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CH619464A5 - Process for the preparation of new 1,2-dithiole derivatives - Google Patents

Process for the preparation of new 1,2-dithiole derivatives Download PDF

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Publication number
CH619464A5
CH619464A5 CH1030979A CH1030979A CH619464A5 CH 619464 A5 CH619464 A5 CH 619464A5 CH 1030979 A CH1030979 A CH 1030979A CH 1030979 A CH1030979 A CH 1030979A CH 619464 A5 CH619464 A5 CH 619464A5
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het
general formula
carbon atoms
part contains
alkyl part
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CH1030979A
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French (fr)
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Michel Barreau
Claude Cotrel
Claude Jeanmart
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Rhone Poulenc Ind
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Publication of CH619464A5 publication Critical patent/CH619464A5/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D241/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with nitrogen atoms directly attached to ring carbon atoms
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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Abstract

The products of formula (I) below, in which Het represents a pyrazinyl, pyridazinyl or pyrimidinyl ring (optionally substituted) and R1 represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms, are obtained by reaction of phosphorus pentasulphide with a product of formula (II) in which Het and R1 have the corresponding definitions and T represents an alcohol functional group protector, and then release of the alcohol functional group by acid hydrolysis. These products have an antibilharzia activity. <IMAGE> <IMAGE>

Description

La présente invention concerne un procédé de préparation de nouveaux dérivés du dithiole-1,2 de formule générale: The present invention relates to a process for the preparation of new 1,2-dithiole derivatives of general formula:

Het-/' NS Het- / 'NS

u. u.

-/ "s - / "s

Het Het

R1-CH- R1-CH-

=0 = 0

dans laquelle Het et Ri sont définis comme ci-dessus et Hai représente un atome d'halogène, de préférence un atome de brome ou de chlore. in which Het and Ri are defined as above and Hai represents a halogen atom, preferably a bromine or chlorine atom.

35 Généralement, la réaction s'effectue par chauffage dans un solvant organique tel que l'acétone. Generally, the reaction is carried out by heating in an organic solvent such as acetone.

Le produit de formule générale (III) peut être obtenu par action d'un agent d'halogénation convenable sur un produit de formule générale: The product of general formula (III) can be obtained by the action of a suitable halogenating agent on a product of general formula:

-/N -/NOT

(I) (I)

R CHOH- R CHOH-

dans laquelle Het représente un radical hétérocyclique aromatique à 6 chaînons contenant 2 atomes d'azote (c'est-à-dire un radical pyridazinyl-3 ou -4, pyrimidinyl-2, -4 ou -5 ou pyrazinyl-2), éventuellement substitué par un atome d'halogène ou par un radical alcoyle contenant 1 à 4 atomes de carbone, alcoyloxyle dont la partie alcoyle contient 1 à 4 atomes de carbone, mercapto, alcoylthio dont la partie alcoyle contient 1 à 4 atomes de carbone, dialcoylamino dont chaque partie alcoyle contient 1 à 4 atomes de carbone, pyrrolidino, pipéridino, morpholino, N-alcoylpipérazi-nyl-1 dont la partie alcoyle contient 1 à 4 atomes de carbone, et Ri représente un atome d'hydrogène ou un radical alcoyle contenant 1 à 3 atomes de carbone. in which Het represents a 6-membered aromatic heterocyclic radical containing 2 nitrogen atoms (that is to say a pyridazinyl-3 or -4, pyrimidinyl-2, -4 or -5 or pyrazinyl-2 radical), optionally substituted by a halogen atom or by an alkyl radical containing 1 to 4 carbon atoms, alkyloxy of which the alkyl part contains 1 to 4 carbon atoms, mercapto, alkylthio of which the alkyl part contains 1 to 4 carbon atoms, dialcoylamino of which each alkyl part contains 1 to 4 carbon atoms, pyrrolidino, piperidino, morpholino, N-alkylpiperazi-nyl-1 in which the alkyl part contains 1 to 4 carbon atoms, and Ri represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms.

