JPH072797A - Collagenase inhibitor - Google Patents

Abstract

PURPOSE:To obtain a collagenase inhibitor useful as an agent for suppressing the neovascularization, cancerous infiltration or cancer metastasis. CONSTITUTION:The compound of formula I [R<1> is NR<4>R<5> (R<4> and R<5> are H or 1-4C alkyl); R<2> is 6-12C alkyl], e.g. N<2>-[2-(R)-(hydroxyaminocarbonyl)methyl-1- oxodecyl]-(S)-piperazinic acid N-methylamide. The compound of formula I can be produced from the compound of formula II via a compound of formula III [A is amino-protecting group (preferably benzyloxycarbonyl group)], etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel piperazine acid derivative having excellent collagenase inhibitory activity.

[0002]

BACKGROUND OF THE INVENTION Collagenase is an enzyme that decomposes collagen, which is one of the major constituents of connective tissue and the like. Among these, type IV collagenase is the major constituent of basement membrane IV.
Decomposes type collagen. It is known that type IV collagenase activity is elevated in angiogenesis during cancer growth, invasion and metastasis of cancer, and plays a major role in destruction of basement membrane (William G. Stetler-Stevenson.
Cancer and Metastasis Reviews, vol.9, 289-30
3, (1990)). Therefore, the collagenase inhibitor is useful for the prevention / treatment of these diseases.

Conventionally, a peptidic compound (Rob) containing a mercapto group has been used as a low molecular weight substance having a collagenase inhibitory action.
ert D. Gray, Hossain H. Saneii and Arno F. Spatola
; Biochemical and Biophysical Research Communicati
ons, Vol. 101, No. 4,, 1251-1258, (1981) / Charles
F. Vencill, David Rasnick, Katherine V. Crumley, No
rikazu Nishino and James C. Powers; Biochemistry
Vol. 24, 3149-3157, (1985)), a peptide compound containing a carboxyl group (Jean-Marie Delaisse, Yves Eeckhout,
Christopher Sear, Alan Galloway, KeithMcCullagh a
nd Gilbert Vaes; Biochemical and Biophysical Rese
archCommunications, Vol.133, 483-490, (1985)), benzyloxycarbonyl-prolyl-leucyl-glycylhydroxamic acid (William M. Moore and Curtis A. Spil
burg; Biochemical and Biophysical Research Commun
ications, Vol.136, 390-395, (1986)), hydroxylamine derivatives (JP-A 1-160997) and the like. In addition, SC44463 (Reuven Reich, Erik W. Thompson,
Yukihide Iwamoto, George R. Martin, James R. Deaso
n, George C. Fuller, and Ruth Miskin; Cancer Resea
rch, Vol.48, 3307-3312, (1988)) has been reported.
It has been confirmed by animal experiments that this SC44463 exhibits a cancer metastasis suppressing activity. However, these are all synthetic products and have not yet been put to practical use.

On the other hand, Tissue Inhibitor of Metalloproteinase (TIMP) and its related substances are known as proteinaceous collagenase inhibitors. TIMP is recombinant DNA
Although technology has enabled mass production, it has not yet been put to practical use (Docherty. AJP, Lyons A, Smith BJ,
Wright EM, Stephens PE, HarrisT. J. R, Murphy G,
and Reynolds JJ; Sequence of human tissueinhibi
tor of metalloproteinases and its identity to eryt
hroid-potentiating activity. Nature, vol.318, 66-6
9, (1985)).

Further, as a compound having a structure of hydroxyaminated 2-pentylsuccinic acid, there is actinonin isolated from the culture filtrate of actinomycetes. This compound has been reported to inhibit aminopeptidase M at low concentrations (Umezawa, H., Aoyagi, T.,
Tanaka, T., Suda, T., Okuyama, A., Naganawa, H., Ha
mada, M. and Takeuchi, T .: J. Antibiot., vol.38, 1
It has not been investigated whether 629-30, (1985)) inhibits type IV collagenase.

Further, a natural product represented by the following formula was isolated from a strain belonging to the genus Streptomyces, and it is known that this natural product has an antibacterial action and a collagenase inhibitory action (JP-A-3- No. 157372).

[0007]

[Chemical 2]

Furthermore, the formula is disclosed in Japanese Patent Laid-Open No. 3-53891.

[0009]

[Chemical 3]

The structure of the compound (1) is described and it is described that the compound has antibacterial activity, but there is no description that it has type IV collagenase inhibitory activity.

[0011]

DISCLOSURE OF THE INVENTION The present inventors have conducted diligent research on the synthesis of a derivative having an excellent type IV collagenase inhibitory activity and its pharmacological activity, and as a result, the novel matristatin derivative has an excellent IV The present invention has been completed based on the finding that it has type collagenase inhibitory activity and can be a useful angiogenesis inhibitor, cancer invasion inhibitor or cancer metastasis inhibitor.

[0012]

Means for Solving the Problems Compound (1) of the present invention
Is the general formula

[0013]

[Chemical 4]

It has

In the above formula, R ¹ is a —NR ⁴ R ⁵ group (in the formula,
R ⁴ and R ⁵ are the same or different and each is a hydrogen atom or has 1 carbon atom.
To 4 alkyl groups) and R ² has 6 carbon atoms.
To 12 alkyl groups are shown.

In the above formula (1), R ⁴ and R in R ¹
The alkyl group having 1 to 4 carbon atoms of ⁵ is methyl,
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and t-butyl, preferably 1 to 4 carbon atoms. It is two, and more preferably a methyl group.

In the general formula (1), the alkyl group having 6 to 12 carbon atoms in R ² is n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-
Methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-
Dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4, 4-dimethylpentyl, n-
Octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,
6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, n-nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,
6-dimethylheptyl, n-decyl, 1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-
Examples thereof include linear or branched alkyl groups such as dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl and dodecyl, preferably having 6 to 10 carbon atoms.
The number is one, and more preferably 8 to 10.

Among the compounds of the present invention, preferred are 2) R ¹ is a —NR ⁴ R ⁵ group (wherein R ⁴ is a hydrogen atom and R ⁵ is a methyl group;
Or R ⁴ and R ⁵ are methyl groups) and R ²
Examples include compounds in which is an alkyl group having 8 to 10 carbon atoms.

The compound (1) of the present invention has stereoisomers having an asymmetric carbon and each of R configuration and S configuration, and each of them or a mixture thereof is included in the present invention. To be done.

As the compounds of the present invention, the compounds listed in Table 1 can be mentioned, but the present invention is not limited to these compounds.

In Table 1, Hex is a hexyl group, Hep is a heptyl group, Oct is an octyl group, Non is a nonyl group, and D is
ec represents a decyl group, Und represents an undecyl group, and Ddc represents a dodecyl group.

[0022]

[Chemical 5]

[0023]

[Table 1] Among the exemplified compounds in the above table, suitable compounds include:
3, 4, 5, 10, 11 and 12.

The compounds of the present invention can be prepared by the methods described below.

[0025]

[Chemical 6]

[0026]

[Chemical 7]

[0027]

[Chemical 8]

[0028]

[Chemical 9]

[0029]

[Chemical 10]

In the above process chart, R ¹ , R ² , R ⁴ and R ⁵ have the same meanings as described above, A represents an amino-protecting group (preferably benzyloxycarbonyl group), and B
¹ represents a carboxyl group protecting group (preferably t-butyl group or benzyl group), B ² represents a carboxyl group protecting group (preferably methyl or ethyl group), and B ³ represents a tri-substituted silyl group ( Preferably a trimethylsilyl group), and B ⁴
Is a carboxyl-protecting group (preferably benzyl, tert-
Butyl, trichloroethyl and tribromoethyl groups), B ⁶ represents a hydroxyl group-protecting group (preferably benzyl group), and Z represents an optically active 2-oxo-oxazolidyl group.

Compound (4) is a known compound (Massall,
CM, Johnson M., and Theobald CJ, J.Chem.Soc.Perki
n I, 1971, p. 1451), but the following 1a, 1
It can also be obtained by steps b and 2.

(Step 1a) In this step, in an inert solvent,
In the presence of a base, the literature is publicly known (literature name Synthetic communic
ation, 1988, p. 2225), which is a step of hydrolyzing the compound (2).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene. ,toluene,
Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol , Glycerin, octanol, cyclohexanol,
Alcohols such as methyl cellosolve; acetone,
Ketones such as methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide Examples thereof include amides; dimethyl sulfoxide, sulfoxides such as sulfolane, and the like, and alcohols are preferable.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonates such as potassium hydrogen carbonate, lithium hydrogen carbonate, lithium hydride, sodium hydride,
Inorganic bases such as alkali metal hydrides such as potassium hydride, alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, and the like can be given. It is a metal hydroxide.

The reaction temperature is usually 20 to 200 ° C.,
It is preferably 50 to 130 ° C. While the reaction time varies depending on the starting materials used, solvent, reaction temperature, etc., it is generally 2 to 72 hours, and preferably 5 to 24 hours.
After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water, such as benzene, ether or ethyl acetate, and then extracted. The product obtained by distilling the solvent from the liquid is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(Step 1b) This step is carried out in an inert solvent,
In this step, the compound (3) is produced by protecting the amino group at the 1-position of the piperazinecarboxylic acid obtained in the step 1a.

The amino-protecting group A is preferably:
An aralkyloxycarbonyl group such as benzyloxycarbonyl.

That is, in the presence of a base in an inert solvent,
It can be carried out by reacting a corresponding commercially available or easily prepared carbamic acid ester synthesis reagent (preferably benzyloxycarbonyl chloride).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but hexane, heptane, ligroin, aliphatic hydrocarbons such as petroleum ether, and benzene. ,toluene,
Aromatic hydrocarbons such as xylene, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol , Glycerin, octanol, cyclohexanol, methyl cellosolve, alcohols such as water, or a mixed solvent of the above-mentioned organic solvent and water, and the like, preferably, the corresponding alcohol and water It is a mixed solvent.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonates such as potassium hydrogen carbonate, lithium hydrogen carbonate, lithium hydride, sodium hydride,
Inorganic bases such as alkali metal hydrides such as potassium hydride, sodium hydroxide, potassium hydroxide, barium hydroxide, and alkali metal hydroxides such as lithium hydroxide, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2]
Examples thereof include organic bases such as octane (DABCO) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and alkali metal hydroxides and organic bases are preferable.

The reaction temperature is usually 0 to 50 ° C, preferably 0 to 20 ° C. The reaction time depends on the raw materials used,
The time is usually 1 to 24 hours, preferably 1 to 3 hours, varying depending on the solvent, the reaction temperature and the like. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, hydrochloric acid,
Acidify with an inorganic acid such as sulfuric acid, extract with a solvent immiscible with water, such as benzene, ether, ethyl acetate,
What is obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods. It

(Second Step) This step is carried out in an inert solvent,
Compound (3) was added with alcohol B ¹ OH in the presence of a condensing agent.
(Particularly benzyl alcohol and t-butyl alcohol) or a step of producing a compound (4) by reacting a reagent for esterifying the compound (3) in an inert solvent.

In the above, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably hexane, heptane,
Aliphatic hydrocarbons such as ligroin, petroleum ether;
Aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate,
Esters such as propyl acetate, butyl acetate, diethyl carbonate, diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethylene glycol dimethyl ether, acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, ketones such as cyclohexanone, nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile, formamide , Dimethylformamide, dimethylacetamide, amides such as hexamethylphosphorotriamide, dimethyl sulfoxide, sulfoxides such as sulfolane, preferably aromatic hydrocarbons, ethers, halogenated hydrocarbons, Nitriles and amides.

Examples of the condensing agent to be used include di-lower alkyl azodicarboxylate-triphenylphosphines such as diethyl azodicarboxylate-triphenylphosphine, N-ethyl-5-phenylisoxazolium-
N-lower alkyl-5-arylisoxazolium-3'-sulphonates such as 3'-sulphonate, N ', N'-similar to N', N'-dicyclohexylcarbodiimide (DCC) Dicycloalkylcarbodiimides, diheteroaryl diselenides such as di-2-pyridyl diselenide, phosphines such as diethylphosphoryl cyanide (DEPC), arylsulfonyl such as p-nitrobenzenesulfonyl triazolide Triazolides, 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide and diphenylphosphoryl azide (DPP
A) diarylphosphoryl azides, N, N'-carbonyldiimidazole (CDI) imidazole derivatives, 1-hydroxybenzotriazole (HOBT) benzotriazole derivatives, N-hydroxy-5-norbornene- Examples include dicarboximide derivatives such as 2,3-dicarboximide (HONB) and carbodiimide derivatives such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAPC), preferably carbodiimide Class (especially DCC, DEPC).

The reaction temperature is usually 0 to 100 ° C., preferably 10 to 50 ° C. The reaction time varies depending on the raw materials used, solvent, reaction temperature, etc., but is usually 1 to 4
8 hours, preferably 1 to 12 hours. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, the insoluble matter is filtered off, and a solvent immiscible with water such as benzene, ether or acetic acid. What is obtained by extracting with ethyl or the like and distilling off the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods. In the above, the esterification reagent is preferably isobutene, which is achieved by reacting in an inert solvent in the presence of an acid catalyst.

As the solvent to be used, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform and carbon tetrachloride, Halogenated hydrocarbons such as dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether
Ethers such as tellurium, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; acetonitrile, isobutyl Nitriles such as ronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane, and the like, preferably ethers (particularly, Dioxane).

The acid catalyst used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, but hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid,
Bronsted acids such as organic acids such as trifluoromethanesulfonic acid or Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride and boron tribromide can be mentioned, preferably organic acids. And more preferably a strong organic acid (especially hydrochloric acid).

The reaction temperature is usually 0 to 50 ° C, preferably 0 to 25 ° C. The reaction time depends on the raw materials used,
The time is usually 1 to 48 hours, preferably 1 to 24 hours, varying depending on the solvent, the reaction temperature and the like. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, the mixture is extracted with a solvent immiscible with water, for example, benzene, ether, ethyl acetate, and the solvent is distilled off from the extract. The product is usually used as it is in the next step.
If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(Third step) In this step, in an inert solvent,
Corresponding alcohol B ² OH (especially methanol, ethanol) and a reactive derivative of malonic acid (5), ie, an acid halide or acid anhydride, are reacted in the presence of a base, or the corresponding alcohol B ² OH alcohol and malon are used. In this step, the compound (6) ester is produced by reacting the acid (5) in the presence of a condensing agent.

The solvent to be used in the above is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate , Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclo Ketones such as xanone; Nitro compounds such as nitroethane and nitrobenzene; Nitriles such as acetonitrile and isobutyronitrile; Amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; dimethyl sulfoxide And sulfoxides such as sulfolane, and alcohols, aromatic hydrocarbons, and halogenated hydrocarbons are preferable.

Examples of the halide moiety of the acid halide used include chlorine, bromine and iodine, preferably chlorine,
It is bromine.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonates such as potassium hydrogen carbonate, lithium hydrogen carbonate, lithium hydride, sodium hydride,
Inorganic bases such as alkali metal hydrides such as potassium hydride, sodium hydroxide, potassium hydroxide, barium hydroxide, and alkali metal hydroxides such as lithium hydroxide, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2]
Examples thereof include organic bases such as octane (DABCO) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), and alkali metal hydroxides and organic bases are preferable.

The reaction temperature is usually 0 to 60 ° C, preferably 0 to 30 ° C. The reaction time depends on the raw materials used,
The time is usually 1 to 24 hours, preferably 1 to 6 hours, varying depending on the solvent, reaction temperature and the like. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, hydrochloric acid,
Acidify with an inorganic acid such as sulfuric acid, extract with a solvent immiscible with water, such as benzene, ether, ethyl acetate,
What is obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods. It

In the above, the solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether are used. Aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, butyl acetate , Esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclo Ketones such as xanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide. However, halogenated hydrocarbons (especially methylene chloride), ethers (especially tetrahydrofuran) and aromatic hydrocarbons (especially benzene) are preferable.

The condensing agent used is preferably DC.
C (dicyclohexylcarbodiimide), CDI (N,
N'-carbonyldiimidazole), DPPA (diphenylphosphoryl azide), HOBT (1-hydroxybenzotriazole), HONB (N-hydroxy-5-).
Norbornene-2,3-dicarboximide) or E
DAPC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide) and the like can be mentioned.

When a condensing agent is used, the reaction can be carried out more efficiently by using a deoxidizing agent together.

Preferable examples of the deoxidizing agent used include organic amines such as pyridine, dimethylaminopyridine and pyrrolidinopyridine. In addition, when the above-mentioned condensing agent is used, the reaction proceeds faster by using this amine.

The reaction temperature is usually 0 to 60 ° C., preferably 0 to 30 ° C. The reaction time depends on the raw materials used,
The time is usually 1 to 48 hours, preferably 1 to 12 hours, varying depending on the solvent, the reaction temperature and the like. The target compound can be collected, separated, and purified by appropriately combining various methods. For example, pour the reaction solution into water,
Add a solvent immiscible with water, such as benzene, ether, ethyl acetate, etc., and if there is insoluble matter, filter it off appropriately, and after separating the extract, wash with dilute hydrochloric acid, sodium hydrogen carbonate, etc., and distill off the solvent. Obtained by The desired compound thus obtained may be further subjected to adsorption or ion exchange chromatography using various carriers such as activated carbon and silica gel, or gel filtration using a Sephadex column, and organic solvents such as ether, ethyl acetate and chloroform, if necessary. It is performed by recrystallization or the like. (Fourth step) In this step, in the presence of a base in an inert solvent,
In this step, the compound (7) is produced by reacting the compound (6) with an alkyl halide R ² X (X represents a halogeno group, and is preferably chloro or bromo).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene. ,toluene,
Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol;
, Ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane, nitrobenzene; acetonitrile, isobutyronitrile Nitriles such as; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane, and preferably ethers (particularly diethyl ether,
Tetrahydrofuran) and amides (especially dimethylformamide). The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. , Alkali metal hydrogen carbonates such as lithium hydrogen carbonate, lithium hydride, sodium hydride, alkali metal hydrides such as potassium hydride, alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium butoxide,
Sodium hydroxide, potassium hydroxide, barium hydroxide,
Inorganic bases such as alkali metal hydroxides such as lithium hydroxide, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N-dimethyl Aniline, N, N-diethylaniline, 1,5-diazabicyclo
[4.3.0] Non-5-ene (DBN), 1,4-diazabicyclo [2.
2.2] Octane (DABCO), 1,8-diazabicyclo [5.4.0]
Organic bases such as undec-7-ene (DBU) can be mentioned, but alkali metal hydroxides, alkali metal alkoxides and organic bases are preferable.

