JPH07258265A - Production of (-)-3(s)-methylpyridobenzoxadine- carboxylic acid derivative and intermediate thereof - Google Patents

Abstract

PURPOSE: To provide novel compounds useful as intermediates in synthesizing antibacterial agents or the like.

CONSTITUTION: Desired novel compounds are represented by formula I (wherein X is F or Cl; X¹ and X² are each a halogen or nitro; and R and R¹-R³ are each 1-18C alkyl) and include, e.g. (+) ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(1-tert- butyldimethylsilyl-oxypropan-2(S)-yl-aminoacrylate. The compounds of formula I can be obtained by reacting a compound of formula II with a benzoyl chloride derivative of formula III in an organic solvent in the presence of a base. The compounds of formula III are novel compounds and further, the compounds of formula IV can easily be obtained from the compounds of formula I as the starting materials.

COPYRIGHT: (C)1995,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a process for producing (-)-3 (S) -methylpyridobenzoxazinecarboxylic acid represented by the general formula (I) and an intermediate thereof. This compound (I) is an antibacterial agent showing a strong bactericidal effect on bacteria,
For example, it is known as an intermediate for producing a compound in which X in the formula (I) is a substituted amino group or a cyclic amino group. (Dr
ugs ofthe Future 1992, 17 (2): 559-563)

[0002]

[Chemical 6]

[In the formula, X represents a fluorine or chlorine atom]

[0004]

2. Description of the Related Art A method for producing a compound of general formula (I) is described in JP-B-62-215591 and JP-B-62-198.
No. 685, European Patent 225,552, etc., but has disadvantages such as long reaction process, low yield, or separation of isomers, which are not suitable for industrial production. .

[0005]

The present invention provides an economical and improved process for the preparation of compounds of formula (I) which does not require complicated reaction steps.

[0006]

The outline of the process for producing the compound of formula (I) according to the present invention is represented by the following reaction scheme.

[0007]

[Chemical 7]

[In the formula, X represents a fluorine or chlorine atom,
X ¹ and X ² represent a halogen atom or a nitro group, and R,
R ¹ , R ² and R ³ represent an alkyl group having 1 to 8 carbon atoms]

Next, the manufacturing method of the present invention will be described in detail.

The starting (+) acrylate derivative (II
I) is new and has the compounds (VII) and (S)-(+)-2-
Amino-1-propanol (VIII) is mixed with an organic solvent such as acetonitrile, tetrahydrofuran, dimethylformamide, dioxane, dimethylacetamide, dimethylsulfoxide, chloroform, methylene chloride, ethylene chloride or diethyl ether at 0 to 25 ° C. for 1 to 1 Obtained by reacting for 10 hours.

[0011]

[Chemical 8]

The compound (V) is novel, and the (+) acrylate derivative (III) is combined with the trialkylsilyl chloride (IV) in an organic solvent such as dimethylformamide, tetrahydrofuran, methylene chloride, acetonitrile, benzene and toluene. , Pyridine, triethylamine, 2,6-lutidine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo [5.4.
[0] in the presence of a base such as undec-7-ene and 1,5-diazabicyclo [4.3.0] none-5-ene, by stirring at 0 to 30 ° C for 1 to 24 hours to react. Obtainable. At this time, the equivalent ratio of the compound (III) to the compound (IV) and the base is 1: 1.1: 1.2-
1: 1.2: 1.5 is desirable.

The (+) 2-benzoyl-3- (silyloxypropan-2 (S) -yl) aminoacrylate derivative (II) is novel, and the (+) silyloxyacrylate derivative (V) is converted into the benzoyl chloride derivative. (VI)
In an organic solvent such as methylene chloride, acetonitrile, diethyl ether, ethylene chloride, dimethylformamide, tetrahydrofuran, chloroform, triethylamine, pyridine, 4-dimethylaminopyridine, imidazole, 2,6-lutidine, 1,8-diazabicyclo. [5.4.0] Undec-7-ene, 1,5-
It can be obtained by reacting at 0 to 100 ° C. for 30 minutes to 12 hours in the presence of a base such as diazabicyclo [4.3.0] none-5-ene.

