JP2002145886A - Method for producing heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a simple and general method for synthesizing thienothiazoles. SOLUTION: This method for synthesizing the thienothiazoles is characterized by using a raw material having sulfur atom and nitro group substituted at adjacent positions on a thiophene ring in synthesizing the thienothiazoles.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a thienothiazole heterocyclic compound.

[0002]

BACKGROUND OF THE INVENTION Thienothiazole compounds represented by the general formula (II) are functional compounds such as photographic additives, sensitizing dyes for photosensitive materials, dyes, laser dyes, pharmaceuticals, and intermediates and raw materials thereof. Useful as As a method for synthesizing thienothiazoles, for example, the following examples have been reported.

(1) Synthesis of thioacetamidothiophene by oxidative ring closure (Doklady Akad. Nauk SS
SR, 120, 1035 (1958) (Chemical Abstr
act, Vol. 52, 20128h (1958)), Chem. Heterocycli
c Compd., Volume 1, Page 417 (1965), Volume 13, Volume 11
Page 94 (1977) and Volume 23, Page 345 (1987)
(2) Synthesis method of thioureathiophene by oxidative ring closure reaction (J. Heterocyclic Chem., Vol. 15, p. 81 (1978)
(3) Synthesis method via reaction of introducing a thiocyano group into a thiophene ring (J. Prakt. Chem., Vol. 315, p. 539 (1)
973), Chem. Heterocyclic Compd., Volume 10, 1045
Page (1974), J. Heterocyclic Chem., Volume 20, 113
(4) Synthesis method via dithiazolium salt (Khim. Gete)
rotsikl. Soedin., vol. 10, p. 1355 (1976), ibid.
15, 477 (1979), Chem. HeterocyclicComp
d., vol. 15, p. 387 (1979)) (5) Synthetic method via Beckmann rearrangement (J. Chem. So
c. Perkin Trans. 1, p. 1037 (1980)) (6) Synthetic method via disulfide compound (Chem. Hetero)
cyclic Compd., vol. 11, p. 1364 (1975), twelfth
Volume, 1123 (1976), Khim. Geterotsikl. Soedi
n., Vol. 12, p. 1607 (1975))

[0004] The oxidative ring closure of (1) and (2)
Although it is a general method in the synthesis of benzothiazole, it often fails when applied to the thiophene ring. In Chemical Abstract, Vol. 52, 20128h (1958), 2-thioacetaminothiophene An example of synthesizing 2-methyl [2,3-d] thienothiazole by reacting with blood salt has been reported, but it is described that the yield is 10.1% and 20.6% of disulfide form can be obtained. Also, J. Hetero
According to cyclic Chem., Vol. 15, p. 81 (1978), when oxidative ring closure with bromine using thiophene derivative-substituted thiophene, the 3-thiourea form is 2-amino
It is reported that [3,2-d] thiophene gives good yield (62-84%), whereas the 2-thiourea form is only brominated at the 3- and 5-positions. As described above, when the oxidative ring closure reaction is performed, it may not be successful depending on the substitution position, and it is found that it is extremely difficult to synthesize [2,3-d] thienothiazoles.

The reaction (3) for introducing a thiocyano group oxidatively is reported in the above-mentioned references, but all of them involve only a substrate substituted at the 4- or 5-position. In this case, the substituted 2-aminothiophene hydrochloride was used as the substrate, but unsubstituted 2-aminothiophene was very unstable, and it was difficult to isolate the free form. J. Heterocyclic Che
m., Vol. 6, p. 147 (1969). It is not preferable to perform production using such unstable raw materials. In addition, when a thiocyano group is introduced, thienothiazole which is easily obtained is a 2-amino form, and when trying to obtain one having another substituent, J. Heterocycli
c As described in Chem., Vol. 20, p. 113 (1983), the number of steps is further increased, and the generality is poor.

[0006] All of the synthesis methods (4) via a dithiazolium salt are only reports on substrates in which the 4- or 5-position is substituted. Further, J. Org. Chem., Vol. 49, No. 1
On page 224 (1984), it is reported that when an unsubstituted 2-aminothiophene hydrochloride is used as a substrate, a dithiazolium salt is not obtained and only a tar-like product is obtained.

The synthesis method (5) via the Beckmann rearrangement is a relatively preferable synthesis method because it does not involve the unsubstituted 2-aminothiophene which was a concern in (3) and (4). However, as described in the above-mentioned literature, the number of steps for synthesizing the substrate increases. In addition, thieno [2,3-d] isothiazole is obtained depending on the conditions of the Beckmann rearrangement, and under the conditions using concentrated sulfuric acid described in the above-mentioned paper, the substrate and the product are sulfonated and the yield is reduced. Let me. Therefore, it cannot be said that this is a simple synthesis method.

In the synthesis method via the disulfide compound of (6), only 2-mercaptothieno [3,2-d] thiazole and benzo [b] thieno [2,3-d] thiazole are reported in the above-mentioned literature. Khim. Geterots found that trying to synthesize thieno [2,3-d] thiazole in the same way did not work.
ikl. Soedin., Vol. 10, p. 1355 (1976).

As described above, in the synthesis of thienothiazoles, the reactivity and stability of the substrate greatly depend on the position of the substituent, and therefore, the structure of the compound represented by the general formula (II) does not depend on the structure. A simple and general synthesis method has not been reported so far.

[0010]

An object of the present invention is to provide a simple and general method for synthesizing a thienothiazole compound represented by the general formula (II).

[0011]

As a result of various studies, the present inventor has found that a thiophene derivative in which a sulfur atom and a nitro group are substituted at adjacent positions, particularly a dinitrothiophene disulfide derivative, is used as a raw material to reduce a nitro group. It has been found that a thienothiazole compound represented by the general formula (II) can be efficiently synthesized by reacting with an electrophile and further closing the thiazole ring.

