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Патент USA US3063995

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United States Patent ?O?lice
3,063,984
Patented Nov. 13, 1962
1
the following formulas:
3 063,984
CYCLOPENTANOPHEIQANTHRENE COMPOUNDS?
CH:
AND PROCESS
a
John A. Zderic, Mexico City, Mexico, assignor, by mesne
assignments, to Syntex Corporation, a corporation of
Panama
No Drawing. Filed Dec. 15, 1960, Ser. No. 75,945
21 Claims. (Cl. 260-239)
2/
6:0
HA5
The present invention relates to novel cyclopenta 10
nophenanthrene compounds and to a process for the pro
duction thereof.
In the above formulas Z indicates a double bond or a
More particularly the present invention relates to 11a
saturated linkage? between C-1 and C-2, R represents
aza-C-homo progestational hormones and more speci?
cally to 1la-aza-C-homo-A4-pregnene-3,207dione, to lla 15 hydrogen, an alkyl or an aralkyl group containing up to
12 carbon atoms and Ac represents the acylradical of
aza~C-homo-Al-?i-pregnadiene-3,ZO-dione, and to N-acyl
ated and N-alkylated derivatives thereof as well as to
quaternary ammonium salts thereof. .
t a hydrocarbon carboxylic acid of less than 12 carbons
saturated or unsaturated, of straight, branched, cyclic or
cyclic-aliphatic chain or aromatic. The acyl radical is
v,
The novel compounds of the present invention which
are progestational agents exhibiting anti-androgenic, anti
preferably the acetyl or a lower alkanoyl radical.? '
' ?The novel compounds of the present invention may be
estrogenic, anti-gonadotrophic and anti-ovulato'ry activie ' 3'- prepared by a process illustrated by the following equa-I
ties as well as hypotensive properties are represented by
tion:
I
' " ~ H53
l
I
1
on,
v
agar/W5 .
V
VI
3,063,984
'4'.
3
1
l
OH;
2:,
/\
z. E?? ii
VII
In the above formulas Ac and Z have the same mean 20 by the following equation:
ing as set forth above and R?- represents hydrogen or a
OH
hydrocarbon carboxylic acyl radical.
In practicing the process outlined above,_ the starting
compound,
.
\O
25
BLN
3ll-one (disclosed by Rothman and Wall in J. Am. Chem.
Soc. 79, 3228 (1957)) with lithium aluminum hydride
.1
to form 1l?,12?<dihydroxy-diosgenin, which, upon re
action with lead tetra-acetate in an inert solvent such as
benzene is converted into the ll,1'2-seco-22a-A5-spirosten
B?-ol-l 1,12-dial (I). The dialdehyde is then reacted with
ammonia in ethanol solution thereby yielding a Schi?
base type intermediate which is then reacted with lithium
30 AC0v
,
tion, thus forming 3?-acyloxy-l1a~N-acetyl-C-homo-22a
A5-spirostene (III) which may then be subjected to degra
dation of the side chain to form the 11a-N-acetyl-C-horno?
A5�-pregnadien-3,9-ol-20-one acylate (IV).
i
H0
EOE
�0
X
(?3H3
011.
0:0
(V:R'=acyl) which. is then preferentially saponi?ed at
C-3 by treatment with methanolic hydrochloric acid to
1
i
acylate
2
=0
R2?N/\i }
R=?N/\
f
l1a-N-acetyl-C-horno-A5-pregnen-318 - o1 - 20 - one
(V:R?=hydrogen). The 3?-hydroxy-A5-group of the last
H0
XI
Selective
1la镹-acctyl-C-homo-A?-pregnen - 3B - ol-20-one
MA
45
hydrogenation of the C-16,17-double bond of the latter
compound over a palladium-charcoal catalyst results in 50
afford
om
1
The degradation of the side
chain may be preceded by acylation, preferably acetyla
1x
(?3113
MAL 1
40
thus forming lla-N-ac?etyl-C-homo-AsJipregnadien-SB
ol-ZO-one acetate (IV).
i
HO 4
aluminum hydride in tetrahydrofuran to form Ila-aza
C-horno-22a-A5-spirosten-3?-ol (II). Degradation of the 35,
spiroketal side chain is then effected by conventional pro
cedure as by reaction with acetic anhydride at about 200�,
oxidation of the resulting pseudo-compound to the di
osone and alkaline hydrolysis and acetylation of the latter
0
0/ 1
.
