DD232267A1 - PROCESS FOR THE PREPARATION OF 1,4-DIHYDRO-CHINAZOLIN-4-ON-1-EATING-SAUCES AND THEIR ESTERS - Google Patents

Abstract

The aim of the invention is to provide new biologically active 2-alkoxycarbonylmethylamino-benzamides and 1,4-dihydro-quinazolin-4-one-1-acetic acids and their esters for use as active ingredients. According to the invention, a 1-alkoxycarbonylmethyl isatozoic anhydride is reacted in solution or suspension with ammonia to give a 2-alkoxycarbonylmethylamino-benzamide and then cyclized with a methine-forming condensing agent to give the 1,4-dihydro-quinazolin-4-one-1-acetic acid esters. The esters can be converted into the corresponding acids by alkaline or acidic hydrolysis. These compounds are of interest for agriculture, horticulture and forestry.

Description

For this 1 page formulas

The invention relates to a process for the preparation of 1,4-dihydro-quinazolin-4-one-1-acetic acids and their esters of the general formula III via 2-alkoxycarbonylmethylaminobenzamides of the general formula II.

Field of application of the invention

The invention is important for agriculture, gardening and forestry

Characteristic of the known technical solutions

A large number of quinazolines are already used in pharmaceutical practice (S.JOHNE, Pharmazie 36, 855 (1981); S. JOHNE, Fortschr. Arzneimittelforschung 26 [1982]). Quinazolines with potential action as phytotherapeutic agents, fungicides, acaricides, insecticides or herbicides are also known (SUSS MASS and S. JOHNE, Z. Chem. 21, 431 [1981]). Of the compounds of general formula II, the compound was characterized with (R) _n = 6-CI, R ¹ = H. The synthesis was carried out by reacting the corresponding o-aminobenzamide with chloroacetic acid in DMF in the presence of magnesium oxide and sodium iodide for 2.5 hours at 90-100 ° C (T. MIKl and M. ASANO, European Patent Application 0009608, C 07 C 103/50 ). However, the yield is only 44% d. th

 A process for the preparation of the compounds of general formula III has not yet been described.

Object of the invention

The aim of the invention is to provide new biologically active compounds of the general formulas II and III as well as known substances of the general formula II more economical practice as active ingredients.

Explanation of the essence of the invention

The object of the invention is to develop a process which gives 2-alkoxycarbonylmethylamino-benzamides of the general formulas and 1,4-dihydro-quinazolin-4-one-1-acetic acids and their esters in good yields.

According to the invention, a 1-substituted isatoic anhydride of the general formula I is reacted in solution or suspension with ammonia to give the corresponding 2-alkoxycarbonylmethylaminobenzamide of the general formula II (R ² = R ¹ ) and then this ester as such (II, R ² = alkyl) or after hydrolysis to the acid (II, R ² = H) by means of a methine-forming condensing agent with 3T heating to the corresponding compound of the general formula IM cyclized. In the case of R ² = alkyl, the acid is also obtained by acidic or alkaline hydrolysis (III, R ² = H). In the formulas I, II and III, R is H, alkyl, alkoxy, OH, NO ₂ , CN or halogen, R ^{1 is} alkyl (C ₁ -C ₄ ), R ^{2 is} H or alkyl (C ₁ -C ₄ ) and η for 1 to 4.

Of the 1-substituted isatoic anhydrides of the general formula I, only two ethyl esters have hitherto been described (R = H, R ¹ = C ₂ H ₅ or (R) _n = 6-CI, R ¹ = C ₂ H ₅ ; GE HARDTMANN, G. KOLETAR and DR PFISTER, J. Heterocycl. Chem. 12, 565 [1975]).

The starting materials for the process according to the invention can be prepared in a similar manner.

The reaction of the 1-substituted isatoic anhydride with ammonia can be carried out both in anhydrous or hydrous organic solvents and in water itself. Ammonia is used as gas or in the form of solutions.

Before the cyclization, the solvent is separated off. However, it is not necessary to isolate or purify the 2-alkoxycarbonylmethylaminobenzamides. It can be further implemented as crude products, whereby the inventive method can be designed very economical.

For example, ethoxymethylenemalononitrile, ethoxymethylenevinylacetic acid ethyl ester or formic acid, but especially trialkyl orthoformate, are suitable condensing agents which provide methine groups for the preparation of the compounds of general formula III. In order to achieve a good yield in the cyclization with orthoformate, it is expedient to separate off most of the resulting alcohol during the reaction. That's why you lead

this reaction preferably in a distillation apparatus with slow heating to about 110-140 ⁰ C by. For large reaction mixtures should for a thorough mixing, z. B. by stirring, are taken care of.

The process according to the invention makes it possible to prepare compounds of the general formulas I! and III in good yields. The starting materials can be displayed in a simple manner.

The 1,4-dihydro-quinazolin-4-one-1-acetic acids and their esters of general formula III are novel, and of the compounds

the general formula II has so far only one acid ([R] _n = 6-CI, R ² = H) described. Surprisingly, compounds of the general formulas II and III are biologically active. Among them are those which show fungicidal and / or plant growth-influencing activity.

The invention will be explained below by some embodiments.

