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Патент USA US3080398

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3,080,388
Patented Mar. 5, 1953
2
glycol in the presence of an acid catalyst, and interacting
the 3,20-diketal of 9‘0c-fl1101‘0-1 l-ketoprogesterone or the
3,080,388
SYNTHESIS OF STEROIDS OF THE 12
ALKYLIDENEPREGNENE
3,20-di-ketal of 9a-?u0ro-A1,4-pregnadiene-3,l1,20-tnione
thus formed with lithium lower alkyl (e.g., lithium
methyl), thereby yielding the 3,20-diketal of l2a-lower
alkyl (e.g., methyD-ll-ketoprogesterone or the 3,2-0-dike-.
tad of 12a-lower alkyl (e.g methyl)-A1'4-pregnadiene
3,11,20-trione, respectively. The resulting diket-als are
Gordon H. Thomas, Birmingham, England, and Josef
Fried, Princeton, N.J., assignors to Olin Mathieson
Chemical Corporation, New York, N.Y., a corporation
of Virginia
No Drawing. Filed Oct. 19, 1959, Ser. No. 847,044
13 Claims. (Cl. 260-—397.3)
This application is a continuation-in-part of our US.
reduced by means of a reducing agent, such as lithium
10
metal in liquid ammonia, ‘to yield the 3,20-diketal of 12a
lower :alkyl-llot-hydroxyprogesterone or the 3,20-diketal
application No. 711,780, ?led January 29, 1958, and now
of (lZzx-lO-Wél' alkyl-Al'i-pregnadiene-11a-ol-3,20=dione,
abandoned.
respectively, and then hydrolyzed in the usual manner,
-
This invention relates to the synthesis of steroids and. 1 -
has for its object the provision of new steroids of the gen
eral formula
15
g5;
C HaY
R
l
1
2
O:
The following examples illustrate the preparation of
these starting materials:
EXAMPLE A
(1 ) Preparation of 9a-Fluor0-JI-Kétoprogesterone 3,20
Bis-Ethylene Kez‘al
A mixture of 10 g. of 9md?uoro-l l~ketoprogesterone,
wherein the 1,2-position is saturated or double-bonded, R
is lower alrkylidene (preferably methylene), Y is hydro
gen, hydroxy or acyloxy, and Z is hydrogen or hydroxy;
a process for preparing these steroids; and new interme
350 ml. of benzene, 80 ml. of ethylene glycol and 200 mg. ,
of para-toluene~sulfonic acid monohydrate is re?uxed
with stirring for 72 hours. The reaction mixture is thenv
cooled to room temperature and neutralized with sodium
bicarbonate solution. The phases are separated and the
aqueous layer reextracted with additional amounts of
diates useful in said preparation.
The new 12-alkylidene steroids of this invention are pre
pared by interacting (A) one of the following: 12a-(low
benzene. The combined benzene extracts are washed
with water, dried over sodium sulfate and evaporated
to dryness in vacuo. The crude residue on crystallization
er alkyl)-1lot-hydroxyprogesteroneg 12a-(lower alkyl)
Al’t-pregnadiene-l lot-ol-3,20-dione; Hot-(lower alkyl)-11a
17a-dihydroxwprogesterone; l2a-(lower aIkyD-AM-preg
from acetone-hexane yields about 11 g. of the essentially
pure bis-ethylene ketal melting at about 179-182". Re
crystallization of this material from methanol gives an
l'l‘adl?l'l?-llOt,17c£-dlJOl-3,20-dl0l'l€, or a 2l-ester ‘of ‘one of
the following steroids: l2oc-(1OW61' a1kyl)-A4-pregnene-1la,
21-diol-3,20-dione; 12a(lower alkyl)-A1’4-pregnadiene
1 1a,21-.diol-3,20-dione;12a-(lower alkyD-M-pregnene-l 10c,
17u,21-triol-3,20-dione; and l2a-(lower alkyl-A1'4-pregna—
as by treatment with a dilute aqueous acid at an elevated
temperature, ‘to the desired l2a-lower alkyl-lla-hydroxy-y
progesterone or the 12a-lower alkyl-AM-pregnadienel1m
ol-3,20-dione respectively. These starting materials are
active progestational agents which can be administered
in lieu of progesterone in the treatment of habitual
abortions.
40
analytical sample of the following properties: M.P.‘ about.
l80—190°; [(111323 ~25".
Analysis.—Calc’d for C25H35O5F(434.53): C, 69.10;‘
diene-l1a,l7a,21-triol-3,20-dione; with (B) a lower alkyl
or monocyclic hydrocarbon aromatic sulfonyl halide, such
H, 8.12. Found: C, 69.19; H, 8.18.
as mesyl chloride and tosyl chloride, whereby the new
intermediates of this invention are formed, namely the
(2 )v Preparation of 12a.-Methyl-11 -Ketoprogester0ne 3,20
Ila-lower alkane (or monocyclic hydrocarbon aromatic)
sulfonyloxy derivatives of the formula
CHIY'
1.‘ i=0
WAIT
Bis-Ethylene Ketal
A solution of 9a-?uoro-ll-ketoprogesterone 3,20-bis
ethylene ketal (10 g.) in benzene (100 ml.) is treated with
50 an ethereal solution of lithium methyl (150 ml., 13.5 mg.
of lithium metal/ml.
The solution is stirred for 4
hours at room temperature and then the excess lithium
methyl is decomposed by the addition of ice. Chlo
reform (300 ml.) is added, and the mixture is washed
65 several times with water, dried over sodium sulfate and
evaporated in vacuo. Trituration of the residue with
hexane gives about 4.2 g. of 12u-methyl-11-ketop/roges
terone 3,20-bis-ethylene ketal, M.P. about 135-138°. A
second crop of crystals (about 2.4 g., M.P. about 124
wherein the 1,2-position is saturated or double-bonded, R 60 130°). is obtained on concentrating’ the hexane mother
and Z are as hereinbefore de?ned, Y’ is hydrogen or
liquor. Crystallizationv from methanol’ gives an analytical
acyloxy, and‘ R’ is lower alkyl (preferably methyl) or
sample melting at about l39-142°, [a]D—-8.8\° (c.0716
monocyclic hydrocarbon aryl (preferably p-tolyl). The
in CHCI3.) ;
reaction is preferably conducted in an organic solvent in
the presence of an organic base such as pyridine.
(.1) The starting steroidal reactants used in the process
Analysz'S.—Calc’d for C26H38O5 (430.56): C, 72.50;
2
0b
of this invention are prepared as follows:
The starting 12u-(lower alkyl)-llwhydroxyprogesten
OHB'l?IlCl 12a-(lower alkyl)-A1,4-pregnadiene-1lu~ol-3,2O—
H; 8.90. Found: c, 72.71; H, 8.90.
Similarly, by substituting an equivalent amount. of
lithium ethyl for the lithium methyl in the procedure of
dione reactants can be prepared by diketalizing 9a-?uoro 70 Example A2, 12oz. - ethyl - 11 - ketoprogesterone 3,20¥bis~
ethylene ketal is'obtained. Furthermore, any diketal may
be substituted‘ for the 3,20-bis-ethylene ketal' in the pro
ll-ketoprogesterone or 9a-?uoro-A1'4-pregnadiene-3,11,20
trione in the usual manner by treating with ethylene
3,080,388
3
.41
cedures of Example A1, thereby yielding the correspond
ing 3,20-diketa1 derivative.
