JPH0616645A - New synthetic intermediate and production of amino acid derivative - Google Patents

Abstract

PURPOSE:To obtain a new synthetic intermediate useful for producing an amino acid derivative having renin inhibiting activity in good yield at a reduced cost. CONSTITUTION:The compound of formula I [R<1> is lower alkyl which may be substituted with a substituent group selected from acyl, OH, lower alkoxy, aryl, lower alkylthio and formula II (R<6> is H or acyl; R<7> is H or lower alkyl), aryl or amino which may be substituted with lower alkyl or acyl; R<2> is H or lower alkyl or R<1> and R<2>, together with the adjacent N atom, form a heterocyclic group which may be substituted (with alkyl, hydroxyalkyl, acyl, etc.); R<3> is H or lower alkyl; R<4> is H or N-protecting group; R<5> is H or carboxy- protecting group]. This compound is obtained by reacting a compound of formula III with a compound of formula IV. The objective amino acid derivative of formula VI is prepared by reacting the compound of formula I or a reactive derivative at the carboxyl group thereof with a compound of formula V (R<10> is lower alkyl) and, as necessary, releasing the N-protecting group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel synthetic intermediate for producing an amino acid derivative having renin inhibitory activity, and a method for producing the amino acid derivative using the synthetic intermediate.

[0002]

[Problems to be Solved by Conventional Techniques and Inventions]

 formula

[0003]

[Chemical 21]

The amino acid derivative represented by the formula [wherein R ¹ , R ² , R ³ and R ¹⁰ are referred to below] has renin inhibitory activity and is essential hypertension, renal hypertension and malignancy. It is known to be useful for treating hypertension such as hypertension and heart failure. Japanese Patent Laid-Open No. 64-19071 discloses that
The following synthetic method is described as a method for producing this compound.

[0005]

[Chemical formula 22]

[In the formula, the definitions of R ¹ , R ² , R ³ , R ⁴ and R ¹⁰ are referred to later.] However, in the above production method, the starting compound (VI) is relatively expensive, and Since the total yield of the whole process is as low as about 40 to 50%, the production cost of the amino acid derivative (I) which is the final product is high, which is not a satisfactory industrial production method. An object of the present invention is to solve the above-mentioned problems of the conventional method and to provide an industrially advantageous production method by which the amino acid derivative (I) can be obtained in a high yield from a cheaper raw material. Another object of the present invention is to provide an intermediate produced from inexpensive raw materials for producing the amino acid derivative (I).

[0007]

[Means for Solving the Problems] The inventors of the present invention have conducted a synthetic method via compound (II), which is a novel intermediate described below, to
The present invention has been completed by finding that the amino acid derivative (I) can be obtained in high yield from an inexpensive raw material.

The present invention has the formula

[0009]

[Chemical formula 23]

[Wherein R ¹ is an acyl group, a hydroxy group,
Lower alkoxy group, aryl group, lower alkylthio group and formula

[0011]

[Chemical formula 24]

(Wherein R ⁶ is hydrogen or an acyl group, R ⁷
Is a hydrogen or a lower alkyl group), and a lower alkyl group optionally substituted with a substituent selected from the group consisting of the groups represented by the following; a aryl group; or a lower alkyl group and an acyl group selected from the group consisting of An amino group optionally substituted with a substituent; R ² represents hydrogen or a lower alkyl group, or R ¹ and R ² together with an adjacent nitrogen atom form a lower alkyl group, hydroxy ( Lower) alkyl group, lower alkoxy (lower)
An alkyl group, an acyl (lower) alkyl group, an oxo group and an acyl group form a heterocyclic group which may be substituted with a substituent selected from the group consisting of, R ³ is hydrogen or a lower alkyl group, and R ⁴ is Hydrogen or an N-protecting group, and R ⁵ represents a hydrogen or a carboxy protecting group] or a salt thereof.

According to the invention, the formula

[0014]

[Chemical 25]

[Wherein R ¹⁰ is a lower alkyl group, R ¹ and R
² and R ³ are each as defined above, and the compound (I) or a salt thereof has the formula

[0016]

[Chemical formula 26]

[Wherein R ¹ , R ² , R ³ and R ⁴ are as defined above] or a reactive derivative thereof at the carboxy group or a salt thereof is represented by the formula:

[0018]

[Chemical 27]

[Wherein R ¹⁰ is as defined above] and reacted with a compound (III) represented by the formula (1) or a reactive derivative of the amino group thereof or a salt thereof, and if necessary, the N-protecting group is removed. It can be manufactured by separating (hereinafter referred to as manufacturing method a).

According to the present invention, compound (I) or a salt thereof has the formula

[0021]

[Chemical 28]

A compound (IV) represented by the formula: wherein R ¹ and R ² are as defined above, or a reactive derivative thereof at the carboxy group or a salt thereof is

[0023]

[Chemical 29]

[Wherein R ³ , R ⁴ and R ⁵ are as defined above] and reacted with a compound (V) represented by the formula

[0025]

[Chemical 30]

[Wherein R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are as defined above] (I
I) or a salt thereof, which is then of the formula

[0027]

[Chemical 31]

It can be produced by reacting with a compound (III) represented by the formula: [wherein R ¹⁰ is as defined above] or a salt thereof, and removing the N-protecting group if necessary. (Hereinafter, referred to as production method b).

Further according to the present invention, compound (I) or a salt thereof has the formula

[0030]

[Chemical 32]

A compound (IV) represented by the formula (wherein R ¹ and R ² are as defined above) or a reactive derivative thereof at the carboxy group or a salt thereof is

[0032]

[Chemical 33]

[Wherein R ⁴ and R ⁵ are as defined above] and reacted with a compound (Va) represented by

[0034]

[Chemical 34]

A compound (IIb) represented by the formula (wherein R ¹ , R ² , R ⁴ and R ⁵ are as defined above) or a salt thereof is obtained, and the compound (IIb) is added to the compound in the presence of a base.

[0036]

[Chemical 35]

[Wherein X represents halogen and R ³ a represents a lower alkyl group], and the compound represented by the formula

[0038]

[Chemical 36]

[In the formula, R ¹ , R ² , R ³ a, R ⁴ and R ⁵
Are each as defined above]
(IIc) or a salt thereof, which is further represented by the formula

[0040]

[Chemical 37]

It can be produced by reacting with a compound (III) represented by the formula [wherein R ¹⁰ is as defined above] or a salt thereof, and by removing the N-protecting group if necessary. (Hereinafter, referred to as production method c).

In this specification and in the description of the claims, suitable examples of the various definitions included within the scope of the invention are set forth in detail below. “Lower” means a group having 1 to 7 carbon atoms, unless otherwise specified. Suitable "lower alkyl group" is a straight chain or branched chain alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, methylhexyl, heptyl and the like. Can be mentioned.

Suitable "acyl" moieties of the "acyl group" and "acyl (lower) alkyl groups" are of the formula

[0044]

[Chemical 38]

[In the formula, R ⁸ and R ⁹ are each hydrogen;
Aryl group; cyclo (lower) alkyl group; heterocyclic group; or lower alkoxycarbonyl group, lower alkoxy group,
A lower alkyl group which may be substituted with a substituent selected from the group consisting of an aryl group and a heterocyclic group, or R ⁸ and R ⁹ together with an adjacent nitrogen atom, is a lower alkyl group. R ¹¹ is an aryl group; a cyclo (lower) alkyl group; a lower alkoxy group and a mono- or di (lower)
A lower alkyl group optionally substituted by a substituent selected from the group consisting of an alkylamino group; or a lower alkoxy group optionally substituted by a substituent selected from a group consisting of a lower alkanoyl group and an aryl group, Meaning], an amino acid residue in which an amino group may be protected, and the like.

