JP6007631B2 - Method for producing 3-halogeno-2-iodothiophene - Google Patents
Method for producing 3-halogeno-2-iodothiophene Download PDFInfo
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本発明は、医薬品原料、有機エレクトロニクス材料の原料として有用な3−ハロゲノ−2−ヨードチオフェンの製造方法に関する。 The present invention relates to a method for producing 3-halogeno-2-iodothiophene, which is useful as a raw material for pharmaceuticals and organic electronics materials.
3−ハロゲノ−2−ヨードチオフェンは医薬品原料(例えば、特許文献1参照)、有機エレクトロニクス材料の原料(例えば、非特許文献1参照)として有用な化合物である。
従来、3−ハロゲノ−2−ヨードチオフェンの製造方法としては、以下の方法が知られている。
3-halogeno-2-iodothiophene is a compound useful as a raw material for pharmaceuticals (for example, see Patent Document 1) and a raw material for organic electronics materials (for example, see Non-Patent Document 1).
Conventionally, the following methods are known as methods for producing 3-halogeno-2-iodothiophene.
(1)下記反応式のように表される、3−ヨードチオフェンをよう素および酸化水銀とベンゼン溶媒中反応させる方法。(非特許文献2参照) (1) A method in which 3-iodothiophene represented by the following reaction formula is reacted with iodine and mercury oxide in a benzene solvent. (See Non-Patent Document 2)
(2)下記反応式のように表される、2,3−ジブロモチオフェンをn−ブチルリチウムおよびよう素と低温(−78℃)で反応させる方法。(非特許文献3参照) (2) A method of reacting 2,3-dibromothiophene with n-butyllithium and iodine at a low temperature (−78 ° C.) represented by the following reaction formula. (See Non-Patent Document 3)
(3)下記反応式のように表される、3−クロロチオフェンをN−ヨードこはく酸イミドと反応させる方法。(特許文献1参照) (3) A method of reacting 3-chlorothiophene with N-iodosuccinimide represented by the following reaction formula. (See Patent Document 1)
(4)下記反応式のように表される、3−ハロゲノチオフェンをよう素、よう素酸および硫酸と反応させる方法。(非特許文献2、4および5参照) (4) A method of reacting 3-halogenothiophene with iodine, iodic acid and sulfuric acid represented by the following reaction formula. (See Non-Patent Documents 2, 4 and 5.)
上記(1)の方法では毒性の高い水銀化合物を用いていること、上記(2)の方法では収率97%と効率は良いものの自然発火性物質であるn−ブチルリチウムを用いて低温反応が必要であること、上記(3)の方法では室温では不安定なN−ヨードスクシンイミドとハロゲン溶媒を用いていること、および上記(4)の方法では、モントリオール議定書(1987年)により使用が規制されている四塩化炭素を使用している。
よって公知の3−ハロゲノ−2−ヨードチオフェンの製造方法は工業生産においては最適な方法ではないことから、本発明は有害物質・危険物質を用いずに効率良く3−ハロゲノ−2−ヨードチオフェンを製造する方法を提供するものである。
In the method (1), a highly toxic mercury compound is used. In the method (2), a low-temperature reaction is performed using n-butyllithium, which is a pyrophoric substance, although the yield is 97% and efficiency is high. The method (3) uses N-iodosuccinimide and a halogen solvent which are unstable at room temperature, and the method (4) is regulated by the Montreal Protocol (1987). It uses carbon tetrachloride.
Therefore, since a known method for producing 3-halogeno-2-iodothiophene is not an optimum method in industrial production, the present invention efficiently converts 3-halogeno-2-iodothiophene without using harmful substances and dangerous substances. A method of manufacturing is provided.
上記目的を達成した本発明の3−ハロゲノ−2−ヨードチオフェンの製造方法は、
項1.
一般式(1);
The method for producing 3-halogeno-2-iodothiophene of the present invention that achieves the above object,
Item 1.
