JP3112728B2 - Method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione - Google Patents
Method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dioneInfo
- Publication number
- JP3112728B2 JP3112728B2 JP03291835A JP29183591A JP3112728B2 JP 3112728 B2 JP3112728 B2 JP 3112728B2 JP 03291835 A JP03291835 A JP 03291835A JP 29183591 A JP29183591 A JP 29183591A JP 3112728 B2 JP3112728 B2 JP 3112728B2
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- Prior art keywords
- benzoxazepine
- tetrahydro
- ester
- dione
- mol
- Prior art date
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
【０００１】[0001]
【産業上の利用分野】本発明は、医薬品製造の中間体と
して重要な２，３，４，５−テトラヒドロ−１，４−ベ
ンゾオキサゼピン−３，５−ジオンの製造法に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione which is important as an intermediate in the production of pharmaceuticals.
【０００２】さらに詳細には、本発明の方法により製造
される２，３，４，５−テトラヒドロ−１，４−ベンゾ
オキサゼピン−３，５−ジオンは、特開平０２−２５６
６７１号公報の方法により、その４位に４−アリール−
１−ピペラジニルアルキル基、例えば４−（４−（２−
ピリミジニル）−１−ピペラジニル）ブチル基、４−
（４−（２−ピリジル）−１−ピペラジニル）ブチル
基、４−（４−フェニル−１−ピペラジニル）ブチル基
等を導入することにより、式（３）：More specifically, 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione produced by the method of the present invention is disclosed in JP-A-02-256.
No. 671 discloses that 4-aryl-
1-piperazinylalkyl groups such as 4- (4- (2-
Pyrimidinyl) -1-piperazinyl) butyl group, 4-
By introducing a (4- (2-pyridyl) -1-piperazinyl) butyl group, a 4- (4-phenyl-1-piperazinyl) butyl group or the like, a compound represented by the formula (3):
【化３】 （式中Ａは２−ピリミジニル基、２−ピリジル基、フェ
ニル基を示す）で表される化合物に誘導することができ
る。Embedded image (Wherein A represents a 2-pyrimidinyl group, a 2-pyridyl group and a phenyl group).
【０００３】この式（３）の化合物は、セロトニン受容
体に対して強力な親和性を有すると共に、抗コンフリク
ト作用を有し、不安神経症、恐怖症、強迫神経症、心的
外傷後ストレス障害、抑うつ神経症、心身症等の精神神
経疾患並びに摂食障害、更年期障害、小児自閉症等のセ
ロトニン神経系が関与する疾患に対する治療薬として有
用である。The compound of formula (3) has a strong affinity for serotonin receptors, has an anti-conflict effect, and has anxiety, phobia, obsessive-compulsive disorder, post-traumatic stress disorder. It is useful as a therapeutic drug for neuropsychiatric disorders such as depressive neurosis and psychosomatic disorders, and for diseases involving the serotonin nervous system such as eating disorders, menopause, and pediatric autism.
【０００４】[0004]
【従来の技術】２，３，４，５−テトラヒドロ−１，４
−ベンゾオキサゼピン−３，５−ジオンを得る方法とし
ては、２−カルバモイルフェノキシ酢酸を脱水閉環させ
る方法が知られており、カッタネオ等（Ａ．Ｃａｔｔａ
ｎｅｏ ｅｔ ａｌ．，Ｂｕｌｌ．Ｃｈｉｍ．Ｐｈａｒ
ｍ．，ｖｏｌ．１０２，ｐ５４１，１９６３）は無水酢
酸を用いる方法を報告しているが、その収率については
何ら記載していない。またチーマン等（Ｈ．Ｔｈｉｅｍ
ａｎｎ，西ドイツ特許１，０８５，８７９号）は無水酢
酸を用いる方法、塩化アセチルを用いる方法および塩化
チオニルを用いる方法を記載し、その収率について、そ
れぞれ６９．５％、９０％およひ４８％と報告してい
る。2. Description of the Related Art 2,3,4,5-Tetrahydro-1,4
As a method for obtaining -benzoxazepine-3,5-dione, a method of dehydrating and cyclizing 2-carbamoylphenoxyacetic acid is known, and Cattaneo et al. (A. Cattta)
neo et al. Bull. Chim. Phar
m. , Vol. 102, p541, 1963) reports a method using acetic anhydride, but does not disclose the yield. In addition, Chiman et al. (H. Thiem
Ann, West German Patent 1,085,879) describes a method using acetic anhydride, a method using acetyl chloride and a method using thionyl chloride, with yields of 69.5%, 90% and 48%, respectively. %.
