JP2007145806A - Oxazole derivative, production method thereof and method for introducing oxazolyl group using them - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide oxazole derivatives capable of synthesizing various analogous compounds of polysubstituted oxazole widely used as a medicine and an organic material, being easily prepared and useful as an oxazolyl group-introducing reagent that can be stably handled, a production method of the oxazole derivatives and a method for introducing an oxazolyl group using them. <P>SOLUTION: The oxazole derivatives are represented by general formula (1) wherein R<SP>1</SP>represents an alkyl group, an aralkyl group, an aromatic group or the like; R<SP>2</SP>represents a hydrogen atom, an alkyl group, an aralkyl group, an aromatic group or the like; and R<SP>3</SP>and R<SP>4</SP>may be the same or different from each other and each represents an alkyl group or the like, and R<SP>3</SP>and R<SP>4</SP>may be combined with each other to form a ring. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to oxazole derivatives, a method for producing them, and a method for introducing an oxazolyl group using them.

  Multi-substituted oxazole derivatives have a common structure widely used in pharmaceuticals and organic materials, and are highly demanded compounds. As a method for synthesizing a polysubstituted oxazole derivative, a cross-coupling reaction using a metal catalyst between an oxazolyl group-introducing reagent and an organic halide or a sulfonic acid ester can be mentioned. Conventionally, as the oxazolyl group introduction reagent, for example, an oxazole zinc reagent (Non-Patent Document 1), a tin reagent (Non-Patent Document 2), and the like are known. However, the production method is complicated, the toxicity of the reagent itself is high, and the yield of the reaction is poor. On the other hand, it has been reported that an aryl boron reagent proceeds with a cross-coupling reaction with an organic halide or a sulfonic acid ester using a metal catalyst (Non-patent Document 3), and an aryl group introduction reagent that can be handled safely and easily. It is widely used in pharmaceutical synthesis and materials fields. However, only one example of the oxazole boron reagent is disclosed as an oxazol-2-ylboronic acid derivative (Patent Document 1), and there is no description regarding the oxazol-4-ylboronic acid derivative related to the present invention. In Patent Document 1, an example is described in which oxazol-2-ylboronic acid is prepared by metalation of the hydrogen atom at the 2-position of the corresponding oxazole with a base and subsequent reaction with boric acid triisopropyl ester. However, the synthesis method has a high substrate specificity, and other oxazol-2-ylboronic acid derivatives may not be prepared (see Comparative Examples), which is not a general method. In addition, it has been reported that oxazol-2-ylboronic acid derivatives have low stability and are easily hydrogenolyzed (Non-Patent Document 4). No cross-coupling reaction with an organic halide or sulfonic acid ester by a metal catalyst using the oxazol-4-ylboronic acid derivative relating to the present invention and its production method has been reported at all.

JP 2004-31743 A Journal of Organic Chemistry, 1999, 64, 1011 Synlett, 1995, p. 415 Chemical Reviews, 1995, 95, 2457. Organic Letters, 2006, Vol. 8, p. 2495

  An object of the present invention is to provide an oxazolyl group-introducing reagent that can synthesize various analogs of polysubstituted oxazoles widely used as pharmaceuticals and organic materials, can be easily prepared, and can be handled stably. There is.

  As a result of intensive studies to solve the above problems, the present inventors have found that the oxazole derivative (1) of the present invention is useful as a reagent for introducing an oxazolyl group, and completed the present invention.

（式中、Ｒ^１は置換していてもよいＣ_１〜Ｃ_８アルキル基、置換していてもよいＣ_３〜Ｃ_８シクロアルキル基、置換していてもよいＣ_７〜Ｃ_１１アラルキル基、置換していてもよいＣ_２〜Ｃ_８アルケニル基、置換していてもよいＣ_２〜Ｃ_８アルキニル基、置換していてもよい芳香族基、水酸基の保護基で保護されていてもよい水酸基、置換していてもよいＣ_１〜Ｃ_８アルコキシ基、ホルミル基、置換していてもよいＣ_２〜Ｃ_８アシル基、置換していてもよいＣ_２〜Ｃ_８アルコキシカルボニル基、置換していてもよいカルバモイル基、カルボキシル基、シアノ基、ニトロ基、置換していてもよいアミノ基、置換していてもよい複素環基または置換していてもよいシリル基を表す。Ｒ^２は水素原子、置換していてもよいＣ_１〜Ｃ_８アルキル基、置換していてもよいＣ_３〜Ｃ_８シクロアルキル基、置換していてもよいＣ_７〜Ｃ_１１アラルキル基、置換していてもよいＣ_２〜Ｃ_８アルケニル基、置換していてもよいＣ_２〜Ｃ_８アルキニル基、置換していてもよい芳香族基、水酸基の保護基で保護されていてもよい水酸基、置換していてもよいＣ_１〜Ｃ_８アルコキシ基、ホルミル基、置換していてもよいＣ_２〜Ｃ_８アシル基、置換していてもよいＣ_２〜Ｃ_８アルコキシカルボニル基、置換していてもよいカルバモイル基、カルボキシル基、シアノ基、ニトロ基、置換していてもよいアミノ基、置換していてもよい複素環基または置換していてもよいシリル基を表す。Ｒ^３及びＲ^４は同一または相異なって水素原子、置換していてもよいＣ_１〜Ｃ_８アルキル基、置換していてもよいＣ_３〜Ｃ_８シクロアルキル基、置換していてもよいフェニル基または置換していてもよいＣ_７〜Ｃ_１１アラルキル基を表す。Ｒ^３とＲ^４が一体となって環を形成してもよい。）で示されるオキサゾール誘導体に関する。 That is, the present invention relates to the general formula (1)

Wherein R ¹ is an optionally substituted C ₁ -C ₈ alkyl group, an optionally substituted C ₃ -C ₈ cycloalkyl group, an optionally substituted C ₇ -C ₁₁ aralkyl group, optionally substituted C ₂ -C ₈ alkenyl group, a substituted and an optionally C ₂ -C ₈ alkynyl group, a substituted and optionally an aromatic group, may be protected by a hydroxyl protecting group hydroxyl , C ₁ -C ₈ alkoxy group which may be substituted, formyl group, C ₂ -C ₈ acyl group which may be substituted, C ₂ -C ₈ alkoxycarbonyl group which may be substituted, substituted An optionally substituted carbamoyl group, a carboxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted heterocyclic group or an optionally substituted silyl group, R ² represents a hydrogen atom; , C ₁ optionally substituted C ₈ alkyl group, substituted with an optionally _C 3 -C ₈ cycloalkyl group, substituted _C 7 _{-C 11} optionally aralkyl group, substituted _C 2 -C ₈ optionally alkenyl group, substituted An optionally substituted C ₂ -C ₈ alkynyl group, an optionally substituted aromatic group, a hydroxyl group optionally protected by a protecting group for a hydroxyl group, an optionally substituted C ₁ -C ₈ alkoxy group, formyl groups, substituted and an optionally C ₂ -C ₈ acyl group, substituted optionally optionally C ₂ -C ₈ alkoxycarbonyl be groups, substituted and optionally also a carbamoyl group, a carboxyl group, a cyano group, a nitro group, a substituted Represents an optionally substituted amino group, an optionally substituted heterocyclic group or an optionally substituted silyl group, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom or an optionally substituted C; _{1 ~C 8} alkyl Groups, substituted and C ₃ -C ₈ optionally cycloalkyl group, substituted .R ³ represents an even better C ₇ -C ₁₁ aralkyl group are a phenyl group or a substituted or optionally and R ⁴ To integrally And may form a ring.)).

（式中、Ｒ^１及びＲ^２は前記と同じ意味を表す。Ｘ^１はハロゲン原子を表す。）で示されるオキサゾール誘導体と、一般式（３）

（式中、Ｒ^５は置換していてもよいＣ_１〜Ｃ_８アルキル基、置換していてもよいＣ_３〜Ｃ_８シクロアルキル基、置換していてもよいフェニル基または置換していてもよいＣ_７〜Ｃ_１１アラルキル基を表す。）で示されるホウ酸エステルとを、塩基存在下に反応させることを特徴とする、一般式（１ａ）

（式中、Ｒ^１、Ｒ^２及びＲ^５は前記と同じ意味を表す。）で示されるオキサゾール誘導体の製造方法に関する。 Furthermore, the present invention relates to a general formula (2)

(Wherein R ¹ and R ² represent the same meaning as described above, X ¹ represents a halogen atom), and the general formula (3)

(In the formula, R ⁵ is an optionally substituted C ₁ -C ₈ alkyl group, an optionally substituted C ₃ -C ₈ cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted group. the boric acid ester represented by the representative.) good C ₇ -C ₁₁ aralkyl group, which comprises reacting in the presence of a base, the general formula (1a)

(Wherein R ¹ , R ² and R ⁵ represent the same meaning as described above).

（式中、Ｒ^１、Ｒ^２及びＲ^５は前記と同じ意味を表す。）で示されるオキサゾール誘導体と、水、あるいは一般式（４）

（式中、Ｒ^６は置換していてもよいＣ_１〜Ｃ_８アルキル基、置換していてもよいＣ_３〜Ｃ_８シクロアルキル基、置換していてもよいフェニル基または置換していてもよいＣ_７〜Ｃ_１１アラルキル基を表す。）で示されるアルコール類、あるいは一般式（５）

（Ｑは置換していてもよいエチレン基、置換していてもよいトリメチレン基または置換していてもよいｏ−フェニレン基を表す。）で示されるジオール類とを、酸触媒存在下に反応させることを特徴とする、一般式（１）

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。）で示されるオキサゾール誘導体の製造方法に関する。 Furthermore, the present invention provides a compound of the general formula (1a)

(Wherein R ¹ , R ² and R ⁵ represent the same meaning as described above) and water, or general formula (4)

(Wherein R ⁶ is an optionally substituted C ₁ -C ₈ alkyl group, an optionally substituted C ₃ -C ₈ cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted group. Represents a good C _{7 to} C ₁₁ aralkyl group.) Or a general formula (5)

(Q represents an optionally substituted ethylene group, an optionally substituted trimethylene group or an optionally substituted o-phenylene group) and a diol represented by an acid catalyst in the presence of an acid catalyst. The general formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above).

（式中、Ｒ^１、Ｒ^２及びＸ^１は前記と同じ意味を表す。）で示されるオキサゾール誘導体と、一般式（３）

（式中、Ｒ^５は前記と同じ意味を表す。）で示されるホウ酸エステルとを、塩基存在下に反応させることにより、一般式（１a）

（式中、Ｒ^１、Ｒ^２及びＲ^５は前記と同じ意味を表す。）で示されるオキサゾール誘導体を得、次いで、水、あるいは一般式（４）

（式中、Ｒ^６は前記と同じ意味を表す。）で示されるアルコール類、あるいは一般式（５）

（Ｑは前記と同じ意味を表す。）で示されるジオール類とを、酸触媒存在下に反応させることを特徴とする、一般式（１）

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。）で示されるオキサゾール誘導体の製造方法に関する。 Furthermore, the present invention relates to a general formula (2)

(Wherein R ¹ , R ² and X ¹ represent the same meaning as described above) and the general formula (3)

(In the formula, R ⁵ represents the same meaning as described above.) By reacting with a borate ester represented in the presence of a base, general formula (1a)

(Wherein R ¹ , R ² and R ⁵ represent the same meaning as described above), and then water or general formula (4)

(Wherein R ⁶ represents the same meaning as described above), or the general formula (5)

(Q represents the same meaning as described above), and is reacted in the presence of an acid catalyst.

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above).

（式中、Ｒ^１及びＲ^２は前記と同じ意味を表す。Ｘ^２は脱離基を表す。）で示されるオキサゾール誘導体と、一般式（７）

（式中、Ｒ^３及びＲ^４は前記と同じ意味を表す。）で示されるホウ素試薬とを、金属触媒存在下に反応させることを特徴とする、一般式（１）

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。）で示されるオキサゾール誘導体の製造方法に関する。 Furthermore, the present invention relates to a general formula (6)

(Wherein R ¹ and R ² represent the same meaning as described above, X ² represents a leaving group), and the general formula (7)

(Wherein R ³ and R ⁴ represent the same meaning as described above), and the reaction is performed in the presence of a metal catalyst.

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above).

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。）で示されるオキサゾール誘導体を成分とするオキサゾリル基導入試薬に関する。 Furthermore, the present invention provides a compound of the general formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meanings as described above).

