JPH1129558A - Production of 1-substituted tetrahydroquinazolines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound in a high yield industrially and advantageotusly, by reacting specific two kinds of compounds, reacting the reaction product with a prescribed a chloroalkanoic acid ester in the presence of an alkali metal iodide and desilylating the reaction product. SOLUTION: (A) A tetrahydroquinazoline of formula I [R1 and R2 are each H a halogen, azide, a (halogen-substituted) alkyl, an acyloxy or the like; R3 is H, a halogen, azide, a (halogen-substituted) alkyl or the like] is reacted with (B) about 0.5-10 mols based on the component A of hexamethyldisilazane as a silylating agent and the reaction product is reacted with (C) about 1-5 mols based on the component A of a chloroalkanoic acid ester of formula II [Z is an (alkyl-substituted) methylene; R6 is an alkyl or an aralkyl] in the presence of (D) about 0.001-1 mol based on the component A of an alkali metal iodide (e.g. potassium iodide) and then desilylated to give the objective compound of formula III.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 1-substituted tetrahydroquinazolines (III), and more particularly, to reacting tetrahydroquinazolines with (I) hexamethyldisilazane, followed by alkali metal iodine. Under the coexistence of
The present invention relates to a method for producing 1-substituted tetrahydroquinazolines (III), which comprises reacting a chloride alkanoate (II), followed by desilylation.

[0002]

BACKGROUND OF THE INVENTION 1-Substituted tetrahydroquinazolines (III) are compounds known as intermediates such as anti-inflammatory agents and therapeutic agents for diabetic complications.
It is also known that the compound is produced by reacting tetrahydroquinazolines (I) with hexamethyldisilazane, followed by reaction with an alkanoic acid bromide, followed by desilylation (for example, see Japanese Unexamined Patent Publication No. 64-64). No. 25767). However, this method has a problem that an expensive brominated alkanoic acid ester is used as a raw material. On the other hand, when an attempt was made to produce 1-substituted tetrahydroquinazolines (III) using inexpensive alkanoic acid chlorides (II) instead of brominated alkanoic acid esters, the problem that the yield was significantly reduced occurred. Was.

[0003]

Means for Solving the Problems The present inventors have solved the above problems by using 1-substituted tetrahydroquinazolines (I
As a result of intensive studies on the production method of (II), alkanoic acid chloride (I
It has been found that the target product can be produced industrially and advantageously in high yield by using I) and reacting in the presence of an alkali metal iodide, thereby completing the present invention.

That is, the present invention provides a compound of the formula (I)

(Where R₁ , R_Two Are each independently water
Element atom, halogen atom, nitro group, azide group, halogen
An alkyl group or a halogen atom which may be substituted by an atom
Alkenyl groups which may be substituted
Aralkyl group, halogen atom which may be substituted
Alkoxy groups and halogen atoms which may be substituted
An alkoxycarbonyl group which may be substituted by a child,
Acyloxy group or XNR _FourR_Five(X is just a bond,
Represents a len group or a carbonyl group. X is a mere bond or
When it is a alkylene group, R_Four, R_Five Are independently
Alkyl group or N, R_Four, R_Five Together with other hetero
5-membered or 6-membered heterocyclic ring which may contain atoms
Represents a ring. When X is a carbonyl group, R_Four, R
_Five Are each independently an acyloxyalkyl or N, R_Four, R_Five
 Together may contain other heteroatoms.
A 5- or 6-membered heterocyclic ring. Other heterogenous
When a hetero atom is included, the hetero atom must have a substituent.
Can also. ). R_Three Is a hydrogen atom,
Halogen atom, nitro group, azide group, halogen atom
Alkyl groups and halogen atoms that may be substituted
Alkenyl group or halogen atom may be substituted
Aralkyl groups and halogen atoms that may be substituted
May be substituted by an alkoxy group or a halogen atom.
The alkoxycarbonyl group which may be replaced
You. )) To hexahydroquinazolines
After reacting tildisilazane, iodination of alkali metal
Compound (II) Cl-Z-CO-OR in the presence of₆ (II) (wherein Z is methyl which may be substituted by an alkyl group)
Rene group is represented by R₆ Represents an alkyl group or an aralkyl group.
You. ) Represented by the chloride alkanoic acid ester,
And then subjecting to the formula (III)

