Process for manufacturing 5-(2,6-di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine

Patent metadata

Field	Value
Publication number	US-9637468-B2
Application number	US-201314437177-A
Country	US
Kind code	B2
Filing date	Oct 21, 2013
Priority date	Oct 23, 2012
Publication date	May 2, 2017
Grant date	May 2, 2017

Abstract

The invention discloses improved processes for manufacturing a compound, 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine, its monohydrochloride salt and intermediates thereof.

First claim

The invention claimed is:

1. A process for manufacturing a compound of formula A

comprising the steps of:
(a) acylating 5-bromo-4-(trifluoromethyl)pyridin-2-amine in a reaction mixture comprising solvents ethyl acetate and heptane, and the acid anhydride acetic anhydride to form N-(5-bromo-4-(trifluoromethyl)pyridin-2-yl)acetamide;
(b) reacting N-(5-bromo-4-(trifluoromethyl)pyridin-2-yl)acetamide with an alkyl Grignard reagent isopropylmagnesium chloride lithium chloride in the solvent tetrahydrofuran followed by an triaklylborate triisopropylborate and 2,2′-azanediyldiethanol in one or more solvents selected from 2-methyltetrahydrofuran or isopropanol to form the boronic ester product, N-(5-(1,3,6,2-dioxazaborocan-2-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide, having the structure

 wherein the Boron to Nitrogen bond is a coordinative bond;
(c) coupling the boronic ester product, N-(5-(1,3,6,2-dioxazaborocan-2-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide, with 4,4′-(6-Chloropyrimidine-2,4-diyl)di[morpholine] via a palladium catalyzed Suzuki coupling reaction comprising (i.) a catalyst comprising triphenylphosphine and one or more solvents selected from dimethoxyethane, tetrahydrofuran or water, with Pd(OAc) 2 , and (ii.) a base potassium carbonate to form N-(5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide; and
(d) hydrolyzing N-(5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide in one or more solvents selected from isopropylacetate or water under acidic conditions to form the compound of formula A.

2. The process of claim 1 , wherein the palladium catalysed Suzuki coupling of step (c) comprises generating the palladium catalyst in-situ from palladium acetate and triphenylphosphine in an organic solvent selected from dimethoxyethane, tetrahydrofuran or water.

3. The process of claim 1 , wherein the hydrolysed N-(5-(2,6-dimorpholinopyrimidin-4-yl)-4-(trifluoromethyl)pyridin-2-yl)acetamide is treated with N-Acetyl-L-cysteine.

Assignees

• Flubacher Dietmar
• Bieri Nicole
• Acemoglu Murat
• Michel Pascal
• Mose Rasmus
• Stettler Hans
• Testa Maria Caterina
• Brozio Joerg
• Schaefer Frank
• Novartis Ag

Inventors

• Flubacher Dietmar
• Bieri Nicole
• Acemoglu Murat
• Michel Pascal
• Mose Rasmus
• Stettler Hans
• Testa Maria Caterina
• Brozio Joerg
• Schaefer Frank

Classifications

• C07D239/28

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms · CPC title

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D213/75

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title