DD232268A1 - PROCESS FOR THE PREPARATION OF CHINAZOLIN-4-ON-3-EATING ACES AND THEIR ESTERS - Google Patents

Abstract

The aim of the invention is to provide biologically active quinazolin-4-one-3-acetic acids and their esters for the practice in sufficient quantity and inexpensively available. According to the invention, an isatoic anhydride is reacted with glycine in solution or suspension at a p H value between 7 and 12 and subsequently cyclized with a methine-producing condensing agent as a function of the reaction conditions to the quinazolin-4-one-3-acetic acids or their esters. These compounds are of interest for medicine as well as for agriculture, horticulture and forestry.

Description

For this 1 page formulas

The invention relates to a process for the preparation of quinazolin-4-one-3-acetic acids and their esters of general formula II.

Field of application of the invention

The compounds of general formula II are biologically active. In particular, they have plant growth regulatory properties and are therefore of interest for agriculture, horticulture and forestry. In addition, they gain importance for medicine z. B. as Äntiallergika.

Characteristic of the known technical solutions

There are a large number of quinazolines which are used as active ingredients in medicines (S.JOHNE, Pharmazie 36, 855 (1981); S. JOHNE, Fortschr. Arneimittelforschung 26, [1982]). Other quinazolines are useful as phyto-effectors, fungicides, acaricides, insecticides or herbicides (M.SÜSEE and S. JOHNE, Z. Chem., 1961 [1981]).

Thus, the compounds of general formula II and the like show. also growth-regulatory properties (W. LEHR-SPLAWINSKI, Zeszyty Nauk Uniw.Jagiel., Ser. Nauk Mat. Przyrod., Mat, Fiz., Chem., (6), 53 (1959), Chem. Abstr.55, 3602 (1961); M.SÜSSE and S.JOHNE, Z. Chem., 1961 [1981]).

8.R-BAKER ₁ MV-QUERRy ₁ A ₁ F-KADISCH and JHWILLIAMS (J.org. Chem. 17, 35 [1952]) synthesized quinazlpine-4-one-3-acetic acid (II, R = H, R ¹ = H). Starting from 4 (3H) -quinazolinone, the sodium salt was formed and reacted with bromon saline ester in 34% yield to give the corresponding quinazolin-4-one-3-malone ester, which gave acid above by acid hydrolysis and decarboxylation.

W.LEHR-SPLAWINSKI (Zeszyty Nauk Uniw. Jagiel., Ser. Nauk Mat. Przyrod., Mat., Fiz., Chem., (6), 53 [1959]) reported a series of quinazolin-4-one 3-acetic acid derivatives. Various anthranilic acids were reacted with formamide to give the corresponding quinazolin-4-ones, which after conversion to their sodium salt by reaction with bromoacetic acid ester afforded the quinazolin-4-one-3-acetic acid esters. Acid hydrolysis gave the carboxylic acids.

These syntheses consist of 4 or 5 reaction steps, wherein in the former case the total yield is less than 20% and in the latter not more than 40%.

Quinazolin-4-one-3-acetic acid ethyl ester (II, R = H, R ¹ = C ₂ H ₅ ) was also reported by BR BAKER and MV QUERRY (US Pat. No. 2,651,633) by reaction of ethyl chloroacetate with 4 (3H) -quinazolinone Section. Ethanol in the presence of sodium methylate and subsequent extraction with chloroform and purification (see also J. MAILLARD, M. BENARD, M. VINCENT, Vo Va TRI,

R. JOLLY, R. MORIN, C. MILLILLET and Mrs. BENHARKATE, Chim. Ther.2 (3), 202 [1967]).

Also, quinazolin-4-one-3-acetic acid ethyl ester (II, R = H, R ¹ = C ₂ H ₅ ) was obtained from 4 (3H) -quinazolinone with ethyl chloroacetate in the presence of anhydrous potassium carbonate (BeIg. Pat.713387).

S.JOHNE and B. JUNG (Pharmazie 33, 299 [1978]) synthesized unsubstituted and substituted in the 6-position compounds of general formula II by reaction of the corresponding isatoic anhydride with glycine methyl ester hydrochloride in abs.

Ethanol in the presence of triethylamine to the corresponding o-Aminohippursäureestern, with the triethyl orthoformate methyl quinazolin-4-one-3-acetate gave. Hydrolysis with concentrated hydrochloric acid gave the corresponding acids.

The disadvantage of these three methods is mainly that absolute solvent and expensive or technically difficult

manageable starting materials must be used.

It is also known that 7-chloro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione was prepared by reaction of chloroisatoric anhydride with glycine in the presence of triethylamine and subsequent refluxing with glacial acetic acid (M.GATES, J.org.Chem.45, [1980]).

Object of the invention

The aim of the invention is to develop a process for the preparation of the biologically active compounds of the general formula II whose technical-economic parameters make it possible to provide the practice of these compounds in a sufficient quantity and at low cost.

Explanation of the essence of the invention

The object of the invention is to develop a simple process for the preparation of quinazolin-4-one-3-acetic acids and their esters of the general. Formula II, which by technically easy to handle and inexpensive starting materials, only a small number of reaction steps and good Yields is characterized. According to the invention, by reacting an isatoic anhydride of the general formula I with glycine in solution or suspension in an organic solvent and / or water at a pH between 7 and 12 until the completion of the CO ₂ evolution and subsequent addition of a methine-producing condensing agent and heating the corresponding quinazolin-4-one-3-acetic acid or an ester of this acid of general formula II. In the formulas I and II R is H, alkyl, alkoxy, halogen, NO ₂ , CN or OH, R ^{1 is} H or alkyl (Ci-C ₄ ) and η is 1 to 4.

The adjustment to pH 7-12 is carried out in a known manner. It has proven to be advantageous, the pH by adding a tertiary amine or using the salts of glycine, z. As the ammonium salt to realize. The use of a buffer system is also possible. The reaction of isatoic anhydride of the general formula I with the glycine is generally carried out at temperatures below 8O ⁰ C. After completion of the CO ² evolution, the solvent is separated off. Purification of the residue prior to the addition of the methine-forming condensing agent is not required. Suitable condensing agents are, for example, ethoxymethylenemalononitrile, ethyl ethoxymethylenecyanoacetate, trialkyl orthoformate or formic acid itself. Formic acid or aqueous solutions thereof are used to prepare quinazolin-4-one-3-acetic acids of the general formula II (R ¹ = H), generally refluxing to give to ensure the required reaction temperatures. When using a trialkyl orthoformate reaction temperature and reaction time are chosen depending on the desired end product. To prepare the acids (II, R ¹ = H) is carried out at bath temperatures of a maximum of 12O ⁰ C and short reaction times, generally 1 to 2 hours. For the preparation of esters (II, R ¹ = alkyl), however, longer reaction times and bath temperatures around 13O ⁰ C and higher are required.

It is expedient to constantly remove the resulting alcohols during the reaction to give the compounds of the general formula II from the reaction mixture, preferably by distilling off. Therefore, a distillation apparatus is particularly suitable as a reaction vessel.

The inventive method is based on easily manageable and inexpensive starting materials. It comprises only two reaction steps and, depending on the chosen conditions, gives the desired quinazolin-4-one-3-acetic acid or its ester. It is not necessary to produce the acid only by hydrolysis of the ester. Another advantage is that no absolute solvents are required, but you can perform the reaction in aqueous solutions or even in water. The overall yield of the process is good, in many cases it is over 80% of theory. The invention will be explained below by embodiments.

Exemplary embodiments Example 1

3.2 g of isatoic anhydride, 1.8 g of glycine, 3.4 ml of triethylamine are stirred in 30 ml of water until the CO ₂ evolution is complete (2 hrs.). Towards the end is heated to 35-40 ⁰ C. The water is distilled off and the residue is slowly heated to 100 ° C. bath temperature with 20 ml of trimethyl orthoformate in a distillation apparatus. If no more methanol distilled off (1 to 2 hours), the excess of orthoester is distilled off in vacuo and the residue recrystallized from methanol. Schmp.243-245 ° C. Yield: 3.2 g (79% of theory) of ^a quinazoline ^ on-S-acetic acid (II, R = H, R ¹ = H).

