Process for Manufacturing Pibrentasvir Active Drug Substance

Patent metadata

Field	Value
Publication number	US-2025051312-A1
Application number	US-202418589930-A
Country	US
Kind code	A1
Filing date	Feb 28, 2024
Priority date	Aug 29, 2018
Publication date	Feb 13, 2025
Grant date	—

Abstract

The present invention relates to compositions of pibrentasvir, drug products thereof, and processes and intermediates for the preparation thereof.

First claim

We claim:

1 . A compound of formula (IIa):

2 . The compound of claim 1 , wherein the compound of formula (IIa) is in solid form.

3 . The compound of claim 1 , wherein the compound of formula (IIa) is in crystalline form.

4 . (canceled)

5 . The compound of claim 3 , having an X-ray powder diffraction pattern comprising peaks at ±0.2 of 11.2, 11.9, 14.7, 16.3, 17.7, 19.4, 19.9, 22.7, 25.0, 27.0° 2θ, when measured at about 25° C. with Cu—K α1 radiation at 1.5406 λ.

6 . A process for preparing (15,4S)-1,4-bis (4-chloro-2-fluoro-5-nitrophenyl)butane-1,4-diol (I) comprising:
separating Compound (IIa),

from Compound (I),

7 . The process of claim 6 , further comprising:
providing a mixture of Compounds (I) and (II).

adding 1,4-diazabicyclo[2.2.2]octane to the mixture; and
forming Compound (IIa).

8 . The process of claim 7 , further comprising precipitating Compound (IIa).

9 . (canceled)

10 . The process of claim 7 , further comprising, reducing Compound (III):

to form a mixture of Compounds (I) and (II).

11 . The process of claim 10 , further comprising oxidizing Compound (IIa) to form Compound (III),

12 . A process for preparing pibrentasvir in substantially pure form comprising, separating Compound (IIa),

from Compound (I)

13 . The process of claim 12 , further comprising:
providing a mixture of Compounds (I) and (II),

adding 1,4-diazabicyclo[2.2.2]octane to the mixture; and
forming Compound (IIa).

14 . The process of claim 13 , further comprising precipitating Compound (IIa).

15 . The process of claim 14 , further comprising separating solid Compound (IIa) from a filtrate comprising Compound (I).

16 . (canceled)

17 . The process of claim 15 , further comprising,
converting Compound (I) to pibrentasvir.

18 - 22 . (canceled)

23 . A drug product comprising a drug substance;
wherein the drug substance comprises at least 97 weight percent of pibrentasvir and not more than 3 weight percent of an impurity; wherein the drug substance is prepared by a process comprising, separating Compound (IIa),

from Compound (I)

24 . The drug product of claim 23 , wherein the impurity is

25 . (canceled)

26 . The drug product of claim 24 , wherein Compound (xi) is converted to Compound (xii)

prior to analysis by chromatography.

27 . The drug product of claim 23 , wherein the process further comprises, providing a mixture of Compounds (I) and (II),

adding 1,4-diazabicyclo[2.2.2]octane to the mixture;
forming Compound (IIa);
precipitating Compound (IIa); and
separating solid Compound (IIa) from a filtrate comprising Compound (I).

28 . The drug product of claim 27 , wherein the process further comprises, oxidizing Compound (IIa) to form Compound (III),

29 . The drug product of claim 28 , wherein the process further comprises,
converting Compound (III) to pibrentasvir.

Assignees

• Abbvie Inc

Inventors

• Hillier Michael
• Gheewala Chirag
• Hastings Riley

Classifications

• C07D487/18

  Bridged systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07C205/45

  the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group · CPC title

• C07C205/19

  having nitro groups bound to carbon atoms of six-membered aromatic rings and hydroxy groups bound to acyclic carbon atoms · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title