JP2007126358A - Phenylalanine derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound having excellent VLA-4 inhibitory activity. <P>SOLUTION: This phenylalanine derivative is represented by general formula (1) [wherein R<SP>1</SP>represents a lower alkyl group, a 3-10C cycloalkyl group, a heterocyclic group, or a 6-10C aromatic hydrocarbon group; Z represents a phenyl group, benzoylamino group, pyridylcarbonylamino group, aralkyloxy group, morpholine-N-carboxy group, or phthalimido-N-yl group, R<SP>2</SP>represents a hydrogen atom or a lower alkyl group; n represents a number of 0 or 1; and when n is 0, Y represents NOR<SP>3</SP>(wherein R<SP>3</SP>represents a hydrogen atom, methyl group, or phenyl group), CCl<SB>2</SB>, CHCL, C(CL)CH<SB>3</SB>, C(CH<SB>3</SB>)OCH<SB>3</SB>, CHCH<SB>3</SB>, CHph, etc.; when n is 1, Y represents NOR<SP>3</SP>(wherein R<SP>3</SP>represents the same as before); A represents a phenyl group, B represents a hydrogen atom, or a lower alkyl group, or A and B may bond to form a cyclopentane ring, cyclohexane ring, or oxane ring, or A and R<SP>1</SP>may bond to form a cyclopentane ring, or cyclohexane ring], and its salts are also included in the invention. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention has an excellent α ₄ integrin {VLA-4 (Very Late Angtigen-4) and α ₄ β ₇ } inhibitory action, and a therapeutic agent for various diseases caused by cell adhesion via α ₄ integrin. The present invention relates to a phenylalanine derivative useful as a salt thereof or a salt thereof and a medicine containing the same.

Since it has been clarified that cell adhesion is strongly involved in the onset and progression of various diseases, attempts have been made to prevent or treat diseases by inhibiting cell adhesion. Many molecules are involved in this cell adhesion. Among them, α ₄ integrin is considered to be the most important, and many α ₄ integrin inhibitors have been reported for the purpose of developing drugs by inhibiting cell adhesion. (Non-Patent Documents 1 to 3, Patent Documents 1 and 2).

That is, eosinophils, monocytes, lymphocytes and the like that play an important role in various inflammatory diseases are adhesion molecules expressed on the cell surface, VLA-4 (Very lateantigen-4, integrin α _4). VCAM-1 (Vascular cell adhesion molecule-1) or fibronectin CS-1 domain or MAdCAM-1 (Mucosal addressincell adhesion molecule-) expressed by inflammatory stimulation in vascular endothelial cells via β ₁ heterodimer or α ₄ β ₇ It is known to bind to 1). This cell adhesion phenomenon between leukocytes and endothelial cells or extracellular matrix is an important process in the inflammatory reaction and immune mechanism, and the subsequent migration and infiltration of inflammatory cells and immunocompetent cells into the inflammatory site Accompany. Thus, compounds that inhibit the adhesion of VLA-4 or alpha ₄ beta ₇ and VCAM-1 or CS-1 domain or MAdCAM-1 can be a drug for preventing or treating their adhesive disease.
Bioorganic & Medicinal Chemistry Letters, 10 (2000), 725-727 Drugs of the Future 2001, 26 (10): 985-998 Medicinal Research Reviews, Vol. 23, No. 3, 369-392, 2003 US Pat. No. 6,229,011 International Publication No. 01/12183 Pamphlet

However, the activity of conventional α ₄ integrin inhibitors is not yet sufficient, and it cannot always be said to be effective by oral administration. Accordingly, an object of the present invention has excellent alpha ₄ integrin inhibiting activity, and to provide orally administered compound.

Therefore, the present inventor has synthesized a large number of compounds using α ₄ integrin inhibitory activity as an index. As a result, the phenylalanine derivative represented by the following general formula (1) having an imino ether structure, a hydroxyimine structure or a methylidene structure or a salt thereof has excellent alpha ₄ integrin inhibiting activity, and found that oral administration is also possible, and completed the present invention.

  That is, the present invention provides the following general formula (1)

(In the formula, R ¹ represents a lower alkyl group which may be substituted by ¹ to 3 halogen atoms; a lower alkyl group, a lower alkoxy group, a lower alkylsulfanyl group or a carboxyl group which may be substituted by 3 carbon atoms. Or a cycloalkyl group optionally substituted by a lower alkyl group or a lower acyl group; or a nitro group, a hydroxy group, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylsulfanyl group, a lower group 1 to 3 groups selected from an alkylsulfinyl group, a lower alkylsulfonyl group, a halogeno lower alkyl group, an aralkyloxy group, a lower alkylamino group, a dilower alkylamino group, a cyano group, a carboxyl group, and an alkylenedioxy group are substituted. An aromatic hydrocarbon group having 6 to 10 carbon atoms which may be:
Z is a halogen atom, a lower alkyl group, a lower alkoxyalkyl group which may be substituted by a halogen atom, a lower alkylsulfanylalkyl group, a lower alkoxyalkyloxyalkyl group, a cycloalkyl (3 to 5 carbon atoms) oxyalkyl group, a halogen atom 1 to 3 selected from an allyloxyalkyl group which may be substituted, a crotyloxyalkyl group which may be substituted by a halogen atom, a hydroxyalkyl group, a lower alkoxy group and a lower alkylsulfanyl group may be substituted. A good phenyl group; a benzoylamino group or a pyridinecarbonylamino group which may be substituted by 1 to 3 halogen atoms; a group of 1 to 3 selected from a halogen atom, a lower alkyl group and a lower alkoxy group may be substituted Good aralkyloxy group; morpholine-N-carboxy group or It indicates phthalimido -N- yl group:
R ² represents a hydrogen atom or a lower alkyl group:
n represents the number 0 or 1:

When n is 1, Y represents NOR ³ (R ³ is the same as above):
A represents a phenyl group, B represents a hydrogen atom or a lower alkyl group, or A and B may be bonded to form a cyclopentane ring, a cyclohexane ring or an oxane ring, and A and R ¹ may be bonded. To form a cyclopentane ring or a cyclohexane ring. )
The phenylalanine derivative represented by these, or its salt is provided.
Moreover, this invention provides the pharmaceutical which uses the said phenylalanine derivative (1) or its salt as an active ingredient.

Since the compound of the present invention has excellent α ₄ integrin inhibitory activity, diseases caused by cell adhesion such as various inflammations (including eczema, psoriasis, contact dermatitis, atopic dermatitis as skin inflammation), rheumatoid arthritis, Allergic diseases including arthritis, bronchial asthma, allergic rhinitis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis), multiple sclerosis, collagen disease (systemic lupus erythematosus, etc.), transplant rejection, atherosclerosis, etc. It is useful as a preventive or therapeutic agent for

  In the various substituents of the general formula (1), examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. As the lower alkyl group, a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, n-butyl group, isopropyl group, isobutyl group, t-butyl group, n -A pentyl group, n-hexyl group, etc. are mentioned. As a lower alkoxy group, a C1-C6 linear or branched alkoxy group, for example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group etc. are mentioned. As a lower acyl group, a C1-C6 acyl group, for example, a formyl group, an acetyl group, a propionyl group, etc. are mentioned.

Examples of the lower alkylsulfanyl group include a linear or branched alkylsulfanyl group having 1 to 6 carbon atoms, such as a methylsulfanyl group and an ethylsulfanyl group. Examples of the lower alkylsulfinyl group include linear or branched alkylsulfinyl groups having 1 to 6 carbon atoms such as a methylsulfinyl group and an ethylsulfinyl group. As a lower alkylsulfonyl group, a C1-C6 linear or branched alkylsulfonyl group, for example, a methylsulfonyl group, an ethylsulfonyl group, etc. are mentioned. As the lower alkoxyalkyl group which may be substituted by halogen, C _1-6 alkoxy-C _1-6 alkyl group which may be substituted by 1 to 3 halogens such as methoxymethyl group, ethoxymethyl group, propoxymethyl Group, ethoxyethyl group, 2-fluoroethoxymethyl group, 2,2-difluoroethoxymethyl group, 2,2,2-trifluoroethoxymethyl group and the like. Examples of the lower alkylsulfanylalkyl group include a C _1-6 alkylsulfanyl-C _1-6 alkyl group such as a methylsulfanylmethyl group and an ethylsulfanylethyl group. Examples of the lower alkoxyalkyloxyalkyl group include a C _1-6 alkoxy-C _1-6 alkyloxy-C _1-6 alkyl group such as a methoxyethoxymethyl group and an ethoxyethoxyethyl group. Examples of the cycloalkyl (having 3 to 5 carbon atoms) oxyalkyl group include a cyclopropoxymethyl group and a cyclobutoxymethyl group. Examples of the allyloxyalkyl group that may be substituted with a halogen atom include an allyloxymethyl group. Examples of the crotyloxyalkyl group that may be substituted by a halogen atom include crotyloxyalkyl groups. Examples of the hydroxyalkyl group include a hydroxymethyl group. Examples of the halogeno lower alkyl group include a linear or branched alkyl group having 1 to 6 carbon atoms in which 1 to 3 halogen atoms are substituted, and examples thereof include a trifluoromethyl group and a chloroethyl group.

As a lower alkylamino group, a C1-C6 linear or branched alkylamino group is mentioned, For example, a methylamino group, an ethylamino group, etc. are mentioned. Examples of the di-lower alkylamino group include a di-C _1-6 alkylamino group, such as a dimethylamino group and a diethylamino group.

Examples of the aralkyloxy group include a phenyl-C _1-6 alkyloxy group, and examples thereof include a benzyloxy group and a phenylethyloxy group. Examples of the alkylenedioxy group include a methylenedioxy group and an ethylenedioxy group.

  Examples of the cycloalkyl group having 3 to 10 carbon atoms include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and an adamantyl group.

  Examples of the heterocyclic group include a 4-membered to 10-membered monocyclic or bicyclic heterocyclic group containing 1 or 2 selected from a nitrogen atom, an oxygen atom and a sulfur atom as a hetero atom, and these are saturated. But it may be unsaturated. Here, examples of the saturated heterocyclic group include a tetrahydrofuryl group, a tetrahydrothienyl group, a pyrrolidinyl group, an oxanyl group, a thianyl group, a piperidinyl group, a thianyl-S-oxide group, and a thianyl-S-dioxide group. Examples of unsaturated heterocyclic groups include furyl, thienyl, thiazolyl, pyridylthiazolyl, pyrrolyl, pyridyl, imidazolyl, indolyl, quinolyl, isoquinolyl, benzodioxolyl, etc. Can be mentioned.

  Examples of the aromatic hydrocarbon group having 6 to 10 carbon atoms include a phenyl group and a naphthyl group.

The lower alkyl group optionally substituted by 1 to 3 halogen atoms represented by R ¹ is preferably a C _1-6 alkyl group or a trifluoromethyl group. Examples of the cycloalkyl group having 3 to 10 carbon atoms which may be substituted by the lower alkyl group, lower alkoxy group, lower alkylsulfanyl group or carboxyl group represented by R ¹ include a C _1-6 alkyl group, C _1-6 A cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or adamantyl group optionally substituted by an alkoxy group, a C _1-6 alkylsulfanyl group or a carboxyl group is preferred. Examples of the heterocyclic group which may be substituted by the lower alkyl group or lower acyl group represented by R ¹ include tetrahydrofuranyl and oxanyl optionally substituted by a C _1-6 alkyl group or a C _1-6 acyl group , Thianyl, thianyl-S-oxide, thianyl-S-dioxide, thienyl, furanyl, pyridyl, thiazolyl or pyridylthiazolyl groups are preferred. The nitro group, hydroxy group, halogen atom, lower alkyl group, lower alkoxy group, lower alkylsulfanyl group, lower alkylsulfinyl group, lower alkylsulfonyl group, halogeno lower alkyl group, aralkyloxy group, lower alkylamino group represented by R ¹ , A di-lower alkylamino group, a cyano group, a carboxyl group and an alkylenedioxy group may be substituted by 1 to 3 aromatic hydrocarbon groups having 6 to 10 carbon atoms, such as a nitro group and a hydroxy group Halogen atom, C _1-6 alkyl group, C _1-6 alkoxy group, C _1-6 alkylsulfanyl group, C _1-6 alkylsulfonyl group, halogeno C _1-6 alkyl group, benzyloxy group, C _1-6 alkylamino groups, one to three selected from di-C _1-6 alkylamino group and a methylenedioxy group which may be substituted Eniru group is preferred.

A halogen atom represented by Z, a lower alkyl group, a lower alkoxyalkyl group optionally substituted by a halogen atom, a lower alkylsulfanylalkyl group, a lower alkoxyalkyloxyalkyl group, a cycloalkyl (having 3 to 5 carbon atoms) oxyalkyl group, 1 to 3 selected from an allyloxyalkyl group which may be substituted by a halogen atom, a crotyloxyalkyl group, a hydroxyalkyl group, a lower alkoxy group and a lower alkylsulfanyl group which may be substituted by a halogen atom are substituted. As the phenyl group which may be used, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkylsulfanyl-C _1-6 alkyl group, a C _1-6 alkoxy-C _1-6 alkyl, a C _1-6 alkoxy- C _1-6 alkyloxy -C _1-6 alkyl group, selected from C _1-6 alkoxy group and a C _1-6 alkylsulfanyl group 1-3 is preferably a phenyl group which may be substituted that. Of these, a phenyl group substituted by 2 or 3 C _1-6 alkoxy groups; or 2 C _1-6 alkoxy groups, a halogen atom, a C _1-6 alkyl group, a C _1-6 alkylsulfanyl group, C _1-6 alkoxy-C _1-6 alkyl group, C _1-6 alkylsulfanyl-C _1-6 alkyl group and C _1-6 alkoxy-C _1-6 alkyloxy-C _1-6 alkyl group, hydroxymethyl group A phenyl group substituted with a group selected from is more preferable. The benzoylamino group or pyridinecarbonylamino group optionally substituted by 1 to 3 halogen atoms is preferably a dichlorobenzoylamino group or a dichloropyridinecarbonylamino group. The aralkyloxy group which may be substituted by 1 to 3 selected from a halogen atom, a lower alkyl group and a lower alkoxy group is preferably a benzyloxy group which may be substituted by 1 to 3 halogen atoms.

R ² is preferably a hydrogen atom. R ³ is preferably a hydrogen atom or a methyl group.

  Examples of the salt of the phenylalanine derivative of the present invention include acid addition salts such as hydrochloride, sulfate, nitrate and acetate, or alkali such as sodium salt, potassium salt, calcium salt, meglumine salt, tris salt, diethanolamine salt and ammonium salt. Salt.

As described above, the compound of the present invention is characterized by having a hydroxyimine structure, an iminoether structure or a methylidene structure, and among these, those having a hydroxyimine, iminoether, monochloromethylidene or dichloromethylidene structure are preferred. . In the case of having a hydroxyimine or imino ether structure, the compound of the present invention has syn type and anti type isomers, and when n = 0, the syn type is preferred. For n = 0 and n = 1, n = 0 is preferable. The present invention also includes isomers based on asymmetric carbon atoms, and includes both optically active substances and optically inactive substances. Here, the syn type and the anti type are the syn type when the OR ³ group of NOR ³ is on the same side as the amide or ester, and the anti type when the opposite is the case.

  Moreover, this invention compound or its salt may exist also in the form of a hydrate and a solvate.

  The phenylalanine derivative (1) or a salt thereof of the present invention can be produced, for example, according to the following reaction formula.

(Wherein M represents hydrogen or an alkali metal, R ^2a represents a lower alkyl group, and Y, A, B, n and Z are the same as above)

  That is, the compound (2) or a reactive derivative thereof is reacted with the phenylalanine ester (3) to obtain the compound (1a) of the present invention, and this is hydrolyzed to obtain the compound (1b) of the present invention. In the formula (3), a compound in which Z is a phenyl group having a substituent is obtained by reacting an N-protected 4-trifluoromethanesulfonyloxyphenylalanine ester with phenylboronic acid and then removing the N-protecting group. Can be obtained.

The condensation reaction between the compound (2) and the phenylalanine ester (3) is carried out using a condensing agent such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide, N, N-dicyclohexylcarbodiimide, and 1 -In the presence of hydroxybenzotriazole or the like, the reaction is preferably performed in the presence or absence of a base such as diisopropylethylamine, dimethylaminopyridine, or triethylamine. The reaction solvent is preferably a polar solvent such as dimethylformamide, dimethylacetamide, or N-methylpyrrolidone. The reaction may be performed at −10 ° C. to 100 ° C., preferably −10 ° C. to room temperature for 30 minutes to 10 hours.

  Examples of the reactive derivative of compound (2) include acid halides such as acid chloride. The condensation reaction between the reactive derivative and the phenylalanine ester (3) is preferably carried out in the presence of a base such as diisopropylethylamine, dimethylaminopyridine, triethylamine. The reaction solvent is preferably a halogenated hydrocarbon solvent such as dichloromethane or chloroform. The reaction may be performed at −10 ° C. to room temperature for 30 minutes to 10 hours.

  The hydrolysis reaction of the compound (1a) can be performed in the presence of a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like.

  The raw material compound (2) can be produced by various methods depending on the structure of the Y portion. For example, a compound having an imino ether or hydroxyimine structure can be obtained as follows.

(Wherein R ⁴ represents an alkyl group, and M, R ¹ and R ³ are the same as above)

(In the formula, R ⁴ represents a lower alkyl group or a substituted benzyl group, M and R ¹ are the same as described above, and R ³ represents a group obtained by removing the phenyl group from the above.)

That is, when the keto acid ester (5) is reacted with a hydroxyamine (6) or the ester (8) is reacted with t-butoxypotassium and isoamylnitrite to obtain an alkoxyimino derivative, O-alkylation is performed. After obtaining (7), the compound (2-1) is then obtained by hydrolysis. Moreover, when setting it as a hydroxyimino derivative, a compound (2-1: R < ³ > = H) is obtained by hydrolyzing (9).

In particular, CCl ₂ and CHCl can be obtained by ester hydrolysis of a compound obtained by the Wittig reaction between the keto acid ester (5) and the corresponding ylide.

(R ₁ and R ₄ are as described above, Y ¹ is CCl ₂ or CHCl)

In the case of CCl ₂ , for example, by the presence of carbon tetrachloride described in Synthetic Communications, 32 (18), 2821 (2002), the method of allowing triphenylphosphine to act, and in the case of CHCl, for example, Bull. Chem. Soc Jpn., 52, 1197 (1979) and the like.
From the methylidene derivative (10) obtained above, the compound (2-2) is obtained by alkaline hydrolysis or acid treatment.

CHCF ₃ is obtained by Heck reaction (for example, according to the method described in J. Fluorine Chem., 105, 169 (2000), etc.) and ester hydrolysis of 3-trifluoromethyl acrylate ester and bromobenzene.

It can be obtained by reaction (for example, according to the method described in J. Org. Chem., 4087-4090, 68 (2003)) and ester hydrolysis.
Further, the compound (2) in which n is 1 can also be produced according to the production method of the compound (2-1) having the imino ether structure.

  Further, depending on the type of substituent Z, it can also be produced according to the following reaction formula.

(Wherein Tf represents a trifluoromethanesulfonyl group, R ⁵ , R ⁶ and R ⁷ represent a halogen atom, an alkoxy group, etc., and R ¹ , Y, A, B, n and R ^2a are the same as above)
That is, the compound (2) and the compound (3-1) are condensed to obtain the compound (11), and this is reacted with the compound (4) in the presence of a metal catalyst such as palladium to obtain a compound (1c). Subsequent hydrolysis yields compound (1d).

  Condensation of compound (2) and compound (3-1) and hydrolysis of compound (1c) are carried out in the same manner as described above. The coupling reaction of compound (11) and compound (4) is carried out in the presence of a base such as potassium carbonate, triethylamine, diisopropylethylamine and a catalyst such as palladium.

  Separation of the syn-type and anti-type isomers of the compound of the present invention may be carried out at the raw material stage such as compound (7), or at the stage after the condensation reaction such as compounds (1a) and (11). You may go.

  After completion of the reaction, the target product can be isolated from the reaction condensate by conventional methods such as recrystallization, washing and chromatography.

The compounds of the invention, eosinophils, monocytes, CS of VCAM-1, MAdCAM-1 or fibronectin expressed by such inflammatory stimuli to alpha ₄ integrin vascular endothelial cells is a cell adhesion molecule expressed such as lymphocytes -1 domain binding is inhibited. Cell adhesion to leukocytes and endothelial cells or extracellular matrix is an important process in the inflammatory reaction and immune mechanism, and is therefore useful as a preventive or therapeutic agent for these adherent diseases. Such diseases include various inflammations (including eczema, psoriasis, contact dermatitis, and atopic dermatitis as skin inflammation), rheumatoid arthritis, arthritis, bronchial asthma, allergic diseases including allergic rhinitis, inflammatory bowel disease (Crohn's disease, ulcerative colitis), multiple sclerosis, collagen disease (systemic lupus erythematosus, etc.), transplant rejection, atherosclerosis and the like.

  The medicament of the present invention can be used externally such as intravenous injection, subcutaneous injection, intramuscular injection, intrathecal administration, suppository, cream, ointment, patch, inhalant, eye drop, nasal drop, etc. Oral administration is preferred.

  Examples of the preparation for oral administration include tablets, powders, granules, capsules, solutions, syrups and elixirs. In preparing these pharmaceutical preparations, various pharmaceutically acceptable carriers, excipients and the like can be used.

  The dose of the pharmaceutical containing the compound of the present invention may vary depending on the route of administration, the age, weight, medical condition of the patient and the target disease, but 0.1 mg to 1000 mg per day per adult as the compound (1), preferably It is preferable to administer 0.1 mg to 1000 mg once to several times.

EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.
Abbreviations are as follows:
DMF; N, N-dimethylformamide, THF; tetrahydrofuran, HOBt; 1-hydroxybenzotriazole monohydrate, EDC; 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, DMSO; dimethyl sulfoxide, DME 1,2-dimethoxyethane, PMB; p-methoxybenzyl, CDCl ₃ ; deuterated chloroform, d6DMSO; deuterated dimethyl sulfoxide, CD ₃ OD; deuterated methanol.
NMR showed a 270 MHz nuclear magnetic resonance spectrum, and TMS (tetramethylsilane) was used as an internal standard substance. MS indicates mass spectrometry, and a measuring instrument whose ionization method is ESI (electrospray ionization method) was used.

Reference example 1
Synthesis of methyl methoxyiminophenylacetate 5 g (0.03 mol) of methyl benzoylformate was dissolved in 30 mL of methanol, and 3.3 g (0.039 mol) of O-methylhydroxylamine hydrochloride and 6.6 mL (0.09 mol) of pyridine were added. The mixture was refluxed overnight. After completion of the reaction, 5% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 30) to obtain the desired product syn type 4.15 g (0.021 mol) and anti type 1.23 g (0.006 mol).

¹ H-NMR (CDCl ₃ ) δ; 3.93 (3H, s), 4.02 (3H, s), 7.33-7.41 (3H, m), 7.52-7.58 (2H, m).

¹ H-NMR (CDCl ₃ ) δ; 3.87 (3H, s), 4.05 (3H, s), 7.36-7.45 (5H, m).

Example 1
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
a) Dissolve 3.00 g (0.016 mol) of methyl methoxyiminophenylacetate (syn) in a mixed solution of 20 mL of methanol and 2 mL of water, add 0.973 g (0.023 mol) of lithium hydroxide monohydrate at room temperature. Stir overnight. After completion of the reaction, the mixture was acidified with 5% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure to obtain 2.11 g of methoxyiminophenylacetic acid (syn).
b) 0.856 g (5.25 mmol) of methoxyiminophenylacetic acid (syn) was dissolved in 30 mL of DMF, 1.056 g (5.51 mmol) of EDC and 1.61 g (10.5 mmol) of HOBt were added, and the mixture was stirred for 0.5 hours under ice cooling. Then, 2.00 g (5.25 mmol) of 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester was added and stirred overnight at room temperature. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous Na ₂ CO ₃ solution and saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1) to obtain 2.85 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.0 Hz), 3.16 (1H, dd, J = 14.0, 6.5 Hz), 3.31 (1H, dd, J = 14.0, 5.4 Hz), 4.01 (3H, s), 4.23 (2H, q, J = 7.0 Hz), 5.07-5.15 (1H, m), 6.49 (1H, d, J = 7.8 Hz), 7.13-7.61 (13H, m).

Example 2
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn) N- (2-methoxyimino-2-phenylacetyl) -4- 2.85 g (4.53 mmol) of (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn) is dissolved in a mixture of 30 mL of THF, 3 mL of water and 3 mL of methanol to obtain 0.567 g of lithium hydroxide monohydrate. (13.6 mmol) was added and stirred at room temperature for 5 hours. After completion of the reaction, 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over Na ₂ SO ₄ , and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol: chloroform = 1: 1) to obtain 2.25 g of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ; 2.88 (1H, dd, J = 13.8, 10.3 Hz), 3.19 (1H, dd, J = 13.8, 4.1 Hz), 3.83 (3H, s), 4.49-4.60 (1H, m), 7.31-7.65 (12H, m), 8.75 (1H, d, J = 8.1 Hz), 10.7 (1H, s) .MS m / z: 512 [M−H] ⁻ .

Example 3
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti) Same as Example 1 using methoxyiminophenylacetic acid (anti) To give the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.12-3.28 (2H, m), 4.00 (3H, s), 4.22 (2H, q, J = 7.0 Hz), 4.88-4.96 (1H, m), 7.16-7.44 (12H, m), 7.59 (2H, d, J = 6.5 Hz).

Example 4
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti) N- (2-methoxyimino-2-phenylacetyl) -4- The title compound was obtained in the same manner as in Example 2 using (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti).

¹ H-NMR (DMSO-d ₆ ) δ; 3.00 (1H, dd, J = 13.8, 8.9 Hz), 3.13 (1H, dd, J = 13.8, 4.9 Hz), 3.92 (3H, s), 4.40-4.53 (1H, m), 7.20-7.66 (12H, m), 8.38-8.49 (1H, m), 10.70 (1H, s) .MS m / z: 512 [M−H] ⁻ .

Example 5
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn) Methoxyiminophenylacetic acid (syn) and 4- (2,6- The title compound was obtained in the same manner as in Example 1 using dimethoxyphenyl) -L-phenylalanine methyl ester.

¹ H-NMR (CDCl ₃ ) δ; 3.20 (1H, dd, J = 14.0, 6.5 Hz), 3.33 (1H, dd, J = 14.0, 5.2 Hz), 3.70 (6H, s), 3.80 (3H, s ), 3.98 (3H, s), 5.09-5.19 (1H, m), 6.59 (1H, d, J = 7.6 Hz), 6.64 (2H, d, J = 8.4 Hz), 7.16-7.41 (8H, m) 7.52-7.64 (2H, m).

Example 6
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) N- (2-methoxyimino-2-phenylacetyl) -4- ( The title compound was obtained in the same manner as in Example 2 using 2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn).

¹ H-NMR (DMSO-d ₆ ) δ; 2.97 (1H, dd, J = 14.0, 10.0 Hz), 3.20 (1H, dd, J = 14.0, 4.1 Hz), 3.65 (6H, s), 3.83 (3H , s), 4.50-4.64 (1H, m), 6.74 (2H, d, J = 8.4 Hz), 7.09-7.58 (10H, m), 8.90-9.07 (1H, m). MS m / z: 461 [M−H] ⁻ .

Example 7
Synthesis of N- (2-methoxyimino-2-phenylacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti) Methoxyiminophenylacetic acid (anti) and -4- (2,6-dimethoxy) The title compound was obtained in the same manner as in Example 1 and Example 2 using (phenyl) -L-phenylalanine methyl ester.

¹ H-NMR (CDCl ₃ ) δ; 3.16-3.30 (2H, m), 3.72 (6H, s), 3.76 (3H, s), 3.99 (3H, s), 4.91-5.02 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.17-7.47 (11H, m).

¹ H-NMR (DMSO-d ₆ ) δ; 3.06-3.26 (2H, m), 3.64 (6H, s), 3.94 (3H, s), 4.50-4.66 (1H, m), 6.74 (2H, d, J = 8.6 Hz), 7.13-7.47 (10H, m), 8.57 (1H, d, J = 8.1 Hz). MS m / z: 461 [M−H] ⁻ .

The following oxime derivatives were obtained from the corresponding glyoxylic acid in the same manner as in Reference Example 1. Reference Examples 2-11
Reference example 2

270MHz ¹ H-NMR (CDCl ₃ ) δ; 1.35 (3H, t, J = 7.0 Hz), 2.04 (3H, s), 4.06 (3H, s), 4.32 (2H, q, J = 7.0 Hz).
Reference example 3

¹ H-NMR (CDCl ₃ ) δ; 1.34 (3H, t, J = 7.3 Hz), 3.63 (3H, s), 4.42 (2H, q, J = 7.3 Hz).
Reference example 4

¹ H-NMR (CDCl ₃ ) δ; 1.40 (3H, t, J = 7.0 Hz), 4.09 (3H, s), 4.46 (2H, q, J = 7.0 Hz), 7.75 (2H, d, J = 9.2 Hz), 8.24 (2H, d, J = 9.2Hz).
Reference Example 5

¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, t, J = 7.0 Hz), 4.09 (3H, s), 4.38 (2H, q, J = 7.0 Hz), 7.58 (2H, d, J = 8.9 Hz), 8.27 (2H, d, J = 8.9 Hz).
Reference Example 6

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 2.27 (3H, s), 2.34 (6H, s), 3.99 (3H, s), 4.27 (2H, q, J = 7.0 Hz), 6.88 (2H, s).
Reference Example 7

¹ H-NMR (CDCl ₃ ) δ; 1.32 (3H, t, J = 7.0 Hz), 2.11 (6H, s), 2.29 (3H, s), 4.04 (3H, s), 4.34 (2H, q, J = 7.0 Hz), 6.89 (2H, s).
Reference Example 8

¹ H-NMR (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.3 Hz), 3.99 (3H, s), 4.43 (2H, q, J = 7.3 Hz), 7.02 (1H, dd, J = 5.1 , 3.8 Hz), 7.12 (1H, dd, J = 3.8, 1.1 Hz), 7.35 (1H, dd, J = 5.1, 1.1 Hz).
Reference Example 9

¹ H-NMR (CDCl ₃ ) δ; 1.41 (3H, t, J = 7.0 Hz), 4.20 (3H, s), 4.43 (2H, q, J = 7.0 Hz), 7.11 (1H, dd, J = 4.9 , 3.8 Hz), 7.55 (1H, dd, J = 5.1, 1.1 Hz), 7.86 (1H, dd, J = 4.1, 1.1 Hz).
Reference Example 10

¹ H-NMR (CDCl ₃ ) δ; 1.16 (6H, d, J = 7.0 Hz), 1.33 (3H, t, J = 7.0 Hz), 2.67 (1H, sevent, J = 7.0 Hz), 3.85 (3H, s), 4.31 (2H, q, J = 7.0 Hz).
Reference Example 11

¹ H-NMR (CDCl ₃ ) δ; 1.19 (6H, d, J = 7.0 Hz), 1.35 (3H, t, J = 7.0 Hz), 3.38 (1H, sevent, J = 7.1 Hz), 4.00 (3H, s), 4.30 (2H, q, J = 7.0Hz).

Corresponding oxime derivatives (Reference Examples 2 to 11) and 4- (2,6b-dichlorobenzoylamino) -L-phenylalanine ethyl ester or 4- (2,6b-dimethoxyphenyl)- The compounds of Examples 8 to 22 were obtained using L-phenylalanine methyl ester.

Example 8
N- (2-methoxyiminopropionyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.27 (3H, t, J = 7.0 Hz), 1.99 (3H, s), 3.06-3.23 (2H, m), 3.98 (3H, s), 4.19 (2H, q , J = 7.0 Hz), 4.81-4.92 (1H, m), 7.12-7.44 (7H, m), 7.57 (2H, d, J = 8.4 Hz).

N- (2-methoxyiminopropionyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.87 (3H, s), 2.96-3.15 (2H, m), 3.94 (3H, s), 4.37-4.51 (1H, m), 7.18 (2H, d, J = 8.4 Hz), 7.46-7.64 (5H, m), 7.87 (1H, d, J = 7.8 Hz), 10.67 (1H, s) .MS m / z: 450 [M−H] ⁻ .

Example 9
N- (2-methoxyiminopropionyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 2.00 (3H, s), 3.18 (2H, d, J = 6.5 Hz), 3.72 (6H, s), 3.97 (3H, s), 4.86-4.98 (1H, m ), 6.65 (2H, d, J = 8.4 Hz), 7.15-7.34 (6H, m).

N- (2-methoxyiminopropionyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.88 (3H, s), 3.10-3.19 (2H, m), 3.64 (6H, s), 3.95 (3H, s), 4.44-4.59 (1H, m) , 6.72 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.28 (1H, t, J = 8.2 Hz), 8.01 (1H, d, J = 7.8 Hz). MS m / z: 399 [M−H] ⁻ .

Example 10
N- (3,3,3-trifluoro-2-methoxyiminopropionyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 3.23-3.25 (2H, m), 3.72 (6H, s), 3.78 (3H, s), 4.06 (3H, s), 4.95-5.02 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.4 Hz), 7.16-7.31 (3H, m), 7.43 (1H, d, J = 7.8 Hz).

N- (3,3,3-trifluoro-2-methoxyiminopropionyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (DMSO-d ₆ ); 2.97 (1H, dd, J = 14.0, 9.2 Hz), 3.16 (1H, dd, J = 14.0, 4.6 Hz), 3.64 (6H, s), 3.93 (3H, s), 4.46-4.55 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.23 ( 1H, t, J = 8.1 Hz), 9.26 (1H, d, J = 7.0 Hz). MS m / z: 453 [MH] ⁻ .

Example 11
N- (3,3,3-trifluoro-2-methoxyiminopropionyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.3 Hz), 3.20-3.35 (2H, m), 4.11 (3H, s), 4.24 (2H, q, J = 7.3 Hz), 4.89-4.95 (1H, m), 7.13 (2H, d, J = 8.1 Hz), 7.29-7.40 (5H, m), 7.59 (2H, d, J = 8.1 Hz).

N- (3,3,3-trifluoro-2-methoxyiminopropionyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine

¹ H-NMR (DMSO-d ₆ ) δ; 2.92 (1H, dd, J = 13.8, 9.5 Hz), 3.12 (1H, dd, J = 13.8, 4.6 Hz), 3.94 (3H, s), 4.49-4.60 (1H, m), 7.23 (2H, d, J = 8.6 Hz), 7.45-7.62 (5H, m,), 9.29 (1H, d, J = 8.4 Hz), 10.69 (1H, s) .MS m / z: 504 [M−H] ⁻ .

Example 12
N- [2-methoxyimino-2- (4-nitrophenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn, anti mixture) (syn: anti = 8: 2 )
¹ H-NMR (CDCl ₃ ) δ; 1.27-1.37 (3H, m), 3.08-3.35 (2H, m), 4.04 and 4.07 (3H, s), 4.20-4.31 (2H, m), 4.86-5.14 ( 1H, m), 7.12-7.44 (6H, m), 7.55-7.64 (4H, m), 7.73 and 7.91 (1H, 2d, J = 9.2 and 8.3 Hz), 8.16-8.32 (2H, m).

N- [2-methoxyimino-2- (4-nitrophenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn, anti-mix)

(syn: anti = 3: 7)
¹ H-NMR (DMSO-d ₆ ) δ; 2.81-3.26 (2H, m), 3.91 and 3.98 (3H, 2s), 4.45-4.71 (1H, m), 7.13-7.65 (9H, m), 8.12- 8.26 (2H, m), 8.53 and 9.15 (1H, 2d, J = 8.1and 8.1 Hz), 10.71 and 10.72 (1H, 2s). MS m / z: 557 [M−H] ⁻ .

Example 13
N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t, J = 7.3 Hz), 2.17 (6H, s), 2.26 (3H, s), 3.09-3.30 (2H, m), 4.03 (3H, s ), 4.21 (2H, q, J = 7.3 Hz), 4.89-5.00 (1H, m), 6.84 (2H, s), 7.17 (2H, d, J = 8.4 Hz), 7.27-7.44 (4H, m) , 7.57 (2H, d, J = 8.6 Hz), 7.86 (1H, d, J = 7.0 Hz).

N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.12 (6H, s), 2.22 (3H, s), 2.93-3.19 (2H, m), 3.86 (3H, s), 4.42-4.58 (1H, m) , 6.82 (2H, s), 7.24 (2H, d, J = 8.4Hz), 7.46-7.64 (5H, m), 8.50 (1H, d, J = 7.8 Hz), 10.69 (1H, s), 12.83 ( MS m / z: 554 [M−H] ⁻ .

Example 14
N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 2.04 (3H, s), 2.06 (3H, s), 2.27 (3H, s), 3.11 (1H, dd, J = 14.0, 6.5 Hz), 3.24 (1H, dd, J = 14.0, 5.7 Hz), 3.97 (3H, s), 4.22 (2H, q, J = 7.0 Hz), 4.87-4.98 (1H, m), 6.86 (2H, s), 7.09-7.21 (3H, m), 7.26-7.43 (4H, m), 7.56 (2H, d, J = 8.6 Hz).

N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.78 (3H, s), 1.97 (3H, s), 2.21 (3H, s), 2.99-3.20 (2H, m), 3.90 (3H, s), 4.51 -4.65 (1H, m), 6.75 (1H, s), 6.82 (1H, s), 7.21 (2H, d, J = 8.4 Hz), 7.46-7.65 (5H, m), 8.20 (1H, d, J = 8.0 Hz), 10.67 (1H, s), 12.90 (1H, bs). MS m / z: 554 [M−H] ⁻ .

Example 15
N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 2.16 (6H, s), 2.21 (3H, s), 3.18-3.31 (2H, m), 3.64 (3H, s), 3.65 (6H, s), 3.86 (3H, s), 4.58-4.78 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 6.83 (2H, s), 7.14 (2H, d, J = 8.1 Hz), 7.22-7.33 ( 3H, m), 8.81 (1H, d, J = 7.6 Hz).

N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.15 (6H, s), 2.21 (3H, s), 3.08-3.18 (2H, m), 3.65 (6H, s), 3.85 (3H, s), 4.44 -4.60 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 6.83 (2H, s), 7.13 (2H, d, J = 8.1 Hz), 7.22-7.32 (3H, m), 8.57 ( 1H, d, J = 7.6 Hz). MS m / z: 505 [M + H] ⁺ .

Example 16
N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 1.86 (3H, s), 2.00 (3H, s), 2.21 (3H, s), 3.17 (2H, d, J = 7.3 Hz), 3.65 (6H, s ), 3.66 (3H, s), 3.91 (3H, s), 4.58-4.69 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 6.80 (1H, s), 6.83 (1H, s) , 7.11 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.28 (1H, t, J = 8.4 Hz), 8.60 (1H, d, J = 8.1 Hz).

N- [2-methoxyimino-2- (2,4,6-trimethylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.86 (3H, s), 2.00 (3H, s), 2.21 (3H, s), 3.13-3.22 (2H, m), 3.65 (6H, s), 3.90 (3H, s), 4.52-4.64 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 6.80 (1H, s), 6.83 (1H, s), 7.11 (2H, d, J = 8.1 Hz), 7.21 (2H, d, J = 8.1 Hz), 7.28 (1H, t, J = 8.4 Hz) 8.30 (1H, d, J = 9.7 Hz).
MS m / z: 505 [M + H] ⁺ .

Example 17
N- (2-methoxyimino-2-thiophen-2-ylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.0 Hz), 3.16 (1H, dd, J = 14.0, 6.2 Hz), 3.30 (1H, dd, J = 14.0, 5.7 Hz), 3.98 (3H, s), 4.23 (2H, q, J = 7.0 Hz), 5.00-5.09 (1H, m), 6.75 (1H, d, J = 7.8 Hz), 7.00 (1H, dd, J = 5.1, 3.5 Hz), 7.16-7.40 (7H, m), 7.45 (1H, bs), 7.57 (2H d, J = 8.1 Hz).

N- (2-methoxyimino-2-thiophen-2-ylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.87 (1H, dd, J = 13.8, 10.5 Hz), 3.17 (1H, dd, J = 13.8, 4.1 Hz), 3.78 (3H, s), 4.45-4.61 (1H, m), 6.78 (1H, dd, J = 3.8, 1.4 Hz), 7.02 (1H, dd, J = 5.1, 3.8 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.46-7.63 ( 6H, m), 9.01 (1H, d, J = 7.8 Hz), 10.70 (1H, s) .MS m / z: 518 [M−H] ⁻ .

Example 18
N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.12-3.30 (2H, m), 4.15 (3H, s), 4.22 (2H, q, J = 7.0 Hz), 4.91-5.02 (1H, m), 7.12 (1H, dd, J = 5.1, 4.1 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.25-7.38 (4H, m), 7.46 (1H, br s ), 7.53-7.60 (3H, m), 8.15 (1H, dd, J = 3.8, 1.1 Hz).

N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.94 (1H, dd, J = 13.5, 10.3 Hz), 3.16 (1H, dd, J = 13.5, 4.9 Hz), 4.05 (3H, s), 4.55-4.69 (1H, m), 7.07 (1H, dd, J = 5.1, 4.1 Hz), 7.14 (1H, dd, J = 4.1, 1.1 Hz), 7.26 (2H, d, J = 8.6 Hz), 7.46-7.62 ( 5H, m), 7.84 (1H, dd, J = 4.9, 1.1 Hz), 8.86 (1H, d, J = 8.4 Hz), 10.71 (1H, s). MS m / z: 518 [M−H] ⁻ .

Example 19
N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 2.97 (1H, dd, J = 14.0, 11.1 Hz), 3.17 (1H, dd, J = 14.0, 3.8 Hz), 3.64 (6H, s), 3.71 (3H , s), 3.80 (3H, s), 4.61-4.74 (1H, m), 6.74 (2H, d, J = 8.1 Hz), 6.95-7.05 (2H, m), 7.13 (2H, d, J = 8.1 Hz), 7.22-7.33 (3H, m), 7.63 (1H, d, J = 4.3), 9.33 (1H, d, J = 7.8 Hz).

N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹H-NMR (DMSO-d₆) δ ; 2.95 (1H, dd, J = 13.8, 10.0 Hz),3.19 (1H, dd, J = 13.8, 4.1 Hz), 3.64 (6H, s), 3.78 (3H, s), 4.47-4.61 (1H, m),6.73 (2H, d, J = 8.4 Hz), 6.99-7.05 (2H, m), 7.15 (2H, d, J = 8.1 Hz),7.23-7.33 (3H, m), 7.61 (1H, dd, J = 4.9, 1.4 Hz), 9.01-9.14 (1H, m)． MS m/z ：467 [M−H]⁻.

¹ H-NMR (DMSO-d ₆ ) δ; 2.95 (1H, dd, J = 13.8, 10.0 Hz), 3.19 (1H, dd, J = 13.8, 4.1 Hz), 3.64 (6H, s), 3.78 (3H , s), 4.47-4.61 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 6.99-7.05 (2H, m), 7.15 (2H, d, J = 8.1 Hz), 7.23-7.33 ( 3H, m), 7.61 (1H, dd, J = 4.9, 1.4 Hz), 9.01-9.14 (1H, m). MS m / z: 467 [M−H] ⁻ .

Example 20
N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 3.04 (1H, dd, J = 14.0, 10.3 Hz), 3.17 (1H, dd, J = 14.0, 5.1 Hz), 3.63 (6H, s), 3.69 (3H , s), 4.06 (3H, s), 4.63-4.75 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 7.05-7.16 (3H, m), 7.22-7.32 (3H, m), 7.40 (1H, d, J = 3.8 Hz), 7.85 (1H, d, J = 4.9 Hz), 9.11 (1H, d, J = 7.8 Hz).

N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.02 (1H, dd, J = 14.0, 9.5 Hz), 3.19 (1H, dd, J = 14.0, 4.9 Hz), 3.63 (6H, s), 4.06 (3H , s), 4.54-4.67 (1H, m), 6.73 (2H, d, J = 8.4 Hz), 7.06 (1H, dd, J = 4.9, 3.8 Hz), 7.12 (2H, d, J = 7.8 Hz) , 7.21-7.32 (3H, m), 7.45 (1H, d, J = 4.1 Hz), 7.84 (1H, dd, J = 4.9, 1.1 Hz), 8.79-8.89 (1H, m).
MS m / z: 467 [M−H] ⁻ .

Example 21
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.20 (6H, dd, J = 6.8, 1.1 Hz), 1.27 (3H, t, J = 7.0 Hz), 3.07-3.25 (2H, m), 3.28-3.47 (1H , m), 3.93 (3H, s), 4.19 (2H, q, J = 7.0 Hz), 4.79-4.90 (1H, m), 7.08 (1H, d, J = 7.8 Hz), 7.17 (2H, d, J = 8.4Hz), 7.28-7.44 (4H, m), 7.56 (2H, d, J = 8.4 Hz).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 0.97 (3H, d, J = 7.0 Hz), 1.05 (3H, d, J = 7.0 Hz), 2.90-3.19 (3H, m), 3.87 (3H, s ), 4.37-4.50 (1H, m), 7.19 (2H, d, J = 8.6 Hz), 7.42-7.61 (5H, m), 8.08 (1H, d, J = 8.1 Hz), 10.65 (1H, s) . MS m / z: 478 [M−H] ⁻ .

Example 22
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl (syn: anti = 3: 7)
¹ H-NMR (CDCl ₃ ) δ; 1.08-1.32 (9H, m), 2.85-3.41 (3H, m), 3.06-3.23 (2H, m), 3.87 and 3.93 (3H, 2s), 4.15-4.27 ( 2H, m), 4.79-4.90 (1H, m), 7.02-7.40 (6H, m), 7.45-7.62 (3H, m).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn: anti = 3: 7)

¹ H-NMR (DMSO-d ₆ ) δ; 0.91-3.10 (6H, m), 2.81-3.23 (3H, m), 3.67 and 3.87 (3H, 2s), 4.39-4.55 (1H, m), 7.16- 7.29 (2H, m), 7.45-7.65 (5H, m), 8.09 and 8.52 (1H, 2d, J = 8.1 and 7.7 Hz), 10.65 (1H, s).
MS m / z: 478 [M−H] ⁻ .

Reference Example 12
Synthesis of ethyl oxo (tetrahydrothiopyran-4-yl) acetate

200 mg (60% inoil; 5 mmol) of sodium hydride was added to 1.22 g (4.3 mmol) of trimethyl methoxymethoxy (phosphono) acetate in THF (5 mL) under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. Tetrahydrothiopyran- 4-ON 500 mg (4.30 mmol) in THF (2 mL) was added, and the mixture was gradually brought to room temperature and stirred overnight. The reaction solution was poured into ice water, neutralized with dilute citric acid solution, and extracted with ethyl acetate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 874 mg of ethyl methoxymethoxy (tetrahydrothiopyran-4-ylidene) acetate.
870 mg of ethyl methoxymethoxy (tetrahydrothiopyran-4-ylidene) acetate was dissolved in 10 mL of ethanol, a catalytic amount of p-toluenesulfonic acid monohydrate was added, the mixture was heated to reflux for 6 hours, brought to room temperature, and concentrated under reduced pressure. Ethyl acetate was added to the resulting residue, washed with aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl oxo (tetrahydrothiopyran-4-yl) acetate. Yield 643mg
¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, t, J = 7.0Hz), 1.65-1.90 (2H, m), 2.15-2.35 (2H, m), 2.63-2.90 (4H, m), 3.05 -3.25 (1H, m), 4.33 (2H, q, J = 7.0Hz).

Reference Example 13
Synthesis of ethyl methoxyimino (tetrahydrothiopyran-4-yl) acetate In the same manner as in Reference Example 1, the following compound was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.34 (3H, t, J = 7.3Hz), 1.68-1.88 (2H, m), 2.10-2.20 (2H, m), 2.40-2.52 (1H, m), 2.63 -2.74 (4H, m), 3.86 (3H, s), 4.32 (2H, q, J = 7.3Hz).

¹ H-NMR (CDCl ₃ ) δ; 1.35 (3H, t, J = 7.3Hz), 1.80-2.00 (2H, m), 2.10-2.30 (2H, m), 2.54-2.65 (2H, m), 2.69 -2.82 (2H, m), 3.07-3.19 (1H, m), 4.01 (3H, s), 4.31 (2H, q, J = 7.3Hz).

Example 23
Synthesis of N- [methoxyimino (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn) Methoxyimino (tetrahydrothiopyran-4-yl) acetic acid Ethyl (syn) (198 mg, 0.616 mmol) was dissolved in THF (2 mL). Under ice cooling, lithium hydroxide monohydrate (27.0 mg) aqueous solution (1 mL) and methanol (0.5 mL) were added dropwise and stirred for 1 hour. . After concentration under reduced pressure, toluene was added and the mixture was concentrated again. The obtained lithium salt was dissolved in 2 mL of DMF, 177 mg (0.923 mmol) of EDC and 250 mg (1.85 mmol) of HOBt were added, and the mixture was stirred at room temperature for 30 minutes, then 4- (2,6 194 mg (0.615 mmol) of -dimethoxyphenyl) -L-phenylalanine methyl ester were added. After stirring overnight at room temperature, the reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1).
¹ H-NMR (CDCl ₃ ) δ; 1.58-1.77 (2H, m), 2.03-2.16 (2H, m), 2.55-2.85 (5H, m), 3.10-3.27 (2H, m), 3.72 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 4.83-5.00 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.12-7.35 (5H, m), 7.54 (1H , d, J = 7.3Hz).

