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Патент USA US3089882

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3,089,873
United States Patent 0
Patented May 14, 1963
2
1
The unique compounds of our invention may be repre
sented in general by the ‘following formulae:
3,089,873
léa-ALKGXYCORTICOIDS
Elliot L. Shapiro, Irvington, and Hans Reimann, Bloom
?eld, N..l., assignors to Schering Corporation, Bloom
?eld, Ni, a corporation of New Jersey
No Drawing. Filed Mar. 12, 1959, Ser. No. 798,819
16 Claims. (Cl. 260-23955)
5
(A)
0H:
(IJH2OR
C---Z
' —-OH
This invention relates to a new series of physiologically
active steroid derivatives and is more particularly con
Y
: ]~-O R1
cerned with the provision of certain unique 16¢x-alkoxy
substituted steroids which possess chemotherapeutic utility
in the treatment of rheumatoid arthritis and similar in
?ammatory disorders, as well as related steroidal com 15
pounds of the general class de?ned which form valuable
intermediates for use in the production of the anti-in?am
matory agents of the invention among other possible syn
(B)
thetic steroids.
It is now well established that the ef?ciency of the early 20
steroidal therapeutic agents such as cortisone and hydro
cortisone can be enhanced substantially through modi?ca
tion of the structures of these hormones in such a manner
as to reduce or delay inactivation of the molecules, be 25
lieved to be promoted by natural mechanisms in the
human body. To this end, past e?orts have resulted in the
provision of the A13 and AL“ derivatives, C-9 halogen
ated and C—6,9 dihalogenated derivatives, C-2 and C-6,
methylated analogs, C-14 and C-l6 hydroxylated deriva 30
tives, C-16 methylated derivatives, and combinations of
and
these analogous structures, among other compounds of
somewhat lesser importance. Signi?cantly, while certain
(C)
of the above-enumerated compounds have demonstrated
35
enhanced anti-inflammatory activity, ‘at least some have
also evidenced untoward side effects such as increased
salt retention and edema-producing characteristics, dis
turbances in estrogenic and androgenic activity, loss of
bone calcium, ulcerogenesis, potassium loss, etc. Of par 40
ticular interest from the standpoint of present research
CH:
Rs
h-z'
n.3,
e?orts are the salt and water retention characteristics in
duced through use of several of the otherwise most e?‘i
cacious anti-in?ammatory agents available today includ
45
ing, for example, the 9a-halo corticoids.
The present invention is based, in part, on our discovery
that the 16a-alkoxy substituents serve to reduce or elimi~
nate the undesirable side effects of salt and Water retention
common to several of the more potent anti-in?ammatory
steroids, thereby converting these derivatives into useful
and valuable chemotherapeutic agents for the treatment
of arthritis and other inflammatory conditions. It is ad
ditionally postulated that the presence of the l6u-alkoxy
wherein W and Z are common members selected from the
group consisting of oxygen and the semicarbazono radical;
W’ is a member selected from the group consisting of
oxygen, hydroxy and acetoxy; X is a member selected
from the group consisting of hydrogen, bromine, chlorine
and ?uorine atoms; Y is a member selected from the group
consisting of oxygen, hydroxy, hydrogen-in which case
groups serves to a limited extent to stabilize or screen the 55 the C—9:C-ll bond is ole?nic and replaces X, and an
active centers of the steriod molecules against metabolic
epoxy radical having one valence linked to C-9- and also
replacing X; Z’ is a member selected from the group con
breakdown, thereby further enhancing the normal anti
sisting of oxygen, cyanohydrin, and cyano-in which case
inflammatory activity of our products through protracted
the C-l7zC-20 ‘bond is ole?nic and replaces R4; R is a
or sustained existence of the same within the body. In
the same manner, the reduction in chemical reactivity to 60 member selected from the group consisting of hydrogen
be expected at 0-20, for example, ‘by reason of the 160:
and lower acyl radicals; R1 is a lower alkyl radical; R2 and
R3 are each members selected from the group consisting
alkoxy substituents, renders the compounds of the inven
tion independenly useful as intermediates in the produc
of hydrogen and bromine; R4 is a member selected from
the group consisting of hydrogen and hydroxy; R5 is a
tion of other steroidal derivatives.
3,089,873
ll
.33
member selected from the group consisting of methyl and
acyloxyrnethylene radicals; and R6 is a member selected
from the group consisting of hydrogen, halogen and lower
alkyl.
spectively. The latter compound may be obtained also by
microbiological oxidation of l6a-methoxy~l7oi-hydroxy
3,1l,20-trioxo-4-pregnen-2l-yl acetate with the microor
ganism Bacillus splzaericus var. fusiformis (A.T.C.C.
The foregoing compounds may be prepared by various
7055).
different routes of synthesis. In general, however, the
The compound l6ot-methoxy-1lp,l7u,2l-trihydroxy-4
preparatory techniques involve the addition of lower
pregnene-3,20-dione (i.e. l6a-methoxyhydrocortisone)
aliphatic alcohols, such as methanol, ethanol, butanol,
may also be prepared by various routes of synthesis. One
propanol and isomeric forms of such alcohols, to suitable
such procedure consists of forming the intermediate 16a
l6-dehydro-20-oxo steroids to yield the corresponding 10 methoxy-3,20-bis(ethylenedioxy) - 1701,21 - dihydroxy - 5
léix-alkoxy-substituted steroids. The latter compounds
pregnene-ll-one by treatment of 16a-mcthoxy-l7a,2l-di
are then subjected to further reactions for their protected
hydroxy~4-pregnene-3,l1,20 - trione (16oz - methoxycorti~
conversion to the useful steroid derivatives depicted by
sone) with ethylene glycol in the presence of a suitable
the foregoing formulae. While the reactions involved in
catalyst such as para-toluenesulfonic acid, with or without
the production of our compounds are described herein 15 an inert solvent medium such as benzene. Reduction of
after with particular reference to the use of methanol for
the oxo-group at C-1l in the latter compound with a
introduction of the methoxy group in tat-orientation to the
suitable reducing agent such as lithium aluminum hydride
C~l6 carbon atom, it is to be understood that the alkoxy
yields the corresponding ll?-hydroxy compound. Hy
substituent is a direct function of the particular alcohol
drolysis of this compound with a suitable acid reagent
employed, and that all of the usual aliphatic alcohols 20 such as acetic acid, or sulfuric acid in methanol provides
can be used interchangeably in the basic reaction mech
the desired 16u-methoxy-1l/S',170:,2l-trihydroxy-4-preg
anisms of the invention.
nene-3,20-dione.
By way of illustration of the general methods applica
Still another procedure consists of the formation of
ble to the production of the unique compounds of the
the intermediate l6oa-methoxy-3,20-bis(semicarbazono)
invention, the 16~en-20-one group of the compound 25 l7a,2l~dihydroxy-4-pregnene-1l-one by the reaction of
11,20-dioxo-5/3-pregn-l6-en-3a-yl acetate may be treated
16m-methoxy-17a,21-dihydroxy-4-pregnene - 3,11,20 - tri
with methanol, for example, in the presence of a suitable
one with semicarbazide. In this manner, the sensitive
acidic or basic catalyst, and with or without an inert
3,20-dioxo groups are protected so that the ll-oxo func
solvent medium such as tetrahydrofuran, to derive the,
tion can be reduced with sodium or potassium borohy
corresponding 16a-methoxy-3a-hydrOXy-S/B-pregnane-I l, 30 dride in aqueous tetrahydrofuran to yield the 16a-meth
20-dione which is then esteri?ed with acetic anhydride in
oxy-3,20-bis (semicarbazon0)-4 - pregnene - 115,17a - 21
conventional manner to obtain the corresponding 3
triol. Thereafter, the 3,20-dioxo functions are regenerat
acetate. Treatment of the latter compound with hydro
ed in conventional manner as, for example, by means
gen cyanide in alcohol yields the intermediate l6a-me
of pyruvic acid, or by hydrolytic procedures involving
thoxy-20-cyano~20-hydroxy-ll-oxo-5?-pregnan-3a-yl ace 35 use of dilute hydrochloric acid or nitrous acid. Acetyla
tate which can be converted, in turn, to l6a-methoxy-20
tion of the foregoing compound yields the corresponding
cyano-l1-oxo-5?-pregn-l7(20)-en-3a-yl acetate by means of
16m-methoxyhydrocortisone ZI-acetate.
