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Патент USA US3075979

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United States Patent ()?ice
Patented Jan. 29, 1%63
hydroxy derivative to the corresponding 4,8-bromo (or
2,4-dibromo) derivative, and thence by dehydrobromina
Josef E. Herz and Josef Fried, New Brunswick, N.J., as
tion to the corresponding M-pregnene (or a mixture of
the corresponding AM-pregnadiene ?and A'i?-pregnadiene)
signors to Olin Mathicson Chemical Corporation, New
York, N.Y., a corporation of Virginia
No Drawing. Filed July 1, 1%5, Ser. No. 519,682
1 Claim. (Cl. 260-23955)
derivative (if the initial All-steroid contains the requi
site 4,5- and/or 1,2;4,5- and 4,5;6,7-unsaturation, step
(d) can, of course, be eliminated); and (e) optionally
oxidizing the ll?-hydroxy steroid, thus formed, to the
This invention relates to the synthesis of valuable
corresponding ll-keto derivative.
steroids; and has for its object the provision of (I) an 10
(A) the
advantageous process of preparing steroidsof the preg~
intermediate 11,8,125-ep0xy steroids of the pregnane (in
nane (including the allopregnane, pregnene and pregna
cluding ?the._allopregnane, pregnene and pregnadiene)
diene) series having a Hot-halogen substituent and an
series; (B) the-intermediate l2ot-halo-ll?-hydroxy ste
ll-keto or ll?-hydroxy substituent, and of (11) certain
steroids useful themselves as physiologically active ster 15 roids of the pregna?e (including the allopregnane) series,
wherein the halo radical is chlorine or ?uorine (i.e. a
oids or in the preparation of physiologically active
halogen of atomic weight greater than 18 and less than
steroid derivatives.
The process of this invention essentially comprises:
36); (C) the intermediate l2a-halo-4l3-bromo-l l?-hy
droxy steroids of the pregnane series; (D) the intermedi
(a) converting a All-steroid of the pregnene (including
the allopregnene, pregnadiene and pregnatriene) series 20 ate 12a-halo-2,4-dibromo-1l?-hydroxy steroids of the
into the corresponding l2a-bromo-ll?-hydroxy steroid
pregnane (including the allopregnane) series; and (E)
the physiologically active IZa-halo-l l?-hydroxy (or
of the pregnane (including the allopregnane, pregnene,
and pregnadiene) series; (b) converting the latter into
11-keto)-A4-steroids of the pregnene (including the A?
the corresponding 115,125-epoxy derivative thereof; (0)
and A?il?-pregnadiene) series.
converting the 1l?,12,3-epoxy derivative into the corre 25
For a clearer understanding of the foregoing general
and following detailed description of the processes of this
sponding 12cc-h310-11?-hYdI?OXY derivative thereof (when
the halo group is bromine, steps (b), and (c) can, of
invention, reference is made? to the following schematic
course, be eliminated); (d) converting said 12a-halo-1l?
wherein the 1,2; 4,5; ?and '6,7-positions are doubleibondjed
or saturated, and wherein individually R is hydrogen, R?
alkali ?metal hydroxide (e.g. potassium hydroxide), in va
30 suitable solvent such as alcohols, lower alkanoic acids, or
,ketones (preferably in an alkanol such as methanol or
is hydroxy, or together R and R? is 0x0 (keto) or a group
ethanol) to form the 115,12p3-epoxy derivatives of this
convertible thereto by hydrolysis (e.g. gketal), R and R?
invention, Compounds B.
as keto being preferred, X is halogen [preferably a halo~
gen of atomic weight greater than 1-8 and ?less than 36 35 Compounds B are then reacted with a hydrogen halide
(e.g. hydrobromic, hydroiodic, and preferably hydro
(Le. chlorine or ?uorine)], Y is hydrogen, hydroxy, or
?uoric or hydrochloric acid) in a suitable solvent, such
acyloxy, Z is hydrogen or m-hydroxy, and GBr is an
as a halogenated alkane (e.g. chloroform), an alcohol
(e.g. methanol), or an ether (e.g. dioxane). By this re
N-bromarnide (including imide) of a carboxylic acid
(including derivatives).
Compounds suitable as initial reactants in ;the process 40 action, Compounds C are formed, wherein the l2a-halo
substituent corresponds to the halide of the hydrohalic
invention include preferably A11-pregnene-3,20?
acid of the reaction. If hydrobromic acid is used, Com
and A11-pregnene-2l-ol-3,20-diones and esters
pounds A are re-forrned; otherwise, new steroid deriva
[particularly carboxylicyacid esters such as hydro
tives having a IZu-halo and 11B- hydroxy substituent are
carboxylic acid esters having less than ten carbon
atoms ?in the acid moiety, as exempli?ed by the lower 45 obtained.
