JP3436314B2 - Method for producing 2-mercapto-5-methoxybenzimidazole - Google Patents

Method for producing 2-mercapto-5-methoxybenzimidazole

Info

Publication number
JP3436314B2
JP3436314B2 JP04219693A JP4219693A JP3436314B2 JP 3436314 B2 JP3436314 B2 JP 3436314B2 JP 04219693 A JP04219693 A JP 04219693A JP 4219693 A JP4219693 A JP 4219693A JP 3436314 B2 JP3436314 B2 JP 3436314B2
Authority
JP
Japan
Prior art keywords
methoxybenzimidazole
mercapto
reaction
producing
nitroanisole
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
Application number
JP04219693A
Other languages
Japanese (ja)
Other versions
JPH06279416A (en
Inventor
諭 中川
利宏 福永
亮三 織田
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Toyo Kasei Kogyo Co Ltd
Original Assignee
Toyo Kasei Kogyo Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Toyo Kasei Kogyo Co Ltd filed Critical Toyo Kasei Kogyo Co Ltd
Priority to JP04219693A priority Critical patent/JP3436314B2/en
Publication of JPH06279416A publication Critical patent/JPH06279416A/en
Application granted granted Critical
Publication of JP3436314B2 publication Critical patent/JP3436314B2/en
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Description

【発明の詳細な説明】Detailed Description of the Invention

【0001】[0001]

【産業上の利用分野】本発明は医薬の中間体として有用
な2−メルカプト−5−メトキシベンズイミダゾールを
4−アミノ−3−ニトロアニソールから一段法によつて
直接、高純度、高収率で簡便、安価に製造する方法に関
するものである。
FIELD OF THE INVENTION The present invention provides 2-mercapto-5-methoxybenzimidazole, which is useful as a pharmaceutical intermediate, directly from 4-amino-3-nitroanisole by a one-step method in a high purity and a high yield. The present invention relates to a simple and inexpensive manufacturing method.

【0002】[0002]

【従来の技術】従来4−アミノ−3−ニトロアニソール
から2−メルカプト−5−メトキシベンズイミダゾール
を製造する方法は一般式〔化2〕に示すようにその中間
体として3,4−ジアミノアニソールを経由している。
(T.Kametani,K.Fukumoto,F.
Satoh,H.Yagi,J.Chem.Soc
(C),1968,3084及びH.E.Fierz
David,L.Blangey,H.Streif
f,Helv.Chim.Acta,1946,29,
1718)かつ該中間体をCSを使用して環化するこ
とにより、目的とする2−メルカプト−5−メトキシベ
ンズイミダゾールを得ることができる。(特開平1−6
2638)
2. Description of the Related Art A conventional method for producing 2-mercapto-5-methoxybenzimidazole from 4-amino-3-nitroanisole is 3,4-diaminoanisole as an intermediate thereof, as shown in the general formula (2). It is via.
(T. Kametani, K. Fukumoto, F .;
Satoh, H .; Yagi, J .; Chem. Soc
(C), 1968, 3084 and H.M. E. Fierz
David, L .; Blankey, H .; Streif
f, Helv. Chim. Acta, 1946, 29,
1718) and cyclization of the intermediate using CS 2 affords the desired 2-mercapto-5-methoxybenzimidazole. (JP-A-1-6
2638)

【0003】上記を一殿式〔化2〕で示すと下記の通り
である。
The above is represented by the formula 1 [Formula 2] as follows.

【化2】 [Chemical 2]

【0004】しかしながら上記の製造方法は3,4−ジ
アミノアニソールが非常に不安定で空気により容易に酸
化されることから収率が著しく低下するとともに副生成
物の生成を招きやすい。従つて2−メルカプト−5−メ
トキシベンズイミダゾールの収率は50〜60%にとど
まっていた。
However, in the above-mentioned production method, 3,4-diaminoanisole is very unstable and is easily oxidized by air, so that the yield is remarkably lowered and a by-product is apt to be produced. Therefore, the yield of 2-mercapto-5-methoxybenzimidazole was 50 to 60%.

