IE922237A1

IE922237A1 - Process for the preparation of the optical isomers of a 2-aminonaphthyridine derivative

Info

Publication number: IE922237A1
Application number: IE223792A
Authority: IE
Inventors: Marie-Therese David-Comte
Original assignee: Rhone Poulenc Rorer Sa
Priority date: 1991-07-12
Filing date: 1992-07-09
Publication date: 1993-01-13
Also published as: CA2112982A1; WO1993001188A1; KR100235374B1; CA2112982C; FR2678933B1; EP0522971A1; EP0594759A1; AU657568B2; NZ243493A; JPH06509084A; IE72501B1; FR2678933A1; ZA925102B; MX9204055A; AU2360792A; MA22588A1; IL102445A0

Abstract

The dextrorotatary isomer of formula (I) and process for the preparation of the dextrorotatary isomer of the product of formula (I) from a salt of the corresponding racemic product with cinchonine cinchonodine

Description

The present invention relates to the preparation of the optical isomers of the 2-aminonaphthyridine derivative of formula: •ci (I) More particularly, the present invention provides a process for the preparation of the dextrorotatory isomer of the compound of formula (I) which is useful for the preparation of the dextrorotatory isomer of the product of formula : ci (II) which exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle-relaxant properties.

It has been shown that, in the product of formula 25 (II), which, with analogous products, is the subject of United States Patent 4,960,779, the active entity or - 2 eutomer is the dextrorotatory (+) isomer. According to this United States patent the separation of the optical isomers of the product of formula (II) was carried out by chiral phase chromatography. However, the industrial application of this process is not always convenient to implement.

According to the present invention, the dextrorotatory isomer of the product of formula (I) is obtained by forming an insoluble salt of the corresponding racemic compound with cinchonine, separating the said insoluble cinchonine salt enriched in the laevorotatory isomer, displacing a compound of said formula enriched in the dextrorotatory isomer from the soluble cinchonine salt residue, precipitating the cinchonidine salt of the pure dextrorotatory isomer by reaction of the said enriched dextrorotatory isomer with cinchonidine, and finally freeing the dextrorotatory isomer from the said precipitated cinchonidine salt.

The dextrorotatory isomer of the product of formula (I), after being displaced from its cinchonidine salt, is converted by cyclisation into the dextrorotatory isomer of the product of formula (II).

The formation of the cinchonine salt of the racemic product of formula (I) is carried out by working in an organic solvent, such as ethanol, in which the salt is insoluble.

The product of formula (I), enriched in the - 3 dextrorotatory isomer in the form of the soluble cinchonine salt, in the filtration mother liquors is displaced from its salt after acidification by means of a strong acid such as hydrochloric acid. The product enriched in the dextrorotatory isomer, when treated with cinchonidine in an organic solvent such as ethanol, leads to the precipitation of the cinchonidine salt of the pure dextrorotatory isomer of the product of formula (I). The pure dextrorotatory isomer of the product of formula (I) is displaced from its cinchonidine salt by means of a strong acid such as hydrochloric acid.

The dextrorotatory isomer of the product of formula (I) can be cyclised to the eutomer of the product of formula (II) by means of thionyl chloride, optionally in the presence of a condensing agent such as imidazole or pyridine, in an organic solvent such as methylene chloride.

The product of formula (I) can be obtained by opening of the pyrrolinone ring of a racemic product of formula (II) in basic medium. Generally, the opening of the pyrrolinone ring is carried out by means of an inorganic base at a temperature of between 0 and 50°C and, preferably, of between 0 and 30°C.

Generally, the process is carried out by stirring an aqueous-organic solution of the product of formula (II) in the presence of an excess of inorganic base chosen from the hydroxides and the carbonates or bicarbonates of alkali or alkaline-earth metals. It is particularly advantageous to use sodium hydroxide as inorganic base and to work in a water-pyridine mixture. It is also possible to carry out the reaction by using a water-dioxane mixture as solvent.

The product of formula (I) can also be obtained 5 by action of an inorganic base on the product of formula: Generally, at least two equivalents of the inorganic base, chosen, preferably, from sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate, are used while working in water or in an aqueous-organic medium at a temperature of between 0 and 50°C, preferably between 0 and 30°C. A dioxane-water mixture is preferably used as aqueous-organic medium.

