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Патент USA US3084199

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April 2, 1963
s. GOTTFRIED a-rm.
3,084,185
GLYCYRRHETINIC ACID DERIVATIVES
Filed July 21, 1960
2 Sheets-Sheet 1
@
O
oi
:m
April 2, 1963
Filed July 21, 1960
s. GOTI‘FRIED EI'AL
3,084,185
GLYCYRRHETINIC ACID DERIVATIVES
2 Sheets-Sheet 2
3,084,185
Patented Apr. 2, 1963
1
2
l2~en-2‘0-carboxylic acid (i.e., glycyrrhetinic acid). How
3,084,185
ever, the method used by Logernann et al. does not give
very high yields and according to a further feature of the
present invention processes are provided for the produc
tion of l8oz- and l8p-keto G.A. which give high yields of
GLYC 1"?‘ ‘Ii TINIC ACID DERIVATIVES
Siegfried Gottfried, ilt'ord, and Lily Baxendale, London,
England, assignors to Biol-ex Laboratories Limited,
London, England, a corporation of the United Kingdom
Filed July 21, 1960, Ser. No. 44,412
high purity.
_
Claims priority, application Great Britain July 24, 1939
1 Claims. (Ci. 26d—488)
18% and 18,3-keto G.A. can be monohalogenated in the
usual manner, such as by dissolving 185 keto G.A. in an
inert organic solvent and adding one molecular equivalent
of halogen. In this case halogenation takes place at the
The present invention is concerned with new and thera
peutically useful derivatives of glycyrrhetinic acid.
2~position.
‘It is known from copending application, Ser. No.
645,898, ?led March 14, 1957, and now abandoned, that
The tri-halogen derivative ' can be prepared in a similar
manner,
i.e., by treating the 18m- and 18,8-keto G.A. in an
glycyrrhetinic acid either alone or in combination with
one or more anti-causative substances is a useful thera 15 inert organic solvent with 2 molecular equivalents of
halogen and, in this case, not only is a halogen atom
peutic agent not only for the treatment of in?ammatory
substituted in the 2-position but two halogen atoms are
conditions but also for the trearnent of a large variety of
also added across the 12,13-double bond. This tri-halogen
skin diseases and pruriginous skin conditions.
derivative is also new. It will be understood, however,
Various esters and hen1i~esters of glycyrrhetinic acid
in the case of the trihalogenation of l8oz- and 18,8-keto
are mentioned in copending application Serial No. 744,133, 20 that
G.A., the same compound is obtained.
‘filed June 26, 1958, and now US. Patent 2,915,825, and,
These halogen derivatives can be dehydrohalogenated
in addition, various other therapeutically useful derivatives
in a known manner, for example, by treatment with a
basic reagent, such as pyridine. In the case of the dehydro
halogenation of the mono-halo compounds, a double bond
of giycyrrhetinic acid are mentioned in copending applica
tions, Serial No. 742,706, ?led June 18, 1958, and Serial
No. 771,182, ?led November 3, 1958.
is formed in the 1,2-position. Thus, the mono-halo-lSoa
keto G.A. and the mono-halo-lS? keto G.A. give rise to
A1-18u-lceto G.A. and A1-18 -keto G.A., respectively.
When the trihalo derivatives are dehydrohalogenated,
We have now found that when glycyrrhetinic acid is
chemically treated in such a manner that double bonds are
introduced therein or that halogen atoms or ethinyl groups
are introduced therein, a potentiation of activity takes
not only is a double bond formed in the 1,2-position but
place. Such glycyrrhetinic acid derivatives have the same
v?eld of therapeutic application as the glycyrrhetinic acid 30 the double bond in the 12,13-position is reformed and a
further double bond is formed in the 18,19-position.
derivatives described and claimed in the aforesaid co
Thus, the trihalo-l-S/i-keto G.A. gives rise to Alils-keto
G.A.
The ZO-carboxylic acid group in N-ISB-keto G.A. and
pending applications, Serial Nos. 744,688; 742,706; and
771,182.
Thus, according to the present invention, there are pro
vided glycyrrhetinic acid derivatives of the general 35 in A1-18a-G.A., as well as in 18¢x-keto G.A. and ISp-keto
G.A., may be converted into the corresponding acid chlo
forrnuia:
ride group by reaction with, for example, thionyl chloride
or, better oxalyl chloride, preferably at elevated tempera
tures. The resulting 20i-acid chlorides are valuable inter
mediates in the preparation of further derivatives, particu
larly for the preparation of the corresponding ethinyl
derivatives.
