METHOD FOR PRODUCING BENZIMIDAZOLE DERIVATIVE

Abstract

The present invention relates to a process to prepare a benzimidazole derivative useful as a medicament, an intermediate for preparing the medicament, and a process to prepare the intermediate.

Claims

1. A process for preparing a compound of formula (1): ##STR00064## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is, independently if there are plural R.sup.1, halogen, cyano, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 the same or different halogen atoms; n is 0, 1, 2, or 3; R.sup.2 and R.sup.3 are independently hydrogen atom; C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of cyano, halogen, and hydroxy group; or C.sub.3-10 cycloalkyl; R.sup.4 is hydrogen atom; C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of cyano, halogen, and hydroxy group; or C.sub.3-10 cycloalkyl; R.sup.5 is C.sub.6-10 aryl or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen atom; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms; m is 1, 2, or 3; and R.sup.6 and R.sup.7 are independently (if there are plural R.sup.6 or R.sup.7, each R.sup.6 or R.sup.7 is also independently) selected from the group consisting of hydrogen atom, deuterium atom, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy (wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 the same or different substituents selected independently from the group consisting of halogen atom and hydroxy group), C.sub.3-7 cycloalkyl, and C.sub.3-7 cycloalkoxy (wherein the cycloalkyl and the cycloalkoxy may be optionally substituted with 1 to 5 the same or different substituents selected independently from the group consisting of halogen atom and hydroxy group), comprising reducing a compound of formula (2): ##STR00065## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined above, and cyclizing the reduced product with a formate equivalent.

2. The process of claim 1, further comprising a step of preparing the compound of formula (2) which comprises reacting a compound of formula (3): ##STR00066## wherein R.sup.1 and n are as defined in claim 1, X.sup.1 is hydroxy, halogen, alkylsulfonyloxy, or arylsulfonyloxy with a compound of (4): ##STR00067## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and m are as defined in claim 1, and then with R.sup.5X.sup.2 wherein R.sup.5 is as defined in claim 1, and X.sup.2 is halogen.

3. A process for preparing a compound of formula (1): ##STR00068## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is, independently if there are plural R.sup.1, halogen, cyano, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 the same or different halogen atoms; n is 0, 1, 2, or 3; R.sup.2 and R.sup.3 are independently hydrogen atom; C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of cyano, halogen, and hydroxy group; or C.sub.3-10 cycloalkyl; R.sup.4 is hydrogen atom; C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of cyano, halogen, and hydroxy group; or C.sub.3-10 cycloalkyl; R.sup.5 is C.sub.6-10 aryl or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen atoms; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms; m is 1, 2, or 3; and R.sup.6 and R.sup.7 are independently (if there are plural R.sup.6 or R.sup.7, each R.sup.6 or R.sup.7 is also independently) selected from the group consisting of hydrogen atom, deuterium atom, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy (wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 the same or different substituents selected independently from the group consisting of halogen atom and hydroxy group), C.sub.3-7 cycloalkyl, and C.sub.3-7 cycloalkoxy (wherein the cycloalkyl and the cycloalkoxy may be optionally substituted with 1 to 5 the same or different substituents selected independently from the group consisting of halogen atom and hydroxy group), comprising the following Step A and Step B; Step A reacting a compound of formula (3): ##STR00069## wherein R.sup.1 and n are as defined above, X.sup.1 is hydroxy, halogen, alkylsulfonyloxy, or arylsulfonyloxy, with a compound of (4): ##STR00070## wherein R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and m are as defined above, and then with R.sup.5X.sup.2 wherein R.sup.5 is as defined above, and X.sup.2 is halogen to prepare a compound of formula (2): ##STR00071## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined above; Step B reducing the compound of formula (2) and cyclizing the reduced product with a formate equivalent to prepare the compound of formula (1).

4. The process of any one of claims 1 to 3, wherein the compound of formula (1) is a compound of formula (1): ##STR00072## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined in claim 1.

5. The process of any one of claims 2 to 4, wherein n is 0; R.sup.2 and R.sup.3 are independently hydrogen atom or C.sub.1-6 alkyl; R.sup.4 is hydrogen atom or C.sub.1-6 alkyl; R.sup.5 is phenyl, or 5- or 6-membered heteroaryl, wherein the phenyl and the heteroaryl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms; m is 1; R.sup.6 and R.sup.7 are independently hydrogen atom, deuterium atom, or C.sub.1-4 alkyl; X.sup.1 is halogen; and X.sup.2 is fluorine atom or bromine atom.

6. The process of any one of claims 1 to 5, wherein R.sup.5 is pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl, wherein the pyridyl, the pyrazinyl, the pyrimidinyl, and the pyridazinyl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms.

7. The process of any one of claims 1 to 6, wherein the reduction reaction is carried out with a reducing metal, a reducing metal salt, or a mixture of a reducing metal and a reducing metal salt.

8. The process of any one of claims 1 to 6, wherein the reduction reaction is carried out with a reducing metal.

9. The process of claim 8, wherein the reducing metal is zinc or iron.

10. The process of any one of claims 7 to 9, wherein an oxide-layer remover is also used in the reduction reaction.

11. The process of claim 10, wherein the oxide-layer remover is lithium bromide, lithium chloride, or chlorotrimethylsilane.

12. The process of any one of claims 1 to 6, wherein the reduction reaction is carried out with a catalyst for catalytic reduction under hydrogen atmosphere.

13. The process of claim 12, wherein the catalyst for catalytic reduction is palladium-carbon or platinum sulfide on carbon.

14. The process of any one of claims 1 to 13, wherein the reduction reaction is carried out in the presence of an acid.

15. The process of any one of claims 1 to 14, wherein the formate equivalent is one or more selected from the group consisting of orthoformate triester, formic acid ester, and formate.

16. The process of claim 15, wherein the formate equivalent is orthoformate triester.

17. The process of any one of claims 1 to 16, wherein the reduction and the cyclization are carried out in one-pot reaction.

18. The process of any one of claims 1 to 16, wherein in the reduction and the cyclization, the nitro is reduced, followed by adding an acid and a formate equivalent to make cyclization.

19. The process of any one of claims 1 to 17, wherein in the reduction and the cyclization, the nitro is reduced in the presence of an acid and a formate equivalent to make cyclization in the reaction system after the reduction.

