Synthesis of isonipecotinoyl analogues of aminopterin and folic acid

The preparation of isonipecotinoyl analogues of aminopterin and methotrexate is described. Condensation of diethyl N-isonipecotinoyl-L-glutamate 4 with 2-amino-5-bromomethyl-3-cyanopyrazine 5 afforded diethyl N-(N-[(2-amino-3-cyanopyrazin-5-yl)methyl]isonipecotinoyl)-L-glutamate 6 . Cyclisation of 6 with guanidine followed by blocking group hydrolysis afforded N-([N-(2,4-diaminopteridin-6-yl)methyl]isonipecotinoyl)-L-glutamic acid 8 . Coupling of N-(2-amino-4(3H)ioxopteridin-6-yl]methyl)isonipecotinic acid 11 with diethyl L-glutamate gave diethyl N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamate 12 . Blocking group hydrolysis afforded N-[(N-[2-amino-4(3H)-oxopteridin-6-yl]methyl)isonipecotinoyl]-L-glutamic acid 13 .     

Heterospirocyclic N‐(2H‐Azirin‐3‐yl)‐L‐prolinates: New Dipeptide Synthons

The synthesis of methyl N‐(1‐aza‐6‐oxaspiro[2.5]oct‐1‐en‐2‐yl)‐L ‐prolinate ( 1e ) has been performed by consecutive treatment of methyl N‐[(tetrahydro‐2H‐pyran‐4‐yl)thiocarbonyl]‐L ‐prolinate ( 5 ) with COCl₂, 1,4‐diazabicyclo[2.2.2]octane (DABCO), and NaN₃ (Scheme 1). As the first example of a novel class of dipeptide synthons, 1e has been shown to undergo the expected reactions with carboxylic acids and thioacids (Scheme 2). The successful preparation of the nonapeptide 16 , which is an analogue of the C‐terminal nonapeptide of the antibiotic Trichovirin I 1B, proved that 1e can be used in peptide synthesis as a dipeptide building block (Scheme 3). The structure of 7 has been established by X‐ray crystal‐structure analysis (Figs. 1 and 2).     

Synthesis of 5′-C- and 2′-O-(Bromoalkyl)-Substituted Ribonucleoside Phosphoramidites for the Post-synthetic Functionalization of Oligonucleotides on Solid Support

The preparation of building blocks for the incorporation of 6′-O-(5-bromopentyl)-substituted β-D -allofuranosylnucleosides and 2′-O-[(3-bromopropoxy)methyl]-substituted ribonucleosides into oligonucleotide sequences is presented (Schemes 1 and 2). These reactive building blocks can be modified with a variety of soft nucleophiles while the (fully protected) sequence is still attached to the solid support. As an example of this strategy, we carried out some preliminary solid-phase substitution and conjugation reactions with DNA sequences containing a 2′-O-[(3-bromopropoxy)methyl]-substituted ribonucleoside (Scheme 3) and determined the pairing properties of duplexes obtained therefrom.     

A ‘One-Pot’ Anellation Method for the Transformation of Heptalene-4,5-dicarboxylates into Benzo[a]heptalenes

It has been found that dimethyl heptalene-4,5-dicarboxylates, when treated with 4 mol-equiv. of lithiated N,N-dialkylamino methyl sulfones or methyl phenyl sulfone, followed by 4 mol-equiv. of BuLi in THF in the temperature range of ?78 to 20°, give rise to the formation of 3-[(N,N-dialkylamino)sulfonyl]- or 3-(phenylsul-fonyl)benzo[a]heptalene-2,4-diols of. (cf. Scheme 4, and Tables 2 and 3). Accompanying products are 2,4-bis{[(N,N-dialkylamino)sulfonyl]methyl}- or 2,4-bis[(phenylsulfonyl)methyl]-4,10a-dihydro-3H-heptaleno[1,10-bc]furan-3-carboxylates as mixtures of diastereoisomers of. cf. Scheme 4, and (Tables 2 and 3) which are the result of a Michael addition reaction of the lithiated methyl sulfones at C(3) of the heptalene-4,5-dicarboxylates, followed by (sulfonyl)methylation of the methoxycarbonyl group at C(5) and cyclization of. (cf. Scheme 5). It is assumed that the benzo[a]heptalene formation is due to (sulfonyl)methylation of both methoxycarbonyl groups of the heptalene-4,5-dicarboxylates of. (cf. Schemes 6 and 8). The resulting bis-enolates 35 are deprotonated further. The thus formed tris-anions 36 can then cyclize to corresponding tris-anions 37 of cyclopenta[d]heptalenes which, after loss of N,N-dialkylamido sulfite or phenyl sulfinate, undergo a ring-enlargement reaction by 1,2-C migration finally leading to the observed benzo[a]heptalenes of. (cf. Schemes 8 and 9). The structures of the new product types have been finally established by X-ray crystal-structure analyses (cf. Figs. 1 and 2 as well as Exper. Part).     