These ethinyl derivatives are prepared in a known
manner by the reaction of the 20-acid chloride with, for
45 example, sodium acetylide in an inert solvent, such as
benzene.
The acyloxy-methyl compounds may be prepared from
the ZO-acid chloride, by reacting the acid chloride with
50'
wherein A, B, C and D are hydrogen atoms or A and
B and/or C and D can together represent a further
bond and X is a hydroxyl, ethinyl 0r acyl~oxymethyl
—CH2.O.acyl) radical.
55
It should also be explained that the two rings Y and Z
in the above-given general formula may be joined in the
cis-or trans-position. .The trans-compounds are herein
‘ after referred to as the war-compounds and the cis
, pounds are
referred to as the lS?-compounds.
3,1l-diketo-18or- ‘and
com
1S?-olean-12~en-20-carboxylic
the reaction scheme.
The following Examples 7, 8, l0 and 11 are given for
the purpose of illustrating the present invention and Ex
amples 1-6 and 9 for the purpose of illustrating the prepa
ration of intermediates, the Roman numerals referring to
the structural formulae in the accompanying drawings:
60
Example 1 .—Preparation of 3,11 -D iket0~18,8-O lean
JZ-En-ZO-Carboxylic Acid -(]8?-Ket0 GA .) (I)
acids, herein referred to as 180:- and 18,8-keto G.A. respec
23.5 g. l8?-glycyrrhetinic acid are dissolved in a mix
:tively, have already been prepared by Logemann et al.
' (Ber. 90, 603/ 19517) from 3-hydroxy~1l-keto-lS?-olean 65 ture of 100 cc. glacial acetic acid and 100 cc. alcohol
free chloroform and 5 g. chromic anhydride dissolved in
3,084,185
25 cc. glacial acetic acid and 5 cc. water carefully mixed
therewith. The temperature of the reaction mixture is
not allowed to rise above 30° C. After a period of three
hours, 10 cc. methanol are added, the mixture reduced to
of M.P. 328-9° C.; [a]D2°=+125° in chloroform
a small volume by evaporation under reduced pressure,
4 times the volume of water is added thereto, the precipi
tate obtained is dried and then dissolved in a solution of
(C=0.8).
Example 4.—-Preparation of 3,1 1-Diketo-18a-0lean-12
En-ZO-Carboxylic Acid .(18a-Ket0-GA.) (IX)
75 cc. 2 N sodium hydroxide in 100 cc. water and 100 cc.
industrial methylated spirit, boiled and ?ltered. (The
technique of boiling to alkaline solution of the product,
4
The precipitate was ?ltered oii with suction and dried at
100°C. 50 g. crude 18a-keto-G.A. are obtained. Re
crystallisation from glacial acetic acid and working up of
the mother liquors gives about 30 g. pure 18u-keto~G.A.
IS?-keto G.A. which may be prepared as described in
Example
1, is isomerised by heating for a period of about
after removal ‘of acetate ions,rresults in the decomposition
30 hours in ‘a 10% solution of potassium hydroxide in
‘of soluble chromium compounds, which otherwise impair
n-propanol. In this way there is obtained 18u-keto:G.A.
the subsequentcrystallisation, to give the insoluble chromic
(IX). Here again the product is obtained in a much
‘oxide which iscompletely removed by ?ltration.) After
acidi?cation of the solution obtained, ‘2.05 g. crude 1816 15 :higher yield and in a purer .state than the product pre
pared by the method described by Logemann et al.
keto G.A. (I) are obtained. This crude compound-is dis
10
»solvediin a mixture of 200 cc. methanol and 125 cc. chloro
Example 5.—Preparati0n of 2-_-Br0m0-3,,11-Dikei0-18B
tormrevaporateddown a little, if necessary, and allowed
Olean-IZ-Ene-ZO-Carboxylic Acid (Monobramo-lt‘i?
to crystallise in an ice chest (M.P. 295“ C.).
