GB2262097A - Manufacture of 4H-3,1-benzoxazin-4-ones - Google Patents

Abstract

A process for the manufacture of 4H-3,1-benzoxazin4-ones of the general formula I <IMAGE> in which R<1> denotes hydrogen, C1-C4 alkyl, C1-C4 alkoxy, carboxyl, sulfo, nitro, or halogen, R<2> denotes C1-C20 alkyl, phenyl, or phenylalkyl having from 1 to 4 carbon atoms in the alkyl group, in which a phenyl nucleus, if present, can be substituted by up to two C1-C4 alkyl groups, C1-C3 haloalkyl groups, C1-C4 alkoxy groups, C1-C3 haloalkoxy groups, C1-C4 alkylmercapto groups, C1-C3 haloalkylmercapto groups, carboxyl groups, sulfo groups, C1-C4 alkylsulfonyl groups, C1-C3 haloalkylsulfonyl groups, nitro groups, or halogen atoms and n is equal to 1 or 2, by the reaction of anthranilic acid or an anthranilic acid derivative of the general formula II <IMAGE> with an acyl halide of the general formula III <IMAGE> in which X denotes chlorine or bromine and R<1>, R<2> and n are as defined above, wherein the anthranilic acid II is reacted with an approximately stoichiometric amount of the acyl halide III, without the addition of a base, in an organic solvent at a temperature of from 60 DEG to 200 DEG C, after which the N-acyl anthranilic acid formed as intermediate is cyclized in known manner in situ.

Description

j - 1 1 - Manufacture of 4-3,1 -Benzoxazin-4-ones Tile present invention

relates to an improved process for the preparation of 4H-3,1 benzoxazin- 4 -ones of the general formula 1 3 R2 W) () in Which n' denotes hydrogen, CI-C4 alkyl, CI"C4 alkoxy, carboxyl, sulfo, nitro, or halogen, R2 denotes cl-C,10 alkyl, phenyl, or phenylalkyl having from 1 to 4 carbon atoms in the alkyl group, in which a phenyl nucleus, if present, can be substituted by one or two C,-C, alkyl groups, Cl-C3 haloalkyl groups, Cl-C4 alkoxy groups, cl-C3 haloalkoxy groups, 01-C4 alkylmercapto groups, Cl-C3 haloalkylmercapto groups, is carboxyl groups, sulfo groups, cl-c., alkylsullonyl groups, cl-C3 haloalkylsuifonyl groups, nitro groups, or halogen atoms, and n is equal to 1 or 2, by the reaction of anthranilic acid or an anthranilic acid derivative of the general formula 11 W2 (R1)n_{:YCOOH is with ail acyl halide of the general formula ill 0 11 X-C-R2 in which X denotes chlorine or bromine.

(11), According to Chein. Ber. 35 (1902) pp. 3480-3485 (Reference 1) anthranilic acid can be reacted with an excess of 2.4 times its weight of benzoyl chloride to give 2plietiyi-4H-3,1 -benzoxazin-4-one in a yield of 62 %. One drawback of this process. however, is that for each mole of anthranilic acid more than two moles of benzoyl chloride are required. Elaborate measures are necessary for the separation of the resulting benzoic acid from the product, which means that the i 2 - process frequently yields Impure products. Another disadvantage of such a method is that tire use thereof for analogous reactions would mean, particularly when difficultly obtainable substituted benzoyl chlorides are used, that at least one Inole of the correspondingly substituted benzoic acid would be discarded as undesirable by-product.

DE-A 3,514,183 (Reference 2) describes a process for the preparation of substituted 2-plieriyl-4H-3,1 -berizoxaziti-4-ories which involves placing anthranilic acids in ail organic solvent which is ininfiscible with aqueous caustic alkali and adding thereto a stoic hionietric aniount of aqueous alkali arid, concurrently or subsequently, an acyl halide in the presence of a phase transfer catalyst, the Nbenzoylanthanilic acids fornied then being cyclized in known manner after the removal of water. The drawback of this method is that the water required in the initial stage must be subsequently removed by laborious means, ie distillation at atmospheric pressure or in vacuo, arid to obtain the product it is further necessary to separate off tire precipitated inorganic salt, eg NaC1, and any insoluble compounds arid finally to distill off residual solvent in order to isolate the end product.