The product of formula (III) can be obtained by hydrolysis in acid medium of a compound of formula: (IV) in which R represents an alkyl radical containing 1 to 10 carbon atoms in a straight or branched chain.

Generally, the hydrolysis is carried out by means - 5 of a strong inorganic acid such as concentrated sulphuric acid while working at a temperature of between 0 and 50°C, preferably approximately 20°C.

The products of formula (III) and (IV) can be obtained under the conditions described in United States Patent No. 4,960,779.

The following Examples illustrate the invention.

EXAMPLE 1 1450 cm3 of 95% (v/v) ethanol, 100 g of cinchonine and 145 g of 2-{l-[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are introduced into a stirred, 2 litre reactor. The suspension is heated to 40°C and then cooled, over 3 hours 30 minutes, to 10°C. The suspension obtained is filtered. The precipitate is washed with 2 times 50 cm3 of ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 Kpa). 99.3 g of the salt of cinchonine and 2-{1-[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [α]^0 = +192.6° (c = 1; methylene chloride) - enantiomeric purity: 98.5%. 250 cm3 of N-methylpyrrolidone and 50 g of the salt obtained previously are introduced into a stirred, 2 litre reactor. 90 cm3 of N hydrochloric acid are added over - 6 30 ainut·· while maintaining the temperature at ao*c. The mixture ia left for 1 hour et thia temperature and then 660 cm5 of distilled water are added over 1 hour. The suspension obtained is filtered. The precipitate ie washed with S time· 100 cm1 of water and than dried at 60'c for is hours under reduced pressure (15 mm of mercury; 2.0 Mpa). 28.6 g of (-)-2-(1-( (7-chloro-l, 8-naphthyridin-2-yl) amina)-6-methYl-3-oxoheptyl) benaoio acid are thus obtained in the form of a white product Whose characteristic· are the following: - optical rotation: - -227.4* (o - 1; methylene chloride) - enantiomeric purity: 99.6%. 2-( 1- [ (7-chloro-l, e-naphthyridin-2-yl) amino) 15 6-methyl-3-oxoheptyl)benaoic acid can he prepared according to one of the following methods: 1) 1400 cm3 of dioxane and 20 g of 2-(7-chloro1,8-naphthyridin- 2-yl) -3-{5-methyl-2-oxohexyl) 1-ieolndclinone are introduced, at a temperature of approximately 20*C, into a stirred, 3 litre reactor. 244 cm3 of an M aqueous solution of sodium hydroxide are added over 5 minutes. The mixture ie left to react for 4 days at a temperature below 30*C.

The dioxane ie removed hy distillation under reduced pressure (40 mm of mercury; 5.3 Xpe) at a temperature below 30’C. 100 cm5 of distilled water ere added during the distillation. - Ί An insoluble product is removed by filtration at 20°C. This product is washed with 3 times 50 cm3 of distilled water and is removed. The combined aqueous phases are acidified by addition, over 3 hours, of 48 cm3 of 5 N hydrochloric acid at a temperature of 20°C. The pH of the suspension is then approximately 3.5.

