JPH09208543A - Production of isocyanate derivative and its related compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce an isocyanate derivative and its related compound, a part of which is a new one, in good yield by reacting a halobenzene derivative with a metal cyanation reagent under the existence of a specific catalyst and thereby substituting a halogen atom bonded directly to a benzene ring for isocyanate group. SOLUTION: This isocyanate derivative is represented by formula II (a group containing R<2> ' of the right side is represented by formula III, formula IV, etc.), and its related compound is obtained by reacting a phenyl halide compound of formula I R<1> and R<2> are each H, an alkyl, an alkenyl, an alkoxy, a group of the formula (CH2 )n ON [(n) is 4], a group of the formula (CH2 )m NR<3> R<4> [R<3> and R<4> are each H or an alkyl; (m) is 0 or 1], a group of the formula COOR<5> (R<5> is H, an alkyl or an alkali metal) ; X is a halogen} with a metal cyanate of the formula MOCN (M is an alkali metal) under the existence of a copper salt as a catalyst. The industrial production cost is reduced significantly because the copper salt used as the catalyst is available easily and in a low cost. Some compounds represented by formula II, e.g. a compound of formula V, are new ones.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing an isocyanate compound and its related compounds. More specifically, the general formula (II)

Embedded image In the formula, X represents a halogen atom, and other symbols have the same meanings as described below. ) And a general formula MOCN [wherein M represents an alkali metal]. ] It reacts in the presence of a copper salt with a metal cyanate represented by the general formula (Ia)

[0002]

Embedded image (Wherein all symbols have the same meanings as described below), and an isocyanate compound represented by the general formula (I
A compound of the general formula (Ib) having a specific substituent R ^{2 at} the ortho position of the halogen atom X of I)

[0003]

Embedded image (Wherein all symbols have the same meanings as described below), a compound of the general formula (Ic)

[0004]

Embedded image (Wherein all symbols have the same meanings as described below), a compound represented by the general formula (Id)

[0005]

[Chemical 21] (Wherein all symbols have the same meanings as described below), and a compound of the general formula (Ie)

[0006]

Embedded image (Wherein all symbols have the same meanings as described below). Further, the present invention is a general formula (II) in the same reaction system from a compound having a COOR ^5a group (wherein R ^5a has the same meaning as described below) at the ortho position of the halogen atom X. Formula R ⁶ OH [R ⁶ has the same meaning as described below. ] In the presence of an alcohol represented by the general formula (III)

[0007]

Embedded image (Wherein all symbols have the same meanings as described below).

[0008]

BACKGROUND OF THE INVENTION Isocyanate compounds react with ammonia or amines to give urea derivatives, alcohols,
Reacts with phenols to produce carbamate compounds and urethanes. It is also known that primary amines can be obtained by hydrolysis with water. Therefore, isocyanate compounds are very useful compounds for the production of urea, carbamates, urethanes and polymers, pharmaceutical industry, chemical industry, resin industry, coating industry and many industrial fields, pharmaceutical intermediates, It is a compound that is regarded as important as a raw material for polyurethane materials, polyurea materials, polyisocyanurate materials, and the like.

As a method of producing an isocyanate compound, a method of reacting alkyl iodide with silver cyanate, a method of dehydrochlorinating alkyl-NHCOCl obtained by reacting phosgene with an alkylamine, and an acid azide have long been known. There is known a method for obtaining nitrogen by removing the nitrogen by thermal decomposition in an inert solvent. Also, a copper salt reagent,
In recent years, many patent applications have been filed that attempt to introduce an isocyanate group using a nickel complex as a catalyst.

[0010]

2. Description of the Related Art Among the many methods for producing an isocyanate compound, the following methods are known, particularly as a method using a copper salt. For example, (A) the following reaction formula (A-1)

Embedded image (In the reaction formula, X ^A represents a chlorine atom, an alkyl group, a cycloalkyl group, an alkenyl group, a phenyl group, a chloromethylphenyl group or a chloromethyl group, nA represents an integer of 0 or 1 to 3, and nA is 2 or as the case of 3 represented by X ^a good .R ^a be different, even in the same represents an aromatic hydrocarbon residue or olefin residue.), chloromethyl group-containing compound and a metal cyanate 0.1 to 20% by weight of the chloromethyl group-containing compound
Cuprous salt equivalent to and nitrogen to 1 gram mol of the copper salt
In a high boiling point solvent having a dielectric constant (ε) of 20 or less in the presence of a catalyst consisting of a combination of 0.05 to 1.25 gram atom of a tertiary amine compound or a quaternary ammonium salt, 150
Disclosed is a method for producing an isocyanate compound, which comprises reacting at a reaction temperature of ˜250 ° C. for 0.1 to 10 hours (see JP-A-52-46026; the above description describes only necessary portions). Excerpt.).