11,12 - seco - 22 - A5 - spirosten-B??-ol-l1,12-dial
(I) isjpre-pared by treating A5-22a-spirosten?3?,12?-diol
TH:
a
(?i=0
55
named compound is converted to the A4-_-3,-,keto moiety by
oxidizing under Oppenauer conditions or with chromic
,__.
O;
XIII
HO
XII
acid in acetone solution followed by treatment with acid
to thus form 1la-N-acetyl-C-homo-M-pregnene-B?,20
dione (VI). Upon reaction with methanolic potassium
60
?
ta
hydroxide, the acetyl group is removed and there is
0=o
formed lla-aza-C-homo-A?i-pregnene-3,20-dione (VIII:
Z=saturated linkage).
RaX_.
\+/\
For introduction of a double bond at C-l,2, the Ila-N 65
acetyl-C-horno-A4-pregnene-3,20-dione (VI) is re?uxed
R??N
Z
with selenium dioxide in a solvent such as t-butanol in
the presence of catalytic amounts of pyridine to form the
corresponding l-dehydro compound, lla-N-acetyl-C
homo-A1�pregnadiene-3,2Q-dione (VII). Upon reaction
with methanolic potassium hydroxide, the lla-aza-C
homo-ul-?t-pregnadiene- 3,20-dione
bond) is obtained.
'
(VIII:
Z=?double
0=
70
-
XIV
In the above formulas, R2 represents an alkyl or aralkyl
group containing up to 12 carbon atoms; R3 represents a
lower alkyl' group; X represents a halogen such as iodine,
The novel lla-N-alkylated-Ohorno compounds of the
bromine or chlorine and Z and Ac have the same mean.
present invention may be prepared by a process illustrated 75 ing as previously set forth.
3,063,984
.
.
.
.
.
6
5
In practicing the process outlined above lla-N-acyl-C
decomposed by careful addition ?of acetone, then a small
horno-A5I16-pregnadien-3lfi-ol-20-one acylate, preferably
11a-N-acetyl-C-homo-A5,ls-pregnadien-3,8-01-20-0ne acyl
amount of saturated aqueous sodium sulfate solution and
?nally solid anhydrous sodium sulfate were added. The
solid was collected by ?ltration and the ?ltrate evaporated
ate (IV) is re?uxed with lithium aluminum hydride in
tetrahydrofuran for 5 hours to form lla-N-ethyl-C
homoA5,16-pregnadiene-3B,20-diol (XI) which upon re
to dryness under reduced pressure. Crystallization from
aqueous ethanol yielded 11a-aza-C-homo-22a-A5-spi
rosten-3B-ol.
action with manganese dioxide in chloroform at room
temperature affords 11a-N-ethyl-C-homo-Ail?-pregna
Example II
dien-3B-ol-20-one (X). The latter compound can also be
formed by ?rst protecting the keto group of lla-N-acetyl 10
C-homo-A5J6-pregnadien-3?-ol-ZO-one acylate (IV) by
formation of the cyclic ethylene ketal thereof by conven
tional methods, followed by reduction with lithium alu?
minum hydride to produce the cyclic ethylene ketal of
11a-N-ethyl-C-homo-A5-16-pregnadien-35-ol-20-one (IX)
ml. of 80% acetic acid; after stirring for three hours at
room temperature, the mixture was diluted with water,
which is then hydrolyzed with acid to form lla-N-ethyl
C-homo-A5'16-pregnadien-3?-ol-ZO-one (X).