Example 24
Synthesis of N- [methoxyimino (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) The compound obtained in Example 23 was prepared in the same manner as in Example 2. To give the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.60-1.75 (2H, m), 2.02-2.16 (2H, m), 2.54-2.85 (5H, m), 3.19 (1H, dd, J = 7.0 and 14.3Hz) , 3.31 (1H, dd, J = 5.4 and14.3Hz), 3.72 (6H, s), 3.83 (3H, s), 4.89-4.97 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.20-7.40 (5H, m), 7.63 (1H, d, J = 6.5Hz). MS m / z: 485 [M−H] ⁻ .

Reference Example 14
Synthesis of ethyl oxo (1,1-dioxotetrahydrothiopyran-4-yl) acetate

After dissolving 550 mg (2.72 mmol) of ethyl oxo (tetrahydrothiopyran-4-yl) acetate in chloroform (20 mL) and adding 1.56 g (> 60% purity) of m-chloroperbenzoic acid under ice-cooling, gradually Stir to room temperature. After one night, the reaction solution was washed with an aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 2). Yield 170mg Yield 27%
¹ H-NMR (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.0Hz), 2.24-2.49 (4H, m), 2.96-3.23 (4H, m), 3.23-3.43 (1H, m), 4.35 (2H, q, J = 7.0Hz).

Reference Example 15
Synthesis of ethyl methoxyimino (1,1-dioxotetrahydrothiopyran-4-yl) acetate

The title compound was obtained in the same manner as in Reference Example 1 using the compound obtained in Reference Example 14.
Methoxyimino (1,1-dioxotetrahydrothiopyran-4-yl) ethyl acetate (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.34 (3H, t, J = 7.3Hz), 2.20-2.42 (4H, m), 2.70-2.80 (1H, m), 2.90-3.05 (2H, m), 3.15 -3.30 (2H, m), 3.90 (3H, s), 4.32 (2H, q, J = 7.3Hz).

Methoxyimino (1,1-dioxotetrahydrothiopyran-4-yl) ethyl acetate (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0Hz), 1.90-2.12 (2H, m), 2.65-2.88 (2H, m), 2.95-3.23 (4H, m), 3.25 -3.40 (1H, m), 4.06 (3H, s), 4.21 (2H, q, J = 7.0Hz).

Example 25
Synthesis of N- [2-methoxyimino-2- (1,1-dioxotetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) Reference Example 15 The title compound was obtained in the same manner as in Example 23 and Example 2 using the compound (syn) obtained in 1.

N- [2-methoxyimino-2- (1,1-dioxotetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 2.05-2.30 (4H, m), 2.90-3.30 (7H, m), 3.73 (6H, s), 3.80 (3H, s), 3.89 (3H, s), 4.85 -5.00 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.10-7.40 (5H, m), 7.78 (1H, d, J = 7.6Hz).

N- [2-methoxyimino-2- (1,1-dioxotetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 2.05-2.30 (4H, m), 2.90-3.22 (6H, m), 3.33 (1H, dd, J = 4.9 and 14.3 Hz), 3.72 (6H, s), 3.87 (3H, s), 4.87-5.00 (1H, m), 6.66 (2H, d, J = 8.4Hz), 7.16-7.35 (5H, m), 7.85 (1H, d, J = 6.6Hz). MS m / z; 517 [M−H] ⁻ .

Reference Example 16
Synthesis of ethyl cis-2- (4-methoxycyclohexyl) -2-oxoacetate and trans-2- (4-methoxycyclohexyl) -2-oxoacetate

The title compound was obtained in the same manner as in Reference Example 12 using 4-methoxycyclohexanone.
cis-2- (4-Methoxycyclohexyl) -2-oxoacetic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.3Hz), 1.45-2.00 (8H, m), 3.06 (1H, tt, J = 9.9, 4.1Hz), 3.29 (3H, s ), 3.42 (1H, tt, J = 4.5, 2.8Hz), 4.32 (2H, q, J = 7.3Hz).

trans-2- (4-Methoxycyclohexyl) -2-oxoacetic acid ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.19-1.49 (7H, m), 1.96-2.07 (2H, m), 2.07-2.19 (2H, m), 3.02 (1H, tt, J = 11.2, 3.5Hz) 3.13 (1H, tt, J = 10.1, 4.0Hz), 3.36 (3H, s), 4.35 (2H, q, J = 7.0Hz).

Reference Example 17
Synthesis of ethyl cis-2- (4-methoxycyclohexyl) -2-methoxyiminoacetate

In the same manner as in Reference Example 1, syn and anti cis-2- (4-methoxycyclohexyl) -2-methoxyiminoethyl acetate were synthesized using ethyl cis-2- (4-methoxycyclohexyl) -2-oxoacetate.
cis-2- (4-Methoxycyclohexyl) -2-methoxyiminoacetic acid ethyl (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, t, J = 7.3Hz), 1.38-1.54 (2H, m), 1.57-1.83 (4H, m), 1.88-2.01 (2H, m), 2.44 (1H, tt, J = 10.5, 4.1Hz), 3.29 (3H, s), 3.37-3.45 (1H, m), 3.84 (3H, s), 4.30 (2H, q, J = 7.3Hz).

cis-2- (4-Methoxycyclohexyl) -2-methoxyiminoacetic acid ethyl (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.30-1.48 (7H, m), 1.95-2.15 (4H, m), 3.02-3.17 (1H, m), 3.30 (3H, s), 3.43-3.29 (1H, m), 3.99 (3H, s), 4.29 (2H, q, J = 7.0Hz).

Reference Example 18
Synthesis of ethyl trans-2- (4-methoxycyclohexyl) -2-methoxyiminoacetate

In the same manner as in Reference Example 1, syn-2-antiethyl trans-2- (4-methoxycyclohexyl) -2-methoxyiminoacetate was synthesized using ethyl trans-2- (4-methoxycyclohexyl) -2-oxoacetate.
trans-2- (4-Methoxycyclohexyl) -2-methoxyiminoacetic acid ethyl (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.15-1.48 (7H, m), 1.90-2.02 (2H, m), 2.05-2.18 (2H, m), 2.29-2.43 (1H, m), 3.04-3.18 ( 1H, m), 3.35 (3H, s), 3.85 (3H, s), 4.30 (2H, q, J = 7.0Hz).

trans-2- (4-Methoxycyclohexyl) -2-methoxyiminoacetic acid ethyl (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.15-1.40 (5H, m), 1.65-1.90 (4H, m), 2.05-2.22 (2H, m), 2.95-3.23 (2H, m), 3.35 (1H, s), 4.00 (3H, s), 4.29 (2H, q, J = 7.0Hz).

Example 26
Synthesis of cis-N- [2- (4-methoxycyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)
The title compound was obtained in the same manner as in Example 23 and Example 2 using ethyl cis-2- (4-methoxycyclohexyl) -2-methoxyiminoacetate (syn).

cis-N- [2- (4-Methoxycyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.36-1.75 (6H, m), 1.86-1.98 (2H, m), 2.67-2.80 (1H, m), 3.15-3.22 (2H, m), 3.29 (3H, s), 3.37-3.47 (1H, m), 3.72 (6H, s), 3.76 (3H, s), 3.82 (3H, s), 4.88-4.99 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.11-7.30 (5H, m), 7.37 (1H, d, J = 6.8Hz).

cis-N- [2- (4-Methoxycyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.40-1.70 (6H, m), 1.86-1.99 (2H, m), 2.68-2.80 (1H, m), 3.15-3.35 (5H, m), 3.38-3.47 ( 1H, m), 3.71 (6H, s), 3.80 (3H, s), 4.87-5.00 (1H, m), 6.64 (2H, d, J = 8.4Hz), 7.20-7.35 (5H, m), 7.45 (1H, d, J = 6.5Hz).
MS m / z: 497 [M−H] ⁻ .

Example 27
Synthesis of trans-N- [2- (4-methoxycyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)
The title compound was obtained in the same manner as in Example 23 and Example 2 using trans-2- (4-methoxycyclohexyl) -2-methoxyiminoethyl acetate (syn).

trans-N- [2- (4-Methoxycyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.20-1.50 (4H, m), 1.85-1.97 (2H, m), 2.03-2.15 (2H, m), 2.57-2.70 (1H, m), 3.03-3.23 ( 3H, m), 3.33 (3H, s), 3.72 (6H, s), 3.77 (3H, s), 3.82 (3H, s), 4.88-4.99 (1H, m), 6.65 (2H, d, J = 8.1Hz), 7.12-7.40 (6H, m).

trans-N- [2- (4-Methoxycyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.15-1.43 (4H, m), 1.85-1.97 (2H, m), 2.03-2.15 (2H, m), 2.58-2.72 (1H, m), 3.04-3.30 ( 3H, m), 3.33 (3H, s), 3.71 (6H, s), 3.81 (3H, s), 4.90-5.00 (1H, m), 6.64 (2H, d, J = 8.4Hz), 7.20-7.35 (5H, m), 7.44 (1H, d, J = 7.0Hz).
MS m / z: 497 [M−H] ⁻ .

Reference Example 19
Synthesis of ethyl methoxyimino (1-methylcyclohexyl) acetate (syn) The title compound was obtained in the same manner as in Reference Example 1 from ethyl (1-methylcyclohexyl) oxooxoacetate (described in JP-A No. 2001-247569).

¹ H-NMR (CDCl ₃ ): 1.18 (3H, s), 1.35 (3H, t, J = 7.3 Hz), 1.40-1.90 (10H, m), 3.85 (3H, s), 4.31 (2H, q, J = 7.3 Hz).
Methoxyimino (1-methylcyclohexyl) acetic acid (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.21 (3H, s), 1.30-1.60 (8H, m), 1.80-1.95 (2H, m), 3.90 (3H, s).

Example 28
Synthesis of N- [2-methoxyimino-2- (1-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) The title was prepared in the same manner as in Example 23 and Example 2. A compound was obtained.

N- [2-methoxyimino-2- (1-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.18 (3H, s), 1.23-1.49 (8H, m), 1.75-1.90 (2H, m), 3.17 (1H, dd, J = 14.0, 6.2 Hz), 3.26 (1H, dd, J = 14.0,5.4 Hz), 3.72 (6H, s), 3.76 (3H, s), 3.81 (3H, s), 4.99-5.07 (1H, m), 6.08 (1H, d, J = 7.6 Hz), 6.64 (2H, d, J = 8.4 Hz), 7.17-7.30 (5H, m).

N- [2-Methoxyimino-2- (1-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.08 (3H, s), 1.20-1.80 (10H, m), 2.98 (1H, dd, J = 14.3, 9.7 Hz), 3.12 (1H, dd, J = 14.3, 4.3 Hz), 3.64 (6H, s), 3.66 (3H, s), 4.44-4.53 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.09 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.27 (1H, t, J = 8.1 Hz), 8.37 (1H, d, J = 6.5 Hz). MS m / z: 481 [MH] ⁻ .

Reference Example 20
Synthesis of methyl (4-methyltetrahydropyran-4-yl) oxoacetate

As in Reference Example 19, starting from ethyl 4-methyltetrahydropyran-4-carboxylate, the methyl (4-methyltetrahydropyran-4-yl) oxoacetate was converted to the title compound by the method described in JP-A No. 2001-247569. Obtained.
¹ H-NMR (CDCl ₃ ) δ; 1.34 (3H, s), 1.53-1.69 (2H, m), 2.07-2.19 (2H, m), 3.48-3.60 (2H, m), 3.73-3.84 (2H, m), 3.87 (3H, s).

Reference Example 21
Synthesis of methyl methoxyimino (4-methyltetrahydropyran-4-yl) acetate (syn)

The title compound was obtained in the same manner as in Reference Example 1 using the compound obtained in Reference Example 20.
¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, s), 1.46-1.59 (2H, m), 1.87-1.98 (2H, m), 3.64-3.76 (4H, m), 3.83 (3H, s) , 3.87 (3H, s).

Example 29
Synthesis of N- [2-methoxyimino-2- (4-methyltetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) Compound obtained in Reference Example 21 The title compound was obtained in the same manner as in Example 23 and Example 2 using 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- [2-methoxyimino-2- (4-methyltetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, s), 1.40-1.55 (2H, m), 1.87-2.06 (2H, m), 3.14 (1H, dd, J = 7.0, 14.0Hz), 3.28 (1H, dd, J = 5.1, 14.0Hz), 3.50-3.85 (16H, m, including 3s at 3.72, 3.76, 3.82ppm), 4.97-5.07 (1H, m), 6.17 (1H, d, J = 7.6 Hz), 6.65 (2H, d, J = 8.4Hz), 7.11-7.36 (5H, m).

N- [2-methoxyimino-2- (4-methyltetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.21 (3H, s), 1.40-1.54 (2H, m), 1.87-2.07 (2H, m), 3.17 (1H, dd, J = 7.6, 14.3 Hz), 3.36 (1H, dd, J = 4.9, 14.3Hz), 3.50-3.78 (10H, m, including 1s at 3.72ppm), 3.81 (3H, s), 4.99-5.09 (1H, m), 6.18 (1H, d, J = 7.3Hz), 6.64 (2H, d, J = 8.4Hz), 7.20-7.35 (5H, m). MS m / z: 483 [M−H] ⁻ .

Reference Example 22
Synthesis of methyl (4-ethyltetrahydropyran-4-yl) oxoacetate In the same manner as in Reference Example 19, starting from ethyl 4-ethyltetrahydropyran-4-carboxylate, the title compound was prepared according to the method described in JP-A-2001-247569. Got.

¹ H-NMR (CDCl ₃ ) δ; 0.82 (3H, t, J = 7.6Hz), 1.53-1.68 (2H, m), 1.79 (2H, q, J = 7.6Hz), 2.08-2.23 (2H, m ), 3.41-3.53 (2H, m), 3.76-3.92 (5H, m).

Reference Example 23
Synthesis of ethyl (4-ethyltetrahydropyran-4-yl) methoxyiminoacetate (syn) The title compound was obtained in the same manner as in Reference Example 1 using the compound obtained in Reference Example 22.

¹ H-NMR (CDCl ₃ ) δ; 0.86 (3H, t, J = 7.6 Hz), 1.46-1.61 (4H, m), 1.84-1.95 (2H, m), 3.66 (2H, ddd, J = 2.2, 10.5, 11.6Hz), 3.76 (2H, ddd, J = 3.8, 4.3, 11.6Hz), 3.81 (3H, s), 3.88 (3H, s).

Example 30
Synthesis of N- [2- (4-ethyltetrahydropyran-4-yl) -2-methoxyimino-acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) Obtained in Reference Example 23 The title compound was obtained in the same manner as in Example 23 and Example 2 using the compound and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- [2- (4-Ethyltetrahydropyran-4-yl) -2-methoxyimino-acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 0.78 (3H, t, J = 7.6 Hz), 1.36-1.70 (4H, m), 1.79-1.91 (1H, m), 1.94-2.06 (1H, m), 3.12 (1H, dd, J = 7.0, 14.3Hz), 3.28 (1H, dd, J = 5.1, 14.3Hz), 3.43-3.90 (16H, m, including 3s at 3.72, 3.78, 3.83ppm), 4.95-5.05 ( 1H, m), 6.10 (1H, d, J = 7.8Hz), 6.64 (2H, d, J = 8.4Hz), 7.13-7.20 (2H, m), 7.23-7.33 (3H, m).

N- [2- (4-Ethyltetrahydropyran-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 0.77 (3H, t, J = 7.6 Hz), 1.36-1.69 (4H, m), 1.81-1.92 (1H, m), 1.93-2.05 (1H, m), 3.15 (1H, dd, J = 7.6, 14.3Hz), 3.36 (1H, dd, J = 5.1, 14.3Hz), 3.43-3.79 (10H, m, including 1s at 3.71ppm), 3.82 (3H, s), 4.97 -5.07 (1H, m), 6.16 (1H, d, J = 7.6Hz), 6.64 (2H, d, J = 8.4Hz), 7.18-7.34 (5H, m).
MS m / z: 497 [M−H] ⁻ .

Reference Example 24
Synthesis of ethyl adamantylmethoxyiminoacetate To a solution of 10 g (39.0 mmol) of p-toluenesulfonic acid 2,2,2-trifluoroethyl in THF (100 ml) was added n-BuLi (49.8 ml, hexane solution) at −80 ° C. It was dripped slowly. A solution of 5.9 g (39.3 mmol) of adamantanone in THF (40 ml) was added dropwise to the mixed solution at −80 ° C. and the temperature was raised to ice cooling as it was. After 5% citric acid aqueous solution was added to the reaction solution to terminate the reaction, the reaction solution was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Water (5.0 ml) and methanesulfonic acid (50 ml) were added to the obtained residue, and the mixture was stirred at 50 ° C. overnight. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Diethyl ether was added to the resulting residue, and the precipitate was collected by filtration to obtain 7.62 g of carboxylic acid.
2.0N sodium hydroxide aqueous solution (80 ml) and THF were added to 7.62 g (21 mmol) of carboxylic acid, and the mixture was heated to reflux for 2 days. The reaction mixture was cooled to room temperature, acidified with 10% aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in DMF (60 ml), 4.18 g of potassium carbonate and 2.43 ml of iodoethane were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, 5.0% citric acid aqueous solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 9.59 g of ethyl adamantyl oxoacetate.

¹ H NMR (CDCl ₃ ); 1.36 (3H, t, J = 6.8 Hz), 1.58-2.38 (14H, m), 3.18-3.22 (1H, m), 4.31 (2H, q, J = 6.8 Hz).
The title compound was obtained in the same manner as in Reference Example 1 using the compound obtained above.

¹ H NMR (CDCl ₃ ); 1.32 (3H, t, J = 7.0 Hz), 1.50-2.17 (14H, m), 2.78 (1H, bs), 3.87 (3H, s), 4.29 (2H, q, J = 7.0 Hz).

Example 31
N- (2-adamantyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)
The following compounds were obtained in the same manner as in Examples 23 and 2 using the compound obtained in Reference Example 24 and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- (2-adamantyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.44-2.19 (14H, m), 2.98 (1H, br s), 3.10-3.30 (2H, m), 3.72 (6H, s), 3.76 (3H, s), 3.84 (3H, s), 4.91-5.03 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 6.74 (1H, d, J = 7.3 Hz), 7.10-7.34 (5H, m).

N- (2-adamantyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.47-2.16 (14H, m), 2.98 (1H, br s), 3.22 (1H, dd, J = 14.3, 6.5 Hz), 3.32 (1H, dd, J = 14.3 , 4.9 Hz), 3.71 (6H, s), 3.82 (3H, s), 4.92-5.05 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 6.76-6.87 (1H, m), 7.15 -7.38 (5H, m). MS m / z: 519 [M−H] ⁻ .

Reference Example 25
Synthesis of methyl hydroxyiminophenylacetate Methyl hydroxyiminophenylacetate was synthesized in the same manner as in Reference Example 1 using hydroxylamine hydrochloride.

270MHz ¹ H-NMR (CDCl ₃ ) δ; 3.97 (3H, s), 7.33-7.47 (3H, m), 7.51-7.61 (2H, m), 8.69 (1H, s).

¹ H-NMR (CDCl ₃ ) δ; 3.88 (3H, s), 7.41-7.59 (5H, m), 9.24 (1H, bs).

Example 32
N- (2-hydroxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)
The title compound was obtained in the same manner as in Example 1 and Example 2 using methyl hydroxyiminophenyl acetate (syn).

N- (2-hydroxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
270MHz ¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 6.8 Hz), 3.12 (1H, dd, J = 14.0, 7.0 Hz), 3.30 (1H, dd, J = 14.0, 5.4 Hz) , 4.24 (2H, q, J = 7.1 Hz), 5.03-5.15 (1H, m), 6.68 (1H, d, J = 8.1 Hz), 7.09-7.59 (13H, m), 9.84 (1H, s).

N- (2-hydroxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

(syn: anti = 6: 4)
¹ H-NMR (DMSO-d ₆ ) δ; 2.80-3.25 (2H, m), 4.59-4.87 (1H, m), 7.28-7.72 (12H, m), 8.29 and 8.92 (1H, 2d, J = 8.4 and J = 8.1 Hz), 10.72 and 10.75 (1H, 2s), 11.60 and 11.92 (1H, 2s). MS m / z; 500 [M + H] ⁺ .

Reference Example 26
Synthesis of methyl ethoxyiminophenylacetate In the same manner as in Reference Example 1, synoxy and methyl ethoxyiminophenylacetate were synthesized using O-ethylhydroxyamine hydrochloride.

¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, t, J = 7.0 Hz), 3.93 (3H, s), 4.27 (2H, q, J = 7.0 Hz), 7.34-7.43 (3H, m), 7.53-7.61 (2H, m).

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.0 Hz), 3.88 (3H, s), 4.33 (2H, q, J = 7.0 Hz), 7.36-7.50 (5H, m).

Example 33
Synthesis of N- (2-ethoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn) Methyl ethoxyiminophenylacetate (syn) and 4- (2,6- The following compounds were synthesized in the same manner as in Example 1 and Example 2 using dichlorobenzoylamino) -L-phenylalanine ethyl ester.

N- (2-Ethoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.27-1.36 (6H, m), 3.17 (1H, dd, J = 14.0, 6.5 Hz), 3.31 (1H, dd, J = 14.0, 5.1 Hz), 4.18-4.32 (4H, m), 5.07-5.16 (1H, m), 6.61 (1H, d, J = 7.6 Hz), 7.17-7.63 (13H, m).

N- (2-Ethoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7.0 Hz), 2.87 (1H, dd, J = 13.5, 10.8 Hz), 3.17 (1H, dd, J = 14.0, 3.8 Hz ), 4.08 (2H, q, J = 7.0Hz), 4.57-4.71 (1H, m), 7.19-7.67 (12H, m), 8.95 (1H, d, J = 8.1 Hz), 10.73 (1H, s) .
MS m / z: 526 [M−H] ⁻ .

Example 34
N- (2-Ethoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)
The following compounds were synthesized in the same manner as in Example 33 using methyl ethoxyiminophenylacetate (anti).

N- (2-Ethoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.25-1.34 (6H, m), 3.12-3.29 (2H, m), 4.16-4.31 (4H, m), 4.87-4.97 (1H, m), 7.17-7.50 ( 12H, m), 7.58 (2H, dd, J = 6.8, 1.9 Hz).

N- (2-Ethoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.25 (3H, t, J = 7.0 Hz), 3.03 (1H, dd, J = 13.8, 10.0 Hz), 3.16 (1H, dd, J = 13.8, 4.9 Hz ), 4.20 (2H, q, J = 7.0Hz), 4.48-4.64 (1H, m), 7.21-7.69 (12H, m), 8.49 (1H, d, J = 8.1 Hz), 10.72 (1H, s) .
MS m / z: 526 [M−H] ⁻ .

Reference Example 27
Synthesis of methyl phenoxyiminophenylacetate Methyl phenoxyiminophenylacetate was synthesized in the same manner as in Reference Example 1 using O-phenylhydroxylamine hydrochloride.

¹ H-NMR (CDCl ₃ ) δ; 4.01 (3H, s), 7.03-7.12 (1H, m), 7.21-7.53 (7H, m), 7.65-7.77 (2H, m).

¹ H-NMR (CDCl ₃ ) δ; 3.93 (3H, s), 7.03-7.13 (1H, m), 7.22-7.39 (4H, m), 7.45-7.51 (3H, m), 7.55-7.63 (2H, m).

Example 35
N- (2-phenoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)
The following compounds were obtained in the same manner as in Examples 1 and 2 using methyl phenoxyiminophenyl acetate.

N- (2-phenoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.0 Hz), 3.19 (1H, dd, J = 14.0, 7.0 Hz), 3.35 (1H, dd, J = 14.0, 5.4 Hz), 4.26 (2H, q, J = 7.0 Hz), 5.16-5.26 (1H, m), 6.54 (1H, d, J = 8.1 Hz), 7.02-7.71 (18H, m).

N- (2-phenoxyimino-2-phenylacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.90 (1H, dd, J = 14.3, 11.3 Hz), 3.25 (1H, dd, J = 14.3, 3.5 Hz), 4.73-4.86 (1H, m), 7.00 -7.18 (3H, m), 7.27-7.69 (14H, m), 9.32 (1H, d, J = 8.1 Hz), 10.77 (1H, s). MS m / z: 576 [M + H] ⁺ .

Reference Example 28
Synthesis of ethyl methoxyimino (p-tolyl) acetate 10 g (0.056 mol) of ethyl p-tolylacetate was dissolved in 120 mL of benzotrifluoride and 0.615 N-hydroxyphthalimide in water 0.915 g (0.0056 mol) n-tetrabutyl 0.362 g (1.12 mmol) of ammonium bromide was added, and the mixture was stirred at 80 ° C. for 24 hours under oxygen substitution. After completion of the reaction, 5% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain 0.96 g of ethyl oxo (p-tolyl) acetate.
0.96 g (5 mmol) of the obtained ethyl oxo (p-tolyl) acetate was dissolved in 10 mL of methanol, and 0.54 g (6.49 mmol) of O-methylhydroxylamine hydrochloride and 1.1 mL (15.0 mmol) of pyridine were added. The mixture was added and stirred at 60 ° C. overnight. After completion of the reaction, 5% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 10) to obtain 0.76 g of the target syn type and 0.16 g of anti type.

Methoxyimino (p-tolyl) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.38 (3H, t, J = 7.0 Hz), 2.37 (3H, s), 4.00 (3H, s), 4.42 (2H, q, J = 7.0 Hz), 7.19 ( 2H, d, J = 8.1 Hz), 7.46 (2H, d, J = 8.1 Hz).

Methoxyimino (p-tolyl) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.35 (3H, t, J = 7.0 Hz), 2.38 (3H, s), 4.05 (3H, s), 4.36 (2H, q, J = 7.0 Hz), 7.22 ( 2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.1 Hz).

In the same manner as in Reference Example 28, the following methoxyiminoacetic acid ester compound was obtained from a suitable phenylacetic acid derivative.
Reference Examples 29-32
Reference Example 29
3-Chlorophenyl (methoxyimino) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.0 Hz), 4.03 (3H, s), 4.43 (2H, q, J = 7.0 Hz), 7.25-7.47 (3H, m), 7.57-7.64 (1H, m).
3-Chlorophenyl (methoxyimi) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0 Hz), 4.07 (3H, s), 4.36 (2H, q, J = 7.1 Hz), 7.25-7.47 (4H, m).

Reference Example 30
Methyl 3,4-dichlorophenyl (methoxyimino) acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 3.95 (3H, s), 4.03 (3H, s), 7.34-7.50 (2H, m), 7.67 (1H, d, J = 1.9 Hz).
Methyl 3,4-dichlorophenyl (methoxyimino) acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 3.90 (3H, s), 4.08 (3H, s), 7.22-7.29 (1H, m), 7.46-7.56 (2H, m).

Reference Example 31
Methoxyimino (4-methoxyphenyl) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.38 (3H, t, J = 7.3 Hz), 3.82 (3H, s), 3.99 (3H, s), 4.42 (2H, q, J = 7.3 Hz), 6.85- 6.95 (2H, m), 7.42-7.56 (2H, m).
Methoxyimino (4-methoxyphenyl) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0 Hz), 3.83 (3H, s), 4.05 (3H, s), 4.36 (2H, q, J = 7.0 Hz), 6.87- 7.00 (2H, m), 7.41-7.52 (2H, m).

Reference Example 32
4-Ethoxyphenyl (methoxyimino) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.34-1.50 (6H, m), 3.99 (3H, s), 4.05 (2H, q, J = 7.0 Hz), 4.42 (2H, q, J = 7.1 Hz), 6.84-6.92 (2H, m), 7.44-7.56 (2H, m).
4-Ethoxyphenyl (methoxyimino) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.34-1.49 (6H, m), 4.00-4.12 (5H, m), 4.36 (2H, q, J = 7.0 Hz), 6.84-6.96 (2H, m), 7.40 -7.50 (2H, m).

  Example 1 using the compound obtained in Reference Examples 28 to 32 and 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester or 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester 2, the following compounds were obtained. Examples 36-48

Example 36
N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.23 (3H, t, J = 7.0 Hz), 2.30 (3H, s), 2.88 (1H, dd, J = 13.8, 11.3 Hz), 3.15 (1H, dd , J = 13.8, 4.3 Hz), 3.82 (3H, s), 4.09-4.26 (2H, m), 4.65-4.78 (1H, m), 7.12-7.35 (6H, m), 7.47-7.70 (5H, m ), 9.13 (1H, d, J = 8.4 Hz), 10.74 (1H, s).

N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.29 (3H, s), 2.87 (1H, dd, J = 14.0, 10.5 Hz), 3.16 (1H, dd, J = 14.0, 3.8 Hz), 3.81 (3H , s), 4.50-4.66 (1H, m), 7.12-7.37 (6H, m), 7.49-7.71 (5H, m), 8.74-8.92 (1H, m), 10.72 (1H, s). MS m / z: 526 [M−H] ⁻ .

Example 37
N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 1.20 (3H, t, J = 7.0 Hz), 2.30 (3H, s), 3.01 (1H, dd, J = 13.5, 9.7 Hz), 3.13 (1H, dd , J = 13.5, 4.9 Hz), 3.93 (3H, s), 4.15 (2H, q, J = 7.0 Hz), 4.54-4.69 (1H, m), 7.11-7.23 (4H, m), 7.27 (2H, d, J = 8.4 Hz), 7.47-7.71 (5H, m), 8.75 (1H, d, J = 8.1 Hz), 10.73 (1H, s).

N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 2.30 (3H, s), 2.98 (1H, dd, J = 13.5,9.7 Hz), 3.15 (1H, dd, J = 13.5, 4.9 Hz), 3.92 (3H , s), 4.50-4.67 (1H, m), 7.07-7.20 (4H, m) 7.26 (2H, d, J = 8.4 Hz), 7.46-7.69 (5H, m), 8.56 (1H, d, J = 8.1Hz), 10.73 (1H, s) MS m / z: 526 [M−H] ⁻ .

Example 38
N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 2.33 (3H, s), 3.20 (1H, dd, J = 14.0,6.5 Hz), 3.32 (1H, dd, J = 14.0, 5.4 Hz), 3.70 (6H, s ), 3.79 (3H, s), 4.11 (3H, s), 5.09-5.19 (1H, m), 6.52 (1H, d, J = 7.8 Hz), 6.64 (2H, d, J = 8.4 Hz), 7.09 -7.32 (7H, m), 7.48 (2H, d, J = 8.4 Hz).

N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.30 (3H, s), 2.96 (1H, dd, J = 14.0, 10.0 Hz), 3.17 (1H, dd, J = 14.0, 3.9 Hz), 3.65 (6H , s), 3.81 (3H, s), 4.55-4.68 (1H, m), 6.74 (2H, d, J = 8.4 Hz), 7.10-7.20 (4H, m), 7.24-7.33 (3H, m), 7.41 (2H, d, J = 8.1 Hz), 9.10 (1H, d, J = 7.6 Hz).
MS m / z: 477 [M + H] ⁺ .

Example 39
N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ); 2.35 (3H, s), 3.22 (2H, d, J = 6.2 Hz), 3.72 (6H, s), 3.75 (3H, s), 3.98 (3H, s), 4.91 -5.04 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.17-7.40 (10H, m).

N- [2-methoxyimino-2- (4-tolyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.30 (3H, s), 3.06-3.21 (2H, m), 3.64 (6H, s), 3.91 (3H, s), 4.42-4.57 (1H, m) , 6.73 (2H, d, J = 8.6 Hz), 7.10-7.33 (9H, m), 8.37-8.48 (1H, m). MS m / z: 477 [M + H] ⁺ .

Example 40
N- [2- (3-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.0 Hz), 3.11-3.29 (2H, m), 4.01 (3H, s), 4.23 (2H, q, J = 7.0 Hz), 4.87-4.98 (1H, m), 7.21 (2H, d, J = 8.4 Hz), 7.25-7.45 (9H, m), 7.59 (2H, d, J = 8.4 Hz).

N- [2- (3-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.96-3.24 (2H, m), 3.96 (3H, s), 4.49-4.60 (1H, m), 7.14-7.19 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.37-7.64 (8H, m), 8.56 (1H, d, J = 8.1Hz), 10.70 (1H, s). MS: 548 [M + H] ⁺ .

Example 41
N- [2- (3,4-Dichlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.22 (3H, t, J = 7.0 Hz), 2.90 (1H, dd, J = 13.8, 10.5 Hz), 3.16 (1H, dd, J = 13.8, 4.9 Hz) ), 3.88 (3H, s), 4.10-4.24 (2H, m), 4.64-4.75 (1H, m), 7.18-7.31 (3H, m), 7.47-7.72 (7H, m), 9.27 (1H, d , J = 8.1 Hz), 10.73 (1H, s).

N- [2- (3,4-Dichlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.87 (1H, dd, J = 13.8, 10.8 Hz), 3.17 (1H, dd, J = 13.8, 4.3 Hz), 3.86 (3H, s), 4.55-4.71 (1H, m), 7.25-7.38 (3H, m), 7.48-7.80 (7H, m), 9.16 (1H, d, J = 8.1 Hz), 10.72 (1H, s) .MS m / z: 580 [ M−H] ⁻ .

Example 42
N- [2- (3,4-Dichlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 1.19 (3H, t, J = 7.0 Hz), 2.97-3.18 (2H, m), 3.98 (3H, s), 4.13 (2H, q, J = 7.0 Hz ), 4.55-4.66 (1H, m), 7.18 (1H, dd, J = 8.4, 1.9 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.47-7.68 (7H, m), 8.78 (1H, d, J = 8.1 Hz), 10.72 (1H, s).

N- [2- (3,4-dichlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.92-3.20 (2H, m), 3.97 (3H, s), 4.47-4.63 (1H, m), 7.08-7.33 (3H, m), 7.42-7.71 ( 7H, m), 8.59 (1H, d, J = 8.6Hz), 10.71 (1H, s).
MS m / z: 580 [M−H] ⁻ .

Example 43
N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.0 Hz), 3.15 (1H, dd, J = 14.0, 6.5 Hz), 3.31 (1H, dd, J = 14.0, 5.4 Hz), 3.81 (3H, s), 3.98 (3H, s), 4.23 (2H, q, J = 7.0 Hz), 5.04-5.16 (1H, m), 6.44 (1H, d, J = 7.8 Hz), 6.83-6.90 (2H, m), 7.13-7.42 (6H, m), 7.44-7.51 (2H, m), 7.54-7.61 (2H, m).

N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.86 (1H, dd, J = 13.5, 11.1 Hz), 3.18 (1H, dd, J = 13.5, 4.3 Hz), 3.77 (3H, s), 3.79 (3H , s), 4.56-4.73 (1H, m), 6.89 (2H, d, J = 8.9 Hz), 7.25-7.34 (4H, m), 7.50-7.73 (5H, m), 8.97 (1H, d, J = 8.1Hz), 10.72 (1H, s).
MS m / z: 542 [M−H] ⁻ .

Example 44
N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.08-3.28 (2H, m), 3.98 (3H, s), 4.11 (3H, s), 4.22 (2H, q , J = 7.1 Hz), 4.87-4.99 (1H, m), 6.91 (2H, d, J = 8.9 Hz), 7.18-7.40 (7H, m), 7.46 (2H, d, J = 8.9 Hz), 7.58 (2H, d, J = 8.6 Hz).

N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.98 (1H, dd, J = 13.8, 9.7 Hz), 3.15 (1H, dd, J = 13.8, 4.9 Hz), 3.77 (3H, s), 3.92 (3H , s), 4.50-4.66 (1H, m), 6.90 (2H, d, J = 8.6 Hz), 7.23-7.32 (4H, m), 7.45-7.68 (5H, m), 8.58 (1H, d, J = 8.4Hz), 10.72 (1H, s).
MS m / z: 542 [M−H] ⁻ .

Example 45
N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 2.98 (1H, dd, J = 14.0, 10.8 Hz), 3.17 (1H, dd, J = 14.0, 4.3 Hz), 3.66 (6H, s), 3.72 (3H , s), 3.74 (3H, s), 3.80 (3H, s), 4.61-4.74 (1H, m), 6.74 (2H, d, J = 8.6 Hz), 6.93 (2H, d, J = 8.9 Hz) , 7.14 (2H, d, J = 8.4 Hz) 7.22-7.33 (3H, m), 7.41 (2H, d, J = 8.9 Hz), 9.22 (1H, d, J = 7.6 Hz).

N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.95 (1H, dd, J = 14.3, 11.1 Hz), 3.18 (1H, dd, J = 14.3, 3.8 Hz), 3.65 (6H, s), 3.74 (3H , s), 3.80 (3H, s), 4.52-4.65 (1H, m), 6.74 (2H, d, J = 8.4 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.13 (1H, d, J = 8.1 Hz) 7.24-7.33 (3H, m), 7.43 (2H, d, J = 8.6 Hz), 8.92-9.07 (1H, m). MS m / z: 493 [M + H] ⁺ .

Example 46
N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 3.09-3.16 (2H, m), 3.64 (6H, s), 3.68 (3H, s), 3.76 (3H, s), 3.94 (3H, s), 4.60 -4.70 (1H, m), 6.74 (2H, d, J = 8.6 Hz), 6.92 (2H, d, J = 8.9 Hz), 7.15 (2H, d, J = 8.4 Hz) 7.22-7.33 (3H, m ), 7.40 (2H, d, J = 8.9 Hz), 8.83 (1H, d, J = 7.6 Hz).

N- [2-methoxyimino-2- (4-methoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.07 (1H, dd, J = 13.8, 8.4 Hz), 3.18 (1H, dd, J = 13.8, 4.3 Hz), 3.64 (6H, s), 3.75 (3H , s), 3.92 (3H, s), 4.47-4.61 (1H, m), 6.73 (2H, d, J = 8.6 Hz), 6.91 (2H, d, J = 8.9 Hz), 7.14 (1H, d, J = 7.1 Hz) 7.21-7.33 (3H, m), 7.39 (2H, d, J = 8.9 Hz), 8.47-8.58 (1H, m). MS m / z: 493 [M + H] ⁺ .

Example 47
N- [2- (4-Ethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.0 Hz), 1.40 (3H, t, J = 7.0 Hz), 3.09-3.36 (2H, m), 3.97 (3H, s), 4.03 (2H, q, J = 7.0 Hz), 4.23 (2H, q, J = 7.0 Hz), 5.03-5.15 (1H, m), 6.45 (1H, d, J = 7.6 Hz), 6.80-6.89 (2H , m), 7.16-7.52 (8H, m), 7.57 (2H, d, J = 8.6 Hz).

N- [2- (4-Ethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.31 (3H, t, J = 7.0 Hz), 2.86 (1H, dd, J = 14.0, 10.8 Hz), 3.15 (1H, dd, J = 14.0, 4.1 Hz ), 3.78 (3H, s), 4.03 (2H, q, J = 7.0 Hz), 4.58-4.69 (1H, m), 6.86 (2H, d, J = 8.9 Hz), 7.22-7.30 (4H, m) , 7.47-7.65 (5H, m), 8.99 (1H, d, J = 8.4 Hz), 10.72 (1H, s). MS m / z: 556 [M−H] ⁻ .

Example 48
N- [2- (4-Ethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 1.41 (3H, t, J = 7.0 Hz), 3.11-3.30 (2H, m), 4.00 (3H, s), 4.05 (2H, q, J = 7.0 Hz), 4.22 (2H, q, J = 7.1 Hz), 4.90-4.99 (1H, m), 6.89 (2H, dd, J = 7.0, 2.2 Hz), 7.21 (2H , d, J = 8.6 Hz), 7.25-7.51 (7H, m), 7.58 (2H, d, J = 8.6 Hz).

N- [2- (4-Ethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.32 (3H, t, J = 7.0 Hz), 2.97 (1H, dd, J = 14.0, 9.5 Hz), 3.16 (1H, dd, J = 14.0, 4.9 Hz) ), 3.92 (3H, s), 4.04 (2H, q, J = 7.0 Hz), 4.51-4.63 (1H, m), 6.87 (2H, d, J = 9.2 Hz), 7.20-7.33 (4H, m) , 7.46-7.65 (5H, m), 8.51 (1H, d, J = 8.4 Hz), 10.71 (1H, s). MS m / z: 556 [M−H] ⁻ .

Reference Example 33
Synthesis of ethyl 3,4-dimethoxyphenyl (methoxyimino) acetate 11.2 g (0.05 mol) of ethyl 3,4-dimethoxyphenylacetate was dissolved in 50 mL of acetic acid and 0.816 g (5 mmol) of cobalt acetate Hydrate 62 mg (0.25 mmol) was added, and the mixture was stirred under oxygen substitution at 40 ° C. for 24 hours. After completion of the reaction, acetic acid was distilled off under reduced pressure, 10% aqueous sodium carbonate solution was added, extraction was performed with ethyl acetate, the organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was distilled under reduced pressure. Left. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 2.27 g (9.53 mmol) of ethyl (3,4-dimethoxyphenyl) oxoacetate.
The obtained 2.27 g (9.53 mmol) of ethyl (3,4-dimethoxyphenyl) oxoacetate was dissolved in 20 mL of methanol, 1.3 g (0.012 mol) of O-methylhydroxylamine hydrochloride and 2.1 mL of pyridine ( 0.029 mol) was added and the mixture was stirred at 50 ° C. overnight. After completion of the reaction, 5% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3), and the isomers were separated to give the title compound. Syn type 1.84 g (6.88 mmol) Anti type 0.26 g (0.97 mmol)

3,4-Dimethoxyphenyl (methoxyimino) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.0 Hz), 3.90 (3H, s), 3.92 (3H, s), 4.00 (3H, s), 4.42 (2H, q, J = 7.0 Hz), 6.84 (1H, d, J = 8.4 Hz), 6.98 (1H, dd, J = 8.4, 2.2 Hz), 7.24 (1H, d, J = 1.9 Hz).

3,4-Dimethoxyphenyl (methoxyimino) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, t, J = 7.0 Hz), 3.88 (3H, s), 3.91 (3H, s), 4.07 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 6.90 (1H, d, J = 8.1 Hz), 7.04-7.11 (2H, m).

Reference Example 34
Synthesis of ethyl methoxyimino (3,4,5-trimethoxyphenyl) acetate In the same manner as in Reference Example 33, the title compound was obtained.

Methoxyimino (3,4,5-trimethoxyphenyl) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.39 (3H, t, J = 7.0 Hz), 3.867 (3H, s), 3.872 (6H, s), 4.02 (3H, s), 4.43 (2H, q, J = 7.0 Hz), 6.80 (2H, s).

Methoxyimino (3,4,5-trimethoxyphenyl) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.38 (3H, t, J = 7.0 Hz), 3.85 (6H, s), 3.89 (3H, s), 4.07 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 6.67 (2H, s).

  Using the appropriate ethyl methoxyiminoacetate derivatives obtained in Reference Examples 33 to 34, the following compounds were obtained in the same manner as in Examples 1 and 2. Examples 49-52

Example 49
N- [2- (3,4-Dimethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.21 (3H, t, J = 7.0 Hz), 2.85-2.97 (1H, m), 3.07-3.17 (1H, m), 3.75 (3H, s), 3.78 (3H, s), 3.80 (3H, s), 4.10-4.22 (2H m), 4.59-4.69 (1H, m), 6.92 (1H, dd, J = 8.4, 1.9 Hz), 6.92 (1H, d, J = 8.6Hz), 7.17 (1H, d, J = 1.9 Hz), 7.27 (2H, d, J = 8.6 Hz), 7.47-7.66 (5H, m), 9.12 (1H, d, J = 8.1 Hz) , 10.71 (1H, s).

N- [2- (3,4-Dimethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.81-2.99 (1H, m), 3.10-3.22 (1H, m), 3.74 (3H, s), 3.77 (3H, s), 3.78 (3H, s) , 4.49-4.64 (1H, m), 6.91 (2H, s), 7.18 (1H, s), 7.28 (2H, d, J = 7.6Hz), 7.45-7.69 (5H, m), 9.01 (1H, d , J = 8.4 Hz), 10.71 (1H, s). MS m / z: 574 [M + H] ⁺ .

Example 50
N- [2-methoxyimino-2- (3,4-dimethoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7.0 Hz), 2.98-3.16 (2H, m), 3.69 (3H, s), 3.78 (3H, s), 3.94 (3H , s), 4.12 (2H, q, J = 7.0 Hz), 4.51-4.63 (1H, m), 6.95 (2H, s), 7.11 (1H, s), 7.27 (2H, d, J = 8.6 Hz) , 7.49-7.71 (5H, m), 8.74 (1H, d, J = 7.6 Hz), 10.71 (1H, s).

N- [2- (3,4-Dimethoxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.96-3.07 (1H, m), 3.09-3.20 (1H, m), 3.68 (3H, s), 3.78 (3H, s), 3.93 (3H, s) , 4.46-4.60 (1H, m), 6.80-6.98 (2H, m), 7.09 (1H, s), 7.27 (2H, d, J = 8.4 Hz), 7.45-7.69 (5H, m), 8.56 (1H , d, J = 8.1Hz), 10.70 (1H, s). MS m / z: 574 [M + H] ⁺ .

Example 51
N- [2-methoxyimino-2- (3,4,5-trimethoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7.0 Hz), 2.88-3.02 (1H, m), 3.05-3.16 (1H, m), 3.69 (3H, s), 3.76 (6H, s), 3.81 (3H, s), 4.13 (2H, q, J = 7.0 Hz), 4.52-4.65 (1H, m), 6.86 (2H, s), 7.27 (2H, d, J = 8.6 Hz), 7.46-7.63 (5H, m), 9.18 (1H, d, J = 7.6 Hz), 10.69 (1H, s).

N- [2-methoxyimino-2- (3,4,5-trimethoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.87-2.97 (1H, m), 3.10-3.20 (1H, m), 3.68 (3H, s), 3.76 (6H, s), 3.78 (3H, s) , 4.35-4.58 (1H, m), 6.94 (2H, s), 7.28 (2H, d, J = 8.4 Hz), 7.42-7.68 (5H, m), 9.06 (1H, d, J = 7.6 Hz), 10.68 (1H, s).
MS m / z: 604 [M + H] ⁺ .

Example 52
N- [2-methoxyimino-2- (3,4,5-trimethoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 1.17 (3H, t, J = 7.3Hz), 3.04-3.12 (2H, m), 3.69 (3H, s), 3.72 (6H, s), 3.95 (3H , s), 4.11 (2H, q, J = 7.3 Hz), 4.50-4.61 (1H, m), 6.71 (2H, s), 7.26 (2H, d, J = 8.6 Hz), 7.46-7.64 (5H, m), 8.71 (1H, d, J = 7.6 Hz), 10.70 (1H, s).

N- [2-methoxyimino-2- (3,4,5-trimethoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.95-3.19 (2H, m), 3.69 (3H, s), 3.71 (6H, s), 3.94 (3H, s), 4.39-4.58 (1H, m) , 6.73 (2H, s), 7.26 (2H, d, J = 8.6Hz), 7.45-7.68 (5H, m), 8.54 (1H, d, J = 7.8 Hz), 10.69 (1H, s). / z: 604 [M + H] ⁺ .

Reference Example 35
2- (4-Chlorophenyl) -2-methoxyiminoacetic acid ethyl ester
a) To a solution of 39.0 g (196 mmol) of ethyl 4-chlorophenylacetate in ethanol (500 mL) was added 33.7 g (300 mmol) of potassium t-butoxy and then 23.4 g (200 mmol) of isoamyl nitrite, and the mixture was stirred at 60 ° C. for 6 hours. did. Ethanol was distilled off under reduced pressure, and the residue was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 100/1) to obtain 15.0 g (65.9 mmol) of ethyl 2- (4-chlorophenyl) -2-hydroxyiminoacetate.
b) To a solution of 2.64 g (66 mmol) of sodium hydride in DMF (100 mL), a solution of 15.0 g (65.9 mmol) of the product obtained above in DMF (30 mL) was added dropwise under ice-cooling and stirred for 30 minutes. . To the mixture, 10.6 g (74.8 mmol) of methyl iodide was added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 9/1), and 1.20 g (5.62 mmol) of ethyl 2- (4-chlorophenyl) -2-methoxyiminoacetate (syn) and 2 Two isomers of 1.20 g (5.62 mmol) of ethyl-(4-chlorophenyl) -2-methoxyiminoacetate (anti) were obtained.

2- (4-Chlorophenyl) -2-methoxyiminoacetic acid ethyl (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.38 (3H, t, J = 7.0 Hz), 4.02 (3H, s), 4.42 (2H, q, J = 7.0 Hz), 7.36 (2H, m), 7.51 ( 2H, m).
2- (4-Chlorophenyl) -2-methoxyiminoethyl acetate (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0 Hz), 4.06 (3H, s), 4.36 (2H, q, J = 7.0 Hz), 7.36 (4H, m).

  Using the corresponding phenylacetic acid derivative in the same manner as in Reference Example 35, the following phenylmethoxyiminoacetic acid ester derivative was obtained. Reference Examples 36-40

Reference Example 36
2- (2-methoxyphenyl) -2-methoxyiminoethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.32 (3H, t, J = 7.0 Hz), 3.79 (3H, s), 4.04 (3H, s), 4.33 (2H, q, J = 7.0 Hz), 6.94 ( 1H, d, J = 8.4 Hz), 7.00 (1H, dt, J = 7.3, 0.8 Hz), 7.30 (1H, dd, J = 7.3, 1.4 Hz), 7.39 (1H, ddd, J = 8.4,7.3, 1.4 Hz).

2- (2-methoxyphenyl) -2-methoxyiminoethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.21 (3H, t, J = 7.2 Hz), 3.79 (3H, s), 4.20 (5H, m), 6.93 (1H, d, J = 8.4 Hz), 7.03 ( 1H, dt, J = 7.6, 0.9 Hz), 7.34-7.41 (1H, m), 7.53 (1H, dd, J = 7.6, 1.8 Hz).

Reference Example 37
Benzo [1,3] dioxol-5-yl-methoxyiminoacetic acid ethyl (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0 Hz), 4.06 (3H, s), 4.36 (2H, q, J = 7.0 Hz), 6.00 (2H, s), 6.84 ( 1H, d, J = 8.1 Hz), 6.94-7.01 (2H, m).