In the examples of the above specification, the following reaction formula (A-2)

Embedded image As described by, the reaction of starting benzyl chloride with sodium cyanate using cuprous chloride as a catalyst to obtain benzyl isocyanate is described.

Further, (B) the following reaction formula (B-1)

Embedded image (In the reaction formula, X ^B and Y ^B each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, an alkyl group or a haloalkyl group, and R ^B and R ′ ^B are each independently a hydrogen atom, a halogen atom or an alkyl group. Represents a group, a haloalkyl group, a nitro group or a cyano group, T ^B represents a halogen atom, a haloalkyl group or a Z ^B R ″ ^B group (wherein Z ^B represents an oxygen atom or a sulfur atom, R ″ ^B represents a hydrogen atom, An alkyl group, a haloalkyl group, a haloalkylene group, an optionally substituted pyridyl group, or an optionally substituted phenyl group.), A benzoyl chloride derivative and a metal cyanate are mixed in an inert solvent. , A urea obtained by reacting a cuprous salt as a catalyst to form a benzoyl isocyanate derivative and further acting an aniline derivative A method for producing a derivative has been disclosed (see US Pat. No. 4529819; the above description extracts only necessary portions).

In the examples of the above specification, the following reaction formula (B-2)

Embedded image The starting material 2-chloro-
A reaction for obtaining a urea derivative by reacting benzoyl chloride with sodium cyanate using copper chloride as a catalyst and allowing 4-chloroaniline to act on the resulting benzoyl isocyanate compound is described.

The following method is known as a method for producing an isocyanate compound using a nickel complex. For example, (C) the following reaction formula (C-1)

Embedded image (In the reaction formula, R ^C is an acyclic or cyclic vinyl group optionally substituted by at least one alkyl group or aryl group, at least one alkyl group, vinyl group, aryl group, halogen atom or alkoxy group. A monocyclic or condensed ring aromatic ring group which may be substituted by, a halogenated heterocyclic group, an alkyl group which may be substituted by at least one alkyl group or aryl group, straight chain, branched chain or ring Represents an aliphatic group of the formula, or a benzyl group which may be substituted by at least one alkyl group or aryl group, X ^C represents a halogen atom, and Z ^C represents an alkoxy group or an amino group). as such, the compound and the metal cyanate represented by R ^C -X ^C, dipolar aprotic solvents, saturated hydrocarbons In an organic solvent composed of at least one solvent selected from a system solvent and an aromatic hydrocarbon solvent, in the presence of a catalyst composed of a nickel complex with an organic ligand of phosphorus, arsenic or a cyclic hydrocarbon or a mixture thereof. The isocyanate compound obtained by

Embedded image A general formula obtained by acting Z ^C H (wherein Z ^C has the same meaning as described above).

Embedded image A method for producing a compound represented by R ^C NHCOZ ^C (wherein all symbols have the same meanings as described above) is disclosed (see US Pat. No. 4,749,806; the above description is given). Only the necessary parts are extracted.).

In the examples of the above specification, the following reaction formula (C-2)

Embedded image As described in (1), a reaction of obtaining a carbamate derivative by reacting sodium cyanate with bromobenzene as a starting material using a nickel complex as a catalyst and reacting the resulting isocyanate compound with ethanol is described.

[0016]

COMPARISON WITH PRIOR ART The present invention is a process for producing a novel isocyanate and its related compounds, which is characterized in that a halogen atom directly bonded to a benzene ring is substituted with an isocyanate group. In the compound represented by the general formula (X ^A ) _nA ^RA CH ₂ Cl, which is the starting material of the above (A), R ^A represents an aromatic hydrocarbon residue or an olefin residue,
It cannot have a structure in which a chlorine atom is directly bonded to the benzene ring. The benzoyl chloride derivative, which is the starting material of (B), also has a chlorine atom bonded to the benzene ring via a carbonyl group, and cannot have a structure in which the chlorine atom to be substituted is directly bonded to the benzene ring.

On the other hand, in the compound represented by the general formula (II), which is the starting material of the present invention, it is essential that a halogen atom is directly bonded to the benzene ring. ) And (B). Further, the compound represented by the general formula R ^C -X ^C , which is the starting material of the above (C), can have a structure in which a substituted halogen atom is directly bonded to the benzene ring. However, in (C), the nickel complex is used as the catalyst, whereas in the present invention, a copper salt is used, and the present invention is different from (C) in this respect. Since the benzene ring has a resonance structure and is energetically stable, it is generally difficult to carry out the substitution reaction of the halogen atom directly bonded to the aromatic ring as in the starting material of the present invention. Are known.