General formula (1);
(式中、Aはハロゲン原子を示す。)で表される3−ハロゲノチオフェンと酸触媒存在下、ヨウ素およびヨウ素酸を炭化水素溶媒中で反応させることを特徴とする、一般式(2);
(Wherein A represents a halogen atom), and iodine and iodic acid are reacted in a hydrocarbon solvent in the presence of an acid catalyst and 3-halogenothiophene represented by the general formula (2);
(式中、Aはハロゲン原子を示す。)で表される3−ハロゲノ−2−ヨードチオフェンの製造方法。
項2.
ハロゲン原子が塩素、臭素、およびヨウ素からなる群より選ばれた項1に記載の製造方法。
項3.
炭化水素溶媒が、ヘキサン、ヘプタン、およびオクタンからなる群より選ばれた項1または2に記載の方法。
項4.
酸触媒が硫酸であることを特徴とする項1〜3いずれかに記載の方法。
(In formula, A shows a halogen atom.) The manufacturing method of 3-halogeno-2-iodothiophene represented.
Item 2.
Item 2. The production method according to Item 1, wherein the halogen atom is selected from the group consisting of chlorine, bromine, and iodine.
Item 3.
Item 3. The method according to Item 1 or 2, wherein the hydrocarbon solvent is selected from the group consisting of hexane, heptane, and octane.
Item 4.
Item 4. The method according to any one of Items 1 to 3, wherein the acid catalyst is sulfuric acid.
本発明によれば、有害物質・危険物質を用いず且つ効率良く3−ハロゲノ−2−ヨードチオフェンを得ることができる。 According to the present invention, 3-halogeno-2-iodothiophene can be obtained efficiently without using harmful substances and hazardous substances.
以下、本発明を詳細に説明する。 Hereinafter, the present invention will be described in detail.
まず、反応に使用する3−ハロゲノチオフェン、ヨウ素、およびヨウ素酸は、どのような方法で製造したものでも使用することが可能であり、市販品を容易に入手できる。ヨウ素の使用量は、上記一般式(1)で表される3−ハロゲノチオフェン1モルに対して0.2モル〜1.0モルが好ましく、0.3モル〜0.5モルがより好ましい。ヨウ素酸の使用料は上記一般式(1)で表される3−ハロゲノチオフェン1モルに対して0.1〜0.7モルが好ましく、0.15〜0.35モルがより好ましい。 First, 3-halogenothiophene, iodine, and iodic acid used in the reaction can be produced by any method, and commercially available products can be easily obtained. The amount of iodine used is preferably 0.2 mol to 1.0 mol, more preferably 0.3 mol to 0.5 mol, per 1 mol of 3-halogenothiophene represented by the above general formula (1). The use amount of iodic acid is preferably 0.1 to 0.7 mol, more preferably 0.15 to 0.35 mol, per 1 mol of 3-halogenothiophene represented by the general formula (1).
ついで反応に使用する炭化水素溶媒について説明する。 Next, the hydrocarbon solvent used for the reaction will be described.
本反応に使用する炭化水素溶媒は、本反応系で不活性であり反応を阻害しないものであれば直鎖状、分岐状、環状など特に制限されない。具体例としては、ペンタン、ヘキサン、シクロヘキサン、メチルシクロヘキサン、ヘプタン、オクタンが挙げられ、ヘキサン、ヘプタンが特に好ましい。当該溶媒を単独でも混合して用いても問題ない。当該溶媒の使用量は、上記一般式(1)で表される3−ハロゲノチオフェン1gに対して0.5mL〜50mLが好ましく0.5mL〜10mLがより好ましい。 The hydrocarbon solvent used in this reaction is not particularly limited as long as it is inert in the present reaction system and does not inhibit the reaction, such as linear, branched or cyclic. Specific examples include pentane, hexane, cyclohexane, methylcyclohexane, heptane, and octane, and hexane and heptane are particularly preferable. There is no problem even if these solvents are used alone or in combination. The amount of the solvent used is preferably 0.5 mL to 50 mL and more preferably 0.5 mL to 10 mL with respect to 1 g of 3-halogenothiophene represented by the general formula (1).
