EP0595964A1 - Verfahren zur herstellung der optischen isomeren eines 2-aminonaphthyridin-derivats - Google Patents

Verfahren zur herstellung der optischen isomeren eines 2-aminonaphthyridin-derivats

Info

Publication number
EP0595964A1
EP0595964A1 EP92916241A EP92916241A EP0595964A1 EP 0595964 A1 EP0595964 A1 EP 0595964A1 EP 92916241 A EP92916241 A EP 92916241A EP 92916241 A EP92916241 A EP 92916241A EP 0595964 A1 EP0595964 A1 EP 0595964A1
Authority
EP
European Patent Office
Prior art keywords
product
formula
oxo
naphthyridine
chloro
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP92916241A
Other languages
English (en)
French (fr)
Inventor
Marie-Thérèse David-Comte
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Aventis Pharma SA
Original Assignee
Rhone Poulenc Rorer SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rhone Poulenc Rorer SA filed Critical Rhone Poulenc Rorer SA
Publication of EP0595964A1 publication Critical patent/EP0595964A1/de
Withdrawn legal-status Critical Current

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

Definitions

  • the present invention relates to a process for the preparation of the optical isomers of the 2-amino naphthyridine derivative of formula:
  • the present invention relates to the preparation of the dextrorotatory isomer of the product of formula (I) which is useful for preparing the dextrorotatory isomer of the product of formula:
  • the dextrorotatory isomer of the product of formula (I) can be obtained by forming a salt of the product of formula (I) racemic with the (+) - ephedrine followed by the release of the dextrorotatory isomer product of formula (I) of its salt.
  • the dextrorotatory isomer of the product of formula (I) is then transformed into the dextrorotatory isomer of the product of formula (II) by cyclization.
  • the formation of the product salt of formula (I) racemic with (+) -ephedrine is carried out by operating in an appropriate organic solvent such as ethanol.
  • the salt of the product of formula (I) dextrorotatory and of (+) -ephedrine precipitates.
  • the pure dextrorotatory isomer of the product of formula (I) is displaced from its salt by means of a strong acid such as hydrochloric acid.
  • the dextrorotatory isomer of the product of formula (I) is cyclized to the eutomer of the product of formula (II) by means of thionyl chloride, optionally operating in the presence of a condensing agent such as imidazole or pyridine in a solvent. organic such as methylene chloride. It is not necessary to separate the dextrorotatory isomer from the product of formula
  • the product of formula (I) can be obtained by opening the pyrrolinone cycle of a product of formula (II) racemic in basic medium.
  • the opening of the pyrrolinone cycle is carried out using a mineral base at a temperature between 0 and 50 ° C and, preferably, between 0 and 30 ° C.
  • the process is implemented by stirring a hydro ⁇ organic solution of the product of formula (II) in the presence of an excess of mineral base chosen from hydroxides and carbonates or bicarbonates of alkali or alkaline-earth metals. It is particularly advantageous to use sodium hydroxide as a mineral base and to operate in a water-pyridine mixture. It is also possible to carry out the reaction using a water-dioxane mixture as solvent.
  • the product of formula (I) can also be obtained by the action of a mineral base on the product of formula:
  • At least two equivalents of the mineral base chosen are made to act, preferably from soda, potash, sodium carbonate or potassium carbonate, operating in water or in a hydro-organic medium with a temperature between 0 and 50 ° C, preferably between 0 and 30 ° C.
  • a hydro-organic medium a dioxane-water mixture is preferably used.
  • the product of formula (III) can be obtained by hydrolysis in acid medium of a product of general formula:
  • R represents an alkyl radical containing 1 to 10 carbon atoms in a straight or branched chain.
  • the hydrolysis is carried out using a strong mineral acid such as concentrated sulfuric acid, operating at a temperature between 0 and 50 ° C, preferably close to 20 ° C.
  • a strong mineral acid such as concentrated sulfuric acid
  • the dioxane is removed by distillation under reduced pressure (40 mm of mercury; 5.3 kPa) at a temperature below 30 ° C. During distillation, 100 cm 3 of distilled water are added.
  • 14.3 g of ⁇ [(7-chloro-naphthyridine-1,8 yl-2) amino] -1-methyl-6-oxo-3 heptyl ⁇ -2 benzoic acid are thus obtained in the form of a white product, the time of which is 14.3 g. retention is 4.8 minutes by high performance liquid chromatography using a column 25 cm long and 0.46 cm in diameter with the stationary phase of "Lichrospher ODS 5 ⁇ m" and as a mobile phase a mixture 200 cm3 of 25 mM pH 3 phosphate buffer, 560 cm3 of acetonitrile and 240 cm3 of methanol at a flow rate of 0.8 cm3 / minute.
  • Ethyl [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-6 oxo-3 heptanoate can be obtained by the method described in US patent US 4,960 779.
  • EXAMPLE 2 In a 1 liter reactor, 20 g of the dextrorotatory acid obtained under the conditions described above and 21J8 g of imidazole are dissolved in 400 cm 3 of methylene chloride. At a temperature of 20 ° C., 7 cm3 of thionyl chloride are introduced using a syringe. The suspension is heated with teflux for 30 minutes, is then cooled to 20 ° C. and then washed twice with 200 cm3 of distilled water. The solution is concentrated, at atmospheric pressure, to half its volume and then 450 cm 3 of absolute ethanol are added. The distillation of methylene chloride is continued until the vapor temperature reaches 78 ° C.
  • (+) -ephedrine salt and ⁇ [(7-chloro-naphthyridine-1,8 yl-2) amino] -1-methyl-6 oxo acid are introduced into a 2.5-liter reactor.
  • the organic solution is washed, at 20 ° C., with 400 cm3 of an aqueous 0.5N 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 cm 3 by addition of dry methylene chloride, then 95.2 g of imidazole are added and then, in 10 minutes, 25 cm 3 of thionyl chloride.
  • the suspension is heated at 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 under atmospheric pressure while adding, at constant volume, 2500 cm 3 of absolute ethanol. When the vapor temperature reaches 78 ° C, the distillation is stopped, then 4 g of bleaching black suspended in 20 cm 3 of absolute ethanol are added. The mixture is left for 30 minutes at 78 ° C. and then filtered while hot.
  • the bleaching black is rinsed with 200 cm3 of ethanol at 77 ° C.
  • the washing and the filtrate are combined and then cooled, at a speed of 20 ° C / hour, at a temperature of 10 ° C.
  • the suspension is filtered.
  • the precipitate is washed with 3 times 140 cm 3 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 recrystallized from 1400 cm3 of ethanol at reflux. After cooling to 10 ° C, the suspension is filtered.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Public Health (AREA)
  • Anesthesiology (AREA)
  • Pain & Pain Management (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
EP92916241A 1991-07-12 1992-07-10 Verfahren zur herstellung der optischen isomeren eines 2-aminonaphthyridin-derivats Withdrawn EP0595964A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9108828 1991-07-12
FR9108828A FR2678932B1 (fr) 1991-07-12 1991-07-12 Procede de preparation des isomeres optiques d'un derive de l'amino-2 naphtyridine.
PCT/FR1992/000668 WO1993001189A1 (fr) 1991-07-12 1992-07-10 Procede de preparation des isomeres optiques d'un derive de l'amino-2 naphtyridine