The general formula (X ^A ) _nA which is the starting material for ( ^A )
Since the halogen atom to be substituted in the benzoyl chloride derivative which is the starting material of R ^A CH ₂ Cl and (B) is not directly bonded to the benzene ring, it is considered that the substitution reaction of the halogen atom proceeds easily. The present invention aims to substitute a halogen atom directly bonded to a benzene ring with an isocyanate group, and the method of the present invention cannot be easily conceived from the methods (A) and (B).

The reaction of (C) using a compound of the general formula R ^C -X ^C , which can have a structure in which a halogen atom is directly bonded to the benzene ring, has a low yield and is used as a catalyst. There is a problem that it is difficult to obtain a nickel complex easily or economically.

The inventors of the present invention continued their research for the purpose of improving the above problems. As a result, when the halobenzene derivative represented by the general formula (II) is reacted with a metal cyanate reagent in the presence of a copper salt, the desired isocyanate compound represented by the general formula (I) is obtained in a preferable yield. I found that Further, it was confirmed that the copper salt used as the catalyst is easily available at low cost, and thus the industrial production cost is significantly reduced as compared with the conventional method.

Further, in the method of the present invention, when a specific substituent is present at the ortho position of the starting halobenzene derivative, the introduced isocyanate group reacts with the specific substituent to give an intermediate compound of a drug. It was found that useful compounds represented by the general formulas (Ib), (Ic), (Id), (Ie) and (III) can be obtained, and the invention was completed based on these findings.

[0022]

DISCLOSURE OF THE INVENTION The present invention relates to a compound of the general formula (II)

Embedded image

[In the formula, a plurality of R ¹ and R ² are each independently (a) a hydrogen atom, (b) a C1-4 alkyl group,
(C) C2-6 alkenyl, (d) C1 -4 alkoxy _{group, (e) - (CH 2} ) m -OH _{group, (f) - (CH 2} ) m -
NR ³ R ⁴ group, (g) CONR ³ R ⁴ group, (h) COOR
⁵ groups, or (i) NO ₂ group (wherein R ³ and R ⁴ are
Each independently represents a hydrogen atom or a C1 -4 alkyl group,, R ⁵ represents a hydrogen atom, C1 -4 alkyl group or an alkali metal, m represents 0 or 1. ), N represents 4, and X represents a halogen atom. ] The phenyl halide compound represented by
OCN [In the formula, M represents an alkali metal. ] The metal cyanate represented by the formula [I] is characterized by reacting in the presence of a copper salt.

[0024]

Embedded image [Where,

Embedded image Is (i) in the general formula (II), R ² is the following (ii) to (v)
When representing groups other than those shown in

Embedded image And (ii) R ² is —CON in the general formula (II).
When representing an HR ³ group

Embedded image And (iii) R ² in the general formula (II) is —CO
When representing an OR ^5a group (in which R ^5a represents a hydrogen atom or an alkali metal)

Embedded image And (iv) R ² in the general formula (II) is-(C
H ₂ ) When an _m- OH group (in the group, m has the same meaning as described above)

Embedded image (V) In the general formula (II), R ² is — (CH
₂ ) When representing an _m- NHR ³ group (wherein all symbols have the same meanings as described above)

Embedded image And the other symbols have the same meanings as described above. ]
Relates to a method for producing an isocyanate derivative or a related compound thereof.

Specifically, the following general formulas (II), (IIb),
General formulas (Ia), (Ib), (Ic), (Id), whose starting materials are compounds represented by (IIc), (IId) and (IIe),
It relates to a method for producing a compound represented by (Ie).

[0026]

Embedded image (The symbols in the formulas have the same meanings as described above.)

[0027]

Embedded image (The symbols in the formulas have the same meanings as described above.)

[0028]

Embedded image (The symbols in the formulas have the same meanings as described above.)

[0029]

Embedded image (The symbols in the formulas have the same meanings as described above.)

[0030]

Embedded image (The symbols in the formulas have the same meanings as described above.)

Further, in the present invention, in the general formula (II), R ² represents a —COOR ^5a group (wherein R ^5a has the same meaning as described above).

Embedded image [In the formula, all symbols have the same meanings as described in claim 1. ] And the general formula MOCN [wherein M represents the same meaning as described above]. And metal cyanates represented by, in the general formula R ⁶ OH [wherein, R ⁶ represents a C1~8 alkyl group. ] The alcohol represented by the general formula (III) characterized by reacting in the presence of a copper salt

Embedded image [In the formula, all symbols have the same meanings as described above. ] The manufacturing method of the anthranilic acid derivative shown by these.