Benzo [1,3] dioxol-5-yl-methoxyiminoacetic acid ethyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.35 (3H, t, J = 7.2 Hz), 4.03 (3H, s), 4.37 (2H, q, J = 7.2 Hz), 6.01 (2H, s), 6.84 ( 1H, d, J = 8.1 Hz), 7.23 (1H, dd, J = 8.1, 1.8 Hz), 7.52 (1H, d, J = 1.8 Hz).

Reference Example 38
2- (4-Dimethylaminophenyl) -2-methoxyiminoacetic acid ethyl (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0 Hz), 3.00 (6H, s), 4.04 (3H, s), 4.36 (2H, q, J = 7.0 Hz), 6.68 ( 2H, d, J = 9.2 Hz), 7.48 (2H, d, J = 9.2 Hz).
2- (4-Dimethylaminophenyl) -2-methoxyiminoethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.38 (3H, t, J = 7.2 Hz), 3.02 (6H, s), 3.91 (3H, s), 4.40 (2H, q, J = 7.2 Hz), 6.68 ( 2H, d, J = 8.9 Hz), 7.94 (2H, d, J = 8.9 Hz).

Reference Example 39
2- (4-Trifluoromethylphenyl) -2-methoxyiminoacetic acid methyl ester (syn)

¹ H-NMR (CDCl ₃ ) δ; 3.96 (3H, s), 4.06 (3H, s), 7.59-7.73 (4H, m).
2- (4-Trifluoromethylphenyl) -2-methoxyiminoacetic acid methyl ester (anti)

¹ H-NMR (CDCl ₃ ) δ; 3.90 (3H, s), 4.08 (3H, s), 7.52 (2H, dd, J = 5.4, 8.6Hz), 7.68 (2H, dd, J = 5.4, 8.6Hz ).

Reference Example 40
2- (4-Methanesulfonylphenyl) -2-methoxyiminoacetic acid ethyl (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.40 (3H, t, J = 7.0 Hz), 3.06 (3H, s), 4.07 (3H, s), 4.45 (2H, q, J = 7.0 Hz), 7.74- 7.82 (2H, m), 7.92-8.00 (2H, m).
2- (4-Methanesulfonylphenyl) -2-methoxyiminoethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, t, J = 7.0 Hz), 3.08 (3H, s), 4.05 (3H, s), 4.38 (2H, q, J = 7.0 Hz), 7.57- 7.65 (2H, m), 7.95-8.03 (2H, m).

Reference Example 41
Synthesis of ethyl 2-methoxyimino-2- (4-pyridyl) acetate
After obtaining ethyl 2-hydroxyimino-2- (4-pyridyl) acetate according to the method described in J. Heterocyclic. Chem., 28, 1715 (1991), 2-methoxyimino- 2- (4-Pyridyl) ethyl acetate was obtained.
2-methoxyimino-2- (4-pyridyl) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.40 (3H, t, J = 7.0 Hz), 4.07 (3H, s), 4.44 (2H, q, J = 7.0 Hz), 7.44 (2H, dd, J = 1.6 , 4.6 Hz), 8.65 (2H, dd, J = 1.6, 4.6 Hz).
2-methoxyimino-2- (4-pyridyl) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.0 Hz), 4.08 (3H, s), 4.37 (2H, q, J = 7.0 Hz), 7.30 (2H, dd, J = 1.6 , 4.6 Hz), 8.69 (2H, dd, J = 1.6, 4.6 Hz).

  The methoxyiminoacetic acid ester derivative obtained in Reference Examples 35 to 41 and 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester or 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester were used. In the same manner as in Examples 1 and 2, the following compounds were obtained. Examples 53-74

Example 53
N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.3 Hz), 3.13 (1H, dd, J = 6.5, 14.0 Hz), 3.31 (1H, dd, J = 5.4, 14.0 Hz), 4.00 (3H, s), 4.24 (2H, q, J = 7.3Hz), 5.07-5.14 (1H, m), 6.56 (1H, d, J = 7.6Hz), 7.20 (2H, d, J = 8.6Hz) ), 7.26-7.51 (8H, m), 7.58 (2H, d, J = 8.6Hz).

N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.85 (1H, dd, J = 10.8, 13.8 Hz), 3.18 (1H, dd, J = 4.3, 13.8 Hz), 3.84 (3H, s), 4.62-4.75 (1H, m), 7.27 (4H, m), 7.39 (2H, d, J = 6.8Hz), 7.46-7.67 (5H, m), 9.10 (1H, d, J = 8.4Hz), 10.7 (1H, s), 12.9 (1H, bs).
MS m / z: 546 [M−H] ⁻ .

Example 54
N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.14 (1H, dd, J = 6.2, 13.8 Hz), 3.23 (1H, dd, J = 5.7, 13.8 Hz), 4.00 (3H, s), 4.22 (2H, q, J = 7.0Hz), 4.84-4.96 (1H, m), 7.19 (2H, d, J = 8.4Hz), 7.28-7.43 (9H, m), 7.58 (2H, d, J = 8.4Hz).

N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.92-3.22 (1H, m), 3.14 (1H, dd, J = 13.2, 4.3 Hz), 3.95 (3H, s), 4.56-4.69 (1H, m) , 7.22 (2H, d, J = 6.8Hz), 7.27 (2H, d, J = 8.4Hz), 7.42 (2H, d, J = 6.8Hz), 7.46-7.67 (5H, m), 8.62 (1H, d, J = 8.6Hz), 10.7 (1H, s), 12.9 (1H, bs).
MS m / z: 546 [M−H] ⁻ .

Example 55
N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 2.97 (1H, dd, J = 11.1, 14.0 Hz), 3.20 (1H, dd, J = 4.1, 14.0 Hz), 3.65 (6H, s), 3.73 (3H , s), 3.86 (3H, s), 4.66-4.79 (1H, m), 6.75 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.20-7.50 (7H, m), 9.32 (1H, d, J = 7.8Hz).

N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.94 (1H, dd, J = 10.8, 14.0Hz), 3.20 (1H, dd, J = 3.8, 14.0Hz), 3.65 (6H, s), 3.84 (3H , s), 4.60-4.72 (1H, m), 6.75 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.23-7.43 (7H, m), 9.19 (1H, d, J = 8.1Hz), 12.9 (1H, bs).
MS m / z: 495 [M−H] ⁻ .

Example 56
N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 3.04-3.23 (2H, m), 3.64 (6H, s), 3.68 (3H, s), 3.96 (3H, s), 4.62-4.73 (1H, m) , 6.74 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.4Hz), 7.29 (1H, t, J = 8.4Hz), 7.35 (2H, dd, J = 2.2, 6.8Hz), 7.44 (2H, dd, J = 2.2, 6.8Hz), 8.86 (1H, d, J = 7.6Hz).

N- [2- (4-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.08 (2H, dd, J = 9.6, 14.0 Hz), 3.19 (1H, dd, J = 4.3, 14.0 Hz), 3.64 (6H, s), 3.96 (3H , s), 4.56-4.68 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.29 (1H, t, J = 8.4Hz), 7.35 (2H, dd, J = 2.2, 6.5Hz), 7.43 (2H, dd, J = 2.2, 6.5Hz), 8.65 (1H, d, J = 8.4Hz) , 12.9 (1H, bs).
MS m / z: 495 [M−H] ⁻ .

Example 57
N- [2-methoxyimino-2- (2-methoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7.0 Hz), 3.10 (2H, d, J = 7.3 Hz), 3.64 (3H, s), 3.91 (3H, s), 4.11 (2H, q, J = 7.0 Hz), 4.49-4.59 (1H, m), 6.94 (1H, t, J = 7.3 Hz), 6.99-7.06 (2H, m), 7.24 (2H, d, J = 8.4 Hz), 7.32-7.39 (1H, m), 7.46-7.66 (5H, m), 8.29 (1H, d, J = 7.8 Hz), 10.71 (1H, s).

N- [2-methoxyimino-2- (2-methoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.99-3.22 (2H, m), 3.63 (3H, s), 3.90 (3H, s), 4.45-4.59 (1H, m), 6.90-6.97 (1H, m), 6.99-7.07 (2H, m), 7.23 (2H, d, J = 8.6 Hz), 7.31-7.49 (1H, m), 7.46-7.65 (5H, m), 8.07 (1H, d, J = 8.1Hz), 10.70 (1H, s).
MS m / z: 544 [M + H] ⁺ .

Example 58
N- [2-methoxyimino-2- (2-methoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 3.13-3.19 (2H, m), 3.62 (3H, s), 3.65 (6H, s), 3.66 (3H, s), 3.92 (3H, s), 4.54 -4.66 (1H, m), 6.73 (2H, d, J = 8.6 Hz), 6.90-7.42 (9H, m), 8.45 (1H, d, J = 7.6 Hz).

N- [2-methoxyimino-2- (2-methoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 3.16 (2H, d, J = 5.9 Hz), 3.62 (3H, s), 3.65 (6H, s), 3.90 (3H, s), 4.44-4.60 (1H , m), 6.73 (2H, d, J = 8.6 Hz), 6.91-7.42 (9H, m), 8.16 (1H, d, J = 7.6 Hz).
MS m / z: 493 [M + H] ⁺ .

Example 59
N- [2- (Benzo [1,3] dioxol-5-yl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.19 (3H, t, J = 7.2 Hz), 3.00 (1H, dd, J = 13.8, 9.7 Hz), 3.13 (1H, dd, J = 13.8, 5.3 Hz ), 3.93 (3H, s), 4.13 (2H, q, J = 7.2 Hz), 4.55-4.67 (1H, m), 6.06 (2H, s), 6.64 (1H, dd, J = 8.1, 1.6 Hz) , 6.88 (1H, d, J = 8.1 Hz), 7.10 (1H, d, J = 1.6 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.46-7.66 (5H, m), 8.77 (1H, d, J = 8.1 Hz), 10.72 (1H, s).

N- [2- (Benzo [1,3] dioxol-5-yl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.98 (1H, dd, J = 14.0, 10.0 Hz), 3.15 (1H, dd, J = 14.0, 3.8 Hz), 3.93 (3H, s), 4.52-4.65 (1H, m), 6.05 (2H, s), 6.54-6.60 (1H, m), 6.85 (1H, d, J = 8.1 Hz), 7.05 (1H, d, J = 1.1 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.46-7.65 (5H, m), 8.60 (1H, d, J = 8.4 Hz), 10.73 (1H, s).
MS m / z: 558 [M + H] ⁺ .

Example 60
N- [2- (Benzo [1,3] dioxol-5-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 3.05-3.18 (2H, m), 3.64 (6H, s), 3.67 (3H, s), 3.94 (3H, s), 4.54-4.71 (1H, m) , 6.05 (2H, s), 6.73 (2H, d, J = 8.6 Hz), 6.84-6.93 (2H, m), 7.06-7.13 (6H, m), 8.83 (1H, d, J = 8.1 Hz).

N- [2- (Benzo [1,3] dioxol-5-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 3.00-3.23 (2H, m), 3.64 (6H, s), 3.93 (3H, s), 4.49-4.64 (1H, m), 6.05 (2H, s) , 6.73 (2H, d, J = 8.4 Hz), 6.86-6.89 (2H, m), 7.05-7.33 (6H, m), 8.62 (1H, d, J = 7.8 Hz).
MS m / z: 507 [M + H] ⁺ .

Example 61
N- [2-methoxyimino-2- (4-dimethylaminophenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn, anti mixture) (syn: anti = 3: 7)
¹ H-NMR (CDCl ₃ ) δ; 1.23-1.33 (3H, m), 2.98 and 3.04 (3H, 2s), 3.10-3.30 (2H, m), 3.96 and 3.99 (3H, 2s), 4.16-4.26 ( 2H, m), 4.89-5.15 (1H, m), 6.61-6.71 (2H, m), 7.19-7.61 (10H, m).

N- [2-methoxyimino-2- (4-dimethylaminophenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn, anti mixture)

(syn : anti = 2 : 8)

(syn: anti = 2: 8)

¹ H-NMR (DMSO-d ₆ ) δ; 2.93 and 3.00 (6H, s), 3.10-3.23 (2H, m), 3.75 and 3.88 (3H, 2s), 4.33-4.57 (1H, m), 6.63 and 6.75 (2H, 2d, J = 10.0 and 9.2 Hz), 7.19-7.36 (4H, m) 7.45-7.66 (5H, m), 8.15-8.32 (1H, m), 10.68 (1H, s).
MS m / z: 557 [M + H] ⁺ .

Example 62
N- [2-methoxyimino-2- (4-dimethylaminophenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn, anti mixture) (syn: anti = 4: 6 )
¹ H-NMR (CDCl ₃ ) δ; 2.96 and 2.97 (6H, 2s), 3.18-3.30 (2H, m), 3.70 and, 3.71 (6H, 2s), 3.74 and 3.76 (3H, 2s) 3.93 and 3.98 ( 3H, 2s), 6.60-6.71 (5H, m), 7.17-7.33 (4H, m), 7.41-7.52 (3H, m).

N- [2-methoxyimino-2- (4-dimethylaminophenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn, anti mixture)

(syn : anti = 3 : 7)

(syn: anti = 3: 7)

¹ H-NMR (DMSO-d ₆ ) δ; 2.90 and 2.91 (6H, 2s), 3.04-3.22 (2H, m), 3.64 (6H, s), 3.75 and 3.89 (3H, s), 4.29-4.44 ( 1H, m), 6.60-6.80 (4H, m) 7.08-7.46 (7H, m).
MS m / z: 506 [M + H] ⁺ .

Example 63
N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.32 (3H, t, J = 7.3 Hz), 3.17 (1H, dd, J = 6.5, 14.0 Hz), 3.32 (1H, dd, J = 5.1, 14.0 Hz), 4.04 (3H, s), 4.25 (2H, q, J = 7.3Hz), 5.05-5.13 (1H, m), 6.67 (1H, d, J = 7.6Hz), 7.21 (2H, d, J = 8.4Hz) ), 7.29-7.44 (3H, m), 7.42 (1H, s), 7.55-7.63 (4H, m), 7.67 (2H, d, J = 8.6Hz).

N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.87 (1H, dd, J = 13.8, 11.3 Hz), 3.12 (1H, dd, J = 13.8, 4.3 Hz), 3.88 (3H, s), 4.62-4.74 (1H, m), 7.27 (2H, d, J = 8.4Hz), 7.45-7.67 (7H, m), 7.71 (2H, d, J = 8.6Hz), 9.14 (1H, d, J = 8.6Hz) , 10.7 (1H, s), 12.9 (1H, bs).
MS m / z: 580 [M−H] ⁻ .

Example 64
N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.18 (1H, dd, J = 7.0, 14.0Hz), 3.35 (1H, dd, J = 4.9, 14.0Hz), 3.70 (6H, s), 3.82 (3H, s ), 4.01 (3H, s), 5.10-5.18 (1H, m), 6.65 (2H, d, J = 8.6Hz), 6.69 (1H, d, J = 8.1Hz), 7.20 (2H, d, J = 8.1Hz), 7.25-7.31 (3H, m), 7.57 (2H, d, J = 8.4Hz), 7.66 (2H, d, J = 8.4Hz).

N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.94 (1H, dd, J = 10.8, 14.3 Hz), 3.21 (1H, dd, J = 3.5, 14.3 Hz), 3.64 (6H, s), 3.89 (3H , s), 4.62-4.74 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.27 (2H, d, J = 8.1Hz), 7.30 (1H, t, J = 8.4Hz), 7.61 (2H, d, J = 8.4Hz), 7.70 (2H, d, J = 8.4Hz), 9.23 (1H, d, J = 8.1Hz), 13.0 (1H , bs).
MS m / z: 529 [MH] ^- .

Example 65
N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.3 Hz), 3.16 (1H, dd, J = 6.2, 13.8 Hz), 3.25 (1H, dd, J = 5.9, 13.8 Hz), 4.02 (3H, s), 4.24 (2H, q, J = 7.3Hz), 4.88-4.97 (1H, m), 7.21 (2H, d, J = 8.4Hz), 7.30-7.41 (5H, m), 7.53 (2H, d, J = 8.1Hz), 7.60 (2H, d, J = 8.4Hz), 7.68 (2H, d, J = 8.1Hz).

N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.02 (1H, dd, J = 9.7, 13.5 Hz), 3.17 (1H, dd, J = 4.6, 13.5 Hz), 3.97 (3H, s), 4.55-4.66 (1H, m), 7.27 (2H, d, J = 8.4Hz), 7.42 (2H, d, J = 8.4Hz), 7.46-7.65 (5H, m), 7.74 (2H, d, J = 8.4Hz) , 8.61 (1H, d, J = 8.4Hz), 10.7 (1H, s) 13.0 (1H, bs).
MS m / z: 580 [M−H] ⁻ .

Example 66
N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 3.15-3.31 (2H, m), 3.72 (6H, s), 3.77 (3H, s), 4.01 (3H, s), 4.93-5.02 (1H, m), 6.66 (2H, d, J = 8.4Hz), 7.21 (2H, d, J = 8.4Hz), 7.24-7.35 (4H, m), 7.53 (2H, d, J = 8.1Hz), 7.64 (2H, d, J = 8.1Hz).

N- [2- (4-trifluoromethylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.10 (1H, dd, J = 14.0, 9.7 Hz), 3.20 (1H, dd, J = 14.0, 4.9 Hz), 3.63 (6H, s), 3.97 (3H , s), 4.57-4.68 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.29 (1H, t, J = 8.4Hz), 7.51 (2H, d, J = 8.1Hz), 7.74 (2H, d, J = 8.1Hz), 8.66 (1H, d, J = 8.1Hz), 13.0 (1H , bs).
MS m / z: 529 [M−H] ⁻ .

Example 67
N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, t, J = 7.3 Hz), 3.04 (3H, s), 3.13 (1H, dd, J = 6.8, 14.0 Hz), 3.32 (1H, dd, J = 5.1, 14.0Hz), 4.05 (3H, s), 4.26 (2H, q, J = 7.3Hz), 5.03-5.12 (1H, m), 6.73 (1H, d, J = 7.8Hz), 7.15-7.63 (7H, m), 7.71 (2H, dd, J = 2.2, 6.8Hz), 7.89 (2H, dd, J = 2.2, 6.8Hz).

N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.84-3.21 (2H, m), 3.23 (3H, s), 3.86 (3H, s), 4.56-4.68 (1H, m), 7.22-7.31 (2H, m), 7.46-7.65 (5H, m), 7.70 (2H, d, J = 8.4Hz), 7.92 (2H, d, J = 8.4Hz), 9.12 (1H, d, J = 8.1Hz), 10.7 ( 1H, s).
MS m / z: 590 [M−H] ⁻ .

Example 68
N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.00 (3H, s), 3.18 (1H, dd, J = 14.0, 7.0 Hz), 3.35 (1H, dd, J = 14.0, 5.4 Hz), 3.71 (6H, s ), 3.83 (3H, s), 4.02 (3H, s), 5.08-5.17 (1H, m), 6.66 (2H, d, J = 8.4Hz), 6.81 (1H, d, J = 7.8Hz), 7.17 -7.32 (5H, m), 7.75 (2H, d, J = 8.6Hz), 7.89 (2H, d, J = 8.6Hz).

N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.95 (1H, dd, J = 14.3, 10.8 Hz), 3.35-3.36 (1H, m), 3.19 (3H, s), 3.65 (6H, s), 3.90 (3H, s), 4.56-4.72 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.11-7.33 (5H, m), 7.70 (2H, d, J = 8.6Hz), 7.90 ( 2H, d, J = 8.6Hz), 9.24 (1H, d, J = 7.8Hz), 13.0 (1H, bs).
MS m / z: 539 [M−H] ⁻ .

Example 69
N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.3 Hz), 3.05 (3H, s), 3.11-3.30 (2H, m), 4.03 (3H, s), 4.24 (2H, q , J = 7.3Hz), 4.87-4.97 (1H, m), 7.21 (2H, d, J = 8.4Hz), 7.31-7.41 (5H, m), 7.47-7.63 (4H, m), 7.97 (2H, d, J = 8.6Hz).

N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.04 (1H, dd, J = 13.8, 9.5 Hz), 3.16 (1H, dd, J = 13.8, 5.1 Hz), 3.24 (3H, s), 3.97 (3H , s), 4.51-4.62 (1H, m), 7.26 (2H, d, J = 8.6Hz), 7.46-7.65 (7H, m), 7.94 (2H, d, J = 8.6Hz), 8.56 (1H, d, J = 8.1Hz), 10.7 (1H, s), 13.0 (1H, bs).
MS m / z: 590 [M−H] ⁻ .

Example 70
N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 3.04 (3H, s), 3.15-3.31 (2H, m), 3.72 (6H, s), 3.76 (3H, s), 4.02 (3H, s), 4.92-5.02 (1H, m), 6.66 (2H, d, J = 8.4Hz), 7.18-7.40 (6H, m), 7.61 (2H, d, J = 8.4Hz), 7.96 (2H, d, J = 8.4Hz) .

N- [2-methoxyimino-2- (4-methylsulfonylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.05-3.21 (2H, m), 3.23 (3H, s), 3.64 (6H, s), 3.98 (3H, s), 4.56-4.69 (1H, m) , 6.74 (2H, d, J = 8.1Hz), 7.15 (2H, d, J = 8.1Hz), 7.20-7.34 (3H, m), 7.54 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.65 (1H, d, J = 7.8Hz), 13.0 (1H, bs).
MS m / z: 539 [M−H] ⁻ .

Example 71
N- [2-methoxyimino-2- (4-pyridyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, t, J = 7.0 Hz), 3.16 (1H, dd, J = 6.8, 14.0 Hz), 3.32 (1H, dd, J = 5.1, 14.0 Hz), 4.05 (3H, s), 4.26 (2H, q, J = 7.0Hz), 5.03-5.13 (1H, m), 6.76 (1H, d, J = 7.0Hz), 7.20 (2H, d, J = 8.4Hz) ), 7.29-7.44 (3H, m), 7.41 (2H, dd, J = 1.6, 4.6Hz), 7.59 (2H, d, J = 8.4Hz), 7.67 (1H, s), 8.58 (2H, dd, J = 1.6, 4.6Hz).

N- [2-methoxyimino-2- (4-pyridyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.84 (1H, dd, J = 11.6, 14.0 Hz), 3.19 (1H, dd, J = 4.3, 14.0 Hz), 3.90 (3H, s), 4.64-4.76 (1H, m), 7.15 (2H, dd, J = 1.6, 4.6Hz), 7.27 (2H, d, J = 8.4Hz), 7.47-7.67 (5H, m), 8.54 (2H, dd, J = 1.6 , 4.6Hz), 9.17 (1H, d, J = 8.4Hz), 10.8 (1H, s).
MS m / z: 513 [M−H] ⁻ .

Example 72
N- [2-methoxyimino-2- (4-pyridyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.17 (1H, dd, J = 13.8, 6.8 Hz), 3.35 (1H, dd, J = 13.8, 5.1 Hz), 3.71 (6H, s), 3.83 (3H, s ), 4.02 (3H, s), 5.08-5.13 (1H, m), 6.65 (2H, d, J = 8.6Hz), 6.74 (1H, d, J = 7.6Hz), 7.19 (2H, d, J = 8.1Hz), 7.22-7.34 (3H, m), 7.43 (2H, dd, J = 1.6, 4.3Hz), 8.57 (2H, dd, J = 1.6, 4.3Hz).

N- [2-methoxyimino- (2-pyridin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.93 (1H, dd, J = 11.3, 14.3 Hz), 3.21 (1H, dd, J = 4.1, 14.3 Hz), 3.64 (6H, s), 3.90 (3H , s), 4.62-4.72 (1H, m), 6.75 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.27 (2H, d, J = 8.4Hz), 7.30 (1H, t, J = 8.4Hz), 7.36 (2H, dd, J = 1.6, 4.3Hz), 8.55 (2H, dd, J = 1.6, 4.3Hz), 9.26 (1H, d, J = 8.1Hz) , 13.0 (1H, bs).
MS m / z: 462 [M−H] ⁻ .

Example 73
N- [2-methoxyimino- (2-pyridin-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.3 Hz), 3.15 (1H, dd, J = 6.2, 14.0 Hz), 3.24 (1H, dd, J = 5.9, 14.0 Hz), 4.03 (3H, s), 4.24 (2H, q, J = 7.3Hz), 4.86-4.96 (1H, m), 7.20 (2H, dd, J = 1.9, 6.5Hz), 7.28-7.39 (6H, m) , 7.60 (2H, dd, J = 1.9, 6.5Hz), 7.70 (1H, bs), 8.64 (2H, dd, J = 1.6, 4.3Hz).

N- [2-methoxyimino- (2-pyridin-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.01 (1H, dd, J = 9.7, 13.8 Hz), 3.17 (1H, dd, J = 4.6, 13.8 Hz), 3.97 (3H, s), 4.55-4.66 (1H, m), 7.16 (2H, dd, J = 1.6, 4.6Hz), 7.26 (2H, d, J = 8.4Hz), 7.47-7.65 (5H, m), 8.60 (2H, dd, J = 1.6 , 4.6Hz), 8.65 (1H, d, J = 8.4Hz), 10.7 (1H, s), 13.0 (1H, bs).
MS m / z: 513 [M−H] ⁻ .

Example 74
N- [2-methoxyimino- (2-pyridin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 3.13-3.30 (2H, m), 3.72 (6H, s), 3.77 (3H, s), 4.02 (3H, s), 4.92-5.01 (1H, m), 6.66 (2H, d, J = 8.1Hz), 7.21 (2H, dd, J = 2.2, 6.5Hz), 7.24-7.36 (6H, m), 8.65 (2H, dd, J = 1.6, 4.3Hz).

N- [2-methoxyimino- (2-pyridin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.10 (1H, dd, J = 14.0, 9.5 Hz), 3.20 (1H, dd, J = 14.0, 4.6 Hz), 3.64 (6H, s), 3.98 (3H , s), 4.56 to 4.68 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.1Hz), 7.21 to 7.33 (5H, m), 8.61 (2H, dd, J = 1.6, 4.3Hz), 8.67 (1H, d, J = 8.1Hz).
MS m / z: 462 [M−H] ⁻ .

Reference Example 42
Synthesis of ethyl 2- (4-isopropylphenyl) -2-methoxyiminoacetate 6.47 g (0.031 mol) of ethyl 4-isopropylphenylacetate was dissolved in 60 mL of ethanol, and 5.28 g (0.047 mol) of potassium tert-butoxide was dissolved. ) And 4.18 mL (0.031 mol) isoamyl nitrite were added, and the mixture was stirred at 60 ° C. for 5 hours. After completion of the reaction, the mixture was acidified with 5% aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5), and 2- (4-isopropylphenyl) -2-hydroxyiminoacetic acid ethyl 2.00 g (8.50 mmol) and anti-type 2 .20 g (9.35 mmol) was obtained. 2.00 g (8.50 mmol) of the obtained ethyl 2- (4-isopropylphenyl) -2-hydroxyiminoacetate (syn type) was dissolved in 30 mL of DMF, and 0.58 mL (9.35 mmol) of methyl iodide and potassium carbonate were dissolved. 1.29 g (9.35 mmol) was added and stirred overnight at room temperature. After completion of the reaction, 5% aqueous citric acid solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5) to obtain 1.99 g (7.98 mmol) of the target syn type. The anti-type was synthesized in the same manner.

2- (4-Isopropylphenyl) -2-methoxyiminoacetic acid ethyl (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.24 (6H, d, J = 7.0 Hz), 1.38 (3H, t, J = 7.2 Hz), 2.82-3.00 (1H, m), 4.00 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 7.24 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz).

2- (4-Isopropylphenyl) -2-methoxyiminoethyl acetate (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.26 (6H, d, J = 6.8 Hz), 1.36 (3H, t, J = 7.2 Hz), 2.83-3.00 (1H, m), 4.06 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.40 (2H, d, J = 8.4 Hz).
Similarly, the following methoxyiminoacetic acid ester compound was obtained from a suitable phenylacetic acid derivative. Reference Examples 43-46

Reference Example 43
2- (2-Chlorophenyl) -2-methoxyiminoacetic acid ethyl (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, t, J = 7.0 Hz), 4.07 (3H, s), 4.35 (2H, q, J = 7.0 Hz), 7.20-7.47 (4H, m).

Reference Example 44
Methyl 2-methoxyimino-2- (4-methylsulfanylphenyl) acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 2.49 (3H, s), 3.91 (3H, s), 4.00 (3H, s), 7.18-7.26 (2H, m), 7.42-7.50 (2H, m).

Methyl 2-methoxyimino-2- (4-methylsulfanylphenyl) acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 2.50 (3H, s), 3.91 (3H, s), 4.06 (3H, s), 7.22-7.30 (2H, m), 7.35-7.43 (2H, m).

Reference Example 45
2-methoxyimino-2- (4-propoxyphenyl) ethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.03 (3H, t, J = 7.4 Hz), 1.38 (3H, t, J = 7.2 Hz), 1.81 (2H, sixt, J = 7.4 Hz), 3.94 (2H, t, J = 7.4 Hz), 3.99 (3H, s), 4.42 (2H, q, J = 7.2 Hz), 6.88 (2H, d, J = 8.9 Hz), 7.49 (2H, d, J = 8.9 Hz) .

2-methoxyimino-2- (4-propoxyphenyl) ethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.03 (3H, t, J = 7.4 Hz), 1.36 (3H, t, J = 7.2 Hz), 1.81 (2H, sixt, J = 7.4 Hz), 3.95 (2H, t, J = 7.4 Hz), 4.05 (3H, s), 4.36 (2H, q, J = 7.2 Hz), 6.91 (2H, d, J = 8.9 Hz), 7.44 (2H, d, J = 8.9 Hz) .

Reference Example 46
2- (4-Benzyloxyphenyl) -2-methoxyiminoacetic acid methyl ester (anti)

¹ H-NMR (CDCl ₃ ) δ; 3.89 (3H, s), 4.06 (3H, s), 5.09 (2H, s), 7.00 (2H, d, J = 8.6 Hz), 7.31-7.51 (7H, m ).

2- (4-Benzyloxyphenyl) -2-methoxyiminoacetic acid methyl ester (syn)

¹ H-NMR (CDCl ₃ ) δ; 3.93 (3H, s), 3.99 (3H, s), 5.09 (2H, s), 6.97 (2H, d, J = 9.2 Hz), 7.30-7.54 (7H, m ).

  The methoxyiminoacetic acid ester derivative and 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester or 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester obtained in Reference Examples 42 to 46 were used. In the same manner as in Examples 1 and 2, the following compounds were obtained. Examples 75-88

Example 75
N- [2- (4-Isopropylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.22 (6H, d, J = 6.8 Hz), 2.82-2.94 (1H, m), 3.20 (1H, dd, J = 13.8, 6.9 Hz), 3.31 (1H, dd , J = 13.8, 5.4 Hz), 3.70 (6H, s), 3.79 (3H, s), 3.96 (3H, s), 5.08-5.18 (1H, m), 6.53 (1H, d, J = 7.3Hz) , 6.64 (2H, d, J = 8.4 Hz), 7.16-7.33 (7H, m), 7.52 (2H, d, J = 8.4 Hz).

N- [2- (4-Isopropylphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.15 (3H, d, J = 2.4 Hz), 1.17 (3H, d, J = 2.2 Hz), 2.80-3.02 (2H, m), 3.18 (1H, dd , J = 14.2, 3.6 Hz), 3.65 (6H, s), 3.81 (3H, s), 4.53-4.64 (1H, m), 6.74 (2H, d, J = 8.4 Hz), 7.12 (2H, d, J = 8.4 Hz), 7.18-7.33 (5H, m), 7.43 (2H, d, J = 8.4 Hz), 8.90-9.00 (1H, m).
MS m / z: 503 [M−H] ⁻ .

Example 76
N- [2- (2-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine alanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0Hz), 3.12-3.37 (2H, m), 4.00 (3H, s), 4.22 (2H, q, J = 7.0Hz), 4.89-4.95 (1H, m), 7.17-7.44 (11H, m), 7.58 (2H, d, J = 8.4Hz).

N- [2- (2-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine alanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 3.02-3.20 (2H, m), 3.95 (3H, s), 4.50-4.61 (1H, m), 7.13 (1H, dd, J = 7.3, 1.9 Hz) , 7.23 (2H, d, J = 8.6Hz), 7.31-7.63 (8H, m), 8.31 (1H, d, J = 8.4Hz), 10.7 (1H, s).
MS m / z: 546 [M−H] ^−.

Example 77
N- [2- (2-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.24 (2H, d, J = 6.2 Hz), 3.73 (6H, s), 3.75 (3H, s), 4.00 (3H, s), 4.92-5.04 (1H, m ), 6.65 (2H, d, J = 8.1Hz), 7.17-7.44 (10H, m).

N- [2- (2-Chlorophenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 3.14-3.21 (2H, m), 3.65 (6H, s), 3.95 (3H, s), 4.55-4.65 (1H, m), 6.73 (2H, d, J = 8.4Hz), 7.13 (2H, d, J = 8.4Hz), 7.16-7.52 (9H, m), 8.38 (1H, d, J = 8.1Hz), 12.9 (1H, bs).
MS m / z: 495 [M−H] ⁻ .

Example 78
N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.3 Hz), 2.48 (3H, s), 3.15 (1H, dd, J = 6.5, 14.0 Hz), 3.31 (1H, dd, J = 5.4, 14.0Hz), 3.99 (3H, s), 4.24 (2H, q, J = 7.3Hz), 5.10-5.14 (1H, m), 6.48 (1H, d, J = 7.8Hz), 7.19 (2H , d, J = 8.4Hz), 7.21 (2H, d, J = 8.1Hz), 7.29-7.40 (4H, m), 7.45 (2H, d, J = 8.4Hz), 7.58 (2H, d, J = 8.6Hz).

N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.86 (1H, dd, J = 11.1, 13.8 Hz), 3.15 (1H, dd, J = 4.1, 13.8 Hz), 3.81 (3H, s), 4.61-4.70 (1H, m), 7.19 (2H, d, J = 8.6Hz), 7.27 (4H, m), 7.47-7.66 (5H, m), 9.04 (1H, d, J = 7.8Hz), 10.7 (1H, s), 12.9 (1H, bs).
MS m / z: 558 [M−H] ⁻ .

Example 79
N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 2.44 (3H, s), 3.18 (1H, dd, J = 7.0, 14.3 Hz), 3.33 (1H, dd, J = 5.4, 14.3 Hz), 3.71 (6H, s ), 3.80 (3H, s), 3.96 (3H, s), 5.10-5.19 (1H, m), 6.52 (1H, d, J = 7.6Hz), 6.65 (2H, d, J = 8.4Hz), 7.17 (2H, d, J = 8.4Hz), 7.19 (2H, d, J = 8.4Hz), 7.23-7.32 (3H, m), 7.47 (2H, dd, J = 1.9,8.4Hz).

N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.43 (3H, s), 2.94 (1H, dd, J = 11.3, 14.3 Hz), 3.19 (1H, dd, J = 3.8, 14.3 Hz), 3.65 (6H , s), 3.81 (3H, s), 4.58-4.69 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.12-7.32 (7H, m), 7.38 (2H, d, J = 8.4 Hz), 9.12 (1H, d, J = 7.8Hz).
MS m / z: 507 [M−H] ⁻ .

Example 80
N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.3 Hz), 2.48 (3H, s), 3.16 (1H, dd, J = 6.2, 13.8 Hz), 3.24 (1H, dd, J = 5.9, 13.8 Hz), 4.00 (3H, s), 4.22 (2H, q, 7.3 Hz), 4.88-4.97 (1H, m), 7.16-7.42 (11H, m), 7.59 (2H, d, J = 8.6Hz).

N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.48 (3H, s), 2.98 (1H, dd, J = 10.3, 13.5 Hz), 3.16 (1H, dd, J = 4.3, 13.5 Hz), 3.94 (3H , s), 4.55-4.66 (1H, m), 7.19-7.23 (4H, m), 7.27 (2H, d, J = 8.4Hz), 7.44-7.65 (5H, m), 8.60 (1H, d, J = 8.4Hz), 10.7 (1H, s), 12.9 (1H, bs).
MS m / z: 558 [M−H] ⁻ .

Example 81
N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 2.47 (3H, s), 3.19-3.25 (2H, m), 3.72 (6H, s), 3.76 (3H, s), 3.99 (3H, s), 4.93-5.02 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.19-7.34 (8H, m), 7.40 (2H, d, J = 8.6Hz).

N- [2-methoxyimino-2- (4-methylsulfanylphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.45 (3H, s), 3.07 (1H, dd, J = 14.3,9.7 Hz), 3.19 (1H, dd, J = 14.3, 4.6 Hz), 3.64 (6H , s), 3.94 (3H, s), 4.56-4.66 (1H, m), 6.74 (2H, d, J = 8.4Hz), 7.15 (2H, d, J = 8.4Hz), 7.29-7.35 (7H, m), 8.63 (1H, d, J = 8.1Hz).
MS m / z: 507 [M−H] ⁻ .

Example 82
N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 0.95 (3H, t, J = 7.3 Hz), 1.22 (3H, t, J = 7.0 Hz), 1.63-1.80 (2H, m), 2.88 (1H, dd , J = 13.8, 11.3 Hz), 3.14 (1H, dd, J = 13.8, 4.5 Hz), 3.80 (3H, s), 3.91-4.00 (2H, m), 4.13-4.26 (2H, m), 4.63- 4.76 (1H, m), 6.88 (2H, d, J = 8.6 Hz), 7.19-7.33 (4H, m), 7.46-7.70 (5H, m), 9.10 (1H, d, J = 8.1 Hz), 10.73 (1H, s).

N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 0.95 (3H, t, J = 7.4 Hz), 1.62-1.78 (2H, m), 2.86 (1H, dd, J = 13.5, 11.1 Hz), 3.14 (1H , dd, J = 13.5, 4.9 Hz), 3.79 (3H, s), 3.88-4.00 (2H, m), 4.57-4.72 (1H, m), 6.87 (2H, d, J = 8.9 Hz), 7.18- 7.32 (4H, m), 7.47-7.68 (5H, m), 9.00 (1H, d, J = 8.4 Hz), 10.73 (1H, s).
MS m / z: 570 [M−H] ⁻ .

Example 83
N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 0.95 (3H, t, J = 7.3 Hz), 1.61-1.78 (2H, m), 2.99 (1H, dd, J = 14.3, 10.5 Hz), 3.17 (1H , dd, J = 14.3, 4.3 Hz), 3.65 (6H, s), 3.72 (3H, s), 3.80 (3H, s), 4.63-4.75 (1H, m), 6.74 (2H, d, J = 8.4 Hz), 6.90 (2H, d, J = 8.9 Hz), 7.14 (2H, d, J = 8.1 Hz), 7.21-7.42 (5H, m), 9.19 (1H, d, J = 7.8 Hz).

N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 0.94 (3H, t, J = 7.3 Hz), 1.63-1.79 (2H, m), 2.95 (1H, dd, J = 14.0, 10.5 Hz), 3.19 (1H , dd, J = 14.0, 3.9 Hz), 3.65 (6H, s), 3.79 (3H, s), 3.84-3.95 (2H, m), 4.52-4.66 (1H, m), 6.74 (2H, d, J = 8.6 Hz), 6.87 (2H, d, J = 8.9 Hz), 7.13 (2H, d, J = 7.8 Hz), 7.23-7.35 (3H, m), 7.39 (2H, d, J = 8.9 Hz), 8.90-9.01 (1H, m).
MS m / z: 519 [M−H] ⁻ .

Example 84
N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4-[(2,6-dichlorobenzoyl) amino] -L-phenylalanine ethyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 0.96 (3H, t, J = 7.3 Hz), 1.20 (3H, t, J = 7.2 Hz), 1.72 (2H, sixt, J = 7.3 Hz), 3.00 ( 1H, dd, J = 13.0, 9.9 Hz), 3.13 (1H, dd, J = 13.0, 4.9 Hz), 3.91-4.00 (5H, m), 4.14 (2H, q, J = 7.2 Hz), 4.59-4.72 (1H, m), 6.89 (2H, d, J = 8.9 Hz), 7.22-7.35 (4H, m) 7.46-7.70 (5H, m), 8.77 (1H, d, J = 7.8 Hz), 10.72 (1H , s).

N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 0.96 (3H, t, J = 7.3 Hz), 1.72 (2H, sixt, J = 7.3 Hz), 2.97 (1H, dd, J = 13.8, 9.7 Hz), 3.15 (1H, dd, J = 13.8, 5.0Hz), 3.89-3.98 (5H, m), 4.33-4.65 (1H, m), 6.88 (2H, d, J = 9.2 Hz), 7.20-7.29 (4H, m) 7.46-7.64 (5H, m), 8.47-8.55 (1H, m), 10.71 (1H, s).
MS m / z: 570 [M−1] ⁻ .

Example 85
N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 0.95 (3H, t, J = 7.3 Hz), 1.71 (2H, sixt, J = 7.3 Hz), 3.03-3.22 (2H, m), 3.64 (6H, s ), 3.68 (3H, s), 3.87-4.00 (5H, m), 4.60-4.76 (1H, m), 6.74 (2H, d, J = 8.4 Hz), 6.89 (2H, d, J = 7.0 Hz) , 7.15 (2H, d, J = 8.1 Hz), 7.22-7.50 (5H, m) 8.84 (1H, d, J = 7.8 Hz).

N- [2-methoxyimino-2- (4-propoxyphenyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 0.95 (3H, t, J = 7.4 Hz), 1.71 (2H, sixt, J = 7.4 Hz), 3.06 (1H, dd, J = 13.8, 8.9 Hz), 3.18 (1H, dd, J = 13.8, 4.3Hz), 3.64 (6H, s), 3.88-3.97 (5H, m), 4.50-4.63 (1H, m), 6.74 (2H, d, J = 8.6Hz) , 6.89 (2H, d, J = 8.6 Hz), 7.14 (2H, d, J = 7.8 Hz), 7.31-7.33 (3H, m) 7.38 (2H, d, J = 7.8 Hz), 8.53-8.60 (1H , m).
MS m / z: 521 [M + H] ⁺ .

Example 86
N- [2- (4-Benzyloxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.30 (3H, t, J = 7.2 Hz), 3.15 (1H, dd, J = 14.3, 5.9 Hz), 3.31 (1H, dd, J = 14.3, 5.4 Hz ), 3.98 (3H, s), 4.23 (2H, q, J = 7.2 Hz), 5.05-5.15 (3H, m), 6.44 (1H, d, J = 7.8 Hz), 6.93 (2H, d, J = 9.2 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.25-7.43 (9H, m), 7.48 (2H, d, J = 9.2 Hz), 7.56 (2H, d, J = 8.6 Hz).

N- [2- (4-Benzyloxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 2.86 (1H, dd, J = 14.0, 11.1 Hz), 3.15 (1H, dd, J = 14.0, 3.8 Hz), 3.79 (3H, s), 4.57-4.69 (1H , m), 5.13 (2H, s), 6.97 (2H, d, J = 8.9 Hz), 7.24-7.66 (14H, m), 9.00 (1H, d, J = 8.4 Hz), 10.73 (1H, s) , 12.4 (1H, bs).
MS m / z: 618 [M−H] ⁻ .

Example 87
N- [2- (4-Benzyloxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 1.29 (3H, t, J = 7.3 Hz), 3.11-3.27 (2H, m), 4.00 (3H, s), 4.22 (2H, q, J = 7.3 Hz ), 4.88-4.97 (1H, m), 5.08 (2H, s), 6.98 (2H, d, J = 8.9 Hz), 7.21 (2H, d, J = 8.6 Hz), 7.25-7.49 (12H, m) 7.58 (2H, d, J = 8.6 Hz).

N- [2- (4-Benzyloxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 2.98 (1H, dd, J = 13.8, 10.0 Hz), 3.15 (1H, dd, J = 13.8, 4.6 Hz), 3.92 (3H, s), 4.55-4.66 (1H , m), 5.13 (2H, s), 6.98 (2H, d, J = 9.2 Hz), 7.23-7.65 (14H, m), 8.59 (1H, d, J = 8.4 Hz), 10.72 (1H, s) .
MS m / z: 620 [M + H] ⁺ .

Example 88
N- [2- (4-Benzyloxyphenyl) 2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.18 (1H, dd, J = 14.0, 7.0 Hz), 3.32 (1H, dd, J = 14.0, 5.7 Hz), 3.70 (6H, s), 3.79 (3H, s ), 3.95 (3H, s), 5.04 (2H, s), 5.09-5.18 (1H, m), 6.49 (1H, d, J = 7.8 Hz), 6.65 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 7.24-7.43 (8H, m), 7.50 (2H, d, J = 8.4 Hz).

N- [2- (4-Benzyloxyphenyl) 2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.90-3.01 (1H, m), 3.13-3.24 (1H, m), 3.64 (6H, s), 3.79 (3H, s), 4.43-4.57 (1H, m), 5.08 (2H, s), 6.74 (2H, d, J = 8.1 Hz), 6.96 (2H, d, J = 8.9 Hz), 7.09 (2H, d, J = 7.8 Hz), 7.21-7.56 ( 10H, m), 8.67-8.81 (1H, m).

Example 89
Synthesis of N- [2- (4-hydroxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)
N- [2- (4-Benzyloxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn) (410 mg, 0.661 mmol) in ethanol (10 ml) 5% Pd / C (82 mg) was added, and the mixture was stirred at room temperature for 10 hours under hydrogen substitution. After completion of the reaction, the mixture was filtered through Celite, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 2) to obtain the desired product (70 mg, 0.132 mmol).

¹ H-NMR (CD ₃ OD) δ; 2.93-3.06 (1H, m), 3.24-3.34 (1H, m), 3.83 (3H, s), 4.66-4.74 (1H, m), 6.71-6.77 (2H , m), 7.24-7.66 (8H, m), 7.90-7.95 (1H, m).
MS m / z: 528 [M−H] ⁻ .

Example 90
Synthesis of N- [2- (4-hydroxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)
The following compounds were obtained in the same manner as in Example 89 using N- [2- (4-benzyloxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti). Got.

¹ H-NMR (CD ₃ OD) δ; 3.03-3.15 (1H, m), 3.25-3.39 (1H, m), 3.96 (3H, s), 4.70-4.77 (1H, m), 6.71-6.79 (2H , m), 7.24-7.67 (8H, m), 7.91-7.96 (1H, m).
MS m / z: 528 [M−H] ⁻ .

Example 91
N- [2- (4-Hydroxyphenyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.90-3.03 (1H, m), 3.15-3.25 (1H, m), 3.64 (6H, s), 3.77 (3H, s), 4.45-4.58 (1H, m), 6.71-6.76 (4H, m), 7.11 (2H, d, J = 8.1 Hz), 7.24-7.44 (5H, m), 8.68-8.80 (1H, m).
MS m / z: 477 [M−H] ⁻ .

Reference Example 47
Synthesis of ethyl 2- (4-methylcyclohexyl) -2-oxoacetate The title compound was obtained in the same manner as in Reference Example 24 using 4-methylchlorohexanone.

¹ H-NMR (CDCl ₃ ) δ; 0.91 (3H, d, J = 6.5 Hz), 0.95-1.08 (2H, m), 1.20-1.40 (2H, m), 1.39 (3H, t, J = 7.3 Hz ), 1.55-1.65 (1H, m), 1.78-1.83 (2H, m), 1.90-1.98 (2H, m), 2.96 (1H, tt, J = 12.2, 3.2 Hz), 4.32 (2H, q, J = 7.3 Hz).

Reference Example 48
Synthesis of ethyl 2- (4-ethylcyclohexyl) -2-oxoacetate Synthesis was performed according to Reference Example 24 from 4-ethylcyclohexanone.

¹ H-NMR (CDCl ₃ ) δ; 0.88 (3H, t, J = 7.6 Hz), 0.91-1.08 (2H, m), 1.10-1.20 (1H, m), 1.20-1.28 (4H, m), 1.37 (3H, t, H = 7.0 Hz), 1.80-2.00 (4H, m), 2.98 (1H, tt, J = 12.2, 3.5 Hz), 4.32 (2H, q, J = 7.0 Hz).

Reference Example 49
Synthesis of ethyl oxo (tetrahydropyran-4-yl) acetate Synthesis was performed according to Reference Example 24 from tetrahydropyran-4-one.

Oxo (tetrahydropyran-4-yl) ethyl acetate
¹ H-NMR (CDCl ₃ ) δ; 1.38 (3H, t, J = 7.3 Hz), 1.60-1.90 (4H, m), 3.28 (1H, tt, J = 11.1, 4.1 Hz), 3.49 (2H, ddd , J = 2.7, 11.1, 11.6Hz), 3.96-4.96 (2H, m), 4.34 (2H, q, J = 7.3Hz).

Reference Example 50
Synthesis of 2-cyclopropyl-2-oxo-ethyl acetate In a suspension of 3.8 g (26.4 mmol) of copper bromide in anhydrous THF (20 mL) at −80 ° C., 4.6 g (52.8 mmol) of lithium bromide was added. Anhydrous THF (50 mL) solution was added dropwise and stirred at the same temperature for 20 minutes. To this mixed solution, 52 mL (26.0 mmol, 0.5 M THF solution) of cyclopropylmagnesium bromide was added dropwise at −80 ° C., and then 3.0 g (22.0 mmol) of ethyl chloroglyoxylate was slowly added dropwise. Stir for 0 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane / ethyl acetate = 10/1) to obtain 370 mg of ethyl 2-cyclopropyl-2-oxoacetate.

¹ H-NMR (CDCl ₃ ) δ; 1.13-1.19 (2H, m), 1.21-1.28 (2H, m), 1.39 (3H, t, J = 7.3 Hz), 2.75 (1H, m), 4.35 (2H , q, J = 7.3 Hz).

