SI8212021A8 - Process for preparing pyrido /1,2,3-de/ /1,4/-benzoxazine-6-carboxylic acid derivatives - Google Patents

Description

There was a need to find a new, technologically advanced process for the preparation of novel pyridobenzoxazine derivatives with antibacterial efficacy, good yields and satisfactory purity.

The state of the art

The compounds of formula (I) mentioned below are novel, and the process for their preparation has not yet been described.

Description of solution to a technical problem with implementation examples

The present invention relates to a process for the preparation of pyrido / 1,2,3-de // 1,4 / benzoxazine-5-carboxylic acid derivatives represented by the formula

(I) «i

- 2 where Εη represents a straight or branched alkyl group of 3 to 6 carbon atoms, Rg represents hydrogen or a straight or branched alkyl group of 3 to 6 carbon atoms and Xzj represents a halogen atom and their pharmaceutically acceptable salts, exhibiting excellent antibacterial activity against grams negative and gram positive bacteria.

The process of the invention can be shown schematically as follows:

(I)

- 3 where Rq, R ₂ and. Χη the meaning given above and represents a halogen atom.

More specifically, the process of the invention comprises the metabolism of the N, N-chelate compound 9, 10-dihalogeno-3-alkyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine 6 carboxylic acids (II) with piperazine compound (III) to prepare the compound of formula (I).

In accordance with the methods of the present invention, there are two types of reaction, i.e., the substitution reaction on the halogen atoms (X ₂ ) in position 10 with a piperazine compound of formula (III) and the decomposition reaction of the Bi ^ -kelate moiety, and both reactions can be carried out either simultaneously (sequentially) or separately. When the reaction is carried out in isolation, an intermediate of formula (IV) can be isolated if desired.

The substitution reaction requires the presence of an acid receiver in the reaction system to remove the resulting halogen (0X ₂ ), and examples of such acid acceptors include inorganic bases such as alkali or alkaline earth metal hydroxides, their carbonates or bicarbonates, and organic bases such as tertiary amines, e.g. . triethylamine, tributylamine, pyridine, etc. The piperazine compound of formula (III) used as the reagent can also be used as an acid acceptor, especially when used in excess. The era of reaction requires predominantly equimelic

- 4 amount of acid receiver against reagent (II), but molar excess of acid receiver is preferably used.

In the chelate degradation reaction, a proton donor is required to form a carboxyl group (COOH). As a proton donor, a compound having an active proton bound to a heteroatom such as nitrogen, oxygen or sulfur may be used, and examples of such compounds are water, alcohols such as methanol or ethanol, thiols, and secondary amines such as diethylamine. Eer M. Piperazine Compound (III) itself is a secondary amine, and may also be used as a proton donor. However, a chelate decomposition reaction can be achieved without the addition of a proton donor because normally there is a small amount of water present in the solvents used in the reaction obtained commercially or is generally absorbed from the air during the reaction.

The decomposition of the B1-kelate is preferably carried out in the presence of an acid receiver by removing the B1-kernel. If the acid receiver is not present, the product of formula (I) can be obtained in the form of a somewhat boron and fluorine adduct, but the adduct is readily converted to the free form in the usual way, i.e. by treatment with an organic or inorganic base. The acid acceptor may be selected from those described above with a substitution reaction and used in this reaction in an equimolar amount or greater.

The reactions of the invention can be carried out in the absence of solvent, but it is convenient to carry out the reactions in the presence of solvent in a 2- to 50-fold amount relative to the reagent

- 5 (against II and III or against IV). Examples of the solvent are non-protic 'polar solvents such as dimethylformamide, dimethylacetamide, dimethylsulfur oxide and the like; ketones such as acetone, ethylmethylketone; esters such as ethyl acetate; alcohols such as ethanol, methanol, propanol and the like; ethers such as diethyl ether or dioxane; tertiary amines such as triethylamine and water. If the reagent or acid receiver is liquid, it can also be used as a solvent.

Depending on the practical embodiments of the process of the present invention, reaction conditions may be selected according to purpose.

The starting materials (II) and (III) react in a molar ratio of about 1: 1, but preferably piperazine Compound III is used in light molar excess as 1.2 moles per 1 mol of compound (II).

