JP2002179664A - Epoxycarboxylic acid amide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a production intermediate from which an α-ketoamide derivative having protease inhibitory activity can be extremely economically and stereoselectively produced. SOLUTION: This epoxycarboxylic acid amide derivative is represented by the formula (R1 is a substituted or unsubstituted straight-chain, branched- chain or cyclic alkyl group; R2 is a substituent group which is a substituted or unsubstituted straight-chain, branched-chain or cyclic alkyl group).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a compound represented by the general formula

Embedded image (Wherein R 1 is a substituted or unsubstituted linear, branched or cyclic alkyl group, and the substituent of the alkyl group is a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted Heterocyclic group, substituted or unsubstituted alkoxyl group,
It is a substituted or unsubstituted alkylthio group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted arylthio group. R 2 is a substituted or unsubstituted linear, branched or cyclic alkyl group, and the substituent of the alkyl group is a hydroxyl group, an oxo group, a halogen atom, a substituted or unsubstituted C 2-6 Linear, branched or cyclic alkenyl group, substituted or unsubstituted heterocyclic group,
Nitro group, substituted or unsubstituted amino group, substituted or unsubstituted sulfonyl group, substituted or unsubstituted alkoxyl group, substituted or unsubstituted alkylthio group, substituted or unsubstituted aryloxy group, substituted or unsubstituted arylthio group A substituted or unsubstituted alkoxycarbonyl group, a substituted carbamoyl group, a substituted sulfonamide group, a substituted amide group, a mercapto group or a cyano group. )). The epoxycarboxylic acid amide derivative represented by the general formula (I) can be used, for example, as an intermediate for producing an α-ketoamide derivative having protease inhibitory activity.

[0002]

2. Description of the Related Art Protease, a protease,
It is known to be involved in the onset and progression of many diseases such as hypertension, thrombosis, pancreatitis, cancer, Alzheimer's disease, emphysema, neurodegenerative disease, allergic disease, muscular dystrophy, rheumatism, osteoporosis, periodontal disease (protein nucleic acid enzymes, 42 , No1
4, (1997), Experimental Medicine, 17 , No. 15, (199)
9)), its inhibitor, ie, a protease inhibitor, is expected as a drug target.

[0003] Among these proteases, it has been reported that they have an inhibitory activity on serine proteases (elastase, tryptase, trypsin, chymotrypsin, prolyl endopeptidase) and cysteine proteases (calpain, cathepsin B, cathepsin L) (Japanese Patent Application Laid-Open No. HEI 9-163873). 4-149166, JP-A-4-21164
8, Tokuyohei 6-504547, WO9816512,
J. Med. Chem. , 39 , 4089 (199
6), Exp. Opin. Ther. Patent
s. , 8 , 1707 (1998)) are compounds that are expected to exhibit sufficient inhibitory activity against cathepsin K, which has recently been reported to be closely involved in bone metabolism. .

A typical method for synthesizing a protease inhibitor having an α-ketoamide structure is described in (A) J. Me.
d. Chem. , 36 , 3472 (1993) further discloses (B) J. Med.
m. , 37 , 2918 (1994) and the like.

[0005]

In the above method (A), an α-keto amide derivative as a target compound cannot be obtained as an optically active substance, and in the method (B), an optically active amino acid as a starting material is used. Problems are that they are expensive, that only amino acids can be used as starting materials to introduce only limited substituents into R1, and that the reaction intermediate is a diastereomeric mixture and that it is difficult to sufficiently purify it. It was not satisfactory to adopt it as an industrial manufacturing method.

[0006]

Means for Solving the Problems As a result of intensive studies to overcome the conventional disadvantages, the present inventors have found that the substituent of R1 is not limited to the amino acid structure, and that the α-ketoamide derivative can be stereoselectively formed. Production raw material that can be constructed (epoxycarboxylic acid amide derivative represented by the general formula (I))
And completed the present invention.

Hereinafter, in describing the present invention in detail, the alkyl group for R 1 may be any of a linear, branched or cyclic alkyl group having 1 to 12 carbon atoms. , Ethyl group, n-propyl group, 1
-Methylethyl group, cyclopropyl group, n-butyl group,
2-methylpropyl group, 1-methylpropyl group, 1,1
-Dimethylethyl group, cyclobutyl group, n-pentyl group, 3-methylbutyl group, cyclopentyl group, 2,2-
Dimethylpropyl group, 1-methylcyclobutyl group, cyclobutylmethyl group, n-hexyl group, 4-methylpentyl group, cyclohexyl group, 1-methylcyclopentyl group, cyclopentylmethyl group, (1-methylcyclobutyl) methyl group, n-heptyl group, 5-methylhexyl group, 4,4-dimethylpentyl group, cycloheptyl group,
Cyclohexylmethyl group, (1-methylcyclopentyl) methyl group, n-octyl group, 6-methylheptyl group, 5,5-dimethylhexyl group, (1-methylcyclohexyl) methyl group, n-nonyl group, 7-methyloctyl Group, 6,6-dimethylheptyl group, n-decyl group, 8
-Methylnonyl group, 7,7-dimethyloctyl group, n-
Examples include an indecacyl group, a 9-methyldecyl group, an 8,8-dimethylnonyl group, an n-dodecasyl group, a 10-methylundecacil group, and a 9,9-dimethyldecacyl group.

The substituted or unsubstituted aromatic hydrocarbon group mentioned as a substituent for the alkyl group of R 1 is monocyclic or polycyclic, and may have one or more of various rings on the ring. Refers to an aromatic hydrocarbon group which may have a substituent, for example, a phenyl group, a 4-methylphenyl group,
4-dimethylphenyl group, 4-methoxyphenyl group,
2,3-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2,3-methylenedioxyphenyl group, 3,4-methylenedioxyphenyl group, 4-nitrophenyl group, 3,4-dinitrophenyl group, 4-chlorophenyl group, 3,4-dichlorophenyl group, 4-bromophenyl group, 3,4-dibromophenyl group, 4-iodophenyl group, 4-fluorophenyl group, 2,3 -Difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 4
-Trifluoromethylphenyl group, 3-phenoxyphenyl group, 4-phenoxyphenyl group, 4- (1-naphthoxy) phenyl group, 4-acetaminophenyl group, 1-
Examples thereof include a naphthyl group and a 2-naphthyl group.

The substituted or unsubstituted heterocyclic group, which is a substituent for the alkyl group of R 1, is a 5-membered ring containing at least one heteroatom such as a nitrogen atom, sulfur atom, oxygen atom or the like as a ring-constituting atom. Or a 6-membered ring group, which may be condensed with a benzene ring, for example, a 2-pyridyl group, a 2-furyl group, a 2-thienyl group, a 2-indolyl group, a 2-quinolyl group, a 3-quinolyl group. Isoquinolyl group, 2-benzofuranyl group, 2-benzothienyl group, 2-imidazolyl group, 2-benzimidazolyl group, 2-thiazolyl group, 2
-Oxazolyl group, 2-pyrazolyl group, 2-pyrimidyl group, 2-pyrimidinyl group, 2-dioxanyl group, 2-thiazolidinyl group, 2-imidazolidinyl group, 2-oxotetrahydrofuran-3-yl group, 2-benzothiazolyl group, 2 Quinazoline group, hexahydro-2-azenopin-3-yl group, morpholino group, thiamorpholino group, pyrrolidino group, piperidino group, piperazino group, perhydro-4-azepin-1-yl group, perhydro-4-azaazepine-1- Il group and the like can be mentioned. The heterocyclic ring may have one or more substituents. Examples of the substituent include an acetyl group, a methoxycarbonyl group, an ethoxycarbonyl group, a 2-methyl-2-propyloxycarbonyl group, and a methyl group. Examples include a sulfonyl group, a methoxy group, and a benzoyl group.

