Claims (21)
1. Postupak za sintezu enantiomera Pirlindola formule II ili III
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ili njegove farmaceutski prihvatljive soli, sadrži slijedeće korake:
dovođenje u reakciju spoja formule VI (S)-6-metil-N-((S)-1-feniletil)-2,3,4,9-tetrahidro-1H-karbazol-1- amina ili spoja formule VIII (R)-6-metil-N-((R)-1-feniletil)-2,3,4,9-tetrahidro-1H-karbazol-1-amina,
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i acilaciju spoja formule XII
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pri čemu
L1 je izlazna skupina odabrana između —Br, -Cl, -OTs, -OMs, OH, —OR1, -OCOR1 ili imidazola,
R1 je vodik, C1-C6 alkil lanac ili aril, u prvom aprotonskom otapalu, u prisutnosti alkalnog sredstva da bi se dobio prinos spoja formule X, 2-supstituiran N-((S)-6-metil-2,3,4,9-tetrahidro-1H-karbazol-1-il)-N-((S)-1-feniletil)acetamid ili spoj formule XI, 2-supstituiran N-((R)-6-metil-2,3,4,9-tetrahidro-1H-karbazol-1-il)-N-((R)-1-feniletil)acetamid
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intramolekularna indol acetamid ciklizacija spoja formule X ili spoja formule XI pri čemu L2 je izlazna skupina odabrana između —Br, -Cl, -I, -OTs, -OMs, -OH, —OR1, u drugom aprotonskom otapalu, u prisutnosti alkalnog sredstva i katalizator faze transfera da bi se dobilo kao prinos spoja formule IV, (S)-8-metil-3-((S)-1-feniletil)-3a,4,5,6-tetrahidro-1H-pirazino[3,2,1-jk]karbazol-2(3H)-on ili spoj formule XIV (R)-8-metil-3-((R)-1-feniletil)-3a,4,5,6-tetrahidro-1H-pirazino[3,2,1-jk]karbazol-2(3H)-on
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reduciranje laktamskog prstena spoja formule IV ili spoja formule XIV u spoj formule V ili spoj formule IX, prema opisanom redoslijedu, u trećem aprotonskom otapalu, u prisustvu redukcijskog sredstva
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i
katalitička hidrogenoliza ili cijepanje kiselim fenolom da bi se dobili kao prinos enantiomeri Pirlindola iz formule II ili III ili njegove farmaceutski prihvatljive soli.1. Process for the synthesis of Pirlindole enantiomers of formula II or III
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or its pharmaceutically acceptable salts, contains the following steps:
reacting the compound of formula VI (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine or the compound of formula VIII (R) -6-methyl-N-((R)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine,
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and acylation of the compound of formula XII
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whereby
L1 is a leaving group selected from —Br, —Cl, —OTs, —OMs, OH, —OR1, —OCOR1 or imidazole,
R1 is hydrogen, a C1-C6 alkyl chain or aryl, in a first aprotic solvent, in the presence of an alkaline agent to yield a compound of formula X, 2-substituted N-((S)-6-methyl-2,3,4, 9-tetrahydro-1H-carbazol-1-yl)-N-((S)-1-phenylethyl)acetamide or compound of formula XI, 2-substituted N-((R)-6-methyl-2,3,4, 9-tetrahydro-1H-carbazol-1-yl)-N-((R)-1-phenylethyl)acetamide
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intramolecular indole acetamide cyclization of a compound of formula X or a compound of formula XI wherein L2 is a leaving group selected from —Br, —Cl, —I, —OTs, —OMs, —OH, —OR1, in another aprotic solvent, in the presence of an alkaline agent and phase transfer catalyst to give as a yield compound of formula IV, (S)-8-methyl-3-((S)-1-phenylethyl)-3a,4,5,6-tetrahydro-1H-pyrazino[3,2 ,1-jk]carbazol-2(3H)-one or compound of formula XIV (R)-8-methyl-3-((R)-1-phenylethyl)-3a,4,5,6-tetrahydro-1H-pyrazino [3,2,1-jk]carbazol-2(3H)-one
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reduction of the lactam ring of a compound of formula IV or a compound of formula XIV to a compound of formula V or a compound of formula IX, according to the described order, in a third aprotic solvent, in the presence of a reducing agent
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and
catalytic hydrogenolysis or cleavage with acidic phenol to yield enantiomers of Pirlindole of formula II or III or a pharmaceutically acceptable salt thereof.
