JPH0332552B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to benzoxazine derivatives and methods for producing the same. More specifically, the present invention relates to the general formula () (In the formula, R ₁ is a hydrogen atom or _a lower alkyl group,
and X ₂ represent the same or different halon atoms. ) and consists of reacting the compound with isopropylidene malonate and orthoformic acid lower alkyl ester () The present invention relates to a method for producing a compound represented by the formula (wherein R ₁ , X ₁ and X ₂ are as defined above) and this compound. A compound represented by the general formula () is a compound represented by the general formula () (In the formula, R ₁ and X ₁ are the same as above; _{R 2} represents a hydrogen atom or a lower alkyl group. It is an extremely important compound as an intermediate. To produce the benzoxazine derivative () of the present invention, the compound represented by the general formula () is mixed with isopropylidene malonate and orthoformic acid lower alkyl ester without a solvent or in a solvent at 0 to 150°C.
Preferably, the reaction may be carried out at 20 to 120°C for 1 to 180 minutes, preferably 2 to 120 minutes. Isopropylidene malonate and orthoformic acid lower alkyl ester may be used in an equimolar amount or more relative to the compound represented by the general formula (), but they are usually used in an equimolar to 1.5 molar amount. Examples of the solvent include toluene, xylene, dimethylformamide, dimethyl sulfoxide, dimethylacetamide, etc. as long as it is inert to the raw materials, and usually 2 to 30 parts (by weight) of the compound represented by the general formula (). weight). After completion of the reaction, the produced benzoxazine derivative of general formula () can be easily isolated and purified from the reaction mixture by an appropriate combination of conventional means such as filtration, recrystallization, column chromatography, etc. The compound of the present invention is useful as an intermediate for the pyridobenzoxazine derivative of the general formula (), and can be led to the final target product as follows. That is, the benzoxazine derivative () of the present invention
in the presence of boron trifluoride or boron trifluoride complex without solvent or in a solvent at 20 to 200°C, preferably at 20°C.
By ring-closing reaction at ~120°C for 1 to 180 minutes, preferably 2 to 120 minutes, the general formula () A chelate compound represented by the formula (wherein X ₁ , X ₂ and R ₁ are as defined above) is obtained. In the ring-closing reaction, various boron trifluoride complexes such as cyclic ether complexes, dialkyl ether complexes, and ketone complexes of boron trifluoride can be used, but specifically, boron trifluoride tetrahydrofuran complexes, diethyl ether complexes, etc. Examples include complexes, acetic acid complexes, and acetone complexes. The amount of boron trifluoride or boron trifluoride complex to be used is preferably in the range of 2 moles, particularly in the range of 1 to 1.5 moles, per mole of the compound represented by the general formula (). As a solvent, it is inert to the raw materials and controls the reaction temperature.
Any substance with a boiling point sufficient to maintain the temperature at 50 to 200°C may be used, such as toluene and xylene, and is usually 5 to 20 parts (by weight) per 1 part (by weight) of the compound represented by the general formula (). is preferably used. After the reaction is completed, the generated chelate compound of general formula () precipitates as crystals by cooling the reaction solution, and can be easily obtained in high yield by filtering the crystals. The resulting chelate compound of the general formula () is the general formula () By reacting with a compound represented by the formula (in which R ₂ is the same as above), the final target product, the pyridobenzoxazine derivative ( ), can be obtained in high yield. When obtaining the final objective pyridobenzoxazine derivative from the benzoxazine derivative () of the present invention, it is also possible to do as follows. That is, by treating the benzoxazine derivative of the general formula () with polyphosphoric acid or sulfuric acid, etc., the general formula () is obtained. (In the formula, R ₁ , X _{1 and}
The desired pyridobenzoxazine derivative of the general formula () can be obtained by reacting the compound represented by: In this way, a medically extremely useful pyridobenzoxazine derivative () can be obtained in higher yield than the benzoxazine derivative () of the present invention, and the compound of the present invention can be used as an intermediate for the pyridobenzoxazine derivative. Extremely useful. Next, Examples and Reference Examples will be described. Example 1 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 1.00g,
A mixture of 0.88 g of ethyl orthoformate, 0.86 g of isopropylidene malonate, and 10 ml of toluene is refluxed for 1.5 hours. Trace amounts of viscous decomposition products are removed by filtration while hot, and the filtrate is concentrated under reduced pressure. Recrystallization of the residue from chloroform-petroleum ether yields isopropylidene.
1.48 g of 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazin-4-ylmethylenemalonate was obtained. (yield
81%) Melting point 186-187℃ Elemental analysis value C ₁₆ H ₁₅ F ₂ NO ₅ Calculated value C 56.64, H 4.46, N 4.13 Actual value C 56.30, H 4.23, N 4.16 ¹ H-NMR (CDCl ₃ , IS: TMS) δ (PPM) 1.54 (3H, d, CH−CH ₃ ) 1.74 (6H, s,

