JPH08816B2 - Method for producing 2-butyl-4-chloroimidazole-5-carbaldehyde - Google Patents
Method for producing 2-butyl-4-chloroimidazole-5-carbaldehydeInfo
- Publication number
- JPH08816B2 JPH08816B2 JP20269293A JP20269293A JPH08816B2 JP H08816 B2 JPH08816 B2 JP H08816B2 JP 20269293 A JP20269293 A JP 20269293A JP 20269293 A JP20269293 A JP 20269293A JP H08816 B2 JPH08816 B2 JP H08816B2
- Authority
- JP
- Japan
- Prior art keywords
- butyl
- chloroimidazole
- carbaldehyde
- parts
- hydroxylmethylimidazole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
【発明の詳細な説明】Detailed Description of the Invention
【０００１】[0001]
【産業上の利用分野】本発明は、医薬等の中間体として
有用な２−ブチル−４−クロロイミダゾール−５−カル
バルデヒドの製造法に関するものである。FIELD OF THE INVENTION The present invention relates to a process for producing 2-butyl-4-chloroimidazole-5-carbaldehyde, which is useful as an intermediate for medicines and the like.
【０００２】[0002]
【発明の背景と解決しようとする課題】２−ブチル−４
−クロロイミダゾール−５−カルバルデヒドは２−ブチ
ル−５−ヒドロキシルメチルイミダゾールをクロル化
し、さらに、ヒドロキシメチル基を酸化することによっ
て得られる。しかし、クロル化工程では２−ブチル−４
−クロロ−５−ヒドロキシルメチルイミダゾールの生成
率が低い上に副生物が多量に生成してしまう。ここで生
成する副生物は、常法での生成により除去することは非
常に困難であり、完全に除去するためには、２−ブチル
−４−クロロ−５−ヒドロキシルメチルイミダゾールの
収率を著しく低下させなければならないという問題点が
あった。ここでの収率が低いために次工程の酸化反応が
ほぼ定量的に進行し、良好な収率で２−ブチル−４−ク
ロロイミダゾール−５−カルバルデヒドが得られるにも
拘らず、２−ブチル−４−クロロ−５−ヒドロキシルメ
チルイミダゾールからのトータル収率は低く、工業的に
は満足し難いものであった。BACKGROUND OF THE INVENTION AND PROBLEMS TO BE SOLVED
-Chloroimidazole-5-carbaldehyde is obtained by chlorinating 2-butyl-5-hydroxylmethylimidazole and further oxidizing the hydroxymethyl group. However, in the chlorination process, 2-butyl-4
The production rate of -chloro-5-hydroxylmethylimidazole is low and a large amount of by-products are produced. The by-product generated here is very difficult to remove by a conventional method, and in order to completely remove it, the yield of 2-butyl-4-chloro-5-hydroxylmethylimidazole is significantly increased. There was a problem that it had to be lowered. Since the yield here is low, the oxidation reaction in the next step proceeds almost quantitatively, and 2-butyl-4-chloroimidazole-5-carbaldehyde is obtained in good yield, but 2- The total yield from butyl-4-chloro-5-hydroxylmethylimidazole was low and was industrially unsatisfactory.
【０００３】[0003]
【課題を解決するための手段】本発明者らは、上記技術
的課題を解決し、目的の２−ブチル−４−クロロイミダ
ゾール−５−カルバルデヒドを収率よく、しかも純度の
高いものとして得る方法を開発すべく研究を重ねた。そ
の結果、２−ブチル−４−クロロ−５−ヒドロキシルメ
チルイミダゾールの酸化反応後に粗製２−ブチル−４−
クロロイミダゾール−５−カルバルデヒドを水中で重亜
硫酸ソーダと付加させることにより、２−ブチル−４−
クロロイミダゾール−５−カルバルデヒドのみを選択的
に水中に溶解させ、水に不溶の副生物を、水に混和しな
い有機溶媒で抽出することにより、目的とする純品の２
−ブチル−４−クロロイミダゾール−５−カルバルデヒ
ドを得る方法を開発した。Means for Solving the Problems The present inventors have solved the above technical problems and obtained 2-butyl-4-chloroimidazole-5-carbaldehyde, which is a target, in high yield and high purity. Research was repeated to develop a method. As a result, after the oxidation reaction of 2-butyl-4-chloro-5-hydroxylmethylimidazole, crude 2-butyl-4-
By adding chloroimidazole-5-carbaldehyde with sodium bisulfite in water, 2-butyl-4-
Only chloroimidazole-5-carbaldehyde is selectively dissolved in water, and the water-insoluble by-product is extracted with an organic solvent immiscible with water to obtain 2
A method for obtaining -butyl-4-chloroimidazole-5-carbaldehyde was developed.
