Compositions and methods for the synthesis of organophosphorus derivatives

• US 5,936,080 A
• Filed: 05/24/1996
• Issued: 08/10/1999
• Est. Priority Date: 05/24/1996
• Status: Expired due to Fees

• Current Assignee: Genta Incorporated, Polska Akademia Nauk
• Original Assignee: Genta Incorporated, Polska Akademia Nauk
• Inventors: Stec, Wojciech J., Wozniak, Lucyna
• Primary Examiner(s): DENTZ, BERNARD I
• Application Number:
  US08/653,204
• Time in Patent Office: 1,173 Days
• Field of Search: 536/26.8, 536/26.7, 536/26.1
• US Class Current: 536/26.7
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

New organophosphorus mononucleoside derivatives, methods of their synthesis and methods for the synthesis of organophosphorus dinucleotide derivatives utilizing the organophosphorus mononucleosides are provided. Synthesized organophosphorus mononucleoside derivatives of the present invention are characterized by the formula; ##STR1## Organophosphorus dinucleoside derivatives prepared from the synthesis methods provided in the present invention are characterized by the formula; ##STR2##

Claims

1. A compound having the formula ##STR5## wherein (a) Y is a primary amine moiety, an S-aryl moiety, an Se-aryl moiety, an S-haloalkyl moiety, or an Se-haloalkyl moiety of 1 to about 10 carbon atoms, or XIR₃, wherein X₁ is O, S, or Se, and R₃ is an aralkyl moiety, a haloaryl moiety, or an alkaryl moiety of 6 to about 20 carbon atoms, or an aromatic heterocyclic moiety of 5 to 10 carbon atoms;

(b) Z is an aralkyl moiety, a haloalkyl moiety, an alkenyl moiety, or an alkaryl moiety of 1 to about 20 carbon atoms, an aminomethyl, or an aminoethyl;

;

(c) R₁ is a protecting group;

(d) R₂ is H, a halogen, an alkyl moiety of 1 to about 20 carbon atoms, an alkaryl moiety or an aralkyl moiety of about 5 to about 20 carbon atoms, CN, N₃, a protected NH₂, CF₃, OCF₃, an S-alkyl moiety, an N-alkyl moiety, an O-alkenyl moiety, an S-alkenyl moiety, an N-alkenyl moiety, an O-alkynyl moiety, an S-alkynyl moiety, an N-alkynyl moiety, an O-aryl moiety, an S-aryl moiety, an N-aryl moiety, or (O)R₄, wherein R₄ is a protecting group; and

(e) B is an optionally protected nucleoside base.

5. A compound according to any of claims 1, 2, 3 or 4, wherein Y is primary amine moiety NHR₅ wherein R₅ is a straight chain or a branched alkyl moiety, an aralkyl moiety, an aryl moiety, or an alkaryl moiety of 1 to about 20 carbon atoms, a cycloalkyl moiety of 3 to about 8 carbon atoms, or a polycycloalkyl moiety of about 10 to about 30 carbon atoms.

7. A compound according to any of claims 1 or 4, wherein R₃ is CH₂ C₆ H₄ R₆ wherein R₆ is H, a straight chain or a branched alkyl moiety of 1 to about 6 carbon atoms, a straight chain or a branched haloalkyl moiety of 1 to about 6 carbon atoms, a halogen, or NO₂.

8. A method for the synthesis of a compound according to any of claims 1, 2, 3, or 4 comprising the steps of;

(a) reacting a Z-substituted dichlorophosphine in the presence of a hydrogen chloride scavenger and a nucleoside of formula (2), wherein R₁ is a protecting group;

R₂ is H or an alkoxide moiety of 1 to about 10 carbon atoms; and

B is an N-protected nucleoside base, and

(b) adding aniline and sulfur or selenium or an oxidizing agent to the reaction mixture to produce a mixture of diastereomers of 3'"'"'-O-(Z-substituted) phosphonoanilidothioates, 3'"'"'-O-(Z-substituted) phosphonoanilidoselenoates, or 3'"'"'-O-(Z-substituted) phosphonoanilidates.

9. A method according to claim 8, wherein the oxidizing agent is selected from the group consisting of iodine/2,6-lutidine/H₂ O, t-butylhydroperoxide, or (±

)-(10-camphorsulfonyl)oxaziridine.

