JPH06107647A - Production of 1,3-benzoxazine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject compound safely, simply and in high yield without using an ammonia gas and a pressure container by reacting a ketone compound with an ammonium salt and a carbonyl compound in the presence of an amine. CONSTITUTION:A ketone compound of formula I (ring A is benzene ring; R<1> is group bonded through C) is reacted with an ammonium salt and a carbonyl compound of formula II (R<2> and R<3> are H or group bonded through C; R<2> and R<3> may be bonded to form a ring) or its equivalent in the presence of a secondary or tertiary amine (e.g. piperidine) to give a compound of formula III. The compound of formula III is useful as medicine, optical material recording material, etc., or its synthetic intermediate.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for producing a 1,3-benzoxazine derivative which can be used as a drug, an optical material, a recording material or the like or a synthetic intermediate material thereof.

[0002]

2. Description of the Related Art 1,3-Benzoxazine derivatives are functional heterocycles having various uses, and particularly, as a drug, a compound having an anti-inflammatory action is disclosed in JP-A-57-130979.
And recently, a new type of compound called a potassium channel opener having a smooth muscle relaxing action is disclosed in JP-A-2-193995. on the other hand,
It is also useful as an optical material and a recording material.
When No. 625 is irradiated with ultraviolet light, the color changes rapidly,
A 1,3-benzoxazine derivative is disclosed as one of the photochromic compounds that return to the original color when irradiation is stopped and in the dark.

However, these 1,3-benzoxazine derivatives are all compounds having a substituent bonded to the 4-position of 1,3-benzoxazine by a hetero atom, and are bonded at the 4-position by a carbon atom. There is no compound having a substituent. Therefore, if a 1,3-benzoxazine derivative having a group bonded by a carbon atom at the 4-position can be produced, 1,3 benzoxazine derivatives having a substituent bonded by a hetero atom at the 4-position thus far can be produced. -Physical properties and pharmacological activities different from those of benzoxazine derivatives can be expected.

To address this problem, the applicant's Japanese Patent Application No. 3-
No. 242112 (corresponding to EP-A 477789) has 1,3-having a group bonded to the 4-position by a carbon atom.
Benzoxazine derivatives have smooth muscle relaxant action, congestive heart failure, angina, arrhythmia, cardiovascular diseases such as hypertension, urinary incontinence, respiratory diseases such as asthma, cerebral vasospasm, cerebral hemorrhage, epilepsy It is disclosed as a potassium channel opener having a therapeutic and preventive effect on brain diseases such as.

In this Japanese Patent Application No. 3-242112, the 1,3-benzoxazine derivative has the formula:

[0006]

[Chemical 11]

[In the formula

[0008]

[Chemical 12] Represents an optionally substituted benzene ring, and R ¹ is 1,3
-Representing a group bonded to the 4-position of the benzoxazine ring by a carbon atom] and a compound of the formula:

[0009]

[Chemical 13]

[In the formula, R ² 'and R ³ ' are each a hydrogen atom or an optionally substituted C _1-6 alkyl or an optionally substituted C _3-6 alkylene group. R'represents a methyl or ethyl group] and is reacted with ammonia in the presence of an acid catalyst.

However, since this reaction needs to be carried out in a pressure vessel by dissolving ammonia gas in a solvent, there are problems in safety and operation such as preparation of ammonia solution and control of concentration, and pressure vessel. There is a problem in terms of equipment such as the use of. And more importantly, the side reaction is likely to occur due to the reaction of ammonia under pressure and heating, and the yield of the target 1,3-benzoxazine derivative is as low as 45%. The substituents are also limited to hydrogen, an optionally substituted C _1-6 alkyl group, or a cyclic C _3-6 alkyl group, which is not advantageous in industrial mass production and has room for improvement.

[0012]

DISCLOSURE OF THE INVENTION Under the circumstances, the present inventors have made various investigations under such circumstances, and as a result, a ketone compound represented by the following formula (II), an ammonium salt, and the following formula If the carbonyl compound represented by (IV) or its equivalent is reacted in the presence of a secondary amine or a tertiary amine, preparation of an ammonia solution and use of a pressure vessel are not required, and it is unexpectedly safe. It was found that it is an industrially advantageous and widely applicable (highly versatile) production method that can obtain a wide range of 1,3-benzoxazine derivatives in a simple and high yield, and the present invention is based on these. It came to completion.

Thus, the present invention is well-known 1,3 useful as pharmaceuticals, optical materials, recording materials or synthetic intermediates thereof.
-A novel 1, having not only a benzoxazine derivative but also a substituent that does not affect the reaction (such as a substituent on the benzene ring);
The present invention provides an industrially advantageous production method capable of producing a 3-benzoxazine derivative in a simple and high yield.

[0014]

According to the manufacturing method of the present invention, the formula:

[Chemical 14] [In the formula,

[Chemical 15]

R is a benzene ring which may be substituted,
¹ represents a group bonded by a carbon atom] and a ketone compound and an ammonium salt represented by the formula:

[0016]

[Chemical 16]

[In the formula, R ² and R ³ each represent a group bonded by a hydrogen atom or a carbon atom, and R ² and R ³ may combine with each other to form a ring] A carbonyl compound or an equivalent thereof, in the presence of a secondary or tertiary amine to give a compound of formula:

[0018]

[Chemical 17]

A compound represented by [each symbol in the formula has the same meaning as described above] is obtained, and it is safe and convenient without the need for preparing an ammonia solution or using a pressure vessel as in the conventional method. Moreover, the compound of formula (I) can be obtained in high yield.

In the process of the present invention, the ketone compound of formula (II) is reacted with an ammonium salt in the presence of a secondary or tertiary amine to give a compound of formula:

[0021]

[Chemical 18]

[Each symbol in the formula is converted to a hydroxyimine compound represented by the above-mentioned], and this is converted into the formula (I
Reaction with a carbonyl compound of formula V) or its equivalent gives the desired compound of formula (I). These ammonium salt and carbonyl compound may be simultaneously present in the reaction system in the presence of a secondary or tertiary amine, or the ammonium salt and carbonyl compound or their equivalents may be sequentially added to the reaction system. . In addition, when a salt-forming group is present in each substituent, the compound of formula (I) can be obtained in the form of a salt, and such a salt is also within the scope of the present invention.

The secondary amine or tertiary amine used in the present invention is not particularly limited as long as the reaction proceeds, but especially as the secondary amine, the number of carbon atoms which may contain 1 to 5 oxygen and sulfur atoms in the side chain. A chain secondary amine having 2 to 20 or a cyclic secondary amine having 2 to 20 carbon atoms which may contain 1 to 5 oxygen and sulfur atoms in the ring is used. For example, as the chain secondary amine, di-C _1-4 alkylamine such as diethylamine, dibutylamine and diisopropylamine, di-C _3-7 cycloalkylamine such as dicyclohexylamine, N
-N-C _1-4 alkylaniline such as methylaniline,
Examples of the cyclic secondary amine include 5 or 6 such as pyrrolidine, biperidine, piperazine, morpholine and thiazolidine.
A membered nitrogen-containing heterocycle or the like is used. Among these, preferably, di-C _1-4 alkylamines such as diethylamine, dibutylamine, diisopropylamine, piperidine,
It is a 5- or 6-membered nitrogen-containing heterocycle such as morpholine.

