NEW PROCESS FOR THE PREPARATION OF N-MONOSUBSTITUTED PIPERAZIN DERIVATIVES

Abstract: A new process for the selective preparation of a compound of formula (I), wherein R<1> is a straight, branched or cyclic C1-C20 alkyl group, or an arylalkyl wherein aryl is C6 aryl and alkyl is C2-C6 alkyl; R<2> is defined as for R<1>, or is benzyl, hydroxy, or an aminoalkyl group wherein alkyl is a straight, branched or cyclic C1-C20 alkyl; Y is OH, a group OR<1> wherein R<1> is as defined above, or NR<3>R<4> wherein R<3> and R<4> independently are hydrogen, C1-C20 alkyl, or aralkyl wherein aryl is C6 aryl and alkyl is C2-C6 alkyl, as well as products obtained by said process and intermediates for use in the process.

Description: NEW PROCESS FOR THE PREPARAΗON OF N-MONOSUBSΗTUTED PIPERAZIN DERIVATIVES Field of the invention The present invention is directed to a new process for the selective preparation of piperazine derivatives. Background of the invention The piperazine nucleus is a constituent of many pharmaceutically useful compounds. Most of these compounds contain different substituents on one or both of the two nitrogens. A problem in the synthesis of these compounds relates to the differentiation of the two nitrogens in the synthesis sequence, such that selective derivatives of each can be made. In Aebischer et al. Helv. Chim. Acta 1989, 72, 1043 and Ger. Pat. DE 3804936 (1988), the preparation of a N-methyl-D-aspartate receptor antagonist is described. There is an obvious problem in the alkyiation reaction of a 2-piperazine carboxylate ester with an allylic bromide because the reported yield is only 60 %. The problem is most likely related to the presence of two possible alkylating sites, i.e. the two nitrogens of the piperazine carboxylate. It is possible to direct the alkyiation to the N-4 nitrogen of the free amino acid, i.e. 2- piperazinecarboxylic acid (hereafter called PZC), by first preparing a copper(II) complex (cf. Bigge et al. Tetrahedron Letters 1989, 30, 5193) that then can be used in an aqueous solvent for the alkyiation. In the same paper the authors also describe another solution to the same problem i.e. a synthesis of N-l -carbobenzyloxy -protected piperazinecarboxylic acid methyl ester in 52 % yield from the free amino acid. The three-step procedure involves full protection followed by selective deprotection. Other N-monosubstituted piperazines are present in the quinolone antibacterials, for example in vermisporine, and in many other compounds of medicinal interest Outline of the invention The present invention is directed to a new process for the selective preparation of piperazine derivatives that are monosubstituted in the 2-position or are disubstituted at carbons 2 and 5, and which additionally, have a single substituent at one of the nitrogens or have two different nitrogen substituents. One aspect of the invention relates to the selective formation of N-protected esters or amides of PZC, of the general formula I wherein R is a straight, branched or cyclic C1-C20 alkyl group, or an arylalkyl wherein aryl is phenyl or substituted phenyl and alkyl is _-C(. alkyl; 2 1 R is defined as for R , or is benzyl, hydroxyalkyl, or an aminoalkyl group wherein alkyl is a straight, branched or cyclic C1-C20 alkyl; Y is OH, a group OR , wherein R 1 is as defined above, or NR 3 R 4 ,wherein R 3 and R 4 independently are hydrogen, C1-C20 alkyl, or aralkyl, wherein aryl is phenyl or substituted phenyl and alkyl is C2-C6 alkyl. 