IP Library › Granted Patent US 9,090,642

Granted Patent B2

US 9,090,642 · App. 13/813,886 · Granted Jul 28, 2015

Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

Inventors: Aesop Cho (Mountain View, CA); Michael O'Neil Hanrahan Clarke (Redwood City, CA); Scott Alan Wolckenhauer (Redwood City, CA)

Assignee: Gilead Sciences, Inc.

C07H1/00 A61K31/7042 A61K31/7052 C07F9/2458 C07F9/6561 C07F9/65586 C07F9/65616 C07H19/02 C07H19/10 C07H19/20

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Quick Facts

Patent No.: US 9,090,642
App. No.: 13/813,886
Granted: Jul 28, 2015
Kind: B2

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Abstract

Provided are methods and intermediates for preparing diastereomerically pure phosphoramidate prodrugs of nucleosides of Formulas Ia and Ib: The compounds of Formula Ia and Ib are useful for the treatment Hepatitis C infections.

Claims (123)

1. A method for preparing a compound of Formula Ia or Ib:

or a pharmaceutically acceptable salt or acid thereof;

wherein:

each R 1 , R 2 , R 7 , R 22 , R 23 or R 24 is independently H, OR 11 , NR 11 R 12 , C(O)NR 11 R 12 , —OC(O)NR 11 R 12 , C(O)OR 11 , OC(O)OR 11 , S(O) n R a , S(O) 2 NR 11 R 12 , N 3 , CN, halogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or aryl(C 1 -C 8 )alkyl;

or any two R 1 , R 2 , R 7 , R 22 , R 23 or R 24 on adjacent carbon atoms when taken together are —O(CO)O— or —O(CR 11 R 12 )O— or when taken together with the ring carbon atoms to which they are attached form a double bond;

each Base is independently a naturally occurring or modified purine or pyrimidine base linked to the furanose ring through a carbon or nitrogen atom;

provided that Base is not uracil;

each n is independently 0, 1, or 2;

each R a , R 4 or R 6 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl;

each R c or R d is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl provided that R c and R d are not the same;

each R 5 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl;

each R 11 or R 12 is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl, heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or R 11 and R 12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S(O) n — or —NR a —; and

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl of each R c , R d , R 1 , R 2 , R 22 , R 23 , R 24 , R 4 , R 5 , R 6 , R 7 , R 11 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 , NH(R a ), NH 2 , NO 2 , C(O)N(R a ) 2 , C(O)NH(R a ), C(O)NH 2 , OC(O)N(R a ) 2 , OC(O)NH(R a ), OC(O)NH 2 , C(O)OR a , OC(O)OR a , C(O)R a , OC(O)R a , S(O) n R a , S(O) 2 N(R a ) 2 , S(O) 2 NH(R a ), S(O) 2 NH 2 , OR a or R a :

said method comprising:

(a) providing a compound of Formula II

and

(b) treating the compound of Formula II with a compound of Formula IIIa and a base

thereby forming a compound of Formula Ia or

thereby forming a compound of Formula Ib;

wherein:

each Ar is a (C 6 -C 20 ) aryl or heteroaryl wherein said (C 6 -C 20 ) aryl or heteroaryl is substituted with one or more halogen, NO 2 , or (C 1 -C 8 )haloalkyl and optionally substituted with with one or more CN, N 3 , N(R a ) 2 , C(O)N(R a ) 2 , OC(O)N(R a ) 2 , C(O)OR a , OC(O)OR a , C(O)R a , OC(O)R a , S(O) n R a , S(O) 2 N(R a ) 2 , OR a or R a with the proviso that Ar is different from R 4 , the method further comprising a method of preparing a compound of Formula IIIa or Formula IIIb

wherein:

each R c or R d is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -(C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl provided that R c and R d are not the same;

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl (C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl of each R c , R d , R 4 , R 5 or R 6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 NH(R a ), NH 2 , C(O)N(R a ) 2 , C(O)NH(R a ), C(O)NH 2 , OC(O)N(R a ) 2 , OC(O)NH(R a ), OC(O)NH 2 , C(O)OR a , OC(O)OR a , S(O) n R a S(O) 2 N(R a ) 2 , S(O) 2 NH(R a ), S(O) 2 NH 2 , OR a or R a ; and

each Ar is a (C 6 -C 20 ) aryl or heteroaryl wherein said (C 6 -C 20 ) aryl or heteroaryl is substituted with one or more halogen, NO 2 , or (C 1 -C 8 )haloalkyl and optionally substituted with with one or more CN, N 3 , N(R a ) 2 C(O)N(R a ) 2 , OC(O)N(R a ) 2 , C(O)OR a , OC(O)OR a , C(O)R a , OC(O)R a , S(O) n R a S(O) 2 N(R a ) 2 , OR a or R a with the proviso that Ar is different from R 4 ;

said method comprising:

(d) providing a diastereomeric compound of Formula VIII

and

(e) dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by addition of a C 5 -C 8 hydrocarbon or C 5 -C 8 cyclic hydrocarbon;

thereby forming a pure diasteromer of Formula IIIa or Formula IIIb.