To produce the intended product (I) directly from compound (II) and piperazine compound (III), the starting materials are heated from about 50 ° to about 180 ° C, in the presence of an acid receiver in a non-contact polar solvent, or heated from about 80 ⁰ to about 200 ° 0 in the presence of an acid receiver, in ketones, esters, alcohols, ethers, nitriles, tertiary amines or water.

- 6 To obtain intermediate (IV), a reaction is carried out between compound (II) and piperazine compound (III) at a relatively low temperature, i.e. either in a non-protic polar solvent at room temperature (15 to 35 ° 0) or less, or in ketone as acetone around its boiling point. The compound (IV) thus prepared can be precipitated, if necessary, by the addition of a suitable solvent such as water, methanol or acetone and collected by filtration.

The intermediate (IV) is then treated with a proton donor, preferably in the presence of an acid receiver, although the reaction takes place at room temperature, it can be accelerated by an elevated temperature, e.g. with the boiling point of the solvent used and complete within 0.5 to 10 hours. The product is easily collected in high yield by filtration.

In a preferred embodiment of the present invention, the product of formula (I) is prepared in two steps, i.e. by the preparation and isolation of an iatermediate of formula (IV) and by treatment with a proton donor, thereby obtaining a product of better purity and higher yield than is obtained by a one-step reaction.

Pharmaceutical _; acceptable salts of the compounds of formula (I) include acid addition salts with inorganic or organic acids such as hydrochloric, sulfuric and methanesulic acid and the like, as well as salts of carboxylic acids with sodium, potassium and the like.

- 7 Compounds (I) produced by the process of the present invention exhibit excellent antibacterial efficacy against both gram positive and gram negative bacteria and are useful for treating various infections as well as urinary tract infections and the like. The in vitro antibacterial efficacy (minimum inhibitory concentration: mcg / ml) of the compounds of the present invention determined by the plate culture dilution method (MuellerHinton broth) are shown in the table below. In this assay, 10 / ml bacteria were vaccinated and incubated for 18 hours at 37 C.

Table

Compound: (I)) inuMIO; (mCK / ml) 1)

Test orgafoism R = CH_ ^ h ₃ ^x i ^{= f} R ₁ = CH R = CH X ₁ = C1 E. coli NIHJ <0.05 <0.05 => J Shigella flexneri 2a, 5503 <0.05 <0.05 Proteus vulgaris, 3167 <0.05 <0.05 Proteus mirabilis, 1287 0.1 0.1 Klebsiella pneumoniae, 501 0.39 0.2 Enterobacter eloacae, 12001 0.1 <0.05 Serratia marcescens, 13001 0.1 0.1 Pseudomonas aeruginosa, 2061 0.78 0.78 Pseudomonas sepacia, IID 5132 12.5 6.25 Staphylococcus aureus, 209 P 0.39 0.2 Streptococcus pyogenes, G-36 1.56 12.5 Bacillus subtilis, ATCC 6633 0.1 0.1

- 8 The starting compound of formula (II) used in the process of the invention can be prepared according to the following reaction scheme.

^X 1

X, (K

(VIII) (VII)

As shown in the reaction scheme, a chelating compound of formula (II) used as starting material can be obtained by conjugating a 7,8-dihalogeno-1,4-benzoxazine compound of formula (VII) with diethylethoxymethylene malonate (EMME) and heating the resulting compound of formula (VIII) with boron trifluoride or a complex thereof.

Reference case 1

Preparation of starting material

A. 20 g of 2,3,4-trifluoronitrobenzene were dissolved in 150 ml of dimethylsulfoxide and a 10% aqueous potassium hydroxide solution was added dropwise thereto, maintaining the temperature at 18 to 20 ° C. The mixture was stirred for 2 h at

- 9 room temperature was added to the reaction mixture and 1 L of water was then shaken with chloroform · The aqueous layer was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried. The chloroform layer was concentrated and the resulting residue was purified by silica gel column chromatography to give 5 »8 g of 2,3-difluoro-6-nitrophenol as prisms from the ground. 62 ° C.

