HU207042B - Process for producing substituted indolinone derivatives - Google Patents

Abstract

The present invention relates to a compound of formula IV wherein X is halogen and n is 1,2 or 3. It is an object of the present invention to provide a reducing cyclization of a compound of formula (III) wherein X and n are as defined above in the presence of at least 2 equivalents of anhydrous iron (1H) chloride and at least 2 equivalents of acetyl halide and a solvent. A compound of formula (I) wherein X and n are as defined above and Z is halogen; dehalogenate to remove the halogen at the Z site. The compounds of the invention are used as intermediates in the preparation of other substituted indo-derivatives. EN 207 042 B Scope of the description: 6 pages (including 1 sheet)

Description

The present invention relates to a process for the preparation of substituted indoline derivatives of formula IV.

These compounds are intermediates for improved processes for the preparation of other indolinone derivatives. The substituted indoline derivative is used in the treatment of cardiovascular diseases according to European Patent 0113 964B.

Processes for the preparation of substituted indolinone derivatives have already been reported in the literature, in particular by carrying out a reductive cyclization of nitrostyrene compounds in the presence of acetyl chloride and ferric chloride [1. for example, Guillanmel J. et al., Tetrahedron 36, 2459-2465 (1980) and Guillanmal J. et al., Heterocycles 17, 1531-1536 (1980)]. The disadvantage of such processes is that the yield of cyclized products is low and a mixture of other non-cyclized products is formed. Only one example of the above publications reports the formation of unique cyclized articles in a yield of only 49%.

It has been found that certain substituted indolinone derivatives can be prepared under significantly reduced yields (up to 98% yield of cyclized products) under reducing cyclization conditions, based on the above data.

Thus, according to our own invention, there is provided a process for the preparation of compounds of formula I wherein R is C 1 -C 5 alkyl and n = 1,2 or 3 and pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION The present invention is directed to a process for the preparation of a compound of Formula IV wherein the compound of Formula H wherein X is halogen and n is a reduction cyclization of at least 2 equivalents of anhydrous ferric chloride and at least 2 equivalents. equivalents of acyl halide, and in the presence of a solvent, to give a compound of formula (ΙΠ), wherein X and n have the meanings given above and

Z is halogen;

then, from the compound of formula (H1), the compound of formula (IV) wherein X and n are as defined above is removed by removal of a halogen atom corresponding to Z.

In the product thus obtained, X is substituted with -N (R) ₂

where R is as defined above, and

optionally converting the compound into a pharmaceutically acceptable salt to form compounds of formula (I).

Acetyl halide is preferably used as the acetyl halide for the cyclization of the compounds of formula (II). Dichloromethane is the preferred solvent.

Preferably X is bromine.

The substituent Z is preferably bromine, preferably chlorine.

n is 1,2 or 3, preferably 2.

The cyclization of the compound of formula (U) is conveniently carried out in the presence of 2 equivalents of acetyl chloride or acetyl bromide and 2 equivalents of ferric chloride. Preferably, 2 equivalents of acetyl chloride and 3 equivalents of ferric chloride are used for cyclization.

The process of the invention is particularly suitable for the preparation of compounds of formula (ΙΠΑ) which are used to convert compounds of formula (IV) into compounds of formula (IA) or their hydrochloride.

The starting nitro-styrene compounds of formula (H) may be prepared by methods well known in the art. For example, isochromane (e.g. from Aldrich Chemical Company) treated with bromine gives the corresponding 2- (2'-bromoethyl) -benzaldehyde which is reacted with nitromethane, for example, in the presence of sodium methoxide, to give the desired nitro-styrene compound, e.g. 2'-Bromoethyl) -beta-nitrostyrene is obtained.

The invention is illustrated by the following examples.

Example 1

Preparation and purification of 2- (2'-Bromoethyl) -benzaldehyde

Bromine (29.6 g, 185.2 mmol) dissolved in dichloromethane (20 mL) was added over 1 hour to isochroman (25 g, 186.0 mmol) in dichloromethane (150 mL) near a strong light source at a rate such that the reaction temperature should be about 35 ° C. The mixture was kept near the light source for another hour, maintaining the temperature below 40 ° C. The mixture was concentrated under reduced pressure to give a heavy yellow oil which was kept in an oil bath at 80 ° C for 1.5 hours under nitrogen. The crude product was dissolved in dichloromethane (150 mL) and washed with water (100 mL). The organic phase was washed with sodium bicarbonate solution (saturated solution diluted with water to 100 mL, 30 mL). The organic layer was washed with water and dried (Mg SO _4). The excess solvent was evaporated under reduced pressure to give 34.07 g (88.9%) of 2- (2'-bromoethyl) -benzaldehyde as a heavy yellow oil.