As the tertiary amine, oxygen is contained in the side chain,
A chain-like tertiary amine having 3 to 30 carbon atoms which may contain 1 to 5 sulfur atoms and a cyclic tertiary amine having 3 to 30 carbon atoms which may contain 1 to 5 oxygen and sulfur atoms in the ring are used. . For example, as the chain tertiary amine, tri-C _1-4 alkylamine such as triethylamine and tributylamine, N, N,
N, N, such as N ', N'-tetramethylethylenediamine
N ', N'-tetra-C _1-4 alkylethylenediamine,
N, N-di-C _1-4 alkylaniline such as N, N-dimethylaniline, N-methylmorpholine as a cyclic tertiary amine, 1,5-diazabicyclo [4.3.0] non-5-ene ( DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, quinoline and the like are used. Of these, triethylamine, tributylamine, DBU and the like are preferable. The salt of the secondary amine or the tertiary amine is not particularly limited as long as it is a salt of an inorganic acid or an organic acid and a secondary amine or a tertiary amine. Examples of the inorganic acid include hydrogen chloride such as hydrogen chloride, hydrogen bromide and hydrogen iodide, mineral acids such as sulfuric acid and nitric acid, perchloric acid, carbonic acid, phosphoric acid, boric acid, fluoroboric acid and hexafluorophosphoric acid. Used. Also,
Examples of the organic acid include C _1-10 alkylcarboxylic acid (eg, acetic acid, propionic acid, butyric acid, etc.), C _6-10 arylcarboxylic acid (eg, benzoic acid, naphthalenecarboxylic acid, etc.), C _1-10 alkylsulfone. Acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), C _6-10 arylsulfonic acid (eg, benzenesulfonic acid, naphthalenesulfonic acid, etc.), phenol [these C _1-10 alkyl, C _6-10 aryl groups are Various organic acids such as halogen (eg, fluorine, chlorine, bromine, etc., 1 to 3 may be substituted with a nitro group) are used, for example, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid. , Toluene sulfonic acid, phenol, picric acid, etc. are used. Of these, trifluoromethanesulfonic acid and the like are preferable.

The ammonium salt used in the present invention is not particularly limited as long as the reaction proceeds, and may be an inorganic ammonium salt or an organic ammonium salt. The inorganic ammonium salt means a salt of various inorganic acids and ammonia. However, for example, salts of hydrogen halide and ammonia such as ammonium chloride, ammonium bromide and ammonium iodide, salts of mineral acid and ammonia such as ammonium sulfate and ammonium nitrate, ammonium carbonate and ammonium perchlorate. , Ammonium borofluoride, etc. are used.

As the organic ammonium salt, an alkylcarboxylic acid having 1 to 10 carbon atoms (eg, acetic acid, propionic acid, butyric acid, etc.), an arylcarboxylic acid having 6 to 10 carbon atoms (eg, benzoic acid, naphthalenecarboxylic acid, etc.) ), Alkylsulfonic acid having 1 to 10 carbon atoms (eg, methanesulfonic acid, ethanesulfonic acid, etc.), arylsulfonic acid having 6 to 10 carbon atoms (eg, benzenesulfonic acid, naphthalenesulfonic acid, etc.), phenol [these alkyls , An aryl group may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.) or a nitro group] and salts of various organic acids with ammonia, for example, ammonium acetate, trifluoroacetic acid. Ammonium, ammonium trifluoromethanesulfonate, ammonium picrate, etc. are used. . Of these, preferably
Examples include ammonium trifluoromethanesulfonate and the like.
Preferred examples of ammonium salts are ammonium halides such as ammonium iodide.

The ketone compound represented by the formula (II), which is the substrate for the reaction of the present invention, has --C at the 2-position with respect to the hydroxyl group.
Any phenol having an O—H group or a —CO— group can be applied regardless of the substituent on the benzene ring and the type of R ¹ . In the above formulas (I), (II) and (III)

[0028]

[Chemical 19] Represents an optionally substituted benzene ring, and in addition to the unsubstituted benzene ring, a benzene ring in which any position is substituted with 1 to 4 substituents (when substituted with 2 or more substituents, May be combined with each other to form a condensed ring). As a benzene ring forming a condensed ring, 1 to 4 selected from oxygen, nitrogen, and sulfur atoms in addition to carbon atoms.
A benzene ring condensed with 1 to 3 5- or 6-membered aromatic rings, each of which may be a constituent atom (these condensed benzene rings may have a substituent at any position) Specifically, a naphthalene ring, anthracene ring, phenanthrene ring, pyrene ring, quinoline ring, acridine ring and the like are used. The compound (II) can be synthesized by a general method for synthesizing an aromatic ketone, for example, “New Organic Chemistry of Solomon (3rd Edition)” (Hanafusa, Nakajima, Ikeda, supervisor) (Hirokawa Shoten, 1992). It can be produced according to the method described in the lower volume, pages 705 to 707, and the like. Specifically, for example, a method of reacting an organolithium compound with a phenol (salicylic acid) having a carboxyl group at the 2-position with respect to a hydroxyl group, an organic lithium compound having a nitrile group at the 2-position with respect to a hydroxyl group It can be produced by using a method of reacting a magnesium compound, a Friedel-Crafts reaction using phenols as a raw material, or a similar reaction such as Fries rearrangement reaction.

Further, as the substituent which may be substituted at any position of the benzene ring and the condensed benzene ring, any substituent may be used as long as it does not adversely affect the reaction,
For example, the following is used. (1) hydroxyl group (2) halogen atom (eg, fluorine, chlorine, bromine, etc.) (3) nitro (4) cyano (5) optionally substituted C _1-6 alkyl (eg, methyl, ethyl, propyl, Butyl) and 1 to 4 groups below are used as the substituents. a) C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) b) C _6-10 aryl (eg, phenyl, naphthyl, etc.) c) C _6-10 aryl-C _1-4 alkyl (eg, benzyl,
Phenethyl etc.) d) hydroxyl group e) nitro f) halogen (eg fluorine, chlorine, bromine etc.) g) cyano (6) optionally substituted C _1-6 alkoxy (eg methoxy, ethoxy, propoxy etc.) As the substituents, the same groups as the 1 to 4 substituents a) to g) in (5) are used. (7) optionally substituted C _2-6 alkenyl (eg, vinyl, propenyl, butenyl, etc.), whose substituents are the same as 1 to 4 substituents a) to g) in (5) Groups are used. (8) optionally substituted C _2-6 alkynyl (eg, ethynyl, propynyl, butynyl, etc.), whose substituents are the same as 1 to 4 substituents a) to g) in (5) Groups are used. (9) optionally substituted C _6-10 aryl (eg, phenyl, naphthyl, etc.), which has the same group as C _1-4 alkyl and the substituents a) to g) in (5) Is used. The number of the substituents is 1 to 4. (10) optionally substituted heteroaryl (eg, thienyl, pyridyl, etc.), the substituent of which is C _1-4
The same groups as the alkyl and the substituents a) to g) in (5) are used. The number of the substituents is 1 to 4.

(11) optionally substituted amino,
As the substituent, one or two of the following groups are used. a) C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.) b) C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) c) Halo C _1-4 alkyl (eg, CF ₃ —, chloro) Methyl etc.) d) Formyl e) Thioformyl f) Hydroxyl group g) Carbamoyl h) C _6-10 aryl (eg phenyl, naphthyl etc.) i) C _6-10 aryl-C _1-4 alkyl (eg benzyl,
Phenethyl etc.) j) C _1-4 alkyl-carbonyl (eg acetyl, propionyl etc.) k) C _6-10 aryl-carbonyl (eg benzoyl, naphthoyl etc.) l) C _6-10 aryl-C _1-4 alkyl -Carbonyl (eg, benzylcarbonyl, naphthylethylcarbonyl, etc.) m) C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.) n) C _6-10 aryloxy-carbonyl (eg, phenoxycarbonyl, naphthyloxy) Carbonyl etc.) o) C _6-10 aryl-C _1-4 alkyloxy-carbonyl (eg phenylmethyloxycarbonyl, naphthylethyloxycarbonyl etc.) p) Heteroarylcarbonyl (eg tenoyl, nicotinoyl etc.) q) C _{1 -4} alkylsulfinyl (e.g., methylsulfinyl, ethyl Sulfinyl, etc.) r) C _1-4 alkoxysulfinyl sulfinyl (e.g., methoxysulfinyl, ethoxy sulfinyl, etc.) s) C _6-10 arylsulfinyl (e.g., phenylsulfinyl, naphthylsulfinyl, etc.) t) C _1-4 alkylsulfonyl (e.g., Methylsulfonyl, ethylsulfonyl, etc.) u) C _1-4 alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.) v) C _6-10 arylsulfonyl (eg, phenylsulfonyl, naphthylsulfonyl, etc.) (12) -CO-R ⁴ [wherein R ⁴ is C _1-4 alkyl (eg,
Methyl, ethyl, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.), C _6-10 aryl-C _1-4 alkyl (eg, benzyl, phenethyl, etc.) or heteroaryl (eg, thienyl, pyridyl, etc.) Indicates. ] (13) -O-CO-R ⁵ [In the formula, R ⁵ has the same meaning as R ⁴ ] (14) Carbamoyl which may be substituted, and the substituent thereof is 1 or 2 of the following groups. Used. a) C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.) b) C _6-10 aryl (eg, phenyl, naphthyl, etc.) c) Heteroaryl (eg, thienyl, pyridyl, etc.) d) C _6-10 Aryl-C _1-4 alkyl (eg, benzyl,
Phenethyl etc.) e) heteroaryl-C _1-4 alkyl (eg thienylmethyl, pyridylmethyl etc.) f) C _1-4 alkoxy-carbonyl (eg acetyl, propionyl etc.)