(1) A method for producing a thienothiazole heterocyclic compound, which comprises using a raw material in which a sulfur atom and a nitro group are substituted at adjacent positions on a thiophene ring in the synthesis of thienothiazoles. (2) The method for producing thienothiazoles according to (1), wherein a heterocyclic compound represented by the following general formula (II) is synthesized using a compound represented by the following general formula (I) as a raw material. . General formula (I)

[0013]

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In the formula, Th represents a thiophene ring, which may have a substituent or may be condensed with another 5- or 6-membered carbon or heterocyclic ring. L represents a hydrogen atom, a metal atom or a monovalent substituent. General formula (II)

[0015]

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In the formula, Th ¹ represents a thiophene ring, which may have a substituent or may be condensed with another 5- or 6-membered carbocyclic or heterocyclic ring. R represents a hydrogen atom or a monovalent substituent. (3) The thieno according to (2), wherein the compounds represented by the general formulas (I) and (II) are represented by the following general formulas (I ′) and (II ′), respectively. A method for producing thiazoles. General formula (I ')

[0017]

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In the formula, V ¹ and V ² each represent a hydrogen atom or a monovalent substituent, and L ¹ represents a hydrogen atom, a metal atom or a monovalent substituent. General formula (II ')

[0019]

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In the formula, V ¹¹ , V ¹² and R ¹ each represent a hydrogen atom or a monovalent substituent. (4) In the general formula (I ') and (II' compound represented ^{by), V 1, V 2,} V 1 1 and V ¹² is hydrogen atom, a halogen atom, a an alkyl group or an aryl group The method for producing thienothiazoles according to the above (3), which is characterized in that: (5) The production of the thienothiazoles according to the above (2), (3) or (4), wherein the compound represented by the general formula (I) or (I ′) is a symmetric disulfide. Method. (6) The compound according to the above (2), (3) or (4), wherein in the compound represented by the general formula (I) or (I ′), L and L ¹ are acyl groups. A method for producing thienothiazoles. (7) In the compound represented by the general formula (II) or (II ′), R and R ¹ are an alkyl group, wherein (2), (3), (4), and ( 5) or the method for producing thienothiazoles according to (6). (8) A method for producing a heterocyclic compound, comprising synthesizing a heterocyclic compound represented by the following general formula (III) using a compound represented by the general formula (I) as a raw material. General formula (III)

[0021]

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In the formula, Th ² represents a thiophene ring, which may have a substituent or may be condensed with another 5- or 6-membered carbocyclic or heterocyclic ring. R ² and R ³ each represent a hydrogen atom, an alkyl group or an aryl group. (9) The compound represented by the general formula (III) is represented by the following general formula
The method for producing a heterocyclic compound according to the above (8), which is represented by (III ′). General formula (III ')

[0023]

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[0024] In the formula, V ^21, V ²² each represent a hydrogen atom, a halogen atom, an alkyl group or an aryl group, R ²¹
Represents a hydrogen atom, an alkyl group or an aryl group. (10) In the compounds represented by the general formulas (I ′) and (III ′), V ¹ , V ² , V ²¹ and V ²² are a hydrogen atom, a halogen atom, an alkyl group or an aryl group. The method for producing a heterocyclic compound according to the above (9). (11) The production of the heterocyclic compound according to the above (8), (9) or (10), wherein the compound represented by the general formula (I) or (I ′) is a symmetric disulfide. Method. (12) The compound according to the above (8), (9) or (10), wherein in the compound represented by the general formula (I) or (I ′), L and L ¹ are acyl groups. A method for producing a heterocyclic compound. (13) reacting the compound represented by the general formula (I) or (I ′) in a water-organic solvent two-phase system in the presence of a reducing agent and an acylating agent to produce the compound represented by the general formula (III) or ( (8) wherein the compound represented by III ′) is synthesized.
(9) The method for producing a heterocyclic compound according to (10), (11) or (12). (14) Using a metal or a metal salt, formula (I) or
The method for producing a heterocyclic compound according to any one of the above (2) to (13), wherein the method is through a reaction of reducing the compound represented by (I ′). (15) General formula using hydrogen sulfide or its metal salt
The method for producing a heterocyclic compound according to any one of the above (2) to (13), which is via a reaction of reducing the compound represented by (I) or (I ′). (16) via a reaction of reducing a compound represented by the general formula (I) or (I ′) with hydrogen,
The method for producing a heterocyclic compound according to any one of the above (2) to (13). (17) A method for producing thienothiazoles, comprising synthesizing a heterocyclic compound represented by the general formula (II) using a compound represented by the general formula (III) as a raw material. (18) The thieno according to (17), wherein the compounds represented by the general formulas (III) and (II) are represented by the general formulas (III ′) and (II ′), respectively. A method for producing thiazoles. (19) The raw material represented by the general formula (III) or (III ′) is reacted in the presence of an acid to produce the compound represented by the general formula (II) or (II ′)
Wherein the compound represented by the formula (1) is synthesized.
7) or the method for producing thienothiazoles according to (18). (20) The method for producing thienothiazoles according to (19), wherein an alcohol solvent is used. (21) The method for producing thienothiazoles according to (1), wherein the reaction is performed in the presence of the raw material, a reducing agent, and an electrophile. (22) Using a compound raw material represented by the general formula (I),
The method for producing thienothiazoles according to the above (2), wherein the thienothiazoles represented by the general formula (II) are synthesized via the compound of the general formula (III). (23) The method for producing a heterocyclic compound according to any one of the above (13) to (16), wherein the reaction temperature is 40 ° C to 105 ° C and the reaction time is 1 hour to 10 hours. . (24) The method for producing thienothiazoles according to the above (19) or (20), wherein the reaction temperature is 50 ° C to 130 ° C and the reaction time is 1 hour to 6 hours.

