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Патент USA US3087948

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United States Patent ‘ O " ice
3,087,938
Patented Apr. 30, 1963
1
2
3,087,938
9a-chloro group may possess an ll?-chloro ‘or an 11,6
?uoro group but cannot contain an 11 ?-iodo or ll?-bromo
17a-CHLOR0 AND 17oc-BROM0-PROGESTERONES
Hans Reimann, Bloom?eld, and David H. Gould, Leonia,
N.J., assignors to Schering Corporation, Bloom?eld,
N.J., a corporation of New Jersey
No Drawing. Filed Aug. 2, 1961, Ser. No. 128,681
6 Claims. (Cl. 260-3973)
group. This arti?cial restriction is imposed in view of
the limitation of the manufacturing process.
Typical derivatives contemplated by our invention are
progesterones such as 911,11[3-dichloro-l7a-hydroxyproges
terone and 9a-bromo-1LB-chloro-17m-hydroxyprogesterone
and the 17-acetate and 17-caproate esters thereof, as well
This invention relates to novel, therapeutically useful
as other 17-substituted progesterones such as 9a,11?,17ac
3,20-diketopregnanes having an unsaturation in the A 10 trichloroprogesterone, 9a-bromo-1 l?-?uoro - Hot-chloro
,ring, and to methods for their manufacture. In partic
progesterone, 9a,17a-dichloro-1 1 13-?uoroprogesterone, 90L,
1 1 p-dichloro-17a-bromoprogesterone, 9a-iOdO-1 lp-chloro
ular, this invention relates to 17a-substituted-9u,1lB-di
halogeno derivatives of A-ring unsaturated pregnane-3,20
l7a-methylprogesterone, 9ot,1 1 B-dichloro- 17a-methylpro—
diones which exhibit valuable progestational properties.
gestertone; and include their l-dehydro analogs and 19-nor
Novel pregnanes prepared by the process of our inven 15 progesterones such as 9a,1I/S-dichloro-l7a-hydroxy-19
tion are the compounds represented by the following
norprogesterone 17-(?-cyclopentylpropionate) and 9m
formula:
bromo-l 1 tit-?llOIO-17oc-hYdI‘OXY - 19 - norprogesterone 17
acetate, and l-allopregnene derivatives exempli?ed by
9a,l l?-dichloro-l7ot-hydroXy-1-alloprognene - 3,20 - dione
20 17-acetate and 9a-bromo-1lB-chloro-17 a-hydroxy-l-allo
pregnene-3,20-dione 17 ~acetate. Although our compounds
(with the exception of the 17-hydroxy substituted com
pounds which are valuable as intermediates) are, in ‘gen
eral, valuable progestins, the 17a-acyloXy-dihalogenated
25 progesterones of the general formula are the preferred
species and, in particular, 9a,1l?-dichloro-lh-hydroxy
progesterone 17-acetate.
Our novel compounds are prepared by reacting a 4,9
(11)-pregnadiene-3,20-dione substituted at the 17-carbon
30 by hydroxy, acyloxy, halogen or methyl (or a similarly
substituted 1,4,9 ( 1 1 )-pregnatriene-3,20-dione ‘or 1,9 ( 1 1 )
allopregnadiene-3,20hdione) with a suitable halogenating
agent. The starting compounds utilized in this invention
are therefore exempli?ed by compounds such as 17a-hy
35
droXy-4,9(ll)-pregnadiene - 3,20 - dione, 17a-acetoxy-4,9
( l 1 ) —pregnadiene-3,20-dione, l7ot-methyl-4,9 ( 1 1 ) -pregna
diene-3,20-dione, 17oc-‘b1‘0m0- 4,9(11) - pregnadiene-3,20
dione, 17a-chloro-4,9(1l)-pregnadiene-3,20=-dione as well
40 as the l-dehydro analogs of the foregoing, and pregnadi
cues such as 17a-hydroxy-4,9(11)-19-n0rpregnadiene—
3,20-dione and 17a-hydroxy-l,9(1l)-allopregnadiene-3,
wherein X is a halogen having an atomic weight greater
than 19; Y is a halogen having an atomic weight less
than 126 and being at least as electronegative as X;
Q is a member of the group consisting of hydrogen and
‘methyl; ‘and R is a member ‘of the group consisting of
‘methyl, halogen of atomic weight greater than 19 and
less than 126, hydroxy and acyloxy. Our novel com
pounds are thus 9a,11?-dihalogeno derivatives of 170:
‘substituted progesterones, Wot-substituted-l9-norproges
terones, Hot-substituted-l-allopregnene-3,ZO-diones and
17 u-substituted-1,4~pregnadiene-3 ,20-diones.
Illustrative of the 17a~acyl groups in the 17a-‘3CY1OXY
derivatives contemplated by our invention are lower alka
noates such as formate, acetate, propionate, butyrate, iso
butyrate, valera-te, isovalerate, pivalate, caproate, isocap
roate, emanthate; substituted alkanoates such as ?-cyclo
pentylpropionate, cyclohexylacetate, ethoxyacetate, phen
ylacetate, phenoxyacetate; unsaturated ‘acyl radicals such
20-dione 17-acetate.
The starting compounds thus necessarily possess a Ali-11
bond and, in the case of 17 a-hydroXy-4,9( l 1)-pregnadiene
3,20-dione (17a~hydroxy- 9(11) - dehydroprogesterone),
the process of preparing this 9(1l)—dehydroprogesterone
is described in the literature. The other aforementioned
starting 9(1l)-dehydro starting compounds are prepared
by a combination of processes analogous to those de
scribed in the literature. The 17a-acyloXy-9(11)-dehy
droprogesterones (i.e. the 17a-acyloXy-4,9(11)-pregnadi
ene-3,20-diones) are prepared from 17a-hydroXy-9(11)
dehydroprogesterone according to known esteri?cation
techniques with a suitable acid such as acetic in the pres
ence of tri?uoroacetic anhydride or with a suitable acid
anhydride (such as acetic) in the presence of an acidic
catalyst such as p-toluenesulfonic acid. When other acids,
such as caproic or B-cyclopentylpropionic are used in
place of acetic in these esteri?cation procedures, the cor
responding 17ec-6St61‘ is obtained, i.e. the 17ot-caproate and
as acrylate and crotonate; aromatic acyl radicals such as
benzoate and toluate, as well as the residues of dibasic
acids such as succinate and phthalate and of fatty acids
such as undecanoate and laurate. The term “acyloxy”
pregnadiene-3,20-dione.
progesterone derivative of our invention containing a
the reagent used,‘ l7a-methyl-21-hydroxy-4,9(l1)~pregna
17 a-?-cyclopentylpropionate
of
170t-hYdI‘0Xy - 4,9(1l)
Some 9(11)-dehydro starting compounds are prepared
thus includes acyl radicals of monocarboxylic and dicar 65 through the ll-hydroxylated proge‘sterones, for example,
17a-methyl-9 ( l 1 ) -dehydroprogesterone ( 17u-methyl-4,9
boxylic acids containing up to 12 carbon atoms.
(1l)-pregnadiene-3,ZO-dione) is prepared from Not-meth
As stated heretofore, the llp-halogen present in a com
yl-l16,21-dihydroxy-4-pregnene-3,ZO-dione ( 17u-methyl
pound of the general formula or an analog thereof, must
corticosterone) by an initial dehydration as e?ected by
be at least as electronegative as the halogen present in
the 9m-positi0n; ?uorine being the most electronegative 70 reagents such as methanesulfonyl chloride in the presence
of pyridine which yields, if methanesulfonyl chloride is
halogen, and iodine the least electronegative. Thus, a
3,087,938
3
4
diene-3,20-dione 2l-methanesulfonate. Conversion of the
21-ester to the Zl-desoxy compound is effected by treat
acetone yielding the corresponding 21-iodo derivative
which, upon addition of acetic acid, for example, yields
lunata. The 1l?-hydroxy-l7a-chloroprogesterone thus
obtained (i.e. Curvularia lzmam is the microorganism
used) is dehydrated by procedures described heretofore
to give the necessary intermediate, 17a-hydroxy-9(ll)
dchydroprogesterone ( 17 ot-hydroxy—4,9 ( 1 1 ) -pregnadiene
the requisite intermediate, 17tx-methyl-9(11)-dehydropro
3,20-dione).
ment of the ester with, for example, sodium iodide in
gesterone.
The l-dehydro intermediates, i.e. 17oc-methyl-1,9( 11)
bisdehydroprogesterone ( l7a-methyl-l,4,9(11)-pregnatri
Another 17-substituted-9(l1)-dehydro starting com
pound prepared from a 2l-hydroxy intermediate is 170:
ene-3,20~dione) , 17a-bromo-1,9(11)-bisdehydroprogester~
hydroxy - 1,9(11)-bisdehydroprogesterone (17a-hydroxy 10 one (17a-bromo-1,4,9(11)-pregnatriene-3,ZO-dione), 17a
l,4,9(11)-pregnatriene-3,20-dione). The starting com
chloro - 1,9(11)-bisdehydroprogesterone (l7a-Chl01'O-l,4,
pound 17a,21-dihydroxy-1,9( 11)-bisdehydroprogesterone
9(11) - pregnatriene - 3,30-dione), 17a-hydroxy-1,9(ll)
21-acetate (17a,21-dihydroxy-1,4,9(11)-pregnatriene-3,20
bisdehydroprogesterone (17a - hydroxy-1,4,9(11)-pregna
triene-3,20-dione), and 17ot-acyloxy intermediates such as
dione 21-acetate) is hydrolyzed to the corresponding 21-01,
170:,21 - dihydroxy-1,9(11)-bisdehydroprogesterone (1704, 15 170a - acetoxy - l,9(11)-bisdehydroprogesterone (l7a-hy
21 - dihydroxy - 1,4,9(11)-pregnatriene-3,ZO-dione). The
droxy-1,4,9(11)-pregnatriene-3,20-dione 17-acetate are
conveniently prepared from the corresponding 17a-substi
latter is then ‘treated with a sulfonating agent, such as p
tuted-9(11)-dehydroprogesterone by microbiological de
toluenesulfonyl chloride in pyridine (or methanesulfonyl
hydrogenation with an organism such as, for example,
chloride in methylene chloride-pyridine) which yields the
corresponding C-21-tosylate (p-toluenesulfonate) or 20 Corynebacterium simplex (A.T.C.C. 6946) in a manner
similar to that described in U.S. Patent No. 2,837,464, or
mesylate (methanesulfonate). The tosylate is replaced
by chemical oxidation through the use of such reagents as
chloranil or selenium dioxide, or by halogenation followed
by iodine by means of sodium iodide in acetone, the 21
iodide upon subsequent reaction with sodium bisul?te
by dehydrohalogenation.
solution yielding the 21-desoxy compound l7a-hydroxy-1,
9(11) - bisdehydroprogesterone (17a-hydroxy-1,4,9(11)
pregnatriene-3 ,20-dione) .
When an ll-hydroxy intermediate is not available, as in
the case of 11/8-hydroxy-17a-bromoprogesterone, the
25
Halogenating agents suitable for use in our process are:
(1) Molecular halogens having a molecular weight
greater than 38 and less than 253. This class includes
heteroatomic halogen molecules such as iodine mono
chloride as well as isoatomic halogen molecules such as
hydroxyl group is introduced microbiologically into the
ll-desoxy analog, 17a-bromoprogesterone, by means of 30 chlorine and bromine. The molecular halogen employed
a microorganism such as Curvularia lunata (N.R.R.L.
may be used alone or in admixture with a halide anion.
2380) by procedures analogous to those described in U.S.
Patent No. 2,658,023. The ll?-hydroxy-lh-bromo
In reactions employing isoatomic molecular halogens, an
anion corresponding to the molecular halogen is used.
For example, in reactions using molecular chlorine, a
progesterone thus produced upon treatment with, for ex
ample, lithium bromide in glacial acetic acid yields 170c 35 suitable chloride salt such as lithium chloride or hydro
chloric acid are suitable anion sources. In reactions which
bromo - 9(11)-dehydroprogesterone (l7oc-b1‘0II10-4,9(11)—
employ a heteroatomic molecular halogen, a source of the
pregnadiene-3,20-dione). In like manner, 17m-acetoxy—
1-allopregnene-3,20-dione (17a-hydroxy-1-allopregnene-3,
more electronegative anion is used, i.e. a suitable chloride
salt or hydrochloric acid is used in a reaction employing
20-dione 17-acetate) is ll-hydroxylated by means of
iodine monochloride.
Curvularia lmzata to give 11B,17a-dihydroxy-1-allopreg
an agent such as methanesulfonyl chloride in pyridine
(2) Addition compounds of molecular halogens, said
molecular halogens having a molecular weight greater than
yields 17a-acetoxy-1,9( 11)-.allopregnadiene-3,20-dione.
38 and less than 253.
nene-3,20—diode 17-acetate which when dehydrated with
Examples of such addition com
pounds are pyridinium bromide perbromide, pyridinium
Our i9(ll)-dehydro starting compounds may also be
prepared by introducing an lla-hydroxyl group into an 45 chloride perchloride, dioxane dibromide, iodobenzene di
chloride, and the like.
ll-desoxy progesterone through the action of a micro
organism such as Rhizopus nigricans (A.T.C.C. 6227b)
(3) N-haloamides in admixture with a halide anion,
the halogen in the halide being at least as electronegative
using procedures analogous to those described in U.S.
