Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3230
~075ZS0
BACKG~ROUND OF THE INVENTION
I-his invent10n relates to intermediates usefui In the
preparation of prostagland1ns and to a process for pre-
paring them.
Each of the known prostaglandins Is a derivative of
prostanoic acid which has the following structure and atom
: numbering;
~COO~
' ~l~i~o
A systematic name for prostanotc acid is 7-~(2~-octyl)-
cyclopent -la -y l]heptanoic acid.
Prostaglandin Ez, "PGE2", has the following structure:
O
~ ~ OOH
HO H OH
Prostaglandin F2a, "PGF2a", has the following struc-
20 ture: HO
~r ^~== ~ OOH
~~/ '~ .
. ~0 H OH
.
The prostaglandtn formulas mentioned above each have
several centers of asymmetry. Each formula represents a
molecule of the parsicular opttcally active form of the
prostaglandin obtained from certatn mammalian ttssues, for
example, sheep vesic~lar glands, swine lung, and human
seminal plasma, or by reduction or dehydration of a prosta-
-2- ~ ~
~230
~075;~:50
glandin so ob~ained. See, for example, Bergstrom et al.,
Pharmacol. Rev. 20, 1 (1968), and references cited therein.
The mirror image of each formula represents a molecule of
the other enantiomeric form of that prostaglandin. The
racemic form of the prostaglandins consists of equal num-
bers of two types of molecules, one represented ~y one of
the above formulas and the other represented by the mirror
image of that formula. Thus, both formulas are needed to
define a racemic prostaglandin See Nature 212, 38 (1966)
for discussion of the stereochemistry of the prostaglandins.
In the formulas above, as well as in the formulas
given hereinafter, broken line attachments to the cyclo-
pentane ring indicate substit~ents in alpha configuration,
i.e., below the plane of the cyclopentane ring. Heavy
solid line attachments to the cyclopentane ring indicate
substituents in beta configuration, i.e. above the plane
of the cyclopentane ring In the formulas above, the
hydroxyl attachment to carbon 1~ is in the alpha configura-
tion, as indicated by the broken line. In formulas below,
this convention is also used for intermediates having
hydroxyl substituted at the corresponding position on the
side chain. A wavy line ~ indicates optional attachment
to carbon 15 in either alpha or beta configuration.
The various optically active and racemic prostaglandins
2~ and thei~ alkyl esters are useful for various pharmacological
purposes. With particular regard to P~F2a s~e, for example,
Bergstrom et al., Pharmacol. Rev. 20, 1 (1968), and refer-
ences cited thereln, Wlqvist et al., The Lancet, 889 (1970),
and ~arlm et al., J. Obstet. Gynaec. Brlt. Cwlth., 76, 769
3~ (1969). As to the other prostaglandTns, see, for example
1075250
Ramwell et al., Nature 221, 1251 (1969).
Previously, the preparation of an inter-
mediate bicyclic lactone ketone of the formula
~0~
)~ C5Hll
OR4
wherein R4 is acetyl was reported by E.J. Corey et al., J. Am.
Chem. Soc. 91, 5675 (1969), and later disclosed in an optically
active form by E.J. Corey et al., J. Am. Chem. Soc. 92, 397 (1970)
Conversion of this intermediate to PGE2 and PGF2a either in
racemic (di-) or optically active form, was disclosed in those
publications. For that compound wherein R4 is benzoyl see U.S.
Patent 3,778,450.
Related compounds of the formula
o, ~
11
~ G
OR4 0
wherein R4 is acetyl or benzoyl have been disclosued as follows:
(1) wherein G is alkyl of one to 10 carbon atoms,
inclusive, substituted with zero to 3 fluoro, U.S. Pate~t No.
3,936,487 (The Upjohn Company, Feb. 3/76);
(2) wherein G is
tS
-C-~CH2)3-CH3
R6
-- 4 --
~075Z50
wherein R5 and R6 are hydrogen, methyl, or ethyl, provided
that at least one of R5 and R6 is not hydrogen, Canadian
Patent No. 984,387 ~The Upjohn Company, Feb. 24/76);
(3) wherein G is
f n 2n 3
R7
wherein CnH2n is alkylene of one to 9 carbon atoms, inclusive,
with one to 6 carbon atoms, inclusive, in the chain between
-CFR7- and terminal methyl and wherein R7 is hydrogen, methyl,
ethyl, or fluoro, British Specification No. 1,396,206; and
(4) wherein G is
IR8
- I - ~ S
wherein R8 and Rg are hydrogen, methyl, or ethyl, wherein T
is alkyl of one to 3 carbon atoms, inclusive, fluoro, chloro,
trifluoro, or -ORlo wherein Rlo is alkyl of one to 3 carbon
atoms, inclusive, and wherein s is zero, one, 2 or 3, with
the proviso that not more than two T's are other than alkyl,
British Specification No. 1,409,~41.
Also disclosed is a compound of the formula:
P ~
~ XR `
AcO
- 5 -
iO75250
wherein Ac represents an acyl radical, either acetyl or
p-phenylbenzoyl, X is an alkylene radical of 2 or 3 carbon
atoms, optionally bearing as substituent or substituents
one or two alkyl radicals each of 1 to 4 carbon atoms, and
Rll is an aryl or thienyl radical, which is unsubstituted or
which is substituted by halogen atoms, nitro radicals, alkyl,
halogenoalkyl or alkoxy radicals each of 1 to 3 carbon atoms
or dialkylamino radicals wherein each alkyl is of 1 to 3
carbon atoms, British Specification No. 1, 372,541.
' A related disclosed compound is
O
N~ ~C~cHz~c ~C2H5 lV
THPO HO~ \H H ~ ~H
wherein THP is tetrahydropyranyl, useful in the synthesis of
PGF3~ E.J. Corey et al. J. Am. Chem. Soc, 93, 1490 (1971).
` SUMMARY ` OF THE INVENTION
It is the purpose of this invention to provide
novel intermediates useful in the preparation of prostaglandins
commerically in substantial amount, with high purity, and
~230
- ~075250
at reasonable cost. It is a further purpose to provide
processes tor preparing these intermediates and for
utitizing them.
Thus there is provided a process for preparing an
optically active bicyclic lactone ketone of the formula
O 4~ '
~'' V
~,Rl2
1~ 0~
or a mixture of that compound and the enantiomer thereof,
wherein Rl2 is
Rl3
(1 ) -C-C9H2g-CH3J
R1 4
(2) -CH2 j C2Hs, or
H ~ C C ~ H
20(~) ~13
I_z~( )S
., I ' R1 4
wherein ~gH29 is alkylene of one to 9 carbon atoms, inclu-
sive, with one to 5 carbon atoms, inclusive, in the chain
~ between -CRI9R~4- and terminal methyl; wherein R19 and R
.~ are hydrogen, alkyl of one to 4 carbon atoms, lnclusive,
or fluoro, being the same or different, wtth the provlso
that R~3 is fluoro only when R14 ts hydrogen or fluoro;
wherein T is alkyl of one to 4 carbon atoms, Inclusive,
_7
3230
1075250
fluoro, chloro, `trifluoromethyl, or -ORl5, wherein R15 is
hydrogen or alkyl of one to 4 carbon atoms, inclusive, and
s is zero, one, 2, or 3, with the proviso that not more
than two T's are other than alkyl; and wherein Z represents
an oxa atom (-0-) or CjH2j, wherein CjHzj Is a valence
bond or alkylene of one to 9 carbon atom , incluslve, sub-
stltuted with zero, one, or 2 fluoro, with one to 6 carbon
atoms, Inclusive, between -CRl~R1~- and the rTng; which
comprises
(a) starting with a tricyclic lactone aldehyde of
the formula 0
O \
~' Vl
~ ~ CH0
;: 15
or a mixture of that compound and the enantiomer thereof,
wherein ~ indicates attachment to the cyclopropane ring
in endo or exo configuratlon, and reacting sald aldehyde
with a nitrlle of the formula
I a 1
CN
: 25 wherein ~al is chloro, bromo, or lodo, the two Hal's belng
the same or different, and whereln Rl2 Is deflned as above,
to form an optically active cyanoepoxide of the formula
3
3230
1075250
o~ Vl I
4 N
or a mixture of that compound and the enantiomer thereof,
wherein R,2 and ~ are as defined above;
(b) reacting said cyanoepoxide with formic acid to
produce an optically active cyanohydrin monoformate of the
formula O
0 4~ :
~ ~ , Vl I I
. ~ '- .
R12
OCHO Ll
or a mixture of that compound and the ena.ntiomer thereof,
' wherein R~2 is as defined above and wherein L1 represents
either HO CN or HO CN; and
(c) transforming the product of step (b) to said
bicyclic lactone ketone by
(d) removing hydrocyanic acid by dehydrocyanation to
convert the
-fi R12 moiety to -If - Rl2
Ll O
and
(e) replacing formyl with hydroxyl, said steps (d) and
(e) being performed either in the order (d)-(e) or (e)-(d).