EP-A 0 17.931 (Reference 3) describes the manufacture of M-3,1 benzoxazin-4ones froni anthranific acids arid acyl halides in an inert organic solvent at a temperature of frorn 0' to 60C but according to the examples given a temperature riot exceeding 3011C, optionally in tile presence of bases acting as acid acceptors. However, nowhere in tile examples given in said reference was (lie process carried out without the use of an equirnolar amount of base with respect to the acyl halide. The acid amide formed as intermediate is purified by treatment willi aqueous hydrochloric acid and by extraction from the organic solvent with aqueous caustic alkali followed by acidification, after which it is dried arid thery cyclized with a dehydrating agent before again being wastled with water. This complicated procedure involving the formation of a dry and dusty intermediate product requiring multistage purification is hardly suitable for continuous opera- tions.

It is thus an object of tile present invention to provide a simple, efficient, and economical process for the pfeparation of 2-plieny]-4H-3,1benzoxazin-4-ones which may be readily carried out on an industrial scale.

Accordingly. we have found the process defined above, wherein the anthranific acid if is reacted with a stoichiornetric amount of the acyl halide Ill. without the addition of a base. in an organic solvent at a temperature or from 60" to 2000C, after which the N-berizoylatitliranific acid formed as intermediate Is cyclized In known manner in situ.

3 - Suitable acyl halides III are acyl bromide (x = Br) and, in particular, acyl chlorides (x = CO.

Suitable radicals R1 which may be attached to the benzene nucleus of the 5 heterocyclic system I in the 5, 6, 7, and/or 8 positions are, besides hydrogen:

- cl-c. alkyl groups such as methyl, ethyl, n-propy], isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl, Cl-C4 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy, tert-butoxy, and methylenedioxy, carboxyl groups, preferably present in the form of free acid, sulfo groups, preferably present in the form of free acid, nitro groups, and halogen atoms such as fluorine, chlorine, and bromine.

Preferred values of R1 are methyl, methoxy, halo, and especially hydrogen.

The number (n) of radicals R' is 2 or, preferably, 1.

Suitable radicals R2 in the 2 position on the benzoxazin-4-one system are:

linear or branched cl-C20 alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyi, n-heptyl, n-octyt, 2ethylhexy], n-nonyl, isononyl, n-decyl, nundecyl, n-dodecy], ntridecyl, isotridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, nheptadecy], noctadecy], and n-eicosyl, phenyl, and phenylalkyl having from 1 to 4 carbon atoms in the alkyl moiety, eg, benzyl, 2-phenylethyl, 3-phenylpropyl, and 4-phenyibuty].

2 5 If a phenyl nucleus is present in the radical R2, it may be substituted by two or, preferably, one of the following radicals in the o, m, or p position:

cl-c., alkyl such as niethy], ethyl, n-propyl, isopropyl, n-buty], isobutyl, sec-butyl. arid tert-butyl, C,_C, haloalkyl such as chloromethyl, dic hlorom ethyl, trichloromethyl, arid trifluoroniethyl, - - - c,-c,, alkoxy such as nietlioxy, ettioxy, n-propoxy, isopropoxy, nbutoxy. isobutoxy, sec-butoxy, tert-butoxy, and niethyienedioxy, C,-c., haloalkoxy such as difluoronlettioxy, trifluoromethoxy, chloro(filluoroiliettioxy, 1,1 2,2 -tetra f 1 u oroettioxy, and 1,1,2trifluoro-2cliloroetlioxy, C,-c,, alkylniet.capto such as niethylniercapto, ettlyfrilercapto, npropyIniercapto, arid r?-butylillercapto, Cl-C3 11-,iioc-ilkylillercapto such as difluoromethylmercapto, trifluorornethylniercapto, citiorodilluoroiiletllyltilercapto, and 1,1,2, 2-tetra fluoroetiiyiillet,capto, carboxy, preferably in the form of free acid, sulfo, preferably in the form of free acid, c,-c,, alkyisuffotiyi such as niettiylsuffonyi, ethyisulfonyi, n- propylsulfonyl, and r;-butyisuiforiyl, cl-c3 lialoalkyisuifonyl such as clilorotyiettlyisuifotiyl and trifluorotilettiyisulforlyi, nitro, and halogen such as fluorine, chlorine, and bromine.

