JP2746926B2 - Preparation of benzoxazine derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to 3-alkyl-3,4-dihydro-2H- [1,
4] A method for producing a benzoxazine derivative.

<Constitution of the Invention> The present invention provides a compound of the formula [III] (Wherein X, Y, and Z each independently represent a hydrogen atom or a halogen atom, and R represents a lower alkyl group.) (R)-(+)-3-alkyl-3,4 -Dihydro-2H- [1,4] benzoxazine derivative is dehydrogenated to give a compound of formula [I] (Wherein X, Y, Z, and R are the same as defined above) to produce a 3-alkyl-2H- [1,4] benzoxazine derivative represented by the following formula: Formula [II] (Wherein, X, Y, Z, and R are the same as defined above.) 3-alkyl-3,4-dihydro-2H-
The present invention relates to a method for producing a [1,4] benzoxazine derivative. The compound of formula [II] is a compound having a strong antibacterial activity, for example, ofloxacin (see JP-A-57-46986), or an optically active form of ofloxacin (3S-
(-) Is useful as a production intermediate of JP-A-62-87577.

In the dehydrogenation reaction for producing the compound represented by the formula [I] from the compound represented by the formula [III],
The compound represented by the formula [III] is reacted with a base and a halogenating agent without solvent or in a solvent at -100 to room temperature, preferably at -80 to 1
The reaction is carried out at 0 ° C. for 1 to 120 minutes.

As the base, any of an organic base and an inorganic base can be used, but an aliphatic tertiary amine such as trimethylamine, triethylamine, or tripropylamine is preferably used, and is equimolar to the compound represented by the formula [III] The amount used is not particularly limited as long as it is as described above, and may also serve as a solvent.

The halogenating agent is not particularly limited, for example, chlorine, bromine,
Sulfuryl chloride, N-chlorosuccinimide (NCS),
Examples include N-bromosuccinimide (NBS), N-bromoacetamide, hypochlorous acid, hypobromous acid, t-butyl hypochlorite, and the like.

The amount of the halogenating agent to be used is not particularly limited as long as it is at least equimolar to the compound represented by the formula [III], and preferably 1 to 10 times the molar amount.

As the solvent used in such a reaction, esters,
For example, ethyl acetate, propyl acetate, etc.
Amides, for example, N, N-dimethylformamide, N, N-
It is not particularly limited as long as it is inert to the reaction, such as dimethylacetamide or the like, or ethers such as tetrahydrofuran or 1,4-dioxane. Usually, the amount is in the range of 0 to 50 parts per 1 part of the compound represented by the formula [III]. Used in.

The compound represented by the formula [I] produced by dehydrogenation of the compound represented by the formula [III] can be isolated as a pure product by a usual isolation method, for example, recrystallization or silica gel chromatography. The hydrogenation of the next step can be continuously performed without isolation.

The hydrogenation of the compound represented by the formula [I] to the compound represented by the formula [I] can be performed by a usual method, for example, reduction with a metal hydride such as sodium borohydride or lithium borohydride, or palladium Catalytic hydrogenation with a catalyst such as carbon, platinum, and Raney nickel.

After completion of the reaction, the resulting compound represented by the formula [II] can be isolated and purified by a usual separation and purification method, for example, extraction, washing, concentration, crystallization, chromatography and the like.

In such separation and purification, when a normal acid such as hydrochloric acid, sulfuric acid or nitric acid is used in an equimolar amount or more with respect to the compound represented by the formula [II], the compound represented by the formula [II] is converted into a salt form from the reaction mixture. It can also be isolated by crystallization.

The optical purity (% ee) of the compound represented by the formula [II] and the compound represented by the formula [III] was determined as follows. That is, 20 mg of the compound represented by the formula [II] or [III] is dissolved in 0.5 ml of tetrahydrofuran, 17 g of pyridine and 54 mg of 3,5-dinitrobenzoyl chloride are added, and the mixture is heated at 30 to 40 ° C. for 30 minutes. An aliquot of the solution was taken and assayed by high performance liquid chromatography (column used: OA-4200 (Sumitomo Chemical), 4.6 mm × 250 mm; solvent: normal hexane: 1,2-dichloroethane: ethanol = 10: 0.
9: 0.1; flow rate: 1.0 ml / min).

