close

Вход

Забыли?

вход по аккаунту

?

Патент USA US3047600

код для вставки
Uit
States
3,047,591
EQQ
Patented July 31, 1962
1
2
methylenepregn-4-ene-3,20-diones having the general
3 047,591
Formula I above, wherein R is a carboxylic acid residue
containing not more than 10 carbon atoms, which process
PREPARATION OF lion-ACYLOXY-?w-METHYL-lti
METHYLENEPREGN-4-ENE-3,20-DIONES
comprises oxidising a 3,8-hydroxy or 3?-acyloxy-6,16-di
Vladimir Petr-0w and David Morton Williamson, London,
England, assignors to The British Drug Houses
Limited
No Drawing. Filed Aug. 25, 1960, Ser. No. 51,801
Claims priority, application Great Britain Aug. 31, 195%
\
6 Claims.
methylpregna-S,l6-dien-20-one having the general formula
Me
OOCHa
/\
(Cl. 260-4974)
l0
This invention is for improvements in or relating to the
at
erence to the preparation of compounds originally be
lieved to be 17ot-acyloxy-6a,l6-dimethylpregn-4~ene~3,20
diones but now believed to be 17a-acyloxy-‘6u-methyl-16
[-Me
Me
preparation of organic compounds and has particular ref
15
R’O—
methy-lenepregn-4-ene-3,20'diones having the general For
Me
(11)
mula I below.
Our co-pending application No. 829,234 describes a
(wherein R’ is hydrogen or a carboxylic acid residue con
process for the preparation of a hydroxy dione originally
taining up to 10 carbon atoms) to the corresponding 16a,
believed to be rl7a-hydroxy~6u,16-dimethylpregn-4-ene-3, 20 17a-epoxide derivative having the general formula
20-dione but now believed to be 17a-hydroXy-6a-methyl-;
Me
16-metl1ylenepregn-4-ene-3,20-dione which process com
o 0 CH3
prises ‘oxidising 3/3-hydroXy-6,16-dimethylpregna-5,l6
I x 0i
dien-20—one by the Oppenauer procedure to give 6G,16‘ldi'
methylpregna-4,16-diene-3,20‘~dione, reacting the 6a,16
dimethylpregna-4,16-diene-3,20-dione with alkaline hy
drogen peroxide to give the corresponding 16,17-epoxide,
25
/\ qLMe
Me
treating the cpoxide with a hydrogen halide and submit
H
ting the resultant product to treatment with Raney nickel.
The resulting compound, ‘originally believed to be ‘17a 30
R'O
hydroxye6a,16-dimethylpregn-4-ene-3,ZO-dione but now
believed to be 17a-hydroxy-6u-methyl-l6-methylenepregn
Me
(III)
4-ene-3,20~dione, may be acylated to give a product origi
(Where R’ has the same meaning as above), acylating the
nally believed to be 17a-acyloXy-6a,16-dimethylpregn-4
I
ene-3,20-dione, but now believed to be l7a-acyloXy-6a
35 16u,17a-epoxide derivative in cases where R'=H, react
methyl-16-methylenepregn-4-ene-3,20-‘dione having the
ing the 160:,17oc-61J0Xid6 derivative with a hydrogen halide
formula
or with sulphuric or perchloric acid in dioXan, to form a
3/3-acyloxy-l7u-hydroXy-6-metl1yl - 16-methylenepregn-5
Me
en-20-one having the general formula
C 0 CH3
40
I-"OR
Me
_CH9
COCHa
/\ ""011
"'CH:
Me
I
Me
R70
(I)
Where R is a carboxylic acid residue containing up to 10
carbon atoms for reasons which have been ‘fully described 50
in our co-pending application No. 829,234. It is further
shown in our co-pending application No. 829,234 that
Me
(IV)
(wherein R’ is a carboxylic acid residue containing up to
10 carbon atoms), acylating the l7m-hydroxyl group to
l7a-acyloxya6a-methyl - 16 - methylenepregn-4-ene-3,20
diones (I; where R has the same meaning as above) rep
resent a novel family of progestational agents of excep
tional potency.
1'1
55
give a 3p,17a-diacyloxy~6-methyl-16-methylenepregn-5
en-ZO-one having the general formula
Me
It is an object of the present invention to provide a new
process for the preparation of the compounds originally
belived to be -17a-acyloXy-6a,l6-dimethylpregn-4-ene-3,
20-diones but now believed to be 17a-acyl0Xy-6oc-methy1
COOHa
60
16-methylenepregn-4-ene-3,20-diones having the general
formula I above where R is a carboxylic acid residue con
taining up to 10 carbons, which are of value on account of
H
their progestational properties.
