EP0585341A1 - New chiral sulphates preparation thereof and utilization in the synthesis of pharmaceutical products - Google Patents

New chiral sulphates preparation thereof and utilization in the synthesis of pharmaceutical products

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Publication number
EP0585341A1
EP0585341A1 EP19920911777 EP92911777A EP0585341A1 EP 0585341 A1 EP0585341 A1 EP 0585341A1 EP 19920911777 EP19920911777 EP 19920911777 EP 92911777 A EP92911777 A EP 92911777A EP 0585341 A1 EP0585341 A1 EP 0585341A1
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EP
European Patent Office
Prior art keywords
chloromethyl
preparation
ethylene
isomer
ethylene sulfate
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EP19920911777
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German (de)
French (fr)
Inventor
Xavier Radisson
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Aventis Pharma SA
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Rhone Poulenc Rorer SA
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Publication of EP0585341A1 publication Critical patent/EP0585341A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/10—1,2,5-Thiadiazoles; Hydrogenated 1,2,5-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • 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
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
    • C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
    • C07D303/22—Ethers with hydroxy compounds containing no oxirane rings with monohydroxy compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D327/00—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms
    • C07D327/10—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms two oxygen atoms and one sulfur atom, e.g. cyclic sulfates

Definitions

  • the present invention relates to new chiral sulfates, their preparation and their use in the synthesis of optically active products.
  • the invention relates to the (R) and (S) isomers of 1-chloromethyl ethylene sulphate, their preparation and their use.
  • the (R) and (S) isomers of 1-chloromethyl ethylene sulfate are obtained from, respectively, the (R) and (S) -isomers of 1,2-chloro-propanediol by passing through the (R) and (S) isomers of the corresponding 1-chloromethyl ethylene sulfite.
  • 1-chloromethyl ethylene sulfite (R) or (S) is obtained from (R) - or (S) -chloro-3-propanediol-1,2 according to known methods and in particular according to the process described for the preparation of racemic 1-chloromethyl ethylene sulfite by DS Breslow and H. Skolnik, "The Chemistry of Heterocyclic Compounds - Multi-Sulfur and Sulfur and Oxygen 5- and 6- Membered Heterocycles", 1966, Part I, p. 1 and Part II, p. 663 or by Van Woerden, Chem. Rev., èl, 557 (1963). It is particularly advantageous to react an excess of thionyl chloride on chloro-3-propanediol-1,2 chiral by operating at a temperature close to 0 ° C.
  • 1-chloromethyl ethylene sulfate (R) or (S) is obtained by oxidation of the corresponding 1-chloromethyl ethylene sulfite in particular according to the process described in French patent FR 2 628 423, that is to say at means of an alkaline or alkaline earth hypohalogenite (hypochlorite or hypobromite), preferably sodium, potassium or calcium hypochlorite, in the presence of a catalytic amount of a ruthenium derivative chosen from, preferably, l ruthenium (IV) oxide (Ru ⁇ 2) and ruthenium chloride (RUCI3).
  • a ruthenium derivative chosen from, preferably, l ruthenium (IV) oxide (Ru ⁇ 2) and ruthenium chloride (RUCI3).
  • the process can be carried out in a two-phase aqueous or hydroorganic medium. ; .
  • the solvent is generally chosen from aliphatic or cycloaliphatic hydrocarbons, optionally halogenated, such as hexane, cyclohexane, methylene chloride, chloroform, carbon tetrachloride or dichloroethane, or esters such as methyl or ethyl acetate.
  • halogenated such as hexane, cyclohexane, methylene chloride, chloroform, carbon tetrachloride or dichloroethane, or esters such as methyl or ethyl acetate.
  • an excess of hypohalogenite is used relative to the sulfite used.
  • 1 to 2 moles of hypohalogenite are used per mole of sulfite.
  • ruthenium derivative of between 1 (H> and 10 "! Mole per mole of sulfite used. It is understood that, by implementing the process according to the invention, the (R) isomer of 1-chloromethyl ethylene sulfate is obtained from (R) -chloro-3-propanediol-1,2 through the (R) isomer of chloromethyl-1 ethylene sulfite and that sulfate of chloromethyl-1 ethylene (S) is obtained from (S) -chloro-3-propanediol-1,2 by passing intermediarily through the (S) isomer of chloromethyl-l ethylene sulfite.
  • the (R) and (S) isomers of chloromethyl ethylene sulfate are particularly useful in the synthesis of chiral products having therapeutic properties such as chiral adrenergic ⁇ -blockers which are characterized by the presence of a 3-aminoamino chain 2-hydroxypropoxy.
  • adrenergic ⁇ -blockers such as acebutolol, atenolol, propranolol, celiprolol, metoprolol, timolol, nadolol, penbutolol, levobunolol or pindolol
  • therapeutic activity is due to the (S) -isomer, the (R) -isomer being, in general, completely inactive. It is therefore particularly advantageous to be able to directly prepare the (S) isomer practically free of the (R) isomer.
