CA2228896A1 - New process for the preparation of n-monosubstituted piperazin derivatives - Google Patents
New process for the preparation of n-monosubstituted piperazin derivatives Download PDFInfo
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- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
A new process for the selective preparation of a compound of formula (I), wherein R1 is a straight, branched or cyclic C1-C20 alkyl group, or an arylalkyl wherein aryl is C6 aryl and alkyl is C2-C6 alkyl; R2 is defined as for R1, or is benzyl, hydroxy, or an aminoalkyl group wherein alkyl is a straight, branched or cyclic C1-C20 alkyl; Y is OH, a group OR1 wherein R1 is as defined above, or NR3R4 wherein R3 and R4 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 PREPARATION OF N-MONOSUBSTITUTED PIPERAZIN
DERIVATIVES
Field of the invention s The present invention is directed to a new process for the selective preparation of piperazine derivatives.
o Back~round of the invention The pipei~ C nucleus is a cnn~tit~lent of many pharr~( eutic ~lly useful compounds. Most of these compounds contain different substituentc on one or both of the two nitrogens. A
problem in the synthesis of ~ese compounds relates to t31e dirrt;l. ~ t;on of the two 15 nitrogens in the synthesis se~3uence, 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-asp~ l~te r~tptor antagonist is ~lesçrihe~ There is an obvious problem in the alkylation reaction of a 2-piperazine carboxylate ester with an allylic bromide 20 because the ~ d 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 alkylation to the N-4 nitrogen of the free amino acid, i.e. 2-piperazinecarboxylic acid (hereafter called PZC), by first plG~aling a copper(~) complex 25 (cf. Bigge et al. Tetrahedron Letters 1989, 30, 5193) that then can be used in an aqueous solvent for the aLkylation. In d~e same paper the authors also describe another solution to the same problem i.e. a synthesis of N- l-carbobenzyloxy-protected ~ er~rboxylicacid methyl ester in 52 % yield from the free amino acid. The three-step procedure involves full protection followed by selective deprotection.
Other N-monosub.,liLulcd ~ ,.dzilles are present in the quinolone ~nhb~cterials, for example in ve~misporine, and in many other compounds of medicinal interest.
5 Olltlin~. of the invention The present invention is directed to a new process for the selective preparation of piperazine derivativeis that are monosub ,lilu~d in the 2-position or are ~licubsti~ted at carbons 2 and 5, and which additionally, have a single substituent at one of the nitrogens or 10 have two dir~rc.ll r~trogen substit~lent~
One aspect of the invention relates to the selective formation of N-protected esters or amides of PZC, of the general formula I
R~l~NH
~N~ I
R~ ~o wherein Rl is a straight, branched or cyclic Cl-C20 alkyl group, or an arylalkyl wh~ l aryl is phenyl or subs~ihlt~ phenyl and alkyl is C2-C6 alkyl;
R is def ned as for R, or is benzyl, hydroxyalkyl, or an ~mino~lkyl group wherein alkyl is a straight, branched or cyclic Cl-C20 alkyl;
Y is OH, a group OR , wherein Rl is as defined above, or NR3 R4 ,wherein R3 and R4 independently are hydrogen, Cl-C20 alkyl, or aralkyl, wherein aryl is phenyl or substituted phenyl and aLkyl is C2-C6 alkyl.
s Preferably R and R are each and independently Cl-C20 alkyl, and Y is ORl whc.t;in Rl is Cl-C20 alkyl.
The process for the selective formation of the compounds I comprises the following steps:
o i) a pyr~7inec~rboxylic ester or amide of the formula II
R2~N~
~o IS wherein R2 and Y are as defined above and which is readily available either colll.ll~ ially 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 Cl-C20 aLlcoxy~l~nyl-donating reagent, which is compat;hle with hydrogenation conditions, e.g. di-tert-butyldicarbonate, in an inert solvent conlyalible with hydrogenation conditions, and at L~,.lly~,.dLIIl~,S and pressures commonly employed in such processes, giving the hitherto unknown N-l protected tetrahy~oyyl~inederivatives of the formula m 3~, R1'o~o ~
wherein Rl, R2 and Y are as defined above, in good yiel ls;
s ii) the compound of the formula m is isolated by conventional laboratory techniques known to one skilled in the art, purified by silica gel cLull-atography or other well-known techniques known to a person skilled in the art, e.g. recryst~lli7~tion, and further converted or, after removal of the solvents and the excessive alkoxycarbonyl-donating reagent, e.g. by o 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 m is S~ tC~I, 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, ~lnmini~ or other 20 inert m~teri~lc 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. Exarnples of inert solvents that can be used are ethyl acetate, W O 97/07106 PCT/SE~6/~7 tetrahydrofuran, dioxane, toluene, dimethylrollllalllide, ethylrnethyL~cetone and diisopropylether.
