JP2002193939A - PRODUCTION METHOD OF 6-AMINOMETHYL-6,11-DIHYDRO-5H- DIBENZ[b,e]AZEPINE - Google Patents
PRODUCTION METHOD OF 6-AMINOMETHYL-6,11-DIHYDRO-5H- DIBENZ[b,e]AZEPINEInfo
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- JP2002193939A JP2002193939A JP2000395744A JP2000395744A JP2002193939A JP 2002193939 A JP2002193939 A JP 2002193939A JP 2000395744 A JP2000395744 A JP 2000395744A JP 2000395744 A JP2000395744 A JP 2000395744A JP 2002193939 A JP2002193939 A JP 2002193939A
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- Prior art keywords
- dibenz
- azepine
- dihydro
- aminomethyl
- formula
- Prior art date
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Abstract
Description
【０００１】本発明は医薬中間体として重要な６−アミ
ノメチルー６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，
ｅ］アゼピンの新規な製造方法に関するものである。The present invention relates to 6-aminomethyl-6,11-dihydro-5H-dibenz [b,
e] A novel method for producing azepine.
【０００２】[0002]
【従来の技術】６−アミノメチルー６，１１−ジヒドロ
−５Ｈ−ジベンズ［ｂ，ｅ］アゼピンは医薬中間体とし
て重要な化合物である。該化合物の製造方法については
式ＩＶで示される６−シアノー１１Ｈ−ジベンゾ［ｂ，
ｅ］アゼピンを、テトラヒドロフラン中水素化リチウム
アルミニウムと１００％硫酸から製造される水素化アル
ミニウムと反応させる方法が知られている（Ａｒｚｎｅ
ｉｍ．−Ｆｏｒｓｃｈ．，４０，４，４４０，１９９０
年；特公平３−６６３１１）。2. Description of the Related Art 6-Aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine is an important compound as a pharmaceutical intermediate. The method for preparing the compound is described by 6-cyano 11H-dibenzo [b,
e] A method is known in which azepine is reacted with lithium aluminum hydride in tetrahydrofuran and aluminum hydride produced from 100% sulfuric acid (Arzne).
im. -Forsch. , 40,4,440,1990
Year; Tokuhei 3-66311).
【化４】 しかしながらこの合成法はコスト的に負荷の大きいテト
ラヒドロフラン溶媒を使用し、反応後に析出する多量の
無機物の濾過など手間のかかる操作を含む。また６−フ
タルイミドメチルー５Ｈ−ジベンズ［ｂ，ｅ］アゼピン
をギ酸とパラジウム炭素で水素化して生成する式Ｖで示
される６−フタルイミドメチルー６、１１−ジヒドロー
５Ｈ−ジベンズ［ｂ，ｅ］アゼピンを単離し、ヒドラジ
ン分解して製造する方法が知られている（特開平４−３
４６９８８）。Embedded image However, this synthesis method uses a tetrahydrofuran solvent having a large cost load, and involves a complicated operation such as filtration of a large amount of inorganic substances precipitated after the reaction. 6-phthalimidomethyl-6,11-dihydro-5H-dibenz [b, e] azepine represented by the formula V, which is formed by hydrogenating 6-phthalimidomethyl-5H-dibenz [b, e] azepine with formic acid and palladium carbon. Is known, and a method of producing the same by hydrazinolysis is known (Japanese Patent Laid-Open No. 4-3).
46988).
【化５】 しかしながらこの方法は発癌性物質であるヒドラジンを
使用している為、工業的生産においてはその安全性が問
題となる。また水素化とヒドラジン分解の間に単離操作
が必要であるが工業規模の製造において単離操作の減少
が望まれることは衆知の事実である。Embedded image However, this method uses hydrazine, which is a carcinogenic substance, so that its safety is a problem in industrial production. It is a well-known fact that an isolation operation is required between hydrogenation and hydrazine decomposition, but a reduction in the isolation operation is desired in industrial-scale production.
【０００３】[0003]
【発明が解決しようとする課題】本発明の目的は６−フ
タルイミドメチルー５Ｈ−ジベンズ［ｂ，ｅ］アゼピン
からの６−アミノメチル６，１１−ジヒドロ−５Ｈ−ジ
ベンズ［ｂ，ｅ］アゼピンの合成において、有害物質の
使用を回避し、効率的な工業製法を提供することにあ
る。It is an object of the present invention to convert 6-aminomethyl 6,11-dihydro-5H-dibenz [b, e] azepine from 6-phthalimidomethyl-5H-dibenz [b, e] azepine. It is an object of the present invention to avoid the use of harmful substances in the synthesis and to provide an efficient industrial production method.