Exemplary embodiments Example 1

In 1.25 g of 1-ethoxycarbonylmethyl-isatoic anhydride (I, R = H, R ¹ = C ₂ H ₅ ) in 40 ml abs. Ethanol are introduced 170 mg ammonia and the solution with slow heating (up to 50 ° C) stirred. The mixture is stirred for 10-30 minutes to complete the evolution of CO ₂ , allowed to cool, filtered off and recrystallized from ethanol. . Mp 148-150 ⁰ C. Yield: 750 mg (68% of theory) of 2-ethoxycarbonylmethylamino-benzamide (II, R = H, R ¹ = C ₂ H _5).

450 mg of 2-ethoxycarbonylmethylamino-benzamide and 10 ml of triethyl orthoformate are slowly heated to 140 ° C. in a distillation apparatus. After 4-5h the excess of orthoester is distilled off in vacuo and the residue recrystallized from ethanol and charcoal. . Mp 160-162 ⁰ C. Yield: 330 mg (71% of theory) 1,4-dihydroquinazolin-4-one-1-acetic acid ethyl ester (III, R = H, R ¹ = C ₂ H _5).

100mg i ^ -Dihydro-quinazolin ^ -one-i-acetic acid ethyl ester are heated under reflux with 20mg NaOH in 0.5ml water and 5ml Methanoi for 1h. The precipitated sodium salt is dissolved in a little water, acidified with hydrochloric acid, filtered off and recrystallized from methanol. Schmp.263-265 ° C. Yield: 82 mg (93% of theory) of 1,4-dihydro-quinazolin-4-one-1-acetic acid (III, R = H, R ¹ = H).

Example 2

1.2 g e-chloro-i-methoxycarbonylmethyl-isatoic anhydride (I, (R) _n = 6-Cl, R ¹ = CH ₃ ), 1 ml of 25% ammonia solution and 30 ml of water at 30-40 ⁰ C 1 -2 hours. touched. After completion of the evolution of CO ₂ is evaporated in vacuo, the residue is slowly heated with 25ml trimethyl orthoformate in a distillation apparatus at 100-105 ⁰ C and kept for one hour at this temperature. The mixture is then boiled under reflux for 1 hr and again distilled off methanol. The excess of orthoester is removed in vacuo and the residue recrystallized from methanol. Mp 201-203 ⁰ C. Yield:. 900 mg (80% of theory) of ^a e-chloro-IAdihydro-quinazolin ^ -one-i-methyl acetate (III, (R) _n = 6-Cl, R ¹ = CH ₃ ). The following Tables 1 and 2 contain further examples of compounds prepared according to the invention. They are synthesized in the same manner as described in Examples 1 and 2.

Table 1 CH ₃ C ₂ H ₅ CH ₃ CH ₃ 151-152 147-148 144 139 H CH ₃ H 285-288 225 283-285 (Z) Yield (%) analogous example 61 54 67 73 - »-» NJ NJ Compounds of the general formula III R. R ² mp (° C) Compounds of the general formula II RR ² mp (° C) 6-CI 6-Br 6-Br Yield (%) analogous example H6-Br6-Br6-CI 79 53 ^a 85 1 2 1 Table 2

based on the corresponding 1-substituted isatoic anhydride

CH ₂ COOR

NHCHoCOOR '

24.MAI1982 * üli879

Claims (14)

Invention claim: 1. A process for the preparation of i ^ -dihydroquinazolin-A-on-i-acetic acids and their esters of the general formula III, which comprises reacting a 1-substituted isatoic anhydride of the general formula I in solution or suspension with ammonia to a Alkoxycarbonylmethylamino-benzamide of the general formula II (R ² = R ¹ ), this as such (II, R ² = alkyl) or after hydrolysis to the acid (II, R ² = H) with a methine-producing condensing agent with heating to the corresponding compound of the general formula III, where in the formulas R is H, alkyl, alkoxy, OH, NO ₂ , CN or halogen, R ^{1 is} alkyl (C ₁ -C ₄ ), R ^{2 is} H or alkyl (C ₁ -C ₄ ) and η stand for 1 to 4. 2. The method according to item 1, characterized in that one uses ammonia as gas or in the form of solutions. 3. The method according to item 1 and 2, characterized in that one does not purify the compounds of general formula II prior to further reaction to the compounds of general formula III, but used as crude products. 4. The method according to any one of items 1 to 3, characterized in that the cyclization of the compounds of general formula Il by means of Ethoxymethylenmalonsäuredinitril, Ethoxymethylencyanessigsäureethylester or formic acid, but preferably by means of trialkyl orthoformate, is performed. 5. The method according to item 4, characterized in that the cyclization is carried out in a distillation apparatus. 6. The method according to any one of items 1 to 5, characterized in that obtained esters of the general formula III (R ² = alkyl) by acid or alkaline hydrolysis in the corresponding acids (R ² = H) transferred. 7. lADihydro-quinazolin ^ -one-i-acetic acids and their esters of general formula III 8. 'M-Dihydro-quinazolin-1-i-acetic acid 9. lA-dihydro-quinazolin ^ -one-i-acetic acid ethyl ester 10. e-chloro-1-dihydro-quinazolinone-1-i-acetic acid 11. ö-chloro-i ^ -dihydro-quinazolin ^ -one-i-acetic acid methyl ester 12. 6-Bromo-1,4-dihydro-quinazolin-4-one-1-acetic acid 13. ö-bromo-IAdihydro-quinazolin ^ -one-i-acetic acid methyl ester 14. 1,4-Dihydro-quinazolin-4-one-1-acetic acids prepared by the process according to any one of items 1 to 6, and esters thereof