IE72500B1 - Process for the preparation of the dextrorotatory isomer of an isoindolinone derivative - Google Patents
Process for the preparation of the dextrorotatory isomer of an isoindolinone derivativeInfo
- Publication number
- IE72500B1 IE72500B1 IE922238A IE922238A IE72500B1 IE 72500 B1 IE72500 B1 IE 72500B1 IE 922238 A IE922238 A IE 922238A IE 922238 A IE922238 A IE 922238A IE 72500 B1 IE72500 B1 IE 72500B1
- Authority
- IE
- Ireland
- Prior art keywords
- formula
- product
- naphthyridin
- salt
- washed
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Anesthesiology (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Process for the preparation of the dextrorotatary isomer of the product of formula: by cyclisation of the dextrorotatary isomer of the product of formula:
Description
The present invention provides a process for the preparation of the dextrorotatory isomer of the isoindolinone derivative of formula:
which exhibits remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle-relaxant properties.
According to United States Patent No. 4,960,779, the dextrorotatory product of formula (I) may be obtained from the corresponding racemic product by chiral phase chromatography. However, the industrial application of this process is not always convenient to implement.
It has now been found, and this is the subject of the present invention, that the dextrorotatory isomer of the compound of formula (I) can be obtained by cyclisation of the dextrorotatory isomer of the compound of formula:
- 2 Generally, the cyclisation is carried out with thionyl chloride while optionally working in the presence of a condensation agent such as imidazole or pyridine in an organic solvent such as methylene chloride.
The process according to the invention may also he used on the product of formula (II) prepared in situ.
The dextrorotatory isomer of the product of formula (II) may be obtained by resolution of the corresponding racemic product by means of a chiral base. To this end, it is particularly advantageous to carry out, in succession, the following operations:
1) formation of a salt with a chiral base or a chiral acid,
2) precipitation of one of the optical isomers and then
3) release of the dextrorotatory optical isomer of the product of formula (II) , either from the precipitated salt or from the filtration mother liquors of the precipitated salt after optional formation of another salt with an appropriate chiral base or appropriate chiral acid.
It is also possible to form a salt of the racemic product of formula (II) with (+)-ephedrine while operating in an appropriate organic solvent such as ethanol. The salt of the dextrorotatory product of formula (II) is displaced from its salt by means of a strong acid such as hydrochloric acid.
It is also possible to prepare a salt of the product of formula (II) with cinchonine in an appropriate solvent such as ethanol. The salt of the laevorotatory product of formula (II) with cinchonine precipitates. After being displaced from its cinchonine salt, the dextrorotatory isomer of the product of formula (II), which is mainly found in the filtration mother liquors of the laevorotatory salt, is converted into an insoluble salt with cinchonidine. The dextrorotatory isomer of the product of formula (II) is displaced from its salt by means of a strong acid such as hydrochloric acid.
The product of formula (II) in the racemic form may be obtained by opening of the pyrrolinone ring of a racemic product of formula (I) in basic medium.
Generally, the opening of the pyrrolinone ring is carried out with 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 (I) 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 using a water-dioxane mixture as solvent.
The racemic compound of formula (I) can also be obtained by action of an inorganic base on the compound of formula:
Generally, at least two equivalents of the inorganic base, preferably 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 reaction medium.
The compound of formula (III) can be obtained by hydrolysis in acid medium of a compound of formula:
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 with 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 compounds 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 present invention.
EXAMPLE 1
g of the dextrorotatory isomer of 2-{l[(7-chloro-l,8“naphthyridin“2-yl)amino]-6-methy13oxoheptvl}benzoic acid and 21..8 g of imidazole in 400 cm3 of methylene chloride are introduced into 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 450 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 one 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-vl)3-(5-methyl-2~oxohexvl)-l-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following:
- optical rotation: [a]p° = +132° (c = 1; methylene chloride)
- enantiomeric purity 98.8%.