（式中、Ｒ^１、Ｒ^２、Ｒ^３及びＲ^４は前記と同じ意味を表す。）で示されるオキサゾール誘導体と、一般式（８）

（式中、Ｒ^７は置換していてもよいＣ_７〜Ｃ_１１アラルキル基、置換していてもよいＣ_２〜Ｃ_８アルケニル基、置換していてもよいＣ_２〜Ｃ_８アルキニル基、置換していてもよい芳香族基、置換していてもよいＣ_２〜Ｃ_８アシル基を表す。Ｘ^３は脱離基を表す。）で示される化合物とを、金属触媒存在下に反応させることを特徴とする、一般式（９）

（式中、Ｒ^１、Ｒ^２及びＲ^７は前記と同じ意味を表す。）で示されるオキサゾール誘導体の製造方法に関するものである。 Furthermore, the present invention provides a compound of the general formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above) and the general formula (8)

Wherein R ⁷ is an optionally substituted C _{7 to} C ₁₁ aralkyl group, an optionally substituted C _{2 to} C ₈ alkenyl group, an optionally substituted C _{2 to} C ₈ alkynyl group, and a substituted group. An aromatic group that may be substituted, a C _{2 to} C ₈ acyl group that may be substituted, and X ³ represents a leaving group) in the presence of a metal catalyst. General formula (9) characterized by

(Wherein R ¹ , R ² and R ⁷ represent the same meaning as described above).

The oxazole derivative represented by the general formula (1) of the present invention is an oxazolyl group-introducing reagent that can be prepared and used by a simple and safe operation as compared with oxazol-2-ylboronic acid derivatives and other metal reagents of oxazole. Further, the oxazole derivative (1) can be synthesized with an organic halide or an organic sulfonic acid ester in the presence of a metal catalyst to synthesize the oxazole derivative (9), which is a telomestatin (non-patent document 5) or anticancer agent having telomerase inhibitory activity. This is extremely useful in terms of use in the production of useful physiologically active substances and functional materials such as urapuaridos (Non-patent Document 6).
Journal of American Chemical Society, 2001, 123, 1262 Journal of American Chemical Society, 1986, 108, 846

In the present invention, the alkyl group having 1 to 8 carbon atoms represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ may be either linear or branched, Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl, 1-methylbutyl, 2- Examples thereof include a methylbutyl group, a hexyl group, an isohexyl group, a heptyl group, a 1-methylhexyl group, and an octyl group. One or more of these alkyl groups may be substituted with a halogen atom, a cycloalkyl group, a cyano group, a nitro group, an alkylthio group, an alkoxy group, a siloxy group, an alkoxycarbonyl group, an acyl group, and the like. 2-chloroethyl group, 3-chloropropyl group, cyclopropylmethyl group, cyclohexylmethyl group, cyanomethyl group, 2-cyanoethyl group, 3-cyanopropyl group, nitromethyl group, 2-methylthioethyl group, methoxymethyl group, ethoxymethyl group Ethoxymethyl group, methoxyethyl group, tert-butyldimethylsiloxymethyl group, methoxycarbonylmethyl group, ethoxycarbonylmethyl group, 1-acetylethyl group, 3-acetylpropyl group and the like. R ¹ and R ² are preferably a methyl group or a tert-butyl group in terms of a good yield. R ³ , R ⁴ , R ⁵ and R ⁶ are preferably a methyl group, an ethyl group, a propyl group or an isopropyl group in terms of a good yield.

Examples of the cycloalkyl group having 3 to 8 carbon atoms represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group. Can be illustrated. In addition, these cycloalkyl groups may be substituted with an alkyl group having 1 to 4 carbon atoms, and more specifically, 1-methylcyclopropyl group, 2-methylcyclopropyl group, 3-methylcyclopentyl group and the like are exemplified. can do.

Examples of the aralkyl group having 7 to 11 carbon atoms represented by R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ include a benzyl group, 1-phenylethyl group, 1-phenylpropyl group and the like. Can be illustrated. One or more of these aralkyl groups may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or the like. . R ¹ and R ² are preferably benzyl groups in terms of good yield.

The alkenyl group having 2 to 8 carbon atoms represented by R ¹ , R ² and R ⁷ may be linear, branched or cyclic, and is a vinyl group, 1-propenyl group, allyl group, 2-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 1-cyclopentenyl group, 2-hexenyl group, 3-hexenyl group, 1-cyclohexenyl group, 2-heptenyl group, A 1-cyclooctenyl group can be exemplified. One or more of these alkenyl groups may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or the like. R ¹ and R ² are preferably a vinyl group, an allyl group, or a 2-methyl-2-propenyl group in terms of a good yield.

The alkynyl group having 2 to 8 carbon atoms represented by R ¹ , R ² and R ⁷ may be linear or branched, and is an ethynyl group, propargyl group, 1-butyn-3-yl. Examples thereof include a group, 3-methyl-1-buten-3-yl group, 2-butynyl group, 2-pentynyl group, and 3-pentynyl group. One or more of these alkynyl groups may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a cyano group, or the like. R ¹ and R ² are preferably an ethynyl group or a propargyl group in terms of a good yield.

Examples of the aromatic group represented by R ¹ , R ² and R ⁷ include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, and a 2-thiazolyl group. 4-thiazolyl group, 5-thiazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-indolyl group, 3-indolyl group, 5-indolyl group , 2-furyl group, 3-furyl group and the like. On these aromatic rings, an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, and 3 to 12 carbon atoms. One or more groups may be substituted with an aromatic group, a silyl group having 3 to 14 carbon atoms, an alkyl sulfonate group having 1 to 8 carbon atoms, and the like. 4-methoxyphenyl group, 4-ethoxycarbonyloxazol-2-yl group , 2-tert-butyldimethylsilyloxazol-2-yl group, 4- (4-trifluoromethanesulfonyloxyoxazol-2-yl) oxazol-2-yl group, and the like. R ¹ and R ² are phenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, 4-thiazolyl in terms of good yield. , 5-thiazolyl group, 2-oxazolyl group, 4-oxazolyl group, and 5-oxazolyl group are preferably used.

Examples of the substituent on the benzene ring of the optionally substituted phenyl group represented by R ³ , R ⁴ and R ⁵ include a halogen atom, an alkyl group having 1 to 8 carbon atoms, and an alkoxy group having 1 to 8 carbon atoms. And an alkoxycarbonyl group having 2 to 8 carbon atoms, a carboxyl group, a cyano group, a nitro group, and the like.

Examples of the hydroxyl protecting group represented by R ¹ and R ² include ester protecting groups such as formyl group, acetyl group, pivaloyl group, benzoyl group, trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, triisopropyl group. Examples include silyl protecting groups such as silyl group and tert-butyldiphenylsilyl group, carbonate protecting groups such as methoxycarbonyl group, ethoxycarbonyl group, allyloxycarbonyl group, and benzyloxycarbonyl group. From the viewpoint of good yield, it is preferable to use a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group.

Examples of the alkoxy group having 1 to 8 carbon atoms represented by R ¹ and R ² include a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a cyclopropyloxy group, a butoxy group, an isobutyloxy group, and a sec-butyloxy group. Tert-butyloxy group, cyclobutyloxy group, cyclopropylmethyloxy, benzyloxy group and the like. One or more of these alkoxy groups may be substituted with an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or the like. A methoxymethoxy group, a methoxyethoxy group, or p-methoxy group. A benzyloxy group etc. can be illustrated. It is preferable to use a methoxy group in terms of good yield.

Examples of the acyl group having 2 to 8 carbon atoms represented by R ¹ , R ² and R ⁷ include an acetyl group, a propionyl group, a pivaloyl group and a benzoyl group. R ¹ and R ² are preferably acetyl groups in terms of good yield.

Examples of the optionally substituted C ₂ -C ₈ alkoxycarbonyl group represented by R ¹ and R ² include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, and sec-butoxy. Examples thereof include a carbonyl group and a tert-butoxycarbonyl group. From the viewpoint of good yield, it is preferable to use a methoxycarbonyl group or an ethoxycarbonyl group.

Examples of the optionally substituted carbamoyl group represented by R ¹ and R ² include a carbamoyl group, an N-methylcarbamoyl group, an N-ethylcarbamoyl group, an N-propylcarbamoyl group, an N-isopropylcarbamoyl group, and an N-butyryl group. Examples thereof include a rucarbamoyl group, N, N-dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N, N-dipropylcarbamoyl group, N, N-diisopropylcarbamoyl group, N, N-dibutylcarbamoyl group and the like.

Examples of the substituent of the amino group which may be substituted represented by R ¹ and R ² include an alkyl group having 1 to 8 carbon atoms, an aralkyl group having 7 to 11 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, Examples thereof include an alkynyl group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 15 carbon atoms, and the like. It may be differently disubstituted. More specifically, methylamino group, ethylamino group, allylamino group, propargylamino group, tert-butylamino group, N, N-dimethylamino group, benzylamino group, acetylamino group, propionylamino group, pivaloylamino group, benzoyl Examples include an amino group, a methoxycarbonylamino group, a benzyloxycarbonylamino group, a tert-butoxycarbonylamino group, a 9-fluorenylmethoxycarbonylamino group, and a trichloroethoxycarbonylamino group.

Examples of the optionally substituted heterocyclic group represented by R ¹ and R ² include aziridinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-piperidyl group, 3-piperidyl group, 4-piperidyl group, piperidino Group, tetrahydrofuran-2-yl group, tetrahydrofuran-3-yl group, 2-dioxanyl group, 2-oxazolidinyl group, 4-oxazolidinyl group and the like. As the substituent on the heterocyclic ring of the heterocyclic group, a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkoxycarbonyl group having 2 to 8 carbon atoms, a carboxyl group, a cyano group, A nitro group etc. can be illustrated.

Examples of the optionally substituted silyl group represented by R ¹ and R ² include a trimethylsilyl group, a triethylsilyl group, a tert-butyldimethylsilyl group, a triisopropylsilyl group, and a tert-butyldiphenylsilyl group. Can do. From the viewpoint of good yield, it is preferable to use a trimethylsilyl group, a triethylsilyl group, or a tert-butyldimethylsilyl group.

等を例示することができる。収率が良い点で、ａ，ｂを用いることが好ましい。 As the ring formed by combining R ³ and R ⁴ , the following formula a, b, c or d

Etc. can be illustrated. From the viewpoint of good yield, it is preferable to use a and b.

Examples of the halogen atom represented by X ¹ include a chlorine atom, a bromine atom, and an iodine atom. From the viewpoint of good yield, it is preferable to use a bromine atom or an iodine atom.

Examples of the leaving group represented by X ² and X ³ include halogen atoms such as chlorine atom, bromine atom and iodine atom, or alkyl or aryl such as methanesulfonyloxy group, trifluoromethanesulfonyl group and p-toluenesulfonyloxy group. A sulfonyloxy group etc. can be illustrated. X ² is preferably a bromine atom, an iodine atom or a trifluoromethanesulfonyl group in terms of a good yield. X ³ is preferably a chlorine atom, a bromine atom, an iodine atom, or a trifluoromethanesulfonyl group in terms of a good yield.

  Examples of the optionally substituted ethylene group represented by Q include an ethylene group, a 1,1,2,2-tetramethylethylene group, a propylene group, and a 1,2-dimethylethylene group. From the viewpoint of good yield, it is preferable to use an ethylene group or a 1,1,2,2-tetramethylethylene group.

  Examples of the trimethylene group which may be substituted represented by Q include trimethylene group, 2,2-dimethyltrimethylene group, 1,1,3,3-tetramethyltrimethylene group, 1,1,3-trimethyltrimethylene group. A methylene group etc. can be illustrated.

  Examples of the optionally substituted o-phenylene group represented by Q include an o-phenylene group, a 3,6-dimethyl-o-phenylene group, and a 2,3-naphthylene group. From the viewpoint of good yield, it is preferable to use an o-phenylene group.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｘ^１、Ｘ^２、Ｘ^３及びＱは前記と同じ意味を表す。） Hereinafter, a method for producing an oxazole derivative belonging to the present invention and a reaction with an organic halide or an organic sulfonic acid ester using a metal catalyst using the same will be described in detail.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , X ¹ , X ² , X ³ and Q have the same meaning as described above.)

  In the step-1, the halogen atom at the 4-position of the oxazole derivative (2) is treated with a base to perform a halogen-metal exchange reaction and react with the boric acid ester (3), whereby the oxazole derivative (1a ).

  The oxazole derivative (2) which is the raw material of this step can be produced according to a conventional method such as 4-position halogenation of the corresponding oxazole or halogenation of the oxazol-4 (5H) -one derivative. These oxazol derivatives and oxazol-4 (5H) -one derivatives serving as halogenated precursors can be prepared by a method described in the literature or a method analogous thereto. (Non-patent document-7). The borate ester (3) is partially commercially available, but can be easily prepared by reaction of boron oxide with the corresponding alcohol, or transesterification of commercially available triisopropyl borate with the corresponding alcohol.

