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Патент USA US3023215

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3,023,206
71cc
a United States Patent.
Patented Feb-27, 19s;
1,
2
nitrobenzene, acetic ‘acid or propyl acetate. The dehy
. 3,023,205
' drogenationreaction is preferably carried out at an ele
PROCESS FOR INTRODUCING A1 UNSATURATION
-
INTO STEROIDS
'
vated temperature and conveniently between 80° C. and
-
Derek Burn, David Neville Kirk, Vladimir Petrow, and
110° C. Theoretically the reaction is best performed in
George Oliver Weston, all of London, England, as
signors to The British Drug Houses Limited, London,
an inert atmosphere such asfor example nitrogen, but
this precaution has little practical signi?cance in the
England, a British company
.
majority of cases herein. The rate of reaction may be
increased by the addition of a catalytic amount of av
No Drawing. Filed Mar. 11, 1-959, Ser. No. 798,609
Claims priority, application Great Britain Mar. 13, 1958
proton donor, and in particular by the addition of a cata
(Cl. 260-—239.55)
10 lytic amount of p-nitrophenol. Completion of the re
improvements in or relating to
action is generally indicated by the discharge of the colourv
has particular reference to the
of the quinone and/ or by the fact that further quantities
certain unsaturated steroidal 3
of 2:3-dicyano-5 :6-dichloro-1 :4 - dihydroxy - benzene arev
no longer deposited from the hot reaction liquors. AL.
Steroids possessing the B-oXo-AM- and 3-oxo-A1’4‘6 15 ternatively, completion of the reaction may be determined
systems are of particular value on account of their bio
by estimating the quantity of the quinone present in the
logical properties which are often considerably enhanced
reaction liquors by standard methods well known to those
in relation to those of the corresponding. 3-oxo-A4?
skilled in the art.
‘
>
and 3-oxo-M‘6- analogues.
The l-de‘nydro steroid derivative is isolated from the
Such l-dehydro steroids have been previously prepared 20 reaction liquor by any convenient procedure. Thus the
by one of the following procedures.
reaction liquors may be ?ltered to remove the sparingly
The corresponding 3-oxo-A4-steroid may be oxidised
soluble hydroquinone, extracted with aqueous alkali to
remove phenolic products, evaporated to dryness, under
with selenium dioxide, or it may be converted into a halo—
genated derivative which is then dehydrohalogenated to
reduced pressure if desired, and the residual solids crystal
yield the required l-dehydro analogue. These processes 25 lised in the usual way. Other methods will be apparent,
12 Ciaims.
This invention is for
organic compounds and
l-dehydro derivatives of
ketones.
.
-
'
are in general unsatisfactory due to the dif?culty' in car~
to those skilled in the art.
rying out the reactions and the low yields obtainable.
In addition, l-dehydro steroids may also be prepared by
microbiological dehydrogenation of a suitable precursor,
and may, in general, be applied to 3-oxo-A4 and 3-oxo—
A4’6- derivatives of androstane, pregnane, stigmastane,
The process of the invention is of wide applicability
which process is however expensive to carry out and re-, 30 cholestane and, spirostane containing additional substitu
quires specialised equipment and techniques.
ents which do not interfere with the process of the in~
vention as hereinunder indicated.
Oxo groups, and in particular oxo groups in positions
' We have now ‘found that 3-ox0-A4- and 3-oxo-A4’6
steroids may be converted in excellent yields into the
corresponding l-dehydro analogues by a simple, one-stage
chemical process.
'
'
-
35
C—11, 17 and 20 (including 20-oxo-16-ene).
Hydroxy, alkoxy and acyloxy groups, and in particular
It is also an object of the invention to provide ‘certain 7
new l-dehydro steroids which are of value on account
of their biological: properties or as intermediates in the
hydroxy, alkoxy and acyloxy groups in positions C-6, 11,
preparation of compounds having useful biological prop-e
tion C-9,
167 17, 20 and 21.
.
up to '5 carbon atoms in positions C42, 4, l6 and 17.
process for the preparation of 3-oxo-1‘4- and 3-oxo-‘A1=4’§- ' . .
'
vVinyl ‘groups and in particular vinyl groups at position
C-17.
Me 'v
'
Alkyl vgroups, and in particular alkyl groups containing
cities as is apparent to those skilled in the art.
According to the present invention there is provided a
steroids having the formula’
'
Fluoro groups, and in particular ?uoro groups in_posi->
'
” Ethynyl and substituted ethynyl groups containing up to
45 4 carbon atoms, and in particular such groups at position
C-l7.
