JPH0551370A - Production of 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione - Google Patents
Production of 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dioneInfo
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- JPH0551370A JPH0551370A JP29183591A JP29183591A JPH0551370A JP H0551370 A JPH0551370 A JP H0551370A JP 29183591 A JP29183591 A JP 29183591A JP 29183591 A JP29183591 A JP 29183591A JP H0551370 A JPH0551370 A JP H0551370A
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- ester
- tetrahydro
- dione
- benzoxazepine
- 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)
Abstract
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。FIELD OF THE INVENTION The present invention relates to a method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione which is important as an intermediate for producing 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 a 4-aryl- group at the 4-position.
1-piperazinylalkyl group, for example 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, 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。[Chemical 3] (In the formula, A represents a 2-pyrimidinyl group, a 2-pyridyl group, or 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 the formula (3) has a strong affinity for serotonin receptors and an anti-conflict action, and is anxiety, phobia, obsessive-compulsive disorder, post-traumatic stress disorder. It is useful as a therapeutic drug for neuropsychiatric diseases such as depressive neuropathy and psychosomatic disease, and diseases involving the serotonergic nervous system such as eating disorders, menopausal disorders, 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 Prior Art 2,3,4,5-Tetrahydro-1,4
As a method for obtaining -benzoxazepine-3,5-dione, a method in which 2-carbamoylphenoxyacetic acid is subjected to dehydration ring closure is known, such as Cattaneo et al. (A. Catta).
neo et al. , Bull. Chim. Phar
m. , Vol. 102, p541, 1963) reported a method using acetic anhydride, but did not describe the yield thereof. Also, Chi-man et al. (H. Thiem
Ann, West German Patent 1,085,879) describe a method using acetic anhydride, a method using acetyl chloride and a method using thionyl chloride, and the yields thereof are 69.5%, 90% and 48%, respectively. % Is reported.
【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 all the reactions reported above are dehydration reactions, the reaction conditions are 140 to 18
Since it requires a high temperature of 0 ° C. and a reaction time of 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 large-scale synthesis, is inexpensive, has mild reaction conditions, is efficient, and is 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。As a result of intensive studies to solve the above problems, the present inventors have replaced 2-carbamoylphenoxyacetic acid reported above with 2-carbamoylphenoxyacetic acid alkyl ester or 2-carbamoylphenoxyacetic acid alkyl ester. By using carbamoylphenoxyacetic acid aralkyl ester as a starting material and treating this with an alkali metal alkoxide of a lower alcohol, 2,3,4,5-tetrahydro-1,4 The present invention has been completed by finding that -benzoxazepine-3,5-dione can be obtained.
【0007】[0007]
【作用】本発明によれば、式(4):According to the present invention, the formula (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):[Chemical 4] (In the formula, 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 Formula (5) consisting of treating a phenoxyacetic acid aralkyl ester with an alkali metal alkoxide of a lower alcohol:
【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。[Chemical 5] A method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione represented by
【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 has 1 to 1 carbon atoms.
5 represents a linear or branched alkyl ester, and examples thereof include methyl ester, ethyl ester, propyl ester, butyl ester, pentyl ester, and the like, with methyl ester and ethyl ester being preferred. The aralkyl ester means a linear or branched aralkyl ester having a carbon number of 7 to 9, and examples thereof include benzyl ester, phenethyl ester, phenylpropyl ester, and the like. Benzyl ester is preferable. Further, 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, but methanol and ethanol are preferable.
【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 2-carbamoylphenoxyacetic acid alkyl ester and the 2-carbamoylphenoxyacetic acid aralkyl ester used in the present invention are represented by, for example, reaction formula (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。[Chemical 6] (Wherein R is the same as 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 equivalent is 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 give 2-carbamoylphenoxyacetic acid alkyl ester. 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 2-carbamoylphenoxyacetic acid ester thus obtained is dissolved in a suitable solvent such as N, N-dimethylformamide and the temperature is kept at 0 to 50 ° C., preferably 25 ° C. or lower, and 0.0 to 2.0 molar equivalents, preferably 1.2 molar equivalents of 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% citric acid water to precipitate crystals,
Targeted 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, and examples thereof 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。The present invention will now 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 acid ethyl ester 100 g (0.73 mol) of salicylamide was added to acetone 4
Dissolve in 00 ml, 111 g of potassium carbonate (0.80 mol = 1.1 mol equivalent), 85 ml of ethyl bromoacetate
(0.77 mol = 1.05 mol equivalent) was added and the mixture was heated under reflux for 5 hours. After completion of the reaction, it is filtered and 200 ml of acetone
Was concentrated under reduced pressure, the residual liquid 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 of the title compound (yield 98.3%).
