WO2003059883A1 - (4-oxopiperidin-1-yl)benzoic acid derivatives and process for their preparation - Google Patents

Abstract

Compounds represented by the general formula (|) or pharmaceutically acceptable salts or solvates thereof: (|) [wherein R1 is C1-6 alkyl, C1-6 alkoxy, halogeno, amino, nitro, or hydroxyl; n is an integer; R2 is CO2R3, hydroxymethyl, or a nitrile group; and R3 is hydrogen, C1-6 alkyl, or aralkyl]. The use of the compounds makes it possible to produce phenylpiperidine derivatives having integrin αvβ3-inhibiting activity safely at a low cost by a relatively short reaction process.

Description

 Description (4-year-old oxopiperidine-11-yl) Benzoic acid derivative and method for producing the same

[Background of the invention]

FIELD OF THE INVENTION.

The present invention relates to a useful (4 one Okiso piperidine one 1-I le) benzoic acid derivatives as synthetic intermediates of Integurinhi _{v /} 5 ₃ inhibitors. More particularly, the present invention is an I Ntegurinhi v ₃ inhibitor (2 S) -? Benzenesulfonyl § amino - 3- [3- menu butoxy one 4- {4 - (1 ₅ 4, 5, 6 Tetrahydropyrimidine-12-ylamino) piperidine-11-yl} benzoylamino] 3-methoxy-14- (4-year-old oxopiperidine-11-yl) benzoic acid useful as an intermediate in the synthesis of propionic acid Alkyl ester. Background art

Integrin _vy 5 ₃ includes many types of extracellular matrix, i.e., Vito Ronekuchin, Fuiburino one Gen, fibronectin, Osuteoponchin, Tron Bosubonjin, von Willebrand factor, and the like are also vital functions collagen deep like the onset of the disease Binds with the involved ligand to form a complex. Therefore, it is considered as targets for drug discovery, integrin Glynn of various low molecular to date; has been reported 5 ₃ inhibitors.

For example, International Publication WO 99/52872 discloses a fenubirubiperidine derivative. These derivatives showed strong activity, combines also Integurinhi _{II b?} 3 inhibitory activity, the development of a medicament has been desired. The chemical structures of these compounds are disclosed in International Publication WO099 / 52872, and their in vivo utility is disclosed in International Publication WO01 / 54726. In these, a phenylbiperidine derivative is produced via an intermediate (a-ii) by a nucleophilic substitution reaction between a piperidine ring and fluorobenzene as a first step as shown in the following scheme a. Is done. Scheme a

(R ^{1 a} ) m

DMSO, 120 ° C

1) MsCI, Et ₃ N, CH ₂ CI ₂

 1) phthalimide, DEAD, THF

2) NaN ₃ , DMF 2) Hydrazine, MeOH

_{3) Pd / C, H 2} , di old hexane

 (a-ii)

(a-iii) [In the scheme a,

R ^la , R ² \ and m can be the same as RR ² and n described below]

 However, when the phenylbiperidine derivative is produced industrially according to the scheme a, there are the following problems:

 (i) the starting materials fluorobenzene and 4-hydroxypiperidine are expensive;

 (ii) In order to carry out the nucleophilic substitution reaction for producing the compound of the formula (a-i), it is necessary to perform severe reaction conditions at 110 ° C or higher;

 (iii) In order to derive a compound of the formula (VII) to be described later from a compound of the formula (a-i), a diazo compound such as an azide intermediate or getyl azodicarboxylate, which may be operationally unsafe, is required. Must be used; and

 (iv) Production of the amine compound (a-ii) from commercially available raw materials requires a relatively long reaction step of 3 to 4 steps.

[Overview of the invention]

The present inventors have recently produced a reaction of 4-nitrobenzoic acid derivative with 1,5-dichloropenten-3-one to give 3-methoxy-4- (4-oxopyridin-1-yl). ) It has been found that benzoic acid derivatives can be obtained. Also, this 3-methoxy - 4- - (4-O Kiso piperidine 1- I le) benzoic acid derivatives used as synthetic intermediates, the production of the phenylene Rubiperi derivative having Integurinhi v5 ₃ inhibitory activity Found a way. According to this method, the desired (2S) -benzenesulfonylamino-1- (3-S) is obtained by a relatively inexpensive and relatively short reaction step under mild reaction conditions that are safer than conventional production methods. [3-Methoxy-1- 4- {4- (1,4,5,6-tetrahydropyrimidine-12-ylamino) piperidine-11-yl] benzoylamino] propionic acid can be produced. The present invention is based on these findings.

Therefore, the present invention provides a method for producing the above-mentioned fermentation using mild reaction conditions with high safety and using shorter reaction steps without using expensive raw materials as compared with the conventional production method. An object of the present invention is to provide a means for producing a rubiperidine derivative.

 According to the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

 [Where,

R ¹ represents a Ci- ₆ alkyl group, d- ₆ alkoxy group, halogen atom, protected amino group, nitro group or hydroxyl group, wherein Ci- ₆ alkyl group and Ci-6 alkoxy group The group may be substituted by a halogen atom, a Ci-6 alkoxy group, an optionally protected amino group, or a hydroxyl group,

n represents an integer of 1 to 4, and when n is 2 or more, each R ¹ may be the same as or different from each other,

R ² represents CO ₂ R ³ , an optionally protected hydroxy d- ₆ alkyl group or nitrile group, wherein R ³ represents a hydrogen atom, a d ₆ alkyl group, or an aralkyl group] .

 The process for producing a compound of the formula (I) according to the present invention comprises reacting a compound of the following formula (a) with a compound of the following formula (IV) to form an oxopiperidine ring with a nitrogen atom of the compound of the formula (a). A method comprising forming:

 (a)

 [In the formula (IV), X represents a halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom;

In the formula (a), I ¹ , R ² and n represent the same meaning as defined in the formula (I). _C According to another embodiment of the present invention, the compound of the formula (I) is synthesized There is provided a process for preparing a compound of formula (X), characterized in that it is used as an intermediate:

[Wherein R ¹ and n have the same meaning as defined in formula (I)].

 According to another aspect of the present invention, there is provided a method for producing a compound of the formula (X), comprising obtaining a compound of the formula (I) by the method for producing a compound of the formula (I) described above. It is.

 Preferably, the production method further comprises a step of subjecting the compound of the formula (I) to a reductive amination reaction to obtain a compound of the following formula (VI):

[Wherein, R ¹ and n represent the same meaning as defined in formula (I)].

 More preferably, the production method comprises reacting the compound of formula (VI) with 2-bromopyrimidine or 2-chloropyrimidine in the presence of a reaction solvent, and hydrolyzing the obtained compound. Further comprising the step of obtaining a compound of formula (VII):

[Wherein R ¹ and n have the same meaning as defined in formula (I)].

More preferably, the production method comprises reacting a compound of the formula (VII) with benzyl (2S) -N-benzenesulfonyl-1,2,3-diaminopropionate represented by the following formula (VIII): And optionally obtaining a compound of formula (IX): NHS0 ₂ Ph

 H Ku N

2Bn NHS0 ₂ Ph

[In the formula (IX), R ¹ and n represent the same meaning as defined in the formula (I)].

 Still more preferably, the production method comprises the step of subjecting a compound of the formula (IX) to a reduction reaction to simultaneously reduce and deprotect the pyrimidine ring of the compound to obtain a compound of the formula (X) .

