JP2000026457A - Production of 3-aminothiophene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 3-aminothiophene derivative useful as a synthetic intermediate of a medicine, an agrochemical, etc., by reacting each specific thienyl halide derivative with an amine derivative in the presence of a copper catalyst, simply at a low cost in a high purity and in a high yield. SOLUTION: This new 3-aminothiophene derivative expressed by formula III is obtained by reacting a 3-thienyl halide derivative expressed by formula I (R1, R2 are each H, F, a lower alkyl, a lower alkoxy, a lower alkoxycarbonyl or a lower acyl; X is a halogen) with an amine derivative expressed by formula II (R3 is H or a lower alkyl; R4 is H, a lower alkyl or a lower alkyl substituted with hydroxyl) in the presence of a copper catalyst (amount of use is preferably 0.001-1 equivalent based on the derivative of formula I) consisting of a single substance or a mixture of two or more kinds selected from a metallic copper powder, metallic copper granules, a metallic copper wire, cuprous (I) oxide, cuprous (I) chloride, cuprous (I) bromide and cuprous (I) iodide, under a pressure of normal pressure to 1 MPa.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a very simple and inexpensive method for producing a 3-aminothiophene derivative. Various aminothiophene derivatives obtained by the production method of the present invention are used in a wide range of fields, such as being used as synthetic intermediates for various physiologically active substances such as pharmaceuticals and agricultural chemicals.

[0002]

2. Description of the Related Art Among 3-aminothiophene derivatives, N
-The following two methods are conventionally known for producing unsubstituted derivatives.

One is a method of directly producing 3-aminothiophene by treating 2-thienyl halide with potassium amide in liquid ammonia [Journal of American Chemical Society (J. Am. Ch.).
em. Soc. 1968, Vol. 90, p. 511, Recueil des Trabow Simikes des Pais-
Bus (Rec. Trav. Chim. Pays-Ba)
s) 1974, 93, 33 pages, Heterocycles 1976, 5, 37
7 pages]. The reaction is dangerous because it uses toxic or non-water ignitable chemicals, such as liquid ammonia or potassium amide, and prevents water from entering the reaction system and controls the reaction temperature to a very low level. Therefore, it was necessary to carefully perform extremely complicated work, and it was not always a simple method.

Another method uses 3-bromothiophene as a starting material and reacts it with phthalimide to produce 3-bromothiophene.
A phthalimidothiophene was synthesized, and then reacted in a polyalkylenepolyamine such as tetraethylenepentamine to decompose the imide.
-A method of recovering aminothiophene by distillation under reduced pressure [JP-A-1-128980]. However, this method requires a multi-step manufacturing process, which is not a simple method.

[0005] Apart from these, N-alkylated-3
-For producing aminothiophene derivatives,
Various methods for producing from the above-mentioned 3-aminothiophene are known. For example, 3-aminothiophene is reacted with formaldehyde in the presence of sodium borohydride,
There is a method for producing N-methyl-3-aminothiophene by a reductive amination reaction [Bretin de la.
Societe Simik de France (Bull. So
c. Chim. Fr. 1986, 259 pages). In addition, the amino group of 3-aminothiophene is acylated with a suitable carboxylic acid derivative or aldehyde derivative and the like to be converted to a corresponding amide or carbamate,
After alkylation, a method of producing various N, N-dialkylated-3-aminothiophene derivatives by subjecting the obtained compound to a reduction treatment with an appropriate reducing agent is also known [Journal of Organic Chemistry (J. Org. Chem.) 1965, Volume 30, 66
2 pages etc.].

However, these methods still require a multi-step production process, and the starting compound 3-
Since aminothiophene is a compound that is extremely unstable at room temperature, it is difficult to store and handle the raw materials until the start of the reaction, and this is not always a good method [Journal of American Chemical Society (J. Am. Chem. Soc.) 1954, 76
Vol. 2447, Recueil Death Trabow Simikes Des Pais-Bass (Rec. Trav. Chi)
m. Pays-Bas) 1982, 101, 205
Page etc.].

[0007] Some methods for producing N, N-dialkylated-3-aminothiophene derivatives which do not involve unstable 3-aminothiophene are also known. For example, 3-
Starting from thiophene carboxylic acid or its ester derivative as a starting material, the carboxyl group or ester group of these compounds is azido-treated to synthesize a carbonyl azide derivative, which is decomposed with an appropriate carboxylic acid or carboxylic acid anhydride, Leading to an acylated-3-aminothiophene derivative. This is subjected to N-alkylation treatment and reduction treatment in the same manner as described above to obtain various N, N-dialkylated-
This is a method for producing a 3-aminothiophene derivative [for example, Recueil des Trabom Simikes des.
Pice-Bus (Rec. Trav. Chim. Pays)
-Bas), 1982, 101, 205, and Journal of Organic Chemistry (J. Or.
g. Chem. 1979, 44, 3292, etc.].

