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WO1997044328A1 - 1-(halogenure d'alcanoyl)-2-carboxamido-1,4,5,6-tetrahydropyrazines - Google Patents

1-(halogenure d'alcanoyl)-2-carboxamido-1,4,5,6-tetrahydropyrazines Download PDF

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WO1997044328A1
WO1997044328A1 PCT/EP1997/002455 EP9702455W WO9744328A1 WO 1997044328 A1 WO1997044328 A1 WO 1997044328A1 EP 9702455 W EP9702455 W EP 9702455W WO 9744328 A1 WO9744328 A1 WO 9744328A1
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group
acid
tert
formula
tetrahydropyrazine
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Sven Doye
Volker Bomm
Martin Fischer
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BASF SE
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BASF SE
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    • 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
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to t - (haloalkanoyl) - 2-carboxamido - 1, 4, 5, 6 - tetrahydropyrazines of the general formula I
  • R 1 , R 2 and R 3 are the same or different and each represents a straight-chain or branched Ci to C ⁇ alkyl group, a C 5 to C ⁇ cycloalkyl group, a Cg to C 7 methylene cycloalkyl group, a C 6 - to Cio-aryl group or a C 7 - to C ⁇ 2 aralkyl group or in which the radicals R 1 and R 2 are interconnected and together with the exocyclic, non-carbonyl- see carbon atom C 1 form a 5- to 6-membered, cycloaliphatic ring and R 3 has the abovementioned meaning or in which R 3 represents hydrogen and R 1 and R 2 are identical or different and have the abovementioned meaning, R 4 is a Ci - to Cig-haloalkyl group which contains one or more identical or different halogen atoms selected from fluorine and / or chlorine as halogen substituents and in which R 5 for hydrogen has a tert.
  • EP-A 541 168 describes a series of HIV-1 protease inhibitors composed of different structural units, the structure of which is characteristic of a piperazine-2-carboxamido group.
  • a particularly preferred HIV protease inhibitor is, inter alia, the compound of the formula VIII
  • the piperazin-2-tert. -butyl-carboxamide group contains as a structural component.
  • the HIV protease inhibitor VIII a medication for AIDS, is also known as the active ingredient "L-735,524" (indinavir). Its synthesis is described in EP-A 541 168, WO 95/21162 and by Askin et al, Tetrahedron Lett. 3_5_, 673 (1994).
  • R 1 , R 2 and R 3 are the same or different and each represents a straight-chain or branched Ci to Ce alkyl group, a C 5 to C 6 cycloalkyl group, a C 6 to C 7 methylene cycloalkyl group group, a Ce - to Cio-aryl group or a C 7 - to -C 2 aralkyl group or in which the radicals R 1 and R 2 are interconnected and together with the exocyclic, non-carbonylic carbon atom C 1 form a 5- to 6-membered, cycloaliphatic ring and R 3 has the abovementioned meaning or in which R 3 represents hydrogen and R 1 and R 2 are identical or different and have the abovementioned meaning, R 4 is one Ci to Cig-haloalkyl group which contains one or more identical or different halogen atoms selected from fluorine and / or chlorine as halogen substituents and in which R 5 for hydrogen has a tert. -Butyloxy
  • R 1 , R 2 and R 3 have the meaning given in Claim 1
  • R 6 is hydrogen, a straight-chain or branched Ci to C 7 alkyl, C 5 to C ⁇ cycloalkyl, a C 6 to Cio Is aryl or a C 7 - to Cn-aralkyl group and Z is a leaving group which can be split off under the conditions mentioned, and the reaction mixture thus obtained in the presence or absence of a solvent is adjusted to a pH of by means of a base 4 to 12, the product obtained is isolated or with a reagent VII for transferring the tert. -Butyloxycarbonylrios or the benzyloxycarbonyl group in the presence or absence of a solvent and in the presence of a base.
