CS221907B2 - Method of preparation of the 3-/alkylthio,alkylsulphinyl or alkylsulphonyl/-4-chinolone - Google Patents

Abstract

The invention relates to a method of preparation 3- (alkylthio, alkylsulfinyl or alkylsulfonyl) -4-quinolones of formula (I) in which the general symbols have the meanings given in point 1. It was found that the general substances Formula I have antihypertensive properties.

Description

(54) A process for preparing 3- (alkylthio, alkylsulfinyl or alkylsulfonyl) -4-quinolones

The invention relates to a process for the preparation of 3- (alkylthio, alkylsulfinyl or alkylsulfonyl) -4-quinolones of the general formula I

in which the general symbols have the meaning given in point 1.

The compounds of formula I have been found to have antihypertensive properties.

The present invention relates to a process for the preparation of -4-quinolones of the general formula I

3- (alkylthio, alkylsulfinyl or alkylsulfonyl)

(I) wherein n is 0, 1 or 2,

R ₍ alkyl optionally substituted by C 1 -C 4 hydroxyl or alkoxycarbonyl, allyl, propenyl or benzyl, wherein the phenyl ring is optionally substituted by one or two C 1 -C 4 alkoxy groups,

R8 alkyl of 1 to 4 carbon atoms with the proviso that when n is 0, R8 is methyl,

R, R and R which may be identical or different denote hydrogen, C, _4 alkyl, alkoxy, Cg_4 alkanoyl, halogen, trifluoromethyl or alkylthio, _R further qualifying

(a) when R 6, R 6 and R 6 are hydrogen and R 8 is methyl, then R 1 contains more than one carbon atom and

b) when R1 and R2 are hydrogen, R1 is hydrogen or 7-methyl and R1 is ethyl, then R8 contains more than one carbon atom.

When R is, the alkyl of 1 to 8 carbon atoms preferably contains 1 to 4 carbon atoms.

Examples of such groups for R 1 to R 8 are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-heptyl, n-octyl, methoxy, ethoxy, propoxy, n-butoxy, isobutoxy, acetyl , propionyl, butyryl, methylthio, ethylthio, propylthio and n-butylthio.

The compounds of formula I have been found to have antihypertensive properties. Administration of non-toxic doses of these substances to warm-blooded animals is effective in reducing elevated blood pressure.

The present invention provides a process for the preparation of these novel 3- (alkylthio, alkylsulfinyl or alkylsulfonyl) -4-quinolones of formula I, which is cyclized at 50 to 150 ° C in the presence of an acid or at 200 to 300 ° C in the absence of an acid , acrylate of formula XI

COOR

with (o) _n n ₂ (II) in which is

R 8 is hydrogen or R 6,

R? lower alkyl or phenyl-lower alkyl (e.g. benzyl), R ₁ to R 8 have the above meaning and n is 0, 1 or 2, with the proviso that R 8 is alkyl when n is 1 or 2, followed by alkylation of the substances, in where Rg is hydrogen, to form substances in which Rg has the meaning of R, and optionally oxidation which *

(a) converting substances in which n is 0 to substances in which n is 1 or 2; or.

(b) converts substances in which n represents 1 to substances in which n represents 2.

It is preferred that R? methyl or ethyl. These cyclization reactions can be carried out by conventional methods for this type of reactions. For example, when R8 is hydrogen, cyclization may be accomplished by heating the acrylate in a suitable inert organic solvent, for example diphenyl ether. When R 8 is R 7, cyclization can be carried out in a mixture of acetic anhydride and concentrated sulfuric acid.

Acrylate of formula II may be prepared by reacting methyl-R ^^ hio or sulfinyl or sulfonyl) acetate with sodium methoxide to give the corresponding anion, sodium salt which is then reacted with methylmravenšanem the sodium salt of methyl 3-hydroxy-2-R ₂ - ( thio or sulfinyl or sulfonyl) acrylate. This compound is then reacted with a suitable NR, ananiline derivative to form an acrylate of formula II. Oxidation of the acrylates of formula II in which n is 0 in a conventional manner gives the corresponding acrylates in which n = 1 or 2.

