JP2004331655A - Method for producing nitrogen-containing heterocyclic compound and production intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To efficiently produce a nitrogen-containing heterocyclic compound useful as an intermediate for producing a pharmaceutical, agrochemical, etc., by solving problems in synthesizing a trifluoromethyltetrazole ring compound. <P>SOLUTION: A method for producing a compound expressed by formula (II) (A is an alkyl which may be substituted, an cycloalkyl which may be substituted or an aromatic homocyclic or heterocyclic ring which may be substituted) comprises mixing a compound expressed by formula (I) or its salt with a trifluoroacetyl compound and an azide compound. Further, a compound expressed by formula (VI) is produced in the method, when a compound expressed by formula (V) (X is a halogen) or its salt is used as the compound expressed by formula (I) or its salt. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel process for producing a trifluoromethyltetrazole ring compound and a production intermediate. More specifically, the present invention provides a simple process for producing a trifluoromethyltetrazole ring compound as an intermediate for producing pharmaceuticals, agricultural chemicals, or many general-purpose chemicals, which can be carried out under mild and safe conditions, and such production Intermediates useful in the process.

Some trifluoromethyltetrazole ring compounds are useful as intermediates in the manufacture of pharmaceuticals, pesticides, or many general-purpose chemicals. However, some methods are known for their production.
See, for example, Journal of Organic Chemistry (J. Org. Chem.), Vol. 27, p. 3248, 1962 and Inorganic Chemistry (Inorg. Chem.), Vol. 28, p. In 1989, trifluoromethyltetrazole was synthesized by reacting sodium azide and trifluoroacetonitrile at -196 to 60 ° C. However, trifluoroacetonitrile is a synthesis method that is industrially problematic in that it is a gas that is difficult to handle and has a very low reaction temperature of -196 ° C.
See also, for example, Bioorganic & Medicinal Chemistry Letters (Bioorg. & Med. Chem. Lett.), 6, 1015, 1996 and Journal of Labeled Compounds and Radio Pharmaceuticals. In Calls (J. Labeled. Cpd. Radiopharm.), Vol. 43, p. 29, 2000, the aniline compound was subjected to trifluoroacetylation in the presence of triethylamine, and once the trifluoroacetamide compound was isolated. , A trifluoromethyltetrazole compound is synthesized by reacting triphenylphosphine with carbon tetrachloride to convert it to an imino chloride compound and then reacting with sodium azide. However, carbon tetrachloride is used as a chlorinating agent also serving as a reaction solvent, and is a synthetic method having an industrial problem in view of toxicity to human bodies and the environment.
On the other hand, Justus Liebigs Annalen der Chemie (Justus. Liebigs. Ann. Chem.), Vol. 725, p. 29, 1969 discloses sodium azide and acyl chloride for triphenylphosphine imide compounds. An alkyltetrazole compound is synthesized by reacting the acylating agent of However, when trifluoroacetic anhydride was used as the acylating agent in this method, the result was that the target trifluoromethyltetrazole compound could not be obtained.
Journal of Organic Chemistry (J. Org. Chem.), 27, 3248, 1962. Inorganic Chemistry, 28, 4629, 1989. Bioorganic and Medicinal Chemistry Letters (Bioorg. & Med. Chem. Lett.), 6, 1015, 1996. Journal of Labeled Compounds and Radio Pharmaceuticals (J. Labeled. Cpd. Radiopharm.), Vol. 43, p. 29, 2000 Justus Liebigs Annalen der Chemie (Justus. Liebigs. Ann. Chem.), 725, 29, 1969

As described above, a problem for synthesizing a trifluoromethyltetrazole ring compound is that there is only a production method which is industrially difficult to carry out. Also, sodium azide used to form the tetrazole ring needs to be handled with care due to dangers such as explosiveness, and is not considered to be suitable as an industrially safe production method. hard.
An object of the present invention is to solve these problems in the synthesis of a trifluoromethyltetrazole ring compound and efficiently produce a nitrogen-containing heterocyclic compound useful as an intermediate for the production of pharmaceuticals, agricultural chemicals, or many general-purpose chemicals. It is.

The present inventors have conducted intensive studies to solve the above problems, and as a result, in a novel combination of an azide compound and a trifluoroacetyl compound other than trifluoroacetic anhydride that do not explode with respect to the triphenylphosphine imide compound. And conditions for producing a trifluoromethyltetrazole compound under mild and safe conditions.
As a result of further study based on such knowledge, the present invention has been completed.

［式中、Ａは置換されていてもよいアルキル基、置換されていてもよいシクロアルキル基、置換されていてもよい芳香族同素または複素環を示す。］で表される化合物またはその塩と、トリフルオロアセチル化合物およびアジ化化合物を混合することを特徴とする式（II）

［式中、各記号は上記と同意義である。］で表される化合物またはその塩の製造法、
（２）式（I）で表される化合物またはその塩が、式(III)

［式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５はそれぞれ同一または異なって水素原子または置換基を示す。］で表される化合物またはその塩であり、式（II）で表される化合物またはその塩が、式（IV）

［式中、各記号は上記と同意義である。］で表される化合物またはその塩である上記（１）記載の製造法、
（３）式（III）で表される化合物またはその塩が、式（V）

[式中、X₁およびX₂は同一または異なって塩素原子または臭素原子を示す。]で表される化合物を式（VI）

[ 式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４およびＲ５はそれぞれ同一または異なって水素原子または置換基を示す。]で表される化合物またはその塩と反応させて得られた化合物またはその塩である上記（２）記載の製造法、
（４）Ｒ１、Ｒ２、Ｒ４およびＲ５が水素原子であり、Ｒ３が水酸基である上記（２）記載の製造法、
（５）上記（４）で得られた式（VII）

で表される化合物またはその塩をホルミル化反応に付することを特徴とする式（VIII）

で表される化合物またはその塩の製造法、
（６）式（VII）

で表される化合物またはその塩を、トリフルオロ酢酸の存在下、ヘキサメチレンテトラミンと反応させることを特徴とする式（VIII）

で表される化合物またはその塩の製造法、
（７）式（VIII）

で表される化合物またはその塩を、炭酸ナトリウムの存在下、ヨウ化メチルと反応させることを特徴とする、式（IX）

で表される化合物またはその塩の製造法、
（８）式（X）

［式中、Ｘはハロゲン原子を示す。］で表される化合物またはその塩、
（９）Ｘが塩素原子である上記（８）記載の化合物またはその塩、
（１０）式（XI）

で表される化合物またはその塩、等に関する。 That is, the present invention
(1) Formula (I)

[In the formula, A represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aromatic homo or heterocyclic ring. Wherein the compound represented by the formula (I) or a salt thereof is mixed with a trifluoroacetyl compound and an azide compound.

