CA1262546A - Quinolone intermediates for the preparation of 1,2,5, 6-tetrahydro-4h-pyrrolo¬3,2,1,ij|-quinoline-4- one - Google Patents

Abstract

ABSTRACT
5-Halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolones of tlle formula IV

Description

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Case 5-13861/ZFO/~/DIV

Qui~olone intermediates for the preparation of 1,2,5,6-Tetrahydro-4H-pyrrolo[3,2,1-ij]-quinollne-4-one.

The present invention relates to nove:L 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolones which are useful in the preparation of 1,2,5l6-tetrahydro-4H-pyrrolo[3,2,1-ij]-quinolin-4~one.
This application is divided from applicant's copending application Serial No. 424 259 ~iled May 16, 1983 relating to a process for producing 1,2,5,6-tetrahydro-4H-pyrrolo-[3,2,1-ij]-quinolin-4-one.
The 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]-quinolin-4-one of aforementioned application Serial No. 424 259 ~ corresponds to the formula :' T~
~i/ ~ (I) and is known also under the trivial name of 4-lilolidone.
The compound can be used as a systemic fungicide for the protection of cultivated plants, for example rice, against infestation by phytopathogenic microorganisms and thus against plant diseases caused by these microorganisms ~cp. G.B. Patent Specification No. 1,394,373).
4-Lilolidone has hitherto been produced by an .
`; intramolecular Friedel-Crafts alkylation from N~
chloropropionyl)-indoline (cp. J. Chem. Soc,:1518, .~ (1964), G.B, Patent Specification No. 1,394,373 and ~; ~$

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, , ~ ~2546 J. Agric. Food Chem. 29, 576 (1981). A large excess of aluminium chloride, high reaction temperatures ar long reaction times are required în this process.
The process is disadvantageous also in that the heat of reaction is difficult to remove) and that the separa~ion of by-products and thP processing of the final product are very lengthy and complicated. The process is for this reason unsuitable for a profitable production of 4-lilolidone on a commercial scale.
It was therefore the object of aforementi~ned applica~
tion Serial No. 424 259 to make 4-lilolidone available in a sirnple and economical manner, in good yields and with a high degree of purity.
It is suggested according to the aformentioned appli-cation Serial No. 424 259 that 4-lilolidone be produced by reacting a haloacetylindoline of the formula II
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/ \ ~ (II), o ~E~ -Hal in which "Hal" is chlorine or bromine, with an addltion product formed from an N,N-disubstituted formamide of the formula III o ~C - (III), in which Rl is Cl-C4-alkyl or phenyl, and R2 is Cl-C4-aLkyl, and an acid halide to give a 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolone of the formula IV