In the present invention, all isomers are included unless otherwise indicated. For example, alkyl, alkoxy and alkenyl groups include straight and branched ones and the double bonds in the alkenyl group include those which are E, Z and mixtures of EZ. Also included are isomers formed by the presence of asymmetric carbon atoms, such as the presence of branched alkyl, alkoxy and alkenyl groups.

In the general formulas (I) and (II), R ¹ , R ² ,
The C1~4 alkyl group represented by R ^3, R ⁴ and R ^5, means a methyl group, an ethyl group, a propyl group, butyl group and isomers thereof. In the general formulas (I) and (II), the C2-6 alkenyl group represented by R ¹ and R ² means an ethenyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group and isomers thereof. In the general formulas (I) and (II), R ¹ and R
^The C1-4 alkoxy group represented by ² means a methoxy group, an ethoxy group, a propoxy group, a butoxy group and isomers thereof.

In the general formula (III), the C1-8 alkyl group represented by R ⁶ means methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group and their isomers. Means the body.

In the general formula (II), examples of the halogen atom represented by X include a bromine atom, a chlorine atom, an iodine atom and a fluorine atom, and particularly preferable ones are a bromine atom, a chlorine atom and an iodine atom. To be In the general formula (II), as the alkali metal represented by R ⁵ and R ^5a , lithium, sodium, potassium,
Examples include cesium.

Examples of the alcohol represented by the general formula R ⁶ OH include methanol, ethanol, propanol, isopropanol, butanol, pentanol and the like, and particularly preferable ones are methanol and ethanol.

Examples of the metal cyanate used in the reaction of the present invention include sodium cyanate, potassium cyanate, lithium cyanate, cesium cyanate and the like, and particularly preferable ones are sodium cyanate and potassium cyanate. . As the copper salt used in the reaction of the present invention, cuprous bromide, cupric bromide, cuprous chloride, cupric chloride, cuprous iodide, cupric iodide, cuprous oxide , Cupric oxide, cuprous cyanide, cuprous thiocyanate, cuprous acetate, copper sulfate and the like, and as particularly preferable ones,
Examples include cuprous bromide and cuprous chloride. Further, not only these, but also a mixture of two or more kinds may be used. Examples of the solvent used in the reaction of the present invention include organic solvents having no active hydrogen atom and having good thermal stability. Representative examples include dimethyl sulfoxide, dimethylformamide, diglyme, toluene, benzene, dimethylimidazolidinone, methylpyrrolidone, dimethylacetamide, pyridine, and the like, and particularly preferable solvents include dimethylsulfoxide, dimethylformamide, and pyridine.

The reaction temperature of the reaction of the present invention is from 50 ° C to
180 degreeC is preferable and 100 degreeC-130 degreeC is especially preferable. The reaction time of the reaction of the present invention is 1 to 50 hours, particularly preferably 5 to 25 hours.

Additives may optionally be added to the reaction of the present invention. Pyridine etc. are mentioned as a preferable additive. The reaction time may be shortened by the addition of pyridine. It is known that an isocyanate compound reacts with an amine compound to form a urea derivative, reacts with an alcohol to form a carbamate compound, and reacts with water to produce a primary amine. For,
The following reaction process formula 1

[0040]

Embedded image

(In the formula, R ⁷ represents a hydrocarbon residue,
Other symbols have the same meanings as described above. ),
When an isocyanate compound represented by the general formula (Ia) is reacted with water, an aniline derivative is obtained, and an alcohol (R
^7- OH) gives a carbamate derivative, and an amide derivative (R ⁷ -CONHR ³ ) or an amine derivative (R ⁷ -NHR ³ ) gives a urea derivative. Further, at the ortho position of the isocyanate group of the compound represented by the general formula (Ia), a CONHR ³ group, a COOR ^5a group,
(CH _{2) m} -OH group or - (CH _{2) m} -NHR ³ groups (. In groups, all symbols have the same meanings as above) The presence of a substituent such as, occur intramolecular cyclization reaction,
In the case of the CONHR ³ group, the compound represented by the above general formula (Ib) is obtained, in the case of the COOR ^5a group, the compound represented by the above general formula (Ic) is obtained, and-(CH ₂ ) _m -OH
In the case of a group, a compound represented by the above general formula (Id) is obtained, and in the case of a — (CH ₂ ) _m —NHR ³ group, the above general formula (I
The compound shown in e) is obtained.

All the starting materials and reagents used in the reactions in the present invention are known per se or can be easily prepared by known methods. For example, 2-bromo-5-methoxybenzamide represented by the general formula (II) is obtained by reacting commercially available 2-bromo-5-methoxybenzoic acid with thionyl chloride and aqueous ammonia to perform amidation. ,Obtainable.