The latter
extracted with ether and the extract was washed with
water, dried over anhydrous sodium sulfate and the ether
was evaporated. The residue was mixed with 200 ml. of
compound is converted to lla-N-ethyl-C-homo-A5-preg
nen-3/8-ol-20~one (XII) by hydrogenation in the presence
60% acetone containing 2 g. of potassium hydroxide and
refluxed for 5 hours, then concentrated to a small volume,
cooled, diluted with water and extracted with ether. The
of a hydrogenation catalyst such as palladium, and, upon
oxidation under Oppenauer conditions there is formed
11a - N - ethyl - C - homo-A4-pregnene-3,20-dione
4 g. of the latter compound was heated with 20 ml. of
acetic anhydride in a sealed tube at 200� C. for 55 min
utes; it was then cooled, the excess of anhydride was hy
drolyzed by the addition of 8 ml. of water and the mix
ture was treated with 2 g. of chromium trioxide in 25
(XIII:
Z=saturated linkage). A double bond may then be in
troduced at C-1,2 by reaction with selenium dioxide to
extract was washed several times with water, dried over
afford the l-dehydro compound (XIII: Z=double bond).
Upon conventional acetylation, followed by recrystalliza
The quaternary ammonium salt of the latter compound
is prepared by conventional methods, as for example,
tion from acetone-hexane, there was obtained 3,8-acetoxy
anhydrous sodium sulfate and evaporated to dryness.
11a-N-acetyl-C-homo-Ati,16-pregnadien-20-one.
the N-ethyl compound (XIII) is reacted with an alkyl or
an aralkyl halide in a solvent such as notroalkane to thus
form the
quaternary ammonium halide
(XIV).
derivative 30
Example III
2 g. of 1?1a-aza-C-homo-22a-spirosten-3B-ol (described
in Example I) was treated with 2 ml. of acetic anhydride
in 10 ml. of pyridine at room temperature. The mixture
was allowed to stand overnight and was then diluted with
Other N-acylated and N-alkylated compounds are pre-?
pared by substituting for the N-acetyl group other acyl
groups of the type mentioned previously. Thus there are
water, the solid was collected by ?ltration, washed with
obtained N-acylated and N-alkylated compounds con 35 water, dried and recrystallized from acetone~hexane thus
taining up to 12 carbon atoms such at N-propionyl, N
aifording 3?-acetoxy-l1a-N-acetyl-C-homo-22a-A5-spiro
benzoyl, N-butyryl and the corresponding N-propyl, N
sten. The latter compound was then treated with acetic
benzyl and N-butyl derivatives.
anhydride at 200�, the resulting pseudo-sapogenin was
The following examples serve to illustrate but are not
intended to limit the scope of the invention:
oxidized to the ?diosone and was then treated with potas
40
sium hydroxide followed by reesteri?cation as described
in Example II to thus yield 3;8-acetoxy-1la-N-acetyl-C
homo-A5,l?-pregnadien-ZO-one, identical with the com
Example I
pound obtained in Example H.
A solution of 10 g?. of A5-22a-spirosten-3?,12/3-diol-l1
one-diacetate (Rothman and Wall, J. Am. Chem. Soc.
Example IV
79, 3228 (1957)) in 300 ml. of anhydrous tetrahydro 45
furan was added dropwise to a suspension of 10 g. of
lithium aluminum hydride in 1 liter of anhydrous tetra
hydrofuran while stirring and the resulting mixture was
re?uxed for 30 minutes. =Acetone was added cautiously
to decompose the excess of the hydride, then treated with
saturated aqueous sodium sulfate, ?nally with anhydrous
sodium sulfate, the solid was ?ltered and the ?ltrate evap
orated to dryness. The residue was triturated with hexane
yielding 1 1B, IZ?-dihydroxy-diosgenin.
A solution of 1.25 g. of 3/3-acetoxy-lla-N-acetyl-C
homo-A5?le-pregnadien-ZO-one in 50 cc. of ethyl acetate
was hydrogenated at room temperature and atmospheric
pressure using 200 mg. of prereduced 10% palladium on
charcoal catalyst, until 1 molar equivalent of hydrogen
was absorbed, the catalyst was ?ltered and the ?ltrate
evaporated to a small volume.
