Cortisone acetate - API Active Pharmaceutical Ingredient

Cortisone acetate

Name	Cortisone acetate
Synonyms	11,20-trione,17,21-dihydroxy-pregn-4-ene-21-acetate; 11-dehydro-17-hydroxycorticosterone-21-acetate; 11-dehydro-17-hydroxycorticosteroneacetate; 17,21-dihydroxypregn-4-ene-3,11,20-trioneacetate; 4-PREGNEN-17ALPHA,21-DIOL-3,11,20-TRIONE ACETATE; 4-PREGNEN-17,21-DIOL-3,11,20-TRIONE 21-ACETATE; 4-PREGNENE-17ALPHA,21-DIOL-3,11,20-TRIONE 21-ACETATE; 17ALPHA,21-DIHYDROXY-4-PREGNENE-3,11,20-TRIONE 21-ACETATE 17,21-DIHYDROXYPREGN-4-ENE-3,11,20-TRIONE 21 ACETATE 17ALPHA,21-DIHYDROXY-4-PREGNENE-3,11,20-TRIONE 21-ACETATE 21-acetoxypregnen-17a-ol-3,11,20-trione 4-PREGNEN-17,21-DIOL-3,11,20-TRIONE 21-ACETATE 4-PREGNEN-17ALPHA,21-DIOL-3,11,20-TRIONE ACETATE 4-PREGNENE-17ALPHA,21-DIOL-3,11,20-TRIONE 21-ACETATE ACETIC ACID 2-((8S,9S,10R,13S,14S,17R)-17-HYDROXY-10,13-DIMETHYL-3,11-DIOXO-2,3,6,7,8,9,10,11,12,13,14,15,16,17-TETRADECAHYDRO-1H-CYCLOPENTA[A]PHENANTHREN-17-YL)-2-OXO-ETHYL ESTER CORTISONE 21-ACETATE CORTISONE ACETATE DELTA4-PREGNEN-17ALPHA-21-DIOL-3, 11, 20-TRIONE-21-ACETATE KENDALL'S COMPOUND 'E' ACETATE 11,20-trione,17,21-dihydroxy-pregn-4-ene-21-acetate 11-dehydro-17-hydroxycorticosterone-21-acetate 11-dehydro-17-hydroxycorticosteroneacetate 17,21-dihydroxypregn-4-ene-3,11,20-trioneacetate 20-trione,21-(acetyloxy)-17-hydroxy-pregn-4-ene-11 21-(acetyloxy)-17-hydroxypregn-4-ene-3,11,20-trione 21-acetoxy-17,alpha-hydroxy-3,11,20-triketopregnene-4 21-acetoxy-17,alpha-hydroxypregn-4-ene-3,11,20-trione acetatecortisone
CAS NO	50-04-4
EINECS	200-006-5
Molecular Weight	402.48
Molecular Formula	C23H30O6
Product Categories	Biochemistry; Hydroxyketosteroids; Steroids; Inhibitors; CORTONE; Hormone Drugs
Mol File	50-04-4.mol

Cortisone acetate Chemical Properties
Melting point	237-240 °C(lit.)
alpha	D25 +164° (c = 0.5 in acetone); D25 +208 to +217° (dioxane)
refractive index	212 ° (C=1, MeOH)
storage temp	2-8°C
solubility	Practically insoluble in water, freely soluble in methylene chloride, soluble in dioxan, sparingly soluble in acetone, slightly soluble in ethanol (96 per cent) and in methanol.
form	neat
Water Solubility	19mg/L(25 ºC)
Merck	14,2539
BRN	2067543
Stability	Stable. Incompatible with strong oxidizing agents.
CAS DataBase Reference	50-04-4(CAS DataBase Reference)
EPA Substance Registry System	Cortisone acetate (50-04-4)

Safety Information
Safety Statements	22-36/37-24/25
WGK Germany	3
RTECS	GM9140000
HS Code	32041200