OXAZOLES: SYNTHESIS, REACTIONS, AND SPECTROCOPY Part A, Edited by D.D. C. Palmer, JOHN WILEY & SONS, INC. 2003

  It is essential to carry out the reaction in the presence of a base. Examples of bases that can be used include butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl). Examples include alkali metal organic bases such as amide, potassium bis (trimethylsilyl) amide, phenylmagnesium bromide, isopropylmagnesium bromide, isopropylmagnesium chloride. From the viewpoint of good yield, it is preferable to use butyl lithium, sec-butyl lithium, or tert-butyl lithium. The amount of the base used is not particularly limited, but it is preferable from the viewpoint of good yield that the base is used in an equal amount or more with respect to the reaction substrate.

  The reaction is preferably carried out in an organic solvent, and any solvent that does not harm the reaction can be used. For example, ether solvents such as tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, hydrocarbon solvents such as hexane, pentane, cyclohexane, aromatic hydrocarbon solvents such as benzene, toluene, xylene, N, N Examples include amide solvents such as dimethylformamide and N-methylpyrrolidone, and two or more of the above solvents may be mixed.

  The reaction proceeds smoothly at a temperature appropriately selected from −78 ° C. to the solvent reflux temperature, but it is preferable to carry out the reaction at −78 ° C. to around room temperature in terms of a good yield. As a post-treatment method, the reaction can be stopped by adding water to the reaction solution, but post-treatment with an acidic aqueous solution such as acetic acid is preferable in terms of a good yield. The method for isolating the target product from the mixed solution after the reaction is not particularly limited, but the target product can be obtained by a general method such as solvent extraction, column chromatography, recrystallization or sublimation. Further, the oxazole derivative (1a) can be directly used in Step-2 without isolation.

  In Step-2, hydrolysis or acetal exchange is carried out in the presence of an oxazole derivative (1a) and water, alcohols (4), or diols (5), which can be produced by the method of Step-1, in the presence of an acid catalyst. This is a process for producing the oxazole derivative (1) of the invention.

  Alcohols (4) or diols which are raw materials for this step are partially commercially available (5), but can be prepared by conventional methods.

  The reaction proceeds rapidly in the presence of an acid catalyst. Examples of acids that can be used include inorganic acids such as hydrochloric acid, odorous acid, sulfuric acid and nitric acid, carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid and propionic acid, sulfonic acids such as p-toluenesulfonic acid and camphorsulfonic acid, Examples thereof include sulfonates such as pyridinium p-toluenesulfonate. Although there are no particular limitations on the amount of acid used, it is preferable to carry out using an equivalent amount of the catalyst to the reaction substrate in terms of a good yield.

  The amount of water, alcohols (4), or diols (5) used in the reaction is not particularly limited, and any of them can be used as a solvent. It is preferable from the viewpoint of good yield that the reaction substrate is used in an equal amount or more.

  Furthermore, in this step, any organic solvent that does not harm the reaction can be used. For example, ether solvents such as tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, nitrile solvents such as acetonitrile, propionitrile, hexane, pentane, cyclohexane And hydrocarbon solvents such as benzene, toluene and xylene, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidone, and two of these solvents The above can be mixed.

  The reaction smoothly proceeds at a temperature appropriately selected from −78 ° C. to the solvent reflux temperature, but it is preferable to carry out the reaction at around room temperature in terms of a good yield. The method for isolating the target product from the solution after the reaction is not particularly limited, but the target product can be obtained by a general-purpose method such as solvent extraction, column chromatography, recrystallization or sublimation.

  Step-3 is a step of producing the oxazole derivative (1) of the present invention by causing the oxazole derivative (6) to undergo a cross-coupling reaction with the diboron derivative (7) in the presence of a metal catalyst.

The oxazole derivative (6) in which X ^{2 as} a raw material in this step is a halogen atom can be produced by the method described in Step-1, and the oxyoxazole derivative (6) in which X ² is a sulfonyloxy group The oxazol-4 (5H) -one derivative can be produced by a method described in the literature (Non-patent document-2) or a method analogous thereto. The precursor oxazol-4 (5H) -one derivative can be produced by the method described above. Although diboron (7) is partly commercially available, it can be prepared from tetrakis (dimethylamido) diboron and the corresponding alcohol by a method described in the literature or a method analogous thereto (Non-patent Document-8).

Inorganic Chemistry, 1968, vol. 7, p. 225

The reaction must be performed in the presence of a metal catalyst, and examples of the metal catalyst that can be used include a palladium catalyst, a nickel catalyst, and a platinum catalyst. These metal catalysts include “metal”, “supported metal”, “metal salts such as chloride, bromide, iodide, nitrate, sulfate, carbonate, oxalate, acetate or oxide of metal” and “ A complex compound such as an olefin complex, a phosphine complex, an amine complex, an ammine complex, or an acetylacetonate complex ”can be used. Further, these metals, supported metals, metal salts and complex compounds and tertiary phosphine ligands can be used in combination. It is preferable to use a palladium catalyst in terms of a good yield.
Examples of the palladium catalyst include palladium metals such as palladium black and palladium sponge, and supported palladium metals such as palladium / alumina, palladium / carbon, palladium / silica, palladium / Y-type zeolite. Moreover, metal salts, such as palladium chloride, palladium bromide, palladium iodide, palladium acetate, can be illustrated. Furthermore, π-allyl palladium chloride dimer, palladium acetylacetonate, dichlorobis (acetonitrile) palladium, dichlorobis (benzonitrile) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tris (dibenzylideneacetone) Dipalladium (chloroform adduct), dichlorodiammine palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tricyclohexylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] Palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1,4-bis (diphenyl) Complex compounds such as phosphino) butane] palladium and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium can be exemplified. Palladium acetate, palladium acetylacetonate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tris (dibenzylideneacetone) dipalladium (chloroform adduct), tetrakis (triphenyl) Phosphine) palladium is preferably used.
These palladium catalysts may be used alone or in combination with a tertiary phosphine. The tertiary phosphine that can be used is triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, trio-tolylphosphine, trioctylphosphine, 9,9-dimethyl. -4,5-bis (diphenylphosphino) xanthene, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis (diphenylphosphino) ethane, 1,3 -Bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'-bis (diphenylphosphino) ferrocene, (R)-(+)-2,2'-bis (diphenyl) Phosphino) -1,1'-binaphthyl (S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, etc. Can be illustrated. From the viewpoint of good yield, it is preferable to use triphenylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, or tri-o-tolylphosphine.
In Step-3, a base may be added to improve the yield. Bases to be added include lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium acetate, triethylamine, butylamine, diisopropyl Examples thereof include inorganic bases and organic bases such as amine and ethyldiisopropylamine. It is preferable to use potassium carbonate, potassium phosphate, or potassium acetate in terms of good yield.
The amount of the metal catalyst and tertiary phosphine used is not particularly limited, but the so-called catalyst amount can be used for the reaction substrate. The amount of the base used is not particularly limited but is preferably 1 to 50 equivalents based on the reaction substrate in terms of a good yield.

  The reaction is preferably carried out in an organic solvent, and any solvent that does not harm the reaction can be used. Ether solvents such as tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, nitrile solvents such as acetonitrile and propionitrile, hydrocarbon solvents such as hexane, pentane and cyclohexane, aroma such as benzene, toluene and xylene Amide solvents such as group hydrocarbon solvents, N, N-dimethylformamide, N-methylpyrrolidone and the like can be exemplified, and two or more of these solvents may be mixed and used.

  The reaction proceeds smoothly at a temperature appropriately selected from −78 ° C. to the solvent reflux temperature, but it is preferable to carry out the reaction from room temperature to around the solvent reflux temperature in terms of a good yield. The method for isolating the target product from the solution after the reaction is not particularly limited, but the target product can be obtained by a general-purpose method such as solvent extraction, column chromatography, recrystallization or sublimation.

  The oxazole derivative (1) of the present invention can be used as a useful oxazolyl group-introducing reagent, and can react with the compound (8) in the presence of a metal catalyst to produce an oxazole derivative.

  Step-4 is a step of producing the oxazole derivative (9) by reacting the oxazole derivative (1) of the present invention with the compound (8) in the presence of a metal catalyst.

The reaction must be carried out in the presence of a metal catalyst, and examples of the metal catalyst that can be used include palladium catalyst, nickel catalyst, iron catalyst, ruthenium catalyst, platinum catalyst, rhodium catalyst, iridium catalyst, and the like. it can. These metal catalysts include “metals”, “supported metals”, “metal salts such as chlorides, bromides, iodides, nitrates, sulfates, carbonates, oxalates, acetates or oxides”, “ A complex compound such as an olefin complex, a phosphine complex, an amine complex, an ammine complex, or an acetylacetonate complex ”can be used. Further, these metals, metal salts and complex compounds and tertiary phosphine ligands can be used in combination. From the viewpoint of good yield, it is preferable to use a palladium catalyst.
Examples of the palladium catalyst include palladium metals such as palladium black and palladium sponge, and supported palladium metals such as palladium / alumina, palladium / carbon, palladium / silica, palladium / Y-type zeolite. Moreover, metal salts, such as palladium chloride, palladium bromide, palladium iodide, and palladium acetate, can be illustrated. Furthermore, π-allyl palladium chloride dimer, palladium acetylacetonate, dichlorobis (acetonitrile) palladium, dichlorobis (benzonitrile) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tris (dibenzylideneacetone) Dipalladium (chloroform adduct), dichlorodiammine palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tricyclohexylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis (diphenylphosphino) ethane] Palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1,4-bis (diphenyl) Complex compounds such as phosphino) butane] palladium and dichloro [1,1′-bis (diphenylphosphino) ferrocene] palladium can be exemplified. Palladium acetate, palladium acetylacetonate, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, tris (dibenzylideneacetone) dipalladium (chloroform adduct), tetrakis (triphenyl) Phosphine) palladium is preferably used.
These palladium catalysts may be used alone or in combination with a tertiary phosphine. As the tertiary phosphine that can be used, triphenylphosphine, trimethylphosphine, triethylphosphine, tributylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, tri-o-tolylphosphine, trioctylphosphine, 9,9- Dimethyl-4,5-bis (diphenylphosphino) xanthene, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 1,2-bis (diphenylphosphino) ethane, 1, 3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1′-bis (diphenylphosphino) ferrocene, (R)-(+)-2,2′-bis ( Diphenylphosphino) -1,1'-binaphthi , (S)-(−)-2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and (±) -2,2′-bis (diphenylphosphino) -1,1′-binaphthyl Etc. can be exemplified. From the viewpoint of good yield, it is preferable to use triphenylphosphine, tri (tert-butyl) phosphine, tricyclohexylphosphine, or tri-o-tolylphosphine.
In Step-4, a base may be added to improve the yield. The base to be added is lithium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, potassium fluoride, cesium fluoride, sodium hydroxide, potassium hydroxide, potassium phosphate, potassium acetate, triethylamine, butylamine, diisopropyl Examples thereof include inorganic bases and organic bases such as amine and ethyldiisopropylamine. It is preferable to use potassium carbonate, potassium phosphate, or potassium acetate in terms of good yield.
The amount of the metal catalyst and tertiary phosphine used is not particularly limited, but the so-called catalyst amount can be used for the reaction substrate. The amount of the base used is not particularly limited but is preferably 1 to 50 equivalents based on the reaction substrate in terms of a good yield.

  The reaction is preferably carried out in an organic solvent, and any solvent that does not harm the reaction can be used. For example, ether solvents such as tetrahydrofuran, diethyl ether, dimethoxyethane, 1,4-dioxane, nitrile solvents such as acetonitrile, propionitrile, hydrocarbon solvents such as hexane, pentane, cyclohexane, benzene, toluene, xylene, etc. And amide solvents such as N, N-dimethylformamide and N-methylpyrrolidone, and two or more of these solvents may be used in combination.

  The reaction proceeds smoothly at a temperature appropriately selected from −78 ° C. to the solvent reflux temperature, but it is preferable to carry out the reaction from room temperature to around the solvent reflux temperature in terms of a good yield. The method for isolating the target product from the solution after the reaction is not particularly limited, but the target product can be obtained by a general-purpose method such as solvent extraction, column chromatography, recrystallization or sublimation.

  EXAMPLES Hereinafter, although an Example and a reference example demonstrate this invention further in detail, this invention is not limited to these.

  Abbreviations used in the figure have the following meanings. TBS: tert-butyldimethylsilyl group, Boc: tert-butoxycarbonyl group, Tf: trifluoromethanesulfonyl group, TMS: trimethylsilyl group.