(3) Preparation of IZa-Methyi-IIa-Hyd‘roxyproges
group to a 21-acyloxy group by treatment with the de
sired acid salt (preferably in the presence of the free acid),
thereby yielding a 2l-ester of l2a-(lower alkyl)-corti
costerone and l2e-(lower alkyl)-A1,4-pregnadiene-11B, 21
diol-3,20-dione, respectively, (1‘) oxidizing the 21-ester of
terone 3,20-Bis-Ethylene Ketal
To a stirred solution of 12oc-methy1-ll-ketoprogesterone
IZOL-(IOWeI' ialkyl)-corticosterone (or the 1,2-unsaturated
3,20-bis-ethylene ketal (640 mg.) in 100 ml. of liquid
thereof) with an oxidizing agent such as chromium tri
ammonia and 20 ml. of methanol, is added 500 mg. of
toxide; (g) hydrolyzing the ll-keto analog thus prepared
lithium in small pieces over 15 minutes. The liquid am
with a base such as potassium carbonate; (h) ketalizing
monia is allowed to evaporate at room temperature and 10 the l2a—(lower a1kyl)-1l-dehydrocorticosterone (or the
the residue is diluted with 50 ml. of water. The precipi~
1,2 - unsaturate thereof), thus obtained, with ethylene
glycol; (i) reducing the 3,20-bis-ethylene ketal with a
tated solid (about 620 mg, M.P. about 193—207°) is col
lected, washed well with water and dried. Crystallization
reducing agent such as lithium in ammonia; and (j)
from methanol gives an analytical sample of the lla
deketalizing the thus obtained 12ot-(l0W61‘ -alkyl)-1lqz-hy
hydroxy compound which melts at about 211—213° C; 15 droxy compounds with a hydrolyzing agent such as a
dilute aqueous acid to obtain 12a-(lower alkyD-M-preg
[ab-285° (c. 1.13 in CHCls).
Similarly, by substituting 1 g. of 12a-ethyl-11-keto pro
Ilene-1104,21edi0l-3,20-di011€ or the 1,2-unsatur'ated thereof.
gesterone 3,20-bis-ethylene ketal for the 12a-methyl-11~
.The'se starting materials are mineralo corticoids which are
physiologically active and can be used in place of such
keto-progesterone 3,20-bis-ethylene ketal in the procedure
of Example A3, 12a-ethyl-1lot-hydroxyprogesterone 3,20 20 known substances as desoxycorticosterone.
The following examples illustrate the preparation of
these starting materials:
bis-ethylene-ketal is obtained.
(4) Preparation of IZa-Methyl-Ila-Hydroxy
progesterone
, A solution of 193 mg. of 12a-methyl-11a-hydroxy
EXAMPLE C
12 a-Methyl-Corticosterone 21 -A cetate
25
progesterone 3,20-bis-ethylene ketal in 5 ml. of methanol
and 1 ml. of 8% sulfuric acid is heated under re?ux for
(1) Preparation 0]"12a - methyl - 1113 - hydroxyproges—
terone 3,20-bis-ethylene ketal.——A solution of 1 g. of 12a
one hour. Dilution with water gives about 147 mg. of
methyl-ll-ketoprogesterone 3,20-bis-ethylene ketal in 50
12a-methyl-1la-hydroxyprogesterone which melts at about
ml. of dry tetrahydrofuran is heated under re?ux with
207~211°. Crystallization from methanol yields a pure 30 1 g. of lithium aluminum hydride for 18 hours. Ice is
sample having melting point 215~218°; [ethyl-155°
added to the cooled solution to decompose excess reagent
(c. 1.02 in CHCls);
'
and then a saturated aqueous solution of sodium sulfate
is added with stirring until the precipitated aluminum
We 241 mp (15,700); A5321 2.95, 5.92, 5.99, 6.22
max.
'Analysis.-Calc’d for CHI-13203 (344.48): C, 76.70;
35
salts are formed into a slurry.
The clear ether solution
H, 9.36. Found: C, 76.50; H, 9.23.
is decanted off and the inorganic material is Washed twice
with chloroform. The combined organic extracts are
ethylene ketal can be hydrolyzed to 12a-ethyl-11a-hy
dried over sodium sulfate and then evaporated in v-acuo.
The residue is dissolved in 10 ml. benzene and absorbed
Similarly, 12u-ethyl-1la-hydroxyprogesterone 3,20-bis
droxyprogesterone.
‘
‘
on a column of 30 g. of alumina. Elution with benzene
EXAMPLE B
(900 ml.) and chloroform-benzene (1:9, 500 ml.), fol
lowed by crystallization from acetone-hexane, yields 12cc
_ _ 1 Zea-Methyl-A1»4-Pregnadiene-1 I et-Ol-3,20-Di0ne
methyl-ll?-hydroxyprogesterone 3,20-bis-ethylene ketal
' By substituting an equal amount of 9ot-?uoro-A1'4-preg—
(about 660 mg.) melting at about 169-175". Crystal
terone in theiprocess of Example A1 and following the 45 lization from acetone-hexane affords an analytical sample
which melts at about 177—179°; [a]D—11.5° (c. 1.24 in
procedure of the remaining steps of the example, 120:
nadiene-3,l1,20‘-trione for the 9a-fluoro - 11 - ketoproges
CHClg);
methyl-Al?-pregnadiene-11a - o1 - 3,20-dione is obtained.
Furthermore, if lithium ethyl is substituted for lithium
methyl in the thus modi?ed process of Example A2, 12a
ethyl-Ale-pregnadiene-l1u-ol-3,20-dione is ultimately ob
tained.
' (2) The starting 21-esters of IZu-(IOWCI' a1kyl)-A4
50
Analysis.—-Calc’d for C26H40O5 (432.58): C, 72.19;
H, 9.32. Found: C, 72.30‘; H, 9.20.
(2) Preparation 0]‘ Hot-methyl - 11B - hydroxyproges
terone.—A
solution of 1.4 g. of 12a-methyl-11?-hydroxy
pregnene-l1a,2l-diol-3,20-dione and l2a-(lower alkyl)—
progesterone 3,20-bis-ethylene ketal in 30 ml. of metha
AM-pregnadiene-I1a,21-di0l-3,20-dione are prepared by:
(a) reducing, with a reducing agent such as lithium alumi 55 nol and 3 ml. of 8% sulfuric acid is heated under re?ux
for one hour. The mixture is diluted with water, the
num hydride, the 3,20-diketal of 12a-(lower alkyl)-l1
precipitated solid collected and crystallized from chloro
form-methanol to give about 1.1 g. of 12a-methyl-115
hydroxyprogesterone, M.P. about 235-238". Crystalliza
ing, the -1 l?-hydroxy derivative with a diester of oxalic acid 60 tion from chloroform-methanol gives an analytical sample
melting at about 238—240°, [0L]§n+199° (c. 1.08 in
(e.g., a lower alkyl ester such as ethyl oxalate) in the
ketop'rogesterone and the 3,20-diketal of 12a-(lower
alkyl)-A1-4-pregnadiene-3,l1,20-trione, respectively to ob
tain the corresponding ll?-hydroxy-derivatives; (b) treat
presence of approximately one equivalent of an alkali
CHCla);
metal alkoxide (e.g., sodium methoxide), whereby the
alkali metal enolate of the ester of 21-hydroxyoxa1y1-12a
AM 241 mp (16,600); was 2.9, 5.91 (in?ection); 5.95,
6.14
(lower alkyl)-11}3-hydroxyprogesterone and 2l-hydroxy
oxalkyl-12a-(lower alkyl) - A1'4-pregnadiene-11;3-ol-3,20
dione are formed; (0) interacting the alkali metal enolate
Analysis.—Calc’d for C22H32O3 (344.48): C, 76.70; H,
9.32. Found: C, 76.59; H, 9.41.
ester with a base, such as an alkali metal hydroxide, to
(3) Preparation of 21-eth0xy0xalyl - 12a - methyl-11p
compounds thus formed with iodine in a basic medium
1.03 ml. of a 2 N methanolic solution of sodium meth
hydr0xyprogesterone.—To a solution of 7.23 g. of 12a
yield a 21-oxalyl-12a-(lower aIkyD-IIB-hydroxyproges
terone and 21-oxalyl-12a-(lower valkyl)-A1"1-pregnadiene 70 methyl-l l?-hydroxyprogesterone in 100 ml. of tertiary
butyl alcohol is added at 50° 10 ml. of ethyl oxalate and
11/3-ol-3,20-dione, respectively; (d) treating the oxalyl
oxide. The mixture is stirred at room temperature for
to yield ZI-iOdO-lZu-(lOWBl' alkyl)-1l?-hydroxy-proges
3'hours during which time the sodium enolate of 21
terone and 21-iodo-l2a-(lower aIkyD-NA-pregnadiene
11p-ol-3,20-dione, respectively; (e) converting the 21-iodo 75 ethoxyoxlal-yl-lZa-methyl-l119 - hydroxyprogesterone sepa
5
3,080,388
rates from solution. The material is collected, dissolved
in water and the solution acidi?ed with dilute hydro
chloric acid. The precipitated 2l-ethoxyoxalyl com
pound is collected, washed with a little dry ether and
dried in vacuo.