These methods for producing N-alkylated-3-aminothiophenes can solve the problem of instability of the raw materials, but require an extremely complicated operation because the number of steps of the reaction process is further increased. . In addition, after the N-acylated-3-aminothiophene derivative as a production intermediate, a subsequent reduction treatment is required, and there is also a problem that an expensive reducing agent such as various metal hydrogen complex compounds is required. .

As described above, all of the methods for producing 3-aminothiophene derivatives have other steps or require complicated processing procedures. Not previously found. In addition, due to the complicated manufacturing process and the necessity of various expensive treatment chemicals or dangerous chemicals, the production cost is not always excellent.

[0010]

SUMMARY OF THE INVENTION An object of the present invention is to solve the above-mentioned many problems in the conventional production method and to provide a simple and inexpensive method for producing various desired 3-aminothiophene derivatives. It is in.

[0011]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of such a situation, and as a result, have used a stable 3-thienyl halide derivative as a starting material, and combined this with an appropriate amine derivative in the presence of a copper catalyst. The reaction is carried out in the same manner as described above, and in one step, N-unsubstituted 3
-Aminothiophene derivatives and various N-alkylations-
The inventors have found that both 3-aminothiophene derivatives can be produced, and have completed the present invention.

That is, the present invention provides a compound represented by the general formula [1]:

[0013]

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[Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom, a fluorine atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a lower acyl group. X represents a halogen atom. 3- represented by
A thienyl halide derivative represented by the general formula [2]:

[0015]

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Wherein R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ represents a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a hydroxyl group; The reaction is carried out at normal pressure or under pressure in the presence of a catalyst, characterized by the following general formula [3]:

[0017]

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Wherein R ¹ , R ² , R ³ and R ⁴ have the same meaning as described above. Hereinafter, the present invention will be described in detail.

First, definitions of terms used in this specification and specific examples thereof will be described. Unless otherwise specified, the term “lower” as used herein refers to a straight-chain, branched or cyclic hydrocarbon having 1 to 6 carbon atoms in a group to which the term is assigned. It shows that it contains a group.

Thus, as the lower alkyl group used for R ¹ , R ² , R ³ or R ⁴ , specifically, for example, methyl group, ethyl group, n-propyl group, isopropyl group,
n-butyl group, isobutyl group, sec-butyl group, te
rt-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl Group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3- Dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2- Methylpropyl group, cyclopropyl group, cyclopropylmethyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, etc.

More preferred lower alkyl groups used for the R ¹ , R ² or R ³ groups are the same or different and are methyl, ethyl, isopropyl and cyclopropyl. Further, as the alkyl group used for the R ⁴ group, a methyl group, an ethyl group, and an n-
Propyl, isopropyl, cyclopropyl, n-
Butyl group, isobutyl group, sec-butyl group or te
rt-butyl group.

Examples of the lower alkoxy group used for R ¹ or R ² include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, te
rt-butoxy group, pentyloxy group, 1-methylbutyloxy group, 2-methylbutyloxy group, 3-methylbutyloxy group, 1,2-dimethylpropyloxy group,
1,1-dimethylpropyloxy group, hexyloxy group, 1-methylpentyloxy group, 1-ethylpropyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 4-methylpentyloxy group, 2
-Dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2,3-dimethylbutyloxy group, 1,1-dimethylbutyloxy group, 2,2-dimethylbutyloxy group, 3,3-dimethylbutyloxy group And the like.
More preferably, they are the same or different and are a methoxy group, an ethoxy group or a propoxy group.

The lower alkoxycarbonyl group used for R ¹ or R ² includes, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, cyclopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl group, tert-
Butoxycarbonyl group and the like. More preferably, they are the same or different and are a methoxycarbonyl group, an ethoxycarbonyl group, and a propoxycarbonyl group.

The lower acyl group used for R ¹ or R ² includes, for example, formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group,
1-methylpropylcarbonyl group, isovaleryl group, pentylcarbonyl group, 1-methylbutylcarbonyl group,
Examples thereof include a 2-methylbutylcarbonyl group, a 3-methylbutylcarbonyl group, a 1-ethylpropylcarbonyl group, and a 2-ethylpropylcarbonyl group. More preferably, they are the same or different and are a formyl group, an acetyl group, and a propionyl group.