 According to yet another aspect of the present invention there is provided the use of a compound of formula (I) as a synthetic intermediate in the preparation of a compound of formula (X).

[Specific description of the invention]

Compounds of formula (I)

In the present specification, the term “C i- ₆ alkyl group” or “( _6- alkoxy group)” as a group or a part of a group refers to a group in which the group is linear, branched or cyclic having 1 to 1 carbon atoms. 6 means an alkyl group or an alkoxy group.

The “d- ₆ alkyl group” is preferably a d- ₄ alkyl group, more preferably a d-3 alkyl group, and still more preferably a C alkyl group.

The "d- ₆ alkoxy group" is preferably a C-4 alkoxy group, more preferably a d-3 alkoxy group, and still more preferably a C- ₂ alkoxy group.

 Examples of d-6 alkyl include methyl, ethyl, n-propyl, i-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, Examples include n-hexyl and cyclohexyl.

Examples of ₆ alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, η-butoxy, i-butoxy, s-butoxy, t-butoxy and the like.

In the present specification, “halogen atom” (halide) refers to a fluorine atom, a chlorine atom Means atom, bromine atom or iodine atom.

 In the present specification, the term “optionally substituted” for an alkyl group means that one or more hydrogen atoms on the alkyl group are substituted by one or more substituents (which may be the same or different). Means that it may be done. It will be apparent to those skilled in the art that the maximum number of substituents can be determined depending on the number of substitutable hydrogen atoms on the alkyl. The same applies to the alkoxy group.

Also, in the present specification, the term “aralkyl group” as a group or a part of a group means a d- ₆ alkyl group substituted by an unsaturated 5- to 7-membered carbocyclic group. Here, in the alkyl group, one or more hydrogen atoms on the group may be substituted with one or more substituents (which may be the same or different). The alkyl moiety is preferably a d- ₄ alkyl group, more preferably C! _-3 alkyl group, more preferably C-2 alkyl group.

 Examples of the aralkyl group include a benzyl group, a diphenylmethyl group, a trityl group and a phenethyl group.

 "Optionally protected amino group" means that the amino group may be protected by any protecting group known to those skilled in the art.

 Examples of the amino-protecting group include, for example, Fmoc group (9-fluorenylmethoxycarbonyl group), tertiary-butyloxycarbonyl group, benzyloxycarbonyl group, P-methoxybenzyloxycarbonyl group, 2,2 , 2-trichloro mouth ethoxycarbonyl group, trifluoroacetyl group, aryloxycarbonyl group and trityl group.

The “optionally protected hydroxyalkyl group” means that the hydroxyl group in the hydroxy- ₆ alkyl group may be protected by any protecting group known to those skilled in the art.

Examples of hydroxyl-protecting groups include acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, benzoyl, 4-nitrobenzoyl, 3-oxobutyryl, benzyl, diphenylmethyl, triphenylmethyl, and 4-phenylmethyl. Methoxybenzyl, 3,4-dimethoxybenzyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, trimethylsilyl, Examples thereof include a tert-butyldimethylsilyl group, a triphenylsilyl group, a 2-tetrahydroviranyl, and a trimethylsilylethoxymethoxy group.

The “hydroxy d- ₆ alkyl group” is preferably a hydroxy d-4 alkyl group, more preferably a hydroxy 3 alkyl group, still more preferably a hydroxy alkyl group, and particularly preferably a hydroxymethyl group.

In the formula (I), the halogen atom which R ¹ can select is preferably a fluorine atom.

R ¹ preferably represents a d- ₆ alkoxy group or a halogen atom, more preferably represents a d-6 alkoxy group, and further preferably represents a methoxy group.

 n preferably represents an integer of 1 to 3, more preferably 1 or 2, and further preferably 1.

According to another preferred embodiment of the present invention, in formula (I), when n is 1, R ¹ is located meta to R ³ on the phenyl group.

According to yet another preferred embodiment of the present invention, in formula (I), when n is 2, R ¹ is located ortho or meta to R ³ on the phenyl group, respectively.

R ² preferably represents C〇 ₂ R ³ and a nitrile group, and more preferably represents CO ₂ R ³ .

R ³ preferably represents a hydrogen atom or a Ct- ₆ alkyl group, more preferably a d-6 alkyl group.

According to one preferred embodiment of the present invention, in formula (I), when R ¹ is a d- ₆ alkoxy group, R ² is C ₂ R ³ . According to a preferred embodiment of the distance _c present invention is preferably n 1, In the formula (I),

R ¹ is a methoxy group,

R ² is C0 ₂ R ³ ;

R ³ is a C ₆ alkyl group; and

n is 1.

According to a preferred embodiment of the present invention, the compound of the formula (I) is preferably a d-6 alkyl ester of 3-methoxy-4- (4-oxopiperidine-11-yl) benzoic acid. It is.

 Preferable examples of the compound of the formula (I) according to the present invention include 3-methoxy-4- (4-oxopiperidine-1-yl) benzoic acid methyl ester, and 3-methoxy-4- (4- Oxopiperidine-11-yl) benzoic acid ethyl ester.

 The compound according to the present invention can be a pharmaceutically acceptable salt thereof. Preferred examples of such salts include inorganic acids such as hydrochlorides, hydrobromides, hydrohalides such as hydroiodide, nitrates, perchlorates, sulfates, and phosphates. Salts, lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, aryl sulfonates such as benzene sulfonate, p-toluene sulfonate, fumarate And organic acid salts such as succinate, citrate, tartrate, oxalate and maleate and amino acid salts such as glutamate and aspartate.

 The compounds according to the invention can be solvates. Such solvates include hydrates, alcoholates (eg, methanol solvates, ethanol solvates), and ether solvates (eg, getyl ether solvates). Preparation of compounds of formula (I)

 The compounds of formula (I) according to the invention can be prepared, for example, according to Scheme 1. The starting materials or starting materials required for the synthesis of the compounds according to the present invention are commercially available or can be easily produced by a conventional method.

 Scheme 1:

a Η, Ν

a

[In the above scheme, RR ² and n represent the same meaning as defined in the above formula (I),

 X represents a halogen atom selected from the group consisting of a chlorine atom, a bromine atom and an iodine atom, preferably a chlorine atom].

 The compound of the formula (I) according to the present invention can be produced by using the compound of the formula (a) as a raw material and performing a cyclization reaction for constructing an oxopiperidine ring. That is, the compound of the formula (I) according to the present invention reacts the compound of the formula (a) with the compound of the formula (IV) to form an oxopiperidine ring together with the nitrogen atom of the compound of the formula (a). Can be produced by a method comprising:

 The reaction between the compound of the formula (a) and the compound of the formula (IV) is carried out in a solvent such as water, methanol, ethanol, isopropyl alcohol, methylene chloride or ethyl acetate at 0 to 100 ° C., preferably 55 ° C. It can be carried out by reacting at a temperature of about 65 ° C. for 1 to 24 hours, preferably 3 to 5 hours. As the solvent, methanol can be preferably used. If necessary, an acid catalyst such as p-toluenesulfonic acid (J. Chem. Soc. Perkin Trans. 1, 191, 1997) or a base catalyst such as sodium carbonate may be added to the reaction solvent. You may add further.

