CAS

71-58-9

Synonyms

17a-hydroxy-6a-methyl-4-pregnene-3,20-dione acetate

17alpha-acetoxy-6-alpha-methylpregn-4-ene-3,20-dione

17ALPHA-ACETOXY-6ALPHA-METHYLPROGESTERONE

17ALPHA-HYDROXY-6ALPHA-METHYL-4-PREGNENE-3,20-DIONE 17-ACETATE

17-ALPHA-HYDROXY-6-ALPHA-METHYL-4-PREGNENE-3,20-DIONE 17-ALPHA-ACETATE

4-PREGNEN-6ALPHA-METHYL-17ALPHA-OL-3,20-DIONE 17-ACETATE

4-PREGNEN-6-ALPHA-METHYL-17-OL-3,20-DIONE ACETATE

6-ALPHA-METHYL-17-ACETOPROGESTERONE

6ALPHA-METHYL-17ALPHA-ACETOXYPROGESTERONE

6ALPHA-METHYL-17ALPHA-HYDROXY-PROGESTERONE ACETATE

DEPO-PROVERA

hydroxymethylprogesterone acetate

MEDROXYPROGESTERONE 17-ACETATE

MEDROXYPROGESTERONE ACETATE

MPA

PROVERA

(6-alpha)-17-(acetyloxy)-6-methylpreg-4-ene-3,20-dione

17-(acetyloxy)-6-methyl-(6-alpha)-pregn-4-ene-20-dione

17-(acetyloxy)-6-methyl-20-dion(6alpha)-pregn-4-ene-

17-acetoxy-6-alpha-methylprogesterone

EINECS(EC#)

200-757-9

[Molecular Formula

C24H34O4

MDL Number

MFCD00010483

Molecular Weight

386.52

Melting point 

206-207 °C(lit.)

alpha 

D +61° (in chloroform)

Boiling point 

432.7°C (rough estimate)

density 

1.0346 (rough estimate)

refractive index 

48 ° (C=1, Dioxane)

storage temp. 

Refrigerator

solubility 

Practically insoluble in water, freely soluble in methylene chloride, soluble in acetone, sparingly soluble in ethanol (96 per cent)

form 

neat

Water Solubility 

<0.1 g/100 mL at 23 ºC

Merck 

13,5817

BRN 

2066112

Stability:

Stable, but weakly air and light sensitive. Incompatible with strong oxidizing agents.

CAS DataBase Reference

IARC

2B (Vol. 21, Sup 7) 1987

EPA Substance Registry System

Hazard Codes 

Risk Statements 

Safety Statements 

WGK Germany 

RTECS 

TU5010000

HS Code 

29372390

Chemical Properties

White or almost white, crystalline powder.

Originator

Provera,Upjohn,US,1959

Uses

Progestogen; an injectable contraceptive.

