KR101432318B1 - Method for producing phenoxypyridine derivative - Google Patents

Abstract

The present invention relates to a condensing agent in the presence Ⅱ formula [wherein, R ¹ is (1) get a good azetidin-1-yl group a substituent, (2) good blood which may have a substituent pyrrolidine-1-yl group, (3 Or a piperidin-1-yl group which may have a substituent, and R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a fluorine atom, or Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, and reacting a salt thereof with a compound represented by the following formula (III): wherein R ⁶ represents a hydrogen atom or a fluorine atom. ⁴ and R ⁵ and R ⁶ have the same meanings as defined above].

Description

METHOD FOR PRODUCING PHENOXYPYRIDINE DERIVATIVE [0002]

The present invention relates to an antitumor agent having a hepatocyte growth factor receptor (abbreviated as " HGFR ") inhibitory action, an antitumor action, an angiogenesis inhibitory action, (Hereinafter abbreviated as " present compound ") and a production intermediate thereof in the production method thereof.

Overexpression of HGFR has been reported in various tumors such as pancreatic cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor and ovarian cancer (Non-Patent Document 1). Since HGFR expressed in these tumor cells is always stimulated or stimulated by hepatocyte growth factor (hereinafter abbreviated as " HGF ") to induce autophosphorylation of tyrosine kinase in the intracellular region, , Invasion or metastatic hyperplasia).

In addition, HGFR is also expressed in vascular endothelial cells, and HGF stimulates HGFR to promote proliferation and migration of vascular endothelial cells, and thus it has been reported that it participates in tumor angiogenesis (Non-Patent Document 2).

It has also been reported that NK4, an HGF antagonistic peptide, inhibits the invasion of cancer cells by inhibiting the HGF-HGFR signal and inhibits tumor angiogenesis (Non-Patent Documents 3 and 4).

Therefore, compounds having HGFR inhibitory activity are expected to be useful as antitumor agents, angiogenesis inhibitors or cancer metastasis inhibitors.

However, although a compound having a structure similar to that of the present compound and a method for producing the same are disclosed in Patent Document 1, there is no description of a production method of the present compound according to the present invention and a production intermediate in the production method thereof as well as the present compound .

Patent Document 1: International Publication No. 2005/082855 pamphlet

Non-Patent Document 1: Oncology Reports, 5, 1013-1024 (1998)

Non-Patent Document 2: Advances in Cancer Research, 67, 257-279 (1995)

Non-Patent Document 3: British Journal of Cancer, 84, 864-873 (2001)

Non-Patent Document 4: Cancer Sci., 94, 321-327 (2003)

Problems to be solved by the invention

It is an object of the present invention to find a production method of a phenoxypyridine derivative having an HGFR inhibitory action and an antitumor action, an angiogenesis inhibitory action, a tumor metastasis inhibitory action, etc., and a production intermediate in the production method thereof .

Means for solving the problem

As a result of intensive studies in view of the above circumstances, the present inventors have found a production method for a phenoxypyridine derivative suitable for industrial large-scale synthesis and a manufacturing intermediate in the production method, and completed the present invention.

That is, the present invention provides the following [1] to [21].

[1] A process for producing a compound represented by the following formula (I), which comprises reacting a compound represented by the following formula (II) or a salt thereof with a compound represented by the following formula (III)

In this formula,

R ¹ is 1) an azetidin-1-yl group which may have a substituent selected from Substituent Group a), 2) a pyrrolidin-1-yl group which may have a substituent selected from Substituent Group a) 4) a piperazin-1-yl group which may have a substituent selected from the following substituent group a, 5) a substituent selected from the following substituent group a, or a piperazin-1-yl group optionally having a substituent selected from Substituent group 6) a morpholin-4-yl group which may have a substituent selected from the following substituent group a, or 7) a group of the formula: -NR ^11a R ^{11b wherein} R ^11a is a hydrogen atom or a methyl group R ^11b represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidin-3-yl group, a piperidin-4-yl group or a tetrahydropyran-4-yl group Provided that R ^11b may have a substituent selected from Substituent Group b shown below).

R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a fluorine atom.

[Substituent group a]

(Excluding a hydroxyl group and a dimethylaminoacetoxy group), each of which is optionally substituted by a hydroxyl group, a hydroxyl group, a hydroxyl group, a hydroxyl group, a dimethylaminoacetoxy group, a methyl group, an ethyl group, May have a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group.

[Substituent group b]

A methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group, and a piperazinyl group. Each of the groups may have a methyl group or a dimethylamino group.

In the above formula, R ⁶ represents a hydrogen atom or a fluorine atom.

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above;

[2] The process according to [1], wherein the compound represented by the formula (II) or a salt thereof is produced by hydrolysis or catalytic hydrogenation of a compound represented by the formula (IV)

In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1].

In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is a methyl group with (1) a halogen atom, (2) a hydroxyl group, (3) nitro, (4) a cyano group, (5) trifluoromethyl on the C _1-6 alkyl group or benzene ring, (6) C _{1- 6} alkyl group, (7) C _1-6 alkoxy group, (8) an amino group, (9) -C _1-6 mono or a substituent 1 is an alkylamino group and (10) di -C _1-6 alkylamino group selected from 2 Means a good benzyl group to carry;

[3] The compound represented by the formula (IV) or a salt thereof may be prepared by reacting a compound represented by the formula (V): (1) azetidine which may have a substituent selected from the substituent group a described in [1] (3) a piperidine which may have a substituent selected from the substituent group a described in [1], (4) a pyrrolidine which may have a substituent selected from Substituent group (5) a diazepan which may have a substituent selected from the substituent group a described in [1], (6) a diazepan which may have a substituent selected from the substituent group (7) HNR ^11a R ^11b (wherein R ^11a and R ^11b are the same as defined in claim 1), or a salt thereof, is reacted with a compound of the formula [2] The process according to [2]

In the above formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2].

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2]. Ar represents a phenyl group which may have 1 or 2 substituents selected from a halogen atom, a methyl group, a methoxy group, a nitro group, a cyano group and a trifluoromethyl group;

[4] The process according to [3], wherein the compound represented by the following formula (V) is produced by reacting a compound represented by the following formula (VI) with a compound represented by the following formula

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2]. Ar is the same as defined in [3].

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2].

Wherein Ar is as defined in [3];

[5] The process according to [4], wherein the compound represented by the following formula (VI) is produced by reacting a compound represented by the following formula (VIII) with a Hoffman potentialing agent:

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2].

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2];

[6] The process according to [5], wherein the compound represented by the following formula (VIII) is produced by reacting a compound represented by the following formula (IX) in the presence of a halogenating agent or a condensing agent:

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1]. R ⁷ is the same as defined in [2].

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [1].

Wherein R < ⁷ > is the same as defined in [2];

[7] A process for producing a 4,6-dimethoxy-1,4,6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (4- (4,6-dimethoxy [1.3. 5] triazin-2-yl) -4-methylmorpholinium chloride hydrate) or 2-chloro-4,6-dimethoxy- 5-triazine) according to [1] or [6];

[8] The compound according to [1], wherein the amine is selected from the group consisting of 1- (2-dimethylaminoethyl) piperazine, 4- (pyrrolidin- 1 -yl) piperidine, 4- (dimethylaminomethyl) Yl) azetidin-3-yl] amine, 1-methyl-4- (piperidin-4-yl) piperidine, N, N-dimethyl- ) Piperazine, 4- (1-methylpiperidin-4-yl) piperazine, 1- (Dimethylamino) pyrrolidine, (3R) -3- (dimethylamino) piperidine, 4- (pyrrolidin- 1 -ylmethyl) Amino) pyrrolidine, azetidine, pyrrolidine, morpholine, 1-methylpiperazine, 3-hydroxyacetidine, 3- (azetidin- 1 -yl) azetidine, 3- (hydroxymethyl) Thiazine, 3- (dimethylamino) azetidine, 3- (dimethylaminomethyl) azetidine, 4-hydroxypiperidine, 4- (hydroxymethyl) piperidine, (3R) (3S) -3-hydroxypyrrolidine, 3- (azetidin-1-ylmethyl) azetidine, 3- (1-ethylpiperidin-4-yl) -N-methylamine, N, N-dimethyl-N'- Methyl propane-1,3-diamine or N, N-diethyl-N'-methylpropane-1,3-diamine;

[9] a process as described in [5] in which the Hofmann precursor is acetic acid iodobenzene or iodobutyric acid trifluoroacetate;

[10] A compound according to any ^one of [ ¹ ] to [10], wherein R ¹ is 4- [2- (dimethylamino) ethyl] piperazin- 1-yl group, 4- (4-azetidin-1-ylpiperidin-1-yl group, 4- (1-methylpiperazin-1-yl) piperidin-1-yl group, 4- Yl group, 4- (pyrrolidin-1-yl) piperazin-1-yl group, 4- (dimethylamino) (3R) -3- (dimethylamino) pyrrolidin-1-yl group, azetidine-1-yl group, 1-yl group, a pyrrolidin-1-yl group, a morpholin-4-yl group, a 4-methylpiperazin-1-yl group, a 3-hydroxyacetidin- Yl group, a 3 - [(dimethylamino) methyl] azetidin-1-yl group, a 4-hydroxymethyl group, (3R) -3-hydroxypyrrolidin-1-yl group, (3S) -3-hydroxypyrrolidin-1-yl group, 1-yl group, methyl (1-methylpiperidin-1-yl) group, 3- (2-dimethylaminoacetoxy) azetidin- (Methyl) amino group or [3- (diethylamino) propyl] (methyl) amino group, A production method according to any one of [1] to [3], which is an amino group;

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, The production method according to any one of [1] to [6], wherein R < 1 >

[12] the production method according to any one of [2] to [6], wherein R ⁷ is a benzyl group;

[13] A compound represented by the following formula (IV-1) or a salt thereof:

In the above formula

R ¹ is (1) an azetidin-1-yl group which may have a substituent selected from the following Substituent group a, (2) a pyrrolidin-1-yl group which may have a substituent selected from Substituent Group (4) a piperazin-1-yl group which may have a substituent selected from the following substituent group a, (5) a substituent group a (6) a morpholin-4-yl group which may have a substituent selected from the following substituent group a, or (7) a group represented by the formula -NR ^11a R ^11b , R ^11b represents a hydrogen atom or a methyl group, R ^11b represents a hydrogen atom or a methyl group, R ^11b represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidin- Pyran-4-yl group, with the proviso that R ^11b may have a substituent selected from Substituent Group b shown below) do.

R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a fluorine atom.

R ⁷¹ is a methyl group with (1) a halogen atom, (2) a hydroxyl group, (3) nitro, (4) a cyano group, (5) trifluoromethyl on the hydrogen atom, a C _1-6 alkyl group or benzene ring, (6) C _1-6 alkyl group, (7) C _1-6 alkoxy group, (8) an amino group, (9) mono- -C _1-6 alkylamino and (10) di -C _1-6 alkylamino group 1 substituents selected from Or two benzyl groups.

[Substituent group a]

(Excluding a hydroxyl group and a dimethylaminoacetoxy group), each of which is composed of a hydroxyl group, a hydroxyl group, a hydroxyl group, a dimethylaminoacetoxy group, a methyl group, an ethyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group and a piperazinyl group, May have a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group.

[Substituent group b]

A methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group and a piperazinyl group, each of which may have a methyl group or a dimethylamino group;

[14] A compound represented by the following formula (V) or a salt thereof:

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [13]. R ⁷ is a methyl group with (1) a halogen atom, (2) a hydroxyl group, (3) nitro, (4) a cyano group, (5) trifluoromethyl in the C _1-6 alkyl group or benzene ring, (6) C _{1- 6} alkyl group, (7) C _1-6 alkoxy group, (8) an amino group, (9) -C _1-6 mono or a substituent 1 is an alkylamino group and (10) di -C _1-6 alkylamino group selected from 2 It means a good benzyl group to have. Ar represents a phenyl group which may have 1 or 2 substituents selected from a halogen atom, a methyl group, a methoxy group, a nitro group, a cyano group and a trifluoromethyl group;

[15] A compound represented by the following formula (VI) or a salt thereof:

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [13]. R ⁷ is the same as defined in [14];

[16] A compound represented by the following formula (VIII) or a salt thereof:

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in [13]. R ⁷ is the same as defined in [14];

[17] A compound according to any ^one of [ ¹ ] to [17], wherein R ¹ is selected from the group consisting of 4- [2- (dimethylamino) ethyl] piperazin-1-yl group, 4-pyrrolidin-1-ylpiperidin- 1-yl group, 4- (4-azetidin-1-ylpiperidin-1-yl group, 4- (1-methylpiperazin-1-yl) piperidin-1-yl group, 4- Yl group, 4- (pyrrolidin-1-yl) piperazin-1-yl group, 4- (dimethylamino) (3R) -3- (dimethylamino) pyrrolidin-1-yl group, azetidine-1-yl group, 1-yl group, a pyrrolidin-1-yl group, a morpholin-4-yl group, a 4-methylpiperazin-1-yl group, a 3-hydroxyacetidin- Yl group, a 3 - [(dimethylamino) methyl] azetidin-1-yl group, a 4-hydroxymethyl group, (3R) -3-hydroxypyrrolidin-1-yl group, (3S) -3-hydroxypyrrolidin-1-yl group, 1-yl group, methyl (1-methylpiperidin-1-yl) group, 3- (2-dimethylaminoacetoxy) azetidin- (Methyl) amino group or [3- (diethylamino) propyl] (methyl) amino group, A compound according to [13] or a salt thereof, which is an amino group;

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로 표시되는 기인 [13] 내지 [16] 중 어느 하나에 기재한 화합물 또는 그의 염;

or

[13] to [16], or a salt thereof;

[19] The compound or a salt thereof according to any one of [14] to [16], wherein R ⁷ is a benzyl group;

(2-fluoro-4 - {[2- ({[4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] carbonyl} amino) pyridin- Yl] oxy} phenyl) -N '- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide;

[21] A crystal according to [20], which has diffraction peaks at diffraction angles (2θ ± 0.2 °) of 6.3 °, 12.3 ° and 17.3 ° in powder X-ray diffraction.

Effects of the Invention

The present invention can provide a method for producing a phenoxypyridine derivative having an HGFR inhibitory action suitable for industrial large-scale synthesis and having an antitumor action, an angiogenesis inhibitory action, a tumor metastasis inhibitory action, and the like. In addition, the present invention can provide a production intermediate which can be used in the above production process.

Brief Description of Drawings

1 is a diagram showing a powder X-ray diffraction pattern of a crystal obtained in Example 9 (Method 3).

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to the definitions of symbols, terms, and the like described in this specification.

In the present specification, the structural formula of the compound may represent a constant isomer for convenience. However, the present invention includes all geometric isomers occurring on the structure of a compound, optical isomers based on asymmetric carbons, stereoisomers, tautomers and isomer mixtures such as tautomers, The present invention is not limited to the description of the formula for convenience, and either of the isomers or a mixture may be used. Therefore, the optically active substance and racemate having asymmetric carbon atoms in the molecule may exist in the compound of the present invention, but in the present invention, the optically active substance and the racemate may be present in the present invention. The crystalline polymorph may be present but not limited thereto, and any single crystalline form may be singly used or a mixture of crystalline forms may be used. The compounds according to the present invention also include anhydrides and hydrates.

The "salt" is not particularly limited as long as it forms a salt with the compound according to the present invention, and examples thereof include salts with inorganic acids, salts with organic acids, salts with inorganic bases, salts with organic bases, Salts and the like.

Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include salts with acetic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lactic acid, stearic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid and the like.

Suitable examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt and a potassium salt, an alkaline earth metal salt such as a calcium salt and a magnesium salt, an aluminum salt, and an ammonium salt. Suitable examples of salts with organic bases include salts with diethylamine, diethanolamine, meglumine, N, N-dibenzylethylenediamine and the like.

Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "C _1-6 alkyl group" means a straight or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a 1-propyl group (n-propyl group) Butyl group), a 2-methyl-1-propyl group (i-butyl group) butyl group) and the like.

The "C _1-6 alkoxy group" means that the oxygen atom is bonded to the terminal of the above-defined "C _1-6 alkyl group", and specific examples thereof include a methoxy group, an ethoxy group, a 1-propoxy group Butoxy group), 2-propoxy group (i-propoxy group), 2-methyl-1-propoxy group (N-butoxy group), 2-butoxy group (s-butoxy group), and the like.

The "mono-C _1-6 alkylamino group" means a group in which one hydrogen atom in the amino group is substituted with the above-defined "C _1-6 alkyl group", and specific examples thereof include methylamino group, ethylamino group, propylamino group (i-butylamino group), 2-methyl-1-propylamino group (i-butylamino group) An amino group (n-butylamino group), and a 2-butylamino group (s-butylamino group).

The "di-C _1-6 alkylamino group" means a group in which two hydrogen atoms in the amino group are the same or different and each is substituted with the above-defined "C _1-6 alkyl group", and specific examples include N, N-dimethyl Amino group, an N, N-diethylamino group, an N, N-di-n-propylamino group, Butylamino group, N, N-di-t-butylamino group, N-ethyl-N-methylamino group, Nn-propyl- N-methylamino group, N-butyl-N-methylamino group, N-butyl-N-methylamino group, Ns-butyl-N-methylamino group and Nt-butyl-

The "condensing agent" in the above [1] and [6] refers to 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4- methylmorpholinium chloride hydrate, 2 Chloro-4,6-dimethoxy-1,3,5-triazine, 2,4,6-trichloro-1,3,5-triazine, dicyclohexylcarbodiimide (DCC) -3, (3'-dimethylaminopropyl) carbodiimide hydrochloride (EDC or WSC HCl), O- (1H-benzothiazol-1-yl) -N, N, N ', N'-tetramethyluronium (HBTU), O- (1H-benzothiazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) Triazin-2-yl) -4-methylmorpholinium chloride hydrate, 2,4,6-trichloro-1,3,5-tri It is azine.

The term " base " in the above [3] means potassium carbonate, sodium carbonate, pyridine, triethylamine, diisopropylethylamine and the like, but is preferably potassium carbonate.

The "salt" of the "amine or its salt" in the above [3] is not particularly limited as long as it forms a salt with an amine, and examples thereof include salts with hydrochloric acid, acetic acid, trifluoroacetic acid and the like.

The " base " in the above [4] means pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate and the like, and is preferably pyridine.

