JP4321800B2 - Process for producing 2-bromothiophene-5-sulfonyl chloride - Google Patents

Description

で表される２−ブロモチオフェンのジメチルホルムアミド溶液を調製し、該溶液を硫酸の存在下にチオニルクロライドまたはクロルスルホン酸と反応させて化学式（２）
【化１８】

で表される２−ブロモチオフェン−５−スルホン酸を製造し、該２−ブロモチオフェン−５−スルホン酸をアルカリ金属塩と反応させて化学式（３）
【化１９】

で表される２−ブロモチオフェン−５−スルホン酸アルカリ金属塩を製造し、該２−ブロモチオフェン−５−スルホン酸アルカリ金属塩をチオニルクロライドまたはクロルスルホン酸と反応させることにより化学式（４）
【化２０】

で表される２−ブロモチオフェン−５−スルホニルクロライドを製造することを特徴とするものである。
【００１０】
また、別の態様として本発明の２−ブロモチオフェン−５−スルホニルクロライドの製造方法は、化学式（１）
【化２１】

で表される２−ブロモチオフェンのジメチルホルムアミド溶液を調製し、該溶液を硫酸の存在下にチオニルクロライドまたはクロルスルホン酸と反応させて化学式（２）
【化２２】

で表される２−ブロモチオフェン−５−スルホン酸を製造し、該２−ブロモチオフェン−５−スルホン酸をチオニルクロライドまたはクロルスルホン酸と反応させることにより化学式（４）
【化２３】

