JPH04364185A - Pyridobenzoxazine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an antimicrobial agent, having low toxicity. CONSTITUTION:S-(-)-9-Fluoro-3-methyl-10-(4-methyl or ethyl-1-piperazinyl)-7- oxo-2,3-dihydro-7H-pyrido[1,2,3-de[[1,4]benzoxazine-6-carboxulic acid. This compound is obtained by subjecting a 3-alkyl-7,8-dihalogeno-1,4-benzoxazine derivative shown by formula I and a cyclic amino acid shown by formula II to amide bond reaction to give a diastereomer mixture shown by formula III. The mixture is subjected to fractional crystallization, separated and the product is hydrolyzed to give a 3S-7,8-dihalogeno-3-alkyl-1,4-benzoxazine shown by formula IV, which is allowed to react with a lower alkoxymethylenemalonic acid di-lower alkyl ester and the product is reacted with a polyphosphoric acid, etc., under heating and the product is reacted with an N-lower alkylpiperazine.

Description

[Detailed description of the invention]

0001

TECHNICAL FIELD This invention relates to novel antibacterial compounds.

[Prior Art] Ofloxacin (ofloxacin,
(±)-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, JP-A-57-4698
(see Publication No. 6) is an excellent synthetic antibacterial agent and is known to be effective in treating various infections of the urinary tract, respiratory tract, etc.

0002

[Problem to be solved] Ofloxasi is a racemic form ((±) form, specific optical rotation 0°) and has an asymmetric carbon atom at the 3rd position, and there are two types: 3S-methyl form and 3R-methyl form. Although the existence of isomers was predicted, the method for resolving isomers of compounds with a pyridobenzoxazine skeleton has not been generalized, and it is not easy to resolve isomers from racemic ofloxacin. I didn't get it. Therefore, it is unclear whether one isomer has greater antibacterial activity or what the side effects are, and it has not been possible to investigate this.

[0003] As a result of repeated research in order to obtain each isomer in a pure form, the present inventor discovered 9,10 as a production intermediate.
-difluoro-3-hydroxymethyl-7-oxo-2
,3-dihydro-7H-pyrido[1,2,3-de][
1,4] ethyl benzoxazine-6-carboxylate and convert it into 3-(3,5-dinitrobenzoyloxy)
The methyl form is derived, and then this is separated into two types of optically active forms using high-performance liquid chromatography, and this is used to obtain the two final isomers in a pure state that does not contain any other isomers. The present invention was completed by studying antibacterial activity, toxicity, and water solubility.

[Structure of the invention]

The present invention provides S-(-)-9-fluoro-3-methyl-10-(4-
methyl or ethyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de
][1,4]Benzoxazine-6-carboxylic acid and its salt. In this specification, the S-(-) form may be referred to as 3S-methyl form, (-) form, S form, S(-) form,
R-(+) form is 3R-methyl form, (+) form, R form, R(
+) Sometimes written as body. Next, the method for producing the optically pure compound of the present invention will be explained, and the reaction formula is illustrated on the last page. In the chemical structure of the reaction formula, X1 and X2 each represent a halogen atom such as fluorine or chlorine. X3 is hydroxyl, halogen, alkoxyl (
It refers to carboxyl groups such as active ester residues), acid anhydride residues, and reactive derivative residues thereof. R1 and R
2 means a lower alkyl group such as methyl, ethyl, propyl, etc., respectively. R3 is p-toluenesulfonyl,
Substituted sulfonyl groups such as benzenesulfonyl and methanesulfonyl, alkoxycarbonyl groups such as tertiary butoxycarbonyl, aralkyloxycarbonyl groups such as benzyloxycarbonyl and p-methoxybenzyloxycarbonyl, and substituted sulfonyl groups, especially p -Toluenesulfonyl group is preferred. R4 means a lower alkyl group, and R5 means a hydrogen atom or a lower alkyl group. n
means an integer from 1 to 3, but usually 1 or 2 is appropriate.

That is, the 3-alkyl-7,8-dihalogeno-1,4-benzoxazine derivative II and the cyclic amino acid or its reactive derivative III are combined by an amide bond forming reaction such as the acid chloride method, the activated ester method, the acid Compound IV is produced by condensation using an anhydride method or a DCC method. Acid chloride III, most commonly where X3 is chlorine
may be reacted with compound II in an organic solvent by stirring at room temperature. The product can be isolated and purified using conventional methods.