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and then converting this compoundg by catalytic hydro-genation9 into 4-lilolidone of the formula I.
The 5 halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolones of the formula IV are novel compounds and form the subject matter of the present invention.
The present invention, together with that of appli-cant's aforementioned application Serial No. 424 259, will now be described in more detail.
The reaction of a haloacetylindoline of the formula II
with the addition product formed from an N,N-disubstituted formamide o~ the formula III and an acid halide i9 advan-tageously performed in an inert solvent. Suitable such solvents are in particular: halogenated aliphatic or aromatic hydrocarbons, such as chloroform, dichloromethane, dichIoroethane, carbon tetrachloride, chlorobenzene~
dichlorobenzenes, toluene and xylene. It is also possible to use as solvent excess N,N-disubstituted formamide of the formula III, and especially excess acid chloride.
Preerred solvents are 1,2-dichloroethane, chloroform and particularly toluene. Especially advantageous is also the use of excess phosphorus oxychloride as solvent.
Acid halides that can be used are in general those which are able to react with an N,N-disubstituted formamide of the formula III to form a Vilsmeier complex. Suitable acid halides are or example: phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus ~ , ~ ~ oxychloride, phosphorus oxybromide, phosgene, carbonyl `; dibromide~ carbonyl difluoride, oxalyl chloride5 hepta-~ ~ chlorobutyric acid chloride, thionyl chloride and thionyl :` , . .
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~2~2546 bromide. Also derivatives of some of the aforementioned acid chlorides can be used, for example 272,2-trichloro-1,3-dioxa-2-phosphaindane and 2,2-dichloro-1,3-dioxa indane, which can be regarded as derivatives of phosphorus oxychloride and phosgene. Preferred acid halides are phosphorus oxychloride and phosgene.
Suitable N,N-disubstituted formamides of ~he formula III are for example: N,N-dimethylformamlde, N,N-diethyl-formamide, N,N-dipropylformamide, N,N-dibutylformamide, N-butyl-N-methylformamide and N-methyl-N-phenylformamide (N-formyl-N-methylaniline).
Preferred N,N-disubstituted formamides of the formula II are N,N-dlmethylformamide and N-methyl-N-phenyl-formamide. N,N-~imethylformamide is especially preferred.
The acid halide is used, when the process is performed in an organic solvent, in an amount of at least 2 mols per mol of N-haloacetylindoline of the formula II. Where the process is carried out in an organic solvent, the acid halide is preferably used in an amoun~ of 2.5 - 5.0 mols per mol of N-haloacetylindoline of the formula II.
The reaction of a haloacetylindoline of the formula II
with the addition product formed from an N,N-disubstituted fonmamide o the formula III and a~ acid halide can be performed by firstly producing the addition product from the N,N-disubsti~uted formamide and the acid halide~ and aterwards adding the haloacetylindoline of the formula II.
The reaction can however also be carried out by adding the addition produc~ formed from an N,N-disubstituted formamide of the formula III and an acid halide to ~he haloa~etylindoLine of the formula II. Furthermore, the reaction can also be advantageously performed by placing . .
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~2tj25~6 a mixture of a haloacetylindoline of the formula II and an N,N-disubs~ituted formamide o the formula III in~o the reaction vessel, and introducing the acid halide into this mixture, thus effecting the formation of the addition produc~ from N,N-disubstituted formamide of the formula III and the acid halide in situ.
The reaction temperatures are 2S a rule between 40 and 100C. The reaction is generally completed within a few hours. The reaction is particularly advantageously performed at temperatures of between 50 and 75C, and at these temperatures the reaction time is 1-2 hours. Under these preferred, relatively mild, conditions, the reaction proceeds in general. with negligible formation of by-products.
After the reaction of the haloacetylindoline of the formula II with the addition product formed from an N,N-disubstituted formamide of the formula III and an acid halide, the reaction mixture can be further processed in a simple manner, for example by pouring it into aqueous sodium hydr~xide solution. There is thus yielded with the use of excess acid halide, especia~ly phosphorus oxychloride, an aqueous suspension of the 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolone of the formula IV, from which the prsduct is easily obtained by filtration and drying. If the reaction of the haloacetyLindoline of thé formula II with the addition product formed from an N,N dlsubstituted formamide of the formula III and an acid halide has been performed in the presence of one of the aforementioned organic solvents, there is obtained, after ~he pouring of the reaction mixture into aqueous sodium hydroxide solution, a 2-phase mixture in which the re~uired 5-halo-1,293-(1,2-dihydropyrrolo)-4-quinolone of the formula IV is present as solution in the organic phase.