  • the radicals R 1 , R 2 and R 3 which may be the same or different, represent straight-chain or branched C 1 -C 8 -alkyl groups, for example the methyl, ethyl, n-propyl , Isopropyl, n-butyl, 2-butyl, isobutyl, n-pentyl or the 2-ethylhexyl group, particularly preferably for the methyl group, or for the methylene-cyclopentyl group or the methylene-cyclohexyl group , or C 5 to C 6 cycloalkyl, such as cyclopentyl or cyclohexyl, or represents C 6 - to Cio-aryl group such as phenyl or naphthyl, preferably phenyl, or C 7 - to C ⁇ 2 - Aralkyl groups, preferably the benzyl group.
  • Cio-aryl group such as phenyl or naphthyl,
  • the radicals R 1 and R 2 can also be linked to one another and, together with the exocyclic, non-carbonyl carbon atom C 1, form a 5- to 6-membered cycloaliphatic ring, for example a cyclopentyl or cyclohexyl ring.
  • the radical R 3 can also be different from R 1 and R 2 and stand for hydrogen, where R 1 and R 2 can have the meaning given above.
  • the radical R 4 in the compounds of the formula I is a Cj - to C 19 -, preferably a Ci to Cio / and particularly preferably a Ci to C 4 haloalkyl group, the one or more, preferably more, the same or different , preferably identical, halogen atoms selected from fluorine and / or chlorine, particularly preferably only fluorine.
  • the possible number of halogen substituents in the haloalkyl group R 4 is of course dependent on the number of carbon atoms in the radical R 4 - the number of halogen substituents can range from 1 to that for a perhalogenated substituent depending on the length of the carbon chain of the radical R 4 required number can be chosen practically arbitrarily.
  • the perhalogenated radicals R 4 the perfluorinated radicals R 4 are particularly preferred.
  • the R 4 radicals are preferably straight-chain.
  • haloalkyl groups are listed below by way of example: monofluoromethyl, monochloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 1-fluoroethyl, 1-chloroethyl, 1, 1-difluoroethyl, 1, 1-dichloroethyl, 1-fluoro-1-chloroethyl, perfluoroethyl, perchloroethyl, perfluoropropyl, perfluorobutyl, perfluoropentyl, perfluorohexyl, perfluoroheptyl, perfluorooctyl, perfluorononyl, perfluorodecyl, perfluorundundecyl , Perfluornonade- cyl-.
  • the radical R 5 can be hydrogen, the tert. -Butyloxycarbonyl- (abbreviated: Boc) or the benzyloxycarbonyl (abbreviated: Cbz) group, preferably R 5 is hydrogen or the Boc group.
  • radicals R 1 , R 2 and R 3 have the meaning given above in the explanation of the compounds according to general formula I.
  • Group Z stands for a leaving group which can be split off under the conditions of haloalkane carboxylic acid catalysis the elimination of which forms the intermediate carbocation under the reaction conditions specified here in situ in the reaction mixture which immediately reacts with the starting compound IV to form the compounds of the general formula I according to the invention in which R 5 is hydrogen.
  • This product can then be isolated by careful work-up and, if desired, converted to the corresponding compounds I which are Boc- or Cbz-substituted in the 4-position of the tetrahydropyrazine ring by reaction with a compound of the formula VII.
  • This reaction to give the 4-Boc- or 4-Cbz-substituted compounds I can also be carried out in situ in the reaction mixture without prior isolation of the corresponding compound I which is unsubstituted in the 4-position of the tetrahydropyrazine ring.
  • onium salts of this compound with Bronsted acids can also be used as starting material in the process according to the invention.
  • Such onium salts form from compound IV in the presence of a Bronsted acid, a secondary amino group of the tetrahydropyrazine ring generally being protonated and charged positively, the anion of the respective Bronsted acid then forming the counterion.
  • onium salts of compound IV can be used with all Brönsted acids.