Patent No. 2,602,769. Subsequent treatment of the lla
as the halogen cation in the N-haloamide, and the com
bined molecular weight of said halogens being greater
hydroxyprogesterone derivative so obtained with a sulfonyl
sulfonyl chloride yields the corresponding lla-sulfonate
than 38 and less than 253. N-haloamides used in these
mixtures are such as N-chlorosuccinimide, N-bromo
which when treated with a base such as pyridine gives the
acetamide, dimethyl-N,N-dibromohydantoin, N-iodosuc
chloride such as methanesulfonyl chloride or toluene
desired 9(11)-dehydroprogesterone derivative.
cinimide and the like. Examples of mixtures of N
The intermediate l7oc-ChlO1‘O-9 ( l 1)-dehydroprogester 55 haloamide and a halide are such as N-chlorosuccinimide
one is obtained from 3?-hydroxy-5-pregnene-20-one 3
and hydrogen chloride; N-bromoacetamide and hydrogen
acetate by employing known chemical techniques. Typi
bromide; N-bromoacetamide and lithium chloride; N
cally, 35-hydroxy-5-pregnene-20-one 3-acetate when treat
bromoacetamide and hydrogen ?uoride; N-iodosuccini
ed wtih acetic anhydride and p-toluenesulfonic acid is
mide and sodium chloride.
These mixtures may have
‘enol-acetylated to give 3/3,20-dihydroxy-5,17(20)-pregna
60 more than one source of halide ion such as in the reagent
diene-3,20-diacetate which, upon chlorination, by a stand
combination N-chlorosuccinimide, hydrogen chloride and
lithium chloride.
Molecular halogens (both isoatomic and heteroatomic)
a‘rd procedure such as with chlorine in carbon tetra
chloride yields 50:,65,17a-trichloro-3?-hydroxypregnane
20-one 3-acet-ate. Dehalogenation of the trichloro inter
mediate utilizing a reagent such as sodium iodide in ace
tone gives l7a-cl1loro-313-hydroxy-S-pregnene-ZO-one 3
acetate which is hydrolyzed and oxidized upon treatment
with the organism Flavobaclerium dehydrogenans (Rut
gers collection No. 130) in a manner analogous to the
such as chlorine, bromine and iodine monochloride, and
65 molecular halogen addition compounds such as iodo
benzene dichloride or pyridinium bromide perbromide
employed in our process may be used directly in their
commercially available form, in which case they are added
directly to the reaction mixture either alone or in a
procedures outlined in Union of South African Patent No. 70 suitable non-reacting solvent such as acetic acid or tetra
3462/55 to give l7a-chloroprogesterone. The double
hydrofuran. The halogenating agent is preferably used
bond between C-9 and C-11 is then introduced into the
in approximately equivalent quantities to that of the
17a-chloroprogesterone through the corresponding 11
steroid.
hydroxy-derivative which is prepared microbiologically,
Alternatively, the halogenating reactant may be pre
for example, by means of Rhizopus nigricans or Curvularia
pared in situ. For example, 0.9-1.2 equivalents of halo
8,087,938
5
6
‘gen cation (based on the amount of steroid) such as ob
tained from N-bromosuccinimide is added to a reaction
mixture containing a halogen anion of greater or equal
gen'ated hydrocarbons such as methylene chloride and
chloroform, saturated ethers such as tetrahydrofuran and
dioxane, and inert solvents such ‘as dimethylsulfoxide, as
well as suitable mixtures of these solvents.
electronegativity than the cationic reagent. The halogen
anion may be supplied by a hydrohalic acid or by a salt
?uoride, or by mixtures of a hydrohalic acid with an
alkali metal halide. Whenever an acid is the source of
Further, when carrying out the above-described process
in a halogenated hydrocarbon solvent such as methylene
chloride, chloroform or carbon teterachloride, the yield
and purity of the dihalogenated progesterone obtained is
a halogen anion, approximate theoretical quantities are
greatly increased by adding pyridine to the reaction mix
such as sodium bromide, lithium chloride, potassium
generally used; whereas if a salt is used as the halogen 10 ture. Preferably from one to ?ve equivalents of pyridine
anion source it may be present in large excess. Such an
is added, based on the amount of steroid being converted.
excess of anion is frequenly useful to obtain an increased
Other organic basic agents which may also be used in con
yield or greater purity of product.
junction with a halogenated hydrocarbon solvent are
Thus, our novel compounds may be prepared by any
aromatic tertiary amines such as lutidine, collidine, alkyl
one of several methods. For example, 9a,11?~>dichloro 15 substituted pyridines, and the like. The reaction is usually
l7a-hydroxyprogesterone l7-acetate may be prepared from
carried out intitially at |~20° C. with subsequent warning
17a-hydroxy - 9(11) - dehydroprogesterone 17-acetate by
to about room temperature.
The reaction time may be
utilizing such reagents, and combinations as (1) chlorine
as short as ?ve minutes or as long as several hours. In
general the optimum reaction time is about one hour.
and lithium chloride, (2) N-chlorosuccinimide and lith~
ium chloride, (3) sodium chloride, N-chlorosuccinimide 20 Our process whereby a l7-substituted-9(11)-dehydro
together with hydrogen chloride, (4) chlorine alone, (5)
progesterone is converted to a l7-substituted-9a,11B-di
halogeno progesterone is also applicable, as mentioned
chlorine and hydrogen chloride, and (6) iodobenzene
dichloride.
previously, to 17-substituted-9(11)-dehydro-19-norproges
An alternate route for preparing the 17a-acyloxy com
terones. With the aforementioned 9(11)-dehydro-19
pounds of our invention is halogenating 17a-hydroxy 25 norprogesterones there are produced the novel progesta—
9(ll)-dehydroprogesterone (or the l-dehydro analog or
tional agents, 9oc-X-1l?-Y-l7oc-R-19-11OI‘PI‘OgESteI‘OI1?S
19-nor analog thereof or a 17ot-hydroxy—1,9(l1)-allo
wherein X, Y, and R are as heretofore described. Thus,
pregnadiene-3,20-dione) by any of the above described
17a — methyl - 9(11) - dehydro-l9-norprogesterone (17cc
halogenating methods of our invention, with subsequent
methyl - 19 - nor - 4,9(11)~pregnadiene-3,20-dione), 170c
esteri?cation of the '9a,1l?-dihalogenod7a-hydroxypro 30 bromo - 9(11)-dehydro-19-norprogesterone (l7oc-br0m0
gesterone (or the l-dehydro or 19-nor analog or the 90:,
19 - nor - 4,9(11)-pregnadiene-3,20-dione), 17a-chloro-9
11,8 - dihalogeno-17a-hydroxy-l-allopregnene-3,ZO-dione)
( 1 1 ) -dehydro-19-norprogesterone
thereby obtained. ‘In this manner l7a-hydroxy-9‘(11)-de
hydroprogesterone, upon chlorination with a reagent such
9 ( 1 1 ) —pregnadiene-3,20-dione) , l7ot-hydroxy-9 ( 11 )-dehy
dro - 19 - norprogesterone
as chlorine in carbon tetrachloride in the presence of 35
pregnadiene-3,20-dione) and 17ot-acyloxy-9(11)-dehydro~
pyridine, yields 9a,1IB-dichloro-l7a-hydroxyprogesterone
( l7a-chloro-19-nor-4,
(17a-hydroxy-19-nor-4,9(11)
19-norprogesterones ( 17 a-acyloxy-19-nor-4,9 ( 11)-pregna
which, when esteri?ed with acetic acid and tri?uoroacetic
diene-3,20-diones), when reacted with chlorine in carbon
anhydride, for example, gives 9u,llB-dichl-or0-l7u-hy
tetrachloride in the presence of pyridine, for example, are
droxyprogesterone 17-acetate. Other acids may be sub
converted to their respective 9a-11B-dichloro derivatives.
stituted for acetic acid in the esteri?cation step torobtain. 40
When preparing a 9a,11j3-dihalogenated il7u-acyloxy
the corresponding l7a-acyloxy dihalogenated progester
19-’norprogesterone by our process the halogenation step is
one.
Our novel halogenating process is also useful in pre
paring the 1,4-pregnadienes of our invention. Thus, a 17
substituted-9051 1p-dihalogeno-l-dehydroprogesterone such
as, for example, 9a,ll?-dichloro-17a-methyl-1-dehydro
progesterone is prepared from l'7a-methyl-1,9(11)-bisde
hydroprogesterone by utilizing any one of the six reagents
preferably performed on the corresponding l7a-hydroxy
9(l1)-dehydro intermediates prior to esteri?cation of the
17-hydroxy group. Thus, 17a-hydroxy-9(11)-dehydro
45. progesterone is ?rst converted to a 9oc,1l,6-dihalogenated
17a-hydroxy-19-norprogesterone which is then esteri?ed
by methods heretofore described to give the 9‘(11)-di
halogenated-l7a-acyloxyprogester0ne.
and combinations listed previously. In addition, our novel
Our novel dihalogenated 17-substituted progesterones,
halogenated l-dehydroprogesterones are obtained from 50. their l-dehydro and l9-nor analogs, as well as the dihalo
the corresponding halogenated progesterones by micro
genated '17-substituted-l-allopregnenes ‘of our invention
biological or chemical dehydrogenation techniques as
(except those having a hydroxy group at C-17) are very
heretofore described. Thus, 9a,1l?-dichloro-lh-methyl
progesterone is converted to 9a,1l?-dichloro-17a-methyl
active progestational agents being speci?c in their action,
Our process, whereby a 17-substituted-9(l1)-dehydro
and devoid of androgenic, estrogenic or corticoid activity.
That our compounds. have progestational activity at all
is surprising in view of the well known fact that substitu
tion in ring~C of progesterone and its derivatives such as,
progesterone is converted to a 17u-substituted-9u,1l?-di
for example,‘ ll-hydroxyprogesterone and the ll-acyloxy
l-dehydroprogesterone by the action of a culture of the
microorganism Corynebactei'ium simplex.
halogeno derivative is generally carried out in the presence
derivatives thereof eliminates progestational activity or
of a non-reacting solvent at temperatures ranging from 60 reduces it to such an extent that the compounds are useless
5 ° C. to 50° C. with reaction times varying from one-half
for therapeutic purposes. Our ring-C halogenated-17-sub
to 24 hours, depending on the reagents involved. It is
stituted progesterones, on the other hand, are signi?cantly
preferred that the halogen cation source be present in
more active than progesterone by the intramuscular route.
amounts of 0.9-1.2 equivalents based upon the amount
Moreover, orally our compounds are several times as
of steroid. The choice of solvent in each reaction is 65 active as ethisterone, the known standard progestational
agent.
,
naturally determined by the solubility of the reactants in
the process. A preferred reaction condition employs
In addition to being active both orally and intramus
glacial acetic acid as the sole or major solvent with the
cularly, our halogenated progestins possess the added ad
reaction being carried out at room temperature for a
vantage of having a minimum effect on water, sodium
process either alone or in combination with acetic acid.
Other solvents which may be employed include lower
Our therapeutically active compounds are useful for
the treatment of conditions requiring progestational
aliphatic acids such as propionic and diethylacetic, halo
agents such as the maintenance of pregnancy, or’ treat
70 and potassium metabolism. Thus, they may be admin
period of approximately two hours.
Although glacial acetic acid is frequently the preferred
istered without causing the usual side e?ects associated
with electrolyte imbalance.
solvent, other solvents are used in our dihalogenation
3,087,938
8
ment of functional dysmenorrhea, premenstrual tension,
habitual or threatened abortion.
EXAMPLE 3
When administered
1 7a-Hydr0xy-4,9(1l ) -Pregnadiene-3,20-Dione
orally, our compounds are preferably used in the form
of tablets containing from 1 to 10 mg. together with the
1 7- ( B~Cycl0pentylpr0pi0nate)
To a solution of 500 mg. of 17a-hydroxy-4,9(11)
excipients such as starch or milk sugar. For subcutane
ous and intramuscular administration, solutions or suspen
pregnadiene-3,20-dione in 10 ml. of ?-cyclopentylpropi
onic acid and 2.5 ml. of 18-cyclopentylpropionic anhydride
sions of our compounds with a non-toxic liquid vehicle
in a vessel flushed with nitrogen, there is added 200 mg.
are used. The dosage required may vary with the indi
of p-toluenesulfonic acid with stirring at a temperature
cations being treated and may range from about 5 to
25 mg. daily.
10 of about 20° C. The reaction mixture is allowed to stand
for 4 hours, then poured into ice-water. Excess acid is
Our halogenated progestins are also valuable in the
neutralized with sodium carbonate, and the crude mixture
veterinary ?eld for treating conditions in both large and
is extracted with ether. The ether extracts are com
small animals which require a progestational agent. In
bined, washed with water, dried over magnesium sulfate,
breeding animals, for example, our compounds are use
ful in preventing threatened abortion. Additional uses 15 ?ltered, and concentrated to a residue. The residue is
crystallized from methanol to give 17ot-hydroxy-4,9(1l)
are in controlling egg and milk production by regulating
the cycle of chickens and cows by the administration of
our progestational agents.