2. The method of claim 1 wherein Formula Ia is Formula IVa, Formula Ib is Formula IVb and Formula II is Formula V:

3. The method of claim 1 wherein Base is selected from the group consisting of:

wherein:

each X 1 is independently N or CR 10 ;

each X 2 is independently NR 11 , O, or S(O) n ;

each R 8 is independently halogen, NR 11 R 12 ,N(R 11 )OR 11 ,NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNHR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl, heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, aryl(C 1 -C 8 )alkyl, OR 11 or SR 11 ;

each n is independently 0, 1, or 2;

each R 9 or R 10 is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11 or SR 11 ;

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl of each R c , R d , R 1 , R 2 , R 22 , R 23 , R 24 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 or R 12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 , NH(R a ), NH 2 , NO 2 , C(O)N(R a ) 2 , C(O)NH(R a ), C(O)NH 2 , OC(O)N(R a ) 2 , OC(O)NH(R a ), OC(O)NH 2 , C(O)OR a , OC(O)OR a , C(O)R a , OC(O)R a , S(O) n R a , S(O) 2 N(R a ) 2 , S(O) 2 NH(R a ), S(O) 2 NH 2 , OR a or R a ; and

provided that Base is not uracil.

4. The method of claim 3 wherein Base is selected from the group consisting of:

5. The method of claim 1 wherein Formula Ia is Formula VIa, Formula Ib is Formula VIb and Formula II is Formula VII:

6. The method of claim 1 wherein Formula Ia is Formula XIa, Formula Ib is Formula XIb and Formula II is Formula XII:

wherein:

each R l is independently H, halogen, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl or optionally substituted (C 2 -C 8 )alkynyl;

each R 2 is independently halogen or OR 11 ;

each R 5 is H; and

each R 22 is OR 11 .

7. The method of claim 1 wherein Formula Ia is Formula XIIIa, Formula Ib is Formula XIIIb and Formula II is Formula XIV:

wherein:

each R 1 is independently H, halogen, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl or optionally substituted (C 2 -C 8 )alkynyl;

each R 2 is independently halogen or OR 11 ;

each R 5 is H; and

each R 22 is OR 11 .

8. The method of claim 1 wherein R 1 is H, halogen, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 2 -C 8 )alkenyl or optionally substituted (C 2 -C 8 )alkynyl.

9. The method of claim 8 wherein R 1 is H, CH 3 or F.

10. The method of claim 1 wherein each R 5 , R 23 and R 24 is H.

11. The method of claim 1 wherein one of R c or R d is H and the other of R c or R d is optionally substituted (C 1 -C 8 )alkyl.

12. The method of claim 1 wherein R 6 is optionally substituted (C 1 -C 8 )alkyl.

13. The method of claim 1 wherein R 8 is NR 11 R 12 or OR 11 .

14. The method of claim 13 wherein R 9 is H or NR 11 R 12 .

15. The method of claim 1 wherein when R 8 or R 9 is OR 11 or NR 11 R 12 then each R 11 and R 12 of said OR 11 or NR 11 R 12 is H.

16. The method of claim 14 wherein R 8 is NH 2 and R 9 is H.

17. The method of claim 1 wherein R 4 is optionally substituted (C 6 -C 20 )aryl.

18. The method of claim 1 wherein the compound of Formula VIII is dissolved in an ether solvent and the crystallization is induced by addition of a C 5 -C 8 hydrocarbon.

19. The method of claim 1 wherein the compound of Formula VIII is dissolved in diethyl ether or methyl-t-butyl ether and crystallization is induced by the addition of hexane.

20. The method of claim 19 wherein the compound of Formula VIII is dissolved in diethyl ether and crystallization is induced by the addition of hexane.