  • the adrenergic ⁇ -blockers in form (S) as defined above can be obtained according to one of the following methods:
  • Ar represents an aromatic radical or an optionally substituted heterocyclic aromatic radical which is encountered in the adrenergic ⁇ -blockers mentioned above and R represents a straight or branched alkyl radical containing 1 to 4 carbon atoms.
  • the condensation of the (R) -isomer of chloromethyl-1 ethylene sulfate with the phenol of formula ArOH, in which Ar is defined as above, is carried out in water or in an organic solvent or in a hydroorganic medium with a temperature between 0 and 80 ° C in the presence of a base chosen from alkali metal hydroxides (soda), alkali metal carbonates or bicarbonates (sodium carbonate), ammonia or quaternary ammonium hydroxides ( tetrabutylammonium hydroxide).
  • a base chosen from alkali metal hydroxides (soda), alkali metal carbonates or bicarbonates (sodium carbonate), ammonia or quaternary ammonium hydroxides ( tetrabutylammonium hydroxide).
  • nitriles acetonitrile
  • ketones acetone
  • alcohols ethanol
  • esters ethyl acetate
  • amides dimethylformamide
  • halogenated aliphatic hydrocarbons methylene chloride
  • condensation of the (S) -isomer of chloromethyl-1 ethylene sulfate on the amine of formula R-NH2, in which R is defined as above, is carried out in an organic solvent chosen, for example, from hydrocarbons halogenated aliphatics such as dichloromethane at a temperature close to the reflux temperature of the reaction mixture.
  • the condensation of the phenol of formula ArOH, in which Ar is defined as above, on the epoxide of form (S), obtained after hydrolysis in basic medium of the reaction product of the amine of formula R-NH2 on the (S) isomer of chloromethyl-1 ethylene sulfate, is carried out under conditions identical to those described above for the condensation of the R-isomer of chloromethyl-1 ethylene sulfate on the phenol of formula Ar-OH.
  • the process for preparing the chiral adrenergic ⁇ -blockers according to the present invention has, over the known processes from chiral epichlorohydrin, the advantage of being very selective, of using a much more reactive chiral cyclic sulfate and of do not offer the possibility of racemization.
  • the isomers (R) and (S) of chloromethyl ethylene sulfate can also be advantageously used in the synthesis of other chiral products such as L-carnitine, the "Platelet Activating Factor” or various (S) -phospholipids or (S) -glycerolphosphates.
  • the yield is 82.1%.
  • reaction mixture darkens throughout the addition. At the end of the addition, the mixture is kept at 0 ° C. for 5 minutes and then 50 cm 3 of methylene chloride are added. After decantation, the aqueous phase is extracted twice with 50 cm3 of methylene chloride. The combined organic phases are washed with 50 cm3 of water. After drying and filtration, the reaction mixture is concentrated to dryness at 50 ° C under reduced pressure (15 mm of mercury; 2 kPa).
  • the yield is 78.3%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Les isomères (R) et (S) du sulfate de chlorométhyl-1 éthylène, leur préparation et leur emploi en particulier dans la synthèse de (S)-beta-bloquants adrénergiques ou de la L-carnitine ou des phospholipides.The (R) and (S) isomers of 1-chloromethyl ethylene sulfate, their preparation and their use in particular in the synthesis of (S) -beta-adrenergic blockers or of L-carnitine or phospholipids.

Description

NOUVEAUX SULFATES CHIRAUX. LEUR PREPARATION NEW CHIRAL SULPHATES. THEIR PREPARATION
ET LEUR EMPLOI DANS LA SYNTHESE DE PRODUITSAND THEIR USE IN THE SYNTHESIS OF PRODUCTS
PHARMACEUTIQUESPHARMACEUTICALS
La présente invention concerne de nouveaux sulfates chiraux, leur préparation et leur emploi dans la synthèse de produits optiquement actifs.The present invention relates to new chiral sulfates, their preparation and their use in the synthesis of optically active products.
Plus particulièrement, l'invention concerne les isomères (R) et (S) du sulfate de chlorométhyl-1 éthylène, leur préparation et leur emploi.More particularly, the invention relates to the (R) and (S) isomers of 1-chloromethyl ethylene sulphate, their preparation and their use.
Selon la présente invention, les isomères (R) et (S) du sulfate de chlorométhyl-1 éthylène sont obtenus à partir, respectivement, des isomères (R) et (S) du chloro-3 propanediol-1,2 en passant intermédiairement par les isomères (R) et (S) du sulfite de chlorométhyl-1 éthylène correspondants.According to the present invention, the (R) and (S) isomers of 1-chloromethyl ethylene sulfate are obtained from, respectively, the (R) and (S) -isomers of 1,2-chloro-propanediol by passing through the (R) and (S) isomers of the corresponding 1-chloromethyl ethylene sulfite.