Reaction L~,.llpe.àtures may vary from room te~ dture to just below the boiling point of s the solvent, and the pl~,SSUlc may vary from atrnospheric ~les~uuc to 200 bar, both palldlll~ depending on the reactivities of the catalyst and the ~ubsLldle.
Particularly ~lcfc.l~ conditions ror obtaining the compounds of the formula m byhydrogenation of a pyrazine involve the use of a palladium catalyst, e.g. 5% Pd on charcoal, 10 in amounts ranging from 0.5-30 mol% in an inert solvent, preferably ethyl acetate, at room L~ aLulc 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 m in step ii) involve removal S of the catalyst by filtration through an inert adsorbent, e.g. Celite or silica gel, conce.lLldLLIlg the IllL~Lulc in vacuo and initi~ting cryst~lli7~tion of a compound of the formula m. The product may be purified by recryst~lli7~tion.
The saturation in step iii) for the conversion of a compound of the formula m into a compound of the formula I can be pclro,llled by a variety of possibilities regarding reagents and conflitiQn~ One ~lcfc~l~d 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 eX~ e glacial acetic acid, ethyl acetate, tetrahydloruldn, dioxan, 2-propanol, toluene, and at a pressure ranging from atmospheric to 200 bar, and at a ~cln~ latulc ranging from room L~ ,.dLulc to just below the boiling point of the solvent. Another equally ~lcfe~-~,d reaction is reduction using a hydride reagent that is known to add hydrogen to double bonds. One particularly plcfellcd reagent in the latter category is sodium cyanoborohydride in a weakly acidic solvent, for example acetic acid, or, when the group Rl is not affected by strong acids, in diethyl ether in the presence of hydrochloric acid. Still another equally preferred rcagent is a metal which ~ fcl~ an electron to the double bond creating a radical anion which then reacts further to give overall W O 97/07106 PCT/SE~GI'~C~//
addition of hydrogen. Preferred conditions for such reactions are the use of m~ . in methanol or lithium in 2-propanol. Conditions can be chosen so that a cis- or trans-isomer is formed predo.~ ,.Lly.
~crcll~d conditions for obtaining the cis-isomer is catalytic hydrogenation.
Particularly prc~ed conditions for hydrogenation of the double bond of a compound of the formula m involve the use of a p~ 1ium catalyst in amounts ranging from 0.1-20 mol% in glacial acetic acid at room tel--p~dture and at a pl~S~ulc of 3-5 bar.
Detailed description of the invention The invention will now be ~leserihe~ in more detail by the following examples.
Examples Ex~m~le 1 Ethyl l-teff-butyloxycarbonyl-1,4,5,6-tetrahydl olJy. ~."-2-carboxylate A solution of ethyl 2-pyr~7inec~rboxylate (6g, 39.5 mmol), (Boc)2O (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 conc~l.LI~ted in ~aczu~ until cry-st~11i7~1~on was initi~t~ The cry-stals were filtered off and l~lysl;llli7~ from hexane to 25 afford 8.4 g (83%) of the title compound.
mp 128-129 ~C; ~H-NMR (CDCl3) o7.10 (d, lH, H-3), 5.23 (br s, lH, NH), 4.18 (q, 2H, OCH2CH3), 3.6-3.2 (m, 4H, H-6, H-5), 1.49 (s, 9H, t-Bu), 1.28 (t, 3H, OCH2CH3).
Anal. Calcd. for C,2H20N204: C, 56.3; H, 7.8; N, 10.9.
Found: C, 56.0; H, 7.8; N, 10.8.
Example 2 Ethyl l-~ert-butyloxycarbonyl-2-piperazine-carboxylate 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 a~pala~us 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 Et~Ac as eluent afforded 5.6 g (4. .~ /e yield) of the title compound as an oil.