Reference Example 51
Synthesis of ethyl 2-cyclobutyl-2-oxoacetate Into a suspension of 1.2 g (29.9 mmol) of sodium hydride in anhydrous THF (20 mL) under ice-cooling, 8.1 g (29.9 mmol) of triethyl methoxymethoxy (phosphono) acetate Anhydrous THF (10 mL) solution was added dropwise, stirred at the same temperature for 30 minutes, and further stirred at room temperature for 1.0 hour. After ice-cooling again, a solution of cyclobutanone 2.0 g (28.5 mmol) in anhydrous THF (10 mL) was added dropwise and stirred overnight at room temperature. Water was added to the reaction solution to complete the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (30 mL), 500 mg (3.0 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was heated to reflux overnight. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane / ethyl acetate = 10/1) to obtain 3.0 g of 2-cyclobutyl-2-oxo-ethyl acetate.

¹ H-NMR (CDCl ₃ ) δ; 1.36 (3H, t, J = 7.3 Hz), 1.80-2.15 (2H, m), 2.20-2.40 (4H, m), 3.84 (1H, quint, J = 8.4 Hz ), 4.31 (2H, q, H = 7.3 Hz).

Reference Example 52
Synthesis of cycloheptyl-ethyl oxoacetate In the same manner as in Reference Example 51, cycloheptyl oxoacetate was obtained from cycloheptanone.

270Hz ¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, t, J = 7.3Hz), 1.44-2.00 (12H, m), 3.15-3.28 (1H, m), 4.32 (2H, q, J = 7.3 Hz).

Reference Example 53
Synthesis of ethyl (1-methylpiperidin-4-yl) oxoacetate Ethyl (1-methylpiperidin-4-yl) oxoacetate was obtained from 1-methylpiperidone in the same manner as in Reference Example 51.

¹ H-NMR (CDCl ₃ ) δ; 1.37 (3H, t, J = 7.3Hz), 1.62-2.13 (6H, m), 2.28 (3H, s), 2.81-3.08 (3H, m), 4.32 (2H , q, J = 7.3Hz).

Example 92
Synthesis of N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester Oxo (tetrahydropyran-4-yl) acetic acid To an ethanol solution of 200 mg (1.07 mmol) of ethyl were added 0.3 mL of pyridine and 95.0 mg (1.14 mmol) of O-methylhydroxylamine hydrochloride, and the mixture was stirred at 50 to 60 ° C. overnight. After concentration under reduced pressure, the mixture was extracted with ethyl acetate-water. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 229 mg of crude ethyl methoxyimino (tetrahydropyran-4-yl) acetate. The obtained ethyl methoxyimino (tetrahydropyran-4-yl) acetate was dissolved in 3 mL of THF, and 1 mL of an aqueous solution of 44 mg of lithium hydroxide monohydrate and 0.5 mL of methanol were added dropwise under ice cooling and stirred for 1 hour. After concentration under reduced pressure, toluene was added and the mixture was concentrated again. The resulting lithium salt was dissolved in 5 mL of N, N-dimethylformamide (DMF), and 300 mg (1.56 mmol) of EDC and 424 mg (3.14 mmol) of HOBt were added and stirred for 10 minutes. , 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester 399 mg (1.05 mmol) was added. After stirring overnight, the reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and the isomers were separated and purified.

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.3 Hz), 1.55-1.75 (4H, m), 2.82-2.99 (1H, m), 3.12 (1H, dd, J = 6.5, 14.0Hz), 3.22 (1H, dd, J = 5.7, 14.0Hz), 3.36-3.50 (2H, m), 3.90 (3H, s), 3.90-4.05 (2H, m), 4.22 (2H, q, J = 7.3Hz), 4.87-4.98 (1H, m), 7.18 (2H, d, J = 8.4Hz), 7.26-7.50 (5H, m), 7.57 (2H, d, J = 8.6Hz).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t, J = 7.3 Hz), 1.30-1.50 (2H, m), 2.20-2.40 (2H, m), 3.02-3.24 (2H, m), 3.24 -3.49 (3H, m), 3.92-4.03 (5H, m, including 1s at 3.95ppm), 4.20 (2H, q, J = 7.3Hz), 4.80-4.90 (1H, m), 7.08-7.22 (3H, m), 7.28-7.44 (4H, m), 7.57 (2H, d, J = 8.6Hz).

Example 93
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)
The title compound was obtained in the same manner as in Example 2 using the product (syn) obtained in Example 92.

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ + CD ₃ OD additive); 1.50-1.75 (4H, m), 2.75-2.94 (1H, m), 3.10 (1H, dd, J = 6.5, 14.0Hz), 3.26 (1H, dd, J = 5.4, 14.0Hz), 3.29-3.50 (2H, m), 3.87 (3H, s), 3.90-4.05 (2H, m), 4.85-4.95 (1H, m), 7.20 (2H, d, J = 8.4Hz), 7.27-7.42 (3H, m), 7.58 (2H, d, J = 8.1Hz).
MS m / z: 520 [M−H] ⁻ .

Example 94
Synthesis of N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,4-dimethoxyphenyl) -L-phenylalanine ethyl ester (syn) 4- (2,6-dimethoxy The title compound was obtained in the same manner as in Example 92 using (phenyl) -L-phenylalanine methyl ester.

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.58-1.75 (4H, m), 2.88-2.99 (1H, m), 3.10-3.27 (2H, m), 3.37-3.48 (2H, m), 3.72 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.90-4.00 (2H, m), 4.89-4.98 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.16 (2H , d, J = 8.4Hz), 7.22-7.32 (3H, m), 7.52 (1H, d, J = 7.3Hz).

Example 95
Synthesis of N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine Example 2 using the compound obtained in Example 94 To give the title compound.

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.55-1.80 (4H, m), 2.87-3.00 (1H, m), 3.19 (1H, dd, J = 7.0, 14.0 Hz), 3.31 (1H, dd, J = 5.1, 14.0Hz), 3.37-3.50 (2H, m), 3.72 (6H, s), 3.84 (3H, s), 3.90-4.05 (2H, m), 4.85-5.00 (1H, m), 6.65 (2H , d, J = 8.4Hz), 7.20-7.40 (5H, m), 7.59 (1H, d, J = 6.8Hz).
MS m / z: 469 [M−H] ⁻ .

Examples 96-108
Example 92 Using 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester or 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester and the corresponding oxoacetic acid derivative as the amino acid ester derivative In the same manner as above, the following compound was obtained.

Example 96
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ): 1.17-1.38 (5H, m), 1.58-1.90 (5H, m), 2.59-2.70 (1H, m), 3.10-3.30 (2H, m), 3.71 (6H, s ), 3.75 (3H, s), 3.82 (3H, s), 4.91-4.98 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.23 -7.30 (4H, m).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.20-1.35 (2H, m), 1.50-2.00 (8H, m), 3.00-3.10 (1H, m), 3.12-3.20 (2H, m), 3.71 (6H, s), 3.73 (3H, s), 3.92 (3H, s), 4.84-4.91 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.10 (1H, d, J = 8.1 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.24-7.30 (3H, m).

Example 97
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ: 1.23-1.34 (3H, m), 1.50-2.00 (10H, m), 2.49-2.60 (1H, m), 3.12-3.20 (2H, m), 3.86 (3H, s), 4.15-4.27 (2H, m), 4.90-5.00 (1H, m), 7.08-7.58 (9H, m).

N- (2-Cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.18-1.29 (4H, m), 1.24 (3H, t, J = 7.0 Hz), 1.50-1.95 (6H, m), 3.00-3.10 (1H, m), 3.10 -3.25 (2H, m), 3.93 (3H, s), 4.12 (2H, q, J = 7.0 Hz), 4.23-4.85 (1H, m), 7.07 (1H, d, J = 8.1 Hz), 7.16 ( 2H, d, J = 8.4 Hz), 7.29-7.38 (3H, m), 7.47 (1H, bs), 7.56 (2H, d, J = 8.4 Hz).

Example 98
N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
(Cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 0.87 (3H, d, J = 6.5 Hz), 0.86-1.01 (2H, m), 1.23-1.37 (2H, m), 1.28 (3H, t, J = 7.3 Hz ), 1.53-1.58 (1H, m), 1.70-1.83 (4H, m), 2.45-2.60 (1H, m), 3.14 (1H, dd, J = 14.0, 8.4 Hz), 3.19 (1H, dd, J = 14.0, 5.4 Hz), 3.86 (3H, s), 4.21 (2H, q, J = 7.3 Hz), 4.90-4.97 (1H, m), 7.12 (1H, d, J = 7.0 Hz), 7.18 (2H , d, J = 8.1 Hz), 7.28-7.39 (4H, m), 7.56 (2H, d, J = 8.1 Hz).

N- [2-Methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti) (cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 0.87 (3H, d, J = 6.5 Hz), 0.86-1.04 (2H, m), 1.26 (3H, t, J = 7.3 Hz), 1.45-1.61 (3H, m ), 163-1.88 (2H, m), 1.82-2.02 (2H, m), 2.99 (1H, tt, J = 12.2, 3.2 Hz), 3.13 (1H, dd, J = 13.8, 5.9 Hz), 3.16 ( 1H, dd, J = 13.8, 5.9 Hz), 3.92 (3H, s), 4.17 (2H, q, J = 7.3 Hz), 4.78-4.86 (1H, m), 7.07 (1H, d, J = 8.1 Hz ), 7.16 (2H, d, J = 8.6 Hz), 7.28 (1H, d, J = 5.9 Hz), 7.32 (1H, d, J = 5.9 Hz), 7.36 (1H, t, J = 5.9 Hz), 7.39 (1H, s), 7.56 (2H, d, J = 8.1 Hz)

Example 99
N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
(Cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 0.87 (3H, d, J = 6.5 Hz), 0.88-1.04 (2H, m), 1.23-1.34 (3H, m), 1.70-1.74 (2H, m), 1.81 -1.85 (2H, m), 2.53-2.62 (1H, m), 3.18-3.25 (2H, m), 3.71 (6H, s), 3.76 (3H, s), 3.83 (3H, s), 4.91-4.98 (1H, m), 6.65 (2H, d, J = 8.1 Hz), 7.12-7.30 (6H, m).

N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti) (a mixture of cis and trans)
¹ H-NMR (CDCl ₃ ) δ; 0.86 (3H, d, J = 6.8 Hz), 0.85-1.02 (2H, m), 1.20-1.40 (1H, m), 1.42-1.60 (2H, m), 1.62 -1.78 (2H, m), 1.80-2.00 (2H, m), 2.95-3.05 (1H, m), 3.10-3.25 (2H, m), 3.71 (6H, s), 3.74 (3H, s), 3.93 (3H, s), 4.83-4.91 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.10 (1H, d, J = 10.0 Hz), 7.18-7.30 (5H, m).

Example 100
N- [2- (4-Ethylcyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn) (cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 0.83-2.04 (11H, m), 0.86 (3H, t, J = 7.3 Hz), 1.28 (3H, t, J = 7.0 Hz), 2.53-2.60 (1H, m ), 3.13 (1H, dd, J = 13.8, 5.9 Hz), 3.21 (1H, dd, J = 13.8, 5.9 Hz), 3.86 (3H, s), 4.23 (2H, q, J = 7.0 Hz), 4.85 -4.97 (1H, m), 7.05-7.20 (3H, m), 7.26-7.39 (4H, m), 7.56 (2H, d, J = 8.6 Hz).

N- [2- (4-Ethylcyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti) (cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 0.86 (3H, t, J = 7.0 Hz), 0.83-0.91 (2H, m), 1.18-1.26 (4H, m), 1.24 (3H, t, J = 7.3 Hz ), 1.50-1.60 (3H, m), 1.76-2.00 (2H, m), 2.95-3.12 (1H, m), 3.05-3.23 (2H, m), 3.92 (3H, s), 4.19 (2H, q , J = 7.3 Hz), 4.79-4.86 (1H, m), 7.07 (1H, d, J = 7.8 Hz), 7.16 (2H, d, J = 8.4 Hz), 7.23-7.39 (4H, m), 7.55 (2H, d, J = 8.4 Hz).

Example 101
N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti) (a mixture of cis and trans)
¹ H-NMR (CDCl ₃ ) δ; 0.83-0.91 (2H, m), 0.86 (3H, d, J = 6.6 Hz), 1.50-1.62 (3H, m), 1.72-2.05 (2H, m), 2.95 -3.10 (1H, m), 3.15-3.23 (2H, m), 3.71 (6H, s), 3.73 (3H, s), 3.92 (3, s), 4.84-4.91 (1H, m), 6.64 (2H , d, J = 7.8 Hz), 7.10 (1H, d, J = 8.1 Hz), 7.15-7.30 (5H, m).

N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn) (a mixture of cis and trans)
¹ H-NMR (CDCl ₃ ) δ; 0.82-1.00 (2H, m), 0.85 (3H, t, J = 7.3Hz), 1.18-1.38 (6 H, m), 1.75-1.90 (3H, m), 2.57-2.63 (1H, m), 3.15-3.30 (2H, m), 3.71 (6H, s), 3.76 (3H, s), 3.82 (3H, s), 4.91-4.98 (1H, m), 6.65 ( 2H, d, J = 8.4 Hz), 7.15-7.30 (6H, m).

Example 102
N- [2-methoxyimino-2- (1-methylpiperidin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.51-1.72 (2H, m), 1.75-1.86 (2H, m), 1.90-2.05 (2H, m), 2.25 (3H, s), 2.56-2.69 (1H, m), 2.81-2.92 (2H, m), 3.10-3.27 (2H, m), 3.71 (6H, s), 3.76 (3H, s), 3.83 (3H, s), 4.89-4.96 (1H, m) , 6.65 (2H, d, J = 8.4Hz), 7.16 (2H, d, J = 8.1Hz), 7.23-7.33 (3H, m), 7.45 (1H, d, J = 6.2Hz).

N- [2-methoxyimino-2- (1-methylpiperidin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.45-1.58 (2H, m), 1.84-1.97 (2H, m), 2.25 (3H, s), 2.19-2.39 (2H, m), 2.79-3.08 (3H, m), 3.10-3.19 (2H, m), 3.71 (6H, s), 3.73 (3H, s), 3.91 (3H, s), 4.81-4.92 (1H, m), 6.64 (2H, d, J = 8.4Hz), 7.09-7.31 (6H, m).

Example 103
N- (2-cycloheptyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.33-1.91 (12H, m), 2.71-2.87 (1H, m), 3.09-3.26 (2H, m), 3.71 (6H, s), 3.76 (3H, s) , 3.81 (3H, s), 4.90-5.00 (1H, m), 6.64 (2H, d, J = 8.4Hz), 7.16 (2H, d, J = 8.4Hz), 7.18-7.39 (4H, m).

N- (2-cycloheptyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.36-1.96 (12H, m), 3.09-3.21 (3H, m), 3.71 (6H, s), 3.72 (3H, s), 3.92 (3H, s), 4.81 -4.92 (1H, m), 6.64 (2H, d, J = 8.4Hz), 7.08-7.35 (6H, m).

Example 104
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.20 (3H, d, J = 7.0 Hz), 1.21 (3H, d, J = 7.0 Hz), 3.17 (2H, d, J = 6.2 Hz), 3.29-3.42 ( 1H, m), 3.72 (6H, s), 3.73 (3H, s), 3.93 (3H, s), 4.85-4.96 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.10 (1H , d, J = 8.4 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.23-7.34 (3H, m).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.10 (6H, d, J = 7.0 Hz), 2.90-3.03 (1H, m), 3.12-3.29 (2H, m), 3.72 (6H, s), 3.77 (3H , s), 3.83 (3H, s), 4.91-5.03 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.25-7.38 (4H, m).

Example 105
N- (2-cyclopropyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 0.78-0.82 (4H, m), 1.85-1.99 (1H, m), 3.12-3.25 (2H, m), 3.71 (6H, s), 3.77 (3H, s) , 3.80 (3H, s), 4.92-4.99 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 6.5 Hz), 7.18-7.30 (3H, m), 7.45 (1H, d, J = 7.8 Hz).

N- (2-Cyclopropyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 0.79-0.87 (2 H, m), 1.41-1.46 (2H, m), 2.08-2.18 (1H, m,), 3.05-3.20 (2H, m), 3.72 ( 6H, s), 3.73 (3H, s), 3.93 (3H, s), 4.79-4.87 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.10-7.20 (3H, m), 7.24 -7.30 (3H, m).

Example 106
N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.77-2.02 (2H, m), 2.10-2.30 (4H, m), 3.10-3.23 (2H, m), 3.45 (1H, quint, J = 8.4 Hz), 3.72 (6H, s), 3.76 (3H, s), 3.87 (3H, s), 4.90-4.97 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.14-7.31 (5H, m), 7.58 (1H, d, J = 6.8 Hz).

N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.80-1.95 (2H, m), 2.10-2.25 (2H, m), 2.41-2.49 (2H, m), 3.10-3.21 (2H, m), 3.60-3.76 ( 1H, m), 3.70 (6H, s), 3.73 (3H, s), 3.92 (3H, s), 4.88-4.91 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.06 (1H , d, J = 8.4 Hz), 7.17-7.30 (5H, m).

Example 107
N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn) (syn: anti = 2: 1)
¹ H-NMR (CDCl ₃ ) δ; 1.27 (3H, t, J = 7.3 Hz), 1.65-2.20 (6H, m), 3.05-3.22 (2H, m), 3.44 (1H, quint, J = 8.4 Hz ), 3.91 (3H, s), 4.19 (2H, q, J = 7.3 Hz), 4.86-4.91 (1H, m), 7.14-7.58 (9H, m).

N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.27 (3H, t, J = 7.0 Hz), 1.82-1.97 (2H, m), 2.14-2.24 (2H, m), 2.39-2.48 (2H, m), 3.15 (2H, m), 3.66 (1H, quint.J = 8.6 Hz), 3.91 (3H, s), 4.17 (2H, q, J = 7.0 Hz), 4.81-4.89 (1H, m), 7.04 (1H, d, J = 7.8 Hz), 7.17 (2H, d, J = 8.4 Hz), 7.27-7.39 (5H, m), 7.57 (2H, d, J = 8.4 Hz).

Example 108
N- (2-cyclopentyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.50-1.91 (8H, m), 2.95-3.06 (1H, m), 3.14-3.23 (2H, m), 3.72 (6H, s), 3.77 (3H, s) , 3.82 (3H, s), 4.90-5.00 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.14-7.33 (6H, m).

N- (2-cyclopentyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.47-1.96 (8H, m), 3.17 (2H, d, J = 6.2 Hz), 3.34-3.49 (1H, m), 3.72 (6H, s), 3.73 (3H , s), 3.93 (3H, s), 4.85-4.96 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.13-7.35 (6H, m).

  The following compounds were obtained in the same manner as in Example 2 using the compounds obtained in Examples 96 to 108. Examples 109-134

Example 109
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.05-1.25 (5H, m), 1.50-1.82 (5H, m), 2.20-2.40 (1H, m), 2.75-3.20 (2H, m), 3.62 ( 6H, s), 3.65 (3H, s), 4.40-4.56 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.22-7.31 (3H , m), 8.61 (1H, d, J = 8.1 Hz).
MS m / z: 467 [MH] ⁻ .

Example 110
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.00-1.30 (3H, m), 1.40-1.75 (7H, m), 2.83-2.95 (1H, m), 3.02 (1H, dd, J = 14.0, 8.4 Hz), 3.12 (1H, dd, J = 14.0, 4.9Hz), 3.63 (6H, s), 3.86 (3H, s), 4.40-4.52 (1H, m), 6.72 (2H, d, J = 8.4 Hz ), 7.09 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.27 (1H, t, J = 8.4 Hz), 8.18 (1H, d, J = 7.8 Hz).
MS m / z: 467 [MH] ⁻ .

Example 111
N- (2-Cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 0.93-1.38 (5H, m), 1.40-1.75 (5H, m), 2.75-2.85 (1H, m), 2.89 (1H, dd, J = 13.8, 10.0 Hz), 3.09 (1H, dd, J = 13.8, 4.6 Hz), 3.85 (3H, s), 4.48-4.52 (1H, m), 7.21 (2H, d, J = 8.4 Hz), 7.46-7.59 (5H m), 8.24 (1H, d, J = 8.6 Hz), 10.66 (1H, s).
MS m / z: 518 [MH] ⁻ .

Example 112
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn: anti = 1: 1)

¹ H-NMR (DMSO-d ₆ ) δ; 0.93-1.35 and 1.43-1.70 and 2.08-2.26 (11H, m), 2.73-3.18 (2H, m), 3.66 and 3.84 (3H, 2s), 4.37-4.55 (1H, m), 7.11-7.27 and 7.42-7.65 (7H, m), 8.11-8.20 and 8.37-8.50 (1H, m), 10.65 (1H, s).
MS m / z: 518 [MH] ⁻ .

Example 113
N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn) (a mixture of cis and trans)

¹ H-NMR (DMSO-d ₆ ) δ; 0.75-0.88 (2H, m), 0.81 (3H, d, J = 6.5 Hz), 1.01-1.50 (3H, m), 1.50-1.70 (4H, m) , 2.00-2.20 (1H, m), 2.86 (1H, dd, J = 14.0, 10.0 Hz), 3.10 (1H, dd, J = 14.0, 10.0 Hz), 3.66 (3H, s), 4.45-4.53 (1H , m), 7.21 (2H, d, J = 8.6 Hz), 7.45-7.61 (5H, m), 8.41 (1H, d, J = 7.0 Hz), 10.64 (1H, s), 12.7 (1H, bs) .
MS m / z: 532 [MH] ⁻ .

Example 114
N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti) (mixture of cis and trans)

¹ H-NMR (DMSO-d ₆ ) δ; 080-0.88 (2H, m), 0.81 (3H, d, J = 6.2 Hz), 1.10-1.48 (3H, m), 1.50-1.70 (4H, m) , 2.70-2.80 (1H, m), 2.91 (1H, dd, J = 14.0, 10.0 Hz), 3.09 (1H, dd, J = 14.0, 4.3 Hz), 3.85 (3H, s), 4.46-4.54 (1H , m), 7.20 (2H, d, J = 8.6 Hz), 7.45-7.59 (5H, m), 8.24 (1H, d, J = 8.6 Hz), 10.68 (1H, s), 12.80 (1H, bs) .
MS m / z: 532 [MH] ⁻ .

Example 115
N- [2-methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) (a mixture of cis and trans)

¹ H-NMR (DMSO-d ₆ ) δ; 0.81 (3H, d, J = 6.5 Hz), 0.82-0.92 (2H, m), 1.10-1.50 (3H, m), 1.60-1.80 (4H, m) , 2.10-2.30 (1H, m), 2.94 (1H, dd, J = 14.0, 10.0 Hz), 3.11 (1H, dd, 14.0, 4.6 Hz), 3.64 (6H, s), 3.66 (3H, s), 4.45-4.55 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.26 (1H, t , J = 8.4 Hz), 8.66 (1H, J = 8.1 Hz).
MS m / z: 481 [MH] ⁻ .

Example 116
N- [2-Methoxyimino-2- (4-methylcyclohexyl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti) (cis, trans mixture)

¹ H-NMR (CDCl ₃ ) δ; 0.85-1.02 (2H, m), 0.86 (3H, d, J = 6.5 Hz), 1.30-1.42 (1H, m), 1.45-1.60 (2H, m), 1.62 -1.80 (2H, m), 1.85-2.02 (2H, m), 2.99 (1H, tt, J = 12.2, 3.2 Hz), 3.19 (1H, dd, J = 14.3, 6.7 Hz), 3.28 (1H, dd , J = 13.8, 5.4 Hz), 3.71 (6H, s), 3.91 (3H, s), 4.82-4.90 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.10 (1H, d, J = 7.6 Hz), 7.21-7.32 (5H, m).
MS m / z: 481 [MH] ⁻ .

Example 117
N- [2- (4-Ethylcyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn) (cis, trans mixture)

¹ H-NMR (DMSO-d ₆ ) δ; 0.82 (3H, t, J = 7.3 Hz), 0.80-0.85 (2H, m), 0.90-1.40 (5H, m), 1.60-1.70 (4H, m) , 2.05-2.20 (1H, m), 2.70-3.20 (2H, m), 3.67 (3H, s), 4.45-4.52 (1H, m), 7.22 (2H, d, J = 8.6 Hz), 7.46-7.59 (5H, m), 8.47 (1H, d, J = 5.4 Hz), 10.45 (1H, s).
MS m / z: 495 [M−1] ⁻ .

Example 118
N- [2- (4-Ethylcyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti) (cis, trans mixture)

¹ H-NMR (DMSO-d ₆ ) δ; 0.82 (3H, t, J = 7.3 H), 0.79-0.84 (2H, m), 0.97-1.03 (1H, m), 1.32-1.35 (2H, m) , 1.46-1.54 (2H, m), 1.50-1.60 (2H, m), 1.66-1.70 (2H, m), 2.70-2.80 (1H, m), 2.93 (1H, dd, J = 13.8, 9.7 Hz) , 3.08 (1H, dd, J = 13.8, 4.6 Hz), 3.86 (3H, s), 4.48-4.52 (1H, m), 7.20 (2H, d, J = 8.4 Hz), 7.46-7.59 (5H, m ), 8.21 (1H, d, J = 8.1 Hz), 10.65 (1H, s), 12.83 (1H, bs).
MS m / z: 456 [MH] ⁻ .

Example 119
N- [2- (4-Ethylcyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti) (cis, trans mixture)

¹ H-NMR (DMSO-d ₆ ) δ; 0.80 (3H, t, J = 7.0 Hz), 0.75-0.90 (2H, m), 0.90-1.17 (3H, m), 1.49-1.69 (6H, m) , 2.75-2.90 (1H, m), 3.02 (1H, dd, J = 14.0, 7.8 Hz), 3.12 (1H, dd, J = 14.0, 5.3 Hz), 3.63 (6H, s), 3.85 (3H, s ), 4.35-4.46 (1H, m), 6.71 (2H, d, J = 8.6 Hz), 7.07 (2H, d, J = 8.1 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.30 (1H , t, J = 8.6 Hz), 7.99 (1H, d, J = 7.0 Hz).
MS m / z: 495 [MH] ⁻ .

Example 120
N- [2- (4-Ethylcyclohexyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) (cis, trans mixture)

¹ H-NMR (DMSO-d ₆ ) δ; 0.79 (3H, t, J = 7.3 Hz), 0.76-0.88 (2H, m), 0.90-1.35 (5H, m), 1.68-1.79 (4H, m) , 2.20-2.35 (1H, m), 2.98 (1H, dd, J = 13.8, 8.4 Hz), 3.11 (1H, dd, J = 13.8, 4.5 Hz), 3.63 (6H, s), 3.67 (3H, s ), 4.35-4.46 (1H, m), 6.71 (2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.1 Hz), 7.27 (1H , t, J = 8.4 Hz), 8.19 (1H, bs), 12.6 (1H, bs).
MS m / z: 495 [M−H] ⁻ .

Example 121
N- [2-methoxyimino-2- (1-methylpiperidin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.61-1.93 (4H, m), 2.65 (3H, s), 2.80-3.20 (7H, m), 3.65 (6H, s), 3.72 (3H, s) , 4.48-4.60 (1H, m), 6.73 (2H, d, J = 8.1Hz), 7.13 (2H, d, J = 8.1Hz), 7.24 (2H, d, J = 8.1Hz), 7.28 (1H, t, J = 8.1Hz), 8.82 (1H, d, J = 7.8Hz).
MS m / z: 482 [M−H] ⁻ .

Example 122
N- [2-methoxyimino-2- (1-methylpiperidin-4-yl) acetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.49-1.62 (1H, m), 1.65-1.79 (1H, m), 1.96-2.27 (2H, m), 2.66 (3H, s), 2.82-3.20 ( 7H, m), 3.64 (6H, s), 3.93 (3H, s), 4.49-4.61 (1H, m), 6.73 (2H, d, J = 8.4Hz), 7.12 (2H, d, J = 8.4Hz ), 7.21 (2H, d, J = 8.4Hz), 7.28 (1H, t, J = 8.4Hz), 8.40 (1H, d, J = 8.1Hz).
MS m / z: 482 [M−H] ⁻ .

Example 123
N- (2-cycloheptyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.20-1.86 (12H, m), 2.38-2.48 (1H, m), 2.96 (1H, dd, J = 14.0,9.7 Hz), 3.11 (1H, dd, J = 14.0, 4.1 Hz), 3.64 (6H, s), 3.66 (3H, s), 4.44-4.55 (1H, m), 6.72 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 7.8Hz), 7.27 (1H, t, J = 8.4Hz), 8.59 (1H, d, J = 7.6Hz), 12.7 (1H, bs).
MS m / z: 481 [M−H] ⁻ .

Example 124
N- (2-cycloheptyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.21-1.79 (12H, m), 2.90-3.18 (3H, m), 3.64 (6H, s), 3.88 (3H, s), 4.46-4.57 (1H, m), 6.72 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 8.4Hz), 7.19 (2H, d, J = 8.4Hz), 7.27 (1H, t, J = 8.4Hz) , 8.15 (1H, d, J = 8.1Hz), 12.8 (1H, bs).
MS m / z: 481 [M−H] ⁻ .

Example 125
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 0.97 (3H, d, J = 7.0 Hz), 1.06 (3H, d, J = 7.0 Hz), 2.46-3.23 (3H, m), 3.63 (6H, s ), 3.88 (3H, s), 4.46-4.59 (1H, m), 6.71 (2H, d, J = 8.4 Hz), 7.10 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4Hz), 7.27 (1H, t, J = 8.4 Hz), 8.22 (1H, d, J = 8.1 Hz).
MS m / z: 427 [M−H] ⁻ .

Example 126
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 0.97 (3H, d, J = 6.8 Hz), 1.00 (3H, d, J = 6.8 Hz), 2.47-2.61 (1H, m), 2.94 (1H, dd , J = 14.2, 10.1 Hz), 3.13 (1H, dd, J = 14.2, 4.2 Hz), 3.64 (6H, s), 3.67 (3H, s), 4.44-4.57 (1H, m), 6.72 (2H, d, J = 8.1 Hz), 7.10 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.28 (1H, t, J = 8.1 Hz), 8.59 (1H, d, J = 8.1 Hz).
MS m / z: 427 [M−H] ⁻ .

Example 127
N- (2-Cyclopropyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 0.79-0.82 (4H, m), 1.89-1.99 (1H, m), 3.22 (1H, dd, J = 14.6, 6.2 Hz), 3.31 (1H, d, J = 14.6, 5.4 Hz), 3.71 (6H, s), 3.78 (3H, s), 4.90-5.00 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.19-7.36 (5H, m), 7.56 (1H, d, J = 7.0 Hz).
MS m / z: 425 [M−H] ⁻ .

Example 128
N- (2-Cyclopropyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 0.78-0.95 (2H, m), 1.37-1.50 (2H, m), 2.02-2.20 (1H, m), 3.16 (1H, dd, J = 14.3, 6.5 Hz) , 3.26 (1H, dd, J = 14.3, 4.9Hz), 3.71 (6H, s), 3.92 (3H, s), 4.78-4.95 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.21-7.27 (3H, m), 7.31 (2H, d, J = 8.4 Hz).
MS m / z: 425 [M−H] ⁻ .

Example 129
N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) (syn: anti = 2: 1)

¹ H-NMR (DMSO-d ₆ ) δ; 1.50-2.20 (6H, m), 2.90-3.05 (1H, m), 3.63 (6H, s), 3.69 (3H, s), 4.48-4.55 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.27 (1H, t, J = 8.4 Hz) , 8.66 (1H, d, J = 7.8 Hz), 12.78 (1H, bs).
MS m / z: 439 [M−H] ⁻ .

Example 130
N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.55-1.70 (1H, m), 1.72-1.89 (1H, m), 1.99-2.20 (4H, m), 3.01 (1H, dd, J = 13.8, 9.5 Hz), 3.14 (1H, dd, J = 13.8, 4.3Hz), 3.51 (1H, quint, J = 8.9 Hz), 3.63 (6H, s), 3.84 (3H, s), 4.50-4.58 (1H, m ), 6.71 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.22 (2H, d, J = 8.1 Hz), 7.27 (1H, t, J = 8.4 Hz), 8.39 (1H, d, J = 8.4 Hz).
MS m / z: 439 [M−H] ⁻ .

Example 131
N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn) (syn: anti = 3: 2)

¹ H-NMR (DMSO-d ₆ ) δ; 1.67-2.08 (6H, m), 2.87-2.98 (1H, m), 3.05-3.08 (2H, m), 3.68 (3H, s), 4.48-4.55 ( 1H, m), 7.23 (2H, d, J = 5.9 Hz), 7.46-7.60 (5H, m), 8.55 (1H, d, J = 8.1 Hz), 10.65 (1H, s), 12.55 (1H, bs ).
MS m / z: 490 [MH] ⁻ .

Example 132
N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.55-1.90 (2H, m), 1.90-2.20 (4H, m), 2.94 (1H, dd, J = 13.2, 9.5 Hz), 3.10 (1H, dd, J = 13.2, 4.3 Hz), 3.45 (1H, quint, J = 9.2 Hz), 3.83 (3H, s), 4.46-4.53 (1H, m), 7.23 (2H, d, J = 8.4 Hz), 7.46 7.60 (5H, m), 8.28 (1H, d, J = 8.4 Hz), 10.64 (1H, s), 12.81 (1H, bs).
MS m / z: 490 [M−H] ⁻ .

Example 133
N- (2-cyclopentyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

N- (2-cyclopentyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.37-1.72 (8H, m), 2.87-3.20 (3H, m), 3.64 (6H, s), 3.67 (3H, s), 4.43-4.57 (1H, m), 6.72 (2H, d, J = 8.6 Hz), 7.11 (2H, d, J = 8.1 Hz), 7.16-7.33 (3H, m), 8.65 (1H, d, J = 7.8 Hz).
MS m / z: 453 [M−H] ⁻ .

Example 134
N- (2-cyclopentyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.38-1.77 (8H, m), 2.96-3.27 (3H, m), 3.64 (3H, s), 3.88 (3H, s), 4.44-4.57 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.11 (2H, d, J = 8.4 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.28 (2H, t, J = 8.4 Hz) , 8.26 (1H, d, J = 7.8 Hz).
MS m / z: 453 [M−H] ⁻ .

Example 135
N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

  N- {2- [1- (tert-butoxycarbonyl) piperidine-] obtained in the same manner as in Example 92 using ethyl 2- [1- (tert-butoxycarbonyl) piperidin-4-yl] -2-oxoacetate 4-yl] -2-methoxyiminoacetyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester in a solution of 0.83 g (1.42 mmol) in ethyl acetate (3 mL) and 4N hydrochloric acid-ethyl acetate solution 1 mL was added and stirred at room temperature for 6 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. To a chloroform (3 mL) solution containing 380 mg (0.786 mmol) of the obtained crude product and 100 mg (0.980 mmol) of triethylamine, 100 mg (0.980 mmol) of acetic anhydride was added with stirring under ice cooling. The mixture was warmed to room temperature and stirred overnight at room temperature. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl)- 70 mg (0.133 mmol) of L-phenylalanine methyl ester (syn) and N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L -Two isomers of 190 mg (0.361 mmol) of phenylalanine methyl ester (anti) were obtained.

N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.20-1.55 (2H, m), 1.72-1.90 (2H, m), 2.00-2.12 (3H, m), 2.54-2.69 (1H, m), 2.86-3.29 ( 4H, m), 3.65-3.82 (10H, m), 3.84 (3H, s), 4.52-4.67 (1H, m), 4.85-5.00 (1H, m), 6.65 (2H, d, J = 8.4Hz) , 7.16 (2H, d, J = 8.6Hz), 7.22-7.31 (3H, m), 7.63 (1H, d, J = 6.2 Hz).

N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.48-1.68 (2H, m), 1.96-2.29 (5H, m), 2.41-2.57 (1H, m), 2.95-3.40 (4H, m), 3.72 (6H, s), 3.73 (3H, s), 3.73-3.90 (1H, m), 3.94 (3H, s), 4.64-4.74 (1H, m), 4.81-4.94 (1H, m), 6.65 (2H, d, J = 8.4Hz), 7.05-7.37 (6H, m).

Example 136
Synthesis of N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) N- [2- (1- The title compound was obtained in the same manner as in Example 2 using acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn).

¹ H-NMR (DMSO-d ₆ ) δ; 1.20-1.47 (2H, m), 1.56-1.77 (2H, m), 1.89-1.97 (3H, m), 2.48-2.62 (1H, m), 2.86- 3.19 (4H, m), 3.60-3.80 (10H, m), 4.16-4.30 (1H, m), 4.45-4.57 (1H, m), 6.72 (2H, d, J = 8.4Hz), 7.12 (2H, d, J = 8.1Hz), 7.19-7.32 (3H, m), 8.70 (1H, d, J = 7.8Hz).
MS m / z: 510 [M−H] ⁻ .

Example 137
Synthesis of N- [2- (1-acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti) N- [2- (1- The title compound was obtained in the same manner as in Example 2 using acetylpiperidin-4-yl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti).

¹ H-NMR (DMSO-d ₆ ) δ; 1.35-1.81 (4H, m), 1.88-1.97 (3H, m), 2.35-2.48 (1H, m), 2.86-3.22 (4H, m), 3.64, (6H, s), 3.65-3.84 (1H, m), 3.89 (3H, s), 4.30-4.57 (2H, m), 6.72 (2H, d, J = 8.4Hz), 7.09-7.31 (5H, m ), 8.34 (1H, d, J = 8.1Hz), 12.9 (1H, bs).
MS m / z: 510 [M−H] ⁻ .

Reference Example 54
Synthesis of [(4-ethoxycarbonyl) cyclohexyl] benzyl oxoacetate Synthesis was performed in the same manner as in Reference Example 51 using diethylphosphono (methoxymethoxy) acetate benzyl.

−trans / cis mixture−
¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, t, J = 8.1 Hz), 1.34-2.18 (8H, m), 2.42-2.55 (1H, m), 2.95-3.15 (1H, m), 4.13 (2H, q, J = 8.1 Hz), 5.23-5.35 (2H, 2s), 7.39 (5H, m).

Reference Example 55
Synthesis of [(4-Ethoxycarbonyl) cyclohexyl] methoxyiminoacetic acid
Benzyl [(4-ethoxycarbonyl) cyclohexyl] methoxyiminoacetate was obtained in the same manner as in Reference Example 1 except that isomers were separated using benzyl [(4-ethoxycarbonyl) cyclohexyl] oxooxoacetate. Pd-BaSO ₄ (100 mg) was added to a methanol solution of 1.0 g (2.88 mmol) of the obtained product, followed by catalytic hydrogenation with stirring at room temperature. After completion of the reaction, insoluble matters were removed by Celite filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound.

2- (4-Ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetic acid (syn and anti mixture) (cis and trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 1.19-1.32 (3H, m), 1.40-1.80 (6H, m), 1.94-2.19 (2H, m), 2.19-2.34 and 2.47-2.75 and 3.02-3.18 (2H , m), 3.96-4.05 (3H, m), 4.08-4.24 (2H, m).

Example 138
N- [2- (4-Ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn) and (anti)
[(4-Ethoxycarbonyl) cyclohexyl] methoxyiminoacetic acid 410 mg (1.59 mmol) was dissolved in N, N-dimethylformamide (DMF) 5 mL, EDC 400 mg (2.07 mmol) and HOBt 280 mg (2.07 mmol) were added, and the mixture was stirred for 30 minutes. 500 mg (1.59 mmol) of-(2,6-dimethoxyphenyl) -L-phenylalanine methyl ester was added. After stirring overnight, the reaction mixture was poured into water and extracted with ethyl acetate. The obtained organic layer was washed with water and then with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N- [2- (4-ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4. 160 mg of-(2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn), N- [2- (4-ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) 400 mg of) -L-phenylalanine methyl ester (anti) was obtained.

N- [2- (4-Ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn) (cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 1.21-1.31 (3H, m), 1.31-1.76 (6H, m), 1.88-2.29 and 2.50-2.88 (4H, m), 3.09-3.27 (2H, m), 3.72 (6H, s), 3.76 and 3.77 (3H, 2s), 3.82 and 3.83 (3H, 2s), 4.07-4.17 (2H, m), 4.90-4.97 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.16 (2H, d, J = 8.1 Hz), 7.15-7.38 (4H, m).

N- [2- (4-Ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti) (cis, trans mixture)
¹ H-NMR (CDCl ₃ ) δ; 1.18-1.30 (3H, m), 1.40-2.35 and 2.50-2.80 and 3.00-3.13 (10H, m), 3.16 (2H, d, J = 6.2 Hz), 3.71 -3.85 (9H, m), 3.90 and 3.93 (3H, 2s), 4.07-4.26 (2H, m), 4.80-4.95 (1H, m), 6.65 (2H, d, J = 8.4 Hz), 7.10-7.29 (6H, m).

Example 139
Synthesis of N- [2- (4-carboxy) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)
N- [2- (4-Ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn) was used in the same manner as in Example 2 to give the title compound. Got.

N- [2- (4-carboxy) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn) (cis, trans mixture)

¹ H-NMR (CDCl ₃ ) δ; 1.20-1.80 and 1.90-2.40 and 2.60-2.80 (10H, m), 3.10-3.40 (2H, m), 3.70 and 3.71 (6H, 2s), 3.78 and 3.80 (3H 2s), 4.79-4.98 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.19-7.46 (6H, m).
MS m / z: 511 [M−1] ⁻ .

Example 140
Synthesis of N- [2- (4-carboxy) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)
N- [2- (4-Ethoxycarbonyl) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti) was used in the same manner as in Example 2 to give the title compound. Got.

N- [2- (4-Carboxy) cyclohexyl-2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti) (cis, trans mixture)

¹ H-NMR (CDCl ₃ ) δ; 1.40-1.70 and 1.95-2.42 and 3.05-3.30 (12H, m), 3.64 and 3.70 (6H, 2s), 3.88 and 3.91 (3H, 2s), 4.70-4.95 (1H , m), 6.64 (2H, d, J = 8.4 Hz), 7.12 (1H, d, J = 7.6 Hz), 7.20-7.31 (5H, m).
MS m / z: 511 [M−H] ⁻ .

  The following compounds are examples using known suitable glyoxylic acid esters and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester or 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester. The target compound was obtained in the same manner as in 92. Examples 141-143

Example 141
N- [2- (1H-Indol-3-yl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn anti mixture)
4- (2,6-Dichlorobenzoylamino) -L-phenylalanine ethyl ester and (1H-indol-3-yl) oxoacetic acid ethyl ester were used as raw materials.
MS m / z: 581 [M + H] ⁺ .

Example 142
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester 4- (2,6-dimethoxyphenyl) -L-phenylalanine as raw material Methyl ester and ethyl (2-furyl) oxoacetate were used.

N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.19 (1H, dd, J = 14.0, 6.7 Hz), 3.31 (1H, dd, J = 14.0, 5.1 Hz), 3.71 (6H, s), 3.80 (3H, s ), 4.00 (3H, s), 5.04-5.11 (1H, m), 6.41 (1H, dd, J = 3.5, 1.9 Hz), 6.65 (2H, d, J = 8.4 H), 6.74 (1H, d, J = 3.5 Hz), 6.88 (1H, d, J = 7.6 Hz), 7.18 (2H, d, J = 8.4 Hz), 7.25-7.31 (3H, m), 7.47 (1H, d, J = 1.9 Hz) .

N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 3.23-3.28 (2H, m), 3.71 (6H, s), 3.76 (3H, s), 4.10 (3H, s), 4.99-5.06 (1H, m), 6.50 (1H, dd, J = 3.5, 1.9 H, z), 6.64 (2H, d, J = 8.1 Hz), 7.15 (1H, d, J = 7.8 Hz), 7.19-7.30 (5H, m), 7.32 ( 1H, d, J = 3.5 Hz), 7.55 (1H, d, J = 1.9 Hz).

Example 143
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn) and (anti)
4- (2,6-Dichlorobenzoylamino) -L-phenylalanine ethyl ester and ethyl (2-furyl) oxoacetate were used as raw materials.

N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.18-3.37 (2H, m), 4.11 (3H, s), 4.22 (2H, q, J = 7.0 Hz), 4.94-5.01 (1H, m), 6.52 (1H, dd, J = 3.5, 1.9 Hz), 7.11 (1H, d, J = 7.8 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.24-7.39 (5H, m), 7.55-7.58 (3H, m).

N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (3H, t, J = 7.3 Hz), 3.17 (1H, dd, J = 13.8, 5.9 Hz), 3.30 (1H, dd, J = 13.8, 5.9 Hz), 4.03 (3H, s), 4.24 (2H, q, J = 7.3 Hz), 5.02-5.05 (1H, m), 6.45 (1H, dd, J = 3.8, 1.9 Hz), 6.73 (1H, dd, J = 3.5, 0.5 Hz), 6.83 (1H, d, J = 7.6 Hz), 7.20 (2H, d, J = 8.4 Hz), 7.28-7.39 (4H, m), 7.49 (1H, dd, J = 1.9, 0.5 Hz), 7.57 (2H, dd, J = 8.4, 1.9 Hz).

  Using the compounds of Examples 141-143, the following compounds were obtained in the same manner as in Example 2. Examples 144-148

Example 144
N- [2- (1H-Indol-3-yl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti) (syn: anti = 1: 10)

¹ H-NMR (DMSO-d ₆ ) δ; 3.04 (1H, dd, J = 13.8, 10.0 Hz), 3.16 (1H, dd, J = 13.8, 4.9 Hz), 3.99 (3H, s), 4.58-4.70 (1H, m), 6.83-6.92 (1H, m), 7.00-7.68 (10H, m), 8.01 (1H, d, J = 2.7Hz), 8.69 (1H, d, J = 8.4Hz), 10.7 ( 1H, s), 11.7 (1H, bs), 12.8 (1H, bs).
MS m / z: 551 [M−H] ⁻ .

Example 145
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.91 (1H, dd, J = 14.3, 10.8 Hz), 3.17 (1H, dd, J = 14.3, 4.3 Hz), 3.64 (6H, s), 3.80 (s , 3H), 4.53-4.62 (1H, m), 6.45 (1H, d, J = 3.5 Hz), 6.53 (1H, dd, J = 3.5, 1.6 Hz), 6.73 (2H, d, J = 8.4 Hz) , 7.13 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.29 (1H, t, J = 8.4 Hz), 7.78 (1H, d, J = 1.6 Hz), 9.15 (1H, d, J = 7.6 Hz), 12.92 (1H, bs).
MS m / z: 451 [M−H] ⁻ .

Example 146
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 3.03 (1H, dd, J = 14.0, 9.2 Hz), 3.16 (1H, dd, J = 14.0, 5.4 Hz), 3.64 (6H, s), 4.01 (3H , s), 4.50-4.62 (1H, m), 6.64 (1H, dd, J = 3.5, 1.9 Hz), 6.73 (2H, d, J = 8.4 Hz), 7.13 (2H, d, J = 8.1 Hz) , 7.17 (1H, d, J = 3.5 Hz), 7.25 (2H, d, J = 8.1 Hz), 7.28 (1H, t, J = 8.4 Hz), 7.76 (1H, d, J = 1.9 Hz), 8.88 (1H, d, J = 7.6 Hz), 12.86 (1H, bs).
MS m / z: 451 [M−1] ⁻ .

Example 147
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 2.95 (1H, dd, J = 13.5, 9.2 Hz), 3.11 (1H, dd, J = 13.5, 5.1 Hz), 4.01 (3H, s), 4.50-4.58 (1H, m), 6.65 (1H, dd, J = 3.5, 1.6 Hz), 7.15 (1H, dd, J = 3.5, 0.5 Hz), 7.33 (2H, d, J = 8.4 Hz), 7.47-7.60 ( 5H, m), 7.75 (1H, dd, J = 1.9, 0.5 Hz), 8.81 (1H, d, J = 8.1 Hz), 10.69 (1H, s).
MS m / z: 502 [MH] ⁻ .

Example 148
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 2.82-3.15 (2H, m), 3.79 (3H, s), 4.50-4.60 (1H, m), 6.34 (1H, d, J = 3.5 Hz), 6.54 (1H, dd, J = 3.5, 1.9 Hz), 7.25 (2H, d, J = 8.6 Hz), 7.47-7.61 (5H, m), 7.78 (1H, d, J = 1.9 Hz), 9.05 (1H, d, J = 8.4 Hz), 10.69 (1H, s), 12.6 (1H, bs).
MS m / z: 502 [M−H] ⁻ .

Reference Example 56
a) Synthesis of methyl 3-chloro-2-phenylacrylate 1.00 M sodium bis (trimethylsilyl) amide in a suspension of 13.2 g (38.1 mmol) of chloromethyltriphenylphosphonium chloride in anhydrous THF (70 mL) under ice-cooling 38.1 mL (38.1 mmol) of a THF solution was slowly added dropwise and stirred at the same temperature for 1.0 hour, and then 5.0 g (30.5 mmol) of methyl benzoylformate was added. After stirring for 30 minutes under ice cooling, the mixture was stirred overnight at room temperature. Water was added to the reaction solution to complete the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane / ethyl acetate = 10/1) to obtain 2.2 g of methyl 3-chloro-2-phenyl-acrylate.

¹ H-NMR (CDCl ₃ ) δ; 3.80 (3H, s), 7.29-7.40 (6H, m).

b) Synthesis of 3-chloro-2-phenylacrylic acid 470 mg (11.2 mmol) of lithium hydroxide monohydrate was added to an ethanol solution of 2.0 g (10.2 mmol) of methyl 3-chloro-2-phenylacrylate. Aqueous solution was added and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, acidified with 20% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-chloro-2-phenylacrylic acid.
¹ H-NMR (CDCl ₃ ) δ; 7.33-7.44 (6H, m).