で表される２−ブロモチオフェン−５−スルホニルクロライドを製造することを特徴とするものである。
【００１１】
前記２−ブロモチオフェン−５−スルホン酸は反応液から単離してチオニルクロライドまたはクロルスルホン酸と反応させてもよいし、単離することなく反応液のまま反応させてもよいが、２−ブロモチオフェン−５−スルホン酸は高い選択性で得られるので、単離することなく反応液のまま反応させた方がより収率が高まるので好ましい。
【００１２】
【発明の効果】
本発明の２−ブロモチオフェン−５−スルホニルクロライドの製造方法は、ジメチルホルムアミド共存下において２−ブロモチオフェンに硫酸を反応させることによって、２−ブロモチオフェンを分解することなく、高い選択性と収率で２−ブロモチオフェン−５−スルホン酸を製造することができる。
【００１３】
また、環境負荷の大きい五塩化リンや１，２−ジクロロエタンを使用することなく、高い選択性と収率で２−ブロモチオフェン−５−スルホニルクロライドを製造することができるため、医薬品中間体として有用な２−ブロモチオフェン−５−スルホニルクロライドを工業的に製造することが可能となる。
【００１４】
【発明の実施の形態】
以下、本発明の内容をさらに詳細に説明する。
２−ブロモチオフェンから２−ブロモチオフェン−５−スルホン酸の合成反応におけるジメチルホルムアミドの使用量は特に限定はされないが、２−ブロモチオフェン１モルに対して０．１〜１０モルが好ましく、さらに０．５〜２モルの範囲であることが好ましい。硫酸の使用量は、２−ブロモチオフェン１モルに対して０．８〜１．５モルが好ましく、さらには１〜１．２モルの範囲であることが好ましい。チオニルクロライドまたはクロルスルホン酸の使用量は２−ブロモチオフェン１モルに対して１〜１０モルの範囲であることが好ましく、さらには２〜４モルの範囲であることが好ましい。この２−ブロモチオフェン−５−スルホン酸の合成反応の反応温度は通常−１０〜８０℃で行うことができるが、３０℃以上ではクロル化も同時に進行する。速やかに反応させるためには０〜３０℃で反応させることが好ましく、１〜２４時間で反応は終了する。
【００１５】
２−ブロモチオフェン−５−スルホン酸の合成反応は反応選択性が極めて良好であるため、反応終了後、２−ブロモチオフェン−５−スルホン酸を単離することなく反応液のまま次のクロル化反応に使用することができる。もちろん、単離した後、クロル化してもよい。２−ブロモチオフェン−５−スルホン酸を単離することなく、反応液のまま次のクロル化反応に供する場合、２−ブロモチオフェン−５−スルホン酸の合成反応において、チオニルクロライドまたはクロルスルホン酸を２−ブロムチオフェン１モルに対し３モル以上使用した場合にはそのまま、３モル以下の場合にはチオニルクロライドまたはクロルスルホン酸を追加して３モル以上とし反応を行うことができる。反応温度は通常３０〜８０℃の範囲で進行し、速やかに反応させるためには６０〜７０℃で反応させることが好ましく、１〜２４時間で反応は終了し、目的とする２−ブロモチオフェン−５−スルホニルクロライドを得ることができる。
【００１６】
２−ブロモチオフェン−５−スルホン酸は、上記のようにそのままクロル化に供することもできるが、アルカリ金属塩で２−ブロモチオフェン−５−スルホン酸アルカリ金属塩とした後、クロル化してもよい。アルカリ金属塩としては、水酸化ナトリウム、水酸化カリウム、炭酸ナトリウム炭酸カリウム、炭酸水素ナトリウム、炭酸水素カリウムなどを用いることができる。アルカリ金属塩の使用量は、使用した全ての酸に対して０．５〜２当量が好ましく、さらには０．９〜１．２当量の範囲であることが好ましい。反応液より２−ブロモチオフェン−５−スルホン酸をアルカリ金属塩として取り出す場合には、反応液を水に分散し、アルカリ金属塩を加えて中和し、冷却晶析して固液分離を行うことが好ましい。固液分離することによって、純度をより高くすることができる。
【００１７】
２−ブロモチオフェン−５−スルホン酸を単離して、あるいは２−ブロモチオフェン−５−スルホン酸アルカリ金属塩から２−ブロモチオフェン−５−スルホニルクロライドを生成させるクロル化反応は、２−ブロモチオフェン−５−スルホン酸、２−ブロモチオフェン−５−スルホン酸アルカリ金属塩それぞれ１モルに対してチオニルクロライドまたはクロルスルホン酸１〜５モル、好ましくは１．２〜３モルを用いる。クロル化反応に際しては、溶媒としてジメチルホルムアミドを用いることが好ましく、その使用量は特に限定はされないが、反応基質（２−ブロモチオフェン−５−スルホン酸あるいは２−ブロモチオフェン−５−スルホン酸アルカリ金属塩）１モルに対し、好ましくは０．１〜１０モル、さらに好ましくは０．５〜２モルである。反応温度は通常３０〜８０℃の範囲で進行し、速やかに反応させるためには６０〜７０℃で反応させることが好ましく、１〜２４時間で反応は終了し、目的とする２−ブロモチオフェン−５−スルホニルクロライドを得ることができる。
【００１８】
２−ブロモチオフェン−５−スルホニルクロライドは、クロル化反応終了後、反応液を水に分散し分液し有機溶媒で抽出し濃縮後、冷却晶析した２−ブロモチオフェン−５−スルホニルクロライドを固液分離等の操作で取り出すことができる。
次に本発明を実施例によってより詳細に説明する。
【００１９】
【実施例】
（実施例１）
２−ブロモチオフェン16.3g(0.100mol)にジメチルホルムアミド5.0g(0.068mol)を加え、10〜30℃で濃硫酸11.0g(0.110mol)を滴下した。続けて、チオニルクロライド40.0g(0.336mol)を10〜20℃で滴下した。滴下終了後、室温で12時間熟成しスルホン化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホン酸96.4%、２−ブロモチオフェン1.5%であった。この反応液を70℃に昇温し２時間熟成、クロル化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホニルクロライド96.0%、２− ブロモチオフェン−５−スルホン酸1.0%、２−ブロモチオフェン0.2%であった。この反応液を水30ml中に5〜15℃で分散し、ヘキサン80mlを加え抽出、水洗後、ヘキサン層を濃縮しヘキサン60mlを回収した。濃縮液に室温でタネ晶を加え結晶を析出させ、５℃まで冷却した後、析出した結晶を濾過し、冷ヘキサンで洗浄し、減圧乾燥して２−ブロモチオフェン−５−スルホニルクロライドの結晶18.3g(0.070mol)を得た。収率70%
