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Патент USA US2108646

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Patented Feb“ 159 1938
23%,645
STERE DERHWA'EHWES
PREPARING 'il‘liti
@F
, Max Eocilhi, Gustav Ehrhart, and iillech
Ruschig, Franlizidrteon-the-Main-Heehst, i as a
y, assianors to Winthrop @hemicail @dlllllil-
,
parry, Tina, New York, N. ‘iii, a corporation oi?
New York
No Drawing, Application Ncvember it, 1935, Se
riali No. taste. in Qermany November i7,
MM
M matures.
The present invention relates toa process of for the tetracyclic ring structure of the sterol
preparing derivatives of the acids of the general series, for instance, of acids of the following
formula:
n
>
formulae
'
'
'
CH2
/
R-C-COOH
\
H
in which R stands for a polycyclic hydroaroinatic
radical, more particularly to a process of pre
W paring isocyanates, amines, alcohols and ketones
corresponding with said acids and t0 produc
obtainable thereby.
'
The‘ketones corresponding with the acids are
known. Hitherto they have been obtained only
in a complicawd manner, viz: by transi'ormina
the esters 'of the said acids with the aid of
15
Grignard’s reagent into tertiary alcohols which, _
after dehydration, were subjected to an oxidation
process.
itli
,
Now We have found that the lretones may ad
-20
vantageously be produced by decomposing the
‘above named acids according to Curtius' method
and transforming the amines thus obtained by
oxidation
25
ketones.
methods
'
into
the vcorresponding
,
The process may be carried out by transform
ing one of these acidsinto the acid halide, pare
ticularly into the acid chloride, then causing the
halide to react with an alkali azidaespecially
30 sodium azide, preferably in an aqueous acetone
solution so as to form the corresponding organic
azide and transforming the last named product
into the isocyanate by heating it. The isocyanate
is converted into the amine by one of the usual
35 methods, such as by addition of mineral acid,
Thus, for instance, in ?i-hydroxy-tbis-norcho
acylhydroxy-bis-norcholenic acid, there is ob
especially sulfuric acid of, for instance, 60%
tained according to the new process the corre
strength. The amine thus obtained may be
treated with oxidizing agents. It the amine is
treated with sodium nitrite the corresponding
amine nitrite is formed and by heating. the cor
responding alcohol is obtained therefrom. By
sponding ketone of the cholane series. Accord“
ing to this process products of the following
general formula are obtained.
treating the alcohol with oxidizing agents, for
R_—~C——X
/
instance, with chromic acid or potassium per
manganate the alcohol may be transformed into
a. in the corresponding ketone.
The new process has proved to be of particular
advantage in the treatment of such acids of the
above named general formula, in which R stands
25
lenic acid or 3-acylhydroxy-bis-nor-’chclenic acid
the side chain may be converted by our new
process into the corresponding lretone. In this
case the double bond standing in 5.6-position
may, if desired, be saturated with bromine and 30
the ketone obtained may be debrominated. If
the double bond is saturated with hydrogen in
the 3-hydroxy-bis-norcholenic acid or in the 3
CH:
H
in which R stands for the tetracyclic ring struc
ture of the sterine series and X stands for the
group
‘
r-NHs, ——N=C=O or ——-0H .
35
2,108,648
2
The amines which correspond with the follow
ing formulae:
are heated in a re?ux apparatus for 2 hours in 50
cc. of dry benzene with 15 grams of thionyl chlo
ride. The reaction solution is evaporated to dry
ness under reduced pressure; the residue is dis
solved in 50 cc. of acetone, the solution is cooled
to 0° 0., and an ice-cooled solution of 1.6 grams of
pure sodium azide in 5 cc. of water is then en
tered gradually drop by drop, while shaking.
The acet-bis-norcholenic acid azide-separates in
the form of a white-reddish precipitate. In order 10
10
to complete the precipitation the reaction solu
in which Y stands for hydroxyl or acylated hy
droxyl
tion is cooled in a mixture of ice and sodium chlo
ride, the azide is immediately ?ltered by suction
and subsequently washed with cold acetone. The
almost dry product is at once taken up in 50 cc.
of dry toluene since it easily assumes an oily
state when exposed to the air; any entrained sod
ium chloride and a small quantity of smeary sub
stances remain. The toluene solution is dried over
sodium sulfate in an ice-chest for 30 minutes.