B. 5,8 g of the above product, 5 »0 g of monochloroacetone,

8.0 g of potassium carbonate and 0.8 g of potassium iodide were added to 100 ml of acetone and the mixture was maintained at reflux for 4 hours.

After removal of the insoluble matter by filtration, the solvent was evaporated and the residue partitioned between chloroform and water. The chloroform layer was washed with water and dried, then the solvent was evaporated. The residue was treated with n-hexane to give 5.0 g of 2-acetonyloxy-3,4-difluoronitrobenzene as soil needles. 41 ° C.

C. 7.1 g of the above product was dissolved in 200 ml of ethanol and 14 ml of Raney nickel was added to the solution. The resulting mixture was catalytically reduced at atmospheric pressure.

After removal of the catalyst by filtration and evaporation of the solvent, the residue was dissolved in chloroform and discolored by passage through a silica gel column to give

- 30 5.1 g of 7,8-difluoro-2,3-dihydro-3-niethyl-4H-1,4-benzoxazine as a prism from the ground. 52 ° C.

H-NMR (CDCl ₃ , IS: TMS) δ (ppm): 16 (3H, d, -CH)

3 ^ 4-3 _; 9 (3H, m,> CH-CH ₂ -)

4j24 (1H, q, -NH-)

6 ^ 1-6 ^ 7 (2H, m, C ⁵ -4h / c ⁶ - = CH-)

D. A mixture of 2.00 g of the above product and 2.57 S of diethylethoxymethylemnalonate was heated at 120-130 ° C for 5 hours. After evaporation of the ethanol produced, an oily residue was obtained. The resulting residue was dissolved in 10 ml of Dowtherm A (product of Dow Chemical Co.), then 2.0 g of the boron trifluoride-tetrahydrofuran complex were added. E 10 ml of Dowtherm A preheated to 250 ° C was added dropwise to the mixture obtained as above for a period of 30 minutes while maintaining the temperature at 220 to 240 ° C. The resulting mixture was allowed to react for 1 hour at 220 to 240 ° C. After cooling, 5 dichloroethane was added to the reaction mixture. The precipitate formed was collected by filtration and washed with dichloroethane and methanol to give 3.58 g of the 9.10-difluoro-3-Bethyl-7 'Oxo-2,3-dihydro-7H-pyrido 9,10-difluoro-3-Bethyl [1 , 2,3-de J [1,4] benzoxazine-6-carboxylic acid (94.2% yield), m.p. above 300 ° C.

H-NMR (DMSO-d6, IS: TMS)

δ (ppm): 1.59 (3H, d, -CH ₃ ) 4.73 (2H, q, -CH ₂ -) 5.35 (IH, m,) CH-CH ₃ ) 8,18 (IH, m, C ⁸ - = CH-) . ? 1 ⁶⁸ (IH, s, C ⁵ - -CH-) Mass spectrum: M ⁺ 5 29

Elemental analysis for

Calcd .: G 4 ?, 45 H 2.45 N 4.26

Found: C 47.69 H 2.46 N 4.21

Reference case 2

A. 10.5 Dissolve 2,4-dichloro-5-fluoronitrobenzene in 50 ml of dimethylsulfoxide and add 8 ml of 40% aqueous sodium hydroxide to the solution. The resulting mixture was stirred for 20 hours at 60 to 70 ° C. Under cooling, 200 ml of water were added to the reaction mixture and the crude starting material was removed by extraction with diethyl ether. The aqueous layer was acidified with acetic acid and extracted with diethyl ether. The extract was washed with water and dried over sodium sulfate, then the solvent was distilled off. The residue was purified by chromatography on silica gel oh using chloroform as eluent to give 5 »4 g

Of 5-chloro-2-fluoro-6-nitrophenol from m.p. 75 ° θ ·

- 12 The above product was treated by similar procedures as described in Reference Example 1, steps B, G and D to give oily 2-acetonyloxy-4-chloro-3-fluoronitrobenzene (VII), 7-chloro-8- fluoro-3-methyl-2,3-dihydro-4-1,4-benzoxazine (VIII) m.p. 68 ° C, resp. The 9-chloro-chelate compound 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7Hpyrido, 2,3-de3,4,4benzoxazine-6-carboxylic acid (II) m.p. above 300 ° C, except that the reaction was carried out between 3-chloro2-fluoro-6-nitrophenol and monochloroacetone in step B by 6-hour reflux and that the reaction was between 7-chloro-8fluoro-3-methyl-2,3-dihydro The -4H-1,4-benzoxazine and the diethylethoxymethylene malonate in step D was carried out at 4.5 to 150 ° C for 4.5 hours.