10 IH-NMR (CDCI3) o 4.53 (d, lH, H-2), 4.22 (q, 2H, OCH2CH3), 3.76-2.58 (m, 6H, H-3, H-5, H-6). 1.48 (s, lH, NH), 1.42 (2 s, 9H, t-Bu), 1.25 (t, 3H, OCH2CH3);
Anal. Calcd. for Cl2H22N2O4: C, 55.8; H, 8.5; N, 10.8.
Found: C, 55.7; H, 8.8; N, 10.8.
F~cample 3 Ethyl l-ter~-butyloxycarbonyl-4-[(3-diethoxyphosphinyl)-prop-2-en~l]-piperazine-2-carboxylate Diethyl (3-bromoprop-1-enyl) phosphonate (11.5 g; 44.5 mrnol) in THF (45 mL) was added 20 to a solution of the compound pr~a~t,d in Example 2 (11.3 g; 43.8 mmol) and Et3N (6.2 mL; 44.7 mmol) in THF (100 mL) at 0 ~C. The solution was stirred at room tem~ aLule for 36 hr. After filtration of the precipitate the solution was conc;e~l.al~i in vacuo. The residue was purified by flash ch.un~a~graphy on silica gel using 2% MeOH in EtOAc as eluent to afford 16.6 g (87%) of the title compound as an oil.
'3C-NMR(CDCl3)ol70.82, 170.51 (esterC=0), 155.67, 155.22(BocC=O), 150.28 (J=2.4 Hz, C-3'), 118.85 (J=183.1 Hz, C-2'), 80.16 [C(CH3)3], 61.38 (J=4.9 Hz, POCH2CH3), 61.08, 61.02 (OCH2CH3), 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; POCH2CH3), 30 14.20, 14.14(CH2CH3).
Ex~-nple 4 Ethyl l-teff-butyloxycarbonyl-5-methyl-1,4,5,6-tetrahydropiperazine-2-carboxylate from ethyl 5-methyl-2-pyr~iner~rboxylate s A solution of ethyl 5-methyl-2-pyr~ oxylate (620 mg, 3.7 mmol), (Boc)20 (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 conc~.-L.dl~l in vacuo. The residue was purified on silica gel using a gradient of 10-50% EtOAc in hexane o as eluent to afford the title compound as an oil (770 mg, 76%).
TLC:Rf 0.39 (CHCl3 MeOH 95:5); ~H-NMR (CDCl3), o 7.03 (d, lH, H-3), 4.52 (br d, lH, NH), 4.224.09 (2H, OCH2CH3), 3.83 (lH, H-6a), 3.42 (lH, H-5), 2.81 (lH, H-6b), 1.43 (s, 9H, t-Bu), 1.26 (t, 3H, OCH2CH3), 1.15 (d, 3H, CH3); MS: m/z 270.
Example 5 Ethyl l-teff-butyloxycarbonyl-5-methyl-2-piperazine-carboxylate A solution of the compound ~r~al~d in Example 4 (770 mg, 2.8 mmol) and Pd(C) (10%) (200 mg) in glacial HOAc (7 ml) was hydrogenated in a Parr a~p~dlus at 60 psi for 24 hr.
The solution was filtered through Celite and concentrated in vacuo. The residue was partitioned b~,~n EtOAc and saturated aqueous NaHCO3. The organic phase was dried (MgSO4) and conc~ ed. The oily residue was purified by flash chromatography on silica gel using 1% MeOH in EtOAc as eluent ar~old~lg 370 mg (48%) of the tide compound as a 2S yellow oil.
IH-NMR (CDCl3 lo~l~ ) o 4.58, 4.40 (lH, H-2), 4.2-3.9 (2H, OCH2CH3), 3.78, 3.64 (lH, H-6a), 3.43 (lH, H-3a), 2.86 (lH, H-3b), 2.7-2.4 (2H, H-5, H-6b), 1.36, 1.42 (9H, t-Bu), 1.23-1.05 (4H, NH, OCH2CH3), 0.95 (3H, CH3); MS: m/z 272.
W O 97/07106 pcTlsE9Gloc97/
The process according to the present invention provides an economical and convenient synthetic route to a wide variety of N-mono~.u~ ,d 1, 4, 5, 6-tetrahydropyrazinederivatives and thereby to the corresponding monoprotected piperazine derivatives which in turn can be converted to a whole range of other compounds.
