Language selection

Search

Patent 1053669 Summary

Third-party information liability

Some of the information on this Web page has been provided by external sources. The Government of Canada is not responsible for the accuracy, reliability or currency of the information supplied by external sources. Users wishing to rely upon this information should consult directly with the source of the information. Content provided by external sources is not subject to official languages, privacy and accessibility requirements.

Claims and Abstract availability

Any discrepancies in the text and image of the Claims and Abstract are due to differing posting times. Text of the Claims and Abstract are posted:

  • At the time the application is open to public inspection;
  • At the time of issue of the patent (grant).
(12) Patent: (11) CA 1053669
(21) Application Number: 1053669
(54) English Title: INTERMEDIATE CYCLOPENTANE DERIVATIVES
(54) French Title: DERIVES INTERMEDIAIRES DU CYCLOPENTANE
Status: Term Expired - Post Grant Beyond Limit
Bibliographic Data
(51) International Patent Classification (IPC):
  • C07D 407/12 (2006.01)
  • C07D 307/77 (2006.01)
  • C07D 309/12 (2006.01)
(72) Inventors :
  • HESS, HANS-JURGEN E.
  • SCHAAF, THOMAS K.
(73) Owners :
  • PFIZER INC.
(71) Applicants :
  • PFIZER INC. (United States of America)
(74) Agent:
(74) Associate agent:
(45) Issued: 1979-05-01
(22) Filed Date:
Availability of licence: N/A
Dedicated to the Public: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data: None

Abstracts

English Abstract


ABSTRACT OF THE DISCLOSURE
Cyclopentane derivatives useful as intermediates
in the preparation of 15-substituted-.omega.-pentanorprostaglandins
and processes for the preparation thereof, the said cyclo-
pentane derivatives having the formula:
<IMG> ...I
wherein A is cycloalkyl of from three to ten carbon atoms,
1-adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl), 2-
indanyl or substituted 2-indanyl wherein the substitutent is
halo, trifluoromethyl, lower alkyl or lower alkoxy;
Q is hydrogen, p-biphenylcarbonyl or 2-tetrahydro-
pyranyl;
n is an integer from 0 to 5;
Y is =0, or <IMG> ; Z is a single bond or
a trans double bond, and X is =0 or <IMG> , wherein Q' is
hydrogen or 2-tetrahydropyranyl and R is hydrogen or lower
alkyl, with the proviso that when Q' is 2-tetrahydropyranyl
Q is also 2-tetrahydropyranyl and when Q is p-biphenylcarbonyl
and X and Y are =0, Z is a trans double bond.


Claims

Note: Claims are shown in the official language in which they were submitted.


The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A process for preparing a compound of the formula:
<IMG> ...I
wherein A is cycloalkyl of from three to ten carbon atoms, 1-
adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl), 2-
indanyl or substituted 2-indanyl wherein the substituent is
halo, trifluoromethyl, lower alkyl or lower alkoxy;
Q is hydrogen, p-biphenylcarbonyl or 2-tetrahydro-
pyranyl;
n is an integer from 0 to 5;
Y is =0, or <IMG> ; Z is a single bond or a trans
double bond, and X is =0 or <IMG> wherein Q' is hydrogen or 2-
tetrahydropyranyl and R is hydrogen or lower alkyl, with the
proviso that when Q' is 2-tetrahydropyranyl Q is also 2-tetrahydro-
pyranyl and when Q is p-biphenylcarbonyl and X and Y are =0, Z is
a trans double bond; which comprises
(a) reacting a compound of the formula:
<IMG>
wherein Q" is p-biphenylcarbonyl, with a compound of the formula:
<IMG>
to form a product of the formula:
24

<IMG>
... IA
wherein A, Q" and n are as defined above;
(b) reducing a compound of the formula IIIa:
<IMG>
...IIIa
wherein A, n and Z are as defined above, and Q3 is hydrogen or
p-biphenylcarbonyl, to form a compound of the formula:
<IMG>
... IV
wherein A, n, Q3 and Z are as defined above and R is hydrogen,
and, if desired, separating the 8 .alpha.- and 8 .beta.-isomers;
(c) reacting a compound of formula IA as defined above,
with a suitable alkylating agent to afford a compound of formula
IV wherein A, n, Q3 and Z are as defined above and R is lower
alkyl;
(d) catalytically hydrogenating a compound of formula IV
above,wherein A, n and R are as defined above, Q3 is hydrogen
and Z is a trans double bond to afford a compound of formula IV
wherein A, n and R are as defined above, Q3 is hydrogen and Z is
a single bond; and if desired, reacting a compound of formula IV
above, wherein A, n, Z and R are as defined above and Q3 is
biphenylcarbonyl with K2CO3 to afford a compound of formula IV

- 26 -
wherein Q3 is hydrogen; and, if desired, separating the 8?-
and 8 .beta. -isomers;
(e) reacting a compound of the formula:
<IMG>
...IVa
wherein A, n, R and Z are as defined above and Y is =0, with
2,3-dihydropyran in the presence of an acid catalyst to afford
a compound of the formula:
<IMG>
...V
wherein A, n, R and Z are as defined above, Y is =0 and Q2 is
2-tetrahydropyranyl;
(f) reacting a compound of formula V, above, wherein A,
n, R and Z are as defined above and Y is =0 with an appropriate
reducing agent to afford a compound of formula V wherein A,
n, R and Z are as defined above and Y is <IMG>;
(g) catalytically hydrogenating a compound of formula V
above, wherein A, n and R are as defined above, Z is a trans
double bond and Y is =0, to afford a compound of formula V
wherein A, n and R are as defined above, Y is =0 and Z is a
single bond.
2. A compound of the formula:
<IMG> ... IA

wherein A and Q" are as defined in claim 1, when prepared by
a process according to claim 1(a) or an obvious chemical
equivalent thereof.
3. A compound of the formula:
<IMG>
...IV
wherein n, A, R, Z and Q3 are as defined in claim 1, when
prepared by a process according to claim 1 or an obvious chemical
equivalent thereof.
27

Description

Note: Descriptions are shown in the official language in which they were submitted.


105~6~9 _ ASE 5446-A_D2
This invention relates to the preparation of
certain novel cyclopentane derivatives useful in the
preparation of novel analogs of the naturally occurring
prostaglandins. In particular, it relates to the preparation
of various novel intermediates useful in the preparation
of the novel 15-substituted-~J-pentanorprostaglandins
described and claimed in Patent Application No. 185,366.
In accordance with the present invention there
is provided a proces, for preparing a compound of the
formula:
_<
Q o~ L--~(CH2)n-~ I
%
wherein A is cycloalkyl of from three to ten carbon atoms,
l-adamantyl, 2-norbornyl, 2-tl,2,3,4-tetrahydronaphthyl), 2-
indanyl or substituted 2-indanyl wherein the substituent is
halo, trifluoromethyl, lower a~kyl or lower alkoxy;
Q is hydrogen, p-b;phenylcarbonyl or 2-tetrahydro-
pyranyl;
n is an integer from O to 5;
H
Y is =0, or < ; Z is a single bond or
OH ,R0 a trans double bond, and X is =O or ~ , wherein Q' is
Q'
hydrogen or 2-tetrahydropyranyl and R is hydrogen or lower
alkyl, with the proviso that when Q' is 2-tetrahydropyranyl
Q is also 2-tetrahydropyranyl and when Q is p-biphenylcarbonyl
and X and Y are =0, Z is a trans douhle bond; which comprises

1053669
(a) reacting a compound of the formula:
o-~
~ O~" C~lo
wherein Q" is p-biphenylcarbonyl, with a compound of the
formula: o
A - (CH2)n - C - CH2 - P(OCH3)2
to form a product of the formula:
o~
.. . .
~ (CH2~n~~
wherein A, Q" and n are as defined above;
(b) reducing a compound of the formula IlIa:
' o~
Q30~ L~(c~2) n~A . ~ ~ IIIa
wherein A, n and Z are as defined above, and Q3 is hydrogen
or p-biphenylcarbonyl, to form a compound of the formula:
0~
Q~O ~ tCH2)n-A . .. I~t
H R
wherein A, n, Q3 and Z are as defined above and R is hydrogen,
and, if des;red, separating the 8d~- and 8 B-isomers;
,
~ -2A-

