# US 10,118,941 B2 · Methods for the preparation of diastereomerically pure phosphoramidate prodrugs

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- Number: US 10,118,941 B2
- Document ID: US10118941B2
- Status: Granted
- Kind: B2
- Application number: 15/511,096
- Filed: 2015-09-11
- Published: 2017-09-28
- Granted: 2018-11-06
- Earliest claimed: 2014-09-15
- Assignees: Medivir AB
- Applicants: Medivir AB
- Inventors: Pedro Pinho; Staffan Torssell
- Web page: https://patentgrep.com/patent/US10118941B2

## CPC

- C07H 1/02: Phosphorylation
- C07H 1/04: Introducing polyphosphoric acid radicals
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

Methods for the preparation of diastereomerically pure phosphoramidate prodrugs of nucleosides, and intermediates useful for the preparation are provided. The nucleosides are useful for the treatment of hepatitis C and cancer.

## Claims

### Claim 1

A method for preparing a compound of Formula Ia or lb:
or a pharmaceutically acceptable salt or acid thereof;
wherein:
each R1, R2, R7, R22, R23 or R24 is independently H, OR11, NR11R12, C(O)NR11R12, —OC(O)NR11R12, C(O)OR11, OC(O)OR11, S(O)nRa, S(O)2NR11R12, N3, CN, halogen, (C1-C8)alkyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclyl alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or aryl(C C8)alkyl; or
any two R1, R2, R7, R22, R23 or R24 on adjacent carbon atoms when taken together are —O(CO)O— or —O(CR11R12)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;
each n is independently 0, 1, or 2;
each Ra or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, (C2-C20)heterocyclyl or heteroaryl;
each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl;
each R4 is phenyl;
each R5 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl;
each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl, or R11 and R12 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),- or —NRa—; and
wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R5, R6, R7, R11 or R12 or the phenyl of R4 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2, NH(Ra), NH2, NO2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, C(O)Ra, OC(O)Ra, S(O)nRa S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra;
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 la, or
(c) treating the compound of Formula II with a compound of Formula Illb and a base
thereby forming a compound of Formula lb;
wherein:
each Ar is 3,5-dichlorophenyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is CH3 or Cl, and R2 is F or Cl.

### Claim 3 (depends on 1)

The method of claim 1, wherein each R5, R23 and R24 is H.

### Claim 4 (depends on 1)

The method of claim 1, wherein one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl.

### Claim 5 (depends on 1)

The method of claim 1, wherein R6 is optionally substituted (C1-C8)alkyl or optionally substituted (C3-C8)cycloalkyl.

### Claim 6 (depends on 1)

The method of claim 1, wherein the compound of formula IIIa or IIIb is selected from the group consisting of
or salts or hydrates thereof.

### Claim 7

A compound of the formula VIII
wherein:
each Ra, or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl;
each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl;
each R4 is optionally substituted phenyl;
each R5 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl;
wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R5 or R6 or the phenyl of R4 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2, NH(Ra), NH2, C(O)N(Ra)2, C(O)NH(Ra), C(O)NH2, OC(O)N(Ra)2, OC(O)NH(Ra), OC(O)NH2, C(O)ORa, OC(O)ORa, S(O)nRa, S(O)2N(Ra)2, S(O)2NH(Ra), S(O)2NH2, ORa or Ra; and
each Ar is 3,5-dichlorophenyl:
or a salt, hydrate or N-oxide thereof.

### Claim 8 (depends on 7)

A diastereomer of the compound of claim 7 with the stereochemistry depicted in Formula IIIa:

### Claim 9 (depends on 7)

A diastereomer of the compound of claim 7 with the stereochemistry depicted in Formula IIIb:

### Claim 10 (depends on 7)

The diastereomer or compound of any one of claim 7, wherein R5 is H.

### Claim 11 (depends on 7)

The diastereomer or compound of claim 7, wherein R5 is H and one of Rc or Rd is H.

### Claim 12 (depends on 7)

The diastereomer or compound of claim 7, wherein R6 is optionally substituted (C1-C8)alkyl or optionally substituted (C3-C8)cycloalkyl.

### Claim 13 (depends on 12)

The diastereomer or compound of claim 12, wherein R6 is methyl, ethyl, 1-methylbutyl, 2-ethylbutyl, cyclopentyl or preferably isopropyl.

### Claim 14 (depends on 7)

The diastereomer or compound of claim 7, wherein R4 is phenyl.

### Claim 15 (depends on 7)

The diastereomer or compound of claim 7, wherein one of Rc and Rd is H and the other one is CH3.

### Claim 16 (depends on 15)

The diastereomer or compound of claim 15, wherein the stereochemistry at the chiral center to which Rc and Rd are directly attached is S.

### Claim 17 (depends on 7)

The diastereomer or compound of claim 7, wherein:
R4 is phenyl;
R5 is H;
R6 is methyl, ethyl, 1-methylbutyl, 2-ethylbutyl, cyclopentyl or preferably isopropyl;
one of Rc and Rd is H and the other one is CH3;
Ar is 3,5-dichlorophenyl.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound of formula Ia is
the compound of formula II is
and the compound of formula IIIb is
wherein Ar is 3,5-dichlorophenyl.