a suitable dehydrating agent such, as for example, phos
Microbiological dehydrogenation of the latter com
phorus oxychloride in pyridine at mild temperatures of
the order of 10—60° C. Upon treatment of the latter 40
intermediate with an oxidizing agent such as osmium
tetroxide in the presence of pyridine or potassium per
manganate and in a solvent such as acetone containing
the corresponding 16u-methoxy-3a,17a - dihydroxy - 5,8
45 (A.T.C.C. 6949) or Bacillus sphaericus var. fusiformis
(A.T.C.C.) provides l6u-methoxy-ll?,l7a-2l-trihydroxy
1,4-pregnadiene-3,20-dione (16oz - methoxyprednisolone)
which upon esteri?cation in conventional fashion yields
tate ion yields 16a-methoxy-3a,17a-dihydroxy-l1-oxo~5?
pregnan-21-yl acetate, which is then oxidized to the cor
responding 3~ketone with chromic acid or other suitable
agents such as N-bromosuccinimide and N-bromoaceta~
mide. Bromination of the 3-ketone with one mole of
bromine followed by dehydrohalogenation either with a
suitable base such as collidine, lutidine, dimethylforma
mide, etc., or reaction with semicarbazide followed by
pyruvic acid treatment yields the l6a-methoxy-17a-hy
idroxy - 3,11,20 - trioxo-4-pregnen-2l-yl acetate (l6a-me
thoxy-cortisone ZI-acetate).
The corresponding prednisone derivative, 16a-methoxy~
(A.T.C.C. 6949) yields léa-methoxy-ll,B,l7a-dihydroxy
3,20-dioxo-1,4-pregnadien-2l-yl acetate (l6a-methoxy~
prednisolone 21-acetate). Alternatively, microbiological
dehydrogenation of the l6u-methoxyhydrocortisone with
either of the microorganisms Coryncbacterium simplex
piperidine, followed by alkaline hydrolysis, one derives
pregnane-1l,20-dione derivative. Treatment of the latter
compound with bromine followed by exchange with ace~
pound with the microorganism Corynebacterium simplex
the corresponding ZI-acetate compound.
‘By treating the 16a-methoxy-1l?,l7a-dihydroxy-3,20
droxo-lA-pregnadien-Zl-yl acetate with a sulfonyl chlo
ride such as methanesulfonyl chloride in a solvent such
as pyridine or dimethylformamide one obtains 16a
5.5
methoxy - l7a-hydroxy-3,20-dioXo-l,4,9( ll)-pregnatrien
21-yl acetate. This compound upon treatment with N—
bromoacetamide in the presence of water and a strong
acid catalyst such as perchloric acid provides the 90:
bromo - 16a - methoxy-l 1,9,17a-dihydroxy-3,ZO-dioxo-1,4
pregnadien-Zl-yl acetate.
Treatment of the latter com
l7a-hydroXy-3,l1,20-trioxo - 1,4-pregnadien-2l-yl acetate 60 pound with a base such as sodium acetate in acetone or
may be prepared by subjecting the l6a-methoxy-l7a-hy
droxy-3,11,20-trioxo-4-pregnen-2l-yl acetate to biochemi
cal synthesis consisting of fermentation in the presence of
the microorganism Corynebacterium simplex (A.T.C.C.
6946), or by reacting 16u-methoxy-17u-hydroxy-3,11,20
trioxo-S?-pregnan-Zl-yl acetate with 2 moles of bromine
followed by dehydrohalogenation with a suitable base
such as collidine, lutidine, or dimethylformamide.
Hydrolysis of l6a-methoxy-17u-hydroxy-3,l1,20-tri
ethanol provides 95,1118 - epoxy - 16oz - methoxy - l7a-hy
droxy - 3,20 - dioxo-l,4-pregnadien-2l-yl acetate, which
upon treatment with hydrogen chloride or hydrogen fluo
ride yields, respectively, 9u-chloro- and 9ot-?UOI‘O-l6u
65 methoxy _ 11B,17cc - dihydroxy-3,20-dioxo-l,4-pregnadien
2l-yl acetates.
These compounds may be converted to
the corresponding ll-oxo derivatives by treatment with a
suitable oxidizing agent as, for example, chromic acid.
By a sequence of reactions similar to those outlined
oxo-4-pregnen-2l-yl acetate (l6a-methoxycortisone 21 70 above, 160: - alkoxy-l1,6,l7e-dihydroxy-3,20-dioxo-4-preg
nen-Zl-yl acetates (l6a-alkoxyhydrocortisone ZI-ace
acetate) or l6a-methoxy-l7a-hydroxy-3,1l,20-trioXo-1,4
tates)
may serve as the precursors for the corresponding
pregnadien-Zl-yl acetate (l6m-methoxyprednisone 21-ace
9ot-halo-substituted l6a-alkoxyhydrocortisones and 16a
tate) with either base or acid yields the corresponding
alkoxycortisone analogues. Of course, any of the 21
l6a-methoxycortisone and l6a-methoxyprednisone, re
acetates described hereinbefore may be converted to the
3,089,873
21-alcohol steroids by mild acidic hydrolysis. The alco
hols thus produced may be converted to useful esters by
treatment with a suitable acid chloride or acid anhydride
in a solvent such as pyridine. Useful esters include, for
example, the acetate, propionate, isovalerate, enanthate,
Another useful intermediate for the preparation of the
compounds depicted hereinbefore is ll?-hydroxy~3,20
dioxo-4,l6-pregnadien-21-yl acetate. A typical synthesis
utilizing this intermediate is the following:
Treatment of the foregoing compound with Z-methyl
tertiary-butyl acetate, cyclopentylpropionate, phenoxyace
2-ethyl-1,3-dioxolane in an inert solvent such as benzene
tate and substituted phenoxyacetates, furoate and substi
tuted furoates. Other valuable ester derivatives include
water-soluble compounds such as monosodium succinate,
phthalate, sulfobenzoate, phosphate, sulfate as well as 10
21-yl acetate. Reaction of the latter compound with
methanol and a base such as potassium hydroxide yields
glycinate salts and gluconates.
As will appear readily to the skilled observer, the prep
and a catalytic amount of para-toluenesulfonic acid yields
3~ethylenedioxy - 115 - hydroxy-20-oxo-5,IG-pregnadien
the corresponding 16u-methoxy-substituted 21-hydroxy
compound which, upon ‘treatment with acetic anhydride
aration of the 16oc-alkoxy steroids identi?ed by formulae
and pyridine in conventional fashion, yields S-ethylene
A, B and C above is not restricted to the procedures out
dioxy-16a-methoxy - 1118 - hydroxy-ZO-oxo-S-pregnen-21
lined hereinbefore. Considering the methoxy derivatives 15 yl acetate. Treatment of the latter intermediate with
hydrogen cyanide followed by phosphorus oxychloride
again for purposes of illustration, the intermediates 16o:
methoxy - 17a - 21 - dihydroxy-4-pregnene-3,20-dione and
and pyridine yields the compound 3-ethylenedioXy-20
16cc - methoXy -l7<x , 21 - dihydroxy-l,4-pregnadiene~3,20
cyano-l6u-methoxy - 5,9(1l),17(20) - pregnatrien-Zl-yl
dione are useful intermediates for the ‘syntheses of such
acetate. When the latter compound is reacted with potas
sium permanganate in the manner outlined above, and
thereafter subjected to alkaline hydrolysis, and 'subse
quent acetylation there is produced the intermediate 3~
compounds.
