1.2.4.6.7.116- Hexahydro isoquinoline

Potassium tetrahydridoborate 1,2,3,4,5,6,7,8-Octahydro-from 3,4,5,6,7,8-hexahydro-isoquinolines... 

Many hydantoins are endowed with significant pharmacological activities as highlighted by 5,5-diphenylhydantoin (Dilantin ), an anticonvulsant and antiepileptic discovered by Parke-Davis in 1940 s. Despite the lapse of more than half a century, Dilantin still plays an important rote in modem medicine. Meanwhile, another anticonvulsant 15 was synthesized from 9,10-dimethoxy-l,3,4,6,7,llb-hexahydro-pyrido[2,l-a]isoquinolin-2-one (14) under the standard Bucherer-Lieb variation in a 2 1 water-ethanol solution (15a 15b = 8 l). ... 

Conformational studies of c/5-6,11/)-H- and /rnns-6,ll/)-H-6-methyl-2,3,4,6,7,1 l/)-hexahydro-l//-pyrimido[6,l-n]isoquinolin-2-ones (136 and 137) by means of the MM2 method implemented in the HyperChem 4.5 suggested, that in the lowest-energy conformations heterocyclic moiety adopted trans-fu ed ring annotation in both cases, with a pseudo-equatorial and -axial methyl group, respectively (97LA1165). 

The mass spectral fragmentations of 9,10-dimethoxy-2,3,4,6,7,ll/)-hexa-hydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140 and -2,4-diones 141, under electron ionization (at 70 eV) were examined by metastable ion analysis, a collosion-induced dissociation technique and exact mass measurement (97RCM1879). Methyl substituent on N(3) in 140 (R = Me) had a larger effect on both the fragmentation and on the peak intensities, than a methyl substituent on C(6) (R = Me). The ionized molecules of 140 (R = H) were rather stable, whereas 4-phenyl substitution on C(4) of 140 (R = Ph) promoted the fragmentations of the molecular ions. The hexahydro-1//-pyrimido[6,l-n]isoquinoline-2,4-diones 141 were more stable, than the hexahydro-l//-pyrimido[6,l-n]isoquinolin-2-ones 140, and the molecular ions formed base peaks. 

Heating 3-hydroxymethyl derivative of epimeric 6-methyl-l,3,4,6,7,l l/>-hexahydro-2//-pyrimido[6,l-n]isoquinolin-2-ones 151 resulted in the formation of 3-unsubstituted derivatives 152 by loss of CH2O (97LA1165). 

Reactions of 3-methyl-1,2,3,4-tetrahydroisoquinoline-1-acetamides 202 (R = H) with 36% aqueous CH2O at 60 °C gave 1,3,4,6,7,1 Ih-hexahydro-2//-pyrimido[6,l-a]isoquinolin-2-ones 152 and their 3-methyl derivatives (97LA1165). When the reaction was carried out in the presence of 37% aqueous NaOH 3-hydroxymethyl derivatives 151 were obtained. Reactions with PhCHO were stereospecific to afford only diastereomers 203. 

Reduction of 8-nitro-l,3,4,6,l 1,1 la-hexahydro[l,4]oxazino[4,3-/)]isoqui-nolin-4-one with BH3 in THF afforded 8-nitro-1,3,4,6,11,1 la-hexahydro [l,4]oxazino[4,3-/)]isoquinoline (97MIP4). Then the nitro group was reduced by catalytic hydrogenation over 5% Pd/C catalyst in acidified MeOH to yield 8-amino derivative. Catalytic hydrogenation of 3-nitro-6,6a,7,... 

Alkoxy-3-(4-biphenyl)perhydropyrido[], 2-c][], 4]oxazines were obtained from 3-hydroxy derivative with PrOH and Br(CH2)30H in a boiling acidified medium (00JMC609, 00MIP13). Spontaneous dehydration of b-hydroxy-1,3,4,6,7,1 lZ -hexahydro[l,4]oxazino[3,4-n]isoquinolin-4-one 258 in CHCI3 gave 3,4,6,7-tetrahydro derivative 259 (97JOC2080). 

The amino group of 8-amino-l,3,4,6,l 1,1 ln-hexahydro[l,4]oxazino[4,3-Z ] isoquinoline was reacted with 5-methyl-2-thiophenecarboximide hydroiodide in DMSO in the presence of pyridine at 50 °C for 4 h to give amidine 260 (X = 0) in 94% yield (97MIP4). 

Cyclization of amide 312 by treatment with TFA gave 1 li-butyl-1,3, 4,6,7,1 l -hexahydro[l,4]oxazino[3,4-a]isoquinolin-4-one 313 (97JOC2080). 

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. 

Nitration of 2-cyclohexyl-8-hydroxy-2,3,4,6,11,11 u-hexahydro-1 //-pyra-zino[l,2-6]isoquinoline-l,4-dione with 70% HNO3 at room temperature for 30 min afforded an 1 1 mixture of 7- and 9-nitro derivatives (98MIP7). 

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. 

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