Addition of methanol
gave the crystalline S/S-acetoxy-I1a-N-acety1-C-homo-A5
pregnen-ZO-one.
1
To a mixture of 8.1 g. of 1l?,IZ?-dihydroxy-diosgenin, 55 A solution of 11 g. of the above compound in 25 cc.
140 ml. of glacial acetic acid and 210 ml. of thiophene
of 2.5% methanolic solution of perchloric acid was kept
free benzene, 12.1 g. of lead tetraacetate were added and
at room temperature for 18 hours, it was then diluted
the mixture was stirred at room temperature for 5 min
with water, the formed precipitate collected by ?ltration,
utes. 200 ml. of water containing 100 g. of sodium ace
washed with water, dried and recrystallized from ace
tate and 4 g. of sodium iodide were added, the color was 60 tone-hexane, thus giving 11a-N-acetyl-C-homo-A5-preg
discharged by the addition of 80 ml. of saturated aqueous
nen-3;8_ol-20-one.
?
sodium thiosulfate solution and the product extracted
1 g. of the latter compound was dissolved in 10 cc. of
twice, using each time 200 ml. of ethyl acetate. The
acetone, cooled to 0� C., flushed with nitrogen and
pooled extracts were washed with aqueous sodium bi
treated under stirring with 8 N chromic acid solution
carbonate and water, dried over anhydrous sodium sul 65 added in a thin stream, at 0� C., until the red color of
fate and evaporated to dryness. The residue was crystal
chromium trioxide persisted in the mixture. (The 8 N
lized from a mixture of 60 ml. of methanol and 12.5 ml.
solution of chromic acid was prepared by dissolving 26.7
of water to a?ord l1,12-seco-22a-A5-spirosten-3,8-01-1l,
g. of chromium trioxide in 23 cc. of concentrated sul
12-diol.
furic acid and diluting with water to 100 cc.) The reac
A mixture of 5 g. of the dialdehyde and 250 ml. of
tion mixture was stirred for 5 minutes further, diluted
ammonia-saturated ethanol was re?uxed during 10 hours.
with water and the product collected by ?ltration, washed
Upon evaporation of the solvent, a crystalline residue was
with water and dried under vacuum.
obtained which was re?uxed with 2.5 g. of lithium alu
The crude product was dissolved in 40 cc. of methanol
minum hydride in mixture with 250 ml. of tetrahydro
and treated at room temperature with a solution of 0.1
furan during 20 hours. The excess of hydride was then 75 g. of oxalic acid in 1 cc. of water. The mixture was kept
7
standing for 3 hours, then diluted with water and the
8
by following the method of Example IV, gave 1?-1a-N=
product was collected by ?ltration, washed with water
to neutral and dried. There was thus obtained Ila-N
ethyl-C-hom'o-A1'4-pregnadiene-3,20-diotie.
acetyliC-homosA4-pregnene-3,ZO-dione.
? A stirred mixture of 500 mg. of the above compound,
25 .cc. of t-butanol, 200 mg. of selenium dioxide and 0.15
cc. of pyridine was re?uxed for 48 hours under an at
Example VII
A mixture of 2 g. of 3B-acetoxy-lla-N-acetyl-C-homoa
A5Y1G-pregnadien-?ZO-Qne, 20 cc. of dry benzene, 16 cc. of
ethylene glycol and 300 mg. of p-toluenesulfonic?acid
monohydrate was re?uxed for 8 hours, using a Dean6
Stark water separator. The cooled reaction solution was
?ltrate was evaporated to dryness under reduced pres
washed with 5% aqueous sodium bicarbonate and water
sure. The residue was dissolved in acetone, treated with 10 to neutral, dried over anhydrous sodium sulfate and the
mosphere of nitrogen, ?ltered through celite, and the
decolorizing charcoal, re?uxed for 1 hour, ?ltered and
the acetone was evaporated. The residue was puri?ed by
chromatography on neutral alumina and the solid eluates
were crystallized from acetone-hexane, thus giving 11a
N-acetyLC-homo-AL?Lpregnadiene-3,20-dione.