~0536~;9
(c) reacting a compound of formula IA as defined
above, with a suitable alkylating agent to afford a compound
of formula IV wherein A, n, Q and Z are as defined above
and R is lower alky';
(d) catalytically hydroyencting a compound of formula
IV above, wherein A, n and R are as defined above, Q is
hydrogen and Z is a trans double bond to afford a compound
of formula IV wherein A, n and R are as defined above, Q3
is hydrogen and Z is a single bond; and, if desired, reacting
a compound of formula IV above, wherein A, n, Z and R are
as defined above and Q3 is biphenylcarbonyl with K2C03 to
afford a compound of formula IV wherein Q3 is hydrogen; and,
if desired, separating the 8 ~- and 8B -isomers;
(e) reacting a compound of the formula:
~y
HO ~ / (CH 2 ) n-A
R~OH . . . IVa
wherein A, n, R and Z are as defined above and Y is =0, with
2,3-dihydropyran in the presence of an acid catalyst to afford
a compound of the formula:
Q- ~ ~
Q20~ ~ (CH2) n-A
R~'~oQ2 . . . v
wherein A, n, R and Z are as defined above, Y is -0 and Q2 jS
2-tetrahydropyranyl,
(f) reacting a compound of formula V, above, wherein
~ -2B-

A, n, R and Z are as defined above and Y is =O with an
appropriate reducing ~gent to afford a compound of formula
V wherein A, n, R and Z are as defined above and Y is <
OH
(g) catalytically hydrogenating a compound of formula
V above, wherein A, n and R are as defined above, Z is a
trans double bond and Y is =O, to afford a compound of formula
V wherein A, n and R are as defined above, Y is =O and Z is
a single bond.
Examples of novel intermediates prepared by the0 process of this invention are of the formulae below:
a compound of the formula:
~- ... IV
~ ~XR
a compound of the formula:
~y
~"'' ~
THPO' _ :~(C~2) nA
THP
a compound of the formula:
~-
~
Ho~f CH2 ) nA
H
-2C-
,.~

l(~S3~69
and a compound of ~he structure:
~,
~ ,~ (C112~A
wherein A is cycloalkyl of from three to ten carbon atoms, 1-
adamantyl, 2-norbornyl, 2-(1,2,3,4-tetrahydronaphthyl) wherein
said group is racemic or optically act;ve, 2-indanyl or
substituted 2-indanyl wherein the substituent is halo, tri-
fluoromethyl, 'ower alkyl or lower alkoxy;
R is hydrogen or lower alkyl;
n is an inte(Jer from O to 5;
~ is hydrogen or p-biphenylcarbonyl;
THP is tetrahydropyranyl,
Z is a single bond or trans double bond; and
'OH ~H
Y is =O, ' or
\ H ~ OH
The process according to the invention may
be illustrated by the reaction schemes which follow.
.
__,
.,

~053669
Scheme A
~_~ ~CH2) n A
~ I
(~L~ 13 2)n A
~9 +
~J32)n~
~,
(~,~Q{2)~

1~53~69
As shown in Scheme A, in 2--3 the oxophosphonate 2 is reacted
with the known /Corey, et al., J. Am. Chem. Soc., 93, 1491
(1971~ aldehyde H to produce, after chromatography or
crystallization, the enone 3. The compound in which the
p-biphenyl carbonyl group is replaced with a p-biphenyl
carbamoyl protecting group is also useful as a substitute for
H and has the added benefit that in the reduction step (3~ 4)
a higher percentage of the desired o~ isomer is produced.
The enone 3 can be converted to a mixture of
tertiary alcohols 13 and 14 by reaction with the appropriate
metallo alkyl and the isomeric 13 and 14 can be separated by
column chromatography. The enone 3 can be reduced with zinc
borohydride or with lithium trialkylborohydrides, such as
lithium triethylborohydride, to a mixture of alcohols, _ and
5 which can be separated as above. In this reaction ethers
such as tetrahydrofuran or l,2-dimethoxyethane are usually
employed as solvents, although occasionally methanol is
preferred to ensure specificity of reduction. Further trans-
formations 4 are shown on Scheme B.
4 -~6 is a base catalyzed transesterification in
whlch the p-biphenyl-carbonyl protecting group is removed.
This is most conveniently conducted with potassium carbonate
in methanol or methanol-tetrahydrofuran solvent. 6~7 involves
the protection of the two free hydroxyl groups with an acid-
labile protecting group. Any sufficiently acid-labile group
is satisfactory; however, the most usual one is tetrahydro-
pyranyl, which can be incorporated in the molecule by treat-
ment with dihydropyran and an acid catalyst in an anhydrous
medium. The catalyst is usually p-toluenesulfonic acid.
--5--

1053669
Scheme B
/;~, \~,~(CH2)A
4 /
~'
",
q~3po~ ~CH2)n~A ~,~CH2)n A
7 8
--6--
,

1053669
Scheme D illustrates the synthesis of precursors
to the 13,14-dihydro-15-substituted-~-pentanorprostaglandins.
In 3~19 + 19' the enone 3 is reduced to the tetra-
hydro compound through the use of any of the complex metal
hydride reducing agents, LiAlH4, NaBH4, KBH4, LiBH4 and
Zn(BH4)2. Especially preferred is NaBH4. The products, 19
and 19', are separated from each other by column chroma-
tography.
Furthermore, the compounds 4 and 5 of Scheme A can
be reduced catalytically with hydrogen to 19 and 19' respec-
tively. The stage at which the double bond is reduced is
not critical and hydrogenation of 6 or 7 of Scheme B will
also afford useful intermediates for the 13,14 dihydro prosta-
glandin analogs of the present invention. This reduction
may be achieved with either a homogenous catalyst such as
tris-tri-phenylphosphinechlororhodium (I), or with a hetero-
geneous catalyst such as platinum, palladium or rhodium. In
a similar way the precursors to the 15-lower alkyl-15-sub-
stituted-~-pentanorprostaglandins are synthesized by sub-
stituting compounds 13 and 14 for 4 and 5 respectively, in
the synthesis jUQt described.

1053669
,1
~t
~ul ` =I~ u~
~X

10536~9
The following examples are merely illustrative and
in no way limit the ~cope of the appended claims. In these
examples it will be appreciated that all temperatures are
expressed in Centigrade, all melting and boiling points are
uncorrected.
EXAMPLE 1
2- [3a~ Phenylbenzoyloxy-Sa-hydroxy-2~-(3-oxo-3-(2-indanyl)-
trans-l-propen-l-yl)-cyclopent-la-yl]acetic acid, y-lactone:
To a solution, cooled in ice under nitrogen, of
17.2 ml. (32.6 mmoles) of a l.90M solution of n-butyllithium
in hexane in lS0 ml. of dry 1,2-dimethoxyethane was added
dropwise 9.2 g. (34.5 mmoles) of dimethyl-2-oxo-2-(2-indanyl)-
ethylphosphonate. The solution was stirred in the cold for
10 minute~ then 11.9 g. (33.5 mmoles) of the known 2- [3a-
lS ~phenylbenzoyloxy-Sa-hydroxy-23-formyl-cyclopent-la-yl]-
acetic acid, y-lactone was added. The ice bath was removed;
the mixture was stirred for 1.0 hour then was quenched by the
addition of glacial acetic acid (pH~S). The mixture was con-
centrated and the resultant mixture was dissolved in methyl-
ene chloride (300 ml.). The organic layer was washed with
water (100 ml.), saturated sodium bicarbonate (S0 ml.),and
saturated brine (50 ml.), was dried (anhydrous magnesium
sulfate) and was concentrated to a semi-solid. Recrystal-
lization of the crude product from isopropyl alcohol:methyl-
ene chloride afforded the de~ired 2- [3a-~-phenylbenzoyloxy-
Sa-hydroxy-2~-(3-oxo-3-(2-indanyl)-trans-1-propen-1-yl)cyclo-
pent-la-yl~acetic acid, ~-lactone as white feathers melting
at 170-172 and weighing 6.8S g. (42.896).
The ir spectrum (CHC13) of the product exhibited
absorptions at 1775 cm~l for the lactone carbonyl,
_g_

1(~53ti69
at 1770 cm~l for the ester carbonyl, 1670 and 1625 cm~l for
the ketone carbonyl and at 975 cm~l for the trans double bond.
-10-
.

