JPH0524915B2 - - Google Patents

Description

[Detailed description of the invention]

[Industrial Application Field] The present invention is based on the general formula () (In the formula, R is a hydrogen atom, a hydroxyl group, a carbon number of 1 to 3
represents an alkoxy group or a halogen atom) and a method for producing the same. More specifically, the 1-benzoxepin-2-one derivative represented by the general formula () is the 1-benzoxepin-2-one derivative represented by the general formula () [In the formula, R ¹ represents a hydrogen atom, a hydroxyl group, a lower alkyl group, or a lower acyl group, R represents a hydrogen atom, a lower alkoxy group, or a halogen atom, and X represents a pyrrolidinyl group, a morpholino group, a thiomorpholino group, an amino group, base (Here, A is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms), a group (Here, B represents a phenyl group or a hydroxyl group, and n
represents 0, 1, or ₂ ), the group -NH-(CH2)m-D (where m represents 0, 1, 2, 3, 4, or 5, and D represents a saturated bridged cyclic hydrocarbon group) , piperidinyl group, morpholino group, thiomorpholino group, pyridyl group, indolyl group, piperazinyl group, pyrrolidinyl group, carboxyl group, hydroxyl group, allyloxyphenyl group, N-acylpiperazinyl group],
base (Here, l represents 2 or 3, p represents 0, 1,
represents 2, 3 or 4, and E is a hydrogen atom, phenyl group, hydroxyl group, pyrrolidine carbonyl group, 4-
(4'-methoxyphenyl)-4-phenylbutyrylamide group or 4-(2'-hydroxy-5'-methoxy)phenyl-4-phenylbutyryl group) or group -O-( _CH2 )r -G (where r represents 2, 3 or 4, and G represents a dialkylamino group having 2 to 6 carbon atoms)] is a useful synthetic intermediate for diallylbutyric acid derivatives. The diallylbutyric acid derivative represented by the general formula () is a compound useful for improving and treating various symptoms based on organic disorders and mental dysfunctions in the brain.
This is also the usefulness of the 1-benzoxepin-2-one derivative represented by the general formula (). The compound of the present invention also has the possibility of being developed into other drugs, such as central nervous system drugs, by reacting with other amines and alcohols. [Prior art] Diallylbutyric acid derivatives have been disclosed, for example, in
It is disclosed in Japanese Patent Application Laid-open No. 24276 and Japanese Patent Application Laid-open No. 19672-1987. The present inventor has proposed a hydroxyl group or an alkyloxy group further derived from a hydroxyl group as a substituent of a phenyl group,
We also conducted research with the aim of synthesizing compounds with acyloxy groups. [Problems to be solved by the invention] A hydroxyl group or an alkyloxy group in which a hydroxyl group is further derived on the phenyl ring using a diallylbutyric acid derivative;
No compound having an acyloxy group is known in the literature, and the development of a method for its synthesis is considered to be very useful. The most applicable synthesis method is to prepare 1-benzoxepin-2-one represented by the general formula (), and develop a method for ring-opening condensation by reacting amines and alcohols with this compound. Seem. [Means for Solving the Problems] The present invention relates to a 1-benzoxepin-2-one derivative of the general formula () above, and this benzoxepin is a new compound as well as a compound of the above general formula (). It is a useful synthetic intermediate for diallylbutyric acid derivatives. The diallylbutyric acid derivative represented by the general formula () is disclosed in the specification (title of the invention ``Diallylbutyric acid derivative and method for producing the same'') filed separately on the same date, patent application 1983.
-268549 (see JP-A-61-155358)), it is a compound effective in improving and treating various symptoms caused by organic disorders and mental dysfunctions in the brain. It is also believed that the compound () of the present invention can be developed into other drugs, such as central nervous system drugs, by reacting with other amines and alcohols. The compound () according to the present invention can be synthesized, for example, as follows. That is, the known compound γ-phenyl-γ-
General formula for butyrolactone (In the formula, R is a hydrogen atom, a hydroxyl group, a carbon number of 1 to 3
(representing an alkoxy group or a halogen atom) in the presence of a base such as sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, or sodium metal, to obtain the general formula () (In the formula, R represents the same meaning as above.) A phenylbutyric acid derivative represented by the following can be obtained. There are no particular limitations on the reaction temperature, reaction time, reaction method, etc. in the presence of a base, but generally the temperature is 80~
Preferably, the reaction is carried out at 170°C for 4 to 10 hours. This phenylbutyric acid derivative () can be easily rearranged and dehydrated by cyclization by treatment with an acid, resulting in the general formula () Compounds of the invention can be synthesized of the formula: (wherein R is as previously defined). Suitable acids used here include polyphosphoric acid, sulfuric acid, phosphorus oxychloride, phosphorus pentoxide, p-toluenesulfonic acid, naphthalene-β-sulfonic acid, boron trifluoride, and aluminum chloride. There are no particular limitations on the reaction temperature, reaction time, reaction method, etc. when treating with an acid, but generally the reaction temperature is between room temperature and
Preferably, the reaction is carried out at 60°C for 4 to 10 hours. Alternatively, the aforementioned γ-phenyl-γ-butyrolactone has the general formula The compound () of the present invention can also be easily obtained by reacting a phenol derivative represented by (wherein R is as defined above) in the presence of an acid. As the acid, it is preferable to use the various acids mentioned above. Although there are no particular limitations on the reaction temperature, reaction time, reaction method, etc. of this reaction, it is generally preferable to carry out the reaction at room temperature to 60°C for 4 to 10 hours. Compound of the present invention obtained as described above ()
is a new compound that is extremely useful as an important intermediate for the synthesis of various drugs that have brain function-improving effects, circulatory system effects, central nervous system effects, and gastrointestinal effects, etc., as explained below. be. For example, formula (a) Formula (a) is obtained by dissolving benzoxepine represented by formula (a) in a hydrocarbon, aromatic hydrocarbon, ether, or chlorine solvent, adding an excess of N-methylpiperazine, and heating to reflux. A diallylbutyric acid derivative represented by can be obtained. This compound (a) is a compound that not only has low toxicity and exhibits activity in experimental model animals of cerebral anoxia at low doses, but also has an anti-lipid peroxidation effect. Examples The present invention will be explained in more detail below according to Examples and Reference Examples, but it goes without saying that the technical scope of the present invention is not limited to the scope of these Examples and Reference Examples. do not have. Example 1 5-phenyl-2-oxo-2,3,4,5-
Production of tetrahydro-1-benzoxepine 4-phenyl-4-phenyloxybutyric acid 25.6g
(0.1 mol) was added to 350 g of 75% polyphosphoric acid and stirred at room temperature for 5 hours. The reaction solution was poured into ice water and extracted with ether, and then the ether layer was washed with a 2N aqueous sodium hydroxide solution and then with water. The ether layer was dried and concentrated to obtain 6.7 g (yield 28%) of the title compound. The results were as shown in Table 1. Example 2 5-phenyl-2-oxo-2,3,4,5-
Production of tetrahydro-1-benzoxepine 9.6 g (0.1 mol) of phenol and γ-phenyl-
16.2 g (0.1 mol) of γ-butyrolactone was stirred in 300 g of 75% polyphosphoric acid at room temperature for 5 hours. The reaction solution was treated in the same manner as in Example 1 to obtain 6.7 g (yield 28%) of the title compound. The results were similar to Example 1. Example 3 7-methoxy-5-phenyl-2-oxo-
Production of 2,3,4,5-tetrahydro-1-benzoxepine 4-(4'-methoxy)phenyloxy-4-phenylbutyric acid was reacted with 75% polyphosphoric acid in the same manner as in Example 1. The title compound was obtained in 30% yield. The obtained crystals could be purified by recrystallization from ethanol. The results were as shown in Table 1. Example 4 7-methoxy-5-phenyl-2-oxo-
Production of 2,3,4,5-tetrahydro-1-benzoxepine 4-methoxyphenol and γ-phenyl-γ-butyrolactone were condensed and cyclized with 75% polyphosphoric acid in the same manner as in Example 2, resulting in a yield of 30%. The title compound was obtained. The results were similar to Example 3. Example 5 8-chloro-5-phenyl-2-oxo-2,
Production of 3,4,5-tetrahydro-1-benzoxepine When 4-(3'-chloro)phenyloxy-4-phenylbutyric acid was reacted with 75% polyphosphoric acid in the same manner as in Example 1, the yield was 27%. The title compound was obtained. The results were as shown in Table 1. Example 6 8-chloro-5-phenyl-2-oxo-2,
Production of 3,4,5-tetrahydro-1-benzoxepine In exactly the same manner as in Example 2, 3-chlorophenyl and γ-phenyl-γ-butyrolactone were condensed and cyclized with 75% polyphosphoric acid, yield 28%. The title compound was obtained. The results were similar to Example 5. Example 7 7-hydroxy-5-phenyl-2-oxo-
Production of 2,3,4,5-tetrahydro-1-benzoxepine In the same manner as in Example 2, p-hydroquinone and γ-phenyl-γ-butyrolactone were condensed and cyclized in 75% polyphosphoric acid. The reaction solution was poured into ice water, extracted with ether, and then washed with water. The obtained ether layer was dried and then concentrated. The residue was purified by silica gel column chromatography to obtain the title compound in a yield of 27%. The results were as shown in Table 1.

【table】

[Table] Reference Example 1 Production of 4-phenyl-4-phenyloxybutyric acid 19.2 g (0.2 mol) of phenol was dissolved in 38.6 ml of commercially available 28% sodium methoxide/methanol, heated under reflux for 1 hour, and then dissolved in γ-phenyl-4-phenyloxybutyric acid. γ
- 32.4 g (0.2 mol) of butyrolactone was added, and the oil bath was heated to 150-160°C to distill off methanol and concentrate. After heating the obtained residue at the same temperature for 4 hours, a 2N aqueous sodium hydroxide solution was added to dissolve the residue, and then cooled. The aqueous layer was washed with ether, acidified with 2N hydrochloric acid, and extracted with ether.
The ether layer was washed with water and then dried over anhydrous magnesium sulfate. After filtration and concentration, the title compound was found to be 24.3
g (yield 80%) was obtained. This was recrystallized from ethanol to obtain a pure product. Physical properties Melting point: 69.5-71.0℃ (ethanol/hexane) IR spectrum (KBr, cm ^-1 ): 3100, 1720 NMR spectrum (CDCl ₃ , δppm): 2.12-2.40 (m, 2H), 2.47-2.71 (m, 2H), 5.17 (dd, 1H, J=4.8, 7.2Hz), 6.77-6.97 (m, 3H), 7.10-7.50 (m, 7H) Reference example 2 4-(4'-methoxy)phenyloxy-4-phenyl -Production of n-butyric acid 24.8 g (0.2 mol) of p-methoxyphenol was mixed with commercially available 28% sodium methoxide and methanol.
Dissolved in 38.6 ml and heated under reflux for 1 hour, then 48.6 g (0.3
mol) of γ-phenyl-γ-butyrolactone was added, and the oil bath was heated to 150-160°C to distill off methanol and concentrate. The obtained residue was heated at the same temperature for 4 hours, then a 2N aqueous sodium hydroxide solution was added to dissolve the residue, and then cooled. The aqueous layer was washed with ether and then acidified with 2N hydrochloric acid to precipitate the product. The product was collected by filtration, washed with water, and then recrystallized from ethanol to obtain 48.6 g of the title compound (yield 85%).
was gotten. Physical properties Melting point: 67~68℃ IR spectrum (KBr, cm ^-1 ): 1760, 3380 NMR spectrum (CDCl ₃ , δppm): 2.12~2.33
(m, 2H), 2.47-2.67 (m, 2H), 3.77 (s,
3H), 5.09 (dd, 1H, J=5.0, 8.0Hz), 6.67
~6.86 (m, 4H), 7.22 ~ 7.41 (m, 5H) High resolution mass spectrum: as C ₁₇ H ₁₈ O ₄ Calculated value: 286.1205 Actual value: 286.1225 Reference example 3 4-(3'-chloro)phenyloxy-4 -Production of phenylbutyric acid 26.1 g (0.2 mol) of m-chlorophenol was dissolved in 38.6 ml of commercially available sodium methoxide/methanol, and after refluxing for 1 hour, γ-phenyl-γ
- Add 32.4 g (0.2 mol) of butyrolactone to 150
The methanol was distilled off by heating to ~160°C. The resulting residue was heated at the same temperature for 4 hours, then dissolved in a 2N aqueous sodium hydroxide solution and cooled. The aqueous layer was washed with ether, acidified with 2N hydrochloric acid, and extracted with ether. The ether layer was washed with water and then dried over anhydrous magnesium sulfate. After filtration and concentration, the title compound was obtained.
35.1 g (yield 75%) was obtained. A pure product was obtained by recrystallization from ethanol. Physical properties Melting point: 104-106℃ (ethanol) IR spectrum (KBr, cm ^-1 ): 3300, 1750 NMR spectrum (CDCl ₃ , δppm): 2.10-2.38 (m, 2H), 2.43-2.70 (m, 2H) 5.17 (dd, 1H, J=5.4, 7.2Hz) 6.69 (dd, 1H, J=1.8, 9.6Hz), 6.80~6.93 (m, 2H), 7.07 (dd, 1H, J=9.6, 10.2Hz), 7.20~7.47 (m, 5H)

Claims (1)

[Claims] 1. General formula (In the formula, R is a hydrogen atom, a hydroxyl group, a carbon number of 1 to 3
1-benzoxepin-2-one derivative having an alkoxy group or a halogen atom). 2 General formula for γ-phenyl-γ-butyrolactone (In the formula, R is a hydrogen atom, a hydroxyl group, a carbon number of 1 to 3
(representing an alkoxy group or a halogen atom) in the presence of a base to form the general formula (wherein R is as defined above) and is then rearranged and dehydrated under acidic conditions. (wherein R is as defined above) A method for producing a 1-benzoxepin-2-one derivative represented by: 3. The production method according to claim 2, wherein the base is one or two bases selected from sodium alkoxide, potassium alkoxide, sodium hydroxide, potassium hydroxide, sodium hydride, or metallic sodium. 4. Claim 2, wherein the acid is an acid selected from polyphosphoric acid, phosphorus oxychloride, phosphorus pentoxide, sulfuric acid, p-toluenesulfonic acid, naphthalene-β-sulfonic acid, aluminum chloride, or boron trifluoride. Manufacturing method described. 5 General formula for γ-phenyl-γ-butyrolactone (wherein R represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 3 carbon atoms, or a halogen atom) A general formula characterized by reacting a phenol derivative represented by the following under acidic conditions: (wherein R is as defined above) A method for producing a 1-benzoxepin-2-one derivative represented by: 6. Claim 5, wherein the acid is an acid selected from polyphosphoric acid, phosphorus oxychloride, phosphorus pentoxide, sulfuric acid, p-toluenesulfonic acid, naphthalene-β-sulfonic acid, aluminum chloride, or boron trifluoride. Manufacturing method described.