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Патент USA US3028391

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United States Patent 0 " lC€
3,028,381
Patented Apr. 3, 1962
2
1
(2' : 3' - diazacyclopent-2’-eno ) -pregn-5-en-20-one
R=H or acyl)
3,028,381
?-METHYL STEROID DERIVATIVES AND
PROCESSES 0F PREPARING SAME
Vladimir Petrow and David Morton Williamson, London,
England, assignors to The British Drug Houses Limited,
London, England, a British company
No Drawing. Filed July 6, 1959, Ser. No. 824,961
Claims priority, application Great Britain July 9, 1958
6 Claims. (Cl. 260-2395)
(III;
Me
0 OMe
LuNzl?
: 1- - —CH2
Me
I
.
r‘:
10
This invention is for improvements in or relating to
R0
organic compounds and has particular reference to the
Me
preparation of new 6:16-dimethylpregnane derivatives
which are of value as intermediates in the preparation of
~
(III)
According to the present invention there is provided a
for the preparation of 3?-hydroxy and 3f3-acyl
17a-hydroxy- and 17a-acyloxy 6:16-dimethyl derivatives 15 process
oxy-6: l6-dimethylpregna-5 : l6-dien-20-one which proc
ess comprises reacting the corresponding B?-acyloxy or
In particular l7a-acetoxy-6a,IG-dimethylprogesterone
313-hydroxy-6-methylpregna-5z l6-dien-20-one (IV) where
is found to be ‘100 times more potent than dimethisterone
of pregnane which are valuable as progrestational agents.
R=H or an acyl group containing up to 10 carbon atoms
(6a,2l - dimethylethisterone; 60:,21 - dimethylanhydrohy
Me
droxyprogesterone) in the Clauberg assay. As dimethi 20
sterone (6a,21-dimethylethisterone) is known to be slight
ly more than 10 times as active as anhydrohydroxyproge
sterone (ethisterone) in the Clauberg assay (David, Hart
ley, 'Millson ‘and Petrow, J. Pharm. Pharmacol, 1957, 9,
i A
929), it will be apparent to those skilled in the art that 25
l7a-acetoxy-6al6-dimethylprogesterone is a proges-tation
a1 agent of quite unexpected and remarkable potency,
and its preparation a matter of importance.
B0
Me
It is an object of the present invention to provide the
'(IV)
new compounds 3,8-hydroxy- and 3?-acyloxy- 6: 16-dimeth 30 with diazomethane to yield the corresponding 16a,17u
ylpregna-5z16-dien-20-one (I; R=H or an acyl group con
taining up to 10 carbon atoms)
. methylene diazo derivative (III) or pyrazoline and ther
mally decomposing the pyrazoline.
Me
OOMe
A
35
e
i
of the residue.
‘Decomposition of the pyrazoline (III) to yield the
6: l6-dimethylpregnane derivative (1) may readily be per
formed by heating the pyrazoline under re?ux in an inert
RO
Me
(I)
organic solvent of B.P. approximately the same as the
MP. of the pyrazoline, such as dibutyl ether, for 3 to 5
The above compounds are valuable and convenient
starting materials for the preparation of the potent pro
hours. p-Cymene and ethylene glycol are other solvents
suitable for e?ecting this thermal decomposition.
‘Conversion of I (‘where R=acyl) into I (where R=H)
may readily be effected by alkaline hydrolysis, for exam
ple by heating the acyl derivative with the carbonate or
ges-tational agent 17a-acetoxy-6a,16-dimethylprogesterone.
Their conversion into this progestational agent may be
accomplished by converting compound I into the 3-oxo
derivative, 60:: 16-dimethylpregna-4: l6-dien-3 :20-dione
Me
50 hydroxide of an ‘alkali metal in an aqueous/ organic sol
O OMe
p
such as diethyl ether and the reaction mixture allowed
to stand at room temperature for periods of 16 to 40
hours, and the pyrazoline subsequently isolated by re
moval of the solvent by evaporation and crystallisation
Me
Me
Addition of diazomethane to the starting material (IV)
is preferably performed in an unreactive organic solvent
vent mixture such ‘as aqueous acetone or aqueous tert.~
butanol.
Following is a description ‘by way of example of meth
ods of carrying the invention into effect.
55
Example 1
3p - ~acetoxy-6-methy-l-16: 17-(2’ : 3'-diazacyclopent-2’
8
H
0_
eno)-pregn-5-en-20-one (III; R=Ac): 3?acetoxy-6-meth
lite
(n)
forming the 16a,17u-epoxide, converting this 1641,17“
epoxide into ‘a 17a-hydroxy-16,8-halo-16a-methyl inter
mediate by reaction with a halohydrin, reductively re
60
lypregna-5:l6-dien-20-one (IV) (20 gm.) was treated
with a solution of diazomethane prepared from N-methyl
N-nitroso-toluene-p-sulphonamide (125 gm.) in diethyl
ether (750 mls.) and the mixture was allowed to stand
at room temperature overnight (16 hours). Excess di
moving the halogen atom and acetylatnig the tert.-hy
65 azomethane was destroyed by addition of dilute acetic
drcxyl group at C17.
acid, and the ethereal layer washed with water, sodium
The present invention also provides the intermediate
pyrazolines 3?-hydroxy- and 3?-acyloxy-6-methyl-l6:17
bicarbonate solution, water and dried.