The xlate compound (II) thus obtained had the following analytical values.

Elemental analysis for ^ ΗθΒΟΙΕ

Calcd: C 45.20 H 2.33 N 4.05

Found: G 44.98 H 2.29 N 4.03

- 13 EXAMPLE 1 ^ A mixture of 1.00 g of the BP ^ -kelate compound 9,10-difluoro-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (II): where Rq is methyl *, this compound will hereinafter be referred to as compound Ha), 0.46 g of N-methylpiperazine, 0.62 g of triethylamine and 5 ml of dimethylsulfoxide are allowed to react for 3 hours at room temperature. After the reaction, 5 ml of water was added to the reaction mixture. The precipitate formed was collected by filtration and washed with water to give 1.23 g (98.9% yield) of the 9-fluoro-3-methyl-10- (4-methyl-1-piperazinyl) BS-chelate compound. ) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxylic acid (IV: where R 1 and R 6 are methyl, leaving this compound hereinafter referred to as compound IVa) from the ground.

252 to 255 ° θ (on decay).

Elemental analysis for C ^ gH ^ BP ^ N ^ O ^

Calc .: 052.84 H 4.68 N 10.2?

H 4.67 N 10.01

Found: 0 52.94

H-NMR (DMSO-d ₆ , IS:

TMS)

1.54 (3H, d, c-ch ₃ ) 2.24 (3H, s, n-ch ₃ ) 1 — s · 3.4 (8H, no , -N_N-) 4,58 (2H, q> -ch ₂ -) 5,21 (IH, m, ) CH-CH ₃ ) 7.83 (IH, d, C ⁸ - = CH-) 9.46 (IH, d, C ⁵ - = CH-)

- 14 Mass spectrum: M ⁺ 409

EXAMPLE 2

A mixture of 5.00 g of compound Ila, 4.57 S of N-methylpiperazine and 25 ml of dimethylacetamide was allowed to react for 2 hours at room temperature. After completion of the reaction, 25 ml of water was added to the reaction mixture. The precipitate formed was collected by filtration and washed with water to give 6.04 g (97 »1% yield) of compound IVa from the ground. 250 to 254 ° C (decomposition).

EXAMPLE 3

A mixture of 0.61 g of compound Ila, 0.58 g of N-methylpiperazine and 12 ml of acetone was maintained for 3.5 hours at reflux. After cooling the reaction mixture, the precipitate formed was collected by filtration and washed with acetone to give 0.43 · g (57.1% yield) of compound IVa from the soil. 250 to 255 ° 0 (on decay).

EXAMPLE 4

A mixture of 3.00 g of compound Ila, 2.44 g of anhydrous piperazine and 15 ml of dimethylacetamide was allowed to react for 2 hours at room temperature. After completion of the reaction, 30 ml of acetone was added to the reaction mixture. We are the resultant mixture

- ί5 cooled down to get a precipitate. The precipitate was collected by filtration and washed with acetone to give 2.97 S BF ^ -kelate compound 9-fluoro-3-methyl-10- (1-piperazim.l) 7-oxo-2,3-dihydro-7H -pyrido [1,2,3-deane [1,4] benzoxazine-6-carboxylic acid (82.4% yield) m.p. 235 ° U (on decay).

Elemental analysis for Οη ^ η, ^ ΒΡ ^ Ν ^ Ο ^

Calc .:

Found:

0 51 , 67 H, 4.34 N, 10.63 C 51 , 15 H, 4.44 H. 10,32 COOH, IS: TMS) 1 ^ 73 (3H, d, -CH ₃ ) V (8H, br, -N ~ ^ N-) 4.63 (2H, br, -CH ₂ -) 5.1 (IH, m,) CH-C h ₃ ) 7.90 (IH, d, C ⁸ - = CH-) 9,20 (IH, Γ ⁵ s, C - = CH-)

ERIKER 5

Using a similar mode of operation as described in Example 4, except that dimethylformamide was used as solvent instead of dimethylacetamide, the same compound was obtained in 96.6% yield. Mp: 230 ° C (decomposition).