[0025]

DETAILED DESCRIPTION OF THE INVENTION The present invention will be described in detail. In the compound used as a raw material in the production method of the present invention, a sulfur atom and a nitro group can be substituted at any adjacent positions on the thiophene ring. Substitution positions are 2- and 3-position, 3-
And the 4- and 5-positions, one of which is a sulfur atom and the other is a nitro group. The sulfur atom is not independently substituted, and is present together with an arbitrary monovalent substituent, a metal atom, a hydrogen atom, and the like. The compound used as a raw material in the present invention is represented by the general formula (I),
The case where the obtained thienothiazoles are represented by the general formula (II) is preferable. General formula (I) each may have a thiophene ring Th ¹ is in a thiophene ring Th and the general formula (II) substituent in, also fused with a carbocyclic or heterocyclic ring other 5-membered or 6-membered You may. Preferred fused rings include carbon rings such as a benzene ring, a cyclopentene ring and a cyclohexene ring, and heterocyclic rings such as a furan ring, a thiophene ring, a pyrrole ring and a pyridine ring.

The thiophene ring Th of the general formula (I) and the general formula
On the thiophene ring Th ¹ of (II), the substitution positions of the nitro group and the sulfur atom are preferably 2-position and 3-position, and further, the nitro group is substituted at the 2-position and the sulfur atom is substituted at the 3-position. Is preferred.

The most preferred forms of the compounds of the general formulas (I) and (II) are represented by the general formulas (I ') and (II'), respectively. V ¹ and V ^{2 in} the general formula (I ′),
V ¹¹ and V ^{12 in} I ′) represent a hydrogen atom or a monovalent substituent. The monovalent substituent is not particularly limited (the following substituents are collectively referred to as “V”), and examples thereof include a halogen atom (eg, chlorine, bromine, iodine, fluorine), a mercapto group, a cyano group, and a carboxyl group. Group, phosphate group, sulfo group, hydroxy group, carbamoyl group having 1 to 10, preferably 2 to 8, more preferably 2 to 5 carbon atoms (eg, methylcarbamoyl, ethylcarbamoyl, morpholinocarbonyl), carbon A sulfamoyl group having a number of 0 to 10, preferably 2 to 8 carbon atoms, more preferably 2 to 5 carbon atoms (eg, methylsulfamoyl, ethylsulfamoyl, piperidinosulfonyl),
A nitro group, an alkoxy group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms (e.g., methoxy, ethoxy, 2-methoxyethoxy,
2-phenylethoxy), having 6 to 20 carbon atoms, preferably 6 to 12 carbon atoms, and more preferably 6 to 1 carbon atoms.
0 aryloxy group (eg, phenoxy, p-methylphenoxy, p-chlorophenoxy, naphthoxy), an acyl group having 1 to 20, preferably 1 to 12, more preferably 1 to 8 carbon atoms (eg, formyl) Acetyl, benzoyl, trichloroacetyl), an acyloxy group having 1 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms (eg, acetyloxy, benzoyloxy), and 1 to 2 carbon atoms.
0, preferably an acylamino group having 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms (eg, acetylamino), 1 to 20 carbon atoms, preferably 1 to 1 carbon atoms
0, more preferably a sulfonyl group having 1 to 8 carbon atoms (for example, methanesulfonyl, ethanesulfonyl, benzenesulfonyl, etc.), a sulfinyl group having 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 8 carbon atoms. Group (eg, methanesulfinyl, benzenesulfinyl), having 1 to 20 carbon atoms, preferably 1 carbon atom
To 10, more preferably a sulfonylamino group having 1 to 8 carbon atoms (eg, methanesulfonylamino, ethanesulfonylamino, benzenesulfonylamino, etc.), an amino group, 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, and Preferably, it is a substituted amino group having 1 to 8 carbon atoms (eg, methylamino, dimethylamino, benzylamino, anilino, diphenylamino);
5, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms of an ammonium group (eg, trimethylammonium group, triethylammonium group), 0 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably A hydrazino group having a number of 1 to 6 (for example, a trimethylhydrazino group), having 1 to 15 carbon atoms, and preferably having 1 carbon atom;
To 10, more preferably a ureido group having 1 to 6 carbon atoms (e.g., ureido group, N, N-dimethylureido group), 1 to 15 carbon atoms, preferably 1 to 1 carbon atoms.
0, more preferably an imide group having 1 to 6 carbon atoms (eg, succinimide group), an alkyl or arylthio group having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms (eg, methylthio, Ethylthio, carboxyethylthio, sulfobutylthio,
Phenylthio, etc.), an unsubstituted or substituted alkenylthio group having 2 to 18 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 5 carbon atoms (for example, vinylthio group,
An ethynylthio group), an alkoxycarbonyl group having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl), and 6 to 20 carbon atoms, preferably Is an aryloxycarbonyl group having 6 to 12 carbon atoms, more preferably 6 to 8 carbon atoms (for example, phenoxycarbonyl), 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, and more preferably 1 to 5 carbon atoms. A substituted alkyl group (eg, methyl, ethyl, propyl, butyl), a substituted alkyl group having 1 to 18 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms (hydroxymethyl, trifluoromethyl,
Benzyl, carboxyethyl, ethoxycarbonylmethyl, acetylaminomethyl, here also preferably have 2 to 18 carbon atoms, more preferably 3 to 1 carbon atoms.
An unsaturated hydrocarbon group having 0, particularly preferably 3 to 5 carbon atoms (for example, a vinyl group, an ethynyl group, a 1-cyclohexenyl group, a benzylidine group, and a benzylidene group) is also included in the substituted alkyl group. ), A substituted or unsubstituted aryl group having 6 to 20 carbon atoms, preferably 6 to 15 carbon atoms, more preferably 6 to 10 carbon atoms (for example, phenyl, naphthyl, p-carboxyphenyl, p-nitrophenyl, 3, 5-dichlorophenyl, p-cyanophenyl, m-fluorophenyl, p-tolyl, p-bromophenyl), having 1 to 20 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 4 to 6 carbon atoms. A heterocyclic group (eg, pyridyl, 5-methylpyridyl,
Thienyl, furyl, morpholino, tetrahydrofurfuryl).