Wherein each symbol is as defined above. A method for producing a compound represented by the formula
(2) The compound represented by the formula (I) or a salt thereof is represented by the formula (III)

[Wherein, R1, R2, R3, R4 and R5 are the same or different and each represent a hydrogen atom or a substituent. Wherein the compound represented by the formula (II) or a salt thereof is represented by the formula (IV)

Wherein each symbol is as defined above. The method according to the above (1), which is a compound represented by the formula:
(3) The compound represented by the formula (III) or a salt thereof is represented by the formula (V)

[Wherein X ₁ and X ₂ are the same or different and represent a chlorine atom or a bromine atom. The compound represented by the formula (VI)

[Wherein, R1, R2, R3, R4 and R5 are the same or different and each represent a hydrogen atom or a substituent. The method according to the above (2), which is a compound or a salt thereof obtained by reacting with a compound represented by the formula
(4) The production method according to the above (2), wherein R1, R2, R4 and R5 are hydrogen atoms, and R3 is a hydroxyl group.
(5) Formula (VII) obtained in the above (4)

Wherein a compound represented by the formula (I) or a salt thereof is subjected to a formylation reaction:

A method for producing a compound represented by or a salt thereof,
(6) Formula (VII)

Reacting a compound represented by the formula or a salt thereof with hexamethylenetetramine in the presence of trifluoroacetic acid,

A method for producing a compound represented by or a salt thereof,
(7) Formula (VIII)

Reacting a compound represented by the formula or a salt thereof with methyl iodide in the presence of sodium carbonate,

A method for producing a compound represented by or a salt thereof,
(8) Formula (X)

[Wherein, X represents a halogen atom. Or a salt thereof,
(9) The compound or a salt thereof according to the above (8), wherein X is a chlorine atom,
(10) Formula (XI)

Or a salt thereof, and the like.

  ADVANTAGE OF THE INVENTION According to this invention, the conventional problem in the synthesis | combination of a trifluoromethyl tetrazole ring compound is solved, and a nitrogen-containing heterocyclic compound useful as a pharmaceutical, an agricultural chemical, or a manufacturing intermediate of many general-purpose chemicals can be manufactured efficiently.

Hereinafter, the contents of the present invention will be described in detail.
First, terms used in the present invention will be described.
In the above formula, examples of the alkyl group in the “optionally substituted alkyl group” represented by A include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, C ₁ such as n-pentyl, isopentyl, neopentyl, 1-methylpropyl, n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, etc. _-6 alkyl and the like can be used. Here, as a substituent of the alkyl group, a lower alkoxy group (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (Eg, C _1-6 alkyl such as methyl, ethyl, propyl, etc.), lower alkenyl group (eg, C _2-6 alkenyl such as vinyl, allyl, etc.), lower alkynyl group (eg, C ₂ such as ethynyl, propargyl, etc.) _-6 alkynyl, etc.), optionally substituted amino group, optionally substituted hydroxyl group, cyano group, nitro group, nitroso group, optionally substituted amidino group, carboxy group, lower alkoxycarbonyl group (eg, , methoxycarbonyl, etc. C _1-6 alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl), an optionally substituted carbamoyl group (e.g., no 5 6-membered monocyclic aromatic heterocyclic ring (e.g., pyridinyl, etc.) optionally substituted C _1-6 alkyl group or an acyl group (e.g., a formyl, C _2-6 alkanoyl, benzoyl, optionally halogenated Carbamoyl group optionally substituted with C _1-6 alkoxycarbonyl, optionally halogenated C _1-6 alkylsulfonyl, benzenesulfonyl, etc., 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl , Piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl, etc.) and the like, and one to three of these optional substituents may be substituted at substitutable positions.

As the `` optionally substituted amino group '' as a substituent of the `` optionally substituted alkyl group '', `` optionally substituted hydroxyl group '', and `` optionally substituted amidino group '' Are an `` optionally substituted amino group '', a `` optionally substituted hydroxyl group '', and a `` optionally substituted And the same as the “amidino group that may be used”.
In the above formula, as the cycloalkyl group in the “optionally substituted cycloalkyl group” represented by A, for example, C _3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl is used. be able to. Here, as the substituent of the cycloalkyl group, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.
In the above formula, examples of the aromatic homo or hetero ring of the “optionally substituted aromatic homo or hetero ring” represented by A include, for example, a monocyclic or condensed polycyclic aromatic carbocyclic ring, or Monocyclic or fused polycyclic aromatic heterocycles can be used. Preferably, a C _6-14 aromatic carbocycle (aryl group) or a 5- to 14-membered aromatic heterocycle (heteroaryl group) can be used, and more preferably, a C _6-10 aromatic carbocycle (aryl group) or 5 to a 10-membered aromatic heterocyclic (heteroaryl group), more preferably C ₆ aromatic carbocyclic (aryl) or 5 or 6-membered aromatic heterocyclic (heteroaryl group).

Specific examples of the "aromatic homocyclic ring" include, for example, pentazole; a _C6-14 aryl group such as phenyl, naphthyl, anthryl, azulenyl, phenanthryl, acenaphthyl and the like are preferable, among which phenyl, 1-naphthyl and 2-naphthyl are preferable. And the like are particularly preferred.
As the "aromatic heterocyclic ring", for example, one to three (preferably one or two) heteroatoms selected from oxygen, sulfur, nitrogen and the like are used as atoms (ring atoms) constituting a ring system. An aromatic heterocyclic ring containing at least one (preferably 1 to 4, more preferably 1 to 2) or the like can be used.
Specific examples of the "aromatic heterocycle" include, for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 5- to 6-membered monocyclic aromatic heterocycles such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazo Ryl, benzoxazolyl, 1,2-benzoyi Soxazolyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatoridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo 4,3- a] pyridyl, 1,2,4-triazolo [4,3- b] can be used 8-12 membered fused polycyclic aromatic heterocyclic rings such as pyridazinyl, and the like. Preferably, a 5- or 6-membered monocyclic aromatic heterocycle can be used.

Here, the substituent of the `` optionally substituted aromatic homo- or heterocyclic ring '' may be protected by an ordinary method of organic chemical synthesis, if necessary, and is not particularly limited as long as it does not affect the reaction. There is no limitation, for example, (i) an optionally substituted alkyl group, (ii) an optionally substituted alkenyl group, (iii) an optionally substituted alkynyl group, (iv) an optionally substituted alkynyl group. Good aryl group, (v) optionally substituted aralkyl group, (vi) optionally substituted cycloalkyl group, (vii) optionally substituted cycloalkenyl group, (viii) optionally substituted A good heterocyclic ring, (ix) an optionally substituted amino group, (x) an optionally substituted imidoyl group (for example, the formula -C (U ') = NU wherein U and U' are Each represents a hydrogen atom or a substituent (U preferably represents a hydrogen atom)] Group, etc.), (xi) an amidino group which may be substituted (for example, formula -C (NT'T ") = NT, wherein T, T 'and T" are each a hydrogen atom or Represents a substituent (T preferably represents a hydrogen atom)]), (xii) an optionally substituted hydroxyl group, (xiii) an optionally substituted thiol group, and (xiv) substituted Alkylsulfinyl group which may be substituted, (xv) a carboxyl group which may be esterified or amidated, (xvi) a thiocarbamoyl group which may be substituted, (xvii) a sulfamoyl group which may be substituted, (xviii) a halogen atom (e.g., fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), (xix) cyano group, (xx) isocyano group, (xxi) cyanate group, (xxii) isocyanate group, (xxii) (xxiii) thiocyanate group, (xxiv) isothiocyanate group, (xxv) nitro group, (xxvi) Loxo group, (xxvii) sulfonic acid-derived acyl group, (xxviii) carboxylic acid-derived acyl group, (xxix) oxo group and the like are used. (Preferably 1 to 3) substituents.
As the alkyl group in the `` optionally substituted alkyl group '' as a substituent of the `` optionally substituted aromatic homo- or heterocyclic ring '', the `` optionally substituted The same as the “alkyl group” can be used.

