Hexahydro-1 H-pyrazino

NMR ROESY experiments indicated molecular proximities (<5 A) between hydrogens 10, 11, and 12 of the aromatic ring of praziquantel and hydrogen H-3 and H-5, in the internal cavity of p-cyclodextrin (06JPB1428). Rotamers of 2-acyl-1,3,4,6,7,11 b-hexahydro-1 H-pyrazino [l,2-a]isoquinolin-4-ones were identified and analyzed by [H and 13C NMR spectroscopy (08EJO895). Commercial praziquantel tablets were analyzed by NMR spectroscopy (07JPB263). 

L5530), (11 W ,2 R)-2-(2 -phenyl-2 methoxy-2 -trifluoromethylacetyl)-1,3,4/6,7/11 b-hexahydro-1 H-pyrazino[l,2-flJisoquinolin-4-one (08EJO895), 2-aminopyrido[l,2-fl]quinoxalinium perchlorate and its thiocyanate monohydrate (08IC9122) were determined by X-ray diffraction studies. 

Cyclization of tetrahydroisoquinoline 284 in the presence of ZnCl2 and MeaSiCN in CF3CH2OH at 23 °C for 1 h afforded three diastereomeric 2,3,4,6,11,1 la-hexahydro-1 /d-pyrazino[l,2-bJ isoquinolines 242 (44%), 243 (12%), and 244 (15%) besides tetracyclic derivative 246 (18%) (05JA16796). A fourth diastereomer 245 (19%) could also be isolated from the reaction mixture after a longer reaction period, 12 h. 

Chloro-, 7-bromo- and 7-iodo derivatives were prepared from 2-cycloalkyl-8-hydroxy-2,3,4,6,11,11 u-hexahydro-1 //-pyrazino[l, 2-6]isoqui-noline-l,4-diones by treatment with NCS and NBS in DMF at 70°C for 24 h, with ICl in diluted HCl at 90 °C for 16h, respectively (98MIP7). 

Aminothiocarbonylphenyl)methoxy] derivative 384 was obtained from 8-[(4-cyanophenyl)methoxy]-2-cyclohexy 1-2,3,4,6,11,11 a-hexahydro-l/7-pyrazino[l,2-i]isoquinoline-l,4-dione by treatment with (EtO)2P(S)SH and one drop of H2O at room temperature for 17 h, then followed by addition of more H2O (98MIP7). Reaction of 8-[(4-aminothiocarbonylphe-nyl)methoxy] derivative 384 and MeCOCH2Cl yielded 8- [4-(4-methylthia-zol-2-yl)phenyl]methoxy derivative 385. 7-Bromomethyl derivative was prepared from the 8-hydroxymethyl-8-[(4-cyanophenyl)methoxy]-2-cyclo-pentyl-2,3,4,6,11,1 la-hexahydro-177-pyrazino[l, 2-i]isoquinoline-1,4-dione with PBr3 in CH2CI2 at room temperature. 7-[(l-Pyrazolyl)methyl] derivative was obtained from 7-bromomethyl derivative by treatment with pyrazole in the presence of NaH in DMF at 50 °C. 

Krapcho decarbomethoxylation of diester 216 provided monoester 217 (06SL1691). Chemoselective Swern oxidation of 3-(3-hydroxypropyl)-1,2,3,4,11, 1 lrt-hexahydro-6/T-pyrazino[l,2-fr]isoquinolin-4-ones 203 followed by silyl enol ether formation with TIPSOTf and Et3N in Et20 for 12 h at room temperature gave compounds 218 as a single isomer in excellent yields (08JA7148,09JOC2046). 

Cyclocondensation of 2-(2-chloroacetyl)-l, 2,3,4-tetrahydroisoquinoline-3-carboxylate 418 (R =N02, R = Me) with liquid NH3 in MeOH in a stainless steel pressure vessel at room temperature overnight gave 8-nitro-2,3,4,6,1 1,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione (419, R=H, R =N02) (97MIP4). (1 la/i)-2-Cycloalkyl-8-hydroxy-2,3,4,6,ll, 1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 419 (R = cycloalkyl, R = OH) were prepared in the reactions of (3/i)-2-chloroace-tyl-l,2,3,4-tetrahydroisoquinoline-3-carboxylate (418, R = OH, R = Et) with cycloalkylamines (98MIP7). 

Treatment of tetracyclic nitrogen bridgehead compound 433 with NaCN resulted the formation of 4-cyano derivative of 1,2,3,4,1 lu-hexahydro-6//-pyrazino[l, 2-h]isoquinoline 434 (00BMC523). 

The treatment of 1,2,3,4,11,lla-hexahydro-6H-pyrazino[l,2-fc]isoqui-noline-l,4-dione 191 (R = cinnamoyl, R1 = C02 Pr) with LiAl(OfBu)3H (6 equiv.), and followed by treatment of the reaction mixture with HC02H at 80 °C, and then with TFA/H2S04 gave l,2,3,4-tetrahydro-6H-pyrazino [l,2-b]isoquinoline-l,4-dione 192 (R = H) in 62% yield (09T2201). Compound 192 (R = H) was also obtained in 82% yield from 191 (R = C02fBu, R1 = CO(Bu) when after the reduction the reaction mixture was treated with boiling TFA. When TFA was applied as acid at room temperature in the case of 191 (R = 1-naphthylcarbonyl, R1 = C02(Bu), 192 (R = 1-naphthylcarbonyl) was obtained in 70%. The treatment of the reaction mixture of 193, after reduction, with HC02H at 80 °C afforded a mixture, which contains 22% of 194. 

When 1 -hydroxy-1,2,3,4,11/1 lfl-hexahydro-6H-pyrazino[l,2-fc]isoqui-nolin-4-one 202 (R = Br, R1 = R2 = H, R3 = Me, R4 = Cbz) was treated with PhSH, instead of EtSH as a nuclephile, tetracyclic compound 249 was formed under the same conditions (08JA7148). 

Reduction of 1,2,3,4,11,1 la-hexahydro-6H-pyrazino[l, 2-b] isoquinoline-1,4-dione 250 (R = cinnamoyl, R1 = C02(Bu) with LiAlH(OfBu)3 (6 equiv.), and followed by treatment of the reaction mixture with boiling TFA gave a mixture of tricyclic 250 (R = cinnamoyl, R1 = H) and pentacylic compounds 251 (09T2201). 

Hydroxy-1, 2,3,4,11/1 lfl-hexahydro-6H-pyrazino[l,2- ]isoquinolin-4-one 204 was obtained in 83% overall yield, when tetrahydroisoquinoline-3-carboxylate 360 was reduced with LiBH4 in a mixture of MeOH and EtaO at room temperature for 4 h, followed by Swern oxidation (08JA7148). 

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