1 2 1 1 Preferably R and R are each and independently C1-C20 alkyl, and Y is OR wherein R is C1-C20 alkyl. The process for the selective formation of the compounds I comprises the following steps: i) a pyrazinecarboxylic ester or amide of the formula II wherein R 2 and Y are as defined above and which is readily available either commercially or by methods known to one skilled in the art (see e.g. Barlin, G.B. (ed.) The Pyrazines, 1982, Wiley-Intersci., N.Y.) is hydrogenated in the presence of a catalyst and at least one equivalent of a C1-C20 alkoxycarbonyl-donating reagent, which is compatible with hydrogenation conditions, e.g. di-tert-butyldicarbonate, in an inert solvent compatible with hydrogenation conditions, and at temperatures and pressures commonly employed in such processes , giving the hitherto unknown N-l protected tetrahydropyrazinederivatives of the formula HI wherein R 1 , R 2 and Y are as defined above, in good yields; ii) the compound of the formula HI is isolated by conventional laboratory techniques known to one skilled in the art, purified by silica gel chromatography or other well-known techniques known to a person skilled in the art, e.g. recrystallization, and further converted or, after removal of the solvents and the excessive alkoxycarbonyl-donating reagent, e.g. by reacting with 2-aminoethanol and then filtering through a pad of silica gel, directly used as the reactant in step iii; and iii) the double bond of a compound of the formula UJ is saturated, giving a compound of the formula I. The catalyst for the hydrogenation in step i) can be selected from a wide variety of transition metals, preferably from the platinum metals. The catalyst can be used as such, or can be supported on carbon, silica, aluminia or other inert materials known to the man skilled in the art, or can be a transition metal which is solubilized by means of organic ligands, e.g. phosphine ligands such as triphenylphosphine. The alkoxycarbonyl-donating reagent in step i) is preferably in the form of an anhydride of a monoester of carbonic acid, for example di-tert-butyl- dicarbonate or dimethyl dicarbonate. The inert solvent in step i) can be chosen among a great variety of inert solvents known to the man skilled in the art. Examples of inert solvents that can be used are ethyl acetate, tetrahydrofuran, dioxane, toluene, dimethylformamide, ethylmethylketone and diisopropylether. Reaction temperatures may vary from room temperature to just below the boiling point of the solvent, and the pressure may vary from atmospheric pressure to 200 bar, both parameters depending on the reactivities of the catalyst and the substrate. Particularly preferred conditions *or obtaining the compounds of the formula HI by hydrogenation of a pyrazine involve the use of a palladium catalyst, e.g. 5% Pd on charcoal, in amounts ranging from 0.5-30 mol in an inert solvent, preferably ethyl acetate, at room temperature and at a hydrogen pressure of 1-5 bar, in the presence of 1.1-1.5 equivalents of di-tert-butyl dicarbonate. Preferred conditions for isolating a compound of the formula ELI in step ii) involve removal of the catalyst by filtration through an inert adsorbent , e.g. Celite or silica gel, concentrating the mixture in vacuo and initiating crystallization of a compound of the formula DI. The product may be purified by recrystallization. The saturation in step iii) for the conversion of a compound of the formula DI into a compound of the formula I can be performed by a variety of possibilities regarding reagents and conditions. One preferred reaction is hydrogenation in the presence of a transition metal catalyst chosen among the platinum metals known to catalyze addition of hydrogen over a double bond, in a suitable solvent, for example glacial acetic acid, ethyl acetate, tetrahydrofuran, dioxan, 2-propanol, toluene, and at a pressure ranging from atmospheric to 200 bar, and at a temperature ranging from room temperature to just below the boiling point of the solvent Another equally preferred reaction is reduction using a hydride reagent that is known to add hydrogen to double bonds. One particularly preferred reagent in the latter