【０００４】[0004]
【課題を解決する為の手段】本発明者らは上記の問題点
を解決すべく鋭意検討を行なった結果、６−フタルイミ
ドメチルー５Ｈ−ジベンズ［ｂ，ｅ］アゼピンを金属水
素化合物または金属水素錯化合物と反応させ、イミン部
分の還元とフタルイミド部分の還元をワンポットで行な
えることを見出した。金属水素化合物によりフタルイミ
ドを脱保護することは公知である（Ｔｅｔｒａｈｅｄｒ
ｏｎＬｅｔｔｅｒｓ，２５，２０，２０９３，１９８４
年）が、同一分子内でフタルイミド部分のみならずイミ
ン部分も同時還元でき、水性溶媒を使った場合でもイミ
ン部分が殆ど加水分解を受けずにアミンに還元される事
は驚くべきことである。さらに生成したＮ−［（６，１
１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン−６
−イル）メチル］ーｏ−ヒドロキシメチルベンズアミド
は単離操作無しに容易に分解可能でワンポットにて６−
アミノメチル−６，１１−ジヒドロ−５Ｈ−ジベンズ
［ｂ，ｅ］アゼピンが得られる事を見出し、本発明を完
成するに至った。The present inventors have conducted intensive studies to solve the above problems, and as a result, have found that 6-phthalimidomethyl-5H-dibenz [b, e] azepine can be converted to a metal hydride or a metal hydride. By reacting with a complex compound, it was found that reduction of an imine moiety and reduction of a phthalimide moiety can be performed in one pot. Deprotection of phthalimide with metal hydrides is known (Tetrahedr).
onLetters, 25, 20, 2093, 1984
However, it is surprising that not only the phthalimide moiety but also the imine moiety can be simultaneously reduced in the same molecule, and even when an aqueous solvent is used, the imine moiety is reduced to an amine with almost no hydrolysis. Further generated N-[(6,1
1-dihydro-5H-dibenz [b, e] azepine-6
-Yl) methyl] -o-hydroxymethylbenzamide can be easily decomposed without isolation operation,
The inventors have found that aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine can be obtained, and have completed the present invention.
【０００５】すなわち本発明の方法は （１） 式ＩThat is, the method of the present invention comprises the following steps:
【化６】 で示される６−フタルイミドメチルー５Ｈ−ジベンズ
［ｂ，ｅ］アゼピンを金属水素化物または金属水素錯化
合物と反応せしめ、生成する式ＩＩEmbedded image Reacting 6-phthalimidomethyl-5H-dibenz [b, e] azepine with a metal hydride or metal hydride complex to form a compound of formula II
【化７】 で示されるＮ−［（６，１１−ジヒドロ−５Ｈ−ジベン
ズ［ｂ，ｅ］アゼピン−６−イル）メチル］ーｏ−ヒド
ロキシメチルベンズアミドを経由する式ＩＩＩEmbedded image Formula III via N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide
【化８】 で示される６−アミノメチル−６，１１−ジヒドロ−５
Ｈ−ジベンズ［ｂ，ｅ］アゼピンの製造方法。 （２） 式ＩＩで示されるＮ−［（６，１１−ジヒドロ
−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン−６−イル）メチ
ル］ーｏ−ヒドロキシメチルベンズアミド。 （３） 金属水素化化合物または金属水素錯化合物が水
素化ホウ素化合物である請求項１記載の６−アミノメチ
ル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］ア
ゼピンの製造方法。 （４） 溶媒としてアルコール類または水性アルコール
類を使う事を特徴とする請求項１記載の６−アミノメチ
ル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］ア
ゼピンの製造方法。 （５） 式ＩＩで示されるＮ−［（６，１１−ジヒドロ
−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン−６−イル）メチ
ル］ーｏ−ヒドロキシメチルベンズアミドを酸または塩
基で処理する事を特徴とする請求項１記載の６−アミノ
メチル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，
ｅ］アゼピンの製造方法。である。Embedded image 6-aminomethyl-6,11-dihydro-5 represented by
A method for producing H-dibenz [b, e] azepine. (2) N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide represented by the formula II. (3) The method for producing 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine according to claim 1, wherein the metal hydride compound or the metal hydride complex compound is a borohydride compound. (4) The method for producing 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine according to claim 1, wherein alcohols or aqueous alcohols are used as the solvent. (5) N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide represented by the formula II is treated with an acid or a base. 6-aminomethyl-6,11-dihydro-5H-dibenz [b,
e] Method for producing azepine. It is.
