302-22-7

Basic information

• Product Name: Chlormadinone acetate
• Synonyms: 17-(Acetyloxy)-6-chloropregna-4,6-diene-3,20-dione;17-Acetoxy-6-chloro-6-dehydroprogesterone;17-alpha-Acetoxy-6-chloro-6,7-dehydroprogesterone;17-alpha-acetoxy-6-chloro-6-dehydroprogesterone;17alpha-Acetoxy-6-chloro-6-dehydroprogesterone;17-alpha-acetoxy-6-chloropregna-4,6-diene-3,20-dione;17alpha-Acetoxy-6-chloropregna-4,6-diene-3,20-dione;20-dione,17-(acetoxy)-6-chloro-pregna-6-diene-3
• CAS NO: 302-22-7
• Molecular Formula: C₂₃H₂₉ClO₄
• Molecular Weight: 404.93
• EINECS: 206-118-0
• Product Categories: Intermediates & Fine Chemicals;Pharmaceuticals;Steroids;Steroid and Hormone;SUICALM
• Mol File: 302-22-7.mol

Chemical Properties

• Melting Point: 212°C
• Boiling Point: 512.5 °C at 760 mmHg
• Flash Point: 172.5 °C
• Appearance: crystalline solid
• Density: 1.1345 (estimate)
• Vapor Pressure: 1.28E-10mmHg at 25°C
• Refractive Index: 1.562
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly), Ethyl Acetate (Slightly), Methanol (Slightly)
• Merck: 14,2102
• BRN: 2633614
• CAS DataBase Reference: Chlormadinone acetate(CAS DataBase Reference)
• NIST Chemistry Reference: Chlormadinone acetate(302-22-7)
• EPA Substance Registry System: Chlormadinone acetate(302-22-7)

Safety Data

• Hazard Codes: T
• Statements: 60-61-40-48
• Safety Statements: 53-22-36/37/39-45
• WGK Germany: 3
• RTECS: TU3750000
• Hazardous Substances Data: 302-22-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Chlormadinone acetate is used as an orally active progestogen with antiandrogenic activity for the development of oral contraceptives. It is particularly effective in combination with other hormones to prevent pregnancy.
Used in Oncology:
Chlormadinone acetate is used as an antineoplastic agent, specifically a hormonal therapy, to treat certain types of cancer. Its mechanism of action involves binding to hormone receptors, which can help control the growth and spread of cancer cells.
Used in Neurology:
In the field of neurology, chlormadinone acetate is used as a tranquilizer to help alleviate anxiety and stress. It may also function as a neuroleptic, which can be beneficial in managing certain psychiatric conditions.
Used in Cardiovascular Medicine:
Chlormadinone acetate is utilized as an alpha adrenergic blocker, which can help regulate blood pressure and improve blood flow in the cardiovascular system. This application can be particularly useful in the treatment of hypertension and related conditions.

Originator

Chlormadinone,Teikoku Hormone Mfg

Manufacturing Process

10 g 6-dehydro-17α-acetoxy-progesterone was dissolved in 400 ml dioxane and 40 ml water. The solution was added to 4 g N-chlorosuccinimide and 2.4 ml 70% perchloric acid. The mixture was left at ambient temperature for 24 hours, whereupon it was poured in water, a dropping precipitate was filtered off, washed with water and dried. It was filtered through aluminum oxide and recrystallized from ether to give 6-chloro-6-dehydro-17α-acetoxyprogesterone (chlormadinone acetate). MP: 204°-206°C. [α]D= +54.6° (chloroform).

