Stable vinamidinium salt and nitrogen-containing heterocyclic ring synthesis using the same

Disclosed is a vinamidinium salt represented by the formula (I):[wherein R1 represents a hydrogen atom, a halogen atom, an optionally substituted hydrocarbon group or the like; R2 and R3 are the same or different and each represents a lower alkyl group, or alternatively R2 and R3 may combine together to form a ring; R4 and R5 are the same or different and each represents a lower alkyl group, or alternatively R4 and R5 may combine together to form a ring; X and Y are the same or different and each represents a bromine atom or a chlorine atom; n represents a number of not less than 2; and m represents 0 or n], and methods for synthesizing a heterocyclic ring compound using the salt.

TECHNICAL FIELD

The present invention relates to a stable vinamidinium salt, crystals thereof, an acetic acid solution thereof, and a method for synthesizing a nitrogen-containing heterocyclic ring using them.

BACKGROUND ART

In the construction of an aromatic ring such as a benzene ring, a quinoline ring, a pyridine ring, a pyrrole ring, a pyrazole ring, or a pyrimidine ring having substituent(s), a method utilizing a vinamidinium salt has been known and, currently, its usefulness has been reevaluated in many reports (see, e.g. Patent Documents 1-3 and non-Patent Documents 1-6, and 9). Among them, the method is carried out industrially as a pyridine ring construction reaction in a synthesis step of Etoricoxib which is a COX-2 inhibitor (see, non-Patent Document 6).

However, when using the vinamidinium salt industrially, there is a difficult point that isolated crystals thereof have hygroscopicity and therefore, cause degradation by deliquescing. Crystals of a halogen anion salt having a counteranion such as Cl−are said to have particularly strong hygroscopicity and therefore, it is problematic to deal with the crystals by isolating them in a larger scale production (see, non-Patent Document 12).

Then, it seems that crystals known from old, for example, crystals of ClO4−salt were used at first. However, as a result of safety evaluation, it has become apparent that the crystals have significantly explosive properties (see, non-Patent Document 7) and therefore, a BF4−salt is now used (see, Patent Document 2). However, there is a problem that the BF4−salt corrodes a glass container in case of carrying out a heating reaction.

DISCLOSURE OF THE INVENTION

Problem To Be Solved By The Invention

Objectives of the present invention are to provide a vinamidinium salt which can be used as a universal reagent useful for the synthesis of various nitrogen-containing heterocyclic aromatic rings having substituent(s), has excellent storage stability and reaction selectivity, is free from corrosivity to glass, and can be produced inexpensively; an acetic acid solution thereof; and a process for constructing a nitrogen-containing heterocyclic aromatic ring such as a quinoline ring, a pyridine ring, a pyrrole ring, a pyrazole ring, or a pyrimidine ring using them.

Means For Solving The Problem

With respect to a method for synthesizing a compound having a substituted quinoline skeleton as a candidate compound for medicine, the present inventors have studied the construction of a quinoline skeleton using a vinamidinium salt intensively and have found that most excellent reaction selectivity can be obtained when using the salt having Cl−as a counteranion. They have further studied intensively and have succeeded in obtaining crystals of a vinamidinium salt having a halogen anion, whose valency number has not ever been known, in the stable form. In addition to this, they have found that an acetic acid solution of the vinamidinium salt having a halogen anion has excellent storage stability. Thus the present invention has been completed.

That is, the present invention provides:(1) A compound represented by the formula (I):

wherein R1represents a hydrogen atom, a halogen atom, a nitro group, a nitroso group, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group, an optionally substituted carbamoyl group, or an optionally substituted sulfonyl group,R2and R3are the same or different and each represents a lower alkyl group, or R2and R3may combine together to form a ring,R4and R5are the same or different and each represents a lower alkyl group, or R4and R5may combine together to form a ring,X and Y are the same or different and each represents a bromine atom or a chlorine atom,n represents a number of 2 or more, andm represents 0 to n;(2) The compound according to the above (1), wherein R1is a halogen atom, a lower alkyl group substituted by N,N-di-lower alkyl-imino group, or a C6-C14aryl group;(3) The compound according to the above (1), wherein R1is a lower alkyl group substituted by N,N-di-lower alkyl-imino group;(4) The compound according to the above (1), wherein R1is a dimethyliminomethyl group;(5) The compound according to the above (1), wherein each of R2, R3, R4, and R5is a lower alkyl group;(6) The compound according to the above (1), wherein n is 2 or 3;(7) The compound according to the above (1) to (6), the following (9) or (10), wherein X and Y are a chlorine atom;(8) The compound according to the above (1) to (6), the following (9) or (10), wherein X and Y are a bromine atom;(9) The compound according to the above (1), wherein R1is a dimethyliminomethyl group and each of R2, R3, R4, and R5is a C1-C6alkyl group;(10) The compound according to the above (1), wherein R1is a dimethyliminomethyl group, each of R2, R3, R4, and R5is a methyl group and n is 3;(11) The compound according to the above (1) to (10), which is isolated;(12) The compound according to the above (1) to (10), which is in a solid state;(13) The compound according to the above (1) to (10), which is a crystalline compound;(14) An acetic acid solution of the compound according to the above (1) to (10);(15) A compound represented by the formula (I):

wherein R1represents a hydrogen atom, a halogen atom, a nitro group, a nitroso group, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group, an optionally substituted carbamoyl group or an optionally substituted sulfonyl group,R2and R3are the same or different and each represents a lower alkyl group, or R2and R3may combine together to form a ring,R4and R5are the same or different and each represents a lower alkyl group, or R4and R5may combine together to form a ring,X and Y are the same or different and each represents a bromine atom or a chlorine atom,n represents 3 when R1is a dimethyliminomethyl group, and otherwise n represents 2 or more; andm represents 0 to n;(16) An acetic acid solution containing a compound represented by the formula (I′):