As stated above, the method of preparing 18ri-keto G.A. 20 Keto G.A.) (V)
20 cc. of a molar solution of ‘bromine in acetic acid is
according to the present invention issuperior to that de
slowly added to 9.4 g. 18?-keto GA. ‘in 300 cc. glacial
scribed'by Logemann et al. in that the yield is higher and
acetic acid at room temperature. ‘The mixture is allowed
the product obtained is considerably purer, i.e., in this
to stand for 30 minutes and 500 cc. cold water then added
‘example the yield of pure vproduct was 19 'g. (80—81%
yield) whereas Logemann’s yield was 70-71%.
25 slowly. The resulting precipitate is ?ltered oil and dried
in vacuo at room temperature.
Example 2.—Preparation of 3,11-Diketo-18?-0lean-12
10.5 .g. crude monobro
mo-18;S-keto-G.A. are obtained. The crude material is
En-ZO-Carboxylz'c Acid (18/8-Ket0-GA.) (I)
puri?ed by dissolving in cold acetone, adding methanol
and allowing the solution to evaporate at room tempera
A solution of 5 g. chromic anhydride in 5 cc. water and
‘25 cc. glacial acetic acid is added slowly to a .cold stirred 30 ture. Recrystallisation gives colourless needles of M.P.
240° C.; [u]D2“=+180° in chloroform (C=0.2).
solution of 23.5 g. 18,6-G.A. in 250 cc. glacial acetic acid.
Analysis.-C30H4304Br. Calculated 0:65.80; H:
The temperature of the reaction mixture is not allowed to
7.92; Br=14.59. Found C=66.30; H=8.01; Br=15.25.
rise above 25—30° C. After standing for about 12 hours,
The solid decomposes on standing and turns pale brown.
the mixture is heated on the steam bath to about 80° C.
In the same manner, 2-brorno—3,11-dikto-18m-olean-12
for ~15 minutes and 10 cc. methanol then added. The ‘
en-20’carboxylic acid (monobromo-18a-keto G.A. .(X'I)
mixture is poured into about one litre water, the precipi
may be prepared from lSu-keto G.A.) (1X). ‘
rated ?ltered off with suction, dried ?rst at 100° C. and
then in vacuo over potassium hydroxide. This ensures
Example 6.-—Preparazion of 2,12,13-Tribr0m0-3,11-Di
that all the ‘acetic acid is removed. ‘A powdery green
40
solid is obtained.
The precipitate is then mixed with 200 cc. methylated
keto-18u-0lean - 20 - Carboxylic Acid (Tribromo-18B
spirit, 100 cc. water and 50 cc. 2 N aqueous sodium hy
droxide and the suspension obtained digested on a steam
40 cc. of a molar solution of bromine in acetic acid is
as chromium ‘hydroxide (Cr(OH3). The hot alkaline so
lution is ?ltered and the ?ltrate poured into 1 litre water
containing 100 cc. 2 N aqueous hydrochloric acid. A
The resulting precipitate is ?ltered off and dried at room
temperature in vacuo. 12 g. of crude material is ob
tained. The substance is puri?ed by dissolving it in a
mixture of chloroform and methanol and allowing the
G.A.) (II )
slowly added to 9.4g. ISB-keto-GA. in 300 cc. glacial
bath ‘for 30 minutes. This process brings all the 183
acetic acid at room temperature. The mixture is left ‘for
_keto-A.G. into solution and precipitates all the chromium 45 30 minutes and 500 cc. cold water then added slowly.
white ‘precipitate of crude IS?-keto-GA. is immediately
thrown down. This precipitate is ?ltered off with suction
50 solution to evaporate. Colourless needles are obtained at
and dried. The dry crude product amounts to 21 g. It
is puri?ed by dissolving in a mixture of 200 cc. methanol
- and '125 cc. chloroform, evaporating the solution down, if
M.P. 255-6° C. The substance slowly decomposes on
standing.
Analysis.—C3oI-I43O4Br3.
Calculated Br=33.89%.
necessary, and allowing to crystallise. Repeated recrystal
Found Br=32.08%. In this tribromo compound, bro
lisation and working up of the mother liquors gives 19 g. 55 mine is substituted in the v2-position and also added to the
12- and Iii-positions, the 12,13 double bond being thereby
(81% of theory) v.pure IS-?-‘lreto-GA. in the "form of
colourless rhomboidal crystals or M.P. 295° _C.; {1131320
eliminated.
=+184° in chloroformw(C=l).
18u-keto G.A. (IX) may be tribrominated in the same
.