【００２０】
（実施例２）
２−ブロモチオフェン16.3g(0.100mol)にジメチルホルムアミド5.0g(0.068mol)を加え、10〜30℃で濃硫酸11.0g(0.110mol)を滴下した。続けて、チオニルクロライド40.0g(0.336mol)を10〜20℃で滴下した。滴下終了後、室温で12時間熟成しスルホン化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホン酸96.4%、２−ブロモチオフェン1.5%であった。この反応液を水30ml中に5〜15℃で分散し、48%水酸化カリウムで中和後、10℃まで冷却し、析出した結晶を濾過し、冷水及びメタノールで洗浄後、減圧乾燥して２−ブロモチオフェン−５−スルホン酸カリウムの結晶20.2gを得た。収率70%
【００２１】
（実施例３）
２−ブロモチオフェン16.3g(0.100mol)にジメチルホルムアミド5.0g(0.068mol)を加え、10〜30℃で濃硫酸11.0g(0.110mol)を滴下した。続けて、チオニルクロライド40.0g(0.336mol)を10〜20℃で滴下した。滴下終了後、室温で12時間熟成しスルホン化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホン酸96.4%、２−ブロモチオフェン1.5%であった。この反応液を70℃に昇温し２時間熟成、クロル化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホニルクロライド96.0%、２−ブロモチオフェン−５−スルホン酸1.0%、２−ブロモチオフェン0.2%であった。この反応液を水30ml中に5〜15℃で分散し、クロロホルム30mlを加え抽出、水洗後、クロロホルム層を濃縮してオイル状の２−ブロモチオフェン−５−スルホニルクロライド23.8g(0.091mol)を得た。収率91%
【００２２】
（実施例４）
２−ブロモチオフェン16.3g(0.100mol)にジメチルホルムアミド5.0g(0.068mol)を加え、10〜30℃で濃硫酸11.0g(0.110mol)を滴下した。続けて、クロルスルホン酸42.6g(0.336mol)を10〜20℃で滴下した。滴下終了後、室温で12時間熟成しスルホン化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホン酸95.2%、２−ブロモチオフェン0.1%、２−ブロモチオフェン−５−スルホニルクロライド1.2%であった。この反応液を70℃に昇温し２時間熟成、クロル化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホニルクロライド93.8%、２−ブロモチオフェン−５−スルホン酸0.5%、２−ブロモチオフェン0.2%であった。この反応液を水30ml中に5〜15℃で分散し、ヘキサン80mlを加え抽出、水洗後、ヘキサン層を濃縮しヘキサン60mlを回収した。濃縮液に室温でタネ晶を加え結晶を析出させた後、５℃まで冷却し、析出した結晶を濾過し、冷ヘキサンで洗浄し、減圧乾燥して２−ブロモチオフェン−５−スルホニルクロライドの結晶18.0g(0.069mol)を得た。収率69%
【００２３】
（実施例５）
２−ブロモチオフェン16.3g(0.100mol)にジメチルホルムアミド5.0g(0.068mol)を加え、10〜30℃で濃硫酸11.0g(0.110mol)を滴下した。続けて、チオニルクロライド40.0g(0.336mol)を10〜20℃で滴下した。滴下終了後、室温で12時間熟成しスルホン化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホン酸96.4%、２−ブロモチオフェン1.5%であった。この反応液を飽和食塩水30ml中に５〜15℃で分散し、０℃まで冷却した後、析出した結晶を濾過し、冷水で洗浄後、減圧乾燥して２−ブロモチオフェン−５−スルホン酸の結晶12.0gを得た。収率48%
【００２４】
（実施例６）
チオニルクロライド40.0g(0.336mol)に２−ブロモチオフェン−５−スルホン酸カリウム28.8g(0.100mol)を加え、ジメチルホルムアミド5.0g(0.068mol)を10〜30℃で滴下した。滴下終了後、70℃に昇温し２時間熟成、クロル化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホニルクロライド98.0%、２−ブロモチオフェン−５−スルホン酸0.3%であった。この反応液を水30ml中に５〜15℃で分散し、クロロホルム30mlを加え抽出、水洗後、クロロホルム層を濃縮してオイル状の２−ブロモチオフェン−５−スルホニルクロライド24.0g(0.092mol)を得た。収率92%
【００２５】
（実施例７）
クロルスルホン酸42.6g(0.336mol)に２−ブロモチオフェン−５−スルホン酸25.0g(0.100mol)を加え、ジメチルホルムアミド5.0g(0.068mol)を10〜30℃で滴下した。滴下終了後、70℃に昇温し２時間熟成、クロル化反応を完結させた。反応液をＨＰＬＣ分析すると２−ブロモチオフェン−５−スルホニルクロライド96.0%、２−ブロモチオフェン−５−スルホン酸0.5%であった。この反応液を水30ml中に５〜15℃で分散し、クロロホルム30mlを加え抽出、水洗後、クロロホルム層を濃縮してオイル状の２−ブロモチオフェン−５−スルホニルクロライド23.5g(0.090mol)を得た。収率90%
【００２６】
以上のように、本発明の２−ブロモチオフェン−５−スルホニルクロライドの製造方法は、ジメチルホルムアミド共存下において２−ブロモチオフェンに硫酸を反応させることによって、２−ブロモチオフェンを分解することなく、高い選択性と収率で２−ブロモチオフェン−５−スルホン酸を製造することができた。[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a method for producing 2-bromothiophene-5-sulfonyl chloride useful as a pharmaceutical intermediate.
[0002]