Uses

antiprotozoal

Uses

A synthetic progesterone receptor agonist

Manufacturing Process

Preparation of 17α-Hydroxyprogesterone 3,20-Bis-(Ethylene Ketal): A solution was prepared containing 50.0 g of 17α-hydroxyprogesterone in 1,000 ml of benzene, 100 ml of ethylene glycol and 2.5 g of p-toluenesulfonic acid monohydrate. This mixture was refluxed for a period of 17 hours using a calcium carbide water-trap to remove the water formed in the reaction. After this period of reflux 6.5 ml of pyridine was added to the solution, and the mixture cooled to room temperature.
The lower glycol layer was separated and washed with benzene. The benzene layer and the benzene washings were combined and the combined solution was divided into two equal portions, one of which was used for the isolation of 17α-hydroxyprogesterone 3,20-bis-(ethylene ketal) as follows. The benzene solution was washed with 5% sodium carbonate solution, water and saturated sodium chloride solution. After being dried over anhydrous magnesium sulfate the solution was concentrated to dryness at reduced pressure, The residue was recrystallized by taking up in hot methylene chloride, adding acetone and boiling to remove the methylene chloride until a final volume of about 200 ml was reached.
The solution was then refrigerated overnight and 17.8 g of crystals were removed by filtration. A second crop was obtained yielding 3.7 g of compound. The total yield of 17α-hydroxyprogesterone 3,20-bis-(ethylene ketal) was 20.3 g (64.3% of theory). Recrystallization of the crude 17αhydroxyprogesterone 3,20-bis-(ethylene ketal) from methanol gave the pure bisketal of MP 209° to 211°C.
Preparation of 5α,6α-Oxido-17α-Hydroxyallopregnane-3,20-dione 3,20-Bis- (Ethylene Ketal): A solution was prepared by heating 19.96 g (0.0477 mol) of 17α-hydroxyprogesterone 3,20-bis-(ethylene ketal) and 500 ml of benzene. After the solution was effected the flask was cooled to 5°C and a mixture of 3.68 g (0.0449 mol) of sodium acetate and 174 ml of 40% peracetic acid was added with stirring. The reaction mixture was stirred in the ice bath for 3 hours. The lower peracid layer was separated, diluted with water and extracted twice with benzene.
The upper layer was neutralized by the addition of cold 10% sodium hydroxide solution while stirring in an ice bath. The rate of addition of the sodium hydroxide was regulated to keep the temperature below 10°C. The benzene extracts from the peracid layer were combined and washed with cold 10% sodium hydroxide solution and with saturated sodium chloride solution. All the aqueous layers were washed again with the same portion of benzene. The combined benzene layers were dried over anhydrous magnesium sulfate and concentrated to dryness at reduced pressure.
The residue was recrystallized from acetone using methylene chloride to aid in solution. The crystalline material was removed by filtration and was recrystallized from methylene chloride-acetone to yield a total of 8 g of 5α,6αoxido-17α-hydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) of MP 211° to 215°C. For analytical purposes, another recrystallization from methylene chloride-acetone gave pure 5α,6α-oxido-17α-hydroxyallopregnane3,20-dione 3,20-bis-(ethylene ketal) of MP 216° to 218.5°C.
Preparation of 5α,17α-Dihydroxy-6β-Methylallopregnane-3,20-dione 3,20-bis- (Ethylene Ketal): To a solution of 91.6 g of 5α,6α-oxido-17αhydroxyallopregnane-3,20-dione 3,20-bis-(ethylene ketal) in 3,500 ml of freshly distilled tetrahydrofuran was added 1,170 ml of commercial 3 molar methyl magnesium bromide in ether solution. The reaction mixture was boiled to remove 1,800 ml of solvent by distillation and thereafter 1,000 ml of freshly distilled tetrahydrofuran was added.