The lower alkyl group substituted by a hydroxyl group used in R ⁴ includes a hydroxymethyl group, a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 1-methyl-2-hydroxyethyl group, a 1,1- Dimethyl-2-hydroxyethyl group, 2-methyl-2-hydroxyethyl group, 2-methyl-2-hydroxypropyl group, 1-methyl-2-hydroxypropyl group, 1-hydroxymethylpropyl group, 1-ethyl-1 -Hydroxymethylpropyl group, 2-ethyl-2-hydroxybutyl group, 2-hydroxybutyl group, 1-ethyl-2-hydroxybutyl group, 3-hydroxypropyl group, 2,3-
Examples include a dihydroxypropyl group, a 2-methyl-3-hydroxypropyl group, and a 2,2-dimethyl-3-hydroxypropyl group. More preferably, 2-hydroxyethyl group, 1-methyl-2-hydroxyethyl group, 1,1
-Dimethyl-2-hydroxyethyl group, 2-methyl-2
-Hydroxyethyl group, 2-methyl-2-hydroxypropyl group or 2,3-dihydroxypropyl group.

In R ¹ and R ² , in addition to the lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group and lower acyl group, the same or different hydrogen atoms or fluorine atoms are preferably used. R
^{In 3} , a hydrogen atom is preferably used in addition to the lower alkyl group described above. In R ⁴ , a hydrogen atom is preferably used in addition to the above-mentioned lower alkyl group and lower alkyl group substituted by a hydroxy group.
-The method for producing the aminothiophene derivative will be described.

The method for producing the compound represented by the above general formula [3] according to the present invention is described in the following reaction formula [I], in which a 3-thienyl halide derivative represented by the general formula [1] It reacts with the amine derivative represented by [2]. Many of the conventional methods for producing these 3-aminothiophene derivatives require a multi-step reaction process, but have the characteristic that they can be simply produced in one step.

Reaction formula [I]

[0029]

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[Wherein, X represents a halogen atom. R ¹ ,
R ² , R ³ and R ⁴ have the same meaning as described above. This reaction is carried out using a copper catalyst under normal pressure or pressure under no solvent or in a solvent.

In the compound represented by the general formula [I], X
Is a halogen atom, specifically, chlorine, bromine, iodine and the like. Particularly preferred is a bromine atom. Such a compound [1] is a compound which is usually stable at room temperature,
It is easier to handle than 3-aminothiophene, and can be stored for a long time. This compound [1]
Is commercially available or can be easily obtained by the method described in the literature as described later.

As the copper catalyst used in the reaction, zero-valent metal copper or monovalent copper salt is particularly preferably used.
Specific examples of the zero-valent metallic copper include metallic copper powder, metallic copper particles, metallic copper wire, and the like. Specific examples of the monovalent copper salt include, for example, copper (I) oxide, copper (I) chloride, copper (I) bromide, and copper (I) iodide. In some cases, copper (II) oxide, copper chloride (I
A divalent copper salt such as I), copper (II) bromide, copper (II) iodide or copper (II) acetate can also be used.

These copper catalysts may be used alone or as a mixture of two or more. The amount of the copper catalyst to be used is preferably 0.001 to 1 equivalent, more preferably 0.1 to 0.5 equivalent, relative to compound [1]. The pressure during the reaction is preferably normal pressure to 1 megapascal (1 MPa), more preferably normal pressure to 0.5 megapascal (0.5 MPa).

The compound [1] and the compound [2] are preferably reacted with each other in an equimolar amount or in an excess molar amount of the compound [2]. Diethyl ether as a reaction solvent,
Ether solvents such as diisopropyl ether, tetrahydrofuran, dioxane, methanol, ethanol, n
-Alcohol solvents such as propyl alcohol and isopropyl alcohol, benzene, toluene, o-xylene,
Aromatic hydrocarbon solvents such as p-xylene, aprotic polar solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide and the like can be used. When the compound [2] is liquid at room temperature, a large excess amount of the compound [2] may be used as a solvent. The reaction temperature and reaction time of this reaction are preferably from room temperature to 200 ° C. and from several minutes to 24 hours, but the preferred values may differ depending on the starting compounds [1] and [2]. Therefore, it is not necessarily limited to this range.

