Processes for the resolution of benzodiazepin-2-one and benzoazepin-2-one derivatives

Patent metadata

Field	Value
Publication number	US-10501422-B2
Application number	US-201816188954-A
Country	US
Kind code	B2
Filing date	Nov 13, 2018
Priority date	Nov 13, 2017
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

The present invention relates to processes and intermediates useful in the preparation of biologically active molecules, especially in the synthesis of Respiratory Syncytial Virus (RSV) inhibitors. The present invention also relates to processes and intermediates for the preparation of compounds of Formula (I-0) and Formula (I):

First claim

What is claimed:

1. A process for the preparation of a compound of Formula (I):

wherein X is N or CH;
said process comprising:
(a) reacting a compound of Formula (I′),

with a compound of Formula (III),

wherein R is optionally substituted phenyl, to yield a compound of Formula (IV),

provided that said reaction takes place in the absence of an aromatic aldehyde; and
(b) treating the compound of Formula (IV) with a base to provide the compound of Formula (I).

2. The process of claim 1 , wherein R is

3. The process of claim 1 , wherein X is N.

4. The process of claim 1 , wherein X is CH.

5. The process of claim 1 , wherein step (a) is carried out in a solvent selected from acetonitrile, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, 1,2-dimethoxyethane, dichloromethane, 1,4-dioxane, toluene, anisole, ethanol, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and isopropyl acetate or a combination of two or more thereof.

6. The process of claim 5 , wherein step (a) is carried out in a solvent selected from tetrahydrofuran and 1,4-dioxane.

7. The process of claim 1 , wherein in step (b), the base is sodium hydroxide, potassium carbonate, ammonium hydroxide, potassium phosphate tribasic or sodium carbonate.

8. The process of claim 7 , wherein the base is 1N sodium hydroxide, 5 wt % potassium carbonate, 28-30% ammonium hydroxide, 10 wt % potassium phosphate tribasic or 5 wt % sodium carbonate.

9. The process of claim 1 , wherein in step (a) the compound of Formula (I′) is in a mixture with its enantiomer.

10. The process of claim 9 , wherein the mixture is a racemic mixture.

11. A process for the preparation of a compound of Formula (I-0):

wherein X is N or CH; R 1 is halogen, CN or optionally substituted C 1 -C 3 alkyl; and n is 0, 1, 2 or 3;
said process comprising:
(a) reacting a compound of Formula (I′-0),

with a compound of Formula (III),

wherein R is optionally substituted phenyl, to yield a compound of Formula (IV-0),

provided that said reaction takes place in the absence of an aromatic aldehyde; and
(b) treating a compound of Formula (IV-0) with a base to provide a compound of Formula (I-0).

12. The process of claim 11 , wherein R is

13. The process of claim 11 , wherein X is N.

14. The process of claim 11 , wherein X is CH.

15. The process of claim 11 , wherein step (a) is carried out in a solvent selected from acetonitrile, methanol, tetrahydrofuran, 2-methyltetrahydrofuran, ethyl acetate, 1,2-dimethoxyethane, dichloromethane, 1,4-dioxane, toluene, anisole, ethanol, acetone, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine and isopropyl acetate, or a combination of two or more thereof.

16. The process of claim 15 , wherein step (a) is carried out in a solvent selected from tetrahydrofuran and 1,4-dioxane.

17. The process of claim 11 , wherein in step (b), the base is sodium hydroxide, potassium carbonate, ammonium hydroxide, potassium phosphate tribasic or sodium carbonate.

18. The process of claim 17 , wherein the base is 1N sodium hydroxide, 5 wt % potassium carbonate, 28-30% ammonium hydroxide, 10 wt % potassium phosphate tribasic or 5 wt % sodium carbonate.

19. The process of claim 11 , wherein in step (a) the compound of Formula (I′-0) is present in a mixture with its enantiomer.

20. The process of claim 19 , wherein the mixture is a racemic mixture.

21. The process of claim 1 wherein step (a) is conducted at a temperature of about 20° C. to about 45° C.

22. The process of claim 11 wherein step (a) is conducted at a temperature of about 20° C. to about 45° C.

Assignees

• Enanta Pharm Inc

Inventors

• Hague Andrew
• Ronsheim Matthew

Classifications

• C07D243/26 Primary

  Preparation from compounds already containing the benzodiazepine skeleton · CPC title

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07B2200/07

  Optical isomers · CPC title

• A61K31/5513

  1,4-Benzodiazepines, e.g. diazepam {or clozapine} · CPC title

• A61P31/14

  for RNA viruses · CPC title