[Prior art]
In the laboratory, sulfonyl chloride can be produced by a method of sulfonating with sulfuric acid and then chlorinating, or a method of chlorosulfonating by reacting sulfur dioxide with chlorine or sulfuryl chloride, but 2-bromothiophene-5-sulfonyl Even if these methods are applied to the synthesis of chloride, the selectivity is very low or the raw material 2-bromothiophene is decomposed, so that these methods cannot provide a yield that can be industrialized.
[0003]
As an example of synthesis of 2-bromothiophene-5-sulfonyl chloride, 2-bromothiophene was reacted in a 1,2-dichloroethane solvent in the presence of chlorosulfonic acid and phosphorus pentachloride at −5 ° C. to 0 ° C. A method of dispersing and extracting a liquid to obtain 2-bromothiophene-5-sulfonyl chloride is known (Patent Document 1 and Patent Document 2).
[0004]
However, since these methods use phosphorus pentachloride, there are the following problems in industrialization. First, phosphorus pentachloride generates harmful fumes when it comes into contact with air and decomposes it, so special equipment is required for handling. Secondly, since phosphorous pentachloride is used, a large amount of phosphoric acid waste liquid is finally generated, and 1,2-dichloroethane, which has a large load on the environment, is used as a solvent. Third, when the target product is isolated after completion of the above reaction, it is necessary to disperse the reaction mixture in water. However, the decomposition of the phosphorus compound is slow at low temperatures and the target 2-bromo compound at high temperatures. There is a problem that thiophene-5-sulfonyl chloride is also decomposed at the same time, and the expected yield cannot be obtained.
[0005]
[Patent Document 1]
JP-A-57-183787 [0006]
[Patent Document 2]
International Publication No. 01/79201 Pamphlet [0007]
[Problems to be solved by the invention]
The present invention has been made in view of the above circumstances, and can produce 2-bromothiophene-5-sulfonyl chloride with high selectivity and yield without using environmentally harmful phosphorus pentachloride or 1,2-dichloroethane. An object of the present invention is to provide a process for producing 2-bromothiophene-5-sulfonyl chloride, which can be performed.
[0008]
[Means for Solving the Problems]
As a result of intensive studies, the present applicant has found that when 2-bromothiophene is reacted with sulfuric acid in the presence of dimethylformamide (DMF), 2-bromothiophene is not decomposed and 2-bromothiophene- It has been found that 5-sulfonic acid can be produced, and has led to the present invention.
[0009]
That is, the method for producing 2-bromothiophene-5-sulfonyl chloride of the present invention has the chemical formula (1)
Embedded image

