General Method of Preparation of N-[(S)-(3-Hydroxy-2-phosphonomethoxypropyl)] Derivatives of Heterocyclic Bases

1993 ◽  
Vol 58 (5) ◽  
pp. 1151-1163 ◽  
Author(s):  
Petr Alexander ◽  
Antonín Holý
Keyword(s):  
Sodium Salt ◽  
Boron Trifluoride ◽  
Boron Trifluoride Etherate ◽  
Cesium Carbonate ◽  
Analogous Reaction ◽  
Sodium Salts ◽  
Heterocyclic Bases ◽  
Derivatives Of ◽  
General Method ◽  
Methanolic Ammonia

Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-trimethylacetylimidazole (II) afforded (R)-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (V) which was reacted with dimethoxymethane in the presence of phosphorus pentoxide to give (R)-2-O-methoxymethyl-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (VI). Compound VI was treated with acetic anhydride and boron trifluoride etherate and the obtained 2-acetoxy derivative VII reacted with bromotrimethylsilane to give the intermediary bromomethyl ether VIII. Compound VIII on reaction with tris(2-propyl) phosphite afforded (R)-2-O-bis(2-propyl)phosphonomethyl-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (IX). Condensation of synthon IX with sodium salts of adenine, 2,6-diaminopurine, or with cytosine, 6-azacytosine or 2-chloroadenine in the presence of cesium carbonate, afforded fully protected diesters X and XIIIb which on methanolysis and reaction with bromotrimethylsilane gave N-[(S)-(3-hydroxy-2-phosphonomethoxypropyl)] derivatives of adenine (XIa), 2- chloroadenine (XIb), 2,6-diaminopurine (XIc), cytosine (XIVa) and 6-azacytosine (XIVb). In an analogous reaction, sodium salt of 4-methoxy-2-pyrimidone reacted with compound IX to give an intermediate XIIIa which on treatment with methanolic ammonia and subsequent deblocking under the same conditions also afforded the cytosine derivative XIVa. Sodium salt of 2-amino-6-chloropurine was in this way converted into the corresponding 2-aminopurine derivative XVIII. Deprotection of this compound gave 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-2-aminopurine (XIX).

Synthesis and Biological Effects of N-(2-Phosphonomethoxyethyl) Derivatives of Deazapurine Bases

1993 ◽  
Vol 58 (6) ◽  
pp. 1419-1429 ◽  
Author(s):  
Hana Dvořáková ◽  
Antonín Holý
Keyword(s):  
Biological Effects ◽  
Sodium Hydride ◽  
Cesium Carbonate ◽  
Cytostatic Effect ◽  
Phosphonic Acids ◽  
Dna Viruses ◽  
Purine Bases ◽  
Heterocyclic Bases ◽  
L 1210 Leukemia ◽  
Derivatives Of

Analogs of antiviral 9-(2-phosphonomethoxyethyl)adenine (PMEA,II), containing modified purine bases 1-deazaadenine (VII, 3-deazapurine (XI), 7-deaza-7-cyanoadenine (XIIIb) and 3-deazaguanine (XXIb) were prepared by alkylation of the heterocyclic bases with bis(2-propyl) 2-chloroethoxymethylphosphonate (V) in dimethylformamide in the presence of sodium hydride or cesium carbonate. The obtained protected derivatives were deblocked with bromotrimethylsilane to give the phosphonic acids. 3-DeazaPMEG (XXIb) is active against DNA viruses and exhibits a marked cytostatic effect against L-1210 leukemia.

Syntheses of Enantiomeric N-(3-Hydroxy-2-phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases

1993 ◽  
Vol 58 (3) ◽  
pp. 649-674 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Benzoyl Chloride ◽  
Sodium Hydride ◽  
Cesium Carbonate ◽  
Amino Groups ◽  
Heterocyclic Base ◽  
Pyrimidine Bases ◽  
Derivatives Of ◽  
General Method

