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Патент USA US3022306

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3,022,296
United States Patent
Patented Feb. 20, 1962
1
2
3,022,296
0
SYNTHESIS OF STEROIDS
OH=§_W
Y
' Josef Fried and Josef E. Herz, New Brunswick, N.J.,
0:0
l--- 2
assignors to Olin Mathieson Chemical Corporation,
New York, N.Y., a corporation of Virginia
Horn
No Drawing. Original application Apr. 2, 1956, Ser.
No. 575,344, now Patent No. 2,920,084, dated Jan.
5, 1960. Divided and this application May 20, 1959,
Ser. No. 817,703
7
'
2 Claims. (Cl. 260--239.55)
This application is a division of our application, Ser
ial No. 575,344, ?led April 2, 156, now Patent No.
11+
10
RI
2,920,084, which in turn is a continuation-in-part of our
RN/SJ
2
I
X
' (m/a
parent applications, Serial No. 434,672, ?led June 4,
wherein at least one of the positions 1,2; 4,5; and 6,7
1954, now Patent No. 2,763,671, and Serial No. 483,166, 15 is double-bonded (those wherein the 1,2 and 6,7-posi
tions are saturated and the 4,5-position is double-bonded
?led January 20, 1955.
being preferred), and wherein R is hydrogen, R’ is hy
This invention relates to the synthesis of valuable
steroids; and has for its objects the provision of an ad
droxy, or together R and R’ is oxo (keto) or ketalized
vantageous process of preparing steroids of the pregnene
keto (it being understood that when R and R’ is a ketal
(including pregnene, allopregnene, pregnadiene, and 20 group, the double bond, if any, in the 4,5-position shifts
pregnatriene) series having a 21-aldo or acetalized aldo
to the 5,6-position), R and R’ as 0x0 being preferred; Z
is hydrogen or preferably a-hydroxy; R" is an alkyl
group, a 9a-halo group, and an llp-hydroxy or ll-keto
radical, particularly a lower alkyl such as methyl, ethyl,
group; and of certain new steroids useful in the prepara
hexyl, etc. and is preferably methyl; X’ is chloro or
tion of said steroids.
,
The process of this invention essentially comprises: (a) 25 bromo; X is halo (i.e. iodo, bromo. chloro or fluoro, and
converting a 21-all<anesulfonyloxy-9}3,1l?-epoxy steroid
preferably is chloro or fluoro); M is a metal, such as an
of the pregnane series to the corresponding 21-bromo or
alkali metal or an alkaline earth metal, the halogen
salt of which is soluble in the solvent employed in the
chloro derivative thereof: (b) converting said 21-bromo
or chloro derivative to the corresponding ZI-quaternary
indicated reaction, and preferably is alkali metal, such as
ammonium salt; (0) converting said 21-quaternary am 30 potassium or lithium; T is a tertiary amine; W is an aro
monium salt to the corresponding 21-nitrone derivative;
matic radical; and Y is CHO, CH(OH)2, CH(OB)2 or
and (d) converting the 21-nitrone to the corresponding
0
ZI-aldehyde or 21~acetal derivative.
Ct \ BI
The new compounds of this invention comprise: (A)
35
21-bromo or chloro-913, llp-epoxy steroids of the preg
nene series; (B) 2l-bromo or chloro-9a-halo-1l/3-hydroxy
wherein B is lower alkyl or benzyl and B’ is lower alkyl
or ll-keto steroids of the pregnene series; (C) 21-quater
ene.
nary ammonium-9a-halo-ll?-hydroxy or ll-keto steroids
The preparation of compounds suitable as initial re
of the pregnene series; and (D) 2l-nitrone-9a-halo-1l?
actants in the process of this invention is disclosed in our
40
hydroxy or keto steroids of the pregnene series.
application, Serial No. 521,915, ?led July 13, 1955.
For a clearer understanding of the foregoing general
These compounds include the 21-alkane-sulfonyl, particu
\0/
and following detailed description of the processes of
this invention, reference is made to the following sche
matic analysis:
CHzOSOzR"
=0
larlyrthe 2l-(lower alkane) sulfonyl, as exempli?ed by
ethanesulfonyl, propanesulfonyl, hexanesulfonyl and espe
cially
methanesulfonyl, derivatives of the following:
45
A4 - pregene-9?,ll?-oxido-Z1-ol-3,20-dione; A4-pregnene
9,8,1l?-oxido-17a,21-diol-3,20-dione; A1'4-pregnadiene-9/3
11/3 - oxido-21-ol—3,20-dione; A1-4-pregnadiene-9?,11?
oxido - 17a,21-diol-3,20-dione; A4'6-pregnadiene-9/L11?
oxido—21-o1-3,20-dione; and A4:6-pregnadiene-9?,11,8-ox
ido-l7a,21-diol-3,20-dione. As disclosed in said applica
tion, these starting materials are prepared by reacting the
corresponding 21-free ol steroid with an alkanesulfonyl
halide under substantially anhydrous conditions.
These starting materials, compounds A, are the reacted
55
with a metal chloride or bromide (MX’), wherein MX’
is as above-de?ned. Particularly preferred metal halides
are lithium chloride and lithium bromide.
Other utiliz
able salts include beryllium chloride, calcium chloride,
60 potassium bromide, calcium bromide and barium bro
mide. The reaction is preferably carried out at elevated
temperature in a substantially anhydrous organic solvent
wherein the metal halide is soluble. Such solvents in
clude the lower alkanolic acids (particularly glacial acetic
acid), ketones (particularly acetone) and lower allkanols.
