JP3266998B2 - Industrial production of 1,4-benzoxazine compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an industrial process for producing 1,4-benzoxazine compounds, which are important intermediates in the production of various pharmaceuticals.

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication (Kokai) No. 2-28182 discloses an antiemetic or irritable enteritis syndrome, which has an excellent serotonin-3 receptor antagonism and suppresses vomiting caused by administration of an anti-neoplastic agent such as cisplatin. (±) -6-chloro-4-methyl-3-oxo-N- (3-quinuclidinyl) -3,4-dihydro-2H-1,4-benzoxazine- useful as a therapeutic agent for gastrointestinal diseases of 8-Carboxamide monohydrochloride (hereinafter referred to as Compound A) is disclosed.

According to the process described in the specification, compound A
Reacts 6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid chloride (hereinafter referred to as compound B) with 3-aminoquinuclidine. After that, it is obtained by hydrochlorination. Compound B can be produced by the following route.

[0004]

Embedded image

(In the above route, R ¹ and R ² are the same or different and each represents hydrogen or alkyl; Ra ³ represents alkyl, phenylalkyl or substituted phenylalkyl;
R ⁴ and R ⁵ are the same or different and are hydrogen, halogen, alkyl, alkoxy, amino, acylamino, alkylamino, hydroxyl or nitro, R ¹⁰ is an ester residue,
Y represents a leaving group such as chlorine, bromine, iodine, methanesulfonyloxy, and paratoluenesulfonyloxy. That is, the compound (a) is nitrated to obtain a compound (b), and the compound (b) is reduced and then closed to obtain a compound (c). Further compound (c) and compound esterified (d), the compound (wherein each symbol is as defined above.) In formula Ra ³ -Y (d) is reacted with compound (e) is obtained The compound (e) is hydrolyzed to obtain the compound (f). It further describes that compound B can be produced by reacting compound (f) with a halogenating agent such as thionyl chloride.

According to the process for producing compound (c) described in this specification, the nitro group of compound (b) is reduced and ring-closed using (1) iron powder or (2) iron (II) sulfate. Is the way. However, these methods have the following problems industrially. (1) In general, a reduction reaction using metal powder (iron powder, tin powder, etc.) does not require special reaction equipment.
When iron powder is used, (i) a large amount of iron powder is required in the case of reduction, so that the wall of the reactor is damaged by mechanical abrasion. (Ii) After completion of the reduction, a large amount of ferric oxide (Fe
₃ O ₄ ) is produced, which requires centrifugation.
The treatment after the reaction is complicated. (iii) The produced iron tetroxide adheres to the vessel wall of the reactor, and there is a problem in occupational safety and health because nitric acid or concentrated sulfuric acid must be used to remove the iron tetroxide. In addition, since there are many multi-product batch production systems for pharmaceutical production facilities, common facilities are generally used, and it is necessary to wash once each time to prevent contamination, which requires a great deal of labor. (Iv) In general, the solubility of the reaction product in the solvent is low, and it is usually necessary to use 40 to 50 times the amount of the solvent in order to extract and separate from a large amount of iron tetroxide residue. Problems such as the need to increase

(2) The reduction reaction using iron (II) sulfate is as follows:
It is necessary to use a large amount of iron (II) sulfate, it must be separated after the completion of the reaction, and since a concentrated ammonia water is usually used as a reaction solvent, a large amount of an acid such as hydrochloric acid is used for crystallization of a target product. This necessitates problems such as poor volumetric efficiency and complicated operation. One of typical methods for reducing a nitro group is a catalytic reduction method using palladium, platinum, Raney nickel or the like as a catalyst. However, the catalytic reduction method usually has to be performed under pressure, and requires special reaction equipment such as an autoclave. Further, in the case of a compound having a substituent such as alkoxycarbonyl in addition to a nitro group in the molecule, these compounds are reduced at the same time, so that a desired compound cannot be obtained.

