Note: Descriptions are shown in the official language in which they were submitted.
3249
BACKGROUND OF THE INVENTION
The prostaglandins are a family of pharmacologically
useful 20 carbon atom cyclopentane derivatives. They in-
clude, for example PGF3a, PGF2a, PGFlaJ and corresponding
PGE, PGA, PGB, and PGF~ compounds. Each of these prcsta-
glandins may be considered as a derivative of prostanoic
acid, which has the following structure and carbon atom
numbering
- ~ H
See for reference~ Bergstrom et al., Pharmacol. Rev. 20, 1
(1968), and the references cited therein.
Heavy solid lines in the above formula and the for-
mulas hereinafter represent attachment of substituents
above the plane of the cyclopentane ring (i.e., the beta
configuration). Broken line attachments indicates attach-
ment of substituents below the plane of the cyclopentane
ring (i.e., the alpha configuration). When wavy lines are
employed in connection with the formulas herein, attach-
ment of substituents is in either the alpha or beta con-
figuration, or as a mixture of a and ~ isomers.
Thus, for example PGF2 a, which is represented as
~5 follows:
HO
~ - " ==~" "--"-`COOH II
HO
--2-
3249
has a hydroxy substituent at each of positions C-9, C-ll,
and C-15 which is in the alpha configuration. Expressions
such as C-9, C-ll, and C-15 refer to the carbon atom of the
prostaglandin or prostaglandin analog which is in the posi-
tion corresponding to the position of the same number inprostanoic acid~
The C-15 alcohol function of PGF2a above is in the S
configuration. See, Nature, 212, 38 (1966), for a discuss-
ion of this and other stereochemical features of the prosta-
glandins.
Likewise there are known in the art analogs of theseprostaglandins which are known to be useful for the same
pharmacological purposes as the prostaglandins~ In parti-
cular, many of these analogs, while maintaining the same
cyclopentane ring structure of one of the various prosta-
glandins, exhibit variation in the C-7 alpha side chain or
C-13 beta side chainj or both.
Further, 3aJ5a-dihydroxy-2~-(3-oxo-trans-l-octenyl)-la
cyclopentaneacetic acid y lactone, 3-acetate or 3-phenyl-
benzoate (E. J. Corey, et al., J. Am. Chem. Soc. 92 ~97(1970) and E. J. Corey, et al., 93, 1491 (1971)) is known
to be a useful 3-oxo bicyclic lactone intermediate in pre-
paring optically active PGF2a and PGE~. This bicyclic lac-
tone is represented by the formula
,0~
0 III
3249
1~6~zo
wherein Rl1 is acetyl or p-phenylbenzoyl. When prosta-
glandin analogs, exhibiting variation in the C-1~ beta
side chain as is known in the art, are to be prepared,
corresponding bicyclic lactones useful in the preparation
of these analogs are known according to the following for-
mula:
~ I V
H
~C=C ~
R12d H `ICl-fi-R7
0 L
wherein L1 is
/ `
R3 R4,
,'~ .R3 R4,
20or a mixture of
/"
R3 R4
and
, \
R3 R4,
wherein R3 and R4 are hydrogen, methyl or fluoro, being the
same or different, with the proviso that one of R3 and R4
is fluoro, only when the other is hydrogen or fluoro;
wherein R7 is (1) -(CH2)k-CH3, wherein k is 2 to 6,
-4-
~249
~0~9~
inclusive,
(2)
o ~--(T)s
whe.rein T is chloro, fluoro, trifluoromethyl, alkyl of
one to 3 carbon atoms, inclusive, or alkoxy of one to 3
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,
the various T's being the same or different,
(3)
-CHe ~_(T)s ,
wherein T and s are as defined above, or (4) cis-CH=CH-CH2-
CH3, with the proviso that R7 is
(T)s
only when R3 and R4 are hydrogen or methyl, being the
same or different; and
wherein R12 is hydrogen or carboxyacyl.