Cleaning

Sodium metabisulfite (25 g) was dissolved in water (25 mL) and methanol-denatured industrial carbon (20 mL) was added. The above benzaldehyde was added, stirred for 30 minutes, and dichloromethane (75 mL) was added. The resulting slurry was filtered to give a white powder, which was added to a solution of sodium carbonate (13.5 g of sodium carbonate in 220 mL of water) and dichloromethane (50 mL) was added. After shaking, the organic and aqueous layers were separated. The extractions were repeated twice. The three extracts were combined, dried (MgSO ₄ ) and evaporated to give 14.99 g of 2- (2'-bromoethyl) -benzaldehyde as a translucent pale yellow oil; yield: 43.9%; boiling point: 110 ° C / 5.33 Nm- ² .

The example

Preparation of 2- (2'-Bromoethyl) -beta-nitrostyrene

Nitromethane (47.9 g, 0.785 mol) was dissolved in methanol (250 mL) under nitrogen and cooled to -10 ° C. Sodium methoxide solution (29.6%, 106.7 g) in methanol (70 mL) was added.

HU 207 042 B

The mixture was stirred at -10 ° C for 50 minutes and the resulting slurry was stirred for an additional 50 minutes at -30 ° C to -35 ° C. To the suspension was added 2- (2'-bromoethyl) -benzaldehyde (106.5 g, 0.5 mol) in dimethylformamide (220 mL) over 30 minutes at -35 ° C. The mixture was further stirred at -30 ° C for 40 minutes and then quenched by pouring into 0 ° C hydrochloric acid solution (1100 mL, 6N). The resulting yellow solid was filtered, washed with water and dried to give 102.0 g (70%) of 2- (2'-bromoethyl) -beta-nitrostyrene; melting point 6768 ^e C.

Example 2B

Preparation of 2- (2'-Bromoethyl) -beta-nitrostyrene

2- (2'-Bromoethyl) -benzaldehyde (10 g) was previously added to a solution of alkaline methanol (200 mL) in a small amount of sodium raethoxide solution (1 g, 30% methanol solution, w / w). methane (3.7 g) was added and the resulting solution was cooled to 0 ° C under nitrogen. A solution of 30% sodium methoxide (9 g) in methanol (50 mL) was then added with stirring for about 30 minutes. The reaction mixture was then stirred at about 0 ° C for 1 hour and then added to 6N hydrochloric acid (200 mL). The yellow crystals precipitated 2- (2'-bromoethyl) -beta-nitrostyrene (9.51 g, 80%) by filtration and air-dried at 20-30 ° C.

The pre-alkalization of methanol allows only one solvent to be used, the addition is safer and the reaction temperature is more readily achieved.

The example

Preparation of 4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one

2- (2'-Bromo) -beta-nitrostyrene (1.69 g, 6.6 mmol) was dissolved in dichloromethane (50 mL) and cooled to 0 ° C with stirring. To the resulting solution was added acetyl chloride (0.96 mL, 1.06 g, 13.5 mmol) followed by powdered anhydrous ferric chloride (4.38 g, 27 mmol). The dark red suspension was stirred vigorously at 0 ° C for 5.5 hours, then poured into a mixture of 100 ml of 5% hydrochloric acid and 100 ml of chloroform, shaken for 5 minutes, and the layers were separated. Dry over MgSO 4 and evaporate the chloroform phase to give 1.78 g (98%) of 4- (2'-bromoethyl) -3-chloro-3-dihydro-2H-indol-2-one as an off-white crystalline powder. Trituration with ether or recrystallization from chloroform / ethanol (15; 1) gives a white powder. The chlorination of the crude product is carried out without further purification.

Example 3B

Preparation of 4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one

2- (2'-Bromoethyl) -beta-nitrostyrene (44 g, 172 mmol) was dissolved in dichloromethane (1000 mL) and acetyl chloride (24 mL, 338 g) was successively stirred at -10 ° C. mmol) and iron (HI) chloride (8.38 g, 615 mmol) were added. The reaction mixture was stirred at -10 ° to 0 ° C for 5 hours and then washed with aqueous 1N hydrochloric acid (2x750 mL). After drying, the dichloromethane is evaporated in vacuo. The remaining viscous brown material (57 g) was suspended in dichloromethane / gasoline (4060 ° C (3: 1, 10 vol)). The resulting light brown solid was collected to give 30.76 g (65%) of 4- (2'-bromoethyl) -3-chloro-3-dihydro-2H-indol-2-one; mp 168-170 ° C.