10. A method for the synthesis of a compound according to any of claims 1 or 4, wherein Y is X₁ R₃, wherein X₁, is S or Se and R₃ is CH₂ C₆ H₄ R₇, wherein R₇ is H, Cl, or NO₂, comprising the steps of;

(a) reacting a Z-substituted dichlorophosphine in the presence of a hydrogen chloride scavenger and a nucleoside of formula (2), wherein R₁ is a protecting group, R₂ is H or an alkoxide moiety of 1 to about 10 carbon atoms, and B is an N-protected nucleoside base,

(b) adding aniline and sulfur or selenium to the reaction mixture to produce a mixture of diastereomers of 3'"'"'-O-(Z-substituted)phosphonoanilidothioates, or 3'"'"'-O-(Z-substituted)phosphonoanilidoselenoates,

(c) reacting the mixture of diastereomers with sodium hydride or with 1,8-diazabicyclo 5.4.0!undec-7-ene and carbon dioxide to produce transient nucleoside (Z-substituted)phosphonothioic acids or (Z-substituted) phosphonoselenoic acids, and

(d) alkylating the transient nucleosides from step (c) by treatment with an alkylating agent of the formula R₈ W, wherein R₈ is CH₂ C₆ H₄ R₇, wherein R₇ is H, Cl, or NO₂ and W is Cl, Br, or I.

11. A method for the synthesis of a compound according to any of claims 1 or 4 comprising the steps of;

(a) reacting Z-substituted dichlorophosphine in the presence of a hydrogen chloride scavenger and a nucleoside of formula (2), wherein R₁ is a protecting group;

R₂ is H or an alkoxide moiety of 1 to about 10 carbon atoms; and

B is an N-protected nucleoside base,

(b) adding aniline and sulfur or selenium to the reaction to produce a mixture of diastereomers of 3'"'"'-O-(Z-substituted)phosphonoanilidothioate, or 3'"'"'-O-(Z-substituted)phosphonoanilidoselenoate, and

(c) oxidizing the mixture of diastereomers by treatment with an oxidizing agent.

12. A method for the synthesis of a compound according to any of claims 1 or 4, wherein Y is X₁ R₃ wherein X₁ is S and R₃ is CH₂ C₆ H₄ R₇, wherein R₇ is H, Cl, or NO₂, comprising the steps of:

(a) reacting Z-substituted dichlorophosphine in the presence of a hydrogen chloride scavenger and a nucleoside of formula (2), wherein R₁ is a protecting group;

R₂ is H or an alkoxide moiety of 1 to about 10 carbon atoms; and

B is an N-protected nucleoside base,

(b) adding aniline and sulfur or selenium to the reaction to produce a mixture of diastereomers of 3'"'"'-O-(Z-substituted) phosphonoanilidothioates, or 3'"'"'-O-(Z-substituted) phosphonoanilidoselenoates,

(c) oxidizing the mixture of diastereomers by treatment with an oxidizing agent to give oxidized diastereomers,

(d) reacting the oxidized diastereomers with sodium hydride or with 1,8-diazabicyclo 5.4.0!undec-7-ene and carbon disulfide to produce a transient nucleoside 3'"'"'-O(Z-substituted)phosphonothioic acid, and

(e) alkylating the transient nucleoside 3'"'"'-a-(Z-substituted)phosphonothioic acid by treatment with an alkylating agent of the general formula R₈ Z, wherein R₈ is CH₂ C₆ H₄ R₇ wherein R₇ is H, Cl, or NO₂, and Z is Cl, Br, or I.

13. A method according to claim 8 wherein R₁ is a protecting group selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, 2(-trimethylsilyl) ethoxy ether, acyl, carbamoyl, substituted silyl, 4,4'"'"'-dimethoxytrityl, and 9-phenylxanthene-9-oxyl.

14. A method according to claim 9 wherein the hydrogen chloride scavenger is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, tertiary alkyl amine and tertiary aryl amine.

15. A method according to claim 8 wherein the oxidizing agent is potassium peroxymonosulfate or hydrogen peroxide.

16. A method according to claim 10 wherein R₁ is a protecting group selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, 2(-trimethylsilyl) ethoxy ether, acyl, carbamoyl, substituted silyl, 4,4'"'"'-dimethoxytrityl, and 9-phenylxanthene-9-oxyl.

17. A method according to claim 11 wherein R₁ is a protecting group selected from the group consisting of ether, methoxyethoxymethyl ether, 2(-trimethylsilyl) ethoxy ether, acyl, carbamoyl, substituted silyl, 4,4'"'"'-dimethoxytrityl, and 9-phenylxanthene-9-oxyl.

18. A method according to claim 12 wherein R₁ is a protecting group selected from the group consisting of methoxymethyl ether, methoxyethoxymethyl ether, 2(-trimethylsilyl) ethoxy ether, acyl, carbamoyl, substituted silyl, 4,4'"'"'-dimethoxytrityl, and 9-phenylxanthene-9-oxyl.

19. A method according to claim 10 wherein the hydrogen chloride scavenger is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, tertiary alkyl amine and tertiary aryl amine.

20. A method according to claim 11 wherein the hydrogen chloride scavenger is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, tertiary alkyl amine and tertiary aryl amine.

21. A method according to claim 12 wherein the hydrogen chloride scavenger is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, tertiary alkyl amine and tertiary aryl amine.