【０００５】[0005]
【発明が解決しようとする課題】上記報告の反応はいず
れも脱水反応であるため、反応条件として１４０〜１８
０℃という高温を必要とし、反応時間も数時間を要する
ので、大量合成としては必ずしも適当な方法ではない。
従って、大量合成に適した、安価で、反応条件が緩和
で、効率良くしかも簡便な２，３，４，５−テトラヒド
ロ−１，４−ベンゾオキサゼピン−３，５−ジオンの製
造法の開発が求められている。Since the above reported reactions are all dehydration reactions, the reaction conditions are 140 to 18
Since a high temperature of 0 ° C. is required and the reaction time is also several hours, it is not always an appropriate method for mass synthesis.
Therefore, a method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione, which is suitable for mass synthesis, inexpensive, has moderate reaction conditions, is efficient and simple. Development is required.
【０００６】[0006]
【課題を解決するための手段】本発明者等は、上記課題
を解決すべく鋭意研究を重ねた結果、上記報告の２−カ
ルバモイルフェノキシ酢酸に代えて、２−カルバモイル
フェノキシ酢酸アルキルエステル又は２−カルバモイル
フェノキシ酢酸アラルキルエステルを出発原料とし、こ
れを低級アルコールのアルカリ金属アルコキシドで処理
することにより、室温で数十分という条件で、極めて効
率良く、２，３，４，５−テトラヒドロ−１，４−ベン
ゾオキサゼピン−３，５−ジオンが得られることを見出
し、本発明を完成した。Means for Solving the Problems The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, in place of 2-carbamoylphenoxyacetic acid in the above report, 2-carbamoylphenoxyacetic acid alkyl ester or 2-carbamoylphenoxyacetic acid was used. By treating an aralkyl carbamoylphenoxyacetate as a starting material and treating it with an alkali metal alkoxide of a lower alcohol, 2,3,4,5-tetrahydro-1,4 is very efficiently obtained at room temperature for several tens minutes. It was found that -benzoxazepine-3,5-dione was obtained, and the present invention was completed.
【０００７】[0007]
【作用】本発明によれば、式（４）：According to the present invention, equation (4):
【化４】 （式中、Ｒは炭素数１〜５の直鎖あるいは分岐のアルキ
ル基又は炭素数７〜９の直鎖あるいは分岐のアラルキル
基を示す）で示される２−カルバモイルフェノキシ酢酸
アルキルエステルまたは２−カルバモイルフェノキシ酢
酸アラルキルエステルを、低級アルコールのアルカリ金
属アルコキシドで処理することからなる、式（５）：Embedded image (Wherein R represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms or a straight-chain or branched aralkyl group having 7 to 9 carbon atoms) 2-carbamoylphenoxyacetic acid alkyl ester or 2-carbamoyl Treating an aralkyl phenoxyacetate with an alkali metal alkoxide of a lower alcohol, formula (5):
【化５】 で表される２，３，４，５−テトラヒドロ−１，４−ベ
ンゾオキサゼピン−３，５−ジオンの製造法が提供され
る。Embedded image And a method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione represented by the formula:
【０００８】ここで、アルキルエステルとは炭素数１〜
５の直鎖あるいは分岐のアルキルエステルを示し、メチ
ルエステル、エチルエステル、プロピルエステル、ブチ
ルエステル、ペンチルエステル等が例示できるが、メチ
ルエステル、エチルエステルが好ましい。また、アラル
キルエステルとは炭素数７〜９の直鎖あるいは分岐のア
ラルキルエステルを示し、ベンジルエステル、フェネチ
ルエステル、フェニルプロピルエステル等が例示できる
が、ベンジルエステルが好ましい。また、低級アルコー
ルとは炭素数１〜５の直鎖あるいは分岐のアルコールを
示し、メタノール、エタノール、プロパノール、ブタノ
ール、ペンタノール等が例示できるが、メタノール、エ
タノールが好ましい。Here, the alkyl ester is a compound having 1 to 1 carbon atoms.
