula (I), wherein Prot0 is Boc)
93.8 mg of (6S,12S,15S,18S,21S,24R,27S,30S,33S,36S)-6-[(lR)-l-hydroxyethyl]-36-[(lR,2R,4E)-l-hydroxy-2-methyl-4-hexen-l-yl]-12,15,18,27,30-pentaisobutyl-33-isopropyl-2,2,8,11,17,21,24,26,32,35-decamethyl-4,7,10,13,16,19,22,25,28,31,34-undecaoxo-3-oxa-5,8,ll,14,17,20,23,26,29,32,35-undecaazaheptatriacontan-37-oic acid was obtained in accordance with the method described in Patent Citation 1.

[0055]
Example 2 (Production of the compound of the formula (II))
50.0 g of Example Compound 1 was dissolved in 500 mL of methylene chloride, followed by cooling to 5°C, and 213.2 g of TFA was added dropwise thereto, followed by stirring for 4 hours. Thereafter, 500 mL of cooled tap water was added thereto, followed by adjustment to pH 6.5 with a 10 (w/v) % aqueous NaaCCh solution. After liquid separation, to the organic layer was added 500 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2C03 solution. After liquid separation, the organic layer was collected by separation, and the lower layer was concentrated to about 250 mL, followed by addition of 500 mL of CPME and concentration to about 250 mL again. 500 mL of CPME was added thereto, followed by concentration under reduced pressure to about 250 mL. About 250 mL of a solution of Example Compound 2 in CPME was obtained.

[0056]
HR-ESIMS Found m/z 1236.8547 (M+H)+
Calcd for C62H114N11014, 1236.8546

[0057]
Example 3 (Production of the compound of the formula (III))
To about 250 mL of the solution of Example Compound 2 in CPME were added 500 mL of CPME and 500 mL of an aqueous phosphate buffer solution at pH 7.6 (the aqueous Na2HP04 solution was adjusted to pH 7.6 with an aqueous KH2PO4 solution; the aqueous Na2HPC"4 solution was prepared by dissolving 6.26 g of NaaHPCv 12H2O in 522 mL of water; the aqueous KH2PO4 solution was prepared by dissolving 0.377 g of KH2PO4 in 81 mL of water), followed by elevating the temperature to 80 to 85°C, stirring for 5 hours, and then cooling to 25°C. The organic layer obtained by liquid separation was washed with 500 mL of tap water twice. The organic layer was concentrated to about 105 mL, and then 115 mL of acetonitrile was added dropwise thereto. Thereafter, 75 mg of the seed crystal of Example Compound 3 was added thereto at an inner temperature of 22°C, and 345 mL of acetonitrile was further added dropwise thereto. The precipitated crystal liquid was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as a white powder. Amount: 22.7 g, Yield: 56.9%

[0058]
13C-NMR(125 MHz, CDCI3, 5):175.7 (s), 174.1 (s), 173.1 (s), 172.8 (s), 172.3 (s), 171.6 (s), 171.0 (s), 170.6 (s), 168.1 (s), 129.0 (d), 126.9 (d), 75.5 (d), 61.2 (d), 60.2 (d), 58.4 (d), 55.3 (d), 54.4 (d), 48.1 (d), 47.8 (d), 47.2 (d), 45.5 (d), 41.3 (t), 41.1 (t), 38.6 (t), 36.1 (t), 36.1 (d), 36.0 (t), 35.9 (t), 34.3 (q), 31.2 (q), 30.8 (q), 30.2 (q), 30.1 (q), 27.0 (d), 25.1 (d), 25.1 (d), 24.9 (d), 24.8 (d), 24.8 (d), 23.6 (q), 23.4 (q), 23.3 (q), 22.9 (q), 22.9 (q), 22.4 (q), 21.9 (q), 21.6 (q), 21.4 (q), 21.3 (q), 19.5 (q), 18.1 (q), 18.0 (q), 16.8 (q), 16.2 (q), 15.4 (q). (main conformers)
HR-ESIMS Found m/z 1064.7697 (M+H)+
CalcdforC55H102N9Oll, 1064.7698

[0059]
Further, a part of the reaction liquid of Example 3 was collected, and by the following analysis results, it was confirmed that 3-(l-hydroxyethyl)-l-methylpiperazine-2,5-dione was produced.