After filtering the suspension, the precipitate is washed with 6 times 100 cm3 of distilled water and is then dried under reduced pressure (15 mm of mercury; 2.0 Kpa) at 60°C for 16 hours. 14.3 g of 2—{1—[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time is 4.8 minutes by high performance liquid chromatography using a column 25 cm long and 0.46 cm in diameter with Lichrospher O.D.S. 5 Mm as the stationary phase and a mixture of 200 cm3 of Ph 3, 25 Mm phosphate buffer, 560 cm3 of acetonitrile and 240 cm3 of methanol, at a flow rate of 0.8 cm3/minute, as the mobile phase. 2-(7-chloro-l,8-naphthyridin-2-yl)-3-(5-methyl2- oxohexyl)-1-isoindolinone can be prepared according to the method described in United States Patent No. 4,960,779. 2) 20 g of 2-(7-chloro-l,8-naphthyridin-2-yl)3- (5-methyl-2-oxohexyl)-1-isoindolinone, 400 cm3 of pyridine and 60 cm3 of a 2N aqueous sodium hydroxide solution are introduced, at a temperature of approximately °C, into a stirred, 1 litre reactor. The mixture is left - 8 to react for 23 hours and the pyridine is then distilled under reduced pressure (15 mm of mercury) at a temperature below 20°C. 500 cm3 of distilled water are added. An insoluble material is separated by filtration. The aqueous phase is acidified to Ph = 3.8 by addition of 40 cm3 of 4N hydrochloric acid. The suspension is filtered, the precipitate is washed with 5 times 140 cm3 of distilled water and then dried for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa) at 60°C. 19.2 g of 2-{1-[(7-chloro-l,8-naphthyridin2- yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose retention time by high performance liquid chromatography is 4.8 minutes under the conditions described previously. 3) A suspension of 30 mg of 2-[2-(7-chloro1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl3- oxoheptanoic acid in 4.7 cm3 of distilled water and 1.32 cm3 of a 0.1N aqueous sodium hydroxide solution is stirred at a temperature of approximately 2 0°C for 72 hours. An insoluble product is removed by filtration and the filtrate is acidified to a pH = 2 by addition of a 0. IN aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with water and dried in air. 10 mg of 2-{l-[(7-chloro-l,8-naphthyridin25 2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained whose characteristics are identical to those of the product obtained previously. - 9 2-[2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxo1- isoindolinyl] -6-methyl-3-oxoheptanoic acid can be prepared in the following manner: A solution of 23 g of ethyl 2-[2-(7-chloro5 1,8-naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl3-oxoheptanoate in 235 cm3 of 98% sulphuric acid is stirred for 20 hours at a temperature of approximately 20°C and is then poured onto 1.5 kg of ice. The precipitate obtained is separated by filtration, washed with water to a pH = 6 and dried in air. The solid obtained is taken up in 3.8 litres of distilled water and 480 cm3 of a 0. IN aqueous sodium hydroxide solution. The insoluble product is separated by filtration and the filtrate is acidified to a pH = 3 by addition of a 0.1N aqueous hydrochloric acid solution. The precipitate obtained is separated by filtration, washed with distilled water and then with isopropyl ether and dried at 20°C under reduced pressure (0.07 kPa). 9.2 g of 2- [2-(7-chloro-l,8-naphthyridin-2-yl)-3-oxol-isoindolinyl ] -6-methyl-3-oxoheptanoic acid, melting at 176°C, are thus obtained.

Ethyl 2-(2-(7-chloro-l,8-naphthyridin-2-yl)3- oxo-l-isoindolinyl]-6-methyl-3-oxoheptanoate can be obtained by the method described in United States Patent No- 4,960,779.

EXAMPLE 2 400 cm3 of methylene chloride, 20 g of the product obtained previously and 21.8 g of imidazole are - 10 introduced, at a temperature of 20°C, into a stirred, 1 litre reactor. 7 cm3 of thionyl chloride are added, using a syringe, over 10 minutes. The suspension is heated at reflux for 30 minutes, it is then cooled to 20°C and washed with 2 times 200 cm3 of distilled water. The washed solution is concentrated to half its volume and then 450 cm3 of absolute ethanol are added. Distillation at atmospheric pressure is continued until the temperature of the vapour is 78°C. 1 g of decolorising charcoal is added and the mixture is then held for 1 hour at 70°C. The suspension is filtered. The precipitate is washed with 50 cm3 of ethanol at 75°C. The filtrate and the wash are combined. After cooling over 2 hours to 15°C, the suspension is filtered. The precipitate is washed with 3 times 35 cm3 of ethanol and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.7 g of (-)-2-(7-chloro-l,8-naphthyridin-2-yl)3-(5-methyl-2-oxohexyl)-1-isoindolinone are thus obtained in a form of a fluffy white product whose characteristics are the following: - optical rotation: [α]θθ = -132° (c = l; methylene chloride) - enantiomeric purity: 100%.