【０００４】[0004]
【作用】本発明は、医薬品等の中間体として有用な２−
ブチル−４−クロロイミダゾール−５−カルバルデヒド
を製造する際、化１に示すように、クロル化工程で副生
する副生物Ａを含む２−ブチル−４−クロロ−５−ヒド
ロキシルメチルイミダゾールをそのまま次工程の酸化工
程に使用するために、２−ブチル−４−クロロ−５−ヒ
ドロキシルメチルイミダゾールを精製することによるロ
スを無くすることができ、更に、酸化により得られた２
−ブチル−４−クロロ−５−ヒドロキシルメチルイミダ
ゾールを重亜硫酸付加物としてＡから単離して得ること
により、従来よりも高収率で目的物を得られるので、経
済面及び製造面で極めて有利である。The present invention is useful as an intermediate for pharmaceuticals and the like.
When producing butyl-4-chloroimidazole-5-carbaldehyde, as shown in Chemical formula 1, 2-butyl-4-chloro-5-hydroxylmethylimidazole containing by-product A by-produced in the chlorination step is used as it is. The loss due to the purification of 2-butyl-4-chloro-5-hydroxylmethylimidazole can be eliminated for use in the subsequent oxidation step, and the 2
-Butyl-4-chloro-5-hydroxylmethylimidazole can be obtained as a bisulfite adduct by isolation from A to obtain the desired product in a higher yield than before, which is extremely advantageous in economic and production aspects. is there.
【０００５】[0005]
【化１】 Embedded image
【０００６】以下、本発明について詳細に説明する。The present invention will be described in detail below.
【０００７】２−ブチル−５−ヒドロキシルメチルイミ
ダゾールのクロル化剤としては、Ｎ−クロロスクシンイ
ミド、Ｎ−クロロスルファミン酸、Ｎ，Ｎ−ジクロロス
ルファミン酸、Ｎ，Ｎ，Ｎ−トリクロロイソシアヌル
酸、更には、塩化ヨウ素等が挙げられる。As the chlorinating agent for 2-butyl-5-hydroxylmethylimidazole, N-chlorosuccinimide, N-chlorosulfamic acid, N, N-dichlorosulfamic acid, N, N, N-trichloroisocyanuric acid, and further , Iodine chloride and the like.
【０００８】クロル化する際の反応溶媒としては、上記
クロル化剤を用いる際に一般的に使用される溶媒が挙げ
られる。具体的には、１，４−ジオキサン、メチルセロ
ソロブ、アセトン、テトラヒドロフラン、更に、酢酸エ
チルを代表とする酢酸エステル等である。Examples of the reaction solvent for chlorination include the solvents generally used when using the above chlorinating agent. Specific examples thereof include 1,4-dioxane, methyl cellosolve, acetone, tetrahydrofuran, and acetic acid ester represented by ethyl acetate.
【０００９】クロル化後は、単離精製に至るまでの処理
を施さず、反応混合物として分離し、直ちに酸化反応を
行なう。酸化反応試薬としては、ヒドロキシメチル基を
ホルミル化しえる試剤ならばいずれでもよく、具体的に
は、二酸化マンガン、硝酸セリウム（ＩＶ）アンモニウ
ム、四酢酸鉛、二酸化セレン等が挙げられる。After the chlorination, the treatment up to the isolation and purification is not performed, the reaction mixture is separated, and the oxidation reaction is immediately performed. The oxidizing reagent may be any reagent as long as it can formylate a hydroxymethyl group, and specific examples thereof include manganese dioxide, cerium (IV) ammonium nitrate, lead tetraacetate and selenium dioxide.
【００１０】酸化反応により得られた２−ブチル−４−
クロロイミダゾール−５−カルバルデヒドは水に懸濁
し、当該懸濁液に重亜硫酸ナトリウムを２−ブチル−４
−クロロイミダゾール−５−カルバルデヒドに対して３
〜５倍当量を投入し、室温で１〜２時間攪拌させて、重
亜硫酸付加物を形成させる。2-Butyl-4-obtained by oxidation reaction
Chloroimidazole-5-carbaldehyde was suspended in water and sodium bisulfite was added to the suspension in 2-butyl-4.