Therapeutic Function

Progestin

World Health Organization (WHO)

Chlormadinone acetate, a synthetic progestogen, was introduced in 1965 as a component in oral contraceptive preparations. In 1967, as a result of new regulations required by the United States Food and Drug Administration, chlormadinone acetate was submitted to long-term toxicity studies and by the early 1970s it was shown to be associated with an increased incidence of mammary tumours in beagle bitches which led to its withdrawal by several regulatory authorities. Subsequently the validity of the beagle bitch model as a predictor of carcinogenicity of steroid contraceptives has been contested by many national regulatory authorities and chlormadinone remains available in some countries for contraceptive purposes. In some instances it is indicated for treatment of progesterone deficiency and endometriosis, and of irregular uterine bleeding due to fibroids. (Reference: (WHODI) WHO Drug Information, 84.1, 5, 1984)

Safety Profile

Suspected carcinogen with experimental carcinogenic and tumorigenic data. Moderately toxic by intraperitoneal route. Human maternal and reproductive effects by ingestion, intramuscular, and possibly other routes: ovary, uterus, cervix, vagina, and fallopian tube changes; menstrual cycle changes or disorders; changes in ferthty; and other unspecified female effects. A human teratogen that causes developmental abnormalities of the endocrine system in the fetus. Experimental teratogenic and reproductive effects. An oral contraceptive. When heated to decomposition it emits toxic fumes of Cl-.

in vitro

when compared with other progesterone derivatives, chlormadinone showed a relatively strong positional effect. chlormadinone was found to have high binding affinity to the progesterone receptor, resulting in strong progestogenic activity at the endometrium level. chlormadinone could also prevent the lh surge in the same way as progesterone. in addition, chlormadinone could weakly bind to the glucocorticoid receptor, but not to either mineralocorticoid nor estrogen receptors. chlormadinone at high doses competed effectively with androgens to block their effects and also downregulated the number of androgen receptors [1].

in vivo

results from previous rat study showed that chlormadinone at low doses, similar to cyproterone acetate, was able to selectively impaire the epididymal function and maturation of spermatozoa without appreciably changing either testicular function or pituitary gonadotrophin secretion [2].

references

[1] bouchard p. chlormadinone acetate (cma) in oral contraception--a new opportunity. eur j contracept reprod health care. 2005;10 suppl 1:7-11.[2] sharma mm,lal g,jacob d. effects of low doses of chlormadinone acetate in the rat. j reprod fertil.1976 sep;48(1):177-9.

InChI:InChI=1/C23H29ClO4/c1-13(25)23(28-14(2)26)10-7-18-16-12-20(24)19-11-15(27)5-8-21(19,3)17(16)6-9-22(18,23)4/h11-12,16-18H,5-10H2,1-4H3/t16?,17?,18?,21-,22+,23+/m1/s1

Upstream product

• 27255-62-5 6-chloro-3-methoxy-17α-hydroxypregna-3,5-dien-20-one 17-acetate 
• 16319-93-0 17-acetoxy-3-ethoxy-pregna-3,5-dien-20-one 
• 1054-64-4 17α-acetoxy-3-methoxypregna-3,5-dien-20-one 
• 4134-58-1 hydroxyprogesterone acetate 
• 5192-72-3 17α-Acetoxy-5α,6β-dichlor-pregnandion-3,20 
• 1961-77-9 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione 
• 108-24-7 acetic anhydride 
• 68-96-2 17-hydroxyprogesterone 
• 2477-60-3 17α-hydroxypregna-4,6-diene-3,20-dione 
• 2133-50-8 17α-acetoxy-6α,7α-epoxy-4-pregnen-3,20-dione 
• 2658-74-4 17α-acetoxy-6β-chloropregn-4-ene-3,20-dione 
• 2477-73-8 17α-acetoxy-6α-chloropregn-4-ene-3,20-dione 

Downstream Products

• 13698-49-2 6-chloro-17a-acetoxy-pregnane-1,4,6-,triene-3,20-dione 
• 3114-44-1 6-chloropregna-4,6-diene-3β,17α-diol-20-one 17-acetate 
• 1961-77-9 6-chloro-17-hydroxypregna-4,6-diene-3,20-dione 

