FR2685330A1 - PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE. - Google Patents
PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE. Download PDFInfo
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- FR2685330A1 FR2685330A1 FR9115860A FR9115860A FR2685330A1 FR 2685330 A1 FR2685330 A1 FR 2685330A1 FR 9115860 A FR9115860 A FR 9115860A FR 9115860 A FR9115860 A FR 9115860A FR 2685330 A1 FR2685330 A1 FR 2685330A1
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- Prior art keywords
- methyl
- naphthyridine
- chloro
- isoindolinone
- oxo
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- 238000000034 method Methods 0.000 title claims abstract description 16
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical compound C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 238000002360 preparation method Methods 0.000 title claims description 6
- PXZQEOJJUGGUIB-UHFFFAOYSA-N isoindolin-1-one Chemical class C1=CC=C2C(=O)NCC2=C1 PXZQEOJJUGGUIB-UHFFFAOYSA-N 0.000 title claims description 5
- 150000002009 diols Chemical group 0.000 claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- 150000001241 acetals Chemical class 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 4
- 239000011707 mineral Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- QPXJVYUZWDGUBO-UHFFFAOYSA-N 1,4-dimethoxybutane-2,3-diol Chemical compound COCC(O)C(O)COC QPXJVYUZWDGUBO-UHFFFAOYSA-N 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract description 4
- 239000001961 anticonvulsive agent Substances 0.000 abstract description 4
- 230000001773 anti-convulsant effect Effects 0.000 abstract description 2
- 230000003556 anti-epileptic effect Effects 0.000 abstract description 2
- 229960003965 antiepileptics Drugs 0.000 abstract description 2
- 230000000147 hypnotic effect Effects 0.000 abstract description 2
- 239000003158 myorelaxant agent Substances 0.000 abstract description 2
- 208000019901 Anxiety disease Diseases 0.000 abstract 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- -1 hypnotic Substances 0.000 description 11
- 230000008018 melting Effects 0.000 description 8
- 238000002844 melting Methods 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- FFWSICBKRCICMR-UHFFFAOYSA-N 5-methyl-2-hexanone Chemical compound CC(C)CCC(C)=O FFWSICBKRCICMR-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 2
- WACQKHWOTAEEFS-UHFFFAOYSA-N cyclohexane;ethyl acetate Chemical compound CCOC(C)=O.C1CCCCC1 WACQKHWOTAEEFS-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- IAQRGUVFOMOMEM-ONEGZZNKSA-N trans-but-2-ene Chemical compound C\C=C\C IAQRGUVFOMOMEM-ONEGZZNKSA-N 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- HTIZLJISEUYGSA-UHFFFAOYSA-N 2-chloro-1,8-naphthyridine Chemical compound C1=CC=NC2=NC(Cl)=CC=C21 HTIZLJISEUYGSA-UHFFFAOYSA-N 0.000 description 1
- XHDGJGJBAQDXON-UHFFFAOYSA-N 4,6,6-trimethylbicyclo[3.1.1]heptane-4,5-diol Chemical compound C1C2(O)C(C)(C)C1CCC2(O)C XHDGJGJBAQDXON-UHFFFAOYSA-N 0.000 description 1
- NIJGHADKRWATHN-UHFFFAOYSA-N CC(C)CCC(CC(c1ccccc1C1=O)N1c1nc2nc(Cl)ccc2cc1)(O)O Chemical compound CC(C)CCC(CC(c1ccccc1C1=O)N1c1nc2nc(Cl)ccc2cc1)(O)O NIJGHADKRWATHN-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- RMRFFCXPLWYOOY-UHFFFAOYSA-N allyl radical Chemical compound [CH2]C=C RMRFFCXPLWYOOY-UHFFFAOYSA-N 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000010009 beating Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
Abstract
Description
PROCEDE DE PREPARATION DES ENANTIOMERES
D'UN DERIVE DE L'ISOINDOLINONE
La présente invention concerne un procédé de préparation des énantiomêres du dérivé de I'isoindolinone de formule:
qui présente des propriétés anxiolytiques, hypnotiques, anticonvulsivantes, antiépileptiques et myorelaxantes remarquables.PROCESS FOR THE PREPARATION OF ENANTIOMERS
FROM AN ISOINDOLINONE DERIVATIVE
The present invention relates to a process for the preparation of enantiomers of the isoindolinone derivative of formula:
which has remarkable anxiolytic, hypnotic, anticonvulsant, antiepileptic and muscle relaxant properties.