If the reaction is conducted in a neutral solvent such as
acetone, the product formed is the corresponding 9,8,1113
epoxy-Zl-halide, compounds B (wherein the halide cor
responds to the halogen of the metal halide reactant). If,
70 however, an acidic solvent, such as glacial acetic acid, is
used, then the epoxy ring is opened to directly yield the
corresponding 1l?-hydroxy-9,B,21-dihalide derivative,
3,022,296
3
compounds C, wherein the halo substituents correspond
with a nitroso compound, preferably an aromatic nitroso
to the halogen of the metal halide reactant.
Compunds B are then reacted with a hydrogen halide
compound (WN=O), such as nitroso benzene and p
nitroso-dimethylaniline, in the presence of a basic reagent
such as potassium bicarbonate. By this procedure, a 21
nitrone, compound E, is formed. These nitrones are
(i.e. hydro?uoric, hydrochloric, hydrobromic, or hydro
iodic acid) in a suitable solvent (e,g. chloroform), as dis
closed in the application of Josef Fried, Serial No.
exempli?ed by those of the following general formula
417,489, ?led March 10, 1954. By this reaction, com
pounds C are formed having a 9ct-halo and llp-hydroxy
radical and a 21-halo substituent corresponding to the
substituent in compound B. The ll?-hydroxy group 10
present in compounds C or the corresponding ll?-hydroxy
group present in compounds D, E, and F, can,‘ if desired,
be oxidized to the corresponding keto group in the usual
manner, as by treating the steroid with chromic acid in
glacial acetic acid. Thus, the ?rst class of novel inter 15
mediates of this invention may be represented by the
general formula
20 wherein one of the positions 1,2; 4,5; and 6,7 is double
bonded (preferably the 4,5 position is double-bonded)
and the 1,2 and 6,7 positions are saturated, R, R’, R”,
R", Z, and X are as hereinbefore-de?ned, and W is an
25
aromatic radical such as phenyl and p-dimethylamino
phenyl.
To convert the ZI-nitrones, compounds E, to an acetal
derivative of a 2l-aldehyde, the former is then reacted, ac
cording to the process of this invention, under anhydrous
wherein at least one of the positions 1,2; 4,5; and 6,7 is 30 conditions in an acidic medium with either a monohydric
alcohol of the formula EOH or a dihydric alcohol [of the
double-bonded (preferably the 1,2 and 6,7 positions are
formula B’(OH)2, wherein B and B’ are as above-de~
saturated and the 4,5-position is double-bonded), R" is
?ned, preferably with an alcohol of the formula BOH,
hydrogen, R'" is B-hydroxy, or together R” and R’” is
wherein B is a lower alkyl (e.g. methyl, ethyl, n~propyl,
keto, and R, R’, X, X’, and Z are as hereinbefore de?ned.
or n-butyl) or benzyl radical. The reaction is preferably
These compounds may also be prepared directly from
carried out by dissolving or suspending the starting ma
the corresponding 21-alkanesulfonyloxy derivatives (ster
terial in an anhydrous organic-solvent, such as chloro
oids which are disclosed in our application, Serial No.
form, acetone, dioxane, etc., and treating the solution
516,333, ?led June 17, 1955) by reaction thereof with the
with a mineral acid such as hydrogen chloride or a strong
metal halide, MX', wherein MX’ is as hereinbefore de
?ned, under substantially anhydrous conditions, prefer
ably at an elevated temperature in the presence of an
40
organic acid, such as trichloroacetic acid or p-toluene sul
fonic acid, dissolved in the alcohol reactant. The ratio
of alcohol to steroid for the reaction is preferably at least
two equivalents of alcohol (i.e. two moles of an alcohol
acid or acetone).
BOH or one mole of an alcohol B’(OH)2) per mole of
Compounds C can then be converted to compounds D
steroid. If the alcohol reactant is a lower alcohol, the
by reacting with a tertiary base (T) at an elevated tem
perature. Among the tertiary bases which can be men 45 nitrone can be suspended directly in the mineral acid-al
organic solvent for the metal halide (e.g. glacial acetic
tioned as examples are the aromatic amines (e.g. pyridine,
cohol solution, thereby eliminating the organic solvent.
picolines, lutidines, and quinolines). The resulting qua
ternary ammonium salts may be represented by the fol
The reaction proceeds readily at room temperature, but
may be conducted at any temperature in the range of
about 25° C. to about 100° C.
50
The acetal derivative formed by this step of the process
of this invention may then be converted to the correspond
lowing general formula
ing free aldehyde by reacting the acetal with an aqueous
mineral acid, such as hydrochloric acid or perchloric
acid, in mixture with an organic solvent, such as acetic
55 acid, dioxane, acetone, etc., preferably at room tempera
ture.
R/ 4 \6/
The free aldehydes can also be prepared directly from
the nitrones by reacting the latter with the aforementioned
mineral acids or strong organic acids, in an inert organic
60 solvent such as acetone, acetic acid, dioxane, etc., prefer
ably at room temperature.