Example 149
Synthesis of N- (3-chloro-2-phenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester To a chloroform solution of 400 mg (2.20 mmol) of 3-chloro-2-phenylacrylic acid At room temperature, 480 μl (6.60 mmol) of thionyl chloride was added, and then several drops of dimethylformamide were added dropwise, followed by stirring at 50 ° C. for 3.0 hours. The reaction solution was cooled to room temperature, the solvent was concentrated under reduced pressure, and then dissolved in dichloromethane. To a dichloromethane solution of 473 mg (1.50 mmol) of 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester and 919 μl (6.60 mmol) of triethylamine, the dichloromethane solution of acid chloride prepared earlier was added dropwise under ice-cooling. After stirring for minutes, the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1), and N- (3-chloro-2-phenylacryloylamino) -4- (2,6-dimethoxyphenyl) -L -640 mg of phenylalanine methyl ester was obtained.

¹ H-NMR (CDCl ₃ ) δ; 3.08 (1H, dd, J = 14.0, 6.8 Hz), 3.22 (1H, dd, J = 14.0, 5.4 Hz), 3.72 (6H, s), 3.76 (3H, s ), 4.94-5.01 (1H, m), 6.11 (1H, d, J = 7.8 Hz), 6.65 (2H, d, J = 8.4 Hz), 7.00 (2H, d, J = 8.1 Hz), 7.20 (2H , d, J = 8.4 Hz), 7.26 (1H, s), 7.28 (1H, t, J = 8.1 Hz), 7.36 (5H, br).

Example 150
Synthesis of N- (3-chloro-2-phenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine The title compound was obtained by treating the compound obtained in Example 149 in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ; 2.87-3.00 (1H, m), 3.19 (1H, dd, J = 14.3, 4.1 Hz), 3.64 (6H, s), 4.53-4.62 (1H, m) , 6.73 (2H, d, J = 8.4 Hz), 7.07 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.36 -7.43 (6H, m), 9.16 (1H, d, J = 8.1 Hz).
MS m / z: 498 [M + Cl] ^- .

Example 151
Synthesis of N- (3-chloro-2-phenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine Using 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester, The title compound was obtained in the same manner as in Example 149 and Example 2.

N- (3-Chloro-2-phenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.3 Hz), 3.08 (1H, dd, J = 14.6, 5.9 Hz), 3.17 (1H, dd, J = 14.6, 5.7 Hz), 4.19 (2H, q, J = 7.3 Hz), 4.88-4.95 (1H, m), 6.10 (1H, d, J = 8.1Hz), 6.97 (2H, d, J = 8.6 Hz), 7.18-7.47 (12H , m).

N- (3-Chloro-2-phenylacryloyl) -4- (2,6-dichloro-benzoylamino) -L-phenylalanine
¹ H-NMR (DMSO-d ₆ ) δ; 2.86 (1H, dd, J = 14.0, 11.3 Hz), 3.11 (1H, dd, J = 14.0, 4.3 Hz), 4.44-4.57 (1H, m), 7.05 -733 (7H, m), 7.46-7.59 (6H, m), 9.08 (1H, d, J = 8.4 Hz), 10.67 (1H, s).
MS m / z: 551 [M + Cl] ^- .

Reference Example 57
Synthesis of 3,3-dichloro-2-phenylacrylic acid

a) 5.0 g of methyl phenylglyoxylate was dissolved in 80 mL of tetrahydrofuran, and 80 g of carbon tetrachloride and 32.0 g of triphenylphosphine were added. After refluxing for 6 hours, the reaction solution was washed with water, dried over MgSO ₄ and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain 2.81 g 3,3-dichloro-2-phenyl acrylate methyl ester.
Methyl 3,3-dichloro-2-phenylacrylate; ¹ H-NMR (CDCl ₃ ) δ; 3.80 (3H, s), 7.26-7.56 (5H, m).
b) The obtained methyl 3,3-dichloro-2-phenylacrylate was dissolved in 50 mL of tetrahydrofuran, an aqueous solution of lithium hydroxide monohydrate (40 mL) was added under ice cooling, and 5 mL of methanol was gradually added to room temperature. Stir for 5 hours. After concentration under reduced pressure, the mixture was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to obtain 2.4 g of 3,3-dichloro-2-phenylacrylic acid as slightly yellow crystals.

3,3-dichloro-2-phenylacrylic acid

¹ H-NMR (CDCl ₃ ) δ; 7.26-7.55 (5H, m).

Example 152
Synthesis of N- (3,3-dichloro-2-phenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester and Synthesis was performed in the same manner as in Example 149 and Example 2 using 3,3-dichloro-2-phenylacrylic acid.

N- (3,3-dichloro-2-phenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.26 (3H, t, J = 7.0 Hz), 3.02-3.24 (2H, m), 4.19 (2H, q, J = 7.0 Hz), 4.86-4.98 (1H, m ), 6.13 (1H, d, J = 8.1Hz), 6.96 (2H, d, J = 8.4Hz), 7.22-7.52 (11H, m).

N- (3,3-dichloro-2-phenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine
¹ H-NMR (CDCl ₃ ) δ; 2.87 (1H, dd, J = 10.5 and 14.0 Hz), 3.12 (1H, dd, J = 4.3 and 14.0 Hz), 4.48-4.60 (1H, m), 7.10-7.70 (13H, m), 9.10 (1H, d, J = 8.4Hz), 10.67 (1H, s).
MS m / z: 551 [M + H] ⁺ .

Example 153
Synthesis of N- (3,3-dichloro-2-phenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester and 3, Synthesis was performed in the same manner as in Example 149 and Example 2 using 3-dichloro-2-phenylacrylic acid.

N- (3,3-dichloro-2-phenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 3.08 (1H, dd, J = 6.6 and 14.0 Hz), 3.22 (1H, dd, J = 5.4 and 14.0 Hz), 3.72 (6H, s), 3.75 (3H, s ), 4.90-5.00 (1H, m), 6.12 (1H, d, J = 7.6Hz), 6.65 (2H, d, J = 8.4Hz), 7.00 (2H, d, J = 8.4Hz), 7.15-7.50 (8H, m).

N- (3,3-dichloro-2-phenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine
¹ H-NMR (CDCl ₃ ) δ; 3.10 (1H, dd, J = 7.6 and 14.6 Hz), 3.29 (1H, dd, J = 5.1 and 14.6 Hz), 3.72 (6H, s), 4.92-5.04 (1H , m), 6.14 (1H, d, J = 7.6Hz), 6.64 (2H, d, J = 8.4Hz), 7.05 (2H, d, J = 8.1Hz), 7.19-7.41 (8H, m).
MS m / z: 498 [M−H] ⁻ .

Reference Example 58
Synthesis of ethyl 3,3-dichloro-2-cyclohexyl acrylate In the same manner as in Reference Example 57a), ethyl 3,3-dichloro-2-cyclohexyl acrylate was obtained from the corresponding ethyl 2-cyclohexyl-2-oxoacetate.

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.37 (8H, m), 1.55-1.90 (5H, m), 2.53-2.74 (1H, m), 4.28 (2H, q, J = 7.0 Hz).

Reference Example 59
Synthesis of 3,3-dichloro-2-cyclohexylacrylic acid
To a methylene chloride solution (4 mL) of 360 mg (1.43 mmol) of ethyl 3,3-dichloro-2-cyclohexylacrylate, 2 mL of a 1M boron tribromide methylene chloride solution was added dropwise at -5 ° C. After gradually bringing to room temperature and stirring for 2 hours, ice and an aqueous sodium hydrogen carbonate solution were added to make the mixture alkaline and washed with methylene chloride. The aqueous layer was acidified with 6M hydrochloric acid and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Yield 199mg

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.50 (5H, m), 1.65-1.95 (5H, m), 2.60-2.80 (1H, m).

Reference Example 60
Synthesis of ethyl 3,3-dichloro-2- (2-thienyl) acrylate The title compound was obtained in the same manner as in Reference Example 57 using ethyl oxo (2-thienyl) acetate.

¹ H-NMR (CDCl ₃ ); 1.38 (3H, t, J = 7.0 Hz), 4.39 (2H, q, J = 7.0 Hz), 7.05 (1H, dd, J = 4.9, 3.8 Hz), 7.16 (1H , dd, J = 3.5, 0.8 Hz), 7.44 (1H, dd, J = 5.4, 0.8 Hz).

3,3-Dichloro-2- (2-thienyl) acrylic acid

¹ H-NMR (CDCl ₃ ); 7.07 (1H, dd, J = 5.1, 3.8 Hz), 7.23 (1H, dd, J = 3.8, 1.1 Hz), 7.47 (1H, dd, J = 5.1, 1.1 Hz) .

Reference Example 61
Synthesis of 3,3-dichloro-2-isopropylacrylic acid The title compound was obtained in the same manner as in Reference Example 57a) and Reference Example 59 using ethyl 3-methyl-2-oxobutanoate.

3,3-Dichloro-2-isopropylethyl acrylate

¹ H-NMR (CDCl ₃ ); 1.13 (6H, d, J = 6.8 Hz), 1.34 (3H, t, J = 7.0 Hz), 3.00 (1H, sevent, J = 6.8 Hz), 4.29 (2H, q , J = 7.0 Hz).

3,3-Dichloro-2-isopropylacrylic acid

¹ H-NMR (CDCl ₃ ); 1.19 (6H, d, J = 7.0 Hz), 3.06 (1H, sevent, J = 7.0 Hz).

Reference Example 62
Ethyl 3,3-dichloro-2-methylacrylate In the same manner as in Reference Example 57a) and Reference Example 59, the title compound was obtained.

¹ H-NMR (DMSO-d ₆ ); 1.33 (3H, t, J = 7.3 Hz), 2.02 (3H, s), 4.27 (2H, q, J = 7.3 Hz).

3,3-Dichloro-2-methylacrylic acid

¹ H-NMR (DMSO-d ₆ ); 2.02 (3H, s).

Example 154
Synthesis of N- (3,3-dichloro-2-cyclohexylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine
Synthesis was performed in the same manner as in Example 149 and Example 2 using 3,3-dichloro-2-cyclohexylacrylic acid.

N- (3,3-dichloro-2-cyclohexylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.80 (10H, m), 2.50-2.64 (1H, m), 3.13 (1H, dd, J = 7.6 and 14.0 Hz), 3.26 (1H, dd, J = 5.4 and 14.0Hz), 3.72 (6H, s), 3.78 (3H, s), 4.95-5.04 (1H, m), 5.95 (1H, d, J = 8.1Hz), 6.64 (2H, d, J = 8.4 Hz), 7.15-7.33 (5H, m).

N- (3,3-dichloro-2-cyclohexylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.00-1.40 (5H, m), 1.55-1.80 (5H, m), 2.50-2.65 (1H, m), 3.17 (1H, dd, J = 7.3 and 14.3 Hz) , 3.33 (1H, dd, J = 5.4 and 14.3Hz), 3.72 (6H, s), 4.97-5.06 (1H, m), 6.10 (1H, d, J = 7.6Hz), 6.64 (2H, d, J = 8.4Hz), 7.19-7.35 (5H, m).

Reference Example 63
Synthesis of 4-oxobenzyl ester of oxo (tetrahydropyran-4-yl) acetic acid 5.4 mL of 1M aqueous sodium hydroxide solution was added to a solution of 1.00 g (5.37 mmol) of ethyl oxo (tetrahydropyran-4-yl) acetate in methanol (5.4 mL). The mixture was stirred for 2 hours at room temperature and then dried under reduced pressure. DMSO (5 mL) was added to the resulting residue, 925 mg of 4-methoxybenzyl chloride was added, and the mixture was stirred at 60 ° C. overnight. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.60-1.75 (4H, m), 3.15-3.35 (1H, m), 3.46 (2H, ddd, J = 11.6, 11.1, 2.7 Hz), 3.81 (3H, s) , 3.98 (2H, ddd, J = 3.2, 4.1, 11.1Hz), 5.23 (2H, s), 6.85-6.95 (2H, m), 7.30-7.40 (2H, m).

Reference Example 64
Synthesis of 3,3-dichloro-2- (tetrahydropyran-4-yl) acrylic acid 4-methoxybenzyl ester 1.38 g (4.96 mmol) of oxo (tetrahydropyran-4-yl) acetic acid 4-methoxybenzyl ester in 80 mL of tetrahydrofuran After dissolution, 5 mL of carbon tetrachloride and 5.20 g of triphenylphosphine were added. After heating to reflux for 6 hours, the reaction mixture was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 1.13 g of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.56-1.75 (4H, m), 2.80-2.96 (1H, m), 3.33-3.46 (2H, m), 3.82 (3H, s), 3.91-4.01 (2H, m), 5.19 (2H, s), 6.85-6.95 (2H, m), 7.28-7.40 (2H, m).

Reference Example 65
Synthesis of 3,3-dichloro-2- (tetrahydropyran-4-yl) acrylic acid
3,3-Dichloro-2- (tetrahydropyran-4-yl) acrylic acid 4-methoxybenzyl ester (500 mg) was dissolved in trifluoroacetic acid, stirred at room temperature for 1 hour, and concentrated under reduced pressure. Water was added to the resulting residue, and the mixture was made alkaline with aqueous sodium hydrogen carbonate and washed with chloroform. The aqueous layer was acidified with 6M hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Yield 322 mg.

¹ H-NMR (CDCl ₃ ) δ; 1.67-1.95 (4H, m), 2.91-3.07 (1H, m), 3.45-3.62 (2H, m), 4.07-4.20 (2H, m)

Example 155
Synthesis of N- [3,3-dichloro-2- (tetrahydropyran-4-yl) acryloyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine
The title compound was obtained in the same manner as in Example 149 and Example 2 using 3,3-dichloro-2- (tetrahydropyran-4-yl) acrylic acid.

N- [3,3-dichloro-2- (tetrahydropyran-4-yl) acryloyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.50-1.85 (4H, m), 2.75-2.92 (1H, m), 3.13 (1H, dd, J = 7.6, 14.3 Hz), 3.22-3.45 (3H, m) , 3.72 (6H, s), 3.79 (3H, s), 3.90-4.03 (2H, m), 4.95-5.10 (1H, m), 5.99 (1H, d, J = 7.8Hz), 6.64 (2H, d , J = 8.4Hz), 7.15-7.45 (5H, m).

N- [3,3-dichloro-2- (tetrahydropyran-4-yl) acryloyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.50-1.88 (4H, m), 2.78-2.90 (1H, m), 3.13 (1H, dd, J = 8.1, 14.0 Hz), 3.30-3.50 (3H, m) , 3.71 (6H, s), 3.89-4.09 (2H, m), 4.98-5.11 (1H, m), 6.06 (1H, d, J = 7.6Hz), 6.64 (2H, d, J = 8.6Hz), 7.20-7.40 (5H, m).
MS m / z: 506 [M−H] ⁻ .

Reference Example 66
Synthesis of oxo (tetrahydrothiopyran-4-yl) acetic acid-4-methoxybenzyl ester The title compound was prepared in the same manner as in Reference Example 63 using ethyl oxo (tetrahydrothiopyran-4-yl) acetate obtained in Reference Example 12. Obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.65-1.85 (2H, m), 2.10-2.25 (2H, m), 2.60-2.80 (4H, m), 3.03-3.20 (1H, m), 3.81 (3H, s), 5.22 (2H, s), 6.85-6.98 (2H, m), 7.26-7.42 (2H, m).

Reference Example 67
Synthesis of 3,3-dichloro-2- (tetrahydrothiopyran-4-yl) acrylic acid The title compound was obtained in the same manner as in Reference Example 57a) and Reference Example 65.

¹ H-NMR (CDCl ₃ ) δ; 1.77-2.00 (2H, m), 2.05-2.18 (2H, m), 2.59-2.87 (5H, m).

Example 156
Synthesis of N- [3,3-dichloro-2- (tetrahydrothiopyran-4-yl) acryloyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine
The title compound was obtained in the same manner as in Example 149 and Example 2 using 3,3-dichloro-2- (tetrahydrothiopyran-4-yl) acrylic acid.

N- [3,3-dichloro-2- (tetrahydrothiopyran-4-yl) acryloyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.67-2.08 (4H, m), 2.50-2.80 (5H, m), 3.13 (1H, dd, J = 7.3, 14.0 Hz), 3.28 (1H, dd, J = 5.4, 14.0Hz), 3.72 (6H, s), 3.79 (3H, s), 4.94-5.07 (1H, m), 6.00 (1H, d, J = 7.8Hz), 6.64 (2H, d, J = 8.4 Hz), 7.15-7.37 (5H, m).

N- [3,3-dichloro-2- (tetrahydrothiopyran-4-yl) acryloyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.65-2.05 (4H, m), 2.55-2.76 (5H, m), 3.16 (1H, dd, J = 7.6, 14.3 Hz), 3.37 (1H, dd, J = 5.1, 14.3Hz), 3.72 (6H, s), 4.95-5.10 (1H, m), 6.04 (1H, d, J = 7.6Hz), 6.64 (2H, d, J = 8.4Hz), 7.20-7.35 ( 5H, m).
MS m / z; 522 [M−H] ⁻ .

Example 157
(Z) -N- (2-phenyl-4,4,4-trifluorocrotonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine
(E / Z) -2-phenyl-4,4,4-trifluorocrotonate and 4- (2,6-dimethoxy) synthesized by the method described in J. Fluorine. Chem., 105, 169 (2000) The title compound was obtained in the same manner as in Example 23 and Example 2 using (phenyl) -L-phenylalanine methyl ester.

N- (2-Phenyl-4,4,4-trifluorocrotonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (E / Z mixture)
¹ H-NMR (CDCl ₃ ); 2.89-2.99 (1H, m), 3.18-3.28 (1H, m), 3.69-3.78 (9H, m), 4.78-4.89 and 5.11-5.22 (1H, m), 5.89 -5.96 and 6.20-6.26 (1H, m,), 5.98-6.08 and 6.62-6.72 (1H, m), 6.62-6.72 (2H, m), 6.83-7.47 (10H, m).

N- (2-Phenyl-4,4,4-trifluorocrotonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (E / Z mixture)

¹ H-NMR (CDCl ₃ ) δ; 2.88-3.34 (2H, m), 3.68 and 3.70 (6H, s), 4.73-4.89 and 5.14-5.23 (1H, m), 5.93-5.98 and 6.41-6.46 (1H , m), 5.98-6.06and 6.74-6.78 (1H, m) 6.61-6.78 (2H, m), 6.88-7.43 (10H, m).
MS m / z; 498 [M−H] ⁻ .

Reference Example 68
Synthesis of (1,3-dithian-2-ylidene) phenylacetic acid methyl ester
To a THF solution of 2.0 g (10.4 mmol) of 2-trimethylsilyl-1,3-dithiane, 8.1 ml (12.5 mmol) of n-BuLi was added dropwise with stirring at −80 ° C., and stirred for 30 minutes at the same temperature. The temperature rose. After cooling again to −80 ° C., 2.0 ml (13.2 mmol) of methyl benzoylformate was added dropwise and stirred at the same temperature for 30 minutes. Thereafter, the temperature was slowly raised to room temperature and stirred overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (hexane / ethyl acetate = 5/1) to obtain 1.5 g of methyl (1,3-dithian-2-ylidene) phenylacetate.

¹ H-NMR (CDCl ₃ ) δ; 2.15 (2H, quint, J = 6.8 Hz), 2.87 (2H, t, J = 6.8 Hz), 3.01 (2H, t, J = 6.8 Hz), 3.67 (3H, s), 7.16-7.40 (5H, m).

Example 158
Synthesis of N- [2- (1,3-dithian-2-ylidene) -2-phenylacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine
The title compound was obtained in the same manner as in Example 1 and Example 2 using (1,3-dithian-2-ylidene) phenylacetic acid methyl ester and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- [2- (1,3-dithian-2-ylidene) -2-phenylacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 2.12 (2H, quint., J = 6.8 Hz), 2.77-3.16 (6H, m), 3.25 (1H, dd, J = 14.3, 5.1 Hz), 3.69 (3H, s), 3.72 (6H, s), 4.81-4.89 (1H, m), 5.46 (1H, d, J = 6.2 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.92 (2H, d, J = 8.1 Hz), 7.08 (2H, dd, J = 8.1, 3.5 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.25-7.40 (4H, m).

N- [2- (1,3-Dithian-2-ylidene) -2-phenylacetyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 2.13 (2H, quint., J = 6.8 Hz), 2.80-3.05 (5H, m), 3.25 (1H, dd, J = 14.0, 5.7 Hz), 3.74 (6H, s), 4.60-4.70 (1H, m), 5.37 (1H, d, J = 7.6 Hz), 6.67 (2H, d, J = 8.4 Hz), 6.90-7.35 (10H, m).
MS m / z: 536 [M + H] ⁺ , 558 [M + Na] ⁺ .

Reference Example 69
Synthesis of ethyl methoxyimino [2- (4-pyridyl) thiazol-4-yl] acetate A dichloromethane solution of 9.2 mL (179 mmol) of bromine was added dropwise to a dichloromethane solution of 14.7 mL (186 mmol) of diketene at −50 ° C. The temperature was raised to an ice cooling temperature, and the mixture was stirred at the same temperature for 30 minutes. The mixture was cooled again to −50 ° C., ethanol was added to complete the reaction, and the mixture was warmed to room temperature. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain 35.4 g of a bromo compound.

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.0 Hz), 3.71 (2H, s), 4.06 (2H, s), 4.23 (2H, q, J = 7.0 Hz).

  Bromo compound (3.0 g, 14.4 mmol) was dissolved in acetic acid (30 ml) and dichloromethane (60 ml), and 1.2 g of a sodium nitrite aqueous solution was added dropwise under ice cooling, followed by stirring for 90 minutes. The reaction solution was added to a mixed solvent of water and THF and extracted. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 1.4 g of an oxime.

Trimethylsilyldiazomethane was added dropwise to the diethyl ether solution of the obtained oxime, stirred at room temperature, and stored in a refrigerator for 2 days. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography to obtain a methoxyimino form.
Methoxyimino compound 510 mg (2.02 mmol) and thioisonicotinamide 279 mg (2.02 mmol) were dissolved in ethanol and heated to reflux overnight. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 30/1) to obtain 420 mg of a thiazole compound.

Example 159
Synthesis of N- {methoxyimino [2- (4-pyridyl) thiazol-4-yl] acetyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester Methoxyimino [2- (4-pyridyl ) Thiazol-4-yl] ethyl acetate and 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester were used in the same manner as in Example 1 and Example 2 to obtain the title compound.

N- {methoxyimino [2- (4-pyridyl) thiazol-4-yl] acetyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.0 Hz), 3.20 (1H, dd, J = 13.8, 5.4 Hz), 3.31 (1H, dd, J = 13.8, 5.9 Hz), 4.13 (3H, s), 4.23 (2H, q, J = 7.0 Hz), 5.04-5.10 (1H, m), 7.09 (1H, d, J = 7.3 Hz), 7.24 (2H, d, J = 8.6 Hz) ), 7.29-7.39 (5H, m), 7.51 (1H, s), 7.53 (2H, d, J = 8.6 Hz), 7.82 (2H, d, J = 5.9 Hz), 8.69 (2H, d, J = (5.9 Hz).

N- {methoxyimino [2- (4-pyridyl) thiazol-4-yl] acetyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine

¹ H-NMR (DMSO-d ₆ ) δ; 2.86 (1H, dd, J = 14.3, 9.7 Hz), 3.09 (1H, dd, J = 14.3, 4.3 Hz), 3.88 (3H, s), 4.50-4.60 (1H, m), 7.23 (2H, d, J = 8.6 Hz), 7.48-7.56 (6H, m), 7.81 (2H, d, J = 5.9 Hz), 8.68 (2H, d, J = 5.9 Hz) , 8.88-8.98 (1H, m), 10.64 (1H, s).

Reference Example 70
Synthesis of ethyl cyclohexylmethoxyiminoacetate 2.0 g (24.1 mmol) of O-methylhydroxylamine hydrochloride in a solution of 3.4 g (18.5 mmol) of ethyl cyclohexyloxoacetate and 4.40 mL (55.5 mmol) of pyridine in methanol (20 mL) ) And heated to reflux overnight. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed successively with 20% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The geometric isomers of the resulting residue were separated and purified by column chromatography (hexane / ethyl acetate = 10/1) to obtain 2.0 g of syn type and 2.34 g of anti type.

Cyclohexylmethoxyiminoethyl acetate (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.88-1.40 (5H, m), 1.33 (3H, t, J = 7.3 Hz), 1.60-1.95 (5H, m), 2.35-2.45 (1H, m), 3.84 (3H, s), 4.30 (2H, q, J = 7.3Hz).

Cyclohexylmethoxyiminoethyl acetate (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.20-1.40 (2H, m), 1.34 (3H, t, J = 7.3 Hz), 1.60-1.82 (8H, m), 3.00-3.18 (1H, m), 3.99 (3H, s), 4.29 (2H, q, J = 7.3Hz).

Example 160
Synthesis of N- (2-cyclohexyl-2-methoxyiminoacetyl) -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (syn) 2.63 g (12.3 mmol) of ethyl cyclohexylmethoxyiminoacetate (syn) obtained above 569 mg (13.6 mmol) of lithium hydroxide monohydrate was added to an ethanol (20 ml) solution, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure to obtain cyclohexylmethoxyiminoacetic acid lithium salt (syn). To a DMF solution of 1.56 g (8.16 mmol) of the obtained lithium salt and 1.66 g (12.2 mmol) of HOBt, 2.34 g (12.2 mmol) of EDC was added and stirred at room temperature for 1.0 hour, then 4-trifluoro A DMF solution of 1.56 g (8.16 mmol) of lomethanesulfonyloxy-L-phenylalanine methyl ester was added dropwise. After stirring overnight at room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1), and N- (2-cyclohexyl-2-methoxyiminoacetyl) -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester. 4.0 g of (syn) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.62-1.85 (5H, m), 2.57-2.70 (1H, m), 3.15 (1H, dd, J = 14.0, 6.2 Hz) , 3.26 (1H, dd, J = 14.0, 5.9Hz), 3.74 (3H, s), 3.85 (3H, s), 4.92-4.99 (1H, m), 7.18-7.27 (5H, m).

Example 161
Synthesis of N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-difluorophenyl) -L-phenylalanine methyl ester (syn) N- (2-cyclohexyl-2-methoxyiminoacetyl) -4 -Trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (syn) 500 mg (1.12 mmol), 2,6-difluorophenylboric acid 223 mg (1.41 mmol), and potassium carbonate 405 mg (2.93 mmol) in DMF (2. 0 mL) and toluene (15 mL) were mixed with tetrakistriphenylphosphine palladium (233 mg, 0.202 mmol) and stirred at 80 ° C. overnight. The reaction solution was cooled to room temperature and water was added, followed by filtration through celite. The filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain 300 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.29 (5H, m), 1.60-1.90 (5H, m), 2.57-2.70 (1H, m), 3.26 (1H, dd, J = 14.0, 5.7 Hz) , 3.15 (1H, dd, J = 14.0, 5.4Hz), 3.72 (3H, s), 3.85 (3H, s), 4.95-5.02 (1H, m), 6.90-7.50 (8H, m).

Example 162
Synthesis of N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,6-difluorophenyl) -L-phenylalanine (syn) In the same manner as in Example 2 using the compound obtained in Example 161. The title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.85 (5H, m), 2.57-2.70 (1H, m), 3.22 (1H, dd, J = 14.0, 6.8 Hz) , 3.35 (1H, dd, J = 14.0, 5.4Hz), 3.80 (3H, s), 4.96-5.03 (1H, m), 6.96 (1H, d, J = 7.8 Hz), 6.99 (1H, d, J = 7.8 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.22-7.32 (2H, m), 7.43 (2H, d, J = 8.1 Hz).
MS m / z: 443 [MH] ⁻ .

  The following compounds were obtained in the same manner as in Example 161 and Example 2 using appropriate phenylboric acid. Examples 163 to 169

Example 163
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-methoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.90 (5H, m), 2.57-2.68 (1H, m), 3.16 (1H, dd, J = 14.0, 6.2 Hz) , 3.24 (1H, dd, J = 14.0, 5.7Hz), 3.77 (3H, s), 3.80 (3H, s), 3.83 (3H, s), 4.94-5.01 (1H, m), 6.98 (1H, d , J = 8.1 Hz), 7.03 (1H, dd, J = 8.1, 1.1 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.18-7.21 (1H, m), 7.35-7.27 (3H, m) , 7.46 (2H, d, J = 8.1 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-methoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.05-1.45 (5H, m), 1.50-1.95 (5H, m), 2.55-2.70 (1H, m), 3.20 (1H, dd, J = 13.5, 6.9 Hz) , 3.32 (1H, dd, J = 13.5, 5.4Hz), 3.78 (3H, s), 3.80 (3H, s), 4.97-5.02 (1H, m), 6.97 (1H, d, J = 7.8 Hz), 7.02 (1H, d, J = 7.8 Hz), 7.26-7.35 (4H, m), 7.48 (2H, d, J = 8.1 Hz).
MS m / z: 437 [MH] ⁻ .

Example 164
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-methylsulfanylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.90 (5H, m), 2.35 (3H, s), 2.58-2.70 (1H, m), 3.18 (1H, dd, J = 13.8, 6.5 Hz), 3.25 (1H, dd, J = 13.8, 5.4 Hz), 3.76 (3H, s), 3.85 (3H, s), 4.96-5.02 (1H, m), 7.18-7.32 (7H , m), 7.35 (1H, d, J = 8.1 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-methylsulfanylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.15-1.35 (5H, m), 1.57-1.82 (5H, m), 2.33 (3H, s), 2.44-2.60 (1H, m), 3.20 (1H, dd, J = 13.8, 6.2 Hz), 3.35 (1H, dd, J = 13.8, 5.4 Hz), 3.79 (3H, s), 4.81-4.88 (1H, m), 7.12-7.20 (2H, m), 7.22-7.35 (6H, m), 7.41 (1H, d, J = 8.6 Hz).
MS m / z: 453 [MH] ⁻ .

Example 165
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-chlorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.90 (5H, m), 2.57-2.70 (1H, m), 3.18 (1H, dd, J = 14.0, 6.2 Hz) , 3.26 (1H, dd, J = 14.0, 5.7Hz), 3.76 (3H, s), 3.84 (3H, s), 4.96-5.03 (1H, m), 7.21 (2H, d, J = 8.4 Hz), 7.20-7.33 (3H, m), 7.34 (2H, d, J = 8.4 Hz), 7.46 (1H, d, J = 5.9 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-chlorophenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.05-1.45 (5H, m), 1.60-1.85 (5H, m), 2.55-2.70 (1H, m), 3.21 (1H, dd, J = 14.0, 6.8 Hz) , 3.34 (1H, dd, J = 14.0, 5.1Hz), 3.82 (3H, s), 4.96-5.03 (1H, m), 7.23-7.32 (5H, m), 7.39 (2H, d, J = 8.1Hz ), 7.43-7.47 (1H, m).
MS m / z: 441 [MH] ⁻ .

Example 166
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-fluorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.35 (5H, m), 1.62-1.90 (5H, m), 2.58-2.68 (1H, m,), 3.17 (1H, dd, J = 14.0, 6.2 Hz ), 3.26 (1H, dd, J = 14.0,5.7 Hz), 3.77 (3H, s), 3.83 (3H, s), 4.96-5.00 (1H, m), 7.10-7.36 (7H, m), 7.41 ( 1H, td, J = 8.1, 1.4 Hz), 7.48 (2H, dd, J = 8.1, 2.2 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2-fluorophenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.12-1.3 (5H, m), 1.60-1.90 (5H, m), 2.57-2.68 (1H, m), 3.21 (1H, dd, J = 14.3, 6.5 Hz) , 3.34 (1H, dd, J = 14.3, 5.4Hz), 3.81 (3H, s), 4.96-5.03 (1H, m), 7.12 (1H, dd, J = 8.1, 1.4 Hz), 7.10-7.45 (7H , m), 7.41 (1H, td, J = 8.1, 1.6 Hz), 7.51 (2H, dd, J = 8.1, 1.6 Hz).
MS m / z: 425 [MH] ⁻ .

Example 167
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.05-1.40 (11H, m), 1.60-1.90 (5H, m), 2.57-2.70 (1H, m), 2.90 (1H, m), 3.15 (1H, dd, J = 13.8, 6.5 Hz), 3.22 (1H, dd, J = 13.8, 5.4 Hz), 3.77 (3H, s), 3.78 (3H, s), 3.83 (3H, s), 4.94-5.01 (1H, m ), 6.91 (1H, d, J = 8.4 Hz), 7.17 (5H, m), 7.46 (2H, d, J = 6.5 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.60 (11H, m), 1.60-1.90 (5H, m), 2.58-2.68 (1H, m), 2.90 (1H, m), 3.20 (1H, dd, J = 13.5, 6.8 Hz), 3.32 (1H, dd, J = 13.5, 5.4 Hz), 3.77 (3H, s), 3.81 (3H, s), 4.94-5.02 (1H, m), 6.94 (1H, d , J = 8.1 Hz), 7.12-7.28 (6H, m), 7.49 (2H, d, J = 8.1 Hz).
MS m / z: 479 [MH] ⁻ .

Example 168
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,5-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.85 (5H, m), 2.58-2.70 (1H, m), 3.16 (1H, dd, J = 13.8, 6.2 Hz) , 3.24 (1H, dd, J = 13.8, 5.4Hz), 3.74-3.83 (12H, 4s), 4.94-5.01 (1H, m), 6.80-6.93 (3H, m), 7.15-7.20 (3H, m) , 7.46 (2H, d, J = 8.4 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,5-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.90 (5H, m), 2.58-2.70 (1H, m), 3.21 (1H, dd, J = 13.8, 7.3 Hz) , 3.32 (1H, dd, J = 13.8, 5.1Hz), 3.73 (3H, s), 3.80 (3H, s), 3.81 (3H, s), 4.93-5.00 (1H, m), 6.82-6.92 (3H , m), 7.24 (2H, d, J = 8.4 Hz), 7.48 (2H, d, J = 8.4 Hz).
MS m / z: 467 [MH] ⁻ .

Example 169
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,4-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.10-1.40 (5H, m), 1.60-1.90 (5H, m), 2.56-2.70 (1H, m), 3.14 (1H, dd, J = 14.0, 6.2 Hz) , 3.23 (1H, dd, J = 14.0, 5.4Hz), 3.77 (3H, s), 3.78 (3H, s), 3.83 (3H, s), 3.85 (3H, s), 4.93-5.00 (1H, m ), 6.55-6.58 (2H, m), 7.15 (2H, d, J = 8.1 Hz), 7.20-7.23 (2H, m), 7.38 (2H, d, J = 8.1 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (2,4-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.10-1.35 (5H, m), 1.60-1.90 (5H, m), 2.52-2.70 (1H, m), 3.19 (1H, dd, J = 13.8, 7.0 Hz) , 3.30 (1H, dd, J = 13.8, 5.7Hz), 3.78 (3H, s), 3.81 (3H, s), 3.85 (3H, s), 4.92-4.99 (1H, m), 6.55-6.58 (2H , m), 7.19-7.26 (4H, m), 7.45 (2H, d, J = 8.1 Hz).
MS m / z: 467 [MH] ⁻ .

Example 170
Synthesis of N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester Oxo (tetrahydropyran-4-yl) obtained in Reference Example 49 Ethyl methoxyimino (tetrahydropyran-4-yl) ethyl acetate (syn type and anti type mixture) obtained from ethyl acetate in the same manner as in Reference Example 1 was prepared in the same manner as in Example 160 to obtain the target syn type and anti type. Obtained.

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.35-1.47 (2H, m), 2.19-2.39 (2H, m), 3.12 (1H, dd, J = 14.0, 6.2 Hz), 3.21 (1H, dd, J = 14.0, 6.1 Hz), 3.24-3.46 (3H, m), 3.73 (3H, s), 3.90-4.04 (5H, m), 4.81-4.93 (1H, m), 7.08 (1H, d, J = 8.4 Hz ), 7.15-7.28 (4H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.58-1.76 (4H, m), 2.83-2.97 (1H, m), 3.15 (1H, dd, J = 14.0, 6.2 Hz), 3.25 (1H, dd, J = 14.0, 5.4 Hz), 3.36-3.50 (2H, m), 3.75 (3H, s), 3.88 (3H, s), 3.93-4.03 (2H, m), 4.89-5.00 (1H, m), 7.16-7.29 (4H, m), 7.50 (1H, d, J = 7.0 Hz).

  Example 161 and Examples using syn or anti N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester and the appropriate phenylboric acid In the same manner as in Example 2, the following compound was obtained. Examples 171-180

Example 171
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-methoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.35-1.48 (2H, m), 2.20-2.43 (2H, m), 3.12-3.21 (2H, m), 3.29-3.47 (3H, m), 3.75 (3H, s), 3.80 (3H, s), 3.91-4.03 (5H, m), 4.83-4.96 (1H, m), 6.94-7.36 (7H, m), 7.46 (2H, d, J = 8.1 Hz).

  N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-methoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.31-1.48 (2H, m), 2.17-2.40 (2H, m), 3.10-3.47 (5H, m), 3.78 (3H, s), 3.83-4.05 (5H, m), 4.83-4.97 (1H, m), 6.91-7.05 (2H, m), 7.11-7.35 (4H, m), 7.47 (2H, d, J = 7.8 Hz).
MS m / z: 439 [M−H] ⁻ .

Example 172
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-methoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.52-1.78 (4H, m), 2.85-3.00 (1H, m), 3.15 (1H, dd, J = 14.0, 6.5 Hz), 3.25 (1H, dd, J = 14.0, 5.4 Hz), 3.36-3.50 (2H, m), 3.78 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 3.91-4.02 (2H, m), 4.90-5.01 (1H , m), 6.94-7.08 (2H, m), 7.17 (2H, d, J = 8.1 Hz) 7.24-7.36 (2H, m), 7.43-7.54 (3H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-methoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.52-1.77 (4H, m), 2.83-3.00 (1H, m), 3.17 (1H, dd, J = 14.0, 6.8 Hz), 3.26-3.52 (3H, m) , 3.78 (3H, s), 3.83 (3H, s), 3.90-4.03 (2H, m), 4.89-5.02 (1H, m), 6.93-7.06 (2H, m), 7.18-7.38 (4H, m) , 7.48 (2H, d, J = 8.1 Hz), 7.57 (1H, d, J = 7.0 Hz).
MS m / z: 439 [M−H] ⁻ .

Example 173
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-difluorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.57-1.76 (4H, m), 2.85-3.00 (1H, m), 3.16 (1H, dd, J = 13.8, 6.5 Hz), 3.27 (1H, dd, J = 13.8, 5.7 Hz), 3.16-3.49 (2H, m), 3.78 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 3.91-4.02 (2H, m), 4.94-5.01 (1H , m), 6.92-7.05 (2H, m), 7.20-7.32 (3H, m), 7.38-7.54 (3H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-difluorophenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.51-1.76 (4H, m), 2.85-3.00 (1H, m), 3.21 (1H, dd, J = 14.0, 7.3 Hz), 3.30-3.51 (3H, m) , 3.83 (3H, s), 3.92-4.02 (2H, m), 4.94-5.05 (1H, m), 6.91-7.06 (2H, m), 7.22-7.36 (3H, m), 7.43 (2H, d, J = 8.1 Hz), 7.55 (1H, d, J = 7.3 Hz).
MS m / z: 445 [M−H] ⁻ .

Example 174
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-chlorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.78 (4H, m), 2.86-2.99 (1H, m), 3.17 (1H, dd, J = 14.0, 6.5 Hz), 3.26 (1H, dd, J = 14.0, 5.7 Hz), 3.36-3.48 (2H, m), 3.77 (3H, s), 3.87 (3H, s), 3.92-4.00 (2H, m), 4.93-5.02 (1H, m), 7.21 (2H , d, J = 8.1 Hz), 7.27-7.34 (3H, m), 7.38 (2H, d, J = 8.1 Hz), 7.44-7.54 (2H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-chlorophenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.53-1.78 (4H, m), 2.85-3.03 (1H, m), 3.21 (1H, dd, J = 14.0, 7.0 Hz), 3.28-3.51 (3H, m) , 3.85 (3H, s), 3.91-4.02 (2H, m), 4.90-5.05 (1H, m), 7.21-7.34 (5H, m), 7.39-7.51 (3H, m), 7.57 (1H, d, J = 7.3 Hz).
MS m / z 443: [M−H] ⁻ .

Example 175
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-fluorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.75 (4H, m), 2.85-2.98 (1H, m), 3.15 (1H, dd, J = 14.0, 6.2 Hz), 3.27 (1H, dd, J = 14.0, 5.4 Hz), 3.36-3.48 (2H, m), 3.78 (3H, s), 3.86 (3H, s), 3.90-4.00 (2H, m), 4.93-5.01 (1H, m), 7.10-7.36 (5H, m), 7.38-7.52 (4H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-fluorophenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.53-1.75 (4H, m), 2.84-3.00 (1H, m), 3.20 (1H, dd, J = 14.3, 7.3 Hz), 3.28-3.50 (3H, m) , 3.84 (3H, s), 3.91-4.04 (2H, m), 4.92-5.02 (1H, m), 7.10-7.36 (5H, m), 7.41 (1H, td, J = 7.7, 1.8 Hz), 7.48 -7.57 (3H, m).
MS m / z: 427 [M−H] ⁻ .

Example 176
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,5-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.57-1.78 (4H, m), 2.87-2.99 (1H, m), 3.14 (1H, dd, J = 14.0, 6.5 Hz), 3.24 (1H, dd, J = 14.0, 5.7 Hz), 3.37-3.48 (2H, m), 3.74 (3H, s), 3.78 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 3.90-4.01 (2H, m ), 4.91-5.00 (1H, m), 6.81-6.94 (3H, m), 7.17 (2H, d, J = 8.4 Hz), 7.43-7.52 (3H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,5-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.53-1.77 (4H, m), 2.86-3.00 (1H, m), 3.19 (1H, dd, J = 14.2, 6.5 Hz), 3.31 (1H, dd, J = 14.2, 5.3 Hz), 3.38-3.49 (2H, m), 3.74 (3H, s), 3.80 (3H, s), 3.85 (3H, s), 3.92-4.01 (2H, m), 4.91-5.01 (1H , m), 6.82-6.94 (3H, m), 7.24 (2H, d, J = 8.6 Hz), 7.49 (2H, d, J = 6.8 Hz), 7.54 (1H, d, J = 6.8 Hz).
MS m / s: 469 [M−H] ⁻ .

Example 177
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-methylsulfanylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.58-1.78 (4H, m), 2.36 (3H, s), 2.87-3.00 (1H, m), 3.16 (1H, dd, J = 14.0, 6.5 Hz), 3.25 (1H, dd, J = 14.0, 5.4Hz), 3.43 (2H, td, J = 11.2, 3.2 Hz), 3.77 (3H, s), 3.88 (3H, s), 3.92-4.01 (2H, m), 4.92-5.01 (1H, m), 7.16-7.22 (4H, m), 7.24-7.40 (4H, m), 7.51 (1H, d, J = 7.8 Hz).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-methylsulfanylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.54-1.78 (4H, m), 2.35 (3H, s), 2.88-3.01 (1H, m), 3.20 (1H, dd, J = 14.3, 7.3 Hz), 3.33 (1H, dd, J = 14.3, 5.1Hz), 3.43 (2H, td, J = 11.3, 3.0 Hz), 3.87 (3H, s), 3.92-4.01 (2H, m), 4.93-5.02 (1H, m ), 7.16-7.21 (2H, m), 7.23-7.41 (6H, m), 7.58 (1H, d, J = 7.6Hz).
MS m / z: 455 [M−H] ⁻ .

Example 178
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine methyl ester (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.26 (6H, d, J = 7.0 Hz), 1.56-1.78 (4H, m), 2.82-2.91 (2H, m), 3.14 (1H, dd, J = 14.0, 6.7 Hz), 3.24 (1H, dd, J = 14.0, 5.7 Hz), 3.36-3.49 (2H, m), 3.77 (3H, s), 3.78 (3H, s), 3.86 (3H, s), 3.90- 4.01 (2H, m), 4.91-5.00 (1H, m), 6.91 (1H, d, J = 8.4 Hz), 7.13-7.20 (4H, m), 7.43-7.50 (3H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.25 (6H, d, J = 7.0 Hz), 1.53-1.76 (4H, m), 2.81-3.00 (2H, m), 3.19 (1H, dd, J = 14.0, 6.8 Hz), 3.32 (1H, dd, J = 14.0, 5.1 Hz), 3.37-3.49 (2H, m), 3.77 (3H, s), 3.84 (3H, s), 3.91-4.01 (2H, m), 4.91-5.01 (1H, m), 6.91 (1H, d, J = 8.4 Hz), 7.13-7.20 (2H, m), 7.24 (2H, d, J = 8.1 Hz), 7.50 (2H, d, J = 8.1 Hz), 7.55 (1H, d, J = 7.0 Hz).
MS m / z: 481 [M−H] ⁻ .

Example 179
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,4-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.52-1.75 (4H, m), 2.85-2.99 (1H, m), 3.13 (1H, dd, J = 13.8, 6.5 Hz), 3.23 (1H, dd, J = 13.8, 5.7 Hz), 3.36-3.49 (2H, m), 3.78 (3H, s), 3.79 (3H, s), 3.85 (3H, s), 3.86 (3H, s), 3.90-4.02 (2H, m ), 6.53-6.60 (2H, m), 7.11-7.24 (3H, m), 7.40-7.50 (3H, m).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,4-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.55-1.75 (4H, m), 2.85-3.00 (1H, m), 3.18 (1H, dd, J = 14.0, 7.0 Hz), 3.30 (1H, dd, J = 14.0, 5.4 Hz), 3.36-3.50 (2H, m), 3.78 (3H, s), 3.84 (3H, s), 3.85 (3H, s), 3.91-4.02 (2H, m), 4.90-5.00 (1H , m), 6.52-6.60 (2H, m), 7.17-7.25 (3H, m), 7.46 (2H, d, J = 8.4 Hz), 7.53 (1H, d, J = 7.3 Hz).
MS m / z: 469 [M−H] ⁻ .

Example 180
N- [2-Methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-cyanophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.54-1.75 (4H, m), 2.85-3.00 (1H, m), 3.14-3.31 (2H, m), 3.33-3.51 (2H, m), 3.77 (3H, s), 3.87-4.02 (5H, m), 4.42-4.54 (1H, m), 7.28 (2H, d, J = 7.8Hz), 7.41-7.69 (6H, m), 7.77 (1H, dd, J = 1.1, 7.6Hz).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2-cyanophenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.27-1.57 (4H, m), 2.40-2.48 (1H, m), 2.99 (1H, dd, J = 10.8, 14.0Hz), 3.16-3.29 (3H, m), 3.65-3.83 (5H, m), 4.53-4.65 (1H, m), 7.43 (2H, d, J = 8.1Hz), 7.52 (2H, d, J = 8.1Hz), 7.59 (2H, d , J = 8.1Hz), 7.74-7.85 (1H, m), 7.94 (1H, d, J = 7.8Hz), 8.73 (1H, d, J = 8.1Hz).
MS m / z: 434 [M−H] ⁻ .

Example 181
Synthesis of N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (syn) 2-methoxyimino- obtained in Reference Example 13 The title compound was obtained in the same manner as in Example 160 using ethyl 2- (tetrahydrothiopyran-4-yl) acetate (syn).

¹ H-NMR (CDCl ₃ ) δ; 1.60-1.77 (2H, m), 2.00-2.14 (2H, m), 2.56-2.81 (5H, m), 3.14 (1H, dd, J = 6.2, 14.0Hz) , 3.25 (1H, dd, J = 5.9, 14.0Hz), 3.74 (3H, s), 3.87 (3H, s), 4.88-4.98 (1H, m), 7.20-7.24 (4H, m), 7.52 (1H , d, J = 7.3Hz).

Example 161 and implementation using N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester (syn) and the appropriate phenylboric acid derivative The following compounds were obtained in the same manner as in Example 2. Examples 182-190

Example 182
N- [2-Methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-chlorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.17 (1H, dd, J = 6.5, 14.0Hz) , 3.26 (1H, dd, J = 5.7, 14.0Hz), 3.77 (3H, s), 3.87 (3H, s), 4.93-5.01 (1H, m), 7.20 (2H, dd, J = 2.2, 6.5Hz ), 7.27-7.34 (3H, m), 7.39 (2H, dd, J = 2.2, 6.5Hz), 7.43-7.50 (1H, m), 7.55 (1H, d, J = 7.0Hz).

N- [2-Methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-chlorophenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.36-1.59 (2H, m), 1.88-2.02 (2H, m), 2.27-2.41 (1H, m), 2.53-2.62 (4H, m), 2.96 ( 1H, dd, J = 10.3, 14.0Hz), 3.18 (1H, dd, J = 4.3, 14.0Hz), 3.68 (3H, s), 4.50 to 4.62 (1H, m), 7.32-7.44 (7H, m) , 7.53-7.59 (1H, m), 8.71 (1H, d, J = 8.1Hz), 12.9 (1H, bs).
MS m / z: 459 [M−H] ⁻ .

Example 183
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-methoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.09-3.29 (2H, m), 3.78 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 4.90-4.99 (1H, m), 6.96-7.06 (2H, m), 7.17 (2H, d, J = 8.4Hz), 7.27-7.36 (2H, m), 7.44-7.53 (3H, m).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-methoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.36-1.59 (2H, m), 1.88-2.00 (2H, m), 2.26-2.40 (1H, m), 2.53-2.62 (4H, m), 2.93 ( 1H, dd, J = 10.3, 13.8Hz), 3.14 (1H, dd, J = 4.1, 13.8Hz), 3.69 (3H, s), 3.75 (3H, s), 4.48-4.60 (1H, m), 6.97 -7.13 (2H, m), 7.22-7.44 (6H, m), 8.64 (1H, d, J = 8.1Hz), 12.8 (1H, bs).
MS m / z: 455 [M−H] ⁻ .