Example 3.—_Preparalion of 3,11-Diketo-18a-0lean-I2
En-ZO-Carboxylic Acid ,(180C-K6t0-G-A.) (IX)
manner and, in this case, the product will be the same as
00 that obtained by the tribromination of 18?-keto G.A. i.e.
compound II. When ~tribromo-18B-keto G.A. is‘recrys
53 g. l8a-G.A. is suspended in 1500 cc. glacial acetic
tallised .from a solvent, such as glacial acetic acid or
acid in a round-bottomed ?ask. A soxhlet extractor con
' taining 8.0 g. chromic anhydride in a Gooch crucible is
methanol, dehydrobromination apparently takes place at
the 12,13 and 18,19 positions to give 2~bromo-3,11-dikcto
clean-12,l8adiene-20-carboxylic acid, i.e. monobromo-Am
placed in the neck of the ?ask and the glacial acid mix 65
ture boiled under re?ux at reduced pressure, the tempera
ture not ‘being allowed to rise above 40° _C. Aiter 8
hours, the mixture is poured into 5 litres water and the
keto-G.A. This substance crystallises from acetic acid
as colourless plates of ‘M.P. 272-274° C.
Analysis-Bromine (found) 14.55%; (calc.) 14.66%.
100° C. and'then in vacuo over potassium hydroxide.
70 Example 7.-Preparation of 3,11-Diket0-18?-0lean-LI2
Dien-ZO-Carboxylic Acid (A1-1843-Keto G.A.) (V1)
The solid product is then digested on the steam bath
resulting suspension ?ltered. The precipitate is dried at
for 30 minutes in a mixture of 75 cc. 2 N aqueous sodium
hydroxide, 100 cc. water and 200 cc. methylated spirit.
11.0 g. pure monobromo-lS?-keto-GA. are mixed with
75
cc. dimethyl formamide and 25 cc. quinaldine and the
‘The alkaline mixture is ?ltered and poured into '2 litres
water containing 100 cc. 2 N aqueous hydrochloric acid. 75 golden solution obtained boiled in an atmosphere of
3,084,185
5
6
nitrogen for 4 hours. The dark green reaction mixture is
spending acetoxy acetyl derivative (XIV). ‘In the same
poured into a mixture of 20 cc. concentrated hydrochloric
acid and 200 cc. water and the resulting precipitate ?l
tered 01f, washed thoroughly with water and dried on a
manner, 3,1 l-diketo-ZO- (w-acetoxyacetyl) -1 8,8-olean-1, 12
diene (acetoacetyl-A1-l8l3-keto G.A.) (XV) may be pre
pared from the acid chloride ‘of A1-l8/3-keto G.A. (V161)
steam bath. The crude material thus obtained is crystal
lised by dissolving in a mixture of acetone and benzene
and evaporating to low bulk. Pure A1-18B-keto-GA. of
MP. 291-2" C. crystallises in the form of colourless
ene (acetoacetyl-A1-18a-keto G.A.) (XVI) ‘from the acid
rhomboids; [a]D20=—j-233° in chloroform B.P. (0:2);
It is to be understood that all the new derivatives of
:glycyrrhetinic acid which come with-in the scope of the
aD20=4.68° (i0.0l°) (2 dm.).
and 3,1l-diketo-ZO-(w-acetoxyacetyl) -18a-olean—1,12-di
chloride of A1-18a-keto G.A.
'
Analysis.~C3uH42O4. Calc.: C 77.21; H 9.07. Found:
C 77.20; H 9.14.
Using the same method, monobromo-l8a-keto-GA.
gives A1-18a-keto-GA. in the form of colourless plates
of MP. 333-4° 'C., [a]D2°=+146° in chloroform 15
(C=1.6): qD2°=+2.41° (i0.0il°) (2 dm.).
Example 8.—Preparati0n 0f 3,11-Diket0-Olean-I,]2,]8
Trien-20-Carboxylic Acid (Aug-Keto-GA.) (III)
present invention may be solubilised ‘by known methods.
Of special utility 'for this purpose there may be men
tioned Girard’s Reagent ‘T’
(H2'NNH.CO.CH2N+(CH3)3.(C1-)
However, similar hydrazine ammonium compounds may
also ‘be used.
