Hydrochloric Acid → Alvespimycin hydrochloride

Participants

Reaction Steps

A mixture of geldanamycin (15 g, 26.75 mmol) (SAIC-Frederick, Lot No. 3155-28-1) and N,N-dimethyl-ethylenediamine (15 mL, 37.83 mmol) (Aldrich, Lot No. HN04216AL) in dry methylene chloride (300 mL) (Mallinckrodt, Lot No. 4881KVJP) was stirred at room temperature for 1 hour and subsequently poured into ice water (500 mL). After the organic layer and aqueous layer became visually separated, the aqueous layer was extracted with methylene chloride (2×100 mL). The combined methylene chloride solution was washed with water (2×100 mL), dried with MgSO4 (Spectrum, Lot No. HJ302), and evaporated in a diaphragm pump. The remaining residue (16.5 g, 26.75 mmol) was dissolved in methylene chloride (130 mL). Dissolved hydrogen chloride (1.1 eq, 29.43 mmol) (Matheson, Lot No. T410242) in dioxane (Aldrich, Lot No. 16619CQ) was added to the solution resulting in immediate precipitation. After stirring for 30 minutes, the solids were collected, rinsed with methylene chloride (50 mL), and air-dried for 18 hours to give the crude hydrochloride salt (17.2 g). A solution of the crude product (17.2 g) in aqueous alcohol (50% v/v, 200 mL) (Aaper Alcohol, Lot. No. 97A28UARAT) was heated to reflux, filtered, and allowed to cool for 30 minutes. After cooling on ice for an additional 30 minutes, the solids were collected, washed with cold anhydrous alcohol (50 mL), and air-dried for 1 hour. The product was dried further at 70° C./0.1 mmHg for 17 hours to give pure target compound. Approximately 13.4 g of 17-Demethoxy-17-[[2(dimethylamino)ethyl]amino]geldanamycin hydrochloride (82%) was isolated as a violet crystalline solid and used in Examples 1 and 2.

Provenance & Evidence