WO2005030714A1 - Process for the production of compounds having 5- to 10-membered aromatic heterocycles with alkylmagnesium monoamides - Google Patents

Abstract

The invention aims at providing an anionizing agent for heteroaromatic compounds which has the following advantages: (1) the reactivity (degree of anionization) is high, (2) the reaction can be conducted at relatively high temperatures and the formed anion is stable at the relatively high temperatures, (3) the formation of by-products is inhibited, and (4) the safety is satisfactory even in the use on an industrial scale; and a process for the production of heteroaromatic compounds which comprises converting a heteroaromatic compound into an anion by the use of the anionizing agent and reacting the anion with an electrophile to conduct electrophilic substitution. The above aim is attained by reacting a compound having a 5- to 10-membered aromatic heterocycle which may have one to three substituents (such as R10), e.g., a compound [(2)-4’] with a compound represented by the general formula (1) (wherein R1 is C1-6 alkyl; A1 is a group represented by the general formula: -NR2R3 or the like; and R2 and R3 are each C1-6 alkyl having piperazinyl or di(C1-6 alkyl)amino) and reacting the obtained anion with an electrophile. (X)

Description

 Specification

 Method for producing 5- to 10-membered aromatic heterocyclic compound using alkylmagnesium monoamide compound

 Technical field

 The present invention relates to a method for producing an aromatic heterocyclic compound by a reaction between an aromatic heterocyclic compound and an electrophilic reagent which have been subjected to aeration using an alkylmagnesium monoamide compound. In particular, the present invention relates to a method for producing an ortho-electrophilic substituent of an aromatic heterocyclic compound having a substituent.

 Background art

 Conventionally, an aromatic heterocyclic compound has been anionized with an organometallic reagent, and then reacted with an electrophile to obtain a desired compound. It is often used as a method for producing raw materials for substances.

 For example, as a raw material of a functional material, as reported in Non-Patent Document 1, 3-hydroxy-6 as an important intermediate in crown ether synthesis showing high affinity for a specific metal ion is used. -Methylpyridine-2-carbaldehyde and the like.

 [0003] Non-Patent Document 2 discloses a report of a [(3-pyridylalkyl) piperidylidene] benzocycloheptapyridine derivative as an antagonist against PAF (platelet aggregation factor) and histamine, and an irritation-inducing substance. . According to the description in this paper, 5-chloromethyl-2-methoxypyridine and 3-chloromethyl-2-methoxypyridine were used as intermediates V, each of which was 6-methoxypyridine-3- The above method is useful because it can be easily prepared from carbaldehyde and 2-methoxypyridine-3-force rubaldehyde, and can be applied to the synthesis of such pharmaceutical intermediates.

 [0004] Examples of an aromatic heterocyclic compound ionic agent include n-butyllithium, lithium disopropylamide (LDA), 2,2,6,6-tetramethylpiperidium lithium (LiTMP, hereinafter referred to as "2 , 2,6,6-tetramethylpiperidium "is abbreviated as TMP), magnesium bis (diisopropinoleamide) ((iPrN) Mg), 2,2,6,6-tetramethinolebiperidide Magnesium chloride

 twenty two

(TMPMgCl), di (2,2,6,6-tetramethylpiperidium) magnesium ((TMP) Mg) Used.

 [0005] For example, the above-mentioned TMPMgCl is described in Non-Patent Documents 3 and 4. These documents disclose the addition reaction of an electrophile to a substituted pyridine. Examples of the electrophile include N-formyl-、 '-methylpiperazine, Ν-formylpiperidine, trimethylborate, bromine, hydrogen chloride, and dimethyldisulphide. In addition, examples of the substituent of the pyridine having a substituent include carboxylic acid amides, aldehydes, and carnomates.

 [0006] For example, the above (TMP) Mg is described in Non-Patent Documents 5 and 6. Non-patented

 2

 Literature 5 describes benzoic acid esters, benzoic acid amides, and cycloproba using (TMP) Mg.

 2

 The present invention discloses the reaction between carboxylic acid amide or cuban carboxylic acid amide and an electrophile, and uses only diacid carbon as the electrophile. Non-patent document 6 uses (TMP) Mg

 Disclose the addition reaction of bromine or iodine to (S) -2,2'-bis (isopropoxycarbol) -1,1'-binaphthyl (see the formula described in [Chemical Formula 1]). thing).

[0007] [Formula 1],

[0008] For example, (i-PrN) Mg is described in Non-Patent Document 7. Non-patent statement

 twenty two

 Reference 7 discloses the addition of an electrophile to the 2-position of indole using (i-PrN) Mg

 twenty two

 I do. It discloses benzaldehyde, iodine, aryl bromide and carbon dioxide as electrophiles.

 Non-Patent Document 1: Tetrahedron, 1991, 47, 357.

 Non-Patent Document 2: J. Med. Chem. 1994, 37, 2697.

 Non-Patent Document 3: J. Org. Chem. 1995, 60, 8414.

 Non-Patent Document 4: Liebigs Ann. 1995, 1441.

 Non-patent document 5: J. Am. Chem. So 1989, 111, 8016.

 Non-Patent Document 6: J. Org. Chem. 2003, 68, 4576.

Non-patent Document 7: J. Chem. Soc. Perkin Trans. 1, 1996, 2331. Disclosure of the invention

 Problems to be solved by the invention

 [0009] However, the above-mentioned method using an aromatizing agent has the following disadvantages: 1) the aroma is unstable unless the temperature is low (around -78 ° C); 2) the reactivity (anionization) Rate), 3) low yield due to the formation of decomposition products of the reaction, 4) safety problems when used on an industrial scale, 5) reverse dripping on the reaction product There are various issues such as the problem of handling on an industrial scale.

 [0010] Therefore, an object of the present invention is to solve the problems of conventional ionizing agents.

 That is, the object of the present invention is to 1) increase the reactivity (a-on-dye ratio) 2) perform the reaction at a relatively high temperature and obtain the a-on at the relatively high temperature. Stable, 3) generation of decomposition products of the reaction is suppressed, 4) safety even when used on an industrial scale, and 5) easy handling on an industrial scale, Method for producing an aromatic heterocyclic compound and a method for producing an electrophilically substituted aromatic heterocyclic compound by aeronizing with the aid of the aeronizing agent and then reacting with an electrophilic reagent It is to provide

 Means for solving the problem

The present inventors have found that the above-mentioned problems can be solved by using an alkylmagnesium monoamido conjugate as an ionizing agent. That is, the inventors have found that the following problems can be solved by the following invention.

 As an alkylmagnesium monoamide compound, butylmagnesium diisopropylamide is known (Aldrich Catalog No. 59,045-2). However, cyclopropanecarboxylic acid is used as a reaction between the compound and an electrophilic reagent. Only the addition reaction of an electrophile to an acid amide is known (Angew. Chem. Int., 2002, 2169). That is, it is not known as a reaction between an aromatic heterocyclic compound and an electrophilic reagent.

 [0012] <1> halogen atom, hydroxyl group, mercapto group, C alkyl group, phenyl group, naphthy

 1-6

 , A C alkoxy group, a C alkoxy C alkoxy group, a C alkylthio group,

1-6 1-6 1-6 1-6

Carboxyl group, C alkoxycarbol group, phenylsulfol group, formula Z ¹ — NR ⁴

1-6 A group represented by R ⁵ (wherein, Z ¹ represents a carboxyl group, a sulfo group or a single bond, and R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group) , Formula N

 1—6

R ⁴ -CO-R ⁷ (wherein, R ⁴ represents a hydrogen atom or a C alkyl group, and R ⁷ is a C alcohol

1-6 1-6 alkoxy means a group), a group represented by and wherein, - z ¹ - z ² (wherein, z ¹ are the same as defined above definition, Z ² is 1-pyrrolidinyl group, 1 over piperidyl Group or 1 morphoyl group) which is a substituent represented by the formula (1), which may have one to three groups which may also be selected. A compound represented by the formula (wherein, R ¹ represents a C alkyl group)

 1—6

A ¹ has a group represented by the formula —NR ² R ³ or a C 1-4 alkyl group

 1-6

Means 1-piperidyl group; R ² and R ³ are each independently C alkyl

 1-6 group, C cycloalkyl group, piperazinyl group optionally having C alkyl group or

3-8 1-6

 Represents a C alkyl group having a di (C alkyl group) amino group)

1-6 1-6

 And then reacting with an electrophile. 5. A process for producing a 5- to 10-membered aromatic heterocyclic compound, comprising:

[0013] [Formula 2]

A \ z ^R (1)

 Mg

[0014] <2> Halogen atom, hydroxyl group, mercapto group, C alkyl group, phenyl group, naphthy

 1-6

 , A C alkoxy group, a C alkoxy C alkoxy group, a C alkylthio group,

1-6 1-6 1-6 1-6

Carboxyl group, C alkoxycarbol group, phenylsulfol group, formula Z ¹ — NR ⁴

 1-6

A group represented by R ⁵ (wherein, Z ¹ represents a carboxyl group, a sulfo group or a single bond, and R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group) , Formula N

 1—6

R ⁴ -CO-R ⁷ (wherein, R ⁴ represents a hydrogen atom or a C alkyl group, and R ⁷ is a C alcohol

1-6 1-6 alkoxy means a group), a group represented by and wherein, - z ¹ - z ² (wherein, z ¹ are the same as defined above definition, Z ² is 1-pyrrolidinyl group, 1 over piperidyl A 5- or 10-membered aromatic heterocyclic compound having at least one first substituent selected from Group A and a 1-morphoyl group). A compound represented by the formula (1) wherein R ¹ is C

A ¹ represents a alkyl group; A ¹ is a group represented by the formula —NR ³ or a C 1-4 alkyl group

 1-6

Having the formula: / means a 1-piperidyl group; R ² and R ³ are each independently C It has an alkyl group, C cycloalkyl group, and C alkyl group!

6 3-8 1-6

 Or a C alkyl group having a di (C alkyl) amino group) and

 1-6 1-6

 Reacting the resulting product with an electrophilic reagent to obtain a 5-10 membered aromatic heterocyclic compound in which the ortho position of the first substituent is electrophilically substituted. A method for producing a 5- to 10-membered aromatic heterocyclic compound in which an ortho position of a substituent is electrophilically substituted.

[0015] [Formula 3]

A ¹

 (1)

 , Mg

<3> In the above item <2>, the 5- to 10-membered aromatic heterocyclic compound having at least one first substituent is represented by the following formula (2) -1- (2) -5 Any of the compounds (wherein, R ¹⁰ represents a first substituent selected from the above-mentioned substituent group A group, and R ¹¹ R ¹² and R ¹³ each independently represent a hydrogen atom or the substituent group A group Represents the selected substituent).

