72-33-3

Basic information

• Product Name: 17a-Ethynyl-1,3,5(10)-estratriene-3,17b-diol 3-methyl ether
• Synonyms: Ethynylestradiol 3-methyl ether,97%;17alpha-19-Norpregna-1,3,5(10)-trien-20-yn;Mestranol,17α-Ethynyl-1,3,5(10)-estratriene-3,17β-diol 3-methyl ether, 17α-Ethynylestradiol 3-methyl ether, 3-Methoxy-17α-ethynylestradiol;Mestranol (200 mg);(17α)-3-Methoxy-19-norpregna-1,3,5(10)-trien-20-yn-17-ol;17α-Ethynyl-3-Methoxy-17β-hydroxy-1,3,5(10)-estratriene;3-Methoxy-17α-ethynylestradiol;17a-Ethynylestradiol-d2 3-Methyl Ether
• CAS NO: 72-33-3
• Molecular Formula: C₂₁H₂₆O₂
• Molecular Weight: 310.43
• EINECS: 200-777-8
• Product Categories: MAXOLON;Steroids;Acetylenes;Biochemistry;Functionalized Acetylenes;Hydroxysteroids;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 72-33-3.mol

Chemical Properties

• Melting Point: 153-155 °C(lit.)
• Boiling Point: 390.58°C (rough estimate)
• Flash Point: 224.1ºC
• Appearance: crystalline solid
• Density: 1.0865 (rough estimate)
• Vapor Pressure: 2.38E-08mmHg at 25°C
• Refractive Index: 1.4900 (estimate)
• Storage Temp.: -20°C Freezer
• PKA: 13.10±0.40(Predicted)
• Merck: 5917
• BRN: 2625905
• CAS DataBase Reference: 17a-Ethynyl-1,3,5(10)-estratriene-3,17b-diol 3-methyl ether(CAS DataBase Reference)
• NIST Chemistry Reference: 17a-Ethynyl-1,3,5(10)-estratriene-3,17b-diol 3-methyl ether(72-33-3)
• EPA Substance Registry System: 17a-Ethynyl-1,3,5(10)-estratriene-3,17b-diol 3-methyl ether(72-33-3)

Safety Data

• Hazard Codes: Xn
• Statements: 36/37/38-40-48-68
• Safety Statements: 22-26-36/37/39-45-36/37
• WGK Germany: 3
• RTECS: RC8960000
• Hazardous Substances Data: 72-33-3(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
17a-Ethynyl-1,3,5(10)-estratriene-3,17b-diol 3-methyl ether is used as an orally active estrogenic steroid for [application reason]. It was the estrogen used in many of the first oral contraceptives, providing hormonal regulation and contraception benefits.
Used as a Pharmacological Estrogen Molecule:
17a-Ethynyl-1,3,5(10)-estratriene-3,17b-diol 3-methyl ether is used as a pharmacological estrogen molecule for [application reason]. Its estrogenic properties make it suitable for various medical applications, including hormone replacement therapy and treatment of certain conditions related to estrogen deficiency.

Originator

Enovid ,Searle ,US ,1957

Manufacturing Process

A stirred solution of 120 parts of 3-methoxy-δ1,3,5-estratrien-17-one in 2,600 parts of anhydrous toluene and 4,300 parts of anhydrous ether is saturated with a slow stream of acetylene. In the course of 30 minutes there is added a solution of 120 parts of potassium tert-amylate in 2,800 parts of anhydrous tert-pentanol. The passage of acetylene and stirring are continued for an additional 5 hours after which the reaction mixture is washed 5 times with 3,000-part portions of saturated ammonium chloride solution and then with water. It is then dried over anhydrous sodium sulfate and concentrated to dryness under vacuum. The residue is recrystallized from methanol. The 3- methoxy-17-ethynyl-δ1,3,5 estratrien-17-ol thus obtained melts at about 143° to 146°C. A further recrystallization from acetone yields crystals melting at about 150° to 151°C.

Therapeutic Function

Estrogen

Safety Profile

Confirmed carcinogen with experimental. neoplastigenic, tumorigenic, and teratogenic data. Moderately toxic by subcutaneous route. Human reproductive effects by ingestion: changes in ovaries and fallopian tubes, ferthty effects. Experimental reproductive effects. Mutation data reported. An FDA proprietary drug. A steroid used in oral contraceptives. When heated to decomposition it emits acrid smoke and irritating fumes.

