DD287034A5 - PROCESS FOR THE PREPARATION OF 2-ALKOXY-4-OXO-CHINAZOLIN-3-YL-ALKANSAEURES AND -ESTERS - Google Patents

Abstract

The invention relates to a process for the preparation of 2-alkoxy-4-oxo-quinazolin-3-yl-alkan acids and esters. According to the invention, an * or its ester is reacted with an ortho-carbonate-tetra-alkyl ester in an inert organic solvent or without solvent under heating to give a 2-alkoxy-4-oxo-quinazolin-3-yl-alkanoic acid ester of general formula II. By subsequent hydrolysis in basic medium, the corresponding acids (R3H) of the general formula II are obtained. Among the compounds of general formula II are fungicidal or plant growth regulatory substances. Formula II {* and esters; * and -ester; Orthokohlensaeuretetraalkylester}

Description

For this 1 page formulas

Field of application of the invention

The invention relates to a process for the preparation of 2-alkoxy-4-oxo-quinazolin-3-yl-alkanoic acids and esters of the general formula II.

The invention is of interest for agriculture, horticulture and forestry, where inventively prepared compounds z. B. can be used as fungicides or plant growth regulators.

Characteristic of the known state of the art A large number of quinazolines with potential action as phyto-effectors, fungicides, acarcides, insecticides or Herbicides are known (M.Suess, S.Johne, Z. Chem. 21, 431 (1981)). Some 4-alkoxy- and 2,4-dialkoxy-quinazolino have hitherto been prepared from the corresponding haloquinazolines and alcoholates

(W.L.F. Armarego, "The Chemistry of Heterocyclic Compounds *, 24th Volume. Fused Pyrimidines, I. Quinazolines", New

York, London, Sydney, 11967. '?.

^ -Alkoxy ^ -oxo-quinazolin-S-yl-alkanoic acids and esters of general formula II are not yet known.

Object of the invention

The aim of the invention is to provide new, biologically active 2-alkoxy-4-oxo-chinaiol-3-yl-alkanoic acids and esters in practice as active ingredients available.

Explanation of the essence of the invention

The object of the invention is to develop a process for the preparation of 2-alkoxy-4-oxo-quinazolin-3-yl-alkanoic acids and esters of the general formula II.

According to the invention, an N- (2-amino-benzoyl) -aminoalkansäure or their esters of general formula I with a Orthokohlonsäuretetraalkylester at temperatures of 110 to 130 ° C to a 2-alkoxy-4-oxo-quinazolin-3-yl-alkanoic acid esters of implemented general formula II. It is surprising that in addition to the cyclization takes place at the same esterification of the carboxyl group. In comparison with previously known reactions of the onhocarbonic tetraalkyl ester is further surprising that the reaction according to the invention to the compounds of general formula II runs only in the narrow temperature range.

The 2-alkoxy-4-oxo-quinazolin-3-yl-alkanoic acids of general formula II are obtained by hydrolysis of the corresponding esters

of the general formula II in the basic medium.

In general formulas I and II, R is alkyl, R ² and R ^{3 are} independently H or alkyl, X is alkylene

(straight chain [C ₁ -C ₀ I or branched, optionally substituted), R ¹ is alkyl, alkoxy, halogen, CF _3, NO _2, CN or Dielkylamino and η is 0 to 4, wherein in the case η = 2.3 or 4 the R ^{1 are the} same or different.

It is possible, the reaction of the compound of general formula I with the Orthokohlensäuretetraalkylester without addition

of a solvent or in an inert organic solvent. Examples of suitable solvents are xylene, DMF, DMSO or acetic anhydride. The Orthokohlensäuretetraalkylester is used in excess. It is expedient to continuously remove low-boiling products, in particular alcohols ROH and water, from the reaction mixture, for example by distillation.

The hydrolysis of the esters of the general formula ¹ (R ³ = alkyl) to the corresponding acids (R ³ = H) takes place at Room temperature or with heating z. B. with an alkali metal hydroxide, alcoholate or carbonate. The compounds of general formula I are readily available from isatoic anhydrides and aliphatic amino acids

(M.Suess, S.Johne, HeIv. Chim. Acta 68, 8112 [1985]) and can be used as crude products.