Further, hydrogen sulfide, hydrazine, and the like are known as reducing agents. However, in the case of a compound having an alkoxycarbonyl or the like as a substituent, these compounds can be obtained only as decomposed products, and the desired product is not formed. Is raised. Meanwhile, Organic Synthesis (Org.Syn.),
Volume 3, pages 69 to 71, describes a method for reducing 5-nitro-2,3-dihydro-1,4-phthalazinedione with sodium dithionite in an aqueous solution in the presence of ammonia as a catalyst. ing. According to this, the compound (b) was subjected to a reduction reaction in an aqueous solution, but the desired compound was not obtained.

[0009]

As described above, in producing the compound (c) from the compound (b), conventionally used methods and other known methods are satisfactory as industrial production methods. Was not. Therefore, there is no damage to the equipment, easy treatment after the reaction, no safety and hygiene problems, excellent volumetric efficiency, no special equipment required,
There has been a demand for an industrially advantageous production method that does not produce a large amount of by-products and that can obtain the desired product in high yield and high purity.

[0010]

Means for Solving the Problems In order to solve the above-mentioned problems, the present inventors have conducted intensive studies, and as a result, by reducing a nitro group with a combination of an aprotic polar solvent and sodium dithionite, an apparatus has been developed. No damage, easy treatment after reaction, no safety and health problems, excellent volumetric efficiency, no special equipment required, no large amount of by-products obtained, and high yield of target The present inventors have found an industrially advantageous production method capable of producing a high purity at a high rate, and have completed the present invention.

That is, the present invention provides (1) a general formula

[0012]

Embedded image

(Wherein, R ¹ and R ² are the same or different and are hydrogen or alkyl, R ³ is an optionally substituted alkoxy, and R ⁴ and R ⁵ are the same or different and are hydrogen, halogen, alkyl, A compound represented by an alkoxy, amino, acylamino, alkylamino or hydroxyl group, and R represents a protecting group for hydrogen or a carboxylic acid)
General formula characterized by reacting with sodium dithionite in an aprotic polar solvent

[0014]

Embedded image

(Wherein each symbol has the same meaning as described above), an industrial production method of a 1,4-benzoxazine compound represented by the following formula:

[0016]

Embedded image

(Wherein R ¹ and R ² are the same or different and are hydrogen or alkyl, R ³ is optionally substituted alkoxy, and R ⁴ is hydrogen, halogen, alkyl, alkoxy, amino, acylamino, alkyl An amino or hydroxyl group, and R represents a hydrogen or carboxylic acid protecting group.)
A compound represented by the general formula characterized by reacting with sodium dithionite in an aprotic polar solvent

[0018]

Embedded image

(Wherein each symbol is as defined above), an industrial production method of a 1,4-benzoxazine compound represented by the following formula (3):
-Chloro-3-oxo-3,4-dihydro-2H-1,
(4) The method according to the above (1) or (2), which is methyl 4-benzoxazine-8-carboxylate, (4) the aprotic polar solvent is dimethylformamide, dimethylsulfoxide,
1,2-dimethyl-2-imidazolidinone
Or (3) wherein the aprotic polar solvent is dimethylformamide.
It relates to the method described.

In the present specification, the halogen in R ⁴ and R ⁵ represents fluorine, chlorine, bromine and iodine, preferably chlorine, and the alkyl in R ¹ and R ² and the alkyl in R ⁴ and R ⁵ each represent a carbon atom. 1 to 8, preferably 1 to 4 carbon atoms
Linear or branched alkyl, methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, heptyl, octyl and the like are shown. As the alkyl of R ¹ and R ² , methyl and ethyl are preferable, and methyl is particularly preferable.

The alkoxy in R ⁴ and R ⁵ is a linear or branched alkoxy having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, and includes methoxy, ethoxy, propoxy, isopropoxy, Butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like.

The acyl in the acylamino of R ⁴ and R ⁵ is a straight or branched alkanoyl having 2 to 5 carbon atoms, such as acetylamino, propionylamino, butyrylamino, pivaloylamino and the like.
The alkyl in the alkylamino of R ⁴ and R ⁵ is a linear or branched alkyl having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, which may be mono- or di-substituted. , Methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, secondary butylamino, tertiary butylamino, pentylamino, hexylamino, heptylamino, octylamino, dimethylamino, diethylamino, dipropyl Amino, diisopropylamino, dibutylamino, dipentylamino, dihexylamino, diheptylamino, dioctylamino and the like.