In this reaction, if one of the two isomers of the cyclic amino acid or its reactive derivative III, ie, the S form or the R form, is used, it is easy to separate the mixture of diastereomers of the compound IV. be. That is,
S-proline or R-proline, derivatives of S-pipecolic acid or R-pipecolic acid, etc. are suitable, and the most preferred examples of compound III include (S)-N-benzenesulfonylproline and (S)-N- There is p-toluenesulfonylproline.

The mixture of diastereomers IV can be separated by fractional crystallization, chromatography using a carrier such as silica gel, or a combination thereof. The separated diastereomer V is hydrolyzed (usually under basic conditions) to form 3S-7,8-dihalogeno-3-
Alkyl-1,4-benzoxazine VI can be obtained by reacting with lower alkoxymethylene malonic acid di-lower alkyl ester by a known reaction.
-(7,8-dihalogeno-3-alkyl-2,3-dihydro-4H-1,4-benzoxazin-4-yl)methylenemalonic acid dialkyl ester VII, which is heated and reacted with polyphosphoric acid or its ester. Let me do 3S
-9,10-dihalogeno-3-alkyl-7-oxo-
2,3-dihydro-7H-pyrido[1,2,3-de]
[1,4]Benzoxazine-6-carboxylic acid or its ester VIII is derived, and if necessary, after hydrolysis, this can be further reacted with N-lower alkylpiperazine to produce the 10-substituted compound I.

[0008] Compound VII or compound VIII
The 10-substituted compound I can also be produced by heating and condensing with boron trifluoride or a boron trifluoride complex to form chelate compound IX, and reacting this with N-lower alkylpiperazine (JP-A-57-46986 No. 58-2
No. 9789, No. 58-43977, No. 58-7258
(See Publication No. 8).

Compound I can also be produced by the method exemplified below. i.e. (±)-9,10-difluoro-3
-Hydroxymethyl-7-oxo-2,3-dihydro-
Ethyl 7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate is treated with 3,5-dinitrobenzoic acid chloride etc. to give (±)-3-(3,5-
This leads to dinitrobenzoyloxy)methyl form. This can be carried out using an appropriate method, such as high performance liquid chromatography (HPL).
C) is used to separate into two optically active substances. The obtained optically active form is treated with sodium hydrogen carbonate or the like to selectively hydrolyze the benzoyl moiety to produce a hydroxymethyl form. This is converted into a 3-iodomethyl form using an iodizing reagent, and reduced with n-tributylstannane or the like to produce a 3-methyl form. If this product is hydrolyzed under acidic conditions without isolation and purification, it can be converted into 3-methyl 6-carboxylic acid. When this is reacted with N-methylpiperazine by heating and stirring, 10-(4-methyl-1-piperazinyl) compound I can be obtained.

The antibacterial activities of the 3S-methyl form I and the 3R-methyl form of this optically active form obtained as the final substance are shown in the table in comparison with that of ofloxacin. The test method is
The standard method specified by the Japanese Society of Chemotherapy was followed.

[0011]

[0012] As described above, the 3S-methyl form has about twice the antibacterial activity as the racemic form, and is less toxic than the 3R-methyl form, with the 3R-methyl form being about 1/10 to 1/1
The excellent effects of the present invention are that although it has an antibacterial activity of 0.00, it has toxicity comparable to that of the racemic form, and that the optically active form has good water solubility and can be used as an injection. The oral dosage of ofloxacin is approximately 100 to 1000 mg per day for adults, usually 100 to 600 mg per day.
mg (U.S. Pat. No. 4,382,8
No. 92, May 10, 1983, European Patent 004
7005-A, published on March 10, 1982, etc.), the appropriate amount of the 3S-methyl form is half the amount, ie, about 50 to 500 mg per day for an adult, usually 50 to 300 mg. As an example of the formulation, the amount of ofloxacin may be half of the amount of ofloxacin in the formulation examples of the above-mentioned US patents and European patents. That is, 50.0 mg of 3S-methyl form, 2
3.0mg, carboxymethylcellulose/calcium 22.5mg, hydroxypropylcellulose 3.
An example may be a 100 mg capsule containing 0 mg and 1.5 mg of magnesium stearate. Ofloxacin, its 3R-methyl form and 3S-methyl form each have a mouse LD50 (i.v.) of 20
3mg/kg, 160mg/kg and 244mg/k
It is g.