DERIVATIVES
Field of the invention s The present invention is directed to a new process for the selective preparation of piperazine derivatives.
o Back~round of the invention The pipei~ C nucleus is a cnn~tit~lent of many pharr~( eutic ~lly useful compounds. Most of these compounds contain different substituentc on one or both of the two nitrogens. A
problem in the synthesis of ~ese compounds relates to t31e dirrt;l. ~ t;on of the two 15 nitrogens in the synthesis se~3uence, 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-asp~ l~te r~tptor antagonist is ~lesçrihe~ There is an obvious problem in the alkylation reaction of a 2-piperazine carboxylate ester with an allylic bromide 20 because the ~ d 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 alkylation to the N-4 nitrogen of the free amino acid, i.e. 2-piperazinecarboxylic acid (hereafter called PZC), by first plG~aling a copper(~) complex 25 (cf. Bigge et al. Tetrahedron Letters 1989, 30, 5193) that then can be used in an aqueous solvent for the aLkylation. In d~e same paper the authors also describe another solution to the same problem i.e. a synthesis of N- l-carbobenzyloxy-protected ~ er~rboxylicacid methyl ester in 52 % yield from the free amino acid. The three-step procedure involves full protection followed by selective deprotection.
Other N-monosub.,liLulcd ~ ,.dzilles are present in the quinolone ~nhb~cterials, for example in ve~misporine, and in many other compounds of medicinal interest.
5 Olltlin~. of the invention The present invention is directed to a new process for the selective preparation of piperazine derivativeis that are monosub ,lilu~d in the 2-position or are ~licubsti~ted at carbons 2 and 5, and which additionally, have a single substituent at one of the nitrogens or 10 have two dir~rc.ll r~trogen substit~lent~
One aspect of the invention relates to the selective formation of N-protected esters or amides of PZC, of the general formula I
R~l~NH
~N~ I
R~ ~o wherein Rl is a straight, branched or cyclic Cl-C20 alkyl group, or an arylalkyl wh~ l aryl is phenyl or subs~ihlt~ phenyl and alkyl is C2-C6 alkyl;
R is def ned as for R, or is benzyl, hydroxyalkyl, or an ~mino~lkyl group wherein alkyl is a straight, branched or cyclic Cl-C20 alkyl;
Y is OH, a group OR , wherein Rl is as defined above, or NR3 R4 ,wherein R3 and R4 independently are hydrogen, Cl-C20 alkyl, or aralkyl, wherein aryl is phenyl or substituted phenyl and aLkyl is C2-C6 alkyl.
s Preferably R and R are each and independently Cl-C20 alkyl, and Y is ORl whc.t;in Rl is Cl-C20 alkyl.
The process for the selective formation of the compounds I comprises the following steps:
o i) a pyr~7inec~rboxylic ester or amide of the formula II
R2~N~
~o IS wherein R2 and Y are as defined above and which is readily available either colll.ll~ ially 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 Cl-C20 aLlcoxy~l~nyl-donating reagent, which is compat;hle with hydrogenation conditions, e.g. di-tert-butyldicarbonate, in an inert solvent conlyalible with hydrogenation conditions, and at L~,.lly~,.dLIIl~,S and pressures commonly employed in such processes, giving the hitherto unknown N-l protected tetrahy~oyyl~inederivatives of the formula m 3~, R1'o~o ~
wherein Rl, R2 and Y are as defined above, in good yiel ls;
s ii) the compound of the formula m is isolated by conventional laboratory techniques known to one skilled in the art, purified by silica gel cLull-atography or other well-known techniques known to a person skilled in the art, e.g. recryst~lli7~tion, and further converted or, after removal of the solvents and the excessive alkoxycarbonyl-donating reagent, e.g. by o 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 m is S~ tC~I, 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, ~lnmini~ or other 20 inert m~teri~lc 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. Exarnples of inert solvents that can be used are ethyl acetate, W O 97/07106 PCT/SE~6/~7 tetrahydrofuran, dioxane, toluene, dimethylrollllalllide, ethylrnethyL~cetone and diisopropylether.
Reaction L~,.llpe.àtures may vary from room te~ dture to just below the boiling point of s the solvent, and the pl~,SSUlc may vary from atrnospheric ~les~uuc to 200 bar, both palldlll~ depending on the reactivities of the catalyst and the ~ubsLldle.