The ether was re
3,028,381
3
4
moved under reduced. pressure and the residue crystal
lised from methanol to yield 3,6-acetoxy-6-methyl-16:17
methane in diethyl ether is added to the steroid starting
material and the reaction mixture allowedto stand at
room temperature for periods of 16 to 40 hours.
3. A process as claimed in claim 1 wherein the 160:,
(2': 3' - diazacyclopent - 2’~ eno)-pregn-5-en-20-one (III;
R=Ac), plates, M.P. 156 to 158° C. with decomposi
tion, [@1323 —l4° (c., 0.44 in chloroform).
5 Not-methylene diazo derivative is decomposed by heat
35 - acetoxy-6:16-dimethylpregna-5:16-dien-20-one (I;
R=Ac): The foregoing pyrazoline (III; R=Ac) (20
ing under re?ux in an inert organic solvent of BF. ap
proximately the same as the M.P. of the 16a,17oc-m6thyl
gm.) was dissolved in dibutyl ether (200 ml.) and the
solution heated under re?ux for 3 hours. The dibutyl
ene ‘diazo derivative.
4. A process asv ‘claimed in claim 3 wherein the inert
ether was removed under reduced pressure and the re
10 organic solvent is dibutyl ether and the heating under re
sidue crystallised from methanol to give 3,8-acetoxy-6: l6
?ux is carried out for 3 to 5 hours.
dimethylpregna-S:l6-dien-20-one (I; R=Ac), plates,
5. 3?-hydroxy- and 35-acyloxy-6:16-dimethylpregna
M.P. 158 to 160° C., [@1324 —41° (c., 0.654 in chloro
5: 16-dien-20-one
form),
Me
A523? 251 my, e=8650
3 ?-hydroxy-6: 16-dimethylpregna-5 : 16-dien-20-one
15
(IZOMe
(I;
/\M_e
R=H): The foregoing 3/3-acetoxy-6:16-dimethylpregna
5:16-dien-20-one (I; R=Ac) (2 gm.) was hydrolysed by
heating under re?ux with potassium hydroxide (2 gm.)
in methanol (80 ml.) and water (20 ml.) for 1 hour.
Me
_
R0
'
The mixture was poured into water and the precipitate 20
?ltered off, washed with water, dried and crystallised
Me
(I)
from methanol to give 3B-hydroxy-6:16-dimethylpregna
5:16-dien-20-one (I; R=H), plates, M.P. 148 to 149° C., 25 where R=H or an acyl group containing up to 10 carbon
atoms.
[aJD24 —99° (c., 0.292 in chloroform),
6. 3l3-hydroxy- and 3B-acyloxy-6-methyl-16:17-(2’:3’
R513? 251 to 253 mp, e 8806
diazacyclopent-2’-eno) -pregn-5-en-20-one
Example 2
3ii-hydroxy-6: 16-dimethylpregna-5: 16-dien-20-one (I;
R=H):
Me
30
COMe
3/3 - hydroxy-6-methylpregna-5:16-dien-20-one
(IV; R=H) (20 g.) was treated with an ethereal solution
of diazomethane in the manner described in Example 1.
The crude pyrazoline (III; R=H) thus obtained was dis
solved in dibutyl ether (200 ml.) and the solution heated 35
under re?ux for 3 hours. After removal of the dibutyl
ether, the residue was crystallised from methanol to give
BO
3?éhydroxy-6: 16-dimethylpregna-5: 16-dien ZO-one, M.P.
‘148 to 149.0 (3., identical with a specimen prepared as ‘de
scribed above.
‘T
'
‘
'
'
'
‘
'
" We claim :'
1. 'A process for the preparation of 3?-hydroxy~ and
3,8}acyloxy-6: 16-‘dimethylpr‘egna-5: 16-dien-2'0-one which
process comprises reacting the corréspondingBB-acyloxy
Me
‘
atoms.
“
2. A process as claimed in claim 1 wherein the diazo~
'
'
References Cited in the ?le of this patent
or‘ 3l8-hydroxy-6-methylpregna-5:16ldien-20—one with di ‘.15 2,888,457
azomethane to yield the corresponding 16a,17a-methyl
ene diazo derivative and heating to thermally decompose
said 1611,1704, methylene diazo derivative.
(In)
40 where R=H or an aeyl group containing up to 19 carbon
IJNITED STATES PATENTS
Beyler et a1. ________ __ May 26, 1959
OTHER REFERENCES
Journal of Chemical Society (1957), article by Burn
et al., pages 40-94 relied on.
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