'
The invention also provides the ‘following new l-de
hydro steroid derivatives which are of value in steroid
H
technology in the preparation of aromatic steroidal struc
tures possessing useful biological properties or as inter
O:
(I)
(with or without a double bond at‘ the 6:7 position)
mediates in the preparation of l-dehydro steroidal deri
' vatives possessing useful biological properties.
. Thus the 1:4:6 trienes can be converted into aromatic
which process comprises treating the corresponding 3
steroids by reaction insolution in acetic anhydride with
oxo-A‘i- or 3-oxo-A4=6-steroids having the formula
55 toluene pv-sulphonic acid. While 9a-?uoro-1 l?zl7B-di
hydroxy-17a-methylandrosta-1:4-dien-3-one is the l-de
Me
hydro analogue of a known anabolic and androgenic
' agent and itself has those properties. I
.
-
60 17a-ethynyl-17/3-hydroxyandrosta-l :4: 6-trien-3 -one
17,8-hydroxy-l 7e-methylandrosta-1 :4: 6~trien-3-one
Pregna-l :4: 6-triene-3 :20-di0ne
.
l le-hydroxyprcgna-l :4-diene-3 : 20-dione
1
(II)
Pregna-l :4-diene-3 : 11 :20-trione
(with or without a double‘bond at. the 6:7 position) with 65 Pregna-l :4: 6-triene-3 :11 : 20-trion'e ’
2: 3-dicyano-l :4-benzoquinone, which may ‘be additionally
Pr‘egna-l :4: 16-triene-3 :20-dione
substituted with one or two chlorine atoms, in a solvent.
Preferably 2:3 - dicyano - 5:6 ~' dichloro ~. 1:4 -.benzo
quinone is employed. (See J.C.S., 1954, 3569, for the
loot-methyl pregna-l :4-diene+3 :ZO-dione
" 9a - ?uoro - 11,8 - 17?-dihydroxy-l7a-methylandrosta-1:4
dien-3-one
'
preparation of these two quinones.)
Ethyl, 3-oxopregna-1 :4: 17 (20 ) -trien-2 l~oate
The solvent may be benzene, dioxan, dimethylene gly 70 20:20-ethylenedioxypregna-1 z4~dien~3~one
col dimethyl ether, chlorobenzene, dimethylformamide,
1 Cholesta-l :44-diene-3 : G-dione
I
e ;
3,023,206
3
The product was isolated as in Example 1 and crystallised
from acetone/hexane to give 17[3~propionoxyandrosta
1:4-dien-3-one as laths, M.P. 144 to 146° C., [a]D2°+33°
A’cetonid‘e of 16a! 17a - dihydroxypregna-l :4-diene-3 :20
dione
~
4
.
.
175-acetoxy-Z-methylandrosta-1 :4-dien-3-one
(c. 0.65 in chloroform), Am“ 244 mp, log 15 4.20.
EXAMPLE 7
1 7l8-Hydroxyana'rosta-l : 4-Die‘n-3-one
Pregna-l :4: 9 ( 1 1 ) -triene-3 : 20-dione
~Following is a description by way of example of
methods of carrying the invention into e?ect.
EXAMPLE 1
17a-Hydr0xypregn-1 :4-Diene-3z20-Di0ne
A solution of testosterone (0.25 g.) and 2:3-dycyano
5:6-dichlorobenzoquinone. (0.25 g.) in dry benzene (5
10 ml.) was heated under re?ux for 15 hours. The product
A solution of17e-hydroxyprogesterone (0.25 g.), 2:3
was isolated as in Example 1 and crystallised from aque
’dicyano-S:6-dichlorobenzoquinone (0.25 g.) and p-nitro
ous methanol to give 17B-hydroxyandrosta-1:4-dien-3#one
as needles, M.P. 167 to 169° C., [a]D21-+22° (c. 0.72 in
phenol (0.05 g.) in dry benzene (5 ml.) was heated under
re?ux for 6 hours, by which time the colour due to the
chloroform), Am“ 244.5. my, log 6 4.18.
quinone was completely discharged. The solution was 15
diluted with, ether and the precipiated hydroquinone was
EXAMPLE 8
removed by ?ltration. The ?ltrate was washed-with 2N
17?-Hydr0xy-17aL1'v1'ethylandr0sta-1 :4-Dien-3-0ne
sodium hydroxide, water, dried over sodium sulphate and
'A solution of 17B-hydroxy-17a¢methylandrost-4-en-3
stirred. with charcoal. Evaporation of the ?ltered extract
under reduced pressure left a crystalline‘ residue which 20 one (0.25 g.), 2:3 - dicyanO-S':6-dichlorobenzoquinone
(0.25 g.) and p-nitrophenol (0.05 g.) in dry benzene (5
on' recrystallisation from chloroform/ethanol gave 170:
ml.) was heated under re?ux for 4 hours. The product
was isolated as in‘ Example 1 and crystallised from aque
ous acetone to give 17&hydroxy-17a-methyl-androsta
hydroxypregn-l:4-diene-3z20-dione as plates, M.P. 230 to
232° C., [oc]D22+36° (c. 0.57 in chloroform), kmx, 244
mu, log 6 4.12.
