WO1997044328A1 - 1-(alkanoyl halide)-2-carboxamido-1,4,5,6-tetrahydropyrazines - Google Patents

Abstract

1-(alkanoyl halide)-2-carboxamido-1,4,5,6-tetrahydropyrazines of general formula (I), in which R?1, R2 and R3¿ are the same or different and represent a straight or branched-chain C¿1? to C8 alkyl group, a C5 to C6 cycloalkyl group, a C6 to C7 methylene cycloalkyl group, a C6 to C10 aryl group or a C7 to C12 aralkyl group or in which the radicals R?1 and R2¿ are bonded together and jointly with the exocyclic non-carbonylic carbon atom C1 form a 5 to 6-component cycloaliphatic ring and R3 has the above meaning or in which R3 is hydrogen and R?1 and R2¿ are the same or different and have the above meaning, R4 is a C¿1? to C19 alkyl halide group containing one or more identical or different halogen atoms selected from fluorine and/or chlorine as the halogen substituent and in which R?5¿ is hydrogen or a tertiary butyl oxycarbonyl or a benzyl oxycarbonyl group. Also described is a process for production of said compounds and the use thereof.

Description

1 (HALOGEN ALKANOYL) -2-CARBOXAMIDO- 1, 4,5,6 - TETR AHYDROPYR AZINE

description

The present invention relates to t - (haloalkanoyl) - 2-carboxamido - 1, 4, 5, 6 - tetrahydropyrazines of the general formula I

R *

in which R ¹ , R ² and R ^{3 are the} same or different and each represents a straight-chain or branched Ci to Cβ alkyl group, a C ₅ to Cβ cycloalkyl group, a Cg to C ₇ methylene cycloalkyl group, a C ₆ - to Cio-aryl group or a C ₇ - to Cχ 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. -Butyloxycarbonyl- or a benzyloxycarbonyl group, a process for their preparation and their use.

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

VIII,

welche die Piperazin-2-tert. -butyl-carboxamid-Gruppe als Struk- turbestandteil enthält. Der HlV-Proteaseinhibitor VIII, ein Medi¬ kament gegen Aids, ist auch als Wirkstoff "L-735,524" (Indinavir) bekannt. Seine Synthese wird in EP-A 541 168, WO 95/21162 und von Askin et al, Tetrahedron Lett. 3_5_, 673 (1994) beschrieben.

which 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).

For the synthesis of 2-carboxamido-piperazines of the general formula IX

R5

0 R ³

in which the radicals R ^x , R ² , R ³ and R ^{5 have} the meaning given in the explanation of formula I and which are required as intermediates for the preparation of the abovementioned HIV protease inhibitors, there have hitherto been only complex, multistage synthetic routes to disposal. For example, in tetrahedron

Lett. 3_5_, 673 (1994) a four-step synthesis for the preparation of a in the 4-position of the piperazine ring with the tert. -Butyloxycarbonyl group protected 2-carboxamido-piperazine derivative be¬ described, in which the 2-pyrazine carboxylic acid is used as the starting material. The production of 2-pyrazine carboxylic acid again requires a multi-stage synthesis (Ann. Chimica 4_8_, 239 (1958)). This synthetic route is too complex for the industrial production of 2-carboxamido-piperazines and would make the price of the AIDS agent produced from it, such as the active ingredient VIII, unreasonably expensive. The disadvantages described above also apply correspondingly to a synthesis of compounds IX recently published in EP-A 680 955, in which 2-cyanopyrazine is used as the starting material.

In Tetrahedron Lett. 3_6_, 6419 (1995) describes the asymmetrical hydrogenation of various (2-tert-butylaminocarbonyl) -1, 4, 5, 6-tetrahydropyrazines which are in the 1- and / or 4-position with acetyl-, tert . -Butyloxycarbonyl- and / or benzyloxycarbonyl groups are substituted. These tetrahydropyrazine derivatives have the disadvantage that the further synthesis steps for the preparation of 2-carboxamido-piperazines IX, in particular of 2-carboxamido-4- (tert-butyloxycarbonyl) piperazines, are unsatisfactory only gender selectivity are feasible. An exception to this is the asymmetric hydrogenation of the compound

represents, in the 4-position with a tert. -Butyloxycarbonyl- group substituted derivative IX is obtained selectively. The disadvantage here, however, is that the hydrogenation destroys the benzyloxycarbonyl group in the 1-position, i.e. the reagent required for the derivatization of Nl is consumed in a stoichiometric amount, since it can no longer be recovered after splitting off under hydrating conditions. This makes this process very expensive.