Examples of the halide moiety of the alkyl halide used include chlorine, bromine and iodine, with chlorine and bromine being preferred.

The reaction temperature is usually -20 to 100 ° C, preferably -10 to 50 ° C. While the reaction time varies depending on the raw materials used, solvent, reaction temperature, etc., it is generally 1 to 48 hours, and preferably 1 to 15 hours. The target compound can be collected, separated, and purified by appropriately combining various methods. For example, the reaction solution is poured into water, a solvent immiscible with water, for example, benzene, ether, ethyl acetate, etc. are added, and if there is an insoluble matter, it is appropriately filtered off, and the extract is separated, and then diluted with dilute hydrochloric acid and sodium hydrogen carbonate. It is obtained by washing and distilling off the solvent. The desired compound thus obtained may be further subjected to adsorption or ion exchange chromatography using various carriers such as activated carbon and silica gel, or gel filtration using a Sephadex column, and organic solvents such as ether, ethyl acetate and chloroform, if necessary. It is performed by recrystallization or the like.

(Fifth Step) This step is a method of producing compound (8) by reacting compound (7) with a base in an inert solvent, followed by hydrolysis and decarboxylation. Solvents used include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene. , Halogenated hydrocarbons such as dichlorobenzene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol Le,
Isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitroethane, nitrobenzene Nitro compounds such as; Nitriles such as acetonitrile and isobutyronitrile;
Examples include amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane, and mixed solvents of these organic solvents and water, and preferably alcohols and It is a mixed solvent with water.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction, but alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate, sodium hydrogen carbonate, Alkali metal hydrogen carbonates such as potassium hydrogen carbonate, lithium hydrogen carbonate, lithium hydride, sodium hydride,
Inorganic bases such as alkali metal hydrides such as potassium hydride, sodium hydroxide, potassium hydroxide, barium hydroxide, and alkali metal hydroxides such as lithium hydroxide, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-
Organic bases such as 7-ene (DBU) Bicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-
Organic bases such as 7-ene (DBU) can be mentioned, but alkali metal hydroxides and organic bases are preferable.

The reaction temperature is usually 0 to 120 ° C, preferably 20 to 120 ° C. While the reaction time varies depending on the starting materials used, solvent, reaction temperature, etc., it is generally 1 to 48 hours, and preferably 1 to 16 hours. In this step, when only the hydrolysis proceeds but the decarboxylation reaction does not proceed sufficiently, it is achieved by adding collidine, lutidine and the like and heating at 100 to 120 ° C.

The target compound can be collected, separated, and purified by appropriately combining various methods. For example, the reaction solution is poured into water, acidified with hydrochloric acid, etc., and a solvent immiscible with water, such as benzene, ether, ethyl acetate, etc. is added, and if any insoluble matter is removed by filtration, the extract is separated and diluted with hydrochloric acid. It is obtained by washing with and distilling off the solvent. The desired compound thus obtained may be further subjected to adsorption or ion exchange chromatography using various carriers such as activated carbon and silica gel, or gel filtration using a Sephadex column, and organic solvents such as ether, ethyl acetate and chloroform, if necessary. It is performed by recrystallization or the like.

(Sixth Step) This step is a step of producing a compound (9) using the carboxylic acid (8) obtained in the fifth step or a commercially available carboxylic acid (8), and this step is Third
It can be performed in the same manner as the process.

(Seventh Step) In this step, an acid halide obtained by reacting the compound (8) with a halogenating reagent for a carboxylic acid in an inert solvent, in the presence of n-butyllithium,
Reacting an optically active oxazolidin-2-one ZH,
This is a step of obtaining the compound (10).

The solvent used for halogenation is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably hexane, heptane,
Aliphatic hydrocarbons such as ligroin, petroleum ether;
Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene.

Examples of the reagent used for halogenation include thionyl halides such as thionyl chloride and thionyl bromide, and phosphorus compounds such as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride and phosphorus oxychloride. .

The reaction temperature is usually 0 to 50 ° C.

The reaction time varies depending on the starting materials used, solvent, reaction temperature, etc., but is usually 0.2 to 5 hours,
It is preferably 0.2 to 1 hour.

After completion of the reaction, the solvent is simply distilled off to use in the next reaction.

The solvent used in the step of reacting oxazolidin-2-one is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.
Particularly preferably, diethyl ether, diisopropyl ether
There may be mentioned ethers such as tellurium, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether.

Optically active oxazolidine-2 used
Examples of the -one include (4S) -isopropyloxazolidin-2-one, (4R) -isopropyloxazolidin-2-one and (4S) -benzyloxazolidin-2-one.
On, (4R) -benzyloxazolidin-2-one.

The reaction temperature is usually -78 to 20 ° C.

The reaction time varies depending on the starting materials used, solvent, reaction temperature, etc., but is usually 0.2 to 5 hours,
It is preferably 0.2 to 2 hours. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water, such as benzene, ether or ethyl acetate, and then extracted. What is obtained by distilling the solvent from the liquid is usually
Used as is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(Step 8) In this step, compound (9) is added to tri-substituted silyl halide B in the presence of a base in an inert solvent.
³ X (X has the same meaning as described above) is reacted,
It is a step of producing the compound (11).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene ,toluene,
Aromatic hydrocarbons such as xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; diethyl ether, diisopropyl ether,
Tetrahydrofuran, dioxane, dimethoxyethane,
Examples thereof include ethers such as diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile.

The base used is not particularly limited as long as it can be used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; triethylamine, tributylamine, diisopropylethylamine, N- Methylmorpholine, pyridine,
4- (N, N-dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-
Organic bases such as 7-ene (DBU) or butyllithium,
Mention may be made of organometallic bases such as lithium diisopropylamide.

Examples of the trialkylsilyl halide used include trimethylsilyl chloride, t-butyldimethylsilyl chloride and the like, with trimethylsilyl chloride being preferred.

The reaction temperature is usually -78 to 20 ° C.

The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 1 to 10 hours.

After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water such as benzene, ether or ethyl acetate. Then, the product obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(Step 9) In this step, α-haloacetic acid ester X is added to compound (10) in the presence of a base in an inert solvent.
In this step, CH ₂ —COOB ⁴ (X has the same meaning as described above) is reacted to produce compound (12).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably it is an aliphatic carbonization such as hexane, heptane, ligroin or petroleum ether. Hydrogen; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; diethyl ether, diisopropyl ether, Ethers such as tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol , Isoamyl alcohol, diethylene glycol, glycerin Octanol, cyclohexanol, methyl cellosolve, alcohols such as - Le acids;
Examples thereof include amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane, and ethers are preferable.

The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium methoxide, sodium ethoxide,
Alkali metal alkoxides such as potassium t-butoxide and lithium methoxide; mercaptan alkali metal such as methyl mercaptan sodium and ethyl mercaptan sodium; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N , N-dimethylamino) pyridine,
N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [Five.
4.0] Organic bases such as undec-7-ene (DBU) or organic metal bases such as butyllithium and lithium diisopropylamide can be mentioned, and lithium diisopropylamide (tetrahydrofuran as a solvent) is preferable. .

Examples of the halo moiety of the α-haloacetic acid ester used include chlorine, bromine and iodine.

Examples of the alkyl moiety of the ester of the α-halocarboxylic acid ester used include methyl, ethyl, benzyl and tert-butyl.

The reaction temperature is usually -78 to 10 ° C.

The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 1 to 10 hours.

After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water such as benzene, ether or ethyl acetate. Then, the product obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(Step 10) In this step, in an inert solvent,
The compound (12) is hydrolyzed in the presence of a base to remove the optically active oxazolidin-2-one, and the compound (1
This is a process of manufacturing 3).

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, it is an aliphatic carbonization such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol , N-propanol, isopropanol
Alcohols such as alcohol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl ethyl ketone, methyl isobutyl ketone , Ketones such as isophorone and cyclohexanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide Included are sulfoxides such as dimethyl sulfoxide and sulfolane.

The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, hydroxide Inorganic bases such as alkali metal hydroxides such as barium and lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, lithium methoxide; methyl mercaptan sodium, ethyl mercaptan Mercaptan like sodium Alkali metals; triethylamine,
Tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino)
Pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8 Mention may be made of organic bases such as -diazabicyclo [5.4.0] undec-7-ene (DBU).

The most preferable method is a method using lithium hydroxide in the presence of hydrogen peroxide in a mixed solvent of tetrahydrofuran and water.

The reaction temperature is usually 0 to 100 ° C.

The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 1 to 24 hours.

After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water such as benzene, ether or ethyl acetate. Then, the product obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(11th step) This step is carried out in an inert solvent,
Α-halocarboxylic acid ester XCH ₂ -in compound (11)
In this step, COOB ⁴ (X has the same meaning as described above) is reacted to produce compound (14).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably it is an aliphatic carbonization such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate, Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide , Jime Le formamide, dimethyl acetamide, amides such as hexamethylphosphoric triamide; dimethylsulfoxide, can be mentioned sulfoxides such as sulfolane.

Examples of the halo moiety of the α-halocarboxylic acid ester used include chlorine, bromine and iodine, with chlorine and bromine being preferred. Examples of the alkyl moiety of the ester of the α-halocarboxylic acid ester used include methyl, ethyl, tert-butyl and benzyl.

The reaction temperature is usually -78 to 30 ° C.
The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but is usually 0.5 to 10 hours. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, hydrochloric acid,
Acidify with an inorganic acid such as sulfuric acid, extract with a solvent immiscible with water, such as benzene, ether, ethyl acetate,
What is obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

(Twelfth Step) This step is carried out in an inert solvent,
In this step, one carboxylic acid of compound (14) is hydrolyzed in the presence of a base to produce compound (13).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably it is an aliphatic carbonization such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol , N-propanol, isopropanol
Alcohols such as alcohol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; acetone, methyl ethyl ketone, methyl isobutyl ketone , Ketones such as isophorone and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane Can be mentioned.

The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; Alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, lithium hydrogen carbonate; alkali metal hydrides such as lithium hydride, sodium hydride, potassium hydride; sodium hydroxide, potassium hydroxide, hydroxide Inorganic bases such as alkali metal hydroxides such as barium and lithium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide and lithium methoxide.

The reaction temperature is usually 0 to 100 ° C.

The reaction time varies depending on the starting materials used, the solvent, the reaction temperature, etc., but it is usually 1 to 24 hours.

After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water such as benzene, ether or ethyl acetate. Then, the product obtained by distilling the solvent from the extract is usually used as it is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

If desired, B ⁴ of the compound (13) may be replaced with another protecting group. The exchange reaction is carried out by a usual method, such as a normal transesterification reaction, or by protecting the free carboxylic acid and removing B ⁴ according to the method of the 14th step described later to introduce a desired protecting group, This can be done by regenerating the carboxylic acid.

(Thirteenth step) In this step, the acid halide of compound (13) obtained by reacting the acid halide-forming reagent in an inert solvent is reacted with compound (4), or in an inert solvent, Compound (4) in the presence of a condensing agent
And the compound (13) are reacted with each other to produce the compound (22).

Acid Halide Method The acid halide is prepared by using a halogenating reagent which is usually used such as oxalyl chloride and thionyl chloride, in an inert solvent (for example, aromatic hydrocarbons such as benzene and toluene), and a compound. (13) and 0 to 100 ° C. (preferably 10 to 50 ° C.) for 1 to 24 hours (preferably 2
To react for 5 hours). After completion of the reaction, the unreacted halogenating reagent and solvent are distilled off under reduced pressure. An inert solvent (for example, ethers such as tetrahydrofuran and ethyl ether) is added thereto, and the compound (4) and a tertiary organic amine (for example, N-ethylamine, N-methylamine,
Triethylamine and the like), and the reaction is carried out at 0 to 100 ° C. (preferably 0 to 40 ° C.) for 1 to 24 hours (preferably 2 to 5 hours).

After the completion of the reaction, the desired product is obtained by, for example, appropriately neutralizing the reaction mixture, and removing insolubles by filtration, and then adding water and an immiscible organic solvent such as ethyl acetate. After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off. Condensation method The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; Ethyl formate, ethyl acetate, propyl acetate, acetic acid Butyl, esters such as diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone,
Ketones such as cyclohexanone; Nitro compounds such as nitroethane and nitrobenzene; Nitriles such as acetonitrile and isobutyronitrile; Formamide, dimethylformamide, dimethylacetamide,
Examples include amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane. As the condensing agent used,
For example, di-lower alkyl-triphenylphosphines such as diethyl azodicarboxylate-triphenylphosphine, N-lower alkyls such as N-ethyl-5-phenylisoxazolium-3'-sulfonate. -Five
-Arylisoxazolium-3'-sulfonates,
Like N ', N'-dicyclohexylcarbodiimide (DCC)
N ', N'-dicycloalkylcarbodiimides, diheteroaryl diselenides such as di-2-pyridyl diselenide, phosphines such as diethylphosphoryl cyanide (DFPC), p-nitrobenzenesulfonyl triazolyl Arylsulfonyl triazolides such as 2-chloro-1-
2-Halo-1-lower alkylpyridinium halides such as methylpyridinium iodide and diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA), imidazole derivatives such as N, N'-carbodiimidazole (CDI), 1- Hydroxybenzotriazole (HOB
Benzotriazole derivatives such as T), N-hydroxy-5
-Norbornene-2,3-dicarboximide (HONB) and other dicarboximide derivatives, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDAPC) carbodiimide derivatives such as, Preferably,
Diarylphosphoryl azides. The reaction temperature is usually 0 to 150 ° C. depending on the raw materials, reagents, solvents used
And preferably 20 to 100 ° C. The reaction time varies depending on the raw materials used, solvent, reaction temperature, etc.,
It is usually 1 to 100 hours, preferably 2 to 24 hours. After completion of the reaction, the desired product is, for example, after neutralizing the reaction mixture appropriately, or removing insolubles by filtration, adding water and an immiscible organic solvent such as ethyl acetate, and washing with water. The organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and then the solvent is distilled off. (14th step) In this step, the compound (2
In this step, the protecting group B ⁴ in 2) is deprotected to produce the compound (23).

The removal of a protecting group depends on its type, but is generally carried out as follows by methods well known in the art.

When the protecting group for the carboxy group is one that can be removed with an acid, such as a t-butyl group or a benzhydryl group, it is achieved under acidic conditions such as trifluoroacetic acid or hydrogen bromide in acetic acid, dioxane-hydrochloric acid. .

When the protecting group for the carboxy group is a trichloroethyl group or a trichlorobromo group, acetic acid or a phosphate buffer (pH = 4.2-7.2) and a solvent of ethers such as tetrahydrofuran are used, and zinc is used. The powder can be reacted and removed.

When the carboxy-protecting group is an aralkyl group such as a benzyl group, it is usually removed by bringing it into contact with a reducing agent in a solvent (preferably catalytic reduction at room temperature under a catalyst). Is done by the method.

(Fifteenth step) This step is carried out in an inert solvent,
Hydroxylamine B ⁶ O protected by compound (23)
This is a step of reacting NH ₂ to produce compound (24), and is performed according to the 13th step.

(16th step) This step is carried out in an inert solvent,
The protecting group B ¹ is deprotected from the compound (24) to give the compound (2
5) is a process of manufacturing.

The removal of the protecting group depends on its type, but is generally carried out as follows by methods well known in the art.

If the protecting group for the carboxy group is one that can be removed with an acid such as a t-butyl group or a benzhydryl group, it can be achieved under acidic conditions such as trifluoroacetic acid or hydrogen bromide in acetic acid, dioxane-hydrochloric acid. .

When the protecting group for the carboxy group is a trichloroethyl group or a tribromoethyl group, acetic acid or phosphate buffer (pH = 4.2-7.2) and a solvent of ethers such as tetrahydrofuran are used. Zinc dust can be reacted and removed.

When the protecting group for the carboxy group is an aralkyl group such as a benzyl group, it is usually removed by bringing it into contact with a reducing agent in a solvent (preferably, catalytic reduction at room temperature under a catalyst). Is done by the method.

(17th step) This step is carried out in an inert solvent,
In the presence of a condensing agent, the compound (25) is treated with an amine R ⁴ R ⁵ NH.
Is a step of producing compound (27), and can be carried out in the same manner as in the 13th step.

(Eighteenth step) This step is carried out in an inert solvent,
In this step, protective groups A and B ⁶ of compound (27) are deprotected to produce compound (1C).

This step depends on the type of protecting group.

For example, when B ⁶ is benzyl and A is a protecting group such as benzyloxycarbonyl which can be removed by catalytic reduction, a catalyst such as palladium carbon or platinum is used in a suitable solvent such as alcohol, ether or acetic acid. It is achieved by catalytic reduction under a hydrogen stream. When A and B ⁶ are t-butoxycarbonyl groups and the like, they are achieved under acidic conditions such as trifluoroacetic acid or hydrogen bromide in acetic acid, dioxane-hydrochloric acid. In any case, the commonly known protecting groups for amino groups and hydroxyl groups can be achieved by eliminating conditions.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene. ,toluene,
Aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate Esters; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol;
, Ethanol, n-propanol, isopropanol,
n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; nitro compounds such as nitroethane, nitrobenzene; acetonitrile, isobutyronitrile Examples thereof include nitriles; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide; sulfoxides such as dimethylsulfoxide and sulfolane.

The reaction temperature is usually -20 to 100 ° C, preferably 0 to 40 ° C.

