Synthetic processes and intermediates
Inventors
Ponnaiah, Ravi • Sunkari, Sudhakar • Soni, Anil Kumar • Athunuri, Savi Rami Reddy • Korrakuti, Thrisulapani • Seelam, Pullarao • Parhi, Ajit K.
Assignees
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Publication Number
US-10513528-B2
Publication Date
2019-12-24
Expiration Date
Abstract
The invention provides synthetic processes and synthetic intermediates that can be used to prepare a compound of formula (I): or a salt thereof.
Core Innovation
The invention relates to synthetic processes for preparing a compound of formula (I), including salts thereof. The method comprises reacting a phenol of formula e with a chloride of formula h to provide the compound of formula (I).
The disclosed synthesis route includes preparing the chloride of formula h from an amino pyridine of formula g with chloroacetic acid, with further upstream conversion from a nitro pyridine of formula f using reducing agents or thiourea. The chloride of formula h is described as a 2-(chloromethyl)-substituted thiazolo[5,4-b]pyridine motif bearing a trifluoromethyl group, and the coupling forms an ether-linked product.
The phenol reactant is accessed by deprotecting a benzyl ether precursor of formula d. The benzyl ether of formula d is prepared by coupling an acid chloride of formula i, or a salt thereof, with an amide of formula c, and alternative phenol preparations, including a phenol of formula j, are also described within the overall synthetic scheme.
Claims Coverage
The independent claim covers a single core inventive concept: preparation of a compound of formula (I) by reacting a phenol of formula e with a chloride of formula h. Across the dependent claims, five main inventive features are specified: preparing chloride h from an amino pyridine and chloroacetic acid, preparing nitro pyridine f using thiourea or reducing agents, preparing phenol e by deprotecting benzyl ether d, preparing benzyl ether d by coupling an acid chloride with an amide, and converting 2,4-difluorophenol to compound a.
Reacting a phenol of formula e with a chloride of formula h
A method for preparing a compound of formula (I) comprising reacting a phenol of formula e with a chloride of formula h to provide the compound of formula (I).
Preparing a chloride of formula h from an amino pyridine and chloroacetic acid
Preparing a chloride of formula h by reacting an amino pyridine of formula g with chloroacetic acid.
Preparing a nitro pyridine using thiourea or reducing agents
Preparing a nitro pyridine of formula f by using thiourea or converting a nitro pyridine of formula f to an amino pyridine of formula g using reducing agents.
Preparing the phenol of formula e by deprotecting a benzyl ether
Preparing a phenol of formula e by deprotecting the corresponding benzyl ether of formula d.
Preparing the benzyl ether of formula d by coupling an acid chloride with an amide
Preparing the benzyl ether of formula d by coupling an acid chloride of formula i, or a salt thereof, with an amide of formula c.
Converting 2,4-difluorophenol to compound a
Preparing the compound of formula a by converting 2,4-difluorophenol into the compound of formula a.
Overall, the claims center on coupling a phenol of formula e with a chloride of formula h to form the compound of formula (I), with dependent claim refinements specifying precursor conversions used to reach the reactants.
Stated Advantages
The processes enable cost-effective, environmentally acceptable commercial manufacture.
Documented Applications
The illustrative example sequence culminates in TXA709 mesylate and TXA709 free base.
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