 [0017] [Formula 4]

 (2) -1 (2) -2 (2) -3

 (2) -4 (2) -5

<4> In the above item 3>, the 5- to 10-membered aromatic heterocyclic compound having at least one first substituent is a compound represented by the following formula (2) -4 ′ (wherein R ^1C> is the first substituent selected from the aforementioned substituent group A). [0019] [Formula 5]

 (2) -4 '

[0020] <5> In any one of the above items <2> to <4>, the substituent group A is a hydroxyl group, a mercapto group, a C alkoxy group, a C alkoxy C alkoxy group, a C alkylthio group,

1-6 1-6 1-6 1-6 carboxyl group, C alkoxycarbol group, formula Z ¹ — NITR ⁵ (where Z ¹ is carb

 1-6

R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group), a group represented by the formula NR ⁴ —CO—R ⁷ ( Where R ⁴

 1-6

Represents a hydrogen atom or a C alkyl group, and R ⁷ represents a C alkoxy group)

 1-6 1-6

A group represented by the formula: and z ^{1 to} z ² (wherein z ¹ has the same meaning as defined above, and z ² means 1 pyrrolidyl group, 1-piperidyl group or 1 morpholinyl group) Substituent A-1 consisting of the group represented by group 1 is preferred.

 [0021] <6> In any one of the above items <2> to <4>, the substituent group A may be selected from a group consisting of a hydroxyl group, a mercapto group, a C alkoxy group, and a C alkoxy C alkoxy group.

 1-6 1-6 1-6

 Is good.

 <7> The substituent according to any of <2> to <4> above,

 1-6 groups are good.

 <8> In any one of the above items <2> to <4>, the substituent group A may be a t-butoxy group.

<9> above <2> - In any one of <8>, A ¹ is better to Ru der diisopropylamino group.

<10> In any one of the above 2> to 9>, R ¹ is preferably an n-butyl group.

 [0022] <11> Halogen atom, hydroxyl group, mercapto group, C alkyl group, phenyl group, naph

 1-6

 Cyl group, C alkoxy group, C alkoxy C alkoxy group, C alkylthio group

1-6 1-6 1-6 1-6 , Carboxyl group, C alkoxycarbol group, phenylsulfol group, formula Z ¹ — N

 1-6

R ⁴ R ⁵ (wherein, Z ¹ represents a carboxyl group, a sulfol group or a single bond, and R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group) Group, formula

 1-6

NR ⁴ -CO-R ⁷ (wherein, R ⁴ represents a hydrogen atom or a C alkyl group, and R ⁷ is a C

1-6 1-6 Kokishi means a group), a group represented by and wherein - z ¹ - z ² (wherein, z ¹ are the same as defined above definition, Z ² is 1-pyrrolidinyl group, 1 over piperidyl Or a substituent represented by the following formula (3) -1 or (3), which may have one to three first substituents which are also selected from the group A groups. ) — Compound represented by 2 (wherein, the combination of Z ⁵ and Z ⁶ (Z5, Z6) is (N (nitrogen atom), C (carbon atom)), (C ゝ N) ゝ (N ゝ N)ゝ represents (C, S (Io atom)), (C, o (Oxygen atom)), and Z ⁷ represents a nitrogen atom, an oxygen atom or an Io atom), and is a compound represented by the formula (1) (wherein, R ¹ represents a C alkyl group; A ¹ is represented by the formula NR ³

 1—6

 Or a 1-piperidyl group which may have one to four C alkyl groups.

 1—6

R ² and R ³ each independently represent a C alkyl group, a C cycloalkyl group, a C

 1-6 3-8 1-6 It has a alkyl group and may have a piperazyl group or a di (C alkyl) amino group.

 1-6

 And then reacting with a C alkyl group) to form an ortho-position of the first substituent.

 1-6

 Is a method for producing an electrophilically substituted compound represented by the following formula (3) -1 or (3) -2 wherein X is electrophilically substituted.

[0023] [Formula 6]

 (3) -1 (3) -2

A ¹ -R ¹

 (1)

 , Mg

[0024] <12> In the above item <11>, the substituent A group hydroxyl group, mercapto group, C alcohol

 1-6 Xyl group, C alkoxy C alkoxy group, C alkylthio group, carboxyl group, C

 1-6 1-6 1-6

Alkoxycarbyl group, formula Z ¹ — NR ⁴ R ⁵ (wherein Z ¹ is a carboxy group, sulfol

1-6

R ⁴ and R ⁵ are each independently a hydrogen atom or C

1-6 Table with NR ⁴ -CO-R ⁷ (wherein, R ⁴ is a hydrogen atom or a ^ alkyl group, R ⁷ means a C alkoxy group) - group represented by means Kill group), the formula Group represented by the formula:

Z ² (wherein z ¹ has the same meaning as defined above, and Z ² represents 1 pyrrolidinyl group, 1-piperidyl group or 1 morpholyl group). There should be.

 <13> In the above <11> or <12>, the substituent group A is a hydroxyl group or a mercapto group.

 C alkoxy group, C alkoxy C alkoxy group power

1—6 1-6 1-6

<14> In the above <11> or <12>, the substituent A group C is an alkoxy group.

 1-6

 There should be.

 <15> In the above item <11> or <12>, the substituent group A is preferably a t-butoxy group.

It is preferred that A ¹ be a diisopropylamino group.

<17> As described above, it is preferable that R ¹ is an n-butyl group.

 The invention's effect

 [0026] According to the present invention, the problems of the conventional anionizing agent can be solved.

 That is, according to the present invention, 1) the reactivity (anigation ratio) is high; 2) the reaction can be performed at a relatively high temperature, and the resulting anion is stable at the relatively high temperature; ) The formation of decomposition products of the reaction is suppressed, and 4) an aromatic heterocyclic compound ionic agent having safety even when used on an industrial scale; and The present invention can provide a method for producing an electrophilically substituted aromatic heterocyclic compound by ionizing and then reacting with an electrophilic reagent.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in detail.

The present invention relates to a method for reacting a 5- to 10-membered aromatic heterocyclic compound, which may have 1 to 3 substituents selected from Group A, with a compound represented by the formula (1), Reacting reagents A method for producing a 5- to 10-membered aromatic heterocyclic compound, characterized in that:

 Further, the present invention provides an electrophilic reaction after reacting a 5- to 10-membered aromatic heterocyclic compound having at least one first substituent, which is also selected as substituent group A, with a compound represented by the formula (1). Reacting the drug to obtain a 5- to 10-membered aromatic heterocyclic compound in which the ortho position of the first substituent is electrophilically substituted, wherein the ortho position of the first substituent is electrophilic. This is a method for producing a substituted 5- to 10-membered aromatic heterocyclic compound.

[0028] <5- to 10-membered aromatic heterocyclic compound>

 As used herein, the term “5- to 10-membered aromatic heterocyclic compound” refers to a compound having 5 to 10 ring-forming atoms and containing one or more heteroatoms in the ring-forming atoms. Refers to an aromatic ring compound.

 Examples of the compound include pyridine, pyrazine, pyrimidine, quinoxaline, indole, phthalazine, thiophene, furan, thiazole, imidazole, pyridazine, quinazoline, benzodiazine, benzothienphen, benzofuran, benzothiazonole, benzimidazole, benzoisoxazonole, Benzoisothiazono, benzoxazono, quinoline or isoquinoline can be mentioned. Of these, pyridine, pyrazine, pyrimidine, quinoxaline or indole are preferred, more preferably pyrazine.

[0029] In particular, the "5- to 10-membered aromatic heterocyclic compound" is a compound represented by the following formula (2) -11- (2) -5 (wherein R ^1C> is a substituent A shows a first substituent selected group power, ^1, R ^{1 2} and R ¹³ is good is each independently represent a hydrogen atom or a substituent a Gunkakara substituent selected).

[0030] [Formula 7]

 (2) -1 (2) -2 (2) -3

 (2) -4 (2) -5

[0031] More preferably, the 5- to 10-membered aromatic heterocyclic compound is a compound represented by the following formula (2) -4 '(wherein R ^1C> is Represents a substituent).

[0032]

 (2) -4 '

The 5- to 10-membered aromatic heterocyclic compound is a compound represented by the following formula (3) -1 or (3) -2, for example, a 5-membered ring containing a nitrogen atom or the 5-membered ring. And a condensate thereof. In the formula, the combination of Z ⁵ and Z ⁶ (Z5, Z6) is (N (nitrogen atom), C (carbon atom)), (C, N), (N, N), (C, S )), (Ji, represents 0 (oxygen atom)), sigma ⁷ represents a nitrogen atom, an oxygen atom or Iou atoms. [0034] [Formula 9]

 (3) -1 (3) -2

When the compound represented by the formula (3) -1 or (3) -2 has a first substituent, the ortho position of the first substituent is determined by the method of the present invention. An electron-substituted substituted product can be obtained. When the compound represented by the formula (3) -1 or (3) -2 does not have the first substituent, the compound represented by the formula (3) -1 or (3) -2 may be used according to the method of the present invention. Thus, an electrophilically substituted compound in which the X position is electrophilically substituted can be obtained.

 <Substituent group 8>

 The 5- to 10-membered aromatic heterocyclic compound may have one to three substituents selected from the following substituent group A.

 In the present invention, the substituent group A includes a halogen atom, a hydroxyl group, a mercapto group, a C alkyl group.

 1-6 group, phenyl group, naphthyl group, C alkoxy group, C alkoxy C alkoxy group

 1—6 1—6 1—6

 , C alkylthio group, carboxyl group, C alkoxycarbol group, phenyls

1—6 1—6

A fluoro group, formula Z ¹ — NR ⁴ R ⁵ (wherein, Z ¹ represents a carboxy group, a sulfo group or a single bond, and R ⁴ and R ⁵ are each independently a hydrogen atom or C Means an alkyl group

 1-6

A group represented by the formula: —NR ⁴ —CO—R ⁷ (wherein R ⁴ represents a hydrogen atom or a C alkyl group)

 1-6

R ⁷ represents a C alkoxy group), and a group represented by the formula Z ¹ — Z ^{2 wherein} Z ¹

 1-6

Has the same meaning as defined above, and Z ² represents a 1-pyrrolidyl group, a 1-piperidyl group or a 1-morpholinyl group).