Généralement, le sulfite de chlorométhyl-1 éthylène (R) ou (S) est obtenu à partir du (R)- ou (S)-chloro-3-propanediol-l,2 selon les méthodes connues et en particulier selon le procédé décrit pour la préparation du sulfite de chlorométhyl-1 éthylène racémique par D.S. Breslow et H. Skolnik, "The Chemistry of Heterocyclic Compounds - Multi-Sulphur and Sulphur and Oxygen 5- and 6- Membered Heterocycles", 1966, Part I, p. 1 and Part II, p. 663 ou par Van Woerden, Chem. Rev., èl, 557 (1963). Il est particulièrement avantageux de faire réagir un excès de chlorure de thionyle sur le chloro-3-propanediol-l,2 chiral en opérant à une températutre voisine de 0°C.Generally, 1-chloromethyl ethylene sulfite (R) or (S) is obtained from (R) - or (S) -chloro-3-propanediol-1,2 according to known methods and in particular according to the process described for the preparation of racemic 1-chloromethyl ethylene sulfite by DS Breslow and H. Skolnik, "The Chemistry of Heterocyclic Compounds - Multi-Sulfur and Sulfur and Oxygen 5- and 6- Membered Heterocycles", 1966, Part I, p. 1 and Part II, p. 663 or by Van Woerden, Chem. Rev., èl, 557 (1963). It is particularly advantageous to react an excess of thionyl chloride on chloro-3-propanediol-1,2 chiral by operating at a temperature close to 0 ° C.
Généralement, le sulfate de chlorométhyl-1 éthylène (R) ou (S) est obtenu par oxydation du sulfite de chlorométhyl-1 éthylène correspondant en particulier selon le procédé décrit dans le brevet français FR 2 628 423 c'est-à-dire au moyen d'un hypohalogénite (hypochlorite ou hypobromite) alcalin ou alcalino-terreux, de préférence l'hypochlorite de sodium, de potassium ou de calcium, en présence d'une quantité catalytique d'un dérivé du ruthénium choisi parmi, de préférence, l'oxyde de ruthénium (IV) (Ruθ2) et le chlorure de ruthénium (RUCI3).Generally, 1-chloromethyl ethylene sulfate (R) or (S) is obtained by oxidation of the corresponding 1-chloromethyl ethylene sulfite in particular according to the process described in French patent FR 2 628 423, that is to say at means of an alkaline or alkaline earth hypohalogenite (hypochlorite or hypobromite), preferably sodium, potassium or calcium hypochlorite, in the presence of a catalytic amount of a ruthenium derivative chosen from, preferably, l ruthenium (IV) oxide (Ruθ2) and ruthenium chloride (RUCI3).
Le procédé peut être mis en oeuvre en milieu aqueux ou hydroorganique biphasique. ;. Lorsque le procédé est mis en oeuvre en milieu hydroorganique biphasique, le solvant est généralement choisi parmi les hydrocarbures aliphatiques ou cycloaliphatiques, éventuellement halogènes, tel que l'hexane, le cyclohexane, le chlorure de méthylène, le chloroforme, le tétrachlorure de carbone ou le dichloroéthane, ou les esters tels que l'acétate de méthyle ou d'éthyle. Généralement on utilise un excès d'hypohalogénite par rapport au sulfite mis en oeuvre. De préférence on utilise 1 à 2 moles d'hypohalogénite par mole de sulfite.The process can be carried out in a two-phase aqueous or hydroorganic medium. ; . When the process is carried out in a two-phase hydroorganic medium, the solvent is generally chosen from aliphatic or cycloaliphatic hydrocarbons, optionally halogenated, such as hexane, cyclohexane, methylene chloride, chloroform, carbon tetrachloride or dichloroethane, or esters such as methyl or ethyl acetate. Generally, an excess of hypohalogenite is used relative to the sulfite used. Preferably, 1 to 2 moles of hypohalogenite are used per mole of sulfite.
Généralement, on utilise une quantité catalytique de dérivé du ruthénium comprise entre 1(H> et 10"! mole par mole de sulfite mis en oeuvre. II est bien entendu que, par la mise en oeuvre du procédé selon l'invention, l'isomère (R) du sulfate de chlorométhyl-1 éthylène est obtenu à partir du (R)-chloro-3-propanediol-l,2 en passant par l'isomère (R) du sulfite de chlorométhyl-l éthylène et que le sulfate de chlorométhyl-1 éthylène (S) est obtenu à partir du (S)-chloro-3-propanediol-l,2 en passant intermédiairement par l'isomère (S) du sulfite de chlorométhyl-l éthylène.Generally, a catalytic amount of ruthenium derivative of between 1 (H> and 10 "! Mole per mole of sulfite used is used. It is understood that, by implementing the process according to the invention, the (R) isomer of 1-chloromethyl ethylene sulfate is obtained from (R) -chloro-3-propanediol-1,2 through the (R) isomer of chloromethyl-1 ethylene sulfite and that sulfate of chloromethyl-1 ethylene (S) is obtained from (S) -chloro-3-propanediol-1,2 by passing intermediarily through the (S) isomer of chloromethyl-l ethylene sulfite.