Examples of the alkenyl group in the “optionally substituted alkenyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” include vinyl, allyl, isopropenyl, 2-methylallyl, -Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-pentenyl And C _2-6 alkenyl such as 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl and the like are used. be able to. Here, as the substituent of the alkenyl, the same number of the same substituents as those in the “optionally substituted alkyl group” as the above substituent can be used.
Examples of the alkynyl group in the “optionally substituted alkynyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” include, for example, ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, etc. _{C 2- 6} alkynyl can be used. Here, as the substituent of the alkynyl group, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.
Examples of the aryl group in the “optionally substituted aryl group” as a substituent of the “optionally substituted aromatic homo- or heterocycle” include, for example, phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. _6-14 aryl and the like can be used. Here, as the substituent of the aryl group, the same number of the same substituents as those of the “optionally substituted alkyl group” as the above substituent can be used.
Examples of the aralkyl group in the “optionally substituted aralkyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” include, for example, C _7- such as benzyl, phenethyl and naphthylmethyl. ₁₁ aralkyl and the like can be used. Here, as the substituent of the aralkyl group, the same number of similar substituents as those in the above-mentioned “optionally substituted alkyl group” as the substituent can be used.

Examples of the cycloalkyl group in the “optionally substituted cycloalkyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” include the above-mentioned “substituted And the like.
Examples of the cycloalkenyl group in the “optionally substituted cycloalkenyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” include, for example, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentyl, C _3-7 cycloalkenyl hexenyl and the like can be used. Here, as the substituent of the optionally substituted cycloalkenyl group, the same number of the same substituents as those of the above-mentioned “optionally substituted alkyl group” as the substituent can be used. .
As the heterocyclic ring in the “optionally substituted heterocyclic ring” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring”, for example, as an atom (ring atom) constituting a ring system, Aromatic containing at least 1 (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from oxygen, sulfur and nitrogen atoms, etc. A heterocyclic ring, a saturated or unsaturated non-aromatic heterocyclic ring (aliphatic heterocyclic ring) or the like can be used.

Here, as the "aromatic heterocycle", for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3, 4-oxadiazolyl, furzanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, 5- to 6-membered monocyclic aromatic heterocycles such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and, for example, benzofuranyl, isobenzofuranyl, benzo [ b ] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzindazolyl, Benzoxazolyl, 1,2-benzoisoxazo Lyl, benzothiazolyl, benzopyranyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, prenyl, buteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, phenatoridinyl, phenatrolinyl, indolizinyl, pyrrolo [1,2- b ] pyridazinyl, pyrazolo [1,5- a ] pyridyl, imidazo [1, 2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3- ] Pyridyl, 1,2,4-triazolo [4,3- b] 8-12 membered fused polycyclic aromatic heterocycle (preferably such as pyridazinyl, monocyclic aromatic heterocycle of 5 to 6-membered above A heterocyclic ring in which the ring is condensed with a benzene ring or a heterocyclic ring in which two identical or different heterocyclic rings of the above 5- or 6-membered monocyclic aromatic heterocyclic ring are condensed, more preferably a 5- or 6-membered monocyclic aromatic heterocycle as described above; A heterocyclic ring in which a cyclic aromatic heterocyclic ring is condensed with a benzene ring, particularly preferably benzofuranyl, benzopyranyl, benzo [ b ] thienyl and the like can be used.

Here, as the "non-aromatic heterocycle", for example, 3- to 8-membered (preferably 5- to 5-membered) such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, and piperazinyl 6-membered) saturated or unsaturated (preferably saturated) non-aromatic heterocycle (aliphatic heterocycle) or the like, or 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroiso Non-aromatic heterocycles in which the double bonds of some or all of the above-mentioned monocyclic aromatic heterocycles or condensed polycyclic aromatic heterocycles, such as quinolyl, are saturated can be used.
Examples of the substituent which the “optionally substituted heterocycle” may have include a lower alkyl group (eg, C _1-6 alkyl such as methyl, ethyl, propyl and the like), a lower alkenyl group (Eg, C _2-6 alkenyl such as vinyl and allyl), lower alkynyl group (eg, C _2-6 alkynyl such as ethynyl and propargyl), acyl group (eg, C _2-6 alkynyl such as formyl, acetyl, propionyl, pivaloyl) _1-6 alkanoyl, benzoyl, etc.), an optionally substituted amino group, an optionally substituted hydroxyl group, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., preferably chlorine, bromine, etc.), substituted And an amidino group which may be substituted. These optional substituents may be substituted at 1 to 5 (preferably 1 to 3) at substitutable positions.
"Optionally substituted hetero group" which may have "optionally substituted amino group", "optionally substituted hydroxyl group", "optionally substituted imidoyl" The `` group '', and `` optionally substituted amidino group '' as `` optionally substituted aromatic homo or heterocycle '' described later `` optionally substituted amino group '' as a substituent, The same groups as the “optionally substituted hydroxyl group”, “optionally substituted imidoyl group”, and “optionally substituted amidino group” can be used.

`` Optionally substituted amino group '', `` optionally substituted imidoyl group '', `` optionally substituted Examples of the substituent in the “amidino group”, the “optionally substituted hydroxyl group”, and the “optionally substituted thiol group” include, for example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkoxy (eg, methoxy, ethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, trichloromethoxy, 2,2,2-trichloroethoxy, etc.) and C _7-11 alkylaryl group (Eg, o-toluyl, m-toluyl, p-toluyl, xylyl, mesityl, etc., preferably C _1-5 alkyl-phenyl, etc.) An optionally substituted lower alkyl group (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.), an acyl group (C _1-6 alkanoyl ( eg formyl, acetyl, propionyl, pivaloyl, etc.), benzoyl, C _1-6 alkylsulfonyl (e.g., methanesulfonyl etc.), benzenesulfonyl, etc.), optionally halogenated C _1-6 alkoxycarbonyl group (e.g., Methoxycarbonyl, ethoxycarbonyl, trifluoromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, etc.), and C _1- that may be substituted by a phenyl group. ₆ alkoxycarbonyl group (e.g., benzyl Alkoxycarbonyl, etc.), aryl (e.g., phenyl, 1-naphthyl, _{C 6-10} aryl such as 2-naphthyl, etc.), aralkyl (e.g., benzyl, _{C 7-10} aralkyl phenethyl, preferably phenyl _{-C 1 4} alkyl, etc.), arylalkenyl (e.g., C _8-10 arylalkenyl cinnamyl etc., preferably phenyl -C _2-4 alkenyl, etc.), heterocyclic ( "optionally substituted heterocycle" as the substituent And the like, preferably pyridyl, more preferably 4-pyridyl and the like. These optional substituents may be substituted one to three times at substitutable positions.
Further, the “amino group” in the “optionally substituted amino group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” is an optionally substituted imidoyl group (for example, , C _1-6 alkylimidoyl (eg, formyl imidoyl, acetyl imidoyl, etc.), C _1-6 alkoxy imidoyl, C _1-6 alkylthioimidoyl, amidino, etc.), 1-2 C _1-6 It may be substituted with an amino group which may be substituted with an alkyl group. One or two of these optional substituents may be substituted at substitutable positions. Further, two substituents may form a cyclic amino group together with the nitrogen atom. In such a case, examples of the cyclic amino group include 1-azetidinyl, 1-pyrrolidinyl, piperidino, thiomorpholino, Morpholino, 1-piperazinyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, etc.), aralkyl (eg, benzyl, phenethyl and the like) C _7-10 aralkyl, etc.), aryl (e.g., phenyl, 1-naphthyl, _{2-C 6-10} may have an aryl, etc.) and 1-piperazinyl of naphthyl, 1-pyrrolyl, 1-imidazolyl, etc. And a 3 to 8 membered (preferably 5 to 6 membered) cyclic amino or the like can be used.