wherein R1′represents a hydrogen atom, a halogen atom, a nitro group, a nitroso group, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group, an optionally substituted carbamoyl group, or an optionally substituted sulfonyl group,R2′and R3′are the same or different and each represents a lower alkyl group, or R2′and R3′may combine together to form a ring,R4′and R5′are the same or different and each represents a lower alkyl group, or R4′and R5′may combine together to form a ring,X′−and Y′−are the same or different and each represents an anion,n′ represents a number of 1 or more, andm′ represents 0 to n′;(17) The acetic acid solution according to the above (16), wherein X′ and Y′ are the same or different and each represents a bromine atom or a chlorine atom;(18) The acetic acid solution according to the above (16), wherein X′ and Y′ are a chlorine atom;(19) The acetic acid solution according to the above (16), wherein X′ and Y′ are a bromine atom;(20) A process for producing a compound represented by the formula (III):

wherein ring A is as defined below, R1is the same as R1in the above (1) and R6, R7, R8, and R9are as defined below, or a salt thereof, which comprises reacting the compound according to the above (1) with a compound represented by the formula (II):

wherein ring A represents a hydrocarbon ring or a heterocyclic ring wherein the carbon atom to which the amino group in the formula (II) is attached has a double bond, R6, R7, R8and R9are the same or different and each represents a hydrogen atom or a substituent, or R6and R7, R7and R8, or R8and R9together with the adjacent atom may form a 5- to 8-membered ring;(21) A process for producing a compound represented by the formula (III′):

wherein ring A is as defined below, R1′is the same R1′in the above (16), and R6, R7, R8and R9are as defined below, or a salt thereof, which comprises reacting an acetic acid solution of the compound according to the above (16) with a compound represented by the formula (II):

wherein ring A represents a hydrocarbon ring or a heterocyclic ring wherein the carbon atom to which the amino group in the formula (II) is attached has a double bond, R6, R7, R8and R9are the same or different and each represents a hydrogen atom or a substituent, or R6and R7, R7and R8, or R8and R9together with the adjacent atom may form a 5- to 8-membered ring;(22) A process for producing a compound represented by the formula (V):

wherein R1is the same as R1in the above (1), and R10and ring B are as defined below, or a salt thereof, which comprises reacting the compound according to the above (1) with a compound represented by the formula (IV):

wherein R10represents a hydrogen atom or a substituent, and ring B represents an optionally substituted benzene ring; and(23) A process for producing a compound represented by the formula (V′):

wherein R1′is the same as R1′in the above (16), and R10and ring B are as defined below, or a salt thereof, which comprises reacting an acetic acid solution of the compound according to the above (16) with a compound represented by the formula (IV):

wherein R10and ring B are the same as R10and ring B in the above (22).

BEST MODE FOR CARRYING OUT THE INVENTION

In the vinamidinium salt represented by the above formula (I) or (I′) of the present invention, R1and R1′represent a hydrogen atom, a halogen atom, a nitro group, a nitroso group, a cyano group, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an optionally substituted hydroxy group, an optionally substituted amino group, an optionally substituted mercapto group, an optionally substituted acyl group, an optionally substituted carbamoyl group or an optionally substituted sulfonyl group.

As used herein, the lower refers to a group having 1 to 6 of carbon atoms, preferably a group having 1 to 4 of carbon atoms.

Examples of the hydrocarbon group of the “optionally substituted hydrocarbon group” represented by R1and R1′include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and an aralkyl group.

Examples of the “alkynyl group” include a C2-6alkynyl group such as ethynyl, 2-propynyl, butynyl, and 3-hexynyl.

Examples of the “cycloalkyl group” include a C3-6cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

Examples of the “aryl group” include a C6-10aryl group such as phenyl, and naphthyl.

Examples of the “aralkyl group” include a C7-10aralkyl group such as benzyl, and phenethyl.

The heterocyclic group of the “optionally substituted heterocyclic group” represented by R1and R1′represents an aromatic heterocyclic group or a non-aromatic heterocyclic group.

Examples of the “non-aromatic heterocyclic group” include a 3- to 8-membered saturated or unsaturated non-aromatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, 3-hexahydrocyclopenta[c]pyrrolyl, homopiperidyl, and homopiperazyl, or a non-aromatic heterocyclic group in which a part or all of the double bonds in the above-described aromatic monocyclic heterocyclic group or aromatic fused heterocyclic group are saturated such as dihydropyridyl, dihydropyrimidyl, 1,2,3,4-tetrahydroquinolyl, and 1,2,3,4-tetrahydroisoquinolyl.

Examples of the “substituent” of “an optionally substituted heterocyclic group” represented by R1and R1′and the number of such substituents include the same group and number as those of the above-described “optionally substituted hydrocarbon group” represented by R1and R1′.

Examples of the substituent of “an optionally substituted hydroxy group” represented by R1and R1′include an optionally substituted hydrocarbon group. Examples of the “optionally substituted hydrocarbon group” include the same group as the above-described “optionally substituted hydrocarbon group” represented by R1and R1′.

Examples of the substituent of “an optionally substituted amino group” represented by R1and R1′include an optionally substituted hydrocarbon group, an optionally substituted C1-6alkyl-carbonyl group (e.g. acetyl), an optionally substituted C6-14aryl-carbonyl group (e.g. benzoyl, and naphthoyl), an optionally substituted C1-6alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl), an optionally substituted C1-6alkyl-sulfonyl group (e.g. methylsulfonyl, and ethylsulfonyl), an optionally substituted C6-14aryl-sulfonyl group (e.g. phenylsulfonyl, 2-naphthylsulfonyl, and 1-naphthylsulfonyl), and the amino group may be mono- or di-substituted by these substituents. Examples of the “optionally substituted hydrocarbon group” include the same group as the above-described “optionally substituted hydrocarbon group” represented by R1and R1′. Examples of the substituent and the number of the substituents of “an optionally substituted C1-6alkyl-carbonyl group”, “an optionally substituted C6-14aryl-carbonyl group”, “an optionally substituted C1-6alkoxy-carbonyl group”, “an optionally substituted C1-6alkyl-sulfonyl group” and “an optionally substituted C6-14aryl-sulfonyl group” include the same group and number as those of the above-described “optionally substituted hydrocarbon group” represented by R1and R1′.