[Formula] 4.28 (28, m, -O-CH ₂ -) 4.90 (1H, m, CH ~ -CH ₃ ) 6.7 - 6.9 (2H, m,

[Formula] 8.33 (1H, s, N-CH=) Example 2 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 1.00g,
A mixture of 0.96 g of ethyl orthoformate, 0.78 g of isopropylidene malonate, and 5 ml of N,N-dimethylformaldehyde was stirred at room temperature for 2.5 hours. Next, 10 ml of water is added to the reaction mixture and when it is cooled, crystals are precipitated. When the crystals are collected by filtration and thoroughly washed with water, isopropylidene 7,8-difluoro-2,3-
1.47 g of dihydro-3-methyl-4H-1,4-benzoxazin-4-ylmethylenemalonate was obtained. (Yield 80%) Melting point 185-186°C Example 3 7,8-difluoro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine 1.00g,
0.88g ethyl orthoformate and isopropylidene
Mix 0.78g of malonate at room temperature and place on an oil bath for 110~
It solidifies when heated at 1120℃ for 5 minutes. When this was recrystallized from chloroform-petroleum ether, 1.67 g of isopropylidene 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazin-4-ylmethylene malonate was obtained. . (Yield 91%) Melting point 186-187°C Example 4 1.00 g of 7,8-dichloro-2,3-dihydro-3-methyl-4H-1,4-benzoxazine,
0.82g of ethyl orthoformate and isopropylidene
Mix 0.66g of malonate at room temperature and place on an oil bath for 110~
Heat at 120℃ for 3 minutes. Recrystallization of the solid from chloroform-petroleum ether yields isopropylidene 7,8-dichloro-2,3-dihydro-3-
Methyl-4H-1,4-benzoxazine-4-
1.35 g of ilmethylene malonate was obtained. (Yield 79%) Melting point 223-224℃ Elemental analysis value C ₁₆ H ₁₅ NO ₅ Calculated value as Cl ₂ C 51.63 H 4.06, N 3.76 Actual value C 51.60, H 4.11, N 3.74 Reference example 1 Boron trifluoride tetrahydrofuran Add 5 ml of toluene to 0.25 g of the complex, and add 0.50 g of isopropylidene 7,8-difluoro-2,3-dihydro-3-methyl-4H-1,4-benzoxazin-4-ylmethylene malonate for 10 minutes under reflux. Add in several portions. Continue refluxing for an additional 5 minutes after addition. After the reaction is completed, when the reaction solution is cooled, crystals are precipitated. The crystals were collected by filtration and washed with methanol to give 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,
0.34 g of 3-de][1,4]-benzoxazine-6-carboxylic acid- _BF2 -chelate was obtained.
(Yield 70%) Melting point 300℃ or higher Elemental analysis value C ₁₃ H ₈ BF ₄ NO ₄ Calculated value C 47.45, H 2.45, N 4.26 Actual value C 47.69 H 2.46, N 4.21 ¹ H-NMR (DMSO-d ⁶ , IS: TMS) δ (PPM) 1.59 (3H, d, -CH ₃ ) 4.73 (2H, q, -CH ₂ -) 5.35 (1H, m, CH ~ -CH ₃ ) 8.18 (1H, q, 8th position = CH-) 9.68 (1H, s, 5th position = CH-) Reference example 2 Isopropylidene 7,8-difluoro-2,
3-dihydro-3-methyl-4H-1,4-benzoxazin-4-ylmethylene malonate 0.5
Add 5 g of polyphosphoric acid to g and heat on an oil bath at 180-190°C for 5 minutes. When ice water is added to the syrupy reaction solution, crystals precipitate. When the crystals are filtered and washed with water,
7,8-difluoro-3-methyl-7-oxo-
2,3-dihydro-7H-pyrido [1,2,3-
0.37 g of de][1,4]benzoxazine-6-carboxylic acid was obtained. (Yield 90%) Melting point 300℃ or higher Elemental analysis value C ₁₃ H ₉ F ₂ NO ₄ Calculated value C 55.52, H 3.23, N 4.98 Actual value C 55.57, H 3.29, N 5.00 Reference example 3 Isopropylidene 7,8 -difluoro-2,
2 ml of concentrated sulfuric acid was added to 0.50 g of 3-dihydro-3-methyl-1,4-benzoxazin-4-ylmethylene malonate at room temperature, and the mixture was stirred for 10 minutes. When ice water is added to the reaction solution, crystals precipitate. When the precipitated crystals were collected by filtration, 7,8-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,
0.22 g of 3-de][1,4]-benzoxazine-6-carboxylic acid was obtained. (Yield 53%) Melting point 300
℃ or higher Reference example 4 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3
A mixture of 2.00 g of -de][1,4]-benzoxazine-6-carboxylic acid-BF ₂ -chelate, 1.85 g of N-methylpiperazine and 10 ml of dimethyl sulfoxide is heated at 120-130° C. for 5 hours. After the reaction is complete,
When the reaction solution is cooled, crystals precipitate. When the crystals are collected by filtration, 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3
-dihydro-7H-pyrido [1,2,3-de]
[1,4]-Benzoxazine-6-carboxylic acid
1.69g was obtained. (Yield 77%) Melting point 254-256℃ Elemental analysis value C ₁₈ H ₂₀ FN ₃ O ₄ Calculated value C 59.82, H 5.58, N 11.63 Actual value C 59.61, H 5.63, N 11.51

Claims (1)

[Claims] 1. General formula (In the formula, R ₁ is a hydrogen atom or _a lower alkyl group,
and X ₂ represent the same or different halogen atoms. )
A benzoxazine derivative represented by 2. A compound in which R ₁ is a methyl group and X ₁ and X ₂ are fluorine atoms in claim 1. 3 General formula (In the formula, R ₁ is a hydrogen atom or _a lower alkyl group,
and X ₂ represent the same or different halogen atoms. )
A general formula characterized by reacting a compound represented by isopropylidene malonate and orthoformic acid lower alkyl ester A method for producing a benzoxazine derivative represented by the formula (wherein R ₁ , X ₁ and X ₂ are the same as above).