Alkylation in the above reaction is accomplished using alkylating agents known in the art, for example halides R 1 -Hal where Hal is a halogen atom (chlorine, bromine or iodine), or di (R 1) sulfates such as dimethyl sulfate. Similarly, oxidation of S to SO or SO ₂ , or oxidation of SO to SO ₂ is accomplished with oxidizing agents known in the art, for example, organic peracids such as perbenzoic acid and 3-chloroperbenzoic acid, and peroxides such as hydrogen peroxide.

For therapeutic use, the active ingredient can be administered orally, rectally or parenterally, preferably orally. Accordingly, pharmaceutical formulations suitable for the compounds of the invention include known forms of pharmaceutical formulations for oral, rectal or parenteral administration. Pharmaceutically acceptable carriers for these forms are well known in the pharmaceutical art.

The therapeutic efficacy of the compounds of formula I has been demonstrated using standard laboratory animal tests. Such assays include, for example (A) oral administration of spontaneously hypertensive rat species and (B) intraduodenal administration of norqiotensive rat species.

In Test (A), groups of four rats were fasted overnight and their blood pressure was determined as follows. The rats were placed in a cage at 38 ° C, with their tails pushed out through the holes.

After 30 minutes in the cage, their blood pressure was measured using an inflatable cuff placed around the root of each tail. Greater pressure was applied to the cuff than expected. This pressure was slowly reduced and the blood pressure was the one at which arterial pulsation occurred. Then, the rats were removed from the germ and were orally administered the test compound as a solution or suspension in a 0.25% aqueous solution of carboxymethylcellulose. In addition to blood pressure readings before drug administration, blood pressure was measured 1.5-5.0 hours after drug administration. A substance was reported to be effective if it gave a 20% or greater reduction in blood pressure at one of these time intervals.

In Test (B), groups of three rats were anesthetized and cannulated into their carotid arteries. In this way duodenal blood pressure was measured by transfer from the arterial cannula. The test substance was administered to the duodenum as a solution or suspension in a 0.25% aqueous solution of carboxymethylcellulose. Blood pressure was recorded before and 30 minutes after drug administration. The substances that acted, 0% or greater reduction in blood pressure, were reported to be effective.

The compounds of Examples 1 to 20 of Formula I were found to be effective according to one or both of tests (A) or (B).

A preferred compound of formula I is 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone.

Preferred dosages of the compounds of formula I are generally in the range of 0.1 to 100 mg / kg / day, more usually 1 to 60 mg / kg / day.

The invention is illustrated by the following non-limiting examples, in which parts and percentages are by weight and the composition of the solvent mixtures is by volume.

The novel compounds were characterized by one or more of the following spectral methods: nuclear magnetic resonance (H ¹ or C ¹ · 4), infrared or mass spectroscopy.

In addition, the products of the examples had satisfactory elemental analyzes.

Example 1

2.2 ml of dimethyl sulfate was added dropwise to a stirred mixture of 7-chloro-6-methoxy-3-methylthio-4-quinolone (5.42 g, containing a small amount of 5-chloro isomer), 3.2 g of anhydrous potassium carbonate, and 400 ml. butanone. The mixture was refluxed overnight and filtered hot. The hot filtrate was allowed to cool to crystallize the product, 7-chloro-6-methoxy-1-methyl-3-methylthio-4-quinolone, m.p. 220-222 ° C.