[0013]

[Example 1] 3S-(+)-7,8-difluoro-3-methyl-4-
[(S)-N-p-toluenesulfonylprolyl-2,
3-dihydro-4H-[1,4]benzoxazine (S
)-N-p-Toluenesulfonylproline (61.9 g) and a solution of the acid chloride prepared from thionyl chloride in dry dichloromethane (350 ml) were added to (±)-7,8-difluoro-3-methyl-2,3-dihydro-4H −[1,4]
The mixture was gradually added dropwise to a solution of 32.8 g of benzoxazine and 28 ml of pyridine in dry dichloromethane (300 ml) under stirring at room temperature, and the mixture was further stirred at room temperature for 4 hours. The reaction solution was washed successively with 10% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated brine, and then dried over anhydrous magnesium sulfate. The oily residue obtained by distilling off dichloromethane was dissolved in 200 ml of ethyl acetate, and 750 ml of n-hexane was added dropwise little by little while stirring, immediately crystals (compound IV: X1=X2=F, R1=CH3, R3=p- Toluenesulfonyl, n=1 (-) form) is precipitated. The precipitated crystals were filtered off, the filtrate was dried under reduced pressure, and the residue was purified with silica gel 5.
The residue was subjected to 00g column chromatography and eluted with benzene-ethyl acetate (50:1 to 25:1) to obtain an oil. This oil is dissolved in 500 ml of ethanol and left at room temperature overnight to precipitate crystals. After adding diethyl ether and n-hexane to the crystals obtained by distilling off the ethanol, the crystals were collected by filtration and dried under reduced pressure to give 3S-(+)-7,8-difluoro-3-methyl-4-[(S) -N-p-toluenesulfonylprolyl]-2,3-dihydro-4H-[1
, 4] benzoxazine (compound IV: X1=X2=F
, R1=CH3, R3=p-toluenesulfonyl, n=
33.4 g of the (+) form of 1 was obtained. Melting point 107-108°C [α]D+70.7° (c=
0.953, chloroform) Elemental analysis value Calculated value as C21H22F2N204S C 57.79 H 5.08 N 6.
42 Analysis value C 58.05 H 5.14 N
6.47

[0014]

[Example 2] S-(-)-7,8-difluoro-3-methyl-2,3
-dihydro-4H-[1,4]benzoxazine 32.8 g of the (+) compound of compound IV obtained in Example 1 was dissolved in 1000 ml of ethanol, and 300 ml of 1N sodium hydroxide solution was dissolved.
ml was added and refluxed for 3 hours. The oily residue obtained by distilling off the ethanol was extracted with benzene. The extract was washed with saturated brine, dried with mirabilite, and benzene was distilled off. The residue was subjected to column chromatography on 200 g of silica gel and eluted with benzene to give S-(-)-7,8-difluoro-3.
-Methyl-2,3-dihydro-4H-[1,4]benzoxazine (VI: X1=X2=F, R1=CH3)
12.7 g (91.4%) were obtained as an oil. [α]D-9.6° (c=2.17, chloroform) The absolute configuration was determined to be S by X-ray analysis of this product as a hydrochloride.

[0015]

[Example 3] S-(-)-9,10-difluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido[1,2,3
-de][1,4]benzoxazine-6-carboxylic acid ethyl ester S-(-)-benzoxazine derivative 1 obtained in Example 2
5.8 g of diethyl ethoxymethylene malonate 2
4.0 g was added, and the mixture was stirred at 130 to 140° C. for 1 hour under reduced pressure. After cooling, the reaction solution was dissolved in 50 ml of acetic anhydride, and 80 ml of an acetic anhydride-concentrated sulfuric acid (2:1 V/V) mixed solution was added dropwise little by little to the solution under ice-cooling and stirring. After stirring at room temperature for 1 hour,
The mixture was stirred for 30 minutes at a bath temperature of 50 to 60°C. After adding ice water to the reaction solution, powdered potassium carbonate was added to neutralize it, and the mixture was extracted with chloroform. The extract was washed with a saturated aqueous sodium bicarbonate solution, then with saturated brine, and dried over Glauber's salt. Chloroform was distilled off, diethyl ether was added to the residue, and the crystals were collected by filtration to give the title compound (VIII: X1=X2=F, R
1=CH3, R5=C2H5) 20.0 g was obtained. Melting point 257-258°C [α]D-68.1° (c=
0.250, acetic acid)