The 17a-hydroxy compounds of our invention, i.e.
pregnadiene-3,20-dione l7-(?-cyclopentylpropionate)
max.
the l7a-hydroxy - 90:,1119 - dihalogenoprogesterones, the 20
EXAMPLE 4
9a,]1?-Dichl0ro-l 7a-Hydroxyprogesterone
l7a-hydroxy-9a,ll?-dihalogeno-l - dehydroprogesterones,
the 17a-hydroxy-9a,1IB-dihalogeno-l9-norprogesterone,
and the '17a-hydroxy-9a,1l?-dihalogeno-l-allopregnene
1 7-A cetate
A solution of l g. of l7a-hydroxy-4,9(ll)-pregnadiene
3,20-dior1es, are valuable mainly as intermediates in the
preparation of the corresponding 17a-acyloxy com 25 3,20-dione ‘17-acetate (the compound of Example 1) and
4 g. of lithium chloride in. 40 ml. of glacial acetic acid is
pounds, which are active progestational egents.
cooled to about 10° C. and there is added 250 mg. of
The following examples are illustrative of the pro
hydrogen chloride in 1 ml. of tetrahydrofuran followed
cedures employed in preparing the compounds of this
by 395 mg. of. 96% N-chlorosuccinimide. The solution
invention, but are not to be construed as limiting the
is stirred at room temperature for 20 minutes in the
scope thereof; the scope of our invention being limited
absence of light, then is poured into ice-water with stir
ring. A precipitate forms which is ?ltered, washed with
only by the appended claims.
This application is a continuation-in-part of our co
water, triturated with ether and crystallized twice from
pending application, Serial No. 113,089, ?led May 29,
acetone-hexane to give 901,11/3-dichloro-17a-hydroxy
progesterone 17-acetate, M.P. 224~233° C. dec., [ab-l
129° (chloroform)
1961.
EXAMPLE 1
AMeOH
m...
1 7a~Hydr0xy-4,9(1 1 ) -Pregnadiene-3,20-Di0ne
238 III/L
1 7-Acetate
e=17,000.
A'nalysis.-Calcd. for C23H30O4Cl2: C, 62.58; H, 6.85;
To a solution of 5.0 g. of 17a-hydroxy-4,9(11)-preg 40
nadiene-3,20-dione in 50 ml. of acetic acid there is added
10 ml. of tri?uoroacetic anhydride. The solution is
heated on the steam bath for 45 minutes, then is poured
into ice-water. A solid separates which is ?ltered and
crystallized from acetone-ether to give 17a-hydroxy 45
4,9(11)-pregnadiene-3,20-dione 17-acetate, M.P. 238
241° C., [u]D+5O° (chloroform);
239 mp.
e=17,000.
Analysis.-Calcd. for CZ3H3OO4: C, 74.56; H, 8.16.
Found: C, 74.64; H, 8.07.
EXAMPLE 2
l 7a-Hydr0xy-4,9 (11 )-Pregnadiene-3,20-Dione
m1. of acetic acid to a mixture of 1 g. of 17a-hydroxy
4,9(11)-pregnadiene-3,20-dione l17-acetate and 4 g. of
lithium chloride in 20 ml. of glacial acetic acid. The
mixture is stirred at room temperature for 3 hours, then
poured into ice-water with stirring. A solid product pre
cipitates which is ?ltered, washed with water, triturated
50 with ether, and crystallized from acetone-hexane to give
9a,l l?-dichloro-17a-hydroxyprogesterone 17-acetate.
A second alternative for the preparation of the com
pound of this example isby reacting 1 g. of 17a-hydroxy
4,9(11)-pregnadiene-3,20-dione l7-acetate dissolved in
55 30ml. of carbon tetrachloride with 1.8 m1. of chlorine in
1 7-Capr0ate
A mixture of 1.0 g. of 17a-hydroxy-4,9(11)-preg
nadiene—3,20-dione and 5 ml. of caproic acid is heated at 60
80° C., in the presence of 1.0 ml. of tri?uoroacetic an
hydride, for 45 minutes. The mixture is poured into ice
waiter and the excess acid neutralized with sodium car
Cl. 16.06. ‘Found: C. 62.63; H, 7.03; CI, 15.90.
Alternatively, the compound of this example is pre
pared by adding a solution of 200mg. of chlorine in 30
carbon tetrachloride (11'1 mg./ml.) in the presence of
0.65 ml. of pyridine at -—20° C. The mixture is stirred
at ~20“ C. for 15 minutes, then is allowed to warm to
room temperature over a period of one-half hour. The
solution is ?ltered and the ?ltrate concentrated in vacuo
to an oily residue. Trituration of this residue with ether
yields solid material which is crystallized from acetone
hexane to give 9a,1l?-dichloro-17a-hydroxyprogesterone
bonate. The crude reaction mixture is extracted with
17-acetate.
methylene chloride. The organic extracts are combined
65
EXAMPLE 5
and concentrated to a residue which is chromatographed
on Florisil. The material eluted with 10-25% ether in
9a-Br0m0-Jl?-Chlor0-1
7a-Hydr0xyprogester0ne
hexane is combined and crystallized from pentane to
1 7-A cetate
yield
17a-hydroxy-4,9(11)-pregnadiene-3,20-dione 17
caproate, M.P. 126~128° C.
One gram of 17a-hydroxy-4,9(1l)-pregnadiene-3,20
70 dione l7-acetate (the compound of Example 1) and 4
g. of lithium chloride is dissolved in 50 ml. of glacial
X2552}! 239 my
acetic acid and there is added 420 mg. of N-bromoacet
amide. The mixture is stirred at room temperature and
(e=‘l6,800), [u]'D+42° (chloroform).
Analysis.—Calcd. for C27H38O4: C, 76.02; H, 8.98.
a slow stream of gaseous hydrogen chloride is passed over
75 the surface until‘ the solution begins to darken (10-30
Found: C, 76.11; H, 8.94.
3,087,938
10
9
crystallized and recrystallized twice from acetone-hexane
to give 90¢,1lp-dibromo-17u-hydroxyprogesterone 17*
acetate,
seconds). ' The hydrogen chloride gas is removed and the
solution is stirred in the dark at room temperature for
about ‘10 minutes. The solution is poured into ice-water
with stirring and the resultant solid is ?ltered, washed
with water, and crystallized from acetone-hexane to give
9a-bromo-ll?-chloro-l7u-hydroxyprogesterone 17 - ace
AM?“ 241 my
EXAMPLE 1o
tate, M.P. 124-129” C. dec., [adv-142° (chloroform)
9a-I0do-1 1 ?-Chloro-I 7 a-Hydroxyprogesterone
e=l5,600.
Analysis.--Calcd. for C23H30O4B1'C1: C, 56.85; H,
6.22; Br, 16.45; Cl, 7.30. Found: C, 56.83; H, 6.28; Br,
16.07; Cl, 7.35.
EXAMPLE 6
QOL-BI'OITlO-J 1 ,B-Fluoro-I 7a-Hydr0xyprogesterone
1 7-A (:etate
To 1a solution of l g. of 17a-hydroxy-4,9(11)-preg
10
nadie‘ne-3,20-dione 17-acetate (the compound of Exam
ple 1) in 40 ml. of tetrahydrofuran which is chilled to
0° C. there is added 3 drops of perchloric acid and 3 g. of
lithium chloride followed by the dropwise addition of a
15 solution of 470 mg. of iodine monochloride in 5 ml. of
tetrahydrofuran. The reaction mixture is stirred at room
1 7-A cetate
temperature of 5 hours, then poured into ice water. A
gummy precipitate forms which is dissolved in methylene
To a solution of 1 g. of 17a-hydroxy-4,9:(11)-preg
nadiene-3,20-dione l7-acetate (the compound of Example
‘chloride, the solution is warmed, decolorizing carbon
1) and 425 mg. of N-bromoacetamide in 50 ml. of di
added, then ?ltered. Pentane is added to the clari?ed
ethylacetic acid there is added a solution of 500‘ mg. of 20 methylene chloride solution and a precipitate is formed
hydrogen fluoride in 4.7 ml. of chloroform-tetrahydro
which is ?ltered and crystallized from acetone-hexane
furan.
The solution is stirred at room temperature for
to give 9a-iodo-1l?-chloro-l7a-hydroxyprogesterone l7
2 hours, then poured into ice-water with stirring. The
acid is neutralized by addition of sodium bicarbonate and
acetate.
EXAMPLE 11
a resinous precipitate forms from which the aqueous solu
9a-Chl0r0-1 1 ?-Fluoro-I 7 -Hy droxyprogesterone
tion is decanted. The precipitate is then dissolved in
1 7-Acetate
methylene chloride and the solution is washed with 5%
aqueous sodium hydroxide, then with water, is dried over
magnesium sulfate, ?ltered and concentrated in vacuo. 30 To a solution of 500 mg. of 17a-hydroxy-4,9(l1)-preg—
nadiene~3,20-dione l7-acetate (the compound of Exam
The resultant residue is triturated with pentane, ?ltered
ple l) in 25 ml. of diethylacetic acid there is added
and crystallized from methylene chloride-pentane to give
195 mg. of N-chlorosuccinimide followed by a solution
of '620 mg. of hydrogen ‘fluoride in 3.2 m1. of a mixture
9a-bromo-l1p-?uoro-l7a-hydroxypr-ogesterone l7-ac‘etate,
MJP. 176-180° C. dec.,
of tetrahydrofuran and chloroform. The reaction mix
35 ture is stirred at room temperature for 48 hours, then is
poured into an aqueous sodium carbonate solution. The
mixture is extracted with methylene chloride. The or
ganic extracts are combined and evaporated to a residue
which is chromatographed on silica gel. The product
Analysis.—Calcd. for C23H30O4BrF: Br, 17.03; F, 4.05.
Found: Br, 17.56; F, 3:85.
EXAMPLE 7
40 eluted with 20% ether in hexane is crystallized with ace
tone-hexane to give 9a-chloro-11?-?uoro-17-hydroxypro
90:, 11 ?-Dich 10r0-1 7 a-Hy droxyprogesterone
gesterone 17-acetate,
1 7-Capr0ate
17a~hydroxy-4,9 ( l 1 ) -pregnadiene-3,20-dione 17 -capro
ate (the compound of Example 2) is reacted with 165
mg. of N-chlorosuccinimide, hydrogen chloride and
238 m,“
EXAMPLE 12
lithium chloride in the manner described in Example 4.
The resultant product is isolated and puri?ed in the de
. 9a-l0d0-l1/3-Fluoro-1 7-Hydr0xypr0gester0ne
.1 7-Acetate
scribed manner to give 9a,1l?-dichloro-l7a-hydroxypro
gesterone 17-caproate,
50
nadiene-3,20-dione 17~acetate (the compound of Exam
ple 1) and 3 .g. of potassium ?uoride in 40 ml. of dimeth
ylsulfoxide there is added 320 mg. of N-iodosuccinimide.
EXAMPLE 8
9a,] 1 fl-Dichloro-l 7 a-Hydroxy progesterone
1 7-( ?-Cyclopentylpropionate)
The reaction mixture is stirred at room temperature
55
17 a-hydroxy-4,9( l 1 )-pregnadiene - 3,20 - dione 17-(5
the ?ltrate concentrated in vacuo.
reacted with chlorine and lithium chloride in the manner
of Example 4 and the resultant product isolated and
puri?ed to give 9a,1LB-dichloro-17a-hydroxyprogesterone
for 16 hours, poured intovice-water and extracted with
methylene chloride. The combined organic extracts are
warmed, decolorizing carbon added, then ?ltered, and
cyclopentylpropion-ate), the compound of Example 3, is
17-(?-cyclopentylpropionate),
To a solution of 500 mg. of 17a-hydroXy-4,9(11)-preg
The resultant res
idue is chromatographed on silica gel. The fraction
60
eluted with 50% ether-hexane yields 9a-iodo-ll?-?uoro
17-hydroxyprogesterone l7-acetate.
'
- ,
EXAMPLE 13
KAISER 238 my.
17a-Hydroxy-1,4,9 (11 ) -Pregnatriene-3,20-Dione
EXAMPLE 9
9a,]1,B-Dibrom0-1.7a-Hydr0xyprogesterone
1 7-A cetate
65
(A) 17a,21~DIHYDROXYy-1,4,9(lb-PREGNATRIENE
‘
ago-moms
A solution of 2 g. of 17a,21-dihydroxy-l,4,9(11)-preg
natriene-3,20~dione ZI-acetate in 100 ml. of a 3:1 meth
ple 1) and 4 g. of lithium bromide in 50 ml. of acetic 70 anol chloroform mixture is chilled in ice to which there
is added dropwise 52 ml. of 0.1 N sodium hydroxide
acid there is added 400 mg. of N-‘bromoacetamide fol
solution ‘(one equivalent). The reaction mixture is
lowed by a solution of 220 mg. of hydrogen bromide in
stirred at 0° C. for 10 minutes, then diluted with water
4.3 ml. of acetic acid. The mixture is stirred at room
To a solution of 1 g. of 17a-hydroxy-4,9'(11)-preg
nadiene-3,20-dione 17-acetate (the compound of Exam
and extracted with methylene chloride. Evaporation of
temperature for one hour, then is poured into ice-water.