(15) An optionally substituted carbamoyloxy, which has 1 or 2 (1
The same groups as the substituents a) to f) in 4) are used. (16) Carboxyl which may be substituted, and the following groups are used as the substituent. a) C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.) b) C _6-10 aryl-C _1-4 alkyl (eg, benzyl,
^{Phenethyl) (17) -CS-R 6} [ wherein, R ⁶ is the same meaning as ^{R 4] (18) -O-} CS-R 7 [ wherein, as defined R ⁷ and R ^4] (19) In thiocarbamoyl which may be substituted, as the substituent, the same groups as 1 or 2 substituents a) to f) in (14) are used. (20) In optionally substituted thiocarbamoyloxy, as the substituent, the same groups as 1 or 2 substituents a) to f) in (14) are used. (21) optionally substituted imino-C _1-6 alkyl, and as the substituent thereof, 1 to 4 groups below are used. a) hydroxyl group b) amino c) C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.) d) C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, etc.) e) C _6-10 aryl (eg, Phenyl, naphthyl, etc.) f) C _6-10 aryl-C _1-4 alkyloxy (eg, benzyloxy, naphthylethyloxy, etc.) g) Heteroaryl-C _1-4 alkyloxy (eg, thienylmethyloxy, pyridylethyl) (Oxy and the like) (22) In mercapto which may be substituted, the following groups are used as the substituent. a) C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.) b) C _6-10 aryl (eg, phenyl, naphthyl, etc.) c) Heteroaryl (eg, thienyl, pyridyl, etc.) d) C _6-10 Aryl-C _1-4 alkyl (eg, benzyl, naphthylethyl, etc.) e) Halo C _1-4 alkyl (eg, CF ₃ —, chloromethyl, etc.) (23) -S (O) n′-R ⁸ [formula Where n'is 1 or 2, R ⁸
Is a hydrogen atom, C _1-4 alkyl (eg, methyl, ethyl, etc.), C _1-4 alkoxy (eg, methoxy, ethoxy, etc.), C _6-10 aryl (eg, phenyl, naphthyl, etc.), heteroaryl (eg, , Thienyl, pyridyl, etc.), C _6-10 aryl-C _1-4 alkyl (eg, benzyl, naphthylethyl, etc.) or amino. ]

(5) to (11), (14) to (1)
6) and C in the substituents in (19) to (23)
_{The 6-10} aryl moiety further includes C _1-4 alkyl (eg, methyl, ethyl, etc.), C _1-4 alkoxy (eg, methoxy,
Ethoxy, etc.), hydroxyl group, nitro, halogen (eg, fluorine, chlorine, bromine, etc.), halo C _1-4 alkyl (eg, CF ₃
-, Chloromethyl etc.), cyano, halo C _1-4 alkoxy (eg CF ₃ O—, chloromethoxy etc.), mercapto, halo C _1-4 alkylthio (eg CF ₃ S—, chloromethylthio etc.) and the like. It may be substituted with 1 to 4. Also, when two substituents are bonded to each other, -CH = CH
—CH— [wherein this group is 1 to 3 C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.), C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, etc.), nitro, halogen. (Fluorine, chlorine, bromine, etc.), CF ₃ ,
It may be substituted with a group selected from C _1-4 alkoxy-carbonyl (eg, acetyl, propionyl, etc.) and cyano], ═N—O—N =, — (CH ₂ ) a— (a is 3 or 4 is _{a), - (CH 2) b} -CO- (b is 2 or _{3), - (CH 2)} b-C (= NOH) - or - (CH ₂₎ b
A group represented by -C (= N-O-C _1-4 alkyl)-may be formed.

Heteroaryl groups include 5- or 6-membered monocyclic or 9- or 10-membered bicyclic heteroaryl, with 5- or 6-membered monocyclic heteroaryl being preferred. Further, the 5 or 6 membered monocyclic or 9 or 10 membered bicyclic heteroaryl preferably contains 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur and more than one. If heteroatoms are present, they may be the same or different. A 5- or 6-membered monocyclic heteroaryl group containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur includes furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl. , Pyridazyl, pyrimidyl, pyrazyl and triazyl. 9 containing 1, 2 or 3 heteroatoms selected from oxygen, nitrogen and sulfur
Or examples of 10-membered bicyclic heteroaryl groups are benzofuranyl, benzothienyl, indolyl, indazolyl,
Included are quinolyl, isoquinolyl and quinazolinyl.

[Chemical 20] Preferably, an unsubstituted benzene ring such as benzene, naphthalene, anthracene, phenanthrene, quinoline or an unsubstituted condensed benzene ring, 5 or 4-chlorobenzene, 5 or 4-bromobenzene, 5 or 4-fluorobenzene, 5 or 4- Trifluoromethylbenzene, 5 or 4-cyanobenzene, 5 or 4-nitrobenzene, 5 or 4-trifluoromethoxybenzene, 4,5-dichlorobenzene, 4,5-dibromobenzene, 4,5-difluorobenzene, 5- Cyano-4-chlorobenzene, 4-cyano-5-chlorobenzene, 5-
The same or different 1 such as cyano-4-bromobenzene, 4-cyano-5-bromobenzene, 5-cyano-4-fluorobenzene, 4-cyano-5-fluorobenzene, etc.
Or 2 halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro, cyano, halo C _1-4 alkyl (eg, CF ₃
-, Etc.), halo C _1-4 alkoxy (eg, CF ₃ O-, etc.)
And the like, such as benzene. Of these, more preferred are 5-bromo-4-chlorobenzene, 5-cyanobenzene, 5-nitrobenzene, and 4,5-dibromobenzene.

In the above formula, R ¹ is a group bonded by a carbon atom, and is a group bonded by a carbon atom at the 4-position of the 1,3-benzoxazine ring of the object (I). Examples of such a group include an optionally substituted heterocyclic group and a hydrocarbon group, and any of these may be used as long as they do not adversely affect the reaction. The heterocyclic group represented by R ¹ is a 5- to 6-membered heterocyclic ring having 1 to 4 oxygen, nitrogen or sulfur atoms other than carbon atoms as ring-constituting atoms or a condensed ring thereof (for example, a benzene ring is 1
Alternatively, a group formed by removing one hydrogen from a ring-constituting carbon atom (eg, two condensed ones) may be used and may have a substituent at any position on the ring.