A dimethylformamide solution of 2-bromothiophene represented by the formula is reacted with thionyl chloride or chlorosulfonic acid in the presence of sulfuric acid to give a chemical formula (2)
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2-bromothiophene-5-sulfonic acid represented by the formula (2), and the 2-bromothiophene-5-sulfonic acid is reacted with an alkali metal salt to give a chemical formula (3)
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2-bromothiophene-5-sulfonic acid alkali metal salt represented by the formula (4), and reacting the 2-bromothiophene-5-sulfonic acid alkali metal salt with thionyl chloride or chlorosulfonic acid,
Embedded image

2-bromothiophene-5-sulfonyl chloride represented by the formula is produced.
[0010]
In another embodiment, the method for producing 2-bromothiophene-5-sulfonyl chloride of the present invention has the chemical formula (1)
Embedded image

A dimethylformamide solution of 2-bromothiophene represented by the formula is reacted with thionyl chloride or chlorosulfonic acid in the presence of sulfuric acid to give a chemical formula (2)
Embedded image

2-bromothiophene-5-sulfonic acid represented by the formula (1), and the 2-bromothiophene-5-sulfonic acid is reacted with thionyl chloride or chlorosulfonic acid to give a chemical formula (4)
Embedded image

2-bromothiophene-5-sulfonyl chloride represented by the formula is produced.
[0011]
The 2-bromothiophene-5-sulfonic acid may be isolated from the reaction solution and reacted with thionyl chloride or chlorosulfonic acid, or may be reacted as it is without isolation. Since thiophene-5-sulfonic acid can be obtained with high selectivity, it is preferable to react with the reaction solution without isolation because the yield is further increased.
[0012]
【The invention's effect】
The method for producing 2-bromothiophene-5-sulfonyl chloride of the present invention is a method in which 2-bromothiophene is reacted with sulfuric acid in the presence of dimethylformamide, whereby high selectivity and yield are obtained without decomposing 2-bromothiophene. 2-Bromothiophene-5-sulfonic acid can be produced.
[0013]
In addition, 2-bromothiophene-5-sulfonyl chloride can be produced with high selectivity and yield without using phosphorus pentachloride or 1,2-dichloroethane, which have a large environmental impact, and is useful as a pharmaceutical intermediate. 2-bromothiophene-5-sulfonyl chloride can be industrially produced.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the contents of the present invention will be described in more detail.
The amount of dimethylformamide used in the synthesis reaction of 2-bromothiophene to 2-bromothiophene-5-sulfonic acid is not particularly limited, but is preferably 0.1 to 10 moles per mole of 2-bromothiophene, and is further 0 It is preferable that it is the range of 0.5-2 mol. The amount of sulfuric acid used is preferably 0.8 to 1.5 mol, more preferably 1 to 1.2 mol, per 1 mol of 2-bromothiophene. The amount of thionyl chloride or chlorosulfonic acid used is preferably in the range of 1 to 10 mol, more preferably in the range of 2 to 4 mol, with respect to 1 mol of 2-bromothiophene. The reaction temperature of the synthesis reaction of 2-bromothiophene-5-sulfonic acid can usually be carried out at −10 to 80 ° C., but chlorination proceeds simultaneously at 30 ° C. or higher. In order to make it react rapidly, it is preferable to make it react at 0-30 degreeC, and reaction is complete | finished in 1 to 24 hours.
[0015]
Since the reaction selectivity of 2-bromothiophene-5-sulfonic acid is extremely good, the next chlorination is carried out without isolating 2-bromothiophene-5-sulfonic acid after the completion of the reaction. Can be used for reaction. Of course, it may be chlorinated after isolation. When 2-bromothiophene-5-sulfonic acid is used for the next chlorination reaction without isolating 2-bromothiophene-5-sulfonic acid, in the synthesis reaction of 2-bromothiophene-5-sulfonic acid, thionyl chloride or chlorosulfonic acid is used. When 3 mol or more is used per 1 mol of 2-bromothiophene, the reaction can be carried out by adding thionyl chloride or chlorosulfonic acid to 3 mol or more as it is when the amount is 3 mol or less. The reaction temperature usually proceeds in the range of 30 to 80 ° C., and it is preferable to react at 60 to 70 ° C. for rapid reaction. The reaction is completed in 1 to 24 hours, and the desired 2-bromothiophene- 5-sulfonyl chloride can be obtained.
[0016]