 According to one preferred embodiment of the present invention, the reaction of the compound of the formula (a) with the compound of the formula (IV) is carried out from the group consisting of water, methanol, ethanol, isopropyl alcohol, methylene chloride and ethyl acetate. Performed in the solvent of choice in the presence of a catalyst.

 The compound of the formula (a) used as a raw material may be a commercially available product, but a compound of the following formula (b) is obtained by, for example, deriving from nitrobenzene, and if necessary, the compound The compound may be obtained by methylating a hydroxyl group or a carboxylic acid which may be present in a product, and then reducing the 2-terminal group of the compound.

 [In the above formula,

R ² and n have the same meaning as defined in the above formula (I)].

At this time, the reduction can be performed according to a conventional method. Specifically, for example, Catalytic reduction using palladium carbon, ruthenium carbon, rhodium carbon, palladium oxide, platinum oxide, ruthenium oxide, platinum rhodium oxide complex, aluminum rhodium complex, raney-nickel, palladium black, etc. as a catalyst may be performed. The reduction may be performed using a metal such as iron, tin, and tin chloride.

Further, the compound of the formula (a) can be obtained, for example, by substituting aniline with an alkyl group, an alkoxy group, a nitro group, a hydroxyl group and a halogen atom. The compound of the formula (IV) can be obtained, for example, by the method described in J. Chem. Soc 1164, 1952, or a modified method thereof. Preferably, the compound of formula (IV) is 1,5-dichloropentan-3-one. Production of phenylbiperidine derivative (compound of formula (X)) having integrin- ₃ inhibitory activity

Using a compound of formula (I) as a synthetic intermediate, a phenylbiperidine derivative having integrin v-3 inhibitor activity, ie, a piperidine described in International Publication WO99 / 528872 The derivative (compound represented by the formula (a-iii) or the formula (X) described below) can be produced according to the following scheme 2.

Scheme 2:

 (VI)

 [In the above scheme,

RR ² and n have the same meaning as defined in the above formula (I)].

(1) Production of compound of formula (VI)

According to the present invention, the compound of the formula (I) can be obtained by the above-mentioned method for producing a compound of the formula (I). The compound of the formula (VI) can be obtained by subjecting the compound of the formula (I) to a reductive amination reaction.

 According to a preferred embodiment of the present invention, the reductive amination reaction comprises reacting a compound of formula (I) with a nitrogen source selected from ammonia, an ammonium salt, and an amine compound to render the compound inert to the reductive amination reaction. It is carried out by reduction in a solvent. More specifically, the reductive amination reaction is performed by, for example, inactivating the compound of formula (I) together with a nitrogen source such as ammonium, ammonium acetate, ammonium chloride, ammonium sulfate, ammonium carbonate, etc. Imine by using a simple solvent (for example, dioxane, tetrahydrofuran, methanol, ethanol, propanol, butanol, methylene chloride, benzene, toluene, dimethylformamide, water, etc.) alone or in combination. And reducing the resulting imine using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or a metal catalyst such as palladium carbon, palladium black, platinum oxide, etc. Reduction by hydrogenation reaction using Can it to practice. At this time, a Lewis acid such as titanium tetraisopropoxide may be further added.

 The reductive amination reaction may be a reaction via a hydroxyme. Specifically, the compound of the formula (I) is combined with hydroxylamine or hydroxylamine hydrochloride in a solvent inert to the reductive amination reaction (for example, dioxane, tetrahydrofuran, methanol, ethanol, propanol, butyl alcohol). In sodium hydroxide, methylene chloride, benzene, toluene, dimethylformamide, water, etc.) using a reducing agent such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, Alternatively, the reduction can be performed by a hydrogenation reaction using a metal catalyst such as palladium carbon, palladium black, and platinum oxide.

The compound of the formula (VI) can also be produced by subjecting the compound of the formula (I) to a two-step reaction including a reductive amination reaction. In this case, the two-step reaction is carried out by performing a reductive amination reaction using benzylamine, paramethoxypendylamine, or the like as a nitrogen source, followed by a benzyl group or a paramethoxybenzyl group. Can be removed by a hydrogenation reaction or the like.

(2) Production of compound of formula (VII)

 The compound of the formula (VII) can be produced by the method described in International Publication WO 99/52872. That is, 2-bromopyrimidine or 2-chloropyrimidine is added to the compound of the formula (VI) obtained above in the presence of a reaction solvent and reacted, and the resulting compound is hydrolyzed to give the compound of the formula (VII) ) Can be obtained. .

 More specifically, a reagent such as 2-bromopyrimidine or 2-cyclopyrimidine is converted to a reaction solvent such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, methanol, ethanol, propanol, toluene, or dioxane. By reacting at 20 ° C. to 120 ° C. in the presence of the compound, pyrimidine に can be introduced into the compound of the formula (VI). At this time, it is preferable to add an organic base such as diisopropylethylamine, triethylamine, N-methylmorpholine, pyridine, or an inorganic base such as sodium hydrogencarbonate, lithium hydrogencarbonate, sodium carbonate, or lithium carbonate as the base.

 The resulting carboxylic acid ester of the compound can then be hydrolyzed by a conventional method to produce the compound of formula (VII).

(3) Preparation of compound of formula (IX)

 The compound of the formula (IX) can be produced using the compound of the formula (VII) and the compound of the formula (VIII) according to the method described in International Publication WO099 / 52872. That is, by reacting a compound of the formula (VII) with a benzyl (2S) -N-benzenesulfonyl-1,2,3-diaminopropionate represented by the formula (VIII), the compound of the formula (IX) ) Can be obtained.

 More specifically, a compound of the formula (IX) is produced by reacting a compound of the formula (VII) by adding a compound of the formula (VIII) in the presence of a reaction solvent and further adding a peptide synthesis reagent. Can be.

Examples of the peptide synthesis reagent include dicyclohexylcarpoimide and diisopro Pilcarposimid, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, benzotriazole-1-yloxytri (dimethylamino) phosphoniumhexafluorophosphate, and the like can be exemplified as preferable examples. The reaction temperature of the above reaction is preferably from 120 to 30 ° C. Preferred examples of the reaction solvent include dimethylformamide, dioxane, tetrahydrofuran, and methylene chloride.

 In order to improve the yield of the reaction, additives such as N-hydroxysuccinimide and 1-hydroxypenttriazole, diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, and triethylamine Such a base may be further added. More preferably, benzotriazole-1-yloxytri (dimethylamino) phosphoniumhexafluorophosphate is used as a peptide synthesis reagent, dimethylformamide is used as a reaction solvent, and N-methylmorpholine as a base is used. Thereby, the yield can be further improved.

The compound of the formula (VIII) can be produced by converting the corresponding carboxylic acid (2S) -benzenesulfonyl-2,3-diaminopropionic acid into a benzyl ester by a conventional method. For example, the corresponding carboxylic acid, (2S) -benzenesulfonyl-1,2,3-diaminopropionic acid, is reacted with an acid such as benzyl alcohol and P-toluenesulfonic acid in a solvent inert to toluene (toluene or benzene). The compound of the formula (VIII) can be produced by dehydrating the mixture under reflux. Alternatively, the corresponding carboxylic acid (2S) -benzenesulfonyl-2:, 3-diaminopropionic acid is reacted with a base such as benzyl halide and cesium carbonate, or benzyl alcohol and DCC Which condensing agent can be reacted to produce the compound of the formula (VIII). C In addition, esters other than benzyl esters, for example, benzhydryl esters (International Publication WO 01/10844) The present production method is effective even if trityl ester or the like is used. Particularly, the usefulness and examples of using t-butyl ester are described in International Publication WO99 / 52872. (4) Production of compound of formula (X)

 The compound of the formula (X) can be obtained by subjecting the compound of the formula (IX) to a reduction reaction, whereby the pyrimidine ring of the compound is simultaneously reduced and deprotected. Preferably, the reduction reaction is performed in a hydrogen atmosphere, in the presence of a catalyst and an acid, in a solvent inert to the reduction reaction.