It was an object of the present invention to provide new intermediate products and a process for their preparation which relate to the preparation of the piperazine-2-carboxamido structural components of the HIV protease inhibitors according to EP-A 541 168 and thus also to the preparation of these Enable HIV protein inhibitors themselves, by a simpler and less expensive process. In addition, the intermediates according to the invention should be simple and with high yield and selectivity in the 2-carboxamido-piperazines of the formula IX (R ⁵ = H) or in the corresponding 4- (tert-butyloxycarbonyl) or 4- (benzyloxycarbonyl) -substituted 2-carboxamido-piperazines of the formula IX can be converted.

Accordingly, 1-haloalkanoyl-2-carboxamido-1, 4, 5, 6-tetrahydropyrazines of the general formula I R5

in which 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. -Butyloxycarbonyl- or a benzyloxycarbonyl group is found.

Furthermore, a process for the preparation of 1- (haloalkanoyl) -2-carboxamido-1,4, 5,6-tetrahydropyrazines of the general formula I according to claim 1 was found, which is characterized in that 1 , 4, 5, 6-tetrahydro-2-cyanopyrazine of the formula IV

or an onium salt of this compound and a Bronsted acid, with a in the presence of a C ₂ - to C ₂ o "haloalkane carboxylic acid which contains one or more, identical or different halogen atoms selected from fluorine and / or chlorine, and at a temperature of -70 ° C to + 130 ° C an intermediate carbocation-forming compound of the general formula V R ^l

_R 2. V

R ³

or VI

HR ^l

\ / VI

R ²

in which 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 Cβ 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. -Butyloxycarbonylgruppe or the benzyloxycarbonyl group in the presence or absence of a solvent and in the presence of a base.

In the compounds of the general formula I, 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 Cι ₂ - Aralkyl groups, preferably the benzyl group.

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. Preference is given to those haloalkyl groups in which the halogen substituents or, in the case of a plurality of halogen substituents, at least some of these substituents, are in the α-position to the carbonyl group. 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. Of the perhalogenated radicals R ⁴ , the perfluorinated radicals R ⁴ are particularly preferred. The R ⁴ radicals are preferably straight-chain.

For the purposes of illustration only, some 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.

Particularly preferred among the intermediates according to the invention are the compounds 1-trifluoroacetyl-2- (tert-butylaminocarbonyl) -1,4,5,6-tetrahydropyrazine of the formula II H

CF ₃

and 1-trifluoroacetyl-2- (tert-butylaminocarbonyl) -4- (tert-butyloxycarbonyl) -1,4, 5, 6-tetrahydropyrazine of the formula III

OC (CH ₃ ) ₃

0 = C

CF ₃

To prepare these compounds, 1,4, 5,6-tetra-hydro-2-cyano-pyrazine of the formula IV is used

H

which, for example, is by the method of EP-A-175364 available from simple starting materials in a one-step synthesis, or an onium salt of this compound and a Bronsted acid with a in the presence of a C ₂ - to C ₂ o ^"Ha lie alkanecarboxylic - Acid into a compound of general formula v or VI which can be converted into an intermediate carbocation.

In the compounds of the general formula V, the radicals R ¹ , R ² and R ³ , as is self-evident, 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.

Instead of the uncharged compound IV, 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. In principle, 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

OCR ⁷

to call.

The radicals 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. For example, R ⁷ for a straight-chain or branched Ci to C ₂ o- _> preferably a C _x - to C _β -alkyl group, a straight-chain or branched, preferably a straight-chain Ci to C20 "haloalkyl group, in particular a Ci to Cβ-haloalkyl group, a C ₃ - to Ca, preferably a C ₅ - to C ₆ cycloalkyl group, a C ₆ - to Cio-aryl group, which phenyl group or a C ₇ preferably - to C ₁₂ aralkyl group , preferably the benzyl group. If desired, the 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.

act, this applies in particular when 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.

