Synthetic intermediates and improved processes for preparing ROCk inhibitors
AssigneeAlcon Inc.
InventorsMichael Scott McClure, Daniel Francis Minkler, Thomas Francis Nelson Haxell
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Abstract
Provided herein are methods of synthesizing netarsudil, and intermediates thereof, in high yield and at large commercial scale. A key intermediate in this synthesis is the preparation of piperidinium (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoate, a salt that has been found to be easily purified by recrystallization.
Claims27
A method of synthesizing a compound of Formula (I-a):
- wherein each R is independently selected from the group consisting of C1-C4alkyl, halogen, C1-C4 alkoxy and cyano;
- and n is an integer from 0 to 3;
- comprising:
- (a) reacting a compound of Formula (II-a), wherein PG is a nitrogen protecting group,
- with 6-aminoisoquinoline to form a compound of Formula (III-a)
- wherein each R is independently selected from the group consisting of C1-4 alkyl, halogen, C1-4 alkoxy and cyano;
- and n is an integer from 0 to 3;
- and
- (b) removing the nitrogen protecting group to form the compound of Formula (I-a).
An amine salt of (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid, chosen from the list of 2-aminoethanol, morpholine, piperidine, dibenzylamine, dicyclohexylamine, diisopropylamine, benzylamine, piperazine, DMAP.
A method of purifying (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid, wherein (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid is reacted to form an amine salt, and the salt is recrystallized and then the purified salt is then converted back into (S)-3-((tert-butoxycarbonyl)amino)-2-(4-(((2,4-dimethylbenzoyl)oxy)methyl)phenyl)propanoic acid.
A method of synthesizing a compound of the following formula
- comprising:
- (a) reacting
- with a chlorinating agent, to form an acid chloride;
- (b) crystallizing the acid chloride from n-heptane to form a purified acid chloride;
- (c) reacting the purified acid chloride with
- in the presence of a base, to form
- (d) reacting the product of step (c) with
- in the presence of a base at a temperature between −50° C. and −0° C. to form
- (e) reacting the product of step (d) with LiOOH to form
- (f) formation of an amine salt and then recrystallizing the product of step (e) to form a purified product of step (e);
- (g) activating the carboxylic acid group of the purified product of step (f) and reacting the activated carboxylic acid with 6-aminoisoquinoline to form
- and
- (h) recyrstallizing the product of step (g);
- (i) reacting the product of step (h) with at least 2 equivalents of MeSO3H to form
A compound, selected from:
The compound of claim 25, wherein the solid form is a crystalline form.
A compound described herein, prepared by one or more processes described herein.
Dependencies are inferred from the claim text.