C. DJERASSI*, L. MIRAMONTES, G. ROSENKRANZ, F. SONDHEIMER (SYNTEX, S.A., Category MEXICO CITY, MEXICO) Chemistry in Steroids. LIV. Synthesis of 19-Nov-17-Ethynyltestosterone and 19-Nor-17-Methyltestosterone Medicine and J. Am. Chem. Soc. 1954, 76, 4092–4094, DOI: 10.1021/ja01645a010. Biology

The First Contraceptive Key words

contraception

steroids O O Δ 1. Li, NH3, then 4 N HCl, CH(OEt)3 progestin 17 2. CrO , AcOH 17 H 3 H H pyridine•HCl 45% yield EtOH H H H H Birch reduction MeO O 3-O-methylestrone

O 1. potassium tert-amylate, acetylene OH H H 2. 50% HCl H H 64–78% yield H H H H EtO O norethisterone

OH OH

H H + H H H H O MeO noretynodrel mestranol

enovid

Significance: The combined oral contraceptive Comment: Norethisterone was synthesized by pill (COCP) gave women unprecedented control Birch reduction of 3-O-methylestrone, followed by over their fertility and helped spark the sexual revo- hydrolysis of the methyl enol ether and reoxidation lution. In 1951, Djerassi and co-workers at Syntex at C17. The enone was protected as the ethyl di- introduced norethisterone, the first orally available eneol ether, followed by addition of acetylene and highly active progestin, thereby enabling the devel- deprotection to yield norethisterone. The structure opment of the COCP. In 1952, chemists at Searle of noretynodrel was not covered by Syntex’s patent synthesized noretynodrel, another orally available and noretynodrel could thus be introduced by Sear- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. progestin and an isomer of norethisterone. The le. FDA approved the first COCP, Enovid, a mixture of noretynodrel and mestranol, in 1957 for menstrual disorders and, in 1960, as a contraceptive.

SYNFACTS Contributors: Dirk Trauner, Alexander J. E. Novak Synfacts 0312020, 16(11), 1365 Published online: 20.10.20201861-19581861-194X

DOI: 10.1055/s-0040-1706358; Reg-No.: T11820SF Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stutgart

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