The synthesis of methyl 2-(benzyloxycarbonyl)amino-3-dimethylaminopropenoate. The synthesis of trisubstituted pyrroles, 3-amino-2H-pyran-2-ones,fused 2H-pyran-2-ones and 4H-pyridin-4-ones

Methyl 2-(benzyloxycarbonyl)aimno-3-dimemylaminopropenoate ( 2 ) was prepared from methyl N-(benzyloxycarbonyl)glycinate ( 1 ) and t-butoxybis(dimethylamino)methane, and used as a reagent for preparation of substituted 3-(benzyloxycarbonyl)amino-4H-quinolizin-4-ones 5 and 6 , ?2H-pyran-2-ones 17–19 , ?2H-1-benzopyran-2-ones 28–31 , and -naphthopyrans 32–35 , ?2H-pyrano[3,2-c]pyridine-2,5-dione 46 , -pyrano-[4,3-b]pyran-2,5-dione 47 , -pyrano[3,2-c]benzopyran-2,5-dione 48 , -pyrano[2,3-c]pyrazol-6-ones 49 and 50 , -pyrano[2,3-d]pyrirnidin-7-ones 51 and 52 derivatives. In the reaction of 2 with 1,3-diketones trisubsti tuted pyrroles 14–16 were formed. Selective removal of benzyloxycarbonyl group was achieved by cat alytic transfer hydrogenation with Pd/C in the presence of cyclohexene to afford free 3-amino compounds 7 , 8 , 20 , 36–38 and 53–57 in yields better than 80%.     

Synthesis of some substituted dibenzodiazepinones and pyridobenzodiazepinones

Some fluoro- and iodo-derivative of 5-[[4-[(4-diisobutylamino)butyl]-1-phenyl]acetyl]-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepin-1l-one and 11-[[4-[(dialkylamino)butyl]-1-phenyl]acetyl]-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-ones 6 (Scheme 1) and their analogues were synthesized. The synthesis of dibenzodiazepinones 1 (Scheme 1) is based on the reaction between 1,4-phenylenediamine and substituted benzoic acids. The intermediate pyridobenzodiazepinones 3 (Scheme 1) were prepared by condensation of 2-chloro-3-aminopyridine with methyl anthranilate and its chlorine derivative. The condensation of 4-[(halo)alkyl]phenylacetyl chloride with dibenzodiazepinones and pyridobenzodiazepinones followed by the reaction of mono- or dialkyl- or dialkenylamine provides 6 (Scheme 1).     

(R)- and (S)-N-(Benzyloxycarbonyl)-3,4-epoxybutylamine. New 4-amino-2-hydroxybutyl synthons for the synthesis of hypusine reagents and (R)-6- and (S)-7-hydroxyspermidine

The synthesis and application of the chiral reagents (R)- and (S)-N-(benzyloxycarbonyl)-3,4-epoxybutylamine is described for the first time. These 4-amino-2-hydroxybutyl synthons are successfully employed in the assembly of two hydroxylated triamines, (R)-6- and (S)-7-hydroxyspermidine, and a previously described hypusine reagent, (2S,9R)-11-[(benzyloxycarbonyl)amino]-7-(benzyloxycarbonyl)-2-[(9-fluorenylmethoxycarbonyl)amino]-9-(tetrahydropyran-2-yloxy)-7-azaundecanoic acid, useful for solution- and solid-phase peptide synthesis.     