5 represents a linear or branched alkyl ester, such as methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, etc., of which methyl ester and ethyl ester are preferred. The aralkyl ester refers to a linear or branched aralkyl ester having 7 to 9 carbon atoms, and examples thereof include benzyl ester, phenethyl ester, and phenylpropyl ester, with benzyl ester being preferred. The lower alcohol refers to a linear or branched alcohol having 1 to 5 carbon atoms, and examples thereof include methanol, ethanol, propanol, butanol, and pentanol, and methanol and ethanol are preferred.
【０００９】本発明に用いる２−カルバモイルフェノキ
シ酢酸アルキルエステルおよび２−カルバモイルフェノ
キシ酢酸アラルキルエステルは、例えば、反応式
（１）：The alkyl 2-carbamoylphenoxyacetate and the aralkyl 2-carbamoylphenoxyacetate used in the present invention can be produced, for example, by the following reaction scheme (1):
【化６】 （式中、Ｒは前記と同様）に示す様に、サリチルアミド
とブロモ酢酸アルキルエステル又はブロモ酢酸アラルキ
ルエステルから容易に合成できる。すなわち、サリチル
アミドをアセトン等の適切な溶媒に溶解し、炭酸カリウ
ムの１．０〜１．２モル当量、好ましくは１．１当量お
よびブロモ酢酸アルキルエステルの１．０〜１．２モル
当量、好ましくは１．０５当量を加え、１〜５時間加熱
還流する。反応後、反応液に水を加えると結晶が析出
し、濾取すると２−カルバモイルフェノキシ酢酸アルキ
ルエステルが得られる。同様に、ブロモ酢酸アルキルエ
ステルに代えてブロモ酢酸アラルキルエステルを用いる
と、２−カルバモイルフェノキシ酢酸アラルキルエステ
ルが得られる。Embedded image (Wherein R is the same as described above), it can be easily synthesized from salicylamide and bromoacetic acid alkyl ester or bromoacetic acid aralkyl ester. That is, salicylamide is dissolved in a suitable solvent such as acetone, and 1.0 to 1.2 molar equivalents of potassium carbonate, preferably 1.1 equivalents and 1.0 to 1.2 molar equivalents of bromoacetic acid alkyl ester, Preferably, 1.05 equivalents are added and the mixture is heated under reflux for 1 to 5 hours. After the reaction, water is added to the reaction solution to precipitate crystals, and the crystals are collected by filtration to obtain alkyl 2-carbamoylphenoxyacetic acid. Similarly, when bromoacetic acid aralkyl ester is used instead of bromoacetic acid alkyl ester, 2-carbamoylphenoxyacetic acid aralkyl ester is obtained.