Column: Waters Atlantis HILIC Silica Column, 2.1x50mm, 3 urn; Gradient: CH3CN-HCOOH=1000-l^CH3CN-H2O-HCOOH=500-500-l(0 min->5 min), CH3CN-H2O-HCOOH=500-500-l(5 min->7 min), CH3CN-H2O-HCOOH=500-500-l)->-CH3CN-

HCOOH=1000-1(7 min->7.1 min), CH3CN-HC00H=1000:1 (7.1 min->-10 min), flow rate: 0.5 mL/min, Detector: diode array (210 run to 600 nm), Retention Time: 1.51 min.
13C-NMR (100MHz, DMSO-de): 166.3,166.2, 68.5, 60.6, 51.2, 32.9, 19.8
'H-NMR (400MHZ, DMSO-d6):1.08 (3H, d, J=6.6Hz), 2.82 (3H, s), 3.52 (1H, brs), 3.66 (1H, d, J=16.8Hz), 3.96 (1H, d, J=16.8Hz), 3.99 to 4.04 (1H, m), 8.26 (1H, brs),
MS: ESI (+)/TOF-MS, Found 173.0922 (M+H)+, Calcd for C7H13N203, 173.0921

[0060]
Example 3-1

(Method for Producing Amorphous Substance)

To a solution of Example Compound 2 in CPME (corresponding to 40.0 g/800 mL) was added 400 mL of an aqueous phosphate buffer solution at pH 7.6 (the pH of the aqueous Na2HP04 solution was adjusted to pH 7.6 with the aqueous KH2PO4 solution; the aqueous Na2HPC>4 solution was prepared by dissolving 6.26 g of Na2HP04-12H20 in 522 mL of water; the aqueous KH2PO4 solution was prepared by dissolving 0.377 g of KH2PO4 in 81 mL of water), followed by elevating the temperature to 80 to 85°C, stirring for 5 hours and 30 minutes, and then cooling to room temperature. The organic layer obtained by liquid separation was washed sequentially with 400 mL of tap water and 400 mL of 20 (w/v) % brine. The organic layer was concentrated to about 280 mL, and then 1800 mL of n-heptane was added dropwise thereto. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as powder. Amount: 32.17 g, Yield: 93.4%

[0061]
(Method for Producing Seed Crystal)
25.0 g of the powder of Example Compound 3 was dissolved in a mixed solvent of 40 mL of CPME and 160 mL of acetonitrile at 25 to 45°C. Thereafter, the mixture was cooled slowly to 20°C over 1 hour, and stirred at 20°C for 18 hours. The precipitated crystal was collected by filtration and then dried under reduced pressure to obtain (2S,3R,4R,6E)-3-hydroxy-4-methyl-2-[methyl(N-methyl-L-leucyl-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)amino]octa-6-enoic acid as a crystal. Amount: 13.02 g, Yield: 52.1%

[0062]
Example 4 (Production of the compound of the formula (IV))
10.0 g of Example Compound 3 was dissolved in 150 mL of EtOAc, and then 50 mL of a phosphate buffer at pH 7.6 (the pH of the aqueous Na2HP04 solution was adjusted to pH 7.6 with the aqueous KH2PO4 solution; the aqueous Na2HP04 solution was prepared by dissolving 1.04 g of Na2HP04-12H20 in 87.5 L of water; the aqueous KH2PO4 solution was prepared by dissolving 0.568 g of KH2PO4 in 12.5 L of water) and 2.54 g of phenylisothiocyanate were added thereto, followed by stirring for 4 hours. Thereafter, the pH was adjusted to 2.3 with 1 M hydrochloric acid. After liquid separation, the organic layer was collected by separation, washed with 100 mL of 20 (w/v) % brine, and then concentrated to about 40 mL. Thus, about 40 mL of a solution of Example Compound 4 in EtOAc was obtained.
LR-ESIMS: 1222.0 (M+Na)+, 1198.1 (M-H)"