These free aldehydes can
wherein one of the positions 1,2; 4,5; and 6,7 is double
then in turn be converted to either the acetalized deriva
bonded (preferably the 4,5-position is double-bonded and
tives by treatment with an alcohol, such as those of the
the 1,2 and 6,7 positions are saturated), T represents the
formula BOH and B’(OH)2, under acidic conditions, or
tertiary amine, and R, R’, R”, R'”, X, X’, and Z are as 65 the diesteri?ed derivatives by treatment, in an organic
hereinbefore de?ned.
base (e.g. pyridine), with an anhydride, such as those of
These 21-quaternary ammonium steroids can also be
the formula
prepared directly from the corresponding 21-alkanesul
fonyloxy derivatives disclosed in said application, Serial
No. 516,333, by reacting the 21-alkanesulfonyloxy steroid 70
with the tertiary amine under substantially anhydrous
conditions, preferably at elevated temperature (eg the
wherein B is as hereinbefore-de?ned, as exempli?ed by
acetic anhydride.
re?ux temperature of the amine).
In the next step of the process of this invention, the
A modi?cation of the process of this invention consists
quaternary ammonium halide, compounds D, are reacted 75 of the direct oxidation of an acetal derivative of a 2l-aldo
3,022,296
steroid having an ll?-hydroxy group to’ the correspond
ing acetal derivative having an ll-keto group. Thus, to
form a 2l-aldo steroid having an ll-keto group, instead
of starting with the corresponding steroid having an 11
keto group and converting this ll-keto steroid to acetal
derivative and thence to the free aldehyde, the llfl-hy
droxy derivative (R” is hydrogen, R'” is IS-hydroxy) is
chosen as the initial reactant, and this reactant is con
verted to the 21-acetal derivative. The acetal derivative 10
is then reacted with a customary oxidizing agent, such as
chromic oxide in a basic medium such as pyridine, to
oxidize the ll?-hydroxy group to keto, and the 11~keto
Zl-acetal derivative thus formed is then converted to the
free 2 l-aldehyde.
15
For the purpose of illustrating one process of this in
vention, reference is made to the following schematic anal
ysis employing A‘*-pregnane-9,6,115-oxids-17u,21-diol-3,
ZO-dione 21-mesylate as starting material:
The acetal derivatives and the free aldehydes which
represent the ?nal products of the processes of this inven
20 tion are active materials which possess glucocorticoid as
well as mineralocorticoid activity. Thus, they vcan be ad
ministered instead of, and in the same manner as, corti
sone or hydrocortisone in the treatment of rheumatoid
arthritis and dermatomyositis, and desoxycorticosterone
in the treatment of Addison’s disease or adrenal insuffi
ciencies. The dosage for such administration is of course
dependent on the relative activity; thus, where the acetal
derivative, for example, has activity of the same order as
hydrocortisone, for example, the dosage is of the same
order.
v
The following examples are illustrative of the inven
tion (all temperatures being in centigrade):
35
A solution of 100 mg. of M-pregnene-QBJl?-oxido
rl7a,2l-diol-3,20-dione Zl-mesylate (I) and 300 mg. of
anhydrous lithium bromide in 5 ml. of acetone is re?uxed
40 for 1/2 hour. After removal of the acetone in vacuo the
residue is taken up in Water and chloroform and the re
sulting chloroform extract washed with dilute sodium bi
carbonate solution and water. ~After drying over sodium
sulfate the chloroform solution is evaporated to dryness in
vacuo and the resulting crystalline residue recrystallized
45 from acetone. Pure 21-bromo-A4-pregnene~9{3,ll?-oxido
17a-ol-3,20-dione has the following properties: M.P. 193°
(dec.); [cc]D23+18° (c, 0.71 in CHCl3);
2.88”, 5.75”, 6.06% 615,7
50
Analysis.——-Calcd. for CHI-12704131‘ (423.33); C, 59.58;
H, 6.42. Found: C, 59.56; H, 6.74.
EXAMPLE 2
21-chl0r0-A4-pregnene-9B,11/3-oxido-17a-0l-3,20
55
dione (III)
A suspension of A4-pregnene-9?,l1,B-oxido-17a,2l-diol
3,20-dione 21-mesylate (I) and 300 mg. of lithium chlo
ride in 6 ml. of acetone is re?uxed for 2 hours. After re
moval of the solvent in vacuo the residue is distributed
60 between water and chloroform. The chloroform solution
is dried over sodium sulfate and concentrated'to dryness
in vacuo. The crystalline residue consisting of 21-chloro
A4-pregnene-9?,11?-oxido-17oc-o1-3,20-dione after recrys
tallization from acetone has the following properties,
65 M.P. about 235—236° (dec.); [a]D2.2-l—28° (c, 0.39 in di
oxane);
Mm, 243 mp. (€>-—~15,200); Ami?‘ 2.87p (OH); 5.78;: (20
keto); 6.08“, 6.14;; (A4-3-ketone)
Analysis.-—Calcd. for C21H27O4C]. (379): C, 66.58; H,
70
7.18. Found: c, 67.01; H, 7.09.
The epoxides formed by the procedures of Examples 1
and 2 can then be converted to the corresponding 9a-halo
11 ,B-hydroxy derivatives as illustrated in the following two
H+ aqueous
(acetone)
75
examples:
3,022,296
8
responding 21-alkanesulfonyloxy derivatives as illustrated
by the following examples:
EXAMPLE 6
9a-?u0r0-21 -bromo-A4-pregnenel-1 113,1 7a-di0l-3,20.
To a’ solution of 42 mg. of .21-bromo-A4-pregnene-9B,
ll?-oxido-l7a-ol-3,20-dione in 8.4 ml. of alcohol-free
chloroform is added, at 0°, 1.8 ml. of 0.5 N hydrochloric
'
dione (I V)
A solution of 100 mg. of 9a-?uorohydrocortisone 21
acid in chloroform. After 60 minutes, ice and dilute bi
mesylate and 160 mg. o‘f'lithium bromide'in 3 ml. of
carbonate are added to Wash out excess acid; and after
glacial acetic acid is refluxed for 1/2 hour. The mixture
is concentrated in vacuo to small volume and the residue
distributed between water and ethyl acetate. The ethyl
acetate layer is washed with dilute sodium bicarbonate
solution and with water, and dried over sodium sulfate.