４−ブロモ−２−フェニルオキサゾール（５２ｍｇ， ０．２３ｍｍｏｌ）のテトラヒドロフラン（２．３ｍｌ）溶液に、アルゴン雰囲気下、ホウ酸トリイソプロピル（６９μｌ， ０．３０ｍｍｏｌ）を加えて−７８゜Ｃに冷却した。混合溶液に、ブチルリチウム（１．５６Ｍ， ヘキサン溶液， ０．１７ｍｌ， ０．２８ｍｍｏｌ）を加えて３０分撹拌後、室温まで昇温して２時間撹拌した。得られたジイソプロポキシ（２−フェニルオキサゾール−４−イル）ボランを含む黄色反応混合液に、ピナコール（４０ｍｇ， ０．３５ｍｍｏｌ）と酢酸（１７μｌ， ０．３０ｍｍｏｌ）を加えて更に１時間攪拌した。反応溶液をろ過し不溶物を除去後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１→１：１）で精製して２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（４１ｍｇ， ６５％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．３７（１２Ｈ， ｓ）， ７．４０−７．４７（３Ｈ， ｍ）、８．０５（１Ｈ， ｓ）， ８．１０−８．１７（２Ｈ， ｍ）． Example-1

To a solution of 4-bromo-2-phenyloxazole (52 mg, 0.23 mmol) in tetrahydrofuran (2.3 ml) was added triisopropyl borate (69 μl, 0.30 mmol) in an argon atmosphere and cooled to −78 ° C. . Butyllithium (1.56M, hexane solution, 0.17 ml, 0.28 mmol) was added to the mixed solution, and the mixture was stirred for 30 minutes, then warmed to room temperature and stirred for 2 hours. To the obtained yellow reaction mixture containing diisopropoxy (2-phenyloxazol-4-yl) borane, pinacol (40 mg, 0.35 mmol) and acetic acid (17 μl, 0.30 mmol) were added and further stirred for 1 hour. . The reaction solution was filtered to remove insolubles, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 1: 1) to give 2-phenyl-4- ( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (41 mg, 65%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.37 (12H, s), 7.40-7.47 (3H, m), 8.05 (1H, s), 8.10-8. 17 (2H, m).

アルゴン雰囲気下、４−ブロモ−５−メチル−２−フェニルオキサゾール（２０ｍｇ， ８４μｍｏｌ）のテトラヒドロフラン（１ｍｌ）溶液を−７８゜Ｃに冷却し、ブチルリチウム（１．５６Ｍ ヘキサン溶液, ５８μｌ， ９２μｍｏｌ）を加えて３０分撹拌した。反応溶液に、ホウ酸トリイソプロピル（２３μｌ， １００μｍｏｌ）を加えて更に１．５時間、室温で１．５時間撹拌した。得られたジイソプロポキシ（５−メチル−２−フェニルオキサゾール−４−イル）ボランを含む黄色反応混合液に、ピナコール（４０ｍｇ， ０．３５ｍｍｏｌ）、酢酸（１７μｌ， ０．３０ｍｍｏｌ）を加えて更に３時間室温で攪拌した。反応溶液をジエチルエーテル（１０ｍｌ）で希釈した後、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１→１：１）精製して、５−メチル−２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（１６ｍｇ， ６５％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．３６（１２Ｈ， ｓ）， ２．５６（３Ｈ， ｓ）， ７．３８−７．５０（３Ｈ， ｍ）， ８．０６−８．１７（２Ｈ， ｍ）． Example-2

Under an argon atmosphere, a solution of 4-bromo-5-methyl-2-phenyloxazole (20 mg, 84 μmol) in tetrahydrofuran (1 ml) was cooled to −78 ° C., and butyllithium (1.56 M hexane solution, 58 μl, 92 μmol) was added. The mixture was further stirred for 30 minutes. Triisopropyl borate (23 μl, 100 μmol) was added to the reaction solution, and the mixture was further stirred for 1.5 hours and at room temperature for 1.5 hours. To the obtained yellow reaction mixture containing diisopropoxy (5-methyl-2-phenyloxazol-4-yl) borane, pinacol (40 mg, 0.35 mmol) and acetic acid (17 μl, 0.30 mmol) were further added. Stir for 3 hours at room temperature. The reaction solution was diluted with diethyl ether (10 ml), washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 1: 1) to give 5-methyl-2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (16 mg, 65%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.36 (12H, s), 2.56 (3H, s), 7.38-7.50 (3H, m), 8.06-8. 17 (2H, m).

４−ブロモ−２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチルオキサゾール（５５ｍｇ， ０．１５ｍｍｏｌ）のテトラヒドロフラン（１．５ｍｌ）溶液に、アルゴン雰囲気下−７８゜Ｃに冷却し、トリイソプロピルボレート（６７μｌ， ０．３ｍｍｏｌ）及びブチルリチウム（１．５８Ｍヘキサン溶液, ０．１８ｍｌ， ０．３ｍｍｏｌ）を加えて、−７８゜Ｃで３０分、室温で３０分反応させた。得られた［２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチルオキサゾール−４−イル］ジイソプロポキシボランの黄色反応混合液にピナコール（５５ｍｇ， ０．３ｍｍｏｌ）、酢酸（１７μｌ， ０．３ｍｍｏｌ）を加え、更に室温で１時間反応させた。反応液をジエチルエーテル（５０ｍｌ）で希釈した後水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝４：１→酢酸エチル）で精製して、２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（３６ｍｇ， ５８％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．１５−１．４０（２４Ｈ， ｍ）， １．６７（６Ｈ， ｂｒｓ）， ２．４９（３Ｈ，ｂｒｓ）， ４．２０−４．３０（１Ｈ， ｍ）， ４．４６−４．５６（１Ｈ， ｍ）． Example-3

4-Bromo-2- (3-tert-butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidin-4-yl) -5-methyloxazole (55 mg, 0.15 mmol) in tetrahydrofuran (1.5 ml) ) The solution was cooled to −78 ° C. under an argon atmosphere, triisopropyl borate (67 μl, 0.3 mmol) and butyl lithium (1.58 M hexane solution, 0.18 ml, 0.3 mmol) were added, and −78 ° The reaction was carried out at C for 30 minutes and at room temperature for 30 minutes. Yellow reaction mixture of the obtained [2- (3-tert-butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidin-4-yl) -5-methyloxazol-4-yl] diisopropoxyborane Pinacol (55 mg, 0.3 mmol) and acetic acid (17 μl, 0.3 mmol) were added to the solution, and the mixture was further reacted at room temperature for 1 hour. The reaction mixture was diluted with diethyl ether (50 ml), washed with water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 → ethyl acetate) to give 2- (3-tert-butoxycarbonyl- 2,2,5-Trimethyl-1,3-oxazolidin-4-yl) -5-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (36 mg, 58%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.15-1.40 (24H, m), 1.67 (6H, brs), 2.49 (3H, brs), 4.20-4. 30 (1H, m), 4.46-4.56 (1H, m).

トリフルオロメタンスルホン酸２−フェニルオキサゾール−４−イル（２ｇ， ６．８ｍｍｏｌ）の１，４−ジオキサン（２５ｍｌ）溶液に、テトラキストリフェニルホスフィンパラジウム（２３６ｍｇ， ０．１９ｍｍｏｌ）、ビスピナコラートジボロン（１．９ｇ， ７．５ｍｍｏｌ）及び酢酸カリウム（１ｇ， １０ｍｍｏｌ）を加えて、アルゴン雰囲気下１２時間加熱還流した。反応溶液をジエチルエーテル（１５０ｍｌ）で希釈した後、水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１→１：１）で精製し、ヘキサン／エーテルで再結晶して２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（９２４ｍｇ， ５０％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．３７（１２Ｈ， ｓ）， ７．４０−７．４７（３Ｈ， ｍ）， ８．０５（１Ｈ， ｓ）， ８．１０−８．１７（２Ｈ， ｍ）． Example-4

To a solution of 2-phenyloxazol-4-yl trifluoromethanesulfonate (2 g, 6.8 mmol) in 1,4-dioxane (25 ml) was added tetrakistriphenylphosphine palladium (236 mg, 0.19 mmol), bispinacolato diboron ( 1.9 g, 7.5 mmol) and potassium acetate (1 g, 10 mmol) were added, and the mixture was heated to reflux for 12 hours under an argon atmosphere. The reaction solution was diluted with diethyl ether (150 ml), washed with water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 1: 1), recrystallized from hexane / ether, and then 2- Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (924 mg, 50%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.37 (12H, s), 7.40-7.47 (3H, m), 8.05 (1H, s), 8.10-8. 17 (2H, m).

トリス(ジベンジリデンアセトン)ジパラジウム（クロロホルム付加物）（１２ｍｇ， １２μｍｏｌ）、トリシクロへキシルホスフィン（１７ｍｇ， ６１μｍｏｌ）の１，４−ジオキサン（１ｍｌ）溶液を、アルゴン雰囲気下室温で１５分間撹拌した。トリフルオロメタンスルホン酸２’−ｔｅｒｔ−ブチルジメチルシリル−２，４’−ビオキサゾール−４−イル（９７ｍｇ， ０．２４ｍｍｏｌ）の１，４−ジオキサン溶液（１．５ｍｌ）、ビスピナコラートジボロン（１２３ｍｇ， ０．４８ｍｍｏｌ）及び酢酸カリウム（７１ｍｇ， ０．７２ｍｍｏｌ）を加えて３０分加熱還流した。反応液を酢酸エチル（５０ｍｌ）で希釈した後、水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２：１→１：１）で精製して、２’−ｔｅｒｔ−ブチルジメチルシリル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２，４’−ビオキサゾール（５７ｍｇ， ６２％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ０．３９（６Ｈ， ｓ）， ０．９９ （９Ｈ， ｓ）， １．３６（１２Ｈ， ｓ）， ８．０６（１Ｈ， ｓ）， ８．５０（１Ｈ， ｓ）． Example-5

A solution of tris (dibenzylideneacetone) dipalladium (chloroform adduct) (12 mg, 12 μmol) and tricyclohexylphosphine (17 mg, 61 μmol) in 1,4-dioxane (1 ml) was stirred at room temperature for 15 minutes under an argon atmosphere. 1,4-dioxane solution (1.5 ml) of trifluoromethanesulfonic acid 2′-tert-butyldimethylsilyl-2,4′-bioxazol-4-yl (97 mg, 0.24 mmol), bispinacolato diboron ( 123 mg, 0.48 mmol) and potassium acetate (71 mg, 0.72 mmol) were added and heated to reflux for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1: 1) to give 2′-tert-butyldimethylsilyl- 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,4′-bioxazole (57 mg, 62%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 0.39 (6H, s), 0.99 (9H, s), 1.36 (12H, s), 8.06 (1H, s), 8 .50 (1H, s).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（４６ｍｇ， ０．１７ｍｍｏｌ）の１，４−ジオキサン（２ｍｌ）溶液に、テトラキス（トリフェニルホスフィン）パラジウム（１０ｍｇ， ０．００８ｍｍｏｌ）、炭酸カリウム（３５ｍｇ， ０．２５ｍｍｏｌ）及びブロモベンゼン（０．０３２ｍｌ， ０．３ｍｍｏｌ）を加えて、アルゴン雰囲気下５時間加熱還流した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して２，４−ジフェニルオキサゾール（１８ｍｇ， ４８％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ７．３０−７．５５（６Ｈ， ｍ）， ７．７９−７．８８（２Ｈ， ｍ）， ７．９７（１Ｈ， ｓ）， ８．１０−８．１９（２Ｈ， ｍ）． Example-6

To a solution of 2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (46 mg, 0.17 mmol) in 1,4-dioxane (2 ml), Tetrakis (triphenylphosphine) palladium (10 mg, 0.008 mmol), potassium carbonate (35 mg, 0.25 mmol) and bromobenzene (0.032 ml, 0.3 mmol) were added, and the mixture was heated to reflux for 5 hours under an argon atmosphere. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 20: 1) to give 2,4-diphenyloxazole (18 mg, 48%). . ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 7.30-7.55 (6H, m), 7.79-7.88 (2H, m), 7.97 (1H, s), 8. 10-8.19 (2H, m).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０．０ｍｇ， ０．２２ｍｍｏｌ）の１，４−ジオキサン（４ｍｌ）溶液に、２−クロロオキサゾール−４−カルボン酸エチル（８６ｍｇ， ０．４９ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（２４ｍｇ， ０．０１７ｍｍｏｌ）及び炭酸カリウム（８５ｍｇ， ０．５１ｍｍｏｌ）を加えて、６時間加熱還流した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝２：１）で精製して、２’−フェニル−２，４’−ビオキサゾール−４−カルボン酸エチル（５０ｍｇ， ８０％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．４１（３Ｈ， ｔ， Ｊ＝５．０Ｈｚ）， ４，４３（２Ｈ， ｑ， Ｊ＝５．０Ｈｚ）， ７．４８−７．５３（３Ｈ， ｍ）， ８．０９−８．１７（２Ｈ， ｍ）， ８．３２（１Ｈ， ｓ）， ８．４３（１Ｈ， ｓ）． Example-7

A solution of 2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60.0 mg, 0.22 mmol) in 1,4-dioxane (4 ml) To the mixture, ethyl 2-chlorooxazole-4-carboxylate (86 mg, 0.49 mmol), tetrakis (triphenylphosphine) palladium (24 mg, 0.017 mmol) and potassium carbonate (85 mg, 0.51 mmol) were added for 6 hours. Heated to reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give 2′-phenyl-2,4′-bioxazole-4. -Ethyl carboxylate (50 mg, 80%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.41 (3H, t, J = 5.0 Hz), 4, 43 (2H, q, J = 5.0 Hz), 7.48-7.53 (3H, m), 8.09-8.17 (2H, m), 8.32 (1H, s), 8.43 (1H, s).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０ｍｇ， ０．２２ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１３ｍｇ， １１μｍｏｌ）、炭酸カリウム（９２ｍｇ， ０．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）懸濁液に、ｐ−ブロモ安息香酸エチル（３６μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で３０分間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝５０：１→２０：１）で精製して４−（４−エトキシカルボニルフェニル）−２−フェニルオキサゾール（５４ｍｇ，８３％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．４２（３Ｈ， ｔ， Ｊ＝７．１Ｈｚ）， ４．４１（２Ｈ， ｑ， Ｊ＝７．１Ｈｚ）， ７．４６−７．５２（３Ｈ， ｍ）， ７．８９−７．９２（２Ｈ， ｍ）， ８．０６（１Ｈ， ｓ）， ８．０９−８．１５（４Ｈ， ｍ）． Example-8

2-Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (0) (13 mg, 11 μmol), potassium carbonate (92 mg, 0.66 mmol) in N, N-dimethylformamide (1 ml) suspension, ethyl p-bromobenzoate (36 μl, 0.22 mmol) was added and stirred at 100 ° C. for 30 minutes. . After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1 → 20: 1) to give 4- (4-ethoxycarbonylphenyl)- 2-Phenyloxazole (54 mg, 83%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 1.42 (3H, t, J = 7.1 Hz), 4.41 (2H, q, J = 7.1 Hz), 7.46-7.52 (3H, m), 7.89-7.92 (2H, m), 8.06 (1H, s), 8.09-8.15 (4H, m).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０ｍｇ， ０．２２ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１３ｍｇ， １１μｍｏｌ）、炭酸カリウム（９２ｍｇ， ０．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）懸濁液に、ｐ−ブロモアニソール（２８μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で１時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝５０：１）で精製して４−（４−メトキシフェニル）−２−フェニルオキサゾール（３１ｍｇ， ５６％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ３．８６（３Ｈ， ｓ）， ６．９５−６．９９（２Ｈ， ｍ）， ７．４５−７．５０（３Ｈ， ｍ）， ７．７４−７．７７（２Ｈ， ｍ）， ８．０９−８．１３（２Ｈ， ｍ）， ８．１１（１Ｈ， ｓ）． Example-9

2-Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (0) (13 mg, 11 μmol) and potassium carbonate (92 mg, 0.66 mmol) in N, N-dimethylformamide (1 ml) suspension, p-bromoanisole (28 μl, 0.22 mmol) was added and stirred at 100 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give 4- (4-methoxyphenyl) -2-phenyloxazole ( 31 mg, 56%). ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 3.86 (3H, s), 6.95-6.99 (2H, m), 7.45-7.50 (3H, m), 7. 74-7.77 (2H, m), 8.09-8.13 (2H, m), 8.11 (1H, s).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０ｍｇ， ０．２２ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１３ｍｇ， １１μｍｏｌ）、炭酸カリウム（９２ｍｇ， ０．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）懸濁液に、ｏ−ブロモトルエン（２７μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で３時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝３０：１）で精製して４−（２−メチルフェニル）−２−フェニルオキサゾール（２８ｍｇ， ５４％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ２．５１（３Ｈ， ｓ）， ７．２５−７．３３（５Ｈ， ｍ）， ７．４５−７．５１（３Ｈ， ｍ）， ７．８２（１Ｈ， ｓ）， ７．９１−７．９４（１Ｈ， ｍ）， ８．１１−８．１５（２Ｈ， ｍ）． Example-10

2-Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (0) (13 mg, 11 μmol) and potassium carbonate (92 mg, 0.66 mmol) in N, N-dimethylformamide (1 ml) suspension was added o-bromotoluene (27 μl, 0.22 mmol), and the mixture was stirred at 100 ° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 30: 1) to give 4- (2-methylphenyl) -2-phenyloxazole ( 28 mg, 54%). ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 2.51 (3H, s), 7.25-7.33 (5H, m), 7.45-7.51 (3H, m), 7. 82 (1H, s), 7.91-7.94 (1H, m), 8.11-8.15 (2H, m).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０ｍｇ， ０．２２ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１３ｍｇ， １１μｍｏｌ）、炭酸カリウム（９２ｍｇ， ０．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）懸濁液に、１−ブロモ−２−メチル−１−プロペン（２３μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で１．５時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して４−（２−メチル−１−プロペニル）−２−フェニルオキサゾール（２８ｍｇ， ６５％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．９４（３Ｈ， ｓ）， ２．０１（３Ｈ， ｓ）， ６．１３（１Ｈ， ｓ）， ７．４２−７．４８（３Ｈ， ｍ）， ７．５６（１Ｈ， ｓ）， ８．０２−８．０７（２Ｈ， ｍ）． Example-11

2-Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (0) (13 mg, 11 μmol) and potassium carbonate (92 mg, 0.66 mmol) in an N, N-dimethylformamide (1 ml) suspension, 1-bromo-2-methyl-1-propene (23 μl, 0.22 mmol) was added to the suspension at 100 ° C. For 1.5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 4- (2-methyl-1-propenyl) -2- Phenyloxazole (28 mg, 65%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 1.94 (3H, s), 2.01 (3H, s), 6.13 (1H, s), 7.42-7.48 (3H, m), 7.56 (1H, s), 8.02-8.07 (2H, m).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０ｍｇ， ０．２２ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１３ｍｇ， １１μｍｏｌ）、炭酸カリウム（９２ｍｇ， ０．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）懸濁液に、２−ブロモピリジン（２１μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で３時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１→４：１）で精製して２−フェニル−４−（ピリジン−２−イル）オキサゾール（３６ｍｇ， ７３％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ７．２１−７．２６（１Ｈ， ｄｄｄ， Ｊ＝１．０， ４．９， ７．５Ｈｚ）， ７．４６−７．５２（３Ｈ， ｍ）， ７．７９（１Ｈ， ｄｔ， Ｊ＝１．７， ７．７Ｈｚ）， ８．０２（１Ｈ， ｄ， Ｊ＝７．９Ｈｚ）， ８．１２−８．１６（２Ｈ， ｍ）， ８．３２（１Ｈ， ｓ）， ８．６１（１Ｈ， ｂｒｄ， Ｊ＝４．３Ｈｚ）． Example-12

2-Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (0) (13 mg, 2-bromopyridine (21 μl, 0.22 mmol) was added to a suspension of 11 μmol) and potassium carbonate (92 mg, 0.66 mmol) in N, N-dimethylformamide (1 ml), and the mixture was stirred at 100 ° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give 2-phenyl-4- (pyridine-2 -Yl) oxazole (36 mg, 73%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 7.21-7.26 (1H, ddd, J = 1.0, 4.9, 7.5 Hz), 7.46-7.52 (3H, m), 7.79 (1H, dt, J = 1.7, 7.7 Hz), 8.02 (1H, d, J = 7.9 Hz), 8.12-8.16 (2H, m), 8.32 (1H, s), 8.61 (1H, brd, J = 4.3 Hz).

２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（６０ｍｇ， ０．２２ｍｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（１３ｍｇ， １１μｍｏｌ）、炭酸カリウム（９２ｍｇ， ０．６６ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）懸濁液に、２−ブロモチアゾール（２０μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で３時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１→４：１）で精製して２−フェニル−４―（チアゾール−２−イル）オキサゾール（４０ｍｇ， ８０％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ７．４０（１Ｈ， ｄ， Ｊ＝３．２Ｈｚ）， ７．４８−７．５２（３Ｈ， ｍ）， ７．８８（１Ｈ， ｄ， Ｊ＝３．２Ｈｚ）， ８．１１−８．１５（２Ｈ， ｍ）， ８．２８（１Ｈ， ｓ）． Example-13

2-Phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (60 mg, 0.22 mmol), tetrakistriphenylphosphine palladium (0) (13 mg, 2-bromothiazole (20 μl, 0.22 mmol) was added to a suspension of N, N-dimethylformamide (1 ml) in 11 μmol) and potassium carbonate (92 mg, 0.66 mmol), and the mixture was stirred at 100 ° C. for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to give 2-phenyl-4- (thiazole-2). -Yl) oxazole (40 mg, 80%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 7.40 (1H, d, J = 3.2 Hz), 7.48-7.52 (3H, m), 7.88 (1H, d, J = 3.2 Hz), 8.11-8.15 (2H, m), 8.28 (1H, s).

５−メチル−２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（２０ｍｇ， ７０μｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（４ｍｇ， ３．５μｍｏｌ）、炭酸カリウム（２９ｍｇ， ２１０μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．５ｍｌ）懸濁液に、ブロモベンゼン（７．４μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で１時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して２，４−ジフェニル−５−メチルオキサゾール（１６ｍｇ， ９８％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ２．６２（３Ｈ， ｓ）， ７．３１−７．３５（１Ｈ， ｍ）， ７．４２−７．４８（５Ｈ， ｍ）， ７．７２−７．７５（２Ｈ， ｍ）， ８．０７−８．１０（２Ｈ， ｍ）． Example-14

5-methyl-2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (20 mg, 70 μmol), tetrakistriphenylphosphine palladium (0) ( Bromobenzene (7.4 μl, 0.22 mmol) was added to a suspension of 4 mg, 3.5 μmol) and potassium carbonate (29 mg, 210 μmol) in N, N-dimethylformamide (0.5 ml) at 100 ° C. for 1 hour. Stir. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 2,4-diphenyl-5-methyloxazole (16 mg, 98 %). ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 2.62 (3H, s), 7.31-7.35 (1H, m), 7.42-7.48 (5H, m), 7. 72-7.75 (2H, m), 8.07-8.10 (2H, m).

５−メチル−２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（２０ｍｇ， ７０μｍｏｌ）、テトラキストリフェニルホスフィンパラジウム（０）（４ｍｇ， ３．５μｍｏｌ）、炭酸カリウム（２９ｍｇ， ２１０μｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（０．５ｍｌ）懸濁液に、２−ブロモチアゾール（６．３μｌ， ０．２２ｍｍｏｌ）を加えて１００℃で２時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して５−メチル−２−フェニル−４−（チアゾール−２−イル）オキサゾール（１５ｍｇ， ８３％）を得た。^１Ｈ ＮＭＲ（５００ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ２．８１（３Ｈ， ｓ）， ７．３４（１Ｈ， ｄ， Ｊ＝３．３Ｈｚ）， ７．４５−７．４９（３Ｈ， ｍ）， ７．８８（１Ｈ， ｄ， Ｊ＝３．３Ｈｚ）， ８．０６−８．１０（２Ｈ， ｍ）． Example-15

5-methyl-2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (20 mg, 70 μmol), tetrakistriphenylphosphine palladium (0) ( 4-bromothiazole (6.3 μl, 0.22 mmol) was added to a suspension of 4 mg, 3.5 μmol) and potassium carbonate (29 mg, 210 μmol) in N, N-dimethylformamide (0.5 ml) at 100 ° C. Stir for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 5-methyl-2-phenyl-4- (thiazole-2). -Yl) oxazole (15 mg, 83%) was obtained. ¹ H NMR (500 MHz, CDCl ₃ , ppm): δ 2.81 (3H, s), 7.34 (1H, d, J = 3.3 Hz), 7.45-7.49 (3H, m), 7.88 (1H, d, J = 3.3 Hz), 8.06-8.10 (2H, m).