The reaction time will differ depending on the starting materials used, solvent, reaction temperature, etc., but is usually 0.5 to 48 hours, and preferably 1 to 5 hours. After completion of the reaction, for example, the solvent is distilled off, the reaction solution is poured into water, acidified with an inorganic acid such as hydrochloric acid or sulfuric acid, and extracted with a solvent immiscible with water, such as benzene, ether or ethyl acetate, and then extracted. What is obtained by distilling the solvent from the liquid is usually
Used as is in the next step. If desired, it can be isolated and purified by various chromatographic methods or recrystallization methods.

[0130]

INDUSTRIAL APPLICABILITY The compound of the present invention has excellent type IV collagenase inhibitory activity and is useful as an angiogenesis inhibitor, cancer invasion inhibitor or cancer metastasis inhibitor.

When the compound of the present invention is used as an angiogenesis inhibitor, cancer invasion inhibitor or cancer metastasis inhibitor, it can be administered in various forms. Examples of the dosage form include oral administration by tablets, capsules, granules, powders, syrups, etc. or parenteral administration by injections (intravenous, intramuscular, subcutaneous), eye drops, suppositories, etc. . These various preparations are usually used in the known pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspending agents, coating agents, etc. It is possible to formulate with known auxiliary agents.
The dose varies depending on symptoms, age, weight, administration method, dosage form, etc., but is usually 50 mg to 10 per day for adults.
00 mg can be administered.

Formulation examples are specifically shown below.

Formulation Example 1 (Hard Capsule) 100 mg of the powdered compound of Example 1, 150 mg of lactose, 50 m in each standard bisecting hard gelatin capsule
A unit capsule was prepared by filling with g cellulose and 6 mg magnesium stearate, and after washing,
Dried.

(Formulation Example 2) (Tablets) According to a conventional method, 100 mg of the compound of Example 1, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 were used. Produced using mg starch and 98.8 mg lactose.

If desired, a coating was applied.

Formulation Example 3 (Injection) 1.5% by weight of the compound of Example 1 was stirred in 10% by volume of propylene glycol, then made up to volume with water for injection and then sterilized. Manufactured.

(Formulation Example 4) (Suspension) In 5 ml, 100 mg of the compound of Example 1 which had been micronised, 100
It was prepared to contain mg sodium carboxymethylcellulose, 5 mg sodium benzoate, 1.0 g sorbitol solution (Japanese Pharmacopoeia) and 0.025 ml vanillin.

[0138]

【Example】

(Example ^{1) N 2 - [2- (} R) - ( hydroxyaminocarbonyl) method
Cyl-1-oxodecyl]-(S) -piperazinic acid N-
Methylamide N ¹ -benzyloxycarbonyl-obtained in Reference Example 24
^{N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxodecyl] - (S) - tetrahydrofuran piperazine acid (44 mg): dimethylformamide (3: 1) mixed solution (3.6 ml) Under a nitrogen atmosphere, methylamine hydrochloride (10 mg), triethylamine (0.025 ml) and DEPC (0.04 ml) were sequentially added, and the mixture was stirred overnight while gradually warming to room temperature. After completion of the reaction, the reaction solution was poured into a 5% potassium hydrogensulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, Chloroform:
It fractionated using methanol = 15: 1) and the N-amide body (15 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δ: 0.88 (3H, t, J = 6.6 Hz), 0.98-2.59 (20H, comple
x), 2.70 (3H, d, J = 4.6 Hz), 3.08 (1H, m), 3.67 (1H, m), 4.11
(1H, m), 4.83 (1H, d, J = 11.2 Hz), 4.88 (1H, d, J = 11.2 Hz),
5.13 (1H, t, J = 5.3 Hz), 5.21 (2H, s), 7.25-7.49 (10H, compl
ex), 7.71 (1H, m ), 8.18 (1H, m) Infrared absorption spectrum ^{film (cm -): 3345 (} m), 3
225 (m), 2945 (s), 1695 (s), 1670
(s) Mass spectrum _{m / z [MH 2 O]} + = 576 N 1 obtained in this manner - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1- The protecting group of [oxodecyl]-(S) -piperazinic acid N-methylamide (14 mg) was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 10 cm, 0.5 mm thickness, chloroform: methanol = 10: 1) was used. Double development, ethyl acetate: methanol = 1
Purification by elution (0: 1) gave the desired compound (9 mg).

Nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δ: 0.88 (3H, t, J = 6.6 Hz), 1.05-2.15 (18H, comple
x), 2.30 (1H, m), 2.53 (1H, m), 2.80 (3H, d, J = 4.6 Hz), 2.83
(1H, m), 3.03 (1H, br.d, J = 11.9 Hz), 3.84 (1H, m), 4.64 (1H,
d, J = 9.9 Hz), 5.05 (1H, br.s), 6.55 (br.s), 9.2-9.8 (1H, b
rs) Infrared absorption spectrum film (cm ^-1 ): 3260 (s), 2930
(s), 1650 (s), 1625 (s) High-resolution mass spectrum [M] ⁺ = 352.2466 (C ₁₈ H ₃₂ O
₃ N ₄ ) Calculated value 352.2466 Specific rotation [α] _D ²⁶ = −3.4 ° (C = 0.82, EtOH) (Example 2) N ² − [2- (R)-(hydroxyaminocarbonyl)
Methyl-1-oxodecyl]-(S) -piperazine acid
N, N-according to the method of dimethylamide Example 1, Reference Example N ¹ obtained in 24 - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxodecyl] - The protecting group of the dimethylamide compound obtained by condensing (S) -piperazine acid (49 mg) with dimethylamine was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, chloroform: Methanol = 13: 1 development, ethyl acetate: methanol = 1
Purification by elution (0: 1) gave the desired compound (25 mg).

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.6 Hz), 1.02-1.78 (16H, complex), 1.8
1-2.04 (2H, complex), 2.29 (1H, dd, J = 14.5 and 4.0 Hz),
2.52 (1H, dd, J = 14.5 and 10.9 Hz), 2.70-3.11 (2H, comple
x), 2.94 (3H, s), 3.06 (3H, s), 3.93 (1H, m), 5.26 (1H, d, J = 1
1.2 Hz), 5.51 (1H, br.s), 8.09-8.62 (1H, br.s), 9.50-9.72
(1H, br.s) Infrared absorption spectrum (film, cm ^-1 ): 3250 (w), 2910 (s),
1635 (s), 1625 (s) Mass spectrum [M] ⁺ = 384 High resolution mass spectrum [M] ⁺ = 384.2738 (C ₁₉ H ₃₆ N ₄ O ₄ ) Calculated value: 384.2737 (Example 3) N ² − [ 2- (R)-(hydroxyaminocarbonyl)
Methyl-1-oxooctyl]-(S) -piperazine acid
According to the method of N- methylamide Example 1, Reference Example 34 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-octyl] - (S ) -Piperazinic acid (45 mg) was condensed with methylamine to remove the protecting group of the N-methylamide compound, which was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, chloroform:
Methanol = 13: 1 development, ethyl acetate: methanol =
Purification by 10: 1 elution) gives the desired compound (10 mg)
was gotten.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.5 Hz), 0.99-1.95 (13H, complex), 2.0
5 (1H, br.d, J = 10.6 Hz), 2.29 (1H, dd, J = 13.9 and 3.3 H
z), 2.52 (1H, br.t, J = 13.9 Hz), 2.79 (3H, d, J = 4.6 Hz), 2.8
1 (1H, 2.79ppm) overlap, 3.02 (1H, d, J = 13.2Hz), 3.88
(1H, m), 4.67 (1H, d, J = 11.9 Hz), 5.06 (1H, s), 6.75 (1H, d, J
= 4.6 Hz), 9.52-9.91 (1H, br.s) Infrared absorption spectrum (film, cm ^-1 ): 3271 (m), 2929 (s),
1648 (s), 1626 (s) Mass spectrum [MH ₂ O] ⁺ = 324 High resolution mass spectrum [M] ⁺ = 342.2256 (C ₁₆ H ₃₀ N ₄ O ₄ ) Calculated value: 342.2267 Specific rotation [α] _D ^{26 = -9.3 ° (C = 0.90} , EtOH) ( example ^{4) N 2 - [2- (} R) - ( hydroxyaminocarbonyl)
Methyl-1-oxooctyl]-(S) -piperazine acid
N, N-dimethylamide in Example 1 of N obtained in Reference Example 34 According to the method ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-octyl] - The protecting group of the N, N-dimethylamide compound obtained by condensing (S) -piperazine acid (41 mg) with dimethylamine was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm) was used. Thick, chloroform: methanol = 13: 1 development, ethyl acetate: methanol = 10: 1 elution) to give the desired compound (2
1 mg) was obtained.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.86 (3H, t, J = 6.6 Hz), 1.12-2.07 (14H, complex), 2.2
9 (1H, dd, J = 13.9 and 4.0 Hz), 2.53 (1H, dd, J = 13.9 and 1
2.2Hz), 2.70-3.19 (2H, 3.06ppm and 2.94ppm and overla
p), 2.94 (3H, s), 3.06 (3H, s), 3.92 (1H, m), 5.26 (1H, d, J = 1
1.9 Hz), 5.51 (1H, br.s), 8.01-8.5. (1H, br.s), 9.41-9.70
(1H, br.s) Infrared absorption spectrum (film, cm ^-1 ): 3249 (m), 2929 (s),
1645 (s), 1625 (s) Mass spectrum [M] ⁺ = 356 High resolution mass spectrum [M + H] ⁺ = 357.2511 (C ₁₇ H ₃₃ N ₄ O ₄ ) Calculated value: 357.2502 Specific rotation [α] _D ^{26 = + 5.9 ° (C =} 1.0, EtOH) ( example ^{5) N 2 - [2- (} R) - ( hydroxyaminocarbonyl)
Methyl-1-oxononyl]-(S) -piperazine acid N
- according to the method of methylamide Example 1, Reference Example 44 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxononyl] - (S) - The protecting group of the N-methylamide derivative obtained by condensing piperazine acid (46 mg) with methylamine was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, chloroform: methanol = 13) was used. : 1 development, ethyl acetate: methanol = 1
Purification by elution (0: 1) gave the desired compound (20 mg).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.6 Hz), 1.00-1.95 (15H, complex), 2.0
5 (1H, br.d, J = 3.3 Hz), 2.28 (1H, br.d, J = 3.3 Hz), 2.51 (1
H, dd, J = 13.9 and 11.2 Hz), 2.78 (3H, d, J = 4.6 Hz), 2.82
(1H, m), 3.02 (1H, br.d, J = 12.5 Hz), 3.87 (1H, m), 4.73 (1H,
d, J = 11.9 Hz), 5.06 (1H, br.s), 6.93 (1H, m), 9.91-10.12 (1
H, br.s) Infrared absorption spectrum (film, cm ^-1 ): 3268 (m), 2928 (s),
1652 (s), 1626 (s) Mass spectrum [M + H] ⁺ = 357 High resolution mass spectrum [M + H] ⁺ = 357.2493 (C ₁₇ H ₃₃ N ₄ O ₄ ) Calculated value: 357.2502 Specific rotation [α ^{_{] D 26 = -9.5 ° (C}} = 1.0, EtOH) ( example ^{6) N 2 - [2- (} R) - ( hydroxyaminocarbonyl)
Methyl-1-oxononyl]-(S) -piperazine acid
N, N-according to the method of dimethylamide Example 1, Reference Example 44 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxononyl] - The protecting group of the N, N-dimethylamide compound obtained by condensing (S) -piperazine acid (49 mg) with dimethylamine was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm) was used. Thick, chloroform: methanol = 13: 1 development, ethyl acetate: methanol = 10: 1 elution) to give the desired compound (1
0 mg) was obtained.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.83 (3H, t, J = 6.6 Hz), 1.05-1.78 (14H, complex), 1.8
0-2.04 (2H, complex), 2.26 (1H, br.d, J = 12.5 Hz), 2.50 (1
H, br.t, J = 12.5 Hz), 2.72-3.12 (2H, complex), 2.93 (3H,
s), 3.05 (3H, s), 3.90 (1H, m), 5.24 (1H, d, J = 11.9 Hz), 5.53
(1H, m) Infrared absorption spectrum (film, cm ^-1 ): 3260 (m), 2940 (s),
1625 (s) Mass spectrum [M + H] ⁺ = 371 High resolution mass spectrum [M + H] ⁺ = 371.2677 (C ₁₈ H ₃₅ N ₄ O ₄ ) Calculated value: 371.2658 Specific rotation [α] _D ²⁶ = + 7.2 ° (C = 0.81, EtOH ) ( example ^{7) N 2 - [2- (} R) - ( hydroxyaminocarbonyl)
Methyl-1-oxododecyl]-(S) -piperazine acid
According to the method of N- methylamide Example 1, Reference Example 54 N ¹ obtained in - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-dodecyl] - (S ) -Piperazic acid (52 mg) was condensed with methylamine to remove the protecting group of the N-methylamide compound by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, chloroform:
Methanol = 13: 1 development, ethyl acetate: methanol =
Purification by elution (10: 1) gave the target compound (7 mg).

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 1.04-2.12 (22H, complex), 2.1
9-2.63 (2H, complex), 2.79 (3H, d, J = 3.3 Hz), 2.80 (1H, m),
3.03 (1H, br.d, J = 13.2 Hz), 3.85 (1H, m), 4.64 (1H, br.d, J =
11.9 Hz), 5.05 (1H, br.s), 6.68 (1H, m), 9.48-9.76 (1H, br.
s) Infrared absorption spectrum (film, cm ^-1 ): 3267 (m), 2855 (s),
1652 (s), 1625 (s) Mass spectrum [M] ⁺ = 398 High resolution mass spectrum [MH ₂ O] ⁺ = 380.2809 (C ₂₀ H ₃₆ N
₄ O ₃₎ Calculated: 380.2787 Specific rotation ^{_{[α] D 26 = -8.9 °}} (C = 0.61, EtOH) ( Example ^{8) N 2 - [2- (} R) - ( hydroxyaminocarbonyl)
Methyl-1-oxododecyl]-(S) -piperazine acid
N, N-according to the method of dimethylamide Example 1, Reference Example 54 N ¹ obtained in - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-dodecyl] The protecting group of the N, N-dimethylamide compound obtained by condensing-(S) -piperazine acid (50 mg) with dimethylamine was removed by catalytic reduction, and silica gel preparative thin layer chromatography (20 cm x 20 cm, 0.5 mm thickness, chloroform: methanol = 13: 1 development, ethyl acetate: methanol = 10: 1 elution) to give the desired compound (27 mg).

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 1.06-1.78 (20H, complex), 1.8
0-2.02 (2H, complex), 2.29 (1H, dd, J = 14.5 and 4.0 Hz),
2.52 (1H, dd, J = 14.5 and 10.9 Hz), 2.70-3.12 (2H, comple
x), 2.94 (3H, s), 3.06 (3H, s), 3.92 (1H, m), 5.26 (1H, d, J = 1
1.9 Hz), 5.50 (1H, br.s), 7.92-8.77 (1H, br.m), 9.59 (1H,
m) Infrared absorption spectrum (film, cm ^-1 ): 3262 (m), 2926 (s),
1649 (s), 1627 (s) Mass spectrum [M] ⁺ = 412 High resolution mass spectrum [M] ⁺ = 412.3036 (C ₂₁ H ₄₀ N ₄ O ₄ ) Calculated value: 412.3049 Specific rotation [α] _D ²⁶ = + 6.8 ° (C = 1.0, EtOH) ( example ^{9) N 2 - [2- (} R) - ( hydroxyaminocarbonyl main
Cyl) -1-oxoundecanyl]-(S) -piperazi
N obtained in phosphate N- methylamide Reference Example 65 ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-undecanyloxy] - (S) - piperazine To a solution of acid N-methylamide (52 mg) in methanol (2.5 ml) was added 10% palladium-carbon (8 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours for catalytic reduction. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5 mm thickness, developed with chloroform: methanol = 10: 1 ethyl acetate: Methanol = 1
Purification by elution (0: 1) gave 28 mg of the desired compound.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.6Hz), 1.05-1.93 (19H, complex), 2.04
(1H, br.d, J = 11.9Hz), 2.28 (1H, dd, J = 13.9 and 3.3Hz), 2.
51 (1H, dd, J = 13.9 and 11.2Hz), 2.78 (3H, d, J = 4.6Hz), 2.8
2 (1H, m), 3.01 (1H, br.d, J = 12.5Hz), 3.87 (1H, m), 4.74 (1H,
d, J = 11.9Hz), 5.06 (1H, s), 6.96 (1H, m), 9.81-10.19 (1H, b
r) Infrared absorption spectrum (liquid film, cm ^-1 ): 3270,2927,1
653,1626 High resolution mass spectrum [M + H] ⁺ = 385.2802 (C ₁₉ H ₃₇ O ₄ N ₄ ) Calculated value: 385.2837 Specific rotation: [α] _D ²⁶ = -7.6 ° (C = 1.0, EtOH) ( example ^{10) N 2 - [2- (} R) - ( hydroxyaminocarbonyl main
Cyl) -1-oxoundecanyl]-(S) -piperazi
According to the method of phosphate N- dimethylamide Example 1, Reference Example 66 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-Okisoundeka The protecting group of Nyl]-(S) -piperazine acid N-dimethylamide (58 mg) was removed by catalytic reduction reaction, and the same treatment was performed to obtain the target compound (23 mg).