Example 184
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,4-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.07-3.28 (2H, m), 3.78 (3H, s), 3.79 (3H, s), 3.85 (6H, s), 4.88-4.98 (1H, m), 6.53-6.60 (2H, m), 7.14 (2H, d, J = 8.1Hz), 7.21 (1H , dd, J = 2.7, 6.5Hz), 7.43 (2H, d, J = 8.1Hz), 7.50 (1H, d, J = 7.3Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,4-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.36-1.59 (2H, m), 1.88-2.02 (2H, m), 2.26-2.39 (1H, m), 2.53-2.58 (4H, m), 2.91 ( 1H, dd, J = 10.5, 13.8Hz), 3.13 (1H, dd, J = 4.1, 13.8Hz), 3.68 (3H, s), 3.74 (3H, s), 3.79 (3H, s), 4.47-4.60 (1H, m), 6.56-6.68 (2H, m), 7.18 (1H, d, J = 8.4Hz), 7.25 (2H, d, J = 8.1Hz), 7.35 (2H, d, J = 8.1Hz) , 8.65 (1H, d, J = 8.1Hz), 12.8 (1H, bs).
MS m / z: 485 [M−H] ⁻ .

Example 185
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,5-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.09-3.29 (2H, m), 3.74 (3H, s), 3.78 (3H, s), 3.80 (3H, s), 3.86 (3H, s), 4.90 to 4.99 (1H, m), 6.81-6.95 (3H, m), 7.17 (2H, d, J = 8.4Hz), 7.43-7.56 (3H, m).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,5-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.36-1.59 (2H, m), 1.88-2.02 (2H, m), 2.26-2.39 (1H, m), 2.53-2.59 (4H, m), 2.92 ( 1H, dd, J = 10.3, 14.0Hz), 3.14 (1H, dd, J = 4.1, 14.0Hz), 3.69 (6H, s), 3.73 (3H, s), 4.49-4.60 (1H, m), 6.81 (1H, d, J = 3.0Hz), 6.88 (1H, dd, J = 3.0, 8.9Hz), 7.02 (1H, d, J = 8.9Hz), 7.28 (2H, d, J = 8.4Hz), 7.41 (2H, d, J = 8.4Hz), 8.67 (1H, d, J = 8.1Hz), 12.8 (1H, bs)
MS m / z: 485 [M−H] ⁻ .

Example 186
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-fluorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.15 (1H, dd, J = 14.2, 6.5Hz) , 3.26 (1H, dd, J = 14.2, 5.7Hz), 3.78 (3H, s), 3.86 (3H, s), 4.92-5.01 (1H, m), 7.10-7.54 (9H, m).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-fluorophenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.34-1.59 (2H, m), 1.86-1.99 (2H, m), 2.25-2.38 (1H, m), 2.53-2.57 (4H, m), 2.95 ( 1H, dd, J = 10.5, 14.0), 3.18 (1H, dd, J = 4.1, 14.0Hz), 3.68 (3H, s), 3.87 (3H, s), 4.51-4.63 (1H, m), 7.25- 7.56 (8H, m), 8.68 (1H, d, J = 8.4Hz), 12.83 (1H, bs).
MS m / z: 443 [M−H] ⁻ .

Example 187
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-methylsulfanylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.03-2.14 (2H, m), 2.36 (3H, s), 2.55-2.83 (5H, m), 3.16 (1H, dd, J = 6.5, 14.0Hz), 3.25 (1H, dd, J = 5.4, 14.0Hz), 3.77 (3H, s), 3.88 (3H, s), 4.91-5.00 (1H, m), 7.15-7.40 (8H , m), 7.55 (1H, d, J = 7.3Hz).

N- [2-Methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-methylsulfanylphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.36-1.59 (2H, m), 1.90-2.02 (2H, m), 2.23-2.42 (1H, m), 2.36 (3H, s), 2.53-2.59 ( 4H, m), 2.95 (1H, dd, J = 10.5, 14.0Hz), 3.16 (1H, dd, J = 4.1, 14.0Hz), 3.69 (3H, s), 4.49-4.60 (1H, m), 7.12 -7.41 (8H, m), 8.71 (1H, d, J = 8.1Hz), 12.82 (1H, bs).
MS m / z: 471 [M−H] ⁻ .

Example 188
N- [2-Methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-difluorophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.16 (1H, dd, J = 6.8, 14.0Hz) , 3.27 (1H, dd, J = 5.7, 14.0Hz), 3.78 (3H, s), 3.85 (3H, s), 4.92-5.01 (1H, m), 6.94-7.04 (2H, m), 7.19-7.36 (3H, m), 7.41 (2H, d, J = 8.1Hz), 7.53 (1H, d, J = 7.6Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-difluorophenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.38-1.59 (2H, m), 1.88-2.02 (2H, m), 2.27-2.39 (1H, m), 2.53-2.59 (4H, m), 2.96 ( 1H, dd, J = 10.5, 14.0Hz), 3.19 (1H, dd, J = 4.3, 14.0Hz), 3.67 (3H, s), 4.50-4.63 (1H, m), 7.15-7.28 (2H, m) , 7.32-7.53 (5H, m), 8.70 (1H, d, J = 8.1Hz), 12.84 (1H, bs).
MS m / z: 461 [M−H] ⁻ .

Example 189
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.26 (6H, d, J = 6.8 Hz), 1.56-1.75 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 2.90 (1H, quint., J = 6.8 Hz), 3.14 (1H, dd, J = 14.0, 6.5Hz), 3.24 (1H, dd, J = 14.0, 5.7 Hz), 3.78 (3H, s), 3.79 (3H , s), 3.86 (3H, s), 4.89-5.00 (1H, m), 6.91 (1H, d, J = 8.1Hz), 7.13-7.21 (4H, m), 7.44-7.54 (3H, m).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.20 (6H, d, J = 6.8Hz), 1.36-1.56 (2H, m), 1.86-1.98 (2H, m), 2.23-2.38 (1H, m) , 2.53-2.58 (4H, m), 2.82-2.98 (2H, m), 3.14 (1H, dd, J = 4.3, 13.8Hz), 3.69 (3H, s), 3.72 (3H, s), 4.50-4.61 (1H, m), 7.00 (1H, d, J = 8.4Hz), 7.09 (1H, d, J = 2.2Hz), 7.18 (1H, dd, J = 2.2, 8.4Hz), 7.27 (2H, d, J = 8.4Hz), 7.38 (2H, d, J = 8.4Hz), 8.67 (1H, d, J = 8.1Hz), 12.81 (1H, bs).
MS m / z: 497 [M−H] ⁻ .

Example 190
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-cyanophenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.56-1.77 (2H, m), 2.01-2.15 (2H, m), 2.55-2.83 (5H, m), 3.11-3.30 (2H, m), 3.77 (3H, s), 3.89 (3H, s), 4.92-5.02 (1H, m), 7.24-7.33 (2H, m), 7.42-7.71 (6H, m), 7.77 (1H, dd, J = 1.1, 7.8Hz) .

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2-cyanophenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.37-1.61 (2H, m), 1.90-2.05 (2H, m), 2.30-2.45 (1H, m), 2.53-2.73 (4H, m), 3.00 ( 1H, dd, J = 10.5, 14.3Hz), 3.21 (1H, dd, J = 4.1, 14.3Hz), 3.67 (3H, s), 4.51-4.65 (1H, m), 7.42 (1H, d, J = 8.4Hz), 7.49-7.64 (5H, m), 7.74-7.84 (1H, m), 7.91-8.00 (1H, m), 8.69 (1H, d, J = 8.1Hz).
MS m / z: 450 [M−H] ⁻ .

  In the same manner as in Example 161, N- (t-butoxycarbonyl) -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester and a suitable phenylboric acid derivative were reacted to obtain the following compound. Examples 191 to 197

Example 191
N- (t-butoxycarbonyl) -4- (2-chlorophenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.43 (9H, s), 3.09 (1H, dd, J = 13.8, 5.9 Hz), 3.18 (1H, dd, J = 5.7 Hz), 3.74 (3H, s), 4.59-4.73 (1H, m), 4.99-5.14 (1H, m), 7.14-7.56 (8H, m).

Example 192
N- (t-butoxycarbonyl) -4- (2,6-difluorophenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.42 (9H, s), 2.94-3.28 (2H, m), 3.72 (3H, s), 4.55-4.74 (1H, s), 4.97-5.11 (1H, m) , 6.96 (2H, d, J = 8.4 Hz), 7.17-7.34 (3H, m), 7.41 (2H, d, J = 8.4 Hz).

Example 193
N- (t-butoxycarbonyl) -4- (2-fluorophenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.41 (9H, s), 3.04 (1H, dd, J = 13.8, 6.5 Hz), 3.18 (1H, dd, J = 13.8, 5.7 Hz), 3.75 (3H, s ), 4.54-4.70 (1H, m), 4.97-5.11 (1H, m), 7.09-7.57 (8H, m).

Example 194
Synthesis of N- (t-butoxycarbonyl) -4- (2-methoxyphenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.41 (9H, s), 2.98-3.24 (2H, m), 3.75 (3H, s), 3.81 (3H, s), 4.53-4.69 (1H, m), 4.95 -5.09 (1H, m), 6.94-7.09 (2H, m), 7.16-7.39 (4H, m), 7.47 (2H, d, J = 6.5 Hz).

Example 195
N- (t-butoxycarbonyl) -4- (2,5-dimethoxyphenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.42 (9H, s), 2.99-3.24 (2H, m), 3.72 (6H, s), 3.79 (3H, s), 4.55-4.69 (1H, m), 4.98 -5.10 (1H, m), 6.78-6.95 (3H, m), 7.16 (2H, d, J = 8.4 Hz), 7.46 (2H, d, J = 8.4 Hz).

Example 196
N- (t-butoxycarbonyl) -4- (2-methylsulfanylphenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.42 (9H, s), 2.36 (3H, s), 2.99-3.24 (2H, m), 3.73 (3H, s), 4.54-4.69 (1H, m), 4.99 -5.14 (1H, m), 7.11-7.41 (8H, m).

Example 197
N- (t-butoxycarbonyl) -4- (5-isopropyl-2-methoxyphenyl) -L-phenylalanine methyl ester

¹ H-NMR (CDCl ₃ ) δ; 1.26 (6H, d, J = 7.02Hz), 1.43 (9H, s), 2.77-3.24 (3H, m), 3.74 (3H, s), 3.77 (3H, s ), 4.57-4.71 (1H, m), 4.99-5.11 (1H, m), 6.90 (1H, d, J = 8.9 Hz), 7.09-7.27 (4H, m), 7.47 (2H, d, J = 8.1 Hz).

Example 198
Synthesis of N- (3,3-dichloro-2-phenylacryloyl) -4- (2-chlorophenyl) -L-phenylalanine N- (tert-butoxycarbonyl) -4- (2-chlorophenyl) obtained in Example 191 To a methylene chloride solution (8 ml) of -L-phenylalanine methyl ester (270 mg, 0.69 mmol), trifluoroacetic acid (787 mg, 6.90 mmol) was slowly added dropwise and stirred for 12 hours. After completion of the reaction, trifluoroacetic acid and methylene chloride were distilled off under reduced pressure, basified with 10% K ₂ CO ₃ aqueous solution, extracted three times with ethyl acetate, and the organic layer was washed successively with water and saturated brine. did. After drying over magnesium sulfate, ethyl acetate was distilled off under reduced pressure to obtain a brown viscous product. To a methylene chloride solution (16 ml) of the obtained brown viscous product (310 mg), 3,3-dichloro-2-phenylacryloyl chloride (278 mg, 0.117 mmol) and N, N-diisopropylethylamine (414 mg, 3.21 mmol) were added at 0 ° C. And stirred at room temperature for 12 hours. After completion of the reaction, 5% aqueous citric acid solution was added, extracted three times with ethyl acetate, washed once with saturated brine, and dried over magnesium sulfate. Thereafter, the organic solvent was distilled off under reduced pressure, and the resulting brown viscous product was purified by NH column chromatography (ethyl acetate: hexane = 1: 3) to give a pale yellow powder N- (3,3-dichloro-2-phenyl). Acrylyl) -4- (2-chlorophenyl) -L-phenylalanine methyl ester (280 mg, 55%) was obtained.
Lithium hydroxide monohydrate (26 mg, 0.62 mmol) was added to a methanol-water solution (10 ml-2 ml) of the obtained compound (280 mg, 0.589 mmol), and the mixture was stirred for 12 hours. After completion of the reaction, 5% aqueous citric acid solution was added, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and ethyl acetate was distilled off under reduced pressure. The resulting mixture was purified by silica gel column chromatography (acetone: hexane = 2: 1) to give the title compound. Yellowish white powder (68mg, 25%)

¹ H-NMR (CDCl ₃ ) δ; 3.14 (1H, dd, J = 14.0, 6.5 Hz), 3.29 (1H, dd, J = 14.0, 5.4 Hz), 4.94-5.09 (1H, m), 6.17 (1H , d, J = 7.6 Hz), 7.64 (2H, d, J = 7.8 Hz), 7.22-7.59 (11H, m). MS m / z: 474 [MH] ^- .

  The following compounds were obtained from the amino acid derivatives obtained in Examples 192 to 197 in the same manner as in Example 198. Examples 199-204

Example 199
N- (3,3-Dichloro-2-phenylacryloyl) -4- (2-methoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 3.10 (1H, dd, J = 14.2, 6.5 Hz), 3.27 (1H, dd, J = 14.2, 5.4 Hz), 3.80 (3H, s), 4.89-5.09 (1H , m), 6.15 (1H, d, J = 7.6Hz), 6.94-7.53 (13H, m). MS m / z: 470 [M + H] ⁺ .

Example 200
N- (3,3-Dichloro-2-phenylacryloyl) -4- (2,6-difluorophenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 3.10-3.35 (2H, m), 4.95-5.05 (1H, m), 6.02 (1H, d, J = 7.3Hz), 6.91-7.10 (5H, m), 7.21 -7.45 (11H, m).
MS m / z: 474 [MH] ^- .

Example 201
N- (3,3-Dichloro-2-phenylacryloyl) -4- (2-methoxy-5-isopropylphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.01 (6H, d, J = 7.6Hz), 2.89 (1H, quint., J = 7.3Hz), 3.02-3.16 (1H, m), 3.20-3.32 (1H, m), 3.75 (3H, s), 4.86-5.00 (1H, m), 6.15-6.24 (1H, m), 6.90 (1H, d, J = 8.4 H), 7.00-7.45 (11H, m).
MS m / z; 510 [MH] ^- .

Example 202
N- (3,3-Dichloro-2-phenylacryloyl) -4- (2-methylsulfanylphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 2.34 (3H, s), 3.11 (1H, dd, J = 13.8, 6.5Hz), 3.28 (1H, dd, J = 13.8, 4.9 Hz), 4.88-5.02 (1H , m), 6.06-6.23 (1H, m), 6.96-7.44 (13H, m).

Example 203
N- (3,3-Dichloro-2-phenylacryloyl) -4- (2,5-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 3.07-3.33 (2H, m), 3.75 (3H, s), 3.81 (3H, s), 4.95-5.05 (1H, m), 6.06 (1H, d, J = 6.2Hz), 6.81-6.96 (3H, m), 7.03 (2H, d, J = 8.1 Hz), 730-7.50 (7H, m).
MS m / z; 498 [M-H] ^- .

Example 204
N- (3,3-Dichloro-2-phenylacryloyl) -4- (2-fluorophenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 3.14 (1H, dd, J = 14.0, 6.2 Hz), 3.27 (1H, dd, J = 14.0, 5.9 Hz), 4.94-5.05 (1H, m), 6.03 (1H , d, J = 7.8 Hz), 7.05 (2H, d, J = 8.1 Hz), 7.10-7.46 (11H, m).
MS m / z; 458 [M + H] ⁺ .

Reference Example 71
N- (tert-butoxycarbonyl) -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

4-[(tert-butyldiphenylsilyl) oxymethyl] -2,6-dimethoxyphenylboronic acid 26.3 g (53.8 mmol) and anhydrous potassium carbonate 22.3 g (161.3 mmol) in DME / H ₂ O (500 mL / 10 mL) To the mixture was added 23 g (53.8 mmol) of N- (tert-butoxycarbonyl) -O-trifluoromethanesulfonyl-L-tyrosine methyl ester under argon. 6.2 g (5.37 mmol) of Pd (PPh ₃ ) ₄ was added and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled and filtered through celite, the filtrate was evaporated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1), and N- (tert-butoxycarbonyl) -4- [4- (tert-butyldiphenylsilyl) oxymethyl-2,6 29.5 g (43.1 mmol) of -dimethoxyphenyl] -L-phenylalanine methyl ester were obtained. 29.5 g (43.1 mmol) of the product obtained above was dissolved in 300 mL of THF, 43.1 mL (43.1 mmol) of tetrabutylammonium fluoride (1.0 MTHF solution) was added under ice cooling, and the mixture was warmed to room temperature and stirred overnight. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 1/1), and N- (tert-butoxycarbonyl) -4- (4-hydroxymethyl-2,6 12.7 g (28.5 mmol) of -dimethoxyphenyl) -L-phenylalanine methyl ester were obtained.

Reference Example 72
Synthesis of 4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methyl ester

a) Stir triethylamine (4 mL) to 10 g (22.4 mmol) of CHCl ₃ (50 mL) of N- (tert-butoxycarbonyl) -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester Added while. Methanesulfonyl chloride (2 mL, 25.8 mmol) was slowly added with stirring at −10 ° C., and the mixture was stirred at −5 ° C. to −10 ° C. for 1.5 hours. Water was added to the reaction solution and extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. Ethyl acetate and hexane were added to the resulting crude product, and the deposited precipitate was filtered, dried under reduced pressure, and N- (tert-butoxycarbonyl) -4- (4-methanesulfonyloxymethyl-2,6-dimethoxyphenyl) 8.7 g (28.5 mmol) of -L-phenylalanine methyl ester was obtained.

b) 4 g (7.64 mmol) of the obtained product was dissolved in methanol (30 mL) and heated to reflux for 0.5 hour. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in ethyl acetate (20 mL), 1.45 g (7.64 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 80 ° C. for 8 hours. The reaction mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate) to obtain 1.36 g (3.78 mmol) of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 2.85 (1H, dd, J = 8.6, 13.5Hz), 3.16 (1H, dd, J = 4.9, 13.5Hz), 3.46 (2H, s), 3.71-3.85 (10H , m), 4.48 (2H, s), 6.63 (2H, s), 7.22 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz).

Reference Example 73
4- (4-Ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

The title compound was obtained in the same manner as in Reference Example 72 except that methanol was changed to ethanol.
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0Hz), 2.85 (1H, dd, J = 8.6, 13.5Hz), 3.16 (1H, dd, J = 6.2, 13.5Hz), 3.46 (2H, q, J = 7.0Hz), 3.64-3.78 (10H, m), 4.53 (2H, s), 6.64 (2H, s), 7.22 (2H, d, J = 8.4Hz), 7.28 (2H , d, J = 8.4Hz).

Reference Example 74
4- (2,6-Dimethoxy-4-propoxymethylphenyl) -L-phenylalanine methyl ester

  The title compound was obtained in the same manner as in Reference Example 72 except that methanol was changed to n-propyl alcohol.

¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.0 Hz), 1.62-1.75 (2H, m), 2.85 (1H, dd, J = 8.6, 13.5 Hz), 3.15 (1H, dd , J = 4.6, 13.5Hz), 3.50 (2H, t, J = 7.0Hz), 3.69-3.83 (10H, m), 4.53 (2H, s), 6.64 (2H, s), 7.20-7.30 (4H, m).

Reference Example 75
4- (2,6-Dimethoxy-4-methoxyethoxymethylphenyl) -L-phenylalanine methyl ester

  The title compound was obtained in the same manner as in Reference Example 72 except that methanol was changed to 2-methoxyethanol.

¹ H-NMR (CDCl ₃ ) δ; 2.85 (1H, dd, J = 8.6, 13.5Hz), 3.16 (1H, dd, J = 4.9, 13.5Hz), 3.42 (3H, s), 3.58-3.84 (14H , m), 4.60 (2H, s), 6.66 (2H, s), 7.20-7.30 (4H, m).

Reference Example 76
4- (Hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester N- (tert-butoxycarbonyl) -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) obtained according to Reference Example 72 -L-Phenylalanine methyl ester was dissolved in tetrahydrofuran (10 mL), 1.45 g (7.62 mmol) of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at 70 ° C. for 3 hours. The reaction mixture was made alkaline with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (530 mg).

¹ H-NMR (CDCl ₃ ) δ; 2.85 (1H, dd, J = 8.6, 13.5Hz), 3.16 (1H, dd, J = 4.9, 13.5Hz), 3.69-3.84 (10H, m), 4.73 (2H , s), 6.67 (2H, s), 7.22 (2H, d, J = 8.0Hz), 7.29 (2H, d, J = 8.0Hz).

Reference Example 77
4- (2,6-Dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester

N- (tert-butoxycarbonyl) -4- (4-methanesulfonyloxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester 2.0 g (3.82 mmol) obtained in Reference Example 72a) was added to DMF (10 mL ), Sodium thiomethoxide 0.40 g (5.71 mmol) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 3/2), and N- (tert-butoxycarbonyl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L -0.95 g (28.5 mmol) of phenylalanine methyl ester was obtained. The obtained product was deprotected in the same manner as in Reference Example 76 to obtain 0.73 g (1.94 mmol) of the title compound.
¹ H-NMR (CDCl ₃ ) δ; 2.10 (3H, s), 2.85 (1H, dd, J = 5.7, 13.5 Hz), 3.16 (1H, dd, J = 4.6, 13.5 Hz), 3.42 (3H, s ), 3.70-3.84 (12H, m), 6.61 (2H, s), 7.22 (2H, d, J = 8.4Hz), 7.29 (2H, d, J = 8.4Hz).

Reference Example 78
4- (4-Ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl

The title compound was obtained in the same manner as in Reference Example 77 except that sodium thioethoxide was used instead of sodium thiomethoxide.
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.3 Hz), 2.55 (2H, q, J = 7.3 Hz), 2.86 (1H, dd, J = 13.5, 8.4 Hz), 3.16 ( 1H, dd, J = 13.5, 4.6 Hz), 3.73 (6H, s), 3.75 (3H, s), 3.76 (2H, s), 3.77-3.84 (1H, m), 6.62 (2H, s), 7.22 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz).

Reference Example 79
4- (2,6-Dimethoxy-4-pyrrolidinylmethylphenyl) -L-phenylalanine methyl ester

  N- (tert-butoxycarbonyl) -4- (4-methanesulfonyloxy-2,6-dimethoxymethylphenyl) -L-phenylalanine methyl ester 2.0 g (3.82 mmol) obtained in Reference Example 72a) was added to DMF (10 mL ), Pyrrolidine 0.55 g (7.73 mmol) was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The obtained crude product was deprotected in the same manner as in Reference Example 76 to obtain 0.49 g (1.23 mmol) of the title compound.

¹ H-NMR (CDCl ₃ ) δ; 1.77-1.92 (4H, m), 2.52-2.67 (4H, m), 2.84 (1H, dd, J = 8.6, 13.5Hz), 3.16 (1H, dd, J = 4.6, 13.5Hz), 3.65 (2H, s), 3.68-3.88 (10H, m), 6.64 (2H, s), 7.22 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1 Hz).

Reference Example 80
4-ethyl-2,6-dimethoxyphenylboronic acid

Under stirring at −78 ° C., 81 ml (122 mmol) of a 1.50 M hexane solution of n-BuLi was added dropwise to a solution of 11.4 g (68.6 mmol) of 3,5-dimethoxyethylbenzene in anhydrous THF (75 ml), followed by stirring at the same temperature for 1.0 hour. The reaction was slowly warmed to room temperature and stirred at room temperature for 2.0 hours. After cooling to −78 ° C. again, 18.2 g (175 mmol) of trimethyl borate was added, and the reaction mixture was slowly warmed to room temperature and stirred overnight. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain 8.7 g of 4-ethyl-2,6-dimethoxyphenylboronic acid.
¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.6 Hz), 2.66 (2H, d, J = 7.6 Hz), 3.91 (6H, s), 6.48 (2H, s), 7.19 ( 2H, s).

Reference Example 81
4- (4-Ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

4.9 g (23.4 mmol) of 4-ethyl-2,6-dimethoxyphenylboronic acid obtained above, 4.0 g (9.36 mmol) of N- (tert-butoxycarbonyl) -4-trifluoromethanesulfonyloxy-L-phenylalanine methyl ester ), A mixed solution of 1.08 g (936 μmol) of tetrakistriphenylphosphine palladium and 6.5 g (46.8 mmol) of potassium carbonate in DMF (50 ml) and water (5.0 ml) was stirred at 80 ° C. for 8.0 hours under argon filling. The reaction mixture was filtered through celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (NH silica gel, hexane / ethyl acetate = 3/1), and N- (tert-butoxycarbonyl) -4- (4-ethyl-2,6-dimethoxyphenyl)- 4.7 g of L-phenylalanine methyl ester was obtained.
To a solution of the obtained N- (tert-butoxycarbonyl) -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester 4.7 g (10.6 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid 4.1. ml (53.1 mmol) was added and stirred overnight at room temperature. The solvent was concentrated, basified with saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and 4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester 3.0. g was obtained.
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 2.69 (2H, q, J = 7.6 Hz), 2.84 (1H, dd, J = 13.5, 8.4 Hz), 3.16 ( 1H, dd, J = 13.5, 5.4 Hz), 3.73 (6H, s), 3.75 (3H, s), 3.76-3.82 (1H, m), 6.50 (2H, s), 7.21 (2H, d, J = 8.4 Hz), 7.29 (1H, d, J = 8.4 Hz).

Reference Example 82
4-isopropyl-2,6-dimethoxyphenylboronic acid

According to Reference Example 80, 4-isopropyl-2,6-dimethoxyphenylboronic acid was obtained from 3,5-dimethoxyisopropylbenzene.
¹ H-NMR (CDCl ₃ ) δ: 1.27 (6H, d, J = 7.0 Hz), 2.91 (1H, quint., J = 7.0 Hz), 3.91 (6H, s), 6.50 (2H, s), 7.18 (2H, s).

Reference Example 83
4- (4-Isopropyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester

4- (4-Isopropyl-2,6-dimethoxy-phenyl) -L-phenylalanine methyl ester was obtained from 4-isopropyl-2,6-dimethoxyphenylboronic acid obtained in Reference Example 82 according to Reference Example 81.
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 7.0 Hz), 2.78-2.98 (2H, m), 3.15 (1H, dd, J = 13.5, 4.6 Hz), 3.73 (6H, s ), 3.75 (3H, s), 3.76-3.81 (1H, m), 6.52 (2H, s), 7.21 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz).

Reference Example 84
4- (2,6-Dimethoxy-4-methylphenyl) -L-phenylalanine methyl ester 2,6-dimethoxy-4-methylphenylboronic acid was obtained from 3.5-dimethoxytoluene according to Reference Example 80, and the resulting boronic acid was obtained. Was used according to Reference Example 81 to give 4- (2,6-dimethoxy-4-methylphenyl) -L-phenylalanine methyl ester.

¹ H-NMR (CDCl ₃ ) δ: 2.40 (3H, s), 2.85 (1H, dd, J = 13.8,8.6 Hz), 3.16 (1H, dd, J = 13.8, 4.6 Hz), 3.71 (6H, s ), 3.72-3.83 (4H, m, including1s at 3.75), 6.47 (2H, s), 7.17-7.25 (2H, m), 7.25-7.34 (2H, m)

Reference Example 85
Synthesis of 4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine methyl ester According to Reference Example 80, 2,6-dimethoxy-4-propylphenylboronic acid was obtained from 3,5-dimethoxypropylbenzene. 4- (2,6-Dimethoxy-4-propylphenyl) -L-phenylalanine methyl ester was obtained according to Reference Example 81 using the obtained boronic acid.

¹ H-NMR (CDCl ₃ ) δ: 1.01 (3H, t, J = 7.3Hz), 1.64-1.78 (2H, m), 2.56-2.68 (2H, m), 2.84 (1H, dd, J = 8.4, 13.5Hz), 3.15 (1H, dd, J = 4.6, 13.5Hz), 3.66-3.79 (10H, m), 6.48 (2H, s), 7.21 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz).

Reference Example 86
4- (2,4,6-trimethoxyphenyl) -L-phenylalanine methyl ester Obtained by obtaining 2,4,6-trimethoxyphenylboronic acid from 1,3,5-trimethoxybenzene according to Reference Example 80 The title compound was obtained according to Reference Example 81 using boronic acid.

¹ H-NMR (CDCl ₃ ) δ: 2.84 (1H, dd, J = 8.4, 13.5Hz), 3.15 (1H, dd, J = 4.9, 13.5Hz), 3.72 (6H, s), 3.75 (3H, s ), 3.76-3.82 (1H, m), 3.86 (3H, s), 6.22 (2H, s), 7.21 (2H, d, J = 8.4Hz), 7.28 (2H, d, J = 8.4Hz).

  In the same manner as in Example 92 using the compounds obtained in Reference Examples 72 to 74, 76 to 78, 81, 83 to 85 and ethyl oxo (tetrahydropyran-4-yl) acetate obtained in Reference Example 49, the following: A compound was obtained. Examples 205-214

Example 205
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CD ₃ OD) δ; 1.25 (3H, t, J = 7.3 Hz), 1.31-1.50 (2H, m), 1.98-2.15 (2H, m), 2.50 (2H, q, J = 7.3 Hz), 3.08 (1H, dd, J = 13.5,8.4 Hz), 3.21 (1H, dd, J = 13.5, 5.4 Hz), 3.28-3.44 (3H, m), 3.67 (6H, s), 3.74 (3H , s), 3.76 (2H, s), 3.83-3.93 (2H, m), 3.95 (3H, s), 4.71-4.79 (1H, m), 6.69 (2H, s), 7.1-7.20 (4H, m ).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CD ₃ OD) δ; 1.25 (3H, t, J = 7.3 Hz), 1.46-1.69 (4H, m), 2.50 (2H, q, J = 7.3 Hz), 2.56-2.66 (1H, m), 3.02 (1H, dd, J = 14.0,9.5 Hz), 3.24 (1H, dd, J = 14.0, 5.1 Hz), 3.34-3.43 (2H, m), 3.68 (6H, s), 3.75 (3H , s), 3.77 (2H, s), 3.78 (3H, s), 3.83-3.91 (2H, m), 4.78-4.84 (1H, m), 6.69 (2H, s), 7.14-7.25 (4H, m ).

Example 206
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.54-1.73 (4H, m), 2.87-3.00 (1H, m), 3.10-3.27 (2H, m), 3.36-3.49 (5H, m), 3.73 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.91-4.02 (2H, m), 4.48 (2H, s), 4.88-4.97 (1H, m), 6.63 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.51 (1H, d, J = 6.8Hz).

Example 207
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0Hz), 1.54-1.73 (4H, m), 2.87-3.00 (1H, m), 3.10-3.27 (2H, m), 3.37 -3.49 (2H, m), 3.61 (2H, q, J = 7.0Hz), 3.73 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.91-4.02 (2H, m), 4.52 (2H, s), 4.87-4.97 (1H, m), 6.64 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.27 (2H, d, J = 8.1Hz), 7.51 (1H , d, J = 7.0Hz).

Example 208
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propoxymethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.3 Hz), 1.54-1.76 (6H, m), 2.86-3.00 (1H, m), 3.10-3.27 (2H, m), 3.36 -3.49 (2H, m), 3.50 (2H, t, J = 6.8Hz), 3.72 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.91-4.01 (2H, m), 4.53 (2H, s), 4.88-4.97 (1H, m), 6.64 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.51 (1H , d, J = 7.0Hz).

Example 209
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.62-1.84 (4H, m), 2.10 (3H, s), 2.85-3.01 (1H, m), 3.08-3.28 (2H, m), 3.36-3.51 (2H, m), 3.71 (2H, s), 3.72 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.91-4.04 (2H, m), 4.87-4.98 (1H, m), 6.61 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.51 (1H, d, J = 7.0Hz).

Example 210
N- [2-methoxyimino-2- (tetrahydropyran-4-yl] acetyl] -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.00 (3H, t, J = 7.3Hz), 1.53-1.82 (6H, m), 2.55-2.67 (2H, m), 2.80-3.01 (1H, m), 3.09 -3.27 (2H, m), 3.36-3.50 (2H, m), 3.71 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.91-4.02 (2H, m), 4.88-4.98 (1H, m), 6.47 (2H, s), 7.15 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz), 7.51 (1H, d, J = 7.0Hz).

Example 211
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl) -4- (2,6-dimethoxy-4-methylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.52-1.76 (4H, m), 2.40 (3H, s), 2.86-3.00 (1H, m), 3.10-3.27 (2H, m), 3.36-3.50 (2H, m), 3.70 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 3.91-4.03 (2H, m), 4.88-4.98 (1H, m), 6.47 (2H, s), 7.15 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.51 (1H, d, J = 7.0Hz).

Example 212
N- [2-Methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-hydroxymethyl-2,6-dimethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.52-1.76 (4H, m), 1.83 (1H, brs), 2.86-3.00 (1H, m), 3.10-3.28 (2H, m), 3.36-3.50 (2H, m), 3.73 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 3.90-4.03 (2H, m), 4.73 (2H, brs), 4.88-4.98 (1H, m), 6.67 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.51 (1H, d, J = 7.0Hz).

Example 213
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 1.60-1.75 (4H, m), 2.69 (2H, q, J = 7.6 Hz), 2.85-3.00 (1H, m ), 3.09-3.27 (2H, m), 3.37-3.49 (2H, m), 3.71 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 3.92-4.02 (2H, m), 4.8-4.98 (1H, .m), 6.50 (2H, s), 7.15 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.51 (1H, d, J = 7.3 Hz).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 1.37-1.47 (2H, m), 2.23-2.40 (2H, m), 2.69 (2H, d, J = 7.6 Hz ), 3.13-3.19 (2H, m), 3.25-3.47 (3H, m), 3.71 (6H, s), 3.74 (3H, s), 3.94 (3H, s), 3.95-4.02 (2H, m), 4.88-4.98 (1H, m), 6.49 (2H, s), 7.15 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz).

Example 214
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-isopropyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ: 1.31 (6H, d, J = 6.8 Hz), 1.54-1.76 (4H, m), 2.84-300 (2H, m), 3.11-3.27 (2H, m), 3.33 -3.50 (2H, m), 3.72 (6H, s), 3.77 (3H, s), 3.84 (3H, s), 3.91-4.02 (2H, m), 4.88-4.98 (1H, m), 6.52 (2H , s), 7.15 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz), 7.51 (1H, d, J = 7.3 Hz).

  The following compounds were obtained in the same manner as in Example 92 using the compounds obtained in Reference Examples 73 and 81 and ethyl (2-furyl) oxoacetate. Examples 215-216

Example 215
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.3 Hz), 3.18 (1H, dd, J = 14.3, 6.8 Hz), 3.31 (1H, dd, J = 14.3, 5.4 Hz), 3.61 (2H, q, J = 7.3 Hz), 3.72 (6H, s), 3.80 (3H, s), 3.99 (3H, s), 4.53 (2H, s), 5.03-5.11 (1H, m), 6.41 (1H, dd, J = 3.5, 1.6 Hz), 6.64 (2H, s), 6.73 (1H, d, J = 3.5 Hz), 6.86 (1H, d, J = 7.6 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz), 7.47 (1H, d, J = 1.6 Hz).

N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ: 1.29 (3H, t, J = 7.0 Hz), 3.22-3.28 (2H, m), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 3.76 (3H, s), 4.10 (3H, s), 4.52 (2H, s), 4.99-5.06 (1H, m), 6.50 (1H, dd, J = 3.8, 1.9 hz), 6.64 (2H, s) , 7.15 (1H, d, J = 7.8 Hz), 7.20 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.32 (1H, dd, J = 3.8, 0.5 Hz) , 7.55 (1H, dd, J = 1.9, 0.5 Hz).

Example 216
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 2.66 (2H, q, J = 7.6 Hz), 3.18 (1H, dd, J = 14.0, 6.5 Hz), 3.30 ( 1H, dd, J = 14.0, 5.1 Hz), 3.71 (6H, s), 3.80 (3H, s), 3.99 (3H, s), 5.03-5.10 (1H, m), 6.41 (1H, dd, J = 3.5, 1.9 Hz), 6.49 (2H, s), 6.73 (1H, dd, J = 3.2, 0.8 Hz), 6.86 (1H, d, J = 7.6 Hz), 7.17 (2H, d, J = 8.1 Hz) , 7.29 (2H, d, J = 8.1 Hz), 7.47 (1H, dd, J = 1.9, 0.8 Hz).

N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 2.68 (2H, q, J = 7.6 Hz), 3.24 (2H, m), 3.71 (6H, s), 3.75 ( 3H, s), 4.01 (3H, s), 4.98-5.06 (1H, m), 6.49 (2H, s), 6.50 (1H, dd, J = 3.8, 1.9 Hz), 7.12-7.23 (3H, m) , 7.28 (2H, d, J = 8.1 Hz), 7.32 (1H, dd, J = 3.5, 0.8 Hz), 7.55 (1H, dd, J = 1.9, 0.8 Hz).

Example 217
N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester (syn and anti)
The title compound was obtained in the same manner as in Example 92 using the ethyl cyclobutyl (oxo) acetate obtained in Reference Example 51 and the compound obtained in Reference Example 77.
N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ: 1.70-2.00 (2H, m), 2.10 (3H, s), 2.11-2.22 (4H, m), 3.15-3.22 (2H, m), 3.40-3.50 (1H, m), 3.71 (2H, s), 3.72 (6H, s), 3.76 (3H, s), 3.87 (3H, s), 4.89-4.98 (1H, m), 6.61 (2H, s), 7.15 (2H , d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.57 (1H, d, J = 7.6 Hz).

N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ: 1.80-2.00 (2H, m), 2.10 (3H, s), 2.12-2.26 (2H, m), 2.36-2.53 (2H, m), 3.60-3.78 (1H, m), 3.71 (2H, s), 3.72 (6H, s), 3.73 (3H, s), 3.92 (3H, s), 4.86-4.96 (1H, m), 6.60 (2H, s), 7.06 (1H , d, J = 7.8Hz), 7.17 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz).

  The compounds obtained in Examples 205 to 217 were hydrolyzed in the same manner as in Example 2 to obtain the following compounds. Examples 218-235

Example 218
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.21 (3H, t, J = 7.3 Hz), 1.22-1.45 (2H, m), 1.70-1.93 (2H, m), 2.44-2.55 (2H, m) , 2.95-3.27 (5H, m), 3.63 (6H, s), 3.69-3.84 (4H, m), 3.89 (3H, s), 4.48-4.59 (1H, m), 6.69 (2H, s), 7.11 (2H, d, J = 8.1 Hz), 7.20 (2H, d, J = 8.1 Hz), 8.36 (1H, d, J = 8.1 Hz). MS m / z: 543 [M−H] ⁻ .

Example 219
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.21 (3H, t, J = 7.3 Hz), 1.34-1.62 (4H, m), 2.45-2.57 (3H, m), 2.92 (1H, dd, J = 14.0, 10.5 Hz), 3.13 (1H, dd, J = 14.0, 3.8 Hz), 3.19-3.30 (3H, m), 3.64 (6H, s), 3.69 (3H, s), 3.72-3.84 (4H, m ), 4.45-4.58 (1H, m), 6.69 (2H, s), 7.11 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 8.71 (1H, d, J = 7.8 Hz).
MS m / z: 543 [M−H] ⁻ .

Example 220
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.54-1.78 (4H, m), 2.87-3.02 (1H, m), 3.19 (1H, dd, J = 7.0, 14.3 Hz), 3.30 (1H, dd, J = 6.8, 14.3Hz), 3.36-3.56 (5H, m), 3.72 (6H, s), 3.83 (3H, s), 3.90-4.02 (2H, m), 4.48 (2H, s), 4.84-4.98 (1H , m), 6.63 (2H, s), 7.22 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz), 7.58 (1H, d, J = 7.0Hz).
MS m / z: 513 [M−H] ⁻ .

Example 221
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0Hz), 1.54-1.80 (4H, m), 2.87-3.02 (1H, m), 3.14-3.34 (2H, m), 3.36 -3.49 (2H, m), 3.61 (2H, q, J = 7.0Hz), 3.72 (6H, s), 3.83 (3H, s), 3.92-4.02 (2H, m), 4.48 (2H, s), 4.87-5.00 (1H, m), 6.64 (2H, s), 7.22 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.58 (1H, d, J = 7.0Hz ).
MS m / z: 527 [M−H] ⁻ .

Example 222
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propoxymethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.3 Hz), 1.56-1.80 (6H, m), 2.86-3.02 (1H, m), 3.18 (1H, dd, J = 6.8, 14.0Hz), 3.29 (1H, dd, J = 5.1, 14.0Hz), 3.37-3.58 (4H, m), 3.72 (6H, s), 3.83 (3H, s), 3.92-4.04 (2H, m), 4.53 (2H, s), 4.87-5.00 (1H, m), 6.64 (2H, s), 7.21 (2H, d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.59 (1H , d, J = 7.0Hz).
MS m / z: 541 [M−H] ⁻ .

Example 223
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.54-1.80 (4H, m), 2.10 (3H, s), 2.87-3.00 (1H, m), 3.19 (1H, dd, J = 6.8, 14.0Hz), 3.30 (1H, dd, J = 5.1, 14.0Hz), 3.48-3.52 (2H, m), 3.71 (2H, s), 3.72 (6H, s), 3.84 (3H, s), 3.93-4.04 (2H, m ), 4.88-5.00 (1H, m), 6.61 (2H, s), 7.23 (2H, d, J = 8.1Hz), 7.30 (2H, d, J = 8.1Hz), 7.59 (1H, d, J = 7.0Hz).
MS m / z: 529 [M−H] ⁻ .

Example 224
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.00 (3H, t, J = 7.3Hz), 1.53-1.80 (6H, m), 2.56-2.67 (2H, m), 2.85-3.02 (1H, m), 3.19 (1H, dd, J = 6.8, 14.0Hz), 3.29 (1H, dd, J = 5.1, 14.0Hz), 3.36-3.51 (2H, m), 3.71 (6H, s), 3.83 (3H, s), 3.92-4.04 (2H, m), 4.86-5.00 (1H, m), 6.47 (2H, s), 7.21 (2H, d, J = 8.1Hz), 7.30 (2H, d, J = 8.1Hz), 7.59 (1H, d, J = 7.0Hz).
MS m / z: 511 [M−H] ⁻ .

Example 225
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.53-1.79 (4H, m), 2.40 (3H, s), 2.87-3.73 (1H, m), 3.19 (1H, dd, J = 7.0, 14.0Hz), 3.29 (1H, dd, J = 5.1, 14.0Hz), 3.37-3.56 (2H, m), 3.70 (6H, s), 3.83 (3H, s), 3.92-4.04 (2H, m), 4.85-5.00 (1H , m), 6.45 (2H, s), 7.21 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz), 7.68 (1H, d, J = 7.0Hz).
MS m / z: 483 [M−H] ⁻ .

Example 226
N-[(2-methoxyimino-2-tetrahydropyran-4-yl) acetyl] -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.31-1.62 (4H, m), 2.45-2.57 (1H, m), 2.92 (1H, dd, J = 10.5, 14.0Hz), 3.07-3.31 (3H, m), 3.64 (6H, s), 3.69 (3H, s), 3.71-3.83 (2H, m), 4.45-4.57 (3H, m), 5.23 (1H, t, J = 5.7Hz), 6.69 (2H , s), 7.10 (2H, d, J = 8.1Hz), 7.23 (2H, d, J = 8.1Hz), 8.71 (1H, d, J = 8.1Hz), 12.8 (1H, bs).
MS m / z: 499 [M−H] ⁻ .

Example 227
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.30 (3H, t, J = 7.6 Hz,) 1.35-1.60 (4H, m), 2.45-2.52 (1H, m), 2.62 (2H, q, J = 7.6 Hz), 2.92 (1H, dd, J = 14.0, 10.3 Hz), 3.12 (1H, dd, J = 14.0, 4.1 Hz), 3.25-3.45 (2H, m), 3.63 (6H, s), 3.69 ( 3H, s), 3.75-3.80 (2H, m), 4.46-4.54 (1H, m), 6.57 (2H, s), 7.09 (2H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 8.67 (1H, d, J = 7.8 Hz).
MS m / z: 499 [M + H] ⁺ , 521 [M + Na] ⁺ .

Example 228
N- {2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl} -4- (2,6-dimethoxyphenyl-4-ethyl) -L-phenylalanine (anti)

¹ H-NMR (DMSO-d ₆ ) δ; 1.23 (3H, t, J = 7.6 Hz), 1.35-1.45 (2H, m), 1.65-1.98 (2H, m), 2.62 (2H, q, J = 7.6 Hz), 3.00 (1H, dd, J = 13.8,9.5 Hz), 3.13 (1H, dd, J = 13.8, 4.1 Hz), 3.10-3.40 (3H, m), 3.63 (6H, s), 3.70- 3.85 (2H, m), 3.89 (3H, s), 4.48-4.56 (1H, m), 6.57 (2H, s), 7.09 (2H, d, J = 8.4 Hz), 7.18 (2H, d, J = 8.4 Hz), 8.33 (1H, d, J = 8.1 Hz).
MS m / z: 499 [M + H] ⁺ , 521 [M + Na] ⁺ .

Example 229
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4- (4-isopropyl-2,6-dimethoxy) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.31 (6H, d, J = 7.0 Hz), 1.54-1.75 (4H, m), 2.83-3.00 (2H, m), 3.17 (1H, dd, J = 14.3, 7.6 Hz), 3.30 (1H, dd, J = 14.3,5.4 Hz), 3.39-3.49 (2H, m), 3.72 (6H, s), 3.83 (3H, s), 3.92-4.04 (2H, m), 4.89-4.96 (1H, m), 6.52 (2H, s), 7.21 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.59 (1H, d, J = 6.5 Hz MS m / z: 511 [MH] ⁻ .

Example 230
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.22 (1H, dd, J = 14.3, 7.0 Hz), 3.38 (1H, dd, J = 14.3, 5.4 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.71 (6H, s), 3.97 (3H, s), 4.53 (2H, s), 5.03-5.18 (1H, m), 6.41 (1H, dd, J = 3.2, 1.6 Hz), 6.64 (2H, s), 6.75 (1H, dd, J = 3.5, 0.8 Hz), 6.92 (1H, d, J = 7.6 Hz), 7.23 (2H, d, J = 8.4 Hz) , 7.28 (2H, d, J = 8.4 Hz), 7.47 (1H, dd, J = 1.6, 0.8 Hz).
MS m / z: 509 [MH] ⁻ .

Example 231
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (anti)

_{^{1 H-NMR (CDCl 3)}} δ; 1.29 (3H, t, J = 7.3 Hz), 3.28 (1H, dd, J = 14.3, 5.9 Hz), 3.35 (1H, dd, J = 14.3, 5.7 Hz), 3.61 (2H, q, J = 7.3 Hz), 3.71 (6H, s), 4.09 (3H, s), 4.53 (2H, s), 5.00-5.07 (1H, m), 6.50 (1H, dd, J = 3.5, 1.6 Hz), 6.63 (2H, s), 7.16 (1H, d, J = 7.8 Hz), 7.23-7.26 (4H, m), 7.32 (1H, dd, J = 3.5, 1.4 Hz), 7.55 ( (1H, dd, J = 1.6, 1.4 Hz).
MS m / z: 509 [MH] ⁻ .

Example 232
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.6 Hz), 2.69 (2H, d, J = 7.6 Hz), 3.22 (1H, dd, J = 14.0, 6.8 Hz), 3.40 ( 1H, dd, J = 14.0, 5.4 Hz), 3.70 (6H, s), 3.98 (3H, s), 5.06-5.12 (1H, m), 6.42 (1H, dd, J = 3.5, 1.9 Hz), 6.49 (2H, s), 6.76 (1H, d, J = 3.5 Hz), 6.92 (1H, d, J = 7.8 Hz), 7.23 (2H, d, J = 8.1 Hz), 7.30 (2H, d, J = 8.1 Hz), 7.47 (1H, d, J = 1.9 Hz).
MS m / z: 479 [MH] ⁻ .

Example 233
N- [2- (2-Furyl) -2-methoxyiminoacetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.6 Hz), 2.68 (2H, d, J = 7.6 Hz), 3.22-3.39 (2H, m), 3.70 (6H, s), 4.10 (3H, s), 5.98-5.05 (1H, m), 6.49 (2H, s), 6.50 (1H, dd, J = 3.8, 1.9 Hz), 7.16 (1H, d, J = 7.8 Hz), 7.24 -7.27 (5H, m), 7.55 (1H, dd, J = 1.9, 0.5 Hz).
MS m / z: 479 [MH] ⁻ .

Example 234
N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.75-2.00 (2H, m), 2.09 (3H, s), 2.05-2.22 (4H, m), 3.08-3.40 (2H, m), 3.38-3.50 (1H, m), 3.71 (6H, s), 3.85 (3H, s), 4.95-5.00 (1H, m), 6.60 (2H, s), 7.22 (2H, d, J = 8.4 Hz), 7.31 (2H, d , J = 8.4 Hz), 7.66 (1H, d, J = 7.0 Hz).

