CS274499B2 - Method of 7-fluor-1-methyl-3-methylthio-4-quinolone production - Google Patents

Abstract

The solution concerns a method of production of the compound of formula I', characteristic by the fact that the compound of formula V is formylated and the obtained product of formula IV is let to react with halogenation agent, which results in origination of compound of general formula III, where R1 is halogen and R2 is hydrogen or halogen. This compound is let to react with sulphuric nucleophile in the form of methanethiolate anion and the obtained product of formula II is cyclized in presences of a base. The produced product shows therapeutic efficiency in treatment of cardiovascular diseases and serves as intermediate product for production of therapeutically significantly active 7-fluor-1-methyl-3-methylsulfinyl-4-quinolone.<IMAGE>

Description

The present invention relates to a process for the preparation of 7-fluoro-1-methyl-3-methylthio-4-quinolone.

British Patent Specification No. 2047691 discloses quinolone compounds exhibiting therapeutic activity as antihypertensive agents, and also various methods of making such compounds. European Patent No. 149519 also discloses some of these chlorolone compounds having therapeutic efficacy in the treatment of heart failure.

British Patent Specification No. 2047691 discloses that certain quinolones may be prepared by reaction of p-ketosulfoxides of the general formula

represents a lower alkyl group.

in which

R with tri (lower alkyl) orthoformate.

The present inventors have now prepared valuable novel compounds useful in the preparation of some of the quinolones described in British Patent Specification No. 2047691. These novel compounds have a property that does not occur in the above-described p-ketosulfoxides that they undergo intramolecular cyclization to form the aforementioned quinolone compounds. Said novel compounds correspond to the general formula (I)

-S (O) _n CH ₃ (I) wherein δ has a value of 0, 1 or 2.

The compounds of formula I exhibit valuable therapeutic efficacy in the treatment of cardiovascular diseases, in particular in the treatment of hypertension and heart failure. A specific compound of formula (I) produced by the process of the present invention is 7-fluoro-1-methyl-3-methylthio-4-quinolone corresponding to formula (I ') below. This compound can be oxidized by known methods, for example by reaction with 3-chloroperoxybenzoic acid (see, for example, British Patent Specification No. 2047691) to give 7-fluoro-1-methyl-3-methylsulfinyl-4-chloro-3-one (flosequinan). Flosequinan shows particularly valuable therapeutic efficacy in the treatment of heart failure and hypertenae.

The compound of formula (I ') can be prepared from compounds of formula (V) by a multi-step reaction without isolation of the intermediates. It has been found that this four-step process, initiated by cyclization of the compound of formula II, provides high yields of the compound of formula I *.

Accordingly, the present invention provides a process for the preparation of 7-fluoro-1-methyl-3-methylthio-4-quinolone of formula (I ').

CS 274 499 B2 characterized in that DC

(a) a compound of formula V

d)

»V) formyl, for example by reaction with mixed formic anhydride and acetic anhydride, to form a compound of formula IV

O

(IV),

b) reacting the product of step a) with a halogenating agent, for example sulfuryl chloride or bromine, to form a compound of formula III

(III) wherein

R 1 represents a halogen atom, for example chlorine or bromine, and

R ₂ represents halogen, for example chlorine use or bromine nsbo hydrogen,

c) reacting the product of step b) with a sulfur nuclosophile in the form of a methanethiolate anion to form a compound of formula II

CS 274 499 B2

and

d) the product of step c) is cyclized in the presence of an organic or inorganic base to give a compound of formula I.

Preferably, the cyclization reaction in a basic medium is carried out in the presence of an amine or ions selected from the group consisting of: hydroxide, alkoxide and thiolate ions. Particularly suitable bases useful in the cyclization reaction of the invention are sodium hydroxide, sodium ethoxide, triethylamine and pyridine. The preferred base is sodium hydroxide in the form of an aqueous solution.

According to a particularly preferred embodiment, the product of step a) is reacted with aulfuryl chloride to give a compound of formula III wherein chlorine and R ₂ are hydrogen, and the product of step b) is reacted with sodium methanethiolate from? to form a compound of formula I \

Compound of Formula V A reaction of a compound of Formula VI can be prepared

O

H

with methylamine, preferably by heating in a closed vessel in the presence of a catalyst, e.g. copper.

Preferably, the 7-fluoro-1-methyl-3-methylthio-4-quinolone produced by the above process is further oxidized to give 7-fluoro-1-methyl-3-methylsulfinyl-4-quinolone (floeequinan), for example by treatment with 3-fluoro-1-methylthio-4-quinolone. -chloroperoxybenzoic acid.

It has been found that the yield of the compound of formula i 'in the above-described four-step process a) to d) can be very high - typically higher than 75%, especially higher than 85%. The high overall yield indicates a very favorable yield in each of the reaction steps. Such a high overall yield could not be expected in advance due to possible side reactions such as halogenation at other sites of the molecule, deformylation of compounds of formulas III and IV in the sieve and substitution of the fluorine substituent. The possibility of progressively carrying out the reaction is also highly advantageous as it leads to a significant reduction in the time required to carry out the entire process by eliminating the need for isolation and purification of the intermediates, which also reduces production costs. In addition, the reagents and reagents used in the above process are readily available and handled. Furthermore, this process can also be used in industrial production.