There is further provTded a process for prepartng an
_g_
3230
1075250
optically ac~ive bicyclic lactone k~tone o~ the formula
O
C~
S ' ¢~ Xl
OH
or a mixture of that compound and the enanttomer thereof,
which comprises
(a) starting with a tricyclic lactone cyanoepox;de of
the formula o
~1 ~' X I I
COOc2Hs
CN
or a mixture of that compound and the enantiomer thereof,
wherein ~ indicates attachment to the cyclopropane ring
in endo or exo configuration, and reacting said cyano-
epoxide with formic acid to produce an optically active
cyanohydrin monoformate of the formula
~ :
X l I I
COOC2H5
OCHO L1
or a mixt~Jre of that compound and the enantiomer thereof,
wherein Ls represents either ~ ~ or ,'~
H~ CN HO ~N;
(b) replacing ~ormyl with hydroxyl to produce an opti-
cally actlve cvanohydrin of the formula
'10-
3230
1075Z50
Q~\ . xlV
~COOC2H5
r~ O~H
or a mixture of that compound and the enantiomer thereof,
wherein Ll is as defined above;
(c) transforming the product of step ~b) to form a
diether of the formula
O
0~
X V I I . - -
15 . OR1~ L2
or a mixture of that compound and the enantiomer thereof,
wherein L2 represents either ~ ~ or
R~O CN
, ~ and wherein Rl~ is 1-ethoxyethyl, tetra-
; Rl~O CN
hydropyranyl, tetrahydrofuranyl, or a group of the
formula . H
R 17 - -C C -R20
R~8
wherein Rl7 ts alkyl of one to 18 carbon atoms, Inclusive,
cycloalkyl of 3 to 10 carbon atoms, inclusTve, aralkyl of
7 to 12 carbon atoms, inc1usive, phenyl, or phenyl sub-
stituted w;th one, 2, or 3 alkyl of one to 4 carbon atoms,
: inctusive, wherein Rl8 and R~ are the same or different,
being hydrogen, alkyl of one to 4 carbon atoms, Inclustve,
: 30 phenyl or phenyl substituted wlth one, ?, or 3 alkyl of one
-11-
3230
iO75Z50
to 4 carbon atoms, inclusive, or, when Rl8 and R18 are
; taken together, ^(CH2)a- or -(CH2)b-0-(CH2)c- wherein a Ts
3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 wlth
the proviso that b plus c is 2, 3, or 4, and whereln R20
Ts hydrogen or phenyl; by
(d) replacing the hydrogen of the hydroxyl groups wtth
Rl~ groups wheretn Rl~ is as defined above, and
(e) replacing the -COOC2H5 moiety with hydrogen, said
steps (d) and (e) being performed either in the order (d)-
(e) or (e)-(d);
(f) transforming the product of step (c) to a compound
of the formula
XV I
~H
or a mixture of that compound and the enantiomer thereof,
wherein ~1 ts as defined above, by the steps of deprotonatlng,
alkylating wlth 1-bromo-cis-2-pentene, and deblocklng, and
(g) removing hydrocyanlc acid by dehydrocyanatlon to
convert the
. .
~ mo~ety to
,.,
., ~~.
,,, O
There Is further provlded a process for preparlng an
opttcally actlve btcycllc lactone ketone of the formula
--12--
3230
~075250
~\
~' Xl
. ~ .
OH
or a mixture of that compound and the enantiomer thereof,
which comprises
(a) starting with a tr7cyclTc lactone aldehyde of the
10 formula
O
.. 0~
., ~~ . Vl
: CHO
:
or a mixture of that compound and the enantiomer thereof,
: wherein indicates attachment to the cyclopropane ring
. in endo or exo configuratton, and reacting said aldehyde
with a nitrile of the formula
l1al
Hal-C-(CH2)2-O-R
CN
- 25 wherein Hal is chloro, bromo, or ~odo, the two Hal's belng
the same or different, and wherein R2l is (1`) Rl~> defined
as 1-ethoxyethyl, tetrahydropyranyl, tetrahydrofuranyl, or
rj a group of the formula H
Rl7-O-l -C-Rzo
.. - I
Rla R
-13-
~)75250
wherein R17 is alkyl of one to 18 carbon atoms, inclusive,cycloalky~ of 3 to 10 carbon atoms, inclusTve, aralkyl of 7
to 12 carbon atons, incluslve, phenyl, or phenyl substituted
with onc, 2, or 3 alkyl of one to 4 carbon dtoms, inclusive,
wherein Rl8 and R~g are ~he same or di.~e.ent, being hydro-
gen, alkyl of one to 4 carbon atoms, inclusive, phenyl or
phenyl substituted with one, 2, or 3 alkyl of one to 4 car-
bon atoms, inclusive, or, when R,8 and Rl~ are taken
together, -(CH2)a- or -(CH2)b-O-(C~2)c- wherein a is 3,- 4,
or 5, b is one, 2, or 3, and c is one, 2, or 3 with the
proviso that b plus c is 2, 3, or 4, and wherein R20 is
. hydrogen or phenyl; or (2) carboxyacyl -C(O)Rz2 wherein
R22 is hydrogen or alkyl of one to 17 carbDn atoms, inclu-
. sive, to form an optically active cyanoepoxide of the
.15 formula O
.' ' ' ~' X I X
' .0
.. ~ ~ ~ OR
CN
or a mixture of that compound and the enantTomer thereof,.
wherein R?, and ~ are as def;ned above;
(b) transforming the produc.t of step (a) to a compound
. of the formula
,, o4~
~ ~ CHO
or a mlxture of that compound and the enantiomer thereofJ
whereln ~ is as defined above, by hydrolyzing
-CH2CH2-O-R2l to -CH2CH2-OH and thereafter oxldlzlng
-14-
3230
~075250
-CH2CH2-OH to -CH2CHO;
: (c) transforming the product of step (b) to a cyano-
~ epoxide of the formula
o4
XXI
~
:: N
, . .or a mixture of that compound and the enant;omer thereof,
wherein ~ is as defined above;
i 10(d) reacting said cyanoepoxide with formic acid to
produce an optically active cyanohydrin monoformate of the
:.~ formula
~ ! O
.~. _/1
~ ~ XXII
OCHO L
~3
or a mlxture of that compound and the enantlomer thereof,
~1) wherein L~ represents either ~ " or ,~\
. HO CN HO CN;
and
: (e) transforming the product of step (d) to said
blcyclic lactone ketone by
:, (f) removing hydrocyanic acld by dehydrocyanat;on to
' convert the
molety to
~ ; and
(g) replaclng formyl wlth hydroxyl, sald steps (f)
; and (g) being performed elther In the order ~f)-(g) or (9)-
;: 30 (f).
,.
3230
-
~07 5ZS0
There is ~urther provided a process for preparlng an
optically active bicyclic lactone ketone of the formula
o
~, XXIII
~ R23
~ o~(T~s
or a mixture of that compound and the enantiomer thereof,
wherein T is alkyl of one to 4 carbon atoms, ;nclusive,
fluoro, chloro, trifluoromethyl, or -ORls, wherein R1s is
hydrogen or alkyl of one to 4 carbon atoms, inclusive, and
s is zero, one, 2, or 3, with the proviso that not more
than t~Jo T's are other than alkyl and when s is 2 or ~ the
T's are either the same or different; and wherein R23 ;s
hydrogen or alkyl of one to 4 carbon atoms, inclusive; which
comprises
(a) starting with a bicyclic lactone cyanohydrin di-
ether of the formula
~, ~
~ ~ ~ XVI I
<
: ~ H
0~ 11
or a mixture of that compound and the enantiomer thereof,
wherein R~ is 1-ethoxyethyl, tetrahydropyranyl, tetrahydro- `~
furanyl, or a group o~ the formula
H
R~7 O~ -R20
- , ~ ¦ , . . .
~8 ~1
11
3230
1075250
wherein R~7 is alkyl of one to 17 carbon atoms, Inclusive,
cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of
7 to 12 carbon atoms, Tncluslve, phenyl, or phenyl substi-
tuted with one, 2, or 3 alkyl of one to 4 carbon atoms,
inclusive, wherein Rl8 and Rl9 are the same or different,
being hydrogen, alkyl of one to 4 carbon atoms, inclusive,
phenyl or phenyl substituted with one, 2, or 3 alkyl of one
to 4 carbon atoms, inclusive, or, when R18 and Rl9 are
taken together, -(CH2)a- or -(CH2)b--(CH2)C- wherein a is
3, 4, or 5, b is one, 2, or 3, and c is one, 2, or 3 with
the proviso that b plus c is 2, ~, or 4, and wherein R20
is hydrogen or phenyl; and wherein L2 represents either
/ " or ,'~ ; and transforming said diether
: R~0 CN R1~0 CN
into an alkoxide of the formula
//
' 1~ XXIV
23
~Rl~ L2
wherein R23 is hydrogen or alkyl of one to 4 carbon atoms,
inclusive, and wherein Rl~ and L2 are as defined above,
- by successively-deprotonating and reacting the carbanion
of sa;d diether with an aldehyde of the formula R23-CH0
wherein R23is as defined above;
(b) arylating the product of step (a) to form a com-
` pound of the formula
-17
_~ 3230
1(~75~50
1/ XXV
~
~ Z 3
OR~ 2
or a mixture of that compoun~ and the enantiomer thereof,
where;n R1~J R23. s, T, and L2 are as defined above;
(c) replacing the Rl6 groups with hydrogen; and
(d) removing hydrocyallic acid by dehydrocyanation
to convcrt the
R23
(T)s moiety to
23 ~ (T)s
O
Accordingly, from the above processes there are pro^
vided new intermediates corresponding to formulas Yll, Vlll J
Xll, XIV, XVII, XVIIIJ XIX, XXJ XXI, XXII, XXIVJ and XXV
above, wherein R~2, R1~, R2l, R23, s, T, Ll, L2, and
are as de~ined above.