Publications (1)

Publication Number Publication Date
EP0595964A1 true EP0595964A1 (de) 1994-05-11

Family

ID=9415046

Family Applications (2)

Application Number Title Priority Date Filing Date
EP92402005A Pending EP0522970A1 (de) 1991-07-12 1992-07-10 Verfahren zur Herstellung von optischen Isomeren eines 2-Aminonaphthyridin-Derivats
EP92916241A Withdrawn EP0595964A1 (de) 1991-07-12 1992-07-10 Verfahren zur herstellung der optischen isomeren eines 2-aminonaphthyridin-derivats

Family Applications Before (1)

Application Number Title Priority Date Filing Date
EP92402005A Pending EP0522970A1 (de) 1991-07-12 1992-07-10 Verfahren zur Herstellung von optischen Isomeren eines 2-Aminonaphthyridin-Derivats

Country Status (13)

Country Link
EP (2) EP0522970A1 (de)
JP (1) JPH06509085A (de)
KR (1) KR100235375B1 (de)
AU (1) AU657569B2 (de)
CA (1) CA2112981C (de)
FR (1) FR2678932B1 (de)
IE (1) IE72508B1 (de)
IL (1) IL102444A0 (de)
MA (1) MA22587A1 (de)
MX (1) MX9204057A (de)
NZ (1) NZ243492A (de)
WO (1) WO1993001189A1 (de)
ZA (1) ZA925101B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2678933B1 (fr) * 1991-07-12 1993-09-24 Rhone Poulenc Rorer Sa Procede de preparation des isomeres optiques d'un derive de l'amino-2 naphtyridine.
FR2678934B1 (fr) * 1991-07-12 1995-01-13 Rhone Poulenc Rorer Sa Procede de preparation de l'isomere dextrogyre d'un derive de l'isoindolinone.
AU783516B2 (en) 2001-04-30 2005-11-03 Warner-Lambert Company Methods, kits and compositions for using pyrrole derivatives
IL164377A0 (en) 2002-03-29 2005-12-18 Indevus Pharmaceuticals Inc Methods of preparation of the 2-(7-chloro-1,8-naphthyridine-2yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2313060A1 (fr) * 1974-11-07 1976-12-31 Rhone Poulenc Ind Nouveaux derives de l'isoindoline, leur preparation et les compositions qui les contiennent
FR2321290A1 (fr) * 1975-04-07 1977-03-18 Rhone Poulenc Ind Nouveaux derives de l'isoindoline, leur preparation et les compositions qui les contiennent
FR2607503B1 (fr) * 1986-12-02 1989-02-24 Rhone Poulenc Sante Nouveaux derives de l'isoindolinone, leur preparation et les compositions pharmaceutiques qui les contiennent
FR2678933B1 (fr) * 1991-07-12 1993-09-24 Rhone Poulenc Rorer Sa Procede de preparation des isomeres optiques d'un derive de l'amino-2 naphtyridine.
FR2678931B1 (fr) * 1991-07-12 1993-09-24 Rhone Poulenc Rorer Sa Nouveau derive de l'amino-2 naphtyridine, sa preparation et son emploi.

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9301189A1 *

Also Published As

Publication number Publication date
AU2360892A (en) 1993-02-11
IE72508B1 (en) 1997-04-23
EP0522970A1 (de) 1993-01-13
KR100235375B1 (ko) 1999-12-15
FR2678932A1 (fr) 1993-01-15
CA2112981A1 (fr) 1993-01-21
CA2112981C (fr) 2004-03-30
MA22587A1 (fr) 1993-04-01
MX9204057A (es) 1993-07-01
JPH06509085A (ja) 1994-10-13
AU657569B2 (en) 1995-03-16
ZA925101B (en) 1993-04-28
NZ243492A (en) 1995-03-28
IL102444A0 (en) 1993-01-14
IE922236A1 (en) 1993-01-13
WO1993001189A1 (fr) 1993-01-21
FR2678932B1 (fr) 1993-09-24

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