Intramolecular electrophilic cyclization of functional derivatives of unsaturated compounds: II. Synthesis and transformation of N-{(2Z)-5-[(arylsulfanyl)methyl]dihydrofuran-2(3H)-ylidene}-N-alkyl(aryl)aminium perchlorates

N-Alkyl(aryl)amides of allylacetic acid when reacting with arylsulfenyl chlorides in acetic acid in the presence of lithium perchlorate undergo a selective cyclization to form N-{(2Z)-5-[(arylsulfanyl)methyl] dihydrofuran-2(3H)-ylidene}-N-alkyl-(aryl)aminium perchlorates. Treating of the latter with sodium acetate leads to the formation of the corresponding 5-[(arylsulfanyl)methyl]lactones, and with sodium ethylate, to 5-[(arylsulfanyl) methyl]-2-iminolactones. In reaction with secondary cycloalkylamines in the presence of water a transamidation and tetrahydrofuran ring opening occurs to afford 5-arylsulfanyl-4-hydroxypentanoic acid amides.     

New (S)-proline derivatives as catalysts for the enantioselective aldol reaction

(2S)-N- 2-[(R)-Hydroxy(phenyl)methyl]phenylpyrrolidine-2-carboxamide, (2 S)-N-{2-[(S)-hydroxy(phenyl)methyl]phenyl}pyrrolidine-2-carboxamide, and (S)-N-{2-[hydroxy-(diphenyl)methyl]phenyl}pyrrolidine-2-carboxamide were obtained and tested as catalysts for an asymmetric aldol reaction of 4-nitrobenzaldehyde with acetone.     

Novel Fluoride‐Labile Nucleobase‐Protecting Groups for the Synthesis of 3′(2′)‐O‐Aminoacylated RNA Sequences

With the aim to develop a general approach to a total synthesis of aminoacylated t‐RNAs and analogues, we describe the synthesis of stabilized, aminoacylated RNA fragments, which, upon ligation, could lead to aminoacylated t‐RNA structures. Novel RNA phosphoramidites with fluoride‐labile 2′‐O‐[(triisopropylsilyl)oxy]methyl (=tom) sugar‐protecting and N‐{{2‐[(triisopropylsilyl)oxy]benzyl}oxy}carbonyl (=tboc) base‐protecting groups were prepared (Schemes 4 and 5), as well as a solid support containing an immobilized N⁶‐tboc‐protected adenosine with an orthogonal (photolabile) 2′‐O‐[(S)‐1‐(2‐nitrophenyl)ethoxy]methyl (=(S)‐npeom) group (Scheme 6). From these building blocks, a hexameric oligoribonucleotide was prepared by automated synthesis under standard conditions (Scheme 7). After the detachment from the solid support, the resulting fully protected sequence 34 was aminoacylated with L ‐phenylalanine derivatives carrying photolabile N‐protecting groups (→ 42 and 43 ; Scheme 9). Upon removal of the fluoride‐labile sugar‐ and nucleobase‐protecting groups, the still stabilized, partially with the photolabile group protected precursors 44 and 45 , respectively, of an aminoacylated RNA sequence were obtained (Scheme 9 and Fig. 3). Photolysis of 45 under mild conditions resulted in the efficient formation of the 3′(2′)‐O‐aminoacylated RNA sequence 46 (Fig. 4). Additionally, we carried out model investigations concerning the stability of ester bonds of aminoacylated ribonucleotide derivatives under acidic conditions (Table) and established conditions for the purification and handling of 3′(2′)‐O‐aminoacylated RNA sequences and their stabilized precursors.     