2-Bromothiophene-5-sulfonic acid can be directly subjected to chlorination as described above, but may be chlorinated after being converted to an alkali metal salt of 2-bromothiophene-5-sulfonic acid with an alkali metal salt. . As an alkali metal salt, sodium hydroxide, potassium hydroxide, sodium carbonate potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc. can be used. The amount of the alkali metal salt used is preferably 0.5 to 2 equivalents, more preferably 0.9 to 1.2 equivalents with respect to all the acids used. When 2-bromothiophene-5-sulfonic acid is taken out from the reaction solution as an alkali metal salt, the reaction solution is dispersed in water, neutralized by adding an alkali metal salt, cooled and crystallized for solid-liquid separation. It is preferable. By performing solid-liquid separation, the purity can be further increased.
[0017]
The chlorination reaction to isolate 2-bromothiophene-5-sulfonic acid or to produce 2-bromothiophene-5-sulfonyl chloride from 2-bromothiophene-5-sulfonic acid alkali metal salt is a 2-bromothiophene- 1 to 5 mol, preferably 1.2 to 3 mol, of thionyl chloride or chlorosulfonic acid is used per 1 mol of 5-sulfonic acid and 2-bromothiophene-5-sulfonic acid alkali metal salt. In the chlorination reaction, it is preferable to use dimethylformamide as a solvent, and the amount used is not particularly limited, but the reaction substrate (2-bromothiophene-5-sulfonic acid or 2-bromothiophene-5-sulfonic acid alkali metal) The salt is preferably 0.1 to 10 mol, more preferably 0.5 to 2 mol, per 1 mol. The reaction temperature usually proceeds in the range of 30 to 80 ° C., and it is preferable to react at 60 to 70 ° C. for rapid reaction. The reaction is completed in 1 to 24 hours, and the desired 2-bromothiophene- 5-sulfonyl chloride can be obtained.
[0018]
2-Bromothiophene-5-sulfonyl chloride is obtained by dispersing the reaction solution in water after separation of the chlorination reaction, separating the solution, extracting with an organic solvent, concentrating, and cooling-crystallized 2-bromothiophene-5-sulfonyl chloride. It can be taken out by operations such as liquid separation.
Next, the present invention will be described in more detail with reference to examples.
[0019]
【Example】
Example 1
To 16.3 g (0.100 mol) of 2-bromothiophene was added 5.0 g (0.068 mol) of dimethylformamide, and 11.0 g (0.110 mol) of concentrated sulfuric acid was added dropwise at 10-30 ° C. Subsequently, 40.0 g (0.336 mol) of thionyl chloride was added dropwise at 10 to 20 ° C. After completion of the dropwise addition, the mixture was aged at room temperature for 12 hours to complete the sulfonation reaction. The reaction mixture was analyzed by HPLC to find that it was 96.4% 2-bromothiophene-5-sulfonic acid and 1.5% 2-bromothiophene. The reaction solution was heated to 70 ° C. and aged for 2 hours to complete the chlorination reaction. As a result of HPLC analysis of the reaction solution, it was 96.0% 2-bromothiophene-5-sulfonyl chloride, 1.0% 2-bromothiophene-5-sulfonic acid, and 0.2% 2-bromothiophene. This reaction solution was dispersed in 30 ml of water at 5 to 15 ° C., extracted with 80 ml of hexane, washed with water, and then concentrated in the hexane layer to recover 60 ml of hexane. Seed crystals were added to the concentrate at room temperature to precipitate crystals, which were cooled to 5 ° C., then the precipitated crystals were filtered, washed with cold hexane, dried under reduced pressure, and crystals of 2-bromothiophene-5-sulfonyl chloride 18.3. g (0.070 mol) was obtained. Yield 70%
[0020]
(Example 2)
To 16.3 g (0.100 mol) of 2-bromothiophene was added 5.0 g (0.068 mol) of dimethylformamide, and 11.0 g (0.110 mol) of concentrated sulfuric acid was added dropwise at 10-30 ° C. Subsequently, 40.0 g (0.336 mol) of thionyl chloride was added dropwise at 10 to 20 ° C. After completion of the dropwise addition, the mixture was aged at room temperature for 12 hours to complete the sulfonation reaction. The reaction solution was analyzed by HPLC to find that it was 96.4% 2-bromothiophene-5-sulfonic acid and 1.5% 2-bromothiophene. This reaction solution was dispersed in 30 ml of water at 5 to 15 ° C., neutralized with 48% potassium hydroxide, cooled to 10 ° C., the precipitated crystals were filtered, washed with cold water and methanol, and then dried under reduced pressure. 20.2 g of crystals of potassium 2-bromothiophene-5-sulfonate were obtained. Yield 70%
[0021]
(Example 3)
