WO1998040363A1

WO1998040363A1 - Method for producing quinazol-4-ones

Info

Publication number: WO1998040363A1
Application number: PCT/EP1998/001254
Authority: WO
Inventors: Gerhard Stucky; Beat Schmidt
Original assignee: Lonza Ag
Priority date: 1997-03-07
Filing date: 1998-03-05
Publication date: 1998-09-17
Also published as: AU6827598A

Abstract

The invention relates to a novel method for producing quinazol-4-ones of general formula (I), wherein an anthranilic acid derivative is cyclized with an N-alkylimido-carboxylic-dialkyl-ester in the presence of an imidazol derivative. The quinazol-4-ones are intermediate products for producing fungicidal active substances.

Description

Process for the preparation of quinazol-4-ones

The invention relates to a process for the preparation of quinazol-4-one derivatives of the general formula

wherein R ¹ , R ² , R ³ and R ^{4 are the} same or different and are hydrogen, alkyl, alkenyl alkoxy, alkoxcarbonyl, aryl, arylalkyl, cyano or a halogen atom and R and R ^{6 are} alkyl or alkenyl

These compounds are valuable intermediates for the production of fungicidal active ingredients (WO-A 94/26722)

According to WO-A 94/26722, the synthesis of the quinazol-4-one derivatives takes place in 3 stages, starting from an anthranilic acid. This is converted into the corresponding thioquinazolidinedione with an isothiocyanate, for example S-methylation, and finally the S-methyl group is achieved by means of For example, sodium hydride / R-OH substituted by alcoholate. This synthesis is complex in terms of technical safety and involves considerable effort for the transfer to the industrial scale. In addition, special efforts are required for the disposal of the sulfur compounds obtained. It was therefore the task to develop a process which does not include this disadvantage

The problem could be solved with the new method according to claim 1. It contains a derivative of anthranilic acid of the general formula

with an N-alkylimidocarbonic acid dialkyl ester of the general formula

wherein R and R 'have the meaning given in the presence of an imidazole derivative of the general formula

wherein R represents hydrogen, alkyl, alkenyl, alkoxy, alkoxycarbonyl, aryl, arylalkyl, cyano, a halogen atom or a radical of an α-amino acid and R represents hydrogen, alkyl, alkenyl, alkoxy, alkoxycarbonyl, aryl, arylalkyl, cyano or a halogen atom , implemented

An alkyl group is understood to mean a straight-chain or branched, optionally substituted alkyl group having 1 to 6 C atoms, preferably 1 to 4 C atoms

Methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl and t-butyl should be mentioned by name

The alkyl groups in alkoxy, alkoxycarbonyl, arylalkyl,

Alkylamino, dialkylamino too

An alkenyl group is understood to mean a straight-chain or branched optionally substituted alkenyl group having 2 to 6 C atoms, preferably 2 to 4 C atoms

Ethenyl, 1-propenyl, 2-propenyl, 3-propenyl and the various isomers of butenyl should be mentioned by name

An aryl group is advantageously an optionally substituted phenyl or naphthyl group Suitable substituents for both the alkyl groups mentioned and for the aryl yeasts can be halogen, nitro, amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkyl, and

Alkanoyl preferably with 1 to 6 carbon atoms

Halogen expediently means fluorine, chlorine, bromine or iodine

The derivatives of the anthranilic acid of the general formula II used as starting product are generally commercially available products, alternatively they can be prepared by known processes from the prior art

The N-alkylimidocarbonic acid dialkyl esters of the general formula III can be easily and, for example, analogously to the specification of US Pat. No. 3,401,201 by reacting an iminocarbonic acid ester of the general formula

wherein R has the meaning given with an ammonium salt of an alkylamine of the general formula

R ⁶ -NH ₃ 'X ^" VI

in which R 'has the meaning given and X denotes an acid residue

An acid residue is understood to mean the rest of a mineral acid such as chloride, sulfate or phosphate, or the rest of a carboxylic acid such as acetate

The imino carbonic acid esters of the general formula

can be prepared again, for example according to the specification of EP-A 0 519 868, from cyanogen chloride and the corresponding alcohol in the presence of a base

Suitable imidazole derivatives of the general formula IV are imidazole, alkylimidazoles such as, for example, 1-methylimidazole, 2-methylimidazole, 2-ethyl-4-methylimidazole, alkenylimidazoles such as, for example, 1-alkylimidazole, arylimidazoles such as, for example, 4-phenylimidazole, arylalkylimidazole -Benzylimidazole or imidazole with a residue of an α-amino acid such as histidine. Imidazole is particularly preferably used