(4) Preparation of ZJ-oxaZyI-IZa-methyl-I]?-hydroxy—
pr0gesler0ne.—To a solution of 800 mg. of potassium hy
6
ture is neutralized by the addition of 1.5 ml. of glacial
acetic acid. Saline solution is then added to precipitate
the 12a-methyl-11-dehydrocor|ticosterone. The solid is
collected, washed with Water, dried and crystallized from
UT acetone-hexane to give 12a-methyl-1l-dehydrocorticos
terone.
(9) Preparation 0]‘ JZa-me'thyl-A5-pregnene-21-0l-3,11,
ZO-tfforre 3,20-bis-ethylene ketal.—A mixture of 3 g. of
enolate of 21 - ethoXyoXaIyLIZa-methyI-Il-?-hydroxyprm
12a-rnethyl~1l-dehydrocorticosterone, 150 ml. of ‘benzene,
gesterone, and the mixture is stirred at room temperature 10 24 ml. of ethylene glycol and 48.4 mg. of p-toluene sul
under nitrogen for 8 hours. The reaction mixture is
fonic acid monohydrate is heated under re?ux for 24
diluted with 1.5 liters of Water and then acidi?ed with
hours, the water formed during the reaction being re
dilute hydrochloric acid. The precipitated 21-oxalyl com
moved azeotropically in a suitable separator. The mix
pound is collected, washed with water and dried in vacuo.
ture is diluted with 200 ml. of chloroform and washed
(5) Preparation of 21Jada-l2a-mez‘hyl-IJ?-hya‘roxy
successively with dilute sodium bicarbonate and Water.
progesterone.—A suspension of 5 g. of 2l-ethoxyoxalyl
Evaporation in vacuo followed by crystallization of the
l2a-methyl-1lB-hydroxyprogesterone in a solution of 1.35
residue from methanol yields 12a-methyl-A5-pregnene-21
g. of potassium hydroxide in 50 ml‘. of ethanol is stirred
ol-3,ll,20-trione 3,20-bis-ethylene ketal.
at room temperature for 6 hours. The mixture is poured
(10) Preparation of 1Zea-methyl-M-pregnene-I]a,21
into 3 liters of water in which has been previously dis
dz'0l-3,20-di0ne 3,20-bis-ethylene ketal.—To a solution of
solved 48 g. of disodium hydrogen phosphate dodecahy
200 mg. of l2ix-methyl-A5-pregnene-21-ol-3,l1,20-trione
drate. To the resultant solution is added ?rst, dropwise
3,20~bi-s-ethylene ketal in 8 ml. of methanol and 50 ml.
with stirring, 4 g. of iodine in 200 ml. of methanol and
of liquid ammonia is added over a ten minute period
then 3.2 g. of potassium hydroxide dissolved in the mini
160 mg. of timely out lithium. The solvent is allowed
mum quantity of Water. After allowing the solution to 25 to evaporate off at room temperature (about 2 hours)
stand at room temperature for 16 hours, the precipitated
and the residue is tritunated with water. The precipi
material is collected, washed with Water and dried in
tated material is collected, Washed with Water and dried
vacuo. Crystallization from acetone-hexane yield-s a pure
in vacuo. Crystallization from acetone-hexane yields
sample of the 2l-iodo compound.
12a - methyl - A5 - pregnene - lla,2l - diol - 3,20 - dione
droxide in 30 ml. of ethanol is added 5 g. of the sodium
(6) Preparation of l2a-methylcorticosterone 21-ace 30 3,20-bis-ethylene (hotel.
(11) Preparation of 12a-methyl-A4»pregnene-1104,21
rate-To a solution of 200 mg. of 21-iodo-l2a-methyl
ll?-hydroxyprogesterone in’ 15 ml. of acetone is added
2 g. of potassium bicarbonate and 1.35 ml. of glacial ace
tic acid. The mixture is then re?uxed for 18 hours.
‘Water is added and the steroids are extracted with chloro
form. The chloroform solution is washed with Water,
dried over sodium sulfate and evaporated to dryness in
vacuo. Crystallization of the residue from acetone-hexane
yields IZa-methylcorticosterone 21-acetate.
Similarly, by substituting l2a-methyl-A1=4-pregnadiene
di0l~3,2-0-dione.-—A solution of 100 mg. of IZa-methyl
A5-pregnene-l la,21-diol-3,20-dione 3,20-bis-ethylene hotel‘
in 20 ml. of methanol and 0.8 ml. of 8% sulfuric acid
35 is re?uxed for 40 minutes. Orr dilution with Water, 120:
methyl-M-pregnene-lla,21-diol-3,20-dione separates from
solution.
The steroid is ?ltered oii, washed with wa
ter and dried in vacuo.
Furthermore, if ll2a-me-thyl-A1A-pregnadiene-l1,8,21
40 diol-3,20-dio~ne 2l-acetate and l2a-ethylconticosterone
2l-acetate are substituted for the IZa-methyIcortiooster
3,11,20-trione 3,20-bis-et-hylene ketal for the IZa-methyl
ll?-ketoprogesterone 3,20-bis-ethylene ketal in the pro
cedure of Example Cl and following the procedures of
Example C2 through 6 the corresponding l-dehydro inter
mediates »are formed, leading ultimately to IZa-methyl
ALLPregnadiene-I1}8-21-diol-3,20-dione ZI-acetate. Fur
thermore, by substituting other 12a-(lower allry1)-l1-keto
progesterone 3,20-bis-ethylene ketal (e.g., 12a-ethyl-11-.
ketoproge-sterone 3,20-bis-ethylene ketal) for the 12a
one 2l~acetate in the procedure of Example C7 and the
procedures of Example C8 through 11 are followed.
the corresponding l-dehydro and l2a~ethyl derivatiwes,
are obtained, respectively.