Selon l'invention, ces nouveaux produits sont obtenus par action du pentasulfure de phosphore sur une dithiole-1,2 one-3 de formule générale: g According to the invention, these new products are obtained by the action of phosphorus pentasulfide on a 1,2-dithiole one-3 of general formula: g

Het- Het-

E1 -CH2- E1 -CH2-

(IV) (IV)

=0 = 0

45 dans laquelle Het et Ri sont définis comme ci-dessus. 45 in which Het and Ri are defined as above.

De préférence, on utilise comme agent d'halogénation le N-bromosuccinimide en opérant dans un solvant organique tel que le tétrachlorure de carbone et en présence d'un initiateur de réactions radicalaires tel que l'azobisisobutyronitrile. Preferably, N-bromosuccinimide is used as the halogenating agent, operating in an organic solvent such as carbon tetrachloride and in the presence of a radical reaction initiator such as azobisisobutyronitrile.

Le produit de formule générale (IV) peut être obtenu par action de l'acétate mercurique sur un produit de formule générale: s The product of general formula (IV) can be obtained by the action of mercuric acetate on a product of general formula: s

50 50

55 55

R- R-

L L

(V) (V)

(II) (II)

0-T 0-T

dans laquelle Het est défini comme ci-dessus et R représente un radical alcoyle contenant 1 à 4 atomes de carbone. in which Het is defined as above and R represents an alkyl radical containing 1 to 4 carbon atoms.

Généralement, la réaction s'effectue à une température comprise entre 50 et 120°C en opérant dans un solvant organique tel qu'un acide comme l'acide acétique. Generally, the reaction is carried out at a temperature between 50 and 120 ° C by operating in an organic solvent such as an acid such as acetic acid.

Le produit de formule générale (V) peut être obtenu par action du pentasulfure de phosphore sur un composé hétérocyclique de . formule générale: The product of general formula (V) can be obtained by the action of phosphorus pentasulfide on a heterocyclic compound of. general formula:

Het—CO—CH—COOR' (VI) Het — CO — CH — COOR '(VI)

I I

R R

3 3

619 464 619,464

dans laquelle Het et R sont définis comme ci-dessus et R' représente un radical alcoyle contenant 1 à 4 atomes de carbone. in which Het and R are defined as above and R 'represents an alkyl radical containing 1 to 4 carbon atoms.

Généralement, la réaction s'effectue dans un solvant organique inerte vis-à-vis du pentasulfure de phosphore tel que la Pyridine, le benzène, le toluène, le xylène ou le chlorobenzène à une température comprise entre 50 et 200° C. Generally, the reaction is carried out in an organic solvent inert with respect to phosphorus pentasulfide such as pyridine, benzene, toluene, xylene or chlorobenzene at a temperature between 50 and 200 ° C.

Lors de l'action du pentasulfure de phosphore sur un produit de formule générale (VI) dans laquelle Het représente un radical hétérocyclique aromatique à 6 chaînons contenant 2 atomes d'azote, substitué en a d'un atome d'azote par un radical alcoy-loxy dont la partie alcoyle contient 1 à 4 atomes de carbone, il se forme, à côté d'un produit de formule générale (I) dans laquelle Het représente un radical hétérocyclique aromatique à 6 chaînons contenant 2 atomes d'azote substitué en a d'un atome d'azote par un radical alcoyloxy dont la partie alcoyle contient 1 à 4 atomes de carbone, un produit de formule générale (I) dans laquelle Het représente un radical aromatique hétérocyclique à 6 chaînons contenant 2 atomes d'azote substitué en a d'un atome d'azote par un radical mercapto. During the action of phosphorus pentasulfide on a product of general formula (VI) in which Het represents a 6-membered aromatic heterocyclic radical containing 2 nitrogen atoms, substituted at a of a nitrogen atom by an alkyl radical -loxy, the alkyl part of which contains 1 to 4 carbon atoms, it forms, next to a product of general formula (I) in which Het represents a 6-membered aromatic heterocyclic radical containing 2 nitrogen atoms substituted at a of a nitrogen atom with an alkyloxy radical, the alkyl part of which contains 1 to 4 carbon atoms, a product of general formula (I) in which Het represents a 6-membered heterocyclic aromatic radical containing 2 nitrogen atoms substituted in has a nitrogen atom through a mercapto radical.