According to the present invention there is provided a 65
process for the preparation of 17a-acyloxy-6a-methyl-16
(V)
3,047,591
A
oxide such as aluminium tert.-butoxide or iso-propoxide
3
(wherein R’ is a carboxylic acid residue containing up to
10 carbon atoms and R has the same meaning as above)
in suitable proportions.
Following is a description by way of example of meth
ods of carrying the invention into eifect.
preferentially hydrolysing the 3?-acyloxy group to give an
acyloxy-hydroxyketone having the general formula
Example 1
Me
3B-ACE~TOXY>6,1G-DIMETHYL-l?a,17a-EPOXYPREGN-5
OOCH;
L-"OR
Me '
EN-20-ONE (III; R':AC)
Ai Ton,
3?-acetoxy - 6,16 - dimethylpregn-5,16-dien-20-one (6.3
g.) dissolved in boiling ethanol (50 ml.) under re?ux, was
treated with 40% aqueous sodium hydroxide solution
(3 ml.) followed by 30% hydrogen peroxide (8.5 ml.)
and the mixture boiled for 30 minutes. The reaction
mixture was cooled and the crystalline product collected,
HO
(VI,
dried and acetylated with acetic anhydride/pyridine at
100° C. for 1 hour, and puri?ed from methanol to give
(wherein R has the same meaning as above) and oxidising
the 3,8-hydroxyl group of the acyloxyhydroxy ketone with
isomerisation of the 5,6-double bond to the conjugate 4,5
one, needles, M.P. 118 to 120° C. [(111323 —49° (c., 0.654
in chloroform).
5H,
position.
3 ,8—aceltoxy - 6,16 - dirnethyl-16a,17a-epoxypregn-5-en-20
20
In carrying out the process according to the present in
vention, it is preferable to employ 3B-acetoxy-6,16-di
methylpregna-S,16-dien-20-one (II; R’=Ac) as starting
3?-ACETOXY-17a-HYDROXY-G-METHYL-lG-METHYLENE
PREGN-5-EN-20-ONE (IV; R'zAc)
3?~acetoxy - 6,16 - dimethyl-16a,17a-epoxypregn-5-en
20-one (8 g.) dissolved in dioxan (200 ml.), cooled in
material, the preparation of which has been described
an ice/water bath, was treated with a 50% solution of
in our co-pending application No. 824,961, now Patent No.
3,028,381. Oxidation of this material to the 16a, 17a
hydrogen bromide in acetic acid (4 ml.) for 15 minutes.
epoxide (III; R’=Ac) may be effected by treating com
pound II wherein R"=Ac, with tenL-butyl hydroperoxide
in alkaline solution or preferably with hydrogen peroxide
The dioxan was diluted with water and the product iso
lated with ether. The residue, after evaporation of the
ether, was ‘dissolved in acetone (200 ml.) and stirred
vigorously with Raney nickel (20 g.) at room tempera
in an alcoholic solution made alkaline with a hydroxide
such as sodium or potassium hydroxide. The reaction
ture, for 4 hours. The Raney nickel was ?ltered off and
washed well with methylene chloride. The ?ltrate was
proceeds readily at 0° C., but may be accelerated by
using temperatures up to the boiling point of the alcohol
used as solvent. Complete saponi?cation of the 3|8-ace~
hexane to give 313 - acetoxy - 17a - hydroxy-6-methyl-16
toxy group occurs during this reaction and the product
[@1324 —161° (c., 0.306 in chloroform).
is acetylated \to give 3?-acetoxy-16u,17a-epoxy-6,l6-di
methyl-pregn-S-en-ZO-one (III; R’=Ac).
evaporated to dryness and the residue crystallised from
methylenepregn-5-ene-20-one needles M.P. 126 to 128° C.,
In an alternative method 3,8-acetoxy-6,16-dimethyl
The epoxy derivative (III; R’=Ac) so obtained is then
16a,l7a-epoxypregn-5-en-20-one (5 g.) dissolved in dioxan
(200 ml.) containing concentrated sulphuric acid (0.5 ml.)
treated in a solvent such as dioxan, acetic acid or benzene,
was left overnight at room temperature (20° C.). The
with a hydrogen halide which is preferably hydrogen bro
reaction mixture was poured into water and the precipi
tated solids were collected by ?ltration and washed with
water and dried. Crystallisation of the solid from hexane
mide at a temperature at or below 25° C. and preferably
within the range 0° C. to 10° C. The product so ob
tained may contain residual halogen which may be re
moved, if desired, by treatment with Raney nickel in an
organic solvent such as ethanol or acetone at or about
room temperature to give 3 B - acetoxy - 17a - hydroxy-6
methyl-l6-methylenepregn-5-en-20-one (IV; R’=Ac).
Alternatively, the epoxy derivative (III; R’=Ac) may
be treated with sulphuric acid or perchloric \acid in a
solvent such as dioxan, preferably at or about room tem
perature to give the 16-methylene compound (IV; R’=Ac)
directly. Acylation of the tertiary 17u-hydroxyl group
present in the latter compound may be achieved by
methods well-known to those skilled in the art.
Such
methods include, for example, treatment of the compound
with an acid anhydride, such as acetic anhydride, or acid
chloride and a catalytic quantity of toluene-p-sulphonic
acid at a temperature of about 20° C. for 8 hour. Acylat
gave 3,8 - acetoxy-l7a-hydroxy - 6 - methyl-16-methylene
pregn-5-en-20-one, M.P. 126 to 128° C.
36,17a-DIACE'I‘OXY-6-METHYL-lG-METHYLENEPREGN
5<EN—20-ONE (V; RzR’zAc)
318 - acetoxy-17a-hydroxy-6-methyl-l6-methylenepregn
5-en-20-one (IV; R’=Ac) (l g.) and toluene-p-sulphonic
50 acid monohydrate (150 mg.) were suspended in acetic
anhydride (35 ml.) and left at room temperature over
night. The clear solution was poured into water, and the
product isolated with ether. The residue from the ether
extracts crystallised from hexane in plates to give 318,170:
diacetoxy-G-methyl-16-methylenepregn-5-en-one, M.P. 166
to 168° C., [@1325 —l78° (c., 0.882 in chloroform).
17a-ACETOXY-3e-HYDROXY-G-METHYIAGMETHYLENE
PREGN-5-EN»20‘-ONE (VI; RzAc)
The foregoing diacetoxyketone (V; R=R'=Ac) (1 g.)
ing agents that can be employed include the anhydrides
and chlorides derived from the following acids, acetic, 60 was heated under re?ux in methanol (100 ml.) contain
ing concentrated hydrochloric acid (1 ml.) for 1 hour.
pnopionic, butyric, valeric, caproic, oenanthic, cyclopentyl
The mixture was poured into water, and the precipitate
propionic, cyclohexanecarboxylic, benzoic, hexahydro
collected and crystallised from aqueous methanol to give
benzoic, toluic, B-phenylpropionic, nicotinic, furoic and
thiophene 1carboxylic. Partial hydrolysis of the resulting
3,8-acyloxy - 17a - acyloxy-6-methyl-16-methylenepregn-5
en-20-one (V; R’=Ac, Rzacyl) may be best effected
with hot ethanolic or methanolic hydrochloric acid, when
17a-acyloxy-3?-hydroxy-6-methyl - 16 - rnethylenepregn-S
en-20-one (VI; R-=acyl) is obtained. Conversion of this
latter compound into the required 17a-acyloxy-6a-rnethyl
16-methylenepregn - 4 - ene-3,20-dione (I; R=acyl) may
17a - acetoxy - 3B - hydroxy - 6 - methyl - 16 - methylene
pregn-5-en-20-one, needles, M.P. 163 to 165° C., [@1325
~175° (c., 0.334 in chloroform).
17a-ACETOXY-Ga-METHYL-lG-METHYLENEPREGN-‘i‘
ENE-3,20-DIONE (I; RzAc)
The foregoing acetoxyhydroxyketone (VI; R=Ac) (1
g). in cyclohexanone (24 ml.) was heated under re?ux
with aluminium tert.-butoxide (1 g.) in dry toluene (16
ml.) for 1 hour. Rochelle salt solution was added to
conveniently be achieved by an oxidation of the Oppenauer
the mixture which was then steam distilled for 6 hours.
type, employing for example, toluene as solvent, cyclo
hexanone as hydrogen acceptor and an aluminium alk 75 The product was isolated with ether, and the residue from
3,047,591
5
6
the ether extracts was crystallised from aqueous methanol
to 10 carbon atoms) with alkaline hydrogen peroxide to
to give 17a-acetoXy-6a-methyl-16-methylenepregn-4-ene
3,20-di0ne (I; R=Ac), needles, M.P. 206 to 208° C.,
[@1322 —99° (c., 0.214 in chloroform),
form the corresponding 16a,17a-epoxide
Me
0 0 CH:
0
A523,“ 240 mp, log 6 4.19
I i
ENEPREGN-5-EN-20-ONE (V; R:CO.CeH5; R'=Ac)
l
'—Me
/\
Example 2
3l3-ACETOXY-l7a-CAPROYLOXY-6-METHYL-1G-METHYL
Me
10
/,
H
33 - acetoxy - 17a - hydroxy - 6 - methyl - 16 - methyl
enepregn-S-en-ZO-one (IV; R'=Ac) (l g.) and toluene
R'o'
p-sulphonic anhydride monohydrate (150 mg.) were sus
pended in caproic anhydride (30 ml.) and the mixture
left at room temperature for 4 days. Pyridine (10 ml.) 15
Me
(III)
(where R’ has the same meaning as above), acylating
the l6u,l7a-epoxide derivative in cases where R'=H by
reaction with an acylating agent providing a residue of
a hydrocarbon carboxylic acid containing up to 10 car
was then added and the mixture steam-distilled until no
more organic matter was present in the distillate, when
the product was extracted from the residual liquor with
ether, and was obtained as a gum after removal of the
ether.
20 bon atoms, reacting the 16a,17u-epoxide derivative with
an acid selected from the group consisting of a hydrogen
halide, sulphuric and perchloric acid to form a 3?-acyl
17a-CAPROYLOXY-3?-HYDROXY-G-METHYL-ISFMETHYL
ENEPREGN-5-EN-20-ONE- (VI; R: CO.C5H11)
oxy - 17a - hydroxy - 6 - methyl - 16 - methylenepregn
The foregoing crude product was heated under re?ux
with methanol (100 ml.) and concentrated hydrochloric 25
acid (1 ml.) for 1 hour, poured into water and the prod
uct isolated with ether.
17a-CAPROYLOXY-6a-METHYL-lB-METHYLENEPREGN
4-ENE-3,20-DIONE (I; R=CO.CsH11)
5-en-20-one having the general formula
Me
O 0 CH3
30
The foregoing crude product in cyclohexanone (20
ml.) and dry toluene (20 ml.) was heated under re?ux
with aluminium tert.-butoxide (l g.) for 1 hour, then
Rochelle salt (20 g.) was added and the mixture steam
distilled for 6 hours. The product, isolated with ether
Me
was a gum which after chromatography on alumina (30
g.) alforded 17a - caproyloxy - 6a - methyl - 16 - methyl
enepregn-4-ene-3,20-dione as a low-melting solid.
We claim:
1. A process for the preparation of 17a-acyloxy-6a
(IV)
(wherein R’ is a carboxylic acid residue containing up to
10 carbon atoms), acylating the l7a-hydroxyl group by
reaction with an acylating agent providing a residue of a
40 hydrocarbon carboxylic acid containing up to 10 carbon
atoms to give a 3J8,17a-diacyloxy-6-methyl-16-methylene
pregn-S-en-ZO-one having ‘the general formula
methyl - 16 ~ methylenepregn - 4 - ene - 3,20 - diones
having the general formula
Me
COCH:
Me
0 0 CH:
/\ LHOR
45
CH;
/\ i’ R
OH;
Me
Me
I
50
H
0:
Me
5
Me
(I)
wherein R is a carboxylic acid residue containing up to
10 carbon atoms, which process comprises oxidising a
steroid selected from the group consisting of a 3p-hydroxy
Me
O 0 CH3
60
/\ ' Ln]: 2H2
Me
i) 0 CH3
Me
/\/\ Me
Me
(V)
preferentially hydrolysing the 3,8-acyloxy group to give
an acyloxyhydroxyketone having the general formula
and 3p - acyloxy - 6,16 - dimethylpregna - 5,16 - dien - 20
one having the general formula
.
(wherein R’ is a carboxylic acid residue containing up to
55
10 carbon atoms and R has the same meaning as above)
‘J
I_
I a
65
HO
1%
CH3
(VI)
70 (wherein R has the same meaning as above) and sub
R’0——
jecting said acyloxyhydroxyketone to Oppenauer oxida
Me
(11)
tion to oxidise the 3?-hydroxyl group with isomerisation
of the 5,6-double bond to the conjugate 4,5 position there
(wherein R’ is a group selected from the class consisting
by providing a compound having the Formula I above.
of hydrogen and a carboxylic acid residue containing up 75 2. A process as claimed in claim 1 wherein B?-acetoxy
3,047,591
8
6,l6-dimethylpregna-5,l6-dien-20-one is oxidised with hy
drogen peroxide in alkaline alcoholic solution.
3. A process as claimed in claim 1 wherein said 16oz,
l7a-epoxide derivative is treated in a solvent with hydro
gen bromide.
4. A process as claimed in claim 1 wherein the prefer
ential hydrolysis of the 3,8-acyloxy group is effected with
hot methanolic hydrochloric acid.
5. A process as claimed in claim 1 wherein oxidation
6. A process as claimed in claim 5 wherein said hydro
gen acceptor is cyclohexanone.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,876,237
2,892,851
2,954,386
Julian et al. __________ __ Mar. 3, 1959
Bergstrom et al. ______ __ June 30, 1959
Beyler ______________ __ Sept. 27, 1960
OTHER REFERENCES
of the 3p-hydroxyl group of said acyloxydioxydione is 10
Fieser
and
Fieser:
Steroids (Reinhold, N.Y.), June 25,
e?ected by the use of an aluminium alkoxide in toluene
in the presence of a hydrogen acceptor.
1959, page 570.
Документ
Категория
Без категории
Просмотров
0
Размер файла
410 Кб
Теги
1/--страниц
Пожаловаться на содержимое документа