These compounds may be obtained from
3?-hydroxy-5,16-pregnadiene-20-one by reactions similar
to those outlined above. Thus, 16-dehydro-pregnenolone,
which may be obtained from diosgenin, is treated with
ethylene-dioxy - 16a - methoxy - 17a - hydroxy - 20 - oxo
5,9(l1)-pregnadien-2l-yl acetate. Reaction of the latter
methanol in the presence of acid or base and is then esteri~
?ed to yield 16a-rnethoxy-20-oxo~5-pregnen-3?-yl ace 25 compound with aqueous acetic acid yields l6a-methoxy
tate. Reaction with hydrogen cyanide, followed by de
l7a~hydroXy-3,20-dioxo-4,9 ( l l ) -pregnadien-21-yl acetate
hydration with phosphorus oxychloride and subsequent
treatment with an oxidizing agent such as osmium tet
one of the compounds disclosed hereinbefore as obtained
by a different route of synthesis.
roxide as described hereinbefore yields l6a-methoxy-3?,
17a-dihydroXy-S-pregnene-20~one. Bromination of the
latter compound followed by treatment with sodium
(3-11 as outlined above, one may also employ this tech
nique for introduction of a 17 oc-hYdI‘OXY group on a num
iodide and then potassium acetate yields the compound
In addition to the microbiological hydroxylation at
16a - methoXy - 35,17ot-dihydroxy-ZO-oxo-S-pregnen-Zl-yl
ber of 16u-methoxy corticosteroids with or without 9a
halogen substitutents. For example, if ‘one treats 3
acetate. By subjecting the latter compound to the action
of the microorganism Flavo bacterium dehydrogenans
pregnen-Zl-yl acetate, previously described above, with
var. hydrolyticum in a manner analogous to that described
aqueous acetic acid, one obtains 16u-methoxy-11B-hy
in Republic of South Africa Patent No. 3462/55, one ob
tains the compound 16a-methoxy-17a,21-dihydroXy-4
ethylenedioxy-l6a-methoxy - 11p - hydroxy - 20 - oxo-S
droxy-3,20-dioXo-4-pregnen-2l-yl acetate (16oc-1I16’thOXY
corticosterone ‘ZI-acetate) which, after hydrolysis of the
pregnene~3,20-dione which, upon treatment with Coryne
C-21 acetate function, is hydroxylated at 0-17 with the
bacterium simplex (A.T.C.C. 6946) is transformed into
the analogous nl-derivative.
microorganism Cephalothecium roseum Cda. (A.T.C.C.
8685) whereby one obtains 16uemethoxy-17w, 115,21
The foregoing intermediates upon being subjected to
C~ll microbiological hydroxylating organisms capable
of introducing an ll/i-hydroxy substituent as, for exam
trihydroxy-4-pregnene-3,20-dione.
Further illustrative of the ‘foregoing procedure, one
may employ the above 16a-methoxy-1l?-hydroxy~3,20
ple, Curvularia lunata (QM. 120 h) yield directly 16a 45 dioXo-4-pregnen-21-yl acetate as an intermediate for the
methoxy-hydrocortisone and 16a-methoxyprednisolone.
preparation of 9a-fluoro-16a-methoxy-1lp-hydroXy-3,20
In addition, the same intermediates upon being subjected
to microbiological hydroxylating organisms such as Dela
croixia coronata which is capable of introducing an 11%
dioXo-l,4-pregnadien-21-yl acetate in a manner similar to
that described hereinbefore.
'I'hus, microbiological de
hydrogenation yields l6a-cmethoxy - 11B - hydroXy-3,20
hydroxy substituent, yield l6ot-methoXy-1la,l7a,2l-tri 60 dioxo-l,4-pregnadien-21-yl acetate. Dehydration of the
hydroxy-4-pregnene~3,ZO-dione and the corresponding
A1 analogue. These lla-hydroxy intermediates may be
esteri?ed selectively with 1 mole of acetic anhydride with
or Without a base such as pyridine to produce the corre
latter substance with methanesulfonyl chloride yields the
Agul) analogue which is treated successively with hydro
bromous acid, potassium ‘acetate and hydrogen ?uoride
and then hydrolyzed with acid as described above. In this
sponding 21-acetates. Treatment, in turn, of these mono 55 manner, one obtains 9cL-?l101'O-l6a-II16ITIOXY-11,8,21,411
acetates with methane-sulfonyl chloride yields the 110:
hydroxy-l,4—pregnadiene-3,20-dione which may the em
mesylate which may be treated with sodium acetate in
ployed as a substrate for the organism Cephalothecium
acetic acid to eliminate methanesulfonic acid with pro
roseum to produce 9a-?uoro-l6a-methoxy-l113,17a,21
duction of the above-mentioned 16a~methoxy-17a-hy
trihydroXy-l,4-pregnadiene-3,20-dione.
droxy-3,20-dioXo-4,9(11)-pregnadien-21-yl acetate and 60 A still further technique for the production of the
1606 - IIIBihOXY-l7OL-hYdl‘OXY-3 ,20-dioXo-l,4,9(1l)-pregna—
trien-Zl-yl acetate.
In addition to diosgenin as mentioned above, smila
compounds of our invention utilizes the reaction of diazo
methane in the presence of boron tri?uoride whereby an
alcohol is transformed to an ether. As illustrative of
this reaction scheme, ‘one may prepare the bis-3,20
genin is also useful as a starting material in the prepara
tion of the novel compounds of our invention. Other 65 ethylenedioxy derivative of 9a-fluoro-1l?,16u,17a,21
important starting materials include the 12-oxygenated
sapogenins, such as hecognenin, rockogenin, and gentrog
enin. For example, hecogenin has been converted to 3,8
hydroxy-l6-dehydro-5a-pregnane-11,20-dione. A 16a
tetrahydroXy-4-prcgnene-3,20-dione by use of ethylene
glycol with paratoluenesulfonic acid as the catalyst.
Treatment with acetic anhydride in the presence of pyr
alkoxy substituent can be introduced on this compound 70 idine then provides the corresponding 21-acetate. This
bis-ethylenedioxy-Zl-acetate compound is then reacted
by means of the desired alcohol and an acid or base cata
with diazomethane in the presence of boron tri?uoride.
lyst. The side chain can then be elaborated as described
After hydrolysis of the ethylenedioxy moieties with hydro
above, and the A-ring modi?ed in conventional manner
chloric acid in methanol, one obtains 9a-ftuoro~16a
to yield the A4- or A1'4- double bond(s) as well as the
characteristic 3-oxo-substituent.
75 methoxy-ll?,l7a,2l-trihydroxy - 4 - pregnene-3,20-dione,
3,089,873‘
'5’
9;
one of the compounds of our invention previously syn
thesized hereinbefore by a different mechanism.
The 6-methyl and 6-halo analogues of the novel corti
Example I
Synthesis of the compound, 16tx-methoxy-17u-hydroxy
3,11,20~trioxo~4-pregnen-2l-yl acetate, as represented by
coids of the invention may be readily produced. A
typical procedure for the production of these compounds
is detailed below.
the formula:
(I)
l6a-methoxy ~ l1B,17a,21 - trihydroxy - 4 - pregnene
CH3
CHrOC'OCHz
3,20-dione is dissolved in benzene, for example, and then
reacted with ethylene glycol in the presence of para
toluenesulfonic acid to yield the corresponding 3,20-bis 10
ethylene ketal, with the double bond shifting to give
the A5 analogue.
Epoxidation with a peracid as, for
example, perphthalic acid, yields the corresponding 5a,6ot
epoxy derivative (as well as the 55,6;3-epoxide).
