IP Library › Granted Patent US 9,150,520

Granted Patent B2

US 9,150,520 · App. 14/216,242 · Granted Oct 6, 2015

Process for 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 J. Kim (Rockville, MD); Eliezer Falb (Giv'atayim, IL); Leigh A. Pearcey (Didcot, GB); Jonathan Cummins (Didcot, GB); Petra Dieterich (Oxfordshire, GB); Jean-Francois Carniaux (Abington, GB); Yi Wang (Chester Springs, PA); Vikram Chandrakant Purohit (Downingtown, PA)

Assignee: Rexahn Pharmaceuticals, Inc.

C07D239/47 C07F7/1892 C07D317/44

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Quick Facts

Patent No.: US 9,150,520
App. No.: 14/216,242
Granted: Oct 6, 2015
Kind: B2

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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 (57)

1. A process for the preparation of (3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (6) from (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2), comprising:

oxidizing (1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5) to form (3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (6).

2. The process of claim 1 , further comprising:

reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi to form (1R,4S,5S)-2-iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).

3. The process of claim 2 , further comprising:

oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4).

4. The process of claim 3 , wherein the step of oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) comprises Swern oxidation with diisopropylcarbodiimide, pyridine, trifluoroacetic acid (CF 3 COOH), and sodium hypochlorite (NaOCl).

5. The process of claim 3 , further comprising:

reacting (3aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro[3,4-d][1,3]dioxol-4-ol (2) with iodoform to form 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3).

6. The process of claim 1 , further comprising:

oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4); and

reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi to form (1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).

7. The process of claim 6 , wherein the step of oxidizing (1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5) to form (3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (6) comprises oxidizing with pyridinium dichromate (PDC).

8. 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:

oxidizing (1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5) to form (3aR,6aR)-5-iodo-2,2-dimethyl-6-((trityloxy)methyl)-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (6); and

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

9. The process of claim 8 , further comprising:

10. The process of claim 9 , further comprising:

oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4).

11. The process of claim 10 , wherein the step of oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) comprises Swern oxidation with diisopropylcarbodiimide, pyridine, trifluoroacetic acid (CF 3 COOH), and sodium hypochlorite (NaOCl).

12. The process of claim 10 , further comprising:

13. The process of claim 12 , further comprising:

oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4); and

14. The process of claim 8 , further comprising:

reacting 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).

15. The process of claim 14 , further comprising:

reacting (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (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).

16. The process of claim 15 , 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 (3 aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl methanesulfonate (11).

17. The process of claim 15 , 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 (3aR,4R,6aR)-5-fluoro-2,2-dimethyl-6-((trityloxy)methyl)-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ylmethanesulfonate (11); and

18. The process of claim 8 , further 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.

19. The process of claim 18 , further comprising:

hydrolysing the boronic acid intermediate with silver trifluoromethane 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).

20. The process of claim 18 , 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).

21. The process of claim 20 , wherein [(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) is formed by reacting 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.

22. The process of claim 20 , 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).

23. The process of claim 22 , wherein [(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) is formed by reacting 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.

24. A compound

(1R,4S,5S)-2-Iodo-4,5-isopropylidenedioxy-1-(trityloxymethyl)cyclopent-2-enol (5).

25. The process for making the compound of claim 24 , comprising reacting 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) with n-BuLi.

26. The process of claim 25 , further comprising

oxidizing 1-((4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4).

27. The process of claim 26 , wherein the step of oxidizing 1-(( 4 (4R,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4) comprises Swern oxidation with diisopropylcarbodiimide, pyridine, trifluoroacetic acid (CF 3 COOH), and sodium hypochlorite (NaOC1).

28. The process of claim 26 , further comprising:

29. The process of claim 25 , further comprising:

reacting (3 aR,6aR)-2,2-dimethyl-6-((trityloxy)methyl)tetrahydrofuro [3,4-d] [1,3] dioxol-4-ol (2) with iodoform to form 1-((4R,5 S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3 -dioxolan-4-yl)-2-(trityloxy)ethanol (3); and

oxidizing 1-((4R,5 S)-5-(2,2-diiodovinyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanol (3) to form 1-((4S,5 S)-5-(2,2-diiodovinyl)-2,2 -dimethyl-1,3-dioxolan-4-yl)-2-(trityloxy)ethanone (4).

Assignments (6)

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 Oct 23, 2014

From: WANG, YI; PUROHIT, VIKRAM CHANDRAKANT

To: TEVA PHARMACEUTICAL INDUSTRIES, LTD.; REXAHN PHARMACEUTICALS, INC.

Reel/Frame 034022/0163 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 23, 2014

From: TEVA PHARMACEUTICAL INDUSTRIES, LTD.

To: REXAHN PHARMACEUTICALS, INC.