The substituted or unsubstituted alkoxy group which is a substituent for the alkyl group of R 1 includes, for example, methoxy group, ethoxy group, n-propoxy group, n-butoxy group, 2,2-
Examples thereof include a dimethylethyloxy group, a cyclohexyloxy group, and a phenylmethyloxy group.

The substituted or unsubstituted alkylthio group which is a substituent for the alkyl group of R 1 includes, for example, a methylthio group, an ethylthio group, an n-propylthio group, a 1-methylethylthio group, an n-butylthio group, a 2-butylthio group. Methylpropylthio group, 1-methylpropylthio group, n-butylthio group,
Examples thereof include a 2,2-dimethylethylthio group, a cyclohexylthio group, and a phenylmethylthio group.

Examples of the substituted or unsubstituted aryloxy group which is a substituent for the alkyl group of R 1 include a phenyloxy group, a 4-methylphenyloxy group, a 4-fluorophenyloxy group, a 4-chlorophenyloxy group, 4
-Nitrophenyloxy group, 2-naphthyloxy group,
3,4-dimethoxyphenyloxy group, 3,4-methylenedioxyphenyloxy group, 2-pyridyloxy group,
2-furyloxy group, 2-thienyloxy group, 2-quinolyloxy group, 3-isoquinolyloxy group, 4-nitrophenylmethyloxy group, 2-naphthylmethyloxy group, 3,4-dimethoxyphenyloxy group, 3 , 4-methylenedioxyphenylmethyloxy group and the like.

The substituted or unsubstituted arylthio group as a substituent for the alkyl group of R 1 includes, for example, phenylthio group, 4-methylphenylthio group, 4-fluorophenylthio group, 4-chlorophenylthio group, 4-chlorophenylthio group, Nitrophenylthio group, 2-naphthylthio group, 3,4-dimethoxyphenylthio group, 3,4-methylenedioxyphenylthio group, 2-pyridylthio group, 2-furylthio group, 2-
Thienylthio, 2-quinolylthio, 3-isoquinolylthio, phenylmethylthio, 4-fluorophenylmethylthio, 4-chlorophenylmethylthio, 4
-Nitrophenylmethylthio group, 2-naphthylmethylthio group, 3,4-dimethoxyphenylmethylthio group, 3,
Examples thereof include a 4-methylenedioxyphenylmethylthio group.

Examples of the alkyl group for R2 include the same groups as the alkyl groups exemplified for R1 above.

The alkenyl group mentioned as a substituent of the alkyl group for R 2 may be any of linear, branched or cyclic alkenyl groups having 2 to 6 carbon atoms. Methyl-1-propenyl group, 1-methyl-2-propenyl group, 2-methyl-2-propenyl group, ethenyl group, 1-methylethenyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2- Butenyl group, 2-pentenyl group, 1-pentenyl group, 1,3-
Butanedienyl group, 1-hexenyl group, 2-hexenyl group, 1,3-pentadienyl group, 1,3-hexadienyl group, and the like. Examples of the substituent of the alkenyl group include the same groups as those described above for the alkyl group of R1.

And a substituent of the alkyl group of R 2,
Examples of the substituted or unsubstituted heterocyclic group include the same groups as the heterocyclic groups exemplified for R1 above.

The substituted amino group, which is a substituent of the alkyl group for R 2, refers to a secondary amino group or a tertiary amino group substituted with various substituents, and these substituents are as described above. Examples include the same groups as the substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted aromatic hydrocarbon groups, and substituted or unsubstituted heterocyclic groups.

Examples of the substituted sulfonyl group which is a substituent of the alkyl group for R 2 include a methylsulfonyl group and n
-Butylsulfonyl, 2,2-dimethylethylsulfonyl, cyclohexylsulfonyl, phenylsulfonyl, 4-methylphenylsulfonyl, 4-fluorophenylsulfonyl, 4-chlorophenylsulfonyl, 4-nitrophenylsulfonyl, 2 -Naphthylsulfonyl group, 3,4-dimethoxyphenylsulfonyl group, 3,4-methylenedioxyphenylsulfonyl group,
2-pyridylsulfonyl group, 2-furylsulfonyl group,
2-thienylsulfonyl group, 2-quinolylsulfonyl group, 3-isoquinolylsulfonyl group, phenylmethylsulfonyl group, 4-fluorophenylmethylsulfonyl group, 4-chlorophenylmethylsulfonyl group, 4-nitrophenylmethylsulfonyl group, 2 -Naphthylmethylsulfonyl group, 3,4-dimethoxyphenylmethylsulfonyl group, 3,4-methylenedioxyphenylmethylsulfonyl group and the like.

The alkoxy group, which is a substituent of the alkyl group for R 2, is an alkyl-substituted oxyl group having an alkyl moiety of 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, and 1-methylethyl. Oxy group, n
-Butoxy group, 2-methylpropyloxy group, 1-methylpropyloxy group, 2-methyl-2-propyloxy group, 2,2-dimethylethyloxy group, n-pentyloxy group, 3-methylbutyloxy group, Examples thereof include an n-hexyloxy group, a 4-methylpentyloxy group, and a cyclohexyloxy group. Examples of the substituent of the alkoxyl group include the same groups as those described above for the alkyl group of R1.

The alkylthio group, which is a substituent of the alkyl group represented by R2, is an alkyl-substituted thio group having an alkyl moiety of 1 to 6 carbon atoms, such as methylthio, ethylthio, n-propylthio, 1-methyl Ethylthio group,
n-butylthio group, 2-methylpropylthio group, 1-methylpropylthio group, 2-methyl-2-propylthio group, 2,2-dimethylethylthio group, n-pentylthio group, 3-methylbutylthio group, n -Hexylthio group, 4
-Methylpentylthio group, cyclohexylthio group and the like. Examples of the substituent of the alkylthio group include the same groups as those described above for the substituent of the alkyl group of R1.

The substituted or unsubstituted aryloxy group, which is a substituent of the alkyl group of R 2, may be the same as the above-described aryloxy group as the substituent of R 1.

The substituted or unsubstituted arylthio group, which is a substituent of the alkyl group for R2, includes the same groups as the arylthio groups exemplified as the substituent for R1.

The substituted or unsubstituted alkoxylcarbonyl group which is a substituent of the alkyl group for R2 includes, for example, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, n-butoxycarbonyl group, 2,2-
Examples thereof include a dimethylethyloxycarbonyl group, a cyclohexyloxycarbonyl group, and a phenylmethyloxycarbonyl group.