Instead of the starting materials of formula V, the compounds of general formula VI

HR ^:

\ / VI

/ \

R 'R ²

be used in the process according to the invention, which likewise easily form intermediate carbocations under the reaction conditions of the process according to the invention. In the compounds of the general formula VI, 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. To prepare the compounds according to the invention, 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. Of course, 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. For example, it is possible to use the haloalkane carboxylic acids as solvents in the process according to the invention, so that these acids are present in a 5- to 100-fold molar excess with respect to compound IV. 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.

In the process according to the invention, C ₂ - to C ₂ o ^{_ are} generally used as haloalkane carboxylic acids. preferably C ₂ - to Cχ 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. Those 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 α-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. Of 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.

Purely for the purpose of illustrating the present invention, some suitable haloalkane carboxylic acids are listed below by way of example: monofluoroacetic acid, monochloroacetic acid, di-fluoroacetic acid, dichloroacetic acid, trifluoroacetic acid, trichloroacetic acid, α-fluoropropionic acid, α-chloropropionic acid, α, α-di-fluoropropionic acid , α, ß-difluoropropionic acid, α, α-dichloropropionic acid, α, ß-dichloropropionic acid, α-fluoro-α-chloropropionic acid, perfluoropropionic acid, perchloropropionic acid, perfluorobutyric acid, perfluorovaleric acid, perfluorocaproic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid and perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid, perfluorofluoronic acid and , Perfluorlauric acid, Perfluormyristinsäure, Perfluorpalmitinsäure, Perfluorstearinsäure, Perfluorarachinsäure. Longer-chain haloalkane carboxylic acids can also be used, owing to their good availability, but the C2- to C ₂ o "haloalkane carboxylic acids are preferred over longer-chain ones.

Of these, for example, monochloroacetic acid, α, α-difluoroacetic acid, trichloroacetic acid, perfluoropropionic acid, perchloropropionic acid and perfluorobutyric acid are preferred. 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

Publishers, Weinheim 1986. 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). α, α-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.

As already mentioned, the 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. the use of trifluoroacetic acid / acetic acid, Difluoressigsaure / acetic acid / propionic acid mixtures trichloroacetic acid / acetic acid or perfluoropropionic acid, or also combinations of Haloge¬ nalkancarbonsäuren 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. In general, the yield of I decreases with higher water contents of the reaction mixture. With 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. When using 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,

Magnesium carbonate, calcium carbonate, magnesium hydroxide, barium carbonate, etc. The use of 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.

It is critical for the process according to the invention that when the reaction mixture is worked up with a base, 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. In general, the reaction mixture with the base up to a pH in the range from 4 to 12, preferably from 5 to 10 and

wern. After the neutralizing workup, 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.

If the production of compounds I substituted in the 4-position of the tetrahydropyrazine ring with Boc or Cbz groups is desired, the product of value I with R ⁵ = H can be obtained either after its isolation or, without prior isolation, in situ in the worked-up reaction mixture, be converted into the product of value I with R ⁵ equal to Boc or Cbz.

To convert the compounds I (R ⁵ = H) into the 4-position of the tetrahydropyrazine ring Boc- or Cbz-substituted compounds I, these compounds are reacted with suitable reagents VII for transferring the Boc or Cbz group, generally in the presence of a base , implemented. Practically all reagents customarily used for this purpose, in particular pyrocarbonic acid di-tert, can be used as transfer reagents VII for the Boc group. - butyl ester, mixed tert. -Butyl carbonic acid esters, such as 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (Bull. Chem. Soc. Jpn. 50, 718 (1977)), tert. -Butoxycarbonylhydroxylamine (Tetrahedron Lett. 14, 231 (1983)), 1, 2, 2,2-tetrachloroethyl-tert. -butyl carbonate (J. Org. Chem. 5_Q_, 3951 (1985)), 4- (dimethylthionium methyl sulfate) phenyl tert. -butyl carbonate (Chem. Express 2., 45 (1988)), pyridine-2-tert. -butyl carbonate (Chem. Ber. 118, 468 (1985)) or (2-thiopyridine) tert. -butyl carbonate, halogen amic acid esters, such as tert. -Butyl chloroformate, tert. -Butylfluoroformate (J. Org. Chem. 3_5, 3291 (1970)) or tert. -Butyl azidoformate (Synthesis 404 (1982)) can be used. Pyrocarbonic acid di-tert is particularly preferred for this purpose. butyl ester (Moroder et al.: Hoppe Seyler's Z. Physiol. Chem. 357, 1651 (1976)) was used as the reagent.