(3) The starting Zl-esters of 12a-(lower alikyl)-A4-.
pregnene-lla,17a,2l-triol—3,20-diones ‘and 12a-(lo-wer al
kyl‘)-A1Y4-pregnadiene-1 la,17a,2l~triol-3,20-diones can be
prepared ‘from l2a-(lower al'kyl)-1l5-hydroxyprogester
methyl steroid in Example (31 and following the proce 50 ones (e.g., 12a-methyl-1l?-hydroxyprogesterone and 12a
dures of Example C2 through ‘6, the corresponding, 12a
ethyl-1l?-hydroxyprogesterone) by the following series
(lower alkyl) intermediates are formed, and the corre;
of reactions: (a) reacting ‘the starting steroid with a di—
sponding IZOt-(IOWCI‘ alkyl) corticosterone 2l-acetate
(e.g., IZa-ethylcorticosterone 21~acetate) are recovered;
ester of oxalic acid (e.g., a lower alkyl ester such as
ethyl oxalate) in the presence of at least two equiva—
lents of an alkali metal alkoxide (erg, sodium methox
as the ?nal products. Moreover, if another acid is sub—
stituted for the glacial acetic acid in Example C6, the
corresponding 2l-ester is formed.
ide) whereby the diester of 2,2l-ox-alyl-12a-(lower al
(7) Preparation of Hot-methyl - 11 - dehydrocorticos
terone 21-ace2‘az‘e.——T0 a stirred solution of 5 g. of 12a
dienolate, is formed; (b) reacting, ‘the diester with ap—
kyl)-1l?-hydroxyprogesterone, as well as its alkali metal
proximately three moles of bromine per mole of steroid
and an alkali metal alkoxide to yield ?rst the 2,2l,21—
tribromide derivative and then the alkyl ester of Z-bromo
methylcortieosterone 21-acetate in 200 ml. of acetone is
added chromium trioxide in 0.67 N sulfuric acid (200
mg./ml.) until a permanent brown coloration is obtained
(about 5 ml. required). The solution is stirred at room
temperature 30~minutes. Methanol is added to destroy
as by treatment with zinc in an acid medium, to yield
water, the ll-ketone separates from solution. The mate
rial is collected, Washed with Water, dried and crystallized
ene-ll?-ol-S-one-Zl-oic acid alkyl ester; (e) reducing the
12oz - (lower alkyl) - A‘lJWO) - pregnadiene - ll? - ol - 3
one-2l-oic acid; (c) debrominating the latter compound,
the excess chromic acid and then the mixture is. concen 65 the corresponding Z-debrominated derivative; (d) treat~
ing the debrominated compound with pyrrolidine to yield
trated to about half its volume in vacuo. On adding
from acetone-hexane.
(8) Preparation of Hot-methyl - 1] - dehydrocorticos
terone-To a stirred solution of 4.3 g. of 12a-methyl
3 - pyrrolidino- - 12a - (lower alkyl) - Abilmm - pregnatri
Zl-acid, as by treatment with lithium aluminum hydride,
to yield 12a,-(lo-wcr iaikyl)-A4117(2°)-pregnadiene-1l?,2l
diol-3-one; (f) acylating the latter compound in the usual
ll-dehydrocorticosterone 2'1-acetate in 50 ml. of methanol‘
manner, as. iby treatment with the acyl halide or acid
is added under nitrogen 10.5 ml. of 10% potassium car
anhydride of a suitable organic carboxylic acid, to yield
bonate solution. After stirring for one hour, the mix 75 the, 2i1-este-r derivative; (g) reducing‘ the ZI-ester by
3,080,388 ‘
EB
"27
A4»17<2°>-pregnadiene-11B-ol-3-one-2l-oic acid methyl ester
treatment with osmium tetroxide and phenyliodosoacetate
to give the 2l-esters of 12a-(lower alkyl) hydrocorti—
sones; (h) oxidizing the 21-esters with an oxidizing agent
(e.g., chromium trioxide) to yield 2l-esters of l2ct-(lower
in 35 ml. of methanol is added 3.5 ml. of pyrrolidine
under nitrogen, the solution then being heated for an
alkyl)_cortisones; (i) hydrolyzing the l2-keto compound
rivative separate from solution. These are collected,
washed with a little cold methanol and dried in vacuo.
additional 3 minutes. Crystals of the 3-pyrrolidino de
with a base such as potassium carbonate; (1') lketalizing
the 12-keto analog, thus obtained, with ethylene glycol;
(k) reducing, as by treatment with an alkali metal (e.g.,
(5) Preparation of JZa-methyl-A‘i-17(2°)-pregnadiene
11B-Z1-di0l-3-0ne.—A solution of 2.8 g. of 3-pyrrolidino~
12cc - methyl - A35,“(zm-pregnatriene-ll?-ol-3-one-2l-oic
lithium) in liquid ammonia, to yield the corresponding
acid methyl ester in 80 ml. of anhydrous tetrahydrofuran
is stirred with 2 g. of lithium aluminum hydride for 1
lla-hydroxy derivatives; and (l) deketalizing the 110:
hydroxy derivative thus obtained by hydrolysis to give
hour at room temperature. The reaction mixture is
cooled and the excess reagent is decomposed by the care
ful addition of methanol. The reaction mixture is then
1la,l7a,2l-triol-3,20-d-iones can then be l-dehydrogenated
microbioallly by means of Bacteriumv cyclooxydans by the 15 re?uxed with an acetate buffer comprising 40 ml. of
methanol, 4 ml. of water, 3.2 ml. of acetic acid and 3.2
method disclosed in Us. Patent No. 2,822,318 to yield
g. of sodium acetate. Water is added and the steroids
the corresponding 12a-(lower alkyl)~A1I4-pregnadiene
are extracted with chloroform, the chloroform extract
lla,17a,21~triol-3,20-diones.
then being washed with water, dilute aqueous sodium
These starting materials are physiologically active sub
stances which possess gluooc-orticoid activity and can be 20 bicarbonate and water. Evaporation of the solvent in
vacuo followed by crystallization of the residue from
used in place of such known steroids ashydrocortisone
acetone-hexane yields the diol.
in the treatment of rheumatoid arthritis.
the desired 12a-(lower ialkylyn‘i-pregnene-lla,17a,2l
triol~3,20-di0nes. The l2a-(lo-wer alkyl)-A4-pregnene
(6) Preparation 0]‘ l2oi-methyl-A4'17(ZW-pregnadiene
The following examples illustrate the preparation of
these star-ting materials:
115,21-diol-3-one 21 -acetate.-—A solution of 2 g. of 12a
‘
25
EXAMPLE D
JZa-Methyl- 4-Pregnene-11 0a,] 7 0:,21 -Tri0l-3 ,2 O-Dione
(1) Preparation of 2,21 - diethoxyoxalyl ~ 120a - methyl—
llp-hydroxyprogesterone and the sodium dienolate there
0f.—To a solution of 7.2 g. of l2e-methyl-l1B-hydroxy
progesterone in 100 ml. of‘ anhydrous tertiary butyl al
cohol at 50° is added with stirring 19 ml. of ethyl oxalate
and 23.3 ml. of a 2 N methanolic solution of sodium
methoxide. .On stirring the mixture for 3 hours -at room _
temperature the sodium dienolate of 2,21-diethoxyoxalyl
12cc - methyl - 11B - hydroxyprogesterone separates.
This
material is collected, washed with a little ether and then
dissolved in water. The aqueous solution is acidi?ed
methyl-A‘i'l'l(2°)-pregnadiene~l1/3-21-diol-3-one in 10 ml.
of pyridine and 2 ml. of acetic anhydride is allowed to
stand at room temperature for 15 hours. The mixture
is then diluted with iced water and the precipitated solid
collected ‘and dried in vacuo. Crystallization from
aceton-hexane yields‘ a pure sample of the 21-acetate.
(7) Preparation of 12a-mez‘hylhydrocortisone 21-ace
tate.—To a solution of 386 mg. of 12a-methyl-A4'17(2°)- '
pregnadiene-l1B-2l-diol-3-one 21-acetate in 15 ml. of
anhydrous tertiary butyl alcohol is added ?rst 322 mg.
of phenyliodoacetate in 0.3 ml. of pyridine and then 15
mg. of osmium tetroxide. The mixture is allowed to
stand at room temperature for 18 hours in the absence
of light. The mixture is then stirred for 21/2 hours with
17 ml. of Water, 20 ml. of benzene, 1.8 g. of sodium
40 sul?te and 1.8 g. of sodium bicarbonate. The inorganic
oxalyl - 12a - methyl - 11B - hydroxyprogesterone sepa
material is'?ltered off and washed several times with
rates from solution. The material is collected, washed
chloroform. The aqueous mother liquor is extracted with
with dilute hydrochloric acid whereupon 2,2l-diethoxy
with water and dried in vacuo.
