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Norgestrel, sold under the brand name Opill among others, is a progestin which is used in birth control pills. It is often combined with the estrogen ethinylestradiol, marketed as Ovral. It is also used in menopausal hormone therapy. It is taken by mouth.
of norgestrel include menstrual irregularities, , nausea, and breast tenderness. The most common side effects of the norgestrel include irregular bleeding, headaches, dizziness, nausea, increased appetite, abdominal pain, cramps, or bloating. Norgestrel is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak activity and no other important hormonal activity.
Norgestrel was patented in 1961 and came into medical use, specifically in birth control pills, in 1966. It was subsequently introduced for use in menopausal hormone therapy as well. Norgestrel is sometimes referred to as a "second-generation" progestin. It is marketed widely throughout the world. Norgestrel is available as a generic drug. In 2022, the version with ethinylestradiol was the 264th most commonly prescribed medication in the United States, with more than 1million prescriptions. In July 2023, the US Food and Drug Administration (FDA) approved norgestrel for over-the-counter sale.
The ovulation-inhibiting dose of norgestrel appears to be greater than 75μg/day, as ovulation occurred in 50 to 75% of cycles with this dosage of norgestrel in studies. The ovulation-inhibiting dosage of levonorgestrel, which is twice as potent as norgestrel, is approximately 50 to 60μg/day. One review lists the ovulation-inhibiting dose of norgestrel as 100μg/day. The endometrial transformation dose of norgestrel is listed as 12mg per cycle and the menstrual delay test dose of norgestrel is listed as 0.5 to 2mg/day.
The chemical synthesis was first proposed by Smith & Hughes:Smith, Hercherl; Hughes, G. A.; Douglas, G. H.; Wendt, G. R.; Buzby, G. C.; Edgren, R. A.; Fisher, J.; Foell, T.; Gadsby, B.; Hartley, D.; Herbst, D.; Jansen, A. B. A.; Ledig, K.; McLoughlin, B. J.; McMenamin, J.; Pattison, T. W.; Phillips, P. C.; Rees, R.; Siddall, J.; Siuda, J.; Smith, Leland L.; Tokolics, J.; Watson, D. H. P. (1964). "856. Totally synthetic steroid hormones. Part II. 13β-Alkylgona-1,3,5(10)-trienes, 13β-alkygon-4-en-3-ones, and related compounds". J. Chem. Soc. 0 (0): 4472–4492. doi:10.1039/JR9640004472.Smith, H.; Hughes, G. A.; Douglas, G. H.; Hartley, D.; McLoughlin, B. J.; Siddall, J. B.; Wendt, G. R.; Buzby, G. C.; Herbst, D. R.; Ledig, K. W.; McMenamin, J. R.; Pattison, T. W.; Suida, J.; Tokolics, J.; Edgren, R. A.; Jansen, A. B. A.; Gadsby, B.; Watson, D. H. R.; Phillips, P. C. (1963). "Totally synthetic (±)-13-Alkyl-3-hydroxy and methoxy-gona-1,3,5(10)-trien-17-ones and related compounds". Experientia 19(8): 394. doi:10.1007/BF02171503.Gordon Alan Hughes & Herchel Smith, (1976 to Individual).Gordon Alan Hughes & Herchel Smith, (1977 to Individual).Hughes Gordon Alan & Smith Herchel, (1968 to SMITH). Commercial: NB: Although the synthesis has involved the formation of no fewer than 6 chiral centers, only two of the possible 64 possible isomers are formed.
The halogenation of 3-(3-methoxyphenyl)propan-1-ol 7252-82-6 ( 1) with phosphorus tribromide gave 1-(3-bromopropyl)-3-methoxybenzene 6943-97-1 ( 2). Treatment with ethynylsodium led to 5-m-methoxyphenylpent-1-yne 1424-70-0 ( 3). ( Ex 1) Mannich reaction with formalin and diethylamine led to 1-Diethylamino-6-m-methoxyphenylhex-2-yne, PC21485597 ( 4). ( Ex 8) An oxymercuration reaction with mercury(II) sulfate in aqueous sulfuric acid gives a mixture of 1-(diethylamino)-6-(3-methoxyphenyl)hexan-3-one 3706-69-2 ( 5) and 6- m-methoxyphenylhex-1-en-3-one, PC10798238 ( 6). ( Ex 17) Treatment with 2-Ethyl-1,3-cyclopentanedione 823-36-9 ( 7) in the presence of pyridine base causes a Michael reaction to occur to give 2-Ethyl-2-6-(m-methoxyphenyl)-3-oxohexyl-1,3-cyclopentanedione, PC21485569 ( 8). ( Ex 43) The cyclodehydration step was achieved by refluxing with a catalytic amount of TsOH in a DS-trap to give 848-07-7 ( 9). ( Ex 68) Catalytic hydrogenation over Raney nickel gives ( 10). ( Ex 83) Reduction with sodium borohydride leads to PC12598343 ( 11). ( Ex 108) Birch reduction with lithium metal in and liquid ammonia in 1-methoxypropan-2-ol gives ( 12). ( Ex 116) Oppenauer oxidation of the alcohol gives the ketone ( 13). ( Ex 121) Reaction with ethynyllithium led to ( 14). ( Ex 170) Hydrolysis in mineral acid completed the synthesis of norgestrel ( 15).
Alternative route: Improved ethynylation procedure: German: Dane's method:
The contraceptive efficacy of norgestrel was established in the U.S. with the original approval for prescription use in 1973.
In July 2023, the FDA approved norgestrel for over-the-counter sale. The FDA granted the approval to Laboratoire HRA Pharma which was acquired by Perrigo Company plc.
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