Another method of making compounds of formula (i). As well as a process for the production of other compounds falling within the scope of the above general formula (I), it is the subject of our patent 274 499 B2 seeding Czechoslovak Patent Specification No. 274 4B7.

Valuable intermediates of the multistage process described above are the N-formyl derivatives of the formula XI (XI) - NCHO

CH in which

R ₄ represents a hydrogen, chlorine or bromine atom, a methylthio group, a methylsulfinyl group or a methylsulfonyl group.

It is assumed that the compounds of formula XI are new.

The compounds of formula (I ') may exist in more than one polymorphic form. The individual polymorphic forms have characteristics of the IR spectrum and different melting temperatures. In some cases, the individual polymorphic forms are interconvertible - for example, a polymorphic form with a lower melting point can be converted to a polymorphic form more thermodynamically more stable by heating and / or grinding or prolonged storage.

The invention is illustrated by the following non-limiting examples. All the parts and percentages mentioned have been minified and the weight percentages of the mixtures of solvents are given in volume ratios. The characterization of the substances is carried out by elemental analysis using one or more of the following spectroscopic techniques: NMR spectroscopy, IR spectroscopy and mass spectroscopy.

Example 1

a) A solution of 161.0 g of 1- (4-fluoro-2-methylaminophenyl) 2-methylsulfinylethanone was added to the mixture of 228.2 g of zinc dust, 210 ml of acetic acid and 392 ml of ethanol with stirring at 80 ° C for 1 hour. (see Preparation) in 770 mL acetic acid. The reaction mixture was stirred at 80 ° C for an additional hour, then allowed to cool to room temperature, filtered and the residue washed with 400 mL of dichloromethane. The filtrate was combined with palpine and concentrated by distillation until the temperature of the distillation residue reached 132 ° C. The remaining mixture was cooled to room temperature, 1 L of water and 330 mL of dichloromethane were added successively, the resulting mixture was stirred for 10 minutes, and then the layers were separated. The aqueous phase is extracted twice with 200 ml of dichloromethane each time, the organic extracts are combined, washed with 200 ml of 5M aqueous sodium hydroxide solution and evaporated in vacuo. Vacuum distillation of the residue (b.p. 74 DEG C./0.5 mbar) gives 4 ' -fluoro-2 '-( methylamino) acetophenone, m.p.

b) A mixture of 63 ml of acetic anhydride and 43 ml of formic acid was heated under stirring at 50-60 ° C under nitrogen for 2 hours. The resulting mixture was cooled in ice water and 52.9 g of 4'-fluoro-2 '- (methylamino) acetophenone was added portionwise over 30 minutes while maintaining the temperature below 30 ° C. The reaction mixture was stirred at room temperature for 1 hour, then cooled in ice-salt and 220 ml of water and 123.5 ml of aqueous sodium hydroxide solution (density 1.5) were added successively while maintaining the temperature below 30 ° C. The mixture was extracted three times with 85 ml of dichloromethane each time, the combined extracts were kept under nitrogen at 0 ° C overnight and then stirred under nitrogen while maintaining the temperature below 2 ° C over a period of 40 minutes.

CS 274 499 B2 flow 56 ml sulfuryl chloride in 75 ml dichloromethane. After stirring at 0 ° C for 2 hours, 190 ml of water are added while maintaining the temperature below 25 ° C, the layers are separated, the organic phase is cooled to 0 ° C in ice-salt mixture and dropped thereto while maintaining the temperature below 5 ° C. within 1 hour 266 ml of 2.0 GBM methanolic sodium methanethiolate solution. The reaction mixture was allowed to warm to room temperature, stirred for 2 hours, then treated with 60.5 mL of 5M hydrochloric acid and 135 mL of water. The layers were separated, the aqueous phase was extracted with 50 mL of dichloromethane, the organic phase was combined and the solvent was distilled off under nitrogen atmosphere at atmospheric pressure. During the distillation, a total of 205 ml of petroleum ether (bp 102-120 ° C) was gradually added to the distillation flask. Distillation is continued until the temperature of the mixture rises to 100 ° C, the remaining mixture is then cooled to 20 ° C, filtered and the residue is washed twice with 50 ml of petroleum ether (bp 102-120 ° C). After drying the solid material under vacuum at 50 ° C, 61.3 g of 7-fluoro-1-methyl-3-methylthio-4-quinolone having a melting point of 147-149 ° C are obtained.

1C (KBr-technology): 3040, 2900, 1625, 1600, 1575, 1465, 1285, 1240, 1165, 1080, 940,

IB3X η

840, 820, 770 cm ^-1 .