Examples of the heterocyclic group include 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 1,2,4.
-Triazol-1-yl, 1,2,3-triazole-
1-yl, 1,3,4-triazol-1-yl, 1,3,
4-triazol-1-yl, 1,2,5-triazol-1-yl, 1-tetrazolyl, 5-tetrazolyl, 2
-Pyridyl, 3-pyridyl, 4-pyridyl, 1-C _1-4
Alkylpyridin-2-yl, 1-C _1-4 alkylpyridin-3-yl, 1-C _1-4 alkylpyridinium-
4-yl, pyridin-N-oxide-2-yl, pyridin-N-oxide-3-yl, pyridin-N-oxide-4-yl, 3 or 4-pyridazinyl, pyridazine-
N-oxide-3 or 4-yl, 4 or 5 pyrimidinyl, pyrimidin-N-oxide-4 or 5-yl,
2-pyrazinyl, pyrazine-N-oxide-2 or 3
-Yl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, quinolin-N-oxide-2-yl, quinolin-
N-oxide-3-yl, quinoline-N-oxide-4
-Yl, isoquinolin-1,3 or 4-yl, isoquinolin-N-oxide-1,3 or 4-yl, 2- or 3-indolyl, 2- or 3-pyrrolyl, formula:

[0036]

[Chemical 21]

[Wherein b is 2 or 3 and n is 0, 1
Or 2, R ⁷ is hydrogen, C _1-6 alkyl (eg, methyl,
2,2,2-), which represents ethyl, propyl, etc.), nitro, C _1-4 alkyl (eg, methyl, ethyl, propyl, etc.) or C _6-10 aryl (eg, phenyl, naphthyl, etc.)] Dimethyl-1,3-dioxane-4,6
-Dione-5-yl and the like.

The hydrocarbon group represented by R ¹ is a linear or branched C such as methyl, ethyl or propyl.
_1-10 alkyl group, C such as cyclopropyl, cyclobutyl, etc.
_3-7 cycloalkyl group, linear or branched C _2-10 alkenyl group such as vinyl and allyl, 2-cyclopentene-
Examples thereof include C _5-7 cycloalkenyl groups such as 1-yl and 2-cyclohexen-1-yl, and linear or branched C _2-10 alkynyl groups such as ethynyl, propynyl and butynyl.

Each of the heterocyclic group or hydrocarbon group represented by R ¹ is unsubstituted or has 1 to 3 halogens (eg, fluorine, chlorine, bromine, etc.), C _1-4 alkyl (eg, , Methyl, ethyl, propyl, etc.), C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, etc.), nitro, hydroxy-C _1-4 alkyloxy (eg, hydroxymethyloxy, hydroxyethyloxy, etc.), hydroxy- C _1-4 alkylaminocarbonyl (eg, hydroxymethylaminocarbonyl, hydroxyethylaminocarbonyl, etc.), trimethylsilyl,
Trimethylsilyl-C _1-4 alkyloxymethyloxy (eg, trimethylsilylmethyloxymethyloxy, trimethylsilylethyloxymethyloxy, etc.), nitro-C _1-4 alkyloxy (eg, nitromethyloxy,
Nitroethyloxy, etc.), nitro-C _1-4 alkylaminocarbonyl (eg, nitromethylaminocarbonyl,
Nitroethylaminocarbonyl etc.), CF ₃ , CF
₃ O, C _1-4 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 arylsulfonyl (eg, phenylsulfonyl, naphthylsulfonyl, etc.), C _1-4 alkyl-carbonyl (eg, acetyl, propionyl) Etc.), C _6-10 arylcarbonyl cyano (eg, benzoyl cyano, naphthoyl cyano, etc.), C
O ₂ H, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), NH ₂ , C _1-8 alkanoylamino (eg, acetylamino, propionylamino, etc.), C _7-11 aroylamino (eg, Benzoylamino, naphthoylamino, etc.), 3-C _1-8 alkyl-2-cyano (eg, 3-methyl-2-cyano, 3-ethyl-2-cyano, etc.) and a group selected from nitroguanidino, etc. It may have been done. Further, as a further substituted hydrocarbon group,

[0040]

[Chemical formula 22]

The groups represented by (the symbols in the formula have the same meanings as described above) are used. R ¹ is preferably, for example, a heterocyclic group, more preferably a pyridyl group.

The compound (IV) used in the present invention can be synthesized by a general method for synthesizing aldehydes and ketones. For example, "Solomon's New Organic Chemistry (Third Edition)" (translated by Hanafusa, Nakajima, Ikeda, supervisor). (Hirokawa Shoten, 1992) Volume 2, p. 701 to 707. Specifically, for example, in the case of an aldehyde, it can be produced by using an oxidation reaction of a primary alcohol with pyridinium chlorochromate, a reduction reaction of an ester or a nitrile with diisobutylaluminum hydride, an oxidative decomposition reaction of an alkene with ozone, and the like. In the case of a ketone, it can be produced by using an oxidation reaction of a secondary alcohol with chromic acid, an oxidative decomposition reaction of an alkene with ozone, an aromatic acylation reaction by a Friedel-Crafts reaction, or the like. The compound (I
The equivalent of V) is derived from compound (IV), and has the same role as compound (IV) in the organic synthesis reaction to give the same product. As such an equivalent, specifically, for example, the formula:

[0043]

[Chemical formula 23]

(Wherein R ² and R ³ have the same meanings as described above,
R represents a lower alkyl group or a lower alkylcarbonyl group, and when two R are present, they may be bonded to each other to form a ring).
The compound (V) can be produced by a general method for synthesizing acetal or ketal, and for example, “Solomon's New Organic Chemistry (3rd Edition)” (translated by Hanafusa, Nakajima, Ikeda, supervised) (Hirokawa Shoten, 1992). (Year) Vol. 714-719. Specifically, for example, by reacting 2 equivalents of a lower alcohol such as methanol or ethanol with an aldehyde or a ketone and dehydrating it, aldehydes such as dimethyl acetals of ketones, ketals or diethyl acetals, and ketals can be obtained. Cyclic acetals and ketals can be obtained by reacting such diols in the same manner. In addition, compound (VI) can be produced by a general method for synthesizing enol ethers and enol esters of aldehydes and ketones, for example, Journal of Organic Chemistry,
Volume 38, page 2910 (1973),
Merck Index, Vol. 11, p. 5091 (19
1989) and the like.

R in formulas (I), (IV), (V) and (VI)
² and R ³ may be a group bonded to each other by a hydrogen atom or a carbon atom, or R ² and R ³ may be bonded to each other to form a ring. The group bonded by the carbon atom represented by R ² and R ³ may be any group as long as it does not adversely affect the reaction, for example, an optionally substituted heterocyclic group or hydrocarbon group, etc. Is used. As the heterocyclic group represented by R ² and R ³ , the same groups as the heterocyclic group described in R ¹ above are used, and specifically, 2-furyl, 3-furyl, 2-thienyl, 3 -Thienyl, 2-
Oxazolyl, 4-oxazolyl, 5-oxazolyl,
2-thiazolyl, 4-thiazolyl, 5-thiazolyl,
1,2,4-triazol-1-yl, 1,2,3-triazol-1-yl, 1,3,4-triazol-1-yl, 1,3,4-triazol-1-yl, 1, 2,5-triazol-1-yl, 1-tetrazolyl, 5-tetrazolyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 1-carbazolyl and the like are used.

The hydrocarbon group represented by R ² and R ³ is a linear or branched C _1-20 alkyl group such as methyl, ethyl and propyl, and a C _3-7 cycloalkyl group such as cyclopropyl and cyclobutyl. Or linear or branched C _2-20 alkenyl groups such as vinyl, allyl, etc., C _5-7 such as 2-cyclopenten-1-yl, 2-cyclohexen-1-yl, etc.
A linear or branched C _2-20 alkynyl group such as cycloalkenyl group, ethyl, propynyl, butynyl, etc., C _6-14 aryl group such as phenyl, naphthyl, anthryl, etc. are used. In addition, when R ² and R ³ are bonded to each other, 1 to 10 oxygen, nitrogen, and sulfur atoms other than carbon atoms are formed together with the carbon atom at the 2-position of the 1,3-benzoxazine ring. A 4- to 30-membered heterocycle, preferably a 4- to 10-membered ring containing 1 to 3 oxygen, nitrogen and sulfur atoms in addition to carbon atoms as ring-constituting atoms (

[0047]

[Chemical formula 24]

Is, for example, tetrahydrothiophene-3
-Ylidene, tetrahydrothiopyran-4-ylidene,
Tetrahydropyran-4-ylidene, (16-crown-5) -3-ylidene, (19-crown-6) -3-ylidene, piperidine-4-ylidene and the like) may be formed. Number 3 to 20 cyclic hydrocarbon group (

[0049]

[Chemical 25]

May represent, for example, cyclopropylidene, cyclohexylidene, cyclopeptylidene, 2-adamantylidene, 2-norbornylidene, 7-norbornylidene, etc.).