V ¹ and V ² , and V ¹¹ and V ¹² may be combined with each other to form a ring, thereby forming a condensed ring with the thiophene ring Th or Th ¹ . The condensed ring may be either saturated or unsaturated, and may be a heterocyclic ring. Preferred are a benzene ring, a naphthalene ring, a pyridine ring, a furan ring, a thiophene ring and a pyrrole ring. These may be further substituted with a monovalent substituent represented by V described above.

In the general formulas (I ') and (II'),
V ¹ and V ¹¹ , and V ² and V ¹² represent substituents on the same carbon atom before and after the reaction, and therefore generally represent the same substituent. The reaction may represent different substituents.

In the general formulas (I ') and (II'),
V ¹ , V ¹¹ , V ² and V ¹² are preferably a hydrogen atom, a halogen atom (for example, fluorine, chlorine, bromine, iodine),
Cyano group, carboxyl group, unsubstituted or substituted alkyl group having 18 or less carbon atoms, unsubstituted or substituted alkenyl group having 18 or less carbon atoms, unsubstituted or substituted aryl group having 6 to 20 carbon atoms, unsubstituted having 20 carbon atoms or less And a substituted alkoxy group,
An unsubstituted and substituted aryloxy group having 6 to 20 carbon atoms,
Unsubstituted and substituted alkylthio groups having 20 or less carbon atoms, unsubstituted and substituted alkenylthio groups having 2 to 18 carbon atoms, unsubstituted and substituted arylthio groups having 6 to 20 carbon atoms, unsubstituted and substituted alkoxy groups having 2 to 20 carbon atoms Carbonyl group,
It is an unsubstituted or substituted heterocyclic group having 20 or less carbon atoms.

More preferably, a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, an unsubstituted alkyl group having 10 or less carbon atoms (eg, methyl, ethyl, propyl, octyl), an unsubstituted alkoxycarbonyl having 2 to 12 carbon atoms Groups (eg, methoxycarbonyl, ethoxycarbonyl) and unsubstituted aryl groups having 10 or less carbon atoms (eg, phenyl, naphthyl). More preferred are a hydrogen atom, a halogen atom, an alkyl group having 5 or less carbon atoms, and a phenyl group, and particularly preferred are a hydrogen atom, a chlorine atom and a bromine atom. Most preferably, V ¹ and V ^{2 in} the general formula (I ′) and V ¹¹ and V ^{12 in} the general formula (II ′) are both hydrogen atoms.

In the general formulas (I) and (I ′), L and L ¹ represent a hydrogen atom, a metal atom or a monovalent substituent.
Examples of the monovalent substituent include the substituents described as examples of V described above. The metal atom may have any valence and may have any ligand. For example, sodium, potassium, calcium, zinc, iron and the like can be mentioned. Preferably, a hydrogen atom, sodium, potassium, a cyano group, an unsubstituted or substituted alkyl group having 18 or less carbon atoms, an unsubstituted or substituted aryl group having 6 to 18 carbon atoms, an unsubstituted or substituted alkylthio group having 18 or less carbon atoms And unsubstituted and substituted arylthio groups having 6 to 18 carbon atoms, unsubstituted and substituted acyl groups having 18 or less carbon atoms, and unsubstituted and substituted heterocyclic groups having 18 or less carbon atoms.
Particularly preferred are a hydrogen atom, sodium, potassium, methyl, ethyl, phenyl, formyl, acetyl, propionyl, benzoyl, methylthio, phenylthio, and thienylthio.

L and L ¹ are represented by the general formulas (I) and (I ')
May represent a disulfide compound as general formulas (I) and (I ′) by denoting L or L ¹ . In this case, it may be a symmetrical disulfide or an asymmetrical disulfide, but it is preferably a symmetrical disulfide. Most preferably, the following general formula (I
It is a symmetric disulfide represented by V). General formula (IV)

[0034]

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In the formula, V ¹ and V ² are the same as those in the general formula (I ′), and preferred ones are also the same.

In the general formulas (II) and (II ′), R and R ¹ represent a hydrogen atom or a monovalent substituent. Examples of the monovalent substituent include the substituents described as examples of V described above. Preferably, a hydrogen atom, a halogen atom, a mercapto group, an unsubstituted and substituted alkyl group having 18 or less carbon atoms, an unsubstituted and substituted aryl group having 6 to 18 carbon atoms, an unsubstituted and substituted alkylthio group having 18 carbon atoms or less, An unsubstituted or substituted arylthio group having 6 to 18 carbon atoms and an amino group. More preferably a hydrogen atom, a chlorine atom, a bromine atom, a mercapto group, a methyl group, an ethyl group,
A phenyl group, a methylthio group and a phenylthio group are particularly preferable, and a hydrogen atom, a mercapto group and a methyl group are particularly preferable. Most preferably, it is a methyl group.