[0063]
Example 5 (Production of the compound of the formula (V))
To about 40 mL of Example Compound 4 in EtOAc was further added dropwise 200 mL of n-heptane. The precipitated powder was collected by filtration, and then dissolved in 100 mL of acetonitrile, and 94 mL of 1 M hydrochloric acid was added thereto, followed by stirring at 20°C for 3 hours and 15 minutes. It was confirmed that Example Compound 5 was obtained.
HR-ESIMS Found m/z 937.6712 (M+H)+
Calcd for C48H89N8O10, 937.6701

[0064]
Example 6 (Production of the compound of the formula (VI), wherein Prot1 is Boc)
A 10 (w/v) % aqueous Na2CC>3 solution was further added to the reaction liquid of Example Compound 5 so as to adjust the pH to about 7. 2.25 g of DIBOC was added thereto, followed by stirring at 25°C for 3 hours and 20 minutes, and then adjustment to pH 2.5 with 1 M hydrochloric acid. The organic layer was collected by separation and 100 mL of 20 (w/v) % brine was added thereto, followed by extraction with 100 mL of EtOAc. The organic layer was collected by separation and then concentrated to about 40 mL and 150 mL of EtOAc was added again thereto, followed by concentration to about 40 mL. To this concentrated liquid was added again 150 mL of EtOAc, followed by concentration to about 40 mL. Then, the mixture was cooled to 5°C and added
dropwise to 40 mL of n-heptane that had been cooled to 5°C in advance. The precipitated powder was filtered and then dried under reduced pressure to obtain (2S,3R,4R,6E)-2-{[N-(tert-butoxycarbonyl)-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl] (methyl)amino}-3-hydroxy-4-methylocta-6-enoic acid as white powder. Amount: 7.6 g, Yield: 77.9%

[0065]
13C-NMR (125 MHz, CDC13, 5) 175.2 (s), 174.4 (s), 173.3 (s), 173.2 (s), 172.8 (s), 172.1 (s), 170.7 (s), 169.9 (s), 155.7 (s), 128.8 (d), 127.1 (d), 79.6 (s), 75.3 (d), 59.2 (d), 57.5 (d), 55.2 (d), 54.6 (d), 49.1 (d), 48.5 (d), 48.2 (d), 45.8 (d), 41.7 (t), 41.1 (t), 36.6 (t), 36.4 (d), 36.0 (t), 36.0 (t), 34.7 (q), 30.8 (q), 30.7 (q), 29.9 (q), 28.2 (q)x3, 27.2 (d), 25.0 (d), 24.9 (d), 24.8 (d), 24.6 (d), 23.4 (q), 23.4 (q), 23.2 (q), 23.0 (q), 22.0 (q), 21.7 (q), 21.5 (q), 21.4 (q), 19.1 (q), 18.2 (q), 18.0 (q), 17.5 (q), 16.8 (q), 15.3 (q). (main conformers)
HR-ESIMS Found m/z 1037.7219 (M+H)+
CalcdforC53H97N8012, 1037.7225