category is sodium cyanoborohydride in a weakly acidic solvent, for example acetic acid, or, when the group R 1 is not affected by strong acids, in diethyl ether in the presence of hydrochloric acid. Still another equally preferred reagent is a metal which transfers an electron to the double bond creating a radical anion which then reacts further to give overall addition of hydrogen. Preferred conditions for such reactions are the use of magnesium in methanol or lithium in 2-propanol. Conditions can be chosen so that a cis- or trans-isomer is formed predominantly. Preferred conditions for obtaining the cis-isomer is catalytic hydrogenation. Particularly preferred conditions for hydrogenation of the double bond of a compound of the formula HI involve the use of a palladium catalyst in amounts ranging from 0.1-20 mol% in glacial acetic acid at room temperature and at a pressure of 3-5 bar. Detailed description of the invention The invention will now be described in more detail by the following examples. Examples Example 1 Ethyl l-tert-butyloxycarbonyM,4,5,6-tetrahydropyrazin-2-carboxylate A solution of ethyl 2-pyrazinecarboxylate (6g, 39.5 mmol), (Boc) 2 O (11.2g, 51.3 mmol) and Pd (C) (10%) (1.3 g) in EtOAc (60 mL) was hydrogenated in a Parr apparatus at 65 psi for 24 hr. The solution was filtered through Celite and concentrated in vacuo until crystallization was initiated. The crystals were filtered off and recrystallized from hexane to afford 8.4 g (83%) of the title compound. mp 128-129 °C; 1H-NMR (CDC1 3 ) 57.10 (d, lH, H-3), 5.23 (br s, 1H, NH), 4.18 (q, 2H, OCH 2 CH 3 ), 3.6-3.2 (m, 4H, H-6, H-5), 1.49 (s, 9H, t-Bu), 1.28 (t, 3H, OCH 2 CH 3 ). Anal. Calcd. for Cι 2 H 20 N 2 O 4 : C, 56.3; H, 7.8; N, 10.9. Found: C, 56.0; H, 7.8; N, 10.8. Example 2 Ethyl l-ferf-butyIoxycarbonyl-2-piperazine-carboxyIate A solution of the compound prepared in Example 1 (5.55g; 21.7 mmol) and Pd(C) (10%) (2g) in glacial acetic acid (40 ml) was hydrogenated in a Parr apparatus at 75 psi for 18 hr. The solution was filtered through Celite, concentrated in vacuo to afford a yellow oil- Purification by flash chromatography on silica gel using 10% MeOH in EtOAc as eluent afforded 5.6 g (quantitative yield) of the title compound as an oil. 1H-NMR (CDC1 3 ) 54.53 (d, IH, H-2), 4.22 (q, 2H, OCH 2 CH 3 ), 3.76-2.58 (m, 6H, H-3, H- 5, H-6). 1.48 (s, IH, NH), 1.42 (2 s, 9H, t-Bu), 1.25 (t, 3H, OCH 2 CH 3 ); Anal. Calcd. for dzH^N^: C, 55.8; H, 8.5; N, 10.8. Found: C, 55.7; H, 8.8; N, 10.8. Example 3 Ethyl l-fert-butyloxycarbonyI-4-[(3-diethoxyphosphinyI)-prop-2-enyI]-piperazine-2- carboxylate Diethyl (3-bromoprop-l-enyl) phosphonate (11.5 g; 44.5 mmol) in THF (45 mL) was added to a solution of the compound prepared in Example 2 (11.3 g; 43.8 mmol) and Et 3 N (6.2 mL; 44.7 mmol) in THF (100 mL) at 0 °C. The solution was stirred at room temperature for 36 hr. After filtration of the precipitate the solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using 2% MeOH in EtOAc as eluent to afford 16.6 g (87%) of the title compound as an oil. 13 C-NMR (CDC1 3 ) δ 170.82, 170.51 (ester C=0), 155.67, 155.22 (Boc C=O), 150.28 (J=2.4 Hz, C-3'), 118.85 (J=183.1 Hz, C-2'), 80.16 [C(CH 3 ) 3 ], 61.38 (J=4.9 Hz, POCH 2 CH 3 ), 61.08, 61.02 (OCH 2 CH 3 ), 56.78 (J=7.3 Hz, C-l '), 55.40, 54.23 (C-2), 53.50 (C-3), 52.51 (C-5), 41.91, 40.97 (C-6), 28.18 (t-Bu), 16.30 (J= 6.1 Hz; POCH 2 CH 3 ), 14.20, 14.14 (CH 2 CH 3 ). Example 4 Ethyl l-tert-butyloxycarbonyl-5-methyI-l,4,5,6-tetrahydropiperazine-2-carboxylate from ethyl 5-methyI-2-pyrazinecarboxyIate A solution of ethyl 5-methyl-2-pyrazinecarboxylate (620 mg, 3.7 mmol), (Boc) 2 O (872 mg, 4 mmol) and Pd(C) (10%) (300 mg) in EtOAc (60 mL) was hydrogenated in a Parr apparatus at 65 psi for 30 hr. The solution was filtered through Celite and concentrated in vacuo. The