At this time, the equivalent ratio of the compound (V) to the compound (VI) and the base was 1: 1.05: 1.1 to 1: 1.
1: 1.2 is preferable.

The product (II) can be isolated and purified by evaporation, filtration, extraction, chromatography, distillation and any combination of these conventional techniques. By way of example, the reaction mixture is concentrated to dryness under reduced pressure and the residual material is stirred in a mixture of water with an organic solvent such as dimethyl chloride, chloroform, diethyl ether or ethyl acetate,
The organic solvent is then concentrated to give the product. When the product includes by-products, it can be further purified by chromatography, redistillation, and recrystallization.

The desired (-)-3 (S) -methylpyridobenzoxazinecarboxylic acid (I) is (+) 2-benzoyl-3- (silyloxypropan-2 (S) -yl).
Amino acrylate derivative (II) is heated in an organic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide with a tetraalkylammonium fluoride or a mixture of tetraalkylammonium halide and a metal fluoride at 30 to 100 ° C. for 1 to 3 hours. After stirring and reacting, it can be obtained by adding water of metal hydroxide or metal carbonate or a mixed solution of water and alcohol, and heating and reacting for 1 to 3 hours.

At this time, the equivalent ratio of the compound (II) to the tetraalkylammonium fluoride is preferably 2-4. The equivalent ratio of the compound (II) to the tetraalkylammonium halide is preferably 2 to 4, and the equivalent ratio of the tetraalkylammonium halide to the metal fluoride is preferably 2. The equivalent ratio of compound (II) to metal hydroxide or metal carbonate is preferably 2 to 4.

Tetraalkylammonium fluorides that can be used in this reaction are tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, etc., and tetraalkylammonium halides are tetramethylammonium chloride, tetramethylammonium chloride and tetramethylammonium chloride. Methylammonium bromide, tetramethylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetrapropylammonium bromide, tetrapropylammonium iodo, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodo, tetrapentylammonium bromide , Tetrapentyl ammoniu It is iodo and the like. Here, the metal fluoride is cesium fluoride, potassium fluoride, calcium fluoride, sodium fluoride or the like.

The metal hydroxides that can be used in this reaction include calcium hydroxide, sodium hydroxide,
It is an alkali metal hydroxide or alkaline earth metal such as potassium hydroxide or lithium hydroxide, and the metal carbonate is an alkali metal carbonate or alkaline earth metal such as potassium carbonate, sodium carbonate, lithium carbonate or barium carbonate. The volume ratio of alcohol and water is preferably 2 to 3.

Since the compound (I) can be produced from the (+) acrylate derivative (III) in a three-step process,
The compound (I) can be obtained in high yield.

If compound (II) is reacted with a tetraalkylammonium halide in a single vessel and then reacted with a base, one-step cyclization reaction, protecting group removal reaction, two-step cyclization reaction and hydrolysis are carried out. It is very economical as the staged process is completed in one reactor.

Reference Example (+) Ethyl 3- (1-hydroxypropane-2 (S))
-Yl) amino acrylate (formula III, R = ethyl) (+)-2-amino-1-propanol (VIII) 3.7
6 g (50 mmol) was added to 80 ml of acetonitrile, and the temperature was 0 ° C.
Cool to. Ethyl propionate (VII) 5.0
7 ml (50 mmol) are slowly added dropwise. Reaction mixture 5
After stirring at a temperature of not higher than 0 ° C. for 8 hours, the mixture is further stirred at room temperature for 1 hour. The solvent of the reaction mixture is removed under reduced pressure (25 ° C./10 mmHg) to give 8.57 g (99% yield) of the title product as a colorless oil. Analysis of the product showed that the Z and E isomers were present in a 7: 3 ratio. IR (KBr) cm ^-1 : 3330, 1660, 1600 (α) ₅₈₉ ²⁰ : + 56.6 ° C (CHCl ₃ , C = 0.242) NMR (CDCl ₃ ) ppm: 7.65-7.82 (1Hx7 / 10, m), 7.50 ( 1Hx3 / 1
0, dd, J = 13.3, 9.3H), 6.74 (1Hx7 / 10, dd, J = 13.1, 8.1
H), 4.82-4.88 (1Hx3 / 10, m), 4.78 (1Hx3 / 10, d, J = 13.3
H), 4.50 (1Hx7 / 10, d, J = 8.1H), 4.10-4.12 (2H, q, J = 7
H), 3.41-3.72 (2H, m), 3.26-3.40 (1H, m), 2.36 (1H, b
rs), 1.25-1.26 (3H, t, J = 7H), 12.0 (3H, d, J = 6.8H)

Example 1 (+) ethyl 3- (1-t-butyldimethylsilyloxy)
Cypropan-2 (S) -yl) amino acrylate (formula
V; R = ethyl, R ¹ , R ² = methyl, R ³ = t-butyl
Preparation of t-butyldimethylsilyl chloride (IV; R ¹ , R ² =
Methyl, R ³ = t-butyl) 3.35 g (22 mmol) and 1,8-diazabicyclo [5.4.0] undec-7
3.6 ml (24 mmol) of ene was added to 40 ml of benzene,
After cooling to 5 ° C., (+) ethyl 3- (1-hydroxypropan-2 (S) -yl) aminoacrylate (III
, R = ethyl) 3.46 g (20 mmol) of benzene 1
It was dissolved in 0 ml and gradually added dropwise. Reaction mixture at room temperature 1
After stirring for 6 hours, the formed precipitate was filtered off. The filtrate was washed successively with 5 ml of 0.2N hydrochloric acid aqueous solution, 5 ml of saturated aqueous sodium bicarbonate solution and 5 ml of saturated saline solution,
It was dried over magnesium sulfate. Under reduced pressure (25 ℃ / 20mm
Hg) evaporated the solvent and gave the title compound as an oil, 5.63.
g (yield 98%) was obtained. This compound was analyzed and found to be Z
And the isomer ratio of E was about 3: 2. BP: 80-90 ℃ / 1.6mmHg (α) _D ²⁰ : +104 ℃ (C = 0.2, CHCl ₃ ) IR (NaCl) cm ^-1 : 3320, 2955, 2930, 2897, 2858, 1668,
1616, 1473 NMR (CDCl ₃ ) ppm: 7.68-7.85 (1Hx0.24, m), 7.48 (1Hx0.2
4, dd, J = 13.2H, 9.5H), 6.71 (1Hx0.76, dd, J = 13.2H,
8H), 4.74 (1Hx0.24, d, J = 13.2H), 4.63-4.73 (1Hx0.24,
m), 4.44 (1Hx0.76, d, J = 8H), 4.10 (2H, q, J = 7.1H),
3.43-3.65 (2H, m), 3.23-3.32m (1H, m), 1.27 (3H, t, J
= 7.1H), 1.18 (3H, d, J = 6.6H), 0.89 (9H, s), 0.037 (6H,
s)

Example 2 (+) ethyl 3- (1-t-butyldimethylsilyloxy)
Cypropan-2 (S) -yl) amino acrylate (formula
V; R = ethyl, R ¹ , R ² = methyl, R ³ = t-butyl
Le) Preparation of (+) ethyl 3- (1-hydroxy-propane -2 (S)
-Yl) amino acrylate (III; R = ethyl)
82 g (10.5 mmol) and t-butyldimethylsilyl chloride (IV, R ¹ , R ² = methyl, R ³ = t-butyl)
1.74 g (11.6 mmol) of tetrahydrofuran 50
put in ml. Imidazole 0.86g (12.6mmol)
Was added to the reaction mixture and stirred at 25 ° C. for 8 hours. The reaction solvent was removed under reduced pressure (25 ° C./20 mmHg), and 50 ml of methylene chloride was added. The reaction mixture was added with 5 ml of 0.1N hydrochloric acid water,
The extract was washed with 5 ml of a saturated aqueous thorium bicarbonate solution and 5 ml of a saturated saline solution, and then dried over magnesium sulfate. Under reduced pressure (20 ℃
The solvent was removed at / 10 mmHg) to obtain 2.74 g (yield 94%) of the title compound as an oil.

