Processes for preparing pyrrolidine compounds

Patent metadata

Field	Value
Publication number	US-11434201-B2
Application number	US-201816635346-A
Country	US
Kind code	B2
Filing date	Aug 2, 2018
Priority date	Aug 2, 2017
Publication date	Sep 6, 2022
Grant date	Sep 6, 2022

Abstract

Processes for preparing 5,5-dimethyl-3-methylenepyrrolidin-2-one, (S)-3,5,5-trimethylpyrrolidine-2-one, (R)-3,5,5-trimethylpyrrolidine-2-one, (S)-2,4,4-trimethylpyrrolidine, and (R)-2,4,4-trimethylpyrrolidine, and their salt forms are disclosed.

First claim

The invention claimed is:

1. A process for preparing (S)-2,2,4-trimethylpyrrolidine or a salt thereof comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform and at least one base;
(b) reacting the products of the reaction in (a) with an acid to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one;
(c) hydrogenating 5,5-dimethyl-3-methylenepyrrolidin-2-one to produce (S)-3,5,5-trimethyl-pyrrolidin-2-one;
(d) reducing (S)-3,5,5-trimethyl-pyrrolidin-2-one to produce (S)-2,2,4-trimethylpyrrolidine; and
(e) optionally treating (S)-2,2,4-trimethylpyrrolidine with acid to produce a salt of (S)-2,2,4-trimethylpyrrolidine.

2. A process for preparing (R)-2,2,4-trimethylpyrrolidine or a salt thereof comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform and at least one base;
(b) reacting the products of the reaction in (a) with an acid to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one;
(c) hydrogenating 5,5-dimethyl-3-methylenepyrrolidin-2-one to produce (R)-3,5,5-trimethyl-pyrrolidin-2-one;
(d) reducing (R)-3,5,5-trimethyl-pyrrolidin-2-one to produce (R)-2,2,4-trimethylpyrrolidine; and
(e) optionally treating (R)-2,2,4-trimethylpyrrolidine with acid to produce a salt of (R)-2,2,4-trimethylpyrrolidine.

3. A process for preparing (S)-3,5,5-trimethylpyrrolidin-2-one comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform and at least one base;
(b) reacting the products of the reaction in (a) with an acid to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one; and
(c) hydrogenating 5,5-dimethyl-3-methylenepyrrolidin-2-one to produce (S)-3,5,5-trimethyl-pyrrolidin-2-one.

4. A process for preparing (R)-3,5,5-trimethylpyrrolidin-2-one comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform and at least one base;
(b) reacting the products of the reaction in (a) with an acid to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one; and
(c) hydrogenating 5,5-dimethyl-3-methylenepyrrolidin-2-one to produce (R)-3,5,5-trimethyl-pyrrolidin-2-one.

5. A process for preparing 5,5-dimethyl-3-methylenepyrrolidin-2-one comprising:
(a) reacting 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof with chloroform and at least one base; and
(b) reacting the products of the reaction in (a) with an acid to produce 5,5-dimethyl-3-methylenepyrrolidin-2-one.

6. The process according to claim 1 , further comprising treating (S)-2,2,4-trimethylpyrrolidine with HCl to generate (S)-2,2,4-trimethylpyrrolidine hydrochloride.

7. The process according to claim 1 or 3 , wherein the at least one base is chosen from potassium t-butoxide, potassium hydroxide, and sodium hydroxide.

8. The process according to claim 7 , wherein the at least one base is sodium hydroxide.

9. The process according to claim 1 or 3 , wherein the at least one base added for the reaction in (a) is in the form of an aqueous solution having a concentration ranging from 20 wt % to 80 wt % relative to the total weight of the aqueous solution.

10. The process according to claim 1 or 3 , wherein the 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof is reacted with chloroform, at least one base, and at least one phase transfer catalyst.

11. The process according to claim 10 , wherein the at least one phase transfer catalyst is chosen from tetraalkylammonium salts and crown ethers.

12. The process according to claim 10 , wherein the at least one phase transfer catalyst is chosen from tetraalkylammonium halides.

13. The process according to claim 10 , wherein the at least one phase transfer catalyst is chosen from tributylmethylammonium chloride, tributylmethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride (TBAC), tetrabutylammonium iodide (TBAI), tetrabutylammonium hydroxide (TBAH), benzyltrimethylammonium chloride, tetraoctylammonium bromide (TOAB), tetraoctylammonium chloride (TOAC), tetraoctylammonium iodide (TOAI), trioctylmethylammonium chloride, and trioctylmethylammonium bromide.

14. The process according to claim 1 or 3 , wherein the acid of the reaction in (b) is chosen from aqueous solutions of protic acids.

15. The process according to claim 14 , wherein the protic acids are chosen from hydrochloric acid, methane sulfonic acid, triflic acid, and sulfuric acid.

16. The process according to claim 1 or 3 , wherein the hydrogenating reaction in (c) comprises reacting 5,5-dimethyl-3-methylenepyrrolidin-2-one with at least one catalyst and hydrogen gas to produce (S)-3,5,5-trimethyl-pyrrolidin-2-one.

17. The process according to claim 16 , wherein the at least one catalyst is chosen from ruthenium hydrogenation catalysts, rhodium hydrogenation catalysts, and iridium hydrogenation catalysts.

18. The process according to claim 1 , wherein the reducing reaction in (d) comprises reacting (S)-3,5,5-trimethyl-pyrrolidin-2-one with a hydride to produce (S)-2,2,4-trimethylpyrrolidine.

19. The process according to claim 18 , wherein the hydride is chosen from lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminumhydride, and borane.

20. The process according to claim 1 or 3 , wherein 2,2,6,6-tetramethyl-piperidin-4-one or a salt thereof is reacted with chloroform, at least one base, and in the presence of at least one solvent.

21. The process according to claim 20 , wherein the at least one solvent is chosen from organic solvents.

22. The process according to claim 21 , wherein the at least one solvent is chosen from dichloromethane, heptane, chloroform, trifluorotoluene, tetrahydrofuran (THF), and N-methylpyrrolidone (NMP).

Assignees

• Vertex Pharma

Inventors

• Angell Paul T
• Hughes Robert M
• Lewandowski Berenice
• Littler Benjamin J
• Nugent William A
• Smith David
• Studley John

Classifications

• A61K31/40

  having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil · CPC title

• C07D207/263

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms · CPC title

• C07D207/06 Primary

  with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms · CPC title

• A61K31/4015

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

• C07D207/12

  Oxygen or sulfur atoms · CPC title