In this reaction, a basic substance may be added, if necessary, for the purpose of accelerating the reaction. Examples of such a basic substance include inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate; and hydrogen such as sodium hydride and lithium hydride. Alkali metal hydrides, alkaline earth metal hydrides such as calcium hydride, n-butyllithium, sec-butyllithium, tert-butyllithium, organolithium compounds such as lithium diisopropylamide, sodium ethoxide, potassium-tert-butoxide, Sodium-t
alkali metal alkoxides such as ert-butoxide; or organic bases such as pyridine, collidine, lutidine, triethylamine, trimethylenediamine, 1,8-diaza-bicyclo [5.4.0] -7-undecene (DBU). Can be.

This reaction is desirably carried out in an inert gas atmosphere for the purpose of preventing undesired side reactions such as an oxidation reaction and a polymerization reaction. Examples of such an inert gas include nitrogen, helium, and argon.

Of the starting compounds used in the above reaction,
Compound [1] may be purchased as a commercial product or may be prepared according to the method described in the literature [Journal of Organic Chemistry (J. Org. Chem) 1971, 36, 1].
8, 2690, 1971, 36, 24, 3
820 pages, Synthesis 1972
Year 10, No. 545, Synthetic Communications (Synth. Commun) 1981, 1
Volume 1, Issue 1, Page 25, Acta Pharmaceuticals
Suesika (Ata Pharm. Suec) 1978
Year, Volume 15, Issue 5, p. 368, Chemica Scripta (C
kem. Scr. 1980, Vol. 16, No. 1-2, 3
8, Archif del Falmatzy (Arch.
Pharm. 1991, Vol. 324, No. 9, 563
Pages and the Journal of Heterocyclic Chemistry (J. Heterocycll. Chem.)
1983, Vol. 20, No. 1, p. 113, etc.], and a method analogous thereto.

A part of the compound [2] can be purchased as a commercial product, and the others (represented by the general formula [2 ']. All [2'] are included in [2]. ) Can be produced, for example, by a synthesis reaction represented by the following reaction formula [II].

Reaction formula [II]

[0040]

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Wherein Y is a leaving group. R ^{3 ′} is the same as R ³ except for the case of a hydrogen atom, that is, a lower alkyl group. R ⁴ has the same meaning as described above. The above reaction is a generally well-known alkylation reaction of an amine, for example, in the presence or absence of a basic substance,
It can be produced by reacting at -80 ° C to 100 ° C for several minutes to 24 hours in a solvent-free or solvent. In the general formula [4], Y is a leaving group, specifically, chlorine, bromine,
Examples thereof include a halogen atom such as iodine, and a sulfonyloxy group such as a methanesulfonyloxy group and a p-toluenesulfonyloxy group. As the basic substance used in the above reaction, the same basic substance used as necessary in the reaction represented by the reaction formula [I] can be used.

The compound [2] is supplied as various solutions such as aqueous solution, methanol solution, ethanol solution or ether solution, or various acid addition salts such as hydrochloride or sulfate from the viewpoint of storage stability and handleability. Sometimes. Among them, when supplied as a solution, the solvent does not necessarily need to be removed and can be used as it is. When the solvent can be removed by a treatment such as distillation, distillation under reduced pressure, or extraction, the solvent can be used after removing the solvent.
When supplied in the form of various acid addition salts, after dissolving or dispersing in water or an alcohol such as methanol, the above-mentioned basic substance is added to convert the compound into a free amine derivative before use. Can be.

In each of the reaction steps described above, if a compound used as a raw material contains a lower alkyl group substituted with a hydroxyl group, an undesirable side reaction may be caused. The lever hydroxyl group can be protected in advance by a protecting group. The protecting group to be used is not particularly limited as long as it is a protecting group for a general aliphatic hydroxyl group. For example, a methoxymethyl group, a 2-methoxyethoxymethyl group,
Examples include a tetrahydropyranyl group, a t-butyldimethylsilyl group, an acetyl group, a formyl group, and a methoxycarbonyl group. When these protecting groups are used, they are deprotected after the above reaction. As the reaction conditions for protection and deprotection, the target compound or the starting compound of the present invention obtained in each of the above steps which can be carried out by a generally well-known method may be subjected to solvent extraction, distillation, recrystallization, or column chromatography. It can be isolated and purified by a usual method such as chromatography.

[0044]

According to the method for producing a 3-aminothiophene derivative of the present invention, a complicated production step often used in the conventional production method is not required, and it can be produced in one step from a stable raw material. The production of the 3-aminothiophene derivative becomes extremely easy, and it is not necessary to use an expensive treatment agent or a dangerous agent, so that the production can be performed at lower cost. Therefore, the method for producing a 3-aminothiophene derivative of the present invention can be widely used not only for production on a small scale when producing these derivatives but also for production on an industrial scale.