【0005】[0005]

【発明が解決しようとする課題】上記の如く従来の二段
反応による2−メルカプト−5−メトキシベンズイミダ
ゾールの製造法は中間体が不安定で空気により酸化され
やすくその収率が低く、かつ副生物の生成を招きやすい
ことに鑑み、本発明は中間体の3,4−ジアミノアニソ
ールを単離することなく、一段法により直接4−アミノ
−3−ニトロアニソールから高品質の2−メルカプト−
5−メトキシベンズイミダゾールを高収率で安価に製造
する方法を提供することを目的とするものである。
As described above, according to the conventional method for producing 2-mercapto-5-methoxybenzimidazole by the two-step reaction, the intermediate is unstable and is easily oxidized by air, and the yield thereof is low. In view of liable to cause the formation of organisms, the present invention does not isolate the intermediate 3,4-diaminoanisole, but directly from 4-amino-3-nitroanisole by a one-step method to obtain high-quality 2-mercapto-.
It is an object of the present invention to provide a method for producing 5-methoxybenzimidazole in high yield at low cost.

【0006】[0006]

【課題を解決するための手段】本発明は、下記反応式で
示される製造法であって、4−アミノ−3−ニトロアニ
ソールを原料とし、MeOH/H2Oを溶媒として、還
元剤である亜鉛又は鉄と塩酸とを使用して還元反応を行
うと共にCS2を使用して環化反応を行う一段法によ
り、中間体の3,4−ジアミノアニソールを単離するこ
となく、2−メルカプト−5−メトキシベンズイミダゾ
ールを製造する方法である。好適な態様としては、4−
アミノ−3−ニトロアニソールに対し、粉末状亜鉛又は
鉄は3〜4倍モル量、塩酸は0.1〜4倍モル量及びC
2は1.5〜3倍モル量使用され、また、混合して反
応する液体は50〜70℃に保たれる。
The present invention is a production method represented by the following reaction formula, wherein 4-amino-3-nitroanisole is used as a raw material, MeOH / H 2 O is used as a solvent, and a reducing agent is used. By a one-step method in which a reduction reaction is carried out using zinc or iron and hydrochloric acid and a cyclization reaction is carried out using CS 2 , 2-mercapto- A method for producing 5-methoxybenzimidazole. In a preferred embodiment, 4-
Powdered zinc or iron is 3 to 4 times molar amount, hydrochloric acid is 0.1 to 4 times molar amount, and C to amino-3-nitroanisole.
S 2 is used in a molar amount of 1.5 to 3 times, and the liquid to be mixed and reacted is kept at 50 to 70 ° C.

【0007】[0007]

【化3】 [Chemical 3]

【0008】本発明は従来の前記一般式〔化2〕に示す
ような前工程の還元反応と後工程の環化反応とを分断す
るものではなく、両反応を同時に進行させることによつ
て、高品質、高収率で4−アミノ−3−ニトロアニソー
ルから2−メルカプト−5−メトキシベンズイミダゾー
ルを得ることが可能である。
The present invention does not divide the reduction reaction in the previous step and the cyclization reaction in the subsequent step as shown in the above-mentioned general formula [Chemical Formula 2], but by allowing both reactions to proceed at the same time, It is possible to obtain 2-mercapto-5-methoxybenzimidazole from 4-amino-3-nitroanisole with high quality and high yield.

【0009】本発明における還元剤M(亜鉛又は鉄)は
反応速度の面から高純度で表面積の大きい粉末状が好適
である。還元に寄与する塩酸は塩化水素36重量%の水
溶液が適当である。反応溶媒には安価で溶解性に富むメ
タノ−ルを使用することが実用的である。Mが亜鉛の場
合は塩酸量は基質に対して本来の化学量論量の6倍モル
量を必要とせずに好適には4倍モル量である。亜鉛の量
は粉末状で純度換算で3〜4倍モル量が望ましい、CS
は1.5〜3倍モル量が望ましい。それ以上の過剰は
経済的に不利である。亜鉛を還元剤に使用する反応系に
おいては副生する塩化亜鉛が環化反応において副生する
硫化水素と反応することにより塩化水素が2当量生成
し、4−アミノ−3−ニトロアニソールの還元に寄与す
る。
The reducing agent M (zinc or iron) in the present invention is preferably in the form of powder having high purity and large surface area from the viewpoint of reaction rate. The hydrochloric acid that contributes to the reduction is suitably an aqueous solution containing 36% by weight of hydrogen chloride. It is practical to use inexpensive and highly soluble methanol as the reaction solvent. When M is zinc, the amount of hydrochloric acid is preferably 4 times the molar amount of the original stoichiometric amount with respect to the substrate, and is preferably 4 times the molar amount. The amount of zinc is preferably 3 to 4 times the molar amount in terms of purity in powder form, CS
The amount of 2 is preferably 1.5 to 3 times. Any further excess is economically disadvantageous. In a reaction system using zinc as a reducing agent, by-product zinc chloride reacts with by-product hydrogen sulfide in the cyclization reaction to generate 2 equivalents of hydrogen chloride, which leads to reduction of 4-amino-3-nitroanisole. Contribute.