The starting material for the reaction is prepared as follows:

7.65 g of sodium are dissolved in anhydrous methanol (450 ml) and the solution is evaporated to dryness. The resulting sodium methoxide was suspended in 300 mL of anhydrous diethyl ether. The suspension was stirred at 0 ° C and 40 g of methyl methyl thioacetate was added dropwise. The mixture was stirred at 0 ° C for one hour and then 21 g of methyl formate was added dropwise. The mixture was stirred at 0 ° C for 1 hour and then stirred at room temperature overnight. The resulting solid suspension was extracted with 300 mL of water and the volume of the aqueous extract was adjusted to 333 mL with water.

This aqueous extract containing 0.33 moles of methyl 3-hydroxy-2-methylthioacrylate sodium salt was added to a stirred solution of 52 g of 3-chloro-4-methoxyaniline in a mixture of 800 ml of water and 33 ml of 11.6 N hydrochloric acid at 0 ° C. The mixture was stirred for 30 minutes and the product was filtered off.

A new intermediate, methyl 3- (3-chloro-4-methoxyanilino) -2-methylthioacrylate, m.p.

Mp 110-112 ° C. 77.6 g of this acrylate are added to 200 ml of diphenyl ether stirred under nitrogen at 250 ° C. After stirring at 250 ° C for 15 minutes, the mixture was cooled. The resulting precipitate was filtered off. A new intermediate, 7-chloro-6-methoxy-3-methylthio-4-quinolone, m.p.

288 DEG-290 DEG C. Thin layer chromatography showed the presence of a smaller amount of the corresponding 5-chloro isomer.

Example 2

Dissolve 1.5 g of 7-chloro-6-methoxy-1-methyl-3-methylthio-4-quinolone in 75 mL of dichloromethane and add dropwise a solution of 3-chloroperbenzoic acid (85%, 1.203 g) at -20 ° C. ) in 75 ml of di-chloromethane. The reaction mixture was poured into 300 mL of saturated aqueous sodium carbonate solution and extracted with 4 x 50 mL of dichloromethane. The peroxide-free organic extracts were dried and evaporated. The resulting solid, and crystallized from ethyl acetate: methanol. There was thus obtained 7-chloro-6-methoxy-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 263 DEG-265 DEG C .;

Example 3

The corresponding quinolones are methylated in a manner similar to that described in Example 1 to give the following compounds (a) to (e). Compounds (f) to (n) are prepared in a similar manner except that compounds (f) to (j) are methylated in aqueous potassium hydroxide at 0-5 ° C and compounds (k) to (n) in aqueous sodium hydroxide. at room temperature.

a) 1-methyl-3-methylthio-7-trifluoromethyl-4-quinolone, m.p. 160-162 ° C,

b) 7-tert. butyl 1-methyl-3-methylthio-4-chnilonone, m.p. 165-168 ° C (from ethyl acetate),

c) 7-chloro-1,6-dimethyl-3-methylthio-4-quinolone, m.p. 211-212 ° C (from ethanol);

d) 1,5,7-trimethyl-3-methylthio-4-quinolone, m.p. 146-147 ° C (from ethanol);

e) 5,7-dichloro-1-methyl-3-methylthio-4-quinolone, m.p. 194-195 ° C;

f) 7-methoxy-1-methyl-3-methylthio-4-quinolone, m.p. 155-157 ° C (with ethyl acetate: light petroleum),

g) 8-fluoro-1-methyl-3-methylthio-4-quinolone, m.p. 145-147 ° C;

(h) 7-chloro-3-ethylthio-1-methyl-4-quinolone, m.p. 146-148 ° C (from ethanol);

(i) 6-acetyl-1-methyl-3-methylthio-4-quinolone, m.p. 183-184 ° C (from ethyl acetate: light petrol);

j) mixture of isomers of 7-acetyl-1-methyl-3-methylthio-4-quinolone and 5-acetyl-1-methyl-3-methylthio-4-quinolone, m.p. 148-156 ° C. HPLC chromatography on silica gel, coated with 11% octadeeylsilane, eluting with methanol: water 35:65 at 100 ml / min gave the pure 7-isomer, mp 245-246 ° C,