The process according to the invention makes it possible for the first time to prepare the compounds of the general formula II. The compounds of general formula II are biologically active. Among them are those that have a fungicidal or

show plant growth regulatory activity.

The invention will be explained below by embodiments. Exemplary embodiments example 1

2.08 g of 2-amino-hippuric acid methyl ester (I: π = 0, X = CH ₂ , R ¹ = CH ₃ ) are heated to 11O ⁰ C with 4.08g Orthokohlensäuretramethylester in a distillation apparatus for 2 hours and the resulting methanol distilled off. The excess of orthocarbonic acid is distilled off in vacuo and the residue is separated by column chromatography (silica gel 60, elution with chloroform to which increasing amounts of methanol are added) and recrystallized from methanol / water. Ri = 0.65 (benzone / acetone = 20: 7), mp: 113-116 ° C, yield: 420 mg of methyl β-dihydro-a-methoxy-oxo-quinazolin-S-yl) acetate: η = 0, R = R ³ = CH ₃ , X = CH ₂ ).

Example 2

1.94 g of 2-amino-hippuric acid (I: η = 0, R ² = H, X = CH ₂ ) are heated with 4.08 g of tetramethyl orthocarbonate in a distillation apparatus for 3 hrs starting at 110 and increasing to 130 ° C with continuous distillation all low-boiling products. Further as in Example 1. Yield: 400 mg of (3,4-dihydro-2-methoxy-4-oxo-quinazolin-3-yl) -acetic acid methyl ester (II: η = 0, R = R ³ = CH ₃ , X = CH ₂ ).

Example 3

2.22 g of 2-amino-hippuric acid ethyl ester (I: η = 0, R ² = C ₂ H ₆ , X = CH ₂ ) are mixed with 5.86 g Orthokölensäuretetraethylester in a

Distillation apparatus heated for 3 hrs. To 130 ° C (bath temperature). Continue as in Example 1.Ri = 0.7 (benzene / acetone = 20: 7), M.p .: 75-77 ⁰ C, yield: 970mg -acetic acid ethyl ester of (2-ethoxy-3,4-dihydro-4-oxo-quinazolin-3-yl) (II: η = 0,

R = R '= C ₂ H ₆ , X = CH ₂ ).

Example 4

2.42 g of OAmino-S-chloro-hippuric acid methyl ester (I: [R ¹ I _n = 5-CI.R ² = CH ₃ , X = CH ₂ ) are reacted with 4.08 g of tetramethyl orthocarbonate according to Example 2. Ri - 0.65 (benzene / acetone = 20: 7), m.p .: 113-115 ⁰ C, yield: 480mg (at (e-chloro-SAdihydro ^ -methoxy ^ -oxo-S-yO-chinazclin-methyl acetate II : [R ¹ I _n = 6-Cl, X = CH ₂ , R = R '=, CH ₃ ).

Example 5

2.22 g of N- (2-aminobenzoyl) -aminopropanoic acid (I: η = 0, X = CH ₂ CH ₂ , R ^: = H) and 3 g of tetramethyl orthocarbonate are slowly dissolved in 20 ml of acetic anhydride in a distillation apparatus to 12O ⁰ C (bath ) and kept at this temperature for 1 hr. The mixture is evaporated to dryness in vacuo and worked up according to Example 1. Ri = 0.6 (benzene / acetone = 20: 7), m.p .: 52-56 ⁰ C. Yield: 430 mg of 3- (3,4-dihydro-2-methoxy-4-oxo-quinazolin-3-yl ) -propanoic acid methyl ester (II: η = 0, X = CH ₂ CH ₂ , R = R ³ = CH ₃ ).