Example 3 (+) ethyl 3- (1-t-butyldimethylsilyloxy)
Cypropan-2 (S) -yl) amino acrylate (formula
V; R = ethyl, R ¹ , R ² = methyl, R ³ = t-butyl
Le) Preparation of (+) ethyl 3- (1-hydroxy-propane -2 (S)
-Yl) amino acrylate (III; R = ethyl) 2.
32 g (13.4 mmol) and t-butyldimethylsilyl chloride (IV; R ¹ , R ² = methyl, R ³ = t-butyl)
2.22 g (14.8 mmol) of dimethylformamide 5
Put in 0 ml. 1.27 g of pyridine (1
(6.1 mmol) was gradually added dropwise. Reactant 10 at 25 ° C
Stir for hours. The reaction product was purified in the same manner as in Example 2 to obtain 3.38 g (yield 91%) of the title compound as an oil.

Example 4 (+) ethyl 2- (2,3,4,5-tetrafluorobe
Nzoyl) -3- (1-t-butyldimethylsilyloxy
Cypropan-2 (S) -yl) amino acrylate (formula
II; X, X ¹ , X ² = fluoro, R = ethyl, R ¹ , R
² = methyl, the manufacture of R ³ = t-butyl) (+) ethyl 3- (1-t-butyldimethylsilyloxy propane -2 (S) - yl) amino acrylate (V; R = ethyl, R ^1, R ² = methyl, R ³ = t-butyl) 2.66 g (9.26 mmol) and triethylamine 1.03ml of (10.2 mmol) were placed in acetonitrile 70 ml. 2,3,4,5-Tetrafluorobenzoyl chloride (VI; X, X ¹ , X ² = fluoro) 2.
06 g (9.7 mmol) was added, and the mixture was stirred at room temperature for 10 hours. After removing the organic solvent under reduced pressure (25 ° C./10 mmHg), 100 ml of methylene chloride was added to the residue. The reaction mixture was washed once with 10 ml of a saturated aqueous solution of ammonium chloride, 10 ml of a saturated aqueous solution of sodium bicarbonate and 10 ml of brine each, and then dried over magnesium sulfate. Under reduced pressure (25 ℃ /
The solvent was removed with 20 mmHg) to give the title compound as an oil.
26 g (yield 99%) was obtained. This compound was analyzed and found to have a ratio of cis to trans or trans to cis of 7: 3.
Was a mixture of isomers. IR (NaCl) cm ^-1 : 3230, 2955, 2933, 2901, 2858, 1701,
1630, 1570, 1523, 1481 (α) _D ¹⁹ : + 64.9 ° C (C = 2, CHCl ₃ ) NMR (CDCl ₃ ) ppm: 10.75-10.91 (1Hx7 / 10, m), 9.45-9.58
(1Hx3 / 10, m), 8.18 (1H, d, J = 14.2H), 7.03-7.14 (1Hx3
/ 10, m), 6.91-7.00 (1Hx7 / 10, m), 3.97-4.06 (2H, q, J
= 7H), 3.48-3.76 (3H, m), 1.34 (3H, d, J = 6.5H), 1.12
(2H, t, J = 7H), 0.89 (9H, s), 0.06 (6H)

Example 5 (+) ethyl 2- (2,3,4,5-tetrafluorobe
Nzoyl) -3- (1-t-butyldimethylsilyloxy
Cypropan-2 (S) -yl) amino acrylate (formula
II; X, X ¹ , X ² = fluoro, R = ethyl, R ¹ , R
² = methyl, the manufacture of R ³ = t-butyl) (+) ethyl 3- (1-t-butyldimethylsilyloxy propane -2 (S) - yl) amino acrylate (V; R = ethyl, R ^1, R ² = methyl, R ³ = t-butyl) 2.10 g (7.32 mmol) and pyridine 0.64
g (8.05 mmol) was placed in 50 ml of tetrahydrofuran. 2,3,4,5-Tetrafluorobenzoyl chloride (VI; X, X ¹ , X ² = fluoro) 1.63 was added to the mixture.
g (7.69 mmol) was added, and the mixture was heated with stirring for 3 hours. The reaction product was purified in the same manner as in Example 4 to obtain 3.22 g (yield 95%) of the title compound as an oil.

Example 6 (+) ethyl 2- (2,3,4,5-tetrafluorobe
Nzoyl) -3- (1-t-butyldimethylsilyloxy
Cypropan-2 (S) -yl) amino acrylate (formula
II; X, X ¹ , X ² = fluoro, R = ethyl, R ¹ , R
² = methyl, the manufacture of R ³ = t-butyl) (+) ethyl 3- (1-t-butyldimethylsilyloxy-2-(yl) amino acrylate (V; R
= Ethyl, R ¹ , R ² = methyl, R ³ = t-butyl)
1.35 g (4.7 mmol) and imidazole 0.38 g
(5.64 mmol) was placed in 50 ml of acetonitrile. To the mixture was added 1.1 g of 2,3,4,5-tetrafluorobenzoyl chloride (VI; X, X ¹ , X ² = fluoro) (5.
(2 mmol) was added and the mixture was heated with stirring for 4 hours. Purification by a method similar to that in Example 4 yielded 2.03 g (yield 93%) of the title compound as an oil.

Example 7 (+) ethyl 2- (2-nitro-3,4,5-triflu)
Orobenzoyl) -3- (1-t-butyldimethylsilyl)
Luoxypropan-2-yl) amino acrylate (formula
II; X, X ¹ = fluoro, X ² = nitro, R = ethyl,
Preparation of R ¹ , R ² = methyl, R ³ = t-butyl) (+) ethyl 3- (1-t-butyldimethylsilyloxypropan-2 (S) -yl) aminoacrylate (V; R = ethyl, R ¹ , R ² = methyl, R ³ = t-butyl) 2.3 g (8 mmol) and triethylamine 1.23
ml (8.8 mmol) in 100 ml of acetonitrile,
Cooled to ° C. 2-nitro-3,4,5-
After 2.01 g (8.4 mmol) of trifluorobenzoyl chloride (VI; X, X ¹ = fluoro, X ² = nitro) was gradually added dropwise, the mixture was stirred at room temperature for 3 hours. The formed precipitate was removed by filtration, and the filtrate was removed under reduced pressure (25 ° C / 20 mmH
concentrated in g). 50 ml of methylene chloride was added to the residue, the reaction mixture was washed successively with 10 ml of saturated aqueous ammonium chloride solution and 10 ml of saturated aqueous sodium bicarbonate solution, and then dried over magnesium sulfate. The solvent was removed under reduced pressure (25 ° C./20 mmHg) to give 3.8 g of the title compound as an oil (yield 9
8%). As a result of analysis, this compound was a mixture of cis and trans or isomers with a trans and cis ratio of 4: 1. IR (NaCl) cm ^-1 : 2951, 1695, 1630, 1550 (α) ₅₈₉ ¹⁹ : + 73.6 ° C (C = 0.2, CHCl ₃ ) ¹ H-NMR (CDCl ₃ ) ppm: 9.60-10.87 (1H, 2brs) , 8.31 (1Hx1 /
5, d, J = 15H), 8.20 (1Hx4 / 5, d, J = 14.3H), 6.86-6.92
(1H, m), 3.96-4.02 (2H, 2q, J = 7.1H), 3.50-3.78 (3H,
m), 1.35 (3H, d, J = 6.4H), 1.13 (3H, t, J = 7.1H), 0.90
(9H, s), 0.07 (6H, d, J = 3H)

Example 8 (-) 9,10-Difluoro-2,3-dihydro-3
(S) -Methyl-7-oxo-7H-pyrido [1,2,
3-de] -1,4-benzoxazine-6-carvone
Preparation of Acid (Formula I; X = Fluoro) (+) ethyl 2- (2-nitro-3,4,5-trifluorobenzoyl) -3- (1-t-butyldimethylsilyloxypropane-2 (S) -Yl) amino acrylate (II; X and X ¹ = fluoro, X ² = nitro, R = ethyl) (0.975 g, 1.99 mmol) was added to 30 ml of tetrahydrofuran, and 1.0 M tetrabutylammonium dissolved in tetrahydrofuran was added thereto. Fluoride 6.9
6 ml (7 mmol) was added and the mixture was heated under reflux for 2 hours. After adding 5 ml of 10% aqueous potassium hydroxide solution to the reaction mixture and heating under reflux for 30 minutes, the reaction product was cooled to room temperature. The solvent was removed from the reaction mixture under reduced pressure (25 ° C./10 mmHg), 20 ml of water was added to the residue, and the mixture was stirred for 10 minutes. After filtering the formed precipitate, the filtrate was washed with 5 ml of chloroform and washed with 1N.
The pH was adjusted to 3 with aqueous hydrochloric acid. The precipitate formed was filtered, washed twice with 5 ml of water and once with 5 ml of an ethanol / ethyl ether solution (1: 4), and then dried to give 0.499 g of the title compound as a solid (yield 89%). Got MP: 284-286 (dec.) (Α) ₅₈₉ ²⁰ : -41.8 ° C (C = 0.091, CHCl ₃ ) IR (KBr) cm ^-1 : 1720, 1620 NMR (TFA-d ₁ ) ppm: 9.39 (1H, 1H, s), 8.10 (1H, t, J = 8H), 5.
11-5.26 (1H, m), 4.65-4.79 (2H, m), 1.82 (3H, d, J = 6.
(7H)

Example 9 (-) 9,10-Difluoro-2,3-dihydro-3
(S) -Methyl-7-oxo-7H-pyrido [1,2,
3-de] -1,4-benzoxazine-6-carvone
Preparation of acid (formula I; X = fluoro) (+) ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3- (1-t-butyldimethylsilyloxypropan-2 (S) -yl ) Amino acrylate (I
I; X, X ¹ , X ² = fluoro, R = ethyl) 0.26
g (0.56 mmol) was added to 15 ml of tetrahydrofuran and the reaction was carried out by the method of Example 8 to give the title compound as a solid.
13 g (yield 84%) was obtained.

Example 10 (-) 9,10-Difluoro-2,3-dihydro-3
(S) -Methyl-7-oxo-7H-pyrido [1,2,
3-de] -1,4-benzoxazine-6-carvone
Preparation of acid (formula I; X = fluoro) (+) ethyl 2- (2,3,4,5-tetrafluorobenzoyl) -3- (1-t-butyldimethylsilyloxypropan-2 (S) -yl ) Amino acrylate (I
I; X, X ¹ , X ² = fluoro, R = ethyl) 0.52
g (1.12 mmol) dissolved in 10 ml of tetrahydrofuran, 0.62 g (2.2 mmol) of tetrabutylammonium chloride hydrate and 0.02 g of potassium fluoride hydrate.
32 g (3.3 mmol) was added. The reaction mixture was heated and stirred for 3 hours. 5 ml of 10% aqueous potassium hydroxide solution
Was added and the mixture was heated under reflux for 1 hour. Under reduced pressure (25 ℃ / 10mm
The solvent was removed with Hg) and 20 ml of water was added to the residue. The aqueous solution was washed once with 5 ml of methylene chloride and then adjusted to pH 3 with a 1N aqueous hydrochloric acid solution. The solid formed was filtered, 5 ml of water, 5 ml of a mixed solution of ethanol and ethyl ether (volume ratio 1: 4).
Washed with water and dried to give 0.27 g of the title compound as a solid.
(Yield 85%) was obtained.

Example 11 (-) 9,10-Difluoro-2,3-dihydro-3
(S) -Methyl-7-oxo-7H-pyrido [1,2,
3-de] -1,4-benzoxazine-6-carvone
Preparation of Acid (Formula I; X = Fluoro) (+) ethyl 2- (2-nitro-3,4,5-trifluorobenzoyl) -3- (1-t-butyldimethylsilyloxypropane-2 (S) - yl) amino acrylate (II; X, X ¹ = fluoro, X ² = nitro, R = ethyl) 0.33 g (0.67 mmol) were reacted in the same manner as in example 10 in tetrahydrofuran 10 ml, the solid title compound 0.157 g (yield 83%) was obtained.

Claims (10)

[Claims] 1. A (+) 2-benzoyl-3- (silyloxypropan-2 (S) -yl) aminoacrylate derivative represented by the general formula (II). [Chemical 1] [In the formula, X represents a fluorine or chlorine atom, and X ¹ and X ²
Represents a halogen atom or a nitro group, and R, R ¹ , R ² and R ³ represent an alkyl group having 1 to 8 carbon atoms] 2. A (+) silyloxy acrylate derivative of the general formula (V) and a benzoyl chloride derivative of the general formula (VI) are reacted in the presence of a base in an organic solvent. 1. A method for producing a (+) 2-benzoyl-3- (silyloxypropan-2 (S) -yl) aminoacrylate derivative represented by the general formula (II) of 1. [Chemical 2] [In the formula, X represents a fluorine or chlorine atom, and X ¹ and X ²
Represents a halogen atom or a nitro group, and R, R ¹ , R ² and R ³ represent an alkyl group having 1 to 8 carbon atoms] 3. The base is triethylamine, pyridine,
4-dimethylaminopyridine, imidazole, 2,6-
Lutidine, 1,8-diazabicyclo [5.4.0] undec-7-ene and 1,5-diazabicyclo [4.3.
0] None-5-ene. 4. A (+) silyloxy acrylate derivative represented by the general formula (V). [Chemical 3] [In the formula, R, R ¹ , R ² and R ³ represent an alkyl group having 1 to 8 carbon atoms] 5. The (+) acrylate derivative of the general formula (III) is reacted with the trialkylsilyl chloride of the general formula (IV) in the presence of a base. The manufacturing method of the (+) silyloxy acrylate derivative of 1). [Chemical 4] [In the formula, R, R ¹ , R ² and R ³ represent an alkyl group having 1 to 8 carbon atoms] 6. (+) 2-Benzoyl-of the general formula (II):
After heating the 3- (silyloxypropan-2 (S) -yl) amino acrylate derivative with a mixture of a tetraalkylammonium fluoride or a tetraalkylammonium halide and a metal fluoride in an organic solvent,
It is characterized in that water or a mixture of water and alcohol of metal hydroxide or metal carbonate is added thereto, and the mixture is heated and reacted.
A method for producing (-)-3 (S) -methylpyridobenzoxazinecarboxylic acid of the general formula (I). [Chemical 5] [In the formula, X represents a fluorine or chlorine atom, and X ¹ and X ²
Represents a halogen atom or a nitro group, and R, R ¹ , R ² and R ³ represent an alkyl group having 1 to 8 carbon atoms] 7. The method according to claim 6, wherein the tetraalkylammonium fluoride is tetramethylammonium fluoride, tetraethylammonium fluoride or tetrabutylammonium fluoride. 8. The tetraalkylammonium halide is tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetrapropylammonium bromide, tetrapropylammonium iodide, tetrabutyl. The production method according to claim 6, which is ammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapentylammonium bromide or tetrapentylammonium iodide. 9. The method according to claim 6, wherein the metal fluoride is cesium fluoride, potassium fluoride, calcium fluoride or sodium fluoride. 10. The method according to claim 6, wherein the metal hydroxide is calcium hydroxide, sodium hydroxide, potassium hydroxide or lithium hydroxide, and the metal carbonate is potassium carbonate, sodium carbonate, lithium carbonate or barium carbonate. Method.