 More specifically, palladium carbon, ruthenium carbon, rhodium carbon, palladium oxide, platinum oxide, ruthenium oxide, platinum oxide rhodium complex, aluminum oxide mouth complex, Raney nickel, palladium black, etc., under a hydrogen atmosphere, In the presence of an acid such as hydrochloric acid or acetic acid, in a solvent inert to the reduction reaction (eg, methanol, ethanol, propanol, butanol, water, dioxane, tetrahydrofuran, methylene chloride, ethyl acetate, etc.) The compound of formula (X) can be produced by reducing the compound of formula (IX).

 According to a more preferred embodiment of the present invention, there is provided the above-mentioned method,

The compound of (X) is (2 S) -benzenesulfonylamino-3- [3-methoxy-4- (4-, 1,4,5,6-tetrahydropyrimidine-1-ylamino) piperidine-11- Benzoylamino] propionic acid. (2S) -benzenesulfonylamino-3- (3-methoxy-1-4- {4- (1,4,5,6,4-tetrahydropyrimidine-1-2-ylamino) piperidine having integrin _{ν- 3} inhibitory activity a compound one 1-I le} Benzoiruamino 1 production equation propionic acid (I) as a synthetic intermediate, Integurin alpha _{[nu? 3} process for preparing a compound of formula (X) to have the inhibitory activity more specifically described I do. As an example of the compound of the formula (X), (2S) -benzenesulfonylamino-3- (3-methoxy-14- {4- (1,4,5) described in WO 99/52872. 6-Tetrahydropyrimidine-1-ylamino) piperidine-11-yl} benzoylamino] propionic acid (Scheme 3 below illustrates the production of (compound of formula (II)).

† 73 Fine 171

 18 Preparation of compound of formula (V)

 As a starting material, a commercially available 3-hydroxy-4-212 benzoic acid represented by the formula (Π) can be used.

 The compound of the formula (III) (where Me represents a methyl group) is a preferred example of the compound of the formula (a) described above. It can be obtained by methylating a hydroxyl group and then reducing the nitro group.

 The compound of formula (IV) is a preferred example of the compound of formula (IV) described above.

 Regarding the reaction conditions and other compounds, the compound of formula (V) can be obtained by carrying out the reaction in accordance with the description of the above-mentioned "Production of compound of formula (I)".

 By using an aniline derivative substituted with an alkyl group, an alkoxy group, a nitro group, a hydroxyl group and a fluorine atom as a raw material instead of the compound of the formula (III), a similar cyclization reaction is carried out to obtain the compound of the formula (V) Compounds can be prepared.

 The compound of the formula (V) can be prepared by the method described in Org. Lett., 1 (8), 1261, 1999, or a modification thereof, with N, N-dialkyl-14-oxobiperidinium salt. Can also be prepared by reacting with a compound of formula (III) c Preparation of a compound of formula (VI ')

 By subjecting the 3-methoxy-4- (4-oxopiperidine-11-yl) benzoic acid methyl ester represented by the formula (V) to reductive amination reaction, Noviperidine-11-yl) -3-Methoxybenzoic acid methyl ester (compound of formula (VI ')) can be converted.

 The reaction can be carried out in accordance with the description of the above-mentioned “(1) Production of compound of formula (VI)” with respect to conditions such as reaction conditions. Preparation of the compound of formula (VI)

By reacting the compound of formula (VI,) with 2-bromopyrimidine or 2-cyclopyrimidine, 3-methoxy-14- {4- (pyrimidine-12-yla Mino) piperidine-1-yl} benzoic acid methyl ester is obtained and then hydrolyzed to give 3-methoxy-14- {4- (pyrimidine-12-ylamino) pi). Lysine-11-yl} benzoic acid (compound of formula (VII ')) can be obtained. The reaction can be carried out in accordance with the description of the above-mentioned “(2) Production of compound of formula (VI)” with respect to conditions such as reaction conditions. Preparation of the compound of formula (IX ')

 By reacting the compound of the formula (νΐΓ) with (2S) -—- benzenesulfonyl 2,3-diaminopropionic acid benzyl ester (compound of the formula (VIII)), (2S) -benzenesulfonyl 1-amino-3- (3-methoxy-4- (4-pyrimidine-2-ylamino) piperidin-1-yl) benzoylamino] propionic acid benzyl ester (compound of formula (II)) Can be.

 The reaction can be carried out according to the description of the above-mentioned “(3) Production of compound of formula (IX)” with respect to conditions such as reaction conditions. Preparation of the compound of formula (Χ ')

 The desired (2S) -benzenesulfonylamino-3- (3-methoxy) compound is obtained by subjecting the compound of the formula (IX ') to a reduction reaction to reductively deprotect and simultaneously reduce the pyrimidine ring. 1-41 {4— (1,4,5,6-tetrahydropyrimidine-12-ylamino) piperidine-11-yl} benzoylamino] propionic acid (compound of formula (Χ ′)) .

 The reaction can be carried out in accordance with the description of the above-mentioned “(4) Production of compound of formula (X)” with respect to conditions such as reaction conditions. Uses of the compound of formula (X)

Phenylene Rubiperijin derivative obtained by using the compound of formula (I) according to the invention (compound of formula (X)) is to have a Integurinhi _[nu 5 ₃ inhibitory activity, International Publication W_〇 99/52872 discloses, And International Publication WO 01/54726. Also use this compound as an integrin 3 inhibitor It will be clear to those skilled in the art, by reference to these publications, about what to do and how to prepare pharmaceutical compositions using this compound. Example]

 Hereinafter, the present invention will be described specifically with reference to Examples, but the present invention is not limited thereto. Example 1: 3-Methoxy-4- (4-oxopiperidine-11-yl) methyl benzoate

DMF (9.5 L) is dissolved in 3-hydroxy-1-412 benzoic acid (950 g, 5.19 mol 1), and potassium carbonate (1.44 kg, 10.5 mol 1) is further added. And suspended. Methyl iodide (2.20 kg, 15.5 mol) was added thereto, and the mixture was stirred at 25 ° C to 30 ° C for 22 hours. After completion of the reaction, the resulting reaction suspension was slowly added to water (17 L) at 13 ° C while maintaining the temperature at 25 ° C or lower. The resulting precipitate was collected by filtration, washed with water (6.8 L), and dried to obtain 3-methoxy-4-nitrobenzoic acid methyl ester (1.04 kg: 4.92 mol) _c 3 Physicochemical properties of 4-methoxy-4-nitrobenzoic acid methyl ester:

 (1) Color and shape: light yellow solid

(2) Molecular formula: C ₉ H ₉ N 0 ₅

(3) Mass spectrum (E IMS): m / z 211 M ⁺

(4) ^J H NMR spectrum (400MHz, CD Cla) δ (ppm):