The substituted carbamoyl group, which is a substituent of the alkyl group of R 2, is a group represented by R 3 —NHCO— in which various substituents are bonded to the nitrogen atom of the carbamoyl-bonding group. As the substituted substituent R3, the above-mentioned substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted amino group And N-methylcarbamoyl group, N, N-dimethylcarbamoyl group, N-butylcarbamoyl group, N, N-dibutylcarbamoyl group, N-
(2,2-dimethylethyl) carbamoyl group, N-cyclohexylcarbamoyl group, N-phenylcarbamoyl group, N- (4-methylphenyl) carbamoyl group, N-
(4-fluorophenyl) carbamoyl group, N- (4-
Chlorophenyl) carbamoyl group, N- (4-nitrophenyl) carbamoyl group, N, N-diphenylcarbamoyl group, N-naphthylcarbamoyl group, N- (3,4-
Dimethoxyphenyl) carbamoyl group, N- (3,4-
Methylenedioxyphenyl) carbamoyl group, N-methyl-N-phenylcarbamoyl group, N-methyl-N-naphthylcarbamoyl group, N- (2-pyridyl) carbamoyl group, N- (2-furyl) carbamoyl group, N- (2
-Thienyl) carbamoyl group, N- (2-quinolyl) carbamoyl group, N- (3-isoquinolyl) carbamoyl group, N- (phenylmethyl) carbamoyl group, N- (4
-Fluorophenylmethyl) carbamoyl group, N- (4
-Chlorophenylmethyl) carbamoyl group, N- (4-
Nitrophenylmethyl) carbamoyl group, N- (2-naphthylmethyl) carbamoyl group, N- (3,4-dimethoxyphenylmethyl) carbamoyl group, N- (3,4-
Methylenedioxyphenylmethyl) carbamoyl group and the like.

The substituted sulfonamide group, which is a substituent of the alkyl group of R 2, is a group represented by R 4 —SO 2 NH— in which various substituents are bonded to a sulfur atom of a sulfonamide bonding group. The substituent R4 bonded to the atom includes the above-mentioned substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted heterocyclic group. Examples include a substituted amino group.

The substituted amide group, which is a substituent of the alkyl group of R 2, is a group represented by R 5 —CONH— in which various substituents are bonded to the carbon atom of the amide bonding group. As the substituted substituent R5, a phenoxy group,
1-naphthyloxy group, 2-naphthyloxy group, the above-mentioned substituted or unsubstituted alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted aromatic hydrocarbon group, substituted or unsubstituted heterocyclic group, Examples thereof include a substituted or unsubstituted amino group and a substituted or unsubstituted alkoxyl group.

The epoxycarboxylic acid amide derivative represented by the general formula (I) can be stereoselectively produced according to the following formula.

Embedded image (In the formula, R1 and R2 are the same as R1 and R2 in the general formula (I).)

(Step 1-1) In this step, the alcohol derivative represented by the general formula (II) is oxidized to produce an epoxy alcohol derivative represented by the general formula (III).

As an oxidation reaction used in this step, for example, a Sharpless oxidation method can be used. As an oxidizing agent, t-butyl hydroperoxide, cumene hydroperoxide, trityl hydroperoxide or the like can be used, and as a catalyst, titanium tetraisopropoxide or the like can be used. As the asymmetric source reagent, for example, an optically active substance such as diisopropyl tartrate, diethyl tartrate, and dimethyl tartrate can be used. The reaction is desirably performed in an inert solvent. For example, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and aromatic hydrocarbons such as benzene, toluene and xylene can be used. still,
The reaction can be carried out by gradually raising the temperature from -40 ° C to room temperature.

In this step, four types of epoxy alcohol derivatives (III) shown in the following table can be stereoselectively produced depending on the steric structures of the alcohol derivative (II) and the asymmetric reagent.

[Table 1] (In the table, R1 is the same as R1 in the formula (I).)

(Step 1-2) In the present step, the epoxy alcohol derivative represented by the general formula (III) is oxidized to maintain the three-dimensional structure, thereby obtaining the compound represented by the general formula (IV)
This is a step of producing an epoxycarboxylic acid derivative represented by the following formula:

In the reaction of oxidizing the epoxy alcohol derivative represented by the general formula (III) in this step, an oxidizing reagent such as sodium periodate or periodate is used as an oxidizing agent.
Ruthenium chloride can be used as a catalyst. As the reaction solvent, it is desirable to use a mixed solvent of acetonitrile / carbon tetrachloride / water, and the reaction temperature is -10C to 30C.
Can be implemented.

(Step 1-3) In this step, the epoxycarboxylic acid derivative represented by the general formula (IV) is condensed with the amine compound (V) to maintain the steric structure, This is a step of producing the epoxycarboxylic acid amide derivative represented by (I).

The epoxy carboxylic acid derivative represented by the above general formula (IV) in this step can be prepared by adding a carboxyl group to pivaloyl chloride, isobutyl chlorocarbonate, or the like in the presence of a base such as triethylamine, pyridine or dimethylaminopyridine.
Ethyl chlorocarbonate, p-toluenesulfonyl chloride,
After conversion into a mixed acid anhydride using methanesulfonyl chloride or the like, it can be condensed with the amine compound represented by the general formula (V). The reaction is preferably performed in an inert solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, dimethoxyethane, tetrahydrofuran, dioxane and the like. Ethers, dimethylformamide, acetonitrile, ethyl acetate and the like can be used alone or as a mixture. The reaction temperature can be carried out at -20C to 40C. The reaction between the epoxycarboxylic acid derivative (IV) and the amine compound (V) can be performed in the presence of a condensing agent. Examples of the condensing agent include dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylamino) A carbodiimide reagent such as propyl) carbodiimide and isopropylcarbodiimide can be used. Further, in this step, using the condensing agent, the epoxycarboxylic acid derivative (IV) is condensed with N-hydroxysuccinimide, p-nitrophenol, 1-hydroxybenzotriazole, or the like to form an active ester, and then an amine ( V).

The epoxycarboxylic acid amide derivative represented by the general formula (I) can be converted into an α-ketoamide derivative (X) having cathepsin K inhibitory activity, for example, by subjecting it to the following reaction.

[0036]

Embedded image (Wherein, R 1 and R 2 are the same as R 1 and R 2 in the formula (I). R 6 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aromatic group) A hydrocarbon group, a substituted or unsubstituted heterocyclic group, R9-O- or R10-N (R11)-.
Is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aromatic hydrocarbon group, or a substituted or unsubstituted heterocyclic group. R10 and R11 are the same or different and are the same as a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, or R10. R11 may be combined to form a ring. R7 and R8 are the same as R10 and R
The same groups as in 11 can be mentioned, and R7 and R8 can be combined to form a ring. X is -O- or -N
(R12)-, wherein R12 may form a ring together with a hydrogen atom, a substituted or unsubstituted alkyl group or R7 or R8. )

(Step 2-1) In this step, the epoxycarboxylic acid amide derivative represented by the general formula (I) is
This is a step of stereoselectively producing the azide derivative represented by the general formula (VI) by regioselectively opening the ring.

As the ring-opening reagent used in this step, sodium azide-anhydrous magnesium sulfate can be used, and ammonium chloride can be used instead of anhydrous magnesium sulfate. As the reaction solvent, for example, an alcohol solvent such as methanol, ethanol, propanol, and 2-methoxyethanol, acetonitrile, and the like can be used. The reaction can be performed at a reaction temperature of 50 ° C to 150 ° C.