1053669
u~ u~ In
t` I` r~
o o o
,, _, _,
_, o o o
, o CO CO
F r~ ~ ~D
~)
1~ -- .
~ o o o
t) `~ a _l _l ,
,~
~ H Il~ O O
U~ ' ~ ~ I` I~
a~ ,~
1 ~
O o o
O ~ . 00 0
I I I ;_
~\
~¦ o 'I N
~rl
In ~a ~
-- 11~ 1~
--11--

10536~9
EXAMPLE 2
2-(3a-~-Phenylbenzoyloxy-5-hydroxy-2~-(3-hydroxy-3-(2-
indanyl)-trans-l-propen-l-yl)cyclopent-la-yl)acetic acid,
y-lactone and 2-(3a-~-phenylbenzoyloxy-5a-hydroxy-3-(2-
indanyl)-)-trans-l-propen-l-yl)cyclopent-la-yl)acetic acid,
y-lactone.
To a solution of 6.73 g. (14.0 mmole) 2-(3a-p-
phenylbenzoyloxy-5a-hydroxy-2~-(3-oxo-3-(2-indanyl)-trans-
l-propen-l-yl)cyclopent-la-yl)acetic acid, y-lactone in 67
ml. dry tetrahydrofuran in a dry nitrogen atmosphere at
ambient temperature was added dropwise 14.0 ml. of a 0.5M
zinc borohydride solution. After stirring at room temperature
for 1.5 hours, a saturated sodium bitartrate solution was
added dropwise 14.0 ml. of a 0.5M zinc borohydride solution.
After stirring at room temperature for 1.5 hours, a saturated
sodium bitartrate solution was added dropwise, until hydrogen
evolution ceased. The reaction m~Nre was allowed to stir for 5
minutes at which time 150 ml. dry methylene chloride was
added. After drying (MgSO4~ and concentrating (water
aspirator) the resultant semisolid was purified by column
chromatography on silica gel (Baker "Analyzed" Reagent
60-200 mesh) using mixtures of ethyl acetate:ether as
eluents. After elution of less polar impurities a fraction
containing 2.21 g. (32.8% yield) 2-(3a-phenylbenzoyloxy-5a-
hydroxy-2~-~3a-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)
cyclopent-la-yl)acetic acid, y-lactone and a fraction contain-
ing 1.79 g. (26.6% yield) of 2-(3a-~-phenylbenzoyloxy-5-
hydroxy-23-(33-hydroxy-3-(2-indanyl)-trans-1-propen-yl)cyclo-
pent-la-yl)acetic acid, lactone were collected.

~(~53S69
The ir spectrum (CHC13) both products had strong
adsorption at 1770 cm~l (lactone carbonyl) and 1705 cm~
(ester carbonyl) and a medium adsorption at 970 cm 1
(trans olefln).
-13-
.

1053669
~ o o U~ U~ o o
~ o~
_ o o U~
Id ~ I` I` I~ I`
1~ 1` ~ ~ 1` 1`
_,
O
o o ~ ~
X ~ , , , , , ,., ~~ ~ N
I 'O I 0 'O 0
s 1~",~ o
o \~ m m a~
~n o
a
o ,~ ~ ~ a
~ ~ ." o m
O O I I N N ~I j
E3
'I ~ O S
~ ~ S ~ ~
~ 0 O~
ES~ Cn
N N ~
-14-
,