  • Onium salts of the compound IV are preferably used with those Bronsted acids which have an approximately equal or lower acid strength than the haloalkane carboxylic acid used as the catalyst.
  • Suitable Bronsted acids for producing such onium salts are e.g. aliphatic and aromatic carboxylic acids, aliphatic and aromatic sulfonic acids, phosphonic acids etc., but also mineral acids such as hydrochloric acid, sulfuric acid or phosphoric acid.
  • the leaving groups Z are, for example, the hydroxyl group OH, ether groups OR 7 or ester groups
  • R 7 of the leaving groups Z can in principle be chosen as desired, since they generally have no particular significance for the ability to split off the group Z.
  • R 7 radicals can also be substituted by substituents which, however, have practically no significance for the cleavage of the Z groups. Because of its very good cleavage, the hydroxyl group is particularly preferred as the leaving group Z.
  • the ester groups can also be advantageous as leaving groups Z.
  • R 7 is a haloalkyl group and the outgoing haloalkane carboxylic acid R 7 -C00H is identical to the haloalkane carboxylic acid used in the process according to the invention. This simplifies the processing of the reaction mixture.
  • Preferred compounds V are e.g. tertiary alcohols, esters of tertiary alcohols such as trifluoroacetic acid tert-butyl ester or tertiary ethers such as methyl tert. Butyl ether. Tert is particularly preferred.
  • -Butanol used as compound V.
  • the radicals R 1 and R 2 can be identical or different and have the meanings given above for R 1 and R 2 .
  • the radical R 6 can be hydrogen, a straight-chain or branched Cj to C 7 alkyl group, a C 5 to C 6 cycloalkyl group, a C 6 to C 0 aryl group or a C 7 to Cn aralkyl - stand group. Isobutene should be mentioned as a particularly preferred compound VI.
  • the starting material of the formula IV with the compounds of the formula V or VI is generally in a molar ratio IV / V or IV / VI from 1: 1 to 1:10, preferably from 1: 1 to 1: 5 and particularly preferably implemented from 1: 1 to 1: 3. Higher surpluses of the
  • Compounds V and VI with respect to IV can also be used, for example compounds V and VI can also be used as cosolvents.
  • the compounds V and VI can also be added in substoichiometric amounts with respect to the 2-cyano-tetrahydropyrazine IV, but this leads to losses in yield.
  • the haloalkane carboxylic acid is expediently used in excess with respect to cyanopyrazine IV, for example in a single to five-fold molar excess, preferably in an approximately three-fold molar excess. It is also possible to use higher molar excesses of these acids with respect to IV without disadvantage.
  • the haloalkane carboxylic acids can be used in the reaction individually or in a mixture with other haloalkane carboxylic acids. It is also possible to use mixtures of haloalkane carboxylic acids and other acids such as carboxylic acids, e.g. Fatty acids, sulfonic acids or phosphonic acids to be used as catalysts in the process according to the invention.
  • the order in which the compounds IV, V or VI are added to the reaction mixture is generally not critical and can be chosen as desired.
  • the haloalkane carboxylic acid can be placed in the reactor or metered into the reactants IV, V or VI placed in the reactor.
  • the haloalkane carboxylic acids used are preferably those which have a pKa value of less than or equal to 4.
  • the pKs value is a measure of the acid strength and e.g. in H.R. Christians, Fundamentals of General and Inorganic Chemistry, 7th Edition, pp. 357-365, Otto Salle Verlag, Frankfurt 1982 or in K.P.C. Vollhardt, N.E. Schore, Organic Chemistry, 2nd Ed., Pp. 188-190, W.H. Freeman and Company, New York 1994 explained and defined.
  • C 2 - to C 2 o _ are generally used as haloalkane carboxylic acids. preferably C 2 - to C ⁇ 0 - and particularly preferably C 2 - to C 4 -haloalkane carboxylic acids which contain one or more, preferably several, identical or different, preferably identical halogen atoms selected from fluorine and / or chlorine, particularly preferably only fluorine, used in the haloalkyl radical.