The term " hoffmann potentiator " in the above [5] means iodobenzene acetate, iodobenzene trifluoroacetate, sodium hypochlorite, potassium hypobromite, bromine, iodine and the like, Iodobenzene, and iodobenzene trifluoroacetic acid.

The "halogenating agent" in the above [6] means thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, and the like, and is preferably thionyl chloride.

Yl) carbonyl} amino) pyridin-4-yl] oxy} -1H-pyrazolo [l, } Phenyl) -N'- (4-fluorophenyl) cyclopropane-1,1-dicarboxyamide was observed in powder X-ray diffraction at diffraction angles (2θ ± 0.2 °) of 6.3 °, 12.3 ° and 17.3 ° And has diffraction peaks at 6.3, 12.3, 17.3, 18.3, 18.4, 19.2, 19.8, 20.0, 20.1, 20.2, 22.1 and 23.7 degrees.

Generally, since the diffraction angle (2?) In the powder X-ray diffraction can be within ± 0.2 °, it is understood that the value of the diffraction angle also includes the numerical value within the range of about ± 0.2 ° There is a need. Therefore, not only crystals whose diffraction angles in powder X-ray diffraction are completely matched but also crystals whose diffraction angles coincide within an error range of 占 0.2 占 are also included in the present invention.

Hereinafter, each substituent in the compound of the present invention represented by the above formula (I) will be described.

[Significance of R ¹ ]

R ¹ is (1) an azetidin-1-yl group which may have a substituent selected from the following Substituent group a, (2) a pyrrolidin-1-yl group which may have a substituent selected from Substituent Group (4) a piperazin-1-yl group which may have a substituent selected from the following substituent group a, (5) a substituent group a (6) a morpholin-4-yl group which may have a substituent selected from the following substituent group a, or (7) a group represented by the formula -NR ^11a R ^11b , R ^11b represents a hydrogen atom or a methyl group, R ^11b represents a hydrogen atom or a methyl group, R ^11b represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidin- Pyran-4-yl group, with the proviso that R ^11b may have a substituent selected from Substituent Group b shown below) it means.

Examples of suitable R ¹ 4- [2- (dimethylamino) ethyl] piperazin-1-yl group, 4-pyrrolidin-1-ilpi piperidine-1-yl group, 4 - [(dimethylamino) methyl] piperidine 1-yl group, 4-azetidin-1-ylpiperidin-1-yl group, 4- [3- (dimethylamino) azetidin- (1-methylpiperazin-1-yl) piperidin-1-yl group, 4- Yl group, 4- (pyrrolidin-1-yl) piperazin-1-yl group, (3S) -3- (dimethylamino) pyrrolidin-1-yl group, azetidine-1-yl group, Yl group, a 3-hydroxyazetidin-1-yl group, a 1,3'-biazetidin-1 'yl group, a pyrimidin- - (dimethylamino) methyl] azetidin-1-yl group, 3- (hydroxymethyl) azetidin- (3S) -3-hydroxypyrrolidin-1-yl group, (3S) -3-hydroxypyrrolidin-1-yl group, (3-hydroxypyrrolidin-1-yl group, 3- (azetidin-1-ylmethyl) azetidin- (Methyl) amino group, a [3- (dimethylamino) propyl] (methyl) amino group or a [3- Amino) propyl] (methyl) amino group.

More preferred examples of R < ¹ > include a 4- (4-methylpiperazin-1-yl) piperidin- Yl group, (3S) -3-hydroxypyrrolidin-1-yl group or methyl (1-methylpiperidin-4-yl) amino group.

[Significance of substituent group a]

Substituent group a means a group consisting of a hydroxyl group, a dimethylaminoacetoxy group, a methyl group, an ethyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group and a piperazinyl group.

Provided that each group (excluding the hydroxyl group and the dimethylaminoacetoxy group) described in the substituent group a may have a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group.

[Significance of substituent group b]

Substituent group b means a group consisting of methyl, ethyl, n-propyl, acetyl, dimethylamino, diethylamino, azetidinyl, pyrrolidinyl and piperazinyl.

Provided that each group described in the substituent group b may have a methyl group or a dimethylamino group.

[Significance of R ² , R ³ , R ⁴ and R ⁵ ]

R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a fluorine atom.

R ² , R ³ , R ⁴ and R ⁵ may be any one of (1) a case where all of R ¹ and R ² are hydrogen atoms, (2) a case in which the whole is a fluorine atom, ² , R < ³ >, R < ⁴ > and R < ⁵ >

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또는

로 표시되는 기를 들 수 있다.In addition,

Suitable examples of groups represented by the formula

or

And the like.

[The significance of R ^6]

R ⁶ represents a hydrogen atom or a fluorine atom.

A suitable example of R ⁶ is a fluorine atom.

[Significance of R ⁷ ]

R ⁷ is a methyl group with (1) a halogen atom, (2) a hydroxyl group, (3) nitro, (4) a cyano group, (5) trifluoromethyl on the C _1-6 alkyl group or benzene ring, (6) C _{1- 6} alkyl group, (7) C _1-6 alkoxy group, (8) an amino group, (9) -C _1-6 mono or a substituent 1 is an alkylamino group and (10) di -C _1-6 alkylamino group selected from 2 It means a good benzyl group to have.

A suitable example of R ⁷ is a benzyl group.

[Significance of R ⁷¹ ]

R ⁷¹ is a methyl group with (1) a halogen atom, (2) a hydroxyl group, (3) nitro, (4) a cyano group, (5) trifluoromethyl on the hydrogen atom, a C _1-6 alkyl group or benzene ring, (6) C _1-6 alkyl group, (7) C _1-6 alkoxy group, (8) an amino group, (9) mono- -C _1-6 alkylamino and (10) di -C _1-6 alkylamino group 1 substituents selected from Or two benzyl groups.

A suitable example of R ⁷¹ is a hydrogen atom or a benzyl group.

[Significance of Ar]

Ar represents a phenyl group which may have one or two substituents selected from a halogen atom, a methyl group, a methoxy group, a nitro group, a cyano group and a trifluoromethyl group.

A suitable example of Ar is a phenyl group.

The manufacturing method according to the present invention will be described in detail below.

Wherein each symbol is the same as defined above.

[Step 1]

This step is a step of producing compound (VIII) by reacting compound (IX) with compound (X) in the presence of a halogenating agent or a condensing agent.

As the compound (IX), a compound which can be easily produced from a compound described in the following examples, a known compound, a commercially available compound, or a commercially available compound by a method commonly practiced by those skilled in the art can be used.

As the compound (X), compounds which can be easily prepared from the compound described in the following examples, a known compound, a commercially available compound or a commercially available compound by a method commonly practiced by those skilled in the art can be used.

The solvent used in this step is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction. Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, tert-butyl methyl ether, Aromatic hydrocarbon solvents such as benzene and toluene; fatty hydrocarbon solvents such as heptane and hexane; aromatic hydrocarbon solvents such as N, N-dimethylformamide, N-methylpyrrolidone, N-methylpyrrolidone, N-dimethylformamide, N-methyl-2-pyrrolidone or a mixed solvent thereof, and the like, preferably tetrahydrofuran.

The halogenating agent means thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride, and the like, but is preferably thionyl chloride.

Condensers are compounds such as 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride hydrate, 2-chloro-4,6-dimethoxy- , 5-triazine, 2,4,6-trichloro-1,3,5-triazine, dicyclohexylcarbodiimide (DCC), 1-ethyl-3, (3'-dimethylaminopropyl) carbodiY (1H-benzothiazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), O- Benzothiazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and the like, but suitably 4- (4,6-dimethoxy [1.3 5] triazin-2-yl) -4-methylmorpholinium chloride hydrate, and 2-chloro-4,6-dimethoxy-1,3,5-triazine.

The reaction temperature varies depending on the starting material, solvent and other reagents used, and is suitably 0 ° C to 50 ° C (temperature in the reaction vessel), more preferably 0 ° C to 30 ° C The temperature inside).

The reaction time varies depending on the starting materials, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 48 hours after adding the reagent. It is more preferable to stir for 4 to 24 hours.

The compound (X) may be used in an amount of 1.0 to 3.0 times the molar equivalent based on the compound (IX), but suitably 1.0 to 1.3 times the molar equivalent may be used.

The halogenating agent may be used in an amount of 1.0 to 2.0 times molar equivalent relative to compound (IX), but suitably 1.1 times as much molar equivalent can be used.

The condensing agent may be used in an amount of 1.0 to 3.0 molar equivalents relative to compound (IX), but suitably 1.1 to 1.3 molar equivalents may be used.

[Step 2]

This step is a step of producing the compound (VI) by reacting the compound (VIII) with a Hofmann precursor.

The solvent used in this step is not particularly limited as far as it dissolves the starting raw material to some extent and does not inhibit the reaction. Examples of the solvent include N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone and the like can be used, and N, N-dimethylformamide and N-methyl-2-pyrrolidone are preferable.

The Hoffmann disazotizing agent means iodobenzene acetate, iodobenzene trifluoroacetate, sodium hypochlorite, potassium hypochlorite, bromine, iodine and the like, but suitably is iodobenzene acetate, iodine trifluoroacetic acid Benzene.

The reaction temperature generally varies depending on the starting materials, solvents and other reagents used, and is preferably -10 ° C to 50 ° C (temperature in the reaction vessel), more preferably 20 ° C to 30 ° C Temperature in the container).

The reaction time varies depending on the starting material, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 24 hours after adding the reagent. It is more preferable to stir for 3 to 5 hours.

The Hoffmann potentiator can be used in an amount of 1.0 to 3.0 times molar equivalent based on compound (VIII), but suitably 1.0 to 1.2 times molar equivalent can be used.

[Step 3]

This step is a step of preparing compound (V) by reacting compound (VI) with compound (VII) in the presence of a base.

As the compound (VII), a compound that can be easily prepared from a known compound, a commercially available compound, or a commercially available compound by a method commonly practiced by those skilled in the art can be used.

The solvent used in this step is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction. Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, tert-butyl methyl ether, Aromatic hydrocarbon solvents such as benzene and toluene, fatty hydrocarbon solvents such as heptane and hexane, acetonitrile solvents such as acetonitrile and methyl ethyl ketone, aliphatic hydrocarbon solvents such as benzene, toluene and the like, ether solvents such as diethyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether, Or a mixed solvent thereof may be used. It is preferably a mixed solvent of tetrahydrofuran and acetonitrile.

The base may be pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or the like, preferably pyridine.

The reaction temperature is usually from -10 to 50 캜 (the temperature in the reaction vessel), more preferably from 0 캜 to 30 캜 (depending on the kind of the reagent used in the reaction) Temperature in the container).

The reaction time varies depending on the starting material, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 24 hours after adding the reagent. It is more preferable to stir for 2 to 5 hours.

The compound (VII) may be used in an amount of 1.0 to 3.0 molar equivalents relative to the compound (VI), but suitably 1.1 to 2.0 molar equivalents may be used.

The base may be used in an amount of 1.0 to 3.0 molar equivalents relative to compound (VI), but suitably 1.1 to 2.0 molar equivalents may be used.

[Step 4]

The present process is a process for producing a compound (IV) or a salt thereof by reacting a compound (V) with a suitable amine (or a salt thereof) in the presence or absence of a base.

As the amine, a compound which can be easily produced from a compound described in the following examples, a known compound, a commercially available compound, or a commercially available compound by a method commonly practiced by those skilled in the art can be used.

The solvent used in this step is not particularly limited as far as it dissolves the starting material to some extent and does not inhibit the reaction. Examples of the solvent include N, N-dimethylformamide, N-methyl- N, N-dimethylacetamide, dimethylsulfoxide and the like can be used, and N-methyl-2-pyrrolidone is preferable.

Examples of the base include potassium carbonate, sodium carbonate, pyridine, triethylamine, diisopropylethylamine, and the like, preferably potassium carbonate.

The reaction temperature generally varies depending on the starting material, solvent and other reagents used in the reaction, and is suitably 10 ° C to 100 ° C (temperature in the reaction vessel), more preferably 20 ° C to 50 ° C The temperature inside).

The reaction time varies depending on the starting material, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 24 hours after adding the reagent. It is more preferable to stir for 1 to 4 hours.

The amine (or a salt thereof) may be used in an amount of 1.0 to 3.0 molar equivalents relative to compound (V), but suitably 1.1 to 1.3 molar equivalents may be used.

The base may be used in an amount of 1.0 to 3.0 times the molar equivalent based on the compound (V), but suitably 1.1 to 1.3 times the molar equivalent may be used.

After the above-described steps, oxidation, reduction, ester formation, amide formation reaction, protecting group introduction reaction, deprotection reaction, hydrolysis reaction, and the like which are generally used for performing substituent conversion on R ¹ It is possible.

[Step 5]

This step is a step of producing compound (II) or a salt thereof by hydrolysis or catalytic hydrogenation of compound (IV) or a salt thereof.

(1) In the case of hydrolysis

Compound (II) or a salt thereof can be produced by hydrolyzing compound (IV) or a salt thereof in the presence of an acid or a base.

The solvent used in this step is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction. Examples of the solvent include alcohol solvents such as methanol, ethanol, propanol, butanol, tetrahydrofuran, 1 , Ether solvents such as 2-dimethoxyethane, tert-butyl methyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether, water or mixed solvents thereof And suitably a mixed solvent of water and methanol, ethanol or tetrahydrofuran.

Acid refers to hydrochloric acid and the like.

Base means sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate and the like.

The reaction temperature usually varies depending on the starting material, solvent and other reagents used in the reaction, and is suitably 0 ° C to 80 ° C (temperature in the reaction vessel), more preferably 30 ° C to 50 ° C The temperature inside).

The reaction time varies depending on the starting material, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 24 hours after adding the reagent. It is more preferable to stir for 2 to 5 hours.

The acid may be used in an amount of 1.0-5.0 molar equivalents relative to compound (IV), but preferably 1.0-2.0 molar equivalents may be used.

The base may be used in an amount of 1.0-5.0 molar equivalents relative to compound (IV), but suitably 1.0-2.0 molar equivalents may be used.

(2) In the case of catalytic hydrogenation

(II) or a salt thereof by catalytic hydrogenation of a compound (IV) or a salt thereof in the presence of a reducing catalyst under a hydrogen atmosphere.

The solvent used in this step is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction. Examples of the solvent include alcohol solvents such as methanol, ethanol, propanol and butanol, tetrahydrofuran, Ether solvents such as tetrahydrofuran, 2-dimethoxyethane, tert-butyl methyl ether, cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether; N- Methyl-2-pyrrolidone, formic acid, water or a mixed solvent thereof may be used. Preferably, water, a mixed solvent of methanol and tetrahydrofuran, water, a mixed solvent of ethanol and tetrahydrofuran, .

The reduction catalyst means palladium carbon, palladium hydroxide, platinum oxide, Raney-nickel or the like, but is preferably palladium-carbon.

The present step can be carried out under a hydrogen atmosphere of 0.1 MPa (normal pressure) to 1.0 MPa, but preferably under a hydrogen atmosphere of 0.1 MPa to 0.3 MPa.

When a mixed solvent containing formic acid or formic acid is used as a solvent in the present step, the present step can be carried out without using hydrogen gas.

The reaction temperature varies depending on the starting material, solvent and other reagents used, and is suitably 0 ° C to 50 ° C (temperature in the reaction vessel), more preferably 20 ° C to 30 ° C The temperature inside).

The reaction time varies depending on the starting materials, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 48 hours after adding the reagent. It is more preferable to stir for 3 to 18 hours.

The reducing catalyst may be used in an amount of 0.1-5.0 molar equivalents relative to compound (IV), but suitably 0.5-1.5 molar equivalents may be used.

[Step 6]

This step is a step of producing Compound (I) by reacting Compound (II) or a salt thereof with Compound (III) in the presence or absence of a base in the presence of a condensing agent.

As the compound (III), a compound that can be easily prepared from a known compound, a commercially available compound, or a commercially available compound by a method commonly practiced by those skilled in the art can be used.

The solvent used in this step is not particularly limited as long as it dissolves the starting material to some extent and does not inhibit the reaction. Examples of the solvent include tetrahydrofuran, 1,2-dimethoxyethane, tert-butyl methyl ether, Ether solvents such as cyclopentyl methyl ether, diethyl ether, diisopropyl ether, dibutyl ether and dicyclopentyl ether, alcohol solvents such as ethanol, 1-propanol and 2-propanol, N, N-dimethylformamide , N-methyl-2-pyrrolidone, N, N-dimethylacetamide or a mixed solvent thereof may be used. A mixed solvent of tetrahydrofuran and N, N-dimethylformamide or tetrahydrofuran Furan and 2-propanol.

Condensers are compounds such as 4- (4,6-dimethoxy [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride hydrate, 2-chloro-4,6-dimethoxy- , 5-triazine, 2,4,6-trichloro-1,3,5-triazine, dicyclohexylcarbodiimide (DCC), 1-ethyl-3, (3'-dimethylaminopropyl) carbodiY (1H-benzothiazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HBTU), O- Benzothiazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate (TBTU) and the like, but suitably 4- (4,6-dimethoxy [1.3 5] triazin-2-yl) -4-methylmorpholinium chloride hydrate, and 2-chloro-4,6-dimethoxy-1,3,5-triazine.

The base means N-methylmorpholine, pyridine, triethylamine, diisopropylethylamine, 1-methylimidazole, potassium carbonate, sodium carbonate and the like, preferably N-methylmorpholine.

The reaction temperature generally varies depending on the starting materials, solvents and other reagents used, and is preferably -10 ° C to 50 ° C (temperature in the reaction vessel), more preferably 20 ° C to 30 ° C Temperature in the container).

The reaction time varies depending on the starting materials, the solvent, the reagent used for the reaction, and the reaction temperature. Preferably, the reaction solution is stirred at the reaction temperature for 1 to 48 hours after adding the reagent. It is more preferable to stir for 3 to 18 hours.

The compound (III) may be used in an amount of 1.0 to 3.0 molar equivalents relative to the compound (II), but may be suitably used in an amount of 1.0 to 2.0 molar equivalents.

The condensing agent may be used in an amount of 1.0 to 3.0 molar equivalents relative to compound (II), but suitably 1.0 to 2.0 molar equivalents may be used.

The base may be used in an amount of from 1.0 to 10 times the molar equivalent based on the compound (II), but preferably 2.0 to 4.0 times the molar equivalent.

In the following, an embodiment has been shown for easier understanding of the present invention, but the present invention is not limited to this.

