Synthesis of N-(3-Fluoro-2-phosphonomethoxypropyl) (FPMP) Derivatives of Heterocyclic Bases

1993 ◽  
Vol 58 (7) ◽  
pp. 1645-1667 ◽  
Author(s):  
Jindřich Jindřich ◽  
Antonín Holý ◽  
Hana Dvořáková
Keyword(s):  
Heterocyclic Ring ◽  
Hydroxyl Group ◽  
Subsequent Removal ◽  
Heterocyclic Base ◽  
Primary Hydroxyl ◽  
Pyrimidine Bases ◽  
Ether Treatment ◽  
Heterocyclic Bases ◽  
Derivatives Of ◽  
Chiral Synthon

A new group of compounds has been prepared: N-(3-fluoro-2-phosphonomethoxypropyl) (FPMP) derivatives of purine and pyrimidine bases which exhibit a significant selective activity against a broad spectrum of retroviruses. Racemic N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of adenin (V), guanine (IX), cytosine (XIII), 2,6-diaminopurine (XXI), 3-deazaadenin e(XVII), xanthine (X) and hypoxanthin (VI) were prepared from the corresponding N-(3-fluoro-2-hydroxypropyl) derivatives after protection of amino group at the heterocyclic ring by selective benzoylation, reaction with diisopropyl p-toluenesulfonyloxymethylphosphonate (II), and subsequent removal of the protecting groups. Chiral FPMP derivatives were prepared by reaction of heterocyclic base with the corresponding chiral synthon (XXX, XXXVII) followed by deprotection. The required chiral synthons were obtained from enantiomeric 3-fluoro-1,2-propanediols by two methods. In the first, the primary hydroxyl group was tritylated, the obtained derivative was reacted with compound II, the trityl group was removed and the product was mesylated to give synthon XXXVII. The second pathway consisted in selective tosylation of the primary hydroxyl group and conversion of the secondary hydroxyl into the acetoxymethyl ether via the methoxymethyl ether; treatment of the acetoxy compound with bromotrimethylsilane and triisopropyl phosphite afforded the desired synthon XXX.

Synthesis of 2-Deoxy-β-D-ribonucleosides and 2,3-Dideoxy-β-D-pentofuranosides on Immobilized Bacterial Cells

1994 ◽  
Vol 59 (10) ◽  
pp. 2303-2330 ◽  
Author(s):  
Ivan Votruba ◽  
Antonín Holý ◽  
Hana Dvořáková ◽  
Jaroslav Günter ◽  
Dana Hocková ◽  
...  
Keyword(s):  
The Other ◽  
Bacterial Cells ◽  
Amino Groups ◽  
E Coli ◽  
Pyrimidine Series ◽  
Acceptor Activity ◽  
Dependent Strain ◽  
Pyrimidine Bases ◽  
Heterocyclic Bases ◽  
Derivatives Of

Alginate gel-entrapped cells of auxotrophic thymine-dependent strain of E. coli catalyze the transfer of 2-deoxy-D-ribofuranosyl moiety of 2'-deoxyuridine to purine and pyrimidine bases as well as their aza and deaza analogs. All experiments invariably gave β-anomers; in most cases, the reaction was regiospecific, affording N9-isomers in the purine and N1-isomers in the pyrimidine series. Also a 2,3-dideoxynucleoside can serve as donor of the glycosyl moiety. The acceptor activity of purine bases depends only little on substitution, the only condition being the presence of N7-nitrogen atom. On the other hand, in the pyrimidine series the activity is limited to only a narrow choice of mostly short 5-alkyl and 5-halogeno uracil derivatives. Heterocyclic bases containing amino groups are deaminated; this can be avoided by conversion of the base to the corresponding N-dimethylaminomethylene derivative which is then ammonolyzed. The method was verified by isolation of 9-(2-deoxy-β-D-ribofuranosyl) derivatives of adenine, guanine, 2-chloroadenine, 6-methylpurine, 8-azaadenine, 8-azaguanine, 1-deazaadenine, 3-deazaadenine, 1-(2-deoxy-β-D-ribofuranosyl) derivatives of 5-ethyluracil, 5-fluorouracil, and 9-(2,3-dideoxy-β-D-pentofuranosyl)hypoxanthine, 9-(2,3-dideoxy-β-D-pentofuranosyl)-6-methylpurine, and other nucleosides.