1053669
EXAMPLE 3
2-[3,5~-Dihydroxy-2~-(3~-hydroxy-3-(2-indanyl)-trans-1-
proleen-l-yl)cyclopent-l~-yl]acetic acid, y-lactone:
A heterogeneous mixture of 2.21 g. (4.46 mmole) of
2-[3-p-phenylbenzoyloxy-5~-hydroxy-23-(3-hydroxy-3-(2-
indanyl)-trans-l-propen-l-yl)cyclopent-la-yl]acetic acid, y-
lactone, 40 ml. of dry tetrahydrofuran, 40 ml. of absolute
methanol and 0.61 g. of finely powdered, anhydrous potassium
carbonate was stirred at room temperature for one hour, then
cooled to 0. To the cooled solution was added 4.46 ml. of
l.ON aqueous hydrochloric acid. After stirring at 0 for an
additional 10 minutes, 75 ml. of water was added with con-
comitant formation of methyl p-phenylbenzoate which was
collected by filtration. The filtrate was concentrated by
rotary evaporation then was extracted with ethyl acetate (3x),
the combined organic extracts were dried ~MgS04) and were
concentrated to give 924 mg. (66%) of viscous, oily 2-[3,5-
dihydroxy-2~-(3-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)-
cyclopent-l-yl]acetic acid, y-lactone.
The ir spectrum ~CHC13) exhibited a strong adsorp-
tion at 1770 cm~l for the lactone carbonyl and a medium
adsorption at 970 cm~l for the trans double bond.
-15-

105~6~ii9
~,,
h O
P~ ~
_
~¢ U . h
~: _ o o 1~
~ ~ I` --I 1` 1` ~ o. O
U d
a o ,~ o
h ~ r o H
11
P~
o ~0
U
O ;, ~ O~1 0 0 0 0 h
O
1 ~q
O
4~
~ O
U ~
O '~
.,~ O
~a u
I O o
d
o
O
J~
I
--16--
,
.

1053669
EXAMPLE 4
2- [5a-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-tetrahydro-
pyran-2-yloxy]-3-(2-1ndanyl)-trans-l-propen-l-yl)cyclopent-
.
la-yl]acetic acid, y-lactone:
To a solution of 0.924 g. (2.94 m~ole)-2-[3,5c~dihydmxy-
2~- (3a-hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-
lc~-yl]acetic acid, y-lactone in 49 ml. anhydrous methylene
chloride and 0.86 ml. of 2,3-dihydropyran at 0 in a dry
nitrogen atmosphere was added a few crystals of p-toluene-
sulfonic acid, monohydrate. After stirring for 15 minutes,
the reaction mixture was combined with 100 ml. ether, the
ether solution washed with saturated sodium bicarbonate
(1 x 15 ml.) then saturated brine (1 x 15 ml.), dried (MgS04)
and concentrated to yield 1.38 g. (97.8%) crude 2- [5a-hydroxy-
3c~-(tetrahydropyran-2-yloxy)-2~B- (3a- [tetrahydropyran-2-yloxy]-
3-(2-indanyl)trans-1-propen-1-yl)cyclopent-la-yl]acetic acid,
y-lactone which was used without purification.
The ir spectrum ~CHC13) of the product exhibited a
strong absorption at 1755 cm~l for the lactone carbonyl and
a medium absorption at 965 cm~l for the trans double bond.

1053669
h
bq
/~ ~ o ".~ ~
O
~a ~ I o o ~
o
" ~!
~
O
C
--18--
.. : .
.
: .. . - . : '
. .

