Synthesis of 3-amino- and 3-azidoanalogs of 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA)

1989 ◽  
Vol 54 (2) ◽  
pp. 446-454 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Acid Hydrolysis ◽  
Sodium Salt ◽  
Catalytic Hydrogenation ◽  
Alkaline Hydrolysis ◽  
Benzoyl Chloride ◽  
Sodium Hydride ◽  
Acid Catalyzed ◽  
Excess Sodium ◽  
Chloride Treatment

1-Azidopropane-2,3-diol (IIb) reacts with p-toluenesulfonyl chloride to give the tosyl derivative IIIa which, on acid catalyzed condensation with 2,3-dihydropyran, afforded 1-azido-2-(tetrahydropyran-2-yloxy-3-(p-toluenesulfonyloxy)propane (IIIb). Treatment of adenine sodium salt with IIIb resulted in the intermediate IV which was transformed by acid hydrolysis to 9-(RS)-(3-azido-2-hydroxypropyl)adenine (V). Catalytic hydrogenation of V led to 9-(RS)-(3-amino-2-hydroxypropyl)adenine (VI). 9-(RS)-(3-Azido-2-hydroxypropyl)-N6-benzoyladenine (VII) was obtained from V by chlorotrimethylsilane/benzoyl chloride treatment. Reaction of the compound VII with dimethyl p-toluenesulfonyloxymethanephosphonate (VIII) in the presence of excess sodium hydride, followed by alkaline hydrolysis, afforded methyl 9-(3-azido-2-phosphonylmethoxypropyl)adenine (IXa) which was transformed to the parent acid IXb by bromotrimethylsilane treatment. Hydrogenolysis of IXb yielded 9-(RS)-(3-amino-2-phosphonylmethoxypropyl)adenine (X).

Stereospecific synthesis of isomeric 4-substituted 9-(2,3-dihydroxybutyl)adenines

1982 ◽  
Vol 47 (1) ◽  
pp. 173-189 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Acid Hydrolysis ◽  
Sodium Borohydride ◽  
Sodium Salt ◽  
Catalytic Hydrogenation ◽  
Sodium Azide ◽  
Sodium Iodide ◽  
Stereospecific Synthesis ◽  
Isopropylidene Derivative

Reduction of ethyl 2,3-O-isopropylidene-D-tartrate with sodium borohydride afforded (4S, 5S)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (Va) which was benzoylated to give monobenzoyl derivative Vd and further transformed into p-toluensulfonyl derivative Ve. Reaction of the compound Ve with sodium salt of adenine followed by methanolysis gave 2,3-O-isopropylidene derivative Vf which on acid hydrolysis afforded 9-(2S, 3S)-(2,3,4-trihydroxybutyl)adenine (Ia). The enantiomer IIa was obtained from 3,4-O-isopropylidene-D-mannitol via (4R, 5R)-2,2-dimethyl-1,3-dioxolane-4,5-dimethanol (VIa) using the same procedure. Reaction of compounds Vf and VIf with p-toluenesulfonyl chloride afforded 4-O-p-toluenesulfonyl derivatives Vg and VIg. These compounds were also obtained from Va and VIa via di-p-toluenesulfonyl derivatives Vc and VIc by reaction with sodium salt of adenine. Treatment of compounds Vg and VIg with sodium iodide gave 4-iodo derivatives Vh and VIh which on reaction with tri-n-butyltin hydride, followed by acid hydrolysis, afforded enantiomeric threo-2,3-dihydroxybutyl derivatives Ib andIIb. Compounds Vg and VIg on treatment with sodium azide, subsequent catalytic hydrogenation of the intermediates Vj and VIj and acid hydrolysis afforded enantiomeric threo-9-(4-amino-2,3-dihydroxybutyl)adenines (Ic,IIc).