To 16.3 g (0.100 mol) of 2-bromothiophene was added 5.0 g (0.068 mol) of dimethylformamide, and 11.0 g (0.110 mol) of concentrated sulfuric acid was added dropwise at 10-30 ° C. Subsequently, 40.0 g (0.336 mol) of thionyl chloride was added dropwise at 10 to 20 ° C. After completion of the dropwise addition, the mixture was aged at room temperature for 12 hours to complete the sulfonation reaction. The reaction mixture was analyzed by HPLC to find that it was 96.4% 2-bromothiophene-5-sulfonic acid and 1.5% 2-bromothiophene. The reaction solution was heated to 70 ° C. and aged for 2 hours to complete the chlorination reaction. The reaction solution was analyzed by HPLC to find that it was 96.0% 2-bromothiophene-5-sulfonyl chloride, 1.0% 2-bromothiophene-5-sulfonic acid, and 0.2% 2-bromothiophene. This reaction solution was dispersed in 30 ml of water at 5 to 15 ° C., extracted with 30 ml of chloroform, washed with water, the chloroform layer was concentrated, and 23.8 g (0.091 mol) of oily 2-bromothiophene-5-sulfonyl chloride was obtained. Obtained. Yield 91%
[0022]
(Example 4)
To 16.3 g (0.100 mol) of 2-bromothiophene was added 5.0 g (0.068 mol) of dimethylformamide, and 11.0 g (0.110 mol) of concentrated sulfuric acid was added dropwise at 10-30 ° C. Subsequently, 42.6 g (0.336 mol) of chlorosulfonic acid was added dropwise at 10 to 20 ° C. After completion of the dropwise addition, the mixture was aged at room temperature for 12 hours to complete the sulfonation reaction. The reaction mixture was analyzed by HPLC to find that it was 95.2% 2-bromothiophene-5-sulfonic acid, 0.1% 2-bromothiophene, and 1.2% 2-bromothiophene-5-sulfonyl chloride. The reaction solution was heated to 70 ° C. and aged for 2 hours to complete the chlorination reaction. As a result of HPLC analysis of the reaction solution, it was 93.8% of 2-bromothiophene-5-sulfonyl chloride, 0.5% of 2-bromothiophene-5-sulfonic acid, and 0.2% of 2-bromothiophene. This reaction solution was dispersed in 30 ml of water at 5 to 15 ° C., extracted with 80 ml of hexane, washed with water, and then concentrated in the hexane layer to recover 60 ml of hexane. Seed crystals were added to the concentrate at room temperature to precipitate crystals, and then cooled to 5 ° C. The precipitated crystals were filtered, washed with cold hexane, and dried under reduced pressure to give 2-bromothiophene-5-sulfonyl chloride crystals. 18.0 g (0.069 mol) was obtained. Yield 69%
[0023]
(Example 5)
To 16.3 g (0.100 mol) of 2-bromothiophene was added 5.0 g (0.068 mol) of dimethylformamide, and 11.0 g (0.110 mol) of concentrated sulfuric acid was added dropwise at 10-30 ° C. Subsequently, 40.0 g (0.336 mol) of thionyl chloride was added dropwise at 10 to 20 ° C. After completion of the dropwise addition, the mixture was aged at room temperature for 12 hours to complete the sulfonation reaction. The reaction mixture was analyzed by HPLC to find that it was 96.4% 2-bromothiophene-5-sulfonic acid and 1.5% 2-bromothiophene. This reaction solution was dispersed in 30 ml of saturated saline at 5 to 15 ° C. and cooled to 0 ° C., then the precipitated crystals were filtered, washed with cold water and dried under reduced pressure to give 2-bromothiophene-5-sulfonic acid. 12.0 g of crystals were obtained. Yield 48%
[0024]
(Example 6)
28.8 g (0.100 mol) of potassium 2-bromothiophene-5-sulfonate was added to 40.0 g (0.336 mol) of thionyl chloride, and 5.0 g (0.068 mol) of dimethylformamide was added dropwise at 10 to 30 ° C. After completion of the dropwise addition, the temperature was raised to 70 ° C. and aging was performed for 2 hours to complete the chlorination reaction. The reaction solution was analyzed by HPLC to find that it was 98.0% 2-bromothiophene-5-sulfonyl chloride and 0.3% 2-bromothiophene-5-sulfonic acid. This reaction solution was dispersed in 30 ml of water at 5 to 15 ° C., extracted with 30 ml of chloroform, washed with water, the chloroform layer was concentrated, and 24.0 g (0.092 mol) of oily 2-bromothiophene-5-sulfonyl chloride was obtained. Obtained. Yield 92%
[0025]
(Example 7)
2-Bromothiophene-5-sulfonic acid (25.0 g, 0.100 mol) was added to chlorosulfonic acid (42.6 g, 0.336 mol), and dimethylformamide (5.0 g, 0.068 mol) was added dropwise at 10-30 ° C. After completion of the dropwise addition, the temperature was raised to 70 ° C. and aging was performed for 2 hours to complete the chlorination reaction. The reaction solution was analyzed by HPLC to find that it was 96.0% 2-bromothiophene-5-sulfonyl chloride and 0.5% 2-bromothiophene-5-sulfonic acid. This reaction solution was dispersed in 30 ml of water at 5 to 15 ° C., extracted with 30 ml of chloroform, washed with water, the chloroform layer was concentrated to obtain 23.5 g (0.090 mol) of oily 2-bromothiophene-5-sulfonyl chloride. Obtained. Yield 90%
[0026]
As described above, the method for producing 2-bromothiophene-5-sulfonyl chloride of the present invention is high without decomposing 2-bromothiophene by reacting 2-bromothiophene with sulfuric acid in the presence of dimethylformamide. 2-Bromothiophene-5-sulfonic acid could be produced with selectivity and yield.