【０００６】以下本発明を詳細に説明する。反応は原
料、溶媒、金属水素化合物または金属水素錯化合物を順
次反応器に加え行なう、反応が終わるまで攪拌した後、
酸または塩基を加え加熱攪拌し分解処理した後、抽出な
どの方法により６−アミノメチルー６，１１−ジヒドロ
−５Ｈ−ジベンズ［ｂ,ｅ］アゼピンをシラップとして
得る。必要に応じて鉱酸または有機酸と塩を形成させて
結晶として取り出すことが可能で、また塩形成後に有機
溶媒により不純物を抽出し精製することが可能である。Hereinafter, the present invention will be described in detail. The reaction is carried out by sequentially adding the starting material, the solvent, the metal hydride or the metal hydride to the reactor.
An acid or a base is added, the mixture is heated and stirred to decompose, and 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine is obtained as a syrup by a method such as extraction. If necessary, a salt can be formed with a mineral acid or an organic acid to be taken out as crystals, and after salt formation, impurities can be extracted and purified with an organic solvent.
【０００７】金属水素化合物または金属水素錯化合物の
使用量としては理論量の６〜６０倍、好ましくは１２〜
３０倍、特に好ましくは１２〜２０倍である。６倍未満
だと未反応物が残りやすい。６０倍を超えると経済的に
好ましくない。添加は粉体、または溶媒に溶解後滴下し
ても良い。The amount of the metal hydride or metal hydride used is 6 to 60 times the theoretical amount, preferably 12 to 60 times the theoretical amount.
It is 30 times, particularly preferably 12 to 20 times. If it is less than 6 times, unreacted substances tend to remain. If it exceeds 60 times, it is not economically preferable. The addition may be carried out dropwise after dissolving in a powder or a solvent.
【０００８】反応溶媒としてはアルコール類または水性
アルコール類が使用される。アルコール類としてはｎ−
ブタノール、イソブタノール、ｎ−プロパノール、イソ
プロパノール、エタノール、メタノール、またはその混
合溶媒が好ましく特にイソプロパノールが好ましい。水
性アルコール中の水の濃度は１〜９９重量％であり、特
に１８％が好ましい。溶媒(水を含む)の使用量としては
６−フタルイミドメチルー５Ｈ−ジベンズ［ｂ，ｅ］ア
ゼピンの重量に対して１〜５０倍容量、好ましくは２〜
２０倍容量、特に好ましくは１０〜１５倍容量である。As the reaction solvent, alcohols or aqueous alcohols are used. N- alcohols
Butanol, isobutanol, n-propanol, isopropanol, ethanol, methanol, or a mixed solvent thereof is preferable, and isopropanol is particularly preferable. The concentration of water in the aqueous alcohol is 1 to 99% by weight, particularly preferably 18%. The amount of the solvent (including water) used is 1 to 50 times, preferably 2 to 50 times the weight of 6-phthalimidomethyl-5H-dibenz [b, e] azepine.
The capacity is 20 times, particularly preferably 10 to 15 times.
【０００９】必要に応じて反応を早める為に無機塩を添
加しても良い、特に限定するものではないが無機塩とし
ては塩化亜鉛、塩化マグネシウム、塩化コバルトが好ま
しい。If necessary, an inorganic salt may be added to accelerate the reaction. The inorganic salt is preferably, but not limited to, zinc chloride, magnesium chloride or cobalt chloride.
【００１０】反応温度は０℃〜還流温度であり好ましく
は１０〜４０℃である。０℃以下だと反応が遅すぎる
為、経済的ではない。[0010] The reaction temperature is 0 ° C to reflux temperature, preferably 10 to 40 ° C. If the temperature is lower than 0 ° C., the reaction is too slow, which is not economical.