(Preparation Example 1) Synthesis of tert-butyl [1- (2-dimethylaminoacetyl) piperidin-4-yl]

N, N-Dimethylglycine (2.97 g), 1-hydroxybenzotriazole (2.97 g), and N, N-dimethylformamide were added to a solution of 4- (tert-butoxycarbonylamino) piperidine (3.89 g) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.27 g) were added, and the mixture was stirred at room temperature under nitrogen atmosphere for 46 hours. Ethyl acetate (400 ml), saturated brine (200 ml) and 1 N aqueous sodium hydroxide solution (50 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes and distributed. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed sequentially with 1N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure to obtain the title compound (8.03 g, quantitative) as colorless crystals.

ESI-MS (m / z): 286 [M + H] < ⁺ >.

(Production Example 2) N- [1- (2-Dimethylaminoethyl) piperidin-4-yl] -N-methylamine

A solution of tert-butyl [1- (2-dimethylaminoacetyl) piperidin-4-yl] carbamate (7.07 g) in tetrahydrofuran (100 ml) was ice-cooled under nitrogen atmosphere. Lithium aluminum hydride (280 mg) was added thereto, and the mixture was stirred on an ice bath for 15 minutes and then at room temperature for 15 minutes. The reaction solution was heated under reflux at 100 占 폚 for 11 hours in a nitrogen atmosphere. The reaction solution was ice-cooled. Water (2.8 ml), 5N aqueous sodium hydroxide solution (2.8 ml) and water (14.0 ml) were successively added thereto, followed by stirring for 2 hours. Insolubles were filtered off. The filtrate was concentrated to give the title compound (4.65 g, quantitative) as a yellow oil.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 1.34-1.43 (2H, m), 1.87-1.90 (2H, m), 2.02-2.08 2.50 (7H, m), 2.90 (2H, m), 3.14-3.27 (1H, m).

ESI-MS (m / z): 186 [M + H] < ⁺ >.

(Preparation Example 3) (4-Benzoylpiperazin-1-yl) acetic acid ethyl ester

(5.1 g) was dissolved in tetrahydrofuran (300 ml) under a nitrogen atmosphere, triethylamine (8.25 ml) and benzoyl chloride (3.44 ml, ). The reaction solution was warmed to room temperature and stirred for 4 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium hydrogen carbonate solution (100 ml). The separated organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution (100 ml), water (100 ml) and saturated brine (100 ml), and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (8.19 g, quantitative) as a colorless oil.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 1.28 (3H, t, J = 7.2Hz), 2.20-2.85 (4H, m), 3.26 (2H, m), 3.48 (2H, m), 3.85 (2H, m), 4.19 (2H, m), 7.41 (5H, m).

(Preparation 4) 1- (Azetidin-1-yl) -2- (4-benzoylpiperazin-1-yl)

Methanol (300 ml) and water (50 ml) were added to ethyl (4-benzoylpiperazin-1-yl) acetic acid ethyl ester (8.19 g), lithium hydroxide (1.34 g) Lt; / RTI > The reaction solution was warmed to room temperature and stirred for 24 hours. After 1N hydrochloric acid (55.9 ml) was added, the reaction solution was concentrated under reduced pressure, and ethanol (200 ml) was added to the obtained residue. The precipitated insoluble matter was filtered out through celite. The filtrate was concentrated under reduced pressure to obtain (4-benzoylpiperazin-1-yl) acetic acid (8.6 g) as a crude product as a white solid. N, N-dimethylformamide (80 ml) was added to (4 g) of (4-benzoylpiperazin-1-yl) acetic acid (2 g) at room temperature under a nitrogen atmosphere, and then azetidine hydrochloride 4.49 ml), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (3.09 g) and 1-hydroxybenzotriazole (2.18 g) were successively added thereto and stirred at room temperature for 66 hours. Ethyl acetate (100 ml) and saturated aqueous sodium bicarbonate solution (50 ml) were added to the reaction mixture and distributed. The organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution (50 ml), water (50 ml) and saturated brine (50 ml), and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent: ethyl acetate). Diethyl ether (10 ml) was added to the residue obtained by concentrating the objective fraction under reduced pressure, and suspended. The solid was filtered off and dried in aeration to give the title compound (731.5 mg) as a white powder.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 2.40-2.80 (6H, m), 3.03 (2H, s), 3.47 (2H, m), 3.83 (2H, m), 4.06 (2H, m) , 4.22 (2H, m), 7.30-7.50 (5H, m).

(Preparation Example 5) 1- [2- (Azetidin-1-yl) ethyl] -4-benzylpiperazine

Lithium aluminum hydride (405 mg) was suspended in tetrahydrofuran (10 ml) under cooling with ice bath in a nitrogen atmosphere, and then 1- (azetidin-1-yl) -2- (4-benzoylpiperazin- Yl) ethanone (730 mg) and tetrahydrofuran (5 ml x 3) were added. The reaction solution was stirred at 60 占 폚 for 3 hours. After the reaction solution was cooled to room temperature, water (0.4 ml), 5N aqueous sodium hydroxide solution (0.4 ml) and water (1.2 ml) were added and stirred for 13 hours. The insolubles of the reaction solution were filtered through celite to be filtered and washed with ethyl acetate (100 ml). The solvent was distilled off under reduced pressure to give the title compound (687 mg) as a crude product as a pale yellow oil.

ESI-MS (m / z): 260 [M + H] < ⁺ >.

(Preparation Example 6) 1- [2- (Azetidin-1-yl) ethyl] piperazine trichloride

(687 mg) was dissolved in methanol (30 ml), 20% palladium hydroxide on carbon (372 mg) was added thereto to obtain a solution of hydrogen And the mixture was stirred under pressure (0.4 MPa) for 10 hours. The catalyst was filtered off and washed with methanol. 4N hydrochloric acid-ethyl acetate (1.33 ml) was added to the filtrate and stirred. The inside of the system was reduced under stirring, and excess hydrochloric acid was distilled off. The solvent was distilled off under reduced pressure to give the title compound (736 mg, quant.) As a light brown oil.

ESI-MS (m / z): 170 [M + H] < ⁺ >.

(Preparation Example 7) 1-benzohydrate azetidin-3-one

To a mixture of 1-benzohydr azetidin-3-ol hydrochloride (5.52 g) and triethylamine (27.9 ml) was added dropwise a dimethylsulfoxide (80 ml) solution of pyridine sulfur trioxide complex (19.7 g) at room temperature. The reaction solution was stirred at 50 占 폚 for 30 minutes. The reaction solution was cooled to room temperature. This was poured into iced water. This was extracted with ethyl acetate, and the organic layer was washed with saturated brine. Activated carbon (5 g) was added to the organic layer, and the mixture was stirred at room temperature for 3 days. The activated carbon was separated by filtration, and the filtrate was concentrated. The residue was dissolved in methanol (200 ml), activated charcoal (10 g) was added thereto, and the mixture was stirred at room temperature for 3 days. The activated carbon was separated by filtration, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (eluent: heptane: ethyl acetate = 4: 1 to 2: 1). The objective fraction was concentrated to obtain the desired product (3.21 g) as a pale yellow oil. Hexane was added thereto to precipitate crystals, and crystals were collected by filtration. And dried by aeration to obtain the title compound (1.11 g, 23.4%) as colorless crystals. The filtrate was concentrated, hexane was added to the obtained residue, and the mixture was allowed to stand at room temperature. After crystal precipitation, the supernatant was removed with a pipette. This was dried under reduced pressure to obtain the title compound (940 mg, 19.8%) as pale yellow crystals.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 4.01 (4H, s), 4.60 (1H, s), 7.22 (2H, m), 7.30 (4H, m), 7.48 (4H, m).

(Preparation Example 8) 3- (Azetidin-1-yl) -1-benzohydrate azetidine

Azetidin-3-one (750 mg) in dichloromethane (12 ml) was added azetidine hydrochloride (326 mg), and the mixture was stirred at room temperature. Thereto, sodium triacetoxyborohydride (1.01 g) was added, and the mixture was stirred at room temperature for 25 hours. To the reaction solution was added sodium carbonate (until the foaming subsided), water (50 ml) and ethyl acetate (100 ml). The organic layer was separated. This was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane: ethyl acetate = 1: 1 to 1: 2 to ethyl acetate) to obtain the title compound (643 mg, 73.1%) as a pale yellow solid.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 2.06 (2H, m), 2.91 (2H, m), 3.16-3.24 (7H, m), 4.35 (1H, s), 7.15 (2H, m) , 7.25 (4H, m), 7.40 (4H, d, J = 7.6Hz).

ESI-MS (m / z): 279 [M + H] < ⁺ >.

(Preparation Example 9) 3- (Azetidin-1-yl) azetidine dihydrochloride

4N hydrochloric acid-ethyl acetate (1.16 ml) was added to an ethyl acetate solution of 3- (azetidin-1-yl) -1-benzohydrate azetidine (643 mg) and the mixture was concentrated. The obtained residue was dissolved in methanol (65 ml), and 20% palladium hydroxide (811 mg) was added thereto. This was stirred for 4 hours at room temperature under hydrogen pressure (0.3-0.4 MPa). The catalyst was filtered off and the filtrate was concentrated. Heptane was added to the residue to suspend the solid. The supernatant was removed by pipette, and the residue was concentrated under reduced pressure to obtain crude product (471.2 mg) of the title compound as a pale yellow oil.

ESI-MS (m / z): 113 [M + H] < ⁺ >.

(Production Example 10) Synthesis of 1-benzohydrile-3- (methanesulfonyloxy) azetidine

Under nitrogen atmosphere, a suspension of pyridine (100 ml) of 1-benzohydr azetidin-3-ol (15.0 g) was cooled to -20 캜, and methanesulfonyl chloride (6.33 ml) was added dropwise thereto. The reaction solution was stirred for 1 hour at -20 占 폚 in a nitrogen atmosphere, and then for 2.5 days on a water bath. Water and ethyl acetate were added to the reaction mixture and the mixture was distributed. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. Ethanol (10 mL) and hexane (50 mL) were added to the residue, and the precipitated crystals were suspended. The crystals were filtered off and washed with hexane. This was air-dried at room temperature to obtain the title compound (5.943 g, 44.8%) as pale yellow crystals. The filtrate was concentrated and the residue was purified by silica gel column chromatography (eluent: heptane: ethyl acetate = 2: 1 to 1: 1 to heptane: ethyl acetate: methanol = 50: 50: 1 to 40: 60: 1 to ethyl acetate: Methanol = 100: 1). The objective fraction was concentrated to obtain the title compound (1.58 g, 11.9%) as pale yellow crystals.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 2.99 (3H, s), 3.18-3.21 (2H, m), 3.62-3.66 (2H, m), 7.18-7.22 (2H, m), 7.26-7.31 (4H, m), 7.39 (4H, d, J = 7.2Hz).

(Production Example 11) 1-benzohydrile-3-cyanoazetidine

Water (7.2 ml) and sodium cyanide (3.48 g) were added to a solution of 1-benzohydrile-3- (methanesulfonyloxy) azetidine (7.52 g) in N, N- dimethylformamide The mixture was stirred at 65 占 폚 for 9 hours. Water, sodium carbonate and ethyl acetate were added to the reaction mixture, and the mixture was partitioned. The aqueous layer was extracted with ethyl acetate. The organic layer was collected, washed with saturated brine, and dried over anhydrous sodium sulfate. This was concentrated under reduced pressure, and diethyl ether (10 ml) was added to the obtained crystal to suspend. The crystals were collected by filtration and washed with diethyl ether. This was air-dried to obtain the title compound (5.43 g, 92.3%) as pale yellow crystals.

¹ H-NMR Spectrum (CDCl ₃ )? (Ppm): 3.20-3.31 (3H, m), 3.47 (2H, m), 4.36 (1H, s), 7.19-7.23 (2H, m), 7.26-7.30 4H, m), 7.39 (4H, m).

(Preparation Example 12) 1-benzohydrate azetidine-3-carboxylic acid

Potassium hydroxide (6.48 g) and water (3.25 ml) were added to a solution of 1-benzohydrile-3-cyanoazetidine (5.43 g) in methoxyethanol (54 ml) and the mixture was stirred at 100 ° C for 4 hours. The reaction solution was cooled to room temperature. The reaction solution was poured into ice. This was adjusted to pH 5 with 1N hydrochloric acid, and then sodium chloride was added thereto. This was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The organic layer after drying was concentrated under reduced pressure to obtain crude product of the title compound as pale yellow crystals. Diethyl ether (15 ml) was added thereto to suspend the crystals. The crystals were collected by filtration and washed with diethyl ether. This was air-dried to obtain the title compound (4.20 g, 71.7%) as pale yellow crystals.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 3.00-3.90 (5H, m), 4.95 (1H, s), 7.25-7.28 m).

(Preparation 13) Methyl 1-benzohydrate azetidine-3-carboxylate

Potassium carbonate (6.53 g) and iodomethane (0.976 ml) were added to a solution of 1-benzohydrate azetidine-3-carboxylic acid (4.20 g) in N, N-dimethylformamide (45 ml) And the mixture was stirred for 30 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: heptane: ethyl acetate = 5: 1 to 3: 1). The objective fraction was concentrated to obtain the title compound (3.57 g, 808%) as yellow crystals.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 3.26 (2H, m), 3.31 (1H, m), 3.44 (2H, m), 3.69 (3H, s), 4.38 (1H, s), 7.16 -7.20 (2H, m), 7.25-7.28 (4H, m), 7.39-7.41 (4H, m).

ESI-MS (m / z): 282 [M + H] < ⁺ >.

(Preparation Example 14) Methyl azetidine-3-carboxylate hydrochloride

4N hydrochloric acid-ethyl acetate (12.7 ml) and 20% palladium hydroxide (3.57 g) were added to a methanol (360 ml) solution of methyl 1-benzohydrate azetidine-3-carboxylate (0.4 MPa) at room temperature for 11 hours. The catalyst was filtered off and washed with methanol and water. The filtrate was concentrated to obtain a crude product as a pale yellow oil. The reaction proceeded quantitatively and 1.93 g was obtained, which was used in the next reaction.

ESI-MS (m / z): 116 [M + H] < ⁺ >.

(Preparation 15) Methyl 1-tert-butoxycarbonyl azetidine-3-carboxylate

Methyl azetidine-3-carboxylate hydrochloride (corresponding to 1.93 g as a pure product) was dissolved in water (26 ml), and sodium hydrogen carbonate (3.2 g) and then di-t -Butyl dicarbonate (2.91 g) in tetrahydrofuran (13 ml) was added, and the mixture was stirred at the same temperature for 30 minutes. The reaction solution was stirred at room temperature for 19 hours and 30 minutes. Tetrahydrofuran in the reaction mixture was distilled off and extracted with ethyl acetate. The organic layer was washed with saturated brine (70 ml) and dried over anhydrous sodium sulfate. The aqueous layer was collected by concentrating the organic layer, and tetrahydrofuran (50 ml) was added thereto. This was stirred with cooling in an ice bath, sodium hydrogen carbonate (3.2 g) and di-t-butyl dicarbonate (2.91 g) were added again. The mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2.5 days. The reaction solution was dispensed, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography (eluent: heptane: ethyl acetate: 2: 1 to 1: 1 to ethyl acetate to ethyl acetate: methanol = 10: 1). The objective fraction was concentrated to obtain the title compound (370 mg, 13.5%) as a colorless oil.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 1.44 (9H, s), 3.35 (1H, m), 3.75 (3H, s), 4.10 (4H, d, J = 7.6Hz).

(Production Example 16) tert-Butyl 3- (hydroxymethyl) azetidine-1-carboxylate

A round bottom flask was charged with lithium aluminum hydride (128 mg) and suspended in tetrahydrofuran (30 ml). This was cooled with an ice bath, and a solution of methyl 1-tert-butoxycarbonyl azetidine-3-carboxylate (970 mg) in tetrahydrofuran (10 ml) was slowly added thereto. Lt; / RTI > Water (0.13 ml), 5N aqueous sodium hydroxide solution (0.13 ml) and water (0.39 ml) were added to the reaction solution under cooling with ice bath, and the mixture was stirred at the same temperature for 1 hour. Insolubles in the reaction mixture were filtered off. The filtrate was concentrated to obtain the title compound (805 mg, 95.3%) as a colorless oil.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 1.44 (9H, s), 2.71 (1H, m), 3.69 (2H, dd, J = 5.2, 8.4Hz), 3.79 (2H, d, J = 6.8 Hz), 4.00 (2H, m).

(Production Example 17) 3- (hydroxymethyl) azetidine trifluoroacetic acid salt

Trifluoroacetic acid (0.413 ml) was added to tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (125 mg) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated to obtain the crude product of the title compound (209.8 mg) as a yellow oil.

ESI-MS (m / z): 88 [M + H] < ⁺ >.

(Preparation 18) tert-Butyl 3 - [(methanesulfonyloxy) methyl] azetidine-1-carboxylate

Triethylamine (1.80 ml) was added to a tetrahydrofuran (25 ml) solution of tert-butyl 3- (hydroxymethyl) azetidine-1-carboxylate (806 mg). The mixture was ice-cooled in a nitrogen atmosphere, methanesulfonyl chloride (0.499 ml) was added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Ethyl acetate (100 ml) and water (70 ml) were added to the reaction mixture and distributed. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate). The objective fraction was concentrated to obtain the title compound (1.05 g, 92.0%) as a colorless oil.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 1.44 (9H, s), 2.93 (1H, m), 3.05 (3H, s), 3.72 (2H, dd, J = 5.0, 9.0Hz), 4.06 (2H, m), 4.35 (2H, d, J = 6.8 Hz).

ESI-MS (m / z): 288 [M + Na] < ⁺ >.

(Preparation 19) tert-Butyl 3- (dimethylaminomethyl) azetidine-1-carboxylate

A solution of 2M dimethylamine-tetrahydrofuran (20 ml) was added to a solution of tert-butyl 3 - [(methanesulfonyloxy) methyl] azetidine-1-carboxylate (1.05 g) in methanol (20 ml) The tube was heated at 70 ° C for 40 hours. The reaction solution was cooled to room temperature. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain the title compound (678 mg, 79.9%) as a yellow oil.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 1.43 (9H, s), 2.22 (6H, s), 2.50 (2H, d, J = 7.6Hz), 2.69 (1H, m), 3.59 (2H , dd, J = 5.2, 8.4 Hz), 4.16 (2H, m).

