Synthesis of 6-substituted pyrimidines by the wittig reaction. I. Via 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde

Condensation of isopropyl 6-phenylhexanoate with ethyl diethoxyacetate followed by guanidine afforded 2 - amino-6-diethoxymethyl-5-phenylbutyl-4-pyrimidinol (VII). Acid hydrolysis of VII gave an excellent yield of 2-amino-4-hydroxy-5-phenylbutylpyrimidine-6-carboxaldehyde (IV); the latter could be condensed with stabilized Wittig reagents such as carbethoxymethylene triphenyl phosphorane and cinnamylidene triphenyl phosphorane, but not unstabilized Wittig reagents such as carbethoxypropylene or cyano-propylene triphenyl phosphorane. Reduction of the Wittig products afforded pyrimidines with functionalized side-chains in the 6-position such as the 6-phenylbutyl (XVIII) and 6-carboxyethyl (XV) derivatives of 2-amino-5-phenylbutyl-4-pyrimidinol.     

Synthesis of 6-substituted pyrimidines by the wittig reaction. III . Via 2-amino-4-hydroxy-5-phenylbutyl-6-pyrimidylmethyl triphenyl phosphonium bromide

2-Amino-6-bromomethyl-5-phenylbutyl-4-pyrimidinol (IV) smoothly alkylated triphenyl phosphine, resulting in a 95% yield of the phosphonium salt (V). This Wittig reagent (V) readily condensed with p-nitrobenzaldehyde, p-nitrocinnamaldehyde, or cinnamalde-hyde in N,N-dimethylformamide to give the 6-(p-nitrostyryl) (X), 6-(p-nitrophenyl-1,3-butadien-1-yl) (VIH), and 6-(phenyl-1,3-butadien-1-yl) (IX) pyrimidinols in 72, 67 and 44% yields, respectively. Catalytic reduction of VIII and IX afforded the corresponding 6-(p-aminophenylethyl) (XII) and 6-(p-aminophenylbutyl) (XI) 4-pyrimidinols.     

Folic acid analogs. III. N-(2-[2-(2,4-diarnino-6-quinazolinyl)ethyl]benzoyl)-l-glutamic acid

A trideaza analog of aminopterin, N-(4[2-(2,4-diamino-6-quinazolinyl)ethyl]benzoyl)-L-glutamic acid, was prepared by a Wittig condensation of 2,4-diaminoquinazoline-6-carboxaldehyde and [P-(N-[1,3-bis(ethoxycarbonyl)propan-1-yl]aminocarbonyl)phenylmethyl]triphenylphosphonium bromide followed by catalytic reduction and mild hydrolysis. This compound was found to have confirmed inhibitory activity against leukemia L1210 in mice.     

Synthesis of aldehyde and carboxylic acid derivatives from 2-hydroxymethyl-3-hydroxy-4H-pyran-4-one (α-hydroxymaltol)

α-Hydroxymaltol (2-hydroxymethyl-3-hydroxy-4H-pyran-4-one) ( 1 ) has been converted to the 3-O-methyl ether 2 and 3-O-p-nitrobenzyl ether 4 by standard methods. The ethers 2 and 4 have been oxidized by barium manganate to the corresponding aldehydes, 3 and 5 , in 91 and 77% yields respectively. Long-term reaction of 5 with hydrogen bromide in acetic acid gives 3-hydroxy-4H-pyran-4-one-2-carboxaldehyde ( 6 ). The aldehyde 3 is readily oxidized by short-term reaction with silver oxide to the corresponding acid 7 .     