Hereinafter, the configuration and effects of the present invention will be specifically described with reference to examples, but the present invention is not limited to these examples.

Example 1: 7,8-difluoro-3-methyl-2H- [1,4]-
Benzoxazine (I, X = H, Y = Z = F, R = CH 3) (R) - (+) - 7,8- difluoro-3-methyl-3,4
-Dihydro-2H- [1,4] benzoxazine (optical purity, 71.7% ee, (R)) 1.54 g, and triethylamine
To a solution of 5.21 ml and 9 ml of ethyl acetate, under a nitrogen stream, a solution of 2.11 ml of t-butyl hypochlorite and 2 ml of ethyl acetate was added dropwise over about 4 minutes while maintaining the internal temperature at -52 ° C or lower, and then -60 ml. ~-
Stirred at 50 ° C. for 30 minutes. The reaction solution was 10 ml of 5% citric acid aqueous solution.
Twice with diluted ammonia water (concentrated ammonia water: water = 1:
4 (v / v)), washed with 10 ml, and the ethyl acetate layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure,
The residual oil was subjected to column chromatography on silica gel (50 g) and eluted with chloroform (lower layer shaken with concentrated aqueous ammonia). The solvent of the eluate was distilled off under reduced pressure, and 7,8-difluoro-3-methyl-2H- [1,4] as pale yellow crystals was obtained as a residue.
-693 mg of benzoxazine were obtained (yield: 60.8%).

Melting point: 51.2 ° C. (measured with an automatic melting point meter FP-61 manufactured by Metra Co., Ltd., heating rate: 1 ° C. per minute)

Calculated elemental analysis _{C 9 H 7 F 2 NO C} 59.02 H 3.85 N 7.65 Analytical values C 58.91 H 3.89 N 7.49 NMR ( CDCl 3) δppm: 2.12 (3H, s, -C H 3), 4.56 (2H, _{s, OC H 2 -),} 6.5-7.2 (2H, m, benzene ring - H) MS (m / Z ): 183 (M +) example 2: 7.8- difluoro-3-methyl-3,4-dihydro −2H- [1,4] benzoxazine (II, X = H, Y = Z = F, R
= CH ₃₎ obtained in Example 1 7,8-difluoro-3-methyl-2
A mixed solution of 641.3 mg of H- [1,4] benzoxazine, 0.32 g of 5% palladium-carbon (containing 50% water), and 13 ml of ethanol was subjected to catalytic reduction under a hydrogen atmosphere at normal temperature and normal pressure. After completion of the reaction, the catalyst was removed by filtration and ethanol was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of ethyl acetate, washed with 5 ml of saturated saline, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, ethyl acetate was concentrated to about half the volume, and 0.31 ml of concentrated hydrochloric acid was added thereto, followed by stirring. The precipitated crystals were cooled with ice water, collected by filtration and washed with cold ethyl acetate to give colorless crystals of 7,8-difluoro-3-methyl-3,4-dihydro-2H- [1,4] benzoxazine hydrochloride. 554.5 mg was obtained (yield: 71.5%).

Melting point: 180.7 ° C (measured with a Mettler FP-61 automatic melting point, heating rate: 1 ° C per minute).

Elemental analysis value C₉H_TenClF_TwoCalculated as NO C 49.02 H 4.61 N 6.38 Analytical value C 48.77 H 4.55 N 6.32 NMR (DMSO-d₆) Δppm: 1.45 (3H, d, -CH ₃), 3.6−4.0 (1H, m, NCH
<), 4.22, 4.56 (each 1H, q, OCH ₂−), 6.8-7.3 (2H, m, benzene ring-H) Optical purity: 0.5% ee, (R), 3S: 3R = 0.99: 1.00 Example 3: 7,8-difluoro-3-methyl-3, 4-dihydro
−2H- [1,4] benzoxazine (II, X = H, Y = Z = F, R
= CH_Three) (R)-(+)-7,8-difluoro-3-methyl-3,4
-Dihydro-2H- [1,4] benzoxazine (optically pure
A solution of 1.154 g of 71.7% e.e., (R) in 9 ml of ethyl acetate
5.21 ml of triethylamine and add
Cool down. 2.11 ml of t-butyl hypochlorite was added to this solution.
About 5 seconds by cooling a solution of 5 ml of
Added in. The reaction solution is further stirred at -60 to -50 ° C for 1 hour,
Twice with cold 5% citric acid aqueous solution (10 ml), cold diluted ammonia
Washed with water (10 ml as above).