The commercial preparation of 4- (2'-bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one is illustrated in Figures 3C, 3D. and 3E. example.

Example 3C

Preparation of 4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one

To a pre-cooled solution of ferric chloride (28.5 kg) in dichloromethane (340 L) at 0 ° C was added acetyl chloride (9.2 kg) at such a rate that the reaction temperature was not higher At 5 ° C. The reaction mixture was stirred at 0 ° to -5 ° C for 15 minutes. A premixed solution of 2- (2'-bromoethyl) -beta-nitrostyrene [12.88 kg (16.22 kg wet weight: water content 20.6%)] in dichloromethane (551) is added at a rate so that the reaction temperature does not exceed 5 ° C. The reaction mixture was stirred at 5-10 ° C for 5 hours. Thin layer chromatography (TLC) showed complete reaction. Water (2401) is then added to the reaction mixture at such a rate that the temperature is not higher than 20 ° C. The mixture was stirred for 30 minutes. The dichloromethane layer was isolated and further washed with water (3 x 120 L). The dichloromethane phase is then concentrated to about 60 L. After cooling (20 ° C), petroleum ether (boiling point 60-80 ° C, 40 L) is added and the resulting precipitate is stirred at 10 ° C for 30 minutes. High performance liquid chromatography (HPLC) analysis of the crude reaction mixture showed a purity of 93.22% of the expected product. 4- (2'-Bromomethyl) -3-chloro-1,3-dihydro-2H-indol-2-one is collected by filtration, the filtrate is washed with petroleum ether (60 L) and dried overnight at 80 ° C. Yield: 10.8 kg (78%).

3D example

Preparation of 4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one

3C is repeated. except that the amount of 2- (2'-bromoethyl) -beta-nitrostyrene was 12.88 kg (16.95 kg wet weight; water content 24%). HPLC analysis of the crude reaction mixture showed the purity of the expected product to be 96.83%. Isolation of the product gave 7.5 kg (54%) of the title compound.

Example 3E

Preparation of 4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one

3C. Example 2 was carried out with the difference that the amount of 2- (2'-bromoethyl) -beta-nitrostyrene was 11.7 kg (15.28 kg wet weight: 23.4%).

EN 207 042 B water content). HPLC analysis of the crude reaction mixture indicated that the expected product was 96.2% pure. Isolation of the product gave 5.7 kg (54%) of the title compound.

Example 4A

Preparation of 4- (2'-Bromoethyl) -1,3-dihydro-2H-indol-2-one

4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one (34.5 g, 126 mmol) with 10% Pd / C (3.5 g) stirring, and sodium hypophosphite hydrate (45 g) dissolved in 99% industrial denatured alcohol / water 19: 1 (400 mL) at 85 ° C. According to HPLC analysis, the reaction was complete within 1 hour. The reaction mixture was filtered and concentrated in vacuo. The remaining yellow solid was suspended in water / industrial denatured alcohol (9: 1 (200 mL)), filtered, stirred, and dried overnight. 26.32 g (87%) of 4- (2'-bromoethyl) -1,3-dihydro-2H-indol-2-one are obtained; mp 140-145 ° C. HPLC analysis showed that the product consisted essentially of one component (92.8% purity).

Example 4B

Preparation of 4- (2'-Bromoethyl) -1,3-dihydro-2H-indol-2-one

4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one (23.6 g, 86 mmol), sodium hypophosphite hydrate (35 g) and 10% Pd / C catalyst (60%, w / w, 2.6 g) in industrial denatured alcohol / water (250 mL: 30 mL) was stirred at 80 ° C. HPLC analysis indicated that the reaction was complete within 2 hours. The inorganic components are removed by filtration and the organic solvent is evaporated in vacuo. The solid residue was suspended in water (100 mL) and dried overnight to give 17.0 g (82%) of 4- (2'-bromomethyl) -1,3-dihydro-2H-indol-2-one.

