Norethindrone

Sample preparation Condition a Bond-Elut CIS SPE cartridge with MeOH and water. Add 500 J1.L plasma to the SPE cartridge, wash with 2 mL water, wash with 2 mL MeOH water 20 80, elute with two 500 pL aliquots of MeOH. Evaporate the eluate to dryness under a stream of nitrogen, reconstitute the residue in 50 pL MeOH water 20 80, inject a 20 pL aliquot. 

Column 100 X 1 5 pm Hypersil ODS Mobile phase MeCN MeOH water 25 25 50 Flowrate 0.1 Injection volume 20 Detector UV 

Extracted androstenedione, 20a-hydro Qr-4-pregnen-3-one, 17oi-hydro gq)rogesterone, progesterone, testosterone 

Taylor, R.B. Kendle, K.E. Reid, R.G. Hung, C.T. Chromatography of progesterone and its major metabolites in rat plasma using microbore high-performance liquid chromatography columns with conventional injection and detection systems. J.Chromatogr., 1987, 385, 383—392 

Sample preparation 2 mL Plasma -t 5 mL hexane dichloromethane 1 1, shake for 10 min, centrifuge at 2000 rpm for 10 min. Remove 4 mL of the organic phase and evaporate it at 55° under nitrogen. Reconstitute residue in 300 pL mobile phase, inject a 150 pL adiquot. 

Chemical Nama 17-hydroxy-19-nor-17o -pregn-4-en-20-yn-3-one Common Nama Norethisteron Structural Formula  

Trade Nama Manufacturer Country Year Introduced 

The oil thus obtained was dissolved in 4O0 cc of methanol and refluxed during one hour with 150 cc of 4N hydrochloric acid. The mixture was poured into a sodium chloride solution and extracted with ethyl acetate, washed to neutral, dried and evaporated to dryness. The product was a yellow oil which showed an ultraviolet absorption maximum characteristic of a A -3-ketone. 

A solution of 2.7 grams of chromic acid in 20 cc of water and 50 cc of acetic acid was added to the stirred solution of the above oil in 100 cc of acetic acid, maintaining the temperature below 20°C. After 90 minutes standing, 50 cc of methanol were added and the mixture concentrated under vacuum (20 mm). The residue was extracted with ether, washed to neutral and evaporated to dryness. The residual semicrystalline product (7 grams) was chromatographed over alumina and the fractions eluted with ether yielded 3.2 grams of A -19-norandrosten-3,17-dione having a MP of 163° to 167°C. 

CHEMICAL NAME= [17a]-17-Hydroxy-19-norpregn4-en-20-yn-3-one CAS NUMBER = 68-22-4 MOLECULAR FORMULA = C20H26O2 MOLAR MASS = 298.4 g/mol COMPOSITION = C(80.5°/o) H(8.8%) 

MELTING POINT = 204°C BOILING POINT = decomposes DENSITY = 1.15 g/cm3 

Contraceptives and other birth control methods have been used throughout human history. Ancient methods included a plethora of potions, condoms made from animal skins, 

Rosenkranzs arrival at Syntex started the next chapter in the development of the pill. Marker left chemical research several years after leaving Syntex and became involved in 

The next chapter in the use of norethindrone as an oral conception involved Luis Pincus (1903—1967). Pincus was a Harvard researcher whose controversial work on fertility and reproduction forced him to leave Harvard. He moved to Clark University in Worcester, Massachusetts, and while there he helped establish the Worcester Foundation for Experimental Biology. Early in 1950, interest in the use of progesterone as a contraceptive developed as a result of concerns about the burgeoning world population and calls from birth control 

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AHylestrenol (37) is prepared from (32), an intermediate in the synthesis of norethindrone. Treatment of (32) with ethanedithiol and catalytic boron trifluoride provides a thioketal. Reduction with sodium in Hquid ammonia results in the desired reductive elimination of the thioketal along with reduction of the 17-keto group. Oxidation of this alcohol with chromic acid in acetone followed by addition of aHyl magnesium bromide, completes the synthesis... 