Particularly ~lcfc.l~ conditions ror obtaining the compounds of the formula m byhydrogenation of a pyrazine involve the use of a palladium catalyst, e.g. 5% Pd on charcoal, 10 in amounts ranging from 0.5-30 mol% in an inert solvent, preferably ethyl acetate, at room L~ aLulc 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 m in step ii) involve removal S of the catalyst by filtration through an inert adsorbent, e.g. Celite or silica gel, conce.lLldLLIlg the IllL~Lulc in vacuo and initi~ting cryst~lli7~tion of a compound of the formula m. The product may be purified by recryst~lli7~tion.
The saturation in step iii) for the conversion of a compound of the formula m into a compound of the formula I can be pclro,llled by a variety of possibilities regarding reagents and conflitiQn~ One ~lcfc~l~d 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 eX~ e glacial acetic acid, ethyl acetate, tetrahydloruldn, dioxan, 2-propanol, toluene, and at a pressure ranging from atmospheric to 200 bar, and at a ~cln~ latulc ranging from room L~ ,.dLulc to just below the boiling point of the solvent. Another equally ~lcfe~-~,d reaction is reduction using a hydride reagent that is known to add hydrogen to double bonds. One particularly plcfellcd reagent in the latter category is sodium cyanoborohydride in a weakly acidic solvent, for example acetic acid, or, when the group Rl is not affected by strong acids, in diethyl ether in the presence of hydrochloric acid. Still another equally preferred rcagent is a metal which ~ fcl~ an electron to the double bond creating a radical anion which then reacts further to give overall W O 97/07106 PCT/SE~GI'~C~//
addition of hydrogen. Preferred conditions for such reactions are the use of m~ . in methanol or lithium in 2-propanol. Conditions can be chosen so that a cis- or trans-isomer is formed predo.~ ,.Lly.
~crcll~d conditions for obtaining the cis-isomer is catalytic hydrogenation.
Particularly prc~ed conditions for hydrogenation of the double bond of a compound of the formula m involve the use of a p~ 1ium catalyst in amounts ranging from 0.1-20 mol% in glacial acetic acid at room tel--p~dture and at a pl~S~ulc of 3-5 bar.
Detailed description of the invention The invention will now be ~leserihe~ in more detail by the following examples.
Examples Ex~m~le 1 Ethyl l-teff-butyloxycarbonyl-1,4,5,6-tetrahydl olJy. ~."-2-carboxylate A solution of ethyl 2-pyr~7inec~rboxylate (6g, 39.5 mmol), (Boc)2O (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 conc~l.LI~ted in ~aczu~ until cry-st~11i7~1~on was initi~t~ The cry-stals were filtered off and l~lysl;llli7~ from hexane to 25 afford 8.4 g (83%) of the title compound.
mp 128-129 ~C; ~H-NMR (CDCl3) o7.10 (d, lH, H-3), 5.23 (br s, lH, NH), 4.18 (q, 2H, OCH2CH3), 3.6-3.2 (m, 4H, H-6, H-5), 1.49 (s, 9H, t-Bu), 1.28 (t, 3H, OCH2CH3).
Anal. Calcd. for C,2H20N204: C, 56.3; H, 7.8; N, 10.9.
Found: C, 56.0; H, 7.8; N, 10.8.
Example 2 Ethyl l-~ert-butyloxycarbonyl-2-piperazine-carboxylate 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 a~pala~us 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 Et~Ac as eluent afforded 5.6 g (4. .~ /e yield) of the title compound as an oil.
10 IH-NMR (CDCI3) o 4.53 (d, lH, H-2), 4.22 (q, 2H, OCH2CH3), 3.76-2.58 (m, 6H, H-3, H-5, H-6). 1.48 (s, lH, NH), 1.42 (2 s, 9H, t-Bu), 1.25 (t, 3H, OCH2CH3);
Anal. Calcd. for Cl2H22N2O4: C, 55.8; H, 8.5; N, 10.8.
Found: C, 55.7; H, 8.8; N, 10.8.