3. 97 (3H, s, OM e), 4. 02 (3H, s, OMe), 7. 70 (1H, dd, C 6 H 3), 7. 76 (1H, d, C 6 H 3) , 7.84 (1H, d _;

C 6 H 3)

Dioxane (5.0 L) and methanol (5.0 L) were added to 3-methoxy-4-nitrobenzoic acid methyl ester (1.00 kg, 4.74 mol) and dissolved. In a reaction vessel purged with nitrogen, 10% palladium carbon (wet) (50.0 g as dry) was added to the obtained solution, suspended in water (1.0 L) in advance, and the solution was added under 1 atm of hydrogen. The mixture was vigorously stirred for 12 hours under the conditions of 35 ° C to 45 ° C. Catalyst After filtration, the obtained filtrate was washed with a 1: 1 mixed solvent of dioxane and methanol (2.0 L), and the filtrate and the washing solution were combined and concentrated under reduced pressure until the remaining amount was 2.0 L. . Water (6.7 L) was added to the suspension and filtered. The obtained solid was collected by filtration, washed with ice (5.0 L), and dried to obtain methyl 4-amino-3-methoxybenzoate (81 1 g, 4.48 mol). .

 Physical and chemical properties of 4-amino-3-methylbenzoic acid methyl ester (compound of formula (III)):

 (1) Color and shape: light yellow solid

 (2) Molecular formula: C ^ HnNC

(3) Mass spectrum (E IMS): m / z 18 1 M ⁺

^! (4) H NMR spectrum _{(400MH z, CD C 1 3} ) δ (ppm):

3. 8 6 (3 H, s , OMe), 3. 9 0 (3 H, s, 〇_Me), 6. 6 6 (1 H , d, C 6 H 3), 7. 46 (1 H, d, C ₆ H ₃ ), 7.55 (1 H, dd ₃

C 6 H 3)

 Methylene chloride methylene (1.7 L) was added to 3-chloropropionyl chloride (1.40 kg, 11.0 mol) and dissolved, and the mixture was cooled to 130 ° C. To this, aluminum chloride (1.87 kg, 14.3 mol) was slowly added so as not to exceed 0 ° C, and the mixture was stirred at 10 ° C to 20 ° C for 6 hours while blowing ethylene gas. Water (5.8 L), concentrated hydrochloric acid (47 Oml), previously cooled to 4 ° C, and methylene chloride

The reaction mixture was slowly poured into the (1.4 L) mixture while keeping the temperature at 13 ° C or lower. The organic layer was separated, the aqueous layer with methylene chloride (1. 4L) 1 times washed _c combined organic layers twice with ice (1. 6 L), 2 times with water (3. 0 L) Wash, then dry over anhydrous magnesium sulfate (3 10 g), concentrate under reduced pressure, 1,5-dichloromouth pentane-3-one (1.74 kg) (compound of formula (IV,)) I got

Methanol (8.0 L) was added to 4-amino-3-methylbenzoic acid methyl ester (804 g, 4.44 mol) and suspended, and the mixture was heated to 60 ° C and dissolved. To this was added 1,5-dichloropentan-3-one (1.44 kg, 9.28 mol 1), and the mixture was stirred for 4 hours. The obtained reaction mixture was poured into water (16 L), and the insoluble matter was filtered using celite. The filtrate was concentrated under reduced pressure until the remaining amount was 8.5 L. 0171

 During the reaction, the by-product dimethyl acetate was hydrolyzed. Activated carbon in the resulting aqueous solution

(80 g) and stirred in a water bath at 50 ° C. for 30 minutes. After filtering the activated carbon, it was washed with ice (2.0 L). Sodium hydrogen carbonate (1.14 kg, 13.6 mol 1) was added to the aqueous solution obtained by combining the filtrate and the washing solution to adjust the pH to 7.0. The obtained solid was collected by filtration, washed with water (3.2 L), dried, and 3-methoxy-4- (4-oxopiperidine-11-yl) benzoic acid methyl ester (1. 01kg, 3.84 mo 1) was obtained.

 Physicochemical properties of 3-methoxy-4- (4-oxobiperidin-1-yl) methyl ester benzoate (compound of formula (V)):

 (1) Color and shape: colorless solid

(2) Molecular formula: C ₁₄ H ₁₇ N0 ₄

(3) Mass spectrum (E IMS): m / z 263 M ⁺

(4) ^J H NMR spectrum (400 MHz, CD C Is) δ (ppm):

_{2. 64 (4 H 5 t,} piperidine), 3. 46 (4 H 5 t, piperidine),

3. 90 (3H, s, OMe ), 3. 96 (3H, s, OMe), 6. 94 (1 H, d, CeHs), 7. 56 (1 H, d, CsH 3), 7. 65 (1H, dd, C 6 H 3) Example 2: 3-Methoxy-4- (4-oxopiperidine-1-yl) Ethyl benzoate

4 one amino-3-methoxybenzoic acid methyl ester (1. 19 g, 6. 55m mo 1) was added with ethanol (20ml) were suspended, here _c dissolved by heating to 60 ° C, 1, 5 —Dichloropentan-3-one (1.50 g, 9.70 mmo 1) was added, and the mixture was stirred for 15 hours. After the obtained reaction mixture was concentrated under reduced pressure, ethyl acetate (2 Oml) and a 2.5% aqueous sodium hydrogen carbonate solution (6 Oml) were added, and the mixture was extracted twice with ethyl acetate. The combined organic layers were washed with 5% sodium hydrogen carbonate solution (15 ml), dried over anhydrous magnesium sulfate, concentrated under reduced pressure and the _c resulting residue and stirred for 4 h by adding 2-propanol (10 ml). The obtained crystals are collected by filtration, washed with 2-propanol, and then washed with 3-methoxy-4- (4-oxo). Sopiperidine-1-yl) benzoic acid ethyl ester (483 mg, 1.76 mmol) was obtained.

 3-Methoxy 4- (4-oxopiperidine) Physicochemical properties of ethyl benzoate:

 (1) Color and shape: colorless solid

(2) Molecular formula: C ₁₅ H ₁₉ N0 ₄

(3) ¹ H NMR spectrum (400 MHz, CD Cla) δ (ppm):

1.39 (3H, t, Et), 2.64 (4H, t, piperidine), 3.46 (4H, t, piperidine), 3.97 (3H, s, OMe), 4.37 (2H , q, E t), 6. 94 (1H, d, C 6 H 3), 7. 56 (1H, d, C 6 H 3), 7. 66 (1 H, dd, CeHs) example 3: ( 2 S) -benzenesulfonylamino-3- (3-methoxy-4- (4- (1,4,5,6-tetrahydropyrimidine-1-ylamino) pyridin-1-1-yl} benzoylamino) propion acid

Preparation of (1 -a) 4- (4-aminobiperidin-1-yl) — 3-methoxybenzoic acid methyl ester (compound of formula (VI ³ )) (1)

3-Methoxy-4- (4-oxopiperidin-1-yl) benzoate methyl ester (16. Omg: 0.0608 mol) was added to methanol (0.5 ml) and dissolved. In the reaction vessel was purged with nitrogen, the reaction solution, 10% palladium on carbon (4. 8 mg) was added, an additional 28% aqueous ammonia (0. 1 ml) to _c resulting reaction solution was added, under 1 atmosphere of hydrogen, Stir vigorously at room temperature for 15 hours. The catalyst was filtered and washed with methanol. The filtrate and the washing were combined and concentrated under reduced pressure. The resulting residue was purified using preparative silica gel thin-layer chromatography (developing solvent: methylene chloride: methanol: concentrated aqueous ammonia = 9: 1: 0.3) to give 4- (4-aminopyridine). Bae lysine - give 1-I le) -3- main butoxy-benzoic acid methyl ester _{(13. 9mg 3 0. 0529 mmo 1} ) and by-product (2. 4mg, 0. 00486 mm o 1).