Selon le brevet américain US 4 960 779, les énantiomères du dérivé de l'isoindolinone de formule (I) peuvent être obtenus à partir du racémique correspondant par chromatographie sur phase chirale. Cependant la mise en oeuvre industrielle de ce procédé n'est pas toujours de réalisation commode. According to American Patent US 4,960,779, the enantiomers of the isoindolinone derivative of formula (I) can be obtained from the corresponding racemic by chromatography on chiral phase. However, the industrial implementation of this process is not always easy to carry out.
I1 a maintenant été trouvé, et c'est ce qui fait l'objet de la présente invention, que les énantiomères du produit de formule (I) peuvent être obtenus3 après préparation, à partir du produit de formule (I) racémique, d'acétals diastéréoisomères de formule générale::
dans laquelle R1, R2, R3 et R4 constituent les restes d'un diol chiral, séparation de ces diastéréoisomères par chromatographie et hydrolyse de chacun des diastéréoisomères,
Généralement, l'hydrolyse de chacun des diastéréoisomères peut être effectuée au moyen d'un acide minéral tel que l'acide chlorhydrique concentré en opérant dans un solvant organique ou d'un acide organique tel que l'acide acétique ou de leurs mélanges, l'acide organique pouvant jouer le rôle de solvant. I1 est particulièrement avantageux d'opérer à une température voisine de 50"C. I1 has now been found, and this is what is the subject of the present invention, that the enantiomers of the product of formula (I) can be obtained3 after preparation, from the product of racemic formula (I), of diastereoisomeric acetals of general formula:
in which R1, R2, R3 and R4 constitute the residues of a chiral diol, separation of these diastereoisomers by chromatography and hydrolysis of each of the diastereoisomers,
Generally, the hydrolysis of each of the diastereoisomers can be carried out using a mineral acid such as concentrated hydrochloric acid by operating in an organic solvent or an organic acid such as acetic acid or their mixtures, l organic acid which can act as a solvent. It is particularly advantageous to operate at a temperature in the region of 50 "C.
Les acétals diastéréoisomères du produit de formule générale (11) peuvent être obtenus par action d'un diol chiral sur un acétal racémique de formule générale:
dans laquelle les symboles R représentent chacun un radical allyle contenant 1 à 4 atomes de carbone. Les symboles R sont identiques et représentent, de préférence, chacun un radical méthyle.The diastereoisomeric acetals of the product of general formula (11) can be obtained by the action of a chiral diol on a racemic acetal of general formula:
in which the symbols R each represent an allyl radical containing 1 to 4 carbon atoms. The symbols R are identical and preferably represent each a methyl radical.
De préférence, les diols choraux qui conviennent particulièrement bien sont choisis parmi le (-)-pinanediol-(IR,2R,3S,5R) et le diméthoxy-1,4 butanediol-2,3 (2S,3S). Preferably, the choral diols which are particularly suitable are chosen from (-) - pinanediol- (IR, 2R, 3S, 5R) and 1,4-dimethoxy-2,3-butanediol (2S, 3S).
L'acétal racémique de formule générale (fui) peut être obtenu par action d'un orthoformiate de triaikyle, de préférence rorthoformiate de triméthyle sur le produit de formule (I) racémique en opérant dans un solvant organique tel que le méthanol en présence d'un acide minéral tel que l'acide sulfurique à une température comprise entre 0 et 500C et de préférence voisine de 20"C. The racemic acetal of general formula (leak) can be obtained by the action of a triaikyl orthoformate, preferably trimethyl rorthoformate, on the racemic product of formula (I) by operating in an organic solvent such as methanol in the presence of a mineral acid such as sulfuric acid at a temperature between 0 and 500C and preferably close to 20 "C.
Généralement, l'action du diol chiral sur l'acétal racémique de formule générale (fil) est effectuée dans un solvant organique inerte tel qu'un hydrocarbure aromatique tel que le toluène ou un hydrocarbure aliphatique halogéné comme le dichloro-1,2 éthane en présence d'un agent tel que le tosylate de pyridinium ou l'acide p.toluènesulfonique en opérant à la température de reflux du mélange réactionnel. Generally, the action of the chiral diol on the racemic acetal of general formula (yarn) is carried out in an inert organic solvent such as an aromatic hydrocarbon such as toluene or a halogenated aliphatic hydrocarbon such as 1,2-dichloroethane. presence of an agent such as pyridinium tosylate or p.toluenesulfonic acid by operating at the reflux temperature of the reaction mixture.