Relevant articles and documents

Preparation method of chlormadinone acetate

A preparation method of chlormadinone acetate includes: using 17a hydroxyl progestin as a raw material, dissolving the same in an organic solvent, reacting with bromine under acid catalysis to obtaina bromination product, and enabling the bromination product to react with lithium bromide and lithium carbonate in the organic solvent for debromination to obtain 6 dehydrogenation product in the organic solvent; dissolving the 6 dehydrogenation product in the organic solvent to react with organic peroxy acid to obtain epoxide; dissolving the epoxide in the organic solvent to be in additive reaction with hydrogen chloride gas, and dehydrating in a strong acid solution to obtain chlormadinone; dissolving chlormadinone in the organic solvent to react with acetic anhydride under acid catalysis toobtain chlormadinone acetate. HPLC content is 99.0-99.5%, and total yield of four-step synthetic reaction is 80-82%. Compared with conventional synthetic methods, the preparation method is simple andconvenient to operate, economical, environment-friendly and high in synthetic total yield and in product quality, and cost is lowered by 40-45%; the solvent used in the method can be recycled, so that industrial production is facilitated greatly.

Novel C-6 substituted and unsubstituted pregnane derivatives as 5α-reductase inhibitors and their effect on hamster flank organs diameter size

The present study is addressed to ascertain the inhibitory effect of several progesterone derivatives having a chlorine substituent at C-6 (12a-12d), 15 with a bromine substituent at C-6 and 14a-14d, without any halogen atom at C-6 all having an ester side chain at C-17 (benzoate ester bearing a Cl, F and a Br atom at C-4 position of the phenyl ring) on the 5α-reductase enzyme activity present in human prostate. In addition, it was also of interest to investigate the pharmacological effect on hamster flank organs diameter size. In order to study the structure-activity relationships of steroids 12a-12d, 14a-14d and 15 we determined the concentration of these steroids that inhibited 50% of the activity of human prostate 5α-reductase enzyme (IC50), as well as the in vivo effect of these compounds in the hamster flank organs diameter size. We also ascertained, the capacity of these steroids to bind to the androgen receptors present in the rat prostate cytosol using labeled mibolerone (MIB) for monitoring the binding to the androgen receptor. The results from this study indicated that compounds 12a-12d (having a chlorine substituent at C-6), 14a-14d (lacking a halogen atom at C-6), 13 and 15 (having a bromine atom at C-6) showed an increased antiandrogenic effect (lower value for the diameter of the flank organs) as compared to the flank organs from testosterone-treated hamsters. On the other hand, the series of compounds containing a chlorine substituent at C-6 compounds (12a-12d) showed a higher antiandrogenic activity as compared to the compounds lacking a halogen atom at C-6 (14a, 14b and 14d). Although compounds 13 and 15 decreased the flank organs diameter size, however, this increase was not statistically significant as compared to that of the commercially available product finasteride. The steroidal derivatives 13, 14a-14d (lacking the chlorine substituent at C-6) and 15 (having a bromine atom at C-6) exhibited a higher 5α-reductase inhibitory activity (lower IC50 values) as compared to the series of compounds 12a-12d having the halogen substituent at C-6. Finasteride reduced the diameter size of the flank organs. The effect of this steroid and compounds 12a-12d, 13, 14a-14d and 15 on hamster flank organs can be explained by the fact that these steroids did not bind to the androgens receptor, which indicates that its mechanism of action is an inhibiting for the 5α-reductase activity. This enzyme is present in the hamster flank organs and was inhibited by the novel steroids in the human prostate homogenates.

Further syntheses of cyproterone acetate

The present invention relates to improved methods for synthesising cyproterone acetate (17α-Acetoxy-6-chloro-1α, 2α-methylene-4,6-pregnadiene-3,20-dione) from solasodine. The methods of the invention are shorter as those of the prior art and therefore more economic.

Synthesis of Steroidal Azides. Part 2. Reaction of 4,6-Dien-3-ones with Lead Tetra-acetate and Trimethylsilyl Azide

The reaction of steroidal 4,6-dien-3-ones with lead tetra-acetate and trimethylsilyl azide is shown to give predominantly 6β,7α-diazido-4-en-3-ones together with minor amounts of 7α-azido-4-ene-3,6-diones.With lead tetra-acetate and a mixture of trimethylsilyl azide and trimethyl silyl bromide, the same substrates yield exclusively 7α-azido-6β-bromo-4-en-3-ones.Reaction mechanisms are proposed to interpret these results.The 6β,7α-diazido-4-en-3-ones may be readily converted into 6-azido-4,6-dien-3-ones.