反応は上記炭化水素溶媒のみでも、酢酸および水を加えても問題ない。酢酸を加えることで反応性が向上し、水を加えることで反応試剤が溶解しやすくなる効果がある。酢酸を使用する場合の使用量は、上記一般式(1)で表される3−ハロゲノチオフェン1gに対して0.1mL〜50mLが好ましい。水を使用する場合の使用量は上記一般式(1)で表される3−ハロゲノチオフェン1gに対して0.1mL〜50mLが好ましい。 There is no problem in the reaction even if only the above hydrocarbon solvent is added or acetic acid and water are added. The reactivity is improved by adding acetic acid, and the reaction reagent is easily dissolved by adding water. The amount of acetic acid used is preferably 0.1 mL to 50 mL with respect to 1 g of 3-halogenothiophene represented by the general formula (1). As for the usage-amount in the case of using water, 0.1 mL-50 mL are preferable with respect to 1 g of 3-halogenothiophene represented by the said General formula (1).
次いで、酸触媒について説明する。 Next, the acid catalyst will be described.
酸は、反応を阻害しなければ無機酸及び有機酸のいずれも使用できる。無機酸としては、例えば、塩酸、臭化水素、硫酸、硝酸、リン酸、ホウ酸、アジ化水素、塩素酸、臭素酸、炭酸、硫化水素などが挙げられ、硫酸が好ましい。酸触媒の使用量は、3−ハロゲノチオフェン1gに対して0.001g〜1gまたは0.001mL〜1mLが好ましい。 Either an inorganic acid or an organic acid can be used as the acid as long as the reaction is not inhibited. Examples of the inorganic acid include hydrochloric acid, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, boric acid, hydrogen azide, chloric acid, bromic acid, carbonic acid, hydrogen sulfide and the like, and sulfuric acid is preferable. The amount of the acid catalyst used is preferably 0.001 g to 1 g or 0.001 mL to 1 mL with respect to 1 g of 3-halogenothiophene.
次いで、本発明の反応について説明する。反応は下記に示すような3−ハロゲノチオフェンと酸触媒存在下、ヨウ素およびヨウ素酸を炭化水素溶媒中反応させることによる3−ハロゲノ−2−ヨードチオフェンの製造方法である。ハロゲン(X)は特に制限無いが塩素、臭素がより好ましい。 Next, the reaction of the present invention will be described. The reaction is a method for producing 3-halogeno-2-iodothiophene by reacting iodine and iodic acid in a hydrocarbon solvent in the presence of an acid catalyst as shown below. Halogen (X) is not particularly limited, but chlorine and bromine are more preferable.
反応温度は低すぎると反応が進行せず、高すぎると異性体・多ヨウ素化体などの副生成物が生じることから10〜80℃程度が好ましく、20℃〜50℃がより好ましい。反応時間は、好ましくは3〜50時間程度、より好ましくは5〜30時間程度である。 If the reaction temperature is too low, the reaction does not proceed, and if it is too high, by-products such as isomers and polyiodinated products are formed, preferably about 10-80 ° C, more preferably 20-50 ° C. The reaction time is preferably about 3 to 50 hours, more preferably about 5 to 30 hours.
反応終了後、抽出・洗浄・脱湿・溶媒留去などの定法によって3−ハロゲノ−2−ヨードチオフェンの粗生成物を得た後、粗生成物を精製することが好ましい。精製手段としては、例えばカラムクロマトグラフィー、蒸留などが挙げられる。 After completion of the reaction, it is preferable to purify the crude product after obtaining a crude product of 3-halogeno-2-iodothiophene by conventional methods such as extraction, washing, dehumidification, and solvent distillation. Examples of the purification means include column chromatography and distillation.
以下、実施例を挙げて本発明をより具体的に説明するが、本発明は以下の実施例によって制限を受けるものではなく、上記・下記の趣旨に適合し得る範囲で適当に変更を加えて
実施することも勿論可能であり、それらはいずれも本発明の技術的範囲に包含される。
EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples. However, the present invention is not limited by the following examples, and appropriate modifications are made within a range that can meet the above and the following purposes. Of course, it is possible to implement them, and they are all included in the technical scope of the present invention.