[0016]

[Example 4] S-(-)-9,10-difluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido[1,2,3
-de][1,4]benzoxazine-6-carboxylic acid 19.5 g of the ester obtained in Example 3 was added to 150 ml of acetic acid.
400 ml of concentrated hydrochloric acid was added and refluxed for 3 hours. After cooling, the precipitated crystals were collected by filtration, washed successively with water, ethanol, and diethyl ether, and dried to obtain the corresponding carboxylic acid (VIII:
X1=X2=F, R1=CH3, R5=H) 16.2g
I got it. Melting point>300℃ [α]D-65.6°(c
=0.985,DMSO)

[0017]

[Example 5] S-(-)-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 (S-(-) form of ofloxacin) 14.3 g of the carboxylic acid obtained in Example 4 was suspended in 600 ml of diethyl ether, 70 ml of boron trifluoride diethyl ether complex was added, and the Stir for hours. The supernatant was removed by decantation, and diethyl ether was added to the residue, which was collected by filtration, washed with diethyl ether, and then dried. This product was dissolved in 100 ml of dimethyl sulfoxide, 14.2 ml of triethylamine and 7.3 ml of N-methylpiperazine were added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue, the yellow powder collected by filtration was suspended in 400 ml of 95% methanol, 25 ml of triethylamine was added, and the mixture was heated under reflux for 25 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 500 ml of 10% hydrochloric acid, washed three times with chloroform, adjusted to pH 11 with 4N aqueous sodium hydroxide solution, adjusted to pH 7.3 again with 1N hydrochloric acid, and dissolved in chloroform (2000 ml x 3). Extracted and dried with mirabilite. Chloroform was distilled off, and the obtained crystalline solid was recrystallized from ethanol-diethyl ether to obtain the S-(-) form of ofloxacin (I: X1=F, R1=R2=CH
3) 12.0g was obtained. Melting point 226-230°C (decomposition) [α]D-76.9° (c=0.655, 0.05
NNaOH)

[0018]

[Example 6] S-(-)-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 S-(-)-9,10-difluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido-[1,2,
281 mg of 3-de][1,4]benzoxazine-6-carboxylic acid was suspended in 30 ml of diethyl ether, and while stirring at room temperature, a large excess of boron trifluoride diethyl ether complex was added and reacted for 45 minutes. The precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain chelate IX (X1=X2=F, R1=R2=CH3). Decomposition point>300℃ [α]D-9.4° (c=0.4
90, DMSO) Elemental analysis Calculated value as C13H8BF4NO4
C 47.46 H 2.46 N 4.2
6 Analysis value C 47.68 H 2.59
N 4.32 Dissolve 310 mg of this in 6 ml of dimethyl sulfoxide and add 0.32 ml of triethylamine.
and 0.13 ml of N-methylpiperazine were added, and the mixture was stirred at room temperature for 17 hours and then dried under reduced pressure. The residue was washed with diethyl ether, dissolved in 20 ml of 95% ethanol containing 0.5 ml of triethylamine, and heated under reflux for 8 hours. After cooling, the residue obtained by drying under reduced pressure was dissolved in dilute hydrochloric acid (5%) and separated from chloroform. The aqueous layer was adjusted to pH 11 with 1N sodium hydroxide, and then adjusted to pH 7.4 with 1N hydrochloric acid.
Adjusted to. This was extracted with chloroform (50 ml x 3), and after drying with mirabilite, the chloroform was distilled off. The obtained powder was recrystallized from ethanol-diethyl ether, and the desired product I (X1=F, R1=R2 =CH3) 120m
I got g. Melting point 225-227℃ (decomposition) Elemental analysis value C18H20FN3O4・1/2H2O
Calculated value: C 58.37 H
5.72 N 11.35 Analysis value: C 58.17 H 5.58 N 11
．． 27

[0019]