【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 crystal Melting point: 126 to 127 ° C. Elemental analysis (theoretical value): C59.19%, H 5.87%, N 6.27% (actual value): C59.31%, H 5. 87%, N 6.26% IR ((nu) 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 = 7.9Hz) 7.13 (1H, t, J = 7.9Hz) 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 (0.0
33 mol = 1.1 mol equivalent), benzyl bromoacetate 7.
21 g (0.0315 = 1.05 molar equivalent) was added and 2
Heated to reflux for hours. 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 crystal Melting point: 136-137 ° C Elemental analysis (theoretical value): C67.36%, H 5.30%, N 4.91% (actual value): C67.28%, H 5. 29%, N 4.87% IR ((nu) cm < -1 >): 3400,1745,1660,1590, (KBr-disk) 1570,1485,1460,1435,1400,1385,1210,1065,955,840,750. , 700. 1 H-NMR (δ ppm): 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 = 7.9Hz) 7.39 (5H, s) 7.45 (1H, m) 8.24 (1H, dd, J = 2.0, 7.9Hz) 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 After dissolving 100 g (0.45 mol) of 2-carbamoylphenoxyacetic acid ethyl ester obtained in Reference Example 1 in 450 ml of N, N-dimethylformamide, 108 ml of 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, 10% aqueous citric acid (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 crystals Melting point: 154-155 ° C Elemental analysis (theoretical value): C61.02%, H 3.98%, N 7.91% (actual value): C61.02%, H3. 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 (δ ppm): 4.72 (2H, s) (CDCl 3 / TMS) 7.15 (1H, dd, J = 1.3,7.9 Hz) 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 2-carbamoylphenoxyacetic acid ethyl ester obtained in Reference Example 1 was dissolved in 30 ml of N, N-dimethylformamide. After that, potassium-t-
1.34 g (0.012 mol = 1.2 mol equivalent) of butoxide was added, and the mixture was stirred at room temperature for 20 minutes. 10% after ice cooling
100 ml of citric acid water 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 then 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 column chromatography on silica gel 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 in agreement 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 2-carbamoylphenoxyacetic acid benzyl ester obtained in Reference Example 2 was treated with N, N-
After dissolving in 15 ml of dimethylformamide, 2.4 ml of a 28% sodium methylate / methanol solution (0.01
(2 mol = 1.2 mol equivalent) was added, and the mixture was stirred at room temperature for 30 minutes. After cooling with ice, 50 ml of 10% citric acid water was added, and the precipitated crystals were collected by filtration to give 1.47 g of the title compound (yield 83.
1%) was obtained. The thin-layer chromatography behavior and 1 H-NMR data of the obtained compound were in agreement 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。EFFECTS OF THE INVENTION According to the present invention, 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione, which is an intermediate of therapeutic agents for mental disorders, can be obtained in high yield. You can Furthermore, the production method of the present invention is particularly suitable for large-scale synthesis because the reaction conditions are mild, the reaction time is short, and the treatment after the reaction is simple as compared with the conventional dehydration ring closure reaction. It is useful as a method for producing synthetic intermediates for these therapeutic agents for mental disorders.
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): (In the formula, 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 Formula (2), characterized in that a phenoxyacetic acid aralkyl ester is treated with an alkali metal alkoxide of a lower alcohol: A method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione represented by:
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 true JPH0551370A (en) | 1993-03-02 |
JP3112728B2 JP3112728B2 (en) | 2000-11-27 |
Family
ID=17774039
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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 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996024594A1 (en) * | 1995-02-10 | 1996-08-15 | Suntory Limited | Benzoxazepine derivatives, salts thereof, and drugs containing the same |
-
1991
- 1991-08-21 JP JP03291835A patent/JP3112728B2/en not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996024594A1 (en) * | 1995-02-10 | 1996-08-15 | Suntory Limited | Benzoxazepine derivatives, salts thereof, and drugs containing the same |
US6187769B1 (en) | 1995-02-10 | 2001-02-13 | Suntory Limited | Benzoxazepine derivatives and their salts and medicaments containing the same |
US6337397B1 (en) | 1995-02-10 | 2002-01-08 | Suntory Limited | Pyrimidine derivatives and their salts, useful for making benzoxazepine derivatives |
Also Published As
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JP3112728B2 (en) | 2000-11-27 |
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