(b) The dry toluene. solution is ?ltered and
15
20
in which Y stands for hydroxyl or acylated hy
droxyl are soluble in organic solvents, capable
of being precipitated with nitrous acids while
forming a salt stable in air, capable of being
readily precipitated in the, form of their hydro
chloride from an alcoholic solution with the aid
of mineral acids to form colorless crystals.
30
The isocyanates of the formulae:
OH;
H!
C CH:
HiC
as
H:
'
I
‘
/c\ 0 §C\H/H\
/CH’
13,0
*0
c
l
CH:
H:
then gradually heated to boiling. The elimina
tion of nitrogen sets in at 40° C.; the course of
the reaction may be observed by collecting the
nitrogen in a cylinder. The amount of gas
evolved on an average amounts to about 250cc.
to 275 cc. After 1 hour the reaction is complete.
The reaction solution is evaporated under re
duced pressure and the crystalline isocyanate is
heated for 3 hours in a re?ux apparatus with a 30
mixture of acetic anhydride and glacial acetic
acid (60 cc. of anhydride and 15 cc. of glacial
acetic acid). The isocyanate may be obtained in
a pure form by recrystallizing it twice from pe
troleum ether. It crystallizes in the form of
clustered needles. It is readily soluble in all
organic solvents. The yield amounts to 1.75
grams to 2.2 grams. The melting point of the
.iso'cyanate is at 103° C., after sintering at 98° C.
40
40
in which Y stands for hydroxyl or acylated hy
droxyl.
'
Calculated ............................ __ C 74. 8
H 9. 1
N 3. 64
Found ________________________________ _- C 74.87
H8.8l
N3.98
45
The saponi?cation of the isocyanate can be‘
controlled by measuring the quantity of carbon
dioxide evolved; the average quantity measured is
300 cc. The residuev produced by the reaction
contains the desired acetylamine which is re- -
60
in which Y stands for hydroxyl or acylated hy
droxyl are readily soluble in organic solvents, even
in petroleum ether, crystallizable in the form of
55 weakly yellowish needles. '
1.2 gramsof 3-acetoxy-ternorcholenylisocyanate
‘The alcohol of the formula:
on. In,
.
60
are dissolved in 30 cc. of ether and 30 cc. of ben
H /cn=
mo /C\CH;
<B-—-—c—c—on
H3
c
~ I
H
\
o
n
/ \ / \H/H\ Ah
0
c
crystallized from ethyl acetate. Yields 2.4
grams; point of decomposition 243° C.
Instead of heating the isocyanate in a mix
ture of acetic anhydride and glacial acetic acid
the process may also be carried out as follows:
c
H:
zene and 40 grams of ice-cold sulfuric acid of
60% strength are added which, however, do not
mix with the solution, but form the lower layer.
The whole is thoroughly stirred at room tempera
ture for 15 minutes, the mixture becoming more
and more viscous in consequence of the precipita
tion of the amine sulfate and ?nally solidifying
65
70
to a thick magma. Water is'then added to the
forms white colorless crystals of the melting point
of between 179° C. to 180° 0., is difficulty soluble
in petroleum ether, readily soluble in alcohol and
crystallizable from acetic ester.
The products mentioned are to be used ‘as ther
apeutics or for the preparation of medicaments.
The following example serves to illustrate our‘
' invention, but it is not intended to limit it thereto:
75
(a) 5 grams of acetoxy-bis-norcholenic Midv
mixture and the amine sulfate'is obtained by
centrifuging. .The amine sulfate is then dissolved
in an alcoholic caustic potash solution of 5%
strength, the mixture is diluted with water and
shaken with ether. On introduction of hydro
gen chloride into the washed and dried ethereal
solution the amine hydrochloride precipitates.
It readily dissolves in alcohol, is precipitated
sparingly on addition of water, but is readily
2, 1 08,648
precipitated on addition of dilute hydrochloric
acid in well formed crystals (prisms). Point of
decomposition at about 348° C. Yield 0.88
gram=about 80% of the theoretical.
(c) The‘ 3-acetoxy-bis-norcholenyl
acetyla
~ 3
crystalline distillate is again crystallized from
ethyl acetate. The substance melts at 179° C.
to 180° C. and has the formula C21H34O2. By
oxidizing the body protected by bromination with
the aid of chromic acid and elimination the bro
mine, the ketone CnHsoOz is obtained which is
identical with progesterone. The second sub
The solution is poured into water, the amine stance is contained in theethyl acetate and pe
being obtained as a solid precipitate. .It is re
troleum ether solutions; it corresponds to the
10 crystallized from aqueous dioxane. Alternatively, j formula C21H32O. It is obtained by recrystalliza
10
mine is deacetylated by boiling it with an alco
holic caustic potash solution of 10% strength.