With regard to lormulas Y to XXYI herein, alkyl groups
of one to 4 carbon atoms, inclusive, include methylJ ethyl,
propyl, butyl, and isomeric forms thereof. Alky1 groups
of one to 17 carbon atoms, inclusive, include those given
2~ above, and pentyl, hexyl, heptyl, octyl, nonyl, decyl,
undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexa-
decyl, heptadecyl J and isomeric forms thereof. Examples
of cycloalkyl of 3 to 10 carbon atoms, inclusive, which
Includes. a)kyl-substituted cycloalkyl, are cyclopropyl,
2-methylcyclopropyl, 2,2-dlmethylcyclopropyl, 2,~-dlethyl`-
~' ' ' '
-18-
3230
~075Z50
cyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclo-
butyl, 3-propylcyclobutyl, 2,3,4-tr;ethylcyclobutyl, cyclo-
pentyl, 2~2-dimethylcyclopentyl, 2-pentylcyclopentyl, ~-
tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl.
3-lsopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, and cyclodecyl. Examples of
aralkyl of 7 to 12 carbon atoms, inclusive, are benzyl,
phenethyl, 1-phenyiethyl, 2-phenylpropyl, 4-pherylbutyl,
3-phenylbutyl, 2-(1-naphthylethyl), and 1-(2-naphthyl-
methyl). Examples of phenyl substituted by one to 3 chloroor alkyl of one to 4 carbon atoms, inclusive, are
(o-, m-, or p-)chlorophenyl, 2,4-dichlorophenyl, 2,4,6-
trichlorophenyl, (o-, m-, or p-)tolyl, p-ethylphenyl,
; p-tert-butylphenyl, 2,5-dimethylphenyl, 4-chloro-2-methyl-
phenyl, and 2,4-dichloro-3-methylphenyl.
Examples of alkylene of one to 9 carbon atoms, inclu-
sive, with one to 5 carbon atoms inclusive, in the chain,
- within the scope of CgH2g as defined above, are methylene,
ethylene, trimethylene, tetramethylene, and pentamethylene,
and those alkylene with one or more alkyl substituents on
one or more carbon atoms thereof, e.g. -CH(CH9)-, -C(CH3)2-,
-CH(CH2CH3)-, -CH2-CH(CH3)-, -CH(CH3)-CH(CH3)-,
-CHz-C(CH3 )2 -~ -CHz-CH(CH3)-CH3-~ -CH2-CH2-CH(CH2CHzCH9)-,
-CH(CH3)-CH(CH3)-CH2-CH2-, -CH2-CH2-CH2-C(CH3 )2 -CH2, and
2~ -CH2-CH2-CH2-CH2-CH(CH3)-. Examples of alkylene of one
to 9 carbon ato~s, inclus;~e, substituted with zero, one,
or 2 fluoro, with one to 6 carbon atoms in the cha;n, with-
in the scope of Cj~2j as tefined above, are those given
- - above for CgH29 and hexamethylene, including hexamethylene
with one or more alkyl substituents on one or more carbon
-19 -
3230
_
1075Z50
atoms thereof, and includlng those alkylene groups with one
or 2 fluoro substituents on one or 2 carbon atoms thereof,
e.g -CHF-CH2-, -CHF-CHF-, -CHz-CH2-CF2-~ -CH2-CHF-CH2-,
-CH2-CH2-CF(CH3)-, -CH2-CH~-CF2-CH2-, -C~(CH9)-CH2-CH2-CHF-,
-CH2-C~2-CH2-CH2-CF2-, -CHF-CH2-CH2-CH2-CH2-CHF-,
-CF2-CH2-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CF2-CH2-CH2-, and
-CH2-CH2-CH2-CH2-CH2-CF2.
Examples of
~(T )s
aS defined above are phenyl, (o-, m-, or p-)tolyl, (o-, m-~
or p-)ethylphenyl, (o-, m-, or p-)propylphenyl, (o-, m-, or
p-)butylphenyl, (o-, m-, or p-)isobutylphenyl, (o-, m-, or
p-)tert-butylphenyl, 2,3-xylyl, 2,4-xylyl, 2,5-xylyl, 2,6-
xylyl, 3,4-xylyl, 2,6-diethylphenyl, 2-ethyl-p-tolyl, 4-ethyl-
: o-tolyl, 5-ethyl-m-tolyl, 2-propyl-(o-, m-, or p-)tolyl,
4-butyl-m-tolyl~ 6-tert-butyl-m-tolyl, 4-isopropyl-2,6-
.Y~ylyl, 3-propyl-4-ethylphenyl, (2,3,4-, 2,3,5-, 2,3,6-, or
- 20 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, 2-
fluoro-(o-, m-, or p-)tolyl, 4-fluoro-2,5-xylyl, (2,4-,
2,5-, 2,6-, 3,4-, or 3,5-)difluorophenyl, (o-, m-, or p-)-
chlorophenyl, 2-chloro-p-tolyl, (3-, 4 -? 5-. or 6-)chloro-
o-tolyl, 4-chloro-2-propylphenyl, 2-isopropyl-4-chloro-
phenyl, 4-chloro-3,5-xylyl, (2,3-, 2,4-, 2,5-, 2,6-, 3,4-,
or 3,5-)dichlorophenyl, 4-chloro-3-fluorophenyl, (3-, or
4-)chloro-2-fluorophenyl, a, a, a - trifluoro-(o-, m-, or p-)-
tolyl, (o-, m-, or p-)methoxyphenyl, (o-, m-, or p-)e~hoxy-
phenyl, (4- or 5-)chloro-2-methoxyphenyl, and 2,4-dTchloro-
~5- or b-Jmethoxyphenyl.
-20-
3230
-
1075ZS0
The processes descrlbed herein and the intermediates
produced in the course of those processes lead to bicycllc
lactone ketones V, Xl, and XXIII which are useful in ~re-
paring prostaglandins or prostaglandin analogs having
pharmacological activity. See the references cited above
under "Background of the Invention".
~ he processes are useful for preparing said ketones
within the scope of the substituent groups R,2, R23, and T
as defined herein. However, certain of said ketones are
' 10preferred for the reason that they are especially useful
in preparing prostaglandins or prostagl'andin analogs having
especially desirable biological response specificity,
potency, and duration of activity, as well as advantageous
qualities for administration by oral, sublingual, intra-
vaginal, buccal or rectal methods.
For example, considering ketone Y, wherein Rl2 is
~13 "
-C-CgHzg~CH9 ,
14
it is preferred that ~gH29 be ethylene, tri~ethylene, or
tetramethylene, and that Rl3 and Rl4 be hydrogen or methyl
or that both R~ 3 and R1 4 be methyl or fluoro. When Rl2 in
ketone V is
2~~R~3
-C-Z- ~ T)s
1 ~
- - and when Z is -oxa- (as also Tn ketone XXIII) it Is pre~
ferred that Rl'9 and R~4 be hydrogen or methyl, that "s" be
-21-
3230
-- 1075ZSO
zcro or one, anc~ that T be methyl, fluoro, chloro, trl-
fluoromethyl, or methoxy; when Z is CjH2j, It is preferred
that CjH2j be a valence bond or a chaln of one to 3 carbon
atomsJ that R13 and Rl 4 be hydrogen or methyl, or that both
R13 and Rl4 be methyl or fluoro, that "s" be zero or one,
; and that ~ be methyl, fluoroJ chloro, trifluoromethyl, or
methoxy. In ketone XXIII it is preferred that R23 be hydro-
gen or methyl.
Reference to Charts A, B, C, and D will make clear
: 10 the steps by which these processes are performed and by
which these compounds are obtained. In these charts, Rl2,
R1~, R2~, R2s~ s, T, Ll, L2, and ~ are as defined above,
namely: R12 is
. (1 ) IR~ ,3
-C-Cg~29-CH3
. Rl4
(2) ~ C=C or
H'' ~ H
(3) Rls
-~( T ) s
- Rl4
wherein CgH29 is alkylene of one to 9 carbon atoms, ;nclu-
sive, with one ~o 5 carbon atoms, inc1usive, in the chain
between -CRI9Rl4- and terminal methyl; wherein Rl3 and R~4
are hydrogen, alkyl of one to 4 carbon atoms, tncluslve,
or fluoro, being the same or dlfferent, with the proviso
_ that R~3 is f!uoro only when Rl4 is hydrogen or fluoro;
wherein ~ is alkyl of one to 4 carbon atoms, Inclusive,
-22-
~ 1075ZS0 3230
CHAR~ A
,0~ , .
- 5 ~,~ Vl
CHO
1 step a
.~ o
O~< .
~ Vll
~R l 2
CN
~¦ step b
I5 O
~"; ,~ Vlll
''' ~ ,
?~Rl2
OCHO L
0
,0~ tep I step~ X
RI Z ¢~ RIZ
O~HO oh L 1
2~ \ step step/
~d O f L~
0'~ V
._ _ ~R~2 . .
OH . o
-23 -
3230
- 1075250
CHART B
C,~
~COOC2Hs
N
step j
o~
~ ~' XIV
~COOC2Hs
OH L
~Sk ep s te~
0~ q~
¢~ XV ~_~ cOXOcVlHs
OH L 1 OR 1 ~ L2
tep s tep/
n ~
,C~' . ' .
/~
H X Y ~ (
~Rl~L2
¦ step p
3
-24 -
32 50
~075250
ÇHART ~ (cont i nued )
l step
O P
o_l~> xvl I ~
OH L
. s tep
,,., ' O ~ ~ ,
J~ X l
~ ., ?~ .