EXAMPLE 2
25
2l-Acetoxypregn-1 :4-Diene-3:20-Dione
A solution of 21-ace'toxypregn-4-ene-3:20-dione (0.25
1:4-dien-3-one as needles‘, M.P. 162 to 164° C., [a]D2°-{-3.°
(c. 0.65 in“ chloroform), 1mm 244.5 III/1., log 6 4.19.
EXAMPLE 9
g.), 2:3-dicyano-5:G-dichlorobenzoquinone (0.25 g.) and
p-nitrophenol (0.05 g.) in dry benzene (5 ml.) was heated 30
under re?ux for 5-1/2 hours. The product was isolated as
described in Example 1 and crystallised from aqueous
methanol to give 21-acetoxypregn-1:4-diene-3z20-dione
as needles, M.P.‘204 to 207° C., [a]D2°‘+137° (c. 0.82
in choloroform), xmx, 244 mmlog e 4.20‘.
EXAMPLE 3
Androsl-1'24-Diene-3:ZO-Dione
A solution of androst-4-ene-3z17-dione (0.25 g.), 2:3
dicyano-S:6-dichlorobenzoquinone (0.25 g.) and p-nitro
phenol (0.05 g.) in dry benzene (5 ml.) was heated un
der re?ux for 5 hours. The product was isolated as in
Example 1 and crystallised from aqueous acetone to give
35 androsta-l:4-diene-3z20-dione as needles, M.P. 137 to
139° C., [a]D19+117° (c. 0.42 in chloroform), hum,
244.5 mp, log .6 4.22.
Pregn-l :‘4-Diene-3 :20-Di0ne
.
A solution of progesterone (0.2 g.), 2:3-dicyano-5z6
dichlorobenzoquinone (0.2 g.) and, p-nitrophenol (0.02
40
-
EXAMPLE 10
Cholest-I :4-Dien-3-0ne
g.) in dry benzene. (5 ml.) was heated under re?ux for
A solution of cholest-4-en-3-one (0.5 g.), 2:3-di'cyano
9 hours. The product was isolated as in Example 1 and.
5:6-dichlorobenzoquinone- (0.5 g.) and p-nit'rophenol (0.1
crystallised from ether/hexane to give pregn-lz4-diene
g.) in dry benzene (10 ml.) was heated under re?ux for
3:20-dione, as prisms, M.P. 151 to 153° C., [a]D21+125°
28 hours. The product was isolated-as in Example 1
(.c. 0.6 in chloroform), Am”; 244.5 mp, log 6 4.21.
45 and‘ crystallised from ethanol to give cholesta-1z4-dien-3
one as prisms, M.P. 111 to 113° C., [a]D2°+27° (c. 0.65
EXAMPLE 4
in chloroform), km“ 244 my, log e 4.20.
' 21~Acet0xy-1 7a-Hydroxypregn-1 :4-Diene-3:1 1 :20
‘
Trione
A solution of cortisone acetate (0.15 g.), 2:3-dicyano 50
EXAMPLE 11
Cholesz‘a-I :4 :6-Trien-3-0ne
5,:6-dichlorobenzoquinone (0.15 g.) and p-nitrophenol
A solution of chol'estae4z6edien-3-one (0.5 g.) (Wilds
(0.04 g.) in dry benzene (40 ml.) was heated under re
and Djerassi, J.A.C.S., 1946, 68, 1712), 2:3-dicyano-5z6
dichlorobenzoquinone (0.5? g.) and p'-nitrophenol (0.1 g.)
?ux for 37 hours. The product was isolated as in Exam
ple 1 and crystallised from acetone/hexane to give'21
acetoxy - 17oz - hydroxypregn-l:4-diener3:11:20etrione
as 55
prisms, M.P. 227 to 230° C., [chm-+182” (c. 0.4 in
dioxan), )Ynjax 238 mp, log e 4.19.
r
crystallised from ethanol to give cholesta-lz4z6-trieu-3
'
one as prisms, M.P. 83 to 84° C., [a]D2°+1° (c. 0.42
in chloroform), Am,“ 224 my‘ (log 2 4.06), 256 my. (log '
e 4.01) and 300 my (log a 4.07).
EXAMPLE 5'
25D-Spirosta-1- :4-Dien-3-0ne‘
A solution of diosgenone (0.25" g.) (Marker, Tsuka
moto and Turner, J.A.C.S., 1940, 62, 2525), 2:3-dicyano
in dry benzene (10 ml.) was. heated under re?ux for 7
hours. The product was isolated as in Example 1 and
60
EXAMPLE 12
.
1 1 “"Hydroxy pregna-I :4 -Diene-3 : 20-Di0ne
5:6-dichlorobenzoquinone (0.25 g.) and p-nitrophenol
A solution of 1la-hydro'xypregn-4-ene-3:20-dione
(0.05 g.) in dry benzene (5 ml.) was heated under re?ux
(1 g.), 2:3-dicyano-5:?-dichlorobenzoquinone (1 g.) and
65
for 15 hours. The product was isolated as in Example 1
p-nitrophenol (0.1 g.) in dry benzene (20 ml.) was
and crystallised from aqueous methanol to give25D
heated under re?ux for 6 hours. The product was iso
spirosta-1:4-dien-3-one as needles, M.P. 192 to 194° C.,
lated as in Example 11 and: crystallised from aqueous‘
[ADM-71° (c. 0.64 in chloroform), Amm 244.5-mn,.log;
e 4.18.
EXAMPLE 6
70
1713-Pr0pi0n0xyandr0sta-1 :4-Dien-3-o‘ne
A solution of testosterone propionate (0.5 g.) and 2:3
dicyauo-S:é-dichlorobenzoquinone (0.4 g.), in dry hen.
zene (5 ml.) was heated under re?ux for 5% hours‘. 75
rnethanol to give. 1 1 a-hydroxypregua-l :4-diene-3 : ZO-dioue
as needles, M.P.’ 223' to 225° C., [cc']D18+1'00.3° (c. 0.68
in‘ . chloroform) . an“, 247" mp,‘ log e - 4.25 .
EXAMPLE 13
Pregna-I :4-Diene-3z11 :ZO-Trione
A; solution'of pregn'-4-ene-3";l‘l‘zz?-trione (1‘ g.), 2:3“
3,023,206
5
6
dicyano-S:6-dichlorobenzoquinone (1 g.) and p-nitro
EXAMPLE 19
phenol (0.1 g.) in dry benzene (20 ml.) was heated under
115 :1 7az21-Trihydrqxypregna-1 :4-D‘iene-3 : 20-Di0ne
re?ux for 7 hours. The product was isolated as in Ex
ample 1 and crystallised from aqueous methanol to give
A solution of 1113:l7a:21-trihydroxypregn-4-ene-3:20~
pregna-1:4-diene-3:11:20-trione as needles, M.P. 167 to
dione (0.5 g.) and 2:3-dicyano-5:6-dich1orobenzoquinone .
169° C., [u]D19+249° (c. 0.9 in chloroform), Am,“
(0.5 g.) in puri?ed dioxan (6 ml.) was heated under ire
238.5 mp, log 5 4.12, 11mm 1702, 1661, 1620, 1602 cmr'l.
flux for 5 hours. The product ‘was isolated as in Ex
ample 1 and crystallised from acetone/hexane to give
EXAMPLE 14
11,8:l7az2l-trihydroxypregna-l:4-diene-3:20-dione as a
10 micro-crystalline powder,~ M.P. 236 to 240° C.,
1 7|3-Hydr0xyandrosta-1 : 4 : 6-Trien-3-ané
A solution of
[a]D2°-l-100° (c. 0.22 in dioxan), Am“. 244 my, log
l7?-hydroxyandrosta-4:6-dien-3-one
e 4.15.
(0.53 g.) (Inho?’en and Zuehlsdorlf, Ber., 1943, 76, 233'),
2:3-dicyano-5:6-dichlorobenzoquinone (0.5 g.) and p
I
EXAMPLE 20
nitrophenol (0.05 g.) in dry benzene (10 ml.) was heated 15
17e-Ethynyl-17p-Hydroxyandrosta-1 : 4-Dien-3wne
under re?ux for 71/2 hours. The product was isolated as
A solution of ‘17a-ethynyl-17}8-hydroxyandrost~4-en-34
in Example 1 and crystallised from aqueous acetone to
one (0.5 g.), 2:3-dicyano-5:6-dichlorobenzoquinone
(0.5 g.) and p-nitrophenol (0.05 g.) in puri?ed dioxan
give 17,8-hydroxyandrosta-l:4z6-trien-3-one as needles,
(10 ml.) was heated under re?ux for 121/2 hours. The
M.P. 155 to 156° C., [a]D2°+l6.5° (c. 0.32 in chloro
form, Am“ 224 my. (log e 4.15), 257 mp. (log e 4.17) 20 product was visolated as in Example 1 and crystallised
from chloroform/ethanol to give 17a-ethynyl-17?-hy
and 298 mp (log 54.16).
»
droxyandrosta-l:4-dien-3-one as prisms, M.P. 225 to
EXAMPLE 15
228° C., [a]D22——13° (c. 0.7 in chloroform), Am“ 244
mu, 10g e‘ 4.2.
25D-Spir0sta-I :4 : 6-Trien-3-orze
EXAMPLE 21
25
A solution of,25D-spirosta-4:6-dien-3-one (0.56 g.)
(Marker and Turner, J.A.C.S., 1941, 63, 767) and 2:3
dicyano~5:6-dichlorobenzoquinone (0.55 g.) in dry ben
A solution of progesterone (0.25 g.), 2:3-dicyano
1:4:6-trien-3-one'as needles, M.P. 209 to 211° C.,
[oz]D21—-101° (c. 0.29 in chloroform), Am“ 223 my
crystallised from ether/hexane to give pregna-1:4-diene
3:20-dione as prisms, M.P. 150 to 152° C., [a]D21+l26°
Pregna-I : 4-Diene-3 :ZO-Dione Y
benzoquinone (0.25 g.) and p-nitrophenol (0.05 g.) in
zene (10 ml.) was heated under re?ux for 10 hours.
The product was isolated as in Example 1 and crystallised 30 dry benzene (5 ml.) was heated under re?ux for 11
hours. The product was isolated as in Example 1 and
from dichloromethane/methanol to give ZSD-spirosta
(c. 0.45 in chloroform), Am“ 244 my, log e 4.21.
(log 5 4.10), 255 my (log 6 4.07) and 299 mu (log 6 4.13).
35
EXAMPLE l6
Pregna-I :4 :6-Triene-3 :ZO-Dione
EXAMPLE 22
16a-Methylpregna-1 :4-Diene-3 :20-Di0ne
A solution of l6a-methylpregn-4-ene-3z20edione (0.5
‘A solution of pregna-4:6-diene-3z20-di0r1e (1.5 g.)
(Wettstein, Helv. Chim. Acta, 1940, 23, 388), 2:3-di 40 g.) (Marker and Crooks, J. Amer. Chem. Soc., 1942, 64,
1280), 2:3-dicyano - 5:6 - dichlorobenzoquinone (0.5 g.)
cyano-5:6-dichlorobenzoquinone ( 1.5 g.) and p-nitro
and p-nitrophenol (0.05 g.) in dry benzene (10 ml.) was
phenol (0.15 g.) in dry benzene (30 ml.) was heated
under re?ux for 71/: hours. The product was isolated
as in Example 1 and crystallised from aqeous methanol
to give pregna-l:426-triene-3z20-dione as prisms, M.P.
150 to 152° C., {a]D1"+l25.l° (c. 1.0 in chloroform),
heated under re?ux for 91/2 hours. The product was
isolated as in Example 1 and crystallised from ether/
petroleum ether (BR 60 to 80° C.) to give l6a-rnethyl
45. pregna-l:4-diene-3:20-dione
as bIadesLMLP. 129 to 133°
C., [oz]D23+l20.8° (c. 0.18 in chloroform), Am“ 244
Am“ 222.5 my (log 6 4.06), 255.5 mp. (log e 3.98) and
299.5 mp. (log e 4.10).
mp, log e 4.24.
,
EXAMPLE 23
EXAMPLE 17
50
. Pregna-I :4: 16-Triene-3 :ZO-Diorze
17p-Hydr0xy-1 7a-Methylandrosta-1 : 4 : 6-Trien-3-0ne
A solution of pregna - 4:16 - diene-3z20-dione (1 g.)
A solution of 17B-hydroxy-17a-methylandrosta-4:6
(Butenandl and Schmidt-Theme, Ber., 1939, 72, 182),
2:3-dicyano-5:6-dichlorobenzoquinone (1 g.) and p-nitro
dien-3-one (1 ~ g.) and 2:3-dicyano-5:6-dichlorobenzo
quinone (l g.) in dry benzene (20 ml.) was heated under
phenol (0.1 g.) in dry benzene (20 ml.) was heated
re?ux for 12 hours. The product was isolated as in Ex
ample 1 and crystallised from aqueous methanol to give
under re?ux for 111/2 hours._ The product was isolated
as in Example 1 and crystallised from dichlormethane/
17/3-hydroxy - 17cc - methylandrosta - 1:4:6 - trien-3-one
methanol to give ‘pregna-1:4: l6"-triene - 3:20 - dione as
as laths, M.P.’ 139 to 140° C., [a]D22—-19.l5° ,(c. 1.0‘
plates, M.P. 208 to 211° C., [a]D21-|~120° (c. 0.46 in
chloroform), Am“ 223 mp (log 5 4.05), 256.5 my. (log. 60 chloroform), Am“ 240 mp, log e 4.31.
6 3.96) and 299 my (log t! 4.11).
EXAMPLE 24
.17m7Ethynyl-17B-Hydroxyandr0sta-1 :4 : 6-Trien-3one
‘EXAMPLE 18
Pregna-I :4 :6-Triene-3 : 1 1 :20-Tri0ne
A solution of 17a-ethynyl-l7p-hydroxyandrosta-4;6
A solution of pregna-4:6-diene-3:11:20-trione (1 g.) 65 dien-3-one (1 g.) (prepared by treatment of 17a-ethynyl
(prepared from pregn-4-ene-3,11,20-trione by reaction
17,8-hydroxyandrost-4-en-3-one with chloranil in the
with chloranil in the manner well-known to the art) and
manner well-known to those skilled in the art) and 2:3
2:3-dicyano-5:6-dichlorobenzoquinone (l g.) in dry ben
dicyano-S:6-dichlorobenzoquinone (1 g.) in puri?ed di
zene (20 ml.) was heated underre?ux for 141/2 hours.
oxan (15 ml.) was heated under re?ux for 71/2 hours.
The product was isolated as in Example 1 and crystal 7.0 The product was isolated as in Example 1 and crystallized
lised from aqueous methanol to give pregna-1:4:6-trienefrom dichloromethane/methanol to give l7u-ethynyl
3:11:20-trione as needles, M.P. 177 to 179° C.,
17B-hydroxyandrosta-l14:6-trien-3-one as prisms, M.P..
[a]D23-|-350.l° (c. 1.05 in chloroform), Amax, 225mg.
233 to 235° C., [oc]D23—104.2° (c. 1.0 in chloroform),
(log 6 4.01), 254.5 my. (log a 3.98) and 296 m/z (logv
Am“, 255 my (log 6 3.93), 254 mp. (log @392) and 296
(4.08).
.
75__
my. (log e 3.97).
.
-
8,096,206
7
EXAMPLE 25
21 ’-Acet0xy-1 7a-Hydr0xypregna-1 :4 : 6-Trien'e3:‘11z20-Trione
>
[‘o:]D2°+90.6° (c. 1.06 in chloroform), km“ 251 Ill/.0, log:
:5 4.17.
‘
EXAMPLE 31
~
A solution of 21 - acet'oxy - 17a -'hydroxypregna-4:6-"
ZOB-Hya'roxypregna-I :4-Dz'en-3-one
diene-SzllzZO-trione (0.2 g.) (Mattox, Woroch, Fleisher
and Kendall, J. Biol. Chem, 1952, 197, 261) and 2:3
A solution of- ZOBLhydIoXypregn-4-en-3-one (1 g.)
(Butenandt and Schmidt, Ber., 1934, 67, 2092), and 2:3
dichloro-S:G-dicyanobenzoquinone (0.75 g.) in dry dioxan
dicyano-5z6-dichlorobenzoquinone (0.2 g.) in puri?ed
dioxan (5 ml.) was heated under re?ux for 221/2 hours.
The product Was isolated as in Example 1 and crystal
. (10 ml.) was heated under re?ux for 10- hours.
from aqueous methanol to‘ give 20li-hydroxypregna-lz4
dien-3-one as needles, M.P. 192 to 194° C., [a]D19+12“‘
(c. 0.85 in chloroform), 1mm 244 111p. (log 6 4.16) and
223 mg (log 5. 4.02), 256 my (log e 3.97),‘an'd‘ 298 mg
(log 6 4.06).
vmamNum 1665, 1620 and 1605 cmrl.
15
. ’
The
product was isolated as in Example 1 and crystallised
lised from acetone/hexane to give 21-acetoxy-17a-hy
droxypregna-l:4:6-triene-3:11:20-trione as needles, M.P.
221 to 225° C., [ethyl-280° (c. 0.4 in dioxan), Amm
EXAMPLE 26
EXAMPLE 32
9-Flu0r0-1I18: 1 7,13-Dihydroxy-I 7a-Mezhylandr0sta
Acetonide of 1 601:] 7a-Dihydroxypregna-1 :4
1 : 4-Dien-3-one
Diene-é‘sZO-Dione'
A solution of thea'cetonide of 160:: 17a-dihydroxypregn
9a-?uoro-11Br17/3 - dihydroxy - 17a - methylaudrosta-v 20.
4-en-3-one (250 mg.) (Herr et al., J. Amer. Chem. Soc., >4-ene-3z20-dione (1.3 g.) (Cooley et al., J.C.S., 1955,
1956, 78, 500)’ and 2:3-di‘chloroe5:6-dicyanobenzoquinone‘
4373), and 2:3-dichloro-5':6-dicyanobenzoquinone (1 g.)
in dry dioxan (20 ml.) was heated under re?ux for 14
(250 mg.) in' dry benzene‘ (5 ml.) and‘ dioxan (5' ml.)
hours. The product was isolated as in Example 1 and
' crystallised from acetone/hexane to give the acetonide of
were heated under re?ux for 32 hours, and’ the product
was isolated as in Example 1. 9u-1luoro-11?z17B-dihy
droxy - 17a - methyla'ndrosta-l':4-dien-3-one crystallised
16m:17a-dihydroxypregna-I:4-diene-3s20-dione' ‘as ‘rods,
from acetone/hexane (1:3) in needles, M.P. 272 to 274°
C., [a]‘D26+55° (c. 0.23 in chloroform), Am“ 239 mu.
M.P. 197 to 199° C., [u]D19+83'.3'5° (c. 1.38 in chloroa
form), xmm 243.5 1111.0 log 6 4.14.
log 5 4.09 in ethanol, yum 3310, 1660, 1622 and .1601
cm.“1 in Nujol.
_
EXAMPLE 33
30'
4-Chl0‘rol17?-Propionoxyandfosmd :4-Dien-3-o'ne
EXAMPLE 27
Ethyl 3-0x0pregna-1 :4 : 1 7(20) ~Trien-21-0ate
A solution of 4-chloro-l7p-propionoxyandrost-4-en-3-s
one (0.55 g.) (Kirk, Patel and Petrow, J.C.S., 1956,;
1184) and 2:3-dichloro-5z?-dicyanobenzoquinone (0.5
g.) in dry dioxan (5 ml.) was heated under re?ux for 20
Ethyl 3-oxopregna-4:17(20')-dien-21-oate (250 mg.)
and 2:3-dich1oro-5-6-dicyanobenzoquinone (220 mg.) in
dry benzene (4 ml.) were heated under re?ux for 24
hours (Patel, Petrow, Royer and Stuart-Webb‘, J.C.S.,
hours. The product was isolated as in Example 1 and
crystallised from aqueous methanol to give 4-chloro-17?
propionoxyandrosta-l:4-dien-3-one as needles, M.P. 140
to 141° C., [a~]D13+75° (c.- 1.0 in‘ chloroform), an,“
1-952, 161) and the product was isolated as in Example
1. Ethyl 3-oxopregna-1z4:17(20)-trien-21-oate crystal
lised from acetone/hexane (1:6) in prisms, M.P. 132 to
133" C., [a]D27+6l°' (c. 0.29 in chloroform), km“ 228.5
246 mp, log e 4.05.
1 7B-A cetoxyr-2i-Methylana'rosta-l : 4-Dien-3-one
1\598-cm.-1 in Nujol.
’
'
EXAMPLE 34
_ mialog e 4.38 in ethanol vmax; 1700, 1660, 1648, 1620 and
EXAMPLE 28‘
20 : ZO-Ethylenediaxypregna-l :4-Dien-3-0ne
45
A solution of x17B-acetoxy-2a-methylandrost-4-ena3-one.
(1 g.) (Ringold. and Rosenkrant'z, J. Org. Chem, 1956,
211-, 1333-) and 2: 3-dichloro-5 : 6-dicyanobenzoquinone
(0.8 g.) in dry dioxan (10 ml.) was heated under re?ux'.
20:20-ethylenedioxypregna-4-en-3-one (200 mg.) and
2:3-dichloro-5:6-dicyan0benzoquinone (180 mg.) in dry
for 11 hours. The product was isolated as in Example 1
benzene (4 ml.) were heated under, re?ux for 30 hours
and crystallised from aqueous methanol to give 175
(Gut, J. Biol‘. Chem, 1956, 21, 1327')‘ and the product 50 acetoxy-Z-methylandtos'ta-1‘:4-dien~3~one as plates, M.P.
was isolated’ as in' Example 11. 20:20-ethylenedioxypregna
165 to 167° C., [a]D19+48.1° (c. 1.12 in chloroform),
1:4-dien-3-one' crystallised. from aqueous methanol;
Amax, 244.5 mg, log 6 4.17.
(80%) in ?akes, M.P. 184 to 186° C.,, [a]‘D22+45° (c.
0.16 in chloroform), Amax, 244 my log e 4.15 in ethanol,
vmam 1665, 1625 and 1600 cm.-1 in Nujol.
