JPS5920668B2 - Process for producing quinazoline derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the general formula (where R1 is a lower alkyl group, R2 is a lower aliphatic acyl group, and X is a bromine atom or a chlorine atom).

) A method for producing a 2-halomethyl-3-phenyl-6-amino-4(3H)-quinazolinone derivative.

According to the present invention, the target compound [1] can be synthesized as shown in the following reaction formula.

That is, N-(2-amino-5
-Nitrobenz) anilide derivative, the 5-position nitro group is reduced to produce the corresponding 2,5-position diamino compound [], and this compound [] is reacted with an N-lower aliphatic acylating agent by a conventional method. It can be produced by preparing a benzanilide derivative represented by the general formula [], and then reacting it with a reactive derivative of the carboxyl group of α-monohalogenoacetic acid represented by the general formula []. (However, Rl,
R2 and X have the same meanings as above, and Y represents a reactive residue.

) Hereinafter, the method of the present invention will be explained in detail according to the above reaction formula.

[First step ([]→[])] First, as a preferable example of the starting material N-(2-amino-5-nitrobenz)-anilide derivative represented by the general formula [], a lower derivative represented by the symbol R1 is used. Examples include compounds in which the alkyl group is a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, or amyl group, and these alkyl substituents can be substituted at any of the 0, m, or p positions on the benzene ring. They may be present in any position, and can be guided to the corresponding target compound [1].

The reaction of reducing the 5-position ditro group of the above raw material compound [ ] to an amino group is, for example, acidic or alkaline reduction using iron, zinc, tin, etc., or catalytic reduction using a catalytic reduction catalyst such as palladium, platinum, Raney nickel, etc. However, the latter catalytic reduction reaction is particularly preferred because it allows the reaction to proceed to the next step without isolating the reaction product. In the case of a catalytic reduction reaction, the reaction is preferably carried out at room temperature or under heating under normal pressure or increased pressure. As the reaction solvent, for example, methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, etc. can be suitably used. [Second step ([] → [])] Since the compound [] thus produced is a compound that is susceptible to air oxidation, this compound [] is reacted with the N-lower aliphatic acylating agent without isolation and purification. It is preferable to let

Examples of N-lower aliphatic acylating agents include reactive derivatives at the carboxyl group of lower aliphatic carboxylic acids such as formic acid, acetic acid, propionic acid, butyric acid, acrylic acid, crotonic acid, and methacrylic acid, such as anhydrides and acid halides. (e.g. acid bromides, acid chlorides, etc.), mixed acid anhydrides (e.g. anhydrides with ethoxycarboxylic acids, etc.), activated stills (e.g. N-hydroxysuccinimide esters, 4-nitrophenyl esters, cyanomethyl esters, etc.) etc. N-
Acylating agents can be suitably used. In the reaction between such N-lower aliphatic acylating agent and compound [], N
When using an acid anhydride, active ester, etc. as a mono-lower aliphatic acylating agent, the reaction is preferably carried out in an appropriate solvent in the presence or absence of an acid deoxidizing agent. It is preferable to use the acylating agent in equimolar to slightly excessive amounts.

In addition, when an acid halide, mixed acid anhydride, etc. is used as the N-lower aliphatic acylating agent, the reaction is carried out by applying the acylating agent to the compound [] in the presence of a deoxidizing agent in an appropriate solvent. It is preferable to use the same molar amount or a slight excess amount. As the deoxidizing agent, for example, potassium carbonate, sodium carbonate pyridine, triethylamine, etc. can be suitably used. In either case, the reaction proceeds suitably at -1'C to around room temperature, and the same reaction solvent as that used in the reaction in the first step can be suitably used. [
Third step ([]+[]→[1))] Thus, a compound [] in which only the 5-position amino group of the compound [] is selectively lower aliphatic acylated is obtained.

The reaction between this compound [] and the starting compound [] is preferably carried out in a suitable solvent. In this case, it is preferable that the raw material compound [] is allowed to act on the compound [] in an amount equal to or more than the same mole, particularly about 2 to 5 moles. Examples of reactive derivatives at the carboxyl group of α-monohalogenoacetic acid, which is the raw material compound, include acid anhydrides and acid halides of α-bromoacetic acid and α-chloroacetic acid. No matter which form of the raw material compound [] is used, the reaction proceeds suitably at room temperature or under heating, particularly around 100 to 150°C,
As the reaction solvent, for example, acetic acid, propionic acid, etc. can be used as appropriate. The target compound thus produced [
1] can be easily isolated by, for example, concentrating the reaction-completed liquid under reduced pressure and using the resulting residue by known purification operations such as extraction and recrystallization. The object compounds [1] of the present invention are all new compounds, and are extremely useful as intermediates for the synthesis of central muscle relaxant 2-fluoromethyl-3-phenyl-6-amino-4(3H)-quinazolinone derivatives. It is.

For example, 2-chloro(or bromo)methyl-3-(0-tolyl)-6-acetamido-4(3H)-quinazolinone, which is one of the target compounds [1], is reacted with an alkali metal fluoride to 2-Fluoromethyl, a central muscle relaxant that has both minor and tranquilizer actions, is produced by converting the chloro (or bromo) methyl group to a fluoromethyl group and then converting the acetamide group to an amino group using a conventional method. -3-(0-tolyl)-6-amino-4(3H)
-Can be derived from quinazolinone. Example 1 2-Amino-5-nitrobenz-10-toluidide 54
, 4f1 and 5% palladium on carbon 6f1 were suspended in 1.11 ml of methanol and stirred for 3 hours while heating to 50° C. under hydrogen pressure 501b.

After cooling, the catalyst is removed, and a benzene 500me solution containing 20.49% of acetic anhydride is added over 3 hours while cooling the solution to 0 to 5°C. After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Isopropanol is added to the resulting residue, and the crystals are taken and dried to obtain 49.09 g of 2-amino-5-acetamidobenz-10-toluidide as colorless crystals. Yield 86.4%. This product 48.5f
! was suspended in 1.71 g of acetic acid, and while stirring at 15° C., 98.0 g of chloroacetyl chloride was added dropwise over 2 hours.

The mixture was stirred at the same temperature for 1.5 hours, and then refluxed for 0.5 hours. After refluxing, the reaction solution was cooled with water, and then acetic acid was distilled off under reduced pressure. The resulting residue was mixed with chloroform 1.2! Extract with This extract is washed with water, dried, and concentrated. Add isopropanol to the resulting residue to crystallize it, and take it by mouth. By recrystallizing this crystal from methanol,
2-chloromethyl-3-(0-tolyl) as colorless crystals
-6-acetamido-4(3H)-quinazolinone 43.3
get g. Yield 74.0%. Reference example 2-Chloromethyl-
3-(0-tolyl)-6-acetamido-4(3H)-quinazolinone 17.19 and anhydrous potassium fluoride 14.
5f! was added to 25d of diethylene glycol, and 160
Stir for 15 minutes at ℃.

Claims (1)

[Claims] 1 Benzanilide derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (where R^1 represents a lower alkyl group and R^2 represents a lower aliphatic acyl group) and general Formula X-CH_
2-COOH (where X represents a bromine atom or a chlorine atom) A general formula characterized by reacting with a reactive derivative of the carboxyl group of α-monohalogenoacetic acid ▲There are mathematical formulas, chemical formulas, tables, etc. 2-halomethyl-3-phenyl-4 (3H
)-Production method of quinazolinone derivative. 2 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 represents a lower alkyl group.) N-(2-amino-5-nitro-benz)
-Reducing the 5-position nitro group of the anilide derivative to obtain the corresponding 2
, a diamino compound at the 5-position is prepared, and this compound is reacted with an N-lower aliphatic acylating agent according to a conventional method to obtain the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (However, R^1 is the same as above. A benzanilide derivative represented by the formula X-CH_2-COOH (wherein, X represents a bromine atom or a chlorine atom) is prepared. ) is a general formula characterized by reacting with a reactive derivative in the carboxyl group of α-monohalogenoacetic acid ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1, R^2 and 2-halomethyl-3-phenyl-4 (3H
)-Production method of quinazolinone derivative.