The heterocyclic group or hydrocarbon group represented by R ² and R ³ may have 1 to 4 substituents, and if such a substituent does not adversely affect the reaction. Any substance such as a hydroxyl group, a halogen atom (eg, fluorine, chlorine, bromine, etc.), a nitro group, a cyano group, a C _1-20 alkyl group (eg, methyl, ethyl, propyl, etc.), a C _1-20 alkoxy group (Eg, methoxy, ethoxy, propoxy, etc.), amino group, N, N- (C _1-20 alkyl) amino group (eg, N, N-dimethylamino, N, N-
Such as diethylamino), or when two substituents are bound to each other, —CH ₂ — (OCH ₂ ) m—, —CH ₂
- (NH-CH ₂₎ m- or _{-CH 2 - (SCH 2) m-} (m is 1 to 10) and a group represented by is used.

As the lower alkyl group represented by R, a C _1-6 alkyl group such as methyl, ethyl, propyl and the like are used, preferably methyl, ethyl and the like. As the lower alkylcarbonyl group, C _1-6 alkyl-carbonyl groups such as acetyl and propionyl are used, and acetyl is preferable.

The ring formed by two Rs bonded to each other is one having 2 to 4 carbon atoms, and preferably a 1,3-dioxolane ring (

[0054]

[Chemical formula 26]

) Etc.

In the method of the present invention, the compound (II) is added in the presence of a secondary amine, a tertiary amine or a salt thereof.
As an equivalent of the carbonyl compound (IV) to be reacted with I), for example, an enamine of the carbonyl compound (IV) and a secondary amine may be used. Such enamines include, for example, the formula:

[0057]

[Chemical 27]

[Wherein R ² and R ³ have the same meanings as described above,
R ⁴ and R ⁵ are each a C _1-10 hydrocarbon group which may contain 1 to 2 oxygen atoms, nitrogen atoms and sulfur atoms, or a nitrogen atom in which R ⁴ and R ⁵ are bonded to each other and are adjacent to each other. And a group which may form a ring together with] is used. As the C _1-10 hydrocarbon group represented by R ⁴ and R ⁵ , the same group as the hydrocarbon group represented by R ¹ is used. Such an enamine can be easily produced by reacting an aldehyde or ketone having α-hydrogen with a secondary amine, and removing water generated by a dehydrating agent or the like. For example, “New Organic Chemistry of Solomon (3rd Edition) ) ”(Hanabo, Nakajima, Ikeda, translated) (Hirokawa Shoten) Vol. 906-9
It can be produced according to the method described on page 10 (1992). As the enamine, 1-morpholino-1-cyclohexanone and the like are preferable.

The production method of the present invention is usually carried out in an inert solvent, for example, alcohols such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, ethers such as tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene and toluene. , Aliphatic hydrocarbons such as hexane, halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane, or a mixed solvent thereof. The reaction may be allowed to proceed in the presence of a dehydrating agent (for example, anhydrous calcium sulfate, molecular sieves, etc.). A 1- to 10-fold molar amount (preferably a 1- to 5-fold molar amount) of ammonium salt, and a 0.1- to 10-fold molar amount (preferably 1-fold) of the ketone compound (II).
1 to 10 times (preferably 1 to 5 times) the amount of the carbonyl compound (IV) or its equivalent to the compound (II). Add body. Usually, it is carried out at a temperature range of 0 ° C to 150 ° C (preferably 20 ° C to 100 ° C) and a reaction time of 3 hours to 40 hours (preferably 4 hours to 8 hours).

As described above, this reaction can be carried out by mixing all the raw materials and the reactants in the solvent at the same time, but in the solvent, the dehydrating agent, ammonium salt, secondary compound, etc. can be reacted with the ketone compound (II). Alternatively, a tertiary amine is added and reacted to convert it to a hydroxyimine compound (III), and then the compound (III) is not isolated but is reacted as it is with a carbonyl compound (IV) or an equivalent thereof to give a compound. It is also possible to obtain (I). in this case,
The reaction between the compounds (III) and (IV) is advantageously promoted by the secondary amine, tertiary amine or salt thereof present in the reaction system. The object compound (I) of the present invention can be easily isolated by a usual method for purifying an organic compound (recrystallization, column chromatography, etc.). Further, when the compound (I) has an acidic or basic substituent, salts thereof are also included in the object of the present invention. For example, when it has an acidic substituent, an alkali metal salt such as sodium salt and potassium salt, an alkaline earth metal salt such as calcium salt and magnesium salt, and ammonium salt are used. When it has a basic substituent, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, salts with inorganic acids such as sulfamic acid, acetic acid,
Salts with organic acids such as tartaric acid, citric acid, fumaric acid, maleic acid, p-toluenesulfonic acid, methanesulfonic acid and glutamic acid are used. When the compound (I) has a substituent such as a hydroxyl group, an amino group and a carboxyl group, those protected with a protecting group are also included in the object of the present invention. Examples of these protecting groups include those described in Green et al., Protective Group in Organic Synthesis (1981) and the like. Examples of the hydroxyl-protecting group include chloroacetyl, benzyl, p-nitrobenzyl, methylthiomethyl, methoxymethyl, trimethylsilyl,
Tertiary butyldimethylsilyl, 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl and the like are used. Examples of the protective group for the carboxyl group include benzyl, benzhydryl, trityl, p-methoxybenzyl, p-nitrobenzyl, tertiary butyl and the like. Examples of the amino group-protecting group include formyl, chloroacetyl, tertiary butoxycarbonyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2- Trichloroethoxycarbonyl, trityl and the like are used.

The production method of the present invention can be used for the synthesis of various compounds, one example of which is shown below. In the ketone compound of formula (II),

[Chemical 28] Is a 5-bromo-4-chlorobenzene, and R ¹ is a 2-pyridyl group, a compound having the same carbonyl compound of formula (V) as R ² and R ³ is a methyl group and R is a methyl group. , Ammonium iodide as an ammonium salt and piperidine as a secondary amine are reacted according to the production method of the present invention, 6-bromo-7-chloro-2,2-dimethyl-
4- (2-Pyridyl) -2H-1,3-benzoxazine is obtained.

When the 2-pyridyl group is N-oxidized with an appropriate oxidizing agent, it has a smooth muscle relaxing action, and has heart / circulatory system diseases such as congestive heart failure, angina, arrhythmia and hypertension, and urine. It is a potassium channel opener having a therapeutic and preventive effect on respiratory system diseases such as incontinence, asthma, cerebral vasospasm, cerebral hemorrhage, epilepsy, etc. 2- (6-
Bromo-7-chloro-2,2-dimethyl-2H-1,3-
Benzoxazin-4-yl) pyridine 1-oxide is obtained.

The same compound can be produced by utilizing the production method of the present invention as follows. In the ketone compound of the above formula (II),

[Chemical 29] Is a 5-bromo-4-chlorobenzene and R ¹ is a 2-pyridyl group, the ketone group of the compound is protected by a suitable protecting group, and then the 2-pyridyl group is N-oxidized and deprotected as described above. 2- (5-bromo-4-chloro-2
-Hydroxybenzoyl) pyridine 1-oxide is obtained.