The imidazole derivative of the general formula IV is used in the reaction according to the invention in an amount of 5 mol% to 200 mol%, preferably from 80 mol% to 120 mol%, based on 1 mol of anthranile acid derivative of the general formula II

It is expedient to work without solvent, but it is entirely possible to work in the presence of a protic or aprotic solvent

The reaction temperature is advantageously chosen between -10 ° C and 50 ° C, preferably between 0 ° C and 20 ° C

The reaction is generally complete after 2 h to 6 h, whereupon the quinazol-4-one derivative of the general formula I obtained can be removed in a professional manner, for example by aqueous work-up with extraction, from the reaction mixture

Preferred quinazol-4-one derivatives which can be prepared by the process according to the invention are derivatives of the general formula I in which R, R, R and R are identical or different and hydrogen, C] - alkyl, C _1-4 alkoxy or represent a halogen and R ⁵ and R ^{6 are the} same or different and are for Cj. ₄ - alkyl Examples:

Example 1 a) Preparation of the Iminokohlensäuredipropylester from Cyanogen Chloride To propanol (919.9 g, 15 mol) was added sodium hydroxide (108.08 g, 2.675 mol)

To room temperature in portions. To the slightly yellowish solution (with traces of undissolved NaOH), chlorine cyanide (155.3 g, 2.5 mol) was introduced at 10-15 ° C. for about 2.5 hours. Stir for 30 minutes at 10 ° C. With 2N aq HCl Solution, the pH was adjusted to 13.5 and the thick suspension was concentrated at 40 ° C. (521.5 g). This crude mixture was used in part source in the next reaction

b) Preparation of N-propylimidocarbonic acid dipropyl ester

To form aq propylammonium chloride, propylamine (188.08 g, 3.15 mol) was added to the aqueous 2N hydrochloric acid solution (1657 g, 3.15 mol) for 20 minutes (pH = 7.51) and then added for 30 minutes at 20 ° C

Imidocarbonic acid dipropyl ester (520 g, -2.25 mol), as a thick suspension, to (not exothermic, pH = 8.08). After 2 hours at room temperature, the aqueous phase was extracted with ethyl acetate, the organic phases were dried over Na ₂ SO ₄ and largely concentrated 391.0 g of colorless liquid (GC-Gew 76, 12% N-propylimidocarbonic acid dipropyl ester, 63.5% yield via stages a and b)

This crude product of dipropyl N-propylimidocarbonate was fractionally distilled at 89 ° C./19 mbar via a Vigreux column 300.65 g (93% by weight, corresponds to 59.7% yield over stages a and b)

Example 2

Preparation of 2-propoxy-3-N-propyl-quinazoI-4-ones

Anthranile acid (8.23 g, 0.06 mol) was added at 0 ° C. to a colorless solution of N-propylimidocarbonic acid dipropyl ester (23.41 g, 0, 12 mol) and imidazole (4, 14 g, 0.06 mol). in a portion to Man Hess, stir the beige suspension at 0 ° C for one hour before warming the mixture to room temperature. Hess Man now started to close the reaction flask evacuate, the reaction propanol and water formed continuously being removed. After a further 4 hours under vacuum at room temperature, the mixture was worked up

260 ml of IN aq LiOH solution were added to the crude mixture and stirring was carried out at room temperature for one hour. The mixture was extracted with 120 ml of ethyl acetate and the phases were separated. The organic phase was washed with 120 ml of IN aq HCl solution and the organic phase was then added 180 ml of water and adjusted the pH of the aqueous phase to 7.0 with a little 2N aq LiOH solution. The organic phase was separated off, dried with Na ₂ SO ₄ and completely concentrated. The light yellow oil was dried in a vacuum drying cabinet at 40 ° C./ 20 mbar dried for 20 hours

10.37 g of yellow oil, according to Η-NMR (CDC1 ₃ )> 95%, corresponds to -67% yield

Η NMR (DMSO) 0.9 (t, 3H, CH ₃ ), 1.05 (t, 3H, CH ₃ ), 1.6, (q, 2H, CH ₂ ), 1.8 (q, 2H, CH ₂ ), 4.0 (q, 2H, CH ₂ ),

4.4 (q, 2H, CH ₂ ), 7.35 (m, 1H, ar-H), 7.42 (d, 1H, ar-H),

7.75 (m, 1H, ar-H),

8.05 (d, 1H, ar-H)