Suitable "aryl group" includes groups such as phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl and the like, among which the preferred one is phenyl group. Suitable "cyclo (lower) alkyl group" includes cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include groups such as cyclohexyl. Suitable "heterocyclic group" for R ⁸ and R ⁹ and suitable "heterocyclic group" as a substituent for the lower alkyl group for R ⁸ and R ⁹ are:
Saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as nitrogen atom, oxygen atom or sulfur atom, preferably N-, O- and / or S-containing 5- or 6-membered heterocycle Groups, of which the most preferred are morpholino, pyridyl and thiazolyl groups.

Preferred "lower alkoxy group" and preferred "lower alkoxy" of "lower alkoxycarbonyl group"
The moieties include straight chain or branched chain alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, hexyloxy and the like, among which the more preferable ones Is a C ₁ -C ₄ alkoxy group.

Suitable "heterocyclic group" formed by R ⁸ , R ⁹ and the adjacent nitrogen atom is morpholino, thiomorpholino, its 1-oxide or 1,1-.
Dioxide, pyrrolidin-1-yl, pyrazolidine-1
-Yl, piperidino, piperazin-1-yl, pyrrolin-1-yl, thiazolidin-3-yl, its 1-oxide or 1,1-dioxide, oxazolidin-3-yl, perhydropyridazin-1-yl, 1, 4-dihydropyridin-1-yl, 1,2,3,6-tetrahydropyridin-1-yl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydroquinoline-1 -Yl, hexamethyleneimino, 1,4-
Examples thereof include diazabicyclo [4.3.0] nonan-4-yl and the like.

Suitable "mono- or di (lower) alkylamino group" is methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, methylethylamino, methylisopropylamino, diethylamino. And other groups. Suitable "lower alkanoyl group" is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, 4
Groups such as -methylvaleryl and the like.

Suitable "amino acid residue with optionally protected amino group" includes glycyl, aralyl, β-aralyl, valyl, leucyl, isoleucyl, histidyl, prolyl, ceryl, threonyl, cystyl, phenylalanyl, In residues such as aspartyl, glutamyl, and tryptophyll, each amino group of these residues is, for example, a substituted or unsubstituted lower alkanoyl group such as formyl, acetyl, propionyl, and trifluoroacetyl, a phthaloyl group such as a tertiary group. Lower alkoxycarbonyl groups such as butoxycarbonyl, tertiary amyloxycarbonyl, etc., substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc., substituted with benzenesulfonyl, tosyl, etc. Was Other unsubstituted arenesulfonyl group, nitrophenyl sulphenyl group, for example trityl,
It may be protected by a conventional N-protecting group such as an aralkyl group such as benzyl.

More preferred examples of the acyl group are:
Formyl, acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Lower alkanoyl group such as 4-methylvaleryl, for example, mono- or di (lower) alkylamino (lower) alkanoyl group such as methylaminoacetyl, methylaminopropionyl, dimethylaminobutyryl, lower such as methoxyacetyl, methoxypropionyl, ethoxypropionyl, etc. Alkoxy (lower) alkanoyl groups such as benzoyl and toluoyl aroyl groups such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl and other cyclo (lower) alkylcarbonyl groups such as glycyl, benzoylglycyl and tertiary Butoxycarbonylglycyl,
Tertiary butoxycarbonyl leucyl, acetyl leucyl, an amino group which may have a protected amino group such as tertiary butoxycarbonyl histidyl, a carbamoyl group, for example, methylcarbamoyl, ethylcarbamoyl,
Mono- or di (lower) alkylcarbamoyl groups such as propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, pentylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl, methylisopropylcarbamoyl, methylisobutylcarbamoyl, etc. Heterocyclic (lower) alkylcarbamoyl groups such as picolylcarbamoyl, pyridylethylcarbamoyl, thiazolylmethylcarbamoyl, morpholinomethylcarbamoyl, morpholinoethylcarbamoyl, such as N-picolyl-N-methylcarbamoyl,
N-heterocyclic (lower) alkyl-N-lower alkylcarbamoyl groups such as N-pyridylethyl-N-methylcarbamoyl, N-morpholinomethyl-N-ethylcarbamoyl, N-morpholinoethyl-N-methylcarbamoyl,
For example, an ar (lower) alkylcarbamoyl group such as benzylcarbamoyl, phenethylcarbamoyl, benzhydrylcarbamoyl and the like, N-benzyl-N-methylcarbamoyl, N-phenethyl-N-methylcarbamoyl, N-phenethyl-N-ethylcarbamoyl and the like N −
N-aryl-N-lower alkylcarbamoyl groups such as ar (lower) alkyl-N-lower alkylcarbamoyl groups such as N-phenyl-N-methylcarbamoyl, eg methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl, ethoxycarbonylethylcarbamoyl. Lower alkoxycarbonyl (lower)
Alkylcarbamoyl groups such as lower alkoxy (lower) alkylcarbamoyl groups such as methoxymethylcarbamoyl, methoxyethylcarbamoyl, ethoxypropylcarbamoyl, etc., aroylcarbamoyl groups such as benzoylcarbamoyl, toluoylcarbamoyl, etc., eg pyridylcarbamoyl, morpholinocarbamoyl, thiazolylcarbamoyl. And other heterocyclic carbamoyl groups, such as N-pyridyl-N-methylcarbamoyl, N-thiazolyl-N-methylcarbamoyl and other N-heterocycle-N-lower alkylcarbamoyl groups, heterocyclic carbonyl groups, and more preferably, for example, morpholinocarbonyl. , Thiomorpholinocarbonyl, piperidinocarbonyl, 4-methyl-1-
N-containing heterocycle-N-ylcarbonyl groups optionally substituted with lower alkyl groups such as piperazinylcarbonyl, 1,2,3,6-tetrahydro-1-pyridylcarbonyl, eg methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl, pentyloxycarbonyl,
Hexyloxycarbonyl and other lower alkoxycarbonyl groups such as iodoethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxycarbonyl, trifluoromethoxycarbonyl and other mono- (or di- or tri) halo (lower) alkoxycarbonyl groups such as hydroxymethoxycarbonyl, hydroxy Hydroxy (lower) alkoxycarbonyl groups such as ethoxycarbonyl, hydroxypropoxycarbonyl, hydroxybutoxycarbonyl, etc., such as benzyloxycarbonyl, phenethyloxycarbonyl, 4-nitrobenzyloxycarbonyl, trityloxycarbonyl, benzhydryloxycarbonyl, etc. ) Alkoxycarbonyl groups, for example vinyloxycarbonyl, allyloxycarbonyl, etc. Alkenyloxycarbonyl groups such as acetylmethoxycarbonyl, propionylmethoxycarbonyl, acetylethoxycarbonyl and other lower alkanoyl (lower) alkoxycarbonyl groups such as mesyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, tertiary butyl Examples thereof include lower alkylsulfonyl groups such as sulfonyl, pentylsulfonyl and hexylsulfonyl, and arylsulfonyl groups such as phenylsulfonyl and tosyl.