Example V
1 g. of 11a-N-acetyl-C-homo-A4-pregnene-3,20-dione,
obtained as described in the preceding example was re
?uxed for 48 hours under an atmosphere of nitrogen with
50 cc. of 4% methanolic potassium hydroxide solution
and then neutralized with acetic acid. Part of the solvent
was removed under reduced pressure, water added and
solvent was evaporated.
Crystallization of the residue
from acetone-ether afforded ZO-ethylenedioxy-lla-N
acetyl-C-homo-A5?16-pregnadien-3B-ol-acetate.
By following the reduction method of the preceding ex
ample, the above compound was reduced with lithium
aluminum hydride in tetrahydrofuran, thus giving 20
ethylenedioxy-lla-N-ethyl - C - homo - A546 - pregnadien
35-01.
A solution of 1 g. of the latter compound in 50 cc.
of acetone was treated with 20 mg. of p-toluenesulfonic
acid monohydrate and the mixture kept at room tem
perature for 16 hours, poured into dilute sodium car
bonate solution and the solid collected by ?ltration.
then extracted with methylene chloride, the organic ex
Crystallization from acetone-hexane gave lla-N-ethyl
tract washed to neutral, dried over anhydrous sodium 25 C-homO-AE'JG-pregnadien-S?-ol-ZO-one, identical with the
sulfate and evaporated to dryness. Chromatography of
the residue gave the pure 1la~aza-C-homo-A4-pregnene
intermediate of Example VI.
Example VIII
3,20-dione.
. In a similar manner, lla-N-acetyl-C-homo-nl-?i-preg
A solution of 200 mg. of l1a-N-ethyl-C-homo-M-preg
nadiene-3,20-dione was converted into lla-aza-C-homo 30 nene-3,20-dione in 20 cc. of nitromethane was treated with
A1�pregna-diene-3,2O-dione.
2 g. of methyl iodide and heated in a sealed tube at 100�
C. for 3 hours concentrated almost to dryness, diluted
Example VI
with a little cold ether and the precipitate was collected
A solution of 5 g. of 3f3-acetoxy-1la-N-acetyl-C-homo 35 by ?ltration, thus giving the methoiodide of lla-N-ethyl
A5'16~pregnadien-2O-one, obtained as described in Ex
C-homo-A4-pregnene-3,ZO-dione.
ample II, in 150 cc. of anhydrous tetrahydrofuran was
In a similar manner, 11a-N-ethyl-C-homo-N-4~preg
added dropwise to a suspension of 5 g. of lithium alumi
nadiene-3,20-dione was converted into the methoiodide
num hydride in 300 cc. of anhydrous tetrahydrofuran
and the mixture re?uxed for 30 hours with stirring. 40
Acetone was added cautiously to decompose the excess of
hydride, then saturated aqueous sodium sulfate solution
and ?nally solid anhydrous sodium sulfate were added.
The solid was ?ltered and washed well with hot ethyl
acetate, and the ?ltrate and washings were evaporated
to dryness under reduced pressure. Crystallization of 45
the residue from acetone-hexane gave llla-N-ethyl-C
homo-A5?15-pregnadiene-3;8,20-diol.
A solution of 3? g. of the above compound in 300 cc.
of chloroform, distilled over calcium chloride was stirred
for 18} hours at room, temperature with 30 g. of freshly
precipitated manganese dioxide. The inorganic material
was ?ltered, washed with hot chloroform and the solu
tion evaporated; the residue crystallized on trituration
with hexane.
Recrystallization from acetone-hexane
gave 11a~N-ethyl-C-homo-A5JS-pregnadien-313-ol-20-one.
A solution of 2 g. of the above compound in 80 cc.
of ethyl acetate was hydrogenated at room temperature
of 11a-N-ethyl-C-homo-Al-4-pregnadiene-3,ZO-dione.
I claim:
1. A compound of the following formula:
. Med
or
wherein Z is selected from the group consisting of a
double bond between C-1 and C-2 and a saturated link
age between C-1 and C-2.
2. 11a-aza-C-homo-M-pregnen-B,20-dione.