Irreversible enzyme inhibitors. LXXXIII. Candidate active-site-directed irreversible inhibitors of dihydrofolic reductase. VIII. Derivatives of 2,4-diaminopyrimidine. II

2,4-Diamino-6-(p-aminophenethyl)pyrimidines with a 5-phenylbutyl (XIX) and 5-(p-chlorophenyl) (VIII) substituent were synthesized by condensation of the corresponding pyrimidine-6-carboxaldehydes (XVI, X) with the Wittig reagent derived from p-nitro-benzyl bromide, followed by catalytic hydrogenation. Selective bromoacetylation of VIII and XIX afforded the candidate active-site-directed irreversible inhibitors of dihydrofolic reductase, namely, 6-(p-bromoacetamidophenethyl)-2,4-diaminopyrimidine with a 5-(p-chlorophenyl)- (IV) and 5-phenylbutyl- (III) substituents. Although III and IV were excellent reversible inhibitors of dihydrofolic reductase, neither showed any inactivation of the enzyme; in contrast, the corresponding 2-amino-6-(p-bromoacetamidophenethyl)-5-phenylbutyl-4-pyrimidinol (II) - which differs from III only in the 4-substituent (NH₂ vs. OH) - was an excellent active-site-directed irreversible inhibitor of dihydrofolic reductase, but II was a poor reversible inhibitor. Thus the conformations of II and III are most probably different when complexed to dihydrofolic reductase.     

Studies on the syntheses of heterocyclic compounds. Part CCCXV erythrinan and related compounds. II . An alternative synthesis of cis-16-hydroxy-15-methoxyerythrinan-8-one and its mass spectrum

Phenolic cyclization of 2-ethoxycarbonylmethylidenecyclohexanone (IV) with 3-hydroxy-4-methoxyphenethylamine (V) were performed in the process of finding a synthetic approach to dihydroerysolidine (I). Thus, 16-hydroxy-15-methoxyerythrinan-6-ene-8-one (VI) and 16-hydroxy-15-methoxyerythrinan-7-ene-8-one (VII) were synthesized, both of which were hydrogenated in the presence of Adams platinum to give the same product (XI). Furthermore, on the basis of the mass spectra of XI and XII, these compounds were assumed to be stereoisomeric at the C₅- and C₆-positions.     

Irreversible enzyme inhibitors. LXXXIX. candidate active-site-directed irreversible inhibitors of dihydrofolic reductase. X. derivatives of 2-amino-5-benzamidopropyl-4-pyrimidinol

Since 2-amino-5-benzamidopropyl-6-methyl-4-pyrimidinol (VII) was a reasonably good reversible inhibitor of dihydrofolic reductase, the benzamido group was substituted with p-bromomethyl (XVIIa), m-bromomethyl (XVIIIa), and p-bromoacetyl (XIXa) groups; these compounds, and the corresponding 6-phenylpyrimidines, were synthesized from the proper 2-amino-5-aminopropyl-4-pyrimidinol (V) by devising methods that were compatible with the high reactivity of the halogen. Compounds XVII-XIX showed in-activation of dihydrofolic reductase; the fact that p-nitrobenzyl bromide inactivated the enzyme as rapidly as XVII and XVIII and phenacyl bromide inactivated the enzyme as rapidly as XIX indicated that these inactivations proceeded by a random bimolecular mechanism and not the desired active-site-directed mechanism.     

Irreversible enzyme inhibitors. XC. candidate active-site-directed irreversible inhibitors of thymidylate synthetase. I. 2-amino-5-(benzenesulfonamidopropyl)-6-methyl-4-pyrimidinol with substituents on the benzene ring

2-Amino-5-[p- (bromoacetamidomethyl)benzenesulfonamidopropyl]-6-methyl-4-pyrimidinol (XV) was synthesized by acylation of 2-amino-5-aminopropyl-6-methyl-4-pyrimidinol (III) with p-cyanobenzenesulfonyl chloride followed by catalytic reduction and reaction of the resultant aminomethyl group with p-nitrophenyl bromoacetate. A second irreversible inhibitor of thymidylate synthetase, namely 2-amino-5-[p-(bromoacetyl)benzene-sulfonamidopropyl]-6-methyl-4-pyrimidinol (XVI), was synthesized by acylation of in with p-acetylbenzenesulfonyl chloride followed by bromination. Both XV and XVI were good reversible inhibitors of thymidylate synthetase and inactivated the enzyme when the candidate compound was incubated with the enzyme. Iodoacetamide, which does not form a complex with enzyme, could inactivate thymidylate synthetase almost as well as XV; therefore it appears that XV inactivated the enzyme by a random bimolecular mechanism rather than by the desired active-site-directed mechanism via an enzyme-inhibitor complex. Similar conclusions were reached with XVI since phenacyl bromide could inactivate the enzyme somewhat more rapidly than XVI.     