22. A method according to claim 11 wherein the oxidizing agent is potassium peroxymonosulfate or hydrogen peroxide.

23. A method according to claim 12 wherein the oxidizing agent is potassium peroxymonosulfate or hydrogen peroxide.

2. A compound having the formula ##STR6## wherein (a) Y is an amine moiety, a halogen, or X₁ R₃, wherein X₁ is O, S or Se,, and R₃ is an alkyl moiety, an aralkyl moiety, a haloalkyl moiety, a haloaryl moiety, an alkaryl moiety, or an aryl moiety of 1 to about 20 carbon atoms, or an aromatic heterocyclic moiety of 5 to 10 carbon atoms;

(b) Z is an alkyl moiety, an aralkyl moiety, a haloalkyl moiety, an alkenyl moiety, an alkynyl moiety, an alkyl moiety, or an aryl moiety of 1 to about 20 carbon atoms, an aminomethyl, or an aminoethyl;

(c) R₁ is a protecting group other than --COPh;

(d) R₂ is H, a halogen, an alkyl moiety of 1 to about 20 carbon atoms, an alkaryl moiety or an aralkyl moiety of about 5 to about 20 carbon atoms, CN, N₃, a protected NH₂, CF₃, OCF₃, an O-alkyl moiety, an S-alkyl moiety, an N-alkyl moiety, an O-alkenyl moiety, an S-alkenyl moiety, an N-alkenyl moiety, an O-alkynyl moiety, an S-alkynyl moiety, an N-alkynyl moiety, an O-aryl moiety, an S-aryl moiety, an N-aryl moiety, or (O)R₄, wherein R₄ is a protecting group; and

(e) B is an optionally protected nucleoside base.

6. A compound according to any of claims 2 or 3, wherein R₃ is CH₃ or CH₂ C₆ H₄ R₆ wherein R ₆ is H, a straight chain or a branched alkyl moiety of 1 to about 6 carbon atoms, a straight chain or a branched haloalkyl moiety of 1 to about 6 carbon atoms, a halogen, or NO₂.

3. A compound having the formula ##STR7## wherein (a) Y is a primary amine, a halogen, or X₁ R₃, wherein X₁ is O, S or Se, and R₃ is an alkyl moiety, an aralkyl moiety, a haloalkyl moiety, a haloaryl moiety, an alkaryl moiety, or an aryl moiety of 1 to about 20 carbon atoms, or an aromatic heterocyclic moiety of 5 to 10 carbon atoms;

(b) Z is an aralkyl moiety, a haloalkyl moiety, an alkenyl moiety, an alkynyl moiety, an alkaryl moiety, or an aryl moiety of 1 to about 20 carbon atoms, an aminomethyl, or an aminoethyl;

(c) R₁ is a protecting group;

(d) R₂ is a halogen, an alkyl moiety of 1 to about 20 carbon atoms, an alkaryl moiety or an aralkyl moiety of about 5 to about 20 carbon atoms, CN, N₃, a protected NH₂, CF₃, OCF₃, an O-alkyl moiety, an S-alkyl moiety, an N-alkyl moiety, an O-alkenyl moiety, an S-alkenyl moiety, an N-alkenyl moiety, an O-alkynyl moiety, an S-alkynyl moiety, an N-alkynyl moiety, an O-aryl moiety, an S-aryl moiety, an N-aryl moiety, or (O)R₄, wherein R₄ is a protecting group; and

(e) B is an optionally protected nucleoside base.

4. A compound having the formula ##STR8## wherein (a) Y is a primary amine moiety, an O-aralkyl, an S-aryl moiety, an Se-aryl moiety, an S-haloalkyl moiety, an Se-haloalkyl moiety, a branched O-alkyl moiety of 3 to about 10 carbon atoms, or X₁ R₃, wherein X₁ is O, S, or Se, and R₃ is an aralkyl moiety, a haloaryl moiety, or an alkaryl moiety of 1 to about 20 carbon atoms, or an aromatic heterocyclic moiety of 5 to 10 carbon atoms;

(b) Z is an aralkyl moiety, a haloalkyl moiety, an alkenyl moiety, an alkynyl moiety, an alkaryl moiety or an aryl moiety of 1 to about 20 carbon atoms, an aminomethyl, or an aminoethyl;

(c) R₁ is a protecting group;

(d) R₂ is a halogen, an alkyl moiety of 1 to about 20 carbon atoms, an alkaryl moiety or an aralkyl moiety of about 5 to about 20 carbon atoms, CN, N₃, a protected NH₂, CF₃, OCF₃, an O-alkyl moiety, an S-alkyl moiety, an N-alkyl moiety, an O-alkenyl moiety, an S-alkenyl moiety, an N-alkenyl moiety, an O-alkynyl moiety, an S-alkynyl moiety, an N-alkynyl moiety, an O-aryl moiety, an S-aryl moiety, an N-aryl moiety, or (O)R₄, wherein R₄ is a protecting group; and

(e) B is an optionally protected nucleoside base.