The thiophene derivative in which the sulfur atom and the nitro group of the raw material are substituted may be synthesized by any conventionally known method. For example, AR Katritzky, C.
W. Rees, `` Comprehensive Heterocyclic Chemistry ''
(Pergamon Press, 1984) Volume 4, Chapter 3.13, A. Weissb
erger, EC Taylor ed., The Chemistry of Heterocycl
ic Compounds, Vol. 44, Thiophene and its derivative
s part 2 (ed. by S. Gronowitz) "(John Wiley and Son
s, 1986) can be synthesized by referring to the method described in detail in Chapter 4, page 523, and the like.

The compounds represented by the general formulas (I) and (I ') can be synthesized with reference to the above-mentioned books as in the case of the above-mentioned thiophene derivatives. For example, V ¹ and V ² in the general formula (I ′) are both hydrogen atoms, and L ′ is a symmetric disulfide (2,2′-dinitrothiophene-3) representing a portion other than L ¹ in the general formula (I ′). , 3 '
-Disulfide) in the case of Khim. Geterotsikl. Soed
in., vol. 10, p. 1355 (1976), and can be synthesized from 3-bromo-2-nitrothiophene. The compounds represented by the general formulas (I) and (I ') may be isolated, or may be prepared from a precursor and subjected to the next reaction without isolation as it is. The general formula (I)
From the compounds represented by the general formulas (II) and (I ′)
In the conversion to the compound represented by I ′),
The compounds of the formulas (II) and (II ′) may be obtained, and after the intermediate (for example, the compound represented by the formula (III)) is isolated, the reaction is further carried out to obtain the compounds of the formulas (II) and (II) ') May be obtained.

In the conversion from the general formulas (I) and (I ') to the general formulas (II) and (II'), it is necessary to carry out a reduction reaction of a nitro group. Reaction conditions such as a reducing agent used for the reduction reaction of the nitro group include, for example, “Reducti” by M. Hudlicky.
ons in Organic Chemistry ”(ACS Monograph 188, 19
96) Chapter 8, Comprehensive Organic, by RC Larock
Transformations "(VCH, 1989), p. 411, etc., any of the conditions known so far may be used.

As the reducing agent, a metal or a metal salt can be used. As the metal or the metal salt, various ones as described in the above-mentioned publications can be used. , Tin and tin (II) chloride.

It is also effective to use hydrogen sulfide gas or a metal salt thereof (for example, sodium sulfide or sodium hydrosulfide) as a reducing agent, or to use a reducing agent such as sodium borohydride or lithium aluminum hydride.

Also, transition metal catalysts (for example, palladium, platinum, ruthenium, rhenium, nickel, copper, etc.)
May be used in the presence of hydrogen gas or a compound serving as a hydrogen source (for example, formic acid, hydrazine, or the like). In particular, it is effective to carry out hydrogenation using a catalyst of ruthenium or rhenium, which is a metal which is hardly poisoned by sulfur compounds.

In order to introduce R or R ¹ in the general formulas (II) and (II ′), a C1 unit in which R or R ¹ (or a precursor thereof) is substituted is substituted with a general formula (I) or (I ′). )
(Or its reaction product). The C1 unit in which R or R ¹ (or a precursor thereof) is substituted is an electrophile capable of reacting with an amino group generated by reduction of a nitro group in the synthetic route of the present invention. For example, when R or R ¹ is a hydrogen atom, an alkyl group, or an aryl group, the corresponding carboxylic anhydride (eg, acetic anhydride, propionic anhydride), carboxylic acid halide (acetyl chloride, propionyl chloride), orthoester (For example, methyl orthoacetate, ethyl orthopropionate), N, N-diethyl-1,1,2,3,3,3-hexafluoropropylamine and the like, when R or R ¹ is a mercapto group, disulfide Carbon and the like. Preferably, acetic anhydride, acetyl chloride, methyl orthoacetate (when R and R ¹ are methyl groups) or carbon disulfide (R,
R ¹ is a mercapto group), particularly preferably acetic anhydride and acetyl chloride.

The C1 unit in which R or R ¹ (or a precursor thereof) is substituted as described above has the general formula (I):
It may be added to the reaction system at any time during the reaction from (I ′) to the general formulas (II) and (II ′). For example, it may be added after the completion of the reduction of the nitro group is confirmed, or may be added from the beginning of the reaction. When the C1 unit and the reducing agent easily react under the latter reaction condition, the reaction is carried out in a two-phase system of water-organic solvent (eg, ethyl acetate), for example, immediately after the reduction occurs in the aqueous layer. It is preferable to form a system in which a C1 electrophile unit is added to the organic layer and the target substance is dissolved in the organic layer.

The reduction of the nitro group and the use of an acylating agent (such as a carboxylic anhydride or a carboxylic acid halide) in C
When one unit is introduced, an intermediate represented by the general formula (III) may be produced and can be isolated.
The thiophene ring Th ² in the general formula (III) may have a substituent and may be condensed with another 5- or 6-membered carbocyclic or heterocyclic ring. ) Is the same as the thiophene ring Th in R ² and R ³ each represent a hydrogen atom, an alkyl group or an aryl group, which may be different from each other, but are usually the same. Preferred are a hydrogen atom, an unsubstituted or substituted alkyl group having 18 or less carbon atoms, and an unsubstituted or substituted aryl group having 6 to 18 carbon atoms. More preferred are a hydrogen atom, a methyl group, an ethyl group and a phenyl group, and particularly preferred are a hydrogen atom and a methyl group. Most preferably, it is a methyl group.