20. The process of any one of claims 1 to 19, wherein the acid is formic acid.

21. A compound of formula (8): ##STR00073## or a salt thereof, wherein R.sup.1a is, independently if there are plural R.sup.1a, halogen, cyano, C.sub.1-6 alkyl, or C.sub.1-6 alkoxy, wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 the same or different halogen atoms; n.sup.a is 0, 1, 2, or 3; R.sup.2a and R.sup.3a are independently hydrogen atom, C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of cyano, halogen, and hydroxy group; or C.sub.3-10 cycloalkyl; R.sup.4a is hydrogen atom; R.sup.5a is formula (9): ##STR00074## wherein R.sup.8a is halogen; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; or C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms; m.sup.a is 1, 2, or 3; and R.sup.6a and R.sup.7a are independently (if there are plural R.sup.6a or R.sup.7a, each R.sup.6a or R.sup.7a is also independently) hydrogen atom, deuterium atom, hydroxy, C.sub.1-4 alkyl, C.sub.1-4 alkoxy (wherein the alkyl and the alkoxy may be optionally substituted with 1 to 5 the same or different substituents selected independently from the group consisting of halogen atom and hydroxy group), C.sub.3-7 cycloalkyl, or C.sub.3-7 cycloalkoxy (wherein the cycloalkyl and the cycloalkoxy may be optionally substituted with 1 to 5 the same or different substituents selected independently from the group consisting of halogen atom and hydroxy group).

Description

DESCRIPTION OF EMBODIMENTS

[0151] Hereinafter, each term used herein is explained in detail.

[0152] The halogen includes fluorine, chlorine, bromine, and iodine.

[0153] The C.sub.1-4 alkyl means a straight or branched chain alkyl having 1 to 4 carbon atoms, and the C.sub.1-6 alkyl means a straight or branched chain alkyl having 1 to 6 carbon atoms. The C.sub.1-3 alkyl includes, for example, methyl, ethyl, propyl, and isopropyl. The C.sub.1-4 alkyl includes, for example, butyl, isobutyl, sec-butyl, and tert-butyl, besides the examples of the above C.sub.1-3 alkyl. The C.sub.1-6 alkyl includes, for example, pentyl, isopentyl, neopentyl, l-ethylpropyl, and hexyl, besides the examples of the above C.sub.1-4 alkyl. The C.sub.1-6 alkyl includes, preferably C.sub.1-4 alkyl, more preferably C.sub.1-3 alkyl, even more preferably methyl and ethyl.

[0154] The C.sub.1-6 alkoxy means oxy group substituted with the above C.sub.1-6 alkyl. The C.sub.1-3 alkoxy includes, for example, methoxy, ethoxy, propoxy, and 1-methylethoxy. The C.sub.1-4 alkoxy includes, for example, butoxy, 1-methylpropoxy, 2-methylpropoxy, and 1,1-dimethylethoxy, besides the examples of the above C.sub.1-3 alkoxy. The C.sub.1-6 alkoxy includes, for example, pentyloxy and hexyloxy, besides the examples of the above C.sub.1-4 alkoxy. The C.sub.1-6 alkoxy includes, preferably C.sub.1-4 alkoxy, more preferably C.sub.1-3 alkoxy, even more preferably methoxy and ethoxy.

[0155] The C.sub.3-10 cycloalkyl means a non-aromatic cyclic hydrocarbon group (i.e., saturated hydrocarbon group and partially-unsaturated hydrocarbon group) having 3 to 10 carbon atoms, which includes a partially-bridged structure thereof. The C.sub.3-6 cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. The C.sub.3-7 cycloalkyl includes, for example, cycloheptyl and cycloheptenyl, besides the examples of the above C.sub.3-6 cycloalkyl. The C.sub.3-10 cycloalkyl includes, for example, cyclooctyl, cyclononanyl, cyclodecanyl, and adamantyl, besides the examples of the above C.sub.3-7 cycloalkyl. The C.sub.3-10 cycloalkyl includes, preferably C.sub.3-7 cycloalkyl, more preferably C.sub.3-6cycloalkyl, even more preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0156] The C.sub.3-7 cycloalkoxy means oxy group substituted with the above C.sub.3-7 cycloalkyl. The C.sub.3-6 cycloalkoxy includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. The C.sub.3-7 cycloalkoxy includes, for example, cycloheptyloxy, besides the examples of the above C.sub.3-6 cycloalkoxy. The C.sub.3-7 cycloalkoxy includes, preferably C.sub.3-6 cycloalkoxy, more preferably cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy, the most preferably cyclohexyloxy.

[0157] The C.sub.6-10 aryl used herein means aromatic hydrocarbon group having 6-10 carbon atoms. The C.sub.6-10 aryl includes, for example, phenyl, 1-naphthyl, and 2-naphthyl. Preferably, it is phenyl.

[0158] The 5- to 12-membered heteroaryl means a mono- or bi-cyclic aromatic heterocyclyl group (mono-cyclic heteroaryl or bi-cyclic heteroaryl) composed of 5 to 12 atoms having 1 to 4 heteroatoms selected from the group consisting of nitrogen atom, oxygen atom, and sulfur atom, which includes preferably 5- or 6-membered heteroaryl, more specifically 5- or 6-membered nitrogen-containing heteroaryl. The bi-cyclic heteroaryl means a condensed ring in which two the same or different mono-cyclic heteroaryls are fused, a mono-cyclic heteroaryl and an aromatic ring (for example, benzene) are fused, or a mono-cyclic heteroaryl and a non-aromatic ring (for example, cyclohexane, piperidine) are fused. The 5- or 6-membered nitrogen-containing heteroaryl means a mono-cyclic aromatic heterocyclyl group composed of 5 to 6 atoms having 1 to 3 nitrogen atoms, which includes, for example, pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, and tetrazolyl. The 5- or 6-membered heteroaryl includes, for example, furyl and thienyl, besides the examples of the above 5- or 6-membered nitrogen-containing heteroaryl. The 5- to 12-membered heteroaryl includes, for example, indolyl, indazolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, and 6,11-dihydrodibenzo[b,e]thiepinyl group, besides the examples of the above 5- or 6-membered heteroaryl. The 5- to 12-membered heteroaryl includes, preferably 5- or 6-membered heteroaryl, more preferably 5- or 6-membered nitrogen-containing heteroaryl, even more preferably pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl, particularly preferably pyridyl.