Les produits de formule générale (VI) peuvent être obtenus par l'un des procédés suivants : The products of general formula (VI) can be obtained by one of the following processes:

a) Action d'un ester de formule générale : a) Action of an ester of general formula:

R-CH2-COOR' (VII) R-CH2-COOR '(VII)

dans laquelle R et R' sont définis comme ci-dessus, sur un dérivé hétérocyclique de formule générale: in which R and R 'are defined as above, on a heterocyclic derivative of general formula:

Het—COOR" (VIII) Het — COOR "(VIII)

dans laquelle Het est défini comme précédemment et R" représente un radical alcoyle contenant 1 à 4 atomes de carbone. in which Het is defined as above and R "represents an alkyl radical containing 1 to 4 carbon atoms.

La réaction s'effectue généralement dans les conditions habituelles de la réaction de Claisen pour la préparation des P-cétoes-ters. Plus particulièrement, la condensation peut être effectuée à une température comprise entre 10 et 100° C en présence d'un alcoolate tel que l'éthylate ou le tertiobutylate de sodium et en opérant éventuellement dans un solvant organique anhydre tel qu'un hydrocarbure aromatique (benzène, toluène, xylène) en éliminant l'alcool R" —OH formé au cours de la réaction par distillation. The reaction is generally carried out under the usual conditions of the Claisen reaction for the preparation of P-ketoes-ters. More particularly, the condensation can be carried out at a temperature of between 10 and 100 ° C. in the presence of an alcoholate such as ethylate or sodium tertiobutylate and optionally operating in an anhydrous organic solvent such as an aromatic hydrocarbon ( benzene, toluene, xylene) by removing the alcohol R "—OH formed during the reaction by distillation.

Il est aussi possible d'effectuer la condensation en présence d'hydrure de sodium dans l'éther éthylique. It is also possible to carry out the condensation in the presence of sodium hydride in ethyl ether.

b) Action d'un ester réactif de formule générale: b) Action of a reactive ester of general formula:

R-Z (IX) R-Z (IX)

dans laquelle R est défini comme ci-dessus et Z représente un reste d'ester réactif tel qu'un atome d'halogène ou un reste d'ester sulfurique ou sulfonique, sur un P-cétoester de formule générale : in which R is defined as above and Z represents a reactive ester residue such as a halogen atom or a residue of sulfuric or sulfonic ester, on a P-ketoester of general formula:

Het—CO—CH2—COOR' (X) Het — CO — CH2 — COOR '(X)

dans laquelle Het et R' sont définis comme précédemment. in which Het and R 'are defined as above.

La réaction s'effectue généralement dans un solvant organique tel que l'acétone en présence d'un agent de condensation tel qu'un carbonate alcalin comme le carbonate de sodium ou de potassium et éventuellement en présence d'un iodure alcalin tel que l'iodure de sodium ou de potassium, ou dans un solvant organique tel qu'un éther ou un hydrocarbure aromatique en présence d'éthy-late de sodium ou d'hydrure de sodium. The reaction is generally carried out in an organic solvent such as acetone in the presence of a condensing agent such as an alkali carbonate such as sodium or potassium carbonate and optionally in the presence of an alkaline iodide such as sodium or potassium iodide, or in an organic solvent such as an ether or an aromatic hydrocarbon in the presence of sodium ethy-late or sodium hydride.

