Organic Syntheses, Coll. Vol. 4, p.192 (1963); Vol. 35, p.39 (1955).
To a 5-l. three-necked flask, equipped with a sealed mechanical stirrer, a dropping funnel, and a take-off reflux condenser
, are added 2 l. of sulfur-free toluene
and two boiling chips. The openings of the dropping funnel and the condenser are protected by drying tubes containing Drierite
. A portion (200 ml.) of the toluene
is distilled from the flask (take-off cock open) in order to dry the system by azeotropic distillation; then 100 g. (0.26 mole) of cholesterol
and 500 ml. of cyclohexanone (Note 1)
are added to the flask. After an additional 50 ml. of toluene
has been distilled, a solution of 28 g. (0.14 mole) of aluminum isopropoxide (Note 2)
in 400 ml. of dry toluene (Note 3)
is added dropwise over a period of approximately 30 minutes. During this time toluene
is distilled at a rate slightly greater than the rate of addition of catalyst solution, so that when the addition is complete about 600 ml. of toluene
has distilled. An additional 300 ml. of toluene
is distilled, and the murky orange-colored reaction mixture is then allowed to cool to room temperature.
Four hundred milliliters of a saturated aqueous solution of potassium-sodium tartrate (Note 4)
is added to the mixture, and the organic layer becomes clear and orange. The stirrer assembly is removed, and the mixture is steam-distilled until about 6 l. of distillate has been collected. The residual mixture is cooled and extracted successively with one 300-ml. portion and two 100-ml. portions of chloroform
. The combined extracts are washed with two 100-ml. portions of water and dried over anhydrous magnesium sulfate
. The chloroform
is removed by distillation on the steam bath
at reduced pressure (water aspirator
). The residual viscous amber oil (Note 5)
is dissolved by heating in 150 ml. of methanol
. When the solution has cooled to about 40°, seeds of cholestenone
are added, and the flask is wrapped with a small towel to ensure slow cooling (Note 6)
. After the bulk of the material has crystallized, which requires several hours, the mixture is stored at 0° overnight (Note 7)
. The product is collected by suction filtration, washed with 40–50 ml. of methanol
previously cooled in an ice-salt bath
, then dried at reduced pressure, first at room temperature and finally at 60°. The yield of light-cream-colored Δ4-cholesten-3-one
is 81–93 g.
), m.p. 76–79°.
Recrystallization from methanol
gives material melting at 79.5–80.5°
recovery (Note 8)
, m.p. 146–149°
, is satisfactory if dried at reduced pressure at 100° for 48 hours. The cyclohexanone
is simply distilled before use, b.p. 153–155°.
Directions for the preparation of aluminum isopropoxide
are given by Young, Hartung, and Crossley.2
This compound is also commercially available. Turbidity of the catalyst solution is to be expected and is not detrimental.
is dried satisfactorily by distilling about 20% of it and using the residue, which is cooled with protection from moisture.
Either Rochelle or Seignette salt is satisfactory. The tartrate ion serves to keep the aluminum ion in solution.
Prolonged heating is not necessary, since the chloroform
remaining with the residual oil does not hamper the crystallization.
Seed crystals may be obtained by transferring a few drops of the solution to a small test tube, then cooling and scratching.
Ordinarily the cholestenone
will separate as an oil from a solution saturated much above 50°. In this event, rather than working with larger volumes of methanol
, small portions of chloroform
may be added to the solution to lower the saturation temperature to a point at which seed crystals do not turn to oil. The best yield of good crystalline product is realized by inducing crystallization at the highest possible temperature in order to obtain a large initial crop of crystals. A second crop is difficult if not impossible to obtain by direct crystallization.
The towel should be placed around the flask only after crystallization, rather than oil formation, is assured. The towel is carefully removed occasionally during the first hour to ascertain whether oil is forming on top of the crystals. If so, the solution is warmed slightly in order to redissolve the oil but not the crystals. The product is quite impure if it first separates as an oil which later crystallizes.
If initial crystallization is not induced at 40° or above, a further period of cooling in an ice-salt bath is necessary to obtain the best yield.
In order to avoid large volumes, it is recommended that 700 ml. of methanol
be employed to recrystallize 90 g. of cholestenone
and that either chloroform
be used to increase the solubility of the cholestenone
to the required amount.
The methods of preparation of Δ4-cholesten-3-one
have been summarized in an earlier volume.3
In addition, it has been obtained by the deacetylation of 3-acetoxy-3,5-cholestadiene
The present modification is less laborious than the earlier3
This preparation is referenced from:
Copyright © 1921-, Organic Syntheses, Inc. All Rights Reserved