(k) 6-chloro-7-methoxy-1-methyl-3-methylthio-4-quinolone, m.p. 227-229 ° C (from butanone);

(l) 7-fluoro-6-methoxy-1-methyl-3-methylthio-4-quinolone, m.p. 210-212 ° C (from ethanol);

m) 1-methyl-3-methylthio-7-isopropyl-4-quinolone, m.p. 114-115 ° C (from ethanol: diethyl ether);

n) mixture of 7-fluoro and 5-fluoro-1-methyl-3-methylthio-4-quinolone isomers. The isomers were separated by high pressure liquid chromatography on silica gel. Elution with ethyl acetate at a flow rate of 200 mL per minute gave 7-fluoro-1-methyl-3-methylthio-4-quinolone, mp 261-263 ° C.

The desired 1-H-4-quinolones for the above reactions were prepared in a manner analogous to Example 1. The corresponding aniline was converted to the acrylate ester of formula III, followed by formation of the quinolone of formula IV, which was then cycled

(III)

In this way, the following intermediates were prepared:

Acrylates of formula III

From W mp ° C

3-CP ₃ ch ₃ 73 to 75 3-tert-butyl ch ₃ 53 toŽ 54 3-C1-4-CH CH, 88 to 90

OF W t Deň: 16 ° C 3,5- _{(CH3) 2} ^CH 3 94 to 96 3,5-Cl ₂ ^CH 3 110 to 125 3-OCH ₃ ^CH 3 76 to 78 2-F ch ₃ oil 3-C1 ^G 2 ^H 5 56 to 58 4-COCH ₃ CH 85 to 87 3-COCH ₃ ^CH 3 73 to 75 3-OCH ₃ -4-Cl CH, 115 to 116 3_B_4_OCH ₃ ^CH 3 85 to 86 3-isopropyl CH ₃ 50 toŽ 52 3-P CH ₃ 80 to 84

Quinolones of formula IV

OF W t. · t. ' 'C 7-CF * CH, 300 to 305 7-tert-butyl - ch ₃ 239 to 241 _7-Cl-6-CH3 CH ₃ 3t0 5.7- (CH3), CH 238 to 240 5.7-Cl ₂ ch ₃ 199 to 201 7-OCH * CH 218 to 220 8-F ch ³ 3 213 to 215 7-C1 ^c 2 ^H 5 248 to 250 6-COCH CH 265 to 269 7-COCH * CH ³ 189 toŽ 191 6-C _7-OCH3 CH ₃ 315 to 320 (ro: zkl. .) _6-OCH3 7-F * CH ₃ 292 toŽ 294 7-isopropyl CH, 149 toŽ 151 7-F * CH3 234 toŽ 236

* Corresponding 5-isomers also present. The product was used in the next step without separation of the isomers.

Example 4

In a similar manner to Example 2, the sulfides a) to k) of Example 3 were oxidized to the following sulfoxides:

(a) 1-methyl-3-methylsulphinyl-7-trifluoromethyl-4-quinolone, m.p. 218-220 ° C (from cyclohexane: ethyl acetate);

b) 7-tert-butyl-1-methyl-3-methylsulphinyl-4-quinolone, m.p. 209-210 ° C (from butane),

c) 7-chloro-1,6-dimethyl-3-methylsulfinyl-4-quinolone, m.p. 257-258 ° C (from ethanol);

d) 1,5,7-trimethyl-3-methylsulfinyl-4-quinolone, m.p. 248-250 ° C (from ethanol);

(e) 5,7-dichloro-1-methyl-3-methylaulfinyl-4-quinolone, m.p. 241-242 ° C (from ethanol);

f) 7-methoxy-1-methyl-3-methylsulfinyl-4-quinolone, mp 233-235 ° C (from ethyl acetate: light petroleum),

(g) 8-fluoro-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 161-162 ° C (from ethyl acetate: light petroleum),

(h) 7-chloro-3-ethylsulfinyl-1-methyl-4-quinolone, m.p. 180-182 ° C (from ethyl acetate: ethanol);

(i) 6-acetyl-1-methyl-3-methylsulphinyl-4-quinolone, m.p. 254-255 ° C (from ethyl acetate: methanol);

j) 7-acetyl-1-methyl-3-methylsulfinyl-4-quinolone, mp 245-246 ° C.