  • haloalkane carboxylic acids are preferably used in which the halogen substituents or, in the case of the use of polyhalogenated haloalkane carboxylic acids, at least some of the halogen substituents are in the ⁇ -position to the carboxyl group.
  • the haloalkanecarboxylic acids which can be used in the process according to the invention can be mono-, di-, tri- or polyhalogenated to perhalogenated, polyhalogenated haloalkanecarboxylic acids being understood as meaning those haloalkanecarboxylic acids which contain more than three halogen atoms and are not yet perhalogenated.
  • the possible number of halogen atoms in the haloalkanecarboxylic acids that can be used depends, of course, on the number of carbon atoms in the haloalkyl radical of the particular haloalkanecarboxylic acid - the number of halogen atoms in the haloalkanecarboxylic acid molecule being chosen from 1 to the number of halogen atoms required for a perhalogenated haloalkanecarboxylic acid in virtually any manner can be.
  • the perhalogenated haloalkane carboxylic acids the perfluoroalkane carboxylic acids are preferably used in the process according to the invention.
  • Straight-chain haloalkane carboxylic acids are preferably used.
  • haloalkane carboxylic acids are listed below by way of example: monofluoroacetic acid, monochloroacetic acid, di-fluoroacetic acid, dichloroacetic acid, trifluoroacetic acid, trichloroacetic acid, ⁇ -fluoropropionic acid, ⁇ -chloropropionic acid, ⁇ , ⁇ -di-fluoropropionic acid , ⁇ , ß-difluoropropionic acid, ⁇ , ⁇ -dichloropropionic acid, ⁇ , ß-dichloropropionic acid, ⁇ -fluoro- ⁇ -chloropropionic acid, perfluoropropionic acid, perchloropropionic acid, perfluorobutyric acid, perfluorovaleric acid, perfluorocaproic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluoro
  • Tri-fluoroacetic acid is particularly preferably used as catalyst in the process according to the invention.
  • Most of the haloalkanecarboxylic acids mentioned are commercially available (Aldrich) or can be prepared by known processes, as described, for example, in Ulimann's Encyclopedia of Industrial Chemistry, 5th Ed., Vol. All, p. 371 ff, VCH Publishers, Weinheim 1988 or ibid., Vol. A6, p. 537, VCH
  • Trifluoroacetic acid and other perfluoroalkane carboxylic acids can e.g. can be obtained by the electrochemical fluorination of carboxylic acid fluorides (see Ullmann's Encyclopedia of Industrial Chemistry, 5th Ed., Vol. All; pp. 371-372; VCH Publishers, Weinheim 1988).
  • ⁇ , ⁇ -di-fluoroacetic acid is e.g. accessible by the reaction of tetrafluoroethylene with ammonia to give 2, 4, 6-tris (difluoromethyl) -s-triazine and its subsequent alkaline hydrolysis.
  • the photochemical chlorination or bromination provides chlorodifluoroacetic acid or bromodifluoroacetic acid (see Kirk-Othmer Encyclopedia of Chemical Technology; 3rd Ed., Vol. 10, pp. 891-900, John Wiley & Sons, New York 1980).
  • Trichloroacetic acid can e.g. by the oxidation of chloral with nitric acid.
  • haloalkanecarboxylic acids can also be used in the process according to the invention in a mixture with other carboxylic acids which expediently have a lower acid strength than the haloalkanecarboxylic acid used in the mixture.
  • Suitable combinations are e.g.
  • trifluoroacetic acid / acetic acid Difluoressigsaure / acetic acid / propionic acid mixtures trichloroacetic acid / acetic acid or perfluoropropionic acid, or also combinations of Haloge ⁇ nalkancarbon Textren with sulfonic acids such as methanesulfonic acid or toluenesulfonic acid, or organophosphonic acids, with the various acids which can be added together or individually to the reaction mixture.