Example 2

a) Smě3 315.8 ml of 33% (w / w) solution of methylamine on an industrial methylated spirits, 291.6 ml industrial methylated spirit, 203.4 g 2 ^{r-chloro-4'-fluoroacetophenone} and 2.0 g of powdered The copper was heated to 80 [deg.] C. in a glass autoclave for 1 hour, stirred at 80 [deg.] C. for a further 2 hours, then allowed to cool to 45 [deg.] C. within an hour. The mixture 9e is transferred to another reaction vessel and the autoclave is washed with 50 ml of methanol-denatured technical alcohol, which is then added to the other reaction vessel. The mixture was heated to 50 ° C, a solution of sodium sulfide nonahydrate (11.2 g) in 117 mL of water was added, the reaction mixture was heated at 50 ° C for another 15 minutes, then filtered and the residue washed with 100 mL. The filtrate was combined with the washings and evaporated to a brown oily residue, which was stirred with 800 ml of 5M hydrochloric acid for 2.5 hours. After the addition of 600 ml of dichloromethane, the layers were separated and the aqueous phase was extracted twice more with 300 ml of dichloromethane each time. The organic phases were combined and evaporated to give ^4-fluoro-# 2 '- (methylamino) acetophenone as a brown oil which solidified at room temperature.

b) A mixture of acetic anhydride (92 ml) and formic acid (62.7 ml) was heated under stirring at 50-60 ° C under nitrogen for 2 hours, then cooled to room temperature, and 77.1 g of the product prepared in para. and). The reaction mixture was stirred at room temperature for 1 hour, then cooled in an ice / salt mixture and 320 ml of water and 180 ml of aqueous sodium hydroxide solution (density 1.5) were added successively while maintaining the temperature below 30 ° C. The mixture was extracted three times with 125 ml of dichloromethane each time and the combined extracts were kept under nitrogen at 0 ° C overnight. To the dichloromethane solution was added a solution of 81.7 mL of sulfuryl chloride in 110 mL of dichloromethane over 35 minutes while stirring under nitrogen and maintaining the temperature by cooling V8 with an ice / salt mixture below 0 ° C. After stirring at 0 ° C for 1.75 hours, while maintaining the temperature below 25 ° C, 280 ml of water are added over 25 minutes, the layers are separated, the organic phases are cooled in a mixture of ice and salt under nitrogen and over 70 minutes. 388 ml of a 2.65 M methanolic sodium methanethiolate solution were added thereto while maintaining the temperature below 5 ° C. The resulting mixture was allowed to warm to room temperature, stirred for 1.5 hours, acidified with 100 mL of 5M hydrochloric acid, allowed to stand overnight, then 200 mL of water was added. The layers were separated, the aqueous phase was extracted with an additional 70 mL of dichloromethane, the organic phases were combined and the solvent was distilled off, replacing 300 mL of petroleum ether (bp 102-120 ° C) during distillation. Distillation was continued until the temperature of the distillation residue rises to 100 ° C, then the remaining mixture cooled to 20 ° C, filtered and the filter residue was washed twice with 70 ml of petroleum ether (b.p. 102-120 ^D C). After drying the residue in vacuo at 50 ° C, it is obtained

EN 274 499 02

72.9 g of an orange-yellow solid, from which a sample of 0.30 g was recrystallized from 3.5 ml of methanol-denatured industrial alcohol, to obtain 0.2 g of 7-fluoro-1-methyl-3-methylthio- Of 4-quinolone, m.p. 162-163 ° C. The iC spectrum is identical to the product spectrum of Example 1.

Preparation

To a solution of 72.2 g of potassium tert-butoxide in 300 ml of dimethylsulfoxide at room temperature under nitrogen was added a solution of 28.9 g of tert-butyl-4-fluoro-2-methylaminobenzoate in 133 ml of dimethylsulfoxide. The mixture was heated to 50 ° C with stirring for 8 hours, then cooled to room temperature and 1300 mL of water was added while maintaining the temperature below 35 ° C.

Extraction with trichloromethane and evaporation of the extract in vacuo gave 1- (4-fluoro-2-methylaminophenyl) -2-methyleulfinylethanone, m.p. 129-134 ° C.

Claims (2)

A process for the preparation of 7-fluoro-1-methyl-3-methylthio-4-quinolone of the formula i 'characterized in that. that is a) reacting the compound of formula V with the formylation formula IV with a reagent at a temperature of from -10 to 40 ° C to form a compound O b) the product of step a) is dissolved in a solvent, e.g. CS 274 499 B2 is between -10 to 40 ^D C, is reacted with a halogenating agent to give a compound of formula IXI O Tt (III) in which R | represents a halogen atom and R 6 represents a halogen atom or a hydrogen atom, c) reacting the product of step b) in a solvent such as dichloromethane at a temperature in the range of -10 to 40 ° C with a simile nucleophile in the form of a methanethiolate anion to form a compound of formula II O e d) the product of step c) is cyclized in the presence of an organic or inorganic base, for example triethylamine or pyridine, at a temperature of from -10 to 40 ° C to give a compound of formula i '. 2. The process of claim 1 wherein the methanthiolate anion is added to the reaction mixture in the form of sodium methantiolate.