５−メチル−２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（１５．６ｍｇ， ０．０５５ｍｍｏｌ）の１，４−ジオキサン（１．５ｍｌ）溶液に、２−クロロオキサゾール−４−カルボン酸エチル（１７．６ｍｇ， ０．１ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（５ｍｇ， ４．３μｍｏｌ）及び炭酸カリウム（１７ｍｇ， ０．１３ｍｍｏｌ）を加えて、５時間加熱還流した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝２：１）で精製して、５’−メチル−２’−フェニル−２，４’−ビオキサゾール−４−カルボン酸エチル（１４ｍｇ， ８６％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．４１（３Ｈ， ｔ， Ｊ＝７．０Ｈｚ）， ２．８２（３Ｈ， ｓ）， ４．４２（２Ｈ， ｑ， Ｊ＝７．０Ｈｚ）， ７．４２−７．５０（３Ｈ， ｍ）， ８．０２−８．１３（２Ｈ， ｍ）， ８．３０（１Ｈ， ｓ）． Example-16

5-methyl-2-phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (15.6 mg, 0.055 mmol) of 1,4-dioxane To a (1.5 ml) solution, ethyl 2-chlorooxazole-4-carboxylate (17.6 mg, 0.1 mmol), tetrakis (triphenylphosphine) palladium (5 mg, 4.3 μmol) and potassium carbonate (17 mg, 0. 13 mmol) was added and heated to reflux for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 2: 1) to give 5′-methyl-2′-phenyl-2,4 ′. -Ethyl bioxazol-4-carboxylate (14 mg, 86%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.41 (3H, t, J = 7.0 Hz), 2.82 (3H, s), 4.42 (2H, q, J = 7.0 Hz) ), 7.42-7.50 (3H, m), 8.02-8.13 (2H, m), 8.30 (1H, s).

２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（５０ｍｇ， ０．１２ｍｍｏｌ）の１，４−ジオキサン（１．５ｍｌ）溶液に、２−クロロオキサゾール−４−カルボン酸エチル（３５ｍｇ， ０．２ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（７．７ｍｇ， ６．５μｍｏｌ）及び炭酸カリウム（５５ｍｇ， ０．４ｍｍｏｌ）を加えて、２時間加熱還流した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝５：１→４：１→２：１）で精製して、２’−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５’−メチル−２，４’−ビオキサゾール−４−カルボン酸エチル（４３ｍｇ， ８３％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．１５−１．５０（９Ｈ， ｍ）， １．３９（３Ｈ， ｄ， Ｊ＝５．０Ｈｚ）， １．４０（３Ｈ， ｔ， Ｊ＝７．５Ｈｚ）， １．７０（６Ｈ， ｓ）， ２．７４（３Ｈ， ｓ）， ４．４１（２Ｈ， ｑ， Ｊ＝７．５Ｈｚ）， ４．３１−４．６０（２Ｈ， ｍ）， ８．２６（１Ｈ， ｓ）． Example-17

2- (3-tert-Butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidine-4-yl) -5-methyl-4- (4,4,5,5-tetramethyl-1,3 , 2-Dioxaborolan-2-yl) oxazole (50 mg, 0.12 mmol) in 1,4-dioxane (1.5 ml), ethyl 2-chlorooxazole-4-carboxylate (35 mg, 0.2 mmol), tetrakis (Triphenylphosphine) palladium (7.7 mg, 6.5 μmol) and potassium carbonate (55 mg, 0.4 mmol) were added, and the mixture was heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 5: 1 → 4: 1 → 2: 1) to give 2 ′-(3- tert-Butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidin-4-yl) -5′-methyl-2,4′-bioxazole-4-carboxylate (43 mg, 83%) was obtained. It was. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.15 to 1.50 (9H, m), 1.39 (3H, d, J = 5.0 Hz), 1.40 (3H, t, J = 7.5 Hz), 1.70 (6H, s), 2.74 (3H, s), 4.41 (2H, q, J = 7.5 Hz), 4.31-4.60 (2H, m ), 8.26 (1H, s).

２’−ｔｅｒｔ−ブチルジメチルシリル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２，４’−ビオキサゾール（５７．０ｍｇ， ０．１５ｍｍｏｌ）の１，４−ジオキサン（３ｍｌ）溶液に、２−ブロモオキサゾール−４−カルボン酸エチル（６３ｍｇ， ０．２９ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（２８ｍｇ， ２４μｍｏｌ）及び炭酸カリウム（１００ｍｇ， ０．７２ｍｍｏｌ）を加えて、２時間加熱還流した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝４：１→２：１）で精製して、２”−ｔｅｒｔ− ブチルジメチルシリル−２，４’：２’，４”−ターオキサゾール−４−カルボン酸エチル（５０ｍｇ， ８５％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ０．４１（６Ｈ， ｓ）， １．０１（９Ｈ， ｓ）， １．４１（３Ｈ， ｔ， Ｊ＝８．３Ｈｚ）， ４．４３（２Ｈ， ｑ， Ｊ＝８．３Ｈｚ）， ８．３１（１Ｈ， ｓ）， ８．４３（１Ｈ， ｓ）， ８．５３（１Ｈ， ｓ）． Example-18

2′-tert-butyldimethylsilyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2,4′-bioxazole (57.0 mg, 0. 15 mmol) in 1,4-dioxane (3 ml), ethyl 2-bromooxazole-4-carboxylate (63 mg, 0.29 mmol), tetrakis (triphenylphosphine) palladium (28 mg, 24 μmol) and potassium carbonate (100 mg, 0.72 mmol) was added and heated to reflux for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 → 2: 1) to give 2 ″ -tert-butyldimethylsilyl-2. , 4 ′: 2 ′, 4 ″ -Teroxazole-4-carboxylate (50 mg, 85%). ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 0.41 (6H, s), 1.01 (9H, s), 1.41 (3H, t, J = 8.3 Hz), 4.43 ( 2H, q, J = 8.3 Hz), 8.31 (1H, s), 8.43 (1H, s), 8.53 (1H, s).

トリス(ジベンジリデンアセトン)ジパラジウム（クロロホルム付加物）（５．６ｍｇ，５．４μｍｏｌ）、トリｏ−トリルホスフィン（１３ｍｇ， ４３μｍｏｌ）を１，４−ジオキサン（０．５ｍｌ）に溶解し、室温で３０分撹拌した。反応混合液にトリフルオロメタンスルホン酸２’−ブロモ−５−トリメチルシリル−２，４’−ビオキサゾール−４−イル（９０ｍｇ， ０．２１ｍｍｏｌ）の１，４−ジオキサン溶液（１．６ｍｌ）、２−フェニル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（８８ｍｇ， ０．３２ｍｍｏｌ）及び炭酸ナトリウム（６９ｍｇ， ０．６５ｍｍｏｌ）を加えて２０時間加熱還流した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝１０：１）で精製して、トリフルオロメタンスルホン酸２”−フェニル−５−トリメチルシリル−２，４’：２’，４”−ターオキサゾール−４−イル（５９ｍｇ， ５７％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ０．４３（９Ｈ， ｓ）， ７．４７−７．５２（３Ｈ， ｍ）， ８．１１−８．１８（２Ｈ， ｍ）， ８．３２（１Ｈ， ｓ）， ８．４２（１Ｈ， ｓ）． Example-19

Tris (dibenzylideneacetone) dipalladium (chloroform adduct) (5.6 mg, 5.4 μmol) and tri-o-tolylphosphine (13 mg, 43 μmol) were dissolved in 1,4-dioxane (0.5 ml) at room temperature. Stir for 30 minutes. To the reaction mixture was added 1,4-dioxane solution (1.6 ml) of 2′-bromo-5-trimethylsilyl-2,4′-bioxazol-4-yl (90 mg, 0.21 mmol) trifluoromethanesulfonic acid, 2- Add phenyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) oxazole (88 mg, 0.32 mmol) and sodium carbonate (69 mg, 0.65 mmol) to add 20 Heated to reflux for hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1) to give trifluoromethanesulfonic acid 2 ″ -phenyl-5-trimethylsilyl-2. , 4 ′: 2 ′, 4 ″ -Teroxazol-4-yl (59 mg, 57%). ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 0.43 (9H, s), 7.47-7.52 (3H, m), 8.11-8.18 (2H, m), 8. 32 (1H, s), 8.42 (1H, s).

トリス(ジベンジリデンアセトン)ジパラジウム（クロロホルム付加物）（４．３ｍｇ，４．２μｍｏｌ）、トリｏ−トリルホスフィン（１０ｍｇ， ３３μｍｏｌ）を１，４−ジオキサン（０．５ｍｌ）に溶解し、室温で３０分撹拌した。反応混合液に、２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチル−４−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）オキサゾール（４０ｍｇ， ０．０９５ｍｍｏｌ）、トリフルオロメタンスルホン酸２’−ヨード−２，４’−ビオキサゾール−４−イル（６８ｍｇ， ０．１７ｍｍｏｌ）の１，４−ジオキサン溶液（１．５ｍｌ）及び炭酸カリウム（６９ｍｇ， １．０ｍｍｏｌ）を加えて２時間撹拌した。反応終了後、反応混合液を室温まで冷却した後、ジエチルエーテルで希釈した。有機層を、水、飽和塩化ナトリウム水溶液で洗浄した後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー（へキサン：酢酸エチル＝４：１）で精製して、トリフルオロメタンスルホン酸２”−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５”−メチル−２，４’：２’，４”−ターオキサゾール−４−イル（３８ｍｇ， ６９％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．３９（３Ｈ， ｄ， Ｊ＝６Ｈｚ）， １．２１−１．７１（１５Ｈ， ｍ）， ２．７６（３Ｈ， ｂｒｓ）， ４．２０−４．３５（１Ｈ， ｍ）， ４．４５−４．５５（１Ｈ， ｍ）， ７．７７（１Ｈ， ｓ）， ８．３０（１Ｈ， ｂｒｓ）． Example-20

Tris (dibenzylideneacetone) dipalladium (chloroform adduct) (4.3 mg, 4.2 μmol) and tri-o-tolylphosphine (10 mg, 33 μmol) were dissolved in 1,4-dioxane (0.5 ml) at room temperature. Stir for 30 minutes. To the reaction mixture was added 2- (3-tert-butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidine-4-yl) -5-methyl-4- (4,4,5,5-tetra Methyl-1,3,2-dioxaborolan-2-yl) oxazole (40 mg, 0.095 mmol), trifluoromethanesulfonic acid 2′-iodo-2,4′-bioxazol-4-yl (68 mg, 0.17 mmol) Of 1,4-dioxane (1.5 ml) and potassium carbonate (69 mg, 1.0 mmol) were added and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and diluted with diethyl ether. The organic layer was washed with water and a saturated aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate = 4: 1) to give trifluoromethanesulfonic acid 2 ″-(3-tert-butoxycarbonyl). -2,2,5-trimethyl-1,3-oxazolidine-4-yl) -5 "-methyl-2,4 ': 2', 4" -teroxazol-4-yl (38 mg, 69%) ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.39 (3H, d, J = 6 Hz), 1.21-1.71 (15H, m), 2.76 (3H, brs), 4.20-4.35 (1H, m), 4.45-4.55 (1H, m), 7.77 (1H, s), 8.30 (1H, brs).

２−フェニルオキサゾール−４（５Ｈ）−オン（５０ｍｇ， ０．３１ｍｍｏｌ）のトルエン（３ｍｌ）溶液に、三臭化リン（０．６ｍｌ）を加えて５時間加熱還流した。反応溶液を０゜Ｃに冷却した後、氷を加えて水層をジエチルエーテル（１００ｍｌ）で抽出し、抽出溶媒を無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製し、４−ブロモ−２−フェニルオキサゾール（３８ｍｇ， ５０％）)を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ７．４０−７．５０（３Ｈ， ｍ）， ７．６９（１Ｈ， ｓ）， ７．９６−８．０５（２Ｈ， ｍ）． Reference Example-1

To a solution of 2-phenyloxazol-4 (5H) -one (50 mg, 0.31 mmol) in toluene (3 ml) was added phosphorus tribromide (0.6 ml), and the mixture was heated to reflux for 5 hours. The reaction solution was cooled to 0 ° C., ice was added, the aqueous layer was extracted with diethyl ether (100 ml), and the extraction solvent was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 4-bromo-2-phenyloxazole (38 mg, 50%). ) ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 7.40-7.50 (3H, m), 7.69 (1H, s), 7.96-8.05 (2H, m).