Irreversible enzyme inhibitors. LXXXI. Further observations on the mode of binding of the anilino moiety of 2-amino-5-(anilinopropyl)-6-methyl-4-pyrimidinol to dihydrofolic reductase and thymidylate synthetase

Replacement of phenyl group of 2-amino-5-(anilinopropyl)-6-methyl-4-pyrimidinol (III) by benzyl (XI) led to a large loss in binding to both dihydrofolic reductase and thymidylate synthetase; the binding by XI returned when the protonated benzylamino group was N-acetylated to XII, which removes the charge at pH 7.4 and changes the ground-state conformation of the benzene ring. Replacement of the benzyl group of the acetamide, XII, with the polar 2-, 3-, or 4-, picolyl groups also led to a loss in binding. Substitution of p-fluoro or m-trifluoromethyl on the anilino group of III, or replacement of the anilino of III by 3-pyridylamino, gave little - if any - enhancement in binding to the enzymes.     

Irreversible enzyme inhibitors. XCI. candidate active-site directed irreversible inhibitors of thymidylate synthetase. II. 2-amino-6-methyl-5-(p-tolylsulfonamidopropyl)-4-pyrimidinols with N-substituents on the sulfonamide moiety

Three derivatives of 2-amino-6-methyl-5-(p-tolylsulfonamidopropyl)-4-pyrimidinol (I) with N - substituents on the sulfonamide group, namely bromoacetamidopropyl (XVI), m-bromoacetamidobenzyl (XXIVa), and p-bromoacetamidobenzyl (XXIVb), were synthesized as candidate active-site-directed irreversible inhibitors of thymidylate synthetase. The bromoacetamidopropyl derivative, (XVI), the p-bromoacetamidobenzyl derivative (XXIVb), and iodoacetamide showed irreversible inhibition of thymidylate synthetase, but XXIVa did not. Since iodoacetamide did inactivate the enzyme, but XXIVa did not, it cannot be ascertained whether XXIVb and XVI inactivate the enzyme by a random bimolecular mechanism or by the active-site-directed mechanism without evaluation of additional candidate inhibitors. Two synthetic routes were employed. The key intermediates for the bromoacetamidobenzyl sulfonamides (XXIV) were the corresponding nitrobenzyl sulfonamides (XXI); the latter were best prepared by reductive alkylation of 2-amino-5-aminopropyl-6-methyl-4-pyrimidinol (XXV) with a nitrobenzaldehyde followed by tosylation. The key intermediate for XVI was a toluenesulfonamide with a carbobenzoxyaminopropyl substituent on the nitrogen (XIV); the latter was synthesized via N-carbobenzoxy-N'-tosyl-1,3-diaminopropane (XI).     

Folic acid analogs. Modifications in the benzene-ring region. 5. 2′,6′-diazafolic acid

The synthesis of 2′,6′-diazafolic acid was accomplished by the condensation of 2-acetylamino-4(3H)pteridinone-6-earboxaldehyde (XIV) with diethyl N-[(5-amino-2-pyrimidinyl)carbonyl]-L-glutamate (XIII) followed by reduction of the anil double bond and alkaline hydrolylic cleavage of the N²-acetyl and ethyl ester protecting groups. Intermediate XIII was prepared by starling with 5-nitro-2-styrylpyrimidine (VI) and proceeding via 5-arnino-2-styrylpyrimidine (IX). The henzyloxycarbonyl derivative of IX was prepared and oxidized to the corresponding 5-benzyloxycarbonylaminopyrimidine-2-carboxylic acid (XI). The coupling of XI with diethyl L-glutamate followed by hydrogenolysis of the henzyloxycarbonyl function afforded the desired intermediate XIII. 2′,6′-Diazafolic acid was a potent inhibitor of Streptococcus faecium and displayed marginal activity against leukemia 1,1210 in mice.     

