JPWO2008078424A1 - Benzoxazole derivatives - Google Patents

Abstract

Benzoxazole derivatives or pharmaceutically acceptable salts or solvates thereof useful for early diagnosis of conformation disease, compositions and kits for conformation disease diagnosis containing the same, and treatment and / or prevention of conformation disease Pharmaceutical compositions and the like are provided by the present invention.

Description

  The present invention relates to a diagnostic probe for a conformational disease, in particular, a diagnostic imaging probe, in particular, a probe labeled with a positron emitting nuclide, and a diagnostic imaging composition containing the probe. Furthermore, the present invention is used for, for example, detection / staining of amyloid β protein and neurofibrillary tangle in brain material, for example, detection / staining of senile plaques in the brain of Alzheimer's disease patients, and prevention and / or treatment of conformation disease. The present invention also relates to a pharmaceutical composition. The present invention also relates to a conformational disease diagnostic composition containing the probe.

  Diseases in which proteins having a β-sheet structure peculiar to conformation diseases accumulate include various diseases characterized by deposition of insoluble fibrillar proteins in various organs and tissues in the body. These diseases include Alzheimer's disease, prion disease, Lewy body disease, Parkinson's disease, Huntington's disease, bulbar spinal muscular atrophy, dentate nucleus / palliary bulbous atrophy, spinal cord / cerebellar degeneration, Machado- joseph disease, Amyophic Lateral Sclerosis (ALS), down's syndrome, pick's disease, FTDP-17 (Frontotemporal Dementia and Parkinsonism linked to Chromosome 17), LNTD (Limbic neurofibrillary Tangle Demetia), Sudanophiloc Leukodystrophy, include amyloidosis like.

  Among them, Alzheimer's disease (AD) is currently regarded as one of the most difficult diseases to treat, and is a disease for which an accurate early diagnosis is desired. Alzheimer's disease is a disease characterized mainly by progressive dementia that occurs from presenescence to old age. Pathologically, it is characterized by general atrophy of the cerebrum, marked degeneration and loss of nerve cells, neurofibrillary tangles and appearance of senile plaques. It is known that the greatest risk factor of dementia represented by Alzheimer's disease is aging. Therefore, the increase in patients accompanying the increase in the aging population is particularly remarkable in Japan, the United States, and European countries, which are aging societies. Yes.

  In Japan, the number of Alzheimer's disease patients is estimated to be about 1 million, and it is expected that the number of patients will increase as the population ages. The cost for Alzheimer's disease patients, including nursing care costs, is considered to be between 1 million and 3 million yen per patient per year, so we have already paid 1 trillion to 3 trillion yen in socio-economic costs in Japan. Will be. It is now common knowledge in the world that treatment in Alzheimer's disease before or after symptoms become apparent, or if it is given as soon as possible, has a great medical economic effect.

  There are various current methods for diagnosing Alzheimer's disease, but in Japan, methods such as the Hasegawa method, ADAS, MMSE, etc., are generally used to quantitatively evaluate the decline in cognitive function of individuals suspected of Alzheimer's disease. In addition, diagnostic imaging methods (MRI, CT, etc.) are used in an auxiliary manner. However, these diagnostic methods are insufficient to determine the disease, and a definite diagnosis requires a biopsy of the brain before birth (biopsy) and a histopathological examination of the postmortem brain. Thus, despite strenuous research on Alzheimer's disease diagnostic methods, there has not been much progress. Many studies have shown that Alzheimer's disease-specific neurodegeneration has already begun long before the first clinical symptoms appear (about 40 years in the longest). In the same disease, when the family or clinician surrounding the patient notices the first clinical symptoms, it is known that the pathological image in the brain has already progressed to an irreversible state. Considering the above-mentioned progression characteristics of the disease state and the rapid increase in the number of patients, the necessity and significance of accurate early diagnosis of Alzheimer's disease are extremely great.

  The histopathology of Alzheimer's disease is represented by two main features. Senile plaques and neurofibrillary tangles. The former main component is amyloid β (Aβ) protein having a β sheet structure, and the latter is hyperphosphorylated amyloid β protein. A definitive diagnosis of Alzheimer's disease relies on the appearance of these pathological features in the patient's brain.

  Amyloid β protein is characteristic of conformation diseases including Alzheimer's disease and has a close relationship. Therefore, detection of amyloid β protein having a β sheet structure in the body, particularly in the brain, as a marker is one of important diagnostic methods for conformation disease, particularly Alzheimer's disease. For the purpose of diagnosing diseases in which amyloid accumulates such as Alzheimer's disease, a search for a substance that specifically binds to and stains amyloid β protein in the body, particularly in the brain, has been performed. Examples of such substances include Congo Red (see Non-Patent Document 1) and Thioflavin S (see Non-Patent Document 2), Thioflavin T (see Non-Patent Document 3), and Chrysamine G and its derivatives (see Patent Document 1 and Patent Document 2). However, there are not a few problems in terms of binding specificity to the amideroid β protein, blood-brain barrier permeability, solubility, toxicity, and the like. The present inventors have found various compounds having characteristics such as high specificity for amyloid β protein, blood-brain barrier permeability, high solubility, and low toxicity (Patent Document 3, Patent Document) 4, Patent Document 5, Patent Document 6 and Patent Document 7).

  There is known a disease in which a protein in the brain itself is caused by a β-sheet structure. In Alzheimer's disease, amyloid β protein and tau protein have a β sheet structure, and thus the protein itself is considered to be an etiology or a part of the etiology. Yanker et al. Reported for the first time that amyloid β protein exerts neurocytotoxicity by adopting a β sheet structure (see Non-Patent Document 4). Thereafter, many additional tests were conducted, and it was confirmed that the amyloid β protein having a β sheet structure has neurotoxicity. Since neurocytotoxicity is observed in amyloid β protein and tau protein that have β-sheet structure in this way, compounds that suppress that cytotoxicity can be caused by the protein itself having β-sheet structure, or part of the pathogenesis. It is suggested that it can be used as a therapeutic agent for a disease that is a conformational disease, such as Alzheimer's disease. However, at present, sufficient results have not been obtained in the development of such therapeutic agents.

  Therefore, there is a growing need for compounds with high specificity for amyloid β protein for the diagnosis of conformation diseases such as Alzheimer's disease, specific stains for amyloid β protein, and the treatment and prevention of conformation disease. Yes.

  Another histopathological symptom of Alzheimer's disease is neurofibrillary tangle and its main component hyperphosphorylated tau protein, which are generally thought to be realized later than amyloid β protein. ing. However, neurofibrillary tangles are thought to correlate well with the degree of dementia compared to amyloid β protein (see Non-Patent Document 5 and Non-Patent Document 6).

  In addition to Alzheimer's disease, diseases that mainly have tau protein accumulation in the brain (tauopathy) include Pick's disease and progressive supranuclear palsy (PSP). These diseases are also included in conformation diseases.

  Thus, tau protein is characteristic of diseases in which tau protein accumulates, including Alzheimer's disease, and is closely related. Therefore, detection of tau protein having a β-sheet structure in the body, particularly in the brain, as a marker is one of important diagnostic methods for diseases in which tau protein accumulates, particularly Alzheimer's disease.

  For the purpose of diagnosing diseases in which tau accumulates such as Alzheimer's disease, methods for quantifying tau in the body, particularly cerebrospinal fluid, have been reported by a few groups (Non-patent document 7 and Non-patent document). 8). However, there are no probes in the world that aim at non-invasively determining tau in vivo.

  Therefore, it is highly specific for neurofibrillary tangles for diagnosis and treatment of diseases in which neurofibrillary tangles such as Alzheimer's disease are etiological or part of the etiology, or for staining neurofibrillary tangles There is a growing need for compounds.

So far, compounds with high specificity for amyloid β protein and neurofibrillary tangles have been reported (see Patent Document 8, Patent Document 9, Patent Document 10, and Patent Document 11). When these compounds are used in vivo, especially in the body of a human patient, it is desirable that the mutagenicity is very low or absent. It is also desirable that there is very little or no bone accumulation. Therefore, there is a need to search for compounds that can be used as diagnostic probes for conformation diseases with very low or no mutagenicity and / or very little or no bone accumulation.
Patent Document 1: International Patent Application PCT / US96 / 05918 Specification Patent Document 2: International Patent Application PCT / US98 / 078989 Patent Document 3: Japanese Patent Application No. 2000-080082 Patent Document 4: Japanese Patent Application No. Japanese Patent Application No. 2001-080083 Patent Document 5: Japanese Patent Application No. 2001-76075 Patent Document 6: International Patent Application PCT / JP01 / 02204 Specification Patent Document 7: International Patent Application PCT / JP01 / 02205 Specification Patent Document 8: International patent application PCT / JP03 / 01783 specification Patent document 9: International patent application PCT / JP03 / 15269 specification Patent document 10: International patent application PCT / JP03 / 15229 specification Patent document 11: International patent application PCT / JP03 Non-Patent Document 1: Puchtler et al., Jour al of Histochemistry, Vol. 10, p. 35, 1962 Non-Patent Document 2: Puchtler et al., Journal of Histochemistry, Vol. 77, p. 431, 1983 Non-Patent Document 3: LeVine, Protein Science, 2, 404-410 Page Non-Patent Document 4: Yankner et al., Science, 245, 417-420, 1989 Non-Patent Document 5: Braak H and Braak E, Acta Neuropathol, 82, 239-259, 1991 Non-Patent Document 6: Wischik et al., Neurobiology of Alzheimer's Disease, pages 103-206, Oxford University Press, Oxford, 20 1 year Non-Patent Document 7: Ishiguro et al., Neufosci. Lett. 270, 81-84, 1999 Non-Patent Document 8: Itoh et al., Ann. Neurol. 50, 150-156, 2001

  In view of the above circumstances, the present invention has high specificity for amyloid β protein and / or neurofibrillary tangle, high brain migration, and low or no mutagenicity, and / or very little bone accumulation, Alternatively, the present invention provides a substance that can be used as a diagnostic probe for conformational diseases. The present invention also provides such a labeled substance used as a diagnostic imaging probe for conformation disease, and a diagnostic imaging composition and kit containing such a probe. Furthermore, the present invention also provides a method for detecting and / or staining amyloid β protein and neurofibrillary tangles in brain material, a kit therefor, and a pharmaceutical composition for prevention and / or treatment of conformation disease. The present invention also provides a compound useful for early diagnosis of conformation disease, a composition for image diagnosis containing the compound, and the like.

［式中、
Ｒ^１及びＲ^２は、それぞれ独立して、水素原子、低級アルキル基、シクロアルキル基を示すか、或いは、
Ｒ^１、Ｒ^２及びそれらが互いに結合する窒素原子が一緒になって形成する３乃至８員の含窒素脂肪族環（該含窒素脂肪族環を構成する炭素原子は、窒素原子、硫黄原子又は酸素原子に置き換わっていてもよく、炭素原子が窒素原子で置き換わっている場合には、該窒素原子は、低級アルキル基で置換されていてもよい）を示し、
Ｘ_１及びＸ_２は、それぞれ独立して、窒素原子、硫黄原子又は酸素原子を示し、
Ｒ^３は、−Ｏ−低級アルキル基（該アルキル基は、ハロゲン原子で置換されており、さらに、ヒドロキシ基で置換されていてもよい）を示し、
ｍは、１乃至３の整数を示す］で表される化合物（ただし、Ｒ^３がハロゲン原子のみで置換された−Ｏ−低級アルキル基であり、かつ、Ｒ^１及びＲ^２がそれぞれ独立して、水素原子又は低級アルキル基である場合を除く）又はその薬学的に許容される塩もしくは溶媒和物が、アミロイドβ蛋白および／または神経原線維変化に対する特異性が高く、脳移行性が高く、しかも変異原性が低いか、あるいはない、コンフォーメーション病の診断プローブとして使用できることを見出し、本発明を完成するに至った。As a result of intensive studies to solve the above problems, the present inventors have found that the compound represented by formula (I)

[Where:
R ¹ and R ² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or
A 3- to 8-membered nitrogen-containing aliphatic ring formed by R ¹ , R ² and the nitrogen atom to which they are bonded together (the carbon atom constituting the nitrogen-containing aliphatic ring is a nitrogen atom, a sulfur atom or An oxygen atom may be substituted, and when a carbon atom is substituted with a nitrogen atom, the nitrogen atom may be substituted with a lower alkyl group),
X ₁ and X ₂ each independently represent a nitrogen atom, a sulfur atom or an oxygen atom,
R ³ represents —O-lower alkyl group (the alkyl group is substituted with a halogen atom, and may be further substituted with a hydroxy group);
m represents an integer of 1 to 3, wherein R ³ is an —O-lower alkyl group substituted with only a halogen atom, and R ¹ and R ² are each independently , Or a pharmaceutically acceptable salt or solvate thereof, has high specificity for amyloid β protein and / or neurofibrillary tangle, high brain migration, In addition, the present inventors have found that it can be used as a diagnostic probe for conformation diseases with low or no mutagenicity, and has completed the present invention.

  In particular, the compound of the present invention having a morpholino group at one end is very low in mutagenicity or is not mutagenic as shown in the Examples. It is one feature of the present invention to include a group of compounds having low or no mutagenicity.

  In addition, a compound having an -O-lower alkyl group (the alkyl group is substituted with a halogen atom and may be further substituted with a hydroxy group) at the other end has low bone accumulation, Or many of them are extremely low. It is a feature of the present invention to include such low or very low bone accumulation compounds.

  The present invention relates to a compound represented by formula (I) having a morpholino group at one end and / or an -O-lower alkyl group at the other end (the alkyl group is substituted with a halogen atom). And may be substituted with a hydroxy group), the compound is safer than the conventional amyloid PET probe or a pharmaceutically acceptable product thereof. A salt or solvate is provided.

  Therefore, the compound of the present invention is extremely safe. Moreover, since the compound of the present invention stains amyloid β protein specifically and clearly, it can be said to enable accurate early diagnosis of Alzheimer's disease, Down's syndrome and the like. Furthermore, the compound of the present invention has high brain transportability, that is, blood-brain barrier permeability. These characteristics allow non-invasive early diagnosis in vivo, particularly in human patients, using the compounds of the present invention.

  For example, WO2004 / 035522 discloses many benzoxazole derivatives as amyloid PET probe diagnostic agents. However, this specification does not disclose a compound in which one terminal is morpholine, and the other terminal is an -O-lower alkyl group (the lower alkyl group is substituted with a halogen atom, Furthermore, there is no disclosure of compounds that are substituted with hydroxy groups).

  The present invention provides a highly safe compound with extremely high specificity for amyloid β protein and / or neurofibrillary tangle, high blood-brain barrier permeability, and low or no mutagenicity. . In addition, the present invention has extremely high specificity for amyloid β protein and / or neurofibrillary tangle, high blood-brain barrier permeability, and low or almost no accumulation in bone. Provides high compound. Therefore, the compound of the present invention can be used to diagnose, treat and / or prevent conformation diseases. In addition, according to the present invention, it is possible to perform image diagnosis of conformation disease, particularly image diagnosis using PET. Therefore, the present invention enables accurate diagnosis, effective treatment and prevention at an early stage of conformation disease.

FIG. 1 is a fluorescence microscopic image (ex vivo) when THK-097 (0.2 mg / kg) was intravenously administered to a Tg mouse (Tg2576) in which amyloid β protein accumulates. FIG. 2 is a fluorescence microscopic image (ex vivo) when THK-525 (4 mg / kg) was intravenously administered to a Tg mouse (Tg2576) in which amyloid β protein accumulates. Open arrows indicate amyloid β protein. FIG. 3 is a fluorescence microscopic image (ex vivo) when THK-727 (4 mg / kg) was intravenously administered to Tg mice (APPswe2576 / TauJPL3) in which amyloid β protein accumulates. Open arrows indicate amyloid β protein. FIG. 4 shows a fluorescence microscope image (upper panel) and an anti-amyloid β (Aβ) antibody-stained image of the same section when THK-702 (4 mg / kg) was intravenously administered to a Tg mouse (Tg2576) in which amyloid β protein accumulates. (Lower panel). FIG. 5 shows an enlarged microscope image of FIG. A, B, and C correspond to A, B, and C in FIG. White and black arrows indicate amyloid β protein. FIG. 6 shows THK-097 (left panel) -stained image and anti-amyloid β (Aβ) antibody-stained image (right panel: adjacent section of left panel) in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 7 is a THK-184 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 8 is a THK-185 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein, and open arrowheads indicate neurofibrillary tangles. FIG. 9 is a THK-203 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 10 is a THK-207 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 11 is a THK-248 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 12 is a THK-254 stained image in a brain section of an Alzheimer's disease patient. Open arrowheads indicate neurofibrillary tangles. FIG. 13 is a THK-258 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein, and open arrowheads indicate neurofibrillary tangles. FIG. 14 is a THK-262 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 15 is a THK-276 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 16 is a THK-281 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 17 is a THK-308 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 18 is a THK-317-stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein, and open arrowheads indicate neurofibrillary tangles. FIG. 19 is a THK-383 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 20 is a THK-385 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 21 is a THK-386-stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein, and open arrowheads indicate neurofibrillary tangles. FIG. 22 shows THK-525 (left panel) -stained image and anti-amyloid β (Aβ) antibody-stained image (right panel: adjacent section of left panel) in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 23 is a THK-556 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 24 is a THK-558 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 25 is a THK-559 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 26 is a THK-561 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 27 is a THK-562 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 28 is a THK-563 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 29 shows THK-565 (left panel) -stained image and anti-amyloid β (Aβ) antibody-stained image (right panel: adjacent section of left panel) in a brain section of Alzheimer's disease patients. Open arrows indicate amyloid β protein. FIG. 30 is a THK-585 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 31 is a THK-702 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 32 is a THK-708 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 33 is a THK-727 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein and open arrowheads indicate neurofibrillary tangles. FIG. 34 is a THK-752 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 35 is a THK-761-stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 36 is a THK-763 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 37 is a THK-766 stained image in a brain section of an Alzheimer's disease patient. Open arrows indicate amyloid β protein. FIG. 38 shows bone accumulation in mice after 2 min, 30 min and 60 min of ¹⁸ F-labeled THK-702, THK-763, THK-761 and BF-227.

  The compound of the present invention is a compound represented by the formula (I), (I ')-(VI), or a salt or solvate thereof described below. In the present specification, the terms “the compound of the present invention” and “the compound of the present invention” refer to compounds of the formulas (I), (I ′)-(VI), and salts thereof, unless otherwise specified. Solvates are intended to be included.

  In the present specification, the “lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically includes, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2- Dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl Group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbuty Group, 1,2,2-trimethyl propyl group, a 1-ethyl-2-methylpropyl group.

  In the present specification, the “cycloalkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, and specifically includes, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. Can be mentioned.

  In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  In the present specification, “amyloid beta protein”, “amyloid β protein”, “Aβ protein”, “amyloid beta”, “amyloid β”, and “Aβ” are synonymous.

  When a double bond exists between two rings in the compound of the present invention, both cis and trans isomers can exist.

  When an asymmetric carbon atom is present in the compound of the present invention, a mixture of isomers and individual isomers thereof are also included in the compound of the present invention.

  For example, when one asymmetric carbon exists in the compound of the present invention, each optically active compound is synthesized separately, or each optical isomer is separated by column chromatography. be able to.

  When optical isomers are separated by column chromatography, examples of the column used include Chiral Pack AD (manufactured by Daicel).

  The solvent used may be any solvent that is usually used to separate isomers, for example, chloroform, acetonitrile, ethyl acetate, methanol, ethanol, acetone, hexane, water, etc. are used alone, or These solvents can be used in combination of two or more.

［式中、各記号は前記に同じ］で表される化合物について、さらに、具体的に開示するために、式（Ｉ）において用いられる各種記号について、具体例を挙げて説明する。Formula (I) according to the present invention

In order to more specifically disclose the compound represented by [in the formula, each symbol is the same as described above], various symbols used in formula (I) will be described with specific examples.

R ¹ and R ² each independently represent a hydrogen atom, a lower alkyl group, or a cycloalkyl group, or R ¹ , R ² and a nitrogen atom to which they are bonded together form 3 to 3 8-membered nitrogen-containing aliphatic ring (the carbon atom constituting the nitrogen-containing aliphatic ring may be replaced with a nitrogen atom, a sulfur atom or an oxygen atom, and when the carbon atom is replaced with a nitrogen atom, The nitrogen atom may be substituted with a lower alkyl group.

The “lower alkyl group” represented by R ¹ and R ² means the same group as the lower alkyl group defined above, and among them, a methyl group, an ethyl group, and a propyl group are preferable, and a methyl group is more preferable.
The “cycloalkyl group” represented by R ¹ and R ² means the same group as the cycloalkyl group defined above.

［式中、Ｚは、Ｏ、Ｓ、ＣＨ_２又はＮＲ^ｅであり、Ｒ^ｅは、水素又はＣ_１−４アルキル基を示す］で表される基等が挙げられ、これらのうち、モルホリノ基が好ましい。

［式中、各記号は前記に同じ］で表される基としては、ジメチルアミノ基又はメチルアミノ基、モルホリノ基が好ましく、ジメチルアミノ基又はモルホリノ基がより好ましい。A 3- to 8-membered nitrogen-containing aliphatic ring formed by R ¹ , R ² and the nitrogen atom to which they are bonded together (the carbon atom constituting the nitrogen-containing aliphatic ring is a nitrogen atom, a sulfur atom or Specifically, for example, the oxygen atom may be substituted, and when the carbon atom is substituted with a nitrogen atom, the nitrogen atom may be substituted with a lower alkyl group.

[Wherein, Z represents O, S, CH ₂ or NR ^e , and R ^e represents hydrogen or a C _1-4 alkyl group], among which a morpholino group Is preferred.

The group represented by [in the formula, each symbol is the same as above] is preferably a dimethylamino group, a methylamino group, or a morpholino group, and more preferably a dimethylamino group or a morpholino group.

X ₁ represents a nitrogen atom, a sulfur atom or an oxygen atom, and among these, an oxygen atom is preferred.

X ₂ represents a nitrogen atom, a sulfur atom or an oxygen atom, and among these, a sulfur atom is preferred.

  m represents an integer of 1 to 3, and m is preferably 1 among these.

で表される基がより好ましい。R ³ represents —O-lower alkyl group (the alkyl group is substituted with a halogen atom and may be further substituted with a hydroxy group), and among these, substituted with a halogen atom -O-lower alkyl group or -O-lower alkyl group substituted with a halogen atom and a hydroxy group is preferred,

Is more preferable.

  Among the compounds of the present invention, pharmaceutically acceptable salts or solvates thereof, preferred are the compounds represented by the formula (I), or pharmaceutically acceptable salts or solvates thereof.

で表される基が、モルホリノ基である場合、又は、式（Ｉ）中のＲ^３が、

で表される化合物又はその薬学的に許容される塩もしくは溶媒和物である場合がより好ましい。Of the compounds of the present invention or pharmaceutically acceptable salts or solvates thereof,

Or when R ³ in the formula (I) is a morpholino group,

Or a pharmaceutically acceptable salt or solvate thereof is more preferable.

で表される基が、モルホリノ基を有する化合物は、変異原性が極めて低いか、或いは実施例に示すように変異原性が認められなかった。In formula (I)

The compound represented by the above formula has a morpholino group having very low mutagenicity or no mutagenicity was observed as shown in the Examples.

である基を有する化合物は、実施例に示すように、骨集積がほとんど認められないか、極めて低いものである。Also,
R ³ in formula (I) is

As shown in the Examples, the compound having a group of which has almost no bone accumulation or is extremely low.

  Furthermore, as shown in the Examples, these compounds, pharmaceutically acceptable salts or solvates thereof have a high specificity for Aβ, a low toxicity, a high ability to enter the brain, and a constant level. Most drugs disappear quickly from the brain after a lapse of time.

  Therefore, the compound of the present invention can be used as a safe probe for diagnostic imaging of conformation diseases.

  The present invention also provides a compound used as a precursor for the synthesis of a compound represented by formula (I). One skilled in the art can readily design and synthesize such precursors from the compounds of the present invention that are aimed at. Alternatively, such precursors can be obtained by modifying commercially available ones.

［式中、
Ｒ^１及びＲ^２は、それぞれ独立して、水素原子、低級アルキル基、シクロアルキル基を示すか、或いは、
Ｒ^１、Ｒ^２及びそれらが互いに結合する窒素原子が一緒になって形成する３乃至８員の含窒素脂肪族環（該含窒素脂肪族環を構成する炭素原子は、窒素原子、硫黄原子又は酸素原子に置き換わっていてもよく、炭素原子が窒素原子で置き換わっている場合には、該窒素原子は、低級アルキル基で置換されていてもよい）を示し、
Ｘ_１及びＸ_２は、それぞれ独立して、窒素原子、硫黄原子又は酸素原子を示し、
Ｒ^４は、−Ｏ−低級アルキル基（該アルキル基は、トシル基で置換されており、さらに、ヒドロキシ基で置換されていてもよい）を示し、
ｍは、１乃至３の整数を示す］で表される化合物（ただし、Ｒ^３がハロゲン原子のみで置換された−Ｏ−低級アルキル基であり、かつ、Ｒ^１及びＲ^２がそれぞれ独立して、水素原子又は低級アルキル基である場合を除く）又はその薬学的に許容される塩もしくは溶媒和物が挙げられる。Examples of the precursor include the formula (I ′)

[Where:
R ¹ and R ² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or
A 3- to 8-membered nitrogen-containing aliphatic ring formed by R ¹ , R ² and the nitrogen atom to which they are bonded together (the carbon atom constituting the nitrogen-containing aliphatic ring is a nitrogen atom, a sulfur atom or An oxygen atom may be substituted, and when a carbon atom is substituted with a nitrogen atom, the nitrogen atom may be substituted with a lower alkyl group),
X ₁ and X ₂ each independently represent a nitrogen atom, a sulfur atom or an oxygen atom,
R ⁴ represents —O-lower alkyl group (the alkyl group is substituted with a tosyl group, and may be further substituted with a hydroxy group);
m represents an integer of 1 to 3, wherein R ³ is an —O-lower alkyl group substituted with only a halogen atom, and R ¹ and R ² are each independently Or a pharmaceutically acceptable salt or solvate thereof).

R ¹ , R ² , X ₁ and X ₂ in the formula (I ′) are the same as those in the formula (I).

で表される基が好ましい。Of R ⁴

The group represented by these is preferable.

［式中、
Ｇはフラン、チオフェン、ピロール、ピリジン、ベンゾフラン、ベンゾチオフェン、ベンゾキサゾール、ベンゾチアゾール、ベンゾイミダゾールまたはインドール環であり；
上記環はハロゲン、ＯＨ、ＣＯＯＨ、ＳＯ_３Ｈ、ＮＯ_２、ＳＨ、ＮＲ^ｆＲ^ｇ、Ｃ_１−６アルキル、Ｏ−Ｃ_１−６アルキル、ＣＮまたはＣ＝Ｏで置換されていてもよく；
Ｒ_７は水素、ハロゲン、ＯＨ、ＣＯＯＨ、ＳＯ_３Ｈ、ＮＯ_２、ＳＨ、ＮＲ^ｆＲ^ｇ、Ｃ_１−６アルキル、Ｏ−Ｃ_１−６アルキル、ＣＮまたはＣ＝Ｏであり；
Ｒ_８は水素、ハロゲン、ＯＨ、ＣＯＯＨ、ＳＯ_３Ｈ、ＮＯ_２、ＳＨ、ＮＲ^ｆＲ^ｇ、Ｃ_１−６アルキル、Ｏ−Ｃ_１−６アルキル、ＣＮ、Ｃ＝Ｏ、ピロリジン環、または

であり；
Ｒ^ｆおよびＲ^ｇは独立して水素またはＣ_１−４アルキルであり；
ｐは１ないし４の整数であり；
Ｚ^ＩＩはＯ、ＣＨ_２、Ｎ−Ｒ^ｅ'であり；
Ｒ^ｅ'は水素またはＣ_１−４アルキルであり、
上記アルキルはハロゲンで置換されていてもよい］で示される化合物、またはその塩もしくは溶媒和物である。Further compounds of the invention are represented by formula (II)

[Where:
G is furan, thiophene, pyrrole, pyridine, benzofuran, benzothiophene, benzoxazole, benzothiazole, benzimidazole or indole ring;
The ring may be substituted with halogen, OH, COOH, SO ₃ H, NO ₂ , SH, NR ^f R ^g , C _1-6 alkyl, O—C _1-6 alkyl, CN or C═O;
R ₇ is hydrogen, halogen, OH, COOH, SO ₃ H, NO ₂ , SH, NR ^f R ^g , C _1-6 alkyl, O—C _1-6 alkyl, CN or C═O;
R ₈ is hydrogen, halogen, OH, COOH, SO ₃ H, NO ₂ , SH, NR ^f R ^g , C _1-6 alkyl, O—C _1-6 alkyl, CN, C═O, pyrrolidine ring, or

Is;
R ^f and R ^g are independently hydrogen or C _1-4 alkyl;
p is an integer from 1 to 4;
Z ^II is O, CH ₂ , N—R ^{e ′} ;
R ^{e ′} is hydrogen or C _1-4 alkyl;
The alkyl may be substituted with halogen], or a salt or solvate thereof.

であり；
好ましいＺ^ＩＩはＯであり；
好ましいＲ^ｆおよびＲ^ｇは独立して水素またはメチルであり；
ｐは１ないし４の整数であり；
上記アルキルはハロゲンで置換されていてもよい。Preferred substituents of the compound of formula (II) are as follows:
Preferred G is furan, thiophene, pyrrole, pyridine, benzofuran, benzothiophene or indole ring;
The ring may be substituted with halogen, C _1-6 alkyl or O—C _1-6 alkyl;
Preferred R ₇ is hydrogen;
Preferred R ₈ is hydrogen or NR ^f R ^g or

Is;
Preferred Z ^II is O;
Preferred R ^f and R ^g are independently hydrogen or methyl;
p is an integer from 1 to 4;
The alkyl may be substituted with a halogen.

Among the compounds of formula (II), those in which R ₈ is a morpholine ring are more preferred because they have very low or no mutagenicity. Such compounds of formula (II) include THK-383, THK-384, THK-385, THK-386 and THK-387. Compounds of formula (II) with high specificity for amyloid β include THK-258, THK-262, THK-383, THK-385 and THK-386. Therefore, the compounds of formula (II) having high specificity for amyloid β and extremely low or no mutagenicity include THK-383, THK-385 and THK-386.

［式中、
Ｘ^ＩＩＩおよびＹ^ＩＩＩは独立してＣＨ_２またはＣ＝Ｏであり；
Ｒ^９は水素、ハロゲン、ＯＨ、ＣＯＯＨ、ＳＯ_３Ｈ、ＮＯ_２、ＳＨ、ＮＲ^ｈＲ^ｉ、Ｃ_１−６アルキル、Ｏ−Ｃ_１−６アルキル、ＣＮまたはＣ＝Ｏであり；
Ｒ^ｈおよびＲ^ｉは独立して水素またはＣ_１−４アルキルであり；
＊には下記の部分が結合し：

または

Ｌは

または

であり；
Ａ^ＩＩＩおよびＢ^ＩＩＩは独立してＣＨまたはＮであり；
Ｒ_１０、Ｒ_１１、Ｒ_１２、Ｒ_１４は独立して水素、ハロゲン、ＯＨ、ＣＯＯＨ、ＳＯ_３Ｈ、ＮＯ_２、ＳＨ、ＮＲ^ＩＲ^ＩＩ、Ｃ_１−６アルキル、Ｏ−Ｃ_１−６アルキル、ＣＮ、Ｃ＝Ｏ、ピロリジン環、または

であり；
Ｒ_１３は水素、ハロゲンまたはＣ_１−４アルキルであり；
Ｒ_１０'、Ｒ_１１'、Ｒ_１２'、Ｒ_１４'は独立して水素、ハロゲンまたはＣ_１−４アルキルであり；
ｒは０ないし２の整数であり；
ａ'は１ないし４の整数であり；
ｂ'は１または２の整数であり；
ｃ'は１ないし４の整数であり；
ｄ'は１ないし４の整数であり；
Ｚ^ＩＩＩはＯ、ＣＨ_２、Ｎ−Ｒ^ｅ''であり；
Ｒ^ｅ''は水素またはＣ_１−４アルキルであり、
上記アルキルはハロゲンで置換されていてもよく；
２つの環部分をつなぐ二重結合まわりの配置は、可能な場合はシス型、トランス型のいずれであってもよい］で示される化合物、またはその塩もしくは溶媒和物である。Further compounds of the invention are of formula (III)

[Where:
X ^III and Y ^III are independently CH ₂ or C═O;
R ⁹ is hydrogen, halogen, OH, COOH, SO ₃ H, NO ₂ , SH, NR ^h R ⁱ , C _1-6 alkyl, O—C _1-6 alkyl, CN or C═O;
R ^h and R ⁱ are independently hydrogen or C _1-4 alkyl;
* Is combined with the following parts:

Or

L is

Or

Is;
A ^III and B ^III are independently CH or N;
R ₁₀ , R ₁₁ , R ₁₂ , R ₁₄ are independently hydrogen, halogen, OH, COOH, SO ₃ H, NO ₂ , SH, NR ^I R ^II , C _1-6 alkyl, O—C _1-6 alkyl CN, C═O, pyrrolidine ring, or

Is;
R ₁₃ is hydrogen, halogen or C _1-4 alkyl;
R ₁₀ ′, R ₁₁ ′, R ₁₂ ′, R ₁₄ ′ are independently hydrogen, halogen or C _1-4 alkyl;
r is an integer from 0 to 2;
a ′ is an integer from 1 to 4;
b ′ is an integer of 1 or 2;
c ′ is an integer from 1 to 4;
d ′ is an integer from 1 to 4;
Z ^III is O, CH ₂ , N—R ^{e ″} ;
R ^{e ″} is hydrogen or C _1-4 alkyl;
The alkyl may be substituted with halogen;
The arrangement around the double bond connecting the two ring moieties may be cis or trans if possible, or a salt or solvate thereof.

または

Ｌは

または

であり；
好ましいＡ^ＩＩＩおよびＢ^ＩＩＩはＣＨであり；
好ましいＲ_１０、Ｒ_１１、Ｒ_１２、Ｒ_１４は独立して水素、Ｃ_１−６アルキルまたはモルホリン環であり；
好ましいＲ_１３は水素またはメチルであり；
好ましいＲ_１０'、Ｒ_１１'、Ｒ_１２'、Ｒ_１４'は独立して水素またはＣ_１−４アルキルであり；
好ましいｒは０または１の整数であり；
置換基が水素以外の場合の好ましいａ'、ｂ'、ｃ'、ｄ'は独立して１または２の整数であり；
上記アルキルはハロゲンで置換されていてもよく；
２つの環部分をつなぐ二重結合まわりの配置は、可能な場合にはシス型、トランス型のいずれであってもよい。Preferred substituents of the compound of formula (III) are as follows:
Preferably one or both of X ^III and Y ^III is C═O;
Preferred R ⁹ is hydrogen;
* Is combined with the following parts:

Or

L is

Or

Is;
Preferred A ^III and B ^III is CH;
Preferred R ₁₀ , R ₁₁ , R ₁₂ , R ₁₄ are independently hydrogen, C _1-6 alkyl or morpholine ring;
Preferred R ₁₃ is hydrogen or methyl;
Preferred R ₁₀ ′, R ₁₁ ′, R ₁₂ ′, R ₁₄ ′ are independently hydrogen or C _1-4 alkyl;
Preferred r is an integer of 0 or 1;
Preferred a ′, b ′, c ′, d ′ when the substituent is other than hydrogen is independently an integer of 1 or 2;
The alkyl may be substituted with halogen;
The arrangement around the double bond connecting the two ring portions may be either cis type or trans type if possible.

Among the compounds of formula (III), those in which R ₁₀ , R ₁₁ , R ₁₂ or R ₁₄ is a morpholine ring are more preferred because they have very low or no mutagenicity. Compounds of formula (III) with high specificity for amyloid β include THK-184 and THK-248.

［式中、
Ｘ^ＩＶはＮまたはＮＲ^ＩＶであり；
ＮＲ^ＩＶは水素またはＣ_１−４アルキルであり；
Ｙ^ＩＶはＣＨまたはＣ＝Ｏであり；
破線は存在してもよい一重結合であり；
＊＊には下記の部分が結合し：

または

Ｌ^ＩＶは

または

であり；
Ａ^ＩＶおよびＢ^ＩＶは独立してＣＨ、ＣＣＨ_３またはＮであり；
Ｒ_１５、Ｒ_１６、Ｒ_１７、Ｒ_１９は独立して水素、ハロゲン、ＯＨ、ＣＯＯＨ、ＳＯ_３Ｈ、ＮＯ_２、ＳＨ、ＮＲ^ｊＲ^ｋ、Ｃ_１−６アルキル、Ｏ−Ｃ_１−６アルキル、ＣＮ、Ｃ＝Ｏ、ピロリジン環、または

であり；
Ｒ^ｊおよびＲ^ｋは独立して水素またはＣ_１−４アルキルであり；
Ｒ_１８は水素、ハロゲンまたはＣ_１−４アルカリであり；
Ｒ_１５'、Ｒ_１６'、Ｒ_１７'、Ｒ_１９'は独立して水素、ハロゲンまたはＣ_１−４アルカリであり；
ｒ'は０ないし２の整数であり；
ａ''は１ないし４の整数であり；
ｂ''は１または２の整数であり；
ｃ''は１ないし４の整数であり；
ｄ''は１ないし４の整数であり；
Ｚ^ＩＶはＯ、ＣＨ_２、Ｎ−Ｒ^ｅ'''であり；
Ｒ^ｅ'''は水素またはＣ_１−４アルキルであり、
上記アルキルはハロゲンで置換されていてもよく；
２つの環部分をつなぐ二重結合まわりの配置は、可能な場合はシス型、トランス型のいずれであってもよい］で示される化合物、またはその塩もしくは溶媒和物である。Further compounds of the invention are represented by formula (IV):

[Where:
X ^IV is N or NR ^IV ;
NR ^IV is hydrogen or C _1-4 alkyl;
Y ^IV is CH or C = O;
The dashed line is a single bond that may be present;
The following parts are combined with **:

Or

L ^IV is

Or

Is;
A ^IV and B ^IV are independently CH, CCH ₃ or N;
R ₁₅ , R ₁₆ , R ₁₇ , R ₁₉ are independently hydrogen, halogen, OH, COOH, SO ₃ H, NO ₂ , SH, NR ^j R ^k , C _1-6 alkyl, O—C _1-6 alkyl CN, C═O, pyrrolidine ring, or

Is;
R ^j and R ^k are independently hydrogen or C _1-4 alkyl;
R ₁₈ is hydrogen, halogen or C _1-4 alkali;
R ₁₅ ′, R ₁₆ ′, R ₁₇ ′, R ₁₉ ′ are independently hydrogen, halogen or C _1-4 alkali;
r ′ is an integer from 0 to 2;
a ″ is an integer from 1 to 4;
b ″ is an integer of 1 or 2;
c ″ is an integer from 1 to 4;
d ″ is an integer from 1 to 4;
Z ^IV is O, CH ₂ , N—R ^{e ′ ″} ;
R ^{e ′ ″} is hydrogen or C _1-4 alkyl;
The alkyl may be substituted with halogen;
The arrangement around the double bond connecting the two ring moieties may be cis or trans if possible, or a salt or solvate thereof.

または

Ｌ^ＩＶは

または

であり；
好ましいＡ^ＩＶおよびＢ^ＩＶは独立してＣＨまたはＮであり；
Ｒ_１５、Ｒ_１６、Ｒ_１７、Ｒ_１９は水素、ＮＨ_２、Ｎ（ＣＨ_３）_２またはモルホリン環
であり；
好ましいＲ_１８は水素であり；
好ましいＲ_１５'、Ｒ_１６'、Ｒ_１７'、Ｒ_１９'は独立して水素またはＣ_１−４アルカリであり；
好ましいｒ'は１であり；
ａ''は１ないし４の整数であり；
ｂ''は１または２の整数であり；
ｃ''は１ないし４の整数であり；
ｄ''は１ないし４の整数であり；
Ｚ^ＩＶはＯ、ＣＨ_２、Ｎ−Ｒ^ｅ'''であり；
Ｒ^ｅ'''は水素またはＣ_１−４アルキルであり、
上記アルキルはハロゲンで置換されていてもよく；
２つの環部分をつなぐ二重結合まわりの配置は、可能な場合はシス型、トランス型のいずれであってもよい。Preferred substituents of the compound of formula (IV) are as follows:
Preferred ^{X IV} is N, NH or NCH _3;
Preferred ^YIV is CH or C = O;
The dashed line is a single bond that may be present;
The following parts are combined with **:

Or

L ^IV is

Or

Is;
Preferred A ^IV and B ^IV are independently CH or N;
R ₁₅ , R ₁₆ , R ₁₇ , R ₁₉ are hydrogen, NH ₂ , N (CH ₃ ) ₂ or a morpholine ring;
Preferred R ₁₈ is hydrogen;
Preferred R ₁₅ ′, R ₁₆ ′, R ₁₇ ′, R ₁₉ ′ are independently hydrogen or C _1-4 alkali;
Preferred r ′ is 1;
a ″ is an integer from 1 to 4;
b ″ is an integer of 1 or 2;
c ″ is an integer from 1 to 4;
d ″ is an integer from 1 to 4;
Z ^IV is O, CH ₂ , N—R ^{e ′ ″} ;
R ^{e ′ ″} is hydrogen or C _1-4 alkyl;
The alkyl may be substituted with halogen;
The arrangement around the double bond connecting the two ring portions may be either cis type or trans type if possible.