Suitable "lower alkylthio group" is
Examples thereof include linear or branched alkylthio groups such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tertiary butylthio, pentylthio, hexylthio and the like, and among them, more preferable ones are C _1-. C ₄ alkylthio group. For suitable “heterocyclic group” formed by R ¹ , R ² and the adjacent nitrogen atom, refer to the heterocyclic group formed by R ⁸ , R ⁹ and the adjacent nitrogen atom as exemplified above. Good. Suitable “hydroxy (lower) alkyl group” includes hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxyisopropyl, hydroxybutyl and the like. Suitable "lower alkoxy (lower) alkyl group" includes methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl and the like.

Suitable "N-protecting group" is, for example, a substituted or unsubstituted lower alkanoyl group such as formyl, acetyl, propionyl, trifluoroacetyl and the like, phthaloyl group, for example, tertiary butoxycarbonyl, tertiary amyl. Lower alkoxycarbonyl groups such as oxycarbonyl, substituted or unsubstituted aralkoxycarbonyl groups such as benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc., substituted or unsubstituted arenesulfonyl groups such as benzenesulfonyl, tosyl, etc. , A nitrophenylsulfenyl group, for example trityl,
Examples thereof include aralkyl groups such as benzyl. Suitable "carboxy protecting group" is a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, secondary butyl, isobutyl, tertiary butyl, pentyl, neopentyl and hexyl, which may be optionally substituted. Good ar (lower) alkyl groups, for example benzyl, 4
Examples thereof include a mono- or di- or tri-phenyl (lower) alkyl group which may be substituted with a nitro group such as -nitrobenzyl, benzhydryl and trityl.

Suitable salts include, for example, organic acid addition salts such as formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, and the like. Examples thereof include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate and phosphate, and acid addition salts such as salts with amino acids such as aspartate and glutamate. In the case of a compound having a carboxy group, in addition to the acid addition salts as suitable salts, for example, alkali metal salts such as sodium salt and potassium salt, for example, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt, Examples thereof include base salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and organic base salts such as N, N′-dibenzylethylenediamine salt.

More preferable specific examples of R ¹ to R ⁵ are shown below. R ¹ is the formula:

[0056]

[Chemical Formula 39]

[Wherein R ⁷ represents hydrogen or a lower alkyl group, and R ⁸ and R ⁹ together with an adjacent nitrogen atom form a heterocycle optionally substituted with a lower alkyl group. ] A lower alkyl group substituted with a group represented by: R ² is a lower alkyl group, R ³ is a hydrogen or a lower alkyl group, R ⁴ is a hydrogen or an N-protecting group, and R ⁵ is a hydrogen or a lower alkyl group.

Particularly preferred examples of the compound (II) include Nα- [2 (S)-[N-methyl-N- [2- {N
- (morpholinocarbonyl) -N- methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -N ^im - trityl -L- histidine or a salt thereof, and Nα- [2 (S) - [N- methyl - N- [2
- {N-(morpholinocarbonyl) -N- methylamino} ethyl] aminocarbonyl) -3-phenylpropionyl] -Nα- methyl -N ^im - trityl -L-
Histidine or its salt is mentioned. Compound (II) may contain one or more stereoisomers based on the asymmetric carbon atom, and all these isomers and mixtures thereof are included in the scope of the present invention.

The compound (II) of the present invention is useful as an intermediate for synthesizing the amino acid derivative (I), and a method for producing the amino acid derivative (I) via the compound (II) will be described below.

[0060]

[Chemical 40]

[Wherein R ¹ , R ² , R ³ , R ⁴ and R ¹⁰ are as defined above] Compound (I) or a salt thereof is compound (IIa) or its reactivity at the carboxy group. The derivative or a salt thereof can be produced by reacting the compound (III) or a reactive derivative thereof at an amino group or a salt thereof, and removing an N-protecting group if necessary.

Suitable reactive derivative at the carboxy group of the compound (IIa) includes acid halide, acid anhydride, activated amide, activated ester and the like. Suitable examples of these reactive derivatives are acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, Sulfuric acid,
Sulfonic acids such as methanesulfonic acid, such as acetic acid,
Mixed acid anhydride with an aliphatic carboxylic acid such as propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid or an aromatic carboxylic acid such as benzoic acid. Symmetric acid anhydrides; activated amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or for example cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N
⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
Pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresyl ester, carboxylmethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8
-Activated esters such as quinolyl thioesters, or for example N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole. Esters with N-hydroxy compounds such as These reactive derivatives can be arbitrarily selected from among them depending on the kind of the compound (IIa) to be used.

Suitable reactive derivative at the amino group of the compound (III) is a Schiff's base type imino group or its enamine type tautomerism produced by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone and the like. Properties: Compound (III) and bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea, 1,1,1,3,3,3-
Examples thereof include a silyl derivative formed by reaction with a silyl compound such as a combination of hexamethyldisilazane and trimethylsilyl chloride; a derivative formed by reaction of compound (III) with phosphorus trichloride or phosgene.

The reaction is usually carried out in a conventional manner such as water, alcohol such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, etrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. The reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used as a mixture with water.

When the compound (IIa) is used in the form of a free acid or a salt thereof in this reaction, for example, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-
Cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide, N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N
-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide and other carbodiimide compounds; N, N'-carbonylbis- (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine 1-alkoxy-1-chloroethylene; trialkyl phosphite; polyalkyl phosphate; isopropyl polyphosphate; isopropyl oxychloride (phosphoryl chloride); phosphorus trichloride; diphenyl azidophosphoryl; thionyl chloride; oxalyl chloride; Lower alkyl haloformates such as ethyl chloroformate and iropropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2
-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; the carbodiimide compound and 1-hydroxy-
Combination with 1H-benzotriazole or N-hydroxysuccinimide; conventional such as so-called Vilsmeier reagent prepared by reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is preferable to carry out the reaction in the presence of the condensing agent.

The reaction may also be performed with an inorganic or organic base such as alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. May be performed in the presence of. The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

When the imidazolyl group of compound (IIa) is protected, the compound (IIa) and compound (II
The final product (I) can be prepared by removing the N-protecting group of the reaction product with I).

Removal of the N-protecting group is carried out by a conventional method such as hydrolysis, reduction and the like. Hydrolysis is preferably carried out in the presence of bases or acids, including Lewis acids. Suitable bases include, for example, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydroxides or carbonates or hydrogen carbonates of these metals, and hydrazines such as triethylamine and triethylamine. Alkylamine, picoline, 1,
5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane, 1,
Inorganic and organic bases such as 8-diazabicyclo [5.4.0] undec-7-ene and the like can be mentioned.

Suitable acids include, for example, organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid and trifluoroacetic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide and hydrogen fluoride. Included are inorganic acids and acid addition salt compounds such as pyridine hydrochloride. The elimination using an acid such as trihaloacetic acid such as trichloroacetic acid or trifluoroacetic acid is preferably carried out in the presence of a cation trapping agent such as anisole and phenol. The reaction is usually carried out in water, an alcohol such as methanol and ethanol, a solvent such as methylene chloride, chloroform, tetrachloromethane, tetrahydrofuran, or a mixture thereof, but other solvents can be used as long as they do not adversely affect the reaction. Can be performed in any solvent. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling or heating.

The reduction method applicable to the elimination reaction includes:
Examples include chemical reduction and catalytic reduction. Suitable reducing agents used for the chemical reduction are, for example, metals such as tin, zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluene. It is a combination with an organic or inorganic acid such as sulfonic acid, hydrochloric acid or hydrobromic acid.