Le p-cétoester de formule générale (X) peut être obtenu par action d'un ester de l'acide acétique de formule générale: The p-ketoester of general formula (X) can be obtained by the action of an acetic acid ester of general formula:

CH3-COOR' (XI) CH3-COOR '(XI)

dans laquelle R' est défini comme précédemment, sur un composé hétérocyclique de formule générale (VIII) dans les conditions données précédemment pour la réaction entre un produit de formule générale (VII) et un produit de formule générale (VIII). in which R 'is defined as above, on a heterocyclic compound of general formula (VIII) under the conditions given above for the reaction between a product of general formula (VII) and a product of general formula (VIII).

Les nouveaux produits selon la présente invention peuvent être éventuellement purifiés par des méthodes physiques telles que la cristallisation ou la Chromatographie. The new products according to the present invention can optionally be purified by physical methods such as crystallization or chromatography.

Les produits de formule générale (I) présentent des propriétés chimiothérapeutiques remarquables. Ils sont particulièrement intéressants comme antibilharziens. Ils ont par ailleurs une faible toxicité et, pour la grande majorité des produits, la dose létale . 50% (DL50) est supérieure à 1000 mg/kg par voie orale chez la souris. The products of general formula (I) have remarkable chemotherapeutic properties. They are particularly interesting as antibilharziens. They also have low toxicity and, for the vast majority of products, the lethal dose. 50% (LD50) is greater than 1000 mg / kg orally in mice.

L'activité antibilharzienne se manifeste chez la souris infestée à Schistosoma monsoni à des doses comprises entre 10 et 1000 mg/kg par jour pendant 5 j par voie orale ou sous-cutanée. Après traitement unique, cette activité se manifeste à des doses comprises entre 100 et 500 mg/kg par voie orale ou sous-cutanée. Antibilharzian activity is manifested in mice infested with Schistosoma monsoni at doses of between 10 and 1000 mg / kg per day for 5 days orally or subcutaneously. After a single treatment, this activity manifests itself at doses of between 100 and 500 mg / kg orally or subcutaneously.

Chez le singe [Maccaca mulatta (var. rhésus)] l'activité antibilharzienne se manifeste à des doses comprises entre 5 et 100 mg/kg par jour pendant 5 j par voie orale. In monkeys [Maccaca mulatta (var. Rhesus)] antibilharzian activity manifests itself at doses between 5 and 100 mg / kg per day for 5 days orally.

Exemple: Example:

On chauffe pendant 15 mn, à une température voisine de 100°C, une suspension de 3,56 g de (diéthoxy-2,2 acétoxyméthyl)-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 et de 2,22 g de pentasulfure de phosphore dans 100 cm3 de dioxanne. Après refroidissement à une température voisine de 20° C, on ajoute au mélange réaction-nel 200 cm3 d'eau distillée et 200 cm3 de chlorure de méthylène. La phase organique est séparée par décantation, lavée avec 100 cm3 d'eau distillée et évaporée à sec sous pression réduite. Au résidu ainsi obtenu on ajoute 50 cm3 de dichloro-1,2 éthane, 10 cm3 d'eau distillée et 10 cm3 d'acide sulfurique 36N et on chauffe le mélange obtenu pendant 10 mn à une température voisine de 85° C. Après refroidissement à une température voisine de 20° C, on ajoute au mélange réactionnel 100 cm3 d'eau distillée et 50 cm3 de chlorure de méthylène. La phase aqueuse est séparée par décantation et lavée avec 3 fois 25 cm3 de chlorure de méthylène. Les fractions organiques réunies sont lavées avec 25 cm3 d'une solution aqueuse saturée en bicarbonate de sodium, séchées sur sulfate de magnésium, filtrées et évaporées à sec sous pression réduite. Après deux recristallisations successives dans l'acide acétique, on obtient 0,14 g d'hydroxyméthyl-4 (pyrazinyl-2)-5 dithiole-1,2 thione-3 fondant à 200° C. A suspension of 3.56 g of (2,2-diethoxyacetoxymethyl) -4 (pyrazinyl-2) -5 1,2-dithiole-1,2 one-3 and of 2.22 g of phosphorus pentasulfide in 100 cm3 of dioxane. After cooling to a temperature in the region of 20 ° C., 200 cm 3 of distilled water and 200 cm 3 of methylene chloride are added to the reaction mixture. The organic phase is separated by decantation, washed with 100 cm3 of distilled water and evaporated to dryness under reduced pressure. To the residue thus obtained is added 50 cm3 of 1,2-dichloroethane, 10 cm3 of distilled water and 10 cm3 of 36N sulfuric acid and the mixture obtained is heated for 10 min at a temperature in the region of 85 ° C. After cooling at a temperature in the region of 20 ° C., 100 cm 3 of distilled water and 50 cm 3 of methylene chloride are added to the reaction mixture. The aqueous phase is separated by decantation and washed with 3 times 25 cm3 of methylene chloride. The combined organic fractions are washed with 25 cm3 of a saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. After two successive recrystallizations from acetic acid, 0.14 g of 4-hydroxymethyl (pyrazinyl-2) -5-dithiole-1,2-thione-3 is obtained, melting at 200 ° C.

