Process for preparing 2-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzoic acid

Patent metadata

Field	Value
Publication number	US-10640467-B2
Application number	US-201916425166-A
Country	US
Kind code	B2
Filing date	May 29, 2019
Priority date	Jun 1, 2018
Publication date	May 5, 2020
Grant date	May 5, 2020

Abstract

Among its various uses, this compound is useful as an intermediate for preparing ampreloxetine and salts thereof.

First claim

What is claimed is:

1. A process for preparing a compound of formula I:

the process comprising:
(a) reacting a compound of formula 1:

with a C 1-6 alkyl 3-oxobutanoate in the presence of piperidine to form a compound of formula 2:

wherein each R is independently selected from C 1-6 alkyl;
(b) reacting the compound of formula 2 with an alkali metal hydroxide to form, after acidification of the reaction product with an acid, a compound of formula 3:

(c) reacting the compound of formula 3 with an ammonia reagent to form a compound of formula 4:

(d) reacting the compound of formula 4 with a reducing agent to form a compound of formula 5 or a salt thereof:

(e) reacting the compound of formula 5 or a salt thereof with di-tert-butyl dicarbonate to form a compound of formula 6:

(f) reacting the compound of formula 6 with an alkyl lithium reagent to form a compound of formula 7:

(g) reacting the compound of formula 7 with carbon dioxide to form the compound of formula I.

2. The process of claim 1 , wherein each R group is independently selected from methyl and ethyl.

3. The process of claim 1 , wherein both R groups are methyl.

4. The process of claim 1 , wherein both R groups are ethyl.

5. The process of claim 1 , wherein the alkali metal hydroxide is lithium hydroxide, sodium hydroxide or potassium hydroxide.

6. The process of claim 5 , wherein the alkali metal hydroxide is potassium hydroxide.

7. The process of claim 1 , wherein the acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or acetic acid.

8. The process of claim 7 , wherein the acid is hydrochloric acid.

9. The process of claim 1 , wherein the ammonia reagent is ammonia, urea, ammonium hydroxide, ammonium chloride or magnesium nitride.

10. The process of claim 9 , wherein the ammonia reagent is urea.

11. The process of claim 1 , wherein the reducing agent is sodium borohydride/boron trifluoride tetrahydrofuran complex or lithium aluminum hydride.

12. The process of claim 11 , wherein the reducing agent is sodium borohydride/boron trifluoride tetrahydrofuran complex.

13. The process of claim 1 , wherein the alkyl lithium reagent is n-butyl lithium or tert-butyl lithium.

14. The process of claim 13 , wherein the alkyl lithium reagent is n-butyl lithium.

15. The process of claim 1 , wherein the alkali metal hydroxide is potassium hydroxide; the acid is hydrochloric acid; the ammonia reagent is urea; the reducing agent is sodium borohydride/boron trifluoride tetrahydrofuran complex; and the alkyl lithium reagent is n-butyl lithium.

16. A process for preparing a compound of formula I:

the process comprising:
(a) reacting a compound of formula 1:

with ethyl 3-oxobutanoate in the presence of piperidine to form a compound of formula 2a:

(b) reacting the compound of formula 2a with an potassium hydroxide to form, after acidification of the reaction product with hydrochloric acid, a compound of formula 3:

(c) reacting the compound of formula 3 with urea to form a compound of formula 4:

(d) reacting the compound of formula 4 with sodium borohydride/boron trifluoride tetrahydrofuran complex to form a compound of formula 5 or a salt thereof:

(e) reacting the compound of formula 5 or a salt thereof with di-tert-butyl dicarbonate to form a compound of formula 6:

(f) reacting the compound of formula 6 with n-butyl lithium to form a compound of formula 7:

(g) reacting the compound of formula 7 with carbon dioxide to form the compound of formula I.

17. The process of claim 16 , wherein step (d) and step (e) are conducted in the same reaction mixture without isolation of the product of step (d).

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Rapta Miroslav
• Filipov Dimitar

Classifications

• C07D211/34 Primary

  with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D211/02 Primary

  Preparation by ring-closure or hydrogenation · CPC title