(Step 2-2) In this step, the azide derivative represented by the general formula (VI) is reduced,
This is a step of producing the amine derivative represented by the general formula (VII) while maintaining the three-dimensional structure.

As the reduction reaction used in this step, a catalytic reduction method can be used.
C, Pd-black or the like can be used. As the reaction solvent, an alcohol solvent such as methanol or ethanol can be used, and the reaction can be carried out at a temperature from room temperature to 40 ° C. In this step, reduction may be performed using triphenylphosphine and water, and it is preferable to use an ether solvent such as tetrahydrofuran or dioxane as a reaction solvent.

(Step 2-3) In this step, the amine derivative represented by the general formula (VII) and the amine derivative represented by the general formula (VIII)
By condensing with a carboxylic acid derivative represented by
This is a step of producing the amino alcohol derivative represented by the general formula (IX) while maintaining the three-dimensional structure.

This step is a condensation reaction.
The production can be carried out using the same reaction reagents and reaction conditions as in the step.

(Step 2-4) This step is a step of oxidizing the amino alcohol derivative represented by the general formula (IX) to produce an α-keto amide derivative represented by the general formula (X). is there.

As the oxidation reaction used in this step, for example, an active dimethyl sulfoxide oxidation method can be used. As the oxidizing agent, dimethyl sulfoxide is used, and an activating agent such as dicyclohexylcarbodiimide, phosphorus pentoxide, pyridine-sulfur trioxide complex, oxazalyl chloride, acetic anhydride, trifluoroacetic acid and the like is used in combination. The activator can be used in an amount of 1 to 12 equivalents to the amino alcohol derivative represented by the general formula (VIII). The reaction is preferably carried out in a solvent. For example, halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane can be used, but dimethyl sulfoxide used as an oxidizing agent can be used in an excess amount as a solvent. The reaction can be carried out at -78C to 30C.

[0045]

DESCRIPTION OF THE PREFERRED EMBODIMENTS Hereinafter, the present invention will be described in more detail with reference to Reference Examples and Examples. Reference Example 1 Synthesis of 1-aminocyclohexanecarboxylic acid phenylmethyl ester / p-toluenesulfonic acid salt

Embedded image 50.8 g of 1-aminocyclohexanecarboxylic acid (35
5 mmol), 81 g of p-toluenesulfonic acid monohydrate
(426 mmol), 180 ml of benzyl alcohol and 360 ml of toluene were placed in a flask, and an oil bath (160 was used) using a Dean-Stark apparatus equipped with a reflux condenser.
C) overnight. The generated water was removed by azeotropic distillation with toluene. After completion of the reaction, the reaction solution was poured into a large amount of ethyl acetate to precipitate crystals. The crystals were washed again with ethyl acetate to obtain 128 g (89%) of the title compound.

1H-NMR (CDCl3, δ): 1.25
-1.43 (2H, m), 1.43-1.58 (2H,
m), 1.59-1.70 (2H, m), 1.83-1.9
4 (2H, m), 1.94-2.02 (2H, m), 2.8
3 (3H, s), 5.13 (2H, s), 7.10 (2H, s)
d, J = 8Hz), 7.24-7.31 (5H, m),
7.76 (2H, d, J = 8 Hz), 8.30 (2H, b
rs) IR (v, KBr, cm-1): 3468, 1746, 1
608 FAB-Mass (m / z,%): 406 (M ++ 1,
2), 234 (100)

Reference Example 2 Synthesis of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester

Embedded image 1-aminocyclohexanecarboxylic acid phenylmethyl ester p-toluenesulfonate 203 g (50
(0 mmol) was neutralized with a 10% sodium carbonate solution, extracted with chloroform, and dried over anhydrous magnesium sulfate.
The solid was filtered, 56 g (550 mmol) of triethylamine was added to the chloroform layer, 75 g (500 mmol) of 4-morpholinecarbonyl chloride was added dropwise, and the mixture was heated in an oil bath (60 ° C.) for 3 days. After completion of the reaction, the reaction solution was washed with water, a 10% aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride in that order, and dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the obtained crystals were washed with ether to give the title compound (1).
51 g (87%) were obtained.

1H-NMR (CDCl3, δ): 1.22
-1.88 (6H, m), 1.85-1.92 (2H,
m), 2.07-2.30 (2H, m), 3.45 (4H,
t, J = 5 Hz), 3.67 (4H, t, J = 5H)
z), 4.53 (1H, s), 5.15 (2H, s),
7.31-7.34 (5H, m) IR (ν, KBr, cm −1): 3316, 1732, 1
690 FAB-Mass (m / z,%): 347 (M ++ 1,
100), 234 (44)

Reference Example 3 Synthesis of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid

Embedded image 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid phenylmethyl ester 15
1 g (452 mmol) is suspended in methanol and 5%
15 g of palladium-active carbon was added, and the mixture was stirred overnight at room temperature under a hydrogen stream. After filtering the catalyst, the catalyst was washed three times with a mixed solvent of chloroform-methanol, and the organic layers were combined and distilled off under reduced pressure to obtain 112 g (100%) of the title compound.

1H-NMR (CDCl3, δ): 1.35
-1.39 (3H, m), 1.64-1.72 (3H,
m), 1.91-1.97 (2H, m), 2.06-2.1
0 (2H, m), 3.43 (4H, t, J = 5Hz),
3.73 (4H, t, J = 5 Hz), 4.50 (1H,
s) IR (ν, KBr, cm −1): 3824, 2568, 1
970 FAB-Mass (m / z,%): 257 (M ++ 1,
8), 98 (100)

Reference Example 4 Synthesis of 2-heptin-1-ol

Embedded image 6.0 g (0.9 mol) of lithium was added to a solution of 180 mg (0.45 mmol) of iron (III) nitrate nonahydrate in 300 ml of liquid ammonia at -30 to -40 ° C. At the same temperature, 25.2 g of 2-propyn-1-ol (0.45 mol
After stirring for 1.5 hours, 41.1 g (0.30 mol) of N-butyl bromide was added.
Was added. The reaction solution was returned to room temperature and stirred overnight. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ether (500 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to give the title compound, 21.0 g (6
2.4%).

1H-NMR (CDCl3, δ): 0.91
(3H, t, J = 7 Hz), 1.36-1.54 (5H,
m), 2.22 (2H, tt, J = 7Hz, 2Hz),
4.25 (1H, dt, J = 6Hz, 2Hz)

Reference Example 5 Synthesis of (trans) -2-hepten-1-ol

Embedded image Under ice-cooling, 65% sodium bis (2-methoxyethoxy) aluminum hydride (Red-Al) toluene solution 1
6 ml (53.49 mmol) of toluene solution of 4.0 g (35.66 mmol) of 2-heptin-1-ol (5.
ml), and the mixture was returned to room temperature and stirred for 3 hours. After the reaction was completed, ice water was added, and the mixture was extracted with petroleum ether (50 ml).
The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 3.3 g (80.6%) of the title compound.

