CS221907B2 - Process for preparing 3- (alkylthio, alkylsulfinyl or alkylsulfonyl) -4-quinolones - Google Patents

Abstract

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

Description

(54) Process for the preparation of 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.

It has been found that the compounds of general formula I 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) in which n is 0, 1 or 2,

R ₍ alkyl optionally substituted with hydroxyl or alkoxycarbonyl of 1 to 4 carbon atoms, allyl, propynyl or benzyl, where the phenyl ring is optionally substituted with one or two alkoxy groups of 1 to 4 carbon atoms,

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

Rj, R^ and R^ which may be the same or different represent hydrogen, C1-4 alkyl, alkoxyl, C8-4 alkanoyl, halogen, trifluoromethyl or alkylthio, _r with further proviso

a) if R^, R^ and R^ are hydrogen and Rg is methyl, then R, contains more than one carbon atom and

b) if Rj and R^ are hydrogen, R^ is hydrogen or 7-methyl and Rj is ethyl then Rg contains more than one carbon atom.

When R is C1-8 alkyl, it preferably contains 1 to 4 carbon atoms.

Examples of such groups for R1 to R8 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.

It has been found that the compounds of general formula I have antihypertensive properties. Administration of non-toxic doses of these compounds 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, alkylsufinyl or alkylsulfonyl)-4-quinolones of general formula I, characterized in that the cyclization at 50 to 150 °C in the presence of acid or at 200 to 300 °C in the absence of acid, an acrylate of general formula XI

COOR

s(o) _n n ₂ (II) in which means

Rg is hydrogen or R^,

R? lower alkyl or phenyl-lower alkyl (e.g. benzyl), R ₁ to Rg are as defined above and n is 0, 1 or 2, with the proviso that Rg is alkyl when n is 1 or 2, followed by alkylation of compounds in which Rg is hydrogen to give compounds in which Rg is R, and optional oxidation, which *

a) converts substances in which n is 0 into substances in which n is 1 or 2, or .

b) converts substances in which n means 1 to substances in which n means 2.

Preferably, R 1 is methyl or ethyl. These cyclization reactions can be carried out by conventional methods for this type of reaction. For example, when R 1 is hydrogen, the cyclization can be carried out by heating the acrylate in a suitable inert organic solvent, for example diphenyl ether. When R 1 is R 2 , the cyclization can be carried out in a mixture of acetic anhydride and concentrated sulfuric acid.

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

Alkylation in the above reaction is carried out using alkylating agents known in the art, for example halides R^-Hal, where Hal represents a halogen atom (chlorine, bromine or iodine), or di(R^)sulfates such as dimethyl sulfate. Similarly, oxidation of S to SO or SO ₂ , or oxidation of SO to SO ₂ is carried out using 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. It follows that pharmaceutical preparations suitable for the compounds of the invention include known forms of pharmaceutical preparations for oral, rectal or parenteral administration. Pharmaceutically acceptable carriers for such forms are well known in the art of pharmacy.

The therapeutic efficacy of the compounds of formula I has been demonstrated by standard laboratory animal tests. These tests include, for example, (A) oral administration of the active compounds to spontaneously hypertensive rats and (B) intraduodenal administration of the active compounds to normotensive rats.

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 protruding through the holes in the cage.

After 30 minutes in the cage, their blood pressure was measured using an inflatable cuff placed around the base of each tail. A greater pressure than the expected pressure was applied to the cuff. This pressure was slowly reduced, and the blood pressure at which arterial pulsations appeared was taken as the blood pressure. The rats were then removed from the cages and the test compound was orally administered to them in the form of a solution or suspension in 0.25% aqueous carboxymethylcellulose. In addition to reading the blood pressure before drug administration, blood pressure was measured 1.5 to 5.0 hours after drug administration. A substance was considered effective if it produced 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 means of a transfer from the arterial cannula. The test substance was administered into the duodenum as a solution or suspension in 0.25% aqueous carboxymethylcellulose. Blood pressure was recorded before and 30 minutes after drug administration. Substances that caused a .0% or greater reduction in arterial pressure were designated as effective.

The compounds of Examples 1 to 20 within the framework of general 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.