【００１０】このようにして得られる２−カルバモイル
フェノキシ酢酸のエステルを、Ｎ，Ｎ−ジメチルホルム
アミド等の適切な溶媒に溶解し、温度を０〜５０℃、好
ましくは２５℃以下に保ちながら、１．０〜２．０モル
当量、好ましくは１．２モル当量のアルカリ金属アルコ
キシドを加え、同じ温度で約３０分程度攪拌する。反応
後、反応液を１０％クエン酸水に注ぐと結晶が析出し、
濾取すると目的とする２，３，４，５−テトラヒドロ−
１，４−ベンゾオキサゼピン−３，５−ジオンを得るこ
とができる。The thus obtained ester of 2-carbamoylphenoxyacetic acid is dissolved in a suitable solvent such as N, N-dimethylformamide, and the temperature is kept at 0 to 50 ° C., preferably at 25 ° C. or lower. 0.0 to 2.0 molar equivalents, preferably 1.2 molar equivalents, of the alkali metal alkoxide are added, and the mixture is stirred at the same temperature for about 30 minutes. After the reaction, the reaction solution was poured into 10% aqueous citric acid to precipitate crystals,
The desired 2,3,4,5-tetrahydro-
1,4-benzoxazepine-3,5-dione can be obtained.
【００１１】本反応に用いる溶媒は、反応に関与しない
ものであれば特に限定されないが、例えば、Ｎ，Ｎ−ジ
メチルホルムアミド、テトラヒドロフラン、１，４−ジ
オキサン、塩化メチレン等が例示でき、Ｎ，Ｎ−ジメチ
ルホルムアミドを用いるのが好ましい。The solvent used in this reaction is not particularly limited as long as it does not participate in the reaction. Examples of the solvent include N, N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and methylene chloride. Preference is given to using dimethylformamide.
【００１２】[0012]
【実施例】次に実施例によって本発明をさらに詳細に説
明するが、本発明の範囲はこれらのみの限定されるもの
ではない。Next, the present invention will be described in more detail by way of examples, which should not be construed as limiting the scope of the present invention.
【００１３】参考例１ ２−カルバモイルフェノキシ酢
酸エチルエステルの合成 サリチルアミド１００ｇ（０．７３モル）をアセトン４
００ｍｌに溶解し，炭酸カリウム１１１ｇ（０．８０モ
ル＝１．１モル当量）、ブロモ酢酸エチル８５ｍｌ
（０．７７モル＝１．０５モル当量）を加え、５時間加
熱還流した。反応終了後、濾過し、アセトン２００ｍｌ
を減圧濃縮した後、残液を水８００ｍｌに注ぎ、析出し
た結晶を濾取し、水で洗浄した後、減圧乾燥して標記化
合物１６０ｇ（収率９８．３％）を得た。Reference Example 1 2-carbamoylphenoxy vinegar
Synthesis of salicylamide 100 g (0.73 mol) of salicylamide in acetone 4
Dissolved in 100 ml, potassium carbonate 111 g (0.80 mol = 1.1 mol equivalent), ethyl bromoacetate 85 ml
(0.77 mol = 1.05 mol equivalent), and the mixture was refluxed for 5 hours. After completion of the reaction, the mixture was filtered and 200 ml of acetone
After concentration under reduced pressure, the residue was poured into 800 ml of water, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 160 g (yield 98.3%) of the title compound.