Examples of the alkylsulfinyl group in the “optionally substituted alkylsulfinyl group” as a substituent of the “optionally substituted aromatic homo or heterocycle” include methylsulfinyl, ethylsulfinyl, propylsulfinyl, and isopropylsulfinyl. And C _1-6 alkylsulfinyl such as butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, pentylsulfinyl and hexylsulfinyl. Here, as the substituent of the alkylsulfinyl, the same number of the same substituents as those in the above-mentioned “optionally substituted alkyl” as the substituent can be used.
As the "carboxyl group which may be esterified or amidated" as a substituent of the "aromatic homo- or heterocyclic ring which may be substituted", a carboxyl group, an alkoxycarbonyl, an aryloxycarbonyl, an aralkyloxy Carbonyl, carbamoyl, N-monosubstituted carbamoyl and N, N-disubstituted carbamoyl can be used.
Here, as the "alkoxycarbonyl", for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyl C _1-6 alkoxycarbonyl (lower alkoxycarbonyl) such as pentyloxycarbonyl and the like can be used, and among them, C _1-3 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl is preferable. The “lower alkoxycarbonyl” may have a substituent, and the substituent may be a hydroxyl group, an amino group which may be substituted [The amino group is, for example, 1 to 5 halogen atoms (eg, fluorine , Chlorine, bromine, iodine, etc.) and lower alkyl groups which may be substituted (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc.). Represents one or two substituents such as methyl, ethyl, etc.), an acyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl, pivaloyl, and benzoyl), a carboxyl group, and C _1-6 alkoxycarbonyl. You may have. ], A halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a nitro group, a cyano group, and a lower alkoxy group optionally substituted with 1 to 5 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (For example, C _1-6 alkoxy such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., preferably methoxy, ethoxy, etc.). It is preferable that these substituents are the same or different and are substituted with 1 or 2 to 3 (preferably 1 or 2).

Here, as the “aryloxycarbonyl”, for example, C _6-14 aryloxycarbonyl such as phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl, 1-phenanthoxycarbonyl and the like are preferable. The “aryloxycarbonyl” may have a substituent, and as the substituent, the same number of the same substituents as in the above “alkoxycarbonyl” as the substituent can be used.
Here, as the “aralkyloxycarbonyl”, for example, C _7-14 aralkyloxycarbonyl such as benzyloxycarbonyl, phenethyloxycarbonyl and the like (preferably C _6-10 aryl-C _1-4 alkoxy-carbonyl and the like) are preferable. The “aralkyloxycarbonyl” may have a substituent, and as the substituent, the same number of the same substituents as in the above “alkoxycarbonyl” as the substituent can be used.
Here, as the “N-monosubstituted carbamoyl”, for example, lower alkyl (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl and the like), lower alkenyl ( examples include vinyl, allyl, isopropenyl, propenyl, butenyl, pentenyl, _{C 2-6} alkenyl hexenyl, etc.), cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, _{C 3-6} cycloalkyl such as cyclohexyl, etc.), Aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl, 2-naphthyl, etc.), aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl, preferably phenyl-C _1-4 alkyl, etc.), arylalkenyl (e.g., _{C 8-10} Arirua of cinnamyl etc. Kenyir, preferably phenyl -C _2-4 alkenyl, etc.), it can be used heterocycles (such as those of the above substituents similar to the "heterocyclic ring" of the "heterocyclic ring which may be substituted", etc.) and the like . The lower alkyl, lower alkenyl, cycloalkyl, aryl, aralkyl, arylalkenyl, and heterocyclic ring may have a substituent, and the substituent may be a substituent in the above-mentioned `` alkoxycarbonyl '' as a substituent. A similar number of similar can be used.

Here, “N, N-disubstituted carbamoyl” means a carbamoyl group having two substituents on a nitrogen atom, and one example of the substituent is “N-monosubstituted carbamoyl” as the above-mentioned substituent. The same substituents as those in "carbamoyl" can be used. As the other examples, lower alkyl (eg, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like) can be used. Alkyl), C _3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _7-10 aralkyl (eg, benzyl, phenethyl, etc., preferably phenyl-C _1-4 alkyl, etc.) and the like. Can be used. In addition, two substituents may form a cyclic amino together with a nitrogen atom. In such a case, examples of the cyclic aminocarbamoyl include 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, Piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl and lower alkyl at the 4-position (eg, C _1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.), 1-pipe which may have aralkyl (eg, C _7-10 aralkyl such as benzyl, phenethyl and the like), aryl (eg, C _6-10 aryl such as phenyl, 1-naphthyl and 2-naphthyl) and the like; A 3- to 8-membered (preferably 5- to 6-membered) cyclic aminocarbonyl such as radinylcarbonyl can be used.
The substituents of the `` optionally substituted thiocarbamoyl group '' and the `` optionally substituted sulfamoyl group '' as the substituents of the `` optionally substituted aromatic homo- or heterocyclic ring '' include the above-mentioned substituents. "N-monosubstituted carbamoyl" and "N, N-disubstitution" in "carboxy group which may be esterified or amidated" as a substituent of "aromatic or heterocyclic ring which may be substituted" The same substituents as those for "carbamoyl" can be used.