Les isomères (R) et (S) du sulfate de chlorométhyl-l éthylène sont particulièrement utiles dans la synthèse de produits chiraux présentant des propriétés thérapeutiques tels que les β-bloquants adrénergiques chiraux qui se caractérisent par la présence d'une chaîne alkylamino-3 hydroxy-2 propoxy. Dans la famille des β-bloquants adrénergiques tels que l'acébutolol, l'aténolol, le propranolol, le céliprolol, le métoprolol, le timolol, le nadolol, le penbutolol, le levobunolol ou le pindolol, il est connu que l'activité thérapeutique est due à l'isomère (S), l'isomère (R) étant, d'une manière générale, totalement inactif. Il est donc particulièrement intéressant de pouvoir préparer directement l'isomère (S) pratiquement exempt de l'isomère (R).The (R) and (S) isomers of chloromethyl ethylene sulfate are particularly useful in the synthesis of chiral products having therapeutic properties such as chiral adrenergic β-blockers which are characterized by the presence of a 3-aminoamino chain 2-hydroxypropoxy. In the family of adrenergic β-blockers such as acebutolol, atenolol, propranolol, celiprolol, metoprolol, timolol, nadolol, penbutolol, levobunolol or pindolol, it is known that therapeutic activity is due to the (S) -isomer, the (R) -isomer being, in general, completely inactive. It is therefore particularly advantageous to be able to directly prepare the (S) isomer practically free of the (R) isomer.
Selon l'invention, les β-bloquants adrénergiques sous forme (S) tels que définis précédemment peuvent être obtenus selon l'une des méthodes suivantes :According to the invention, the adrenergic β-blockers in form (S) as defined above can be obtained according to one of the following methods:
1) par action d'un phénol préalablement anionisé sur l'isomère (R) du sulfate de chlorométhyl-l éthylène suivi de l'action d'une alkylamine sur l'époxyde obtenu selon le schéma suivant :1) by the action of a phenol previously anionized on the (R) -isomer of chloromethyl-1 ethylene sulfate followed by the action of an alkylamine on the epoxide obtained according to the following scheme:
R-NH.R-NH.
"-*- ArO" 'NH-R " - * - ArO " ' NH-R
(S) 0 OH (S) Dans ce schéma, Ar représente un radical aromatique ou un radical aromatique hétérocyclique éventuellement substitué que l'on rencontre dans les β- bloquants adrénergiques mentionnés ci-dessus et R représente un radical alcoyle droit ou ramifié contenant 1 à 4 atomes de carbone. Généralement, la condensation de l'isomère (R) du sulfate de chlorométhyl-l éthylène sur le phénol de formule ArOH, dans laquelle Ar est défini comme précédemment, est effectuée dans l'eau ou dans un solvant organique ou dans un milieu hydroorganique à une température comprise entre 0 et 80°C en présence d'une base choisie parmi les hydroxydes de métaux alcalins (soude), les carbonates ou bicarbonates de métaux alcalins (carbonate de sodium), l'ammoniaque ou les hydroxydes d'ammonium quaternaires (hydroxyde de tétrabutylammonium).(S) 0 OH (S) In this scheme, Ar represents an aromatic radical or an optionally substituted heterocyclic aromatic radical which is encountered in the adrenergic β-blockers mentioned above and R represents a straight or branched alkyl radical containing 1 to 4 carbon atoms. Generally, the condensation of the (R) -isomer of chloromethyl-1 ethylene sulfate with the phenol of formula ArOH, in which Ar is defined as above, is carried out in water or in an organic solvent or in a hydroorganic medium with a temperature between 0 and 80 ° C in the presence of a base chosen from alkali metal hydroxides (soda), alkali metal carbonates or bicarbonates (sodium carbonate), ammonia or quaternary ammonium hydroxides ( tetrabutylammonium hydroxide).
Comme solvants organiques peuvent être utilisés les nitriles (acétonitrile), les cétones (acétone), les alcools (éthanol), les esters (acétate d'éthyle), les amides (diméthylformamide) ou les hydrocarbures aliphatiques halogènes (chlorure de méthylène).As organic solvents, nitriles (acetonitrile), ketones (acetone), alcohols (ethanol), esters (ethyl acetate), amides (dimethylformamide) or halogenated aliphatic hydrocarbons (methylene chloride) can be used.
Généralement, on utilise un léger excès molaire, de préférence voisin de 10 %, de sulfate cyclique par rapport au phénol.Generally, a slight molar excess, preferably close to 10%, of cyclic sulfate relative to the phenol is used.