Suitable catalysts used for catalytic reduction are platinum catalysts such as platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, such as palladium sponge, palladium black, palladium oxide, palladium-carbon. Palladium catalysts such as colloidal palladium, palladium-barium sulfate and palladium-barium carbonate, nickel catalysts such as reduced nickel, nickel oxide and Raney nickel,
For example, a conventional cobalt catalyst such as reduced cobalt or Raney cobalt, an iron catalyst such as reduced iron or Raney iron, or a copper catalyst such as reduced copper, Raney copper or Ullmann copper. The reduction is usually carried out in conventional solvents which do not adversely influence the reaction such as water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Furthermore, if the acids used for the chemical reduction are liquids, they can also be used as solvents. Furthermore, suitable solvents used for catalytic reduction include the above solvents and other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran and the like, or mixtures thereof. The reaction temperature for this reduction is not particularly limited, and the reaction is usually performed under cooling or heating.

[0072]

[Chemical 41]

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ¹⁰ is each as defined above] Step 1 Compound (II) or a salt thereof is compound (IV) or a reactive derivative thereof at a carboxy group or a salt thereof is a compound (V) or a salt thereof at an amino group. It can be produced by reacting with a reactive derivative or a salt thereof. Since this reaction can be carried out in substantially the same manner as the condensation reaction of the production method a, the reaction scheme of this reaction and the reaction conditions such as the reactive derivative, the condensing agent, the solvent and the reaction temperature are the same as those of the production method a. The description of the condensation reaction may be referred to.

Step 2 Compound (I) or a salt thereof is prepared by reacting compound (II) or its reactive derivative at a carboxy group or a salt thereof with compound (III) or a reactive derivative at an amino group or a salt thereof. React and, if necessary, N-
It can be produced by removing the protecting group. Since this reaction can be carried out in substantially the same manner as the condensation reaction of the production method a, the reaction scheme of this reaction and the reaction conditions such as the reactive derivative, the condensing agent, the solvent and the reaction temperature are the same as those of the production method a. The description of the condensation reaction may be referred to.

When the imidazolyl group of compound (V) is protected, the final product (I) is further removed by eliminating the N-protecting group of the reaction product of compound (II) and compound (III). ) Can be manufactured. Since this elimination reaction can be carried out in substantially the same manner as the elimination reaction of the production method a, this reaction method and, for example, base, acid, reducing agent,
Regarding the reaction conditions such as the catalyst, the solvent and the reaction temperature, the production method a
See the description of the elimination reaction of.

In the case of producing the compound (I) in which R ³ is lower alkyl, the compound (V) in which lower alkyl is introduced into R ³ may be used as a starting material, or the following production method c
As described above, a compound (Va) in which R ³ is hydrogen is used as a starting material, and after condensation of (IV) and (Va), the obtained compound (IIb) is subjected to an alkylation reaction to give R ³ a lower alkyl group. May be introduced.

[0077]

[Chemical 42]

[Wherein R ¹ , R ² , R ³ a, R ⁴ ,
R ⁵ and R ¹⁰ are each as defined above] Step 1 Compound (IIb) or its salt is compound (IV) or its reactive derivative at the carboxy group or its salt, compound (Va) or amino It can be prepared by reacting with a reactive derivative of the group or a salt thereof. Since this reaction can be carried out in substantially the same manner as the condensation reaction of the production method a, the reaction scheme of this reaction and the reaction conditions such as the reactive derivative, the condensing agent, the solvent and the reaction temperature are the same as those of the production method a. The description of the condensation reaction may be referred to.

Step 2 Compound (IIc) or a salt thereof can be produced by subjecting compound (IIb) or a salt thereof to a lower alkylation reaction. Suitable lower alkylating agent used in this reaction includes, for example, methyl iodide, ethyl iodide,
Examples thereof include lower alkyl halides such as propyl iodide, butyl iodide, butyl chloride and pentyl chloride. This reaction is usually carried out by alkali metals such as sodium and potassium, alkaline earth metals such as magnesium and calcium, hydrides or hydroxides of these metals such as sodium methoxide, sodium ethoxide, potassium tertiary butoxide. Etc. in the presence of a base such as an alkali metal alkoxide and the like. This reaction is usually
Water, for example, alcohols such as methanol, ethanol and propanol, tetrahydrofuran, dioxane, ethyl acetate, methylene chloride, N, N-dimethylformamide,
The reaction is carried out in a conventional solvent such as dimethyl sulfoxide or diethyl ether, but the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. If the lower alkylating agent is a liquid, it can be used as a solvent. The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature, under heating or under heating.

Step 3 Compound (Ia) or a salt thereof is prepared by reacting compound (IIc) or a reactive derivative thereof at a carboxy group or a salt thereof with compound (III) or a reactive derivative thereof at an amino group or a salt thereof. It can be produced by reacting. Since this reaction can be carried out in substantially the same manner as the condensation reaction of the production method a, the reaction scheme of this reaction and the reaction conditions such as the reactive derivative, the condensing agent, the solvent and the reaction temperature are the same as those of the production method a. The description of the condensation reaction may be referred to.

When the imidazolyl group of the compound (Va) is protected, the compound (IIc) and the compound (II
The final product (Ia) can be prepared by removing the N-protecting group of the reaction product with I). Since this elimination reaction can be carried out in substantially the same manner as the elimination reaction of the production method a, this reaction method and, for example, a base, an acid,
For the reaction conditions such as the reducing agent, the catalyst, the solvent and the reaction temperature, the description of the elimination reaction of the production method a may be referred to.

In the production method of the present invention, the starting compound (III)
Each of (IV) and (IV) can be produced by the following methods. Compound (III) is Tetrahedron: Asymmetry, Vol.1,
It can be produced according to the method described in 375-378 (1990), for example, the method described in the production examples below. Compound (IV)
Can be produced according to the method described in JP-A 64-19071. In the present specification, “Nα-”
Means a substituent bonded to the nitrogen atom of the α-amino acid amino group, and “N ^im −” means a substituent bonded to the nitrogen atom on the imidazole ring.

[0083]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Production Example 1 L-phenylalanine (50 g), ground potassium carbonate (167.34 g), sodium iodide (22.68)
g) was added to N, N-dimethylacetamide (500 ml) with stirring, and water (25 ml) was added. After raising the temperature to 60 ° C,
Benzyl chloride (118.78 g) was added dropwise. After completion of dropping, the mixture was vigorously stirred at 60 to 65 ° C for 6 hours. After the reaction was completed, the reaction solution was cooled to 20 to 30 ° C, and water (750 m
l) and ethyl acetate (500 ml) were added for extraction. After separating the ethyl acetate layer, water (500 ml), 10% aqueous sodium hydrogen sulfite solution (500 ml) twice, and further water (500 ml).
ml), and the ethyl acetate layer is concentrated to dryness under reduced pressure to give N, N
-Dibenzyl-L-phenylalanine benzyl ester (136.88g) was obtained as a yellow oil. NMR
(CDCl ₃ , δ): 2.94-3.19 (2H, m), 3.72 (1H, t,
J = 0.77Hz), 3.73 (4H, ABsystem, J = 7.86Hz, 1.40Hz), 5.1
7 (2H, ABsystem, J = 2.51Hz, 1.23Hz), 6.98-7.35 (20H, m)