As the “sulfonic acid-derived acyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring”, for example, the above-mentioned “N-monosubstituted carbamoyl” has one on a nitrogen atom substituent and the sulfonyl or the like can be used bound, but preferably, methanesulfonyl, may be used acyl such as C _1-6 alkylsulfonyl such as ethanesulfonyl.
The “carboxylic acid-derived acyl group” as a substituent of the “optionally substituted aromatic homo- or heterocyclic ring” includes a hydrogen atom or the above-mentioned “N-monosubstituted carbamoyl” on a nitrogen atom. A compound in which a carbonyl is bonded to a substituent having two or more substituents can be used. Preferably, an acyl such as C _1-6 alkanoyl such as formyl, acetyl, propionyl, and pivaloyl, and benzoyl can be used.
In the above formula, the “substituent” represented by R 1, R 2, R 3, R 4 and R 5 means the same number of the same substituents as the above-mentioned “optionally substituted aromatic homo- or heterocyclic”. Can be used. Preferably, a lower alkoxy group (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a lower alkyl group (eg, methyl, ethyl, propyl, etc.) C _1-6 alkyl, etc.), lower alkenyl group (eg, C _2-6 alkenyl such as vinyl, allyl, etc.), lower alkynyl group (eg, C _2-6 alkynyl such as ethynyl, propargyl, etc.), substituted An optionally substituted amino group, an optionally substituted hydroxyl group, a cyano group, an optionally substituted amidino group, a carboxy group, a lower alkoxycarbonyl group (eg, C _1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl and the like) ), An optionally substituted carbamoyl group (eg, a 5- or 6-membered monocyclic aromatic heterocyclic ring (eg, pyridinyl, etc.)) Conversion which may be C _1-6 alkyl group or an acyl group (e.g., formyl, C _2-6 alkanoyl, benzoyl, a C _1-6 alkoxycarbonyl which may be halogenated, an optionally halogenated C Carbamoyl group which may be substituted with _1-6 alkylsulfonyl, benzenesulfonyl, etc., 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, piperidinocarbonyl, morpholinocarbonyl, 1-piperazinylcarbonyl, etc.) And so on. Here, the “optionally substituted amino group”, “optionally substituted hydroxyl group”, and “optionally substituted amidino group” include the above-mentioned “optionally substituted aromatic group”. And the same as the `` optionally substituted amino group '', `` optionally substituted hydroxyl group '', and `` optionally substituted amidino group '' as substituents of it can.

As the “trifluoroacetyl compound” used in the present invention, for example, trifluoroacetyl chloride, trifluoroacetyl anhydride, trifluoroacetylimidazole and the like can be used.
As the "azide compound" used in the present invention, for example, sodium azide, diphenylphosphoryl azide, trioctyltin azide and the like can be used.

The salt of the compound used in the present invention is not particularly limited, but a pharmaceutically acceptable salt is preferable, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and a salt with an organic acid. And salts with basic or acidic amino acids. Preferable examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferred examples of the salt with an organic base include, for example, salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine, and the like. Preferable examples of the salt with an inorganic acid include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, Salts with p-toluenesulfonic acid and the like can be mentioned. Preferable examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine, and preferable examples of the salt with an acidic amino acid include, for example, salts with aspartic acid, glutamic acid, and the like. Can be
Preferable examples of compound (III) and compound (IV) include, for example, R1, R4 and R5 are hydrogen atoms, R2 is a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.) or hydrogen atom, and R3 is lower alkoxy. Groups (eg, C _1-6 alkoxy such as methoxy, ethoxy, propoxy, etc.) or a hydroxyl group. Among them, those in which R1, R2, R4 and R5 are hydrogen atoms and R3 is a hydroxyl group are preferred.

Next, the general method of the present invention will be described more specifically by way of examples, but the present invention is not limited thereto.
In the present invention, after adding a solvent to the compound represented by the above formula (I) or a salt thereof (hereinafter abbreviated as compound (I)), a trifluoroacetyl compound and an azide compound are added and stirred. As a result, a trifluoromethyltetrazole compound represented by the above formula (II) or a salt thereof (hereinafter abbreviated as compound (II)) is obtained.
The solvent used in the ring closure reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane, pentane and heptane. , Ethyl acetate, esters such as butyl acetate, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, methylene chloride, chloroform, aliphatic halogen hydrocarbons such as dichloroethane, methanol, ethanol, 1 Alcohols such as -propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpiperidone, dimethyl Sulfoxide, hexamethylphosphoric amide, dimethylimidazo Examples thereof include organic acids such as lydinone, formic acid, and acetic acid, and water, among which the above-mentioned aromatic hydrocarbons, ethers, and alcohols are preferable. These may be used alone or in combination of two or more at an appropriate ratio.
The amount of the solvent to be used in the ring closure reaction is 1 to 50 times by weight, and preferably 2 to 25 times by weight, relative to compound (I).
As the trifluoroacetyl compound used in the ring closure reaction, for example, trifluoroacetyl chloride, trifluoroacetylimidazole and the like are used, and among them, trifluoroacetylimidazole is preferable. Further, trifluoroacetylimidazole may be formed in the reaction system. The amount of the trifluoroacetyl compound to be used is 1 to 5 mol, preferably 1 to 1.5 mol, per 1 mol of compound (I).
As the azide compound used for the ring closure reaction, for example, sodium azide, diphenylphosphoryl azide, trioctyltin azide and the like are used, and among them, diphenylphosphoryl azide is preferable. The amount of the azide compound to be used is 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (I).
Regarding the order of adding the trifluoroacetyl compound and the azide compound in the ring closure reaction, any of them may be added first, but the trifluoroacetyl compound is preferably added first.
The reaction temperature in the ring closure reaction is usually 0 to 150 ° C, preferably 20 to 120 ° C. The reaction time in the ring closure reaction is usually 0.5 to 5 hours.

  In the method for isolating compound (II), each reaction solution is separated with water and an organic solvent, and the solution extracted with the organic solvent is concentrated. Thereafter, for the purpose of removing impurities, a hydrocarbon solvent is added to remove insolubles, and then the mother liquor is concentrated and isolated. Further, purification operations such as distillation and recrystallization may be performed as necessary. In the case of a crystalline compound, it is also possible to obtain the compound directly from the reaction solution by omitting the above liquid separation operation.

Compound (I) is synthesized by adding a solvent to various amine compounds, adding a base and a triphenylphosphine compound, and stirring.
The solvent used in the addition reaction is not particularly limited as long as it does not affect the reaction. Examples thereof include aromatic hydrocarbons such as benzene, toluene, and xylene; and aliphatic hydrocarbons such as hexane, pentane, and heptane. , Ethyl acetate, esters such as butyl acetate, ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran, methylene chloride, chloroform, aliphatic halogen hydrocarbons such as dichloroethane, methanol, ethanol, 1 Alcohols such as -propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpiperidone, dimethyl Sulfoxide, hexamethylphosphoric amide, dimethylimidazo Examples thereof include organic acids such as lydinone, formic acid, and acetic acid; water; and the above-mentioned aromatic hydrocarbons and ethers are preferable. These may be used alone or in combination of two or more at an appropriate ratio.
As the base used in the addition reaction, for example, alkali metal hydrides such as potassium hydride and sodium hydride, for example, lithium ethoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, carboxyl-tert-butoxide A metal alkoxide having 1 to 6 carbon atoms such as, for example, lithium hydroxide, potassium hydroxide, sodium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and the like; an inorganic base such as 1,4-diazabicyclo [2.2. 2] Octane (abbreviation: DABCO), triethylamine, diisopropylethylamine, tri (n-propyl) amine, tri (n-butyl) amine, 1,8-diazabicyclo [5.4.0] -7-undecene (abbreviation: DBU) ), Tetramethylethylenediamine, dimethyl Niline, 1,4-dimethylpiperazine, 1-methylpiperidine, 1-methylpyrrolidine, 4-dimethylaminopyridine, pyridine, diethylamine, cyclohexyldimethylamine, lutidine, γ-collidine, N, N-dimethylaniline, N-methylpiperidine And tertiary amines such as N-methylpyrrolidine and N-methylmorpholine. Of these, tertiary amines are preferred. The amount of the base to be used is 1 to 30 mol, preferably 1 to 15 mol, per 1 mol of the amine compound.
As the triphenylphosphine compound used in the addition reaction, for example, triphenylphosphine, dichlorotriphenylphospholane, dibromotriphenylphospholane and the like are used, and among them, dichlorotriphenylphospholane is preferable. Further, dichlorotriphenylphosphorane may be formed in the reaction system. The amount of the triphenylphosphine compound used is 1 to 10 mol, preferably 1 to 6 mol, per 1 mol of the amine compound.
Regarding the order of adding the base and the triphenylphosphine compound in the addition reaction, any of them may be added first, but preferably, the base is added first.
The reaction temperature in the addition reaction is usually 0 to 150 ° C, preferably 0 to 100 ° C. The reaction time in the addition reaction is usually 0.5 to 5 hours.