Each of the formulas herein which represents a prosta-
glandin, a prostaglandin analog, or an intermediate there-
for depicts the optically active form of the compound. ::
tn particular the optical isomer so represented is of the
same relative stereochemical configuration as the corres-
ponding prostaglandin obtained from mammalian tissues, or,
if an intermediate,is of that stereochemical configuration
which will yield the corresponding prostaglandin-type pro-
3249
~O~
duct which is of the same relative stereochemical configura-
tion as the corresponding prostaglandin obtained from
mammalian tissues.
Each of the above prostaglandins or prostaglandin
analogs (i.e., prostaglandin-type compounds~ is named
according to the system of nomenclature which designates
each skeletal position and the particular substitution or
structural variation from the corresponding parent prosta-
glandin at that position. This system of nomenclature is
described in N. A. Nelson, J. of Med. Chem. 17, 911 (1974) .
For the 3-oxo lactones of formula IV to be transformed
to corresponding prostaglandin-type compounds (i.e., prosta-
glandins or prostaglandin analogs) the 3-oxo moiety of the
beta side chain of the formula III or formula IV compound
must be reduced to form a corresponding 3-hydroxy lactone
wherein the 3-hydroxy is the potential 15-hydroxy of an
ultimate PG-type compound.
In many cases it is desirable to obtain the 3a-hydroxy
epimer in preference to the 3~-hydroxy epimer since this
stereochemical feature is preserved in subsequent transfor-
mations to prostaglandin-type compounds by methods known in
the art. Thus, there are prepared compounds with the same
configuration at C-15 as PGF2a of formula II, and these com-
pounds exhibit in many cases the more desired pharmacolo-
gical properties. Accordingly, muth effort has been direc-
ted at achieving stereochemical control of the reduction
described above.
Methods disclosed in the prior art for effecting
stereochemical control of the reduction have used various
organic moieties in place of the Rll or Rl2 group in the
3~1~9
~C~ 2 0
-formula-lll or formula-lV compound together with certain
agents. For a discussion of the use of p-phenylbenzoyl/
andcarbamoyls such as p-phenylphenyl carbamoyl and phenyl-
carbamoyl moieties in place of R11 or R12 in combination with
reducing agents such as lithium limonene thexyl borohydride,
i.e .J
H C(CH3 )2 -CH(CH3 )2
\B/
l ~
"-'f CH3 J
lithium thexyl-di-sec-butyl borohydride, and lithium tri-
sec-butyl borohydride, see E. J. Corey, et al., J. Am.
Chem. Soc. 94, 8616 (1972).
FurtherJ a discussion of the preparation and use of
lithium tri-sec-butyl borohydride is provided by H. C.
BrownJ et al.J J. Am. Chem. Soc. 94: 7159 (1972). Like-
wiseJ a discussion of the preparation and use of potassium
tri-sec-butyl borohydride is provided by C. A. erown, J. Am.
~hem. Soc. 9~. 4101 (1973).
SUMMARY OF THE INVENTION
A purpose of this invention is to provide a novel pro-
cess suitable for large-scale production of bicyclic ~-
hydroxy lactone intermediates useful in the preparation ofprostaglandin-type compounds.
A further purpose is to provide in the above-described
process a method, which highly stereoselectively reduces the
3-oxo bicyclic lactone (e.g. formula lll or IV) to a corres-
ponding 3~-hydroxy bicyclic lactone.
324y
~6~ S Z~
Accordingly, the present inv~ntion provides a novel
process for preparing highly stereoselectively a 3a-hydroxy
bicyclic lactone of the formula
10 4~
Rl30 ~ ~/C - C - R7 V
0.
wherein L1 and R7 are as defined above; and
wherein Rl3 is a directing group as is defined below;
from a corresponding 3-oxo bicyclic lactone of the formula
~
,0 >
R ~ ~ C=C~ Vl
Il 11
0 L
which comprises: .
highly stereoselectively reducing said bicyclic 3-oxo
lactone with a potassium trialkyl borohydride of the formula
25K B~3H ( H (CH2)m-cH3 ~
(cH2)m+l-cH3J 9
wherein m is zero, one, 2, or 3.