【0010】反応溶液の温度は還流が観測される50〜
70℃にまで加熱することが望ましく、この温度以下の
温度では反応の進行が遅く実用的ではない。本反応系に
おける還流温度の最高は約70℃である。系内に残存す
る塩化亜鉛は溶解性の面から分離除去が困難であるため
硫化ナトリウムを使用して、不溶性の硫化亜鉛に変換す
ると同時に2−メルカプト−5−メトキシベンズイミダ
ゾールを水溶性ナトリウム塩に導くことによつて単離が
容易である。得られた2−メルカプト−5−メトキシベ
ンズイミダゾールのナトリウム塩を主成分とする反応生
成物を当量の塩酸で中和すれば目的とする2−メルカプ
ト−5−メトキシベンズイミタゾールを容易に製造する
ことができる。
The temperature of the reaction solution is 50 to 50 at which reflux is observed.
It is desirable to heat up to 70 ° C., and at a temperature below this temperature, the reaction proceeds slowly and is not practical. The maximum reflux temperature in this reaction system is about 70 ° C. Since zinc chloride remaining in the system is difficult to separate and remove from the viewpoint of solubility, sodium sulfide is used to convert it to insoluble zinc sulfide, and at the same time, 2-mercapto-5-methoxybenzimidazole is converted into a water-soluble sodium salt. By guiding, the isolation is easy. The desired 2-mercapto-5-methoxybenzimidazole can be easily produced by neutralizing the obtained reaction product containing 2-mercapto-5-methoxybenzimidazole sodium salt as a main component with an equivalent amount of hydrochloric acid. can do.

【0011】還元剤Mが鉄の場合は反応機構が亜鉛の場
合と異なり、触媒量の塩酸で加熱撹拌することより還元
反応が進行する。鉄は基質に対して4〜5倍モル量が望
ましく、撹拌効率や温度が反応速度に大きく影響する。
反応温度はCSと溶媒との共沸還流による70℃が上
限で反応完結に6時間を必要とする。この場合CS
量は1.5倍モルが経済的に好適であり、それ以上多く
ても少なくても、共沸還流温度との関連から反応進行が
遅くなり実用的に不利である。反応終了後酸化鉄(未反
応の鉄を含む)は濾過により容易に除去可能である。還
元剤Mが亜鉛の場合と鉄の場合とを比較すると後者の場
合の方が収率で約10%優れており、安価で簡便な点か
らも工業的製造法に適している。
When the reducing agent M is iron, unlike the case where the reaction mechanism is zinc, the reduction reaction proceeds by heating and stirring with a catalytic amount of hydrochloric acid. The amount of iron is preferably 4 to 5 times the molar amount of the substrate, and the stirring efficiency and temperature greatly influence the reaction rate.
The upper limit of the reaction temperature is 70 ° C. by azeotropic reflux of CS 2 and a solvent, and 6 hours are required to complete the reaction. In this case, the amount of CS 2 is economically preferable to be 1.5 times the molar amount, and if the amount is more or less than that, it is practically disadvantageous because the reaction progress is delayed in relation to the azeotropic reflux temperature. After completion of the reaction, iron oxide (including unreacted iron) can be easily removed by filtration. Comparing the case where the reducing agent M is zinc and the case where it is iron, the latter case is superior in yield by about 10%, and is suitable for the industrial production method from the viewpoint of being inexpensive and simple.

【0012】次に実施例によつて本発明を説明するが、
本発明はこれらの実施例のみに限定されるものではな
い。
The present invention will be described below with reference to examples.
The invention is not limited to these examples only.