【００１４】下に標記化合物の物性値を示す。 性 状 ： 白色針状結晶 融 点 ： １２６〜１２７℃ 元素分析 （理論値） ：Ｃ５９．１９％，Ｈ ５．８７％，Ｎ ６．２７％ （実測値） ：Ｃ５９．３１％，Ｈ ５．８７％，Ｎ ６．２６％ ＩＲ（ν ｃｍ−１） ：３４００，１７４５，１６６５，１５９５， （ＫＢｒ−ｄｉｓｋ） １４８５，１４６０，１３８５，１２７５， １２３０，１１５０，１１００，１０７０， １０２０，８３５，７６０．１ Ｈ−ＮＭＲ（δｐｐｍ）：１．３４（３Ｈ，ｔ，Ｊ＝７．３Ｈｚ） （ＣＤＣｌ３／ＴＭＳ） ４．３２（２Ｈ，ｑ，Ｊ＝７．３Ｈｚ） ４．７４（２Ｈ，ｓ） ５．８６（１Ｈ，ｂｓ） ６．８６（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ） ７．１３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ） ７．４７（１Ｈ，ｍ） ８．２５（１Ｈ，ｄｄ，Ｊ＝１．３，７．９Ｈｚ） ８．３８（１Ｈ，ｂｓ）The physical properties of the title compound are shown below. Properties: White needle-like crystals Melting point: 126-127 ° C Elemental analysis (theoretical value): C 59.19%, H 5.87%, N 6.27% (actual value): C 59.31%, H 5. 87%, N 6.26% IR (ν cm −1 ): 3400, 1745, 1665, 1595, (KBr-disk) 1485, 1460, 1385, 1275, 1230, 1150, 1100, 1070, 1020, 835, 760 . 1 H-NMR (δ ppm): 1.34 (3H, t, J = 7.3 Hz) (CDCl 3 / TMS) 4.32 (2H, q, J = 7.3 Hz) 4.74 (2H, s) 5.86 (1H, bs) 6.86 (1H, d, J = 7.9 Hz) 7.13 (1H, t, J = 7.9 Hz) 7.47 (1H, m) 8.25 (1H, dd, J = 1.3, 7.9 Hz) 8.38 (1H, bs)
【００１５】参考例２ ２−カルバモイルフェノキシ酢
酸ベンジルエステルの合成 サリチルアミド４．１１ｇ（０．０３０モル）をアセト
ン５０ｍｌに溶解し，炭酸カリウム４．５５ｇ（０．０
３３モル＝１．１モル当量）、ブロモ酢酸ベンジル７．
２１ｇ（０．０３１５＝１．０５モル当量）を加え、２
時間加熱還流した。反応終了後、溶媒を留去し、残渣に
水２００ｍｌを加え、析出した結晶を濾取し、水で洗浄
した後、減圧乾燥して標記化合物８．０２ｇ（収率９
３．７％）を得た。Reference Example 2 2-carbamoylphenoxy vinegar
Synthesis of acid benzyl ester 4.11 g (0.030 mol) of salicylamide was dissolved in 50 ml of acetone, and 4.55 g (0.03 mol) of potassium carbonate was dissolved.
33 mol = 1.1 mol equivalent), benzyl bromoacetate 7.
21 g (0.0315 = 1.05 molar equivalents)
Heated to reflux for an hour. After completion of the reaction, the solvent was distilled off, 200 ml of water was added to the residue, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 8.02 g of the title compound (yield 9).
3.7%).
【００１６】下に標記化合物の物性値を示す。 性 状 ： 白色プリズム状結晶 融 点 ： １３６〜１３７℃ 元素分析 （理論値） ：Ｃ６７．３６％，Ｈ ５．３０％，Ｎ ４．９１％ （実測値） ：Ｃ６７．２８％，Ｈ ５．２９％，Ｎ ４．８７％ ＩＲ（ν ｃｍ−１） ：３４００，１７４５，１６６０，１５９０， （ＫＢｒ−ｄｉｓｋ） １５７０，１４８５，１４６０，１４３５， １４００，１３８５，１２１０，１０６５， ９５５，８４０，７５０，７００．１ Ｈ−ＮＭＲ（δｐｐｍ）：４．７８（２Ｈ，ｓ） （ＣＤＣｌ３／ＴＭＳ） ５．２８（２Ｈ，ｓ） ５．６８（１Ｈ，ｂｓ） ６．８３（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ） ７．１３（１Ｈ，ｔ，Ｊ＝７．９Ｈｚ） ７．３９（５Ｈ，ｓ） ７．４５（１Ｈ，ｍ） ８．２４（１Ｈ，ｄｄ，Ｊ＝２．０，７．９Ｈｚ） ８．