  In the method for isolating compound (I), insolubles are removed from each reaction solution by filtration, washed with an organic solvent, and then the filtrate is concentrated. Further, purification operations such as distillation and recrystallization may be performed as necessary. In the case of a crystalline compound, it is also possible to obtain the compound directly from the reaction solution by omitting the above liquid separation operation.

The compound or a salt thereof obtained by the production method of the present invention is useful, for example, as a raw material for producing a compound or a salt thereof used for treating or preventing a central nervous system disease. See, for example, Bioorganic & Medicinal Chemistry Letters (Bioorg. & Med. Chem. Lett.), 6, 1015, 1996, and Journal of Labeled Compounds and Radio Pharmaceuticals. (J. Labeled. Cpd. Radiopharm.), Vol. 43, p. 29, 2000, as an intermediate for producing an antiemetic, a compound represented by the above formula (IX) or a salt thereof (hereinafter, compound (IX) IX)) is useful.
Compound (IX) can be obtained by methylating the compound represented by the above formula (VIII) or a salt thereof (hereinafter abbreviated as compound (VIII)). The methylation reaction of compound (VIII) is carried out by using, for example, methyl iodide as a methylating agent. In this case, it has been found that sodium carbonate is particularly preferred as the base to be used and a high yield can be obtained. Specifically, after adding a solvent to compound (VIII), methyl iodide and sodium carbonate are added and stirred to produce compound (IX).
The solvent used in the methylation reaction is not particularly limited as long as it does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, and aliphatic hydrocarbons such as hexane, pentane and heptane. Hydrogens, ethyl acetate, esters such as butyl acetate, diethyl ether, diisopropyl ether, t-butyl methyl ether, ethers such as tetrahydrofuran, methylene chloride, chloroform, aliphatic halogen hydrocarbons such as dichloroethane, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, alcohols such as 2-methyl-1-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, amides such as N-methylpiperidone, Dimethyl sulfoxide, hexamethylphosphoramide, dimethylimi Examples thereof include organic acids such as dazolidinone, formic acid, and acetic acid, and water, among which the above-mentioned amides and alcohols are preferable. These may be used alone or in combination of two or more at an appropriate ratio.
The amount of the solvent to be used in the methylation reaction is 1 to 50 times by weight, and preferably 2 to 25 times by weight, relative to compound (VIII).
The amount of these methyl iodide and sodium carbonate to be used is 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (VIII).
Regarding the order of adding methyl iodide and sodium carbonate in the methylation reaction, any may be added first, but preferably, sodium carbonate is added first.
The reaction temperature in the methylation reaction is usually from 0 to 150C, preferably from 20C to 100C. The reaction time in the methylation reaction is usually 0.5 to 10 hours.
The compound (IX) is isolated by filtering off insolubles from each reaction solution, washing with an organic solvent, and concentrating the filtrate. Further, purification operations such as distillation and recrystallization may be performed as necessary. In the case of a crystalline compound, it is also possible to obtain the compound directly from the reaction solution by omitting the above liquid separation operation.
The compound (VIII) can be obtained by formylating the compound represented by the formula (VII) or a salt thereof (hereinafter, abbreviated as compound (VII)). The formylation reaction of compound (VII) is carried out by reacting hexamethylenetetramine in the presence of an acid catalyst. As the acid catalyst, trifluoroacetic acid is particularly preferred, and it has been found that a high yield can be obtained. Specifically, compound (VIII) is produced by adding hexamethylenetetramine and trifluoroacetic acid to compound (VII) and stirring.
A solvent may be used in the formylation reaction, and the solvent to be used is not particularly limited as long as it does not affect the reaction.For example, benzene, toluene, aromatic hydrocarbons such as xylene, hexane, Aliphatic hydrocarbons such as pentane and heptane; esters such as ethyl acetate and butyl acetate; ethers such as diethyl ether, diisopropyl ether, t-butyl methyl ether and tetrahydrofuran; and aliphatic halogens such as methylene chloride, chloroform and dichloroethane Hydrocarbons, alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol, N, N-dimethylformamide, N, N-dimethylacetamide, Amides such as N-methylpiperidone, dimethyl sulfoxide, hexamethylphos Examples thereof include organic acids such as holic amide, dimethylimidazolidinone, formic acid, and acetic acid, and water, among which the above-mentioned aromatic hydrocarbons, esters, and ethers are preferable. These may be used alone or in combination of two or more at an appropriate ratio.
The amount of hexamethylenetetramine to be used is 1 to 10 mol, preferably 1 to 5 mol, per 1 mol of compound (VII). The amount of trifluoroacetic acid to be used is 1-100 mol, preferably 1-10 mol, per 1 mol of compound (VII).
Regarding the order of adding hexamethylenetetramine and trifluoroacetic acid in the formylation reaction, any order may be added, but preferably, hexamethylenetetramine is added first.
The reaction temperature in the formylation reaction is usually 0 to 150 ° C, preferably 20 to 120 ° C. The reaction time in the formylation reaction is usually 1 to 48 hours, preferably 1 to 20 hours.
The compound (VIII) is isolated by filtering off insolubles from each reaction solution, washing with an organic solvent, and concentrating the filtrate. Further, purification operations such as distillation and recrystallization may be performed as necessary. In the case of a crystalline compound, it is also possible to obtain the compound directly from the reaction solution by omitting the above liquid separation operation.
Hereinafter, the present invention will be described in more detail with reference to Test Examples, Examples, and Reference Examples, but the present invention is not limited thereto.

Synthesis of N- (4-methoxyphenyl) triphenylphosphinimide 616 mg (5 mmol) of 4-methoxyaniline was dissolved in 25 mL of toluene. 1.518 g (15 mmol) of triethylamine and 2.499 g (7.5 mmol) of dichlorotriphenylphosphorane were added, and the mixture was stirred at room temperature for 1 hour. An additional 500 mg (1.5 mmol) of dichlorotriphenylphosphorane was added, and the mixture was further stirred for 1 hour. The precipitated crystals were removed by filtration and washed three times with 12 mL of toluene. The filtrate was concentrated under reduced pressure to obtain 2.400 g of N- (4-methoxyphenyl) triphenylphosphineimide as an orange oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 3.69 (s, 3H), 6.61 (dd, 2H), 6.72 (dd, 2H), 7.40-7.57 (m, 9H). , 7.64-7.77 (m, 6H).