For this ketone compound (II), the formula
In the equivalent of the carbonyl compound of (V), a compound in which R ² and R ³ are methyl groups and R is a methyl group is reacted with ammonium iodide as an ammonium salt and piperidine as a secondary amine by the production method of the present invention. And potassium channel opener 2- (6-bromo-7-chloro-2,2-dimethyl-2H-1,3-benzoxazine-
4-yl) pyridine 1-oxide is obtained. The compound (I) obtained by the production method of the present invention has a smooth muscle relaxing action, and has heart / circulatory system diseases such as congestive heart failure, angina pectoris, arrhythmia and hypertension, urinary incontinence, breathing such as asthma, etc. Systemic diseases,
In addition to being used as a potassium channel opener that has therapeutic and preventive effects on cerebral vasospasm, cerebral hemorrhage, epilepsy, and other brain diseases, it also has optical materials and recording materials as functional dyes whose color changes with external energy such as light, heat, and magnetic fields. Used for.

[0065]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited thereto. Reference Example 1 Preparation of 5-bromo-4-chlorosalicylic acid 4-chlorosalicylic acid (2.7 kg) and triethylamine
Dissolve (1.75 kg) in methylene chloride (60 liters),
Cooled to -70 ° C. A solution of bromine (1 kg) in methylene chloride (12.5 liters) was added dropwise with stirring at the same temperature, and the mixture was further stirred for 1 hour. The reaction solution at room temperature (25 ° C; the same applies below)
The solvent was distilled off under reduced pressure, water (50 liters) and concentrated hydrochloric acid (5 liters) were added to the residue, and the mixture was extracted with ethyl acetate (15 liters and 10 liters). The organic layer was washed twice with 20% saturated saline (30 liters) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with n-hexane (12.5 liter) and then recrystallized from acetonitrile (3 liter) to give 5-bromo-4-chlorosalicylic acid (1657 g). m. p. : 208~213 ℃ NMR (DMSO-d 6) δppm: 7.30 (1H, s), 8.02
(1H, s)

Reference Example 2 5-Bromo-4-chloro-2-hydroxyphenyl 2
-Production of pyridyl ketone Under a stream of argon, 2-bromopyridine (74.3 g) was dissolved in toluene (300 ml) and cooled to -78 ° C. 1.6M hexane solution of n-butyllithium (250m
l) was added dropwise near the same temperature, and the mixture was stirred for another 30 minutes. Then, a solution of 5-bromo-4-chlorosalicylic acid (16.8 g) in tetrahydrofuran (50 ml) was added dropwise at the same temperature, and the mixture was further stirred for 1 hour. The reaction solution is heated to -20 ° C and methanol is added.
The reaction was terminated by adding (32 ml) and water (350 ml). After completion of the reaction, ethyl acetate (350 ml) and 5% hydrochloric acid (460 ml) were added to the reaction mixture to separate it. Water the organic layer (5
(00 ml) three times, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The residue was washed with ethanol (42 ml) to give 5-bromo-4-chloro-2-hydroxyphenyl 2-pyridyl ketone (12.2 g).

Reference Example 3 5-Bromo-4-chloro-2-hydroxyphenyl 2
-Production of pyridyl ketone Under a stream of argon, 2-bromopyridine (5151 g) was dissolved in tetrahydrofuran (21 liters) and cooled to -78 ° C. While stirring, n-butyllithium 1.6M hexane solution (12.0 kg) was added dropwise at about the same temperature for another 30 minutes.
Stir for minutes. Then, a solution of 5-bromo-4-chlorosalicylic acid (1169 g) in tetrahydrofuran (5 liters) was added dropwise at the same temperature, and the mixture was further stirred for 1 hour. The reaction solution is -20
Raise to ℃, methanol (2.3 liters) and water
(30 liters) was added to terminate the reaction. After completion of the reaction, the reaction solution was extracted with ethyl acetate (25 liters, 12.5 liters and 12.5 liters) three times. The whole extract was washed twice with 5% hydrochloric acid (17 liters) and three times with water (30 liters), and then the solvent was distilled off under reduced pressure. Ethanol residue
The crystals were recrystallized from (2.4 liters) to give 5-bromo-4-chloro-2-hydroxyphenyl 2-pyridyl ketone (77
8.1 g) was obtained.

M. p. : 124-128 ° C ¹ H-NMR (CDCl ₃ ) δppm: 7.21 (1H, s), 7.56
-7.65 (1H, m), 7.95-8.14 (2H, m), 8.62
(1H, s), 8.72-8.79 (1H, m) MS (EI): 315 (M + 4), 313 (M + 2), 311
(M)

Reference Example 4 2- (6-Bromo-7-chloro-2,2-dimethyl-2H
Method for producing -1,3-benzoxazin-4-yl) pyridine 1-oxide 6-bromo-7-chloro-2,2-dimethyl-4- (2-
Pyridyl) -2H-1,3-benzoxazine (150 g)
Was dissolved in methylene chloride (2.1 L) and cooled with ice.
Metachloroperbenzoic acid (16.3g) in methylene chloride
A solution of (2.3 liters) was added dropwise. After completion of dropping, the mixture was reacted at room temperature for 4 hours and cooled with sodium bisulfite (471
The reaction was terminated by dropwise addition of a solution of g) in water (1.8 liter). After completion of the reaction, the mixture was separated, and the organic layer was washed twice with 5% sodium carbonate solution (3 liters and 1.5 liters), further washed with saturated saline (3 liters), dried over anhydrous magnesium sulfate, and then depressurized. It was concentrated under. The residue was subjected to silica gel column chromatography (eluent: acetonitrile) and recrystallized from ethanol to give 2- (6-bromo-7-chloro-2,2-dimethyl-4- (2-pyridyl)).
-2H-1,3-benzoxazin-4-yl) pyridine 1-oxide (64.9 g) was obtained. m. p. : 185 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 1.69 (1H, s), 7.01
(1H, s), 7.16 (1H, s), 7.32-7.48 (3H, m),
8.25-8.31 (1H, m) MS (EI): 370 (M + 4), 368 (M + 2), 366
(M) Elemental analysis (theoretical value) C: 49.01, H: 3.29, N: 7.62 (analysis value) C: 48.98, H: 3.28, N: 7.51

Reference Example 5 5-Bromo-4-chloro-2-hydroxyphenyl 2
-Preparation of pyridyl ketimine Ethanol (400 ml) in anhydrous calcium sulfate (43.
6 g) was added, and ammonia gas (15.2 g) was bubbled in under ice cooling. 5-Bromo-4-chloro-2-hydroxyphenyl 2-pyridyl ketone (20 g) and ethanol (20 ml) were added at the same temperature, and the mixture was further stirred at room temperature for 1.5 hours. After completion of the reaction, insoluble matter was filtered off, and the filtrate was concentrated to 5
-Bromo-4-chloro-2-hydroxyphenyl 2-
Pyridyl ketimine (17.8 g) was obtained. MS (EI): 314 (M + 4), 312 (M + 2),
310 (M) Elemental analysis (theoretical value) C: 46.26, H: 2.59, N:
8.99 (analytical value) C: 46.03, H: 2.62, N: 8.33

Reference Example 6 Preparation of Morpholine Hydrochloride Morpholine (38.4 g) was added to ethanol (70 ml), and the mixture was stirred under ice cooling. At the same temperature, 4.15N hydrogen chloride ethanol solution (193 ml) was added dropwise. The crystallized crystals were collected by filtration, washed with cold ethanol (100 ml), and heated to 50 ° C.
After drying under reduced pressure for 15 hours, morpholine hydrochloride (40.7
g) was obtained.