  • the haloalkane carboxylic acids are preferably used alone as a catalyst.
  • the process according to the invention is preferably carried out under essentially anhydrous conditions.
  • the yield of I decreases with higher water contents of the reaction mixture.
  • a water content of the reaction mixture of up to 10 to 20% by weight, based on the entire reaction mixture, no disadvantageous consequences for the result of the process have yet been found.
  • haloalkane carboxylic acids which have a strong tendency to add water molecules to the acid molecule, for example trichloroacetic acid
  • higher water contents of the reaction mixture can also be tolerated without disadvantages, since the water of the reaction mixture is removed by hydrating the acid.
  • the process according to the invention is generally carried out at temperatures from -70 to + 130 ° C., preferably at -20 to + 50 ° C., in particular at 0 to + 40 ° C., under atmospheric pressure or elevated pressure, preferably under the Own pressure of the reaction system carried out.
  • the process according to the invention can be carried out batchwise, e.g. in stirred tanks, or continuously, e.g. in stirred tank cascades or tubular reactors.
  • the reaction mixture is advantageously worked up by hydrolysis or alcoholysis with water, ice or ice water or alcohols at temperatures between -20 ° C. and + 40 ° C.
  • Any base can be used to neutralize the excess acid.
  • Organic bases which are water-soluble or partially water-soluble, e.g. lower aliphatic amines, pyridine, piperidine, tertiary amines, such as trimethylamine, triethylamine, ethyldiisopropylamine or inorganic bases, such as ammonia, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, barium hydroxide,
  • aqueous ammonia, amine or alkali metal or alkaline earth metal carbonate or hydrogen carbonate solutions and of alkali metal hydroxide solutions in concentrations of 0.5 to 40% by weight at temperatures below 20 is particularly preferred ° C.
  • the pH of the reaction mixture does not exceed the pH of 12 for a prolonged period, since otherwise the haloalkanoyl group on Nl of the tetrahydropyrazine ring increases to a considerable extent or is completely split off.
  • Longer time means that the pH of the entire reaction mixture should not exceed the pH of 12 for more than about 5 to 10 minutes, a short-term exceeding of the pH of 12, for example caused by mixture inhomogeneities or overdosing of the base, caused, for example, by the inertia of the pH meter and the associated metering device or by less than optimal mixing, can be tolerated.
  • the temperature used in the workup also has an influence on the rate of cleavage of the halogenoalkanoyl group from Nl of the tetrahydropyrazine ring: at temperatures of, for example, 0 to 5 ° C. and pH 12, the cleavage takes place relatively slowly, whereas at pH 12 and 30 to 40 ° C, however, a significant acceleration of the hydrolysis is observed.
  • the reaction mixture with the base up to a pH in the range from 4 to 12, preferably from 5 to 10 and
  • the product I in which R 5 is hydrogen can be isolated by the customary techniques, such as extraction, sedimentation, filtration, centrifugation or phase separation, in particular by crystallization.
  • the cleaning of the valuable product I can e.g. by recrystallization from organic solvents, water or mixtures of water and / or organic solvents.
  • the desired product I often precipitates in a purity of more than 98% during the neutralizing workup.
  • Reagents VII constructed analogously to the introduction of the Boc group can be used to introduce the Cbz group into the 4-position of the tetrahydropyrazine ring.
  • Pyrocarbonic acid dibenzyl esters Tetrahedron Lett. 22, 5375 (1986)
  • benzyl chloroformate Ber. 6JL, 1192 (1932); Synthesis 1032 (1984)
  • the type of Cbz group transfer reagents used is generally not critical.
  • a base to the reaction mixture.
  • Any bases can be used for this purpose, for example bases such as those previously used in the neutralizing work-up of the reaction mixture.