Example 4C

Preparation of 4- (2'-Bromoethyl) -1,3-dihydro-2H-indol-2-one

10% Pd / C (0.5 g, 0.2 mmol), 4- (2'-Bromoethyl) -3-chloro-1,3-dihydro-2H-indol-2-one (5 g, 19.2) a suspension of ethyl acetate (100 mL) was heated to reflux with stirring and aqueous sodium hypophosphite (5 g in 30 mL, 472 mmol) dissolved in water over 15 minutes. Thin layer chromatography (methanol: dichloromethane, 1:30) immediately after addition confirmed the completion of the reaction. The reaction mixture was filtered through a "Hi-Flow" bed while hot, the aqueous layer was removed and the filtrate was evaporated to dryness in vacuo. The solid residue was suspended in water (120 mL) and the suspension was filtered off with suction. 4- (2'-Bromoethyl) -1,3-dihydro-2H-indol-2-one (4.16 g, 95%) is obtained as a white solid. The purity of 4- (2'-bromoethyl) -1,3-dihydro-2H-indol-2-one as determined by HPLC was 99.11%.

Example 5A

Preparation of 4- [2- (Dipropylamino) ethyl] -1,3-dihydro-2H-indol2-one

Under a nitrogen atmosphere, 4- (2'-bromoethyl) -1,3-dihydro-2H-indol-2-one (245 mg, 102 mmol) in di- (n-propyl) amine previously degassed with nitrogen (1.00 g, 10 mmol) (1.35 mL). After stirring for 30 min, degassed acetonitrile (5 mL) was added to give a pale yellow solution. After 1 hour, the solution is heated and refluxed for 5 hours. After cooling to ambient temperature, the solution was poured into 1N hydrochloric acid (35 mL) and extracted with ether (50 mL). The aqueous phase was neutralized with solid sodium bicarbonate (pH 7-7.5) and extracted with dichloromethane (50 mL). The layers were dried individually and the ether layer evaporated to give 4-vinylindol-2-one (60 mg, 37.7%). Evaporation of the dichloromethane phase afforded 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one (155 mg, 58.5%) as the free base which was obtained in anhydrous ethanol. 5 mL) and saturated with hydrogen chloride gas. The solvent was evaporated in vacuo to give the crude hydrochloride salt (170 mg) as a pale yellow solid. Recrystallization from anhydrous ethanol (2 mL) gave pale yellow crystals of 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one hydrochloride (110 mg, 63% of free base); mp 242244 ° C.

Example 5B

Preparation of 4- [2- (Dipropylamino) ethyl] -1,3-dihydro-2H-indol2-one hydrochloride

Water (200 mL) was heated under nitrogen and then cooled to room temperature. 4- (2'-Bromomethyl) -1,3-dihydro-2H-indol-2-one (10 g) and di-propylamine (42 g) were added to the water, stirred vigorously for 90 minutes. Heat at <RTI ID = 0.0> C </RTI>. All starting materials were consumed by HPLC analysis. Excess di- (n-propyl) amine is removed in vacuo by azeotropic distillation and the reaction mixture is stirred at about 30 ° C. The reaction mixture was extracted with ethyl acetate (60 mL), the organic layer was removed, dried (MgSO ₄ ), filtered and diluted with isopropanol (100 mL). The ethyl acetate / isopropanol solution was stirred at 0 ° C and concentrated hydrochloric acid (3 mL) was added. The resulting yellow precipitate was filtered off with suction, washed with isopropanol (50 mL) and dried overnight at 80 ° C in a "Mash Vacuum". 4- [2- (dipropylamino) ethyl] -1,3-dihydro-2H-indol-2-one hydrochloride (6.6 g, 53%) was obtained as a yellow powder with a purity of 97.00 by HPLC. %.

Typically, samples of the resulting material are further purified by recrystallization from isopropanol or by basification and re-acidification; the purity of the product thus obtained is 98-99%.

Claims (6)

A process for the preparation of a compound of formula IV wherein X is halogen and n is 1, 2 or 3, wherein a compound of formula II is wherein HU 207 042 Β X and n are the above reducing cyclization in the presence of at least 2 equivalents of anhydrous ferric chloride and at least 2 equivalents of acetyl halide and a solvent, and the resulting compound of formula III wherein X and n are as defined above and Z is halogen; dehalogenating to remove the halogen at Z. 2. The process of claim 1 wherein the acetyl halide is acetyl bromide. 3. A process according to claim 1 wherein the acetyl halide is acetyl chloride. 4. The process of claim 3 wherein 2 equivalents of acetyl chloride and 3 equivalents of ferric chloride are used. 5. Process according to any one of claims 1 to 3, characterized in that the starting material of the formula (II) is used, wherein X represents a bromine atom 10 and n are as defined in claim 1.