The dextrorotatory isomer of 2~{1-[(7-chloro1.8- naphthyridin-2~yl)amino]-6-methyl~3~ oxoheptylj-benzoic acid can be prepared according to one of the following methods:
1) = 1450 cm3 of 95% (v/v) ethanol, 100 g of of cinchonine and 145 g of 2-{l~[(7-chloro~
1.8- naphthyridin-2-yl) amino]-6-methy 1-3“ oxoheptyl}benzoic acid are introduced into a stirred, 2 litre reactor. The suspension is heated to 40°C and then cooled, over 3 hours 3 0 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-{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]= +192.6° (c = 1; methylene chloride)
- enantiomeric purity: 98.5%.
1274.3 g of ethanolic liquors (corresponding to the filtrate of the cinchonine salt obtained
-7previously with addition of the ethanol wash). 260 cm3 of an N aqueous hydrochloric acid solution are added at
°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-{l~[(7-chloro1,8-naphthyridin-2-yl)amino]-6-methy1-3oxoheptyl}benzoic acid are thus obtained, whose characteristics are the following:
-optical rotation: [a]£° = +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 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-3oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following:
- optical rotation: [Ci]£° = -137.7° (c = 1; methylene chloride)
- enantiomeric purity: 100%.
g of the cinchonidine salt obtained previously are dissolved in 250 cm3 of
N-methyIpyrrolidone in a 1 litre reactor. 90 cm3 of N hydrochloric acid are added over 30 minutes while holding 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~{1-[(7-chloro1,8-naphthyridin-2-yl)amino]-6-methy1-3oxoheptyl}benzoic acid are thus obtained in the form of a white product whose characteristics are the following:
- optical rotation: [a]£° = 222.8° (c = 1; methylene chloride)
- enantiomeric purity: 100%.
2) - 250 g of 2-{l-[(7-chloro1.8- naphthyridin-2-y1) amino]~6~methy1-3oxoheptyl}benzoic acid, 97 g of (+)-ephedrine and 875 cm3 of 95% (v/v) ethanol are introduced, at a temperature of approximately 20°C, into a 2 litre reactor. After dissolving the suspension at 40°C, the reaction mixture is cooled to approximately 2°C. The precipitate obtained is separated off by filtration, washed with 2 times 125 cm3 of 95% (v/v) ethanol at 2°C and then dried for 16 hours at 60°C under reduced pressure (15 mm of mercury; 2.0 kPa). 156.,6 g of the salt of (+)-ephedrine and 2-{l-[(7-ehloro1.8- naphthyridin-2-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]£θ = -64° (c = 1; methylene chloride)
- enantiomeric purity 100%.
2.75 g of the salt obtained previously and 5 cm3 of N-methyIpyrrolidone are introduced into a 50 cm3 flask. 1.2 cm3 of concentrated hydrochloric acid and then, over 10 minutes, 15 cm3 of distilled water are added while maintaining the temperature at 20°C. The suspension obtained is filtered. The precipitate is washed with 5 times 10 cm3 of distilled water and then dried for 16 hours at 60°C under reduced pressure (15 mm of mercury; 2.0 kPa).
1.97 g of 2-{l-[(7-chloro-l,8-naphthyridin2-yl)amino]-6-methyl-3-oxoheptyl}banzoic acid are thus obtained in the form of a white product whose characteristics are the following:
- optical rotation: [α]ο° = +222.8° (c = 1; methylene chloride) ~ enantiomeric purity: 100%.
2-{l~[(7-chloro-l,8~naphthyridin-2-yl)amino]6-methy1-3-oxoheptyl}benzoic acid can be prepared according to one of the following methods:
A - 1400 cm3 of dioxane and 20 g of 2-(7-chloro-l,8~naphthyridin-2-yl)-3-(5-methyl2-oxohexyl)-l-isoindolinone are introduced, at a temperature of approximately 2 0°C, into a stirred, litre reactor. 244 cm3 of an N aqueous solution of sodium hydroxide are added over 5 minutes. The mixture is left to react for 4 days at a temperature below
°C.
The dioxane is removed by distillation under reduced pressure (40 mm of mercury; 5.3 kPa) at a temperature below 30°C. 100 cm3 of distilled water are added during the distillation.
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 5N 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 δ 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-{l-[(7-chloro-l,8-naphthvridin2-yl)amino]-6-methy1-3-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-naphthvridin~2-yl)-3-(5methy1-2-oxohexyl)-1-isoindolinone can be prepared according to the method described in United States Patent No. 4,960,779.