Selon la nature du diol utilisé le nombre d'acétals diastéréoisomères obtenus varie. Par exemple, il est de 4 dans le cas du (-)-pinanediol-(1R,2R,3S,5R) et il est de 2 dans le cas du diméthoxy-1,4 butanediol-2,3-(2S,3S). Depending on the nature of the diol used, the number of diastereoisomeric acetals obtained varies. For example, it is 4 in the case of (-) - pinanediol- (1R, 2R, 3S, 5R) and it is 2 in the case of 1,4-dimethoxy-2,3-butanediol (2S, 3S ).
Les exemples suivants illustrent la présente invention. The following examples illustrate the present invention.
EXEMPLE 1
A une suspension de 0,6 g de (4-{(chloro-7 naphtyridine-138 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 pinène-2 acétal-(lR,2R,3S,5R) (forme A) dans 50 cm3 d'acide acétique, on ajoute 5 cm3 d'une solution aqueuse d'acide chlorhydrique 12N. La solution obtenue est agitée pendant 6 heures à une température voisine de 50"C, puis laissée pendant 12 heures à une température voisine de 200C. Le mélange réactionnel est dilué par 250 cm3 d'eau distillée et extrait par 3 fois 50 cm3 d'acétate d'éthyle.Les phases organiques réunies sont lavées par 2 fois 50 cm3 d'eau, 2 fois 5 cm3 d'une solution aqueuse saturée d'hydrogénocarbonate de sodium, séchées sur sulfate de magnésium et concentrées à sec sous pression réduite à 40"C. On obtient ainsi, après recristallisation dans l'éthanol, 0,26 g de (+)-(chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1 fondant à 174"C dont le pouvoir rotatoire est:
[a]20D = +1350+20 (c = 1,13 to; CHCl3).EXAMPLE 1
To a suspension of 0.6 g of (4 - {(chloro-7 naphthyridine-138 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone-2 pinene-2 acetal- (1R, 2R , 3S, 5R) (form A) in 50 cm3 of acetic acid, 5 cm3 of an aqueous solution of 12N hydrochloric acid are added. The solution obtained is stirred for 6 hours at a temperature in the region of 50 "C., then left for 12 hours at a temperature in the region of 200 C. The reaction mixture is diluted with 250 cm 3 of distilled water and extracted with 3 times 50 cm 3 of ethyl acetate. The combined organic phases are washed with 2 times 50 cm 3 of water, 2 times 5 cm3 of a saturated aqueous sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40 "C. 0.26 g is thus obtained, after recrystallization from ethanol of (+) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo hexyl) -3 isoindolinone-1 melting at 174 "C whose rotary power is:
[a] 20D = + 1350 + 20 (c = 1.13 to; CHCl3).
A - Le (+)-[chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 pinène-2 acétal-(1R,2R,3S,5R) (forme A) peut être préparé de la manière suivante:
A un mélange contenant 7 g de (chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 diméthoxy-2,2 hexyl)-3 isoindolinone-1-(RS) et 0,97 g'de tosylate de pyridinium en solution dans 100 cm3 de dichloro-1,2 éthane, on ajoute 0,84 g de (-)-pinanediol (1R,2R,3S,5R). Le mélange est chauffé à reflux pendant 3 heures puis est concentré à sec sous pression réduite. Le résidu obtenu est repris dans 100 cm3 d'un mélange acétate d'éthyle-cyclohexane (30-70 en volumes). Le solide est séparé par filtration et le filtrat est concentré à sec sous pression réduite.Après une première filtration sur silice (éluant: acétate d'éthyle-cyclohexane (30-70 en volumes) et évaporation des solvants sous pression réduite, le mélange des diastéréoisomères obtenu est purifié par chromatographie sur silice (chlorure de méthylène-méthanol (99-1 en volumes)). A - (+) - [chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone-2 pinene-2 acetal- (1R, 2R, 3S, 5R ) (form A) can be prepared as follows:
To a mixture containing 7 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy-hexyl) -3 isoindolinone-1- (RS) and 0.97 g of tosylate of pyridinium dissolved in 100 cm3 of 1,2-dichloroethane, 0.84 g of (-) - pinanediol (1R, 2R, 3S, 5R) is added. The mixture is heated at reflux for 3 hours then is concentrated to dryness under reduced pressure. The residue obtained is taken up in 100 cm3 of an ethyl acetate-cyclohexane mixture (30-70 by volume). The solid is separated by filtration and the filtrate is concentrated to dryness under reduced pressure. After a first filtration on silica (eluent: ethyl acetate-cyclohexane (30-70 by volume) and evaporation of the solvents under reduced pressure, the mixture of diastereoisomers obtained is purified by chromatography on silica (methylene chloride-methanol (99-1 by volume)).