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.9Hz), 1.10-2.02 (20H, complex), 2.28
(1H, dd, J = 14.2 and 4.3Hz), 2.52 (1H, dd, J = 14.2 and 10.
9Hz), 2.70-3.13 (2H, complex), 2.94 (3H, s), 3.06 (3H, s),
3.94 (1H, m), 5.26 (1H, d, J = 11.9Hz), 5.51 (1H, m), 9.65 (1H,
br.s) Infrared absorption spectrum (liquid film, cm ^-1 ): 3263,2856,1
645,1622 Calculated by elemental analysis C ₂₀ H ₃₈ N ₄ O ₄ 1 / 2H ₂ O: C, 58.94%; H, 9.64%; N, 1
3.75% Measured value: C, 58.69%; H, 9.32%; N, 13.60% Specific rotation: [α] _D ²⁶ = + 9.6 ° (C = 1.0, EtOH) (Reference Example 1) N-benzyloxycarbonyl- (L) -isoleucine
(N-Methyl-N-methoxy) amide To a solution of N-benzyloxycarbonyl-L-isoleucine (15 g) in methylene chloride (200 ml) cooled to 0 ° C. was added N, O-dimethylhydroxylamine hydrochloride (5.8 g).
g), dicyclohexylcarbodiimide (DCC, 11.7
g), diisopropylethylamine (10 ml) and 4-dimethylaminopyridine (70 ml) were sequentially added, and the mixture was stirred at 0 ° C for 2.
Stir for 3 hours. After filtering off the crystals, the reaction mixture was poured into hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 5: 2) to obtain 16.9 g of the objective compound as a colorless crystalline substance. Recrystallization from methanol-water gave colorless crystals with a melting point of 64-66 ° C.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 7.3 Hz), 0.93 (3H, d, J = 6.8 Hz), 1.12 (1
H, m), 1.57 (1H, m), 1.73 (1H, m), 3.22 (3H, s), 3.79 (3H, s),
4.67 (1H, br, t, J = 8.1 Hz), 5.06 (1H, d, J = 12.5 Hz), 5.13 (1
H, d, J = 12.5 Hz), 5.35 (1H, br.d, J = 9.8 Hz), 7.23-7.41 (5
H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3306 (m), 171
9 (s), 1654 (s) High resolution mass spectrum [M + H] ⁺ = 309.1804 (C ₁₆ H ₂₅ N ₂ O ₄ ) Calculated value: 309.1813 Specific rotation [α] _D ²⁶ = -4.68 ° (C = 2.01, CHCl ₃₎ (reference example 2) (4S, 5S) -4- benzyloxycarbonylamino
N-benzyloxycarbonyl- (L) -isoleucyl (N-methyl-N-) cooled to -15 ° C under a nitrogen atmosphere of -5-methyl-3- oxoheptane.
Methoxy) amide (1.71 g) in tetrahydrofuran (4
Ethyl magnesium bromide (0.99 M tetrahydrofuran solution) (16 ml) was added dropwise to the solution (0 ml) and the mixture was stirred for 0.6 hours. After warming to room temperature and stirring for 0.6 hours, the reaction solution was poured into a 5% aqueous potassium hydrogen sulfate solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 and 2: 1) to obtain 861 mg (56.2%) of the target compound. Also, the starting material N-benzyloxycarbonyl- (L) -isoleucyl (N-methyl-N-methoxy) amine (508 mg) was recovered.
The target compound was recrystallized from methanol-water and had a melting point of 57-5.
It became colorless crystals at 8 ° C.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 7.3 Hz), 0.98 (3H, d, J = 6.8 Hz), 1.08 (3
H, t, J = 7.3 Hz), 1.27 (1H, m), 1.90 (1H, m), 2.52 (1H, dd, J =
7.3 and 3.9 Hz), 4.36 (1H, dd, J = 8.5 and 4.6 Hz), 5.09
(2H, s), 5.36 (1H, br.d, J = 8.3 Hz), 7.24-7.40 (5H, comple
x) Infrared absorption spectrum (liquid film, cm ^-1 ): 3270 (w), 171
0 (s) High resolution mass spectrum [M + H] ⁺ = 278.1750 (C ₁₆ H ₂₄ NO ₃ ) calculated value: 278.1756 (Reference Example 3) 4- (S) -isopropyl-3- (1-oxohepti
) -2-oxazolidinone 4- (S) -isopropyl -2-oxazolidinone (5.
Tetrahydrofuran (125 ml) under nitrogen atmosphere
And was cooled to -78 ° C. n-Butyllithium (1.65M hexane solution) (25 ml) was added dropwise, and the mixture was stirred for 10 minutes. Then, heptanoyl chloride (6.4 ml) was added, and the mixture was stirred at -78 ° C for 1.5 hr. The reaction solution was poured into a 5% ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and then dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 8: 1) to obtain the target compound (9.69 g) as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.82-0.97 (3H, t, 0.87ppm and 0.92ppm and overlappe
d), 0.87 (3H, d, J = 6.8 Hz), 0.92 (3H, d, J = 6.8 Hz), 1.22-1.
45 (6H, complex), 1.58-1.75 (2H, complex), 2.38 (1H, d, he
p, J = 3.4 and 6.8 Hz), 2.77-3.06 (2H, complex), 4.19 (1H,
dd, J = 8.3 and 3.4 Hz), 4.26 (1H, t, J = 8.3 Hz), 4.43 (1H, d
t, J = 8.3 and 3.4 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 1784 (s), 170
3 (s) High-resolution mass spectrum [M] ⁺ = 241.1675 (C ₁₃ H ₂₃ NO ₃ ) calculated value: 241.1677 (Reference Example 4) 4- (S) -isopropyl -3- (2- (R) -t- Bu
Toxycarbonylmethyl-1-oxoheptyl) -2-
Oxazolidinone Lithium diisopropylamide (0.58 M tetrahydrofuran solution) in a tetrahydrofuran (15 ml) solution of 4- (S) -isopropyl-3- (1-oxoheptyl) -2-oxazolidinone (519 mg) cooled to -15 ° C under a nitrogen atmosphere. (39 ml) was added and the mixture was stirred at -78 ° C for 10 minutes. Then, a tetrahydrofuran solution (5 ml) of t-butyl bromoacetate (1.7 ml) was added, and the temperature was gradually raised to -55 ° C while continuing stirring for 5.5 hours. 5% of reaction liquid
Poured into an aqueous solution of ammonium chloride, extracted with ethyl acetate,
The organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, silica gel column chromatography (hexane: ethyl acetate = 10:
697 mg of the target compound by purification with (1)
(91.2%) was obtained. Recrystallized from methanol-water, melting point 51-53 ° C.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.86 (3H, t, J = 6.4 Hz), 0.91 (3H, d, J = 6.3 Hz), 0.93 (3
H, d, J = 6.3 Hz), 1.14-1.51 (7H, complex), 1.41 (9H, s), 1.6
2 (1H, m), 2.38 (1H, d, hep, J = 3.4 and 6.3 Hz), 2.43 (1H, d
d, J = 16.6 and 4.9 Hz), 2.74 (1H, dd, J = 16.6 and 10.3 H
z), 4.15 (1H, m), 4.20 (1H, dd, J = 7.9 and 3.4 Hz), 4.25 (1
H, t, J = 7.9 Hz), 4.43 (1H, dt, J = 7.9 and 3.4 Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 1763 (s), 1730
(s), 1702 (s) High-resolution mass spectrum [M + H] ⁺ = 356.2449 (C ₁₉ H ₃₄ NO ₅ ) calculated: 356.2437 Specific rotation [α] _D ²⁶ = + 50.8 ° (C = 1.03, CHCl ₃ ) (Reference Example 5) 2- (R)-(t-butoxycarbonylmethyl) -hep
Tanoic acid 4- (S) -isopropyl-3-obtained in Reference Example 4
[2- (R)-(t-butoxycarbonylmethyl) -1
-Oxoheptyl] -2-oxazolidinone (691m
g) was dissolved in a mixed solvent of tetrahydrofuran-water (3: 1, 40 ml) and cooled to 0 ° C. Next, lithium hydroxide hydrate (165 mg) and 31% hydrogen peroxide aqueous solution (1 m
l) were sequentially added, and the mixture was stirred at 0 ° C. for 1.5 hours. After adding 1.5 N sodium sulfite aqueous solution (7.3 ml) and stirring for several minutes,
It was poured into a 1N aqueous sodium hydroxide solution and washed with methylene chloride. The aqueous layer was adjusted to pH 1-2 with 1N hydrochloric acid, extracted with ethyl acetate, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 8: 1) to obtain 452 mg (95.1%) of the target compound as a colorless oily substance.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 7.4 Hz), 1.21-1.41 (6H, complex), 1.43
(9H, s), 1.52 (1H, m), 1.65 (1H, m), 2.38 (1H, dd, J = 16.5 and
5.3Hz), 2.62 (1H, dd, J = 16.5 and 9.2 Hz), 2.80 (1H, m) Infrared absorption spectrum (liquid film, cm ^-1 ): 1734 (s), 17
09 (s) High resolution mass spectrum [M + H] ⁺ = 245.1752 (C ₁₃ H ₂₅ O ₄ ) Calculated value: 245.1752 Specific rotation [α] _D ²⁶ = + 14.5 ° (C = 1.97, EtOH) (Reference example) 6) 3- (R) -benzyloxycarbonyloctanoic acid t-
Butyl ester A solution of 2- (R)-(t-butoxycarbonylmethyl) heptanoic acid (440 mg) obtained in Reference Example 5 in dimethylformamide (DMF, 18 ml) was added with sodium hydrogen carbonate (305 mg) and benzyl bromide (1.0 ml). Were sequentially added, and the mixture was stirred overnight at room temperature. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:
The product was purified with ethyl acetate = 20: 1) to obtain 476 mg of the desired product as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.85 (3H, t, J = 6.6 Hz), 1.17-1.32 (6H, complex), 1.41
(9H, s), 1.50 (1H, m), 1.61 (1H, m), 2.36 (1H, dd, J = 16.5 and
5.3Hz), 2.65 (1H, dd, J = 16.5 and 9.2Hz), 2.83 (1H, m),
5.09 (1H, d, J = 12.5 Hz), 5.18 (1H, d, J = 12.5 Hz), 7.24-7.4
2 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 1731 (s) High resolution mass spectrum [M + H] ⁺ = 335.2230 (C ₂₀ H ₃₁ O ₄ ) Calculated value: 335.2223 Specific rotation [ α] _D ²⁶ = + 0.22 ° (C = 7.9, CHCl ₃ ) (Reference Example 7) 3- (R) -benzyloxycarbonyloctanoic acid 3- (R) -benzyloxycarbonyloctanoic acid obtained in Reference Example 6 4M in t-butyl ester (983mg)
-Hydrochloric acid-dioxane solution (15 ml) was added, and the mixture was stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 30: 1) to obtain 838 mg of the target compound as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.85 (3H, t, J = 6.6Hz), 1.10-1.38 (6H, complex), 1.42-
1.77 (2H, complex), 2.48 (1H, dd, J = 16.5 and 4.6Hz), 2.78
(1H, dd, J = 16.5 and 9.2 Hz), 2.88 (1H, m), 5.14 (2H, s), 7.
23-7.48 (5H, complex), 7.60-9.50 (1H, m) Infrared absorption spectrum (liquid film, cm ^-1 ): 1735 (s), 171
2 (s) High resolution mass spectrum [M] ⁺ = 278.1527 (C ₁₆ H ₂₂ O ₄ ) Calculated value: 278.1518 Specific rotation [α] _D ²⁶ = + 2.4 ° (C = 0.99, EtOH) (Reference example 8) 3- (R) -benzyloxycarbonyloctanoic acid 2,
2,2-Trichloroethyl ester Under a nitrogen atmosphere, oxalic acid chloride (2 ml) was added to a solution of 3- (R) -benzyloxycarbonyloctanoic acid (671 mg) obtained in Reference Example 7 in benzene (10 ml).
The mixture was stirred at 0 ° C for 2 hours. Benzene was added to the reaction solution, and the unreacted oxalic acid chloride was removed by distillation under reduced pressure, and the residue was dissolved in tetrahydrofuran (13 ml) under a nitrogen atmosphere to give -1.
After cooling to 5 ° C., trichloroethanol (1.7 ml) and pyridine (0.23 ml) were sequentially added. After stirring at -15 ° C for 3.3 hours, the reaction solution was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extracted solution was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1.
The target compound (793 mg)
Was obtained as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.85 (3H, t, J = 6.6 Hz), 1.12-1.39 (6H, complex), 1.47-
1.79 (2H, complex), 2.60 (1H, dd, J = 15.5 and 3.3 Hz), 2.8
9 (1H, dd, J = 15.5 and 9.2 Hz), 4.64 (1H, d, J = 11.9 Hz), 4.
72 (1H, d, J = 11.9 Hz), 5.10 (1H, d, J = 11.9 Hz), 5.18 (1H, d,
J = 11.9 Hz), 7.23-7.42 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 1757 (s), 173
6 (s) High resolution mass spectrum [M + H] ⁺ = 409.0734 (C ₁₈ H ₂₄ O ₄ Cl ₃ ) calculated value: 409.0740 Specific rotation [α] _D ²⁶ = -1.0 ° (C = 6.0, CHCl ₃ ). (Reference Example 9) 2- (R)-(2,2,2-trichloroethoxycarbo
Yl) obtained in heptanoate Reference Example 8 3- (R) - 10% palladium on carbon in methanol (8 ml) solution of benzyloxycarbonyl octanoic acid 2,2,2-trichloroethyl ester (924 mg) (52 mg) In addition, the mixture was stirred under a hydrogen atmosphere for 2 hours for catalytic reduction. After completion of the reaction, the catalyst was removed by filtration through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give the desired compound (678 mg) as a colorless oil. Obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.89 (3H, t, J = 6.5 Hz), 1.18-1.47 (6H, complex), 1.47-
1.82 (2H, complex), 2.61 (1H, dd, J = 15.2 and 2.9 Hz), 2.8
8 (1H, dd, J = 15.2 and 9.3 Hz), 2.94 (1H, m), 4.72 (1H, d, J =
12.0 Hz), 4.79 (1H, d, J = 12.0Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 1758 (s), 170
9 (s) High-resolution mass spectrum [M + H] ⁺ = 319.0261 (C ₁₁ H ₁₈ O ₄ Cl ₃ ) calculated: 319.0271 Specific rotation [α] _D ²⁶ = + 11.1 ° (C = 3.96, EtOH) ( Reference Example 10) N ¹ -benzyloxycarbonyl-N ^2- [1-oxo
-2- (R)-(2,2,2-trichloroethoxycal
Bonyl) methylheptyl]-(S) -piperazine acid t-
Butyl ester 2- (R)-(2, obtained in Reference Example 9 under nitrogen atmosphere
Oxalic acid chloride (0.6 ml) was added to a solution of 2,2-trichloroethoxycarbonyl) methylheptanoic acid (573 mg) in benzene (10 ml), and the mixture was stirred at 50 ° C. for 2 hours.
Anhydrous benzene was added to the reaction solution and the mixture was concentrated under reduced pressure to remove excess oxalic acid chloride. The residue (acid chloride) obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (4 ml). (S) -N ^1- cooled to -15 ° C under nitrogen atmosphere
The acid chloride solution prepared above was added dropwise to a solution of benzyloxycarbonylpiperazine acid t-butyl ester (584 mg) and N-ethylmorpholine (0.37 ml) in tetrahydrofuran (7 ml), and the mixture was stirred overnight and gradually warmed to room temperature. Warmed. The reaction solution was poured into 0.2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 6: 1) to give the desired compound (10
04 mg) was obtained as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.80 (3H, t, J = 6.6Hz), 0.85-2.12 (12H, complex), 1.43
(9H, s), 2.61 (1H, dd, J = 17.2 and 3.3Hz), 2.94 (1H, dd, J = 1
7.2 and 10.0Hz), 3.13 (1H, m), 3.42 (1H, m), 4.28 (1H, br.
d, J = 11.3Hz), 4.61 (1H, d, J = 11.9Hz), 4.77 (1H, d, J = 11.9H
z), 5.13 (1H, d, J = 11.9Hz), 5.21 (1H, d, J = 11.9Hz), 5.27 (1
H, dd, J = 4.6 and 3.9Hz), 7.22-7.41 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 1739 (s), 167
6 (s) High-resolution mass spectrum [M] ⁺ = 620.1799 (C ₂₈ H ₃₉ N ₂ O ₇ Cl ₃ ) calculated value: 620.1822 Specific rotation [α] _D ²⁶ = -7.5 ° (C = 2.04, CHCl ₃ ). (reference example 11) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Carboxymethyl-1-oxoheptyl]-(S)-
Piperazine acid t- butyl ester in Reference Example 10 obtained in N ¹ - benzyloxycarbonyl -N ² - [1- oxo-2-(R) - (2,2,2-trichloroethoxycarbonyl) methylheptyl] -
(S) -Piperazine acid t-butyl ester (920 mg)
1N-Ammonium acetate aqueous solution (2.5 ml) and zinc (1.93 g) were added to the tetrahydrofuran solution of, and the mixture was vigorously stirred at room temperature for 4 hours. After the reaction was completed, zinc was filtered off, and the reaction solution was mixed with 5
% Potassium hydrogen sulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the objective. Compound (63
2 mg) as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.80 (3H, t, J = 6.3 Hz), 0.85-2.12 (12H, complex), 1.43
(9H, s), 2.48 (1H, dd, J = 17.2 and 4.0 Hz), 2.82 (1H, dd, J =
17.2and 11.1 Hz), 3.09 (1H, m), 3.42 (1H, m), 4.25 (1H, m),
5.12 (1H, d, J = 11.9 Hz), 5.21 (1H, d, J = 11.9 Hz), 5.27 (1H,
dd, J = 4.6 and 4.0 Hz), 7.19-7.41 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 1737 (s), 171
4 (s), 1675 (s) High resolution mass spectrum [M + H] ⁺ = 491.2724 (C ₂₆ H ₃₉ N ₂ O ₇ ) Calculated value: 491.2756 Specific rotation [α] _D ²⁶ = -23.1 ° (C = 1.03, EtOH) (example 12) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Soheptyl]-(S) -t-butyl ester of piperazinate
Le Reference Example 11 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - carboxy-methyl-1-oxo-heptyl] - (S) - piperazine acid t- butyl ester (598 mg) mixed solvent (Tetrahydrofuran: DMF
= 3: 1, 20 ml)) and cooled to -15 ° C.
O-benzylhydroxylamine (202 mg), diethyl cyanophosphonate (DEPC, 0.28 ml) and triethylamine (0.34 ml) were sequentially added, and the mixture was stirred for 2.1 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 60:
(Eluted with 1) to give the desired compound (452 mg). Also, the starting material (piperazine acid ester, 164 mg)
Was recovered.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.79 (3H, t, J = 6.8 Hz), 0.82-2.10 (12H, complex), 1.42
(9H, s), 2.10-2.46 (2H, complex), 3.19 (1H, m), 3.42 (1H,
m), 4.24 (1H, br.d, J = 11.7 Hz), 4.82 (1H, d, J = 11.2 Hz), 4.
89 (1H, d, J = 11.2 Hz), 5.12 (1H, d, J = 12.2 Hz), 5.20 (1H, d,
J = 12.2 Hz), 5.26 (1H, t, J = 3.9 Hz), 7.20-7.48 (10H, compl
ex), 7.99 (1H, m) infrared absorption spectrum (liquid film, cm ^-1 ): 3426 (m), 173
4 (s), 1674 (s) High resolution mass spectrum [M + H] ⁺ = 596.3328 (C ₃₃ H ₄₆ N ₃ O ₇ ) Calculated value: 596.3335 Specific rotation [α] _D ²⁶ = -30.7 ° (C = 1.03, CHCl ₃₎ (reference example 13) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Sohepuchiru] - (S) - piperazine acid Reference Example 12 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - benzyloxy aminocarbonyl) methyl-1-oxo-heptyl] - (S) - Trifluoroacetic acid (1.5 ml) was added to a methylene chloride solution of piperazine acid t-butyl ester (421 mg), and the mixture was stirred at room temperature for 2.6 hours. After completion of the reaction, toluene was added and the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 15: 1) to obtain the target compound (351 mg) as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.50-3.40 (17H, complex), 4.11 (1H, m), 4.81 (1H, d, J = 1
1.2 Hz), 4.88 (1H, d, J = 11.2 Hz), 4.99-5.38 (3H, comple
x), 7.05-7.55 (10H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3224 (m), 171
9 (s), 1672 (s) (Reference Example 14) 4- (S) -isopropyl-3- (1-oxodecyl)
2-Oxazolidinone According to the method of Reference Example 3, 4- (S) -isopropyl-2-
Oxazolidinone (4.74 g) and decanoyl chloride (7.35 g) were used as starting materials and the same reaction treatment was carried out to obtain the target compound (9.85 g).