3. 'l1a-aza-C-homo-A1I4-pregnadiene-3,20-dione.
4. A compound of the following formula:
and atmospheric pressure using 400 mg. of 10% pal
ladium- on charcoal catalyst, in accordance with the meth
od' of Example IV. There was thus obtained lla-N
ethyl-C-homo-A5-pregnen-3?-ol-20-one.
A solution of 1 g. of the latter compound in 80 cc. of
toluene and 20 cc. of cyclohexanone was dried by dis
tilling oil, 10 cc. of solvent. A solution of 1 g. of alumi
.
IQ
num isopropoxide dissolved in 7 cc. of anhydrous 65
toluene was then added and the mixture was re?uxed for
45?minutes; 4 cc. of acetic acid were added and the sol
vents removed by steam distillation. The product was
wherein R2 is selected from the group consisting of alkyl
extracted several times with ethyl acetate and the organic
extracts washed with 5% hydrochloric acid solution, 70 and aralkyl containing up to 12 carbon atoms and Z is
selected from the group consisting of a double bond be
water, 10% sodium carbonate solution and water until
tween C-1 and 0-2 and a saturated linkage between C-1
neutral, dried over anhydrous sodium sulfate and evapo
and C-2.
rated until crystallization started. There was thus ob
tained l1a-N-ethyl-C-homo-A4-pregnene-3,ZO-dione.
Selenium dioxide oxidation of the above compound, 75
5. 1la-N-ethyl-C-homo-A4-pregnene-3,ZO-dione.
6. 1 1 a-N-ethyl-C-homo-A1e-pregnadiene-iZO-dione.
8,068,984
9
10
7. The lower alkyl quaternary ammonium salts of a
compound of the following formula:
from the group consisting of a double bond between 0-1
and 0-2 and a saturated linkage between 0-1 and C-2.
1 1. 1 la-N-acetyl-C-homo-M-pregnene-3,20-dione.
CH8
12. lla-N-acetyl-C-homo - A1�- pregnadiene - 3,20
4}_
5 dione.
?0
13. A compound of the following formula:
BLN/\
0H,
2
=0
1?
wherein R2 is selected from the group consisting of alkyl 15
and aralkyl containing up to 12 carbon atoms and Z is
RIO
selected from the group consisting of a double bond be-
-
.
neg�
' ?
.
.
_
_
ggggolodlde of ll'a'N'ethyl'c hOmO'N Preg'
'
'.
group of less than 12 carbon atoms; and R' is selected
20 from the group consisting of hydrogen and a hydrocar
bon carboxylic acyl group of less than 12 carbon atoms.
.
14.
nag?iegg 525312811051? of 11a'N'ethyl'c'homo'Al'Lpreg'
acetate.
25
OH:
(5:0
z
11a-N-acetyl-C-homo-A5-pregnen-3p-ol-2O-one.
15. lla-N-acetyl-C-homo - A5 - pregnen-3?-ol-20-one
10. A compound of the following formula:
Ae__N/\?
-
wherein Ac represents a hydrocarbon carboxylic acyl
Zigzag g4 and C_?2 and a saturated linkage between 0-1
" '
Tom -
16. 11a-N~acety1-C-homo - A5116 - pregnadien-3p-ol-20
one acetate.
17. lla-N-ethyl-C-homo - A5,? - pregnadien-3p-ol-20
one.
18. 1 1a-N-ethyl-C-homo-A5-pregnen-3B-ol-20-one.
30 20.
19. 11,12-seco-22a-A5-spirosten-3?-ol-11,12-dial.
1 1a-aza-C-homo-22a-A5-spirosten-3p-ol.
21. 11a-N-acetyl-C-homo-22a - A5 - spirosten - 3B - ol
acetate.
0_
35
References Cited in the ?le of this patent
UNITED STATES PATENTS
wherein Ac represents a hydrocarbon carboxylic acyl
group of less than 12 carbon atoms and Z is selected
2,806,028
2,806,029
Mazur ______________ __ Sept. 10, 1957
Mazur ______________ _._ Sept. 10, 1957
UNITED STATES PATENT OFFICE
Certi?cate of Correction
Patent No. 3,063,984
November 13, 1962
John A. Zderie
It?is hereby certified that error appears in the above numbered patent requiring
correct-1011 and that the said Letters Patent should read as corrected below.