Evaporation of the solvent in vacuo leaves the 21-bromo
compound as a crystalline residue, which after recrystal
separation of the layers, the chloroform solution is washed
with water, dried over sodium sulfate and evaporated to
dryness. The crystalline residue is recrystallized twice
from acetone to give pure 2l-bromo-9a-chloro-A4-preg
nene-l 1]3,l7a-diOl-3,20—di_0l1€.
'If hydro?uoric acid is substituted for the hydrochloric
acid in the procedure of Example 3, 2l-bromo-9a-fluoro
A4-pregnene-11B,17a-diol-3,20-dione (IV) is formed.
lization from 95% ethanol has the following properties,
IVLP. about 252° (dec.); [a]D23+140° (c, 0.43 in di
EXAMPLE 4
oxane);
21 -chl0ro-9a-?uor0-A4-pregnene-1 15,1 7a-di0l-3,20
2.88”, 3.08[.L (OH), 5.86u
20
dione (VIII)
Anhydrous hydrogen fluoride is added to a solution of
66 mg. of 21-chloro-A4-pregnene-9?,11?-oxide-17a-ol-3,
ZO-dione in 9.5 ml. of chloroform and 0.5 ml. of alcohol
(contained in a polyethylene vessel provided with a cop
Analysis.—-Calcd. for C21H28O4FBr (443.35): C, 56.89;
H, 6.37; Br, 18.26. Found: C, 56.85; H, 6.37; Br, 18.10.
EXAMPLE 7
2.5
per inlet tube). During the addition, the solution is main
tained in an ice bath and agitated by magnetic stirring,
A solution of 9a-?uorohydrocortisone 21-1nesylate and
until the solution assumes a prominent red color. The
inlet tube is then replaced by a polyethylene cap, and the
200 mg. of anhydrous lithium chloride in 3 ml. of glacial
reaction allowed to proceed with stirring for 1.5 hours at 3.0 acetic acid are heated under re?ux for one hour. The
0°. Concentrated aqueous sodium bicarbonate solution
solution is concentrated in vacuo and the residue dis
tributed between water and ethyl acetate. The ethyl ace~
is then added until the mixture is slightly alkaline, and
the two layers are separated. The now light-yellow
tate layer is washed with dilute bicarbonate solution and
with water and dried over sodium sulfate. Evaporation
chloroform solution is washed with water; and after dry
ing over sodium sulfate, it, is evaporated to dryness in 3.5 of the solvent in vacuo leaves the 21-chloro compound
vacuo. The residue is then taken up in hot ethyl acetate,
as a crystalline residue (about 85 mg), which after re
the resulting suspension ?ltered, and the ?ltrate, on cool
crystallization from 95% ethanol melts at about 267—269°
ing, deposits a crystalline precipitate. This material is es
(dec.); [aha-H53“ (c, 0.30 in dioxane);
s‘entially pure 21-chloro-9o¢-?uoro-A4-pregnene-115,1711:
diol-3,20-dione which is recrystallized from ethyl acetate
to give a pure product having the properties described in
Example
7.
'
‘
i
'
'
'
40
(ZO-keto), 6.08M (A4-3-ketone)
bromo and 9a-iodo derivatives are formed.
'
Analysis.--Calcd. for C21H28O4FCl (398.89): C, 63.23;
"
If hydrochloric acid is substituted for the hydro?uoric
acid in the procedure of Example 4, 9a,21-dichloro-A4
pregnene-l1B,17u-diol-3,20-dione (IX) is formed.
Similarly if hydrobromic or hydroiodic acid is substi
tuted for the hydrochloric or hydro?uoric acid in the
procedures of Examples 3 and 4, the corresponding 90:
A213; 238 mp (6.=V17,7OO); REL-if" 2.88% 3.031.; (OH), 5.83;;
H, 7.08; Cl, 8.89. Found: C, 63.25; H, 7.34; Cl, 8.44. '
The reactions of Examples 6 and 7 can also be carried
4.5
out with acetone as the solvent.
_
Similarly, by substituting either 9a-chlorohydrocorti
sone 21-mesylate or 9a-brornohydrocortisone 2l-mesylate
50
9:»,2l-dichloro-M-pregnene-l118,170‘ - diol - 3,20’ - dione
(IX) can also be prepared directly from A4-pregnene-9/3,
1l?-oxido-17a,21-diol-3,20-dione 21 mesylate (I) as dis
closed in the following example:
for the 9tX-?UOI'OhydTG‘COI'tlSOI1e 2l-mesylate in the pro
cedures of Examples 6 and 7, the corresponding 2l-bromo
and 2l-chloro derivatives are obtained, respectively.
The 9a-halo-11,8-hydroxy-21-bro-mo or chloro steroids
produced by the procedures of Examples 3 through 7 can
be oxidized to the corresponding 9oc-l1?lO-1l-kC'EO-21
brorno or chloro derivatives as illustrated by the follow
55 ing example:
EXAMPLE 5
9a,21-dichl0r0-A4-pregnene-11BJ 7a-diQl-3,20-di0n_c (IX)
A solution of 100mg. ofv A4-pregnene-9B,11?-oxido
17¢,21-diol-3,20-dione 21-mesylate (I) and 300 mg. of
lithium chloride in 6 ml. of glacial acetic acid is heated
To a solution of 100 mg. of 9a-?uoro-21-chloro-A4
60
pregnene-l1/3,17a~diol~3,20-dione in 5 ml. of glacial acetic
on the steam bath for 30 minutes. After removal of the
acid is added a solution of 40 mg. of chromic acid in 4 ml.
solvent in'vacuo the residue is taken up in ethyl acetate
and water. The ethyl acetate layer is extracted with dilute
sodium bicarbonate solution and water and dried over
sodium sulfate. The solvent is removed in vacuo and the
65
of acetic acid. A half-hour later, 0.05 ml. of methanol is
added, and the resulting mixture is concentrated in vacuo.
The residue is distributed between chloroform and water,
and the resulting chloroform extract is washed with water,
70
drying over sodium sulfate and evaporation of the sol
vent in vacuo, the residue is crystallized from 95 %
ethanol to give pure 9a-?uoro-2l-chloro-A‘i-pregnene-17a
ol-3 ,11,20-trione.
crystalline residue recrystallized from 95% alcohol. Pure
9a,2l-dichloro-A4-1lB,l7u-diol-3,20-dione has the follow
sodium bicarbonate solution and again with water. After
ing properties M.P. about 275-277" (dec.); [ot]D23+1S6?
(c, 0.39 in dioxane);
'
“"59 289p, 3.04 (OH) ; 5.83” (20-keto) ; _6.0° (A4.-3-l'etone)>\
Analysis.—Calcd. for C21H2aO4Cl2 (414.34): C, 60.73;
H, 6.79; Cl, 17.07. Found: C, 61.01; H, 6.89; CI, 17.55.
The 9a-halo, ll?-hydroxy steroids having a '2l-bromo
Similarly, by substituting 9a-fluoro-21-bromo-A4-preg
nene-l1/3,17u-diol-3,20-dione (IV), 9u-chloro-21-bromo
A4-pregnene-1l?,l7a-diol-3.20-dione (V), or 90¢,21-di
or chloro substituent can also be prepared from the'cor— 75 chloro-M-pregnene-ll?J7a-diol-3,20-dione (IX) for the
3,022,296
ium chloride, M.P. about 287° (dec.) and is used without
further puri?cation in the nitrone formation reaction.
one (VIII) in the procedure of Example 8, 9a-?uoro-2l
bromo-M-pregnene-17a-ol-3,11,20-trione (VI), 9a-chloro
21-bromo-A4-pregnene-l7a-ol-3,l1,20-trione (VII), and
Concentration of the mother liquor afford an additional
crop of this substance and then two crops of a lower melt
9a,2l-dichloro-n‘l-pregnene-1711-01-3,11,20-trione (XI) are
obtained, respectively.
10
washed with acetone.v It represents the desired 2l-pyridin
9a-?uoro-2l-chloro-M-pregnene-l15,17“ -'diol --3,20 5di
ing substance, M.P. about 235—237°, which is recrystal
lized from 95% alcohol. The latter substance represents
7
The 9a-halo-llB-hydroxy (or 1l-keto)-21-bromo or
chloro steroids formed in the procedures of Examples 3
9a,2l-dichloro-A‘l-pregnene-1118,170‘ - diol - 3,20 - dione;
[a]D23-[-178° (c, 0.28 in absolute alcohol);
through 8 can be converted to their 21-pyridinium deriva
10 x515, 241 mu (e=16,000); A513?‘ 2.87“ (11—-OH)3.01p
tives as illustrated in the following example:
(17—OH), 5.83;‘ (20-keto), 6.08,“ (3-keto)
EXAMPLE 9
Analysis.--Calcd. for C21H28O4Cl2 (415.34): C, 60.72;
H, 6.79; Cl, 17.08. Found: C, 60.79; H, 6.70; Cl, 16.66.
If p-toluenesulfonyl bromide is substituted for p-tolu
15 enesulfonyl chloride in Example 11, the resulting mixture
will consist of the 2l-pyridinium bromide (XIII) and the
21-bromide (V). Furthermore, upon the substitution of 90a
chlorocortisone for the 9oc-Cl'llOl'O-l'lYdI‘OCOI‘tlSOIlC, either a
A solution of 156mg. of 9a-?uoro-21-chloro-A4-preg
nene-l1?,l7a-diol-3,20-dione in 3 ml. of dry pyridine is
heated on the steam bath for 30 minutes and after cool
ing 5 ml. of acetone is added. Cooling produced a crop 20 mixture of 9a-chloro-A4-pregnene-17u-ol,3,11,20-trione 2l
pyri‘dinium chloride (XIX) and 9a,2l-dichloro-A4-preg
of crystals (about 123 mg.), M.P. 319-321" (dec.), which
represent the Zl-pyridinium chloride. From‘the mother
liquors about 32 mg. of starting material M.P. 263°
nene-17a-ol-3,11,20-trione (XI), or 9a-chlo1‘o4A4-preg
nene-l7or-ol-3,11,20-trione 2l-pyridinium bromide (XV)
and 9u-chloro-2l-bromo-M-pregnene-l7a-ol-3,11,20-trione
(dec.) is recovered.
;
p The 2l-pyridinium halides can be prepared directly 25 (VII), depending on whether tosyl chloride or tosyl bro
mide is used, will be formed.
from the 21-alkanesulfonyloxy derivatives as illustrated
Since the tertiary base is eliminated in the next step of
by the following two examples:
the process, the exact chemical composition of the base is
EXAMPLE 10
of no importance, so that any other tertiary base may be
substituted for pyridine in the processs of the above Ex
30 amples 9, 10, and 11 to yield other quaternary ammonium
salts. Examples of such bases include the lutidines, the
A solution of 500 mg. of 9a-?uorohydrocortisone 2l
mesylate in 5 ml. of anhydrous pyridine is heated on the
steam bath for 30 minutes. To this solution which con
tained 9a-?uoro-A4-pregnene ll?,l7a-diol—3,20-dione-2l
collidines, the tri(lower alkyl)amines (e.g. trimethylamine
and triethylamine), N-alkylated piperidine, etc.
The formation of the nitrones in the next step of the
35 process of this invention is illustrated by the following
pyridinium rnesylate is added after cooling 3 ml. of 2%
examples, using p-nitrosodimethyl aniline as a source of
methanolic hydrogen chloride and ‘shortly thereafter 20
the nitroso reactant:
ml. of acetone. Crystallization-of 9a-?uoro-A4-pregnene
EXAMPLE 12
11}3.l7u-diol-3,20-dione 21-pyridinium chloride ensues
rapidly and is complete after several hours in the refrig 40
erator.
.
The resulting crystals are ?ltered off and washed with
acetone. Recrystallization from methanol furnishes the
pure Zl-pyridinium chloride, M.P. about 320-321 ° (dec.);
- pregnene-I 1,8,1 7u-di0l-3,20-di0ne 21 -pyridinium chlo- ride (XVI)
45 T
[a]D23+200° (c, 0.22 in methanol);
Ania. 239 m,‘ (e=19,600)
‘
To a warm solution of 250 mg. (0.52 millimole) of
9a-?uoro-A4-pregnene-11B,l7aidiol 3,20-dione ZI-pyridin
ium chloride in 7 ml. of methanol and 4.5 ml. water is
Analysis.—Calcd. for C26H33O4NC1F (477.99): C,
added 89 mg. (0.58 millimole) of p-nitrosodimethyl ani
65.33; H, 6.96; CI, 7.42. Found: C, 65.48; H, 6.82;
line and shortly thereafter a solution of 55 mg. of potas
Cl, 7.37.
50 sium bicarbonate (0.55 millimole) in 0.7 ml, of water.
Following the procedure of Example 9, by substituting
The mixture is gently warmed on a steam bath and then
9a-?uoro-2l-bromo-M-pregnene-l118,17a-dio1-3,20 - dione
allowed to remain in the refrigerator overnight. The re
(IV), 9a-chloro-21-bromo-A4-pregnene-1 1?,l7u-diol-3,20—
dione (V), 9a-?uoro-2l-brom0-A4-pregnene-1705-01-3,1l,
20-trione (VII), 901,21-dichloro-A4-pregnene-11?,17a-diol
3,20-dione (IX), 9a-?uoro~2l-chloro-N-pregnene-l7a-ol
sulting red crystals (about 170 ,mg.) are ?ltered off,
washed with 1:1 methanol-water and the mother liquors
55 concentrated in vacuo. An additional crop (about 47
mg.) is obtained in this manner. The nitrone is used in
3,11,20-trione (X), and 9a,2l-dichloro-M-pregnene-17a
3,11,20-trione (XI) for the 9a-?uoro-2l-chloro-M-preg
nene-l1B,17a-diol-3,20-dione, there is obtained compounds
XII, XIII, XIV, XV, XVII, XVIII, and XIX, respectively. 60
' Compounds XII through XIX can also be prepared di
the preparation of the aldehyde without further puri?ca
tion. For analysis the unstable nitrone is recrystallized
from methanol, M.P. about 226° (dec.);
kg}; 240 mu (e=25,000), 304 my (e=9,400) and 415 mp,
(e=12,850)
Analysis.—Calcd. for C29H3qO5N2F (512.61): C, 67.94;
rectly from the corresponding 9a-halohydrocortisone or
9a-halocortisone by reaction thereof with p-toluenesul
fonyl chloride or bromide in anhydrous pyridine at an ele
H, 7.28; N, 5.47. Found: C, 68.87; H, 7.36; N, 6.28.
vated temperature as illustrated by the following example: 65
EXAMPLE 11
methyl-aminophenyl)-nitr0ne (XXI) from 9a-chl0r0
Qua-chloro-M-pregnene-IIBJ7a-diol-3,20-diane ZI-pyridin- “
ium chloride (XVII) and 9:1,21-dichloro-A4-pregnene
115,1 7a-di0l-3,20-di0ne (IX) from 9a-chl0r0hydr0‘cor
tisone
EXAMPLE 13
9a-chl0ro-A4-pregnene-1]}3,17a-di0l-3,20-dione 21 - (p-di_
'
A solution of 500 mg. of 9a-chlorohydrocortisone and _
M-pregnene-I1,3,17a-di0l-3,20 - dione
70
21 - pyridinium
chloride (XVII)
To a warm suspension of 140 mg. of 9a-chloro-A4-preg
nene-ll?,17a-diol-3,20-dione 2l-pyridinium chloride in
3.8 ml. of methanol and 2.4 ml. water is added 477mg. of
p-nitrosodimethyl aniline. When the latter has dissolved
crystalline precipitate appears which is ?ltered o? and 75 a solution of 30 mg. of potassium bicarbonate in 0.38 ml.
300 mg. p-toluenesulfonyl chloride in 3 ml. of anhydrous
pyridine is heated on the steam bath for 15 minutes. A
3,022,996“ I
11
r
of water is added and the mixture warmed on the steam
bath until all the pyridinium salt has dissolved, and has
been replaced by the red crystals of the nitrone. The re-.
to
12
90:": chloro - A4 - pregnene - 1113,1711 - diol _ 3,20
dione-Zl-al hydrate as described in Example 14 for the
corresponding ?uoro compound.
action mixture is then cooled and allowed to remain in
the refrigerator for one hour. The crystals are ?ltered
and washed with 50% methanol-water and ?nally with
Water. The yield of nitrone is about 104 mg, M.P_ about
206°. The substance is used in the preparation or" the
The pure 9a - chloro - A4 pregnene - 115,171: - diol
3,20-dione-21-al hydrate, after recrystallization from di
lute acetone, has the following properties: M.P. great
er than 345° with darkening at 195 °; [0111323 +132” (0,
0.35 in methanol);
aldehyde without further puri?cation.
In an analogous manner the pyridiniurn bromides (XII) 10 Min. 240 11114 (e = 18,400) ; m...
5.85” (20-keto), 6.712,‘ (3-keto)
and (XIII) can be converted to the 9ix-?uoro and 9a
chloro derivatives, respectively.
If 9u-?uoro-A4-pregnene-l7ot-ol-3,11,20-trione 21 pyri
, dinium chloride (XVIII) or bromide (XIV) is substituted
for the pyridinium chloride in Example'12, 9a-?uoro-A4 15
p-regnene-17a-ol-3,11,20-trione 21-(p-dimethylaminophen
8.66.
'
90c - chloro - A4 - pregnene - 115,170; - diol - 3,720
tisone acetate in the rat liverglycogen assay. It is about
3 times as active as desoxyécorticosterone in the sodium
A4-pregnene~17ot-ol-3,11-20-trione 21-pyridinium chloride
(XIX) or bromide (XV) is substituted for the pyridinium
chloride in Example 13, 9a-chloro-A4-pregnene-1701-01-3, 20
21 - (p - dimethylaminophenyl) -.nitrone
(XXIII) is produced. Analogously, the quaternary am
monium salts of the corticosterone and dehydrocorticos
retention assay in the rat.
25
Although the above examples employ p-nitrosodimethyl
'
If 9a-?uoro-A4-pregnener17a-ol-3,11,20-trione 21-(p!
dimethylamino phenyl)-nitrone ()OGI) is substituted for
the
terone derivatives are converted to the corresponding ni
trones.
Analysis.-—Calcd. for C21H2qO5CLH2O (412.90): C,
61.08; H, 7.08; Cl, 8.59. Found: C, 61.43; H, 6.73; Cl,
dione-2l-al hydrate shows about 1/a the activity, of cor
yl)-r.itrone (XXII) is formed. vSimilarly, if 9oc-Chl01‘0
11,20-trione
2.92pm, 3.05-3.09” (OH),
90: - ?uoro - A4 - pregnene - 115,170: - diol - 3,20
dione 21-(p-dimethylaminophenyl~)-nitrone of Example
14, or if 9u-chlor0-A4-pregnene-1701-01-3,11,20-trione ;2'1
(p-dimethylaminophenyl)-nitrone (XXIII) is substituted
for the 9e-chloro-11B-hydroxy derivative of Example 15,
aniline as the source of the nitroso radical, any other
aromatic nitroso-containing compound (such as nitroso
then
94! -?uoro - A4 - pregnene - 17a - 01 ~ 3,11,20a
trione-Zl-al hydrate (XXVI) and 9a-ch1oro-A4-pregnene
17pt-ol-3,11,20-trione-21-al hydrate (XXVII) are formed,
respectively. Similarly, by substituting the 21-(p-di
benzene) may be used instead, since in the next step of
the process the nitroso group is replaced by an aldo or 30
acetalized aldo substituent.
The nitrone is then converted either to the 21-acetalized
methylaminophenyl)nitrone derivatives of 9oz-?ll01'0 (or
aldo or the free 21-aldo as illustrated by the following
chloro) - A4 - pregnene - 11B - ol - 3,20 - dione, or of
examples:
9u-?uoro (or chloro)-A4-pregnene-3,l1,20-trione, or of
35 9a-?u0ro (or chloro)-A4-pregnene-l l ?-o1-3,20-dione-18+
al for the nitrone employed in Example 14, 9a.-?uoro
EXAMPLE 14
9a .- ?uora - A4 - pregnene - 115,170: - diol - 3,20 - dione
(or chloro) [A4 - pregnene - 115 ~ 01 - 3,20‘ - dione.
21 - a! hydrate (XXIV) from 90c - ?uoro - A4 - preg
nene - 11/1170: - diol = 3,2,0 .- dione 21 - (p-dimethyl
2l-al hydrate, and 9a.-?uoro (or chloro)-A4-pregnene
40 11,B-ol-3,20-dione-18,21¢diol ZL-hydrate, respectively, are
produced.
aminophenyl) -nitr0ne (XX)
The ZI-acetals can be produced directly from the ni
To a suspension of 120 mg.'0f 9a-?uoro-A4-pregnene
trones as illustrated by the following Example:
11}8,l7a-diol-3,20-d_ione (2l-p-dimethylaminophenyl)-ni
trone in 2 ml. of acetone is added at roomtemperature
1 ml. of 2 N aqueous hydrochloric acid. Gentle agita 45
tion causes the nitrone to ‘dissolve rapidly to form a yel
low solution. After centrifugation of some insoluble
matter 4 ml. of water is added, which causes the alde
hyde hydrate to crystallize in ?ne needles. After one
hour at 5° the crystals are separated from the mother .59
liquors and washed thoroughly with water. The resulting
crystals (about 81.5 mg), after recrystallization from
EXAMPLE 16
90: - ?uoro - A4 - pregnene - 115,170: - diol - 3,20 - dione
21 - al dimelhyl-acetal (XX VIII )
from 9st - ?uoro
A‘t-pregene - 1118,17“ - diol - 3,20 - dione - 12 - (p-di
methylaminophenyl)-nitr0ne (XX)
To a suspension of 120 mg. of 9u-?uoro-A4-pregnene
1113,1711. - diol - 3,2" - dione - 2'1 - (p -dimethy_lam_ino
acetone-water melt at about, 190491", (“L323 —1,26°
phenyl')-nitrone in 2 m1. of acetone is added at room
(c, 0.48 in methanol);
.55 temperature 1 ml. of 2 N methanolic hydrogen chloride.
The mixture is taken up. in.20 ml. of chloroform and 4
mtg-L 238 mp (e=18,300); 70,331?‘ 3.0-3.2p (OH), 5.86;» (20
ml. of .water. After separation of the phases, the chloro
keto), 6.1511 (4-ket0)
form layer is extracted with dilute bicarbonate and wa
Analysis.—-Calcd. for C21'H27O5F-I-I2O (396.44): C,
ter and after drying. over sodium sulfate, is evaporated
63.62; H, 7.37; F, 4.79. Found: C, 63.71; H, 7.18; F, 60 to dryness in vacuum. The residue represents the di-,
4.87.
methyl acetal of -9,u~?uoro-A4-pregnene-11p,18¢¢diol-3,
90; - ?uoro - A4 - pregnene - 115,170: - diol - 3.20 - dione
21-01 hydrate possesses about 1/3 the activity of cortisone
acetate in the rat liver glycogen assay and is about
equal in activity to desoxycorticosterone in the sodium
retention assay in the rat.
EXAMPLE 15
(XXV)
.
Similarly, by substituting 9e-chloro-A4=pregnene-115,
17m - diol - 3,20 - dione - 21 -.(p - dimethylaminophenyD
65
_
nitrone (XXI), 9a - ?uoro - A‘1v - pregnene .- 17a - 01,
3,1 1,20 - trione - 21 - (p - dirnethylaminophcnyl) -nitr0ne
(XXII), or 90: - chloro ,- A4 - pregnene - 17a - ol - 3,11,
2O trione-Zl-(p-dimethyl-aminophenyl)-nitrone (XXIII)
9a - chloro - A4 - pregnene - 116,170: - diol - 3,20
dione - 21 - al hydrate
20-dione-21-al.
from 90: - chloro
A4 - pregnene - 1113,1704 - diol - 3,20 - dione - 21 - (p
dimethylaminophenyl)-nitr0ne (XXI)
the nitrone of Example 16, the respective ZI-diinethyl
70 for
acetals, XXIX, XXX, and XXXI, are produced. Fur
thermore, if 1% ethanolic hydrogen chloride is substi
9a - chloro - A4 - pregnene - 1119,17‘): - diol - 3,20
dione 2l-(p-dimethylaminophenyl)-nitrone is converted 75
tuted for the methanolic hydrogen chloride in the pro
cedure of Example 16, the correspondingdiethyl acetals
are formed.
"
3,022,296
13
14
2. A process for preparing a steroid of the general
formula
The invention may be variously otherwise embodied
within the scope of the appended claims.
We claim:
1. A process for preparing a steroid of the general
formula
H01
wherein at least one of the positions 1,2; 4,5; and 6,7
is double-bonded, and R is hydrogen, R’ is hydroxy and
together R and R’ is selected from the group consisting
of keto and ketalized keto, Z is selected from the group
consisting of hydrogen and a-hydroxy, and X’ is selected
from the group consisting of bromo and chloro, which
wherein at least one of the positions 1,2; 4,5; and 6,7 is
double-bonded and R is hydrogen, R’ is hydroxy and to 20 comprises treating a steroid of the general formula
gether R and R’ is selected from the group consisting
omosomw
of keto and ketalized keto, Z is selected from the group
=0
consisting of hydrogen and a-hydroxy, and X’ is selected
---z
from the group consisting of bromo and chloro, which
comprises treating a steroid of the general formula
0
1
CHgOSOiR’m
2
R
5
fl
30
RI/ 4
6
wherein at least one of the positions 1,2; 4,5; and 6,7
is double-bonded, R"" is alkyl, and R, R’, and Z are
as above-de?ned with a salt selected ‘from the group con
35 sisting of light metal bromide and light metal chloride
in an acid organic solvent for said salt.
wherein at least one of the positions 1,2; 4,5; and 6,7
is double-bonded, R"" is alkyl, and R, R’ and Z are 40
as above-de?ned with a salt selected from the group
consisting of light metal bromides and light metal chlo
rides under substantially anhydrous conditions in a new
tral organic solvent for the salt, and recovering the re 45
sultant steroid.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,268,084
2,664,428
2,665,274
2,842,568
2,851,455
2,903,449
Reichstein __________ __ Dec. 30,
Miescher et a] _________ __ Dec. 29,
Conbere ______________ .. Jan. 5,
Fried et al. ___________ .... July 8,
Fried et al. __________ __ Sept. 9,
Fried et al. __________ ...- Sept. 8,
1941
1953
1954
1958
1958
1959
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