The
5u,6a-epoxide is then reacted with Grignard reagent 15
(methyl magnesium iodide, for example) to provide the
5e-hydroxy-6?-n1ethyl-3,2O-bisethylene-ketal of the me
thoxyhydrocortisone. Hydrolysis with acetic acid (90%)
yields
6B~'11ethyl-16et-methoxy-l 1,8, l7u,2l-trihydroxy-4
pregnene-3,20-dione. Alternatively,hydrolysis of the 3 20 A. Preparataion of the intermediate, 16u-methoxy-3a
hydroxy-S?-pregnane-l1,20-dione, as represented by the
ketal with oxalic acid in methanol provides the 3-oxo
formula:
5ot-hydroxy~6t3-methylsteroid which, upon treatment with
hydrogen chloride in ethanol, is transformed directly into
6a-methyl-l6u-methoxy - 11B,17a,21 - trihydroxy-4-preg
(H)
CH3
CH3
nene-3,20-dione. The latter compound is also obtained 25
by treatment of the above 3-oxo-A4-6/3-methyl derivative
with hydrogen chloride in ethanol. Treatment of the
=0
16u-methoxy-6ot-methylhydrocortisone with acetic an
0H30
hydride, for example, yields the corresponding 2l-acetate.
By the series of transformations outlined previously, the 30
-OCH2
2l-acetate derivative may be readily converted to the
following compounds: 6a-methyl-16u-methoxy-17a-hy
droxy-3,l1,20-trioxo-4-pregnen-2l-yl acetate; 6a-methyl—
130-
90: - ?uoro-l6u-methoxy-1l?,‘l7a-dihydroxy-3,20-doxo-4
pregnen-Zl-yl acetate; 6u~methyl-9a-?uoro-16a-methoxy
H
35
llB,l7a,21-trihydroxy - 4 - pregnene - 3,20 - dione; 6a
methyl-16u-methoxy - l1B,17a,21 - trihydroxy~1,4—preg
nadiene-3,20-dione ;
A solution consisting of 2.4 grams of 11,20-dioxo-5?
6iz-methyl-l 6a-methoxy-1 13,17a-di
pregn-16-en-3a-yl acetate in 260 milliliters of a four
hydroxy-3,20-dioxo-1,4-pregnadien - 21 - yl acetate; 6a
methyl-l6tz-methoxy - 17a - hydroxy—3,l1,20-trioxo-1,4
percent (4%) methanolic potassium hydroxide solution
pregnadien ~ 21 - yl acetate; 6a-methyl - 9a - Ch10I‘0-16a
methoxy-ll?,l7a-dihydroxy - 3,20 - dioxowlA-pregnadien
was cooled, evaporated to approximately 20 milliliters,
was re?uxed under nitrogen for 3 hours. The solution
and added to 120 milliliters of Water. The resulting pre
21-yl acetate; 6a-methyl-9a-?uoro-l6u-methoxy-1 15,170‘
cipitate was ?ltered, washed with water, and, after dry
ing, was crystallized from acetone-hexane, to yield the
dihydroxy-S,20-dioxo - 1,4 - pregnadien-Zl-yl acetate; 6:»
methyl-9a-?uoro-l6a-methoxy - 1lB,17oz,21 - trihydroxy
1,4-pregnadiene-3,20-dione; 6a-methyl - 9a - ?uor0¢16a~
desired 16u-methoxy - 3a - hydroxy - 5,8 - pregnane-11,20
dione of Formula II.
methoxy - 17a - hydroxy-3,11,20-trioxo-l,4~pregnadien
B. Preparation of the intermediate, 16u-methoxy-1l,20—
dioxo-5?-pregnan-3a-yl acetate, as represented by the
formula:
The corresponding 6-?uoro or 6-chloro derivatives, by 50
2-l-yl acetate; and 6u-rnethyl-9a-?uoro-l6a-methoxy
17a,2l-dihydroxy-1,4-pregnadien-3,l1,20-trione.
way of illustration, may be produced as follows: The
5a,6a-epoxide as obtained above, is treated with hydrogen
(III)
CH2
CH3
?uoride to yield the Soc-hf/dIOXY-G?-?HOI‘O derivative.
The hydrolysis as described above (i.e. oxalic acid) gives 55
the 3,20-diketo analogue which, upon treatment with
90% acetic acid, followed by hydrogen chloride in
—OCH3
ethanol, yields successively the 3-oxo-A4-6B-?uoro and
then the 3-oxo-A4-6a-?uoro derivatives.
Alternatively,
in the manner described above, treatment of the 3-keto 60
5a-hydroxy compound with hydrogen chloride in ethanol
CHaOCO-
yields the 16a-methoxy-6ct-fluorohydrocortisone directly.
Similarly, substitution of hydrogen chloride for hydrogen
fluoride in the foregoing synthesis yields the l6oa-methoxy
6ot-chlorohydrocortisone derivative via the corresponding
intermediates described above for the ?uoro analogue.
Furthermore, by the same series of transformations pre
viously described, one may obtain the 6u-?uoro or 604
chloro analogues of the 6a-rnethyl steroids listed above.
It is believed that the above as well as other features
and objects of our invention will best be understood by
reference to the following examples illustrating the actual
preparation of novel compounds of the invention via
various different syntheses:
To one (1) gram of the 16a-methoxy-3a~hydroxy-5,9
pregnane-l1,20-dione of step A, there were added 5
milliliters of pyridine and 2 milliliters of acetic anhydride
under anhydrous conditions. The reaction solution was
permitted to remain at room temperature for 24 hours
7' and then diluted with 30 milliliters of water. The pre
cipitate thereby ‘formed was ?ltered, washed with water
and dried. Crystallization from aqueous methanol yielded
the desired ldwmethoxy-substituted Zia-acetate steroid of
Formula III.
75 C. Preparation of the intermediate, 16a-methoxy-20
3,089,873
9
10
at room temperature overnight, ?ltered, made acid with
cyano-20-hydroxy-1 l-oxo-5B-pregnan-3a-y1 acetate, as
represented by the formula:
acetic acid and then concentrated under vacuum to a vol
ume of approximately 5 milliliters. Water was then
added and the mixture extracted with methylene chloride.
The organic phase was dried over magnesium sulfate,
?ltered, and the ?ltrate evaporated to dryness under
vacuum.
The crude residue thus obtained was crystal
lized from acetone-hexane to yield the desired 160c
methoxy-3a,17 a-dihydroxy - 55 - pregnane-11,20-dione of
Formula VI.
The corresponding S-acetate of the foregoing compound
may be produced by treating, for example, 1.0 gram with
0.5 gram of acetic anhydride in 2.5 milliliters of pyridine
for 4 hours. Upon the addition of water, a precipitate
is formed which is separated by ?ltration and dried.
Crystallization from acetone-hexane yields the desired
To a solution consisting of 1.9 grams of the inter
mediate of Formula III in 19 milliliters of ethanol and
7.0 milliliters of acetic acid maintained at approximately
0° C., there were added 6.5 :grams of potassium cyanide. 20
acetate ‘derivative, namely 16a-methoXy-l7oc-hydroxy-11,
20~di=oxo-5?-pregnan-3oc-yl acetate.
F. Preparation of the intermediate, l60t-Il'l6thOXy-3oc,17ot—
dihydroxy-l1,20-dioxo-5?-pregnan-21-yl acetate, as rep
The mixture was stirred for 80 minutes and allowed to
resented by the formula:
warm to room temperature. The stirred mixture was
thereafter permitted to remain at room temperature for
4 hours, diluted with water to obtain a precipitate which
was collected by ?ltration and washed with water. The 25 V II)
crude cyanohydrin was then crystallized from ethyl ace
tate-hexane to yield the desired compound of Formula IV.
CH3
GHzO C 0 CH3
D. Preparation of the intermediate, l6a-methoxy-20
cyano-ll-oxo-S/i-pregn-ITQO)-en-3a~yl acetate, as rep
30
resented by the formula:
(V)
CH3
on.
110-
O_/\
H304‘
35
-OCH3
0113000» 3
A solution consisting of 0.38 gram of the compound of
40 Formula VI in 19 milliliters of CF. chloroform (to which
there was added a few drops of chloroform saturated
with hydrogen bromide) was cooled to -25° C. Bro—
H
mine (0.164 gram) in 11 milliliters of chloroform was
To a solution of 5 milliliters of pyridine containing 1.4
added dropwise over a period of 2 hours. The chloroform
grams of the compound of Formula IV, there \was added 45 solution was then washed with water and evaporated under
0.7 milliliter of phosphorus oxychloride. After standing
reduced pressure to a residue to which was added one
at room temperature for 18 hours, water was added, and
gram ‘of sodium acetate and 10 milliliters of dimethyl
the resulting precipitate was thereafter washed with water
formamide. The mixture was stirred at 65° C. for 4
hours and then allowed to stand overnight at room tem
and dried. Crystallization from aqueous ethanol yielded
the desired steroid of Formula V.
perature. The mixture was thereafter poured into water
and the resulting solid ?ltered and dried. Crystallization
from ‘acetone-hexane yielded the desired acetate of For
mula VII.
E. Preparation of the intermediate, l6a-methoxy-3a,17a
dihydroxy-S?-pregnane-l1,20-dione, as represented by
the formula:
G. Preparation of the intermediate, l6oc-meth0XY-17a
(VI)
55
hydroxy-3,1 1,20-trioxo-5e-pregnan-2l-yl acetate, as rep
resented by the formula:
(VIII)
60
CH3
CHZOCOCHK
=0
110H
65
The compound of Formula V, in amount 0.87 gram,
was dissolved in 10 milliliters of dry benzene and 0.4
milliliter of pyridine. Osmium tetroxide, in amount 1.0
gram, was added and the solution stirred for 18 hours at
room temperature. A solution of 2.0 grams of sodium 70
sul?te in 30 milliliters of water was then added and the
A solution consisting of 370 milligrams of the com
mixture Was stirred for one hour. The organic phase
pound
of Formula VII in 35 milliliters of 80% acetone
was separated and concentrated under vacuum to a volume
Water solution was cooled to 10° C. N-bromosuccinimide,
of approximately 3 milliliters. Ethanol, in amount 30
milliliters, was then added and the mixture was stirred 75 in amount 155 milligrams, together with one drop of con
3,089,873
11
l2
centrated hydrochloric acid were added and the mixture
was maintained in the dark at 10° C. for 23 hours.
Sodium sul?te solution was added until starch iodide paper
was negative. The mixture was then concentrated under
reduced pressure to a small volume.
droxy‘-4-pregnene-3,11,20-trione, as represented by the
formula:
(X)
CH;
0112011
Water was then
added and the precipitated solid separated by ?ltration 5
and dried, whereby there was obtained an impure form
of the desired acetate. Puri?cation of this impure sub
I :0
"OH
0-—/\
stance was etfected by treatment with zinc dust in aqueous
acetone containing a few drops of acetic acid. The zinc 10
was removed by ?ltration and the ?ltrate then concen
trated to a small volume. Addition of water yielded the
‘0on3
H30
desired compound of Formula VIII.
H. Preparation of the intermediate, 4-bromo-16a-me
thoxy-l7u-hydroxy-3, 1 1,ZO-trioxo-S?-pregnan-Zl-yl ace
One gram of the acetate of Formula I was dissolved in
15 30 milliliters of methanol and 5 milliliters of water con
tate, as represented by the formula:
(1):)
taining 0.2 gram of potassium bicarbonate. This solu
tion 'was re?uxed for 30 minutes, and then concentrated
under reduced pressure. Water was then added to the
residue and the resulting precipitate ?ltered and dried.
on,
c1120 0 0 CH3
20 Crystallization from acetone-ketone yielded the desired
compound of Formula X.
Example III
Synthesis of the compound, 16et-II16ihOXY-11B,l7a,2l
25 trihydroxy-4-pregnene-3,ZO-dione, as represented by the
formula:
1 :0
"OH
0—/\
-oom
H30
(XI)
CH3
0__
g 11
CHzOH
=0
' --OH
0011;
30
Br
H0
H30
A solution consisting of 64 milligrams of bromine in
6 milliliters of tertiary-butyl alcohol was added to 173 35
milligrams of the compound of Formula VIII contained in
6 milliliters of tertiary-butyl alcohol and 6 milliliters of
methylene chloride. The reaction solution was main
tained at 30-35“ C. until the bromination was complete
(approximately 3 hours). The solution was then evapo
rated to ‘dryness under reduced pressure and the residue
slurried with water. The resultant precipitate was col
lected on a Biichner funnel, washed with water and dried.
In this manner, there was obtained the desired acetate of
0:
A. Preparation of the intermediate, 16a-meth0xy-3,20
40
bis(semicarbazono) - 17a,21 - dihydroxy - 4 - pregnene
ll-one, as represented by the formula:
(XII)
CH3
0112011
=N.NH.CO.NH:
Formula IX which may be used directly, or initially puri 45
?ed, and thereafter subjected to the following ?nal trans
formation.
O
'
3,11,20-trioxo-4-pregnen-2l-yl acetate of formula I:
The compound of Formula IX, in amount of 180 milli
-OOHs
H30
1. Preparation of the desired l6a-methoxy-l7a-hydroxy
50
grams, was dissolved in a mixture of 8 milliliters of
tertiary-butyl alcohol and 4 milliliters of methylene chlo
ride. Eighty (80) milligrams of semicarbazide were 55
added and the reaction solution was stirred under an at
mosphere of nitrogen for 2 hours at 25—30° C. The sol
vent was removed under reduced pressure and the residue
dissolved in 12 milliliters of 80% acetic acid-water solu
tion. Pyruvic acid (70%), in an access, was then added
and the mixture was allowed to remain at room tempera
A mixture consisting of 5.0 grams of the compound of
Formula X (Example II), 8.5 grams of semicarbazide
hydrochloride, 6 grams of pyridine, 50 milliliters of water
and 200 milliliters of methanol was re?uxed for 17 hours.
The solution was concentrated to about 50 milliliters, and
60 then poured into water to precipitate the desired bis-semi
carbazone derivative of Formula XII.
ture for 23 hours. Dilute sodium hydroxide (5%) was
B. Preparation of the intermediate, 16a-methoxy-3,20
added until the pH was adjusted to approximately 7.0.
bis(semicarbazono)-4-pregnene~11?,17a,21-triol, as rep
Water was added and the mixture extracted with methyl
resented by the formula:
ene chloride. The combined methylene chloride extracts
011.
were evaporated to dryness ‘and the residue subjected to 65 (XIII)
0112011
chromatographic resolution on activated magnesium sili
cate. The fractions collected between 50% ether-in
I =N.NH.OO.NH1
"OH
hexane and ether were evaporated and crystallized from
HO—/\
acetone-hexane, thereby yielding the desired compound of
Formula I
70
E30
()\?,‘§,2“=239 III/.1)
Example II
Synthesis of the compound, 16a-methoxy-17a,21~dihy 75
HIN.CO.NH.N=
0 on,
3,089,873
14
'13
To a solution consisting of 0.6 gram of the compound
of Formula XIV of Example IV in 10 milliliters of py
ridine there was added 0.4 milliliter of methanesulfonyl
chloride in 6.0 milliliters of pyridine. The solution was
liliters of water was re?uxed for 6 hours. The solution
was cooled and acetic acid was ‘added to approximately 5 allowed to stand for 12 hours and was then poured into
ice-hydrochloric acid. A solid precipitated which was
pH 5.5. The organic solvent was removed under reduced
A solution consisting of 6.0 grams of the bis-semicar
bazone of Formula XII, 4.0 grams of potassium borohy
dride in 200 milliliters of tetrahydrofu-ran and 100 mil
recovered by ?ltering. Crystallization from acetone
hextane yielded the desired intermediate of Formula
pressure and the solids in the residue were ?ltered to
yield the desired compound of Formula XIII.
C. Preparation of the 16a-methoxy-11/3,17a,21-trihydroxy
4-pregnene-3,2‘0-dione of Formula XI:
XVI.
10
Five (5) grams of the intermediate of Formula XIII
were dissolved under nitrogen atmosphere in 250 mil
liliters of 2.4 N-hydrochloric acid. The solution was
cooled to 5° C., and 2.5 grams of sodium nitrite in 25
'
B. Preparation of the 9u-bromo-l6a-methoxy-l1?,17u-di
hydroxy-3,20-dioxo-4-pregnen-2l-yl acetate of Formula
Puri?ed dioxane, in amount 40 milliliters, was added
to 0.4 gram of the intermediate of Formula XVI, fol
milliliters of water were added over a ?fteen (15) minute 15 lowed by the addition of 4 milliliters of water, 0.2 gram
of N-bromo-acetamide and 2 milliliters of 1.5 N-per
period at 5° C. The reaction mixture was stirred an ad
chloric acid. The mixture was stirred for 3 hours, and
ditional 30 minutes, then cooled to below 15° C., neu
then 0.4 gram of sodium sul?te in 4 milliliters of water
tralized with 20% sodium hydroxide, and extracted sev
was added and the mixture extracted with methylene chlo
eral times with chloroform. The solvent was evaporated
under reduced pressure to give a solid residue which, 20 ride. The organic extracts were washed with water,
dried and evaporated to a solid residue which was crys
tallized from acetone-hexane to yield the desired com
after crystallization from acetone-hexane, yielded the de
sired hydrocortisone derivative of Formula XI.
'
pound of Formula XV.
Example IV
Synthesis of the compound 16a-methoxy-11?,17u-di 25
hydroxy-3,20-dioxo-4-pregnen-21-yl acetate, as repre
sented by the formula:
(XIV)
on;
0112000 on,
=()
30
I --on
-0 on;
HO
Example VI
Synthesis of the compound, 9a-bromo-l6a-methoxy
11B,170:,21-trihydroxy-4-pregnene-3,20-dione, as repre
sented by the formula:
CH3
0112011
(XVII)
11.0
35
E0
' --on
"00113
H30
0:
To one (1) gram of the compound of Formula XI,
there was added 0.6 milliliter of acetic anhydride in 2.4 40
milliliters of pyridine.
After standing for 3 hours at
room temperature, the mixture was poured into ice and
hydrochloric acid. The resulting precipitate was ?ltered
and recrystallized from aqueous methanol to yield the
desired acetate derivative of Formula XIV.
Example V
Synthesis of the compound, 9u-bro'mo-l6a-methoxy—
1 15, l7a-dihydroxy-3 ,20-dioxo-4-pregnen-2 l-yl acetate, as
represented by the formula:
(XV)
CH3
45
A mixture of one (1) gram of the acetate of Formula
XV, Example V, in 200 milliliters of methanol, 40 milli
liters of chloroform, 10 milliliters of water, and 10 milli
liters of concentrated hydrochloric acid was permitted to
stand at room temperature for 48 hours. Water was then
50 added and the mixture extracted with methylene chloride.
The organic extracts were Washed with water, dried and
then concentrated to a residue. Crystallization from
acetone yielded the desired steroid of Formula XVIII.
01-120 0 0 CH3
=0
l "on
-0 CH3
E0
H30
55
I
17a-dihydroxy-3,20-dioxo-4-pregnen-21-yl acetate, as rep
resented by the formula:
/g\/
Br I
O-
Example VII
Synthesis of the compound, 9nt-?l10I'O-16a-1116th0XY-1113,
60
(XVIII)
A. Preparation of the intermediate, 16a-methoxy-l7u-hy
»droxy-3,20-dioxo-4,9(11)-pregnadiene-21-y1 acetate, as
represented by the formula:
(XVI)
0H,
=0
65
01120 0 0 CH3
.
CH3
:0
l _._0H
m i To CH:
OH;
OHaOCOCHa
I —-OH
: T0011.
70
75 A. Preparation of the intermediate, 9‘B,11;8-epoxy-16a
3,089,873
I5
methoxy-17a-hydroxy-3,20-dioxo-4-pregnen-2l-yl
tate, as represented by the formula;
(XIX)
16
ace
l‘la-21~trihydroxy-4-pregnenc-3,ZO-dione, as represented
by the formula:
CH3
CHzOCOCHa
,
“OH
—OCH:
10
0
4
Q:
In exactly the same manner as previously described in
Example VI, 1.0 gram of the acetate of Formula XVIII,
Example VII was hydrolyzed to the steriod alcohol of
Formula XXI.
To 0.6 gram of the compound of Formula XV, Ex
Example X
-‘ ample V, in 40 milliliters of ethanol, there was added 0.6
'gram of potassium acetate. The mixture was re?uxed for 20
Synthesis ‘of the compound, 16a-methoxy'17u-hydroxy
6 hours, and then concentrated under reduced pressure to
3,1 1,20-trioxo-1,4-pregnadien-21-yl acetate, as represented
a residue which was treated with water.
The solid ma—
by the formula:
terial present was ?ltered-01f and dried. Crystallization
from acetone-hexane yielded the desired 9,8,11,8-epoxy
25
derivative of Formula XIX.
(XXII)
on,
01-110 0 0 CH:
B. Preparation of the 9a-?uoro-16u-methoxy-11/8,17a-di
hydroxy - 3,20 - dioxo-4-pregnen-21-yl acetate of For
mula XVIII:
To a solution containing 0.5 gram of the compound of
Formula XIX in 20 milliliters of alcohol~free chloro
0
H10
30
=0
' --OH
OCH;
form at 0° C., there was added an aliquot of 32.2 milli
liters of a solution consisting of hydrogen ?uoride in
alcohol-free chloroform and tetrahydrofuran (prepared by
dissolving 41.4 grams of hydrogen ?uoride in 65.3 milli
0.__
35
A. Preparation of the intermediate, 2,4-dibromo-16a~
liters of tetrahydrofuran and 31.5 milliliters of ethanol
methoxy - 17a-hydroxy-3,11,20-trioxo-5?-pregnan-2l-yl
free chloroform). The mixture was permitted to stand
acetate, as represented by the formula:
for 4 hours at 0° C., and was then poured into ice-water.
The pH was adjusted to 7 with sodium bicarbonate, and 40
the mixture then extracted with methylene chloride. The
organic extracts were evaporated under reduced pressure
to a residue which, upon crystallization from acetone
hexane, yielded the desired compound of Formula XVIII.
Example VIII
Synthesis of the compound, 9ot-Cl‘ll0I‘O-l6m-II16HJOXY
1 1,8,17a-dihydroxy-3,20-dioxo-4-pregnen-2l-yl acetate, as
represented by the formula:
45
50
(XX)
CH;
(EH20 C O CH;
I —-OH
: To om
To a solution of 234 milligrams of the compound of
Formula VIII, Example I~G, in 6 milliliters of dioxane,
55 there was rapidly added 260 milliliters of bromine con
tained in 2 milliliters of dioxane. The 2,4-dibromide thus
formed was precipitated by the addition of water and then
separated by ?ltering. The resulting compound of Form
ula XXIII thus produced was of su?icient purity for use
60 in vthe conversion described in step B below.
B. Preparation of the 16a-methoxy-l7a-hydroxy-3,l1,20
trioxo-lA-pregnadien-Zl-yl acetate of Formula XXII.
To 4 milliliters of re?uxing dimethylfonnamide con
A solution consisting of 0.4 gram of the 95,1113-epoxy 65 taining 20 milligrams of calcium carbonate, there were
‘derivative of Formula XIX, Example VII-A in 60 milli
added 180 milligrams of the compound of Formula XXIII.
liters of alcohol-free chloroform was saturated at 0° C.
After two (2) hours of re?ux, the mixture was cooled and
‘with anhydrous chloride and the mixture permitted to
poured into dilute hydrochloric acid. The resulting mix
stand at 0° C. for six (6) hours. The solvent was dis
ture was extracted with methylene chloride and the or
tilled under reduced pressure and the remaining residue 70 ganic extracts evaporated to a solid residue which was
crystallized from acetone-water to yield the desired com
then subjected to chromatographic resolution on activated
pound of Formula XX.
Example 1X
magnesium silicate. The fractions obtained by elution
with 30% ether in hexane to 70% ether in hexane were
collected and, upon treatment with acetone-hexane,
Synthesis of the compound, 9a~?uoro-16a-methoxy-1118, 75 yielded
the desired compound of Formula XXII.
3,089,873
17
(A.T.C.C. 7055) in the manner described in Example >
Example XI
Synthesis of the compound, 16a-methoxy-17a,2l-di
hydroxy-1,4-pregnadiene-3,l1,20-trione, as represented by
XI-—B to yield the desired prednisolone derivative of
7 Formula XXV.
Example XIII
Synthesis of the compound, 16a-methoxy-1 113,17 oz-di
the formula:
(XXIV)
CH:
hydroxy-3,20-dioxo-1,4-pregnadien-2l-yl acetate, as repre
(EHQOH
sented by the formula:
(XXVI)
‘
OH,
01120 O 0 OH:
10
15
'A. The compound of Formula XXII, Example X—B,
in amount 0.5 gram, was hydrolyzed with aqueous
alcoholic potassium bicarbonated in the manner described
in Example II to yield the desired compound of Formula 20
XXIV above.
B. In an alternate synthesis for the compound of
anhydride and 2.4 milliliters of pyridine in the manner
described in Example IV to yield the methoxy-prednisolone
formula XXIV, the microorganism Bacillus sphaericus
‘acetate derivative of Formula XXVI.
var, fusiformis (A.T.C.C. 7055) was incubated on a nu
trient medium :of the following composition for 24 hours 25
at 28° C.:
Bacto-beef extract ____________________ __grams__
3
Bacto-peptone _________________________ __do____
Sodium chloride _______________________ _._do____
5
8
Agar _
__
__do____ 15
The compound of Formula XXV (Example XII), in
amount 1.0 gram, Was treated with 0.6 milliliter of acetic
Example XIV
Synthesis of the ‘compound, 16a-methoxy-l7a-hydroxy
3,11,204trioxo-1,4-pregnadien-21-yl propionate, as repre
sented by the formula:
om
30 (XXVII)
Tap water
liter-.. 1
To 100 milliliters of 1a sterile nutrient broth consisting
of 3 grams of Bacto‘beef extract and 5 grams of Bacto
peptone per liter of tap water, contained in a 300 milliliters 35
?ask, was added one loopful of the incubated culture as
prepared above, and the broth mixture was further incu
bated for 24 hours at 28° C. on a shaking machine. The
broth culture thus produced Was employed as an inoculum
40
(1 % ).
Into each of ten (10) ?asks containing 100 milliliters of
sterile nutrient broth, was added 1 milliliter of the inocu
The compound of Formula XXIV (Example XI), in
amounts 1.0 gram, was reacted with propionic anhydr-ide
in pyridine in the manner described in Example IV to yield
lum. The flasks were agitated on a shaker for 8 hours at
28° C. at 240 strokes per minute. After this growth
the compound of Formula XXVII.
period, a solution of 25 milligrams of the 16a-methoxy 45
Example XV
17 11,21-dihydroxy-4-pregnene#3,11,2O~trione (Formula X)
Synthesis of the command, 9a-b-romo-l6a-methoxy~
of Example II in 0:5 milliliter of methanol, was added to
each ?ask under asceptic conditions. The ?asks were
11f},l7a-dihydroxy-3,20-dioxo - 1,4-pregnadien-21~yl ace
agitated again and incubated for an additional 24 hours.
The ?nal pH was 7.8.
The contents of the ?asks were then combined and ex
tate, as represented by the formula:
50 (XXVIII)
on,
01110 G 0 OH:
u-acted three (3) times with 2 liters of chloroform per ex
traction. The combined chloroform extracts were evapo
0:0
rated to dryness to yield 300 milligrams of crude product.
The crude steroid was crystallized from acetone to yield 55
the desired compound of Formula XXIV.
Example XII
war
I --011
O
—O OH:
1130
Synthesis of the compound, 16a-methoxy-11B,17a,21
trihydroxy-1,4-pregnadiene-3,ZO-dione, as represented by 60
the formula:
(XXV)
A. Preparation of the intermediate, l6a-methoxy-l7a-l
hydroxy-3,20-dioxo- 1,4,9 ( l 1 ) -pregnatrien-2 l-yl acetate, as
OH:
O'HzOH.
=0
l --on
HO
represented by the formula:
OH;
65 (XXIX)
-O OH:
H3O
70
The compound of Formula XI (Example III), in
amount of 250 milligrams, was fermented by means of
the microorganism Bacillus splzaericus var. fusiformis 75
'
3,089,878
'
'
'
20
'19
A solution consisting of 0.5 gram of the compound of
11,8,l7a,2l-trihydroxy-1,4-pregnadiene-3,20-dione, as rep
resented by the formula:
Formula XXVI (Example XIII), in 3 milliliters of ‘pyri
dine was reacted with 0.3 milliliter of methanesulfonyl
(XXXII)
chloride in 5 milliliters of pyridine. The solution Was al
CH1
011,011
lowed to stand for 15 hours and was then poured into ice
hydrochloric acid. A solid precipitate formed which was
recovered by ?ltration and crystallized from acetone
hexane to yield the desired intermediate of‘ Formula
I "OH
HO——/\
"OOH:
mo I
XXIX.
B. Preparation of the 90c-bI‘OIt1O-16ct-1'Il?thOXY-l15,1700 10
dihydroxy-3,20-dioxo~1,4-pregnadien-21-yl acetate of
Formula XXVII:
To a suspension of 1.0 gram of the compound of
The compound of Formula X)O( (Example XVI), in
Formula XXIX in 100 milliliters of puri?ed dioxane were 1 OK
amount 1.0 gram, was converted to the desired steroid
added 10 milliliters of water, 0.4 gram of N-bromo
of Formula XXXII by means of‘ hydrochloric acid in
acetamide and 4 milliliters of 1.5 N perchloric acid. The
methanol-ch10roform-water in the manner described in
mixture was agitated for 4 hours, and thereafter 1.0
Example VI.
gram of sodium sul?te in 10 milliliters of water was added,
Example XVIII
and the reaction mixture was extracted with methylene 20
chloride. The organic extracts were washed with Water,
Synthesis of the compound, 9a-bromo-16a-methoxy
dried over magnesium sulfate, ?ltered and evaporated.
11/3,l7a,21-.trihydroxy-1,4-pregnadiene-3,ZO-dione, as rep
The resulting solid was crystallized from acetone to yield
resented by the formula:
the desired compound of Formula XXVIII.
Example XVI
25
(XXXIII)
CH3
>
CHaOH
Synthesis of the compound,- 9u-?uoro-l6a-methoxy
11B,17a-dihydroxy - 3,20 - dioxo - 1,4 - pregnadien-Zl-yl
acetate, as represented by the formula:
30
(XXX)
CH3
(‘31120000133
Q...
35
The compound of Formula XXVIII (Example XV)
was converted to the desired compound of Formula
XXXIII by means of hydrochloric acid in methanol
‘chloroform-water in the manner described in Example VI.
40
11?,17a-dihydroxy - 3,20 - dioxo - 1,4 - pregnadien-21-yl
A. Preparation of ‘ the intermediate, 95,11B-epoxy-16a
acetate, as, represented by the formula:
methoxy-lh-hydroxy - 3,20 - dioxo-1,4-pregnadien-2l
yl acetate, as represented by the formula:
Example XIX
Synthesis of the compound, 9a-chloro-16a-methoxy
45 (XXXIV)
CH3.
01120 C O CH:
(XXXI)
(‘1:0
on;
(‘31110 C O OH:
C=O
CH3
|-__OH
a‘
q -0 CH:
\
___i
231A 5921011.,
50
/\/s
or) or
\/
55
_ The compound of Formula XXXI (Example XVI-A),
in amount 1.0 gram, was treated with gaseous hydrogen
One (1) gram of the compound of Formula XXVIII
(Example XV) was added to 70 milliliters of acetone and
chloride in the manner described inExample VIII to yield
the desired compound of Formula XXXIV.
1.0 gram of potassium acetate and the mixture re?uxed 60
for 5 hours and then concentrated to a residue. Water
Was added to the residue and the resulting solid was re
covered by ?ltrationand then crystallized from methanol
water to give the desired intermediate of Formula XXXI.
B. Preparation of the 9oc-?l1OI‘0-16a-II161ZIIOXY-l1?,17o!_7
dihydroxy-3,20-dioxo-1,4-pregnadien-21-yl acetate of
Formula XXX:
A solution consisting of 0.8 gram of the intermediate
of Formula XXXI was treated with hydrogen ?uoride in
the manner described in Example XI-B to yield the de
sired compound of Formula XXX.
Example XVII
Synthesis of the compound, 9a-?uoro-16a-methoxy
Example XX
Synthesis of the compound, 9a-chloro-l6armethoxy
‘11/3,17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione, as rep
resented by the formula:
65 txxxv)
on,
‘
HO
omon
o=0
3,089,873
21
22
Example XXIV
Synthesis of the compound, 9a-chloro-16a-methoxy
By the same procedure as described in Example VI, the
acetate of Formula XXXIV (Example XIX), in amount
0.5 gram, was converted to the desired compound of For
l7u,21-dihydroxy-1,4-pregnadiene-3,l1,20-trione, as rep
mula XXXV.
resented by the formula:
Example XXI
Synthesis of the compound, 9a_?uoro-16a-methoxy
0H3
CHzOH
(XXXVIII)
17a - hydroxy - 3,11,20 - trioxo - 1,4 - pregnadien - 21 - yl
acetate, as represented by the formula:
(XXXVI)
CH3
10
CHQO o 0 CH;
=0
|---0H
/:
it
-0 CH3
15
it i
20
To a solution consisting of 0.6 gram of the compound
of Formula XXX (Example XVI) in 30 milliliters of
In exactly the same manner as previously described
for the synthesis of Example VI, 1.0 gram of the com
pound of Formula XXXVII (Example XXIII) was con
verted by reaction with hydrochloric acid in methanol
acetic acid there Was added dropwise a solution of 120
chloroform-water to the desired steroid of Formula
milligrams of chromium trioxide in 2 milliliters of Water
and 6 milliliters of acetic acid. The reaction solution was 25 XXXVIII.
Example XXV
permitted to stand for 5 hours, then diluted with water
and ?nally extracted with methylene chloride. The or
Synthesis of the compound, 9a—bromo-l6u-methoxy
ganic extracts were washed with water, dried over mag
170a - hydroxy - 3,11,20 - trioxo - 1,4 - pregnadien - 21 - yl
nesium sulfate, ?ltered and ?nally evaporated to a residue
acetate, as represented by the formula:
which, upon treatment with acetone, yields the desired 30
compound of 'Formula XXXVI.
(XXXIX)
Example XXII
Synthesis of the compound, 9u-?uoro-l6a-methoxy
l7ol-2l-dihydroxy-1,4-pregnadiene-3,l1,20-trione, as rep
resented by the formula:
CH3
CHaOCOCH:
=0
0=l/\ Geffen:
CH3
CHzOH
(XXXVII)
CH3
40
In the same manner as described in connection with the
synthesis of Example XXI, 0.6 gram of the compound of
Formula XXVIII (Example XV), was reacted with chro
~miurn trioxide in aqueous acetic acid to yield the acetate
derivative of Formula XXXIX.
EXAMPLE XXVI
In exactly the same manner, as described in Example
II, the compound of Formula XXXVI (Example XXI),
Synthesis of the compound, 9a-bromo-l6a-methoxy-t
in amount 1.0 gram, was saponi?ed with potassium bi
carbonate to yield the desired steroid of Formula
XXXVII.
Example XXIII
Synthesis of the compound, 9a-chloro-l6a-methoxy~
17¢,21 - dihydroxy - 1,4 - pregnadiene - 3,11,20 - trione,
as represented by the formula:
55
(XL)
CH:
011,011
17a - hydroxy - 3,11,20 - trioxo - 1,4 - pregnadien - 21 - yl
acetate, as represented by the formula:
(XXXVII)
1:0
"011
60
CH3
o—/\
H301/a
01120 0110 CH:
=0
65
-0o11=
in
O.
\/
In the manner described for the synthesis of Example
O:
The compound of Formula XXXIV (Example XIX),
70 VI, 1.2 grams of the compound of Formula XXXIX (Ex
ample XXV) Was reacted with hydrochloric acid in
methanol-chloroforrn-water to yield the desired steroid of
Formula XL.
in amount 0.6 gram, was reacted with chromium trioxide
Having thus described the subject matter of our inven
in aqueous acetic acid in the manner described in Example
XXI to yield the desired steroid of Formula XXXVII.
75 tion, what it is desired to secure by Letters Patent is:
3,089,873
23
24
1. A 16-alkoxy steroid selected from the group consist
selected from the group consisting of oxygen, cyanohy
ing of compounds represented by the formulae:
drin and cyano-in which case the C-17: C-20 bond is
ole?nic and replaces R4; Q is an arrangement of atoms
CH3
Rs
about the C—9: C-ll positions selected from the group
consisting of
In and 0/6
/\
a
./
10
\c.
Q’ is a member selected from the group consistingof oxy
gen and hydroxy; R is a member of the group consisting
of hydrogen and lower acyl radicals; R1 is a lower alkyl
radical; R2 and R3 are each members selected from the
group consisting of hydrogen and bromine; R4 is a mem
ber selected from the group consisting of hydrogen and hy
m.
CH;
GHzOR.
droxy; ‘and R5 is a member selected from the group con
sisting of methyl and lower acyloxymethyl radicals.
2. The chemical compound 16u-methoxy-3u-hydroxy
S?-Pregnane-I 1,20-di0ne.
3. The chemical compound 16a~methoxy-1l,20'dioxo
5?-pregnan,3oz-yl acetate.
4. The chemical compound 16tx-methoxy-20-cyano-20
hydroxy-l l-oxo-S?-pregnan-Sa-yl acetate.
5. The chemical compound IGa-methoXy-ZO-cyano-II
oXo-5B-pregn-17(20)-en-3a-yl acetate.
6. The chemical compound l6a~methoxy~3a,17a-dihy
droxy-S?-pregnanc-l1,20-dione.
30
35
7. The chemical compound 16a-methoxy-3a,17a-dihy
droxy-l1,20-dioxo-5?-pregnan 2l-yl acetate.
8. The chemical compound 16a-metl1oxy-17a-hydroxy
3,11,20-trioX0-5 a-pregnan-21,yl acetate.
9. The chemical compound 4-brom0-16a-methoxy-17a
hydroXy-3,1 1,20-trioxo-5B-pregnan-2l-yl acetate.
10. The chemical compound 16a—methoxy-3,20-bis
(semicarbazono)-1705,21-dihydroxy-4-pregnene-1l-one.
11. The chemical compound 16or-methoxy-3,20‘bis
(semicarbazono)~4-pregnene-1 1,8,17a,21-triol.
40
0H3
13. The chemical compound 9?,1l?-cpoxy-16a-meth
OHQOR
‘
Q
1130
I --on
'03:
12. The chemical compound l6a-methoxy-17a-hy
droxy-3,20-dioxo-4,9( l1)-pregnadien-21-yl acetate.
45
oxy-l7a-hydroxy-3,20-dioxo-4-pregnen-2l-yl acetate.
14. The chemical compound 2,4-dibromo-16a-methoxy
17a-hydroxy-3,11,ZO-trioxo-S?-pregnan-Zl-yl acetate.
15. The chemical compound 16a-methoxy-17a-hy
droxy-3,20-dioxo-l,4,9(11)-pregnatrien-2l-yl acetate.
16. The chemical compound 9B,1lB-epoxy-16a-meth
oxy-17a-hydroxy-3,20-dioxo-1,4-pregnadien-21-y1 acetate.
50
wherein W’ is a member selected from the group con
sisting of oxygen, hydroxy and acetoxy; Z’ is a member
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,946.812
Fried et a1 ____________ __ July 26, 1960
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