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).

scholarly journals SYNTHESIS OF 1,2;3,4-DI-O-ISOPROPYLIDENE-6- O-[4-(1H-AZOL-1-YLMETHYL) PHENYL]- ¯-D-GALACTOPYRANOSE AND 1,2,3,4-TETRA-O-ACETYL-6- O-[4-(1H-AZOL-1- YLMETHYL)PHENYL]-¯-D-GLUCOPYRANOSE

2017 ◽  
Vol 17 (5) ◽  
pp. 122-128
Author(s):  
Z.P. Belousova ◽  
P.P. Purygin ◽  
A.P. Tyurin
Keyword(s):  
Hydroxyl Group ◽  
Hydroxyl Groups ◽  
Secondary Hydroxyl ◽  
Primary Hydroxyl ◽  
Derivatives Of

Derivatives of D-galactose and D-glucose substituted for the primary hydroxyl group, which contain an aglycone azolylmethylphenyl fragments (for imidazole, 1,2,4-triazole, benzimidazole and benzotriazole) has been synthesized. Toprotect the secondary hydroxyl groups of monosaccharides acetyl and isopropylidene groups were used.

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 Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. I. The Stepwise Approach

1995 ◽  
Vol 60 (7) ◽  
pp. 1196-1212 ◽  
Author(s):  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Acid Hydrolysis ◽  
High Activity ◽  
Aluminum Hydride ◽  
Heterocyclic Base ◽  
Stepwise Approach ◽  
Pyrimidine Bases ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Very High

The (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) exhibit very high activity against retroviruses. This paper describes the synthesis of enantiomeric 9-(2-phosphonomethoxypropyl)adenines (I and XXVII), 9-(2-phosphonomethoxypropyl)-2,6-diaminopurines (II and XXXI), 9-(2-phosphonomethoxypropyl)guanines (III and XXIX) and 1-(R)-(2-phosphonomethoxypropyl)cytosine (XIX) by alkylation of N-protected N-(2-hydroxypropyl) derivatives of the corresponding bases with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (X), followed by stepwise N- and O-deprotection of the intermediates. The key intermediates, N-(2-hydroxypropyl) derivatives IX and XXV, were obtained by alkylation of the appropriate heterocyclic base with (R)- or (S)-2-(2-tetrahydropyranyloxy)propyl p-toluenesulfonate (VII or XXIII) and acid hydrolysis of the resulting N-[2-(2-tetrahydropyranyloxy)propyl] derivatives VIII and XXII. The chiral synthons were prepared by tosylation of (R)- or (S)-2-(2-tetrahydropyranyloxy)propanol (VI or XXI) available by reduction of enantiomeric alkyl 2-O-tetrahydropyranyllactates V and XXI with sodium bis(2-methoxyethoxy)aluminum hydride. This approach was used for the synthesis of cytosine, adenine and 2,6-diaminopurine derivatives, while compounds derived from guanine were prepared by hydrolysis of 2-amino-6-chloropurine intermediates. Cytosine derivative IXe was also synthesized by alkylation of 4-methoxy-2-pyrimidone followed by ammonolysis of the intermediate IXf.

