Progesterone crystals

Bisethylenedioxypregn-5-ene. Method A. A mixture of progesterone (10 g), freshly distilled ethylene glycol (80 ml) and benzene (350 ml) is slowly distilled for 15 min to remove traces of water. p-Toluenesulfonic acid monohydrate (0.3 g) is added and the mixture is heated under reflux with stirring for 5 hr with a water separator. Saturated sodium bicarbonate solution is added to the cooled mixture and the benzene layer is separated. The organic layer is washed twice with water, dried and evaporated in vacuo. The residue is crystallized twice from acetone-methanol to give 4.15 g (32%) of bisketal, mp 178-181°. 

Methoxypregna-3,5-dien-20-oned A solution of progesterone (0.3 g) dissolved in 5 ml of 2,2-dimethoxypropane-dimethylformamide (1 1) is treated with p-toluenesulfonic acid monohydrate (8 mg) and 0.1 ml of methanol and then heated under reflux for 3.5 hr. The cooled solution is neutralized with 45 mg of sodium bicarbonate, dissolved in 200 ml of ice water, stirred for 0.5 hr and filtered. The enol ether thus obtained (0.29 g, 92%) is purified by crystallization from acetone-methanol containing a trace of pyridine mp 135-160° [a]o —61° (CHCI3). 

The precipitate was washed carefully with water and was then dissolved in 10 ml of methanol and 1.5 ml of methylene chloride. The solution was concentrated to 10 ml, diluted with 0.5 ml of 10% sodium hydroxide, boiled for one minute and cooled. The product, which crystallized on cooling, was recrystallized to give flakes of 6a-methyl-17a-hvdroxy-progesterone 17-acetate, having a MP 205° to 209°C, according to U.S. Patent 3,147,290. 

A single crystallisation is unlikely to lead to the isolation of pure crystals. In practice the product recovered in this process contains about 90% 11 a-hydroxyprogeterone with low levels of other products (especially 5 a-pregnane-3,20-dione and 60, lla-dihydroxyprogesterone). An example of a manufacturer who uses microbial 11a hydroxylation is Upjohn progesterone is used as substrate. 

Williams PA, Cosine J, Vinkovic DM et al (2004) Crystal structures of human cytochrome P450 3A4 bound to metyrapone and progesterone. Science 305 683-686... 

There are six crystal structures reported in the Protein Data Bank two without ligand (ltqnand IwOe), one cocrystallized with progesterone (7) (IwOf), one with mytrapone (8) (IwOg), one with ketoconazole (9) (2j0c) and one with erythromycin (10) (2j0d). 

Examples of solvent-mediated transformation monitoring include the conversion of anhydrous citric acid to the monohydrate form in water [235,236], CBZ with water [237] and ethanol-water mixtures [238,239], and cocrystallization studies of CBZ, caffeine, and theophylline with water [240]. Raman spectroscopy was used to monitor the crystallization rate and solute and solvent concentrations as griseofulvin was removed from an acetone solution using supercritical CO2 as an antisolvent [241]. Progesterone s crystallization profile was monitored as antisolvent was added [242]. 

Frisoni GB, De Leo D, Rozzini R, et al Psychic correlates of sleep symptoms in the elderly. Int J Geriatr Psychiatry 7 891-898, 1992 Fritschy J, Benke D, Mertens S, et al 5 types of type A GABA receptors identified in neurons by double and triple immunofluorescence staining with subunit specific antibodies. Proc Natl Acad Sci USA 89 6726-6730, 1992 Frye CA, Duncan JE Progesterone metabolites effective at the GABAa receptor complex attenuate pain sensitivity in rats. Brain Res 643 194-203, 1994 Erye CA, Cuevas CA, Crystal S, et al Diet and estrous cycle influence pain sensitivity in rats. Pharmacol Biochem Behav 45 255-260, 1993 Erye PE, Arnold LE Persistent amphetamine-induced compulsive rituals response to pyridoxine (B6). Biol Psychiatry 16 583-587, 1981... 

Colourless crystals or a white or slightly yellowish-white, crystalline powder. There are two forms, one melts at 126° to 131° and the other, known as jS-progesterone, at about 121°. Practically insoluble in water soluble I in 8 of ethanol, I in less than 1 of chloroform, and I in 16 of ether. 

Egerer-Sieber et al. (2006) reported on the purification and crystallization of recombinant 5p-POR from D. lanata. Later on, Gavidia et al. (2007) predicted that the 5p-POR belongs to the SDR family (Oppermann et al, 1997). Finally, Thorn et al. (2008) fully characterized the crystal structure and found that the progesterone reductase from D. lanata defines a novel class of short-chain dehydrogenases / reductases. 

Egerer-Sieber, C., Herl, V., Miiller-Uri, R, Kreis, W. and Muller, Y.A. (2006) Crystallization and preliminary crystallographic analysis of selenomethionine-labelled progesterone 5p-reductase from Digitalis lanata Ehrh. Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun., 62, 186-8. 

This cyclization has obvious applications to the synthesis of steroids and indeed Johnson et al. applied this reaction to a synthesis of dZ-progcsterone. The key step in the synthesis involves the cyclization of (3) to give (4). This reaction was carried out with trifluoroacetic acid as above, but ethylene carbonate was added to the reaction to trap the vinyl cation. After cyclization potassium carbonate was added to hydrolyze the enol complex. In this way (3) was converted into (4) in 71 % yield. The tetracyclic ketone (4) was converted into progesterone (6) by ozonization followed by intramolecular aldol condensation. Nole that (4) is a 5 1 mixture of the 17/7- and 17a-epimeric ketones. The mixture was converted into (6) and then separated by fractional crystallization. 

Variations in lattice energies between amorphous and crystalline forms can significantly influence a drug s aqueous solubility, and increases of several hundredfold were observed for morphine and benzimidazole derivatives. Furthermore, a substance may exist in more than one crystalline form, such as chloramphenicol, dehydroepiandrosterone (DHEA), progesterone, sul-fathiazole, carbamazepine, cortisone, or prednisolone, to name a few. Polymorphic transformations, routinely observed for pharmaceuticals, are structural differences resulting from different crystal arrangements of molecules in the solid state. Although thermodynamic differences between polymorphs disappear once dissolved. 

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