1H-NMR (CDCl3, δ): 0.90
(3H, t, J = 7 Hz), 1.27-1.41 (5H,
m), 2.31 (2H, dt, J = 7Hz, 6Hz),
4.09 (2H, dd, J = 5 Hz, 5 Hz), 5.60
-5.74 (2H, m)

Reference Example 6 Synthesis of (2R-trans) -3-butyloxirane methanol

Embedded image Under argon atmosphere, molecular sieves 4A 3.4g
In anhydrous methylene chloride suspension (150 ml)
3.3 g of (-)-diisopropyl tartrate (14.08 mm
ol), 3.3 g of titanium tetraisopropoxide (11.
73 mmol) and 2-hepten-1-ol 13.4
g (117.30 mmol) was added at −30 to −40 ° C., and the mixture was stirred for 10 minutes. The reaction solution was cooled to −60 ° C., and 105 ml of a toluene solution of 2.23 Mt-butyl hydroperoxide was added dropwise with stirring over 20 minutes, and the temperature was returned to room temperature over 2 hours. After completion of the reaction, the reaction solution was treated with an aqueous solution of iron (III) sulfate heptahydrate (80 g) and L-tartaric acid (40 g) (40 g).
0 ml) and extracted with methylene chloride (400 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue contains ether (4
00 ml) and 1N sodium hydroxide (200 ml)
Was added and stirred at room temperature for 1 hour. After completion of the reaction, the organic layer was separated, and the aqueous layer was extracted with ether (50 ml). The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was distilled under reduced pressure to obtain 11.6 g (76.2%) of the title compound.

1H-NMR (CDCl3, δ): 0.92
(3H, t, J = 7 Hz), 1.34-1.48 (4H,
m), 1.56-1.61 (2H, m), 1.73 (1H,
brs), 2.91-2.98 (2H, m), 3.63.
(1H, ddd, J = 12Hz, 8Hz, 4Hz), 3.
92 (1H, ddd, J = 12 Hz, 6 Hz, 3 Hz) IR (ν, NaCl (film), cm −1): 345
6,2936,2864,1470,1030,880 FAB-Mass (m / z,%): 131 (M ++ 1,
58), 113 (84), 95 (100), 69 (9
3)

Reference Example 7 Synthesis of (2S-trans) -3-butyl-oxiranecarboxylic acid / dicyclohexylamine salt

Embedded image Under ice-cooling, a mixed solution of 1.30 g (10 mmol) of (2R-trans) -3-butyloxirane methanol in 20 ml of acetonitrile, 20 ml of carbon tetrachloride and 30 ml of water was added with 5.70 g (25 mmol) of periodic acid and then ruthenium chloride After addition of 41 mg of hydrate,
Stirred for hours. Ethyl acetate was added to the reaction solution, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The insolubles were filtered off and the filtrate was added with dicyclohexylamine 1.63.
After adding g (9 mmol), the solvent was distilled off under reduced pressure. Petroleum ether was added to the obtained residue, and the mixture was stirred for 2 hours. The crystals were collected by filtration and washed with petroleum ether to give 2.30 g (70%) of the title compound.

1H-NMR (CDCl3, δ): 0.91
(3H, t, J = 7 Hz), 1.10-1.30 (6H,
m), 1.31-1.57 (9H, m), 1.58-1.7
1 (3H, m), 1.74-1.82 (4H, m), 1.
96-2.04 (4H, m), 2.90-2.94 (1H,
m), 2.97-3.06 (2H, m), 3.08 (1H,
d, J = 2 Hz) IR (ν, KBr, cm −1): 2932, 2856, 1
604, 1400 FAB-Mass (m / z,%): 326 (M ++ 1,
7), 182 (100)

Example 1 Synthesis of (2S-trans) -N-[(1S, 2S) -2-hydroxycyclohexane-1-yl] -3-butyloxiranecarboxamide

Embedded image Under ice cooling, 2.3 g of (2S-trans) -3-butyloxiranecarboxylic acid and dicyclohexylamine salt (7 m
mol) was added to a solution of 844 mg (7 mmol) of pivaloyl chloride in 2 ml of anhydrous tetrahydrofuran, and the mixture was stirred at the same temperature for 15 minutes. Further, the reaction solution was returned to room temperature and stirred for 2 hours. After filtration of the insolubles in the reaction solution, (1S, 2S) -2
806 mg (7 mmol) of aminocyclohexanol
Was added to a solution of 20 ml of anhydrous tetrahydrofuran, followed by stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 1.69 g (100%) of the title compound.

@ 1 H-NMR (CDCl3, .delta.): 0.92
(3H, t, J = 7 Hz), 1.11-1.48 (8H,
m), 1.52-1.62 (1H, m), 1.64-1.
76 (3H, m), 1.83-1.89 (1H, m),
2.03-2.10 (1H, m), 2.90-2.95 (1
H, m), 3.27 (1H, d, J = 2 Hz), 3.3
0-3.38 (1H, m), 3.54-3.65 (1H,
m), 6.13 (1H, d, J = 8 Hz) IR (ν, KBr, cm −1): 2932, 2860, 1
650 FAB-Mass (m / z,%): 242 (M ++ 1,
100), 98 (95)

Reference Example 8 Synthesis of (2S, 3S) -N-[(1S, 2S) -2-hydroxycyclohexane-1-yl] -3-azido-2-hydroxyheptanamide

Embedded image 1.64 g (7 mmol) of (2S-trans) -N-[(1S, 2S) -2-hydroxycyclohexane-1-yl] -3-butyloxiranecarboxamide, 910 mg (14 mmol) of sodium azide and 868 mg of anhydrous magnesium sulfate ( A suspension of 7.2 mmol) in 30 ml of methanol was heated at reflux for 5 hours. After returning the reaction solution to room temperature, it was poured into 300 ml of water and stirred for 2 hours.
The crystals were collected by filtration, washed with water, and dried to give 1.45 g (73%) of the title compound.

1 H-NMR (CDCl 3, δ): 0.91
(3H, t, J = 7 Hz), 1.19-1.53 (9H,
m), 1.58-1.78 (3H, m), 1.89-1.
98 (1H, m), 2.03-2.11 (1H, m),
3.31-3.39 (1H, m), 3.52 (1H, d,
J = 6 Hz), 3.61-3.71 (2H, m), 4.1
5 (1H, d, J = 4 Hz), 4.29 (1H, t, J
= 4 Hz), 6.78 (1H, d, J = 8 Hz) IR (ν, KBr, cm −1): 2936, 2864, 2
096, 1636 FAB-Mass (m / z,%): 285 (M ++ 1,
100), 116 (97)

Reference Example 9 Synthesis of (2S, 3S) -N-[(1S, 2S) -2-hydroxycyclohexane-1-yl] -3-amino-2-hydroxyheptanamide

Embedded image 150 mg of 5% palladium on carbon in a solution of 1.45 g (5 mmol) of (2S, 3S) -N-[(1S, 2S) -2-hydroxycyclohexan-1-yl] -3-azido-2-hydroxyheptanamide in 30 ml of methanol Was added and stirred under a hydrogen atmosphere for 18 hours. The insolubles were filtered off, and the filtrate was evaporated under reduced pressure to give 1.18 g of the title compound (9
1%).