【００１１】Ｎ−［（６，１１−ジヒドロ−５Ｈ−ジベ
ンズ［ｂ，ｅ］アゼピン−６−イル）メチル］ーｏ−ヒ
ドロキシメチルベンズアミドの分解処理は酸または塩基
どちらでも可能である、酸としては鉱酸、有機酸類が使
用できるが、塩酸、硫酸、メタンスルホン酸、酢酸、ギ
酸が好ましく、特に塩酸、酢酸が好ましい。塩基として
は無機塩基、有機塩基が使用できるが、アルカリ金属の
塩または水酸化物、アルキルアミン類が好ましく、特に
水酸化ナトリウムが好ましい。The decomposition treatment of N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide is possible with either an acid or a base. Although mineral acids and organic acids can be used, hydrochloric acid, sulfuric acid, methanesulfonic acid, acetic acid and formic acid are preferable, and hydrochloric acid and acetic acid are particularly preferable. As the base, an inorganic base or an organic base can be used, but alkali metal salts or hydroxides and alkylamines are preferable, and sodium hydroxide is particularly preferable.
【００１２】[0012]
【実施例】実施例によって本発明を具体的に説明する
が、本発明がこれらの実施例に限定されるものではな
い。EXAMPLES The present invention will be described specifically with reference to examples, but the present invention is not limited to these examples.
【００１３】原料である６−フタルイミドメチルー５Ｈ
−ジベンズ［ｂ，ｅ］アゼピンは、Ｊ．Ｈｅｔｅｒｏｃ
ｙｃｌ．ｃｈｅｍ．，１７，２，３４１，１９８０年記
載の方法に従って合成した。Raw material 6-phthalimidomethyl-5H
-Dibenz [b, e] azepine is described in Heteroc
ycl. chem. , 17, 2, 341, 1980.
【００１４】実施例１ 攪拌機、還流冷却機、温度計の備わった１００ｍｌフラ
スコに６−フタルイミドメチルー５Ｈ−ジベンズ［ｂ，
ｅ］アゼピン３．０ｇ（８．５ｍｍｏｌ）、イソプロパ
ノール４５．０ｍｌおよび水７．５ｍｌを仕込んだ後、
室温攪拌下、水素化ホウ素ナトリウム１．３ｇ（３５．
１ｍｍｏｌ）を添加した。添加後白色のスラリーとなっ
た内容物を一昼夜室温で攪拌した。この反応液に室温に
て酢酸を滴下し水素化ホウ素ナトリウムの残を分解した
後、８０℃で１．５時間攪拌した。室温になるまで放冷
後、２５％ＮａＯＨでｐＨ＝１１に調整しトルエン抽出
した。抽出液を減圧濃縮し褐色シラップ３．１ｇを得
た。褐色シラップをメタノールに溶解し、メタノールに
溶解したフマル酸０．８９ｇを滴下した。室温で結晶の
析出を確認後、０℃で３時間攪拌し減圧濾過した。ケー
キを冷メタノールで洗浄、次いで乾燥した。 収量：６−アミノメチル６，１１−ジヒドロ−５Ｈ−ジ
ベンズ［ｂ，ｅ］アゼピン・フマル酸塩２．０ｇ（理論
量の６９．０％）Example 1 A 6-phthalimidomethyl-5H-dibenz [b, b) was placed in a 100 ml flask equipped with a stirrer, a reflux condenser and a thermometer.
e] After charging 3.0 g (8.5 mmol) of azepine, 45.0 ml of isopropanol and 7.5 ml of water,
1.3 g of sodium borohydride (35.