This compound was isolated by evaporation of the organic extract to give a solid which was purified (including removal of the 5-acetyl isomer) by high pressure liquid chromatography. A column of 5.7 cm x 30 cm containing 420 g of silica gel impregnated with 11% octadecylsilane is used. The product was eluted in reverse phase with methanol: water 35:65 at 100 ml / min.

k) 6-chloro-7-methoxy-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 278-279 ° C (from ethanol).

Example 5

An aqueous solution of 3-hydroxy-2-methylthioacrylate was prepared in the same manner as in Example 1 using 17.5 g of sodium, 91.2 g of methyl methylthioacetate and 54.9 g of methyl formate. The product is then treated with 101 g of N-methyl-3-ethylaniline in the same manner as in Example 1 and the product is extracted with ethyl acetate. There was obtained methyl 2- (3-ethyl-N-methylanilino) -1-methylthioacrylate as an oil. 10 ml of concentrated sulfuric acid is added dropwise to a stirred solution of 10 g of this acrylate in 20 ml of acetic anhydride at room temperature, whereby the mixture is boiled.

The mixture was cooled to room temperature, poured into ice / water (300 mL) and extracted with ethyl acetate (3 x 200 mL) followed by dichloromethane (2 x 150 mL). The combined extracts were dried and evaporated. A mixture of isomers of 5-ethyl-1-methyl-3-methylthio-4-quinolone and 7-ethyl-1-methyl-3-methylthio-4-quinolone is obtained as an oily solid. The isomers were separated by high pressure liquid chromatography using 325 g of silica gel (5.7 cm x 30 cm).

Elution with dichloromethane: isopropanol 96: 4 at a flow rate of 200 ml per minute gives the isomers:

(a) 5-ethyl-1-methyl-3-methylthio-4-quinolone, m.p. 148-150 ° C; and

b) 7-ethyl-1-methyl-3-methylthio-4-quinolone, m.p. 138-140 ° C.

Products a) and b) were crystallized from toluene and characterized by NMR.

The following compounds were prepared in the same way without using high pressure liquid chromatography:

c) 1-methyl-3-propylthio-4-quinolone, m.p. 74-76 ° C (from ethyl acetate: light petrol),

d) 3-ethylthio-1-methyl-4-quinolone, m.p. 115-117 ° C (from ethanol: diethyl ether);

e) 3-t-butylthio-1-methyl-4-quinolone, mp 53-55 ° C (from ethyl acetate: light petrol),

f) 8-methoxy-1-methyl-3-methylthio-4-quinolone, m.p. 133-135 ° C (from ethyl acetate: light petroleum),

g) mixture of isomers of 1,6,7-trimethyl-3-methylthio-4-quinolone and 1,5,6-trimethyl-3-methylthio-4-quinolone, m.p. 132-134 ° C.

The starting acrylates for the above quinolones c) to g) were isolated as an oil which was cyclized to quinolones without purification.

Example 6

In the same manner as in Example 2, the sulfides a) to g) of Example 5 were oxidized to the following sulfoxides:

a) 5-ethyl-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 196-197 ° C. The product purified by crystallization from ethanol followed by high pressure liquid chromatography on silica gel and eluting with a mixture of methylene chloride: isopropanol (9: 1) at a flow rate of 200 ml per minute,

b) 7-ethyl-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 227-229 ° C;

c) 1-methyl-3-propylsulfinyl-4-quinolone, m.p. 153-155 ° C. Purified by preparative thin layer silica gel chromatography eluting with dichloromethane: ethanol 95: 5 and extracting the product with ethanol,

d) 3-ethylsulfinyl-1-methyl-4-quinolone, m.p. 160-163 ° C. The product is purified as described above under c)

e) 3-n-butylsulfinyl-1-methyl-4-quinolone, m.p. 105-106 ° C. purified as above (c) after crystallization from ethyl acetate: light petroleum followed by toluene: diethyl ether,

f) 8-methoxy-1-methyl-3-methylsulfinyl-4-quinolone (m.p. 147-148 ° C from ethyl acetate: light naphtha).