Production Example 2 N, N-dibenzyl-L-phenylalanine benzyl ester (27.24 g) was added to methanol (79.6 ml).
Aqueous sodium hydroxide solution (sodium hydroxide 4.8 g, water 19.9 ml) was added, and the mixture was refluxed for 1.5 hours with stirring. After completion of the reaction, methanol was concentrated under reduced pressure, and water (99
ml) and ethyl acetate (99 ml) were added for extraction. The ethyl acetate layer was separated and washed with 5% brine (99 ml), and the ethyl acetate layer was concentrated under reduced pressure to dryness. Acetone (20m
l) was added and the internal temperature was raised to 45 to 50 ° C, and 17.5% hydrochloric acid (50 ml) was added dropwise at the same temperature. After the completion of the dropping, acetone (30 ml) was added dropwise at the same temperature, the mixture was stirred at the same temperature for 30 minutes, cooled to an internal temperature of 20 to 25 ° C, stirred for 1 hour, cooled to 5 ° C or lower, and stirred for 2 hours or more. The precipitated crystals are filtered,
N, N-dibenzyl-L-phenylalanine hydrochloride (21.19 g) was obtained as white crystals. Melting point: 129 to 156 ° C (decomposition) IR (Nujol): 3350, 2600, 1740, 1600, 1590 cm ^-1 NMR (CDCl ₃ , δ): 2.93-3.29 (2H, m), 3.70-
3.78 (1H, m), 3.77 (4H, ABsystem, J = 2.70Hz, 1.36Hz),
6.69 (1H, bs), 7.03-7.32 (15H, m)

Production Example 3 N, N-Dibenzyl-L-phenylalanine hydrochloride (50 g) was dissolved in methylene chloride (500 ml), and an aqueous sodium hydroxide solution (sodium hydroxide 6 g, water 500 ml) was added to the solution to give 30 After stirring for minutes, the layers were separated, the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure to give N, N-dibenzyl-L-phenylalanine as an oil. Tetrahydrofuran (1000 ml) in pivaloyl chloride (4
4.90 g) was dissolved, cooled to -20 ° C., and dissolved in tetrahydrofuran (500 ml) to obtain the above N, N-.
Dibenzyl-L-phenylalanine and triethylamine (18.84g) were added dropwise at -20 to -15 ° C. After dropping, the mixture was stirred for 30 minutes at the same temperature. Separately, magnesium (21.12 g) and isoamyl bromide (150.0
3 g) and isoamyl magnesium bromide prepared from tetrahydrofuran (500 ml) at -15 to 0 ° C for 2
It dripped over time. Immediately after the addition, acetic acid (50 ml) was added dropwise at the same temperature, and the reaction solution was added with 20% aqueous ammonium chloride (50
0 ml). In addition to this, toluene (500m
l) and 7% hydrochloric acid (500 ml) were added for liquid separation. The organic layer was washed with 7% hydrochloric acid (500 ml), then with 5% aqueous sodium hydrogen carbonate solution (500 ml) and then with saturated brine (500 ml). The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure, and 2 (S)-(N, N-dibenzylamino) -1-phenyl-3-oxo-6-methylheptane (100.2
g) was obtained as a yellow oil. IR (Neat): 2700-3150, 1950, 1870, 1805, 1710, 1
600, 1450 cm ^-1 NMR (CDCl ₃ , δ): 0.80-1.43 (4H, m), 2.05-
2.60 (2H, m), 2.86-3.22 (2H, m), 3.53-3.67 (1H, m),
3.70 (4H, ABsystem, J = 3.71Hz, 1.36Hz), 7.08-7.33 (15
H, m)

Production Example 4 2 (S)-(N, N-dibenzylamino) -1-phenyl-3-oxo-6-methylheptane (100 g) was added to methanol (500 ml) and tetrahydrofuran (500 m).
It was dissolved in the mixed solution of l) and cooled to -20 ° C. Sodium borohydride (63 g) was slowly added at the same temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and ethyl acetate (500 ml) and water (500 ml) were added to the residue for extraction. The aqueous layer was re-extracted with ethyl acetate (250 ml), the organic layers were combined, washed with saturated brine (500 ml), and the organic layer was concentrated. Further, water (100 ml) was added to the residual oily substance to perform azeotropic distillation.
After performing the azeotropic operation 8 times, toluene (100 ml) was added to further perform azeotropic distillation, and 2 (S)-(N, N-dibenzylamino) -1-phenyl-3 (S) -hydroxy-6-methyl was added. I got heptane. IR (Nujol): 3400, 3350, 1950, 1890, 1810, 1600,
1590 cm ^-1 , NMR (CDCl ₃ , δ): 0.74 (6H, d, J = 0.64Hz),
0.95-1.43 (5H, m), 2.81-2.92 (1H, m), 2.88 (2H, ABXsy
stem, J = 6.75Hz, 1.40Hz, 0.61Hz), 3.55 (1H, dt, J = 0.63H
z, 0.26Hz), 3.64 (4H, ABsystem, J = 10.60Hz, 1.32Hz), 4.4
9 (1H, bs), 7.19-7.36 (15H, m)

Production Example 5 2 (S)-(N, N-dibenzylamino) -1-phenyl-3 (S) -hydroxy-6-methylheptane (25
g) was dissolved in methanol (250 ml) and added with 10%
Palladium-carbon (1.25 g) was suspended in water (10 ml), ammonium formate (15.70 g) was further added, the mixture was stirred at room temperature for 5 hr, and the reaction mixture was concentrated under reduced pressure.
The residue was dissolved in methylene chloride, washed with water, the organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and 2 (S) -amino-1-phenyl-3 (S) -hydroxy-6-methylheptane (14 0.0 g) was obtained. IR (Nujol): 3350, 3300, 3000, 2730, 1600, 1500
cm ^-1 NMR (CDCl ₃ , δ): 0.90 (6H, d, J = 0.63Hz),
1.16-1.63 (5H, m), 1.85 (2H, bs), 2.84-2.97 (2H, m),
3.30-3.38 (1H, m), 7.18-7.36 (5H, m)

Production Example 6 2 (S) -Amino-1-phenyl-3 (S) -hydroxy-6-methylheptane (13 g) was added to acetic acid (130 ml).
Platinum oxide (1.3 g) was added to the solution and the medium pressure (4 atm) was applied.
Catalytic reduction was performed. The reaction solution was heated to 45 ° C. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride, washed with 5% aqueous sodium hydrogen carbonate solution, the organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and 2 (S) -amino-1-cyclohexyl-
3 (S) -hydroxy-6-methylheptane (11.2
5 g) was obtained. IR (Nujol): 3410, 3350, 3300, 2900, 2700, 1600
cm ^-1 NMR (CDCl ₃ , δ): 0.90 (6H, d, J = 0.8Hz), 0.
77-1.74 (21H, m), 2.60-2.70 (1H, m), 3.13-3.21 (1H,
m)

Production Example 7 L-tartaric acid (6.60 g) was heated (70-75) to a mixture of isopropyl alcohol (90 ml) and water (10 ml).
C.) and dissolved at the same temperature, 2 (S) -amino-1-cyclohexyl-3 (S) -hydroxy-6-methylheptane (1
A solution of 0 g) in isopropyl alcohol (100 ml) was added dropwise. After completion of dropping, the mixture was cooled, and the precipitated crystals were collected by filtration, and 2
(S) -Amino-1-cyclohexyl-3 (S) -hydroxy-6-methylheptane L-tartrate (11.6
7 g) was obtained.