OH o
- .
.
. _ . _ . . . . _ . . . .. , . _ . .
.. 30
-~5 -
3230
~075250
CHART C
0~
~_ Vl
CH0
l step r
O
,o ,4~ ,
~ ' X I X
OR
CN
¦ s tep s
,o~
~CH0
CN
O ~
<~-I XX I
CN
s tep u
.
-26 -
3230
~ 1075250
CHART C (cont I nued )
s tep u
o
'~ XXII
?~
OCHO L 1
l 5 tep v
o
~ . .
~ ~ Xl
f~
. OH
.
,
-27 -
3230
- 1075ZS0
CllAR T D
0~
~ ~ XVI I
~ H
~R~e 2
step w
O, 4~ XXIV '
~--1 R2-~
10 \~
dR le L2
o ¦ step x
' ' o~~4( \~
XXV
~3
~ Rle L2
~ ¦ s tep y
: O ~
~ XXYI
~ ~T~5
OH Ll
l s~ep
2~ O
~ R23 XXI
<~0 ~( T )s
. . . . dH O
-28 -
1075'~50 32~0
fluoro, chloro, trifluoromethyl, or -ORl5, wherein Rs5 is
hydrogen or alkyl of one to 4 carbon atoms, inclusive, and
s is zero, one, 2, or 3, with the proviso that not more
than two T's are other than alkyl; and wherein Z represents
an oxa atom (-0-) or CjH2j, wherein CjHzi ;s a valence bond
or alkylene of one to 9 carbon atoms, inclusive" substituted
with zero, one, or 2 fluoro, with one to 6 carbon atoms,
inclusive, between -CR13R~4- and the ring; R1~ is 1-ethoxy-
ethyl, tetrahydropyranyl, ~etrahydrofuranyl, or a group of
the formula
I H
R 17 - -C C -R20
Rl8 R~9
wherein R~7 is alkyl of one to 17 carbon atoms, inclusive,
cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of
; 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substi-
tuted with one, 2, or 3 alkyl of one to 4 carbon atoms,
inclusive, wherein R18 and R~9 are the same or different,
being hydrogen, alkyl of one to 4 carbon atoms, inclusive,
phenyl or phenyl substituted with one, 2, or 3 alkyl of
one to 4 carbon atoms, inclusive, or, when R18 and R~
are taken to4ether, -(CH2)a- or -(CH2)b-0-(CH2)C- wherein
a is 3, 4, or 5,-b is one, 2, or 3, and c is one, 2, or 3
with the proviso that b plus c is 2, 3, or 4, and wherein
R20 is hydrogen or phenyl; R~ is (1) R1~ as defined above
or (2) carboxyacyl -C(O)R22 wherein R22 is hydrogen or
alkyl of one to 17 carbon atoms, inclusive; R23 is hydro-
- gen or alkyl of one to 4 carbon atoms, lnclus1ve; L~ repre-~- ~~~~~
~0 sents / " or ,' \ ; L2 represents ~
H0 CN H0 CN R~0 CN
.
-29 -
-~ 1075ZS0 3230
or ,'\ , wherein Rto is as defined above; and ~
r~. "r,
;ndicates at~achment to thc cyclopropane ring in cndo or
exo configuration.
The formulas as depicted herein are intended to repre-
sent those specific stereoisomers which will lead to prosta-
glandins or prostaglandin analog products having the same
or similar pharmacological activity as correspondtng prosta-
glandins obtained from natural sources. In Charts A-D the
formulas as drawn represent speci~ic optical isomers, fol-
l~ lowing that convention. However, for purposes of conven-
ience and brevity it is intended that such representations
of the process steps for the optically active intermediates
are also ap~licable to those same process steps as used for
the corresponding racemic intermediates or mixtures of the
- 15 enantiomeric forms of the intermediates.
Referring to Chart A, there are shown the steps by
which tricyclic lactone aldehyde VI is transformed to bi-
cyclic lactone ketone V. Starting material Vl is readily
available. See U.S. Patent No. 3,816,462. That isomer is
used which 1eads to prostaglandins having the same config-
uration as prostaglandins obtained from mammalian tissues:
for example, for the endo form of aldehyde VI, m.p. 61-64 C.,
D-30 (see R.C. Kelly et al., J. Am. Chem. Soc. 95, 2746
(1973)). Either the endo or exo form may be used. In step
"a" aldehyde VI is reacted with dihalonitrile of the formula
I a 1
Hal-f _ R 12
wherein Hal is chloro, bromo, or iodo, the two Hal's being
-3o-
~230
~075250
the same or different, and wherein R~2 is defined above, to
form cyanoepoxide Vll.
The reagent dihalonitrile is available by methods known
in the art, for example halogenation of a nitrile. Thus,
2,2-dibromoheptanenitrile is obtained ~y bromination of
heptanenitrile. Alterna~ely, a dihaloaldehyde i~ converted
~o the dihalonitrile by methods known in the art, following
the seguence:
c~Ja-dihaloaldehyde
~,a-dihaloacid
,`~' , ; . .
a,~-dihaloacid chloride
., ~,, .
a,a-dihaloamide
;"
a,a -dihalonitrile-
Thus, 2,2-dibromo-4-phenyl-butanal is converted to 2,2-
dibromo-4-phenylbutyronitrile,
Br
~- ( CH2 )2 -C -CN
Br
' '
Similarly, 2,2-di-bromo-cis-4-heptenal is converted to 2,2-
dibromo-cis-4-heptenenitrile,
C2H5~ ~CH2-CBr2-CN
,C=C~
... _ . _ . _ . .. ... . .. . .......... .. . .
` 30 Examples of dthalonitriles useful for the purposes of
-31-
3230
`` 1075'~0
this in~en~ion as depicted in Chart A are:
2,2-dibromohexanenitrile
2,2-dichlorooctanenitrile
2,2-diiodo-3-methylhexanenitrile
2,2-dibromo-3,3-dimethylheptanenitrile
2,2-diiodo-3-fluorooctanenitrile
2,2-dibromo-3J~-difluoroheptanenitrile
2,2-dibromo-cis-4-heptenenitrile
~,2-dibron~-3-phenylpropionitrile
0 2,2-dibromo-4-phenylbutyronitrile
2,~-dichloro-4-(4-chlorophenyl)butyronitrile
2,~-dibromo-4[(3-trifluoromethyl)phenyl]butyronitrile
2,2-diiodo-4-(2-fluorophenyl)butyronitrile
2,2-dibromo-4-(4-methoxypheny)butyronitrile
2,2-dibromo^~-phenoxypropionitrile.
In "a" , the reaction o~ aldehyde V! with the dihalo-
nitrile is done in the presenc~ of a reducing agent in an
inert (aprotic) solvent such as tetrahydrofuran at about Q
to -15 C. For the reducing agent, trivalent phosphorus
compounds are useful, including phosphines, phosphites, and
phosphorous triamides. Particularly useful is hexamethyl-
phosphorous triamide, ~(CH3)2N]3P. Certain metals or com- -
binations of metals are also useful, including magnesium,
strontium, barium, caicium, and zinc. The dihalon;trile
and reduc;ng agent are used in slight excess, 5-10% over
the theoretical amounts based on aldehyde Vl.
In step "b", the cyanoepoxide Vll is solvolyzed in sub-
stantially anhydrous formic ac;d at about 25 C. Advan-
tageously-the formic acid may be rendered anhydrous by con-
tact with acet;c anhydride prior to use. An inert solvent
-~2-
3230
lV75Z50
such as dichloromethane, ben~ene, or diethyl ether may be
employed.
The product of step "b" is converted to the formula-V
ketone either by steps c-d or e-f. In step "c", hydrocyanic
acid is removed by dehydrocyanation, e~loving a has~ stJch
as an alkali metal carbonate, hydroxide or alkoxide, pre-
ferably potassium carbonate, at about 25 C. either in
water or in an inert liquid medium such as tetrahydrofuran
or benzene In step "d" the monoformate is hydrolyzed
under either acidic or basic conditions, using aqueous
mineral acids or sulfonic acids, for example p-toluene-
sulfonic acid, or aqueous weak bases such as alkaii metal
carbonates, b;carbonates, or phosphates, preferably sodium
or potassium bicarbonate, together with a lower alkanol for
improved solubility. For this hydrolysis, a temperature
range of 10 C. to 50 C. is operable, preferably about
25 C.
In step "e", the hydrolysis of the monoformate precedes
the dehydrocyanation and for this hydrolysis acidic condi-
tions are employed using aqueous mineral acids or sulfonicacids, preferably p-toluenesulfonic acid at about 10-50 C.,
preferably about 25 C. Finally in step "f" the dehydro-
cyanation is effected as in step "c" above, for example with
potassium carbonate in tetrahydrofuran or benzene or mixtures
thereof at about 25 C.
In the processes of Chart A as well as Charts B, C, and
D, the intermediate.products are separated from the starting
materials and impurities by methods described herein or known .
in the art, tncluding partitlon extractlon, fractional crys-
tallization, and silica gei column chromatography. For con
~33-
3230
1075ZS0
venience the product of an intermed;ate step may generally
be used directly without isolation or purification.
Intermediates VII, VIII and X are obtalned as various
diastereomers or mixtures thereof. Although these may be
separated by methods kn~wn in the art, for example ~y silica
gel chromatography, such separation is generally not neces--
sary for the purposes of this process as any or all of said
diastereomers are useful for the purposes disclosed herein. i
Thus, from optical1y active aldehyde Yl as 5 tarting material,
- 10 the product V of Chart A is obtained in an optically active
form. Similarly, from racem;c aldehyde VI, product V ;s
obtained as a racemic mixture.