(2) Preparation of 2 - bromo ~ 124x - methyl - Minam
chloroform. The combined chloroform extracts are then
washed with water, dried over sodium ‘sulfate and evapo
pregnadiene-I1/8-0l-3-0ne-21-0ic acid methyl ester.—To a
rated to dryness in vacuo. Crystallization of the residue
stirred mixture of 8.1 g. of 2,21-diethoxyoxalyl-12a
from acetone-hexane yields IZa-methylhydrocortisone 21
methyl-1l?-hydroxyprogesterone and 5.9 g. of anhydrous
acetate.
potassium acetate in 140 ml. of methanol is added at
Similarly, by substituting other 12a-(lower alkyD-ll?
0°, 10% wt/v. of bromine in methanol over a period
hydroxy-progesterones (e.g., 12a-ethyl-11B-hydroxypro
of 30 minutes until the bromine is no longer decolorized 50 gesterone) for the IZa-methyl steroid in Example D1
immediately (about 74 ml. of bromine solution re
and following the procedures of Examples D2 through 7
quired). 50 mg. of phenol is added and the solution
the corresponding l2u-(lower alkyl) intermediates are
of the 2,21,21-tribromo compound is treated with 67 ml.
formed and the corresponding l2ot-(lower alkyl) hydro
of 1.5 N methanolic sodium methoxide. The mixture is
corti-sone 2l-acetate (e.g., 12a-ethylhydrocortisone 21
heated at 80° for 5 minutes, cooled and diluted with iced 55 acetate) are recovered.
water. The precipitated 2-br0mo compound is collected,
washed with water and dried in vacuo.
(8) Preparation of IZa-methylcortisOne 21-acetate.—
To a stirred solution of 5 g. of 12a-methylhydrocortisone
21-acetate in 200 ml. of acetone is added chromium tri
11B-ol-3-0ne-2Loic acid methyl ester.-_A mixture of 5
oxide in 0.67 N sulfuric acid (200 mg./ml.) until a per
g. of 2-bromo-l2a-methyl-A4'17(zm-pregnadiene-11,8-01-3 60 manent brown coloration is obtained (about 5 ml. re
one-21-oic acid methyl ester and 5 g. of zinc in 100
quired). The solution is stirred at room temperature
ml. of benzene, 50 ml. of methanol and 10 ml. of acetic
30 minutes. Methanol is added to destroy the excess
acid is stirred at room temperature for 4 hours. The
chromic acid and then the mixture is concentrated to
inorganic material is ?ltered off and washed with 300
about
half its volume in vacuo. On adding water, the
ml. of benzene. The mother liquors from the reaction 65
ll-ketone separates from solution. The material is col
are diluted with water and extracted with benzene. The
lected, washed with water, dried and crystallized from
combined benzene extracts are washed successively with
acetone~hexane.
water, dilute aqueous sodium bicarbonate and Water, then
(9) Preparation of 12a-methylc0rtis0ne.-—To a stirred
dried over sodium sulfate and evaporated to dryness in
vacuo. Crystallization from acetone-hexane gives 12a 70 solution of 4.3 g. of IZa-methylcortisone 21-acetate in
50 ml. of methanol is added under nitrogen, 10.5 ml. of
methyl - A4,17(2°> - pregnadiene - 11B - o1 - 3 - one - 21
(3) Preparation of IZa-methyl-Aé"17<2°)-pregnadiene
oic acid methyl ester.
(4) Preparation of 3-pyrr0lidin0-l Za—metltyl—A3'5'17(2°)
pregnatriene-1l18-0l-3-0ne-21-0ic acid methyl ester.-—-To
10% potassium carbonate solution. After stirring for
one hour, the mixture is neutralized by the addition of
1.5 ml. of glacial acetic acid. Saline solution is then
a re?uxing solution of 3 g. of Z-bI‘OmO-IZoz-HléthYl 75 added to precipitate the 12a-methylcortisone. The solid
3,080,388
1 0. .
is collected, washed with water, dried and crystallized
pounds are then ketalized; as by treatment with a dihydric
from acetone-hexane to give l2a-methylcortisone.
(10) Preparation of ZZOz-methyI-M-pregnene-I70:,21
alcohol (cg. ethylene glycol) to yield the corresponding
dial-3,11,20-trione 3,20-biséethylene ketall-~A mixture of
treatment with an alkali metal (e.g., lithium) in liquid
3,20-dilcetal derivatives, which in turn are reduced, .as by
ammonia,to yield the corresponding lla-hydroxy deriva
3 g. ‘of l2a-methylcortisone, 150 ml. of benzene, 24 ml.
of ethylene glycol and 48.4 mg. of p-toluene sulionic acid
monohydrate is heated under re?ux for 24 hours, the
water formed during the reaction being removed azeo
tropically in a suitable separator. The mixture. is diluted
with ‘200 ml. of chloroform and Washed successively with 10
and l2ra~(lower =alkyl)~A1I4-pregnadiene-lla,17a— dio1-3,
methanol yields lZa-methyl-M-pregnened7a,2l-diol-3,ll,
active pr-ogestational agents which can be used in lieu of
such known substances as progesterone in treatment of
20-trione 3,20-bis-ethylene ketal.
habitual abortion.
dilute sodium ‘bicarbonate and water. Evaporation in
vacuo followed by crystallization of the residue from
'
(11) Preparation of 12a-methyl-Aipregnene-ll0a,]7a,
a dilute aqueous acid at an elevated temperature, to, yield
l2a-( lower \alkyl),-A4-pregnene-l1a,17a~diol-3,20 - diones
2.0~diones. These starting materials are physiologically
-
The following examples illustrate the preparation of
these starting materials:
21-tri0l-3,20-dione 3,20-bis-ethylene ketal._-To a solu
tion of 200 mg. of 12a-methyl-A5-pregnene-l7a,21-diol
3,11,20-trione 3,20-bis-ethylene ketal in 8 ml. of meth
EXAMPLE Fv
anol and 50 ml. of liquid ammonia is added over a ten
minute period, 160 mg. of ?nely cut lithium. The sol 20
vent is allowed to evaporate of}? at room temperature
JZa-Methyl-N-Pregnene-J1 0a,] 7 oc-Di0l—3,20-D ione
(1) Preparation of 12a-methyllzydr0c0rtis0ne.--To a
stirred solution of 304 mg. of IZa-methylhydrocortisone
(about 2 hours) and the residue is titurated with water.
The precipitated material is collected, washed with Water
and dried in vacuo.
tives. These l-la-hydroxy steriods can then be hydrolyzed,
as by treatment in :a suitable solvent such as methanol with
ZI-acetate in 18 ml. of methanol is added under nitrogen
3.6ml. of 10% potassium carbonate solution. After stir
ring for 30 minutes the reaction mixture is neutralized by
Crystallization from acetone-hexane
yields l2a-methyl-A5-pregnene - lla,l7a,2l - triol - 3,20
dione 3,20ebis-ethylene ketal.
the addition of 0.6 ml. of glacial acetic acid.
On dilution
(12) Preparation of J2a-methyl-A4-pregnene-11a,17a,
with saline solution, l2a-methylhydrocortisone separates
methyl-A5-pregnene-11a,17a,21-triol-3,20-dione 3,20-bis
2}_1-tri0l-3,20-di0ne.-A solution of 100 mg. of 12a!
from-solution. The material is ?ltered off, washed succes
sively with water and a little ice-cold methanol and then
ethylene ketal in 20 ml. of methanol and 0.8 ml. of 8%
sulfuric acid is re?uxed for 40 minutes. On dilution
dried in vacuo.
with water, IZa-methyIeA‘l-Pregnene-l la,17zx,21-tri0l—3,
20-dione separates from solution. The steroid is ?ltered
ylale.—,To a solution of 174 mg. of l2a-methylhydrocor
tisone in 4 ml. of anhydrous pyridine is added, at 0°, 0.15
ml. of methane sulfonyl chloride. in 1 ml. of chloroform.
