Process for preparing [(3-hydroxypyridine-2-carbonyl)amino]alkanoic acids, esters and amides
Inventors
Lanthier, Christopher M. • Gorin, Boris • Oudenes, Jan • Dixon, Craig Edward • Lu, Alan Quigbo • Copp, James Densmore • Janusz, John Michael
Assignees
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Publication Number
US-11267785-B2
Publication Date
2022-03-08
Expiration Date
Abstract
Disclosed are processes for preparing [(3-hydroxypyridine-2-carbonyl)amino]-alkanoic acids, derivatives, inter alia, 5-aryl substituted and 5-heteroaryl substituted [(3-hydroxypyridine-2-carbonyl]amino}acetic acids. Further disclosed are methods for making prodrugs of [(3-hydroxypyridine-2-carbonyl)-amino]acetic acids, for example, [(3-hydroxypyridine-2-carbonyl]amino}acetic acid esters and {[3-hydroxypyridine-2-carbonyl]amino}acetic acid amides. The disclosed compounds are useful as prolyl hydroxylase inhibitors or for treating conditions wherein prolyl hydroxylase inhibition is desired.
Core Innovation
The disclosure describes a process for preparing compound (5) through a sequence of defined intermediate transformations starting from (3-chlorophenyl)boronic acid and 3,5-dichloro-2-cyanopyridine. The process forms 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine in the presence of a catalyst and a base, followed by conversion to a methoxy intermediate using sodium methoxide. It then produces 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid by treatment with hydrobromic acid or hydrochloric acid.
The process continues by coupling 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid with glycine methyl ester using a coupling reagent to form methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate. A further reaction with sodium hydroxide is then carried out to form compound (5), completing the preparation route. The described sequence specifies the identities of key starting materials and intermediates, and fixes the order of functional group interconversions.
The document also describes extensive structural substituent options for prolyl hydroxylase inhibitor scaffolds, including R10 substituents on a substituted or unsubstituted phenyl or heteroaryl ring, a heteroaryl ring-A having C1-C9 heteroaryl and substituted variants, and ring constructions in which two R10 units form larger heterocycles containing N or O. It further addresses intermediate structures and their acid salt or anion-cation salt forms, including monovalent and divalent salts with example cations and anions, and a process overview for preparing 5-aryl or 5-heteroaryl-3-halo-2-cyanopyridine intermediates by condensation of a borate precursor A1 with 3,5-dihalo-2-cyanopyridine A2 to form A3.
Claims Coverage
The provided material includes one independent claim that defines a multi-step process to prepare compound (5). The claim set also includes dependent refinements to the catalyst and base used in step (A), and to the acid used in step (C), for a total of five inventive features.
Sequential preparation of compound (5) from chlorinated cyanopyridine intermediates
A process for preparing compound (5) by reacting (3-chlorophenyl)boronic acid with 3,5-dichloro-2-cyanopyridine in the presence of a catalyst and a base to form 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine, then reacting that intermediate with sodium methoxide to form 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, then reacting with hydrobromic acid or hydrochloric acid to form 5-(3-chlorophenyl)-3-hydroxypyridine-2-carboxylic acid, then reacting with glycine methyl ester in the presence of a coupling reagent to form methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate, and reacting the methyl {[5-(3-chlorophenyl)-3-hydroxypyridin-2-yl]amino}acetate with sodium hydroxide to form compound (5).
Use of a specific Pd catalyst for forming 5-(3-chlorophenyl)-3-chloro-2-cyanopyridine
The process wherein, in step (A), the catalyst is [1,1′-bis(diphenyphosphino)ferrocene]dichloro palladium(II).
Restriction of step (A) base to defined inorganic bases/salts
The process wherein the base used in step (A) is selected from a list of inorganic bases or salts including LiOH, NaOH, KOH, Ca(OH)2, Li2CO3, Na2CO3, K2CO3, and CaCO3.
K2CO3 as the step (A) base
The process wherein the base of step (A) is K2CO3.
Hydrochloric acid as the step (C) acid
The process wherein the acid used in step (C) is hydrochloric acid.
Across the provided independent claim, the inventive core is the defined sequence of intermediate conversions from 3-chlorophenyl-substituted chlorinated cyanopyridine to a methoxy derivative, to a hydroxypyridine-2-carboxylic acid, to a glycine-methyl-ester-coupled aminoacetate, and finally to compound (5), with refinements specifying a named Pd catalyst, defined inorganic bases for step (A), and hydrochloric acid for step (C).
Stated Advantages
Not explicitly described in patent.
Documented Applications
The document includes schemes that illustrate conversion of the ester/prodrug to amide/prolyl hydroxylase inhibitor forms.
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