A solid forms which is ?ltered, washed with water, then 75 the solvent and crystallization of the residue from ace
3,087,938
11
12
tone-hexane affords l7a,2l-dihydroxy-l,4,9(ll)-pregna
triene-3,20-dione, M.P. 220-228C. (dec.);
The flask is incubated at 28° C. for 24 hours. A sec
AM°°H 238 mp
sterile 17a - hydroxy - 1,4,9(ll) - pregnatriene - 3,20
ond 300 ml. Erlenmeyer ?ask containing 150 mg. of
dione 17-acetate in 5.0 ml. acetone is inoculated with
e=15,500.
Analysis.—Calcd. for C21H26O4: C, 73.66; H, 7.66.
Found: C, 73.58; H, 7.54.
(B) 17a-HYDROXY-1,4,9 (1‘1)-PREGNATRIENE
3,20-DIONE
A solution of 10 g. of 17a,21~dihydroxy-1,4,9(11)
the 24-hour culture of Corynebacterium simplex (A.T.C.C.
6946). The culture-containing steroid solution is in
cubated for 48 hours at 28-30" C.
After termination of the transformation period, the
pH is 7.2-7.3. The culture is now directly extracted
10 with 3 equal volumes of CHCl3, the solvent volumes
pregnatriene-3,-20-dione (the compound of Example 13A)
combined and concentrated on a steam bath to a residue
in 100 ml. of dry pyridine is chilled in a Dry Ice-acetone
bath vand there is added a solution of 6 g. of p-toluene
sulfonyl chloride in 50 ml. of methylene chloride. The
mixture is stirred in the cold bath for 2 hours and then
kept at »-20° C. for 24 hours. At the end of this time,
the reaction mixture is diluted with methylene chloride
and the solution washed ?rst with water, then with 10%
which is crystallized from acetone-hexane to give 9a,11f3
dichloro-l7a-hydroxy-1,4-pregnadiene-3,20-dione l7-ace
tate.
A second alternative method for the preparation of
the compound of this example is as follows.
17a-hydroxy-1,4,9‘( ll)-pregnatriene - ‘3,20 - dione (the
compound of Example 13B) is reacted with 220 mg.
sulfuric acid, 10% sodium bicarbonate, very dilute hy
of chlorine gas in carbon tetrachloride in the presence
drochloric acid and ?nally with water. The solution is 20 of pyridine in the manner of the ‘alternative procedure
dried over a magnesium sulfate, ?ltered and concentrated
of Example 4 to give 9a,1l?-dichloro-17a-hydroxy-1,4
to a residue which is dissolved in acetone. The acetone
pregnadiene-3,20-dione, M.P. 235-239° C. dec.
solution is warmed on the steam bath, decolorizing car
AMQOH 238 mu
bon added, and the solution ?ltered. To the clari?ed
soluiton there is added a warm solution of 10 g. of sodi 25
um iodide in acetone. After :heating this mixture on
the steam bath for ?ve minutes, three ml, of acetic acid
is added, and the mixture is warmed brie?y, and then
e=15,000 [ethyl-129° (chloroform).
Analysis.—-Calcd. for C21H23O3Clz: C, 63.48; H, 6.60;
Cl, 17.85. Found: C, 63.13; H, 6.57; Cl, 17.86.
The 17-hydroxy ‘group is then esteri?ed in the manner
aqueous sodium bisul?te. The resulting pale yellow
described in Example 14 by means of tri?uoroacetic an
solution is poured into Water and the. resulting precipi 30 hydride and acetic acid to give 9a,11B-diChlOI‘O-17a-hy
tate is ?ltered and washed with water, and crystallized
droxy-1,4-pregnadiene-3,20-dione 17-acetate.
from acetone-ether to give 17u-hydroxy-1,4,9i(11)-preg
uatriene-3,20—dione, M.P. 233-235° C.
EXAMPLE 16
X3522“ 238 mu, e=15,600
9a-I0do-1l?-Chloro-17u-Hydr0xy-1,4-Pregnadiene
35
[a]D—19° (chloroform).
3,20-Dione 1 7-A cetate
EXAMPLE 14
To a solution of 1.0 g. of l7a-hydroxy-1,4,9(1l)
pregnatriene-3,20-dione 17-acetate (the compound of Ex
1 7a-Hydr0xy-1,4,9(1'1)-Pregnatriene-3,20-Dione
1 7-Acetate
40 ample 14) in 40 ml. of tetrahydrofuran is chilled to 0°
C., there is added 3 drops of perchloric acid and 3. g.
A solution of 5 g. of 17a-hydroxy-1,4,9(I11)-pregnatri
of lithium chloride, ‘followed by dropwise addition of
ene-3,2‘O-dione (the compound of Example 13)‘ is dis~
a solution of 470 mg. of iodine monochloride in 5 ml.
solved in 50 ml. of glacial acetic acid and 10
of
of tetrahydrofuran. The reaction mixture is stirred at
tri?uoroacetic anhydride. The solution is left at room
45 room temperature for 5 hours, then poured into ice
temperature for 24 hours, then poured into ice-water.
water. A gummy precipitates forms which is dissolved
A solid separates which is ?ltered, washed. with water,
in methylene chloride. The solution is warmed, de
and crystallized from acetone-hexane to give 1'7a-hy
droxy—1,4,9 ( l 1 )-pregnat‘riene-3',20-dione l7-acetate,
AMeOH
238 mp
max.
EXAMPLE 15
colorizing carbon added, then ?ltered. Pentane is added
to the clari?ed methylene chloride solution and a solid
50 forms which is ?ltered and crystallized from acetone
hexane to ‘give 9a-iodo-11/8-chloro-17a-hydroxy-l,4-preg~
nadiene-3,20-dione 17-acetate.
Alternatively, 9a-iodo-1 l B-chloro- l 7a-hydroxyproges
9a,11?-Diclzl0r0-1 7u-Hydr0xy-1,4-Pregnadiene
3,20-Dione 17-Acetate
terone 17-acetate (the compound of Example 10) is sub
One gram of l‘7a-hydroxy-1,4,9(11)~pregnatriene~3,20 55 jected to the action of a culture of Corynebacterium
simplex in the manner described in the alternative pro
dione 17-acetate (the compound of Example 14) is re
cedure of Example 15 to give 9a-iOdO-l1B-Chl01‘O-l7a
acted with 395 mg. of N-chl'orosuccinimide in the pres
hydroxy-l,4~pregnadiene-3,20-dione 17-acetate.
ence of hydrogen chloride and lithium chloride in the
manner of Example 4 to give 9a,1l1/3-di(>hl0l‘O-17u-hy
droxy-l,4-pregnadiene-3,'2.0—dione 17-acetate,
Amos 237 m”
max.
e=l5,300, M.P. 230~235° C. dec. [MD-H15“ (chloro
form).
Analysis.—Calcd. for C23H23Ol4Cl2: C, 62.87; H, 6.42;
Cl, 16.14. Found: C, 62,26; H, 6.73; Cl, 15.85.
Alternatively, the compound of this example is pre
60
EXAMPLE l7
9a-Chl0r0-J I?-Fluoro-I 7a-Hydr0xy-1,4-Pregnadiene
3,20~Di0ne 1 7-A cetate
17oz - hydroxy - 1,4,9(11) - pregnatriene - 3,20 - dione
65 17-acetate (the compound of Example 14) is reacted
with N-chlorosuccinimide and hydrogen ?uoride, and the
resultant product isolated and puri?ed in the manner
pared by the microbiological oxidation of 9a,1l}3-diChl0r0
described in Example 11 to give 9a-chloro-l1?-?uoro
17a-hydroxyprogesterone 17-iacetate (the compound of
17a-hydroxy-1,4-pregnadiene-3,20—dione l7-acetate.
Example 4) in the following manner.
70
Alternatively, 9a-chloro-1 1?-?uoro-17u-hydroxyproges
A one hundred ml. broth culture containing a 0.1%
terone 17~acetate (the compound of Example 11) is
yeast extract concentration, 9.0 ml. of 0.2 M KH2PO4
and 9.0 ml. of 0.2 M Nazi-IP04, contained in a 300 ml.
Erlenmeyer ?ask, is seeded with 1 m1. of a 24-hour broth
subjected to the action of a culture of Corynebacterium
simplex in the manner described in the alternative pro
cedure of Example 15 to give 9oc-ChlO1'0-11?-?UOI‘O-l7a
culture of Corynebacterium simplex (A.T.C.C. 6946). 75 hydroxy-l,4-pregnadiene-3,20-dione 17-acetate.
3,087,938
13
14
EXAMPLE 1:;
plex in the manner described in the alternative procedure
of Example 15' to give 17a-hydroxy-1,4,9(11)-pregnatri
9a-Brom0-1 1?-Chl0ro-17a-Hydroxy-1,4-Pregnadiene
3,20-Dione 17-Acetate
17u-hydroxy-1,4,‘9(11)~pregnatriene - 3,20 - dione
ene-3,20-dione 17-caproate.
17
acetate (the compound of Example 14) is reacted with
Nibromoacetamide, lithium chloride and gaseous hydro
U!
17-(?-Cyclopentylpropionate)
gen chloride in acetic acid in the manner described in
Example 5 to give 9u-brom0-LIB-chloro-lh-hydroxy-l,4
pregnadiene—3,20-dione 17-acetate.
Alternatively,
9a-‘br0m0-1 1?-'Ch1OI‘O-17a - hydroxypro
EXAMPLE 22
1 7a-Hydroxy-1 ,4,9 (1 I ) -Pregnatriene-3,20-Dione
17oc-hYdl‘OXY - 1,4,9(1l) - pregnatriene-3,20-dione (the
compound of Example 13) is reacted with jB-cyclopentyl
10 propionic acid and B-cyclopentylpropionic anhydride and
the resultant product is isolated and puri?ed in the man
ner described in Example 3 to give 17oc~hydroxy-1,4,9‘(11)
gesterone 17-acetate ‘(the compound of Example 5) is
subjected to the action of a culture of Corynebacterium
simplex in the manner described in the alternative pro
pregnatriene-3,20-dione 17-(?-cyclopentylpropionate) .
Alternatively, 17a-hydroxy - 4,9(11)-pregnadiene-3,20
cedure of Example 15 to ‘give 90t-bI‘0lI10-11?-Ch1OI‘O-170t 15 dione 17-(.B-cyclopentylpropionate), the compound of
hydroxy-1,4-pregnadiene-3,20-dione 17-acetate.
Example 3, is subjected to the action of a culture of
Corynebacterium simplex in the manner described in the
EXAMPLE 19
alternative procedure of Example 15 to give 17 a-hydroxy
9a-Br0m0-l1p-Fluoro-I7a-Hydr0xy-1,4-Pregnadiene
3,20-Di0ne 1 7-Aceiate
1,4,9(11) - pregnatriene - 3,20 - dione 17-(?-cyclopentyl
20 propionate) .
17a-hydr0xy-1,4,9‘( 11 ) ~pnegnatriene-3,20-dione 17-ac
etate (the compound of Example 14) is reacted with
EXAMPLE 23
N-bromoacetamide in the presence of hydrogen ?uoride
and the resultant product isolated and puri?ed in the
manner described in Example 6 to give 9a-bromo-11? 25
?uoro-17a-hydroxy-1,4-pregnadiene-3,20~dione
17 - ace
Dione 1 7- ( p-Cyclopem‘ylpropionate
17a-hydroxy - l,4,9(11) - pregnatriene - 3,20-di0ne 17
(/3—cyclopentylpropionate), the compound of Example 22,
is reacted with N-chlorosuccinimide in the presence of hy
drogen chloride and lithium chloride in the manner de
tate.
Alternatively,
9a,] 1 ?-Dich'loro-l 7a-Hydr0xy-1 ,4-Pregnadiene-3,20
9a-bromo-11/i-?uoro-17a - hydroxypro
gesterone 17-acetate (the compound of Example 6) is
scribed in Example 15 to give 9a,11j8-dichloro-17a-hy~
cedure of Example 15 to give 9a-bromo-1 1,3-?uoro-l7a
hydroxy-l,4-pregnadiene-3,20>dione 17-acetate.
pregnadiene-3 ,20-dione 17 - ( ,B-cyclopentylpropionate) , the
subjected to the action of a culture of Corynebacterium 30 droxy-1,4-pregnadiene-3,20-dione 17 - (/B-cyclopentylpro
pionate).
simplex in the manner described in the alternative pro
A second alternative procedure is as follows.
17a-hydroxy~1,4,9(11)-pregnatriene - 3,20 - dione (500
Alternatively, 9‘a,11? - dichloro - 170t-hYdI‘OXy-4,9(11)
compound of Example 8, is subjected to the action of a
35 culture of Coryne‘bacterium simplex in the manner de
scribed in the alternative procedure of Example 15 to
mg), the compound of Example 13, is reacted with 210
mg. of N~bromoacetamide in the presence of hydrogen
give 90:,11/3 - dichloro - 17a - hydroxy-1,4-pregnadiene-3,
ample 14 to give 9a-bromo-1lB-?uoro-lh-hydroxy-l,4
pregnadiene-3,20-dione 17-acetate.
caproate (the compound of Example 21) is reacted with
ZO-dione 17-(?-cyclopentylpropionate).