Example 3

Preparation of 6-chloro-2-propoxy-3-N-propyl-quinazol-4-one

To a colorless solution of N-propylimidocarbonic acid dipropyl ester (35.48 g, 0.18 mol), propanol (7.2 g) and imidazole (6.87 g, 0.1 mol) was added at 0 ° C 2-amino 5-chloro-benzoic acid (17, 1 g, 0, 1 mol) in one portion to Man Hess the brown suspension for one hour at 0 ° C, before heating the mixture to room temperature. Hess One now began to evacuate the reaction flask, whereby continuously formed reaction propanol and water was withdrawn. After a further 4 hours under vacuum at room temperature, the mixture was worked up 210 ml of 2N aq LiOH solution were added to the crude mixture and the mixture was stirred at room temperature for one hour. The mixture was extracted with 180 ml of ethyl acetate and the phases were separated. The organic phase was washed with 60 ml of IN aq HCl solution and the organic phase was then added 180 ml of water and adjusted the pH of the aqueous phase to 7.0 with a little IN aq HCl solution. The reaction mixture was heated under normal pressure and the ethyl acetate / water solvent mixture was distilled off continuously until a top temperature of 97 ° C. was reached. The emulsion became cooled to 5 ° C. and the precipitated solid was filtered off. This was dried in a vacuum drying cabinet at 40 ° C./20 mbar for 20 hours. 19.7 g of yellowish orange solid, GC 91.8%, corresponds to 64.4% yield

The solid was recrystallized from ethanol / hexane

Mp 66.6 to 68.6 Η-NMR (CDC1 ₃₎ 0.95 (t, 3H, CH _3), l, 05 (t, 3H, CH _3), l, 7 (q, 2H, CH ₂₎ , l, 85 (q, 2H, CH ₂ ),

4.05 (q, 2H, CH ₂ ), 4.22 (q, 2H, CH ₂ ),

7.4 (dd, 1H, ar-H),

7.55 (dd, 1H, ar-H),

8, 15 (d, 1H, ar-H)

Example 4

Preparation of 6,7-dimethoxy-2-propoxy-3-N-propyl-quinazol-4-one

To a colorless solution of N-propylimidocarbonic acid dipropyl ester (17.74 g, 0.09 mol), propanol (3.6 g) and imidazole (3.44 g, 0.1 mol) were added 2-amino at 0 ° C. 4,5-dimethoxy-benzoic acid (9.85 g, 0.05 mol) in one portion to Man Hess, stir the dark suspension for one hour at 0 ° C. before warming the mixture to room temperature. Hess One now began to close the reaction flask evacuate while continuously forming reaction propanol and water was removed After a further 4 hours under vacuum at room temperature, the mixture was worked up

100 ml of 2N aq LiOH solution were added to the crude mixture and Hess was stirred at room temperature for one hour. The mixture was extracted with 90 ml of ethyl acetate and the phases were separated. The oiganic phase was washed with 30 ml of IN aq HCl solution and the organic phase was then added 90 ml of water and adjusted the pH of the aqueous phase to 7.0 with a little 2N aq NaOH solution. The reaction mixture was heated under normal pressure and the ethyl acetate / water solvent mixture was distilled off continuously until a top temperature of 97 ° C. was reached. The emulsion became cooled to 5 ° C. and the precipitated solid was filtered off. This was dried in a vacuum drying cabinet at 40 ° C./20 mbar for 20 hours. 7.98 g of beige solid, GC 93.7%, corresponds to 75.8% yield

The solid was recrystallized from cyclohexane / toluene, mp 1 13.6-1.0 14

Η NMR (CDCU) 0.95 (t, 3H, CH ₃ ),

1.05 (t, 3H, CH ₃ ), l, 7 (q, 2H, CH ₂ ), l, 85 (q, 2H, CH ₂ ),

3.95 (s, 3H, OMe),

4.05 (q, 2H, CH ₂ ),

4.4 (q, 2H, CH ₂ ),

6.9 (s, 1H, ar-H), 7.55 (s, 1H, ar-H)

Example 5 a) Preparation of the Imiuokohlensäuredipropyiester from cyanogen chloride To propanol (910.6 g, 15 mol), sodium hydroxide (106.06 g, 2.625 mol) was added

Room temperature in portions to the slightly yellowish solution (with traces of undissolved NaOH), chlorine cyanide (155.3 g, 2.5 mol) was introduced at 10-15 ° C. for about 2.5 hours. Stir for 30 minutes at 10 ° C. With 49.5 g 10% aqueous HCl solution, the pH was adjusted to 14.7 and the thick suspension was concentrated

40 ° C on (583.3 g, 56.5% according to GC = 90.8% yield)