Nucleotides. Part LXXVIII

Several N(‐hydroxyalkyl)‐2,4‐dinitroanilines were transformed into their phosphoramidites (see 5 and 6 in Scheme 1) in view of their use as fluorescence quenchers, and modified 2‐aminobenzamides (see 9, 10, 18 , and 19 in Scheme 1) were applied in model reactions as fluorophors to determine the relative fluorescence quantum yields of the 3′‐Aba and 5′‐Dnp‐3′‐Aba conjugates (Aba=aminobenzamide, Dnp=dinitroaniline). Thymidine was alkylated with N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to give 25 which was further modified to the building blocks 27 and 28 (Scheme 3). The 2‐amino group in 29 was transformed by diazotation into the 2‐fluoroinosine derivative 30 used as starting material for several reactions at the pyrimidine nucleus (→ 31, 33 , and 35 ; Scheme 4). The 3′,5′‐di‐O‐acetyl‐2′‐deoxy‐N²‐[(dimethylamino)methylene]guanosine ( 37 ) was alkylated with methyl and ethyl iodide preferentially at N(1) to 43 and 44 , and similarly reacted N‐(2‐chloroethyl)‐2,4‐dinitroaniline ( 24 ) to 38 and the N‐(2‐iodoethyl)‐N‐methyl analog 50 to 53 (Scheme 5). The 2′‐deoxyguanosine derivative 53 was transformed into 3′,5′‐di‐O‐acetyl‐2‐fluoro‐1‐{2‐[(2,4‐dinitrophenyl)methylamino]ethyl}inosine ( 54 ; Scheme 5) which reacted with 2,2′‐[ethane‐1,2‐diylbis(oxy)]bis[ethanamine] to modify the 2‐position with an amino spacer resulting in 56 (Scheme 6). Attachment of the fluorescein moiety 55 at 56 via a urea linkage led to the doubly labeled 2′‐deoxyguanosine derivative 57 (Scheme 6). Dimethoxytritylation to 58 and further reaction to the 3′‐succinate 59 and 3′‐phosphoramidite 60 afforded the common building blocks for the oligonucleotide synthesis (Scheme 6). Similarly, 30 reacted with N‐(2‐aminoethyl)‐2,4‐dinitroaniline ( 61 ) thus attaching the quencher at the 2‐position to yield 62 (Scheme 7). The amino spacer was again attached at the same site via a urea bridge to form 64 . The labeling of 64 with the fluorescein derivative 55 was straigthforward giving 65 . and dimethoxytritylation to 66 and further phosphitylation to 67 followed known procedures (Scheme 7). Several oligo‐2′‐deoxynucleotides containing the doubly labeled 2′‐deoxyguanosines at various positions of the chain were formed in a DNA synthesizer, and their fluorescence properties and the T_ms in comparison to their parent duplexes were measured (Tables 1–5).     

[(1,3-Dioxolan-2-yliden)methyl]phosphonate und -phosphinate als (einfache) Synthone in der Heterocyclensynthese

[(1,3-Dioxolan-2-ylidene)methyl]phosphonates and -phosphinates as [simple] Synthons in Heterocyclic Synthesis The readily available [(1,3-dioxolane-2-ylidene)methyl]phosphonates and -phosphinates 2a–f (Scheme 1) can be transformed with amines to aliphatic ketene N,O-and N,N-acetales (see Scheme 2, 2a → 3–7 ). Alkanediamines yield with 2a–f the imidazolidines 8a–f and the hexahydropyrimidines 9a–d (Scheme 3). the oxazolidine derivatives 10a–e and the thiazolidine 11 are accessible under special reaction conditions starting from 2a, b (Scheme 4). Hydrazines react with the CN-group-containing ketene O,O-acetals 2a–c to the pyrazoles 12a–g , whereof 12a, d, e can be cyclized to pyrazolo[1,5-a]pyrimidines 13a–d (Scheme 5). Amidines as starting materials transform 2a–c in an analogous way to the pyrimidine derivatives 14a–c (Scheme 6).     

Synthesis and Properties of a 2-Diazohistidine Derivative: A New Photoactivatable Aromatic Amino-Acid Analog

N^α[(tert-Butoxy)carbonyl]-2-diazo-L -histidine methyl ester 1 was synthesized starting from the corresponding L-histidine derivative. The physico-chemical properties of this new photoactivatable amino-acid derivative were established. The synthetic precursor of 1 , 2-amino-L -histidine derivative 3 , was best isolated and characterized as 2-amino-N^α-[(tert-butoxy)carbonyl]-N^τ-tosyl-L -histidine methyl ester ( 4 ). Selective deprotections of 4 (N^α-Boc, N^α-Tos, COOMe) were achieved, thus allowing the use of the corresponding products in peptide synthesis. The optically active dipeptides 8 and 9 were synthesized by coupling 2-amino-N^τ-tosyl-L -histidine methyl ester ( 5 ) with N-[(tert-butoxy)carbonyl]-L -alanine and N^α-[(tert-butoxy)carbonyl]-N^τ-tosyl-L -histidine ( 6 ) with L-alanine methyl ester, respectively. The question of selective diazotization of a 2-aminohistidine residue in a synthetic peptide was studied using competitive diazotizations between 2-amino-1H-imidazole and several amino-acid derivatives susceptible to undergo nitrosylation. The results show that synthetic photoactivatable peptides incorporating a 2-diazohistidine residue might become useful photoaffinity probes.     