比較例1 3−ブロモ−2−ヨードチオフェンの合成(四塩化炭素溶媒、上記非特許文献4を参考)
100mL四つ口フラスコに3−ブロモチオフェン(10g、61.3mmol)、ヨウ素(4.98g、19.6mmol)、ヨウ素酸(2.04g、11.6mmol)、酢酸(20mL)、四塩化炭素(10mL)、水(8mL)、および濃硫酸(0.4mL)を加え、40℃で16時間反応させた。反応終了後、室温まで冷却した後にジエチルエーテルを用いて抽出した。得られた有機層を飽和炭酸水素ナトリウム水溶液、10%亜硫酸水素ナトリウム水溶液、飽和食塩水溶液で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品を蒸留精製(〜125℃、〜9torr)することで、3−ブロモ−2−ヨードチオフェンが13.3g(収率75%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)
1H NMR (400MHz, CDCl3): 7.39 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
Comparative Example 1 Synthesis of 3-bromo-2-iodothiophene (carbon tetrachloride solvent, see Non-Patent Document 4 above)
In a 100 mL four-necked flask, 3-bromothiophene (10 g, 61.3 mmol), iodine (4.98 g, 19.6 mmol), iodic acid (2.04 g, 11.6 mmol), acetic acid (20 mL), carbon tetrachloride ( 10 mL), water (8 mL), and concentrated sulfuric acid (0.4 mL) were added and reacted at 40 ° C. for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and extracted with diethyl ether. The obtained organic layer was washed successively with a saturated aqueous sodium hydrogen carbonate solution, a 10% aqueous sodium hydrogen sulfite solution, and a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The crude product obtained by filtration and concentration was purified by distillation (˜125 ° C., ˜9 torr) to obtain 13.3 g (yield 75%) of 3-bromo-2-iodothiophene as an almost colorless liquid. . The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.)
1 H NMR (400MHz, CDCl 3 ): 7.39 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
実施例1 3−ブロモ−2−ヨードチオフェンの合成(ヘキサン溶媒)
100mL四つ口フラスコに3−ブロモチオフェン(10g、61.3mmol)、ヨウ素(5.61g、22.1mmol)、ヨウ素酸(2.27g、12.9mmol)、酢酸(20mL)、n−ヘキサン(30mL)、水(8mL)、および濃硫酸(0.4mL)を加え、40℃で17時間反応させた。反応終了後、室温まで冷却した後に飽和炭酸水素ナトリウム水溶液(40mL)およびn−ヘキサン(50mL)を加えて抽出した。得られた有機層を10%亜硫酸水素ナトリウム水溶液(30mL)、飽和食塩水溶液(30mL)で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品を蒸留精製(〜125℃、〜9torr)することで、3−ブロモ−2−ヨードチオフェンが15.0g(収率85%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)1H NMR (400MHz, CDCl3): 7.39 (d, J= 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
Example 1 Synthesis of 3-bromo-2-iodothiophene (hexane solvent)
In a 100 mL four-necked flask, 3-bromothiophene (10 g, 61.3 mmol), iodine (5.61 g, 22.1 mmol), iodic acid (2.27 g, 12.9 mmol), acetic acid (20 mL), n-hexane ( 30 mL), water (8 mL), and concentrated sulfuric acid (0.4 mL) were added and reacted at 40 ° C. for 17 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted by adding a saturated aqueous sodium hydrogen carbonate solution (40 mL) and n-hexane (50 mL). The obtained organic layer was washed with a 10% aqueous sodium hydrogen sulfite solution (30 mL) and a saturated aqueous sodium chloride solution (30 mL) in that order, and dried over magnesium sulfate. The crude product obtained by filtration and concentration was purified by distillation (˜125 ° C., ˜9 torr) to obtain 3-bromo-2-iodothiophene as an almost colorless liquid at 15.0 g (yield 85%). . The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.) 1 H NMR (400 MHz, CDCl 3 ): 7.39 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
実施例2 3−ブロモ−2−ヨードチオフェンの合成(シクロヘキサン溶媒)