Synthesis of N- (3-chloro-4-methoxyphenyl) triphenylphosphineimide 158 mg (1 mmol) of 3-chloro-4-methoxyaniline was dissolved in 3 mL of tetrahydrofuran. 303 mg (3 mmol) of triethylamine and 333 mg (1 mmol) of dichlorotriphenylphosphorane were added, and the mixture was stirred at room temperature for 1 hour. 167 mg (0.5 mmol) of dichlorotriphenylphosphorane was added, and the mixture was further stirred for 1 hour. The precipitated crystals were removed by filtration and washed three times with 2 mL of tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain 577 mg of N- (3-chloro-4-methoxyphenyl) triphenylphosphinimide as a purple oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 3.76 (s, 3H), 6.62 (s, 2H), 6.81 (s, 1H), 7.43-7.57 (m, 9H). , 7.64-7.76 (m, 6H).

Synthesis of N- (4-hydroxyphenyl) triphenylphosphine imide 1.091 g (10 mmol) of 4-aminophenol was dissolved in 40 mL of tetrahydrofuran. 12.143 g (120 mmol) of triethylamine and 9.996 g (30 mmol) of dichlorotriphenylphospholane were added, and the mixture was stirred at 50 ° C. for 1 hour. The precipitated crystals were collected by filtration and washed three times with 20 mL of tetrahydrofuran. Ethyl acetate (80 mL) and 2N sodium hydroxide (80 mL) were added to the crystals to separate them. The organic layer was washed three times with 40 mL of water. The organic layer was concentrated under reduced pressure to obtain 6.027 g of N- (4-hydroxyphenyl) triphenylphosphine imide as light brown crystals.
¹ H NMR (300 MHz, in DMSO-d ₆ ): δ 6.36 (d, 2H), 6.44 (d, 2H), 7.49-7.62 (m, 9H), 7.67-7. 74 (m, 6H), 8.32 (s, 1H).

Synthesis of N- (4-hydroxyphenyl) triphenylphosphine imide 4.68 g (18 mmol) of triphenylphosphine was dissolved in 32 mL of diethyl ether. Under an ice bath, 2.88 g (18 mmol) of bromine was added dropwise. The mixture was stirred under an ice bath for 15 minutes. The organic layer was concentrated under reduced pressure. 0.64 g (6 mmol) of 4-aminophenol and 7.28 g (72 mmol) of triethylamine were dissolved in 48 mL of tetrahydrofuran and added carefully. The mixture was heated to 50 ° C. and stirred for 1 hour. Under an ice bath, 150 mL of city water was added and stirred for 2 hours. The precipitated crystals were collected by filtration and washed three times with 50 mL of city water. After vacuum drying, 3.06 g of N- (4-hydroxyphenyl) triphenylphosphine imide as pale brown crystals was obtained.
¹ H NMR (300 MHz, in DMSO-d ₆ ): δ 6.36 (d, 2H), 6.44 (d, 2H), 7.49-7.62 (m, 9H), 7.67-7. 74 (m, 6H), 8.32 (s, 1H).

Synthesis of 1- (4-methoxyphenyl) -5- (trifluoromethyl) -1H-tetrazole 480 mg of N- (4-methoxyphenyl) triphenylphosphinimide was dissolved in 5 mL of toluene. 197 mg (1.2 mmol) of trifluoromethylacetylimidazole was added, and the mixture was stirred for 2 hours. 688 mg (2.5 mmol) of diphenylphosphoryl azide and 1 mL of ethanol were added, and the mixture was stirred at 100 ° C for 1 hour. 5 mL of 2N sodium hydroxide and 4 mL of ethanol were added, and the mixture was stirred at 100 ° C. for 1 hour. Toluene (10 mL) was added and the layers were separated, and the organic layer was washed sequentially with 10 mL of water, 10 mL of 1N hydrochloric acid, and 10 mL of water, and then concentrated under reduced pressure. Heptane (10 mL) was added to the residue, and the insoluble material was removed by filtration, followed by washing with heptane (5 mL) twice. The filtrate was concentrated under reduced pressure to obtain 170 mg of 1- (4-methoxyphenyl) -5- (trifluoromethyl) -1H-tetrazole as a pale orange oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 3.91 (s, 3H), 7.08 (d, 2H), 7.41 (d, 2H).

Synthesis of 1- (3-chloro-4-methoxyphenyl) -5- (trifluoromethyl) -1H-tetrazole 209 mg of N- (3-chloro-4-methoxyphenyl) triphenylphosphinimide was dissolved in 4 mL of tetrahydrofuran. 98 mg (0.6 mmol) of trifluoromethylacetylimidazole was added, and the mixture was stirred for 1 hour. 81 mg (1.25 mmol) of sodium azide was added, and the mixture was refluxed for 16 hours. 4 mL of 2N sodium hydroxide and 4 mL of ethyl acetate were added, and the mixture was separated. The organic layer was washed twice with 4 mL of water, and then concentrated under reduced pressure. 5 mL of heptane was added to the residue, and the insoluble material was removed by filtration, followed by washing with 2 mL of heptane twice. The filtrate was concentrated under reduced pressure to obtain 117 mg of 1- (3-chloro-4-methoxyphenyl) -5- (trifluoromethyl) -1H-tetrazole as an orange oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 4.02 (s, 3H), 7.11 (d, 1H), 7.38 (dd, 1H), 7.55 (d, 1H).

Synthesis of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole 6.027 g of N- (4-hydroxyphenyl) triphenylphosphineimide was dissolved in 100 mL of toluene. 1.97 g (12 mmol) of trifluoromethylacetylimidazole and 6.88 g (25 mmol) of diphenylphosphoryl azide were added, and the mixture was refluxed at 100 ° C. for 2 hours. 20 mL of ethanol was added to the reaction solution, and the mixture was stirred for 1 hour. 30 mL of ethanol and 50 mL of 2N sodium hydroxide were added to the reaction solution, and the mixture was stirred for 1 hour. 25 mL of water was added and the layers were separated. The aqueous layer was washed with 50 mL of toluene, and then 20 mL of 6N hydrochloric acid was added. After extracting twice with 50 mL of ethyl acetate, the organic layer was sequentially washed twice with 50 mL of 6N hydrochloric acid and 50 mL of water. The organic layer was concentrated under reduced pressure to obtain 2.634 g of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole as a brown oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 7.05 (d, 2H), 7.36 (d, 2H).

Synthesis of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole 0.19 g (2.8 mmol) of imidazole was suspended in 3 mL of toluene. It was dissolved by heating to 100 ° C. 0.29 g (1.4 mmol) of trifluoroacetic anhydride was carefully added dropwise, and the mixture was stirred at the same temperature for 1 hour. After cooling to room temperature, 17 mL of toluene was added to the reaction solution. 1.02 g of N- (4-hydroxyphenyl) triphenylphosphinimide was added. 0.43 g (1.6 mmol) of diphenylphosphoryl azide was added, and the mixture was stirred at 100 ° C. for 2 hours. 4 mL of ethanol was added, and the mixture was stirred at the same temperature for 1 hour. After cooling to room temperature, 6 mL of ethanol and 10 mL of 2N sodium hydroxide were added to the reaction solution, and the mixture was stirred for 3 hours. 50 mL of water was added and the layers were separated to obtain an aqueous layer. After the aqueous layer was washed with 10 mL of toluene, 4 mL of 6N hydrochloric acid was added. Extracted twice with 10 mL of ethyl acetate. The organic layer was successively washed twice with 10 mL of 6N hydrochloric acid and 10 mL of water. The organic layer was concentrated under reduced pressure to obtain 0.45 g of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole as a brown oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 7.05 (d, 2H), 7.36 (d, 2H).