Ethynodiol diacetate (53) is prepared by reduction of the 3-oxo group of norethindrone (28) with lithium tributoxyalurninum hydride, followed by acylation with acetic anhydride-pyridine (78,79). It has been reported that higher yields can be obtained in the reduction step by using triethylanainoalurninum hydride (80). 

LynestrenoL Lynestrenol (73) has been used in oral contraceptives and to treat menstrual disorders. It is converted in vivo to its active metabohte norethindrone (102,103). It can be recrystallized from methanol, and is soluble in ethanol, ether, chloroform, and acetone, and insoluble in water (102). The crystal stmcture (104) and other spectral and analytical data have been reported for lynestrenol (62). 

Lynestrenol is the des-3-oxo derivative of norethindrone (28). It has been prepared through a similar synthetic pathway as aHylestrenol (37) (52), ie, addition of potassium acetyUde, rather than aHyl magnesium bromide, affords lynestrenol (73). Lynestrenol is also available from norethindrone (28). Reduction of the 3-keto group is accompHshed by treating norethindrone (28) with sodium borohydride in the presence of trifluoro- or trichloroacetic acid... 

Norethindrone andISlorethindrone Acetate. Norethindrone (28) and its acetate or enanthate are used in oral contraceptives. 

Norethindrone may be recrystakhed from ethyl acetate (111). It is soluble in acetone, chloroform, dioxane, ethanol, and pyridine slightly soluble in ether, and insoluble in water (112,113). Its crystal stmcture has been reported (114), and extensive analytical and spectral data have been compiled (115). Norethindrone acetate can be recrystakhed from methylene chloride/hexane (111). It is soluble in acetone, chloroform, dioxane, ethanol, and ether, and insoluble in water (112). Data for identification have been reported (113). The preparation of norethindrone (28) has been described (see Fig. 5). Norethindrone acetate (80) is prepared by the acylation of norethindrone. Norethindrone esters have been described ie, norethindrone, an appropriate acid, and trifiuoroacetic anhydride have been shown to provide a wide variety of norethindrone esters including the acetate (80) and enanthate (81) (116). 

Examination by nmr of eight analogues of norethindrone, where stmctures varied at the C-11, C-18, and position, suggests a correlation... 

H. Ringold, in M. J. Pramik, ed., Norethindrone the First Three Decades, Syntex Laboratories, Palo Alto, Calif., 1978, p. 1. 

Ethinyl estradiol-norethindrone unless otherwise noted. 

Fused Pellets. Another form of an implant is a fused pellet. The pellets may be composed of either the dmg alone, or the dmg fused with cholesterol (29,36), and are formed as small cylinders by melting the dmg and then soHdifying it under pressure. Clinical studies with norethindrone pellets have been in progress for a number of years. Effective rates of release of the dmg from the implantation site were originally difficult to achieve. 

In further modifications of these norprogestins, reaction of norethindrone with acetic anhydride in the presence of p-toluene-sulfonic acid, followed by hydrolysis of the first-formed enol acetate, affords norethindrone acetate (41). This in turn affords, on reaction with excess cyclopentanol in the presence of phosphorus pentoxide, the 3-cyclopentyl enol ether (42) the progestational component of Riglovic . Reduction of norethindrone affords the 3,17-diol. The 33-hydroxy compound is the desired product since reactions at 3 do not show nearly the stereoselectivity of those at 17 by virtue of the relative lack of stereo-directing proximate substituents, the formation of the desired isomer is engendered by use of a bulky reducing agent, lithium aluminum-tri-t-butoxide. Acetylation of the 33,173-diol iffords ethynodiol diacetate, one of the most potent oral proves tins (44). ... 

Melengestrol Acetate Norethindrone Norethindrone Acetate Norethinodrel... 

Medroxyprogesterone Acetate Megestrol Acetate Melengestrol Acetate Norethindrone Pregnenolone Acetate Progesterone... 

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