Example 235
N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine (anti)

_{^{1 H-NMR (CDCl 3)}} δ; 1.80-2.00 (2H, m), 2.09 (3H, s), 2.10-2.23 (2H, m), 2.38-2.50 (2H, m), 3.16 (1H, dd, J = 14.3, 6.8 Hz), 3.27 (1H, dd, J = 14.3, 5.4 Hz), 3.58-3.70 (1H, m), 3.71 (6H, s), 3.91 (3H, s), 4.88-4.95 (1H , m), 6.60 (2H, s), 7.09 (1H, d, J = 7.8 Hz), 7.23 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.4 Hz).

  The following compounds were obtained in the same manner as in Example 23 and Example 2 using the amino acid derivatives obtained in Examples 72 to 79, 81, 83, 85 and 86 and the appropriate methoxyiminoacetic acid ester. Examples 236-261

Example 236
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 1.21 (3H, t, J = 7.3 Hz), 1.43-1.62 (2H, m), 1.92-2.04 (2H, m), 2.31-2.43 (1H, m) , 2.45-2.62 (6H, m), 2.96 (1H, dd, J = 14.4, 10.7 Hz), 3.11 (1H, dd, J = 14.4, 4.2 Hz), 3.64 (6H, s), 3.66 (3H, s ), 3.70 (3H, s), 3.76 (2H, s), 4.51-4.63 (1H, m), 6.69 (2H, s), 7.12 (2H, d, J = 8.1 Hz), 7.22 (2H, d, J = 8.1 Hz), 8.81 (1H, d, J = 7.6 Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.21 (3H, t, J = 7.3 Hz), 1.40-1.62 (2H, m), 1.93-2.05 (2H, m), 2.31-2.43 (1H, m) , 2.45-2.60 (6H, m), 2.93 (1H, dd, J = 14.2, 10.4 Hz), 3.12 (1H, dd, J = 14.2, 3.5 Hz), 3.64 (6H, s), 3.69 (3H, s ), 3.76 (2H, s), 4.47-4.58 (1H, m), 6.69 (2H, s), 7.12 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz), 8.69 (1H, d, J = 8.1 Hz). MS m / z: 559 [M−1] ⁻ .

Example 237
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.63-1.77 (2H, m), 2.02-2.17 (2H, m), 2.54-2.84 (5H, m), 3.09-3.26 (2H, m), 3.73 (6H, s), 3.78 (3H, s), 3.85 (3H, s), 4.74 (2H, s), 4.86-4.99 (1H, m), 6.67 (2H, s), 7.16 (2H, d, J = 8.1Hz ), 7.28 (2H, d, J = 8.1Hz), 7.54 (1H, d, J = 7.3Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.52-1.76 (2H, m), 1.91-2.09 (2H, m), 2.25-2.43 (1H, m), 2.54-2.69 (4H, m), 2.93 ( 1H, dd, J = 10.3, 13.8Hz), 3.12 (1H, dd, J = 4.1, 13.8Hz), 3.64 (6H, s), 3.69 (3H, s), 4.44-4.61 (3H, m), 5.23 (1H, t, J = 5.7Hz), 6.69 (2H, s), 7.11 (2H, d, J = 8.1Hz), 7.22 (2H, d, J = 8.1Hz), 8.69 (1H, d, J = 8.1Hz), 12.8 (1H, brs).
MS m / z: 515 [M−H] ⁻ .

Example 238
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.63-1.77 (2H, m), 2.02-2.17 (2H, m), 2.54-2.84 (5H, m), 3.11-3.26 (2H, m), 3.46 (3H, s), 3.69 (6H, s), 3.73 (3H, s), 3.84 (3H, s), 4.48 (2H, s), 4.84-4.97 (1H, m), 6.63 (2H, s), 7.15 (2H , d, J = 8.1Hz), 7.28 (2H, d, J = 8.1Hz), 7.54 (1H, d, J = 7.0Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.43-1.68 (2H, m), 1.94-2.05 (2H, m), 2.31-2.46 (1H, m), 2.54-2.69 (4H, m), 2.93 ( 1H, dd, J = 10.0, 14.0Hz), 3.13 (1H, dd, J = 4.1, 14.0Hz), 3.65 (6H, s), 3.69 (3H, s), 4.43 (2H, s), 4.46-4.57 (1H, m), 6.68 (2H, s), 7.12 (2H, d, J = 8.1Hz), 7.23 (2H, d, J = 8.1Hz), 8.69 (1H, d, J = 7.8Hz).
MS m / z: 529 [M−H] ⁻ .

Example 239
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propoxymethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.3Hz), 1.60-1.79 (4H, m), 2.02-2.16 (2H, m), 2.54-2.83 (5H, m), 3.09 -3.27 (2H, m), 3.50 (2H, t, J = 6.8Hz), 3.72 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 4.53 (2H, s), 4.84- 4.97 (1H, m), 6.64 (2H, s), 7.15 (2H, d, J = 8.1Hz), 7.27 (2H, d, J = 8.1Hz), 7.54 (1H, d, J = 6.8Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propoxymethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 0.92 (3H, t, J = 7.3Hz), 1.43-1.68 (4H, m), 1.94-2.05 (2H, m), 2.31-2.46 (1H, m) , 2.54-2.69 (4H, m), 2.94 (1H, dd, J = 10.5, 14.0Hz), 3.13 (1H, dd, J = 3.5, 14.0Hz), 3.43 (2H, t, J = 6.5Hz), 3.64 (6H, s), 3.69 (3H, s), 4.42-4.57 (3H, m), 6.68 (2H, s), 7.12 (2H, d, J = 7.8Hz), 7.23 (2H, d, J = 7.8Hz), 8.69 (1H, d, J = 8.1Hz).
MS m / z: 557 [M−H] ⁻ .

Example 240
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- [2,6-dimethoxy-4- (2-methoxyethoxymethyl) phenyl] -L-phenylalanine methyl ester (syn )
¹ H-NMR (CDCl ₃ ) δ; 1.59-1.79 (2H, m), 2.04-2.16 (2H, m), 2.54-2.85 (5H, m), 3.09-3.27 (2H, m), 3.42 (3H, s), 3.59-3.76 (10H, m), 3.78 (3H, s), 3.84 (3H, s), 4.60 (2H, s), 4.85-4.97 (1H, m), 6.66 (2H, s), 7.15 (2H, d, J = 8.1Hz), 7.27 (2H, d, J = 8.1Hz), 7.54 (1H, d, J = 6.8Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- [2,6-dimethoxy-4- (2-methoxyethoxymethyl) phenyl] -L-phenylalanine (syn)

270Hz ¹ H-NMR (CDCl ₃ ) δ; 1.58-1.76 (2H, m), 2.02-2.15 (2H, m), 2.52-2.85 (5H, m), 3.13-3.35 (2H, m), 3.42 (3H , s), 3.59-3.78 (10H, m), 3.83 (3H, s), 4.60 (2H, s), 4.85-4.98 (1H, m), 6.65 (2H, s), 7.21 (2H, d, J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz), 7.62 (1H, d, J = 6.8Hz).
MS m / z: 573 [M−H] ⁻ .

Example 241
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.6 Hz), 1.60-1.78 (2H, m), 2.03-2.15 (2H, m), 2.59-2.81 (7H, m), 3.08 -3.28 (2H, m), 3.71 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 4.88-4.95 (1H, m), 6.50 (2H, s), 7.14 (2H, d , J = 8.4Hz), 7.28 (2H, d, J = 8.4 Hz), 7.54 (1H, d, J = 7.6 Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-ethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.30 (3H, t, J = 7.6 Hz), 1.59-1.78 (2H, m), 2.03-2.15 (2H, m), 2.58-2.82 (7H, m), 3.18 (1H, dd, J = 14.3, 7.2 Hz), 3.29 (1H, dd, J = 14.3, 5.3 Hz), 3.71 (6H, s), 3.82 (3H, s), 486-4.93 (1H, m), 6.49 (2H, s), 7.21 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.64 (1H, d, J = 6.8 Hz).
MS m / z: 514 [M + H] ⁺ , 537 [M + Na] ⁺ .

Example 242
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-isopropyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.31 (6H, d, J = 7.0 Hz), 1.61-1.74 (2H, m), 2.05-2.18 (2H, m), 2.58-2.81 (5H, m), 2.86 -3.01 (1H, m), 3.09-3.26 (2H, m), 3.72 (6H, s), 3.77 (3H, s), 3.84 (3H, s), 4.87-4.94 (1H, m), 6.52 (2H , s), 7.15 (2H, d, J = 8.1 Hz), 7.29 (2H, d, J = 8.1 Hz), 7.54 (1H, d, J = 7.3 Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-isopropyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.31 (6H, d, J = 6.8 Hz), 1.61-1.74 (2H, m), 2.03-2.18 (2H, m), 2.55-2.82 (5H, m), 2.86 -3.01 (1H, m), 3.18 (1H, dd, J = 14.3, 7.4 Hz), 3.30 (1H, dd, J = 14.3, 5.3 Hz), 3.71 (6H, s), 3.82 (3H, s), 4.89-4.60 (1H, m), 6.51 (2H, s), 7.21 (2H, d, J = 8.1 Hz), 7.31 (2H, d, J = 8.1 Hz), 7.62 (1H, J = 6.8 Hz). MS m / z: 527 [MH] ⁻ .

Example 243
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.55-1.75 (2H, m), 2.00-2.15 (5H, m), 2.55-2.80 (5H, m), 3.08-3.26 (2H, m), 3.71 (2H, s), 3.72 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 4.88-4.96 (1H, m), 6.61 (2H, s), 7.15 (2H, d, J = 8.1 Hz ), 7.28 (2H, d, J = 8.1 Hz), 7.54 (1H, d, J = 7.0 Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.48-1.60 (2H, m), 1.98-2.10 (5H, m), 2.38-2.50 (1H, m), 2.50-2.65 (4H, m), 2.93 ( 1H, dd, J = 14.3, 10.3 Hz), 3.12 (1H, dd, J = 14.3, 4.3 Hz), 3.60 (6H, s), 3.64 (3H, s), 3.72 (2H, s), 4.48-4.55 (1H, m), 6.69 (2H, s), 7.12 (2H, d, J = 7.8 Hz), 7.23 (2H, d, J = 7.8 Hz), 8.32 (1H, d, J = 8.1 Hz), 12.7 (1H, brs). MS m / z: 545 [MH] ⁻ .

Example 244
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
_{^{1 H-NMR (CDCl 3)}} δ; 1.29 (3H, t, J = 7.0 Hz), 1.60-1.78 (2H, m), 2.03-2.20 (2H, m), 2.52-2.80 (5H, m), 3.09 -3.27 (2H, m), 3.61 (2H, q, J = 7.0 Hz), 3.73 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 4.52 (2H, s), 4.88- 4.95 (1H, m), 6.64 (2H, s), 7.15 (2H, d, J = 8.1 Hz), 7.27 (2H, d, J = 8.1 Hz), 7.54 (1H, d, J = 6.6 Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.18 (3H, t, J = 7.0 Hz), 1.48-1.62 (2H, m), 1.96-2.03 (2H, m), 2.35-2.47 (1H, m) , 2.49-2.62 (4H, m), 2.93 (1H, dd, J = 14.3, 10.0 Hz), 3.12 (1H, dd, J = 14.3, 3.8 Hz), 3.52 (2H, q, J = 7.0 Hz), 3.64 (6H, s), 3.68 (3H, s), 4.47 (2H, s), 4.48-4.55 (1H, m), 6.68 (2H, s), 7.11 (2H, d, J = 8.1 Hz), 7.23 (2H, d, J = 8.1 Hz), 8.73 (1H, d, J = 7.8 Hz). MS m / z: 543 [MH] ⁻ .

Example 245
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,4,6-trimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.59-1.79 (2H, m), 2.04-2.16 (2H, m), 2.54-2.85 (5H, m), 3.09-3.27 (2H, m), 3.71 (6H, s), 3.78 (3H, s), 3.84 (3H, s), 3.86 (3H, s), 4.85-4.97 (1H, m), 6.22 (2H, s), 7.14 (2H, d, J = 8.4Hz ), 7.27 (2H, d, J = 8.4Hz), 7.54 (1H, d, J = 7.3Hz).

N- [2-Methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,4,6-trimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.43-1.68 (2H, m), 1.94-2.05 (2H, m), 2.31-2.46 (1H, m), 2.54-2.69 (4H, m), 2.92 ( 1H, dd, J = 10.5, 14.3Hz), 3.11 (1H, dd, J = 3.8, 14.3Hz), 3.64 (6H, s), 3.69 (3H, s), 3.81 (3H, s), 4.43-4.57 (1H, m), 6.30 (2H, s), 7.09 (2H, d, J = 8.1Hz), 7.20 (2H, d, J = 8.1Hz), 8.67 (1H, d, J = 7.8Hz), 12.8 (1H, brs).
MS m / z: 515 [M−H] ⁻ .

Example 246
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.01 (3H, t, J = 7.3Hz), 1.63-1.77 (4H, m), 2.03-2.15 (2H, m), 2.55-2.82 (7H, m), 3.09 -3.26 (2H, m), 3.71 (6H, s), 3.77 (3H, s), 3.84 (3H, s), 4.87-4.96 (1H, m), 6.47 (2H, s), 7.14 (2H, d , J = 8.1Hz), 7.29 (2H, d, J = 8.1Hz), 7.54 (1H, d, J = 7.8Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.00 (3H, t, J = 7.3Hz), 1.59-1.76 (4H, m), 2.02-2.15 (2H, m), 2.51-2.83 (7H, m), 3.18 (1H, dd, J = 7.0, 14.3Hz), 3.29 (1H, dd, J = 5.4, 14.3Hz), 3.70 (6H, s), 3.83 (3H, s), 4.87-5.00 (1H, m), 6.47 (2H, s), 7.21 (2H, d, J = 8.1Hz), 7.31 (2H, d, J = 8.1Hz), 7.62 (1H, d, J = 6.8Hz).
MS m / z: 527 [M−H] ⁻ .

Example 247
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- [2,6-dimethoxy-4- (pyrrolidin-1-yl) methylphenyl] -L-phenylalanine methyl ester ( syn)
¹ H-NMR (CDCl ₃ ) δ; 1.64-1.89 (6H, m), 2.03-2.15 (2H, m), 2.52-2.83 (9H, m), 3.09-3.26 (2H, m), 3.64 (2H, s), 3.72 (6H, s), 3.77 (3H, s), 3.84 (3H, s), 4.87-4.99 (1H, m), 6.64 (2H, s), 7.15 (2H, d, J = 8.1Hz ), 7.28 (2H, d, J = 8.1Hz), 7.55 (1H, d, J = 7.3Hz).

N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4- [2,6-dimethoxy-4- (pyrrolidin-1-yl) methylphenyl] -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.42-1.61 (2H, m), 1.75-2.05 (6H, m), 2.33-2.45 (1H, m), 2.50-2.63 (4H, m), 2.78- 3.20 (6H, m), 3.66 (6H, s), 3.69 (3H, s), 4.01 (2H, s), 4.45-4.57 (4H, m), 6.86 (2H, s), 7.11 (2H, d, J = 8.1Hz), 7.23 (2H, d, J = 8.1Hz), 8.62 (1H, d, J = 7.6Hz).
MS m / z: 568 [M−H] ⁻ .

Example 248
N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (DMSO-d ₆ ) δ; 0.96 (3H, d, J = 7.0 Hz), 1.05 (3H, d, J = 7.0 Hz), 1.21 (3H, t, J = 7.4 Hz), 2.44- 2.58 (2H, m), 2.98-3.22 (3H, m), 3.63 (6H, s), 3.65 (3H, s), 3.76 (2H, s), 3.88 (3H, s), 4.50-4.65 (1H, m), 6.69 (2H, s), 7.10 (2H, d, J = 8.4 Hz), 7.19 (2H, d, J = 8.4 Hz), 8.47 (1H, d, J = 7.8 Hz).

N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.20 (3H, d, J = 7.0Hz), 1.21 (3H, d, J = 7.0Hz), 1.29 (3H, t, J = 7.3 Hz), 2.54 (2H, q, J = 7.3 Hz), 3.14-3.41 (3H, m), 3.72 (6H, s), 3.76 (2H, s), 3.92 (3H, s), 4.80-4.91 (1H, m), 6.61 (2H , s), 7.12 (1H, d, J = 7.8 Hz), 7.20-7.34 (4H, m). MS m / z: 501 [M−H] ⁻ .

Example 249
N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (DMSO-d ₆ ) δ; 0.97 (3H, d, J = 7.0 Hz), 0.99 (3H, d, J = 7.0 Hz), 1.21 (3H, t, J = 7.3 Hz), 2.43- 2.60 (3H, m), 2.95 (1H, dd, J = 14.2,10.4 Hz), 3.11 (1H, dd, J = 14.2, 4.6 Hz), 3.63 (6H, s), 3.65 (3H, s), 3.70 (3H, s), 3.76 (2H, s), 4.49-4.64 (1H, m), 6.69 (2H, s), 7.11 (2H, d, J = 8.4Hz), 7.22 (2H, d, J = 8.4 Hz), 8.78 (1H, d, J = 7.8 Hz).

N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.097 (3H, d, J = 7.0Hz), 1.101 (3H, d, J = 7.0Hz), 1.29 (3H, t, J = 7.4 Hz), 2.54 (2H, q, J = 7.4 Hz), 2.90-3.03 (1H, m), 3.20 (1H, dd, J = 14.2, 6.9 Hz), 3.31 (1H, dd, J = 14.2, 5.1 Hz), 3.72 (6H, s ), 3.76 (2H, s), 3.81 (3H, s), 4.92-5.00 (1H, m), 6.62 (2H, s), 7.20-7.34 (4H, m), 7.38 (1H, d, J = 7.0 Hz). MS m / z: 501 [M−H] ⁻ .

Example 250
N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CD ₃ OD) δ; 1.10 (3H, d, J = 7.0Hz), 1.14 (3H, d, J = 7.0Hz), 1.25 (3H, t, J = 7.1 Hz), 3.08 (1H , dd, J = 13.8, 8.1 Hz), 3.15-3.36 (2H, m), 3.58 (2H, q, J = 7.1 Hz), 3.66 (6H, s), 3.72 (3H, s), 3.92 (3H, s), 4.51 (2H, s), 4.70-4.79 (1H, m), 6.68 (2H, s), 7.12-7.24 (4H, m).

N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.20 (3H, d, J = 7.0 Hz), 1.21 (3H, d, J = 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz), 3.13-3.41 ( 3H, m), 3.61 (2H, q, J = 7.0Hz), 3.72 (6H, s), 3.92 (3H, s), 4.53 (2H, s), 4.79-4.91 (1H, m), 6.64 (2H , s), 7.11 (1H, d, J = 7.6 Hz), 7.20-7.34 (4H, m). MS m / z: 485 [M−H] ⁻ .

Example 251
N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CD ₃ OD) δ; 1.057 (3H, d, J = 7.0 Hz), 1.062 (3H, d, J = 7.0 Hz), 1.25 (3H, t, J = 7.0 Hz), 2.56-2.73 (1H, m), 3.04 (1H, dd, J = 14.0,9.2 Hz), 3.22 (1H, dd, J = 14.0, 5.1 Hz), 3.59 (2H, q, J = 7.0 Hz), 3.66 (6H, s), 3.73 (3H, s), 3.75 (3H, s), 4.52 (2H, s), 4.78-4.83 (1H, m), 6.69 (2H, s), 7.12-7.24 (4H, m).

N- (2-methoxyimino-3-methylbutyryl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.097 (3H, d, J = 7.0 Hz), 1.101 (3H, d, J = 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz), 2.88-3.04 ( 1H, m), 3.20 (1H, dd, J = 14.3, 7.0 Hz), 3.31 (1H, dd, J = 14.3, 5.5 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s ), 3.81 (3H, s), 4.53 (2H, s), 4.89-5.02 (1H, m), 6.64 (2H, s), 7.18-7.33 (4H, m), 7.38 (1H, d, J = 7.0 Hz). MS m / z: 485 [M−H] ⁻ .

Example 252
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.100 (3H, d, J = 7.0Hz), 1.104 (3H, d, J = 7.0Hz), 2.10 (3H, s), 2.89-3.02 (1H, m), 3.11-3.28 (2H, m), 3.71 (2H, s), 3.72 (6H, s), 3.77 (3H, s), 3.83 (3H, s), 4.93-5.01 (1H, m), 6.60 (2H, s), 7.16 (2H, d, J = 8.1Hz), 7.27 (2H, d, J = 8.1Hz).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-methylsulfanylmethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.096 (3H, d, J = 7.0 Hz), 1.100 (3H, d, J = 7.0 Hz), 2.10 (3H, s), 2.89-3.02 (1H, m), 3.20 (1H, dd, J = 7.0, 14.3Hz), 3.31 (1H, dd, J = 5.1, 14.3Hz), 3.72 (8H, s), 3.81 (3H, s), 4.92-5.01 (1H, m) , 6.60 (2H, s), 7.23 (2H, d, J = 8.1Hz), 7.30 (2H, d, J = 8.1Hz), 7.37 (1H, d, J = 6.5Hz).
MS m / z: 487 [M−H] ⁻ .

Example 253
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.00 (3H, t, J = 7.3 Hz), 1.099 (3H, d, J = 7.0 Hz), 1.103 (3H, d, J = 7.0 Hz), 1.63-1.79 ( 2H, m), 2.62 (2H, t, J = 7.3Hz), 2.89-3.03 (1H, m), 3.12-3.24 (2H, m), 3.70 (6H, s), 3.77 (3H, s), 3.82 (3H, s), 4.90-5.00 (1H, m), 6.47 (2H, s), 7.15 (2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CD ₃ OD) δ; 0.99 (3H, t, J = 7.3 Hz), 1.061 (3H, d, J = 7.0 Hz), 1.067 (3H, d, J = 7.0 Hz), 1.63-1.79 (2H, m), 2.57-2.71 (3H, m), 3.06 (1H, dd, J = 14.0, 9.2 Hz), 3.22-3.30 (1H, m), 3.65 (6H, s), 3.75 (3H, s ), 4.77-4.84 (1H, m), 6.54 (2H, s), 7.15 (2H, d, J = 8.4 Hz), 7.22 (2H, d, J = 8.4 Hz) .MS m / z: 469 (M −H] ⁻ .

Example 254
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.10 (6H, d, J = 6.5 Hz), 2.87-3.03 (1H, m), 3.11-3.29 (2H, m), 3.46 (3H, s), 3.73 (6H , s), 3.77 (3H, s), 3.83 (3H, s), 4.48 (2H, s), 4.91-5.04 (1H, m), 6.63 (2H, s), 7.16 (2H, d, J = 7.8 Hz), 7.20-7.36 (3H, m).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.097 (3H, d, J = 7.0Hz), 1.101 (3H, d, J = 7.0Hz), 2.88-3.04 (1H, m), 3.20 (1H, dd, J = 14.6, 7.2 Hz), 3.31 (1H, dd, J = 14.6, 5.3 Hz), 3.46 (3H, s), 3.72 (6H, s), 3.81 (3H, s), 4.49 (2H, s), 4.91 . -5.00 (1H, m), 6.63 (2H, s), 7.20-7.34 (4H, m), 7.38 (1H, d, J = 7.3 Hz) MSm / z: 471 [M-H] -.

Example 255
N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-propoxymethylphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.3 Hz), 1.100 (3H, d, J = 7.0 Hz), 1.104 (3H, d, J = 7.0 Hz), 1.62-1.78 ( 2H, m), 2.88-3.04 (1H, m), 3.11-3.3.29 (2H, m), 3.50 (3H, t, J = 6.8 Hz), 3.72 (6H, s), 3.77 (3H, s) , 3.82 (3H, s), 4.53 (2H, s), 4.92-5.03 (1H, m), 6.64 (2H, s), 7.16 (2H, d, J = 8.4Hz), 7.20-7.34 (3H, m ).

N- (2-methoxyimino-3-methylbutyryl) -4- (2,6-dimethoxy-4-propoxymethylphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.3 Hz), 1.10 (6H, d, J = 7.3 Hz), 1.60-1.79 (2H, m), 2.87-3.04 (1H, m ), 3.20 (1H, dd, J = 14.3, 7.0Hz), 3.31 (1H, dd, J = 14.3, 5.4 Hz), 3.50 (3H, t, J = 6.8 Hz), 3.72 (6H, s), 3.81 (3H, s), 4.53 (2H, s), 4.91-5.01 (1H, m), 6.64 (2H, s), 7.20-7.34 (4H, m), 7.37 (1H, d, J = 6.8 Hz). MS m / z: 499 [M−H] ⁻ .

Example 256
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.17-1.37 (7H, m), 1.51-2.00 (6H, m), 2.99-3.24 (3H, m), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 3.73 (3H, s), 3.92 (3H, s), 4.52 (2H, s), 4.83-4.93 (1H, m), 6.64 (2H, s), 7.10 (1H, d, J = 7.8Hz), 7.16 (2H, d, J = 8.1 Hz), 7.26 (1H, d, J = 8.1 Hz).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (anti)

¹ H-NMR (CDCl ₃ ) δ; 1.20-1.37 (7H, m), 1.52-2.34 (6H, m), 2.91-3.37 (3H, m), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 3.91 (3H, s), 4.53 (2H, s), 4.79-4.91 (1H, m), 6.64 (2H, s), 7.12 (1H, d, J = 7.3 Hz), 7.20- 7.33 (4H, m). MS m / z: 525 [M−H] ⁻ .

Example 257
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.19-1.36 (7H, m), 1.50-1.88 (6H, m), 2.56-2.73 (1H, m), 3.16-3.24 (2H, m), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 3.77 (3H, s), 3.82 (3H, s), 4.52 (2H, s), 4.91-5.00 (1H, m), 6.64 (2H, s ), 7.16 (2H, d, J = 8.4 Hz), 7.21-7.31 (3H, m).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.18-1.40 (7H, m), 1.60-1.89 (6H, m), 2.59-2.72 (1H, m), 3.20 (1H, dd, J = 14.3, 6.5 Hz) , 3.30 (1H, dd, J = 14.3, 5.7Hz), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 3.80 (3H, s), 4.53 (2H, s), 4.90- 5.00 (1H, m), 6.64 (2H, s), 7.20-7.40 (5H, m). MS m / z: 525 [M−H] ⁻ .

Example 258
N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.20-1.37 (7H, m), 1.60-1.89 (6H, m), 2.55 (2H, q, J = 7.3 Hz), 2.59-2.71 (1H, m), 3.17 -3.24 (2H, m), 3.72 (6H, s), 3.76 (5H, s), 3.82 (3H, s), 4.90-5.00 (1H, m), 6.62 (2H, s), 7.22-7.33 (3H , m).

N- (2-cyclohexyl-2-methoxyiminoacetyl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.18-1.37 (6H, m), 1.62-2.37 (7H, m), 2.55 (2H, q, J = 7.3 Hz), 2.60-2.73 (1H, m), 3.16 (1H, dd, J = 14.3, 7.3 Hz), 3.30 (1H, dd, J = 14.3, 5.4 Hz), 3.72 (6H, s), 3.76 (2H, s), 3.80 (3H, s), 4.90- 5.00 (1H, m), 6.62 (2H, s), 7.20-7.40 (5H, m). MS m / z: 541 [M−H] ⁻ .

Example 259
N- [2-Methoxyimino-2- (2-thienyl) acetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.18 (1H, dd, J = 14.3, 6.6 Hz), 3.31 (1H, dd, J = 14.3, 5.1 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.71 (6H, s), 3.80 (3H, s), 3.95 (3H, s), 4.52 (2H, s), 5.06-5.14 (1H, m), 6.64 (2H, s), 6.78 (1H, d, J = 7.6 Hz), 6.96 (1H, dd, J = 3.8, 1.4 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.22-7.33 (4H, m).

N- [2-Methoxyimino-2- (2-thienyl) acetyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.21 (1H, dd, J = 14.3, 7.0 Hz), 3.38 (1H, dd, J = 14.3, 5.1 Hz), 3.62 (2H, q, J = 7.0 Hz), 3.70 (6H, s). 3.93 (3H, s), 4.53 (2H, s), 5.10-5.18 (1H, m), 6.64 (2H, s), 6.84 (1H, d, J = 7.6 Hz), 6.96 (1H, dd, J = 5.1, 4.3 Hz), 7.26 (6H, m). MS m / z: 526 [MH] ⁻ .

Example 260
N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 3.18 (1H, dd, J = 14.3, 6.8 Hz), 3.31 (1H, dd, J = 14.3, 5.4 Hz), 3.46 (3H, s), 3.72 (6H, s ), 3.80 (3H, s), 3.95 (3H, s), 4.48 (2H, s), 5.06-5.14 (1H, m), 6.63 (2H, s), 6.79 (1H, d, J = 7.6 Hz) , 6.96 (1H, dd, J = 4.6, 3.8 Hz), 7.18 (2H, d, J = 8.1 Hz), 7.24-7.35 (4H, m).

N- [2-methoxyimino-2- (2-thienyl) acetyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine (syn)

¹ H-NMR (CDCl ₃ ) δ; 3.21 (1H, dd, J = 14.6, 6.8 Hz), 3.39 (1H, dd, J = 14.6, 5.1 Hz), 3.46 (3H, s), 3.71 (6H, s ), 3.93 (3H, s), 4.49 (2H, s), 5.09-5.16 (1H, m), 6.63 (2H, s), 6.83 (1H, d, J = 7.3 Hz), 6.96 (1H, dd, J = 4.5, 3.8 Hz), 7.22-7.31 (6H, m). MS m / z: 511 [MH] ⁻ .

Example 261
N- [2-methoxyimino-2- (1-methylcyclohexyl) acetyl] -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.00 (3H, t, J = 7.3 Hz), 1.18 (3H, s), 1.20-1.58 (8H, m), 1.70 (2H, sixt, J = 7.3 Hz), 1.78-1.90 (2H, m), 2.61 (2H, t, J = 7.3 Hz), 3.19 (1H, dd, J = 14.3, 6.8 Hz), 3.33 (1H, dd, J = 14.3, 6.8 Hz), 3.70 (6H, s), 3.76 (3H, s), 3.80 (3H, s), 4.99-5.06 (1H, m), 6.14 (1H, d, J = 7.3 Hz), 6.47 (2H, s), 7.23 ( 2H, d, J = 8.1 Hz), 7.28 (2H, d, J = 8.1 Hz)

N- [2-methoxyimino-2- (1-methylcyclohexyl) acetyl] -4- (2,6-dimethoxy-4-propylphenyl) -L-phenylalanine (syn)

_{^{1 H-NMR (CDCl 3)}} δ; 1.00 (3H, t, J = 7.3 Hz), 1.17 (3H, s), 1.23-1.50 (8H, m), 1.71 (2H, sixt, J = 7.3 Hz), 1.75-1.95 (2H, m), 2.62 (2H, t, J = 7.3 Hz), 3.19 (1H, dd, J = 14.3, 6.5 Hz), 3.33 (1H, dd, J = 14.3, 5.1 Hz), 3.70 (6H, s), 3.79 (3H, s), 4.98-5.05 (1H, m), 6.14 (1H, d, J = 7.3 Hz), 6.47 (2H, s), 7.20-7.34 (4H, m).
MS m / z: 523 [MH] ⁻ .

Reference Example 87
Synthesis of ethyl 2-cyclobutyl-2-methoxyiminoacetate The ethyl 2-cyclobutyl-2-methoxyiminoacetate of syn and anti was prepared from 2-cyclobutyl-2-oxoethyl acetate obtained in Reference Example 51 in the same manner as in Reference Example 1. Synthesized.

2-cyclobutyl-2-methoxyiminoethyl acetate (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.33 (3H, t, J = 7.0 Hz), 1.77-2.06 (2H, m), 2.09-2.33 (4H, m), 3.18-3.32 (1H, m), 3.87 (3H, s), 4.31 (2H, q, J = 7.0Hz).
2-cyclobutyl-2-methoxyiminoethyl acetate (anti)
_{^{1 H-NMR (CDCl 3)}} δ; 1.35 (3H, t, J = 7.0Hz), 1.75-2.05 (2H, m), 2.16-2.38 (4H, m), 3.56-3.72 (1H, m), 3.98 (3H, s), 4.31 (2H, q, J = 7.0Hz).

Example 262
N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)
The title compound was obtained in the same manner as in Example 23 and Example 2 using the ethyl 2-cyclobutyl-2-methoxyiminoacetate (syn) obtained in Reference Example 87 and the compound obtained in Reference Example 73.

N- (2-Cyclobutyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0Hz), 1.70-2.03 (2H, m), 2.10-2.23 (4H, m), 3.16-3.22 (2H, m), 3.61 (2H, q, J = 6.8Hz), 3.72 (6H, s), 3.76 (3H, s), 3.86 (3H, s), 4.53 (2H, s), 4.87-4.98 (1H, m), 6.07 ( 1H, d, J = 7.6Hz), 6.64 (2H, s), 7.17 (2H, d, J = 8.1Hz), 7.25 (2H, d, J = 8.1Hz)

N- (2-cyclobutyl-2-methoxyiminoacetyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine (syn)

¹ H-NMR (DMSO-d ₆ ) δ; 1.18-1.22 (3H, m), 1.59-2.21 (6H, m), 1.62-1.79 (2H, m), 2.87-3.20 (3H, m), 3.47- 3.58 (2H, m), 3.64 (6H, s), 3.69 (3H, s), 4.44-4.58 (3H, m), 6.68 (2H, s), 7.11 (2H, d, J = 7.8Hz), 7.23 (2H, d, J = 7.8Hz), 8.67 (1H, d, J = 8.1Hz), 12.8 (1H, brs).
MS m / z: 497 [M−H] ⁻ .

  Using 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester, the amino acid derivative obtained in Reference Examples 72, 73 and 78 and 3,3-dichloro-2-isopropylacrylic acid obtained in Reference Example 61 The following compounds were obtained in the same manner as in Example 149 and Example 2. Examples 263-265

Example 263
N- (3,3-dichloro-2-isopropylacryloyl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.07 (3H, d, J = 7.0 Hz), 1.10 (3H, d, J = 7.0 Hz), 1.29 (3H, t, J = 7.3 Hz), 2.54 (2H, q, J = 7.3 Hz), 2.87-3.01 (1H, m), 3.10 (1H, dd, J = 14.3, 8.1 Hz), 3.28 (1H, dd, J = 14.3, 5.4 Hz), 3.72 (6H, s ), 3.76 (2H, s), 3.78 (3H, s), 4.99-5.08 (1H, m), 5.92 (1H, d, J = 8.4 Hz), 7.16-7.32 (5H, m).

N- (3,3-dichloro-2-isopropylacryloyl) -4- (4-ethylsulfanylmethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.06 (3H, d, J = 7.0 Hz), 1.08 (3H, d, J = 7.0 Hz), 1.29 (3H, t, J = 7.3 Hz), 2.54 (2H, q, J = 7.3 Hz), 2.87-3.02 (1H, m), 3.12 (1H, dd, J = 14.3, 8.4 Hz), 3.38 (1H, dd, J = 14.3, 5.7 Hz), 3.72 (6H, s ), 3.76 (2H, s), 4.98-5.09 (1H, m), 5.93 (1H, d, J = 7.0 Hz), 6.61 (2H, s), 7.21-7.36 (4H, m) .MS m / z : 538 [M−H] ⁻ .

Example 264
N- (3,3-dichloro-2-isopropylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.07 (3H, d, J = 7.0 Hz), 1.10 (3H, d, J = 7.0 Hz), 2.87-3.01 (1H, m), 3.10 (1H, dd, J = 14.3, 8.1 Hz), 3.28 (1H, dd, J = 14.3, 5.7 Hz), 3.72 (6H, s), 3.78 (3H, s), 4.98-5.10 (1H, m), 5.93 (1H, d, J = 8.1 Hz), 6.64 (2H, d, J = 8.1 Hz), 7.17-7.34 (5H, m).

N- (3,3-dichloro-2-isopropylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.06 (3H, d, J = 6.8 Hz), 1.10 (3H, d, J = 6.8 Hz), 2.86-3.02 (1H, m), 3.07-3.20 (1H, m ), 3.33-3.44 (1H, m), 3.71 (6H, s), 4.98-5.10 (1H, m), 5.97 (1H, d, J = 7.3 Hz), 6.64 (2H, d, J = 8.4 Hz) , 7.21-7.36 (5H, m). MS m / z: 464 [M−H] ⁻ .

Example 265
N- (3,3-dichloro-2-isopropylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.05 (3H, d, J = 7.0 Hz), 1.09 (3H, d, J = 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz), 2.87-3.01 ( 1H, m), 3.10 (1H, dd, J = 13.8, 8.1 Hz), 3.28 (1H, dd, J = 13.8, 5.4 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s ), 3.78 (3H, s), 4.52 (2H, s), 4.98-5.11 (1H, m), 5.93 (1H, d, J = 7.8Hz), 6.63 (2H, s), 7.16-7.32 (4H, m).

N- (3,3-dichloro-2-isopropylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.05 (3H, d, J = 7.0 Hz), 1.09 (3H, d, J = 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz), 2.87-3.03 ( 1H, m), 3.13 (1H, dd, J = 14.6, 8.4 Hz), 3.37 (1H, dd, J = 14.6, 5.7 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s ), 4.53 (2H, s), 4.99-5.11 (1H, m), 5.93 (1H, d, J = 7.6 Hz), 6.63 (2H, s), 7.20-7.33 (4H, m) .MS m / z : 522 [M−H] ⁻ .

  The following compounds were obtained in the same manner as in Example 149 and Example 2 using the compounds obtained in Reference Examples 72 and 76 and 3,3-dichloro-2-phenylacrylic acid obtained in Reference Example 57. Examples 266-267

Example 266
N- (3,3-Dichloro-2-phenylacryloyl) -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.76 (1H, t, J = 5.9 Hz), 3.08 (1H, dd, J = 6.8, 14.3 Hz), 3.22 (1H, dd, J = 5.7, 14.3 Hz), 3.74 (6H, s), 3.76 (3H, s), 4.74 (2H, d, J = 5.9Hz), 4.94-5.03 (1H, m), 6.16 (1H, d, J = 7.8Hz), 6.66 (2H , s), 6.99 (2H, d, J = 8.1Hz), 7.18 (2H, d, J = 8.1Hz), 7.33-7.40 (5H, m).

N- (3,3-Dichloro-2-phenylacryloyl) -4- (4-hydroxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (DMSO-d ₆ ) δ; 2.92 (1H, dd, J = 10.5, 14.0 Hz), 3.18 (1H, dd, J = 4.3, 14.0 Hz), 3.64 (6H, s), 4.50-4.62 (3H, m), 5.24 (1H, t, J = 4.9Hz), 6.70 (2H, s), 7.06 (2H, d, J = 8.1Hz), 7.21 (2H, d, J = 8.1Hz), 7.33 -7.45 (5H, m), 9.14 (1H, d, J = 8.1Hz), 12.8 (1H, brs).
MS m / z: 528 [M−H] ⁻ .

Example 267
N- (3,3-Dichloro-2-phenylacryloyl) -4- (4-methoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 3.08 (1H, dd, J = 6.8, 14.3 Hz), 3.22 (1H, dd, J = 5.7, 14.3 Hz), 3.46 (3H, s), 3.73 (6H, s ), 3.75 (3H, s), 3.76 (3H, s), 4.49 (2H, s), 4.94-5.03 (1H, m), 6.16 (1H, d, J = 8.1Hz), 6.64 (2H, s) , 6.99 (2H, d, J = 8.1Hz), 7.18 (2H, d, J = 8.1Hz), 7.29-7.46 (5H, m)

N- (3,3-Dichloro-2-phenylacryloyl) -4- (4-methoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 3.11 (1H, dd, J = 6.5, 14.0Hz), 3.28 (1H, dd, J = 7.8, 14.0Hz), 3.47 (3H, s), 3.73 (6H, s ), 4.49 (3H, s), 4.92-5.05 (1H, m), 6.15 (1H, d, J = 7.3Hz), 6.64 (2H, s), 7.04 (2H, d, J = 8.1Hz), 7.19 (2H, d, J = 8.1Hz), 7.29-7.44 (5H, m) .MS m / z: 542 [M−H] ⁻ .

  The following compounds were obtained in the same manner as in Example 149 and Example 2 using the compounds obtained in Reference Examples 72 and 73 and 3,3-dichloro-2- (2-thienyl) acrylic acid obtained in Reference Example 60. It was. Examples 268-269

Example 268
N- [3,3-dichloro-2- (2-thienyl) acryloyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.08 (1H, dd, J = 14.3, 8.4 Hz), 3.34 (1H, dd, J = 14.3, 5.4 Hz), 3.61 (2H, q, J = 7.0Hz), 3.72 (6H, s), 3.81 (3H, s), 4.53 (2H, s), 5.07-5.19 (1H, m), 6.20 (1H, d, J = 8.4 Hz), 6.64 (2H, s), 6.98 (1H, dd, J = 4.9, 3.8 Hz), 7.11 (1H, dd, J = 4.9, 1.1 Hz), 7.17 (2H, d, J = 8.1 Hz) , 7.22-7.28 (2H, m), 7.38 (1H, dd, J = 5.1, 1.1 Hz).

N- [3,3-Dichloro-2- (2-thienyl) acryloyl] -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 3.09 (1H, dd, J = 14.6, 8.4 Hz), 3.40 (1H, dd, J = 14.6, 5.4 Hz), 3.61 (2H, q, J = 7.0Hz), 3.71 (6H, s), 4.53 (2H, s), 5.07-5.20 (1H, m), 6.31 (1H, d, J = 7.3 Hz), 6.63 (2H , s), 6.87-7.00 (1H, m), 7.09 (1H, d, J = 3.2 Hz), 7.16-7.31 (4H, m), 7.36 (1H, d, J = 5.1 Hz). MS m / z : 562 [M−1] ⁻ .

Example 269
N- [3,3-dichloro-2- (2-thienyl) acryloyl] -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methylestyl
¹ H-NMR (CDCl ₃ ) δ; 3.08 (1H, dd, J = 14.3, 8.4 Hz), 3.34 (1H, dd, J = 14.3, 5.2 Hz), 3.46 (3H, s), 3.72 (6H, s ), 3.81 (3H, s), 4.48 (2H, s), 5.08-5.18 (1H, m), 6.20 (1H, d, J = 8.4 Hz), 6.63 (2H, s), 6.98 (1H, dd, J = 5.1, 3.8 Hz), 7.11 (1H, dd, J = 3.8, 1.4 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.23-7.28 (2H, m), 7.38 (1H, dd, J = 5.1, 1.1 Hz).

N- (3,3-Dichloro-2-thienylacryloyl) -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 3.08 (1H, dd, J = 14.3, 8.6 Hz), 3.40 (1H, dd, J = 14.3, 4.3 Hz), 3.46 (3H, s), 3.70 (6H, s ), 4.49 (2H, s), 5.04-5.20 (1H, m), 6.40 (1H, d, J = 7.8 Hz), 6.62 (2H, s), 6.91-7.00 (1H, m), 7.09 (1H, d, J = 3.0 Hz), 7.20-7.31 (4H, m), 7.35 (1H, d, J = 4.6 Hz) .MS m / z: 562 [M−H] ⁻ .

  The following compounds were obtained in the same manner as in Example 149 and Example 2 using the compounds obtained in Reference Examples 72 and 73 and 3,3-dichloro-2-methylacrylic acid obtained in Reference Example 62. Examples 270-271

Example 270
N- (3,3-dichloro-2-methylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 2.01 (3H, s), 3.14 (1H, dd, J = 13.8, 8.1 Hz), 3.29 (1H, dd, J = 13.8, 5.4 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.73 (6H, s), 3.79 (3H, s), 4.53 (2H, s), 4.91-5.00 (1H, m), 6.23 (1H, d, J = 7.6 Hz), 6.64 (2H, s), 7.15 (2H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.8 Hz).

N- (3,3-dichloro-2-methylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 2.00 (3H, s), 3.17 (1H, dd, J = 14.6, 8.4 Hz), 3.38 (1H, dd, J = 13.9, 5.7 Hz), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 4.53 (2H, s), 4.90-5.02 (1H, m), 6.24-6.34 (1H, m) , 6.63 (2H, s), 7.20-7.32 (4H, m). MS m / z: 494 [M−H] ⁻ .

Example 271
N- (3,3-dichloro-2-methylacryloyl) -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 2.00 (3H, s), 3.14 (1H, dd, J = 14.3, 7.3 Hz), 3.29 (1H, dd, J = 14.3, 5.9 Hz), 3.45 (3H, s ), 3.73 (6H, s), 3.79 (3H, s), 4.48 (2H, s), 4.91-5.00 (1H, m), 6.23 (1H, d, J = 7.3 Hz), 6.63 (2H, s) , 7.15 (2H, d, J = 7.8 Hz), 7.26 (2H, d, J = 7.3 Hz).

N- (3,3-dichloro-2-methylacryloyl) -4- (2,6-dimethoxy-4-methoxymethylphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.99 (3H, s), 3.16 (1H, dd, J = 14.0, 7.6 Hz), 3.37 (1H, dd, J = 14.0, 5.4 Hz), 3.45 (3H, s ), 3.71 (6H, s), 4.49 (2H, s), 4.90-5.00 (1H, m), 6.41 (2H, s), 7.18-7.32 (4H, m). MS m / z: 480 [M− H] ⁻ .

Reference Example 88
Synthesis of cyclobutyloxoacetic acid 4-methoxybenzyl ester The title compound was obtained in the same manner as in Reference Example 63 from ethyl cyclobutyloxoacetate obtained in Reference Example 51.

¹ H-NMR (CDCl ₃ ) δ; 1.78-1.95 (1H, m), 1.96-2.11 (1H, m), 2.15-2.36 (4H, m), 3.73-3.90 (4H, m, including 1s at 3.81ppm ), 5.20 (2H, s), 6.86-6.96 (2H, m), 7.29-7.38 (2H, m).

Reference Example 89
Synthesis of 3,3-dichloro-2-cyclobutylacrylic acid The title compound was obtained in the same manner as in Reference Examples 57 and 65.

¹ H-NMR (CDCl ₃ ) δ; 1.73-2.01 (2H, m), 2.06-2.33 (4H, m), 3.44-3.59 (1H, m).

Example 272
Synthesis of N- (3,3-dichloro-2-cyclobutylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine 3,3-Dichloro-2 obtained in Reference Example 89 Synthesis was performed in the same manner as in Example 149 and Example 2 using cyclobutylacrylic acid and the compound of Reference Example 73.

N- (3,3-dichloro-2-cyclobutylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 1.62-1.92 (2H, m), 1.97-2.20 (4H, m), 3.13 (1H, dd, J = 14.9, 7.0 Hz), 3.29 (1H, dd, J = 14.9,5.4 Hz), 3.34-3.50 (1H, m), 3.61 (2H, q, J = 7.0 Hz), 3.72 (6H, s), 3.79 (3H, s), 4.52 (2H, s), 5.00-5.11 (1H, m), 6.02 (1H, d, J = 8.4 Hz), 6.63 (2H, s), 7.19 (2H, d, J = 8.1 Hz), 7.26 (2H, d, J = 8.1 Hz).

N- (3,3-dichloro-2-cyclobutylacryloyl) -4- (4-ethoxymethyl-2,6-dimethoxyphenyl) -L-phenylalanine

¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.3 Hz), 1.63-1.92 (2H, m), 1.95-2.20 (4H, m), 3.15 (1H, dd, J = 14.3, 8.4 Hz), 3.33-3.48 (2H, m), 3.61 (2H, q, J = 7.3Hz), 3.72 (6H, s), 4.53 (2H, s), 5.02-5.11 (1H, m), 5.99 ( 1H, d, J = 7.6 Hz), 6.63 (2H, s), 7.21-7.32 (4H, m).
MS m / z: 534 [MH] ⁻ .

Example 273
N- [2-methoxyimino-2- (tetrahydrothiopyran-4-yl) acetyl] -4-[(3,5-dichloropyridin-4-carbonyl) amino] -L-phenylalanine ethyl ester (syn and anti) Of 4-[(3,5-dichloropyridine-4-carbonyl) amino] -L-phenylalanine ethyl ester and ethyl 2-methoxyimino-2- (tetrahydropyran-4-yl) acetate as in Example 92 To give the title compound.

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-[(3,5-dichloropyridine-4-carbonyl) amino] -L-phenylalanine ethyl ester (syn)
¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.0 Hz), 1.53-1.76 (4H, m), 2.84-3.00 (1H, m), 3.12 (1H, dd, J = 13.8, 6.2 Hz), 3.23 (1H, dd, J = 13.8, 5.4 Hz), 3.38-3.50 (2H, m), 3.90 (3H, s), 3.94-4.04 (2H, m), 4.22 (2H, q, J = 7.0 Hz), 4.89-4.99 (1H, m), 7.19 (2H, d, J = 8.4 Hz), 7.41-7.50 (2H, m), 7.55 (2H, d, J = 8.4 Hz), 8.59 (2H , s).

N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-[(3,5-dichloropyridine-4-carbonyl) amino] -L-phenylalanine ethyl ester (anti)
¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t, J = 7.0 Hz), 1.36-1.48 (2H, m), 2.21-2.41 (2H, m), 3.11 (1H, dd, J = 13.5, 5.7 Hz), 3.20 (1H, dd, J = 13.5, 4.9 Hz), 3.27-3.48 (3H, m), 3.96 (3H, s), 3.97-4.04 (2H, m), 4.21 (2H, q, J = 7.0 Hz), 4.80-4.91 (1H, m), 7.12 (1H, d, J = 8.1 Hz), 7.19 (2H, d, J = 8.4Hz), 7.37 (1H, s), 7.55 (2H, d , J = 8.4 Hz), 8.60 (2H, s).