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.8 Hz), 0.87 (3H, d, J = 6.6 Hz), 0.92 (3
H, d, J = 6.6 Hz), 1.17-1.43 (12H, complex), 1.59-1.73 (2H,
complex), 2.37 (1H, d.hep, J = 3.3 and 6.6 Hz), 2.78-3.05
(2H, complex), 4.20 (1H, dd, J = 9.2 and 3.3 Hz), 4.26 (1H,
dd, J = 9.2 and 7.9 Hz), 4.44 (1H, d, t, J = 7.9 and 3.3 Hz)
Infrared absorption spectrum (liquid film, cm ^-1 ): 2927 (s),
1785 (s), 1703 (s) High resolution mass spectrum [M] ⁺ = 283.2144 (C ₁₆ H ₂₉ NO ₃ ) Calculated value: 283.2147 Specific optical rotation [α] _D ²⁶ = + 61.4 ° (C = 1.00, CHCl ₃ (Reference Example 15) 4- (S) -isopropyl-3- [2- (R) -t-bu
Toxycarbonylmethyl-1-oxodecyl] -2-o
4- (S) obtained in Reference Example 14 according to the method of Xazolidinone
-Isopropyl-3- (1-oxodecyl) -2-oxazolidinone (9.85 g) and t-butyl bromoacetate (25.4
ml) as a starting material and the same reaction treatment was carried out to obtain the target compound (9.17 g). (Melting point 58 to 59 ° C) Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δppm): 0.87 (3H,
t, J = 6.8 Hz), 0.88 (3H, d, J = 6.6 Hz), 0.93 (3H, d, J = 6.6 H
z), 1.13-1.37 (12H, complex), 1.41 (9H, s), 1.53-1.70 (2H,
complex), 2.38 (1H, d.hep, J = 3.3 and 6.6 Hz), 2.43 (1H, d
d, J = 16.6 and 4.7Hz), 2.74 (1H, dd, J = 16.6 and 10.6 H
z), 4.08-4.30 (3H, complex), 4.44 (1H, dt, J = 7.3 and 3.3H
z) Infrared absorption spectrum (liquid film, cm ^-1 ): 2925 (m), 176
4 (s), 1730 (s), 1702 (s) High resolution mass spectrum [M + H] ⁺ = 398.2910 (C ₂₂ H ₄₀ NO ₅ ) Calculated value: 398.2907 Specific rotation [α] _D ²⁶ = + 46.6 ° (C = 1.00, CHCl ₃ ) (Reference Example 16) 2- (R)-(t-butoxycarbonylmethyl) decane
Acid 4- (S) obtained in Reference Example 15 according to the method of Reference Example 5
Using -isopropyl-3- [2- (R) -t-butoxycarbonylmethyl-1-oxodecyl] -2-oxazolidinone (9.08 g) as a starting material and the same reaction treatment, the target compound (6.14 g) was obtained.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 1.18-1.40 (12H, complex), 1.43
(9H, s), 1.51 (1H, m), 1.67 (1H, m), 2.38 (1H, dd, J = 16.5 and
5.3Hz), 2.61 (1H, dd, J = 16.5 and 9.2 Hz), 2.80 (1H, m) Infrared absorption spectrum (liquid film, cm ^-1 ): 2858 (s), 173
3 (s), 1709 (s) High resolution mass spectrum [M + H] ⁺ = 287.2213 (C ₁₆ H ₃₁ O ₄ ) calculated value: 287.2223 Specific rotation [α] _D ²⁶ = + 14.2 ° (C = 1.00, EtOH) (Reference Example 17) 3- (R) -benzyloxycarbonylundecanoic acid t
-Butyl ester 2- (R) obtained in Reference Example 16 according to the method of Reference Example 6
-(T-Butoxycarbonylmethyl) decanoic acid (4.64
The target compound (5.69 g) was obtained by the same reaction treatment using g) as the starting material.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.6 Hz), 1.10-1.34 (12H, complex), 1.41
(9H, s), 1.50 (1H, m), 1.61 (1H, m), 2.36 (1H, dd, J = 16.2 and
5.3Hz), 2.64 (1H, dd, J = 16.2 and 9.2 Hz), 2.83 (1H, m),
5.09 (1H, d, J = 12.5 Hz), 5.17 (1H, d, J = 12.5 Hz), 7.28-7.4
4 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2956 (m), 173
3 (s) High resolution mass spectrum [M + H] ⁺ = 377.2658 (C ₂₃ H ₃₇ O ₄ ) Calculated value: 377.2692 Specific rotation [α] _D ²⁶ = + 1.1 ° (C = 1.00, CHCl ₃ ) (Reference) Example 18) 3- (R) -Benzyloxycarbonylundecanoic acid 3- (R) obtained in Reference Example 17 according to the method of Reference Example 7
-Benzyloxycarbonyl undecanoic acid t-butyl ester (5.62 g) was used as a starting material and the same reaction treatment was performed to obtain the target compound (4.07 g).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.6 Hz), 1.10-1.38 (12H, complex), 1.44
-1.73 (2H, complex), 2.49 (1H, dd, J = 16.2 and 4.3 Hz), 2.
79 (1H, dd, J = 16.2 and 9.6 Hz), 2.87 (1H, m), 5.12 (1H, d,
J = 13.2 Hz), 5.17 (1H, d, J = 13.2 Hz), 7.13-7.43 (5H, compl
ex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927 (s), 173
7 (s), 1713 (s) High resolution mass spectrum [M] ⁺ = 320.1989 (C ₁₉ H ₂₈ O ₄ ) calculated value: 320.1987 Specific rotation [α] _D ²⁶ = +3.3 ° (C = 1.00, EtOH) (Reference Example 19) 3- (R) -benzyloxycarbonylundecanoic acid
2,2,2-Trichloroethyl ester 3- (R) obtained in Reference Example 18 according to the method of Reference Example 8
-Benzyloxycarbonyl undecanoic acid (3.65 g) was used as the starting material and the target compound (3.18 g
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 1.14-1.38 (12H, complex), 1.48
-1.79 (2H, complex), 2.60 (1H, dd, J = 15.2 and 4.0 Hz), 2.
90 (1H, dd, J = 15.2 and 9.2 Hz), 2.96 (1H, m), 4.65 (1H, d, J
= 12.9 Hz), 4.73 (1H, d, J = 12.9Hz), 5.10 (1H, d, J = 12.2 H
z), 5.18 (1H, d, J = 12.2 Hz), 7.28-7.43 (5H, complex) Infrared absorption spectrum (film, cm ^-1 ): 2927 (s), 1737 (s), 17
13 (s) High resolution mass spectrum [M] ⁺ = 452.1099 (C ₂₁ H ₂₉ O ₄ ³⁵ Cl ₂
³⁷ Cl) Calculated: 452.1102 Specific rotation ^{_{[α] D 26 = -0.44 °}} (C: 5.00, CHCl 3) ( Reference Example 20) 2- (R) - ( 2,2,2- trichloro ethoxycarbonyl
Nyl) methyldecanoic acid 3- (R) obtained in Reference Example 19 according to the method of Reference Example 9
-Benzyloxycarbonyl undecanoic acid 2,2,2-
The target compound (1.87 g) was obtained by the same reaction treatment using trichloroethyl ester (3.08 g) as a starting material.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 1.17-1.46 (12H, complex), 1.51
-1.82 (2H, complex), 2.61 (1H, dd, J = 15.1 and 3.0 Hz), 2.
81-3.10 (2H, complex), 4.72 (1H, d, J = 12.2 Hz), 4.79 (1H,
d, J = 12.2 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2928 (s), 175
9 (s), 1710 (s) High resolution mass spectrum [M + H] ⁺ = 361.0736 (C ₁₄ H ₂₄ O ₄ ³⁵ C
l ₃ ) Calculated value: 361.0740 Specific rotation [α] _D ²⁶ = + 11.5 ° (C = 1.00, EtOH) (Reference Example 21) N ¹ -benzyloxycarbonyl-N ^2- [1-oxo
-2- (R)-(2,2,2-trichloroethoxycal
Bonyl) methyldecyl]-(S) -piperazinate t-bu
Chiller ester obtained in Reference Example 20 according to the method of Reference Example 10
By using (R)-(2,2,2-trichloroethoxycarbonyl) methyldecanoic acid (583 mg) and (S) -N ¹ -benzyloxycarbonylpiperazine acid t-butyl ester (490 mg) as starting materials, the same reaction treatment was performed. A compound (704 mg) was obtained.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 0.93-2.14 (18H, complex), 1.43
(9H, s), 2.60 (1H, dd, J = 17.5 and 3.6 Hz), 2.95 (1H, dd, J =
17.5 and 10.9 Hz), 3.14 (1H, m), 3.42 (1H, br.t, J = 11.3
Hz), 4.27 (1H, br.d, J = 12.5 Hz), 4.61 (1H, d, J = 12.2 Hz),
4.78 (1H, d, J = 12.2 Hz), 5.14 (1H, d, J = 11.9 Hz), 5.21 (1H,
d, J = 11.9 Hz), 5.27 (1H, t, J = 4.3 Hz), 7.23-7.40 (5H, comp
lex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2929 (m), 174
0 (s), 1677 (s) High resolution mass spectrum [M + 2H] ⁺ = 664.2264 (C ₃₁ H ₄₅ O ₇ ³⁵
Cl ₃₎ Calculated: 664.2263 Specific rotation ^{_{[α] D 26 = -6.8 °}} (C = 1.00, CHCl 3) ( Reference Example 22) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Carboxymethyl-1-oxodecyl]-(S) -pi
Perazine acid t- butyl ester Reference Example 11 N ¹ obtained in Reference Example 21 in accordance with the method - benzyloxycarbonyl -N ² - [1- oxo-2-
Using (R)-(2,2,2-trichloroethoxycarbonyl) methyldecyl]-(S) -piperazine acid t-butyl ester (645 mg) as a starting material, the target compound (455 mg) was obtained by the same reaction treatment.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6 Hz), 0.93-2.11 (18H, complex), 1.43
(9H, s), 2.49 (1H, dd, J = 17.2 and 3.3 Hz), 2.82 (1H, dd, J =
17.2and 11.2 Hz), 3.09 (1H, m), 3.32 (1H, dd, J = 14.2 and
10.7 Hz), 4.25 (1H, br.d, J = 8.5 Hz), 5.13 (1H, d, J = 12.5 H
z), 5.20 (1H, d, J = 12.5 Hz), 5.27 (1H, d, J = 4.3 Hz), 7.20-
7.40 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3189 (w), 292
9 (m), 1736 (s), 1678 (s) High resolution mass spectrum [M + H] ⁺ = 533.3249 (C ₂₉ H ₄₅ N ₂ O ₇ ) Calculated value: 533.3227 Specific rotation [α] _D ²⁶ =- 21.3 ° (C = 1.00, EtO
H) (Reference Example 23) ^{N 1} - benzyloxycarbonyl -N ² - [2-
(R)-(benzyloxyaminocarbonyl) methyl-
1-oxodecyl]-(S) -t-butyl piperazinate
Ester Reference Example 12 N ¹ obtained in Reference Example 22 according to the method of -
Benzyloxycarbonyl ^{-N 2 - [2- (R)} - carboxy-methyl-1-oxodecyl] - (S) - object compound by a similar reaction processes as the starting material piperazine acid t- butyl ester (437 mg) and (490 mg) Obtained.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.6 Hz), 0.92-2.52 (18H, complex), 1.43
(9H, s), 2.10-2.46 (2H, complex), 3.20 (1H, m), 3.41 (1H,
m), 4.24 (1H, m), 4.82 (1H, d, J = 11.6 Hz), 4.89 (1H, d, J = 11.
6 Hz), 5.12 (1H, d, J = 12.5 Hz), 5.20 (1H, d, J = 12.5 Hz), 5.
27 (1H, t, J = 2.4 Hz), 7.22-7.48 (10H, complex), 8.12 (1H,
m) Infrared absorption spectrum (liquid film, cm ^-1 ): 3255 (w), 292
8 (s), 1733 (s), 1675 (s) High resolution mass spectrum [M + H-tBu] ⁺ = 581.3104 (C ₃₂ H ₄₃ N
₃ O ₇₎ Calculated: 581.3101 Specific rotation ^{_{[α] D 26 = -34.30 °}} (C = 1.00, CHCl 3) ( Reference Example 24) N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} -
(Benzyloxyaminocarbonyl) methyl-1-oxy
Sodeshiru] - (S) - piperazine acid Reference Example 13 N ¹ obtained in Reference Example 23 in accordance with the method - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxodecyl ]
-(S) -piperazine acid t-butyl ester (433m
Target compound (379 mg) was obtained by the same reaction treatment using g) as a starting material.