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)) or benzyl chloroformate (Ber. 6JL, 1192 (1932); Synthesis 1032 (1984)). The type of Cbz group transfer reagents used is generally not critical.

In order to accelerate the reaction of the tetrahydropyrazine derivatives I which are unsubstituted in the 4 position with the reagents which transmit Boc or Cbz groups, it may be advantageous to add 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. If the Boc or Cbz group is introduced into the reaction mixture in situ, ie without prior separation of the product I (R ⁵ = H), the acidic reaction mixture is advantageously added beforehand with the addition of a nonaqueous, for example alcoholic, base solution neutralized or made basic. 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.

If, instead of the isolated compounds I (R ⁵ = H), the product mixture obtained in the hydrolytic workup with a base is used as the starting material for the preparation of the compounds I with R ⁵ = Boc or Cbz, a further base addition is generally to be carried out this derivatization is not required.

The reaction of the compounds I with R ⁵ = H with the reagents transferring Boc or Cbz groups is generally carried out at temperatures from -70 to 150 ° C., preferably from -20 to 120 ° C., in particular from 0 up to 120 ° C. The pressure used in this reaction is generally not critical, which is why work is preferably carried out at atmospheric pressure. If desired, 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.

in which 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.

In principle, 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.

The hydrogenation of the double bond of the compounds I generally gives rise to the racemates of the compounds X.

Commercially available 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. Examples of such 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. Of course, other phosphine ligand, in place of triphenylphosphine used wer¬ 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-butyldiphosphinomethane, 1,2-bis (dimethylphosphino) ethane, 1,2-bis (diethylphosphino) ethane, 1,2-bis (dipropylphosphino) ethane, 1,2-bis (diisopropylphosphino) ethane, 1,2-bis (dibutylphosphino) ethane, 1,2-bis (di-t-butylphosphino) ethane, 1,2-bis (dicyclohexylphosphino) ethane, and the bisphosphine ligands described in EP-A 279 018, EP-A 311 619, WO 90/06 810 and EP-A 71 281. In addition to the processes described in the aforementioned patent applications, the 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.

If homogeneous catalysts of this type are used, the racemate of the 1-haloalkanoyl-2-carboxamido-piperazine X in question also generally forms during the hydrogenation.

For the hydrogenation of the CC double bond of the 1-alkanoyl-2-carboxamido-tetrahydropyrazine I it is also possible to use optically active, homogeneous hydrogenation catalysts which enable the enantioselective hydrogenation of the compounds I to give the corresponding 1-alkanoyl-2-carboxamido Enable piperazines X of the desired configuration.

For this purpose, 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). The chiral phosphine ligands mentioned are commercially available (for example Aldrich). 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

Φ

• rt

Examples

example 1

5 1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-tert. -butyl-carbox-amide II

In a 2 1 four-necked flask with thermometer, reflux condenser and stirrer, 1400 g of trifluoro

10 acetic acid submitted. At a temperature of 5 to 10 ° C., 109 g (1.0 mol) of 1,4, 5, 6-tetrahydro-2-cyanopyrazine IV were added in portions with cooling. Then 61.1 g (1.1 mol) of isobutene were gassed in at 5 to 10 ° C. while cooling. The reaction mixture thus obtained was stirred for 8 h, the temperature being slow

15 was allowed to rise to room temperature.

After the completion of the reaction, the majority of the excess trifluoroacetic acid was distilled off under reduced pressure. The residue was dissolved in 400 ml of methanol and this solution was diluted with 20 1000 ml of water. Triethylamine was added dropwise to this solution with cooling until the pH of the solution was 8. The product II separated out as a crystalline solid. This was filtered off, washed with water and dried.

25 Yield: 229 g (- 82% of theory)

Melting point: 156 ° C (colorless crystals)

¹ H-NMR data (in CDC1 ₃ ; internal standard: tetramethylsilane; 250 MHz):

30

7.08 ppm d; J = 6Hz [1H]

5, 30 ppm sbr [1 H]

5.19 ppm sbr [1 H]

3.76 ppm sbr [2 H]

35 3, 43 ppm sbr [2 H]

1.35 ppm s [9 H]

¹³ C NMR data: 183.7 ppm (C = 0)

155.6 ppm (C = 0)

40 131.1 ppm (CH)

116.2 ppm q; J = 290 Hz (CF ₃ )

104.5 ppm c: 48.9 ppm C) 41.5 ppm CH ₂ )

45 28.6 ppm CH _3, )

(s: singlet; sbr broad singlet; d doublet; q: quadruplet) Mass spectrum (EI): 279 (M ⁺ ), 207, 179, 165, 126, 97.