Methods of preparation of N-(3-hydroxy-2-phosphonomethoxypropyl) (HPMP) derivatives of (2S)- and (2R)-configuration (compounds I and XXVII, respectively) are described. The general method starts from the corresponding N-(2,3-dihydroxypropyl) derivatives which were converted either into the (R)-enantiomers XIII by reaction of the base with (R)-glycidol butyrate (XII) in the presence of cesium carbonate and subsequent methanolysis, or into the (S)-enantiomers XI by alkylation of the base with (R)-2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane (V) in the presence of the same reagent. The amino groups on the heterocyclic base in compounds XI and XIII were benzoylated by silylation followed by reaction with benzoyl chloride and the obtained N-benzoates XV and XVII on reaction with trityl chloride afforded the corresponding 3'-O-trityl derivatives XVI and XVIII. These compounds were condensed with bis(2-propyl) p-sulfonyloxymethylphosphonate (XXIII) in dimethylformamide in the presence of sodium hydride to give the fully protected diesters XXIV and XXVIII. These compounds could be selectively acid-hydrolyzed to remove the trityl group only under formation of compounds XXXV, or methanolyzed and then acid-hydrolyzed to remove the trityl and N-benzoyl groups and lead to compounds XXVI and XXX, or treated with bromotrimethylsilane to remove the trityl and 2-propyl group to give phosphonates of the type XXXI. All the three types of compounds were then converted into free phosphonates of the (S)-series (I) and the (R)-series (XXVII). Derivatives of cytosine (Ia, XXVIIa), adenine (Ib, XXVIIb), 2,6-diaminopurine (Ic, XXVIIc) and guanine (Id, XXVIId) were prepared. Condensation of the partially blocked adenine deriavtive XXXV with the tosyl derivative XXIII and subsequent deprotection afforded 9-(S)-(2,3-diphosphonomethoxy propyl)adenine (XLIII). Reaction of the same compound XXXV or its (R)-enantiomer XXXVIII with diethyl phosphonate , followed by deblocking, afforded 3'-O-phosphoryl derivatives (S)-HPMPA (XXXVII) and (R)-HPMPA (XL).

Synthesis of N-(2-(2-phosphonylethoxy)ethyl) derivatives of heterocyclic bases

1990 ◽  
Vol 55 (3) ◽  
pp. 809-818 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Rosenberg ◽  
Hana Dvořáková
Keyword(s):  
Triethyl Phosphite ◽  
Sodium Salts ◽  
Subsequent Hydrolysis ◽  
Pyrimidine Bases ◽  
Heterocyclic Bases ◽  
Derivatives Of

Reaction of bis(2-chloroethyl) ether (II) with triethyl phosphite afforded diethyl 2-chloroethoxyethylphosphonate (III). This compound reacts with sodium salts of heterocyclic bases to give diethyl esters of N-(2-(2-phosphonylethoxy)ethyl) derivatives of purine and pyrimidine bases IV. Compounds IV on reaction with bromotrimethylsilane and subsequent hydrolysis were converted into N-(2-(phosphonylethoxy)ethyl) derivatives IV.

Synthesis of N-(3-Azido-2-hydroxypropyl), N-(3-Phthalimido-2-hydroxypropyl) and N-(3-Amino-2-hydroxypropyl) Derivatives of Heterocyclic Bases

1994 ◽  
Vol 59 (5) ◽  
pp. 1153-1174 ◽  
Author(s):  
Maria Spassova ◽  
Hana Dvořáková ◽  
Antonín Holý ◽  
Miloš Buděšínský ◽  
Milena Masojídková
Keyword(s):  
Aqueous Medium ◽  
Cesium Carbonate ◽  
Subsequent Reaction ◽  
Weakly Alkaline ◽  
Basic Catalysis ◽  
Palladium On Carbon ◽  
Heterocyclic Bases ◽  
Derivatives Of

Alkylation of heterocyclic bases with azidomethyloxirane (I) under basic catalysis with potassium or cesium carbonate afforded N-(3-azido-2-hydroxypropyl) derivatives II. Hydrogenation of these compounds over palladium on carbon gave the corresponding 3-amino-2-hydroxypropyl derivatives III. The same compounds III were prepared by alkylation of heterocyclic bases with phthalimidomethyloxirane (VII) in the presence of cesium carbonate and subsequent reaction of the formed N-(3-phthalimido-2-hydroxypropyl) derivatives VIII with hydrazine. The phthalimido derivatives VIII are easily hydrolyzed already in weakly alkaline aqueous medium to give 9-[3-(o-carboxybenzoylamino)-2-hydroxypropyl] derivatives IX and X.