 [0037] In the substituent A group, the following substituent A-1 group is preferable. That is, a hydroxyl group, a mercapto group, a C alkoxy group, a C alkoxy C alkoxy group, a C alkylthio group,

1-6 1-6 1-6 1-6

Ruboxyl group, C alkoxycarbonyl group, formula Z ¹ — NR ⁴ R ⁵ (wherein Z ¹ is

 1-6

A group represented by the formula NR ⁴ —CO—R ⁷ (wherein R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group). , R ⁴

 1-6

Represents a hydrogen atom or a C alkyl group, and R ⁷ represents a C alkoxy group).

1-6 1-6 And a group represented by the formula z ¹ —z ² (wherein z ¹ has the same meaning as defined above, and Z ² represents 1 pyrrolidinyl group, 1-piperidyl group or 1 morpholyl group) The substituent A—is preferably a group 1.

 In the substituent group A, the following substituent group A-2 is more preferable. That is, substitution comprising a hydroxyl group, a mercapto group, a C alkoxy group, and a C alkoxy C alkoxy group

 1-6 1-6 1-6

 Group A—more preferably two groups.

 Further, in the substituent A-2 group, a t-butoxy group is preferable.

[0038] The electrophilic substituent of the 5- to 10-membered aromatic heterocyclic compound obtained by the method of the present invention may be a first substituent selected from substituent group A (hereinafter simply referred to as "first substituent"). (May be abbreviated as "group"), the presence or absence of a substituent, and the number of substituents, if any.

 When the compound has the first substituent, the method of the present invention can provide an electrophilic substituent of a 5- to 10-membered aromatic heterocyclic compound in which the ortho position of the first substituent is electrophilically substituted. . Note that when there are a plurality of first substituents and the ortho position is not substituted with another substituent, the plurality of ortho positions corresponding to the plurality of first substituents are electrophilically substituted.

 [0039] Even when the compound does not have a first substituent, an electrophilic substituent of a 5- to 10-membered aromatic complex ring compound can be obtained by the method of the present invention. In particular, the 5- to 10-membered aromatic heterocyclic compound is a 5-membered ring containing a nitrogen atom or a condensate with the 5-membered ring as represented by the above formula (3) -1 or (3) -2. In this case, an electrophilic substituted product in which the ortho position of the nitrogen atom is electrophilically substituted can be obtained by the method of the present invention.

 Note that when there are a plurality of first substituents and the ortho position is not substituted with another substituent, the plurality of ortho positions corresponding to the plurality of first substituents are electrophilically substituted.

 [0040] <Compound represented by Formula (1)>

 The present invention has a step of reacting a 5- to 10-membered aromatic heterocyclic compound, which may have 113 groups selected from substituent group A, with a compound represented by the above formula (1).

A ^{1 in the} compound represented by the formula (1) means a 1-piperidyl group which may have a group represented by the formula NR ² R ³ or have 14 C alkyl groups. R and R in the group represented by the formula NR are each independently a C alkyl group,

 1-6 Having a 3-cycloalkyl group or a C alkyl group! /, May be !, piperazyl group or di (C

8 1-6 1 alkyl group) means a C alkyl group having an amino group.

 6 1-6

A ¹ is a diisopropylamino group, a 2,2,6,6-tetramethylpiperidyl group, a tert-butylmethylamino group, a tert-butylethylamino group, an isopropylethylamino group, a cyclohexylmethylamino group, Cyclohexylethylamino, cyclohexylisopropylamino, 2,6-dimethylbiperidyl, 2-ethylbiperidyl, ethylbutylamino, methyl 1- (1-methylbiperidin-4-y A) an amino group, or a diisopropylamino group or a 2,2,6,6-tetramethylpiperidyl group, which is more preferably an Ν, Ν, Ν'-triethylenediamino group or the like. The most preferred is a diisopropylamino group! / ,.

R ¹ represents a linear or branched C alkyl group. Of these, R ¹ is η-buty

 1-6

 It is preferably a benzyl group.

 [0042] <Electrophilic reagent>

 In the present application, the term "electrophilic reagent" refers to a reagent having electrophilicity in an organic chemical reaction, and a nucleophilic reagent (an aminy conjugate or an alcohol conjugate having an unshared electron pair, having a negative charge Organic compounds). In the present application, the following (a) to (f) can be mentioned.

 (A) Electrophile having a carbonyl group in the molecule

 Specifically, aldehyde, ketone, acylamide, Ν, Ν-dimethylformamide, ア ミ ド -formylmorpholine, formaldehyde, Ν-formylpiperidine, 1-formyl-4-methylpiperazine, formate, acid chloride, acid anhydride Product, or thioester, etc.

(B) Alkylating agent

 Examples include alkyl halide, aryl halide, and alkyl sulfonate.

 (c) Halogenating agent

Bromine, 1,2-dibromoethane, 1,2-jodoethane, trichloroisocyanuric acid, 1,3-dibromo-5,5-dimethinolehydantoin, bromopentafunole Examples include o-benzene, NBS (N-bromosuccinimide), iodine, iodopentafluorobenzene, NIS (N-odosuccinimide), and NCS (N-chlorosuccinimide).

(0045) borate

 Examples include trialkyl borates such as trimethyl borate and triisopropyl borate.

( _e ) Silyl halide

 (f) Biacetic acid, heavy water.

 [0046] Of the above (a)-(f), Ν, Ν-dimethylformamide, Ν-formylmorpholine, formylide, Ν-formylpiperidine, 1-formyl-4-methylbiperazine, formate and the like are preferred. More preferably, it is Ν, Ν-dimethylformamide! /.

 [0047] In the present application, the power that the structural formula of a compound may represent a certain isomer for convenience is considered to be all geometric isomers and optical isomers based on asymmetric carbons that occur in the structure of the compound. It includes all isomers and isomer mixtures such as isomers, stereoisomers, and tautomers, and is not limited to the description of formulas for convenience.

 The present invention also includes any anhydride, hydrate or solvate of the compound which may form a salt. Further, there is no particular limitation on the form of the compound, whether crystalline or non-crystalline.

 Hereinafter, terms and the like described in the present application will be described.

 As used herein, the term "C alkyl group" refers to a group having 1 carbon atom.

1-6 A straight-chain or branched-chain alkyl group having 1-16 carbon atoms, which is a monovalent group derived by removing one hydrogen atom from 16 aliphatic hydrocarbons. Means Specifically, for example, a methyl group, an ethyl group, a 1-propyl group, a 2-propyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-butyl group, a 2-butyl group, a 1-pentyl group, a 2-pentyl group -Pentyl group, 3-pentyl group, 2-methyl-1 butyl group, 3-methyl-1 butyl group, 2-methyl-2 butyl group, 3-methyl-2-butyl group, 2,2 dimethyl-1-propyl group, 1-hexyl Group, 2-hexyl group, 3 monohexyl group, 2-methyl-1 pentyl group, 3-methyl-1 pentyl group, 4-methyl-1 pentyl group, 2-methyl-2 pentyl group, 3-methyl-2 pentyl group, 4-methyl- 2— Pentyl group, 2-methyl-3 pentyl group, 3-methyl-3 pentyl group, 2,3 dimethyl-1 butyl group, 3,3-dimethyl-1 butyl group, 2,2-dimethyl-1 butyl group, 2-ethyl-1 butyl Group, 3,3 dimethyl-2-butyl group, 2,3 dimethyl-2-butyl group and the like.

 [0049] The "C cycloalkyl group" represented in the present application is a cyclic aliphatic having 3 to 8 carbon atoms.

 3-8

 It means a group hydrocarbon group, and specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, and the like.

 [0050] In the present application, the "c alkoxy group" is a group to which the "c alkyl group" defined above is bonded.

 1—6 1-6

 It means a xy group. Specifically, for example, methoxy group, ethoxy group, 1-propyloxy group, 2-propyloxy group, 2-methyl-1-propyloxy group, 2-methyl-2-propyloxy group, 1-butyloxy group, 2-butyloxy group, 1 pentyloxy group, 2 —Pentyloxy group, 3-pentyloxy group and the like.

 [0051] The "C alkylthio group" represented in the present application is a "C alkyl group" as defined above.

 1-6 1-6

 Means a bound thio group. Specifically, for example, a methylthio group, an ethylthio group, a 1-propylthio group, a 2-propylthio group, a 2-methyl-1-propylthio group, a 2-methyl-2-propylthio group, a 1-butylthio group, a 2-butylthio group, a 1-pentylthio group , 2-pentylthio, 3-pentylthio and the like.

 [0052] The "halogen atom" represented in the present application means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

 [0053] The "C alkoxycarbonyl group" represented in the present application is the above-mentioned "C alkoxy group".

 1-6 1-6 "means a carboxy group bonded thereto. Specifically, for example, methoxycarbon, ethoxycarbonyl, n-propoxycanoleboninole, isopropoxycanoleboninole, n-butoxycarbonyl, isobutoxycarbonyl, sec. Butoxycarbonyl, t. Butoxycarbonyl, pentylo Xyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbol, hexyloxycarbol and the like can be mentioned.

 [0054] The "C alkoxy C alkoxy group" represented in the present application is the above-mentioned "C alkoxy

1-6 1-6 1-6 means the above-mentioned “c alkoxy group” bonded to a “oxy group”. Specifically, for example, Toximethoxy, methoxyethoxy (1-methoxyethoxy, 2-methoxyethoxy), methoxypropoxy, methoxybutoxy, methoxypentyloxy, methoxyhexyloxy, ethoxymethoxy, ethoxyethoxy, ethoxypropoxy, ethoxybutoxy, ethoxypentinole Xyloxy, ethoxyhexynoleoxy, propoxymethoxy, propoxyethoxy, propoxypropoxy, propoxybutoxy, propoxypentinoleoxy, propoxyhexanoloxy, butoxymethoxy, butoxyethoxy, butoxypropoxy, butoxybutoxy, butoxypentyloxy, butoxypentoxyl, butoxypentyloxy Methoxy, pentyloxy ethoxy, pentyloxypropoxy, pentyloxybutoxy, pentyloxy Pentyloxy, pentyloxyhexyloxy, hexyloxymethoxy, hexyloxyethoxy, hexinoleoxypropoxy, hexinoleoxybutoxy, hexinoleoxy pentyloxy, hexyloxyhexyloxy, and the like. Preferable examples include methoxymethoxy and methoxyethoxy.

[0055] The term "1-pibelidine which may have one to four C alkyl groups" described in the present application is used.

 1-6

 Is a 1-piperidyl group having one to four of the above-mentioned "C alkyl group" or "

 1-6

 "C 1 -alkyl group" means a 1-piperidyl group.

