Claims (14)
1. Postupak za sintezu enantiomera pirlindola iz formule II i III
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ili njegove farmaceutski prihvatljive soli, sadrži korake:
ciklizacije između spoja formule VI (S)-6-metil-N-((S)-1-feniletil)-2,3,4,9-tetrahidro-1H-karbazol-1-amina ili njegovog spoj enantiomera od formule VIII (R)-6-metil-N-((R)-1-feniletil)-2,3,4,9-tetrahidro-1H-karbazol-1-amina
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i spoj od formule X
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pri čemu L je izlazna skupina izabrana od -OTs, -OMs, -OTf, -Cl ili -Br, -I u 1,3-dimetil-2-imidazolidinonu (DMI), u prisustvu pogodnog alkalnog sredstva da bi se dobio prinos (S)-8-metil-3-((S)-1-feniletil)-2,3,3a,4,5,6-heksahidro-1H-pirazino[3,2,1-jk]karbazol VII ili enantiomer (R)-8-metil-3-((R)-1-feniletil)-2,3,3a,4,5,6-heksahidro-1H- pirazino[3,2,1-jk]karbazol IX
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i podvrgavanje spoja formule VII ili IX katalitičkoj hidrogenolizi da bi se dobio prinos enantiomera pirlindola formule II ili III ili njegovih farmaceutski prihvatljivih soli.1. Process for the synthesis of pyrlindole enantiomers from formulas II and III
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or its pharmaceutically acceptable salts, contains the steps:
cyclization between the compound of formula VI (S)-6-methyl-N-((S)-1-phenylethyl)-2,3,4,9-tetrahydro-1H-carbazol-1-amine or its enantiomer 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 a compound of formula X
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wherein L is a leaving group selected from -OTs, -OMs, -OTf, -Cl or -Br, -I in 1,3-dimethyl-2-imidazolidinone (DMI), in the presence of a suitable alkaline agent to yield ( S)-8-methyl-3-((S)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole VII or enantiomer ( R)-8-methyl-3-((R)-1-phenylethyl)-2,3,3a,4,5,6-hexahydro-1H-pyrazino[3,2,1-jk]carbazole IX
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and subjecting the compound of formula VII or IX to catalytic hydrogenolysis to yield a pyrlindole enantiomer of formula II or III or a pharmaceutically acceptable salt thereof.
2. Postupak sukladno patentnom zahtjevu 1, pri čemu molarni odnos pogodnog alkalnog sredstva: međuproizvoda VI ili VIII: spoj formule X je od 1:1:1 do 5:1:3.2. Process according to claim 1, wherein the molar ratio of a suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 1:1:1 to 5:1:3.
3. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu molarni odnos pogodnog alkalnog sredstva: međuproizvoda VI ili VIII: spoj formule X je od 1,2:1:1 do 5:1:3.3. The process according to any of the preceding patent claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 1.2:1:1 to 5:1:3.
4. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu molarni odnos pogodnog alkalnog sredstva: međuproizvoda VI ili VIII: spoj formule X je od 2,2:1:1,2 do 4:1:2.4. The process according to any of the preceding patent claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 2.2:1:1.2 to 4:1:2.
5. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu molarni odnos pogodnog alkalnog sredstva: međuproizvoda VI ili VIII: spoju formule X je od 3:1:1,2 do 4:1:1,5.5. The process according to any of the preceding patent claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 3:1:1.2 to 4:1:1.5.
6. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu molarni odnos pogodnog alkalnog sredstva: međuproizvoda VI ili VIII: spoj formule X je od 3:1:1,2 do 4:1:1,2.6. The process according to any of the preceding patent claims, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is from 3:1:1.2 to 4:1:1.2.
7. Postupak sukladno patentnom zahtjevu 1-4, pri čemu molarni odnos pogodnog alkalnog sredstva: međuproizvoda VI ili VIII: spoj formule X je 4:1:2.7. Process according to claim 1-4, wherein the molar ratio of suitable alkaline agent: intermediate VI or VIII: compound of formula X is 4:1:2.
8. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu je pogodno alkalno sredstvo natrijev hidrid.8. The process according to any of the preceding claims, wherein the suitable alkaline agent is sodium hydride.
9. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu spoj formule X je etan-1,2-diil bis(4-metilbenzensulfonat).9. Process according to any of the preceding patent claims, wherein the compound of formula X is ethane-1,2-diyl bis(4-methylbenzenesulfonate).
10. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu farmaceutski prihvatljiva sol je sol acetata, hidrokloridna sol, hidrobromidna sol, sol mandelata, sol citrata, sol sukcinata, sol tartrata, sol malonata, sol maleata, sol metansulfonata, sol laktata, sol etansulfonata, sol glutamata ili sol fosfata.10. The method according to any of the preceding patent claims, wherein the pharmaceutically acceptable salt 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, a methanesulfonate salt, a lactate salt, ethanesulfonate salt, glutamate salt or phosphate salt.
11. Postupak sukladno patentnom zahtjevu 10, pri čemu farmaceutski prihvatljiva sol je sol hidrohlorida ili sol metansulfonata.11. The method according to patent claim 10, wherein the pharmaceutically acceptable salt is a hydrochloride salt or a methanesulfonate salt.
12. Postupak sukladno patentnom zahtjevu 10, pri čemu farmaceutski prihvatljiva sol je sol laktata, sol etansulfonata, sol mandelata, sol citrata ili sol sukcinata.12. The method according to claim 10, wherein the pharmaceutically acceptable salt is a lactate salt, an ethanesulfonate salt, a mandelate salt, a citrate salt or a succinate salt.
13. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se korak ciklizacije provodi na temperaturama između 50 °C i 120 °C, poželjno na 60 °C.13. The process according to any of the preceding patent claims, wherein the cyclization step is carried out at temperatures between 50 °C and 120 °C, preferably at 60 °C.
14. Postupak sukladno bilo kojem od prethodnih patentnih zahtjeva, pri čemu se katalitička hidrogenoliza provodi na 20-70 °C, poželjno tokom 2-8 sati i s tlakom vodika između 500-2000 KPa.14. The process according to any of the previous patent claims, wherein the catalytic hydrogenolysis is carried out at 20-70 °C, preferably for 2-8 hours and with a hydrogen pressure between 500-2000 KPa.