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Патент USA US3078295

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3,078,285
United tates atent' O
Patented Feb. 19, 1963
1
2
3,078,285
carboxylic acids, to yield the corresponding Ila-ester
derivatives.
IZ-ALKYL STEROIDS OF THE PREGNANE SERIES
The ?nal products of this invention, wherein free keto
groups are present in the 3 and 20 positions are physio
Josef Fried, Princeton, N.J., assignor to Olin Mathieson
Chemical Corporation, New York, N.Y., a corporation
of Virginia
No Drawing. Filed Dec. 6, 1957, Ser. No. 700,937
2 Claims. (Cl. 260-39145)
logically active substances which possess progestational
activity. Hence, these steroids of this invention can be
used in lieu of known progestational steroids, such as
_
progesterone, in the treatment of habitual abortion, being
This invention relates to the synthesis of steroids, and > formulated for such administration in the same type of
has for its object the provision of a new class of physio 10 peroral preparations as progesterone, for example, with
logically active steroids, which may be represented by
concentrations and/or dosage based on the activity ‘of
the formula
the particular compound.
'
'
'
The series of steps employed to form the ?nal prod
.OHa
ucts of this invention can be illustrated by the follow
15
ing equations wherein 12u-methylhydrocortisone mesylate
is employed as the starting material. All of the starting
materials used in the process of this invention can be
prepared by the method disclosed in my U.S. applica
tion, Serial No. 700,934, ?led on even date herewith,
20 now abandoned.
CHZI
CHzOSOzCHs
O:
9H3
wherein R is hydrogen, R’ is a-hydroxy, Ot-BCYIOXY, orv t
?-hydroxy, or together R and R’ is keto, and R” is lower 25
alkyl (preferably methyl).
These new steroids of this invention are prepared
through the new 21-iod-o intermediate compounds of
this invention from a 2l-alkane sulfonic acid ester of
a 120c-(1OW61‘ alkyl)hydrocortisone.
Suitable starting 30
materials include the lower alkane sulfonic acid esters
(e.g. mesyl and ethanesulfonyl) of 12u-methylhydro
cortisone and 12a-ethylhydroc0rtis0ne. These starting
=0
I
v 0 mp5“
to
materials are interacted with an alkali metal iodide (e.g.
sodium iodide), preferably at an elevated temperature
in an organic solvent for the steroid reactant, thereby
yielding the corresponding 21-iodo derivatives [i.e. a
2:1 - iodo - 12oz - (lower
alkyl) - 115,170: - dihydroxy
0.01);
progesterone]. The new 21-iodo compounds thus formed‘
are then treated with an alkali metal bisul?te (e.g. sodium 40
bisul?te) to deioda-te the intermediate thereby forming
the 12OL-‘(1OWB1‘ alkyl)-11?,17a-dihydroxyprogesterones of
this invention.
I
' The lid-hydroxy ‘steroids thus formed can then be
oxidized in the ‘usual manner, as by treatment with a
hexavalent chromic compound (e.g. chromium trioxide)
to yield the corresponding ll-keto derivatives [i;e. a
12cc - (lower
one].
alkyl) - l1 - keto - 17a - hydroxyprogester
The ll-keto compounds, moreover, can be ke
t-alized, as by treatment with a dihydric alcohol, (e.g. 50
V
ethylene glycol) to yield the corresponding 3,20i-diketal
l
123%:
derivatives, which in turn can be reduced as by treat
ment with an alkali metal (e.g. lithium) in liquid am
monia, to yield the corresponding lla-hydroxy deriva
tives. These lla-hydroxy steroids can thenbe hydro 55
lyzed, as by treatment in a suitable solvent such as meth
anol with a dilute aqueous acid at an elevated tempera
ture, to yield the corresponding 3,20-diketone derivatives.
Furthermore, the resulting 12¢x~(lower alkyl)-A4-preg
sition by treatment with a suitable acylhalide or acid
anhydride, such as the acyl chloride or acid anhydride
acid), the monocyclic aralkanoic acids (e.g. phenacetic
and B-phenylpropionic acid), the lower alkenoic acids,
the cycloalkane carboxylic ‘acids, and the cycloalkene
I /O—CH3
Ts
Dene-11M,l.7tZ-'dlO1-e3,20'-dlOnB can ‘be acylated in Ila-po 60
of a hydrocarbon carboxylic acid having less than ten
carbon atoms, as exempli?ed by the lower alkanoic acids
(e.g. acetic, propionic and enanthic acid), the mono
cyclic aromatic carboxylic ‘acids (e.g. benzoic and toluic
CH3
I
G
In?ll -*
3,078,285
4
vacuo followed by crystallization of the residue from
methanol yields 12u-methyl-A5-pregnene-17a—ol-3,l1,20
trione 3,20—bis-ethylene ket-al (IV).
EXAMPLE 5
12a-Methyl-M-Pregnene-I1a,17u-Diol'3,20—Dione 3,20
Bis-Ethy‘lene Ketal (V)
The following examples are illustrative of the inven
tion (all temperatures being in centigrade):
1,5
EXAMPLE 1
To a solution of 200 mg. of l2or-methyl-A5~pregnene
l7a-diol-3,ll,20-trione 3,20-bis-ethylene ketal in 8 ml.
of methanol and 50 ml. of liquid ammonia is added over
a ten minute period, 160 mg. of ?nely cut lithium. The
solvent is allowed to evaporate off at room temperature
(about 2 hours) and the residue is triturated with water.
The precipitated material is collected, washed with water
and dried in vacuo. Crystallization from acetone-hexane
yields
21-I0d0-12a-Methyl-l 1 {3,1 7 a-Dihydroxyprogesterone (I )
‘12a - methyl - A5 - pregnene - 1la,17a - diol - 3,20
dione 3,20-1bis-ethylene ketal ('V).
A mixture of 200 mg. of IZa-methylhydrocortisone
21-mesylate and 500 mg. of sodium iodide in 10 ml. of
EXAMPLE 6
acetone is heated under re?ux for 15 minutes. The re 20
action mixture is then diluted with water, the precipi
tated solid collected, washed with water and dried in
J 2or-Methyl-A4-Pregn cue-1 1 0a,] 7u-Di0l-3,20-D ione (VI )
A solution of 100 mg. of 12a-metl1yl-A5-pregnene-11a,
17u-diol-3,20-dione, 3,20-bis-ethylene ketal in 20 ml. of
methanol and 0.8 ml. of 8% sulfuric acid is re?uxed for
40 minutes. On dilution with water, l2u-methyl-A4
vacuo. Crystallization from acetone-hexane yields a pure
sample of the 21oc-i0d0 compound (1).
pregnene~1la,-l7a-diol-3,20-dione (VI) separates from
EXAMPLE 2
solution. The steroid is ?ltered olf, Washed with water
1 Za-Melhyl-l 113,1 7 a-Dz'hydroxyprogesterone (II)
and dried in vacuo.
To a solution of 127 mg. of 2l-iodo-12u-methyl-l1?'
EXAMPLE 7
17a-dihydroxyprogesterone in 1.5 ml. of dioxane is 30
1Za-Methyl-M-Pregnene-I
1 0a,] 7vt-Di0l-3,20-Di0ne
added at 80° 1.5 ml. of 5% aqueous sodium bisul?te,
l 1 -A cetate
the reaction mixture then being heated for 30 minutes.
The solution is cooled, water added and the steroids ex
A solution of 50 mg. of l2u-methyl-A4-pregnene—11a,
tracted with chloroform. The chloroform extract is
17a-diol-3,20-dione in 1 ml. of pyridine and 0.4 ml. of
washed with water, dried over sodium sulfate and evapo
acetic anhydride is heated at 80° for 3 hours. The mix
rated to dryness in vacuo. Crystallization from acetone
ture is then diluted with iced water, the precipitate col
hexane yields a sample of 12oc-methyl-4-pregnene-11B,
lected, washed with water and dried in vacuo. Crystal
17m-diol-3,20-dione (II).