Furopyridines. XX. Wittig-horner reaction of a phosphonate of reissert analogues of furo[3,2-c]-, -[2,3-c]- and -[3,2-b]pyridines

Furo[3,2-c]-( 1a ), -[2,3-c]- ( 1b ) and -[3,2-b]pyridine ( 1c ) were reacted with isopropyl chloroformate and trimethyl phosphite to give dimethyl 5-isopropoxycarbonyl-4,5-dihydrofuro[3,2-c]pyridine-4-phosphonate ( 2a ), dimethyl 6-isopropoxycarbonyl-6,7-dihydrofuro[2,3-c]pyridine-7-phosphonate ( 2b ) and dimethyl 4-isopropoxycarbonyl-4,7-dihydrofuro[3,2-b]pyridine-7-phosphonate ( 2c ) as unstable syrups. Reaction of 2b and 2c with n-butyllithium and then with benzaldehyde, p-methoxybenzaldehyde, p-cyanobenzalde-hyde or propionaldehyde afforded the normal Wittig reaction products 5b-H, 5b-OMe, 5b-CN, 5b-Et, 5c-H, 5c-H, 5c-OMe and 5c-CN , except for 2b with propionaldehyde. While, the same reactions of compound 2a and the reaction of 2b with propionaldehyde afforded the unexpected products, 5-isopropoxycar-bonylfuro[3,2-c]pyridinio-4-aryl-(or ethyl)methoxides 3a-H, 3a-OMe, 3a-CN and 3a-Et , 4-(1′-aryl(or ethyl)-1′-hydroxymethyl)furo[3,2-c]pyridines 4a-H, 4a-OMe, 4a-CN and 4a-Et accompanying formation of the normal products. Treatment of the normal Wittig reaction products with lithium diisopropylamide and then with acetone gave the derivatives alkylated at the 2-or the benzylic positions.     

Reactions of regioisomeric 3,3-dimethyl- and 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrones with N-nucleophiles

Reactions of 2,2-dimethyl-6-trifluoromethyl-2,3-dihydro-4-pyrone with ethylenediamine, hydrazine, or hydroxylamine yield 5-methyl-7-trifluoromethyl-2,3-dihydro-1H-1,4-diazepine, 3(5)-(2-hydroxy-2-methylpropyl)-5(3)-trifluoromethylpyrazole, and 5-hydroxy-3-(2-hydroxy-2-methylpropyl)-5-triflouromethyl-Δ², respectively. The same compounds were obtained from 2-amino-1,1,1-trifluoro-6-hydroxy-6-methylhept-2(Z)-en-4-one and 2-hydroxy-6, 6-dimethyl-2-trifluoromethyltetrahydro-4-pyrone.     

Azocalixarenes. 6: Synthesis, complexation, extraction and thermal behaviour of four new azocalix[4]arenes