[0045]

EXAMPLES The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Synthesis of N-methyl-3-aminothiophene 75 g of 3-bromothiophene, 280 ml of a 40% methanol solution of methylamine and 16.6 g of copper (I) oxide were placed in a 1-liter autoclave made of metal. After filling the inside of the container with nitrogen gas, the container was closed and stirred at 50 ° C. for 6 hours. The internal pressure at this time is 0.23 MPa
Met. After completion of the reaction, the obtained reaction solution was diluted with 750 ml of diethyl ether, and the reaction solution was separated into two layers. Of these, only the upper layer was gently taken out by decantation, and some insolubles composed of copper oxide and the like were removed by filtration using celite. The obtained filtrate was acidified by adding 450 ml of a 1N aqueous hydrochloric acid solution, and then washed with diethyl ether. Collect the aqueous layer, 5N until pH is around 10
Caustic soda aqueous solution was added for neutralization. After ether was added to the mixture and the mixture was repeatedly extracted, the organic layer was collected, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 35 g of the desired N-methyl-3-aminothiophene.

¹ H-NMR (500 MHz, CDCl ₃ ,
δ ppm) 2.83 (s, 3H), 3.65 (brs,
1H), 5.96 (dd, J = 1.5, 3.0, 1
H), 6.63 (dd, J = 1.5, 5.0, 1H),
7.17 (dd, J = 3.0, 5.0, 1H).

Example 2 Synthesis of N- (2-hydroxyethyl) -N-methyl-3-aminothiophene 15 g of 3-bromothiophene, 41.5 g of N-methylethanolamine and 3.3 g of copper (I) oxide were replaced with nitrogen. Under an atmosphere, the mixture was heated and stirred at atmospheric pressure and 70 ° C. for 18 hours. After completion of the reaction, the reaction mixture was filtered through celite to remove copper oxide and insolubles, and then 300 ml of water was added, followed by extraction with diethyl ether. The collected organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 6: 1) to obtain the desired N- (2-hydroxyethyl) -N-methyl-3.
-13.2 g of aminothiophene were obtained.

¹ H-NMR (500 MHz, CDCl ₃ ,
δ ppm) (s, 1H), 2.88 (s, 3H), 3.
33 (t, J = 5.5 Hz, 2H), 3.75-3.8
1 (m, 2H), 6.02-6.07 (m, 1H),
6.82-6.86 (m, 1H), 6.05 (dd, J
= 1.5 Hz, 1H), 6.83 (dd, J = 1.5H)
z, 1H), 7.22-7.26 (m, 1H) IR (neat, cm ^-1 ) 3360, 2940, 28
60, 1550, 1415, 1045, 745

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Yasuaki Hanasaki 4-40-9-203 Shonandai, Fujisawa-shi, Kanagawa (72) Inventor Kimio Katsuura 2-23-3 Nishi-Ochiai, Shinjuku-ku, Tokyo F-term (reference) 4C023 GA01 4H039 CA42 CA71 CD10 CD20

Claims (5)

[Claims] 1. A compound of the general formula [1] [Wherein R ¹ and R ² are the same or different and each represent a hydrogen atom,
It represents a fluorine atom, a lower alkyl group, a lower alkoxy group, a lower alkoxycarbonyl group or a lower acyl group. X
Represents a halogen atom. A 3-thienyl halide derivative represented by the general formula [2]: [Wherein R ³ represents a hydrogen atom or a lower alkyl group, R ⁴
Represents a hydrogen atom, a lower alkyl group or a lower alkyl group substituted with a hydroxyl group] with an amine derivative represented by the following formula: General formula [3] [Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above]. 2. A copper catalyst comprising metallic copper powder, metallic copper particles, metallic copper wire,
The single substance selected from copper oxide (I), copper chloride (I), copper bromide (I), and copper (I) iodide, or a mixture of two or more kinds thereof. A method for producing a 3-aminothiophene derivative of the above. 3. The amount of the copper catalyst added is 0.001 to 1 with respect to the 3-thienyl halide derivative represented by the general formula [1].
3. The method according to claim 1, wherein the amount is equivalent.
-A method for producing an aminothiophene derivative. 4. The method according to claim 1, wherein the pressure during the reaction is from normal pressure to 1 megapascal.
-A method for producing an aminothiophene derivative. 5. The method according to claim 1, wherein the halogen atom represented by X is a bromine atom.
Method for producing aminothiophene derivative.