２７（１Ｈ，ｂｓ）The physical properties of the title compound are shown below. Properties: White prism-shaped crystals Melting point: 136 to 137 ° C Elemental analysis (theoretical value): C 67.36%, H 5.30%, N 4.91% (actual value): C 67.28%, H 5. 29%, N 4.87% IR (ν cm −1 ): 3400, 1745, 1660, 1590, (KBr-disk) 1570, 1485, 1460, 1435, 1400, 1385, 1210, 1065, 955, 840, 750 , 700. 1 H-NMR (δppm): 4.78 (2H, s) (CDCl 3 / TMS) 5.28 (2H, s) 5.68 (1H, bs) 6.83 (1H, d, J = 7. 9Hz) 7.13 (1H, t, J = 7.9 Hz) 7.39 (5H, s) 7.45 (1H, m) 8.24 (1H, dd, J = 2.0, 7.9 Hz) 8.27 (1H, bs)
【００１７】実施例１ ２，３，４，５−テトラヒドロ
−１，４−ベンゾオキサゼピン−３，５−ジオンの合成 参考例１で得た２−カルバモイルフェノキシ酢酸エチル
エステル１００ｇ（０．４５モル）を、Ｎ，Ｎ−ジメチ
ルホルムアミド４５０ｍｌに溶解後、２８％ナトリウム
メチラート／メタノール溶液１０８ｍｌ（０．５４モル
＝１．２モル当量）を加え、室温で３０分間攪拌した。
氷冷後、１０％クエン酸水１．２１を加えて析出した結
晶を濾取し、１５０ｍｌの水で２回洗浄して、標記化合
物７５．０ｇ（収率９４．５％）を得た。Example 1 2,3,4,5-tetrahydro
Synthesis of -1,4-benzoxazepine-3,5-dione 100 g (0.45 mol) of 2-carbamoylphenoxyacetic acid ethyl ester obtained in Reference Example 1 was dissolved in 450 ml of N, N-dimethylformamide. 108 ml of a 28% sodium methylate / methanol solution (0.54 mol = 1.2 mol equivalent) was added, and the mixture was stirred at room temperature for 30 minutes.
After cooling with ice, 1.21 citric acid aqueous solution (1.21) was added, and the precipitated crystals were collected by filtration and washed twice with 150 ml of water to obtain 75.0 g (yield 94.5%) of the title compound.
【００１８】下に標記化合物の物性値を示す。 性 状 ： 白色針状結晶 融 点 ： １５４〜１５５℃ 元素分析 （理論値） ：Ｃ６１．０２％，Ｈ ３．９８％，Ｎ ７．９１％ （実測値） ：Ｃ６１．０２％，Ｈ ３．９７％，Ｎ ７．９１％ ＩＲ（ν ｃｍ−１） ：３３００〜３０００，１７１５，１６６０， （ＫＢｒ−ｄｉｓｋ） １６００，１４８５，１４５５，１３３５， １１３０，１０５０，１０３０，８６０， ７９０，７６０，６９０．１ Ｈ−ＮＭＲ（δｐｐｍ）：４．７２（２Ｈ，ｓ） （ＣＤＣｌ３／ＴＭＳ） ７．１５（１Ｈ，ｄｄ，Ｊ＝１．３，７．９Ｈｚ） ７．３０（１Ｈ，ｍ） ７．５８（１Ｈ，ｍ） ８．１４（１Ｈ，ｄｄ，Ｊ＝１．３，７．９Ｈｚ） ８．３１（１Ｈ，ｂｓ）The physical properties of the title compound are shown below. Properties: White needle-like crystals Melting point: 154 to 155 ° C Elemental analysis (theoretical value): C 61.02%, H 3.98%, N 7.91% (actual value): C 61.02%, H 97%, N 7.91% IR (ν cm −1 ): 3300 to 3000, 1715, 1660, (KBr-disk) 1600, 1485, 1455, 1335, 1130, 1050, 1030, 860, 790, 760, 690 . 1 H-NMR (δppm): 4.72 (2H, s) (CDCl 3 / TMS) 7.15 (1H, dd, J = 1.3,7.9Hz) 7.30 (1H, m) 7. 58 (1H, m) 8.14 (1H, dd, J = 1.3, 7.9 Hz) 8.31 (1H, bs)
【００１９】実施例２ ２，３，４，５−テトラヒドロ
−１，４−ベンゾオキサゼピン−３，５−ジオンの合成 参考例１で得た２−カルバモイルフェノキシ酢酸エチル