Nuclear magnetic resonance spectrum (270 MHz, CDCl
₃ ) δ: 0.88 (3H, t, J = 6.6 Hz), 0.92-2.59 (20H, comple
x), 2.51-3.18 (2H, complex), 4.10 (1H, br.d, J = 12.5 Hz),
4.83 (1H, t, J = 4.5 Hz), 4.93 (1H, d, J = 11.2 Hz), 5.00 (1H,
d, J = 11.2 Hz), 5.01 (1H, d, J = 11.9 Hz), 5.18 (1H, d, J = 11.9
Hz), 7.14 (1H, br.s), 7.20-7.51 (10H, complex), 12.3 (1H,
br.s) Infrared absorption spectrum FT film (cm ^-1 ): 3228 (w)
, 2927 (s), 1705 (s), 1672 (s), 16
04 (s) Specific rotation [α] _D ²⁶ = −29.0 ° (c = 1.00, Et
OH) (Reference Example 25) 4- (S) -isopropyl-3- (1-oxooctyl)
) -2-oxazolidinone 4- (S) -isopropyl -2-oxazolidinone (5.
The target compound (9.39 g) was obtained as a colorless oil from 06 g) and octanoyl chloride (6.67 g) by the same reaction treatment as in Reference Example 3.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, d, J = 6.6 Hz), 0.88 (3H, t, 0.87ppm and 0.
92ppm and overlapped), 0.92 (3H, d, J = 6.6Hz), 1.09-1.42
(8H, complex), 1.50-1.73 (2H, complex), 2.38 (1H, m), 2.70
-3.06 (2H, complex), 4.20 (H, dd, J = 9.2 and 3.3 Hz), 4.26
(1H, t, J = 9.2 Hz), 4.44 (1H, dt, J = 9.2 and 3.3 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2929 (m), 17
84 (s), 1702 (s) Mass spectrum [M] ⁺ = 255 High resolution mass spectrum [M] ⁺ = 255.1832 (C ₁₄ H ₂₅ O ₃ N) Calculated value: 255.1835 Specific optical rotation [α] _D ²⁶ = + 74.9 ° (C = 1.0, CHCl ₃ ) (Reference Example 26) 4- (S) -isopropyl-3- (2- (R) -t-bu
Toxycarbonylmethyl-1-oxooctyl) -2-
Oxazolidinone 4- (S) -isopropyl-3-obtained in Reference Example 25
(1-oxooctyl) -2-oxazolidinone (5.51
g) and t-butyl bromoacetate (17 ml) were treated in the same manner as in Reference Example 4 to obtain the target compound (4.13 g).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 7.3 Hz), 0.91 (3H, d, J = 6.3 Hz), 0.93
(3H, d, J = 6.3 Hz), 1.15-1.50 (9H, complex), 1.41 (9H, s),
1.62 (1H, m), 2.36 (1H, m), 2.42 (1H, dd, J = 16.6 and 4.4 H
z), 2.74 (1H, dd, J = 16.6 and 10.3 Hz), 4.08-4.30 (3H, com
plex), 4.43 (1H, dt, J = 7.6 and 3.7 Hz) Infrared absorption spectrum (liquid film, KBr pellet): 2931
(m), 1764 (s), 1730 (s), 1703 (s) Mass spectrum [M + H] ⁺ = 370 High resolution mass spectrum [M + H] ⁺ = 370.2587 (C ₂₀ H ₃₆ NO ₅ ) Calculated value : 370.2593 mp50-51 ° C. H ₂ O-MeOH Specific rotation [α] _D ²⁶ = + 51.9 ° (C = 1.0, CHCl ₃ ) (Reference Example 27) 3- (R) -benzyloxycarbonylnonanoic acid t-bu
Chil ester 4- (S) -isopropyl -3-obtained in Reference Example 26
A tetrahydrofuran solution of (2- (R) -t-butoxycarbonylmethyl-1-oxooctyl) -2-oxazolidinone (3.98 g) was cooled to 0 ° C., and tetrahydrofuran (30 ml), benzyl alcohol (2.4 ml),
Lithium benzyl oxide solution (42m) prepared by water cooling with n-butyllithium (1.66M hexane solution 9.8ml)
l) was added and the mixture was stirred at 0 ° C. for 40 minutes. The reaction solution was poured into a 5% aqueous solution of potassium hydrogensulfate and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluted with hexane: ethyl acetate = 20: 1) to obtain the target compound (3.86 g) as a colorless oily substance.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.86 (3H, t, J = 6.6 Hz), 1.10-1.72 (10H, complex),
1.41 (9H, s), 2.36 (1H, dd, J = 16.2 and 5.3 Hz), 2.64 (1H, d
d, J = 16.2 and 9.2 Hz), 2.83 (1H, m), 5.09 (1H, d, J = 12.5 H
z), 5.17 (1H, d, J = 12.5 Hz), 7.26-7.41 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2931 (m), 17
32 (s) Mass spectrum [M + H-tBu] ⁺ = 292 High-resolution mass spectrum [M + H-tBu] ⁺ = 2
_{92.1677 (C 17 H 24 O 4} ) Calculated: 292.1675 Specific rotation [α] ^{_{D 26 = + 0.38 ° (C}} = 6.9, CHCl 3) ( Reference Example 28) 3- (R) - benzyloxycarbonyl nonane Acid 3- (R) -benzyloxycarbonylnonanoic acid t-butyl ester (3.86 g) obtained in Reference Example 27 was treated in the same manner as in Reference Example 7 to obtain the target compound (2.73 g).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.86 (3H, t, J = 6.6 Hz), 1.09-1.37 (8H, complex), 1.
41-1.78 (2H, complex), 2.49 (1H, dd, J = 16.3 and 4.4Hz),
2.79 (1H, dd, J = 16.3 and 9.3 Hz), 2.88 (1H, m), 5.12 (1H,
d, J = 12.2 Hz), 5.17 (1H, d, J = 12.2 Hz), 7.23-7.42 (5H, com
plex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2930 (m), 17
36 (s), 1712 (s) Mass spectrum [M] ⁺ = 292 High resolution mass spectrum [M] ⁺ = 292.1679 (C ₁₇ H ₂₄ O ₄ ) Calculated value: 292.1675 Specific optical rotation [α] _D ²⁶ = + 2.0 ° (C = 2.0, EtOH) (Reference Example 29) 3- (R) -benzyloxycarbonylnonanoic acid 2,
2,2-Trichloroethyl ester 3- (R) -benzyloxycarbonylnonanoic acid (2.7 g) obtained in Reference Example 28 and trichloroethanol (1.7
ml) was treated in the same manner as in Reference Example 8 to obtain the target compound (3.1
7 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.86 (3H, t, J = 6.8H
z), 1.11-1.37 (8H, complex),
1.48-1.78 (2H, complex), 2.6
0 (1H, dd, J = 15.9 and 3.7 H
z), 2.89 (1H, dd, J = 15.9 and
9.0 Hz), 2.96 (1H, m), 4.65 (1
H, d, J = 12.0 Hz), 4.72 (1 H, d,
J = 12.0 Hz, 5.10 (1H, d, J = 1
2.4 Hz), 5.18 (1H, d, J = 12.4
Hz), 7.25-7.42 (5H, complex) Infrared absorption spectrum (liquid film, cm)
^-1 ): 2930 (m), 1758 (s), 1736
(S) Mass spectrum [M] ⁺ = 422 High resolution mass spectrum [M] ⁺ = 422.0826 (C ₁₉ H ₂₅ O ₄ (35C
l) ₃ ) Calculated value: 422.0819 Specific rotation [α] _D ²⁶ = -0.99 ° (C = 5.9, EtoH) (Reference Example 30) 2- (R)-(2,2,2-trichloroethoxycarbo)
Nyl) methyloctanoic acid 3- (R) -benzyloxycarbonylnonanoic acid 2,2,2-trichloroethyl ester (3.12 g) obtained in Reference Example 29 was treated in the same manner as in Reference Example 9 to obtain the target compound ( 2.39 g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.88 (3H, t, J = 6.8 Hz), 1.18-1.45 (8H, complex), 1.
49-1.81 (2H, complex), 2.61 (1H, dd, J = 15.1 and 2.9 Hz),
2.88 (1H, dd, J = 15.1 and 9.3 Hz), 2.94 (1H, m), 4.72 (1H,
d, J = 12.2 Hz), 4.79 (1H, d, J = 12.2 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2930 (m), 17
59 (s), 1710 (s) Mass spectrum [M + H] ⁺ = 333 High resolution mass spectrum [M + H] ⁺ = 333.0453 (C ₁₂ H ₂₀ O
₄ (35Cl) ₃ ) Calculated value: 333.0428 Specific rotation [α] _D ²⁶ = + 11.7 ° (C = 4.0, EtOH) (Reference Example 31) N ¹ -benzyloxycarbonyl-N ^2- [1-oxo
-2- (R)-(2,2,2-trichloroethoxycal
Bonyl) methyloctyl]-(S) -piperazine acid t-
Butyl ester 2- (R)-(2,2,2-trichloroethoxycarbonyl) methyloctanoic acid (464) obtained in Reference Example 30
The acid chloride obtained from (mg) and (S) -N ¹ -benzyloxycarbonylpiperazine acid t-butyl ester were reacted according to the method shown in Reference Example 10 to obtain the target compound (772 mg).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.84 (3H, t, J = 6.6 Hz), 0.90-2.12 (14H, complex),
1.43 (9H, s), 2.60 (1H, dd, J = 17.2 and 4.0 Hz), 2.97 (1H, d
d, J = 17.2 and 9.2 Hz), 3.13 (1H, m), 3.43 (1H, m), 4.28 (1
H, m), 4.61 (1H, d, J = 11.9 Hz), 4.78 (1H, d, J = 11.9 Hz), 5.1
3 (1H, d, J = 11.9 Hz), 5.21 (1H, d, J = 11.9 Hz), 5.27 (1H, dd,
J = 4.6 and 4.0 Hz), 7.24-7.41 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2931 (m), 17
36 (s), 1677 (s), mass spectrum [M] ⁺ = 634 High resolution mass spectrum [M] ⁺ = 636.1935 (C ₂₉ H ₄₁ O ₇ N
₂ (35Cl) ₂ (37Cl)) Calculated value: 636.1950 Specific rotation [α] _D ²⁶ = -6.9 ° (C = 2.0, CHCl ₃ ) (Reference Example 32) N ¹ -benzyloxycarbonyl-N ^2- [2 -(R)
-Carboxymethyl-1-oxooctyl]-(S)-
Piperazine acid t- butyl ester in Reference Example 31 obtained in N ¹ - benzyloxycarbonyl -N ² - [1-oxo-2-(R) - (2,2,2-trichloroethoxycarbonyl) methyloctyl] -
(S) -Piperazine acid t-butyl ester (765 mg)
Was treated according to the method described in Reference Example 11 to obtain the target compound (495 mg).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.83 (3H, t, J = 6.6 Hz), 0.96-2.12 (14H, complex),
1.43 (9H, s), 2.48 (1H, dd, J = 17.2 and 3.6 Hz), 2.82 (1H, d
d, J = 17.2 and 10.6 Hz), 3.08 (1H, m), 3.12 (1H, m), 4.25 (1
H, m), 5.13 (1H, d, J = 12.2 Hz), 5.20 (1H, d, J = 12.2 Hz), 5.2
7 (1H, dd, J = 4.6 and 4.0 Hz), 7.22-7.48 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3186 (w), 29
31 (m), 1736 (s), 1678 (s) Mass spectrum [M + H] ⁺ = 505 High resolution mass spectrum [M + H] ⁺ = 505.2913 (C ₂₇ H ₄₁ O
₇ N ₂₎ Calculated: 505.2914 Specific rotation [α] ^{_{D 26 = -23.5 ° (C =}} 1.0, EtOH) ( Example 33) ^{N 1} - benzyloxycarbonyl -N ² - [2-
(R) -benzyloxyaminocarbonyl) methyl-1
-Oxooctyl]-(S) -piperazinate t-butyl
Ester Reference Example 32 obtained in N ¹ - benzyloxycarbonyl -N ² - [2- (R) - carboxy-methyl-1-oxo-octyl] - (S) - piperazine acid t- butyl ester (485 mg) O- Benzylhydroxylamine was condensed by the reaction treatment shown in Reference Example 12 to give the desired compound (5
77 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.83 (3H, t, J = 6.6 Hz), 0.88-2.08 (15H, complex),
1.42 (9H, s), 2.30 (1H, m), 3.20 (1H, m), 3.43 (1H, m), 4.24 (1
H, m), 4.82 (1H, d, J = 11.6 Hz), 4.88 (1H, d, J = 11.6 Hz), 5.1
3 (1H, d, J = 12.2 Hz), 5.20 (1H, d, J = 12.2Hz), 5.25 (1H, br.
t, J = 4.0 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 3251 (w), 29
31 (m), 1735 (s), 1675 (s) Mass spectrum [M] ⁺ = 609 High resolution mass spectrum [M] ⁺ = 609.3395 (C ₃₄ H ₄₇ O ₇ N ₃ ) Calculated value: 609.3414 Specific rotation α] ^{_{D 26 = -37.8 ° (C =}} 1.0, CHCl 3) ( reference example 34) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Sookuchiru] - (S) - piperazine acid Reference Example 33 obtained in N ¹ - benzyloxycarbonyl -N ² - [2-(R) - benzyloxy aminocarbonyl) methyl-1-oxo-octyl] - (S) - The target compound (458 mg) was obtained by subjecting piperazine acid t-butyl ester (565 mg) to the same reaction treatment as in Reference Example 13.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 6.6 Hz), 0.92-2.62 (16H, complex),
2.82-3.29 (2H, complex), 4.10 (1H, m), 4.71-5.40 (5H, comp
lex), 7.00-7.58 (10H, complex), 8.02 (1H, br.s) Infrared absorption spectrum (liquid film, cm ^-1 ): 3227 (m), 29
30 (s), 1718 (s), 1672 (s), 1608 (s) Mass spectrum [MC ₆ H ₅ ] ⁺ = 476 Specific rotation [α] _D ²⁶ = -17.3 ° (C = 1.0, EtOH) ( Reference Example 35) 4- (S) -isopropyl-3- (1-oxononyl)
2-oxazolidinone 4- (S) -isopropyl -2-oxazolidinone (4.
Reference Example 3 from 99 g) and nonanoyl chloride (7.16 g)
The target compound (10.12 g) was obtained as a colorless oil by the same reaction treatment as described above.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, d, J = 7.3 Hz), 0.88 (3H, t, J = 6.8 Hz), 0.92
(3H, d, J = 7.3 Hz), 1.18-1.45 (12H, complex), 1.56-1.75 (2
H, complex), 2.38 (1H, d, hep, J = 3.3 and 7.3 Hz), 2.78-3.
07 (2H, complex), 4.20 (1H, dd, J = 9.2 and 3.3Hz), 4.26 (1
H, t, J = 9.2 Hz), 4.44 (1H, dt, J = 7.9 and 3.3 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2928 (m), 17
85 (s), 1703 (s), Mass spectrum [M] ⁺ = 269 High resolution mass spectrum [M] ⁺ = 269.2001 (C ₁₅ H ₂₇ O ₃ N) Calculated value: 269.1991 Specific optical rotation [α] _D ²⁶ = + 67.4 ° (C = 1.0, CHCl ₃ ) (Reference Example 36) 4- (S) -isopropyl-3- (2- (R) -t-bu
Toxycarbonylmethyl-1-oxononyl) -2-o
Xazolidinone 4- (S) -isopropyl -3-obtained in Reference Example 35
(1-Oxononyl) -2-oxazolidinone (10.09
g) and bromoacetic acid t-butyl ester (30 ml) were treated in the same manner as in Reference Example 4 to obtain the target compound (12.62 g).
Got

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 6.9 Hz), 0.91 (3H, d, J = 6.6 Hz), 0.93
(3H, d, J = 6.6 Hz), 1.17-1.50 (11H, complex), 1.41 (9H, s),
1.60 (1H, m), 2.37 (1H, m), 2.43 (1H, dd, J = 16.5 and 4.0 H
z), 2.74 (1H, dd, J = 16.5 and 9.9 Hz), 4.09-4.31 (3H, comp
lex), 4.43 (1H, dt, J = 7.9 and 4.0 Hz) Infrared absorption spectrum (liquid film, kBr pellet): 2925
(m), 1763 (s), 1731 (s), 1704 (s) Mass spectrum [M + H] ⁺ = 384 High resolution mass spectrum [M + H] ⁺ = 384.2752 (C ₂₁ H ₃₈ O ₅ N) Calculation Value: 384.2750 mp 49-51 ° (H ₂ O-MeOH) Specific optical rotation [α] _D ²⁶ = + 48.5 ° (C = 1.0, CHCl ₃ ) (Reference Example 37) 3- (R) -benzyloxycarbonyldecane Acid t-bu
Chil ester 4- (S) -isopropyl -3-obtained in Reference Example 36
(2- (R) -t-butoxycarbonylmethyl-1-oxononyl) -2-oxazolidinone (12.44 g) was treated in the same manner as in Reference Example 63 to give the target compound (10.88 g).
Got

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 6.6 Hz), 1.14-1.33 (10H, complex),
1.40 (9H, s), 1.49 (1H, m), 1.62 (1H, m), 2.36 (1H, dd, J = 16.5
and6.5 Hz), 2.64 (1H, dd, J = 16.5 and 9.2 Hz), 2.84 (1H,
m), 5.09 (1H, d, J = 12.2 Hz), 5.17 (1H, d, J = 12.2 Hz), 7.29-
7.40 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2929 (s), 17
36 (s), mass spectrum [M + H] ⁺ = 363 High resolution mass spectrum [M + H] ⁺ = 363.2525 (C ₂₂ H ₃₅ O ₄ ) calculated value: 363.2535 (Reference Example 38) 3- (R)- Benzyloxycarbonyldecanoic acid 3- (R) -benzyloxycarbonyldecanoic acid t-butyl ester (10.50 g) obtained in Reference Example 37 was treated in the same manner as in Reference Example 7 to obtain the target compound (8.29 g). .

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 6.6 Hz), 1.10-1.38 (10H, complex),
1.42-1.77 (2H, complex), 2.48 (1H, dd, J = 16.2 and 4.6 H
z), 2.79 (1H, dd, J = 16.5 and 9.2 Hz), 2.88 (1H, m), 5.12 (1
H, d, J = 12.5 Hz), 5.17 (1H, d, J = 12.5 Hz), 7.25-7.42 (5H, c
omplex) Specific rotation [α] _D ²⁶ = + 3.0 ° (C = 1.0, EtOH) (Reference Example 39) 3- (R) -benzyloxycarbonyldecanoic acid 2,
2,2-Trichloroethyl ester 3- (R) -benzyloxycarbonyldecanoic acid (8.26 g) obtained in Reference Example 38 and trichloroethanol (1
1.5 ml) was treated in the same manner as in Reference Example 8 to obtain the target compound (11.44 g).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 6.6 Hz), 1.10-1.39 (10H, complex),
1.46-1.82 (2H, complex), 2.60 (1H, dd, J = 15.2 and 4.0 H
z), 2.89 (1H, dd, J = 15.2 and 9.2 Hz), 2.96 (1H, m), 4.65 (1
H, d, J = 12.2 Hz), 4.72 (1H, d, J = 12.2 Hz), 5.10 (1H, d, J = 1
1.9 Hz), 5.18 (1H, d, J = 11.9 Hz), 7.25-7.45 (5H, complex) Mass spectrum [M] ⁺ = 436 High resolution mass spectrum [M] ⁺ = 436.0992 (C ₂₀ H ₂₇ O ₄ ( 35C
l) ₃ ) Calculated value: 436.0974 Specific rotation [α] _D ²⁶ = -0.69 ° (C = 4.1, CHCl ₃ ) (Reference Example 40) 2- (R)-(2,2,2-trichloroethoxycarbo)
Nyl) methylnonanoic acid 3- (R) -benzyloxycarbonyldecanoic acid 2,2,2-trichloroethyl ester (11.39 g) obtained in Reference Example 39 was treated in the same manner as in Reference Example 9 to obtain the target compound (7.66). g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.88 (3H, t, J = 6.8 Hz), 1.15-1.45 (10H, complex),
1.50-1.82 (2H, complex), 2.61 (1H, dd, J = 15.1 and 3.4 H
z), 2.80-3.01 (2H, complex), 4.72 (1H, d, J = 11.7 Hz), 4.79
(1H, d, J = 11.7 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2929 (s), 17
59 (s), 1710 (s) Mass spectrum [M + H] ⁺ = 347 High resolution mass spectrum [M + H] ⁺ = 347.0604 (C ₁₃ H ₂₂ O ₄ (3
5Cl) ₃ ) Calculated value: 347.0584 Specific rotation [α] _D ²⁶ = + 11.8 ° (C = 1.0, EtOH) (Reference Example 41) N ¹ -benzyloxycarbonyl-N ^2- [1-oxo
-2- (R)-(2,2,2-trichloroethoxycal
Bonyl) methylnonyl]-(S) -piperazinate t-bu
Obtained in Chiruesuteru Reference Example 40 2- (R) - (2,2,2- trichloroethoxycarbonyl) methylnonanoic acid (376m
The acid chloride obtained from g) and (S) -N ¹ -benzyloxycarbonylpiperazine acid t-butyl ester (349 mg) were reacted according to the method shown in Reference Example 10 to obtain the target compound (542 mg).