Referring to Chart B, there are shown the steps by which
cyanoepoxide Xll is transformed into ketone XI. The start-
ing material XII is prepared from aldehyde VI similar1y to
step "a" of Chart A but replacing the dihalonitrile reagent
w;th the ethyl ester of dibromocyanoacetic acid:
0 Br
.' 1~ ~ .
C2HsO-C-C-CN . . . -.
Br
The react~on is carried out in an inert solvent in the pres-
ence of a reducing agent, preferably hexamethylphosphorous
triamide, at about 0 to -15 C.
In step "j", the cyanoepoxide XI1 is solvo~yzed in
formic acid as discussed above for step "a" of Chart A.
The product of step "j" is converted to cyanohydrin
diether XVII either by steps k-l or m-n. In step "k", carb-
ethoxy cyanohydrin XIV is hydrolyzed to effectively cleave
the ester and decarboxylate to compound XV. Dllute mlneral
~0 acld and a mtscible solvent such as tetrahydrofuran are
-34 ~
---- 3~30
1075Z50
used. In step "l" cyanohydrin XV is converted to diether
XVII as follows.
When R~ is tetrahydropyranyl or tetrahydrofuranyl,
the appropriate reagent, e.g. 2,3-dihydropyran or 2,3-di-
hydrofuran, is used in an inert solven~. such as dichloro-
methane, in the presence of an acid condensing agent such
as p-toluenesulfonic acid or pyridine hydrochloride. ~he
reagent is used in slight excess, preferably 1.0 to 1.2
times theory. The reaction is carried out at about 20-50 C.
When Rl~ is of the formula Rl7-0-~(RlB)-CHRl~R~o~ as
defined above, the appropriate reagent is a vinyl ether,
e.g. ethyl vinyl ether or any vinyl ether of the formula
Rl7-0-C(Rl8)=CR19R20 wherein Rl7, Rl8, Rl9, and R20 are as
defined above; or an unsaturated cyclic or heterocyclic
compound, e.g. 1-cyclchexen-1-yl methyl ether
CH30 ~
or 5,6-dihydro-4-methoxy-2H-pyran
CH30- ~
See C.B. Reese et al., J. Am~ Chem. Soc. 89, ~66 (1967).
The reaction conditions for such vinyl ethers and unsatu-
rates are similar to those for dihydropy~an above.
In step "m", the etherification precedes the decarboxy-
lation using the conditions and reagents for step "l" above.
In step "n'~, the conversion to compound XVII ts done con-
veniently in dimethyl sulfoxide in the presence of sodium
cyanide at temperatures above 120 C., preferably at about
- -- - ---- 160 C. ~ ~-~~ ~~ ~ ~~
3 In step "p", the three successive reactions of depro-
~35~
3230
--` 1075250
tonating, alkylating with 1-bromo-cis-2-pentene, and de-
blocking are carried out. Deprotonation to form a carbanion
is done with an alkali metal amide, preferably lithium di-
isopropylamide, in an inert (aprotic) sol~ent such as tetra-
hydrofuran at below about -40 C. Alkyldtion occurs readi'y
on addition of 1-bromo-cis-2-pentene. Deblocking (for
example, replacement of 1-ethoxy-ethoxy groups with hydroxy)
is done under midly acidic conditions using for example
aqueous organic acids such as acetic or citric acid at pH
2.0 at about 25-~0 C.
In step "q", dehydrocyanation is achieved as for steps
"c" and "f" in Chart A, for example by contacting the formula-
XVIII compound with dilute aqueous sodium bicarbonate at
about 25 C.
Referring to Chart C, there are shown the steps for an
alternate process by which aldehyde VI is transformed into
ketone XI. In this process the key intermediate XX is an
aldehyde which is subjected to a Wittig alkylation at step
"t" to extend the side chain.
In step "r", aldehyde Vl is reacted with a dihalobutyro-
nitrile of the formu~a
~Hal
Hal-C-(CHz )2 - -R2 1 .
CN
wherein R2~ is (1) R~ as defined above or (2) carboxyacyl
-C(0)~22 wherein R22 is hydrogen or alky1 of one to 17 car-
bon atoms, inclusive. Examples of the reagent are the 2l2-
dibromo-4-hydroxybutyronitri)e ester of acetic actd:
,, . - .
- __ , 0 8r
3o CH9C-0-(CH2 )2 -t -CN
Br
-36-
32~0
10752~0
and the 1-ethoxyethyl ether of 2~2-dibromo-4-hydroxybutyro-
nitrile:
Ir
C2~5-CH2-0-(CH2 )2 -C -CN
CH3 Pr
The conditions for this reaction, done in the presence of a
reducing agent such as hexamethylphosphorous triamide, are
essentially the same as for step "a" of Chart A.
In step "s", cyanoepoxide XIX is hydrolyzed to replace
R2~ with hydro~en, using conditions suitable for hydrolysis
of esters or ethers. See, for example, step "d" and step
"p", above, as to deblocking. The alcohol moiety thus
formed is then oxidized to an aldehyde moiety by methods
known in the art, for example with Collins reagent (Tetra-
hedron Lett. 3366~ (1968)).
In step "t", the aldehyde compound XX is alkylated with
an ylid by the Wittig reaction. The ylid is preferably formed
from propyltriphenylphosphonium bromide and butyl1ithium
using methods known in the art.
In step "u", cyanoepoxide XXI is solvolyzed in formic
acid. See step "b" of Chart A above.
In step "v", monoformate XXII is converted to ketone
Xl either by first dehydrocyanating and then hydrolyzing
the monoformate or by the reverse order. See steps c-d
and e-f of Chart A discussed above.
Referring to Chart D, there are shown the steps by
wh~ch cyanohydrin XVII (of Chart 8) is transformed ~o
~ ketone XXIII. Ketone XXIII Is a useful intermedlate In ~ ~~~~
preparing 16-phenoxy-PGF2~-type analogs.
-37-
:~2~0
1075;~50
In step "w" two successive reactions are carried out:
deprotonating and reacting the carbanion thus produced with
an aldehyde of the formula R23CHO wherein R23 is hydrogen
or alkyl of one to 4 carbon atoms, inclusive. The condi-
tions for deprotonating are those used above in ste~ "p"of Chart B. The reaction with the aldehyde is done under
anhydrous conditions, generally in an inert solvent such as
tetrahydrofuran at about 25 C.
- In step "x", alkoxide anion XXIV of step "w" is arylated,
- 10 for example by reaction with diphenyliodonium bromide or
other suitable substituted phenyliodonium halide to provide
the terminal group:
`'' ~--(T)S
wherein T and s are as defined above. See for example Fieser
et al., Reagents for Organic Synthesis, Vol. 1, p. 340,
Wiley, New York, (1967).
In step "y", cyanohydrin diether XXV is deblocked to
replace R1~ groups with hydrogen, preferably using mildly
2G acidic conditions. See step "p" of Chart B.
Finally, in step "z" the cyanohydrin XXVI i~ converted
by dehydrocyanation to ketone XXIII. See step "q" of Chart
B. Those formula-XXIII ketones wherein R23 is not hydrogen
exist as two epimers, both having the same configuration at
the other asymmetric cent~rs. These are separable by
methods commonly applied to diastereomers, for example silica
gel chromatography.
In the processes of Charts B, C, and D, as for Chart
A, the-products~XI and XXIII are optically actlve tf derlved
from optlcally actlve aldehyde Vl, and racemtc If dertved
3230
- 1075Z50
from racemic aldehyde Vl.
For convenience herein, names of racemic intermediates
or products include the prefix "racemlc" ("rac" or "dl");
when ~hat prefix is absent, the intent is to designate an
optically active compound.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention can be more fully understood by the fol-
lowing examples.
All temperatures are in degrees centigrade.
Infrared absorption spectra are recorded on a Perkin-
Elmer Model 257 infrared spectrophotometer. Except when
specified otherwise, chloroform solutions are used.
NMR spectra are recorded on a Varian A-60, A-60D, or
T-60 spectrophotometer using deuterochloroform solutions
with tetramethylsilane as an internal standard (downfield).
Mass spectra are recorded on a Varian Model MAT CH7
mass spectrometer or an LKB Model 9000 Gas Chromatograph-
Mass Spectrometer (ionization voltage 70 ev)
"Brine", herein, refers to an aqueous saturated sodium
chloride solution.
Silica gel chromatography, as used herein, is under-
stood to include elution, collection of fractions, and com-
bination of those fractions shown by TLC (thin layer chroma-
tography) to contain the desired product free of starting
material and impurities.
Ske1lysolve~ consists of mixed isomeric hexanes.
Example 1 2,2-Dibromoheptanenitrile
8romine (14 ml.) is added to heptanenltrlle, CH9(CH2)sCN
(26.64 9.) at 16-38 C., followed by phosphorus trlbromide
(3.75 ml.) added in four portions. The mixture Is heated
~39-
3~30
~075Z50
at 60-80 C. for 45 min. Additional bromine (24 ml.) is
ad<~e~ within 1() nlin. The heating bath temperature is
ra;sed so that the reaction tcmperature is 88 C. for about
30 min. Th~ mixture is coole~ and shciken with a mixture of
5 cold 9% sodium sulfite solution and Skellysolve 8. The
organic phase is washed with 20% aqueous su1fate, dried ov~r
sodium sul~ate, and concentrated. Distillation yields the
title compound, 36.47 9., b.p. 52-~7~ C.