The directing groups (R~3) which are useful for the
~49
~0~9~20
purposes of the present invention are
(1) -C-NH ~ R1
R2
wherein R1 and R2 are hydrogen chloro, fluoro, bromo, alkyl
of one to ~ carbon atoms, inclusive, or alkoxy of one to
carbon atoms, inclusive, being the same or different; or
(2) -C-N ~ - ~ Re
~1
R2
wherein R1 and R2 are as defined above, being the same or
different for each phenyl ring.
Especially preferred directing groups for the pur-
poses of this invention are phenylcarbamoyl, i.e.,
-l-NH~
and p-tolylcarbamoyl, i..e.,
-C-NH ~ CH3
Other preferred directing groups include those wherein one
of R1 and R2 is hydrogen and the other is methyl, methoxy,
or chloro.
The reducing agents useful in this invention are a
g
3249
1069SZ0
g~rlus ol polussiulll Lriall<yl borolly(l~ s, i.e.
~ (CH2 )m-Cl l~
K~ B~ H ~ -CH
(CH2)m+l-CH3 J 3
'' ' /
wherein m i5 as defined above. For the purposes of this
invention, it is especially preferred that the borohydride
of the above formula wherein m = 0 be employed, that is,
potassium tri sec-butyl borohydride.
Accordingly, the present invention, and particularly
the preferred embodiments thereof, described above, provide
surprising and unexpected advantages over procedures des-
cribed in the prior art in the accomplishment of the pur-
poses of the invention.
First, the present invention is surprisingly and un-
expectedly more stereoselective than prior art procedures,
and accordingly the ratio of alpha to beta hydroxy bicyclic
lactone product produced is surprisingly and unexpectedly
increased.
Second, the present invention is surprising and un-
expectedly more useful for large scale or commercial produc-
tion of its end-products in that:
(1) the direçting groups employed herein avoid the
use of.groups (eOgO, p-phenylphenylcarbamoyl) known to pro-
duce carcinogenic or suspected-carcinogenic by-products, .. ;~
(2) the reducing agent employed herein is simply,
directly, and economically prepared,
(3) the reaction conditions required to achieve opti-
~0 mum stereoselectivity are less severe than those of the
-10-
~249
~5~)
prior art, and,
(4) the employment of this process permits crystalli-
zation of an essentially pure 2J3,4,5,6-pentanor-PGF1a-
type compound, to the exclusion of the 15P-hydroxy epimer,
thereby obviating the need for a chromatographic separation
of C-15 epimeric mixtures of PG-type products.
Reference to Chart A will make clear the operation of
the novel process of this invention. L1, R7, and R13 are
as defined above. M is potassium~ sodiumJ or lithium.
The formula Xl compound is known in the art or readily
prepared by methods known in the art. The formula Xl com-
pound is transformed into the formula Xll compound by
replacement of the cyclopentane ring ~-hydroxy hydrogen
with a directing group according to Rl3. When R13 is a
phenyl or substituted phenylcarba~oyl directing group, the
corresponding phenyl or substituted phenyl isocyanate of
the formula
0=C-N ~ R1
R2
wherein R1 and R2 are as defined above, is employed. The
reaction is carried out preferably at zero to 25 C. The
reaction is advantageously carried out in a pyridine dilu-
ent or in a diluent such as tetrahydrofuran which containsa catalytic amount of pyridine. AlternativelyJ other
pyridine-type bases may be employed such as the picolines
and lutidines. Stronger tertiary amine bases (e.g. tri-
ethylamine) are likewise useful. However, by the preferred
~0 method pyridine alone is used as a reaction diluent.