The optionally substituted alkoxy in R ³ is a linear or branched alkoxy having 1 to 8 carbon atoms, and is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary alkoxy. And tert-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and the like. Among them, preferred are alkoxy having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, and tertiary butoxy, with methoxy and ethoxy being particularly preferred. . The alkoxy may be substituted by phenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl and the like. Specific examples of these include benzyloxy, 4-chlorobenzyloxy, 4-methoxybenzyloxy, and 3,4-dimethoxybenzyloxy.

The term "protecting group for carboxylic acid in R" refers to "New Experimental Chemistry Course", "Synthesis and Reaction of Organic Compounds (V),
Vol. 2535-2544 (1978), McCormie (JFWMcOmie) Protective Groups in Organic Chemistry (PROTECTIVE GRO)
UPS IN ORGANIC CHEMISTRY, pp. 183-215 (1973) and Protective Groups in Organics, Inc. from THEODORA W. GREENE.
Synthesis (PROTECTIVE GROUPS IN ORGANIC SYNTHESI
S), page 224 to page 276 (1990), etc., as long as it is a carboxylic acid protecting group usually used in organic synthesis reactions. Specifically, alkyl (methyl, ethyl, tertiary butyl, etc.), substituted alkyl (methoxymethyl, ethoxymethyl, isopropoxymethyl, methoxyethoxymethyl, methylthiomethyl,
Methylthioethyl, 2,2,2-trichloroethyl, benzyloxymethyl, phenacyl, 2- (p-toluenesulfonyl) ethyl, etc.), tetrahydropyranyl, tetrahydrofuranyl, benzyl, substituted benzyl (4-chlorobenzyl, 4-methoxy) Benzyl, 3,4-dimethoxybenzyl, 2,4,6-trimethylbenzyl, 2,
6-dimethoxybenzyl, diphenylmethyl, etc.), but is not limited thereto.

The compound of the general formula (II) or (IV) produced by the present invention includes (1) 6-chloro-
Methyl 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (2) 6-chloro-2-methyl-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-8-carboxylic acid, (3) 6
-Methyl-chloro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (4) 6-chloro-2,2-dimethyl-3-oxo-3 Methyl, 4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (5) 6-chloro-2,2
-Dimethyl-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-8-carboxylic acid, (6) 6
-Chloro-3-oxo-3,4-dihydro-2H-1,
4-benzoxazine-8-carboxylic acid, (7) 6-methyl-3-oxo-3,4-dihydro-2H-1,4-
Benzoxazine-8-carboxylic acid, (8) 7-amino-6-chloro-3-oxo-3,4-dihydro-2H-
1,4-benzoxazine-8-carboxylic acid, (9)
6,7-dichloro-3-oxo-3,4-dihydro-2
H-1,4-benzoxazine-8-carboxylic acid, (1
0) 6-bromo-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid, (11) 6-chloro-2-ethyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-carboxylic acid, (12) 3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid,
(13) 6-amino-3-oxo-3,4-dihydro-2
H-1,4-benzoxazine-8-carboxylic acid, (1
4) 6-methoxy-3-oxo-3,4-dihydro-2
Methyl H-1,4-benzoxazine-8-carboxylate, (15) 6-chloro-7-hydroxy-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
Methyl 8-carboxylate, (16) methyl 6-chloro-7-methoxy-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (17) 5-amino-6 -Chloro-3-oxo-3,4-dihydro-2
Methyl H-1,4-benzoxazine-8-carboxylate, (18) 5-amino-6-chloro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine Methyl 8-carboxylate, (19) methyl 5-acetylamino-6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (20) 6-acetyl Amino-3-oxo-3,
4-dihydro-2H-1,4-benzoxazine-8-
Methyl carboxylate, (21) methyl 5-methylamino-6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (22) 5-dimethylamino-3 -Oxo-3,4-dihydro-2H-
Methyl 1,4-benzoxazine-8-carboxylate,
(23) 6-fluoro-2-methyl-3-oxo-3,4
Methyl-dihydro-2H-1,4-benzoxazine-8-carboxylate, (24) 6-chloro-7-methoxy-2
-Methyl-3-oxo-3,4-dihydro-2H-1,
Methyl 4-benzoxazine-8-carboxylate, (25)
6-hydroxy-3-oxo-3,4-dihydro-2H
Methyl-1,4-benzoxazine-8-carboxylate,
(26) methyl 6-methylamino-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (27) 6-chloro-3-oxo-3,4-dihydro- Ethyl 2H-1,4-benzoxazine-8-carboxylate, (28) methyl 6-bromo-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate, (29) 6-bromo-3-oxo-3,4-
Ethyl dihydro-2H-1,4-benzoxazine-8-carboxylate, (30) 6-chloro-2-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate Acid methyl, (31) 6-chloro-3-
Oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid 4-chlorobenzyl, (32)
6-chloro-3-oxo-3,4-dihydro-2H-
Methoxymethyl 1,4-benzoxazine-8-carboxylate, (33) 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylic acid 2,2,2 -Trichloroethyl, and a preferable compound is methyl 6-chloro-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate.