[0006] (Wherein, Z, R ₁ , R ₂ , R ₃ , and R ₆ have the same meanings as described above). The present invention provides an industrially excellent method for producing a 1-substituted tetrahydroquinazoline represented by the formula: .

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
I do. Tetrahydroquinazolines as raw materials of the present invention
Substituent R in (I)₁ , R _Two Are each independently water
Element atom, halogen atom, nitro group, azide group, halogen
An alkyl group or a halogen atom which may be substituted by an atom
Alkenyl groups which may be substituted
Aralkyl group, halogen atom which may be substituted
Alkoxy groups and halogen atoms which may be substituted
An alkoxycarbonyl group which may be substituted by a child,
Acyloxy group or XNR_FourR_Five(X is just a bond,
Represents a len group or a carbonyl group. X is a mere bond or
When it is a alkylene group, R_Four, R_Five Are independently
Alkyl group or N, R_Four, R_Five Together with other hetero
5-membered or 6-membered heterocyclic ring which may contain atoms
Represents a ring. When X is a carbonyl group, R_Four, R
_Five Are each independently an acyloxyalkyl or N, R_Four, R_Five
 Together may contain other heteroatoms.
A 5- or 6-membered heterocyclic ring. Other heterogenous
When a hetero atom is included, the hetero atom must have a substituent.
Can also. ). R_Three Is a hydrogen atom,
Halogen atom, nitro group, azide group, halogen atom
Alkyl groups and halogen atoms that may be substituted
Alkenyl group or halogen atom may be substituted
Aralkyl groups and halogen atoms that may be substituted
May be substituted by an alkoxy group or a halogen atom.
Represents an alkoxycarbonyl group which may be substituted.

The halogen atom is, for example, chlorine, bromine, fluorine or the like. The alkyl group which may be substituted by the halogen atom is, for example, methyl, ethyl,
Propyl, i-propyl, butyl, i-butyl, t-butyl,
Lower alkyl groups such as pentyl, i-pentyl and hexyl,
Monohalo lower alkyl groups such as chloromethyl, bromomethyl and chloropropyl; dihalo lower alkyl groups such as 1,2-dichloroethyl, 1,2-dibromoethyl and 2,2-dichloroethyl; trihalo lower alkyl groups such as trifluoromethyl And the like. Examples of the alkenyl group which may be substituted with a halogen atom include, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, Lower alkenyl groups such as 4-pentenyl, monohalo lower alkenyl groups such as 3-chloro-1-propenyl and 3-chloro-1-butenyl, dihalo lower alkyl groups such as 3,4-dichloro-1-butenyl, 3,4 And trihalo lower alkenyl groups such as 1,5-trichloro-1-pentenyl and the like. Examples of the aralkyl group which may be substituted with a halogen atom include, for example, benzyl, phenylethyl, 4-chlorobenzyl, 2,4-dichlorobenzyl, 2,4-dibromobenzyl and the like.

The alkoxy group which may be substituted by a halogen atom includes, for example, methoxy, ethoxy,
Propoxy, i-propoxy, butoxy, i-butoxy, t-
Butoxy, pentyloxy, i-pentyloxy, lower alkoxy groups such as hexyloxy, chloromethoxy, bromomethoxy, 1-, 2-chloroethoxy, 1-, 2-, 3-chloropropoxy, dichloromethoxy, cibromomethoxy, 1,
Lower alkoxy groups substituted by halogen atoms such as 2-dichloroethoxy, 2,2-dichloroethoxy, trifluoromethoxy and the like can be mentioned. Examples of the alkoxycarbonyl group which may be substituted by a halogen atom include, for example, a carbonyl group having a lower alkoxy group which may be substituted by a halogen atom as described above. Examples of the acyloxy group include lower alkylcarbonyloxy groups such as acetoxy, propionyloxy, butyryloxy, i-butyryloxy, valeryloxy, i-valeryloxy and pivaloyloxy, and arylcarbonyloxy groups such as benzoyloxy.

The alkylene group in XNR ₄ R ₅ includes, for example, methylene, dimethylene, trimethylene,
Lower alkylene groups such as tetramethylene;
₄ The R _4, R ₅ as alkyl group in R _5, include lower alkyl groups similar to the above, specific examples of this case, for example dimethylamino, diethylamino,
Dipropylamino, dibutylamino and the like. N
Specific examples of the case where the _{R 4 R 5 N, R 4} , R 5 represents a 5-membered heterocyclic ring or 6-membered heterocyclic ring also to contain other hetero atoms together, for example pyrrolyl, 2
H, 4H-pyrrolyl, pyrrolidino, pyrazolyl, piperidino, piperazinyl, morpholino, imidazolyl and the like. When the other heteroatom is N, N may have a substituent. Examples of such a substituent include an alkyl group as described above, an aralkyl group which may be substituted with a halogen atom as described above, an aralkyl group which may be substituted with an alkoxy group, and an alkoxy group which may be substituted. And a phenylcarbonyl group which may be present.

Representative compounds of the tetrahydroquinazolines (I) include, for example, 2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-chloro-2,4 -Dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-
Bromo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-fluoro-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline, 5,6-, 5,7-, 5,8-, 6,7-, 6,
8-, 7,8-dichloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5,6-, 5,7-, 5,8-, 6,7-, 6,8- , 7,8-Dibromo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5,6-, 5,7-, 5,8-, 6,7-, 6,8-, 7 , 8-Difluoro-
2,4-dioxo-1,2,3,4-tetrahydroquinazoline,

5-bromo-6-chloro-2,4-dioxo-1,2,
3,4-tetrahydroquinazoline, 5-bromo-7-chloro-2,
4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-bromo-8-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-bromo-5-chloro-2, 4-dioxo-1,2,
3,4-tetrahydroquinazoline, 6-bromo-7-chloro-2,
4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-bromo-8-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 7-bromo-5-chloro-2, 4- dioxo-1,2,3,4
-Tetrahydroquinazoline, 7-bromo-6-chloro-2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline, 7-bromo-
8-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 8-bromo-5-chloro-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline, 8-bromo-6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 8-bromo
-7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,

5,6,7-, 5,6,8-, 5,7,8-, 6,7,8-trichloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,
5,6,7-, 5,6,8-, 5,7,8-, 6,7,8-tribromo-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5,6, 7-, 5,6,
8-, 5,7,8-, 6,7,8-trifluoro-2,4-dioxo-1,2,
3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-nitro-
2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5
-, 6-, 7-, 8-azido-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-carboxy-2,4-dioxo-1, 2,3,4-tetrahydroquinazoline, 5-, 6-, 7-,
8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-ethyl-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline, 5-, 6-, 7-, 8-propyl-2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6
-, 7-, 8-i-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-chloromethyl-2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-,
7-, 8-bromomethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (1-chloroethyl) -2,
4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6
-, 7-, 8- (2-chloroethyl) -2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline, 5-, 6-, 7-, 8-dichloromethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,
5-, 6-, 7-, 8- (1,2-dichloroethyl) -2,4-dioxo-1,
2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (2,
2-dichloroethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline,

5-, 6-, 7-, 8-ethenyl-2,4-dioxo-
1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (1-
(Propenyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (2-propenyl) -2,4-dioxo-1,2,3,4 -Tetrahydroquinazoline, 5-, 6-, 7-, 8-
(1-butenyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (1-pentenyl) -2,4-dioxo-1,2, 3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-
(3-chloro-1-propenyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (3,4-dichloro
-1-butenyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (3,4,5-trichloro-1-propenyl) -2, 4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-methoxy-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline, 5-, 6-, 7-, 8-ethoxy-2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6
-, 7-, 8-propoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-i-propoxy-2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-,
7-, 8-t-butoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,

5-, 6-, 7-, 8-chloromethoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-,
8-bromomethoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (2-chloroethoxy) -2,
4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6
-, 7-, 8- (1-chloropropoxy) -2,4-dioxo-1,2,3,
4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (2-chloropropoxy) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8 -(3-chloropropoxy) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-,
7-, 8-dichloromethoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-dibromomethoxy
-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5
-, 6-, 7-, 8-trifluoromethoxy-2,4-dioxo-1,
2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-methoxycarbonyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8 -Chloromethoxycarbonyl
-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5
-, 6-, 7-, 8-bromomethoxycarbonyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8-
(1-chloroethoxycarbonyl) -2,4-dioxo-1,2,3,4
-Tetrahydroquinazoline, 5-, 6-, 7-, 8- (2-chloroethoxycarbonyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8 -(1-chloropropoxycarbonyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline,

5-, 6-, 7-, 8-dichloromethoxycarbonyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,
5-, 6-, 7-, 8-dibromomethoxycarbonyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-,
8- (1,2-dichloroethoxycarbonyl) -2,4-dioxo-
1,2,3,4-tetrahydroquinazoline, 5-, 6-, 7-, 8- (2,
2-dichloroethoxycarbonyl) -2,4-dioxo-1,2,3,
4-tetrahydroquinazoline, 5-, 6-, 7-, 8-trifluoromethoxycarbonyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 7,8-dimethyl-2,4-dioxo- 1,
2,3,4-tetrahydroquinazoline, 7,8-diethyl-2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline, 6-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,
6- (2-phenylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (4-chlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydro Quinazoline, 6- (2,4-dichlorobenzyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (2,4-dibromobenzyl) -2,4-dioxo-1,2 , 3,4-tetrahydroquinazoline,

5,6-dimethoxy-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline, 6,8-dimethoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5,8-dipropoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,
6- (N, N-dimethylamino) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (N, N-diethylamino) -2,
4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (N, N
-Dipropylamino) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (N, N-dibutylamino)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline , 6- (1-pyrrolyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (1-imidazolyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline , 6- (1-pyrazolyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (2H, 4H-pyrrolyl) -2,4-dioxo-1,2,3,4- Tetrahydroquinazoline, 6-piperidino-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-morpholino-2,4-dioxo-1,2,3,4
-Tetrahydroquinazoline, 6- (4-methylpiperazinyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (4-chloromethylpiperazinyl)-2,4-dioxo
-1,2,3,4-tetrahydroquinazoline, 6- (4-benzylpiperazinyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (4- (3-methoxybenzyl) ) Piperazinyl)-
2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-
(4- (phenylcarbonyl) piperazinyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,

6- (4- (3,4-dimethoxyphenylcarbonyl) piperazinyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6- (1-pyrrolylmethyl) -2,4-dioxo -1,2,3,4-tetrahydroquinazoline, 6-morpholinomethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 7- (4-methylpiperazinylmethyl)-2,4- Dioxo
-1,2,3,4-tetrahydroquinazoline, 6- (4- (3-phenylcarbonylpropyl) piperazinylcarbonyl) -2,4-
Dioxo-1,2,3,4-tetrahydroquinazoline, 7- (4- (methylpiperazinylcarbonyl) -2,4-dioxo-1,2,3,4
-Tetrahydroquinazoline, 6- (4-benzylpiperidinocarbonyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-acetoxy-2,4-dioxo-1,2,3,4 -Tetrahydroquinazoline, 6-propionyloxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-butyryloxy 2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-i- Butyryloxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 6-valeryloxy-2,4-dioxo
-1,2,3,4-tetrahydroquinazoline, 6-pivaloyloxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline,
6-benzoyloxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 5,7-dimethyl-6-propionyloxy
-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 8-
Chloro-5,6-dimethoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline and the like.

Hexamethyldisilazane as a silylating agent is generally used in an amount of 0.5 to 10 to quinazolines (I).
It is used on a molar basis, preferably about 1 to 5 molar basis.
The silylation reaction is usually carried out in a solvent at room temperature to reflux of the solvent, but is carried out in the presence of a salt such as ammonium sulfate, ammonium chloride, guanidine hydrochloride, pyridine hydrochloride, or a mineral acid such as sulfuric acid or hydrochloric acid. Thereby, the reaction can be promoted. In this case, the salt, mineral acid and the like are generally used in an amount of about 0.01 to 1 mol, preferably about 0.05 to 0.5 mol, based on the quinazoline (I). Further, the silylation reaction is preferably carried out under reduced pressure and / or under an inert gas stream, whereby the reaction time can be shortened and the amount of hexamethyldisilazane used can be reduced. The degree of the reduced pressure is not particularly limited, but may be, for example, a small reduced pressure of about 750 mmHg, preferably a small reduced pressure of about 600 mmHg, and a degree at which the solvent is refluxed. In particular, it is more effective if the solvent is refluxed. The inert gas is not particularly limited as long as it does not inhibit the reaction, and examples thereof include nitrogen, helium, and argon. The inert gas may be a mixture. There is no particular limitation on the flow rate of the inert gas. Generally, the higher the flow rate is, the more effective the flow rate is. However, for example, about 5 to 1000 ml / min per liter of the reactor, preferably 10 to
It is about 500ml / min.

The solvent is not particularly limited as long as it does not inhibit the reaction. For example, benzene, toluene,
Aromatic hydrocarbons such as xylene, chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, and bromobenzene;
Examples include halogenated hydrocarbons such as dichloromethane and chloroform, ether solvents such as tetrahydrofuran and dioxane, and mixtures thereof. The solvent is usually used in an amount of about 0.5 to 10 times, preferably about 1 to 5 times the weight of the tetrahydroquinazoline (I). The generated silyl compound may be taken out from the reaction mass and used in the next step, or may be directly used in the next step.

After the silylation, the alkanoic acid ester (II) is reacted in the presence of an alkali metal iodide, followed by desilylation. The substituent Z in the alkanoic acid chloride (II) is an alkyl group. Represents a methylene group which may be substituted, and R ₆ represents an alkyl group or an aralkyl group. Here, examples of the alkyl group include the same lower alkyl groups as described above. Representative examples of a methylene group which may be substituted with an alkyl group include, for example, methylene and methylmethylene, but methylene is preferred. Examples of the aralkyl group include an aralkyl group in which an aromatic ring such as benzyl, 4-nitrobenzyl, phenylethyl, benzhydryl, and trityl may be substituted with a nitro group.

As the chloroalkanoate (II),
Preferred are those in which R ₆ is a lower alkyl group. Typical examples of such compounds include methyl chloroacetate, ethyl chloroacetate, propyl chloroacetate, t-butyl chloroacetate,
Ethyl 2-chloropropionate and the like. The chloride alkanoate (II) is usually used in an amount of about 1 to 5 moles per mole of the tetrahydroquinazoline (I).

The present invention is characterized in that the above-mentioned alkanoic acid ester (II) is reacted in the presence of an alkali metal iodide. Examples of the alkali metal iodide include: Potassium iodide, sodium iodide, lithium iodide and the like can be mentioned. Potassium iodide and sodium iodide are preferably used. Alkali metal iodides include tetrahydroquinazolines (I)
To about 0.001 to 1 mole times, preferably 0.1
It is used up to about 1 mole times. The solvent is not particularly limited as long as it does not inhibit the reaction, and examples thereof include the same aromatic hydrocarbons, halogenated hydrocarbons, ether solvents, and mixtures thereof as described above. Hydrocarbons are preferably used. Chlorobenzene,
Halogen-substituted aromatic hydrocarbons such as o-dichlorobenzene, m-dichlorobenzene, and bromobenzene are more preferable, and the use of such hydrocarbons can improve equipment productivity such as shortening the reaction time. The solvent is
It is usually used in an amount of about 0.5 to 10 times by weight, preferably about 1 to 5 times by weight, based on the used tetrahydroquinazoline (I). The temperature at which the alkanoic acid chloride (II) is reacted is usually from 0 ° C. to the boiling point of the solvent, preferably from 80 ° C.
It is about the boiling point of the solvent. As the reaction proceeds, low-boiling components such as trimethylchlorosilane are generated, but the reaction can be carried out while distilling off the low-boiling components.

The desilylation is carried out by adding alcohols such as water, methanol, ethanol and i-propanol. These are usually about 2 to 30 mol times, preferably about 1 to 30 mol times, based on the tetrahydroquinazolines (I).
It is used in an amount of about 10 to 20 times.

Thus, the desired 1-substituted tetrahydroquinazolines (III) are produced. When the desired substance is precipitated as a solid in the reaction mass, it is removed by filtration. Thereby, when the target substance is dissolved in the reaction mass, for example, after distilling off the solvent,
It can be carried out by adding water and extracting with an organic solvent, and then distilling off the organic solvent. 1-substituted tetrahydroquinazolines (III) are, for example, alkali metal salts, alkaline earth metal salts, salts with inorganic bases such as ammonium salts, and organic bases such as organic amine salts, in accordance with known methods. Addition salts with inorganic acids such as salts, hydrochlorides, hydrobromides, sulfates, phosphates, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzene It can also be taken out in the form of a salt such as an addition salt with an organic acid such as a sulfonate and a toluenesulfonate. The obtained 1-substituted tetrahydroquinazoline (III) or a salt thereof is recrystallized,
It can be further purified by various chromatographic treatments and the like.

[0026]

According to the present invention, 1-substituted tetrahydroquinazolines (III), which are the object of the present invention, are obtained. According to the present invention, alkanoic acid chlorides (II) can be obtained in the presence of alkali metal iodides. By reacting the above, the target product can be produced in high yield.

[0027]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1 17.3 g of toluene and 7-chloro-2,4-dioxo-1, under stirring.
A mixture of 2,3,4-tetrahydroquinazoline (10 g), hexamethyldisilazane (19.7 g) and ammonium sulfate (1 g) was refluxed for 2 hours. Distilled off. Next, 8.45 g of potassium iodide and 27.6 g of ethyl chloroacetate were added thereto, and the mixture was stirred at 110 to 120 ° C. for 12 hours, and then 40 g of ethanol was added thereto and refluxed for 1 hour. After cooling to room temperature, the precipitated crystals were filtered, washed with ethanol and water, and dried to obtain 13.9 g of crystals. The content of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate in the crystals was 100%. 96.4% yield

Example 2 In Example 1, after refluxing for 5 hours using 38.2 g of hexamethyldisilazane, excess hexamethyldisilazane and 40.8 g of toluene were distilled off at 55 ° C. under reduced pressure of 20 to 30 mmHg. The procedure of Example 1 was repeated, except that stirring was performed for 32 hours using 1.69 g of potassium iodide to obtain 14.1 g of crystals.
The content of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate in the crystals was 9%.
5.5%. 93.7% yield

Comparative Example 1 The procedure of Example 1 was repeated, except that potassium iodide was not used, and the precipitated crystals were washed with water. 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline in this crystal
-1-yl) The ethyl acetate content was 56.8%. yield
45.7%

Example 3 A mixture comprising 17 g of o-dichlorobenzene, 10 g of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 19 g of hexamethyldisilazane and 1 g of ammonium sulfate was stirred under stirring. After stirring at 120 ° C. for 10 hours, excess hexamethyldisilazane was distilled off at 55 ° C. under a reduced pressure of 50 mmHg. Then
1.6 g of potassium iodide and 27 g of ethyl chloroacetate were added thereto, and stirring was continued at 130 ° C. When the progress of the reaction was monitored by high performance liquid chromatography, it took 16 hours for the residual ratio of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline to be 1% or less. The yield of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate was 95%.

Example 4 The procedure of Example 3 was repeated, except that 17 g of chlorobenzene was used instead of o-dichlorobenzene, and stirring after adding ethyl chloroacetate was carried out at 120 ° C. . It took 21 hours for the residual ratio of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline to be 1% or less. The yield of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate was 91%.

Example 5 In Example 3, 17 g of toluene was used instead of o-dichlorobenzene, excess hexamethyldisilazane and toluene were distilled off at 25 ° C. and a reduced pressure of 20 mmHg, and ethyl chloroacetate was added. Example 3 except that the stirring was carried out at 120 ° C.
It was carried out in accordance with. 7-chloro-2,4-dioxo-1,2,3,4
-It took 57 hours for the residual ratio of tetrahydroquinazoline to be 1% or less. 2- (7-chloro-2,4-dioxo-1,2,
The yield of 3,4-tetrahydroquinazolin-1-yl) ethyl acetate was 90%.

Example 6 A mixture composed of 40 g of o-dichlorobenzene, 20 g of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, 30 g of hexamethyldisilazane and 2 g of ammonium sulfate was stirred. After stirring at 150 ° C. for 3 hours, excess hexamethyldisilazane was distilled off at 55 ° C. under a reduced pressure of 10 mmHg. Then
3.4 g of potassium iodide and 37 g of ethyl chloroacetate were added thereto, and stirring was continued at 130 ° C. while distilling off low boiling components such as trimethylchlorosilane produced as the reaction proceeded.
It took 21 hours for the residual ratio of 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline to be 1% or less. After cooling to room temperature, ethyl acetate and water were added, and the precipitated crystals were filtered, washed with methanol and water, and dried to obtain 27.4 g of crystals. The content of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate in the crystals was 98%. 94% yield

Example 7 The procedure of Example 6 was repeated, except that excess hexamethyldisilazane and low-boiling components such as trimethylchlorosilane were not distilled off. 7-chloro
It took 25 hours for the residual ratio of -2,4-dioxo-1,2,3,4-tetrahydroquinazoline to be 1% or less. By post-treatment according to Example 6, 25.7 g of crystals were obtained. The content of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate in this crystal is 97%
Met. 88% yield

Example 8 While flowing nitrogen at a flow rate of 20 ml / min, o-dichlorobenzene 8
A mixture of 2 g, 70.4-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline 20.4 g, hexamethyldisilazane 16.4 g and sulfuric acid 0.8 g was stirred at 140 ° C. for 7 hours. Then, excess hexamethyldisilazane and a part of o-dichlorobenzene were distilled off under reduced pressure. Next, 2.9 g of sodium iodide and 17.7 g of ethyl chloroacetate were added thereto, and
After stirring at 30 ° C. for 30 hours, ethyl acetate / methanol was added, and the precipitated crystals were filtered, washed with methanol and water,
By drying, 25.1 g of crystals were obtained. In this crystal
The content of ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) acetate was 99%.
92% yield