Example β

1.63 g of 2H-3,1-benzoxazine-2,4 (1H) -dione are added with stirring to 70 ml of an aqueous solution of 1.1 g of 4-amino-butyric acid and 1.1 g of triethylamine and at 30-PO ⁰ C stirred until completion of the evolution of CO ₂ (2 hrs.). The reaction solution is concentrated in vacuo and the residue is reacted with 4.08 g of tetramethyl orthocarbonate according to Example 2. R ₍ = 0.6 (benzene / acetone = 20: 7), yield: 310 mg (oil) of methyl 4- (3,4-dihydro-2-methoxy-4-oxo-quinazolin-3-yl) butanoate (II : η = 0, X = CH ₂ CH ₂ CH ₂ , R = R ³ = CH ₃ ).

Example 7

1.63 g of 2H-3,1-benzoxazine-2,4 (1H) -dione are added with stirring to a solution of 1.7 g of 4-aminobutyrate hydrochloride and 1.1 g of triethylamine in 50 ml of abs. Given methanol. It is stirred at 30-50 ⁰ C until the completion of CO ₂ evolution (2-3 hrs.). It is evaporated to dryness in vacuo and taken up with chloroform, filtered and again the filtrate evaporated to dryness. The residue is further reacted with 4 g of tetramethyl orthocarbonate and 10 g of acetic anhydride according to Example 2. Yield: 400 mg of 4- (3,4-dihydro-2-methoxy-4-oxo-rhinazolin-3-yl) -butanoic acid methyl ester (II: η = 0, X = CH ₂ CH ₂ CH ₂ , R = R ³ = CH ₃ ).

Example 8

100 mg of O, -dihydro-methoxy-oxo-quinazolin-S-yD-acetic acid methyl ester (II: η = O, R = R ³ = CH ₃ , X = CH ₂ ) are dissolved in 5 ml of methanol and 2 ml of 2N sodium hydroxide solution are added , After standing overnight acidified with acetic acid (pH 6-7), concentrated in vacuo and the residue of 40 g of silica gel 60 (Merck, 0.063-0.2 mm grain size) with chloroform / methanol / 25% ammonia = 80/20 / 0.5 chromatographed. Yield: 40 mg of O-dihydro-methoxy-oxo-quinazolin-S-yl) -acetic acid (II: η = 0, R = CH ₃ , R ³ = H, X = CH ₂ ).

(R ¹ )

NH-X-COOR ²

(R ¹ ) _n

N-X-C00R3 Λ,

OR

Claims (6)

1. A process for the preparation of 2-alkoxy-4-oxo-quinazolin-3-yl-alkanoic acids and their esters of the general formula II, characterized in that one N- (2-amino-benzoyl) -aminoalkansäura or esters thereof of the general formula I with a Orthokohlensäuretetraalkylester at temperatures of 110 to 13O ⁰ C to give a 2-alkoxy-4-oxoquinazolin-3-yl-alkanoic acid ester of the general formula II, from which by subsequent hydrolysis in a basic medium, the corresponding 2-alkoxy 4-oxo-quinazolin-3-yl-alkanoic acid of the general formula II (R ³ = H) is obtained, wherein in the general formulas I and II R is alkyl, R ² and R ^{3 are} independently H or alkyl, X is Alkylene (straight-chain [C ₁ -C ₁₀ ] or branched, optionally substituted), R ^{1 is} alkyl, alkoxy, halo, CF ₃ , NO ₂ , CN or dialkylamino, andfrom 0 to 4, where in case of = 2,3 or 4 the R ^{1 are the} same or different stand. 2. The method according to claim 1, characterized in that one uses the compounds of general formula I as crude products. 3. The method according to claim 1 or 2, characterized in that one carries out the reaction of the compound of general formula I with the Orthokohlensäuretetraalkylester in an inert organic solvent. 4. The method according to any one of claims 1 to 3, characterized in that one uses the Orthokohlensäuretetraalkylester in excess. 5. The method according to any one of claims 1 to 4, characterized in that low-boiling products (alcohols) continuously removed au3 the reaction mixture. 6. The method according to claim 1, characterized in that the ester (R ³ = alkyl) of the general formula II at room temperature or with heating with an alkali metal hydroxide, alcoholate or carbonate to an acid (R ³ = H) of the general formula Il implements.