Il n'est pas nécessaire d'isoler le sulfate et l'alcool chiral intermédiaires pour obtenir l'époxyde sous forme (S). La condensation de l'aminé de formule R-NH2, dans laquelle R est défini comme précédemment, sur l'époxyde sous forme (S) est réalisée dans les conditions analogues à celles connues qui sont utilisées pour préparer les β-bloquants adrénergiques racémiques à partir de l'époxyde racémique.It is not necessary to isolate the sulfate and the intermediate chiral alcohol to obtain the epoxide in (S) form. The amine of formula R-NH2, in which R is defined as above, is condensed on the epoxide in form (S) is carried out under conditions analogous to those known which are used to prepare the racemic adrenergic β-blockers with from racemic epoxide.
2) par action d'une aminé de formule R-NH2 sur l'isomère S du sulfate de chlorométhyl-l éthylène suivie de l'action d'un phénol Ar-OH préalablement anionisé selon le schéma suivant : 2) by the action of an amine of formula R-NH2 on the S isomer of chloromethyl-1 ethylene sulfate followed by the action of a phenol Ar-OH previously anionized according to the following scheme:
Dans ce schéma, Ar et R sont définis comme précédemment.In this scheme, Ar and R are defined as above.
Généralement, la condensation de l'isomère (S) du sulfate de chlorométhyl-l éthylène sur l'aminé de formule R-NH2, dans laquelle R est défini comme précédemment, est effectuée dans un solvant organique choisi, par exemple, parmi les hydrocarbures aliphatiques halogènes tels que le dichlorométhane à une température voisine de la température de reflux du mélange réactionnel.Generally, the condensation of the (S) -isomer of chloromethyl-1 ethylene sulfate on the amine of formula R-NH2, in which R is defined as above, is carried out in an organic solvent chosen, for example, from hydrocarbons halogenated aliphatics such as dichloromethane at a temperature close to the reflux temperature of the reaction mixture.
Généralement, la condensation du phénol de formule ArOH, dans laquelle Ar est défini comme précédemment, sur l'époxyde de forme (S), obtenu après hydrolyse en milieu basique du produit de réaction de l'aminë de formule R-NH2 sur l'isomère (S) du sulfate de chlorométhyl-l éthylène, est effectuée dans des conditions identiques à celles décrites précédemment pour la condensation de l'isomère R du sulfate de chlorométhyl-l éthylène sur le phénol de formule Ar-OH. Le procédé de préparation des β-bloquants adrénergiques chiraux selon la présente invention présente, sur les procédés connus à partir de l'épichlorhydrine chirale, l'avantage d'être très sélectif, de mettre en oeuvre un sulfate cyclique chiral beaucoup plus réactif et de ne pas offrir de possibilité de racémisation.Generally, the condensation of the phenol of formula ArOH, in which Ar is defined as above, on the epoxide of form (S), obtained after hydrolysis in basic medium of the reaction product of the amine of formula R-NH2 on the (S) isomer of chloromethyl-1 ethylene sulfate, is carried out under conditions identical to those described above for the condensation of the R-isomer of chloromethyl-1 ethylene sulfate on the phenol of formula Ar-OH. The process for preparing the chiral adrenergic β-blockers according to the present invention has, over the known processes from chiral epichlorohydrin, the advantage of being very selective, of using a much more reactive chiral cyclic sulfate and of do not offer the possibility of racemization.
Les isomères (R) et (S) du sulfate de chlorométhyl-l éthylène peuvent également être avantageusement utilisés dans la synthèse d'autres produits chiraux tels que la L-carnitine, le "Platelet Activating Factor" ou divers (S)-phospholipides ou (S)-glycérolphosphates .The isomers (R) and (S) of chloromethyl ethylene sulfate can also be advantageously used in the synthesis of other chiral products such as L-carnitine, the "Platelet Activating Factor" or various (S) -phospholipids or (S) -glycerolphosphates.
Les exemples suivants montrent comment l'invention peut être mise en pratique.The following examples show how the invention can be put into practice.
EXEMPLE ?EXAMPLE?