@ 1 H-NMR (CDCl3, .delta.): 0.90
(3H, t, J = 7Hz), 1.18-1.43 (8H,
m), 1.51-1.77 (4H, m), 1.89-1.1.9
7 (1H, m), 2.02-2.09 (1H, m), 3.
03-3.09 (1H, m), 3.31-3.39 (1H,
m), 3.61-3.69 (1H, m), 3,90 (1
H, d, J = 6 Hz), 7.31 (1H, d, J = 8H)
z) IR (ν, KBr, cm −1): 3344, 2936, 2
860, 1650 FAB-Mass (m / z,%): 259 (M ++ 1,
100), 86 (92)

Reference Example 10 N-[(2S, 3S) -2-hydroxy-1- [N-
[(1S, 2S) -2-hydroxycyclohexane-1
-Yl] amino] -1-oxo-3-heptyl] -1
Synthesis of-[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

Embedded image Under ice-cooling, 256 mg of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid (1 mmol
l) and a solution of 121 mg (1 mmol) of pivaloyl chloride in 1 ml of anhydrous tetrahydrofuran were added to a solution of 202 mg (2 mmol) of triethylamine in 10 ml of anhydrous tetrahydrofuran, and the mixture was stirred at the same temperature for 2 hours. Further, the reaction solution was returned to room temperature and stirred for 18 hours. The insolubles in the reaction solution were filtered and the (2S, 3S) -N-[(1S, 2S)
258 mg of 2--2-hydroxycyclohexane-1-yl] -3-amino-2-hydroxyheptanamide (1 m
mol) in 80 ml of chloroform and stirred for 3 hours. Chloroform was added to the reaction solution, and the mixture was washed with a 10% aqueous solution of potassium hydrogen sulfate, a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to give 468 mg of the title compound.
(94%).

@ 1 H-NMR (CDCl3, .delta.): 0.88
(3H, t, J = 7 Hz), 1.17-1.44 (11
H, m), 1.45-1.58 (1H, m), 1.59-
1.77 (6H, m), 1.82-1.97 (4H, m),
2.01-2.07 (2H, m), 3.31-3.44 (5
H, m), 3.59-3.69 (1H, m), 3.72
(4H, t, J = 5 Hz), 3.76 (1H, d, J =
4Hz), 4.05-4.14 (2H, m), 4.75
(1H, s), 5.02 (1H, d, J = 6 Hz), 6.
56 (1H, d, J = 8 Hz), 7.03 (1H, d,
J = 8 Hz) IR (ν, KBr, cm −1): 3380, 2931, 2
859, 1675, 1629 FAB-Mass (m / z,%): 497 (M ++ 1,
55), 211 (100)

Reference Example 11 N-[(S) -1,2-dioxo-1- [N-[(S)
Synthesis of 2-oxocyclohexyl] amino] -3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

Embedded image Under a nitrogen stream at 0 ° C., 1.45 g (11.2 mmol) of N, N-diisopropylethylamine was added to 1.78 g (11.2 mmol) of sulfur pyridine complex complex in anhydrous dimethyl sulfoxide (5 ml) and anhydrous methylene chloride (5 m).
l) It was added dropwise to the solution. Further, N-[(2S, 3S)
-2-Hydroxy-1- [N-[(1S, 2S) -2-
Hydroxycyclohexane-1-yl] amino] -1-
Oxo-3-heptyl] -1- [N- (morpholine-4
A solution of 465 mg (0.94 mmol) of-(carbonyl) amino] cyclohexanecarboxamide in anhydrous methylene chloride (5 ml) was added, and the mixture was stirred at 0 ° C for 3 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to give the title compound (402 m).
g (87%).

1H-NMR (CDCl3, δ): 0.88
(3H, t, J = 7 Hz), 1.23-1.46 (8H,
m), 1.56-2.00 (10H, m), 2.03-2.
20 (3H, m), 2.36-2.70 (3H, m),
3.39 (4H, t, J = 5 Hz), 3.72 (4H, t,
J = 5Hz), 4.36-4.47 (1H, m), 4.4
6 (1H, s), 5.20-5.25 (1H, m), 7.
76 (1H, d, J = 6 Hz), 7.93 (1H, d,
J = 7 Hz) IR (ν, KBr, cm −1): 3380, 2931,
2859, 1675, 1629 FAB-Mass (m / z,%): 493 (M ++ 1,
25), 239 (54), 211 (100)

Example 2 Synthesis of (2S-trans) -N-butyl-3-butyloxiranecarboxamide

Embedded image Under ice-cooling, (2S-trans) -3-butyl-oxiranecarboxylic acid, 299 mg of dicyclohexylamine salt
(1.84 mmol) of anhydrous tetrahydrofuran 10 m
To the solution, 222 mg of pivaloyl chloride (1.84 mm
ol) in 2 ml of anhydrous tetrahydrofuran, and the mixture was stirred at the same temperature for 15 minutes. Further, the reaction solution was returned to room temperature and stirred for 2 hours. After filtering the insolubles in the reaction solution, under ice cooling,
To a solution of 135 mg (1.84 mmol) of N-butylamine in 10 ml of anhydrous tetrahydrofuran,
Stirred for hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 366 mg (100%) of the title compound.

1H-NMR (CDCl3, δ): 0.93
(3H, t, J = 7 Hz), 0.94 (3H, t, J =
7Hz), 1.26-1.70 (10H, m), 2.89
-2.93 (1H, m), 3.17-3.25 (3H,
m), 6.10 (1H, s) IR (ν, NaCl, cm −1): 2932, 2872,
1662

Reference Example 12 Synthesis of (2S, 3S) -N-butyl-3-azido-2-hydroxyheptanamide

Embedded image 366 mg (1.84 mmol) of (2S-trans) -N-butyl-3-butyloxiranecarboxamide,
239 mg (3.68 mmol) of sodium azide and 228 mg (1.89 mmol) of anhydrous magnesium sulfate
Of methanol in 30 ml was heated under reflux for 5 hours.
After returning the reaction solution to room temperature, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 304 mg (68%) of the title compound.

@ 1 H-NMR (CDCl3, .delta.): 0.93
(3H, t, J = 7 Hz), 0.95 (3H, t, J =
7Hz), 1.20-1.70 (10H, m), 2.86
(1H, d, J = 4 Hz), 3.25-3.35 (2H,
m), 3.68-3.72 (1H, m), 4.21 (1H,
t, J = 4 Hz), 6.54 (1H, brs) IR (ν, NaCl, cm −1): 2960, 2872,
2100, 1648

Reference Example 13 Synthesis of (2S, 3S) -N-butyl-3-amino-2-hydroxyheptanamide

Embedded image 30 mg of 5% palladium carbon was added to a solution of 304 mg (1.25 mmol) of (2S, 3S) -N-butyl-3-azido-2-hydroxyheptanamide in 30 ml of methanol.
Was added and stirred under a hydrogen atmosphere for 18 hours. The insoluble material was filtered, and the filtrate was distilled off under reduced pressure to give 254 mg of the title compound.
(94%).

