Compounds and methods for the synthesis of 5-(N-protected-tryptaminocarboxyamide)-2′-deoxyuridine phosphoramidite for incorporation into a nucleic acid

Patent metadata

Field	Value
Publication number	US-10634679-B2
Application number	US-201716078859-A
Country	US
Kind code	B2
Filing date	Mar 13, 2017
Priority date	Mar 14, 2016
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

Abstract

Modified Tryptamine, Tryptamine-2′-deoxy-uridine (TrpdU) and TrpdU-phosphoramidites for oligonucleotide synthesis are provided, as well as improved methods of their synthesis and oligonucleotides comprising at least one modified TrpdU nucleotide.

First claim

I claim:

1. A compound having the structure:

or a salt thereof;
wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl;
X 1 and X 2 are each independently selected from methoxy and hydrogen; and
X 3 is selected from methoxy, fluoro, hydrogen, and tert-butyldimethylsilyloxy.

2. The compound of claim 1 , selected from:

and salts thereof.

3. A compound having the structure:

or a salt thereof;
wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl;
X 1 and X 2 are each independently selected from methoxy and hydrogen; and
X 3 is selected from a methoxy, fluoro, hydrogen, and tert-butyldimethylsilyloxy.

4. The compound of claim 3 , selected from:

and salts thereof.

5. A compound having the structure:

or a salt thereof;
wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl.

6. The compound of claim 5 , wherein the compound is:

or a salt thereof.

7. A compound having the structure:

wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl.

8. The compound of claim 7 , wherein the compound is:

9. A method of producing a compound having the structure:

or a salt thereof;
wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl;
the method comprising reacting N-α-BOC-tryptamine with an acid chloride selected from pivaloyl chloride, 2,2-dimethylbutyroyl chloride, 2,2-dimethylvaleroyl chloride, 1-methylcyclopentane-1-carbonyl chloride, 1-methylcyclohexane-1-carbonyl chloride, 2-chlorobenzoyl chloride, and 2-cyanobenzoyl chloride.

10. The method of claim 9 , wherein R 1 is tent-butyl, and wherein the acid chloride is pivaloyl chloride.

11. The method of claim 9 , wherein the compound is:

12. A method of producing a compound having the structure:

wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl;

the method comprising reacting the compound

with trifluoroacetic acid.

13. The method of claim 12 , wherein the method produces a compound of the structure:

14. A method of producing a compound having the structure:

or a salt thereof;
wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl;
X 1 and X 2 are each independently selected from methoxy and hydrogen;
X 3 is selected from a methoxy, fluoro, hydrogen, and tert-butyldimethylsilyloxy;

the method comprising reacting the compound

with 5′-O-DMT-5-(2,2,2-trifluoroethyoxy-carbonyl)- 2′-deoxyuridine (TFEdU).

15. The method of claim 14 , wherein the method produces a compound selected from:

and salts thereof.

16. The method of claim 14 , wherein the method further comprises reacting the compound

with trifluoroacetic acid to form the compound

17. The method of claim 16 , wherein the method further comprises reacting N-α-BOC-tryptamine with an acid chloride selected from pivaloyl chloride, 2,2-dimethylbutyroyl chloride, 2,2-dimethylvaleroyl chloride, 1-methylcyclopentane-1-carbonyl chloride, 1-methylcyclohexane-1-carbonyl chloride, 2-chlorobenzoyl chloride, and 2-cyanobenzoyl chloride, to form the compound

18. A method of producing a compound having the structure:

or a salt thereof;
wherein,
R 1 is selected from tent-butyl, 1,1-dimethyl-propyl; 1,1-dimethyl-butyl; 2-chlorophenyl; 2-cyanophenyl; 1-methyl-cyclopentyl; and 1-methyl-cyclohexyl;
X 1 and X 2 are each independently selected from methoxy and hydrogen;
X 3 is selected from a methoxy, fluoro, hydrogen, and tert-butyldimethylsilyloxy;

the method comprising reacting the compound

with 2-cyanoethyl-N,N,N′,N′-tetraisopropylphosphor-amidite.

19. The method of claim 18 , wherein the method comprises reacting the compound

with 5′-O-DMT-5-(2,2,2-trifluoroethyoxy-carbonyl)- 2′-deoxyuridine (TFEdU) to form the compound

20. The method of claim 19 , wherein the method comprises reacting the compound

with trifluoroacetic acid to form the compound

Assignees

• Somalogic Inc

Inventors

• ROHLOFF John

Classifications

• C07H19/073 Primary

  with 2-deoxyribosyl as the saccharide radical · CPC title

• C07H1/00 Primary

  Processes for the preparation of sugar derivatives · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title

• C07H19/10

  with the saccharide radical esterified by phosphoric or polyphosphoric acids · CPC title

• C07H21/04

  with deoxyribosyl as saccharide radical · CPC title