- 16 EXAMPLE - A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of 95% aqueous ethanol was maintained at reflux for 6 hours. After completion of the reaction, the reaction mixture was cooled to give a precipitate. The precipitate was collected by filtration and washed with cold aqueous methanol to give 0.76 g (86% yield) of 9-fluoro-3-methyl-10- (4methyl-1-piperazinyl) -7-oxo-2. 3-Dihydro-7H-pyrido [1,2,3-de? [1,4] benzoxazine-6-carboxylic acid (I: where and R 2 are methyl, hereinafter referred to as la). The product was recrystallized from a mixture of chloroform and methanol (10: 1 vol.) And dried under vacuum for 5 hours at 100-110 ° C. Melting point: 254 to 256 ° G (decay).

Elemental analysis of zi ^a ° 18 ^Η 20 ^{£ ϊί} 3 ° 4 Calc .: 0 59.82 H, 5.58 N Found: C, 59.61 H 5.63 R · H-NMR (DN [SO-d ⁶ , IS: TMS) δ (ppm): 1 * 45 (3H, d, ch-ch ₃ ) 2.22 (3H, s, N-CH ₃ ) 3 * 4 (8H, br, -bfjH 4.49 (2H, q, -CH ₂ -) 4.93 (1H, m,) CH-CH ₃ ) 7 * 59 (1H, d, C ⁸ - = CH-) 8.98 (1H, d, C ⁵ - = CH-)

- 17 EXAMPLE 7

A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of methanol was maintained at reflux for 4 hours. After completion of the reaction, the reaction mixture was cooled to give a precipitate. The ohorina was collected by filtration and washed with methanol to give 0.69 g (78% yield) of compound Ia. The product was recrystallized from dimethylformamide.

Melting point: 253 to 255 °° (decay).

EXAMPLE 8

A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of water was maintained at reflux for 2 hours. The water was distilled off in vacuo and 20 ml of methanol was added to the residue. The precipitate was collected by filtration and washed with methanol to give 0.66 g (75% yield) of compound 1a. The product was dissolved in a mixture of 2 ml of concentrated aqueous ammonia and 20 ml of ethanol at room temperature, after which the resulting solution was treated with activated charcoal. All excess ammonium and ethanol were distilled off by heating to give 0.62 g of pure crystalline product from the ground. 254 to 255 ° θ (on decay).

- 18 EXAMPLE 9

A mixture of Ί, 00 g of compound IVa and 20 ml of ethanol was maintained at reflux for 4 hours. After cooling, the precipitate formed was collected by filtration and washed with ethanol to give 0.88 g (84% yield) of compound la from the ground. 253 to 255 ° ^C (decomposition).

Elemental analysis for ΟηθΗ ^ θΡΝ ^ Ο ^. HF * BOP

Calcd .: 0 50.61 H 4.95 N 9.84

Found: 0 50.52 H 5.05 N 9.79

EBIMER110

Mixture of 1.00 g of N, N-chelate compound 9-fluoro-3-methyl10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de 3 [1,43benzoxazine] -6-carboxylic acids, 0.62 g of triethylamine and 5 ml of dimethyl sulfoxide were heated at 120 to 130 ° C for 3 hours. After cooling, the precipitate formed was collected by filtration and washed with methanol. The product was recrystallized from a mixture of chloroform, methanol and water to give 0.67 S 9-fluoro-3-methyl-10- (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido [1,2. 3-de3 [1,43benzoxazine-6-carboxylic acid (72% yield) m.p. 258 to 260 ° C (decomposition)

Elemental analysis for O ^ rjH ^ gPH ^ O ^. H ^ O

Calc .: 0 54.69 H 5.40 R 11.25

Found: 0 54.82 H 5.06 R 11.13

- 19 EXAMPLE 11

A mixture of 5.21 g of compound Ila, 4.76 g of N-methylpiperazine and 26 ml of dimethylsulfoxide was heated at 110-120 ° C for 2 hours. After cooling, the precipitate formed was collected by filtration and washed with cold ethanol to give 4.25 6 (74.3% yield) of Compound 1a. The product was dissolved in a mixture of concentrated aqueous ammonia and methanol (1:20 vol) at room temperature. All the excess ammonia was distilled off by heating to give a pure crystalline product from the ground. 254 to 255% (at breakup).

