Removal of Hydroxyl Impurities from a Solid Product at Scale by Chemical Reaction

KiloMentor has several times proposed the purification of a substance by selective reaction of its impurities to produce new impurities that can be separated by simple aqueous base extraction. One of the proposed methods for removing an alcohol impurity from a predominantly non-alcohol product is the reaction with succinic anhydride or phthalic anhydride and then water extraction of the carboxylic acid product impurity with dilute aqueous base. 

This is precisely the method patented for the purification of some samples of the drug substances citalopram and escitalopram in CA558198 ( WO2005/084643).

In these particular patented instances, the reason for needing to get these hydroxyl impurities reduced was that the size and the crystal polymorph being formed was dependent on their concentrations. The hydroxyl-containing impurity in citalopram or escitalopram was Z-4-(4-dimethylamino-1-(4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl- benzonitrile. Reduction of this impurity by a factor of 10 was easily achieved heating with succinic anhydride or phthalic anhydride and then extracting. 

Example 1 

Scavenging of hydroxyl-containing impurity by succinic anhydride

 A mixture of R- and S-Citalopram (55.5 g) containing 0.6% of Z-4-(4-dimethylamino1-( 4-fluorophenyl)-but-l-enyl)-3-hydroxymethylbenzonitriIe is dissolved in dry toluene (145.0 g). Succinic anhydride (0.5 g) and aqueous ammonia (25% by weight) (3 ml) is added (pH = 10.5-11.0). The phases are separated and the toluene phase is washed with water (3x 120 ml). The toluene phase is evaporated and the yield is 53.0 g (95%). The product contains 0.06% of Z-4-(4-dimethylamino1-( 4-fluorophenyl)-but-1-enyl)-3-hydroxymethyl-benzonitrile.

But this is only indicated if one knows first that your product constituting non-nucleophilic material, does have hydroxyl-containing impurities. One potential means to test for free hydroxyls and indeed all nucleophilic species (NH and SH also) is to first, in an analytical amount, derivatize any nucleophilic functional-group-containing compounds to give colored materials that can be seen in a developed thin layer chromatogram as distinct from the unreactive main component. A colored derivatizing agent such as p-phenylazobenzoyl chloride or 4’-nitroazobenzene-4-carboxylic acid chloride

( Fieser & Fieser Reagents for Organic Synthesis Vol. 1), can be expected to produce colored spots on a TLC of the crude organic solution obtained by treating with such a reagent in an inert organic solvent and then washing with a dilute aqueous base to remove excess reagent. 

If such colored spots are present, a treatment with succinic anhydride or phthalic anhydride, or other hydroxyl scavenging agent can be useful for purification.