IP Library › Granted Patent US 8,946,475

Granted Patent B2

US 8,946,475 · App. 13/720,298 · Granted Feb 3, 2015

Processes for preparing a polymeric compound

Inventors: Robert W. Kavash (Radnor, PA); Haizhong Tang (Radnor, PA); Carol Mulrooney (Radnor, PA); Dahui Liu (Radnor, PA)

Assignee: Cellceutix Corporation

C07C231/14 C07C231/12 C07C235/12 C07C271/22 C07C271/52

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,946,475
App. No.: 13/720,298
Granted: Feb 3, 2015
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides methods for preparing a polymeric compound of Formula I: or pharmaceutically acceptable salt thereof. The present invention also provides useful intermediates for preparing the compound of Formula I or pharmaceutically acceptable salt thereof.

Claims (92)

1. A method for preparing a compound of Formula I:

or pharmaceutically acceptable salt thereof, comprising:

a) removing the Cbz groups from a compound of Formula II:

or pharmaceutically acceptable salt thereof, under a hydrogen source chosen from H 2 gas, formic acid, ammonium formate, and 1,4-cyclohexadiene, and a metal catalyst chosen from Pd/C, Pd black, Pd(OH) 2 , PdCl 2 , Raney Ni, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst to form the compound of Formula I, or pharmaceutically acceptable salt thereof; and

b) optionally isolating the compound of Formula I, or pharmaceutically acceptable salt thereof.

2. The method of claim 1 further comprising:

c) removing the Boc group from a compound of Formula III:

or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, or H 2 SO 4 , or TMSOTf/2,6-lutidine, optionally in a solvent chose from CH 2 Cl 2 , EtOAc, tetrahydrofuran, dichloromethane, methanol, ethanol, dioxane, and water, or a mixture of any two or more of these solvents, to form the compound of Formula II, or pharmaceutically acceptable salt thereof.

3. The method of claim 2 further comprising:

d) reacting a compound of Formula IV:

or pharmaceutically acceptable salt thereof, with a compound of Formula V:

or pharmaceutically acceptable salt thereof, in the presence of a coupling reagent chosen from benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC or EDAC), dicyclohexylcarbodimide (DCC), N,N′-diisopropylcarbodiimide (DIC), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (Py-BOP), N,N′-carbonyldiimidazole (CDI), N-hydroxybenzotriazole (HOBt), 1H-Benzotriazolium 1-[bis(dimethyl-amino)methylene]-5-chloro-hexafluorophosphate (1-),3-oxide (HCTU), 2,4,6-trichloro-1,3,5-triazine, 2-chloro-4,6-diphenoxy-1,3,5-triazine, 2-chloro-4,6-dibenzyloxy-1,3,5-triazine, 2-chloro-4,6-dimethoxy-1,3,5-triazine, 2,4-dichloro-6-phenoxy-1,3,5-triazine, 2,4-dichloro-6-benzyloxy-1,3,5-triazine, and 2,4-dichloro-6-methoxy-1,3,5-triazine, or a mixture of two or more thereof; and an organic base chosen from triethylamine (TEA), diisopropylethylamine (DIEA), N-methylmorpholine (NMM), N—N-dimethylaminopyridine (DMAP), pyridine, and imidazole, to form the compound of Formula III, or pharmaceutically acceptable salt thereof.

4. The method of claim 3 further comprising:

e) reacting a compound of Formula IV:

or pharmaceutically acceptable salt thereof, with ammonia or NH 4 Cl, in the presence of an activating reagent chosen from ethyl chloroformate, isobutyl chloroformate, thionyl chloride, oxalyl chloride, cyanuric chloride, and PBr 3 , and an organic base which is N,N-diisopropylethylamine to form a compound of Formula VI:

or pharmaceutically acceptable salt thereof; and

f) removing the Boc group from the compound of Formula VI, or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , trifluoroacetic acid, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula V, or pharmaceutically acceptable salt thereof.

5. The method of claim 4 further comprising:

g) hydrolyzing a compound of Formula VII:

or pharmaceutically acceptable salt thereof, in the presence of a base chosen from LiOH, NaOH, KOH, Ba(OH) 2 , Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 , to form the compound of Formula IV.

6. The method of claim 5 further comprising:

h) reacting a compound of Formula VIII:

or pharmaceutically acceptable salt thereof, with a compound of Formula IX:

or pharmaceutically acceptable salt thereof, in the presence of a coupling reagent and an organic base to form the compound of Formula VII, or pharmaceutically acceptable salt thereof.

7. The method of claim 6 further comprising:

i) hydrolyzing a compound of Formula X:

or pharmaceutically acceptable salt thereof, in the presence of a base chosen from LiOH, NaOH, KOH, Ba(OH) 2 , Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 , to form the compound of Formula IX; and

j) removing the Boc group from a compound of Formula X, or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula VIII, or pharmaceutically acceptable salt thereof.

8. The method of claim 7 further comprising:

k) reacting a compound of Formula XI:

or pharmaceutically acceptable salt thereof, with a compound of Formula XII:

or pharmaceutically acceptable salt thereof, in the presence of a coupling reagent and an organic base to form the compound of Formula X, or pharmaceutically acceptable salt thereof.

9. A method for preparing a compound of formula I:

or pharmaceutically acceptable salt thereof, comprising:

a1) removing the Cbz groups from a compound of Formula II-1:

or pharmaceutically acceptable salt thereof, under a hydrogen source chosen from H 2 gas, formic acid, ammonium formate, and 1,4-cyclohexadiene, and a metal catalyst chosen from Pd/C, Pd black, Pd(OH) 2 , PdCl 2 , Raney Ni, a platinum catalyst, a rhodium catalyst, and a ruthenium catalyst, to form the compound of Formula I, or pharmaceutically acceptable salt thereof; and

b1) optionally isolating the compound of Formula I, or pharmaceutically acceptable salt thereof.