EXAMPLE 12

A mixture of 2.00 g of compound Ila, 0.75 S of N-methylpiperazine, 1.23 g of triethylamine and 10 ml of dimethyl sulfoxide was heated at 120-130 ° C for 5 hours. After cooling, the precipitate formed was collected by filtration to give 1.69 S (7θ, 9% yield) of Compound 1a. The product was recrystallized from a mixture of concentrated aqueous ammonia and .ethanol (1:20 vol.).

Mp 254 to 256 ° C (decomposition).

EXAMPLE 13

A mixture of 0.70 g of compound Ila, 0.66 g of N-methylpiperazine and 7 ml of pyridine was refluxed for 2 hours. The reaction mixture was concentrated in vacuo and methanol was added to the residue. The precipitate formed was collected by filtration and washed with methanol to give 0.60 g (78% yield) of compound 1a from the ground.

253 to 256 ° 0 (on decay).

- 20 EXAMPLE 14

A mixture of 0.77 S of Ha, 0.73 g of N-methylpiperazine and 4 ml of dimethyl acetamide was heated at 110-120 ° C for 5 hours. After precipitation, the precipitate was collected by filtration. The precipitate was washed with ethanol to give 0.65 g (77% yield) of compound 1a. This product was recrystallized from dimethylformamide. Melting point: 254 to 256 ° 0 (decay).

EXAMPLE 15

Using a similar method as described in Example 14, 9-fluoro-3-ethyl-10 (1-piperazinyl) -7-oxo-2,3-dihydro-7H-pyrido was obtained [1,2,3 -de] [1,4] benzoxazine-6-carboxylic acid in 73 »4% yield. The product was recrystallized from a mixture of chloroform, methanol and water. Melting point: 260 ° C (decomposition).

Elemental analysis for Ο ^^^ θΕΝ ^ Ο ^. 3 / 2H2O

Calcd: C 54.69 H 5.40 N 11.25

Found: 054.74 H 5.19 N 11.33

- EXAMPLE 16 f

A mixture of 0.50 g of the EE ^ -kelate compound 9-chloro-10-fluoro3-methyl-7-oxo-2,3-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine

The 6-carboxylic acids, 0.44 g of N-methyl-piperazine and 2.5 ml of dime til-sulfide oxide were heated at 110-130 ° C for 5 hours.

After coating, methanol was added to the reaction mixture. The precipitate formed was collected by filtration and washed with methanol to give 0.43 g of 9-chloro-3-methyl-10- (1-piperazinyl) 7- oxo-2,3-dihydro-? H-pyrido [1. 2,3-de] [1,4] benzoxazine-6-carboxylic acid (78% yield). The product was recrystallized from a mixture of chloroform and methanol. Tal .:

280 ° C (decomposition).

Elemental analysis for ΟηθΗ ^ θΟΙΝ ^ Ο ^

Calcd .: 0 57.22 H 5.34- N 11.12

Found: C 56.78 H 5.34 N 11.07

-2.2An indication of the best known applicant for the economic exploitation of the invention

Mixture of 1.00 g of 9,10-difluoro-5-methyl-7-oxo-2,5-dihydro-7H-pyrido [1,2,3-de] [1,4] benzoxazine-6-carboxyl Bi-chelate compound acids (II): wherein R 2 is methyl; this compound will hereinafter be referred to as compound Ha), 0.46 g of H-methylpiperazine, 0.62 g of triethylamine and 5 πύ. of dimethylsulfur oxide was allowed to react for 5 hours at room temperature. After the reaction, 5 ml of water was added to the reaction mixture. The precipitate formed was collected by filtration and washed with water to give 1.25 β (98.9% yield) of the 9-fluoro-5-methyl-1O- (4-methyl-1- BF2-chelate compound). piperazinyl) -7-oxo-2,5-dihydro-7H-pyrido [1,2,5-de] [1,4] benzoxazine-6-carboxylic acid (IV: where R 1 and R 2 are methyl, leaving this compound hereinafter referred to as compound IVa) from the ground.