La (diéthoxy-2,2 acétoxyméthyl)-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 peut être préparée en chauffant, pendant 'A h à une température voisine de 50° C, une suspension de 2 g de bromométhyl-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 et de 1,31 g de diéthoxy-2,2 acétate de sodium dans 100 cm3 d'acétone. Après refroidissement à une température voisine de 20° C, le mélange réactionnel est évaporé à sec sous pression réduite. Au résidu ainsi obtenu, on ajoute 25 cm3 d'eau distillée et 50 cm3 de chlorure de méthylène. La phase aqueuse est séparée par décantation et lavée avec 2 fois 25 cm3 de chlorure de méthylène. Les fractions organiques réunies sont lavées par décantation avec 2 fois 20 cm3 d'eau distillée, séchées sur sulfate de magnésium, filtrées et évaporées à sec sous pression réduite. Le résidu ainsi obtenu est dissous dans 100 cm3 de chlorure de méthylène et filtré sur 40 g de gel de silice contenus dans une colonne de 2,2 cm de diamètre. On élue avec 550 cm3 de chlorure de méthylène pur. Cet éluat est rejeté. On élue ensuite avec 800 cm3 de chlorure de méthylène pur. L'éluat correspondant est évaporé à sec sous pression réduite. On obtient ainsi 1,3 g de (diéthoxy-2,2 acétoxyméthyl)-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 fondant à 74-76° C. (2,2-diethoxy acetoxymethyl) -4 (pyrazinyl-2) -5 dithiole-1,2 one-3 can be prepared by heating, for 'A h at a temperature close to 50 ° C, a suspension of 2 g bromomethyl-4 (pyrazinyl-2) -5 dithiole-1,2 one-3 and 1.31 g of diethoxy-2,2 sodium acetate in 100 cm3 of acetone. After cooling to a temperature in the region of 20 ° C., the reaction mixture is evaporated to dryness under reduced pressure. To the residue thus obtained, 25 cm3 of distilled water and 50 cm3 of methylene chloride are added. The aqueous phase is separated by decantation and washed with 2 times 25 cm3 of methylene chloride. The combined organic fractions are washed by decantation with 2 times 20 cm3 of distilled water, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue thus obtained is dissolved in 100 cm3 of methylene chloride and filtered through 40 g of silica gel contained in a column 2.2 cm in diameter. Eluted with 550 cm3 of pure methylene chloride. This eluate is rejected. Then eluted with 800 cm3 of pure methylene chloride. The corresponding eluate is evaporated to dryness under reduced pressure. 1.3 g of (2,2-diethoxy acetoxymethyl) -4 (pyrazinyl-2) -5-dithiole-1,2 one-3 are thus obtained, melting at 74-76 ° C.