4- (4-Aminobiperidine-11-yl) -1-3-Methoxybenzoic acid methyles Physicochemical properties of ter (compound of formula (VI ³ )):

 (1) Color and shape: colorless solid

(2) Molecular formula: C ₁₄ H _2. N ₂ 0 ₃

(3) ^J H NMR spectrum _{(400MHz, CD C 1 3)} δ (ppm):

1.57 (2 H, ₃ d, piperidine), 1.95 (2 H, br d, piperidine),

2.70 (2H, dt, piperidine), 2.82 (1H, tt, piperidine),

3.57 (2 H, br d, piperidine), 3.88 (3H, s, OMe), 3.92 (3H, s, OMe), 6.91 (1 H, d, C ₆ H ₃ ), 7. 50 (1 H, d, CeHs), 7. 65 (1 H 3 dd, CeHs)

Preparation of (1-b) 4- (4-aminobiperidine-1-yl) -13-methoxybenzoic acid methyl ester (compound of formula (VI)) (2)

 3-Methoxy-4- (4-oxopiperidine-11-yl) Methylester benzoate (41.3 g, 157mmo1) was suspended by adding methanol (500ml). Cooled to C. To this, pendylamine (25 ml, 229 mmo 1) was added, and sodium triacetoxyborohydride (67.3 g, 317 mmo 1) was further added, followed by stirring at 10 ° C. or lower for 2.5 hours. To the obtained reaction mixture, 1 M hydrochloric acid (500 ml) was added at 5 ° C, and concentrated hydrochloric acid (200 ml) was further added. The precipitated solid was collected by filtration, washed with ethyl acetate (400 ml), dried, and dried with 4- (4-benzylaminobiperidine-11-yl) -3-methylbenzoic acid methyl ester hydrochloride ( 64.7 g, 97%).

 Physicochemical properties of methyl 4- (4-benzylaminobiperidine-1-yl) -1-methoxybenzoate hydrochloride:

 (1) Color and shape: colorless solid

(2) Molecular formula: C ₂₁ H ₂₆ N ₂ 0 ₃

(3) Mass spectrum (FABMS): m / z 355 (M + H) ⁺

(4) ^X NMR spectrum (400MHz, CD ₃ OD) (as hydrochloride) (5 (ppm): 2.40 (2H, brq, piperidine), 2.56 (2Η, brd, piperidine) , 3.75 (3H, m, piperidine), 3.89 (2 H, br d, pi peridine), 3. 94 (3 H 3 s, OMe), 4. 09 (3 H, s, OMe), 4. 35 (2 H, s, CHzCeHs), 7. 47 (3 H, m, CeHa or C ₆ H ₅ ), 7.60 (2H, m, C ₆ H ₃ or CeHs), 7.80 (3H, m, C ₆ H ₃ or CeHs)

The 4- (4-benzylaminobiperidine-11-yl) -13-methoxybenzoic acid methyl ester hydrochloride (642 mg, 1.50 mmol) obtained above was treated with methylene chloride (25 ml). ) And washed with a saturated aqueous solution of sodium hydrogencarbonate (40 ml). The separated aqueous layer was extracted with methylene chloride (10 ml), and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated to give 4- (4-benzylaminonopiperidine-11-yl) -13-methyl Toxic benzoic acid methyl ester (468 mg, 1.32 mmo 1) was obtained. Next, this compound (52.3 mg, 0.148 mmol) was dissolved in methanol (1.0 ml), and 10% palladium on carbon (5.9 mg) was added. The reaction mixture was stirred under 1 atmosphere of hydrogen for 15 hours. The resulting reaction solution was concentrated and filtered to give the 4 one (4 Aminobiperijin one 1-I le) Single 3 main butoxy benzoic acid methyl ester _{(38. 9 mg 3 0. 147 mmo} l).

(1-c) 4- (4-aminobiperidine-1-yl) -13-methoxybenzoic acid methyl ester (compound of formula (VD)) (3)

3-Methoxy-14- (4-year-old oxopiperidine-11-yl) benzoate methyl ester (99. Omg, 0.376 mmo 1) was dissolved in dioxane (2 ml). To this was added hydroxylammonium chloride (29.6 mg, 0.414 mmol) and water (0.1 ml), and the mixture was stirred at room temperature for 1.5 hours. Methanol (0.1 ml) was added to the obtained reaction solution, which was used for the next reduction reaction without isolation of the hydroxyme form. Platinum oxide (10 mg) was added to the reaction solution, and the mixture was vigorously stirred at room temperature under 1 atm of hydrogen for 20 hours. Then the catalyst was filtered and washed with methanol. The filtrate and the washings were combined and concentrated under reduced pressure. The obtained residue was diluted with methylene chloride (10 ml) and extracted with water (20 ml × 2). To the aqueous layer was added a 2M aqueous solution of potassium carbonate (10 ml), and the mixture was extracted with ethyl acetate (20 ml × 2). The organic layers are combined and concentrated under reduced pressure to give 4- (4-aminobiperidine-11-yl)-3-methoxyamine. Methyl benzoate (89. Omg, 0.337 mmo 1) was obtained.

(2) Add 4-butanol (1.35 L) to 4- (4-aminobiperidine-11-yl) -1-3-methoxybenzoic acid methyl ester (270 g, 1.02 mol 1) and dissolve. —Black mouth pyrimidine (117g, 1.02mo1) and sodium hydrogencarbonate (171g, 2.04mo1) were added and suspended. The reaction mixture was stirred at 100 ° C .; 110 ° C. for 27 hours, cooled to 50 ° C., and methanol (2.7 L) was added. The suspension was poured into water (13.5 L). The resulting solid is filtered and washed with water

(1.0 L), dry and wash with 3-Methoxy-4- {4- (pyrimidine-2-ylamino) piperidine-1-yl} benzoic acid methyl ester and 3-Methoxy-4 A mixture of butyryl benzoic acid (297 g, 0.867 mol) was obtained from 1- (4- (pyrimidine-2-ylamino) piperidine-11-yl) benzoate.