プロパルギルアミン（０．５９ｍｌ， ８．５７ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液を０゜Ｃに冷却した後、トリエチルアミン（１．４ｍｌ， １０ｍｍｏｌ）とベンゾイルクロリド（１ｍｌ， ８．５７ｍｍｏｌ）を加えて３０分撹拌した。反応溶液をジエチルエーテル（１５０ｍｌ）で希釈した後、水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２：１）で精製して、Ｎ−プロパルギルベンズアミド（８６８ｍｇ， ６３％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ２．２７−２．２９（１Ｈ， ｍ）， ４．２０−４．３０（２Ｈ， ｍ）， ６．２０−６．６０（１Ｈ， ｂｒｓ）， ７．３２−７．５６（３Ｈ， ｍ）， ７．３０−７．８０（２Ｈ， ｍ）． Reference example-2

A solution of propargylamine (0.59 ml, 8.57 mmol) in dichloromethane (20 ml) was cooled to 0 ° C., triethylamine (1.4 ml, 10 mmol) and benzoyl chloride (1 ml, 8.57 mmol) were added, and the mixture was stirred for 30 minutes. did. The reaction solution was diluted with diethyl ether (150 ml), washed with water and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give N-propargylbenzamide (868 mg, 63%). . ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 2.27-2.29 (1H, m), 4.20-4.30 (2H, m), 6.20-6.60 (1H, brs ), 7.32-7.56 (3H, m), 7.30-7.80 (2H, m).

水素化ナトリウム（１２２ｍｇ， ３．３ｍｍｏｌ）を１，４−ジオキサン（２５ｍｌ）に懸濁させ、Ｎ−プロパルギルベンズアミド（５９２ｍｇ， ３．３ｍｍｏｌ）を加えて３０分室温で撹拌し、さらに４時間加熱還流した。反応溶液を室温まで戻した後に飽和塩化アンモニウム水溶液（１０ｍｌ）を加えて反応を停止させた。反応混合液をジエチルエーテル（１０ｍｌ）で抽出し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して、５−メチル−２−フェニルオキサゾール（４０５ｍｇ、７７％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ２．４０（３Ｈ， ｍ）， ６．８３（１Ｈ， ｍ）， ７．４０−７．４５（３Ｈ， ｍ）， ７．９６−８．０５（２Ｈ， ｍ）． Reference example-3

Sodium hydride (122 mg, 3.3 mmol) was suspended in 1,4-dioxane (25 ml), N-propargylbenzamide (592 mg, 3.3 mmol) was added, and the mixture was stirred at room temperature for 30 minutes, and further heated under reflux for 4 hours. did. After returning the reaction solution to room temperature, a saturated aqueous ammonium chloride solution (10 ml) was added to stop the reaction. The reaction mixture was extracted with diethyl ether (10 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 5-methyl-2-phenyloxazole (405 mg, 77%). ) ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 2.40 (3H, m), 6.83 (1H, m), 7.40-7.45 (3H, m), 7.96-8. 05 (2H, m).

５−メチル−２−フェニルオキサゾール（１９５ｍｇ， １．２ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１２ｍｌ）溶液に、Ｎ−ブロモコハク酸イミド（２６１ｍｇ， １．５ｍｍｏｌ）を加え、室温で６時間撹拌した。反応溶液をジエチルエーテル（５０ｍｌ）で希釈した後、水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して、４−ブロモ−５−メチル−２−フェニルオキサゾール（９４ｍｇ， ３２％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ２．３９（３Ｈ， ｓ）， ７．４０−７．４７（３Ｈ， ｍ）， ７．９１−８．００（２Ｈ， ｍ）． Reference example-4

N-bromosuccinimide (261 mg, 1.5 mmol) was added to a solution of 5-methyl-2-phenyloxazole (195 mg, 1.2 mmol) in N, N-dimethylformamide (12 ml), and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with diethyl ether (50 ml), washed with water, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 4-bromo-5-methyl-2-phenyloxazole ( 94 mg, 32%). ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 2.39 (3H, s), 7.40-7.47 (3H, m), 7.91-8.00 (2H, m).

１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（１．０３ｇ， ５．４ｍｍｏｌ）、１−ヒドロキシベンゾトリアゾール（１．６５ｇ， １１ｍｍｏｌ）のジクロロメタン（２０ｍｌ）溶液に、プロパルギルアミン（０．６２ｍｌ， ９．０ｍｍｏｌ）を加えて３０分撹拌した後、３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−カルボン酸（９３２ｍｇ， ３．６ｍｍｏｌ）のジクロロメタン溶液（２０ｍｌ）を加えて室温で１２時間撹拌した。反応溶液を酢酸エチル（３００ｍｌ）で希釈し、３％塩酸、飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝１：１）で精製して３−ｔｅｒｔ−ブトキシカルボニル−Ｎ−プロパルギル−２，２，５−トリメチル−１，３−オキサゾリジン−４−カルボキサミド（８９２ｍｇ， ８４％）を得た。得られた３−ｔｅｒｔ−ブトキシカルボニル−Ｎ−プロパルギル−２，２，５−トリメチル−１，３−オキサゾリジン−４−カルボキサミド（４００ｍｇ， １．３５ｍｍｏｌ）の１，４−ジオキサン溶液（１２ｍｌ）を、アルゴン雰囲気下室温で、水素化ナトリウム（５０ｍｇ， １．３５ｍｍｏｌ）の１，３−ジオキサン（１４ｍｌ）懸濁液に加えて室温で３０分撹拌し、さらに１時間加熱還流した。反応溶液を室温に戻した後に飽和塩化アンモニウム水溶液を加えて反応を停止させ、ジエチルエーテル（１５０ｍｌ）で抽出した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝１０：１）で精製して２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチルオキサゾール（１６８ｍｇ、４２％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．２１−１．５０（９Ｈ， ｍ）， １．３５（３Ｈ， ｄ， Ｊ＝６．０Ｈｚ）， １．６９（６Ｈ， ｓ）， ２．３１（３Ｈ， ｓ）， ４．２０−４．３０（１Ｈ， ｍ）， ４．３５−４．５０（１Ｈ， ｍ）， ６．６９（１Ｈ， ｍ）． Reference Example-5

To a solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.03 g, 5.4 mmol) and 1-hydroxybenzotriazole (1.65 g, 11 mmol) in dichloromethane (20 ml) was added propargylamine (0 .62 ml, 9.0 mmol) was added and stirred for 30 minutes, and then 3-tert-butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidine-4-carboxylic acid (932 mg, 3.6 mmol) in dichloromethane. The solution (20 ml) was added and stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate (300 ml), washed with 3% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 3-tert-butoxycarbonyl-N-propargyl-2,2 , 5-trimethyl-1,3-oxazolidine-4-carboxamide (892 mg, 84%) was obtained. A 1,4-dioxane solution (12 ml) of the obtained 3-tert-butoxycarbonyl-N-propargyl-2,2,5-trimethyl-1,3-oxazolidine-4-carboxamide (400 mg, 1.35 mmol) was added. At room temperature under an argon atmosphere, sodium hydride (50 mg, 1.35 mmol) was added to a suspension of 1,3-dioxane (14 ml), stirred at room temperature for 30 minutes, and further heated to reflux for 1 hour. After returning the reaction solution to room temperature, the reaction was stopped by adding a saturated aqueous ammonium chloride solution, followed by extraction with diethyl ether (150 ml). The organic layer was washed with water and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 2- (3-tert-butoxycarbonyl-2,2, 5-Trimethyl-1,3-oxazolidine-4-yl) -5-methyloxazole (168 mg, 42%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.21-1.50 (9H, m), 1.35 (3H, d, J = 6.0 Hz), 1.69 (6H, s), 2.31 (3H, s), 4.20-4.30 (1H, m), 4.35-4.50 (1H, m), 6.69 (1H, m).

２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５―メチルオキサゾール（３００ｍｇ， １．０１ｍｍｏｌ）のＮ，Ｎ−ジメチルホルムアミド（１０ｍｌ）溶液に、Ｎ−ブロモコハク酸イミド（２１６ｍｇ， １．２１ｍｍｏｌ）を加えて、遮光下４８時間室温で攪拌した。反応混合液をジエチルエーテル（１００ｍｌ）で希釈した後、水、３％塩酸で洗浄し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製して４−ブロモ−２−（３−ｔｅｒｔ−ブトキシカルボニル−２，２，５−トリメチル−１，３−オキサゾリジン−４−イル）−５−メチルオキサゾール（２５８ｍｇ， ６８％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ １．２３−１．５０（９Ｈ， ｍ）， １．３５（３Ｈ， ｄ， Ｊ＝７．５Ｈｚ）， １．６７（６Ｈ， ｓ）， ２．３０（３Ｈ， ｓ）， ４．１９−４．３１（１Ｈ， ｍ）， ４．３２−４．５０（１Ｈ， ｍ）． Reference Example-8

2- (3-tert-Butoxycarbonyl-2,2,5-trimethyl-1,3-oxazolidine-4-yl) -5-methyloxazole (300 mg, 1.01 mmol) in N, N-dimethylformamide (10 ml) N-bromosuccinimide (216 mg, 1.21 mmol) was added to the solution, and the mixture was stirred at room temperature for 48 hours under light shielding. The reaction mixture was diluted with diethyl ether (100 ml), washed with water and 3% hydrochloric acid, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1) to give 4-bromo-2- (3-tert-butoxycarbonyl- 2,2,5-Trimethyl-1,3-oxazolidin-4-yl) -5-methyloxazole (258 mg, 68%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 1.23-1.50 (9H, m), 1.35 (3H, d, J = 7.5 Hz), 1.67 (6H, s), 2.30 (3H, s), 4.19-4.31 (1H, m), 4.32-4.50 (1H, m).

２−ブロモオキサゾール−４−カルボキサミド（１．０ｇ， ５．２ｍｍｏｌ）のジクロロメタン（５０ｍｌ）懸濁液に塩化オキサリル（０．４６ｍｌ， ５．２ｍｍｏｌ）を加え、室温で２時間撹拌し、さらに１２時間加熱還流した。反応液の溶媒を減圧下留去後、残渣をテトラヒドロフラン（５０ｍｌ）に溶解した。その溶液にトリメチルシリルジアゾメタン（２．０Ｍジエチルエーテル溶液、２．６２ｍｌ， ５．２ｍｍｏｌ）を加え、室温で３０分間反応させた後、−７８゜Ｃに冷却しトリエチルアミン（１．４５ｍｌ， １０．４ｍｍｏｌ）とトリフルオロメタンスルホン酸無水物（０．９７ｍｌ， ５．７ｍｍｏｌ）を加えて、−７８゜Ｃで２時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加えて反応を停止させた後、ジエチルエーテル（２００ｍｌ）で抽出し無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝５０：１）で精製してトリフルオロメタンスルホン酸２’−ブロモ−５−トリメチルシリル−２，４’−ビオキサゾール−４−イル（４２７ｍｇ、２０％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ０．４０（９Ｈ， ｓ）， ８．２９（１Ｈ， ｓ）． Reference Example-9

Oxalyl chloride (0.46 ml, 5.2 mmol) was added to a suspension of 2-bromooxazole-4-carboxamide (1.0 g, 5.2 mmol) in dichloromethane (50 ml), and the mixture was stirred at room temperature for 2 hours and further for 12 hours. Heated to reflux. After the solvent of the reaction solution was distilled off under reduced pressure, the residue was dissolved in tetrahydrofuran (50 ml). Trimethylsilyldiazomethane (2.0 M diethyl ether solution, 2.62 ml, 5.2 mmol) was added to the solution, reacted at room temperature for 30 minutes, cooled to −78 ° C., and triethylamine (1.45 ml, 10.4 mmol). And trifluoromethanesulfonic anhydride (0.97 ml, 5.7 mmol) were added and stirred at −78 ° C. for 2 hours. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, followed by extraction with diethyl ether (200 ml) and drying over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1) to give trifluoromethanesulfonic acid 2′-bromo-5-trimethylsilyl-2. , 4′-bioxazol-4-yl (427 mg, 20%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 0.40 (9H, s), 8.29 (1H, s).