InChI:InChI=1/C29H52/c1-7-22(20(2)3)12-11-21(4)25-15-16-26-24-14-13-23-10-8-9-18-28(23,5)27(24)17-19-29(25,26)6/h20-27H,7-19H2,1-6H3/t21-,22-,23+,24+,25-,26+,27+,28+,29-/m1/s1

Upstream product

• 39845-30-2 3-(tert-butyldimethylsilyloxy)-17α-ethynyl-β-estradiol 
• 346700-38-7 3-(tert-butyldimethylsilyloxy)-17α-trimethylsilylethynyl-β-estradiol 
• 57-63-6 ethinyl estradiol 
• 74-88-4 methyl iodide 
• 53-16-7 Estrone 
• 1624-62-0 estrone 3-methyl ether 
• 75-20-7 calcium carbide 
• 4301-14-8 acetylenemagnesium bromide 
• 1066-54-2 trimethylsilylacetylene 
• 74-86-2 acetylene 

Downstream Products

• 77955-79-4 1,3,5(10)-estratrien-17α-(E-1'-phenylseleno-2'-chloroethenyl)-3β,17β-diol 3-methyl ether 
• 1624-62-0 estrone 3-methyl ether 
• 2137-18-0 17-alpha-Hydroxy-19-norprogesterone 
• 31981-44-9 17α-acetoxy-19-norpregna-4-ene-3,20-dione 
• 58652-19-0 17α-acetoxy-6-methylene-19-norpregn-4-ene-3,20-dione 
• 58652-20-3 nomegestrol acetate 
• 57-63-6 ethinyl estradiol 
• 26011-40-5 2-hydroxy-mestranol 

Relevant articles and documents

Microbial transformation of mestranol by Cunninghamella elegans

The microbial transformation of an oral contraceptive, mestranol (1) by Cunninghamella elegans yielded two hydroxylated metabolites, 6β-hydroxymestranol (2) and 6β,12β-dihydroxymestranol (3). Metabolite 3 was found to be a new compound. These metabolites were structurally characterized on the basis of spectroscopic techniques.

Triazole-estradiol analogs: A potential cancer therapeutic targeting ovarian and colorectal cancer

1,2,3-triazoles have continuously shown effectiveness as biologically active systems towards various cancers, and when used in combination with steroid skeletons as a carrier, which can act as a drug delivery system, allows for a creation of a novel set of analogs that may be useful as a pharmacophore leading to a potential treatment option for cancer. A common molecular target for cancer inhibition is that of the Epidermal Growth Factor Receptor/Mitogen Activated Protein Kinase pathways, as inhibition of these proteins is associated with a decrease in cell viability. Estradiol-Triazole analogs were thus designed using a molecular modeling approach. Thirteen of the high scoring analogs were then synthesized and tested in-vitro on an ovarian cancer cell line (A2780) and colorectal cancer cell line (HT-29). The most active compound, Fz25, shows low micromolar activity in both the ovarian (15.29 ± 2.19 μM) and colorectal lines (15.98 ± 0.39 μM). Mechanism of action studies proved that Fz25 moderately arrests cells in the G1 phase of the cell cycle, specifically inhibiting STAT3 in both cell lines. Additionally, Fz57 shows activity in the colorectal line (24.19 ± 1.37 μM). Inhibition studies in both cell lines show inhibition against various proteins in the EGFR pathway, namely EGFR, STAT3, ERK, and mTOR. To further study their effects as therapeutics, Fz25 and Fz57 were studied against drug efflux proteins, which are associated with drug resistance, and were found to inhibit the ABC transporter P-glycoprotein. We can conclude that these estradiol-triazole analogs provide a key for future studies targeting protein inhibition and drug resistance in cancer.

Fluoride-assisted activation of calcium carbide: A simple method for the ethynylation of aldehydes and ketones

The fluoride-assisted ethynylation of ketones and aldehydes is described using commercially available calcium carbide with typically 5 mol % of TBAF·3H2O as the catalyst in DMSO. Activation of calcium carbide by fluoride is thought to generate an acetylide "ate"-complex that readily adds to carbonyl groups. Aliphatic aldehydes and ketones generally provide high yields, whereas aromatic carbonyls afford propargylic alcohols with moderate to good yields. The use of calcium carbide as a safe acetylide ion source along with economic amounts of TBAF·3H2O make this procedure a cheap and operationally simple method for the preparation of propargylic alcohols.