[0159] The alkylsulfonyloxy means sulfonyloxy group substituted with the above C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms. The alkylsulfonyloxy includes, for example, methanesulfonyloxy and trifluoromethanesulfonyloxy.

[0160] The arylsulfonyloxy means sulfonyloxy group substituted with the above C.sub.6-10 aryl which may be optionally substituted with C.sub.1-4 alkyl. The arylsulfonyloxy includes, for example, para-toluenesulfonyloxy.

[0161] The reducing metal, reducing metal salt, or mixture of a reducing metal and a reducing metal salt means a metal or a metal salt which can undergo reduction reaction by emitting an electron, or a mixture thereof. The reducing metal includes, for example, zinc, iron, tin, and titanium. The reducing metal salt includes, for example, ferric chloride, tin chloride, and titanium chloride. The reducing metal, reducing metal salt, or mixture of a reducing metal and a reducing metal salt includes, preferably zinc or iron.

[0162] The catalyst for catalytic reduction is a metal dispersed/loaded on a carrier such as carbon, which means a catalyst for reducing an unsaturated bond, a nitro, etc. under hydrogen atmosphere. The catalyst for catalytic reduction includes, for example, palladium catalysts such as palladium-carbon and palladium hydroxide-carbon; nickel catalysts such as Raney nickel; cobalt catalysts; platinum catalysts such as platinum sulfide on carbon; ruthenium catalysts; and rhodium catalysts. The catalyst for catalytic reduction includes, preferably palladium catalysts and platinum catalysts; more preferably palladium-carbon and platinum sulfide on carbon.

[0163] The formate equivalent means a compound which can undergo a similar chemical conversion to formic acid in organic synthetic chemistry. The formate equivalent includes, for example, an orthoformate triester such as trimethyl orthoformate and triethyl orthoformate; a formic acid ester such as methyl formate and ethyl formate; and a formate such as zinc formate, sodium formate, and ammonium formate. The formate equivalent includes, preferably an orthoformate, more preferably trimethyl orthoformate and triethyl orthoformate, even more preferably trimethyl orthoformate.

[0164] The acid which may be used in the reduction and/or the cyclization means a substance which ionizes to produce hydrogen ion when the substance is dissolved in water. The acid includes, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, and nitric acid; and an organic acid such as formic acid, acetic acid, and butyric acid. The acid includes, preferably hydrochloric acid, formic acid, and acetic acid; more preferably hydrochloric acid and formic acid; even more preferably formic acid.

[0165] The reduction and cyclization steps of a compound of formula (2) may be carried out in order of reduction step and then cyclization step, or the both reactions may be carried out in one-pot.

[0166] The one-pot reaction means a synthetic technique to carry out multistep reactions by throwing reactants in order into a reaction vessel. The one-pot reaction does not require isolation/purification in each step, thus it is expected to reduce a number of waste materials such as solvents, reaction time, and labor effort. In addition, one-pot reaction can bring in an economical merit such as greatly-simplified process, as well as a reduction in environment load since one-pot reaction requires only one reaction vessel.

[0167] The an oxide-layer remover means a compound which can remove an oxide on the surface of a metal such as iron and zinc to enhance the activity suitably. The an oxide-layer remover includes, for example, a lithium salt such as lithium chloride and lithium bromide; an inorganic acid such as hydrochloric acid and sulfuric acid; an organic acid such as formic acid and acetic acid; a dihalogenated hydrocarbon such as 1,2-diiodoethane and 1,2-dibromoethane; and a halogenated silane such as chlorotrimethylsilane and dichlorodimethylsilane. The an oxide-layer remover includes, preferably formic acid, lithium chloride and lithium bromide, more preferably lithium chloride and lithium bromide, even more preferably lithium bromide.

[0168] The make cyclization in the reaction system after the reduction means that the precursor for cyclization which is obtained by reducing the nitro group in the reduction reaction is used in the cyclization reaction with an acid and a formate equivalent, without isolating the precursor.

[0169] Preferred embodiments of the present invention are in detail shown below.

[0170] R.sup.1 includes preferably halogen; more preferably fluorine atom and chlorine atom.

[0171] n includes preferably 0, 1, and 2; more preferably 0 and 1;

[0172] even more preferably 0.

[0173] R.sup.2 and R.sup.3 includes preferably hydrogen atom and C.sub.1-6 alkyl;

[0174] more preferably hydrogen atom and C.sub.1-4 alkyl; even more preferably C.sub.1-3 alkyl; particularly preferably methyl and ethyl; the most preferably methyl.

[0175] R.sup.4 includes preferably hydrogen atom and C.sub.1-6 alkyl; more preferably hydrogen atom and C.sub.1-3 alkyl; even more preferably hydrogen atom, methyl, and ethyl, the most preferably hydrogen atom.

[0176] R.sup.5 includes preferably C.sub.6-10 aryl and 5- or 6-membered heteroaryl (wherein the aryl and the heteroaryl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen atom; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms); more preferably phenyl and 5- or 6-membered nitrogen-containing heteroaryl (wherein the phenyl and the heteroaryl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms); even more preferably phenyl and 6-membered heteroaryl (wherein the phenyl and the heteroaryl may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; and alkoxy which may be optionally substituted with 1 to 5 fluorine atoms); particularly preferably pyridyl optionally-substituted with C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; the most preferably pyridyl which may be optionally substituted with trifluoromethyl.

[0177] m includes preferably 1 and 2; more preferably 1.

[0178] R.sup.6 and R.sup.7 include preferably hydrogen atom, deuterium atom, hydroxy group, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms, and C.sub.3-7 cycloalkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; more preferably hydrogen atom, deuterium atom, C.sub.1-4 alkyl, and C.sub.3-7 cycloalkyl; even more preferably hydrogen atom, and deuterium atom; particularly preferably hydrogen atom.

[0179] R.sup.8 includes preferably halogen, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; more preferably fluorine atom, chlorine atom, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; even more preferably fluorine atom, chlorine atom, and C.sub.1-3 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; even more preferably C.sub.1-3 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; particularly preferably trifluoromethyl.

[0180] X.sup.1 includes preferably halogen, alkylsulfonyloxy, and arylsulfonyloxy; more preferably halogen; even more preferably fluorine atom and chlorine atom; particularly preferably fluorine atom.

