IP Library › Granted Patent US 9,533,958
Granted Patent B2
US 9,533,958 · App. 14/845,968 · Granted Jan 3, 2017

Process or the preparation of 4-amino 1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-Enyl)-1H-pyrimidin-2-one

Inventors: Haifeng Yin (Shanghai, CN); Deog Joong Kim (Rockville, MD); Eliezer Falb (Givatayim, IL); Leigh Andre Pearcey (Didcot, GB); Jonathan Cummins (Didcot, GB); Petra Dieterich (Abingdon, GB); Jean-Francois Carniaux (Abington, GB); Yi Wang (Chester Springs, PA); Vikram Chandrakant Purohit (Downingtown, PA)
Assignee: Rexahn Pharmaceuticals, Inc.
C07D239/47C07D317/44C07D405/04C07F7/1892
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Quick Facts
Patent No.
US 9,533,958
App. No.
14/845,968
Granted
Jan 3, 2017
Kind
B2
Abstract

Processes for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-hydroxymethyl-cyclopent-2-enyl)-1H-pyrimidin-2-one (13, RX-3117) and its intermediates are described.

Claims (46)

1. A process for preparing tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9) from tert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (8), comprising:

converting tert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (8) to a boronic acid intermediate.

2. The process of claim 1 , further comprising:

hydrolysing the boronic acid intermediate with silver trifloromethane sulfonate to form a hydrolysate; and

reacting the hydrolysate with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) to form tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9).

3. The process of claim 1 , wherein the boronic acid intermediate is selected from a group consisting of [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronic acid (9c-1) and [(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane (9c-2).

4. The process of claim 3 , wherein the boronic acid intermediate is [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronic acid (9c-1) and is formed by reacting the tert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (8) with trimethylborate.

5. The process of claim 3 , wherein the bonoric acid intermediate is [(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane (9c-2) and is formed by reacting the tert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (8) with 4,4,5,5-tetramethyl-1,3,2 dioxaborolane.

6. A process for the preparation of 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13) comprising:

converting tert-butyl(((3aR,4R,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (8) to a boronic acid intermediate;

hydrolysing the boronic acid intermediate with silver trifloromethane sulfonate to form a hydrolysate;

reacting the hydrolysate with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) to form tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9); and

isolating the 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).

7. The process of claim 6 , wherein the boronic acid intermediate is [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronic acid (9c-1).

8. The process of claim 6 , wherein the boronic acid intermediate is [(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane (9c-2).

9. The process of claim 6 , further comprising:

reacting the tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9) with tetra-n-butylammonium fluoride to form (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10).

10. The process of claim 9 , further comprising:

reacting the (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10) with MsCl to form (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11).

11. The process of claim 10 , further comprising:

reacting the (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11) with cytosine to form 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12).

12. The process of claim 11 , further comprising:

reacting the 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12) with an acid to form 4-amino-1-((1 S,4R,5 S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).

13. The process of claim 6 , wherein the boronic acid intermediate is [(3aR,6S,6aR)-6-[tert-butyl(diphenyl)silyl]oxy-2,2-dimethyl-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-5-yl]boronic acid (9c-1), further comprising:

reacting the hydrolysate with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) to form tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9); and

reacting the tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9) with tetra-n-butylammonium fluoride to form (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10).

14. The process of claim 13 , further comprising:

reacting the (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10) with MsCl to form (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11);

reacting the (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11) with cytosine to form 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12); and

reacting the 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12) with an acid to form 4-amino-1-((1S,4R,5 S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).

15. The process of claim 6 , wherein the boronic acid intermediate is [(3aR,6S,6aR)-2,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trityloxymethyl)-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-6-yl]oxy-tert-butyl-diphenyl-silane (9c-2), further comprising:

reacting the hydrolysate with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) to form tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9); and

reacting the tert-butyl(((3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)oxy)diphenylsilane (9) with tetra-n-butylammonium fluoride to form (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10).

16. The process of claim 15 , further comprising:

reacting the (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10) with MsCl to form (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11);

reacting the (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11) with cytosine to form 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12); and

reacting the 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12) with an acid to form 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).

17. A method of making 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13), comprising:

reacting (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11) with cytosine to form 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12).

18. The method of claim 17 , further comprising:

reacting (3 aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10) with MsCl to form (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11).

19. The method of claim 17 , further comprising:

reacting the 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12) with an acid to form 4-amino-1-((1S,4R,5S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).

20. The method of claim 17 , further comprising:

reacting (3aS,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol (10) with MsCl to form the (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11); and

reacting the 4-amino-1-(3aS,4S,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)pyrimidin-2(1H)-one (12) with an acid to form the 4-amino-1-((1 S,4R,5 S)-2-fluoro-4,5-dihydroxy-3-(hydroxymethyl)-cyclopent-2-en-1-yl)-pyrimidin-2(1H)-one (13).

Assignments (2)
CHANGE OF NAME Recorded Nov 4, 2021
From: REXAHN PHARMACEUTICALS, INC.
To: OCUPHIRE PHARMA, INC.
Reel/Frame 058032/0161 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 11, 2015
From: YIN, HAIFENG; KIM, DEOG JOONG; PEARCEY, LEIGH ANDRE; CUMMINS, JONATHAN; DIETERICH, PETRA; CARNIAUX, JEAN-FRANCOIS; WANG, YI; PUROHIT, VIKRAM CHANDRAKANT
To: REXAHN PHARMACEUTICALS, INC.
Reel/Frame 036588/0756 →
Continuity (3)
Continuation 14216242 · Mar 17, 2014
Provisional Application 61800475 · Mar 15, 2013
Related Publication 20150376142A1 · Dec 31, 2015