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Патент USA US3033873

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3,@33,853
Patented May 8, 1962
2
3,033,863
butyric acid, valeric acid, isovaleric acid, trimethyl acetic
Gaston Amiard, Noisy-ie-Sec (Seine), and Rene Heymes,
acid, lauric acid, myristic acid, palmitic acid and stearic
acid, caproic acid, ?-trimethyl propionic acid, heptanoic
acid, caprylic acid, pelarginic acid, capric acid, undecylic
18-NOR-CORTISONES AND PRGCESS FOR
THEE PREPARATEGN
Romainville (Seine), France, assignors, by mesne as
signments, to Roussel-UCEAF, §.A., Paris, France, a
corporation of France
No Drawing. Filed (Set. 10, 1961, Ser. No. 144,836
Claims priority, application France Get. 2t), 1969
14 Claims. (Cl. 260-23955)
The invention relates to novel 16a-methyl-18-nor
cortisones having the formula
acid; alkenoic ‘acids such as undecylenic acid and oleic
acid; cycloalkyl carboxylic acids such as cyclopentyl car
boxylic acid, cyclopropyl carboxylic acid, cyclobutyl car
boxylic acid and cyclohexyl carboxylic acid; cyc-loalkyl
alkanoic acids such as cyclopentyl acetic acid, cyclohexyl
acetic acid, cyclopentyl propionic acid and cyclohexyl
propionic acid; arylalkanoic acids such as phenyl acetic
acid and phenyl propionic acid; aryl carboxylic acids
such as :benzoic acid and 2,4-dinitrobenzoic acid; phenoxy
alkanoic acids such as phenoxy acetic acid, p-chloro
phenoxy acetic acid, 2,4-dichlorophenoxy acetic acid, 4
ter-butylphenoxy acetic acid, 3-phenoxy propionic acid
and 4-phenoxy butyric acid; heterocyclic carboxylic acids
such as furane-Z-carboxylic acid, S-ter-butylfurane-Z
carboxylic acid, 5-bromofurane-2-carboxylic acid and
nicotinic acids; ,B-ketoalkanoic acids, such as acetylace
tic acid, propionylacetic acid and butyrylacetic acid;
I
amino acids such as diethylaminoacetic acid and aspartic
wherein R is selected from the group consisting of hydro
acid.
gen and an acyl radical of an organic carboxylic acid
The 16ot-methyl-18-nor-cortisone and its esters are
having 1 to 18 carbon atoms. The invention further
relates to a novel process for the preparation of said com 25 prepared by reacting 3-ethylenedioxy-16a-methyl-18-nor
pregnane-11,20-dione with oxygen in the presence of an
pounds and novel intermediates thereof.
alkali metal tertiary butylate to form 3-ethylenedioxy
Compounds such as cortisone, hydrocortisone, predni
sone, prednisolone and dexarnethasone are known to
17cc - hydroperoxy - 16cc - methyl-18-nor-pregnane-11,20
possess glucocorticoidal activity, but it is also known that
dione, reducing the latter to form 3-ethylenedioxy-16u
mum of side e?ects.
nane-17ot-o1-3,11,20-trione, dehydrobrominating the said
these products when administered over a period of time 30 methyl-18-nor-pregnane-17a-ol-11,20-dione, hydrolyzing
the latter under acidic conditions to form 16a-methy1-18
have undesirable side e?ects such as the retention of sodi~
nor-pregnane-lh-ol-SJ1,20-trione, reacting the latter
um and water and are ulcergenic. The compounds of
with bromine to form 4,8-bromo-16a-methyl-18-nor-preg
Formula I possess glucocorticoidal activity with a mini
'' 4B-bromo-steroid to form 16u-methyl-18-nor-A4-preg
It is an object or" the invention to provide novel 18
nor-cortisones of Formula I.
nene-17a-0l-3,11,20-trione, introducing a hydroxyl group
in the 21-position of the latter to form 16a-methyl-18
It is another object of the invention to provide a novel
nor-cortisone and recovering the latter. The 16a-methyl
process for the preparation of 18-nor-cortisones of
18-nor-cortisone may be esteri?ed in the 21-position by
Formula I.
40
reacting the said cortisone with an esterifying agent such
It is a further object of the invention to provide novel
as an acid anhydride or acid halide.
intermediates for ls-nor-cortisones of Formula I and
particularly:
16a-methyl-18-nor-pregnane-17a-ol-3J 1,20-trione may
‘also be produced by reacting 3-ethylenedioXy-16a-rnethyl
(a) 3-ethylenedioxy-l7a-hydroperoxy - 16cc - methyl
18-nor-pregnane-1 1,20-dione
(b) 3-ethylenedioxy-16a-methyl-18-nor-pregnane-l7a
ol-l1,20-dione
(c) 16a-methy1-18-nor-pregnane-‘17u-ol-3,11,20-trione
45
A17<2°>-pregnene-11-one reacting the latter with a peracid
such as perbenzoic acid to form 3-ethylenedioxy-16a
methyl-17,20-epoxy-20-acetoxy-18-nor - pregnane-ll-one
(d) 4B-bromo - 16a - methyl-18-nor-pregnane-1h-ol
3,11,20-trione
50
(e) 16u-methyl - 18 - nor-A‘i-pregnene-17¢x-0l-3,11,20
formed chemically by reacting 16a-methyl-18-nor-A4
pregnene-17a-ol-3,11,20-trione with iodine in the presence
obvious from the following detailed description.
55 of a mixture of calcium chloride and calcium oxide to
The compounds of the invention have the formula
form the corresponding 21-diiodo derivative of the said
CH2OR
11
CH3
and subjecting the latter to acid hydrolysis to form 16m
methyl-18-nor~pregnane-17ot-ol-3,11,20-trione.
The introduction of the ZI-hydroxy group may be per
trione.
These and other objects and advantages will become
0_/\
18-nor-pregnane-11,20-dione with acetic acid anhydride
to form 3-ethylenedioxy~16a-rnethyl-20-acetoxy-18-n0r
steroid, reacting the latter with an alkali metal salt of a
=0
lower - alkanoic acid to form the corresponding 21
'--on
acyloxy derivative of said steroid and hydrolyzing the
latter to the corresponding ZI-hydroxy steroid. The 21
60
hydroxy steroid may also be formed by the action of
: i-CHS
diastases secreted by microorganisms such as ColletO
trichum lindemuthianum (ATCC 12,611) as described in
0:
U.S. Patent No. 2,805,978.
I
wherein R is selected from the group consisting of hydro
gen and an acyl radical of an organic carboxylic acid
having 1 to 18 carbon atoms.
The acyl radical of the organic carboxylic acid having
65
A preferred mode of the process of the invention com
prises reacting 3-ethylenedioXy-16a-methy1-18-nor-preg
nane-11,20-dione with oxygen in the presence of potas
sium tertiary butylate at room temperature to form 3
ethylenedicxy - 17a - hydroperoxy - 16a - methyl - 18
1 to 18 carbon atoms may be derived from an aliphatic,
nor-pregnane-l1,20-dione, reacting the latter with zinc
aromatic, cycloaliphatic or heterocyclic carboxylic acid. 70 and acetic acid to form 3-ethylenedioxy-16a-rnethyl-l8
Examples of suitable acids are alkanoic acids such as
formic acid, acetic acid, propionic acid, butyric acid, iso
norapregnane~17wol~11,20-dione, hydrolyzing the latter
with hydrochloric acid at re?ux temperatures to form
3,033,868
"
V
"
V
>
*
4
l6a-methyl-1S-nor-pregnane-lh-ol-L1LZOQtIione, react- '
ing the latter with bromine in acetic ‘acid to form 45
bromo - 16oz - methyl - 18 - nor - pregnane - 17oz - 01
wherein R is selected from the group consisting of hydro~
gen ‘and an acyl radical of an organic carboxylic acid
having 1 to 18 carbon atoms.
The starting material, S-ethylenedioxy-l6a-methyl-18~
nor-pregnane~1 1,20-dione, is prepared by reacting 3-ethyl
enedioxy-l8-nor-A16-pregnene-l1,20-dione described by
3,l1,720-7tri0ne, dehydrobrorninating the latter with a miX1
ture of lithium bromide and lithium carbonate to form
160a - methyl - l8 - nor - A4 - pregnene -17u - ol - 3,11,20
Velluz et ‘all. in Comptes Rendus Acad. 80., vol. 250 (196),
trione, introducing .a hydroxyl group in the 21-position
page 371, with a methyl magnesium halide in the pres
of the latter to form 16u-rnethyl-l8-nor-cortisone and
ence of cuprons chloride.
recovering the latter. The reaction schemes are outlined
10
In the following examples there are described sev
in Table I.
O
3
H
it
'
'
//
moo-0H3 /
0
cm
7
3,033,863
6
eral preferred embodiments to illustrate the invention.
However, it should be understood that the invention is
B was dissolved in 60 cc. of acetone and 12 cc. of 5 N
hydrochloric acid were added thereto. The mixture was
heated to re?ux for a period of ?ve minutes, 20 cc. of
‘not intended to be limited to the speci?c embodiments.
The melting points are instantaneous melting points as
water were added and the acetone was removed under
determined on the Maquenne block.
5 vacuum. 16a-methyl-18-nor-pregnane-17a - ol - 3,11,20
EXAMPLE I
_
trione crystallized. The crystals were vacuum ?ltered
Preparation of 3-Ethylenedi0xy-16oc-Methyl-18
washed with water, dissolved in methylene chloride,
Nor-Pregnane-l1,20-Di0ne, II
treated with animal black, ?ltered and concentrated to a
small volume. On the addition of hot ether, 16a-methyl
To 40 cc. of ethereal solution of methylmagnesium
iodide prepared from 2.2 gm. of magnesium and 9.0 cc. 10 18-nor-pregnane-17a-ol-3,11,20-trione precipitated. The
crystals were vacuum ?ltered to give 4.32 gm. of product
of methylene iodide, there was added, after cooling to
(being 45% with reference to 3-ethylenedioxy-l6ct
methyl-l8-nor-pregnane-l1,20-dione), melting at 202° C.
and directly utilizable for the next step of the synthesis.
precipitate was formed and after having cooled to 0° C.,
By evaporation of the mother liquors, it was possible
500 mg. of cuprous chloride were added in two por 15
0° C., 120 cc. of tetrahydrofurane without allowing the
interior temperature to mount above +5 ° C.
A White
to recover 1.5 gm. of
tions, cooling each time to 0° C., and then 14 gm. of 3
win 65 cc. of tetrahydrofuran were introduced over sev
eral minutes under ‘agitation. The reaction mixture was
agitated for a period of forty-?ve minutes, then poured
into a mixture of 300 gm. of ice and 15 gm. of am
monium chloride. After decantation, the solvents were
removed under vacuum.
The residue comprising 3-ethylenedioXy-16a-methyl—
l8-nor-pregnane-11,20-dione crystallized. The aqueous
phase resulting from the decantation was extracted with
16a-methyl-lS-nor-pregnane
3,1 1,20-‘trione.
For analysis, the 16a-methyl-18-nor-pregnane-17a-ol
ethylenedioxy ~ 18 - nor - A16 - pregnene _ 11,20 - dione
3,11,20-trione was puri?ed by recrystallization from
methylene chloride to give a sample melting at 204—206°
C. and having a speci?c rotation [a]D2°=—|-21° (c.=1%
in chloroform). The product occurred in the form of
colorless crystals. It was very soluble in chloroform,
soluble in alcohol and acetone and slightly soluble in
25 ether and insoluble in water.
Analysis. —- CHI-13004; molecular weight = 346.45.
Calculated: C, 72.80%; H, 8.73%. Found: C, 72.6%;
H, 8.8%.
ether and the said pregnane as vacuum ?ltered was re
dissolved in combined ethereal extracts. The ethereal
The infrared spectra con?rmed the presence of a hy
solution was washed with N/lO hyposul?te, then with
droxyl by a band at 3607 cmrl.
water, dried over magnesium sulfate, passed in the car 30
This compound is not described in the literature.
‘bon black and concentrated to a small volume. The prod
Step D.--Preparali0n of 4,8-br0m0-16a-metlzyl-18-n0r
uct crystallized.
Hexane was added, the ether was re
moved, the solution was iced, vacuum ?ltered, washed
pregnane-J7a-ol-3,11,20-trione.—4 gm. of l6a-methyl-l8
nor-pregnane-17a-ol-3,l1,20-trione were dissolved in 90
with hexane and dried. 12.4 gm. of 3—ethylenedioxy
16a-methyl-18-nor-pregnane-11,20-dione were obtained 35 cc. of anhydrous chloroform. 9 cc. of acetic acid were
added and then 11.5 cc. of a solution cooled to —-60° C.
(being a yield of 85%) having a melting point of 148
of bromine in acetic acid were introduced drop by drop.
150° C. and a specific rotation [a]D2°=+32°-_'-2°
The solution was prepared from 14.55 gm. of bromine,
(c.=1% in chloroform). The product was soluble in
7.3 gm. of hydrobromic acid and a suflicient quantity of
‘alcohol, acetone, benzene, chloroform, slightly soluble in
ether, hexane, insoluble in water.
40 acetic acid in order to give a volume of 90 cc.
9.1%.
'
This compound is not described in the literature.
EXAMPLE II
to. The mixture was poured onto a mixture of water and
The extracts were
washed with a solution of sodium bicarbonate and water,
45 ice and extracted with chloroform.
Preparation of the Acetate of 16u-Methyl-18-N0r
_
The re
action mixture was agitated for a period of thirty minutes
at —60° C. and then 2.8 gm. of sodium acetate contain
ing 3 mols of water in 15 cc. of water were added there
Analysis.-—C23H34O4; molecular weight=374.50. Cal
culated: C, 73.76%; H, 9.15%. Found: C, 73.9%; H,
then dried over magnesium sulfate.‘ The solution was
concentrated to a small volume, vacuum ?ltered and 3.8
Cortisone
gm. (being 80%) of 4/3-bromo-16a-methyl-18-nor-preg
Step A.——Preparati0n of 3-ethylenedioxy-J(fa-methyl
] 7a-hydr0per0xy-18-nor-pregnane-11,20-a’i0ne.——2 gm. of 50 nane-17a-ol-3,11,20-trione were obtained which was uti
potassium were dissolved in 170 cc. of tertiary butanol
under agitation and an atmosphere of nitrogen. The mix
ture was cooled to 25° C. and 10 gm. of 3-ethylenedioxy
lized in the raw state for the next step of the synthesis.
This compound is not described in the literature.
By treatment with zinc and acetic acid, 0.44 gm. of
16a-methyl-l8-nor-pregnane-11,20-dione were introduced.
the 16ot-methy1-18-nor-pregnane-17a - ol - 3,11,20 - trione
Oxygen was bubbled into the mixture for a period of 55 were recovered from the mother liquors.
Step E.—Preparati0n of l6a-methyl-l8-nor-A4-preg
forty-?ve minutes until the absorption of about 650 cc.
of oxygen. A solution of 3-ethylenedioxy-17a-hydro
peroxy-16a-methyl-18-nor-pregnane-11,20-dione was thus
obtained.
nene-17a-0l-3,11 ,20-trz'0ne.——3.8 gm. of 4?-bromo-16a~
>methyl-18-nor-pregnane-17a-ol-3,11,20-trione were intro
Step B.-—Preparation of 3-ethylenedi0xy-16a-methyl
60 gm. of lithium bromide and 1 gm. of lithium carbonate
were added and the mixture was heated under agitation
18-n0r-pregnane-1 7a-ol-11,20-dione.—-To the refrigerated
duced into 38 cc. of anhydrous dimethlformamide.
2
and an atmosphere of nitrogen to 135° C. ‘for a period
solution obtained in Step A were added 60 cc. of acetic
'of forty minutes. After cooling and addition of water
acid and then 20 gm. of zinc. The mixture was agitated
and several cc. of acetic acid, the mixture was extracted
for a period of twenty minutes at room temperature, then
heated to 60° C. for a period of ?fteen minutes. The 65 with methylene chloride. The extracts were washed with
water, dried and concentrated under vacuum. The 16w
.zinc was ?ltered, water was added and the organic sol
methyl-18-nor-A4-pregnene-17a-ol-3,11,20 - trione crystal
vents were eliminated by distillation. After alkaliniza
lized and was recovered by vacuum ?ltration. 2.5 gm.
tion by addition of sodium hydroxide solution, the mix
(being a yield of 81%) of raw productwere obtained
ture was extracted with ether. The ethereal solution was
was recrystallized from methanol, yielding a prod
washed with water, dried, evaporated to dryness and 3 70 which
uct having a meltingpoint of ZZZ-224° 7C. and a speci?c
_ethylenedioxy-16a-methyl-18 - nor - pregnane - 17a-ol
_ 11,20-dione was obtained as a residue.
This compound
, was used as such for the next step of the synthesis.
Step C.—-—Preparati0n of 16a-methyl-18-n0r-pregnane
v17ct-ol43,11,20-trione.---The compound prepared in Step 75
rotation [a]D2°=-i-l65°i2° (c.=1% in chloroform).
The product occurred in the form of colorless leaflets,
very soluble in chloroform, soluble in acetone, very
slightly soluble‘ in'alcohol and’ ether and insoluble in
water.
"
3,033,863
7
7.0 by potassium hydroxide and it was sterilized by heat
ing thirty minutes to a temperature of 120° C. After
?ve days of culturing at 25° on a shaking apparatus (85
Calculated: C, 73.22%; H, 8.19%. Found: C, 73.0%.;
H, 8.2%.
.
8
g The pH of this medium was previously adjusted to _6.8
Analysis. -— CHI-12804; molecular weight = 344.44.
.
Ultraviolet spectra: Amax- 238 my, e=15',1'00.
This compound is not described in the literature.
strokes per minute, 8 cc. stroke), 10 cc. of an acetonic
solution containing 1% of 16u—methyl->18-nor-A4-preg
Step F.—Preparation of 16ot-methyl-2I-dii0d0-18-rwr
nene-17u-ol-3,11,20-trione obtained according to Exam
A4-pregnene-17m-ol-3J1,20-tri0ne.-— 850 mg. of 16a
methyl-lS-nor-N-pregnerie-l704-0143,l 1,20-trione were in
ple II, were added‘ to 1,000 cc. of culture. A new incuba
tion of twenty-four'hours gave 16a-methyl-l8-nor-corti
troduced in 7.5 cc. of methanol. '850 mg. of quick lime
10 some as is evidenced by chromatographic determinations
on paper which were effected as follows on 50 cc. of cul
were added and the mixture was cooled to -10° C. To
ture
broth.
the mixture were added 1.27 gm. of pulverized iodine and
and 3‘cc. of methanol containing 10% calcium chloride
The broth was ?ltered and the mycelium washed two
times with 5 cc. of acetone which was added to the ?l
" A4-pregnene-17a-ol-3J1,20-ttrione formed was vacuum .15 trate. The mycelium was next extracted with 2 aliquots of
50 cc. of chloroform and the preceding ?ltrate was ex
?ltered. The residue was washed with a dilute solution
tracted with these 100 cc. of chloroform. Then the ex
of acetic acid and with water and utilized without puri?ca
tractions were made again two times with 20 cc. of ' chlo
tion for the next step of the synthesis.
roform each time. The chloroformic extracts were com
This compound is not described in the literature.
the mixture was agitated in a closed vessel ‘for a period
of one hour: The draw 2lv-diiodo-l6wmethyl-l8-nor
Step G.—-Preparati0n of the acetate 0]‘ 16a-methyl-18 20 bined and were washed ?rst with an aqueous solution of
sodium bicarbonate, then with water and dried over mag
n0r-cortis0ne.—,The 21-iodo derivative prepared in 'Step
nesium sulfate. The solutions were then evaporated to
F was dissolved in acetone. 0.2 cc. of acetic acid and
‘dryness under vacuum. The residue was taken up with
1 cc. of methanol and subjected to paper chromatography.
Previous to the chromatographic adsorption, the paper
strip was immersed in a solution of 30% propylene glycol.
3 gm. of potassium acetate were added. The mixture was
heated to re?ux for a period of one hour and a half and
then 10 cc. of water were added and the acetone was re
moved under vacuum. The acetate of l6m-methyl-18-nor
cortisone crystallized. The product was vacuum ?ltered,
washed with water, dried, and taken up by a mixture of
After allowing it. to drip, the steroid is chromato
graphed with toluene saturated with propylene glycol. and
a. development of eight to ?fteen hours is effected. The
acetic acid and acetone. 300 mg. of zinc were added.
The mixture was re?uxed for a period of several minutes. .30 detection of spots was made by the color reaction of Mader
et al. (Anal. Chem. 1952, 24, p. 666) with triphenyl tet
The mixture was treated with animal‘ black, ?ltered, con
razolium chloride which gives a red-coloration on a white
centrated to a small volume and vacuum ?ltered. 'The
foundation with steroids possessing the ketol function
product was recrystallized from aqueous acetone to give
a product melting at 247-248° C. and having a speci?c
R—CO—OH2OH.
.
'
Various modi?cations of the process of the invention
rotate .[a]'D2°=+ll5°:2° . (c.=1% in chloroform). 35 may be made without departing from, the spirit or scope
The product occurred in the form of square lea?ets, very
thereof, and it is to-be understood that the invention is to
soluble in chloroform, soluble in acetone, very slightly
‘be limitedonly' as de?ned in the-appended claims.
soluble in alcohol and insoluble in water and ether.
Weclaim:
Analysis.—-C23H3o06; molecular weight=402.47. Cal
40
culated: C, 68.63%; H, 7.51%. Found: C, 68.5%; H,
1. 3-ethylenedioxy - 16a - methyl-l7u-hydroperoxy-l8
nor-pregnane-l1,20-dione.
7.7%.
'
.
Ultraviolet spectra: Am“. 238 mu, e=15,000.
'
01-1 1,20-_dione.
This compound is not described in the literature.
EXAMPLE III
.
2. 3-ethylenedioxy - 16a - methyl-l8~nor-pregnane-l7a
3. 16a-rnethyl - 18 - nor-pregnane-17a-ol-3,l1,20-tri
.
.45
Preparation of 16a-Methyl-18-Nor-Cortis0ne
'
one.
'
'
'
'
'
.
4. 45 - bromo - 16o: - methyl-18-nor-pregnane-17a-ol
3,11,20-trione.
1 gm. of the acetate of, mot-methyl-18<nor-cortisone
5. 16h - methyl - l8 -, nor-M-pregnene-lh-ol-3,11,20
produced in Example III was introduced into 10 cc. of
methanol. 0.1 'cc. of a normal solution of‘ sodium meth 50
6-. 16a-methyl-2l-diiodo - l8. - nor-A4-pregnene-17'a-ol
ylate in methanol was added and the mixture was heated
3,11,2Q-tri‘one.
'
'
at re?ux for aperiod of ?fteen minutes under nitrogen;
7. A process for the preparation of compounds having’
After neutralization and dilution with an equal volume
'the formula
of, water, the methanol was removed under vacuum and
the 16¢x-methyl-l8-nor-cortisone was recovered.‘
55
H
trione.
This compound is not described in the literature. .
_
"
cal Hydrgoxylation in the 21-P0sition1
V
7
~
7
EXAMPLE IV
Preparation of 16ot-methyl-I8-N0r-C0rtis0ne by Biologi
.
I
7
H
"-on
: *Lon.
60
Colletotrz‘clium lindemuthianum (ATCC, 12,611) was
cultivated for a period of ten days at 249 on an agar medi:
um containing 2% of saccharose and 20% of potato ex- '
. tract. The conidies were collected in distilled water. The
wherein R is selected from the group consisting of hydro
suspension obtained was used to sterilely inoculate a 1 65 gen and' an acyl radical of an organic carboxylic acid
having 1 to 18 carbon atoms which comprises oxidizing 3
liter Erlenmeyer ?ask containing 100 cc. of’ a medium
composed as ‘follows:
1
,
Pure glucose
'
Y
'
'_ "Malt extract _
g
‘
___
10
.._
_____' "5
_..
Sodium‘ chloride
Dry cornv steep.
'
Grams.
Soy bean meal
,
a
7
V
7
V
__ .._
5
_____c
'5
'7 'Calcium carbonate ~'____'___r_____' ______ -2 _____ __’__
"i. '' Tap water to make 1,000'cc. '
10
1
ethylenedioxy '- 16oz - methyl-1Y8-nor-pregnane-l”l,20-di
, one with oxygen in the presence of an alkali metal tertiary
~butylate ,to form ' 3-ethylenedioxy4l7a-hydroperoxy-16m
70 methyl-lS-nonpregnane-l1,20-dione, reducing the latter
'to form 3gethylenedioxyrl6a-methyl-l8-nor7pregnane-17a- ~
.ol-ll,20-dione,1hydi‘olyzing the latter under-acidic condi
tions to form 16ot-methyl-l8-nor-pregnane-17br-ol-3,11,20
trione, reacting the latter with bromine to form lip-bromo
l6qc-methyl-18-nor-pregnane-17a-ol-3,l1,20-triohe, dehy
3,083,863
A
Z’
19
drobrominating the latter to form I6a~methyl-18-nor-A4
with oxygen in the presence of potassium tertiary butylate
pregnene-l7a-ol-3,l1,20-trione, introducing a hydroxyl
to form 3-ethylenedioxy-l7a-hydroperoxy-l6tx-methyl-18
group in the 21-position by microbiological means with
Colletotrichum lindemuthianum to form 16a-methyl-18
nor-cortisone and recovering a compound of the above
nor-pregnane-l1,20-dione, reducing the latter with zinc
and acetic acid to form 3-ethylenedioxy-16a-methy1-18
nor-pregnane~17ot—o1-l1,20-dione, hydrolyzing the latter
formula.
under acidic conditions to form 16ot-methyl-18-nor-preg
8. The process of claim 7 wherein the oxidation is
nane-l7a-ol-3,l1,20-trione, reacting the latterwith bro
re?ected with oxygen in the presence of potassium tertiary
mine in acetic acid to form 4B-bromo-16ct-methyl-18-nor
.butylate.
pregnane-17a-ol—3,l1,20-trione, dehydrobrominating the
9. The process of claim 7 wherein the reduction is ef 10 latter in the presence of a mixture of lithium bromide and '
fected with zinc and acetic acid.
lithium carbonate to form 1oat-methyl;ls-nor-A‘i-preguene
10. The process of claim 7 wherein the dehydro
17u-ol-3,11,20-trione, subjecting the latter to the action
bromination is effected with a mixture of lithium bromide
of diastases secreted by Colletotrichum lindemuthianum
and lithium carbonate.
to form l6a-methyl-18-nor-cortisone and recovering a
11. A process for the preparation of a compound hav 15 compound of the above formula.
ing the formula
13. A process for the preparation of 16a-methyl-18
nor-pregnane-17a-ol-3,l1,20-trione which comprises react
CHnOR
E
0
ing 3-ethylenedioxy-16a-methyl-‘1S-nor-pregnane-l1,20-di
=0
one with acetic acid anhydride to form 3-ethylenedioxy
Mon
OH
I mam
20 IGa-methyl - 20 - acetoxy-l8-nor-A17(2°)-pregnene-1l-one
reacting the latter with perbenzoic acid to form 3-ethyl
enedioxy-l6a-methyl - 17,20v - epoxy-20-acetoxy-18-nor
pregnane-l l-one and subjecting the latter to acid hydroly
sis to form 16oc-methyl-l8-nor-pregnane-17u'-ol~3,11,20
25
trione.
‘
14. A process for the preparation of compounds hav
wherein R is selected from the group consisting of hydro
ing the formula
gen and an acyl radical of an organic carboxylic acid
-
having 1 to 18 carbon atoms which comprises oxidizing
3-ethylenedioxy - 16oz - methyl-18-nor-pregnane-11,20-di
H
_ one wtih oxygen in the presence of potassium tertiary 30
butylate to form 3~ethylenedioxy-17a-hydroperoxy-16a
methyl-lS-nor-pregnane-l1,20-dione, reducing the latter
CH3
with zinc and acetic acid to form 3-ethylenedioxy-16a
methyl-18-nor-pregnane-l7a-ol-11,20-dione, hydrolyzing
the latter under acidic conditions to form 16u-methyl-18
0..
nor-pregnane-17a<ol-3,11,20-trione, reacting the latter with
bromine in acetic acid to form 4B-bromo-l6a-methyl-18
nor-pregnane-17u~ol-3,11,20 - trione, dehydrobrominating
the latter in the presence of a mixture of lithium bromide
and lithium carbonate to form 16tz-methyl-l8-nor-A4
wherein R is selected from the group consisting of hydro~ 7
gen and an acyl radical of an organic carboxylic acid hav
ing 1 to 18 carbon atoms which comprises oxidizing 3
ethylenedioxy-16a-methyl - 18 - nor-pregnane-11,20-dione
pregnene-17a-ol-3,l1,20-trione, reacting the latter with
with oxygen in the presence of an alkali metal tertiary
iodine in the presence of a mixture of calcium oxide and
butylate to form 3-ethylenedioxy-l7u-hydroperoxy-l6a
methyl-18-nor-pregnane-11,20-dione, reducing the latter to
calcium chloride to form 2l-diiodo-l6a-methyl-l8-nor-A4
pregnene-17a-ol-3,l1,20-trione, reacting the latter with an
form 3-ethylenedioxy-l6a-methyl-l8-nor-pregnane-17ot
alkali metal salt of a lower alkanoic acid to form 21-acyl 45 ol-11,20-dione, hydrolyzing the latter under acidic condi
oxy-16a-methyl - 18 - nor-N-pregnene-l7a-o1-3,11,20-tri
tions to form l6a-methyl-18-nor-pregnane-17a-ol-3,11,20
one, hydrolyzing the latter to form 16a-methyl-18-nor
cortisone and recovering a compound of the above
trione, reacting the latter with bromine to form 4B-bromo
l6a-methyl é l8 - nor-pregnane-l7a-ol-3,l1,20-trione, de
formula.
hydrobrominating the latter to form 16oc-methyl-18-nor
,A4-pregnene-17u-ol-3,11,20-trione, reacting the latter with
12. A process for the preparation of a compound hav
ing the formula
iodine in the presence of a mixture of calcium oxide and,
calcium chloride to form 21-diiodo-16u-methyl-18-nor
onion
n
0
on .
A4-pregnene-17 u-ol-3,11,20-trione, reacting the latter with
=0
'--on
55
L0H’
an alkali metal salt of a lower alkanoic acid to form 21
acyloxy-16a-methyl - 18 - nor-A4—pregnenel7a-ol-3,11,20
trigone and hydrolyzing the latter to form 16a-methyl-18
nor-cortisone.
60
wherein R is selected from the group consisting of hydro
gen and an acyl radical of an organic carboxylic acid hav
ing 1 to 18 carbon atoms which comprises oxidizing 3
ethylenedioxy - 16a - methyl-18-nor-pregnane-11,20-dione 65
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,961,441
Bogert et al ___________ _._ Nov. 22, 1960
OTHER REFERENCES
Arth et al.: I.A.C.S., June 20, 1958, page 3160'.
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