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On removal of the organic phase, there remains a solution o~ the desired 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolone of the formula IV in the employed solvent, which solution, especially wi~h the use of toluene as the solvent, can be used directly for the subsequent catalytic hydrogenatisn.
The catalytic hydrogenation of the 5-halo-1,2,3-~1,2-dihydropyrrolo)-4-quinolone of the formula IV, which proceeds with the removal of the 5-halogen, is advan-tageously performed in an inert organic solvent, and, for neutralising the formed hydrogen halide, in the presence of a base. Suitable inert solvents are in particular: aliphatic and aromatic hydrocarbons, such as cyclohexane, toluene or xylene, as well as lower aliphatic carboxylic acids, particularly acetic acid. The bases used, in the presence of which the catalytic hydrogenation is carried out, are advantageously hydroxides, carbonates and hydrogen carbonates of alkali metals and alkaline-earth metals, and also a~monia or amines. Also alkali metal acetates, especially sodium acetate, can be used as bases.
There may be mentioned as further bases, in the presence of which the catalytic hydrogenation of the 5-halo-1,2,3-(1,2 dihydropyrrolo)-4-quinolones of the ~form-~la IV can be carried out, for example: sodium hydroxide, potassium hydroxide, ammonia, ~riethylamine and pyridine.
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Suitable as catalysts for the catalytic hydrcgenation ~ ~ of the 5-halo-1,2,3~-(1,2-dihydropyrrolo)-4-quinolones of the - formula IV are noble metals o~ thè group VIII of the ~periodic system, particularly ni~ckel,`palladium and platinum. The catalysts are used in a very finely divided .: . .
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~X~ 6 form, for ex2mple as Raney nickel, or on a carrier, for example palladium on charcoal, or platinum on charcoal.
The catalytic hydrogenation of the 5-halo-1,2,3-(1,2-dihydropyrro~o)-4-quinolone of the formula IV is performed as a rule under norma~ pressure or under a sLightly elevated pressure. Catalytic hydrogenation is carried out in practice advantageously under pressures of 1-10 bar, preferably 3-5 bar.
The temperatures at which catalytic hydrogenation can be performed are in general between room temperature and looc. Temperatures of 40-75C have proved to be particularly advantageous.
After compl,etion o~ hy,drogenation, ur~her processing of the reaction mixture comprises filteri'ng off the catalyst and evaporating off the solvent.
It is possible with the process accordin~ to the aforementioned application Serial No. 424 259 to produce 4-lilolidone, starting with haloacetylindolines of the formula II, in a yield o~ about 9o % of theory. The process is easy to carry out, and is therefore well suited also for production of 4-lilolidone on a commercial scale. The haloacetylindolines of the formula II, required as starting material, can be produced in a simple manner, commencing with indoline, by reaction thereof with haloacetyl halides, especially haloacetyl chloride, or by reaction of indole with haloacetyl'chloridej and catalytic hydrogenation of the N-haloacetylindole obtained.
The process according to the aforementionea application Serial No. 424 259 is further illustrated by the following Examples.
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Example _ a) Production of 5-chloro-1,2,3-(1,2-dihydropyrrolo)-4-quinolone 19.55 g (0.1 mol) of N-chloroacetylindoline are added por~ionwise to a mixture of 150 ml (251.2 g; 1.64 mols~
of phosphorus oxychloride and 20 ml (19.0 g; o.26 mol) of N,N-dimethylformamide. After the addition of the N-chloroacetylindoline is completed, the mixture is heated for 1.75 hours at 70-75C internal temperature. The unreacted phosphorus oxychloride is afterwards evaporated off at 40C under reduced pressure. The residue is poured into cold sodium hydroxide solution (10%), upon which the pxoduct precipitates. After a stirring time of 1 hour, the precipitate is filtered off and dried. The yield is 20.05 g (97.8~/o of theory) of 5-chloro-1,2,3-(1,2-dihydro-pyrrolo) 4-quinolone in the form o a beige powder; melting point: 190-192C:
IR spectrum (CHC13): 1660, 1640 (C0, C=C)cm 1. Hl-NMR
spectrum (100 MHz, CDC13): 3.33 (broad t, 2H), 4.30 (broad t, 2H), 6.95 - 7.30 (m, 3H), 7.85 ts, lH> ppm.
3C-NMR spectrum (CDC13: 156.6, 141~3, 130.4, 123.7, 116.5, 47.8 and 27.3 (all s), as well as 134.7, 125.1, 123.8 and 122.8 (all d) ppm.
The phosphorus oxychloride which was evaporated off is pure and can be used again. The N-chloroacetylindoline required as starting material is produced, in the usual manner, from indoline and chloroacetyl chloride; melting point: 129-130C.
; ~ ~b) Production o 4-lilolidone 20.0 g (0.097 mol) of 5-chloro-1,2,3~(1,2-dihydro-pyrrolo)-4-quinolone are dissolved with 8.0 g of sodium acetate in 200 ml of glacial acetic acid, and3 after the addition of 7.0 g of palladium on charcoal (5%), the ', . :
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g mixture is hydrogenated at 70C under 4 bar. The absorp~ion of hydrogen ceases af~er 3 hours. The catalyst is filtered off, and subsequently washed on the filter with glacial acetic acid. The filtrate is concentrated by evaporation~ and the residue is taken up in ethyl acetate, washed with water, dried over magnesium sulfate and conce~ltrated by evaporation. The yield is 15.3 g (91~/o of theory) of 4-lilolidone in the form of a white crystalline powder, the entire physical data of which is in agreement with the relevant data in ~he literature.
Exæm~le 2 a) Production of 5-chloro-1,2,3-(1,2-dihydropyrrolo)-4-quinolone 19.55 g (0.1 mol) of N-chloroacetylindoline is introduced portionwise into a solution of 40.0 g to.26 mol) of phosphorus oxychloride and 19.0 g (o.26 mol) of N,N-dimethylformamide in 150 ml of chloroform. After the addition of N-chloroacetylindoline is completed, the mixture is heated for 24:hours at the reflux temperature.
The reactio~ mixture is afterwards further processed ~y the injection of (10%) sodium hydroxide solution, separation of the aqueous phase and removal of the chloroform by evaporation. There are obtained 12.5 g (61% of theory) of 5-chloro-1,2,3-(1,2 dihydropyrroLo)-4-quinolone 7 m.p. 190-192C.
Exam~ Production of 5-chloro-1,2,3-(L,2-dihydro-pyrrolo)-4-quinolone 40~g (0.4 mol) of phosgene are introduced at 35C into a soLution of: 14.6 g (0.2 mol) of N,N-dimethylformamide in 70~ml of ~,2-aichloroe~hane. There are subsequently added portionwise 19.55 g (0.1 mol) of N-chloroacetyl-indoline~ and stirring is maintained at 65C for 2 hours.
The reaction mixture is then poured onto ice and .