Examples of the substituent of “an optionally substituted mercapto group” represented by R1and R1′include an optionally substituted hydrocarbon group. Examples of the “optionally substituted hydrocarbon group” include the same group as the above-described “optionally substituted hydrocarbon group” represented by R1and R1′.

Examples of the substituent of “an optionally substituted acyl group” represented by R1and R1′include an optionally substituted hydrocarbon group, and an optionally substituted hydroxy group. Examples of the “optionally substituted hydrocarbon group” include the same group as the above-described “optionally substituted hydrocarbon group” represented by R1and R1′, and examples of the “optionally substituted hydroxy group” include the substituted hydroxy group in the above-described “optionally substituted hydroxy group” represented by R1and R1′.

Examples of the substituent of “an optionally substituted carbamoyl group” represented by R1and R1′include an optionally substituted hydrocarbon group. Examples of the “optionally substituted hydrocarbon group” include the same group as the above-described “optionally substituted hydrocarbon group” represented by R1and R1′and the hydrocarbon group may be mono- or di-substituted by these substituents.

Examples of the substituent of “an optionally substituted sulfonyl group” represented by R1and R1′include an optionally substituted hydrocarbon group. Examples of the “optionally substituted hydrocarbon group” include the same group as the above-described “optionally substituted hydrocarbon group” represented by R1and R1′.

R1and R1′are preferably a hydrogen atom, a halogen atom, a nitro group, a nitroso group, a cyano group, an optionally substituted hydrocarbon group, and an optionally substituted hydroxy group. In particular, a halogen atom, a nitro group, a cyano group, and an optionally substituted hydrocarbon group are preferred. Examples of the optionally substituted hydrocarbon group include an optionally substituted C1-6alkyl group (preferably, a lower alkyl group substituted by N,N-di-lower alkyl-imino group), and an optionally substituted C6-14aryl group (preferably, a C6-10aryl group). In particular, an optionally substituted methyl and an optionally substituted phenyl are preferred. Among them, an optionally substituted methyl is preferred. Examples of the substituent of “an optionally substituted methyl” are preferably a dimethylimino group. Preferred examples of R1and R1′include a dimethyliminomethyl group, i.e., a methyl group having a dimethylimino group as a substituent.

In the vinamidinium salt represented by the above formula (I) of the present invention, n represents a number of 2 or more. The number of 2 or more represented by n is preferably 2 to 5. Among them, n is preferably 2 to 3.

In the vinamidinium salt represented by the above formula (I′) of the present invention, n represents a number of 1 or more. The number of 1 or more represented by n is preferably 1 to 5. Among them, n is preferably 1 to 3.

R2and R3or R2′and R3′are the same or different and each represents a lower alkyl group, or R2and R3or R2′and R3′may combine together to form a ring.

R2and R3or R2′and R3′may combine together to form a ring and examples of the ring include an aromatic heterocyclic group and a non-aromatic heterocyclic group.

Examples of the non-aromatic heterocyclic group include a 5- or 6-membered monocyclic non-aromatic heterocyclic group and a fused non-aromatic heterocyclic group containing 1 to 4 nitrogen atoms as ring-constituting atoms or a 5- to 6-membered monocyclic non-aromatic heterocyclic group and a fused non-aromatic heterocyclic group containing 1 to 4 heteroatoms selected from an oxygen atom and a sulfur atom in addition to carbon and nitrogen atoms. Examples of the fused aromatic heterocyclic group include those wherein the above 5- to 6-membered monocyclic non-aromatic heterocyclic group is fused to one or two rings such as a 5- or 6-membered ring containing 1 to 2 nitrogen atoms, a 5-membered ring containing one sulfur atom and a benzene ring.

The non-aromatic heterocyclic group is preferably a 5- to 6-membered monocyclic non-aromatic heterocyclic group. Among them, piperidine is preferred.

Preferred examples of R2and R3or R2′and R3′include a C1-C6alkyl. Among them, for example, a methyl group is preferred.

R4and R5or R4′and R5′are the same or different and each represents a lower alkyl group, or R4and R5or R4′and R5′may combine together to form a ring.

R4and R5or R4′and R5′may combine together to form a ring and examples of the ring include an aromatic heterocyclic group or a non-aromatic heterocyclic group.

Examples of the non-aromatic heterocyclic group include a 5- to 7-membered monocyclic non-aromatic heterocyclic group and a fused non-aromatic heterocyclic group having 1 to 5 nitrogen atoms as a ring-constituting atom, or a 5- or 7-membered monocyclic non-aromatic heterocyclic group and a fused non-aromatic heterocyclic group having 1 to 4 heteroatoms selected from an oxygen atom or a sulfur atom in addition to carbon and nitrogen atoms. Examples of the fused non-aromatic heterocyclic group include those wherein the above 5- to 7-membered monocyclic non-aromatic heterocyclic group is fused to one or two rings such as a 5- or 6-membered ring containing 1 to 2 nitrogen atoms, a 5-membered ring containing one sulfur atom and a benzene ring.

The non-aromatic heterocyclic group is preferably a 5- to 7-membered monocyclic non-aromatic heterocyclic group. Among them, piperidine is preferred.

Preferred examples of R4and R5or R4′and R5′include a C1-C6alkyl. Among them, for example, a methyl group is preferred.

Specific examples of the vinamidinium salt represented by the formula (I) include 3-(dimethylimino)-2-[(dimethylimino)methyl]-N,N-dimethyl-1-propen-1-aminium trichloride.

R6, R7, R8and R9are the same or different and each represents a hydrogen atom or a substituent, or R6and R7, R7and R8, or R8and R9may combine together to form a 5- to 8-membered ring.

R10represents a hydrogen atom or a substituent;ring A represents a hydrocarbon ring or a heterocyclic ring; andring B represents a benzene ring having substituent(s).