Synthesis of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases

1989 ◽  
Vol 54 (8) ◽  
pp. 2190-2210 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Rosenberg ◽  
Hana Dvořáková
Keyword(s):  
Alkali Metal ◽  
Metal Salts ◽  
Alkali Metal Salts ◽  
Phosphonic Acids ◽  
Pyrimidine Bases ◽  
Methyl Derivatives ◽  
Heterocyclic Bases ◽  
Derivatives Of

The preparation of N-(2-phosphonylmethoxyethyl) derivatives of purine and pyrimidine bases, IV, as analogs of the antiviral 9-(2-phosphonylmethoxyethyl)adenine (PMEA, I), is described. The synthesis consists in alkylation of alkali metal salts of heterocyclic bases or their N- or O-substituted derivatives with diethyl 2-p-toluenesulfonyloxyethoxymethylphosphonate (IIa), 2-chloroethoxymethylphosphonate (IIb) or 2-bromoethoxymethylphosphonate (IIc). The obtained N-(2-diethoxyphosphonylmethoxyethyl) derivatives of heterocyclic bases (III) were treated with bromotrimethylsilane to give phosphonic acids IV. Compounds IV were prepared from pyrimidines (uracil, cytosine and their 5-methyl derivatives), purines (adenine and its N6- and C(2)-substituted derivatives, hypoxanthine, guanine, 6-hydrazinopurine and 6-methylthiopurine etc.) and their analogs (3-deazaadenine etc.).

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.

Synthesis of (3-hydroxy-2-phosphonylmethoxypropyl) derivatives of heterocyclic bases

1989 ◽  
Vol 54 (9) ◽  
pp. 2470-2501 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Rosenberg ◽  
Hana Dvořáková
Keyword(s):  
Aqueous Sodium Hydroxide ◽  
Biologically Active ◽  
Isomeric Mixture ◽  
Heterocyclic Base ◽  
Regioselective Substitution ◽  
Methyl Derivatives ◽  
Heterocyclic Bases ◽  
Isomeric Mixtures ◽  
Derivatives Of ◽  
Biologically Active Derivatives

Analogs of the antiviral 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA, I), containing modified heterocyclic base, were prepared from racemic or (S)-N-(2,3-dihydroxypropyl) derivatives II. Compounds II are heated with chloromethylphosphonyl dichloride (XVII), the formed chloromethylphosphonylester chlorides of compounds II react with water to give a mixture of 2'- and 3'-chloromethylphosphonyl derivatives XVIII and XIX, respectively, which on isomerization by boiling with water in the arising acidic medium affords predominantly the 3'-isomer XIX. Treatment of this isomeric mixture with aqueous sodium hydroxide yields a mixture of 2'-O-phosphonylmethyl ethers (predominating, XXI) and 3'-O-phosphonylmethyl ethers of compounds II (XX). This approach has been applied to the synthesis of isomeric mixtures in the racemic as well as in the (S)-series derived from C-2, C-8 and N-6 substituted derivatives of adenine, from hypoxanthine and additional 6-substituted derivatives of purine, from guanine, 3-deazaadenine and other modified purine bases, from uracil, cytosine, their 5-methyl derivatives and 5-fluorouracil. Regioselective synthesis of compounds XXI was performed for biologically active derivatives (derivative of 2-aminoadenine (XXIe), guanine (XXIn), 3-deazaadenine (XXIp) and cytosine (XXIt)) as well as some other compounds (derivative of hypoxanthine (XXIj), uracil (XXIr), thymine (XXIs) and 5-methylcytosine (XXIu)): the former were obtained either from 3'-O-chloromethylphosphonyl derivatives XIX, isolated from the above-mentioned mixtures by ion-exchanger chromatography or HPLC, or by regioselective substitution, whereas the latter compounds were prepared by deamination (compound XXIj from adenine derivative I or the uracil and thymine derivatives XXIr and XXIu from the cytosine derivatives XXIt and XXIu). N-(S)-(3-Hydroxy-2-benzoyloxypropyl) derivative of N4-benzoylcytosine (XXIX) and N2-benzoylguanine (XXIV), obtained from compounds IIn and IIt by successive N-benzoylation, reaction with dimethoxytrityl chloride, benzoylation and mild acid treatment, were subjected to reaction with the chloride XVII and subsequent neutral and alkaline hydrolysis (compound XXIV), or to reaction with sodium methoxide followed by treatment with bromotrimethylsilane (compound XXIX), being thus converted into 1-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (XXIt, HPMPC) and 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)guanine (XXIn, HPMPG), respectively. The starting compounds (S)-II were synthesized from sodium salt of the corresponding heterocyclic base by reaction with 1-O-p-toluenesulfonyl-2,3-O-isopropylidene-(R)-glycerol (IIIa) (the (RS)-derivatives by reaction with 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (IIIb)), followed by acid hydrolysis.

Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach

1995 ◽  
Vol 60 (8) ◽  
pp. 1390-1409 ◽  
Author(s):  
Antonín Holý ◽  
Hana Dvořáková ◽  
Milena Masojídková
Keyword(s):  
Subsequent Reaction ◽  
Heterocyclic Base ◽  
Benzyl Ethers ◽  
Pyrimidine Bases ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Hydrolytic Deamination ◽  
Adenine Derivatives

Another approach to (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) I and II is described, consisting in alkylation of the heterocyclic base with (R)- and (S)-2-[bis(2-propyl)phosphonylmethoxy]propyl p-toluenesulfonates (X and XVIII) followed by transsilylation of the intermediary N-[2-bis(2-propyl)phosphonylmethoxypropyl] derivatives XI and XIX. The key intermediates X and XVIII were obtained from 1-benzyloxypropanols VI and XIV by two routes: (i) condensation with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (XIII), hydrogenolysis of the obtained 1-benzyloxy-2-bis(2-propyl)phosphonylmethoxypropanes VIII and XVI over Pd/C to 2-bis(2-propyl)phosphonylmethoxypropanols IX and XVII and tosylation of the latter or (ii) chloromethylation of compounds VI and XIV and subsequent reaction of the chloromethyl ethers VII and XV with tris(2-propyl) phosphite and further processing of the benzyl ethers VIII and XVI analogous to the enantiomeric propanols IX and XVII. This approach was used for the synthesis of derivatives of adenine (Ia, IIa), 2,6-diaminopurine (Ib, IIb) and 3-deazaadenine (Ic, IIc). Their guanine counterparts Ie and IIe were prepared by hydrolysis of 2-amino-6-chloropurine intermediates XId and XIXd. 6-Chloropurine was converted into diester XIi by reaction with tosylate X, which on reaction with thiourea and subsequent ester cleavage afforded the 6-thiopurine derivative Ij. Analogously, 2-amino-6-chloropurine derivative XId reacted with thiourea to give 9-(R)-(2-phosphonomethoxypropyl)-2-thioguanine (If), or with dimethylamine under formation of (2-phosphonomethoxypropyl)-2-amino-6-dimethylaminopurine (Ig). Hydrogenolysis of compound XId gave 9-(R)-(2-phosphonomethoxypropyl)-2-aminopurine (Ik). Hydrolytic deamination of adenine derivatives Ia and IIa led to enantiomeric (2-phosphonomethoxypropyl)hypoxanthines Ih and IIh.

Inductive effect in EI-mass spectra of some 5,6-dihalogenides and 5,6-halohydrins of 5α-cholestan-3β-ol and 3β-acetoxy-5α-cholestane

1982 ◽  
Vol 47 (11) ◽  
pp. 2946-2960 ◽  
Author(s):  
Antonín Trka ◽  
Alexander Kasal
Keyword(s):  
Mass Spectra ◽  
Inductive Effect ◽  
Molecular Ions ◽  
Hydroxyl Group ◽  
Halogen Atoms ◽  
Derivatives Of

Partial EI-mass spectra of 3β-hydroxy- and 3β-acetoxy-5α-cholestanes substituted in positions 5α-, 6β- or 5α,6β- with a hydroxyl group or halogen atoms (fluorine, chlorine, bromine) are presented. The molecular ions of 5α,6β-disubstituted derivatives of 3β-hydroxy-5α-cholestane (or of its 3-acetate) are considerably more stable than the corresponding monosubstituted derivatives if at least one of the pair of the vicinal substituents is chlorine or fluorine. This increase in stability, most striking in 5α- and 6β-fluoro compounds, is explained by the inductive effect.

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