Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

Patent metadata

Field	Value
Publication number	US-9090642-B2
Application number	US-201113813886-A
Country	US
Kind code	B2
Filing date	Jul 19, 2011
Priority date	Jul 19, 2010
Publication date	Jul 28, 2015
Grant date	Jul 28, 2015

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.

First claim

What is claimed is:

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
(c) treating the compound of Formula II with a compound of Formula IIIb and a base

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 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;
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 ,

Assignees

• Cho Aesop
• Clarke Michael O'Neil Hanrahan
• Wolckenhauer Scott Alan
• Gilead Sciences Inc

Inventors

• Cho Aesop
• Clarke Michael O'Neil Hanrahan
• Wolckenhauer Scott Alan

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D309/10

  Oxygen atoms · CPC title

• C07H19/10

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

• A61K31/7052

  having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides · CPC title