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Estropipate,ZYF Pharm Chemical

Estrogen.

Estropipate is used in post-menopausal women for hormonal replacement therapy, with benefits to improved cognition and prevention of osteoporosis.

ChEBI: Estropipate is a steroid sulfate and a piperazinium salt. It is functionally related to an estrone.

Step 1). A 100 L quantity of urine is adjusted by the addition of acid (hydrochloric acid is preferred but not essential) to a pH of 4 and extracted with a suitable solvent such as n-butyl alcohol, benzol, chloroform or ether in a continuous extraction apparatus. By using the countercurrent principle we find that this volume of urine may readily be extracted during one day's time and the active fraction transferred completely to a 4 L volume of butyl alcohol. This alcoholic solution is chilled and filtered from salts and other insoluble matter.
Step 2). The butyl alcohol extract is distilled to dryness in vacuum and the brown tarry residue (300 to 600 g). Residue is extracted with benzol using successive volumes of 1.5, 1.0, and 0.75 L of hot benzol, which treatment dissolves the active principle.
Step 3). The benzol solution is then chilled, poured from the insoluble matter and distilled using a vacuum to complete removal of benzol. The residue from the distillation is treated with e 200 mL of butyl alcohol to which solution or suspension 4 L of petroleum ether (boiling point 60-80°C) are added. The resultant solution and suspension then extracted five to eight times with 800 mL of water to each portion of which sufficient 10% NaOH is added to maintain a reaction alkaline to phenolphthalein. In this manner the hormone is transferred to the alkaline aqueous solution. This solution is chilled to 2°C for a day and poured from tarry material which separates. Subsequent purification of the hormone is based upon the fact that it possesses a sufficient acidic property so that it can be removed from certain organic solvents by means of alkali, and that it can be removed in turn from alkaline solutions by successive extractions with organic solvents.
Step 4). The slightly alkaline aqueous solution is extracted five times with successive (800-1200 mL) portions of ether (peroxide-free). This combined ether extract is then distilled and the active residue treated first with 80 mL butyl alcohol and then with 1500 mL of petroleum ether as in Step 3.
Step 5). The petroleum ether solution is then extracted 4 to 6 times with 300 mL portions of dilute NaOH solution and filtered. The alkaline filtrate is then extracted six times with 400 mL portions of sulfuric ether, thus again transferring the hormone to ether solution. Up to this stage usually 60-75% of the total activity is accounted for. For example in a typical experiment the original crude material contained 300.000 units and the assay of the ether solution obtained at the end of Step 5, assayed fully 200.000 units. In the subsequent steps, however, a considerable amount of scattering of the active material occurs and hence all by-products are worked back into the process.
Step 6). The ether solution is distilled to dryness and yields a yellowish oil. The oil is leached with 200-240 mL of cold 0.2 N NaOH solution, repeating the extraction 4 or 5 times, and combining and filtering the alkaline extract. This aqueous alkaline solution is then extracted with six successive portions of sulfuric ether using about 300 mL of peroxide-free ether extract.
Step 7). The ether solution resulting from Step 6 is distilled and the residue crystallized from 25% aqueous ethyl alcohol or from 25% aqueous acetone.
As an alternative method of procedure, the following may be substituted for Steps 4 to 7 inclusive of the above process. After distilling the benzol, the tarry mass may be stirred directly with 2000 mL of hot 0.3 N NaOH with a mechanical stirrer. The suspension is chilled and the supernatant Liquid poured or siphoned off. Repetition of the extraction two or three times is advisable. The alkaline aqueous solution is then extracted five or six times with 400 mL portions of sulfuric ether, thus transferring the hormone to ether solution. After distillation of the ether the residue is steam distilled as long as a distillate other than water is obtained. The condensed water is removed by vacuum distillation and the small amount of dark tarry residue leached 5 times with 50 mL of hot 0.3 N NaOH. This solution is filtered and the filtrate extracted with sulfuric ether (100 mL, 6 times). The ether solution is distilled and the residue leached with cold 0.3 N NaOH using 20 mL five times. This alkaline solution is filtered and extracted with 50 mL of sulfuric ether five times. Upon distillation of the ether and solution of the residue in a small quantity of hot ethyl alcohol, the hormone separates in semi-crystalline balls which may be filtered off. A further quantity is obtained by adding 3 volumes of water to the alcoholic solution. It may be recrystallized from 25% aqueous ethyl alcohol or from 25% aqueous acetone or from any of the following: chloroform, benzol, ethyl acetate, ethyl ether or petroleum ether. The final product consists of colorless crystals which, when crystallized from dilute alcohol, possess a distinct rhomboid outline. The crystals melt at 242-243°C (248-249°C corrected) with some decomposition.
Hormone was used with piperazine (1:1).

Ogen (Pharmacia & Upjohn); Ortho-EST (Sun).

Estrogen

All the estrone 3-sulfate salts have the obvious pharmaceuticaladvantage of increased water solubility and better oralavailability. Acids convert the salts to the free 3-sulfate estersand cause some hydrolysis of the ester. This does not seem toaffect absorption adversely, but precipitation of the free sulfateesters in acidic pharmaceutical preparations should beavoided. The dibasic piperazine molecule acts as a buffer,giving it somewhat greater stability.

Estrogen receptor agonist. Also inhibits organic anion transporting polypeptide 1B1 (OATP1B1) (IC 50 = 70 nM).

Estropipate is the piperazine salt of the estrogen receptor agonist estrone-3-sulfate and a potent, specific inhibitor of the organic anion transporting polypeptide 1B1 (OATP1B1, IC50 = 60 nM).