Continuous process for manufacturing alkyl 7-amino-5-methyl-[1,2,5]oxadiazolo[3,4-b]pyridine-carboxylate

Patent metadata

Field	Value
Publication number	US-11976082-B2
Application number	US-202117326383-A
Country	US
Kind code	B2
Filing date	May 21, 2021
Priority date	May 22, 2020
Publication date	May 7, 2024
Grant date	May 7, 2024

Abstract

This invention relates to a novel continuous process for making alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo¬[3,4-b]pyridine-carboxylate,

wherein R is C 1-3 -alkyl. The process of the invention present invention overcomes disadvantages of processes of the prior art by avoiding the highly energetic intermediates, using readily available and inexpensive starting materials and reagents, and avoiding the isolation of intermediates. The process according to the invention is suitable for use on industrial scale.

First claim

The invention claimed is:

1. Process for manufacturing alkyl 7-amino-5-methyl-[1,2,5]-oxadiazolo-[3,4-b]pyridine-carboxylate 5

wherein R is C 1-3 -alkyl,
by combining an integrated continuous flow system under overpressure, with a batch reactor, said process comprising the following steps:
(a) reacting malononitrile with sodium nitrite in the presence of a suitable acid in a suitable solvent;
(b) reacting the reaction mixture obtained by step (a) with a suitable toluenesulfonic acid derivative to obtain compound 2;

(c) reacting compound 2 in a suitable solvent with hydroxylamine or a suitable hydroxylamine salt to obtain compound 3;

(d) cyclisation of compound 3 in the presence of a base under heating to about 120° C. in a suitable solvent to obtain the oxadiazole 4;

(e) removal of the by-product water formed in step (d) from the reaction mixture by phase separation;
(f) in situ-condensation of compound 4 in the reaction mixture obtained after step (e) with the appropriate beta-keto ester of formula

wherein R is C 1-3 -alkyl, in a batch reactor in the presence of a Lewis acid in a suitable solvent; and
(g) isolating compound 5 from the batch reactor.

2. The process according to claim 1 characterized in that in step (a), hydrochloric acid, hydrobromic acid or acetic acid are used as the suitable acid, and water is used as a solvent.

3. The process according to claim 1 characterized in that step (a) is carried out under an overpressure of at least 2 bar at a temperature of 20 to 40° C. for 15 sec to 5 min.

4. The process according to claim 1 characterized in that in step (a), acetic acid is used as the suitable acid, and water is used as a solvent at a temperature about 30° C. for 15 sec to 5 min.

5. The process according to claim 1 characterized in that in step (b) the suitable toluenesulfonic acid derivative is toluenesulfonic acid anhydride or toluenesulfonic acid chloride, and the reaction is carried out at a temperature of 20 to 40° C. for 15 sec to 5 min.

6. The process according to claim 1 characterized in that in step (b) the suitable toluenesulfonic acid derivative is toluenesulfonic acid chloride, and the reaction is carried out at a temperature of about 30° C. for 15 sec to 5 min.

7. The process according to claim 1 characterized in that in step (c), the reaction is carried out at a temperature of 20 to 40° C. for 15 s to 5 min, using a solvent comprising ethers, water, or mixtures thereof.

8. The process according to claim 1 characterized in that in step (c), the reaction is carried out at a temperature of about 30° C. for 15 s to 5 min; using a solvent comprising 2-methyl-tetrahydrofuran, 1,4-dioxane, water, or mixtures thereof; and the suitable hydroxylamine salt is hydroxylammonium chloride.

9. The process according to claim 1 characterized in that in step (d), the cyclisation is carried out in the presence of triethylamine, an alkali acetate, an alkali carbonate or an alkali hydrogencarbonate; using a solvent comprising ethers, water, or mixtures thereof; at a temperature of 110 to 130° C. for 15 s to 5 min; and under a pressure of at least 2 bar.

10. The process according to claim 1 characterized in that in step (d), the alkali acetate is selected from the group consisting of lithium acetate, sodium acetate, and potassium acetate; the alkali carbonate is selected from the group consisting of sodium carbonate and potassium carbonate; and the alkali hydrogencarbonate is selected from the group consisting of sodium hydrogencarbonate and potassium hydrogencarbonate; and using 1,4-dioxane or 2-methyl-tetrahydrofuran as a solvent.

11. The process according to claim 1 characterized in that in step (e), water is removed by extraction at about 20 to 45° C., using a non-polar extraction solvent selected from the group consisting of toluene, methyl tert-butyl ether, heptane, and isopropyl acetate.

12. The process according to claim 1 characterized in that in step (e), water is continuously removed by extraction at about 20 to 45° C. using toluene or methyl tert-butyl ether as an extraction solvent.

13. The process according to claim 1 characterized in that in step (e), water is continuously removed by extraction at about 30° C. using methyl tert-butyl ether as extraction solvent.

14. The process according to claim 1 characterized in that in step (e), water is removed in a batch-process at about 20° C. using methyl tert-butyl ether as an extraction solvent.

15. The process according to claim 1 characterized in that in step (1), the in situ-condensation is carried out in the presence of a zinc salt as the Lewis acid at a temperature of 60 to 100° C. for 2 to 24 hours, in a solvent selected from the group consisting of an ether, alcohol, non-polar solvents, and mixtures thereof.

16. The process according to claim 1 characterized in that in step (1), the in situ-condensation is carried out in the presence of zinc acetate as the Lewis acid at a temperature of 60 to 100° C. for 2 to 24 hours, in a solvent selected from the group consisting of 1,4-dioxane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, ethanol, and mixtures thereof.

17. The process according to claim 1 characterized in that in step (g), compound 5 is precipitated via addition of an antisolvent and then isolated via filtration.

18. The process according to claim 1 characterized in that in step (g), compound 5 is precipitated via addition of water and then isolated via filtration.

19. The process according to claim 1 wherein R is ethyl.

Assignees

• Boehringer Ingelheim Int

Inventors

• Werner Bernd
• Alt Tobias
• Brusoe Andrew T
• Buono Frederic Gerard
• Klumb Michael
• Stahl Bjoern
• Tampone Thomas G

Classifications

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• B01J19/002

  Avoiding undesirable reactions or side-effects, e.g. avoiding explosions, or improving the yield by suppressing side-reactions · CPC title

• B01J2219/00029

  Batch processes · CPC title

• B01J2219/00033

  Continuous processes · CPC title

• B01J2219/00051

  Controlling the temperature · CPC title