20
the aqueous alkaline mixture may be shaken with
tion from aqueous alcohol in the form of well
chloroform, the chloroform solution dried with
sodium sulfate‘ and the amine precipitated by
introduction of hydrogen chloride. It is like
wise obtained by taking up the amine hydro
chloride in alcoholic caustic potash solution, pre~
cipitating the amine with water and recrystal
livzing it from aqueous dioxane. Point of decom
position 243.5° C., after previous sintering at
crystallized needles. Melting point 120° C.
239° C.
We claim:
1. The process which comprises transforming
into the acid halide a compound of the following
general formula:
"
'
CH3
'R——C——COOH
.
20
in which R stands for a polycyclic hydroaromatic
CnHuONJ mo] of H10
Calculated ____________________________ _. ‘(375.22 £111.04
Found _________________________________ __ 075.2
H109
N4.18
N4.l
radical of-the sterine series, transforming the
acid halide into the azide by causing it to act
upon an alkali azide, transforming the azide by
heating-it into the isocyanate and saponifying the 25
With the aid of suitable oxidizing agents, such
latter to form the amine and converting said
as chromic acid in glacial acetic acid or nitrous
amine into the alcohol.
-
' 2. The process which comprises transforming.
acid, the amine is ‘transformed, after protection
of its double bond with bromine, in known man
into the acid halide a compound of the follow
ner into the corresponding ketone or pregnene
ing general formula:
diol respectively.
.~
OH:
30
|
(d) An ethereal solution of 0.8 gram of acet
oxy-ternorcholenylamine is shaken with 30 cc.
$5 of an ice-cold solution ‘of HNO2 made from 1
gram of NaNO: and 0.5 gram of concentrated
sulfuric acid. The amine nitrite is immediately
precipitated in the form of ?akes and is obtained
by centrifuging. The amine nitrite is of good
u Iv
stability, even to air. In order to oxidize the
amino group the amine nitrite is suspended in
a solution of HNO; vwhich has been prepared from
70 cc. of alcohol, 8 cc. of 2N acetic acid, 20 cc.
of water and 1.6 grams of NENOz and cooled to
0° C‘.v The mixture is then gradually heated on a
steam bath; at 50° C. the amine nitrite is dis
solved; at 55° C. to 60° C. the evolution of nitrogen
in which R stands for the tetracyclic ring struc
ture of the sterine series, transforming the acid
halide into the azide by causing it to act upon
an alkali azide, transforming the azide by heating ‘
it into the isocyanate and saponifying the latter 40
to form the amine.
8. The process which comprises transforming
into the acid halide a. compound of the following
formula:
-
45
'sets in and after 1 hour it is ?nished (?nal tem- _
Derature 75° 0.). The solution-is then mixed
all with water and the colloidal mixture is shaken
with ether. On evaporation of the ether the resi
due amounts to 0.56 gram. It is crystalline and
free from nitrogen
55
stances.
and
consists of two
sub- '
.
For the purpose of separation the’ residue is
heated in a reflux apparatus for 30 minutes in 15
cc. of an alcoholic caustic potash solution of 10%
strength and the solution is then poured into ice-.
cold water acidi?ed with dilute sulfuric acid.
rlf'he colloidal mixture is shaken with ether and
50
transforming the acid halide ‘into the azide by
causing it to act upon‘an alirali azide, transform
ing the azide by heating it into the isocyanate
and saponifying the latter to form the amine.
4. The process which comprises transforming
into the acid halide a compound of the following
60
formula:
the ethereal solution is dried. The residue ob
tained by evaporating the ether contains the al
cohol expected to be produced by the reaction
till with nitrite and the hydrocarbon obtained by
simultaneous elimination of water.
‘
The whole is then dissolved in a small quantity
of ethyl acetate and"the solution is mixed with
much petroleum ether. The alcohol above men
70 tioned is thus obtained in a well crystalline
state. Yield 250 mg. In order to better purify
it the alcohol is distilled preferably in a high vac
uurn. lit distills at a temperature between 170°
C. and 220‘’ C. under a pressure of il.02 mm. The
transforming the acid halide into the azide by
causing it to act upon an alkali azide, trans
forming the azide by heating it into the isocya
hate and saponiiying the latter to form the
amine.