ESI-MS (m / z): 215 [M + H] < ⁺ >, 269 [M + Na + MeOH] < ⁺ >.

(Preparation 20) 3- (Dimethylaminomethyl) azetidine 2 Trifluoroacetic acid salt

Trifluoroacetic acid (1.95 ml) was added to tert-butyl 3- (dimethylaminomethyl) azetidine-1-carboxylate (678 mg) under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution was concentrated, and then toluene was added thereto to azeotropically obtain a crude title compound (1.79 g) as a yellow oil.

ESI-MS (m / z): 115 [M + Na] < ⁺ >.

(Preparation 21) tert-Butyl 3-methoxyazetidine-1-carboxylate

A tetrahydrofuran (50 ml) suspension of sodium hydride (2.89 g) was stirred under cooling with an ice bath. Thereto was slowly added a tetrahydrofuran (50 ml) solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.00 g) and the mixture was stirred at the same temperature for 30 minutes. Thereafter, the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was again stirred for 15 minutes in an ice bath. Iodomethane (3.09 ml) was added dropwise to the reaction solution, and the mixture was directly stirred for 2 hours. Water was added to the reaction solution little by little. The organic layer was collected when the foaming had subsided. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: heptane: ethyl acetate = 3: 1 to 2: 1 to 1: 1 to ethyl acetate). The objective fraction was concentrated to obtain the title compound (1.80 g, 33.3%) as a colorless oil. Further, the raw material fraction was recovered by concentration (2.10 g, 42.0%).

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 1.44 (9H, s), 3.28 (3H, s), 3.82 (2H, m), 4.06 (2H, m), 4.14 (1H, m).

(Preparation 22) 3-Methoxyacetyl trifluoroacetic acid salt

tert-Butyl 3-methoxyazetidine-1-carboxylate (125 mg) was dissolved in dichloromethane (0.618 ml), trifluoroacetic acid (0.618 ml) was added thereto, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated to give the title compound (232 mg) as a yellow oil.

ESI-MS (m / z): 88 [M + H] < ⁺ >.

(Preparation Example 23) 3- (Azetidin-1-ylcarbonyl) -1-benzhydryl azetidine

1-Benzhydryl azetidine-3-carboxylic acid (1.52 g) was dissolved in N, N-dimethylformamide (30 ml) at room temperature under a nitrogen atmosphere. (3.17 ml), BOP reagent (benzotriazol-1-yl-oxy-tris- (dimethylamino) -phosphonium hexafluorophosphate 5.03 g) and azetidine hydrochloride (1.06 g) Followed by stirring for 24 hours. To the reaction solution was added 1N aqueous sodium hydroxide (50 ml) and the mixture was stirred. Subsequently, ethyl acetate (100 ml) was added and extracted. The organic layer was washed successively with 1N aqueous sodium hydroxide solution, water and saturated brine, and dried over anhydrous sodium sulfate. Ethyl acetate (2 ml) and tert-butyl methyl ether (10 ml) were added to the residue (1.83 g) obtained by distilling off the solvent, and the crystals were precipitated. The crystals were collected by filtration and air-dried to obtain the title compound (1.14 g, 65%) as pale yellow crystals.

¹ H-NMR Spectrum (CDCl ₃ )? (Ppm): 2.15-2.30 (2H, m), 3.20-3.50 (5H, m), 3.90-4.10 7.45 (10 H, m)

ESI-MS (m / z): 307 [M + H] < ⁺ >.

(Preparation 24) 3- (Azetidin-1-ylmethyl) -1-benzhydryl azetidine

(1.14 g) was added to the suspension of lithium aluminum hydride (300 mg) in tetrahydrofuran (10 ml) at room temperature under a nitrogen atmosphere, and then 3- (azetidin- 1 -ylcarbonyl) In tetrahydrofuran (30 mL) was added dropwise. After the addition, the reaction solution was stirred at 60 ° C for 2 hours. Water (0.3 ml), a 5N aqueous sodium hydroxide solution (0.3 ml) and water (0.9 ml) were added to the reaction solution and the mixture was stirred overnight. Insolubles were filtered off and washed with ethyl acetate (100 ml). The filtrate was concentrated under reduced pressure to obtain the title compound (1.115 g, quant.) As a light brown oil.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 2.07 (2H, m), 2.40-2.60 (3H, m), 2.74 (2H, m), 3.11-3.15 (4H, m), 3.32 (2H, m), 4.29 (1H, s), 7.14-7.40 (10H, m).

ESI-MS (m / z): 293 [M + H] < ⁺ >.

(Preparation 25) 3- (Azetidin-1-ylmethyl) azetidine dihydrochloride

3- (Azetidin-1-ylmethyl) -1-benzhydryl azetidine (1.115 g) was dissolved in methanol (25 ml). 10% palladium-carbon (1.1 g) was added under a nitrogen atmosphere, and the mixture was stirred under hydrogen pressure (0.4 MPa) for 12 hours. After the inside of the system was purged with nitrogen, the catalyst was filtered and washed with methanol. 4N hydrochloric acid-ethyl acetate (4 ml) was added to the filtrate, and the mixture was concentrated under reduced pressure. Heptane (25 mL) was added to the residue, and the supernatant was removed. This operation was repeated once again. The obtained residue was dried under reduced pressure for 2 days to obtain the title compound (680 mg, 90%) as a pale brown oil.

ESI-MS (m / z): 127 [M + H] < ⁺ >.

(Preparation 26) Synthesis of 1-benzohydrile-3- (hydroxymethyl) azetidine

1-Benzohydrile-3-azetidinecarboxylic acid (3.12 g) was suspended in tetrahydrofuran (60 mL) and cooled in an ice-ethanol bath under a nitrogen atmosphere. After triethylamine (1.96 ml) was added dropwise, a tetrahydrofuran (5 ml) solution of ethyl chlorocarbonate (1.34 ml) was added dropwise over 20 minutes. After the addition, the mixture was stirred at the same temperature for 30 minutes. The reaction solution was filtered, and the filtrate was washed with tetrahydrofuran (30 ml). The filtrate was added dropwise to a water (15 ml) solution of sodium borohydride (1.33 g) in an ice-water bath over 15 minutes. After the dropwise addition, the reaction solution was stirred at room temperature. To the reaction solution, 1N hydrochloric acid (35 ml) was gradually added to decompose excess sodium borohydride, and then 1N aqueous sodium hydroxide solution (35 ml) was added dropwise. This was extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was concentrated, and the residue was dried under reduced pressure to obtain the title compound (1.59 g, 54%) as a pale brown solid.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 2.57 (1H, m), 3.03 (2H, m), 3.24 (2H, m), 3.80 (2H, d, J = 5.2Hz), 4.33 (1H , < / RTI > s), 7.15-7.45 (10H, m).

ESI-MS (m / z): 254 [M + H] < ⁺ >.

(Preparation 27) 3- (Hydroxymethyl) azetidine hydrochloride

(1.59 g) was dissolved in methanol (30 ml), palladium hydroxide-carbon (1.0 g) was added under a nitrogen atmosphere and hydrogen (0.4 MPa) was added thereto, Lt; / RTI > After the inside of the system was purged with nitrogen, the catalyst was filtered and washed with methanol. 4N hydrochloric acid-ethyl acetate (2 ml) was added to the filtrate, and the mixture was concentrated under reduced pressure. Heptane (15 mL) was added to the residue, and the supernatant was removed. This operation was repeated once again. The residue was dried under reduced pressure overnight to obtain the title compound (832 mg) as a pale yellow oil.

ESI-MS (m / z): 88 [M + H] < ⁺ >.

(Production Example 28) 1- (Benzyloxy) -2,5-difluoro-4-nitrobenzene

Potassium carbonate (11.1 g) was added to a solution of 2,4,5-trifluoronitrobenzene (9.48 g) and benzyl alcohol (5.54 ml) in N, N-dimethylformamide (40 ml), and the mixture was stirred at room temperature for 60 hours Respectively. Water (120 ml) was added to the reaction solution at 0 占 폚, and the mixture was stirred at 4 占 폚 for 24 hours. The precipitated crystals were collected by filtration and washed with water. The crystals were dried under reduced pressure to obtain the title compound (11.5 g, 81%) as pale yellow crystals.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): Dd, J = 7.2, 10.8 Hz), 7.20 (2H, s), 7.40-7.50

(Preparation 29) 4-Amino-2,5-difluorophenol

10% palladium carbon (921 mg) was added to a solution of 1- (benzyloxy) -2,5-difluoro-4-nitrobenzene (9.21 g) in methanol (300 ml) Lt; / RTI > The inside of the flask was kept under a nitrogen atmosphere to stop the reaction, and then the catalyst was filtered using Celite. The filtrate was distilled off under reduced pressure to obtain the title compound (4.96 g, 99%) as a brown solid.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03 (1H, s).

(Example 1) Synthesis of 1- (benzyloxycarbonyl) cyclopropanecarboxylic acid

(Method 1)

1,1-Cyclopropanedicarboxylic acid (5.02 g) was dissolved in tetrahydrofuran (50 ml) under nitrogen atmosphere, and then triethylamine (5.38 ml) was added dropwise with cooling in an ice bath. After stirring at the same temperature for 30 minutes, thionyl chloride (2.82 ml) was added dropwise under cooling in an ice water bath. After stirring at the same temperature for 30 minutes, a tetrahydrofuran (25 ml) solution of benzyl alcohol (4.39 ml) was added under cooling in an ice water bath, the temperature was gradually raised to room temperature, and the mixture was stirred overnight. A 2N aqueous sodium hydroxide solution (100 ml) was added to the reaction solution, and then tetrahydrofuran was distilled off under reduced pressure. To the resulting aqueous solution was added tert-butyl methyl ether (25 ml) and the mixture was stirred. The organic layer and the aqueous layer were separated. The aqueous layer was cooled in an ice-water bath, and 2N hydrochloric acid (50 mL) was added to adjust the pH to 4. Ethyl acetate (150 ml) was added and stirred briefly. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was dried under reduced pressure to obtain the title compound (6.29 g, 74%) as a pale yellow oil.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): 1.30-1.40 (4H, m), 5.15 (2H, s), 7.30-7.38 (5H, m).

ESI-MS (m / z): 243 [M + Na] < ⁺ >.

(Method 2)

1,1-Cyclopropanedicarboxylic acid (50 g) was dissolved in acetonitrile (500 ml) under a nitrogen atmosphere, and N-methylimidazole (31 ml) was added dropwise under ice-cooling bath stirring. After stirring at the same temperature for 30 minutes, thionyl chloride (29 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a mixed solution of benzyl alcohol (45.7 g) and N-methylimidazole (31 ml) was added under cooling in an ice bath and the mixture was stirred at the same temperature for 6 hours. To the reaction solution, a 2N sodium hydroxide aqueous solution (900 ml) was added to adjust the pH to 8. To the resulting aqueous solution was added tert-butyl methyl ether (500 ml) and the mixture was stirred. The organic layer and the aqueous layer were separated, and the organic layer was extracted with a 5% aqueous solution of sodium hydrogencarbonate (200 ml). The combined aqueous layers were cooled in an ice-water bath and adjusted to pH 4 with 5N hydrochloric acid (300 ml). Ethyl acetate (1000 ml) was added and stirred briefly. The organic layer was separated, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was dissolved in methanol (120 ml), and water (120 ml) was added dropwise with stirring at room temperature. After stirring at room temperature for 30 minutes, the mixture was stirred for 2 hours under cooling in an ice water bath, and the resultant solid was subjected to suction filtration and washed with water (60 ml, twice). The obtained solid was dried at 40 캜 under reduced pressure to obtain the title compound (59 g, 69%).

(Example 2) 4- (4-Amino-3-fluorophenoxy) pyridine-2-carboxamide

(Method 1)

4-Amino-3-fluorophenol (5.7 g) was dissolved in dimethyl sulfoxide (57 ml) under a nitrogen stream, tert-butoxy potassium (5.6 g) was added at room temperature and the mixture was stirred for 15 minutes. 4-Chloropyridine-2-carboxyamide (5.0 g) was added to the reaction solution, and the mixture was stirred for 50 minutes using an oil bath at an external temperature of 80 캜 under a nitrogen stream. The reaction solution was allowed to cool to room temperature. To the reaction mixture was added 1N aqueous sodium hydroxide solution (85.5 ml) and the mixture was stirred. The precipitated solid was filtered off and washed with water. The filtrate was air-dried, and then dried with warm air at 100 ° C to obtain the title compound (5.88 g, 74.3%) as a pale brown powder.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): (2H, m), 6.80 (1H, dd, J = 2.4,8.4Hz), 6.81-6.90 (1H, m), 7.02 (1H, dd, J = 2.4, 11.6Hz), 6.99-7.14 1H, m), 7.32-7.39 (1H, m), 7.69 (1H, brs), 8.10 (1H, brs), 8.48 (1H, m).

(Method 2)

Tert-Butoxy potassium (214 g) was dissolved in dimethyl sulfoxide (750 ml) and tetrahydrofuran (250 ml) under a nitrogen stream, to which 4-amino-3-fluorophenol · 1/2 naphthalene A solution of 2,6 disulfonate (242 g) and 4-chloropyridine-2-carboxyamide (100 g) in dimethylsulfoxide (1000 ml) was added dropwise with ice cooling. The mixture was stirred at room temperature for 30 minutes and then stirred for 2 hours using an oil bath at an external temperature of 90 ° C. The reaction solution was allowed to cool to room temperature, water (3000 ml) was added, and the mixture was stirred for 2 hours. The precipitated solid was collected by filtration and washed with water (500 mL, twice). The filtrate was suspended in water (2000 mL), stirred for 30 minutes, filtered again, and washed with water (500 mL, twice). And warm-air dried at 60 DEG C to obtain the title compound (119 g, 75.3%).

(Example 3) 1- [4- (2-Carbamoylpyridin-4-yloxy) -2-fluorophenylcarbamoyl] cyclopropanecarboxylic acid benzyl ester

(Method 1)

To a mixture of 1- (benzyloxycarbonyl) cyclopropanecarboxylic acid (11.5 g) was added a mixture of tetrahydrofuran (148 ml) and N-methylmorpholine (10.9 g) under ice-cooling. Thionyl chloride (6.19 g) was added dropwise at an internal temperature of 4.4 캜 to 25.2 캜 and stirred for 47 minutes. (9.89 g) was added thereto at an internal temperature between 1.9 ° C and 13.4 ° C over 2 minutes, and maintained at an internal temperature of 3 ° C to 6 ° C And stirred for 4 hours and 40 minutes. Ethyl acetate (346 ml), 2N sodium hydroxide aqueous solution (100 ml), tetrahydrofuran (49 ml) and water (20 ml) were added to the reaction solution and dispensed. The organic layer was washed twice with 5% brine solution (49 ml). The organic layer was concentrated under reduced pressure, and the precipitated crystals were triturated with a mixed solution of ethyl acetate (15 ml) and heptane (15 ml). This was filtered and washed with a mixture of ethyl acetate (5 ml) and heptane (5 ml) to obtain the title compound (13.44 g).

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): (1H, s), 7.20 (1H, s), 7.18-7.23 (1H, 1H, s), 8.51-8.56 (1H, m), 8.75 (1H, t, J = 8.4 Hz), 10.71 (1H, s).

(Method 2)

N-Methylmorpholine (12.8 g) was added to a solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (24.5 g) in tetrahydrofuran (625 ml) Lt; 0 > C to 27.5 < 0 > C. After stirring at room temperature for 50 minutes, 1- (benzyloxycarbonyl) cyclopropanecarboxylic acid (24.5 g) was added at the same temperature. After 10 minutes, 4- (4-amino-3-fluorophenoxy) pyridine-2-carboxamide (25.5 g) was further added with stirring at room temperature. The mixture was stirred at room temperature for 12 hours and 50 minutes. A 5% aqueous solution of sodium hydrogen carbonate (1250 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. The mixture was filtered, filtered and the obtained crystals were washed with 100 ml of water. The crystals were dried at 60 DEG C for 13 hours to obtain the target compound (45.4 g).

(Example 4) 1- [4- (2-Aminopyridin-4-yloxy) -2-fluorophenylcarbamoyl] cyclopropanecarboxylic acid benzyl ester

(Method 1)

Cyclopropanecarboxylic acid benzyl ester (2 g) was dissolved in N, N-dimethylformamide (20 ml), and the mixture was stirred at room temperature for 2 hours. ML) at room temperature and water (0.481 mL) was added. This iodobenzene acetate (2.87 g) was added thereto at room temperature with stirring, and the mixture was stirred for 2.5 hours. Water (40 ml) was added to the reaction solution, and a 2N aqueous sodium hydroxide solution was added thereto until the pH of the solution reached 11, quenched, and ethyl acetate was added to the solution to form a layer. The organic layer was washed with water and 5% brine, dried over magnesium sulfate, filtered and concentrated. The obtained crude brown oil was purified by silica gel column chromatography (eluent: heptane: ethyl acetate = 1: 1 to 1: 2) to obtain the title compound (819 mg) as cream-colored crystals.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): (2H, s), 5.85 (1H, d, J = 2.4 Hz), 5.96 (1H, m), 6.15 (1H, d, J = 5.6Hz), 7.30-7.42 (4H, m), 7.81 7.96 (1 H, m), 10.62 (1 H, s).

(Method 2)

Cyclopropanecarboxylic acid benzyl ester (10 g) was dissolved in N, N-dimethylformamide (100 ml) and the mixture was stirred at room temperature for 2 hours. ) At room temperature, and water (2.41 ml) was added. This iodobenzene acetate (7.91 g) was added thereto at room temperature with stirring, followed by stirring for 3 hours. This iodobenzene acetate (360 mg) was further added and stirred for 2 hours. Ethyl acetate (100 ml) and a 5% aqueous solution of sodium hydrogencarbonate (100 g) were added to the reaction solution and layered. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated. Ethyl acetate (30 ml) was added to the obtained crude crystals, and the mixture was heated and stirred at 60 占 폚 to confirm dissolution of the crystals, followed by cooling to room temperature. (50 mg) obtained in (Method 1) was added and stirred for 30 minutes to confirm the precipitation of crystals. Then, heptane (100 ml) was added, and the mixture was further stirred for 30 minutes. The crystals were collected by filtration and dried to obtain the title compound (6.84 g).