Example 1 6-Bromo-7-chloro-2,2-dimethyl-4- (2-
Preparation of Pyridyl) -2H-1,3-benzoxazine 5-Bromo-4-chloro-2-hydroxyphenyl 2-pyridyl ketone (15
0 g), ammonium iodide (347.8 g), anhydrous calcium sulfate (300 g), piperidine (204.3 g) and acetonitrile (3 liters) were added and the mixture was stirred at room temperature for 5 hours. Then add 2,2-dimethoxypropane (499.8g) and add 3
Heated to reflux for hours. After cooling, the insoluble matter was filtered off from the reaction solution, and the mother liquor was concentrated. Isopropyl ether (3
Liter) and a 0.1N aqueous sodium hydroxide solution (1.5 liter) were added for liquid separation. Add isopropyl ether layer to 0.
The extract was washed twice with a 1M aqueous sodium hydroxide solution (1.5 liters), further twice with water (1.5 liters), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethanol (350 ml) to give 6-bromo-7-chloro-2,2-dimethyl-4- (2-pyridyl) -2H-.
1.3-Benzoxazine (136.2 g) was obtained. Yield 80.7% m. p. : ^{100 to} 103 ° C. ¹ H-NMR (CDCl ₃ ) δppm: 1.67 (6H, s), 7.02
(1H, s), 7.37-7.45 (1H, m), 7.80-7.87
(2H, m), 8.07 (1H, s), 8.68-8.73 (1H, m) MS (EI): 354 (M + 4), 352 (M + 2), 350
(M)

Example 2 6-Bromo-7-chloro-2,2-dimethyl-4- (2-
Preparation of Pyridyl) -2H-1,3-benzoxazine 5-Bromo-4-chloro-2-hydroxyphenyl 2
-Pyridyl ketone (10 g, 32 mmol), ammonium iodide (23.2 g, 160 mmol), anhydrous calcium sulphate (20 g), piperidine (13.6 g, 160 mmol), acetonitrile (200 ml) were mixed and at room temperature 5 Stir for hours. Then 2,2-dimethoxypropane (33.
(3 g, 320 mmol) was added and the mixture was heated under reflux for 3 hours.
After allowing to cool, the insoluble matter was filtered off from the reaction solution, and the mother liquor was concentrated under reduced pressure. Isopropyl ether (200 ml) and 0.1 to the residue
An aqueous solution of N sodium hydroxide (100 ml) was added to separate the layers. The isopropyl ether layer was washed twice with a 0.1N aqueous sodium hydroxide solution (100 ml), further twice with water (100 ml), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol (25 ml) to give 6
-Bromo-7-chloro-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (8.64 g)
Got Yield 76.8%

Examples 3 to 16 Under the same conditions as in Example 2, 6-bromo-7-chloro when various investigations were carried out on the three reagents of secondary or tertiary amine, ammonium salt, carbonyl compound or its equivalent. -2,2-dimethyl-4- (2-pyridyl) -2H-1,
Tables 1 and 2 show the production examples of 3-benzoxazine.

[0075]

[Table 1]

[0076]

[Table 2]

Example 17 6-Bromo-7-chloro-2,2-dimethyl-4- (2-
Preparation of Pyridyl) -2H-1,3-benzoxazine 5-Bromo-4-chloro-2-in ethanol (200 ml)
Hydroxyphenyl 2-pyridyl ketone (10 g), anhydrous calcium sulfate (20 g), ammonium iodide (23.2)
g), piperidine (13.6 g) and acetone (37.2 g) were added, and the mixture was reacted at room temperature for 36 hours. After completion of the reaction, the insoluble matter was filtered off and the mother liquor was concentrated under reduced pressure. Isopropyl ether (200 ml) and 0.1N aqueous sodium hydroxide solution (10 ml) were added to the residue.
0 ml) was added and the layers were separated. Add isopropyl ether layer to 0.
Wash twice with 1N aqueous sodium hydroxide solution (100 ml),
The extract was washed twice with water (100 ml) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is ethanol (2
The crystals were recrystallized from 5 ml) to give 6-bromo-7-chloro-2,2-dimethyl-4- (2-pyridyl) -2H-1,3-benzoxazine (6.86 g). Yield 61.0%

Example 18 Spiro [6-bromo-7-chloro-4- (2-pyridyl)]
Preparation of -2H-1,3-benzoxazine-2,1'-cyclohexane] 5-Bromo-4-chloro-in acetonitrile (200 ml)
2-hydroxyphenyl 2-pyridyl ketone (10
g), anhydrous calcium sulfate (20 g), ammonium iodide
(23.2 g) and triethylamine (16.2 g) were added, and the mixture was stirred at room temperature for 4 hours. Then cyclohexanone (31.4g)
Was added and the mixture was heated to reflux for 3 hours. After cooling, the insoluble material was filtered off from the reaction solution, and the mother liquor was concentrated under reduced pressure. Isopropyl ether (200 ml) and 0.1N aqueous sodium hydroxide solution (100 ml) were added to the residue for partitioning. The isopropyl ether layer was washed 3 times with a 0.1N aqueous sodium hydroxide solution (100 ml), further washed with water (100 ml) 3 times, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethanol (25 ml) and spiro [6-bromo-7-chloro-4- (2-pyridyl) -2H-1,3-benzoxazine-2,1'-cyclohexane] (9.92 g). Got

Yield 79.2% ¹ H-NMR (CDCl ₃ , 90 MHz) δ ppm: 1.20-2.
50 (10H, br), 7.05 (1H, s), 7.25-7.50
(1H, m), 7.60-8.00 (2H, m), 8.16 (1H, s),
8.5-5.75 (1H, m) MS (EI): 394 (M + 4), 392 (M + 2), 390
(M) Elemental analysis (theoretical value) C: 55.20, H: 4.12, N:
7.15 (analytical value) C: 54.95, H: 4.00, N: 7.25

Example 19 Spiro [6-bromo-7-chloro-4- (2-pyridyl-
Preparation of 2H-1,3-benzoxazine-2,2′-adamantane] 5-Bromo-4-chloro-in acetonitrile (200 ml)
2-hydroxyphenyl 2-pyridyl ketone (10
g), anhydrous calcium sulfate (20 g), ammonium iodide
(23.2 g) and piperidine (13.6 g) were added, and the mixture was stirred at room temperature for 4 hours. Then, 2-adamantanone (14.4 g) was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, ethyl acetate (100 ml) was added to the reaction solution and heated to 50 ° C. to remove insoluble matter by filtration, and the mother liquor was concentrated under reduced pressure. Isopropyl ether (500 ml), 0.1N aqueous sodium hydroxide solution (3
(00 ml) was added and the layers were separated. The isopropyl ether layer was washed 3 times with a 0.1N aqueous sodium hydroxide solution (100 ml), further washed with water (200 ml) 3 times, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Ethanol residue
(30 ml), heated under heating at 80 ° C., allowed to cool and then filtered to obtain spiro [6-bromo-7-chloro-4- (2-pyridyl) -2].
H-1,3-benzoxazine-2,2'-adamantane]
(11.7 g) was obtained.

Yield 82.3% ¹ H-NMR (CDCl ₃ , 90 MHz) δ ppm: 1.40-2.
70 (14H, br), 7.10 (1H, s), 7.23-7.50
(1H, m), 7.66-8.10 (2H, m), 8.26 (1H, s),
8.56-8.76 (1H, m) MS (EI): 446 (M + 4), 444 (M + 2), 442
(M) Elemental analysis (theoretical value) C: 59.54, H: 4.54, N:
6.31 (analysis value) C: 59.57, H: 4.59, N: 6.37

Example 20 Preparation of 6-bromo-7-chloro-2- (3,4-dimethoxyphenyl) -4- (2-pyridyl) -2H-1,3-benzoxazine 5-acetonitrile (200 ml) Bromo-4-chloro-
2-hydroxyphenyl 2-pyridyl ketone (10
g), anhydrous calcium sulfate (20 g), ammonium iodide
(23.2 g) and piperidine (13.6 g) were added, and the mixture was stirred at room temperature for 3 hours and 30 minutes. Then, 3,4-dimethoxybenzaldehyde was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, the reaction solution was concentrated, methylene chloride (400 ml) was added to the residue, and the insoluble material was filtered off. The methylene chloride solution was washed with 0.1N aqueous sodium hydroxide solution (200 ml) three times, further with saturated saline solution (200 ml) three times and water (200 ml) three times, dried over anhydrous sodium sulfate, and then depressurized. The lower solvent was distilled off. The residue was washed with ethanol (300 ml) under heating at 80 ° C, allowed to cool and then filtered to obtain 6-bromo-7-chloro-.
2- (3,4-Dimethoxyphenyl) -4- (2-pyridyl) -2H-1,3-benzoxazine (12.9 g) was obtained.