[0181] X.sup.2 includes preferably fluorine atom and bromine atom; more preferably fluorine atom.

[0182] R.sup.1a includes preferably halogen; more preferably fluorine atom and chlorine atom.

[0183] n.sup.a includes 0, 1, and 2; more preferably 0 and 1; even more preferably 0.

[0184] R.sup.2a and R.sup.3a include preferably hydrogen atom and C.sub.1-6 alkyl; more preferably hydrogen atom and C.sub.1-4 alkyl; even more preferably C.sub.1-3 alkyl; particularly preferably methyl and ethyl; the most preferably methyl.

[0185] m.sup.a includes preferably 1 and 2; more preferably 1.

[0186] R.sup.6a and R.sup.7a include preferably hydrogen atom, deuterium atom, hydroxy group, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms, and C.sub.3-7 cycloalkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; more preferably hydrogen atom, deuterium atom, C.sub.1-4 alkyl, and C.sub.3-7 cycloalkyl; even more preferably hydrogen atom and deuterium atom; particularly preferably hydrogen atom.

[0187] R.sup.8a includes preferably halogen, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; more preferably fluorine atom, chlorine atom, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms, and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms; even more preferably fluorine atom, chlorine atom, and C.sub.1-3 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; even more preferably C.sub.1-3 alkyl which may be optionally substituted with 1 to 5 fluorine atoms; particularly preferably trifluoromethyl.

[0188] One embodiment of the compound of formula (1) includes (A). (A) The compound or a pharmaceutically acceptable salt thereof, wherein [0189] n is 0, 1, or 2; [0190] R.sup.1 is, independently if there are plural R.sup.1, halogen or C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; [0191] R.sup.2 and R.sup.3 are independently C.sub.1-6 alkyl; [0192] R.sup.4 is hydrogen atom; [0193] m is 1; [0194] R.sup.5 is 6-membered heteroaryl which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms, and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms; and [0195] R.sup.6 and R.sup.7 are independently hydrogen atom, deuterium atom, or C.sub.1-4 alkyl.

[0196] One embodiment of the compound of formula (1) includes (A). (A) The compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined in the above (A).

[0197] One embodiment of the compound of formula (1) includes (B). (B) The compound or a pharmaceutically acceptable salt thereof, wherein [0198] n is 0; [0199] R.sup.2 and R.sup.3 are independently C.sub.1-6 alkyl; [0200] R.sup.4 is hydrogen atom; [0201] m is 1; [0202] R.sup.5 is pyridyl (which may be optionally substituted with 1 to 5 the same or different substituents selected from the group consisting of halogen, C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms, and C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms); and [0203] R.sup.6 and R.sup.7 are independently hydrogen atom, deuterium atom, or C.sub.1-4 alkyl.

[0204] One embodiment of the compound of formula (1) includes (B). (B) The compound of formula (1) or a pharmaceutically acceptable salt thereof, wherein R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined in the above (B).

[0205] One embodiment of the compound of formula (8) includes (a). (a) The compound or a pharmaceutically acceptable salt thereof, wherein [0206] n.sup.a is 0, 1, or 2; [0207] R.sup.1a is, independently if there are plural R.sup.1a, halogen or C.sub.1-6 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; [0208] R.sup.2a and R.sup.3a are independently C.sub.1-6 alkyl; [0209] R.sup.4a is hydrogen atom; [0210] m.sup.a is 1; [0211] R.sup.5a is formula (9); [0212] R.sup.6a and R.sup.7a are independently hydrogen atom, deuterium atom, or C.sub.1-4 alkyl; and [0213] R.sup.8a is halogen; C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 the same or different halogen atoms; or C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 the same or different halogen atoms.

[0214] One embodiment of the compound of formula (8) includes (a). (a) The compound of formula (8) or a pharmaceutically acceptable salt thereof, wherein R.sup.1a, R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, m.sup.a, and n.sup.a are as defined in the above (a).

[0215] One embodiment of the compound of formula (8) includes (b). (b) The compound or a pharmaceutically acceptable salt thereof, wherein [0216] n.sup.a is 0; [0217] R.sup.2a and R.sup.3a are independently C.sub.1-6 alkyl; [0218] R.sup.4a is hydrogen atom; [0219] m.sup.a is 1; [0220] R.sup.5a is formula (9); [0221] R.sup.6a and R.sup.7a are independently hydrogen atom, deuterium atom, or C.sub.1-4 alkyl; and [0222] R.sup.8a is C.sub.1-4 alkyl which may be optionally substituted with 1 to 5 fluorine atoms, or C.sub.1-4 alkoxy which may be optionally substituted with 1 to 5 fluorine atoms.

[0223] One embodiment of the compound of formula (8) includes (b). (b) The compound of formula (8) or a pharmaceutically acceptable salt thereof, wherein R.sup.2a, R.sup.3a, R.sup.4a, R.sup.5a, R.sup.6a, R.sup.7a, R.sup.8a, m.sup.a, and n.sup.a are as defined in the above (b).

[0224] The pharmaceutically acceptable salt includes an acid addition salt and a base addition salt. The acid addition salt includes, for example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, hydroiodide, nitrate, and phosphate; and organic acid salts such as citrate, oxalate, phthalate, fumarate, maleate, succinate, malate, acetate, formate, propionate, benzoate, trifluoroacetate, methanesulfonate, benzenesulfonate, para-toluenesulfonate, and camphorsulfonate. The base addition salt includes, for example, inorganic basic salts such as sodium salt, potassium salt, calcium salt, magnesium salt, barium salt, and aluminium salt; and salts with organic base such as trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, dicyclohexylamine, and N,N-dibenzylethylamine. In addition, the pharmaceutically acceptable salt also includes salts with basic amino acid or acidic amino acid such as arginine, lysine, ornithine, aspartate, and glutamate.

[0225] The starting materials and intermediates used herein may be salts thereof. Salts of the starting materials and intermediates are preferably conventional non-toxic salts. The salts include acid-addition salts such as organic acid salts (e.g. acetate, trifluoroacetate, maleate, fumarate, citrate, tartrate, methanesulfonate, benzenesulfonate, formate, para-toluenesulfonate, etc.) and inorganic acid salts (e.g. hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.); salts with amino acid (e.g. arginine, aspartate, glutamate, etc.); metal salts such as alkali metal salts (e.g. sodium salt, potassium salt, etc.) and alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.); ammonium salts; and organic basic salts (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexyl amine salt, N,N-dibenzylethylenediamine salt, etc.), which may be suitably selected by a skilled person.