The compound represented by the general formula (III)
In the most preferred case where the compound of (I ′) is used as a raw material, the general formula
The compound represented by (III ′) is obtained. In the general formulas (I ′) and (III ′), V ¹ and V ²¹ and V ² and V ²² represent the same substituent on the same carbon atom before and after the reaction, and therefore, generally the same substitution It represents a group, but these substituents may react during a series of reactions to represent different substituents. V ²¹ and V ²² are preferably a hydrogen atom, a halogen atom (eg, fluorine, chlorine, bromine, iodine),
Cyano group, carboxyl group, unsubstituted and substituted alkyl group having 18 or less carbon atoms, unsubstituted and substituted alkenyl group having 18 or less carbon atoms, unsubstituted and substituted aryl group having 18 or less carbon atoms, unsubstituted and substituted with 18 carbon atoms or less Substituted alkoxy group, unsubstituted or substituted aryloxy group having 18 or less carbon atoms, unsubstituted or substituted alkylthio group having 18 or less carbon atoms, 1 carbon atom
A substituted or unsubstituted arylthio group having 18 or less carbon atoms, an unsubstituted or substituted arylthio group having 18 or less carbon atoms, an unsubstituted or substituted alkoxycarbonyl group having 18 or less carbon atoms, and an unsubstituted or substituted heterocyclic group having 18 or less carbon atoms.

More preferably, a hydrogen atom, a halogen atom, a cyano group, a carboxyl group, an unsubstituted alkyl group having 8 or less carbon atoms (eg, methyl, ethyl, propyl, octyl), and an unsubstituted alkoxy group having 2 to 10 carbon atoms A carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl); and an unsubstituted aryl group having 10 or less carbon atoms (eg, phenyl, naphthyl). More preferably, a hydrogen atom, a halogen atom, an unsubstituted alkyl group having 8 or less carbon atoms,
An unsubstituted aryl group having 10 or less carbon atoms, particularly preferably a hydrogen atom, a chlorine atom and a bromine atom. Most preferably, both V ²¹ and V ²² are hydrogen atoms.

In the general formula (III ′), R ²¹ is the same as the general formula (II)
Preferred are the same as R ² and R ^{3 in} I), and more preferred are a hydrogen atom, a methyl group, an ethyl group and a phenyl group. More preferably a hydrogen atom or a methyl group,
Particularly preferred is a methyl group.

In the conversion from the general formulas (I) and (I ') to the general formulas (III) and (III'), it is necessary to carry out a reduction reaction of a nitro group. Reaction conditions such as the same as those used in the conversion of the above-mentioned general formulas (I) and (I ′) into the general formulas (II) and (II ′) can be used. Preferred reducing agents include metals or metal salts (eg, iron, zinc, tin, tin (II) chloride), hydrogen sulfide gas or its metal salts (eg, sodium sulfide, sodium hydrosulfide), sodium borohydride, hydride A reducing agent such as lithium aluminum; and a compound serving as a hydrogen gas or a hydrogen source using a transition metal catalyst (eg, palladium, platinum, ruthenium, rhenium, nickel, copper, etc., particularly preferably ruthenium or rhenium). The reduction may be performed in the presence of (for example, formic acid, hydrazine, etc.).

R ² and R in the general formulas (III) and (III ′)
^In order to introduce ³ or R ²¹ , R ² , R ³ or R
^A reaction between the C1 unit substituted with ²¹ (or a precursor thereof) and the general formulas (I) and (I ′) (or a reaction product thereof) is required. Examples of the C1 unit in which R ² , R ³ or R ²¹ (or a precursor thereof) is substituted include, for example, a corresponding carboxylic anhydride (eg, acetic anhydride, propionic anhydride) and a carboxylic acid halide (acetyl chloride, propionyl chloride) ), Orthoesters (eg, methyl orthoacetate, ethyl orthopropionate) and the like. Preferably, acetic anhydride, acetyl chloride, methyl orthoacetate (when R ² , R ³ or R ²¹ is a methyl group),
Particularly preferred are acetic anhydride and acetyl chloride. Most preferred is acetic anhydride.

The above-mentioned C1 unit substituted with R ² , R ³ or R ²¹ (or a precursor thereof) is converted from the general formulas (I) and (I ′) to the general formulas (III) and (III ′). May be added to the reaction system at any time during the reaction. For example, it may be added after the completion of the reduction of the nitro group is confirmed, or may be added from the beginning of the reaction. When the C1 unit and the reducing agent easily react under the latter reaction condition, the reaction is carried out in a two-phase system of water-organic solvent (eg, ethyl acetate), for example, immediately after the reduction occurs in the aqueous layer. To C1
It is preferable to form a system in which an electrophile unit is added and the target substance is dissolved in the organic layer.

The compound represented by formula (III) or (III ′) may be isolated or may be subjected to the next reaction without isolation. Isolation is preferred for conversion to the compound of general formula (II). Formula (III) or (II
The compound represented by I ′) is a thiol (or a metal salt or ester thereof) represented by the general formula (I) or (I ′) or a symmetric disulfide (preferably, a disulfide of the general formula (IV))
Is produced by the action of a reducing agent and an acylating agent as a starting material, and at the time of the reaction, sodium sulfide or hydrosulfide is used as a reducing agent in a two-phase system of water-organic solvent (preferably ethyl acetate or n-propyl acetate). When sodium or a carboxylic anhydride is used as an acylating agent, the compound represented by the general formula (III) or (III ′) can be isolated in high yield.
In addition, under conditions where sodium sulfide or sodium hydrosulfide is used as the reducing agent, nitrothiophene halide, a precursor of the thiol represented by the general formula (I) or (I '), is used as a raw material to introduce sulfur atoms and reduce nitro groups. , C1 unit can be introduced at once.