The compound of the general formula (I) or the general formula (III) includes (1 ′) ethyl 4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate, (2 ′) 2-
(2-carboxy-4-chloro-6-nitrophenoxy) propionic acid, (3 ′) 2- (4-chloro-2-methoxycarbonyl-6-nitrophenoxy) propionic acid, (4 ′) 2- (4- Ethyl chloro-2-methoxycarbonyl-6-nitrophenoxy) isobutyrate, (5 ')
Ethyl 2- (2-carboxy-4-chloro-6-nitrophenoxy) isobutyrate, (6 ') 2-carboxy-4-
Ethyl chloro-6-nitrophenoxyacetate, (7 ') 2
-Ethyl carboxy-4-methyl-6-nitrophenoxyacetate, (8 ') 3-amino-2-carboxy-4-chloro-6-nitrophenoxyacetate, (9') 2-
Ethyl carboxy-3,4-dichloro-6-nitrophenoxyacetate, (10 ') 2- (4-bromo-2-carboxy-6-nitrophenoxy) propionic acid, (11') 2
Ethyl- (2-carboxy-4-chloro-6-nitrophenoxy) butyrate, ethyl (12 ′) 2-carboxy-6-nitrophenoxyacetate, (13 ′) 4-amino-2-carboxy-6-nitrophenoxyacetic acid Ethyl, (14 ') 4
-Methoxy-2-methoxycarbonyl-6-nitrophenoxyacetate, (15 ') 4-chloro-3-hydroxy-2-methoxycarbonyl-6-nitrophenoxyacetate, (16') 4-chloro-3-methoxy Methyl 2-methoxycarbonyl-6-nitrophenoxyacetate,
(17 ′) methyl 5-amino-4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate, (18 ′) 2-
(5-amino-4-chloro-2-methoxycarbonyl-
Ethyl 6-nitrophenoxy) isobutyrate, (19 ') 5-
Methyl acetylamino-4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate, (20 ') 4-acetylamino-2-methoxycarbonyl-6-nitrophenoxyacetate, (21') 5-methylamino-4 Methyl-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate, (22 ') 5-dimethylamino-2-methoxycarbonyl-6-nitrophenoxyacetate, (2
3 ′) 2- (4-Fluoro-2-methoxycarbonyl-
6-nitrophenoxy) propionic acid, (24 ') 2-
(4-chloro-3-methoxy-2-methoxycarbonyl-6-nitrophenoxy) propionic acid, (25 ') 4-
Methyl hydroxy-2-methoxycarbonyl-6-nitrophenoxyacetate, (26 ') 4-methylamino-2-methoxycarbonyl-6-nitrophenoxyacetate,
(27 ′) 4-chloro-2-ethoxycarbonyl-6-nitrophenoxyacetic acid · 4-chlorobenzyl, (28 ′) 4
-Bromo-2-methoxycarbonyl-6-nitrophenoxyacetate-4-methoxybenzyl, (29 ') 4-bromo-2-ethoxycarbonyl-6-nitrophenoxyacetate benzyl, (30') 2- (4-chloro- 2-methoxycarbonyl-6-nitrophenoxy) propionic acid / 3
4-dimethoxybenzyl, (31 ') 4-chloro-2-
Methyl (4-chlorobenzyloxycarbonyl) -6-nitrophenoxyacetate, (32 ') 4-Chloro-2-methoxymethoxycarbonyl) -6-nitrophenoxyacetate, (33') 4-chloro-2- (2 , 2,2-trichloroethoxycarbonyl) -6-nitrophenoxyacetate, and a preferred compound is ethyl 4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate.