エステル２．２３ｇ（０．０１０モル）を、Ｎ，Ｎ−ジ
メチルホルムアミド３０ｍｌに溶解後、カリウム−ｔ−
ブトキシド１．３４ｇ（０．０１２モル＝１．２モル当
量）を加え、室温で２０分間攪拌した。氷冷後、１０％
クエン酸水１００ｍｌを加え、酢酸エチル１５０ｍｌで
抽出した。水層をさらに酢酸エチル１００ｍｌで抽出
し、酢酸エチル層を合わせて水６０ｍｌで、次いで飽和
食塩水６０ｍｌで洗浄後、無水硫酸マグネシウムで乾燥
した。濾過後、溶媒を留去し、残渣をシリカゲルのカラ
ムクロマトグラフィーを用い、塩化メチレン：酢酸エチ
ル（１０：１）で溶出し、標記化合物１．２６ｇ（収率
７１．２％）を得た。得られた化合物の薄層クロマトグ
ラフィーの挙動および１Ｈ−ＮＭＲのデータは、実施例
１で得られた化合物のそれらと一致した。Example 2 2,3,4,5-tetrahydro
Synthesis of -1,4-benzoxazepine-3,5-dione 2.23 g (0.010 mol) of ethyl 2-carbamoylphenoxyacetic acid obtained in Reference Example 1 was dissolved in 30 ml of N, N-dimethylformamide. Later, potassium-t-
1.34 g of butoxide (0.012 mol = 1.2 mol equivalent) was added, and the mixture was stirred at room temperature for 20 minutes. After ice cooling, 10%
100 ml of citric acid solution was added, and the mixture was extracted with 150 ml of ethyl acetate. The aqueous layer was further extracted with 100 ml of ethyl acetate, and the ethyl acetate layers were combined, washed with 60 ml of water and then with 60 ml of saturated saline, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off, and the residue was eluted with methylene chloride: ethyl acetate (10: 1) using silica gel column chromatography to obtain 1.26 g (yield: 71.2%) of the title compound. The thin layer chromatography behavior and 1 H-NMR data of the obtained compound were consistent with those of the compound obtained in Example 1.
【００２０】実施例３ ２，３，４，５−テトラヒドロ
−１，４−ベンゾオキサゼピン−３，５−ジオンの合成 参考例２で得た２−カルバモイルフェノキシ酢酸ベンジ
ルエステル２．８５ｇ（０．０１０モル）を、Ｎ，Ｎ−
ジメチルホルムアミド１５ｍｌに溶解後、２８％ナトリ
ウムメチラート／メタノール溶液２．４ｍｌ（０．０１
２モル＝１．２モル当量）を加え、室温で３０分間攪拌
した。氷冷後、１０％クエン酸水５０ｍｌを加え、析出
した結晶を濾取し、標記化合物１．４７ｇ（収率８３．
１％）を得た。得られた化合物の薄層クロマトグラフィ
ーの挙動および１Ｈ−ＮＭＲのデータは、実施例１で得
られた化合物のそれらと一致した。Example 3 2,3,4,5-tetrahydro
Synthesis of -1,4-benzoxazepine-3,5-dione 2.85 g (0.010 mol) of benzyl 2-carbamoylphenoxyacetic acid obtained in Reference Example 2 was added to N, N-
After dissolving in 15 ml of dimethylformamide, 2.4 ml of 28% sodium methylate / methanol solution (0.01 ml
(2 moles = 1.2 mole equivalents) and stirred at room temperature for 30 minutes. After cooling on ice, 50 ml of 10% aqueous citric acid solution was added, and the precipitated crystals were collected by filtration to obtain 1.47 g of the title compound (yield: 83.30 g).