0.47 g of sodium borohydride and 2 ml of ethanol were added to the ethyl acetate layer, and the mixture was stirred at room temperature for 2 hours and hydrogenated. The reaction solution was washed twice with 10 ml of a 5% aqueous citric acid solution and 10 ml of dilute aqueous ammonia (described above), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, 0.72 ml of concentrated hydrochloric acid was added, and the mixture was stirred. The precipitated crystals were cooled with ice water and collected by filtration, washed with cold ethyl acetate to give colorless crystals of 7,8-difluoro-3-methyl-3,4-dihydro-.
1.236 g of 2H- [1,4] benzoxazine hydrochloride was obtained.
Optical purity: 1.0% ee, (S), 3S: 3R = 1.02: 1.00. 1.078 g of this hydrochloride was suspended in 10 ml of chloroform, and a 5%
10 ml was added and stirred. The chloroform layer was washed with water, dried over magnesium sulfate, the desiccant was removed by filtration, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1 ml of methanol, and 5 ml of 50% aqueous methanol was added. The precipitated crystals were cooled with ice water and collected by filtration to obtain 0.596 g of the title compound (yield: 60.9%).

Melting point: 51.0 ° C. (measured by FP-61 automatic melting point meter manufactured by Metra Corporation, heating rate: 1 ° C. per minute).

Elemental analysis value Calculated value for C ₉ H ₉ F ₂ NO C 58.38 H 4.90 N 7.56 Analysis value C 58.36 H 5.06 N 7.64 Example 4: 7,8-Difluoro-3-methyl-3,4-dihydro-2H- [ 1,4] benzoxazine (II, X = H, Y = Z = F, R
_{= CH 3) (R) -} (+) - 7,8- difluoro-3-methyl-3,4
1.154 g of dihydro-2H- [1,4] -benzoxazine (optical purity, 71.7% ee, (R)) and triethylamine
A solution of 5.21 ml and 5.8 ml of N, N-dimethylformamide is cooled to −60 to −50 ° C. under a stream of nitrogen. To this solution, 1.00 g of N-chlorosuccinimide (NCS) was added, and the mixture was stirred at the same temperature for 35 minutes. Then, 0.47 g of sodium borohydride was added, and the mixture was stirred at room temperature for 20 minutes. Add 50 ml of ethyl acetate to the reaction solution and add 5%
2 times with 10 ml of citric acid aqueous solution, diluted ammonia water (described above) 10
Wash with ml and dry over anhydrous magnesium sulfate. After filtering off the desiccant, the solution was concentrated to about 30 ml, concentrated hydrochloric acid (0.72 ml) was added, and the precipitated crystals were cooled with ice water and collected by filtration. 0.984 g of the hydrochloride of the title compound was obtained (yield: 51.4%).

Optical purity 7.6% e.e., (R), 3R: 3S = 1.00: 0.86

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁶ , DB name) C07D 265/36 REGISTRY (STN) CA (STN)

Claims (2)

(57) [Claims] (1) Expression (Wherein, X, Y, and Z each independently represent a hydrogen atom or a halogen atom, and R represents a lower alkyl group.) (R)-(+)-3-alkyl-3,4 -Dihydro-2H- [1,4] benzoxazine derivative is dehydrogenated to give the formula (Wherein, X, Y, Z, and R are the same as defined above) to produce a 3-alkyl-2H- [1,4] benzoxazine derivative represented by the formula: Expression characterized by (Wherein, X, Y, Z, and R are the same as defined above.) 3-alkyl-3,4-dihydro-2H-
[1,4] Method for producing benzoxazine derivatives. 2. The compound according to claim 1, wherein X is a hydrogen atom, Y and Z are each a fluorine atom, and R is a methyl group. Production method of 4-dihydro-2H- [1,4] benzoxazine.