The aprotic polar solvent used in the reaction may be any solvent capable of dissolving sodium dithionite, such as dimethylformamide,
Examples include dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and methyl ethyl ketone. Of these, dimethylformamide, dimethylsulfoxide, 1,3-
Dimethyl-2-imidazolidinone, particularly preferably dimethylformamide.

The compound represented by the general formula (I) or (III) is synthesized by using a method described in Organic Synthesis, Vol. 3, 69-7.
When the reaction was carried out according to the method described on page 1 and when the solvent used in the method was changed to tetrahydrofuran and the reaction was carried out, the target compound was not obtained, but in the aprotic polar solvent of the present invention, According to the method performed, the reduction reaction proceeds easily.

Since sodium dithionite is oxidized in the presence of water to reduce its reducing ability, the compound represented by the general formula (I) or (III) is prepared by dissolving sodium dithionite in an aprotic polar solvent. It is preferable to add dropwise an aprotic polar solvent-water mixed solution of the compound of formula This reaction is 80
Since it starts with heat generation from around about ° C, the general formula (I)
Or an aprotic polar solvent of the compound of the general formula (III)
The water mixed solution is preferably added dropwise little by little.
0 minutes to 6 hours, preferably 30 minutes to 2 hours.

The reaction temperature is 60 to 120 ° C., preferably 1
The reaction time is 30 minutes to 6 hours, preferably 1 to 2 hours. Since sodium bisulfite as a reaction product also has a reducing ability, the amount of sodium dithionite used is determined by the general formula (I) or the general formula (III).
Is preferably 1 to 3 equivalents to the compound of the formula (1).

Another feature of this reaction is that the desired product can be obtained without using an auxiliary agent such as a catalyst. In this reaction, since sodium bisulfite, a by-product of the reaction, is soluble in water, it can be separated by simply adding water to the reaction solution after the reaction. Since the target compound can be crystallized at the same time as the separation, the target compound of high yield and high purity can be obtained by a very simple method.

The obtained target product can be isolated by appropriately combining ordinary means such as centrifugation, washing and drying. The compound of the general formula (II) or the general formula (IV) produced by the present invention has an excellent serotonin-3 receptor antagonism, and suppresses vomiting and the like caused by administration of an anti-neoplastic agent such as cisplatin or Useful as a therapeutic agent for digestive diseases such as irritable enteritis syndrome (±)-
Examples of benzoxazine compounds represented by 6-chloro-4-methyl-3-oxo-N- (3-quinuclidinyl) -3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride Useful as an intermediate.

[0033]

According to the present invention, a 1,4-benzoxazine compound represented by the compound of the general formula (II) or the general formula (IV), which is an intermediate useful as a medicine, can be obtained in a high yield by a simple method. It is very excellent as an industrial production method that can be produced with high purity.

