Pyrimidine hexahydro derivatives

Characteristic H NMR data of (4a/ ,55)- and (4n5,5R)-2-substituted 5- [A-(/e/ /-butoxycarbonyl)-L-tryptophyl]amino perhydropyrido[l,2-c]pyri-midine-l,3-diones were tabulated (01JMC2219). C CPMASS NMR data of 4-(4-methoxyphenyl)perhydropyrido[l,2-c]pyrimidine were reported (00JST73). C NMR data were reported for eight 4-aryl-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidin-l,3-diones in the solid state and in CDCI3 solution (00JPO213). The structure of 4-aryl-3,4-dihydro-2//-pyrido [l,2-c]pyrimidine-l,3-diones and their 2,3,5,6,7,8-hexahydro derivatives were characterized by H and C NMR data (99JHC389). Conformational analysis of 6-methyl-2,3,4,6,7,ll/)-hexahydro-l//-pyrimido[6,l-n]isoquino-lin-2-ones 138 and 139 were carried out by H and C NMR studies (97LA1165). 

Attempts to reduce the quaternary salts of 4-oxo-4//-pyrido[l,2-a]-pyrimidines with sodium borohydride or lithium aluminum hydride remained unsuccessful.137 At the same time the 6,7,8,9-tetrahydro quaternary salts may readily be reduced with sodium borohydride to the 1-alkyl-l,6,7,8,9,9a-hexahydro derivatives.75-77,133 1481269 270 Sodium borohydride reduction of the 1,6- and l,7-dimethyl-3-carbamoyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[l,2-a]pyrimidinium salts proceeds stereoselectively and yields the thermodynamically controlled product.271 The l-methyl-3-carbamoyl-4-oxo-l,6,7,8,9,9a-hexahydropyrido[l,2-a]pyrimidines were also prepared by the catalytic (Pd/C) hydrogenation of the 1,6,7,8-tetrahydro derivatives,270-272 but this reaction led to a diastereoisomeric mixture.271... 

The UV,117 350 353354 luminescence,355 ESCA,356 IR,117 354,357 H-NMR,117,358 and 13C-NMR358 spectral behavior of 4-oxo-4//-pyrido-[l,2- ]pyrimidines and their tetrahydro and hexahydro derivatives is well documented. 

The octanol-water (pH 5) partition coefficients of alkyl-substituted 4H-pyrido[l,2-a]pyrimidines-4-ones 10 and 11, 3-phenyl and 3-ester derivatives (R2 = Ph, COOEt), and some tetra- and hexahydro derivatives were determined by the classical shake-flask technique at ambient temperature (81MI4 82MI9). Hansch-type 7r values of the substituent (R-R2) were also calculated. The apparent octanol-water partition coefficients of seg-anserine 6 and its 7-methyl derivative were measured (88MI14). The pAa values and apparent octanol-water partition coefficients (at pH 7.4) of risperidone 7 (92MI20, 92MI30), its 9-hydroxy derivative (92MI30), and ocaperidone 8 were reported (92MI20). 

Starting from a pyrimidine, sodium borohydride reduces the C=N bond in various 1,2,5,6-tetrahydropyrimidines to the hexahydro derivative <79RTC282>. Overreduction can be seen because C2 in the product, the hexahydropyrimidine, is an aminal carbon with the possibility for a dynamic equilibrium with imine and immonium forms which may be reduced to propane-1,3-diamines either by catalytic hydrogenation or by metal hydrides in the formation of an open-chain 1,3-diamine <67AJC1643, 68JA771>. 

Perhydropyrido[l,2-a]pyrimidin-2-one was A -alkylated with 1,4-dibro-mobutane to yield a 1-(4-bromobutyl) derivative (94MIP6). 6-Methyl-4-oxo-4/f-],6,7,8,9,9a-hexahydro-4//-pyrido[],2-a]pyrimidine-3-carboxylate 138 was alkylated with alkyl chlorides 139 to give 1-substituted derivatives 140 (97MIP2). 

Semiempirical PM 3 MO calculations were performed on eight 4-aryl-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidin-l,3-diones and on their dimers (00JPO213). In all of the calculated structures the aromatic ring is almost perpendicular to the plane of the pyrido[l,2-c]pyrimidin-l,3-dione fragment, which is in accordance with the X-ray data for 4-(4-methylphenyl) derivative. 

Reaction of 4-cyano-3-imino-2,3,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyr-imidin-l-one 169 with 2-chloroethyl isocyanate at ambient temperature and under reflux gave N-acylated 170 and tetracyclic derivative 171, respectively (95MI1). Similar reaction of 3-amino-4-cyano-2,4a5,6,7,8-hexahydro-l// pyrido[l,2-c]pyrimidin-1-ones 172 afforded tricyclic compounds 173. 

The bromine atom of 4-aryl-2-(4-bromobutyl)-2,3,5,6,7,8-hexahydro-177- ancj -perhydropyrido[l,2-c]pyrimidine-l,3-diones was displaced with 4-substituted piperazines <2002FES959, 2004APH139, 2004PHA99>. Heating 3-hydroxymethyl derivatives of epimeric 6-methyl-l,3,4,6,7,llb-hexahydro-277-pyrimido[6,l-,2]isoquinolin-2-ones 152 resulted in the formation of the 3-unsubstituted derivatives 153 by loss of CH20 (Equation 26) <1997LA1165>. 

Methyl-4-oxo-47/-l,6,7,8,9,9a-hexahydro-47/-pyrido[l,2- ]pyrimidine-3-carboxylate has been N-alkylated <1997WO97/007116>. l-(Hetaryl) derivatives were prepared from l,2,3,4-tetrahydro-67/-pyrido[l,2-tf]pyrimidin-6-ones... 

A series of 6- and 7-aciylamide derivatives of 4-(phenylamino)-quinazoline and 4-(phenylainino)-pyridopyrimidine, classes of epidermal growth factor receptor (EGER) inhibitors, have been prepared from the corresponding amino compounds by reaction with actoyl chloride/base <99JMC1803>. Reaction of thionyl chloride with hexahydro-7-methyl-pyrimido[l,6-a]-pyrimidine-6,8-dione yields the corresponding 9,9 -thiobispyriiiudopyrimidine derivative <99JHC453>. 

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