Example 274
N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-[(3,5-dichloropyridine-4-carbonyl) amino] -L-phenylalanine (syn)
Performed with N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-[(3,5-dichloropyridin-4-carbonyl) amino] -L-phenylalanine ethyl ester (syn) The title compound was obtained in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ; 1.21-1.48 (4H, m), 2.32-2.47 (1H, m), 2.93 (1H, dd, J = 14.0, 10.5 Hz), 3.05-3.26 (3H, m), 3,69 (3H, s), 3.69-3.84 (2H, m), 4.48-4.63 (1H, m), 7.26 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.6 Hz), 8.64 (1H, d, J = 8.4 Hz), 8.79 (2H, s), 10.87 (1H, s) .MS m / z: 521 [M−H] ⁻ .

Example 275
Synthesis of N- [2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-[(3,5-dichloropyridin-4-carbonyl) amino] -L-phenylalanine (anti) N- [ 2-methoxyimino-2- (tetrahydropyran-4-yl) acetyl] -4-[(3,5-dichloropyridin-4-carbonyl) amino] -L-phenylalanine (anti) was used in the same manner as in Example 2. To give the title compound.

¹ H-NMR (DMSO-d ₆ ) δ; 1.09-1.19 (1H, m), 1.33-1.43 (1H, m), 1.47-1.63 (1H, m), 1.73-1.90 (1H, m), 2.93 ( 1H, dd, J = 13.5, 10.1 Hz), 3.01-3.38 (4H, m), 3.71-3.84 (2H, m), 3.88 (3H, s), 4.47-4.59 (1H, m), 7.24 (2H, d, J = 8.6 Hz), 7.54 (2H, d, J = 8.6 Hz), 8.32 (1H, d, J = 8.4 Hz), 8.79 (2H, s), 10.86 (1H, s) .MS m / z : 521 [M−H] ⁻ .

Example 276
Synthesis of N- (methoxyiminophenylacetyl) -O- (2,6-dichlorobenzyl) -L-tyrosine Methoxyiminophenylacetic acid methyl (syn) and O- (2,6-dichlorobenzyl) -L-tyrosine methyl ester The title compound was obtained in the same manner as in Example 1 and Example 2.

N- (Methoxyiminophenylacetyl) -O- (2,6-dichlorobenzyl) -L-tyrosine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 3.12 (1H, dd, J = 14.0, 6.5 Hz), 3.27 (1H, dd, J = 14.0, 5.1 Hz), 3.78 (3H, s), 3.99 (3H, s ), 5.05-5.17 (1H, m), 5.24 (2H, s), 6.47 (1H, d, J = 7.8 Hz), 6.94 (2H, d, J = 8.6 Hz), 7.12 (2H, d, J = 8.6 Hz), 7.20-7.43 (6H, m), 7.50-7.59 (2H, m).

N- (methoxyiminophenylacetyl) -O- (2,6-dichlorobenzyl) -L-tyrosine
¹ H-NMR (CDCl ₃ ) δ; 3.15 (1H, dd, J = 14.6, 7.3 Hz), 3.34 (1H, dd, J = 14.6, 4.9 Hz), 3.97 (3H, s), 5.08-5.17 (1H , m), 5.23 (2H, s), 6.48 (1H, d, J = 8.1 Hz), 6.95 (2H, d, J = 8.6 Hz), 7.13-7.43 (8H, m), 7.47-7.56 (2H, m). MS m / z: 499 [M−H] ⁻ .

Reference Example 90
Synthesis of 4- (4-morpholinylcarbonyloxy) -L-phenylalanine methyl ester N-Boc-L-tyrosine methyl ester (5.00 g, 16.9 mmol) was dissolved in DMF (50 ml) and potassium carbonate as the base. (2.57 g, 18.6 mmol) was added, 4-morpholinylcarbonyl chloride (2.13 ml, 18.6 mmol) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate; hexane = 1: 1) to obtain 10.23 g of N-Boc-4- (4-morpholinylcarbonyloxy) -L-phenylalanine methyl ester. The obtained product was dissolved in dichloromethane (50 mL), trifluoroacetic acid (2.6 mL, 33.8 mmol) was added and stirred overnight at room temperature, and trifluoroacetic acid (2.6 mL, 33.8 mmol) was further added. Stir at 35 ° C. overnight. After completion of the reaction, the solvent was distilled off under reduced pressure, 10% Na ₂ CO ₃ aqueous solution was added and the mixture was extracted with chloroform. The obtained organic layer was washed with saturated brine, and then dried over Na ₂ SO _4. The desired product (3.41 g, 11.1 mmol) was obtained.

¹ H-NMR (CDCl ₃ ) δ; 2.85 (1H, dd, J = 13.8, 8.0 Hz), 3.08 (1H, dd, J = 13.8, 5.1 Hz), 3.51-3.91 (12H, m), 7.06 (2H , d, J = 8.6 Hz), 7.19 (2H, d, J = 8.6 Hz).

Example 277
N- (2-methoxyimino-2-phenylacetyl) -4- (4-morpholinylcarbonyloxy) -L-phenylalanine (syn)
The title compound was obtained in the same manner as in Example 1 and Example 2 using 4- (4-morpholinylcarbonyloxy) -L-phenylalanine methyl ester and methyl 2-methoxyimino-2-phenylacetate.

¹ H-NMR (CDCl ₃ ) δ; 3.18 (1H, dd, J = 14.0, 5.9 Hz), 3.28 (1H, dd, J = 14.0, 5.7 Hz), 3.52-3.80 (11H, m), 4.00 (3H , s), 5.06-5.14 (1H, m), 6.53 (1H, d, J = 7.6 Hz), 7.04 (2H, d, J = 8.6 Hz), 7.17 (2H, d, J = 8.6 Hz), 7.33 -7.40 (3H, m), 7.54-7.60 (2H, m).

¹ H-NMR (CDCl ₃ ) δ; 3.12-3.84 (10H, m), 3.99 (3H, s), 5.08-5.18 (1H, m), 6.63 (1H, d, J = 7.8 Hz), 7.03 (2H , d, J = 8.4Hz) 7.18-7.44 (5H, m), 7.52-7.62 (2H, m). MS m / z: 454 [M−H] ⁻ .

Reference Example 91
Methyl 1- (1-methoxyiminoethyl) cyclopentanecarboxylate Methyl 1-acetylcyclopentanecarboxylate synthesized according to the method described in JP-A No. 2001-172218 was subjected to oximation by the same production method as in Reference Example 1. One compound, methyl 1- (1-methoxyiminoethyl) cyclopentanecarboxylate, was obtained.
¹ H-NMR (CDCl ₃ ) δ; 1.60-1.70 (4H, m), 1.78 (3H, s), 2.02-2.14 (4H, m), 3.69 (3H, s), 3.86 (3H, s).

Example 278
N- [1- (1-methoxyiminoethyl) cyclopentanecarbonyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine 1- (1-methoxyiminoethyl) cyclopentanecarboxylic acid obtained in Reference Example 91 The title compound was obtained in the same manner as in Example 1 and Example 2 using methyl acid and 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester.

N- [1- (1-Methoxyiminoethyl) cyclopentanecarbonyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.26 (3H, t, J = 7.0Hz), 1.52-1.74 (7H, m), 1.89-2.13 (4H, m), 3.02-3.17 (2H, m), 3.85 (3H, s), 4.17 (2H, q, J = 7.0Hz), 4.75-4.85 (1H, m), 6.09 (1H, d, J = 8.1Hz), 7.12 (2H, d, J = 8.4Hz) , 7.27-7.42 (3H, m), 7.55 (2H, d, J = 8.4Hz).

N- [1- (1-Methoxyiminoethyl) cyclopentanecarbonyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine
¹ H-NMR (DMSO-d ₆ ) δ; 1.35-1.58 (7H, m), 1.75-2.03 (4H, m), 2.88-3.12 (2H, m), 3.77 (3H, s), 4.38-4.52 ( 1H, m), 7.16 (2H, d, J = 8.4Hz), 7.40 (1H, d, J = 8.1Hz), 7.45-7.63 (5H, m).
MS m / z: 518 [M−H] ⁻ .

Example 279
N- [1- (1-methoxyiminoethyl) cyclopentanecarbonyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine 1- (1-methoxyiminoethyl) cyclopentanecarboxylic acid obtained in Reference Example 91 The title compound was obtained in the same manner as in Example 1 and Example 2 using methyl and 4- (2,6-dimethoxyphenyl) -L-phenylalanine ethyl ester.

N- [1- (1-methoxyiminoethyl) cyclopentanecarbonyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.50-1.70 (7H, m), 1.78-2.16 (4H, m), 3.00 (1H, dd, J = 7.8, 14.0Hz), 3.21 (1H, dd, J = 5.4, 14.0Hz), 3.71 (6H, s), 3.74 (3H, s), 3.85 (3H, s), 4.76-4.86 (1H, m), 6.06 (1H, d, J = 7.6Hz), 6.64 ( 2H, d, J = 8.6Hz), 7.16 (2H, d, J = 8.1Hz), 7.20-7.34 (3H, m).

N- [1- (1-methoxyiminoethyl) cyclopentanecarbonyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine
¹ H-NMR (CDCl ₃ ) δ; 1.50-1.74 (7H, m), 1.78-1.92 (1H, m) 2.08-2.14 (3H, m), 3.04 (1H, dd, J = 8.9, 14.0Hz), 3.30 (1H, dd, J = 5.1, 14.0Hz), 3.71 (6H, s), 3.84 (3H, s), 4.72-4.83 (1H, m), 6.10 (1H, d, J = 7.6Hz), 6.64 (2H, d, J = 8.4 Hz), 7.17 (2H, d, J = 8.1 Hz), 7.23-7.32 (3H, m).
MS m / z: 467 [M−H] ⁻ .

Reference Example 92
Synthesis of methyl 4- (1-methoxyiminoethyl) tetrahydropyran-4-carboxylate 4-acetyl-4-methoxycarbonyltetrahydropyran synthesized according to the method described in JP-A-2001-172274 was the same as in Reference Example 1. Oxidation was performed by the production method to obtain methyl 4- (1-methoxyiminoethyl) tetrahydropyran-4-carboxylate as a single compound.
¹ H-NMR (CDCl ₃ ) δ; 1.77 (3H, s), 1.85-2.05 (2H, m), 2.10-2.20 (2H, m), 3.49-3.61 (2H, m), 3.67-3.91 (8H, m).

Example 280
N- [4- (1-methoxyiminoethyl) tetrahydropyran-4-carbonyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine 4- (1-methoxyiminoethyl) obtained in Reference Example 92 Obtained in the same manner as in Example 1 and Example 2 using methyl tetrahydropyran-4-carboxylate and 4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester.

N- [4- (1-methoxyiminoethyl) tetrahydropyran-4-carbonyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t, J = 7.3Hz), 1.69 (3H, s), 1.85-2.11 (4H, m), 3.01-3.18 (2H, m), 3.60-3.72 (4H, m), 3.88 (3H, s), 4.19 (2H, q, J = 7.3Hz), 4.78-4.88 (1H, m), 6.11 (1H, d, J = 8.1Hz), 7.10 (2H, d, J = 8.4Hz), 7.28-7.41 (3H, m), 7.57 (2H, d, J = 8.4Hz).

N- [4- (1-methoxyiminoethyl) tetrahydropyran-4-carbonyl] -4- (2,6-dichlorobenzoylamino) -L-phenylalanine
¹ H-NMR (CDCl ₃ ) δ; 1.69 (3H, s), 1.84-2.12 (4H, m), 3.07 (1H, dd, J = 14.0, 6.5 Hz), 3.17 (1H, dd, J = 14.0, 5.4Hz), 3.54-3.73 (4H, m), 3.87 (3H, s), 4.74-4.85 (1H, m), 6.25 (1H, d, J = 8.1Hz), 7.12 (2H, d, J = 8.4 Hz), 7.27-7.43 (3H, m), 7.58 (2H, d, J = 8.4Hz).
MS m / z: 534 [M−H] ⁻ .

Example 281
N- [4- (1-methoxyiminoethyl) tetrahydropyran-4-carbonyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine 4- (1-methoxyiminoethyl) tetrahydro obtained in Reference Example 92 It was obtained in the same manner as in Example 1 and Example 2 using methyl pyran-4-carboxylate and 4- (2,6-dimethoxyphenyl) -L-phenylalanine ethyl ester.

N- [4- (1-methoxyiminoethyl) tetrahydropyran-4-carbonyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.62 (3H, s), 1.78-2.14 (4H, m), 2.98 (1H, dd, J = 8.4, 14.0 Hz), 3.23 (1H, dd, J = 4.9, 14.0Hz), 3.55-3.74 (10H, m), 3.76 (3H, s), 3.87 (3H, s), 4.59-4.80 (1H, m), 6.06 (1H, d, J = 8.1Hz), 6.64 ( 2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.1Hz), 7.23-7.31 (3H, m).

N- [4- (1-methoxyiminoethyl) tetrahydropyran-4-carbonyl] -4- (2,6-dimethoxyphenyl) -L-phenylalanine
¹ H-NMR (CDCl ₃ ) δ; 1.62 (3H, s), 1.82-2.12 (4H, m), 3.03 (1H, dd, J = 9.2, 14.3 Hz), 3.34 (1H, dd, J = 4.9, 14.3Hz), 3.42-3.70 (4H, m), 3.71 (6H, s), 3.87 (3H, s), 4.77-4.87 (1H, m), 6.05 (1H, d, J = 7.3Hz), 6.64 ( 2H, d, J = 8.4Hz), 7.16 (2H, d, J = 8.1Hz), 7.21-7.33 (3H, m).
MS m / z: 483 [M−H] ⁻ .

Reference Example 93
Synthesis of ethyl 1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarboxylate To a solution of 3 g (124.5 mmol) of sodium hydride in DMF (50 mL) under ice-cooling, 3- (4-chlorophenyl) -3- 9.4 g (41.5 mmol) of ethyl oxopropionate in DMF (30 mL) was added dropwise and stirred for 30 minutes. A solution of 10 g (46.3 mmol) of 1,4-dibromobutane in DMF (30 mL) was added dropwise to the mixture under ice cooling, and the mixture was slowly warmed to 80 ° C. and stirred at 80 ° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to obtain 4.7 g (16.7 mmol) of ethyl 1- (4-chlorobenzoyl) cyclopentanecarboxylate. The product obtained above was subjected to oximation by the same production method as in Reference Example 1, followed by separation and purification by silica gel column chromatography (hexane / ethyl acetate = 20/1) to give 1-[(4-chlorophenyl). ) 1.0 g of isomer A (lower polarity) and 1.3 g of isomer B (higher polarity) ethyl methoxyiminomethyl] cyclopentanecarboxylate were isolated.

Isomer A
¹ H-NMR (CDCl ₃ ) δ; 1.28 (3H, t, J = 7.0 Hz), 1.40-1.77 (6H, m), 2.27-2.42 (2H, m), 3.87 (3H, s), 4.19 (2H , q, J = 7.0 Hz), 7.26-7.40 (4H, m).
Isomer B
¹ H-NMR (CDCl ₃ ) δ; 1.23 (3H, t, J = 7.3 Hz), 1.62-1.74 (4H, m), 2.02-2.24 (4H, m), 3.81 (3H, s), 4.11 (2H , q, J = 7.3 Hz), 7.05-7.13 (2H, m), 7.28-7.36 (2H, m).

Example 282
N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer A)
To an ethanol solution of 1.0 g (3.35 mmol) of isomer A obtained in Reference Example 93 was added 4 mL of 2N aqueous sodium hydroxide solution, and the mixture was stirred at 70 ° C. overnight. Further, 3 mL of 2N sodium hydroxide aqueous solution was added and stirred at 70 ° C. for 1 day. Ethanol was distilled off under reduced pressure, followed by extraction with chloroform. The aqueous layer was acidified with 10% aqueous citric acid and extracted again with chloromorph. The organic layer was washed with water and brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. 160 mg of the crude product obtained above was prepared in the same manner as in Example 1b) by using N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino). 200 mg of -L-phenylalanine ethyl ester was obtained.

¹ H-NMR (CDCl ₃ ) δ; 1.27 (3H, t, J = 7.3 Hz), 1.60-1.78 (6H, m), 2.33-2.54 (2H, m), 3.06-3.22 (2H, m), 3.86 (3H, s), 4.19 (2H, q, J = 7.3Hz), 4.83-4.95 (1H, m), 6.97 (1H, d, J = 7.6Hz), 7.14 (2H, d, J = 8.6Hz) , 7.18-7.41 (7H, m), 7.54 (2H, d, J = 8.6 Hz).

  200 mg of the product obtained above was hydrolyzed in the same manner as in Example 2 to obtain 120 mg of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ; 1.22-1.65 (6H, m), 2.10-2.28 (2H, m), 2.95-3.15 (2H, m), 3.63 (3H, s), 4.47-4.59 ( 1H, m), 7.21 (2H, d, J = 8.4Hz), 7.26-7.35 (3H, m), 7.44 (2H, d, J = 8.4 Hz), 7.47-7.62 (5H, m), 10.7 (1H , s), 12.7 (1H, brs).
MS m / z; 614 [MH] ^- .

Example 283
N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer B)
Using the isomer B obtained in Reference Example 93, the compound was synthesized in the same manner as in Example 282.

N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.27 (3H, t, J = 7.0 Hz), 1.42-1.71 (4H, m), 1.79-2.18 (4H, m), 3.07 (1H, dd, J = 7.0, 14.0Hz), 3.16 (1H, dd, J = 5.7, 14.0Hz), 3.83 (3H, s), 4.19 (2H, q, J = 7.0Hz), 4.80-4.91 (1H, m), 6.60 (1H, d, J = 8.4Hz), 6.94-7.01 (2H, m), 7.13 (2H, d, J = 8.4Hz), 7.23-7.40 (5H, m), 7.46 (1H, s), 7.54 (2H, d , J = 8.4Hz)

N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer B)
¹ H-NMR (DMSO-d ₆ ) δ; 1.33-1.59 (4H, m), 1.67-2.01 (4H, m), 2.95-3.17 (2H, m), 3.74 (3H, s), 4.44-4.55 ( 1H, m), 6.81 (2H, d, J = 8.4Hz), 7.19-7.29 (4H, m), 7.45-7.65 (65H, m), 10.67 (1H, s).
MS m / z: 614 [M−H] ⁻ .

Example 284
N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) phenylalanine (isomer A)
The compound was synthesized in the same manner as in Example 282 using isomer A obtained in Reference Example 93 and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- {1-[(4-Chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) phenylalanine methyl ester (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.40-1.73 (6H, m), 2.33-2.52 (2H, m), 3.08-3.26 (2H, m), 3.69 (6H, s), 3.77 (3H, s) , 3.79 (3H, s), 4.89-5.00 (1H, m), 6.64 (2H, d, J = 8.4Hz), 6.93 (1H, d, J = 7.8Hz), 7.14 (2H, d, J = 8.1 Hz), 7.20-7.32 (7H, m)

N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) phenylalanine (isomer A)
¹ H-NMR (DMSO-d ₆ ) δ; 1.27-1.60 (6H, m), 2.12-2.30 (2H, m), 3.01-3.20 (2H, m), 3.74 (9H, s), 4.52-4.64 ( 1H, m), 6.71 (2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.1Hz), 7.19-7.48 (8H, m), 12.74 (1H, brs).
MS m / z: 563 [M−H] ⁻ .

Example 285
N- {1-[(4-chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer B)
The compound was synthesized in the same manner as in Example 282 using isomer B obtained in Reference Example 93 and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- {1-[(4-Chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.50-1.70 (4H, m), 1.82-2.16 (4H, m), 3.05 (1H, dd, J = 8.1, 14.0 Hz), 3.23 (1H, dd, J = 5.1, 14.0Hz), 3.68 (6H, s), 3.75 (3H, s), 3.82 (3H, s), 4.81-4.91 (1H, m), 6.58 (1H, d, J = 7.8Hz), 6.64 ( 2H, d, J = 8.4Hz), 6.98 (2H, d, J = 8.6Hz), 7.15 (2H, d, J = 8.4Hz), 7.21-7.32 (5H, m).

N- {1-[(4-Chlorophenyl) methoxyiminomethyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.33-1.58 (4H, m), 1.73-2.03 (4H, m), 3.00-3.19 (2H, m), 3.61 (6H, s), 3.74 (3H, s) , 4.45-4.57 (1H, m), 6.71 (2H, d, J = 8.4Hz), 6.95 (2H, d, J = 8.4Hz), 7.11 (2H, d, J = 8.1Hz), 7.18-7.33 ( 5H, m), 7.67 (1H, d, J = 8.4Hz).
MS m / z: 563 [M−H] ⁻ .

Reference Example 94
Synthesis of ethyl 1- [2-furyl (methoxyimino) methyl] cyclopentanecarboxylate The title compound was obtained in the same manner as in Reference Example 93 using ethyl 3- (2-furyl) -3-oxopropionate.

Ethyl 1- [2-furyl (methoxyimino) methyl] cyclopentanecarboxylate (less polar isomer: isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.04 (3H, t, J = 7.0 Hz), 1.65-1.85 (4H, m), 2.15-2.33 (4H, m), 4.03 (3H, s), 4.09 (2H , q, J = 7.0Hz), 6.45 (1H, dd, J = 1.9, 3.5Hz), 7.30 (1H, dd, J = 0.8, 3.5Hz), 7.48 (1H, dd, J = 0.8, 1.9Hz) .

Ethyl 1- [2-furyl (methoxyimino) methyl] cyclopentanecarboxylate (higher polarity isomer: isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.23 (3H, t, J = 7.0 Hz), 1.54-1.79 (4H, m), 1.84 to 2.00 (2H, m), 2.27-2.41 (2H, m), 3.90 (3H, s), 4.15 (2H, q, J = 7.0Hz), 6.42 (1H, dd, J = 1.9, 3.2Hz), 6.56 (1H, dd, J = 0.8, 3.2Hz), 7.48 (1H, dd, J = 0.8, 1.9Hz).

Example 286
N- {1- [2-furyl (methoxyimino) methyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer A)
Synthesis was performed in the same manner as in Example 282 using the compound (isomer A) obtained in Reference Example 94.

N- {1- [2-Furyl (methoxyimino) methyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.22 (3H, t, J = 7.3Hz), 1.57-1.79 (4H, m), 1.88-2.13 (2H, m), 2.29-2.53 (2H, m), 2.87 -3.05 (2H, m), 4.02 (3H, s), 4.11 (2H, q, J = 7.3Hz), 4.78-4.88 (1H, m), 5.92 (1H, d, J = 8.4Hz), 6.47 ( 1H, dd, J = 1.9, 3.5Hz), 6.86 (2H, d, J = 8.4Hz), 7.28-7.47 (8H, m).

N- {1- [2-Furyl (methoxyimino) methyl] cyclopentanecarbonyl} -4- (2,6-dichlorobenzoylamino) -L-phenylalanine
¹ H-NMR (DMSO-d ₆ ) δ; 1.46-1.67 (4H, m), 1.82-2.27 (4H, m), 2.93 (2H, d, J = 6.5Hz), 3.95 (3H, s), 4.33 -4.44 (1H, m), 6.52 (1H, dd, J = 1.9,3.5Hz), 6.92-7.05 (3H, m), 7.21 (1H, dd, J = 0.8, 3.5Hz), 7.44-7.65 (6H , m), 10.63 (1H, s), 12.69 (1H, brs).
MS m / z: 570 [M−H] ⁻ .

Example 287
N- {1- [2-furyl (methoxyimino) methyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer A)
Synthesis was performed in the same manner as in Example 282 using isomer A obtained in Reference Example 94.

N- {1- [2-furyl (methoxyimino) methyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.59-1.80 (4H, m), 1.95-2.42 (4H, m), 2.90-3.06 (2H, m), 3.64 (3H, s), 3.71 (6H, s) , 4.01 (3H, s), 4.82-4.92 (1H, m), 5.95 (1H, d, J = 8.1Hz), 6.42 (1H, dd, J = 1.9, 3.5Hz), 6.64 (2H, d, J = 8.4Hz), 6.93 (2H, d, J = 8.4Hz), 7.18 (2H, d, J = 8.4Hz), 7.27 (1H, t, J = 8.4Hz), 7.30 (1H, dd, J = 0.81 , 3.5Hz), 7.36 (1H, dd, J = 0.81, 1.6Hz)

N- {1- [2-furyl (methoxyimino) methyl] cyclopentanecarbonyl} -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer A)
¹ H-NMR (DMSO-d ₆ ) δ; 1.48-1.68 (4H, m), 1.90-2.27 (4H, m), 3.01 (2H, d, J = 6.8 Hz), 3.64 (6H, s), 3.94 (3H, s), 4.39-4.50 (1H, m), 6.52 (1H, dd, J = 1.6, 3.5Hz), 6.72 (2H, d, J = 8.4Hz), 6.96-7.06 (4H, m), 7.17-7.24 (2H, m), 7.28 (1H, t, J = 8.4Hz), 7.50 (1H, dd, J = 0.81, 1.6Hz), 12.65 (1H, brs).
MS m / z: 519 [M−H] ⁻ .

Reference Example 95
Ethyl 3-methoxyimino-2-phenylbutyrate Oxygenated ethyl 3-oxo-2-phenylbutyrate synthesized according to the method described in US-5547954 by the same production method as in Reference Example 1 gave two isomers. A mixture, ethyl 3-methoxyimino-2-phenylbutyrate, was obtained.
¹ H-NMR (CDCl ₃ ) δ; 1.19-1.33 (3H, m), 1.80 (3H, s), 3.87and3.89 (3H, 2s), 4.16-4.29 (2H, m), 4.56 and 5.21 (1H , 2s), 7.19-7.41 (5H, m).

Example 288
Synthesis of N- (3-methoxyimino-2-phenylbutyryl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine Performed using ethyl 3-methoxyimino-2-phenylbutyrate obtained in Reference Example 95 The title compound was obtained in the same manner as in Example 1.

N- (3-methoxyimino-2-phenylbutyryl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.76-1.84 (3H, m), 3.01-3.25 (2H, m), 3.65-3.89 (12H, m), 4.36-4.42 (1H, m), 4.85-5.00 ( 1H, m), 6.62-7.38 (13H, m)

N- (3-methoxyimino-2-phenylbutyryl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine

1H-NMR (DMSO-d ₆ ) δ; 1.60-1.73 (3H, m), 2.82-3.15 (2H, m), 3.60-3.79 (9H, m), 4.44-4.64 (2H, m), 6.73 (2H , d, J = 8.4Hz), 6.99-7.38 (10H, m), 8.53-8.67 (1H, m), 12.77 (1H, brs).
Mass m / z: 489 [MH] ^- .

Reference Example 96
Synthesis of ethyl 2-methoxyiminocyclopentanecarboxylate 10 g (0.064 mol) of ethyl 2-oxocyclopentanecarboxylate was dissolved in 50 mL of methanol, 6.95 g (0.083 mol) of O-methylhydroxylamine hydrochloride and pyridine 13 .9 mL (0.192 mol) was added and the mixture was allowed to stir at 40 ° C. overnight. After completion of the reaction, 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over Na ₂ SO ₄ , and then the solvent was distilled off under reduced pressure to obtain 12.3 g of a crude product (syn and anti mixture).

¹ H-NMR (CDCl ₃ ) δ; 1.21-1.32 (3H, m), 1.62-2.23 (4H, m), 2.39-2.61 (2H, m), 3.38-3.55 (1H, m), 3.82 and 3.87 ( 3H, 2s), 4.10-4.25 (2H, m).

Example 289
Synthesis of N- (2-methoxyiminocyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn and anti mixture) Ethyl 2-methoxyiminocyclopentanecarboxylate obtained in Reference Example 96 (Syn and anti mixture) 2.29 g (0.012 mol) was dissolved in ethanol 20 mL-water 2 mL mixed solvent, lithium hydroxide monohydrate 0.774 g (0.018 mol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was acidified with 5% aqueous citric acid solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over Na ₂ SO ₄ , and then the solvent was distilled off under reduced pressure to obtain 1.41 g of a residue. 247 mg (1.57 mmol) of the obtained crude product was dissolved in 60 mL of DMF, 499 mg (1.65 mmol) of EDC and 482 mg (3.15 mmol) of HOBt were added, and the mixture was stirred for 0.5 hours under ice cooling, and then 4- (2,6 -Dichlorobenzoylamino) -L-phenylalanine ethyl ester (600 mg, 1.57 mmol) was added and stirred overnight at room temperature. After completion of the reaction, water was added and extracted with ethyl acetate. The obtained organic layer was washed with a 10% aqueous Na ₂ CO ₃ solution and saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate; hexane = 1: 1), and N- (2-methoxyiminocyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester ( 550 mg of a mixture of syn and anti).

N- (2-methoxyiminocyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn, anti mixture)
¹ H-NMR (DMSO-d ₆ ) δ; 1.11-1.21 (3H, m), 1.48-1.93 (4H, m), 2.22-2.37 (2H, m), 2.81-3.09 (2H, m), 3.43- 3.55 (1H, m), 3.56 and 3.64 and3.72 and 3.74 (3H, 4s), 4.03-4.15 (2H, m), 4.34-4.51 (1H, m), 7.15-7.25 (2H, m), 7.46- 7.64 (5H, m), 8.20-8.33 (1H, m), 10.68 (1H, s).

60 mg (0.115 mmol) of N- (2-methoxyiminocyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (syn and anti mixture) in ethanol 5 mL-water 0.5 mL- Dissolved in a mixed solution of 1 mL of THF, 7 mg (0.173 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was acidified with 5% aqueous citric acid solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol: chloroform = 1: 2) to obtain 40 mg of the title compound (syn and anti mixture).

N- (2-methoxyiminocyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (syn, anti mixture)
¹ H-NMR (DMSO-d ₆ ) δ; 1.45-1.94 (4H, m), 2.22-2.48 (2H, m), 2.83-3.10 (2H, m), 3.41-3.54 (1H, m), 3.55 and 3.63 and 3.72 and 3.73 (3H, 4s), 4.33-4.51 (1H, m), 7.14-7.27 (2H, m), 7.45-7.64 (5H, m), 8.04-8.18 (1H, m), 10.67 (1H , s). MS m / z: 490 [M−H] ⁻ .

Reference Example 97
Synthesis of ethyl 2-methoxyimino-1-methylcyclopentanecarboxylate 14.04 g (0.09 mol) of ethyl 2-oxocyclopentanecarboxylate was dissolved in a mixed solution of 40 mL of THF-40 mL of DMF, and potassium hydride (35% inoil). 3.97 g (0.99 mol) and 6.16 mL (0.99 mol) of methyl iodide were added and stirred overnight at room temperature. After completion of the reaction, 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 8.28 g (0.049 mol) of ethyl 1-methyl-2-oxocyclopentanecarboxylate. 8.28 g (0.049 mol) of the obtained product was dissolved in 100 mL of methanol, 5.3 g (0.064 mol) of O-methylhydroxylamine hydrochloride and 10.5 mL (0.147 mol) of pyridine were added, and the mixture was dissolved in 50 ml. The mixture was stirred overnight. After completion of the reaction, methanol was distilled off under reduced pressure, 5% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3) to obtain 7.31 g of isomer A (lower polarity) and 1.57 g of isomer B (higher polarity) of the title compound.

Ethyl 2-methoxyimino-1-methylcyclopentanecarboxylate (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.25 (3H, t, J = 7.3 Hz), 1.40 (3H, s), 1.57-1.91 (3H, m), 2.23-2.34 (1H, m), 2.48-2.55 (2H, m), 3.86 (3H, s), 4.07-4.19 (2H, m).

Ethyl 2-methoxyimino-1-methylcyclopentanecarboxylate (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.24 (3H, t, J = 7.3 Hz), 1.39 (3H, s), 1.67-2.17 (4H, m), 2.47-2.58 (2H, m), 3.75 (3H , s), 4.08-4.25 (2H, m).

Reference Example 98
Synthesis of ethyl 2-methoxyimino-1-methylcyclohexanecarboxylate The title compound was obtained in the same manner as in Reference Example 97 using ethyl 2-oxocyclohexanecarboxylate.
Ethyl 2-methoxyimino-1-methylcyclohexanecarboxylate (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.26 (3H, t, J = 7.0 Hz), 1.31-1.93 (9H, m), 2.31-2.42 (1H, m), 3.08-3.20 (1H, m), 3.85 (3H, s), 4.11-4.25 (2H, m).

2-Methoxyimino-1-methylcyclohexanecarboxylate ethyl (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.25 (3H, t, J = 7.0 Hz), 1.36 (3H, s), 1.46-2.00 (6H, m), 2.13-2.28 (1H, m), 2.43-2.53 (1H, m), 3.73 (3H, s), 4.08-4.22 (2H, m).

Example 290
Synthesis of N- (2-methoxyimino-1-methyl-cyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer A) 2-methoxyimino- obtained in Reference Example 98 2 g (0.01 mol) of ethyl 1-methylcyclopentanecarboxylate (isomer A) is dissolved in a mixed solution of 20 mL of ethanol and 2 mL of water, 0.629 g (0.015 mol) of lithium hydroxide monohydrate is added, and Stirred overnight. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 2.08 g of 2-methoxyimino-1-methylcyclopentanecarboxylic acid lithium salt (isomer A). The obtained crude product was dissolved in 60 mL of DMF, 453 mg (2.361 mmol) of EDC and 642 mg (4.72 mmol) of HOBt were added, and the mixture was stirred for 0.5 hour under ice cooling, and then 4- (2,6-dichlorobenzoylamino)- L-Phenylalanine ethyl ester (600 mg, 1.57 mmol) was added, and the mixture was stirred overnight at room temperature. After completion of the reaction, water was added and extracted with ethyl acetate. The obtained organic layer was washed with a 10% aqueous Na ₂ CO ₃ solution and saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate; hexane = 1: 1), and N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L- Phenylalanine ethyl ester (isomer A) was obtained.
¹ H-NMR (CDCl ₃ ) δ; 1.11-1.33 (3H, m), 1.37 and (3H, 2s), 1.47-1.76 (3H, m), 2.35-2.52 (3H, m), 2.99-3.19 (2H , m), 3.73 and 3.80 (3H, 2s), 4.06-4.25 (2H, m), 4.74-4.85 (1H, m), 7.05-7.21 (2H, m), 7.27-7.45 (5H, m), 7.52 -7.61 (2H, m).

710 mg (1.33 mmol) of the obtained product was dissolved in 60 mL of ethanol and 6 mL of water, 84 mg (2.01 mmol) of lithium hydroxide monohydrate was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was acidified with 5% aqueous citric acid solution and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (methanol; chloroform = 1: 1) to obtain the title compound. 538 mg was obtained.
N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer A)

¹ H-NMR (DMSO-d ₆ ) δ; 1.24 and 1.25 (3H, 2s), 1.33-1.69 (3H, m), 2.15-2.41 (3H, m), 2.94-3.12 (2H, m), 3.73 and 3.74 (3H, 2s), 4.41-4.51 (1H, m), 7.08-7.19 (2H, m), 7.32-7.63 (5H, m), 10.68 (1H, s). MS m / z: 506 [M + H] ⁺ .

Example 291
N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer A)
Synthesis was performed in the same manner as in Example 290 using 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester.

N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.32 and 1.41 (3H, 2s), 1.45-1.73 (3H, m), 2.32-2.51 (3H, m), 2.98-3.26 (2H, m), 3.70 (6H, s), 3.72 and 3.76 (3H, 2s), 3.82 and 3.84 (3H, 2s), 4.78-4.88 (1H, m), 6.64 (2H, d, J = 8.4 Hz), 7.06-7.30 (5H, m) , 7.38 (0.5H, d, J = 7.6 Hz), 7.55 (0.5H, d, J = 7.8 Hz).

N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer A)

¹ H-NMR (DMSO-d ₆ ) δ; 1.23 and 1.26 (3H, 2s), 1.36-1.67 (3H, m), 2.14-2.40 (3H, m), 2.94-3.18 (2H, m), 3.63 ( 6H, s), 3.76 (3H, s), 4.45-4.58 (1H, m), 6.72 (2H, d, J = 8.4 Hz), 7.05-7.31 (5H, m), 7.42 (0.5H, d, J = 8.1 Hz), 7.57 (0.5H, d, J = 7.8 Hz). MS m / z: 455 [M + H] ⁺ .

Example 292
N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer B)
The reaction was carried out in the same manner as in Example 291 using ethyl 2-methoxyimino-1-methylcyclopentanecarboxylate (isomer B) obtained in Reference Example 97.

N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.22-1.33 (3H, m), 1.49 (3H, s), 1.59-1.81 (3H, m), 2.29-2.53 (3H, m), 3.05-3.19 (2H, m), 3.71 and 3.75 (3H, 2s), 4.08-4.24 (2H, m), 4.79-4.81 (1H, m), 6.90-6.98 (1H, m), 7.11-7.19 (2H, M), 7.27- 7.41 (4H, m), 7.54-7.61 (2H, m).

N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer B)

¹ H-NMR (DMSO-d ₆ ) δ; 1.27 (3H, 2s), 1.47-1.78 (3H, m), 2.31-2.48 (3H, m), 2.89-3.09 (2H, m), 3.48 and 3.54 ( 3H, 2s), 4.38-4.52 (1H, m), 7.19 (2H, d, J = 7.6 Hz), 7.26-7.31 (1H, m), 7.45-7.63 (5H, m), 10.66 (1H, s) MS m / z: 506 [M + H] ⁺ .

Example 293
N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer B)
Reaction was carried out in the same manner as in Example 290 using ethyl 2-methoxyimino-1-methylcyclopentanecarboxylic acid (isomer B) and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester obtained in Reference Example 97. To give the title compound.

N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (isomer B)
¹ H-NMR (CDCl ₃ ) δ; 1.48 and 1.49 (3H, 2s), 1.57-1.75 (4H, m), 2.28-2.52 (2H, m), 3.02-3.21 (2H, m), 3.62 and 3.71 ( 3H, 2s), 3.70 (6H, s), 3.74 and 3.75 (3H, 2s), 4.82-4.95 (1H, m), 6.64 (2H, dd, J = 8.4, 1.6 Hz), 7.03 (1H, d, J = 7.8 Hz), 7.06-7.16 (2H, m), 7.21-7.35 (3H, m).

N- (2-methoxyimino-1-methylcyclopentanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer B)

¹ H-NMR (DMSO-d ₆ ) δ; 1.27 and 1.28 (3H, 2s), 1.44-2.12 (4H, m), 2.29-2.48 (2H, m), 2.96-3.19 (2H, m), 3.46 and 3.56 (3H, 2s), 3.63 (6H, s), 4.43-4.57 (1H, m), 6.72 (2H, d, J = 8.6 Hz), 7.06-7.22 (4H, m), 7.27 (1H, t, J = 8.6 Hz), 7.38 (1H, d, J = 9.7 Hz). MS m / z: 455 [M + H] ⁺ .

Example 294
N- (2-methoxyimino-1-methylcyclohexanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer A)
The title compound was obtained in the same manner as in Example 290 using ethyl 2-methoxyimino-1-methylcyclohexanecarboxylate (isomer A) obtained in Reference Example 98.

N- (2-methoxyimino-1-methylcyclohexanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.15-1.83 (12H, m), 2.35-2.51 (1H, m), 2.99-3.23 (3H, m), 3.84 and 3.86 (3H, 2s), 4.11-4.25 ( 2H, m), 4.74-4.87 (1H, m), 6.16-6.28 (1H, m), 7.07-7.20 (2H, m), 7.25-7.47 (4H, m), 7.55-7.64 (2H, m).

N- (2-methoxyimino-1-methylcyclohexanecarbonyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine (isomer A)

¹ H-NMR (DMSO-d ₆ ) δ; 1.00-1.66 (9H, m), 2.20-2.40 (1H, m), 2.90-3.16 (3H, m), 3.74 and 3.75 (3H, 2s), 4.39- 4.55 (1H, m), 7.10-7.35 (3H, m), 7.44-7.62 (5H, m), 10.64 (1H, s). MS m / z: 520 [M + H] ⁺ .

Example 295
N- (2-methoxyimino-1-methylcyclohexanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer A)
Reaction was carried out in the same manner as in Example 290 using ethyl 2-methoxyimino-1-methylhexanetancarboxylate (isomer A) and 4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester obtained in Reference Example 98. To give the title compound.

N- (2-methoxyimino-1-methylcyclohexanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester (isomer A)
¹ H-NMR (CDCl ₃ ) δ; 1.11-1.83 (9H, m), 2.38-2.50 (1H, m), 2.93-3.28 (3H, m), 3.70 (6H, s), 3.74 and 3.75 (3H, 2s), 3.84 and 3.86 (3H, 2s), 4.74-4.86 (1H, m), 6.14-6.25 (1H, m), 6.64 (2H, d, J = 8.1 Hz), 7.07-7.16 (2H, m) , 7.23-7.32 (3H, m).

N- (2-methoxyimino-1-methylcyclohexanecarbonyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine (isomer A)

¹ H-NMR (DMSO-d ₆ ) δ; 1.01-1.66 (9H, m), 2.19-2.34 (1H, m), 2.88-3.18 (3H, m), 3.63 (6H, s), 3.75 (3H, s), 4.37-4.50 (1H, m), 6.71 (2H, d, J = 8.6 Hz), 7.01-7.32 (6H, m). MS m / z: 469 [M + H] ⁺ .

Example 296
Synthesis of N- (2,3-diphenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine α-phenylcinnamic acid (Tokyo Kasei T-1300) and 4- (2,6-dichlorobenzoyl) Amino) -L-phenylalanine ethyl ester was used and synthesized in the same manner as in Example 1b) and Example 2.

N- (2,3-Diphenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine ethyl ester
¹ H-NMR (CDCl ₃ ) δ; 1.25 (3H, t, J = 7.0Hz), 3.04 (1H, dd, J = 5.9, 13.8Hz), 3.13 (1H, dd, J = 5.4, 13.8Hz), 4.15 (2H, q, J = 7.0Hz), 4.85-4.94 (1H, m), 5.89 (1H, d, J = 7.6Hz), 6.93-7.04 (4H, m), 7.09-7.23 (5H, m) , 7.28-7.52 (8H, m), 7.83 (1H, s).

N- (2,3-Diphenylacryloyl) -4- (2,6-dichlorobenzoylamino) -L-phenylalanine
¹ H-NMR (DMSO-d ₆ ) δ; 2.86-3.14 (2H, m), 4.51-4.63 (1H, m), 6.97-7.61 (18H, m), 10.71 (1H, s), 12.86 (1H, brs).
Mass m / z: 557 [MH] ^- .

Example 297
Synthesis of N- (2,3-diphenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine α-phenylcinnamic acid (Tokyo Kasei T-1300) and 4- (2,6-dimethoxyphenyl) ) -L-phenylalanine methyl ester was used in the same manner as in Example 1b) and Example 2 to synthesize.

N- (2,3-Diphenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine methyl ester
¹ H-NMR (CDCl ₃ ) δ; 2.95 (1H, dd, J = 7.6, 14.0Hz), 3.21 (1H, dd, J = 5.4, 14.0Hz), 3.71 (6H, s), 3.74 (3H, s ), 4.84-4.94 (1H, m), 5.89 (1H, d, J = 7.6 Hz), 6.66 (2H, d, J = 8.4 Hz), 6.92-7.03 (4H, m), 7.07-7.18 (5H, m), 7.21 (2H, d, J = 8.1Hz), 7.28 (1H, t, J = 8.4Hz), 7.33-7.40 (3H, m), 7.82 (1H, s).

N- (2,3-Diphenylacryloyl) -4- (2,6-dimethoxyphenyl) -L-phenylalanine
¹ H-NMR (CDCl ₃ ) δ; 2.99 (1H, dd, J = 8.4, 14.3Hz), 3.31 (1H, dd, J = 4.9, 14.3Hz), 3.72 (6H, s), 4.73-4.85 (1H , m), 5.90 (1H, d, J = 6.5 Hz), 6.66 (2H, d, J = 8.6 Hz), 6.95-7.40 (15H, m), 7.84 (1H, s).
Mass m / z: 506 [MH] ^- .

Test example 1
α ₄ integrin inhibitory activity (method)
(1) Cell adhesion inhibition assay
Jurkat cells (ATCC, TIB-152) and CHO cells in which VCAM-1 was forcibly expressed (CHO-VCAM-1) were used in the cell adhesion assay. CHO-VCAM-1 cells were seeded in a 96-well microplate and cultured for one day. RPMI medium 1640, 25 mM HEPES + 1% FBS was used as the assay medium. The same amount of the test compound solution (final 0.1% DMSO) was added to Jurkat cells (3 × 10 ⁶ cells / mL) fluorescently labeled with BCECF-AM, and cultured for 15 minutes in a 37 ° C., 5% CO ₂ environment. 0.2 mL of this cell suspension was added to a 96-well microplate (3 × 10 ⁵ cells / well), and cultured in a 37 ° C., 5% CO ₂ environment for 30 minutes for adhesion reaction. Non-adherent cells were removed by washing and aspirating the wells three times with assay medium. Cells were lysed with 50 mM Tris-HCl, 0.1% SDS (pH 8.4) solution, and fluorescence intensity was measured with a fluorescence plate reader (excitation wavelength 485 nm, measurement wavelength 535 nm). Using the number of adherent cells to CHO cells not expressing VCAM-1 as background (BKG), the inhibition rate of adhesion to control (the number of adherent cells in wells not containing the test compound) was determined using the following formula, IC ₅₀ was calculated.

(Equation 1)
Adhesion inhibition rate (%) = (1- (number of adherent cells in well containing test compound−BKG) / (control-BKG)) × 100

(2) DNFB-induced mouse ear edema model
Ddy mice (female, 5 weeks old) were sensitized by applying 100 μL of 0.5% DNFB once a day for 2 days. Five days after this initial sensitization, 20 μL of 0.4% DNFB was applied to the right auricle of mice to induce the mice. Only the solvent (acetone / olive oil) was applied to the left ear. Forty-eight hours after induction, the auricle was removed with a punch (diameter: about 3 mm) and the weight was measured. The test compound was orally administered 24 times, 2 hours before and 6 hours after induction. The auricular swelling rate and edema inhibition rate were calculated by the following formulas.

(Equation 2)
Auricular swelling rate (%) = (A−B) / B × 100
A = right auricle (DNFB application) weight
B = left auricle (solvent applied) weight edema inhibition rate (%) = (a−b) / a × 100
a = swell rate of solvent control group
b = swelling rate of test compound administration group

Test example 2
Measurement of plasma concentration Each test compound was orally administered at 100 mg / kg, and whole blood was collected using a syringe heparinized from the abdominal aorta or vein under ether anesthesia at 0.5, 1 and 2 hours after administration. The obtained blood was centrifuged (3000 rpm, 10 min, 4 ° C.) to obtain plasma. After adding 100 μL of acetonitrile to 100 μL of the plasma sample and stirring, let stand at 4 ° C. for more than 1 hour, and then centrifuge (15,000 rpm, 10 min, 4 ° C.). It was transferred and centrifuged again (15,000 rpm, 10 min, 4 ° C.), and the obtained supernatant was used as a plasma sample for HPLC. A blank plasma sample was prepared by adding acetonitrile to 100 μL of mouse blank plasma to give a blank plasma sample, and each test compound was added to 100 μL of mouse blank plasma at 0.3, 1, 3, 10, and 30 μg / mL. The plasma sample for the calibration curve was processed as described above. The unchanged substance concentration in each sample was calculated from the calibration curve.
As a result, among the compounds of the present invention, for example, the compounds of Examples 24, 109, 153, and 224 showed a high blood concentration of 10-100 μg / mL 30 minutes after administration, and good oral absorption. found.

Obviously the present invention compounds from Tables 1 to 3 have excellent alpha ₄ integrin inhibiting activity and are orally absorbability good, useful as a therapeutic drug for a disease caused by cell adhesion.

Claims (3)

General formula (1)

(In the formula, R ¹ represents a lower alkyl group which may be substituted by ¹ to 3 halogen atoms; a lower alkyl group, a lower alkoxy group, a lower alkylsulfanyl group or a carboxyl group which may be substituted by 3 carbon atoms. Or a cycloalkyl group optionally substituted by a lower alkyl group or a lower acyl group; or a nitro group, a hydroxy group, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylsulfanyl group, a lower group 1 to 3 groups selected from an alkylsulfinyl group, a lower alkylsulfonyl group, a halogeno lower alkyl group, an aralkyloxy group, a lower alkylamino group, a dilower alkylamino group, a cyano group, a carboxyl group, and an alkylenedioxy group are substituted. An aromatic hydrocarbon group having 6 to 10 carbon atoms which may be:
Z is a halogen atom, a lower alkyl group, a lower alkoxyalkyl group which may be substituted by a halogen atom, a lower alkylsulfanylalkyl group, a lower alkoxyalkyloxyalkyl group, a cycloalkyl (3 to 5 carbon atoms) oxyalkyl group, a halogen atom 1 to 3 selected from an allyloxyalkyl group which may be substituted, a crotyloxyalkyl group which may be substituted by a halogen atom, a hydroxyalkyl group, a lower alkoxy group and a lower alkylsulfanyl group may be substituted. A good phenyl group; a benzoylamino group or a pyridinecarbonylamino group which may be substituted by 1 to 3 halogen atoms; a group of 1 to 3 selected from a halogen atom, a lower alkyl group and a lower alkoxy group may be substituted Good aralkyloxy group; morpholine-N-carboxy group or It indicates phthalimido -N- yl group:
R ² represents a hydrogen atom or a lower alkyl group:
n represents the number 0 or 1:

When n is 1, Y represents NOR ³ (R ³ is the same as above):
A represents a phenyl group, B represents a hydrogen atom or a lower alkyl group, or A and B may be bonded to form a cyclopentane ring, a cyclohexane ring or an oxane ring, and A and R ¹ may be bonded. To form a cyclopentane ring or a cyclohexane ring. )
Or a salt thereof.   The pharmaceutical which uses the phenylalanine derivative or its salt of Claim 1 as an active ingredient.   The medicament according to claim 2, which is a preventive or therapeutic agent for a disease caused by cell adhesion.