kilomentor | 12 November, 2012 15:04
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 reaction with succinic anhydride or phthalic anhydride and then
water extraction of the carboxylic acid product impurity with dilute aqueous
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 purity by a factor of 10 was easily achieved heating with succinic anhydride or phthalic anhydride and then extracting.
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-hydroxymethyl-benzonitriIe 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 first knows 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 a tiny 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 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 to be useful for purification.