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, t, J = 6.6 Hz), 0.95-1.68 (13H, complex),
1.43 (9H, s), 1.73-2.16 (3H, complex), 2.60 (1H, dd, J = 17.2
and3.6 Hz), 2.94 (1H, dd, J = 17.2 and 10.6 Hz), 3.12 (1
H, m), 3.43 (1H, m), 4.28 (1H, m), 4.61 (1H, d, J = 12.0 Hz), 4.
77 (1H, d, J = 12.0 Hz), 5.14 (1H, d, J = 12.5 Hz), 5.21 (1H, d,
J = 12.5 Hz), 5.27 (1H, t, J = 4.3 Hz), 7.24-7.41 (5H, comple
x) Infrared absorption spectrum (liquid film, cm ^-1 ): 2930 (s), 17
33 (s), 1678 (s) Mass spectrum [M] ⁺ = 648 High resolution mass spectrum [M] ⁺ = 648.2146 (C ₃₀ H ₄₃ O ₇ N ₂ (3
5cl) ₃₎ Calculated: 648.2136 Specific rotation [α] ^{_{D 26 = -7.3 ° (C =}} 1.0, CHCl 3) ( Reference Example 42) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Carboxymethyl-1-oxononyl]-(S) -pi
Perazine acid t- butyl ester in Reference Example 41 obtained in N ¹ - benzyloxycarbonyl -N ² - [1-oxo -2- (R) - (2,2,2- trichloroethoxycarbonyl) methylnonyl] - (S )
-Piperazine acid t-butyl ester (541 mg) was reacted according to the method described in Reference Example 11 to give the target compound (3
04 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.86 (3H, t, J = 7.0 Hz), 0.91-2.11 (16H, complex),
1.43 (9H, s), 2.48 (1H, dd, J = 17.2 and 3.3 Hz), 2.81 (1H, d
d, J = 17.2 and 10.6 Hz), 3.06 (1H, m), 3.32 (1H, br.t, J = 1
1.2 Hz), 4.24 (1H, m), 5.13 (1H, d, J = 11.9 Hz), 5.20 (1H, d,
J = 11.9 Hz), 5.27 (1H, br.t, J = 4.0 Hz), 7.23-7.41 (5H, com
plex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3184 (m), 29
29 (s), 1733 (s), 1640 (s) Mass spectrum [M + H] ⁺ = 519 High resolution mass spectrum [M + H] ⁺ = 519.3064 (C ₂₈ H ₄₃ O
₇ N ₂₎ Calculated: 519.3070 (Example 43) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Sononiru] - (S) - N obtained with piperazine acid t- butyl ester in Reference Example 42 ¹ - benzyloxycarbonyl -N ² - [2-(R) - carboxy-methyl-1-oxononyl] - (S) - piperazine Acid t-butyl ester (300 mg) and O-benzylhydroxyamine were condensed by the reaction treatment shown in Reference Example 12 to give the desired compound (34
7 mg) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.86 (3H, t, J = 7.1 Hz), 0.90-2.08 (16H, complex),
1.43 (9H, s), 2.10-2.50 (2H, complex), 3.20 (1H, m), 3.42 (1
H, m), 4.25 (1H, m), 4.82 (1H, d, J = 11.2 Hz), 4.89 (1H, d, J = 1
1.2 Hz), 5.13 (1H, d, J = 12.4 Hz), 5.20 (1H, d, J = 12.4 Hz),
5.26 (1H, dd, J = 4.4 and 3.4 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 3252 (m), 29
29 (s), 1735 (s), 1675 (s) Mass spectrum [M + H] ⁺ = 624 High resolution mass spectrum [M + H] ⁺ = 624.3658 (C ₃₅ H ₅₀ O
₇ N ₃₎ Calculated: 624.3648 Specific rotation [α] ^{_{D 26 = -41.8 ° (C =}} 1.0, CHCl 3) ( Reference Example 44) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Sononiru] - (S) - piperazine acid Reference Example 43 obtained in N ¹ - benzyloxycarbonyl -N ² - [2-(R) - benzyloxy aminocarbonyl) methyl-1-oxononyl] - (S) - piperazine The target compound (249 mg) was obtained by subjecting the acid t-butyl ester (339 mg) to the same reaction treatment as in Reference Example 13.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.89 (3H, t, J = 6.7 Hz), 0.92-2.07 (16H, complex),
2.10-2.52 (2H, complex), 2.88-3.22 (2H, complex), 4.10 (1
H, m), 4.68-5.33 (5H, complex), 7.00-7.50 (10H, complex),
12.30 (1H, m), Infrared absorption spectrum (liquid film, cm ^-1 ): 3220 (m), 29
28 (s), 1713 (s), 1672 (s), 1601 (s) Mass spectrum [M-NHOBn] ⁺ = 445 Specific rotation [α] _D ²⁶ = -23.1 ° (C = 1.0, EtOH) (Reference) Example 45) 4- (S) -isopropyl-3- (1-oxododecyl
) -2-oxazolidinone 4- (S) -isopropyl -2-oxazolidinone (5.
The target compound (11.31 g) was obtained as a colorless oil from 39 g) and dodecanoyl chloride (9.46 g) by the same reaction treatment as in Reference Example 3.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.87 (3H, d, J = 6.9 Hz), 0.88 (3H, t, 0.87ppm and 0.
92ppm and overlapped), 0.92 (3H, d, J = 6.9 Hz), 1.17-1.43
(16H, complex), 1.53-1.78 (2H, complex), 2.38 (1H, d, hep,
J = 3.3 and 6.9 Hz), 2.77-3.07 (2H, complex), 4.20 (1H, d
d, J = 8.6 and 3.3 Hz), 4.26 (1H, t, J = 8.6 Hz), 4.44 (1H, d
t, J = 8.6 and 3.3 Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2925 (s), 17
85 (s), 1704 (s) Mass spectrum [M + H] ⁺ = 312 High resolution mass spectrum [M + H] ⁺ = 312.2532 (C ₁₈ H ₃₄ O ₃ N) Calculated value: 312.2539 Specific rotation [α] _D ²⁶ = + 54.1 ° (C = 1.0, CHCl ₃ ) (Reference Example 46) 4- (S) -isopropyl-3- (2- (R) -t-bu
Toxycarbonylmethyl-1-oxododecyl) -2-
Oxazolidinone 4- (S) -isopropyl-3-obtained in Reference Example 45
(1-oxododecyl) -2-oxazolidinone (11.2
7 g) and bromoacetic acid t-butyl ester (30 ml) were treated in the same manner as in Reference Example 4 to obtain the target compound (14.10).
g) was obtained.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ
ppm): 0.88 (3H, t, J = 7.3 Hz), 0.91 (3H, d, J = 6.6 Hz), 0.93
(3H, d, J = 6.6 Hz), 1.11-1.51 (17H, complex), 1.41 (9H, s),
1.61 (1H, m), 2.37 (1H, m), 2.42 (1H, dd, J = 16.6 and 4.4 H
z), 2.74 (1H, dd, J = 16.6 and 10.3 Hz), 4.09-4.30 (3H, com
plex), 4.43 (1H, dt, J = 7.8 and 3.7 Hz) Infrared absorption spectrum (liquid kBr pellet cm ^-1 ): 2922
(s), 1764 (s), 1730 (s), 1700 (s) Mass spectrum [M + H-tBu] ⁺ = 369 High resolution mass spectrum [M + H-tBu] ⁺ = 369.2505 (C ₂₀ H ₃₅
O ₅ N) Calculated value: 369.2515 mp 42-43 ° (H ₂ O-MeOH) Specific rotation [α] _D ²⁶ = + 45.0 ° (C = 1.0, CHCl ₃ ) (Reference Example 47) 3- (R) -Benzyloxycarbonyl tridecanoic acid t
-Butyl ester 4- (S) -isopropyl-3-obtained in Reference Example 46
(2- (R) -t-butoxycarbonylmethyl-1-oxododecyl) -2-oxazolidinone (13.67 g) was treated in the same manner as in Reference Example 27 to obtain the target compound (11.92).
g) was obtained.

C ₂₅ H ₄₀ O ₄ (FW = 404) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.6 Hz), 1.15-1.71 (18H, complex), 1.40 (9H, s), 2.
36 (1H, dd, J = 16.2 and 5.3 Hz), 2.64 (1H, dd, J = 16.2 and
9.2 Hz), 2.83 (1H, m), 5.09 (1H, d, J = 12.5 Hz), 5.17 (1H, d,
J = 12.5 Hz), 7.27-7.40 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927 (s), 17
34 (s) Mass spectrum [M + H-tBu] ⁺ = 348 High resolution mass spectrum [M + H-tBu] ⁺ = 348.2318 (C ₂₁ H ₃₂
O ₄ ) Calculated value: 348.2301 Specific rotation [α] _D ²⁶ = + 0.76 ° (C = 5.0, CHCl ₃ ) (Reference Example 48) 3- (R) -benzyloxycarbonyltridecanoic acid Obtained in Reference Example 47. 3- (R) -benzyloxycarbonyltridecanoic acid t-butyl ester (11.62 g) was treated in the same manner as in Reference Example 7 to obtain the target compound (9.41 g).

C ₂₁ H ₃₂ O ₄ (FW = 348) nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.6 Hz), 1.12-1.35 (16H, complex), 1.40-1.75 (2H,
complex), 2.49 (1H, dd, J = 16.1 and 4.4 Hz), 2.79 (1H, dd,
J = 16.1 and 9.3 Hz), 2.88 (1H, m), 5.12 (1H, d, J = 12.7 H
z), 5.17 (1H, d, J = 12.7 Hz), 7.25-7.41 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2926 (s), 17
37 (s), 1713 (s) Mass spectrum [M] ⁺ = 348 High resolution mass spectrum [M] ⁺ = 348.2308 (C ₂₁ H ₃₂ O ₄ ) Calculated value: 348.2300 Specific optical rotation [α] _D ²⁶ = + 2.8 ° (C = 1.0, EtOH) (Reference Example 49) 3- (R) -benzyloxycarbonyl tridecanoic acid
2,2,2-Trichloroethyl ester 3- (R) -benzyloxycarbonyl tridecanoic acid (9.35 g) obtained in Reference Example 48 and trichloroethanol (11.0 ml) were treated in the same manner as in Reference Example 8, The target compound (10.86 g) was obtained.

C ₂₃ H ₃₃ O ₄ Cl ₃ (FW = 478, Cl = 35) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.6 Hz), 1.13-1.39 (16H, complex), 1.48-1.79 (2H,
complex), 2.60 (1H, dd, J = 15.1 and 3.4 Hz), 2.81-3.02 (2
H, complex), 4.65 (1H, d, J = 12.0 Hz), 4.72 (1H, d, J = 12.0 H
z), 5.10 (1H, d, J = 12.4 Hz), 5.18 (1H, d, J = 12.4 Hz), 7.28-
7.42 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2926 (s), 17
59 (s), 1737 (s) Mass spectrum [M] ⁺ = 478 High resolution mass spectrum [M] ⁺ = 478.1428 (C ₂₃ H ₃₃ O ₄ (35C
l) ₃ ) Calculated value: 478.1445 Specific rotation [α] _D ²⁶ = -0.57 ° (C = 3.0, CHCl ₃ ) (Reference Example 50) 2- (R)-(2,2,2-trichloroethoxycarbo)
Nyl) methyldodecanoic acid 3- (R) -benzyloxycarbonyl tridecanoic acid 2,2,2-trichloroethyl ester (10.78 g) obtained in Reference Example 29 was treated in the same manner as in Reference Example 9 to obtain the target compound. (7.01 g) was obtained.

C ₁₆ H ₂₇ O ₄ Cl ₃ (FW = 388, Cl = 35) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.5 Hz), 1.15-1.45 (16H, complex), 1.50-1.82 (2H,
complex), 2.61 (1H, dd, J = 15.2 and 3.2 Hz), 2.80-3.01 (2
H, complex), 4.72 (1H, d, J = 11.9 Hz), 4.79 (1H, d, J = 11.9 H
z) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927 (s), 17
59 (s), 1710 (s) Mass spectrum [M + H] ⁺ = 389 High resolution mass spectrum [M + H] ⁺ = 389.1.
036 (C ₁₆ H ₂₈ O ₄ (35Cl) ₃ ) calculated value: 389.1053 Specific optical rotation [α] _D ²⁶ = + 11.7 ° (C = 1.0, EtOH) (Reference Example 51) N ¹ -benzyloxycarbonyl-N ² -[1-oxo
-2- (R)-(2,2,2-trichloroethoxycal
Bonyl) methyldodecyl]-(S) -piperazine acid t-
Butyl ester 2- (R)-(2,2,2-trichloroethoxycarbonyl) methyldodecanoic acid (329 obtained in Reference Example 30)
The acid chloride obtained from (mg) and (S) -N ¹ -benzyloxycarbonylpiperazine acid t-butyl ester (258 mg) were treated according to the method shown in Reference Example 10 to obtain the target compound (492 mg).

C ₃₃ H ₄₉ O ₇ N ₂ Cl ₃ (FW = 690, Cl = 35) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.6 Hz), 0.94-1.39 (18H, complex), 1.43 (9H, s), 1.
49-1.71 (2H, complex), 1.78-2.13 (2H, complex), 2.60 (1H,
dd, J = 17.5 and 3.6 Hz), 2.94 (1H, dd, J = 17.5 and 10.9 H
z), 3.14 (1H, m), 3.43 (1H, m), 4.27 (1H, m), 4.61 (1H, d, J = 1
1.9 Hz), 4.77 (1H, d, J = 11.9 Hz), 5.14 (1H, d, J = 11.9 Hz),
5.21 (1H, d, J = 11.9 Hz), 5.27 (1H, t, J = 4.0 Hz), 7.23-7.41
(5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927 (s), 17
40 (s), 1677 (s) Mass spectrum [M] ⁺ = 690 High resolution mass spectrum [M] ⁺ = 690.2598 (C ₃₃ H ₄₉ O ₇ N ₂ (3
5cl) ₃₎ Calculated: 690.2606 Specific rotation [α] ^{_{D 26 = -7.0 ° (C =}} 2.0, CHCl 3) ( Reference Example 52) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Carboxymethyl-1-oxododecyl]-(S)-
N obtained by the piperazine acid t- butyl ester Reference Example 51 ¹ - benzyloxycarbonyl -N ² - [1-oxo-2-(R) - (2,2,2-trichloroethoxycarbonyl) methyldodecyl] -
(S) -Piperazine acid t-butyl ester (489 mg)
Was treated according to the method described in Reference Example 11 to obtain the target compound (407 mg).

C ₃₁ H ₄₈ O ₇ N ₂ (FW = 560) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.6 Hz), 0.94-2.11 (22H, complex), 1.43 (9H, s), 2.
48 (1H, dd, J = 17.5 and 3.6 Hz), 2.82 (1H, dd, J = 17.5 and
10.9 Hz), 3.07 (1H, m), 3.31 (1H, br.t, J = 10.1 Hz), 4.25 (1
H, m), 5.13 (1H, d, J = 11.8 Hz), 5.20 (1H, d, J = 11.8 Hz), 5.2
7 (1H, dd, J = 5.3 and 3.3 Hz), 7.23-7.40 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3185 (w), 29
27 (s), 1736 (s), 1678 (s) Mass spectrum [M-tBuO] ⁺ = 487 High resolution mass spectrum [M-tBuO] ⁺ = 487.2820 (C ₂₇ H ₃₉ O ₆
N ₂₎ Calculated: 487.2808 Specific rotation [α] ^{_{D 26 = -20.5 ° (C =}} 1.0, EtOH) ( Example 53) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Sododecyl]-(S) -t-butyl ester of piperazinate
Le Reference Example 52 obtained in N ¹ - benzyloxycarbonyl -N ² - [2- (R) - carboxy-methyl-1-oxo-dodecyl] - (S) - piperazine acid t- butyl ester (403 mg) O- Benzylhydroxylamine was condensed by the reaction treatment shown in Reference Example 12 to give the desired compound (4
63 mg) was obtained.

C ₃₈ H ₅₅ O ₇ N ₃ (FW = 665) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t, J = 6.6 Hz), 0.94-2.45 (24H, complex), 1.42 (9H, s), 3.
21 (1H, m), 3.46 (1H, m), 4.23 (1H, m), 4.82 (1H, d, J = 11.2 H
z), 4.87 (1H, d, J = 11.2 Hz), 5.13 (1H, d, J = 12.5 Hz), 5.20
(1H, d, J = 12.5 Hz), 5.24 (1H, m), 7.20-7.49 (10H, comple
x), 8.41 (1H, m) infrared absorption spectrum (liquid film, cm ^-1 ): 3252 (w), 29
27 (s), 1733 (s), 1675 (s) Mass spectrum [M + H] ⁺ = 666 High resolution mass spectrum [M + H] ⁺ = 666.4136 (C ₃₈ H ₅₆ O
₇ N ₃₎ Calculated: 666.4118 Specific rotation [α] ^{_{D 26 = -36.2 ° (C =}} 1.0, CHCl 3) ( Reference Example 54) N ¹ - benzyloxycarbonyl -N ² - [2-(R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Sododeshiru] - (S) - piperazine acid Reference Example 53 obtained in N ¹ - benzyloxycarbonyl -N ² - [2-(R) - benzyloxy aminocarbonyl) methyl-1-oxo-dodecyl] - (S) - The target compound (370 mg) was obtained by subjecting piperazine acid t-butyl ester (457 mg) to the same reaction treatment as in Reference Example 13.

C ₃₄ H ₄₇ O ₇ N ₃ (FW = 609) Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δ ppm): 0.88 (3
H, t), 0.96-1.38 (16H, complex), 1.38-1.69 (3H, complex),
1.82-2.06 (2H, complex), 2.21-2.59 (2H, complex), 2.90-
3.18 (3H, complex), 4.11 (1H, br.d, J = 12.5 Hz), 4.85 (1H, b
rs), 4.89-5.08 (3H, complex), 5.17 (1H, d, J = 11.9 Hz), 7.
02-7.51 (11H, complex), 12.32 (1H, s) Infrared absorption spectrum (liquid kBr pellet): 3231 (w), 29
26 (s), 1710 (s), 1672 (s), 1604 (s) Specific rotation [α] _D ²⁶ = -28.1 ° (C = 1.0, EtOH) (Reference Example 55) 4- (S) -isopropyl -3- (1-oxoundeca
Nyl) -2-oxazolidinone 4- (S) -isopropyl- 2-oxazolidinone (3.
Tetrahydrofuran (85 ml) under nitrogen atmosphere
And was cooled to -78 ° C. n-Butyllithium (1.68M hexane solution) (15 ml) was added dropwise, and the mixture was stirred for 25 minutes. Then undecanoyl chloride (5.5 m
1) was added, and the mixture was stirred at -78 ° C for 1.5 hours. Reaction mixture 5
% Ammonium chloride aqueous solution, extracted with ethyl acetate,
The organic layer was washed with water and saturated saline and then dried over sodium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the target compound (6.77 g) as a colorless oil.

Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ , δpp
m): 0.87 (3H, d, J = 6.6Hz), 0.88 (3H, t, J = 6.8Hz), 0.92 (3H,
d, J = 6.6Hz), 1.18-1.42 (14H, complex), 1.54-1.74 (2H, com
plex), 2.38 (1H, m), 2.85 (1H, ddd, J = 16.4,8.4 and 6.8H
z), 2.98 (1H, ddd, J = 16.4,8.5 and 6.7Hz), 4.20 (1H, dd, J =
9.1 and 3.2Hz), 4.26 (1H, t, J = 9.1Hz), 4.43 (1H, dt, J = 9.1
and 3.2Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2959,1784,1
704 High resolution mass spectrum [M] ⁺ = 297.2296 (C ₁₇ H ₃₁ O ₃ N) Calculated value: 297.2304 Specific rotation: [α] _D ²⁶ = + 61.2 ° (C = 1.0, CHCl ₃ ) (Reference example 56) 4- (S) -isopropyl-3- (2- (R) -t-bu
Toxycarbonylmethyl-1-oxoundecanyl)-
2-Oxazolidinone Tetrahydrofuran (15 ml of 4- (S) -isopropyl-3- (1-oxoundecanyl) -2-oxazolidinone (6.77 g) obtained in Reference Example 55 cooled to −15 ° C. under nitrogen atmosphere. ) Lithium diisopropylamide (0.62M tetrahydrofuran solution) (39 ml)
Was added and the mixture was stirred at −78 ° C. for 10 minutes. Then, t-butyl bromoacetate (18 ml) was added, and the temperature was gradually raised to -55 ° C while continuing stirring for 2.5 hours. The reaction solution was poured into a 5% aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline and then dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluting with hexane: ethyl acetate = 10: 1) to give the target compound 5.86 (62.5%).
Got Recrystallized from methanol-water, melting point 57-58
° C.

Nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ , δpp
m): 0.87 (3H, t, J = 6.9Hz), 0.88 (3H, d, J = 7.0Hz), 0.91 (3H,
d, J = 7.0Hz), 1.17-1.48 (15H, complex), 1.41 (9H, s), 1.60
(1H, m), 2.37 (1H, m), 2.43 (1H, dd, J = 16.7 and 4.6Hz), 2.7
4 (1H, dd, J = 16.7 and 10.3Hz), 4.10-4.29 (3H, complex),
4.43 (1H, dt, J = 7.0 and 3.7Hz) Infrared absorption spectrum (KBr pellet, cm ^-1 ): 2923,1764,17
31,1699 High resolution mass spectrum [M + H] ⁺ = 412.3047 (C ₂₃ H ₄₂ O ₅ N) Calculated value: 412.3063 Specific rotation: [α] _D ²⁶ = + 49.4 ° (C = 0.99, CHCl ₃ ) ( Reference Example 57) 3- (R) -benzyloxycarbonyldodecanoic acid t-
Butyl ester Under nitrogen atmosphere, n-butyl lithium (1.68M hexane solution) (12 ml) was added to a solution of benzyl alcohol (2.8 ml) in tetrahydrofuran (40 ml) at room temperature for 10 minutes.
Lithium benzyl oxide-benzyl alcohol (tetrahydrofuran solution) prepared by stirring for minutes was used as Reference Example 56.
4- (S) -isopropyl-3- (2-
(R) -t-Butoxycarbonylmethyl-1-oxoundecanyl) -2-oxazolidinone (5.51 g) was added to a tetrahydrofuran (40 ml) solution, and the mixture was stirred at room temperature for 1 hr. The reaction solution was poured into a 5% aqueous solution of potassium hydrogen sulfate and extracted with ethyl acetate. The organic layer was washed with water and saturated saline solution in that order, and dried over sodium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to obtain 4.74 g of the desired product as a colorless oil.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6Hz), 1.16-1.33 (14H, complex), 1.40
(9H, s), 1.42-1.71 (2H, complex), 2.36 (1H, dd, J = 16.5 and
5.6Hz), 2.64 (1H, dd, J = 16.5 and 9.2Hz), 2.83 (1H, m), 5.
09 (1H, d, J = 12.2Hz), 5.17 (1H, d, J = 12.2Hz), 7.25-7.39 (5
H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2928,1732 High resolution mass spectrum [M + H] ⁺ = 391.2837 (C ₂₄ H ₃₉ O ₄ ) calculated value: 391.2848 Specific rotation: [α] _D ²⁶ = + 1.0 ° (C = 6.0, CHCl ₃ ) (Reference Example 58) 3- (R) -benzyloxycarbonyl dodecanoic acid 3- (R) -benzyloxycarbonyl dodecanoic acid obtained in Reference Example 57 To a solution of t-butyl ester (2.85 g) in dioxane (10 ml) was added 4M-hydrochloric acid-dioxane solution (35 ml), and the mixture was stirred overnight. The reaction solution was poured into water and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (chloroform: methanol =
The target compound 2.
43 g was obtained as a colorless oil.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6Hz), 1.13-1.39 (14H, complex), 1.42-
1.76 (2H, complex), 2.48 (1H, dd, J = 16.2 and 4.0Hz), 2.78
(1H, dd, J = 16.2 and 9.2Hz), 2.88 (1H, m), 5.12 (1H, d, J = 1
2.5Hz), 5.17 (1H, d, J = 12.5Hz), 7.25-7.42 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927,1736,1
713 High-resolution mass spectrum [M] ⁺ = 334.2152 (C ₂₀ H ₃₀ O ₄ ) Calculated value: 334.2144 Specific rotation: [α] _D ²⁶ = + 3.6 ° (C = 1.0, EtOH) (Reference Example 59) 3- (R) -benzyloxycarbonyl dodecanoic acid 2,
2,2-Trichloroethyl ester Under a nitrogen atmosphere, oxalic acid chloride (2.5 ml) was added to a toluene (50 ml) solution of 3- (R) -benzyloxycarbonyldodecanoic acid (2.43 g) obtained in Reference Example 58, and 60 Stir for 2 hours at ° C. Benzene was added to the reaction solution, which was distilled off under reduced pressure to remove unreacted oxalic acid chloride. The residue was dissolved in tetrahydrofuran (40 ml) under a nitrogen atmosphere, cooled to -15 ° C, and then trichloroethanol (3.2 ml) and pyridine. (0.70 ml) were added sequentially. −
After stirring at 15 ° C for 2.5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate extracted solution was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane: ethyl acetate = 30: 1) to obtain the target compound (2.53 g ) Was obtained as a colorless oil.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.91 (3H, t, J = 6.9Hz), 1.11-1.36 (14H, complex), 1.43-
1.81 (2H, complex), 2.63 (1H, dd, J = 15.2 and 3.3Hz), 2.92
(1H, dd, J = 15.2 and 9.2Hz), 2.95 (1H, m), 4.68 (1H, d, J = 1
1.9Hz), 4.75 (1H, d, J = 11.9Hz), 5.14 (1H, d, J = 12.5Hz), 5.2
1 (1H, d, J = 12.5Hz), 7.26-7.42 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927,1759,1
736 High resolution mass spectrum [M + H] ⁺ = 465.1351 (C ₂₂ H ₃₂ O ₄ (35C
l) ₃ ) Calculated value: 465.1366 Specific rotation: [α] _D ²⁶ = -0.35 ° (C = 6.0, CHCl ₃ ) (Reference Example 60) 2- (R)-(2,2,2-trichloroethoxycarbo)
Nyl) methyl undecanoic acid 3- (R) -benzyloxycarbonyldodecanoic acid 2,2,2-trichloroethyl ester (2.53 g) obtained in Reference Example 59 was added to a solution of methanol (30 ml) in 10% palladium carbon (130 mg). Under a hydrogen atmosphere 1.3
Catalytic reduction was carried out with stirring. After completion of the reaction, the catalyst was removed by filtration through Celite, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (chloroform:
Purified with methanol = 40: 1) and the target compound (1.65g)
Was obtained as a colorless oil.

Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.9Hz), 1.15-1.46 (14H, complex), 1.60
(1H, m), 1.72 (1H, m), 2.61 (1H, dd, J = 16.0and4.2Hz), 2.87
(1H, dd, J = 16.0and9.2Hz), 2.93 (1H, m), 4.72 (1H, d, J = 12.0
Hz), 4.78 (1H, d, J = 12.0Hz) Infrared absorption spectrum (liquid film, cm ^-1 ): 2927,1759,1
710 High resolution mass spectrum [M + H] ⁺ = 375.0909 (C ₁₅ H ₂₆ O ₄ (35C
l) ₃ ) Calculated value: 375.0897 Specific rotation: [α] _D ²⁶ = + 11.0 ° (C = 6.4, EtOH) (Reference Example 61) N ¹ -benzyloxycarbonyl-N ^2- [1-oxo
-2- (R)-(2,2,2-trichloroethoxycal
Bonyl) methyl undecanyl]-(S) -piperazine acid
2- (R) -obtained in Reference Example 60 under t-butyl ester nitrogen atmosphere
Oxalic acid chloride (0.44 ml) was added to a solution of (2,2,2-trichloroethoxycarbonyl) methylundecanoic acid (470 mg) in toluene (6.0 ml), and the solution was added at 60 ° C. to 2.5.
After stirring for an hour, anhydrous benzene was added to the reaction solution and the mixture was concentrated under reduced pressure to remove excess oxalic acid chloride. The residue (acid chloride) obtained by concentration under reduced pressure was dissolved in tetrahydrofuran (4 ml). A solution of (S) -N ¹ -benzyloxycarbonylpiperazine acid t-butyl ester (399 mg) and N-ethylmorpholine (0.24 ml) in tetrahydrofuran (4 ml) cooled to −15 ° C. under a nitrogen atmosphere was added to the acid prepared above. After the chloride solution was added dropwise, stirring was continued overnight and the temperature was gradually raised to room temperature. The reaction solution was poured into 0.2 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1) to obtain the target compound (740 mg) as a colorless oil.

Nuclear magnetic resonance spectrum (270 MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6Hz), 0.93-1.70 (18H, complex), 1.43
(9H, s), 1.78-2.12 (2H, complex), 2.60 (1H, dd, J = 17.2 and
3.3Hz), 2.94 (1H, dd, J = 17.2 and 10.6Hz), 3.12 (1H, m),
3.42 (1H, m), 4.27 (1H, m), 4.61 (1H, d, J = 11.9Hz), 4.77 (1H,
d, J = 11.9Hz), 5.14 (1H, d, J = 12.5Hz), 5.21 (1H, d, J = 12.5H)
z), 5.27 (1H, t, J = 4.0Hz), 7.23-7.42 (5H, complex) Infrared absorption spectrum (liquid film, cm ^-1 ): 2928,1740,1
678 High resolution mass spectrum [M] ⁺ = 676.2451 (C ₃₂ H ₄₇ O ₇ N ₂ (35C
l) ₃₎ Calculated: 676.2449 Specific ^{_{rotation: [α] D 26 = -7.0}} ° (C = 1.0, CHCl 3) ( Reference Example 62) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Carboxymethyl-1-oxoundecanyl]-
(S) - piperazine acid t- butyl ester in Reference Example 61 obtained in N ¹ - benzyloxycarbonyl -N ² - [1- oxo -2- (R) - (2,2,2- trichloroethoxycarbonyl) methyl Undecanyl]-
(S) -Piperazine acid t-butyl ester (735 m
1N-ammonium acetate aqueous solution (1.6 ml) and zinc (1.43 g) were added to a tetrahydrofuran solution of g) at room temperature.
Stir vigorously for 2.7 hours. After completion of the reaction, zinc was filtered off, the reaction solution was poured into a 5% potassium hydrogensulfate aqueous solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 40: 1) to obtain the objective. The compound (504 mg) was obtained as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6Hz), 0.93-1.58 (18H, complex), 1.43
(9H, s), 1.69-2.12 (2H, complex), 2.48 (1H, dd, J = 17.2 and
3.3Hz), 2.81 (1H, dd, J = 17.2 and 10.6Hz), 3.07 (1H, m),
3.31 (1H, m), 4.25 (1H, m), 5.13 (1H, d, J = 11.9Hz), 5.20 (1H,
d, J = 11.9Hz), 5.26 (1H, br.t, J = 4.7Hz), 7.23-7.42 (5H, com
plex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3193,2928,1
733,1679,1651 High resolution mass spectrum [M + H] ⁺ = 547.3361 (C ₃₀ H ₄₇ O ₇ N ₂ ) Calculated value: 547.3383 Specific rotation: [α] _D ²⁶ = -22.0 ° (C = 1.0, EtOH ) (reference example 63) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
[Soundecanyl]-(S) -piperazinate t-butyl ester
Ester Reference Example 62 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - carboxy-methyl-1-oxo-undecanyloxy] - piperazine acid t- butyl ester (484mg) - (S) Mixed solvent (tetrahydrofuran:
It was dissolved in DMF = 3: 1 (15 ml) and cooled to 0 ° C. O-benzylhydroxylamine hydrochloride (241
mg), diethyl cyanophosphonate (DEPC,
0.17 ml) and triethylamine (0.31 ml) were sequentially added, and the mixture was stirred for 2.1 hours. The reaction solution was poured into 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated saline,
After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 80: 1) to obtain the target compound (493 mg).

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.9Hz), 0.90-2.50 (22H, complex), 1.42
(9H, s), 3.21 (1H, m), 3.46 (1H, m), 4.25 (1H, m), 4.82 (1H, d,
J = 11.9Hz), 4.88 (1H, d, J = 11.9Hz), 5.13 (1H, d, J = 12.5Hz),
5.20 (1H, d, J = 12.5Hz), 5.25 (1H, m), 7.21-7.48 (10H, compl
ex) Infrared absorption spectrum (liquid film, cm ^-1 ): 3249,2928,1
733,1675 High resolution mass spectrum [M + H] ⁺ = 652.3945 (C ₃₇ H ₅₄ O ₇ N ₃ ) Calculated value: 652.3970 Specific rotation: [α] _D ²⁶ = -38.2 ° (C = 1.0, CHCl ₃ ) (reference example 64) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-Benzyloxyaminocarbonyl) methyl-1-oxy
Soundekaniru] - (S) - piperazine acid Reference Example 63 obtained in N ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - benzyloxy aminocarbonyl) methyl-1-oxo-undecanyloxy] - (S ) -Piperazinic acid t-butyl ester (478 mg) was added to a methylene chloride solution, trifluoroacetic acid (1.8 ml) was added, and the mixture was stirred at room temperature for 7 hours. After completion of the reaction, toluene was added and the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 30: 1) to obtain the target compound (382 mg) as a colorless oil.

Nuclear magnetic resonance spectrum (270MHz, CDCl ₃ , δpp
m): 0.88 (3H, t, J = 6.6Hz), 0.87-2.59 (22H, complex), 2.88-
3.27 (2H, complex), 4.10 (1H, br.d, J = 11.2Hz), 4.69-5.39
(5H, complex), 7.13 (1H, br.s), 7.24-7.51 (10H, comple
x), 12.3 (1H, s) Infrared absorption spectrum (liquid film, cm ^-1 ): 3223,1714,1
671,1602 Calculated by elemental analysis C ₃₃ H ₄₅ N ₃ O ₇・ H ₂ O: C, 64.58%; H, 7.71%; N, 6.85
% Measured value: C, 64.77%; H, 7.31%; N, 6.96% Specific rotation: [α] _D ²⁶ = -24.3 ° (C = 1.0, EtOH) (Reference Example 65) N ¹ -benzyloxycarbonyl- N ² - [2- (R)
-(Benzyloxyaminocarbonyl) methyl-1-o
X-unodecanyl]-(S) -piperazinate N-methyl
Amides 0 ° C. N obtained in Reference Example 64 was cooled to ¹ - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-undecanyloxy] - (S) - To a mixed solution of piperazine acid (52 mg) in tetrahydrofuran: dimethylformamide (1: 1) (4.0 ml) was added methylamine hydrochloride (27 ml) under a nitrogen atmosphere.
mg), triethylamine (0.035 ml), DEPC
(0.03 ml) are added sequentially, while gradually warming to room temperature
Stirred for 3.3 hours. After completion of the reaction, the reaction solution was poured into a 5% potassium hydrogensulfate aqueous solution and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel preparative thin layer chromatography (20 cm × 20 cm, 0.5
mm thickness, developed with chloroform: methanol = 30: 1)
Was collected using a to give the desired compound (52 mg). It contained a small amount of impurities but was used in the next step (Example 9) without further purification.

[0213] (Reference Example 66) N ¹ - benzyloxycarbonyl -N ² - [2- (R)
-(Benzyloxyaminocarbonyl) methyl-1-o
X-unodecanyl]-(S) -piperazinate N-dimethyl
Ruamido Reference Example 65 N ¹ obtained in Reference Example 64 in accordance with the method - benzyloxycarbonyl ^{-N 2 - [2- (R)} - ( benzyloxy aminocarbonyl) methyl-1-oxo-undecanyloxy] - (S) -By similar reaction treatment using piperazine acid (55 mg) and dimethylamine hydrochloride (32 mg) as starting materials, the target compound (58 mg) was obtained. It contained a small amount of impurities but was used in the next step (Example 10) without further purification.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tomio Kobayashi 1-2-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (2)

[Claims] 1. A general formula: [In the formula, R ¹ represents a —NR ⁴ R ⁵ group (in the formula, R ⁴ and R ⁵ are the same or different and are a hydrogen atom or an alkyl group having 1 to 4 carbon atoms), and R ² is 6 to 6 carbon atoms. Represents 12 alkyl groups]. 2. An angiogenesis inhibitor, a cancer invasion inhibitor, or a cancer metastasis inhibitor containing the compound according to claim 1 as an active ingredient.