Furthermore, in addition to the new com
pounds within the purview of the present application, it is
also possible to solubilise in this manner, 3, ll-diketo
12 g. tn'bromo-18B-keto G.A., which may be prepared
as described in Example 6, is mixed with 75 cc. dimethyl 20 20-(m-acetoxy-acetyl)-l8a- and 18;3-olean-l2~ene, these
two compounds having already been described by Loge
formamide and 25 cc. quinaldine and the golden solution
mann et al. (v. supra).
- . .
obtained boiled in an atmosphere of nitrogen for 4 hours.
What we claim is:
i
The crude green mixture obtained is poured into a mix
ture of 20 cc. concentrated hydrochloric acid and 200 cc. 25
Water and ‘the resulting precipitate ?ltered off, washed
thoroughly with water and dried on a steam bath. The
l. 3,1l-diketo-l8/8~olean-1,12-dien-20~carboxylic acid.
2. 3,1l-diketo-l8a-olean-1,>12~dien-20-carboxylic acid.
3. 3,11-diketo-olean-1,12,18-trien~20-carboxylic acid.
4. 3,11-diketo-2O-(ethinyl _ carbonyl)-18a-olean-1,12
diene.
anolic chloroform and evaporating to a small bulk; MP.
5. 3,11-diketo-20-(ethinyl - carbonyl) - clean-1,12,18
306-7“ C. The same product is obtained if, instead of 30 triene.
Al'ls-keto-GA. there is used 11 g. monobromo-Als-keto
crude material is recrystallised by ‘dissolving in meth
G.A.
6. 3,11-diketo-20~(ethinyl - carbonyD-lS? - olean-12
ene.
Example 9.—Preparati0n of 3,1J-Diket0-I8/3-0lean-1,12~
Dien-ZO-Carboxylic Acid Chloride (A1—18,8-Ket0 G.A.
Chloride) (VIa)
7. 3,11-diketo-20-(ethinyl 7 carbonyl)-l8a-olean - 12
ene.
35
A1-18,8-keto GA. which may ‘be prepared in the man
ner described in Example 7, is treated With oxalyl chlo
ride at an elevated temperature. In this manner, the
45
,
,
~
.
._
clean-1,l2-dien-20-carboxylic acid, which comprises sub
,jecting the corresponding
3,1Ldiketo-l8ot-olean-12-en—20
of a dehydrobrominating agent, whereby the‘ correspond
'
'
>13. A process [for theprep'aration of a 3,11-diketo
l-SB-olean-l,IZ-dieh-ZO-Carboxylic acid, which comprises
subjecting the corresponding 3,1l-diketo-lS?-olean-lZ-en
ZO-canboxylic acid to ‘the action of bromine until one
bromine atom has added on, thereby yielding the cor
responding 2-bromo compound, and subjecting the lat
ter to the action of a dehydrobrominating agent, whereby
the corresponding 1,12-diene is produced.
12-ene (ethinylketo-ltlp-keto G.A.) (VIII) from the acid
chloride of 18j6-keto G.A. ('Ia), 3,11-diketo-20-(ethinyl
GA .) (XIV)
.
50 1 ing 1,~12-diene is produced. ‘
G.A.-(IIIa), 3,1l-diketo-20-(ethinyl-carbonyl) ISB-olean
A cetyl) -Olean-] ,12,I 8-Triene(A cetoacety l-A1118 - Kezo
-
2-bromo compound, and ‘subjecting the latter to the action
may be prepared vfrom the acid chloride of Allls-keto
chloride of A1-18a-keto G.A. (XI-Ia).
Example 1] .—Preparation 0f 3,11-Diket0-20- (w-Acetoxy
diene.
atom has added on, thereby yielding the“ corresponding
clean-1,12,18-triene(ethinylketo - A1118 - keto G.A. (IV)
(ethinyl-keto-dl-l8u-keto G.A.) (XIII) ‘from the acid
v
carboxylic acid to the action‘ of bromine until one bromine
ing rise to ethinyl keto A1-18?-keto GA. (VII).
In the same manner, 3,1l-diketo-ZO-(ethinyl-carbonyl)
(X) from the acid chloride of ISa-keto G.A. (IXa) and
v
12. A process for the preparation of a 3,11-diketo-18ct
(In this manner, the acid chlo'.
ride group is converted into an ethinyl keto group giv
3,1l-diketo-20-(ethinyl-carbonyl)-18u-olean - 1,12 - diene
_
10. 3,11,diketo-2Q.-(wgacetoxyacetyl) - 18?-olean-1,12
_ diene.
prepared in the manner described in Example 9, is caused
carbonyl) -18a~olean-12-ene(ethinylketo-18a-keto (G.A.)