Ribonucleosides of 3-amino- and 3,5-diaminopyrazole-4-carboxylic acid and their open-chain analogues: Synthesis and reactions

1986 ◽  
Vol 51 (7) ◽  
pp. 1512-1531 ◽  
Author(s):  
Maria K. Spassova ◽  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Carboxylic Acid ◽  
Acid Hydrolysis ◽  
Carboxylic Acids ◽  
Sodium Salt ◽  
Alkaline Hydrolysis ◽  
Trimethylsilyl Derivative ◽  
Open Chain ◽  
Silyl Derivatives ◽  
Hydrolysis Of

Bis(trimethylsilyl) derivative of ethyl 3-aminopyrazole-4-carboxylate (VI) and tris(trimethylsilyl) derivative of ethyl 3,5-diaminopyrazole-4-carboxylate (VII) on reaction with 2,3,5-tri-O-benzoyl-D-ribofuranolyl chloride and subsequent debenzoylation afforded the respective β-D-ribofuranosyl derivatives VIIIa and Xa. Their alkaline hydrolysis led to 1-(β-D-ribofuranosyl)-3-aminopyrazole-4-carboxylic acid (VIIIc) and 1-(β-D-ribofuranosyl)-3,5-diaminopyrazole-4-carboxylic acid (Xb). The esters VIIIa and Xa were not ammonolyzed under normal conditions. Contrary to nucleosidation of the silyl derivatives VI and VII, sodium salt of ethyl 3-aminopyrazole-4-carboxylate was alkylated with 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (XI) or 5-(p-toluenesulfonyloxy)-1,3-dioxane (XVIIb) to give a mixture of the N-isomeric derivatives XIIIa, XIXa and XIIa, XVIIIa, respectively; sodium salt of the 3,5-diamino derivative V reacted with these synthons under formation of the corresponding compounds XIIIb and XXa. Subsequent alkaline and acid hydrolysis of XIIa and XIIIb gave the open-chain analogs of nucleosides XV and XVI. The N-(1,3-dioxan-5-yl) derivatives XVIIIc and XXa resisted acid hydrolysis, giving rise only to carboxylic acids XVIIIb and XXb.

Synthesis of 9-(2-phosphonylmethoxyethyl)adenine and related compounds

1987 ◽  
Vol 52 (11) ◽  
pp. 2801-2809 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Rosenberg
Keyword(s):  
Methyl Ester ◽  
Ethyl Ester ◽  
Sodium Salt ◽  
Alkaline Hydrolysis ◽  
Inorganic Phosphate ◽  
Sodium Hydride ◽  
Analogous Reaction ◽  
Hydrolysis Of ◽  
Related Compounds

Diethyl 2-hydroxyethoxymethanephosphonate (VIII) was converted into diethyl 2-halogenoethoxymethanephosphonates IXa and IXb by reaction with triphenylphosphine and tetrachloromethane or tetrabromomethane; analogous reaction of VIII with p-toluenesulfonyl chloride afforded diethyl 2-(p-toluenesulfonyloxy)ethoxymethanephosphonate (IXc). Reaction of sodium salt of adenine with compounds IX led to 9-(2-diethoxyphosphonylmethoxyethyl)adenine (X). Compound X was converted into 9-(2-phosphonylmethoxyethyl)adenine (II) by treatment with bromotrimethylsilane whereas alkaline hydrolysis of X gave ethyl ester Vb. Reaction of 9-(2-hydroxyethyl)adenine (IIIa) or its N6-benzoyl derivative IIIb with dimethyl p-toluenesulfonyloxymethanephosphonate (IV) in the presence of sodium hydride, followed by alkaline hydrolysis yielded methyl ester Va. Morpholide XI reacted with an inorganic phosphate and diphosphate to give 9-(2-phosphorylphosphonylmethoxyethyl)adenine (XII) and 2-(diphosphorylphosphonylmethoxyethyl)adenine (XIII), respectively.