The preferred dosage of the compounds of general formula I is generally in the range of 0.1 to 100 mg/kg/day, more usually from 1 to 60 mg/kg/day.

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

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

In addition, the products according to the examples had satisfactory elemental analyses.

Example 1

2.2 ml of dimethyl sulfate were added dropwise to a stirred mixture of 7-chloro-6-methoxy-3-methylthio-4-quinolone (5.42 g, containing a small amount of the 5-chloro isomer), 3.2 g of anhydrous potassium carbonate and 400 ml of 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 above reaction is prepared as follows:

7.65 g of sodium was dissolved in anhydrous methanol (450 ml) and the solution was 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 methylthioacetate 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 overnight at room temperature. The resulting suspension of solid 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 mol of sodium methyl 3-hydroxy-2-methylthioacrylate 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. is obtained.

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

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

Example 2

1.5 g of 7-chloro-6-methoxy-1-methyl-3-methylthio-4-quinolone is dissolved in 75 ml of dichloromethane and a solution of 3-chloroperbenzoic acid (85%, 1.203 g) in 75 ml of dichloromethane is added dropwise at -20 °C to the resulting solution. The reaction mixture is poured into 300 ml of saturated aqueous sodium carbonate solution and the mixture is extracted 4 x 50 ml of dichloromethane. The peroxide-free organic extracts are dried and evaporated. The resulting solid is crystallized from ethyl acetate:methanol. 7-chloro-6-methoxy-1-methyl-3-methylsulfinyl-4-quinolone is obtained, m.p. 263-265 °C,

Example 3

The corresponding quinolones are methylated in a similar manner 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 to 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 to 162 °C,

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

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

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

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

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

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

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

i) 6-acetyl-1-methyl-3-methylthio-4-quinolone, m.p. 183 to 184 °C (from a mixture of ethyl acetate: light naphtha),

j) a mixture of isomers of 7-acetyl-1-methyl-3-methylthio-4-quinolone and 5-acetyl-1-methyl-3-methylthio-4-quinolone, m.p. 148 to 156 °C. High-pressure liquid chromatography on silica gel coated with 11% octadeeylsilane, eluting with a mixture of methanol:water 35:65 at a rate of 100 ml per minute, gives the pure 7-isomer, m.p. 245 to 246 °C,

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

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

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

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

The desired 1-H-4-quinolones for the above reactions are prepared in a similar manner to Example 1. The corresponding aniline is converted to the acrylate ester of formula III, to give the quinolone of formula IV which is then cyclized.

(III) (IV)

The following intermediates were prepared in this way:

Acrylates of formula III

Z W t. t. °C

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

From W v. 1 .. °C 3,5-( _CH3 ) ₂ ^CH 3 94 until 96 3,5-Cl ₂ ^CH 3 110 until 125 3-OCH ₃ ^CH 3 76 until 78 2-F ch ₃ oil 3-C1 ^G 2 ^H 5 56 until 58 4-COCH ₃ CH 85 until 87 3-COCH ₃ ^CH 3 73 until 75 3-OCH ₃ -4-Cl CH, 115 until 116 3_B_4_OCH ₃ ^CH 3 85 until 86 3-isopropyl CH ₃ 50 to 52 3-P CH ₃ 80 until 84

Quinolones of formula IV

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

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

Example 4

In a manner similar to the procedure in Example 2, sulfides a) to k) from Example 3 are oxidized to the following sulfoxides:

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

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

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

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

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

f) 7-methoxy-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 233 to 235 °C (from a mixture of ethyl acetate: light naphtha),

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

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

i) 6-acetyl-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 254 to 255 °C (from a mixture of ethyl acetate: methanol),

j) 7-acetyl-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 245 to 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 5.7 cm x 30 cm column containing 420 g of silica gel impregnated with 11% octadecylsilane was used. The product was eluted by reverse phase with a 35:65 methanol:water mixture at a rate of 100 ml/min.

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

Example 5

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

The mixture was cooled to room temperature, poured into ice/water (300 ml) and extracted with 3 x 200 ml ethyl acetate and then 2 x 150 ml dichloromethane. 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 was obtained as an oily solid. The isomers were separated by high pressure liquid chromatography using 325 g silica gel (5.7 cm x 30 cm).