Example 2

4 g of 6-chloro-isatoic anhydride (I, (R) _n = 6-Cl), 1.9 g of glycine, 3.5 ml of triethylamine are dissolved in 40 ml of water at 30-40 ° C for 2 h. touched. The water is stripped off in vacuo and the residue is slowly heated to 140 ^° C. with 30 ml of triethyl orthoformate in a distillation apparatus. After 6 hours, the excess of orthoester is distilled off in vacuo and the residue recrystallized from ethanol. M.p. 146-148 ° C. Yield: 3.5 g (66% of theory) of ^a e-chloro-quinazolin ^ -one-S-acetic acid ethyl ester (II, (R) _n = 6-Cl, R ¹ = C ₂ H _5).

Example 3

4.6 g of eS-dichloro-isatoic anhydride (I, (R) _n = 6,8-Cl ₂ ), 1.9 g of glycine, 3.5 ml of triethylamine in 150 ml of water initially at 30-40 ⁰ C, towards the end at 50 ⁰ C. until the CO ₂ evolution ceases (approximately 2 to 3 hours). The water is removed in vacuo and the residue with 100 ml of 80-85% formic acid 6-10Sdt. heated to reflux. The formic acid is distilled off in vacuo and the residue is recrystallized from glacial acetic acid. Sch mp. 284 ^ 286 ⁰ C. Yield: 5.1 g (93% of theory) of ^a eS-dichloro-quinazolin ^ -one-S-acetic acid (II, (R) _n = 6,8-Cl _2, R ¹ = H).

The following table contains further examples of compounds of the general formula II prepared according to the invention. They are synthesized in the same way as described in Examples 1 to 3.

(M) _n R ¹ M.p. ( ⁰ C) Yield (%) ^a H C ₂ H ₅ 75-77 73 6-Br CH ₃ - 160-162 49 - .-. ' 6-Br H 275-277 91 6-Cl H 274-276 88 6,8-Br ₂ H 283-285 89

based on the corresponding substituted isatoic anhydride

CH ₂ COOR

Claims (8)

Invention claim: 1. A process for the preparation of quinazolinone-S-acetic acids and their esters of the general formula II, characterized in that an isatoic anhydride of the general formula I with glycine in solution or suspension in an organic solvent and / or water at a pH Value between 7 and 12 implemented until the completion of CO ₂ evolution and by subsequent addition of a methine-producing condensing agent and heating the corresponding quinazoline-on-S-acetic acid or an ester of this acid of the general formula II is prepared, wherein in the Formulas I and Il R are H, alkyl, alkoxy, halogen, NO ₂ , CN or OH, R ^{1 is} H or alkyl (C ₁ -C ₄ ) and η is 1 to 4. 2. The method according to item 1, characterized in that the pH is adjusted by adding a tertiary amine or inserting the salts of glycine or using a buffer system. 3. The method according to item 1 or 2, characterized in that prior to the addition of the methine-producing condensing agent, the solvent is separated. 4. The method according to any one of the items 1, 2 or 3, characterized in that ethoxymethylenemalonylacetic acid ethyl ester, trialkyl orthoformate or formic acid is used as condensing agent. 5. The method according to item 4, characterized in that when using a trialkyl orthoformate for the preparation of the acids of the general formula II (R ¹ = H) at bath temperatures below 120 ⁰ C and reaction times up to 2 hours. 6. The method according to item 4, characterized in that when using a trialkyl orthoformate for the preparation of the esters of the general formula II (R ¹ = alkyl) at bath temperatures above 13O ⁰ C and reaction times over 2 hours. 7. The method according to item 3, characterized in that when using formic acid or its aqueous solutions by refluxing acids of the general formula II (R ¹ = H) are prepared. 8. The method according to any one of the items 4 to 7, characterized in that alcohols formed during the reaction are distilled off during the reaction.