(Method 3)

Cyclopropanecarboxylic acid benzyl ester (17.9 g) was dissolved in N-methyl-2-pyrrolidone ( 125 mL) at room temperature and water (7.2 mL) was added. This iodobenzene acetate (14.1 g) was added at room temperature with stirring, and the mixture was stirred for 4 hours and 7 minutes. Ethyl acetate (268 ml) and 1 N aqueous sodium hydroxide solution (179 ml) were added to the reaction solution and layered. The organic layer was washed three times with 5% brine solution (179 ml) and once with water (179 ml), then dried over magnesium sulfate, filtered and concentrated. Toluene (72 ml) was added to the obtained crude crystals, and the mixture was heated and stirred at 90 占 폚 to confirm dissolution of the crystals, followed by cooling to room temperature. The precipitated crystals were collected by filtration, washed with toluene (18 ml) and dried under reduced pressure at 50 占 폚 for 4 hours to obtain the title compound (11.9 g) as pale orange crystals.

(Example 5) 1- [2-Fluoro-4- (2-phenoxycarbonylaminopyridin-4-yloxy) phenylcarbamoyl] cyclopropanecarboxylic acid benzyl ester

Cyclopropanecarboxylic acid benzyl ester (6.0 g, content: 5.51 g) was added tetrahydrofuran (41 ml) and the mixture was stirred at room temperature for 2 hours. And acetonitrile (41 ml) and pyridine (2.07 g) were charged and dissolved by stirring. To this solution was added phenyl chloroformate (4.1 g) dropwise at an internal temperature of 8.8 to 14.9 캜 under ice-cooling. The reaction solution was stirred at the same temperature for 2 hours and 9 minutes, and further stirred at room temperature for 3 hours and 5 minutes. The precipitate was collected by filtration, washed with a mixed solution of tetrahydrofuran-acetonitrile (2: 1, 16 ml) and air-dried to obtain the title compound (6.39 g).

Example 6 Synthesis of 1- [2-fluoro-4- (2 - {[4- (4-methylpiperazin- 1 -yl) piperidine- 1 -carbonyl] amino} piperidin- Yloxy) phenylcarbamoyl] cyclopropanecarboxylic acid benzyl ester

(Method 1)

Cyclopropanecarboxylic acid benzyl ester (2.75 g) and N, N-dimethylformamide (2.75 g) were added to a solution of 1- [2- fluoro-4- (2- phenoxycarbonylaminopyridin-4- yloxy) phenylcarbamoyl] cyclopropanecarboxylic acid benzyl ester 13.8 ml) was added potassium carbonate (772 mg) and stirring was started. 1-Methyl-4- (piperidin-4-yl) piperazine (1.02 g) was added thereto and stirred for 6 hours. Ethyl acetate (41 ml) and water (27.5 ml) were added to the reaction mixture and distributed. The obtained organic layer was washed with water (13.8 ml, 3 times). After drying with sodium sulfate, the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate: methanol = 30: 1). The eluate was concentrated under reduced pressure, and tert-butyl methyl ether (3 ml) was added thereto to stimulate the reaction, and precipitation was observed. tert-Butyl methyl ether (40 ml) was further added and the mixture was stirred overnight. The obtained precipitate was collected by filtration, washed with tert-butyl methyl ether (3 ml) and air-dried to obtain the title compound (1.61 g).

¹ H-NMR spectrum (DMSO-d ₆ )? (Ppm): 1.20-1.34 (2H, m), 1.57 (4H, s), 1.72 (2H, d, J = 10.8Hz) , 2.18-2.40 (4H, m), 2.45 (3H, br s), 2.74 (2H, t, J = 11.6 Hz), 3.30 (1H, s), 6.43-6.55 (1H, m), 6.97-7.10 (1H, m), 7.22-7.29 (1H, m), 7.30-7.44 8.13 (1H, d, J = 6.0 Hz), 9.21 (1H, s), 10.67 (1H, s).

(Method 2)

Cyclopropanecarboxylic acid benzyl ester (3.60 g) and N-methyl-2-pyrrolidone (3.00 g) were added to a solution of 1- [2- fluoro-4- (2-phenoxycarbonylaminopyridin- 1-methyl-4- (piperidin-4-yl) piperazine (1.46 g) was added to a mixed solution of sodium hydride and potassium hydride (25 ml) and stirred for 1 hour and 51 minutes while heating at 40 ° C. Ethyl acetate (180 ml) and water (90 ml) were added to the reaction mixture and distributed. The obtained organic layer was washed with water (36 mL, twice) and 10% brine (36 mL). The extract was dried over anhydrous magnesium sulfate (10 g), filtered and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; heptane: ethyl acetate = 1: 1 - ethyl acetate - ethyl acetate: isopropyl alcohol = 9: 1). The eluent was concentrated under reduced pressure, and tert-butyl methyl ether (60 ml) and the seed crystal obtained in (Method 1) were added to precipitate. The resulting precipitate was filtered off, washed with tert-butyl methyl ether (10 ml), and dried under reduced pressure at 40 占 폚 for 2 hours to obtain the target compound (2.57 g).

(Example 7) 1- [2-Fluoro-4- (2 - {[4- (4-methylpiperazin- 1 -yl) piperidine- 1- carbonyl] amino} piperidin- Yloxy) phenylcarbamoyl] cyclopropanecarboxylic acid benzyl ester trichloride

(Method 1)

1-carbonyl] amino} piperidin-4-yloxy) phenylcarbamate The title compound was prepared in accordance with the general method of Example 1 from 1- [2-fluoro-4- (2- { Benzoyl] cyclopropanecarboxylic acid benzyl ester (189 mg) was dissolved in ethyl acetate (6 ml), and a 4N hydrogen chloride-ethyl acetate solution (0.3 ml) was added. The obtained mixed solution was concentrated under reduced pressure, and methanol (0.5 ml) and ethyl acetate (4 ml) were added. The precipitate was filtered and, as a result of moisture absorption, was recovered with methanol (10 ml). The recovered solution was again concentrated under reduced pressure, and methanol (0.5 ml) and tert-butyl methyl ether (4 ml) were added. The precipitate was filtered to obtain the title compound (102 mg).

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): (2H, t, J = 12.4 Hz), 3.50-3.57 (2H, m), 1.58 (4H, s), 1.60-1.74 (1H, m), 7.30-7.42 (6H, m), 7.30 (2H, ), 7.46 (1H, dd, J = 2.4,8.8Hz), 8.14 (1H, t, J = 8.8Hz) , brs).

(Method 2)

Cyclopropanecarboxylic acid benzyl ester (2.0 g) and N-methyl-2-pyrrolidone (2.0 g) were added to a solution of 1- [2- fluoro-4- (2- phenoxycarbonylaminopyridin- 1-methyl-4- (piperidin-4-yl) piperazine (812 mg) was added to a mixture of diisopropyl ether and tetrahydrofuran (14 ml), and the mixture was stirred at 40 占 폚 for 2 hours and 31 minutes. Ethyl acetate (60 ml) and water (40 ml) were added to the reaction mixture and distributed. The organic layer was washed with 5% brine (10 mL, 3 times) and water (10 mL). A 4N hydrogen chloride-ethyl acetate solution (0.5 ml) was added to a part (10 ml) of the obtained organic layer, and the seed crystal obtained in (Method 1) was added. Isopropyl alcohol (1 ml) was added and sonication was carried out to form precipitates. The resulting precipitate was filtered and washed with ethyl acetate (2 ml) to obtain the title compound (322 mg).

(Method 3)

Cyclopropanecarboxylic acid benzyl ester (6.63 g) and N-methyl-2-pyrrolidone (6.00 g) were added to a solution of 1- [2- fluoro-4- (2- phenoxycarbonylaminopyridin- 1-Methyl-4- (piperidin-4-yl) piperazine (2.68 g) was added to a mixture of water (33 ml) and the mixture was stirred at 40 占 폚 for 2 hours and 10 minutes. Ethyl acetate (132 mL) and water (99 mL) were added to the reaction mixture and distributed. The organic layer was washed with 5% brine (33 mL, twice) and water (33 mL). A 4N hydrogen chloride-ethyl acetate solution (10 ml) was added to isopropyl alcohol (13 ml), 8 ml of the organic layer after the washing was added dropwise thereto, the seed crystal obtained in (Method 2) was added, . Isopropyl alcohol (13 ml) was added during the dropwise addition, ultrasonic treatment was performed, and then the dropping was continued. After completion of dropwise addition, the mixture was stirred for 5 hours and 38 minutes. The precipitate was filtered, washed with a mixture of ethyl acetate-isopropyl alcohol (5: 1, 20 ml), and solvent exchanged with ethyl acetate (20 ml). The mixture was air-dried under nitrogen flow, and further dried under reduced pressure at 40 占 폚 for 2 hours to obtain the target compound (6.12 g).

(Method 4)

Cyclopropanecarboxylic acid benzyl ester (16.1 g) and N-methyl-2-pyrrolidone (16.1 g) were added to a solution of 1- [2-fluoro-4- (2- phenoxycarbonylaminopyridin- Pyrrolidone solution (24.8%, 26.3 g) of 1-methyl-4- (piperidin-4-yl) piperazine was added to a mixture of N- And washed with 2-pyrrolidone (15 ml). And the mixture was stirred at 37 ° C for 1 hour and 52 minutes. Ethyl acetate (242 ml) and water (242 ml) were added to the reaction mixture and distributed. The organic layer was washed with 1N hydrochloric acid (81 ml). The aqueous layer was separated, ethyl acetate (161 ml) was added, and 2N sodium hydroxide aqueous solution (81 ml) was further added and distributed. The organic layer was separated and washed with 1% brine (81 g) to obtain an organic layer (151.3 g). A portion (104.2 g) of the above organic layer was added to ethanol (48 ml), and concentrated hydrochloric acid (7.41 ml) was added with stirring under ice-cooling. A portion (about 15 ml) of the remaining organic layer was added, seed crystal (48.3 mg) was added thereto, and the mixture was stirred at room temperature for 1 hour and 14 minutes. The entire amount of the remaining organic layer was added dropwise over 29 minutes, and stirring was further performed for 16 hours and 19 minutes. The precipitate was filtered off, washed with a mixed solution of ethyl acetate-ethanol (3: 1, 32.4 ml), and solvent was replaced with ethyl acetate (32.2 ml). The mixture was air-dried under nitrogen flow and further dried under reduced pressure at 40 DEG C for 2 hours and 20 minutes to obtain the title compound (15.0 g).

(Example 8) 1- [2-Fluoro-4- (2 - {[4- (4-methylpiperazin- 1 -yl) piperidine- 1 -carbonyl] amino} pyridin- ) Phenylcarbamoyl] cyclopropanecarboxylic acid

(Method 1)

1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] Cyclopropanecarboxylic acid benzyl ester (800 mg) was dissolved in a mixture of tetrahydrofuran (4 ml) and ethanol (4 ml), palladium carbon (400 mg) was added and the mixture was hydrogenated at 0.15 MPa for 4 hours at room temperature Lt; / RTI > Water (4 ml) was added to the reaction solution, followed by filtration. The filtration residue was washed with 50% aqueous ethanol (8 ml) and water (4 ml), and the filtrate was concentrated. Tetrahydrofuran (8 ml) and ethanol (8 ml) were added to the concentrated residue and concentrated. Tetrahydrofuran (8 ml), ethyl acetate (8 ml) and ethanol (2 ml) were added to the concentrated residue, and the mixture was concentrated. Tetrahydrofuran (8 ml) and ethanol (16 ml) were added to the concentrated residue, and the mixture was concentrated to precipitate crystals. The crystals were suspended in tetrahydrofuran (16 ml), stirred for 40 minutes at room temperature, and then the crystals were filtered and dried to obtain the title compound (550 mg) as white crystals.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): M), 1.70-1.80 (2H, m), 2.41-2.50 (2H, br s), 2.50 (3H, s), 2.60-2.90 (9H, m) D, J = 2.4 Hz, 5.6 Hz), 6.93 (1H, d, J = 8.8 Hz), 7.17 Hz), 7.33 (1H, d, J = 2.4Hz), 8.10 (1H, d, J = 5.6Hz), 8.35 (1H, t, J = 8.8Hz), 9.21 (1H, s).

(Method 2)

1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] Cyclopropanecarboxylic acid benzyl ester (500 mg) was dissolved in a mixture of tetrahydrofuran (2.5 ml), ethanol (2.5 ml) and water (1.5 ml), and palladium carbon (100 mg) Of hydrogen atmosphere at room temperature for 3 hours. The reaction solution was filtered, and the filtration residue was washed with a 90% aqueous ethanol solution (1 ml), and the filtrate was concentrated. Ethanol was added to the concentrated residue and concentration was repeated three times. Ethanol (2.5 ml), tetrahydrofuran (2.5 ml) and the seed crystal obtained in (Method 1) were added to the concentrated residue, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (5 ml) was added and the mixture was stirred for an additional hour. The crystals were filtered and dried to obtain the title compound (420 mg) as white crystals.

(Method 3)

1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] Cyclopropanecarboxylic acid benzyl ester hydrochloride (2 g) was dissolved in water (20 ml) and ethyl acetate (20 ml), and a 2N aqueous sodium hydroxide solution (4 ml) was added and layered. The organic layer was washed with water and concentrated. Tetrahydrofuran was added and the concentration was repeated three times. The concentrated residue was dissolved in a mixture of tetrahydrofuran (8 ml) and water (1.6 ml), palladium on carbon (200 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere of 0.2 MPa for 5 hours. Tetrahydrofuran (4 ml) and methanol (6 ml) were added to the reaction mixture, followed by filtration. The filtration residue was washed with a 90% aqueous methanol solution (3 ml). Tetrahydrofuran (12 ml) and the seed crystal obtained in (Method 1) were added to the filtrate, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (32 ml) was added and the mixture was stirred for further 14 hours. The crystals were filtered and dried to obtain the title compound (1.2 g) as white crystals.

(Example 8-2) 1- [2-Fluoro-4- (2 - {[4- (4-methylpiperazin- 1 -yl) piperidine- 1- carbonyl] amino} pyridin- - yloxy) phenylcarbamoyl] cyclopropanecarboxylic acid trichloride

(Method 1)

1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] Cyclopropanecarboxylic acid benzyl ester trichloride (2 g) was dissolved in a mixture of water (4 ml) and ethanol (8 ml), palladium on carbon (100 mg) The mixture was stirred at room temperature for 10 minutes. The reaction solution was filtered, and the filtration residue was washed with a mixture of water (1 ml) and ethanol (2 ml). To the filtrate was added 20 ml of ethanol and concentrated. Ethanol (10 ml) was added to the resulting mixture and the concentrating operation was repeated four times. The mixture was added dropwise with stirring to ethyl acetate (40 ml) while being heated (hot). After stirring at room temperature for 25 hours and 30 minutes, the crystals were filtered while washing with a mixture of ethanol (2 ml) and ethyl acetate (2 ml) to obtain the title compound (1.56 g) as a white solid.

¹ H-NMR spectrum (DMSO-d ₆ )? (Ppm): 1.50-1.78 (8 H, m), 2.04-2.22 (2H, m), 2.46 (3H, s), 2.80-3.90 , 7.22 (1H, s), 7.43 (1H, J = 12.4 Hz), 8.22-8.32 (2H, m) (2H, m), 11.30 (1H, s).

(Method 2)

1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] Cyclopropanecarboxylic acid benzyl ester trichloride (5 g) was dissolved in a mixture of water (10 ml) and ethanol (20 ml), palladium on carbon (250 mg) And the mixture was stirred at room temperature for several minutes. The reaction solution was filtered, and the filtration residue was washed with a mixture of water (6 ml) and ethanol (10 ml). To the filtrate was added 50 mL of ethanol, azeotropically concentrated, and then water (0.6 g) and ethanol (8.3 mL) were added. 2-Propanol (10 ml) was added to the solution, and the mixture was stirred at room temperature for 5 minutes. 1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] Cyclopropanecarboxylic acid trichloride (150 mg) was added thereto, followed by stirring for 13 hours and 45 minutes. 2-Propanol (50 ml) was added and the mixture was stirred at room temperature for 24 hours and 35 minutes, and then the crystals were filtered and dried to obtain the title compound (4.26 g) as a white solid.

(Example 9) N- (2-Fluoro-4 - {[2 - ({[4- (4-methylpiperazin- 1 -yl) piperidin- 1 -yl] carbonyl} amino) Yl] oxy} phenyl) -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

(Method 1)

1-carbonyl] amino} pyridin-4-yloxy) phenylcarbamoyl-2-oxo- ] To a mixed suspension of cyclopropanecarboxylic acid (100 mg) in tetrahydrofuran (1 ml), N, N-dimethylformamide (0.2 ml) and 4-fluoroaniline (0.0526 ml) was added 4- -Dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (164 mg) was added thereto, followed by stirring at room temperature for 2.5 hours. A 5% aqueous solution of sodium hydrogencarbonate was added to the reaction solution and the mixture was quenched, and ethyl acetate was added thereto to effect layer separation. The organic layer was washed with water and then concentrated. The concentrated residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 95: 5). The eluate was concentrated. Ethyl acetate (2 ml) was added to the residue, and the mixture was stirred at room temperature for 30 minutes. Heptane (2 ml) was added, and the mixture was stirred for 30 minutes. The crystals were collected by filtration and dried to obtain the title compound (74 mg) as white crystals.

¹ H-NMR spectrum (DMSO-d ₆ )? (Ppm): 1.22-1.33 (2H, m), 1.54-1.63 (4H, m), 1.68-1.78 (2H, m), 6.60 (1H, dd, J = 2.4 Hz, 5.6 Hz), 2.12-2.40 (5H, m), 2.40-2.60 (4H, m), 2.68-2.78 , 7.00 (1H, m), 7.19 (2H, t, J = 8Hz), 7.22 (1H, dd, J = 2.4Hz, 11.2Hz) Hz), 7.93 (1H, t, J = 8.8Hz), 8.13 (1H, d, J = 5.6Hz), 9.21 (1H, s), 9.90 (1H, brs), 10.55 (1H, brs).