 1-6

 [0056] The "piperazyl group optionally having a C alkyl group" represented in the present application is:

 1-6

 A piperazyl group having the above-mentioned alkyl group or a `` c alkyl group ''

 1-6 1-6

 When substituted, it means a piperazyl group.

 [0057] "C alkyl group having di (C alkyl group) amino group" described in the present application

 1-6 1-6

 Means that any one hydrogen atom of the aforementioned “c alkyl group” is a di (C alkyl group)

 1-6 1-6

 A group which is substituted with a phenyl group.

 <Specific Reaction Production Method A->

 The production method of the present invention will be described in more detail. In the following description, the compound represented by the above formula (2) -4 ′ is referred to as a 5- to 10-membered aromatic heterocyclic compound because of ease of description and a preferred compound in the present invention. Is used.

In the following formulas (A) and (B), AR \ and R ^1C) are as defined above. E ¹ is a group derived from an electrophilic reagent, and represents a formyl group, a deuterium atom, an aryl group, a phenylcarbonyl group, or the like. [0059] [Formula 10]

Formula (A)

 (1) (2) -4 '(4)

Formula (B)

The formula (A) is represented by the formula (2) -4 ′ by reacting the compound (1) represented by the formula (1) with the compound represented by the formula (2) -4 ′. The step of obtaining a compound of formula (4) is shown below.

 The solvent that can be used in this step depends on the reagents used, etc., and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent.Preferably, for example, tetrahydrofuran (hereinafter, THF May be abbreviated as "), toluene, n-hexane, C-hexane, methinole-1-butynoleatenole, cyclopentinolemethinoleatenole, getinolete, dimethoxyethane, 2-methyltetrahydrofuran , Di-iso-propyl ether, dibutyl ether and dicyclopentyl ether. The organic solvent selected is one or a mixed solvent of 2-3, and more preferably THF, 2-methyltetrahydrofuran. Furan, toluene, n-hexane, c-hexane or methyl-t-butyl ether can be mentioned.

 The reaction temperature in this step can be performed at a relatively higher temperature than in the conventional method. For example, it can be performed at a temperature of 40-+ 20 ° C.

According to this step, the aeon compound represented by (4) can be obtained, and the position where the electron density of the aion compound is high corresponds to the ortho position of the R ^1G group.

In the formula (B), an aniony anilide represented by (4) is electrophilically attacked by an electrophilic reagent, and the ortho position of the R ^1C> group is electrophilically substituted by a group derived from the electrophilic reagent. The step of obtaining a dangling product (5) is shown. The reaction step of the formula (B) also depends on the compound (1) used, the 5- to 10-membered aromatic heterocyclic compound used, and the like. When the solution containing the a-on-yahide compound represented by the formula (4) is dropped into the solution containing the electrophile, the method can also be used to obtain the solution containing the a-on-yahide compound represented by the formula (4). The method can also be carried out by adding a solution containing an electronic reagent dropwise, but preferably, a solution containing an aeonidani represented by the formula (4) is added dropwise to a solution containing an electrophilic reagent. It can be done in such a way. In addition, since the reactivity of the aeonide varies depending on the temperature, the reaction can be carried out by adding an electrophilic reagent to the aeonide cooled at a low temperature and raising the temperature.

 The reaction temperature in this step can be performed at a relatively higher temperature than in the conventional method. For example, it can be carried out at -80 to 30 ° C.

 The solvent that can be used in this step depends on the reagents used, etc., and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, for example, THF, toluene, methyl- One organic solvent selected from the group consisting of t-butyl ether, cyclopentyl methyl ether, dimethyl ether, di-iso-propyl ether, dibutyl ether and dicyclopentyl ether or a mixed solvent of 2-3 can be mentioned. Preferably, THF, toluene or methyl-t-butyl ether can be mentioned.

 The solvent that can be used in this step depends on the reagents used, etc., and is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, for example, THF, toluene, n- Hexane, c-hexane, methyl-t-butyl ether, cyclopentyl methyl ether, getyl ether, dimethoxyethane, 2-methyltetrahydrofuran, di-iso-propyl ether, dibutyl ether and dicyclopentyl ether An organic solvent or a mixed solvent of 2-3 is also selected, and more preferably THF, 2-methyltetrahydrofuran, toluene, n-hexane, c-hexane or methyl-t -Butyl ether.

As described above, in the formulas (A) and (B), the compound (2) -4 ′ was used for description, but instead of the compound, the above-mentioned “substituent group A group was selected. The reaction can be carried out in the same manner using “a 5-10 membered aromatic heterocyclic compound which may have 13 groups”. [0063] The reaction operation is not particularly limited, but preferably is performed in an inert gas (nitrogen or argon) atmosphere.

 [0064] The compound produced by the present invention, for example, the compound (4) in the above formula (B) can be obtained with sufficient purity only by filtering the reaction solution and concentrating the filtrate. Can be isolated and purified by the method used for isolation and purification. For example, water is added to the reaction mixture, and then an organic solvent such as hexane, toluene, xylene, tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, ethyl acetate, or butyl acetate is added, and the mixture is extracted. After concentration, the resulting crude product can be purified by distillation, recrystallization, chromatography, etc., if necessary.

 (Example)

 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.

[0066] (Reference example 1)

 3—tert-Butoxypyrazine 2 Synthesis of carboxaldehyde

 (2.2.6.6-Method with lithium tetramethylpiperidinium)

 2.2 ml of 2,2,6,6-tetramethylpiperidine was dissolved in 40 ml of tetrahydrofuran and cooled to 50 ° C. Under a nitrogen atmosphere, 5.25 ml of n-butyllithium (2.6 M n-xane solution) was added dropwise. After stirring for 25 minutes, the mixture was ice-cooled and further stirred for 35 minutes. After cooling to 78 ° C, 2-tert-butoxypyrazine [CAS No. 70090-30-1] 1.89 g of a tetrahydrofuran solution (5 ml) was added dropwise. After stirring for 15 minutes, 1.25 ml of NN-dimethylformamide was added dropwise. After 10 minutes, water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (solvent; ethyl acetate xane) to give the title compound 1.

00g (45% yield) was obtained.

 lH-NMR (400MHz, CDC13); δ (ppm) 1.68 (9H, s), 8.28 (1H, d, J = 2.4 Hz), 8.30 (1H, d, J = 2.4 Hz), 10.33 (1H, s) .

[0067] (Reference Example 2)

3 tert Butoxypyrazine 2 Synthesis of carboxaldehyde “magnesium bis (diisopropane Mouth pyramide) method 1

 N-Butylmagnesium chloride (hereinafter sometimes abbreviated as “n-BuMgClJ”) cooled in a dry ice-shiridani calcium aqueous solution bath was added to a THF solution (0.9 M, 33.3 ml, 30 mmol) in n-butyl. A solution of lithium (hereinafter sometimes abbreviated as “BuLi”) in n-hexane (1.58 M, 19 ml, 30 mmol) was added to potassium chloride (internal temperature 2− + 5 ° C), and after dropwise addition at room temperature, Stirred for minutes. Diisopropylamine (6.07 g, 60 mmol) was added to the obtained product and heated at 50 ° C. for 58 minutes to prepare a magnesium amide solution. To this solution, a solution of 2-tert-butoxypyrazine (3.04 g, 2 Ommol) in tetrahydrofuran (4 ml, of which 1 ml was washed and used for washing) was added dropwise while cooling in a dry ice-chloride calcium salt aqueous solution bath. After the dropwise addition, the mixture was stirred for 1 hour and 29 minutes while maintaining the temperature at around 25 ° C.

 A solution of DMF (23 ml, 30 mmol) in tetrahydrofuran (5 ml) was cooled in a dry ice-acetone bath, and the above solution was added dropwise over 20 minutes (internal temperature 76.2—up to 63.7—-69.2. (C) at the same temperature for 55 minutes. A solution of water (1.08 g, 60 mmol) in tetrahydrofuran (15 ml) was added dropwise to the reaction solution (internal temperature-75.2 ° C-65.3 ° C). After the dropwise addition, the dry ice-acetone bath was removed, and the mixture was stirred for 6 minutes. Then, a solution of acetic acid (7.2 g, 120 mmol) in water (15 ml) was added for 1 minute, and the mixture was heated (internal temperature −50 ° C. −3 ° C.). Rise to C). The obtained two-layer liquid was extracted with ethyl acetate (50 ml). The obtained organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The content of each component of the obtained oil was determined by gas chromatography. Formyl body 71.0%, raw material recovery 14.6%.

Example 1

 3 tert Butoxypyrazine 2 Synthesis of carboxaldehyde

 After the inside of the reaction vessel was replaced with nitrogen, 2.15 kg (3.22 mol) of an n-BuMgCKTHF solution (1.5 mol / kg) was charged under a nitrogen pressure, and washed with 1.1 L of THF. After stirring, a refrigerant at -10 ° C was circulated through the jacket, and when the internal liquid temperature reached 4.3 ° C, the force was also n-BuLi (hexane solution, 2.3 mol / kg): l.42kg (3 .27mol). Set the refrigerant at 30 ° C, and after 1 hour, add 367 g (3.63 mol) of diisopropylamine (hereinafter sometimes abbreviated as “iPr NH”) (

 2

(Internal solution temperature: 28.2 ° C to 37.5 ° C). The refrigerant was set at 45 ° C, the internal liquid temperature exceeded 40 ° C, and the power was 1.5 hours later. After that, the refrigerant temperature was set to −30—35 ° C, and the internal liquid temperature was lowered. When the internal solution temperature became −21.7 ° C., a solution of 250 g (l. 64 mol) of 2-tert-butoxypyrazine in THF (250 mL) was added over 10 minutes. At this time, the internal solution temperature was -21.2 ° C. The refrigerant was set at −20 ° C. and stirred overnight under nitrogen.

 [0069] — When circulating a refrigerant at 80 ° C and the internal liquid temperature reaches 69.7 ° C, dimethylformamide (hereinafter sometimes abbreviated as “DMF”) 3.60kg (49 (28 mol) was charged at -60 ° C or less (time required: about 1.5 hours, the internal solution temperature showed a maximum of 60.5 ° C, and finally reached 65.5 ° C. ). — Recirculating the refrigerant at 37 ° C, when the internal liquid temperature exceeds 45 ° C and the power is also 1 hour later, when the refrigerant setting is -80 ° C and the internal liquid temperature reaches -67.0 ° C Toluene 5. OL was introduced at a temperature of 60 ° C or less (time required: about 30 minutes, the internal solution temperature showed a maximum of 59.5 ° C, and was finally 62.9 ° C). Subsequently, water: 178 ml ZTHF: 750 mL was added at 60 ° C or less (time required: about 20 minutes, internal solution temperature:-62.7 ° C) o

 [0070] The refrigerant was set at -40 ° C, and when the internal liquid temperature exceeded 45 ° C, the refrigerant in the jacket was drained. Add acetic acid 1.03LZ water 5.OL here (time required: 2 minutes, internal liquid temperature changed from 40.3 ° C to 1.0 ° C), then jacketed with 30 ° C refrigerant Circulated. After stirring for about 1 hour, the liquid separation was started when the internal liquid temperature reached 12.6 ° C.