-
‘
to
2,108,640
*
saponifying
the
latter
to form the amine and
5.‘ The process which comprises transforming’
into the acid halide a compound of the following transforming the amine into the ketone with
4-
.
the aid of an oxidizing agent.
‘
9. The process which comprises transforming
in the acid chloride a compound of the follow
ing formula:
transforming the acid halide into the azide by
causing it to act upon an alkali azide, trans
forming the azide by heating it into the isocya~
nate and saponifying the latter to form the amine
and transforming the amine into the lretone with
the aid of an oxidizing agent.
15
into the acid chloride a compound of the fol
transforming the acid chloride into the azide by
causing it to act with sodium azide, saponifying
the latter with sulfuric acid and transforming
the amine thus obtained into the corresponding 20
alcohol by meansof nitrous acid and causing
lowing forinuia:
chromic acid to act upon said alcohol.
6. The process which ‘comprises transforming
'
\10. The process which comprises transform
ing into the acid chloride a compound of the fol
25
lowing formula:
CH;
H:
30
transforming the acid chloride into the azide by
causing it to act upon sodium azide, saponifying
the latter with sulfuric acid and transforming
35 the amine thus obtained into the corresponding
alcohol by means of nitrous acid and causing
chromic acid to act upon said alcohol.
'7. The process which comprises transforming
into the acid chloride 2. compound of the follow
40 ing formula:
-
a
CH;
45
/C\(|3Ha
H /CH: .
o-—-o—o—-oo0u
i
'
/°\ E/[C\H/H\ /H,
0
o
o
t
I
a
H’
mo
causing it to act upon sodium azide in aqueous
acetone, dissolving the azide in toluene and heat
ing this solution, isolating the isocyanate, sa
ponifying the latter with sulfuric acid of 60%
H
of nitrous acid and causing chromic acid 'to act
upon said alcohol
11. As new products the compounds of the fol
lowing general formula:
no 0
_
H:
CH:
' H \ /§\ / H’
,
-
/
.
\
R-C-X
o
H:
‘
50 transforming the acid chloride into the‘ azide
by causing it to act upon sodium azide in aqueous
acetone, ‘dissolving the azide in toluene and heat
ing this solution, isolating the isocyanate, saponi
fying the latter with sulfuric acid of 60%
55 strength and transforming the aminethus ob
tained into the corresponding alcohol by means
60
35
strength and transforming the amine ‘thus ob
tained into the corresponding alcohol by means
K H;
H1O
H:
transforming the acid chloride into the azide by
H
in which R stands for the tetracyclic ring struc
ture of the sterine series and X is a memberof
the group consisting of -NH:, —N=C=O and
_-OH.
-
12. As new products the compounds of the fol
55
lowing general formula:
of nitrous acid. and causing chromic acid to act
upon said alcohol.
8. The process which comprises transforming
into the acid halide a compound of the following _
formula:
65
65
mo
o---o-c—coon
in which Y is a member of the group consisting
of lnvdroxyl and acyloxy; said products being sol
uble in organic solvents, capable of being precipi
tated with nitrous acid while forming a, salt sta
transforming the acid ‘halide into the azide by
causing it to act upon an alkali azide, ‘transform
‘ 75- ing'the-azide‘byheating it-into thelsocyanate and *'
blev at the air, capable of being easily precipl
tated in the form ‘of their hydrochlorides from
an alcoholic solution with the aid of mineral
acids ‘to form'colorless crystals.
70
2,108,046
18. As new products the compounds of the fol
lowing general formula: '
.5
14. As a new product the compound of the fol
‘lowing formula:
on
m
'0
cm
10
10
v in which Y stands for hydroxyl or an ac‘yloxy
radical, said products being soluble in organic
15 solvents, capable of being precipitated with ni
trous acid while forming a salt stable at the
air, capable of being easily precipitated in the
form‘ of their hydrochlorides from an alcoholic
solution with the aid of mineral acids to form
20 colorless crystals.
said product forming white colorless crystals of
the melting point 01’ between 179° C. to 180° 0.,
di?icultly soluble in petroleum ether, readily sol
uble in alcohol and crystalliz'ablé from acetic 15
ester.
MAX BOCKM‘UHL.
aus'mv EHRHART.
mammen 'RUSCHIG. \
20
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