Example 7 Production of benzoyloxy compound (±)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[1,
1 g of ethyl 2,3-de][1,4]benzoxazine-6-carboxylate and 500 mg of pyridine were suspended in 100 ml of anhydrous tetrahydrofuran (THF).
Add 1.6 g of 5-dinitrobenzoyl chloride to 90
It was refluxed at °C. Once the suspension is dissolved, a colorless precipitate is deposited. After reacting for 1.5 hours, the precipitate was collected by filtration after cooling, washed with methanol and ether, and dried to form a colorless powder (±).
-9,10-difluoro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine- 1.2 g of 6-carboxylic acid ethyl ester was obtained. Melting point 240-242°C NMR (CDCl3/5%DMSO-d6) δ (ppm
); 1.30 (3H, t, J=7.0Hz, -CH2C
H3), 4.26 (2H, q, J=7.0Hz, -CH
2 CH3) 4.4-5.4 (5H, m), 7.76 (1H, dd,
J=11.0Hz, 7.0Hz, C8-H), 8.8(
1H, s, C5-H) 9.0 (2H, d, J=3.0Hz, aromatic ring proton)
, 9.2 (1H, t, J = 3.0Hz, aromatic ring proton)

[0020]

[Example 8] 6 mg of dinitrobenzoyloxy compound obtained in optical resolution Example 7
Dimethylformamide (DMF) purified by distillation of
The solution was dissolved in approximately 0.6 ml, filtered through a Millipore filter, and then injected into a column for HPLC. Column: Sumipax 0A-4200 (2 x 25 cm) solution
Medium: n-hexane/1,2-dichloroethane/ethanol = 6/3/1 Flow rate: 8 ml/min The first eluting fraction ((+) fraction) contains some racemic raw materials. Mixed (D
(partially hydrolyzed when dissolved in MF), only the previous fraction was further purified by silica gel chromatography using CHCl3 to 10% MeOH/CHCl3 as the eluent. By repeating the above purification, 250 mg each of two optically active substances, S(-) form and R(+) form, were obtained from 600 mg of dinitrobenzoyloxy form. R(+) form: retention time 56-76 minutes, column temperature 22°C
S(-) form: retention time 78-98 minutes, column temperature 22°C

[0021]

Example 9 S-(-)-9,10-difluoro-3-hydroxymethyl-7-oxo-2,3-dihydro-7H-pyrido[
1,2,3-de][1,4]benzoxazine-6-
120 mg of ethyl carboxylate S-(-) dinitrobenzoyloxy compound was suspended in 10 ml of ethanol and 4 ml of saturated sodium bicarbonate solution.
Heat and stir at 0 to 60°C for 2 hours. After concentration, water was added and insoluble materials were collected by filtration, and washed successively with water, 95% ethanol, and ether to obtain 68 mg of S-(-)-3-hydroxymethyl compound as colorless crystals. Melting point 235-240℃ Elemental analysis value as C15H13F2NO5
Calculated value C 55.39 H 4.0
3 N 4.31 Analysis value
C 55.44 H 4.01 N 4
．． 49 Similarly, R(+)-3-hydroxymethyl compound was obtained from R(+) dinitrobenzoyloxy compound. Melting point 2
31-234℃

[0022]

Example 10 S-(-)-9,10-difluoro-3-iodomethyl-7-oxo-2,3-dihydro-7H-pyrido
[1,2,3-de][1,4]benzoxazine-
63 mg of ethyl 6-carboxylate S-(-)-3-hydroxymethyl compound was added to anhydrous D
It was suspended in 12 ml of MF, heated and stirred at 70 to 80°C to dissolve, and then returned to room temperature. To the obtained solution, 340 mg of triphenylphosphite methiodide was added and stirred for 1.5 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in chloroform and partitioned between an aqueous sodium thiosulfate solution and then a saturated saline solution.The chloroform layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. Diethyl ether was added to the residue and stirred, and the precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to obtain 78 mg of the title compound as a white powder. Melting point 214-217℃ Elemental analysis value as C15H12F2INO4
Calculated value C 41.40 H
2.78 N 3.22
Analysis value C 41.16 H 2.58
N 2.99 The R(+) form could be obtained in the same manner.