The folloWing Values of R2 are preferred:

linear or bfanched cl-C4 alkyl, especially niettly], unsubstituted t)hpnvi.

phenyl substituted by CI-C4 alkyl, especially niethyl, phenyl substituted by cl-c. haloalkyl, phenyl substituted by C,-C4 alkoxy, especially methoxy, phenyl substituted by c,-c3 haloalkoxy, phenyl substituted by Cl-C3 tialoalkylniercapto, phenyl substituted by CVC4 alkylsulfonyl, especially methylsulfonyl, plienyl substituted by CI-C3 haloalkylsulfanyl, phenyl substituted by nitro, and phenyl substituted by halogen.

The reaction of the anthranilic acid 11 with the acyl halide III is carried out at a temperature of from 60' to 2001C and preferably from 80' to 18011C and more preferably from 1001 to 1 501C. The use of temperatures below 60cC gives rise to only incomplete conversions, whilst temperatures above 2000C lead to excessive amounts of by-products and decomposition products.

Suitable organic solvents, which are advantageously inert to tile reactants, are, in particular: aliphatic and aromatic hydrocarbons such as hexane, heptane, cyclohexane, petroleum ether, gasoline, ligroin, toluene, ethylbenzene, o-, in-, and p-xylenes, curnene, naphthalene, arid diplienyl, halohydrocarbons, particularly chlorinated hydrocarbons suqh as tetrachloronlethane, 1,2-dicliloroetilane, 1,1,1- and 1,1,2trichloroethane, chlarobenzene, o-, m-, and p-diclilorobenzenes, and o-, ni-, and p-chlorotoluenes, nitrohydrocarbons such as nitrobenzene, nitroethane, and o-, m-, and p- clilororiitroberizenes, aliphatic and aromatic ethers such as di-n-propyl ether, diisopropyl ether. tetraliydrofuran, dioxane, and diphenyl ether, carboxylic acid esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, ethyl butyrate, ethyl acetoacetate, ethylene glycol butyl ether acetate, and niethyl berizoate, carboxanlides, eg, fornlamide, acetamide, and dimethylfornlanlide.

Mixtures of said organic solvents may also be used, if desired.

It is advantageous to use the organic solvent in ail amount of from 300 to 300Owt1A and preferably from 1000 to 180OwtYr, based on the weight of the anthranilic acid 11.

By "the reaction of the anthranilic acid 11 with a stoichiornetric amount of the acyl halide 1W' we inean that ideally the compounds 11 and 111 are reacted in a molar ratio of 1 A. llowever, since the usually highly reactive acyl halide 111 tends to produce side reactions, especially with traces of moisture, or is so volatile under the reaction conditions used that sniall portions thereof are transferred from the reaction mixture to the gas phase, it is advantageous to use a small excess of compound lit so as to give a niolar ratio of 11 to ill of, say, 1A.2 and preferably of 1A.05.