Four new azocalix[4]arenes {5,11,17,23-tetrakis[(2-hydroxy-5-tert-butylphenylazo)]-25,26,27,28-tetrahydroxycalix[4]arene (1), 5,11,17,23-tetrakis[(2-hydroxy-5-nitro phenylazo)]-25,26,27,28-tetrahydroxycalix[4]arene (2), 5,11,17,23-tetrakis[(2-amino-5-carboxylphenylazo)]-25,26,27,28-tetrahydroxycalix[4]arene (3) and 5,11,17,23-tetrakis[(1-amino-2-hydroxy-4-sulfonicacidnapthylazo)]-25,26,27,28-tetrahydroxycalix[4]arene (4)} have been synthesized from p-tert-butylphenol, p-nitrophenol, p-aminobenzoic acid and 1-amino-2-hydroxy-4-sulphonic acid by diazo coupling reaction with p-aminocalix[4]arene. The resulting ligands (1–4) were treated with three transition metal salts (e.g., CuCl₂·2H₂O, NiCl₂·6H₂O or CoCl₂·6H₂O). Cu(II), Ni(II) and Co(II) complexes of the azocalix[4]arene derivatives were obtained and characterized by UV-vis, IR, ¹H-NMR spectroscopic techniques and elemental analysis. All the complexes have a metal:ligand ratio of 2:1. The Cu(II) and Ni(II) complexes of azocalix[4]arenes are square-planar, while the Co(II) complexes of azocalix[4]arenes are octahedral with water molecules as axial ligands. The solvent extraction of various transition metal cations from the aqueous phase to the organic phase was carried out by using azocalix[4]arenes (1–4). It was found that, azocalix[4]arenes 1, 2 and 3 examined selectivity for transition metal cations such as Ag⁺, Hg⁺ and Hg²⁺. In addition, the thermal stability of metal:azocalix[4]arene complexes were also reported. Dedicated to Prof. Dr. Mustafa Yılmaz on the occasion of his 50th birthday     

Dibenzo-18-crown-6 modified with kojic acid fragments

Diazonium salts were prepared by diazotization of 4′-amino-, 4′,4″-, and 4′,5″-diaminodibenzo-18-crown-6. Their coupling products with kojic acid (5-hydroxy-2-hydroxymethyl-γ-pyrone) were synthesized for the first time: 4′-(6-aza-5-hydroxy-2-hydroxymethyl-γ-pyronyl)-, 4′,4″-di-(6-aza-5-hydroxy-2-hydroxymethyl-γ-pyronyl)-, and 4′,5″-di-(6-aza-5-hydroxy-2-hydroxymethyl-γ-pyronyl)-dibenzo-18-crown-6. __________ Translated from Khimiya Prirodnykh Soedinenii, No. 5, pp. 415–416, September–October, 2006.     

Synthesis of 4H-furo[3,2-b]indole derivatives A new heterocyclic ring system

4H-Furo[3,2-b]indole (III) was prepared from deoxygenation of 2-(2-nitrophenyl)furan (II) with triethyl phosphite and thermolysis of 2-(2-azidophenyl)furan (VI). 4H- or 4-alkylfuro [3,2-b]indole-2-carboxaldehydes (VIII, IXa-c) were obtained by Vilsmeier formylation of the corresponding furo[3,2-b]indoles (III, VIIa-c). 4H-Furo[3,2-b]indole-2-carboxaldehyde (VIII) was submitted to the Cannizzaro, Wittig and reduction reactions. The Shiff's bases were obtained by the reaction of 4-ethylfuro[3,2-b]indole-2-carboxaldehyde (IXb) with amines. J. Heterocyclic Chem., 14, 975 (1977)     

Synthesis of pyrido[1,2-a]pyrimido[4,5-d]pyrimidin-5-ones. Cyclization reaction of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid with acetic anhydride

Treatment of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid (X) with acetic anhydride under refluxing conditions afforded 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]-pyrimido[4,5-d]pyrimidin-5-one acetate (IX). The intermediate X was prepared from 4-chloro-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (V). The reaction of V with the sodium salt of 2-amino-3-hydroxypyridine at room temperature gave 4-(2-amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester (VI). Treatment of VI with a hot aqueous sodium hydroxide solution and subsequent acidification gave X. Involvement of 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecaroboxylic acid ethyl ester (VIII) (Smiles rearrangement product) as an intermediate in the above alkaline hydrolysis reaction of VI to X was demonstrated by the isolation of VIII and its subsequent conversion into X under alkaline hydrolysis conditions. Acetylation of VIII with acetic anhydride in pyridine solution gave 4-[(3-hydroxy-2-pyridyl)amino]-2-phenyl-5-pyrimidinecarboxylic acid ethyl ester acetate (XI), which afforded IX on fusion at 220°. This alternative synthesis of IX from XI supported the structural assignment of IX. Fusion of VI gave 10-hydroxy-2-phenyl-5H-pyrido[1,2-a]pyrimido]4,5-d]pyrimidin-5-one (VII). The latter was also obtained when VIII was fused at 210°. Acetylation of VII with acetic anhydride afforded IX.     