[0034]

EXAMPLES The present invention will now be described specifically with reference to comparative examples and examples, but the present invention is not limited to these examples. Comparative Example 16.9 kg of water, 708 g of ammonium chloride,
8.5 kg of dimethylformamide and 6.72 K of iron powder
g and heated to 80 ° C. With vigorous stirring, 25 kg of a dimethylformamide solution of 10.68 kg of ethyl 4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate was added dropwise, and the mixture was stirred at 80 to 90 ° C. for 1.5 hours. 67 Kg of dimethylformamide was added to precipitate crystals of the target substance, and the mixture was centrifuged while hot. The filtered residue was washed with 40 kg of dimethylformamide. The combined filtrate was poured into 400 kg of water to give 6-chloro-3-
Methyl oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxylate precipitated as crystals.
The crystals were centrifuged and dried. Yield 6.48 Kg, yield 79.9%. Example 1 A reaction vessel was charged with 40 kg of dimethylformamide and 21.6 kg of sodium dithionite, and stirred at 100 ° C.
Until heated. There, 13.3 kg of ethyl 4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate was added to dimethylformamide (26.6 kg) -water (3.1 Kg).
g) The mixed solution was added dropwise at 100 to 120 ° C over 1 hour. After the reaction at the same temperature for 2 hours, the mixture was cooled and 133 kg of water was added dropwise to give 6-chloro-3-oxo-3,4-dihydro-.
Crystals of methyl 2H-1,4-benzoxazine-8-carboxylate precipitated. After cooling, the crystals were centrifuged. After washing with methanol water, it was dried. Yield 9.3Kg, 91.9% yield, purity 99.8% or more, melting point 242-244.
° C.

The following compounds are prepared in the same manner as in the above Examples. (2) 6-chloro-2-methyl-3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine-8-carboxylic acid, mp 319-320 ° C. (3) 6-chloro-2-methyl-3-oxo-3,4-
Methyl dihydro-2H-1,4-benzoxazine-8-carboxylate, mp 186-189 ° C. (4) 6-chloro-2,2-dimethyl-3-oxo-
3,4-dihydro-2H-1,4-benzoxazine-
8-Methyl carboxylate, mp 178-179 ° C. (5) 6-chloro-3-oxo-3,4-dihydro-2
H-1,4-benzoxazine-8-carboxylic acid, mp 324 ° C. (6) 7-amino-6-chloro-3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine-8-carboxylic acid, melting point 250 DEG C. (decomposition). (7) 6-bromo-2-methyl-3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine-8-carboxylic acid, mp 303-305 ° C (decomposition). (8) 6-chloro-2-ethyl-3-oxo-3,4-
Dihydro-2H-1,4-benzoxazine-8-carboxylic acid, mp 277-279 ° C.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-2-28182 (JP, A) JP-A-4-217970 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 265/36 CA (STN) CAOLD (STN) REGISTRY (STN)

Claims (5)

(57) [Claims] 1. A compound of the general formula (Wherein, R ¹ and R ² are the same or different and each represents hydrogen or alkyl; R ³ represents an optionally substituted alkoxy;
R ⁴ and R ⁵ are the same or different and each represents hydrogen, halogen, alkyl, alkoxy, amino, acylamino, alkylamino or a hydroxyl group, and R represents hydrogen or a carboxylic acid protecting group. A) reacting the compound represented by the formula (I) with sodium dithionite in an aprotic polar solvent. (Wherein each symbol has the same meaning as described above), an industrial method for producing a 1,4-benzoxazine compound. 2. A compound of the general formula (Wherein, R ¹ and R ² are the same or different and each represents hydrogen or alkyl; R ³ represents an optionally substituted alkoxy;
R ⁴ represents hydrogen, halogen, alkyl, alkoxy, amino, acylamino, alkylamino or a hydroxyl group;
Represents a hydrogen or carboxylic acid protecting group. ) Is reacted with sodium dithionite in an aprotic polar solvent. (Wherein each symbol has the same meaning as described above), an industrial method for producing a 1,4-benzoxazine compound. 3. The method according to claim 1, wherein the 1,4-benzoxazine compound is 6-
Chloro-3-oxo-3,4-dihydro-2H-1,4
3. The method according to claim 1, wherein the compound is methyl-benzoxazine-8-carboxylate. 4. The aprotic polar solvent is dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2.
The method according to claim 1, 2, or 3, which is imidazolidinone. 5. The method according to claim 1, wherein the aprotic polar solvent is dimethylformamide.