  • Tertiary amines in particular tertiary alkylamines, for example trimethylamine, triethylamine, 4-N, N-dimethylamino-pyridine or ethyldiisopropylamine, are preferably used for introducing the Boc or Cbz group, the type of tertiary amine used being generally not critical .
  • the use of such bases can be particularly advantageous when halogen formic acid esters are used as Boc or Cbz group transfer reagents, when using transfer reagents in which practically neutral leaving groups are released in the course of the reaction, for example with activated carbonic acid esters or pyrocarbonic acid esters, such a base addition is not absolutely necessary.
  • the introduction of the Boc or Cbz group is preferably carried out with the addition of a base.
  • the pressure used in this reaction is generally not critical, which is why work is preferably carried out at atmospheric pressure.
  • a customary solvent which is inert under the reaction conditions used can be added to the reaction mixture, for example hydrocarbons, halogenated hydrocarbons, ethers, ketones, N, N-dialkylformamides, esters, etc.
  • R 1 , R 2 , R 3 , R 4 and R 5 have the abovementioned meaning can be carried out in a conventional manner with the aid of heterogeneous or homogeneous hydrogenation catalysts.
  • all hydrogenation catalysts which are suitable for the hydrogenation of CC double bonds can be used as heterogeneous hydrogenation catalysts.
  • Commercial hydrogenation catalysts which contain at least one element from Group VIIIB of the Periodic Table of the Elements, such as platinum, rhodium or palladium supported catalysts or Raney nickel, in particular rhodium-on-activated carbon, rhodium-on-aluminum oxide, are preferably used -, Palladium or platinum on activated carbon, palladium on barium sulfate, palladium or platinum on graphite, palladium on alumina or platinum dioxide catalysts. If R 5 is a Cbz group, it may be advantageous to use hydrogenation catalysts other than supported palladium catalysts, since this makes it easier to control the course of the reaction and the course of the reaction.
  • the above-mentioned supported catalysts suitable for hydrogenating the CC double bond of 1-halogenoalkanoyl-2-carboxamido-tetrahydropyrazine generally contain 0.1 to 10% by weight, preferably 0.5 to 8% by weight. , based on the total weight of the catalyst, of the platinum metal in question and, if they are not commercially available, can be produced in a conventional manner by impregnating the carrier material in question with a platinum metal compound.
  • catalysts which contain an element from Group VIIIB of the Periodic Table of the Elements and in which this element is complexed with the same or different ligands, preferably carbonyl and / or phosphine ligands, can likewise be used as homogeneous hydrogenation catalysts.
  • homogeneous catalysts are the compounds Rh (PPh 3 ) 3 Cl, HRuCl (PPh 3 ) 3 , HRuCl (CO) (hexyldiphenylphosphine) 3 , RuH 2 (CO) (PPh 3 ) 3 or RuH 2 (PPh 3 ) 3 called, where the abbreviation PPh 3 means triphenylphosphine.
  • triphenylphosphine ligand in place of triphenylphosphine used was ⁇ to, such as trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tributylphosphine, trioctylphosphine, cylphosphin tridecanol, traphenyldiphosphinomethan tricyclopentylphosphine, tricyclohexylphosphine, triphenylphosphine, tritolylphosphine, cyclohexyldiphenylphosphine, Te, 1, 2 Bis (diphenylphosphino) ethane, tetramethyldiphosphinomethane, tetraethyldiphosphinomethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, tetra-t-t
  • alkyl or arylphosphine ligands can be prepared by conventional methods, for example according to the methods described in Houben-Weyl, Methods of Organic Chemistry, Volume XII / 1, 4 Edition, pp. 17-65 and pp. 182-186, Thieme, Stuttgart, 1963 and volume E 1, 4th edition, pp. 106-199, Thieme, Stuttgart, 1982.
  • racemate of the 1-haloalkanoyl-2-carboxamido-piperazine X in question also generally forms during the hydrogenation.