Fast and Reliable Automated Synthesis of RNA and Partially 2′-O- Protected Precursors (`Caged RNA') Based on Two Novel,Orthogonal 2′-O-Protecting Groups,Preliminary Communication

Two sets of RNA phosphoramidites, carrying the (fluoride-labile) 2′-O-[(triisopropylsilyl)oxy]methyl (=tom) group and the (photolabile) [(R)-1-(2-nitrophenyl)ethoxy]methyl (=(R)-npeom) group, were prepared (see 1 – 4 and 5 – 8 , resp.). The two protecting groups were completely orthogonal to each other. Three ribozyme-substrate constructs, protected each by a (R)-npeom group, were synthesized; on photolysis, efficient cleavage of this remaining protecting group occurred (Scheme 3). It could be demonstrated that the presence of one (R)-npeom group within a RNA strand has only a minor influence on the pairing properties of corresponding duplexes.     

Enantioselective Syntheses of Conformationally Rigid,Highly Lipophilic Mesityl‐Substituted Amino Acids

Three N‐Boc‐protected amino acids substituted with a mesityl (=2,4,6‐trimethylphenyl) group were synthesized in enantiomerically pure form, either by asymmetric epoxidation or by aminohydroxylation as the source of chirality. The 3‐mesityloxirane‐2‐methanol 7 , easily available in high enantiomer purity by Sharpless epoxidation, was converted into 3‐{[(tert‐butoxy)carbonyl]amino}‐3‐mesitylpropane‐1,2‐diol 9 by a regio‐ and stereoselective ring opening with an ammonia equivalent (sodium azide or benzhydrylamine), followed by hydrogenation and in situ treatment with (Boc)₂O (Boc=[(tert‐butoxy)carbonyl]) (Scheme 3). Oxidative cleavage of the diol fragment in 9 afforded N‐[(tert‐butoxy)carbonyl]‐α‐mesitylglycine 1 of >99% ee. This amino acid was also prepared in enantiomerically pure form starting from 2,4,6‐trimethylstyrene ( 11 ) by a regioselective Sharpless asymmetric aminohydroxylation, followed by a 2,2,6,6‐tetramethylpiperidin‐1‐yloxyl (TEMPO)‐catalyzed oxidation (Scheme 4). On the other hand, 1‐[(tert‐butoxy)carbonyl]‐2‐{{[(tert‐butyl)dimethylsilyl]oxy}methyl}‐3‐mesitylaziridine 14 was prepared from 9 by a sequence involving selective protection of the primary alcohol (as a silyl ether), activation of the secondary alcohol as a mesylate, and base‐induced (NaH) cyclization (Scheme 5). The reductive cleavage of the aziridine ring (H₂, Pd/C), followed by alcohol deprotection (Bu₄NF/THF) and oxidation (pyridinium dichromate (PDC)/DMF or (TEMPO)/NaClO) provided, in high yield and enantiomeric purity, N‐[(tert‐butoxy)carbonyl]‐β‐mesitylalanine 2 . Alternatively, the regioselective ring opening of the aziridine ring of 14 with lithium dimethylcuprate, followed by silyl‐ether cleavage and oxidation lead to N‐[(tert‐butoxy)carbonyl]‐β‐mesityl‐β‐methylalanine 3 . A conformational study of the methyl esters of the N‐Boc‐protected amino acids 1 and 3 carried out by variable‐temperature ¹H‐NMR and semi‐empirical (AM1) calculations shows the strong rotational restriction imposed by the mesityl group.     

Novel Synthesis of Agaritine,a 4-Hydrazinobenzyl-Alcohol Derivative Occurring in Agaricaceae

The 4-hydrazinobenzyl alcohol ( 3 was prepared (58%)) by diiobutylaluminiumhydride reduction of methyl 4-hydrazinobenzoate ( 4 ), whereas LiA1H₄ or LiBh₄ reduction of 4 proceeded further to yield (via intermediate 3 ) (4-tolyl)hydrazine ( 5 ). The alcohol 3 was stable under O₂-free conditions and exhibited no tendency to eliminate H₂O, neither thermally nor with H⁺ catalysis. Oxidation of 3 with SeO₂ yielded 4-(hydroxymethyl)benzine-diazonium ion ( 8 ), identified by its azo coupling product 9 with 2-naphthol. Condensation of 3 with 1-benzyl 5-Hydrogen N-(benzyloxycarbonyl)-L-glutamate ( 10 ) in presence of dicyclohexylcarbodiimide afforded 81% of N²-(benzyloxycarbonyl)-L- glutamic acid 1-(benzyl-ester) 5-{2-[4-(hydroxymethyl)phenyl]hydrazide} ( 11 ) which upon controlled hydrogenolysis (quinoline-sulfur-poisoned Pd/C catalyst) gave 82% of L-Glutamic acid 5-{2-[4-(hydroxymethyl)phenyl] hydrazide} ( 1 ), i. e. agaritine, a metabolite of Agaricus bisporus. Without poisoning of the catalyst, hydrogenolysis of ( 11 ) yielded L-glutamic acid 5-[2-(4-tolyl)hydrazide] ( 12 ).     