Example 2

1-trifluoroacetyl-1,4,5,6-tertrahydropyrazine-2-tert. -butylcarb- oxyamide II

In a 2 1 four-necked flask with a thermometer, reflux condenser and stirrer, 128.2 g of water-moist 1,4,5,6-tetrahydro-2-cyano-pyrazine IV (water content: 15% by weight; 1.0 mol) submitted. 500 ml of toluene were added and the mixture obtained was heated to boiling until water no longer separated on a connected water separator. After cooling this mixture to a temperature of 5 to 10 ° C, 700 g of trifluoroacetic acid were added dropwise at this temperature with cooling. Then 61.1 g (1.1 mol) of isobutene were gassed into this solution with cooling. The reaction mixture was stirred for 8 hours, the reaction temperature being allowed to slowly rise to room temperature. There were 2 phases in the implementation, which were separated. The CF ₃ COOH phase was distilled at reduced pressure to remove solvent and excess trifluoroacetic acid.

The residue was taken up in 400 ml of methanol and this solution was then diluted with 1000 ml of water. Triethylamine was added dropwise to this solution while cooling until its pH was 8.

The product II, which separated as a crystalline solid, was filtered off and dried. Yield: 190 g (≤ 68% of theory)

Example 3

Preparation of compound II - neutralizing workup with NaHC0 ₃

The reaction of 2-cyano-1, 4, 5, 6-tetrahydropyrazine IV with trifluoroacetic acid and isobutene was carried out as described in Example 1. After the majority of the excess trifluoroacetic acid had been separated off by distillation, the residue obtained was taken up in 850 ml of water and solid sodium bicarbonate (NaHC0 ₃ ) was added to this mixture with cooling until its pH was between 7 and 8. The resulting precipitate was filtered off and dried. The solid thus obtained was taken up in 1000 ml of ethyl acetate and heated to boiling. NaHC0 ₃ residues still present in the precipitate were separated by filtration of the hot ethyl acetate solution. When the solution cooled, the product II crystallized out in the form of colorless crystals. These were filtered off and dried.

Yield: 72% of theory

Example 4

Preparation of compound II - neutralizing workup with Na ₂ HP0 ₄

The reaction of 2-cyano-1, 4, 5,6-tetrahydropyrazine IV with trifluoroacetic acid and isobutene was carried out as described in Example 1. The residue obtained after the main amount of excess trifluoroacetic acid had been removed by distillation was taken up in 800 ml of ethyl acetate and added dropwise to 10 l of a 0.1N disodium hydrogenphosphate (Na ₂ HP0 ₄ ) solution. After the addition had ended, the two phases were separated and the aqueous phase was extracted again with 1000 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated.

Product II was isolated in a yield of 67% of theory.

Example 5

Preparation of compound II - neutralizing workup with NH ₃

1400 g of trifluoroacetic acid were placed in an apparatus according to Example 1 under a nitrogen atmosphere and cooled to a temperature of less than 10 ° C. using an ice bath. 109 g (1.0 mol) of 2-cyano-1,4, 5, 6-tetrahydropyrazine IV were added in portions so that the temperature of the mixture did not exceed 10 ° C. After IV had completely dissolved, 1.3 mol of isobutene were passed into the reaction mixture at a temperature of less than 10 ° C. No re-emergence of the isobutene from the mixture was observed. When the addition of isobutene had ended, the mixture was stirred overnight at room temperature and then the excess trifluoroacetic acid was distilled off under reduced pressure.

The residue was taken up in 300 ml of methanol and this mixture was diluted with 1000 ml of water. The resulting suspension-like mixture was cooled to below 10 ° C. by means of an ice bath and a 25% strength by weight aqueous ammonia solution was added dropwise until the pH of the mixture was 8. The ammonia solution was added dropwise so that the temperature of the mixture did not exceed 10 ° C. The failed product II was filtered off, washed successively with water and diisopropyl ether and then dried in a drying cabinet at 30 ° C. to constant weight.

