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Патент USA US3068261

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Patented Dec, ll 7 1%82
inert organic solvent, e.g., acetonitrile, tetrahydrofuran,
3,068,251
PROCESS FOR THE FREPARATEGN 0F loot-Hal
dioxane, acetone, and the like, or mixtures thereof, to
obtain the compounds of Formula II, such as 115,205,21
trihydroxy-1,4,16-pregnatrien-3-one ZI-acetate. The reac
tion is usually conducted ‘between 0° and 100° C., prefer
ably at re?ux temperature. Completion of the reaction
DRQXYLATED STERQHD?) AND NOVEL ENTER
MEDKATES
Barney .l. Magerlein, Portage Township, Kalamazoo
County, and Robert D. Birkenmeyer and Fred Hagan,
Kalamazoo, Mich, assignors to The ‘Upjohn Company,
Kalamazoo, Miclm, a corporation of Delaware
No Drawing. Filed Jan. 11, E60, §er. No. 1,423
17 Claims. (Cl. zen-397.45)
can take from about 5 minutes to about 2 hours, depend
ing in part on the temperature employed and the solvent
employed.
10
This invention relates to a novel process for the prepara
tion ‘of l6a-hydroxylated steroids ‘and novel A16 com
pounds of the pregnane series used in the preparation
thereof.
The novel process of. the present invention is repre
sented by the following reaction scheme:
CH3
CHzOAc
CH3
Groom;
CHM Y
CHM/v on
no
in the presence of an inert organic solvent, such as ace
tonitrile, tetrahydrofuran, dioxane, acetone, nitromethane,
and the like, preferably acetonitrile, followed by reaction
' with water to yield the compounds of Formula II. The
reaction with Water can take place on a Florisil (synthetic
magnesium silicate having Water of hydration) column
or water can be added to the reaction product obtained by
reacting the starting steroid with the silver salt.
.
20
The thus obtained compounds of Formula II are re
covered from the reaction mixture by conventional meth
ods, such as, for example, dilution of the reaction mixture
no—/\
CH~
. _
CHsi
/
X__
with water, extraction with a water-immiscible solvent
/
25
|
I
"Q
O-
II
i
I
noC?l
CIJHQOAC
chloroform, methylene chloride, a hydrocarbon solvent,
e.g., benzene, or the like, preferably ethyl acetate, using
0:0
a
no?
-on
CH5,
/
0 I
V :
ZI-acetate. The oxidation reaction is carried out in the
presence of an inert organic solvent, such as ethyl acetate,
CH3
CIEHZOAC
0:0
X
trihydroxy-l,4,16-pregnatrien-3-one Zl-acetate are selec
tively oxidized to obtain the compounds of Formula HI,
3 O such as 115,2l-dihydroxy-L4,l6-pregnatriene-3,20-dione
2
CH3
X_
IV ‘—*~
OJ
V i
z
such as methylene chloride, ethyl acetate, benzene, toluene
and the like, followed by chromatography, recrystalliza
tion, or a combination of these.
The compounds of Formula II, such as 115,208,21
()_
z
Alternatively, the starting steroids of Formula I can be
reacted with the silver salt under anhydrous conditions,
III
manganese dioxide. The reaction is usually conducted at
between about 0° and 100° C., room temperature being
preferred. Completion of the reaction can take from 1
to 24 hours depending on the temperature and solvent
employed. The thus obtained compounds of Formula
40
111 are recovered from the reaction mixture by conven
tional means, such as, for example, concentration of the
reaction mixture, precipitation, or extraction, and are
puri?ed by conventional ‘means such as chromatography
2
wherein X is selected from the group consisting of
45 or crystallization or a combination of these.
The compounds of Formula III, such as ll,B,2l-dihy
droxy-1,4,l6-pregnatriene-3,20-dione 21-acetate are then
1?
~én-orn
and
subjected to hydroxylation, followed by hydrolysis, to ob
tain the compounds of Formula IV, such as 11,8,160L,170L,
50
i‘
—C=OH~
21 - tetrahydroxy-1,4-pregnadiene - 3-20 - dione 21 - ace
tate. The hydroxylation reaction is carried out in the
presence of a tertiary amine and an inert organic solvent
using osmium tetroxide. Suitable solvents are hydrocar
bon solvents, e.g., benzene, toluene, ethyl acetate, tertiary
R being attached at the 2~position and selected from the
group consisting of hydrogen and methyl, Y represents 55 butyl alcohol, ethers, and the like. Suitable tertiary
amines are pyridine, lutidine, triethylamine, and the like.
chlorine or bromine, and Z represents hydrogen, ?uorine,
In the preferred embodiment, the osmium tetroxide hy
or methyl, and Ac is the acyl radical of an organic car
droxylation reaction is carried out in the presence of ben
zene and pyridine. The reaction is usually conducted at
containing from 1 to 12 carbon atoms, inclusive.
In this application the wavy line ( E) represents a 60 between about 0° and 100° 0., preferably at. about room
temperature. Completion of the reaction can take from
generic expression including the (a) and (/3) con?gura
tion.
about 1 hour to several days, depending in part on the
boxylic acid, particularly a hydrocarbon carboxylic acid
temperature, solvent and tertiary amine employed. After
The starting compounds of the process of this invention,
the compounds of Formula I, are prepared according to
the hydroxylation reaction is completed, the reaction mix
the procedures disclosed in US. application Serial No. 65 ture is hydrolyzed in a basic medium, for example, aque
1,449, ?led on January 11, 1960, of even date herewith.
ous alcoholic solutions containing sodium sul?te, sodium
The process of the present invention comprises react
or potassium bicarbonate, or mixtures thereof. The mildly
ing steroids of the type represented by Formula I, such
alkaline solution can conveniently contain a water-mis
as 20a - chloro-l1?,21-dihydroxy-1,4,16-pregnatrien-3-one
cible organic solvent such as methanol, ethanol, tertiary
Zl-acetate, with a silver salt, preferably a silver inorganic 70 butyl alcohol, dioxane and the like, and if desired a water
salt, e.g., silver ?uoride, silver nitrate, silver oxide and
immiscible organic solvent, such as benzene, or combina
the like, and water, in the presence of a water-miscible,
tions of a water-miscible and water-immiscible solvent.
3,068,251
a
isobutyrate, the 21-isovalerate, the 21-tertiarybutylacetate,
the 21-(?-cyclopentylpropionate), the 21-cyclohexane
carboxylate, the 21-cyclohexylacetate, the 21-benzoate,
the 2l-phenylacetate, the ZI-(B-phenylpropionate), the
The hydroxylation of the compounds of Formula III
to the compounds of Formula IV can also be carried out
using osmium tetroxide and hydrogen peroxide, in the
presence of an inert organic solvent, or potassium per
manganate in aqueous acetone.
The following examples are illustrative of the process
21-(o-, m-, p-toluate), the 21-hemisuccinate, the 21-hemi
adipate, the 2l-acrylate, the 21-crotonate, the 2l-pro
piolate, the 21-(2-butynoate), the 21-undecolate, the 21
cinnamate, the 21-maleate, the 21-citraconate, and the
and products of this invention. In the examples which
follow, the Roman numeral following the name of a com
like, of 11?,20,B,2l-trihydroxy-l,4-16-pregnatrien-3-one.
pound is used to indicate the relation of the compound
Likewise, substituting a stoichiometric equivalent
to the reaction scheme depicted above.
10
amount of
EXAMPLE 1
20u-bromo- and 20a-chloro-11?,21-dihydroxy-4,16-preg
1118,205,21-Trihydroxy-1,4,16-Pregnatrien-3-One
nadien-3-one 21-acetate (or other 2l-acylates),
21-Acetate (11)
6a-?uoro-20a-bromo- and 6a-?uoro-20ot-chloro-1118,21
dihydroxy-4,16-pregnadien-3-one 21-acetate (or other
A. 5.0 g. (0.0123 mole) of 20a-chloro-11B,21-di 15 21-acylates),
hydroxy-1,4,16-pregnatrien-3-one 21-acetate (I), 5.0 g.
6a-?uoro - 20oz - bromo- and 6a-?uoro-20a-chloro-1,4,16
(0.039 mole) of dry silver ?uoride and 500 ml. of ace
pregnatrien-3-one 21-acetate (or other 21-acylates),
Goc-IIIBthYl-ZOot-bI‘OITlOand 6a-methyl-20a-chloro-11,3,21
for 1 hour. The reaction mixture was then cooled,
dihydroxy-4,16-pregnadien-3-one 21-acetate (or other
?ltered, and the ?ltrate thus obtained was evaporated to 20
21-acylates),
dryness leaving a solid residue weighing 4.7 g. The thus
Goa-methYl-ZOmbIOIIIO- and 6ot-methyl-20u-chloro-1,4,l6
obtained solid residue was dissolved in methylene chloride
pregnatrien-3-one 21-acetate (or other 21-acylates),
and poured onto a 400 g. Florisil (synthetic magnesium
2ot-methyl-20a-bromo- and Za-methyl-ZOa-chloro-l15,21
silicate) chromatographic column packed wet in Skelly
dihydroxy-4,16-pregnadien-3-one Zl-acetate (or other
solve B hexanes. The chromatographic column was
2l-acylates),
developed by eluting with Skellysolve B hexanes contain
2-methyl-20a-bromo- and 2-methyl-20a-chloro-1,4,16
ing increasing amounts of acetone. The eluate fractions
pregna-trien-S-one 21-acetate (or other 2l-acylates),
were freed of solvent and those fractions eluted with
2a-methyl-6a-fluoro-20m-bromo- and Za-II'IClZhYl-Goc-HHOI‘O
Skellysolve B hexanes containing 15% to 18% acetone
tonitrile were heated, under a stream of nitrogen, at re?ux
20ot-chloro-1118,2l-dihydroxy - 4,16 - pregnadien-3-one
were combined to yield 3.8 g. of crystalline material which 30
21-acetate (or other 21-acylates),
was recrystallized from an ethyl acetate-Skellysolve B
2-methyl-6a-?uoro-20ot-bromo- and 2-methyl-6a-?uoro
hexanes mixture to give an analytical sample of
ZOa-chloro-1,4,16=-pregnatrien-3~one
11,8,2013,2l-trihydroxy - 1,4,16 - pregnatrien-S-one 21-ace
tate (II) having a melting point of 194~196° C.,
A532? 243 mp, aM 15,600
and the following analysis:
21 - acetate
(or
other acylates),
35
2a,6a-dimethyl - 20a - bromo- and 2a,6a-dimethyl - 20cc -
chloro — 11,8,21 - dihydroxy - 4,16-pregnadien-3-one 21
acetate (or other 21-acylates), and
2,6tx-dimethyl-20a-bromo- and 2,6a-dimethyl-20ut-chlor0—
1,4,16-pregnatrien-3-one 21-acetate (or other 21-acyl
Analysis.—-Calcd. for C23H30O5: C, 71.48; H, 7.82.
Found: C. 71.29; H, 7.73.
B. A solution of 45.8 g. (0.27 mole) of silver nitrate 40 ates), for
20a-chloro-1118,21-dihydroxy-1,4,16-pregnatrien-3-one 21
and 50 g. (0.138 mole) of 20tx-chloro-11,8,2l-dihydroxy
acetate is productive of
1,4,16-pregnatrien-3-one 21-acetate (I) in 3 l. of 90%
1113,205,21-trihydroxy-4,16-pregnadien - 3 - one 21-acetate
acetonitrile-water was heated under re?ux for 1 hour.
The reaction mixture thus obtained was distilled in vacuo
(or other 21-acylates),
leaving a solid residue. The residue obtained was parti 45 6a-?uoro-1113,205,21-trihydroxy - 4,16 - pregnadien-3-one
2l-acetate (or other acylates),
tioned between methylene chloride and water and the
6a - ?uoro-l 15,20531-trihydroxy-1,4,16-pregnatrien-3-one
silver salts which had precipitated were removed by ?ltra
Zl-acetate (or other 2l-acylates),
tion. The organic phase was separated, washed with
6a-methyl-11,8,205,21-trihydroxy - 4,16 - pregnadien-3-one
saturated sodium chloride solution and dried over sodium
2l-acetate (or other 21-acylates),
sulfate. The organic phase was then poured onto a 1 kg. 50
Florisil (synthetic magnesium silicate) chromatographic
60t-II16thyl-11/3,ZOB,21 - trihydroxy - 1,4,16 - pregnatrien-3
column packed in Skellysolve B hexanes. The chromato
graphic column was developed by eluting with Skellysolve
B hexanes containing increasing amounts of acetone. The
2aJmethyl-11B,20,8,21-trihydroxy - 4,16-pregna-dierr3one‘v
eluate fractions were freed of solvent and those semi
one 21-acetate (or other 2l-acylates),
Zl-acetate (or other 21-acylates),
55 2-methyl-1 1,8,20/821 - trihydroxy-1,4,16-pregnatrien-3-one
21-acetate (or other 21-acylates),
crystalline fractions which had been eluted with Skelly
solve B hexanes containing 15-20% acetone were com
2a-methyl-6a-?uoro - 1lB,20/3,21 - trihydroxy - 4,16-preg
bined and recrystallized from an ethyl acetate-Skellysolve
B hexanes mixture to yield 18.8 g. of 115,205,21-tri
2-methyl-6et-?uoro-11,B,20?,21-trihydroxy - 1,4,16-pregna~
hydroxy-1,4,16-pregnatrien-3-one 21-acetate (II) having
nadien-3-one 21-acetate (or other acylates),
60
trien-S-one 21-acetate (or other 21-acylates),
a melting point or" 189—190° C. Further recrystalliza
2a,6ot-dimethyl-116,205,21-trihydroxy - 4,16 - pregnadiend
tion from ethyl acetate-Skellysolve B hexanes raised the
3-one 2l-acetate (or other acylates), and
melting point to 194—196° C.
2,6OL- dimethyl-11/3,20,8,21 - trihydroxy-1,4,16-pregnatrien
Similarly substituting a stoichiometric equivalent
3-one 21-acetate (or other 21-acylates), respectively.
amount of 20ot-bromo-11,8,21-dihydroxy-L4,lé-pregnatri 65 In the preceding paragraph the term “other 21-acylates”
en-3-one 21-acetate for 20oc-chloro-11,8,21-dihydroxy
includes, for example, the 2l-formate, the 21-propionate,
1,4,16-pregnatrien-3-one 21-acetate in the procedure of
the ZI-butyrate, the 2l-valerate, the 21-hexanoate, the 21
Example 1A or 1B is productive of 115,205,21-trihy
laurate, the 21-trimethylacetate, the 2l-isobutyrate, the
droxy-l,4,16-pregnatrien-3-one 21-acetate.
In like manner, substituting other 21-acylates of 2004 70 2l-isovalerate, the 2l-tertiarybutylacetate, the 2l-(?-cy_
clopentylpropionate), the 21-cyclohexanecarboxylate, the
bromo~ and 20a-chloro-l113,2l-dihydroxy-1,4,16-pregna
21-cyclohexylacetate, the 21-benzoate, the 21-phenylace~
trien-3-one Zl-acetate is productive of the corresponding
tate, the Zl-(?-phenylpropionate), the 21-(o-, m-, p2l-acylates, such as, for example, the 2l-formate, the 21
toluate), the 21-hemisuccinate, the 2l-hemiadipate, the:
propionate, the ZI-butyrate, the 2l-valerate, the 21-hex
anoate, the ZI-Iaurate, the 21-trimethylacetate, the 21 75 21-acrylate, the ZI-crotonate, the 21-pr0pio1ate,‘ the 2,1:
5
3,068,251
0
(Z-butynoate), the 21-undecolate, the ZI-cinnamate, the
21-maleate, the 21-citraconate, and the like.
2a-methy1-6a-?uoro-115,205,21-trihydroxy-4,16 - pregna
In like manner, substituting a mixture comprising the
2-methyl-6a-?uoro-1 1,8,205,21-trihydroxy-1,4,16 - pregna
dien-S-one 21~acetate (or other 21-acylates),
20m- and 20/3-epimeric forms of the 20-ch1oro or 20
bromo compounds described in Examples 2A and 23, re
trien-3-one 21~acetate (or other 21-acylates),
2a,6a-dimethyl-l1B,20B,21-trihydroxy-4,16 - pregnadien -
spectively, of copending application Serial No. 1449, ?led
on January 11, 1960, of even date herewith, for 200:
chloro-l 1 ,6,21-dihydroxy-1,4,16-pregnatrien-3-one 21-ace
3-one 21-acetate (or other 21-acylates), and
2,6ot-dimethyl~l1?,20,B,2l-trihydroxy-1,4,16 - pregnatrien
3-one 21-acetate (or other 2l-acylates) for
115,20531-trihydroxy?1,4,16-pregnatrien-3 -one 21-acetate
one 2l-acetate) is productive of a mixture comprising the 10
is productive of
tate (or ZOti-bromo-l15,21-dihydroxy-1,4-pregnatrien-3
ZOoc-llYdI‘OXY compounds, otherwise corresponding to the
ZOB-hydroxy compounds described above, and the 2013
hydroxy compounds. This mixture comprising the 200:
115,21-dihydroxy-4,16-pregnadiene-3,20-dione 21-acetate
(or other 21-acylates),
6a-?uoro-115,21-dihydroxy-4,16-pregnadiene-3,20 - dione
hydroxy and 20B-hydroxy compounds can be used in
Example 2 without further treatment. The mixture com
21-acetate (or other 21-acylates),
15 6a-?uoro-116,21-dihydroxy - 1,4,16 - pregnatriene - 3,20
prising the ZOa-hydroxy compounds can be chromato
dione Zl-acetate (or other 21-acylates),
graphed or countercurrently extracted, followed by crys
6a-methy1-l16,21-dihydroxy-4,16-pregnadiene - 3,20 - di
tallization to separate the 20ot-hydroxy compounds from
one 21-acetate (or other 21-acylates),
the ZOQ-hydroxy compounds and thus obtain them as
6a-methyl-115,21-dihydroxy-L4,16-pregnatriene-3,20 - di
separate entities.
one 21-acetate (or other 21-acylates),
20
2a-methyl-11,8,21-dihydroxy-4,l6-pregnadiene- 3,20 - di
EXAMPLE 2
one 21-acetate (or other 21-acylates),
2-methyl-115,21-dihydroxy-L4,l6~pregnatriene-3,20- - di
1 1,8,2] -Dihydi'0xy-1,4,1 6-Pregnatriene-3-20-Di0ne
21 -Acetate (III)
one 21-acetate (or other 21-acylates),
25 2ot-rnethyl-6a-?uoro-1 15,21-dihydroxy-4,16 - pregnadiene
3,20-dione 21-acetate (or other 2l-acylates),
1.3 g. (0.00336 mole) of 115,205,21-trihydroxy-L4,16
2-methyl-6a-?uoro-11,8,21 - dihydroxy - 1,4,16 - pregnatri
pregnatrien-3-one 21-acetate (II), 140 ml. of ethyl ace
ene-3,20-dione 21-acetate (or other 21-acylates),
ta'te and 5.0 g. of activated manganese dioxide were
2a,6o¢-dirnethyl-11B,21-dihydroxy~4,16-pregnadiene - 3,20
shaken at about 25° C. for about 17 hours. The reaction
dione 21-acetate (or other acylates), and
mixture was ?ltered and following concentration and 30
2,6a-dimethyl—l 1B,21-dihydroxy-1,4,16 - pregnatriene - 3,
chilling of the reaction mixture there was obtained 925
20-dione 21~acetate (or other 21-acylates), respectively.
mg. of a white solid precipitate melting at 200-208" C.
The term “other Zl-acylates” as used in the preceding
Recrystallization from ethyl acetate gave an analytical
paragraph includes, for example, those named in the
one 21-acetate (III), having a melting point of 208-209“ 35 penultimate paragraph of Examplel.
In like manner, substituting the mixture comprising the
C., [0L]D+146° (cHcn),
sample of 11,8,2l-dihydroxy~l,4,16-pregnatriene~3,20-di
20a-hydroxy and 20,8-hydroxy compounds described in
max.
Example 1 is productive of the 20-keto compounds de
scribed in this example.
242 m”, aM 23,750
40
and the following analysis:
Found:
Analysis.-—Calcd.
C, 72.08; H, 7.30.
fOI' 0231‘1313051 C,
H,
Similarly, substituting other 21-acylates, for example,
those named in the penultimate paragraph of Example 1,
of 115,20521~trihydroxy-1,4,16-pregnatrien~3-one for
115,205,21-trihydroxy-L4,16-pregnatrien-3 - one 21-ace
tate, is productive of the corresponding 21-acylates, such
as, for example, the 21~formate, the 21-propi0nate, the
21-butyrate, the 21~valerate, the 21-hexanoate, the 21
laurate, the ZI-trimethylacetate, the 21-isobutyrate, the
21-isovalerate, the 21-tertiarybutylacetate, the 21-(B-cy
clopentylpropionate), the 21-cyclohexanecarboxylate, the
21-cyclohexylacetate, the 21-benzoate, the 21-phenylace
EXAMPLE 3
1118,] 6 c<,1 704,21-Tetrahydr0xy-1,4-Pregnadiene
3,20-Dz‘0ne 21-Acetate (IV)
1.19 g. (0.0031 mole) of 110,21-dihydroxy-1,4,16-preg
natriene-3,20-dione 21-acetate (III), 25 ml. of benzene,
1.2 ml. of pyridine and 785 mg. (0.031 mole) of osmium
tetroxide were allowed to stand at about 25° C. for about
50 100 hours. The thus obtained dark brown reaction mix
ture was then poured into a solution made up of 55 ml.
of water, 20 ml. of benzene, 36 ml. of methanol, 5.6 g.
sodium sul?te and 5.6 g. of potassium bicarbonate and
stirred for 4 hours. This mixture was extracted with six
tate, the 21~(?-phenylpropionate), the 21-(o-, m-, p
toluate), the 2l-hemisuccinate, the 21-hemiadipate, the 55 100-ml. portions of hot chloroform and the chloroform
extracts thus obtained were combined and washed with
21-acrylate, the 21-crotonate, the 21-propiolate, the 21
dilute hydrochloric acid and then with Water. The com
(Z-butynoate), the 21-undecolate, the 21~cinnamate, the
bined washed extracts were ?ltered and following evapo
21-maleate, the 21-citraconate, and the like, of 115,21
dihydroxy-1,4,16-pregnatriene-3,20-dione.
ration of the chloroform, 670 mg. of a tan solid was
In like manner, substituting a stoichiometric equivalent 60 obtained.
Recrystallization from methanol gave 230 mg.
amount of
of 1l?3,160c,17ot,21 - tetrahydroxy - 1,4 - pregnadiene - 3,
l1?,20?,21~trihydroxy-4,16-pregnadien-3-one 21 - acetate
20-dione 21-acetate (IV), as a methanol solvate having
an [ethyl-67° (CI-I013).
(or other Zl-acylates) ,
6a-?uoro-11p,206,21-trihydroxy-4,16-pregnadien - 3 - one
21-acetate (or other ZI-acylates),
65
AEROH 24:3 mu, 01M
max.
6ix-?uoro-115,205,21-trihydroxy - 1,4,16 - pregnatrien - 3 -
one 21~acetate (or other 21-acylates),
6a-methy1-113,20521-trihydroxy,4,16-pregnadien-3 - one
21-acetate (or other 21-acylates),
6oi-methyl-1116,205;l-trihydroxy-IA,16-pregnatrien - 3 -
one 21-acetate (or other 21-acy1ates),
2aFmethyl-1l ?,20,8,21-trihydroxy-4,16-pregnadien-3 - one
21-acetate (or other 21-acylates),
2-methyl»115,20631-trihydroxy-1,4,16-pregnatrien-3 - one
21-acetate (or other Zl-acylates),
The thus obtained methanol solvate of 11?,l‘60c,17ot,21
tetrahydroxy-l,4-pregnadiene-3,20-dione 21--acetate was
dried at 120° C. to give 11,8,16oc,17u,2l-tetrahydroxy-1,4
70 pregnadiene-3,20~dione 21-acetate (IV) which had the
following analysis:
Analysis.-—Calcd. for C23H30O7: C, 66.01; H, 7.23.
Found: C, 66.15; H, 7.60.
Similarly, substituting other ZI-acylates, for example,
75 those named in the last paragraph of Example 1, of 1119,
3,068,251
O
7
to
We claim:
1. A compound of the formula:
21 - dihydroxy - 1,4,16 - pregnatriene - 3,20 - dione for
11,8,21 - dihydroxy - 1,4,16 - pregnatriene - 3,20 - dione
21-acetate is productive of the corresponding 21-acylates,
such as, for example, the 21-formate, the 21-propionate,
the 21-butyrate, the 21-valerate, the 2l-hexanoate, the
2l-laurate, the ZI-trimethylacetate, the 21-isobutyrate,
the 21-isova1erate, the ZI-tertiaryhutylacetate, the 2l-(?
CH3
CHzOAC
HNW OH
HO /\
cyclopentylpropionate), the 21-cyclohexanecarboxylate,
the 21-cyclohexylacetate, the 2l-benzoate, the 2l-pheny1—
acetate, the ZI-(B-phenylpropionate), the 21-(o-, m-, p
toluate) , the ZI-hemisuccinate, the 21-hemiadipate, the 21
acrylate, the 2l-crotonate, the 2l-propiolate, the 21-(2
butynoate), the 21-undecolate, the 21-cinnamate, the 21
maleate, and the 21-citraconate, and the like, of 11,13,160‘,
l70:,21-tetrahydroxy-1,4-pregnadiene-3,20-dione.
15
In like manner substituting a stoichiometric equivalent
wherein X is selected from the group consisting of
R
amount of
—('JE—-CHQ—- and _e=on_
1 1?,21-dihydroxy-4,16-pregnadiene-3,20-dione ZI-aCeta’w
(or other 2l-acylates),
6a-?uoro-1 1,8,2l-dihydroxy-4,16-pregnadiene-3,20~
R being attached at the 2-position and selected from the
group consisting of hydrogen and methyl, Z is selected
from the group consisting of hydrogen, ?uorine and
methyl, and Ac is the acyl radical of a hydrocarbon car
boxylic acid containing from 1 to 12 carbon atoms, in
elusive.
dione 2l-acetate (or other 2l-acylates),
6oc-?uoro-11,6,21-dihydroxy-1,4,16-pregnatriene-3,20~
dione 21-acetate (or other 2l-acylates),
Goa-methYl-l 16,21-dihydroxy-4,16-pregnadiene-3,20
2. A mixture comprising 115,20521-trihydroxy-1,4,16
pregnatrien-3-one 21-acetate and 11?,20a,21-trihydroxy
dione 21-acetate (or other 21-acylates),
6a-rnethyl-1 l/3,2l-dihydroxy-1,4,16-pregnatriene-3,20
1,4,16-pregnatrien-3-one 21-acetate.
dione 21-acetate (or other 21-acylates),
2a-methyl-11B,21-dihydroxy-4,16-pregnadiene-3,20
dione 21-acetate (or other 21-acylates),
2-methyl-1l,B,21-dihydroxy-1,4,16-pregnatriene-3,20
3. 115,20,2l - trihydroxy - 1,4,16 - pregnatrien - 3
30
dione 21-acetate (or other 21-acylates),
4. 11,8,20,B,21 - trihydroxy - 1,4,16 - pregnatrien - 3
2a - methyl - 60c - ?uoro - 1118,21 - dihydroxy - 4,16
pregnadiene-3,20-dione 21-acetate (or other 21-acyl
ates),
one 21-acylate in which the acyl radical is that of a hy
drocarbon carboxylic acid containing from 1 to 12 carbon
atoms, inclusive.
one 2l-acetate.
35
5. 11/5’,20e,21-trihydroxy-1,4,16-pregnatrien-3-one 21
acetate.
6. A process which comprises: reacting the compounds
of Formula I,
2 - methyl - 6o: - ?uoro - 1118,21 - dihydroxy - 1,4,16
pregnatriene-3,20-dione 21-acetate (or other acylates),
20¢,6oc - dimethyl - 11,8,21 - dihydroxy - 4,16 - pregna
CH3
CHzOAC
diene-3,20-dione 21-acetate (or other 2l-acylates), and 40
2,6oc - dimethyl - 115,21 - dihydroxy - 1,4,16 - pregna
triene-3,20-dione 2l-acetate (or other 21-acylates), for
11B,2l-dihydroXy-1,4,16-pregnatriene-3,ZO-dione 21
acetate is productive of
1113,16a,17a,21-tetrahydroxy-4-pregnene-3,20-dione 21
acetate (or other 21-acylates),
CH3
45
_l
6a-?uoro-1 1B,16oc,17a,2l-tetrahydroxy-4-pregnene-3,20
dione ZI-acetate (or other 21-acylates),
6a - ?uoro - 11[3,160c,17oz,21 - tetrahydroxy - 1,4 - pregna
diene-3,20-dione 2l-acetate (or other 2l-acylates),
6a-methyl-11,8,16a,17u,21-tetrahydroxy-4-pregnene
50
wherein X is selected from the group consisting of
, 3,20-dione 21-acetate (or other 21-acylates),
r
6a'- methyl - 11B,16a,17cc,21 - tetrahydroxy - 1,4 - preg~
ZOC-IIIBthYl-l 113,16a,17a,2l-tetrahydroxy-4-pregnene~
55 R being attached at the 2-position and selected from
the group consisting of hydrogen and methyl, Y is se
lected from the group consisting of chlorine and bromine,
Z is selected from the group consisting of hydrogen,
?uorine and methyl, and Ac is an acyl radical, with a
3,20-dione 21-acetate (or other 21-acylates),
2 - methyl - 1lp,l6a,17a,21 - tetrahydroxy - 1,4 - preg
nadiene-3,20-dione 21-acetate (or other acylates),
‘20c - methyl - 6a - ?uoro - 11,8,l6u,17u,21 - tetrahydroxy
4-pregnene 3,20-dione 21-acetate (or other 21-acyl
ates),
60 silver salt and water in the presence of an inert organic
solvent, to obtain the compounds of Formula II,
CH3
CH2OAC
2 - methyl - ‘6oz - ?uoro - 11,8, 16a,17ot,21 - tetrahydroxy
1,4 - pregnadiene - 3,20 - dione 21 - acetate (or other
21-acylates) ,
204,601. - dimethyl - 11B,16a,170z,21 - tetrahydroxy - 4
i‘
—CH—OH2~ and —R=CH—
nadiene-3,20-dione 2l-acetate (or other 21-acylates),
I
65
CHM OH
pregnene-3,20-dione 21-acetate (or other 21~acy1ates),
and
2,60; - dimethyl - 11,3,16oc,17a21 - tetrahydroxy - 1,4
pregnadiene-3,20-dione 21-acetate (or other 21-aeyl 70
ates), respectively.
The term “other 21-acylates” as used in the preceding
paragraph includes, for example, those 2l-acylates named
in the penultimate paragraph of Example 1.
75
7. The process of claim 6 in which the silver salt is
3,068,251
9
10
silver nitrate, and the inert organic solvent is acetonitrile.
8. The process of claim 7 in which the starting material
CH3
CHzOAO
is 20u-chloro-l15,21-dihydroxy-1,4,16-pregmatrien-3-one
H2OH
2l-acetate.
9. A process which comprises reacting the compounds 5
of Formula I,
HO /]
CH
X___
0%
10
I
Z
10. The process of claim 9 in which the silver salt is
15 silver ?uoride, the inert organic solvent is acetonitrile,
and the reaction with water takes place on a Florisil
(synthetic magnesium silicate) column.
11. The process of claim 10 in which the starting ma
terial is 20a-ch1oro-11,3,21-dihydroxy-L4,16-pregnatrien
20 3-one Zl-acetate.
12. 6a - methyl - 11,8,20,21 - trihydroxy - 1,4,16 - preg
natrien-B-one 21-acylate in which the acyl radical is that
of a hydrocarbon carboxylic acid containing from 1 to
12 carbon atoms, inclusive.
wherein X is selected ?rom the group consisting of
R
25
-— 61 H- 0 Hr
13. 6a - methyl - 1l?,205,21 - trihydroxy - 1,4,16-p-reg
natrien-3-one ZI-acetate.
14. 6a - methyl - 11/3,20a,21 - trihydroxy - 1,4,16-preg
natrien-3-one Zl-acetate.
and
15. 60c - ?uoro - 11;3,20‘,21 - trihydroxy - 1,4,16-preg
30 natrien-3-one 21-aeylate in which the acyl radical is that
of a hydrocarbon carboxylic acid containing from 1 to
12 carbon atoms, inclusive.
16. 6a - ?uoro - 11?,20/3,2l - tlrihydroxy - 1,4,16-preg
natrien-3-one 21-acetate.
R being attached at the 2-position and selected from the 35
group consisting of hydrogen and methyl, Y is selected
from the group consisting of chlorine and bromine, Z
is selected from the group consisting of hydrogen, ?uorine
and methyl, and Ac is an acyl ‘radical, with a silver salt
in the presence of an inert organic solvent under an 40
hydrous conditions and reacting the thus-obtained product
with water to obtain the compounds of Formula II, and
reacting the compounds of Formula 111 with osmium
17. 6a - fluoro - l1}3,2()a,21 - trihydroxy - 1,4,16-preg
natrien-S-one 2l~acetate.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,900,382
Sondheimer et a1 ______ .._ Aug. 18, 1959
OTHER REFERENCES
tetroxide, followed by alkaline ‘hydrolysis, to obtain the
Bernstein et al.: Journal of Organic Chemistry (1959),
compounds of Formula IV,
45 vol. 24, pages 871-872 relied on.
UNITED STATES PATENT ‘OFFICE
CERTIFICATE OF CORRECTION
Patent NO‘, 3,068,251
December 11, 19621
Barney J. Magerlein et 31.
It is hereby certified that error appears in the above numbered pat
ent requiring correction and that the said Letters Patent should read as
corrected below.
Column 9Y lines 42 to 45, strike out "and reacting the
compounds of Formula III with osmium tetroxide, followed by
alkaline hydrolysis, to obtain the compounds of Formula IV,";
column 10, lines 1 to 12, the formula should appear as shown
below instead of as in the patent:
Signed and sealed this 16th day of July l963q.
( SEAL)
Attest:
ERNEST W. SWIDER
DAVID L. LADD
Attesting Officer
Commissioner of Patents
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