Among the compounds of formula (IV), those in which R ₁₅ , R ₁₆ , R ₁₇ or R ₁₉ are morpholine rings are more preferred because they have very low or no mutagenicity. Such compounds of formula (IV) include THK-276, THK-277 and THK-308. Compounds of formula (IV) with high specificity for amyloid β are THK-185, THK-254, THK-276, THK-308 and the like. Therefore, compounds of formula (IV) with high specificity for amyloid β and very low or no mutagenicity include THK-276 and THK-308.

［式中、
Ｒ_２０は水素またはＣ_１−４アルキル、ピロリジン環、または

であり；
Ｚ^ＶはＯ、ＣＨ_２またはＮ−Ｒ^ｅVであり；
Ｒ^ｅVは水素またはＣ_１−４アルキルである］で示される化合物、またはその塩もしくは溶媒和物である。Further compounds of the invention are represented by formula (V):

[Where:
R ₂₀ is hydrogen or C _1-4 alkyl, a pyrrolidine ring, or

Is;
Z ^V is O, CH ₂ or N—R ^eV ;
R ^eV is hydrogen or C _1-4 alkyl], or a salt or solvate thereof.

Preferred substituents of the compound of formula (V) are as follows:
Preferred R ₂₀ is hydrogen, methyl or morpholine ring. A compound in which R ₂₀ is a morpholine ring is a more preferable compound because it has very low or no mutagenicity. A compound of formula (V) with high specificity for amyloid β is THK-317 and the like.

［式中、
Ｒ_１ ^ＶＩは水素、Ｃ_１−６アルキル、ハロゲン、またはＣ_１−６アルキル−ハロゲンであり、
Ｒ_２ ^ＶＩおよびＲ_３ ^ＶＩはそれぞれ独立して水素またはＣ_１−６アルキルであり、
Ｒ_４ ^ＶＩは水素またはＣ_１−６アルキルであり、
Ｅ^ＶＩはＣＨ_２または不存在であり、
Ａ^ＶＩは５員環または６員環で、下記の構造：

または

または

を有し；
Ｘ^ＶＩおよびＹ^ＶＩは独立してＮまたはＣＨであり；
Ｚ^ＶＩはＯ、Ｓ、ＣＨ_２またはＮ−Ｃ_ｐＨ_２ｐ＋１であり；
Ｇ^ＶＩはＮまたはＣＨであり；
Ｊ^ＶＩはＯ、Ｓ、ＣＨ_２またはＮ−Ｃ_ｑＨ_２ｑ＋１であり；
Ｒ_５ ^ＶＩは水素、Ｃ_１−６アルキル、ピロール、ピラゾール、イミダゾール、トリアゾール、またはＮＲ_Ｉ ^ＶＩＲ_ＩＩ ^ＶＩであり、
Ｒ_６ ^ＶＩは水素、Ｃ_１−６アルキル、またはハロゲンであり、
Ｒ_Ｉ ^ＶＩ、Ｒ_ＩＩ ^ＶＩはそれぞれ独立して水素またはＣ_１−６アルキルであるか、あるいは一緒になってピロリジン環、モルホリン環、ピペリジン環または窒素原子がＣ_１−３アルキルで置換されていてもよいピペラジン環を形成し、
ｎ_１ ^ＶＩは１ないし４の整数であり；
ｎ_１' ^ＶＩは１ないし４の整数であり；
ｎ^ＶＩは１ないし４の整数であり；
ｐ^ＶＩは１ないし４の整数であり；
ｑ^ＶＩは１ないし４の整数であり；
上の式では２つの環部分をつなぐ二重結合まわりの配置がトランス型であるが、この配置はシス型、トランス型のいずれであってもよい］
で示される化合物、またはその塩もしくは溶媒和物を提供する。Further compounds of the invention are represented by formula (VI):

[Where:
R ₁ ^VI is hydrogen, C _1-6 alkyl, halogen, or C _1-6 alkyl-halogen;
R ₂ ^VI and R ₃ ^VI are each independently hydrogen or C _1-6 alkyl;
R ₄ ^VI is hydrogen or C _1-6 alkyl;
E ^VI is CH ₂ or absent,
A ^VI is a 5- or 6-membered ring and has the following structure:

Or

Or

Having
X ^VI and Y ^VI are independently N or CH;
Z ^VI is O, S, CH ₂ or N—C _p H _{2p + 1} ;
G ^VI is N or CH;
J ^VI is O, S, CH ₂ or N—C _q H _{2q + 1} ;
R ₅ ^VI is hydrogen, C _1-6 alkyl, pyrrole, pyrazole, imidazole, triazole, or NR _I ^VI R _II ^VI ;
R ₆ ^VI is hydrogen, C _1-6 alkyl, or halogen;
R _I ^VI and R _II ^VI are each independently hydrogen or C _1-6 alkyl, or together, the pyrrolidine ring, morpholine ring, piperidine ring or nitrogen atom is substituted with C _1-3 alkyl. Forming a good piperazine ring,
n ₁ ^VI is an integer from 1 to 4;
n _{1 ′} ^VI is an integer from 1 to 4;
n ^VI is an integer from 1 to 4;
p ^VI is an integer from 1 to 4;
q ^VI is an integer from 1 to 4;
In the above formula, the arrangement around the double bond connecting the two ring parts is trans, but this arrangement may be either cis or trans]
Or a salt or solvate thereof.

または

または

を有し；
Ｘ^ＶＩおよびＹ^ＶＩは独立してＮまたはＣＨであり；
好ましいＺ^ＶＩはＳであり；
Ｇ^ＶＩはＮまたはＣＨであり；
好ましいＪ^ＶＩはＯ、ＳまたはＣＨ_２であり；
好ましいＲ_５ ^ＶＩは水素、Ｎ（ＣＨ_３）_２またはモルホリン環であり；
好ましいＲ_６ ^ＶＩはすべて水素であり；
好ましいｎ_６ ^ＶＩは１または２の整数であり；
２つの環部分をつなぐ二重結合まわりの配置はシス型、トランス型のいずれであってもよい。Preferred substituents of the compound of formula (VI) are as follows:
Preferred R ₁ ^VI is hydrogen, C _1-3 alkyl, fluorine, chlorine or bromine,
Preferred R ₂ ^IV and R ₃ ^VI are methyl,
Preferred R ₄ ^IV is hydrogen,
E ^VI is CH ₂ or absent,
A ^VI is a 5- or 6-membered ring and has the following structure:

Or

Or

Having
X ^VI and Y ^VI are independently N or CH;
A preferred Z ^VI is S;
G ^VI is N or CH;
Preferred ^JVI is O, S or CH ₂ ;
Preferred R ₅ ^VI is hydrogen, N (CH ₃ ) ₂ or a morpholine ring;
Preferred R ₆ ^VI are all hydrogen;
Preferred n ₆ ^VI is an integer of 1 or 2;
The arrangement around the double bond connecting two ring parts may be either cis type or trans type.

Among the compounds of formula (VI), those in which R ₅ ^VI is a morpholine ring are more preferred because they have very low or no mutagenicity. Such compounds of formula (VI) are THK-330, THK-336, HK-533, THK-651, THK-652, THK-653, THK-655 and the like. Compounds of formula (VI) with high specificity for amyloid β are THK-556, THK-558, THK-559, THK-561, THK-562, THK-563, THK-565, THK-585 and the like.

  Examples of specific compounds represented by formulas (I) and (I ′) are shown in the table below.

［表１−２］

［表１−３］

［表１−４］

［表１−５］

［表１−６］

［表１−７］

[Table 1-1]

[Table 1-2]

[Table 1-3]

[Table 1-4]

[Table 1-5]

[Table 1-6]

[Table 1-7]

  Examples of specific compounds represented by formula (II) are shown in the table below.

[Table 1-8]

  Examples of specific compounds represented by the formula (III) are shown in the following table.

[Table 1-9]

  Examples of specific compounds represented by formula (IV) are shown in the table below.

[Table 1-10]

  Examples of specific compounds represented by the formula (V) are shown in Table 1 below.

[Table 1-11]

  Examples of specific compounds represented by the formula (VI) are shown in Table 1 below.

[Table 1-12]

  Among the compounds of the present invention or pharmaceutically acceptable salts or solvates thereof, preferred are the compounds represented by formula (I), or pharmaceutically acceptable salts or solvates thereof. Also preferred are compounds of formula (I ') which are precursors of compounds of formula (I), or pharmaceutically acceptable salts or solvates thereof.

［式中、各記号は前記に同じ］で表される基が、モルホリノ基又はジメチルアミノ基である（１）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（６）Ｒ^３が

で表される基である（１）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（７）式（Ｉ）で表される化合物が、
６−（２−フルオロ−エトキシ）−２−［２−（２−モルホリン−４−イル−チアゾール−５−イル）−ビニル］ベンゾキサゾール、
トルエン−４−スルホニックアシド ２−［２−［２−（２−モルホリン−４−イル−チアゾール−５−イル）−ビニル−ベンゾキサゾール−６−イロキシ］エチル エステル、
２−フルオロメチル−３−［２−［２−（２−モルホリン−４−イル−チアゾール−５−イル）−ビニル］ベンゾキサゾール−６−イルオキシ］−プロパン−１−オール、
（Ｅ）−２−［２−（２−モルホリノチアゾール−５−イル）エテニル］−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−ジメチルアミノ−チアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−メチルアミノチアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（２−フルオロメチル−３−ヒドロキシ）プロポキシ］−２−［２−（２−ピペリジノチアゾール−５−イル）エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−（２−ピペリジノチアゾール−５−イル）エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−（４−メチルピペラジン−１−イル）チアゾール−５−イル）エテニル］ベンゾキサゾール、
（Ｅ）−６−［（２−フルオロメチル−３−ヒドロキシ）プロポキシ］−２−［２−［２−（ピロリジン−１−イル）チアゾール−５−イル）エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−（ピロリジン−１−イル）−チアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−（［１，３］オキサジナン−３−イル）−チアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−ホモピペリジン−１−イル］チアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−（２−ホモモルホリノチアゾール−５−イル）エテニル］ベンゾキサゾール、、及び
（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−（２−チオモルホリノチアゾール−５−イル）エテニル］ベンゾキサゾール
からなる群より選択される化合物である（１）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（８）標識された（１）乃至（７）のいずれかに記載の化合物、またはその薬学的に許容される塩もしくは溶媒和物；
（９）標識が放射性核種によるものである、（８）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（１０）放射性核種がγ線放出核種である、（９）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（１１）標識が陽電子放出核である（８）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（１２）陽電子放出核が、^１１Ｃ、^１３Ｎ、^１５Ｏ、^１８Ｆ，^６２Ｃｕ、^６８Ｇａ及び^７６Ｂｒからなる群より選択されるものである、（１１）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（１３）陽電子放出核が^１１Ｃ又は^１８Ｆである（１１）記載の化合物又はその薬学的に許容される塩もしくは溶媒和物；
（１４）（１）乃至（１３）のいずれか１項に記載の化合物又はその薬学的に許容される塩もしくは溶媒和物を含有する医薬組成物；
（１５）（１）乃至（１３）のいずれか１項に記載の化合物又はその薬学的に許容される塩もしくは溶媒和物と溶解補助剤とを含む医薬組成物；
（１６）溶解補助剤がポリソルベート８０、ポリエチレングリコール、エタノール及びプロピレングリコールからなる群より選択されるものである、（１５）記載の医薬組成物；
（１７）注射剤である（１４）乃至（１６）のいずれか１項に記載の医薬組成物；
（１８）（１）乃至（１３）のいずれか１つに記載の化合物又はその薬学的に許容される塩もしくは溶媒和物を含有する、コンフォーメーション病診断用組成物；
（１９）（１）乃至（１３）のいずれか１つに記載の化合物又はその薬学的に許容される塩もしくは溶媒和物を含有する、コンフォーメーション病を治療及び／又は予防するための医薬組成物；
（２０）（１）乃至（１３）のいずれか１つに記載の化合物又はその薬学的に許容される塩もしくは溶媒和物を必須の構成要素として含む、コンフォーメーション病診断用キット；
（２１）（１）１乃至（１３）のいずれか１つに記載の化合物又はその薬学的に許容される塩もしくは溶媒和物を必須の構成要素として含む、βシート構造をとった蛋白又は神経原線維変化を検出又は染色するための組成物又はキット；
（２２）画像診断用である、（２０）記載又は（２１）記載のキット；
（２３）（１）乃至（１３）のいずれか１項に記載の化合物、又はその薬学的に許容される塩もしくは溶媒和物を対象に投与することを特徴とする、対象におけるコンフォーメーション病の治療及び／または予防方法；
（２４）（１）乃至（１３）のいずれか１項に記載の化合物、又はその薬学的に許容される塩もしくは溶媒和物を対象に投与することを特徴とする、対象におけるコンフォーメーション病の診断方法；
（２５）対象におけるコンフォーメーション病の診断用組成物又はキットを製造するための、（１）乃至（１３）のいずれか１項に記載の化合物、又はその薬学的に許容される塩もしくは溶媒和物の使用；
（２６）対象におけるコンフォーメーション病の治療及び／又は予防のための医薬組成物を製造するための、（１）乃至（１３）のいずれか１項に記載の化合物又はその薬学的に許容される塩もしくは溶媒和物の使用；
（２７）（１）乃至（１３）のいずれか１項に記載の化合物又はその薬学的に許容される塩もしくは溶媒和物を用いて試料を染色することを特徴とする、試料中のβシート構造をとった蛋白または神経原線維変化を検出又は染色する方法；
（２８）試料中のβシート構造をとった蛋白又は神経原線維変化を検出又は染色するための組成物またはキットを製造するための、（１）乃至（１３）のいずれか１項に記載の化合物又はその薬学的に許容される塩もしくは溶媒和物の使用；
（２９）化合物が６−（２−フルオロ−エトキシ）−２−［２−（２−モルホリン−４−イル−チアゾール−５−イル）−ビニル］ベンゾキサゾール、２−フルオロメチル−３−［２−［２−（２−モルホリン−４−イル−チアゾール−５−イル）−ビニル］ベンゾキサゾール−６−イルオキシ］−プロパン−１−オール、（Ｅ）−２−［２−（２−モルホリノチアゾール−５−イル）エテニル］−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］ベンゾキサゾール又は（Ｅ）−６−［（１−フルオロメチル−２−ヒドロキシ）エトキシ］−２−［２−［２−ジメチルアミノ−チアゾール−５−イル］エテニル］ベンゾキサゾールである（２１）記載の組成物又はキット、（２７）記載の方法、或いは、（２８）記載の使用；
（３０）式（Ｉ’）

［式中、
Ｒ^１及びＲ^２は、それぞれ独立して、水素原子、低級アルキル基、シクロアルキル基を示すか、或いは、
Ｒ^１、Ｒ^２及びそれらが互いに結合する窒素原子が一緒になって形成する３乃至８員の含窒素脂肪族環（該含窒素脂肪族環を構成する炭素原子は、窒素原子、硫黄原子又は酸素原子に置き換わっていてもよく、炭素原子が窒素原子で置き換わっている場合には、該窒素原子は、低級アルキル基で置換されていてもよい）を示し、
Ｘ_１及びＸ_２は、それぞれ独立して、窒素原子、硫黄原子又は酸素原子を示し、
Ｒ^４は、−Ｏ−低級アルキル基（該アルキル基は、ｐ−トルエンスルホニル基、メタンスルホニル基又はトリフルオロメタンスルホニル基で置換されており、さらに、ヒドロキシ基で置換されていてもよい）を示し、
ｍは、１乃至３の整数を示す］で表される化合物（ただし、Ｒ^３がハロゲン原子のみで置換された−Ｏ−低級アルキル基であり、かつ、Ｒ^１及びＲ^２がそれぞれ独立して、水素原子又は低級アルキル基である場合を除く）；
（３１）Ｒ^４が式

で表される基である（３０）記載の化合物；
（３２）式（Ｉ’）で表される化合物が、
トルエン−４−スルホニックアシド ２−［２−［２−（２−モルホリン−４−イル−チアゾール−５−イル）−ビニル−ベンゾキサゾール−６−イロキシ］エチル エステル、
（Ｅ）−６−［（３−ヒドロキシ−２−トシロキシメチル）プロポキシ］−２−［２−（２−モルホリノチアゾール−５−イル）エテニル］ベンゾキサゾール、
（Ｅ）−６−［２−ヒドロキシ−１−トシロキシメチル）エトキシ］−２−［２−［２−ジメチルアミノ−チアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（２−ヒドロキシ−１−トシロキシメチル）エトキシ］−２−［２−［２−メチルアミノチアゾール−５−イル］エテニル］ベンゾキサゾール、
（Ｅ）−６−［（３−ヒドロキシ−２−トシロキシメチル）プロポキシ］−２−［２−（２−ピペリジノチアゾール−５−イル）エテニル］ベンゾキサゾール、
（Ｅ）−６−［（２−ヒドロキシ−１−トシロキシメチル）エトキシ］−２−［２−（２−ピペリジノチアゾール−５−イル）エテニル］ベンゾキサゾール、又は
（Ｅ）−６−［（１−ヒドロキシメチル−２−トシロキシ）エトキシ］−２−［２−［２−（ピロリジン−１−イル）−チアゾール−５−イル］エテニル］ベンゾキサゾール
である（３０）記載の化合物。
を提供するものである。Thus, the present invention provides:
(1) A compound represented by the above formula (I), or a pharmaceutically acceptable salt or solvate thereof;
(2) The compound according to (1), wherein X ₁ is an oxygen atom, or a pharmaceutically acceptable salt or solvate thereof;
(3) The compound according to (1), wherein X ₁ is an oxygen atom, and X ₂ is a sulfur atom, or a pharmaceutically acceptable salt or solvate thereof;
(4) The compound or a pharmaceutically acceptable salt or solvate thereof according to (1), wherein R ³ is —O-lower alkyl group substituted with a hydroxy group and a halogen atom;
(5) Formula in formula (I):

[Wherein the symbols are the same as defined above], the compound according to (1), or a pharmaceutically acceptable salt or solvate thereof, wherein the group is a morpholino group or a dimethylamino group;
(6) R ³ is

Or a pharmaceutically acceptable salt or solvate thereof according to (1), which is a group represented by:
(7) The compound represented by the formula (I) is
6- (2-fluoro-ethoxy) -2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazole,
Toluene-4-sulfonic acid 2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl-benzoxazole-6-yloxy] ethyl ester,
2-fluoromethyl-3- [2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazol-6-yloxy] -propan-1-ol,
(E) -2- [2- (2-morpholinothiazol-5-yl) ethenyl] -6-[(1-fluoromethyl-2-hydroxy) ethoxy] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(2-fluoromethyl-3-hydroxy) propoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (4-methylpiperazin-1-yl) thiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(2-fluoromethyl-3-hydroxy) propoxy] -2- [2- [2- (pyrrolidin-1-yl) thiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (pyrrolidin-1-yl) -thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(1-Fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-([1,3] oxazinan-3-yl) -thiazol-5-yl] ethenyl] benzo Xazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-homopiperidin-1-yl] thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-homomorpholinothiazol-5-yl) ethenyl] benzoxazole, and (E) -6-6 [(1-Fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-thiomorpholinothiazol-5-yl) ethenyl] benzoxazole is a compound selected from the group consisting of (1) A compound or a pharmaceutically acceptable salt or solvate thereof;
(8) the labeled compound according to any one of (1) to (7), or a pharmaceutically acceptable salt or solvate thereof;
(9) The compound according to (8) or a pharmaceutically acceptable salt or solvate thereof, wherein the label is derived from a radionuclide.
(10) The compound according to (9) or a pharmaceutically acceptable salt or solvate thereof, wherein the radionuclide is a γ-ray emitting nuclide;
(11) The compound according to (8), wherein the label is a positron emitting nucleus, or a pharmaceutically acceptable salt or solvate thereof;
(12) The compound according to (11) or a pharmaceutically acceptable product thereof, wherein the positron emitting nucleus is selected from the group consisting of ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁶² Cu, ⁶⁸ Ga and ⁷⁶ Br. Acceptable salts or solvates;
(13) The compound according to (11) or a pharmaceutically acceptable salt or solvate thereof, wherein the positron emitting nucleus is ¹¹ C or ¹⁸ F;
(14) A pharmaceutical composition comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof;
(15) A pharmaceutical composition comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof and a solubilizing agent;
(16) The pharmaceutical composition according to (15), wherein the solubilizing agent is selected from the group consisting of polysorbate 80, polyethylene glycol, ethanol and propylene glycol;
(17) The pharmaceutical composition according to any one of (14) to (16), which is an injection;
(18) A composition for diagnosing conformation disease, comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof;
(19) A pharmaceutical composition for treating and / or preventing conformational disease, comprising the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof. object;
(20) A kit for diagnosing a conformation disease, comprising as an essential component the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof;
(21) (1) A protein or nerve having a β-sheet structure comprising the compound according to any one of 1 to (13) or a pharmaceutically acceptable salt or solvate thereof as an essential component A composition or kit for detecting or staining fibrillar changes;
(22) The kit according to (20) or (21), which is for diagnostic imaging;
(23) Conformation disease in a subject, characterized by administering to the subject a compound according to any one of (1) to (13), or a pharmaceutically acceptable salt or solvate thereof Treatment and / or prevention methods;
(24) Conformation disease in a subject, characterized by administering the compound according to any one of (1) to (13), or a pharmaceutically acceptable salt or solvate thereof. Diagnostic method;
(25) The compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof for producing a composition or kit for diagnosing conformation disease in a subject. Use of goods;
(26) The compound according to any one of (1) to (13) or a pharmaceutically acceptable product thereof for producing a pharmaceutical composition for the treatment and / or prevention of conformation disease in a subject. Use of salts or solvates;
(27) A β sheet in a sample, characterized in that the sample is stained with the compound according to any one of (1) to (13) or a pharmaceutically acceptable salt or solvate thereof. A method for detecting or staining a structured protein or neurofibrillary tangle;
(28) The method according to any one of (1) to (13), for producing a composition or kit for detecting or staining a protein or neurofibrillary tangle having a β sheet structure in a sample. Use of a compound or a pharmaceutically acceptable salt or solvate thereof;
(29) The compound is 6- (2-fluoro-ethoxy) -2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazole, 2-fluoromethyl-3- [ 2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazol-6-yloxy] -propan-1-ol, (E) -2- [2- (2- Morpholinothiazol-5-yl) ethenyl] -6-[(1-fluoromethyl-2-hydroxy) ethoxy] benzoxazole or (E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2 -[2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole, the composition or kit according to (21), the method according to (27), or the use according to (28);
(30) Formula (I ′)

[Where:
R ¹ and R ² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or
A 3- to 8-membered nitrogen-containing aliphatic ring formed by R ¹ , R ² and the nitrogen atom to which they are bonded together (the carbon atom constituting the nitrogen-containing aliphatic ring is a nitrogen atom, a sulfur atom or An oxygen atom may be substituted, and when a carbon atom is substituted with a nitrogen atom, the nitrogen atom may be substituted with a lower alkyl group),
X ₁ and X ₂ each independently represent a nitrogen atom, a sulfur atom or an oxygen atom,
R ⁴ represents —O-lower alkyl group (the alkyl group is substituted with p-toluenesulfonyl group, methanesulfonyl group or trifluoromethanesulfonyl group, and may be further substituted with hydroxy group). ,
m represents an integer of 1 to 3, wherein R ³ is an —O-lower alkyl group substituted with only a halogen atom, and R ¹ and R ² are each independently , A hydrogen atom or a lower alkyl group)
(31) R ⁴ is the formula

The compound according to (30), which is a group represented by:
(32) The compound represented by the formula (I ′) is
Toluene-4-sulfonic acid 2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl-benzoxazole-6-yloxy] ethyl ester,
(E) -6-[(3-hydroxy-2-tosyloxymethyl) propoxy] -2- [2- (2-morpholinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6- [2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(3-hydroxy-2-tosyloxymethyl) propoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole, or (E) -6 The compound according to (30), which is-[(1-hydroxymethyl-2-tosyloxy) ethoxy] -2- [2- [2- (pyrrolidin-1-yl) -thiazol-5-yl] ethenyl] benzoxazole .
Is to provide.

［式中、Ｘは、ハロゲン原子を示し、Ｒはジメチルアミノ基、モルホリノ基等を示し、Ｒ^３’は、Ｒ^３を意味するか、又は、Ｒ^３がヒドロキシ基を有する場合には、ヒドロキシ基が保護されたＲ^３を意味し、Ｍｓはメシル（メタンスルホニル）基を示し、他の記号は前記に同じ］
の記号は前記に同じ］Next, the manufacturing method of the compound based on this invention is demonstrated. The compound represented by the formula (I) or (I ′) can be produced, for example, by the following method.

[Wherein, X represents a halogen atom, R represents a dimethylamino group, a morpholino group or the like, and R ³ ′ represents R ³ , or when R ³ has a hydroxy group, The group represents protected R ³ , Ms represents a mesyl (methanesulfonyl) group, and other symbols are the same as above]
Is the same as above]

(Process 1)
This step is a method for producing compound (A-2) by reacting compound (A-1) with amino compound (B-1).

  As X in (A-1), a bromine atom is preferable.

  The amount of compound (B-1) used is usually 1 to the amount of solvent relative to 1 equivalent of compound (A-1).

  The reaction time in this step is usually 1 to 24 hours, preferably 1 to 10 hours.

  The reaction temperature in this step is usually 50 to 200 ° C, preferably 80 to 150 ° C.

  As the reaction solvent in this step, (B-1) is used in an amount of solvent, or dimethylformamide and the like can be mentioned.

  The compound (A-2) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

  Compound (A-2) may be a known compound, or can be produced by a method commonly used in the field of organic chemistry or a method analogous thereto using a known compound as a raw material.

(Process 2)
This step is a method for producing compound (A-3) by reacting compound (A-2) and compound (B-2) in the presence of a base.
Examples of the base to be used include sodium hydride, butyl lithium, lithium diisopropylamide (LDA) and the like, and among these, lithium diisopropylamide is preferable. Lithium diisopropylamide can also be prepared from butyllithium and diisopropylamine before use.

  The amount of the base to be used is generally 0.5 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (A-2).

  The reaction temperature is generally −78 ° C. to 50 ° C., preferably −78 ° C. to room temperature.

  The reaction time is usually 0.1 hour to 24 hours, preferably 0.1 hour to 6 hours.

  The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include N, N-dimethylformamide (DMF), tetrahydrofuran (THF), 1-methylimidazolidinone and the like.

  The compound (A-3) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography and the like, or isolation and purification. It can attach to the next process, without doing.

(Process 3)
This step is a method for producing compound (A-5) by reacting compound (A-4) with compound (B-3). The reaction in this step is a so-called Mitsunobu reaction, and in the presence of a phosphine compound and an azo compound, a method described in the literature (for example, “Use of diethyl azodicarboxylate and triphenyl” by Mitsunobu. O). The phosphine in synthesis and transformation of natural products (The use of diethylazoboxylate and triphenylphosphine in synthesis and transformation, and the 1st volume, 198). Can be done in combination with conventional methods .

  As the compound (A-4) to be used, a known compound may be used, or a compound produced by using a known compound as a raw material by a method usually used in the field of organic chemistry or a method analogous thereto.

  The amount of the compound (B-3) used is usually 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (A-4).

  Examples of the phosphine compound used in this step include triphenylphosphine and triethylphosphine.

  The amount of the phosphine compound to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-4).

  Examples of the azo compound used include diethyl azodicarboxylate and diisopropyl azodicarboxylate.

  The amount of the azo compound used is usually 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-4).

  The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours.

  The reaction temperature is generally 0 ° C. to the reflux temperature of the reaction solvent, preferably 10 to 50 ° C.

  The reaction solvent used in this step is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran (THF), toluene and the like.

  The compound (A-5) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or isolation and purification. It can attach to the next process, without doing.

(Process 4)
This step is a method for producing compound (A-6) by reacting compound (A-5) with compound (A-3) in the presence of a base.

  The amount of the base used is generally 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-5).

  Examples of the base used include lithium diisopropylamide (LDA).

  The reaction temperature is generally −78 ° C. to 50 ° C., preferably −78 ° C. to room temperature.

  The reaction time is usually 0.1 to 24 hours, preferably 0.1 to 6 hours.

  The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran (THF).

  The compound (A-6) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or isolation. The product can be subjected to the next step without purification.

(Process 5)
This step is a method for producing compound (A-7) by reacting compound (A-6) with MsCl in the presence of a base.

  The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-6).

  Examples of the base used include triethylamine and diisopropylethylamine.

  The amount of MsCl used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-6).

  The reaction temperature is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.

  The reaction time is usually 0.1 to 48 hours, preferably 0.1 to 24 hours.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, tetrahydrofuran, dimethylformamide and the like.

  The thus obtained compound (A-7) is isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or is isolated and purified. Without being attached to the next step.

In the case where R ³ in compound (A-7) does not have a protecting group for hydroxy group, compound (A-7) corresponds to compound (I) according to the present invention.

When R ³ in the compound (A-7) has a protecting group for a hydroxy group, the compound (I) according to the present invention can be produced by performing the next step 6.

(Step 6)
This step is a method for producing the compound (I) according to the present invention by removing the protective group for the hydroxy group of R ^{3 in} the compound (A-7).

The introduction of the protecting group for the hydroxy group of R ³ and the removal of the protecting group can be carried out by methods described in the literature (for example, Protective Groups in Organic Synthesis, TW Green, No. 1). 2nd edition, John Wiley & Sons, 1991, etc.), a method according to them, or a combination of these with conventional methods.

  The compound (I) according to the present invention thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

In addition, when one of R ^{1 and} R ² of the compound (B-1) used in Step 1 is a hydrogen atom, a protective group is introduced into the amino group of the compound (B-1), and if necessary Thus, the protecting group of the amino group can be removed. The introduction of the protecting group of the amino group and the removal of the protecting group are described in Protective Groups in Organic Synthesis), T. et al. W. It can be carried out by the method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method.

  The compound represented by the formula (A-7) can also be produced, for example, by the following method.

(Step 7)
This step is a method for producing compound (A-7) by reacting compound (A-8) with compound (B-3). The reaction in this step is a so-called Mitsunobu reaction, and can be performed by the same method as in Step 3, a method according to this, or a combination of these with a conventional method.

  The compound (A-7) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

［式中、Ｐｒｏは、水酸基の保護基を示し、他の記号は前記に同じ］
（工程８）
本工程は、塩基の存在下、化合物（Ａ−９）と化合物（Ａ−３）とを反応させることにより、化合物（Ａ−１０）を製造する方法である。Compound (A-8) used in Step 7 can be produced, for example, by the following method.

[Wherein Pro represents a protecting group for a hydroxyl group, and other symbols are the same as above]
(Step 8)
This step is a method for producing compound (A-10) by reacting compound (A-9) with compound (A-3) in the presence of a base.

  Examples of the base used include NaOH and the like.

  The amount of the base to be used is generally 1 to 50 equivalents, preferably 1 to 20 equivalents, relative to 1 equivalent of compound (A-9).

  The reaction temperature is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.

  The reaction time is usually 1 to 100 hours, preferably 1 to 30 hours.

  The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include DMSO, methanol, ethanol, or a mixed solvent of these and water.

  The compound (A-10) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 9)
This step is a method for producing compound (A-8) by removing the protecting group for the hydroxy group of compound (A-10). Removal of the protecting group of the hydroxy group is described in Protective Groups in Organic Synthesis), T. et al. W. It can be carried out by the method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method.

  Thus obtained compound (A-8) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

［式中、Ｃ_１−６alkylは、炭素数１乃至６の直鎖または分岐のアルキル基を示し、他の記号は前記に同じ］で表される化合物は、例えば、以下の式（Ａ−１１）

［式中、各記号は前記に同じ］で表される化合物を用いて製造することができる。

（工程１０）
本工程は、化合物（Ａ−４）と化合物（Ｂ−４）とを反応させることにより、化合物（Ａ−１１）を製造する方法である。
本工程における反応は、前記工程３と同様の方法、これに準じた方法又はこれらと常法とを組み合わせることにより製造することができる。In addition, compound (I-2) according to the present invention

[Wherein C _1-6 alkyl represents a linear or branched alkyl group having 1 to 6 carbon atoms, and other symbols are the same as described above], for example, a compound represented by the following formula (A- 11)

[In the formula, each symbol is the same as described above].

(Process 10)
This step is a method for producing compound (A-11) by reacting compound (A-4) with compound (B-4).
The reaction in this step can be produced by the same method as in Step 3 above, a method analogous thereto, or a combination of these with conventional methods.

The amount of the compound (B-4) used is usually 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (A-4).

  Thus obtained compound (A-11) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

  The compound (I-2) included in the formula (I) is obtained by using the compound (A-11) in the same manner as in steps 4, 5, and 6, a method analogous thereto, or these and conventional methods. It can manufacture by combining.

［式中、各記号は前記に同じ］で表される化合物は、例えば、以下の方法によって製造される化合物（Ａ−１７）から合成することができる。

［式中、Ｐｒｏは、ヒドロキシ基の保護基を示し、Ｂｎはベンジル基を示し、他の記号は前記に同じ］Further, the formula (I-3) included in the formula (I) according to the present invention.

[Wherein each symbol is the same as above] can be synthesized, for example, from compound (A-17) produced by the following method.

[Wherein, Pro represents a protecting group for a hydroxy group, Bn represents a benzyl group, and other symbols are the same as above]

(Step 11)
This step is a method for producing compound (A-12) by reacting compound (A-4) with compound (B-5). The reaction in this step is a so-called Mitsunobu reaction, and can be performed by the same method as in step 3 or 7, a method according to this, or a combination of these with a conventional method.

  The amount of the compound (B-5) used is usually 0.5 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (A-4).

  Compound (B-5) can be produced using a commercially available compound, or using glycerol as a raw material, a method well known to those skilled in the art, a method analogous thereto, or a combination of these with a conventional method.

  Thus, the obtained compound (A-12) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. The product can be subjected to the next step without purification.

(Step 12)
This step is a method for producing compound (A-13) by removing the protecting group for the hydroxy group of compound (A-12).
Removal of protecting groups for hydroxy groups is described in Protective Groups in Organic Synthesis), T.W. W. The method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method can be used. When a (benzyl) group is used, the protecting group can be removed by using Pd—C in a hydrogen atmosphere.

  The compound (A-13) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 13)
This step is a method for producing compound (A-14) by protecting one of the two hydroxy groups of compound (A-13).

  The introduction of protecting groups in this step is described in Protective Groups in Organic Synthesis), T.W. W. The method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method can be used. Examples of the protecting group include TBS (tert -Butyldimethylsilyl) group and the like.

  The compound (A-14) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or isolation and purification. It can attach to the next process, without doing.

(Step 14)
This step is a method for producing compound (A-15) by reacting compound (A-14) with MsCl in the presence of a base.

  Examples of the base used include triethylamine and diisopropylamine.

  The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-14).

  MsCl used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-14).

  The reaction temperature is 0 ° C. to room temperature.

  The reaction time is 0.1 hour to 10 hours, preferably 0.1 hour to 5 hours.

  The reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include dichloromethane, dimethylformamide, tetrahydrofuran and the like.

  The compound (A-15) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 15)
This step is a method for producing compound (A-16) by introducing a fluorine atom into compound (A-15) and removing a TBS group which is a protecting group for a hydroxy group.

  Introduction of a fluorine atom and removal of a TBS group can be performed by using TBAF (tetrabutylammonium fluoride).

  The amount of TBAF to be used is generally 1 to 50 equivalents, preferably 1 to 20 equivalents, relative to 1 equivalent of compound (A-15).

  The reaction temperature is usually 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.

  The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours.

  The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include tetrahydrofuran, dichloromethane, dimethylformamide and the like.

  The compound (A-16) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 16)
This step is a method for producing compound (A-17) by introducing a protecting group into the hydroxy group of compound (A-16).

  The introduction of protecting groups for hydroxy groups is described in Protective Groups in Organic Synthesis), T.W. W. It can be carried out by the method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method.

  The compound (A-17) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

  Compound (I-3) according to the present invention is produced by using compound (A-17) as a raw material in the same manner as in Steps 4, 5 and 6 above, a method analogous thereto or a combination thereof with a conventional method. can do.

［式中、各記号は前記に同じ］で表される化合物又は式（Ｉ’−１）

［式中、Ｔｓはトシル（ｐ−トルエンスルホニル基）を示し、他の記号は前記に同じ］で表される化合物は、例えば、以下の方法によっても製造することができる。

［式中、各記号は前記に同じ］Formula (I-3) according to the present invention

[Wherein each symbol is as defined above] or a compound represented by formula (I′-1)

[In the formula, Ts represents tosyl (p-toluenesulfonyl group), and other symbols are the same as above]], for example, can also be produced by the following method.

[Wherein each symbol is the same as above]

(Step 19)
This step is a method for producing compound (A-18) by reacting compound (A-13) with 2,2-dimethoxypropane. The reaction in this step was conducted according to the above-mentioned Protective Groups in Organic Synthesis), T. et al. W. It can be carried out by the method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method.

  The compound (A-18) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 20)
This step is a method for producing compound (A-19) by reacting compound (A-18) with compound (A-3) in the presence of a base. The reaction in this step can be carried out by the same method as in Step 8, a method analogous thereto, or a combination of these with conventional methods.

  The compound (A-19) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 21)
This step is a method for producing compound (A-20) by removing the diol-protecting group of compound (A-19).

  The reaction in this step was conducted according to the above-mentioned Protective Groups in Organic Synthesis), T. et al. W. It can be carried out by the method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method.

  The compound (A-20) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or isolation and purification. It can attach to the next process, without doing.

(Step 22)
This step is a method for producing compound (I′-1) according to the present invention by reacting compound (A-20) with p-toluenesulfonic anhydride in the presence of a base.

Examples of the base used include triethylamine and diisopropylethylamine.
Further, a catalytic amount of dimethylaminopyridine or the like may be added to the reaction system.

  The amount of the base to be used is generally 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (A-20).

  The amount of p-toluenesulfonic acid used is usually 0.5 to 1 equivalent with respect to 1 equivalent of compound (A-20).

  The reaction temperature is usually room temperature to the boiling point of the solvent, preferably 50 ° C to 80 ° C.

  The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours.

  The reaction solvent is not particularly limited as long as it does not hinder the reaction, and examples thereof include dimethoxyethane and dimethylformamide.

  The compound (I′-1) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or isolation. It can be used in the next step without purification.

(Step 23)
This step is a method for producing compound (I-3) according to the present invention by reacting compound (I′-1) with TBAF.
The reaction in this step can be carried out by the same method as in Step 15, a method analogous thereto, or a combination of these with conventional methods.

  Thus obtained compound (I-3) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

［式中、各記号は前記に同じ］で表される化合物は、例えば、以下の方法によって製造することができる。

［式中、Ｒ"ＯＨは、

を意味し、他の記号は前記に同じ］Further, the formula (I′-2) according to the present invention

[Wherein each symbol is the same as described above] can be produced, for example, by the following method.

[Wherein R ″ OH is

And other symbols are the same as above]

(Step 24)
This step is a method for producing compound (A-21) by reacting compound (A-4) with compound (B-6).

  The reaction in this step is a so-called Mitsunobu reaction, and can be performed by the same method as in Step 3, a method according to this, or a combination of these with a conventional method.

  The compound (A-21) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 25)
This step is a method for producing compound (A-22) by reacting compound (A-21) with compound (A-3) in the presence of a base.
This step can be performed by the same method as in Steps 8 and 20, etc., a method according to this, or a combination thereof with a conventional method.

  The compound (A-22) thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or isolation and purification. It can attach to the next process, without doing.

(Step 26)
This step is a method for producing compound (A-23) by treating compound (A-22) with an acid.
The reaction in this step was conducted according to the above-mentioned Protective Groups in Organic Synthesis), T. et al. W. It can be carried out by the method described in Green, 2nd edition, John Wiley & Sons, 1991, etc., a method according to this, or a combination thereof with a conventional method.

  The compound (A-23) thus obtained is isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like, or isolation and purification. It can attach to the next process, without doing.

(Step 27)
This step is a method for producing the compound (I′-2) according to the present invention by reacting the compound (A-23) with p-toluenesulfonic anhydride in the presence of a base. The method can be carried out by the same method as that of No. 22, a method according to this, or a combination of these and conventional methods.

  Thus obtained compound (I′-2) can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.

［式中、各記号は前記に同じ］で表される化合物は、例えば、前記（Ｉ’−２）とＴＢＡＦとを反応させることにより、製造することができ、該反応は、前記工程２３と同様の方法、これに準じた方法又はこれらと常法とを組み合わせることにより行うことができる。In addition, compound (I-4) according to the present invention

[Wherein each symbol is the same as defined above] can be produced, for example, by reacting (I′-2) with TBAF, and the reaction is carried out as described in Step 23. It can be carried out by the same method, a method according to this, or a combination of these and conventional methods.

  Further, in place of 2,2-dimethyl-1,3-dioxane-5-methanol used in the step 24, 2-phenyl-1,3-dioxane-5-ol was used, and the steps 24, 25, (I′-1) can also be produced by the same method as 26 and 27, a method according to this, or a combination of these and conventional methods.

When the compound (I) or (I ′) according to the present invention is produced, when a hydrochloride of an amino compound or the like is used, a base may coexist in the reaction system.

  Salts of the compounds of the present invention are also encompassed by the present invention. The salt can be produced according to a conventional method using the compound represented by the formula (I) or (I ′) provided by the present invention.

  Specifically, when the compound of the above formula (I) or (I ′) has a basic group derived from, for example, an amino group or a pyridyl group in the molecule, the compound is converted to an acid. Can be converted to the corresponding salt.

  Examples of the acid addition salt include hydrohalides such as hydrochloride, hydrofluoride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate, carbonate Inorganic acid salts such as salts; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; aryl sulfonates such as benzene sulfonate and p-toluene sulfonate; Organic acid salts such as acid salts, succinates, citrates, tartrates, oxalates and maleates; and acid addition salts which are organic acids such as amino acids such as glutamates and aspartates it can.