3 for chloroimidazole-5-carbaldehyde
Charge ~ 5 times equivalents and allow to stir for 1-2 hours at room temperature to form bisulfite adduct.
【００１１】反応終了後、トルエン、ヘキサン、ＣＨ2
Ｃｌ2 、ＣＨＣｌ3 、エーテル等の水と混和しない有機
溶媒を前記懸濁時に用いた水に対して１／８〜１／２容
量、好ましくは１／８容量を投入し、抽出、分離を行な
う。抽出は４〜１０回、好ましくは５回以上繰り返し、
副生物を完全に抽出する。After completion of the reaction, toluene, hexane, CH 2
An organic solvent immiscible with water such as Cl 2 , CHCl 3 and ether is added to 1/8 to 1/2 volume, preferably 1/8 volume of the water used for the suspension to perform extraction and separation. . Extraction is repeated 4 to 10 times, preferably 5 times or more,
Completely extract by-products.
【００１２】抽出終了後、重亜硫酸ソーダに対して１〜
２当量、好ましくは１．１当量の炭酸ソーダにより中和
して弱アルカリ性とした後、加温、加水分解反応を行な
う。加水分解反応終了後、さらに、重亜硫酸ソーダに対
して１〜２当量、好ましくは１．０１当量のＨ2Ｏ2 を
添加することにより目的物が結晶化する。これを濾過、
乾燥して２−ブチル−４−クロロイミダゾール−５−カ
ルバルデヒドを得る。After the extraction, 1 to 1 part of sodium bisulfite is added.
After neutralizing with 2 equivalents, preferably 1.1 equivalents of sodium carbonate to make it weakly alkaline, heating and hydrolysis reaction are carried out. After the completion of the hydrolysis reaction, the target substance is crystallized by further adding 1 to 2 equivalents, preferably 1.01 equivalents of H 2 O 2 to sodium bisulfite. Filter this,
Dry to give 2-butyl-4-chloroimidazole-5-carbaldehyde.
【００１３】粗製２−ブチル−４−クロロ−５−ヒドロ
キシルメチルイミダゾールからの目的物の純度換算収率
は９３〜９５％である。The purity-equivalent yield of the desired product from crude 2-butyl-4-chloro-5-hydroxylmethylimidazole is 93 to 95%.
【００１４】[0014]
【発明の効果】本発明によれば、クロル化工程で得られ
た２−ブチル−４−クロロ−ヒドロキシルメチルイミダ
ゾールを粗製のまま次工程に使用する事により、精製を
行なう事によるロスをなくし、そこで生成した精製困難
な副生物は、次工程の酸化反応後に官能基の性質を利用
する事により容易に除去することができ、且つ最終目的
物は、純品の形で取り出すことができ、工業上極めて有
利な実施を可能にするものである。According to the present invention, 2-butyl-4-chloro-hydroxylmethylimidazole obtained in the chlorination step is used in the next step as it is in a crude state, thereby eliminating loss due to purification. The difficult-to-purify by-product generated there can be easily removed by utilizing the property of the functional group after the oxidation reaction in the next step, and the final target product can be taken out in a pure form, which is an industrial product. This makes possible an extremely advantageous implementation.
【００１５】[0015]
【実施例】次に、本発明の方法について実施例を示し具
体的に説明する。以下「部」とは、特に断りのない限り
「重量部」を示す。 比較例 ２−ブチル−５−ヒドロキシルメチルイミダゾール４０
０部をアセトン４０００部中に懸濁し、冷却下、Ｎ−ク
ロロスクシンイミド３５０部を内温１０℃を越えないよ
うに徐々に加え反応を行なった。反応終了後、内温４０
℃以下を保って反応液を減圧回収し、内容物を乾固した
後、水２５００部と３５％ＨＣｌ ４００部にて溶解し
た。次に、２５％ＮａＯＨをｐＨ２．２になるまで滴下
して副生物を結晶化させた。これを濾過して除き、別取
りした濾液を２５％ＮａＯＨにてｐＨ７．２に調整する
事により、結晶が析出し、これを濾過、水洗、乾燥し
た。EXAMPLES Next, the method of the present invention will be specifically described with reference to examples. Hereinafter, "parts" means "parts by weight" unless otherwise specified. Comparative Example 2-Butyl-5-hydroxylmethyl imidazole 40
0 part was suspended in 4000 parts of acetone, and 350 parts of N-chlorosuccinimide was gradually added to the reaction mixture while cooling so that the internal temperature did not exceed 10 ° C. After the reaction is completed, the internal temperature is 40
The reaction solution was recovered under reduced pressure while maintaining the temperature below ℃, and the contents were dried and dissolved in 2500 parts of water and 400 parts of 35% HCl. Next, 25% NaOH was added dropwise until the pH reached 2.2 to crystallize the by-product. This was removed by filtration, and the separated filtrate was adjusted to pH 7.2 with 25% NaOH to precipitate crystals, which were filtered, washed with water, and dried.
