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Description  |
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BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to novel compounds represented by the formula
##STR1##
wherein R.sub.1 is lower alkyl of from 1 to 5 carbon atoms; W is one of
the partial formulas
##STR2##
where R is hydrogen, lower alkyl, cycloalkyl, lower alkanoyl or aroyl;
R.sub.2 taken independently is hydrogen; R.sub.3 taken independently is a
3-hydroxy, 3-lower alkanoyloxy, 3-keto or 3-keto-.DELTA..sup.4 group; and
R.sub.2 and R.sub.3 taken together with carbon atoms 2 and 3 of the
steroid nucleus represent a 5-membered heteroaromatic ring wherein one
heteroatom is attached to carbon atom 3; R.sub.10 is hydrogen or methyl;
and Z is one of the groups carbonyl, ketal protected carbonyl,
##STR3##
R.sub.7 is hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sub.8
is hydrogen, lower alkyl, cycloalkyl, lower alkanoyl or aroyl; R.sub.9 is
hydrogen, hydroxy, or lower alkanoyloxy; R.sub.20 is hydroxy or lower
alkanoyloxy; and R.sub.21 is hydrogen, hydroxy, lower alkanoyloxy or
halogen.
More specifically, the present invention is concerned with the two classes
of subgeneric steroids represented by the formulas
##STR4##
WHEREIN R, R.sub.1, R.sub.2, R.sub.3, R.sub.10 and Z are as above.
As used throughout the specification and the appended claims, the term
"alkyl group" refers to a monovalent radical of up to 20 carbon atoms
consisting solely of carbon and hydrogen and containing no unsaturation;
the term "alkenyl group" refers to a monovalent radical consisting solely
of carbon and hydrogen of up to 20 carbon atoms containing olefinic
unsaturation; the term "alkynyl group" refers to a monovalent radical
consisting solely of carbon and hydrogen of up to 20 carbon atoms
containing acetylenic unsaturation. The term "cycloalkyl group" denotes a
monovalent radical consisting solely of carbon and hydrogen possessing at
least one carbocyclic ring, said ring containing from 3 to 8 carbon atoms.
The term "alkanoyl" refers to the residue of a saturated aliphatic
carboxylic acid containing up to 20 carbon atoms obtained by removing the
hydroxyl from the carboxyl moiety. The term "alkanoyloxy group" refers to
the residue of a saturated aliphatic carboxylic acid containing up to 20
carbon atoms obtained by removal of the hydrogen from the carboxyl moiety.
The term " aroyl" refers to the residue of a monocyclic aromatic
carboxylic acid obtained by removing the hydroxyl from the carboxyl
moiety. The term "halogen" refers to fluorine, chlorine, bromine and
iodine. The term "ketal protected carbonyl" refers to a group which may be
hydrolyzed to regenerate a carbonyl group under conventional hydrolysis
conditions, such as a carbonyl protected as a di(lower alkyl)ketal, an
alkylene ketal or an arylene ketal. Examples of di(lower alkyl)ketals are
dimethyl ketals, diethyl ketals and so forth. Alkylene ketals are derived
from 1,2 or 1,3 glycols, e.g. ethylene glycol, 1,3-propyleneglycol,
2,3-butyleneglycol and so forth. Arylene ketals are derived from
catechols, e.g. phenylene-1,2-diol, alkyl-substituted-phenylene-1,2-diols,
naphthalene-1,2- or 2,3-diols, and so forth. The term "heteroaromatic
ring" comprehends a monocyclic ring system having aromatic unsaturation
and which has at least one ring member which is not a carbon atom. The
term "lower", as applied to any of the foregoing groups, denotes a group
having a carbon skeleton containing up to and including 8 carbon atoms.
In the formulas presented herein, the various substituents on cyclic
compounds are joined to the cyclic nucleus by one of three notations: a
solid line (--) indicating a substituent which is in the
.beta.-orientation (i.e., above the plane of the paper), a dotted line (-
- - -) indicating a substituent which is in the .alpha.-orientation (i.e.,
below the plane of the paper), a wavy line ( ) indicating a substituent
which is in either the .alpha.- or the .beta.-orientation. Although the
position of the angular methyl group at carbon atom 13 of the steroid
nucleus has been arbitrarily indicated as the .beta.-orientation, i.e.,
the "natural" steroid series, the invention is not to be construed as
limited to the "natural" steroid series and is meant to include the
corresponding "unnatural" and racemic series of steroids.
The 15-oxasteroids represented by formulas Ia and Ib can be prepared from
the corresponding carboxylic 17-oxosteroids, as depicted in Reaction
Scheme A below.
##STR5##
Compounds of formula II are known and are prepared from 17-keto-steroids by
oxidative cleavage of the D-ring by methods known per se. Compounds of
formula III
##STR6##
wherein R.sub.4 is hydrogen or lower alkyl,
R.sub.5 is hydrogen or lower alkanoyl and
R.sub.1 and W' are as above,
are novel and constitute part of the present invention.
The preparation of a compound falling within the genus of formula IIIa
purported to be 3.beta.,14-diacetoxy-14,17-seco-D-bis-norandrostan-17-oic
acid 17-methyl ester has been described by Banerjee and Gut, J. Org.
Chem., 34, 1614 (1969). The material was prepared via a series of
reactions from a compound purported to be
3.beta.-acetoxy-15,17-seco-D-norandrostan-15,17-dioic acid 17-methyl
ester, a compound falling within the genus of formula II.
During the course of the present invention it has been discovered that both
above compounds are erroneously described. It has been shown that the
starting diacid monomethyl ester was in reality
3.beta.-acetoxy-15,17-seco-D-norandrostan-15,17-dioic acid 15-methyl ester
and the degradation product prepared therefrom
3.beta.,13-diacetoxy-13,15-seco-D-bisnorandrostan-15-oic acid 15-methyl
ester. The preparation of
3.beta.-acetoxy-15,17-seco-D-norandrostan-15,17-dioic acid 17-methyl
ester, agreeing in physical properties with that prepared herein, was
described by Fetizon and Moreau, Bull. Soc. Chim. France, 4385 (1969).
Furthermore, it has been demonstrated that the series of reactions
described by Banerjee and Gut as leading from their dioic acid dimethyl
ester to their monomethyl ester acetate is not operative for the analogous
conversion of compound II to compound IIIa.
According to the present invention, the degradation of a compound of
formula II to one of formula IIIa is suitably effected by contacting the
former with a tetra(alkanoyloxy)lead, most preferably lead tetraacetate.
This reaction is generally carried out in the presence of a weak base, for
example, an organic amine, preferably pyridine. An inert organic solvent
is suitably employed as a diluent, preferably a hydrocarbon such as
benzene or toluene. A temperature of from about 40.degree. to about
150.degree. C. may be employed although it is generally preferred to
carried out the reaction at the reflux temperature of the reaction medium.
In the next step, compound IIIa is hydrolyzed to the hydroxy acid of
formula IIIb. Where R or R" in partial formula W' is lower alkanoyl or
aroyl, these groups are also hydrolyzed to a hydroxy group under the
reaction conditions. Suitable reaction conditions are readily suggested to
one skilled in the art, and include heating a compound of formula IIIa
with a dilute alcoholic solution of an alkali metal hydroxide, e.g.
refluxing with a 3% methanolic potassium hydroxide solution.
The hydroxy group at carbon atom 14 (and, if present, one at carbon atom 3)
may then be reacylated by treatment with the desired acid chloride or
anhydride to afford a compound of formula IIIc. The next step is the
preparation of a diazo ketone of formula IV
##STR7##
wherein R.sub.1, R.sub.5 and W' are as above.
Accordingly, the carboxyl group of the alkanoyloxy acid of formula IIIc is
converted to a diazo ketone moiety by treatment of an activated derivative
of the acid with diazomethane. Suitable activated acid derivatives include
acid halides, most preferably the acid chloride. The conversion to the
diazoketone is suitably effected by contacting a solution of the acid
halide in an inert organic solvent, e.g. an ether, with an excess of
diazomethane, in the cold. Suitably, the reaction is carried out at about
0.degree. to prevent evaporation of the low boiling diazomethane.
The 14-acyloxy group of the diazo ketone of formula IVa, as well as any
acylated hydroxyl groups present at carbon atom 3, are next hydrolyzed to
the free hydroxy groups by alkaline saponification. Suitable
saponification agents include alkali metal hydroxides, e.g. sodium
hydroxide and potassium hydroxide. Saponification is suitably carried out
in an inert organic solvent preferably an alcohol, e.g. methanol or
ethanol. A suitable reaction temperature is about room temperature.
The diazo ketone alcohol of formula IVb is next cyclized to afford the
15-oxasteroid of formula I. This cyclization reaction is carried out in
the presence of an acidic cyclization catalyst. Suitable acidic
cyclization catalysts include Lewis acids, most preferably boron
trifluoride and its ether complexes. The cyclization reaction is suitably
performed in any anhydrous inert organic solvent; preferred organic
solvents include hydrocarbons, e.g. benzene and toluene. The cyclization
is preferably effected at a temperature between about 0.degree. and about
40.degree. C., most preferably about room temperature. The reaction may be
monitored by following the evolution of nitrogen, and is continued until
this evolution is substantially complete.
The compounds of formula I', thus formed, may be further converted to the
remaining members of the genus represented by formula I by standard
transformations at the 3- and 17-positions.
Members of the subgenuses Ia and Ib may be interconverted by a number of
procedures well known in the art. For example, the A-ring aromatic
15-oxasteroids represented by formula Ia, may be converted to
19-nor-15-oxasteroids, represented by formula Ib where R.sub.10 is
hydrogen by, for example, Birch reduction of the aromatic ring and
subsequent hydrolysis of the resulting enol ether. In another procedure,
15-oxa-androstanes of formula Ib where R.sub.10 is methyl may be converted
to 15-oxaestrone derivatives of formula Ia by aromatization of the A-ring
according to well known procedures.
Compounds of formula I' having a 17-keto group may be converted to the
corresponding pregnanes by addition of the requisite 2-carbon side chain
at the 17-position by methods known per se for 17-keto steroids.
The conversion of the 17-keto group to other moieties represented by the
substituent Z may be accomplished in the normal manner utilized for
carbocyclic 17-keto steroids, for example, by reduction of the carbonyl
group to a 17.beta.-hydroxyl function and optional acylation; or by
addition of an organometallic reagent to introduce a 17.alpha.-alkyl,
alkenyl or alkynyl group; and so forth. The R.sub.3 function in compounds
of formula Ib may be modified according to standard procedures known in
the art involving, for example, oxidation of the 3-hydroxy to a 3-ketone;
introduction of a .DELTA..sup.4 -double bond; and so forth.
Compounds of formula Ib wherein R.sub.3 is a 3-keto or 3-keto-.DELTA..sup.4
function, may be converted, according to well known procedures, to
steroids having a heterocyclic ring fused to the 2- and 3-positions of the
A-ring. For example, 3-keto-15-oxasteroids of formula Ib may be converted,
via the 2-hydroxymethylene derivatives, to the corresponding [2,3-d] or
[3,2-c]-isoxazoles or [3,2-c]pyrazoles.
Preferred compounds of the present invention are those of subgenus Ia.
Particularly preferred are those wherein R.sub.1 is methyl, Z is carbonyl
or .beta.-hydroxymethylene and R is hydrogen or a cycloalkyl group.
The compounds of formula I exhibit hormonal activity. In particular,
compounds of formula Ia are potent estrogens when tested in the standard
estrogenic (uterotrophic) assay. In this test, the test compound is
administered once daily for 3 consecutive days to a group of 10 immature
female rats. Uteri are removed by autopsy on the fourth day and weighed on
a torsion balance and the organ ratio (mg. organ/100 g. body weight) is
calculated for each rat and the mean determined for each group. The
percent difference from the value for the control group is computed. By
way of example, 15-oxaestrone, when tested in the above assay exhibits an
oral estrogenic activity approximately 12 times that of estrone, and
approximately twice that of Mestranol. These compounds are thus useful in
the treatment of various conditions in which estrogenic agents are
indicated such as estrogen deficiencies, menopause, and the like. The
compounds of formula Ia may also be utilized in conjunction with a
progestational agent for the control of fertility.
Compounds of formula Ib wherein Z is carbonyl or the group
##STR8##
exhibit androgenic/anabolic activity in the standard levator ani and
ventral prostrate assays. Compounds of formula Ib wherein Z is
##STR9##
exhibit progestational activity in the standard Clauberg assay.
Compounds of formula I can be administered internally, for example, orally
or parenterally, with dosages adjusted to individual requirements.
Compounds of formula I may be administered in unit or divided dosages to
make up the daily dosage regimens. The selection of the specific dosages
and dosage regimens should be left to the discretion of the trained
medical practitioner. By way of example, an approximate daily dosage for
15-oxaestrone in an adult human would be from about 0.01 to about 1.0 mg.
per day.
The above compounds of formula I can be administered in the form of
conventional pharmaceutical preparations; for example, they can be
administered in conventional pharmaceutical solid or liquid forms, such as
tablets, pills, capsules, solutions, suspensions, emulsions or the like.
These pharmaceutical preparations can contain conventional pharmaceutical
carriers and excipients such as water, talc, corn starch, polyalkylene
glycol, emulsifying agents, buffering agents, agents for the adjustment of
osmotic pressure, vaseline and the like. The pharmaceutical compositions
described above can additionally contain other active ingredients.
The following examples serve to further illustrate the practice of the
present invention and are not to be construed in any sense as limitative
thereof.
EXAMPLE 1
3.beta.-Hydroxy16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
To a solution of 400 g. (1.38 mole) of isoandrosterone in 6 l. of 3%
methanolic potassium hydroxide was added 275 g. (1.82 mole) of
o-nitrobenzaldehyde. The mixture was stirred at room temperature under
nitrogen for 18 hours, then concentrated under vacuum to a volume of
approximately 2 l. The solution was then cooled and with stirring
acidified with 1.2 l. of 3N hydrochloric acid. The resulting yellow
precipitate was collected by filtration, washed thoroughly with water and
dried. The product was then stirred in 2 l. of cold acetone, filtered and
dried to give 356 g. of
3.beta.-hydroxy-16,17-seco-16-norandrostan15(2'-indoxyliden)-17-oic acid,
mp 272.degree.-274.degree..
EXAMPLE 2
3.beta.-Hydroxy-16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
17-methyl ester
To a mixture of 356 g. of
3.beta.-hydroxy-16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
in 3 l. of methanol was added dropwise 40 ml. of acetyl chloride. After
refluxing for 4 hours, the methanol was removed under reduced pressure and
2 l. of water was added to the residue. The resulting precipitate was
filtered, washed with water and dried. The product was then dissolved in a
minimum of methylene chloride and treated with Norit and dried
(MgSO.sub.4). The mixture was filtered and the methylene chloride removed
under reduced pressure. Trituration of the residue with ether afforded 325
g. of
3.beta.-hydroxy-16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
17-methyl ester, mp 258.degree.-261.degree..
EXAMPLE 3
3.beta.-Acetoxy-16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
17-methyl ester
A solution of 325 g. of
3.beta.-hydroxy-16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
17-methyl ester, 325 ml. of acetic anhydride and 1300 ml. of pyridine was
stirred overnight. The mixture was divided into three portions and each
then added to 3 l. of cold (0.degree.) 3N hydrochloric acid. The resulting
precipitates were filtered and the combined product washed with water and
dried to give 350 g. of
3.beta.-acetoxy-16,17-seco-16-norandrostan-15-(2'-indoxyliden)-17-oic acid
17-methyl ester, mp 260.degree.-262.degree..
EXAMPLE 4
3.beta.-Acetoxy-15,17-seco-D-norandrostane-15,17-dioic acid 17-methyl ester
To a suspension of 350 g. of
3.beta.-acetoxy-16,17-norandrostan-15-(2'-indoxyliden)-17-oic acid
17-methyl ester in 5 l. of glacial acetic acid was added dropwise 290 ml.
of a 90% aqueous chromium trioxide solution prepared by dissolving 90G
chromium trioxide in 100 ml. water. Solution soon occurred with the
evolution of heat (the temperature was kept below 70.degree. with external
cooling). After stirring overnight the acetic acid was removed under high
vacuum and the residue treated with 4 l. of water. The precipitate was
filtered, washed thoroughly with water and dried. The product was then
dissolved in benzene and the solution treated with Norit and anhydrous
magnesium sulfate. The mixture was filtered and the benzene removed under
reduced pressure. Trituration of the residue with hexane afforded 255 g.
of 3.beta.-acetoxy-15,17-seco-D-norandrostane-15,17-dioic acid 17-methyl
ester, mp 152.degree.-158.degree..
EXAMPLE 5
A mixture of 255 g. of
3.beta.-acetoxy-15,17-seco-D-norandrostane-15,17-dioic acid 17-methyl
ester, 745 g. of lead tetra-acetate (dried in vacuo over P.sub.2 O.sub.5),
108 ml. of pyridine and 3.8 l. of dry benzene was stirred and refluxed for
7 hours. The mixture was cooled and the lead salts filtered and thoroughly
washed with ether. The filtrate was washed with a 10% solution of sodium
thiosulfate, 1N hydrochloric acid and then a saturated sodium chloride
solution. The solution was dried (MgSO.sub.4) and the solvent removed
under reduced pressure to give 270 g. of crude product. This material was
dissolved in a minimum of benzene and washed through 1300 g. of neutral
Alumina (grade 1). Elution with 3 l. of benzene followed by 1 l. of a 1%
ethyl acetate benzene solution afforded 215 g. of crude material. This
product was then dissolved in 1230 ml. of 3% methanolic potassium
hydroxide and stirred at 0.degree. for 1 hour. The mixture was acidified
with 700 ml. of 1N hydrochloric acid at 0.degree. and the precipitate
filtered and dried to give 108 g. of
3.beta.-hydroxy-14.beta.-acetoxy-14,17-seco-D-bisnorandrostan-17-oic acid
17-methyl ester, mp 127.degree.-130.degree.. The methanol was removed from
the filtrate under reduced pressure and the mixture extracted with
methylene chloride and the resulting solution dried (MgSO.sub.4). The
solvent was removed under reduced pressure and the residue triturated with
methanol to give 2 g. of
3.beta.-hydroxy-14.beta.-acetoxy-14,17-seco-D-norandrostan-17-oic acid
17-methyl ester, mp 126.degree.-130.degree.. A third crop of 3 g., mp
124.degree.-128.degree., was obtained by removing a portion of the
methanol under reduced pressure. Crystallization from methanol afforded an
analytical sample containing one mole of methanol, mp
134.degree.-136.degree. [.alpha.].sub.D.sup.25 -164.76.degree. (c, 1.11%,
CHCl.sub.3).
Anal. Calcd. for C.sub.21 H.sub.36 O.sub.6 : C, 65.59; H, 9.44. Found: C,
65.85; H, 10.09.
Acetylation with pyridine-acetic anhydride afforded
3.beta.,14.beta.-diacetoxy-14,17-seco-D-bisnorandrostan-17-oic acid
17-methyl ester, mp 105.degree.-106.degree., [.alpha.].sub.D.sup.25
-16.23.degree. (c, 0.758%, CHCl.sub.3).
Anal. Calcd. for C.sub.22 H.sub.34 O.sub.6 : C, 66.98; H, 8.69. Found: C,
67.11; H, 8.93.
EXAMPLE 6 3.beta.,14.beta.-Dihydroxy-14,17-seco-D-bisnorandrostan-17-oic
acid
A solution of 86 g. of
3.beta.-hydroxy-14.beta.-acetoxy-14,17-seco-D-bisnorandrostan-17-oic acid
17-methyl ester in 2.74 l. of 3% methanolic potassium hydroxide was
refluxed for 6 hours. The methanol was removed under reduced pressure and
200 ml. of water added to the residue. The solution was cooled to
0.degree. and acidified with concentrated hydrochloric acid. The
precipitate was filtered and dried to give 72.2 g. of
3.beta.,14.beta.-dihydroxy-14,17-seco-P-bis norandrostan-17-oic acid, mp
285.degree.-287.degree.. Crystallization from methanol afforded an
analytical sample, mp 285.degree.-287.degree., [.beta.].sub.D.sup.25
+11.94.degree. (c, 0.9047%, CH.sub.3 OH).
Anal. Calcd. for C.sub.17 H.sub.28 O.sub.4 : C, 68.88; H, 9.52. Found: C,
69.16; H, 9.71.
EXAMPLE 7
3.beta., 14.beta.-Dihydroxy-16-diazo-17-oxo-14,16-seco-D-norandrostane
To a solution of 350 ml. of acetic anhydride in 350 ml. of pyridine was
added 70 g. of 3.beta.,14.beta.-dihydroxy-14,17-seco-D-norandrostan-17-oic
acid. The solution was stirred at room temperature overnight and then
poured into 6 l. of ice water. The mixture was stirred for 2 hours and
then extracted with ether. The ether solution was washed with 1N
hydrochloric acid and then water until neutrality. The solution was dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give 83 g.
of crude 3.beta.,14.beta.-diacetoxy-14,17-seco-D-bisnorandrostan-17-oic
acid as an oil.
The crude diacetate (83 g.) was treated with 90 ml. of oxalyl chloride and
stirred at room temperature overnight. The excess oxalyl chloride was then
removed under reduced pressure and the residue diluted with hexane and the
solvent again removed under reduced pressure to give 85 g. of crude acid
chloride.
To an ethereal solution of diazomethane prepared from 150 g. of
N-methylnitrosourea was added dropwise with stirring at 0.degree. a
solution of 85 g. of the crude acid chloride in 200 ml. of ether. The
solution was stirred at 0.degree. for 2 hours and the solvent and excess
diazomethane then evaporated under a stream of nitrogen to afford
3.beta.,14.beta.-diacetoxy-16-diazo-17-oxo-14,16-seco-D-norandrostane.
This diazoketone was then added to 790 ml. of a 6% methanolic potassium
hydroxide solution and stirred at room temperature for 5 hours. The
reaction mixture was then cooled to 5.degree. and the precipitate filtered
to give 63 g. of
3.beta.,14.beta.-dihyroxy-16-diazo-17-oxo-14,16-seco-D-norandrostane, mp
145.degree.-150.degree.. Crystallization from ether-methylene chloride
afforded an analytical sample, mp 154.degree.-156.degree.,
[.alpha.].sub.D.sup.25 -8.46.degree. (c, 0.9697%, CHCl.sub.3).
Anal. Calcd. for C.sub.18 H.sub.28 N.sub.2 O.sub.3 : C, 67.47; H, 8.81
Found: C, 67.22; H, 8.91.
EXAMPLE 8
3.beta.-Hydroxy-15-oxa-5.alpha.-androstan-17-one
To a suspension of 63 g. of
3.beta.,14.beta.-dihydroxy-16-diazo-17-oxo-14,16-seco-D-norandrostane in
1.2 l. of dry benzene was added dropwise with stirring a solution of 15
ml. of boron trifluoride-etherate in 20 ml. of benzene. The evolution of
nitrogen began immediately, and after the addition was completed
(.about.15 minutes) the reaction was stirred for an additional 10 minutes.
The benzene solution was then washed with 5% sodium bicarbonate solution
and the aqueous extracts backwashed with ether. The organic layers were
then combined, dried (MgSO.sub.4), heated with Norit and then filtered.
The solvent was removed under reduced pressure and the residue triturated
with hexane to give 54.5 g. of
3.beta.-hydroxy-15-oxa-5.alpha.-androstan-17-one, mp
145.degree.-150.degree.. Crystallization from ether-methylene chloride
afforded an analytical sample, mp 152.degree.-154.degree.,
[.alpha.].sub.D.sup.25 +54,07.degree.(c, 0.505%, CHCl.sub.3).
Anal. Calcd. for C.sub.18 H.sub.28 O.sub.3 : C, 73.93; H, 9.65. Found: C,
73.90; H, 9.82.
Acetylation with pyridine-acetic anhydride followed by crystallization from
methanol afforded the 3-acetoxy derivative, mp 164.degree.-167.degree.,
[.alpha.].sub.D.sup.25 +45.19.degree.(c, .9249%, CHCl.sub.3).
Anal. Calcd. for C.sub.20 H.sub.30 O.sub.4 : C, 71.82; H, 9.04. Found: C,
71.56; H, 8.86.
EXAMPLE 9
15-Oxa-5.alpha.-androstan-3,17-dione
To a cooled (0.degree.) solution of 10 g of
3.beta.-hydroxy-15oxa-5.alpha.-androstan-17-one in 100 ml. of acetone was
added dropwise with stirring 10 ml. of Jones reagent. After the addition
was complete the mixture was stirred at 0.degree. for 10 minutes. The
solvent was then removed under reduced pressure and the residue treated
with 300 ml. of ice water. The precipitate was filtered and washed
thoroughly with water and dried. The product was then dissolved in a
minimum of methylene chloride and the solution treated with Norit and
filtered. The solvent was removed under reduced pressure to give 9.2 g. of
15oxa-5.alpha.-androstan-3,17-dione, mp 176.degree.-180.degree..
Crystallization from ether-methylene chloride afforded an analytical
sample, mp 182.degree.-185.degree., [.alpha.].sub.D.sup.25
+77.39.degree.(c, 1.1798%, CHCl.sub.3).
Anal. Calcd. for C.sub.18 H.sub.26 O.sub.3 : C, 74.44; H, 9.03. Found: C,
74.18; H, 9.01.
EXAMPLE 10
2.alpha.,4.alpha.-Dibromo-15oxa-5.alpha.-androstan-3,17-dione
To a solution of 16.5 g. of 15-oxa-5.alpha.-androstan-3,17-dione in 160 ml.
of dry tetrahydrofuran was added 216 g. of phenyltrimethylammonium
perbromide. The brominating agent quickly dissolved and after a short time
phenyltrimethylammonium bromide began to precipitate. The mixture was
stirred for 4.5 hours and the precipitate filtered and washed with
benzene. An additional 100 ml. of benzene was added to the filtrate and
the resulting solution was then washed with a 5% solution of sodium
sulfite, water and then dried (MgSO.sub.4). The solvent was removed under
reduced pressure and the residue triturated with cold ether to give 14.2
g. of 2.alpha.,4.alpha.-dibromo-15-oxa-5.alpha.-androstan-3,17-dione, mp
212.degree.-214.degree.. Crystallization from methylene chloride-ether
afforded an analytical sample, mp 213.degree.-215.degree. d,
[.alpha.].sub.D.sup.25 +18.05.degree. (c, 0.9861%, CHCl.sub.3).
Anal. Calcd. for C.sub.18 H.sub.24 Br.sub.2 O.sub.3 : C, 48.24; H, 5.40.
Found: C, 48.20; H, 5.50.
EXAMPLE 11
15-Oxa-1,4-androstadiene-3,17-dione
To a solution of 19.6 g. of lithium bromide and 19.6 g. of lithium
carbonate in 200 ml. of dry dimethylformamide at 95.degree. was added
dropwise a solution of 14.7 g. of
2.alpha.,4.alpha.-dibromo-15-oxa5.alpha.-androstan-3,17-dione in 150 ml.
of the same solvent. The mixture was stirred and maintained at 95.degree.
for 18 hours and most of the dimethylformamide was then removed under high
vacuum. To the residue was then added 200 ml. of ice water followed by 50
ml. of 1N hydrochloric acid. The precipitated semi-solid was then
extracted with methylene chloride and the organic layer washed thoroughly
with water and dried (MgSO.sub.4). The solvent was then removed under
reduced pressure and the residue dissolved in a minimum of methylene
chloride and passed through 50 g. of neutral alumina (grade 1). Elution
with methylene chloride gave 9.5 g. of crude product which when triturated
with ether afforded 7 g. of 15-oxa-1,4-androstadiene-3,17 -dione, mp
181.degree.-185.degree.. Crystallization from methylene chloride-ether
afforded an analytical sample, mp 185.degree.-187.degree.,
[.alpha.].sub.D.sup.25 +70.50.degree. (c, 0.9050%, CHCl.sub.3).
Anal. Calcd. for C.sub.18 H.sub.22 O.sub.3 : C, 75.49; H, 7.74. Found: C,
75.77; H, 7.97.
EXAMPLE 12
15-Oxa-1,4-androstadiene-3,17-dione-17-ethylene ketal
A mixture of 7 g. of 15-oxa 1,4-androstadiene-3,17-dione, 14 ml. of
ethylene glycol, 0.28 g. of p-toluenesulfonic acid and 350 ml. of benzene
was placed in a 500 ml. flask fitted with a Soxhlet extractor which was
charged with Linde 3A molecular sieves. After refluxing for 6 hours, the
reaction was cooled and washed with a 5% sodium bicarbonate solution,
water, and dried (Na.sub.2 SO.sub.4). The solvent was removed under
reduced pressure and the residue triturated with ether to give 6.5 g. of
15-oxa-1,4-androstadiene-3,17-dione-17-ethylene ketal, mp
147.degree.-150.degree.. Crystallization from methylene chloride-ether
afforded an analytical sample, mp 147.degree.-150.degree.,
[.alpha.].sub.D.sup.25 +6.50.degree. (c, 0.9545%, CHCl.sub.3).
Anal. Calcd. for C.sub.20 H.sub.26 O.sub.4 : C, 72.70; H, 7.93. Found: C,
72.76; H, 7.89.
EXAMPLE 13
15-Oxaestrone-17-ethylene ketal
To a solution of 86.2 g. of biphenyl in 1.5 l. of dry tetrahydrofuran was
added 4.35 g. of lithium wire. The mixture was stirred at room temperature
for 4 hours after which time the lithium had completely dissolved. The
dark blue solution was then warmed to 50.degree. and a solution of 25.4 g.
of 15-oxa-1,4-androstadiene-3,17ethylene ketal and 38.8 g. of diphenyl
methane in 100 ml. of tetrahydrofuran was added dropwise over a period of
30 minutes. The temperature was maintained at 50.degree.-52.degree. and
the mixture was stirred for an additional hour. The reaction was then
cooled to 0.degree. and 45 g. of ammonium chloride was added in small
portions (color changed from dark green to light brown). Small pieces of
ice were then cautiously added causing the reaction to become colorless,
followed by the addition of 100 ml. of ice water. The resulting two layers
were separated and the aqueous solution extracted with methylene chloride.
The organic layers were combined, dried (MgSO.sub.4), and the solvent
removed under reduced pressure to give an oily residue. Hexane (800 ml.)
was added and the mixture stirred until precipitation took place. The
crude precipitate (25 g.) was dissolved in a minimum of methylene chloride
and passed through 250 g. of silica gel. Elution with 1% ethyl
acetate-benzene and 5% ethyl acetatebenzene gave 15.5 g. of
15-oxaestrone-17-ethylene ketal. Trituration with hexane-ether gave 12.5
g., mp 212.degree.-215.degree.. Crystallization from methylene
chloride-ether afforded an analytical sample, mp 214.degree.-216.degree.,
[.alpha.].sub.D.sup.25 +18.99.degree. (c, 0.89%, CHCl.sub.3).
Anal. Calcd. for C.sub.19 H.sub.24 O.sub.4 : C, 72.12; H, 7.65. Found: C,
71.98; H, 7.53.
EXAMPLE 14
15-Oxaestrone
A solution of 12 g. of 15-oxaestrone-17-ethylene ketal, 250 ml. of dioxane,
and 20 ml. of an 8% aqueous sulfuric acid solution was stirred and
refluxed for 4 hours. The solution was cooled, poured into 2 l. of ice
water and the precipitate filtered. The product was washed thoroughly with
water and air dried. The crude material was then dissolved in a minimum of
1:1 methylene chloride-tetrahydrofuran solution, dried (MgSO.sub.4), and
heated with charcoal. The mixture was filtered and the solvent removed
under reduced pressure. The resulting residue was triturated with ether to
give 9.2 g. of 15-oxaestrone. Crystallization from methanol afforded two
crops of product: 7.0 g. mp 254.degree.-256.degree.; 1.4 g., mp
252.degree.-254.degree.. Crystallization from methanol of the first crop
afforded an analytical sample, mp 255.degree.-256.degree.,
[.alpha.].sub.D.sup.15 +108.45.degree. (c, 0.876%, CHCl.sub.3).
Anal. Calcd. for C.sub.17 H.sub.20 O.sub.3 : C, 74.97; H, 7.40. Found: C,
75.28H, 7.84.
EXAMPLE 15
15-Oxaestradiol
A solution of 0.5 g. of 15-oxaestrone in 10 ml. of dry tetrahydrofuran was
added dropwise with stirring to a cooled (0.degree.) solution of 1.35 g.
of lithium tri-t-butoxyaluminum hydride in 50 ml. of dry tetrahydrofuran.
After 15 minutes at 0.degree. chloroform (100 ml.) was added and the
mixture washed with cold 1N hydrochloric acid. The solution was then dried
(MgSO.sub.4) and the solvent removed under reduced pressure. The crude
semi-solid was crystallized from acetone-water to give 0.4 g. of
15-oxaestradiol, mp 180.degree.-182.degree., [.alpha.].sub.D.sup.25
+74.91.degree. (c, 0.949%, CH.sub.3 OH).
Anal. Calcd. for C.sub.17 H.sub.22 O.sub.3 : C, 74.42; H, 8.08. Found: C,
74.11; H, 8.19.
EXAMPLE 16
15-Oxa-3-methoxy-19-nor-17.alpha.-pregna-1,3,5-(10)-trien-20-yn-17-ol
To a dioxane solution (48 ml.) saturated with acetylene at 0.degree. was
added 4.8 g. of lithium acetylide-ethylene diamine followed by the
dropwise addition (30 min.) of 0.8 g. of 15-oxaestrone dissolved in 16 ml.
of dry dioxane. During the addition and for 40 minutes thereafter
acetylene was bubbled through the reaction mixture. The reaction was then
stirred at room temperature for 3.5 hours after which time 100 ml. of 20%
hydrochloric acid was added slowly with stirring at 0.degree.. The mixture
was then extracted with ether, and the ether solution washed with 0.1N
hydrochloric acid, water, and then dried (MgSO.sub.4). The solvent was
then removed under reduced pressure to afford
15-oxa-3-hydroxy-19-nor-17.alpha.-pregna-1,3,5(10)-trien-20-yn-17-ol. This
was treated directly for 3 days with an ethereal solution of diazomethane.
When the reaction was complete (tlc) the solvent and excess diazomethane
were blown off by a stream of nitrogen and the resulting product dissolved
in a minimum of benzene and passed through 1 g. of silica gel. Elution
with benzene afforded 0.75 g. of crude material which when triturated with
hexane gave 0.57 g. of
15-oxa-3-methoxy-19-nor-17.alpha.-pregna-1,3,5(10)-trien-20-yn-17-ol, mp
112.degree.-124.degree.. Drying at 95.degree./0.1 mm for 18 hours afforded
0.5 g., mp 140.degree.-142.degree., [.alpha.].sub.D.sup.25 0.degree. (c,
0.8725%, CHCl.sub.3).
Anal. Calcd for C.sub.20 H.sub.24 O.sub.3 : C, 76.64; H, 8.04. Found: C,
76.74; H, 7.80.
EXAMPLE 17
3.beta.,17.beta.-Dihydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstane
To a solution of 2 g. of 3.beta.-hydroxy-15-oxa-5.alpha.-androstan-17-one
dissolved in 20 ml. of dry tetrahydrofuran was added dropwise at
-70.degree., 10.8 ml. of a 1.9 molar solution of methyl lithium in ether.
The resulting thick gelatinous mass was stirred for 10 minutes and then
added to 100 ml. of a 5% aqueous solution of sodium dihydrogen phosphate.
The mixture was then extracted with methylene chloride, the solution dried
(MgSO.sub.4), and the solvent removed under reduced pressure. The residue
was then crystallized from acetone to give 1.5 g. of
3.beta.,17.beta.-dihydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstane, mp
227.degree.-229.degree., [.alpha.].sub.D.sup.25 -13.58.degree. (c,
0.5303%, CHCl.sub.3).
Anal. Calcd. for C.sub.19 H.sub.32 O.sub.3 : C, 73.98; H, 10.46. Found: C,
73.67; H, 10.76.
EXAMPLE 18
17.beta.-Hydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstan-3-one
To a suspension of 1.8 g. of crude
3.beta.,17.beta.-dihydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstane in
20 ml. of acetone was added with stirring at 0.degree. 2 ml. of Jones
reagent. Dissolution soon occurred and after 10 minutes the oxidation was
found to be complete (tlc). The solution was then poured into 100 ml. of
ice water, and the reaction mixture extracted with methylene chloride
after saturation of the aqueous solution with sodium chloride. The organic
layer was dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give 1.5 g. of
17.beta.-hydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstan-3-one.
Crystallization from methylene chloride-ether afforded an analytical
sample, mp 196.degree.-198.degree., [.alpha.].sub.D.sup.25 +6.43.degree.
(c, 0.9646%, CHCl.sub.3).
Anal. Calcd. for C.sub.19 H.sub.30 O.sub.3 : C, 74.47; H, 9.87. Found: C,
74.73; H, 10.08.
EXAMPLE 19
15-Oxa-17.beta.-hydroxy-17.alpha.-methyl-5.alpha.-androstane[3,2-c]pyrazole
A solution of 2.5 g. of
17.beta.-hydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstan-3-one, 0.84 g.
of sodium methoxide, 4.6 ml. of ethyl formate and 25 ml. of pyridine was
stirred under nitrogen for 18 hours. The mixture was then poured into 300
ml. of ice water containing 46 ml. of glacial acetic acid. The resulting
precipitate was filtered, washed with water and dissolved in a small
amount of ether. The cloudy solution was dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give 2 g. of white crystalline
(2-formyl-17.beta.-hydroxy-17.alpha.-methyl-15-oxa-5.alpha.-androstan-3-on
e), mp 262.degree.-269.degree.; .lambda..sub.max.sup.C.sub.2 H.sub.5 OH 285
(.epsilon.7,430).
A solution of 2 g. of the formylated material, 50 ml. of absolute ethanol
and 0.48 ml. of hydrazine hydrate (85%) was refluxed for one hour. The
ethanol was removed under reduced pressure and the residue triturated with
ether to give 1.8 g. of
15-oxa-17.beta.-hydroxy-17.alpha.-methyl-5.alpha.-androstan[3,2-c]pyrazole
. Crystallization from chloroform afforded an analytical sample, mp
175.degree. d, [.alpha.].sub.D.sup.25 +31.45.degree. (c, 0.9826%, CH.sub.3
OH).
Anal. Calcd. for C.sub.20 H.sub.30 N.sub.2 O.sub.2 : C, 72.69; H, 9.15; N,
8.50. Found: C, 72.86; H, 8.77; N, 8.31.
EXAMPLE 20
15-Oxaestrone cyclopentyl ether
A solution of 0.29 g. of 15-oxaestrone, 3 ml. of absolute ethanol, 1 ml. of
cyclopentyl bromide and 1.5 ml. of a lithium methoxide-methanol solution
(10.23%, sp gr. 0.853) was refluxed for 18 hours. The solution was then
poured into 50 ml. of water and the mixture extracted with methylene
chloride. The methylene chloride solution was then dried (MgSO.sub.4) and
most of the solvent removed under reduced pressure. The residue was then
passed through a 3 g. of neutral alumina (grade 1) and the product
crystallized from methylene chloride-ether to give 0.2 g. of 15-oxaestrone
cyclopentyl ether, mp 198.degree.-201.degree., [.alpha.].sub.D.sup.25
+117.85.degree. (c, 1.125%, CHCl.sub.3).
Anal. Calcd. for C.sub.22 H.sub.28 O.sub.3 : C, 77.61; H, 8.29. Found: C,
77.75; H, 8.58.
EXAMPLE 21
Estrone 3-methyl ether was converted to
3-methoxy-16,17-seco-16-norestra-1,3,5(10)trien-15-(2'-indoxyliden)-17-oic
acid, mp 255.degree.-257.degree. according to the procedure of example 1.
The material was converted to the methyl ester, i.e.
3-methoxy-16,17-seco-16-norestra-1,3,5(10)-trien-15-(2'-indoxyliden)-17-oi
c acid 17-methyl ester, mp 259.degree.-260.degree. (dec.), according to the
procedure of example 2.
EXAMPLE 22
3-Methoxy-16,17-seco-16-norestra-1,3,5(10)-trien-15-(2'-indoxyliden)-17-oic
acid 17-methyl ester was converted to 15-oxaestrone 3-methyl ether
according to the procedures in examples 4 through 8 via the following
intermediates:
3-methoxy-15,17-seco-D-norestra-1,3,5(10)-trien-15,17-dioic acid 17-methyl
ester,
3-methoxy-14.beta.-acetoxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic
acid 17-methyl ester,
3-methoxy-14.beta.-hydroxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic
acid,
3-methoxy-14.beta.-acetoxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic
acid,
3-methoxy-14.beta.-acetoxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-
triene, and
3-methoxy-14.beta.-hydroxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-
triene.
EXAMPLE 23
Estrone was converted to 15-oxaestrone according to the procedures in
examples 1 through 8 via the following intermediates:
3-hydroxy-16,17-seco-16-norestra-1,3,5(10)-trien-15-(2'-indoxyliden)-17-oic
acid,
3-hydroxy-16,17-seco-16-norestra-1,3,5(10)-trien-15-(2'-indoxyliden)-17-oic
acid 17-methyl ester,
3-acetoxy-16,17-seco-16-norestra-1,3,5(10)-trien-15-(2'-indoxyliden)-17-oic
acid 17-methyl ester,
3-acetoxy-15,17-seco-D-norestra-1,3,5(10)-trien-15,17-dioic acid 17-methyl
ester,
3,14.beta.-diacetoxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic acid
17-methyl ester,
3-hydroxy-14.beta.-acetoxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic
acid 17-methyl ester,
3,14.beta.-dihydroxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic acid,
3,14.beta.-diacetoxy-14,17-seco-D-bisnorestra-1,3,5(10)-trien-17-oic acid,
3,14.beta.-diacetoxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5(10)-triene
, and
3,14.beta.-dihydroxy-16-diazo-17-oxo-14,16-seco-D-norestra-1,3,5
(10)-triene.
EXAMPLE 24
15-Oxaestrone 3-methyl ether was converted to 15-oxa-19-nortestosterone,
according to well known procedures for the conversion of estrone 3-methyl
ether to 19-nortestosterone, i.e. lithium-ammonia reduction to
3-methoxy-15-oxa-estra-2,5(10)dien-17.beta.-ol followed by strong acid
acid hydrolysis. 15-oxa-19-nortestosterone was converted to
15-oxa-19-norandrost-4-en-3,17-dione by oxidation with chromium trioxide.
EXAMPLE 25
15-Oxaestrone 3-methyl ether was converted to 15-oxa-19-norprogesterone,
according to the procedure in U.S. Pat. No. 3,385,849, via the following
intermediates:
3-methoxy-15-oxa-19-norpregna-1,3,5(10),17(20)-tetraene,
3-methoxy-15-oxa-19-norpregna-1,3,5(10)-trien-20-ol,
3-methoxy-15-oxa-19-norpregna-2,5(10)-dien-20-ol, and
15-oxa-19-norpregn-4-en-3-on-20-ol
EXAMPLE 26
15-Oxa-19-norandrost-4-en-3,17-dione was converted to
17.alpha.-ethynyl-15-oxa-19-norandrost-4-en-3-on-17.beta.-ol according to
well known procedures for ethynylation of 19-norandrost-4-en-3,17-dione,
in U.S. Pat. No. 2,962,509.
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