Process for the preparation of fexofenadine and of intermediates used therein

Patent metadata

Field	Value
Publication number	US-10696633-B2
Application number	US-201615769661-A
Country	US
Kind code	B2
Filing date	Oct 21, 2016
Priority date	Oct 22, 2015
Publication date	Jun 30, 2020
Grant date	Jun 30, 2020

Abstract

A new process for the preparation of fexofenadine and of related intermediates, which can be used in the preparation of fexofenadine, is provided.

First claim

The invention claimed is:

1. A process for preparing a compound of formula II

wherein R1 is CN, CONH 2 , or COOR2, wherein R2 is C1-4 alkyl, comprising reacting a compound of formula V

wherein R1 is CN, CONH 2 or COOR2, wherein R2 is C1-4 alkyl, with the compound of formula IV

at a temperature above 80° C. without any solvent or at a temperature above 80° C. in the presence of an amount of solvent up to 50 wt % of the sum of the weights of the compound of formula V and the compound of formula IV,
and in the presence of a salt, wherein the salt is a lithium, sodium, potassium, rubidium, caesium, magnesium, calcium, strontium, barium, scandium, manganese, iron, copper, zinc, silver, boron, aluminium, gallium, indium, cerium, europium, ytterbium or bismuth salt, to form the compound of formula II.

2. The process according to claim 1 , wherein the amount of solvent is up to 20 wt % of the sum of the weights of the compound of formula V and the compound of formula IV.

3. The process according to claim 1 , wherein when R1 is COOR2, the temperature is in the range of 80 to 150° C.

4. The process according to claim 1 , wherein when R1 is CN or CONH 2 , the temperature is in the range of 80 to 350° C.

5. The process according to claim 1 , wherein the salt is a lithium, sodium, magnesium, calcium, barium, scandium, manganese, iron, copper, silver, zinc, aluminium, gallium, indium, cerium, europium, ytterbium or bismuth salt.

6. The process according to claim 1 , wherein the salt is a lithium, sodium, calcium, barium, magnesium, silver, europium or iron salt.

7. The process according to claim 1 , wherein the salt is a lithium salt.

8. The process according to claim 1 , wherein the anion in the salt is selected from the group consisting of chloride, bromide, iodide, perchlorate, nitrate, trifluoromethanesulfonate and trifluoroacetate.

9. The process according to claim 1 , wherein the salt is selected from the group consisting of lithium perchlorate, lithium trifluoromethanesulfonate, lithium bromide, lithium tifluoroacetate, lithium nitrate, lithium iodide, barium perchlorate, barium trifluoromethanesulfonate, calcium trifluoromethanesulfonate, and sodium trifluoromethanesulfonate.

10. A process for preparing a compound of formula I

or a pharmaceutically acceptable salt thereof
comprising:
preparing the compound of formula II according to claim 1 ,
and converting the compound of formula II into the compound of formula I or a pharmaceutically acceptable salt thereof.

11. The process according to claim 10 , wherein the compound of formula II is converted into the compound of formula I by sequentially or simultaneously reducing the ketone moiety and hydrolyzing the nitrile, the amide, or the ester moiety in R1 of the compound of formula II.

12. The process according to claim 11 , wherein the compound of formula II is first reduced to a compound of formula VI

13. The process according to claim 12 , wherein the compound of formula II prepared is not isolated and is directly converted into the compound of formula VI.

14. The process according to claim 11 , wherein the compound of formula II is converted into the compound of formula I by simultaneously reducing the ketone moiety and hydrolyzing the nitrile, the amide or the ester moiety in R1 of the compound of formula II.

15. The process according to claim 10 , wherein the compound of formula I is converted into a pharmaceutically acceptable salt thereof.

16. The process according to claim 1 , wherein R1 is CN.

17. The process according to claim 1 , wherein the salt is lithium perchlorate.

18. A compound of formula II-B having the following structure:

Assignees

• Sanofi Aventis Deutschland

Inventors

• Wehlan Hermut
• Rossen Kai
• Billen Guenter

Classifications

• C07D211/22

  by oxygen atoms · CPC title

• 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