~ . .
3249
S20
CHART A
<~\ C~H XI
H 0 H~ \C - C - R7
~I ;
' ' ' ~0~ ~
~ C-C-- '
R 13H/ ~ IC - ~ - R7
,1, . ~ .
: lo ~
. Xlll
~H
~C=C ,;,~
R 1 30 ~ L
~ :
.
3
-12 -
~ ' .
3249
~l)69SZ~3 .
CHART A (conti nued)
HO
,~ ~", CH2COO M+
<~ /H X I V
~r-C
13 H /C~ 5_ R7
- bH L-
:
HO~
, CH2 -COO -M+
< I XV
HO' H~ ~C -C R7
H ~)H Ll .
-
\ / ~ ' ,
HO
`~ , CH2 - C OOH
<~~[ XVI
? H
HOH . /C~--C R7
H OH L,
- ~ .
0
/1 .
0~ ~
~' XVI I
~ C=C / H
HO H~ /C~ C R7
H OH
-13- .
'~ .'
-~ .
3249
~ 2 ~
When the reaction is complete, by-products, such as
N,N'-diphenylurea, or a corresponding substituted phenyl
urea, are separated from the formula Xll product by cry-
stallization thereof. However, by the preferred method
purification by crystallization is omitted and the crude
reaction product is used in the subsequent process steps
of Chart A, as discussed above.
When R13 is a diphenyl carbamoyl directing group, the
formula Xll compound is prepared from the formula Xl com-
pound using the corresponding diphenyl carbamoyl chlorideor substituted diphenyl carbamoyl chloride of the formula
R ~ \ N C ~
R1 / \ Cl
wherein R~ and R2 are as defined above. The reaction pro- -`
ceeds by addition of one equivalent of sodium hydride to
the above mixture. When the reaction is complete, any ex-
cess sodium hydride is destroyed by the addition of an
organic acid, e.g. acetic acid. Pure product is optionally
recovered from the reaction mixture using conventional
methods.
The formula XIII compound is obtained from the formula
X!l compound by the novel highly stereoselective reduction
of the present invention. This reduction proceeds at low
temperatures, from -78 C. to -120 C., in order to achieve
high selectivity. It is especially preferred that temper-
-14-
~2 49
1Vf~9~20
atures of about -110 C. be employed. The reaction diluent
for this reduction preferably comprises a mixture of
diethyl ether and tetrahydrofuran in a ratio of ~ to 1.
While different ratios of this diluent mixture are useful
in this invention, the freezing point of tetrahydrofuran
(-65 C.) prohibits its exclusive use. However, the pre-
sence of sufficient tetrahydrofuran to insure solution of
reactants is desired.
A further requirement for this reduction, and the
successive steps herein prior to the extraction of the
borane (fro~ formula XIV), is that all reactants
be made oxygen-free by bubbling nitrogen there through.
This procedure is required in order ~o avoid destruction
of the trialkyl borane produced in the reduction of the
formula XII compound.
The reduction is then accomplished by the addition
of a potassium trialkyl borohydride of the formula
~ / (CH2)m-CH
K~3 B ( -CH
~ (CH2)m+1-C ~ 3
wherein m is as defined above. Preferably 1.2 to 1.4
molecular equivalents of potassium trialkyl borohydride
per molecular equivalent of formula XII compound are
employed.
The potassium trialkyl borohydrides of the above for-
mula are prepared from the corresponding trialkyl boranes
of the formula
3o
-15-
32~9
~069~Z~3
~ / (CH2)m-CH3 ~
B ~ -CH ) ,
(CH2)m~1-C ~ 3
wherein m is as defined above, by reaction of these boranes
with potassium hydride. Procedures known in the art for
potassium hydride reactions of trialkyl boranes are
employed. See, for reference, C. A. Brown cited above.