Claims (11)

Chemical formula (1)

A dimethylformamide solution of 2-bromothiophene represented by the formula is reacted with thionyl chloride or chlorosulfonic acid in the presence of sulfuric acid to give a chemical formula (2)

2-bromothiophene-5-sulfonic acid represented by the formula (2), and the 2-bromothiophene-5-sulfonic acid is reacted with an alkali metal salt to give a chemical formula (3)

2-bromothiophene-5-sulfonic acid alkali metal salt represented by the formula (4), and reacting the 2-bromothiophene-5-sulfonic acid alkali metal salt with thionyl chloride or chlorosulfonic acid,

The manufacturing method of 2-bromothiophene-5-sulfonyl chloride characterized by manufacturing 2-bromothiophene-5-sulfonyl chloride represented by these. The reaction solution of 2-bromothiophene-5-sulfonic acid is dispersed in water, neutralized with an alkali metal salt, and the crystallized alkali metal of 2-bromothiophene-5-sulfonic acid is solid-liquid separated. The method for producing 2-bromothiophene-5-sulfonyl chloride according to claim 1. 3. The 2-bromothiophene-5-sulfonyl chloride according to claim 1, wherein the alkali metal salt is sodium hydroxide, potassium hydroxide, sodium potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate. Production method. Chemical formula (1)

A dimethylformamide solution of 2-bromothiophene represented by the formula is reacted with thionyl chloride or chlorosulfonic acid in the presence of sulfuric acid to give a chemical formula (2)

2-bromothiophene-5-sulfonic acid represented by the formula (1), and the 2-bromothiophene-5-sulfonic acid is reacted with thionyl chloride or chlorosulfonic acid to give a chemical formula (4)

The manufacturing method of 2-bromothiophene-5-sulfonyl chloride characterized by manufacturing 2-bromothiophene-5-sulfonyl chloride represented by these. Chemical formula (1)

A dimethylformamide solution of 2-bromothiophene represented by the formula is reacted with thionyl chloride or chlorosulfonic acid in the presence of sulfuric acid to give a chemical formula (2)

A process for producing 2-bromothiophene-5-sulfonic acid, characterized in that 2-bromothiophene-5-sulfonic acid represented by the formula: Chemical formula (1)

A dimethylformamide solution of 2-bromothiophene represented by the formula is reacted with thionyl chloride or chlorosulfonic acid in the presence of sulfuric acid to give a chemical formula (2)

2-bromothiophene-5-sulfonic acid represented by the formula (2), and the 2-bromothiophene-5-sulfonic acid is reacted with an alkali metal salt to give a chemical formula (3)

The manufacturing method of 2-bromothiophene-5-sulfonic acid alkali metal salt represented by these is manufactured. The reaction solution of 2-bromothiophene-5-sulfonic acid is dispersed in water, neutralized with an alkali metal salt, and the crystallized alkali metal of 2-bromothiophene-5-sulfonic acid is solid-liquid separated. A process for producing an alkali metal salt of 2-bromothiophene-5-sulfonic acid according to claim 6. The alkali metal 2-bromothiophene-5-sulfonate according to claim 6 or 7, wherein the alkali metal salt is sodium hydroxide, potassium hydroxide, sodium carbonate potassium carbonate, sodium bicarbonate, potassium bicarbonate. A method for producing a metal salt. Chemical formula (2)

2-bromothiophene-5-sulfonic acid represented by the formula (4) is reacted with thionyl chloride or chlorosulfonic acid.

The manufacturing method of 2-bromothiophene-5-sulfonyl chloride characterized by manufacturing 2-bromothiophene-5-sulfonyl chloride represented by these. Chemical formula (3)

2-bromothiophene-5-sulfonic acid alkali metal salt represented by the formula (4) is reacted with thionyl chloride or chlorosulfonic acid.

The manufacturing method of 2-bromothiophene-5-sulfonyl chloride characterized by manufacturing 2-bromothiophene-5-sulfonyl chloride represented by these. The method for producing 2-bromothiophene-5-sulfonyl chloride according to claim 10, wherein the alkali metal salt is sodium hydroxide, potassium hydroxide, sodium potassium carbonate, sodium hydrogen carbonate, or potassium hydrogen carbonate. .