The oxidation product of Example (g) was isolated with extra dichloromethane. It was purified by high pressure liquid chromatography on silica gel. Elution with a mixture of ethyl acetate: methylene chloride: ethanol (45:45:10) at a rate of 200 ml per minute s> gives:

(g) 1,5,6-trimethyl-3-methylsulfinyl-4-quinolone, m.p. 250-252 ° C (from ethanol); and

h) 1,6,7-trimethyl-3-methylsulfinyl-4-quinolone, m.p. 253 DEG-254 DEG C. (from ethanol).

Example 7

A mixture of 1.035 g of 3-methylsulfinyl-4-quinolone, 1.38 g of anhydrous potassium carbonate,

0.685 g of n-butyl bromide and 50 ml of dry acetone are refluxed for 24 hours. The mixture was filtered and the filtrate was evaporated to dryness. The resulting oil was dissolved in 50 mL of chloroform. The solution was washed with water, dried and evaporated. The resulting oil was triturated with light gasoline. A solid product is obtained, 1-n-butyl-3-methylsulfinyl-4-quinolone, m.p. 103-105 ° C.

In a similar manner, 3-methylsulfinyl-4-quinolone is alkylated with the following alkylating agent of formula R 1 -V, where V = Br or Cl, to give 1-R, Q-3-methylsulfinyl-4-quinolones having longer melting points. :

^R 10 IN m.p. of product (° C) n-pentyl Br 83 to 85 n-hexyl Br 77 to 78 benzyl Br 210 to 212 allyl Br 144 to 146 propargyl Br 245 (decomposition) ch ₂ cooc ₂ h ₅ Cl 229 to 230 ch ₂ ch ₂ oh Br 190 to 191 3,4-dimethoxybenzyl Cl 151 to 152 *

* recrystallized from ethyl acetate

The starting 3-methylsulfinyl-4-quinolone was prepared by cyclizing methyl 3-anilino-2-methylthioacrylate as described in Example 1 followed by oxidation of the resulting 3-methylthio-4-quinolone by the method of Example 2.

Example 8

Using the method described in Example 2, the following oxidations were carried out with 3-chlorobenzoic acid as the oxidizing agent.

a) 7-methoxy-1-methyl-3-methylthio-4-quinolone is oxidized in chloroform at 0-5 ° C to give 7-methoxy-1-methyl-3-methylsulfonyl-4-quinolone, mp 212-214 ° C (from ethyl acetate: methanol),

b) 7-fluoro-1-methyl-3-methylthio-4-quinoline is oxidized in dichloromethane at 20 ° C to give 7-fluoro-1-methyl-3-methylsulfonyl-4-quinolone, mp 231-236 ° C (from ethanol),

c) 1-methyl-3-methylsulfinyl-7-trifluoromethyl-4-quinolone is oxidized in dichloromethane at 0 ° C to give 1-methyl-3-methylsulfonyl-7-trifluoromethyl-4-quinolone, mp 300-301 ° C (from methanol: ethyl acetate),

d) 3-n-butylthio-1-methyl-4-quinolone is oxidized in chloroform at 0 ° C to give 3-n-butylsulfonyl-1-methyl-4-quinolone, mp 107-107.5 ° C). mixtures of ethyl acetate; ethanol)

e) 3-ethylthio-1-methyl-4-quinolone is oxidized in dichloromethane at 20 ° C to give 3-ethylsulfonyl-1-methyl-4-quinolone, m.p. 164-166 ° C;

f) 7-tert-butyl-1-methyl-3-methylsulfinyl-4-quinolone is oxidized in chloroform at 20 ° C to give 7-tert-butyl-1-methyl-3-methylsulfonyl-4-quinolone, m.p. 247-248 ° C (from ethanol),