These boranes are prepared by any of several methods known
in the art. By a preferred method they are obtained from
the reaction of diborane with an olefin of the formula
CH3-(CH2)m-CH=CH-(CH2)~-CH3
wherein m is as defined above, by prior art procedures.
The formula XIV compound is then prepared by opening
the lactone ring of the formula XIII compound. For this
purpose sodium, potassium, or lithium hydroxide is advan-
tageously employed in an aqueous solution as is known in
the art.
The above solution containing the formula XIV com-
pound further contains the trialkyl borane produced in the
reduction of the formula XII compound to the formula XIII
compound. It is preferred that the trialkyl borane be
separated from the formula XIV compound, for example, by
extraction with diethyl ether, and that the trialkyl borane
so obtained be reacted with potassium hydride, as discussed
above, to regenerate the potassium trialkyl borohydride
useful in the reduction step XII to XIII.
The formula XV compound i5 then prepared from the
-16-
3249
S2Q
formu1a XIV compound by hydrolysis of the directing group.
This hydrolysis is accomplishéd by methods known in the
art, for example, by addition of lithium, potassium, or
preferably sodium hydroxide to the formula XIV compound
with heating. The reaction is normally complete 7n about
24 hours at a reaction temperature of about 85 C., al-
though higher temperatures are employed to shorten the
reaction time.
The formula XVI compound is then prepared from the
formula XV compound by separation of the formula XV com-
pound from undesired organic by-products, followed by
acidification and crystallization. The extraction of the
undesired organic by-product proceeds by first adjusting
the pH of the solution containing the formula XV compound
to about 9.0 by addition of a mineral acid, e.g. phosphoric
acid. Extraction of the resulting pH-adjusted mixture
then proceeds by addition of an organic diluent, prefer-
ably dichloromethane. The dichloromethane extract con-
tains these undesired organic by-products, and such extract
is accordingly discarded. Acidification thereafter pro-
ceeds by careful cooling of the aqueous phase (0-5 C.)
and acidifying to pH 4 by further addition of a mineral
acid. Thereafter the desired formula XVI product may be
recovered by extraction, for example, with ethyl acetate,
and crystallization, which is achieved by conventional
methods.
As obtained by the above procedure, the formula XVI
compound is obtained in crystalline form which substan-
tially excludes the corresponding 15~-hydroxy epimer of the
formula XVI compound. Accordingly, the above procedure
-17~
~249
10~
eliminates the need for chromatographic separation of the
15a- and 15~-hydroxy epimers produced by the reduction
described for the preparation of the formula XIII compound
from the formula XII compound.
The formula XVII compound is known to be a highly use-
ful intermediate for preparing various PGFJ PGE, PGA, and
PGB-type compounds. For example, the formula XVI compound
is converted to the corresponding formula XVII lactone by
methods known in the art, and the formula XVII lactone is
known to be a highly useful intermediate in the prepara-
tion of the above-mentioned prostaglandin-type compounds.
DESCRIPTION OF THE PREFERRED EMBOD!MENTS
The invention can be more fully understood by the
following examples and preparation:
All temperatures are in degrees centigrade.
IR (infrared) absorption spectra are recorded on a
Perkin-Elmer Model 421 infrared spectrophotometer. Except
when specified otherwise, undiluted (neat) samples are used.
UV (ultraviolet) spectra are recorded on a Cary Model
15 spectrophotometer.
NMR (Nuc!ear Magnetic Resonance) spectra are recorded
on a Varian A-60, a-60D, or T-60 spectrophotometer on a
deuterochloroform solutions with tetramethylsilane as an
interna1 standard.
Mass spectra are recorded on an CEG model 1108 Double
Focusing High Resolution Mass Spectrometer or an LKB Model
9000 Gas-Chromatograph-Mass Spectrometer. Trimethylsilyl
derivatives are used, except where otherwise specified.
"Brine", herein, refers to an aqueous saturated sodium
chloride solution.