[0226] Processes to prepare the compounds of the present invention are mentioned below. The starting materials that are not described in the explanation below are commercially available, or can be prepared in a known manner or in a similar manner to a known one.

[0227] Process 1:

##STR00021##

[0228] In the above scheme, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined in Item 1, and X.sup.1, X.sup.2 are as defined in Item 2.

[0229] Step 1:

[0230] Compound a4 can be prepared by reacting Compound a1 and Compound a2 in the presence or absence of a suitable base in a suitable solvent, and then reacting the product with Compound a3. The step can be also carried out in one-pot reaction. In addition, it is possible to reverse the reaction-order of each compound, i.e., Compound a4 can be also prepared by reacting Compound a1 and Compound a3, and then reacting the product with Compound a2.

[0231] The base used herein includes inorganic bases such as sodium bicarbonate, sodium hydroxide, potassium hydroxide, potassium carbonate, and cesium carbonate; and organic bases such as triethylamine, diisopropylethylamine, and DABCO (1,4-diazabicyclo[2.2.2]octane); preferably diisopropylethylamine, sodium bicarbonate, potassium carbonate, and cesium carbonate. When an excessive amount of Compound a2 is used, the reaction does not necessarily require the use of a base.

[0232] The solvent used herein includes ether solvents such as tetrahydrofuran, dimethoxyethane, and 1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidone, and acetonitrile; preferably N-methylpyrrolidone.

[0233] The reaction time is generally 10 minutes to 30 hours, preferably 2 hours to 25 hours, for each step, the reaction of Compound a1 and Compound a2, and the subsequent reaction with Compound a3.

[0234] The reaction temperature is generally 0 C. to boiling point of a solvent used herein, preferably 60 C. to 130 C., for each step, the reaction of Compound a1 and Compound a2, and the subsequent reaction with Compound a3.

[0235] Step 2:

[0236] Compound (1) can be prepared by reducing the nitro group of Compound a4 under a suitable reduction condition in a suitable solvent and then cyclizing the product with formic acid or a formate equivalent in the presence of a suitable catalyst in a suitable solvent. The step can be also carried out in one-pot reaction. In addition, the cyclization of the present step can be also carried out after isolating the phenylenediamine compound (precursor for cyclization) that is obtained by the reduction of the nitro group.

[0237] The reduction condition used herein includes nitro-reduction conditions which are broadly used in organic synthetic reaction, for example, catalytic reduction with palladium-carbon, sulfur-poisoning platinum-carbon, etc. under hydrogen atmosphere; metal reduction with zinc, iron, tin, etc.; hydride reduction with lithium aluminum hydride, etc. When a metal reduction with zinc is used as the reduction condition, it is preferable to use an oxide-layer remover (such as lithium bromide, lithium chloride, and chlorotrimethylsilane) with the metal. And, zinc used herein may be pretreated before the reaction by washing its surface with diluted hydrochloric acid or acetic acid and drying the washed zinc.

[0238] The solvent used in the reduction reaction includes general solvents used in each reduction condition. In case of catalytic reduction, the solvent includes, for example, methanol, ethanol, tetrahydrofuran, and ethyl acetate. In case of metal reduction, the solvent includes, for example, tetrahydrofuran, acetic acid, methanol, ethanol, and isopropanol. In case of hydride reduction, the solvent includes, for example, diethyl ether, and tetrahydrofuran. In order to adjust the reducing power or keep the stability of phenylenediamine compound obtained by reducing Compound a4, it is possible to use an additive such as hydrochloric acid and acetic acid.

[0239] The reaction time of the reduction reaction is generally 10 minutes to 24 hours, preferably 10 minutes to 5 hours.

[0240] The reaction temperature of the reduction reaction is generally 0 C. to boiling point of a solvent used herein, preferably 0 C. to 65 C.

[0241] As the cyclization condition used herein, formic acid or a formate equivalent may be added to the reaction solution after the reduction reaction, or formic acid or a formate equivalent may be added to the reduction reaction, i.e., without separating reduction reaction and cyclization reaction.

[0242] The formate equivalent includes orthoformates such as trimethyl orthoformate and triethyl orthoformate, more preferably trimethyl orthoformate and triethyl orthoformate. The catalyst used herein includes organic acid such as formic acid and acetic acid; Lewis acid such as ytterbium triflate; and inorganic acid such as hydrochloric acid and sulfuric acid; preferably formic acid.

[0243] The solvent used herein includes alcohol solvents such as methanol and ethanol; preferably methanol and ethanol. Or, formic acid or an orthoformate, etc. which is used as a catalyst or a formate equivalent may be also used as a solvent.

[0244] The reaction time of the cyclization is generally 10 minutes to 24 hours, preferably 5 hours to 16 hours.

[0245] The reaction temperature of the cyclization is generally 00 C. to boiling point of a solvent used herein, preferably 10 C. to 65 C.

[0246] Process 2:

[0247] The compound of formula (1) can be also prepared, for example, in a manner shown below.

##STR00022##

[0248] In the above scheme, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, m, and n are as defined in Item 1, and X.sup.1 and X.sup.2 are as defined in Item 2.

[0249] Step 3:

[0250] Compound a5 can be prepared from Compound a1 and Compound a2, according to the manner of Step 1.

[0251] Step 4:

[0252] Compound a6 can be prepared from Compound a5, according to the manner of Step 2.

[0253] Step 5:

[0254] The compound of formula (1) can be prepared from Compound a6 and Compound a3, according to the manner of Step 1.

EXAMPLES

[0255] The present invention is explained in more detail in the following by referring to Examples and Reference examples, however, the technical scope of the present invention should not be limited thereto.

[0256] Each compound was identified with a proton nuclear magnetic resonance spectrum (.sup.1H-NMR spectrum), high-performance liquid chromatograph-mass spectrometer; LCMS, etc.

[0257] The measuring condition of high-performance liquid chromatography-mass spectrometer; LCMS is shown below, and the detected value of mass spectrography [MS (m/z)] is shown as M+H, and the retention time (min) is shown as T.