Cortisone acetate Usage And Synthesis
Chemical Properties	solid
Originator	Cortone Acetate,MSD,US,1950
Uses	Cortisone Acetate is a glucocorticoid. Cortisone Acetate is an antiinflammatory agent. Cortisone Acetate is bioavailable and readily converted to the therapeutically active form, Hydrocotisone (H71461 5).
Manufacturing Process	The following technique is described in US Patent 2,541,104. A solution of 2.0 g of 3(α)-hydroxy-21-acetoxy-11,20-diketo-pregnane, which can be prepared as described in Helv. Chim. Acta 27, 1287 (1944), is treated in a mixture of 25 cc of alcohol and 6.4 cc of acetic acid at 0°C with 6.0 g of potassium cyanide. The solution is allowed to warm to room temperature and after 3 hours is diluted with water. The addition of a large volume of water to the alcohol-hydrogen cyanide mixture precipitates a gum which is extracted with chloroform or ethyl acetate. The extract is washed with water, and evaporated to small volume under reduced pressure. The crystalline precipitate (1.3 g) consists of 3(α),20-dihydroxy-20-cyano-21-acetoxy-11-keto-pregnane; dec. 175° to 185°C. A solution of 0.60 g of chromic acid in 1.2 cc of water and 11 cc of acetic acid is added to a solution containing about 1.2 g of 3(α),20-dihydroxy-20-cyano- 21-acetoxy-11-ketopregnane at room temperature. After 1 hour, water is added and the product, which precipitates, is filtered and recrystallized from ethyl acetate to produce 3,11-diketo-20-hydroxy-20-cyano-21-acetoxypregnane; dec. 214° to 217°C. 0.40 cc of phosphorus oxychloride is added to a solution containing about 950 mg of 3,11-diketo-20-hydroxy-20-cyano-21-acetoxy-pregnane dissolved in 3 cc of pyridine. After standing at room temperature for 24 hours, the solution is poured into water and dilute hydrochloric acid, extracted with benzene and concentrated to dryness. The crude product, after chromatography gives one main constituent, namely δ17-3,11-diketo-20-cyano-21-acetoxy-pregnene; MP 189° to 190°C. A solution of 1.0 g of δ17-3,11-diketo-20-cyano-21-acetoxy-pregnene in 10 cc of benzene is treated with 1.0 g of osmium tetroxide and 0.43 g of pyridine. After standing at room temperature for 18 hours, the resulting solution is treated successively with 50 cc of alcohol, and with 50 cc of water containing 2.5 g of sodium sulfite. The mixture is stirred for 30 hours, filtered, and the filtrate acidified with 0.5 cc of acetic acid and concentrated to small volume in vacuo. The aqueous suspension is then extracted four times with chloroform, the chloroform extracts are combined, washed with water and concentrated to dryness in vacuo. Recrystallization of the residue from acetone gives 9°C. This compound is then treated with acetic anhydride and pyridine for 15 minutes at room temperature to produce 3,11,20-triketo-17(α)-hydroxy-21-acetoxypregnane or cortisone acetate.
Therapeutic Function	Glucocorticoid
General Description	Cortisone acetate, 21-(acetyloxy)-17-hydroxypregn-4-ene-3,11,20-trione, is the 21-acetate of naturally occurring cortisone with good systemicanti-inflammatory activity and low-to-moderate salt-retentionactivity after its in vivo conversion to hydrocortisoneacetate. This conversion is mediated by 11β-hydroxysteroiddehydrogenase. It is used for the entire spectrum of uses discussedpreviously under the heading, “Therapeutic Uses ofAdrenal Cortex Hormones”—collagen diseases, Addisondisease, severe shock, allergic conditions, chronic lymphocyticleukemia, and many other indications. Cortisone acetateis relatively ineffective topically, mainly because itmust be reduced in vivo to hydrocortisone. Its plasma halflifeis only about 30 minutes, compared with 90 minutes to3 hours for hydrocortisone.
Purification Methods	Crystallise -1cortisone-21-acetate from acetone or CHCl3. The UV has 15,800 M-1cm at 238nm in dioxane. [Sarett J Biol Chem 162 601 1946, Beilstein 8 III 4058, 5 IV 3481.]

Hydrocortisone acetate Preparation Products And Raw materials
Raw materials	Hydrogen peroxide-->Nickel-->Chromium(VI) oxide-->16-Dehydropregnenolone acetate-->Potassium Acetate-->16a,17a-Epoxyprogesterone-->Chromic acid-->Saponin-->CORTISONE-->16-Dehydropregnenolone-->POTASSIUM CYANIDE-->Acetic acid-->Osmium tetroxide
Preparation Products	Hydrocortisone-->Prednisone-->Prednisone 21-acetate

Hydrocortisone acetate Preparation Products And Raw materials

Raw materials

Hydrogen peroxide-->Nickel-->Chromium(VI) oxide-->16-Dehydropregnenolone acetate-->Potassium Acetate-->16a,17a-Epoxyprogesterone-->Chromic acid-->Saponin-->CORTISONE-->16-Dehydropregnenolone-->POTASSIUM CYANIDE-->Acetic acid-->Osmium tetroxide