100mL四つ口フラスコに3−ブロモチオフェン(10g、61.3mmol)、ヨウ素(5.61g、22.1mmol)、ヨウ素酸(2.27g、12.9mmol)、酢酸(20mL)、シクロヘキサン(30mL)、水(8mL)、および濃硫酸(0.4mL)を加え、40℃で17時間反応させた。反応終了後、室温まで冷却した後に飽和炭酸水素ナトリウム水溶液(40mL)およびジエチルエーテル(30mL)を加えて抽出した。得られた有機層を10%亜硫酸水素ナトリウム水溶液(30mL)、飽和食塩水溶液(30mL)で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品を蒸留精製(〜125℃、〜9torr)することで、3−ブロモ−2−ヨードチオフェンが15.6g(収率88%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)1H NMR (400MHz, CDCl3): 7.39 (d, J= 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
Example 2 Synthesis of 3-bromo-2-iodothiophene (cyclohexane solvent)
3-Bromothiophene (10 g, 61.3 mmol), iodine (5.61 g, 22.1 mmol), iodic acid (2.27 g, 12.9 mmol), acetic acid (20 mL), cyclohexane (30 mL) in a 100 mL four-necked flask , Water (8 mL), and concentrated sulfuric acid (0.4 mL) were added and reacted at 40 ° C. for 17 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted by adding a saturated aqueous sodium hydrogen carbonate solution (40 mL) and diethyl ether (30 mL). The obtained organic layer was washed with a 10% aqueous sodium hydrogen sulfite solution (30 mL) and a saturated aqueous sodium chloride solution (30 mL) in that order, and dried over magnesium sulfate. The crude product obtained by filtration and concentration was purified by distillation (˜125 ° C., ˜9 torr) to obtain 15.6 g (yield 88%) of 3-bromo-2-iodothiophene as an almost colorless liquid. . The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.) 1 H NMR (400 MHz, CDCl 3 ): 7.39 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
実施例3 3−ブロモ−2−ヨードチオフェンの合成(ヘプタン溶媒)
500mL四つ口フラスコに3−ブロモチオフェン(50g、306.7mmol)、ヨウ素(28.0g、110.4mmol)、ヨウ素酸(11.3g、64.4mmol)、酢酸(100mL)、n−ヘプタン(150mL)、水(40mL)、および濃硫酸(2mL)を加え、40℃で24時間反応させた。反応終了後、室温まで冷却した後に飽和炭酸水素ナトリウム水溶液(200mL)およびn−ヘプタン(250mL)を加えて抽出した。得られた有機層を10%亜硫酸水素ナトリウム水溶液(150mL)、飽和食塩水溶液(150mL)で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品を蒸留精製(〜125℃、〜9torr)することで、3−ブロモ−2−ヨードチオフェンが73.5g(収率83%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)1H NMR (400MHz, CDCl3): 7.39 (d, J= 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
Example 3 Synthesis of 3-bromo-2-iodothiophene (heptane solvent)
In a 500 mL four-necked flask, 3-bromothiophene (50 g, 306.7 mmol), iodine (28.0 g, 110.4 mmol), iodic acid (11.3 g, 64.4 mmol), acetic acid (100 mL), n-heptane ( 150 mL), water (40 mL), and concentrated sulfuric acid (2 mL) were added and reacted at 40 ° C. for 24 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted with saturated aqueous sodium hydrogen carbonate solution (200 mL) and n-heptane (250 mL). The obtained organic layer was washed with a 10% aqueous sodium hydrogen sulfite solution (150 mL) and a saturated aqueous sodium chloride solution (150 mL) in that order and dried over magnesium sulfate. The crude product obtained by filtration and concentration was purified by distillation (˜125 ° C., ˜9 torr) to obtain 73.5 g (yield 83%) of 3-bromo-2-iodothiophene as an almost colorless liquid. . The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.) 1 H NMR (400 MHz, CDCl 3 ): 7.39 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 5.3 Hz, 1H).