Dans un ballon tricol, on introduit 25 g de (R)-chloro-3-propanediol-l,2 (0,226 mole). Sous lente agitation, on ajoute en 1 heure, à 0°C, 26,9 g de chlorure de thionyle (0,226 mole). On observe un important dégagement gazeux ainsi qu'une fluidification du mélange réactionnel. Après la fin de l'addition, on laisse la température monter au voisinage de 25°C puis le mélange réactionnel est dégazé sous pression réduite puis distillé sous pression réduite (15 mm de mercure ; 2 kPa). On obtient ainsi 29,05 g de l'isomère (R) du sulfite de chlorométhyl-l éthylène dont les caractéristiques sont les suivantes :25 g of (R) -chloro-3-propanediol-1,2 (0.226 mole) are introduced into a three-necked flask. With slow stirring, 26.9 g of sodium chloride are added over 1 hour at 0 ° C. thionyl (0.226 mole). A significant gas evolution is observed as well as a fluidification of the reaction mixture. After the end of the addition, the temperature is allowed to rise to around 25 ° C. then the reaction mixture is degassed under reduced pressure and then distilled under reduced pressure (15 mm of mercury; 2 kPa). 29.05 g of the (R) -isomer of chloromethyl-ethylene sulfite are thus obtained, the characteristics of which are as follows:
- P.E 5 = 97-100°C- P.E 5 = 97-100 ° C
- ratio diastéréoisomérique : 37/63- diastereoisomeric ratio: 37/63
- pouvoir rotatoire : [α]27D = -37,5° (c = 10,45 x 10**3 ; chloroforme contenant 0,6 % d'éthanol) f«]27365 = -140,9° (c = 10,45 x 10"3 ; chloroforme contenant 0,6 % d'éthanol)- rotary power: [α] 27 D = -37.5 ° (c = 10.45 x 10 ** 3 ; chloroform containing 0.6% ethanol) f "] 27 365 = -140.9 ° (c = 10.45 x 10 "3; chloroform containing 0.6% ethanol)
- pureté énantiomérique : supérieure à 99 %.- enantiomeric purity: greater than 99%.
Le rendement est de 82,1 %.The yield is 82.1%.
A une suspension de 10 g de l'isomère (R) du sulfite de chlorométhyl-l éthylène (0,0639 mole) dans 80 cm3 d'eau refroidie à 5°C, on ajoute en 40 minutes, 40 cm3 d'une solution aqueuse d'hypochlorite de sodium 2.1M contenant 6 mg de Ruθ2, 2H2O.To a suspension of 10 g of the (R) -isomer of chloromethyl-1 ethylene sulfite (0.0639 mol) in 80 cm3 of water cooled to 5 ° C., 40 cm3 of a solution are added in 40 minutes aqueous 2.1M sodium hypochlorite containing 6 mg of Ruθ2, 2H2O.
Le mélange réactionnel noircit tout au long de l'addition. A la fin de l'addition, on maintient pendant 5 minutes à 0°C puis on ajoute 50 cm3 de chlorure de méthylène. Après décantation, la phase aqueuse est extraite 2 fois par 50 cm3 de chlorure de méthylène. Les phases organiques réunies sont lavées par 50 cm3 d'eau. Après séchage et filtration, le mélange réactionnel est concentré à sec à 50°C sous pression réduite (15 mm de mercure ; 2 kPa).The reaction mixture darkens throughout the addition. At the end of the addition, the mixture is kept at 0 ° C. for 5 minutes and then 50 cm 3 of methylene chloride are added. After decantation, the aqueous phase is extracted twice with 50 cm3 of methylene chloride. The combined organic phases are washed with 50 cm3 of water. After drying and filtration, the reaction mixture is concentrated to dryness at 50 ° C under reduced pressure (15 mm of mercury; 2 kPa).
On obtient ainsi 8,85 g de l'isomère (R) du sulfate de chlorométhyl-l éthylène dont les caractéristiques sont les suivantes :8.85 g of the (R) isomer of chloromethyl-1 ethylene sulfate are thus obtained, the characteristics of which are as follows:
- pouvoir rotatoire :- rotating power :
[α]27D = +13,5° (c = 17,58 x 10**3 ; chloroforme contenant 0,6 % d'éthanol) [≈]27365 = +38,2° (c = 17,58 x 10'3 ; chloroforme contenant 0,6 % d'éthanol)[α] 27 D = + 13.5 ° (c = 17.58 x 10 ** 3 ; chloroform containing 0.6% ethanol) [≈] 27 365 = + 38.2 ° (c = 17.58 x 10 '3; chloroform containing 0.6% ethanol)
- pureté énantiomérique : supérieure à 99 % - pureté chimique : voisine de 97 %- enantiomeric purity: greater than 99% - chemical purity: close to 97%
Le rendement est de 80 % par rapport au sulfite mis en oeuvre. EXEMPLE 2The yield is 80% relative to the sulfite used. EXAMPLE 2
Dans un ballon, on introduit 20 cm3 d'acétone, 2,21 g d'acétyl-2 butyramido- 4 phénol (10 mmoles), 2 g de l'isomère (R) du sulfate de chlorométhyl-l éthylène (11,6 mmoles). On ajoute ensuite 0,54 g de soude en pastilles. On agite pendant 3 heures à une température comprise entre 20 et 28βC jusqu'à l'obtention d'une solution homogène. On chauffe ensuite pendant 1 heure 30 minutes à la température de reflux du mélange réactionnel en présence de 0,8 g d'hydrogénosulfate de potassium et de 0,2 cm3 d'acide sulfurique. Le précipité qui apparaît est séparé par filtration. Au filtrat, on ajoute 1,2 g de soude en pastilles. On maintient pendant 2 heures 30 minutes à une température voisine de 20°C. On reprend par de l'eau puis élimine l'acétone sous pression réduite (15 mm de mercure ; 2 kPa). Le précipité obtenu est séparé par filtration, lavé à l'eau puis séché sous pression réduite.20 cm3 of acetone, 2.21 g of 2-acetyl-butyramido-phenol (10 mmol), 2 g of the (R) isomer of chloromethyl-ethylene sulfate (11.6) are introduced into a flask. mmoles). Then added 0.54 g of sodium hydroxide pellets. The mixture is stirred for 3 hours at a temperature between 20 and 28 β C until a homogeneous solution is obtained. Then heated for 1 hour 30 minutes at the reflux temperature of the reaction mixture in the presence of 0.8 g of potassium hydrogen sulfate and 0.2 cm3 of sulfuric acid. The precipitate which appears is separated by filtration. To the filtrate, 1.2 g of sodium hydroxide pellets are added. Is maintained for 2 hours 30 minutes at a temperature close to 20 ° C. It is taken up in water and then the acetone is removed under reduced pressure (15 mm of mercury; 2 kPa). The precipitate obtained is separated by filtration, washed with water and then dried under reduced pressure.