  • a number of homogeneous, rhodium, ruthenium, palladium or platinum-containing catalysts with optically active phosphine ligands are commercially available which are suitable for carrying out the enantioselective hydrogenation of the CC double bond of the compounds I, for example optically active rhodium, Ruthenium, palladium or platinum complexes with the chiral phosphine ligands, 4, 5-bis (diphenylphosphino-methyl) -2, 2-dimethyl-1,3-dioxolane (DIOP), 2,2 '-Bis- ( diphenylphosphino) -1,1 '-binaphthyl (BINAP) or bis (diphenylphosphino) butane (CHIRAPHOS).
  • DIOP 2-dimethyl-1,3-dioxolane
  • BINAP 2,2 '-Bis- ( diphenylphosphino) -1,1
  • Optically active complexes of the platinum metals mentioned with optically active ferrocenyldiphosphine ligands as described, for example, in EP-A 646 590, J. Am. Chem. Soc. 116. 4062 (1994), Organometallics ü, 4481 (1994) or Chimia 5.0., 86 (1996) are also well suited for the asymmetric hydrogenation of the CC double bond of tetrahydropyrazine I. u
  • the mixture was taken up with 300 ml of methanol and 1000 ml of water, and 25% strength by weight aqueous ammonia solution was added dropwise at about 10 ° C. until a pH of 8 had been established.
  • the product II which precipitated out was filtered off, washed successively with water and diisopropyl ether and dried to constant weight at 30.degree.
  • the excess trifluoroacetic acid was distilled off from 395.5 g of the reaction mixture obtained at 45 ° C. and 50 mbar.
  • the low-volatility residue was diluted with 100 ml of methanol and 250 ml of water and 25% NH 4 OH solution was slowly added to this solution, with cooling, until a pH of 8 had been established.
  • the neutralized mixture was made with crystals the compound II inoculated and cooled to about 5 ° C.
  • the resulting precipitate was filtered off, washed twice with a little water and then again with about 20 ml of diisopropyl ether and then dried under reduced pressure.

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Abstract

L'invention concerne des 1-(halogénure d'alcanoyl)-2-carboxamido-1,4,5,6-tetrahydropyrazines de formule générale (I), dans laquelle R?1, R2 et R3¿ sont identiques ou différents et représentent respectivement un groupe alkyle C¿1?-C8 à chaîne linéaire ou ramifiée, un groupe cycloalkyle C5-C6, un groupe méthylène-cycloalkyle C6-C7, un groupe aryle C6-C10 ou un groupe aralkyle C7-C12, ou dans laquelle les radicaux R?1 et R2¿ sont liés et forment avec l'atome de carbone C1 exocyclique, non carbonylique, un cycle cycloaliphatique à 5 ou 6 chaînons, et R3 a la signification mentionnée ci-dessus, ou dans laquelle R3 représente hydrogène et R1 et R2 sont identiques ou différents et ont la signification mentionnée ci-dessus, R4 représente un groupe halogénure d'alkyle C¿1?-C19 contenant, comme substituant halogène, un ou plusieurs atomes d'halogène identiques ou différents sélectionnés parmi le fluor et/ou le chlore, et dans laquelle R?5¿ représente hydrogène ou un groupe butyloxycarbonyle tertiaire ou benzyloxycarbonyle. L'invention concerne également un procédé de fabrication et l'utilisation desdits composés.
PCT/EP1997/002455 1996-05-21 1997-05-14 1-(halogenure d'alcanoyl)-2-carboxamido-1,4,5,6-tetrahydropyrazines Ceased WO1997044328A1 (fr)

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WO1996022981A1 (fr) * 1995-01-23 1996-08-01 Lonza Ag Procede pour la production d'amides d'acide 1,4,5,6-tetrahydropyrazine-2-carboxylique
EP0744401A2 (fr) * 1995-05-23 1996-11-27 Lonza Ag Procédé pour la préparation des dérivés de l'acide 2-pipérazinique optiquement actif

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