Example 2 Tricyclic Lactone Cyanoepoxide (Formula Vll
wherein Rl2 is n-pentyl and ~ is endo).
Refer to Chart A, step "a". The formula-VII tricyclic
lactone cyanoepoxide, name!y 6-endo-(3-cyano-3-pentyl -2-
oxiranyl)-3-exo-hydroxybicyclo[3.1.0]hexane-2-exo-acetic acid,
y-lactone, is prepared as follows. A mixture of the formula-
Vl endo tricyclic lactone aldehyde (U.S. Patent 3,816,462,
4.0 9.), 2,2-dibromoheptanenitrile (Example 1, 7.75 9. ),
and 35 ml. of tetrahydrofuran is cooled to -~5 C. and
treated with hexamethylphosphorous triamide (5.26 ml. ) in
portions of about 0.5 ml. every 5 min., with the reaction
temperature at -8 to -14Q C. The mixture Ts stirred 2 hr.
at a temperature of -10 to 0 C. The mixture is then
shaken with 180 ml. of toluene and ~0 ml. of brine. The
organic phase is concentrated under reduced pressure to
the formula-VII title compound, an oil, 8.54 9., having
~ 0.42 (TLC on silica ~el in ethyl acetate-benzene ~1:4));
mass spectral peaks at 275, 246, and 217; infrared a~sorp-
tion at 2960, 2935, 2B62, 2253, 1770, 1460, and 1190 cm ';
and NMR peaks at 4.9, 3.2-2.5, 2.3, 2.0-1.2, and 1.0 ~;
Example 3 Bicyclic Lactone Cyanohydrin Monoformate
~ (Formula Vlll wherein Rl2 Is n-pentyl)
-40-
~2~0
1 0 7 5Z50
Refer to Ch~r~ A, step "b". The formula-VIII bicyclic
cyanohydrin ~nonororn~tc, namely 2~-(3-cyano-3-hydroxy-1-
octenyl)-3~-(formyloxy)-5a-hydroxy -la -cyC lopentaneacetic acid,
y-lactone~ is pr~pared as follows. A soiu~ion of the formula-
Vll cyanoepoxide (Example 2, 148 mg.) in C,2 ml. of d7chloro
methane is added to a mixture of anhydrous formic dCi d
(0.95 ml ) and acetic anhydride (0.05 ml.) previously stir-
red for 0.5 hr. The reaction mixture is then stirred at
about 25 C. for one hr. whereupon water (2.0 ml.) sodium
carbonate (o.685 g ) and ethyl acetate ~15 ml.) are added.
The upper organic phase is washed with lN.sodium bicarbonate
(4.0 ml.) and both aqueous layers are washed with additional
ethyl acetate (10 ml.). The combined organic extracts are
dried and concentrated to yield the formula-VIII title com-
pound in about 80~ purity, 150 mg. Fureher purification by
silica gel chromatography, eluting with ethyl acetate-benzene
(1:4), yields the title compound, 75 mg.; having infrared
absorption at 3580 -3210, 3013, 2960, 2941, 2872, 2263, 1771,
1724, 1182, and 925 cm 1 ~nd NMR peaks at 8.oo, 5.45-5.42,
5.25-4.90, 2.46-2.40, 2.40-1.08, and 0.91 6,
Example 4 Bicyclic Lactone Monoformate (Formula IX
wherein R12 is n-pentyl).
Refer to Chart A, step "c". The formula-lX bicyclic
lactone monoformate, namely 3a-(formyloxy)-5a-hydroxy-2~--
(3-oxo-trans-1-octenyl)-1a-cyclopentaneacetic acid, y-
lactone, is prepared as follows.
A mixture of the formula-~lll bicycltc lactone cyano-
hydrin monoformate ~xample 3, 200 mg.) in tetrahydrofuran
~4.0 ml.) is treated with 200 mg. of potassium carbonate
and stirred at about ~5 C. for 3.5 hr. The mixture is
-41-
3230
1075250
diluted with benzene (7 ml.), filtered, and concentrated to
yield the formula-lX title compound, an oil, 190 mg., having
infrared absorption at 2987, 2937, 1773, 1725, 1671, 1630,
1240, and 1178 cm 1; and NMR peaks at ~.0, 6.6, 6.2, 5.1, 4.7-
3.5, 3.5-1.9, and 3.6 ~.
The formula-lX bicyclic lactone monoformate of Example
4 is converted to PGF2~ by (a) reducing with excess z;nc
borohydride in dimethoxyethane at about 20 C. for 0.5 hr.,
(b) separating the 3-hydroxy epimers thereby formed, using
silica ~el chromatography, (c) deformylating by contacting
the appropriate 3a-hydroxy epimer with water and p-toluene-
sulfonic acid in tetrahydrofuran at about 25-40 C. to yield
the corresponding bicyclic lactone diol, and (d) transforming
the diol to PGF2a by methods known in the art. See E.J.
Corey et al , J. Am. Chem. Soc. 92, 397 (1970).
Example 5 Bicyclic Lactone Ketone (Formula V wherein
R~2 i s n-pentyr ) .
Refer to Chart A, step "d". The formula-V brcyclic
lactone ketone, namely 3aJ5a-dihydroxy-2B-(3-oxo-trans-1-
octenyl)-la-cyclopentaneacetic acid, y-lactone, is prepared
as follows. A mixture of the formul3-lX bicyclic lactone
monoformate (Example 4, 0.10 g.), 1 ml. of tetrahydrofuran,
0.05 ml. of water, and p-toluenesulfonic acid monohydrate -~
(0.010 g.) is stirred at about 25 C. for i7 hr. Then 0.05
ml. of water is added and stirring ts continued at 40 C.
for 7 hr. The mixture is diluted with benzene and washed
with dilute aqueous sodium bicarbonate. The organic phase
is dried and concentrated to yield the title compound,
o.o8 g., having Rf 0.27 (TLC on si)ica gel in ethyl acetate-
benzene (1 1)); in~rared absorption at 3605-3250, 3030, 3000,
-42-
3230
1075250
2962, 2938, 28~, 1768, 1691, 1626! 1180, 1092, and 993 cm
mass spectral peaks (TMS derivative) at 338, 323, 295, 281,
267, 248, 239, 221, 166, 145, 99, and 73; and NMR peaks at
6.99. 6.17, 4.95, 4.14, 3.25-2.9, 2.83-1.85, 1.76-1.07, and
5 o.88 ~.
The formula-V bicyclic lactone ketone of Example 5 is
converted to PGF2a by (a) benzoylating with benzoyl chloride
in pyridine at about 20-40 C. thereby forming 3~-benzoxy-
5a-hydroxy-2~3-(3-oxo-trans-1-octenyl )-la-cyc'lopentaneactic
acid, y-lactone, (b) forming the corresponding bicyclic
lactone diol, and ~c) transforming the diol to PGF2a. See
U.S. Patent No. 3,778,450.
Example 6 Bicyclic Lactone Cyanohydrin (Formula X
wherein R 12 is n-pentyl).
Refer to Chart A, step "e". The formula-X bicyclic
lactone cyanohydrin, namely 2a-(3-cyano -3 -hydroxy-1-octenyl)-
3a,5a-dihydroxy-1a-cyclopentaneacetic acid, y-lactone, is
prepared as follows. ~he formula-VIII bicyclic lactone cyano-
hydrin monoformate (Example 3, 150 mg.) is dissolved in
acetone (2 ml.), water (0.05 ml.) and p-toluenesulfonic acid
(1 mg.), and the mixture is stirred at about 25 C. for 19
. hr. Thereafter the mixture is extracted with ethyl acetate,
dried, and concentrated to yield the formula-X title compound,
an oil, 120 mg., having mass spectral peaks (TMS derivative)
at 437, 442, 410, 367, 239, and 197; infrared absorption at
3600-3150, 3012, 2960, 2941, 2872, 1769, 1460, 1180, 984,
and 922 cm ~; and NMR peaks at 5.78, 4.95, 3.90-4.45, 2.51-
2.70, 1.14-2.35, and 0.91 ~.
Example 7 Bicyclic Lactone Ketone (Formula V where;n
R~2 is n-pentyl).
~43-
~30
10'7S250
Re~er to Chart A, steps "b", "c", and "d". The formula-
V bicyclic lactone ketone, namsly ~a,5a-dlhydroxy-2~-(3-
oxo-trans-1-octenyl)-1a-cyclopentaneacetlc acid, y-lactone,
is prepared as follows.
I. The formula-VIII bicycllc lactone cyanohydrin mono-
formate wherein R~2 is n-pentyl is first ptepared. A solu-
tion of the formula-VII cyanoepoxide (Example 2, 8.54 9.) in
7 ml. dichloromethane is added to a mixture of anhydrous
formic acid (44.4 ml.) and acetic anhydride (1.16 ml.) pre-
viously stirred for 0.5 hr. The reaction mixture is then
stirred at about 25 C. for 23 hr., concentrated, and the
resulting cyanohydrin monoformate used directly.
Il. The product of part I is taken up in tetrahydro-
furan (72 ml.) and treated with 24 ml. of 10~ sulfuric
acid, with stirring continued at about 25 C. for 21 hr.
Thereafter sodium carbonate (2.18 9.) is added and the
tetrahydrofuran removed under reduced pressure. The resi-
due is extracted with ethyl acetate and the resulting ethyl
acetate solution is backwashed with water (60 ml.) and then
lN. sodium bicarbonate solut;on. The aqueous phases are
backwashed with ethyl acetate and all of the ethyl ace~ate
extracts are combined, stirred with lN. sodium bicarbonate
solu~ion and separated. The upper (organic) layer is washed
w;th brine, dried.over sodium sulfate, and concentrated to
yield the formula-Y title compound, 7.19 g. in about 65%
purity.
The formula-V product is further-purified either by
silica gel chromatography, or, preferably, by liquid-ltqu;d
extraction followed by crystallization, as follows.
~0 Ill. A solutton of ~he formula-V ketone ofpart I
- -44-
3230
1075250
(6.~8 g.) in 1(~ ml. of ethyl acetate is subjected to a
multi-stage liquid-l;quid extraction. Each stage contains
a lower phase (412 ml.) and an upper phase (206 ml.) from
equilibrated acetone-Skellysolve B (isomeric hexanes)-water
(1:1:1).
The impurities are concentrated in the upper phase.
The product is obtained by concentrating the lower phase and
extracting with ethyl acetate (washing each extract with
brine). The ethyl acetate solution is dried over sodium
sulfate and concentrated to yield the formula-V title com-
pound, 5.707 9. in about 80~ purity.
IV. Further purification is achieved by crystallization
as follows. A solution of the formula-V compound from part
lll (5.626 9.) in tetrahydrofuran (4.0 ml.) and isopropyl
ether (15 ml.) is cooled to -15 C. and seeded. Additional
isopropyl ether (25 ml.) is added slowly while cooling at
-25 C. The resulting solid is washed with cold ;sopropyl
ether (5 ml.) and dried. The resulting semisolid product
(4.688 9.) is recrystallized from tetrahydrofuran (2.4 ml.)
and isopropyl ether (5.0 ml.) as above to yield the formula-V
title compound, 4.1147 9. Additional product is obtained
~rom the mother liquors by silica gel chromatography,
eluting with ethyl acetate-benzene (1:4) 0.514 9.
Example 8 Bicyclic Lactone Ketone (Formula V wherein
Rl2 is n-pentyl).
Refer to Chart A, step "f". The formula-V bicyclic
lactone ketone, namely 3a,5a-dihydroxy-2~-(3-oxo-trans-1-
octenyl)-la-cyclopentane-acetic acid, y-1actone, Is pre-
pared as follows. A mixture of the ~ormula-X bicycllc
lactone cyanohydrin (Example 6, 4.35 9.) in 45 ml. o~
-45-
3230
1075'~50
tetrahydrofuran and 45 ml. of benzene, with potassium
carbonate (4.5 9.), is stirred at about 25 C. for 21 hr.
The mixture is diluted with benzene (100 ml.), flltered,
and concentrated to an cil, 3.618 9. The oil is subjected
to silica gel chromatography, eluti~g with ethyl acetate-
benzene (1:4), and concentrating to yield the fo.rmula-V
title compound, an oil, 1.4753 9., having the same properties
as reported above ;n Example 5.
Following the procedures of Examples 1-8 but replacing
heptanenitrile with 3,3-dimethylheptanenitrile, there is
first obtained 2,2-dibromo-3,3-dimethylheptanenitrile which
is further reacted as in Example 2 to yield the formula-
VII 6-endo{3-cyano-3-(1,1-dimethylpentyl)-2-oxiranyl]-3-
exo-hydroxybicyclo-[3.1.0lhexane-2-exo-acetic acid, y-
lactonei there is finally obtained the corresponding formula-
V bicyclic lactone ketone wherein R12 is
CH3
-e -(CH2) 3 -CHs
H3
name1y 3a,5a-dihydroxy-2~-(4,4-dimethyl-3-oxo-trans-1-
octenyl)-1a-cyclopentaneacetic acid, y-lactone. That
ketone is useful in preparing 16,16-dimethyl-PGF2a by
methods known in tHe art.
Likewise following the procedures of Examples 1-8 but
replacing heptanenitrile with 3,~-difluoroheptanenitrlte,
there is finally obtained the corresponding formula-V
bicyclic lactone ketone wherein Rl2 is -CF2-(CH2)9-CH3,
nameIy 3a,~a-dihydroxy-2~-(4,4-difluoro-3-oxo-trans-1-
octenyl3-1~-cyclopentaneacetic acid, y-lactone, use~ul for
3 prepartng 16~16-d;fluoro-PGF2a by methods known In the art.
-46-
~230
10'75Z~O
Following the procedures o~ Example 2-8 but replacing
2,2-dibromoheptanenitrile with 2,2-dibromo-4-phenylbutyro-
nitrile, there is obtained the corresponding formula-V bi-
cyc)ic lactone ketone whcrein Rl2 is
-(CH2)2- ~ ,
namely 3a)5~-dihydroxy-2~-(3-oxo-5-pheny)-trans-1-pentenyl)-
l~-cyclopentaneacetic acid, y-lactone, useful for preparing
17-phenyl-18,19,20-trinor-PGF2~ by methods known in the art.
Likewise ~o)lowing the procedures of Examples 2-8 but
replacing 2,2-dibromoheptanenitrile with each of the fol-
lowing dihalonitriles:
(a) 2,2-dibromohexanenitrile
(b) 2,2-dichlorooctanenitrile
(c) 2,2-diiodo-3-methylhexanenitrile
(d ) 2,2 -di i odo-3-fluorooctanenitrile
(e) 2,2-dibromo-cis-4-heptenenitrile
(f ) 2,2-di bromo-3-phenylpropionitrile
(9) 2,2-dichloro-4-(4-chlorophenyl)butyronitrile
(h) 2,2-dibromo-4-r(3-trifluoromethyl)phenyl~butyro-
nitrile
(i) 2,2-diiodo-4-(2-fluorophenyl)butyronitrile
(~) 2,2-dibromo-4-(4-methoxyphenyl)butyronitrile
(k) 2,2-dibromo-3-phenoxypropionitrile,
there are obtained the corresponding formula-Y blcyclic
lactone ketones wherein R12 is, respective)y:
(a) -(CH2~3-CH9
(b ~ - (CH2 )5 -Cff3
3 (c) -CH(CH3)-(CHz )2 -CH9
~47-
3230
~075250
(d) -CHF-~CH2)~-CH3
(e) -CH2~ C C~ C2Hs
H~ ` H
tf) -CH
(g) -CH2 )2 -~-C 1
(h ) - (C~2 )2 - ~ F3
(j) -(CH2 )2-~
(j ) -(cH2)2-~o-cH3
(k) -CH2-0 ~
Following the procedures of Examples 2-8 and of the
paragraphs following Example 8 but replacing the endo form
of the formula-VI aldehyde with the exo form, the correspond-
ing formula-VII exo tricyclic lactone cyanoepoxides are.
obtained which are finally converted to the formula-V
bicyclic lactone ketones.
Also following the procedures of Examples 2-8 and of
the paragraphs following Example 8, but replacing the opti-
cally active formula-VI aldehyde with the racemic m7xture
of either the endo or exo form, there are obtained the
racemic mixtures corresponding to the compounds of formulaS
V, Vll, Vlll, IX, and X.
Example~ Tricyclic Lactone Cyanoepoxide (Formula Xll
whereTn ~ Is endo).
-48 -
3230
1075ZS0
Re~er to Chart B, The formula-XII trlcyclic lactone
cyanoepoxide, namely 6-endo-(3-carbethoxy-3-cyano-2-
oxiranyl)-3-exo-hydroxybicyclo[3.1.0]hexane-2-exo-acetic
aci4 y-lactone, is prepared as follows. A mixture of the
formula-VI (Chart A) endo tricyclic lactone aldehyde (U,S.
Patent 3,816,462, 166 9.), the ethyl ester of dibromocyano-
acetic acid (2.98 9.), and 35 ml. of tetrahydrofuran pre-
viously cooled to -10 C. is treated dropwise with hexa-
methylphosphorous triamide (1.79 9.) added ~ropwise.- After
complete reaction, as shown by TLC, the mixture is worked
up to yie;d the title compound, as isomeric epoxides.
Example 10 Bicyclic Lactone Carbethoxy Cyanohydrin
-(Formula XIV).
Refer to Chart B, step "j". The formula-XlV bicyclic
lactone carbethoxy cyanohydrin, namely ?~-(3-carbethoxy-3-
cyano-3-hydroxy-1-propenyl)-3a,5a-dihydroxy -la-cyc 10pentane-
acetic acid, y-lactone, is prepared as follows. ~The formula-
Xll tricyclic lactone cyanoepoxide (Example 9) is dissolved
in a minimum volume of dichloromethane and, using a mixture
of anhydrous formic acid and acetic anhydride following the
procedure of Example 3, transformed to the 3-monoformate
of the title compound. After replacement of formyl with
hydroxyl by hydrolysis with dilute sulfuric acid in tetra-
hydrofuran solution and work-up as Tn Example 6, the t;tle
compound is obtained.
Example 11 Bicycl;c Lactone Cyanohydrin (Formula XV).
Refer to Chart 8, step "k", The formula-XV bicyclic
lactone cyanohydrin, namely 2~-(3-cyano-3-hydroxy-1-pro-
penyl~-3a,5a-dihydroxy-la-cyclopentaneacetic acid, y-
3 lactone, is prepared as follows, The formula-XlV bicyclic
-49-
,
3230
;1075250
lactone carbethoxy cyanohydrin (Example 10) is hydrolyzed
under vigorous conditions in dilute sulfuric acid and
tetrahydrofuran so that ester cleavage and decarboxylation
occur to yield the title compound. Example 12 Bicyclic Lactone Cyanohydrin Diether (Formula
XVII wherein R~ is 1-ethoxyethyl).