[0258] MS detector: ACUITY SQD

[0259] HPLC: ACUITY UPLC

[0260] Column: ACUITY BEH C18 1.7 m, 2.150 mm

[0261] Mobile phase: A: 0.05% aqueous formic acid [0262] B: acetonitrile

[0263] Gradient Program:

TABLE-US-00001 1 0.0-1.3 min A:B = 90:10 => 1:99 2 1.3-1.5 min A:B = 1:99 3 1.5-2.0 min A:B = 90:10

[0264] Flow rate: 0.75 mL/min

[0265] Wave length: 254 nm

[0266] The HPLC area percentage of compounds was measured according to the following HPLC condition.

[0267] HPLC: Pump: Shimadzu 30A series, [0268] Monitor: Shimadzu 20A series

[0269] Column: Kinetex 1.7 m, C18 100A (1002.1 mm)

[0270] Mobile phase: A: 0.05% trifluoroacetic acid/water [0271] B: 0.05% trifluoroacetic acid/acetonitrile

[0272] Gradient Program:

TABLE-US-00002 0-1 min A/B = 100:0 1-9 min A/B = 100:0 => 10:90 9-13 min A/B = 10:90

[0273] Flow rate: 0.3 mL/min

[0274] Wave length: 220 nm or 240 nm

[0275] Column temperature: 40 C.

[0276] In the following Examples and Reference examples, abbreviations shown below may be sometimes used to simplify the description of the present specification.

[0277] J: coupling constant, s: singlet, d: doublet, t: triplet, dd: double doublet, m: multiplet, brs: broad singlet.

Example Ex1

Preparation of 2-methyl-1-((2-nitro-5-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)amino)propan-2-ol

[0278] ##STR00023##

Synthetic Step 1-1

[0279] Under nitrogen atmosphere, a solution of 1-amino-2-methylpropan-2-ol (16.65 g) and sodium bicarbonate (6.68 g) in N-methylpyrrolidone (50 g) was warmed to 120 C., and a solution of 3-fluoro-4-nitrophenol (25 g) in N-methylpyrrolidone (75 g) was added thereto dropwise. The reaction mixture was stirred at 120 C. for 4 hours, and then cooled to room temperature. 2-Fluoro-5-(trifluoromethyl)pyridine (31.53 g) and potassium carbonate (37.39 g) were added to the reaction mixture, and the reaction mixture was stirred at 100 C. for 4 hours. The reaction mixture was cooled to 75 C., and then water (125 g) was added thereto to separate layers. The mixture was cooled to 50 C., and methanol (37.5 g) was added thereto. The mixture was cooled to 7 C., and stirred at 7 C. for 2 hours. Water (50 g) was added thereto dropwise, and the mixture was stirred for 2 more hours. The precipitated crystal was collected on a filter, washed with cooled 67% aqueous methanol (56 g) twice, and dried in vacuo to give the title compound (55.27 g, yield 93.5%).

[0280] HPLC area percentage: 99.7% (254 nm)

[0281] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.55-8.43 (m, 2H), 8.26 (d, J=9.4 Hz, 1H), 7.97 (dd, J=8.6, 2.4 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.42 (dd, J=9.4, 2.4 Hz, 1H), 3.26 (d, J=5.5 Hz, 2H), 1.37 (s, 6H).

Synthetic Step 1-2

[0282] Under nitrogen atmosphere, a solution of 1-amino-2-methylpropan-2-ol (187.3 g) and diisopropylethylamine (600.1 g) in N-methylpyrrolidone (370 g) was warmed to 120 C., and a solution of 3-fluoro-4-nitrophenol (300 g) in N-methylpyrrolidone (900 g) was added thereto dropwise. The reaction mixture was stirred at 120 C. for 7 hours, and then cooled to room temperature. 2-Bromo-5-(trifluoromethyl)pyridine (561.0 g) and potassium carbonate (792.2 g) were added to the reaction mixture, and the reaction mixture was stirred at 100 C. for 15 hours. The reaction mixture was cooled to 75 C., and then water (1500 g) was added thereto to separate layers. The mixture was cooled to 25 C., and isopropanol (600 g) and water (1200 g) were added thereto. The mixture was cooled to 0 C. and left to stand at 0 C. for 1 hour. After a precipitated crystal was observed, water (1200 g) was added thereto, and the mixture was stirred for 20 hours. The precipitated crystal was collected on a filter, washed with cooled 33% aqueous isopropanol (900 g) twice, and dried in vacuo to give the title compound (592.2 g, yield 83.4%).

Example Ex2

Preparation of 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol

[0283] ##STR00024##

Synthetic Step 2-1

[0284] Under nitrogen atmosphere, to a solution of lithium bromide (18.95 g) in methanol (162 g) were added zinc powder (47.54 g) and methanol (108 g). And then, a solution of Example 1 compound (54 g) in methanol (270 g) and formic acid (40.16 g) were added to the reaction mixture dropwise keeping the temperature at 30 C. or lower. The mixture was stirred at 20 C. for 1 hour, and trimethyl orthoformate (77.16 g) and formic acid (20.08 g) were added thereto. The mixture was stirred at 20 C. for 18 hours. The reaction solution was warmed to 45 C. and stirred for 1 hour, and then the zinc residue was removed by filtration and washed with hot methanol (162 g) twice. The filtrate was concentrated in vacuo, and isopropyl acetate (540 g) was added to the residue. The solution was concentrated in vacuo. Isopropyl acetate (627 g) and water (540 g) were added to the concentrated solution to separate layers at 75 C. The organic layer was washed at 75 C. with 23% aqueous trisodium citrate (702 g), 7% aqueous sodium bicarbonate (581 g), and then water (540 g), and concentrated in vacuo. The concentrated solution was cooled to room temperature, and left to stand at room temperature for 1 hour. The precipitated crystal was collected on a filter, washed with isopropyl acetate (108 g), and dried in vacuo to give the title compound as a crude crystal (48.38 g, yield 94.7%). The obtained crude crystal (47 g) was recrystallized with isopropanol to give the title compound (44.33 g, yield after recrystallization 94.3%) HPLC area percentage: 99.9% (220 nm)

[0285] .sup.1H-NMR (CD.sub.3OD, 400 MHz) : 8.44-8.40 (m, 1H), 8.19 (s, 1H), 8.08 (dd, J=8.8, 2.2 Hz, 1H), 7.71 (d, J=8.7 Hz, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 7.08 (dd, J=8.7, 2.2 Hz, 1H), 4.20 (s, 2H), 1.21 (s, 6H).