(Method 2)

1- [2-fluoro-4- (2 - {[4- (4-methylpiperazin- 1 -yl) -piperidine- 1 -carbonyl] -amino} -pyridin-4- yloxy) phenyl To a mixed suspension of tetrahydrofuran (4.5 ml), N, N-dimethylformamide (1 ml) and 4-fluoroaniline (0.131 ml) of cyclopentanecarboxylic acid (500 mg, 0.925 mmol) 4- (4,6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate was added thereto, followed by stirring at room temperature for 16 hours. Ethyl acetate (75 ml) was added to the reaction solution, and a 5% aqueous solution of sodium hydrogencarbonate (7.5 ml) was added thereto, quenched, and layered. A 1N hydrochloric acid aqueous solution (5 ml) was added to the organic layer and layered. To the aqueous layer was added tetrahydrofuran (7.5 ml), neutralized by adding 2N aqueous sodium hydroxide (3 ml), and ethyl acetate (7.5 ml) was added and layered. The organic layer was washed with water and then concentrated. To the concentrated residue, ethyl acetate was added and the concentration was repeated three times.

Ethyl acetate was added to the residue to a total weight of 2.34 g, and seed crystals obtained in (Method 1) were added thereto, followed by stirring at room temperature for 30 minutes. Ethyl acetate (2.5 ml) was added, and the mixture was stirred for 1 hour, then heptane (5 ml) was added, and the mixture was further stirred for 2 hours. The crystals were collected by filtration and dried to obtain the title compound (427 mg) as white crystals.

(Method 3)

To a mixed solution of tetrahydrofuran (4400 g) and 2-propanol (2159 g) of 2-chloro-4,6-dimethoxy-1,3,5-triazine (238 g) was added N- methylmorpholine ) Was added under stirring, and the mixture was washed with tetrahydrofuran (122 g) and stirred at 25 占 폚 for 33 minutes. To the reaction solution was added 1- [2-fluoro-4- (2 - {[4- (4-methylpiperazin- 1 -yl) piperidine- 1 -carbonyl] amino} piperidin- ) Phenylcarbonyl] -cyclopropanecarboxylic acid benzyl ester trichloride (550 g) was added to the reaction mixture, the mixture was washed with tetrahydrofuran (245 g), and 4-fluoroaniline (132 g) was added thereto to obtain tetrahydrofuran 122 g), and the mixture was stirred at 25 占 폚 for 4 hours and 20 minutes. Isopropyl acetate (7194 g) and a 1N hydrochloric acid aqueous solution (5593 g) were added to the reaction solution and layered. Tetrahydrofuran (1147 g) and isopropyl acetate (7194 g) were added to the water layer, and a 2N sodium hydroxide aqueous solution (5401 g) was added to neutralize the mixture. The organic layer was washed twice with 5% brine (1650 g) and once with water (1650 g), and then concentrated to about 3 L in volume. To the concentrate was added isopropyl acetate (1440 g) and the mixture was stirred at 25 占 폚 for 1 hour and 20 minutes. Isopropyl acetate (959 g) was added, and the mixture was further stirred at the same temperature for 3 hours and 7 minutes. Isopropyl acetate (2398 g) was added thereto, followed by further stirring at the same temperature for 16 hours and 28 minutes. The precipitated crystals were collected by filtration and dried to obtain the title compound (408 g) as white crystals.

(Example 10) 4- (4-Amino-2,5-difluorophenyl) pyridine-2-carboxamide

4-Amino-2,5-difluorophenol (4.95 g) was dissolved in dimethyl sulfoxide (50 ml) under a nitrogen stream, tert-butoxy potassium (4.05 g) was added at room temperature and the mixture was stirred for 25 minutes. To this solution was added 4-chloropyridine-2-carboxyamide (2.70 g), which was stirred for 2.5 hours at 80 deg. After the reaction solution was cooled to room temperature, a 1N aqueous sodium hydroxide solution (74.25 ml) was added, and the mixture was stirred for 10 hours. The precipitated solid was collected by filtration, and the obtained solid was washed with water. This solid was warm-air dried at 100 占 폚 for 24 hours to obtain the title compound (3.38 g, 74%) as a purple powder.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): (2H, d, J = 6.0 Hz), 6.75-6.80 (1H, m), 7.17-7.20 (1H, m), 7.26 (1H, dd, J = 7.2, 10.8 Hz), 7.38 , 7.73 (1H, s), 8.14 (1H, s), 8.52 (1H, d, J = 5.6Hz).

ESI-MS (m / z): 288 [M + Na] < ⁺ >.

Example 11 Synthesis of benzyl 1 - {[(4 - {[2- (aminocarbonyl) pyridin-4-yl] oxy} -2,5-difluorophenyl) amino] carbonyl} cyclopropanecarboxylate

1 - [(benzyloxy) carbonyl] cyclopropanecarboxylic acid (1.04 g) was dissolved in tetrahydrofuran (15 ml) under a nitrogen atmosphere. At 0 ° C, N-methylmorpholine (0.520 ml) was added and the mixture was stirred for 15 minutes. To this mixture was added thionyl chloride (0.345 ml) at 0 ° C and the mixture was stirred at the same temperature for 30 minutes, and then 4- (4-amino-2,5-difluorophenoxy) pyridine-2-carboxamide , And N-methylmorpholine (0.520 ml) were added thereto, followed by stirring at room temperature for 2 hours and 50 minutes. To the reaction solution, 1N sodium hydroxide (15 ml) and ethyl acetate (20 ml) were added and dispensed. The organic layer was washed successively with 1N aqueous sodium hydroxide solution (15 ml), water (15 ml) and saturated brine (15 ml), and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent: heptane: ethyl acetate = 1: 1 to 1: 2). The objective fraction was concentrated under reduced pressure to obtain the title compound (822.7 mg, 93%) as a white powder.

¹ H-NMR spectrum (DMSO-d ₆ )? (Ppm): 1.58-1.63 (4H, m), 5.20 (2H, s), 7.24-7.27 (1H, m), 7.30-7.42 (1H, d, J = 5.6 Hz), 7.43 (1H, , 10.93 (1H, br s).

ESI-MS (m / z): 490 [M + Na] < ⁺ >.

Example 12 Benzyl 1 - [({4 - [(2-aminopyridin-4-yl) oxy] -2,5-difluorophenyl} amino) carbonyl] cyclopropanecarboxylate

Carbonyl} cyclopropanecarboxylate (1.55 g) was added to a solution of 1 - {[(4 - {[2- (aminocarbonyl) pyridin- 4-yl] oxy} -2,5-difluorophenyl) Was dissolved in N, N-dimethylformamide (33 mL). Water (0.299 ml) and iodobenzene diacetate (1.18 g) were added at room temperature, and the mixture was stirred for 15 hours and 20 minutes. Iodobenzene diacetate (215 mg) was added again, and the mixture was stirred for 2 hours and 20 minutes. Water (150 ml) was added to the mixture, and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate (200 ml) and ethyl acetate (300 ml) were added and dispensed. The organic layer was washed with water (200 mL, twice) and saturated brine (150 mL), and then dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent: heptane: ethyl acetate = 1: 2). The objective fraction was concentrated under reduced pressure to obtain the title compound (1.217 g, 83%) as a pale yellow solid.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): (2H, brs), 6.18 (1H, dd, J = 2.4, 5.6Hz), 7.30 (1H, d, J = D, J = 7.2, 10.8 Hz), 7.82 (1H, d, J = 5.6 Hz), 8.05-8.20 (1H, m), 10.86 (1H, brs).

ESI-MS (m / z): 440 [M + H] < ⁺ >.

(Example 13) Synthesis of benzyl 1 - ({[4 - ({2- [(phenoxycarbonyl) amino] pyridin-4-yl} oxy) -2,5- difluorophenyl] amino} carbonyl) Propanecarboxylate

To a solution of benzyl 1 - [({4 - [(2-aminopyridin-4-yl) oxy] -2,5-difluorophenyl} amino) carbonyl] cyclopropanecarboxylate (1.15 g) And dissolved in tetrahydrofuran (12 mL). Pyridine (0.424 ml) and phenyl chloroformate (0.657 ml) were added at room temperature, and the mixture was stirred for 20 minutes. To this mixture was added a saturated aqueous solution of sodium hydrogencarbonate (36 ml) and hexane (36 ml), and the mixture was stirred for 55 minutes. The precipitated solid was filtered off. The resulting solid was washed with hexane, air-dried, and then warm-air dried (60 ° C) for 5 hours. Water (150 ml) was added to the solid and stirred for 2 hours. The solid was filtered off, and the obtained solid was washed with water. This solid was subjected to hot air drying (60 DEG C) for 3 days to obtain the title compound (1.117 g, 76%) as a white solid.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 1.69-1.90 (4H, m), 5.19 (2H, s), 6.62 (1H, dd, J = 2.4,6.0Hz), 6.95-7.04 (1H, m), 7.12-7.21 (1H, m), 7.28-7.45 (9H, m), 7.56 (1H, d, J = 2.4Hz), 8.19 J = 7.2, 12.0 Hz), 8.49 (1H, brs), 11.27 (1H, brs).

(Example 14) benzyl 1 - [({2,5-difluoro-4 - [(2 - {[(3-hydroxyacetidin- 1 -yl) carbonyl] amino} pyridin- Oxy] phenyl} amino) carbonyl] cyclopropanecarboxylate

To a solution of benzyl 1 - ({[4 - ({2- [(phenoxycarbonyl) amino] pyridin-4-yl} oxy) -2,5- difluorophenyl] amino} carbonyl) cyclopropane (0.100 ml) was added at room temperature to a mixture of 3-hydroxyacetidine hydrochloride (39.1 mg) and N, N-dimethylformamide (4.0 ml) Lt; / RTI > 3-hydroxyazetidine hydrochloride (10.0 mg) and triethylamine (0.025 ml) were added at room temperature, and the mixture was stirred for 1 hour and 20 minutes. A saturated aqueous solution of sodium hydrogencarbonate (16 ml) and hexane (5 ml) were added to the mixture and stirred, and the precipitated solid was collected by filtration. The solid was washed with water (2 mL, 3 times) and air dried. The resulting solid was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 10: 1). The objective fraction was concentrated under reduced pressure to obtain the title compound (86.7 mg, 45%) as a white solid.

¹ H-NMR Spectrum (CDCl ₃ )? (Ppm): 1.72-1.86 (4H, m), 3.93 (2H, dd, J = 4.4,10.0Hz), 4.26-4.32 (2H, m), 4.66-4.73 (1H, d, J = 7.2, 10.4 Hz), 7.30-7.43 (1H, m), 5.20 (1H, d, J = 6.0Hz), 8.34 (1H, dd, J = 7.2, 12.0Hz), 11.27 .

ESI-MS (m / z): 537 [MH] ^<">.

Example 15: Synthesis of 1 - [({2,5-difluoro-4 - [(2 - {[(3-hydroxyacetidin- 1 -yl) carbonyl] amino} pyridin- ] Phenyl} amino) carbonyl] cyclopropanecarboxylic acid triethylamine salt

(2 - {[(3-hydroxyazetidin- 1 -yl) carbonyl] amino} pyridin-4-yl) oxy] Phenyl} amino) carbonyl] cyclopropanecarboxylate (84.2 mg) was dissolved in tetrahydrofuran-methanol (1: 1) (2 ml). 10% palladium carbon (33.2 mg) was added to the reaction system to adjust the hydrogen atmosphere, followed by stirring at room temperature for 20 hours. After the inside of the reaction system was purged with nitrogen, triethylamine (0.0435 ml) was added and the mixture was stirred for 30 minutes. The catalyst was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (75.3 mg, 88%) as a white solid.

ESI-MS (m / z): 447 [MH] ^<">.

Example 16: Synthesis of N- {2,5-difluoro-4 - [(2 - {[(3-hydroxyacetidin- 1 -yl) carbonyl] amino} pyridin- } -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxamide

({2,5-difluoro-4 - [(2 - {[(3-hydroxyazetidin- 1 -yl) carbonyl] amino} pyridin- Amino) carbonyl] cyclopropanecarboxylic acid triethylamine salt (75.3 mg), 4-fluoroaniline (0.026 ml) and tetrahydrofuran (1.0 ml) at room temperature was added 4- (1, 5, 5-triazin-2-yl) -4-methylmorpholinium chloride hydrate (80.8 mg) was added thereto, followed by stirring for 5 hours. 4- (4,6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (80.8 mg) was added at room temperature and the mixture was stirred for 87 hours. A saturated aqueous sodium hydrogen carbonate solution (5 ml) was added to the reaction mixture and stirred. Ethyl acetate (20 ml) and water (20 ml) were added and distributed. The organic layer was washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 10: 1). The objective fraction was concentrated under reduced pressure to obtain the title compound (68.1 mg, 92%) as a white solid.

¹ H-NMR spectrum _{(DMSO-d 6) δ (} ppm): 1.54-1.68 (4H, m), 3.65-3.72 (2H, m), 4.09-4.15 (2H, m), 4.33-4.41 (1H, m ), 5.60 (1H, d, J = 6.4 Hz), 6.62-6.66 (1H, m), 7.14-7.22 (2H, m), 7.50-7.65 (4H, m), 8.05-8.15 8.13 (1H, d, J = 5.6Hz), 9.19 (1H, brs), 9.79-9.84 (1H, m), 10.95-11.02 (1H, m).

ESI-MS (m / z): 540 [MH] ^<">.

Example 17: Benzyl 1 - ({[(2,5-difluoro-4- {2- [3-methyl- 3- (1- methylpiperidin-4-yl) ureido] pyridin- Yl} oxy) phenyl] amino} carbonyl) cyclopropanecarboxylate

To a solution of benzyl 1 - ({[4 - ({2- [(phenoxycarbonyl) amino] pyridin-4-yl} oxy) -2,5- difluorophenyl] amino} carbonyl) cyclopropane Carboxylate (200 mg) was suspended in N-methylpyrrolidinone (2.0 ml). At room temperature, 1-methyl-4- (methylamino) piperidine (0.104 ml) was added and stirred overnight. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 ml) and the mixture was stirred. And extracted with ethyl acetate (20 ml). The organic layer was washed with water (10 ml), saturated aqueous ammonium chloride solution (10 ml) and saturated brine (10 ml), and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 95: 5). The target fraction was concentrated under reduced pressure, and the residue was dried under reduced pressure to obtain the title compound (62.3 mg, 29%) as a white powder.

¹ H-NMR spectrum _{(CDCl 3) δ (ppm)} : 1.60-1.90 (8 H, m), 2.05-2.20 (2H, m), 2.32 (3H, s), 2.89 (3H, s), 2.90-3.00 (2H, m), 4.19 (1H, m), 5.20 (2H, s), 6.53 (1H, dd, J = 2.4, 5.6Hz), 7.00 D, J = 7.2, 12.0 Hz), 11.27 (1H, brs), 7.45 (5H, m), 7.68 ).

ESI-MS (m / z): 616 [M + Na] < ⁺ >.

Example 18: 1 - ({[(2,5-Difluoro-4- {2- [3-methyl- 3- (1 -methylpiperidin-4-yl) ureido] pyridin- Yl} oxy) phenyl] amino} carbonyl) cyclopropanecarboxylic acid

To a solution of benzyl 1 - ({[(2,5-difluoro-4- {2- [3-methyl- 3- (1- methylpiperidin- (60 mg) was dissolved in tetrahydrofuran-methanol (1: 1) (4.0 ml), and 10% palladium carbon (45 mg) was added Respectively. The inside of the reaction system was put into a hydrogen atmosphere, and then stirred at room temperature for 3.5 hours. After the inside of the reaction system was purged with nitrogen, tetrahydrofuran-methanol (1: 1) (4.0 ml) was added and diluted. The catalyst was filtered off and washed with methanol. The filtrate was distilled off under reduced pressure to obtain the title compound (49.2 mg, 95%) as a white solid.

ESI-MS (m / z): 502 [MH] ^<">.

Example 19: Synthesis of N- (2,5-difluoro-4 - {[2 - ({[methyl (1 -methylpiperidin-4- yl) amino] carbonyl} amino) pyridin- ] Oxy} phenyl) -N '- (4-fluorophenyl) cyclopropane-1, 1-dicarboxyamide

To a solution of 1 - ({[(2,5-difluoro-4- {2- [3-methyl- 3- (1- methylpiperidin- 4- yl) ureido] pyridin- (4,6-dimethoxyphenyl) amino] carbonyl) cyclopropanecarboxylic acid (49.2 mg) and 4-fluoroaniline (0.0186 ml) and tetrahydrofuran (3-methylpiperazin-1-yl) ethoxy] -1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (57.6 mg) was added thereto and stirred for 15 hours. To the reaction mixture was added a saturated aqueous sodium hydrogencarbonate solution (5 ml) and the mixture was stirred. Subsequently, ethyl acetate (20 ml) and water (15 ml) were added and distributed. The organic layer was washed with saturated brine (10 mL), and dried over anhydrous sodium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 95: 5). The objective fraction was concentrated under reduced pressure to obtain the title compound (41.5 mg, 71%) as a white solid.

¹ H-NMR spectrum (CDCl ₃ ) 隆 (ppm): 1.61-1.83 (8 H, m), 2.03-2.10 (2H, m), 2.28 (3 H, s), 2.88 (2H, m), 4.10-4.20 (1H, m), 6.55 (1H, dd, J = 2.4,5.6Hz), 6.98-7.08 d, J = 7.2, 12.0 Hz), 8.57 (1H, s), 9.59 (1H, d, J = (1H, s)

ESI-MS (m / z): 597 [M + H] < ⁺ >.

Example 20: Preparation of benzyl 1 - [({2,5-difluoro-4 - [(2 - {[(S) -3-hydroxypyrrolidin- 1 -yl) carbonyl] amino} Yl) oxy] phenyl} amino) carbonyl] cyclopropanecarboxylate

To a solution of benzyl 1 - ({[4 - ({2- [(phenoxycarbonyl) amino] pyridin-4-yl} oxy) -2,5- difluorophenyl] amino} carbonyl) cyclopropane (S) -3-hydroxypyrrolidine (0.0577 ml) was added to a mixture of the carboxylate (200 mg) and N-methylpyrrolidinone (4.0 ml) at room temperature and the mixture was stirred for 2 hours. To this mixture was added a saturated aqueous solution of sodium hydrogencarbonate (20 ml) and the mixture was stirred for 30 minutes. The precipitated solid was collected by filtration, and the solid was washed with water (20 mL, 3 times) and the solid was subjected to hot air drying (80 DEG C) for 1 day to obtain the title compound (159.0 mg, 81%) as a white solid .

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 1.71-1.88 (4H, m), 2.00-2.17 (2H, m), 3.47-3.69 (4H, m), 4.53-4.59 Dd, J = 7.2, 10.4 Hz), 7.08 (1H, brs), 7.30-7.44 (5H, m) , 7.70 (1H, d, J = 2.0Hz), 8.05 (1H, d, J = 5.6Hz), 8.31-8.38 (1H, m), 11.27 (1H, brs).