Les fractions contenant les deux diastéréoisomères majoritaires, sont collectées et concentrées à sec sous pression réduite à 400C. On obtient ainsi après recristallisation dans l'acétate d'éthyle 1,0 g de (+)-[(chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 pinène-2 acétal-(lR,2R,3S,5R) (forme A, premier diastéréoisomère majoritaire d'élution) fondant à 2340C dont le pouvoir rotatoire est:
[a]20D +130" f 20 (c = 1,0 %;CHCl3) et 0,6 g de (-)-[(chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1J-2 méthyl-5 hexanone-2 pinène-2 acétal-(1R,2R,3S,5R) (forme B, second diastéréoisomère majoritaire d'élution) fondant à 197"C dont le pouvoir rotatoire est:
[a]20D = -1230 + 20 (c =0,68%; CHCl3).The fractions containing the two majority diastereoisomers are collected and concentrated to dryness under reduced pressure at 400C. 1.0 g of (+) - [(7-chloro-naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone is thus obtained after recrystallization from ethyl acetate -2 pinene-2 acetal- (1R, 2R, 3S, 5R) (form A, first majority eluting diastereoisomer) melting at 2340C whose rotary power is:
[a] 20D +130 "f 20 (c = 1.0%; CHCl3) and 0.6 g of (-) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl- 1J-2 methyl-5 hexanone-2 pinene-2 acetal- (1R, 2R, 3S, 5R) (form B, second majority eluting diastereoisomer) melting at 197 "C whose rotary power is:
[a] 20D = -1230 + 20 (c = 0.68%; CHCl3).
B - La (chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 diméthoxy-2,2 hexyl)-3 isoindolinone-1-(RS) peut être préparée de la manière suivante:
A une suspension de 25 g de (chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1-(RS) dans 600 cm3 de méthanol, on ajoute 27,5 cm3 (28 g) d'orthoformiate de triméthyle et 1,5 cm3 d'acide sulfurique concentré. Le mélange réactionnel est agité pendant 12 heures à une température voisine de 200C puis est dilué par 200 cm3 de dichlorométhane et amené à un pH voisin de 7 par addition de triéthylamine. L'évaporation des solvants sous pression réduite conduit à un résidu pâteux qui par battage dans l'acétonitrile donne 19 g de (chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 diméthoxy-2,2 hexyl)-3 isoindolinone-1-(RS) fondant à 140"C. B - (Chloro-7 naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy-hexyl) -3 isoindolinone-1- (RS) can be prepared in the following way:
To a suspension of 25 g of (chloro-7 naphthyridine-1,8 yl-2) -2 (methyl-5 oxo-2 hexyl) -3 isoindolinone-1- (RS) in 600 cm3 of methanol, 27 is added, 5 cm3 (28 g) of trimethyl orthoformate and 1.5 cm3 of concentrated sulfuric acid. The reaction mixture is stirred for 12 hours at a temperature in the region of 200C and is then diluted with 200 cm3 of dichloromethane and brought to a pH in the region of 7 by addition of triethylamine. Evaporation of the solvents under reduced pressure leads to a pasty residue which, by beating in acetonitrile, gives 19 g of (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2,2-dimethoxy-hexyl) -3 isoindolinone-1- (RS) melting at 140 "C.
La (chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1-(RS) peut être préparée selon la méthode décrite dans le brevet américain US 4960779. (7-Chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo hexyl) -3 isoindolinone-1- (RS) can be prepared according to the method described in American patent US Pat. No. 4,960,779.
EXEMPLE 2
On opère comme à l'exemple 1 mais à partir de 0,1 g de (-)-[(chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 pinène-2 acétal-(lR,2R,3S,5R) (forme B) préparé selon l'exemple 1A, de 10 cm3 d'acide acétique et de 1 cm3 d'une solution aqueuse d'acide chlorhydrique 12N. On obtient ainsi, après recristallisation dans l'éthanol, 0,03 g de (-l-(chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1 fondant à 171"C dont le pouvoir rotatoire est:
[a]20D = -1340 + 30 (c =0,63%; CHCl3).EXAMPLE 2
The procedure is as in Example 1 but starting with 0.1 g of (-) - [(7-chloro-naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone -2 pinene-2 acetal- (1R, 2R, 3S, 5R) (form B) prepared according to Example 1A, 10 cm3 of acetic acid and 1 cm3 of an aqueous solution of 12N hydrochloric acid. 0.03 g of (-l- (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 is thus obtained, after recrystallization from ethanol at 171 "C whose rotary power is:
[a] 20D = -1340 + 30 (c = 0.63%; CHCl3).