This crude mixture was used in part of the source in the next reaction

b) Preparation of N-propylimidocarbonic acid dipropyl ester

To form aq propylammonium chloride, propylamine (268.68 g, 4.5 mol) was added to the 37.9% strength hydrochloric acid solution (432.91 g, 4.5 mol) over the course of 20 minutes (pH = 8.00) were added during 10 minutes at 10 ° C imidocarbonic acid dipropylester (582.0 g, ~ 2.26 mol), as a thick suspension (not exothermic, pH = 7.87). After 4 hours at room temperature, the aqueous phase was mixed with

Toluene extracted and the org phases largely concentrated at 40 ° C / 20 to 30 mbar 440.0 g colorless liquid (GC-Gew 76.64% N-propylimidocarbonic acid dipropyl ester, 71.4% yield in stages a and b)

Example 6

Preparation of 6,7-dimethoxy-2-propoxy-3-N-propyl-quinazol-4-one

To a colorless solution of N-propylimidocarbonic acid dipropyl ester (33.86 g, 0.15 mol) and imidazole (3.44 g, 0.1 mol) was added at 0 ° C to 2-amino-4,5-dimethoxy-benzoic acid ( 20.33 g, 0.1 mol) in two portions. The reaction flask was now evacuated (20 mbar), the reaction propanol and water formed continuously being withdrawn and Hess stirring the dark suspension for 1 h at 0 ° C. After a further 5 Hours under vacuum at room temperature. 50 ml of 4N aq KOH solution (0.2 mol) were added to the crude mixture, the mixture was heated to 50 ° C. and Hess was stirred for 2 hours. The mixture was extracted at 50 ° C. with 50 ml of toluene and separated the aqueous phase was warm off. The organic phase was largely freed from solvents on a rotary evaporator. The bubble residue with 6,7-dimethoxy-2-propoxy-3-N-propyl-quinazol-4-one was mixed with 20 ml of water, with 2.8 aq 20% sulfuric acid pH <8.63 and in a toluene separator at approx. 100 ° C of remaining organic solvents free from the contents (distilled volume 16.5 ml)

The aqueous emulsion was cooled and a brownish solid precipitated at 48 ° C. The suspension was stirred for 2 hours at about 0-5 ° C. The precipitated brown solid was filtered, washed with 20 ml of water and dried at 40 ° C. in a vacuum drying cabinet for 24 hours. 19.42 g of brown solid (1H-NMR> 90% product, corresponded to -57% yield)

The solid was recrystallized from cyclohexane / toluene

M.p. 113.6-114.0

Η NMR (CDC1) 0.95 (t, 3H, CH ₃ ), 1.05 (t, 3H, CH ₃ ), l, 7 (q, 2H, CH ₂ ), l, 85 (q, 2H, CH ₂ ),

3.95 (s, 3H, OMe),

4.05 (q, 2H, CH ₂ ), 4.4 (q, 2H, CH ₂ ),

6.9 (s, 1H, ar-H),

7.55 (s, 1H, ar-H)

Claims

Claims:

Process for the preparation of quinazol-4-one derivatives of the general formula

wherein R, R, R ^" and R are identical or different and are hydrogen, alkyl, alkenyl, alkoxy, alkoxcarbonyl, aryl, arylalkyl, cyano or a halogen atom, R ⁵ and R 'are alkyl, characterized in that a derivative of anthranilic acid the general formula

with an N-alkylimidocarbonic acid dialkyl ester of the general formula

wherein R ^{7 represents} hydrogen, alkyl, alkenyl, alkoxy, alkoxycarbonyl, aryl, arylalkyl, cyano, a halogen atom or a radical of an α-amino acid and R represents hydrogen, alkyl, alkenyl, alkoxy, alkoxycarbonyl, aryl, arylalkyl, cyano or a halogen atom stands, is implemented

A method according to claim 1, characterized in that the imidazole derivative of the general formula IV is used in an amount of 5 mol% to 200 mol% based on 1 mol of anthranilic acid derivative of the general formula II

Missed according to claim 1 or 2, characterized in that imidazole derivative of the general formula IV imidazole is used

Missed according to one of claims 1 to 3, characterized in that the reaction is carried out at a temperature between -10 ° C and 50 ° C

Method according to one of claims 1 to 4, characterized in that the N-alkylimidocarbonic acid dialkyl ester of the general formula III by reacting an iminocarbonate of the general formula

wherein R ^{^ has} the meaning given with an ammonium salt of an alkylamine of the general formula

R ⁶ -NH ₃ 'X ^" VI

wherein R 'has the meaning given and X represents an acid residue is obtained