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-2021363157-A1
Application number	US-202117326383-A
Country	US
Kind code	A1
Filing date	May 21, 2021
Priority date	May 22, 2020
Publication date	Nov 25, 2021
Grant date	—

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.

First claim

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 hydroxylamine ammonium 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 (f), 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 (f), 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

• B01J2219/00029

  Batch processes · CPC title

• C07D498/04 Primary

  Ortho-condensed systems · CPC title

• B01J2219/00162

  controlling the pressure · CPC title

• B01J2219/00033

  Continuous processes · CPC title

• B01J19/002

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