On obtient ainsï 2, 17 g de (2S)-(acétyl-2' butyramido-4' phénoxy)-l époxy- 2,3 propane dont les caractéristiques sont les suivantes : -P.F. = 139°C - pouvoir rotatoire : [α]27*D ≈ 13,9° (c = 3,88 x 10**3 ; chloroforme contenant Q.6 % d'éthanol)Thus, 2.17 g of (2S) - (acetyl-2 'butyramido-4' phenoxy) -l epoxy- 2,3 propane are obtained, the characteristics of which are as follows: -PF = 139 ° C. - rotary power: [α ] 27 * D ≈ 13.9 ° (c = 3.88 x 10 ** 3 ; chloroform containing Q.6% ethanol)
[α]27365 = - 1. ° (c = 3,88 x 10"3 ; chloroforme contenant 0,6 % d'éthanol) - pureté énantiomérique : supérieure à 99 %.[α] 27 365 = - 1. ° (c = 3.88 x 10 "3; chloroform containing 0.6% ethanol) - enantiomeric purity: greater than 99%.
Le rendement est de 78,3 %. The yield is 78.3%.

Claims

REVENDICATIONS
1 - Les isomères (R) et (S) du sulfate de chlorométhyl-l éthylène.1 - The (R) and (S) isomers of chloromethyl ethylene sulfate.
2 - Procédé de préparation des isomères (R) et (S) du sulfate de chlorométhyl-l éthylène caractérisé en ce que l'on oxyde les isomères (R) et (S) du sulfite de chlorométhyl-l éthylène au moyen d'un hypohalogénite alcalin ou alcaline- terreux en présence d'une quantité catalytique d'un dérivé du ruthénium en opérant en milieu aqueux ou hydroorganique à une température inférieure à 10°C.2 - Process for the preparation of (R) and (S) isomers of chloromethyl-1 ethylene sulphate characterized in that the isomers (R) and (S) of chloromethyl-1 ethylene sulphite are oxidized by means of a alkaline or alkaline earth hypohalogenite in the presence of a catalytic amount of a ruthenium derivative operating in an aqueous or hydroorganic medium at a temperature below 10 ° C.
3 - Procédé selon la revendication 2 caractérisé en ce que le dérivé du ruthénium est choisi parmi l'oxyde de ruthénium (IV) et le trichlorure de ruthénium.3 - Process according to claim 2 characterized in that the ruthenium derivative is chosen from ruthenium oxide (IV) and ruthenium trichloride.
4 - Procédé selon l'une des revendications 2 ou 3 caractérisé en ce que l'on utilise de 10**6 à 10"1 mole de dérivé du ruthénium par mole de sulfite.4 - Method according to one of claims 2 or 3 characterized in that 10 ** 6 to 10 "is used 1 mole of ruthenium derivative per mole of sulfite.
5 - Procédé selon la revendication 2 caractérisé en ce que l'hypohalogénite alcalin ou alcalino-terreux est choisi parmi l'hypochlorite de sodium, l'hypochlorite de potassium et l'hypochlorite de calcium.5 - Process according to claim 2 characterized in that the alkaline or alkaline earth hypohalogenite is chosen from sodium hypochlorite, potassium hypochlorite and calcium hypochlorite.
6 - Procédé selon l'une des revendications 2 ou 5 caractérisé en ce que l'on utilise 1 à 2 moles d'hypohalogénite par mole de sulfite.6 - Method according to one of claims 2 or 5 characterized in that one uses 1 to 2 moles of hypohalogenite per mole of sulfite.
