68-22-4 Usage
Description
Norethindrone is a synthetic progestin, a hormone with properties similar to progesterone, and is best known as the first female oral contraceptive, or the "pill." Its global impact on society and culture has made it one of the most important inventions in history.
Used in Pharmaceutical Industry:
Norethindrone is used as a progestin contraceptive for preventing ovulation. It works by producing pregnant-like conditions in a female, suppressing the development of egg follicles and ovulation. In combination with estrogen, it also thickens cervical mucus, making it harder for sperm to enter the uterus and for an egg to implant on the uterine wall.
Used in Hormone Therapy:
Norethindrone is used as a synthetic progestin for hormone therapy, helping to regulate menstrual cycles and treat conditions related to hormonal imbalances.
Note: The statement "It is reasonably anticipated to be a human carcinogen" is not an application but a potential health concern that should be considered when using Norethindrone.
Originator
Norlutin,Parke Davis ,US,1957
History
The development of norethindrone as a female oral contraceptive took place indirectly over 30 years as a result of steroid research.This research accelerated in the 1930s when structures and medical applications of steroidal compounds were determined.Steroids are lipids, which include cholesterol, bile salts,and sex hormones,that are characterized by a structure of three fused six-carbon rings and a five-carbon ring. In 1957, both norethindrone and norethynodrel were approved by the Food and Drug Administration (FDA) for treating menstrual problems and infertility. In 1960, the FDA approved Searle's norethynodrel under the trade name Enovid. Norethindrone was approved as an oral contraceptive in 1962 under the trade name Ortho-Novum.
Manufacturing Process
7.5 grams of 3-methoxyestrone were dissolved in 750 cc of anhydrous dioxane in a three-neck flask, placed in a box and insulated with cotton wool. 2 liters of anhydrous liquid ammonia and 15 grams of lithium metal in the form of wire were added to the mechanically stirred solution. After stirring for one hour, 150 cc of absolute ethanol were added at such speed that no bumping occurred; when the blue color had disappeared, 500 cc of water were added in the same way. The ammonia was evaporated on the steam bath and the product collected with 2 liters of water. It was extracted with ether and then with ethyl acetate and the combined extract was washed to neutral and evaporated to dryness under vacuum, leaving 7.4 grams of a slightly yellow oil.
The oil thus obtained was dissolved in 400 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 ?4-3-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 ?4-19norandrosten-3,17-dione having a MP of 163° to 167°C.A solution of 2 grams of ?4-19-norandrosten-3,17-dione and 0.4 gram of pyridine hydrochloride in 50 cc of benzene free of thiophene was made free of moisture by distilling a small portion; 4 cc of absolute alcohol and 4 cc of ethyl orthoformate were added and the mixture was refluxed during 3 hours. 5 cc of the mixture were then distilled and after adding an additional 4 cc of ethyl orthoformate the refluxing was continued for 2 hours longer. The mixture was evaporated to dryness under vacuum and the residue was taken up in ether, washed, dried and evaporated to dryness. The residue was crystallized from hexane-acetone and then from ether to give ?3,5-19-nor-3ethoxy-androstadien-17-onewith a MP of 140° to 142°C.
One gram of potassium metal was dissolved in 25 cc of tertiary amyl alcohol by heating under an atmosphere of nitrogen. One gram of ?3,5-19-nor-3ethoxyandrostadien-17-onein 25 cc of anhydrous toluene was added and nitrogen was passed during 15 minutes. Then acetylene (especially dried and purified) was passed during 14 hours through the mechanically stirred solution, at room temperature.The mixture was poured in water, acidified to pH 1 with dilute hydrochloric acid, heated on the steam bath for 30 minutes and then subjected to steam distillation to remove the organic solvents. The residue was filtered, dried and recystallized several times from ethyl acetate. The ?4-19-nor-17αethinylandrosten-17β-ol-3-onethus obtained had a MP of 198° to 200°C (in sulfuric acid bath), 200° to 204°C (Kofler).