Boiling was continued under reflux for a period of 16 hours. The solution was then concentrated to about one-half its original volume by distillation and was poured slowly with vigorous stirring into a large volume of ice water containing 340 g of ammonium chloride. The aqueous solution was saturated with sodium chloride and extracted with benzene. The benzene extract was washed with saturated brine, and both aqueous layers were washed again with the same portions of benzene.
The combined benzene layers were dried over anhydrous sodium carbonate and the solvent was removed at reduced pressure to give 90.5 g of crude crystalline 5α,17α-dihydroxy-6β-methylallopregnane-3,20-dione 3,20-bis- (ethylene ketal). Half of the residue, 45.2 g, was recrystallized from acetone and some methylene chloride to give 34.4 g of 5α,17α-dihydroxy-6βmethylallopregnane-3,20-dione 3,20-bis-(ethylene ketal). A sample recrystallized from acetone and methylene chloride for analysis melted at 160° to 163°C.
Preparation of 5α,17α-Dihydroxy-6β-Methylallopregnane-3,20-dione: A solution was prepared containing 38.9 g of 5α,7α-dihydroxy-6βmethylallopregnane-3,20-dione 3,20-bis-(ethylene ketal) in 389 ml of boiling acetone. Thereto was added 39 ml of 1 N sulfuric acid in portions under swirling and seeding with product. Boiling was continued for a period of 2 minutes and the mixture was allowed to stand at room temperature. Thereafter the mixture was diluted with 1,500 ml of water, chilled and filtered.
The precipitate was washed with water, dilute ammonium hydroxide and water, and dried in a vacuum oven overnight. The yield was 31.2 g which was recrystallized by dissolving in 1,200 ml of dimethylformamide, heating to 150°C, cooling slightly, and adding 12 ml of hot water. The recrystallized 5α,17α-dihydroxy-6β-methylallopregnane-3,20-dione thus obtained was 28.75 g of MP 270° to 275.5°C. After an additional recrystallization from aqueous dimethylformamide, the MP was 274° to 279°C.
Preparation of 6α-Methyl-17α-Hydroxyprogesterone: A suspension was made by introducing 2 g of 5α,17α-dihydroxy-6β-methylallopregnane-3,20-dione into 200 ml of chloroform. The suspension was chilled in an ice bath with stirring, and thereupon hydrogen chloride was bubbled through the reaction mixture for 80 minutes with continuous cooling and stirring. After bubbling in nitrogen for a period of 15 minutes the solution was washed with water, 1 N sodium bicarbonate solution and again with water.
The aqueous layers were rewashed with one portion of chloroform, and the washings combined with the remainder of the chloroform solution. After drying over anhydrous magnesium sulfate, the chloroform solution was concentrated to dryness, then taken up in a small volume of methylene chloride, treated with Magnesol anhydrous magnesium silicate and filtered. Acetone was added to the solution and the solution was boiled to remove the methylene chloride. After the solution was concentrated to a volume of about 15 ml it was chilled and the crystals were collected through filtration. The 1.37 g of crystals so obtained were recrystallized from acetone to give pure 6α-methyl-17α-hydroxyprogesterone of MP 220° to 223.5°C.
Preparation of 6α-Methyl-17-Hydroxyprogesterone 17-Acetate: 1 g of 6αmethyl-17α-hydroxyprogesterone was dissolved in a mixture of 10 ml of acetic acid and 2 ml of acetic anhydride by heating. After solution was effected the mixture was cooled to 15°C, and 0.3 g of p-toluenesulfonic acid was added. After allowing the mixture to stand for a period of 2.5 hours at room temperature, the pink solution was poured into ice water to give an amorphous solid which was recovered by filtration.
The precipitate was washed carefully with water and was then dissolved in 10 ml of methanol and 1.5 ml of methylene chloride. The solution was concentrated to 10 ml, diluted with 0.5 ml of 10% sodium hydroxide, boiled for one minute and cooled. The product, which crystallized on cooling, was recrystallized to give flakes of 6α-methyl-17α-hydroxyprogesterone 17- acetate, having a MP 205° to 209°C, according to US Patent 3,147,290.