La bromométhyl-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 peut être préparée en chauffant pendant 6 'A h, à une température voisine de 75° C, une suspension de 2,1 g.de méthyl-4 (pyrazinyl-2)-5 dithiole-1,2 one-3, de 1,8 g de N-bromosuccinimide et de 0,16 g d'azobisisobutyronitrile dans 30 cm3 de tétrachlorure de carbone anhydre. Après refroidissement à une température voisine de Bromomethyl-4 (pyrazinyl-2) -5 dithiole-1,2 one-3 can be prepared by heating for 2.1 hours, at a temperature in the region of 75 ° C, a suspension of 2.1 g of methyl- 4 (pyrazinyl-2) -5 dithiole-1,2 one-3, 1.8 g of N-bromosuccinimide and 0.16 g of azobisisobutyronitrile in 30 cm3 of anhydrous carbon tetrachloride. After cooling to a temperature close to

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619 464 619,464

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20° C, on verse 50 cm3 de chlorure de méthylène dans le mélange réactionnel et l'insoluble est séparé par filtration, puis lavé avec 2 fois 25 cm3 de chlorure de méthylène. Le filtrat et les lavages sont réunis et évaporés à sec sous pression réduite. Après recristallisation du résidu ainsi obtenu dans 50 cm3 d'acétonitrile, on obtient 1,1 g de bromométhyl-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 fondant à 153°C. 20 ° C, 50 cm3 of methylene chloride are poured into the reaction mixture and the insoluble material is separated by filtration, then washed with 2 times 25 cm3 of methylene chloride. The filtrate and the washes are combined and evaporated to dryness under reduced pressure. After recrystallization of the residue thus obtained in 50 cm3 of acetonitrile, 1.1 g of bromomethyl-4 (pyrazinyl-2) -5 dithiole-1,2 one-3, melting at 153 ° C., are obtained.

La méthyl-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 peut être préparée en chauffant pendant l'A h, à une température voisine de 100°C, une suspension de 14,7 g de méthyl-4 (pyrazinyl-2)-5 dithiole-1,2 thione-3 et de 31,06 g d'acétate mercurique dans 650 cm3 d'acide acétique. Après refroidissement à une température voisine de 20° C, le produit insoluble est séparé par filtration et est lavé avec 2 fois 100 cm3 d'acide acétique. Le filtrat et les lavages sont réunis et sont concentrés à sec sous pression réduite. Le résidu solide obtenu est repris avec 250 cm3 d'acétone. La suspension obtenue est agitée pendant 1 h à une température voisine de 20° C et l'insoluble est séparé par filtration, puis lavé Methyl-4 (pyrazinyl-2) -5 dithiole-1,2 one-3 can be prepared by heating during A h, at a temperature close to 100 ° C, a suspension of 14.7 g of methyl-4 (pyrazinyl-2) -5 dithiole-1,2 thione-3 and 31.06 g of mercuric acetate in 650 cm3 of acetic acid. After cooling to a temperature in the region of 20 ° C., the insoluble product is separated by filtration and is washed with 2 times 100 cm 3 of acetic acid. The filtrate and the washes are combined and are concentrated to dryness under reduced pressure. The solid residue obtained is taken up with 250 cm3 of acetone. The suspension obtained is stirred for 1 h at a temperature in the region of 20 ° C and the insoluble material is separated by filtration, then washed