  In addition, when the compound of the present invention has an acidic group in the group, for example, when it has a carboxyl group or the like, the corresponding pharmaceutically acceptable can also be obtained by treating the compound with a base. Can be converted to a salt. Examples of the base addition salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, salts with organic bases such as ammonium salts, guanidine, triethylamine, and dicyclohexylamine.

  The method for preparing the compounds of the formulas (I) and (I ′) of the present invention and the salts thereof have been described above. It can be easily prepared.

  Furthermore, the compounds of the present invention may exist as any hydrate or solvate of the free compound or salt thereof.

In the diagnosis of conformation disease, the compound of the present invention can be used as a probe without labeling. For example, the presence or absence of a portion to be stained may be examined by contacting a biopsy material with the compound of the present invention. However, it is common to use a labeled compound of the present invention as a diagnostic probe for conformation disease. Labels may include fluorescent materials, affinity materials, enzyme substrates, radionuclides, and the like. A radionuclide-labeled probe is usually used for diagnostic imaging of conformation disease. The compounds of the present invention can be labeled with various radionuclides by methods well known in the art. For example, ³ H, ¹⁴ C, ³⁵ S, ¹³¹ I and the like are radionuclides that have been used for a long time and are frequently used in vitro. General requirements for diagnostic imaging probes and detection means include: in vivo diagnostic imaging, minimal damage to patients (especially non-invasive), high detection sensitivity, and appropriate half-life Long length (label probe preparation time and diagnosis time are appropriate). Therefore, recently, positron emission tomography (PET) using γ-rays exhibiting high detection sensitivity and material permeability or computer tomography (SPECT) using γ-ray emitting nuclides has been used. Of these, PET is preferable because it detects two γ-rays radiated from the positron emitting nuclide in the opposite directions by a coincidence method with a pair of detectors, so that information excellent in resolving power and quantification can be obtained. . For SPECT, the compound of the present invention can be labeled with γ-ray emitting nuclides such as ^99m Tc, ¹¹¹ In, ⁶⁷ Ga, ²⁰¹ Tl, ¹²³ I, ¹³³ Xe. ^99m Tc and ¹²³ I are commonly used for SPECT. For PET, the compound of the present invention can be labeled with a positron emitting nuclide such as ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁶² Cu, ⁶⁸ Ga, and ⁷⁶ Br. Among positron emitting nuclides, ¹¹ C, ¹³ N, ¹⁵ O, and ¹⁸ F are preferable, ¹⁸ F and ¹¹ C are more preferable, and ¹⁸ F is more preferable in terms of appropriate half-life and ease of labeling. Particularly preferred. The labeling position of the compound of the present invention may be any position on the radionuclide, for example, the radiation emitting nuclide such as positron emitting nuclide, γ-ray emitting nuclide, etc., but preferred labeling positions are alkyl group and / phenyl in the compound. On the ring. Such labeled compounds of the present invention are also encompassed by the present invention. For example, when the compound of the present invention is labeled with ¹⁸ F, any group in the side chain may be labeled with ¹⁸ F, or the hydrogen on the ring may be replaced with ¹⁸ F. For example, hydrogen contained in any of the alkyl substituents may be substituted with ¹⁸ F. In the case of labeled compounds of the present invention at ^{11 C,} it may be replaced with carbon contained in any of the alkyl substituents in the side chain at ^{11 C.} As is obvious to those skilled in the art, ^{m in 99m} Tc represents a metastable ^nucleoisomer .

  The radionuclide used in the compound according to the present invention is produced by a device called a cyclotron or a generator. A person skilled in the art can select a production method and apparatus according to the production nuclide. The nuclide thus produced can be used to label the compound of the present invention.

Methods for producing labeled compounds labeled with these radionuclides are well known in the art. Typical methods include chemical synthesis methods, isotope exchange methods, and biosynthesis methods. Chemical synthesis methods have been widely used in the past, and are essentially the same as ordinary chemical synthesis methods except that radioactive starting materials are used. By this method, various nuclides are introduced into the compound. In the isotope exchange method, ³ H, ³⁵ S, ¹²⁵ I and the like in a compound having a simple structure are transferred into a compound having a complex structure, and a compound having a complex structure labeled with these nuclides is obtained. . The biosynthetic method is a method in which a compound labeled with ¹⁴ C, ³⁵ S or the like is given to a cell such as a microorganism to obtain a metabolite introduced with these nuclides.

  As for the label position, a label can be introduced at a desired position by designing a synthesis scheme according to the purpose in the same manner as in the usual synthesis. Such designs are well known to those skilled in the art.

Also, for example, when using positron emitting nuclides such as ¹¹ C, ¹³ N, ¹⁵ O, and ¹⁸ F, which have a relatively short half-life, a desired nuclide is obtained from an (ultra) small cyclotron installed in a facility such as a hospital. It is also possible to label a desired compound at a predetermined position by the above method and immediately use it for diagnosis, examination, treatment or the like.

  By a method known to those skilled in the art, a desired nuclide can be introduced and labeled at a desired position of the compound of the present invention.

  Administration of the labeled compound of the present invention to a subject may be local or systemic. The administration route includes intradermal, intraperitoneal, intravenous, arterial, or spinal fluid injection or infusion, but can be selected depending on the type of disease, the nuclide used, the compound used, the condition of the subject, and the factors of the examination site. After the administration of the probe of the present invention and sufficient time for binding to and disruption of amyloid β protein, the site to be examined can be examined by means of PET, SPECT or the like. These means can be appropriately selected depending on factors such as the type of disease, the nuclide used, the compound used, the condition of the subject, and the site to be examined.

The dose of the compound of the present invention labeled with a radionuclide varies depending on the type of disease, the nuclide used, the compound used, the age, physical condition, sex, degree of disease, examination site, etc. of the subject. In particular, it is necessary to pay close attention to the target exposure. For example, the radioactivity of a compound of the present invention labeled with a positron emitting nuclide such as ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F is usually 3.7 to 3.7 gigabecrel, preferably 18 to It is in the range of 740 megabecquerel.

を有するものは、骨への集積が極めて低いか、ほとんどないので人体への投与に適している。For the compound of the present invention or a salt or solvate thereof, the following treatment method for conformation disease, diagnostic method, therapeutic composition, diagnostic composition, diagnostic kit, these composition and kit are produced. Although preferred for use as well as other uses, the compounds exemplified in the above description for the compounds of formulas (I)-(VI) or salts or solvates thereof are preferred, the compounds of formula (I) or salts thereof Or what is included in a solvate is especially preferable. Among the compounds of the present invention, those having a morpholino group, particularly a morpholino group as a terminal group are suitable for administration to the human body because they have no or very low mutagenicity. Of the compounds of the present invention, R ^{3 in} formula (I)

Are suitable for administration to the human body because they have very low or little accumulation in the bone.

The present invention provides a composition for diagnostic imaging of conformation disease comprising the compound of the present invention. The composition of the invention comprises a compound of the invention and a pharmaceutically acceptable carrier. The compound of the present invention in the composition is preferably labeled. There are various labeling methods as described above, but for in vivo diagnostic imaging, it must be labeled with a radionuclide (especially positron emitting nuclides such as ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F for PET). Is desirable. For the purpose of carrying the composition of the present invention, it is preferably in a form that can be injected or infused. Accordingly, the pharmaceutically acceptable carrier is preferably a liquid, and is an aqueous solvent such as potassium phosphate buffer, physiological saline, Ringer's solution, distilled water, or polyethylene glycol, vegetable oil, ethanol, glycerin, dimethyl. There are non-aqueous solvents such as, but not limited to, sulfoxide, propylene glycol and the like. The mixing ratio of the carrier and the compound of the present invention can be appropriately selected according to the application site, detection means, etc., but is usually a ratio of 100,000 to 1 to 2: 1, preferably 10,000 to 1 to 10 pairs. The ratio is 1. In addition, the composition of the present invention further comprises known antibacterial agents (for example, antibiotics), local anesthetics (for example, procaine hydrochloride), buffers (for example, Tris-HCl buffer, hepes buffer, etc.), osmotic pressure regulators (for example). For example, glucose, sorbitol, sodium chloride, etc.) may be contained.

  Furthermore, the present invention provides a kit for diagnostic imaging of conformation disease comprising the compound of the present invention as an essential component. Usually, the kit contains each component of the compound of the present invention, a solvent for dissolving it, a buffer, an osmotic pressure adjusting agent, an antibacterial agent, a local anesthetic agent, etc. separately or together in each container. It is a collection of what you put in. The compound of the present invention may be unlabeled or labeled. When unlabeled, the compound of the present invention can be labeled before use by a conventional method as described above. In addition, the compound of the present invention may be provided as a solid such as a lyophilized powder or may be provided by dissolving in a suitable solvent. The solvent may be the same as the carrier used in the above-described composition of the present invention. In addition, each component such as a buffer, an osmotic pressure regulator, an antibacterial agent, and a local anesthetic may be the same as that used in the above-described composition of the present invention. Various containers can be selected as appropriate, but the container can have a shape suitable for the label-introducing operation to the compound of the present invention, and can be made of a light-shielding material depending on the properties of the compound. For convenience of administration, it may be shaped like a vial or a syringe. The kit may appropriately include instruments necessary for diagnosis, for example, a syringe, an infusion set, or an instrument used for a PET apparatus or a SPECT apparatus. Usually, instructions are attached to the kit.

  Furthermore, since the compound of the present invention specifically binds to amyloid β protein, the compound of the present invention is left unlabeled or labeled and brought into contact with a sample specimen in vitro, whereby amyloid β in the specimen is obtained. It can also be used for protein detection and quantification. For example, the compound of the present invention may be used for staining amyloid β protein in a microscopic specimen, colorimetric determination of amyloid β protein in a sample, or quantification of amyloid β protein using a scintillation counter. The preparation of the microscope specimen and the staining using the compound of the present invention can be carried out by a usual method known to those skilled in the art.

  As described above, the compound of the present invention has high specificity for amyloid β protein. Therefore, the compound of the present invention is useful for, for example, research of amyloid β protein accumulation disease or diagnosis before birth or after death, and for example, useful as a stain for senile plaques in the brain of Alzheimer's disease patients. A specimen such as a brain section using the compound of the present invention can be stained by a conventional method known to those skilled in the art.

を有するものは、骨への集積が極めて低いか、ほとんどない。したがって、これらの本発明の化合物は極めて安全なコンフォーメーション病診断プローブであるばかりでなく、後述のような治療薬または予防薬として用いた場合にも安全性が高い。As described above, among the compounds of the present invention, those having a morpholino group as a terminal group have very little or no mutagenicity, and among the compounds of the present invention, the compounds of formula (I) As R ³ in

Have a very low or almost no accumulation in the bone. Therefore, these compounds of the present invention are not only extremely safe conformational disease diagnostic probes, but also have high safety when used as therapeutic or prophylactic agents as described below.

  Therefore, the present invention provides a composition for staining amyloid β protein in a sample containing a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof, as well as a compound of the present invention or a pharmaceutically acceptable salt thereof. The present invention relates to a kit for staining amyloid β protein in a sample, which contains a salt or a solvate as an essential component. Furthermore, the present invention relates to a method for staining amyloid β protein in a sample, which comprises using the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof. A suitable sample for these stains is a brain section.

  As described above, it has been found that neurocytotoxicity is observed in amyloid β protein having a β sheet structure. Since the compound of the present invention specifically binds to amyloid β protein having a β sheet structure, it is considered to suppress the neurotoxicity. Therefore, the compound of the present invention is considered to be a therapeutic or prophylactic agent for the pathogenesis of conformation disease, for example, Alzheimer's disease, which becomes a part of the pathogenesis by the protein itself having a β sheet structure.

Therefore, the present invention
A method of treating and / or preventing an amyloid β protein accumulation disease, comprising administering a compound of formula (I) or a salt or solvate thereof;
A method for diagnosing amyloid β protein accumulating disease, comprising using a compound of formula (I) or a salt or solvate thereof; and a composition or kit for treating, preventing or diagnosing amyloid β protein accumulating disease Use of a compound of formula (I) or a salt or solvate thereof for the preparation of

  The form of such a pharmaceutical composition is not particularly limited, but a liquid formulation is preferable, and an injection formulation is particularly preferable. Such injectable formulations can be injected directly into the brain, or, as shown in the Examples, the compounds of the present invention have high blood / brain barrier permeability, so that the pharmaceutical composition can be used for intravenous injection or intravenous infusion. It can also be prescribed and administered. Such a liquid formulation can be prepared by a method known in the art. For preparing the solution, for example, the compound of the present invention is dissolved in an appropriate carrier, water for injection, physiological saline, Ringer's solution, etc., sterilized with a filter or the like, and then filled into an appropriate container such as a vial or an ampoule. It is also possible to freeze-dry the solution and restore the solution again with an appropriate carrier at the time of use. Suspension preparation can be accomplished, for example, by sterilizing the compound of the invention, for example, by exposure to ethylene oxide and then suspending in a sterile liquid carrier.

When such a pharmaceutical composition is used as a liquid formulation, particularly an injection formulation, a solubilizing agent can be added to the benzoxazole derivative according to the present invention to make an injection.
As the solubilizer, nonionic surfactants, cationic surfactants, amphoteric surfactants and the like used in the art can be used. Among these, as a solubilizing agent, polysorbate 80, polyethylene glycol, ethanol or propylene glycol is preferable, and polysorbate 80 is more preferable.

  The dose of the compound of the present invention to the human subject in the above treatment method, prevention method, and use depends on the patient's medical condition, sex, age, weight, etc., but generally in the case of an adult weighing 70 kg. The daily dose is 0.1 mg to 1 g, preferably 1 mg to 100 mg, more preferably 5 mg to 50 mg. Treatment can be carried out with such a dose for a certain period, and the dose can be increased or decreased depending on the result.

  Furthermore, the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof can be used as a diagnostic probe for conformation disease, preferably as a diagnostic imaging probe labeled with a radionuclide. Furthermore, the compounds of the present invention are also effective in the treatment and / or prevention of conformation diseases.

Therefore, the present invention
A compound of the present invention or a salt or solvate thereof used as a diagnostic imaging probe for conformation disease;
A composition or kit for diagnostic imaging of conformation disease comprising a compound of the present invention or a salt or solvate thereof;
A pharmaceutical composition for prevention and / or treatment of conformation disease, comprising the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier;
A method for diagnosing conformation disease, which comprises using a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof;
Use of a compound of the invention or a pharmaceutically acceptable salt or solvate thereof for diagnosing conformation disease;
A method for the prophylaxis and / or treatment of conformation disease, comprising administering the compound of the present invention or a pharmaceutically acceptable salt or solvate thereof to a subject;
Use of a compound of the present invention or a pharmaceutically acceptable salt or solvate thereof for preventing and / or treating conformation disease; and a pharmaceutical composition for preventing and / or treating conformation disease. It also relates to the use of the compounds of the invention in the manufacture.

  The dose of the compound of the present invention to the human subject in the above therapeutic and prophylactic methods is as described above.

  Among the compounds of the present invention, certain compounds recognize neurofibrillary tangles, and therefore can be used as probes for detecting neurofibrillary tangles or staining agents for neurofibrillary tangles. Therefore, the present invention also relates to the use of the compound of the present invention or a salt or solvate thereof as a diagnostic probe for neurofibrillary tangle, particularly as an imaging diagnostic probe. Preferred compounds of the present invention as a staining agent for neurofibrillary tangles include THK-185, THK-258, THK-317, THK-386, THK-702, THK-761, THK-727, THK-763 and the like.

Thus, the present invention provides:
A composition for detecting or staining a neurofibrillary tangle comprising the compound of the present invention or a salt or solvate thereof;
A kit for detecting or staining a neurofibrillary tangle comprising the compound of the present invention or a salt or solvate thereof;
A method for detecting or staining a neurofibrillary tangle characterized by using the compound of the present invention or a salt or solvate thereof; and the present invention for producing a composition for detecting or staining a neurofibrillary tangle. Or a salt or solvate thereof.

  Methods known to those skilled in the art can be applied to the above-described methods such as preparation and staining of sample specimens in the detection or staining of neurofibrillary tangles.

  The present invention will be described in more detail and specifically with reference to the following examples, but the present invention is not limited to the examples.

Synthesis of Compounds of the Present Invention Synthesis examples of the compounds of the present invention are shown below.
For silica gel column chromatography in the examples, silica gel BW300 manufactured by Fuji Silysia Chemical Ltd. was used. For basic silica gel column chromatography using amino group-bonded silica gel, Chromatrex NH-DM1020 manufactured by Fuji Silysia Chemical Ltd. was used.
¹ H-NMR was measured using UNITY INOVA500 (500 MHz) manufactured by VARIAN, JNM-LA400 (400 MHz) manufactured by JEOL Ltd., Gemini 2000 (300 MHz) tetramethylsilane manufactured by VARIAN, and all δ values were measured in ppm. Measured with
The mass spectrum was measured by the atmospheric pressure chemical ionization method (APCI) using LCQ-Advantage manufactured by ThermoQuest or SSQ-7000C manufactured by FinniganMAT.
For the infrared spectrum, Parakin 1000 FT-IR manufactured by Perkin-Elmer was used, and for measuring the melting point, B-545 manufactured by BUCHI was used.

The meanings of the abbreviations in the NMR measurement are shown below.
s: singlet d: doublet dd: double doublet ddd: double double doublet t: triplet dt: double triplet q: quartet m: multiplet br: broad J: coupling loop constant Hz: Hertz CDCl _3: deuterated chloroform _DMSO-d 6: Heavy dimethyl sulfoxide

２の製造
１（７．１９ｇ、４３．８４ｍｍｏｌ）のモルホリン（１８．７ｍｌ）溶液を１２０℃で９時間攪拌した。反応液を放冷、不溶物をろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝５／１）で精製し２（７．４６ｇ、１００％）を淡黄色油状物として得た。
ＩＲ（Ｎｅａｔ）２８５４、１５２４ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ１７１［Ｍ＋Ｈ］^＋

３の製造
ジイソプロピルアミン（７．４１ｍｌ、５２．５８ｍｍｏｌ）のテトラヒドロフラン（１００ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５８Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（３３．３ｍｌ、５２．５８ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で２（７．４６ｇ，４３．８２ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を滴下し−７８℃で１ 時間撹拌した。同温で、ジメチルホルムアミド（５．０８ｍｌ，６５．７３ｍｍｏｌ）を一度に加え同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチル／ｎ−ヘキサンで再結晶し３（７．５４ｇ，８７％）を淡黄色結晶として得た。
ｍｐ１６４〜１６５℃、ＩＲ（Ｎｕｊｏｌ）１６５０ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ１９９［Ｍ＋Ｈ］^＋

５の製造
４（０．９５ｇ、６．３７ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液に２−フルオロエタノール（０．８２ｍｌ、１４．０１ｍｍｏｌ）、トリフェニルホスフィン（３．６７ｇ、１４．０１ｍｍｏｌ）を加え、氷冷攪拌下ジイソプロピルアゾジカルボキシレート（２．７６ｍｌ、１４．０１ｍｍｏｌ）を滴下し室温で１６時間撹拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）で精製し５（０．８２ｇ、６６％）を淡黄色油状物として得た。
ＩＲ（Ｎｅａｔ）１７２６、１６３２、１６１８ｃｍ⁻
ＡＰＣＩ−ＭＳ ｍ／ｚ１９６［Ｍ＋Ｈ］^＋

６の製造
ジイソプロピルアミン（０．８８ｍｌ、６．２３ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５４Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（４．０４ｍｌ、６．２３ｍｍｏｌ）を滴下、除々に０℃まで昇温した。次に−７０℃以下で５（０．８１ｇ、４．１５ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で、３（１．２３ｇ、６．２３ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液を一度に加え同温で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〜酢酸エチル）で精製し６（１．４０ｇ、８６％）を淡黄色結晶として得た。
ｍｐ１５７．５〜１５８．０℃、ＩＲ（Ｎｕｊｏｌ）３３０６、１６２８、１６１７ｃｍ^−１ＡＰＣＩ−ＭＳ ｍ／ｚ３９４［Ｍ＋Ｈ］^＋

７の製造
６（０．８８ｇ、２．２４ｍｍｏｌ）のジクロロメタン（１００ｍｌ）溶液にトリエチルアミン（１．２５ｍｌ、８．９５ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．３５ｍｌ、４．４７ｍｍｏｌ）を滴下し室温で３０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチル／ｎ−ヘキサンで再結晶し７（０．４９ｇ、５９％）を黄色結晶として得た。
ｍｐ１７４．５〜１７５．２℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ３．５７（４Ｈ、ｔ、Ｊ＝５．０Ｈｚ），３．８３（４Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、４．２７（２Ｈ、ｄｔ、Ｊ＝２７．８、４．２Ｈｚ）、４．７９（２Ｈ、ｄｔ、Ｊ＝４７．２、４．２Ｈｚ）、６．４２（１Ｈ、ｄ、Ｊ＝１５．６Ｈｚ）、６．９４（１Ｈ、ｄｄ、Ｊ＝８．７、２．２Ｈｚ）、７．０４（１Ｈ、ｄ、Ｊ＝２．２Ｈｚ）、７．３６（１Ｈ、ｓ）、７．５４（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６８（１Ｈ、ｄ、Ｊ＝１５．６Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） １６３１ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ３７６［Ｍ＋Ｈ］^＋ THK-525 (6- (2-Fluoro-ethoxy) -2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazole): 7

A morpholine (18.7 ml) solution of Preparation 1 (7.19 g, 43.84 mmol) of 2 was stirred at 120 ° C. for 9 hours. The reaction solution was allowed to cool, the insoluble material was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5/1) 2 (7.46 g, 100%) as a pale yellow oil.
IR (Neat) 2854, 1524 cm ⁻¹ , APCI-MS m / z 171 [M + H] ⁺

Preparation of 3 To a solution of diisopropylamine (7.41 ml, 52.58 mmol) in tetrahydrofuran (100 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.58 M n-butyllithium / n-hexane solution (33. 3 ml, 52.58 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 2 (7.46 g, 43.82 mmol) in tetrahydrofuran (10 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. At the same temperature, dimethylformamide (5.08 ml, 65.73 mmol) was added all at once and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate / n-hexane to give 3 (7.54 g, 87%) as pale yellow crystals.
mp 164 to 165 ° C., IR (Nujol) 1650 cm ⁻¹
APCI-MS m / z199 [M + H] +

2-fluoroethanol (0.82 ml, 14.01 mmol) and triphenylphosphine (3.67 g, 14.01 mmol) were added to a solution of Preparation 4 (0.95 g, 6.37 mmol) in tetrahydrofuran (30 ml). Diisopropyl azodicarboxylate (2.76 ml, 14.01 mmol) was added dropwise with cold stirring, and the mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to give 5 (0.82 g, 66%) as a pale yellow oil.
IR (Neat) 1726, 1632, 1618 cm ⁻
APCI-MS m / z 196 [M + H] ⁺

Preparation of 6 To a solution of diisopropylamine (0.88 ml, 6.23 mmol) in tetrahydrofuran (40 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.54 M n-butyllithium / n-hexane solution (4. 04 ml, 6.23 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 5 (0.81 g, 4.15 mmol) in tetrahydrofuran (10 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. At the same temperature, a solution of 3 (1.23 g, 6.23 mmol) in tetrahydrofuran (50 ml) was added all at once and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1 / 1-ethyl acetate) to give 6 (1.40 g, 86%) pale. Obtained as yellow crystals.
mp 157.5-158.0 ° C., IR (Nujol) 3306, 1628, 1617 cm ⁻¹ APCI-MS m / z 394 [M + H] ⁺

Triethylamine (1.25 ml, 8.95 mmol) was added to a solution of 7 (6) (0.88 g, 2.24 mmol) in dichloromethane (100 ml), and methanesulfonyl chloride (0.35 ml, 4.47 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate / n-hexane to give 7 (0.49 g, 59%) as yellow crystals.
mp 174.5 to 175.2 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.57 (4H, t, J = 5.0 Hz), 3.83 (4H, t, J = 5.0 Hz), 4 .27 (2H, dt, J = 27.8, 4.2 Hz), 4.79 (2H, dt, J = 47.2, 4.2 Hz), 6.42 (1H, d, J = 15.6 Hz) ), 6.94 (1H, dd, J = 8.7, 2.2 Hz), 7.04 (1H, d, J = 2.2 Hz), 7.36 (1H, s), 7.54 (1H , D, J = 8.7 Hz), 7.68 (1H, d, J = 15.6 Hz)
IR (Nujol) 1631 cm ⁻¹ , APCI-MS m / z 376 [M + H] ⁺

８の製造
エチレングリコール（１３０ｍｌ）を入れ、アルゴン雰囲気室温攪拌下６０％水素化ナトリウム（４．８３ｇ、１２０．６ｍｍｏｌ）を少しづつ加え室温４０分攪拌、トルエンスルホニルクロライド（２０．００ｇ、１０４．９ｍｍｏｌ）を加え同温で６時間攪拌した。ジクロロメタン（１００ｍｌ）を加え室温で１６時間攪拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝５／１〜１／１）で精製し８（７．３０ｇ、３２％）を無色油状物として得た。

１０の製造
９（１．００ｇ、５．１８ｍｍｏｌ）及び３（１．０３ｇ、５．１８ｍｍｏｌ）をジメチルスルホキシド（１０ｍｌ）溶液に室温撹拌下５０％（ｗ／ｗ）水酸化ナトリウム水溶液（２．０ｍｌ）を加え室温で３０分撹拌した。反応液に水を加え、ろ取、水洗、乾燥し１０（１．５５ｇ、８０％）を黄色結晶として得た。
ｍｐ１５６．０〜１５６．６℃、ＩＲ（Ｎｕｊｏｌ）１６３１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ３７４［Ｍ＋Ｈ］^＋

１１の製造
１０（１．５５ｇ、４．１４ｍｍｏｌ）のジクロロメタン（２５ｍｌ）溶液に氷冷撹拌下トリフルオロ酢酸（１７．５ｍｌ）を滴下し室温で４０分撹拌した。反応液に冷水を加え、炭酸カリウム溶液でｐＨ１０とし、酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチルで再結晶し１１（１．０４ｇ、７６％）を黄色結晶として得た。
ｍｐ２３３〜２３４℃、ＩＲ（Ｎｕｊｏｌ）３４９１、１６３１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ３３０［Ｍ＋Ｈ］^＋

１２の製造
１１（０．５０ｇ、１．５２ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に８（０．７２ｇ、３．３４ｍｍｏｌ）、トリフェニルホスフィン（０．８８ｇ、３．３４ｍｍｏｌ）を加え、氷冷攪拌下ジイソプロピルアゾジカルボキシレート（０．６６ｍｌ、３．３４ｍｍｏｌ）を滴下し室温で１６時間撹拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：トルエン／酢酸エチル＝２／１）で精製、酢酸エチルで再結晶し１２（０．３８ｇ、４８％）を橙色結晶として得た。
ｍｐ１６８〜１６９℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２．４４（３Ｈ、ｓ），３．５５〜３．６２（４Ｈ、ｍ）、３．７７〜３．８７（４Ｈ、ｍ）、４．１１〜４．２２（２Ｈ、ｍ）、４．３７〜４．４３（２Ｈ、ｍ）、６．３８（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、６．７８（１Ｈ、ｄｄ、Ｊ＝８．７、２．３Ｈｚ）、６．９０（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．３４（２Ｈ、ｄｄ、Ｊ＝７．６、０．７Ｈｚ）、７．３７（１Ｈ、ｓ）、７．４９（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６７（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、７．７１〜７．８４（２Ｈ、ｍ）
ＩＲ （Ｎｕｊｏｌ） １６３３ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ５２８［Ｍ＋Ｈ］^＋ THK-575 (toluene-4-sulphonic acid 2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl-benzoxazol 6-yloxy] ethyl ester): (12 )Manufacturing of

Preparation of 8 Ethylene glycol (130 ml) was added, 60% sodium hydride (4.83 g, 120.6 mmol) was added little by little with stirring in an argon atmosphere at room temperature, and stirring was continued for 40 minutes at room temperature, toluenesulfonyl chloride (20.00 g , 104.9 mmol) and stirred at the same temperature for 6 hours. Dichloromethane (100 ml) was added and stirred at room temperature for 16 hours. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 5/1 to 1/1) to obtain 8 (7.30 g, 32%). Obtained as a colorless oil.

10 Preparation 9 (1.00 g, 5.18 mmol) and 3 (1.03 g, 5.18 mmol) in a dimethyl sulfoxide (10 ml) solution with stirring at room temperature with 50% (w / w) aqueous sodium hydroxide (2.0 ml) ) And stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was collected by filtration, washed with water and dried to obtain 10 (1.55 g, 80%) as yellow crystals.
mp 156.0 to 156.6 ° C., IR (Nujol) 1631 cm ⁻¹
APCI-MS m / z 374 [M + H] ⁺

To a solution of No. 11 10 (1.55 g, 4.14 mmol) in dichloromethane (25 ml), trifluoroacetic acid (17.5 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for 40 minutes. Cold water was added to the reaction mixture, the pH was adjusted to 10 with a potassium carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 11 (1.04 g, 76%) as yellow crystals.
mp 233-234 [deg.] C., IR (Nujol) 3491, 1631 cm < ^-1 >
APCI-MS m / z 330 [M + H] ⁺

No. 12 Preparation 11 (0.50 g, 1.52 mmol) in tetrahydrofuran (20 ml) was added 8 (0.72 g, 3.34 mmol) and triphenylphosphine (0.88 g, 3.34 mmol), and the mixture was stirred under ice cooling. Diisopropyl azodicarboxylate (0.66 ml, 3.34 mmol) was added dropwise and stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: toluene / ethyl acetate = 2/1) and recrystallized from ethyl acetate to give 12 (0.38 g, 48%) as orange crystals. It was.
mp 168 to 169 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.44 (3H, s), 3.55 to 3.62 (4H, m), 3.77 to 3.87 (4H, m), 4.11 to 4.22 (2H, m), 4.37 to 4.43 (2H, m), 6.38 (1H, d, J = 15.7 Hz), 6.78 (1H, dd, J = 8.7, 2.3 Hz), 6.90 (1H, d, J = 2.3 Hz), 7.34 (2H, dd, J = 7.6, 0.7 Hz), 7.37 (1H, s), 7.49 (1H, d, J = 8.7 Hz), 7.67 (1H, d, J = 15.7 Hz), 7.71-7.84 (2H, m)
IR (Nujol) 1633 cm ⁻¹ , APCI-MS m / z 528 [M + H] ⁺

１４の製造
１３（４．９０ｇ、４６．１７ｍｍｏｌ）のテトラヒドロフラン（１５０ｍｌ）懸濁液に室温攪拌下アセトンジメチルアセタール（６．５６ｍｌ、５３．５４ｍｍｏｌ）、トルエンスルホン酸・水和物（０．２６ｇ、１．３９ｍｍｏｌ）を加え室温３時間攪拌した。反応液にトリエチルアミン（３ｍｌ）を加え減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール＝１０／１）で精製し１４（６．３８ｇ、９５％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ１４７［Ｍ＋Ｈ］^＋

１５の製造
１４（６．３８ｇ、４３．６４ｍｍｏｌ）のジクロロメタン（１００ｍｌ）溶液にトリエチルアミン（９．０８ｍｌ、６５．４７ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（３．６９ｍｌ、４８．０１ｍｍｏｌ）を滴下し同温で３０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／２）で精製し１５（９．６６ｇ、９９％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ２２５［Ｍ＋Ｈ］^＋

１６の製造
１５（９．６６ｇ、４３．０７ｍｍｏｌ）のテトラヒドロフラン（１００ｍｌ）溶液に室温攪拌下１Ｍテトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（２６０ｍｌ、２６０ｍｍｏｌ）を加え還流３０分した。反応液を放冷、冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝９／１）で精製し１６（５．２２ｇ、８２％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ１４９［Ｍ＋Ｈ］^＋

１７の製造
１６（５．２２ｇ、３５．２３ｍｍｏｌ）のアセトン（１００ｍｌ）溶液に１Ｎ塩酸（１０ｍｌ、１０ｍｍｏｌ）を加え室温２時間攪拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝４／１〜１／１）で精製し１７（３．１６ｇ、８３％）
を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ１２６［Ｍ＋ＮＨ４］^＋

１８の製造
１７（３．１６ｇ、２９．２３ｍｍｏｌ）のジクロロメタン（４０ｍｌ）溶液にトリエチルアミン（１０．１９ｍｌ、７３．０８ｍｍｏｌ）を加え氷冷攪拌下ｔ−ブチルジメチルシリルクロライド（４．４１ｇ、２９．２３ｍｍｏｌ）を加え室温１６時間攪拌した。反応懸濁液を減圧溶媒留去、残渣を酢酸エチルで懸濁し、ろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝９／１）で精製し１８（５．１６ｇ、７９％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ２２３［Ｍ＋Ｈ］^＋

１９の製造
１１（０．５５ｇ、１．６７ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）懸濁液に１８（０．８２ｇ、３．６７ｍｍｏｌ）、トリフェニルホスフィン（０．９６ｇ、３．６７ｍｍｏｌ）を加え、氷冷攪拌下ジイソプロピルアゾジカルボキシレート（０．７２ｍｌ、３．６７ｍｍｏｌ）を滴下し室温で１６時間撹拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝４／１）で精製し１９（０．６７ｇ、７５％）を黄色粘体物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ：５３４［Ｍ＋Ｈ］^＋

２０の製造
１９（０．６７ｇ、１．２６ｍｍｏｌ）のジクロロメタン（５０ｍｌ）溶液に氷冷攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１．２６ｍｌ、１．２６ｍｍｏｌ）を滴下し室温で４０分攪拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝４／１〜１／１）で精製、酢酸エチル／ｎ−ヘキサンで再結晶し２０（０．３４ｇ、６５％）を黄色結晶として得た。
ｍｐ１３４〜１３５℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２．３８〜２．５３（１Ｈ、ｍ），３．６４（４Ｈ、ｍ）、３．８５（４Ｈ、ｍ）、３．９２（２Ｈ、ｄ、Ｊ＝５．２Ｈｚ）、４．１６（２Ｈ、ｄ、Ｊ＝５．５Ｈｚ）、４．７１（２Ｈ、ｄｄ、Ｊ＝４７．２、５．３Ｈｚ）、６．４２（１Ｈ、ｄ、Ｊ＝１５．８Ｈｚ）、６．９２（１Ｈ、ｄｄ、Ｊ＝８．８、２．３Ｈｚ）、７．０４（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．３９（１Ｈ、ｓ）、７．５４（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．６７（１Ｈ、ｄ、Ｊ＝１５．８Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３３２４、１６３４ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ４２０［Ｍ＋Ｈ］^＋ THK-727 (2-fluoromethyl-3- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazol-6-yloxy] -propan-1-ol): (20) Production

14 Preparation 13 (4.90 g, 46.17 mmol) suspension in tetrahydrofuran (150 ml) with stirring at room temperature with acetone dimethyl acetal (6.56 ml, 53.54 mmol), toluenesulfonic acid hydrate (0.26 g, 1.39 mmol) was added and the mixture was stirred at room temperature for 3 hours. Triethylamine (3 ml) was added to the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: chloroform / methanol = 10/1) to obtain 14 (6.38 g, 95%) as a colorless oil. It was.
APCI-MS m / z 147 [M + H] ⁺

Triethylamine (9.08 ml, 65.47 mmol) was added to a solution of No. 15 14 (6.38 g, 43.64 mmol) in dichloromethane (100 ml), and methanesulfonyl chloride (3.69 ml, 48.01 mmol) was added with stirring under ice cooling. The solution was added dropwise and stirred at the same temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/2) to purify 15 (9.66 g, 99%) as a pale yellow oil. Got as.
APCI-MS m / z 225 [M + H] ⁺

To a solution of No. 16 Preparation 15 (9.66 g, 43.07 mmol) in tetrahydrofuran (100 ml) was added 1M tetrabutylammonium fluoride / tetrahydrofuran solution (260 ml, 260 mmol) with stirring at room temperature, and the mixture was refluxed for 30 min. The reaction mixture was allowed to cool, cold water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 9/1) to obtain 16 (5.22 g, 82%) as a pale yellow oil Got as.
APCI-MS m / z 149 [M + H] ⁺

17 Preparation 16 (5.22 g, 35.23 mmol) in acetone (100 ml) was added 1N hydrochloric acid (10 ml, 10 mmol) and stirred at room temperature for 2 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4/1 to 1/1) 17 (3.16 g, 83%)
Was obtained as a colorless oil.
APCI-MS m / z 126 [M + NH4] ⁺

18 Preparation 17 (3.16 g, 29.23 mmol) in dichloromethane (40 ml) was added triethylamine (10.19 ml, 73.08 mmol), and t-butyldimethylsilyl chloride (4.41 g, 29.23 mmol) was stirred with ice cooling. ) And stirred at room temperature for 16 hours. The reaction suspension was evaporated under reduced pressure, the residue was suspended in ethyl acetate, filtered, the filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 9/1). To give 18 (5.16 g, 79%) as a colorless oil.
APCI-MS m / z 223 [M + H] ⁺

19 Preparation 11 (0.55 g, 1.67 mmol) in tetrahydrofuran (40 ml) suspension was added 18 (0.82 g, 3.67 mmol) and triphenylphosphine (0.96 g, 3.67 mmol), and ice-cooled. Diisopropyl azodicarboxylate (0.72 ml, 3.67 mmol) was added dropwise with stirring, and the mixture was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4/1) to obtain 19 (0.67 g, 75%) as a yellow viscous product.
APCI-MS m / z: 534 [M + H] ⁺

20 Preparation 19 (0.67 g, 1.26 mmol) in dichloromethane (50 ml) was added dropwise with 1M tetrabutylammonium fluoride / tetrahydrofuran solution (1.26 ml, 1.26 mmol) under ice-cooling and stirring at room temperature for 40 minutes. did. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4/1 to 1/1) and recrystallized from ethyl acetate / n-hexane. 20 (0.34 g, 65%) was obtained as yellow crystals.
mp 134-135 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.38-2.53 (1H, m), 3.64 (4H, m), 3.85 (4H, m), 3.92 ( 2H, d, J = 5.2 Hz), 4.16 (2H, d, J = 5.5 Hz), 4.71 (2H, dd, J = 47.2, 5.3 Hz), 6.42 (1H , D, J = 15.8 Hz), 6.92 (1H, dd, J = 8.8, 2.3 Hz), 7.04 (1H, d, J = 2.3 Hz), 7.39 (1H, s), 7.54 (1H, d, J = 8.8 Hz), 7.67 (1H, d, J = 15.8 Hz)
IR (Nujol) 3324, 1634 cm ⁻¹ , APCI-MS m / z 420 [M + H] ⁺

２１の製造
４（３．００ｇ、２０．１１ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液に１，３−ジベンジルオキシ−２−プロパノール（６．５７ｇ、２４．１４ｍｍｏｌ）、トリフェニルホスフィン（６．３３ｇ、２４．１４ｍｍｏｌ）を加え、アルゴン雰囲気氷冷攪拌下４０％ジエチルアゾジカルボキシレート／トルエン溶液（１０．５１ｇ、２４．１４ｍｍｏｌ）を滴下し室温で３日間撹拌した。反応液を減圧溶媒留去、残渣をイソプロピルエーテルで不溶物を懸濁させ、ろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝９／１）で精製し２１（７．２２ｇ、８９％）
を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ４０４［Ｍ＋Ｈ］^＋

２２の製造
２１（７．２２ｇ、１７．８９ｍｍｏｌ）のメタノール／酢酸（５０／１０ｍｌ）溶液にアルゴン雰囲気下１０％パラジウムー炭素（０．７ｇ）を加え、水素雰囲気下、常圧、５０℃２４時間攪拌した。反応液のパラジウムー炭素をろ別、ろ液を減圧溶媒留去、残渣を酢酸エチルで希釈し、炭酸カリウム水溶液洗、水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝３／１〜１／１）で精製し２２（３．０１ｇ、７５％）を赤茶色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ２２４［Ｍ＋Ｈ］^＋

２３の製造
２２（３．０１ｇ、１３．４８ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液にトリエチルアミン（４．７０ｍｌ、３３．７１ｍｍｏｌ）を加え、室温攪拌下ｔ−ブチルジメチルシリルクロライド（２．０３ｇ、１３．４８ｍｍｏｌ）を加え室温２日間攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝９／１〜１／１）で精製し２３（２．００ｇ、４４％）を赤色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ３３８［Ｍ＋Ｈ］^＋

２４の製造
２３（２．００ｇ、５．９３ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液にトリエチルアミン（１．２４ｍｌ、８．８９ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．５５ｍｌ、７．１１ｍｍｏｌ）を滴下し同温で３０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１）で精製し２４（２．４６ｇ、１００％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ４１６［Ｍ＋Ｈ］^＋

２５の製造
２４（２．４６ｇ、５．９２ｍｍｏｌ）に１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（２３．７ｍｌ、２３．７ｍｍｏｌ）を加え７０℃１６時間攪拌した。反応液を放冷、冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝９／１）で精製し２５（０．８９ｇ、６７％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ２２６［Ｍ＋Ｈ］^＋

２６の製造
２５（０．７５ｇ、３．３３ｍｍｏｌ）のジメチルホルムアミド（１０ｍｌ）溶液にイミダゾール（０．２７ｇ、４．００ｍｍｏｌ）を加え、室温攪拌下ｔ−ブチルジメチルシリルクロライド（０．６０ｇ、４．００ｍｍｏｌ）を加え室温１６時間攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝９／１〜４／１）で精製し２６（０．９９ｇ、８８％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ３４０［Ｍ＋Ｈ］^＋

２７の製造
ジイソプロピルアミン（０．６２ｍｌ、４．３７ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５７Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（２．７９ｍｌ、４．３７ｍｍｏｌ）を滴下し、除々に０℃まで昇温した。次に−７０℃以下で２６（０．９９ｇ、２．９２ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を滴下し−７８℃で１ 時間撹拌した。同温で、３（０．６４ｇ、３．２１ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を一度に加え、同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〜１／２）で精製し２７（１．２６ｇ、８０％）を黄色泡状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ５３８［Ｍ＋Ｈ］^＋