The procedure adopted to carry out the process is advantageously one in which the acyl lialide 111 is fed to the arithranilic acid 11 over a period of from ca 30 nfin 180min, usually at atmospheric pressure, the latter compound being partially dissolved but for the rilost part suspended in the organic solvent. The reaction is allowed to continue for a further 3 to 811, approximately, after which period the conversion to the intermediate N- benzoylanthranilic acid is complete. An advantageous way of increasing the reaction rate is to bubble nitrogen or some other. inett gas through the reaction solution. The gaseous hydrogen halide formed during the reaction can be absorbed by conventional scrubbers.

The second reaction step of the process of the invention, the cyclization of the intermediate N-berizoylantliranilic acid with the elimination of water to yield the end product 1, is carried out without previously isolating said intermediate. To this end, a conventional dehydrating cyclization agent is used - advantageously one which is at the sanle tirne economical in use.

Examples of suitable cyclization agents of this kind are:

3 - symmetrical and mixed carboxylic anhydrides, eg, acetic anhydride, z 7 propiorlic anhydride. butyric anhydride, formic/acetic anhydride. for inic/pr opionic anhydtide, arid acelic/propionic anhydride, or thoesters of carboxylic acids, eg, trimethyl ortholormate and triethyl ortlioformate, acid halides, eg, phosgene, thionyl chloride, sulluryl chloride, phosphorus uxytticilloride. arid acetyl chloride, phosphorus hilides, eg, phosphorus trichloride, phosphorus tribromide. phosphorus pentachlodde, arid phosphorus peritabromide, dicycluliexyl carbodiiniide.

Mixtures of said cyclization agents iltay also be used.

Advantageously. use is made of phosgene, phosphorus oxytrichloride, phosphorus trictiloritle, phosphorus pentacilloride, arid. most particularly. thionyl chloride and acetic anhydride.

1 lie cycli71tion reaction normally requires froill one to ten tinies, and in particular 15 from one to lliree tinjes, tile molar aniount of cyclization agent, based oil the -1111ount of arithrallilic acid 11 used. It is normally carried out at atmospheric pressure arid a temperature of from 401 to 1500C depending oil the cyclization age nt used. fir the care of all acid halide, a temperature of from 201 to 80C is required for the initial phase, after which the reaction is allowed to continue with slirring for- ftom 1 to 3h it a temperature of from 1301 to 1500C until the elimination of gas and water is complete. If use is niade of ail acid halide such as 11m temperalure initially used can be as high as from 501 to 1ITC, after which it can br., r aised to 130-1 501C.

When cycliz,-.itiori is effected with the elimination of water, the acid anlide character of [fie intermediate is lost and it passes into solution if a suitable organic solvent has been used as suspending inedium.

In order tu isolate the end product 1, the organic solvent is advantageously distilled off, ifter which the desired product is purified by, say, distillation or crystallization in a suitable solvent. -1here are thus obtained 4113,1 -benzoxazirl-4 -ones having 3 0 litir ities excee(ling 98 /,,.

Both of the reaction steps of the process of (lie invention can be carried out - 8 batchwisp- for example ill a stirred autoclave, or continuously, for example in a tubular reactor or n cascade of stirred autoclaves.

I lie resulting compounds 1 rilay, if desired, be formulated by usual methods, for exalliple by granulation floill the melt or. by extrusion or atomization.

11 the starting materials used are urisubstituted antliranilic acid and, as acyl fialide, berizoyl clifutide. the course of the reaction may be illustrated by tile following shuctul at diaglaIll:

cool 1 0 1 cl 1120 C: c '1 0.1 rll 12 [1 '10 N 0,-0 A 11 1 I fie process of the invention makes it possible to produce 411-3,1 - berizoxazin-4ofies 1 iti a simple. efficient. alld ecotionlical manner. The process of the invention is suitable fur use on a laboratory scale arid oil ail industrial scale. Tile product is obtained in -a satisfactorily pure form arid in adequate yield.