1053669
EXAMPLE 5
2-[5-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydro-
pyran-2-yloxy]-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-
la-yl]acetaldehyde, y-hemiacetal:
A solution of 1.39 g. (2.9 mmole) 2-[5a-hydroxy-3a-
(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydropyran-2-yloxy]-3-
(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]acetic acid,
y-lactone in 20 ml. dry toluene was cooled to -78, in a dry
nitrogen atmosphere. To this cooled solution was added
4.2 ml. of 20~ diisobutylaluminum hydride in n-hexane (Alfa
Inorganics) dropwise at such a rate so that the internal
temperature never rose above -65 (15 minutes). After an
additional 30 minutes of stirring at -78, anhydrous methanol
was added until gas evolution ceased and the reaction mixture
was allowed to warm to room temperature and was concentrated
by rotary evaporation. The resultant oil was slurried in
methanol then was filtered to remove aluminum salts. Concen-
tration of the filtrate afforded the crude product which was
purified by silica gel (Baker "Analyzed" 60-200 mesh) column
chromatography using mixtures of benzene:ethyl acetate as
elements. After removal of less polar impuritie~ the desired
2-[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-[tetrahydro-
pyran-2-yloxy)-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-
la-yl]acetaldehyde, r-hemiacetal as a viscous oil weighing
1.17 g. (84.3%).
The ir spectrum (CHC13) of the purified product
exhibited a medium absorption at 975 cm~l for the trans double
bond and no carbonyl absorption.
--19--

lOS;~669
U C~ U
.C m ~ ~¦ U
O ~ H a~ n h
O \~~ _ O
O
O
~1 ~
a
O
_~ O
S
--20--

10S~669
EXAMPLE 6
2-[5-Hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-tetrahydro-
pyran-2-yloxy)-8-(1-adamantyl)oct-1-yl)cyclopent-la]acetic
ac$d, y-lactone (24e):
A heterogeneous mixture of 2.39 g. (4.2 mmoles) 2-
[5a-hydroxy-3a-(tetrahydropyran-2-yloxy)-2~-(3a-(tetrahydro-
pyran-2-yloxy)-8-(1-adamantyl)-trans-1-octen-1-yl)cyclopent-
la-yl]acetic acid, y-lactone and 239 mg. of 5% palladium in
carbon in 25 ml. of absolute methanol is stirred under 1
atmosphere of hydrogen for 2 hours. The reaction mixture is
filtered (Celite) and concentrated to provide 2-[5a-hydroxy-
3a-(tetrahydropyran-2-yloxy)-23-(3a-(tetrahydropyran-2-
yloxy)-8-(1-adamantyl)oct-1-yl)cyclopent-la-yl]acetic acid,
y-lactone.
EXAMPLE 7
2-[3a-~-Phenylbenzoyloxy-5a-hydroxy-2~-(3a-hydroxy-3~-methyl-
5-tl-adamantyl)-trans-1-penten-1-yl)cyclopent-la-yl]acetic
acid, y-lactone and 2-[3-~-phenylbenzoyloxy-5-hydroxy-2~-
(3~-hydroxy-3a-methyl-5-(1-adamantyl)-trans-1-penten-1-yl)-
cyclopent-la-yl]acetic acid, y-lactone:
To a solution of 2.15 g. (4.0 mmoles) of 2-[3a-~-
phenylbenzoyloxy-5a-hydroxy-2~-(3-oxo-5-(l~adamantyl)-trans-
l-penten-l-yl)cyclopent-la-yl]acetic acid, y-lactone in 21
ml. of anhydrous ether and 20 ml. of tetrahydrofuran in a dry
nitrogen atmosphere at -78 is added dropwise 4.0 ml. of a
(l.OM) solution of methyllithium in ether (Alfa). After stir-
ring at -78 for 15 minutes the reaction is quenched by the
addition of glacial acetic acid until the pH of the mixture
21-

