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Патент USA US3029270

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3,029,25d
Patented Apr. 10, 1962
1
2
halo-S-hydroxy-Sa-pregnan-ZO-ones and parent alcohols
3,029,260
3,17,20-TRIOXYGENATED tip-CHLORG?-METHYL
19-NOR-5?-PREGN-9-ENES
Joseph S. Miliina, Slrokie, Ill., assignor to G. D. Searle &
Co., Chicago, 111., a corporation of Delaware
No Drawing. Filed Aug. 23, 1960, Ser. No. 51,293
6 Claims. (Cl. Mil-397.4)
This invention relates to 3,17,20-trioxygenated G?-halo
S-methyl-l9-nor-5/8-pregn-9-enes and processes for the 10
manufacture thereof. More particularly, this invention
relates to chemical compounds of the formula
Z\/Z
|
HQ Hal
(IDHQXII
me if’
wherein Z represents a hydroxymethylene or alkanoyl
15 oxymethyleneradicaland Hal, X’, and X" are de?ned as
before, by heating such compounds, concurrently or seria
tim,‘ under appropriate esterifying and dehydrating con
ditions-for example, with an alkanoic acid anhydride in
the presence of potassium acid sulfate or sulfuric acid, and
20 with a corresponding alkanoic acid added to increase solu
bility if desired. The esters which result are completely
saponi?ed in aqueous‘ alcoholic caustic after 4 hours; alter
natively, when allowed to stand for up to 2 hours at room
temperatures with merely 1 or 2 equivalents of alkali
carbonate, they afford mixtures of mono~ or diesters, re
(6Q *
wherein Hal represents halogen; at least one of the sym
hols X’ and X" represents a hydroxy or alkanoyloxy
(-OCOR) radical and the other represents hydrogen or
a hydroxy or alkanoyloxy radical; and Z’ and Z" each
represent a carbonyl (>CO), hydroxymethylene
(>CHOH)
or alkanoyloxymethylene (>CHOCOR) radical, R in the
parenthetical formulas standing for an alkyl radical.
Among the halogens represented by Hal, especially
spectively, separable by chromatography on silica gel, us
ing benzene and ethyl acetate as developing solvents.
From the 3-hydroxy compounds so produced, on oxida
tion with chromium trioxide in a heterogeneous medium
30 comprising aqueous acetic acid and an inert solvent for
the steroid present, the corresponding 3-ones are obtained.
The 20-ols of the invention derive from corresponding 20
ones via lithium aluminum hydride in tetrahydrofuran at
35
the boiling point.
The following examples describe in detail compounds
illustrative of the present invention and methods which
those having an atomic number less than 53—-which is
have been devised for their manufacture. However, the
to say fluorine, chlorine, and bromine-are preferred.
invention is not to be construed as limited thereby, either
The alkanoyloxy and alkanoyloxymethylene radicals rep
in spirit or in scope, since it will be apparent to those
resented by X’, X", Z’, and Z" are best adapted to the
purposes of this invention when the alkyl constituent (R) 40 skilled in the art of organic synthesis that many modi?ca~
tions, both of materials and of methods, may be practiced
is of lower order; and the hydroxyrnethylene and alka
without departing from the purpose and intent of this dis
noyloxymethylene radicals comprehended by Z” are de
closure. Throughout the examples hereinafter set forth,
sirably in the )3 con?guration. Lower alkyl radicals in
temperatures are given in degrees centigrade and relative
clude methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neo— 45 amounts of materials in parts by weight, except as other
wise noted. Speci?c rotations, observed at 26° centigrade,
pentyl, hexyl, isohexyl, heptyl, octyl, and like CnH2n+1
aggregates wherein n is a positive integer amounting to
refer to the D line of sodium.
less than 9. Alkanoyloxy and alkanoyloxymethylene radi
EXAMPLE 1
cals of the preferred type are hereinafter referred to as
lower alkanoyloxy and lower alkanoyloxymethylene radi~ 50 A. 17a-Acet0xy-5,6a-epoxy-3,B-hydroxy--5a-pregrzalt-20
cals, respectively. Those skilled in the art will recognize
one.-To a solution of 100 parts of l7a-acetoxy-3l8-hy
that when X’, X", Z’, and Z" designate such radicals,
droxypregn-S-en-ZO-one and 5 parts of sodium acetate in
the compounds contemplated are esters of the alcohols
depicted when the symbols referred to designate hydroxy
and/or hydroxymethylene radicals.
4450 parts of benzene at 10° is added a solution of ap
proximately 43 parts of perbenzoic acid in 525 parts of
benzene.
The resultant mixture is allowed to warm to
The products of this invention are useful because of
their valuable pharmacological properties. Thus, for ex
room temperature, whereupon it is washed with aqueous
5% sodium bicarbonate and then to neutrality (until the
ample, they are eurhythmic agents; and they inhibit the
washings are neutral to litmus) with water. Solvent is
incorporation of mevalonic acid in the biosynthesis of 60 removed by vacuum distillation, and the residue is crys
cholesterol. The intermediates whence these products are
tallized from a mixture of acetone and ethyl acetate.
obtained--especially, 3?,(17u and/or 2l)-polyalkanoyl
The 170: - acetoxy-S,6a-epoxy-3B-hydroxy-5a-pregnan-20
oxy - 65 - halo - 5-hydroxy-5a-pregnan-20-ones-—are, of
one thus obtained melts at approximately 249—250° and
has a speci?c rotation of -—70.8° in 1.010% chloroform
course, likewise useful.
Manufacture of the subject compositions proceeds from
the aforesaid 316,070; and/or 2l)-polyalkanoyloxy-6?~
solution.
B. 35,1704 - Diacetoxy-6p-chZora-5-hydroxy-5a-pregnan
.
8,029,260
3
4
20-one.—A mixture of 56 parts of 17m-acetoxy-5,6u
epoxy-3,8-hydroxy-5ez-pregnan-20-one, 830 parts of 37%
hydrochloric acid, and 2000 parts of dichloromethane is
in 1.014% chloroform solution. The product has the
formula
CH3
maintained with vigorous agitation for 15 minutes at room
temperatures, then diluted with 1900 parts of water. The
dichloromethane phase is separated and consecutively
(U
washed with aqueous 10% sodium bicarbonate and water,
the water wash being continued until the washings are
neutral to litmus. The resultant dichloromethane solu
tion is dried over anhydrous sodium sulfate and stripped 10
of solvent by vacuum distillation.
The residue is heated at 100~120° with 350 parts of
OHZCOO
Cl
acetic anhydr-ide for 1 hour, then dumped into water.
After 2 hours, the precipitate which forms is ?ltered off,
washed on the ?lter with water, and dried in air. Crys 15 Likewise recrystallized from a mixture of methanol and
ethanol, 33,170‘ - diacetoxy - 6,8 - chloropregn-4-en-20-one
tallized from ethyl acetate, it melts at ZOO-202° and is
melts at l59—161° and has a speci?c rotation of +27° in
further characterized by a speci?c rotation of —45.8° in
1.007% chloroform solution._ This product has the
1.003% chloroform solution. The material thus ob
formula
tained is 3,8,l7ot-diacetoxy-6?-chloro-5-hydroxy-Set-preg
_ nan-ZO-one.
C. 318,170: ~ Dz'acetoxy - 6f? - chloro-S-methyl-19-n0r-5?
pregn-9-en-20-one.-A mixture of 56 parts of 17u-acet
oxy-5,6a-epoxy-3B-hydroxy-Sa-pregnan-20-one, 830 parts
of 37% hydrochloric acid, and 2000 parts of methylene
chloride is processed as described in the ?rst paragraph 25
of the foregoing part B of this example and the residue
is heated at 100-120° with 350 parts of acetic anhydride
for 1 hour, whereupon approximately 13 parts of pow
dered potassium acid sulfate is introduced. The mixture
thus obtained is heated at 40-50° for 1 hour and then 30
poured into 2000 parts of aqueous 5% sodium chloride.
These two products manifest valuable progestational
After 2 hours, the resultant mixture is extracted with
activity.
;
ethyl acetate; and the acetate extract is washed with
aqueous 10% sodium bicarbonate and then to neutrality
EXAMPLE 2
with water.
The extract is then dried over anhydrous 35
sodium sulfate and concentrated by vacuum distillation
6/8-Chl0r0-3 [3,1 7a-dihydr0xy-5-methyl-19-n0r-5?-pregn
9-en-20-0ne.-—T0 a solution of 4 parts of 35,17u-di
to the point of incipient turbidity (approximately % its
acetoxy - 6p - chloro - 5 - methyl ~ 19 - nor - 5B - pregn
original volume). From the concentrate, on chilling and
9 - en - 20 - one in 118 parts of methanol is added a solu
standing, there is precipitated 35,17a-diacetoxy-65-chloro
tion of approximately 5 parts of potassium hydroxide in
S-methyl-l9-n0r-5B-pregn-9-en-20-one, melting at approx~ 40 15 parts of water. The resultant mixture is allowed to
imately 186-187° and with a speci?c rotation at 25° of
+132.8° in 1.005% chloroform solution. The product
has the formula
stand at room temperatures for 4 hours, then diluted with
10 parts of 37% hydrochloric acid in 2000 parts of water.
The precipitate thrown down is ?ltered off, washed on
the ?lter with water, and dried in air. Recrystallized
45
from methanol, it melts at 187-l89° and is further char
acterized by a speci?c rotation of +154° in 1.002%
chloroform solution. This material is 6?-chloro-3?,l7zx
dihydroxy-S-methyl-l9-nor~5,8-pregn-9-en-20-one, of the
50
formula
‘
0113000
55
H30
1
D. 35,17“ - Diacetoxy - 6 - chloropregn-S-en-ZO-one and
35,1711 - diacetoxy - 6/8 - chloropregn - 4-en-20-0ne.--The
mother liquor remaining after isolation of 3?,17a-diace
HO
60
toxy-G?-chloro-S-methyh19-nor-55-pregn-9-en-20 - one in
the foregoing part C of this example is stripped of solvent
by vacuum distillation, and the residue ‘is taken up in
benzene. The benzene solution is chromatographed on 65
silica gel, using benzene and ethyl acetate as developing
solvents. From eluates comprising 19 parts of benzene for
each part of ethyl acetate present there are obtained, on
evaporation of solvent, 3B,17u-diacetoxy-6-chloropregn
H30 01
EXAIVIPLE 3
63 ~ Chloro - 17oz - hydroxy - 5 - methyl - 19 - nor - 5p
pregn - 9V - ene - 3,20 ‘- di0ne.—-To a solution of approxi
mately 2 parts of 6?-chloro-3B,l7a-dihydroxy-5-methyl
19-nor-5?-pregn-9-en-20-one in 66 parts of benzene and
79 parts of acetic acid is added, with agitation, a solution
of approximately 1 part of chromium trioxide in 10 parts
5-en-20-one and 35,17a-diacetoxy-6?-chloropregn-4-en 70 of Water. Agitation is continued for 5 hours, whereupon
20-one, respectively, the latter product being somewhat
1 part of sodium sul?te is mixed in. The benzene phase
is separated and washed, ?rst with aqueous 10% sodium
bicarbonate and then to neutrality with water. The
' 313,l7a-diacetoxy-6-chloropregn-5-en-20-one melts at ap
resultant benzene solution is dried over anhydrous sodium
proximately 208—209° and has a speci?c rotation of ---79° 75 sulfate and stripped of solvent by vacuum distillation.
more ?rmly retained on the silica gel than the former.
Recrystallized from a mixture of methanol and ethanol,
3,029,260
6
The residue, crystallized from 95% ethanol, affords 6B
The mother liquor remaining after crystallization of
the foregoing 6?-chloro-5-methyl-5?-pregn-9-ene-3?,17a,
chloro - 17oz - hydroxy - 5 - methyl - 19 - nor - 5,3 - pregn
9 - ene - 3,20 - dione, melting at 193—195° and with a
20-triol, distilled to dryness in vacuo, affords a'residue
which, chromatographed in benzene solution on silica
gel, using benzene and ethyl acetate as developing sol
speci?c rotation of +91° in 1.002% chloroform solution.
The product has the formula
vents, yields the 20-epimer of the aforesaid product.
CH1
What is claimed is:
1. A compound of the formula
Hi0 ‘i=0
'"OH
re
Q_
2I
15
(\
HaC Cl
EXAMPLE 4
NY
6,3 - Chloro - 5 - methyl - 5B - pregn - 9 - ene - $13,170:,
20 - triol.—To a slurry of 1 part of lithium aluminum hy
I---0X
20
dride in 50 parts of pure tetrahydrofuran is slowly added,
ZII
at room temperatures, 2 parts of 35,17u-diacetoxy-6?
chloro-S-methyl-19-nor-5p-pregn49-en-2O-one dissolved in
50 parts of pure tetrahydrofuran. The resultant mixture
is heated at the boiling point under re?ux for 11/: hours,
whereupon it is cooled to 5°, at which temperature
cracked ice is introduced to decompose excess lithium
aluminum hydride. Approximately 60 parts of 10%
hydrochloric acid is then added, followed by 200 parts
wherein X represents a member selected from the class
of water. The mixture thus obtained is extracted with
isopropyl acetate. The acetate extract is washed to
neutrality with water, dried over anhydrous sodium sul
Z’ and Z" each represent a member selected from the
consisting of hydrogen and lower allranoyl radicals; and
class consisting of carbonyl, hydroxymethylene, and low
er alkanoyloxymethylene radicals, the hydroxy and low
er alkanoyloxy constituents of the radicals represented
residue, crystallized from ethyl acetate, a?ords 6?-chloro
5-methyl-5p~pregn-9-ene-3,8,17a,20-triol, melting at ap 35 by Z" being in the B con?guration, and the selection of
Z’ and Z" being such that when Z" represents a carbonyl
proximately 174-175" and with a speci?c rotation of
radical Z' unexceptionably represents a carbonyl radical
+142° in 0.5% chloroform solution. The product has
fate, and stripped of solvent by vacuum distillation. The
also.
the formula
2. 3?,17u - Diacetoxy - 613 - chloro - 5 - methyl - 19
(ll-Ha
40
3. 65 - Chloro - 35,17a - dihydroxy - 5 - methyl - 19
ESE CHOH
il-u-or
nor-5B-pregn-9-en-20-one.
nor—5?-pregn-9-en-20-one.
45
4. 6p - Chloro - 17oz - hydroxy - 5 - methyl - 19 - nor
5,6 - pregn - 9 -ene - 3,20 - dione.
5. 6,8 - Chloro - 5 - methyl - 5p - pregn - 9 - ene
3,8,17a,20 - triol.
6. 35,170: - Diacetoxy - 6p - chloro - 5 - hydroxy - 5a
HO
pregnan - 20 - one.
H10 Cl
No references cited.
UNITED STATES PATENT OFFICE
CERTIFICATE OF CORRECTION
Patent No. 3,029 ,260
April 10a 1962
Joseph S. Mihina
in the above numbered pat
It is hereby certified that error appears ters Patent should read as
ent requiring correction an d that the said Let
corrected below.
Column 1' lines 14 to 25I the formula should appear as
shown below instead of as in the patent:
H C
3
Hal
Signed and sealed this 11th day of December 1962
(SEAL)
Attest:
ERNEST W. SWIDER
Atlesting Officer
DAVID L. LADD
Commissioner of Patents
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