Process for preparing N-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-acetimidic acid ethyl ester

Patent metadata

Field	Value
Publication number	US-9604914-B2
Application number	US-201314376143-A
Country	US
Kind code	B2
Filing date	Feb 1, 2013
Priority date	Feb 3, 2012
Publication date	Mar 28, 2017
Grant date	Mar 28, 2017

Abstract

This invention relates to novel processes for synthesizing N-(4-cyclohexyl-3-trifluoromethyl-benzyloxy)-acetimidic acid ethyl ester and to the compound of formula I below and other intermediates that are used in such processes.

First claim

The invention claimed is:

1. A process for preparing a compound of the following formula:

comprising reacting a compound of the formula

wherein X 2 is bromo, chloro, iodo, mesylate, tosylate, triflate or another suitable leaving group, with the compound of formula

in the presence of a strong base, wherein the starting material of formula IX is synthesized comprising the steps of:
(a) reacting a compound of the formula

wherein X is chloro, bromo, or iodo, with a Grignard reagent to form the compound of the formula

(b) reacting the compound of formula Ill with strong acid to form the compound of formula

(c) subjecting the compound of formula IV to catalytic hydration to form the compound of formula

(d) converting the compound of formula V into a compound of the formula

wherein X 1 is bromo, chloro or iodo, by reacting the compound of formula V with 1,3-dibromyl-5,5-diethylhydantoin when X 1 in formula VI is bromo, or by reacting the compound of formula V with the appropriate analogous compound when X 1 is chloro, fluoro or iodo, in the presence of an acid;
(e) reacting the compound of formula VI with a Grignard reagent and carbon dioxide to form the compound of formula

or, alternatively, when carrying out the above reaction of step “e”, adding dimethylformamide to the Grignard reagent to form the corresponding aldehyde of formula

(f) reducing the compound of formula VII or VIIA to form the compound of formula

(g) reacting the compound of formula VIII with the appropriate compound of the formula HX 2 , wherein X 2 is defined as it is for formula IX, to form the desired compound of formula IX.

2. A process according to claim 1 , wherein, in step “a”, X is chloro and the Grignard reagent is isopropylmagnesium chloride lithium chloride complex.

3. A process according to claim 1 , wherein, in step “b”, the acid is sulfuric acid.

4. A process according to claim 1 , wherein, in step “d”, X 1 is bromo.

5. A process according to claim 1 , wherein, in step “d”, the acid is sulfuric acid, trifluoroacetic acid or a mixture of trifluoroacetic acid and sulfuric acid.

6. A process according to claim 1 , wherein, in step “e”, the Grignard reagent is a butyl lithium butylmagnesiumchloride complex or a butyl lithium i-propylmagnesiumchloride complex.

7. A process according to claim 1 , wherein, wherein, in step “e”, an aldehyde of formula VIIA is formed.

8. A process according to claim 1 , wherein, in step “f”, the reducing agent is lithium aluminum hydride.

9. A process for preparing a compound of the following formula:

comprising reacting a compound of the formula

wherein X 2 is bromo, chloro, iodo, mesylate, tosylate, triflate or another suitable leaving group, with the compound of formula

in the presence of a strong base, wherein the starting material of formula IX is synthesized comprising the steps of:
(a) reacting a compound of the formula

with the compound of formula

to form the compound of formula

(b) subjecting the compound of formula XIII to catalytic hydrogenation, to form the compound of formula

 and
(c) subjecting the compound of formula XIV to radical bromination with N-bromosuccinamide, or to standard bromination with hydrobromic acid, to form the compound of formula IX wherein X 2 is bromo, or, alternatively, reacting the compound of formula XIV with the appropriate compound of formula HX 2 , wherein X 2 is defined as it is for formula IX, to form the desired compound of formula IX.

10. A process according to claim 9 , wherein, in step “c”, the compound of formula XIV is reacted with N-bromosuccinimide, bromine or 1,3-dimethyl-2,5-dibromohydantoine and a radical starter.

11. A process according to claim 10 wherein the compound of formula XIV is reacted with N-bromosuccinimide and a radical starter which is azoisobutyronitrile.

12. A process according to claim 9 , wherein step “a” is conducted in the presence of a base, a phosphine and a palladium catalyst.

13. A process according to claim 12 , wherein the palladium catalyst is palladium acetate and the base is sodium methylate and the phosphine is triphenylphosphine.

14. A process according to claim 9 , wherein the reaction of step “a” is conducted in methanol.

Assignees

• Novartis Ag

Inventors

• Gallou Fabrice
• Sedelmeier Joerg Matthias
• Vogel Caspar

Classifications

• C07C17/04

  to unsaturated halogenated hydrocarbons · CPC title

• C07C22/08

  containing fluorine · CPC title

• C07C251/52 Primary

  of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups · CPC title

• C07C2101/16

  Chemistry & Metallurgy · mapped topic

• C07C45/27

  by oxidation (with ozone C07C45/40) · CPC title