2- -1,2,3,6,7,116-hexahydro 4//-pyrazino isoquinoline

A related substance of quinapril, 3-methyl-a-(2-phenylethyl)-l,4-dioxo-1,3,4,6,11,1 lfl-hexahydro-2//-pyrazino[l,2-A]isoquinoline-2-acetic acid, was determined by a HPLC method in drug substance (00MI55). 

Structure of 4//-pyrido[l,2-a]pyrazines 348-350 was confirmed by X-ray investigations (99JPR332). The stereostructure of 1,3,4,6,1 l,lla-hexahydro-2/f-pyrazino[l,2-A]isoquinoline-l,4-dione 351 was determined by X-ray investigation (01TL543). 

Reduction of a 7-(2-oxoethyl) derivative with NaBH4 in EtOH at room temperature gave 7-(2-hydroxyethyl)-2-(2-pyrimidinyl)perhydropyrido[l, 2-u]pyrazine (99MIP6). Reduction of 7-formyl-8-[(4-cyanophenyl)methoxy]-1,3,4,6,11,1 lu-hexahydro-2//-pyrazino[l,2-A]isoquinoline-l,4-dione with NaBH4 yielded a 7-hydroxymethyl derivative (98MIP7). 

The side chain C=C double bond of 2,3,4,6,ll,lln-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones 354 was saturated by catalytic hydrogenation over Pd/C catalysts in EtOH to give 355 (98MIP7). 7-(2-Pyridylmethyl)amino derivative was obtained by reduction of 7-[(2-pyridylmethylene)amino]-2,3,11,11 n-tetrahydro-6//-pyrazino[l, 2-i]isoqui-noline-l,4-dione (356) with NaBH4 in EtOH at ambient temperature for 24 h. 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

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. 

Treatment of 8-[(4-cyanophenyl)methoxy]-7-formyl-2-cyclopentyl-2,3,4,6,11,1 la-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-dione with (Et0)2P(0)CH2C00Et and NaH in THF at 40 °C overnight, or with (2-pyridylmethyl)-, 4-[(ethoxycarbonyl)benzyl]-, (4-nitrobenzyl)-, and (meth-oxymethyl)triphenylphosphonium halogenide in the presence of KH in THF at room temperature gave 7-ethylene derivatives 386 (98MIP7). 

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). 

Stereostructures of a co-crystal of (li )-l- 4-[(9aA)-perhydropyrido[l,2- ]pyrazin-2-yl]phenyl -2-phenyl-7-hydroxy-l, 2,3,4-tetrahydroisoquinoline with ERa-LBD301-553/C — S triple mutant <2005JME364> and iV-[2-(4-hydroxyphenyl)ethyl]-a-propyl-3-[(4-hydroxyphenyl)methyl]-l,4-dioxo-l,2,3,4,ll,l la-hexahydro-67/-pyrazino[l,2- ]isoquinoline-3-acetamide with fructose-1,6-biphosphatase <2003JBC51176> were determined by X-ray crystallography. The structure of a complex formed from 3-[( -methylphenyl)amino]-4-[(4-methylphenyl)imino]-4//-pyrido[l,2-tf]pyrazine with sodium bis(trimethylsilyl)amide and (norbornadiene)Mo(CO)4 in THF was characterized by single crystal X-ray diffraction <1995JPR38>. 

Structures of 3-[(4-methylphenyl)amino]-47/-pyrido[l,2-tf]pyrazine-4-thione, iV-tosyl-3-[(4-methylphenyl)a-mino]-4//-pyrido[l,2-tf]pyrazine 4-imine, and 246 were confirmed by X-ray investigations <1999JPR332>. The stereostructures of (4A,llaA)-lla-ethoxycarbonylT,3,4,6,lla-hexahydro-l,3,4,6,ll,lla-hexahydro-4-methox-ycarbonyl-l-oxo-[l,4]oxazino[4,3-A isoquinoline <1995ZK787>, 2//-pyrazino[l,2- ]isoquinolinc-l,4-dione 247 <2001TL543>, 4-benzyl-2-methyl-1,3,4,6,7,11 b-hcxahydro-2//-pyrazino[2,l -zz] isoqu incline-3,6-dione... 

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