EXEMPLE 3
On opère comme à l'exemple 1 mais à partir de 0,07 g de (+)-[(chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 (diméthoxy1,4 butène-2 acétal-(2S,3S) (forme A), de 3 cm3 d'acide acétique et de 0,5 cm3 d'une solution aqueuse d'acide chlorhydrique 12N. On obtient ainsi 0,02 g de (+)-(chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)3 isoindolinone-1 fondant à 172 C et présentant un excès énantiomérique supérieur à 99 %.EXAMPLE 3
The procedure is as in Example 1 but starting with 0.07 g of (+) - [(7-chloro-naphthyridine-1,8 yl-2) -2 3-oxo-isoindolinyl-1] -2 5-methyl hexanone -2 (dimethoxy1,4 butene-2 acetal- (2S, 3S) (form A), 3 cm3 of acetic acid and 0.5 cm3 of an aqueous solution of 12N hydrochloric acid. This gives 0, 02 g of (+) - (chloro-7 naphthyridine-1,8 yl-2) -2 (methyl-5 oxo-2 hexyl) 3 isoindolinone-1 melting at 172 C and having an enantiomeric excess greater than 99%.
Le (+)-[(chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 (diméthoxy-1,4 butène-2) acétal-(2S,3S) (forme A) peut être préparé en opérant d'une manière analogue à celle décrite à l'exemple 1A mais à partir de 3,2 g de (chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 diméthoxy-2,2 hexyl)3 isoindolinone-1-(RS) préparé selon l'exemple 3, de 0,7 g de diméthoxy-1,4 butanediol-(2S,3S) et de 0,3 g de tosylate de pyridinium.On obtient ainsi après recristallisation dans l'oxyde de diisopropyle 0,45 g de (+)-[(chloro-7 naphtyridine1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 (diméthoxy-1,4 butène-2) acétal-(2S,3S) (forme A, premier produit d'élution) fondant à 98 C dont le pouvoir rotatoire est:
[α]20D = +100 3 (c = 0,45 %; CHCl3) et 0,35 g de (-)-[(chloro-7 naphtyridine-1,8 yl-2)-2 oxo-3 isoindolinyl-1]-2 méthyl-5 hexanone-2 (diméthoxy-1,4 butène-2) acétal-(2S,3S) (forme B, second produit d'élution) fondant à 115 C dont le pouvoir rotatoire est:
[α]20D = -102 2 (c =0,66%; CHCl3).(+) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S , 3S) (form A) can be prepared by operating in a manner analogous to that described in Example 1A but from 3.2 g of (7-chloro-naphthyridine-1,8 yl-2) -2 ( 5-methyl-2,2-dimethoxy-hexyl) 3 isoindolinone-1- (RS) prepared according to Example 3, 0.7 g of 1,4-dimethoxy butanediol- (2S, 3S) and 0.3 g of pyridinium tosylate. 0.45 g of (+) - [(7-chloro-naphthyridine 1.8 yl-2) -2 oxo-3 isoindolinyl-1] -2 methyl-5 is thus obtained after recrystallization from diisopropyl ether hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S, 3S) (form A, first elution product) melting at 98 ° C with rotational power:
[α] 20D = +100 3 (c = 0.45%; CHCl3) and 0.35 g of (-) - [(chloro-7 naphthyridine-1,8 yl-2) -2 oxo-3 isoindolinyl- 1] -2 5-methyl-hexanone-2 (1,4-dimethoxy-2-butene-2) acetal- (2S, 3S) (form B, second elution product) melting at 115 C whose rotary power is:
[α] 20D = -102 2 (c = 0.66%; CHCl3).
Le diméthoxy-1,4 butanediol-(2S,3S) peut être préparé selon la méthode décrite par H. FUJIOKA et coll., Chem. Pharm. Bull., 37, 1488-1492 (1989). Dimethoxy-1,4-butanediol- (2S, 3S) can be prepared according to the method described by H. FUJIOKA et al., Chem. Pharm. Bull., 37, 1488-1492 (1989).
EXEMPLE 4
On opère comme à exemple 1 mais à partir de 0,1 g de (-)-[(chloro-7 naphtyridine-1 , 8 yl-2)-2 oxo-3 isoindolinyl-1] -2 méthyl-5 hexanone-2 (diméthoxy1,4 butène-2) acétal-(2S,3S) (forme B) préparé selon l'exemple 3A, de 5 cm3 d'acide acétique et de 1,0 cm3 d'une solution aqueuse d'acide chlorhydrique 12N. On obtient ainsi 0,06 g de (-)-(chloro-7 naphtyridine-1,8 yl-2)-2 (méthyl-5 oxo-2 hexyl)-3 isoindolinone-1 fondant à 172 C et dont le pouvoir rotatoire est:
[ocl20D = -1390 +30 (c =0,73%; CHOl3). EXAMPLE 4
The procedure is as in Example 1 but starting from 0.1 g of (-) - [(7-chloro-naphthyridine-1, 8 yl-2) -2 3-oxo-isoindolinyl-1] -2 5-methyl-2-hexanone (dimethoxy1,4 butene-2) acetal- (2S, 3S) (form B) prepared according to Example 3A, 5 cm3 of acetic acid and 1.0 cm3 of an aqueous solution of 12N hydrochloric acid. This gives 0.06 g of (-) - (7-chloro-naphthyridine-1,8 yl-2) -2 (5-methyl-2-oxo-hexyl) -3 isoindolinone-1 melting at 172 C and whose rotary power East:
[ocl20D = -1390 +30 (c = 0.73%; CHOl3).
Claims (6)
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9115860A FR2685330B1 (en) | 1991-12-20 | 1991-12-20 | PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE. |
| CA 2122025 CA2122025A1 (en) | 1991-12-20 | 1992-12-18 | Process for the preparation of enantiomeres from an iso-indolinon derivative |
| JP5511482A JPH07502282A (en) | 1991-12-20 | 1992-12-18 | Method for producing enantiomers of isoindolinone derivatives |
| PCT/FR1992/001207 WO1993013098A1 (en) | 1991-12-20 | 1992-12-18 | Method for preparing enantiomers of an isoindolinone derivative |
| EP93902350A EP0643711A1 (en) | 1991-12-20 | 1992-12-18 | Method for preparing enantiomers of an isoindolinone derivative |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9115860A FR2685330B1 (en) | 1991-12-20 | 1991-12-20 | PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| FR2685330A1 true FR2685330A1 (en) | 1993-06-25 |
| FR2685330B1 FR2685330B1 (en) | 1994-02-04 |
Family
ID=9420276
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| FR9115860A Expired - Fee Related FR2685330B1 (en) | 1991-12-20 | 1991-12-20 | PROCESS FOR THE PREPARATION OF ENANTIOMERS OF AN ISOINDOLINONE DERIVATIVE. |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0643711A1 (en) |
| JP (1) | JPH07502282A (en) |
| CA (1) | CA2122025A1 (en) |
| FR (1) | FR2685330B1 (en) |
| WO (1) | WO1993013098A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PT1490363E (en) | 2002-03-29 | 2006-06-30 | Indevus Pharmaceuticals Inc | PREPARATION PROCESSES OF 2- (7-CHLORO-1,8-NAFTHYRIDINE-2-YL) -3- (5-METHYL-2-OXO-HEXYL) -1-ISOINDOLINONE |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4960779A (en) * | 1986-12-02 | 1990-10-02 | Rhone-Poulenc Sante | Pyrrole derivatives, and pharmaceutical compositions which contain them and pharmacological methods of use |
-
1991
- 1991-12-20 FR FR9115860A patent/FR2685330B1/en not_active Expired - Fee Related
-
1992
- 1992-12-18 EP EP93902350A patent/EP0643711A1/en not_active Withdrawn
- 1992-12-18 JP JP5511482A patent/JPH07502282A/en active Pending
- 1992-12-18 CA CA 2122025 patent/CA2122025A1/en not_active Abandoned
- 1992-12-18 WO PCT/FR1992/001207 patent/WO1993013098A1/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4960779A (en) * | 1986-12-02 | 1990-10-02 | Rhone-Poulenc Sante | Pyrrole derivatives, and pharmaceutical compositions which contain them and pharmacological methods of use |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0643711A1 (en) | 1995-03-22 |
| CA2122025A1 (en) | 1993-07-08 |
| FR2685330B1 (en) | 1994-02-04 |
| WO1993013098A1 (en) | 1993-07-08 |
| JPH07502282A (en) | 1995-03-09 |
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