From the compounds of the general formulas (I) and (I ')
Compounds of the formulas (II) and (II ′) or of the general formulas (III) and (II)
The reaction of I ′) with the compound is preferably performed using a solvent. As the solvent, any of water, a two-phase system of a water-organic solvent, a water-containing organic solvent or a homogeneous organic solvent may be used. Examples of the organic solvent include hydrocarbon solvents such as toluene, xylene and hexane, halogen solvents such as methylene chloride, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide, and ether solvents such as tetrahydrofuran, dioxane and diglyme. Solvents, alcohol solvents such as methanol and ethanol, nitrile solvents such as acetonitrile, acetone,
Ketone solvents such as cyclohexanone, ester solvents such as ethyl acetate, and heterocyclic solvents such as pyridine can be used. Further, two or more kinds of organic solvents may be mixed and used. Further, the reaction may be carried out by using an excess amount of a C1 unit (for example, acetic anhydride) substituted with R, R ¹ , R ² , R ³ or R ²¹ (or a precursor thereof) as a solvent. From the compounds of the general formulas (I) and (I ′), the compounds of the general formulas (II) and (II ′) or the general formulas (III) and
The reaction of the compound (III ′) with the compound may be performed at any reaction temperature of 0 ° C. to 150 ° C. Preferably from 20 ° C to 120
° C, more preferably from 40 ° C to 105 ° C.
The reaction temperature may be changed in the middle. Although the reaction time varies depending on the reaction temperature and the like, the total reaction time is preferably 30 minutes to 15 hours, more preferably 1 hour to 10 hours. The reaction temperature is from 40 ° C. to 105 ° C., and the reaction time is 1
It is preferably for 10 hours to 10 hours.

As described above, the general formulas (III) and (II)
When the compound of the formula (I ′) is isolated, the compounds of the general formulas (II) and (I)
It is necessary to remove the acyl group on the sulfur atom in order to convert to the compound of I ′), Bull. Soc. Chim. Fra
nce, p. II-151 (1980), heating to 200 ° C., J. Heterocyclic Chem., Vol. 20, p. 113 (1983)
Heating with zinc powder as described in (Year) has been conventionally performed, but in any case, the yield is low, the reproducibility is low, and only substances such as black charcoal can be obtained. Often. The present inventor also studied this reaction, and as a result, by treating the compounds of general formulas (III) and (III ′) in the presence of an acid, the general formula (I)
It has been found that conversion of I) and (II ') to compounds can be achieved.

The acid used in the reaction may be a protonic acid or a Lewis acid. Examples of the protic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and the like. Aluminum chloride, magnesium bromide, boron trifluoride, iron (III) bromide, zinc iodide, titanium chloride (I
V), tin (IV) chloride, phosphorus trichloride, phosphorus pentachloride, antimony pentachloride, silicon tetrafluoride, scandium triflate and the like. Of these, the use of a protonic acid is particularly effective, and among the protic acids, the use of methanesulfonic acid or p-toluenesulfonic acid is preferred.

As the solvent, any of water, a two-phase system of water-organic solvent, a water-containing organic solvent or a homogeneous organic solvent may be used. Examples of the organic solvent include toluene, xylene, and the like.
Hydrocarbon solvents such as hexane, halogen solvents such as methylene chloride, sulfoxide solvents such as dimethyl sulfoxide, amide solvents such as dimethylformamide,
Ether solvents such as tetrahydrofuran, dioxane and diglyme; alcohol solvents such as methanol and ethanol; nitrile solvents such as acetonitrile; ketone solvents such as acetone and cyclohexanone; ester solvents such as ethyl acetate; heterocyclic systems such as pyridine. A solvent or the like can be used. Further, two or more kinds of organic solvents may be mixed and used. Among them, the use of an alcohol solvent significantly improves the yield of the compounds of the general formulas (II) and (II ′). Examples of alcohol solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, isobutanol, tert-butanol, ethylene glycol, methyl cellosolve, 2-ethoxyethanol, and 2- (2-ethoxyethoxy). Ethanol, polyethylene glycol and the like can be used, among which n-propanol,
The use of n-butanol, sec-butanol, isobutanol is particularly preferred. Most preferably, it is n-propanol.

The reaction from the compounds of the general formulas (III) and (III ') to the compounds of the general formulas (II) and (II') is carried out at 0.degree.
The reaction may be performed at any reaction temperature of 00 ° C. Preferably 2
0 ° C to 150 ° C, more preferably 50 ° C to 1 ° C.
20 ° C. The reaction temperature may be changed in the middle. The reaction time varies depending on the reaction temperature, etc.
30 minutes to 10 hours are preferable, and 1 hour to 6 hours are more preferable. Preferably, the reaction temperature is from 50 ° C to 130 ° C, and the reaction time is from 1 hour to 6 hours.

The production method of the present invention comprises the general formulas (I), (I ′), (I)
The present invention is applicable even when the compounds represented by (I), (II ′), (III), (III ′) and (IV) contain isotopes (for example, ² H, ³ H, and ¹³ C).

Specific examples of the compounds represented by formulas (I), (II) and (III) are shown below, but the present invention is not limited thereto. General formulas (I) and (I ') (including symmetric disulfides of general formula (IV))

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Formulas (II) and (II ')

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Formulas (III) and (III ')

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The present invention will be described in more detail by way of examples.

Example 1 <Direct synthesis of compound II-2 from compound I-38> 5 g of iron and 0.5 g of ammonium chloride were mixed with 5 ml of water, and
Stir for 5 minutes on an oil bath set to ° C. Add acetic acid to this.
5 ml was added and the mixture was stirred for 5 minutes on the same temperature oil bath. Further, 10 ml of acetic anhydride was added, followed by 5 g (15.6 mmol) of bis (2-nitro-3-thienyl) disulfide (compound I-38). The reaction mixture was reacted for 5 hours on an oil bath set at 100 ° C. (the temperature (internal temperature) of the reaction mixture was about 70 ° C.). The reaction mixture was filtered through celite, washed with ethyl acetate, and the filtrate was concentrated. The obtained crude product was purified by column chromatography on silica gel to obtain 2-methylthieno [2,3-d] thiazole (compound II-2). Yield 1.7 g (35% yield). The physical properties of the obtained product were determined by J. C.
hem. Soc. Perkin Trans. I, page 1029 (1980).