EXAMPLE 3 1274.3 g of ethanolic liquors (corresponding to the filtrate of the cinchonine salt obtained previously in Example 1 plus addition of the ethanol wash) are introduced - 11 into a 2 litre reactor. 2 60 cm3 of an N aqueous hydrochloric acid solution are added at 20°C. After stirring for 15 minutes, 650 cm3 of distilled water are added. The solution is concentrated under reduced pressure (25 mm of mercury; 3.3 Kpa) at a temperature below 30°C in order to remove the ethanol. The suspension is then filtered. The precipitate is washed with 6 times 100 cm3 of water and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 79.6 g of a white product mainly consisting of the dextrorotatory isomer of 2-(1-[(7-chloro1,8-naphthyridin-2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained whose characteristics are the following: - optical rotation: [α]ρ° = +160° (c = 1; methylene chloride) - enantiomeric purity: 73.2%. 78.5 g of the product obtained previously, 54.3 g of cinchonidine and 700 cm3 of 95% (v/v) ethanol are 20 introduced into a 1 litre reactor. The solution is heated to reflux and then cooled over 3 hours to a temperature of 10°C. A product crystallises. The suspension is filtered. The precipitate is washed with 2 times 50 cm3 of 95% ethanol and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 92.8 g of the cinchonidine salt of (+)-2-(1[(7-chloro-l,8-naphthyridin-2-yl) amino]-6-methyl-3-oxoIE 922237 - 12 heptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [α]θ° = -137.7° (c = 1; methylene chloride) - enantiomeric purity: 100%. g of the cinchonidine salt obtained previously are dissolved in 250 cm3 of N-methylpyrrolidone in a 1 litre reactor. 90 cm3 of N hydrochloric acid are added over 30 minutes while maintaining the temperature below 20°C.

After stirring for 15 minutes at 20°C, 600 cm3 of distilled water are added over 1 hour. The suspension obtained is filtered. The precipitate obtained is washed with 5 times 100 cm3 of distilled water and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 29.7 g of (+)-2-{l-[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3-oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following: - optical rotation: [a] 1° = 222.8° (c = 1; methylene chloride) - enantiomeric purity: 100%. - 13 EXAMPLE 4 g of the dextrorotatory acid obtained previously in Example 3 and 21.8 g of imidazole are dissolved in 400 cm3 of methylene chloride in a 1 litre reactor. 7 cm3 of thionyl chloride are introduced, using a syringe, at a temperature of 20°C. The suspension is heated at reflux for 30 minutes, is subsequently cooled to 20°C and is then washed 2 times with 200 cm3 of distilled water. The solution is concentrated, at atmospheric pressure, to half its volume and then 4 50 cm3 of absolute ethanol are added. The distillation of the methylene chloride is continued until the temperature of the vapour reaches 78°C. 1 g of decolorising charcoal is then added and the mixture is then left for 1 hour at 78°C. The suspension is filtered. The precipitate is washed with 50 cm3 of absolute ethanol at 75°C. The filtrate and the washes are combined and then cooled to 15°C over 2 hours. The suspension is filtered. The precipitate is washed with 3 times 35 cm3 of absolute ethanol at 15°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 16.8 g of (+)-2-(7-chloro-l,8-naphthyridin-2-yl)3-(5-methyl-2-oxohexyl)-1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following: - optical rotation: [α]£° = +132° (c = 1; methylene chloride) - enantiomeric purity: 98.8%.

Claims

1. Process for the preparation of the dextrorotatory isomer of the compound of formula: 10 which comprises forming an insoluble salt of the corresponding racemic compound with cinchonine, separating the said insoluble cinchonine salt enriched in the laevorotatory isomer, displacing a compound of said formula enriched in the dextrorotatory isomer from the soluble 15 cinchonine salt residue, precipitating the cinchonidine salt of the pure dextrorotatory isomer by reaction of the said enriched dextrorotatory isomer with cinchonidine, and finally freeing the dextrorotatory isomer from the said precipitated cinchonidine salt. 20

2. Process according to claim 1, in which the cinchonine salt of the racemic compound is precipitated in an organic solvent such as ethanol.

3. Process according to claim 1 or 2, in which the compound enriched in the dextrorotatory isomer is 25 displaced from its cinchonine salt with a strong acid such as hydrochloric acid. Process according to claim 1, 2 or 3, in - 15 which the cinchonidine salt of the product enriched in the dextrorotatory isomer is precipitated in an organic solvent such as ethanol.

4. 5. Process according to any one of claims 1 to 5 4, in which the pure dextrorotatory isomer is displaced from its cinchonidine salt with a strong acid such as hydrochloric acid.

5. 6. Process according to claim 1 substantially as described in the Examples.

6. 10

7. The dextrorotatory isomer of the compound of formula: when obtained according to the process of one of claims 1 to 6. 20

8. Use of the product according to claim 6 for the preparation of the dextrorotatory isomer of the compound of formula: