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Патент USA US3077481

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Unite
States Patent
r“
3,077,471
.
EQQ
Patented Feb. 12, 1963
R
thereof, as more fully described in our application, Serial
3,077,471
No. 129,234, ?led on even date herewith.
STEROIDS 0F Tl-m 19-NORPREGNANE SERIES
The compounds of this invention can be prepared by
pyrolyzing a compound of the Formula II
Josef Fried, Princeton, and Mariano A. Guiducci, Edison,
N.J., assignors to Olin Mathieson Chemical Corpora
tion, New York, N.Y., a corporation of Virginia
N0 Drawing. Filed Aug. 4, 1961, Ser. No. 129,233
13 Claims. ({Jl. zen-239.55)
(H)
CH3
This invention relates to, and has for its objects the
provisions of new physiologically active steroids, methods
for preparing the same, and intermediates useful in such
preparations.
The ?nal products of this invention are steroids which
are 16,17-acetal and ketal derivatives of 16a,17a-dihy
droxy-l9-nor-3alkoxy-1,3,5(10)-pregnatriene steroids, and
15
include steroids of the general Formula I
wherein R' (in either the alpha or beta position), P and
Q are as hereinbefore de?ned.
The pyrolysis is preferably conducted by heating the
steroid reactant to a temperature above about 400° C.,
preferablyrabout 500° C. to about 700° C., and results in
the preparation of the 3-hydroxy-20-keto ?nal products
25 of this invention of the Formula III
(III)
wherein R is in either the alpha or beta position and rep 30
resents hydrogen or lower alkyl; R’ is hydrogen or lower
alkyl (preferably methy); R” is hydroxy or acyloxy
(preferably the acyloxy radical of a hydrocarbon car
boxylic acid of less than ten carbon atoms); R’” is hydro
gen; or together R” and R'” is 0x0 (0:); P is hydrogen,
lower alkyl, halo lower alkyl, monocyclic cycloalkyl,
monocyclic cycloalkyl lower alkyl, monocyclic aryl, mono~
cyclic aryl lower alkyl, monocyclic heterocyclic or mono
cyclic heterocyclic lower alkyl; Q is lower alkyl, halo
lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl
lower alkyl, monocyclic aryl, monocyclic aryl lower alkyl,
40 wherein R, P and Q are as hereinbefore de?ned.
The S-hydroxy-ZO-keto products can then be etheri?ecl
monocyclic heterocyclic or monocyclic heterocyclic lower
by treatment with a lower alkyl halide or sulfate (e.g.,
alkyl; or together with the carbon to which they are joined
P and Q is a monocyclic cycloalkyl or monocyclic hetero
chloride, and n-hexyl chloride), in the presence of a base,
cyclic radical.
such as potassium hydroxide, to yield the corresponding
3-ether derivatives of the Formula IV
The ?nal products of this invention are physiologically
active substances which possess estrongenic activitiy when
administered both in the form of tablets and as a solution
or suspension and hence can be used in lieu of known
estrogenic agents, such as estrone or estradiol benzoate
in the treatment of menopausal symptoms. For this pur
dimethyl sulfate, dicthyl sulfate, propyl chloride, n-butyl
(IV)
pose, they can be administered in the same manner as
estrone or ,estadiol benzoate, for example, the dosage be
ing adjusted for the relative potency of the particular
steroid.
Those compounds of this invention wherein P is hydro
gen, lower alkyl, halo lower alkyl, monocyclic cycloalkyl,
or monocyclic cycloalkyl lower alkyl, Q is lower alkyl,
halo lower alkyl, monocyclic cycloalkyl or monocyclic
E
R
cycloalkyl lower alkyl, or together with the carbon to 60
which they are joined P and Q is monocyclic cycloalkyl,
are also useful as intermediates in the preparation 19-nor
160:,17 a - dihydroxyprogesterone, 19-nor-5( l0)-pregnene
16a,17a-diol-3,20-dione, or acetal or ketal derivatives
wherein R, R’, P. and Q are as hereinbefore de?ned,
which are new compounds of this invention.
The resulting 3-ether-20~keto steroids can then be re
duced, as by treatment with lithium aluminum hydride or
3,077,471
-
45
3%
sodium borohydride to yield the corresponding ZOtt-hy
These free 16,17-dihydroxy steroids can then be reacted
droxy derivatives of the Formula V
with an aldehyde or ketone of the formula: '
> ~'
(V)
wherein P and Q are as hereinbefore de?ned, to give the
final acetal and ketal derivatives of this invention.
In those instances where the starting steroids are new
10 compounds, they can be prepared by reacting a compound?
of the formula
CH3
0
15
wherein R, R’, P and Q are as hereinbefore de?ned, which
are also new compounds of this invention; and these 205
hydroxy compounds can then be esteri?ed in the usual
manner by treatment with an acid anhydride or acyl 20
halide, preferably in the presence of a basic catalyst, such
as pyridine, to yield products of this invention of the
Formula VI
‘
(VI)
CH3
gig
25 wherein R, P and Q are as hereinbefore de?ned, with 2,3~
dichloro-S,6-dicyanobenzoquinone, whereby a double
bond is introduced between the 1 and 2 positions, thereby
yielding the starting steroids of this invention. The re
action is preferably conducted in an organic solvent for
30 the steroid reactant at an elevated temperature, prefer
ably the re?ux temperature of the solvent. These steroids
may also be prepared by microbiological dehydrogena
tion using an organism such as C. simplex or B. cyclo
oxidarzs.
If a ketal or acetal grouping other than that present
35
in the starting steroid reactant is desired, the resulting
product may be cleaved by treatment with aqueous formic
acid to yield 16a,17a-dihydroxy intermediates of the for
wherein R, R’, P and Q are as hereinbefore de?ned and
mula.
Y is an acyl radical, preferably the acyl radical of a hydro
carbon carboxylic acid of less than ten carbon atoms, as 40
CH;
exempli?ed by the lower alkanoic acids (e.g., acetic, pro
O
pionic, butyric and enanthic acid), lower alkenoic acids,
monocyclic aryl carboxylic acids (e.g., benzoic and
m-toluic acid), monocyclic aryl lower alkanoic acids (e.g.,
phenacetic and B-phenylpropionic acid), monocyclic aryl
lower alkenoic acids, cycloalkanecarboxylic acids, and
cycloalkenecarboxylic acids.
The 16,17-acetal and ketal derivatives, and especially
the acetals and ketals with aromatic aldehydes and ketones,
can also be prepared by hydrolyzing compounds of the 50
Formulae III or IV to yield new intermediates of this
invention of the Formula VII
(VII)
wherein R is as hereinbefore de?ned.
CH3
60
to;
' '
wherein R is as hereinbefore de?ned and R" is hydrogen
If concentrated
aqueous formic acid is used (e.g., 90% formic acid), a
55 16-formic acid ester is formed, which is then hydrolyzed
by treatment with 10% aqueous potassium carbonate in
methanol to yield the free 16,l7-dihydroxy steroid deriva
tive.
These intermediates are than reacted with an aldehyde
or ketone of the formula:
'
'
65 wherein P and Q are as hereinbefore de?ned.
The re
action is preferably carried out by treating a suspension
or solution of the dihydroxy steroid in the aldehyde or
ketone (or an organic solvent and the aldehyde or ketone,
or lower alkyl. This hydrolysis is accomplished by treat
if the aldehyde or ketone is a solid) with an acid catalyst
ing the steroid with formic acid. If concentrated aqueous 70 (e.g., perchloric acid, p-toluenesulfonic acid, hydrochloric
formic acid is used (e.g., 90% formic acid), a 16~formic
acid, etc.), neutralizing the acid and recovering the acetal
acid ester or, if R" is hydrogen, a 3,16-diester is formed
or ketal derivative formed.
~
initially, which is then hydrolyzed by treatment with 10%
Suitable aldehyde and ketone reactants include lower
aqueous potassium carbonate in methanol to yield the free
alkanals of at least two carbon atoms, such asparalde
16,17,-dihydroxy steroid derivative.
75 hyde, propanal and hexanal; di(lower alkyl)ketones,vv such
5
3,077,471
5
alkoxy)phenyl lower alkyl ketones, hydroxy-phenyl lower
alkyl ketones, dihydroxyphenyl lower alkyl ketones (e.g.
resacetophenone), (lower alkyl)lphenyl lower alkyl
ketones (eg. methyl p-tolyl ketone), di(lower alkyl)
phenyl lower alkyl ketones (o,p-xylyl methyl ketone);
nitrophenyl lower alkyl ketones (e.g. p-nitroacetophe
none), acylamidophenyl lower alkyl ketones (e.g. acetyl
anilines), and cyanophenyl lower alkyl ketones; benzo
as acetone, diethyllcetone, dibutylketone, methylethyl
ketone, and methylisobutylketone; cycloalkanones, such
as cyclobutanone, cyclopetanone, cyclohexanone, suber
one, and cyclodexanone; cycloalkyl (lower alkanals),
such as cyclopropylcarboxaldehyde, cyclobutylcarboxy
aldehyde, cyclopentylcarboxaldehyde, cyclohexylcarbox
aldehyde, cycloheptylcarboxaldehyde, cyclooctylcarbox~
aldehyde, cyclopropylacetaldehyde, cyclobutylacetalde
hyde, cyclopentylacetaldehyde, cyclohexylacetaldehyde,
?-cyclopentylpropionaldehyde, y-cyclohexylbutyraldehyde,
phenone, and mono or his substituted halo, lower alkoxy,
hydroxy, lower alkyl, nitro, acylamido and cyano deriva
tives thereof; monocyclic carbocyclic aromatic lower
alkanones, such as 1-phenyl-3-butanone and l-phenyl-4
pentanone, and aromatically substituted derivatives there
of; monocyclic heterocyclic ketones, such as 2-acety1furan,
yl methyl ketone, cyclohexylmethyl ethyl ketone, cyclo~
pentylethyl ethyl ketone, cyclopropylpropyl methyl ketone, 15 2-benzoylfuran, Z-acetyl-thiophene and alloxan; and mono
cyclic heterocyclic lower alkanones.
cyclohexyl n~penyl ketone, cyclohexyl methyl ketone, and
Among the suitable initial steroid reactants may be
cyclooctyl methyl ketone; dicycloalkyl ketones, such as di
10
and 3-cyclopropylcaproaldehyde; cycloalkyl?ower alka
nones), such as cyclopropyl methyl ketone, cyclobutyl
ethyl ketone, cyclopentyl propyl ketone, cyclopentylmeth
cyclopropyl ketone, dicyclobutyl ketone, dicyclopentyl
lcetone, dicyclohexyl lretone, cyclopentyl cyclohexyl
ketone, cyclopropylmethyl cyclopropyl ketone, 2-cyclo
butylethyl cyclopropyl ketone, B-cycIopentylmethyl cyclo
pentyl ketone, S-cyclohexylhexyl cyclohexyl ketone, di
(cyclopentylmethyl) ketone, cyclohexylmethyl cyclopentyl
mentioned the 16,17-acetals and ketals of each of the
following steroids with one of the aldehydes or ketones
20 listed hereinbefore: 16a,l7a-dihydroxy-l-clehydro-proges
terone, and 6-(lower alkyl)46a,17u-dihydroxy-1-dehydro
progesterones, such as 6a-methyl-16a,17a~dihydroxy-l-de
hydroprogesterone, 6,6-methyl-16a,l7a-dihydroxy~l-dehy
droprogesterone and éa-ethyl-16u,17a-dihydroxy-1~dehy
ketone, and di(4-cyclohexylpentyl) ketone; cycloalkyl
monocyclic aromatic ketones, such as cyclopropyl phenyl 25 droprogesterone.
The following examples illustrate the preparation of
ketone, cyclohexyl p-chlorophenyl ketone, cyclopentyl o
methoXyphenyl ketone, cyclopentyl o,p-dihydroxyphenyl
ketone, cyclohexyl m-tolyl ketone, cyclopropyl p-ethyl
suitable starting steroids useful in the process of this
invention (all temperatures being in centigrade):
phenyl ketone, cyclopropyl p-nitrophenyl ketone, and cy
clohexyl p-actamidophenyl ketone; cycloalkyl(lower
30
alkyl) monocyclic aromatic ketones, such as cyclopentyl
methyl phenyl ketone; cycloalkyl monocyclic aromatic
Acetonide
A solution of 12.3 g. of 16a,17a-dihydroxyprogesterone
160:,17oc-E1C6t011id? and 8.6 g. of 2,3-dichloro-5,6-dicyano
benzoquinone in 100 ml. of anhydrous vdioxane is re
?uxed for 6 hours. The cooled reaction mixture is
?ltered and washed several times with 5 ml. portions of
dioXane. The crude product obtained after evaporating
the solvent in vacuo is puri?ed by chromatography on 100
lower alkyl) kctones, such as cyclopentyl benzyl ketone,
cyclohexyl phenethyl ketone, and cyclobutyl benzyl
ketone; cycloalkyl?ower alkyl) monocyclic aromatic
(lower alkyl) ketones, such as cyclopentylmethyl benzyl
ketones; cycloalkyl monocyclic heterocyclic ketones, such
as cyclopentyl Z-furyl ketone, cycloheXyl Z-thienyl ketone,
and cyclopropyl 2~pyridinyl ketone; cycloalkyl (lower
alkyl) monocyclic heterocyclic ketones, such as cyclo
pentylmethyl 2-piperidinyl ketone, cyclohexylethyl 2-mor
pholinyl ketone and cyclopropyl Z-thienyl ketone; cyclo
g. of neutral alumina. Elution of the column with benzene
(1.5 l.) and chloroform-benzene 1:20 (2. l.) furnishes
about 8.86 g. (72% yield) of the pure l-dehydro deriva
tive. Recrystallization from acetone-hexane furnishes the
alkyl monocyclic heterocyclic (lower alkyl) ketones, such
as cyclopentyl thenyl ketone, cyclohexyl furfuryl ketone
and cyclopropyl 2-piperidinylmethyl ketone; halo-lower
alkanals, such as chloral hydrate, triiluoroacetaldehyde
hemiacetal, and hepta?uorobutanal ethyl hemiacetal; halo
45
EXAMPLE B
cyclic carbocyclic aromatic aldehydes such as benzalde
lower alkyl benzaldehydes (e.g. m-tolualdehyde and p
analytically pure product.
.1-Dehydr0-16J 701-1)ihydroxyprogesterone 1604,17“
Acetophenonia‘e
lower alkanones, such as 1,1,l-tri?uoroacetone; mono
hyde, halobenzaldehydes (e.g., p-chlorobenzaldehyde and
p-?uorobenzaldehyde), lower alkoxybenzaldehydes (e.g.,
o-anisaldehyde), di(l.ower alkoxy)benzaldehydes (e.g.
veratraldehyde), hydroxybenzaldehydes (e.g., salicylalcle
hyde), dihydroxybenzaldehydes (e.g. resorcyaldehyde),
EXAMPLE A
1 -Dehydro-1 6 0a,] 7 a-Dihydroxyprogesterone 1 604,] 7rd
Following exactly the procedure of Example vA but sub
stituting 16a,17a-dihydroXyprogesterone acet‘ophenonide
for the acetonide, l-dehydro-l6a,l7u-dihydroxyprogester
one 16u,l7a-acetophenonide is formed. Recrystallization
55 from ether-hexane furnishes the pure product.
‘ethylbenzaldehydeL di(lower alkyDbenZaldehydes (e.g.
o,p-dimethylbenzaldenyde), nitrobenzaldehydes, acyl
'ainido‘oenzaldehydes -(e.g. N-acetylanthranilaldehyde),
and cyanobenzaldehydes; monocyclic carboxylic aromatic 60
‘
EXAMPLE C
160:,17a-Chl0h1l Derivative of AIA-Pregnadie‘ne-Ma, .
1 7a-Diol-3‘,20-Dione
'
lower alkanals, such as phenylacetaldehyde, a-phenylpro
Following‘the procedure of Example A but substituting
pionaldehyde, ?-phenylpropionaldehyde, 'y-phenylbutyr
‘an equivalent amount of the l6cz,17a-Chl(>fal derivative
of 16a,l7a-dihydroxyprogesterone for the 16¢,l7a-dihy
aldehyde, and aromatically-substituted halo lower alkoxy,
droxyprogesterone 16,17-acetonide, the 116:2,l7oc-Chl0l‘3l
hydroxy, lower allcyl, nitro, acylamido and cyano deriva
tives thereof; monocyclic heterocyclic aldehydes, such as 65 derivative of A114-pre‘gnadiene-16tz,l7a-diol-3,20-dione is
obtained.
picolinaldehydes, furfural, thiophene carbonals, and halo,
lower alkoxy, hydroxy, lower alkyl, nitro, and cyano de_
EXAMPLE D
rivatives thereof; monocyclic heterocyclic lower alkanals;
Dicyclopropyl
Ketone
Derivative of A1-4-Pregnadiene
monocyclic carbocyclic aromatic ketones, such as aceto
70
phenone, a,a,a-tri?uoroacetophenone, propiophenone,
16ot-17et-Di0l-3,20-Di0ne
~
butyrophenone, valerophenone, isocaprophenone halo
Following the procedure of Example A but substituting
phenyl lower alkyl ketones (eg. p~chloroacetophenot1e
an equivalent amount of the l6a,17a-dicyclopropyl ketoné
and p-chloropropiophenone), (lower alkoxy) phenyl low
derivative of 160:,17a - dihydroxyprogesterone for the
fer alkyl ketones (eg. p-anisyl methyl ketone), di(lower 75 16a,17u-dihydroxyprogesterone 16,17-acetonide, the. di
3,077,471
8.
cyclopropyl ketone derivative of- A1’4-pregnadiene-16a,17a
diol-3,20-dione is obtained.
Similarly, the methylisobutyl ketone derivative, the
cyclopropyl phenyl ketone derivative, the cyclohexyl
methyl ketone derivative, the 1,1,l-tri?uoroacetonide de
rivative, the hepta?uorobutanal derivative, the p-chloro
acetophenone derivative, the p-nitroacetophenone deriva
tive, the benzaldehyde derivative, the furfural derivative,
Similarly,
3,20-dione 16,17-acetonide yields 6a-methyl-A114-pregna
diene 16a,17a-diol-3,20-dione.
EXAMPLE I
5
A1 A-Pregnadi ens-1 604-1 7 a-D i0l—3,20-Dione
16,17-Acet0nide
To a suspension of 500 mg. of A1-‘‘- pregnadiene
16a,l7cL-diOl-3,20-di0l16 in 75 ml. of acetone is added 0.05
the benzophenone derivative and the 2-acetylfuran de
rivative of l6a,17a-dihydroxyprogesterone, yield the meth
of 72% perchloric acid and the mixture is agitated at
room temperature for three hours. The mixture is then
neutralized with dilute‘ sodium bicarbonate and the ace-.
tone removed in vacuo. The resulting crystalline suspen
sion is ?ltered and the crystals washed with water to yield,
ylisobutyl ketone, the cyclopropyl phenyl ketone, the cy
clohexyl methyl ketone, the 1,1,1-tri?u0roacetonide, the
hepta?uorobutanal, the p—chloroace_tophenone, the p-nitro
acetophenone, the benzaldehyde, the furfural, the benzo
phenone and the Z-acetylfuran derivatives of A1»4-pregna
after recrystallization from acetone, Ab'i-pregnadiene
diene-16u,17a-diol-3,20-dione, respectively.
16a,17a-diol-3,20-dione 16,17-acetonide, identical to the
product obtained in Example A.
EXAMPLE E
Similarly, the 6-(lower alkyl)-A1’4-pregnadiene~l6a,17a
60L-Methyl-1 -Dehydr0-1 6(1,1 7a-D ihydroxyprogesterone
'
.16a,17a-Acet0nide
6a-methyl-Alr‘i-pregnadiene - 16a,17ot -diol
diol-3,20 diones can be converted to their acetonide de
20
rivatives. Moreover, by substituting other aldehydes and
A solution of 12.5 g. of 6a-methyl-16a,17u-dihydroxy
ketones for the acetone in Example I, the other acetal
and ketal starting steroids of this invention can be pre_-'
progesterone 16u,17ot-acet0nide and 8.7 g. of 2,3-dichloro
5,6-dicyanobenzoquinone in 100 ml. of anhydrous dioxane
pared.
,
is re?uxed for 10 hours. The cooled reaction mixture is
The following examples illustrate the process of this
?ltered and washed several times with 5 ml. portions of di 25
invention:
oxane, and the solvent removed in vacuo. The crude mate
rial is then chromatographed as in Example A to yield
-
1 6 11,1 7zx-Acetonide
30
6?-Methyl-1-Dehydro-1 6a,] 7a-Dihydroxyprogesterone
an [equivalent amount of 6?-methyl-16a,17ot-dihydr0xy
progesterone 16,17-acetonide for the 6a-methyl-16a,17u
A solution of 2 g. of A1460‘,17a-dihydroxyprogesterone
v16<r,17ot-acetonide in'200 ml.- of mineral oil, heated to
100° to maintain solution, is dropped through a glass
1 6a,] 7u-A cetom'de
Following the procedure of Example E but substituting
-
19-N0r-1,3,5 (1 0 ) -Pregnatriene-3,I 6 11,1 7 oc-Tri0l-20-0ne
the l-dehydro product.
EXAMPLE F
.
EXAMPLE 1
tube 11 mm. in diameter and 30 cm. long, a 17 cm. length
of which is ?lled with glass helices and heated to 640°
35 in an electric furnace. The rate of addition is adjusted to
permit re?uxing but not ?ooding. The temperature of
dihydroxyprogesterone 16,17-acetonide, 6?-methyl-Al?
the furnace drops by 30 to 40° when the mineral oil solu
tion passes through the tube thus establishing a pyrolysis
temperature of 600—610°, which is maintained during the
40 experiment. The e?luent solution is diluted with an equal
EXAMPLE G
volume of hexane and extracted with 5% alkali. The
6a-Methyl-A1'4-Pregnadien e-] 6“,1 7a-Diol-3,20-Di0ne
resulting alkaline extract of crude phenolic compounds is
16,1 7-A cetoph enonide
acidi?ed with dilute hydrochloric acid and extracted with
A Following the procedure of Example E but substituting
chloroform. The chloroform layer is washed with sodium
an equivalent amount of oa-methyl-l6u,17a-dihydroxyf 45 bicarbonate and sodium chloride solutions, dried over
pregnadiene-l6a,17a-diol-3,20-dione 16,17 -acetonide is
obtained.
progesterone 16,17-acetophenonide for the oer-methyl
sodium sulfate and the solvent removed in vacuo. The
crude residue, about 0.9 g., is dissolved in 25 ml. of
(benzene and chromatographed on 25 g. of neutral alumina.
Elution of the column with benzene:ether 4:1 (1.5 1.)
16a,17u - dihydroxyprogcsterone 16,17 - acetonide, 6oz
methyl-A1=4-pregnadiene-160;,17ct-di01 - 3,20 - dione 16,17
.acetophenonide is obtained.
EXAMPLE H
50
provides about 220 mg. (10% yield) of 19-nor-1,3,5(10)
pregnatriene-B‘,l6a,17a-triol - 20 - one
AIA-Pregnadiene-IGuJ 7a-Diol-3,20-Dione
16a,17ot-acetonide,
M.P. about 190‘-195°. Recrystallization from acetone
hexane gives the pure compound of the following prop
A solution of 900 mg. of Al-‘i-pregnadiene-loa,17a-diol
3,20-dione 16,17-acetonide in 15 ml. of 90% formic acid
erties: M.P. about 203-204"; [a]D23-]—1O2°(C., 1.1 in
is heated at 42° for 22 hours. The solvents are removed 55 chlf. ) ;
in vacuo, the crude residue dissolved in 50 ml. of methanol
k221i?‘ 2 89, 5.86, 6.15 and 6.30”; A31; 281 mu (e=2430),
and treated under nitrogen with stirring with 10 ml. of a
shoulder at 286 m” (6:2250) minimum at 247 my
10% oxygen~free solution of potassium carbonate in
Analysis.—Calcd. for C23H30O4 (370):
Water. After 13 minutes at room temperature the mix
ture is neutralized with 1 ml. of glacial acetic acid and 60 8.16. Found: C, 74.54; H, 8.39.
the solution concentrated in vacuo after the addition of
EXAMPLE 2
water. Extraction with chloroform followed by drying
over sodium sulfate and evaporation in vacuo furnishes
a residue which on recrystallization from 95% ethanol
furnishes about 200 mg. of pure A1’4-pregnadiene-160:,17a 65
diol-3,20-dione.
EXAMPLE I
C, 74.56; H,
J 9-Nor-I,3,5 (10 )Prcgnatriene-3,I6a,] 7a-Triol-20-0ne
1600,] 7 u-A cetophenonide
A solution of 4 g. of the acetophenone derivative of
A1-16ot,17a-dihydroxyprogesterone in 400 ml. of mineral
oil is treated as described in Example 1. To the crude
pyrolysis solution is added 400 ml. of hexane, which re
sults in the formation of a precipitate, which is removed
6a-Methyl-A1'4-Pregnadiene-I 604,1 7a-Di0l-3,20-Dione
Following the procedure of Example H, but substitut -70 by ?ltration (1.4 g.). The precipitate is dissolved in 50
ing an equivalent amount of ?a-methyl-AlA-pregnadiene
ml. of benzene and chromatographed on 40g. of neutral
alumina. Elution of the column with benzene:ether 5:1
'16¢,17a-'diol-3,'20~dione 16,17-acetonide for the AM
pregnadiene-l6a,17a-diol-3,20-dione 16,17-acetonide, 6a
(1 l.) and 1:1 (21.) provides about 250 mg. (6% yield)
methyl-A1-4-pregnadiene-16a,17ot-diol-3,20~dione is ob
of the 16a,17a-acetophenone derivative of 19-nor.-l,3,
tained.
75 5 (10) - pregnatriene - 3,16a,17a-triol-20-one, M.P. about
3,077,471
to
185-190°. Recrystallization from acetone-hexane fur
EXAMPLE 8
nishes analytically pure material having the following
properties: M.P. about 193-195"; [a]D23 +46” (c., 1.0 in
1 9-N0r-3-Meth0xy-1 ,3 ,5 (10) -Pregnatriene-.16a,1 71z-Di0l~
ZO-One 1 6a,] 7a-Acet0nide
A re?uxing solution of 130 mg. of 19-nor-1,3,5(10)
chlf.);
A231,?‘ 202, 5.85, 0.13, 6.29, 13.05 and 142%; X513; 280 my 5 pregnatriene-3,16a,17a-triol-20~one 16a,17a-acetonide in
(er-2370), shoulder at 285 ml.‘ (e=1980)
10 m1. of ethanol is treated four times, alternatively, with
Analysis.—Calcd. for Cad-13204 (432): C, 77.75; H,
0.45 ml. of 40% potassium hydroxide solution and 0.35
7.46. Found: C, 77.76; H, 7.53.
ml. of dimethyl sulfate. After ten minutes the mixture
EXAMPLE 3
10 is cooled, diluted With Water and the product collected
and recrystallized from acetone-hexane to give about 120
mg. of ?ne needles, M.P. about 179-180". Further re
1601,17cz-Chl0i'dl Derivative 0f 19-N0i=1,3,5(10)-Pregna
metre-3,16a,I7ot-Tri0l-20-One
orystallizations from acetone-hexane yields the analyticaL
1y pure sample of the methyl ether having the following
an equivalent amount of the l6ot,l7u-chloral derivative 15 properties: M.P. about 183—185°; [0411323 +880 (c., 1.0
of ol-‘i-pregnadiene-léa,l7a-diol-3,20-dione for the ace
in chlf. );
tonide, the 160:,17a-Chl01‘31 derivative of 19-nor-1,3,5(10)
Ami“ 5 83, 6.19 and 6.34%; A315,, 278 mp (e=2400), 287
pregnatriene-ll?a,17a-triol~20-one is obtained.
Following the procedure of Example 1 but substituting
EXAMPLE 4
20
16st,] 7 a-Dicyclopropyl Ketone Derivative of I 9-N0r-1 ,3,
5 (10 ) -Pregnatriene-3,16a,1 704-1‘riol-ZO-One
Following the procedure of Example 1 but substitut
ing an equivalent amount of the 16u,17a-dicyclopropyl 25
ketone derivative of hm-pregnadiene-loa,17a-diol-3,20
dione for the acetonide, the 16u,17c¢-dicyclopropyl ketone
derivative of 19-nor-1,3,5(10) - pregnatriene - 3,16ut,170L
Analysis.—-Calod. for C24H32O4 (384); C, 74.97; H,
8.39; O‘CHB, 8.07. Found: C, 74.90; H, 8.22; OCH3,
7.89.
EXAMPLE 9
19-N0r-3-Methoxy-1 ,3,5 (1 0) -Pregnatriene-16a,1 7 a
ZO-One 1 5a,] 7ot-Acetophenonide
A solution of 52 mg. of the 16a,17u-acetophenone de
rivative of 19-nor-1,3,5(l0)-pregnatriene-3,16a,17a-triol
3-one in 4 ml. of ethanol is treated with alkali and di
triol-ZO-one is obtained.
Similarly, the methylisobutyl ketone derivative, the cy 30 rnethyl sulfate as described in Example 8. Crystallization
of the crude product from methanol yields about 40 mg.
clopropyl phenyl ketone derivative, the cyclohexyl methyl
of the acetophenone derivative of l9-nor-3-methoxy-l,3,
ketone derivative, the 1,1,1-tri?uoroacetonide derivative,
5 (10)-pregnatriene-16<x,l7et-di0l-20-one, M.P. about 142
the hepta?uorobutanol derivative, the p-chloroacetophe~
145“, which on recrystallization from chloroform-metha
none derivative, the p-nitroacetophenone derivative, the
benzaldehyde derivative, the furfural derivative, the ben 35 nol furnishes analytically pure compound of the follow
ing properties: M.P. about 147-449"; [M1023 +41° (c.,
zophenone derivative and the 2-acetylfuran derivative of
1.0 in chlf.);
A1'4-pregnadiene-16a,17w ,20-dione, yield the methyliso
butyl ketone, the cyclopropyl phenyl ketone, the cyclo
A232‘ 5.82, 619, 6.30, 12.92 and 14.15,u; hilt-x, 278 m]; (e
hexyl methyl ketone, the 1,1,l-tri?uoroacetonide, the
=2150), 287 mp (e=l950), minimum at 246 mp
hepta?uorobutanol, the p-chloroacetophenone, the p-nitro 40 Analysis.——Calcd. for C2gH34O4 (446); C, 77.99; H,
acetophenone, the benzaldehyde, the furfural, the heme
7.67; OCH3, 6.94. Found: C, 78.14; H, 7.72; OCHg,
phenone and the Z-acetylfuran derivatives of 19-n0r-1,3,
7.02.
5 ( 10)-pregnatriene-3,16a, 17 u-triol-20-one.
EXAMPLE 10
EXAMPLE 5
Ga-Methy Z-J 9-N0r-1 ,3 ,5 (1 '0) -Pregnatriene-3,1 6 a,1 7 Ot
16<x,1 7ot-Chi01'al Derivative of 19-N0r-3-Meth0xy-L3, ,
Triol-ZO-One 1605,1705-146‘82‘0’11’618
Following the procedure of Example 1 but substituting
Following the procedure of Example 8 but substituting
5 (10 ) ~Pregnatriene-J 6 0a,] 7 oL-DiOl-Z O-One
an equivalent amount of 1611,170c-Ch101‘31 derivative of
van equivalent amount of 6e-rnethyl-1-dehydro-16ot,17a
l9-nor-l,3,5 ( 10)-pregnatriene-3,16a,17¢x-triol-20-one for
dihydroxyprogesterone l6a,l7qi-acetonide for the A1
50 the acetonide, 16a,17e-chloral derivative of 19-nor-3
methoxy-l,3,5 (10) - pregnatriene - 16a,l7tx-diol-20-one is
l6a,17ot-dihydroprogesterone 16a,l7a-acetonide, éoz-rneth
‘ yl-19-nor-1,3,5(10) - pregnatriene - 3,16a,17wtriol-20-one
obtained.
‘
'
A
EXAMPLE 1 l
EXAMPLE 6
6,8-Methyl-19-Isf0r-Li5 (10)-Pregnatriene-3,16a,17a
Triol-ZO-One 160t-17oL-A68Z0ilid6
Following the procedure of Example 1 but substituting
‘an equivalent amount or" 6,8-methyl-l-dehydro-léadh
55
16%] 7 DL-DITCYC‘ZOPI'OPYI Ketone Derivative of Z9-N0r-3
Methoxy-1,3,5(1 0 ) -Pregnatriene-1 6 (1,1 7 (1-D i0l-20-0ne
Following the procedure of Example 8 but substitut
ing an equivalent amount of 16a,1_7a-dicyclopropyl .ke
60 tone derivative of 19-nor-1,3,5(10)-pregnatriene-3,l6<x,
dihydroxyprogesterone 16s.,17et~acetonide for the A1-16a,
l7u-triol-20-one for the acetonide, the l6ot,17a—dicyclo
propyl ketone derivative of 19-nor-3-methoxy-1,3,5(10)
pregnatriene-l6a-17a-diol-20-one is obtained.
1§-nor - 1,3,5(10) - pregnatriene - 3,160t,17o: - triol-ZG-one
l6ct,l7u.-acetonide is obtained.
Similarly, the methylisobutyl ketone derivative, the
65 cyclopropyl phenyl ketone derivative, the cyclohexyl
EXAMPLE 7
methyl ketone derivative, the 1,1,1-tri?uoroacetonide de
rivative, the hepta?uorobutanal derivative, the p-chloro
' 605-191ethyl-1 9-Nor-I ,3,5 ( l’ 0)~Pregitatriene-3,] 6a,] 70:
acetophenone derivative, the p-nitroacetophenone deriva
Triol-ZU-One 1 601,1 7a-Acetophenonide
tive, the benzaldehyde derivative, the furfural derivative,
Following the procedure of Example 1 but substituting
the benzophenone derivative and the 2~acetylfuran de
l7m-dihydroxyprogesterone 16¢,l7a-acet0nide, 6/3-methyl
an equivalent amount of 6a-methyl-Allé-pregnadiene
16a,l7<z-diol-3,20-dione 16a,17u-acetophenonide for the
AI-lSa,l7a-dihydroxyprogesterone 16a,17oc-3C$t0lflid6, 60c
rne'thyl-l9-nor-l,3,5 ( l0) - pregnatriene-B,l6a,l7a-triol-20
one l6a,17a-acetophenonide is obtained.
rivative of
l9-nor - l,3,5(l0) - pregnatriene-3,16a,17u
triol-ZO-one, yield the methylisobutyl ketone, the cyclo
propyl phenyl ketone, the cyclohexyl methyl ketone, the
i,l,l-tri?uoroacetonide, the hepta?uorobutanal, the p
chloroacetophenone, the p-nitroacetophenone, the benzal
sprayer];
1l
dehyde, the furfural, the benzophenone and the 2-acetyl
furan derivatives of 19-nor-3—rnethoxy-l,3,5(l0)-pregna
160:,1704-(1101-20-0116 in 15 ml. of tetrahydrofuran is added
100 mg. of lithium borohydride.
The mixture is re
triene-l6a,17rx-diol-20-one.
?uxed for 8 hours, cooled and excess borohydride de
composed by the addition of water. After the evapora
EXAMPLE 12
tion of the organic solvent the aqueous solution is ex
6a-Methyl-19-Nor-3-Methoxy-1 ,3 ,5 (1 O ) ~Pregnatriene
tracted with chloroform and the resulting chloroform
1604,17oz-Di0l-20-O?6 16a,]7wAcet0nide
extract washed with saturated sodium chloride solution,
dried over sodium sulfate and evaporated to dryness in
Following the procedure of Example 8 but substitut~
vacuo. The product, about 40 mg., cannot be induced
ing an equivalent amount of 6a-methyl-l9-nor-l,3,5 (10)
pregnatriene - 3,16a,17cc—t1‘l0l - 20 - one 16a,17u-acetonide 10 to crystallize even after column chromatography.
for the acetonide, 6a-methyl-19-nor-3-methoxy-1,3,5 (10)
pregnatriene-16u,17u-diol-20-one 16¢,17a-acetonide is ob
2.80, 5.79 (very weak); 13.05 and 14.20,.
tained.
EXAMPLE l8
EXAMPLE 13
160e,] 7a-Chloral Derivative of 19-N0r-3-Methoxy
1 ,3,5 (1 0 ) -Pregnatriene-16a,1 7a,Z0-Tri0l
6/3-Methyl-1 9-Nor-3-Methoxy-1 ,3 ,5 (1 0 ) -Pregnatriene
1 6 a,1 7a-Di0l-20-0ne 1 6 “,1 7a-A celonia'e
Following the'procedure of Example 8 but substitut
ing an equivalent amount of 6?-methyl-l9-nor-l,3,5(10)
pregnatriene-3,16a,17a-triol-20-one 16a,17a-acetonide for
the acetonide, 6,6-methyl-l9-nor-3-methoxy-1,3,5(10)
pregnatriene 160:,17oc-di01-20-O118 16oc,17oc-8.C6t0?ld6 is ob
Following the procedure of either Example 15 or Ex
ample 16, but substituting an equivalent amount of the
160:,170c-Cl1101‘?1 derivative of 19-nor-3-methoxy-1,3,5(10)
20 pregnatriene-l6a,l7a-diol-20-one for the acetonide, the
16m, l7a-chloral derivative of l9-nor-3-methoxy-l,3,5 ( l0)
pregnatriene-l6a,17a,20,8-trio1 is obtained.
tained.
-
EXAMPLE 19
EXAMPLE 14
6a-Methyl-19-N0r-3-Methoxy-1,3,5 (10 ) -Pregnatriene
'
25
16a,17a-Dicyclopropyl Ketone Derivative of 19-N0r-3
Methoxy-1,3,5 (10) -Pregnatriene-16a,17a-Triol
16a,]7a-Di0l-20-0ne 16u,17a-Acet0phen0nide
Following the procedure of Example 8 but substitut
ing an equivalent amount of 6/3-methyl-19-nor-1,3,5(l0)
Following the procedure of either Example 15 or Ex
ample 16, but substituting an equivalent amount of the
pregnatriene-3,16a,17a-triol-20-one 16a,17a-acetopheno 30 l6a,17u-dicyclopropyl ketone derivative of l9-nor-3
methoxy-l ,3,5 ( 10)-pregnatriene-16a,17a-diol-20-one for
nide for the acetonide, 6e-methyl-l9-nor-3-methoxy-l,3,
5( 10)-pregnatriene-16<x,17a-diol-20-one
the acetonide, the 16a,17a-dicyclopropyl ketone derivative
of 19-nor-3-methoxy- 1,3,5 ( 10) -pregnatriene- 1 6oz, 1711,205
1611,17“ - aceto
phenonide is obtained.
triol is obtained.
EXAMPLE 15
35
19-N0r-3-Meth0xy-1,3,5 (10) -Pregnatriene-16a,1 7“,20p
Triol 160a,] 7a-Acet0nide
A solution of 280 mg. of 19-nor-3-methoxy-1,3,S(10)
pregnatriene-16a,l7u-diol-20-one l6a,17u-acetonide and
340 mg. of lithium aluminum hydride in 50 ml. of an
hydrous ether is re?uxed for 2 hours and then stirred
at room temperature for 18 hours. Saturated sodium
sulfate solution is added carefully until a precipitate
forms. The ether is decanted and the precipitate washed
four times with 20 ml. portions of ether. After removal
of the solvent the crude residue (about 277 mg.) is
crystallized from acetone-hexane yielding about 225 mg.
of product. The ZOyS-hydroxy compound is obtained in
two polymorphic modi?cations, which melt respectively 50
at about 108—l10° and about 149-151°. The analytically
pure sample has the following properties: M.P. about
149-151° (3.; [a]D23+49° (c., 0.9 in chit);
E1231?‘ 2.60, 2.65, 6.18 and 6.32;‘; x353, 277 my (e=2040),
287 my. (6=1910)
Similarly, the methylisobutyl ketone derivative, the
cyclopropyl phenyl ketone derivative, the cyclohexyl meth
yl ketone derivative, the 1,1,1-tro?uoroacetonide deriva
tive, the hepta?uorebutanal derivative, the p-chloroace
tophenone derivative, the p-nitroacetophenone derivative,
the benzaidehyde derivative, the furfural derivative, the
benzophenone derivative and the Z-acetylfuran derivative
of l9-nor-3-methoxy-1,3,5 ( l0)-pregnatriene-l6a,17a-diol
20-one, yield the respective 16a, 17a-cyclic ketal deriva
tives of 19-nor-3-methoxy-l,3,5(10)-pregnatriene-16a,17a,
20/3-triol.
EXAMPLE 20
6a-Methyl-1 9-N0r-3-Il4ethoxy-1,3,5 (1 0) -Pregnatriene
1 6a,] 7 0:,205-1‘riol 16a,17a-Acet0nide
Following the procedure of either Example 15 or Ex
ample 16, but substituting 6a-methyl-19-nor-3-meth0xy
' 1,3,5 ( l 0) -pregnatriene-l 6a, 17oc-di0l-20-01’18
5(l0)-pregnatriene-16c¢,17a,20?-triol-16a,17u - acetonide
is obtained.
Aizalysis.—Calcd. for (3241-1340., (386): C, 74.57; H,
8.87. Found: C, 74.45; H, 8.52.
7
EXAMPLE 21
6,8-Melhyl-J9-Nor-3-Methoxy-1,3,5 (10) -Pregnatriene
EXAMPLE 16
To a solution of 30 mg. of l9-nor-3-methoxy~l,3, 60
5(10)-pregnatriene-160;,17m-di0l-20 - one
16a,17m-ace
tonide for the acetonide, Got-methyl-l9-nor-3-methoxy-l,3,
16¢,17a - ace
tonide in 10 ml. of isopropyl alcohol is added 100 mg.
of sodium borohydride. The resulting mixture is re
?uxed for '18 hours, cooled and the excess borohydride
decomposed by the addition of water. After concentra 65
tion in vacuo and dilution with distilled water the re
duction product precipitates. It is removed by ?ltration,
16a,17o:,20,B-Tri0l 1611,] 7a-A cetonide
ample 16, but substituting 6,8-methyl-19-nor-3-methoxy
1,3,5 ( 10)-pregnatriene-16a,17o¢-diol-20-one l6a,17a-ace
tonide for the acetonide, 6/3-methyl-l9-nor-3-methoxy-1,
3,5 ( l0) -pregnatriene- 1 6a, 1 7:1,20B-t1‘i01 1602,17oc-21C6t011id6
is obtained.
EXAMPLE 22
6a-Methyl-1 9-Nor-3-Methoxy-1 ,3,5 ( 1 0 ) -Pregnatrielze
the precipitate washed with water and recrystallized from
16e,17rx, 20,8-Tri0l 16a,17u-Acet0phen0rzide
acetone-hexane.
Following the procedure of either Example 15 or Ex
70
EXAMPLE 17
ample 16, but substituting éa-methyl-l9-nor-3-methoxy
- 19-NOT-3-M6th0xy-I ,3,5 (1 0 ) —Pregnatriene~1 611,] 711,205
1,3,5(lO)~pregnatriene-16a,l7a-diol-20-one l6a,l7a ace
tephenonide for the acetonide, 6a-methyl-l9-nor-3-me
To a solution of 33 mg. of the 160:,17ot-3C6i013h5110116
:derivative 7 of 3-methoxy-19-nor-1,3,5(10)~pregnatriene
‘
Following the procedure of either Example 15 or Ex
thoxy-1,3,5(l0)-pregnatriene-16a,17a,20/8-triol 160:,1711
ac-etophenonide is obtained.
13
3,077,471
i4
EXAMPLE 23
pregnatriene-1'6u,17a-diol-20-one l6a,l7a-acetonide for
19-N0r-3-Meth0xy-1,3,5 (1 0 ) -Pre‘.gnalriene-16a,1 7 a205
the‘ acetonide, l9-nor-3-methoxy-1,3,5(10)-pregnatriene
160:,17ez-di0i-20-0I16 is obtained.
Trial 1 611,1 7u-Aceionide 20‘8-Acetate
A solution of 25 mg. of l9-nor-3-methoxy-1,3,5(10)
pregnatriene-16a,17u,2()?-triol 16a,17o:-acetonide in 0.5
EXAMPLE 29
ml. of acetic anhydride and 0.5 ml. of pyridine is per
6 a-Methyl-1 9-N0r-3-M ethoxy-I ,3,5 (1 0 ) -Pregnatrien e
mitted to remain at room temperature for 18 hours. The
160:,17cc-Di0l-20-0I16
reagents are then evaporated in vacuo and the residue
Following the procedure of Example .25 but substituting
crystallized from acetoneehexane. The pure acetate has 10 an ‘equivalent amount of éa-methyl-l9-nor-3-methoxyl,3,5
the following properties: MP. about 158—160°;
(10)-pregnatriene-16a,17a-diol-20-one 1611,17a-3C3i01’1id6,
for
[a]n23+'66°
acetonide,
6a-methyl-19-nor-3-meth|oxy-1,3,5(10)
pregnatriene-lGa,17u-diol-20-one is obtained.
hm?‘ 5.73, 6.20, 6.31, 7.98 and 8.08/1.
EXAMPLE 30
EXAMPLE 24
6,8-Methyl-1 9-N0r-3-Meth0xy-1,3,5 (10 ) -Pregnatriene
160:,17oL-Di0l-20-0H8
J 9-N0r-3-Methoxy—1,3,5 (1 0 ) -Pregnatriene-16a,1 7 a,20?-*
Triol 1612,17d-AC81‘OHid8 ZOB-PropiOnate
Following the procedure of Example 25 but substituting
Following the procedure of Example 23 but substitut 20 an equivalent amount- of 6?-methyl-l9-nor-3-methoxy-1,3,
ing an equivalent amount of propionic anhydride for the
5 ( 10) v-pregnatriene-16a, 17a-diol-2‘O-one 160:,17cc-21C6t0t1id?
acetic anhydride, the 20/3-propionic acid ester is obtained.
for the acetonide, 6,8-methyl-19-nor-3-methoxy-1,3,5(10)
Similarly, by substituting other acylating agents, such
pregnatrierie-l6a,17a-diol-20-one is obtained.
as benzoyl chloride,- for acetic anhydride in Example 23
the corresponding esters are obtained. Moreover, any of 25
the other steroids of this invention can be substituted for
the ‘steroid reactant in the procedure of Example 23 to
yield the corresponding ZO?-acetate derivatives.
EXAMPLE 2s
EXAMPLE 31
A cetoph enone Derivative of 19-N0r-1,3,5 (10) --Preg
‘
30
natriene-3,1 6 11,1 7a-Tri0l-20-One
A suspension of 100 mg. of 19-nor-l,3,5(10)-preg
; 19-Nar-1,3,5,(10 )-Pregnatriene-3,16a17a-Tri0l-20-One
natriene-3,16a,l7a-triol-20-one in 5 ml. of redistilled ace
pletely in vacuo and the residue is dissolved in 83 ml.
of oxygen-free methanol. To this solution’ is added under
nitrogen 16.6 ml. of an oxygen-free 10% potassium car
bonate solution and the mixture is allowed to remain at
room temperature under nitrogen for 30 minutes. 1.7 ml.
of glacial acetic acid is then added, followed by 100 ml.
of water. Upon removal of the bulk of the methanol in
vacuo crystallization of the resulting 19-n0r-1,3,5(10)
pregnatriene-3,16a,17u-triol-20-one ensues. The crystal
chloroform and acetophenone in high vacuum leaves a
residue, which on recrystallization from acetone-hexane
tophenone and 0.025 ml. of 70% perchloric acid is stirred
at room temperature for 1% hours. The resulting solution
;_ A solution of 830 mg. of 194nor-1,3,5(10)-pregnatriene
3,l6a,17a-triol-20-one 16oz,l7oz-ac€t0l'lide in 25 ml. of 88% 35 is neutralized‘ with sodium bicarbonate solution and after
the addition of chloroform, the layers are separated and
formic acid‘ is allowed to remain at 42° for 22 hours. At
the organic phase washed with water. Removal of the
the end of that period the formic acid is removed com
gives the pure acetophenone derivative of 19-nor-1,3,
5 ( l0 ) ~pregnatriene-3,16a,17a-triol-20-one.
EXAMPLE 32
Benzaldehyde Derivatives of 1 9-Nor-1,3,5 (10) -Pregna
Mame-3,1 6 01,1 7 cz-Triol-ZO-One
line precipitate is ?ltered, dried and recrystallized from
acetone-hexane.
Following the procedure of Example 31 but substitut
ing an equivalent amount of benzaldehyde for the aceto
phenone, the two isomeric benzaldehyde derivatives of
EXAMPLE 26
6a-il/Iethyl-19-N0r-],3,5 (10 )-Pregnatriene-3,16a,1 70:
50
19 - nor -
Tri0l-20-One
separation on alumina.
Following the procedure of Example 25 but substitut
ing an equivalent amount of 6a-methyl-l9-nor-1,3,5(10)
pregnatriene-3,l6a, l7a-triol-20-one l6a,l7oz-acetonide for 55
the acetonide, 6a-methyl-19-nor-1,3,5(10)-pregnatriene-3,
EXAMPLE 33
Furfural Derivatives of 19-N0r-1,3,5(10) -Pregnatriene
3,1- 6 11,1 7e-Tri0l-20-One
1611,17ct-t1‘iO1-20-0I16 is obtained.
EXAMPLE 27
Following the procedure of Example 31 but substitut
60 ing an equivalent amount of furfural for the aceto
phenone, the two isomeric furfural derivatives of l9-nor
1,3,5(10)~pregnatriene-3,16a,17a-triol-20-one are ob
6,e-Merhyl-19-Nar-1,3‘,5 (1 0 ) -Pregnatriene-3,1 60a,] 7a
Triol~20~0ne
tained, and are separated by chromatographic separation
Following the procedure of Example 25 but substitut
ing an equivalent amount og 6?-methyl-19-n0r-l,3,5(10)
on alumina.
pregnatriene-3,16a,17a-triol-20-one 16a17a-acetonide for 65
the acetonide, 6?-methyl-19-nor-1,3,5(10)-pregnatriene-3,
l6al7wtriol-20-one is obtained.
EXAMPLE 28
19-Nor-3-Methoxy-1,3,5(I0)-Pregnatriene-16a,17a
Di0l~20-One
1,3,5(10)-pregnatriene-3,l6a,17u-triol-20-one
are obtained, and are separated by chromatographic
EXAMPLE 34
Thiophene-Z-Carboxaldehyde Derivatives of 19-N0r
1 ,3 ,5 ( .7 0 ) ~Pregnatriene-3J 6 a,1 7a-Tri0l-20-One
Following the procedure of Example 31 but substitut
70
ing an equivalent amount of thiophene-Z-carboxaldehyde
for the acetophenone, the two isomeric thiophene-Z-car
boxaldehyde derivatives of 19-nor-1,3,5(10)-pregnatriene
Following the procedure of Example 25 but substituting
3,16a,17et-triol-20;one are obtained, and are separated
an equivalent amount of 19-nor-3-methoxy-l,3',5(1O); 75 ‘by chromatographic separation on alumina.
3,077,471
16
15
What is claimed is:
1. A compound of the formula
EXAMPLE 35
Z-Acetylfuran Derivative 0]‘ 19-N0r-1,3,5(10)Pregna
triene-3,] 6 04,1 7a-Tri0l-20-0ne
Following the procedure of Example 31 but substituting
CH3
an equivalent amount of Z-acetylfuran for the aceto
phenone, the Z-acetylfuran derivative of 19-nor-1,3,5( 10')
pregnatriene-3,16a,17a-triol-20-one is obtained.
' ---- --o
mes
EXAMPLE 36
Z-Acetylthiophene Derivative of 19-N0r~1,3,5(10)
,
10
O
Pregnatriene-3,16a,1 7a-Tri0l-20-One
Following the procedure of Example 31 but substitut
ing an equivalent amount of 2-acetylthiophene for the
acetophenone, the 2-acetylthiophene derivative of 19
nor-1,3,5(l0)-pregnatriene-3,l6a,17a-triol-20-one is ob 15
tained.
.Similarly, by substituting any other aldehyde or ketone
for the acetop'henone in the procedure of Example 31,
P
/
5
wherein R is selected from the group consisting of hydro‘
vgen and lower alkyl; R’ is selected from the group con~
sisting of hydrogen and lower alkyl; R” is selected from
the group consisting of B-hydroxy and ?-acyloxy wherein
the acyl radical is from a hydrocarbon carboxylic acid
all other acetals and ketals of this invention can be pre
pared.
EXAMPLE 37
Acetophenone Derivative of 6a-Methyl-19-Nor-1,3,5(10) -
‘of less than ten carbon atoms; R’” is hydrogen, and to
gether R" and R'” is 01m; P is selected from the group
Pregnatriene-3,I6a,1 7oc-T7'i0l-20-0I1e
consisting of hydrogen, lower alkyl, halo lower alkyl,
Following the procedure of Example 31 but substitut 25 monocyclic cycloalkyl, monocyclic cycloalkyl lower
alkyl, monocyclic aryl, monocyclic aryl lower alkyl,
ing an equivalent amount of 9a-methyl-19-nor-1,3,5(l0)
'monocyclic heterocyclic and monocyc-lic heterocyclic
pregnatriene - 3,l6oc,l7oz - triol-ZO-one for the 19-nor
lower alkyl; Q is selected from the group consisting of
lower alkyl, halo lower alkyl, monocyclic- cycloalkyl,
1,3",5('10)-pregnatriene-3,16a,17a-triol-20-one, the aceto
phenone derivative of 6a: - methyl - 19-nor-l,3,5(10)
.pregnatriene-3,1-6a,17a-triol-20-one is obtained.
30
EXAMPLE 38
monocyclic heterocylie lower alkyl; and together with
the carbon to which they are joined P and Q is selected
from the group consisting of monocyclic cycloalkyl and
iAcetophenone Derivative of 6/8-Methyl—19-N0r-1,3,5 (10) -
Pregnatriene-3,16a,17a-Tri0l-20-One
Following the procedure of Example 31 but substitut
ing an equivalent amount of 6B-methyl-19-nor-1,3,5(10)
35
monocyclic heterocyclic.
2. 19 - nor - 1,3,5 (10)-pregnatriene-3,16a,17a=triol-20
one l6a,l7a-acetonide.
pregnatriene-3,16a,l7a - triol - 20-0ne for the 19-nor
1,3,5 (l0)-pregnatriene-3,16a,17a-triol-20-one, the aceto~
phenone derivative of 65-rnethyl-19-nor-1,3,5(10)-pregna
triene-3,l6a,17a-triol-20-one is obtained.
monocyclic cycloalkyl lower alkyl, monocyclic aryl,
monocyclic aryl lower alkyl, monocyolic heterocyclic and
3. 6-(lower alkyl) - 19 - nor - 1,3,5(lO)—pregnatriene-3,
40
16a,17ot-tl‘101—20-01'16 16a,l7a-acetonide.
4. 6 - methyl - 19 - nor-1,3,5(10)-pregnatriene-3,16u,
17a-triol-20-one 16a,17a-acetonide.
5. 19 - nor - 3(lower alkoxy) - 1,3,5(10)pregnatriene
EXAMPLE 39
16a,17a-diol-20-one 16a,17a-acetonide.
Acetophenone Derivative 0;f_ 19-N0r-3-Meth0x'y
6. 19 - nor - 3 - met-hoxy-1,3,5(l0)-pregnatriene-16a,
1,3,5 ( 1 0 ) -Pregrzatriene-16ot,1 7a-Di0l-20-One
45 17a-diol-20-one 16a,17a-acetonide.
7. l9 - nor - 3-(lower alkoxy)-1,3,5(10)—pregnatriene
Following the procedure of Example 31 but substitut
16a,17a,20;8-triol-16a,17u-acetonide.
.
ing an equivalent amount of 19-nor-3-methoxy-1,3,5( 10)
8. l9 - nor - 3 - methoxy-1,3,5(10)-pregnatriene-l6e,
' pregnatriene - 1605,17“ - diol - 20-one for the 19-nor
1,3,5( 10)-pregnatriene-3,16a,17a-triol—20-one, the aceto
phenone derivative of 19 - nor - 3-methoXy-1,3,5(10)
l7ot,20}8-triol l6a,l7a-acetonide.
50
EXAMPLE 40
Acetophenone Derivative of 6a-Methyl-1 9-N0r-3
Meth0xy-1,3,5 (10 ) -Pregnatriene-16<x,1 7 a-Diol-ZO-One
9. 19 - nor - 3 - (lower alkoxy)-1,3,5(l0)-pregnatriene~
16a,17a,20?-trio1 16a,17a-acetonide 20,8-(lower alkano
ate).
pregnatriene-l6a,l7u-diol-20-one is obtained.
10. 19 - nor - 3 - methoxy-1,3,5(10)-pregnatriene-16ot,
l7ot,20/3-triol 16a,17a-acetonide ZO?-acetate.
55
11. A compound of the formula
Following the procedure of Example 31 but substitut
ing an equivalent amount of 6a-methyl-19-nor-3-methoxy
>1,3,5(10)-pregnatriene-16a,17a~diol-20-one for the 19
nor-1,3,5(l0)~pregnatriene-3,16ot,17ot-triol - 2O - one, the
CHa
0:0
60
'acetophenone derivative of 6a-methyl-19-nor-3-methoxy
1,3,5( l0)—pregnatriene-l6a,17a-diol-20-one is obtained.
EXAMPLE 41
65
A cetophenone Derivatives of 6?-Methyl-1 9-N0r-3
Meth0xy-1,3,5 (l 0) -Pregnatriene-1 6 a,1 7 a-Diol-ZO-One
Following the procedure of Example 31 but substitut~
ing an equivalent amount of 6,8-methyl-19-nor-3-rnethoxy
1,3,5 (10)-pregnatriene-16a,17a-diol-20-one for the 19 70
nor-1,3,5(10)-pregnatriene-3,16a,17ot-triol - 20 - one, the
acetophenone derivative of 6l3-rnethyl-19-nor-3-methoxy
1,3,5( 10) -pregnatriene-16a,17a-diol-20-one is obtained.
E
R
wherein R is selected from the group consisting of hydro
gen and lower alkyl, and R" is selected from the group
consisting of hydrogen and lower alkyl.
This invention may be variously otherwise embodied
12. 19
Within the scope of the appended claims.
75 20-one.
- nor - 1,3,5(10) - pregnatriene - 3,16u,17ot-triol
3,077,471
1
13. 19 - nor - 3 - metho§3Z1,3,5(10)-pregnatriene-16a,
17°"di°1'2°'°n°References Cited in the ?le of this patent
UNITED STATES PATENTS
2,280,828
Inho?en ____________ ._ Apr. 28, 1942
2,753,342
'Djerassi et a1. __________ __ July 3, 1956
3,200,968
Bernstein at 881. ________ __ Oct. 3, 1961
FOREIGN PATENTS
854,343
Great Britain -------- -- NOV- 16, 1960
OTHER REFERENCES
5
Loewenthal: Tetrahedron, 1959, vol. 6, pp. 281 and
282.
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