1%). The thin layer chromatography behavior and 1 H-NMR data of the obtained compound were consistent with those of the compound obtained in Example 1.
【００２１】[0021]
【発明の効果】本発明によれば、精神疾患治療薬の中間
体である２，３，４，５−テトラヒドロ−１，４−ベン
ゾオキサゼピン−３，５−ジオンを、収率良く得ること
が出来る。さらに本発明の製造方法は、従来の脱水閉環
反応に比べて、反応条件が緩和であり、反応時間も短時
間であり、反応後の処理も簡便であるので、特に大量合
成に適しており、これらの精神疾患治療薬の合成中間体
の製造法として有用である。According to the present invention, 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione, which is an intermediate of a drug for treating mental disorders, can be obtained in good yield. I can do it. Furthermore, the production method of the present invention is particularly suitable for large-scale synthesis because the reaction conditions are milder, the reaction time is shorter, and the treatment after the reaction is simpler than the conventional dehydration ring closure reaction, It is useful as a method for producing a synthetic intermediate of these drugs for treating mental disorders.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 Ｅｇｙｐｔ．Ｊ．Ｐｈａｒｍ．Ｓｃ ｉ．，22（１−４），１−７（1981) (58)調査した分野(Int.Cl.7，ＤＢ名) C07D 267/14 ＣＡ（ＳＴＮ) ＲＥＧＩＳＴＲＹ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (56) References Egypt. J. Pharm. Sc i. , 22 (1-4), 1-7 (1981) (58) Fields investigated (Int. Cl. 7 , DB name) C07D 267/14 CA (STN) REGISTRY (STN)
Claims (1)
ル基又は炭素数７〜９の直鎖あるいは分岐のアラルキル
基を示す）で示される２−カルバモイルフェノキシ酢酸
アルキルエステルまたは２−カルバモイルフェノキシ酢
酸アラルキルエステルを、低級アルコールのアルカリ金
属アルコキシドで処理することを特徴とする、式
（２）： 【化２】 で表される２，３，４，５−テトラヒドロ−１，４−ベ
ンゾオキサゼピン−３，５−ジオンの製造法。(1) Formula (1): (Wherein R represents a straight-chain or branched alkyl group having 1 to 5 carbon atoms or a straight-chain or branched aralkyl group having 7 to 9 carbon atoms) 2-carbamoylphenoxyacetic acid alkyl ester or 2-carbamoyl A treatment of an aralkyl phenoxyacetate with an alkali metal alkoxide of a lower alcohol, characterized by the following formula (2): A method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione represented by the formula:
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03291835A JP3112728B2 (en) | 1991-08-21 | 1991-08-21 | Method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP03291835A JP3112728B2 (en) | 1991-08-21 | 1991-08-21 | Method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0551370A JPH0551370A (en) | 1993-03-02 |
| JP3112728B2 true JP3112728B2 (en) | 2000-11-27 |
Family
ID=17774039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP03291835A Expired - Fee Related JP3112728B2 (en) | 1991-08-21 | 1991-08-21 | Method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP3112728B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2187541C (en) | 1995-02-10 | 2008-04-08 | Toshio Tatsuoka | Benzoxazepine derivatives, salts thereof, and drugs containing the same |
-
1991
- 1991-08-21 JP JP03291835A patent/JP3112728B2/en not_active Expired - Fee Related
Non-Patent Citations (1)
| Title |
|---|
| Ｅｇｙｐｔ．Ｊ．Ｐｈａｒｍ．Ｓｃｉ．，２２（１−４），１−７（１９８１） |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0551370A (en) | 1993-03-02 |
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