21. The method of claim 1 further comprising a method of preparing a compound of Formula VIII

wherein:

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl of each R c , R d , R 4 , R 5 or R 6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 , NH(R a ), NH 2 , C(O)N(R a ) 2 , C(O)NH(R a ), C(O)NH 2 , OC(O)N(R a ) 2 , OC(O)NH(R a ), OC(O)NH 2 , C(O)OR a , OC(O)OR a , S(O) n R a , S(O) 2 N(R a ) 2 , S(O) 2 NH(R a ), S(O) 2 NH 2 , OR a or R a ; and

said method comprising:

(f) providing a chirally pure amino acid ester of Formula IX or a salt thereof

(g) treating the compound of Formula IX with a compound of Formula X in the presence of a base

wherein each X 3 is halogen; and

(h) treating the resulting mixture with ArOH;

thereby forming a compound of Formula VIII.

22. A method of preparing a compound of Formula IIIa or Formula IIIb

or a salt or ester thereof,

wherein:

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl of each R c , R d , R 4 , R 5 or R 6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 , NH(R a ), NH 2 , C(O)N(R a ) 2 , C(O)NH(R a ), C(O)NH 2 , OC(O)N(R a ) 2 , OC(O)NH(R a ), OC(O)NH 2 , C(O)OR a , OC(O)OR a , S(O) n R a , S(O) 2 N(R a ) 2 , S(O) 2 NH(R a ), S(O) 2 NH 2 , OR a or R a ; and

said method comprising:

(d) providing a diastereomeric compound of Formula VIII

and

(e) dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by addition of a C 5 -C 8 hydrocarbon or C 5 -C 8 cyclic hydrocarbon;

thereby forming a pure diasteromer of Formula IIIa or Formula IIIb.

23. The method of claim 22 wherein the compound of Formula VIII is dissolved in an ether solvent and the crystallization is induced by addition of a C 5 -C 8 hydrocarbon.

24. The method of claim 23 wherein the compound of Formula VIII is dissolved in diethyl ether or methyl-t-butyl ether and crystallization is induced by the addition of hexane.

25. The method of claim 24 wherein the compound of Formula VIII is dissolved in diethyl ether and crystallization is induced by the addition of hexane.

26. The method of claim 22 further comprising a method of preparing a compound of Formula VIII

or a salt or ester thereof,

wherein

wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )carbocyclyl, (C 4 -C 8 )carbocyclylalkyl, aryl(C 1 -C 8 )alkyl, heterocyclyl(C 1 -C 8 )alkyl, (C 6 -C 20 )aryl, (C 2 -C 20 )heterocyclyl or heteroaryl of each R c , R d , R 4 , R 5 or R 6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2 , NH(R a ), NH 2 , C(O)N(R a ) 2 , C(O)NH(R a ), C(O)NH 2 , OC(O)N(R a ) 2 , OC(O)NH(R a ), OC(O)NH 2 , C(O)OR a , OC(O)OR a , S(O) n R a , S(O) 2 N(R a ) 2 , S(O) 2 NH(R a ), S(O) 2 NH 2 , OR a or R a ; and

said method comprising:

(f) providing a chirally pure amino acid ester of Formula IX or a salt thereof

(g) treating the compound of Formula IX with a compound of Formula X in the presence of a base

wherein each X 3 is halogen; and

(h) treating the resulting mixture with ArOH;

thereby forming a compound of Formula VIII.

27. The method of claim 22 wherein R 5 is H and one of R c or R d is H.

28. The method of claim 22 wherein R 6 is optionally substituted (C 1 -C 8 )alkyl and R 4 is optionally substituted (C 6 -C 20 )aryl.

29. The method of claim 22 wherein R 4 is optionally substituted phenyl.

30. The method of claim 22 wherein one of R c or R d is H and the other of R c or R d is CH 3 .

31. The method of claim 22 wherein Ar is optionally substituted para-nitrophenyl.

32. The method of claim 22 wherein the chirality at the carbon directly attached to R c and R d is S.

33. The method of claim 22 wherein the chirality at the carbon directly attached to R c and R d is R.

34. The method of claim 22 wherein the compound is selected from the group consisting of

or salts or esters thereof.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 15, 2013

From: CHO, AESOP; CLARKE, MICHAEL O'NEIL HANRAHAN; WOLCKENHAUER, SCOTT ALAN

To: GILEAD SCIENCES, INC.

Reel/Frame 030418/0350 →

Continuity (2)

Provisional Application 61365621 · Jul 19, 2010

Related Publication 20130281686A1 · Oct 24, 2013