F~cample 3 Ethyl l-ter~-butyloxycarbonyl-4-[(3-diethoxyphosphinyl)-prop-2-en~l]-piperazine-2-carboxylate Diethyl (3-bromoprop-1-enyl) phosphonate (11.5 g; 44.5 mrnol) in THF (45 mL) was added 20 to a solution of the compound pr~a~t,d in Example 2 (11.3 g; 43.8 mmol) and Et3N (6.2 mL; 44.7 mmol) in THF (100 mL) at 0 ~C. The solution was stirred at room tem~ aLule for 36 hr. After filtration of the precipitate the solution was conc;e~l.al~i in vacuo. The residue was purified by flash ch.un~a~graphy on silica gel using 2% MeOH in EtOAc as eluent to afford 16.6 g (87%) of the title compound as an oil.
'3C-NMR(CDCl3)ol70.82, 170.51 (esterC=0), 155.67, 155.22(BocC=O), 150.28 (J=2.4 Hz, C-3'), 118.85 (J=183.1 Hz, C-2'), 80.16 [C(CH3)3], 61.38 (J=4.9 Hz, POCH2CH3), 61.08, 61.02 (OCH2CH3), 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; POCH2CH3), 30 14.20, 14.14(CH2CH3).
Ex~-nple 4 Ethyl l-teff-butyloxycarbonyl-5-methyl-1,4,5,6-tetrahydropiperazine-2-carboxylate from ethyl 5-methyl-2-pyr~iner~rboxylate s A solution of ethyl 5-methyl-2-pyr~ oxylate (620 mg, 3.7 mmol), (Boc)20 (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 conc~.-L.dl~l in vacuo. The residue was purified on silica gel using a gradient of 10-50% EtOAc in hexane o as eluent to afford the title compound as an oil (770 mg, 76%).
TLC:Rf 0.39 (CHCl3 MeOH 95:5); ~H-NMR (CDCl3), o 7.03 (d, lH, H-3), 4.52 (br d, lH, NH), 4.224.09 (2H, OCH2CH3), 3.83 (lH, H-6a), 3.42 (lH, H-5), 2.81 (lH, H-6b), 1.43 (s, 9H, t-Bu), 1.26 (t, 3H, OCH2CH3), 1.15 (d, 3H, CH3); MS: m/z 270.
Example 5 Ethyl l-teff-butyloxycarbonyl-5-methyl-2-piperazine-carboxylate A solution of the compound ~r~al~d in Example 4 (770 mg, 2.8 mmol) and Pd(C) (10%) (200 mg) in glacial HOAc (7 ml) was hydrogenated in a Parr a~p~dlus at 60 psi for 24 hr.
The solution was filtered through Celite and concentrated in vacuo. The residue was partitioned b~,~n EtOAc and saturated aqueous NaHCO3. The organic phase was dried (MgSO4) and conc~ ed. The oily residue was purified by flash chromatography on silica gel using 1% MeOH in EtOAc as eluent ar~old~lg 370 mg (48%) of the tide compound as a 2S yellow oil.
IH-NMR (CDCl3 lo~l~ ) o 4.58, 4.40 (lH, H-2), 4.2-3.9 (2H, OCH2CH3), 3.78, 3.64 (lH, H-6a), 3.43 (lH, H-3a), 2.86 (lH, H-3b), 2.7-2.4 (2H, H-5, H-6b), 1.36, 1.42 (9H, t-Bu), 1.23-1.05 (4H, NH, OCH2CH3), 0.95 (3H, CH3); MS: m/z 272.
W O 97/07106 pcTlsE9Gloc97/
The process according to the present invention provides an economical and convenient synthetic route to a wide variety of N-mono~.u~ ,d 1, 4, 5, 6-tetrahydropyrazinederivatives and thereby to the corresponding monoprotected piperazine derivatives which in turn can be converted to a whole range of other compounds.
Claims (29)
1. A process for the preparation of a compound of the formula I
wherein R1 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;
R2 is defined as for R1, or is hydrogen, benzyl, hydroxyalkyl, or an aminoalkyl group wherein alkyl is a straight, branched or cyclic C1-C20 alkyl;
Y is OH, a group OR1 wherein R1 is as defined above, or NR3 R4 wherein R3 and R4 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 II
wherein R2 and Y are as defined above, in the presence of at least one equivalent of a C1-C20 alkoxycarbonyl-donating reagent in an inert solvent to produce a compound of the formula III
wherein R1, R2 and Y are as defined above; and ii) saturating the double bond of the compound of the formula III to produce a compound of the formula I.
wherein R1 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;
R2 is defined as for R1, or is hydrogen, benzyl, hydroxyalkyl, or an aminoalkyl group wherein alkyl is a straight, branched or cyclic C1-C20 alkyl;
Y is OH, a group OR1 wherein R1 is as defined above, or NR3 R4 wherein R3 and R4 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 II
wherein R2 and Y are as defined above, in the presence of at least one equivalent of a C1-C20 alkoxycarbonyl-donating reagent in an inert solvent to produce a compound of the formula III
wherein R1, R2 and Y are as defined above; and ii) saturating the double bond of the compound of the formula III to produce a compound of the formula I.