Example 9 596 g of o-dichlorobenzene, 7-chloro-2,4-dioxo-1,
A mixture consisting of 151 g of 2,3,4-tetrahydroquinazoline, 134 g of hexamethyldisilazane, and 6 g of sulfuric acid is mixed at 360 to 200 mmHg.
The mixture was stirred at 100 to 140 ° C. for 12 hours under reduced pressure. Then, excess hexamethyldisilazane and a part of o-dichlorobenze were distilled off under reduced pressure. Then, 23 g of sodium iodide and 185 g of ethyl chloroacetate are added thereto, and the mixture is stirred at 135 ° C. for 24 hours. Ethyl acetate / methanol is added, and the precipitated crystals are filtered, washed with methanol and water, and dried. As a result, 207.7 g of crystals were obtained. 2- (7-chloro-2,
The content of 4-dioxo-1,2,3,4-tetrahydroquinazolin-1-yl) ethyl acetate was 97%. 95% yield

Claims (10)

[Claims] (1) Formula (I)(Where R₁ , R_Two Is independently a hydrogen atom, a halo
Gen atom, nitro group, azide group, halogen atom
May be substituted by an alkyl group or halogen atom
Alkenyl group or halogen atom
Aralkyl groups and halogen atoms
May be substituted with an alkoxy group or halogen atom
Alkoxycarbonyl group, acyloxy group
Or XNR _FourR_Five(X is a mere bond, an alkylene group or
Represents a rubonyl group. X is a mere bond or an alkylene group
In some cases, R_Four, R_Five Are each independently an alkyl group or
Is N, R_Four, R_Five Together with other heteroatoms
Represents a 5-membered or 6-membered heterocyclic ring which may be present.
When X is a carbonyl group, R_Four, R_Five Are each
Independently acyloxyalkyl or N, R_Four, R_Five Together
A 5-membered heterocyclic ring which may contain other heteroatoms
Alternatively, it represents a 6-membered heterocyclic ring. When other heteroatoms are included
In some embodiments, the heteroatom may have a substituent. )
Represents a group represented by R_Three Is a hydrogen atom, a halogen atom
Substituents, nitro group, azide group and halogen atom
May be substituted with an alkyl group or halogen atom.
Alkenyl group and halogen atom
Aralkyl group and halogen atom
Is substituted by a certain alkoxy group or halogen atom
Represents an alkoxycarbonyl group which may be present. )
Hexamethyldisilazane to tetrahydroquinazolines
After reacting, in the presence of alkali metal iodide,
Formula (II) Cl-Z-CO-OR₆ (II) (wherein Z is methyl which may be substituted by an alkyl group)
Rene group is represented by R₆ Represents an alkyl group or an aralkyl group.
You. ) Represented by the chloride alkanoic acid ester,
And then subjecting to the formula (III)(Where Z, R₁ , R_Two , R_Three , R₆ Are the above and
Represent the same meaning. 1) -substituted tetrahydroquina
A method for producing zolines. 2. The method according to claim 1, wherein the substituent R _{1 of the} tetrahydroquinazolines (I) is a halogen atom, and R ₂ and R ₃ are hydrogen atoms. 3. The process according to claim 1, wherein the tetrahydroquinazoline (I) is 7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazoline. 4. The process according to claim 1, wherein R _{6 of the} chloroalkanoic acid ester (II) is an alkyl group. 5. The process according to claim 1, wherein Z in the alkanoic acid chloride (II) is methylene or methylmethylene. 6. The process according to claim 1, wherein the alkanoic acid chloride (II) is ethyl chloroacetate. 7. The process according to claim 1, wherein the chloride alkanoate (II) is used in an amount of 1 to 5 moles per mole of the tetrahydroquinazoline (I). 8. The process according to claim 1, wherein the alkali metal iodide is potassium iodide or sodium iodide. 9. The method according to claim 1, which is carried out in at least one solvent selected from aromatic hydrocarbons, halogenated hydrocarbons and ether solvents. 10. The process according to claim 1, wherein the reaction between the tetrahydroquinazolines (I) and hexamethyldisilazane is carried out under reduced pressure and / or under an inert gas flow.