Production Example 8 Methyl 2 (S) -amino-3-cyclohexylpropionate hydrochloride (150 g) was dissolved in N, N-dimethylformamide (1200 ml) and ground potassium carbonate (33 g) was added.
0.7 g) was added and benzyl bromide (2
54.6 g) was added dropwise. After the dropping, the internal temperature was raised to 50 ° C., the mixture was stirred at the same temperature for 9 hours, then the reaction liquid was cooled and filtered. Water (600 ml) and diisopropyl ether (600 ml) were added to the filtrate for liquid separation, and the organic layer was separated. The aqueous layer was re-extracted with diisopropyl ether (300 ml), both organic layers were combined and washed with 5% hydrochloric acid (600 ml), then with 5% aqueous sodium hydrogen carbonate solution (600 ml) and 25% brine, and magnesium sulfate. After drying, the solvent is concentrated and 2
Methyl (S)-(N, N-dibenzylamino) -3-cyclohexylpropionate (204.6 g) was obtained. NMR (CDCl ₃ , δ): 0.58-1.69 (13H, m), 3.3
7-3.44 (1H, m), 3.70 (4H, ABsystem, J = 8.17Hz, 1.38Hz),
3.74 (3H, s), 7.17-7.48 (10H, m)

Production Example 9 Methyl 2 (S)-(N, N-dibenzylamino) -3-cyclohexylpropionate (200 g) was dissolved in methanol (1 liter), and an aqueous sodium hydroxide solution (sodium hydroxide was added thereto). (32.8 g, 200 ml of water) was added, and the mixture was refluxed for 6 hours. After completion of the reaction, the reaction solution was concentrated, ethyl acetate (1 liter) was added to the residue to dissolve it, and water (4
(00 ml) was added and the layers were separated. 10% after collecting the organic layer
Wash with citric acid (400 ml), saturated saline solution (400 m
l), dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 2 (S)-(N, N-dibenzylamino) -3 was used.
-Cyclohexylpropionic acid (91.1 g) was obtained. NMR (CDCl ₃ , δ): 0.69-1.64 (13H, m), 3.45
(1H, t, J = 0.70Hz), 3.75 (4H, ABsystem, J = 2.46Hz, 1.36H
z), 7.21-7.38 (10H, m), 7.90 (1H, bs)

Production Example 10 Pivaloyl chloride (5.15 g) was dissolved in tetrahydrofuran (30 ml) and cooled to -30 ° C. To this, a solution of 2 (S)-(N, N-dibenzylamino) -3-cyclohexylpropionic acid (5.0 g) and triethylamine (4.32 g) in tetrahydrofuran (20 ml) was added dropwise at the same temperature over 15 minutes. After dropping, the mixture was stirred at 20 ° C. for 1 hour. The reaction solution was cooled again to -50 ° C, and isoamyl bromide (21.49 g) and magnesium (3.46) were separately added.
g) and an isoamylmagnesium bromide-tetrahydrofuran solution prepared from tetrahydrofuran (50 ml) were added dropwise at the same temperature over 15 minutes. After dropping, the mixture was stirred at the same temperature for 30 minutes, 15 ° C. for 30 minutes, and 25 ° C. for 1 hour, and then 2
The mixture was added to a 0% ammonium chloride aqueous solution (100 ml), toluene (100 ml) was added, the pH was adjusted to 6 to 7 with 7% hydrochloric acid, and the organic layer was separated. The organic layer is 7% hydrochloric acid (100 ml)
Twice with 5% aqueous sodium hydrogen carbonate solution (100 ml),
The extract was washed with saturated brine (100 ml), dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 2 (S)-(N, N-dibenzylamino) -cyclohexyl-3-oxo-6-methylheptane (9 , 41 g) was obtained. NMR (CDCl ₃ , δ): 0.85 (6H, dd, J = 0.63Hz, 0.
09Hz), 1.13-1.74 (16H, m), 2.24-2.61 (2H, m), 3.32
(1H, q, J = 0.46Hz), 3.61 (4H, ABsystem, J = 3.48Hz, 1.37H
z), 7.19-7.36 (10H, m)

Production Example 11 2 (S)-(N, N-dibenzylamino) -1-cyclohexyl-3-oxo-6-methylheptane (2 g)
To methanol (20 ml) and tetrahydrofuran (20
ml) and then cooled to -20 ° C. Sodium borohydride (0.2g) was added to the reaction solution at -20 ° C.
It was added while keeping. After the addition, the reaction was carried out at the same temperature for 1.5 hours. After completion of the reaction, water (50 ml) was added to the reaction solution, and methylene chloride (50 ml) was added for extraction. After drying the methylene chloride layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure,
2 (S)-(N, N-dibenzylamino) -1-cyclohexyl-3 (S) -hydroxy-6-methylheptane (2.01 g) was obtained. NMR (CDCl ₃ , δ): 0.85 (6H, ABsystem, J = 0.6)
4Hz, 0.21Hz), 0.79-1.74 (18H), 2.46-2.56 (1H, m), 3.
37-3.49 (1H, m), 3.62 (4H, ABsystem, J = 8.76Hz, 1.35H
z), 4.48 (1H, bs), 7.16-7.37 (10H, m)

Production Example 12 2 (S)-(N, N-dibenzylamino) -1-cyclohexyl-3 (S) -hydroxy-6-methylheptane (5 g) was dissolved in methanol (50 ml). Further, ammonium formate (6.18 g) was added, 10% palladium-carbon (50% wet, 0.5 g) was added, and the mixture was vigorously stirred at room temperature. After completion of the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and ethyl acetate and water were added to the concentrated residue for extraction. Further, after washing with saturated saline, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2 (S) -amino-1.
-Cyclohexyl-3 (S) -hydroxy-6-methylheptane (4.13 g) was obtained. NMR (CDCl ₃ , δ): 0.90 (6H, d, J = 0.8Hz), 0.
77-1.74 (21H, m), 2.60-2.70 (1H, m), 3.13-3.21 (1H,
m)

Example 1 L-histidine (100 g) was suspended in methylene chloride (2.0 liter), dichlorodimethylsilane (83.2 g) was added at an internal temperature of 20 to 30 ° C., and the mixture was heated under reflux for 3 hr. Then, under reflux, triethylamine (66.5 g) was added to 15-
It takes 30 minutes to add dropwise, and the mixture is heated under reflux for another 30 minutes. After completion of the silylation reaction, the reaction solution was cooled to an internal temperature of 20 to 30 ° C., and a solution of trityl chloride (188.6 g) in methylene chloride (300 ml) was added dropwise over 1 hour at the same temperature. The reaction is carried out at warm temperature for 1 hour. After completion of the tritylation reaction, the reaction mixture was concentrated under reduced pressure and the residue was methanol (200 ml).
Is added, and after stirring for 15 minutes, water (1.0 liter) is added dropwise at an internal temperature of 20 to 30 ° C. over 30 minutes. After dropping, the pH is adjusted to 6.5 to 7.5 using triethylamine. Then, the precipitated crystals are collected at the same temperature. The crystals collected by filtration were washed with water (400 ml) and methylene chloride (500 ml), respectively, and dried under vacuum overnight to give N ^im -trityl-L-histidine (192.3 g). Yield 75% NMR (DMSO-d ₆ , δ): 6.76 (1H, s), 7.08-7.
13 (6H, m), 7.29 (1H, s), 7.37-7.43 (9H, m)