?uoride in diethylacetic acid in the manner of Example 6.
The product is isolated and puri?ed in the described man 40
EXAMPLE 24
ner to give 9a-bromo-11?-?uoro-17a-hydroxyprogesterone,
9a,]
1,8-Dichlor0-1
7u-Hydroxy-Z ,4 -Pregnadiene—
which is then esteri?ed with acetic acid in the presence
3,20-Di0ne
17-Capr0ate
of tri?uoroacetic acid in the manner described in Ex
EXAMPLE 20‘
17a-hydroxy-1,4,9(11)-pre-gnatriene - 3,20 - dione 17
45 N-chlorosuccinimide in the presence of hydrogen chloride
and lithium chloride in the manner of Example 15 to
give 911,11,8-dichloro-l7ot-hydroXy-1,4-pregnadiene - 3,20‘
9a,11;8-Dibr0m0-1 7oc-Hydr0xy-1,4-Pregnadiene
dione 17-caproate.
3,20-Di0ne 17-Acetate
17a-hydroxy - 1,4,9(11) - pregnatriene-3,20-dione l7
acetate (the compound of Example 14) is reacted With N
bromoacetamide, lithium bromide and hydrogen bromide
in acetic acid and the resultant product isolated and puri
?ed in the manner described in Example 9 to give 9'a,11,8
dibromo-17a-hydroxy-1,4-pregnadiene-3,ZO-dione l7-ace
tate.
Alternatively,
50
is subjected to the action of a culture of Coirynebacterium
simplex in the manner described in the alternative pro
cedure of Example 15 to give '9a,11B-dichloro-17a-hy
droxy-l,4-pregnadiene-3,ZO-dione 17-caproate.
EXAMPLE 25
9ot-I0d0-1 1 B-Bromo-I 7a-Hydroxy progesterone
one l7-acetate (the compound of Example 9) is subjected
ample 15 to give 90;,1l?-dibromo-lh-hydroxy-1,4-preg
nadiene-3,20-dione 17-acetate.
EXAMPLE 21
1 7a-Hydroxy-1 ,4 ,9 (1 1 )-Pregnatriene-3,20-Dione
I 7-Capr0ate
1 7-A c‘ctate
To a solution of 1 g. of 17et-hydroxy-4,9'(1l)-pregnadi
ene-3,20-dione l7-acetate (prepared as described in Ex
ample 1), and 4 g. of lithium bromide in 50 ml. of acetic
acid, there is added 620 mg. of N-iodosuccinimid‘e fol
lowed by a solution of 220 mg. of hydrogen bromide in
65 4.5 m1. of acetic acid. The mixture is stirred at room
temperature for one hour, then is poured into ice-water.
A solid forms which is ?ltered, and then chromatographed
on silica gel. The substance eluted with 301% ether in
hexane is crystallized from acetone-hexane to give 9oc-10d0
17a-hydroxy - l,4,9(11) - pregnatriene—3,20'-dione (the
compound of Example 13) is reacted with caproic acid
in the presence of tri?uoroacetic anhydride and the re
sultant product isolated and puri?ed in the manner de
.
55
90¢,11/3-dibromo-17u~hydroxyprogester
to the action of a culture of Corynebacterium simplex in
the manner described in the alternative procedure of Ex
Alternatively, 911,1 l?-dichloro-l7a-hydroxy-4-pregnene
3,20-dione 17-caproate (the compound of Example 7)
70
scribed in Example 14 to give 17a-hydroxy-1,4,9(11)
pregnatriene-3,20-dione 17-caproate.
Alternatively, l7a-hydroxy-4,9( 11 ) ~pregnadiene-3 ,20
dione 17-caproate (the compound of Example 2) is sub
jected to the action of a culture of Corynebacterium sim 75
1lp-brorno-17a-hydroxyprogesterone 17-acetate.
EXAMPLE 26
17a-Hydroxy-19-N0r-4,9 (11 )-Pregnadiene-3,20-Dione
(A) 115,17a-DIHYDROXY-19~NORPROGESTERONE
A living culture of the organism Curvulariw lunata
3,087,938
15
16
(N.R.R.L. 2380) is rinsed from an agar slant under sterile
conditions into a sterile medium having the following com
in the above procedure, the corresponding l7-esters are
prepared, that is, the l7-propionate, 17-butyrate and 17
position:
caproate of 9a,1l?-dichloro-17u-hydroxy-l9-norproges
Percent
terone.
Malt extract _______________________________ __ 5
Sucrose
__________________________________ __
1
EXAMPLE 28
"
Potassium chloride __________________________ __ 0.05
9a,]15-Dichloro-1 7oc-Hydr0xy-19-Norpr0gesterone
17-(?-Cyclopentylpropionale)
Magnesium sulfate heptahydrate ______________ __ 0.05
Ferrous sulfate heptahydrate _________________ __ 0.05
Dipotassium acid phosphate __________________ __ 0.1
compound of Example 27A, is esteri?ed by means of 13
Sodium nitrate _____________________________ __ 0.2
9:1,115 - dichloro-lh-hydroxy-l9-norprogester0ne, the
cyclopentylpropionic acid and ?-cyclopentylpropionic an
hydride under an atmosphere of nitrogen in the presence
of p-toluenesulfonic acid in the manner of Example 3
Distilled water, to adjust to pH 7.0 with potassium
hydroxide.
100 ml. of this medium is placed in each of several 300'
to give 9a,1lp-dichloro-lh-hydroxy-19-norprogesterone
ml. ?asks. To each ?ask is added 50 mg. of l7a-hydroxy 15 17- (,B-cyclopentylpropionate) .
19-nor-progesterone dissolved in a smallvolume of acetone.
The mixture is shaken for a period of 7 days at a room
EXAMPLE 29
temperature of about 28° C. The contents of the ?asks
9a-Br0m0-l 1,8-Chl0r0-1 7a-Hydr0xy-1 9-Norpr0gester0ne
are then combined and extracted with several portions of
1 7—A cetate
ethylene dichloride using one-?fth the volume of the 20
aqueous phase each time. The combined organic extracts
(A) 9a-BROMO-llB-CHLORO-l7a-HYDROXY
are dried over sodium sulfate, ?ltered and concentrated
IQ-NORPROGESTERONE
in vacuo to a residue having a volume of 1-2 ml.
The ethylene dichloride residue is then placed on a
chromatographic column consisting of silica gel, mixed
500 mg. of 17u-hydroxy-l9-nor-4,9(1l)-pregnadiene
25 3,20-dione, the compound of Example 26B, is added to a
solution of 220 mg. of N-bromoacetamide and 2 g. of
with a small volume of methylene chloride. The column
is developed with methylene chloride and the eluates are
lithium chloride in 20 ml. of glacial acetic acid. The
mixture is stirred at room temperature for about 30 min
combined and concentrated in vacuo to a residue which is
crystallized from acetone-hexane to give 116,17a-dihy
droxy- 19-nor-progesterone.
utes then poured into ice-water. A solid product sep
30 arates which is ?ltered, washed well with water and crys
tallized from methylene chloride-pentane to give 9a
(B) 17a-HYDROXY-19—NORJ4,9(11)-PREGNADIENE
3,20-DIONE
bromo-l 1,8Lc’hloro-17a-hydroxy-19-norprogesterone.
(B) 9a-BROMO-l'l?-CHLORO-l'l'a-HYDROXY-LLQ
Two grams of 11B,17a-dihydroxy-19-norprogesterone,
NORPROGESTERONE l7-ACETATE
prepared as described in Example 26A, in 50 ml. of pyri 35
dine is chilled to 0° C., and there is added 5 ml. of meth
In the manner described in Example 1, 9a-bromo-l1?
anesulfonyl chloride dissolved in 10 ml. of pyridine. The
chloro-l7a-hydroxy-19-norprogesterone, the compound of
mixture is allowed to stand in the ice-box for 96 hours.
Example 29A, is esteri?ed with acetic acid in the pres
A small amount of ice is added to the reaction mixture,
ence of tri?uoroacetic anhydride to give 9a-bromo-ll?
40
and the solution is diluted with chloroform, washed with
chloro-17a-hydroxy—19-norprogesterone ‘l7-acetate.
water, then with 5% hydrochloric acid, 5% sodium bi
In a similar fashion, other lower alkanoic acid esters
carbonate and ?nally again with water. The solution
of the compound of Example 29A are prepared by sub
is dried over sodium sulfate, ?ltered, and concentrated
stituting suitable acids such as propionic, butyric and
in vacuo to a residue which is crystallized from methyl
45 caproic for acetic acid in the above procedure.
ene chloride-hexane to give 17a-hydroxy-19-nor-4,9(1l)
pregnadiene-3,20-dione.
EXAMPLE 3O
EXAMPLE 27
90:,11/3-D ich loro-l 7a-Hydr0xy-1 9-Norprogester0ne
1.7-Acetate
9a-Br0mo-1 1 B-Fluoro-I 7a-Hydr0xy-l 9-N0rpr0ges
terone 1 7—A cetate
50
(A) 9a-BROMO~1l?-FLUORO—17a-HYDROXY-l9
NORPROGESTERONE
(A) 9o1,1l?-DICHLORO-17a-HYDROXY-l9-NOR>
PRO GESTERONE
In the manner described in Example 6, 250 mg. of
‘One gram of 17a-hydroxy-19-nor-4,9(11)-pregnadi
17a-hydroxy-19-nor-4,9(11)-pregnadiene-3,20-dione (the
ene-3,20-dione, prepared as in Example 26B, is dissolved 55 compound of Example 26B) is reacted with 110 mg. of
in 30 ml. of carbon tetrachloride and at —20° C., there
is added 220 mg. of chlorine dissolved in 30 ml. of car
bon tetrachloride in the presence of 0.75 ml. of pyridine.
N-bromoacetamide in 50 ml. of diethylacetic acid and a
solution of 250 mg. of hydrogen ?uoride in 2 ml. of a
The mixture is stirred at —20° C. for 15 minutes, then
product isolated and puri?ed to give 9a-bI'0InO-llB-?ll
chloroform-tetrahydrofuran mixture, and the resultant
allowed to warm to room temperature over a period of 60
one-half hour.
The solution is ?ltered and the ?ltrate
(B) 9oz-BROMO-1l?-FIJUORO-17a-HYDROXY-19
concentrated in vacuo to a residue which is crystallized
from acetone-hexane to give 90:,11/3 - dichloro-l7a-hy
droxy-19-norprogesterone.
oro-l7a-hydroxy-l9-norprogesterone.
NORPROGESTERONE 17-ACETATE
65
In the manner described in Example 1, 9a-bromo-1l/3
(B) ‘9a,1l?-DICHLORO-17a-HYDROXY-19-NOR
?uoro-17a-hydroxy-19-norprogesterone (the compound
PROGESTERONE 17>ACETATE
of Example 30A) is esteri?ed with acetic acid in the pres
ence of tri?uoroacetic anhydride to give 9a-bromo-ll?
The 90;,115 - dichloro-17a-hydroxy-19-norprogesterone
fluoro-17a-hydroxy-l9-norprogesterone 17-acetate.
of Example 27A is esteri?ed with acetic acid in the pres
In a similar fashion, by substituting other lower al
ence of tri?uoroacetic anhydride and the resultant prod 70
kanoic acids such as propionic, butyric and caproic for
uct isolated and puri?ed in the manner described in Ex
acetic acid in the above procedure, the corresponding
l7-lower alkanoates are formed, that is, the l7-propionate,
17-butyrate 0r 17-caproate respectively of 9a-bromo
Similarly, by substituting other lower alkanoic acids
75 l 1 ?-?uoro- 17 u-hydroxy- 19-norpro gesterone.
such as propionic, butyric or caproic acid for acetic acid
ample 1 to give 90¢,1l?-dichloro-l7a-hydroxy-l9-norpro
gesterone l7-acetate.
3,087,938
17
18
EXAMPLE 31
9(11)-pregnadiene-3,20-dione, the compound‘ of Example
32, is reacted with N-bromoacetamide and hydrogen chlo
9a-Iodo-l 1,8-Chl0ro-1 7a-Hydroxy-19-N0rprogesterone '
1 7-A cetate
ride in the presence of lithium chloride. The product is
isolated and puri?ed in the described manner to give 9a
(A) 9uz-IODO-11B-CHLORO-l'Ta-HYDROXY-19
bromo-l lit-chloro-17a-methylprogesterone.
N ORPROG-EJSTERONE‘
EXAMPLE 36
In the manner described in Example 10, 17a-hydroxy
17a-Methyl-1,4,9(11 ) -Pregnatriene-3,20-Dione
19-nor-4,9(11)-pregnadiene-3,20-dione (the compound of
Example 26B), is reacted with iodine monochloride in
In the manner described in the alternative procedure
tetrahydrofuran and the resultant product isolated and 10 of Example 15, 17a-methyl-4,9(11)-pregnadiene-3,20-di—
puri?ed to give ‘9u-iodo-1lit-chloro-17a-hydroxy-19-nor—
one is subjected to the action of a culture of Corynebac
progesterone.
terium simplex and the resultant product isolated and puri—
?ed to give 17a-methyl-1,4,9(1l)-pregnatriene-3,20-dione.
(B) 9wIODO-11.13-CHLORO-I'icrHYDROXY-IQ
NORPROGESEL‘ERONE 17-ACETATE
The 17u-hydroxy-19-n0rprogesterone of Example 31A
is esteri?ed to the corresponding 17-acetoxy compound by
15
EXAMPLE 3 7
means of acetic acid in the presence of tri?uoroacetic an
90:,11?-DiChIOfO-1 7 a-M ethyl-1 ,4 -Pregnadiene-3,20-D tone
The l7ot-methylpregnatriene of Example 36 is reacted
hydride in the manner described in Example 1 to give
With N-chlorosuccinirnide in the presence of hydrogen
906 - iodo-l 118-chloro-17ot-hydroxy-19-norprogesterone 17 - 20
acetate.
?ed in the described manner to give 90¢,11?-dlClJl0l‘O-17ot
EXAMPLE 32
methyl-1,4-pregnadiene-3,ZO-dione.
1 7rx-Methyl-4,9 (.1 1 )-Pregnadiene-3,20-Dione
‘ (A) 17MMETHYL-2l-HYDROXY=4=,9(11)<PREGNADIENE—
3‘20-DIONE 21-METHANESULF'ONATE
chloride and lithium chloride in the manner described in
Example 4, and the resultant product isolated and puri
EXAMPLE 38
25
A solution of 5 g. of 17a-methyl-11,8,21-dihydroxy-4
The 17a-methylpregnatriene of Example 36 is reacted
pregnene-3,20-dione in 100 ml. of pyridine is chilled to
With N-bromoacetarnide and hydrogen ?uoride in diethyl
0° C. and a solution of 10 ml. of methanesulfonyl chlo
ride in 20 ml. of chloroform is added dropwise. The 30 acetic acid and the resultant product isolated and puri?ed
in the manner of Example 6 to give 9oc-‘b1‘01'I10-11?-?tt01‘0
mixture is allowed to stand in the ice box for 100 hours,
17u-1'I16il'lYl-1 ,4-pregnadiene-3 ,ZO-dione.
then a little ice is added and the solution diluted with
chloroform. The organic solution is washed with Wa
EXAMPLE 39
ter, 5% hydrochloric acid, 5% aqueous sodium bicar
bonate, and again with water. The solution is dried over
magnesium sulfate, ?ltered and concentrated in rvacuo to
a residue which is crystallized twice from acetone-hexane
9a-Chl0r0-J 1 [i-Flzzoro-I 7ot-Methyl-1,4-Pregnadiene
3 ,2 O-Dione
The l7a-methylpregnatriene of Example 36 is reacted
to give 17 ot-methyl-21-hydroxy-4,9( 11)-pregnadiene-3,20
with N-chlorosuccinimide and hydrogen fluoride and the
dione 21~methanesulfonate.
resultant product isolated and puri?ed in the described
40 manner of Example 11 to give 9ot-chloro-lLB-?uoro-17a
(B) 17a-METHYL—4,9(‘11)-PREGNADIENE-3,20~DIONE
To a solution of 2.0 g. of 17a-methyl-21-hydroxy-4,
methyl-1,4-pregnadiene-3,20-dione.
9(1'1)-pregnadiene-3,20-dione ZI-methanesulfonate (the
EXAMPLE 4O
compound of Example 32A), in 30v ml. of acetic acid is
90:,11/3-Dibl‘0h’10-1 7(PMethyl-1 ,4-Pregnadi ene—3,20-Di0ne
added 4.0 g. of sodium iodide. The mixture is heated 45
In the manner described in Example 9, 17a-methyl-1,4,
on the steam-bath for 30 minutes, then cooled and de
9(11)-pregnatriene-3,ZO-dione, the compound of Exam
colorized by the addition of aqueous sodium bisul?te
ple 36, is brominated by means of N-‘bromoacetamide in
solution. The solution is then poured into ice water.
the presence of hydrogen bromide and lithium bromide
A precipitate forms which is ?ltered, Washed with Water,
the product isolated and puri?ed to give 90¢,l15-di
and crystallized from acetone-hexane to give 17aémethy1 50 and
bromo-l7a-methyl-1,4-pregnadiene-3,ZO-dione.
4,9 ( 1 1)-pregnadiene-3,20-dione.
EXAMPLE 3 3
9a,] 1 ?-Dich l0r0-1 7a-Methylpr0gesterone
One gram of 17/x-methyl-4,9(l1)-pregnadiene-3,20-di
one, the compound of Example 32, is reacted with N
chlorosuccinimide (430 mg.) in the presence of hydrogen
chloride and lithium chloride in the manner of Example 4.
The resultant product is isolated and puri?ed in the de
scribed manner to give 9a,1l?-dichloro-17a-methylpro
gesterone.
'
EXAMPLE 34
EXAMPLE 41
9oc-I0tl'0-1 l?-Chloro-I 7a-M ethylprogesterone
In the manner described in Example 10, 500 mg. of
17a-methyl-4,9(11)-pregnadiene - 3,20 - dione, the com
pound of Example 32, is reacted With 250 mg. of iodine
monochloride and the resultant product isolated and puri
?ed to give 9a-iodo-1Iii-chloro-17ot-methylprogesterone.
EXAMPLE 42
J 7a-Br0m0-4,9 (J1 ) -Pregnaa'iene-3 ,2 O-Dione
(A) 17a.-BROMO-11B-I-IYDROXYPROGES-TERONE
9ot-Br0m0-1 1 ?-Fluoro-l 7 a-Methy [progesterone
‘17u-bromoprogesterone is subjected to the action of a
In the manner described in Example 6, one gram of 65 culture of Curvularia lzmata in the manner described in
17ot-methy1-4,9‘(11)-pregnadiene-3,20-dione, the com
Example 26A and the resultant product isolated in the
pound of Example 32, is reacted with N-bromoacetamide
described manner and crystallized twice from ethylacetate
(450 mg.) and hydrogen ?uoride in diethylacetic acid.
The isolated product is crystallized from methylene chlo
ride-pentane to give 9a-bromo-11?-?uoro-17rx-methylpro
gesterone.
to give 17ot-bromo-1l?-hydroxyprogesterone.
(B) 170z-BROMO-4,9 (11) -PREGNADIENE-3,20-DIONE
A mixture of 2 g. of 17a-bromo-1l?-hydroxyprogester
one, prepared as in Example 42A, and 4 g. of dry lithium
EXAMPLE 35
bromide in 50 ml. of glacial acetic acid is re?uxed under
9oc-BI‘0I7'tO-1 1 ?-Chloro-l 7 a-Methy lprogesterone
anhydrous conditions for 30 minutes. The solution is
In the manner described in Example 5, 17a-methyl-4, 75 then cooled and poured into ice water. A Solid precipi
3,087,938
20
19
EXAMPLE 49
tates which is ?ltered ‘washed well with water and recrys
tallized twice from acetone-hexane to give l7a-bromo-4,
9(11)-pregnadiene-3,20-dione.
9a,]7a-Dibr0m0-11?-Fluoro-I,4-Pregnadiene-3,20-Dione
'
In the manner described in Example 6, 17a-bromo
EXAMPLE 43
1,4,9(l1)—pregnatriene-3,20-dione, the compound of Ex
ample 42, is reacted with N-bromoacetamide and hydro
gen ?uoride in diethylacetic acid. The resultant product
9a,] 1/3-Dichl0r0-1 7u-Bromoprogesterone
One gram of 17a-bromo-4,9(l l)-pregnadiene-3,20-di
one, the compound of Example 42, is reacted With 370 mg.
of N-chlorosuccinimide in the presence of hydrogen chlo
is isolated and puri?ed in the described manner to give
9a,17or-dibromo-1 l?-?uoro-1,4-pregnadiene-3,20-dione.
ride and lithium chloride in the manner described in Ex 10
ample 4. The resultant product is isolated in the de
scribed manner and crystallized from methylene chloride
hexane to give 911,1lB-dichloro-l7a-bromoprogesterone.
EXAMPLE 44
I
In the manner described in Example 9, l7a-bromo
1,4,9(l1)-pregnatriene-3,20-dione (the compound of Ex
15 ample 42) is reacted with lithium bromide, N-bromo
acetamide and hydrogen bromide in acetic acid and the
9a,] 7a-Dibr0m0-Z lp-Chloroprogesterone
resultant product isolated and puri?ed to give 9<x,1l 3,1704
tribromo-l,4-pregnadiene-3,20-dione.
500 mg. of the 17a-bromopregnadiene of Example 42
is reacted with 190 mg. of N-bromoacetamide in the pres
ence of hydrogen chloride and lithium chloride in the 20
manner described in Example 5. The resultant product
is isolated in the described manner and crystallized from
acetone-hexane to give 9a,17a-dibromo-ll?-chloroproges
EXAMPLE 5 1
1 7 oc-Ch loroprogesterone
(A) - 17a-HYDROXY-5a,GBJ'Ya-TRICHLOROaXLLO
PREGNANE-ZO-ONE S-ACETATE
terone.
EXAMPLE 45
EXAMPLE 5 0
9a,]1B,17a-Tribr0m0-1,4-Pregnadiene-3,20-Di0ne
25
The requisite starting compound, 5,17(20)-pregnadi
ene-3?,20-diol diacetate, is prepared as follows.
To a solution of 5 g. of 3B-hydroxy-5-pregnene-20-one
3-acetate in 250 ml. of acetic anhydride there is added
1.5 g. of p-toluenesulfonic acid. The mixture is slowly
concentrated to about one-fourth the original volume by
distillation over a six hour period. The remaining solvent
is then distilled in vacuo. The resulting residue is taken
up in ether, washed with water, then with aqueous sodium
bicarbonate solution and then again with water. The
ether solution is dried over magnesium sulfate, ?ltered,
then passed through a column of Florisil in ether. The
eluate is concentrated to a residue which crystallizes
upon the addition of hexane. The crystalline material
is ?ltered and air dried to give 5,17(2‘0‘)-pregnadione
500 mg. of the 17o<~bromopregnadiene of Example 42 is
reacted with 180 mg. of N-chlorosuccinimide in the pres
ence of hydrogen ?uoride in the manner described in Ex
ample 11. The resultant crude product is chromato
graphed on silica gel and the material eluted with 30%
ether in hexane is crystallized twice from methylene chlo
ride-pentane to give 9a-chloro-ll?-?uoro-lh-bromopro
gesterone.
EXAMPLE 46
1 7OL-BI'OI?ZO-1,4,9 ( I 1 )-Prcgnatriene-3,20-Dione
The 17or-brorno-4,9(11)-pregnadiene-3,20-dione of Ex 40 35,20-diol diacetate.
The 5-pregnene diacetate prepared as described above
is dissolved in 100 ml. of carbon tetrachloride, 2 ml. of
pyridine is added, the solution chilled to ~20" C. and
tive procedure of Example 15 and the resultant product
ample 42 is subjected to the action of a culture of Coryne
bacterium simplex in the manner described in the alterna
then there is added dropwise a solution of 1 g. of
isolated and puri?ed in the described manner to give 17a
bromo-1,4,9 ( l l ) —pregnatriene-3,20-dione.
45 chlorine dissolved in 8.4 ml. of carbon tetrachloride.
The mixture is stirred at —20° C. for one-half hour,
EXAMPLE 47
then allowed to come to room temperature.
The solu
tion is diluted with methylene chloride, washed with
9a,11?-Dicl1l0r0-1 7 ot-Brom 0-1 ,4 —Pregnadiené-3 ,2 O-Dione
water, 5% sodium bicarbonate, 5% hydrochloric acid
The 17a-bromopregnatriene of Example 46 is reacted 50 and again with water, dried over magnesium sulfate,
with N-chlorosuccinimide in the presence of hydrogen
chloride and lithium chloride in the manner described in
Example 4. The resultant product is isolated and puri
?ed in the described manner to give 90:,11B-diChIOI‘O-17ot
bromo-l,4-pregnadiene-3,20-dione.
then concentrated in Vacuo to a residue which is crystal
lized from acetone-hexane to give 3B-hydroxy-5a,6;8,l7a
trichloroallopregane-ZO-one 3-acetate.
55
Alternatively, the compound of this example is pre
pared from 9a,1LB-dichloro-17a-bromoprogesterone, the
compound of Example 43, with the aid of a culture of
(B) 3B-I-IYDROXY-1 7a-CHLORO-5-PREGNENE-ZO-ONE
8-ACETATE
A solution of 2 g. of the compound of Example 51A
in 50 ml. of methyl ethyl ketone containing 2 g. of
sodium iodide is re?uxed under nitrogen for 2 hours, then
Corynebacterium simplex in the manner of the alternative
procedure of Example 15.
60 poured into cold water. A precipitate forms which is
?ltered, Washed with water and crystallized from ethyl
acetate to give 3/3-hydroxy-17a-chloro-S-pregnene-ZO-one
3-acetate.
EXAMPLE 48
9a,]7oc-Dibl'0l710-1 1B-Chloro-I,4-Pregnadiene-3,20-Dione
17a-bI‘OI1‘10-1,4,9( 1 1 ) -pregnatriene-3,20-dione, prepared 65
as in Example 42, is reacted vwith lithium chloride, N
bromoacetamide and hydrogen chloride, and the resul
(C) 17a-CHLOROPROGESTERONE
3B-hydroxy - 17oz - chlOro-S-pregnene-ZO-One
3-acetate,
prepared as in Example 51B, is subjected to the action
tant product isolated and puri?ed in the manner de
of a culture of Flavobacterium dehydrogenans (Rutgers
Collection No. 150) as follows.
scribed in Example 5 to give 9a,17a-dibromo-1l?-chloro
l,4-pregnadiene-3,20-dione.
70 . The culture of the organism is prepared by propagating
Alternatively, the compound of this example is pre
it in a nutrient agar medium at 30° C. for 24 to 72
pared from 9oz,l7oc-dibromo-llB-chloroprogesterone, the
compound of Example 44, With the aid of a culture of
Corylzebacterimn simplex in the manner described in the
alternative procedure of Example 15.
hours. During incubation, the inoculated tube is exposed
to light with the resultant development of a yellow pig
ment characteristic of the species. The developed cul
75 ture is rinsed from an agar slant under sterile conditions
3,087,938
21
22
into a sterile medium of pH 6.8 and having the follow
EXAMPLE 56
ing composition:
Yeast extract (Difco) ___________________ _.
Potassium phosphate monobasic __________ ..Sodium phosphate dibasic _______________ __
Tap water ____________________________ __
10 gm.
4.48 gm.
4.68 gm.
to 1 liter.
In the manner described in Example 11, the 4,9(11)
pregnadiene of Example 52B is reacted with N-chloro
succinimide and hydrogen ?uoride and the resultant prod
uct isolated and puri?ed to give 90¢,17ot-(li0h101‘O-11?
This culture medium has previously been autoclaved,
?uoroprogesterone.
at 15 lb. pressure, for twenty minutes to obtain aseptic
EXAMPLE 57
conditions, and cooled. The variant is grown in the 10
1 7 oc~Cll Zora-1 ,4,9 (1 1 )-Pregnatriene-3,20-Dione
medium under constant illumination, using the visible
range of the spectrum. The incubation temperature is
17a-Chl01‘O-4,9( ll)-pregnadiene-3,20-dione, the com
maintained at about 33° C. and is conducted under
pound of Example 52B, is subjected to the action of a
aerobic conditions. Aeration is accomplished by agi
culture of Corynebacterium simplex in the manner de
tation and/or blowing air through the culture medium. 15 scribed in the alternative procedure of Example 15. The
After the organism has grown for 12 to 24 hours (or
resultant product is isolated and puri?ed in the described
longer, if desired), 100 ml. of the growing culture are
manner to give 17a-chloro-1,4,9(ll)-pregnatriene-3,20
introduced into each of ten ?asks, and to each ?ask are
dione.
added 200 mg. of 3,8-hydroxyil7u-chloro-5-pregnene-20
EXAMPLE 58
one 3-acetate dissolved in a minimum volume of ethanol.
901,1 15,1 7a-Trichl0ro-1 ,4-Pregnad iene-3,20-Di0ne
The reaction mixtures are then shaken at 30° C. for 12
to 72 hours. The reaction is stopped when paper chro
In the manner described in Example 4, 17a-Chl01‘0
matography indicates that there is no more starting mate
1,4,9(ll)-pregnatriene-3,ZO-dione, the compound of Ex
rial.
ample 57, is reacted with N-chlorosuccinimide in the
The contents of the ?asks are combined and extracted 25 presence of hydrogen chloride and lithium chloride and
with methylene chloride. The extracts are concentrated
the resultant product isolated and puri?ed to give 9a,l1?,
and the residue is crystallized from acetone-hexane yield—
17a-trichloro-l,4-pregnadiene-3,20-dione.
ing 17u-chloroprogesterone.
Alternatively, the compound of this example is pre
pared from 9a,l1B,17a-trichloroprogesterone, the com
pound of Example 53, with the ‘aid of a culture of Coryne
bacterium simplex in the manner described in the alter
EXAMPLE 5 2
1 7a-Chl0ro-4,9 (11 )-Pregnadiene-3,20-Di0ne
(A) 1l?-HYDROXY-l7a-CI-ILOROPROGESTERONE
native procedure of Example 15.
17u-chloroprogesterone, prepared as described in Ex
ample 51, is subjected to the action of a culture of
Curvularia lunam and the resultant product isolated in
the manner described in Example 26A to give a residue
which is crystallized from ethyl acetate to give 1113
EXAMPLE 59
Qa-Bromo-l 1B,].7a-Dichlore-1,4-Pregnadiene-3,20-Dione
In the manner described in Example 5, the 17er
chloropregnatriene of Example 57 is reacted with N-bro
moacetamide in the presence of hydrogen chloride and
lithium chloride, and the resultant product isolated and
hydroxy-17a-chloroprogesterone.
( B) 1‘7a-CHLORO-‘4,9 (11)-PREGNADIENE—3,20-DIONE
1l?-hydroxy-l7a-chloroprogesterone, prepared as in
Example 52A, is reacted with lithium bromide in glacial
acetic acid in the manner described in Example 42B
and the resultant product isolated and puri?ed to give
17a-chloro-4,9(l1)-pregnadiene-3,20-dione.
puri?ed to give 9a-brorno-l1B,17a-dichloro-l,4>pregna
diene_-3,20-dione.
Alternatively, 9a - bromo - ll?,l7a-dichloroprogester
one, prepared as in Example 54, is subjected to the ac
45 tion of a culture of Corynebacterium simplex in the man~
ner described in the alternative procedure of Example 15
EXAMPLE 5 3
to give 9ot-bromo-11B,17a-dichloro-1,4-pregnadiene-3,20
dione.
9a,]1?-1 7u-Trichloroprogesterone
One gram of l7a-chloro-4,9(1l)-pregnadiene-3,20
dione, prepared as in Example 52B, is reacted with 390' 50
mg. of N-chlorosuccinimide in the presence of hydrogen
chloride and lithium chloride in the manner described
described‘ manner and crystallized from acetone-hexane
of Example 15, 9a-bromo-llit-?uoro-17a-chloroprogester
55 one, the compound of Example 55, is subjected to the ac
tion of a culture of Corynebacterium simplex and the
resultant product isolated and puri?ed to give 9a-bromo
EXAMPLE 54
11 I3-?uoro- l7u-chloro-1,4-pregnadiene-3,20-dione.
9ot-Br0m0-1 1,8,1 7u-Dichl0roprogesterone
One gram of l7a-chloroe4,9(1l)-pregnadiene-3,20i
dione, the compound of Example 523, is reacted with
400 mg. of N-bromoacetamide in the presence of hydro
gen chloride and lithium chloride according to the pro
cedure of Example 5. The resultant product is isolated
9a-Brom0-1 1 ?-Fluora-l 7a-Chl0r0-1,4-Pregnadiene
3,20-Di0ne
In the manner described in the alternative procedure
in Example 4. The resultant product is isolated in the
to give 9a,1l?,17a-trichloroprogesterone.
EXAMPLE 60
EXAMPLE K61
60
9a,]7a-Dichl0ra-11j3-Flrz0r0-l,4-Pregnadiene-3,20-Diane
In the manner described in the alternative procedure
of Example 15, 9a,17a-dichloro-1lp-?uoroprogesterone,
in the described manner and crystallized twice from 65 is subjected to the action of a culture of Corynebacterium
simplex and the resultant product isolated and puri?ed
methylene chloride-pentane to give 9a-bromo-11/3,17a
fdichloroprogesterone.
EXAMPLE 55
to give 9a,17ot-dichloro-1lit-?uoro-1,4-pregnadiene-3,20
dione.
EXAMPLE 62,
9a-Bnomo-1 1 ,B-Fluoro-I 7 a-Chloroprogesteronei
70
In the manner described in Example 6, the 4,9(1l)
pregnadiene of Example 52B is reacted with N-bromo
In the manner described in Example 9, 17¢x-Ch101'0
acetamide and hydrogen ?uoride in diethyl acetic acid and
1,4,9(11)-pregnatriene-3,20-dione, is reacted with iN-bro
the resultant product isolated and puri?ed. to give 9a
bromo-l Iii-?uoro-17a-chlor0progesterone.
75 moacetamide in the presence of lithium bromide and hy
3,087,938
23
24
drogen bromide and the resultant product isolated and
‘dione is reacted with 220 mg. of chlorine in carbon tetra
chloride in the presence of pyridine in the manner de
scribed in the alternative procedure of Example 4 to give
puri?ed to give 9a,ll?-dibromo-l7a-chloro-l,4-pregna
diene-3,20-dione.
EXAMPLE 63
. 9a,ll?~dichloro-l7a-hydroxyprogesterone.
xfjgi?“ 238 mp
(B) 9e,11,B-DI'CHLORO-17a-HYDROXYPROGESTERONE
‘17-ACETATE
In the manner described in the alternative procedure
of Example 15 9oc-iodo-ll?-chloro-l7a-methylprogester
In the manner described in Example 14, 90:,1lB-di
one (the compound of Example 41) is subjected to the 10 chloro-17a-hydroxyprogesterone (the compound of Ex
action of a culture of Corynebacterium simplex and the
ample 69A) is esteri?ed by means of tri?uoroacetic an
resultant product isolated and puri?ed to give 9oc-i0d0
hydride in acetic acid to give 9a,11?-dichloro-17a-hy
droxyprogesterone 17-acetate.
In similar manner, ‘by substituting other lower alkanoic
1 l?-ch'loro-l 7a-methyl-1,4epregnadiene-3 ,20-dione.
EXAMPLE 64
acids, such as butyric and valeric, ‘for acetic acid in the
esteri?cation procedure, other lower alkanoyl esters are
prepared such as the 17-butyrate and 13-valerate of
9a,] 1 fi-Dibrom 0-1 7 oc-Methylprogesterone
17 a-methyl-4,9( 1 1)-pregnadiene-3,20-di0ne (the com
pound of Example 32B) is reacted with N-bromoaceta
mide, lithium bromide. and hydrogen bromide and the
911,1 1 ?-dichloro-l7a-hydroxyprogesterone.
Alternatively, the compound of this example is prepared
according to the following procedure.
resultant product isolated and puri?ed in the manner de
scribed in Example 9 to give 904,11B-dibromo-17a-methyl
(C) 9a,11B~DIC'HLORO-17a-HYDROXYPROGESTERONE
17-A‘CETATE
progesterone.
EXAMPLE 65
One gram of 17a-hydroxy-4,9(11)-pregnadiene-3,20
dione 17-acetate (the compound of Example 1) and 850
mg. of p-iodotoluene dichloride are dissolved in 20 ml.
of methylene chloride. The solution is stirred at room
temperature for 5 hours, then concentrated in vacuo to
a residue which is crystallized ‘from acetone-hexane to
17oc-bIOII10-4,9 ( l 1 )-pregnadiene-3,20-dione (the com
pound of Example 42B) is reacted with lithium bromide,
hydrogen bromide and N-iodo-succinimide in the man
ner described in Example 25. The resultant product is
isolated and puri?ed in the described manner to give
give 9a,1l?-dichloro-17a-hydr0xyprogesterone 17-acetate.
EXAMPLE 7O
9oc-iOdO-1 l?,17a-dibromoprogesterone.
9oc~Br0m0-1 1 ?-Ch lore-1 7oc-Hydroxy progesterone
1 7-A ceate
In the manner of Example 9, 170t-b1'OIl'10-4,9(11)
(A) 9a-BROMO-11?~CHLORO-17a-HYDROXY
35
PROGESTERONE
pregnadiene-3,20-dione (the compound of Example 42B)
One gram of 17u-hydroxy-4,9(ll)-pregnadiene-3,20
is reacted with N-bromoacetamide, lithium bromide and
dione and 4 g. of lithium chloride are dissolved in 50
hydrogen bromide, and the resultant product isolated and
ml.
of glacial acetic acid. There is ?rst added 420 mg.
puri?ed to give 911,11B,17a-tribromoprogestr0ne.
40 of N-bromoacetamide and then 111 mg. of hydrogen
EXAMPLE 67
9oc~lado-1 1 16,1 7 u-D ibromo-J ,4-Pregnadiene-3,20-Di0ne
chloride in 40 ml. of acetic acid. The mixture is stirred
at room temperature for about 30 minutes then is poured
into ice-water with stirring and the resultant solid is
?ltered, washed with water, and crystallized from acetone
9a~Iodo-l1/8,17a-dibromoprogesterone (the compound
of Example 65) is subjected to the action of a culture of 45 hexane to give 9a-bromo-1l?-chloro-17a-hydroxyproges
Corynebacterium simplex and the resultant product iso
terone,
lated and puri?ed in the manner described in the alter
A3552“ 241 mm
native procedure of Example 15 to give 9u-iodo-11?,17oc
dibromo-1,4-pregnadiene-3,20-di0ne.
EXAMPLE 68
(B) 9a-BROM0-11B-CHLORO-17a-HYDROXYPROGE
50
9a,]1?-Dibr0mo-17a-Hydr0xy-19-N0rpr0gesterone
17-Acetate
(A) 9a,11?-DIBROMO-17a~HYDROXY-19~
NORPROGE‘STERONE
STERONE ’17-ACETATE
The 17a-hydroxy compound of Example 70A is esteri
tied with acetic acid in the presence of tri?uoroacetic an
hydride in the manner of Example 14 to give 9a-bromo
55
1l?-chloro-17u-hydroxyprogesterone 17-acetate.
In similar fashion, by substituting other lower alkanoic
acids such as butyric and valeric ‘for acetic acid in the
esteri?cation procedure, other lower alkanoyl esters are
prepared, such as the 17-‘butyrate and 17-valerate of 9a
To a solution of 1 g. of l7u-hydroxy-4,9(11)-19
norpregnadiene-3,20-dione (the compound of Example
26B) and 4 g. of lithium bromide in 50 ml. of acetic acid
is added 420 mg. of N-brornoacetamide. The mixture is 60 bromo-l l?-chloro- l7a-hydroxyprogesterone.
EXAMPLE 71
stirred at room temperature for one hour, then is poured
into ice-water. A solid separates which is ?ltered, Washed
17a-Hydr0xy-1,9:(11 )—Allopregnadicne-3,20-Dione
with water, and crystallized from acetone-hexane to give
17-Acetale
9a,l1,8-dibromo-17a-hydroxy-l9-norprogester0ne.
(A) 1113,17a-DIHYDROXY-1-ALLOPREGNENE-3,20
(B) 9a,1l?-DIBROMO-17a-HYDROXY-19-NOR
65
DIONE 1‘7'A‘CETATE
PROGESTERONE 17-ACETATE
In the manner described in Example 26A, 17a-hydroxy
The dibrom0-l7a-progesterone of Example 68A is
1-allopregnene-3,20-dione 17-acetate is subjected to the
esteri?ed in the manner described in Example 1 to give
9a,1l?-dibromo-lh-hydroxy - 19 - norprogesterone 17
acetate.
EXAMPLE 69
action of a culture of the organism Curvularia lunata.
The resultant product is isolated and puri?ed in the de
70 scribed manner to give 1118,17a-dihydroxy-l-allopregnene
9a,] 1j9-Dichl0r0-1 7a-Hydroxy progesterone 1 7-A cetate
(A) 9a,115=DICHLOR0-17a-HYDROXYPROGESTERONE
One gram of 17a-l1ydroxy-4,9(l1)-pregnadiene-3,2O 75
3,20-dione 17-acetate.
(B) 17a—HYDROXY-1,9(11)-ALLOPREGNADIENE-3,20
DIONE 17-ACETATE
The ll?-hydroxy allopregnene of Example 71A is
3,087,938
,
.
26
25
rated. The organic layer is washed with 5% aqueous
hydrochloric acid and water, dried over magnesium sul~
fate, ?ltered, and evaporated to a residue which is crys
tallized from acetone-hexane to give l7a-methyl-1-allo
reacted with methanesulfonyl chloride in pyridine and the
resultant product isolated and puri?ed in the manner de
scribed in Example 2613 to give 17u-hydroxy-1,9(l1)-a1lo
pregnadiene-3,20-dione 17-acetate.
pregnene-3,20-dione.
‘EXAMPLE 72
EXAMPLE 76
1 7u-Methyl-1 ,9 (11 ) -A llopregnadiene-3,20-Di0ne
9a,11?-Dichloro-I7a-Hydroxy-1-Allopregnenie-3,20
Dione 1 7-A cetate
17a - hydroxy - l,9(11)-allopregnadiene-3,20-dione 17
acetate (the compound of Example 71) is chlorinated l0
17a~Methyl~1-allopregnene-3,20-dione (the compound
with chlorine in carbon tetrachloride in the presence of
pyridine and the resultant product isolated and purified
in the manner described in Example 27A to give 90:,11?
dichloro-17a¢hydroxy-1-allopregnene-3,20-dione
tate.
17-ace
‘
EXAMPLE 73
9u-Br0mo-1 1 B-ChZOro-l 7 a-Hydroxy-I -A llopregnené
3,20-Dione 17-Acetate
of Example 75) (2.0 g.) is ll?-hydroxylated by fermen
tation ‘with Curvularia lunata (N.-R.1R.L. 2380) in the
manner of Example 26. The product is isolated in
15 the described manner and crystallized (from acetone-hex
ane to give 1l?-hydroxy-lh-methyl-1-allopregnene-3,20
dione.
(B) 17a-METHYL-l—,9 (11) -ALLOPREGNADIENE~
‘3,20-DIONE
17a - hydroxy - 1,9(11)-allopregnadiene-3,20-dione l7
The lip-hydroxy compound of Example 76A (2.0‘ g.)
acetate (the compound of Example 71) is reacted with 4
g. of lithium chloride, 420 mg. ‘of N-bromoacetamide and
anhydrous hydrogen chloride in acetic acid in the man
ner of Example 5. The resultant product is isolated and
puri?ed in the described manner to give 9u-bromo-11B
Chloro - 17a - hydroxy-1-al-lopregnene-3,20~dione
(A) ll?-HYDRQXY-l7a-METHYL~1-ALLOPREGNENE
3,20-DIONE
is dehydrated by ‘treatment with methanesul-fonyl chloride
in pyridine in the manner described in Example 2613.
The product is isolated in the described manner and crys
tallized from acetone-hexane to give 17u-methyl-1,9(11)
vallopregnadiene-3,20-dione.
17-ace
tate.
EXAMPLE 77
EXAMPLE 74
‘ 9a,] 1 B-Dichloro-I 7a-Hydr0xy-1,4-Pregnadiene~
3,20-Dione 17-Acetwte
One gram of 9a,l1?~dichloro-17a-hydroxy-l-allopreg
30
90:,11B-Di0hl0l‘0-1 7 a-Methyl-1 -A l lopregnene-3,20-Dione
17 a-Methyl-1,9 ( 1 l ) aallopregnadiene-3,ZO-dione (the
compound of Example 76) is chlorinated with chlorine in
72) and 0.3 g. of selenium dioxide in 50 ml. of t-‘butyl
carbon tetrachloride in the presence of pyridine in the
manner of Example 27A. The resultant product is iso
lated and puri?ed in the described manner to give 911,1 118
alcohol and 1 ml. of acetic acid are re?uxed under an
dichloro-17a-Methyl-l-allopregn'ene~3,20-dione.
nene-3,20~dione l7-acetate (the compound of Example
atmosphere of nitrogen for 24 hours. The reaction mix
ture is ?ltered through supercel and the ?ltrate poured
EXAMPLE 78
'
9a-Br0mo-11 l8-Chlor0-1 7a-Methyl-1-All0pregnene-3,20
into water. A solid separates which is ?ltered, washed
with water and crystallized from acetone-hexane to give
Dione
9a,11?-dichloro - 17a - hydroxy-1,4-pregnadiene-3,20-di~
l7a-methyl-l,9(1 l )-allopregnadiene-3 ,20-dione
one l7-acetate.
(the
EXAMPLE 75
compound of Example 76) is reacted with 4 g. of lithium
chloride, 420 mg. of N-bromo-aceta-mide and anhydrous
1 7a-Methyl-1 -A llopregnene-3,20-Di0ne
hydrogen chloride in acetic acid in the manner of Exam~
(A) 17a-ME’I‘HYLALLOPREGNANE-3,20'—DION E
45 ple 5.
The resultant product is isolated and puri?ed in
the ‘described manner to give 9a-bromo-l lB-ChlOI‘O-17oc
A solution of 1.0 g. of 17a-methylprogesterone in 25
methyl-l-allopregnene-3,20-dione.
ml. of tetrahydrofuran is added in a slow stream with
EXAMPLE 79
stirring to a solution of 400 mg. of lithium metal in 200
ml. of liquid ammonia chilled to about —70° C. in a
90:,11B-Di0hl07‘0-1
7 a-Methyl-1 ,4-Pregnadiene-3,20
Dry Ice-acetone 'bath. The reaction mixture is allowed 50
Dione
to stir for 2 minutes, then sufficient solid ammonium
One gram of 9a,ll?-dichloro-17m-methyl-1-allopreg
chloride is added to discharge the blue color. The solu
nene-3,20-dione (the compound of Example 78) is re
tion is allowed to evaporate to a residue. Water is added
acted with 0.3 g. of selenium ‘dioxide in 50 ml. of t-butyl
to the residue and the mixture extracted with ether. The
55 alcohol and 1 ml. of acetic acid under nitrogen in the
extracts are combined and washed with water, dried over
manner described in Example 74. The resultant product
magnesium sulfate, ?ltered, and evaporated to a residue
is isolated and puri?ed in the described manner to give
which is crystallized from acetone-hexane to give 170:
9oz,l IB-dichloro-lh-methyl- 1,4-pregnadiene-3,20-dione.
methylallopregnane-3,ZOadione.
(B) 2'-BROMO-17aJHETHYLALLOPREGNANE-‘3,20-DIONE 60
To a solution of 2.0 g. of the allopregnane of Example
75A in 100 ml. of acetic acid is added a drop of hy
drogen bromide in acetic acid solution, ‘followed by the
stirred for a few minutes until the bromine color is dis
3,20-dione.
(A) 17a-HYDROXY-1,9 (’11)-ALLOPREGNADIENE
A solution of 1 g. of 17a-‘hydroxy-1,9(11)-allopreg
nadiene-3,20-dione l7-acetate (the compound of Exam
ple 71) in 100 ml. of a 3:1 methanol-chloroform mixture
is chilled in ice and there is added dropwise 52 ml. of 0.1
A solid
precipitate forms which is ?ltered and crystallized from
acetone-ether to give 2-‘bromo-17a-methylal1opregnane
9a-l1,B-Dichlorw17a-Hydr0xy-All0pregnene-3,20-Di0ne
aaomoun 1
dropwise addition, with stirring, of a solution of 1.0 g.
of ibromine in 36 ml. of acetic acid. The solution is 65
charged, and then diluted with cold water.
EXAMPLE 80
Normal sodium hydroxide solution (1 equivalent). The
70 reaction mixture is stirred at 0° C. ‘for 10 minutes, then
(C) 17a-METHYL-1-ALLOPREGNENE-3,20-DIONE
1.5 grams of the Z-bromo compound of Example 75B
is re?uxed in 30 m1. of collidine for one hour. The mix
ture is diluted with chloroform and the layers are sepa 75
diluted with Water and extracted with methylene chloride.
The organic layer is washed with water, dried over mag
nesium sulfate, ?ltered and evaporated to a residue which
is crystallized from acetone-hexane to give Net-hydroxy
1,9 ( l l ) -allopregnadiene-3,20-dione.
3,087,938
28
(B) ‘901,1l?—DICHLORO-l7a-HYDROXY—l-ALLO
PREGNENE—3,20-DIONE
In similar fashion, other lower alkanoic acid esters of
the compound of Example 80 are prepared by substituting
suitable acids such as propionic and butyric for caproic
‘acid in the above procedure to give the 17-propionate and
17a-hydr0xy-1,9(11)-allopregnadiene-3,ZO-dioue (pre
pared as in Example 80A) is chlorinated with chlorine in
carbon tetrachloride in the presence of pyridine and the 5 17~butyrate respectively of 9oc,1l?-dichloro-lh-hydroxy
1-allopregnene-3,20-dione.
resultant product isolated and puri?ed in the manner de~
We claim:
scribed in Example 27 to give 9a,11?-dichloro-17a-hy
1. A compound selected from the group consisting of
droxy-1-allopregnene-3,20-dione.
17oz-R—9( l1)~dehydnoprogesterone, 17oc-R-1,9 ( 1 1 )-bisde
Alternatively, the compound of this example is prepared
from 9a,\1l?-dichloro-lh-hydroxy-1-allopregnene-3,20 10 hydroprogesterone and 17a-R-1l?-hydroxyprogesterone
wherein -R is a halogen having an ‘atomic weight greater
dione (the compound of Example 72) by reaction with
one equivalent of 0.1 Normal sodium hydroxide solution
in the manner described in Example 80A to give 90:,11?
than 19 and less than 126.
dichloro-l7ot-hydroxy-1-allopregnen'e-3,20-dione.
EXAMPLE 81
15
9a,IJ/3-Dichl0r0-1 7u-Hydr0xy-1-All0pregnene-3,20
Dione 17-Capr0ate
In the manner described in Example 2, 90¢,l1B-Di
chloro-17a-hydroxy-l-allopregnene-3,20-dione (the com 20
pound of Example 80) is reacted with caproic acid and
tri?uoroacetic \anhydride to give 9a,11?-dichloro~17a-hy
droxy-l-allopregnene-3,20-dione 17-caproate.
2.
3.
4.
5.
17a-Bromo-9 ( 11)-dehydroprogesterone.
17a-Chloro-9 ( 1 1 )-idehydroprogesterone.
1 1,B-Hydroxy-17a-br0moprogesterone.
1l?-Hydroxy-17a-chloroprogesterone.
6. 17a-Chloro-1,9( 11)-bisdehydroprogesterone.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,838,550
Lyttle et al ___________ __ June 10, 1958
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