252 to 255 ° θ (on decay).

Elemental analysis for ΟηθΗη ^ ΒΡ ^ Ν ^ Ο ^

C 52.84 H 4.68 N 10.27

Calc .:

Found: C 52.94

H-NMR (DMSO-d ₆ , IS:

H 4.67 R 10.01 TMS)

δ (ppm): 1, 54 (3H, d, C-CH ₃ ) 2.24 (3H, s, N-CH ₃ ) / -S. 3.4 (8H, no , -N ^ _N-) 4,58 (2H, q, -ch ₂ -) 5,21 (IH, m, ; ch-ch ₃ ) 7.83 (IH, d, c ⁸ - = CH-) 9.46 (IH, d, c ⁵ - = CH-) Mass spectrum: M ⁺ 409

23A mixture of 1.00 g of compound IVa, 0.50 g of triethylamine and 20 ml of 95% aqueous ethanol was maintained at reflux for 6 hours. After completion of the reaction, the reaction mixture was cooled to give a precipitate. The precipitate was collected by filtration and washed with cold aqueous methanol to give 0.76 g (86% yield) of 9-fluoro-3-methyl-10- (4methyl-1-piperazinyl) -7-oxo-2. 3 _T dihydro-7H-pyrido [1,2,3-d. . The product was recrystallized from a mixture of chloroform and methanol (10: 1 vol.) And dried in vacuo for 5 hours at 100-110 ° C. Melting point: 254 to 256 ° C (decomposition).

Elemental analysis for

Calc .: 0 59, 82 Found: c 59, 61 H-NMR (DM ISO-d ⁶ , IS: δ (ppm): 1.45 (3H, 2.22 (3H, 3.4 (8H, 4,49 (2H, 4.93 (IH, 7.59 (IH, 8.98 (IH,

^C 18 ^H 20 ^EW 3 ° 4 H 5.58 N 11.63

H 5.63 N 11.51

TMS) d, ch-ch ₃ ) s, N-CH ₃ ) br, -N_ ^ I-) q, -CH ₂ -) m,) CH-CH ₃ ) d, C ⁸ - = CH-) d. C ⁵ - = CH-)

For

DAIICHI SEIYAKU CO., LTD .:

Claims (1)

PATENT APPLICATION A process for the preparation of pyrido / 1,2,3-de // 1,4 / benzoxazine-6-carboxylic acid derivatives of formula I (I) in which a straight or branched alkyl group of 1 to 6 carbon atoms represents hydrogen or a straight or branched alkyl group of 1 to 6 carbon atoms and a halogen atom and their pharmaceutically acceptable salts, characterized in that the BF? a compound of the formula r ~ \ (III) - 2j wherein it has the above meaning, in the presence of an acid acceptor as an inorganic base as hydroxides, carbonates or bicarbonates of alkali or alkaline earth metal, or an organic base such as tert.amines or piperazine reagent, and in the presence of a hydrogen donor such as water, alcohols, thiols and secondary amines , in the absence or presence of a solvent selected from non-protic, polar solvents such as dimethylformamide, dimethylacetamide or dimethylsulfoxide, ketones such as acetone or ethylmethylketone, esters such as ethyl acetate, ects of ket diethyl ether or dioxane, tertiamines such as triethylamine, alcohols such as ethanol, inanol as ethanol, in ethanol, propanol water _? at a temperature of about 5C to about 200C to give a compound of formula I, or optionally isolating an intermediate of formula CO in which R ₁ represents a straight or branched alkyl group of 1 to 6 carbon atoms, R ₂ represents hydrogen or a straight or branched alkyl group of 1 to 6 carbon atoms and represents a halogen atom, and by decomposition of the BF _2- chelate portion of said intermediate .