Refer to Chart B. The formula-XVII bicyclic lactone
cyanohydrin diether namely2~-L3-cyano-3-(1-ethoxyethoxy)-i-
propenyl]-3a-(1-ethoxyethyl)-5a-hydroxy-1a-cyclopentane-
acetic acid, y-lactone, is prepared as follows.
I. Refer to step "l". The formula-XV bicyclic lactone
cyanohydrin (Example 11, 2.2 9. ) in 72 ml, of toluene is
cooled to -10 C. and treated with 9.6 ml. of ethyl vinyt
ether and p-toluenesulfonic acid (5 mg.). After the reaction
is complete, after about 18 hr. at -10 to 0 C., excess
reagent is removed under reduced pressure and the catalyst
is neutralized with triethylamine. The mixture is concen-
trated to yield the title compound.
Il. Refer to step "m". Alternately, there is first
prepared the formula-XVI bicyclic lactone carbethoxy cyano-
hydrin diether, namely 2B-~3-carbethoxy 3-cyano-(1-3-ethoxy-
ethoxy)-1-propenyl~ -(1-ethoxyeth~xy)-5~-hydroxy -la-cyc 1 o-
pentaneacetic acid, y-lactone as follows. The formula-XIV
bicyclic lactone-carbethoxy cyanohydrin (Example 10) is
2~ treated with ethyl vinyl ether, following the procedure in
part I above.
lil. Refer to step "n". Next, the title compound is
prepared by decarboxylation as follows. The formula-XVI di-
ether of Part ll above (1.0 9.) is treated in dimethyl sul-
3 foxide (10 ml.) with sodium cyanide (0.2 9.) and heated to
-5o-
la 75~50 3230
160 C. The reaction mixture is diluted with 30 ml. of
water and extracted with benzene. The organic extract is
backwashed with brine, dried, and concentrated under re-
duced pressure to yield the title compound.
Example 1~ Bicyclic Lactone Cyanohydrin (Formula XVIII).
Re~er to Chart B, step "p". The formula-XVII bicyclic
lactone cyanohydrin, namely 2~-(3-cyano-3-hydroxy-trans-1,
cis-5-octadienyl)-3a,5~-dihydroxy-la-cyclopentaneacetic
acid, y-lactone is prepared as follows.
I. Deprotonation.
The formula-XVII bicyclic lactone cyanohydrin diether
(Example 12, 3.67 9.) in tetrahydrofuran is treated at
about -78 C. with lithium diisopropylamide (10 mmole) and
the mixture warmed to -40 C.
Il. Alkylation and Deblocking.
The anion of part I above in tetrahydrofuran solution
is treated with 1-bromo-cis-2-pentene (1.48 9.). After
reaction is complete as shown by TLC, aqueous citric acid
is added to pH 2.0 and the mixture is stirred at 30 C. for
about 4 hr. to effect deblocking (replacement of 1-ethoxy-
ethoxy groups with hydroxy). The mixture is concentrated
under reduced pressure to remove tetrahydrofuran. Ethyl
acetate (10 ml.) is added, the phases are separated, and
the aqueous layer again extracted with ethyl acetate. The
combined organic extracts are concentrated under reduced
pressure to yield the t;tle compound.
xamp1e 14 8icyclic ~actone Ketone (Formula Xl).
Refer to Chart B, step "q". The formula-XI bicyclic
lactone ketone, namely 3a,5a-dihydroxy-2~-(3-oxo-trans-1,
3 cis-5-octadienyl)-1~-cyclopentaneacetic acid, r-lactone,
3230
1075250
is prepal-ed as follows. The formula-XVIII bicyclic lactone
cyanohydrln (Example 13)in ethyl acetate is sti~rred with
lN. sodium bicarbonate (10 ml.) at about 25 C. for 4 hr.
to effect dehydrocyanation. The organic phase is separate(~,
dried over sodium sulfate, and concèntrated to obtain the
title compound.
Example 15 Bicyclic Lactone Ketone (Formula Xl)
Refer to Chart C. The formula-XI bicyclic lactone
ketone, namely 3~,5~-dihydroxy-2~-(3-oxo-trans-1,cis-5-
octadienyl)-la-cyclopen~aneacetic acid, y-lactone, is pre-
pared as follows.
I. Refer tO step "r". A mixture of the formula-VI
endo tricyclic lactone aldehyde (4.0 g.), the 2,2-dibromo-
~-hydroxybutyronitrile ester of acetic acid (8.2 9.), and
~5 ml. of tetrahydrofuran is cooled to -15 C. and treated
with hexamethylphosphorous triamide (5.26 ml.) in portions
at about -10 C~J continuing stirring for an additional 2
hr. at 10 C. The mixture is worked up to yield the formula-
XIX cyanoepoxide.
Il. Refer to step "s". The product of part I is -
hydrolyzed in d;lute sulfuric acid to replace thP acetyl
group (R2l) with hydrogen. Thereafter, using Collins
reagent (Tetr. Lett. 336~ (1968)) in dichloromethane at
about 0 C., the formula-XX aldehyde is obtained.
Ill. Refer to step "t". The product of part ll ;s
subjected to Wittig alkylation, adding it to a suspension
of propyltriphenylphosphonium bromide in benzene containing
the equivalent amount of n-butyllithium. The mixture is
finally heated at about 50-70 C. for 2.5 hr. The mixture
is cooled and filtered, and the solids washed with benzene.
,
-52-
107525~D 32~0
The combined filtrate and washes are concentra~ed somewhat,
then washed with dilute hydrochloric acid and water. The
organic phase is dried and concentrated to yield the
formula-XXI cyanoepoxide.
9 IV. Refer to step "u". The product of part lll is
added to a mixture of anhydrous formic acid (2.0 ml.) and
acetic anhydride (0.1 ml.) previously stirred for 0.5 hr.
The mixture is then stirred at about 25 C. for one hr. and
quenched with aqueous sodium carbonate. The product is ex-
~10 tracted into ethyl acetate and worked up to yield the
formula-XXII cyanohydrin monoformate.
Y. Refer to step "v". Thereafter, the product of
part IV is first hydrolyzed in tetrahydrofuran wTth 10~
sulfuric acid at about 40 C. The solvent is removed and
the residue extracted with ethyl acetate. The formyl-free
cyanohydrin obtained by concentration is then contacted
wtth potassium carbonate in tetrahydrofuran and benzene
at about 25 C. for 21 hr. to produce the formula-XI ketone.
Example 16 B;cyclic Lactone Ketone (Formula XXIII
wherein R23 is hydrogen and "s" is zero).
Refer to Chart D. The formula-XXIII bicyclic lactone
ketone, namely 3a,9a-d;hydroxy-2~-(3-oxo-4-phenoxy-trans-
l-butenyl)-la-cyclopentaneacetic acid, y-lactone is pre-
pared as follows.
I. Refer to step "w". The formula-XYII b;cyclic
lactone cyanohytrin diether (Example 12, 3.67 9.) is de-
protonated following the procedure of Example 13, part 1.
Then, to a solution of the an;on in tetrahydrofuran is
added gaseous formaldehyde formed by pyrolyzing paraform-
3 aldehyde. The resulttng formula-XXlV al~oxide wherein R
3230
1075'~50
is hydrogen and "s" is zero is used directly without iso-
lation.
,I. Refer to step "x". The reaction mixture of part
I is arylated by treatment with diphenyliodonium bromide.
See Fieser et al., Rea~ents for Organic Synthesis, Vol. 1,
p. 340, Wiley, New York (1967). The formula-XXV diether
is isolated, either by extraction or chromatography.
Ill. Refer to step "y". The formula-XXVI cyanohydrin
is obtained by deblocking the product of part ll. A mixture
of the formula-XXV diether (0.5 9.) in tetrahydrofuran (10
ml. with aqueous citric acid (ca. 2N.) added to pH 2.0 is
stirred at about 30 C. until the reaction is complete as
shown by TLC. The tetrahydrofuran is removed under reduced
pressure, and the remainder is extracted repeatedly with
ethyl acetate. The combined extracts contain the formula-
XXVI cyanohydrin wherein R23 is hydrogen and "s" is zero.
IV. Refer to step "z". Finally, the title compound
is obtained by dehydrocyanation of the product of part lll
in aqueous sodium bicarbonate (10 ml.,lN) for 4 hr. at
about 25 C. The phases are separated and the organic phase
is dried and concentrated under reduced pressure to yield
the formula-XXIII bicyclic lactone ketone.
Following the procedures of Example 16 but replacing
formaldehyde in step I with acetaldehyde, there is obtained
the corresponding formula-XXIII bicyclic lactone ketone in
which R29 is methyl, namely 3a~5a-dihydroxy-2~-(3-oxo-4-meth
4-phenoxy-trans-1-butenyl)-la-cyclopentaneacetic acid, y-
lactone.
Likewise following the procedures of Example 16 but
replacing the optically active formula-XVII start;ng mate
~ -54-
~ 3230
1075250
ria1 with the corrcsponding raccmic mixture, there are ob-
tained the racemic mixtures corresponding to the compounds
of formulas XXIII, XXIV, XXV, and XXVI.
This application is a division of copending
Canadian application Serial No. 247,284, filed March 5,
1976.