【００１６】更に、この結晶を酢酸エチルで再結精製す
る事により、２−ブチル−４−クロロ−５−ヒドロキシ
ルメチルイミダゾール２７６．３部を得た。（収率６０
％） 上記結晶を２−プロパノール１４００部に懸濁し、ここ
に活性化ＭnＯ2 ６４０部を仕込み６時間反応を行なっ
た。反応終了後、ＭnＯ2 を濾別し、濾液を減圧回収
し、乾固状態とした。Further, the crystals were recrystallized and purified with ethyl acetate to obtain 276.3 parts of 2-butyl-4-chloro-5-hydroxylmethylimidazole. (Yield 60
%) The crystals were suspended in 1400 parts of 2-propanol, the activated M n O 2 640 parts was carried was charged 6 hours here. After the reaction was completed, M n O 2 was filtered off, and the filtrate was collected under reduced pressure to give a dry state.
【００１７】これに、メタノール２００部と７０℃の温
水１９００部を仕込み、内容物を溶解した。水冷し、析
出後、濾過、水洗し、乾燥した。To this, 200 parts of methanol and 1900 parts of hot water at 70 ° C. were charged and the contents were dissolved. After cooling with water, precipitation, filtration, washing with water, and drying.
【００１８】更に、この結晶をアセトニトリル５００部
で再結精製することにより、２−ブチル−４−クロロイ
ミダゾール−５−カルバルデヒド２２６．４部を得た。
（収率９０％） ２−ブチル−５−ヒドロキシルメチルイミダゾールから
のトータル収率は５４％であった。 実施例 ２−ブチル−５−ヒドロキシルメチルイミダゾール４０
０部をアセトン４０００部中に懸濁し、冷却下、Ｎ−ク
ロロスクシンイミド３５０部を内温１０℃を越えないよ
うに徐々に加え反応を行なった。反応終了後、内温４０
℃以下を保って反応液を減圧回収し、内容物を乾固させ
た。Further, the crystals were recrystallized and purified with 500 parts of acetonitrile to obtain 226.4 parts of 2-butyl-4-chloroimidazole-5-carbaldehyde.
(Yield 90%) The total yield from 2-butyl-5-hydroxylmethylimidazole was 54%. Example 2-Butyl-5-hydroxylmethyl imidazole 40
0 part was suspended in 4000 parts of acetone, and 350 parts of N-chlorosuccinimide was gradually added to the reaction mixture while cooling so that the internal temperature did not exceed 10 ° C. After the reaction is completed, the internal temperature is 40
The reaction solution was collected under reduced pressure while keeping the temperature below ℃, and the contents were dried.
【００１９】上記乾固物を２−プロパノール３０００部
に懸濁し、ここに活性化ＭnＯ2 ８００部を仕込み６時
間反応を行なった。反応終了後、ＭnＯ2 を濾別し、濾
液を減圧回収し、粗製２−ブチル−４−クロロイミダゾ
ール−５−カルバルデヒドを得た。[0019] The above dried product was suspended in 3000 parts of 2-propanol, the activated M n O 2 800 parts was carried was charged 6 hours here. After completion of the reaction, M n O 2 was filtered off and the filtrate was recovered under reduced pressure to obtain crude 2-butyl-4-chloroimidazole-5-carbaldehyde.
【００２０】上記粗製物を水３２００部に懸濁し、ここ
に重亜硫酸ナトリウム５７０部を投入して室温で１時間
攪拌を行った。この懸濁液に、トルエン４００部を投入
し１０分間攪拌後、分離を行なう。同様の抽出を５回繰
り返した。The above crude product was suspended in 3200 parts of water, 570 parts of sodium bisulfite was added thereto, and the mixture was stirred at room temperature for 1 hour. 400 parts of toluene is added to this suspension, and the mixture is stirred for 10 minutes and then separated. The same extraction was repeated 5 times.