10. The method of claim 9 further comprising:

c1) reacting a compound of Formula III-1:

or pharmaceutically acceptable salt thereof, with a compound of Formula IV-1:

or pharmaceutically acceptable salt thereof, in the presence of a coupling reagent chosen from BOP, HBTU, HATU, EDAC, DCC, DIC, Py-BOP, CDI, HOBt, HCTU, 2,4,6-trichloro-1,3,5-triazine, 2-chloro-4,6-diphenoxy-1,3,5-triazine, 2-chloro-4,6-dibenzyloxy-1,3,5-triazine, 2-chloro-4,6-dimethoxy-1,3,5-triazine, 2,4-dichloro-6-phenoxy-1,3,5-triazine, 2,4-dichloro-6-benzyloxy-1,3,5-triazine, and 2,4-dichloro-6-methoxy-1,3,5-triazine, or a mixture of two or more thereof, and an organic base chosen from TEA, DIEA, NMM, DMAP, pyridine, and imidazole, to form the compound of Formula II-1, or pharmaceutically acceptable salt thereof.

11. The method of claim 10 further comprising:

d1) reacting a compound of Formula VI-1:

or pharmaceutically acceptable salt thereof, with a compound of Formula VII-1:

or pharmaceutically acceptable salt thereof; and

e1) removing the Boc group from the compound of Formula V-1, or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula III-1, or pharmaceutically acceptable salt thereof.

12. The method of claim 10 further comprising:

f1) reacting a compound of Formula VIII-1:

or pharmaceutically acceptable salt thereof, with a compound of Formula VII-1:

or pharmaceutically acceptable salt thereof; and

g1) removing the Boc group from the compound of Formula IX-1, or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula VI-1, or pharmaceutically acceptable salt thereof.

13. The method of claim 12 further comprising:

h1) reacting a compound of Formula XI-1:

or pharmaceutically acceptable salt thereof, with a compound of Formula XII-1:

or pharmaceutically acceptable salt thereof, optionally in the presence of an organic base chosen from TEA, DIEA, NMM, DMAP, pyridine, and imidazole, to form a compound of Formula X-1:

or pharmaceutically acceptable salt thereof; and

i1) removing the Boc group from the compound of Formula X-1 or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula VIII-1, or pharmaceutically acceptable salt thereof.

14. The method of claim 12 further comprising:

j1) reacting a compound of Formula XI-1:

or pharmaceutically acceptable salt thereof, with a compound of Formula XIII-1:

or pharmaceutically acceptable salt thereof, in a solvent chosen from CH 2 Cl 2 , EtOAc, tetrahydrofuran, and dichloromethane, or a mixture of any two or more of these solvents, to form the compound of Formula VII-1, or pharmaceutically acceptable salt thereof.

15. The method of claim 14 further comprising:

k1) reacting a compound of Formula XIV-1:

or pharmaceutically acceptable salt thereof, with a compound of Formula XIII-1:

or pharmaceutically acceptable salt thereof, to form the compound of Formula IV-1, or pharmaceutically acceptable salt thereof.

16. The method of claim 9 further comprising:

c2) reacting a compound of Formula III-2:

or pharmaceutically acceptable salt thereof, with a compound of Formula IV-2:

17. The method of claim 16 further comprising:

d2) removing the Boc group from a compound of Formula V-2:

or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula III-2, or pharmaceutically acceptable salt thereof.

18. The method of claim 17 , further comprising:

e2) reacting a compound of Formula VI-2:

or pharmaceutically acceptable salt thereof, with a compound of Formula VII-2:

19. The method of claim 18 further comprising:

f2) removing the Boc group from a compound of Formula VIII-2:

or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula VI-2, or pharmaceutically acceptable salt thereof.

20. The method of claim 19 further comprising:

g2) reacting a compound of Formula IX-2:

or pharmaceutically acceptable salt thereof, with a compound of Formula VII-2:

21. The method of claim 20 further comprising:

h2) removing the Boc group from a compound of Formula X-2:

or pharmaceutically acceptable salt thereof, in the presence of an acid chosen from H 3 PO 4 , TFA, HCl, TsOH, and H 2 SO 4 , or TMSOTf/2,6-lutidine, to form the compound of Formula IX-2, or pharmaceutically acceptable salt thereof.

22. The method of claim 21 further comprising:

i2) reacting a compound of Formula VII-2:

or pharmaceutically acceptable salt thereof, with a compound of Formula XI-2:

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 25, 2013

From: KAVASH, ROBERT W.; TANG, HAIZHONG; MULROONEY, CAROL; LIU, DAHUI

To: POLYMEDIX, INC.

Reel/Frame 031667/0916 →

BANKRUPTCY COURT ORDER/ASSET PURCHASE AGREEMENT Recorded Nov 12, 2013

From: POLYMEDIX, INC.

To: CELLCEUTIX CORPORATION

Reel/Frame 031626/0156 →

INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Jan 17, 2013

From: POLYMEDIX, INC.; POLYMEDIX PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL SBIC, LP, AS ADMINISTRATIVE AGENT

Reel/Frame 029660/0322 →

Continuity (3)

Continuation 12908977 · Oct 21, 2010

Provisional Application 61253975 · Oct 22, 2009

Related Publication 20130274502A1 · Oct 17, 2013