Examples of the “hydrocarbon ring” represented by ring A include an optionally substituted cycloalkyl group wherein the carbon atom to which the amino group in the formula (II) is attached has a double bond, and an optionally substituted C6-C14aryl group. Examples of the “heterocyclic ring” represented by ring A include an optionally substituted heterocyclic group. Preferred examples of ring A include a phenyl group.

Also, examples of the substituent in ring B include 1 to 5, preferably, 1 to 3 substituents selected from the group consisting of the above (1) to (55).

Examples of the 5- to 8-membered ring formed by R6and R7, R7and R8, or R8and R9together with the adjacent atom include a C3-C6cycloalkyl group, a C6-C14aryl group, and a heterocyclic group. Examples of the preferred group of R6, R7, R8and R9include a hydrogen atom, or an optionally substituted C1-6alkyl-carbonylamino group (e.g. acetylamino), an optionally substituted C6-14aryl-carbonylamino group (e.g. benzoylamino, and naphthoylamino). Among them, an optionally substituted C6-14aryl-carbonylamino group (e.g. benzoylamino, and naphthoylamino) is preferred. Examples of the preferred group of R10include a methyl group.

The definition of each symbol used herein will be described in detail below.

As used herein, examples of the “halogen” include fluorine, chlorine, bromine, and iodine.

As used herein, examples of the “C2-C6alkynyl group” include ethynyl, prop-2-yn-1-yl, pent-4-yn-1-yl, and hex-5-yn-1-yl.

As used herein, examples of the “C3-C6cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, examples of the “C6-C14aryl group” include phenyl, naphthyl (e.g. 1-naphthyl, 2-naphthyl), anthryl, and phenanthryl, preferably phenyl or naphthyl, and more preferably phenyl.

As used herein, examples of the “optionally halogenated C1-C6alkyl group” include the above “C1-C6alkyl group” which may be substituted by 1 to 5 “halogens” as described above. Examples thereof include methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, and trifluoromethyl.

As used herein, examples of the “optionally halogenated C1-C6alkoxy group” include the above “C1-C6alkoxy group” which may be substituted by 1 to 5 “halogens” as described above. Examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, trifluoromethoxy, and 2-fluoroethoxy.

As used herein, examples of the “heterocyclic group” include a 4- to 14-membered (preferably, 5- to 10-membered) (monocyclic, bicyclic or tricyclic) heterocyclic group containing one to four of 1 or 2 kinds of heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atom(s) as a ring-constituting atom, preferably (i) a 5- to 14-membered (preferably, 5- to 10-membered) aromatic heterocyclic group, and (ii) a 4- to 10-membered (preferably, 5- to 10-membered) non-aromatic heterocyclic group, unless otherwise noted.

As used herein, examples of the “C6-C14aryloxy group” include phenoxy, 1-naphthyloxy, and 2-naphthyloxy.

As used herein, examples of the “C7-C16aralkyloxy group” include benzyloxy, and phenetyloxy.

As used herein, examples of the “heterocyclic-oxy group” include a heterocyclic-oxy group wherein the heterocyclic moiety is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing one to four of 1 to 2 kinds of heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atom(s) as a ring-constituting atom. Suitable examples of the “heterocyclic-oxy group” include tetrahydrofuranyloxy (e.g. tetrahydrofuran-3-yloxy), tetrahydropyranyloxy (e.g. tetrahydropyran-4-yloxy), and piperidinyloxy (e.g. piperidin-4-yloxy).

As used herein, examples of the “heterocyclic-C1-C6alkyloxy group” include a heterocyclic-(C1-C6) alkyloxy group wherein the heterocyclic moiety is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing one to four of 1 or 2 kinds of heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atom(s) as a ring-constituting atom. Suitable examples of the “heterocyclic-C1-C6alkyloxy group” include tetrahydrofuranylmethoxy (e.g. tetrahydrofuran-3-ylmethoxy), tetrahydropyranylmethoxy (e.g. tetrahydropyran-4-ylmethoxy), and piperidinylmethoxy (e.g. piperidin-4-ylmethoxy).

As used herein, examples of the “di(C1-C6) alkylamino group” include an amino group di-substituted by the above “C1-C6alkyl group”. Examples thereof include dimethylamino, diethylamino, and N-ethyl-N-methylamino.

As used herein, examples of the “C6-C14arylamino group” include an amino group mono-substituted by the above “C6-C14aryl group”. Examples thereof include phenylamino, 1-naphthylamino, and 2-naphthylamino.

As used herein, examples of the “di(C6-C14) arylamino group” include an amino group di-substituted by the above “C6-C14aryl group”. Examples thereof include diphenylamino, and dinaphthylamino.

As used herein, examples of the “C7-C16aralkylamino group” include an amino group mono-substituted by the above “C7-C16aralkyl group”. Examples thereof include benzylamino, and phenethylamino.

As used herein, examples of the “di(C7-C16) aralkylamino group” include an amino group di-substituted by the above “C7-C16aralkyl group”. Examples thereof include dibenzylamino, and diphenethylamino.

As used herein, examples of the “N—(C1-C6) alkyl-N—(C6-C14) arylamino group” include an amino group substituted by the above “C1-C6alkyl group” and the above “C6-C14aryl group”. Examples thereof include N-methyl-N-phenylamino, and N-ethyl-N-phenylamino.

As used herein, examples of the “N—(C1-C6) alkyl-N—(C7-C16aralkylamino group” include an amino group substituted by the above “C1-C6alkyl group” and the above “C7-C16aralkyl group”. Examples thereof include N-methyl-N-benzylamino, and N-ethyl-N-benzylamino.

As used herein, examples of the “optionally esterified carboxy group” include a carboxy group, a C1-C6alkoxy-carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl), a C6-C14aryloxy-carbonyl group (e.g. phenoxycarbonyl), a C7-C16aralkyloxy-carbonyl group (e.g. benzyloxycarbonyl, and phenethyloxycarbonyl).

As used herein, examples of the “C3-C10cycloalkyl-carbonyl group” include cyclopentylcarbonyl, cyclohexylcarbonyl, and adamantylcarbonyl.