[0023]

[Example 11] S-(-)-9,10-difluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido[1,2,3
-de][1,4]benzoxazine-6-carboxylic acid 78 mg of the compound of Example 10 was added to 18 ml of absolute ethanol.
The mixture was suspended in water, heated and stirred at 60 to 70°C to dissolve, and then returned to room temperature. Add 0.0% n-tributylstannane to the obtained solution.
2 ml was added and stirred at 50-60°C for 1 hour and at room temperature for 1 hour. The solvent was distilled off, and the residue was subjected to column chromatography on 8 g of silica gel and eluted with chloroform-methanol (40:1) to obtain a crude methyl compound. This was dissolved in 2 ml of glacial acetic acid, 4 ml of concentrated hydrochloric acid was added, and the mixture was heated under reflux for 40 minutes. The reaction solution was concentrated, water was added, and the precipitated crystals were collected by filtration. After washing with water, ethanol and ether, the residue was dried under reduced pressure to obtain 22 mg of crystals of the title compound. Melting point>300℃ Elemental analysis value as C13H9F2NO4
Calculated value C 55.52 H
3.23 N 4.98
Analysis value C 55.79 H 3.20 N
(+) body was also obtained in the same manner as 4.91.

[0024]

[Example 12] S-(-)-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 S-(-)-9,10-difluoro-3-methyl-7-
Oxo-2,3-dihydro-7H-pyrido-[1,2,
3-de] [1,4] 21 mg of benzoxazine-6-carboxylic acid and 30 mg of N-methylpiperazine were dissolved in 3 ml of anhydrous dimethyl sulfoxide, and 130-140
The mixture was stirred at ℃ for 1 hour. The solvent was distilled off under reduced pressure, 2 ml of ethanol was added to the residue, and the precipitated solid was collected by filtration and washed successively with small amounts of ethanol and ether. Obtained powder 1
4 mg was subjected to column chromatography on 5 g of silica gel, and chloroform-methanol-water (7:3:1)
S-(-)-9-fluoro-3 was eluted with the lower layer solution of
-Methyl-10-(4-methyl-1-piperazinyl)-
7-oxo-2,3-dihydro-7H-pyrido[1,2
,3-de][1,4]benzoxazine-6-carboxylic acid was obtained. In addition, the mother liquor obtained by filtration was separated and subjected to thin layer chromatography (silica gel, 20 x 20 cm, 0.5 mm).
) and chloroform-methanol-water (15:3:
It was developed and purified with the lower layer solution of 1). Both were combined to obtain 14 mg of crystals of the desired product. Melting point 220-228℃ (decomposition) Elemental analysis value As C18H20FN3O4
Calculated value C 59.82 H
5.58 N 11.63
Analysis value C 60.01 H 5.69
N 11.53 MS (m/e); 361 (M+) NMR (CDCl3) δ (ppm): 1.63 (3
H, d, J = 7, C3-CH3), 2.38 (3H, s
, N-CH3), 2.54-2.60 (4H, m, 2xCH2N), 3.
40-3.44 (4H, m, 2xCH2N), 4.35
~4.52 (3H, m, CH & CH2), 7.76 (1
H, d, aromatic ring C8-H), 8.64 (1H, s, C5
-H) R(+) form was obtained in the same manner. Melting point 218-226℃ (
decomposition), MS (m/e): 361 (M+),

00
25]

[Example 13] S-(-)-10-(4-ethyl-1-piperazinyl)
-9-Fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de] [1,
4] Benzoxazine-6-carboxylic acid Using N-ethylpiperazine instead of N-methylpiperazine, Example 5
The title compound was obtained by treatment in the same manner as above. Melting point 229-230°C (decomposition) [α]D-67.0° (c=0.585, H2O) NM
R (CDCl3) δ (ppm) 1.16 (3H, t, J = 7Hz, -CH2CH3),
1.63 (3H, d, J = 7Hz, CH3) 2.53 (
2H, q, J=7Hz, -CH2CH3), 2.57~
2.69 (4H, m, 2×CH2) 3.40-3.53
(4H, m, 2×CH2), 4.32-4.58 (3H
, m, CH and CH2) 7.77 (1H, d
, J=12Hz, C8-H), 8.67(1H,s
,C5-H)

Claims (1)

[Claims] [Claim 1] S-(-)-9-fluoro-
3-Methyl-10-(4-methyl or ethyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-
Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid and its salts