Yield 87.9% ¹ H-NMR (CDCl ₃ , 90 MHz) δ ppm: 3.96 (3
H, s), 3.97 (3H, s), 6.60-7.10 (4H, m), 7.
16 (1H, s), 7.20-7.33 (2H, m), 7.76-7.
93 (1H, m), 7.93 (1H, s), 8.20-8.40 (1
H, m) MS (EI): 462 (M + 4), 460 (M + 2), 458
(M) Elemental analysis (theoretical value) C: 54.87, H: 3.51, N:
6.09 (analytical value) C: 54.95, H: 3.55, N: 6.16

Example 21 Spiro [6-bromo-7-chloro-4- (2-pyridyl)]
-2H-1,3-benzoxazine-2,4 '-(1'-methyl-piperidine)] in acetonitrile (200 ml) 5-bromo-4-chloro-2-hydroxyphenyl 2-pyridyl ketone (10
g), anhydrous calcium sulfate (20 g), ammonium iodide (23.2 g) and triethylamine (16.2 g) were added and the mixture was stirred at room temperature for 5 hours. After that, N-methyl-4-piperidone (36.2 g) was added, and the mixture was further stirred at room temperature for 38 hours. After completion of the reaction, the insoluble matter was filtered off, and the insoluble matter was washed with tetrahydrofuran (750 ml). Concentrate the filter wash,
The concentrated residue was partitioned between isopropyl ether (100 ml), tetrahydrofuran (100 ml) and 0.1N aqueous sodium hydroxide solution (100 ml). The organic layer was washed with 0.1N aqueous sodium hydroxide solution (100 ml) 7 times and water (100 m).
It was washed 5 times with l), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was recrystallized from ethanol (25 ml) to prepare spiro [6-bromo-7-chloro-4- (2-pyridyl) -2H-1,3-benzoxazine-2,4 '-(1'-methyl- Piperidine)] (9.05 g). Yield 69.6% ¹ H-NMR (CDCl ₃ , 90 MHz) δppm: 1.80-
2.90 (8H, m), 2.25-2.45 (3H, s),
6.93-7.16 (1H, s), 7.16-7.53 (1
H, m), 7.63-8.03 (2H, m), 8.06-8.
26 (1H, s), 8.43-8.80 (1H, m) MS (EI): 409 (M + 4), 407 (M + 2),
405 (M) Elemental analysis (theoretical value) C: 53.16, H: 4.21, N:
10.33 (analytical value) C: 53.41, H: 4.30, N: 10.6
7

Example 22 Preparation of spiro (4-phenyl-2H-1,3-benzoxazine-2,2'-adamantane) 2-hydroxybenzophenone (10 g) and anhydrous calcium sulfate (31.6 g) were added to acetonitrile (150 ml). ),
Ammonium iodide (36.5 g) and triethylamine (25.5 g) were added, and the mixture was stirred at room temperature for 44.5 hours. Thereafter, 2-adamantanone (22.7 g) and acetonitrile (50 ml) were added, and the mixture was heated under reflux for 7.5 hours. After cooling, the insoluble matter was filtered off from the reaction solution, and the insoluble matter was washed with tetrahydrofuran (500 ml). The filtrate was concentrated, and the concentrated residue was partitioned between isopropyl ether (100 ml), tetrahydrofuran (100 ml) and 0.1N aqueous sodium hydroxide solution. The organic layer was washed 7 times with a 0.1 N aqueous sodium hydroxide solution (100 ml), 15 times with a 1 N aqueous sodium hydroxide solution (50 ml), and 5 times with water (150 ml), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. did. After washing the concentrated residue with ethanol (50 ml) at 80 ° C with heating,
It was left to cool and collected. Repeat this purification procedure again
(4-phenyl-2H-1,3-benzoxazine-2,
2'-adamantane) (11.6 g) was obtained. Yield 69.9% ¹ H-NMR (CDCl ₃ , 90 MHz) δppm: 1.26
-2.63 (14H, m), 6.60-7.80 (9H, m) MS (EI): 329 (M) Elemental analysis (theoretical value) C: 83.85, H: 7.04, N :
4.25 (analytical value) C: 83.80, H: 6.91, N: 4.07

Example 23 Preparation of 6-bromo-7-chloro-2- (3,4-dimethoxyphenyl) -4- (2-pyridyl) -2H-1,3-benzoxazine Acetonitrile (50 ml) in anhydrous sulfuric acid Calcium (1
0.9 g) was added and the mixture was stirred at room temperature for 10 minutes. Then three,
4-dimethoxybenzaldehyde (7.98 g), 5-bromo-4-chloro-2-hydroxyphenyl 2-pyridylketimine (4.99 g), morpholine hydrochloride (9.
89 g) and acetonitrile (75 ml) were added and the mixture was heated under reflux for 4.5 hours. After completion of the reaction, the reaction solution was concentrated, methylene chloride (200 ml) was added to the residue, and the insoluble material was filtered off. The methylene chloride solution was washed 8 times with a 0.1N aqueous sodium hydroxide solution (100 ml) and 5 times with water (100 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrated residue was washed with ethanol (150 ml) under heating at 80 ° C., allowed to cool, and collected by filtration to give 6-bromo-7-chloro-2-
(3,4-dimethoxyphenyl) -4- (2-pyridyl)-
2H-1,3-benzoxazine (4.51 g) was obtained. Yield 61.3%

[0087]

According to the present invention, unlike the known method,
Safe without using ammonia gas or pressure vessel,
1,3-benzoxazine or a salt thereof can be easily produced in high yield, which is advantageous for industrial mass production. Further, by using the production method of the present invention, a novel compound having a substituent bonded to the 2,4-position of 1,3-benzoxazine, which has not been reported previously, at a carbon atom is obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 31/535 ABS ABU ACD (C07D 413/04 213: 00 265: 00)

Claims (8)

[Claims] 1. The formula: [In the formula, Represents an optionally substituted benzene ring, and R ¹ represents a group bonded by a carbon atom] and a compound represented by the formula: Wherein, R ² and R ³ represents a group bonded at each hydrogen atom or a carbon atom, R ² and R ³ may also have bonded to each other to form a ring] carbonyl compound represented by Or the equivalent thereof is reacted in the presence of a secondary or tertiary amine: embedded image A method for producing a compound represented by [each symbol in the formula has the same meaning as defined above]. 2. A compound of the formula: ## STR5 ## in the presence of a secondary or tertiary amine. [Wherein each symbol in the formula has the same meaning as in claim 1], a ketone compound is reacted with an ammonium salt, and then a compound represented by the formula: The production method according to claim 1, wherein a carbonyl compound represented by [each symbol in the formula has the same meaning as in claim 1] or an equivalent thereof is reacted. 3. The formula: [Wherein each symbol in the formula has the same meaning as in claim 1], and a compound of the formula: [Wherein each symbol in the formula has the same meaning as in claim 1] and the carbonyl compound or an equivalent thereof are reacted in the presence of a secondary amine, a tertiary amine or a salt thereof: [Chemical 9] A process for producing a compound represented by [each symbol in the formula has the same meaning as in claim 1]. 4. The method according to claim 3, wherein an enamine of the carbonyl compound and a secondary amine is used as an equivalent of the carbonyl compound. 5. The production method according to claim 1, wherein the group bonded by a carbon atom is an optionally substituted heterocyclic group. 6. The production method according to claim 5, wherein the heterocyclic group is a pyridyl group. 7. The method according to claim 1, wherein R ² and R ³ are each a hydrogen atom or an optionally substituted hydrocarbon group. 8. embedded image Is a benzene ring substituted with halogen, R ¹ is an optionally substituted pyridyl group, and R ² and R ³ are C _1-4 alkyl.