Therapeutic Function
Progestin
Biochem/physiol Actions
19-norethindrone is an oral contraceptive involved in the inhibition of cytosolic sulfotransferases (SULT).
Clinical Use
Progestogen:
Breast cancer, contraception, dysfunctional
uterine bleeding, menorrhagia, dysmenorrhoea,
endometriosis, premenstrual syndrome,
postponement of menstruation
Safety Profile
Confirmed carcinogen
with experimental carcinogenic,
tumorigenic, and teratogenic data. Mddly
toxic by ingestion. Human systemic effects
by ingestion: dermatitis and androgenic
effects. Human teratogenic effects:
developmental abnormalities of the
musculoskeletal system and urogenital
system; and behavioral effects in the
newborn. Human reproductive effects:
spermatogenesis; testes, epididymis, sperm
duct changes; impotence; male breast
development; other male effects; ovaries,
fallopian tube changes; menstrual cycle effects; postpartum effects; changes in
female fertility. Experimental reproductive
effects. Human mutation data reported.
When heated to decomposition it emits
acrid smoke and irritating fumes.
Synthesis
Norethindrone, 17α-ethynyl-17β-hydroxyestra-4-en-4-one (28.3.12),
is made from 19-nor-4-androsten-3,17-dione (28.3.10), which is in turn synthesized by
partial reduction of the aromatic region of the 3-O-methyl ether of estrone with lithium
in liquid ammonia, and simultaneously of the keto-group at C17 to and hydroxyl group,
which is then oxidized back to a keto-group by chromium (VI) oxide in acetic acid. The
conjugated with the double bond carbonyl group at C3 is then transformed to dienol ethyl
ether (28.3.11) using ethyl orthoformate. The obtained product is ethynylated by acetylene
in the presence of potassium tert-butoxide. After hydrochloric acid hydrolysis, of
the formed O-potassium derivative, during which the enol ether is also hydrolyzed, and
the remaining double bond is shifted, the desired norethindrone (28.3.12) is obtained.
Drug interactions
Potentially hazardous interactions with other drugs
Antibacterials: metabolism of progestogens
accelerated by rifamycins (reduced contraceptive
effect).
Anticoagulants: progestogens antagonise
anticoagulant effect of phenindione; may enhance or
reduce anticoagulant effect of coumarins.
Antidepressants: contraceptive effect reduced by St
John’s Wort - avoid.
Antiepileptics: metabolism accelerated by
carbamazepine, eslicarbazepine, fosphenytoin,
lamotrigine, oxcarbazepine, phenobarbital,
phenytoin, rufinamide and topiramate (reduced
contraceptive effect); concentration of lamotrigine
reduced; concentration reduced by high dose
perampanel.
Antifungals: reduced contraceptive effect with
griseofulvin.
Antivirals: contraceptive effect reduced by
efavirenz; metabolism accelerated by nevirapine
(reduced contraceptive effect); atazanavir increases
norethisterone concentration.
Aprepitant: possible contraceptive failure.
Bosentan: possible contraceptive failure.
Ciclosporin: progestogens inhibit metabolism of
ciclosporin (increased plasma concentration).
Cytotoxics: possibly reduced contraceptive effect with
crizotinib, dabrafenib, olaparib and vemurafenib.
Dopaminergics: concentration of selegiline increased
- avoid.
Fosaprepitant: possible contraceptive failure.
Lumacaftor: possible contraceptive failure.
Tacrolimus: tacrolimus levels are greatly increased -
avoid (anecdotal evidence).
Ulipristal: contraceptive effect of progestogens
possibly reduced.
Carcinogenicity
Norethisterone is reasonably anticipated to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in experimental animals.
Environmental Fate
Waste streams from manufacturing plants producing contraceptives
containing norethisterone can be sources of its release
to the environment. If released to the air, norethisterone exists in
both vapor and particulate phases in the atmosphere as deduced
from a vapor pressure of 3.1× 10-7mmHg at 20 ℃. This vapor
pressure indicates that norethisterone is not expected to be
volatile from dry soil surfaces. Furthermore, based on an estimated
Henry’s law constant of 5.8×10-10 atm m3 mol-1 for
norethisterone, volatilization from water and moist soil surfaces
is not plausible.
