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Патент USA US3031480

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United States Patent 0 F "ice
_
3,031,47 l
Patented Apr. 24, 1962
2
1
The following examples describe in detail the prepara
tion of representative substituted estrones and estradiols
3,031,471
of the present invention.
NEW 15,17-DISUBSTITUTED 1,3,5(10)-ESTRATRI
ENS AND METHODS OF PREPARING THE SAME
EXAMPLE 1
Seymour Bernstein, New City, and Edward W. Cantrall,
Preparation
of
1
5
?-Cyano-3 -Methoxy-1 ,3 ,5 (1O ) N.J.,
Pearl River, N.Y., and Ruddy Littell, River Vale, New
Estratrien-I 7-0ne
assignors to American Cyanamid Company,
York, N.Y., a corporation of Maine
A Solution of 200 mg. of 15-dehydroestrone methyl
No Drawing. Filed Oct. 24, 1961, Ser. No. 147,151
ether in‘ 7 ml. of 't'et'rahydrofuran-containing 5 ‘drops of
10 Claims. (Cl. 260-397.4)
10 water is treated with 500 mg. .of sodium cyanide and the
mixture is re?uxed for 2.5 hours. Upon cooling, the mix
This invention relates to new steroid compounds. More
ture is poured into ice Water and the resulting precipitate,
particularly, it relates ‘to substituted estrones and estra
200 mg, melting point 131-135“ ‘C., is collected by ?ltra
diols and methods of preparing the same.
tion. Three crysta'llizations from ether give the pure l5
The novel steroids of the present invention may be
15 cyano product, melting point 154-155 ° C.
illustrated by the following formula:
CH9
EXAMPLE 2
C11
Preparation of 15(3-Cyan0-3-Hydr0xy-1,3,5 (1 0 ) /
Estratrien-I 7-0ne
20
wherein R is selected from the group consisting of hydro
gen and lower alkyl radicals, Rl'is selected from the group
consisting of diloweralkylamino and cyano radicals and
C17 is a divalent radical selected from the group consist
ing of
' (5)011
\o=o, \o/
/
/ \H
(in-o C-—lower alkyl
and \o/
/ \H
A solution of 1.2 g. of l6~bromoestrone acetate and
220 mg. of p-toluenesulfonic acid monohydrate in 60 ml.
of toluene and 5 ml. of ethyleneglycol is distilled slowly
through a Vigreux column for 44 hours. (Total distillate
45 ml.) The reaction mixture is cooled, neutralized with
25
- saturated sodium bicarbonate solution diluted with ethyl
acetate, washed with saturated saline, dried and evaporat
ed. Crystallization of the crude residue from methanol
gives 825 mg. of white crystals, melting point 234—236°
C. whose infrared absorption spectrum shows complete
30
a i‘)
radicals.
absence of acetate or carbonyl bonds. Two further crys
tallizations from the same solvent gives the pure bromo
ketal, melting point 246-247“ C. '
A solution of 400 mg. of potassium in 20 ml. of t-butyl
35 ‘alcohol is evaporated when 20 ml. of xylene is added and
the evaporation is repeated. A solution of 600 mg. of
the bromoketal in 40 ml. of xylene is added to the potas
solids relatively insoluble in water but soluble in meth
sium t-butoxide and the mixture is heated under re?ux
anol, ethanol, ethyl ‘acetate, acetone and the like.
in an atmosphere of nitrogen for 18 hours. Upon cool
The compounds of the present invention having a keto
group in the 17-p0sition usually described as estrone de 40 ing, the mixture is diluted with ether, washed with satu
rated saline, dried and evaporated to give 275 mg. of a
rivatives can be prepared by reacting the steroid 3-meth
pasty solid which is crystallized from methanol to give
oxy-1,3,5(10),l5-estratetraen-l7-one with a nucleophilic
130 mg. of white crystals, melting point 2l5—219° C.
reagent such as an alkali metal cyanide or a secondary
The present compounds are,in general, white crystalline
Two additional crystallizations from acetone-petroleum
amine such as dimethylamine, diethylamine, dipropylam
inc and the like. The preparation of the starting material 45 'ether gives the pure ketal tetraene, melting point 218
3-methoxy-1,3,5(10),l5-estratetraen-17-one is described
220° vC. '
hereinafter and in our copending application Serial No.
147,150, '?led October 24, 1961, in which application the
corresponding 3-hydroxy steroid is described and claimed
estratetraen-3-ol and 60 mg. of p-tolue'nesulfonic acid
monohydrate in 70 m1. of acetone and 12 ml. of water
as a new compound.
The 17-hydroxy steroids of the present invention usual
ly described as substituted estradiol derivatives can be
prepared by reducing the corresponding estrones described
above with sodium borohydride, potassium borohydride,
lithium aluminum hydride or the like,
The compounds of the present invention are pharma
cologically active. They are useful in the treatment of
hypercholesterolemia and disorders associated therewith.
Their biological activity is selective and they can achieve
other responses of the estrogenic hormones without pro
'
A solution of 1.0 g. of 17-ethylenedioxy-1,3,5(10),l5
.50 is stirred at room temperature for 1.5 hours.