Preparation of conjugates of uridine with proteins by the imido ester condensation method

1981 ◽  
Vol 46 (4) ◽  
pp. 933-940 ◽  
Author(s):  
Helmut Pischel ◽  
Antonín Holý ◽  
Günther Wagner
Keyword(s):  
Human Serum ◽  
Acid Hydrolysis ◽  
Ester Hydrochloride ◽  
Protein Conjugates ◽  
Condensation Method ◽  
Ester Condensation ◽  
Acid Catalyzed

Reaction of 5'-O-p-toluenesulfonyl-2',3'-O-isopropylideneuridine (I) with sodium 4-cyanophenoxide afforded 2',3'-O-isopropylidene-5'-O-(4-cyanophenyl)uridine (II) which was converted by acid hydrolysis into 5'-O-(4-cyanophenyl)uridine (IIIa). Acid-catalyzed addition of ethanol to compound IIIa gave the imido ester hydrochloride IIIb which on reaction with ammonia or ethylamine was transformed into the amidine derivatives IIIc and IIId. Compound IIIb reacted with human serum albumine or bovine gamma-globuline at pH 9.2 to give protein conjugates with uridine, bound covalently by an amidine bond (IIIe,f).

Kinetic Study of Hydrolysis of Benzoates. Part XXV. Ortho Substituent Effect in Alkaline Hydrolysis of Phenyl Esters of Substituted Benzoic Acids in Water

2006 ◽  
Vol 71 (1) ◽  
pp. 107-128 ◽  
Author(s):  
Vilve Nummert ◽  
Mare Piirsalu ◽  
Vahur Mäemets ◽  
Ilmar Koppel
Keyword(s):  
Acid Hydrolysis ◽  
Alkaline Hydrolysis ◽  
Substituent Effect ◽  
Ethyl Esters ◽  
Benzoic Acids ◽  
Neat Water ◽  
Substituted Benzoic Acids ◽  
Hydrolysis Of Esters ◽  
Hydrolysis Of

The second-order rate constants k2 for alkaline hydrolysis of phenyl esters of meta-, para- and ortho-substituted benzoic acids, X-C6H4CO2C6H5 (X = H, 3-Cl, 3-NO2, 3-CH3, 4-NO2, 4-Cl, 4-F, 4-CH3, 4-OCH3, 4-NH2, 2-NO2, 2-CN, 2-F, 2-Cl, 2-Br, 2-I, 2-CH3, 2-OCH3, 2-CF3, 2-NH2), and of substituted phenyl esters of benzoic acid, C6H5CO2C6H4-X (X = 2-I, 2-CF3, 2-C(CH3)3, 4-Cl, 4-CH3, 4-OCH3, 4-NH2), have been measured spectrophotometrically in water at 25 °C. The substituent effect in alkaline hydrolysis of phenyl esters of para-substituted benzoic acids, similar to that for ethyl esters of para-substituted benzoic acids, was found to be precisely described by the Hammett relationship (ρ = 1.7 in water). The log k value for alkaline hydrolysis of phenyl and ethyl esters of meta-, para- and ortho-substituted benzoic acids, X-C6H4CO2R, was nicely correlated with log km,p,ortho = log ko + (ρ)m,pσ + (ρI)orthoσI + (ρ°R)orthoσ°R + δorthoEsB where σ, σI, σ°R are the Hammett polar, Taft inductive and Taft resonance (σ°R = σ° - σI) substituent constants, respectively. EsB is the steric scale for ortho substituents calculated on the basis of the log k values for the acid hydrolysis of ortho- substituted phenyl benzoates in water owing to the ortho substituent in the phenyl of phenyl benzoates. In water, the main factors responsible for changes in the ortho substituent effect in alkaline hydrolysis of phenyl and ethyl esters of ortho-substituted benzoic acids, X-C6H4CO2R, were found to be the inductive and steric factors while the role of the resonance term was negligible ((ρ°R)ortho ca. 0.3). In alkaline hydrolysis of substituted benzoates in neat water, the ortho inductive effect appeared to be 1.5 times and steric influence 2.7 times higher than the corresponding influences from the ortho position in the phenyl of phenyl benzoates. The contributions of the steric effects in alkaline hydrolysis of esters of ortho-substituted benzoic acids was found to be approximately the same as in acid hydrolysis of esters of ortho-substituted benzoic and acid esterification of ortho-substituted benzoic acids.