.
l1. 3,11~diketor20-(oracetoxyacetyl) _-.’ 18a-olean_-1,;l_2,
Keto G.A.) (VII)
The acid chloride of N-lS?-keto G.A., which may be
to react with one molecular equivalent of sodium acetylide
in the presence of benzene.
.
‘9. 3,1l-diketo-20-(w-acetoxy acetyl) -o1ean-1,12,18-tri
In the same manner, 18?-keto G.A., 18:2-k6t0 G.A.,
A1-18a-keto GA. and 131,13 GA. may be converted into
the corresponding ZO-acid chlorides.
Carbonyl-lé’?-Olean - 1,12-Diene(Ethinylket0-A1~18?
.
ene.
ZO-carboxylic acid group is converted into an acid chlo 40
ride group.
Example J0.—Preparation of 3,1J-Dikeio-20-Ethinyl
,
8. 3,11-diketo-20-(ethinyl - carbonyl)-18,3—olean-1,12
diene.
14. A process for the preparation of a 3,11-diketo18
60
clean-1,12,18-triene~20-carboxylic acid, which comprises
subjecting the corresponding 3,1l-diketo-l8a-olean-12-en
ZO-carboxylic acid to the action of bromine until three
bromine atoms have added on, thereby yielding the cor
responding 2,l2,l3-tribromo compound, and subjecting
. the latter to the action
of a dehydrobrominating agent,
whereby the corresponding 1,12,18-triene is produced.
15. A process for the preparation of a 3,1l~diketo-18
olean-l,12,1S-triene-Z-O-carboxylic acid, which comprises
subjecting the corresponding 3,1l-diketo-lSB-olean-l2-en
The ZO-acid chloride Al’ls-keto G.A. (Ilia), which may
be prepared in the manner described in Example 9, is 70 20-carboxylic acid to the action of bromine until three
bromine atoms have added on, thereby yielding the
caused to react with diazomethane to‘ give the correspond
corresponding 2,12,13~tribromo compound, and sub
ing diazoketone which, in turn, is caused to react with
jecting the latter to the action of a dehydrobrominating
acetic acid in the presence of potassium acetate. In this
agent, whereby the corresponding 1,12,18-triene is pro
manner, the 20-acid chloride is converted into the corre
75 duced.
3,084,185
‘s8
' 20. .A process ‘for the preparation of a compound of
1 1-76. A process‘ifor the‘preparation of a compound vof
the formula
the formula
'
O O -acy'loxymethyl
10
15
.
.
wherein
the moiety
20
is a member selected tfrom the group consisting of
>
1’
is a member selected from the group consisting of
H
H
‘I
25
and
and i
the moiety
the :moiety
30
D
G
is aimember selected from the group consisting of
is a member selected :from the group ‘consisting of p
35
and
and ‘the rings Y and Z being in one of the relationships
cis and trans with respect to each other, which comprises
subjecting-the corresponding 20-acid chloride to the action
of diazome'thane, and then reacting the resultant diaz0~
suhiecting the corresponding ZO-COOH compound to vthe
‘ketone with the corresponding carboxylic acid.
vaction of a chlorina'ting agent, whereby the corresponding
21. A process according to claim 20, wherein the car
acid chloride results, and subjecting the said acid chlo 45 iboxylic acid is acetic acid.
ride to the action of an ethinyla'ting agent, whereby the
References Cited in the ?le of this patent
desired ethinyl-substituted compound is obtained.
17. A process according to claim 16, wherein the
Wagner et aL: “Synthetic Organic Chemistry,” John
chlorinating agent is selected from the group consisting
Wiley & Sons, Inc., New York (1953), page 80.
50
'Logermann et a1.: “Chemische Berichte,” 90, 601-4
of thionyl chloride and oxalyl chloride.
40
and the rings Y__ and .Z being in one of the relationships
cis and trans with respect to each other, which comprises
’
18. A process according to claim 17, wherein the
ethiny'iating agent 'is sodium 'acetylide.
_
19. A process according to claim 16, wherein the
ethinylating agent is sodium acetylide.
‘(1957).
iFieser et aL: “Steroids,” Reinhold Publishing Corp,
‘New York (1959), pages .280 to 294, 557 and 623.
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