Synthetic Step 2-2

[0286] Under nitrogen atmosphere, to a solution of Example 1 compound (100 mg) in ethanol (0.5 g) were added 3% platinum sulfide on carbon (wetted) (10 mg) and concentrated hydrochloric acid (136 mg). The gas in the reaction vessel was replaced by hydrogen, and then the reaction mixture was stirred at room temperature for 7 hours. The gas in the reaction vessel was replaced by nitrogen, and then trimethyl orthoformate (764 L) was added thereto. The mixture was stirred at room temperature for 3 hours and at 50 C. for 1 hour, and then filtrated with Celite and washed with ethanol. The filtrate was concentrated in vacuo. Isopropyl acetate and aqueous sodium bicarbonate were added to the concentrated solution to separate layers. The organic layer was washed with brine to give the title compound as a crude crystal (83.5 mg).

Synthetic Step 2-3

[0287] To a solution of Example 1 compound (0.50 g) in methanol (6.7 mL) were added trimethyl orthoformate (3.7 mL), formic acid (0.52 mL) and zinc powder (0.44 g), and the reaction mixture was stirred at 70 C. for 2 hour. The reaction mixture was filtrated with Celite and the filtrate was concentrated in vacuo. The obtained residue was dissolved in ethyl acetate, washed with aqueous Rochelle salt and brine, and dried over anhydrous sodium sulfate. The solution was concentrated to give a crude crystal. The crude crystal was recrystallized with hexane/ethyl acetate (1/5) to give the title compound (0.33 g).

Reference Example RE1

[0288] ##STR00025##

Preparation of 3-[(2-hydroxy-2-methylpropyl)amino]-4-nitrophenol (Compound Q1)

[0289] Under nitrogen atmosphere, a solution of 1-amino-2-methylpropan-2-ol (15.6 g) and diisopropylethylamine (30.9 g) in N-methylpyrrolidone (25 g) was warmed to 120 C., and a solution of 3-fluoro-4-nitrophenol (25 g) in N-methylpyrrolidone (91 g) was added thereto dropwise. The reaction mixture was stirred at 120 C. for 7 hours, and cooled to room temperature. The reaction solution was added to 1 mol/L hydrochloric acid (1041 g) dropwise, and the mixture was stirred at room temperature for 1 hour. The precipitated crystal was collected on a filter, washed with water (100 g) three times, and dried in vacuo to give the title compound (29.3 g, yield 81.4%).

[0290] HPLC area percentage: 99.8% (254 nm)

[0291] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) : 10.75 (s, 1H), 8.47 (t, J=5.0 Hz, 1H), 7.97 (d, J=9.4 Hz, 1H), 6.20 (d, J=2.4 Hz, 1H), 6.17 (dd, J=9.4, 2.4 Hz, 1H), 4.82 (s, 1H), 3.13 (d, J=5.0 Hz, 2H), 1.20 (s, 6H).

Preparation of 1-(2-hydroxy-2-methylpropyl)-1H-benzimidazol-6-ol (Compound Q2)

[0292] Under nitrogen atmosphere, to a solution of Compound Q1 (5 g) in ethanol (50 g) were added lithium bromide (1.9 g), zinc powder (7.2 g), and trimethyl orthoformate (58.6 g). Then, formic acid (10.2 g) was added to the reaction mixture dropwise at room temperature, and the reaction mixture was stirred for 3 hours. The reaction mixture was filtrated with Celite, and the filtrate was concentrated. The obtained residue was charged on amino silica gel (50 g), and eluted with chloroform/methanol (1 L/250 mL). The filtrate was concentrated in vacuo, and the precipitated solid was recrystallized with isopropanol (25 g) to give the title compound (3.5 g, yield 76.3%).

[0293] HPLC area percentage: 100.0% (254 nm)

[0294] .sup.1H-NMR (DMSO-d.sub.6, 400 MHz) : 9.20 (br s, 1H), 7.88 (s, 1H), 7.38 (d, J=8.6 Hz, 1H), 6.91 (d, J=2.2 Hz, 1H), 6.66 (dd, J=8.6, 2.2 Hz, 1H), 4.74 (br s, 1H), 4.00 (s, 2H), 1.09 (s, 6H).

Preparation of 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol (Reference example RE-3)

[0295] Under argon atmosphere, to a solution of Compound Q2 (1.10 kg) in N,N-dimethylformamide (31.4 kg) were added cesium carbonate (2.61 kg) and 2-fluoro-5-(trifluoromethyl)pyridine (1.14 kg). The reaction mixture was warmed to 60 C. and stirred for 25 hours. The reaction solution was cooled to room temperature. Water (16.5 kg), ethyl acetate (7.93 kg), and toluene (6.68 kg) were added to the reaction solution to separate layers. To the aqueous layer was added salt (2.2 kg), and the mixture was stirred. Ethyl acetate (1.98 kg) and toluene (3.81 kg) were added thereto, and the organic layer was collected. The recovery procedure was repeated twice. The combined organic layer was concentrated in vacuo to give the title compound as a crude crystal (1.11 kg, yield 59.5%). The obtained crude crystal was recrystallized with ethyl acetate (20.0 kg) and hexane (3.77 kg) to give the title compound (0.97 kg, yield after recrystallization 87.3%).

[0296] HPLC area percentage: 99.7% (254 nm)

Examples Ex3-6

[0297] According to the process of the above-mentioned Example Ex1, the following compounds of Examples Ex3-6 were prepared with each corresponding starting material.

TABLE-US-00003 [00026] LCMS data Example R.sup.A [M + H].sup.+ T (min) Ex3 [00027] 386 1.028 Ex4 [00028] 372 1.117 Ex5 [00029] 386 1.023 Ex6 [00030] 386 1.019

Examples Ex7-10

[0298] According to the process of the above-mentioned Example Ex2, the following compounds of Examples Ex7-10 were prepared with each corresponding starting material.