1 mmol) was added. The content which became a white slurry after the addition was stirred at room temperature for 24 hours. Acetic acid was added dropwise to the reaction solution at room temperature to decompose the residue of sodium borohydride, and the mixture was stirred at 80 ° C for 1.5 hours. After allowing to cool to room temperature, the pH was adjusted to 11 with 25% NaOH and extracted with toluene. The extract was concentrated under reduced pressure to obtain 3.1 g of a brown syrup. The brown syrup was dissolved in methanol, and 0.89 g of fumaric acid dissolved in methanol was added dropwise. After confirming the precipitation of crystals at room temperature, the mixture was stirred at 0 ° C. for 3 hours and filtered under reduced pressure. The cake was washed with cold methanol and then dried. Yield: 2.0 g of 6-aminomethyl 6,11-dihydro-5H-dibenz [b, e] azepine fumarate (69.0% of theory)
【００１５】実施例２ 攪拌機、還流冷却機、温度計の備わった３００ｍｌフラ
スコに６−フタルイミドメチルー５Ｈ−ジベンズ［ｂ，
ｅ］アゼピン３．０ｇ（８．５ｍｍｏｌ）、イソプロパ
ノール４５．０ｍｌおよび水７．５ｍｌを仕込んだ後、
室温攪拌下、水素化ホウ素ナトリウム１．３ｇ（３５．
１ｍｍｏｌ）を添加した。添加後白色のスラリーとなっ
た内容物を一昼夜室温で攪拌した。この反応液に室温に
て１規定塩酸を滴下し水素化ホウ素ナトリウムの残を分
解した後、８０℃で１．５時間攪拌した。室温になるま
で放冷後、２５％ＮａＯＨでｐＨ＝１１に調整しトルエ
ン抽出した。抽出液を減圧濃縮し褐色シラップ３．０ｇ
を得た。褐色シラップをメタノールに溶解し、メタノー
ルに溶解したフマル酸０．８９ｇを滴下した。室温で結
晶の析出を確認後、０℃で３時間攪拌し減圧濾過した。
ケーキを冷メタノールで洗浄、次いで乾燥した。 収量：６−アミノメチル６，１１−ジヒドロ−５Ｈ−ジ
ベンズ［ｂ，ｅ］アゼピン・フマル酸塩２．２ｇ（理論
量の７６．１％）Example 2 In a 300 ml flask equipped with a stirrer, a reflux condenser and a thermometer, 6-phthalimidomethyl-5H-dibenz [b,
e] After charging 3.0 g (8.5 mmol) of azepine, 45.0 ml of isopropanol and 7.5 ml of water,
1.3 g of sodium borohydride (35.
1 mmol) was added. The content which became a white slurry after the addition was stirred at room temperature for 24 hours. 1N hydrochloric acid was added dropwise to the reaction solution at room temperature to decompose the residue of sodium borohydride, and the mixture was stirred at 80 ° C. for 1.5 hours. After allowing to cool to room temperature, the pH was adjusted to 11 with 25% NaOH and extracted with toluene. The extract was concentrated under reduced pressure to obtain a brown syrup (3.0 g).
Got. The brown syrup was dissolved in methanol, and 0.89 g of fumaric acid dissolved in methanol was added dropwise. After confirming the precipitation of crystals at room temperature, the mixture was stirred at 0 ° C. for 3 hours and filtered under reduced pressure.
The cake was washed with cold methanol and then dried. Yield: 2.2 g of 6-aminomethyl 6,11-dihydro-5H-dibenz [b, e] azepine fumarate (76.1% of theory)
【００１６】実施例３ 攪拌機、還流冷却機、温度計の備わった３００ｍｌフラ
スコに６−フタルイミドメチルー５Ｈ−ジベンズ［ｂ，
ｅ］アゼピン３．０ｇ（８．５ｍｍｏｌ）、イソプロパ
ノール４５．０ｍｌおよび水７．５ｍｌを仕込んだ後、
室温攪拌下、水素化ホウ素ナトリウム１．３ｇ（３５．
１ｍｍｏｌ）を添加した。添加後白色のスラリーとなっ
た内容物を一昼夜室温で攪拌した。この反応液に室温に
てＭｅＯＨを滴下し水素化ホウ素ナトリウムの残を分解
した後、２５％ＮａＯＨを加え溶液を塩基性とした後、
８０℃で１．５時間攪拌した。内温が室温になるまで放
冷しトルエン抽出後、抽出液を減圧濃縮し褐色シラップ
３．０ｇを得た。褐色シラップをに溶解し、メタノール
に溶解したフマル酸０．８９ｇを滴下した。室温で結晶
の析出を確認後、０℃で３時間攪拌し減圧濾過した。ケ
ーキを冷メタノールで洗浄、次いで乾燥した。 収量：６−アミノメチル６，１１−ジヒドロ−５Ｈ−ジ
ベンズ［ｂ，ｅ］アゼピン・フマル酸塩２．１ｇ（理論
量の７２．４％）Example 3 A 6-phthalimidomethyl-5H-dibenz [b, b) was placed in a 300 ml flask equipped with a stirrer, reflux condenser and thermometer.
e] After charging 3.0 g (8.5 mmol) of azepine, 45.0 ml of isopropanol and 7.5 ml of water,
1.3 g of sodium borohydride (35.