【実施例1】ガラス製丸底反応容器(300ml、撹拌
装置つき)に4−アミノ−3−ニトロアニソール10
g、粉末亜鉛13g及びメタノ−ル70mlを加えて窒
素雰囲気下に撹拌した後、36%塩酸24.1gを滴下
する。1時間、撹拌を保持してCS13.6g、メタ
ノール50mlを加える。装置内温度を50〜55℃に
保つて4時間撹拌を続ける。同温度にて硫化ナトリウム
9水和物47.1g、濾過助剤として珪藻土5g、活性
炭1g及びメタノ−ル50mlを加え、1時間30分、
撹拌を維持した後、濾紙にて濾過をする。得られた濾過
溶液を反応容器に入れ36%塩酸を室温に保ちながら徐
々に滴下する。晶出した薄茶色結晶を濾過して採取する
と9.2gの2−メルカプト−5−メトキシベンズイミ
ダゾールを収率86%で得られた。このものの高速液体
クロマトグラフによる含量分析は94%である。
Example 1 4-Amino-3-nitroanisole 10 was placed in a glass round bottom reaction vessel (300 ml, equipped with a stirrer).
g, 13 g of powdered zinc and 70 ml of methanol were added and stirred under a nitrogen atmosphere, and then 24.1 g of 36% hydrochloric acid was added dropwise. With stirring maintained for 1 hour, 13.6 g CS 2 and 50 ml methanol are added. The temperature inside the apparatus is maintained at 50 to 55 ° C. and stirring is continued for 4 hours. At the same temperature, 47.1 g of sodium sulfide nonahydrate, 5 g of diatomaceous earth as a filter aid, 1 g of activated carbon and 50 ml of methanol were added, and 1 hour and 30 minutes,
After maintaining the stirring, the mixture is filtered with a filter paper. The obtained filtered solution is placed in a reaction vessel and 36% hydrochloric acid is gradually added dropwise while keeping the temperature at room temperature. The light brown crystals that crystallized were collected by filtration to obtain 9.2 g of 2-mercapto-5-methoxybenzimidazole in a yield of 86%. The content analysis of this product by high performance liquid chromatography is 94%.

【0013】[0013]

【実施例2】実施例1と同様に21反応容器に窒素雰囲
気下で4−アミノ−3−ニトロアニソール80g、粉末
鉄106.3g、水120g及びメタノール560ml
を加えて36%塩酸4.8gを滴下した後、更にCS
を加えて6時間の還流撹拌を行う。排ガスの硫化水素は
容器上部の冷却器を通して排出される。原料4−アミノ
−3−ニトロアニソールが消費されたことを確認して4
8%水酸化ナトリウム水溶液79.0gを投入して十分
に撹拌後、鉄化合物を濾紙により取り除く。得られた濾
過溶液を36%塩酸96.5gで実施例1と同様の操作
にて処理を行うと76.7gの2−メルカプト−5−メ
トキシベンズイミダゾールを収率90%で得られる。こ
のものの高速液体クロマトグラフによる含量分析は99
%である。
Example 2 In the same manner as in Example 1, in a reaction vessel of 21 under a nitrogen atmosphere, 80 g of 4-amino-3-nitroanisole, 106.3 g of iron powder, 120 g of water and 560 ml of methanol.
Was added and 4.8 g of 36% hydrochloric acid was added dropwise, and then CS 2 was added.
Is added and the mixture is stirred under reflux for 6 hours. The hydrogen sulfide of the exhaust gas is discharged through the cooler above the container. After confirming that the raw material 4-amino-3-nitroanisole was consumed, 4
79.0 g of an 8% aqueous sodium hydroxide solution was added and the mixture was sufficiently stirred, and then the iron compound was removed by a filter paper. The obtained filtered solution is treated with 36% hydrochloric acid 96.5 g in the same manner as in Example 1 to obtain 76.7 g of 2-mercapto-5-methoxybenzimidazole in a yield of 90%. The content analysis of this product by high performance liquid chromatography is 99
%.

【0014】[0014]

【発明の効果】本発明は従来中間体として3,4−ジア
ミノアニソールを経由して4−アミノ−3−ニトロアニ
ソールから2−メルカプト−5−メトキシベンズイミダ
ゾールを製造されていたため、中間体が非常に不安定で
空気により容易に酸化され、製品の2−メルカプト−5
−メトキシベンズイミダゾールの純度及び収率が著しく
低かつた。そこで本発明者によつて4−アミノ−3−ニ
トロアニソールから一段反応で直接2−メルカプト−5
−メトキシベンズイミダゾ−ルを製造する方法が見付け
られ、高純度、高収率かつ安価、簡便に該最終製品の目
的物質を製造することが可能になつた。
INDUSTRIAL APPLICABILITY According to the present invention, 2-mercapto-5-methoxybenzimidazole has been conventionally produced from 4-amino-3-nitroanisole via 3,4-diaminoanisole as an intermediate. Unstable and easily oxidized by air to give the product 2-mercapto-5
-The purity and yield of methoxybenzimidazole were extremely low. Therefore, the present inventors have proposed that 2-mercapto-5 can be directly produced from 4-amino-3-nitroanisole in a one-step reaction.
A method for producing -methoxybenzimidazole has been found, and it has become possible to easily and easily produce the target substance of the final product with high purity, high yield, low cost.