ESI-MS (m / z): 551 [MH] ^<">.

(Example 21) Synthesis of 1 - [({2,5-difluoro-4 - [(2 - {[(S) -3-hydroxypyrrolidin- 1 -yl) carbonyl] amino} 4-yl) oxy] phenyl} amino) carbonyl] cyclopropanecarboxylic acid triethylamine salt

To a solution of benzyl 1 - [({2,5-difluoro-4 - [(2 - {[(S) -3- hydroxypyrrolidin- 1 -yl) carbonyl] amino} 1-yl) oxy] phenyl} amino] carbonyl] cyclopropanecarboxylate (156.8 mg) was dissolved in tetrahydrofuran-methanol (1: 1) (4 ml) After the inside of the reaction system was purged with nitrogen, triethylamine (0.0991 ml) was added, and the mixture was stirred for 30 minutes. The catalyst was filtered and washed with methanol . The filtrate was concentrated under reduced pressure to obtain the title compound (174.9 mg, quant.) As a white solid.

ESI-MS (m / z): 461 [MH] ^<">.

(Example 22) N- {2,5-Difluoro-4 - [(2 - {[((S) -3-hydroxypyrrolidin- 1 -yl) carbonyl] amino} pyridin- Yl) oxy] phenyl} -N '- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide

(S) -3-hydroxypyrrolidin-1-yl) carbonyl] amino} pyridin-4 To a mixture of 4-fluoroaniline (0.0587 ml) and tetrahydrofuran (4.0 ml) was added dropwise a solution of 4 (trimethylsilyl) aminocarbonylcyclopropanecarboxylic acid triethylamine - (4,6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (365 mg) was added and the mixture was stirred for 68 hours and 30 minutes. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 ml) and the mixture was stirred. Ethyl acetate-tetrahydrofuran (1: 1) (40 ml) and water (30 ml) were added and distributed. The organic layer was washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 10: 1). The objective fraction was concentrated under reduced pressure to obtain the title compound (128.5 mg, 75%) as a white solid.

¹ H-NMR Spectrum (CDCl ₃ )? (Ppm): 1.67-1.77 (4H, m), 2.00-2.16 (2H, m), 3.46-3.67 (4H, m), 4.52-4.58 D, J = 5.6 Hz), 6.55-6.59 (1H, m), 6.97-7.10 (4H, m), 7.45-7.52 , 8.28 (1H, dd, J = 7.6,12.0Hz), 8.64-8.70 (1H, m), 9.49-9.55 (1H, m).

ESI-MS (m / z): 554 [MH] ^<">.

(Example 23) benzyl 1 - [({2,5-difluoro-4 - [(2 - {[((R) -3-hydroxypyrrolidin- 1 -yl) carbonyl] amino} pyridine Yl) oxy] phenyl} amino) carbonyl] cyclopropanecarboxylate

To a solution of benzyl 1 - ({[4 - ({2- [(phenoxycarbonyl) amino] pyridin-4-yl} oxy) -2,5- difluorophenyl] amino} carbonyl) cyclopropane To a mixture of the carboxylate (200 mg), (R) -3-hydroxypyrrolidine hydrochloride (88.2 mg) and N-methylpyrrolidinone (4.0 ml) was added N, N-diisopropylethylamine (0.249 ml) was added thereto, followed by stirring for 5 hours. (R) -3-hydroxypyrrolidine hydrochloride (44.1 mg) and N, N-diisopropylethylamine (0.125 ml) at room temperature, and the mixture was stirred for 15 hours and 40 minutes. Saturated aqueous sodium hydrogencarbonate solution (20 ml) was added to the mixture to stop the reaction. Ethyl acetate-tetrahydrofuran (1: 1) (50 ml) and water (30 ml) were added and distributed. The organic layer was washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 10: 1). The objective fraction was concentrated under reduced pressure to obtain the title compound (178.2 mg, 90%) as a white solid.

¹ H-NMR spectrum (CDCl ₃ )? (Ppm): 1.71-1.88 (4H, m), 2.00-2.17 (2H, m), 3.47-3.69 (4H, m), 4.53-4.59 Dd, J = 7.2, 10.4 Hz), 7.08 (1H, brs), 7.30-7.44 (5H, m), 5.20 (2H, m), 654 (1H, dd, J = 2.0,5.6Hz) , 7.70 (1H, d, J = 2.0Hz), 8.05 (1H, d, J = 5.6Hz), 8.31-8.38 (1H, m), 11.27 (1H, brs).

ESI-MS (m / z): 551 [MH] ^<">.

(Example 24) 1 - [({2,5-Difluoro-4 - [(2 - {[((R) -3- hydroxypyrrolidin- 1 -yl) carbonyl] amino} 4-yl) oxy] phenyl} amino) carbonyl] cyclopropanecarboxylic acid triethylamine salt

(R) -3-hydroxypyrrolidin-1-yl) carbonyl] amino} pyridine-l- Yl) oxy] phenyl} amino) carbonyl] cyclopropanecarboxylate (156.8 mg) was dissolved in tetrahydrofuran-methanol (2: 1) (6 ml). 10% palladium carbon (68.6 mg) was added to the reaction system to adjust the hydrogen atmosphere, followed by stirring at room temperature for 16 hours and 30 minutes. After the inside of the reaction system was purged with nitrogen, triethylamine (0.112 ml) was added and stirred for 30 minutes. The catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (185.3 mg, quantitative) as a white solid.

ESI-MS (m / z): 461 [MH] ^<">.

(Example 25) N- {2,5-Difluoro-4 - [(2 - {[((R) -3-hydroxypyrrolidin- 1 -yl) carbonyl] amino} pyridin- Yl) oxy] phenyl} -N '- (4-fluorophenyl) cyclopropane-1,1-dicarboxamide

(R) -3-hydroxypyrrolidin-1-yl) carbonyl] amino} pyridin-4 To a mixture of 4-fluoroaniline (0.0623 ml) and tetrahydrofuran (4.0 ml) was added dropwise a solution of 4 (trimethylsilyl) aminocarbonylcyclopropanecarboxylic acid triethylamine - (4,6-dimethoxy [1,3,5] triazin-2-yl) -4-methylmorpholinium chloride hydrate (388 mg) was added thereto, followed by stirring for 68 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate (10 ml) and the mixture was stirred. Ethyl acetate-tetrahydrofuran (1: 1) (40 ml) and water (30 ml) were added and distributed. The organic layer was washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Fuji Sylisia NH, eluent; ethyl acetate - ethyl acetate: methanol = 10: 1). The objective fraction was concentrated under reduced pressure to obtain the title compound (132.8 mg, 73%) as a white solid.

¹ H-NMR Spectrum (CDCl ₃ )? (Ppm): 1.67-1.77 (4H, m), 2.00-2.16 (2H, m), 3.46-3.67 (4H, m), 4.52-4.58 (2H, m), 7.67 (1H, d, J = 2.0Hz), 8.07 (1H, d, J = 5.6Hz), 6.55-6.59 (1H, m), 6.97-7.10 , 8.28 (1H, dd, J = 7.6,12.0Hz), 8.64-8.70 (1H, m), 9.49-9.55 (1H, m).

ESI-MS (m / z): 554 [MH] ^<">.

It is possible to carry out the production method of the present invention by performing the same reaction as the above-mentioned examples as an starting material with an amine or a known amine described in the above Production Examples.

[Pharmacological Test Example]

The biochemical activity of the present compound and its action and effect as a medicament (hepatocyte growth factor receptor inhibitory activity, antitumor activity, angiogenesis inhibitory activity and cancer metastasis inhibitory activity) were evaluated according to the following methods.

In addition, a list of the abbreviations or terms used in the following pharmacological test examples is shown below.

<List of abbreviations>

HGFR (hepatocyte growth factor receptor)

DNA (deoxyribonucleic acid)

The human placenta

PCR (Polymerase chain reaction)

VEGFR2 (vascular endothelial growth factor receptor 2, vascular endothelial growth factor receptor 2)

FGFR1 (fibroblast growth factor receptor 1, fibroblast growth factor receptor 1)

PDGFR? (Platelet derived growth factor receptor?, Platelet derived growth factor receptor?)

EGFR (epidermal growth factor receptor)

FBS (fetal bovine serum, FBS)

PBS (phosphate buffered saline)

Tris (Tris (buffer), Tris (hydroxymethyl) aminomethane)

PMSF (phenylmethylsulfonyl fluoride)

NP-40 (Nonidet P-40, Nonidet P-40)

EGTA (2-aminoethyleneglycol-N, N, N ', N'-tetraacetic acid)

SDS (sodium dodecylsulfate)

BSA (bovine serum albumin, bovine serum albumin)

Hepes (buffer), N- [2-Hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]

ATP (adenosine 5'-triphosphate, Adenosine 5'-triphosphate)

EDTA (ethylenediaminetetraacetic acid)

HTRF (Homogenous Time-Resolved Fluorescence)

HRP (Horseradish peroxidase, horseradish peroxidase)

ELISA (Enzyme-linked immunosorbent assay)

Pharmacological Test Example 1: Inhibitory effect on receptor tyrosine kinase activity

1. Cloning of receptor type tyrosine kinase and preparation of recombinant baculovirus solution

The cytoplasmic domain of HGFR (Genbank accession number J02958) is a 1.3 kb DNA fragment starting from lysine 974 and also containing a truncation codon, Park et al. [Proc. Natl. Acad. Sci. USA 84 (18), 6379-6383, 1987). This DNA fragment was amplified by PCR using two kinds of primers (SEQ ID NO: 1: 5'-CCGGCCGGATCCAAAAAGAGAAAGCAAATTAAA-3 'and SEQ ID NO: 2'5'-TTAATTCTGCAGCTATGATGTCTCCCAGAAGGA-3', Invitrogen) from a human placental cDNA library (purchased from Clontech) (Purchased from TaKaRa) using the PCR method (TaKaRa Ex Taq ^TM Kit, purchased from TaKaRa). This DNA fragment was cloned into a baculovirus transposition vector [pFast Bac ^TM -HT (purchased from GIBCO BRL)] to obtain a recombinant construct. This was transfected with insect cells (Spodoptera frugiperda9 (Sf9)) to prepare HGFR recombinant baculovirus solutions. (Recombinant baculovirus preparations were found in the standard Bac-to-Bac Baculovirus Expression System (GIBCO BRL) . Cloning and recombinant baculovirus solutions of other receptor tyrosine kinases were prepared by replacing HGFR with the cytoplasmic fragments starting from lysine 791 (VEGFR2, Genbank Accession No. L04947), the cytoplasmic fragments starting from lysine 398 (FGFR1, Genbank Accession No. X52833) or a cytoplasmic fragment starting from lysine 558 (PDGFRβ, Genbank Accession No. M21616). EGFR was also purchased from Sigma (product number E-2645).

2. Expression and purification of receptor tyrosine kinases

The above-mentioned HGFR recombinant baculovirus solution (4 ml) was added to Sf9 cells (3 × 10 ⁸ ) suspended in SF-900 II medium (purchased from Invitrogen) containing 2% FBS and incubated at 27 ° C. And cultured with shaking for 48 hours. The HGFR recombinant baculovirus-infected cells were centrifuged at 4 ° C for 5 minutes at 1000 rpm to remove the supernatant. The precipitated infected cells were suspended in 80 ml of ice-cold PBS, centrifuged at 4 ° C for 5 minutes at 1000 rpm, and the supernatant was removed. The precipitated infected cells were resuspended in 40 ml of ice-cold Lysis Buffer (50 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 1 mM PMSF, 1% &Lt; / RTI &gt; The suspension was centrifuged at 4 ° C for 30 minutes at 12,000 rpm to obtain supernatant.

The supernatant was equilibrated with 30 ml of Buffer A (20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 500 mM KCl, 20 mM imidazole, 10% (v / v) glycerol) NTA agarose column (3 mL, purchased from KIAGEN). The column was washed with 30 ml of Buffer A, 6 ml of Buffer B (20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 1 M KCl, 10% (v / v) glycerol) Buffer A, respectively. Subsequently, 6 ml of Buffer C (20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 100 mM KCl, 100 mM imidazole, 10% (v / v) glycerol) To obtain an eluate. The eluate was placed in a dialysis membrane (purchased from Spectrum Laboratories Inc.), a 1 ℓ dialysis buffer (20 mM Tris-HCl (pH 7.5), 10% (v / v) glycerol, 1 mM dithiothreitol, 0.1 mM Na ₃ VO ₄ , 0.1 mM EGTA) overnight at 4 ° C and stored at -80 ° C until use. A portion of the dialyzed effluent was subjected to SDS electrophoresis to provide a recombinant protein (His6-HGFR, a fusion of six histidines at the N terminus) detected in a Coomassie Brilliant Blue (CBB) staining with a molecular weight of approximately 60 kDa The cytoplasmic domain of HGFR) was quantified as BSA (purchased from Sigma) as a standard substance. (His6-VEGFR2, His6-FGFR1 or His6-PDGFR [beta]) in which 6 histidines were fused to N-terminus using the same method for the cytoplasmic domain of VEGFR2, the cytoplasmic domain of FGFR1 or the cytoplasmic domain of PDGFR [beta] .

3. Measurement of inhibitory effect on HGFR tyrosine kinase activity

To each well of a 96 well bottom round plate (product number 163320, purchased from NUNC) was added 10 μl of kinase reaction solution (200 mM Hepes (pH 7.4), 80 mM MgCl ₂ , 16 mM MnCl ₂ , 2 mM Na ₃ VO ₄ ), 30 ng of His6-HGFR (0.4% BSA solution), 250 ng of biotin-poly (GT), purchased from Japan Schering Co. (diluted 15 times with distilled water) , And 10 μl of a diluted solution (100 μl with 0.1% BSA, 4 μl) dissolved in dimethylsulfoxide were added to make the total volume 30 μl. Thereafter, 10 쨉 l of 4 쨉 M ATP (purchased from Sigma) diluted with distilled water was added and incubated at 30 째 C for 10 minutes. 10 쨉 l of 500 mM EDTA (pH 8.0) (purchased from Wako Pure Yaku Kogyo Co., Ltd.) To obtain a kinase reaction solution.

Tyrosine phosphorylated biotin-poly (GT) was detected by the homogeneous time-resolved fluorescence (HTRF) method (Analytical Biochemistry, 269 , 94-104, 1999). Namely, 20 μl of the kinase reaction solution and 30 μl of a dilution solution (50 mM Hepes (pH 7.4), 20 mM MgCl ₂ , 4 mM MnCl ₂ , 0.5 mM Na ₃ VO ₄ , 0.1% BSA and 100 mM EDTA) Was added to each well of a 96 well black half plate (purchased from COSTAR, product no. 3694). Each well was diluted 250 fold with 7.5 ng (20 mM Hepes (pH 7.0), 0.5 M KF, 0.1% BSA) of anti-phosphotyrosine antibody labeled with europium cryptate (Eu (K) -PY20 (25 μl diluted to 62.5 fold with 250 ng (20 mM Hepes (pH 7.0), 0.5 M KF, 0.1% BSA) of XL665-labeled streptavidin (XL665-SA, And fluorescence intensities of 665 nm and 620 nm when irradiated at an excitation wavelength of 337 nm of each well with a Discovery HTRF microplate analyzer (Packard Co.) were immediately measured. The tyrosine phosphorylation rate of biotin-poly (GT) was calculated using the deltaF% value described in the text of the HTRF standard test method of Shering, Japan. That is, the deltaF% value of the well to which His6-HGFR was added without adding the test substance was set to 100%, the deltaF% value of the well to which the test substance and His6-HGFR were not added was set to 0% (%) Of the deltaF% value of the sample. The concentration (IC ₅₀ ) of the test substance required to inhibit the HGFR kinase activity by 50% was calculated by this ratio (%) and is shown in Table 1.

Example No. IC ₅₀ ([mu] M) 9 0.053 16 0.004 19 0.049 22 0.016 25 0.010

4. Measurement of inhibitory effect on receptor type tyrosine kinase activity other than HGFR

The inhibitory action on VEGFR2, FGFR1 or EGFR tyrosine kinase activity was inhibited by using 15 ng of His6-VEGFR2, 15 ng of His6-FGFR1 or 23 ng of EGFR, respectively, instead of HGFR, and the same inhibitory action on HGFR tyrosine kinase activity .

On the other hand, the inhibitory activity against PDGFR? Tyrosine kinase activity was evaluated by detecting 50 ng of His6-PDGFR? And detecting tyrosine phosphorylated biotin-poly (GT) by the following method after obtaining the kinase reaction solution as described above.

34 [mu] l of kinase reaction solution and 16 [mu] l of dilution solution were added to each well of a 96-well streptavidin coated plate (purchased from PIERCE, product number 15129) and incubated at room temperature for 30 minutes. Each well was then washed three times with 150 μl of a washing solution (20 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20, 0.1% BSA) and incubated with anti-phosphotyrosine PY20) -HRP conjugate (2000-fold diluted with 20 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20, 1% BSA) at 70 ㎕ (purchased from Transduction Laboratories, And incubated for 1 hour. Thereafter, each well was washed three times with 150 μl of the washing solution, and 100 μl of TMB Membrane Peroxidase Substrate (purchased from Funakosha, Ltd., No. 50-5077-03) was added. After incubation at room temperature for 10 minutes, 100 쨉 l of 1 M phosphoric acid was added to each well, and the absorbance at 450 nm was immediately measured with a plate reader MTP-500 (manufactured by Corona Denshoku). (%) Of each well to which the test substance was added at the absorbance of 100% of the well to which His6-PDGFR? Was added without addition of the test substance and the absorbance of the well to which the test substance and His6-PDGFR? Respectively. The concentration (IC ₅₀ ) of the test substance required to inhibit PDGFR beta kinase activity by 50% was calculated by this absorbance ratio (%).