Synthesis of 5'-O-phosphonomethyl derivatives of pyrimidine 2'-deoxynucleosides

1990 ◽  
Vol 55 (10) ◽  
pp. 2521-2536 ◽  
Author(s):  
Marcela Krečmerová ◽  
Hubert Hřebabecký ◽  
Antonín Holý
Keyword(s):  
Sodium Salt ◽  
Catalytic Hydrogenation ◽  
Bond Cleavage ◽  
Diethyl Ester ◽  
Derivatives Of

Reaction of sodium salt of 3-N,3'-O-bis(benzyloxymethyl)-2'-deoxyuridine (X) and 3-N,3'-O-bis(benzyloxymethyl)-2'-deoxythymidine (XI) with diethyl p-toluenesulfonyloxymethanephosphonate in dimethylformamide afforded diesters of the respective 5'-O-phosphonomethyl derivatives XII and XVII. Diethyl esters of 5'-O-phosphonomethyl-2'-deoxynucleosides XV and XIX, obtained after hydrogenolytic removal of the benzyloxymethyl groups, were converted into free 2'-deoxy-5'-O-phosphonomethyluridine (XVI) and a mixture of anomeric 1-(2-deoxy-5-O-phosphonomethyl-β-D-erythro-pentofuranosyl)thymines (XXIIIa, XXIIIb), respectively. Analogously, 2'-deoxy-5'-O-phosphonomethylcytidine (XXXIV) was prepared from 4-N-benzoyl-2'-deoxy-3'-O-(tetrahydro-2H-pyran-2-yl) cytidine (XXX) via diethyl ester of 2'-deoxy-5'-O-phosphonomethylcytidine (XXXIII). This compound reacted with bromotrimethylsilane to give compound XXXIV without anomerization and nucleoside bond cleavage. Condensation of the protected nucleosides X and XI with dibenzyl p-toluenesulfonyloxymethanephosphonate afforded dibenzyl esters of the corresponding 5'-O-phosphonomethyl derivatives XIII and XVIII. The free 5'-O-phosphonomethyl derivatives XVI and XXIIIa were obtained from XIII and XVIII by catalytic hydrogenation.

Convenient new synthesis of 1,3-diaroylureas

1969 ◽  
Vol 47 (11) ◽  
pp. 2097-2099 ◽  
Author(s):  
James F. Wolfe ◽  
George B. Trimitsis
Keyword(s):  
Sodium Hydride ◽  
Aromatic Esters ◽  
New Synthesis ◽  
Excess Sodium

It has been found that symmetrical 1,3-diaroylureas can be prepared in good yields by allowing urea to react with aromatic esters and excess sodium hydride in refluxing 1,2-dimethoxyethane. Applications of this method to the synthesis of unsymmetrical 1,3-diaroylureas and substituted monoaroylureas are also described.

Isocarbostyrils. II. The Conversion of 2-Methyl-4-acyl-5-nitroisocarbostyrils to 2-Substituted Indole-4-carboxylic Acids

1971 ◽  
Vol 49 (17) ◽  
pp. 2797-2802 ◽  
Author(s):  
D. E. Horning ◽  
G. Lacasse ◽  
J. M. Muchowski
Keyword(s):  
Sulfuric Acid ◽  
Carboxylic Acid ◽  
Carboxylic Acids ◽  
Alkaline Hydrolysis ◽  
Mannich Reaction ◽  
Reductive Cyclization ◽  
Acid Catalyzed ◽  
Acid Anhydrides ◽  
Hydrolysis Of ◽  
Derivatives Of

The sulfuric acid catalyzed acylation of 2-methyl-5-nitroisocarbostyril with carboxylic acid anhydrides gave the corresponding 4-acylated derivatives 3, which underwent reductive cyclization to 2-substituted derivatives of 4-methyl-1,3,4,5-tetrahydropyrrolo[4.3.2.de]isoquinolin-5-one (4). Alkaline hydrolysis of the six-membered lactam in 4 was accompanied by a retro-Mannich reaction to produce 2-substituted indole-4-carboxylic acids in about 40 % overall yield from 3.

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