If ?the initial reactant or the intermediate Compounds
alkanoic acid esters (e.g. the acetate, propionate, butyr
A and B are saturated in the 1,2; 4,5; and 6,7 positions
gate, and enanthate) and the Tmonocyclic hydrocarbon
of this
jaromatic carboxylic acid esters ?(e.g. the ,benzoate)], al
though otherstarting materials may alsobeused, such as:
(such intermediates being preferred), the resulting in
active CompoundsC can be converted to physiologically
.50 active steroids by introducing a double-bond in the 4,5
dione and esters thereof; 'A4-1l-pregnadiene-Novel-3,20
_dione; A4-11-pregnadiene-.17a,21-diol-3,2O-dione and esters
?thereof; An-pregnene - 17oz - ol-3,20-dione; AU-pregnene
-l7a,2l-diol-3,20-dione and esters thereof; 'AM?u-ipregnatri
ene - 3,20 - dione; A1All-pregnatriene-17a-ol-3,20-dione; 55
A1�11-pregnatriene-21-ol-3,20-dione and esters thereof;
dli?i-n-pregnatriene - 1701,21 ~ diol-3,20-dione and esters
thereof; A4'GJ1-pregnat1'iene-3,20-dione; A4-6�-pregnatri
ene-l7a-ol-3,20-dione; A4-6111-pregnatriene - :21 ,-_ol - 3,20
position. This may be done by: (l) reacting Compounds
C, wherein the steroid nucleus is saturated and of the
pregnane con?guration, with approximately one mole of
bromine per?mole of steroid, thereby forming Compounds
D containing a 4?-bromo substituent, and dehydrobro
minating as by treatment
(such as an alkali metal
lithium chloride) or with
dinitrophenylhydrazine or
with an alkali metal halide
chloride, as exempli?ed by
a hydrazine derivative (e.g.
semicarbazide) to form the
dione and esters thereof; and A4'6-l1籶regnatric-170:,21 60 corresponding hydrazone or semicarbazone, followed by
decomposition of the latter with a keto acid (e.g. pyruvic
diol-3,20-dione and esters thereof.
acid) to prepare a A4-pregnene, Compounds E, which cor
These compounds are reacted with a compound .pf the
respond to Compounds C wherein the 4,5 position is
formula 631-, wherein GBr is as above-de?ned, and is
preferably an N-bromamidc of a lower allganoic acid
double-bonded; or (2) reacting Compounds C, wherein
the steroid nucleus is saturated and may be either of the
(e.g. N-bromacetamide), an _N-bromamide of a lower
alkendioic acid (e.g. N-br'omosuccinimide), or 1di
pregnane or allopregnane con?guration, with two moles
bromodimethylhydantoin. This reaction is optimally car
ofjbromine per mole of steroid, thereby forming Com
r-ied out in the presence of a strong acid (e.g. perchloric
pounds F containing 2,4-dibromo substituent (20:,40: if
acid) whereby the desired brominated product is formed
C are allopregnanes and 25,45 if Compounds
70 Compounds
to the exclusion of undesired by-products.
C are pregnanes), and dehydrobrominating by treatment
The reaction results , in the production of Compounds
A (preferably wholly-saturated and of cis'con?guratio'n
with an organic base such as pyridine or collidine, to pre
pare a mixture (which is separable by chromatography)
in the 5-position), which are then reacted with a basic
of dl?-pregnadiene, Compounds G, and A?e?- pregnadiene,
reagent, such as an alkali metal salt of a weak organic
acid (e.g. an alkali metal acetate or carbonate) or an 75 Compounds G?. These derivatives correspond to Coma
pounds C wherein the 4,5-position and one of the posi
tions 1,2 or 6,7 is double-bonded.
?Compounds C, E, G, or G? can be oxidized, if desired,
to the corresponding ll-keto derivatives, Compounds H,
by treatment with an oxidizing agent such as a heXavalent
chromium compound (e.g. chromic acid).
The new l2a-halo-llB-hydroxy (or 11-keto)-A?1-preg
nene (including the pregnadiene) steroids of this inven
tion (Compounds E, G, G?, and H) and particularly those
J /
of the general formula
(III) X=Cl
(IV) X=F
(V) X=Cl
(VI) X=F
(VII) X=Cl
(IX) X=Cl
4 )
The following examples are illustrative of the inven
wherein the 1,2- and 6,7-positions are saturated or
tion (all temperatures being in centigrade):
double~bonded; R, R?, X, Y, and Z are as hereinbefore
de?ned; and individually R? is hydrogen, R?" is hydroxy,
and together R" and R?? represent keto or ketalized keto, 30
are physiologically active steroids which possess gluco
corticoid as well as mineralocorticoid activity. Thus, the
new steroids of this invention can be administered instead
of, and in the same manner as, cortisone or hydrocorti
sone in the treatment of rheumatoid arthritis and der
matomyositis, or in the same manner as desoxycorti
costerone in the treatment of Addison?s disease or adrenal
IZa-Bromopregnane-l 1,8-0l-3,20-Di0ne (I )
To a solution of 300 mg. of A11-pregnene-3,20-dione in
40 ml. of pure dioxane and 4 ml. of water is added 240
mg. of N-bromoacetamide and shortly thereafter 2.0 ml.
of 1 N aqueous perchloric acid. After 25 minutes at room
temperature 5% aqueous sodium sul?te is added to de
stroy the excess N-bromoacetamide and shortly there
iusu?ciencies. The dosage for such administration is,
after 75 ml. of chloroform. After separating oi? the
of course, dependent on the relative activity of the com
aqueous layer the chloroform layer is washed with dilute
pound; thus, where the steroid derivative has approxi 40 sodium bicarbonate, and water, and dried over sodium
mately the same activity or" cortisone, the dosage of the
sulfate. After evaporation of the solvent in vacuo, the
former to be employed should be approximately equal to
residue is leached with ethyl acetate leaving about 262
the employed dosage of the latter. The lZa-bromo-l 1
mg. of crystalline material, melting at about 228-230�
keto-steroids of this invention are of further use as inter
(dec.). This material on recrystallization from tetrahy
mediates in the preparation of the corresponding 12 45 drofurane-hexane gives pure 12u-bromopregnane-1 l?
debromo derivatives, to which they are converted by
ol-3,20-dione, having the following properties: M.P. about
treatment either with bromine in acetic acid or chromous
251?252� (dec.); [@1323 +76� (c., 0.37 in dioxane).
Analysis.-Calc?d. for C21H31O3Br (411.38): C, 61.31;
For the purpose of illustrating the preferred process
H, 7.60; Br, 19.43. Found: C, 61.70; H, 7.19; Br. 19.73.
of this invention, reference is made to the following sche 50' This steroid has previously been described by Hegner
matic analysis employing A11-pregnene-3,20?dione as the
and Reichstein [Helv. Chim. Acta 26, 721 (1943)]. In a
starting material:
similar manner, A11-pregnene-21-ol-3,20-dione 2l-acetate,
A4?u-pregnadiene-3,20-dione and A4?11-pregnadiene-21-ol
3,20-dione 21-acetate can be converted to 12a-bromopreg
nane-l1,8,21-di0l~3,20-dione 21-acetate, 12Ot-bl'OmO-A4
pregnane-l1/8-ol-3,20-dione and 12a-bromo-A4-pregnene
ll?,2l-diol-3,20-dione 21-acetate, respectively.
1 113,1 ZB-Epoxy-Pregnane-3,20-Di0ne (II)
To a solution of 271 mg. of 12u-bromopregnane-11,8-01
3,20-dione in 24 ml. of methanol is added 220 mg. of
potassium carbonate in 1.2 ml. of water. The mixture
is agitated at room temperature for 18 hours, after which
the methanol is removed in vacuo. Extraction of the
residual mixture with ether furnishes about 247 mg. of
crystalline material which is recrystallized from acetone
hexane. Pure 11,6,1ZB-epoxy-pregnane-B,20-dione has the
following properties: M.P. about 139-140"; [01],;23 +89??
(c., 0.38 in chlf.);
Analysis.?Calc?d. for C21H30O3 (330.45): C, 76.32; H,
9.15. Found: C, 76.15; H, 8.90.
Similarly, 12cc - bromopregnane-l1,8,21-di0l-3,20-dione
11;8-ol-3,20-dione, M.P. about l84.?_._l86� _(dec.); [01.];323
2l-acetate, 12a-brorno-A4-pregnene-l l?-o1-3,20-dione and
+100" ((2., 0.5 in 01315.);
RM? 2.95;; (OH), 5.78;; (.4-bromo-3-ketone), 5.92;;
12u-brom0-A4-pregnene-1lti,2l-diol-3,20-dione ZI-acetate,
can be converted to l113,IZB-epoxy-pregnane-Zl- l-3,20
dione ill-acetate, 11B,l2B-epoxy-A4-pregnene - 3,20-dione
and 1118,12,3-epoxy-A4-pregnene-21'ol-3,20'dione 21-ace
tate, respectively.
45-Brom0-12a-Fiuoropregnane-I1B-0l-3,20-Di0ne (VI )
12u-Chloropregnane-I1?-ol-3,20-Dione (-IIIY)
Following the procedure of Example 5 but substituting
10 50 mg. of 12a-fiuoropregnane?11B-ol-3,20-dione for the
l2a.-c~hloropregnane-11B-ol-3,20-dione, about '70 mg. of
To a solution of 63 mg. of 11?,12;8-epoXy-pregnane
3,20-dione in 10 ml. of pure dioxane is added 2.5 ml. of
4,8-bromo - 12cc - ?uoropregnane-ll?-ol-3,20-dione are ob
2.5 N-aqueous hydrochloric acid. The mixtureis stirred
at room temperature for 1 hour after which 30 ml. of
Similarly, 12a-chloropregnane-11,8,21-diol - 3,20-dione
chloroform is added. Separation of the layers followed by
washing ?of the chloroform-dioxane phase with dilute so
2l-acetate can be convertedto 4?~bromo-l2u-chloropreg~
ill-acetate and lzrd�uoropregnane-l1;9,2l-diol-3,20-dione
dium bicarbonate solution and with water and subsequent
drying over sodium sulfate furnishes after evaporation of
nane-l1;3,2l-diol-3,20-dione _2_1-,_acetate and 4B-brorno
the solvent in vacuo about 65 mg. of essentially pure 12a
chloropregnane-l1B-ol-3,20-dione; M.P. about 241-244?
12a-?uoropregnane-11_�,21-diol-3,20-dione ZI-acetate, re
(dec.). The analytically pure substance has the follow
ing properties: M.P. about 246-248" (dec.); [M1323 +80�
(0., 0.31 in chlf.);
Am?? 2.96;; (OH), 5.83 (8-keto), 5.95 (20-keto)
Analysis.--.Calc?d. for C21H31O3Cl (366.92): C, 68.74;
H, 8.52; Cl, 9.66. Found: C, 69.16; H, 8.50; Cl 9.36.
12u-Chloro-M-Pregnane-l1.;8a0l-3,20!Di0ne [1 Zen-Chloro
1 1 B-Hydmxypmgestemne] (VII)
A solution of 73 mg. of i2a-chloro-4B-bromopregnane
25 11B-o1-3,20-dione and 135 mg. of anhydrous lithium chlo
ride in 5 ml. of redistilled di-methylformamide is heated
at 100� under nitrogen for 21/2 hours. The solution is
1'2a-Fluor0pregnane-1 1 {3-01-3 ,ZO-Dione (IV)
To a mixture of 1 ml. of methanol and 1.5 ml. of liquid
then diluted with chloroform and extracted with water,
dilute sodium bicarbonate solution and again with water.
30 After drying over sodium sulfate the solvent is evaporated
vin vacuo leaving a crystalline residue (about 47 mg.) of
essentially pure 12cc - chloro - A4 - pregnene-1l?-ol-3,20
hydrogen ?uoride is added at ~76", 75 mg. of 115,125
epoxy-p'regnane-i?i,20-dione. The resulting solution is al
lowed to warm up slowly to 0� and at thatkpoint another 35
1 ml. of hydrogen ??uoride is added. The mixture is then
dione. The latter is obtained in pure form after recrystal
lization from acetone-hexaneand has the, following prop
erties: M.P. about 218-220", [u]D23 +:146� (0., ?0.46 in
keptat room temperature for 5 hours during which time
it?assumes' a deep red color. Chloroformis added, the re
sulting solution? is immersed into an ice-bath and the hy
dro?ge'n ?uoride neutralized; by the addition of a suspension
'ofvso'dium bicarbonate in water. Extraction of the chloro~
form solution with water gives after drying over sodium
sulfateand evaporation of the solvent in vacuo about 84
mg. of an amorphous residue. The'latter is chromato
12a. - chloro - A?iipregnene - _11?<ol-3,20-dionepossesses
about one-half the activity of cortisone acetate in ?the rat
?liverglycogen assay.
graphed on 2 g. of sulfuric acid-washed alumina and the
?IZwFIuOrO-M-PregHene-I 1 [3-02.13 ,2 O-Dione ['1 Zea-.Fluoro
11 ?-Hydroxyprogest閞one] ( VIII )
column eluted with 200 ml. of benzene-hexane lily, ?3700
ml. benzene-hexane 3:1 and 250 ml. of benzene. ?The last
two eluants furnishes 12a-lluoropregnane-lidol-3,20
Following the procedure of Example 7 but substituting
72 mg. of 12a.-?uoro-4;8-bromopregnane-11?-ol-3,20-dione
hexane has the following properties: M.P. about 186
for .the v12ot-chloro-ll?-bromopregnane-I1t3-ol-3,20-dione,
dione vwhich after ?recrystallization? from ethyl acetate
.there is obtained about 45 mg. of 12a-?uoro-A4-pregnene
?187�'[�D230哀[9%]54623 0� (6!, 0-29 in. Q1111); '
12a-?uoro籄4-pregnene-1l?-ol-3,20-dione possesses ac
ti-vity equal to hydrocortisone in theliver glycogen assay.
?If '113,1ZB-epoxy-pregnane-Z1-ol-3,2Qione _2l-acetate,
11,3,12B-epoxy-A4-pregnene-3,20fdione, or l1?p,12}3-e'poxy
l118,21-diol-3,20-dione ZI-acetate canbe converted to 120:
chlorocorticosterone 21-acetate and 12m-?uorocorticoster
A4-pregnene-2l-ol-3,20-dionew Zl-acetate is substituted for
95,1l?-epoxy-pregnane-S,ZO-dione in the procedure of
Example 3 or 4, the corresponding IZa-ChlOI?Q-llB-hY
one 21-acetate, respectively.
droxy and 12u-?uoro-11B-hydroxy steroid derivatives are 60
prepared, respectively.
Similarly, 4;8-brorno-12a-chloropregnane - 1113,2l-diol
3,20-dione 21-acetate and 4?-bromo-l2a-?uoropregnane
IZa-Chloro-A4-Pregnenea3J1,20~Trione [1 Zea-Chloro
1 1 -Ket0pr0gester0ne] (IX)
To a solution of 10 mg. of lZa-chloro-M-pregnene
To aysolutionof 50 mg.,of 12a-chloropregnane-?1ltkol
'-3,20-dione_in,1OIml. of glacialacetic?acid'is added a
65 l1;9-ol-3,20-dione in 1 ml. of glacial acetic acid is added
a solution of ?3.5 mg. of chromium trioxide in 1 ml. of
glacial acetic acid. Ten minutes later the chromium
is destroyed by the addition of 1A1 ml. of ethanol
a solution of 25 mg. of bromine in 1 mLof
and the solution concentrated to asyrup in vacuo. The
vglacial aceticv acid. After addition of 30mg. .ofsolid
sodium acetate the solvent is removed in vacuo and the 70 residue is taken up in chloroform and extracted with
water, dilutesodium bicarbonate and again with water.
residue taken up in chloroform. The resulting chloro
After drying over sodium sulfate the chloroform is evap
form solution 'is washed with dilutesodiurn bicarbonate
orated in vacuo and the semi-crystalline residue chro
and" water and after drying over isodium sulfate evap
drop/of ?10% hydrogen bromide inacetieaeid and then
matographed on200 mg. of sulfuric acid~washed alumina.
?consists of essentially pure ' l2b;-chloro-4B-bromopregnane~ 75 Elution of the column with a mixture containing 25%
orated to dryness. The'crys'tallineresidue (about 75mg.)
benzene and 75% hexane furnishes crystalline material
which on recrystallization from 95% ethanol melts at
and 12a-?uorocorticosterone ZI-acetate can be oxidized
to 12a.-chloro-1l-dehydrocorticosterone acetate and 12a
about 170-173";
?uoro-ll-dehydrocorticosterone acetate, respectively.
The invention may be otherwise embodied within the
A315,; 236 mu (?=9,000)
12a.-chloro-A4-pregnene-3,'11,20-trione possesses about 5 scope of the appended claim.
We claim:
1/2 the activity of cortisone acetate in the rat liver glycogen
1 1,6, lZB-epoxypregnane-B,ZO-dione.
12a-Flu0r0-A4-Pregnene-3,1 1,20-Tri0ne [1 Zea-Fluore
1 1 -Ketoprogester0ne] (X)
Following the procedure of Example 9 but Substituting
10 mg. of IZm-?uoro-M-pregnene-l1/3-ol-3,20-dione for
the l2a-chloro-A4-pregnene-l lp-ol-3,20-dione, there is ob
tained 12a-?uoro-A4-pregnene,3,l1,20~trione.
In a similar manner, 12a-chlor0Corticosterone ZI-a-eetate
References Cited in the ?le of this patent
Rechstein ____________ __ May 29, 1951
Wettstein et a1 ________ __ Feb. 19, 1957
Fieser et 211.; Natural Products Related to Phenanthrene,
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