Example 2 2 (S)-[N-methyl-N- [2- {N- (morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3- in methylene chloride (1000 ml)
Cyclohexylamine salt of phenylpropionic acid (10
0 g) was added, and the internal temperature was cooled to 10 ° C., and then 5% hydrochloric acid (50
0 ml), and the mixture is stirred at an internal temperature of 10 to 15 ° C for 10 minutes to make it free. After allowing to stand, collect the methylene chloride layer, 20%
Wash with brine (500 ml). The obtained methylene chloride layer is dried over magnesium sulfate and then filtered off to obtain a free methylene chloride solution. N-hydroxysuccinimide (25.7 g) was added to this solution, and the internal temperature was cooled to 0 ° C.
N, N'-dicyclohexylcarbodiimide (46.1
A solution of g) in methylene chloride (200 ml) is added at an internal temperature of 5 ° C or lower. React for 2 hours at an internal temperature of 0 to 5 ° C. After the reaction,
The precipitated N, N'-dicyclohexylurea is filtered off and washed with methylene chloride (200 ml). The filtrate and washings were combined and 5% citric acid aqueous solution (500 ml) and water (50
Wash each with 0 ml). The methylene chloride layer is separated, dried over magnesium sulfate and then concentrated under reduced pressure to a residue amount (100 ml) to obtain an active ester solution. On the other hand, 1,1,1,3,3,3-hexamethyldisilazane (44.6 g), N ^im -trityl-L-histidine (85.4 g) and trimethylsilyl chloride (33.1 g) in methylene chloride (1000 ml). ) Is added and the silylation reaction is carried out for 1 hour under heating under reflux. After completion of the reaction, the internal temperature is cooled to 30 ° C or lower, the active ester solution is added, and the condensation reaction is performed at the internal temperature of 20 to 30 ° C for 1 hour. After completion of the reaction, water (1000 ml) is added, the mixture is stirred and allowed to stand, and the methylene chloride layer is separated. The methylene chloride layer is a 5% aqueous citric acid solution (1000 ml),
Wash each with water (1000 ml). The methylene chloride layer was separated and concentrated to dryness, and Nα- [2 (S)-[N-methyl-N
- obtaining a trityl -L- histidine (174.6g) - [2-{N-(morpholinocarbonyl) -N- methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -N ^im. Yield 111% NMR (CDCl ₃ , δ): 2.73-2.97 (8H, m), 3.01-
3.61 (14H, m), 4.46 (1H, br), 5.18 (1H, br), 6.75-6.9
0 (1H, m), 7.09-7.34 (20H, m), 7.40-7.55 (1H, m)

Example 3 Nα- [2 (S)-[N-methyl-N- [2- {N-
(Morpholinocarbonyl) -N- methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -N ^im - trityl -L- histidine (100 g)
Was dissolved in tetrahydrofuran (1000 ml), water (1.0 g) was added, the internal temperature was cooled to -10 ° C, sodium hydride (60%, 11.4 g) was added, and then methyl iodide (110.2 g) was added. ) Is added dropwise at an internal temperature of -5 ° C or lower,
Further, the reaction is performed at an internal temperature of 0 to 5 ° C for 3 hours. After completion of the reaction, the reaction solution was mixed with 5% citric acid aqueous solution (500 ml) and methylene chloride (5
(00 ml), and the mixture is stirred and allowed to stand, and the organic layer is separated. The organic layer is washed with water (500 ml) and then concentrated to dryness under reduced pressure. Ethyl acetate (1000 ml) on the concentrated residue,
5% sodium bicarbonate water (2000 ml) was added and dissolved, and the mixture was allowed to stand with stirring and the aqueous layer was separated. The pH of the collected aqueous layer is 4 to 4 due to citric acid.
Adjust to 4.5, add methylene chloride (2000 ml),
Extract the target product. The methylene chloride layer is separated and further washed with water (500 ml). The methylene chloride layer was dried over magnesium sulfate and then concentrated to dryness under reduced pressure to give Nα- [2
(S)-[N-methyl-N- [2- {N- (morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -Nα-
Methyl -N ^im - trityl -L- histidine (94.7
g) is obtained. Yield 93% NMR (CDCl ₃ , δ): 2.71-2.90 (8H, m), 3.03-
3.62 (17H, m), 5.29-5.34 (2H, m), 6.60-6.80 (1H, m),
7.02-7.38 (20H, m), 7.50-7.75 (1H, m)

Example 4 2 (S) -Amino-1-cyclohexyl-3 (S) -hydroxy-6-methylheptane L-tartrate (48.
0 g) to methylene chloride (400 ml), and with stirring, 2
5% ammonia water (150 ml) and water (50 ml) were added to make it free, and after standing, the methylene chloride layer was separated and water (150 ml) was collected.
ml). The separated methylene chloride layer is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. Tetrahydrofuran (800 ml), Nα- [2 (S)-[N
-Methyl-N- [2- {N- (morpholinocarbonyl)
-N-methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -Nα-methyl-N
^im -trityl-L-histidine (100.0 g), 1-
Hydroxy-1H-benzotriazole (20.6 g)
Was added and dissolved, then cooled to −5 ° C. to −10 ° C., N, N ′
-Dicyclohexylcarbodiimide (28.8g), N
-Methylmorpholine (6.43 g) is added, and the mixture is reacted at the same temperature for 24 hours. After completion of the reaction, the precipitated N, N'-dicyclohexylurea is filtered off and washed with ethyl acetate (50 ml). The filtrate and washings are combined, ethyl acetate (1000 ml) and 5% citric acid (1000 ml) are added to the solution,
After stirring and standing, the organic layer is separated. The organic layer obtained is 2
Wash with 5% saline, cold 5% aqueous sodium hydroxide, 25% saline (1000 ml each). The organic layer was concentrated to dryness under reduced pressure and purified by silica gel column (developing solvent: methylene chloride and 3% methanol, 97% methylene chloride mixed solution).
2 (S)-[Nα- [2 (S)-[N-methyl-N- [2- {N- (morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3-
Phenylpropionyl] -Nα-methyl-N ^im -trityl-L-histidyl] amino-1-cyclohexyl-3
(S) -Hydroxy-6-methylheptane (114.1
g) is obtained. Purification yield 91% NMR (CDCl ₃ , δ): 0.83 (6H, dd, J = 6.0Hz, 6.0H
z), 1.15-1.63 (18H, m), 2.74-3.62 (21H, m), 4.05-4.1
5 (1H, m), 5.02-5.11 (1H, m), 6.60-6.80 (1H, m), 7.03
(5H, m), 7.26 (16H, m)

Example 5 2 (S)-[Nα- [2 (S)-[N-methyl-N-
[2- {N- (morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -Nα-methyl-N ^im -trityl-L
-Histidyl] amino-1-cyclohexyl-3 (S)
50-hydroxy-6-methylheptane (100 g)
% Dissolved in water containing acetic acid (1000ml), internal temperature 50-55 ℃
The detrityl reaction is carried out for 2 hours. After the reaction is completed, the internal temperature is 20
The mixture is cooled to -30 ° C, ethyl acetate (1000 ml) is added, the pH is adjusted to 7.8-8.0 with 25% aqueous ammonia, the mixture is stirred and left standing, and the organic layer is separated. 10% for organic layer
Aqueous citric acid solution (1000 ml) was added, and the mixture was allowed to stand with stirring.
Re-extract with 0 ml). The citric acid layers are combined and washed with ethyl acetate (500 ml). Ethyl acetate (500 ml) was added to the separated citric acid layer, and the pH was adjusted to 25% with aqueous ammonia.
Adjust to 7.8-8.0, stir and leave still, and then separate the organic layer. The separated organic layer was washed with 20% saline (500 ml), dried over magnesium sulfate, and concentrated to dryness under reduced pressure.
(S)-[Nα- [2 (S)-[N-methyl-N- [2
-{N- (morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -Nα-methyl-L-histidyl] amino-1-cyclohexyl-3 (S) -hydroxy-6-
Methylheptane (70.1 g) is obtained. Yield 93%