トリフルオロメタンスルホン酸２’−ブロモ−５−トリメチルシリル−２，４’−ビオキサゾール−４−イル（４２５ｍｇ， ０．９８ｍｍｏｌ）のテトラヒドロフラン（３ｍｌ）溶液に、フッ化水素−ピリジン錯体（６５〜７０％， ０．２８ｍｌ）を加えて室温で３時間撹拌した。反応混合液に酢酸エチル（５０ｍｌ）を加えて希釈した後、飽和塩化アンモニウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１）で精製してトリフルオロメタンスルホン酸２’−ブロモ−２，４’−ビオキサゾール−４−イル（２８８ｍｇ， ８１％）を得た。そのトリフルオロメタンスルホン酸２’−ブロモ−２，４’−ビオキサゾール−４−イル（５９６ｍｇ， １．６ｍｍｏｌ）の酢酸（１０ｍｌ）溶液に、亜鉛粉末（５６０ｍｇ， ８．５ｍｍｏｌ）を加えて、６０゜Ｃで５時間、８０゜Ｃで４間加熱した。反応液を冷却後、不溶物をセライトろ過して除き、ろ液を減圧下濃縮した。残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝２０：１→４：１）で精製してトリフルオロメタンスルホン酸２，４’−ビオキサゾール−４−イル（３３０ｍｇ， ７１％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ７．７８（１Ｈ， ｓ）， ８．０２（１Ｈ， ｍ）， ８．３２（１Ｈ， ｍ）． Reference Example-10

To a solution of 2′-bromo-5-trimethylsilyl-2,4′-bioxazol-4-yl (425 mg, 0.98 mmol) in trifluoromethanesulfonic acid in tetrahydrofuran (3 ml) was added a hydrogen fluoride-pyridine complex (65 to 70%). 0.28 ml) and stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate (50 ml), washed with a saturated aqueous ammonium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1), and trifluoromethanesulfonic acid 2′-bromo-2,4′-bioxazol-4-yl ( 288 mg, 81%). To a solution of 2′-bromo-2,4′-bioxazol-4-yl (596 mg, 1.6 mmol) in trifluoromethanesulfonic acid in acetic acid (10 ml) was added zinc powder (560 mg, 8.5 mmol), and 60 Heated at 80 ° C. for 5 hours and at 80 ° C. for 4 hours. After cooling the reaction solution, insolubles were removed by Celite filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 20: 1 → 4: 1) to obtain 2,4′-bioxazol-4-yl trifluoromethanesulfonate (330 mg, 71%). ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 7.78 (1H, s), 8.02 (1H, m), 8.32 (1H, m).

トリフルオロメタンスルホン酸２，４’−ビオキサゾール−４−イル（８９ｍｇ， ０．３１ｍｍｏｌ）のテトラヒドロフラン（３ｍｌ）溶液に、アルゴン雰囲気下−７８゜Ｃでリチウムビストリメチルシリルアミド（１Ｍテトラヒドロフラン溶液, ０．３４ｍｌ， ０．３４ｍｍｏｌ）を加えて３０分間撹拌した。反応混合液に、トリフルオロメタンスルホン酸ｔｅｒｔ−ブチルジメチルシリル（７８μｌ， ０．３４ｍｍｏｌ）を加えて、更に２時間攪拌した。反応混合液に飽和塩化アンモニウム水溶液（２ｍｌ）を加えて、混合液をジエチルエーテル（５０ｍｌ）で抽出し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝５０：１→４：１）で精製してトリフルオロメタンスルホン酸２’−ｔｅｒｔ−ブチルジメチルシリ−２，４’−ビオキサゾール−４−イル（９７ｍｇ， ７８％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ０．４０（６Ｈ， ｓ）， ０．９９（９Ｈ， ｓ）， ７．７３（１Ｈ， ｓ）， ８．４１（１Ｈ， ｓ）． Reference Example-11

To a solution of 2,4′-bioxazol-4-yl trifluoromethanesulfonate (89 mg, 0.31 mmol) in tetrahydrofuran (3 ml) was added lithium bistrimethylsilylamide (1M tetrahydrofuran solution, 0.34 ml) at −78 ° C. under an argon atmosphere. , 0.34 mmol) and stirred for 30 minutes. To the reaction mixture was added tert-butyldimethylsilyl trifluoromethanesulfonate (78 μl, 0.34 mmol), and the mixture was further stirred for 2 hours. A saturated aqueous ammonium chloride solution (2 ml) was added to the reaction mixture, and the mixture was extracted with diethyl ether (50 ml) and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 1 → 4: 1) to give 2′-tert-butyl trifluoromethanesulfonate. Dimethylsil-2,4′-bioxazol-4-yl (97 mg, 78%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 0.40 (6H, s), 0.99 (9H, s), 7.73 (1H, s), 8.41 (1H, s).

トリフルオロメタンスルホン酸２，４’−ビオキサゾール−４−イル（１００ｍｇ， ０．３５ｍｍｏｌ）のテトラヒドロフラン（２ｍｌ）溶液に、アルゴン雰囲気下−７８゜Ｃでリチウムビストリメチルシリルアミド（１Ｍテトラヒドロフラン溶液、 ０．３９ｍｌ， ０．３９ｍｍｏｌ）を加え３０分間撹拌した。反応溶液に、ヨウ素（１００ｍｇ， ０．３９ｍｍｏｌ）のテトラヒドロフラン溶液（２ｍｌ）を加えて、更に１０分間撹拌した。反応混合液に飽和塩化アンモニウム水溶液（２ｍｌ）を加えて反応を停止させ、ジエチルエーテル（５０ｍｌ）で抽出し、無水硫酸ナトリウムで乾燥した。乾燥剤をろ別した後、ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー（へキサン：酢酸エチル＝１０：１）で精製してトリフルオロメタンスルホン酸２’−ヨード−２，４’−ビオキサゾール−４−イル（１２８ｍｇ， ８９％）を得た。^１Ｈ ＮＭＲ（２５０ＭＨｚ， ＣＤＣｌ_３， ｐｐｍ）： δ ７．７６（１Ｈ， ｓ）， ８．３４（１Ｈ， ｓ）． Reference Example-12

To a solution of 2,4′-bioxazol-4-yl trifluoromethanesulfonate (100 mg, 0.35 mmol) in tetrahydrofuran (2 ml) was added lithium bistrimethylsilylamide (1M tetrahydrofuran solution, 0.39 ml) at −78 ° C. under an argon atmosphere. , 0.39 mmol) and stirred for 30 minutes. To the reaction solution was added iodine (100 mg, 0.39 mmol) in tetrahydrofuran (2 ml), and the mixture was further stirred for 10 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride (2 ml), extracted with diethyl ether (50 ml), and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1), and trifluoromethanesulfonic acid 2′-iodo-2,4′-. Bioxazol-4-yl (128 mg, 89%) was obtained. ¹ H NMR (250 MHz, CDCl ₃ , ppm): δ 7.76 (1H, s), 8.34 (1H, s).

Comparative Example-1
Lithium diisopropylamide (1M tetrahydrofuran solution, 1.6 ml, 1.60 mmol) was added to a solution of oxazole (100 mg, 1.45 mmol) in tetrahydrofuran (4 ml) at −78 ° C. under an argon atmosphere, and the mixture was stirred for 2 hours. To the reaction solution was added a tetrahydrofuran solution (2 ml) of trimethyl borate (312 mg, 3.0 mmol), and the mixture was further stirred for 2 hours and stirred at room temperature for 2 hours. The reaction mixture was quenched with agricultural hydrochloric acid (2 ml), extracted with diethyl ether (10 ml), and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, but the desired oxazol-2-ylboronic acid was not produced.

Comparative Example-2
To a solution of ethyl oxazol-4-ylcarboxylate (100 mg, 0.71 mmol) in tetrahydrofuran (4 ml) was added lithium diisopropylamide (1M tetrahydrofuran solution, 0.78 ml, 0.78 mmol) at −78 ° C. under an argon atmosphere for 2 hours. Stir for a while. To the reaction solution was added a tetrahydrofuran solution (2 ml) of trimethyl borate (156 mg, 1.5 mmol), and the mixture was further stirred for 2 hours and stirred at room temperature for 2 hours. The reaction mixture was quenched with agricultural hydrochloric acid (1 ml), extracted with diethyl ether (10 ml), and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate could be concentrated under reduced pressure, but the desired 4-ethoxycarbonyloxazol-2-ylboronic acid was not produced.

Claims (13)

General formula (1)

Wherein R ¹ is an optionally substituted C ₁ -C ₈ alkyl group, an optionally substituted C ₃ -C ₈ cycloalkyl group, an optionally substituted C ₇ -C ₁₁ aralkyl group, optionally substituted C ₂ -C ₈ alkenyl group, a substituted and an optionally C ₂ -C ₈ alkynyl group, a substituted and optionally an aromatic group, may be protected by a hydroxyl protecting group hydroxyl , C ₁ -C ₈ alkoxy group which may be substituted, formyl group, C ₂ -C ₈ acyl group which may be substituted, C ₂ -C ₈ alkoxycarbonyl group which may be substituted, substituted An optionally substituted carbamoyl group, a carboxyl group, a cyano group, a nitro group, an optionally substituted amino group, an optionally substituted heterocyclic group or an optionally substituted silyl group, R ² represents a hydrogen atom; , C ₁ optionally substituted C ₈ alkyl group, substituted with an optionally _C 3 -C ₈ cycloalkyl group, substituted _C 7 _{-C 11} optionally aralkyl group, substituted _C 2 -C ₈ optionally alkenyl group, substituted An optionally substituted C ₂ -C ₈ alkynyl group, an optionally substituted aromatic group, a hydroxyl group optionally protected by a protecting group for a hydroxyl group, an optionally substituted C ₁ -C ₈ alkoxy group, formyl groups, substituted and an optionally C ₂ -C ₈ acyl group, substituted optionally optionally C ₂ -C ₈ alkoxycarbonyl be groups, substituted and optionally also a carbamoyl group, a carboxyl group, a cyano group, a nitro group, a substituted Represents an optionally substituted amino group, an optionally substituted heterocyclic group or an optionally substituted silyl group, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom or an optionally substituted C; _{1 ~C 8} alkyl Groups, substituted and C ₃ -C ₈ optionally cycloalkyl group, substituted .R ³ represents an even better C ₇ -C ₁₁ aralkyl group are a phenyl group or a substituted or optionally and R ⁴ To integrally And may form a ring.). General formula (2)

(Wherein R ¹ and R ² represent the same meaning as described above, X ¹ represents a halogen atom), and the general formula (3)

(In the formula, R ⁵ is an optionally substituted C ₁ -C ₈ alkyl group, an optionally substituted C ₃ -C ₈ cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted group. the boric acid ester represented by the representative.) good C ₇ -C ₁₁ aralkyl group, which comprises reacting in the presence of a base, the general formula (1a)

(Wherein R ¹ , R ² and R ⁵ represent the same meaning as described above). The production method according to claim 2, wherein the base is butyllithium, sec-butyllithium or tert-butyllithium. General formula (1a)

(Wherein R ¹ , R ² and R ⁵ represent the same meaning as described above) and water, or general formula (4)

(Wherein R ⁶ is an optionally substituted C ₁ -C ₈ alkyl group, an optionally substituted C ₃ -C ₈ cycloalkyl group, an optionally substituted phenyl group, or an optionally substituted group. Represents a good C _{7 to} C ₁₁ aralkyl group.) Or a general formula (5)

(Q represents an optionally substituted ethylene group, an optionally substituted trimethylene group or an optionally substituted o-phenylene group) and a diol represented by an acid catalyst in the presence of an acid catalyst. The general formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above). General formula (2)

(Wherein R ¹ , R ² and X ¹ represent the same meaning as described above) and the general formula (3)

(In the formula, R ⁵ represents the same meaning as described above.) By reacting with a borate ester represented in the presence of a base, general formula (1a)

(Wherein R ¹ , R ² and R ⁵ represent the same meaning as described above), and then water or general formula (4)

(Wherein R ⁶ represents the same meaning as described above), or the general formula (5)

(Q represents the same meaning as described above), and is reacted in the presence of an acid catalyst.

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above). 6. The production method according to claim 5, wherein the base is butyl lithium, sec-butyl lithium or tert-butyl lithium. General formula (6)

(Wherein R ¹ and R ² represent the same meaning as described above, X ² represents a leaving group), and the general formula (7)

(Wherein R ³ and R ⁴ represent the same meaning as described above), and the reaction is performed in the presence of a metal catalyst.

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above). The production method according to claim 7, wherein the metal catalyst is a palladium catalyst. The production method according to claim 7 or 8, wherein the compound represented by the general formula (7) is bis (catecholate) diboron, bis (pinacolato) diboron, bis (ethylene glycolate) diboron, or bis (neopentylglycolate) diboron. . General formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above), an oxazolyl group-introducing reagent containing the oxazole derivative as a component. General formula (1)

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above) and the general formula (8)

Wherein R ⁷ is an optionally substituted C _{7 to} C ₁₁ aralkyl group, an optionally substituted C _{2 to} C ₈ alkenyl group, an optionally substituted C _{2 to} C ₈ alkynyl group, and a substituted group. An aromatic group that may be substituted, a C _{2 to} C ₈ acyl group that may be substituted, and X ³ represents a leaving group) in the presence of a metal catalyst. General formula (9) characterized by

(Wherein R ¹ , R ² and R ⁷ represent the same meaning as described above). The production method according to claim 11, wherein the metal catalyst is a palladium catalyst. The production method according to claim 11 or 12, wherein R ⁷ is an optionally substituted aromatic group.