- 20 g of 2-(7-chloro-l,8-naphthyridin-2yl)-3-(5-methy1-2-oxohexyl)-1-isoindolinone, 400 cm3 of pyridine and 60 cm3 of a 2N aqueous sodium hydroxide solution are introduced, at a temperature of approximately 20°C, into a stirred, 1 litre reactor.
The mixture is left to react for 23 hours and the pyridine is then distilled under reduced pressure (15 mm of mercury; 2.0 kPa) at a temperature below
-1220°C. 500 cm3 of distilled water are added. An insoluble material is separated off 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 at 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.
C - 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 20°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 off by filtration, washed with water and dried in air. 10 mg of 2-{l[(7-chloro-l,8-naphthyridin-2-yl)amino]-6-methyl3-oxoheptyl}benzoic acid are thus obtained whose characteristics are identical to those of the product obtained previously.
2-[2-(7-chloro-l,8-naphthyridin-2~yl)-3-oxo13
1-isoindolinyl]-6-methyl-3~oxoheptanoic acid can be prepared in the following manner:
A solution of 23 g of ethyl 2-[2-(7-chloro
1.8- naphthyridin-2-yl)-S-oxo-l-isoindolinylJ-S-methylS-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 off 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 0.1N aqueous sodium hydroxide solution. The insoluble product is separated off 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 off by filtration, washed with distilled water and then with isopropyl ether and dried at 20°C under reduced pressure (0.07 kPa). 9.2 q of 2-[2-(7-chloro1.8- naphthyridin-2-yl)-3-oxo-l-isoindolinyl]-6-methyl3-oxoheptanoic acid, melting at 176°C, are thus obtained.
Ethyl 2-[2-(7-chloro-l,8-naphthyridin-2-yl)3-oxo-l-iso.indolinyl]-6-methyl-3-oxoheptanoate can be obtained by the method described in United States Patent No. 4,960,779.
EXAMPLE 2
118.3 g of the salt of (+)-ephedrine and
- 14 2- {1-[(7-chloro-l,8-naphthyridin-2~yl)amino]-e-methyl3- oxoheptyl}benzoic acid and 1700 cm3 of methylene chloride are introduced into a 2.5 litre reactor. The organic solution is washed, at 20°C, with 400 cm3 of a 0.5N aqueous hydrochloric acid solution and then with 400 cm3 of distilled water. The organic phase is dehydrated by azeotropic distillation at 20°C under reduced pressure (250 mm of mercury; 33.3 kPa). The volume of the organic phase is adjusted to 1700 cm3 by addition of dry methylene chloride, 95.2 g of imidazole are then added and then, over 10 minutes, 25 cm3 of thionyl chloride. The suspension is heated to 40°C for 30 minutes, then cooled to 20°C and washed with 2 times 700 cm3 of distilled water. The methylene chloride is removed by distillation at atmospheric pressure while adding, to keep the volume constant, 2500 cm3 of absolute ethanol. When the temperature of the vapour reaches 78°C, the distillation is halted and 4 g of decolorising charcoal in suspension in 20 cm3 of absolute ethanol are then added. The mixture is left for 30 minutes at 78°C and then filtered while hot. The decolorising charcoal is rinsed with 200 cm3 of ethanol at 77°C. The wash and the filtrate are combined and then cooled, at a rate of 20°C/hour, to a temperature of 10°C. The suspension is filtered. The precipitate is washed with 3 times 140 cm3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). The slightly yellow product obtained (68.9 g) is recrvstallised from 1400 cm3 of ethanol at reflux. After cooling to 10°C, the suspension is filtered. The precipitate is washed with 3 times 100 cm3 of absolute ethanol at 10°C and then dried at 60°C for 16 hours under reduced pressure (15 mm of mercury; 2.0 kPa). 65.1 g of (+)~2~(7-chloro1,8~naphthyridin-2-yl)-3-(5-methy1-2-oxohexyl)~ 1-isoindolinone are thus obtained in the form of a fluffy white product whose characteristics are the following:
· optical rotation: [c]d° = +132° (c = 1; methylene chloride)
- enantiomeric purity 100%.