 3-Methoxy-1 4- {4- (pyrimidine-2-ylamino) piperidine-1-yl} Physicochemical properties of methyl benzoate:

 (1) Color and shape: colorless solid

(2) Molecular formula: C ₁₈ H ₂₂ N ₄ 0 ₃

(3) Mass spectrum (ES IMS): m / z 343 (M + H) ⁺

(4) ^X H NMR spectrum _{(400MHz, CD C 1 3)} d (ppm):

1.75 (2H, dq, piperidine), 2.20 (2H, brd, piperidine), 2.86 (2H, ddd, piperidine), 3.58 (2H, brd, piperidine), 3. 89 (3H, s, C0 2 Me), 3. 93 (3H, s, CeHsOMe), 4. 02 (1H, m, piperidine), 6. 54 (1H, t, pyrimidine), 6. 94

_{(1H, d, C 6 H} 3 CO), 7. 51 (1 H, d, CeHaCO), 7. 64 (1 H, dd, CeHsCO), 8. 29 (2H, d, pyrimidine)

 3-Methoxy-1- (4- (pyrimidine-2-ylamino) piperidine-1-yl) Methyl benzoate (290 g, 0.847mo 1) in methanol

(1.45 L) was added and dissolved, 1.2 M aqueous sodium hydroxide solution (1.45 L) was added, and the mixture was stirred at 50 ° C for 2 hours. The obtained reaction solution was concentrated under reduced pressure to a residual amount of 1.45 L, and water (580 ml) was added thereto, and further concentrated under reduced pressure to a residual amount of 1.45 L. 7 ° to the reduced the ₉ resulting residue C;.. ~ 1 0 ° ( in 2] ^ HCl (adjusted to 8 5 5 ml) was added pH 4 5 water was added (5 9 5 ml) to the mixture The resulting precipitate was collected by filtration, washed with water (60 Oml), dried, and dried with 3-methoxy-14- {4- (pyrimidine-12-ylamino) piperidine-1-yl} benzoic acid (272 g , 0.8 2 8 mo 1).

 3-Methoxy-1- 4- (pyrimidine-2-ylamino) piperidine-11-yl} Benzoic acid (compound of formula (VII ')) physicochemical properties:

 (1) Color and shape: colorless solid

(2) Molecular formula: C ₁₇ H _2Q N ₄ 0 ₃

(3) Mass spectrum (ES IMS): m / z 32 9 (M + H) ⁺

(4) ^J H NMR spectrum (400 MHz, DMS 0-_d ₆ ) δ (m): 1.64 (2 H, dq, piperidine), 1.93 (2 H, br d, piperidine), 2. 70 (2H, brt, piperidine), 3.50 (2H, brd, piperidine), 3.83 (3H, s, CeHaOMe), 3.85 (1H, m, piperidine) ), 6.55 (1 H ₃ t, pyrimidine), 6.93 (1 H, d, C ₆ H ₃ CO), 7.41

(1 H, d, CeHs CO), 7.49 (1 H, dd, C ₆ H ₃ CO), 8.27

(2 H, d, pyrimidine)

(3) Toluene (22 ml) was suspended in (2S) -N-benzenesulfonyl- 1,2,3-diaminopropionic acid (3.00 g, 12.3 mmol 1), and benzyl was added. Add alcohol (12.7 ml, 12.3 mmo 1) and p-toluenesulfonic acid hydrate (2.57 g, 12.9 mmo 1) and dehydrate with Dean-Stark. While refluxing for 7 hours. 1 M hydrochloric acid (40 ml) was added to the obtained reaction mixture, and the mixture was washed three times with hexane (40 ml). The obtained aqueous layer was cooled to 4 ° C and adjusted to pH 9.0 using sodium hydroxide. The mixture was extracted three times with ethyl acetate (40 ml). The combined organic layer was dried using anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: methylene chloride-methanol = 7: 1) to give (2S) -N-benzenesulfonyl-2,3-diaminopropionic acid benzyl ester ( 3.99 g, 1 1. 9mmo 1) was obtained.

 Physicochemical properties of (2S) —N-benzenesulfonyl 2,3-benzylaminopropionate benzyl ester (compound of formula (viir)):

 (1) Color and shape: colorless amorphous

(2) Molecular _{formula: C 16 H 18 N 2 0} 4 S

(3) ^! H NMR spectrum (400MHz, CD ₃ OD) δ (ppm):

2. 98 (1H, dd, CONHCJ ^ CH), 3. 05 (1 H, dd, CON HCH..2CH), 3. 96 (1H, dd, CONHCH 2 CIi), 4. 97 (2 H, s , CH.2C6H5), 7.20 (2H, m, CH ₂ C ₆ J1 ₅ ), 7.35 (3H, m, CH ₂ C6ii5), 7.45 (2 H ₃ t, S0 ₂ C ₆ Ji ₅ ), 7.55 (1H, t, S OzCelis), 7.83 (2H, m, S O2C6H.5)

(4) 3-Methoxy-1- (4- (pyrimidine-2-ylamino) piperidine-1-yl) benzoic acid (12.6 mg, 0.0385 mmo 1) and dimethylformamide (0.5 ml) ) And suspended. (2S) _N-benzenesulfonyl-1,2,3-diaminopropionic acid benzyl ester (11.7 mg, 0.035 Ommo 1) and diisopropylethylamine (7 3 and 0.0420 mmo 1) were added and the mixture was cooled to 4 ° C. To this was added benzotriazol-1-yloxytri (dimethylamino) phosphoniumhexafluorophosphatate (18.6 mg, 0.042 Ommo 1), and the mixture was stirred at room temperature for 17 hours. Then, the reaction was stopped by adding saturated sodium hydrogen carbonate (10 ml), and ethyl acetate was added.

(20 ml) three times. The combined organic layer was washed twice with a mixed solution of saturated saline (5 ml) and water (5 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified using preparative silica gel thin-layer chromatography (developing solvent: hexyl monoacetate = 1: 4) to give (2S) -benzenesulfonylamino-3- (3-me Toxic-1-41- (pyrimidine-1-ylamino) piperidin-1-yl} benzoylamino] propionate benzyl ester (15.9 mg, 0.0247 mmo 1) was obtained.

(2S) dibenzenesulfonylamino-3 3-methoxy-1 4--14-dipyri Physicochemical properties of benzyl-2-propionate (compound of formula (IX '))

 (1) Color and shape: colorless oil

(2) Molecular _{formula: C 33 H 36 N 6 0} 6 S

(3) 'Ε NMR scan Bae spectrum _{(400 MHz, CD C 1 3} ) δ (ppm):

1.76 (2 H, br dq ₃ piperidine), 2.20 (2 H, br d, piperidine),

2.84 (2H, brd, piperidine), 3.54 (2H, brd, piperidine),

3. 66 (1 H, ddd, CONHCH 2 CH), 3. 89 (1H, m, CONHC iI 2 CH), 3. 92 (3 H, s, CeHsOMe), 4. 01 (1H, m, piper idine ), 4 · '1 1 ( 1H, m, CONHCH2CH), 5. 02 (2 H 3 dd, CH2C6H5), 6. 53 (1 H, t, pyrimidine), 6. 9 1 (1 H, d, Ce HaCO), 7.21 (3H, m, CHzCeHs), 7.31 (3H, m, CH2 Cells and CeHaCO), 7.36 (1H, d, CeHsCO), 7.43 (2H, brt, S0 ₂ C ₆ ) ₅ ), 7.53 (1H, brt, S O2C6H.5), 7.83

(2 H, m, S OzCells), 8.29 (2 H, d, pyrimidine)

