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Патент USA US3068236

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.i‘trnt nice
Patented Dec. 11, 1962
2
As starting materials in the present process, there are
3 968,226
employed 1,6-lower alkyl-Aw-steroids represented by the
partial formula:
PR?CESd FUR THE PiREPARATION 0F Iii-METH
YLENE CGMPGUNDEE 0F HE PREGNANE SERIES
David Tani), Metnchen, Norman L. Wendler, Summit, and
Robert D. Hoti’sommer, in, Metuchen, Ni, assignors
to Merck Sr (10., line, Railway, Psi-3., a corporation of
New Jersey
No Drawing. Filed Dee. 22, 1961, Ser. No. 161,396
16 Ciaims. (Ci. 26ti-—239.55)
This invention relates to an improved process for the
preparation of lo-alkylene steroids of the pregnane series
CH2 0B.
10
wherein R1 is lower alkyl and P represents an unsaturated
pregnane ring nucleus having an oxygen substituent, such
novel two-step process for the conversion of 16-lower 15 as keto or hydroxyl at 0-11, hydrogen or halogen at G9,
a keto group at C—3 and unsaturation in the A ring at
alkyl-Al?-steroids of the pregnane series to the correspond
as well as the l6-lower alkyl-16,17-oxido intermediates
thereof. More particularly, this invention relates to a
C-4 or C-1 and C-4. The R group may be hydrogen but
it is preferably an ester group derived from an organic
ing 16~alkylene compounds whereby both the l6~alkylene
end product and l6-lower alkyl 16,17-oxido intermediate
carboxylic acid, especially such acids as formic, ‘acetic,
are formed in high yield.
This application is a continuation-in-part of copending 20 propionic, benzoic and the like. Typical ‘examples of
suitable 16-lower aIkyLAIG-steroid starting materials are:
applications Serial No. 801,429, ?led March 24, 1959, and
Serial No. 818,017, ?led June 4, 1959.
The 16-alkylene steroids produced in accordance with
the present invention possess extermely high anti-in?am
16-methyl-2l-hydroxy-4,16-pregnadiene-3,l 1,20-trione 21
acetate,
matory activity and are especially effective for the treat 25
ment of arthritis and related diseases since they can be
administered for their cortisone-like action in low dosage
thereby minimizing undesired side effects.
16-,methyl-11?,21-dihydroxy-4,16-pregnadiene-3,20rdi
one Zl-acetate,
9a-?uoro-16-methyl-21-hydroxy~4,16-pregnadiene-37,1‘l,
ZO-trione 21-acetate,
9oc-?l101‘O-l6-m6thYl-l 1,8,21-dihydroxy-4,16-pregnadienc
One method which has been employed to convert 16
lower alkyl-A16-steroids to the corresponding 16~alkylene 30
compounds has been to react the 16—lower alkyl-A16~steroid
starting material with an alkaline solution of hydrogen
‘peroxide or with an alkyl hydroperoxide in the presence
of a strong base, as for example, hydrogen peroxide in
the presence of sodium hydroxide, to obtain the corre 35
sponding 16-lower alkyl-16,l7-oxido compound, which,
3,20—dione 21-acetate,
16-methyl-21-hydroxy-1,4,16-pregnatriene~3,11,20-tri
one ZI-acetate,
16-rnethyl-11,8,21-dihydroxy-1,4,16-pregnatriene-3,20-di
one 21-acetate,
9a-fiuoro-l6-methyl-2l-hydroxy-1,4,16-pregnatricne43
11,20-trione 21-acetate,
9a-?uoro-16-methyl-1 l}8,21-dihydroXy-1,4,16-pregnatri
upon contact with a hydrohalic acid such as hydrochloric
ene-3,20-dione ZI-acetate, and the like.
In the ?rst step of the present process, the ,16-lowcr
compound.
The primary disadvantages of having to use a strong 40 alkyl-16,-l7-oxido compounds are prepared by reacting the
l6-lower alkyl-Aw-starting material with an organic per
base in the ?rst step of this process are (1) the resulting
acid of a strong carboxylic acid. Thus, peracids ‘of
alkaline hydrolysis of any 21-ester groups present as well
formic acid, trichloroacetic acid, di?uoroacetic acid and
as (2) the danger of cleavage of the whole l7-side chain
the like may satisfactorily ‘be employed in this process, al
with the resulting loss of yield. In the second step of this
process, the use of hydrohalic acids is likewise undesirable 45 through peroxytri?uoroacetic acid has been found to be
particularly effective in the conversion of the AIS-steroid
because of the formation of many unwanted yet closely
to ‘the corresponding ‘l6oc,l7oc~0XidO compound. When
related steroid by-products from which it is di?icult to
peroxytri?uoroacetic acid is employed, the reaction is con
separate the desired 16-alkylene product without using
veniently carried out by dissolving the l6-1ower .a1kyl-A16
elaborate chromatographic procedures. Thus, for exam
ple, the reaction of 9a-?uoro-11B,21-dihydroxy-1GB-meth 50 ‘steroid in an inert organic solvent such as benzene, toluene
or the like and preferably methylene chloride, adding ,a
yl-l6a,17a-oxido-l,4-pregnadiene-3,20-dione 21 - acetate
basic alkaline buffering agent, as for example, disodium
with hydrogen chloride results in the production of a mix
hydrogen phosphate or sodium bicarbonate and adding to
ture of ( 1) 9rx-?uoro-115,17a,21-trihydroxy-lo-rnethylene
acid, results in the formation of the 16-alkylene steroid
this mixture peroxytrifluoroacetic acid in a compatible
1,4-pregnadiene-3,ZO-dione ZI-acetate, (2) 9a-?uoro-11B,
17c¢,2l-trihydroxy~16-methyl - 1,4,15 — pregnatriene-3,20'
dione ZI-acetate, (3) 9a-?uoro-l1/3,21~dihydroxy-l6-meth
ly-1,4,l4,l6-pregnatetraene-3,ZO-dione 21-acetate, and (4)
9a - ?uoro-lS-chloro - 11/3,2l-dihydroxy - l6 - methyl-1,4,
55
organic solvent, for example, methylene chloride. The
reaction mixture is desirably stirred at a temperature of
about 0° C. for a period of about 10-30 minutes .and
‘thereafter for about l~2 hours at room temperature. The
16-pregnatriene~3,ZO-dione 21-acetate. In view of these
resulting l6-lower alkyl-16,17-oxido compound is then
minimize the formation of by-products and thus enhance
the yield of the desired lo-alkylene steroid product.
ing the extract. Crystallization of the residue from ,a
steroid compounds by reacting the 16-lower alkyl-Am
in carrying out thisstep of the process, it has "been
‘found desirable to employ about 1 mole ofiperacid ‘for
dit?culties, it Was desirable to ?nd a process which would 60 conveniently recovered by adding Water to the mixture,
extracting the solution with methylene chloride and dry
suitable solvent such as acetone, ethyl acetate or acetone
It has now been found in accordance with the present
ether mixtures yields the 16-lower alkyl-16,17-oxido ste
invention that 16-lower alkyl~A16-steroids of the pregnane
roid.
series may be converted to the corresponding lo-alkylene 65
steroid starting material with an organic peracid of a
strong carboxylic acid in the presence of an alkaline‘buffer
each mole of starting material in order to avoid reaction
of
the peroxytri?uoroacetic acid with any other double
ing agent, and contacting the resulting 16-methyl-l6,17
‘bonds
than the 16:17 double bond which may be‘present
70
oxido compound with a strong carboxylic acid to obtain
in the steroid nucleus.
the 16-alkylene steroid in high yield.
The peroxytri?uoroacetic acid reagent is conveniently
3,068,226
3
prepared by adding tri?uoroacetic anhydride to a stirred
solution of 90% hydrogen peroxide dissolved in methylene
chloride. A fresh mixture of this reagent is then reacted
with the steroid starting material.
In the second step of this process, the l6~lower alkyl
16,17-oxido steroid is reacted with a strong carboxylic
acid such as formic, chloroacetic, trichloroacetic, halo
genated propionic acid, oxalic acid and the like to form
the corresponding l6-methylene steroid. It has been
found that tri?uoroacetic acid is particularly effective in 10
carrying out this reaction. Thus, the 16-lower alkyl
16,17-oxido compound is conveniently reacted with tri
?uoroacetic acid at room temperature for a period of
about 1-3 hours. In general, while no additional solvent
is necessary, it has been found that by carrying out this
‘
contemplates the conversion of the 16-lower alkyl-Am
steroids to the corresponding 16-alkylene compound in
a single step, thus eliminating the formation and isolation
of the'intermediate 16,17-oxido compound. This is ac
complished by reacting the 16-1ower alkyl-A1G-steroid dis
solved in an inert organic solvent such as methylene
chloride with a mixture of a percarboxylic acid and a
16a,17a—oxido-2l-hydroxy-4-pregnene-3,l1,20-trione 21
acetate.
In accordance with the foregoing procedure, but start
ing with 9st - ?uoro - 16 - methyl-1l/i,2l-dihydroxy-4,l6
pregnadiene-3,20-dione 2l-acetate there is obtained 9a
?uoro - 16,6 - methyl - 16¢,l7a-oxido-11,3,21-dihydroxy-4
pregnene-3,20-dione 21-acetate.
Example 3
To a stirred mixture of 2.00 g. of l6-methyl-21-hy
droxy-1,4,16-pregnatriene-3,l1,20-trione 2l-acetate and
aqueous potassium bicarbonate, saturated sodium chloride
and dried over magnesium sulfate. Crystallization of
the residue from acetone-ether gives 16,8-methyl-16a,l7a
oxido-2l-hydroxy-1,4-pregnadiene-3,l1,20-trione 2l-ace
tate.
tone, ether or acetone-ether mixtures.
In addition to the foregoing two-step process for the
production of l6-alkylene steroids, this invention also
Crystallization of the
residue from acetone-ether gives 9a-?uoro-l6B-rnethyl
30 g. of disodium hydrogen phosphate in 60 ml. of hen
zene at 0° C. is added 10 ml. of 2.0 M peroxytri?uoro
acetic acid reagent. After 10 minutes at 0° C. and 1
hour at 25° C., water is added and the mixture extracted
with benzene. The organic extract is Washed with
process in the presence of benzene, a purer product free
of any l4,l6~diene by-product is obtained. The 16
alkylene-l7-hydroxy steroid product is conveniently re
covered by chromatography over neutral alumina and
elution with benzene-chloroform mixtures. Alternatively, the reaction mixture may be extracted with methyl
ene chloride, dried, and the residue crystallized from ace
4
dried over magnesium sulfate.
In accordance with the foregoing procedure, but start
25
in g with 16-met'nyl-l1?,21-dihydroxy-1,4,16-pregnatriene
3,20-dione 21-acetate there is obtained 165-methyl
l6a,17<x - oxido - 115,21-dihydroxy-l,4-pregnadiene-3,20
dione 21-acetate.
Example 4
To a stirred mixture of 2.00 g. of 9ct-?uoro-16-methyl
115,21-dihydroxy-L4,l6-pregnatriene-3,20-dione 2l-ace
tate and 15 g. of disodium hydrogen phosphate in 40 ml.
carboxylic acid, as for example, a mixture of peroxytri
of methylene chloride at 0° C. is added 5.0 ml. of 2.0 M
?uoroacetic acid and tri?uoroacetic acid, in the absence
of any basic buffering agent. The reaction is conveniently 35 peroxytri?uoroacetic acid (prepared by adding 5.1 ml. of
tri?uoroacetic anhydride to a stirred solution of 0.82 ml.
carried out by stirring the reaction mixture at 0° C. for
90% hydrogen peroxide in 5 ml. of methylene chloride).
about 10-30 minutes followed by further stirring at room
After 1 hour at 0° C., water is added and the mixture
temperature for 1-2 hours. After extracting the reaction
extracted with methylene chloride. The organic extract
mixture with methylene chloride and drying, the l6-alkyl
ene-l7-hydroxy steroid is readily recovered by chromatog 40 is washed with water and saturated salt solution and dried
over magnesium sulfate. Crystallization of the residue
raphy or crystallization.
from acetone-ether gives 9a-fluoro-16?-methyl-l6a,17a
The following examples illustrate methods of carrying 1
oxido - 115,21 - dihydroxy-l,4-pregnadiene-3,20-dione 21
out the present invention, but it is to be understood that
acetate.
these examples are given for purposes of illustration and
In accordance with the foregoing procedure, but start
45
not of limitation.
ing with 9oc-?uoro-l6-methyl-2l-hydroxy-1,4,16-pregna
Example 1
triene-3,l1,20-trione 21-acetate there is obtained 9a
To a stirred mixture of 2.00 g. of 16-methyl-21-hydroxy
?uoro - l6/3-methyl-16a,17u-oxido-2l-hydroxy-l,4-pregna
4,l6-pregnadiene-3,11,20-trione 2l-acetate and 30 g. of di
diene-3,11,20-trione 2l-acetate.
sodium hydrogen phosphate in 60 ml. of methylene
chloride at 0° C. is added 10 ml. of 2.0 M peroxytri?uoro
acetic acid reagent (prepared by cautiously adding 5.1 ml.
of trifluoroacetic anhydride to a stirred solution of 0.82
Example 5
To 240 mg. of 16?-methyl-16a,l7rx-oxido-2l-hyroxy-4
pregnene-3,ll,20-trione Zl-acetate is added 3 ml. of tri
?uoroacetic acid mixed with 2 ml. of benzene. After 2
chloride). After 10 minutes at 0° C. and 1 hour at 25° 55 hours at 25° C., water is added and the mixture is ex
ml. 90% hydrogen peroxide in 5 ml. of methylene
C., water is added and the mixture extracted with methyl
ene chloride.
The organic extract is washed with aqueous
potassium bicarbonate, saturated sodium chloride and
dried over magnesium sulfate. Crystallization of the
residue from acetone-ether gives 16,8-methyl-16a,17a
oxido-21-hydroxy-4-pregnene-3,11,20-trione 2 l-acetate.
In accordance with the foregoing procedure, but start
ing with l6-methyl-l1,8,2l-dihydroxy-4,l6-pregnadiene
3,20-dione 2l-acetate there is obtained 16B-methyl
1611,1701. - oxido - 113,2l-dihydroxy-4-pregnenc-3,20-dione
ZI-acetate.
Example 2
To a stirred mixture of 2.00 g. of 906-?llOI‘O-16-l'l’l6ii1Yl
21-hydroxy-4,16-pregnadiene-3,l1,20-trione 2l-acetate and
tracted with methylene chloride. The organic extract is
washed with aqueous potassium bicarbonate, saturated
sodium chloride and dried over magnesium sulfate.
Crystallization of the residue from acetone-ether gives
16 - methylene - 17a,2l-dihydroxy-4-pregnene-3,11,20-tri
one 2l-acetate.
In accordance with the foregoing procedure, but start
ing with 16B-methyl-l6oc,l7e-oxido-115,21-dihydroxy-4
pregnene-3,20-dione ZI-acetate there is obtained 16
methylene - 1118,170;,21-trihydroxy-4-pregnene-3,20-dione
21-acetate.
Example 6
To 240 mg. of 9e-?uoro-16,8-methyl-16a,17e-oxido-21
30 g. of sodium bicarbonate in 60 ml. of methylene 70 hydroxy-4-pregnene-3,l1,20-trione 2l-acetate is added 3
ml. of trichloroacctic acid. After 2 hours at 25° C.,
chloride at 0° C. is added 10 ml. of 2.0 M performic acid.
water is added and the mixture is extracted with methyl
After 10 minutes at 0° C. and 1 hour at 25° C., water
ene chloride. The organic extract is washed with aqueous
is added and the mixture extracted with methylene
potassium bicarbonate, saturated sodium chloride and
chloride. The organic extract is washed with aqueous
potassium bicarbonate, saturated sodium chloride and 75 dried over magnesium sulfate. Crystallization of the resi
5
3,068,226
6
due from acetone-ether gives 9a-?uoro-16-methylene-17a,
dium hydrogen phosphate, thereby forming the corre
sponding 16?-methyl-16a,l7a-oxido-steroid compound and
2l-dihydroxy-4-pregnene-3,11,20-trione 21-acetate.
In accordance with the foregoing procedure, but start
reacting this compound with tri?uoroacetic acid to obtain
ing with 9a-?uoro-l6B-methyl-16a,17o¢~oxido-l1?,21-di
16 - methylene-1If},17a,2l-trihydroxy-4-pregnene-3,20-di
one 21-acetate
hydroxy-4—pregnene-3,ZO-dione ZI-acetate there is ob
tained 9a - fluoro - 16~methylene-1.15,17a,21-trihydroxy-4
3. The process which comprises reacting 9a-?uoro-l6
pregnene-3,20-dione 21-acetate
Example 7
To 240 mg. of 165-methyld6a,17a-oxido-21-hydroxy
1,4—pregnadiene-3,11,20~trione Ill-acetate is added 3 ml. 10
responding 16/3-methyl-16a,17a-oxido~steroid compound
of oxalic acid. After 2 hours at 25° C., water is added
and the mixture is extracted with methylene chloride.
obtain 90: - ?uoro-16-methylene-l1,3,17a,21~trihydroxy-4
methyl-1 1?,21-dihydroxy-4,16-pregnadiene-3,20-dione 21
acetate with peroxytri?uoroacetic acid in the presence of
disodium hydrogen phosphate, thereby forming the cor
and reacting this compound with tri?uoroacetic acid to
pregnene-3,20‘-dione 21-acetate.
The organic extract is washed with aqueous potassium
bicarbonate, saturated sodium chloride and dried over 15 '4. The process which comprises reacting 16-methyl
1118,21 - dihydroxy-1,4,l6-pregnatriene-3,ZO-dione 21-ace
magnesium sulfate. Crystallization of the residue from
tate with peroxytri?uoroacetic acid in the presence of
acetone-ether gives 16-methylene-17a,21-dihydroxy-l,4
disodium hydrogen phosphate, thereby forming the cor
pregnadiene-3,l1,20-trione 2l-acetate.
responding 16?-methyl-16a,17a-oxido-steroid compound
In accordance with the foregoing procedure, but start
and reacting this compound with tri?uoroacetic acid to
ing with l6?-methyl-16u,17o<-oxido-1lB,21-dihydroxy-l,4
20 obtain 16 - methylene - 11,8,17a,21-trihydroxy-1,4-pregna
pregnadiene-3,20-dione 21-acetate there is obtained l6~
diene-3,20-dione 21-acetate.
methylene - 11,3,170c,21 - trihydroxy - 1,4 - pregnadiene
3,20-dione 2l-acetate.
5. The process which comprises reacting 9oc-?1101‘0-16
i
methyl - 1 1,8,21-dihydroxy-1,4,16-pregnatriene-3,20-dione
Example 8
To a stirred solution of 1.00 g. of 9cc-?l10I‘O-16/3-II16111Y1
21-acetate with peroxytri?uoroacetic acid in the presence
25
of disodium hydrogen phosphate, thereby forming the
16cc, l7u-oxido-l15,2l-dihydroxy-l,4-pregnadiene-3,20-di
corresponding 16,8 - methyl - 160:,170t-0Xid0-S16f0id com
bonate is added and the mixture extracted with ethyl
acetate. The organic layer is washed with saturated so
dium chloride solution, dried over magnesium sulfate and
concentrated to dryness. Crystallization of the solid resi
series with a strong percarboxylic acid in the presence
of an alkaline buffering agent to form the correspond
pound and reacting this compound with tri?uoroacetic
one 21-acetate in 20 ml. of benzene at 10° C. is added a
acid to obtain 9a-?uoro-16-methylene-11B,17a,2,1-trihy~
mixture of 4 ml. of tri?uoroacetic acid and 10 ml. of ben
zene. After 18 hours at 20—25° C. cold 5% sodium car 30 droxy-l,4-pregnadiene-3,20-dione 21-acetate.
6. The process which comprises reacting a 16-lower
alkyl-l1,21-bisoxygenated-Al‘i-steroid of the pregnane
due from ethyl acetate gives 9a-?uoro-l6-methylene-l113, 35 ing 16,8-lower alkyl-l1,2l-bisoxygenated-l6u,17o¢-oxido
steroid compound.
17a,2l-trihydroxy-1,4-pregnadiene-3,20-dione Zl-acetate.
7. The process according to claim 6, wherein the
percarboxylic acid is peroxytri?uoroacetic acid and the
Example 9
buffering agent is disodium hydrogen phosphate.
To a stirred mixture of 2.00 g. of 9a-fluoro-l6-rnethyl
8. The process according to claim 6 wherein the
115,21 - dihydroxy-4,16-pregnadiene-3,20-dione ZI-acetate 40
percarboxylic acid is performic acid and the bu?fering
in 60. ml. of methylene chloride at 0° C. is added 10 ml.
agent is sodium carbonate.
of a mixture of peroxytri?uoroacetic acid reagent and tri
9. The process according to claim 6 wherein the
?uoroacetic acid in a ratio of 1:1. After 10 minutes at
percarboxylic
acid in peroxydi?uoroacetic acid and the
0° C. and 1 hour at 25° 0, water is added and the mix
ture extracted with methylene chloride. The organic ex 45 buifering agent is disodium hydrogen phosphate.
10. The process which comprises reacting a 16,8-lower
tract is washed with aqueous potassium bicarbonate, sat
urated sodium chloride and dried over magnesium sulfate.
alkyl-l1,21-bisoxygenated-16u,17o¢-oxido-steroid of the
pregnane series with a strong carboxylic acid to obtain
Crystallization of the residue from acetone-ether gives 90:
the corresponding 16'lower alkylene-17zx-hydroxy-steroid
?uoro - l6-methylene-1 1,8,17a,2l-trihydroxy-4,16-pregna
diene-3,20-dione 21-acetate.
In accordance with the foregoing procedure, but start
ing with 900 - ?uoro-16-methyl-11?,21-dihydroxy-1,4,16
pregnatriene-lZO-dione ZI-acetate there is obtained 90:
?uoro - 16 - methylene-11,8,17a,21-trihydroxy-1,4,16-preg
50
compound.
11. The process according to claim 10 wherein the
reaction is carried out in the presence of the organic
solvent benzene.
12. The process according to claim 10‘ wherein the
natriene~3,20>dione ZI-acetate.
55 carboxylic acid is tri?uoroacetic acid.
13. The process according to claim 101 wherein the
Various changes and modi?cations may be made in
carboxylic acid is trichloroacetic acid.
carrying out the present invention without departing ‘from
14. The process according to claim 10‘ wherein the
carboxylic acid is oxalic acid.
15. The process which comprises reacting a 16-lower
claims, they are to be considered as part of our invention. 60
alkyl-l1,21-bisoxygenated-A16-steroid of the pregnane
We claim:
series with a mixture of a strong percarboxylic acid and
1. The process which comprises reacting a l6-lower
a strong carboxylic acid thereby forming the correspond
alkyl-Aw-steroid of the pregnane series with a strong per
ing l6-lower alkylene-17a-hydroxy-steroid compound of
carboxylic acid in the presence of an alkaline butfering
agent, thereby forming the corresponding 16,8-lower al 65 the pregnane series.
16. The process which comprises reacting 9oc-?110rO-16~
kyl-16oz,17a-0Xid0 steroid compound, and reacting this
the spirit and scope thereof. Insofar as these changes
and modi?cations are within the purview of the annexed
compound with a strong carboxylic acid to obtain the
corresponding 16-lower alkylene-17-hydroxy steroid of
the pregnane series.
methyl -1 16,21- dihydroxy-l,4, 16 - pregnatriene - 3,20-dione
21-acetate with a mixture of pcroxytri?uoroacetic acid
and tri?uoroacetic acid thereby forming the correspond
2. The process which comprises reacting 16-methyl 70 ing 9a-?uoro-16-methylene~1 1,8, l7a,21-trihydroxy-1,4,16
pregnatriene-3,20-dione 21-acetate.
11B, 2 l -dihydroxy-4, l 6-pregnadiene-3,20-dione 21-acetate
with peroxy tri?uoroacetic acid in the presence of diso
No references cited.
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