Susan D. Van Arnum

A convenient preparation of cyclobutyl ketones: Naphthalene-catalyzed reductive cyclization of substituted 1,4-dihalobutanes

Abstract Acyl-substituted succinates are useful starting materials for the synthesis of cyclobutyl ketones. The key step, reductive cyclization of the intermediate dihalide, afforded yields of 32–60% of cyclobutyl-containing products.

HPLC method validation studies on a specific assay for monomethoxypoly(ethylene glycol) succinimido carbonate (mPEG-SC)

An UV-HPLC method for the determination of the potency of mPEG-SC, 5 kDa (1) has been developed and validated. Validation acceptance criteria that is typical of small molecule method validation was successfully applied for this method. The method relies on the HPLC separation of mPEG-OH, 5 kDa (2) and a derivatized form of mPEG-SC, 5 kDa (1). 1-Naphthylmethylamine reacts with mPEG-SC, 5 kDa (1) to form a stable, strongly UV absorbing carbamate 3. When the eluent is analyzed by UV detection at 220 nm, the method was shown to be linear, precise and accurate. The limit of detection of the method was 0.1 microg.

A green synthetic process for the preparation of water-soluble drugs: pegylation of menadiol and podophyllotoxin

Abstract Pegylation of drugs is a frequently employed strategy used to improve the pharmacokinetics and pharmacodynamics of drugs. Despite this, the virtues of pegylation as a green synthetic approach to enhance the water solubility of drugs has not been discussed. Using two well-known active pharmaceutical ingredients, menadiol sodium diphosphate (1) and the semisynthetic natural product, etoposide phosphate (3), green metrics for the processes of pegylation versus phosphorylation are presented and discussed. Menadiol (2) was prepared by an ultrasound mediated reduction of menadione (9). In a study done by the National Cancer Institute, PEG podophyllotoxin 12 was screened for activity against 60 different human cancer cell lines and the desired anticancer properties of podophyllotoxin (5) were retained. As podophyllotoxin (5) is a natural product, the concept of “green drugs” is espoused.

Analytical method development for a specific assay method for monomethoxypoly(ethylene glycol)succinimido carbonate (mPEG-SC) : A comparison of spectrophotometric, titrimetric and chromatographic methods

Three different quantitative methods, which rely on base-mediated reactions for the purity assessment of the hydrolytically unstable activated ester, mPEG-SC (1) are discussed. In a spectrophotometric assay, controlled base-catalyzed hydrolysis of mPEG-SC (1) affords N-hydroxysuccinimide and its concentration can be determined by UV analysis. Reaction of mPEG-SC (1) with benzylamine and a non-aqueous back titration of the remaining benzylamine can also be used for purity determination of mPEG-SC (1). HPLC analysis of derivatized forms of mPEG-SC (1) affords a potential specific assay for these polymers. The relative attributes and shortcomings of these methods are elaborated. Although the titration assay is intermediate in specificity, the greater precision of the method makes it the preferred method at this stage of development of an HPLC-ELSD or HPLC-UV assay method. The percent relative standard deviation (%R.S.D.) of the titration method was 2.9% as opposed to 8.8% for the HPLC assay. The accuracy of the titration method was shown to be 101+/-4.0% and was sufficient to justify a blending operation according to FDA cGMP guidelines.

An unexpected oxidative decarboxylation reaction of frenolicin-B

Abstract In the presence of free radicals, frenolicin-B (1) undergoes an unexpected oxidative decarboxylation reaction to afford 2 in an overall yield of 51%. Theoretical calculations support the proposed mechanism.

Selective crystallization of an allylic 7α-bromide : A facile synthesis of (1α,3β)-3-hydroxycholeste-5,7-diene-1,25-diol diacetate

An efficient synthesis of (3β)-7-dehydro-1α,25-diacetoxycholesterol (1) is described. When acetonitrile was used as the crystallizing solvent, only the 7α-bromide 6a was isolated and bromide 6a was prepared in a 69% yield starting from 3β-TBDMS-1α,25-diacetoxycholesterol (5). Dehydrobromination with sym-collidine led to the regioselective formation of only the 5,7-diene 7. After deprotection with concentrated hydrochloric acid, the diene diacetate 1 was obtained in an overall yield of 44% without chromatographic separations. When tetrabutylammonium fluoride trihydrate was used as the base, the 7β-fluoride 10 was isolated.

Preparation of 2-styrylthiazoles from 2-methylthiazoles: An improved procedure and mechanistic aspects

Abstract An improved procedure for the preparation of styrylthiazoles from 2-methylthiazoles is described. Using acetic acid as the solvent and the catalyst, yields of 49–80% of styrylthiazoles are obtained. A plausible mechanism is proposed.