avec 4 fois 50 cm3 d'acétone. Le filtrat et les lavages sont réunis et sont concentrés à sec sous pression réduite. Après recristallisation du résidu obtenu dans 300 cm3 d'éthanol, on obtient 11,1 g de méthyl-4 (pyrazinyl-2)-5 dithiole-1,2 one-3 fondant à 119°C. 5 On obtient 3,42 g de méthyl-4 (pyrazinyl-2)-5 dithiole-1,2 thione-3 (fondant à 164° C) par chauffage de 41,2 g de méthyl-2 (pyrazinyl-2)-3 oxo-3 propionate d'éthyle et de 42,4 g de pentasulfure de phosphore en suspension dans 410 cm3 de toluène, pendant 1 h à une température voisine de 110° C, lavage de la suspen-io sion avec une solution aqueuse saturée de bicarbonate de soude, Chromatographie sur silice (éluant: chlorure de méthylène) et recristallisation dans 30 cm3 de chlorure de méthylène. with 4 times 50 cm3 of acetone. The filtrate and the washes are combined and are concentrated to dryness under reduced pressure. After recrystallization of the residue obtained in 300 cm3 of ethanol, 11.1 g of methyl-4 (pyrazinyl-2) -5-dithiole-1,2 one-3 are obtained, melting at 119 ° C. 5 3.42 g of methyl-4 (pyrazinyl-2) -5 dithiole-1,2 thione-3 (melting at 164 ° C.) are obtained by heating 41.2 g of methyl-2 (pyrazinyl-2) - 3 ethyl oxo-3 propionate and 42.4 g of phosphorus pentasulfide suspended in 410 cm3 of toluene, for 1 h at a temperature in the region of 110 ° C, washing the suspension with a saturated aqueous solution of sodium bicarbonate, chromatography on silica (eluent: methylene chloride) and recrystallization from 30 cm3 of methylene chloride.

Le méthyl-2 (pyrazinyl-2)-3 oxo-3 propionate d'éthyle peut être préparé à partir de 38,8 g de (pyrazinyl-2)-3 oxo-3 propionate 15 d'éthyle, de 34,8 g d'iodure de méthyle et de 25,8 g de carbonate de potassium sec en suspension dans 50 cm3 d'acétone. On obtient ainsi 41,2 g de méthyl-2 (pyrazinyl-2)-3 oxo-3 propionate d'éthyle sous forme d'une huile jaune. Ethyl 2-methyl (2-pyrazinyl) -3 oxo-propionate can be prepared from 38.8 g of (2-pyrazinyl-2) -3 oxo-propionate, from 34.8 g methyl iodide and 25.8 g of dry potassium carbonate suspended in 50 cm3 of acetone. 41.2 g of methyl-2 (pyrazinyl-2) -3-3-oxo-propionate are thus obtained in the form of a yellow oil.

R R

Claims (2)