7 - Procédé selon la revendication 2 caractérisé en ce que, lorsque l'on opère en milieu hydroorganique, le solvant est choisi parmi les hydrocarbures aliphatiques ou cycloaliphatiques éventuellement halogènes et les esters.7 - Process according to claim 2 characterized in that, when operating in a hydroorganic medium, the solvent is chosen from aliphatic or cycloaliphatic hydrocarbons optionally halogenated and esters.
8 - Utilisation de l'isomère (R) du sulfate de chlorométhyl-l éthylène pour la préparation de β-bloquants adrénergiques (S) de formule générale :8 - Use of the (R) -isomer of chloromethyl-1 ethylene sulfate for the preparation of adrenergic β-blockers (S) of general formula:
'NH-R ÔH dans laquelle Ar représente un radical aromatique ou un radical aromatique hétérocyclique éventuellement substitué et R représente un radical alcoyle droit ou ramifié contenant 1 à 4 atomes de carbone, caractérisé en ce que l'on fait réagir l'isomère (R) du sulfate de chlorométhyl-l éthylène sur un phénol de formule Ar-OH préalablement anionisé, en présence d'un excès de base, pour obtenir, après hydrolyse, un époxyde sous forme (S) de formule générale : dans laquelle Ar est défini comme précédemment, sur lequel on fait réagir, selon les méthodes connues, une aminé de formule R-NH2 dans laquelle R est défini comme précédemment. ' NH-R ÔH in which Ar represents an aromatic radical or an optionally substituted heterocyclic aromatic radical and R represents a straight or branched alkyl radical containing 1 to 4 carbon atoms, characterized in that the (R ) chloromethyl-1 ethylene sulfate on a phenol of formula Ar-OH previously anionized, in the presence of an excess of base, to obtain, after hydrolysis, an epoxide in the form (S) of general formula: in which Ar is defined as above, on which is reacted, according to known methods, an amine of formula R-NH2 in which R is defined as above.
9 - Utilisation de l'isomère (S) du sulfate de chlorométhyl-l éthylène pour la préparation de β-bloquants adrénergiques (S) de formule générale :9 - Use of the isomer (S) of chloromethyl-1 ethylene sulfate for the preparation of β-adrenergic blockers (S) of general formula:
'NH-R ÔH dans laquelle Ar et R sont définis comme dans la revendication 8 caractérisé en ce que l'on fait réagir l'isomère (S) du sulfate de chlorométhyl-l éthylène sur une aminé de formule R-NH2, puis, après hydrolyse alcaline du mélange réactionnel, fait réagir un phénol de formule Ar-OH, préalablement anionisé, sur l'époxyde de formule générale : ' NH-R ÔH in which Ar and R are defined as in claim 8 characterized in that the (S) isomer of chloromethyl-1 ethylene sulfate is reacted with an amine of formula R-NH2, then, after alkaline hydrolysis of the reaction mixture, reacts a phenol of formula Ar-OH, previously anionized, on the epoxide of general formula:
dans laquelle R est défini comme précédemment, ainsi obtenu. in which R is defined as above, thus obtained.
10 - Utilisation des isomères (R) et (S) du sulfate de chlorométhyl-l éthylène selon les revendications 8 et 9 pour la préparation de β-bloquants adrénergiques (S) de formule générale :10 - Use of the isomers (R) and (S) of chloromethyl-ethylene sulfate according to claims 8 and 9 for the preparation of adrenergic β-blockers (S) of general formula:
"NH-R ÔH dans laquelle Ar représente le reste aromatique de l'acébutolol, de l'aténolol, du propranolol, du céliprolol, du métoprolol, du timolol, du nadolol, du penbutolol, du levobunolol ou du pindolol, et R représente un radical alcoyle droit ou ramifié contenant 1 à 4 atomes de carbone. " NH-R ÔH in which Ar represents the aromatic residue of acebutolol, atenolol, propranolol, celiprolol, metoprolol, timolol, nadolol, penbutolol, levobunolol or pindolol, and R represents a straight or branched alkyl radical containing 1 to 4 carbon atoms.
11 - Utilisation de l'isomère du sulfate de chlorométhyl-l éthylène pour la préparation de la L-carnitine, de (S)-phospholipides et de (S)-glycérolphosphates. 11 - Use of the isomer of chloromethyl-ethylene sulfate for the preparation of L-carnitine, (S) -phospholipids and (S) -glycerolphosphates.
EP19920911777 1991-05-23 1992-05-21 New chiral sulphates preparation thereof and utilization in the synthesis of pharmaceutical products Withdrawn EP0585341A1 (en)

Applications Claiming Priority (2)

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FR9106235 1991-05-23
FR9106235A FR2676736B1 (en) 1991-05-23 1991-05-23 NOVEL CHIRAL SULPHATES, THEIR PREPARATION AND THEIR USE IN THE SYNTHESIS OF PHARMACEUTICAL PRODUCTS.

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FI935170A (en) 1993-11-22
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FI935170A0 (en) 1993-11-22
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