residue was purified on silica gel using a gradient of 10-50% EtOAc in hexane as eluent to afford the title compound as an oil (770 mg, 76%). TLC: R f 0.39 (CHCl 3 MeOH 95:5); 1H-NMR (CDC1 3 ), δ 7.03 (d, IH, H-3), 4.52 (br d, IH, NH), 4.22-4.09 (2H, OCH 2 CH 3 ), 3.83 (IH, H-6a), 3.42 (IH, H-5), 2.81 (IH, H-6b), 1.43 (s, 9H, t-Bu), 1.26 (t, 3H, OCH 2 CH 3 ), 1.15 (d, 3H, CH 3 ); MS: m/z 270. Example 5 Ethyl l-tert-butyloxycarbonyl-5-methyI-2-piperazine-carboxylate A solution of the compound prepared in Example 4 (770 mg, 2.8 mmol) and Pd(C) (10%) (200 mg) in glacial HOAc (7 ml) was hydrogenated in a Parr apparatus at 60 psi for 24 hr. The solution was filtered through Celite and concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO 3 . The organic phase was dried (MgSO 4 ) and concentrated. The oily residue was purified by flash chromatography on silica gel using 1% MeOH in EtOAc as eluent affording 370 mg (48%) of the title compound as a yellow oil. 1H-NMR (CDC1 3 rotamers) δ 4.58, 4.40 (IH, H-2), 4.2-3.9 (2H, OCH 2 CH 3 ), 3.78, 3.64 (IH, H-6a), 3.43 (IH, H-3a) , 2.86 (IH, H-3b), 2.7-2.4 (2H, H-5, H-6b), 1.36, 1.42 (9H, t- Bu), 1.23-1.05 (4H, NH, OCH 2 CH 3 ), 0.95 (3H, CH 3 ); MS: m/z 272. The process according to the present invention provides an economical and convenient synthetic route to a wide variety of N-monoprotected 1, 4, 5, 6-tetrahydropyrazine derivatives and thereby to the corresponding monoprotected piperazine derivatives which in tum can be converted to a whole range of other compounds.

Claims: Qaims 1. A process for the preparation of a compound of the formula I wherein R is a straight, branched or cyclic C1-C20 alkyl group, or an arylalkyl wherein aryl is phenyl or substituted phenyl and alkyl is C2-C6 alkyl; 2 1 R is defined as for R , or is benzyl, hydroxyalkyl, or an aminoalkyl group wherein alkyl is a straight, branched or cyclic -C20 alkyl; Y is OH, a group OR wherein R 1 is as defined above, or NR 3 R 4 wherein R 3 and R 4 independently are hydrogen, C1-C20 alkyl, or aralkyl wherein aryl is phenyl or substituted phenyl and alkyl is C2-C6 alkyl; comprising: i) catalytically hydrogenating a pyrazinecarboxylic ester or amide of the formula H wherein R 2 and Y are as defined above, in the presence of at least one equivalent of a C 1 -C 20 alkoxycarbonyl-donating reagent to produce a compound of the formula HI wherein R 1 , R 2 and Y are as defined above; and ii) saturating the double bond of the compound of the formula HI to produce a compound of the formula I. 2. A process according to claim 1, wherein the formula (HI) compound is isolated, purified and optionally further converted. 1 2 3. A process according to claim 1, wherein R and R is each and independently C1-C2 0 alkyl, and Y is OR wherein R is C1-C20 alkyl. 4. A process according to claim 1, whereby the catalyst in step i) is a transition metal, preferably a platinum metal. 5. A process according to claim 4, whereby the catalyst is palladium, preferably in an amount of 0.1-20 mol % palladium. 6. A process according to claim 1 , whereby the catalyst in step i) is supported on an inert material. 7. A process according to claim 6, whereby the inert material is selected from carbon, silica or aluminia. 8. A process according to claim 1, whereby the alkoxycarbonyl-donating reagent in step i) is in the form of an anhydride of a monoester of carbonic acid. 9. A process according to claim 8, whereby the alkoxycarbonyl-donating reagent is di- tert-butyldicarbonate. 10. A process according to claim 1, whereby the inert solvent in step i) is selected from ethyl acetate, tetrahydrofuran, dioxane, toluene, dimethylformamide, ethyl-methylketone and diisopropylether. I I. A process according to claim 1, whereby the reaction temperature in step i) is in the range from room temperature to just below the boiling point of the solvent, and the pressure is in the range from atmospheric pressure to 200 bar. 12. A process according to claim 5, whereby the palladium catalyst is supported on 0.5-30 mol-% of charcoal. 13. A process according to claim 11, whereby the reaction temperature is room temperature and the pressure is in the range 1-5 bar. 14. A process according to claim 9, whereby the amount of di-tert-butyl-dicarbonate is 1.1- 1.5 equivalents. 15. A process according to claim 2, whereby the isolation of the compound of the formula HI is performed by filtration through Celite or silica gel, concentration of the mixture, and thereafter crystallization. 16. A process according to claim 15, further comprising purification of the compound EH. 17. A process according to claim 1, whereby the saturation of the double bound in step ii) is performed by hydrogenation in the presence of a transition metal catalyst and a suitable solvent, and at a suitable temperature and pressure, preferably at room temperature and at a pressure in the range 3-5 bar. 18. A process according to claim 17, whereby the solvent is selected from glacial acetic acid, ethyl acetate, tetrahydrofuran, dioxan, 2-propanol and toluene, preferably glacial acetic acid . 19. A process according to claim 17, whereby the pressure is in the range from atmospheric pressure to 200 bar, and the temperature is in the range from room temperature to just below the boiling point of the solvent used. 20. A process according to claim 1, whereby the saturation in step ii) is performed by the use of a hydride reagent 21. A process according to claim 20, whereby the hydride reagent is sodium- cyanoborohydride in a weakly acidic solvent 22. A process according to claim 21, whereby the weakly acidic solvent is acetic acid, or diethyl ether in the presence of hydrochloric acid when R 1 in a compound of the formula EQ is not affected by strong acids. 23. A process according to claim 1, whereby the saturation in step ii) is performed with a metal transferring an electron to the double bond and thereby creating a radical anion which in turn reacts further, giving the hydrogen addition. 24. A process according to claim 23, whereby the saturation is performed with magnesium in methanol, or lithium in 2-propanol. 25. A product according to the formula I wherein R 1 , R 2 and Y are as defined in claim 1, produced by the process of claim 1. 1 2 26. A product according to claim 25, wherein R and R each and independently is C1-C20 alkyl, and Y is OR wherein R is C1-C20 alkyl. 27. A product according to claim 26, being ethyl l-tert-butyloxycarbonyl-2-piperazine-carboxylate; ethyl l-tert-butyloxycarbonyl-4-[3-(diethylphosphonyl)-prop-2-enyl]-piperazine-2- carboxylate; or ethyl 1 -tert-butyloxycarbonyl-5-methyl-2-piperazine-carboxylate. 28. A product according to the formula HI wherein R is a straight, branched or cyclic C1-C20 alkyl, or an arylalkyl wherein aryl is phenyl or substituted phenyl and alkyl is C2-C6 alkyl; 2 1 R is hydrogen, phenyl or substituted phenyl, benzyl or substituted benzyl, or is a group R as defined above; and Y is a straight, branched or cychc C 1 .C20 alkoxy group, or NR 3 R 4 wherein R 3 and R 4 each and independently are hydrogen or a group R as defined above, produced by the process of claim 1. 29. A product according to claim 27, being ethyl l-tert-butyloxycarbonyl-l,4,5,6-tetrahydropyrazin-2-carboxylate; or ethyl l-tert-butyloxycarrx ) nyl-5-me yl-l,4,5,6-tetrahydropiperazine-2-carboxylate.

Inventors: BESIDSKI YEVGENI, CLAESSON ALF, LUTHMAN KRISTINA, BESIDSKI, YEVGENI, CLAESSON, ALF, LUTHMAN, KRISTINA
Applicants: ASTRA AB, BESIDSKI YEVGENI, CLAESSON ALF, LUTHMAN KRISTINA, ASTRA AKTIEBOLAG, BESIDSKI, YEVGENI, CLAESSON, ALF, LUTHMAN, KRISTINA
Application year: 1996
Main classification: C07D241
IPC codes: C07D241