実施例4 3−クロロ−2−ヨードチオフェンの合成(ヘキサン溶媒)
30mL四つ口フラスコに3−クロロチオフェン(2g、16.9mmol)、ヨウ素(1.54g、6.1mmol)、ヨウ素酸(0.62g、3.5mmol)、酢酸(4mL)、n−ヘキサン(6mL)、水(1.5mL)、および濃硫酸(2滴)を加え、40℃で15時間反応させた。反応終了後、室温まで冷却した後に飽和炭酸水素ナトリウム水溶液(10mL)およびジエチルエーテル(10mL)を加えて抽出した。得られた有機層を10%亜硫酸水素ナトリウム水溶液(10mL)、飽和食塩水溶液(10mL)で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品をカラムクロマトグラフィー(シリカゲル:ヘキサン溶媒)で精製することで、3−クロロ−2−ヨードチオフェンが3.7g(収率90%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)1H NMR (400MHz, CDCl3): 7.45 (d, J= 5.2 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H).
Example 4 Synthesis of 3-chloro-2-iodothiophene (hexane solvent)
In a 30 mL four-necked flask, 3-chlorothiophene (2 g, 16.9 mmol), iodine (1.54 g, 6.1 mmol), iodic acid (0.62 g, 3.5 mmol), acetic acid (4 mL), n-hexane ( 6 mL), water (1.5 mL), and concentrated sulfuric acid (2 drops) were added and reacted at 40 ° C. for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted by adding a saturated aqueous sodium hydrogen carbonate solution (10 mL) and diethyl ether (10 mL). The obtained organic layer was washed successively with a 10% aqueous sodium hydrogen sulfite solution (10 mL) and a saturated aqueous sodium chloride solution (10 mL), and dried over magnesium sulfate. The crude product obtained by filtration and concentration is purified by column chromatography (silica gel: hexane solvent) to obtain 3.7 g (yield 90%) of 3-chloro-2-iodothiophene as an almost colorless liquid. It was. The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.) 1 H NMR (400 MHz, CDCl 3 ): 7.45 (d, J = 5.2 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H).
実施例5 3−クロロ−2−ヨードチオフェンの合成(オクタン溶媒)
30mL四つ口フラスコに3−クロロチオフェン(2g、16.9mmol)、ヨウ素(1.54g、6.1mmol)、ヨウ素酸(0.62g、3.5mmol)、酢酸(4mL)、n−オクタン(6mL)、水(1.5mL)、および濃硫酸(2滴)を加え、40℃で20時間反応させた。反応終了後、室温まで冷却した後に飽和炭酸水素ナトリウム水溶液(10mL)およびジエチルエーテル(10mL)を加えて抽出した。得られた有機層を10%亜硫酸水素ナトリウム水溶液(10mL)、飽和食塩水溶液(10mL)で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品をカラムクロマトグラフィー(シリカゲル:ヘキサン溶媒)で精製することで、3−クロロ−2−ヨードチオフェンが3.5g(収率85%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)1H NMR (400MHz, CDCl3): 7.45 (d, J= 5.2 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H).
Example 5 Synthesis of 3-chloro-2-iodothiophene (octane solvent)
In a 30 mL four-necked flask, 3-chlorothiophene (2 g, 16.9 mmol), iodine (1.54 g, 6.1 mmol), iodic acid (0.62 g, 3.5 mmol), acetic acid (4 mL), n-octane ( 6 mL), water (1.5 mL), and concentrated sulfuric acid (2 drops) were added and reacted at 40 ° C. for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted by adding a saturated aqueous sodium hydrogen carbonate solution (10 mL) and diethyl ether (10 mL). The obtained organic layer was washed successively with a 10% aqueous sodium hydrogen sulfite solution (10 mL) and a saturated aqueous sodium chloride solution (10 mL), and dried over magnesium sulfate. The crude product obtained by filtration and concentration is purified by column chromatography (silica gel: hexane solvent) to obtain 3.5 g (yield 85%) of 3-chloro-2-iodothiophene as an almost colorless liquid. It was. The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.) 1 H NMR (400 MHz, CDCl 3 ): 7.45 (d, J = 5.2 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H).