1 mmol) was added. The content which became a white slurry after the addition was stirred at room temperature for 24 hours. MeOH was added dropwise to the reaction solution at room temperature to decompose the residue of sodium borohydride, and then 25% NaOH was added to make the solution basic.
Stirred at 80 ° C. for 1.5 hours. After allowing the internal temperature to cool to room temperature and extracting with toluene, the extract was concentrated under reduced pressure to obtain 3.0 g of a brown syrup. The brown syrup was dissolved in, and 0.89 g of fumaric acid dissolved in methanol was added dropwise. After confirming the precipitation of crystals at room temperature, the mixture was stirred at 0 ° C. for 3 hours and filtered under reduced pressure. The cake was washed with cold methanol and then dried. Yield: 2.1 g of 6-aminomethyl 6,11-dihydro-5H-dibenz [b, e] azepine fumarate (72.4% of theory)
【００１７】実施例４ 攪拌機、還流冷却機、温度計の備わった１００ｍｌフラ
スコに６−フタルイミドメチルー５Ｈ−ジベンズ［ｂ，
ｅ］アゼピン３．０ｇ（８．５ｍｍｏｌ）、イソプロパ
ノール４５．０ｍｌおよび水７．５ｍｌを仕込んだ後、
室温攪拌下、水素化ホウ素ナトリウム１．３ｇ（３５．
１ｍｍｏｌ）を３０℃以下を保つように３０分かけて添
加した。添加後白色のスラリーとなった内容物を一昼夜
室温で攪拌した。この反応液に室温にてＭｅＯＨ５．０
ｍｌを滴下し、水素化ホウ素ナトリウムの残を分解し
た。水４０ｍｌを滴下し析出した結晶を濾過、乾燥しＮ
−［（６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］
アゼピン−６−イル）メチル］ーｏ−ヒドロキシメチル
ベンズアミドを単離した。 １Ｈ−ＮＭＲ（ＤＭＳＯ）δ３．７−３．８（ｍ，１
Ｈ），３．９−４．１（ｍ，２Ｈ），４．４（ｄ，１
Ｈ），４．７（ｄ，２Ｈ），５．１（ｍ，１Ｈ），５．
３（ｔ，１Ｈ），５．８（ｄ，１Ｈ），６．６−６．７
（ｍ，２Ｈ），６．９−７．１（ｍ，２Ｈ），７．３−
７．７（ｍ，８Ｈ），８．７（ｔ，１Ｈ）Example 4 A 6-phthalimidomethyl-5H-dibenz [b, b) was placed in a 100 ml flask equipped with a stirrer, a reflux condenser and a thermometer.
e] After charging 3.0 g (8.5 mmol) of azepine, 45.0 ml of isopropanol and 7.5 ml of water,
1.3 g of sodium borohydride (35.
1 mmol) was added over 30 minutes to keep the temperature below 30 ° C. The content which became a white slurry after the addition was stirred at room temperature for 24 hours. The reaction solution was added with MeOH 5.0 at room temperature.
ml was added dropwise to decompose the residue of sodium borohydride. 40 ml of water is added dropwise, and the precipitated crystals are filtered, dried and dried.
-[(6,11-dihydro-5H-dibenz [b, e]
Azepin-6-yl) methyl] -o-hydroxymethylbenzamide was isolated. 1H-NMR (DMSO) δ 3.7-3.8 (m, 1
H), 3.9-4.1 (m, 2H), 4.4 (d, 1
H), 4.7 (d, 2H), 5.1 (m, 1H), 5.
3 (t, 1H), 5.8 (d, 1H), 6.6-6.7
(M, 2H), 6.9-7.1 (m, 2H), 7.3-
7.7 (m, 8H), 8.7 (t, 1H)
【００１８】[0018]
【発明の効果】本発明の製造法によると、有害性の高い
原料の使用を避け、中間物単離が不要で簡単な操作で６
−アミノメチル６，１１−ジヒドロ−５Ｈ−ジベンズ
［ｂ，ｅ］アゼピンの製造が可能になり、その製造コス
トの大幅な削減を図ることができる。According to the production method of the present invention, the use of highly hazardous raw materials is avoided, the isolation of intermediates is not required, and the operation is simple.
-Aminomethyl 6,11-dihydro-5H-dibenz [b, e] azepine can be produced, and the production cost can be significantly reduced.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 高橋 康弘 福島県相馬郡小高町蛯沢字笠谷26 株式会 社コニカケミカル内 Ｆターム(参考） 4C034 DS01 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Yasuhiro Takahashi 26 Kasaya, Ebizawa, Kodaka-cho, Soma-gun, Fukushima Prefecture F-term in Konica Chemical Co., Ltd. 4C034 DS01
Claims (5)
［ｂ，ｅ］アゼピンを金属水素化物または金属水素錯化
合物と反応せしめ、生成する式ＩＩ 【化２】 で示されるＮ−［（６，１１−ジヒドロ−５Ｈ−ジベン
ズ［ｂ，ｅ］アゼピン−６−イル）メチル］ーｏ−ヒド
ロキシメチルベンズアミドを経由する式ＩＩＩ 【化３】 で示される６−アミノメチル−６，１１−ジヒドロ−５
Ｈ−ジベンズ［ｂ，ｅ］アゼピンの製造方法。1. A compound of the formula I Reacting 6-phthalimidomethyl-5H-dibenz [b, e] azepine with a metal hydride or a metal hydride complex to form a compound of formula II Formula III via N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide represented by 6-aminomethyl-6,11-dihydro-5 represented by
A method for producing H-dibenz [b, e] azepine.
ヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン−６−イ
ル）メチル］ーｏ−ヒドロキシメチルベンズアミド。2. N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide of the formula II.
物が水素化ホウ素化合物である請求項１記載の６−アミ
ノメチル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，
ｅ］アゼピンの製造方法。3. The 6-aminomethyl-6,11-dihydro-5H-dibenz [b, 2] according to claim 1, wherein the metal hydride compound or the metal hydride complex compound is a borohydride compound.
e] Method for producing azepine.
コール類を使う事を特徴とする請求項１記載の６−アミ
ノメチル−６，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，
ｅ］アゼピンの製造方法。4. The method according to claim 1, wherein an alcohol or a hydroalcohol is used as the solvent.
e] Method for producing azepine.
ヒドロ−５Ｈ−ジベンズ［ｂ，ｅ］アゼピン−６−イ
ル）メチル］ーｏ−ヒドロキシメチルベンズアミドを酸
または塩基で処理する事を特徴とする請求項１記載の６
−アミノメチル−６，１１−ジヒドロ−５Ｈ−ジベンズ
［ｂ，ｅ］アゼピンの製造方法。5. Treating N-[(6,11-dihydro-5H-dibenz [b, e] azepin-6-yl) methyl] -o-hydroxymethylbenzamide of the formula II with an acid or a base. 6. The method according to claim 1, wherein:
A method for producing -aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine.
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|---|---|---|---|
| JP2000395744A JP4290325B2 (en) | 2000-12-26 | 2000-12-26 | Process for producing 6-aminomethyl-6,11-dihydro-5H-dibenz [b, e] azepine |
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003084932A1 (en) * | 2002-04-11 | 2003-10-16 | Konica Minolta Chemical Co., Ltd. | Method for preparing 6-aminomethyl-6,11-dihydro-5h-dibenz[b,e]azepine |
| CN102895702A (en) * | 2012-11-09 | 2013-01-30 | 四川大学华西医院 | Composite artificial bile duct and preparation method thereof |
| CN104447760A (en) * | 2014-11-26 | 2015-03-25 | 千辉药业（安徽）有限责任公司 | Preparation method of epinastine |
-
2000
- 2000-12-26 JP JP2000395744A patent/JP4290325B2/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003084932A1 (en) * | 2002-04-11 | 2003-10-16 | Konica Minolta Chemical Co., Ltd. | Method for preparing 6-aminomethyl-6,11-dihydro-5h-dibenz[b,e]azepine |
| US7196193B2 (en) * | 2002-04-11 | 2007-03-27 | Konica Minolta Chemical Co., Ltd. | Method for preparing 6-aminomethyl-6, 11-dihydro-5h-dibenz[b,e]azepine |
| CN102895702A (en) * | 2012-11-09 | 2013-01-30 | 四川大学华西医院 | Composite artificial bile duct and preparation method thereof |
| CN104447760A (en) * | 2014-11-26 | 2015-03-25 | 千辉药业（安徽）有限责任公司 | Preparation method of epinastine |
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