Yield: 70% of theory

Example 6

Preparation of compound II - Use of 2-cyano-1, 4, 5, 6-tetrahydropyrazinium methanesulfonate as starting material

285 g of trifluoroacetic acid were placed in a reaction apparatus according to Example 1 under a nitrogen atmosphere and 205.2 g (1.0 mol) of 2-cyano-1,4,5,6-tetrahydropyrazinium were added with cooling (5 to 10 ° C.) -Methanesulfonate given. At a temperature of about 5 ° C., 73 g (1.3 mol) of isobutene were introduced into this mixture. The mixture was then stirred overnight at room temperature.

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.

Yield: 40% of theory

Example 7

4-tert. -Butyloxycarbonyl-1-trifluoroacetyl-1,4,5,6-tetrahydropyrazine-2-tert. -butylcarboxamide III

279 g (1.0 mol) of 1-trifluoroacetyl-1, 4, 5, 6-tetrahydropyrazine-2-tert. -butylcarboxamide II and 36.0 g (0.3 mol) of 4- (N, N-dimethylamino) pyridine (DMAP) were suspended in a nitrogen atmosphere in 2000 ml of ethyl acetate and 260 g (1.2 mol ) Pyrocarbonic acid di-tert. -butyl ester. The mixture was stirred at room temperature overnight, with complete conversion being achieved. The reaction mixture was then washed successively once in each case with 0.5 N hydrochloric acid and saturated sodium bicarbonate solution, the organic phase was dried over sodium sulfate and then concentrated. The crude product was purified by column chromatography on silica gel (mobile phase: ethyl acetate / hexane-1/1 v / v). Sales bond III was obtained in a yield of 84% of theory.

iH-NMR (CDC1 ₃ ; standard: tetramethylsilane; 250 MHz):

7.44 ppm sbr [1 H]

3.80 ppm sbr [4 H]

1.54 ppm s [9 H]

1.40 ppm s [9 H]

MS: CI (= chemical ionization) with isobutene gave the molar peak (M + 1): 380.

Example 8

Preparation of compound III

Example 8 was carried out as in Example 7, with the only difference that 2000 ml of the solvent methylene chloride were used instead of the solvent ethyl acetate. 340 g (0.9 mol = 90% yield) of reddish-colored III were obtained as the crude product.

Example 9

II

54.6 g of compound IV were so slowly dissolved in 570 g of trifluoroacetic acid that the temperature did not rise above 30 ° C. 143.5 g of trifluoroacetic acid-tert were added to this solution. -butyl ester and the mixture obtained was stirred overnight at room temperature.

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.

Yield: 57%.

Example 10

H H

CF ₃ CF ₃

II X (R ⁵ = H)

A solution of 5 g II in 100 ml tetrahydrofuran was in the presence of 8 g hydrogenation catalyst (0.5% by weight palladium on aluminum oxide) at 140 ° C. and a hydrogen pressure of 200 to 250 bar for 4 hours hydrated. After releasing the pressure in the autoclave, the catalyst was filtered off and the solvent was distilled off under reduced pressure.

Yield: 93%.

Claims

claims 1. 1- (haloalkanoyl) -2-carboxamido-1,4,5,6-tetrahydropyrazine of the general formula I

in which R ¹ , R ² and R ^{3 are the} same or different and each represents a straight-chain or branched Ci to Cβ alkyl group, a C ₅ to C _δ cycloalkyl group, a C _& to C ₇ methylene cy cloalkyl 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 connected to one another and together with the exocyclic, non-carbonylic carbon atom C ¹ a 5 - Form up 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 bis 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 is} hydrogen, a tert. -Butyloxycarbonyl- or a benzyloxycarbonyl group. 2. 1- (haloalkanoyl) -2-carboxamido-1, 4,5,6-tetrahydropyrazine of the formula I in which R ¹ , R ² , R ³ and R ^{5 have} the meaning given in claim 1 and R ⁴ is a Ci to C ₁₉ fluoroalkyl group containing one or more fluorine atoms or a Ci to C ₁₉ perfluoroalkyl group. 3. 1-trifluoroacetyl-2- (tert-butylaminocarbonyl) -1,4,5,6-tetra¬ hydropyrazine according to claim 1 of formula II

CF ₃ 4. 1-trifluoroacetyl-2- (tert-butylaminocarbonyl) -4- (tert-butyl-oxycarbonyl) -1,4,5,6-tetrahydropyrazine according to claim 1 of the formula III 0 C (CH ₃ ) ₃ 0 = C

CF ₃ 5. A process for the preparation of 1- (haloalkanoyl) -2-carboxamido-1, 4, 5,6-tetrahydropyrazines of the general formula I according to claim 1, characterized in that 1, 4, 5, 6-tetrahydro- 2-cyanopyrazine of the formula IV H

or an onium salt of this compound and a Brönsted acid, with a in the presence of a C ₂ - to C ₂ o-haloalkane carboxylic acid which contains one or more, identical or different halogen atoms selected from fluorine and / or chlorine and at a temperature of -70 ° C to + 130 ° C an intermediate carbocation-forming compound of the general formula V Ri

R ³ or VI Rl \ / VI λ R r ⁶ R ² in which R ¹ , R ² and R ^{3 have} the meaning given in Claim 1, R ^{6 is} hydrogen, a straight-chain or branched <Zχ - to C ₇ -alkyl-, C5- to C ₆ -cycloalkyl-, a C ₆ - bis Cio-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 converts the reaction mixture thus obtained in the presence or absence of a solvent to a pH by means of a base -Values from 4 to 12, the product obtained is isolated or reacted with a reagent VII for transferring the tert-butyloxycarbonyl group or the benzyloxycarbonyl group in the presence or absence of a solvent and in the presence of a base. 6. The method according to claim 5, characterized in that the 2-cyano-tetrahydropyrazine of the formula IV or its salts is reacted with a compound of the general formula V in which Z is one of the groups OH, OR ⁷ or OOC-R ⁷ , wherein R ^{7 is} a straight-chain or branched Ci to C ₂₀ alkyl, a C ₃ to C ₈ cycloalkyl, a C ₆ to Cio aryl or a C ₇ to Cχ ₂ aralkyl group and the radicals R ¹ , R ² and R ^{3 have} the meaning given in claim 1. Process according to Claims 5 and 6, characterized in that a haloalkane carboxylic acid with a pKa value which is less than or equal to 4 is used as the haloalkane carboxylic acid. Process according to claims 5 to 7, characterized gekennzeich¬ net that a C ₂ - to C ₂₀ fluorocarboxylic acid or a C ₂ - to C ₂ o * perfluorocarboxylic acid containing one or more fluorine atoms is used as the haloalkane carboxylic acid. 9. The method according to claims 5 to 8, characterized gekennzeich¬ net that trifluoroacetic acid is used as the haloalkane carboxylic acid. 10. The method according to claims 5 to 9, characterized gekennzeich¬ net that tert as the compound V. -Butanol used. 11. The method according to claims 5 to 9, characterized gekennzeich¬ net that isobutene is used as compound VI. 12. A process for the preparation of HIV protease inhibitors containing the 2-carbamoyl-piperazine-1,4-diyl structural unit, characterized in that a 1- (haloalka noyl) -2-carboxamido-1 , 4, 5, 6-tetrahydropyrazine of the formula I according to claim 1 R ⁵

R ⁴ in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given in claim 1, in the presence of a heterogeneous or a homogeneous hydrogenation catalyst which is soluble in the reaction medium and hydrogen to give the corresponding 2-carbamoyl-piperazine of the formula X R5 I.

in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the abovementioned meaning, or their enantiomers are hydrogenated and the 2-carbamoyl-piperazine of the formula IX thus obtained is synthesized in a manner known per se for the synthesis of the HIV- Protease inhibitors used. 13. The method according to claim 12, characterized in that 1-trifluoroacetyl-2-tert. -butylaminocarbonyl-1,4,5,6-tetrahy¬ dropyrazine of the formula II

CF ₃ or 1- (trifluoroacetyl) 2- (tert-butyl-aminocarbonyl) -4- (tert-butyloxycarbonyl) -1,4,5,6-tetrahydropyrazine of the formula III 0 C (CH ₃ ) ₃ H, N CH ₃ III \ CH. 0 = 0 CH ₃ CF ₃ for the synthesis of the HIV protease inhibitor of the formula VIII

used.