(2) Preparation of l2a-methylhydrocorlisone 21 -mes
off, washed with water and dried in vacuo.
Similarly, if 12a-ethylhydrocortisone acetate is substi
, The reaction is left for three hours. at 0°. Dilution with
iced , water precipitates l2a-methylhydrocortisone 21
tuted for the l2a-methylhydrocortisone acetate in the
procedure ‘of Example D8 and the procedures of Examples
D9 through 12 are followed, the corresponding 12a
mesylate.
('3), Preparation of 21 -i0d0-12a-methyl-11,B,1 7a-dihy
ethyl derivative is obtained.
droxyprogesterone.--A mixture of 200 mg. of 1206-Il'l5?1y1
4.0 hydrocortisone Zl-mesylate and 500 mg. of sodium iodide
in 10 ml. of acetone is heated under reflux for 15 minutes.
1_2a-Methyl-A114-PregnadieneJ1a,] 7a,21-Tri0l-3,20-Di0ne
The reaction. mixture is then diluted with Water, the pre
cipitated solid collected, washed with water and dried in
Following the procedure of Example 1 of US. Patent
vacuo. Crystallization from acetone-hexane yields a pure
No. 2,822,318 but substituting 12ot-methyl-A4-pregnene
EXAMPLE E
lla,17a,2l-triol-l3,20-dione for the. lla-hydroxyproges
' , sample of the 27-1 a-iodo compound.
(_4) Preparation of JZa-InethyLJ15,17a-dihydrQxypra
terone, IZa-methyl - A1"1 - pregnadiene-lla,l7a,2l-triol-3,
gester0ne.-~To a solution of 127 mg. of 21-iodo-l2cz
ZO-dione is obtained.
Similarly, other 12a-( lower .alkyl) >A4-pregnene-l 1oz, 17a,
methyl-ll,5,l7cx-dihydroxyprogesterone in 1.5 ml. of di
2l-triol-3,20~diones, such as 12a-ethyl-A4-pregnene-11a,
l7a,2l-triol-3,20~dione, ‘are converted to their respective
roxane is added at 80° l.,5_,ml. of 5% aqueous sodium bi
sul?te, the reaction mixture then-being heated‘for 30 min
l-dehydro derivatives.
utes. The solution is cooled, water added and the ste
roids extracted with chloroform. The chloroform extract
is-washedwith water, dried over sodium sulfate and evap
orated, to dryness in vacuo. Crystallization from ace
(4) The 12a - (lower :alkyl) - lla,l7a - dihydroxypro
gestrerone, and 12a - (lower alkyl) - A1'4-pregnadiene-lla,
l7a-diol-3,20-dione reactants can be prepared by interact
ing a 2l-alkane sulfonic acid ester (e.g., mesyl and 55 tonehexane?yields a sample of12u-methyl-4-pregnene-11B,
l7a—diol-3,20-di0ne.
ethanesulfonyl) of a Hay-(lower, alkyl)hydrocortisone
Similarly, by substituting) other l2a-(lower alkyl)hy
drocortiso‘ne 2l__~acetate_s (e>.g., l2aV-ethylhydrocortisone 21
(e_.g., l2u-methylhydrocortisone or 12a-ethylhydrocorti
sone)or l2a~(lower alkyl) prednisolone (e.g., 12a~methyl
acetate), for the v‘Ha-methyl steriod in Example F1 and
following the procedures of F2 through 4, the correspond
iDEQLI-iOClO-IZct-(IQWQI‘ alkyl) intermediates are ‘formed
and the corresponding 12a-(lower alkyl)-1l,8,l7u-dihy
droxyprogesterones (e.g., IZa-ethyl-l1,3,l7a-dihydroXy
prednisolone) with an alkali metal iodide (e.g., sodium
iodide), preferably at an elevated temperature in an or
ganic solvent ‘for the steriod reactant, thereby yielding the
corresponding 2l-iodo derivatives [i.e. a ZI-iOdO-lZa
(lower alkyl)-1l)3-l7a-dihydroxyprogesterone ‘and a 21
iodo-l2a-(lower .alkyl)-A114-pregnadiene-l113,12a-dio1 - 3,
20-dione]. The 21-iodo compounds thus formed are then
treated with an alkali metal bisul?te (e.g. sodium bisul‘
65
?te) to deiodate the intermediate thereby ‘forming 12oz
(lower alkyl)-11,6,17a-dihydroxyprogesterones. The 115
progesterone) are recovered as, the ?nal products.
(5-). Preparation of JZa-meIhyI-II-ket0-17a-hydr0xy
progester0ne.-—To a stirred solution of 5 g. of IZa-methyl
1118,l7wdihydroxyprogesterone in 200 ml. of acetone is
‘added chromium trioxide in 0.67 N sulfuric acid (200
hy-droxy steriods thus formed are then oxidized in the usual 70 mg./ ml.) until a permanent brown coloration is obtained
(about 5' ml. required). The solution is stirred at room
manner, as by treatment with a hexavalent chromic com
pound (e.g., chromium trioxide) to yield the correspond
ing ll-lceto derivatives [e.g., a Hot-(lower alkyl)-l1-keto
l7a~hydroxyprogesterone and a Hot-(lower ialkyl)-A1-4
pregnadiene~17a-ol-3,l1,20~trione]. The ll-keto com 75
temperature 30 minutes. Methanol is added to destroy
the excess chromic acid and then the mixture is concen
trated to about half its volume in vacuo.
On adding Wa
ter, the ll-ketone separates from solution. The material
8,080,388
12
11
administration in the same type of parenteral preparations
as progesterone, for example, with concentration and/or
dosage based on the activity of the particular compound.
The following examples are illustrative of the invention
is collected, Washed with Water, dried and crystallized
from acetone-hexane.
(6) Preparation of IZoc-methyl - A5 - pregnene-l7a-ol
3,11,20-trz'0ne 3,20-bis'ethylene ketal.—A mixture of 3
(all temperatures being in centrigrade):
g. of l2a-methyl-1l-keto-l7u-hydroxyprogesterone, 150
ml. of benzene, 24 ml. of ethylene glycol and 48.4 mg.
EXAMPLE 1
of p-toluene sulfonic acid monohydrate is heated under
l 2 zx-Methyl-1 1 a-Hydroxyprogesterone 1 1 oc-Mesy late
re?ux for 24 hours, the water formed during the reaction
being removed azeotropically in a suitable separator.
A solution of 1.4 g. of 12a-methyl-1lot-hydroxyproges
The mixture is diluted with 200 ml. of chloroform and 10 terone in 10 ml. of pyridine and 0.5 ml. of mesyl chlo
washed successively with dilute sodium bicarbonate and
ride is kept at 0“ for 16 hours. The solution is then
water. Evaporation in vacuo followed by crystallization
diluted with iced water, the precipitated solid collected,
of the residue from methanol yields 12a-methyl-A5-preg—
washed well with water to give about 1.7 g. of the 110:
nene-17a-ol-3,11,20-trione 3,20-bis-ethylene ketal.
lmesylate. Crystallization of a sample from acetone
(7) Preparation of J2a-methyl-A5-pregnene-lla,17a 15 hexane furnishes an analytical sample having M.P. 172
diol-3,20-di0ne 3,20-bz's-ethylene ketal.—To a solution of
174° (dec.); [0:113 -+141° (c. 0.93 in CHCIE);
200 mg. of 12a-methyl-A5-pregnene-17a-diol-3,1l,20-tri—
W 238 mu (14,500) ;
5.91, 5.98, 6.22, 7.52”.
one 3,20-bis-ethylene ketal in 8 ml. of methanol and 50
ml. of liquid ammonia is added over a ten minute period,
Analysis.—Calcd. for C23H34O5S (422.56): S, 7.59.
160 mg. of ?nely cut lithium. The solvent is allowed to 20 Found: S, 7.13.
Similarly, the lla-mesylates of l2a-ethyl-lla-hydroxy
evaporate off at room temperature (about 2 'hours) and
the residue is triturated with'water. The precipitated
progesterone and 12CL-mCthYI-AI'4-PIBgHQdlCDE-11LX-Ol-3,
material is collected, washed with water and dried in
20-dione can be prepared. Furthermore if another lower
vacuo. Crystallization from acetone-hexane yields 12a
alkane sulfonyl chloride, such as ethane sulfonyl chloride,
methyl-M-pregnene-l 1a,17a-diol-3,20-dione 3 ,20-bis-eth 25 or a monocyclic hydrocarbon aromatic sulfonyl chloride
ylene ketal.
such as tosyl chloride is substituted for the mesyl chloride
(8) Preparation of l2a-methyl-M-pregrzene-I1a,]7a
in the procedure of Example 1, the corresponding 11oz
di0l-3,20-di0ne.-—~A solution of 100 mg. of l2m-methyl
lower alkane or 11ot-monocyclic hydrocarbon aromatic
A5-pregnene-1la,17a-diol-3,20-dione 3,20-bis-ethylene ke
sulfonyloxy derivative is obtained.
tal in 20 ml. of methanol and 0.8 ml. of 8% sulfuric acid 30
EXAMPLE 2
is re?uxed for 40 minutes. On dilution with water, 12a
1 2 -Methyleneprogesterone
methyl-M-pregnene-l1a,17a - diol - 3,20 - dione separates
from solution. The steroid is ?ltered 01f, washed with
A solution of 1.58 g. of IZwmethyI-Ilot-hydroxypro
water and dried in vacuo.
gesterone lla-mesylate in 16 ml. of glacial acetic acid is
Similarly, if 12rx-ethyl-11B,17a-dihydroxyprogesterone 35 heated under re?ux with 1.6 g. of anhydrous sodium ace
max.
is substituted for the IZa-methyl-l l,B,l7a-dihydroxypro—
tate for one hour. The mixture is diluted with water,
and the steroids extracted with chloroform. The chloro
form is washed several times with water, dried over sodi
gesterone in the procedure of Example F5 and the pro
cedures of Example F6 through 8 are followed, the cor
> responding l2a-ethyl derivatives are obtained respectively.
EXAMPLE G
40
12 a-Methyl-A1A-Pregnadiene-J 1 oz,17ot-Dl'0l-3,20-Di0ne
um sulfate and the solvent removed in vacuo. The resi
due is taken up in 10 ml. of hexane-benzene (1:1) and
absorbed on 30 g. of acid-Washed alumina. Flution with
benzene (900 ml.) and with chloroform-benzene (1:9)
(400 ml.) followed by crystallization from acetone
ing the procedure of Example 1 of U.S. Patent No. 2,822,
hexane yields about 460 mg. of 12-methyleneprogester
318 but substituting 12oc-methylhydrocortisone for the 45 one, M.P. 135-138°; [@113 +168“ (c. 1.19 in CHCI3);
lla-hydroxyprogesterone, 12oc-methylprednisolone is ob
ABM‘ 24.0 111,417,200); ANuiul
,W, 5.86, 6.00, 6.19;;
tained.
(1) Preparation of l2ot-methylprednisolone.—Follow
Analysis.—Calcd. for CHI-13002 (326.46); C, 80.93; H,
Similarly, other IZa-(IOWSI‘ alkyl)hydrocortisones, such
9.26. Found: C, 81.34; H, 9.22.
as l2ot-ethylhydrocortisone are converted to their respec
(2) Preparation of 12a~methyl-Am-pregnadiene-l1a,
Similarly, the lla-mesylates of IZoc-cthYl-lloa-hYdI'OXY
progesterone and 12a-methyl-Alfi-pregnadiene-l1a-ol-3,
17a-diol-3,20-diorze.—Following the procedure of Exam
20-dione can be converted to 12-ethylideneprogesterone
tive l-dehydro derivatives.
50
and 12~methylene-A1-4-pregnadiene 3,20-dione, respec
ple F2 through 8, but substituting 12a-methylprednisolone
tively.
for the 12a-methylhydrocortisone in the procedure of Ex
ample F2, lZa-methyl-AlA-pregnadiene-11a,17a-diol-3,20
55
dione is obtained.
Similarly, other 12a-(lower alkyl) prednisolones, such
as 12a-ethylprednisolone are converted to their corre
EXAMPLE 3
1 2-Methylene-1 7a-Hydr0xypr0gester0ne
Following the procedures of Examples 1 and 2 but sub
stituting 1.6 g. of 12a-methyl-11u,17a-dihydroxyproges
sponding — (lower alkyl)-A1-4-pregnadiene-11a,17a-diol-3,
60 terone for the 12a-methyl-1la-hydroxyprogesterone in the
20-dione derivatives.
The intermediate Ila-lower alkane (or monocyclic hy
drocarbon aromatic) sulfonyloxy derivatives are then
treated with a salt of a strong base and weak acid (e.g.
sodium acetate) in the presence of a weak acid (e.g.,
acetic acid) whereby the alkane (or monocyclic hydro 65
carbon aromatic) sulfonic acid is split off to give the
procedure of Example 1, there is obtained 12a-methyl
11a,17a-dihydroxyprogesterone llu-mesylate and 12
methylene-A‘i-pregnene-17a-ol-3,20-dione, respectively.
EXAMPLE 4
1 Z-Methyl- 4-Pregnene-1 1 06,21-DiUl-3,20'Di0ne
desired 12-alkylidene ?nal products. If a 21-ester is em
l1 a-M esy late 21 -A cetate
ployed as the starting material and a free 21-hydroxyl
(a)
Preparation
of JZa-methyl - A4 -pregnene-11u,21
compound is desired, the steroid may be hydrolyzed in the
usual manner to yield a free 21-hydroxyl steroid.
70 diol-3,20-di0ne 21 -mon0acez‘ate.—A solution of 720 mg.
of 12a-methyl-A4-pregnene-1la,21-diol-3,20-dione in 10
The 12-alkylidene steroids of this invention are physi
m1. of pyridine and 220 mg. of acetic anhydride is kept at
ologically active substances which possess progestational
0° for six hours. The solution is then concentrated in
activity. Hence, these steroids can be used in lieu of
vacuo, the residue taken up in chloroform, and the solu
known progestational steriods, such as progesterone in the
treatment of habitual abortion, being formulated for such 75 tion extracted with dilute sulfuric acid, dilute bicarbonate
3,030,388?
13
‘further puri?cation.
'
14
3,2>0,-dione ZI-acetate, and I‘Z-inethylenerMQregneneI17a
and water. Evaporation of thev solvent in vacuo leaves
the monoacetate as a syrup, which is used in step b without
21-diol-3,20‘-dione are tormed, respectively. ‘ Similarly,
other IZa-(lOWCI' alkyl) starting materials yield the cor
'
responding l2-(lower alkylidene)derivatives.
(12) Preparation of IZa-methyl - A‘? - pregame-111x31
The invention may be variously otherwise embodied
within the scope of the appended claims.
di0l-3,20-di0ne 11a-mesy‘late ZI-acetata-TO a solution
of 804 mg. of IZa-rnethyl-M-pregnene-Ila,2l-diolq3,20
dione Zl-Vmonoacetate in 10 ml. of anhydrous pyridine
is added at 0°, 0.4 ml. of methianesulfonyl chloride. The
What is claimed‘is: '
1. A compound selected from the group consisting of
a steroid of the general formula
mixture is‘ allowed to remain at 0° for 18 hours. Ice is
then added and the mixture extracted with chloroform. 1.0.
The chloroform extract is washed with dilute sulfuric acid,
cm
water, dilute bicarbonate and again with water, dried, and
o=o
then evaporated to dryness in vacuo. The residue on
crystallization from methanol gives the pure mesylate.
Similarly, by substituting the' anhydrides or‘ acid chlo
rides of other acids in step av of Example 4, the corre
' I52
1.5.
sponding Z-l-esters are formed. In this reaction the pre
ferred acid anhydrides and acyl chlorides are those of
hydrocarbon carboxylic acids having less than ten carbon
atoms, asexempli?ed ‘by the lower alkanoic acids (e.g., 20
and the 1,2-position unsaturate thereof, wherein R is lower
acetic, propionic and enanthic acid), the monocyclic aro
alkylidene, Y is selected \from the group consisting of hy
matic c-arboxylic acids (e.g., benzoic and toluic acid), the
drogen, hydroxy, and the acyloxy radical of ‘a hydrocar
monocyclic aralkanoic acids (e.g., phenacetic and B-phen
bon canboxylic acid of less than ten carbon atoms, and Z
ylpropionic acid), the lower alkenoic acids, the cyclo
alkane carboxylic acids, and the cycloalkene carboxylic 25 is selected from the group consisting of hydrogen and
hydroxy.
acids.
2. IZ-methylene progesterone.
EXAMPLE 5
1Z-Methylene-M-Pregnene-ZI -Ol-3 ,2 O-Dione
21 -A aerate
A solution of 500 mg. of IZu-methyl-M-pregnene
lla,2l-diol-3,20-dione lla-mesylate 21-acetate in 10‘ ml.
,
3. IZ-methylene-M-pregnene-l7u.-ol-3,20-dione.
4. The 21-ester of 12-methylene-A4-pregnene-3,ZO-di
30 one-21-ol with a hydrocarbon carboxylic acid of less than
ten carbon atoms.
5. The 21-e'ster of lZ-methylene-M-pregnene-l7a-21
diol-3,20~dione with a hydrocarbon canboxylic acid of less
of glacial acetic acid is heated under re?ux with 1.0 g. of
than ten carbon atoms.
anhydrous sodium acetate for one hour. The mixture is
6. A compound ‘selected from the group consisting of a
diluted with water, and the steroids extracted with chloro 35
steroid of the general formula
form. The chloroform extract is washed several times
with water, dried over sodium sulfate and the solvent re
moved in vacuo. Crystallization of the resulting residue
from acetone-hexane yields pure 12-methylene-A4-preg
40
nene-2l-ol-3,20‘-dione 21-acetate.
R
:
R’SO20——
EXAMPLE 6
JZ-Methylene-M-Pregnene-Z1-Ol-3,20-Di0ne
i
2
To a solution of 100 mg. of 1Z-methylene-M-pregnene
45
21-ol-3,20-dione ZI-acetate in 12 ml. of methanol is added
O:
under nitrogen 0.207 ml. of an oxygen-free 10% aqueous
solution of potassium carbonate. After 30 minutes at
and the 1,2-position unsaturate thereof, wherein R is lower
room- temperature the mixture is neutralized with acetic
alkyl, R’ is selected from the group consisting of lower
acid and taken up in chloroform and water. The chloro 50 alkyl and monocyclic hydrocarbon aromatic, Y’ is selected
form extract is dried over sodium sulfate and after evapo
from the group consisting of hydrogen and the acyloxy
ration in vacuo leaves lZ-methylene-Mpregnene-Z1~01
radical of a hydrocarbon carboxylic acid of less than ten
3,2.0-dione, which is recrystallized from acetone-hexane.
carbon atoms, and Z is selected from the ‘group consisting
Similarly, if lZea-methyl-Al-‘l-pregnadiene-11a,21-di0l
of hydrogen and hydroxy.
3,20-dione is substituted for the 12a-methyl-A4-pregnene 55 7. IZa-methyl-lla-hydroxyprogesterone lla-mesylate.
lIla,21-diol-3,2O-d-ione in the procedure of Example 4 and
8. A process for the preparation of a compound se
the procedures of Examples 4, 5 and 6 are followed, 12a
lected from the group consisting of a steroid of the gen~
methyI-AM-pregnadiene-I la,2l-d-iol—3,20‘-dione ZI-acetate,
eral formula:
12a - methyl-A1»4-pregnadiene-llu,2l—diol-3,20-dione 110c
mesylate ZI-acetate, 12a-methylene-A1'4-pregnadiene-21
ol-3,20-dione 2l-acetate, and lZ-methylene-Al'4-tpregn-adi
60
ene-21-o1-3,20edione are formed, respectively. Further
more, if other 12a-(1ower alkyl) steroid derivatives are
substituted for the 12a-methyl steroid in Example 4, the
corresponding 12a-(lower alkyl) steroids are formed.
65
EXAMPLE 7
1Z-Methylene-A‘l-Pregnene-l 7 11,21 -Di0l-3,20-Di0ne
Following the procedures of Examples 4, 5 and 6, but
gni i
CHgY'
substituting 12a—methyl-A4-pregnene-11a,l7a,2l<triol-3,20~
70 and the 1,2-position unsaturate thereof, wherein R is
dione for the 12a-methyl-A4-pregnene-l1a,2-1-diol-3,20~
dione in the procedure of Example 4, 12a.-methyl-A4
pregnene- 1la,17a,21-tr-iol-3,20-dione 21-acetate, 12a
lower alkylidene, Y’ is selected from the group consisting
of hydrogen and the acyloxy radical of a hydrocarbon
carboxylic acid of less than ten carbon atoms, and Z is
selected from the group consisting of hydrogen and hy
methyl-A‘Lpregnene-l1a,17a,2l-triol-3,2O-dione 11a - mes
ylate ZI-acetate, IZ-methylene-M-pregnene-17a-2l-diol 75 droxy, which comprises interacting a compound selected
3,080,888
15
16
from the group consisting [of corresponding steroids of
the formula
9. The process of claim 8 wherein the steroid reactant
(lower alkyl)
2
ii
I
(llHzY’
|0=0
---z
R’SOzO——/\l: ]
2
01/
and ‘the 1,2-position unsaturate thereof, wherein R’ is se
lected ‘from the group consisting of lower alkyl ‘and mono 15
is 12a-methyl-11a-lhydroxyprogesterone llwmesylate.
10. The process of claim 8 wherein the steroid reactant
is 12a-methy1-11a.,17a-dihydroxyprogesterone lla-mesyl
ate.
11. The process of claim 8 wherein the steroid reactant
is IZa-methyl - A4 - pregnene-l1a,21-diol-3,20-dione 11a
mesylate 21-acetate.
12. The process of claim 8 wherein the steroid reactant
is
12udmethyl - A4 - pregnene-l1u,17u,21-triol-3,20-dione
1 l a-mesylate 21~acetate.
13. The process of claim 8 wherein an alkali metal
‘acetate and ‘acetic acid are employed in the reaction.
References Cited in the ?le of this patent
UNITED STATES PATENTS
cyclic aryl ‘and Z ‘and Y’ are as de?ned, with an alkali
metal salt [of a weak organic acid in the presence of an
2,751,397
Nathan et al ___________ __ June 19, 1956
excess of said acid and separating the product thus formed.
2,891,076
Fried ________________ __ June 16, 1959
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