Rhodium-catalyzed hydroformylation of 1,1-disubstituted allenes employing the self-assembling 6-DPPon system

Abstract A rhodium-catalyzed hydroformylation of 1,1-disubstituted allenes is reported. Using a RhI/6-DPPon catalyst system, one can obtain β,γ-unsaturated aldehydes in high regio- and chemoselectivity. The Z-configured product is formed with up to >95% selectivity when unsymmetrically 1,1-disubstituted allenes are submitted to the reaction conditions. This is the first time that these interesting building blocks are accessible by hydroformylation of allenes. The utility of this methodology is demonstrated by further transformations of one of the obtained products. β,γ-Unsaturated aldehydes are obtained by a rhodium-catalyzed hydroformylation of 1,1-disubstituted allenes. For unsymmetrically 1,1-disubstituted allenes the Z-configured product is formed in up to about 95% selectivity. This is the first time that these building blocks are accessible by hydroformylation of allenes. The utility of this methodology is demonstrated by further transformations of one of the obtained products.

An improved synthesis of nomegestrol acetate

Oral contraceptives (OCs) are synthetic steroids, or progestins, which are structurally related to testosterone or to progesterone. Many progestins have been synthesized and approved for OCs, hormonal replacement therapy (HRT), or the treatment of some gynecological disorders. Nomegestrol acetate (NOMAc) is a newly approved OC and has gained rapid acceptance in many countries for OC or HRT. The synthesis of NOMAc remains challenging and costly. We have developed a novel and improved procedure for the synthesis of NOMAc with a total of 11 steps and an overall good yield without the use of hazardous reagents.

Amphidynamic crystals of a steroidal bicyclo[2.2.2]octane rotor: A high symmetry group that rotates faster than smaller methyl and methoxy groups

The synthesis, crystallization, single crystal X-ray structure, and solid state dynamics of molecular rotor 3 provided with a high symmetry order and relatively cylindrical bicyclo[2.2.2]octane (BCO) rotator linked to mestranol fragments were investigated in this work. By use of solid state 13C NMR, three rotating fragments were identified within the molecule: the BCO, the C19 methoxy and the C18 methyl groups. To determine the dynamics of the BCO group in crystals of 3 by variable temperature 1H spin-lattice relaxation (VT 1H T1), we determined the 1H T1 contributions from the methoxy group C19 by carrying out measurements with the methoxy-deuterated isotopologue rotor 3-d6. The contributions from the quaternary methyl group C18 were estimated by considering the differences between the VT 1H T1 of mestranol 8 and methoxy-deuterated mestranol 8-d3. From these studies it was determined that the BCO rotator in 3 has an activation energy of only 1.15 kcal mol-1, with a barrier for site exchange that is smaller than those of methyl (Ea = 1.35 kcal mol-1) and methoxy groups (Ea = 1.92 kcal mol-1), despite their smaller moments of inertia and surface areas.

One-pot ethynylation and catalytic desilylation in synthesis of mestranol and levonorgestrel

A one-pot ethylnylation and catalytic desilylation reaction was developed for the synthesis of mestranol and levonorgestrel. Addition of trimethylsilylacetylide to the carbonyl group at C-17 of the steroids yielded the C-17α-trimethylsilylacetylenyl adducts, which were desilylated with a catalytic amount of TBAF (0.050 equiv) in one pot to provide the corresponding mestranol and levonorgestrel both in 90% yields. A plausible mechanism was proposed for the catalytic desilylation through the regeneration of the fluoride ion from the reaction of alkoxide on the steroid with Me3SiF. The one-pot ethynylation and catalytic desilylation methodology provided an alternative route and avoided the traditional use of flammable and explosive acetylene gas toward the synthesis of mestranol and levonorgestrel.

Water-soluble steroid compounds

Beta-cyclodextrin forms a water-soluble complex or inclusion compound with steroid compounds having a molecular structure smaller than the interior cavity in the doughnut-shaped molecular structure of beta-cyclodextrin. The resulting inclusion compounds can be used for a variety of applications including aqueous topical ophthalmic preparations and topical dermatological ointments.

17β-Ethynyl-3,17α-estradiol and derivatives thereof

17β-ethynyl-3,17α-estradiol and derivatives thereof are prepared by epimerization of 17-acyl esters of 17α-ethynyl-3,17β-estradiol 3-ethers. 17α-ethynyl-3,17α-estradiol and its derivatives are active as post-coital antifertility agents and inhibit the growth of or reduce the size of the prostate gland and the seminal vesicle.