Example 9

A mixture of 8.23 g of 7-methoxy-1-methyl-3-methylthio-4-quinolone, 75 ml of glacial acetic acid and 75 ml of hydrobromic acid is stirred and refluxed for 2 days. The mixture was cooled and poured into 500 mL of saturated aqueous sodium carbonate. The resulting precipitate was filtered off and dried. 7-Hydroxy-1-methyl-3-methylthio-4-quinolone is obtained, m.p. 285-288 ° C.

A mixture of 1.65 g of this compound, 3.105 g of potassium carbonate, 1.5 g of 1-iodobutane and 150 ml of dry acetone is refluxed overnight. The hot reaction mixture was filtered. The filtrate was evaporated to give a sticky solid which was triturated with diethyl ether. There was obtained 7-n-butoxy-1-methyl-3-methylthio-4-quinolone, m.p. 88-92 ° C.

A portion of this sulfide was oxidized with 3-chloroperbenzoic acid in chloroform at -20 ° C as described in Example 2. 7-n-butoxy-1-methyl-3-methylsulfinyl-4-quinolone, mp 148-150 ° C, was obtained. C (from ethyl acetate: light petrol).

He did

Using the procedure described in Example 5 using N-methyl-3-fluoroaniline instead of N-methyl-3-ethylaniline, a mixture of 7-fluoro-1-methyl-3-methylthio-4-quinolone and 5-fluoro-1-methyl 3-methylthio was prepared. -4-quinolone. As in the example, the mixture of isomers is oxidized to the corresponding sulfoxide. The product was purified by high pressure liquid chromatography on silica gel to give 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone, mp 226-228 ° C.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of 3- (alkylthio, alkylsulfinyl, or alkylsulfonyl) -4-quinolones of formula I wherein n is 0, 1 or 2, R C ^ _G alkyl optionally substituted by hydroxy or 0, _ ₄ alkoxycarbonyl, allyl, propynyl or benzyl, wherein the phenyl ring is optionally substituted by one or two C ^ _ ₄ alkoxy groups, ^R 2 ^C-4 and R, R₁ and R₃, which may be identical or different denote hydrogen, C ^ _ ₄ alkyl, C, _ ₄ alco-, cyclohexyl, -C 4 alkanoyl, halogen, trifluoromethyl or C ^ _ ₄ alkylthio, with the provided that a) when R, R and R are hydrogen and R ₂ is methyl, R contains more than one carbon atom and b) when R 1 and R 2 are hydrogen, R 2 is hydrogen or 7-methyl and R ₂ is ethyl, R ₂ contains more than one carbon atom, characterized in that it is cyclized at 50 to 150 - 0 in the presence of an acid or at 200 to 300 ° C in the absence of an acid, an acrylate of the formula II in which it represents R 8 is hydrogen or R 11; R? θΐ ^all-θ y ^£ ^ ° ^{1 no} phenyl-C ^ _ ₄ alkyl, R 1 to R 8 are as defined above and n is 0, 1 or 2, with the proviso that R 8 is alkyl when n is 1 or 2, followed by the following alkyl moieties wherein R 8 is hydrogen to form those wherein R 8 is has the meaning of R, and an optional oxidation that converts substances in which n is 0 to substances in which n is 1 or 2, or converts substances in which n is 1 to substances in which n is 2. 2. The process according to claim 1, for the preparation of 7-fluoro-1-methyl-3-methylthio-4-quinolone, characterized in that the corresponding substituted acrylate of the general formula II is used as the starting compound.