JPH0551370A - Production of 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione - Google Patents

Abstract

PURPOSE:To provide a production method suitable for synthesizing a large amount of 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione which is an intermediate for therapeutic agents for psychopathy in good yield under mild conditions. CONSTITUTION:The subject method is a method for producing 2,3,4,5- tetrahydro-1,4-benzodixoazepine-3,5-dione characterized in that an alkyl 2- carbamoylphenoxyacetate or an aralkyl 2-carbamoylphenoxyacetate is treated with an alkali metallic alkoxide of a lower alcohol.

Description

Detailed Description of the Invention

[0001]

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.

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):

[Chemical 3] (In the formula, A represents a 2-pyrimidinyl group, a 2-pyridyl group, or a phenyl group).

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]

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]

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]

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]

According to the present invention, the formula (4):

[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:

[Chemical 5] A method for producing 2,3,4,5-tetrahydro-1,4-benzoxazepine-3,5-dione represented by

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.

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):

[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.

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.

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]

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.

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%).

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)

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%).

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)

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.

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)

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.

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]

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)

[Claims] 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: