WO2005030718A1 - Novel method of preparing cis-octahydro-isoindole - Google Patents

Novel method of preparing cis-octahydro-isoindole Download PDF

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WO2005030718A1
WO2005030718A1 PCT/FR2004/002413 FR2004002413W WO2005030718A1 WO 2005030718 A1 WO2005030718 A1 WO 2005030718A1 FR 2004002413 W FR2004002413 W FR 2004002413W WO 2005030718 A1 WO2005030718 A1 WO 2005030718A1
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cis
isoindole
octahydro
preparation
branched
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PCT/FR2004/002413
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French (fr)
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Rimane Aoun
Christian Bruneau
Pierre Dixneuf
Jean-Luc Renaud
Jean-Claude Souvie
Claude Fugier
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Les Laboratoires Servier
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles

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  • the present invention relates to a new process for the preparation of cis-octahydro-isoindole.
  • Cis-octahydro-isoindole is a widely used synthetic intermediate, especially in the preparation of pharmaceutical active ingredients.
  • cis-octahydro-isoindole is an important intermediate in the synthesis of 2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -butyric acid of formula (I) :
  • the compound of formula (I), as well as its addition salts and its hydrates, have particularly advantageous pharmacological properties. They are very powerful insulin secretors, which makes them useful in the treatment of non-insulin dependent diabetes.
  • the compound of formula (I), its preparation and its use in therapy have been described in patent EP 0 507 534. Its industrial preparation is described in patent WO 99/01430. Given the pharmaceutical interest of this compound, it was important to be able to access the intermediate cis-octahydro-isoindole with an efficient industrial synthesis process.
  • Patent application JP 06298727 describes the preparation of cis-octahydro-isoindole by catalytic hydrogenation, at 150 bars and 250 ° C, of cis-tetrahydrophthalimide in the presence of Raney nickel. This method again requires particularly drastic conditions.
  • the present invention relates to a process for the preparation of cis-octahydro-isoindole from cis-tetrahydrophthalimide, the imide function of which is protected, to lead to the compound of formula (II), of relative cis configuration:
  • P represents an arylmethyl group
  • aryl group phenyl optionally substituted by one or more groups, identical or different, chosen from halogen, linear or branched (Ci-C 6 ) alkyl and alkoxy (C ⁇ -C 6 ) linear or branched, which is subjected to a reduction reaction with the compound of formula (III):
  • Rj and R 2 each preferably represent the phenyl group.
  • the preferred rhodium catalyst (I) is RhCl .H 2 O
  • the cis-octahydro-isoindole thus obtained is particularly useful as an intermediate in the synthesis of active principles such as the compound of formula (I), and more particularly its calcium salt and the dihydrate of its calcium salt.
  • an autoclave 80 mg of the compound obtained in the preceding stage, 16 mg of Pd on carbon (20% by mass) and 5 ml of ethanol are introduced under argon.
  • the autoclave is then pressurized to 20 bars of hydrogen and heated at 50 C for 23 h, then, after return to ambient pressure and temperature, the contents of the autoclave are filtered and the ethanol is evaporated, to yield the cis -octahydro-isoindole in the form of a colorless oil, with a quantitative yield.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Indole Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The invention relates to a method for the synthesis of cis-octahydro-isoindole from cis-tetrahydrophthalimide. The invention can be used for the synthesis of 2-(S)-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)-butyric acid, the pharmaceutically-acceptable salts thereof and the hydrates of same.

Description

NOUVEAU PROCEDE DE PREPARATION DU CIS-OCTAHYDRO-ISOINDOLE NEW PROCESS FOR THE PREPARATION OF CIS-OCTAHYDRO-ISOINDOLE
La présente invention concerne un nouveau procédé de préparation du cis-octahydro- isoindole.The present invention relates to a new process for the preparation of cis-octahydro-isoindole.
Le cis-octahydro-isoindole est un intermédiaire de synthèse largement utilisé, notamment dans la préparation de principes actifs pharmaceutiques.Cis-octahydro-isoindole is a widely used synthetic intermediate, especially in the preparation of pharmaceutical active ingredients.
En particulier, le cis-octahydro-isoindole est un intermédiaire important dans la synthèse de l'acide 2-(S)-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)-butyrique de formule (I) :In particular, cis-octahydro-isoindole is an important intermediate in the synthesis of 2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -butyric acid of formula (I) :
Figure imgf000002_0001
H de ses sels pharmaceutiquement acceptables et de ses hydrates.
Figure imgf000002_0001
H of its pharmaceutically acceptable salts and its hydrates.
Le composé de formule (I), ainsi que ses sels d'addition et ses hydrates, possèdent des propriétés pharmacologiques particulièrement intéressantes. Ce sont des insulinosécréteurs très puissants, ce qui les rend utiles dans le traitement des diabètes non insulino- dépendants. Le composé de formule (I), sa préparation et son utilisation en thérapeutique ont été décrits dans le brevet EP 0 507 534. Sa préparation industrielle est décrite dans le brevet WO 99/01430. Compte-tenu de l'intérêt pharmaceutique de ce composé, il était important de pouvoir accéder au cis-octahydro-isoindole intermédiaire avec un procédé de synthèse industrielle performant.The compound of formula (I), as well as its addition salts and its hydrates, have particularly advantageous pharmacological properties. They are very powerful insulin secretors, which makes them useful in the treatment of non-insulin dependent diabetes. The compound of formula (I), its preparation and its use in therapy have been described in patent EP 0 507 534. Its industrial preparation is described in patent WO 99/01430. Given the pharmaceutical interest of this compound, it was important to be able to access the intermediate cis-octahydro-isoindole with an efficient industrial synthesis process.
Plusieurs méthodes de préparation du cis-octahydro-isoindole sont déjà connues.Several methods for preparing cis-octahydro-isoindole are already known.
Ainsi, la publication Bull. Soc. Chim. France 1966, 1315-1324, décrit la préparation du cis-octahydro-isoindole par hydrogénation catalytique, à 120 bars et 20O°C, du cis- tétrahydrophtalimide en présence de nickel de Raney, suivie de la réduction chimique par l'hydrure de lithium aluminium de la cis-octahydro-isoindol-1-one ainsi obtenue. Cette méthode présente plusieurs inconvénients : la première étape nécessite des conditions drastiques, tandis que la deuxième étape nécessite l'utilisation en large excès d'hydrure de lithium aluminium, qui produit des sels d'aluminium et de lithium difficiles à éliminer.Thus, the publication Bull. Soc. Chim. France 1966, 1315-1324, describes the preparation of cis-octahydro-isoindole by catalytic hydrogenation, at 120 bars and 20O ° C, of cis- tetrahydrophthalimide in the presence of Raney nickel, followed by chemical reduction by lithium aluminum hydride of the cis-octahydro-isoindol-1-one thus obtained. This method has several disadvantages: the first step requires drastic conditions, while the second step requires the use in large excess of lithium aluminum hydride, which produces aluminum and lithium salts difficult to remove.
La demande de brevet JP 06298727 décrit la préparation du cis-octahydro-isoindole par hydrogénation catalytique, à 150 bars et 250°C, du cis-tétrahydrophtalimide en présence de nickel de Raney. Cette méthode nécessite, là encore, des conditions particulièrement drastiques.Patent application JP 06298727 describes the preparation of cis-octahydro-isoindole by catalytic hydrogenation, at 150 bars and 250 ° C, of cis-tetrahydrophthalimide in the presence of Raney nickel. This method again requires particularly drastic conditions.
Compte-tenu de l'intérêt du cis-octahydro-isoindole en tant qu'intermédiaire de synthèse de principes actifs pharmaceutiques et notamment de l'acide 2-(S)-benzyl-4-oxo-4-(cis- perhydroisoindol-2-yl)-butyrique, il était important de trouver un procédé permettant son obtention avec un bon rendement, et dans des conditions douces, facilement transposables à l'échelle industrielle.In view of the interest of cis-octahydro-isoindole as an intermediate for the synthesis of pharmaceutical active principles and in particular of 2- (S) -benzyl-4-oxo-4- (cis- perhydroisoindol-2) acid -yl) -butyrique, it was important to find a process allowing its obtaining with a good output, and in soft conditions, easily transposable on an industrial scale.
La demanderesse a entrepris des recherches approfondies qui ont abouti à la mise au point d'un procédé remplissant ces conditions.The Applicant has undertaken in-depth research which has led to the development of a process fulfilling these conditions.
Plus spécifiquement, la présente invention concerne un procédé de préparation du cis- octahydro-isoindole à partir du cis-tétrahydrophtalimide, dont on protège la fonction imide, pour conduire au composé de formule (II), de configuration relative cis :More specifically, the present invention relates to a process for the preparation of cis-octahydro-isoindole from cis-tetrahydrophthalimide, the imide function of which is protected, to lead to the compound of formula (II), of relative cis configuration:
Figure imgf000003_0001
dans laquelle P représente un groupement arylméthyle, étant entendu que par groupement aryle, on entend phényle éventuellement substitué par un ou plusieurs groupements, identiques ou différents, choisis parmi halogène, alkyle (Ci-C6) linéaire ou ramifié et alkoxy (Cι-C6) linéaire ou ramifié, que l'on soumet à une réaction de réduction par le composé de formule (III) :
Figure imgf000003_0001
in which P represents an arylmethyl group, it being understood that by aryl group is meant phenyl optionally substituted by one or more groups, identical or different, chosen from halogen, linear or branched (Ci-C 6 ) alkyl and alkoxy (Cι-C 6 ) linear or branched, which is subjected to a reduction reaction with the compound of formula (III):
R!R2SiH2 (III) dans laquelle R] représente un atome ou groupement choisi parmi hydrogène, phényle et alkyle (Cι-C6) linéaire ou ramifié, et R2 représente un groupement choisi parmi phényle et alkyle (C C6) linéaire ou ramifié,R ! R 2 SiH 2 (III) in which R] represents an atom or group chosen from hydrogen, phenyl and alkyl (Cι-C 6 ) linear or branched, and R 2 represents a group chosen from phenyl and alkyl (CC 6 ) linear or branched
en présence d'un catalyseur de rhodium(I) ou de précurseur de rhodium(I) à ligand chlorure, hydrure, monoxyde de carbone, diène ou phosphine, pour conduire au composé de formule (IV), de configuration relative cis : H
Figure imgf000004_0001
ïî dans laquelle P est tel que défini précédemment,in the presence of a rhodium catalyst (I) or a rhodium precursor (I) with a chloride, hydride, carbon monoxide, diene or phosphine ligand, to lead to the compound of formula (IV), of relative cis configuration: H
Figure imgf000004_0001
ïî in which P is as defined above,
que l'on soumet à une réaction d'hydrogénation catalysée par le palladium sur charbon, à une température supérieure à 20°C, pour conduire au cis-octahydro-isoindole.which is subjected to a hydrogenation reaction catalyzed by palladium on carbon, at a temperature above 20 ° C., to lead to cis-octahydro-isoindole.
Rj et R2 représentent chacun préférentiellement le groupement phényle.Rj and R 2 each preferably represent the phenyl group.
Le catalyseur de rhodium(I) préféré est RhCl .H2OThe preferred rhodium catalyst (I) is RhCl .H 2 O
Le cis-octahydro-isoindole ainsi obtenu est particulièrement utile comme intermédiaire dans la synthèse de principes actifs tels que le composé de formule (I), et plus particulièrement son sel de calcium et le dihydrate de son sel de calcium.The cis-octahydro-isoindole thus obtained is particularly useful as an intermediate in the synthesis of active principles such as the compound of formula (I), and more particularly its calcium salt and the dihydrate of its calcium salt.
A titre d'illustration, sa réaction avec l'anhydride de formule (V) :
Figure imgf000005_0001
conduit au composé de formule (VI) :By way of illustration, its reaction with the anhydride of formula (V):
Figure imgf000005_0001
leads to the compound of formula (VI):
Figure imgf000005_0002
dont l'hydrogénation catalytique en présence d'un catalyseur asymétrique conduit au composé de formule (I).
Figure imgf000005_0002
whose catalytic hydrogenation in the presence of an asymmetric catalyst leads to the compound of formula (I).
EXEMPLE : Cis-octahydro-isoindoleEXAMPLE: Cis-octahydro-isoindole
Stade A : Cis-2-ben∑yl-tétrahydrophtalimideStage A: Cis-2-ben∑yl-tetrahydrophthalimide
Dans un tube de Schlenk, on introduit sous atmosphère inerte 756 mg de cis- tétrahydrophtalimide, 132 mg d'hydrure de sodium, 0,65 ml de bromure de benzyle et 170 mg d'iodure de tétrabutylammonium dans 20 ml de tétrahydrofurane. Le mélange est agité à température ambiante pendant 15 h, puis du dichlorométhane est ajouté. La phase organique est lavée puis séchée, filtrée et concentrée. Une purification sur colonne de silice permet d'obtenir le cis-2-benzyl-tétrahydrophtalimide sous la forme d'un solide blanc, avec un rendement de 70%.756 mg of cis-tetrahydrophthalimide, 132 mg of sodium hydride, 0.65 ml of benzyl bromide and 170 mg of tetrabutylammonium iodide in 20 ml of tetrahydrofuran are introduced into a Schlenk tube under an inert atmosphere. The mixture is stirred at room temperature for 15 h, then dichloromethane is added. The organic phase is washed then dried, filtered and concentrated. Purification on a silica column makes it possible to obtain cis-2-benzyl-tetrahydrophthalimide in the form of a white solid, with a yield of 70%.
Stade B : Cis-2-benzyl-hexahydro-isoindoleStage B: Cis-2-benzyl-hexahydro-isoindole
Dans un tube de Schlenk, on introduit sous atmosphère inerte 694 mg du composé obtenu au stade précédent, 2,7 ml de diphénylsilane, 7,5 mg de RhCl3.3H2O et 6 ml de tétrahydrofurane. Le mélange est agité à température ambiante pendant 5h, puis dilué à l'éther et extrait avec une solution d'acide chlorhydrique 1M. La phase aqueuse est basifiée par une solution de soude 1M et est extraite par l'acétate d'éthyle. La phase organique est ensuite séchée, filtrée et évaporée, pour conduire au cis-2-benzyl-hexahydro-isoindole sous la forme d'une huile incolore, avec un rendement de 70%.694 mg of the compound obtained in the preceding stage, 2.7 ml of diphenylsilane, 7.5 mg of RhCl 3 .3H 2 O and 6 ml of tetrahydrofuran are introduced into a Schlenk tube under an inert atmosphere. The mixture is stirred at room temperature for 5 h, then diluted with ether and extracted with a 1M hydrochloric acid solution. The aqueous phase is basified with a 1M sodium hydroxide solution and is extracted with ethyl acetate. The organic phase is then dried, filtered and evaporated, to yield cis-2-benzyl-hexahydro-isoindole in the form of a colorless oil, with a yield of 70%.
Stade C : Cis-octahydro-isoindoleStage C: Cis-octahydro-isoindole
Dans un autoclave, on introduit sous argon 80 mg du composé obtenu au stade précédent, 16 mg de Pd sur charbon (20% en masse) et 5 ml d'éthanol. L'autoclave est ensuite pressurisé à 20 bars d'hydrogène et chauffé à 50 C pendant 23 h, puis, après retour à pression et température ambiantes, le contenu de l'autoclave est filtré et l'éthanol est évaporé, pour conduire au cis-octahydro-isoindole sous la forme d'une huile incolore, avec un rendement quantitatif. In an autoclave, 80 mg of the compound obtained in the preceding stage, 16 mg of Pd on carbon (20% by mass) and 5 ml of ethanol are introduced under argon. The autoclave is then pressurized to 20 bars of hydrogen and heated at 50 C for 23 h, then, after return to ambient pressure and temperature, the contents of the autoclave are filtered and the ethanol is evaporated, to yield the cis -octahydro-isoindole in the form of a colorless oil, with a quantitative yield.

Claims

REVENDICATIONS
1. Procédé de préparation du cis-octahydro-isoindole à partir du cis- tétrahydrophtalimide, dont on protège la fonction imide, pour conduire au composé de formule (II), de configuration relative cis :1. Process for the preparation of cis-octahydro-isoindole from cis-tetrahydrophthalimide, the imide function of which is protected, to lead to the compound of formula (II), of relative cis configuration:
Figure imgf000007_0001
dans laquelle P représente un groupement arylméthyle, étant entendu que par groupement aryle, on entend phényle éventuellement substitué par un ou plusieurs groupements, identiques ou différents, choisis parmi halogène, alkyle (C^CÔ) linéaire ou ramifié et alkoxy (Cî-Cβ) linéaire ou ramifié, que l'on soumet à une réaction de réduction par le composé de formule (III) :
Figure imgf000007_0001
in which P represents an arylmethyl group, it being understood that by aryl group is meant phenyl optionally substituted by one or more groups, identical or different, chosen from halogen, linear or branched (C ^ C Ô ) alkyl and alkoxy (C î - Cβ) linear or branched, which is subjected to a reduction reaction with the compound of formula (III):
R!R2SiH2 (III) dans laquelle R1 représente un atome ou groupement choisi parmi hydrogène, phényle et alkyle (CÎ-CÔ) linéaire ou ramifié, et R représente un groupement choisi parmi phényle et alkyle (Ci-Ce) linéaire ou ramifié, en présence d'un catalyseur de rhodium(I) ou de précurseur de rhodium(I) à ligand chlorure, hydrure, monoxyde de carbone, diène ou phosphine, pour conduire au composé de formule (IV), de configuration relative cis :
Figure imgf000008_0001
dans laquelle P est tel que défini précédemment, que l'on soumet à une réaction d'hydrogénation catalysée par le palladium sur charbon, à une température supérieure à 20°C, pour conduire au cis-octahydro-isoindole.R ! R 2 SiH 2 (III) wherein R 1 represents an atom or group selected from hydrogen, phenyl and alkyl (C i -C o) linear or branched, and R represents a group selected from phenyl and alkyl (Ci-Ce) linear or branched, in the presence of a rhodium catalyst (I) or a rhodium precursor (I) with a chloride, hydride, carbon monoxide, diene or phosphine ligand, to lead to the compound of formula (IV), of relative cis configuration :
Figure imgf000008_0001
in which P is as defined above, which is subjected to a hydrogenation reaction catalyzed by palladium on carbon, at a temperature above 20 ° C., to lead to cis-octahydro-isoindole.
2. Procédé selon la revendication 1, caractérisé en ce que R\ et R2 représentent chacun un groupement phényle.2. Method according to claim 1, characterized in that R \ and R 2 each represent a phenyl group.
3. Procédé selon la revendication 1, caractérisé en ce que le catalyseur de rhodiu (I) est RhCl3.H2O.3. Method according to claim 1, characterized in that the rhodium catalyst (I) is RhCl 3 .H 2 O.
4. Procédé de préparation de l'acide 2-(S)-benzyl-4-oxo-4-(cis-perhydroisoindol-2-yl)- butyrique à partir du cis-octahydro-isoindole, caractérisé en ce que ledit cis-octahydro- isoindole est préparé selon le procédé de la revendication 1.4. Process for the preparation of 2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -butyric acid from cis-octahydro-isoindole, characterized in that said cis- octahydro-isoindole is prepared according to the process of claim 1.
5. Procédé de préparation du sel de calcium de l'acide 2-(S)-benzyl-4-oxo-4-(cis- perhydroisoindol-2-yl)-butyrique à partir du cis-octahydro-isoindole, caractérisé en ce que ledit cis-octahydro-isoindole est préparé selon le procédé de la revendication 1.5. Process for the preparation of the calcium salt of 2- (S) -benzyl-4-oxo-4- (cis- perhydroisoindol-2-yl) -butyric acid from cis-octahydro-isoindole, characterized in that that said cis-octahydro-isoindole is prepared according to the process of claim 1.
6. Procédé de préparation du dihydrate de bis-2-(S)-benzyl-4-oxo-4-(cis- perhydroisoindol-2-yl)-butyrate de calcium à partir du cis-octahydro-isoindole, caractérisé en ce que le cis-octahydro-isoindole de départ est préparé selon le procédé de la revendication 1. 6. Process for the preparation of bis-2- (S) -benzyl-4-oxo-4- (cis-perhydroisoindol-2-yl) -butyrate dihydrate from cis-octahydro-isoindole, characterized in that the starting cis-octahydro-isoindole is prepared according to the process of claim 1.
PCT/FR2004/002413 2003-09-25 2004-09-24 Novel method of preparing cis-octahydro-isoindole WO2005030718A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100441570C (en) * 2006-05-24 2008-12-10 严洁 Preparation of mitiglinide calcium and its quality control method
CN103450069A (en) * 2013-06-24 2013-12-18 山西大同大学 Preparation method of mitiglinide calcium

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06298727A (en) * 1993-02-19 1994-10-25 New Japan Chem Co Ltd Production of cyclic amines
WO1999001430A1 (en) * 1997-07-03 1999-01-14 Adir Method for preparing a substituted perhydroisoindole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06298727A (en) * 1993-02-19 1994-10-25 New Japan Chem Co Ltd Production of cyclic amines
WO1999001430A1 (en) * 1997-07-03 1999-01-14 Adir Method for preparing a substituted perhydroisoindole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CASREACT [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002280529, retrieved from STN Database accession no. 122:187383 *
KUWANO R ET AL: "Reduction of Amides to Amines via Catalytic Hydrosilylation by a Rhodium Complex", TETRAHEDRON LETTERS, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 39, no. 9, 26 February 1998 (1998-02-26), pages 1017 - 1020, XP004106864, ISSN: 0040-4039 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100441570C (en) * 2006-05-24 2008-12-10 严洁 Preparation of mitiglinide calcium and its quality control method
CN103450069A (en) * 2013-06-24 2013-12-18 山西大同大学 Preparation method of mitiglinide calcium

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