The solu
tion is then diluted with 350 ml. of ether, washed once
with dilute sulfuric acid, once with dilute sodium bi
carbonate solution and ?nally with saturated saline.
After evaporation of the solvents, the resulting solid is
55 crystallized from methanol to give 475 mg. of 15-dehydro
estrone, melting point 249-251" C. Further crystalliza
tion of the product from methanol and from chloroform
methanol gives the pure sample, melting point 250
252° C.
To a solution of 250 mg. of IS-dehydrcestrone in 10
m1. of tetrahydrofuran containing 7 drops of water is
added 700 mg. of sodium cyanide and the mixture is re
fluxed for 3 hours. After cooling, the reaction mixture
and circulatory disorders often ‘associated with or indi
is poured into ice water and the resulting precipitate
cated by higher content of cholesterol in the animal sys-'
?ltered to give 180 mg. of lS?-cyanoestrone, melting
65
tem. They are useful as intermediates in the preparation
point 260-265° C. Two crystallizations from methanol
of other estrones and estradiols as will be apparent to
gives the pure product, melting point 274-276° C.
ducing a corresponding feminization. , The compounds
are therefore useful in the treatment of cardiovascular
those skilled in the art.
3,031,471
3
4
4. The compound
EXAMPLE 3
15B-cyano-l,3,5 ( 10) -est-ratrien-3,
17?-diol.
Preparation of 15?-Cyan0-],3,5 (1-0)-Estratrien\e-3,1 7;?
5. The compound l5?-dimethylamino-3~methoxy-1,3,
Biol
A solution of 280 mg. of ISB-cyanoestrone and 200
mg. of sodium borohydride in 5 ml. of tetrahydrofuran
5 ( 10) -estratrien-l7-one.
6. A method of preparing a compound of the formula:
and 35 ml. of methanol is stirred at room temperature for
2 hours. Water is ‘added and 245 mg. of -a white powder,
CH3
0
II
melting point 280—282° C. is collected by ?ltration. Two
crystallizations from methanol give pure IS?-cyanoestra
Q1.
10
diol, melting point 284-286“ C.
The above compound when reacted with methyl iodide,
potassium carbonate and ethyl alcohol produces the cor
responding 3-methyl ether which on heating with pyridine
and acetic anhydride produces 17?-acetoxy-15?-cyano-3
methoxy-1,3 ,5 ( 10) -est-ratriene.
R0
15
EXAMPLE 4
wherein R is selected from the group consisting of hydro
gen and lower alkyl radicals and R1 is selected from the
Preparation of 1SIB-Dimethylamino-3-Methoxy-1,3,5(10)
group consisting of diloweralkylamino andcyano radicals
. which comprises reacting a steroid of the formula:
Estratrien-I 7-one
A solution of 300 mg. of IS-dehydroestrone methyl 20
CH1,
ether in 4 ml. of tetrahydrofuran and 6 ml. of dimethyl
0
amine containing 0.4 ml. of 25 % aqueous potassium hy
l
droxide is stirred at room temperature in an atmosphere
of nitrogen for 20 hours. The reaction mixture is diluted
with ether, washed three times with saturated saline, 25
dried and evaporated at room temperature to give 260
mg. of the ISIS-dimethyIamine derivative, melting point
1l5~117° C. Crystallization of the product from ether
petroleum ether and from methanol does not 'alter the
melting point.
We claim:
1. A compound of the formula:
from the group consisting of alkali metal cyanides and di
loweralkylamines and recovering said compounds there
from.
CH3
7. A method according to claim 6 wherein the result
ing product is subsequently reacted with a compound se
/\/C"
I
l
30 wherein R is as de?ned above with a member selected
lected from .the group consisting of alkali metal borohy
drides and lithium aluminum hydride and the correspond
ing 17-hydroxy steroid recovered therefrom.
8. A method of preparing 15,B-cyano~3-methoXy-1,3,5
I R.
11
(10)-estratrien-l7-one which comprises heating IS-dehy
droestrone methyl ether with an alkali metal cyanide in
the presence of a solvent inert to the reactants and re
wherein R is selected from the group consisting of hy
covering 'said compound therefrom,
drogen and lower alkyl radicals, R1 is selected from the
group consisting of diloweralkylamino and cyano radicals 45 9. A method of preparing 15/8-diloweralkylamino-3
methoxy- 1,3,5 (l0t)-estratrien-l7-one which comprises
and CH is a divalent radical selected from the group con
contacting 15-dehydroestrone methyl ethers with a di-,
sisting of
\
loweralkylamine in a solvent inert to the reactants and
\ /
/O=O, /C\
(13) O H
‘H
\ /
and
C
(5) O --—0 —lower alkyl
‘H
recovering said compound therefrom.
50' 10. A method of preparing 1SB-dimethylamino-S-meth
oxy-1,3,5(l0)-estratrien-17-one which comprises contact
II
O
radicals.
2. The compound lS?-cyano-S-methoxy-1,3,5(l0)-es
tratrien-17-one.
-
ing IS-dehydroestrone methyl others with dimethylamine
in a solvent inert to the reactants until a signi?cant amount
of said product is obtained and recovering said product
therefrom.
3. The compound l5l3-cyano-3-hydroxy-l,3,5(10)-es 55
vtratrien-17-one.
No references cited,
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