[0066]
Example 7 (Production of the compound of the formula (VII) wherein Prot1 is Boc and Prot is methyl)
7.5 g of Example Compound 6 was dissolved in 75 mL of methylene chloride, and 1.47 g of L-threonine methyl ester hydrochloride and 1.47 g of HOBt-monohydrate were added thereto, followed by cooling to 0 to 10°C. Further, 1.12 g of WSC was added thereto, followed by stirring at 5°C for about 20 hours, and then the organic layer was washed with 75 mL of tap water. The aqueous layer was re-extracted with 38 mL of methylene chloride and the organic layer was combined. The organic layer was washed with 68 mL of 0.3 M hydrochloric acid and the aqueous layer was re-extracted with 38 mL of methylene chloride again. The organic layer was combined, then washed sequentially with 76 mL of a 5(w/v) % aqueous NaHCC>3 solution and 55 mL of 20 (w/v) % brine, and concentrated to about 30 mL. The concentrated liquid was added dropwise to 300 mL of heptane. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain (N-[(2S,3R,4R,6E)-2-{[N-(tert-butoxycarbonyl)-L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl](methyl)amino}-3-hydroxy-4-methylocta-6-enoyl]-L-threoninemethyl ester as white powder. Amount: 7.12 g, Yield: 85.5%

[0067]
13C-NMR(125 MHz, CDC13, 5):174.1 (s), 174.0 (s), 173.5 (s), 172.5 (s), 172.4 (s), 171.4 (s), 171.2 (s), 170.8 (s), 170.4 (s), 155.7 (s), 128.5 (d), 127.3 (d), 79.5 (s), 74.5 (d), 67.7 (d), 58.3 (d), 58.3 (d), 57.3 (d), 55.1 (d), 54.9 (d), 52.6 (q), 49.1 (d), 48.0 (d), 47.7 (d), 45.8 (d), 42.0 (t), 40.8 (t), 36.4 (t), 36.1 (t), 35.5 (t), 35.4 (d), 34.6 (q), 30.9 (q), 30.7 (q), 30.3 (q), 28.3 (q) x3, 27.0 (d), 25.0 (d), 25.0 (d), 24.9 (d), 24.7 (d), 23.4 (q), 23.4 (q), 23.3 (q), 23.1 (q), 22.1 (q), 21.8 (q), 21.4 (q), 21.3 (q), 20.2 (q), 19.4 (q), 18.1 (q), 18.0 (q), 17.0 (q), 17.0 (q), 15.7 (q). (main conformers)
HR-ESIMS Found m/z 1152.7864 (M+H)+ Calcd for C58H106N9O14, 1152.7859

[0068]
Example 8 (Production of the compound of the formula (VIII), wherein Prot is methyl)
20.0 g of Example Compound 7 was dissolved in 120 mL of methylene chloride, followed by cooling to -5°C. 98.9 g of TFA was added dropwise thereto, followed by stirring for 2 hours and 40 minutes and then washing with 200 mL of cooled tap water. The organic layer obtained by liquid separation was further washed with 200 mL of cooled tap water. To the organic layer was added 200 mL of cooled tap water, followed by further adjustment to pH 6.5 to 7 using a 10 (w/v) % aqueous Na2CC>3 solution. To the organic layer obtained by liquid separation was added 200 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2CC"3 solution. The organic layer obtained by liquid separation was added to 200 mL of cooled tap water again, followed by adjustment to pH 6.5 to 7 with a 10 (w/v) % aqueous Na2C03 solution. The organic layer obtained by liquid separation was concentrated under reduced pressure to about 50 mL. The concentrated liquid was added dropwise to 1500 mL of heptane. The precipitated powder was collected by filtration and then dried under reduced pressure to obtain N-{(2S,3R,4R,6E)-3-hydroxy-2-[(L-leucyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-L-leucyl-N-methyl-L-valyl)(methyl)amino]-4-methylocta-6-enoyl}-L-threoninemethyl ester as white powder. Amount: 16.82 g, Yield: 92.1%.

As a result of comparison of the obtained Example Compound 8 with the compound of Prep 3 of Patent Citation 1 in terms of NMR and MS data, it was confirmed that they have the same structures.