As used herein, examples of the “C6-C14aryl-carbonyl group” include benzoyl, 1-naphthoyl, and 2-naphthoyl.

As used herein, examples of the “C7-C16aralkyl-carbonyl group” include phenylacetyl, and 3-phenylpropanoyl.

As used herein, examples of the “aC1-C6lkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and tert-butoxycarbonyl.

As used herein, examples of the “C6-C14aryloxy-carbonyl group” include phenoxycarbonyl, 1-naphthyloxycarbonyl, and 2-naphthyloxycarbonyl.

As used herein, examples of the “C7-C16aralkyloxy-carbonyl group” include benzyloxycarbonyl, and phenethyloxycarbonyl.

As used herein, examples of the “heterocyclic-carbonyl group” include those wherein the heterocyclic moiety is a 5- or 6-membered aromatic or non-aromatic heterocyclic ring containing one to four of 1 or 2 kinds of heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom in addition to carbon atom(s) as a ring-constituting atom. Suitable examples of the “heterocyclic-carbonyl group” include 1-pyrrolidinylcarbonyl, piperidinocarbonyl, 1-piperadinylcarbonyl, morpholinocarbonyl, and thiomorpholinocarbonyl.

As used herein, examples of the “thiocarbamoyl group” include a thiocarbamoyl group mono-substituted by the above “C1-C6alkyl group”. Examples thereof include methylthiocarbamoyl, and ethylthiocarbamoyl.

As used herein, examples of the “C1-C6alkyl-carbamoyl group” include a carbamoyl group mono-substituted by the above “C1-C6alkyl group”. Examples thereof include methylcarbamoyl, and ethylcarbamoyl.

As used herein, examples of the “di(C1-C6) alkyl-carbamoyl group” include a carbamoyl group di-substituted by the above “C1-C6alkyl group”. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

As used herein, examples of the “C6-C14aryl-carbamoyl group” include a carbamoyl group mono-substituted by the above “C6-C14aryl group”. Examples thereof include phenylcarbamoyl, 1-naphthylcarbamoyl, and 2-naphthylcarbamoyl.

As used herein, examples of the “di(C6-C14) aryl-carbamoyl group” include a carbamoyl group di-substituted by the above “C6-C14aryl group”. Examples thereof include diphenylcarbamoyl, and dinaphthylcarbamoyl.

As used herein, examples of the “C1-C6alkylsulfamoyl group” include a sulfamoyl group mono-substituted by the above “C1-C6alkyl group”. Examples thereof include methylsulfamoyl, and ethylsulfamoyl.

As used herein, examples of the “di(C1-C6) alkylsulfamoyl group” include a sulfamoyl group di-substituted by the above “C1-C6alkyl group”. Examples thereof include dimethylsulfamoyl, diethylsulfamoyl, and N-ethyl-N-methylsulfamoyl.

As used herein, examples of the “C6-C14arylsulfamoyl group” include a sulfamoyl group mono-substituted by the above “C6-C14aryl group”. Examples thereof include phenylsulfamoyl, 1-napthylsulfamoyl, and 2-napthylsulfamoyl.

As used herein, examples of the “di(C6-C14) arylsulfamoyl group” include a sulfamoyl group di-substituted by the above “C6-C14aryl group”. Examples thereof include diphenylsulfamoyl, and dinaphthylsulfamoyl.

As used herein, examples of the “hydroxy-C1-C6alkyl group” include hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl, and 1-hydroxy-1-methylethyl.

As used herein, examples of the “C1-C6alkoxy-C1-C6alkyl group” include methoxymethyl, 2-methoxyethyl, 1-methoxyethyl, ethoxymethyl, and 2-ethoxyethyl.

Crystals of the trivalent vinamidinium salt having halogen anions of the present invention are free from hygroscopicity and deliquescent nature, and hence they are stable and are excellent in storage stability. Therefore, the salt is characterized in that it can be produced industrially.

In addition, specific examples of the vinamidinium salt represented by the formula (I′) include 2-dimethylaminomethylene-1,3-bis(dimethyliminio)propane dichloride. An acetic acid solution of the vinamidinium salt represented by the formula (I′) is also characterized in that it is excellent in storage stability.

Further, as seen from the results of Comparative Example 1 hereinafter, the vinamidinium salt having halogen anions of the present invention has very high reaction selectivity in the construction reaction of quinoline skeleton and the like as compared with the reaction using a salt such as PF6salt, BF4salt or ClO4salt.

The vinamidinium salt represented by the formula (I) can be produced, for example, by the following process.

wherein R11represents a chlorine atom or a bromine atom, when R1is a dimethyliminomethyl group, otherwise it is the same as R1, DMF represents N,N-dimethylformamide, and the other symbols are as defined above.

If the compound represented by the formula (VI) is commercially available, a commercially available product can be used as it is. Alternatively, the compound represented by the formula (VI) can be produced by a per se known method or a modification thereof.

Usually, phosphorus oxychloride (POCl3), oxalyl chloride ((COCl)2) or thionyl chloride (SOCl2) can be used in an amount of about 0.1 to 100 mol, preferably, about 1 to 10 mol per mol of the compound represented by the formula (VI).

N,N-dimethylformamide (DMF) is usually used in an amount of about 0.1 to 100 mol, preferably about 1 to 10 mol per mole of the compound represented by the formula (VI).

The reaction temperature is usually about −70 to 200° C., preferably, about 0 to 150° C.

The reaction time is usually about 0.5 hour to 1 week, preferably, about 0.5 to 24 hours.

The compound represented by the formula (I) thus obtained can be isolated from a reaction mixture and purified by a per se known separation means (e.g. concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, re-extraction, and chromatography). In particular, crystallization is preferably used for isolation of the compound represented by the formula (I).

The compound represented by the formula (I) can be obtained by carrying out an “acid treatment” during the reaction or at an isolation stage of the product. The “acid treatment” is preferably carried out at the isolation stage of the compound. Specifically, the “acid treatment” is carried out by addition of, for example, an enough amount of hydrogen chloride or hydrogen bromide. Hydrogen chloride or hydrogen bromide used may be in a gaseous state or a solution state.

The enough amount used herein means an amount enough for protonation or cationization of all groups present in the compound represented by the formula (I) which can be protonated or cationized.

The crystallization is preferably carried out under the following conditions.

The crystallization temperature is usually about −70 to 100° C., preferably, about 0 to 40° C.

The crystallization time is usually about 0.5 to 48 hours, preferably, about 0.5 to 24 hours.

Crystals obtained by the crystallization can be isolated by carrying out filtration and drying. Since an excess amount of the acid adheres to wet crystals obtained by filtration, aeration-drying with nitrogen or argon gas of low humidity is carried out to volatilize the acid. The dew point of nitrogen or argon gas for using aeration-drying is preferably −40° C. or lower, more preferably, −60° C. or lower.

Hereinafter, synthetic methods of quinoline derivatives using the vinamidinium salt of the present invention will be explained.

1. Synthetic Method of Substituted Quinoline Derivative

(a) A Method Using the Vinamidinium Salt Represented by the Formula (I)

The above vinamidinium salt represented by the formula (I) can be reacted with a compound represented by the formula (II) to synthesize a quinoline derivative represented by the formula (III).

In the formula (II) and the formula (III), the ring A represents a hydrocarbon ring or a heterocyclic ring wherein the carbon atom to which the amino group in the formula (II) is attached has a double bond. R2R3, R4and R5are the same or different and each represents a hydrogen atom or a substituent, or R2and R3, R3and R4, or R4and R5may combine together with the adjacent atom to form a 5- to 8-membered ring. Examples of the “substituent” include an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and the same group as the substituent of the “optionally substituted hydrocarbon group” represented by the above R1and R1′. Examples of the “optionally substituted hydrocarbon group” include the same group as the above “optionally substituted hydrocarbon group” represented by R1and R1′. Examples of the “optionally substituted heterocyclic group” include the same group as the above “optionally substituted heterocyclic group” represented by R1and R1′.

Preferred examples of the compound represented by the formula (II) include those wherein R2and R3are a hydrogen atom, R4is a C1-6alkyl-carbonylamino group (e.g. acetylamino), or aryl-carbonylamino group (e.g. a C6-14benzoylamino, or naphthoylamino), and R5is a hydrogen atom or a C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl). Specifically, for example, N-(3-aminophenyl)acetamide is preferred.

In addition, in the formula (III), R1is as defined with respect to the formula (I).

If the compound represented by the formula (II) is commercially available, a commercially available product can be used as it is. Alternatively, the compound represented by the formula (II) can be produced by a per se known method or a modification thereof.

The compound represented by the formula (I) can be used in an amount of about 0.1 to 10 mol, preferably, about 1 to 5 mol per mol of the compound represented by the formula (II).

This reaction is optionally and preferably carried out in an inert solvent for the reaction.

The reaction temperature is usually about −70 to 200° C., preferably about 50 to 150° C.

The reaction time is usually 0.5 hours to 2 weeks, preferably about 0.5 to 72 hours.

The compound represented by the formula (III) thus obtained can be isolated from a reaction mixture and purified by a per se known separation means (e.g. concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, re-extraction, and chromatography). In particular, crystallization is preferably used for isolation of the compound represented by the formula (III).

The same solvent as the above “inert solvent” used for the reaction of the compound represented by the formula (I) with the compound represented by the formula (II) can be used as a solvent used for the crystallization,

The crystallization temperature is usually about −70 to 100° C., preferably about 0 to 40° C.

The crystallization time is usually about 0.5 to 48 hours, preferably about 0.5 to 24 hours.

(b) A Method Using an Acetic Acid Solution of the Vinamidinium Salt Represented by the Formula (I′)

The quinoline derivative represented by the formula (III′) can be synthesized by reacting an acetic acid solution of the vinamidinium salt represented by the above formula (I′) with the compound represented by the above formula (II). In the formula (III′), R1′is as defined with respect to the formula (I′), and R2, R3, R4and R5are as defined with respect to the formula (II).

An acetic acid solution of the vinamidinium salt represented by the formula (I′) may be mixed with the acetic acid solution of the vinamidinium salt represented by the formula (I) in an arbitrary ratio.

If the compound represented by the formula (II) is commercially available, a commercially available product can be used as it is. Alternatively, the compound represented by the formula (II) can be produced by a per se known method or a modification thereof.

The compound represented by the formula (I′) can be used in an amount of about 0.1 to 10 mol, preferably about to 5 mol per mol of the compound represented by the formula (II).

The reaction temperature is usually about −70 to 200° C., preferably about 50 to 150° C.

The reaction time is usually 0.5 hours to 2 weeks, preferably about 0.5 to 72 hours.

The compound represented by the formula (III′) thus obtained can be isolated from a reaction mixture and purified by a per se known separation means (e.g. concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, re-extraction, and chromatography). In particular, crystallization is preferably used for isolation of the compound represented by the formula (III′).

The above “inert solvent” used for the reaction of the compound represented by the formula (I) with the compound represented by the formula (II) can be used as a solvent used for the crystallization,

The crystallization temperature is usually about −70 to 100° C., preferably about 0 to 40° C.

The crystallization time is usually about 0.5 to 48 hours, preferably about 0.5 to 24 hours.

2. Synthetic Method of Tri-Substituted Quinoline Derivative

(a) A Method Using the Vinamidinium Salt Represented by the Formula (I)

The quinoline derivative represented by the formula (V) can be synthesized by reacting the vinamidinium salt represented by the formula (I) with the compound of the formula (IV).

In the formula (IV) and the formula (V), R10represents a hydrogen atom or a substituent, and the ring B represents a substituted benzene ring.

Examples of the “substituent” represented by R10include an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, and the same group as the substituent of the “optionally substituted hydrocarbon group” represented by the above R1and R1′. Examples of the “optionally substituted hydrocarbon group” include the same group as the “optionally substituted hydrocarbon group” represented by the above R1and R1′. Examples of the “optionally substituted heterocyclic group” include the same group as the “optionally substituted heterocyclic group” represented by the above R1and R1′.

Examples of the substituent of the ring B include the same group as the “substituent” represented by the above R10. The ring B has 1 to 3 substituents selected from these substituents at possible positions. The number of the substituents is preferably 1, and the substituent at the para position is more preferred. Preferred examples of the substituent include a halogen atom (e.g. fluorine, chlorine, bromine, and iodine), a nitro group, a nitroso group, a cyano group, an optionally substituted hydrocarbon group, a C1-6alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy), a C1-6alkyl-carbonylamino group (e.g. acetylamino), and C6-14aryl-carbonylamino group (e.g. benzoylamino, and naphthoylamino). Among them, a C1-6alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy) is preferred, with a cyclopropylmethoxy group being particularly preferred.

Examples of the compound represented by the formula (IV) include those wherein R10is a hydrogen atom or a C1-6alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl), and the ring B has a C1-6alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy) as a substituent at the para position. Specific examples thereof include N-(3-amino-2-methylphenyl)-4-(cyclopropylmethoxy)benzoic acid amide.

Further, in the formula (V), R1is as defined with respect to the formula (I).

If the compound represented by the formula (IV) is commercially available, a commercially available product can be used as it is. Alternatively, the compound represented by the formula (IV) can be produced by a per se known method or a modification thereof.

The compound represented by the formula (I) can be used in an amount of about 0.1 to 10 mol, preferably about to 5 mol per mol of the compound represented by the formula (IV).

This reaction is optionally and preferably carried out in an inert solvent for the reaction.

The reaction temperature is usually about −70 to 200° C., preferably about 50 to 150° C.

The reaction time is usually 0.5 hours to 2 weeks, preferably about 0.5 to 72 hours.

The compound represented by the formula (V) thus obtained can be isolated from a reaction mixture and purified by a per se known separation means (e.g. concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, re-extraction, and chromatography). In particular, crystallization is preferably used for isolation of the compound represented by the formula (V).

The above “inert solvent” used for the reaction of the compound represented by the formula (I) with the compound represented by the formula (IV) can be used as a solvent used for the crystallization,

The crystallization temperature is usually about −70 to 100° C., preferably about 0 to 40° C.

The crystallization time is usually about 0.5 to 48 hours, preferably about 0.5 to 24 hours.

In this reaction, when a compound wherein R1is a lower alkyl group substituted with N,N-di-lower alkyl-imino group is used as the starting compound, sometimes, it becomes aldehyde or a lower alkyl group substituted with aldehyde in the end product.

(b) A Method Using an Acetic Acid Solution of the Vinamidinium Salt Represented by the Formula (I′)

The quinoline derivative represented by the formula (V′) can be synthesized by reacting an acetic acid solution of the vinamidinium salt represented by the formula (I′) with the compound of the formula (IV). In the formula (V′), R1′is as defined with respect to the formula (I′), and the ring A is as defined with respect to the formula (IV).

An acetic acid solution of the vinamidinium salt represented by the formula (I′) may be mixed with the acetic acid solution of the vinamidinium salt represented by the formula (I) in an arbitrary ratio.

If the compound represented by the formula (IV) is commercially available, a commercially available product can be used as it is. Alternatively, the compound represented by the formula (IV) can be produced by a per se known method or a modification thereof.

The compound represented by the formula (I′) can be used in an amount of about 0.1 to 10 mol, preferably about to 5 mol per mol of the compound represented by the formula (IV).

The reaction temperature is usually about −70 to 200° C., preferably about 50 to 150° C.

The reaction time is usually 0.5 hours to 2 weeks, preferably about 0.5 to 72 hours.

The compound represented by the formula (V′) thus obtained can be isolated from a reaction mixture and purified by a per se known separation means (e.g. concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, re-extraction, and chromatography). In particular, crystallization is preferably used for isolation of the compound represented by the formula (V′).

The above “inert solvent” used for the reaction of the compound represented by the formula (I) with the compound represented by the formula (IV) can be used as a solvent used for the crystallization,

The crystallization temperature is usually about −70 to 100° C., preferably about 0 to 40° C.

The crystallization time is usually about 0.5 to 48 hours, preferably about 0.5 to 24 hours.

In this reaction, when a compound wherein R1′is a lower alkyl group substituted with N,N-di-lower alkyl-imino group is used as the starting compound, sometimes, it becomes aldehyde or a lower alkyl group substituted with aldehyde in the end product.

Hereinafter, the present invention will be explained in more detail by means of Examples and Comparative Example. However, the present invention is not limited thereto.

Chloroacetic acid (40 g) was added to N,N-dimethylformamide (186 g) and dissolved therein. Phosphorus oxychloride (260 g) was added dropwise thereto with cooling. Then, the resulting mixture was heated to 85° C., followed by stirring for 1 hour. The temperature was raised to 95° C. and the mixture was stirred for 1 hour. Further, the temperature was raised to 105° C. and the mixture was stirred for 1 hour, followed by cooling to room temperature. Conc. hydrochloric acid (71 mL) and tetrahydrofuran (800 mL) were added dropwise thereto at the same temperature and the resulting mixture was stirred for 1 hour. Precipitated crystals were collected by filtration under pressure in an atmosphere of nitrogen (dew point: about −65° C.) and washed with a mixture of tetrahydrofuran/ethanol (120 mL/20 mL). Subsequently, the crystals were dried by aeration with nitrogen (dew point: about −65° C.) to obtain the title compound (51 g).