Claims (6)
1. Process for the preparation of the dextrorotatory isomer of the compound of formula: which comprises cyclising the dextrorotatory isomer of 5 the compound of formula:
2. Process according to claim 1, in which the cyclisation is carried out with thionyl chloride in the presence of a condensation agent.
3. Process according to claim 2, in which the 10 condensation agent is imidazole or pyridine.
4. Process according to any one of claims 1 to 3, in which the cyclisation is carried out in an organic solvent such as methylene chloride.
5. Process according to claim 1 substantially as 15 described in Example l or 2.
6. The dextrorotatory isomer of the compound of formula: when obtained by the process of any one of claims 1 to 5.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9108830A FR2678934B1 (en) | 1991-07-12 | 1991-07-12 | PROCESS FOR THE PREPARATION OF THE DEXTROGYRE ISOMER OF AN ISOINDOLINONE DERIVATIVE. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE922238A1 IE922238A1 (en) | 1993-01-13 |
| IE72500B1 true IE72500B1 (en) | 1997-04-23 |
Family
ID=9415049
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE922238A IE72500B1 (en) | 1991-07-12 | 1992-07-09 | Process for the preparation of the dextrorotatory isomer of an isoindolinone derivative |
Country Status (13)
| Country | Link |
|---|---|
| EP (2) | EP0594775A1 (en) |
| JP (1) | JPH06509083A (en) |
| KR (1) | KR100235373B1 (en) |
| AU (1) | AU658662B2 (en) |
| CA (1) | CA2112980C (en) |
| FR (1) | FR2678934B1 (en) |
| IE (1) | IE72500B1 (en) |
| IL (1) | IL102446A0 (en) |
| MA (1) | MA22589A1 (en) |
| MX (1) | MX9204054A (en) |
| NZ (1) | NZ243494A (en) |
| WO (1) | WO1993001187A1 (en) |
| ZA (1) | ZA925099B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU783516B2 (en) | 2001-04-30 | 2005-11-03 | Warner-Lambert Company | Methods, kits and compositions for using pyrrole derivatives |
| EP1490363B1 (en) | 2002-03-29 | 2006-01-25 | Indevus Pharmaceuticals, Inc. | Methods of preparation of the 2-(7-chloro-1,8-naphthyridine-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2313060A1 (en) * | 1974-11-07 | 1976-12-31 | Rhone Poulenc Ind | Pyrrolidinone deriirrivs as tranquillizers - 1-Heterocyclyl-5(1-piperazinyl-carbonyloxy)-2(5H)-pyrrolidinone derivs prepd. from 5-aryloxycarbonyloxy cpds. and piperazine (OE060576) |
| FR2321290A1 (en) * | 1975-04-07 | 1977-03-18 | Rhone Poulenc Ind | 1,8-naphthyridine tranquillisers, e hypnotics, anti-epileptics etc. - 2-substd. by isoindoline, pyrrolo-(3,4-b)-pyrazines, pyrrolo-(3,4-b)-pyridine or oxathino-(1,4)(2,3-c)-pyrrole |
| FR2607503B1 (en) * | 1986-12-02 | 1989-02-24 | Rhone Poulenc Sante | NOVEL ISOINDOLINONE DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR2678931B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | NEW DERIVATIVE OF AMINO-2 NAPHTYRIDINE, ITS PREPARATION AND ITS USE. |
| FR2678933B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
| FR2678932B1 (en) * | 1991-07-12 | 1993-09-24 | Rhone Poulenc Rorer Sa | PROCESS FOR THE PREPARATION OF OPTICAL ISOMERS OF A DERIVATIVE OF AMINO-2 NAPHTYRIDINE. |
-
1991
- 1991-07-12 FR FR9108830A patent/FR2678934B1/en not_active Expired - Fee Related
-
1992
- 1992-07-08 MA MA22873A patent/MA22589A1/en unknown
- 1992-07-08 ZA ZA925099A patent/ZA925099B/en unknown
- 1992-07-08 IL IL102446A patent/IL102446A0/en unknown