 [0071] Discard the lower layer (ρΗ: 7), wash with water (2.5 L, 1.25 L, pH: 4, 3.5), and 8% NaHCO aqueous solution

 Washing was performed with three solutions (1.25 kg) (pH: 8.5) and water (1.25 L, 1.25 L, pH: 6, and no pH data). The upper (organic) layer was concentrated with an evaporator (bath temperature: 35 ° C) to obtain 399.8 g of a brown product. As a result of quantification by gas chromatography (hereinafter abbreviated as "GC"), the starting compound (259.9 g (yield: 87.8%) was contained, and the starting material (2-tert-butoxypyrazine) was 4.8 g ( l. 9%).

[GC analysis conditions]

 The analysis conditions of GC were as follows.

 Column: DB-1 (length 30m x inner diameter 0.53mm, film thickness: 3 ^ m);

 Caryagas: N;

 2

 Injection temperature: 180 ° C;

 Detection temperature: 230 ° C;

Oven temperature: 100 ° C (hold for 5 minutes) → 10 ° C rise for Z minutes → 200 ° C (hold for 5 minutes); Retention time: 15.4 minutes (3-tert-butoxypyrazine-2-carboxaldehyde); 11.7 minutes (2-tert-butoxypyrazine).

 The yield and recovery were calculated by using a purified sample, using a GC under the same conditions as above, creating a calibration curve, and using that.

 Example 2

 [0073] A THF-toluene solution of n-butylmagnesium chloride (1.76M, 34.1ml, 60mmol) was cooled to 7 ° C, and a solution of n-butyllithium in cyclohexane (2.44M, 24.6ml, 60mmol) was added. Was added over 5 minutes (internal temperature 8.0-13.6 ° C), and the mixture was stirred at the same temperature for 1 hour and 11 minutes. To this solution, add diisopropylamine (8.4 ml, 60 mmol) over 2 minutes (internal temperature 7.5-14.6 ° C), stir for 1 hour and 40 minutes at the same temperature, and set the bath temperature to -23 ° C. The mixture was stirred for 2 hours and 56 minutes to prepare a magnesium amide solution.

To this solution, 2-tert-butoxypyrazine (4.57 g, 30 mmol) was added dropwise at the same temperature, and the mixture was washed with THF (3 ml) (internal temperature-22.1-20.7 ° C). Stirred at ° C overnight. The reaction solution was cooled in a dry ice-acetone bath, DMF (34.8 ml, 45 mmol) was added over 20 minutes (internal temperature-76.3-64.3 ° C), and the mixture was added dropwise in a dry ice-acetonitrile bath. Time Stirred for 25 minutes. Toluene (36.6 ml) was added dropwise to the reaction solution over 9 minutes (internal temperature-45.1-39.8 ° C), and after stirring for 10 minutes, THF (6.5 ml) of water (3.24 g, 180 mmol) was added. The solution was added over 5 minutes (internal temperature-44.3-38.6 ° C) and stirred at the same temperature for 19 minutes. Acetic acid (19 ml, 330 mmol) in water (45.7 ml) was added over 2 minutes (internal temperature-41.8--2.8 ° C). The obtained organic layer was separated and washed sequentially with water (46 ml), water (23 ml), 8% aqueous sodium bicarbonate (23 ml), water (23 ml), and water (23 ml). The organic layer was concentrated under reduced pressure to obtain 10.09 g of an oil containing the desired product. As a result of quantification by GC, it was found that the starting compound was contained in 4.42 _§ (yield: 81.7%) and 0.324 g (7.1%) of the starting material was recovered. Example 3

[0074] Method by using magnesium monoamide test sink synthesized using dibutylmagnesium (Method A) [0075] [Formula 11]

<Preparation of Magnesium Monoamide Reagent>

 Diisopropylamine (0.84 ml, 6 mmol) was added to a heptane solution of dibutylmagnesium (1.0 M, 6 ml, 6 mmol) and stirred at room temperature overnight to prepare a magnesium amide solution. <Anionization and electrophilic substitution>

To this solution, a solution of 2-tert-butoxypyrazine (457 mg, 3 mmol) in THF (1 ml)) was added dropwise while cooling in a dry ice-acetone bath. After the addition, the mixture was stirred at -23 ° C for about 6 hours. The reaction solution was cooled in a dry ice-acetone bath, and heavy water (2 ml) was added. Ethyl acetate, water and acetic acid were added to the reaction solution and partitioned. The organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, diluted to 100 ml with ethyl acetate, and the recovery was measured by GC. The ethyl acetate layer was concentrated under reduced pressure, and the obtained residue was analyzed by ¹ H-NMR to determine the Die ratio.

 D conversion rate: 77.5%, recovery rate: 84.4%

[0077] [GC analysis conditions]

 The GC analysis conditions are as follows.

 Column: DB-1 (length 30m x inner diameter 0.53mm, film thickness: 3 ^ m);

 Caryagas: N;

 2

 Mode: split, split ratio: 10.0;

 Injection temperature: 180 ° C;

 Detection temperature: 230 ° C;

 Oven temperature: 100 ° C (hold for 5 minutes) → 10 ° C Z minute rise → 200 ° C (hold for 5 minutes); Hold time: 11.7 minutes.

 The yield and recovery were calculated by using a purified sample, using a GC under the same conditions as above, creating a calibration curve, and using that.

[Method of Calculating D Conversion Rate]

The calculation method of the D-Dani rate is as follows. That is, 2-tert-butoxypyrazine It was calculated from the integral value X (for one proton) and the integral value Y (for two protons) of the 5-position and 6-position protons according to the following formula.

 (D conversion rate (%)) = (Y-2X) / YX 100

 Example 4

 [0079] Method using Magnesium Monoamide Sample Synthesized with n-butylmagnesium chloride and n-butyllithium (Method B)

 <Preparation of magnesium monoamide reagent>

 To a THF solution of n-butylmagnesium chloride (0.9 M, 6.7 ml, 6 mmol) was added an n-hexane solution of n-butyllithium (1.58 M, 3.8 ml, 6 mmol), and the mixture was stirred at room temperature for about 1 hour. , 2,6,6-tetramethylpiperidine (1.0 ml, 6 mmol) was heated at about 55 ° C. for about 30 minutes to prepare a magnesium amide solution.

 <Anionization and electrophilic substitution>

To this solution, a solution of 2-tert-butoxypyrazine (457 mg, 3 mmol) in tetrahydrofuran (1 ml) was added dropwise while cooling in a dry ice-acetone bath. After the addition, the mixture was stirred at -23 ° C overnight. The reaction solution was cooled in a dry ice-acetone bath, and heavy water (2 ml) was added. Ethyl acetate, water and acetic acid were added to the reaction solution and partitioned. The organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, diluted with ethyl acetate to 100 ml, and the recovery was measured by GC. The ethyl acetate layer was concentrated under reduced pressure, and the obtained residue was analyzed by ¹ H-NMR. The D conversion was measured in the same manner as in Example 2.

 D conversion rate: 86.2%, recovery rate: 99.4%.

 Example 5

 [0080] Method using Magnesium Monoamide Test Go synthesized using isopropylmagnesium chloride and n-butyllithium (Method C)

 <Preparation of magnesium monoamide reagent>

A n-hexane solution of n-butyllithium (1.58 M, 3.8 ml, 6 mmol) was added to a THF solution of isopropylmagnesium chloride (2.0 M, 3 ml, 6 mmol) under ice-cooling, and the mixture was stirred for about 1 hour. 0.84 ml, 6 mmol) and stirred at room temperature overnight to prepare a magnesium amide solution. <Anionization and electrophilic substitution>

To this solution, a solution of 2-tert-butoxypyrazine (457 mg, 3 mmol) in THF (1 ml) was added dropwise while cooling in a dry ice-acetone bath. After the addition, the mixture was stirred at -32 ° C for about 4 hours. The reaction solution was cooled in a dry ice-acetone bath, and heavy water (2 ml) was removed. Ethyl acetate, water and acetic acid were added to the reaction solution and partitioned. The organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, diluted to 100 ml with ethyl acetate, and the recovery was measured by GC. The ethyl acetate layer was concentrated under reduced pressure, and the obtained residue was analyzed by ¹ H-NMR. The D conversion was measured in the same manner as in Example 3.

 D conversion rate: 80.2%, recovery rate: 86.7%

 Example 6

 [0081] The method A of Example 3 was repeated, except that tert-butylmethylamine was used instead of diisopropylamine, and stirring after dropwise addition of a THF solution of 2-tert-butoxyvirazine was performed at -32 ° C for about 4 hours. According to

 D conversion rate: 43.8%, recovery rate: 95.3%.

 Example 7

 [0082] The method of Example 3 was repeated, except that cyclohexylethylamine was used instead of diisopropylamine, and stirring after dropwise addition of a THF solution of 2-tert-butoxypyrazine was performed at -32 ° C for about 4 hours. According to A.

 D conversion rate: 56.1%, recovery rate: 88.1%.

 Example 8

 [0083] The method A of Example 3 was repeated, except that cyclohexylisopropylamine was used instead of diisopropylamine, and stirring after the dropwise addition of the THF solution of 2-tert-butoxypyrazine was performed at -32 ° C for about 4 hours. According to.

 D conversion rate: 48.7%, recovery rate: 88.7%

 Example 9

[0084] Except that Ν, Ν, Ν'-triethylethylenediamine was used instead of diisopropylamine, and the stirring after the dropwise addition of the THF solution of 2-tert-butoxypyrazine was performed at -32 ° C. for about 4 hours. According to Method A of Example 3. D conversion rate: 14.1%, recovery rate: 93.0% o

 Example 10

 [0085] Method B of Example 4 was followed except that diisopropylamine was used instead of 2,2,6,6-tetramethylpiperidine.

 D conversion rate: 84.9%, recovery rate: 96.5%.

 Example 11

 [0086] Magnesium amide was prepared using diisopropylamine instead of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and the stirring after the dropwise addition of a THF solution of 2-tert-butoxypyrazine was performed at room temperature (external temperature). 24.7 ° C) for 1 hour, according to the method B of Example 4.

 D conversion rate: 87.2%, recovery rate: 93.8%.

 Example 12

 [0087] Magnesium amide was prepared using tert-butylmethylamine instead of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and stirred after dropping a THF solution of 2-tert-butoxypyrazine. Except that the stirring was performed at -32 ° C for about 4 hours, the method was the same as that in Example 4 Method B.

 D conversion rate: 18.7%, recovery rate: 92.3%.

 Example 13

 [0088] Magnesium amide was prepared using tert-butylethylamine in place of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and the dropwise addition of the THF solution of 2-tert-butoxypyrazine was carried out. Method B of Example 4 was followed except that stirring was performed at −32 ° C. for about 4 hours.

 D conversion rate: 70.5%, recovery rate: 94.8%.

 Example 14

 [0089] Magnesium amide was prepared using diisopropylethylamine in place of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and the stirring after the dropwise addition of the THF solution of 2-tert-butoxypyrazine was performed. Except for about 4 hours at 32 ° C., the method was the same as that in Example 3, Method B.

 D conversion rate: 21.5%, recovery rate: 96.6%.

 Example 15

Using cyclohexylmethylamine instead of 2,2,6,6-tetramethylpiperidine, The procedure of Example 4 was repeated except that the preparation of magnesium amide was performed overnight, and stirring after the dropwise addition of the THF solution of 2-tert-butoxypyrazine was performed at −32 ° C. for about 4 hours.

 D conversion rate: 10.5%, recovery rate: 94.0%.

 Example 16

 [0091] Cyclohexylethylamine was used in place of 2,2,6,6-tetramethylpiperidine, and magnesium amide was prepared at room temperature overnight, followed by stirring after dropwise addition of a THF solution of 2-tert-butoxypyrazine. Example 4 was carried out in the same manner as in Example 4, except that the reaction was carried out at -32 ° C for about 4 hours.

 D conversion rate: 21.0%, recovery rate: 96.2%

 Example 17

 [0092] Using cyclohexylisopropylamine instead of 2,2,6,6-tetramethylpiperidine, magnesium amide was prepared at room temperature overnight, and stirring after dropping a THF solution of 2-tert-butoxypyrazine was performed. Except for about 4 hours at 32 ° C., the method was the same as that in Example 4, Method B.

 D conversion rate: 61.3%, recovery rate: 96.3%.

 Example 18

 [0093] Magnesium amide was prepared using 2,6-dimethylbiperidine instead of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and the solution of 2-tert-butoxypyrazine in THF was added dropwise. The procedure was carried out in accordance with the method B of Example 4, except that stirring was carried out at -32 ° C for about 4 hours.

 D conversion rate: 41.9%, recovery rate: 89.2%

 Example 19

 [0094] Magnesium amide was prepared at room temperature overnight using 2-ethylbiperidine instead of 2,2,6,6-tetramethylpiperidine, and stirring after dropping the THF solution of 2-tert-butoxypyrazine was -32 °. Except for about 4 hours at C, the procedure was as in Method B of Example 4.

 D conversion rate: 7.1%, recovery rate: 92.2%

 Example 20

[0095] Magnesium amide was prepared using ethyl butylamine instead of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and the stirring after the dropwise addition of the THF solution of 2-tert-butoxypyrazine was performed. Except for about 4 hours at 32 ° C., the method was the same as that in Example 4, Method B. D conversion rate: 11.9%, recovery rate: 95.1%.

 Example 21

 [0096] Using methyltri (1-methylbiperidin-4-yl) amine instead of 2,2,6,6-tetramethylpiperidine, magnesium amide was prepared at room temperature overnight, and 2-tert-butoxypyrazine was obtained. The method was performed in the same manner as in the method B of Example 4, except that stirring after the addition of the THF solution was performed at -32 ° C for about 4 hours. D conversion rate: 7.9%, recovery rate: 94.3%.

 Example 22

[0097] [Formula 12] No

 N OMe N, OMe

[0098] The method A of Example 3 except that 2_methoxypyrazine was used instead of 2-tert-butoxypyrazine, and the stirring after the dropwise addition of the 2_methoxypyrazine in the THF solution was performed at -23 ° C for about 0.5 hour. According to

D conversion rate: 71.7%, recovery rate: 72.5%.

 GC analysis was performed under the same conditions as in Method A of Example 3, and the result was a retention time of 8.2 minutes.

 The recovery rate and the conversion to D were calculated according to the method A of Example 3.

 Example 23

 [0099] Magnesium amide was prepared using diisopropylamine instead of 2,2,6,6-tetramethylpiperidine at room temperature overnight, and 2-methoxypyrazine was used instead of 2-tert-butoxypyrazine, Method B of Example 4 was followed except that stirring after the dropwise addition of the methoxypyrazine solution in THF was carried out at −23 ° C. for about 2 hours.

 D conversion rate: 87.9%, recovery rate: 84.2%

Example 24 [0100] [Formula 13] Me

[0101] The method of Example 3 was repeated, except that 3-methoxypyridine was used instead of 2-tert-butoxypyrazine, and stirring after dropping a solution of 3_methoxypyridine in tetrahydrofuran was performed at -23 ° C for 2 hours. According to A.

 D conversion rate: 46.1%, recovery rate: 86.3%.

 GC analysis was performed under the same conditions as in Method A of Example 3, and a result with a retention time of 10.1 minutes was obtained. The recovery was calculated according to Method A of Example 3. The method of calculating the D-Dani rate is as follows. That is, it was calculated from the integral value X of the 2-position proton of 3-methoxypyridine and the integral value Y of the 6-position proton according to the following formula.

 D conversion rate (%) = (Y-X) / YX 100

 Example 25

 [0102] Method B of Example 4 was followed except that diisopropylamine was used instead of 2,2,6,6-tetramethylpiperidine and 3-methoxypyridine was used instead of 2-tert-butoxypyrazine.

 D conversion rate: 50.8%, recovery rate: 86.8%.

 Example 26

 [0103] The method C of Example 5 was repeated, except that 3_methoxypyridine was used instead of 2-tert-butoxypyrazine, and stirring after the dropwise addition of the 3_methoxypyridine in the THF solution was carried out at −23 ° C. for about 2 hours. According to. D conversion rate: 45.8%, recovery rate: 89.0%.

 Example 27

<Preparation of Magnesium Monoamide Reagent>

A THF solution of n-butylmagnesium chloride (0.9M, 6.7ml, 6mmol) was cooled to a bath temperature of 7 ° C while cooling an n-hexane solution of n-butyllithium (1.58M, 3.8ml, 6mmol). . After the dropwise addition, the mixture was stirred for 53 minutes while cooling the bath temperature to -23 ° C. Diisopropylamine (0.84 ml, 6 mmol) was stirred for 2 minutes at the same temperature for 1 hour to prepare a magnesium amide solution. <Anionization and electrophilic substitution>

To this solution, a solution of 2-tert-butoxypyrazine (457 mg, 3 mmol) in THF (1 ml) was added dropwise while cooling in a dry ice-acetone bath. After the addition, the mixture was stirred at -23 ° C overnight. The reaction solution was cooled in a dry ice-acetone bath, and heavy water (2 ml) was removed. Ethyl acetate, water and acetic acid were added to the reaction solution and partitioned. The organic layer was washed with aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, diluted to 100 ml with ethyl acetate, and the recovery was measured by GC. The ethyl acetate layer was concentrated under reduced pressure, and the obtained residue was analyzed by ¹ H-NMR. The D conversion was measured in the same manner as in Example 3. D conversion rate: 85.3%, recovery rate: 88.5%.

 Example 28

 [0105] Preparation of n-butylmagnesium diisopropylamide solution

 A THF solution of n-butylmagnesium chloride (0.9 M, 6.7 ml, 6 mmol) was added with an n-hexane solution of n-butyllithium (1.58 M, 3.8 ml, 6 mmol), and the mixture was stirred at room temperature for 1 hour and 10 minutes. Diisopropylamine (0.84 ml, 6 mmol) was added, and the mixture was stirred at room temperature overnight to prepare an n-butylmagnesium diisopropylamide solution.

 Example 29

 [0106] <1-benzenesulfol-1H-indole-2-carbaldehyde>

[0107] [Formula 14]

A solution of 1-benzenesulfol-1H-indole (771 mg, 3 mmol) in THF (1.5 ml) was added to the n-butylmagnesium diisopropylamide solution prepared in Example 28 while cooling in a dry ice-acetone bath. After dropwise addition, the mixture was stirred at 0 ° C for 2 hours. Ν, Ν-dimethylformamide (DMF, 1.4 ml, 18 mmol) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was diluted with aqueous ammonium chloride, and aqueous ammonium chloride was further added until no insoluble material was found, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate, hexane) to give 1-benzenesulfol-1H-indole-2 Rudehydride (262 mg, 30.6%) was obtained.

 1H-NMR (400MHz, CDC1); δ (ppm) 7.29-7.58 (m, 6H), 7.63 (d, 1H), 7.79 (d, 1H),

 Three

 8.24 (d, 1H), 10.53 (s, 1H).

 Example 30

 <(1-benzenesulfol-1H-indole-2-yl) phenol methanol>

[0110] [Formula 15]

[Oil 1] 1-benzenesulfol-1H-indole (771 mg, 3 mmol) in n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 while cooling with a dry ice-acetone bath in THF (1.5 ml) The solution was added dropwise, and the mixture was stirred at 0 ° C for 1 hour and 48 minutes. Benzaldehyde (0.91 ml, 9 mmol) was added dropwise to the reaction solution, and the mixture was stirred at the same temperature for 14 minutes. The reaction solution was diluted with aqueous acetic acid and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain (1-benzenesulfol-1H-indole-2-yl) phenolmethanol (129 mg, 11.8%).

 1H-NMR (400 MHz, CDC1); δ (ppm) 6.39 (d, 1H), 7.26-7.44 (m, 12H), 7.73-7.77

 Three

 (m, 2H), 8.09 (d, lH) s.

 Example 31

 [0112] 2-Aryl-1-benzenesulfurthioyl-1H-indole>

[0113] [Formula 16]

While cooling the n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 to −25 ° C., 1-benzenesulfol-1H-indole (771 mg, 3 mmol) in THF (1. 5 ml) solution was added dropwise, and after the addition, the mixture was stirred at 10 ° C for 2 hours and 40 minutes. Copper iodide (114 mg, 0.6 mmol) was added to the reaction solution, and aryl bromide (2.2 ml, 15 mmol) was added dropwise under ice cooling, followed by stirring for 30 minutes. The reaction solution was quenched with salt water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) and further recrystallized to obtain 2-aryl-1-benzenesulfothioyl-1H-indole (71 mg, 8.0%).

^J H-NMR (400 MHz, CDC1); δ (ppm) 3.77 (dd, 2H), 5.16-5.23 (m, 2H), 5.98-6.09

 Three

 (m, 1H), 6.41 (s, 1H), 7.18-7.30 (m, 2H), 7.39-7.45 (m, 3H), 7.50-7..56 (m, 1H), 7.74-7.79 (m, 1H ), 8.16 (d, 1H).

 Example 32

 [0115] <2-Methoxypyridine-3-carbaldehyde>

[0116] [Formula 17] ぺ

 , OMe N OMe

[0117] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled at -25 ° C, and a solution of 2-methoxypyridine (327mg, 3mmol) in THF (1ml) was added dropwise. The mixture was stirred at 12 ° C for 12 minutes, at -5 ° C for 1 hour and 31 minutes, and at 25 ° C for 3 hours and 29 minutes. The reaction solution was cooled in a dry ice-acetone bath, DMF (2.3 ml, 30 mmol) was added dropwise, and the mixture was stirred at the same temperature for 3 minutes and further under ice cooling for 22 minutes. The reaction solution was diluted with ammonia solution of Shii-dani, further added with water of Shii-dori ammonia until there was no more insoluble material, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 2-methoxypyridine-3-carbaldehyde (104 mg, 25.3%).

 'H-NMR (400MHZ, CDCl); δ (ppm) 4.08 (s, 3H), 7.02 (dd, 1H), 8.11 (dd, 1H),

 Three

8.39 (dd, 1H), 10.38 (s, 1H). [0118] Ku (2-methoxypyridine-3-yl) phenolmethanol>

[0119] [Formula 18]

[0120] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled to -25 ° C, and a solution of 2-methoxypyridine (327mg, 3mmol) in THF (1ml) was added dropwise. The mixture was stirred at ° C for 1 hour and further at 25 ° C for 3 hours. The reaction solution was cooled in a dry ice-acetone bath, and benzaldehyde (0.91 ml, 9 mmol) was added dropwise, followed by stirring at the same temperature for 18 minutes and further at room temperature for 1 hour. The reaction solution was diluted with aqueous ammonia in salt and aqueous ammonia was added to remove insolubles, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain (2-methoxypyridine-3-yl) phenylmethanol (79 mg, 12.2%).

 'H-NMR (400MHZ, CDCl)

 3; δ (ppm) 2.98 (d, 1H), 3.96 (s, 3H), 5.98 (d, 1H), 6.88

(dd, 1H), 7.27-7.40 (m, 5H), 7.52-7.56 (m, 1H), 8.08 (dd, 1H).

 Example 34

 [0121] <6-Mouth-2-methoxypyridine-3-carbaldehyde>

[0122] [Formula 19]

[0123] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled in a dry ice-acetone bath, and a solution of 2-chloro-6-methoxypyridine (431 mg, 3 mmol) in THF (1 ml) was added dropwise. After the dropwise addition, the mixture was stirred at -5 ° C for 1 hour, at 5 ° C for 30 minutes, and further at 15 ° C for 40 minutes. The reaction solution was cooled to -25 ° C, DMF (2.3 ml, 30 mmol) was added dropwise, and the mixture was further heated at the same temperature for 2 minutes. The mixture was stirred at −5 ° C. for 13 minutes. The reaction solution was diluted with aqueous ammonia in salt and aqueous ammonia was added until no insoluble material was found, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 6-chloro-2-methoxypyridine-3-carbaldehyde (336 mg, 65.2%).

 1H-NMR (400MHz, CDC1); δ (ppm) 4.10 (s, 3H), 7.03 (d, 1H), 8.07 (d, 1H), 10.31

 Three

 (s, 1H).

 Example 35

 [0124] 3-aryl-6-chloro-2-methoxypyridine>

[0125] [Formula 20]

The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled in a dry ice-acetone bath, and a solution of 2-chloro-6-methoxypyridine (431 mg, 3 mmol) in THF (1 ml) was added dropwise. After the addition, the mixture was stirred at 10 ° C for 2 hours and 17 minutes. Copper iodide in the reaction solution

 (114 mg, 0.6 mmol) was further added, and further acrylyl bromide (2.2 ml, 15 mmol) was added dropwise, followed by stirring at the same temperature for 2 hours and 52 minutes. The reaction solution was diluted with aqueous ammonia and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give 3-aryl-6-chloro-2-methoxypyridine (93 mg, 8.4%).

 JH-NMR (400MHz, CDC1); δ (ppm) 3.28 (d, 2H), 3.96 (s, 3H), 5.07-5.11 (m, 2H),

 Three

 5.86 (m, 1H), 6.84 (d, 1H), 7.34 (d, 1H).

 Example 36

[0127] <2,6-Dimethoxypyridine-3-carbaldehyde> [0128] [Formula 21]

The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled to −25 ° C., and a THF (1 ml) solution of 2,6-dimethoxypyridine (417 mg, 3 mmol) was added dropwise. The mixture was stirred at the same temperature for 1 hour and 31 minutes, and further at room temperature for 5 hours. The reaction solution was cooled in a dry ice-acetone bath, DMF (2.3 ml, 30 mmol) was added dropwise, and the mixture was heated at the same temperature for 8 minutes. After removing the cooling bath, the temperature was raised to -10 ° C over 6 minutes, and then recooled in a dry ice-acetone bath. The reaction solution was diluted with aqueous ammonium chloride, and aqueous ammonium chloride was further added until there was no more insoluble material, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 2,6-dimethoxypyridine-3-carbaldehyde (123 mg, 24.6%).

 'H-NMR (400MHZ, CDCl); δ (ppm) 4.01 (s, 3H), 4.06 (s, 3H), 6.39 (d, 1H), 8.04

 Three

 (d, 1H), 10.21 (s, 1H).

 Example 37

 [0130] <3-Bromo-6-methoxypyridine-2-carbaldehyde>

[0131] [Formula 22]

^Br

[0132] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled to -25 ° C, and a solution of 5-bromo-2-methoxypyridine (564 mg, 3 mmol) in THF (1 ml) was added dropwise. After the addition, the mixture was stirred at the same temperature for 4 hours and 18 minutes. The reaction solution was cooled in a dry ice-acetone bath, DMF (2.3 ml, 30 mmol) was added dropwise, the temperature was raised to −10 ° C. over 11 minutes, and then cooled again in a dry ice-acetone bath. The reaction solution was diluted with water, and after adding insoluble aqueous ammonia until no more insoluble matter was removed, the mixture was extracted with ethyl acetate. Organic layer is saturated with sodium chloride After washing with an aqueous solution of sodium chloride, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 3-bromo-6-methoxypyridin-2-carbaldehyde (59 mg, 9.1%).

 1H-NMR (400MHz, CDC1); δ (ppm) 4.02 (s, 3H), 6.85 (d, 1H), 7.83 (d, 1H), 10.15

 Three

 (s, 1H).

 Example 38

 [0133] 2-tert-butyl-1-hydroxy-1,2-dihydropyrro [3,4-c] pyridin-3-one>

[0134] [Formula 23]

[0135] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled in a -dry ice-acetone bath, and N-tert-butylnicotinamide [CAS No.

 15828-08-7] (535 mg, 3 mmol) in THF (1.5 ml) was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour and further at room temperature (22.4 ° C.) for 1 hour. The reaction solution was ice-cooled, DMF (1.5 ml, 18 mmol) was added dropwise, and the mixture was stirred for 18 minutes. The reaction solution was ice-cooled, quenched with aqueous sodium chloride solution, and further added with aqueous sodium chloride solution until no insolubles remained, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system), and 2-tert-butyl-1-hydroxy-1,2-dihydropyrro [3,4-c] pyridin-3-one (285 mg, 46.0 %).

^J H-NMR (400MHz, CDC1); δ (ppm) 1.61 (s, 9H), 4.99 (s, br.s), 6.02 (d, 1H), 7.47

 Three

 (dd, 1H), 8.51 (d, 1H), 8.65 (s, 1H).

 Example 39

<(3-Methoxypyrazine-2-yl) phenylethanol> [0137] [Formula 24]

The η-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled in a dry ice-acetone bath, and a solution of 2-methoxypyrazine (303 mg, 3 mmol) in tetrahydrofuran (lml) was added dropwise. The mixture was stirred at 23 ° C for 2 hours and 4 minutes. The reaction solution was cooled in a dry ice-acetone bath, benzaldehyde (0.91 ml, 9 mmol) was added dropwise, and after 2 minutes at the same temperature, the dry ice-acetone bath was removed and the internal temperature was raised to -1.6 ° C. . The reaction solution was cooled in a dry ice-acetone bath, diluted with water, and partitioned between ethyl acetate and aqueous acetic acid. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain (3-methoxypyrazin-2-yl) phenylmethanol (361 mg, 55.6%).

 'H-NMR (400MHZ, CDCl); δ (ppm) 3.93 (s, 3H), 4.91 (d, 1H), 5.89 (d, 1H),

 Three

 7.22-7.40 (m, 5H), 8.05 (d, 1H), 8.12 (d, 1H).

 Example 40

[0139] <2-tert-butoxyquinoxaline>

[0140] [Formula 25]

[0141] To a solution of 2-chloromouth quinoxaline (5.00 g, 30.4 mmol) in THF (60 ml) was added potassium tert-butoxide (3.75 g, 33.4 mmol) at room temperature, and the mixture was heated at the same temperature for 20 minutes and further heated to reflux for 1 hour. Stirred for 20 minutes. The reaction solution was poured into ice water and extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered through silica gel, and the obtained solution was concentrated under reduced pressure to obtain 2-tert-butoxyquinoxaline (5.99 g, 98%). 1H-NMR (400MHz, CDC1); δ (ppm) 1.71 (s, 9H), 7.53 (ddd, 1H), 7.64 (ddd, 1H),

 Three

 7.80 (dd, 1H), 7.97 (dd, 1H), 8.34 (s, 1H).

[0142] <3-tert-butoxyquinoxaline-2-carbaldehyde>

[0143] [Formula 26]

[0144] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled to -25 ° C, and a solution of 2-tert-butoxyquinoxaline (607 mg, 3 mmol) in THF (1.5 ml) was added dropwise. Thereafter, the mixture was stirred at -25 ° C for 1 hour and 25 minutes. The reaction solution was cooled in a dry ice-acetone bath, DMF (2.3 ml, 30 mmol) was added dropwise, and the mixture was stirred for 10 minutes. Then, the dry ice-acetone bath was removed, and the internal temperature was raised to -4.3 ° C. The reaction solution was cooled in a dry ice-acetone bath, diluted with water, and the salt water was removed until no further insoluble matter was removed, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 3-tert-butoxyquinoxaline-2-carbaldehyde (253 mg, 36.6%).

 JH-NMR (400MHz, CDC1); δ (ppm) 1.77 (s, 9H), 7.58-7.64 (m, 1H), 7.74-7.80 (m,

 Three

 1H), 7.82-7.87 (m, 1H), 8.13--8.17 (m, 1H), 10.47 (s, 1H).

 Example 41

[0145] 2,6-di-tert-butoxypyrazine>

[0146] [Formula 27]

[0147] A solution of potassium tert-butoxide (16.8g, 150mmol) in THF (130ml) was cooled to 5 ° C, and a solution of 2,6-dichlorovirazine (8.94g, 60mmol) in tetrahydrofuran (30ml) was added thereto. The temperature was dropped at such a rate that the temperature did not exceed 25 ° C. Stir for 15 minutes after dropping, then at room temperature for 1 hour 30 minutes The mixture was stirred at 45 ° C for 2 hours and 30 minutes and at 55 ° C for 28 hours. The reaction solution was partitioned between ethyl acetate and water, and the obtained organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 2,6-di-tert-butoxypyrazine (9.74 g, 74.1%).

 1H-NMR (400MHz, CDC1); δ (ppm) 1.57 (s, 18H), 7.66 (s, 2H).

 Three

 [0148] <3,5-di-tert-butoxyquivirazine 2-carbaldehyde>

[0149] [Formula 28]

The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled to −25 ° C., and a solution of 2,6-di-tert-butoxypyrazine (672 mg, 3 mmol) in THF (1.5 ml) was added. Dropped. After the addition, the mixture was stirred at the same temperature for 2 hours and 18 minutes, and then DMF (2.3 ml, 30 mmo) was added dropwise to the reaction solution. The mixture was stirred at the same temperature for 31 minutes, quenched with salt and water, and further added with salt and water until no insoluble material was found, and extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain 3,5-di-tert-butoxyquivirazine 2-carbaldehyde (194 mg, 25.7%).

 1H-NMR (400MHz, CDC1); δ (ppm) 1.65 (s, 9H), 1.67 (s, 9H), 7.83 (s, 1H), 10.19

 Three

 (s, 1H), 10.21 (s, 1H).

 Example 42

 [0151] <2,4-dimethoxypyrimidine-5-carbaldehyde>

[0152] [Formula 29]

[0153] The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was dried. The mixture was cooled in an ice-acetone bath, and a solution of 2,4-dimethoxypyrimidine (420 mg, 3 mmol) in THF (1 ml) was added dropwise. After the dropwise addition, the mixture was stirred at 0 ° C for 45 minutes and at 5 ° C for 1 hour and 30 minutes. After cooling the reaction solution to −25 ° C., DMF (2.3 ml, 30 mmo) was added dropwise. The mixture was stirred at the same temperature for 29 minutes, quenched with salt water, and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to give 2,4-dimethoxypyrimidine-5-methylvalaldehyde (23 mg, 4.6%).

 'H-NMR (400MHZ, CDCl)

 3; δ (ppm) 4.09 (s, 3H), 4.12 (s, 3H), 8.79 (s, 1H), 10.18

(s, 1H).

 Example 43

 <(2,4-Dimethoxypyrimidine-5-yl) phenylethanol>

[0155] [Formula 30]

The n-butylmagnesium diisopropylamide solution prepared in the same manner as in Example 28 was cooled in a dry ice-acetone bath, and a solution of 2,4-dimethoxypyrazine (420 mg, 3 mmol) in THF (1 ml) was added dropwise. After the dropwise addition, the mixture was stirred at -5 ° C for 2 hours and 48 minutes. To the reaction solution was added benzaldehyde (0.91 ml, 9 mmol) dropwise at the same temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was diluted with ammonia solution of Shii-dani, the aqueous solution of Shii-dori ammonia was further removed until no insoluble material was found, and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain (2,4-dimethoxypyrimidine-5-yl) phenylmethanol (183 mg, 24.7%).

^J H-NMR (400 MHz, CDCl); δ (ppm) 3.94 (s, 3H), 4.03 (s, 3H), 4.38 (d, 1H), 5.58

 Three

 (d, 1H), 6.23 (s, 1H), 7.28-7.42 (m, 5H).

Claims

 The scope of the claims

 [1] rho, logen atom, hydroxyl group, mercapto group, c alkyl group, phenyl group, naphthyl group,

 1-6 c alkoxy group, c alkoxy C alkoxy group, C alkylthio group, carboxyl

1-6 1-6 1-6 1-6

A sil group, a C alkoxycarbol group, a phenylsulfol group, a formula Z ¹ — NR ⁴ R ⁵ (wherein

 1—6

, Z ¹ represents a carboxyl group, a sulfol group or a single bond, R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group), a group represented by the formula NR ⁴ — CO—

 1-6

R ⁷ (wherein, R ⁴ represents a hydrogen atom or a C alkyl group, and R ⁷ represents a C alkoxy group

 1-6 1-6

A group represented by the following formula: and z ¹ — z ² (wherein z ¹ is as defined above, and z ² is

1 means a pyrrolidinyl group, 1-piperidyl group or 1 morpholinyl group) which may have 1 to 3 groups selected from the group A 5 to 10-membered aromatic complex rings A compound represented by the formula (1) (wherein R ¹ represents a C alkyl group;

 1-6

¹ may have a group represented by the formula NR ³ or 1 to 4 C alkyl groups 1

 1-6

-Piperidyl group; R ² and R ³ are each independently a C alkyl group,

 1-6 3-8 Having a cycloalkyl group or a C alkyl group! /, Good! /, Piperazinyl group or di (C

 1-6 1-6 alkyl group) which has an amino group and means a C alkyl group)

 1-6

 A method for producing a 5- to 10-membered aromatic heterocyclic compound, which comprises reacting a reagent.

 [Formula 31]

A \ R (1)

 Mg

[2] rho, logen atom, hydroxyl group, mercapto group, C alkyl group, phenyl group, naphthyl group, C

 1-6

 Alkoxy group, c alkoxy C alkoxy group, C alkylthio group, carboxy

1-6 1-6 1-6 1-6

A sil group, a C alkoxycarbol group, a phenylsulfol group, a formula Z ¹ — NR ⁴ R ⁵ (wherein

 1—6

, Z ¹ represents a carboxyl group, a sulfol group or a single bond, R ⁴ and R ⁵ each independently represent a hydrogen atom or a C alkyl group), a group represented by the formula NR ⁴ — CO—

 1-6

R ⁷ (wherein, R ⁴ represents a hydrogen atom or a C alkyl group, and R ⁷ represents a C alkoxy group

 1-6 1-6

A group represented by the following formula: and z ¹ — z ² (wherein z ¹ is as defined above, and z ² is

1 means pyrrolidinyl group, 1-piperidyl group or 1 morpholinyl group) A 5- to 10-membered aromatic heterocyclic compound having at least one first substituent, which is also selected as a group A, is a compound represented by the formula (1) (wherein R ¹ is C 1-6 A ¹ represents a group represented by the formula —NR ³ or a group having 114 C alkyl groups;

 1-6

V means a 1-piperidyl group; R ² and R ³ are each independently C alkyl

 1-6 alkyl group, C cycloalkyl group, piperazinyl group which may have C alkyl group

3-8 1-6

 Or di (C alkyl) means a C alkyl group having an amino group)

 1-6 1-6

 Reacting with an electrophile to obtain a 5-10 membered aromatic heterocyclic compound in which the ortho position of the first substituent is electrophilically substituted. A method for producing a 5- to 10-membered aromatic heterocyclic compound in which the ortho position is electrophilically substituted.

 [Formula 32]

A \ R ₍₁₎

 Mg

[3] The 5- to 10-membered aromatic heterocyclic compound having at least one first substituent is a compound represented by the following formula (2) -1-1 (2) -5 (wherein R ^1C> represents a first substituent whose substituent group A is also selected, and R ¹¹ R ¹² and R ¹³ each independently represent a hydrogen atom or a substituent selected from substituent group A). Item 2. The method according to item 2.

[Formula 33]

R 11 /, Ν ', R

 (2) -1 (2) -2 (2) -3

 (2) -4 (2) -5

[4] A 5- to 10-membered aromatic heterocyclic compound having at least one first substituent is represented by the following formula (2)

4. The method according to claim 3, wherein the compound is a compound represented by 4 ′ (wherein, R ^1C> represents a first substituent selected from the substituent group A).

 [Formula 34]

 (2) -4 '

[5] The substituent A group hydroxyl group, mercapto group, C alkoxy group, C alkoxy C

 1-6 1-6 1-6 Alkoxy group, C alkylthio group, carboxyl group, C alkoxycarbol group

 1—6 1—6

, Formula Z ¹ — NR ⁴ R ⁵ (wherein, Z ¹ represents a carboxyl group, a sulfol group or a single bond, and R 4 and R ⁵ each independently represent a hydrogen atom or a C alkyl group. To)

 1-6

A group represented by the formula -NR ⁴ -CO-R ⁷ (wherein R ⁴ represents a hydrogen atom or a C alkyl group, and R ⁷ represents

 1-6

c represents an alkoxy group), and a group represented by the formula z ¹ — z ² wherein z ¹ is as defined above.

1-6

And Z ² is 1 pyrrolidinyl group, 1-piperidyl group or 1 morphoyl group. 5. The method according to claim 2, wherein the substituent is a group of substituents A-1.

 [6] The substituent A group hydroxyl group, mercapto group, C alkoxy group, C alkoxy C

 The method according to any one of claims 2 to 4, wherein the group strength is selected from the group consisting of 1-6, 1-6, and 1-6.

[7] The method according to any one of claims 2 to 4, wherein the substituent group A is a C alkoxy group.

 1-6

 Law.

 [8] The method according to any one of claims 2 to 4, wherein the substituent group A is a t-butoxy group.

[9] The method according to [ ¹ ] or [2], wherein A ¹ is a diisopropylamino group.

[10] The method according to [2] or [1], wherein R ¹ is an n-butyl group.