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

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

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

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

The following compounds were prepared in the same manner without the use of high-pressure liquid chromatography:

c) 1-methyl-3-propylthio-4-quinolone, m.p. 74 to 76 °C (from a mixture of ethyl acetate: light petroleum),

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

e) 3-tert-butylthio-1-methyl-4-quinolone, m.p. 53 to 55 °C (from a mixture of ethyl acetate: light petroleum),

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

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

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

Example 6

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

a) 5-ethyl-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 196 to 197 °C. The product was purified by crystallization from ethanol and subsequent high-pressure liquid chromatography on silica gel and elution 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 to 229 °C,

c) 1-methyl-3-propylsulfinyl-4-quinolone, m.p. 153-155 °C. Purified by preparative thin layer chromatography on silica gel using a mixture of dichloromethane:ethanol 95:5 as eluent and extraction of the product with ethanol,

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

e) 3-n-butylsulfinyl-1-methyl-4-quinolone, m.p. 105 to 106 °C. purified by the method described above under c) after crystallization from a mixture of ethyl acetate: light naphtha and then toluene: diethyl ether,

f) 8-methoxy-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 147-148 °C from a mixture of ethyl acetate: light gasoline).

The oxidation product from example (g) was isolated by extraction with dichloromethane. It was purified by high pressure liquid chromatography on silica gel. Elution with ethyl acetate : methylene chloride : ethanol (45:45:10) at a rate of 200 ml per minute gave:

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

h) 1,6,7-trimethyl-3-methylsulfinyl-4-quinolone, m.p. 253-254 °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 is filtered and the filtrate is evaporated to dryness. The resulting oil is dissolved in 50 ml of chloroform. The solution is washed with water, dried and evaporated. The resulting oil is triturated with light petroleum. The solid product, 1-n-butyl-3-methylsulfinyl-4-quinolone, m.p. 103-105 °C is obtained.

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

^R10 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 is prepared by cyclization of methyl-3-anilino-2-methylthioacrylate as described in Example 1, followed by oxidation of the resulting 3-methylthio-4-quinolone as described in 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 to 5 °C, yielding 7-methoxy-1-methyl-3-methylsulfonyl-4-quinolone, m.p. 212 to 214 °C (from a mixture of ethyl acetate: methanol),

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

c) 1-methyl-3-methylsulfinyl-7-trifluoromethyl-4-quinolone is oxidized in dichloromethane at 0 °C, yielding 1-methyl-3-methylsulfonyl-7-trifluoromethyl-4-quinolone, m.p. 300-301 °C (from a mixture of methanol:ethyl acetate),

d) 3-n-butylthio-1-methyl-4-quinolone is oxidized in chloroform at 0 °C, yielding 3-n-butylsulfonyl-1-methyl-4-quinolone, m.p. 107 to 107.5 °C) from a mixture 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, yielding 7-tert.butyl-1-methyl-3-methylsulfonyl-4-quinolone, m.p. 247 to 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 was stirred and heated to reflux 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 was 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 was refluxed overnight. The hot reaction mixture was filtered. The filtrate was evaporated to give a sticky solid which was triturated with diethyl ether. 7-n-butoxy-1-methyl-3-methylthio-4-quinolone was obtained, m.p. 88-92°C.

Part of this sulfide is oxidized with 3-chloroperbenzoic acid in chloroform at -20°C, as described in Example 2. 7-n-butoxy-1-methyl-3-methylsulfinyl-4-quinolone is obtained, m.p. 148-150°C (from ethyl acetate: light petroleum).

Example

A mixture of 7-fluoro-1-methyl-3-methylthio-4-quinolone and 5-fluoro-1-methyl-3-methylthio-4-quinolone was prepared by the method described in Example 5, using N-methyl-3-fluoroaniline instead of N-methyl-3-ethylaniline. The mixture of isomers was oxidized to the corresponding sulfoxide by the method described in the example. The product was purified by high-pressure liquid chromatography on silica gel to give 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone, m.p. 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.