@ 1 H-NMR (CDCl3, .delta.): 0.91
(3H, t, J = 7 Hz), 0.93 (3H, t, J =
7Hz), 1.18-1.80 (10H, m), 3.01
-3.50 (1H, m), 3.23-3.29 (3H,
m), 3.83 (1H, d, J = 5 Hz), 7.45 (1
H, brs) IR (ν, KBr, cm −1): 3320, 2932, 2
860, 1642

Reference Example 14 N-[(2S, 3S) -2-hydroxy-1- [N-
(Butyl) amino] -1-oxo-3-heptyl] -1
Synthesis of-[N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide

Embedded image 254 mg (1.21 mmol) of (2S, 3S) -N-butyl-3-amino-2-hydroxyheptanamide,
310 mg of 1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid (1.21 mmol)
1) and 1-hydroxybenzotriazole 230
(1.45 mmol) was dissolved in anhydrous methylene chloride, followed by 278 mg (1.4 mg) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide at 0 ° C under a nitrogen stream.
5 mmol) was added. Thereafter, the reaction solution was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 80 ml of ethyl acetate, washed sequentially with water, 10% aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 489 mg (89%) of the title compound.

@ 1 H-NMR (CDCl3, .delta.): 0.87
(3H, t, J = 7 Hz), 0.94 (3H, t, J =
7Hz), 1.24-1.41 (8H, m), 1.45-
1.78 (8H, m), 1.84-1.94 (2H, m),
1.98-2.05 (2H, m), 3.18-3.30 (2
H, m), 3.70 (4H, t, J = 5 Hz), 3.89
(4H, t, J = 5 Hz), 4.10-4.14 (1H,
m), 4.26 (1H, dd, J = 6Hz, 6Hz),
4.65 (1H, s), 5.18 (1H, d, J = 6H
z), 6.73 (1H, d, J = 8 Hz), 6.80 (1
H, brs) IR (ν, KBr, cm −1): 3368, 2932, 2
860, 1650

Reference Example 15 N-[(S) -1,2-dioxo-1- [N- (butyl) amino] -1-oxo-3-heptyl] -1- [N
Synthesis of-[(morpholine-4-carbonyl) amino] cyclohexanecarboxamide

Embedded image Under a nitrogen stream, at 0 ° C., 838 mg (6.48 mmol) of N, N-diisopropylethylamine was added to 1.03 g (6.48 mmol) of sulfur trioxide complex salt in anhydrous dimethyl sulfoxide (5 ml) and anhydrous methylene chloride (5 ml).
l) It was added dropwise to the solution. Further, N-[(2S, 3S)-
2-hydroxy-1- [N- (butyl) -amino] -1
-Oxo-3-heptyl] -1- [N- (morpholine-
A solution of 489 mg (1.08 mmol) of 4-carbonyl) amino] cyclohexanecarboxamide in anhydrous methylene chloride (5 ml) was added, and the mixture was stirred at 0 ° C for 3 hours. After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to give the title compound (415 m).
g (85%).

1 H-NMR (CDCl 3, δ): 0.88
(3H, t, J = 7 Hz), 0.93 (3H, t, J =
7Hz), 1.22-1.42 (9H, m), 1.49-
1.70 (6H, m), 1.85-2.00 (3H, m),
2.06-2.15 (2H, m), 3.26-3.38 (2
H, m), 3.38 (4H, t, J = 5 Hz), 3.72
(4H, t, J = 5Hz), 4.44 (1H, s), 5.
17-5.20 (1H, m), 6.86 (1H, t, J =
6 Hz), 7.94 (1 H, d, J = 7 Hz) IR (ν, KBr, cm −1): 3344, 2932, 2
860, 1658

Example 3 Synthesis of (2S-trans) -N-[(2S) -1-methoxy-1-oxo-3-phenyl-2-propyl] -3-butyloxiranecarboxamide

Embedded image Under ice cooling, (2S-trans) -3-butyloxiranecarboxylic acid, 299 mg of dicyclohexylamine salt
(1.84 mmol) of anhydrous tetrahydrofuran 10 m
To the solution, 222 mg of pivaloyl chloride (1.84 mm
ol) in 2 ml of anhydrous tetrahydrofuran, and the mixture was stirred at the same temperature for 15 minutes. Further, the reaction solution was returned to room temperature and stirred for 2 hours. After filtering the insolubles in the reaction solution, under ice cooling,
After adding 187 mg (1.84 mmol) of triethylamine, 397 mg (1.84 mmol) of L-phenylalanine methyl ester hydrochloride was added, and the mixture was added at room temperature.
Stirred for hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with a 10% aqueous potassium hydrogen sulfate solution, a saturated aqueous sodium hydrogen carbonate solution, and then a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 558 mg (100%) of the title compound.

@ 1 H-NMR (CDCl3, .delta.): 0.91
(3H, t, J = 7 Hz), 1.20-1.45 (4H,
m), 1.46-1.63 (2H, m), 2.58-2.6
1 (1H, m), 3.01 (1H, dd, J = 14 Hz,
7Hz), 3.16 (1H, d, J = 2Hz), 3.2
0 (1H, dd, J = 14Hz, 7Hz), 3.74
(3H, s), 4.81-4.87 (1H, m), 6.4
8 (1H, d, J = 8 Hz), 7.05-7.10 (2H,
m), 7.24-7.31 (3H, m) IR (v, NaCl, cm-1): 2960, 2868,
1684

Reference Example 16 (2S, 3S) -N-[(2S) -1-methoxy-1-
Oxo-3-phenyl-2-propyl] -3-azido-
Synthesis of 2-hydroxyheptaneamide

Embedded image 558 mg (1.84 mmol) of (2S-trans) -N-[(2S) -1-methoxy-1-oxo-3-phenyl-2-yl] -3-butyloxiranecarboxamide
l), 239 mg of sodium azide (3.68 mmol
l) and anhydrous magnesium sulfate 228 mg (1.89 m
(mol) of methanol was heated to reflux for 5 hours. After returning the reaction solution to room temperature, the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed with water and then with saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 442 mg (69%) of the title compound.

@ 1 H-NMR (CDCl3, .delta.): 0.90
(3H, t, J = 7 Hz), 1.21-1.62 (6H,
m), 2.87 (1H, d, J = 4 Hz), 3.09 (1
H, dd, J = 14Hz, 7Hz), 3.16 (1H,
dd, J = 14 Hz, 7 Hz), 3.59-3.63 (1
H, m), 3.75 (3H, s), 4.20 (1H, d
d, J = 4 Hz, 4 Hz), 4.88-4.93 (1H,
m), 7.00 (1H, d, J = 8 Hz), 7.14 (2
H, d, J = 8 Hz), 7.25-7.33 (3H, m) IR (ν, KBr, cm −1): 2856, 2100, 1
658

Reference Example 17 (2S, 3S) -N-[(2S) -1-methoxy-1-
Oxo-3-phenyl-2-propyl] -3-amino-
Synthesis of 2-hydroxyheptaneamide

Embedded image (2S, 3S) -N-[(2S) -1-methoxy-1-
Oxo-3-phenyl-2-propyl] -3-azido-
442 mg of 2-hydroxyheptanamide (1.27 m
(mol)) in 30 ml of methanol was added with 45 mg of 5% palladium on carbon, and the mixture was stirred under a hydrogen atmosphere for 18 hours.
The insolubles were filtered off and the filtrate was evaporated under reduced pressure to give the title compound 3
85 mg (94%) were obtained.