Synthesis and molecular structure of 6-aryl-3-ethoxycarbonyl-4-hydroxypyridazines

EthylZ-5-aryl-2-diazo-5-hydroxy-3-oxopent-4-enoates interact with triphenylphosphine to give 6-aryl-3-ethoxycarbonyl-4-hydroxypyridazines (Ar=Ph, 4-MeC₆H₄, 4-ClC₆H₄). Quantum-chemical calculations (MNDO) were performed to estimate the tautomeric equilibrium in the latter using a 6-phenyl-substituted derivative as an example. Acetylation of the 4-hydroxypyridazines led to 4-acetoxy-6-aryl-3-ethoxycarbonylpyridazines. The structure of the latter was confirmed by an X-ray diffraction analysis of 4-acetoxy-3-ethoxycarbonyl-6-(p-tolyl)pyridazine. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2260–2263, December, 1997.     

Synthesis and biological activities of tetrahydroquinazoline analogs of aminopterin and methotrexate

(6R,6S)-5,8-Dideaza-5,6,7,8-tetrahydroaminopterin ( 1 ) and (6R,6S)-5,8-dideaza-5,6,7,8-tetrahydromethotrexate ( 2 ) were synthesized as potential inhibitors of dihydrofolate reductase (DHFR) and as antitumor agents. Cyclohexanone-4-carboxaldehyde dimethyl acetal, a key intermediate [10] was synthesized from cyclohexane-1,4-dione monoethylene ketal, which was converted via a Wittig reaction to its exocyclic 4-methylene derivative which in turn, was converted to the 4-aldehyde via a hydroboration-oxidation sequence. Selective protection of the 4-aldehyde as the dimethylacetal and cyclization with dicyandiamide afforded the 6-dimethylacetal of 2,4-diamino-5,6,7,8-tetrahydroquinazoline. Protection of the 2,4-diamino moieties and selective deprotection of the 6-aldehyde followed by reductive amination with p-aminobenzoyl-L-glutamate afforded 2,4-bisacetamido-5,8-dideaza-5,6,7,8-tetrahydroaminopterin ( 11 ). Deprotection of 11 afforded 1 . Compound 2 was obtained from 11 via N¹⁰-methylation and deprotection. The N¹⁰-methyl analogue 2 was 2–10 fold more potent than 1 as an inhibitor of various DHFRs. In the in vitro preclinical screening program of the National Cancer Institute, compound 2 inhibited the growth of eighteen of the twenty nine tumor cell lines in culture at a GI₅₀ > 1.0 × 10^?8 M.     

The vilsmeier reaction in the synthesis of 3-substituted [1]benzopyrano[4,3-b]pyridin-5-ones. An unusual pyridine ring closure

Starting from 4-chlorocoumarin-3-carbaldehyde (1) and Wittig phosphoranes 2a-d the title compounds 6a-c have been synthesized via a four-step sequence. The intermediate 4-alkylamino-3-vinylcoumarins 5a-k have been prepared by the reaction of 4-chloro-3-vinylcoumarins 3a-d with primary amines 4a-h . The coumarin derivatives 5 (except 5k ) underwent an unusual pyridine ring closure under Vilsmeier conditions to form the benzopyrano[4,3-b]pyridines 6 . When the aminoaldehydes 7 were treated with the Wittig reagent 2b the fused N-alkyl-2 (1H) -pyridinones 8 have been obtained as expected.