2. A process according to claim 1, wherein the formula (III) compound is isolated, purified and optionally further converted.
3. A process according to claim 1, wherein R1 and R2 is each and independently C1-C20 alkyl, and Y is OR1 wherein R1 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.
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.
11. 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 III 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 III.
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 R1 in a compound of the formula III 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 R1, R2 and Y are as defined in claim 1, produced by the process of claim 1.
wherein R1, R2 and Y are as defined in claim 1, produced by the process of claim 1.
26. A product according to claim 25, wherein R1 and R2 each and independently is C1-C20 alkyl, and Y is OR1 wherein R1 is C1-C20 alkyl.
27. A product according to claim 26, being ethyl 1-tert-butyloxycarbonyl-2-piperazine-carboxylate;
ethyl 1-tert-butyloxycarbonyl-4-[3-(diethylphosphonyl)-prop-2-enyl]-piperazine-2-carboxylate; or ethyl 1-tert-butyloxycarbonyl-5-methyl-2-piperazine-carboxylate.
ethyl 1-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 III
wherein R1 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;
R2 is hydrogen, phenyl or substituted phenyl, benzyl or substituted benzyl, or is a group R1 as defined above;
and Y is a straight, branched or cyclic C1-C20 alkoxy group, or NR3R4 wherein R3 and R4 each and independently are hydrogen or a group R1 as defined above, produced by the process of claim 1.
wherein R1 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;
R2 is hydrogen, phenyl or substituted phenyl, benzyl or substituted benzyl, or is a group R1 as defined above;
and Y is a straight, branched or cyclic C1-C20 alkoxy group, or NR3R4 wherein R3 and R4 each and independently are hydrogen or a group R1 as defined above, produced by the process of claim 1.
29. A product according to claim 28, being ethyl 1-tert-butyloxycarbonyl-1,4,5,6-tetrahydropyrazin-2-carboxylate; or ethyl 1-tert-butyloxycarbonyl-5-methyl-1,4,5,6-tetrahydropiperazine-2-carboxylate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9502876A SE9502876D0 (en) | 1995-08-18 | 1995-08-18 | New process |
| SE9502876-7 | 1995-08-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2228896A1 true CA2228896A1 (en) | 1997-02-27 |
Family
ID=20399215
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002228896A Abandoned CA2228896A1 (en) | 1995-08-18 | 1996-07-29 | New process for the preparation of n-monosubstituted piperazin derivatives |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0846106A2 (en) |
| AU (1) | AU6539796A (en) |
| CA (1) | CA2228896A1 (en) |
| NO (1) | NO980607D0 (en) |
| SE (1) | SE9502876D0 (en) |
| WO (1) | WO1997007106A1 (en) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4997836A (en) * | 1988-11-11 | 1991-03-05 | Takeda Chemical Industries, Ltd. | Trisubstituted piperazine compounds, their production and use |
-
1995
- 1995-08-18 SE SE9502876A patent/SE9502876D0/en unknown
-
1996
- 1996-07-29 EP EP96925241A patent/EP0846106A2/en not_active Withdrawn
- 1996-07-29 AU AU65397/96A patent/AU6539796A/en not_active Abandoned
- 1996-07-29 CA CA002228896A patent/CA2228896A1/en not_active Abandoned
- 1996-07-29 WO PCT/SE1996/000977 patent/WO1997007106A1/en not_active Application Discontinuation
-
1998
- 1998-02-12 NO NO980607A patent/NO980607D0/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU6539796A (en) | 1997-03-12 |
| WO1997007106A1 (en) | 1997-02-27 |
| SE9502876D0 (en) | 1995-08-18 |
| NO980607L (en) | 1998-02-12 |
| NO980607D0 (en) | 1998-02-12 |
| EP0846106A2 (en) | 1998-06-10 |
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