(5) (2S) -benzenesulfonylamino-3- (3-methoxy-14- {4- (pyrimidine-2-ylamino) piperidine-1-yl} benzoylamino] propenyl acid benzyl ester (11. Omg, 0.0171 mmo 1), dioxane (0.2 ml) was added and dissolved, and 10% palladium on carbon (1 lmg) and acetic acid (4.9 l, 0.00853 mmo 1) were added. And stirred vigorously at room temperature under 1 atm of hydrogen for 24 hours. After insolubles were filtered from the obtained reaction solution, the mixture was washed with methanol (2 ml), and the filtrate and the washing solution were combined and concentrated under reduced pressure. The obtained residue was purified using silica gel thin layer chromatography for separation (developing solvent: methylene chloride-ethanol solution-concentrated aqueous ammonia = 8: 8: 1: 1), and then Sephadex LH-20 ( (2S) -benzenesulfonylamino-3- [3-methoxy-1 4-1 {4- (1,4,5,6-tetrahydrovirimidine-1-2-ylamino)] ) Piperidine-1-yl} benzoylamino] propionic acid (6.1 mg, 0.0109 mmo 1) was obtained. (2S) -benzenesulfonylamino-3- (3-methoxy-4- {4- (1,4,5,6-tetrahydropyrimidine-2-ylamino) pyridin-1-yl) benzoylamino Ίpropion Physicochemical properties of the acid (compound of formula (Χ ')):

(1) Color and shape: colorless solid

(2) Molecular formula: C ₂₆ H ₃₄ N ₆ 〇 ₆ S

(3) Mass spectrum (FABMS): m / z 559 (M + H) ⁺

 (4) Έ NMR spectrum (400MHz, CDsOD) δ (pm):

1.68 (2 H, br dq, piperidine), 1.96 (2 H, quintet, tetrahydro pyrimidine), 1.99 (2 H, m, piperidine), 2.72 (2 H, br t, pi peridine) ), 3.37 (4H, t, tetrahydropyrimidine), 3.45 (3H, m, piperidine), 3.56 (1H, dd, C ONH CH.2 CH), 3.68 (1H, dd) , CONHCIizCH), 3. 75 (1H , dd, CONHCH2C), 3. 9 1 (3 H, s, C 6 H 3 OMe), 6. 9 5 (1 H, d, C 6 H 3 C 0), 7. 39 (1 H, dd, C 6 H 3 CO), 7. 43 (1 H, d, CeHaC 0), 7. 48 (2H, dt, C 6 Dan _{5), 7. 55 (1 H} , br t, CeJHs), 7.87 (2 H, m, C ₆ H ₅ )

Claims

Scope of Claim 1. Compound of the following formula (I) or a pharmaceutically acceptable salt or solvate thereof

 [Where, R ¹ represents a d- ₆ alkyl group, Ci- ₆ alkoxy group, halogen atom, protected amino group, nitro group or hydroxyl group, wherein the d-6 alkyl group and d-6 alkoxy group The group may be substituted by a halogen atom, a Ci- ₆ alkoxy group, an optionally protected amino group, or a hydroxyl group, n represents an integer of 1 to 4, and when n is 2 or more, each R ¹ may be the same as or different from each other, R ² is C0 ₂ R ^3, represents an optionally protected hydroxy ds alkyl group or a tolyl group, wherein R ³ is a hydrogen atom, C - represents an _alkyl group or Araruki group,]! . 2. The compound according to claim 1, wherein the halogen atom which R ¹ can select is a fluorine atom. 3. The compound according to claim 1, wherein R ² is a hydroxy- ₆ alkyl group which can be selected, is a hydroxymethyl group. 4.: R ¹ is a methoxy group, R ² is C0 ₂ R ³ ; R ³ is a d- ₆ alkyl group, and  n is 1, A compound according to claim 1. 5.3 3-Methoxy 4- (4-oxopiperidin-1-yl) benzoic acid methyl ester and 3-methoxy-14- (4-one-year-old pipepiperidin-1-yl) benzoic acid ethyl ester The compound according to claim 1, which is selected from the group consisting of: or a pharmacologically acceptable salt or solvate thereof. 6. A process for producing a compound of formula (I) according to claim 1, wherein  Reacting a compound of the following formula (a) with a compound of the following formula (IV) to form an oxopiperidine ring with a nitrogen atom of the compound of the formula (a): X

 (IV) (a)  [In the formula (IV), represents a halogen atom selected from the group consisting of a chlorine atom, a bromine atom, and an iodine atom; In the formula (a), ¹ , R ² and n represent the same meaning as defined in the formula (I)] _c 7. Catalytic reaction of the compound of formula (a) with the compound of formula (IV) in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, methylene chloride and ethyl acetate. 7. The method of claim 6, wherein said method is performed in the presence. 8. The method according to claim 6 or 7, wherein the compound of formula (IV) is 1,5-dichloropentan-3-one. 9. The method according to any one of claims 6 to 8, wherein the compound of the formula (a) is a compound represented by the following formula (III):

, ■ '■ ノ [Wherein Me represents a methyl group]. 10. The method further comprising the step of methylating the hydroxyl group and the carboxylic acid using 3-hydroxy-4,2-nitrobenzoic acid as a raw material and reducing the nitro group to obtain a compound of the formula (III). The method described in. 11. A process for the preparation of a compound of formula (X), comprising obtaining a compound of formula (I) by the method of any one of claims 6 to 10.  H H

[Wherein R ¹ and n have the same meaning as defined in formula (I)]. 12. The method according to claim 11, further comprising the step of subjecting the compound of formula (I) to a reductive amination reaction to obtain a compound of formula (VI):

[Wherein, R ¹ and n represent the same meaning as defined in formula (I)]. 13. The reductive amination reaction reduces the compound of the formula (I) together with a nitrogen source selected from ammonia, an ammonium salt and an amine compound in a solvent inert to the reductive amination reaction. 13. The method of claim 12, wherein the method is performed by: 14. 2-bromopyrimidine or 2-chloropyrimidine is added to the compound of the formula (VI) in the presence of a reaction solvent to cause a reaction, and the resulting compound is hydrolyzed to give a compound of the following formula (VII) 14. The method of claim 12 or 13, further comprising the step of obtaining a compound of the formula:

[Wherein R ¹ and n have the same meaning as defined in formula (I)]. 15. The reaction solvent is an organic base selected from diisopropylethylamine, triethylamine, N-methylmorpholine, or pyridine, or an inorganic base selected from sodium hydrogencarbonate, lithium hydrogencarbonate, sodium carbonate, or lithium carbonate. 15. The method c according to claim 14, comprising further adding a base. 16. By reacting a compound of the formula (VII) with (2S) -N-benzenesulfonyl 2,3-diaminopropionate benzyl ester of the following formula (VIII), 16. The method of claim 14 or 15, further comprising the step of obtaining a compound of IX).

[In the formula (IX), R ¹ and n represent the same meaning as defined in the formula (I)]. 17. further comprising the step of subjecting the compound of the formula (IX) to a reduction reaction to simultaneously reduce and deprotect the pyrimidine ring of the compound to obtain a compound of the formula (X) 17. The method of claim 16, wherein the method comprises: 18. The method according to claim 17, wherein the reduction reaction is carried out in a solvent inert to the reduction reaction in a hydrogen atmosphere in the presence of a catalyst and an acid. 19. The compound according to any one of claims 11 to 18, wherein the compound of formula (I) is 3-methoxy-4- (4-oxopiperidine-11-yl) benzoic acid methyl ester. Method. 20. When the compound of formula (X) is (2S) -benzenesulfonylamino-3- [3-methoxy-14- {4- (1,4,5,6-tetrahydrovirimidine-12-ylamino) 20. The method according to any one of claims 11 to 19, which is [piperidine-11-yl} benzoylamino] propionic acid.