619 464 619,464 2 2 REVENDICATION CLAIM Procédé de préparation d'un nouveau dérivé du dithiole-1,2 de formule générale: Process for the preparation of a new derivative of 1,2-dithiole of general formula: A AT Het- Het- Rj-CH- Rj-CH- LI. LI. (i) (i) OH OH dans laquelle Het représente un radical hétérocyclique aromatique à 6 chaînons contenant 2 atomes d'azote, éventuellement substitué par un atome d'halogène ou par un radical alcoyle contenant 1 à 4 atomes de carbone, alcoyloxyle dont la partie alcoyle contient 1 à 4 atomes de carbone, mercapto, alcoylthio dont la partie alcoyle contient 1 à 4 atomes de carbone, dialcoylamino dont chaque partie alcoyle contient 1 à 4 atomes de carbone, pyrrolidino, pipéridino, morpholino, N-alcoylpipérazinyl-1 dont la partie alcoyle contient 1 à 4 atomes de carbone, et Ri représente un atome d'hydrogène ou un radical alcoyle contenant 1 à 3 atomes de carbone, caractérisé en ce qu'on fait réagir le pentasulfure de phosphore sur un produit de formule générale : in which Het represents a 6-membered aromatic heterocyclic radical containing 2 nitrogen atoms, optionally substituted by a halogen atom or by an alkyl radical containing 1 to 4 carbon atoms, alkyloxy of which the alkyl part contains 1 to 4 atoms carbon, mercapto, alkylthio in which the alkyl part contains 1 to 4 carbon atoms, dialkoylamino in which each alkyl part contains 1 to 4 carbon atoms, pyrrolidino, piperidino, morpholino, N-alkylpiperazinyl-1 in which the alkyl part contains 1 to 4 atoms of carbon, and Ri represents a hydrogen atom or an alkyl radical containing 1 to 3 carbon atoms, characterized in that the phosphorus pentasulfide reacts with a product of general formula: Het- Het- R, -CH- R, -CH- A AT 1 1 S S io dans laquelle Het et Ri sont définis comme précédemment et T représente un groupe protecteur de la fonction alcool, suivie du remplacement du radical T par un atome d'hydrogène par hydrolyse en milieu acide. io in which Het and Ri are defined as above and T represents a protecting group for the alcohol function, followed by the replacement of the radical T by a hydrogen atom by hydrolysis in an acid medium. 5 Comme groupe protecteur de la fonction alcool on utilise plus particulièrement un radical dialcoxyacétyle (dont chaque partie alcoyle contient 1 à 3 atomes de carbone), formyle, acétyle, trifluoroacétyle. 5 As protecting group for the alcohol function, a dialkoxyacetyl radical (in which each alkyl part contains 1 to 3 carbon atoms), formyl, acetyl and trifluoroacetyl is used more particularly. Généralement, on fait réagir le pentasulfure de phosphore sur io un produit de formule générale (II) en suspension dans un solvant organique inerte vis-à-vis du pentasulfure de phosphore tel que le dioxanne, la pyridine, le benzène, le toluène, le xylène ou le chlorobenzène à une température comprise entre 50 et 200° C. Generally, the phosphorus pentasulfide is reacted with a product of general formula (II) suspended in an organic solvent inert with respect to phosphorus pentasulfide such as dioxane, pyridine, benzene, toluene, xylene or chlorobenzene at a temperature between 50 and 200 ° C. Le remplacement du groupe protecteur par un atome d'hydro-15 gène s'effectue généralement par chauffage en milieu hydroorganique acide. De préférence, l'hydrolyse s'effectue dans un solvant organique tel que l'acétone en présence d'acide sulfurique ou chlorhydrique en solution aqueuse. The replacement of the protecting group by a hydrogen atom is generally carried out by heating in an acidic hydroorganic medium. Preferably, the hydrolysis is carried out in an organic solvent such as acetone in the presence of sulfuric or hydrochloric acid in aqueous solution. Le produit de formule générale (II) peut être obtenu par 20 action d'un sel alcalin d'un acide carboxylique tel que l'acide formique, acétique, trifluoroacétique ou dialcoxyacétique (dont chaque portion alcoyle contient 1 à 3 atomes de carbone) sur une dithiole-1,2 one-3 de formule générale: The product of general formula (II) can be obtained by the action of an alkaline salt of a carboxylic acid such as formic, acetic, trifluoroacetic or dialkoxyacetic acid (each alkyl portion of which contains 1 to 3 carbon atoms) on a 1,2-dithiole one-3 of general formula: Het-/ S Hal-CH-! 1 Het- / S Hal-CH-! 1 (III) (III) =0 = 0 OT OT dans laquelle Het et Ri sont définis comme ci-dessus et T représente un groupe protecteur de la fonction alcool, puis remplace le groupement T par un atome d'hydrogène par hydrolyse en milieu acide. in which Het and Ri are defined as above and T represents a protective group for the alcohol function, then replaces the group T with a hydrogen atom by hydrolysis in an acid medium.
CH1030979A 1976-12-23 1979-11-19 Process for the preparation of new 1,2-dithiole derivatives CH619464A5 (en)

Applications Claiming Priority (1)

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FR7638901A FR2374906A2 (en) 1976-12-23 1976-12-23 Heterocyclic (1,2)-dithiole-(3)-thione derivs. - for treatment of bilharziasis (BE 9.8.77)

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