The 411-3,1 -betizoxaziii-4-ories 1 are important compounds for a variety of puiposes. I-or, example, they are suitable for use as plant protectants, medicines, detergent additives, or uv stabilizers. Ibus compounds containing halogen, nietflyl, or riletlioxy as radical Fir arid lialophenyl, haloalkylplienyl, lialoalkoxypilenyf, li,ilu-iikyliilerc,ii)tol)iieiiyi. or- lialoalkyisulloriyil)flerlyl -as radical F12, ill wilich the ilkyl gioups contain from 1 to 3 carbon atotils, may be used as selective herbicides. Gettain 2-substiluted 41-1-3,1berizoxaziri-4ories are suitable for use as cold bleach activators ill detergents.

Examples Example 1 2 0 16.4 g (0. 12 niol) of anthranific acid were suspended in 100 int, of ethylene glycol butyl ellier acetate arid slowly heated to 13TIC. 17.7g (0.126tivol) of benzoyl chlotide wore then added dropwise to the solution over a period of 20sitist. Nitrogen was bubbled vigorously through the solution during this operation arid during subsequent stirring, which was continued for a period of 51t at a 2 5 teivili(,rttui e of 13011C to complete tile reaction. To effect cyclization, tile reaction mixtut c was cooled to 6011C. arid 15 g (0. 126 m(A) of thionyl chloride were added. 'I lie mixture was then heated to 1 3011C and stirred at this temperature for another i - 9 hour. on completion of the reaction, the solvent was distilled off under water-jet suction, and the ci ude prodLICt WEIS pUrified by distillation at 1 60OC/ 1 inkii. There were obtained 24.35g of 2-plieriyl-4ii-3,1betizoxaziri-4-orie (equivalent to a yield of 91:;.- based oil anthranilic acid used) in the form of a colorless oil which crystallized on cooling. Its inelting point was 1 230C.

Example 2

16.4 g (0. 12 mol) of anthranilic acid were suspended in 130 ml- of ethylene glycol bidyl ether acetate arid slowly heated to 1 300C. 19.5,, (0.126 mol) of /tiinethylbenzoic chloride were then added dropwise to the solution over a period of 20 miti. Nilrogen was bubbled vigorously through the SOlUtiOIl during this operation and during subsequent sl4ring, which was continued for a period of 511 at a temperature of 1 30'C to complete the reaction. To effect cyclization, the reaction mixtut-e was cooled to 60'C, and 15 g (0. 126 inol) of thionyl chloride were added. The mixture was then heated to 1 30('C and stirred at this temperature for a further hour. Oil completion of the reaction, the solvent was removed by distillation under water-jet suction, atid the crude product was recrystallized from ettlanol. There were obtained 25.3g of [ii-iiietl)yll)lieriyl-4ii-3,1-berizoxaziii-4-olle (equivalent to a yield of 89,X; based on anthranilic acid used) in the form of colorless crystals having a melting point of 121 IC.

Example 3

In a manner analogous to that described in Example 2, 16.4 g (0.12 inol) of 20 an(hranilic acid, 22.1 g (0. 126 mol) of fri-chlorobenzoyl chloride, arid 15 g (0. 126 mol) of thionyl chloride were used to give 26.9 g of ni-chlorophenyl-414-3,1 benzoxazin-4-one (equivalent to a yield of 87,A, based oil anthraniliG acid used) in the form of colorless crystals having a melting point of I 57cIC.

Example ii

20.6g (0.15stiol) of anthranilic acid were suspended in 40Ornt- of 1,2 diclilotoettlarle arid heated to 6011C. 23.2g (0.155m01) of betizoyl chloride were added dropwise over a period of 5 h at a temperature of 600C. In order to effect cyclization. 21.4 g (0.155 mol) of thionyl chloride were added, and the mixture was refluxed for one flour. The solvent was then removed by distillation, and the crude product was distilled at 160'C/1 inbar. 'The yield of 2-plieriyi-4i-3,1 - benzoxazin 4- one was 15.7 g (equivalent to a yield of 47 7r based on antliranilic acid used).

This example was carried out in a manner similar to Example 3, although no base was used as acid acceptor. Neither was the intermediate product isolated. Even so, it is clearly evident that the yield is far worse ill a temperature range lower than that used thei.e.

- 11 lr,jaims 1. A process for the manufacture of a 411-3,1 -ben zoxazi n-4-one of the general formula I in which Ri denotes hydrogen, r-l-C4 alkyl, Cl-CA alkoxy, carboxyl, sulfo, rlitro or. halogen, denotes r-1-C20 alky], plieny], or plienylalkyl having from 1 to 4 car-bon atoms ill tile alkyl group, in which a plienyl nucleus, if present, is optionally substituted by one or two substituents selected i"r0111 Cl-C4 alkyl groups, rll-C3 lialoalkyl groups, ClC4 alkoxy groups, Cl-C3 lialoalkoxy groups, Cl-C4 alkylmercapto groups, r-l-r-3 lialoalkylmercapto groups, carboxyl groups, sulfo gr"PS, Cl-C4 alkylsulfonyl groups, Cl-C3 haloalkylsulfonyl groups, nitro groups arid halogen atoms, arid N -R2 i 0 Q) P2 11 is equal to 1 or 2, by tile reaction of anthrariffic acid or a substituted anthranilic acid of tile general formula II NH2 (R1)n-e 1 COOH (11) in whicii R' arid ri have the above meanings, with an acyl halide of the general formula Ill 0 11 X-C-112 GII) in which X denotes chlorine or bromine and R2 has the above meaning, wherein the anthr-anilic acid (II) is reacted with a stoichiometric amount of the acyl halide (111), without the addition of a base, in an 12 - organic solvent at a temperature of from 60 to 20WC, after which the N- berizoyliiltiir-anilic acid formed as intermediate is cyclized in the organic sulvent.

2. A process as claimed in claim 1, wherein the reaction between the anthranilic acid (11) and the acyl halide (III) is carried OUt at a temperature of from 80' to 180"C.

3. A process as claimed in claim I or 2, wherein the molar ratio or the anthranilic acid (11) to the acyl halide (III) employed is f rom 1: 1.0 to 1: 1.2.

4. A process as claimed in any of claims 1 to 3, wherein the reaction or the anthranilic acid (II) with the acyl halide (III) is carried out in the presence of 300 to 3000 wt%, based on the anthranilic acid (11), of an inert organic solvent selected from aliphatic and aromatic hydrocarbons, halohydrocarbons, nitrohydrocarbons, aliphatic and aromatic ethers, carboxylic acid esters, carboxamides and mixtures of two or more thereof.

5. A process as claimed in any of claims 1 to 4, wherein the cyclization of the N-benzoylanthranilic ester formed as intermediate is carried out using a known dehydrating cyclization agent without previously isolating the intermediate.

6. A process as claimed in claim 5, wherein the cyclization of the intermediate N-benzoylanthranilic acid formed is carried out using as cyclization agent phosgene, phosphorus oxytrichloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, acetic anhydride, or a mixture or two or more thereof.

7. A process as claimed in claim 5 or 6, wherein an acid halide is used as the cyclization agent and, after heating at a lower temperature in an initial phase, the final phase of the cyclization is carried out at a temperature of 130 to 150'C.

8. A process for the manufacture of a 4H-3,1-benzoxazin-4-one by reaction of an anthranilic acid with a stoichiometric amount of an acyl halide carried out substantially as hereinbefore described or as 1 - 13 illustrated in any of the foregoing Examples.

9. 4H-3,1-Beiizoxazicie-4-ones when manufactured by a process as clairned in any of claims 1 to 8.

10. 411-3,1-Benzoxaziii-4-ories of the formula (I) as claimed in clairn 9, wherein R' is halogen, methyl or metlioxy and R2 is iialoi)iit-tiyl, lialoalkyll)lletiyl, lialoalkoxyplieriyl, lialoalkylmercaptoplienyl orhaloal kyl still) 1 ion yl phen y].