Process to manufacture N-[(3S)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-5-oxo-pyrrolidin-3-yl]acetamide

Patent metadata

Field	Value
Publication number	US-9562009-B2
Application number	US-201615139668-A
Country	US
Kind code	B2
Filing date	Apr 27, 2016
Priority date	Oct 29, 2013
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention provides processes to manufacture crystalline N-[(3S)-1-[4-[(3-fluorophenyl)methoxy]phenyl]-5-oxo-pyrrolidin-3-yl]acetamide. Also disclosed are compounds useful as intermediates in the methods of the invention.

First claim

We claim:

1. A crystalline form (polymorph A) of a compound of formula 1 characterized by an X-Ray

Powder Diffraction Pattern (XRPD) having characteristic peaks expressed in values of degrees 2-theta at approximately 8.4, 15.8, 16.9, 22.9 and 24.5.

2. A crystalline polymorph A according to claim 1 characterized by an XRPD having characteristic peaks expressed in values of degrees 2-theta at approximately

degree 2-theta

5.8

8.4

9.8

11.7

14.1

15.8

16.9

19.8

20.4

21.5

22.0

22.9

24.5

26.4

28.2.

3. A crystalline polymorph A according to claim 1 characterized by an XRPD as shown in FIG. 1 .

4. A crystalline form (polymorph B) of a compound of formula 1 characterized by an XRPD having characteristic peaks expressed in values of degrees 2-theta at approximately 15.9, 21.3, 23.6 and 26.7.

5. A crystalline polymorph B according to claim 4 characterized by an XRPD having characteristic peaks expressed in values of degrees 2-theta at approximately

degree 2-theta

11.6

13.3

15.9

16.9

18.1

19.7

20.7

21.3

22.5

23.6

24.1

26.7

27.8

29.0.

6. A crystalline polymorph B according to claim 4 characterized by an XRPD as shown in FIG. 4 .

7. A process to synthesize a compound according to claim 1 comprising the intramolecular cyclization of

7 to afford 1.

8. A process according to claim 7 comprising the steps of:
(a) treating 3-acetamido-N-(4-((3-fluorobenzyl)oxy)phenyl)-4-hydroxybutanamide (6) with a chlorinating agent to afford 7

and,
(b) cyclizing 7 to afford 1

9. A process according to claim 8 wherein the chlorination step and the intramolecular cyclization step is

carried out as a one-pot reaction.

10. A process according to claim 7 comprising the steps of:
(a) treating (S)—N-(5-oxotetrahydrofuran-3-yl)acetamide (3) with 4-((3-fluorobenzyl)oxy)benzenaminium chloride (5) to afford 6

and,
(b) treating 6 with a chlorinating agent to afford (S)-3-acetamido-N-(4-((3-fluorobenzyl)oxy)phenyl)-4-hydroxybutanamide (7)

and,
(c) cyclizing 7 to afford 1

11. A process according to claim 7 comprising the steps of:
(a) treating (S)-5-oxotetrahydrofuran-3-aminium chloride with an acetylating agent to afford (S)—N-(5-oxotetrahydrofuran-3-yl)acetamide (3)

and,
(b) treating 3 with 4-((3-fluorobenzyl)oxy)benzenaminium chloride (5) to afford 6

and,
(c) treating 6 with a chlorinating agent to afford (S)-3-acetamido-N-(4-((3-fluorobenzyl)oxy)phenyl)-4-hydroxybutanamide (7)

and,
(d) cyclizing 7 to afford 1

12. A process according to claim 7 which process further comprises the step of:
(a) reacting 3-fluorobenzyl chloride (4) and 4-hydroxy aniline (4a) to afford 4-((3-fluorobenzyl)oxy)benzenaminium chloride (5); (b) treating (S)-5-oxotetrahydrofuran-3-aminium chloride with an acetylating agent to afford (S)—N-(5-oxotetrahydrofuran-3-yl)acetamide (3), (c) treating 3 with 4-((3-fluorobenzyl)oxy)benzenaminium chloride (5) to afford 6; (d) treating 6 with a chlorinating agent to afford (S)-3-acetamido-N-(4-((3-fluorobenzyl)oxy)phenyl)-4-hydroxybutanamide (7); (e) cyclizing 7 to afford 1.

13. A process according to claim 8 comprising the steps of:

(a) reducing 2-acetamido-4-((4-((3-fluorobenzyl)oxy)phenyl)amino)-4-oxobutanoic acid (10) to afford (S)-3-acetamido-N-(4-((3-fluorobenzyl)oxy)phenyl)-4-hydroxybutanamide (6); (b) chlorinating 6; and (c) cyclizing 6 to afford 1.

14. A process according to claim 13 which process further comprises the step of:
(a) condensing (S)-3-acetamido-4-methoxy-4-oxobutanoic acid (9) and 5 to afford 10

and,
(b) reduci

Assignees

• Hoffmann La Roche

Inventors

• Grassmann Olaf
• Hildbrand Stefan
• Meier Roland
• Scalone Michelangelo
• Schwitter Urs
• Wirz Beat
• Zutter Ulrich

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/4015

  having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide · CPC title

• C07D207/273 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title