TABLE-US-00004 [00031] Ex- ample R.sup.B NMR data Ex7 [00032] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.42- 8.42 (m, 1H), 8.04 (s, 1H), 7.89 (dd, J = 8.7, 2.7 Hz, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.06 (dd, J = 8.7, 2.3 Hz, 1H), 7.02 (d, J = 8.7 Hz, 1H), 4.34-4.30 (m, 2H), 2.05-2.01 (m, 2H), 1.31 (s, 6H). Ex8 [00033] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.40 (s, 1H), 7.97 (s, 1H), 7.88 (dd, J = 8.9, 2.1 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.00 (m, 2H), 3.94 (s, 2H), 1.73 (s, 6H). Ex9 [00034] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.41 (d, J = 2.4 Hz, 1H), 8.11 (s, 1H), 7.88 (dd, J = 8.5, 2.4 Hz, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.9, 2.1 Hz, 1H), 7.00 (d, J = 9.2 Hz, 1H), 4.27 (q, J = 7.1 Hz, 1H), 1.73 (s, 1H), 1.64 (d, J = 7.3 Hz, 3H), 1.33 (s, 3H), 1.15 (s, 3H). Ex10 [00035] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.41 (s, 1H), 8.10 (s, 1H), 7.88 (dd, J = 8.7, 2.7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.02 (dd, J = 8.7, 2.3 Hz, 1H), 6.99 (d, J = 8.7 Hz, 1H), 4.27 (q, J = 7.2 Hz, 1H), 1.82 (s, 1H), 1.64 (d, J = 7.3 Hz, 3H), 1.33 (s, 3H), 1.14 (s, 3H).

Reference Example RE2-16

[0299] According to the process of the above-mentioned Reference example RE1, the following compounds of Reference examples RE2-16 were prepared with each corresponding starting material.

TABLE-US-00005 [00036] Reference example R.sup.C NMR data RE2 [00037] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 7.92 (d, J = 3.1 Hz, 1H), 7.89 (s, 1H), 7.65 (d, J = 9.2 Hz, 1H), 7.38-7.33 (m, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.94 (dd, J = 8.9, 2.1 Hz, 1H), 6.82 (dd, J = 9.2, 3.7 Hz, 1H), 4.00 (s, 2H), 1.22 (s, 6H). RE3 [00038] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.24 (dd, J = 4.9, 1.8 Hz, 1H), 7.99-7.97 (m, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 1.8 Hz, 1H), 7.08-7.04 (m, 2H), 4.08 (s, 2H), 1.65 (s, 1H), 1.28 (s, 6H). RE4 [00039] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.29 (d, J = 5.5 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.17 (d, J = 5.5 Hz, 1H), 7.13 (s, 1H), 7.04 (dd, J = 8.9, 2.1 Hz, 1H), 4.07 (s, 2H), 1.75 (s, 1H), 1.28 (s, 6H). RE5 [00040] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 7.98 (s, 1H), 7.82-7.75 (m, 2H), 7.36-7.35 (m, 2H), 7.05-7.03 (m, 2H), 4.07 (s, 2H), 1.69 (s, 1H), 1.28 (s, 6H). RE6 [00041] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.24 (s, 1H), 7.95 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 1.8 Hz, 1H), 7.04-6.97 (m, 2H), 6.63 (t, J = 55.8 Hz, 1H), 4.07 (s, 2H), 1.95 (s, 1H), 1.28 (s, 6H). RE7 [00042] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.08 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.63-7.60 (m, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 9.2, 1.8 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 4.06 (s, 2H), 1.81 (s, 1H), 1.28 (s, 6H). RE8 [00043] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 7.98 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.78 (d, J = 9.8 Hz, 1H), 7.39 (d, J = 2.1 Hz, 1H), 7.30 (d, J = 9.8 Hz, 1H), 7.10 (dd, J = 8.5, 2.1 Hz. 1H), 4.08 (s, 2H), 1.63 (s, 1H), 1.28 (s, 6H). RE9 [00044] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.49 (s, 1H), 8.40 (s, 1H), 7.99 (s, 1H), 7.82 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 2.1 Hz, 1H), 7.06 (dd, J = 8.9, 2.1 Hz, 1H), 4.08 (s, 2H), 1.66 (s, 1H), 1.29 (s, 6H). RE10 [00045] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 7.93 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 7.15 (d, J = 9.2 Hz, 1H), 7.06 (dd, J = 8.5, 2.4 Hz, 1H), 4.03 (s, 2H), 2.05 (s, 1H), 1.26 (s, 6H). RE11 [00046] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 7.95 (s, 1H), 7.83-7.83 (m, 1H), 7.77-7.75 (m, 1H), 7.51-7.49 (m, 1H), 7.27-7.27 (m, 1H), 7.06-7.03 (m, 1H), 4.07 (s, 2H), 1.82 (s, 1H), 1.28 (s, 6H). RE12 [00047] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.13 (d, J = 2.4 Hz, 1H), 7.98 (s, 1H), 7.80 (d, J = 8.9 Hz, 1H), 7.68 (dd, J = 9.5, 2.1 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.07 (dd, J = 8.9, 2.1 Hz, 1H), 4.08 (s, 2H), 1.68 (s, 1H), 1.29 (s, 6H). RE13 [00048] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.43-8.42 (m, 1H), 7.97 (s, 1H), 7.90 (dd, J = 8.7, 2.3 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.26 (d, J = 2.3 Hz, 1H), 7.03-7.00 (m, 2H), 4.07 (s, 2H), 1.81 (s, 1H), 1.28 (s, 6H). RE14 [00049] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.77 (s, 2H), 7.99 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.08 (dd, J = 8.5, 2.4 Hz, 1H), 4.08 (s, 2H), 1.71 (s, 1H), 1.29 (s, 6H). RE15 [00050] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.19 (d, J = 5.5 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.00-6.98 (m, 1H), 6.78-6.77 (m, 2H), 4.08 (s, 2H), 1.70 (s, 1H), 1.28 (s, 6H). RE16 [00051] .sup.1H-NMR (CDCl.sub.3, 400 MHz) : 8.07 (d, J = 3.1 Hz, 1H), 7.96 (s, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.57-7.53 (m, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.5, 2.4 Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 4.07 (s, 2H), 1.61 (s, 1H), 1.28 (s, 6H).

[0300] According to the processes of Examples Ex1 and Ex2, and Reference example RE1, the following compounds can be prepared.

TABLE-US-00006 [00052] R.sup.D [00053] [00054] [00055] [00056] [00057] [00058] [00059] [00060] [00061] [00062] [00063]

INDUSTRIAL APPLICABILITY

[0301] The present invention can provide a process of preparing a benzimidazole derivative, which can prepare the desired product in short reaction processes without a protection/deprotection process.