In each reaction in the present specification, the reaction product is subjected to a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, or column chromatography or washing, re-purification. It can be purified by a method such as crystallization.

[0044]

EXAMPLES The present invention will be described in detail below with reference examples and examples, but the present invention is not limited to these examples.
The solvent in parentheses shown at the separation point by chromatography indicates the elution solvent or developing solvent used,
Percentages represent volume ratios.

Reference Example 1 2-Bromo-5-methoxybenzamide

Embedded image

2-Bromo-5-methoxybenzoic acid (10
Dimethylformamide (1.7 ml) was added to a solution of 0 g, a commercial product) in ethyl acetate (210 ml). Next, thionyl chloride (45 ml) was added dropwise at room temperature, and then the mixture was stirred at 55 ° C. for 4 hours. Toluene (150 ml) was added to the reaction solution,
Concentrated. Furthermore, the operation of adding toluene (150 ml) and concentrating was performed twice. Ethyl acetate (83
ml) was added. The ethyl acetate solution was cooled 28
% Ammonia water (333 ml) was added dropwise. 6N-hydrochloric acid was added to the mixed solution to neutralize it. The precipitate was filtered, washed with water, and dried under reduced pressure. The organic layer of the filtrate was separated, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The precipitate and the residue obtained above were combined and mixed solution (ethanol: water = 2:
(3,380 ml), and the obtained crystal product was dried under reduced pressure to give the title compound (90.2
g) was obtained with a yield of 91%.

TLC: Rf 0.72 (ethyl acetate); NMR (CD ₃ OD): δ 7.48 (1H, d, J = 14.0Hz), 7.02 (1H, d, J)
= 4.0Hz), 6.88 (1H, dd, J = 4.0,14.0Hz), 3.81 (3H, s).

Reference Example 2 N-allyl-2-bromo-5-methoxybenzamide

Embedded image

2-Bromo-5-methoxybenzoic acid (5.0
g, a commercial product) was dissolved in ethyl acetate (20 ml), and thionyl chloride (1.89 ml) was added dropwise. Dimethylformamide (0.5 ml) was slowly added to the reaction mixture solution under ice cooling, and the mixture was stirred at 30 ° C. for 1 hr. The solvent was evaporated, and dimethoxyethane (25 ml) was added to the obtained residue. Allylamine (1.78 ml) was dissolved in dimethoxyethane (50 ml) in another reaction vessel, and the allylamine solution prepared as described above was slowly added under ice cooling. The mixture was stirred at 0 ° C for 2 hours, and then the solvent was distilled off. The residue was washed with ethyl acetate (8
0 ml) and dissolved twice with 1N-hydrochloric acid (50 ml).
N-sodium hydroxide aqueous solution (50 ml) was washed once with water (50 ml) and then washed successively. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7) to give the title compound (4.7 g) having the following physical data as a white solid in a yield of 81%.

TLC: Rf 0.2 (ethyl acetate: n-hexane = 3: 7); MS (EI): m / z 271 (M ⁺ ), 269 (M ⁺⁺ 2), 215, 213, 190,
187, 172, 170, 135; NMR (CDCl ₃ ): δ 7.45 (1H, d, J = 9Hz), 7.10 (1H, d, J = 3H
z), 6.82 (1H, dd, J = 3,9Hz), 6.15 (1H, brs), 6.05-5.85 (1
H, m), 5.35 (1H, dd, J = 1,17Hz), 5.20 (1H, dd, J = 1,10Hz),
4.10 (2H, m), 3.90 (3H, s).

Example 1 Synthesis of 6-methoxy-2,4 (1H, 3H) -quinazolinedione

Embedded image

Cuprous bromide (9.85 g, purity 95%), 2-
A solution of bromo-5-methoxybenzamide (110 g) and potassium cyanate (5.29 g) in dimethylacetamide (43.5 ml) at 110 ° C. under an argon atmosphere at 2 ° C.
Stir for 8 hours. After cooling the reaction solution to room temperature, 1N under ice cooling.
-Add hydrochloric acid (150 ml), stir for 30 minutes, 30%
Hydrogen peroxide solution (7.5 ml) was added, stirred for 15 minutes, and filtered. 2N-hydrochloric acid (30 ml) was added to the residue, stirred for 20 minutes, and filtered. The residue was washed with water and dried. The residue was purified by silica gel column chromatography (chloroform: methanol = 17: 3) to obtain the compound of the present invention (5.85 g) having the following physical properties at a yield of 70%.

TLC: Rf 0.56 (chloroform: methanol = 9: 1); NMR (DMSO-d ₆ ): δ 11.24 (1H, s), 11.00 (1H, s), 7.36
-7.27 (2H, m), 7.12 (1H, d, J = 9Hz), 3.80 (3H, s).

Examples 1 (1) to 1 (14) 2-bromo-5-methoxybenzamide to 6-methoxy-2,4 (1H, 3 ) under various conditions shown in Table 1 below.
H) -quinazolinedione Examples 1 (1) to 1 (1
The reaction of 4) was performed. The reaction operation was performed in the same manner as in Example 1.

[0055]

[Table 1]

In Table 1, the copper reagent (eq) is the starting material 2
Represents the equivalent of the copper reagent to bromo-5-methoxybenzamide, KOCN (eq) represents the equivalent of potassium cyanate to the starting material 2-bromo-5-methoxybenzamide, and the additive (eq) represents the starting Raw material 2
Represents the equivalent of additive to bromo-5-methoxybenzamide, DMSO represents dimethylsulfoxide, digram represents digram, DMA represents dimethylacetamide, DMF represents dimethylformamide, DMI represents dimethylimidazolidinone. , HPLC area% at 240 nm is 6-methoxy-2,4 (1H, 3H) of the reaction solution after heating under reflux.
-High performance liquid chromatography of quinazolinedione (HP
LC) Area% value. HPLC analysis was performed under the following conditions. Column: YMC-ODS-AM-302 (4.6 mm φ X 150 mm); Elution solvent: 20 mM NH ₄ H ₂ PO ₄ / CH ₃ CN = 85
/ 15; Flow rate: 1.0 mL / min; Detection: 240 nm; Temperature: 25 ° C.

Example 1 (15) Separate synthesis of 6-methoxy-2,4 (1H, 3H) -quinazolinedione 2-bromo-5-methoxybenzamide (2.0 g), cuprous bromide (250 mg, 95%) ) And potassium cyanate (1.06 g) were added with pyridine (8.7 ml) under an argon atmosphere, and the mixture was heated under reflux at 110 to 120 ° C. for about 5 hours. The reaction mixture solution was cooled to room temperature, water (20 ml) and 6N-hydrochloric acid (20 ml) were added under ice cooling, and the mixture was stirred for 20 minutes. The solid was collected by filtration and washed with water (10 ml). 1N-sodium hydroxide aqueous solution (2
5 ml) was added and dissolved by heating at 50 ° C. The insoluble material was removed by filtration and washed with 1N-aqueous sodium hydroxide solution (5 ml). Under cooling with ice, 6N-hydrochloric acid (7 ml) was added to the filtrate, and 1
Stir for 5 minutes. After confirming that the pH of the reaction solution was acidic, the produced solid was collected by filtration. Solid 3 with water (5 ml)
After washing twice, it is dried overnight to yield the compound of the present invention (1.48 g)
Obtained at 88.7%.

Examples 1 (16) to 1 (19) Separate Synthesis of 6-Methoxy-2,4 (1H, 3H) -quinazolinedione 2-Bromo-5-methoxy under various conditions shown in Table 2 below. 6-Methoxy- (1H, 3H) -from benzamide
Example 1 (16) to obtain quinazoline-2,4-dione
Reaction 1 (19) was performed. The reaction operation was performed by the method shown below. Dioxane (4.5 ml) was added to a mixture of 2-bromo-5-methoxybenzamide (1.0 g), cuprous bromide (131 mg, purity 95%) and potassium cyanate (529 mg) under an argon atmosphere. Various additives are added to the reaction mixture solution at 110 to 120 ° C. for about 5 minutes.
Reflux with heating for hours.

[0059]

[Table 2] In Table 2, DMAP represents 4-dimethylaminopyridine, and other symbols have the same meanings as described above.

Example 1 (20) Separate synthesis of 6-methoxy-2,4 (1H, 3H) -quinazolinedione A mixture of 2-bromo-5-methoxybenzamide (5.0 g) and potassium cyanate (2.64 g) was added. Pyridine (21.7 ml) was added under an argon atmosphere, and the freeze degassing operation was repeated 3 times. Cuprous bromide (66 mg, purity 95%) was added to the reaction mixture solution, and freeze deaeration operation was further performed twice,
The mixture was heated to reflux at 10 to 120 ° C for about 20 hours. The HPLC analysis result of the reaction solution after heating under reflux was 80.7% (HPLC
ea% at 240 nm (meaning the same as above)).

Example 2 Synthesis of 5-methoxy-2-aminobenzoic acid ethyl ester

Embedded image

A solution of 2-bromo-5-methoxybenzoic acid / cesium salt (1.09 g), potassium cyanate (0.73 g) and cuprous bromide (1.3 g) in ethanol (10 ml) was added to 1.
Stir for 5 hours. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated. Ethyl acetate (10 ml) was added to the residue, which was filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 6: 4), and the compound of the present invention (289 mg) having the following physical data.
Was obtained in a yield of 49%.

TLC: Rf 0.75 (ethyl acetate); NMR (CDCl ₃ ): δ 7.38 (1H, d, J = 3.0Hz), 6.95 (1H, dd, J)
= 7.5,3.0Hz), 6.64 (1H, d, J = 7.5Hz), 4.34 (2H, q, J = 7.5H
z), 3.78 (3H, s), 1.39 (3H, t, J = 7.5Hz).

Example 3 3-allyl-6-methoxy-1H-quinazoline-2,4
-Dione synthesis

Embedded image Compound (1.5 g) produced in Reference Example 2, cuprous bromide (1
68 mg, purity 95% and potassium cyanate (67
6 mg) was suspended in pyridine (10 ml) and heated under reflux for 20 hours. After cooling to room temperature, the solvent was evaporated, 2N-hydrochloric acid (15 ml) was added to the residue, and ethyl acetate (20 m
Extracted twice in l). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue is mixed solvent (ethyl acetate: n
-Hexane = 1: 1, 10 ml) was used for recrystallization to obtain the compound of the present invention (502 mg) having the following physical properties as a white solid in a yield of 39%.

TLC: Rf 0.35 (ethyl acetate: n-hexane = 3: 7); MS (EI): m / z 232 (M ⁺ ), 217, 176, 163, 149, 134,
120, 106; NMR (DMSO-d ₆ ): δ 11.35 (1H, brs), 7.40-7.20 (2H, m),
7.15 (1H, d, J = 8Hz), 6.00-5.80 (1H, m), 5.20-5.00 (2H,
m), 4.60-4.40 (2H, m), 3.85 (3H, s).

Example 4 Synthesis of 2,4 (1H, 3H) -quinazolinedione

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2-Bromo-benzamide (1.0 g, commercial product), cuprous bromide (151 mg, purity 95%) and potassium cyanate (608 mg) were suspended in pyridine (5 ml) and heated for 2.5 hours. Refluxed. After cooling to room temperature,
Water (10 ml) and 6N-hydrochloric acid (12 ml) were added under ice cooling, and the mixture was stirred for 10 minutes. The produced solid was collected by filtration and washed with water (5 ml). The obtained solid was heated and dissolved with a 2N-sodium hydroxide aqueous solution (20 ml). The insoluble matter was filtered off while hot, and the filtrate was cooled to 0 ° C. 6N- in the filtrate
Hydrochloric acid (9 ml) was added, and the mixture was stirred at 0 ° C for 10 minutes. The produced solid was collected by filtration and dried to obtain the compound of the present invention (520 mg) having the following physical properties as a white solid in a yield of 64%.

TLC: Rf 0.64 (chloroform: methanol = 9: 1); MS (EI): m / z 62 (M ⁺ ), 92; NMR (DMSO-d ₆ ): δ 11.30 (1H, brs), 11.15 (1H, brs),
7.90 (1Hd, J = 8Hz), 7.65 (1H, t, J = 8Hz), 7.20 (2H, m).

Example 5 1,4-Dihydro-2H-3,1-benzoxazine-
2-one synthesis

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2-bromobenzyl alcohol (2.0
g, commercial product), cuprous bromide (323 mg, purity 95%)
And potassium cyanate (1.3 g) with pyridine (11
ml) and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the solvent was distilled off, and the residue was 6N-hydrochloric acid (100 ml).
And ethyl acetate (100 ml) were added and extraction operation was performed. The organic layer was washed with 1N-hydrochloric acid (100 ml) and then with a saturated aqueous sodium hydrogen carbonate solution (100 ml). The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: n-hexane = 3: 7) to obtain the compound of the present invention (170 mg) having the following physical properties as a white solid in a yield of 11%.

TLC: Rf 0.2 (ethyl acetate: n-hexane = 3: 7); MS (EI): m / z 149 (M ⁺ ), 105, 78; NMR (CDCl ₃ ): δ 8.90 (1H, brs). ), 7.25 (1H, m), 7.15-
7.00 (2H, m), 6.90 (1H, d, J = 8Hz), 5.35 (2H, s).