- 1992-07-09 NZ NZ243494A patent/NZ243494A/en not_active IP Right Cessation
- 1992-07-09 IE IE922238A patent/IE72500B1/en not_active IP Right Cessation
- 1992-07-10 WO PCT/FR1992/000666 patent/WO1993001187A1/en not_active Application Discontinuation
- 1992-07-10 AU AU23606/92A patent/AU658662B2/en not_active Expired
- 1992-07-10 CA CA002112980A patent/CA2112980C/en not_active Expired - Lifetime
- 1992-07-10 EP EP92916240A patent/EP0594775A1/en not_active Withdrawn
- 1992-07-10 EP EP92402007A patent/EP0522972A1/en active Pending
- 1992-07-10 MX MX9204054A patent/MX9204054A/en unknown
- 1992-07-10 JP JP5502043A patent/JPH06509083A/en active Pending
- 1992-07-10 KR KR1019940700068A patent/KR100235373B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| EP0522972A1 (en) | 1993-01-13 |
| FR2678934B1 (en) | 1995-01-13 |
| EP0594775A1 (en) | 1994-05-04 |
| KR100235373B1 (en) | 1999-12-15 |
| IE922238A1 (en) | 1993-01-13 |
| CA2112980A1 (en) | 1993-01-21 |
| MX9204054A (en) | 1993-07-01 |
| IL102446A0 (en) | 1993-01-14 |
| CA2112980C (en) | 2003-09-30 |
| NZ243494A (en) | 1995-03-28 |
| AU2360692A (en) | 1993-02-11 |
| AU658662B2 (en) | 1995-04-27 |
| ZA925099B (en) | 1993-04-28 |
| JPH06509083A (en) | 1994-10-13 |
| MA22589A1 (en) | 1993-04-01 |
| WO1993001187A1 (en) | 1993-01-21 |
| FR2678934A1 (en) | 1993-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| IE912250A1 (en) | Process for the preparation of an N-phenylacetic derivative of tetrahydrothieno [3,2-c] pyridine and its chemical intermediate | |
| KR100870804B1 (en) | Process for production of 3-alkenylcephem compounds | |
| IE72500B1 (en) | Process for the preparation of the dextrorotatory isomer of an isoindolinone derivative | |
| US20160280646A1 (en) | Novel method for synthesizing key intermediate of apixaban | |
| US5498716A (en) | 2-amino naphthyridine derivative, its preparation and its use | |
| IE922235A1 (en) | New 2-aminonaphthyridine derivatives, their preparation and their use | |
| KR100235375B1 (en) | Method for preparing optical isomers of a 2-amino naphthyridine derivative | |
| KR100235374B1 (en) | Method for preparing optical isomers of a 2-amino naphthyridine derivative | |
| AU705887B2 (en) | New process for preparing (-)-trans-N-p-fluor obenzoylmethyl-4-(p-fluorophenyl)-3-{{3,4-(methylenedioxy)ph noxy}methyl}-piperidine | |
| CA2208129C (en) | Process for the preparation of chiral, nonracemic (4-aryl-2, 5-dioxoimidazo-lidin-1-yl)acetic acids | |
| JP2013544787A (en) | Method for preparing azaindazole derivatives | |
| CN109528716B (en) | Application of chalcone compound containing carboxymethyl rhodanine structure | |
| JP2823679B2 (en) | Method for producing optically active 2-methylpiperazine | |
| WO2022003405A1 (en) | One-pot process to obtain a pyrrolidine-2-carbonitrile intermediate compound and industrial scale telescopic process to prepare (2s)-1-[n-(3-hydroxyadamantan-1-yl)glycyl]-2-pyrrolidinecarbonitrile (vildagliptin) using same | |
| US5688956A (en) | Method for preparing N-methyl 2-(3-pyridyl) (1R,2R)-2-tetrahydrothiopyrancarbothioamide-1-oxide | |
| WO2019242692A1 (en) | Compound and use thereof in synthesis of brivaracetam intermediate and crude drug | |
| KR19990080559A (en) | Manufacturing Method of Cemfe derivatives | |
| HUT63406A (en) | Process for producing tetrazolylacryl nitrile derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK9A | Patent expired |