２８の製造
２７（１．２６ｇ、２．３４ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液にトリエチルアミン（１．３１ｍｌ、９．３６ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．４０ｍｌ、５．１５ｍｍｏｌ）を滴下し室温で５０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）で精製し２８（１．２２ｇ、１００％）を黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ５２０［Ｍ＋Ｈ］^＋

２９の製造
２８（１．２２ｇ、２．３５ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（２．３５ｍｌ、２．３５ｍｍｏｌ）を加え室温３０分した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残さをシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／１〜酢酸エチル）で精製、酢酸エチルで再結晶し２９（０．４４ｇ、４６％）を黄色結晶として得た。
ｍｐ１５２〜１５３℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２．０６（ｔ、Ｊ＝５．３Ｈｚ、Ｄ_２Ｏ消去）、３．５７（４Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、３．８３（４Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、３．９４（２Ｈ、ｍ）、４．５０〜４．５７（１Ｈ、ｍ）、４．６７（１Ｈ、ｄｄ、Ｊ＝４６．８、２．２Ｈｚ）、４．６９（１Ｈ、ｄｄ、Ｊ＝４６．８、２．３Ｈｚ）、６．３８（１Ｈ、ｄｄ、Ｊ＝１５．８、０．５Ｈｚ）、６．９８（１Ｈ、ｄｄ、Ｊ＝８．７、２．３Ｈｚ）、７．１３（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．３７（１Ｈ、ｔ、Ｊ＝０．６Ｈｚ）、７．５４（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６９（１Ｈ、ｄｄ、Ｊ＝１５．８、０．８Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３２８４、１６３１ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ４０６［Ｍ＋Ｈ］^＋ THK-702 ((E) -2- [2- (2-morpholinothiazol-5-yl) ethenyl] -6-[(1-fluoromethyl-2-hydroxy) ethoxy] benzoxazole): (29) Manufacturing

Preparation of No. 21 4 (3.00 g, 20.11 mmol) in tetrahydrofuran (50 ml) was added 1,3-dibenzyloxy-2-propanol (6.57 g, 24.14 mmol), triphenylphosphine (6.33 g, 24 .14 mmol) was added, and a 40% diethylazodicarboxylate / toluene solution (10.51 g, 24.14 mmol) was added dropwise with stirring under ice-cooling in an argon atmosphere, followed by stirring at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, the residue was suspended in insoluble matter with isopropyl ether, filtered, the filtrate was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 9 / Purified in 1) 21 (7.22 g, 89%)
Was obtained as a colorless oil.
APCI-MS m / z 404 [M + H] ⁺

No. 22 Preparation 21 (7.22 g, 17.89 mmol) in methanol / acetic acid (50/10 ml) solution was added 10% palladium-carbon (0.7 g) under an argon atmosphere, and under a hydrogen atmosphere at normal pressure and 50 ° C. for 24 hours. Stir. Palladium-carbon in the reaction solution was filtered off, the filtrate was evaporated under reduced pressure, the residue was diluted with ethyl acetate, washed with aqueous potassium carbonate solution, washed with water, dried, evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent: acetic acid). Purification by ethyl / n-hexane = 3/1 to 1/1) gave 22 (3.01 g, 75%) as a red-brown solid.
APCI-MS m / z 224 [M + H] ⁺

Triethylamine (4.70 ml, 33.71 mmol) was added to a solution of No. 23 22 (3.01 g, 13.48 mmol) in tetrahydrofuran (50 ml), and t-butyldimethylsilyl chloride (2.03 g, 13.48 mmol) was stirred at room temperature. ) And stirred at room temperature for 2 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 9/1 to 1/1) to give 23 (2.00 g, 44%). Obtained as a red oil.
APCI-MS m / z 338 [M + H] ⁺

Triethylamine (1.24 ml, 8.89 mmol) was added to a solution of 24 (23 g, 2.00 g, 5.93 mmol) in dichloromethane (20 ml), and methanesulfonyl chloride (0.55 ml, 7.11 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at the same temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1) to give 24 (2.46 g, 100%) as a pale yellow oil. Got as.
APCI-MS m / z 416 [M + H] ⁺

1M tetrabutylammonium fluoride / tetrahydrofuran solution (23.7 ml, 23.7 mmol) was added to Preparation 24 (2.46 g, 5.92 mmol) of 25 and stirred at 70 ° C. for 16 hours. The reaction mixture was allowed to cool, cold water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 9/1) to obtain 25 (0.89 g, 67%) as a pale yellow oil. Got as.
APCI-MS m / z 226 [M + H] ⁺

Preparation of No. 26 To a solution of dimethylformamide (10 ml) in 25 (0.75 g, 3.33 mmol), imidazole (0.27 g, 4.00 mmol) was added, and t-butyldimethylsilyl chloride (0.60 g, 4.3 mmol) was stirred at room temperature. 00 mmol) was added and stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 9/1 to 4/1) to obtain 26 (0.99 g, 88%). Obtained as a colorless oil.
APCI-MS m / z 340 [M + H] ⁺

Preparation of 27 To a solution of diisopropylamine (0.62 ml, 4.37 mmol) in tetrahydrofuran (20 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.57 M n-butyllithium / n-hexane solution (2. 79 ml, 4.37 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 26 (0.99 g, 2.92 mmol) in tetrahydrofuran (10 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. At the same temperature, a solution of 3 (0.64 g, 3.21 mmol) in tetrahydrofuran (20 ml) was added all at once, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 1/2) to obtain 27 (1.26 g, 80%). Obtained as a yellow foam.
APCI-MS m / z 538 [M + H] ⁺

Preparation of 28 No. 27 (1.26 g, 2.34 mmol) in dichloromethane (20 ml) was added triethylamine (1.31 ml, 9.36 mmol), and methanesulfonyl chloride (0.40 ml, 5.15 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 50 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to give 28 (1.22 g, 100%) as a yellow oil. Obtained.
APCI-MS m / z 520 [M + H] ⁺

Preparation of 29 No. 28 (1.22 g, 2.35 mmol) in tetrahydrofuran (20 ml) was stirred at room temperature, and 1M tetrabutylammonium fluoride / tetrahydrofuran solution (2.35 ml, 2.35 mmol) was added, and the mixture was stirred for 30 minutes at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1 to ethyl acetate) and recrystallized with ethyl acetate 29 (0.44 g). 46%) as yellow crystals.
mp 152-153 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.06 (t, J = 5.3 Hz, D ₂ O erased), 3.57 (4H, t, J = 5.0 Hz). 83 (4H, t, J = 5.0 Hz), 3.94 (2H, m), 4.50 to 4.57 (1H, m), 4.67 (1H, dd, J = 46.8, 2 .2 Hz), 4.69 (1H, dd, J = 46.8, 2.3 Hz), 6.38 (1H, dd, J = 15.8, 0.5 Hz), 6.98 (1H, dd, J = 8.7, 2.3 Hz), 7.13 (1H, d, J = 2.3 Hz), 7.37 (1H, t, J = 0.6 Hz), 7.54 (1H, d, J = 8.7 Hz), 7.69 (1H, dd, J = 15.8, 0.8 Hz)
IR (Nujol) 3284, 1631 cm ⁻¹ , APCI-MS m / z 406 [M + H] ⁺

３０の製造
４（１．７４ｇ、１１．６７ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）溶液に１４（２．０５ｇ、１４．００ｍｍｏｌ）、トリフェニルホスフィン（３．６８ｇ、１４．００ｍｍｏｌ）を加え、氷冷攪拌下４０％ジエチルアゾジカルボキシレート／トルエン溶液（６．１１ｇ、１４．００ｍｍｏｌ）を滴下し室温で３日間撹拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝４／１）で精製し３０（２．８０ｇ、８７％）を無色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ２７８［Ｍ＋Ｈ］^＋

３１の製造
３０（２．０６ｇ、 ７．４３ｍｍｏｌ）及び３（１．４７ｇ、７．４３ｍｍｏｌ）のジメチルスルホキシド（２０ｍｌ）溶液に室温撹拌下５０％（ｗ／ｗ）水酸化ナトリウム水溶液（２．８ｍｌ）を加え室温で１．５時間撹拌した。反応液に水を加え、ろ取、水洗、乾燥し３１（２．５８ｇ、７６％）を黄色結晶として得た。
ｍｐ１８２．０〜１８２．５℃、ＩＲ（Ｎｕｊｏｌ）１６２１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４５８［Ｍ＋Ｈ］^＋

３２の製造
３１（２．５８ｇ、５．６４ｍｍｏｌ）のメタノール（４０ｍｌ）懸濁液に１Ｎ塩酸（１１．３ｍｌ、１１．３ｍｍｏｌ）を加え室温１時間攪拌した。反応液を減圧溶媒留去、残渣を水／酢酸エチルで溶解、炭酸カリウム溶液でｐＨ１０とし、分液後、有機層を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチル／ｎ−ヘキサンで再結晶し３２（２．３５ｇ、１００％）を黄色結晶として得た。
ｍｐ１６２．０〜１６３℃、ＡＰＣＩ−ＭＳ ｍ／ｚ４１８［Ｍ＋Ｈ］^＋

３３の製造
３２（１．８５ｇ、４．４３ｍｍｏｌ）のエチレングリコールジメチルエーテル（２２０ｍｌ）懸濁液にトリエチルアミン（０．９３ｍｌ、６．６５ｍｍｏｌ）、トルエンスルホン酸無水物（１．４５ｇ、４．４３ｍｏｌ）、ジメチルアミノピリジン（０．０５４ｇ、０．４４ｍｍｏｌ）を加え、７０℃で１６時間攪拌した。反応液を放冷、酢酸エチルで希釈、水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し３３（１．００ｇ、３９％）を黄色結晶として得た。
ｍｐ１３９〜１４０℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．８４（１Ｈ、ｔ、Ｊ＝５．６Ｈｚ、Ｄ_２Ｏ消去）、２．３７（３Ｈ、ｓ）、２．４３（１Ｈ、ｍ）、３．５２〜３．６２（４Ｈ、ｍ）、３．７８〜３．８７（６Ｈ、ｍ）、４．２９（２Ｈ、ｄｄ、Ｊ＝５．２、１．０Ｈｚ）、６．３８（１Ｈ、ｄｄ、Ｊ＝１５．８、０．６Ｈｚ）、６．７６（１Ｈ、ｄｄ、Ｊ＝８．８、２．３Ｈｚ）、６．９０（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．２６（２Ｈ、ｄｄ、Ｊ＝８．６、０．５Ｈｚ）、７．３７（１Ｈ、ｔ、Ｊ＝０．６Ｈｚ）、７．４９（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．６８（１Ｈ、ｄｄ、Ｊ＝１５．８、０．８Ｈｚ）、７．７７（２Ｈ、ｄ、Ｊ＝８．２Ｈｚ）ＩＲ （Ｎｕｊｏｌ） ３４９０、１６３３ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ５７２［Ｍ＋Ｈ］^＋ THK-726 ((E) -6-[(3-hydroxy-2-tosyloxymethyl) propoxy] -2- [2- (2-morpholinothiazol-5-yl) ethenyl] benzoxazole): (33) Manufacturing of

No. 30 Preparation 4 (1.74 g, 11.67 mmol) in tetrahydrofuran (40 ml) was added 14 (2.05 g, 14.00 mmol) and triphenylphosphine (3.68 g, 14.00 mmol), and the mixture was stirred under ice cooling. A 40% diethyl azodicarboxylate / toluene solution (6.11 g, 14.00 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4/1) to obtain 30 (2.80 g, 87%) as a colorless solid.
APCI-MS m / z 278 [M + H] ⁺

Preparation of 31 To a solution of 30 (2.06 g, 7.43 mmol) and 3 (1.47 g, 7.43 mmol) in dimethyl sulfoxide (20 ml) with stirring at room temperature, 50% (w / w) aqueous sodium hydroxide solution (2.8 ml) ) And stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was collected by filtration, washed with water, and dried to obtain 31 (2.58 g, 76%) as yellow crystals.
mp 182.0-182.5 ° C., IR (Nujol) 1621 cm ⁻¹
APCI-MS m / z 458 [M + H] ⁺

To a suspension of No. 32 Preparation 31 (2.58 g, 5.64 mmol) in methanol (40 ml), 1N hydrochloric acid (11.3 ml, 11.3 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, the residue was dissolved in water / ethyl acetate, adjusted to pH 10 with potassium carbonate solution, and the layers were separated. Crystallization gave 32 (2.35 g, 100%) as yellow crystals.
mp 162.0-163 ° C., APCI-MS m / z 418 [M + H] ⁺

Preparation of 33 32 (1.85 g, 4.43 mmol) in ethylene glycol dimethyl ether (220 ml) suspension in triethylamine (0.93 ml, 6.65 mmol), toluenesulfonic anhydride (1.45 g, 4.43 mol), Dimethylaminopyridine (0.054 g, 0.44 mmol) was added and stirred at 70 ° C. for 16 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) and recrystallized from ethyl acetate 33 (1.00 g, 39% ) Was obtained as yellow crystals.
mp 139-140 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.84 (1H, t, J = 5.6 Hz, D ₂ O erased), 2.37 (3H, s), 2.43 (1H, m), 3.52 to 3.62 (4H, m), 3.78 to 3.87 (6H, m), 4.29 (2H, dd, J = 5.2, 1.0 Hz), 6. 38 (1H, dd, J = 15.8, 0.6 Hz), 6.76 (1H, dd, J = 8.8, 2.3 Hz), 6.90 (1H, d, J = 2.3 Hz) 7.26 (2H, dd, J = 8.6, 0.5 Hz), 7.37 (1H, t, J = 0.6 Hz), 7.49 (1H, d, J = 8.8 Hz), 7.68 (1H, dd, J = 15.8,0.8Hz), 7.77 (2H, d, J = 8.2Hz) IR (Nujol) 3490,1633cm -1 APCI-MS m / z572 [M + H] +

３５の製造
４（１．００ｇ、６．７０ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液に３４（１．４５ｇ、８．０５ｍｍｏｌ）、トリフェニルホスフィン（２．１１ｇ、８．０５ｍｍｏｌ）を加え、氷冷攪拌下４０％ジエチルアゾジカルボキシレート／トルエン溶液（３．５０ｇ、８．０５ｍｍｏｌ）を滴下し室温で４日間撹拌した。更に３４（１．４５ｇ、８．０５ｍｍｏｌ）、トリフェニルホスフィン（２．１１ｇ、８．０５ｍｍｏｌ）を加え、氷冷攪拌下４０％ジエチルアゾジカルボキシレート／トルエン溶液（３．５０ｇ、８．０５ｍｍｏｌ）を滴下し室温で１日間撹拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝４／１）で精製し３５（１．７１ｇ、８２％）を無色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ３１２［Ｍ＋Ｈ］^＋

３６の製造
３５（０．８０ｇ、２．５７ｍｍｏｌ）及び３（０．５１ｇ、２．５７ｍｍｏｌ）のジメチルスルホキシド（８ｍｌ）溶液に室温撹拌下５０％（ｗ／ｗ）水酸化ナトリウム水溶液（０．９６ｍｌ）を加え室温で１時間撹拌した。反応液に水を加え、ろ取、水洗、乾燥した。得られた粗結晶を酢酸エチル／ｎ−ヘキサンて゛再結晶し３６（０．７４ｇ、５９％）を黄色結晶として得た。
ｍｐ２０２〜２０３℃、ＩＲ（Ｎｕｊｏｌ）１６３７ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４９２［Ｍ＋Ｈ］^＋

３７の製造
３６（０．７４ｇ、１．５１ｍｍｏｌ）のメタノール（４０ｍｌ）懸濁液に１Ｎ塩酸（３．０１ｍｌ、３．０１ｍｍｏｌ）を加え７０℃１時間攪拌した。反応液を減圧溶媒留去、残渣を水（５ｍｌ）／トリエチルアミン（３ｍｌ）／酢酸エチルで加熱溶解、シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチル／ｎ−ヘキサンで再結晶し３７（０．５２ｇ、８５％）を黄色結晶として得た。
ｍｐ１７２〜１７４℃、ＡＰＣＩ−ＭＳ ｍ／ｚ４０４［Ｍ＋Ｈ］^＋

３８の製造
３７（１．３７ｇ、３．４０ｍｍｏｌ）のエチレングリコールジメチルエーテル（２００ｍｌ）懸濁液にトリエチルアミントルエン（０．７１ｍｌ、５．１０ｍｍｏｌ）、トルエンスルホン酸無水物（１．１１ｇ、３．４０ｍｏｌ）、ジメチルアミノピリジン（０．０４１ｇ、０．３４ｍｍｏｌ）を加え７０℃１６時間攪拌した。反応液を放冷、酢酸エチルで希釈、水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し３８（０．４２ｇ、２２％）を黄色結晶として得た。
ｍｐ１８４〜１８５℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２．０３（ｔ、Ｊ＝６．４Ｈｚ、Ｄ_２Ｏ消去）、２．４２（３Ｈ、ｓ）、３．５５〜３．６３（４Ｈ、ｍ）、３．８０〜３．９４（６Ｈ、ｍ）、４．２８（２Ｈ、ｄ、Ｊ＝４．９Ｈｚ）、４．４９〜４．５６（１Ｈ、ｍ）、６．３８（１Ｈ、ｄｄ、Ｊ＝１５．８、０．６Ｈｚ）、６．８４（１Ｈ、ｄｄ、Ｊ＝８．８、２．４Ｈｚ）、７．００（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．３０（２Ｈ、ｄｄ、Ｊ＝８．６、０．７Ｈｚ）、７．３７（１Ｈ、ｔ、Ｊ＝０．７Ｈｚ）、７．４８（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．６９（１Ｈ、ｄｄ、Ｊ＝１５．８、０．６Ｈｚ）、７．７６（２Ｈ、ｄ、Ｊ＝
８．２Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３３２０、１７３３、１６３２ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ５５８［Ｍ＋Ｈ］^＋ THK-703 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole): (38) Manufacturing of

35 preparation of 4 (1.00 g, 6.70 mmol) in tetrahydrofuran (30ml) was added 34 (1.45 g, 8.05 mmol), triphenylphosphine (2.11 g, 8.05 mmol) was added, stirring under cooling with ice A 40% diethylazodicarboxylate / toluene solution (3.50 g, 8.05 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 days. Further, 34 (1.45 g, 8.05 mmol) and triphenylphosphine (2.11 g, 8.05 mmol) were added, and a 40% diethylazodicarboxylate / toluene solution (3.50 g, 8.05 mmol) was stirred with ice cooling. Was added dropwise and stirred at room temperature for 1 day. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4/1) to obtain 35 (1.71 g, 82%) as a colorless solid.
APCI-MS m / z 312 [M + H] ⁺

Preparation 36 of 35 (0.80 g, 2.57 mmol) and 3 (0.51 g, 2.57 mmol) in dimethyl sulfoxide (8 ml) was stirred at room temperature with 50% (w / w) aqueous sodium hydroxide (0.96 ml). ) And stirred at room temperature for 1 hour. Water was added to the reaction solution, which was collected by filtration, washed with water and dried. The obtained crude crystals were recrystallized from ethyl acetate / n-hexane to obtain 36 (0.74 g, 59%) as yellow crystals.
mp 202-203 ° C., IR (Nujol) 1637 cm ⁻¹
APCI-MS m / z 492 [M + H] ⁺

1N hydrochloric acid (3.01 ml, 3.01 mmol) was added to a methanol (40 ml) suspension of 37 production 36 (0.74 g, 1.51 mmol), and the mixture was stirred at 70 ° C. for 1 hour. The reaction solution was evaporated under reduced pressure, the residue was heated and dissolved in water (5 ml) / triethylamine (3 ml) / ethyl acetate, purified by silica gel column chromatography (elution solvent: ethyl acetate), and recrystallized from ethyl acetate / n-hexane. 37 (0.52 g, 85%) was obtained as yellow crystals.
mp 172 ° -174 ° C., APCI-MS m / z 404 [M + H] ⁺

38 Preparation 37 (1.37 g, 3.40 mmol) in ethylene glycol dimethyl ether (200 ml) suspension in triethylamine toluene (0.71 ml, 5.10 mmol), toluenesulfonic anhydride (1.11 g, 3.40 mol) Dimethylaminopyridine (0.041 g, 0.34 mmol) was added and stirred at 70 ° C. for 16 hours. The reaction mixture was allowed to cool, diluted with ethyl acetate, washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) and recrystallized from ethyl acetate 38 (0.42 g, 22% ) Was obtained as yellow crystals.
mp 184-185 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.03 (t, J = 6.4 Hz, D ₂ O erased), 2.42 (3H, s), 3.55-3.63 ( 4H, m), 3.80 to 3.94 (6H, m), 4.28 (2H, d, J = 4.9 Hz), 4.49 to 4.56 (1H, m), 6.38 ( 1H, dd, J = 15.8, 0.6 Hz), 6.84 (1H, dd, J = 8.8, 2.4 Hz), 7.00 (1H, d, J = 2.4 Hz), 7 .30 (2H, dd, J = 8.6, 0.7 Hz), 7.37 (1H, t, J = 0.7 Hz), 7.48 (1H, d, J = 8.8 Hz), 7. 69 (1H, dd, J = 15.8, 0.6 Hz), 7.76 (2H, d, J =
8.2Hz)
IR (Nujol) 3320, 1733, 1632 cm ⁻¹
APCI-MS m / z 558 [M + H] ⁺

４０の製造
ジオール２２（３．７ｇ、１６．５７ｍｍｏｌ）をトルエン（１００ｍｌ）に加え、さらに２，２−ジメトキシプロパン３９（２．０８ｇ，２０ｍｍｏｌ），ｐ−トルエンスルホン酸（１００ｍｇ）を加えて加熱攪拌し９５℃にて１時間反応させた。反応終了後、酢酸エチルで希釈し、飽和炭酸水素ナトリウム溶液を加えて中和した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥。溶媒留去後、得られた粗生成物はへキサンージイソプロピルエーテル中で固化し、４０（３．１０ｇ、７１％）を無色結晶として得た。
ｍｐ６６−６８℃
ＩＲ（Ｎｕｊｏｌ）１６２１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ２６４［Ｍ＋Ｈ］^＋
１ＨＮＭＲ（ＣＤＣｌ_３） δ１．４６０（３Ｈ，ｓ）１．５０４（３Ｈ，ｓ）２．６０（３Ｈ，ｓ）３．９３（２Ｈ，ｄｄ）４．１３（２Ｈ，ｄｄ）４．３１−４．３９（１Ｈ，ｍ）６．９１（１Ｈ、ｄｄ、Ｊ＝１１．５Ｈｚ，Ｊ＝３．２Ｈｚ）７．０３（１Ｈ，ｄ、Ｊ＝３．２Ｈｚ）７．５１（１Ｈ，ｄ、Ｊ＝１１．５Ｈｚ）

４２の製造
アルデヒド４１（２ｇ、１２．８ｍｍｏｌ） とベンゾキサゾール誘導体４０ （３．３ｇ、１２．８ｍｍｏｌ）を溶解させたジメチルスルホキシド（３０ｍｌ）溶液に５０％水酸化ナトリウム水溶液（５ｍｌ）を滴下し、室温にて２時間攪拌反応させた。黄色の固体が析出した。反応液に水１００ｍｌを加え２０分程攪拌した後、黄色固体をろ取、水洗し、７０℃にて減圧乾燥し、４２（３．３４ｇ，６５％）を得た。
ｍｐ１６１〜１６３℃
ＩＲ（Ｎｕｊｏｌ）１６３５ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４０２［Ｍ＋Ｈ］＋

４３の製造
メタノール１２０ｍｌに４２（３．５２ｇ、８．８９ｍｍｏｌ）を加え、室温にて攪拌しながら１Ｎ 塩酸（１８ｍｌ）を滴下した。反応液はしばらく攪拌すると均一な透明溶液になった。２時間反応させた後、溶媒を減圧にて留去し、残渣を水に溶解し、続いて炭酸カリウム水溶液でアルカリ性にすると黄色の沈殿物が析出した。これをろ取し、水洗、減圧乾燥により４３（２．８２ｇ、８７．５％）を得た。
ｍｐ１９０〜１９２℃
ＩＲ（Ｎｕｊｏｌ）３２３６，１６２９ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ３６２［Ｍ＋Ｈ］^＋

４４の製造
ジオール４３（３．０ｇ、８．３ｍｍｏｌ）を無水ジメトキシエタン（１７０ｍｌ）に加え、更にｐ−トルエンスルホン酸無水物（２．７１ｇ、８．３ｍｍｏｌ）とジメチルアミノピリジン（９０ｍｇ），トリエチルアミン（１．３ｇ）を加えて攪拌、油浴にて加熱し、７０〜７５℃にて８ 時間反応させた。反応液を冷却し、不溶物をろ去し、ろ液を濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／２、１／４、酢酸エチル、酢酸エチル／メタノール＝１／１０）にて精製し、未反応の４３（１．４４ｇ、４８％）と４４（１．６４ｇ、３８％）を得た。
ｍｐ２０１〜２０２℃
ＩＲ（Ｎｕｊｏｌ）３２００，１６１７ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ：５１６［Ｍ＋Ｈ］^＋
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ２．３６０（３Ｈ，ｓ）３．１３１（６Ｈ，ｓ）３．５４−３．６２（２Ｈ，ｍ）４．１８−４．３３（２Ｈ，ｍ）４．５４（１Ｈ，ｂｒ）５．０６（１Ｈ，ｔ，Ｊ＝５．５Ｈｚ）６．３３（１Ｈ，ｄｄ，Ｊ＝１５．７Ｈｚ，Ｊ＝０．５４Ｈｚ）６．８４（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，２．４Ｈｚ）７．１８７（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）７．３９（（２Ｈ，ｄ）７．４８（２Ｈ，ｄ，Ｊ＝８．８Ｈｚ）７．６０（１Ｈ，ｓ）７．７２（１Ｈ，ｄ，Ｊ＝８．３Ｈｚ）７．７６（１Ｈ，ｄｄ，Ｊ＝１５．７Ｈｚ，Ｊ＝０．５４Ｈｚ）

４５の製造
トシレート４４（１．６ｇ、３．１ｍｍｏｌ）をテトラヒドロフラン（１５ｍｌ）に溶解させ、フッ化テトラｎ−ブチルアンモニウムのテトラヒドロフラン １モル溶液１５ｍｌ
（１５ｍｍｏｌ）を加えて攪拌、２時間加熱還流させた。反応終了後、反応液を酢酸エチルで希釈し、水洗、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥。溶媒留去後、得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／アセトン＝５／４）で分離精製し、４５（６６０ｍｇ）を得た。さらに酢酸エチルから再結晶し淡黄色結晶として４５（４９０ｍｇ、４４％）を得た。
ｍｐ１６４−１６５℃
ＩＲ（Ｎｕｊｏｌ）３１７３，１６３３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ３６４［Ｍ＋Ｈ］^＋
１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ３．１２７（６Ｈ，ｓ）３．６１−３．６７（２Ｈ，ｍ）４．５４−４．８２（３Ｈ，ｓ）５．０６（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ）６．３３（１Ｈ，ｄｄ，Ｊ＝１５．７５Ｈｚ，Ｊ＝０．５４Ｈｚ）６．９９（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，Ｊ＝２．４Ｈｚ）７．３６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）７．５３（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ）７．５９（１Ｈ，ｂｒ，ｓ）７．７５（１Ｈ，ｄｄ，Ｊ＝１５．７５Ｈｚ，Ｊ＝０．５４Ｈｚ）７．５３（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ）７．５９（１Ｈ，ｂｒ，ｓ）７．７５（１Ｈ，ｄｄ，Ｊ＝１５．７５Ｈｚ，Ｊ＝０．５４Ｈｚ） THK-762 ((E) -6- [2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole): (44 ),as well as
THK-763 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole): (45 )Manufacturing of

Preparation of 40 Diol 22 (3.7 g, 16.57 mmol) was added to toluene (100 ml), followed by 2,2-dimethoxypropane 39 (2.08 g, 20 mmol), p-toluenesulfonic acid (100 mg). And heated and stirred and reacted at 95 ° C. for 1 hour. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and neutralized with a saturated sodium bicarbonate solution. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After distilling off the solvent, the obtained crude product was solidified in hexane-diisopropyl ether to obtain 40 (3.10 g, 71%) as colorless crystals.
mp66-68 ° C
IR (Nujol) 1621 cm ⁻¹
APCI-MS m / z 264 [M + H] ^+
1 HNMR (CDCl ₃ ) δ 1.460 (3H, s) 1.504 (3H, s) 2.60 (3H, s) 3.93 (2H, dd) 4.13 (2H, dd) 4.31- 4.39 (1H, m) 6.91 (1H, dd, J = 11.5 Hz, J = 3.2 Hz) 7.03 (1H, d, J = 3.2 Hz) 7.51 (1H, d, J = 11.5Hz)

Preparation of 42 50% aqueous sodium hydroxide solution (5 ml) was added to a solution of aldehyde 41 (2 g, 12.8 mmol) and benzoxazole derivative 40 (3.3 g, 12.8 mmol) in dimethyl sulfoxide (30 ml). ) Was added dropwise, and the mixture was stirred at room temperature for 2 hours. A yellow solid precipitated out. After adding 100 ml of water to the reaction solution and stirring for about 20 minutes, a yellow solid was collected by filtration, washed with water, and dried under reduced pressure at 70 ° C. to obtain 42 (3.34 g, 65%).
mp 161-163 ° C
IR (Nujol) 1635 cm ⁻¹
APCI-MS m / z 402 [M + H] +

Preparation of 43 42 (3.52 g, 8.89 mmol) was added to 120 ml of methanol, and 1N hydrochloric acid (18 ml) was added dropwise with stirring at room temperature. The reaction solution became a homogeneous transparent solution when stirred for a while. After reacting for 2 hours, the solvent was distilled off under reduced pressure, the residue was dissolved in water, and then made alkaline with an aqueous potassium carbonate solution, whereby a yellow precipitate was deposited. This was collected by filtration, washed with water, and dried under reduced pressure to obtain 43 (2.82 g, 87.5%).
mp 190-192 ° C
IR (Nujol) 3236, 1629 cm ⁻¹
APCI-MS m / z 362 [M + H] ⁺

Preparation of 44 Diol 43 (3.0 g, 8.3 mmol) was added to anhydrous dimethoxyethane (170 ml), and p-toluenesulfonic anhydride (2.71 g, 8.3 mmol) and dimethylaminopyridine ( 90 mg) and triethylamine (1.3 g) were added, and the mixture was stirred and heated in an oil bath, and reacted at 70 to 75 ° C. for 8 hours. The reaction mixture is cooled, insolubles are removed by filtration, and the filtrate is concentrated to give a crude product. The crude product is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/2, 1/4, acetic acid). Purification with ethyl, ethyl acetate / methanol = 1/10) gave unreacted 43 (1.44 g, 48%) and 44 (1.64 g, 38%).
mp 201-202 ° C
IR (Nujol) 3200, 1617 cm ⁻¹
APCI-MS m / z: 516 [M + H] ^+
1 H-NMR (DMSO-d ₆ ) δ 2.360 (3H, s) 3.131 (6H, s) 3.54-3.62 (2H, m) 4.18-4.33 (2H, m) 4.54 (1H, br) 5.06 (1H, t, J = 5.5 Hz) 6.33 (1H, dd, J = 15.7 Hz, J = 0.54 Hz) 6.84 (1H, dd, J = 8.8 Hz, 2.4 Hz) 7.187 (1H, d, J = 2.4 Hz) 7.39 ((2H, d) 7.48 (2H, d, J = 8.8 Hz) 7.60 (1H, s) 7.72 (1H, d, J = 8.3 Hz) 7.76 (1H, dd, J = 15.7 Hz, J = 0.54 Hz)

Preparation of 45 Tosylate 44 (1.6 g, 3.1 mmol) was dissolved in tetrahydrofuran (15 ml), and tetra-n-butylammonium fluoride in 1 mol tetrahydrofuran solution 15 ml.
(15 mmol) was added, and the mixture was stirred and heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was separated and purified by silica gel column chromatography (elution solvent: n-hexane / acetone = 5/4) to obtain 45 (660 mg). Further, recrystallization from ethyl acetate gave 45 (490 mg, 44%) as pale yellow crystals.
mp164-165 ° C
IR (Nujol) 3173, 1633 cm ⁻¹
APCI-MS m / z 364 [M + H] ^+
1 H-NMR (DMSO-d ₆ ) δ 3.127 (6H, s) 3.61-3.67 (2H, m) 4.54-4.82 (3H, s) 5.06 (1H, t, J = 5.7 Hz) 6.33 (1H, dd, J = 15.75 Hz, J = 0.54 Hz) 6.99 (1H, dd, J = 8.8 Hz, J = 2.4 Hz) 7.36 ( 1H, d, J = 2.4 Hz) 7.53 (1H, d, J = 8.6 Hz) 7.59 (1H, br, s) 7.75 (1H, dd, J = 15.75 Hz, J = 0.54 Hz) 7.53 (1 H, d, J = 8.6 Hz) 7.59 (1 H, br, s) 7.75 (1 H, dd, J = 15.75 Hz, J = 0.54 Hz)

４７の製造
４６（１０．０ｇ、９９．９ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に（Ｂｏｃ）２Ｏ（２７．５ｍｌ、１１９．９ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応液の溶媒を減圧留去、得られた結晶にｎ−ヘキサンを加えて粉砕し４７（１９．２５ｇ、９６％）を無色結晶として得た。
ｍｐ１８１．５〜１８２．５℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．６０（９Ｈ、ｓ）、６．８８（１Ｈ、ｄ、Ｊ＝３．７Ｈｚ）、７．３８（１Ｈ、ｄ、Ｊ＝３．７Ｈｚ）、１１．９（１Ｈ、ｓ）
ＩＲ（Ｎｕｊｏｌ）１７１３ ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ２０１［Ｍ＋Ｈ］＋

４８の製造
４７（１０．０ｇ、４９．９ｍｍｏｌ）のテトラヒドロフラン（１００ｍｌ）溶液に０℃攪拌下、ｔ−ブトキシカリウム（６．７２ｇ、５９．９ｍｍｏｌ）を加え、同温で１０分攪拌、ヨードメタン（４．６６ｍｌ、７４．９ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応液の不溶物をろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝９／１）で精製し４８（６．５３ｇ、６１％）を無色固体として得た。
ｍｐ５１〜５２℃、^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−Ｄ_６）δ １．５３（９Ｈ、ｓ）、３．４７（３Ｈ、ｓ）、７．２５（１Ｈ、ｄ、Ｊ＝３．５Ｈｚ）、７．４５（１Ｈ、ｄ、Ｊ＝３．５Ｈｚ）、ＩＲ（Ｎｅａｔ）１７３４ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ２１５［Ｍ＋Ｈ］^＋

４９の製造
ジイソプロピルアミン（５．１２ｍｌ、３６．４ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液に、アルゴン雰囲気下、−６０℃以下で１．５８Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（２３．０ｍｌ、３６．４ｍｍｏｌ）を滴下、除々に０℃まで昇温した。次に−７０℃以下で４８（７．０８ｇ、３３．１ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を滴下し、−７８℃で１ 時間撹拌した。同温で、Ｎ−ホルミルモルホリン（４．９８ｍｌ、４９．６ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を一度に加え、同温で３０分撹拌した。反応液に冷水を加え、酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝４／１）で精製し４９（６．４０ｇ、８０％）を黄色固体として得た。
ｍｐ８０〜８１℃、 ^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−Ｄ_６）δ １．５５（９Ｈ、ｓ）、３．５２（３Ｈ、ｓ）、８．３８（１Ｈ、ｓ）、９．９０（１Ｈ、ｓ）
ＩＲ（Ｎｕｊｏｌ）１７１４、１６５９ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ２４３［Ｍ＋Ｈ］^＋

５０の製造
ジイソプロピルアミン（０．９０ｍｌ、６．３６ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液に、アルゴン雰囲気下、−６０℃以下で１．５７Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（４．０５ｍｌ、６．３６ｍｍｏｌ）を滴下、除々に０℃まで昇温した。次に−７０℃以下で２６（１．４４ｇ、４．２４ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を滴下し、−７８℃で１ 時間撹拌した。同温で、４９（１．２３ｇ、５．０９ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を一度に加え、同温で３０分撹拌した。反応液に冷水を加え、酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝２／１）で精製し５０（２．０６ｇ、８４％）を淡黄色粘体物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ５８２［Ｍ＋Ｈ］^＋

５１の製造
５０（２．０６ｇ、３．５４ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液にトリエチルアミン（１．９８ｍｌ、１４．１６ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．６０ｍｌ、７．７９ｍｍｏｌ）を滴下し室温で１時間撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝４／１）で精製し５１（１．８５ｇ、９３％）を淡黄色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ５６４［Ｍ＋Ｈ］^＋

５２の製造
５１（１．８５ｇ、３．２８ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に氷冷攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（３．２８ｍｌ、３．２８ｍｍｏｌ）を滴下し室温で１時間攪拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１〜１／１）で精製、酢酸エチルで再結晶し５２（１．０２ｇ、６９％）を黄色結晶として得た。
ｍｐ１８１．０〜１８１．５℃、ＩＲ （Ｎｕｊｏｌ） ３３５２、１７００、１６３１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４５０［Ｍ＋Ｈ］^＋

５３の製造
５２（１．１３ｇ、２．５１ｍｍｏｌ）のジクロロメタン（１８ｍｌ）懸濁液に氷冷攪拌下トリフルオロ酢酸（１２ｍｌ）を滴下し室温で１時間２０分攪拌した。反応液に冷水を加え酢酸エチルで希釈、炭酸カリウム液でｐＨ＝９とし、分液後抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し５３（０．７２ｇ、８２％）を黄色結晶として得た。
ｍｐ１７８〜１７９℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ３．０６（３Ｈ、ｓ）、３．８９〜４．０１（２Ｈ、ｍ）、４．５０〜４．７８（３Ｈ、ｍ）、５．５０（１Ｈ、ｍ、Ｄ_２Ｏ消去）、６．３８（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、６．９９（１Ｈ、ｄｄ、Ｊ＝８．７、２．４Ｈｚ）、７．１４（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．３２（１Ｈ、ｓ）、７．５５（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６９（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３２３１、１６３１ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ３５０［Ｍ＋Ｈ］^＋ THK-761 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole): (53) Manufacturing of

(Boc) 2 O (27.5 ml, 119.9 mmol) was added to a solution of 47 (46) (10.0 g, 99.9 mmol) in tetrahydrofuran (20 ml), and the mixture was stirred at room temperature for 16 hours. The solvent of the reaction solution was distilled off under reduced pressure, and n-hexane was added to the obtained crystals and pulverized to obtain 47 (19.25 g, 96%) as colorless crystals.
mp 181.5-182.5 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.60 (9H, s), 6.88 (1H, d, J = 3.7 Hz), 7.38 (1H, d , J = 3.7 Hz), 11.9 (1H, s)
IR (Nujol) 1713 cm ⁻¹ , APCI-MS m / z 201 [M + H] +

48 Preparation 47 To a solution of 47 (10.0 g, 49.9 mmol) in tetrahydrofuran (100 ml) was added t-butoxypotassium (6.72 g, 59.9 mmol) with stirring at 0 ° C., and the mixture was stirred at the same temperature for 10 min. 4.66 ml, 74.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. Insolubles in the reaction solution were filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 9/1) to purify 48 (6.53 g, 61%) as a colorless solid. Got as.
mp 51-52 ° C., ¹ H NMR (500 MHz, DMSO-D ₆ ) δ 1.53 (9H, s), 3.47 (3H, s), 7.25 (1H, d, J = 3.5 Hz), 7.45 (1H, d, J = 3.5 Hz), IR (Neat) 1734 cm ⁻¹ , APCI-MS m / z 215 [M + H] ⁺

Preparation of 49 To a solution of diisopropylamine (5.12 ml, 36.4 mmol) in tetrahydrofuran (50 ml) under an argon atmosphere at −60 ° C. or lower, a 1.58 M n-butyllithium / n-hexane solution (23. 0 ml, 36.4 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 48 (7.08 g, 33.1 mmol) in tetrahydrofuran (10 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. At the same temperature, a solution of N-formylmorpholine (4.98 ml, 49.6 mmol) in tetrahydrofuran (10 ml) was added in one portion and stirred at the same temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain 49 (6.40 g, 80%) as a yellow solid.
mp 80-81 ° C., ¹ H NMR (500 MHz, DMSO-D ₆ ) δ 1.55 (9H, s), 3.52 (3H, s), 8.38 (1H, s), 9.90 (1H, s)
IR (Nujol) 1714, 1659 cm ⁻¹ , APCI-MS m / z 243 [M + H] ⁺

Preparation of 50 To a solution of diisopropylamine (0.90 ml, 6.36 mmol) in tetrahydrofuran (30 ml) under an argon atmosphere at −60 ° C. or lower, a 1.57 M n-butyllithium / n-hexane solution (4. 05 ml, 6.36 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 26 (1.44 g, 4.24 mmol) in tetrahydrofuran (20 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. At the same temperature, a solution of 49 (1.23 g, 5.09 mmol) in tetrahydrofuran (20 ml) was added in one portion and stirred at the same temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to give 50 (2.06 g, 84%) as a pale yellow viscous product. .
APCI-MS m / z 582 [M + H] ⁺

Triethylamine (1.98 ml, 14.16 mmol) was added to a solution of 51 (50 ml, 2.06 g, 3.54 mmol) in dichloromethane (20 ml), and methanesulfonyl chloride (0.60 ml, 7.79 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 1 hour. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to obtain 51 (1.85 g, 93%) as a pale yellow solid.
APCI-MS m / z 564 [M + H] ⁺

No. 52 Preparation 51 (1.85 g, 3.28 mmol) in tetrahydrofuran (20 ml) was added dropwise with 1M tetrabutylammonium fluoride / tetrahydrofuran solution (3.28 ml, 3.28 mmol) under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 hour. did. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 to 1/1) and recrystallized with ethyl acetate 52 (1. 02 g, 69%) was obtained as yellow crystals.
mp 181.0-181.5 ° C, IR (Nujol) 3352, 1700, 1631 cm ^-1
APCI-MS m / z 450 [M + H] ⁺

To a suspension of 53 (52) (1.13 g, 2.51 mmol) in dichloromethane (18 ml), trifluoroacetic acid (12 ml) was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 1 hour and 20 minutes. Add cold water to the reaction solution, dilute with ethyl acetate, adjust to pH = 9 with potassium carbonate solution, wash the extract with water, dry, evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (elution solvent: ethyl acetate). Recrystallization from ethyl acetate gave 53 (0.72 g, 82%) as yellow crystals.
mp 178-179 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.06 (3H, s), 3.89-4.01 (2H, m), 4.50-4.78 (3H, m), 5.50 (1H, m, D ₂ O erased), 6.38 (1H, d, J = 15.7 Hz), 6.99 (1H, dd, J = 8.7, 2.4 Hz), 7. 14 (1H, d, J = 2.4 Hz), 7.32 (1H, s), 7.55 (1H, d, J = 8.7 Hz), 7.69 (1H, d, J = 15.7 Hz) )
IR (Nujol) 3231, 1631 cm ⁻¹ , APCI-MS m / z 350 [M + H] ⁺

５４の製造
２２（５．５１ｇ、２４．６８ｍｍｏｌ）のジメチルホルムアミド（５０ｍｌ）溶液にイミダゾール（４．０３ｇ、５９．２４ｍｍｏｌ）を加え、室温攪拌下ｔ−ブチルジメチルシリルクロライド（８．９３ｇ、５９．２４ｍｍｏｌ）を加え室温２時間攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝５０／１〜２０／１）で精製し５４（１１．２ｇ、１００％）を無色油状物として得た。

５５の製造
ジイソプロピルアミン（２．３８ｍｌ、１６．９１ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液に、アルゴン雰囲気下、−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（１０．６３ｍｌ、１６．９１ｍｍｏｌ）を滴下、除々に０℃まで昇温した。次に−７０℃以下で５４（５．０９ｇ、１１．２７ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液を滴下し、−７８℃で１ 時間撹拌した。同温で、４９（２．７３ｇ、１１．２７ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液を一度に加え、同温で３０分撹拌した。反応液に冷水を加え、酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝４／１〜３／１）で精製し５５（６．９０ｇ、８８％）を黄色粘体物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ６９５［Ｍ＋Ｈ］^＋

５６の製造
５５（６．９０ｇ、９．９４ｍｍｏｌ）のジクロロメタン（７０ｍｌ）溶液にトリエチルアミン（５．５５ｍｌ、３９．８ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（１．６９ｍｌ、２１．９ｍｍｏｌ）を滴下し室温で５０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（ｎ−ヘキサン／酢酸エチル＝９／１）
で精製し５５（６．２０ｇ、９２％）を淡黄色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ６７７［Ｍ＋Ｈ］^＋

５７の製造
５６（６．２０ｇ、９．１７ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１８．３４ｍｌ、１８．３４ｍｍｏｌ）を加え室温１時間した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残さをシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／１〜酢酸エチル）で精製、酢酸エチルで再結晶し５７（３．２１ｇ、７８％）を黄色結晶として得た。
ｍｐ１８０〜１８１℃、ＡＰＣＩ−ＭＳ ｍ／ｚ４４８［Ｍ＋Ｈ］^＋

５８の製造
５７（３．２１ｇ、７．１７ｍｍｏｌ）のエチレングリコールジメチルエーテル（２００ｍｌ）懸濁液にトリエチルアミン（１．５０ｍｌ、１０．８ｍｍｏｌ）、トルエンスルホン酸無水物（２．３４ｇ、７．１７ｍｏｌ）、ジメチルアミノピリジン（０．０８８ｇ、０．７２ｍｍｏｌ）を加え、還流２４時間した。反応液を放冷、酢酸エチルで希釈、水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１〜酢酸エチル）で精製、酢酸エチルで再結晶し５８（１．６５ｇ、３８％）を黄色結晶として得た。
ｍｐ１０８〜１０９℃、ＡＰＣＩ−ＭＳ ｍ／ｚ６０２［Ｍ＋Ｈ］^＋

５９の製造
５８（０．７８ｇ、１．３０ｍｍｏｌ）のジクロロメタン（１８ｍｌ）懸濁液に氷冷攪拌下トリフルオロ酢酸（１２ｍｌ）を滴下し室温で１時間１５分攪拌した。反応液に冷水を加え酢酸エチルで希釈、炭酸カリウム液でｐＨ＝９とし、分液後抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し５９（０．５２ｇ、７９％）を黄色結晶として得た。
ｍｐ１７４．５〜１７５．５℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２．３６（３Ｈ、ｓ）、２．８９（３Ｈ、ｄ、Ｊ＝４．６Ｈｚ、Ｄ_２Ｏ、ｓ）、３．５３〜３．６４（２Ｈ、ｍ）、４．１９〜４．３３（２Ｈ、ｍ）、４．５４（１Ｈ、ｍ）、５．０６（１Ｈ、ｔ、Ｊ＝５．６Ｈｚ、Ｄ_２Ｏ消去）、６．２９（１Ｈ、ｄ、Ｊ＝１５．８Ｈｚ）、６．８４（１Ｈ、ｄｄ、Ｊ＝８．７、２．３Ｈｚ）、７．１８（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．３９（２Ｈ、ｄ、Ｊ＝８．１Ｈｚ）、７．４８（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．５２（１Ｈ、ｓ）、７．７３（２Ｈ、ｄ、Ｊ＝８．１Ｈｚ）７．７５（１Ｈ、ｄ、Ｊ＝１５．８Ｈｚ）、８．２７（１Ｈ、ｑ、Ｊ＝４．６Ｈｚ、Ｄ_２Ｏ消去）、ＩＲ （Ｎｕｊｏｌ） ３２２７、１６３４、１６２１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ５０２［Ｍ＋Ｈ］^＋ THK-760 ((E) -6-[(2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole): (59 )Manufacturing of

54 was added to a dimethylformamide (50 ml) solution of 22 (5.51 g, 24.68 mmol) in dimethylformamide (4.03 g, 59.24 mmol), and t-butyldimethylsilyl chloride (8.93 g, 59.24 mmol) was stirred at room temperature. 24 mmol) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 50/1 to 20/1) to obtain 54 (11.2 g, 100%). Obtained as a colorless oil.

Preparation of 55 To a solution of diisopropylamine (2.38 ml, 16.91 mmol) in tetrahydrofuran (50 ml) under an argon atmosphere at −60 ° C. or lower, a 1.59 M n-butyllithium / n-hexane solution (10. 63 ml, 16.91 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 54 (5.09 g, 11.27 mmol) in tetrahydrofuran (30 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. At the same temperature, a solution of 49 (2.73 g, 11.27 mmol) in tetrahydrofuran (30 ml) was added all at once, and the mixture was stirred at the same temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1 to 3/1) to obtain 55 (6.90 g, 88%) as a yellow viscous product. Got as.
APCI-MS m / z 695 [M + H] ⁺

56 Preparation 56 (6.90 g, 9.94 mmol) in dichloromethane (70 ml) was added triethylamine (5.55 ml, 39.8 mmol), and methanesulfonyl chloride (1.69 ml, 21.9 mmol) was added with stirring under ice cooling. The solution was added dropwise and stirred at room temperature for 50 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate = 9/1).
To give 55 (6.20 g, 92%) as a pale yellow solid.
APCI-MS m / z 677 [M + H] ⁺

A 1 M tetrabutylammonium fluoride / tetrahydrofuran solution (18.34 ml, 18.34 mmol) was added to a solution of 57 (56 ml, 6.20 g, 9.17 mmol) in tetrahydrofuran (60 ml) at room temperature with stirring at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1 to ethyl acetate) and recrystallized with ethyl acetate 57 (3.21 g). 78%) as yellow crystals.
mp 180-181 ° C., APCI-MS m / z 448 [M + H] ⁺

Preparation of 58 57 (3.21 g, 7.17 mmol) in ethylene glycol dimethyl ether (200 ml) suspension in triethylamine (1.50 ml, 10.8 mmol), toluenesulfonic anhydride (2.34 g, 7.17 mol), Dimethylaminopyridine (0.088 g, 0.72 mmol) was added and refluxed for 24 hours. The reaction mixture is allowed to cool, diluted with ethyl acetate, washed with water, dried, evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 to ethyl acetate), and ethyl acetate is added. Recrystallization gave 58 (1.65 g, 38%) as yellow crystals.
mp 108-109 ° C., APCI-MS m / z 602 [M + H] ⁺

To a suspension of No. 59, 58 (0.78 g, 1.30 mmol) in dichloromethane (18 ml), trifluoroacetic acid (12 ml) was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature for 1 hour and 15 minutes. Add cold water to the reaction solution, dilute with ethyl acetate, adjust to pH = 9 with potassium carbonate solution, wash the extract with water, dry, distill off the solvent under reduced pressure, and purify the residue by silica gel column chromatography (elution solvent: ethyl acetate). Recrystallization from ethyl acetate gave 59 (0.52 g, 79%) as yellow crystals.
mp 174.5-175.5 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.36 (3H, s), 2.89 (3H, d, J = 4.6 Hz, D ₂ O, s), 3 .53 to 3.64 (2H, m), 4.19 to 4.33 (2H, m), 4.54 (1H, m), 5.06 (1H, t, J = 5.6 Hz, D ₂ O elimination), 6.29 (1H, d, J = 15.8 Hz), 6.84 (1H, dd, J = 8.7, 2.3 Hz), 7.18 (1H, d, J = 2. 3 Hz), 7.39 (2H, d, J = 8.1 Hz), 7.48 (1H, d, J = 8.7 Hz), 7.52 (1H, s), 7.73 (2H, d, J = 8.1 Hz) 7.75 (1H, d, J = 15.8 Hz), 8.27 (1H, q, J = 4.6 Hz, D ₂ O erased), IR (Nujol) 3227, 1 634, 1621 cm ^-1
APCI-MS m / z 502 [M + H] ⁺

６０の製造
１（１５．０ｇ ９１．４５ｍｍｏｌ）のピペリジン（７０ｍｌ）溶液を１００℃で２．５時間攪拌した。反応液を放冷、不溶物をろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝９／１）で精製し６０（１５．３９ｇ、１００％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １６９［Ｍ＋Ｈ］^＋

６１の製造
ジイソプロピルアミン（１５．４７ｍｌ、１０９．７ｍｍｏｌ）のテトラヒドロフラン（２００ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（６９．０ｍｌ、１０９．７ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で６０（１５．３９ｇ，９１．４５ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）溶液を滴下し−７８℃で１ 時間撹拌した。同温で、ジメチルホルムアミド（１４．１５ｍｌ、１８２．９ｍｍｏｌ）を一度に加え同温で４０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し６１（１７．５５ｇ、９８％）を淡黄色固体として得た。
ｍｐ ５８〜５９℃、ＡＰＣＩ−ＭＳ ｍ／ｚ １９７［Ｍ＋Ｈ］^＋

６２の製造
４（０．５３ｇ、３．５５ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に１８（０．７９ｇ、３．５５ｍｍｏｌ）、トリフェニルホスフィン（０．９３ｇ、３．５５ｍｍｏｌ）を加え、氷冷攪拌下４０％ジエチルアゾジカルボキシレート／トルエン溶液（１．５５ｇ、３．５５ｍｍｏｌ）を滴下し室温で３日撹拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し６２（１．１２ｇ、８９％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ３５４［Ｍ＋Ｈ］^＋

６３の製造
ジイソプロピルアミン（０．６７ｍｌ、４．７５ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５７Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（３．０３ｍｌ、４．７５ｍｍｏｌ）を滴下し、除々に０℃まで昇温した。次に−７０℃以下で６２（１．１２ｇ、３．１７ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で、６１（０．７５ｇ、３．８０ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液を一度に加え、同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１．５／１）で精製し６３（１．５０ｇ、８６％）を黄色粘体物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５５０［Ｍ＋Ｈ］^＋

６４の製造
６３（１．５０ｇ、２．７３ｍｍｏｌ）のジクロロメタン（３０ｍｌ）溶液にトリエチルアミン（１．５２ｍｌ、１０．９ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．４６ｍｌ、６．００ｍｍｏｌ）を滴下し室温で２０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し６４（１．３１ｇ、９０％）を黄色固体として得た。
ｍｐ ９６〜９８℃、ＩＲ （Ｎｕｊｏｌ） １６２８ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ５３２［Ｍ＋Ｈ］^＋

６５の製造
６４（１．３１ｇ、２．４６ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（２．４６ｍｌ、２．４６ｍｍｏｌ）を加え室温で４０分した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残さをシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１〜１／１）で精製、酢酸エチルで再結晶し６５（０．６８ｇ、６６％）を黄色結晶として得た。
ｍｐ １６９〜１７０℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．７２（６Ｈ、ｓ）、２．３８〜２．５３（１Ｈ、ｍ）、３．６２（４Ｈ、ｓ）、３．９１（２Ｈ、ｄ、Ｊ＝５．７Ｈｚ）、４．１６（２Ｈ、ｄｄ、Ｊ＝５．８、０．５Ｈｚ）、４．７１（２Ｈ、ｄｄ、Ｊ＝４７．０、５．３Ｈｚ）、６．３５（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、６．９１（１Ｈ、ｄｄ、Ｊ＝８．７、２．３Ｈｚ）、７．０３（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．３５（１Ｈ、ｓ）、７．５２（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６４（１Ｈ、ｄｄ、Ｊ＝１５．７Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３３４３、１６２３ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４１８［Ｍ＋Ｈ］^＋ THK-711 ((E) -6-[(2-fluoromethyl-3-hydroxy) propoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole): (65 )Manufacturing of

A solution of 60 Preparation 1 (15.0 g 91.45 mmol) in piperidine (70 ml) was stirred at 100 ° C. for 2.5 hours. The reaction mixture was allowed to cool, insolubles were filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9/1) to give 60 (15.39 g, 100%) as a colorless oil.
APCI-MS m / z 169 [M + H] ⁺

Preparation of 61 To a solution of diisopropylamine (15.47 ml, 109.7 mmol) in tetrahydrofuran (200 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.59 M n-butyllithium / n-hexane solution (69. 0 ml, 109.7 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 60 (15.39 g, 91.45 mmol) in tetrahydrofuran (40 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. At the same temperature, dimethylformamide (14.15 ml, 182.9 mmol) was added all at once and stirred at the same temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 61 (17.55 g, 98%) as a pale yellow solid. Obtained.
mp 58-59 ° C., APCI-MS m / z 197 [M + H] ⁺

18 (0.79 g, 3.55 mmol) and triphenylphosphine (0.93 g, 3.55 mmol) were added to a tetrahydrofuran (20 ml) solution of Preparation 4 of 62 (0.53 g, 3.55 mmol), and the mixture was stirred under ice-cooling. A 40% diethyl azodicarboxylate / toluene solution (1.55 g, 3.55 mmol) was added dropwise, and the mixture was stirred at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 62 (1.12 g, 89%) as a pale yellow oil.
APCI-MS m / z 354 [M + H] ⁺

Preparation of 63 To a solution of diisopropylamine (0.67 ml, 4.75 mmol) in tetrahydrofuran (20 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.57 M n-butyllithium / n-hexane solution (3. 03 ml, 4.75 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 62 (1.12 g, 3.17 mmol) in tetrahydrofuran (10 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. At the same temperature, a solution of 61 (0.75 g, 3.80 mmol) in tetrahydrofuran (10 ml) was added all at once, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1.5 / 1) to give 63 (1.50 g, 86%) as a yellow viscous body Obtained as a thing.
APCI-MS m / z 550 [M + H] ⁺

Triethylamine (1.52 ml, 10.9 mmol) was added to a dichloromethane (30 ml) solution of 63 (1.50 g, 2.73 mmol) of 64, and methanesulfonyl chloride (0.46 ml, 6.00 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 20 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 64 (1.31 g, 90%) as a yellow solid. It was.
mp 96-98 ° C., IR (Nujol) 1628 cm ⁻¹
APCI-MS m / z 532 [M + H] ⁺

To a solution of 65, 64 (1.31 g, 2.46 mmol) in tetrahydrofuran (20 ml), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (2.46 ml, 2.46 mmol) was added with stirring at room temperature, and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 to 1/1) and recrystallized with ethyl acetate 65 (0. 68 g, 66%) was obtained as yellow crystals.
mp 169-170 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72 (6H, s), 2.38-2.53 (1H, m), 3.62 (4H, s), 3.91 (2H, d, J = 5.7 Hz), 4.16 (2H, dd, J = 5.8, 0.5 Hz), 4.71 (2H, dd, J = 47.0, 5.3 Hz), 6.35 (1H, d, J = 15.7 Hz), 6.91 (1H, dd, J = 8.7, 2.3 Hz), 7.03 (1H, d, J = 2.3 Hz), 7 .35 (1H, s), 7.52 (1H, d, J = 8.7 Hz), 7.64 (1H, dd, J = 15.7 Hz)
IR (Nujol) 3343, 1623 cm ⁻¹ , APCI-MS m / z 418 [M + H] ⁺

６６の製造
３０（１．５０ｇ、５．４１ｍｍｏｌ）及び６１（１．０６ｇ、 ５．４１ｍｍｏｌ）のジメチルスルホキシド（１４．２ｍｌ）溶液に室温撹拌下５０％（ｗ／ｗ）水酸化ナトリウム水溶液（２．０３ ｍｌ）を加え室温で１．５時間撹拌した。反応液に水を加え、ろ取、水洗、乾燥、粗結晶を酢酸エチルで再結晶し６６（１．２６ｇ、５１％）を黄色結晶として得た。
ｍｐ １５１．０〜１５１．５℃、ＩＲ（Ｎｕｊｏｌ）１６０１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４５６［Ｍ＋Ｈ］^＋

６７の製造
６６（１．２６ｇ、２．７７ｍｍｏｌ）のメタノール（３０ｍｌ）懸濁液に１Ｎ塩酸（５．５３ｍｌ、５．５３ｍｍｏｌ）を加え室温１時間攪拌した。反応液を減圧溶媒留去、残渣を水／酢酸エチルで溶解、炭酸カリウム溶液でｐＨ１０とし、分液後、有機層を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチルで再結晶し６７（１．０９ｇ、９５％）を黄色結晶として得た。
ｍｐ １７０〜１７１℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ４１６［Ｍ＋Ｈ］^＋

６８の製造
６７（１．０９ｇ、２．６２ｍｍｏｌ）のエチレングリコールジメチルエーテル（１００ｍｌ）懸濁液にトリエチルアミン（０．５５ｍｌ、３．９３ｍｍｏｌ）、トルエンスルホン酸無水物（０．８６ｇ、２．６２ｍｏｌ）、ジメチルアミノピリジン（０．０３２ｇ、０．２６ｍｍｏｌ）を加え、７０℃１６時間攪拌した。反応液を放冷後、酢酸エチルで希釈し、水洗、乾燥、減圧溶媒留去の操作後、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／２〜酢酸エチル）で精製、酢酸エチルで再結晶し６８（０．７６ｇ、５１％）を黄色結晶として得た。
ｍｐ １４９〜１５０℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．７２（６Ｈ、ｍ）、２．３７（３Ｈ、ｓ）、２．４１（１Ｈ、ｍ）、３．６３（４Ｈ、ｍ）、３．８３（２Ｈ、ｄ、Ｊ＝５．７Ｈｚ）、４．０２（２Ｈ、ｄｄ、Ｊ＝５．８、４．３Ｈｚ）、６．３５（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、６．７７（１Ｈ、ｄｄ、Ｊ＝８．８、２．４Ｈｚ）、６．９０（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．２４〜７．２８（２Ｈ、ｍ）、７．３６（１Ｈ、ｓ）、７．４９（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．６４（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、７．６６〜７．７９（２Ｈ、ｍ）
ＩＲ （Ｎｕｊｏｌ） ３２９８、１６３０ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ５７０［Ｍ＋Ｈ］^＋ THK-710 ((E) -6-[(3-hydroxy-2-tosyloxymethyl) propoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole): ( 68) manufacture

Preparation of No. 66 30 (1.50 g, 5.41 mmol) and 61 (1.06 g, 5.41 mmol) in dimethyl sulfoxide (14.2 ml) in 50% (w / w) aqueous sodium hydroxide solution (2 0.03 ml) was added and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, filtered, washed with water, dried, and the crude crystals were recrystallized with ethyl acetate to obtain 66 (1.26 g, 51%) as yellow crystals.
mp 151.0-151.5 ° C., IR (Nujol) 1601 cm ⁻¹
APCI-MS m / z 456 [M + H] ⁺

1N Hydrochloric acid (5.53 ml, 5.53 mmol) was added to a suspension of No. 67 preparation 66 (1.26 g, 2.77 mmol) in methanol (30 ml) and stirred at room temperature for 1 hour. The reaction solution was evaporated under reduced pressure, the residue was dissolved in water / ethyl acetate, adjusted to pH 10 with potassium carbonate solution, and after separation, the organic layer was washed with water, dried, evaporated under reduced pressure, and the residue was recrystallized with ethyl acetate 67 ( 1.09 g, 95%) was obtained as yellow crystals.
mp 170-171 ° C., APCI-MS m / z 416 [M + H] ⁺

68 Preparation 67 (1.09 g, 2.62 mmol) in ethylene glycol dimethyl ether (100 ml) suspension in triethylamine (0.55 ml, 3.93 mmol), toluenesulfonic anhydride (0.86 g, 2.62 mol), Dimethylaminopyridine (0.032 g, 0.26 mmol) was added and stirred at 70 ° C. for 16 hours. The reaction solution is allowed to cool, diluted with ethyl acetate, washed with water, dried and evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/2 to ethyl acetate). Purification and recrystallization from ethyl acetate gave 68 (0.76 g, 51%) as yellow crystals.
mp 149-150 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72 (6H, m), 2.37 (3H, s), 2.41 (1H, m), 3.63 (4H, m ), 3.83 (2H, d, J = 5.7 Hz), 4.02 (2H, dd, J = 5.8, 4.3 Hz), 6.35 (1H, d, J = 15.7 Hz) 6.77 (1H, dd, J = 8.8, 2.4 Hz), 6.90 (1H, d, J = 2.4 Hz), 7.24-7.28 (2H, m), 7. 36 (1H, s), 7.49 (1H, d, J = 8.8 Hz), 7.64 (1H, d, J = 15.7 Hz), 7.66-7.79 (2H, m)
IR (Nujol) 3298, 1630 cm ⁻¹ , APCI-MS m / z 570 [M + H] ⁺

６９の製造
３５（３．００ｇ、９．６４ｍｍｏｌ）及び６１（３．２８ｇ、１６．７１ｍｍｏｌ）のジメチルスルホキシド（３６．５ｍｌ）溶液に室温撹拌下５０％（ｗ／ｗ）水酸化ナトリウム水溶液（５．２３ｍｌ）を加え室温で１．５時間撹拌した。反応液に水を加え、ろ取、水洗、乾燥、粗結晶を酢酸エチルで再結晶し６９（３．５５ｇ、７５％）を黄色結晶として得た。
ｍｐ ２０７〜２０８℃、ＩＲ（Ｎｕｊｏｌ）１６３１ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４９０［Ｍ＋Ｈ］^＋

７０の製造
６９（３．５５ｇ、７．２５ｍｍｏｌ）のメタノール（６０ｍｌ）懸濁液に１Ｎ塩酸（１４．５ｍｌ、１４．５ｍｍｏｌ）を加え７０℃１時間攪拌した。反応液を減圧溶媒留去、残渣をトリエチルアミン（３ｍｌ）、水（５ｍｌ）及び酢酸エチルで溶解、溶解液をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し７０（２．５７ｇ、８８％）を黄色結晶として得た。
ｍｐ １６１．０〜１６１．５℃、ＩＲ（Ｎｕｊｏｌ）３３３２、１６３２ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４０２［Ｍ＋Ｈ］^＋

７１の製造
７０（２．５７ｇ、６．４０ｍｍｏｌ）のエチレングリコールジメチルエーテル（１００ｍｌ）懸濁液にトリエチルアミン（１．３４ｍｌ、９．６０ｍｍｏｌ）、トルエンスルホン酸無水物（２．０９ｇ、６．４０ｍｏｌ）、ジメチルアミノピリジン（０．０７８ｇ、０．６４ｍｍｏｌ）を加え、７０℃２４時間攪拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／１〜酢酸エチル）で精製、酢酸エチルで再結晶し７１（１．４７ｇ、４１％）を黄色結晶として得た。
ｍｐ １７０〜１７２℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．７２（６Ｈ、ｍ）、２．１５（１Ｈ、ｍ、Ｄ_２Ｏ消去）、２．４２（３Ｈ、ｓ）、３．６２（４Ｈ、ｍ）、３．８１〜３．９５（２Ｈ、ｍ）、４．２８（２Ｈ、ｄ、Ｊ＝５．１Ｈｚ）、４．４８〜４．５６（１Ｈ、ｍ）、６．３４（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、６．８４（１Ｈ、ｄｄ、Ｊ＝８．７、２．２Ｈｚ）、７．００（１Ｈ、ｄ、Ｊ＝２．２Ｈｚ）、７．３０（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．３６（１Ｈ、ｓ）、７．４８（２Ｈ、ｄ、Ｊ＝８．５Ｈｚ）、７．６６（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、７．７６（２Ｈ、ｄ、Ｊ＝８．５Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３３３２、１６３２ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ５５６［Ｍ＋Ｈ］^＋

７２の製造
７１（１．０５ｇ、１．８９ｍｍｏｌ）にテトラヒドロフラン（１０ｍｌ）懸濁液に１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（９．４５ｍｌ、９．４５ｍｍｏｌ）を加え還流７．５時間した。反応液を放冷、冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／１）で精製、酢酸エチルで再結晶し７２（０．３５ｇ、４６％）を黄色結晶として得た。
ｍｐ １４６．５〜１４７．５℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．７１（６Ｈ、ｍ）、２．３５（１Ｈ、ｍ、Ｄ_２Ｏ消去）、３．６０（４Ｈ、ｍ）、３．９５（２Ｈ、ｍ）、４．５５（１Ｈ、ｍ）、４．６８（２Ｈ、ｄｄｄ、Ｊ＝４７．７、４．６、２．６Ｈｚ）、６．３３（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）、６．９８（１Ｈ、ｄｄ、Ｊ＝８．７、２．３Ｈｚ）、７．１３（１Ｈ、ｄ、Ｊ＝２．３Ｈｚ）、７．３４（１Ｈ、ｓ）、７．５３（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６６（１Ｈ、ｄ、Ｊ＝１５．７Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３３２３、１６２５ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋ THK-713 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole): (72 )as well as
712 ((E) -6-[(2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole
): Production of (71)

69 Preparation 35 (3.00 g, 9.64 mmol) and 61 (3.28 g, 16.71 mmol) in dimethyl sulfoxide (36.5 ml) were stirred at room temperature with 50% (w / w) aqueous sodium hydroxide solution (5 .23 ml) was added and stirred at room temperature for 1.5 hours. Water was added to the reaction solution, filtered, washed with water, dried, and the crude crystals were recrystallized with ethyl acetate to obtain 69 (3.55 g, 75%) as yellow crystals.
mp 207-208 ° C., IR (Nujol) 1631 cm ⁻¹
APCI-MS m / z 490 [M + H] ⁺

1N hydrochloric acid (14.5 ml, 14.5 mmol) was added to a suspension of 70 in Preparation 69 (3.55 g, 7.25 mmol) in methanol (60 ml), and the mixture was stirred at 70 ° C. for 1 hour. The reaction solution was evaporated under reduced pressure, the residue was dissolved in triethylamine (3 ml), water (5 ml) and ethyl acetate. The solution was purified by silica gel column chromatography (elution solvent: ethyl acetate) and recrystallized from ethyl acetate. 2.57 g, 88%) was obtained as yellow crystals.
mp 161.0-161.5 [deg.] C., IR (Nujol) 3332, 1632 cm < ^-1 >
APCI-MS m / z 402 [M + H] ⁺

Preparation of 71 70 (2.57 g, 6.40 mmol) in ethylene glycol dimethyl ether (100 ml) suspension in triethylamine (1.34 ml, 9.60 mmol), toluenesulfonic anhydride (2.09 g, 6.40 mol), Dimethylaminopyridine (0.078 g, 0.64 mmol) was added and stirred at 70 ° C. for 24 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-ethyl acetate) and recrystallized from ethyl acetate 71 (1.47 g, 41%). Was obtained as yellow crystals.
mp 170-172 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.72 (6H, m), 2.15 (1H, m, D ₂ O erased), 2.42 (3H, s), 3. 62 (4H, m), 3.81 to 3.95 (2H, m), 4.28 (2H, d, J = 5.1 Hz), 4.48 to 4.56 (1H, m), 6. 34 (1H, d, J = 15.7 Hz), 6.84 (1H, dd, J = 8.7, 2.2 Hz), 7.00 (1H, d, J = 2.2 Hz), 7.30 (1H, d, J = 8.7 Hz), 7.36 (1H, s), 7.48 (2H, d, J = 8.5 Hz), 7.66 (1H, d, J = 15.7 Hz) , 7.76 (2H, d, J = 8.5 Hz)
IR (Nujol) 3332, 1632 cm ⁻¹ , APCI-MS m / z 556 [M + H] ⁺

72 Preparation 71 (1.05 g, 1.89 mmol) was added 1 M tetrabutylammonium fluoride / tetrahydrofuran solution (9.45 ml, 9.45 mmol) to a suspension of tetrahydrofuran (10 ml) and refluxed for 7.5 hours. The reaction mixture was allowed to cool, cold water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/1) and recrystallized from ethyl acetate 72 (0.35 g, 46% ) Was obtained as yellow crystals.
mp 146.5-147.5 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.71 (6H, m), 2.35 (1H, m, D ₂ O erased), 3.60 (4H, m ), 3.95 (2H, m), 4.55 (1H, m), 4.68 (2H, ddd, J = 47.7, 4.6, 2.6 Hz), 6.33 (1H, d) , J = 15.7 Hz), 6.98 (1H, dd, J = 8.7, 2.3 Hz), 7.13 (1H, d, J = 2.3 Hz), 7.34 (1H, s) 7.53 (1H, d, J = 8.7 Hz), 7.66 (1H, d, J = 15.7 Hz)
IR (Nujol) 3323, 1625 cm ⁻¹ , APCI-MS m / z 404 [M + H] ⁺

７３の製造
１（１０ｇ、６１．０ｍｍｏｌ）とＮ−メチルピペラジン（４０ｍｌ）の混合物を、１４０℃で１時間攪拌した。反応液を放冷し、氷−１０％水酸化ナトリウム水溶液で希釈して酢酸エチルで抽出した。抽出液を乾燥後、減圧下溶媒を留去して残渣を塩基性シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１）で精製し７３（８．６２ｇ、７７％）を黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １８４［Ｍ＋Ｈ］^＋

７４の製造
ジイソプロピルアミン（３．３９ｇ、３３．５ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（２１．１ｍｌ、３３．５ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で７３（５ｇ、３０．５ｍｍｏｌ）のテトラヒドロフラン（４０ ｍｌ）溶液を滴下し−７８℃で４０分撹拌した。同温で４−ホルミルモルホリン（５．２６ｇ、４５．７ｍｍｏｌ）のテトラヒドロフラン（４０ ｍｌ）溶液を滴下し、同温で３０分撹拌した。反応液に飽和塩化アンモニウム水を加え、飽和重曹水で塩基性として酢酸エチルで抽出した。抽出液を水、飽和食塩水で順に洗浄後、乾燥して溶媒を減圧留去した。残渣をｎ−ヘキサン−ジイソプロピルエーテルで洗浄して７４（４．１４ｇ、６５％）を淡黄色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ２１２［Ｍ＋Ｈ］^＋

７５の製造
ジイソプロピルアミン（３２６ｍｇ、３．２２ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（２．０３ｍｌ、 ３．２２ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で２６（９１１ｍｇ、２．６８ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を滴下し−７８℃で４０分撹拌した。同温で７４（６８０ｍｇ、３．２２ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を滴下し、同温で３０分撹拌した。反応液に飽和塩化アンモニウム水を加え、飽和重曹水で塩基性として酢酸エチルで抽出した。抽出液を水、飽和食塩水で順に洗浄後、乾燥して溶媒を減圧留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１および酢酸エチル）で精製し７５（１．２８ｇ、８７％）を黄色固体として得た。

７６の製造
７５（１．２８ｇ、２．３２ｍｍｏｌ）のクロロホルム（２５ｍｌ）溶液にトリエチルアミン（１．９４ｍｌ、１３．９ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．３６ｍｌ、４．６５ｍｍｏｌ）を滴下し室温で３０分撹拌した。反応液に氷水を加え酢酸エチルで抽出した。抽出液を水、飽和食塩水で順に洗浄後、乾燥して溶媒を減圧留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／３）で精製し７６（１．０７ｇ、８６％）を黄色油状物質として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５３３［Ｍ＋Ｈ］^＋

７７の製造
７６（１．０７ｇ、２．０１ｍｍｏｌ）のテトラヒドロフラン（２５ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（２．２１ｍｌ、２．２１ｍｍｏｌ）を加え室温で３０分攪拌した。反応液に氷水を加え酢酸エチルで抽出した。抽出液を水、飽和食塩水で順に洗浄して、乾燥後溶媒を減圧留去した。残渣を塩基性シリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルムおよびクロロホルム／メタノール＝５０／１）で精製後、酢酸エチルで洗浄し７７（４８５ｍｇ、５８％）を黄色固体として得た。
ｍｐ １５１〜１５３℃
ＩＲ （Ｎｕｊｏｌ） １６２９ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４１９［Ｍ＋Ｈ］^＋ THK-707 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (4-methylpiperazin-1-yl) thiazol-5-yl] ethenyl] Benzoxazole): Preparation of (77)

A mixture of Preparation 1 of 73 (10 g, 61.0 mmol) and N-methylpiperazine (40 ml) was stirred at 140 ° C. for 1 hour. The reaction mixture was allowed to cool, diluted with ice-10% aqueous sodium hydroxide solution and extracted with ethyl acetate. The extract was dried, the solvent was distilled off under reduced pressure, and the residue was purified by basic silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1) to give 73 (8.62 g, 77%). Obtained as a yellow oil.
APCI-MS m / z 184 [M + H] ⁺

Preparation of 74 A 1.59 M n-butyllithium / n-hexane solution (21. 1 ml, 33.5 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 73 (5 g, 30.5 mmol) in tetrahydrofuran (40 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 40 minutes. A solution of 4-formylmorpholine (5.26 g, 45.7 mmol) in tetrahydrofuran (40 ml) was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was made basic with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was washed with n-hexane-diisopropyl ether to obtain 74 (4.14 g, 65%) as a pale yellow solid.
APCI-MS m / z 212 [M + H] ⁺

Preparation of 75 To a solution of diisopropylamine (326 mg, 3.22 mmol) in tetrahydrofuran (20 ml) was added 1.59 M n-butyllithium / n-hexane solution (2.03 ml, at −60 ° C. or lower with stirring in an argon atmosphere). 3.22 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 26 (911 mg, 2.68 mmol) in tetrahydrofuran (20 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 40 minutes. A solution of 74 (680 mg, 3.22 mmol) in tetrahydrofuran (20 ml) was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was made basic with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1 and ethyl acetate) to obtain 75 (1.28 g, 87%) as a yellow solid.

Triethylamine (1.94 ml, 13.9 mmol) was added to a solution of No. 76 75 (1.28 g, 2.32 mmol) in chloroform (25 ml), and methanesulfonyl chloride (0.36 ml, 4.65 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/3) to give 76 (1.07 g, 86%) as a yellow oil.
APCI-MS m / z 533 [M + H] ⁺

A 1M tetrabutylammonium fluoride / tetrahydrofuran solution (2.21 ml, 2.21 mmol) was added to a solution of 77, 76 (1.07 g, 2.01 mmol) in tetrahydrofuran (25 ml) with stirring at room temperature, and the mixture was stirred at room temperature for 30 minutes. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: chloroform and chloroform / methanol = 50/1) and then washed with ethyl acetate to obtain 77 (485 mg, 58%) as a yellow solid.
mp 151-153 ° C
IR (Nujol) 1629 cm ⁻¹ , APCI-MS m / z 419 [M + H] ⁺

７８の製造
１（１０．２１ｇ、６２．２５ｍｍｏｌ）のピロリジン（６０ｍｌ）溶液を９０℃で１．３時間攪拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し７８（９．４７ｇ、９９％）を無色固体として得た。
ｍｐ ４５〜４６℃、ＡＰＣＩ−ＭＳ ｍ／ｚ １５５［Ｍ＋Ｈ］^＋

７９の製造
ジイソプロピルアミン（１０．３８ｍｌ、７３．６８ｍｍｏｌ）のテトラヒドロフラン（１５０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（４６．３４ｍｌ、７３．６８ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で７８（９．４７ｇ，６１．４０ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で、ジメチルホルムアミド（９．５０ｍｌ、１２２．８ｍｍｏｌ）を一度に加え同温で４０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）で精製、ｎ−ヘキサン／酢酸エチルで再結晶し７９（１０．４１ｇ、９３％）を淡黄色結晶として得た。
ｍｐ ９２．０〜９２．５℃、ＩＲ （Ｎｕｊｏｌ） １６３５ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ １８３［Ｍ＋Ｈ］^＋

８０の製造
３０（３．００ｇ、１０．８２ｍｍｏｌ）及び７９（１．９７ｇ、 １０．８２ｍｍｏｌ）のジメチルスルホキシド（１５．０ｍｌ）溶液に室温撹拌下５０％（ｗ／ｗ）水酸化ナトリウム水溶液（４．０７ｍｌ）を加え室温で１時間撹拌した。反応液に水を加え、ろ取、水洗、乾燥、粗結晶をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１：１〜酢酸エチル）で精製、酢酸エチルで再結晶し８０（２．１０ｇ、４４％）を黄色結晶として得た。
ｍｐ １７５〜１７６℃、ＩＲ（Ｎｕｊｏｌ）１６３３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４４２［Ｍ＋Ｈ］^＋

８１の製造
８０（３．５３ｇ、７．９９ｍｍｏｌ）のメタノール（９０ｍｌ）懸濁液に１Ｎ塩酸（１６．０ｍｌ、１６．０ｍｍｏｌ）を加え室温３５分攪拌した。反応液を減圧溶媒留去、残渣を水／酢酸エチルで溶解、炭酸カリウム溶液でｐＨ１０とし、分液後、有機層を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチルで再結晶し８１（３．１０ｇ、９７％）を黄色結晶として得た。
ｍｐ １９６．０〜１９６．５℃、ＩＲ（Ｎｕｊｏｌ）３３３０、１６２４ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４０２［Ｍ＋Ｈ］^＋

８２の製造
８１（３．１０ｇ、７．７２ｍｍｏｌ）のエチレングリコールジメチルエーテル（２００ｍｌ）懸濁液にトリエチルアミン（１．６２ｍｌ、１１．６ｍｍｏｌ）、トルエンスルホン酸無水物（２．５２ｇ、７．７２ｍｏｌ）、ジメチルアミノピリジン（０．０９４ｇ、０．７７ｍｍｏｌ）を加え、７０℃１６時間攪拌した。反応液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／１〜酢酸エチル）で精製、酢酸エチルで再結晶し８２（１．２６ｇ、２９％）を黄色結晶として得た。
ｍｐ １６８〜１７０℃、ＩＲ （Ｎｕｊｏｌ） ３３１１、１７３６、１６３６ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ５５６［Ｍ＋Ｈ］^＋

８３の製造
８２（１．２６ｇ、２．２７ｍｍｏｌ）にテトラヒドロフラン（１０ｍｌ）懸濁液に１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１１．３ｍｌ、１１．３ｍｍｏｌ）を加え還流１時間１０分した。反応液を放冷、冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／２）で精製、酢酸エチルで再結晶し８３（０．５９ｇ、６４％）を黄色結晶として得た。
ｍｐ １７５．５〜１７６．５℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２．０６〜２．１８（４Ｈ、ｍ）、２．３５〜２．５３（２Ｈ、ｍ、Ｄ_２Ｏ、１Ｈ）、３．５８（４Ｈ、ｔ、Ｊ＝６．４Ｈｚ）、３．９１（２Ｈ、ｄ、Ｊ＝５．７Ｈｚ）、４．１６（２Ｈ、ｄ、Ｊ＝６．０Ｈｚ）、４．７０（２Ｈ、ｄｄ、Ｊ＝４７．０、５．５Ｈｚ）、６．３５（１Ｈ、ｄｄ、Ｊ＝１５．７、０．６Ｈｚ）、６．９０（１Ｈ、ｄｄ、Ｊ＝８．７、２．４Ｈｚ）、７．０３（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．３８（１Ｈ、ｓ）、７．５２（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６５（１Ｈ、ｄｄ、Ｊ＝１５．７、０．６Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３２１８、１６２５ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋ THK-708 ((E) -6-[(2-fluoromethyl-3-hydroxy) propoxy] -2- [2- [2- (pyrrolidin-1-yl) thiazol-5-yl) ethenyl] benzoxazole : Production of (83)

A solution of 78 Preparation 1 (10.21 g, 62.25 mmol) in pyrrolidine (60 ml) was stirred at 90 ° C. for 1.3 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1) to obtain 78 (9.47 g, 99%) as a colorless solid.
mp 45-46 ° C., APCI-MS m / z 155 [M + H] ⁺

Preparation of 79 To a solution of diisopropylamine (10.38 ml, 73.68 mmol) in tetrahydrofuran (150 ml) under stirring in an argon atmosphere at −60 ° C. or lower, a 1.59 M n-butyllithium / n-hexane solution (46. 34 ml, 73.68 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 78 (9.47 g, 61.40 mmol) in tetrahydrofuran (50 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. At the same temperature, dimethylformamide (9.50 ml, 122.8 mmol) was added all at once and stirred at the same temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1), recrystallized with n-hexane / ethyl acetate 79 (10. 41 g, 93%) was obtained as pale yellow crystals.
mp 92.0-92.5 ° C., IR (Nujol) 1635 cm ⁻¹
APCI-MS m / z 183 [M + H] ⁺

Preparation of 80 30 (3.00 g, 10.82 mmol) and 79 (1.97 g, 10.82 mmol) in dimethyl sulfoxide (15.0 ml) were stirred at room temperature with 50% (w / w) aqueous sodium hydroxide solution (4 0.07 ml) and stirred at room temperature for 1 hour. Water was added to the reaction mixture, filtered, washed with water, dried, and the crude crystals were purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1: 1 to ethyl acetate), recrystallized with ethyl acetate 80 ( 2.10 g, 44%) was obtained as yellow crystals.
mp 175-176 [deg.] C., IR (Nujol) 1633 cm < ^-1 >
APCI-MS m / z 442 [M + H] ⁺

Preparation of No. 81 To a suspension of 80 (3.53 g, 7.9 mmol) in methanol (90 ml) was added 1N hydrochloric acid (16.0 ml, 16.0 mmol), and the mixture was stirred at room temperature for 35 minutes. The reaction solution was evaporated under reduced pressure, the residue was dissolved in water / ethyl acetate, adjusted to pH 10 with potassium carbonate solution, and after liquid separation, the organic layer was washed with water, dried, evaporated under reduced pressure, and the residue was recrystallized with ethyl acetate 81 3.10 g, 97%) was obtained as yellow crystals.
mp 196.0-196.5 ° C., IR (Nujol) 3330, 1624 cm ⁻¹
APCI-MS m / z 402 [M + H] ⁺

Preparation of 82 To a suspension of ethylene glycol dimethyl ether (200 ml) in 81 (3.10 g, 7.72 mmol), triethylamine (1.62 ml, 11.6 mmol), toluenesulfonic anhydride (2.52 g, 7.72 mol), Dimethylaminopyridine (0.094 g, 0.77 mmol) was added and stirred at 70 ° C. for 16 hours. The reaction solution was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1 / 1-ethyl acetate) and recrystallized from ethyl acetate 82 (1.26 g, 29%). Was obtained as yellow crystals.
mp 168-170 ° C., IR (Nujol) 3311, 1736, 1636 cm ⁻¹
APCI-MS m / z 556 [M + H] ⁺

To a suspension of tetrahydrofuran (10 ml), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (11.3 ml, 11.3 mmol) was added to a suspension 82 of product 83 (1.26 g, 2.27 mmol) and refluxed for 1 hour and 10 minutes. The reaction mixture was allowed to cool, cold water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/2) and recrystallized with ethyl acetate 83 (0.59 g, 64% ) Was obtained as yellow crystals.
mp 175.5-176.5 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.06-2.18 (4H, m), 2.35-2.53 (2H, m, D ₂ O, 1H ), 3.58 (4H, t, J = 6.4 Hz), 3.91 (2H, d, J = 5.7 Hz), 4.16 (2H, d, J = 6.0 Hz), 4.70 (2H, dd, J = 47.0, 5.5 Hz), 6.35 (1H, dd, J = 15.7, 0.6 Hz), 6.90 (1H, dd, J = 8.7, 2 .4 Hz), 7.03 (1 H, d, J = 2.4 Hz), 7.38 (1 H, s), 7.52 (1 H, d, J = 8.7 Hz), 7.65 (1 H, dd) , J = 15.7, 0.6 Hz)
IR (Nujol) 3218, 1625 cm ⁻¹ , APCI-MS m / z 404 [M + H] ⁺

８４の製造
アルデヒド７９（２．５５ｇ、１４ｍｍｏｌ） とベンゾキサゾール誘導体４０ （３．７ｇ、１４ｍｍｏｌ） を溶解させたジメチルスルホキシド（３７．５ｍｌ）溶液に５０％水酸化ナトリウム水溶液（５．４ｍｌ）を滴下し、室温にて２時間攪拌反応させた。黄色の固体が析出した。反応液に水１５０ｍｌを加え２０分程攪拌した後、黄色固体をろ取、水洗し、７０℃にて減圧乾燥した。さらに酢酸エチルから再結晶させて８４（２．８５ｇ， ４８％）を得た。
ｍｐ１９３−１９４℃
ＩＲ（Ｎｕｊｏｌ）１６２８，１６００ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４２８［Ｍ＋Ｈ］^＋

８５の製造
メタノール９０ｍｌに８４（２．６５ｇ、６．０８ｍｍｏｌ）を加え、室温にて攪拌しながら１Ｎ塩酸（１２ｍｌ）を滴下した。反応液は直ちに均一な透明溶液になった。４時間反応させた後、溶媒を減圧にて留去、残渣を水に溶解し、炭酸カリウム水溶液でアルカリ性にすると黄色の沈殿物が析出した。これを酢酸エチルにて抽出、有機層を水洗、飽和食塩水で洗浄後、無水硫酸マグネシウムにて乾燥した。溶媒を減圧留去して８５（２．２６ｇ，９６％）を得た。
ｍｐ１７９−１８２℃
ＡＰＣＩ−ＭＳ ｍ／ｚ３８８［Ｍ＋Ｈ］^＋

８６の製造
ジオール８５（３．５０ｇ，９．６８ｍｍｏｌ）を乾燥ジメトキシエタン（２００ｍｌ）に溶解させ、これにｐ−トルエンスルホン酸無水物（３．１６ｇ，９．６８ｍｍｏｌ）、トリエチルアミン（１．５ｇ，１４．８５ｍｍｏｌ）、ジメチルアミノピリジン（１００ｍｇ）を加えて攪拌、７５℃の加熱下に６時間半反応させた。反応終了後、反応液を室温まで冷却し、沈殿物をろ去、ろ液を減圧留去して反応混合物を得た。これをシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〜１／２〜酢酸エチル）にて分離精製し、８６（２．１０ｇ，４０％）及び未反応ジオール８５（１．４０ｇ，３７％）を得た。
ｍｐ１４７−１４８℃
ＩＲ（Ｎｕｊｏｌ）３２３１，１６２９，１６１３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ５４２［Ｍ＋Ｈ］^＋
１ＨＮＭＲ（ＤＭＳＯ−ｄ_６）δ１．９８−２．０５（４Ｈ，ｍ）２．３６（３Ｈ，ｓ）３．４２−３．５０（４Ｈ，ｍ）３．５５−３．６２（２Ｈ，ｍ）４．２６（２Ｈ，ｍ）４．４０−４．６０（１Ｈ，ｍ）５．０６（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ）６．３２（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ）６．４８（１Ｈ．ｄｄ，Ｊ＝８．６Ｈｚ，２．４Ｈｚ）７．１８（１Ｈ，ｄ，Ｊ＝２．２Ｈｚ）７．３９（２Ｈ，ｄ，Ｊ＝７．９Ｈｚ）７．４８（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ）７．６１（１Ｈ，ｓ）７．７２（２Ｈ，ｄ，８，０Ｈｚ）７．７６（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ）

８７の製造
モノトシル体８６（１．２７ｇ，２．３４ｍｍｏｌ）を乾燥テトラヒドロフラン（１２ｍｌ）に溶解させ、フッ化テトラｎ−ブチルアンモニウムのテトラヒドロフラン１モル溶液（１０ｍｌ）を加えて加熱２時間半還流下に反応させた。反応終了後、反応液を酢酸エチルで希釈し、水を加えて分液し、有機層を水洗、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた粗生成物をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１）で精製後、酢酸エチルにて再結晶させて８７（５２０ｍｇ、５７％）を得た。
ｍｐ１５９−１６１℃
ＩＲ（Ｎｕｊｏｌ）３１９２，１６３０ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ３９０［Ｍ＋Ｈ］^＋
１ＨＮＭＲ（ＤＭＳＯ−ｄ_６）δ１．９７−２．０４（４Ｈ，ｍ）３．４５（４Ｈ，ｂｒ ｔ）３．６４（２Ｈ，ｂｒ ｔ）４．５５−４．８３（３Ｈ，ｍ）５．０６（１Ｈ，ｔ，Ｊ＝５．７Ｈｚ）６．３１（１Ｈ，ｄ，Ｊ＝１５．８Ｈｚ）６．９９（１Ｈ，ｄｄ，Ｊ＝８．６Ｈｚ，２．４Ｈｚ）７．３６（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）７．５３（１Ｈ，ｄ，Ｊ＝８．６Ｈｚ）７．６０（１Ｈ，ｓ）７．７５（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ） THK-751 ((E) -6-[(1-hydroxymethyl-2-tosyloxy) ethoxy] -2- [2- [2- (pyrrolidin-1-yl) -thiazol-5-yl] ethenyl] benzoxa Zol): (86) and
752 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (pyrrolidin-1-yl) -thiazol-5-yl] ethenyl] benzoxazole) : Production of (87)

Preparation of 84 A 50% aqueous solution of sodium hydroxide (5 4 ml) was added dropwise, and the reaction was stirred at room temperature for 2 hours. A yellow solid precipitated out. After adding 150 ml of water to the reaction solution and stirring for about 20 minutes, the yellow solid was collected by filtration, washed with water, and dried under reduced pressure at 70 ° C. Further recrystallization from ethyl acetate gave 84 (2.85 g, 48%).
mp 193-194 ° C
IR (Nujol) 1628, 1600 cm ⁻¹
APCI-MS m / z 428 [M + H] ⁺

Preparation of 85 84 (2.65 g, 6.08 mmol) was added to 90 ml of methanol, and 1N hydrochloric acid (12 ml) was added dropwise with stirring at room temperature. The reaction solution immediately became a homogeneous clear solution. After reacting for 4 hours, the solvent was distilled off under reduced pressure, the residue was dissolved in water, and made alkaline with an aqueous potassium carbonate solution, whereby a yellow precipitate was deposited. This was extracted with ethyl acetate, the organic layer was washed with water, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 85 (2.26 g, 96%).
mp 179-182 ° C
APCI-MS m / z 388 [M + H] ⁺

Preparation of 86 Diol 85 (3.50 g, 9.68 mmol) was dissolved in dry dimethoxyethane (200 ml) to which p-toluenesulfonic anhydride (3.16 g, 9.68 mmol), triethylamine ( 1.5 g, 14.85 mmol) and dimethylaminopyridine (100 mg) were added, and the mixture was stirred and reacted for 6 and a half hours under heating at 75 ° C. After completion of the reaction, the reaction solution was cooled to room temperature, the precipitate was removed by filtration, and the filtrate was distilled off under reduced pressure to obtain a reaction mixture. This was separated and purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 1/2 to ethyl acetate), and 86 (2.10 g, 40%) and unreacted diol 85 (1 .40 g, 37%).
mp 147-148 ° C
IR (Nujol) 3231, 1629, 1613 cm ⁻¹
APCI-MS m / z 542 [M + H] ^+
1 HNMR (DMSO-d ₆ ) δ 1.98-2.05 (4H, m) 2.36 (3H, s) 3.42-3.50 (4H, m) 3.55-3.62 (2H, m) 4.26 (2H, m) 4.40-4.60 (1H, m) 5.06 (1H, t, J = 5.7 Hz) 6.32 (1H, d, J = 15.7 Hz) 6.48 (1H.dd, J = 8.6 Hz, 2.4 Hz) 7.18 (1H, d, J = 2.2 Hz) 7.39 (2H, d, J = 7.9 Hz) 7.48 ( 1H, d, J = 8.6 Hz) 7.61 (1H, s) 7.72 (2H, d, 8, 0 Hz) 7.76 (1H, d, J = 15.7 Hz)

Preparation of 87 Monotosyl compound 86 (1.27 g, 2.34 mmol) was dissolved in dry tetrahydrofuran (12 ml), and 1 mol solution of tetra n-butylammonium fluoride in tetrahydrofuran (10 ml) was added and heated for 2 hours. The reaction was carried out under half reflux. After completion of the reaction, the reaction solution was diluted with ethyl acetate, and water was added for separation. The organic layer was washed with water, saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1) and then recrystallized from ethyl acetate to obtain 87 (520 mg, 57 %).
mp 159-161 ° C
IR (Nujol) 3192, 1630 cm ⁻¹
APCI-MS m / z 390 [M + H] ^+
1 HNMR (DMSO-d ₆ ) δ 1.97-2.04 (4H, m) 3.45 (4H, br t) 3.64 (2H, br t) 4.55-4.83 (3H, m) 5.06 (1H, t, J = 5.7 Hz) 6.31 (1H, d, J = 15.8 Hz) 6.99 (1H, dd, J = 8.6 Hz, 2.4 Hz) 7.36 ( 1H, d, J = 2.4 Hz) 7.53 (1H, d, J = 8.6 Hz) 7.60 (1H, s) 7.75 (1H, d, J = 15.7 Hz)

８９の製造
４７（５．００ｇ、２５．０ｍｍｏｌ）のジメチルホルムアミド（５０ｍｌ）溶液に、アルゴン雰囲気攪拌下室温で６０％水素化ナトリウム（１．５０ｇ、３７．５ｍｍｏｌ）を数回に分けて加え、室温２０分攪拌した。次に８８（１２．６５ｇ、５０．０ｍｍｏｌ）を加え室温２時間攪拌した。反応液に氷片を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝３０／１）で精製し８９（７．８９ｇ、８５％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ３７３［Ｍ＋Ｈ］^＋

９０の製造
８９（７．８９ｇ、２１．１８ｍｍｏｌ）のジクロロメタン（３０ｍｌ）溶液に氷冷撹拌下トリフルオロ酢酸（３０ｍｌ）を滴下し室温で３日撹拌した。反応液を減圧溶媒留去、残渣を酢酸エチルで希釈、炭酸カリウム溶液でｐＨ８とし、分液後有機層を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１〜酢酸エチル）で精製し９０（３．３５ｇ、１００％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １５９［Ｍ＋Ｈ］^＋

９１の製造
９０（２．９５ｇ、１８．６５ｍｍｏｌ）の水（７３ｍｌ）溶液に室温撹拌下３６％ホルムアルデヒド水溶液（３７ｍｌ）を加え室温で５分撹拌した。反応液に酢酸エチル／ｎ−ヘキサン＝２／１（１１００ｍｌ）を加え、室温１６時間攪拌した。分液後、水層を酢酸エチルで抽出、有機層を合わせ、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１）で精製し９１（１．７５ｇ、５５％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １７１［Ｍ＋Ｈ］^＋

９２の製造
ジイソプロピルアミン（２．５１ｍｌ、１７．８０ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（１１．１９ｍｌ、 １７．８０ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で９１（２．０２ｇ，１１．８７ｍｍｏｌ）のテトラヒドロフラン（４０ ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で、ジメチルホルムアミド（１．８４ｍｌ、２３．７４ｍｍｏｌ）を一度に加え同温で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１）で精製、ｎ−ヘキサン／酢酸エチルで再結晶し９２（１．８９ｇ、８０％）を無色結晶として得た。
ｍｐ ９４．０〜９４．５℃、ＩＲ （Ｎｕｊｏｌ） １６５５ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ １９９［Ｍ＋Ｈ］^＋

９３の製造
ジイソプロピルアミン（２．０２ｍｌ、１４．３ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（８．９９ｍｌ、 １４．３ｍｍｏｌ）を滴下し、除々に０℃まで昇温した。次に−７０℃以下で５４（４．３１ｇ、９．５４ｍｍｏｌ）のテトラヒドロフラン（４０ ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で、９２（１．８９ｇ、９．５４ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液を一度に加え、同温で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１〜１／１）で精製し９３（４．６０ｇ、７４％）を黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ６５０［Ｍ＋Ｈ］^＋

９４の製造
９３（４．６０ｇ、７．０８ｍｍｏｌ）のジクロロメタン（５０ｍｌ）溶液にトリエチルアミン（３．９５ｍｌ、２８．３ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（１．２１ｍｌ、１５．６ｍｍｏｌ）を滴下し室温で３０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し９４（３．９０ｇ、８７％）を黄色固体として得た。
ｍｐ １３１〜１３２℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ６３２［Ｍ＋Ｈ］^＋

９５の製造
９４（３．９０ｇ、６．１７ｍｍｏｌ）のテトラヒドロフラン（４０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１２．３４ｍｌ、１２．３４ｍｍｏｌ）を加え室温１時間攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残さをシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し９５（１．９６ｇ、７９％）を黄色結晶として得た。
ｍｐ １６３〜１６５℃、ＩＲ （Ｎｕｊｏｌ） ３２７６、１６２９ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４０４［Ｍ＋Ｈ］^＋

９６の製造
９５（１．６６ｇ、４．１１ｍｍｏｌ）のエチレングリコールジメチルエーテル（８０ｍｌ）懸濁液にトリエチルアミン（０．８６ｍｌ、６．１７ｍｍｏｌ）、トルエンスルホン酸無水物（１．３４ｇ、４．１１ｍｏｌ）、ジメチルアミノピリジン（０．０５０ｇ、０．４１ｍｍｏｌ）を加え、７０℃１６時間攪拌した。反応液を放冷、酢酸エチルで希釈、水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／２〜酢酸エチル）で精製、酢酸エチル／ｎ−ヘキサンで再結晶し９６（０．７４ｇ、３２％）を黄色結晶として得た。
ｍｐ １１５〜１１７℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ５５８［Ｍ＋Ｈ］^＋

９７の製造
９６（１．９２ｇ、３．４４ｍｍｏｌ）にテトラヒドロフラン（２０ｍｌ）懸濁液に１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１７．２２ｍｌ、１７．２２ｍｏｌ）を加え還流６時間した。反応液を放冷、冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／１〜酢酸エチル）で精製、酢酸エチルで再結晶し９７（０．２９ｇ、２１％）を黄色結晶として得た。
ｍｐ １６２〜１６３℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．８２〜１．９２（２Ｈ、ｍ）、１．９７（１Ｈ、ｔ、Ｊ＝６．３Ｈｚ、Ｄ_２Ｏ消去）、３．８０（２Ｈ、ｔ、Ｊ＝５．７Ｈｚ）、３．９１〜４．００（４Ｈ、ｍ）、４．５１〜４．５９（１Ｈ、ｍ）、４．６８（２Ｈ、ｄｄｄ、Ｊ＝４６．７、４．７、２．３Ｈｚ）、５．１０（２Ｈ、ｓ）、６．４０（１Ｈ、ｄｄ、Ｊ＝１５．８、０．６Ｈｚ）、６．９８（１Ｈ、ｄｄ、Ｊ＝８．８、２．４Ｈｚ）、７．１４（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．３７（１Ｈ、ｔ、Ｊ＝０．６Ｈｚ）、７．５４（１Ｈ、ｄｄ、Ｊ＝８．８、０．４Ｈｚ）、７．６９（１Ｈ、ｄｄ、Ｊ＝１５．８、０．６Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３２６５、１６３４ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４０６［Ｍ＋Ｈ］^＋ THK-757 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-([1,3] oxazinan-3-yl) -thiazol-5-yl ] Ethenyl] benzoxazole): Preparation of (97)

To a solution of 89 of 47 (5.00 g, 25.0 mmol) in dimethylformamide (50 ml), 60% sodium hydride (1.50 g, 37.5 mmol) was added in several portions at room temperature under argon atmosphere stirring. Stir at room temperature for 20 minutes. Next, 88 (12.65 g, 50.0 mmol) was added and stirred at room temperature for 2 hours. Ice pieces were added to the reaction solution and extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 30/1) to give 89 (7.89 g, 85%) as a colorless oil. Obtained.
APCI-MS m / z 373 [M + H] ⁺

To a solution of 90 No. 89 (7.89 g, 21.18 mmol) in dichloromethane (30 ml), trifluoroacetic acid (30 ml) was added dropwise under ice-cooling and stirring, and the mixture was stirred at room temperature for 3 days. The reaction solution was evaporated under reduced pressure, the residue was diluted with ethyl acetate and adjusted to pH 8 with potassium carbonate solution. Purification by n-hexane = 2/1 to ethyl acetate) gave 90 (3.35 g, 100%) as a pale yellow oil.
APCI-MS m / z 159 [M + H] ⁺

To a solution of No. 91 90 (2.95 g, 18.65 mmol) in water (73 ml), 36% aqueous formaldehyde solution (37 ml) was added with stirring at room temperature, and the mixture was stirred at room temperature for 5 minutes. Ethyl acetate / n-hexane = 2/1 (1100 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 16 hours. After separation, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1) 91 ( 1.75 g, 55%) was obtained as a pale yellow oil.
APCI-MS m / z 171 [M + H] ⁺

Preparation of 92 To a solution of diisopropylamine (2.51 ml, 17.80 mmol) in tetrahydrofuran (20 ml) under stirring in an argon atmosphere at −60 ° C. or lower, a 1.59 M n-butyllithium / n-hexane solution (11. 19 ml, 17.80 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 91 (2.02 g, 11.87 mmol) in tetrahydrofuran (40 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. At the same temperature, dimethylformamide (1.84 ml, 23.74 mmol) was added in one portion and stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1) and recrystallized from n-hexane / ethyl acetate 92 (1. 89 g, 80%) as colorless crystals.
mp 94.0-94.5 ° C., IR (Nujol) 1655 cm ⁻¹
APCI-MS m / z 199 [M + H] ⁺

Preparation of 93 To a solution of diisopropylamine (2.02 ml, 14.3 mmol) in tetrahydrofuran (40 ml) under stirring in an argon atmosphere at −60 ° C. or lower, a 1.59 M n-butyllithium / n-hexane solution (8. 99 ml, 14.3 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 54 (4.31 g, 9.54 mmol) in tetrahydrofuran (40 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. At the same temperature, a solution of 92 (1.89 g, 9.54 mmol) in tetrahydrofuran (30 ml) was added in one portion, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 1/1) to obtain 93 (4.60 g, 74%). Obtained as a yellow oil.
APCI-MS m / z 650 [M + H] ⁺

94 Preparation 93 (4.60 g, 7.08 mmol) in dichloromethane (50 ml) was added triethylamine (3.95 ml, 28.3 mmol), and methanesulfonyl chloride (1.21 ml, 15.6 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 94 (3.90 g, 87%) as a yellow solid. It was.
mp 131-132 ° C., APCI-MS m / z 632 [M + H] ⁺

To a solution of No. 95 94 (3.90 g, 6.17 mmol) in tetrahydrofuran (40 ml) was added 1M tetrabutylammonium fluoride / tetrahydrofuran solution (12.34 ml, 12.34 mmol) with stirring at room temperature, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) and recrystallized from ethyl acetate to obtain 95 (1.96 g, 79%) as yellow crystals.
mp 163-165 ° C., IR (Nujol) 3276, 1629 cm ⁻¹
APCI-MS m / z 404 [M + H] ⁺

96 Preparation 95 (1.66 g, 4.11 mmol) in ethylene glycol dimethyl ether (80 ml) suspension in triethylamine (0.86 ml, 6.17 mmol), toluenesulfonic anhydride (1.34 g, 4.11 mol), Dimethylaminopyridine (0.050 g, 0.41 mmol) was added and stirred at 70 ° C. for 16 hours. The reaction solution is allowed to cool, diluted with ethyl acetate, washed with water, dried, evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/2 to ethyl acetate). Recrystallization from n-hexane gave 96 (0.74 g, 32%) as yellow crystals.
mp 115-117 ° C., APCI-MS m / z 558 [M + H] ⁺

To a suspension of tetrahydrofuran (20 ml), 1M tetrabutylammonium fluoride / tetrahydrofuran solution (17.22 ml, 17.22 mol) was added to 97 of Production 96 (1.92 g, 3.44 mmol) and refluxed for 6 hours. The reaction mixture was allowed to cool, cold water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/1 to ethyl acetate) and recrystallized with ethyl acetate 97 (0.29 g). 21%) as yellow crystals.
mp 162-163 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.82-1.92 (2H, m), 1.97 (1H, t, J = 6.3 Hz, D ₂ O erased), 3 .80 (2H, t, J = 5.7 Hz), 3.91 to 4.00 (4H, m), 4.51 to 4.59 (1H, m), 4.68 (2H, ddd, J = 46.7, 4.7, 2.3 Hz), 5.10 (2H, s), 6.40 (1H, dd, J = 15.8, 0.6 Hz), 6.98 (1H, dd, J = 8.8, 2.4 Hz), 7.14 (1H, d, J = 2.4 Hz), 7.37 (1H, t, J = 0.6 Hz), 7.54 (1H, dd, J = 8.8, 0.4 Hz), 7.69 (1H, dd, J = 15.8, 0.6 Hz)
IR (Nujol) 3265, 1634 cm ⁻¹ , APCI-MS m / z 406 [M + H] ⁺

９８の製造
１（１０．０ｇ、６０．９７ｍｍｏｌ）のホモピペリジン（２０．６１ｍｌ、１８２．９ｍｍｏ）及びトリエチルアミン（４２．５５ｍｌ、３０４．８ｍｍｏｌ）溶液を９５℃で１６時間、１１５℃で８時間攪拌した。反応液を放冷、不溶物をろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝９／１〜４／１）で精製し９８（８．７７ｇ、７９％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １８３［Ｍ＋Ｈ］^＋

９９の製造
ジイソプロピルアミン（１０．１７ｍｌ、７２．１７ｍｍｏｌ）のテトラヒドロフラン（１３０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５９Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（４５．３９ｍｌ、 ７２．１７ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で９８（８．７７ｇ、４８．１１ｍｍｏｌ）のテトラヒドロフラン（５０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温でジメチルホルムアミド（７．４０ｍｌ、９６．２ｍｍｏｌ）を一度に加え、同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝３／１〜２／１）で精製し９９（９．３６ｇ、９３％）を黄色固体として得た。
ｍｐ ３２〜３４℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ２１１［Ｍ＋Ｈ］^＋

１００の製造
ジイソプロピルアミン（１．６１ｍｌ、１１．４ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５７Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（７．２６ｍｌ、 １１．４ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で４０（２．００ｇ，７．６０ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で９９（１．９２ｇ、９．１２ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液を一度に加え、同温で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）で精製、酢酸エチル／ｎ−ヘキサンで再結晶し１００（２．８０ｇ、７８％）を淡黄色結晶として得た。
ｍｐ １４９〜１５０℃、ＩＲ （Ｎｕｊｏｌ） ３２７３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４７４［Ｍ＋Ｈ］^＋

１０１の製造
１００（２．８０ｇ、５．９１ｍｍｏｌ）のジクロロメタン（３０ｍｌ）溶液にトリエチルアミン（３．３０ｍｌ、２３．７ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（１．０１ｍｌ、１３．０ｍｍｏｌ）を滴下し室温で３０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１〜１／２）で精製、酢酸エチル／ｎ−ヘキサンで再結晶し１０１（２．３５ｇ、８７％）を橙色結晶として得た。
ｍｐ １５２〜１５３℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ４５６［Ｍ＋Ｈ］^＋

１０２の製造
１０１（２．３５ｇ、５．１６ｍｍｏｌ）のメタノール（６０ｍｌ）懸濁液に１Ｎ塩酸（５．６７ｍｌ、５．６７ｍｍｏｌ）を加え室温で４時間、６０℃で３０分攪拌した。反応液を減圧溶媒留去、残渣を水／酢酸エチルで溶解、炭酸カリウム溶液でｐＨ１０とし、分液後、有機層を水洗、乾燥、減圧溶媒留去、残渣を酢酸エチルで再結晶し１０２（２．１１ｇ、９８％）を黄色結晶として得た。
ｍｐ １６１〜１６２℃、ＩＲ（Ｎｕｊｏｌ）１６２４ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ４１６［Ｍ＋Ｈ］^＋

１０３の製造
１０２（２．１１ｇ、５．０８ｍｍｏｌ）のエチレングリコールジメチルエーテル（１００ｍｌ）懸濁液にトリエチルアミン（１．０６ｍｌ、７．６２ｍｍｏｌ）、トルエンスルホン酸無水物（１．６６ｇ、５．０８ｍｏｌ）を加え８０℃で１６時間攪拌した。反応液を酢酸エチルで希釈、水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝１／２〜酢酸エチル）で精製、酢酸エチルで再結晶し１０３（１．３５ｇ、４７％）を黄色泡状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５７０［Ｍ＋Ｈ］^＋

１０４の製造
１０３（１．３５ｇ、２．３７ｍｍｏｌ）にテトラヒドロフラン（１０ｍｌ）溶液に１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１１．８５ｍｌ、１１．８５ｍｍｏｌ）を加え４時間還流した。反応液を放冷、冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロホルム／メタノール／２５％アンモニア水＝１０００／１０／１）で精製、酢酸エチルで再結晶し１０４（０．４２ｇ、４２％）を黄色結晶として得た。
ｍｐ １３７〜１３８℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．５４〜１．６８（４Ｈ、ｍ）、１．８１〜１．９１（４Ｈ、ｍ）、２．００（１Ｈ、ｔ、Ｊ＝６．２Ｈｚ、Ｄ_２Ｏ消去）、３．６４（４Ｈ、ｔ、Ｊ＝５．９Ｈｚ）、３．８８〜４．０２（２Ｈ、ｍ）、４．５０〜４．５８（１Ｈ、ｍ）、４．６８（２Ｈ、ｄｄｄ、Ｊ＝４６．８、４．６、２．３Ｈｚ）、６．３１（１Ｈ、ｄ、Ｊ＝１５．４Ｈｚ）、６．９７（１Ｈ、ｄｄ、Ｊ＝８．７、２．４Ｈｚ）、７．１３（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．３６（１Ｈ、ｓ）、７．５３（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．６９（１Ｈ、ｄ、Ｊ＝１５．４Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３２３２、１６３０ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４１８［Ｍ＋Ｈ］^＋ THK-765 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-homopiperidin-1-yl] thiazol-5-yl] ethenyl] benzoxazole ): Production of (104)

98 Preparation 1 (10.0 g, 60.97 mmol) in homopiperidine (20.61 ml, 182.9 mmol) and triethylamine (42.55 ml, 304.8 mmol) was stirred at 95 ° C. for 16 hours and 115 ° C. for 8 hours. did. The reaction mixture was allowed to cool, insolubles were filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 9/1 to 4/1) 98 ( 8.77 g, 79%) was obtained as a colorless oil.
APCI-MS m / z 183 [M + H] ⁺

Preparation of 99 To a solution of diisopropylamine (10.17 ml, 72.17 mmol) in tetrahydrofuran (130 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.59 M n-butyllithium / n-hexane solution (45. 39 ml, 72.17 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 98 (8.77 g, 48.11 mmol) in tetrahydrofuran (50 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. Dimethylformamide (7.40 ml, 96.2 mmol) was added at once at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 3/1 to 2/1) to give 99 (9.36 g, 93%). Obtained as a yellow solid.
mp 32-34 ° C, APCI-MS m / z 211 [M + H] ⁺

Preparation of 100 To a solution of diisopropylamine (1.61 ml, 11.4 mmol) in tetrahydrofuran (60 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.57 M n-butyllithium / n-hexane solution (7. 26 ml, 11.4 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 40 (2.00 g, 7.60 mmol) in tetrahydrofuran (60 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. A solution of 99 (1.92 g, 9.12 mmol) in tetrahydrofuran (60 ml) at the same temperature was added in one portion, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) and recrystallized from ethyl acetate / n-hexane 100 (2. 80 g, 78%) was obtained as pale yellow crystals.
mp 149-150 ° C., IR (Nujol) 3273 cm ⁻¹
APCI-MS m / z 474 [M + H] ⁺

Preparation of 101 To a solution of 100 (2.80 g, 5.91 mmol) in dichloromethane (30 ml) was added triethylamine (3.30 ml, 23.7 mmol), and methanesulfonyl chloride (1.01 ml, 13.0 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1 to 1/2) and recrystallized from ethyl acetate / n-hexane. 101 (2.35 g, 87%) was obtained as orange crystals.
mp 152-153 ° C., APCI-MS m / z 456 [M + H] ⁺

1N Hydrochloric acid (5.67 ml, 5.67 mmol) was added to a suspension of 102 of Preparation 101 (2.35 g, 5.16 mmol) in methanol (60 ml) and stirred at room temperature for 4 hours and at 60 ° C. for 30 minutes. The reaction solution was evaporated under reduced pressure, the residue was dissolved in water / ethyl acetate, adjusted to pH 10 with potassium carbonate solution, and after separation, the organic layer was washed with water, dried, evaporated under reduced pressure, and the residue was recrystallized with ethyl acetate. 2.11 g, 98%) was obtained as yellow crystals.
mp 161-162 ° C., IR (Nujol) 1624 cm ⁻¹
APCI-MS m / z 416 [M + H] ⁺

103 Preparation 102 (2.11 g, 5.08 mmol) in ethylene glycol dimethyl ether (100 ml) suspension of triethylamine (1.06 ml, 7.62 mmol) and toluenesulfonic anhydride (1.66 g, 5.08 mol) The mixture was further stirred at 80 ° C. for 16 hours. The reaction solution is diluted with ethyl acetate, washed with water, dried, evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 1/2 to ethyl acetate) and recrystallized from ethyl acetate. 103 (1.35 g, 47%) was obtained as a yellow foam.
APCI-MS m / z 570 [M + H] ⁺

104 Preparation 103 (1.35 g, 2.37 mmol) was added a 1 M tetrabutylammonium fluoride / tetrahydrofuran solution (11.85 ml, 11.85 mmol) to a tetrahydrofuran (10 ml) solution, and the mixture was refluxed for 4 hours. The reaction mixture was allowed to cool, cold water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform / methanol / 25% aqueous ammonia = 1000/10/1), recrystallized with ethyl acetate 104 (0. 42 g, 42%) was obtained as yellow crystals.
mp 137-138 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.54-1.68 (4H, m), 1.81-1.91 (4H, m), 2.00 (1H, t, J = 6.2 Hz, D ₂ O erased), 3.64 (4H, t, J = 5.9 Hz), 3.88 to 4.02 (2H, m), 4.50 to 4.58 (1H, m), 4.68 (2H, ddd, J = 46.8, 4.6, 2.3 Hz), 6.31 (1H, d, J = 15.4 Hz), 6.97 (1H, dd, J = 8.7, 2.4 Hz), 7.13 (1H, d, J = 2.4 Hz), 7.36 (1H, s), 7.53 (1H, d, J = 8.7 Hz), 7 .69 (1H, d, J = 15.4 Hz)
IR (Nujol) 3232, 1630 cm ⁻¹ , APCI-MS m / z 418 [M + H] ⁺

１０５の製造
１（６．０６ｇ、３６．９ｍｍｏｌ）のジイソプロピルエチルアミン（６４．５ｍｌ、３６９ｍｍｏｌ）溶液にホモモルホリン塩酸塩（５．０８ｇ、３６．９ｍｍｏｌ）を加え、アルゴン雰囲気攪拌下１２５℃で２４時間攪拌した。反応液を放冷、メタノールで溶解、シリカゲル（１００ｍｌ）を加え減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝９／１〜２／１）で精製し１０５（２．１０ｇ、３１％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １８５［Ｍ＋Ｈ］^＋

１０６の製造
ジイソプロピルアミン（２．４１ｍｌ、１７．１ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５７Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（１０．８９ｍｌ、１７．１ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で１０５（２．１０ｇ、１１．４ｍｍｏｌ）のテトラヒドロフラン（３０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温でジメチルホルムアミド（１．７５ｍｌ、２２．８ｍｍｏｌ）を一度に加え、同温で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）で精製し１０６（１．５６ｇ、６５％）を黄色固体として得た。
ｍｐ ７０〜７２℃、ＩＲ （Ｎｕｊｏｌ） １６３３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ２１３［Ｍ＋Ｈ］^＋

１０７の製造
ジイソプロピルアミン（０．５０ｍｌ、３．５３ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５７Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（２．２５ｍｌ、３．５３ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で２６（０．８０ｇ、２．３６ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で１０６（０．６０ｇ、２．８３ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を一度に加え、同温で４０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製し１０７（１．３０ｇ、１００％）を淡黄色粘体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５５２［Ｍ＋Ｈ］^＋

１０８の製造
１０７（１．３０ｇ、２．３６ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液にトリエチルアミン（１．３２ｍｌ、９．４４ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．４０ｍｌ、５．１９ｍｍｏｌ）を滴下し室温で３０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝１／１）で精製し１０８（１．１０ｇ、８７％）を黄色粘体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５３４［Ｍ＋Ｈ］^＋

１０９の製造
１０８（１．１０ｇ、２．０６ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（２．０６ｍｌ、２．０６ｍｍｏｌ）を加え室温で１時間攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１〜酢酸エチル）で精製、酢酸エチルで再結晶し１０９（０．４５ｇ、５３％）を黄色結晶として得た。
ｍｐ １１９〜１２０℃、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ １．９９（１Ｈ、ｔ、Ｊ＝６．３Ｈｚ、Ｄ_２Ｏ消去）、２．０４〜２．１８（２Ｈ、ｍ）、３．７７〜３．９８（１０Ｈ、ｍ）、４．５１〜４．５９（１Ｈ、ｍ）、４．６８（２Ｈ、ｄｄｄ、Ｊ＝４６．７、４．６、２．２Ｈｚ）、６．３４（１Ｈ、ｄ、Ｊ＝１５．３Ｈｚ）、６．９８（１Ｈ、ｄｄ、Ｊ＝８．８、２．４Ｈｚ）、７．１３（１Ｈ、ｄ、Ｊ＝２．４Ｈｚ）、７．３５（１Ｈ、ｓ）、７．５３（１Ｈ、ｄ、Ｊ＝８．８Ｈｚ）、７．６９（１Ｈ、ｄ、Ｊ＝１５．３Ｈｚ）
ＩＲ （Ｎｕｊｏｌ） ３３１０、１６２４ｃｍ^−１、ＡＰＣＩ−ＭＳ ｍ／ｚ ４２０［Ｍ＋Ｈ］^＋ THK-766 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-homomorpholinothiazol-5-yl) ethenyl] benzoxazole): (109) Manufacturing of

Homomorpholine hydrochloride (5.08 g, 36.9 mmol) was added to a solution of 105 prepared 1 (6.06 g, 36.9 mmol) in diisopropylethylamine (64.5 ml, 369 mmol) and stirred at 125 ° C. for 24 hours with stirring in an argon atmosphere. Stir. The reaction solution is allowed to cool, dissolved in methanol, silica gel (100 ml) is added, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1 to 2/1). (2.10 g, 31%) was obtained as a pale yellow oil.
APCI-MS m / z 185 [M + H] ⁺

Preparation of 106 To a solution of diisopropylamine (2.41 ml, 17.1 mmol) in tetrahydrofuran (30 ml) under stirring in an argon atmosphere at −60 ° C. or lower, a 1.57 M n-butyllithium / n-hexane solution (10. 89 ml, 17.1 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 105 (2.10 g, 11.4 mmol) in tetrahydrofuran (30 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. Dimethylformamide (1.75 ml, 22.8 mmol) was added in one portion at the same temperature, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 1/1) to give 106 (1.56 g, 65%) as a yellow solid. It was.
mp 70-72 ° C., IR (Nujol) 1633 cm ⁻¹
APCI-MS m / z 213 [M + H] ⁺

Preparation of 107 To a solution of diisopropylamine (0.50 ml, 3.53 mmol) in tetrahydrofuran (20 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.57 M n-butyllithium / n-hexane solution (2. 25 ml, 3.53 mmol) was added dropwise, and the temperature was gradually raised to 0 ° C. Next, a solution of 26 (0.80 g, 2.36 mmol) in tetrahydrofuran (20 ml) was added dropwise at −70 ° C. or lower, and the mixture was stirred at −78 ° C. for 1 hour. A solution of 106 (0.60 g, 2.83 mmol) in tetrahydrofuran (20 ml) at the same temperature was added in one portion, and the mixture was stirred at the same temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 107 (1.30 g, 100%) as a pale yellow viscous body.
APCI-MS m / z 552 [M + H] ⁺

108 Preparation 107 (1.30 g, 2.36 mmol) in dichloromethane (20 ml) was added triethylamine (1.32 ml, 9.44 mmol), and methanesulfonyl chloride (0.40 ml, 5.19 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 30 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1/1) to give 108 (1.10 g, 87%) as a yellow viscous body. It was.
APCI-MS m / z 534 [M + H] ⁺

To a solution of 109 No. 108 (1.10 g, 2.06 mmol) in tetrahydrofuran (10 ml) was added 1M tetrabutylammonium fluoride / tetrahydrofuran solution (2.06 ml, 2.06 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 2 / 1-ethyl acetate) and recrystallized with ethyl acetate 109 (0.45 g). 53%) as yellow crystals.
mp 119-120 ° C., ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.99 (1H, t, J = 6.3 Hz, D ₂ O erased), 2.04-2.18 (2H, m), 3 .77-3.98 (10H, m), 4.51-4.59 (1H, m), 4.68 (2H, ddd, J = 46.7, 4.6, 2.2 Hz), 6. 34 (1H, d, J = 15.3 Hz), 6.98 (1H, dd, J = 8.8, 2.4 Hz), 7.13 (1H, d, J = 2.4 Hz), 7.35 (1H, s), 7.53 (1H, d, J = 8.8 Hz), 7.69 (1H, d, J = 15.3 Hz)
IR (Nujol) 3310, 1624 cm ⁻¹ , APCI-MS m / z 420 [M + H] ⁺

１１０の製造
ブロモチアゾール１（８ｇ，４８．７ｍｍｏｌ）にチオモルホリン（２０ｇ，１９４ｍｍｏｌ）を加え、攪拌しながら加熱、８５〜９０℃で終夜反応させた。反応終了後、反応物を酢酸エチルに溶解させ、不溶物をろ去し、ろ液を減圧留去して粗生成物の混合物を得た。これをシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−へキサン／酢酸エチル＝４／１）にて精製し、１１０（８．８０ｇ、１００％）を褐色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ１８７［Ｍ＋Ｈ］^＋

１１１の製造
５℃に冷却した乾燥ジメチルフォルムアミド（１０．３ｇ，０．１４ｍｏｌ）にオキシ塩化リン（８．８６ｇ，５７．８ｍｍｏｌ）を滴下し、５℃で３０分攪拌した。この溶液にチアゾール誘導体１１０（８．８ｇ、４７ｍｍｏｌ）とジメチルフォルムアミド（３５ｇ，０．４８ｍｏｌ）を含む１，２−ジクロルエタン（４０ｍｌ）溶液を滴下した後、反応温度を上げて還流下、４時間反応させた。反応終了後、反応液を室温まで冷却し、氷を含む炭酸カリウム水溶液に加えて中和させた後、生成物をクロロフォルムで抽出。有機層を分離し、水洗、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた粗生成物を酢酸エチルから再結晶して、１１１（８．９２ｇ，８８％）を得た。
ｍｐ１３７−１３８℃
ＩＲ（Ｎｕｊｏｌ）１６５７ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ２１５［Ｍ＋Ｈ］^＋

１１２の製造
アルデヒド１１１（２．３５ｇ、１１ｍｍｏｌ） とベンゾキサゾール誘導体４０ （２．９ｇ、１１ｍｍｏｌ） を溶解させたジメチルスルホキシド（３０ｍｌ）溶液に５０％水酸化ナトリウム水溶液（５．０ｍｌ）を滴下し、室温にて３時間半攪拌反応させた。黄色の固体が析出した。反応液に水５０ｍｌを加え２０分程攪拌した後、黄色固体をろ取、水洗し、７０℃にて減圧乾燥し、１１２（４．０６ｇ， ８０％）を得た。
ｍｐ１７３−１７５℃
ＩＲ（Ｎｕｊｏｌ）１６３３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４６０［Ｍ＋Ｈ］^＋

１１３の製造
メタノール１２０ｍｌに１１２（４．５６ｇ、９．９２ｍｍｏｌ）を加え、室温にて攪拌しながら１Ｎ塩酸（２０ｍｌ）を滴下した。その後、反応液を加熱し、５５℃にて３時間反応させた。反応終了後、溶媒を減圧にて留去、残渣を水に溶解し、続いて炭酸カリウム水溶液でアルカリ性にすると黄色の沈殿物が析出した。これをろ取、水洗を繰り返した後、酢酸エチル−メタノール混液中で洗浄後、再びろ取し減圧乾燥して１１３（３．７７ｇ，９０％）を得た。
ｍｐ１７７−１７８℃
ＡＰＣＩ−ＭＳ ｍ／ｚ４２０［Ｍ＋Ｈ］^＋

１１４の製造
ジオール１１３（３．７０ｇ，８．８２ｍｍｏｌ）を乾燥ジメトキシエタン（１７０ｍｌ）に溶解させ、これにｐ−トルエンスルホン酸無水物（２．８７ｇ，８．８ｍｍｏｌ）、トリエチルアミン（１．３８ｇ，１３．７ｍｍｏｌ）、ジメチルアミノピリジン（９５ｍｇ）を加えて攪拌、７５℃に加熱、５時間反応させた。反応終了後、反応液を室温まで冷却し、沈殿物をろ去、ろ液を酢酸エチル（２００ｍｌ）で希釈した後、水を加えて分液した。有機層を水洗、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して粗生成物を得、これをシリカゲルカラムクロマトグラフィー（溶出溶媒：クロロフォルム／メタノール＝２０／１）にて分離精製し、１１４（１．８５ｇ，３６．５％）
及び未反応ジオール１１３（１．５２ｇ，４１％）を得た。
ｍｐ１９１−１９３℃
ＡＰＣＩ−ＭＳ ｍ／ｚ５７４［Ｍ＋Ｈ］^＋

１１５の製造
モノトシル体１１４（１．８ｇ，３．１３ｍｍｏｌ）を乾燥テトラヒドロフラン（１６ｍｌ）に溶解させ、フッ化テトラｎ−ブチルアンモニウムのテトラヒドロフラン１モル溶液（１６ｍｌ）を加えて加熱１時間半還流下に反応させた。反応終了後、反応液を酢酸エチルで希釈し、水を加えて分液し、有機層を水洗、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去して得られた粗生成物を塩基性シリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／アセトン＝３／２）で精製し、さらにエタノールにて再結晶させて１１５（４７０ｍｇ、３６％）を得た。
ｍｐ１３７−１３８℃
ＩＲ（Ｎｕｊｏｌ）３２４８，１６３３ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４２２［Ｍ＋Ｈ］^＋
１ＨＮＭＲ（ＤＭＳＯ−ｄ_６）δ２．７０−２．７５（４Ｈ，ｍ）、３．６２−３．６４（２Ｈ，ｂｒ．ｔ）、３．８４−３．９０（４Ｈ，ｍ）４．５８−４．７９（３Ｈ，ｍ）５．０７（１Ｈ，ｔ，Ｊ＝５．７５Ｈｚ）６．３７（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ）７．００（１Ｈ，ｄｄ，Ｊ＝８．７Ｈｚ，２．２Ｈｚ）７．３７Ｈｚ（１Ｈ，ｄ，Ｊ＝２．３Ｈｚ）７．５５（１Ｈ，ｄ，Ｊ＝８．７Ｈｚ）７．６１（１Ｈ，ｓ）７．７７（１Ｈ，ｄ，Ｊ＝１５．７Ｈｚ） THK-767 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-thiomorpholinothiazol-5-yl) ethenyl] benzoxazole): (115) Manufacturing of

Preparation of 110 Thiomorpholine (20 g, 194 mmol) was added to bromothiazole 1 (8 g, 48.7 mmol), and the mixture was heated and stirred at 85 to 90 ° C. overnight. After completion of the reaction, the reaction product was dissolved in ethyl acetate, the insoluble material was removed by filtration, and the filtrate was distilled off under reduced pressure to obtain a mixture of crude products. This was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 110 (8.80 g, 100%) as a brown oil.
APCI-MS m / z 187 [M + H] ⁺

Preparation of 111 Phosphorous oxychloride (8.86 g, 57.8 mmol) was added dropwise to dry dimethylformamide (10.3 g, 0.14 mol) cooled to 5 ° C., and the mixture was stirred at 5 ° C. for 30 minutes. To this solution, a 1,2-dichloroethane (40 ml) solution containing thiazole derivative 110 (8.8 g, 47 mmol) and dimethylformamide (35 g, 0.48 mol) was added dropwise, and then the reaction temperature was raised and refluxed for 4 hours. Reacted. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized by adding to an aqueous potassium carbonate solution containing ice, and the product was extracted with chloroform. The organic layer was separated, washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was recrystallized from ethyl acetate to obtain 111 (8.92 g, 88%).
mp137-138 ° C
IR (Nujol) 1657 cm ⁻¹
APCI-MS m / z 215 [M + H] ⁺

Preparation of 112 A 50% aqueous sodium hydroxide solution (5.0 ml) was added to a solution of aldehyde 111 (2.35 g, 11 mmol) and benzoxazole derivative 40 (2.9 g, 11 mmol) in dimethyl sulfoxide (30 ml). ) Was added dropwise, and the mixture was stirred at room temperature for 3 and a half hours. A yellow solid precipitated out. After adding 50 ml of water to the reaction solution and stirring for about 20 minutes, the yellow solid was collected by filtration, washed with water, and dried under reduced pressure at 70 ° C. to obtain 112 (4.06 g, 80%).
mp173-175 ° C
IR (Nujol) 1633 cm ⁻¹
APCI-MS m / z 460 [M + H] ⁺

Preparation of 113 112 (4.56 g, 9.92 mmol) was added to 120 ml of methanol, and 1N hydrochloric acid (20 ml) was added dropwise with stirring at room temperature. Thereafter, the reaction solution was heated and reacted at 55 ° C. for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in water, and then made alkaline with an aqueous potassium carbonate solution to form a yellow precipitate. This was collected by filtration and washed with water, and then washed in an ethyl acetate-methanol mixture, and then collected again by filtration and dried under reduced pressure to obtain 113 (3.77 g, 90%).
mp 177-178 ° C
APCI-MS m / z 420 [M + H] ⁺

Preparation of 114 Diol 113 (3.70 g, 8.82 mmol) was dissolved in dry dimethoxyethane (170 ml) to which p-toluenesulfonic anhydride (2.87 g, 8.8 mmol), triethylamine ( 1.38 g, 13.7 mmol) and dimethylaminopyridine (95 mg) were added, stirred, heated to 75 ° C., and reacted for 5 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the precipitate was removed by filtration, and the filtrate was diluted with ethyl acetate (200 ml), and then water was added for liquid separation. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, which was separated and purified by silica gel column chromatography (elution solvent: chloroform / methanol = 20/1) and 114 (1.85 g, 36.5%).
And unreacted diol 113 (1.52 g, 41%) was obtained.
mp191-193 ° C
APCI-MS m / z 574 [M + H] ⁺

Production of 115 Monotosyl derivative 114 (1.8 g, 3.13 mmol) was dissolved in dry tetrahydrofuran (16 ml), and 1 molar solution (16 ml) of tetra-n-butylammonium fluoride in tetrahydrofuran was added and heated for 1 hour. The reaction was carried out under half reflux. After completion of the reaction, the reaction solution was diluted with ethyl acetate, and water was added for separation. The organic layer was washed with water, saturated brine, and dried over anhydrous magnesium sulfate. The crude product obtained by distilling off the solvent under reduced pressure was purified by basic silica gel column chromatography (elution solvent: n-hexane / acetone = 3/2), and further recrystallized from ethanol to give 115 (470 mg, 36%).
mp137-138 ° C
IR (Nujol) 3248, 1633 cm ⁻¹
APCI-MS m / z 422 [M + H] ^+
1 HNMR (DMSO-d ₆ ) δ 2.70-2.75 (4H, m), 3.62-3.64 (2H, br.t), 3.84-3.90 (4H, m) 58-4.79 (3H, m) 5.07 (1H, t, J = 5.75 Hz) 6.37 (1H, d, J = 15.7 Hz) 7.00 (1H, dd, J = 8. 7 Hz, 2.2 Hz) 7.37 Hz (1 H, d, J = 2.3 Hz) 7.55 (1 H, d, J = 8.7 Hz) 7.61 (1 H, s) 7.77 (1 H, d, J = 15.7Hz)

１１７の製造
ジイソプロピルアミン（４．１５ｍｌ、２９．５ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液に、アルゴン雰囲気攪拌下−６０℃以下で１．５８Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液（１８．６４ｍｌ、 ２９．５ｍｍｏｌ）を滴下し除々に０℃まで昇温した。次に−７０℃以下で２６（４．００ｇ、１１．７８ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液を滴下し−７８℃で１時間撹拌した。同温で１１６（４．０３ｇ、１７．７ｍｍｏｌ）のテトラヒドロフラン（８０ｍｌ）溶液を一度に加え、同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル ＝４／１〜１／１）で精製し１１７（５．２０ｇ、７８％）を淡黄色泡状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５６８［Ｍ＋Ｈ］^＋

１１８の製造
１１７（５．２０ｇ、９．１６ｍｍｏｌ）のクロロホルム（８０ｍｌ）溶液にトリエチルアミン（５．１１ｍｌ、３６．６ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（１．５６ｍｌ、２０．２ｍｍｏｌ）を滴下し室温で１時間撹拌した。更にトリエチルアミン（２．５６ｍｌ、１８．３ｍｍｏｌ）を加え、氷冷撹拌下メタンスルホニルクロライド（０．７８ｍｌ、１０．１ｍｍｏｌ）を滴下し室温で２０分撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し１１８（５．０３ｇ、１００％）を淡黄色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５５０［Ｍ＋Ｈ］^＋

１１９の製造
１１８（５．０３ｇ、９．１６ｍｍｏｌ）のテトラヒドロフラン（６０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１８．３ｍｌ、１８．３ｍｍｏｌ）を加え室温４０分攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残さをシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１〜１／１）で精製し１１９（３．３６ｇ、８４％）を黄色固体として得た。
ｍｐ ２１８〜２１９℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ４３６［Ｍ＋Ｈ］^＋

１２０の製造
１１９（３．３６ｇ、７．７２ｍｍｏｌ）のクロロホルム（３６ｍｌ）溶液に氷冷撹拌下トリフルオロ酢酸（２４ｍｌ）を滴下し室温で２時間４０分撹拌した。反応液を酢酸エチルで希釈、炭酸カリウム溶液でｐＨ９とし、分液後有機層を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチル／ｎ−ヘキサンで再結晶し１２０（１．９７ｇ、７６％）を黄色結晶として得た。
ｍｐ ２２０〜２２０℃、ＡＰＣＩ−ＭＳ ｍ／ｚ ３３６［Ｍ＋Ｈ］^＋

１２２の製造
１２０（１．９７ｇ、５．８７ｍｍｏｌ）、１２１（１．００ｇ、７．０４ｍｍｏｌ）及びトルエンスルホン酸１水和物（５６ｍｇ、０．２９ｍｍｏｌ）のトルエン（２００ｍｌ）懸濁液を１６時間還流した。
反応液を放冷、酢酸エチルで希釈、シリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル）で精製、酢酸エチルで再結晶し１２２（０．７７ｇ、３４％）を黄色結晶として得た。
ｍｐ ２０５〜２０７℃、^１Ｈ ＮＭＲ（５００ＭＨｚ、ＤＭＳＯ−Ｄ_６）δ ３．６６（２Ｈ、ｔ、Ｊ＝５．０Ｈｚ）、４．５９〜４．７９（３Ｈ、ｍ）、５．０９（１Ｈ、ｔ、Ｊ＝５．６Ｈｚ、Ｄ_２Ｏ消去）、７．０８（１Ｈ、ｄ、Ｊ＝１６．３Ｈｚ）、７．０６（１Ｈ、ｍ）、７．４４（１Ｈ、ｄ、Ｊ＝２．１Ｈｚ）、７．６５（１Ｈ、ｄ、Ｊ＝８．７Ｈｚ）、７．９６（１Ｈ、ｄ、Ｊ＝１６．３Ｈｚ）、８．１９（１Ｈ、ｓ）、９．３１（２Ｈ、ｓ）
ＩＲ （Ｎｕｊｏｌ） ３３３３、１６３７、１６２０ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ ３８８［Ｍ＋Ｈ］^＋ THK-775 ((E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (1,2,4-triazol-4-yl) -thiazole-5- Yl) ethenyl] benzoxazole) (122)

Preparation of 117 To a solution of diisopropylamine (4.15 ml, 29.5 mmol) in tetrahydrofuran (60 ml) under argon atmosphere stirring at −60 ° C. or lower, a 1.58 M n-butyllithium / n-hexane solution (18. 64 ml, 29.5 mmol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 26 (4.00 g, 11.78 mmol) in tetrahydrofuran (60 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. A solution of 116 (4.03 g, 17.7 mmol) in tetrahydrofuran (80 ml) at the same temperature was added all at once, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1 to 1/1) to obtain 117 (5.20 g, 78%). Obtained as a pale yellow foam.
APCI-MS m / z 568 [M + H] ⁺

118 Preparation 117 (5.20 g, 9.16 mmol) in chloroform (80 ml) was added triethylamine (5.11 ml, 36.6 mmol), and methanesulfonyl chloride (1.56 ml, 20.2 mmol) was added under ice-cooling and stirring. The solution was added dropwise and stirred at room temperature for 1 hour. Further, triethylamine (2.56 ml, 18.3 mmol) was added, and methanesulfonyl chloride (0.78 ml, 10.1 mmol) was added dropwise with stirring under ice cooling, followed by stirring at room temperature for 20 minutes. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1) to give 118 (5.03 g, 100%) as a pale yellow solid. Obtained.
APCI-MS m / z 550 [M + H] ⁺

Preparation of 119 To a solution of 118 (5.03 g, 9.16 mmol) in tetrahydrofuran (60 ml) was added 1M tetrabutylammonium fluoride / tetrahydrofuran solution (18.3 ml, 18.3 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 40 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 1/1) to obtain 119 (3.36 g, 84%). Obtained as a yellow solid.
mp 218-219 ° C., APCI-MS m / z 436 [M + H] ⁺

Preparation of 120 119 (3.36 g, 7.72 mmol) in chloroform (36 ml) was added dropwise trifluoroacetic acid (24 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 2 hours and 40 minutes. The reaction solution is diluted with ethyl acetate, adjusted to pH 9 with potassium carbonate solution, and after separation, the organic layer is washed with water, dried, evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: ethyl acetate), ethyl acetate / n -Recrystallized with hexane to obtain 120 (1.97 g, 76%) as yellow crystals.
mp 220-220 ° C., APCI-MS m / z 336 [M + H] ⁺

Preparation of 122 120 (1.97 g, 5.87 mmol), 121 (1.00 g, 7.04 mmol) and toluenesulfonic acid monohydrate (56 mg, 0.29 mmol) in toluene (200 ml) suspension for 16 hours Refluxed.
The reaction mixture was allowed to cool, diluted with ethyl acetate, purified by silica gel column chromatography (elution solvent: ethyl acetate), and recrystallized from ethyl acetate to give 122 (0.77 g, 34%) as yellow crystals.
mp 205-207 ° C., ¹ H NMR (500 MHz, DMSO-D ₆ ) δ 3.66 (2H, t, J = 5.0 Hz), 4.59-4.79 (3H, m), 5.09 ( 1H, t, J = 5.6 Hz, D ₂ O erase), 7.08 (1H, d, J = 16.3 Hz), 7.06 (1H, m), 7.44 (1H, d, J = 2.1 Hz), 7.65 (1H, d, J = 8.7 Hz), 7.96 (1H, d, J = 16.3 Hz), 8.19 (1H, s), 9.31 (2H, s)
IR (Nujol) 3333, 1637, 1620 cm ⁻¹
APCI-MS m / z 388 [M + H] ⁺

１２４の製造
４−アミノ安息香酸エチルエステル１２３（２０ｇ，０．１２ｍｏｌ）を溶解したトルエン（２００ｍｌ）溶液に１２１（１３．２ｇ，０．０９３ｍｏｌ）、ｐ−トルエンスルホン酸（３００ｍｇ）、酢酸（２０ｍｌ）を加え、終夜、加熱還流させた。反応液を５℃に冷却し、析出物をろ取、減圧にて乾燥し、６．８７ｇ（３４％）の無色結晶１２４を得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ２１８［Ｍ＋Ｈ］^＋
ＩＲ（Ｎｕｊｏｌ）１７００，１６３０，１６１１ｃｍ^−１

１２５の製造
エステル１２４（６．８ｇ，３１．３ｍｍｏｌ）をエタノール（７０ｍｌ）に分散させ、１Ｎ水酸化ナトリウム（７０ｍｌ）を加えて、３０分加熱還流させた。反応終了後、減圧にて溶媒を留去し、得られた残留物を水に溶解させた。１Ｎ塩酸（７０ｍｌ）を加え、析出した無色固体をろ取、水洗後、減圧乾燥し、１２５（５．８８ｇ、９９％）を得た。
＞ｍｐ３３０℃
ＡＰＣＩ−ＭＳ ｍ／ｚ１９０［Ｍ＋Ｈ］^＋
ＩＲ（Ｎｕｊｏｌ）１６９２，１６０９ｃｍ^−１

１２７の製造
アルコール１２６（２４ｇ、０．１３ｍｏｌ）、ベンゾキサゾール誘導体４ （１９．４ｇ、０．１３ｍｏｌ）を溶解した乾燥テトラヒドロフラン（５００ｍｌ）溶液にトリフェニルフォスフィン（４０．９ｇ、０．１６ｍｏｌ）を加えて溶解させ、この溶液を５℃に冷却下、４０％ジエチルアゾジカルボキシレート（６９．５ｇ、０．１６ｍｏｌ）のトルエン溶液を滴下した。その後、反応液を室温にて終夜攪拌反応させた。さらにトリフェニルフォスフィン（８．１８ｇ、０．０３１ｍｏｌ）、４０％ジエチルアゾジカルボキシレート（１３ｇ、０．０３１ｍｏｌ）を反応液に加え、室温にて４時間攪拌させたのち、反応を終結させた。溶媒を減圧にて留去し、残渣をイソプロピルエーテルに溶解後、氷水にて冷却するとトリフェニルフォスフィンオキシドが析出、これをろ去し、ろ液をシリカゲルに吸着後、カラムクロマトグラフィー（シリカゲルＢＷ３００；溶出液 ｎ−へキサン−酢酸エチル＝３：１）により粗生成物を得た。さらにカラムクロマトグラフィー（シリカゲルＢＷ３００；溶出液 クロロフォルム：メタノール＝５０：１）にて精製し、無色透明油状物として１２７（２７．７ｇ、６８％）を得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ３１６［Ｍ＋Ｈ］^＋

１２８の製造
ベンゾキサゾール誘導体１２７（１０．０ｇ、３１．７ｍｍｏｌ）をエタノール（５０ｍｌ）に溶解させ、これに水（３０ｍｌ）と６Ｎ塩酸（２０ｍｌ）を加えて攪拌、加熱還流下で４時間反応させた。反応終了後、反応液を室温まで冷却し、減圧にて溶媒を留去、得られた粗生成物を酢酸エチルと飽和重曹水にて分液し、有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥させた。溶媒留去後、得られた生成物をイソプロピルエーテルと酢酸エチル混液で処理して固化させ、無色固体として１２８（６．５ｇ，７１％）を得た。
ｍｐ１１５〜１１７℃
ＡＰＣＩ−ＭＳ ｍ／ｚ２９２［Ｍ＋Ｈ］^＋

１２９の製造
カルボン酸１２５（１．８９ｇ、１０ｍｍｏｌ）を乾燥ジメチルフォルムアミド（５０ｍｌ）に溶解させ、さらに１−ヒドロキシベンゾトリアゾール（２．０２６ｇ、１５ｍｍｏｌ）、水溶性カルボジイミド塩酸塩（ＷＳＣ−ＨＣｌ）（２．８７５ｇ、１５ｍｍｏｌ）、トリエチルアミン（２．０２ｇ、２０ｍｍｏｌ）を加えて、室温にて２時間攪拌し反応させた。つぎに１２８（２．９２ｇ、１０ｍｍｏｌ）を反応液に加え温度を５０℃に上げてさらに３時間反応させた。冷却後、反応液を水に注ぎ、生成物を酢酸エチルで抽出、水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥。溶媒留去後、得られた粗生成物をカラムクロマトグラフィー（シリカゲルＢＷ３００、溶媒 クロロフォルム：メタノール＝２０：１）で精製して１２９（２．５２ｇ、５４％）を得た。
ｍｐ１７５−１７７℃
ＩＲ（Ｎｕｊｏｌ）３３１２，１６５２，１６１０ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ４６３［Ｍ＋Ｈ］^＋

１３０の製造
アミド１２９（２．５２ｇ、５．４ｍｍｏｌ）を乾燥テトラヒドロフラン（８０ｍｌ）に溶解させ、この溶液にトリフェニルフォスフィン（２．１４ｇ、８．１７ｍｍｏｌ）、４０％ジエチルアゾジカルボキシレート（３．５２ｇ、８．１７ｍｍｏｌ）を加え、室温にて終夜攪拌反応させた。反応終了後、反応液をＮＨ−シリカ（富士シリシア）に吸着させ、カラムクロマトグラフィー（ＮＨ−シリカ；溶媒 ｎ−へキサン−酢酸エチル＝１：３）にて精製し、１３０（２．２２ｇ、９２％）を無色固体として得た。
ｍｐ１０５−１０７℃
ＡＰＣＩ−ＭＳ ｍ／ｚ４４５［Ｍ＋Ｈ］^＋

１３１の製造
化合物１３０（２．２２ｇ、５ｍｍｏｌ）をメタノール（１００ｍｌ）、酢酸（１０ｍ）の混液に溶解させ、１０％パラジウム炭素触媒（１．０ｇ）を加えて、水素雰囲気下に５０℃に加熱し７時間攪拌反応させた。反応終了後、ろ過して触媒を除き、ろ液を減圧にて留去し、１３１（１．２５ｇ、７０％）を得た。メタノールより再結晶し無色結晶として１３１を得た。
ｍｐ２１９−２２０℃
ＩＲ（Ｎｕｊｏｌ）３４８４，１６１８ｃｍ^−１
ＡＰＣＩ−ＭＳ ｍ／ｚ３５５［Ｍ＋Ｈ］^＋
１Ｈ ＮＭＲ（ＤＭＳＯ−ｄ_６）δ３．６８（２Ｈ，ｂｔ）、４．５９−４．８３（３Ｈ，ｍ）、５．１１（１Ｈ，ｔ，Ｊ＝５．６Ｈｚ）、７．１０（１Ｈ，ｄｄ，Ｊ＝８．８Ｈｚ，２．４Ｈｚ）、７．５５（１Ｈ，ｄ，Ｊ＝２．４Ｈｚ）、７．７３（１Ｈ，ｄ，Ｊ＝８．８Ｈｚ）、７．９８（２Ｈ，ｂｄ，Ｊ＝８．８Ｈｚ）、８．３０（２Ｈ，ｂｄ，Ｊ＝８．８Ｈｚ）、９．２９（２Ｈ，ｓ） Preparation of THK-774 (6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [4- (1,2,4-triazol-4-yl) -phenyl] benzoxazole): (131)

Preparation of 124 To a solution of 4-aminobenzoic acid ethyl ester 123 (20 g, 0.12 mol) dissolved in toluene (200 ml), 121 (13.2 g, 0.093 mol), p-toluenesulfonic acid (300 mg), acetic acid (20 ml) ) And heated to reflux overnight. The reaction solution was cooled to 5 ° C., and the precipitate was collected by filtration and dried under reduced pressure to obtain 6.87 g (34%) of colorless crystals 124.
APCI-MS m / z 218 [M + H] ⁺
IR (Nujol) 1700, 1630, 1611 cm ⁻¹

Preparation of 125 Ester 124 (6.8 g, 31.3 mmol) was dispersed in ethanol (70 ml), 1N sodium hydroxide (70 ml) was added, and the mixture was heated to reflux for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in water. 1N Hydrochloric acid (70 ml) was added, and the precipitated colorless solid was collected by filtration, washed with water, and dried under reduced pressure to give 125 (5.88 g, 99%).
> Mp 330 ° C
APCI-MS m / z 190 [M + H] ⁺
IR (Nujol) 1692, 1609 cm ⁻¹

Preparation of 127 Triphenylphosphine (40.9 g,) was added to a solution of alcohol 126 (24 g, 0.13 mol) and benzoxazole derivative 4 (19.4 g, 0.13 mol) in dry tetrahydrofuran (500 ml). 0.16 mol) was added and dissolved, and a 40% diethylazodicarboxylate (69.5 g, 0.16 mol) solution in toluene was added dropwise while cooling the solution to 5 ° C. Thereafter, the reaction solution was stirred at room temperature overnight. Further, triphenylphosphine (8.18 g, 0.031 mol) and 40% diethylazodicarboxylate (13 g, 0.031 mol) were added to the reaction solution, and the mixture was stirred at room temperature for 4 hours, and then the reaction was terminated. . The solvent was distilled off under reduced pressure, the residue was dissolved in isopropyl ether, and then cooled with ice water to precipitate triphenylphosphine oxide. This was filtered off, and the filtrate was adsorbed onto silica gel, followed by column chromatography (silica gel BW300). A crude product was obtained by eluent n-hexane-ethyl acetate = 3: 1). Further purification by column chromatography (silica gel BW300; eluent chloroform: methanol = 50: 1) gave 127 (27.7 g, 68%) as a colorless transparent oil.
APCI-MS m / z 316 [M + H] ⁺

Preparation of 128 Benzoxazole derivative 127 (10.0 g, 31.7 mmol) was dissolved in ethanol (50 ml), water (30 ml) and 6N hydrochloric acid (20 ml) were added thereto, and the mixture was stirred and heated to reflux. For 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, the resulting crude product was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate, and the organic layer was washed with saturated brine and then anhydrous. Dried over magnesium sulfate. After distilling off the solvent, the resulting product was solidified by treatment with a mixed solution of isopropyl ether and ethyl acetate to obtain 128 (6.5 g, 71%) as a colorless solid.
mp 115-117 ° C
APCI-MS m / z 292 [M + H] ⁺

Preparation of 129 Carboxylic acid 125 (1.89 g, 10 mmol) was dissolved in dry dimethylformamide (50 ml) and further 1-hydroxybenzotriazole (2.026 g, 15 mmol), water-soluble carbodiimide hydrochloride (WSC). -HCl) (2.875 g, 15 mmol) and triethylamine (2.02 g, 20 mmol) were added, and the reaction was stirred at room temperature for 2 hours. Next, 128 (2.92 g, 10 mmol) was added to the reaction solution, the temperature was raised to 50 ° C., and the mixture was further reacted for 3 hours. After cooling, the reaction solution is poured into water, and the product is extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the resulting crude product was purified by column chromatography (silica gel BW300, solvent chloroform: methanol = 20: 1) to obtain 129 (2.52 g, 54%).
mp175-177 ° C
IR (Nujol) 3312, 1652, 1610 cm ⁻¹
APCI-MS m / z 463 [M + H] ⁺

Preparation of 130 Amide 129 (2.52 g, 5.4 mmol) was dissolved in dry tetrahydrofuran (80 ml) and triphenylphosphine (2.14 g, 8.17 mmol), 40% diethylazodi was dissolved in this solution. Carboxylate (3.52 g, 8.17 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction solution was adsorbed on NH-silica (Fuji Silysia) and purified by column chromatography (NH-silica; solvent n-hexane-ethyl acetate = 1: 3), and 130 (2.22 g, 92%) was obtained as a colorless solid.
mp105-107 ° C
APCI-MS m / z 445 [M + H] ⁺

Preparation of 131 Compound 130 (2.22 g, 5 mmol) was dissolved in a mixed solution of methanol (100 ml) and acetic acid (10 m), 10% palladium carbon catalyst (1.0 g) was added, and hydrogen atmosphere was added. The mixture was heated to 50 ° C and stirred for 7 hours. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was distilled off under reduced pressure to obtain 131 (1.25 g, 70%). Recrystallization from methanol gave 131 as colorless crystals.
mp 219-220 ° C
IR (Nujol) 3484, 1618 cm ⁻¹
APCI-MS m / z 355 [M + H] ^+
1 H NMR (DMSO-d ₆ ) δ 3.68 (2H, bt), 4.59-4.83 (3H, m), 5.11 (1H, t, J = 5.6 Hz), 7.10 ( 1H, dd, J = 8.8 Hz, 2.4 Hz), 7.55 (1H, d, J = 2.4 Hz), 7.73 (1H, d, J = 8.8 Hz), 7.98 (2H , Bd, J = 8.8 Hz), 8.30 (2H, bd, J = 8.8 Hz), 9.29 (2H, s)

１４６の製造
１４５（５.１８ｇ、４５.７８ｍｍｏｌ）のエタノール（６２ｍｌ）溶液にオルトギ酸トリエチル（1０ｍｌ）及びＳＰ−１１２[Ｈ^＋](１.０ｇ)を加え５時間還流した。反応液のＳＰ−１１２[Ｈ^＋]をろ別、ろ液を減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝４／１）で精製し１４６（８.５７ｇ、１００％）を無色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ １８８[Ｍ＋Ｈ]^＋

１４７の製造
１４６（９.０２ｇ、４８.１７ｍｍｏｌのテトラヒドロフラン(１００ｍｌ)溶液に、アルゴン雰囲気攪拌下−７０℃以下で１.６０Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液(４５.２ｍｌ、７２.３ｍｍｏｌ)を滴下し、−７８℃で1時間撹拌した。同温でジメチルホルムアミド（７.４５ｍｌ、９６.３ｍｍｏｌ）を一度に加え、同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル ＝９／１）で精製し１４７（５.５５ｇ、５４％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ２１６[Ｍ＋Ｈ]^＋

１４８の製造
ジイソプロピルアミン（２.８５ｍｌ、２０.２０ｍｍｏｌ）のテトラヒドロフラン(６０ｍｌ)溶液に、アルゴン雰囲気攪拌下−６０℃以下で１.６０Ｍ ｎ−ブチルリチウム／ｎ−ヘキサン溶液(１２.６２ｍｌ、 ２０.２０ｍｏｌ)を滴下し除々に０℃まで昇温した。次に−７０℃以下で６２（４.７６ｇ、１３.４７ｍｍｏｌ）のテトラヒドロフラン（２０ｍｌ）溶液を滴下し−７８℃で1時間撹拌した。同温で１４７（３.２０ｇ、１６.１６ｍｍｏｌ）のテトラヒドロフラン(２０ｍｌ)溶液を一度に加え、同温で３０分撹拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル ＝４／１〜１／1）で精製し１４８（５.２５ｇ、６９％）を淡黄色油状物として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５６９[Ｍ＋Ｈ]^＋

１４９の製造
１４８（５.２５ｇ、９.２３ｍｍｏｌ）のジクロロメタン（５０ｍｌ）溶液にトリエチルアミン(５.１５ｍｌ、３６.９ｍｍｏｌ)を加え、氷冷撹拌下メタンスルホニルクロライド(１.５７ｍｌ、２０.３ｍｍｏｌ)を滴下し室温で２時間撹拌した。反応液に冷水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝４／１）で精製し１４９（４.２４ｇ、８３％）を淡黄色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ５５１[Ｍ＋Ｈ]^＋

１５０の製造
１４９（１.００ｇ、１.８２ｍｍｏｌ）のテトラヒドロフラン（１０ｍｌ）溶液に室温攪拌下１Ｍ テトラブチルアンモニウムフロリド／テトラヒドロフラン溶液（１.８２ｍｌ、１.８２ｍｍｏｌ）を加え室温で１.５時間攪拌した。反応液に水を加え酢酸エチルで抽出した。抽出液を水洗、乾燥、減圧溶媒留去、残さをシリカゲルカラムクロマトグラフィー（溶出溶媒：酢酸エチル／ｎ−ヘキサン＝２／１〜１／１）で精製し１５０（０.６５ｇ、８２％）を黄色固体として得た。
ＡＰＣＩ−ＭＳ ｍ／ｚ ４３７[Ｍ＋Ｈ]^＋

１５１の製造
１５０（０.６５ｇ、１.４９ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液に２、４、６−コリジン（１.１８ｍｌ、８.９４ｍｍｏｌ）を加え、氷冷撹拌下トリメチルシリルトリフルオロメタンスルホネート（１.０８ｍｌ、５.９６ｍｍｏｌ）を滴下し同温で４０分攪拌した。反応液に水(２０ｍｌ)を加え室温で１時間攪拌、酢酸エチル(４０ｍｌ) を加え７０℃で１２時間攪拌した。反応液を放冷、分液後有機層を水洗、乾燥、減圧溶媒留去、残渣をシリカゲルカラムクロマトグラフィー（溶出溶媒：ｎ−ヘキサン／酢酸エチル＝２／１〜１／１）で精製し１５１（０.４８ｇ、８９％）を黄色固体として得た。
ｍｐ １３４〜１３５℃、ＩＲ (Ｎｕｊｏｌ) １６８５ｃｍ⁻¹
ＡＰＣＩ−ＭＳ ｍ／ｚ ３６３[Ｍ＋Ｈ]^＋

１５２の製造
１５１（０.４８ｇ、１.３２ｍｍｏｌ）のエタノール（２７ｍｌ）溶液にマロノニトリル（０.１１ｇ、１.５８ｍｍｏｌ）及びビペリジン（０.００４ｍｌ、０.０４ｍｍｏｌ）を加え、６０℃で４０分攪拌した。
反応液を氷冷、ろ取、エタノール洗浄、乾燥し１５２（０.４５ｇ、８３％）を赤紫色結晶として得た。、
ｍｐ １９２〜１９３℃（ｄｅｃ）、^１Ｈ ＮＭＲ（３００ＭＨｚ、ＣＤＣｌ_３）δ ２.３９〜２.５５ (１Ｈ、ｍ)、３.９３（２Ｈ、ｄ、Ｊ＝５.７Ｈｚ）、４.１９（２Ｈ、ｄ、Ｊ＝５.９Ｈｚ）、４.７２（２Ｈ、ｄｄ、Ｊ＝４７.１、５.４Ｈｚ）、６.９７（１Ｈ、ｄｄ、Ｊ＝８.８、２.３Ｈｚ）、７.０７（１Ｈ、ｄｄ、Ｊ＝１６.１、０.４Ｈｚ）、７.０８（１Ｈ、ｄ、Ｊ＝２.３Ｈｚ）、７.６２ (１Ｈ、ｄ、Ｊ＝８．８Ｈｚ)、７.８２（１Ｈ、ｄｄ、Ｊ＝１６.１、０.６Ｈｚ）、７.９４（１Ｈ、ｓ）、８.２５（１Ｈ、ｓ）
ＩＲ (Ｎｕｊｏｌ) ２２２５、１６１７ｃｍ⁻¹、ＡＰＣＩ−ＭＳ ｍ／ｚ ４１１[Ｍ＋Ｈ]^＋ THK-683 ((E) -2- [2- (2,2-dicyanoethenylthiazol-5-yl) ethenyl] -6-[(2-fluoromethyl-3-hydroxy) propoxy] benzoxazole ): Production of (152)

Preparation of 146 To a solution of 145 (5.18 g, 45.78 mmol) in ethanol (62 ml) were added triethyl orthoformate (10 ml) and SP-112 [H ⁺ ] (1.0 g), and the mixture was refluxed for 5 hours. The reaction solution SP-112 [H ⁺ ] was filtered off, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 4/1) to 146 (8. 57 g, 100%) as a colorless oil.
APCI-MS m / z 188 [M + H] ⁺

Preparation of No. 147 146 (9.02 g, 48.17 mmol in tetrahydrofuran (100 ml) solution under argon atmosphere stirring at −70 ° C. or lower with 1.60 M n-butyllithium / n-hexane solution (45.2 ml, 72.3 mmol) Was added dropwise and stirred for 1 hour at −78 ° C. Dimethylformamide (7.45 ml, 96.3 mmol) was added in one portion at the same temperature, and the mixture was stirred for 30 minutes at the same temperature. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 9/1) to purify 147 (5.55 g, 54%) as a pale yellow color. Obtained as an oil.
APCI-MS m / z 216 [M + H] ⁺

Preparation of 148 A solution of diisopropylamine (2.85 ml, 20.20 mmol) in tetrahydrofuran (60 ml) was added to a 1.60 M n-butyllithium / n-hexane solution (12. 62 ml, 20.20 mol) was added dropwise and the temperature was gradually raised to 0 ° C. Next, a solution of 62 (4.76 g, 13.47 mmol) in tetrahydrofuran (20 ml) was added dropwise at −70 ° C. or lower and stirred at −78 ° C. for 1 hour. A solution of 147 (3.20 g, 16.16 mmol) in tetrahydrofuran (20 ml) at the same temperature was added in one portion, and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 4/1 to 1/1) to obtain 148 (5.25 g, 69%). Obtained as a pale yellow oil.
APCI-MS m / z 569 [M + H] ⁺

149 was added to a solution of 148 (5.25 g, 9.23 mmol) in dichloromethane (50 ml) with triethylamine (5.15 ml, 36.9 mmol), and methanesulfonyl chloride (1.57 ml, 20.3 mmol) was added with stirring under ice cooling. The solution was added dropwise and stirred at room temperature for 2 hours. Cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane / ethyl acetate = 4/1) to give 149 (4.24 g, 83%) as a pale yellow solid. Obtained.
APCI-MS m / z 551 [M + H] ⁺

150 Preparation 149 (1.00 g, 1.82 mmol) in tetrahydrofuran (10 ml) was stirred at room temperature with 1M tetrabutylammonium fluoride / tetrahydrofuran solution (1.82 ml, 1.82 mmol) and stirred at room temperature for 1.5 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate / n-hexane = 2/1 to 1/1) to obtain 150 (0.65 g, 82%). Obtained as a yellow solid.
APCI-MS m / z 437 [M + H] ⁺

151 , 2,4,6-collidine (1.18 ml, 8.94 mmol) was added to a solution of 150 (0.65 g, 1.49 mmol) in dichloromethane (20 ml), and trimethylsilyltrifluoromethanesulfonate (1. 08 ml, 5.96 mmol) was added dropwise and stirred at the same temperature for 40 minutes. Water (20 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (40 ml) was added, and the mixture was stirred at 70 ° C. for 12 hours. The reaction solution is allowed to cool, and after separation, the organic layer is washed with water, dried, evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 2/1 to 1/1). 151 (0.48 g, 89%) was obtained as a yellow solid.
mp 134-135 ° C, IR (Nujol) 1685 cm ^-1
APCI-MS m / z 363 [M + H] ⁺

Preparation of 152 To a solution of 151 (0.48 g, 1.32 mmol) in ethanol (27 ml) was added malononitrile (0.11 g, 1.58 mmol) and biperidine (0.004 ml, 0.04 mmol) and stirred at 60 ° C. for 40 minutes. did.
The reaction solution was ice-cooled, filtered, washed with ethanol, and dried to obtain 152 (0.45 g, 83%) as reddish purple crystals. ,
mp 192 to 193 ° C. (dec), ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.39 to 2.55 (1H, m), 3.93 (2H, d, J = 5.7 Hz), 4.19 (2H, d, J = 5.9 Hz), 4.72 (2H, dd, J = 47.1, 5.4 Hz), 6.97 (1H, dd, J = 8.8, 2.3 Hz), 7.07 (1H, dd, J = 16.1, 0.4 Hz), 7.08 (1H, d, J = 2.3 Hz), 7.62 (1H, d, J = 8.8 Hz), 7 .82 (1H, dd, J = 16.1, 0.6 Hz), 7.94 (1H, s), 8.25 (1H, s)
IR (Nujol) 2225, 1617 cm ⁻¹ , APCI-MS m / z 411 [M + H] ⁺

Examination in amyloid β protein brain accumulation model Examination using transgenic (Tg) mice in which amyloid accumulates in the brain (1) Tg mice (Tg2576 or APPswe2576 / Tau JPL3) were used. A test compound was administered from the tail vein of a Tg mouse, and 1 hour later, the chest was opened under pentobarbital Na deep anesthesia, and transcardially fixed with 10% neutral buffered formalin.
(2) The brain was cleaved and the brain was removed and immersed in 30% sucrose for 12 hours or more. Next, the extracted brain is quickly frozen in finely pulverized dry ice, and a cryosection (Bright, Model-OT) is used to place a frozen section on a poly-L-lysine-coated slide glass. Created.
(3) In a state where the prepared brain section was not encapsulated, it was microscopically examined with a fluorescence microscope (Nikon, Eclipse 80i) and photographed with a digital camera (Nikon Dxm1200F or Photometrics Cool SNAP ES). The results are shown in Fig. 1-3.
The test compound administered intravenously crossed the blood-brain barrier and bound to amyloid plaques in the Tg mouse brain.