An unusual reaction of propargylamines with CH2I2 and Et3Al

N-{2-[(1-R-Cyclopropyl)methyl]prop-2-enyl}-N,N-dimethylamines were prepared in 80-90% yields by the reaction (5 h, 23-25 C) of propargylamines R-C=C-CH₂NMe₂ (where R = alkyl, Ph) with a system of reactants CH2I2-Et₃Al taken in the molar ratio [propargylamine]: [Et₃Al]: [CH₂I₂] = 1: 6: 6. In the case of phenyl-substituted propargyl- amine, N-({1-[(1-phenylcyclopropyl)methyl]cyclopropyl}methyl)-N,N-dimethylamine is selectively formed in 76% yield upon the elongation of the reaction time to 4 days.     

Intramolecular photocyclization of N-[(2-haloaryl)methyl]pyridinium and n-(arylmethyl)-2-halopyridinium salts

Various N-[(2-haloaryl)methyl]pyridinium, N-(arylmethyl)-2-halopyridinium and N-(2-halobenzyl)iso-quinolinium salts have been synthesized and their intramolecular photocyclization reactions studied. Upon irradiation the aqueous solution of N-[(2-haloaryl)methyl]pyridinium, and N-arylmethyl-2-halopyridinium salts 1, 2 were cyclized to give isoindolium salts. In contrast to the pyridinium salts 1, 2 , the aqueous solution of N-(2-halobenzyl)isoquinolinium salts 3 appear not to undergo photocyclization. N-Benzyl-2-chloropyridinium salts 1c is more reactive than N-(2-chlorobenzyl)pyridinium salt 1a in the photocyclization. N-(2-Chlorobenzyl)-2-chloropyridinium salt 1d is three times more reactive than 1c . A mechanism of π-complex formation of the halogen moiety of the pyridinium ring with the phenyl ring is suggested for the reactive pyridinium salt. The triplet energy of the isoquinolinium salts 3 is tool low to photocyclize.     

Synthesis and urease inhibition studies of some new quinazolinones

In this study, novel quinazolinones were designed, synthesized, characterized by FT-IR, ¹H-NMR, ¹³C-NMR spectral data, and LC–MS. New compounds inhibitory activities on urease were assessed. All of the compounds exhibited potent urease inhibitory activities. Especially in the synthesized compounds, 2-benzyl-3-({5-[(4-nitrophenyl)amino]-1,3,4-thiadiazol2-yl}methyl)quinazolin-4(3H)-one has the best inhibitory effect against Jack bean urease with IC₅₀ = 3.30 ± 0.09 μg/mL. And also, N-(4-nitrophenyl)-2-[(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazinecarbothioamide, N-(4-fluorophenyl)-2-[(4-oxoquinazolin-3(4H)-yl)acetyl] hydrazinecarbothioamide, and 2-benzyl-3-({5-[(4-fluorophenyl)amino]-1,3,4-thiadiazol-2yl} methyl)quinazolin-4(3H)-one have best activities among the synthesized compounds.     

Synthese von 3-(2-Carboxy-4-Pyridyl)- und 3-(6-Carboxy-3-pyridyl)-DL-alanin

Synthesis of 3-(2-Carboxy-4-pyridyl)-and 3-(6-Carboxy-3-pyridyl)-DL-alanine As starting materials for potential photochemical approaches to betalaines C(R = COOH) and to muscaflavine F(R = COOH), β-(2-carboxy-4-pyridyl)- and β-(6(carboxy-3-pyridyl))-DL-alanine ( A and D with R = COOH or 4 and 11 ), respectively, were prepared (Scheme 1). The synthesis of 4 (= A, R = COOH) started with the 2-[(4-pyridyl)methyl]malonate 1 and proceeded via the N-oxide 2 , cyanation and hydrolysis (Scheme 2). Amino acid 11 was obtained from (3-pyridyl)methyl-bromide ( 6 ) via the malonate 7 by an analogous sequence of reactions (Scheme 3).