@ 1 H-NMR (CDCl3, .delta.): 0.89
(3H, t, J = 7 Hz), 1.18-1.70 (6H,
m), 2.86-2.91 (1H, m), 3.06 (1H,
dd, J = 14Hz, 7Hz), 3.18 (1H, dd,
14Hz, 7Hz), 3.73 (3H, s), 3.76
(1H, d, J = 7 Hz), 4.86-4.92 (1H, d, J = 7 Hz)
m), 7.15 (1H, d, J = 7 Hz), 7.21-
7.31 (5H, m), 8.15 (1H, d, J = 8H
z) IR (ν, KBr, cm −1): 3364, 2956, 2
860, 1652

Reference Example 18 N-[(2S, 3S) -2-hydroxy-1- [N-
Of [(2S) -1-methoxy-1-oxo-3-phenyl-2-propyl] amino] -1-oxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide Synthesis

Embedded image (2S, 3S) -N-[(2S) -1-methoxy-1-
Oxo-3-phenyl-2-yl] -3-amido-2-
385 mg of hydroxyheptaneamide (1.19 mmol
l), 305 mg of 1 .- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxylic acid (1.19 m
mol) and 1-hydroxybenzotriazole 226
(1.43 mmol) was dissolved in anhydrous methylene chloride, followed by 274 mg (1.4 mg) of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide at 0 ° C under a nitrogen stream.
3 mmol) was added. Thereafter, the reaction solution was returned to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 80 ml of ethyl acetate, washed sequentially with water, 10% aqueous potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 587 mg (88%) of the desired product.

1H-NMR (CDCl3, δ): 0.86
(3H, t, J = 7 Hz), 1.20-1.70 (12
H, m), 1.80-1.90 (2H, m), 1.92-
2.02 (2H, m), 3.05-3.17 (2H, m),
3.36 (4H, t, J = 5 Hz), 3.69 (4H,
t, J = 5 Hz), 3.70 (3H, s), 4.09-4.
14 (1H, m), 4.34 (1H, dd, J = 6 Hz,
6Hz), 4.63 (1H, s), 4.80-4.86
(1H, m), 5.00 (1H, d, J = 6 Hz), 6.
57 (1H, d, J = 8 Hz), 7.14 (1H, d,
J = 8 Hz), 7.20-7.30 (5H, m) IR (ν, KBr, cm −1): 3392, 2932, 2
860, 1658

Reference Example 19 N-[(S) -1,2-dioxo-1- [N-[(2
S) -1-Methoxy-1-oxo-3-phenyl-2-
Propyl] amino] -1-oxo-3-heptyl] -1
Synthesis of-[N-[(morpholine-4-carbonyl) amino] cyclohexanecarboxamide

Embedded image Under a nitrogen stream at 0 ° C., 814 mg (6.30 mmol) of N, N-diisopropylethylamine was added to 1.00 g (6.30 mmol) of sulfur trioxide complex salt in anhydrous dimethyl sulfoxide (5 ml) and anhydrous methylene chloride (5 ml).
l) It was added dropwise to the solution. Further, N-[(2S, 3S)-
2-hydroxy-1- [N-[(2S) -1-methoxy-1-oxo-3-phenyl-2-propyl] amino]
-1-Oxo-3-heptyl] -1- [N- (morpholine-4-carbonyl) amino] cyclohexanecarboxamide (587 mg, 1.05 mmol) in anhydrous methylene chloride (5 ml) was added, and the mixture was stirred at 0 ° C for 3 hours. . After completion of the reaction, ice water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by neutral silica gel column chromatography to give the title compound 4.
87 mg (83%) were obtained.

1H-NMR (CDCl3, δ): 0.87
(3H, t, J = 7 Hz), 1.20-1.42 (7H,
m), 1.54-1.76 (4H, m), 1.80-1.9
6 (3H, m), 2.05-2.18 (2H, m), 3.
06-3.18 (2H, m), 3.36 (4H, t, J =
5Hz), 3.71 (4H, t, J = 5Hz), 3.72
(3H, s), 4.46 (1H, d, J = 6 Hz), 4.
80-4.85 (1H, m), 5.17-5.19 (1H,
m), 7.09 (1H, d, J = 8 Hz), 7.12 (1
H, dd, J = 8 Hz, 2 Hz), 7.23-7.31
(4H, m), 7.96 (1H, d, J = 7 Hz) IR (ν, KBr, cm −1): 2932, 2860, 1
678

[0089]

According to the present invention, a novel epoxycarboxylic acid amide derivative can be provided. The derivative is an α-ketoamide derivative having protease inhibitory activity.
It can be used as a production intermediate which can be derived very economically and stereoselectively.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takashi Fujita 2-62-5 Nihonbashi-Hamacho, Chuo-ku, Tokyo Inside Fujirebio Inc. (72) Inventor Satoshi Nishimura 2-62-5 Nihonbashi-Hamacho, Chuo-ku, Tokyo Fujirebio Inc. (72) Inventor Akihiko Hosoda 2-62-5 Nihonbashi-hama-cho, Chuo-ku, Tokyo F-rebio Inc. F-term (reference) 4C048 AA01 BB29 CC01 UU03 XX04

Claims (11)

[Claims] 1. A compound of the general formula An epoxycarboxylic acid amide derivative represented by the formula:
1 is a substituted or unsubstituted linear, branched or cyclic alkyl group, the substituent of the alkyl group is a substituted or unsubstituted aromatic hydrocarbon group, a substituted or unsubstituted heterocyclic group, It is a substituted or unsubstituted alkoxyl group, a substituted or unsubstituted alkylthio group, a substituted or unsubstituted aryloxy group, or a substituted or unsubstituted arylthio group. R 2 is a substituted or unsubstituted linear, branched or cyclic alkyl group, and the substituent of the alkyl group is a hydroxyl group, an oxo group, a halogen atom, a substituted or unsubstituted C 2-6 Linear, branched or cyclic alkenyl group, substituted or unsubstituted heterocyclic group, nitro group,
A substituted or unsubstituted amino group, a substituted or unsubstituted sulfonyl group, a substituted or unsubstituted alkoxyl group,
A substituted or unsubstituted alkylthio group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted arylthio group, a substituted or unsubstituted alkoxycarbonyl group, a substituted carbamoyl group, a substituted sulfonamide group, a substituted amide group, a mercapto group, or It is a cyano group. ). 2. A compound of the general formula The epoxycarboxylic acid amide derivative according to claim 1, which is represented by the following formula: 3. A compound of the general formula The epoxycarboxylic acid amide derivative according to claim 1, which is represented by the following formula: 4. A compound of the general formula The epoxycarboxylic acid amide derivative according to claim 1, which is represented by the following formula: 5. A compound of the general formula The epoxycarboxylic acid amide derivative according to claim 1, represented by 6. The method according to claim 1, wherein R 1 is an unsubstituted alkyl group.
6. The epoxycarboxylic acid amide derivative according to any one of claims 1 to 5. 7. The epoxycarboxylic amide derivative according to claim 6, wherein R1 is an n-butyl group. 8. The epoxycarboxylic acid amide derivative according to claim 1, wherein R2 is a substituted or unsubstituted cyclic alkyl group. 9. The epoxycarboxylic amide derivative according to claim 8, wherein R2 is a substituted or unsubstituted cyclohexyl group. 10. The epoxycarboxamide derivative according to claim 8, wherein the substituent on the alkyl group of R2 is a hydroxyl group. 11. R2 has the structural formula: The epoxycarboxylic acid amide derivative according to claim 10, which is represented by the following formula: