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Патент USA US3056825

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3,056,815
United States Patent 0 " ice
Patented Oct. 2, 1962
1
and
3,056,815
2a-METHYL~6-CHLURG-PREGNANE-DERIVATIVES
Howard J. Ringold, Octavio Mancera, and George Rosen
kranz, ail of Mexico City, Mexico, assignors, by mesne
assignments, to Syntex Corporation, a corporation of
Panama
No Drawing. Filed Oct. 13, 1958, Ser. No. 766,708
Claims priority, application Mexico Oct. 15, 1957
14- Claims. (Cl. 260—397.45)
The present invention relates to cyclopentanophenan
threne compounds and to a process for the production
thereof.
More particularly the present invention relates to 2
methyl - 6a - chloro-prednisone, 2-methyl-6ot-chloro-9a
?uoro-prednisone, Z-methyl-6u-chloro-prednisolone and
In the above formulas R represents hydrogen or R
15 represents an acyl group of a hydrocarbon carboxylic acid
of less than 12 carbon atoms. These acyl groups as is Well
known in the art may be saturated or unsaturated, straight
or branched chain aliphatic, cyclic or mixed cyclic-ali
2l-monoesters of these compounds of hydrocarbon car
boxylic acids of less than 12 carbon atoms. All of the
compounds just enumerated are potent cortical hormones
having anti-in?ammatory properties.
phatic.
They may be conventionally substituted as by
Typical acyl groups are acetate,
20 halogen or methoxy.
propionate, cyclopentylpropionate, benzoate, B-chloropro
In accordance with the present invention it has been
discovered that the aforementioned compounds may be
prepared from Za-IIlGthYl-COItiSOIlC acetate or Zea-methyl
9ct-?uoro-eortisone acetate or from the 21-acetate of 2a
rnethyl-Aé-pregnen - 170;,21 - diol-3,20-dione (ZOC-IHBthYl
pionate, monosuccinate etc.
?uoro.
X represents hydrogen or
The novel compounds above set forth are prepared by a
25
process illustrated in part by the following equation:
“S”) by preparing the 3-enol-ether of these compounds
C HZOAC
treating the enol ether with hypochlorous acid to form the
C HzOAc
0
2a-methyl-6?-chloro intermediates and inverting the 6B~
chloro group with dry hydrogen chloride in acetic acid.
The 1(2)-double bond is then introduced by the action 30
of selenium dioxide and to prepare the prednisolone type
compounds the “S” type intermediates are conventionally
treated with Curvularia hmata to introduce the 11B-hy
droxy group. By conventional esteri?cation the afore
35
mentioned esters are then prepared.
Certain of the novel ?nal products and novel inter
mediates of the present invention are illustrated by the fol
<50
H3 0 ——
H3 0....
R1
__
0"
ort
h 0-
formats
R10
_
hypochlorous
acid
lowing formula:
0 Hz 0 R
40
'
C HzOAc
(:10
-- -- O H
I"-0 O H
O:
0=/\
‘X
45
H30 —-
H01
<___._
O:
O:
l
l
50
selenium
dioxide
0112013.
CHaOR
to
<50
on or
(31
Hi1; U »
l
CHzOR
55
w
60
3,056,815
3
In the above equation R and X represent the same
groups as heretofore. R1 represents lower alkyl and Ac
represents acetate.
In practicing the process above set forth the 21-acetate
of 2a-methyl-cortisone or of 2oc-1'I16thYl-9 ot-?uoro-cortisone
Curzmlaria
Ztmata
Curuularz'a
lunata
in an organic solvent was treated with a lower alkyl ortho
OHsOR
CHzOR
do
350
formate to form the corresponding 3-lo‘wer alkyl enol
ether. These ethers were then treated with the elements
of hypochlorous acid preferably by reaction of an aqueous
acetone solution of the ether with N-chlorosuccinimide in 10
the presence of sodium acetate and acetic acid. The re
sultant compounds namely the ZI-acetates of 2ot-methyl
6?-chloro-cortisone and of 6?-chloro-9a-?uoro-cortisone
H30
]
selenium H3O"
mm”
(_____
O:
dioxide
0:
\/i
1
d1
61
are then treated with anhydrous hydrogen chloride in
glacial acetic acid at a low temperature to prepare the 15
In the above equation R1, R and Ac represent the same
corresponding 6a-chloro compounds. Conventional sa
groups as heretofore set forth.
poni?cation of these compounds gave the free 2a-methyl
As indicated above the starting material for this portion
6u-Chl0l'O-COI‘tlSOI1E and 2a-methyl-9a-?uoro-6ot-chloro
of the process of the present invention was the Zl-acetate
cortisone. Conventional esteri?cation of these com
of Za-methyl-M-pregnen-17a,21-diol-3,20-dione (2l-ace
pounds with an acid anhydride of a hydrocarbon car 20 Late of 2ct-rnethyl-“S”) disclosed and claimed in US.
boxylic acid of less than 12 carbon atoms gave the 21
patent application Serial No. 636,858, ?led January 29,
rnono esters indicated by R as previously de?ned. Treat
1957. This compound upon treatment with a lower alkyl
ment of these esters or the free compounds with selenium
orthoforrnate under the conditions previously described
dioxide preferably by re?uxing in the presence of anhy
gives the corresponding 3-lower alkyl enol ether; treat
drous t-butanol and pyridine gave the corresponding 1 25 ment with hypochlorous acid gives 6?-chloro compound
dehydro compounds. Preferably the esters were used for
which is inverted with HCl to the 6u-chloro derivative
this reaction and the products namely the i2~methyl-6u
i.c. the ZI-acetate of 2a-methyl-6a-chloro “S.” This last
chloro-prednisone esters or 2-In6tl'1yl-60t-Ch101'0-902-flt101‘0
acetate is saponi?ed to the free compound and conven~
prednisone esters were converted to the free compounds
by vconventional saponi?cation.
tionally esteri?ed to give the esters indicated.
If the next
30 step is dehydrogenation at C-l(2) the esters are used
Another portion of the process of the present invention
and if the next step is the addition of an ll?-hydroxy
group the free compound is most suitable. For the addi
tion of the ll?-hydroxy the compound is reacted with
Curvularia lunata according to the process described in
.is illustrated by the following equation:
35 U.S. Patent No. 2,658,023, Shull et al., granted Novem
ber 3, 1953. As indicated in the above equation
either step may be performed ?rst with the produc
tion of 2vt-methyl-6ot-chloro-AlA-pregnadien-17u,2l-diol
3,20-dione and its esters, 2ot-methyl-6a-chloro-A4-pregnen—
40 l1,8,l7a,2l-triol-3,20-dione and its esters and ?nally
‘if’...
0 I3
Zu-methyl-6ot-chloro-prednisolone and its esters. As may
be understood following the reaction with Curvularz'a
lunala the resultant free compound may be conventionally
esteri?ed and following the reaction with selenium dioxide
the resultant ester compound may be conventionally
saponi?ed.
l R1 orthoformate
The following specific examples serve to illustrate but
are not intended to limit the present invention.
CHzOAG
CHzOAc
0
6D
I :I-“OH
H 3 o--
i-BOH
hYP°' n 3 o-chlorous
——>
R10
acid
VO_
50
Example I
A suspension of 6 g. of the 2l-acetate of 2u-methyl
cortisone in a mixture of 7 cc. of ethyl orthoformate,
0.4 cc. of anhydrous ethanol and 30 cc. of anhydrous
dioxane was treated with 0.5 cc. of dioxane containing
55 0.075 cc. of concentrated sulfuric acid and the mixture
was rapidly stirred for 5 minutes. It was then kept
standing for 20 minutes at 25° C., treated with 3 cc.
of pyridine and evaporated to dryness under reduced
pressure. The residue crystallized upon trituration with
1
60 5 cc. of methanol containing a few drops of water.
Recrystallization from methanol containing a little pyr
idine furnished the ZI-acetate of 2rx-methyl-3-ethoxy
l HCI
OHIO R
Hi0
0
O
I :L- OH
‘ :I-"OH
Selenium ZERO-~
dioxide
'
or
5 g. of this enol-ether was mixed with 100 cc. of
65 acetone, 20 cc. of water and 2 g. of sodium acetate,
cooled to 0° C. and treated with 1.8 g. of N-chloro
succinimide followed by 2 cc. of glacial acetic acid.
After stirring for one hour at 0° C. the mixture was
poured into water and the precipitate was collected,
70 washed with water, dried and recrystallized from ether,
thus producing the 21-acetate of 2ot-methyl-6p-chloro
cortisone.
‘_.__
o_
A3’5-pregnadien-17u,21-diol-11,20-dione.
CHzO R
0:
t
or
A slow stream of dry hydrogen chloride was allowed
to pass into a solution of 3 g. of the above compound
75 in 150 cc. of glacial acetic acid while the temperature was
8,056,815
kept below 18° C.
09a ?uoro analogue produced the corresponding
After- 2 hours, the solution was
Zl-esters of 2-methyl-6cz-chloro-prednisone or its C-9a
poured into water, the precipitate was collected by
?ltration, washed with water and recrystallized from
acetone-hexane.
?uoro analogue, respectively.
Example VIII
There was thus obtained the 21-acetate
of 2u-methyl-oa-chloro-cortisone.
A mixture of 2 g. of the 21-acetate of 2a-methyl
A mixture of 6 g. of the 21-acetate of Za-methyl-M
6a-chloro-cortisone, 100 cc. of anhydrous t-butanol, 0.8 g.
pregnen-l7a,21-dio1-3,20-dione, 6 cc. of ethyl orthoform
ate, 0.3 cc. of absolute ethanol and 30 cc. of anhydrous
of selenium dioxide and 0.5 cc. of pyridine was re?uxed
under nitrogen for 18 hours, cooled and ?ltered through
dioxane was treated with 1.5 cc. of dioxane containing
celite. The precipitate was washed with 20 cc. of hot 10 0.075 cc. of concentrated sulfuric acid. The mixture was
vigorously stirred for 5 minutes, kept standing at 25° C.
t-butanol and the combined ?ltrate and washings was
for 20 minutes and then treated with 3 cc. of pyridine and
evaporated to dryness under reduced pressure. The
evaporated to dryness under reduced pressure. The
residue was dissolved in 50 cc. of acetone, treated with
residue was recrystallized from methanol containing a
decolorizing charcoal and anhydrous sodium sulfate,
?ltered and evaporated to dryness. Chromatographic 15 little pyridine, thus yielding the ZI-acetate of 3-ethoxy-2a
methyI-A3'5-pregnadien-17a,21-diol-20-0ne.
puri?cation of'the residue on neutral alumina yielded
A mixture of 5 g. of the above compound, 100 cc. of
the 21-acetate of 2-methyl-6a-chloro-prednisone.
acetone, 20 cc. of water and 2 g. of sodium acetate Was
Example 11
cooled to 0° C. and mixed with 1.8 g. of N-chlorosuc
By the method of Example I, the 2l-acetate of 20 cinimide followed by 2 cc. of glacial acetic acid. The
mixture was stirred at 0° C. for one hour, poured into
water and the precipitate was collected, washed with
2a-methyl-9a-?uoro~cortisone was converted into the
2l-acetates of 2ot-methyl-9a-?uoro-3-ethoxy-Asy5-pregna
water, dried and recrystallized from ether, thus giving the
di611~17oc,2l-dlOl-11,20-Cli0l'16, of 2a-methyl~6?-chloro-9a
2l-acetate of Zoe-methyl-6B-chloro-A4-pregnen-17a,21-diol~
?uoro-cortisone and of 2a-methyl-6m-chloro-9a-?uoro
cortisone, as intermediate products; the ?nal compound 25 3,20-dione.
was
the
21~acetate
of
A slow stream of dry hydrogen chloride Was introduced
2-methyl-6u-chloro-9a-?uoro
for 2 hours into a solution of 4.5 g. of the above compound
prednisone.
in 100 cc. of glacial acetic acid keeping the temperature
below 18° C. The mixture Was diluted with ice Water and
Example III
1 g. of the 21-acetate of 2a-methyl-6a-chloro-cortisone
the precipitate formed was collected, washed with water,
dried and recrystallized from acetone-hexane, thus furnish
was mixed with 10 cc. of absolute methanol, coo-led to
0° C. and treated with a cold solution of sodium meth
ing the 21-acetate of 2a-methyl-Ga-chloro-M-pregnen-17a,
oxide prepared by dissolving 70 mg. of sodium metal
21-diol-3,20-dione.
in 5 cc. of absolute methanol; the reagent was added drop
Wise to the stirred solution which was kept under nitrogen
at a temperature around 0° C.
4 g. of the above compound was mixed With 200 cc. of
anhydrous t-butanol, 1.6 g. of selenium dioxide and 0.8
cc. of pyridine. The mixture was re?uxed under nitrogen
for 72 hours, ?ltered through celite, Washed with 80 cc.
of hot t-butanol and the combined ?ltrate and Washing
was evaporated to dryness under reduced pressure. The
The stirring was con
tinued under nitrogen for half an hour at 0° C. and the
mixture was then poured into cold saturated aqueous
sodium chloride solution containing 0.5 cc. of acetic acid.
The precipitate was collected, washed with water, dried 40 residue was dissolved in acetone, treated with decoloriz
and recrystallized from acetone-hexane, thus yielding the
ing charcoal and anhydrous sodium sulfate, ?ltered and
free Zoe-methyl-Got-ChlOIO-COftiSOIIB.
evaporated to dryness. Chromatographic puri?cation of
Example IV
By the method of Example III, there were saponi?ed
the 21-acetates of 2-methyl-6a-chloro-prednisone, of
2a-methyl-6a-chloro-9a-?uoro~cortisone and of 2-methyl
6wcl1loro~9a-fluoro-prednisone to produce the correspond
the residue on neutral alumina produced the 21-acetate of
ing free 21-‘1ydroxy compounds.
Example V
2 - methyl - 6a - chloro - Alt‘i-pregnadien-l7oc,2l-diol-3,
20-dione.
A mixture of 3 g. of this acetate and 30 cc. of absolute
methanol was cooled to 0° C. and treated with a solution
of sodium methoxide prepared by dissolving 210 mg. of
sodium metal in 15 cc. of absolute methanol. The reagent
50 was added dropwise, with stirring under an atmosphere
A mixture of 1 g. of 2-methyl-6ct-chloro~prednisone,
of nitrogen and keeping the temperature around 0° C.
10 cc. of pyridine and 1 cc. of propionic anhydride was
The stirring was continued for half an hour at 0° C. and
the mixture was then poured into 100 cc. of ice cold
kept overnight at room temperature and then poured
into water. The precipitate formed was collected, washed
saturated aqueous solution of sodium chloride containing
0.5 cc. of acetic acid and the precipitate formed was col
with water, dried and recrystallized from acetone-hexane,
thus giving the 2lv-propionate of 2-methyl-6a-chloro
lected, Washed With Water, dried and recrystallized from
prednisone. By the same method other esters of hydro
carbon carboxylic acids of less than 12 carbon atoms
methyl - 60c - chloro - A114 - pregnadien - 17a,21-diol-3,20
acetone-hexane.
dione.
were prepared including the cyclopentylpropionate, and
benzoate.
Example VI
By the method of Example V, 2a-rnethyl-6a-chloro
cortisone, Za-methyl-6a-chloro-9ot-?uoro-cortisone and
2-methyl-6a-chloro-9a-?uoro-prednisone was esteri?ed at
C-21 to make the propionate, cyclopentylpropionate and
benzoate.
There was thus obtained the free 2
60
The above compound was incubated with a recent cul
ture of Carvularia lanata which had been prepared in the
following manner: 1 lt. of a sterilized medium of 20 g.
of peptone and 50 cc. of corn syrup was mixed with 30
cc. of a growing culture of Carvularia lanata N.R.R.L.
2380 which had been prepared in a medium of ‘the same
composition by inoculation with an aqueous suspension
rich in spores of Car-valaria lanata; this suspension had
Example VII
been prepared from a culture of the fungus in an agar
medium. The mixture was then stirred for 48 hours at
1 g. of the 21-propionate of 2a-methyl-6a-chloro-9a
fluoro-cortisone, obtained in accordance with the method 70 28° C. With aeration. At the end of this time the pH of
the culture varied from 3.0 to 4.0 and there was an abund
of Example V, was dehydrogenated with selenium dioxide
ant growth of the fungus.
as described for this reaction in Example I, to form the
21-propionate of Z-methyl-6a-chloro-9a-?uoro-prednisone.
To each half a liter of the culture thus obtained there
was added 33 cc. of a 1% ethanol solution of Zoe-methyl
Similarly, the dehydrogenation of the other C-21 esters
of Example VI of 2-methyl-6a-chloro-cortisone or its 75 6<x — chloro - Aly‘l-pregnadien-17a,21-diol-3,20-dione. The
3,056,815
7
2. The process of claim 1 wherein the compounds have
mixture was again stirred with aeration at 28° C. for 48
hours and then extracted several times with methylene
dichloride. The extract was Washed with water, dried
over anhydrous sodium sulfate, ?ltered and concentrated
a 9a-?uoro group.
3. A process for the production of 2a-methyl-6u-chloro
prednisolone compounds comprising forming the 3-enol
ether of 2a—methyl-“S”.acetate with'a lower alkyl formate
to form the corresponding 3-enol ether, reacting the ether
to a small volume under reduced pressure, avoiding over
heating. The concentrated solutions obtained from several
with hypochlorous acid to form 2a-methyl-6B-chloro
similar incubations were combined and chromatographed
on silica. Elution of the column with mixtures of chloro
“S” acetate, inverting the 6,6-chloro group by reaction
with hydrogen chloride to a 6a-chloro group, adding an
form-ether furnished crystalline fractions which were
combined and recrystallized from acetone-hexane, thus 10 ll?-hydroxy group and dehydrogenating at C-1(2) by
re?uxing with selenium dioxide.
giving the pure Z-methyl-6ot-chloro-prcdnisolone.
4. 2a-methyl-6a-chloro-9a-?uoro-cortisone.
Example IX
5. The 21-mono hydrocarbon carboxylic acid esters of
By the same method of saponi?cation described in the
less than 12 carbon atoms of 2vc-In6l11y1-6a-Chl0I‘O-9oc
previous example there was saponi?ed the 2l-acetate of
2a-methyl-6ot-chloro-A4-pregnen-1704,2l-diol-3,20-dione to
the free 2a-methyl-éa-chloro-M-pregnen-17u,21-diol-3,20
?uoro-cortisone.
_
6. 2-methyl-6u-chloro-9a-?uoro-prednisone.
7. The 21-mono hydrocarbon carboxylic acid esters of
less than 12 carbon atoms of 2-methyl-6a-chloro-9a
dione.
The above compound was then incubated with a grow
?uoro-prednisone.
ing culture of Curvularia lunata, in accordance with the 20
method described in Example VIII, thus producing 2oz
A3’5-pregnadien-17a,2l-diol-l1,2O-dione.
methyl-6a-chloro-hydrocortisone.
8. The 21-acetate of 2a-methyl-9w?uoro-3-ethoxy
9. The 2l-acetate of 2u-methyl-6,6-chloro-cortisone.
10. The 2l-acetate of 2a-methyl-65-ch1oro-9a-?u0ro
cortisone.
A mixture of l g. of 2a-metl1yl-6a—chloro-hydrocorti~
sone, 10 cc. of pyridine and 1 cc. of propionic anhydride
was kept overnight at room temperature and then poured
11. A compound of the following formula:
into Water. The precipitate was collected by ?ltration,
Washed with water, dried and recrystallized from acetone
hexane, thus yielding the 21-propionate of Zoc-rn6'thYl-6oz
chloro-hydrocortisone.
By subsequent re?uxing of the above compound with
CHzOR
30
selenium dioxide, in accordance with the method of de
hydrogenation described in Example VIII, there was ob
tained the 2l-propionate of 2-methyl-6a-chloro-predniso
lone.
Example X
By the method to that of the previous Example, 2
rnethyl-6a-chIoro-prednisolone, the ?nal compound of
Example VIII, was esteri?ed by reaction with acetic anhy
dride to produce the 2l-acetate of 2-methyl-6a-chloro
prednisolone.
Example XI
wherein R is selected from the group consisting of hy
4.0 drogen and a hydrocarbon carboxylic acyl group of less
than 12 carbon atoms.
12. Zea-methyl - 60c - ch1oro-A4-pregnen-17a,21-diol-3,
By the method of Example IX, there was esteri?ed both
ZO-dione.
13. The 21-mono hydrocarbon carboxylic acid esters of
less than 12 carbon atoms of 2a-methyl-6u-chloro-A4
2a - methyl - 6cc-ChlOI‘O-hYdI‘OCOI‘lISOI16 and 2-methyl-6ot
chloroprednisolone at 021 by conventional reaction with
acid anhydrides or chlorides including the cyclopentyl
propionate and benzoate.
We claim:
1. A process for the production of 2-methyl-6ot-chloro
prednisone compounds comprising reacting 2a-methyl
cortisone acetate with a lower alkyl formate to form the
corresponding 3-enol ether, reacting the ether with hypo
chlorous acid to form the corresponding acetate of a 20c
methyl-6?-chloro-cortisone compound, inverting the 618
chloro group by reaction with hydrogen chloride to a 61x
chloro group and dehydrogenating at C-1(2) the 6m
chloro compound by re?uxing with selenium dioxide.
pregnen-l7a,2l-diol-3,20-dione.
14. The ZI-acetate :of 2a-methyl-??-chloro-A'ipregnen
17a,21-diol-3,20-dione.
50
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,835,667
2,857,406
Ercoli et a1 ___________ __ May 20, 1958
Herzog ______________ __ Oct. 21, 1958
766,708
Great Britain __________ __ Apr. 16, 1958
FOREIGN PATENTS
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