When immunostaining the same section, it was performed as follows.
(1) About 150 μl of 90% formic acid was dropped on the same section and allowed to stand at room temperature for 5 minutes. After washing with tap water for 5 minutes, it was immersed in cold PBS-Tween 20 for 2 minutes, and then 150 μl of 0.05% trypsin solution was dropped and reacted at 37 ° C. for 15 minutes.
(2) After washing with cold PBS-Tween 20 for 5 minutes × 2 times in an ice bath, 2 drops of blocking serum was dropped and reacted at 37 ° C. for 30 minutes. After removing excess water, amyloid β About 150 μl of 4G8 (Chemicon, 1: 100 dilution), a protein specific antibody, was dropped and reacted at 37 ° C. for 1 hour.
(3) Further, after washing with cold PBS-Tween 20 for 2 minutes × 5 times, 2 drops of anti-mouse Ig (H + L), goat and biotin-binding solution were dropped and reacted at 37 ° C. for 1 hour, and then with cold PBS-Tween 20 After washing 2 times × 3 times, 2 drops of ABC solution (streptavidin-biotin-peroxidase complex solution) was dropped and allowed to stand for 30 minutes. Again, after washing with cold PBS-Tween 20 for 3 minutes for 2 minutes, DAB solution (10 mg of DAB was dissolved in 20 ml of 0.05 mol / Tris-HCl buffer and 100 μl of 3% hydrogen peroxide solution was added immediately before use) was added. 150 μl was added dropwise to obtain sufficient color, and then washed with distilled water for 1 minute to stop the reaction.
The results are shown in FIG. 4 and FIG. THK-702 crossed the blood-brain barrier and bound to the amyloid plaques of Tg mice (FIG. 3 upper panel), and the binding site coincided with the anti-Aβ antibody staining site of the same section (FIG. 3 lower panel). . FIG. 4 shows the strongly enlarged image of FIG. A, B, and C correspond to A, B, and C in FIG. THK-702 bound to amyloid plaques of Tg mice (FIG. 4 left panel), and the binding site completely coincided with the anti-Aβ antibody staining site of the same section (FIG. 4 right panel).

The procedure for the staining test of the compound of the present invention on a brain section of an Alzheimer's disease patient will be described below.
(1) Brain specimens in the temporal lobe or hippocampus of patients and normal elderly who were pathologically confirmed as Alzheimer's disease were used. Specimens were provided by the collaborative research welfare village hospital Longevity Medical Research Institute, and have been approved by the bereaved family for use for research purposes (license No. 20 of the welfare village hospital ethics committee).
(2) The paraffin-embedded brain tissue was sliced at a thickness of 6 μm or 8 μm, spread on a slide glass, and dried. The paraffin brain sections were deparaffinized in the order of xylene 10 minutes × 2, 100% ethanol 5 minutes × 2, 90% ethanol 5 minutes, and running water 10 minutes.
(3) In the present invention, as a pretreatment for staining with a compound, a treatment for removing autofluorescence by lipofuscin was performed. First, the brain paraffinized section was immersed in a 0.25% KM _n O ₄ solution for 20 minutes. After washing with PBS for 2 minutes × 2 times, it was immersed in a 0.1% K ₂ S ₂ O ₅ / oxalic acid solution for about 5 seconds, and further washed with PBS for 2 minutes × 3 times.
(4) About 150 μl of a 100 μM compound solution of the present invention dissolved in 50% ethanol was dropped and reacted for 10 minutes. After being immersed in tap water five times, it was sealed with a Flour Save Reagent (Calbiochem) and microscopically examined using a fluorescence microscope (Nikon, Eclipse 80i). Images were taken with a digital camera (Nikon Dxin 1200F or Photometrics Cool SNAP ES).

Immunostaining was performed as follows.
(A) Immunostaining method for amyloid β protein:
(1) After deparaffinization, washing was performed in distilled water for 2 minutes × 2, and the tissue was surrounded with immunopen, and then about 150 μl of formic acid was added dropwise and allowed to stand at room temperature for 5 minutes. After washing with tap water for 5 minutes, it was immersed in cold PBS-Tween 20 for 2 minutes, and then approximately 150 μl of 0.05% trypsin solution was dropped and reacted at 37 ° C. for 15 minutes.
(2) After washing with cold PBS-Tween 20 for 5 minutes × 2 times in an ice bath, drop 2 drops of blocking serum and react at 37 ° C. for 30 minutes to remove excess water, then amyloid β protein About 150 μl of 6F / 3D (DAKO, diluted 1:50), which is a specific antibody, was dropped at 37 ° C. for 1 hour.
(3) Further, after washing with cold PBS-Tween 20 for 2 minutes × 5 times, 2 drops of anti-mouse IgG (H + L), goat and biotin-binding solution were dropped and reacted at 37 ° C. for 1 hour, and then with cold PBS-Tween 20 After washing 2 times × 3 times, 2 drops of ABC solution (streptavidin-biotin-peroxidase complex solution) was dropped and allowed to stand for 30 minutes. Again, after washing with cold PBS-Tween 20 for 3 minutes for 2 minutes, DAB solution (10 mg of DAB was dissolved in 20 ml of 0.05 mol / Tris-HCl buffer and 100 μl of 3% hydrogen peroxide solution was added immediately before use) was added. 150 μl was added dropwise to obtain sufficient color, and then washed with distilled water for 1 minute to stop the reaction.
(B) Immunostaining method for neurofibrillary tangle (1) After deparaffinization, after washing twice in chilled PBS-Tween 20 for 5 minutes x 2 drops of blocking serum was added and reacted at 37 ° C for 30 minutes. It was. After removing excess water, two drops of AT-8 (Mia Nobel, 1: 100 dilution), which is a tau specific antibody, was added dropwise and reacted at 4 ° C. overnight.
(2) The following day, after washing with cold PBS-Tween 20 for 2 minutes × 5 times, 2 drops of anti-rabbit IgG, goat and biotin-binding solution were dropped and reacted at 37 ° C. for 1 hour for 2 minutes with cold PBS-Tween 20 × After washing 3 times, 2 drops of ABC solution (streptavidin-biotin-peroxidase complex solution) was dropped and allowed to stand for 30 minutes.
(3) After washing again with cold PBS-Tween 20 for 2 minutes x 3 times, DAB solution (10 mg of DAB was dissolved in 20 ml of 0.05 mol / Tris-HCl buffer and 100 μl of hydrogen peroxide solution was added immediately before use) About 150 μl was dropped to obtain a sufficient color, and then washed with distilled water for 1 minute to stop the reaction. The blocking serum, anti-rabbit IgG, goat, biotin binding solution, and ABC solution were those included in the Phosphorylated Tau Immunohistostein Kit (Wako299-57301).

The result of the said dyeing | staining test about the compound of this invention is shown in FIGS. THK-097 (FIG. 1), THK-525 (FIG. 2), THK-727 (FIG. 3), and THK-702 (FIG. 4 and FIG. 5) inhibit amyloid β protein in Tg mice that accumulate amyloid β protein. Staining was confirmed. The compound of the present invention was also confirmed to bind to amyloid β protein in brain sections of Alzheimer's disease patients (FIGS. 6 to 37). THK-097 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 6). THK-184 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 7). THK-185 bound to amyloid β protein and neurofibrillary tangles in Alzheimer's disease patient brain sections (FIG. 8). THK-203 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 9). THK-207 bound to amyloid β protein in the brain of Alzheimer's disease patients (FIG. 10). THK-248 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 11). THK-254 bound to neurofibrillary tangles in Alzheimer's disease patient brain sections (FIG. 12). THK-258 bound to amyloid β protein and neurofibrillary tangles in Alzheimer's disease patient brain sections (FIG. 13). THK-262 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 14). THK-276 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 15). THK-281 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 16). THK-308 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 17). THK-317 bound to amyloid β protein and neurofibrillary tangles in Alzheimer's disease patient brain sections (FIG. 18). THK-383 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 19). THK-385 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 20). THK-386 bound to amyloid β protein and neurofibrillary tangles in Alzheimer's disease patient brain sections (FIG. 21). THK-525 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 22). THK-556 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 23). THK-558 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 24). THK-559 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 25). THK-561 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 26). THK-562 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 27). THK-563 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 28). THK-565 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 29). THK-585 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 30). THK-702 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 31). THK-708 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 32). THK-727 bound to amyloid β protein and neurofibrillary tangles in Alzheimer's disease patient brain sections (FIG. 33). THK-752 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 34). THK-761 bound to amyloid β protein in a brain section of Alzheimer's disease patients (FIG. 35). THK-763 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 36). THK-766 bound to amyloid β protein in brain sections of Alzheimer's disease patients (FIG. 37).
Thus, it was found that the compound of the present invention specifically recognizes amyloid β protein and neurofibrillary tangles in brain sections of Alzheimer's disease patients. It was also found that the compounds of the present invention other than the above also specifically bind to amyloid β protein.
Below, the test method regarding the characteristic of the compound of this invention is demonstrated.

Acute toxicity test The acute toxicity of the compound of the present invention was examined by intravenous administration using mice. Crj: CDI male mice were used as 4 mice per group (average weight of each group was 31 to 32 g). Each compound was dissolved in a mixture of 1N HCl, polyethylene glycol 400 and distilled water, or dissolved in DMSO, diluted with distilled water, administered via the tail vein, and observed up to 7 days thereafter. The observation results are shown in Table 2.

Brain transfer test Brain translocation test using HPLC The compound of the present invention was intravenously administered to mice, and brain translocation in vivo was measured.
(1) 30-40 g (n = 3) Slc: ICR (Japan SLC) was used for the mouse.
(2) The test compound was dissolved in a mixed solution of 5% Tween 80-5% ethyl alcohol-5% 1N HCl-saline solution, injected through the tail vein, and cervical dislocation under ether anesthesia 2 minutes after administration. The blood was collected from the heart using a heparinized syringe and the brain was collected.
(3) The blood was centrifuged at 4 ° C. and 10,000 rpm for 10 minutes after blood collection, and the supernatant was stored as plasma at −80 ° C. The brain (including cerebellum) was stored at −80 ° C. after sampling.
(4) 0.1 ml of plasma was taken, 0.3 ml of acetonitrile was added and vortexed, followed by centrifugation at 4 ° C. and 10,000 G for 5 minutes. 0.2 ml of the supernatant after centrifugation was transferred to Mini-Uniprep (Whatman), 0.2 ml of 20 mM phosphate buffer was added and filtered. Of the filtered solution, 0.2 ml was analyzed by HPLC (SHISEIDO NANOSPACE SI-2, pump: 3001, UV-VIS detector: 3002, column thermostat: 3004, fluorescence detector: 3013).
(5) The brain was homogenized by adding 2 ml of methanol, and centrifuged at 4 ° C., 3000 or 4000 rpm for 10 minutes. 500 μl of the supernatant after centrifugation was taken and diluted 10-fold with 20 mM phosphate buffer. (I) 2 to 3 ml of acetonitrile, (ii) 2 to 5 ml of methanol, and (iii) 4 to 6 ml of ultrapure water are passed through the cartridge for solid phase extraction in this order, and the cartridge for solid phase extraction (JT Baker Speeddisk). The supernatant solution diluted 10-fold was passed through. Water was removed by passing air through a cartridge for solid phase extraction 2-3 times with an empty syringe, and then eluted with about 500 μl of acetonitrile or methanol, and diluted 2-fold with 20 mM phosphate buffer. 0.2 ml of the solution was analyzed by HPLC.
(6) For each plasma and brain, the content of the test compound in the brain and plasma relative to the dose (% ID (injected dose) / g or ml) was determined.

Table 3 shows the brain migration 2 minutes after intravenous administration of the test compound in mice. It is considered that 0.5% ID / g or more is sufficient for the brain migration of a compound for PET or SPECT targeting the central nervous system. In that sense, the test compound is a compound with extremely high brain transportability.

Brain transfer test II. Examination using [ ¹⁸ F] -labeled compound The compound of the present invention can be labeled using methods known to those skilled in the art. The following illustrates some synthesis examples of ^{[18 F]} labeled forms of compounds of the present invention.

^[18 F] THK-525-labeled synthetic cyclotron HM12 (Shigeru Sumitomo Industries Ltd.) proton beam accelerated 12MeV 95% or more isotopic purity of ^[18 O] was irradiated for 30 minutes in _{H 2} O ¹⁸ F ^- Was synthesized. Then ¹⁸ through the solution to an anion exchange resin (AG1-X8) F ^- was captured on the resin, and eluted with 33 mM K ₂ CO ₃ solution. 300 μL (3.28 GBq) of this ¹⁸ F ^- containing K ₂ CO ₃ aqueous solution is placed in a brown vial (capacity 10 mL), Kryptofix 222 (16 mg) and acetonitrile (3 mL) are added, and He gas is heated while heating in an oil bath (110 ° C.). The acetonitrile was completely removed while spraying and azeotropically with water. Further, the operation of adding acetonitrile (3 mL) and removing acetonitrile under the same heating conditions was repeated three times to make the inside of the vial anhydrous. A DMSO solution (0.8 mL) in which the labeling precursor THK-575 (1.9 mg) was dissolved was added thereto, and the mixture was heated and stirred in an oil bath (110 ° C.) for 10 minutes. Thereafter, this DMSO reaction solution was passed through a Sep-Pak (registered trademark) Alumina cartridge (Waters) and a filter (0.5 μm), and the obtained filtrate was subjected to semi-preparative HPLC (column: Inertsil (registered trademark) ODS-). 3 (10 × 250 mm), mobile phase: EtOH / MeCN / 20 mM NaH ₂ PO ₄ = 15/45/40, flow rate: 5.0 mL / min), eluting at about 11-12 minutes [ ¹⁸ F] THK525 The radioactive peak of was fractionated. The radiochemical yield after attenuation correction obtained from the radioactivity of this fraction was 42%.

^[18 F] THK-702 labeled synthetic cyclotron HM12 ¹⁸ was irradiated (Shigeru Sumitomo Industries Ltd.) accelerated 12MeV proton beam isotopic purity of 95% or higher in the ^[18 O] _{H 2} O in 30 min F ^- Was synthesized. Then ¹⁸ through the solution to an anion exchange resin (AG1-X8) F ^- was captured on the resin, and eluted with 33 mM K ₂ CO ₃ solution. Take 200 μL (3.24 GBq) of this ¹⁸ F ^- containing K ₂ CO ₃ aqueous solution in a brown vial (capacity 10 mL), add Kryptofix 222 (16 mg) and acetonitrile (3 mL), and heat He gas while heating in an oil bath (110 ° C.). The acetonitrile was completely removed while spraying and azeotropically with water. Further, the operation of adding acetonitrile (3 mL) and removing acetonitrile under the same heating conditions was repeated three times to make the inside of the vial anhydrous. A DMSO solution (0.8 mL) in which the labeling precursor THK-703 (2.2 mg) was dissolved was added thereto, and the mixture was heated and stirred in an oil bath (110 ° C.) for 10 minutes. Thereafter, the reaction solution is diluted with distilled water (8 mL) and loaded onto a Sep-Pak tC18 cartridge (manufactured by Waters). After washing the cartridge with distilled water, the crude product solution eluted with EtOH is subjected to semi-preparative HPLC. (Column: Inertsil® ODS-3 (10 × 250 mm), mobile phase: MeCN / 20 mM NaH ₂ PO ₄ = 40/60, flow rate: 7.0 mL / min) and elute in about 11 minutes [ ¹⁸ F] A radioactive peak derived from THK-702 was collected. The radiochemical yield after attenuation correction obtained from the radioactivity of this fraction was 21%.

Labeled synthesis of [ ¹⁸ F] THK-727 [ ¹⁸ O] H ₂ O having an isotope purity of 95% or more was irradiated for 30 minutes with a 12 MeV proton beam accelerated by cyclotron HM12 (manufactured by Sumitomo Heavy Industries), and ¹⁸ F ⁻ Was synthesized. Then ¹⁸ through the solution to an anion exchange resin (AG1-X8) F ^- was captured on the resin, and eluted with 33 mM K ₂ CO ₃ solution. Take 100 μL (1.27 GBq) of this ¹⁸ F ^- containing K ₂ CO ₃ aqueous solution in a brown vial (capacity 10 mL), add Kryptofix 222 (10 mg) and acetonitrile (3 mL), and heat He gas while heating in an oil bath (110 ° C.). The acetonitrile was completely removed while spraying and azeotropically with water. Further, the operation of adding acetonitrile (3 mL) and removing acetonitrile under the same heating conditions was repeated three times to make the inside of the vial anhydrous. A DMSO solution (0.4 mL) in which the labeling precursor THK-726 (1.9 mg) was dissolved was added thereto, and the mixture was heated and stirred in an oil bath (110 ° C.) for 10 minutes. Thereafter, the DMSO reaction solution was passed through a Sep-Pak (registered trademark) Allumina cartridge (manufactured by Waters) and a filter (0.5 μm). Further, DMSO (0.2 mL) was further passed through, and the obtained filtrate was semi-prepared. Elute in about 23 minutes by HPLC (column: Inertsil® ODS-3 (10 × 250 mm), mobile phase: MeCN / 20 mM NaH ₂ PO ₄ = 40/60, flow rate: 5.0 mL / min) A radioactive peak derived from ¹⁸ F] THK-727 was collected. The radiochemical yield after attenuation correction determined from the radioactivity of this fraction was 44%.

^[18 F] THK-761 labeled synthetic cyclotron HM12 ¹⁸ was irradiated (Shigeru Sumitomo Industries Ltd.) accelerated 12MeV proton beam isotopic purity of 95% or higher in the ^[18 O] _{H 2} O in 30 min F ^- Was synthesized. Then ¹⁸ through the solution to an anion exchange resin (AG1-X8) F ^- was captured on the resin, and eluted with 33 mM K ₂ CO ₃ solution. 400 μL (3.73 GBq) of this ¹⁸ F ^- containing K ₂ CO ₃ aqueous solution is placed in a brown vial (capacity 10 mL), Kryptofix 222 (16 mg) and acetonitrile (2 mL) are added, and He gas is heated while heating in an oil bath (110 ° C.). The acetonitrile was completely removed while spraying and azeotropically with water. Further, the operation of adding acetonitrile (2 mL) and removing acetonitrile under the same heating conditions was repeated three times to make the inside of the vial anhydrous. A DMSO solution (0.7 mL) in which the labeling precursor THK-760 (4.0 mg) was dissolved was added thereto, and the mixture was heated and stirred in an oil bath (110 ° C.) for 10 minutes. Thereafter, the reaction solution was diluted with distilled water (7 mL), loaded onto a Sep-Pak tC18 cartridge (manufactured by Waters), and then added with distilled water and MeCN / 20 mM NaH ₂ PO ₄ (v / v = 3/7, 2 mL). After sequentially washing the cartridge, the crude product solution eluted with EtOH was subjected to semi-preparative HPLC (column: Inertsil® ODS-3 (10 × 250 mm), mobile phase: MeCN / 20 mM NaH ₂ PO ₄ = 30 / 70, flow rate: 5.5 mL / min), a radioactive peak derived from [ ¹⁸ F] THK-761 eluting at about 15.5 to 16.0 minutes was collected. The radiochemical yield after attenuation correction obtained from the radioactivity of this fraction was 11%.

Labeled synthesis of [ ¹⁸ F] THK-763 [ ¹⁸ O] H ₂ O having an isotope purity of 95% or more was irradiated for 30 minutes with a 12 MeV proton beam accelerated by cyclotron HM12 (manufactured by Sumitomo Heavy Industries), and ¹⁸ F ⁻ Was synthesized. Then ¹⁸ through the solution to an anion exchange resin (AG1-X8) F ^- was captured on the resin, and eluted with 33 mM K ₂ CO ₃ solution. Take 200 μL (3.02 GBq) of this ¹⁸ F ^- containing K ₂ CO ₃ aqueous solution in a brown vial (capacity 10 mL), add Kryptofix 222 (16 mg) and acetonitrile (2 mL), and heat He gas while heating in an oil bath (110 ° C.). The acetonitrile was completely removed while spraying and azeotropically with water. Further, the operation of adding acetonitrile (2 mL) and removing acetonitrile under the same heating conditions was repeated three times to make the inside of the vial anhydrous. A DMSO solution (0.7 mL) in which the labeling precursor THK-762 (3.1 mg) was dissolved was added thereto, and the mixture was heated and stirred in an oil bath (110 ° C.) for 10 minutes. Thereafter, the reaction solution was diluted with distilled water (7 mL), loaded onto a Sep-Pak tC18 cartridge (manufactured by Waters), and then added with distilled water and MeCN / 20 mM NaH ₂ PO ₄ (v / v = 3/7, 5 mL). After sequentially washing the cartridge, the crude product solution eluted with EtOH was purified by semi-preparative HPLC (column: Inertsil® ODS-3 (10 × 250 mm), mobile phase: MeCN / 20 mM NaH ₂ PO ₄ = 35 / 65, flow rate: 6.0 mL / min), a radioactive peak derived from [ ¹⁸ F] THK-763 eluting at about 24-25 minutes was collected. The radiochemical yield after attenuation correction obtained from the radioactivity of this fraction was 38%.

(Preparation example)
^[18 F] BF-227 labeled synthetic cyclotron HM12 (Shigeru Sumitomo Industries Ltd.) accelerated 12MeV proton beam isotopic purity of 95% or higher in the ^[18 O] was irradiated for 30 minutes in _{H 2} O ¹⁸ F ^- Was synthesized. Then ¹⁸ through the solution to an anion exchange resin (AG1-X8) F ^- was captured on the resin, and eluted with 33 mM K ₂ CO ₃ solution. Take 200 μL (1.58 GBq) of this ¹⁸ F ^- containing K ₂ CO ₃ aqueous solution in a brown vial (capacity 10 mL), add Kryptofix 222 (16 mg) and acetonitrile (2 mL), and heat He gas while heating in an oil bath (110 ° C.). The acetonitrile was completely removed while spraying and azeotropically with water. Further, the operation of adding acetonitrile (2 mL) and removing acetonitrile under the same heating conditions was repeated three times to make the inside of the vial anhydrous. A DMSO solution (0.7 mL) in which a labeling precursor (TsO body, 2.0 mg) was dissolved was added thereto, and the mixture was heated and stirred in an oil bath (110 ° C.) for 10 minutes. Thereafter, the reaction solution was diluted with distilled water (8 mL), loaded onto a Sep-Pak tC18 cartridge (manufactured by Waters), and then added with distilled water and MeCN / H ₂ O (v / v = 1/1, 1.5 mL). After sequentially washing the cartridge, the crude product solution eluted with EtOH was subjected to semi-preparative HPLC (column: YMC-Pack Pro C18 RS (10 × 250 mm), mobile phase: EtOH / MeCN / 20 mM NaH ₂ PO ₄ = 15 / 40/45, flow rate: 5.0 mL / min), a radioactive peak derived from [ ¹⁸ F] BF-227 eluting at about 12-13 minutes was collected. The radiochemical yield after attenuation correction obtained from the radioactivity of this fraction was 42%.

Preparation of labeled compound-containing physiological saline Solution containing [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761, [ ¹⁸ F] THK-763 or [ ¹⁸ F] BF-227 obtained by the above-described labeling synthesis The preparative HPLC fraction was diluted with distilled water (about 20 ml), loaded onto a Sep-Pak tC18 cartridge (manufactured by Waters), washed with distilled water (5-10 ml), and labeled with EtOH (3-5 ml). Was eluted. An appropriate amount of 5% polysorbate 80 ethanol solution is added to this EtOH eluate, the solvent is distilled off with a rotary evaporator while heating at 80 ° C., and the resulting residue (mixture of labeled compound and polysorbate 80) is dissolved in physiological saline. Thus, a physiological saline solution containing a labeled compound was prepared. The radiochemical purity of the drug solution after preparation was 95% or more.

Evaluation of Mouse brain-localizing and bone accumulation of the labeled compound ^{[18 F] BF-227,} [18 F] THK-702, saline containing [18 F] THK-761 or ^[18 F] THK-763, The fluid was administered to male ICR mice (6-7 weeks old) via the tail vein, and the radioactivity accumulation in the brain tissue and bone tissue after 2, 30, and 60 minutes led to the brain migration and bone accumulation of each labeled compound. Sex was evaluated.
BF-227 (2- [2- (2-dimethylaminothiazol-5-yl) ethenyl] -6- (2-fluoroethoxy) benzoxazole) has a chemical structure relatively different from those of the compound of the present invention. Similarity, and BF-227 has been used as a [ ¹¹ C] label but has F in its chemical structure (Kudo et al., Journal of Nuclear Medicine, Vol. 48, 553). Therefore, in the experiment, the difference in properties between [ ¹⁸ F] BF-227 as a PET probe for diagnosing Alzheimer's disease and the [ ¹⁸ F] -labeled compound of the present invention was examined.
The labeled compound-containing physiological saline used had a radiochemical purity of 95% or more, a specific activity of 18.5 to 148 GBq / μmol, and 1.11 to 2.22 MBq of labeled compound per mouse was administered. In the evaluation of radioaccumulation, the ratio of radioactivity per unit weight of the evaluated tissue (% Injected dose / g of tissue;% ID / g) relative to the total dose radioactivity was used as an index. For the measurement of radioactivity, a gamma counter (1480 WIZARD, manufactured by PerkinElmer) was used. As an experimental procedure, the labeled compound was administered into the tail vein, and after 2, 30, and 60 minutes, the mouse was subjected to cervical dislocation under ether anesthesia, and blood was immediately collected from the heart, and then the whole brain (including the cerebellum and brain stem). ) And femur. And the radioactivity and tissue weight of each sample were measured, and% ID / g was calculated using the data.
Table 4 summarizes the results of this evaluation experiment. Further, FIG. 38 shows the result of evaluating the bone accumulation property.

It is considered that 0.5% ID / g or more is sufficient for the brain migration of the labeled compound for PET or SPECT targeting the central nervous system. ^{[18 F]} labeled compounds of the present invention in this sense is an extremely brain of ^{[18 F]} labeled compounds.
Often problematic in [ ¹⁸ F] -labeled compounds is bone accumulation of ¹⁸ F ions based on in vivo defluorination (Tipre et al., Journal of Nucleic Medicine, 47, 345-353, 2006). . ^{Since 18} F ions have a high bone accumulation property, if a [ ¹⁸ F] -labeled compound that is susceptible to defluorination is used as a diagnostic probe for Alzheimer's disease, the resulting PET image is as if it were a bone (skull) image. I will. However, at present, it cannot be said that a labeling compound that is hardly susceptible to defluorination has been obtained (Cai et al., Journal of Medicinal Chemistry, vol. 47, pages 2208-2218, 2004, Zhang et al., Journal. of Medicinal Chemistry, 48, 5980-5988, 2005, Chang et al., Nuclear Medicine and Biology, 33, 811-820, 2006, and Stephenson et al., Bioconjugate Chemistry-2, 18, 200, 7200. See year).
Table 4 shows the results of bone accumulation of [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761, [ ¹⁸ F] THK-763, and [ ¹⁸ F] BF-227, which were simultaneously measured at the time of evaluating brain migration. It was as follows. [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761 and [ ¹⁸ F] THK-763 did not show bone accumulation, whereas [ ¹⁸ F] BF-227 was time-dependent. Marked bone accumulation was observed. From the above, [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761 and [ ¹⁸ F] THK-763 are not subject to defluorination in vivo, whereas [ ¹⁸ F] BF-227 is easily defluorinated. It was suggested that ¹⁸ F ions accumulate in bone.

Summarizing the above experimental results, the [ ¹⁸ F] -labeled compounds of the present invention, particularly [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761 and [ ¹⁸ F] THK-763, are clearly washed out from the brain. [ ¹⁸ F] BF-227 (Table 4), and the bone accumulation of ¹⁸ F ions based on defluorination observed in [ ¹⁸ F] BF-227 is the [ ¹⁸ F] -labeled compound of the present invention, In particular, [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761 and [ ¹⁸ F] THK-763 were hardly observed, and it was found that defluorination was suppressed to a satisfactory level (Table). 4).
From the above, when viewed as a PET probe for Alzheimer's disease diagnosis, the [ ¹⁸ F] labeled compound of the present invention, particularly [ ¹⁸ F] THK-702, [ ¹⁸ F] THK-761 and [ ¹⁸ F] THK-763, Compared with BF-227 which does not have the structure of the compound of the present invention, it is extremely useful.

Mutagenicity test It is desirable that the compound of the present invention is at a level that does not cause mutagenicity or does not cause a problem because of its use. In order to examine the gene mutagenicity of the compounds of the present invention, a reverse mutation test using histidine-requiring Salmonella typhimurium TA100 and TA98 strains was performed. The test was conducted twice: a dose setting test and this test.
The test method and the mutagenicity test of the compound of the present invention are shown below. In the dose setting test, 0.160, 0.800, 4.00, 20.0, 100, and 500 μg / plate were used as the maximum dose, and this test was conducted at about 6 doses (common ratio 2).

First, test compounds were dissolved or suspended in DMSO, and then diluted sequentially to prepare test compound solutions of various concentrations.
100 μl of test compound solution or negative control (DMSO) solution is dispensed into a sterilized test tube, and then in the absence of metabolic activation system (−S9mix), 0.1 mol / sodium phosphate buffer (pH 7) .4) was 500 μl, and in the presence of a metabolic activation system (+ S9mix), 500 μl of S9mix was dispensed.
Subsequently, 100 μl of the test strain suspension cultured at 37 ° C. for 8 hours with shaking was added, and then incubated at 37 ° C. for 20 minutes using a shaking incubator. After shaking, 2 ml of top agar was added and the contents were mixed.
Then, the mixture is poured onto a minimal glucose agar plate medium (plate), spreads uniformly, the top agar is solidified, the growth state of the test strain on the plate is observed using a stereomicroscope, and the test substance is further precipitated. After observing the state with the naked eye, the number of colonies produced by reverse mutation was counted.
Regarding the measurement, a colony analyzer was used to calculate the number of colonies by performing area correction and count correction. When the use of the colony analyzer was inappropriate due to precipitation of the test compound or growth inhibition, it was counted visually.
When the number of revertant colonies increased more than twice as much as the negative control, and when the increase was dose-dependent or reproducible, it was determined as positive. In addition, when it determined with positive, the specific activity which is a relative comparison value of the intensity | strength of mutagenicity was calculated | required with the following formula.
Specific activity =
{(Number of colonies per plate at that concentration) − (number of colonies per plate of negative control)} / concentration value (mg / plate)

Mutation tests were performed after reversion by the method described above. Table 5 below shows specific activity values, which are relative comparative values of the mutagenic strength of the test compound.
THK-097, THK-336, THK-525, THK-683, THK-702, THK-708, THK-711, THK-713, THK-727, THK-752 are restored regardless of the absence or presence of S9mix. The number of mutant colonies did not increase more than twice that of the negative control, the specific activity was negative, and the activities of THK-707, THK-761, and THK-763 in the presence of S9mix were weak, while FDDNP ( Agdepppa et al., Journal of Neuroscience (J. Neurosci.), 21, RC189, 2001) and IMPY (Kung et al., Brain Research, 956, 202, 2002) S9mix. The specific activity in the presence was very high. From the results shown in Table 5, it was confirmed that the compounds of the present invention subjected to this test were not mutagenic or even if their specific activity was very weak compared to FDDNP and IMPY. .

Next, the screening method for the compound of the present invention will be described. Some of the compounds of the present invention cannot be screened because the fluorescence wavelength overlaps with thioflavin T by the thioflavin T method. For these compounds, the following new screening was introduced.
Fluorescent Congo Red Method (1) Amyloid β protein 1-40 (purchased from Peptide Institute) was dissolved in phosphate buffer (pH 7.4) and allowed to stand at 37 ° C. for 4 days.
(2) 50 μl of Congo red dissolved in the same buffer was dispensed into a 96-well microplate (final concentrations 0.1, 0.3, 1 μM).
(3) 100 μl of amyloid β protein was added (final concentration 5 μM) and left for 30 minutes.
(4) 100 μl of test compound dissolved in the same buffer was added (final concentration 10 μM) and left for 60 minutes.
(5) Using a fluorescence microplate reader (Spectra Max 190, manufactured by Molecular Devices Co., Ltd.), measurement was performed at the optimum excitation and measurement wavelength that had been measured in advance.
(6) Fluorescence in the presence of test compound, amyloid β protein, and Congo red is A, B in the presence of test compound and Congo red, C, that of test compound and amyloid β protein, D of test compound alone Then, the β structure recognition degree of the test compound was calculated by the following formula.
Test compound β structure recognition degree (%) = {(AB) / (CD)} × 100
(7) It can be said that the greater the β structure recognition degree, the higher the binding specificity of the test compound for amyloid β protein.

Table 6 shows the results. The binding of the test compound to Aβ was suppressed in a concentration-dependent manner by Congo red that specifically binds to Aβ. From the above, it was revealed that the test compound recognizes the β structure of Aβ.

  The conformational disease diagnostic probe compound of the present invention, in particular, the diagnostic imaging probe compound, and the pharmaceutical composition for treatment and / or prevention of conformational disease containing the same, is a conformational disease which is currently regarded as the most incurable disease, for example, It is extremely useful for early detection, treatment and prevention of Alzheimer's disease, and is used in the field of production of diagnostics and diagnostic kits for conformation disease, the field of production of therapeutic and preventive drugs for conformation disease, and research of conformation disease. Is possible.

Claims (32)

Formula I:

[Where:
R ¹ and R ² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or
A 3- to 8-membered nitrogen-containing aliphatic ring formed by R ¹ , R ² and the nitrogen atom to which they are bonded together (the carbon atom constituting the nitrogen-containing aliphatic ring is a nitrogen atom, a sulfur atom or An oxygen atom may be substituted, and when a carbon atom is substituted with a nitrogen atom, the nitrogen atom may be substituted with a lower alkyl group),
X ₁ and X ₂ each independently represent a nitrogen atom, a sulfur atom or an oxygen atom,
R ³ represents —O-lower alkyl group (the alkyl group is substituted with a halogen atom, and may be further substituted with a hydroxy group);
m represents an integer of 1 to 3, wherein R ³ is an —O-lower alkyl group substituted with only a halogen atom, and R ¹ and R ² are each independently , A hydrogen atom or a lower alkyl group) or a pharmaceutically acceptable salt or solvate thereof. The compound according to claim 1, wherein X ₁ is an oxygen atom, or a pharmaceutically acceptable salt or solvate thereof. The compound according to claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein X ₁ is an oxygen atom and X ₂ is a sulfur atom. The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof, wherein R ³ is a -O-lower alkyl group substituted with a hydroxy group and a halogen atom. Formula in Formula (I):

The compound represented by [wherein each symbol is the same as defined above] is a morpholino group or a dimethylamino group, or a pharmaceutically acceptable salt or solvate thereof. R ³ is

The compound according to claim 1, or a pharmaceutically acceptable salt or solvate thereof. The compound represented by formula (I) is:
6- (2-fluoro-ethoxy) -2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazole,
Toluene-4-sulfonic acid 2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl-benzoxazole-6-yloxy] ethyl ester,
2-fluoromethyl-3- [2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazol-6-yloxy] -propan-1-ol,
(E) -2- [2- (2-morpholinothiazol-5-yl) ethenyl] -6-[(1-fluoromethyl-2-hydroxy) ethoxy] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(2-fluoromethyl-3-hydroxy) propoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (4-methylpiperazin-1-yl) thiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(2-fluoromethyl-3-hydroxy) propoxy] -2- [2- [2- (pyrrolidin-1-yl) thiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2- (pyrrolidin-1-yl) -thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(1-Fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-([1,3] oxazinan-3-yl) -thiazol-5-yl] ethenyl] benzo Xazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- [2-homopiperidin-1-yl] thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-homomorpholinothiazol-5-yl) ethenyl] benzoxazole, and (E) -6- [ The compound according to claim 1, which is a compound selected from the group consisting of (1-fluoromethyl-2-hydroxy) ethoxy] -2- [2- (2-thiomorpholinothiazol-5-yl) ethenyl] benzoxazole. Or a pharmaceutically acceptable salt or solvate thereof.   The labeled compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvate thereof.   The compound according to claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein the label is derived from a radionuclide.   The compound according to claim 9, or a pharmaceutically acceptable salt or solvate thereof, wherein the radionuclide is a γ-ray emitting nuclide.   9. The compound according to claim 8, or a pharmaceutically acceptable salt or solvate thereof, wherein the label is a positron emitting nucleus. Positron emission nuclei are from ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ³⁵ mCl, ⁷⁶ Br, ⁴⁵ Ti, ⁴⁸ V, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Cu, ⁶⁶ Ga, ⁸⁹ Zr, ^{94 m} Tc and ¹²⁴ I The compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of: The compound according to claim 11 or a pharmaceutically acceptable salt or solvate thereof, wherein the positron emitting nucleus is ¹¹ C or ¹⁸ F.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof.   A pharmaceutical composition comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, and a solubilizing agent.   The pharmaceutical composition according to claim 15, wherein the solubilizer is selected from the group consisting of polysorbate 80, polyethylene glycol, ethanol and propylene glycol.   The pharmaceutical composition according to any one of claims 14 to 16, which is an injection.   A composition for diagnosing conformation disease, comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof.   A pharmaceutical composition for treating and / or preventing a conformational disease, comprising the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof.   A kit for diagnosing a conformation disease, comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof as an essential component.   A protein or neurofibrillary tangle having a β sheet structure, comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof as an essential constituent element is detected or Composition or kit for staining.   The kit according to claim 20 or 21, which is for diagnostic imaging.   The treatment and / or prevention of conformation disease in a subject, comprising administering the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, to the subject. Method.   A method for diagnosing conformation disease in a subject, comprising administering the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, to the subject.   Use of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a composition or kit for diagnosing conformation disease in a subject.   14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or solvate thereof, for producing a pharmaceutical composition for the treatment and / or prevention of conformation disease in a subject. Use of.   A protein having a β sheet structure in a sample, wherein the sample is stained with the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt or solvate thereof. Alternatively, a method for detecting or staining neurofibrillary tangles.   The compound according to any one of claims 1 to 13 or a pharmaceutical thereof, for producing a composition or kit for detecting or staining a protein or neurofibrillary tangle having a β sheet structure in a sample Use of salts or solvates that are acceptable to   The compound is 6- (2-fluoro-ethoxy) -2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazole, 2-fluoromethyl-3- [2- [ 2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl] benzoxazol-6-yloxy] -propan-1-ol, (E) -2- [2- (2-morpholinothiazole- 5-yl) ethenyl] -6-[(1-fluoromethyl-2-hydroxy) ethoxy] benzoxazole or (E) -6-[(1-fluoromethyl-2-hydroxy) ethoxy] -2- [2 29. The composition or kit of claim 21, the method of claim 27, or the use of claim 28 which is-[2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole. Formula (I ′)

[Where:
R ¹ and R ² each independently represent a hydrogen atom, a lower alkyl group, a cycloalkyl group, or
A 3- to 8-membered nitrogen-containing aliphatic ring formed by R ¹ , R ² and the nitrogen atom to which they are bonded together (the carbon atom constituting the nitrogen-containing aliphatic ring is a nitrogen atom, a sulfur atom or An oxygen atom may be substituted, and when a carbon atom is substituted with a nitrogen atom, the nitrogen atom may be substituted with a lower alkyl group),
X ₁ and X ₂ each independently represent a nitrogen atom, a sulfur atom or an oxygen atom,
R ⁴ represents —O-lower alkyl group (the alkyl group is substituted with p-toluenesulfonyl group, methanesulfonyl group or trifluoromethanesulfonyl group, and may be further substituted with hydroxy group). ,
m represents an integer of 1 to 3, wherein R ³ is an —O-lower alkyl group substituted with only a halogen atom, and R ¹ and R ² are each independently , A hydrogen atom or a lower alkyl group). R ⁴ is the formula

The compound of Claim 30 which is group represented by these. The compound represented by the formula (I ′) is
Toluene-4-sulfonic acid 2- [2- [2- (2-morpholin-4-yl-thiazol-5-yl) -vinyl-benzoxazole-6-yloxy] ethyl ester,
(E) -6-[(3-hydroxy-2-tosyloxymethyl) propoxy] -2- [2- (2-morpholinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6- [2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- [2-dimethylamino-thiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- [2-methylaminothiazol-5-yl] ethenyl] benzoxazole,
(E) -6-[(3-hydroxy-2-tosyloxymethyl) propoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole,
(E) -6-[(2-hydroxy-1-tosyloxymethyl) ethoxy] -2- [2- (2-piperidinothiazol-5-yl) ethenyl] benzoxazole, or (E) -6 31. The compound of claim 30, which is-[(1-hydroxymethyl-2-tosyloxy) ethoxy] -2- [2- [2- (pyrrolidin-1-yl) -thiazol-5-yl] ethenyl] benzoxazole. .

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