Brand name

Amen (Amarin); Curretab (Solvay Pharmaceuticals); Cycrin (ESI); Provera (Pharmacia & Upjohn);Clinovie;Cliovir;Dep0-clinover;Dep0-map;Depcorlutin;Depo-prodasone;Depo-progevera;Depo-promone;Deporone;Dugen;Farlurin;Farlutale;Gesinal;Gestapuran;Gestapuron;G-farlutal;Hysron;Intex;Luteocrin orale;Luteodione;Luteos;Lutoporal;Metigestene;Nadigest;Nogest;Onco-provera;Perlutest;Petogen;Piermap;Povera;Promone-e;Pronone;Proverone;Provest;Sindomens;Sodelut "g";Supprestal;Verafen;Veramix plus v.

Therapeutic Function

Progestin

World Health Organization (WHO)

A depot preparation containing 150 mg medroxyprogesterone acetate was introduced over 20 years ago for use as a long-acting injectable contraceptive.
Subsequently, positive results of carcinogenicity studies carried out in beagle bitches led to refusal of registration in the United States.
These findings were later considered irrelevant to contraceptive use in women and the drug was approved by the Food and Drug Administration.
Menstrual irregularities are the most common adverse effect associated with depot medroxyprogesterone acetate.
Risk-benefit judgements differ significantly from country to country, having regard to differing national circumstances.
The preparation is, however, widely available and is included in the WHO Model List of Essential Drugs.
(Reference: (WHTAC4) The Use of Essential Drugs, 4th Report of the WHO Expert Committee, 796, , 1990)

General Description

MPA, 17-acetyloxy-6α-methylpregn-4-ene-3,20-dione (Provera), adds a6α-methyl group to the basic 17α-hydroxyprogesteronestructure to greatly decrease the rate of reduction of the 4-ene-3-one system.
The 17α-acetate group also decreases reductionof the 20-one, similar to the 17α-caproate.
MPA isvery active orally and has such a long durationof action intramuscularly that it cannot be routinely usedintramuscularly for treating many menstrual disorders.
The IM formulation is useful in the palliative treatment of advancedendometrial, breast, and renal carcinomas. MPA alsohas an important role in several birth control products (Depo-Provera, Depo-SubQ Provera 104).

General Description

Odorless white to off-white microcrystalline powder.

Air & Water Reactions

Medroxyprogesterone 17-acetate is sensitive to prolonged exposure to air and light. Insoluble in water.

Reactivity Profile

Flammable and/or toxic gases are generated by the combination of alcohols with alkali metals, nitrides, and strong reducing agents.
They react with oxoacids and carboxylic acids to form esters plus water.
Oxidizing agents convert them to aldehydes or ketones. Alcohols exhibit both weak acid and weak base behavior. They may initiate the polymerization of isocyanates and epoxides.

Hazard

Possible carcinogen.

Fire Hazard

Flash point data for Medroxyprogesterone 17-acetate are not available; however, Medroxyprogesterone 17-acetate is probably combustible.

Safety Profile

Suspected carcinogen with experimental carcinogenic, neoplastigenic, tumorigenic, and teratogenic data.
Human systemic effects by intravenous route: increased intraocular pressure.
Human teratogenic effects by an unspecified route: developmental abnormalities of the urogenital system.
Human reproductive effects by multiple routes: spermatogenesis, menstrual cycle changes or dlsorders, postpartum effects, female fertility effects, abortion, newborn behavioral effects. Human mutation data reported.
Experimental reproductive effects.
A drug for the treatment of secondary amenorrhoea and dysfunctional uterine bleeding.
When heated to decomposition it emits acrid smoke and irritating fumes.

Veterinary Drugs and

In cats, MPA has been used when either castration is ineffective or undesirable to treat sexually dimorphic behavior problems such as roaming, inter-male aggressive behavi

Treatments

ors, spraying, mounting, etc.
MPA has also been used as a tranquilizing agent to treat syndromes such as feline psychogenic dermatitis and alopecia, but treatment with “true” tranquilizing agents may be preferable.
In humans, parenteral MPA has been used as a long-acting contraceptive in females, to decrease sexually deviant behavior in males, and as an antineoplastic agent for some carcinomas (see Pharmacology section above). Oral MPA is used in human females to treat secondary amenorrhea and to treat abnormal uterine bleeding secondary to hormone imbalances.

Metabolism

Among the first of these substituted 17α-acetoxyprogesterone analogues to be utilized therapeutically was medroxyprogesterone acetate, a 6α-methyl progesterone analogue.
This analogue is 25-fold more active than ethisterone.
Following oral administration, medroxyprogesterone acetate is completely and rapidly deacetylated by first-pass metabolism to medroxyprogesterone.
Medroxyprogesterone is extensively metabolized via pathways similar to those for progesterone, except for 6α-hydroxylation.
Most medroxyprogesterone acetate metabolites are excreted in the urine, primarily as glucuronide conjugates.
Plasma protein binding for medroxyprogesterone is approximately 86%, primarily to serum albumin, with no binding to SHBG.

Raw materials