EXAMPLE 29
17?-Acet0xy-4-Methylaizdr/ostall :4-Dien-3-0ize
4-methyltestosterone acetate (1 g.) (Sondheimer and
Mazur, J. Amer. Chem. Soc, 1957, 79, 2906) and 2:3
dichloro-S:6-dicyanobenzoquinone (860 mg.) in dry ben
zene (12 ml.) were heated under re?ux for 36 hours and
55
EXAMPLE 3S
P'regna-I :4 :9 (1 1 ) -Tr'ie‘ne-3. :20-Dione
A. solution of p‘regna-4:9(1'1')'-diene-3:20-dione- (0.35
g‘.) (Shoppee and. Reichstein, Helv. Chim. Acta, 1941, 24,
351') and 2:3-dichloro-5:6adicyanobenzoquinone (0.3 g.)
in dry dioxan (5 ml.) was‘ heated under re?ux for 12
hours.
The product was isolated as in Example 1 and
crystallised from aqueous methanol to give pregna
1:4:9(11)-trienel3:ZO-dione as small plates, M.P. 124 to
126° C., vmax_N“5°1 1700, 1660, 1620 and 1600 cm.-1
the product isolated as‘ in Example 1.‘ 17?-acetoxy-4
methylandrost-a-l :4-dien-3-one crystallised from methanol 65 We" claim:
in prisms, M,.P. 1.75 to 177°’ C., [a]D21+62° (.c. 0.24 in‘
1. A process comprising reacting a steroid‘ compound:
chloroform),f7tmax_ 245 me- log 6 4.19 in ethanol.
selected from the group consisting of 3-oxo-A4 and 3-'
o'xo-M-6 derivatives of steroid compounds of the andros
7
EXAMPLE 30v
Cholesta-I :4-diene-3:6-Di0ne
A solution‘ of cholest-4~ene-3:'6ldione (3 g.) Heilbron
et1a1., ILC.S.~, 1938, 102) and‘2‘:3'—dicliloro-5:6-dicyano
benzoquinone (2 g.) in dry dioxan (201111.) washeatedI
under re?ux for~ 1.4‘ hours. The product was‘ isolated. as
in Example 1 and crystallised from hexane ‘to givechm
tane‘, pregn'ane, stigmastane, cholestane and spirost'ane
series‘ with a compound selected from the group consist
ing of 2:3-dicyano-1:4-benzoquinone, and chlorine-sub
stituted 2:3dicyano-1:4-benzoquinone having up to two»
chlorine atoms, in an organic solvent, to thereby pro-'
vide/the-corresponding l-dehydro compound.
2. A process as claimed in claim 1 wherein 2:3-cli-r
3,023,206
9
10
cyano-5z6-dichloro-1:4-benzoquinone is reacted with said
steroid starting material.
8. The process of claim 1 wherein the starting material
is 17a-hydroxyprogesterone.
3. A process as claimed in claim 1 wherein said sol
vent is selected from the groups consisting of benzene and
dioxan.
4. A process as claimed in claim 1 wherein the reac
tion is carried out at a temperature between 80° C. and
110° C.
5. A process as claimed in claim 1 wherein the reac
tion is carried out in the presence of a catalytic quantity 10
of p-nitrophenol.
6. The process of claim 1 wherein the ?rst two rings
of the steroid nucleus of the steroid starting material
have the following structure:
15
9. The process of claim 1 wherein the starting material
is cortisone acetate.
10. The process of claim 1 wherein the starting ma
terial is 11u-hydroxypregn-4-ene-3:20-dione.
11. The process of claim 1 wherein the starting ma
terial is 90c - ?uoro - 11,3:l7?-dihydroxy-17a-methylan
drosta-4-ene-3-one.
12. The process of claim 1 wherein the starting ma
terial is the acetonide of 16a:l7u-dihydroxypregn-4-ene
3:20-dione.
References Cited in the ?le of this patent
UNITED STATES PATENTS
2,705,719
2,793,208
2,880,217
Rubin ________________ __ Apr. 5,
Korman et al. ________ __ May 21,
Nobile _______________ _._ June 3,
Agnello et al. ________ .._ Mar. 10,
Thoma et al. ________ __ Mar. 31,
2,882,282
Agnello et a1 __________ .._ Apr. 14, 1959
2,883,379
2,899,447
Moreland et a1 _________ __ Apr. 21, 1959
Gould et al ___________ .._ Aug. 11, 1959
2,837,464
7. The process of claim 1 wherein the ?rst two rings 20
of the steroid nucleus of the steroid starting material
have the following structure:
an
25
2,877,239
OTHER REFERENCES
Cooley et al.: J.C.S., vol. 80 (1955), pp. 4373-76.
1955
1957
1958
1959
1959
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