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neutralised with sodium hydroxide solution, the 1,2-dichloroethane is afterwards distilled off, and the precipitate is iltered off and dried. The yield is 18.9 g (92% of theory) of 5-chloro-1,2,3-(1,2-dihydro-pyrrolo)-4-quinolone, m.p. 191-192C.
Example 4 19.0 g (o.26 mol) of N,N-dimethylformamîde are added dropwise at 25-30C, in the course of 1 hour, to 190 g (2.28 mols) of thionyl chloride. There are subsequently added 19.55 g (0.1 mol) of N-chloroacetylindoline, and the mixture is stirred at 60C for 3 hours. The excess thionyl chloride is afterwards dis~illed off at 40C
under reduced pressure; the residue is stirred up with 200 g of ice and neutralised with sodium hydroxide solution.
The yield after filtration and drying is 8.6 g (42% of theory) of 5-chloro-1,2,3-(1,2-dihydropyrrolo~-4-quinolone, m.p. 190-192C.

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Claims (3)

What is claimed is:

1. A 5-halo-1,2,3-(1,2-dihydropyrrolo)-4-quinolone of the formula IV

(IV) in which "Hal" is chlorine or bromine.

2. A 4-quinolone according to claim 1, where "Hal" is chlorine.

3. A 4-quinolone according to claim 1, where "Hal" is bromine.