Example 6 6-Methoxy-4H-3,1-benzoxazine-2,
Synthesis of 4 (1H) -dione

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2-Bromo-5-methoxybenzoic acid (1.15
5 g), cuprous bromide (150 mg, purity 95%) and potassium cyanate (610 mg) in pyridine (5 ml)
And was heated to reflux for 25 minutes. After cooling to room temperature,
The reaction mixed solution was poured into a mixed solution of 2N-hydrochloric acid (30 ml) and ethyl acetate (30 ml) to separate an organic layer and an aqueous layer. The aqueous layer was extracted with ethyl acetate (30 ml). The organic layers were combined, water (20 ml) and saturated saline (20 m).
It wash | cleaned one by one by 1). The organic layer was dried over anhydrous magnesium sulfate and then concentrated to obtain the compound of the present invention (873 mg) having the following physical properties at a yield of 91%.

TLC: Rf 0.65 (ethyl acetate); MS (EI): m / z 193 (M ⁺ ), 149, 134, 121, 106; NMR (CD ₃ OD): δ 7.45 (1H, d, J = 3Hz), 7.40 (1H, dd, J =
3,9Hz), 7.10 (1H, d, J = 9Hz), 3.85 (3H, s).

Claims (5)

[Claims] 1. A compound of the general formula (II) [In the formula, a plurality of R ¹ and R ² are each independently (a) a hydrogen atom, (b) a C1-4 alkyl group, (c) C2.
To 6 alkenyl groups, (d) C1 to 4 alkoxy groups, (e)
- (CH _{2) m} -OH _{group, (f) - (CH 2} ) m -NR 3 R 4
Group, (g) CONR ³ R ⁴ group, (h) COOR ⁵ group, or (i) NO ₂ group, (wherein R ³ and R ⁴ are each independently a hydrogen atom or a C1-4 alkyl group) And R
⁵ represents a hydrogen atom, a C1-4 alkyl group or an alkali metal, and m represents 0 or 1. ), N represents 4, and X represents a halogen atom. ] And a phenyl halide compound represented by the general formula MOCN [in the formula, M
Represents an alkali metal. ] The metal cyanate represented by the formula [I] is characterized by reacting in the presence of a copper salt. [Wherein (I) when R ² in general formula (II) represents a group other than the groups represented by the following (ii) to (v): (Ii) When R ² represents a —CONHR ³ group in the general formula (II), (Iii) When R ² represents a —COOR ^5a group (in the group, R ^5a represents a hydrogen atom or an alkali metal) in the general formula (II): And (iv) R ² in the general formula (II) is — (CH ₂ ) _m —O
When representing an H group (wherein m represents the same meaning as described above): And (v) R ² in the general formula (II) is — (CH ₂ ) _m —NH
When R ³ group is represented (in the group, all symbols have the same meanings as described above) And the other symbols have the same meanings as described above. ]
A method for producing an isocyanate derivative or a related compound thereof. 2. The general formula (II) according to claim 1, wherein R ² represents a —CONHR ³ group. (Wherein all symbols have the same meanings as in claim 1) and the general formula MOCN [wherein M represents the same meaning as in claim 1]. ] The metal cyanate represented by the formula [Ib] is characterized by reacting in the presence of a copper salt. (In the formula, all symbols have the same meanings as in claim 1.) A method for producing a quinazolinedione derivative. 3. A general formula (II) according to claim 1, wherein R ² represents a —COOR ^5a group (wherein all symbols have the same meanings as in claim 1).
c) [Chemical formula 11] (Wherein all symbols have the same meanings as in claim 1) and the general formula MOCN [wherein M represents the same meaning as in claim 1]. ] The metal cyanate represented by the formula [Ic] is characterized by reacting in the presence of a copper salt. (In the formula, all symbols have the same meanings as in claim 1.) A method for producing a quinazolinedione derivative. 4. In the general formula (II) according to claim 1, R ² is a — (CH ₂ ) _m —OH group (wherein m is
It has the same meaning as described. Is represented by the general formula (IId): (Wherein all symbols have the same meanings as in claim 1) and the general formula MOCN [wherein M represents the same meaning as in claim 1]. ] It reacts in the presence of a copper salt with a metal cyanate represented by the general formula (Id) (In the formula, all symbols have the same meanings as in claim 1.) A method for producing a quinazolinedione derivative. 5. A general formula (IIc) in which R ² represents a —COOR ^5a group (wherein R ^5a has the same meaning as in claim 1) in the general formula (II) according to claim 1. [Chemical 15] [In the formula, all symbols have the same meanings as described in claim 1. ] And a general formula MOCN [wherein M represents the same meaning as described in claim 1]. ] And a metal cyanate represented by the general formula R ⁶ OH
[In the formula, R ⁶ represents a C1-8 alkyl group. ] The alcohol represented by the general formula (III) is characterized by reacting in the presence of a copper salt. [In the formula, all symbols have the same meanings as described above. ] The manufacturing method of the anthranilic acid derivative shown by these.