Example 6 2 (S)-[Nα- [2 (S)-[N-methyl-N-
[2- {N- (morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -Nα-methyl-L-histidyl] amino-1-cyclohexyl-3 (S) -hydroxy- 6
-Methylheptane (100 g) was added to ethyl acetate (1000
ml) and clarify filtration with a 0.6μ filter. After washing with ethyl acetate (200 ml), combine the filtrate and washings,
4N-hydrochloric acid / ethyl acetate solution (3
3.2 ml) is added and stirred for 20 minutes. It was concentrated to dryness under reduced pressure, and ethyl acetate (800 ml) and acetone (160 ml) were added to the residue.
ml) and dissolve. After melting, n- at an internal temperature of 55 to 60 ° C
Hexane (800 ml) is added dropwise over 30 minutes. After the dropping, seed crystals (0.05 g) are added and the mixture is stirred at the same temperature for 13.5 hours or more to sufficiently precipitate crystals. After cooling to an internal temperature of 20 to 30 ° C. and stirring at the same temperature for 1 hour, the precipitated crystals are collected by filtration. The crystals are ethyl acetate-n-hexane (100 ml to 20 ml).
(0 ml), and dried under vacuum overnight, then 2 (S)-
[Nα- [2 (S)-[N-methyl-N- [2- {N-
(Morpholinocarbonyl) -N-methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -Nα-methyl-L-histidyl] amino-1-
Cyclohexyl-3 (S) -hydroxy-6-methylheptane monohydrochloride (82.2 g) is obtained. Yield 78% (N
Total yield from ^im -trityl-L-histidine 68%) NMR (D ₂ O, δ): 0.83 (6H, d, J = 6.0Hz), 1.04-
1.82 (18H, m), 2.64-3.88 (24H, m), 3.90-4.05 (1H, m),
5.12-5.20 (1H, m), 7.2-7.4 (6H, m), 8.61 (1H, s)

[0101]

According to the manufacturing method of the present invention, the starting material N ^im
The total yield from -trityl-L-histidine was 68%, which was an improvement in yield as compared with the conventional method. Inexpensive L-
Final product (I) in high yield starting from histidine
Therefore, the manufacturing cost can be significantly reduced, and the manufacturing method is extremely useful in industry. The compound (II) is a novel compound and is useful as a synthetic intermediate in the production method of the present invention.

Claims (4)

[Claims] 1. The formula: [Wherein R ¹ is an acyl group, a hydroxy group, a lower alkoxy group, an aryl group, a lower alkylthio group or a compound represented by the formula: (Wherein R ⁶ represents hydrogen or an acyl group, R ⁷ represents hydrogen or a lower alkyl group, respectively), and a lower alkyl group optionally substituted by a substituent selected from the group consisting of: aryl A group; or an amino group which may be substituted with a substituent selected from the group consisting of a lower alkyl group and an acyl group; R ² represents hydrogen or a lower alkyl group, or R ¹ and R ² are adjacent to each other. Together with the nitrogen atom, a lower alkyl group, a hydroxy (lower) alkyl group, a lower alkoxy (lower) alkyl group,
R ³ is hydrogen or a lower alkyl group, R ⁴ is hydrogen or N, which forms a heterocyclic group which may be substituted with a substituent selected from the group consisting of an acyl (lower) alkyl group, an oxo group and an acyl group. A protecting group, R ⁵ represents hydrogen or a carboxy protecting group] or a salt thereof. 2. R ¹ is of the formula: [In the formula, R ⁷ represents hydrogen or a lower alkyl group, and R ^7
8 and R ⁹ together with the adjacent nitrogen atom form a heterocyclic group which may be substituted with a lower alkyl group], a lower alkyl group substituted with a group represented by the following formula, R ² is a lower alkyl group, The compound according to claim 1, wherein R ⁵ is hydrogen or a lower alkyl group. 3. Nα- [2 (S)-[N-methyl-N-
[2-{N- (morpholinocarbonyl) -N- methylamino} ethyl] aminocarbonyloxy] -3-phenylpropionyl] -N ^im - trityl -L- histidine and Nα- [2 (S) - [N- methyl -N- [2- {N
- (morpholinocarbonyl) -N- methylamino} ethyl] aminocarbonyl) -3-phenylpropionyl] -Nα- methyl -N ^im - compound of claim 2 selected from trityl -L- histidine. 4. The formula: [Wherein R ¹ is an acyl group, a hydroxy group, a lower alkoxy group, an aryl group, a lower alkylthio group or a compound represented by the formula: (Wherein R ⁶ represents hydrogen or an acyl group, R ⁷ represents hydrogen or a lower alkyl group, respectively), and a lower alkyl group optionally substituted by a substituent selected from the group consisting of: aryl A group; or an amino group which may be substituted with a substituent selected from the group consisting of a lower alkyl group and an acyl group; R ² represents hydrogen or a lower alkyl group, or R ¹ and R ² are adjacent to each other. Together with the nitrogen atom, a lower alkyl group, a hydroxy (lower) alkyl group, a lower alkoxy (lower) alkyl group,
R ³ is hydrogen or a lower alkyl group, and R ¹⁰ is a lower alkyl group, which forms a heterocyclic group which may be substituted with a substituent selected from the group consisting of an acyl (lower) alkyl group, an oxo group and an acyl group. A method for producing a compound represented by the formula: or a salt thereof, comprising: [In the formula, R ⁴ is hydrogen or an N-protecting group, R ¹ , R ² , R
³ is each as defined above] or a reactive derivative thereof at the carboxy group or a salt thereof is represented by the formula: [Wherein R ¹⁰ is as defined above] or a reactive derivative of the amino group thereof or a salt thereof is reacted, and if necessary, the N-protecting group is eliminated to give a compound of the formula: 8] [Wherein R ¹ , R ² , R ³ and R ¹⁰ are as defined above] or a salt thereof, or (b) a compound represented by the formula: [In the formula, R ¹ and R ² are as defined above]
Or a reactive derivative thereof at the carboxy group or a salt thereof is represented by the formula: [Wherein R ⁵ is hydrogen or a carboxy protecting group, R ³ and R
Each of ⁴ is as defined above] and is reacted with a compound represented by the formula: [Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above] or a salt thereof, which is then of the formula [Wherein R ¹⁰ is as defined above] or a salt thereof is reacted with the compound to remove the N-protecting group, if necessary. A compound represented by the formula: wherein R ¹ , R ² , R ³ , and R ¹⁰ are as defined above, or a salt thereof, or (c) [In the formula, R ¹ and R ² are as defined above]
A compound represented by or a reactive derivative thereof at the carboxy group or a salt thereof is represented by the formula: [In the formula, R ⁴ and R ⁵ are as defined above]
A compound represented by the formula: [Wherein each of R ¹ , R ² , R ⁴ and R ⁵ is as defined above] or a salt thereof is obtained, which is then prepared in the presence of a base. [Wherein X represents halogen and R ³ a represents a lower alkyl group], and the compound represented by the formula: [Wherein R ¹ , R ² , R ³ a, R ⁴ and R ⁵ are as defined above] or a salt thereof, which is further represented by the formula: [Wherein R ¹⁰ is as defined above] or a salt thereof is reacted, and the N-protecting group is removed, if necessary, to give a compound of the formula: [Wherein R ¹ , R ² , R ³ a, and R ¹⁰ are as defined above] or a process for obtaining a salt thereof.