Example 2 <Synthesis of Compound III-1 from Compound I-38> Bis (2-nitro-3
-Thienyl) disulfide (Compound I-38) 32.0 g (0.1mo
l) with 100 ml of acetic anhydride and 300 ml of ethyl acetate,
The mixture was stirred on an oil bath set at 70 ° C. under a nitrogen atmosphere. Sodium hydrosulfide n-hydrate at an internal temperature of 50 ° C (content 70%)
When a solution prepared by dissolving 8.4 g in 300 ml of water was added dropwise over 15 minutes, the disulfide was dissolved to form two layers, an aqueous layer and an organic layer. Raise the temperature of the oil bath to 100 ° C (with an internal temperature of about 70
After heating and refluxing for 1 hour, 100 ml of acetic anhydride was added and the mixture was further refluxed for 2 hours. After cooling, the precipitated crystals were separated by filtration, dissolved in acetone, filtered, and the filtrate was concentrated and recrystallized with ethanol to obtain S- (2-acetamido-3-thienyl) thioacetate (Compound III-1). . Yield 29.6 g (69% yield). The physical properties of the obtained product are described in J. Heterocyclic Chem.
0, page 113 (1983).

Example 3 <Synthesis of Compound II-2 from Compound III-1> 0.44 g of S- (2-acetamido-3-thienyl) thioacetate (Compound III-1)
(2.0 mmol) and p-toluenesulfonic acid monohydrate 0.50 g
Was dissolved in 10 ml of n-propanol and heated on an oil bath set at 125 ° C. (internal temperature about 95 ° C.) for 2 hours. After cooling, the mixture was filtered, added with 30 ml of ethyl acetate, washed with aqueous sodium bicarbonate, concentrated, and distilled under reduced pressure (50 ° C./0.1 Torr) to give 2-methylthieno [2,2.
[3-d] thiazole (compound II-2) was obtained. Yield 0.22 g (71% yield). The physical properties of the obtained product are as described in J. Chem. Soc. P.
erkin Trans. I, page 1029 (1980).

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By using the synthesis method of the present invention, thienothiazoles, especially thienothiazoles represented by the general formula (II) can be easily produced.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Takanori Hioki 210 Nakanakanuma, Minamiashigara, Kanagawa Prefecture Fuji Photo Film Co., Ltd. F-term (reference) 4C023 GA03 4C071 AA01 BB01 CC11 CC21 DD02 EE13 FF15 HH11 HH17 JJ01 KK11 LL07 4C072 AA01 BB02 BB03 BB06 CC01 CC17 CC18 EE13 FF19 GG01 GG06 GG07 GG08 GG09 HH02 UU08

Claims (8)

[Claims] 1. A method for producing a thienothiazole heterocyclic compound, which comprises using a raw material in which a sulfur atom and a nitro group are substituted at adjacent positions on a thiophene ring in the synthesis of thienothiazoles. 2. The production of a heterocyclic compound according to claim 1, wherein the compound represented by the following general formula (I) is used as a raw material to synthesize a heterocyclic compound represented by the following general formula (II). Method. General formula (I) In the formula, Th represents a thiophene ring, which may have a substituent or may be condensed with another 5- or 6-membered carbon or heterocyclic ring. L represents a hydrogen atom, a metal atom or a monovalent substituent. General formula (II) In the formula, Th ¹ represents a thiophene ring, which may have a substituent or may be condensed with another 5- or 6-membered carbon or heterocyclic ring. R represents a hydrogen atom or a monovalent substituent. 3. The compound according to claim 2, wherein the compounds represented by the general formulas (I) and (II) are represented by the following general formulas (I ′) and (II ′), respectively. A method for producing a heterocyclic compound. General formula (I ') In the formula, V ¹ and V ² each represent a hydrogen atom or a monovalent substituent, and L ¹ represents a hydrogen atom, a metal atom or a monovalent substituent. General formula (II ') In the formula, V ¹¹ , V ¹² and R ¹ each represent a hydrogen atom or a monovalent substituent. 4. A method for producing a heterocyclic compound, comprising synthesizing a compound represented by the following general formula (III) using the compound represented by the general formula (I) as a raw material. General formula (III) In the formula, Th ² represents a thiophene ring, which may have a substituent or may be condensed with another 5- or 6-membered carbocyclic or heterocyclic ring. R ² and R ³ each represent a hydrogen atom, an alkyl group or an aryl group. 5. A compound represented by the general formula (III):
The method for producing a heterocyclic compound according to claim 4, wherein the method is represented by the following general formula (III '). General formula (III ') In the formula, V ²¹ and V ²² represent a hydrogen atom, a halogen atom,
Represents an alkyl group or an aryl group, wherein R ²¹ is a hydrogen atom,
Represents an alkyl group or an aryl group. 6. The compound represented by the general formula (I) or (I ′) is treated with a water-organic solvent 2 in the presence of a reducing agent and an acylating agent.
The method for producing a heterocyclic compound according to claim 4 or 5, wherein the compound represented by the general formula (III) or (III ') is synthesized by reacting in a phase system. 7. A compound represented by the general formula (I) or a metal salt, hydrogen sulfide or a metal salt thereof, or hydrogen.
The method for producing a heterocyclic compound according to any one of claims 1 to 6, wherein the method is via a reaction of reducing the compound represented by (I '). 8. A process for producing a thienothiazole heterocyclic compound, comprising synthesizing a heterocyclic compound represented by the general formula (II) using a compound represented by the general formula (III) as a raw material. .