2. Postupak sukladno prethodnom patentnom zahtjevu pri čemu je to alkalno sredstvo odabrano između tercijarnog organskog amina, karbonata soli alkalnog metala, bikarbonata soli alkalnog metala, ili soli alkalnog metala.2. The method according to the previous patent claim, wherein the alkaline agent is selected from a tertiary organic amine, an alkali metal salt carbonate, an alkali metal salt bicarbonate, or an alkali metal salt.
3. Postupak sukladno prethodnom patentnom zahtjevu pri čemu je tercijarni organski amin piridin ili trimetilamin.3. Process according to the previous patent claim, wherein the tertiary organic amine is pyridine or trimethylamine.
4. Postupak sukladno patentnom zahtjevu 2 pri čemu je karbonat soli alkalnog metala kalijev karbonat ili natrijev karbonat, bikarbonat soli alkalnog metala je natrijev bikarbonat ili kalijev bikarbonat, sol alkalnog metala je natrijev hidroksid ili kalijev hidroksid.4. Process according to patent claim 2, wherein the carbonate of the alkali metal salt is potassium carbonate or sodium carbonate, the bicarbonate of the alkali metal salt is sodium bicarbonate or potassium bicarbonate, the alkali metal salt is sodium hydroxide or potassium hydroxide.
5. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je alkalno sredstvo natrijev hidroksid, posebno alkalno sredstvo je 50% (tež/ob) vodenasta otopina natrijevog hidroksida.5. The process according to any of the previous patent claims, wherein the alkaline agent is sodium hydroxide, especially the alkaline agent is a 50% (w/v) aqueous solution of sodium hydroxide.
6. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je prvo aprotonsko otapalo i drugo aprotonsko otapalo neovisno odabrani između kloroforma, diklorometana, dimetoksietana, dietil eter ili toluena, poželjno prvo aprotonsko otapalo je toluen, poželjno drugo aprotonsko otapalo je toluen.6. The method according to any of the preceding claims, wherein the first aprotic solvent and the second aprotic solvent are independently selected from chloroform, dichloromethane, dimethoxyethane, diethyl ether or toluene, preferably the first aprotic solvent is toluene, preferably the second aprotic solvent is toluene.
7. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je treće aprotonsko otapalo odabrano između diklorometana, tetrahidrofurana, dietil etera ili toluena, poželjno treće aprotonsko otapalo je tetrahidrofuran.7. The method according to any of the previous patent claims, wherein the third aprotic solvent is selected from dichloromethane, tetrahydrofuran, diethyl ether or toluene, preferably the third aprotic solvent is tetrahydrofuran.
8. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri je čemu L1—Cl, L2 je —Cl.8. The process according to any of the preceding claims wherein L1 is —Cl, L2 is —Cl.
9. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je R1 alkilni lanac.9. Process according to any of the preceding claims, wherein R1 is an alkyl chain.
10. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je molarni odnos između alkalnog sredstva: spoju formule VI ili VIII: spoju formule XII između 1:1:1 i 15:1:4, poželjno molarni odnos između alkalnog sredstva: spojevi formula VI ili VIII: spoju formule XII je 10:1:3.10. Process according to any of the preceding patent claims, wherein the molar ratio between the alkaline agent: the compound of formula VI or VIII: the compound of formula XII is between 1:1:1 and 15:1:4, preferably the molar ratio between the alkaline agent: compounds of the formula VI or VIII: to the compound of formula XII is 10:1:3.
11. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je molarni odnos između alkalnog sredstva: spoju formule X ili XI: katalizatoru faze transfera je između 1:1:0,005 i 15:1:0,1, poželjno molarni odnos između alkalnog sredstva: spoju formula X ili XI: katalizatoru faze transfera je 10:1:0,01.11. The process according to any of the preceding claims, wherein the molar ratio between the alkaline agent: the compound of formula X or XI: the phase transfer catalyst is between 1:1:0.005 and 15:1:0.1, preferably the molar ratio between the alkaline agent : compound of formula X or XI: phase transfer catalyst is 10:1:0.01.
12. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je molarni odnos između redukcijskog sredstva: spoju formule IV ili spoju formule XIV, je između 1:1 i 4:1, poželjno molarni odnos između redukcijskog sredstva: spoju formule IV ili spoju formule XIV, je 3,3:1.12. The process according to any of the preceding claims, wherein the molar ratio between the reducing agent: the compound of formula IV or the compound of formula XIV is between 1:1 and 4:1, preferably the molar ratio between the reducing agent: the compound of formula IV or the compound of formula XIV, is 3.3:1.
13. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se redukcijsko sredstvo izabire od kompleksa litijevog aluminij hidrida (LiAlH4), diizobutilaluminijevog hidrida (Dibal-H), aluminijevog hidrida (AlH3), natrijevog bis(2-metoksietoksi)aluminijevog hidrida ili kompleksa boran tetrahidrofurana (THF), poželjno natrijevog bis(2-metoksietoksi)aluminijevog hidrida.13. The method according to any of the previous patent claims, wherein the reducing agent is selected from lithium aluminum hydride complex (LiAlH4), diisobutylaluminum hydride (Dibal-H), aluminum hydride (AlH3), sodium bis(2-methoxyethoxy)aluminum hydride or complex of borane tetrahydrofuran (THF), preferably sodium bis(2-methoxyethoxy)aluminum hydride.
14. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je katalizator faze transfera halogena sol kvaternarnog amonijaka odabrana od tetrabutil amonijak bromida, tetraetil amonijak bromida, benziltributil amonijak bromida, tetrabutil amonijak hidrogen sulfata i benziltributil amonijak klorida, poželjno je da je katalizator faze transfera tetrabutil amonijak bromid.14. The method according to any of the preceding patent claims, wherein the halogen transfer phase catalyst is a quaternary ammonium salt selected from tetrabutyl ammonia bromide, tetraethyl ammonia bromide, benzyltributyl ammonia bromide, tetrabutyl ammonia hydrogen sulfate and benzyltributyl ammonia chloride, it is preferable that the transfer phase catalyst is tetrabutyl ammonia bromide.
15. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva pri čemu je acilacirajući spoj XII kloroacetil klorid.15. The process according to any of the preceding claims, wherein the acylating compound XII is chloroacetyl chloride.
16. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu je farmaceutski prihvatljiva sol Pirlindol enatiomera II ili III sol acetata, sol hidroklorida, sol hidrobromida, sol mandelata, sol citrata, sol sukcinata, sol tartrata, sol malonata, sol maleata, sol metansulfonata, sol laktata, sol etansulfonata, sol glutamata ili sol fosfata.16. The method according to any of the preceding patent claims, wherein the pharmaceutically acceptable salt of Pirlindole enantiomer II or III is an acetate salt, a hydrochloride salt, a hydrobromide salt, a mandelate salt, a citrate salt, a succinate salt, a tartrate salt, a malonate salt, a maleate salt, methanesulfonate, lactate salt, ethanesulfonate salt, glutamate salt or phosphate salt.
17. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se katalitička hidrogenoliza provodi na 20-70 °C, poželjno 50 °C.17. The process according to any of the preceding patent claims, wherein the catalytic hydrogenolysis is carried out at 20-70 °C, preferably 50 °C.
18. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se katalitička hidrogenoliza provodi tokom 2-8 sati, poželjno 5 sati.18. The method according to any of the previous patent claims, wherein the catalytic hydrogenolysis is carried out during 2-8 hours, preferably 5 hours.
19. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se katalitička hidrogenoliza provodi s tlakom vodika između 500 -2000 KPa, poželjnije 700 KPa.19. The method according to any of the previous patent claims, wherein the catalytic hydrogenolysis is carried out with a hydrogen pressure between 500 -2000 KPa, preferably 700 KPa.
20. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se katalitička hidrogenoliza provodi na 20-70 °C, tokom 2-8 sati i s tlakom vodika između 500 KPa - 2000 KPa.20. The process according to any of the previous patent claims, wherein the catalytic hydrogenolysis is carried out at 20-70 °C, during 2-8 hours and with a hydrogen pressure between 500 KPa - 2000 KPa.
21. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se katalitička hidrogenoliza provodi sa zakiseljenom smjesom otapala odabranog između etilacetata, dimetil formamida, metanola, etanola, izopropanola i diklorometana, poželjno da je zakiseljena smjesa otapala mješavina protonskog otapala s diklorometanom, poželjnije metanola sa diklorometanom.21. The method according to any of the previous patent claims, wherein the catalytic hydrogenolysis is carried out with an acidified solvent mixture selected from ethyl acetate, dimethyl formamide, methanol, ethanol, isopropanol and dichloromethane, preferably the acidified solvent mixture is a mixture of a protonic solvent with dichloromethane, preferably methanol with dichloromethane.