[0069]
HR-ESIMS Found m/z 1052.7347 (M+H)+ Calcd for C53H98N9012, 1052.7335 [Table 2]

Industrial Applicability

[0070]
The present production method is superior in operability from the viewpoints that a diamino acid can be eliminated in a single step. According to the present production method, for example, since the compound of the formula (III) or a salt thereof of the present invention does not cause by-production of thiohydantoins or the like in a step in which an Edman degradation reaction can be omitted, even without purification by means of chromatography, the compound of the formula (A), an intermediate for producing the same, or a salt of each thereof can be obtained at a high purity by crystallization. Accordingly, it can be scaled up to the industrial level.

Claims

[Claim 1]
A method for producing a compound of the formula (III) or a salt thereof: [Chem. 23]
(wherein Rx means -H or a protective group, iBu means isobutyl, iPr means isopropyl, and Me means methyl),
which comprises eliminating a diamino acid from a compound of the formula (II) or a salt thereof:
[Chem. 22]

[Claim 2]
A method for producing a compound of the formula (VI) or a salt thereof: [Chem. 25]
(wherein Rx means -H or a protective group, iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot0 and Prot1 mean protective groups),
which comprises subjecting a compound of the formula (I) or a salt thereof: [Chem. 24]
to a deprotection reaction to obtain a compound of the formula (II) or a salt thereof, and introducing a protective group to the compound of the formula (III) or a salt thereof obtained by the step described in claim 1.

[Claim 3]
A method for producing a compound of the formula (A) or a salt thereof:
R1 is -H, or lower alkyl;
R is -H, aryl, or lower alkyl,
wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, carbamoyloxy which may be substituted, and amino which may be substituted;
[Chem. 29]
is a nitrogen-containing heterocycle; and
Yis

[Chem. 30]
R3 is cycloalkyl, aryl, a heterocycle which may be substituted, or lower alkyl, wherein the lower alkyl may be substituted with one suitable substituent selected from the group consisting of hydroxy, cycloalkyl, lower alkoxy, aryl, aralkoxy, lower ft 7
alkoxy-lower alkylene-O, amino which may be substituted, and -OC(0)NR R ,
(wherein R6 and R7 each independently represent -H or lower alkyl, or R6 and R7, together with a nitrogen atom to which they bind, represent a nitrogen-containing heterocycle, which may be substituted with lower alkyl);
R4 and R5 each independently represent -H or lower alkyl;
— represents a single bond or a double bond.

(provided that if R is-H, R is cycloalkyl, aryl, a heterocycle which may be substituted, lower alkoxymethyl, aralkyl, t-butyl, sec-butyl, cycloalkyl, or ethyl,
wherein the ethyl may be substituted with one suitable substituent selected from the group consisting of lower alkyl, or hydroxy, lower alkyl-O-, aryl-lower alkylene-O-, lower alkyl-O-lower alkylene-O-, amino which may be substituted, and -OC(O) NR6R7)), from the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof by the production method of claim 2.

[Claim 4]
A method for producing a compound of the formula (VIII) or a salt thereof:
(wherein iBu means isobutyl, iPr means isopropyl, Me means methyl, and Prot means a protective group),
which comprises subjecting the compound of the formula (VI) or a salt thereof obtained from the compound of the formula (I) or a salt thereof according to the production method of claim 2 to condensation with a protected threonine at the carboxylic acid terminal, and deprotecting the amino terminal.

[Claim 5]
A method for producing a compound of the formula (A) or a salt thereof, which comprises subjecting the compound of the formula (VIII) or a salt thereof
obtained from the compound of the formula (I) or a salt thereof according to the method
described in claim 3 to condensation with a diamino acid at the amino terminal, carrying
out deprotection, and then carrying out cyclization.

[Claim 6]
A compound or a salt thereof selected from the group consisting of:
(wherein iBu means isobutyl, iPr means isopropyl, Boc means tertiary butoxycarbonyl, Me means methyl, and Ph means phenyl).