Similarly, by substituting other IZa-(IOWCI‘ alkyl)hy
drocortisone mesylates (e.g. 12a-ethylhydrocortisone
lization from acetone-hexane gives the pure Ila-acetate.
Similarly, by substituting other acylating agents for the
40
mesylate) for the IZtX-I'l'lClhYl steroid in Example 1 and
following the procedures of Examples 1 and 2, the cor
responding 2l-iodo-12a(lower alkyl) intermediates are
formed and the corresponding l2a-(lower alkyl)-l1 16,170?
dihydroxyprogesterones
(e.g.
acetic anhydride in Example 7, the corresponding acyloxy
derivatives are formed. Thus, propionic anhydride and
benzoyl chloride yield the propionate and benzoate esters,
12a - ethyl - 11?,-17a - di 45
hydroxyprogesterone) are recovered as the ?nal products,
EXAMPLE 3
1 Zea-Methyl-1 1 ~Keto-1 7a-Hydr0xyprogester0ne (Ill )
respectively.
Furthermore, if 12a-ethyl-1 118,17a-dihydroxyprogester
one is substituted for the IZa-methyl-l1?,17a-dihydroxy
progesterone in the procedure of Example 3 and the
procedures of Examples 4 through 7 are followed, the
corresponding l2a-ethyl derivatives are obtained, respec
tively.
The invention may be variously otherwise embodied
within the scope of the appended claims.
What is claimed is:
chromium trioxide in 0.67 N sulfuric acid (200 mg./
1. An Ila-ester of l2a-(lower alkyD-M-pregnene-lla,
ml.) until a permanent brown coloration is obtained
(about 5 ml. required). The solution is stirred at room 55 l7oc-di0l~3,20-di0n6 and a hydrocarbon carboxylic acid
having less than ten carbon atoms.
temperature 30 minutes. Methanol is added to destroy
'2. 12a-methyl-A4-pregneneJl1oz,17o:-diol-3,20=dione ll
the excess chromic acid and then the mixture is con
To a stirred solution of 5 g. of 12oc-methy1-l1B,17oc
dihydroxyprogesterone in 200 ml. of acetone is added
centrated to about half (its volume in vacuo.
acetate.
On add
ing water, the ll-ketone (HI) separates from solution.
References Cited in the ?le of this patent
UNITED STATES PATENTS
The material is collected, Washed with Water, dried and 60
crystallized from acetone-hexane.
EXAMPLE 4
12a-Methyl-M-Pregnene-l 7or-Ol-3,11,20-Tri0ne 3,20-Bis
Ethylene Ketal (IV)
A mixture of 3 g. of 12ot-methyl111-keto-17a-hydroxy
progesterone 150 ml. of benzene, 24 ml. of ethylene
glycol and 48.4 mg. of p-toluene sulfonic acid monohy
drate is heated under re?ux for 24 hours, the water
2,602,769
2,713,587
65
formed during the reaction being removed azeotropically 7
in a suitable separator. The mixture is diluted with
200 ml. of chloroform and washed successively with
dilute sodium bicarbonate and water. Evaporation in
‘2,865,935
2,867,633
2,870,177
2,897,219
Murray et al. _________ __ July 8,
,Bergstrom ___________ __ July 19,
Schneider et a1 _________ .._ Dec. 23,
Lincoln et al. __________ __ Jan. 6,
Conbere et al. ________ .... Jan. 20,
Wettstein et al. _______ __ July 28,
1952
1955
1958
1959
1959
1959
OTHER REFERENCES
Kritchevsky et al.: .T.A.C.S., vol. 74, pages 483-6
(1952).
Levin et al.: J.A.C.S., vol. 76, pages 546-52 (1954).
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