lOS~6~9
ie approximately 7. ~he mixture is then diluted with methyl-
ene chlor~de and the diluted organic solution i9 washed with
water and saturated brine, is dried (anhydrous magne~ium
sulfate) and 19 concentrated to afford the epimeric alcohols.
The crude product is purified by column chroma-
tography on silica gel to provide the 2-[3-~-phenylbenzoyl-
oxy-Sa-hydroxy-2~-(3~-hydroxy-3~-methyl-5-(1-adamantyl~-trans-
l-penten-l-yl)cyclopent-la-yl]acetic acid, y-lactone and the
2-13a-~-phenylbenzoyloxy-Sa-hydroxy-2~-(3~-hydroxy-3-methyl-
5-(1-adamantyl)-trans-1-penten-1-yl)cyclopent-1~-yl]acetic
acid, y-lactone.
EXAMPLE 8
N-Benzoyl 9-oxo-11~,15-bi~-(tetrahydropyran-2-yloxy)-15-
(2-(5,6-dimethoxylndanyl))-5-ci~-13-tran~-~-pentanorpro~ta-
dienamides
To a olutlon, undor nltrogon, of 594 mg. (1.0
mmolo) of tho 9-oxo-11~,15~-bl~-~totrahydropyran-2-yloxy)-
15-~5,6-dlmethoxylndanyl))-S-cl~-13-tran--~-pentanorprosta-
dlenoic acld in 6 ml. of dry tetrahydrofuran i~ added 102 mg.
(1.0 mmole~) of trlethylamlne. The solution 1~ stlrred for
1 mlnute then 1.2 ml. of a l.OM ~olutlon of benzoyl i90-
cyanate in tetrahydrofuran is added. The solutlon i5 stirred
for an additional 10 minute~, then is quenched by the addi-
tion of glacial acetic acid. The quenched solution is concen-
-22-

10536~9
trated and the residue dissolved in ethyl acetate (20 ml.),
is washed with water (lx), dried (anhydrous magnesium
sulfate) and is concentrated to provide the desired N-benzoyl
9-oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-15-(2-(5~6-di-
methoxyindanyl))-5-cls-13-trans-~-pentanorprostadienamide
which is used without purification.
EXAMPLE 9
2-[3a,5a-Dihydroxy-2~-(3a-hydroxy-3-(2-indanyl)-trans-1-
_
ProPen-l-Yl)cYclopent-l-yl]acetaldehyde, y-hemiacetal:
To a solution, cooled to -78, of 750 mg. (1.5
mmole) of the 2-[3a-~-phenylbenzoyloxy-5a-hydroxy-2~-(3a-
hydroxy-3-(2-indanyl)-trans-1-propen-1-yl)cyclopent-la-yl]-
acetic acid, y-lactone in 15 ml. of toluene is added 7.5 ml.
of a 20% solution of diisobutylaluminum hydride in hexane
(Alfa). The reaction mixture is stirred in the cold for 1.0
hour, then is quenched by the addition of methanol until gas
evolution ceases. The quenched mixture is let warm to room
temperature then is concentrated. The residue is stirred
with methanol (3x) and is concentrated. Purification of the
crude product by silica gel chromatography affords the desir-
ed 2-[3a,5a-dihydroxy-2~-(3a-hydroxy-3-(2-indanyl)-trans-1-
propen-l-yl)cyclopent-la-yl]acetaldehyde, y-hemiacetal.
-23-

Representative Drawing

Sorry, the representative drawing for patent document number 1053669 was not found.

Administrative Status

2024-08-01:As part of the Next Generation Patents (NGP) transition, the Canadian Patents Database (CPD) now contains a more detailed Event History, which replicates the Event Log of our new back-office solution.

Please note that "Inactive:" events refers to events no longer in use in our new back-office solution.

For a clearer understanding of the status of the application/patent presented on this page, the site Disclaimer , as well as the definitions for Patent , Event History , Maintenance Fee  and Payment History  should be consulted.

Event History

Description Date
Inactive: Expired (old Act Patent) latest possible expiry date 1996-05-01
Grant by Issuance 1979-05-01

Abandonment History

There is no abandonment history.

Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
PFIZER INC.
Past Owners on Record
HANS-JURGEN E. HESS
THOMAS K. SCHAAF
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
Documents

To view selected files, please enter reCAPTCHA code :



To view images, click a link in the Document Description column. To download the documents, select one or more checkboxes in the first column and then click the "Download Selected in PDF format (Zip Archive)" or the "Download Selected as Single PDF" button.

List of published and non-published patent-specific documents on the CPD .

If you have any difficulty accessing content, you can call the Client Service Centre at 1-866-997-1936 or send them an e-mail at CIPO Client Service Centre.


Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Cover Page 1994-04-22 1 15
Abstract 1994-04-22 1 24
Claims 1994-04-22 4 75
Drawings 1994-04-22 1 5
Descriptions 1994-04-22 25 492