_
Column 2, lines 2 to 12, the formulas should appear as shown below instead of as
111 the patent:
columns 1 and 2, Formulas II, III, IV, V and VI should appear as shown below instead
of as in the patent:
J
O
?Al/J
m H
m
M05 w
Mom
MQEY
CH|
CH1
=
=0
columns 3 and. 4, Formulas VIII and VII should appear as shown below instead of as
in the patent:
OH:
OH:
z i
0Q
VIII
0
Q
v11
3,063,984
column 4, Formulas IV, IX, XI, X, XIII, XII and XIV should appear as shown below
instead of as in the patent:
CH1
OH:
e=o
M15
Ac 0s
.
"<31
mm
110C
IV
on,
om
HOH
=0
R'-?N/\ /�
110
m-nAi?
Cb?
:10
x1
3:;
O5
x
ii;
Mm
0Q
11:
3%
xm
HCPC
1:11
on.
x?
2
=0
?
0Q
xxv
colungn 8,l lines 41 to 52, the formula should appear as shown below instead of as in the
patent :
OH:
m
m
column 8, lines 58 to 68, the formula; should appear as shown below instead of as in the
patent:
3,063,984
column 9, lines 5 to 14, the formula should appear as shown below instead of as in the
patent:
CHI
6:0
Z
Iii-NA,
of;
column 9, lines 26 ?to 36, the formula. should appear as shown below instead of as in the
patent:
0H:
column 10, lines 7 to 17, the formul
paten1;:
2� should appear as shown below instead of as in the
Ara-NA?
Signed and sealed this 6th day of August 1963.
[SEAL]
Attest:
ERNEST W. SWIDER,
Attestz'ng U?icer.
DAVID L. LADD,
Oomndssz'mer of Patents.
UNITED STATES PATENT OFFICE
Certi?cate of Correction
Patent No. 3,063,98I
November 13, 1062
John A. Zderio
It, is hereby certiliecllhnl error appears in the above numbered patent requiring
correction and that the srud Letters Patent should read as corrected below.
_
Column 2, lines 2 Lo 12, the formulas should appear as shown below instead of as
m the patent:
W50 Mo
(1/ no?
columns 1 and 2, Formulas II, III, IV, V and VI should appear as shown below inslead
of as in the patent:
O
UNA?:
? / I
no
n
We
we
Rob v
o5 w
columns 3 and 4, Formulas VIII and VII should appear as shown below instead of as
in the patent;
2%
o5
Mu
0o
3,063,984
column 4:, Formulas IV, IX, XI, X, XIII, XII and XIV should appear as shown below
instead of as in the patent:
TH?
OH;
/0
=0
癨0]
m
w
M005 RG3?
MW
Rm
H003 H005
rv
1x
0H;
0 E:
HOE
:0
x1
Z
I:
OH:
OH:
=
5:0
nI-NAi
R1-N/\\
4
0Q
XIII
1104C
x11
CH]
x?
=0
Egon
m m
oohun閘 8, lines 41 to 52, the formula, should appear as shown below instead. of as in the
pat/en? :
Z
III-NA
of)
O
column 8, lines 58 to 68, the formula, shoulzl appear as shown below instead of as in the
patent :
nI-NA
3,083,984
column 9, lines 5 to 14, the formula should appear as shown below instead of as in the
patent:
m
o?
column 9, lines 26 ?to 36, the formula should appear as shown below instead of as in the
patent:
Q
ol
ooltl閙n 10, lines 7 to 17, the formula should appear as shown below instead of as in the
pa. nt:
mm
?1115
Signed and sealed this 6th day of August 1963.
[SEAL]
Attest:
ERNEST W. SWIDER,
Attestz'ng Oy?cer.
DAVID L. LADD,
Oomwnissz'amr of Patents.
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