【００２１】抽出終了後、分離した水層に炭酸ナトリウ
ム６４０部を徐々に投入し、ｐＨを弱アルカリ性とした
後、６０℃で３０分加温して加水分解反応を行う。反応
終了後、更に、３５％Ｈ2Ｏ2 ５４０部を徐々に滴下し
て結晶を析出させる。After completion of the extraction, 640 parts of sodium carbonate is gradually added to the separated aqueous layer to make the pH weakly alkaline, and then the mixture is heated at 60 ° C. for 30 minutes to carry out a hydrolysis reaction. After completion of the reaction, 540 parts of 35% H 2 O 2 is gradually added dropwise to precipitate crystals.
【００２２】析出物を濾過、水洗、乾燥して、２−ブチ
ル−４−クロロイミダゾール−５−カルバルデヒド３１
５部を得た。The precipitate is filtered, washed with water and dried to give 2-butyl-4-chloroimidazole-5-carbaldehyde 31.
5 parts were obtained.
【００２３】２−ブチル−５−ヒドロキシルメチルイミ
ダゾールからのトータル収率は６５．１％であった。The total yield from 2-butyl-5-hydroxylmethylimidazole was 65.1%.
Claims (1)
ダゾールをクロル化して、２−ブチル−４−クロロ−５
−ヒドロキシルメチルイミダゾールを製造し、更にこの
２−ブチル−４−クロロ−５−ヒドロキシルメチルイミ
ダゾールを酸化して２−ブチル−４−クロロイミダゾー
ル−５−カルバルデヒドを製造する方法において、前記
２−ブチル−４−クロロ−５−ヒドロキシルメチルイミ
ダゾールを単離精製することなく酸化を行ない、その
後、重亜硫酸ナトリウムと反応させて、重亜硫酸付加物
を生成させ、その後加水分解反応により２−ブチル−４
−クロロイミダゾール−５−カルバルデヒドを選択的に
得ることを特徴とする２−ブチル−４−クロロイミダゾ
ール−５−カルバルデヒドの製造法。1. 2-Butyl-5-hydroxylmethylimidazole is chlorinated to give 2-butyl-4-chloro-5.
-Hydroxylmethylimidazole is produced, and further 2-butyl-4-chloro-5-hydroxylmethylimidazole is oxidized to produce 2-butyl-4-chloroimidazole-5-carbaldehyde. Oxidation of 4-chloro-5-hydroxylmethylimidazole without isolation and purification is followed by reaction with sodium bisulfite to form a bisulfite adduct, followed by hydrolysis reaction to 2-butyl-4.
A method for producing 2-butyl-4-chloroimidazole-5-carbaldehyde, which comprises selectively obtaining -chloroimidazole-5-carbaldehyde.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20269293A JPH08816B2 (en) | 1993-07-23 | 1993-07-23 | Method for producing 2-butyl-4-chloroimidazole-5-carbaldehyde |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20269293A JPH08816B2 (en) | 1993-07-23 | 1993-07-23 | Method for producing 2-butyl-4-chloroimidazole-5-carbaldehyde |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0753524A JPH0753524A (en) | 1995-02-28 |
| JPH08816B2 true JPH08816B2 (en) | 1996-01-10 |
Family
ID=16461579
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP20269293A Expired - Fee Related JPH08816B2 (en) | 1993-07-23 | 1993-07-23 | Method for producing 2-butyl-4-chloroimidazole-5-carbaldehyde |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH08816B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2175420C (en) * | 1995-05-17 | 2007-04-10 | Gareth Griffiths | Process for the preparation of optionally 2-substituted 5-chloroimidazole-4-carbaldehydes |
| JP4841053B2 (en) * | 2001-04-06 | 2011-12-21 | 日本合成化学工業株式会社 | Method for producing formylimidazoles |
| CN111592495A (en) * | 2020-07-06 | 2020-08-28 | 上海启讯医药科技有限公司 | Preparation method of 2-n-butyl-4-chloro-5-formylimidazole |
-
1993
- 1993-07-23 JP JP20269293A patent/JPH08816B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0753524A (en) | 1995-02-28 |
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