Synthesis of antiviral compound

Patent metadata

Field	Value
Publication number	US-9056860-B2
Application number	US-201313800202-A
Country	US
Kind code	B2
Filing date	Mar 13, 2013
Priority date	Jun 5, 2012
Publication date	Jun 16, 2015
Grant date	Jun 16, 2015

Abstract

The present disclosure provides processes for the preparation of a compound of formula I:

which is useful as an antiviral agent. The disclosure also provides compounds that are synthetic intermediates to compounds of formula I.

First claim

We claim:

1. A process for making a compound of formula I:

or a pharmaceutically acceptable salt thereof, comprising
(A) coupling a compound of formula (i)

with a compound of formula (ii)

in the presence of a metal catalyst which is PdCl 2 [P(t-Bu) 2 Ph] 2 or Pd(OAc) 2 /2-dicyclohexylphosphino-2′-methylbiphenyl, and base to yield a compound of formula (iii) or a salt thereof:

(B) deprotecting a compound of formula (iii) to yield a compound of formula (iv):

or a salt thereof;
(C) contacting the compound of formula (iv) with (5)-2-(methoxycarbonylamino)-3-methylbutanoic acid:

to yield a compound of formula I; wherein
each PG independently is an amine protecting group;
Y is —B(OR)(OR′) and Z is Br; and
R and R′ are independently selected from the group consisting of hydrogen and straight or branched C 1-8 -alkyl,
or R and R′ together represent a straight or branched C 1-8 -alkylene, C 3-8 -cycloalkylene, or C 6-12 -arylene,
wherein any alkyl, alkylene, cycloalkylene, or arylene is optionally substituted with one or more substituents selected from the group consisting of C 1-6 -alkyl, —C(O)N(C 1-6 -alkyl) 2 , and —C(O)O(C 1-6 -alkyl).

2. The process according to claim 1 , further comprising the step of in situ generation of the compound of formula (i),

comprising sequentially contacting a compound of formula (a)

with a source of palladium and then a borylation agent comprising the moiety

in the presence of a second base, whereby the compound of formula (i) is formed in situ, and X is a halide selected from Cl, Br, and I.

3. The process according to claim 2 , wherein the step of in situ generation of the compound of formula (i) and step (A) are carried out sequentially in one pot.

4. The process according to claim 2 , where the borylation agent is selected from bis(pinacolato)diboron and bis(neopentylglycolato)diboron.

5. The process according to claim 4 , where the borylation agent is bis(pinacolato)diboron.

6. The process according to claim 4 , where the borylation agent is bis(neopentylglycolato)diboron.

7. The process according to claim 3 , wherein X is Br and PG is tert-butoxycarbonyl.

8. The process according to claim 1 , wherein the metal catalyst is PdCl 2 [P(t-Bu) 2 Ph] 2 .

9. The process according to claim 1 , wherein the metal catalyst is Pd(OAc) 2 /2-dicyclohexylphosphino-2′-methylbiphenyl.

10. The process according to claim 2 , wherein the second base is a propionate salt.

11. The process according to claim 10 , wherein the propionate salt is potassium propionate.

12. A process for making a compound of formula I:

or a pharmaceutically acceptable salt thereof, comprising
(1) sequentially contacting a compound of formula (a′)

with a catalytically effective amount of PdCl 2 [P(t-Bu) 2 Ph] 2 and bis(neopentylglycolato)diboron in the presence of potassium propionate to yield a reaction mixture comprising a compound of formula (ia):

(2) contacting the reaction mixture from step (1) with a compound of formula (ii′):

and potassium phosphate to yield a compound of formula (iii′):

and
optionally contacting the compound of formula (iii′) with oxalic acid to yield an oxalate salt of formula (iii″):

(3) contacting the compound of formula (iii′) or formula (iii″) with HCl to yield a compound of formula (iv′):

(4) contacting the compound of formula (iv′) with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid:

to yield a compound of formula I;
wherein Boc in each instance represents tert-butoxycarbonyl.

13. A process for making a compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, comprising
(1) sequentially contacting a compound of formula (a′)

with a catalytically effective amount of PdCl 2 [P(t-Bu) 2 Ph] 2 and bis(pinacolato)diboron in the presence of potassium propionate to yield a reaction mixture comprising a compound of formula (ib):

(2) contacting the reaction mixture from step (1) with a compound of formula (ii′):

and potassium phosphate to yield a compound of formula (iii′):

and
optionally contacting the compound of formula (iii′) with oxalic acid to yield an oxalate salt of formula (iii″):

(3) contacting the compound of formula (iii′) or formula (iii″) with HCl to yield a compound of formula (iv′):

(4) contacting the compound of formula (iv′) with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid:

to yield a compound of formula I;
wherein Boc in each instance represents tert-butoxycarbonyl.

Assignees

• Gilead Pharmasset Llc

Inventors

• Scott Robert William
• Vitale Justin Philip
• Matthews Kenneth Stanley
• Teresk Martin Gerald
• Formella Alexandra
• Evans Jared Wayne

Classifications

• A61P31/14

  for RNA viruses · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• C07D403/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title