Synthesis of Isomeric N-(3-Fluoro-2-hydroxypropyl) and N-(2-Fluoro-3-hydroxypropyl) Derivatives of Purine and Pyrimidine Bases

1992 ◽  
Vol 57 (7) ◽  
pp. 1466-1482 ◽  
Author(s):  
Jindřich Jindřich ◽  
Hana Dvořáková ◽  
Antonín Holý
Keyword(s):  
Hydrogen Fluoride ◽  
Potassium Carbonate ◽  
Sodium Salt ◽  
Methyl Derivative ◽  
Chloro Derivative ◽  
Pyrimidine Bases ◽  
Heterocyclic Bases ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Subsequent Acid

Reaction of fluoromethyloxirane (III) with heterocyclic bases in the presence of potassium carbonate afforded N-(3-fluoro-2-hydroxypropyl) derivatives of adenine (VI), 3-deazaadenine (VII), 2-amino-6-chloropurine (XII), 6-nitro-1-deazapurine (IX), 4-methoxy-2-pyrimidone (XVIII) and its 5-methyl derivative (XIX). Acid hydrolysis of compounds XII, XVIII, and XIX gave 9-(3-fluoro-2-hydroxypropyl)guanine (XIII), 1-(3-fluoro-2-hydroxypropyl)uracil (XX) and -thymine (XXI). The intermediates XVIII and XIX were ammonolyzed to give 1-(3-fluoro-2-hydroxypropyl)cytosine (XXII) and -5-methylcytosine (XXIII). Reaction of chloro derivative XII with sodium azide followed by hydrogenation of the formed 2-amino-6-azidopurine (XIV) led to 9-(3-fluoro-2-hydroxypropyl)-2,6-diaminopurine (XV). 9-(3-Fluoro-2-hydroxypropyl)-1-deazaadenine (X) was obtained by hydrogenation of compound IX. Benzyloxymethyloxirane (XXIV) was reacted with pyridine-hydrogen fluoride adduct to give 3-benzyloxy-2-fluoropropanol (XXV) whose tosylate XXVI on reaction with sodium salt of adenine and subsequent hydrogenolysis of the intermediate XXVII afforded 9-(2-fluoro-3-hydroxypropyl)adenine (XXVIII). The same compound was obtained by reaction of 3-benzyloxy-1-bromo-2-fluoropropanol (XXX) with sodium salt of adenine followed by methanolysis. Condensation of sodium salt of XI, XVI, and XVII with synthon XXX and subsequent acid deblocking gave 9-(2-fluoro-3-hydroxypropyl)guanine (XXXIII), 1-(2-fluoro-3-hydroxypropyl)uracil (XXXVI), and 1-(2-fluoro-3-hydroxypropyl)thymine (XXXVII). 1-(2-Fluoro-3-hydroxypropyl) derivatives of cytosine (XXXVIII) and 5-methylcytosine (XXXIX) were obtained by ammonolysis of the corresponding 4-methoxypyrimidine intermediates XXXIV and XXXV.

2-Acylated derivatives of ergoline

1982 ◽  
Vol 47 (6) ◽  
pp. 1757-1761 ◽  
Author(s):  
Jan Beneš ◽  
Jiří Křepelka
Keyword(s):  
Molecular Weight ◽  
Boron Trifluoride ◽  
Hypotensive Effect ◽  
Boron Trifluoride Etherate ◽  
Low Molecular Weight ◽  
Aliphatic Acids ◽  
Derivatives Of

Reactions of ergoline derivatives Ia-VIIa with anhydrides of low-molecular-weight aliphatic acids, catalysed by boron trifluoride etherate, gave 2-acylated derivatives Ib-Id, IIb-IId, IIIb-Vb, or 1,2-diacylated derivatives VIb and VIIb. The compound IIb exhibited a hypotensive effect.

Bufadienolides. 17. Synthesis of 14α- and 14β-Artebufogenin

1973 ◽  
Vol 51 (12) ◽  
pp. 1973-1976 ◽  
Author(s):  
Yoshiaki Kamano ◽  
George R. Pettit
Keyword(s):  
Sulfuric Acid ◽  
Hydrochloric Acid ◽  
Perchloric Acid ◽  
Boron Trifluoride ◽  
Periodic Acid ◽  
Boron Trifluoride Etherate ◽  
Similar Reaction ◽  
Analogous Reaction ◽  
Dihydroxy Derivative

Treatment of resibufogenin (1a) or its acetate (1b) with perchloric acid or hydrochloric acid gave 14α-and 14β-artebufogenin (5a and 6a, or 5b and 6b), in addition to 15α-hydroxy-bufalin (4a or b). Reaction of epoxide 1b with chloranil or boron trifluoride etherate easily afforded 14α- and 14β-artebufogenin acetate (5b and 6b) in good yields. Analogous reaction of the isomeric 3β-hydroxy-14α,15α-epoxide 3a with perchloric acid, hydrochloric acid, or sulfuric acid again led to 14α- and 14β-artebufogenin (5a and 6a) and the 14β,15α-dihydroxy-derivative 4a, Similar reaction with periodic acid gave 6a and 4a.

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