Phenylacetic acid (11.9 g) was added to N,N-dimethylformamide (14 g) and dissolved therein. Phosphorus oxybromide (25 g) dissolved in dichloroethane (10 mL) was added dropwise thereto at a temperature of not higher than 40° C. The resulting mixture was concentrated under reduced pressure and the residue thus obtained was stirred at 90 to 110° C. for 3 hours. The reaction mixture at the same temperature was added dropwise to THF (250 mL) at a temperature of not higher than 30° C. and the mixture was stirred at room temperature for 30 minutes. A precipitated solid was collected by filtration, washed with THF (100 mL) and dried under reduced pressure to obtain a solid (10.6 g). The solid (0.5 g) thus obtained was dissolved in acetonitrile (30 mL) and active charcoal (0.25 g) was added thereto. Insoluble materials were filtered off and the filtrate was concentrated under reduced pressure to obtain a residue (0.47 g). The residue (0.1 g) thus obtained was placed in a 100 mL Schlenk tube, and the tube was filled with HBr gas and allowed to stand overnight. HBr gas was removed with a diaphragm pump to obtain the title compound (0.13 g).

Synthesis of N-(3-formylquinolin-7-yl)acetamide

Triethylamine (1.52 g), N-(3-aminophenyl)acetamide (0.50 g) and n-butanol (2 mL) were added to a suspension of 3-(dimethylimino)-2-[(dimethylimino)methyl]-N,N-dimethyl-1-propene-1-aminium trichloride (1.45 g) in n-butanol (8 mL) at room temperature and were dissolved therein. The resulting solution was heated to 80° C., stirred for 3 hours and then cooled to room temperature. After addition of water (1 mL) to the reaction mixture, the solvent was distilled off under reduced pressure. The residue thus obtained was dissolved by addition of acetic acid (2 mL) and water (10 mL) and, again, the solvent was distilled off under reduced pressure. The resulting residue was dissolved by addition of water (10 mL) and the solution was adjusted to pH 8 with sodium hydrogen carbonate. After stirred at room temperature for 1 hour, precipitated crystals were collected by filtration and washed with water (10 mL). The crystals were dried under reduced pressure to obtain the title compound (0.63 g) as pale yellow crystals. Yield: 89%.

Preparation of Acetic Acid Solution of Vinamidinium Salt

Bromoacetic acid (40.0 g, 288 mmol) was dissolved in dimethylformamide (126 g, 1.73 mol). Phosphorus oxychloride (177 g, 1.15 mol) was added dropwise thereto at a temperature of −5 to 10° C., and the mixture was stirred at 75° C. for 1 hour, then at 95° C. for 1 hour and further at 105° C. for 1 hour. Ethanol (160 mL) was added dropwise thereto at 20 to 30° C. and then tetrahydrofuran (800 mL) was added dropwise thereto at 20 to 30° C., followed by stirring at 20 to 30° C. for 2 hours. Precipitated crystals were filtered off, washed with ethanol/tetrahydrofuran (40 mL/200 mL), and then dried by aeration. The crystals thus obtained were dissolved in acetic acid (320 g). Additional acetic acid (175 g) was added to prepare a 10 w/w % acetic acid solution.

Synthesis of N-(3-formylquinolin-7-yl)acetamide

To a 6 w/w % acetic acid solution of 2-dimethylaminomethylene-1,3-bis(dimethyliminio)propane dichloride (3.2 mL, 0.75 mmol) was added N-(3-aminophenyl)acetamide (75 mg, 0.5 mmol). The mixture was refluxed at an external bath temperature of 140° C. for 2.5 hours, and the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Water (3.2 mL) was added to the concentrated residue and the resulting mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration, washed three times with water (1 mL) and dried under reduced pressure to obtain N-(3-formylquinolin-7-yl)acetamide (93 mg, yield: 86.9%) as white crystals.

COMPARATIVE EXAMPLE 1

According to the same manner as that described in Example 4, N-(3-aminophenyl)acetamide was used as the substrate and reacted with an acetic acid solution of each kind of vinamidinium salts (Cl salt, BF4salt, ClO4salt and PF6salt). After 2 hours, the formation rate of N-(3-formylquinolin-7-yl)acetamide was measured by HPLC (ODS column; mobile phase: phosphate buffer/acetonitrile=8/2); flow rate: 1 mL/min.; UV 254 nm). The results are as follows.

Formation rate (HPLC area %) in Cl salt: 84.4%

As seen from the above results of the measurement, the vinamidinium salt having halogen atoms as the anions has the very high reaction selectivity as compared with the other vinamidinium salts, and hence it is a useful starting material as the industrial synthesis of the nitorgen-containing heteroaromatic ring.

Synthesis of 4-(cyclopropylmethoxy)-N-[3-formyl-8-methylquinolin-7- yl]benzoic acid amide

Momorpholine (8.84 g), N-(3-amino-2-methylphenyl)-4- (cyclopropylmethoxy)acetic acid amide (5.00 g) and n-butanol (25 mL) were added to a suspension of 3-(dimethylimino)-2-[(dimethylimino)methyl]-N,N-dimethyl-1- propene-1-aminium trihalide (8.59 g) in n-butanol (50 mL) at room temperature and dissolved therein. The resulting solution was heated to 80° C. and stirred for 4 hours. Acetic acid (12.5 mL) and water (12.5 mL) were added thereto at the same temperature and the mixture was stirred for 30 minutes, followed by cooling to room temperature. After stirring at room temperature for 1 hour, precipitated crystals were collected by filtration and washed in turn with a mixture of acetic acid (25 mL) and water (25 mL), and water (25 mL). The crystals were dried under reduced pressure to obtain the title compound (5.60 g) as white crystals. Yield: 92%.

INDUSTRIAL APPLICABILITY

The vinamidinium salt having halogen anions of the present invention whose valency number has not been known heretofore in the prior art can be produced in a larger scale because the salt is excellent in reaction selectivity, and free from glass corrosiveness, and can be produced cheaply, and further the salt is excellent in storage stability because of its improved hygroscopicity. Further, an acetic acid solution of the vinamidinium salt having halogen anions is also excellent in storage stability and reaction selectivity, and has superior properties as compared with BF4−salt and PF6−salt. Therefore, according to the present invention, it is possible to provide the stable vinamidinium salt having the above properties which can be used as a universal reagent useful for synthesizing various substituted nitrogen-containing heteroaromatic rings, its crystals and acetic acid solution, and a method for constructing nitrogen-containing heteroaromatic rings such as quinoline skeleton using them.