Pharmacological Test Example 2: Proliferation inhibition effect on human gastric cancer cells (MKN-45)

Human gastric cancer cells (MKN-45) were suspended in RPMI 1640 medium (purchased from Sigma) containing 1% FBS. The cell suspension (1 × 10 ⁴ cells / ml) was added to a cell culture 96-well plate (purchased from NUNC, product number 167008) at 0.1 ml / well and incubated overnight in a 5% CO ₂ incubator . After culturing, 0.1 ml of the test substance diluted in RPMI1640 medium containing 1% FBS was added to each well and further cultured in a 5% CO ₂ incubator (37 ° C) for 3 days. 10 μl of Cell Counting Kit-8 (purchased from DOJINDO, product number 343-07623) was added to each well, followed by incubation for about 1 hour and 30 minutes in a 5% CO ₂ incubator (37 ° C.). After incubation, the absorbance of each well was measured using a plate reader MTP-500 (manufactured by Corona Dentistry) with a measurement wavelength of 450 nm and a reference wavelength of 660 nm. The ratio (%) of the absorbance of each well to which the test substance was added to the absorbance of the well to which the test substance was not added was determined, and the concentration (IC ₅₀ ) of the test substance required to inhibit cell proliferation by 50% , Are shown in Table 2.

Example No. IC ₅₀ ([mu] M) 9 0.017 16 0.005 19 0.0049 22 0.0024 25 0.0022

Pharmacological Test Example 3: HGFR auto-phosphorylation inhibition using ELISA

1. Preparation of cell extract

Human gastric cancer cells (MKN-45) were suspended in RPMI 1640 medium (purchased from Sigma) containing 1% FBS. The cell suspension (1 × 10 ⁵ cells / ml) was added to a cell culture 96-well plate (purchased from NUNC, product number 167008) at 0.1 ml / well and incubated overnight in a 5% CO ₂ incubator . After incubation, the supernatant was removed from each well, and RPMI 1640 medium containing 0.05 ml of 1% FBS was added. Thereto was added 0.05 ml of the test substance (diluted with RPMI1640 medium containing 1% FBS) dissolved in dimethyl sulfoxide and incubated for 1 hour in a 5% CO ₂ incubator (37 ° C). The supernatant was removed from each well, each well was washed with 150 μl of PBS, and 50 μl of solubilization buffer (50 mM Hepes (pH 7.4), 150 mM NaCl, 10% (v / v) glycerol, 1% Triton X- _{, 1.5 mM MgCl 2, 1 mM} EDTA (pH 8.0), 100 mM NaF, 1 mM PMSF, 10 ㎍ / ㎖ Aprotinin, 50 ㎍ / ㎖ Leupeptin, 1 ㎍ / ㎖ Pepstatin a, 1 mM Na 3 VO 4) , 100 Mu] l. The plate was shaken at 4 DEG C for 1 hour to prepare a cell extract.

2. Preparation of Antiphosphotyrosine Antibody Solidification Plate

A 60 mM bicarbonate buffer (pH: 33) containing 50 μg / ml of anti-phosphotyrosine antibody (PY20, purchased from Transduction Laboratory, product number P-11120) in a 96 well plate for ELISA (purchased from COSTAR, 9.6) was added. The plates were incubated overnight at &lt; RTI ID = 0.0 &gt; 4 C. &lt; / RTI &gt;

3. Measurement of HGFR auto-phosphorylation inhibition

Each well of the plate prepared in 2. was washed three times with 200 占 퐇 of PBS, and 150 占 퐇 of 3% BSA / PBS was added thereto, followed by incubation at room temperature for 2 hours. Each well was washed three times with 200 μl of PBS, to which 50 μl of the above-described cell extract was added, followed by incubation at 4 ° C. overnight. After incubation, each well was washed three times with 250 μl of washing solution [0.1% BSA, 20 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20] anti-HGFR antibody (h-Met (C-12), purchased from Santa Cruz, product number sc-10) diluted 2000-fold with 200 mM Tris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween- Was added. This was incubated at room temperature for 1 hour, washed with 250 μl of washing solution three times, 70 μl of peroxidase-labeled anti-rabbit Ig antibody (purchased from Cell Signaling, product number 7074) diluted 2000 times with the reaction solution was added Respectively. Further, it was incubated at room temperature for 1 hour, and each well was washed three times with 250 μl of washing solution, and then 70 μl of TMB Membrane Peroxidase Substrate (purchased from Funakoshi, No. 50-5077-03) was added. This was incubated at room temperature for 10 minutes, then 70 μl of 1 M phosphoric acid was added to each well, and the absorbance at 450 nm was immediately measured with a plate reader MTP-500 (Corona Denshi Co., Ltd.). The absorbance of the well to which the cell extract without addition of the test substance was added was adjusted to 100% of the HGFR magnetic phosphorylation activity and the absorbance of the well to which 50 μl of the solubilization buffer was added was adjusted to 0% of the HGFR magnetic phosphorylation activity. Activity (%) was determined. The concentration of the test substance (IC ₅₀ ) required to inhibit the HGFR self-phosphorylation activity of the test substance by 50% was determined by changing the concentration of the test substance in various steps to obtain the HGFR self-phosphorylation activity (%) in each case, Table 3 shows the results.

Example No. IC ₅₀ ([mu] M) 9 0.016 16 0.0084 19 0.011 22 0.0045 25 0.0034

(Powder X-ray diffraction measurement)

About 5 mg of the sample obtained in Example 9 (Method 3) was pulverized with a mortar and placed on an aluminum pan for measurement, and the measurement was carried out under the following conditions.

Apparatus: X-ray DSC system: TTR-III (manufactured by Rigaku Denki Kogyo Co., Ltd.)

Used X-ray: CuKα line

Goniometer: TTR-Ⅲ Horizontal Goniometer

Counter: Scintillation counter

Tube voltage: 50 kV

Tube current: 300 mA

Scan speed: 5 ° / min

Scan axis: 2? /?

Scanning range: 2θ = 5 ° to 35 °

Diverging slit: 0.5 °

Divergent vertical slit: 2 mm

Scatter Slit: Open

Receiving slit: Open

Sampling width: 0.02 °

Cumulative count: 1

Powder X-ray diffraction patterns of the crystals obtained in Example 9 (Method 3) are shown in Fig. 1, and representative peaks and relative intensities of diffraction angles (2?) Of the crystals are shown in Table 4.

The method for producing a phenoxypyridine derivative according to the present invention is useful as an antineoplastic agent, an angiogenesis inhibitor or a metastasis inhibitor for various tumors such as pancreatic cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor and ovarian cancer. It is possible to provide a phenoxypyridine derivative useful as an inhibitor.

                         SEQUENCE LISTING &Lt; 110 > Eisai R & D Manamation Co., Ltd. <120> PROCESS FOR PREPARING PHENOXYPYRIDINE DERIVATIVES <130> FP06-0349-00 &Lt; 150 > US 60 / 824,192 <151> 2006-08-31 <150> JP 2006-285,327 <151> 2006-10-19 &Lt; 150 > US 60 / 855,117 <151> 2006-10-30 <160> 2 <170> PatentIn version 3.1 <210> 1 <211> 33 <212> DNA <213> Artificial <220> An artificially synthesized primer sequence <400> 1 ccggccggat ccaaaaagag aaagcaaatt aaa 33 <210> 2 <211> 33 <212> DNA <213> Artificial <220> An artificially synthesized primer sequence <400> 2 ttaattctgc agctatgatg tctcccagaa gga 33

Claims (21)

A compound represented by the following formula (II) or a salt thereof and a compound represented by the following formula (III) in the presence of a condensing agent:

[In the above formula, R ¹ is (1) an azetidin-1-yl group which may have a substituent selected from the following Substituent group a, (2) a pyrrolidin-1-yl group which may have a substituent selected from Substituent Group (4) a piperazin-1-yl group which may have a substituent selected from the following substituent group a, (5) a substituent group a (6) a morpholin-4-yl group which may have a substituent selected from the following substituent group a, or (7) a group represented by the formula -NR ^11a R ^11b , R ^11a represents a hydrogen atom or a methyl group; R ^11b represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidin- pyran-4-yl group refers to, it provided that R ^11b is a group represented by the good when you get the substituents selected from the group b to the substituents), And R ² , R ³ , R ⁴ and R ⁵ are the same or different and represent a hydrogen atom or a fluorine atom; [Substituent group a] (Excluding a hydroxyl group and a dimethylaminoacetoxy group), each of which is optionally substituted by a hydroxyl group, a hydroxyl group, a hydroxyl group, a hydroxyl group, a dimethylaminoacetoxy group, a methyl group, an ethyl group, May have a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group, [Substituent group b] And each of the groups may have a methyl group or a dimethylamino group], the alkyl group may be a methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group and a piperazinyl group,

[Wherein R ⁶ represents a hydrogen atom or a fluorine atom],

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above. The process according to claim 1, wherein the compound represented by the formula (II) or a salt thereof is prepared by hydrolysis or catalytic hydrogenation of a compound represented by the formula (IV)

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 1,

Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 1, R ⁷ is a C _1-6 alkyl group or a benzene ring, (1) a halogen atom, (2 A hydroxyl group, (3) a nitro group, (4) a cyano group, (5) a trifluoromethyl group, (6) a C _1-6 alkyl group, (7) a C _1-6 alkoxy group, Mono-C _1-6 alkylamino group, and (10) di-C _1-6 alkylamino group]. The compound represented by the formula (IV): or a salt thereof may be prepared by reacting a compound represented by the formula (V): (1) azetidine which may have a substituent selected from the substituent group (3) a piperidine which may have a substituent selected from the substituent group a described in (1), (4) a substituent selected from the group consisting of (5) a diazepan which may have a substituent selected from the substituent group a described in (1), (6) a diazabicycarbonyl group which may have a substituent selected from the group consisting of (7) HNR ^11a R ^11b (wherein R ^11a and R ^11b are the same as defined in claim 1), or a salt thereof, which may have a substituent selected from Substituent group a, In the presence of a base.

[Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 2, and R ⁷ is as defined in claim 2]

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 2, R ⁷ is the same as defined in claim 2, and Ar is a halogen atom, a methyl group, a methoxy group, A phenyl group which may have one or two substituents selected from a nitro group, a cyano group and a trifluoromethyl group]. The process according to claim 3, wherein the compound represented by the following formula (V) is produced by reacting a compound represented by the following formula (VI) in the presence of a base with a compound represented by the following formula

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 3, R ⁷ is the same as defined in claim 3, and Ar is as defined in claim 3 and Same],

[Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 3, and R ⁷ is the same as defined in claim 3]

[Wherein Ar is the same as defined in claim 3]. The process according to claim 4, wherein the compound represented by the formula (VI) is prepared by reacting a compound represented by the following formula (VIII) with a Hofmann precursor:

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 4 and R ⁷ is as defined in claim 4,

[Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 4, and R ⁷ is the same as defined in claim 4]. The process according to claim 5, wherein the compound represented by the formula (VIII) is prepared by reacting a compound represented by the formula (IX): wherein X is a halogen atom or a condensing agent,

[Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 5, and R ⁷ is the same as defined in claim 5]

[Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 5]

[Wherein R ⁷ is the same as defined in claim 5]. The method of claim 1, wherein the condensation agent is 4- (4,6-dimethoxy [1,3,5] triazin-2-yl) -4- methylmorpholinium chloride hydrate [1.3.5] triazin-2-yl) -4-methylmorpholinium chloride hydrate) or 2-chloro-4,6-dimethoxy-1 , 3,5-triazine). 4. The method of claim 3 wherein the amine is selected from the group consisting of 1- (2-dimethylaminoethyl) piperazine, 4- (pyrrolidin-1-yl) piperidine, 4- (dimethylaminomethyl) (Piperidin-4-yl) azetidin-3-yl] amine, 1-methyl-4- (piperidin- 4-yl) piperazine, 4- (1-methylpiperidin-4-yl) piperazine, 1- (3S) -3- (dimethylamino) pyrrolidine, and (3R) -3-tert-butoxycarbonylamino- - (dimethylamino) pyrrolidine, azetidine, pyrrolidine, morpholine, 1-methylpiperazine, 3-hydroxyacetidine, 3- (azetidin- (Dimethylamino) azetidine, 3- (dimethylaminomethyl) azetidine, 4-hydroxypiperidine, 4- (hydroxymethyl) piperidine, (3R) (3S) -3-hydroxypyrrolidine, 3- (azetidin-1-ylmethyl) azetidine N- (1-ethylpiperidin-4-yl) -N-methylamine, N (1-methylpiperidin-4-yl) , N-dimethyl-N'-methylpropane-1,3-diamine or N, N-diethyl-N'-methylpropane-1,3-diamine. The process according to claim 5, wherein the Hofmann precursor is acetic acid iodobenzene or trifluoroacetic acid iodobenzene. The method of claim 1, wherein R ¹ is selected from the group consisting of 4- [2- (dimethylamino) ethyl] piperazin-1-yl group, 4-pyrrolidin- 4-azetidin-1-ylpiperidin-1-yl group, 4- [3- (dimethylamino) azetidin- 1 -yl] piperidin- (4-methylpiperazin-1-yl) piperidin-1-yl group, 4- (1-methylpiperidin- Yl group, 4- (pyrimidin-1-yl) piperazin-1-yl group, Yl group, (3S) -3- (dimethylamino) pyrrolidin-1-yl group, Yl group, 3-hydroxyazetidin-1-yl group, 1,3'-biazethy-1-yl group, pyrrolidin-1-yl group, morpholin- (Dimethylamino) methyl] azetidine-1-yl group, 3- (dimethylamino) (3R) -3-hydroxypyrrolidin-1-yl group, (3S) - (4S) -2-hydroxypiperidin- (3-hydroxypyrrolidin-1-yl group, 3- (azetidin- 1 -ylmethyl) azetidin-1-yl group, 3- (2-dimethylaminoacetoxy) azetidin- (Methyl) amino group, [3- (dimethylamino) propyl] (methyl) amino group or [3- (diethylamino) ) Propyl] (methyl) amino group. The compound according to claim 1,

The gigabyte

or

Lt; / RTI &gt; 3. The process according to claim 2, wherein R &lt; ⁷ &gt; is a benzyl group. A compound represented by the formula (IV-1): &lt; EMI ID =

[In the above formula R ¹ is (1) an azetidin-1-yl group which may have a substituent selected from the following Substituent group a, (2) a pyrrolidin-1-yl group which may have a substituent selected from Substituent Group (4) a piperazin-1-yl group which may have a substituent selected from the following substituent group a, (5) a substituent group a (6) a morpholin-4-yl group which may have a substituent selected from the following substituent group a, or (7) a group represented by the formula -NR ^11a R ^11b , R ^11a represents a hydrogen atom or a methyl group; R ^11b represents an n-propyl group, an n-butyl group, a pyrrolidin-3-yl group, a piperidin- Pyran-4-yl group, with the proviso that R ^11b may have a substituent selected from the following Substituent group b) and, R ² , R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom or a fluorine atom, R ⁷¹ is a methyl group with (1) a halogen atom, (2) a hydroxyl group, (3) nitro, (4) a cyano group, (5) trifluoromethyl on the hydrogen atom, a C _1-6 alkyl group or benzene ring, (6) C _1-6 alkyl group, (7) C _1-6 alkoxy group, (8) an amino group, (9) mono- -C _1-6 alkylamino and (10) di -C _1-6 alkylamino group 1 substituents selected from Or two benzyl groups which may be present; [Substituent group a] (Excluding a hydroxyl group and a dimethylaminoacetoxy group), each of which is composed of a hydroxyl group, a hydroxyl group, a hydroxyl group, a dimethylaminoacetoxy group, a methyl group, an ethyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group and a piperazinyl group, May have a hydroxyl group, a methyl group, a dimethylamino group, an azetidinyl group, a pyrrolidinyl group or a piperidinyl group, [Substituent group b] A methyl group, an ethyl group, an n-propyl group, an acetyl group, a dimethylamino group, a diethylamino group, an azetidinyl group, a pyrrolidinyl group and a piperazinyl group; each of the above groups may have a methyl group or a dimethylamino group. A compound represented by the formula (V): &lt; EMI ID =

Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 13, R ⁷ is a C _1-6 alkyl group or a benzene ring, (1) a halogen atom, (2) (3) a nitro group, (4) a cyano group, (5) a trifluoromethyl group, (6) a C _1-6 alkyl group, (7) a C _1-6 alkoxy group, _1-6 alkyl group and (10) di -C _1-6 substituent means a group of one or two take good benzyl is selected from an alkyl group, Ar is a halogen atom, a methyl group, a methoxy group, a nitro group, a cyano group and A phenyl group which may have 1 or 2 substituents selected from a trifluoromethyl group]. A compound represented by the formula (VI): &lt; EMI ID =

[Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 13, and R ⁷ is the same as defined in claim 14]. A compound represented by the formula (VIII): &lt; EMI ID =

[Wherein R ² , R ³ , R ⁴ and R ⁵ are the same as defined in claim 13, and R ⁷ is the same as defined in claim 14]. The method of claim 13, wherein R ¹ is selected from the group consisting of 4- [2- (dimethylamino) ethyl] piperazin-1-yl group, 4-pyrrolidin- 4-azetidin-1-ylpiperidin-1-yl group, 4- [3- (dimethylamino) azetidin- 1 -yl] piperidin- (4-methylpiperazin-1-yl) piperidin-1-yl group, 4- (1-methylpiperidin- Yl group, 4- (pyrimidin-1-yl) piperazin-1-yl group, Yl group, (3S) -3- (dimethylamino) pyrrolidin-1-yl group, Yl group, 3-hydroxyazetidin-1-yl group, 1,3'-biazethy-1-yl group, pyrrolidin-1-yl group, morpholin- 3- (dimethylamino) methyl] azetidin-1-yl group, 3- (hydroxymethyl) (3S) -3-hydroxypyrrolidin-1-yl group, (3S) -3-hydroxypyrrolidin-1-yl group, (3-hydroxypyrrolidin-1-yl group, 3- (azetidin-1-ylmethyl) azetidin- (Methyl) amino group, a [3- (dimethylamino) propyl] (methyl) amino group or a [3- Amino) propyl] (methyl) amino group. 14. The process according to claim 13,

The gigabyte

or

&Lt; / RTI &gt; or a salt thereof. 15. The compound or a salt thereof according to claim 14, wherein R &lt; ⁷ &gt; is a benzyl group. delete Yl) carbonyl} amino) pyridin-4-yl] oxy} -1H-pyrazolo [l, (2 &amp;thetas; +/- 0.2 DEG) 6.3 DEG, 12.3 DEG and 17.3 DEG in powder X-ray diffraction, respectively, as crystals of 2- (4-fluorophenyl) 18.3 DEG, 18.4 DEG, 19.2 DEG, 19.8 DEG, 20.0 DEG, 20.1 DEG, 20.2 DEG, 22.1 DEG and 23.7 DEG.

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