───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 昭50−84537(JP,A) 特開 昭48−28430(JP,A) 特開 昭64−62638(JP,A) 西独国特許出願公開2358244(DE, A1) 欧州特許出願公開130729(EP,A 2) (58)調査した分野(Int.Cl.7,DB名) C07D 235/28 CAOLD(STN) CAPLUS(STN) REGISTRY(STN)─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-50-84537 (JP, A) JP-A-48-28430 (JP, A) JP-A-64-62638 (JP, A) West German patent application publication 2358244 (DE, A1) European Patent Application Publication 130729 (EP, A2) (58) Fields searched (Int.Cl. 7 , DB name) C07D 235/28 CAOLD (STN) CAPLUS (STN) REGISTRY (STN)

Claims (3)

(57)【特許請求の範囲】(57) [Claims] 【請求項1】 下記反応式で示される製造法であって、
4−アミノ−3−ニトロアニソールを原料とし、メタノ
ール及び水(以下MeOH/H2Oと略称)を溶媒とし
て、還元剤である亜鉛又は鉄と塩酸とを使用して還元反
応を行うと共にCS2を使用して環化反応を行う一段法
により、中間体の3,4−ジアミノアニソールを単離す
ることなく、2−メルカプト−5−メトキシベンズイミ
ダゾールを製造する方法。 【化1】
1. A production method represented by the following reaction formula:
4-amino-3-nitroanisole is used as a raw material, methanol and water (hereinafter abbreviated as MeOH / H 2 O) are used as solvents, and a reducing reaction is performed using zinc or iron as a reducing agent and hydrochloric acid, and CS 2 A method for producing 2-mercapto-5-methoxybenzimidazole by a one-step method in which the intermediate 3,4-diaminoanisole is isolated by a cyclization reaction using. [Chemical 1]
【請求項2】 4−アミノ−3−ニトロアニソールに対
し、粉末状亜鉛又は鉄が3〜4倍モル量、塩酸が0.1
〜4倍モル量及びCS2が1.5〜3倍モル量使用され
る、請求項1記載の2−メルカプト−5−メトキシベン
ズイミダゾールの製造法。
2. Powdered zinc or iron in an amount of 3 to 4 times the molar amount of 4-amino-3-nitroanisole and 0.1% of hydrochloric acid.
The method for producing 2-mercapto-5-methoxybenzimidazole according to claim 1, wherein the molar ratio is about 4 to 4 times and CS 2 is about 1.5 to 3 times.
【請求項3】 混合して反応する液体が50〜70℃に
保たれる、請求項1又は2記載の2−メルカプト−5−
メトキシベンズイミダゾールの製造法。
3. The 2-mercapto-5 according to claim 1, wherein the liquid to be mixed and reacted is kept at 50 to 70 ° C.
Method for producing methoxybenzimidazole.
JP04219693A 1993-02-05 1993-02-05 Method for producing 2-mercapto-5-methoxybenzimidazole Expired - Fee Related JP3436314B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP04219693A JP3436314B2 (en) 1993-02-05 1993-02-05 Method for producing 2-mercapto-5-methoxybenzimidazole

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP04219693A JP3436314B2 (en) 1993-02-05 1993-02-05 Method for producing 2-mercapto-5-methoxybenzimidazole

Publications (2)

Publication Number Publication Date
JPH06279416A JPH06279416A (en) 1994-10-04
JP3436314B2 true JP3436314B2 (en) 2003-08-11

Family

ID=12629259

Family Applications (1)

Application Number Title Priority Date Filing Date
JP04219693A Expired - Fee Related JP3436314B2 (en) 1993-02-05 1993-02-05 Method for producing 2-mercapto-5-methoxybenzimidazole

Country Status (1)

Country Link
JP (1) JP3436314B2 (en)

Also Published As

Publication number Publication date
JPH06279416A (en) 1994-10-04

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