In aquatic systems, norethisterone is expected to adsorb to
suspended solids and sediments given by its Koc value (soil
organic carbon–water partitioning coefficient) of 220.
In the air, the vapor phase of norethisterone can be
degraded by reaction with photochemically produced hydroxyl
radicals with an estimated half-life of 1.1 h; the particulate
phase can be removed by wet or dry deposition. Norethisterone
is likely susceptible to photolysis by sunlight because of the
presence of chromophores that absorb at wavelengths more
than 290 nm. Hydrolysis of norethisterone is not anticipated
under environmental conditions because of the lack of a functional
group to hydrolyze.
In terrestrial systems, the Koc value of 220 suggests that
norethisterone has moderate mobility in soil.
An estimated bioconcentration factor (BFC) of 42 for norethisterone
indicates that its potential for bioconcentration in
aquatic organisms is moderate.
Metabolism
It is metabolised in the liver with 50-80% of a dose being
excreted in the urine and up to 40% appearing in the faeces.
Toxicity evaluation
As a synthetic progestin, norethisterone enters the target cells
by passive diffusion and binds to its intracellular receptor to
initiate transcription and protein synthesis. It changes the
cervical mucus so that sperm migration or implantation of
the fertilized ovum in the uterus is inhibited. Repeated low
doses of norethisterone can change the rate of ovum transport
by affecting motility and secretion in the fallopian
tubes. When administered at high doses, norethisterone can
suppress ovulation and cause ovarian and endometrial
atrophy. Variable suppression of follicle stimulating
hormone (FSH) and luteinizing hormone (LH) occurs with
low doses.
Check Digit Verification of cas no
The CAS Registry Mumber 68-22-4 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 6 and 8 respectively; the second part has 2 digits, 2 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 68-22:
(4*6)+(3*8)+(2*2)+(1*2)=54
54 % 10 = 4
So 68-22-4 is a valid CAS Registry Number.
InChI:InChI=1/C20H26O2/c1-3-20(22)11-9-18-17-6-4-13-12-14(21)5-7-15(13)16(17)8-10-19(18,20)2/h1,12,15-18,22H,4-11H2,2H3/t15-,16?,17?,18?,19-,20-/m0/s1
68-22-4Relevant articles and documents
Biocatalytic modifications of ethynodiol diacetate by fungi, anti-proliferative activity, and acetylcholineterase inhibitory of its transformed products
Nurfazilah Wan Yusop, Sharifah,Imran, Syahrul,Ilham Adenan, Mohd,Ashraf, Kamran,Sultan, Sadia
, (2021/04/15)
The fungal transformations of ethynodiol diacetate (1) were investigated for the first-time using Botrytis cinerea, Trichothecium roseum, and R3-2 SP 17. The metabolites obtained are as following: 17α-Ethynyl-17β-acetoxyestr-4-en-3-one-15β-ol (2), 19-nor-
Preparation method of norethindrone acetate (by machine translation)
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Paragraph 0008; 0029; 0032, (2020/11/23)
The invention discloses a preparation method of norethindrone acetate and belongs to the technical field of drug preparation and processing. The method uses 19 - demethyl -4 - androstenedione as a starting raw material, protects, acetylenically, hydrolyses and esterifies 4 steps to prepare the norethindrone acetate. To the preparation method of the norethindrone acetate, the defects of a traditional process are overcome, reaction conditions are mild, impurities are reduced, overall conversion rate is high, operation is simple and convenient, and the method is suitable for industrial production and has a wide market prospect. (by machine translation)
KIT FOR FEMALE MAMMALS, COMPRISING A COMBINATION OF GESTAGEN AND OESTROGEN
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, (2008/06/13)
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