Synthesis of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole 1.28 g (11.2 mmol) of trifluoroacetic acid was dissolved in 18 mL of toluene. 1.82 g (11.2 mmol) of N, N'-carbonyldiimidazole was added, and the mixture was stirred at room temperature for 1 hour. 82 mL of toluene was added. 3.72 g of N- (4-hydroxyphenyl) triphenylphosphinimide were added. It was dissolved by heating to 100 ° C. 1.55 g (5.6 mmol) of diphenylphosphoryl azide was added, and the mixture was stirred at 100 ° C. for 2 hours. 20 mL of ethanol was added and the mixture was stirred at the same temperature for 1 hour. After cooling to room temperature, 30 mL of ethanol and 50 mL of 2N sodium hydroxide were added to the reaction solution, and the mixture was stirred for 3 hours. The layers were separated to obtain an aqueous layer. After the aqueous layer was washed with 50 mL of toluene, 20 mL of 6N hydrochloric acid was added. Extracted twice with 50 mL of ethyl acetate. The organic layer was successively washed twice with 50 mL of water, 50 mL of 5% aqueous sodium bicarbonate, and 50 mL of water. The organic layer was concentrated under reduced pressure to obtain 1.18 g of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole as a brown oil.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 7.05 (d, 2H), 7.36 (d, 2H).

Test example 1

The reaction with 230 mg (1 mmol) of 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole and 421 mg (3 mmol) of hexamethylenetetramine was heated and stirred in trifluoroacetic acid or acetic acid to give 2 The conversion rate to -hydroxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde was determined by HPLC (ODS column, mobile phase: phosphate buffer / acetonitrile = 5/5, flow rate: 1 ml / min, detection: UV 254 nm) ).
Conversion in the system of trifluoroacetic acid: 87%
Conversion in acetic acid system: 46% (high decomposition)

Synthesis of 2-hydroxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde 1- (4-hydroxyphenyl) -5- (trifluoromethyl) -1H-tetrazole 19.6 g (80 mmol) and hexamethylene 16.8 g (120 mmol) of tetramine was suspended in 61.6 mL (800 mmol) of trifluoroacetic acid. The mixture was heated to 100 ° C. and stirred for 8 hours. After the reaction solution was concentrated under reduced pressure, 320 mL of ethyl acetate was added. Under ice cooling, 200 mL of 2N sodium hydroxide was carefully added. The layers were separated and the aqueous layer was extracted with 320 mL of ethyl acetate. The organic layers were combined, and washed sequentially twice with 160 mL of water, 160 mL of 1N hydrochloric acid, and 160 mL of water. After concentrating the organic layer under reduced pressure, toluene (130 mL) was added and suspended, and silica gel (21 g) was added. The mixture was heated to 80 ° C. and stirred for 1 hour. The silica gel was removed by filtration and washed twice with 120 mL of toluene. The filtrate was concentrated under reduced pressure. The concentrated residue was suspended in 50 mL of toluene and dissolved at 70 ° C. After cooling to room temperature to precipitate crystals, 100 mL of heptane was added and the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration and washed with 50 mL of a mixed solvent of toluene / heptane = 1: 4. The crystals were dried under reduced pressure to obtain 8.4 g of 2-hydroxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde as white yellow crystals.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 7.25 (d, 1 H), 7.64 (dd, 1 H), 7.75 (d, 1 H), 9.98 (s, 1 H), 11.39 (S, 1H).

Test example 2

Reaction of 8.40 g (32.5 mmol) of 2-hydroxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde and 5.54 g (39.0 mmol) of methyl iodide with sodium carbonate or potassium carbonate. The yield and area percentage of 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde were determined by HPLC (ODS column, mobile phase: phosphate buffer / acetonitrile = 5/5, flow rate: 1 ml / min, detection: UV 254 nm).
Yield in the system of sodium carbonate: 74% (area 85%)
Yield in the system of potassium carbonate: 65% (area 76%)

Synthesis of 2-methoxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde 8.40 g (32.5 mmol) of 2-hydroxy-5- (5-trifluoromethyltetrazol-1-yl) benzaldehyde was dissolved in dimethyl Dissolved in 84 mL of formamide. 5.17 g (48.8 mmol) of sodium carbonate and 5.54 g (39.0 mmol) of methyl iodide were added, and the mixture was stirred at 50 ° C. for 4 hours. Under an ice bath, 259 mL of water was added. Stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration and washed three times with 172 mL of water. The crystals were dried under reduced pressure to obtain 7.66 g of white crystals.
¹ H NMR (300 MHz, in CDCl ₃ ): δ 4.08 (s, 3H), 7.26 (d, 1H), 7.68 (dd, 1H), 7.96 (d, 1H), 10.50. (S, 1H).

As described above, according to the present invention, a trifluoromethyltetrazole ring compound can be easily produced under mild conditions using an aniline compound as a raw material.

Claims (10)

Formula (I)

[In the formula, A represents an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aromatic homo or heterocyclic ring. Wherein the compound represented by the formula (I) or a salt thereof is mixed with a trifluoroacetyl compound and an azide compound.

Wherein each symbol is as defined above. Or a salt thereof. The compound represented by the formula (I) or a salt thereof is represented by the formula (III)

[Wherein, R1, R2, R3, R4 and R5 are the same or different and each represent a hydrogen atom or a substituent. Wherein the compound represented by the formula (II) or a salt thereof is represented by the formula (IV)

Wherein each symbol is as defined above. The method according to claim 1, which is a compound represented by the formula: or a salt thereof. The compound represented by the formula (III) or a salt thereof is represented by the formula (V)

[Wherein X ₁ and X ₂ are the same or different and represent a chlorine atom or a bromine atom. The compound represented by the formula (VI)

[Wherein, R1, R2, R3, R4 and R5 are the same or different and each represent a hydrogen atom or a substituent. The method according to claim 2, which is a compound or a salt thereof obtained by reacting with a compound or a salt thereof represented by the formula:   3. The method according to claim 2, wherein R1, R2, R4 and R5 are hydrogen atoms and R3 is a hydroxyl group. Formula (VII) obtained in claim 4

Wherein a compound represented by the formula (I) or a salt thereof is subjected to a formylation reaction:

A method for producing a compound represented by the formula or a salt thereof. Formula (VII)

Reacting a compound represented by the formula or a salt thereof with hexamethylenetetramine in the presence of trifluoroacetic acid,

A method for producing a compound represented by the formula or a salt thereof. Formula (VIII)

Reacting a compound represented by the formula or a salt thereof with methyl iodide in the presence of sodium carbonate,

A method for producing a compound represented by the formula or a salt thereof. Expression (X)

[Wherein, X represents a halogen atom. Or a salt thereof.   9. The compound according to claim 8, wherein X is a chlorine atom, or a salt thereof. Formula (XI)

Or a salt thereof.