実施例6 2,3−ジヨードチオフェンの合成(ヘキサン溶媒)
30mL四つ口フラスコに3−ヨードチオフェン(2g、9.5mmol)、ヨウ素(0.87g、3.4mmol)、ヨウ素酸(0.35g、2.0mmol)、酢酸(4mL)、n−ヘキサン(6mL)、水(1.5mL)、および濃硫酸(2滴)を加え、40℃で15時間反応させた。反応終了後、室温まで冷却した後に飽和炭酸水素ナトリウム水溶液(10mL)およびジエチルエーテル(10mL)を加えて抽出した。得られた有機層を10%亜硫酸水素ナトリウム水溶液(10mL)、飽和食塩水溶液(10mL)で順に洗浄し硫酸マグネシウムで乾燥した。ろ過・濃縮により得られた粗品をカラムクロマトグラフィー(シリカゲル:ヘキサン溶媒)で精製することで、2,3−ジヨードチオフェンが2.5g(収率78%)でほぼ無色の液体として得られた。NMRによる分析結果は以下の通りである。NMRは、試料約5mgをCDCl3に溶解してから分析した。(バリアン社製400−MR:400MHzで分析。)
1H NMR (400MHz, CDCl3): 7.14 (d, J = 5.2 Hz, 1H), 6.67 (d, J = 5.2 Hz, 1H).
上記の実施例により、比較例および既知の方法のように有害、危険な物質を用いず簡便な方法で効率良く3−ハロゲノ−2−ヨードチオフェンが得られる効果を確認した。
Example 6 Synthesis of 2,3-diiodothiophene (hexane solvent)
In a 30 mL four-necked flask, 3-iodothiophene (2 g, 9.5 mmol), iodine (0.87 g, 3.4 mmol), iodic acid (0.35 g, 2.0 mmol), acetic acid (4 mL), n-hexane ( 6 mL), water (1.5 mL), and concentrated sulfuric acid (2 drops) were added and reacted at 40 ° C. for 15 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and extracted by adding a saturated aqueous sodium hydrogen carbonate solution (10 mL) and diethyl ether (10 mL). The obtained organic layer was washed successively with a 10% aqueous sodium hydrogen sulfite solution (10 mL) and a saturated aqueous sodium chloride solution (10 mL), and dried over magnesium sulfate. The crude product obtained by filtration and concentration was purified by column chromatography (silica gel: hexane solvent) to obtain 2.5 g (yield 78%) of 2,3-diiodothiophene as an almost colorless liquid. . The analysis results by NMR are as follows. NMR was analyzed after dissolving about 5 mg of sample in CDCl 3 . (Varian 400-MR: analyzed at 400 MHz.)
1 H NMR (400MHz, CDCl 3 ): 7.14 (d, J = 5.2 Hz, 1H), 6.67 (d, J = 5.2 Hz, 1H).
The above examples confirmed the effect of efficiently obtaining 3-halogeno-2-iodothiophene by a simple method without using harmful and dangerous substances as in the comparative examples and known methods.
本発明の製造方法によれば、3−ハロゲノ−2−ヨードチオフェンを商用プラントのような大規模スケールでも有害、危険な物質を使用せずに効率良く製造できる。本発明の製造方法によって得られた3−ハロゲノ−2−ヨードチオフェンは、医薬品・有機エレクトロニクス材料として有用な化合物である。 According to the production method of the present invention, 3-halogeno-2-iodothiophene can be efficiently produced without using harmful and dangerous substances even on a large scale such as a commercial plant. 3-halogeno-2-iodothiophene obtained by the production method of the present invention is a useful compound as a pharmaceutical / organic electronic material.
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