-18-
- 324
5~
.
The A-IX solvent system used in thin layer chromato-
graphy is made up from ethyl acetate-acetic acid-2,2,4-tri-
methylpentane-water (90:20:50:100) according to M. Hamberg
and B. Samuelsson, J. Biol. Chem. 241, 257 (1966).
"Skellysolve-B (SSB) refers to mixed isomeric hexanes.
Silica gel chromato~raphy, as used herein, is under-
stood to include elution, collection of fractions, and
co~bination of those ~ractions shown by TLC (thin layer
chromatography) to contain the desired product free of
starting material and impurities.
Melting points (MP) are determined on a Fisher-Johns
melting point apparatus.
THF refers to tetrahydrofuran.
Specific Rotations, [a], are determined for solutions
f a compound in the specified solvent at ambient tempera-
ture with a Perkin-Elmer Model 141 Automatic Polarimeter.
Example 1 2,~,4,5,6-Pentanor-PGF1a prepared from 3a,
5a-dihydroxy 2~-(3-oxo-trans-1-octenyl)-1a-
cyclopentaneacetic acid y lactone using a
phenylca~ ~oyl directing group (Formula
XVI:
L1
is n-pentyl).
A. 3a,5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-1a-
cyclopentaneacetic acid y lactone (3.97 9.) ;s dissolved in
6 ml. of dry pyridine. To the resulting solution under a
nitrogen atmosphere is added a solution of phenylisocyanate
(2.14 9.) and dry pyridine (6 ml.) cooled to ~ C. The
addition proceeds dropwise over a perTod of 3~ min. The
-19-
.~ ,, .
32119
~ s~
above reaction mixture is then stirred at 0 C. for an
additional ~0 min. then allowed to warm to room temperature
with stirring until the reaction is shown to be complete
by thin layer chromatography (ethyl acetate in Skellysolve~
B; 1 lJ . The reaction proceeds to completion in about 18
hours, thereby yieIding the phenylurethane deiivative
of the lactone starting material.
The pure product above is optionally recovered by
adding 10 to 15 volumes of water to the reaction mixture
and thereafter extracting with 45 ml. of ethyl acetate. The
combined ethyl acetate layers are washed once with water and -
twice with a one molar aqueous solution of phosphoric acid.
Finally, the organic phase is then washed with water, dried
over sodium sulfateJ and evaporated under reduced pressure
at 35 C. to yield an oil. This oil is then dissolved in
benzene and cooled to about 5 C., maintaining that tem- ~
perature for one hour. A diphenylurea precipitate forms and
this precipitate is filtered and washed with cold benzene.
The organic phase is then evaporated under vacuum yielding
6.05 9. of the pnenylurethane derivative of the lactone
starting material. On recrystallization from methanol this
product exhibits a melting point at 92-94 C. NMR absorp-
tions in deuterochloroform at 5.1, 6.15, 6.7, and 7.3 ~.
Also characteristic infrared absorptions are observed at
1695, 1730, and 1770 cm. 1.
B. With exclusion of moisture 6.0 9. of the reaction
product of part A above is dissolved in 25 ml. of dry
tetrahydrofuran and the resulting mixture is thereafter
diluted wlth 120 ml. of dry diethyl ether. Oxygen is then
excluded from this solution by bubbling nitrogen through the
-20-
3 i i~
. ~, ~, ~, , .
~2~'3
~N~9 ~ Z ~ '
solution for several minutesO This solution under nitrogen
atmosphete is then cooled to -110 C. in a 95 percent
ethanol-bath cooled first with dry ice to -78 C. and
thereafter further cooled to -110 C. with intermi~ent
addition of liquid nitrogen so as to maintain the reaction
temperature. To this cooled solution is then ad~ed 54.8
ml. of 0.5 M potassium tri-sec-butyl borohydride in tetra-
hydrofuran diluted to a 100 ml. volume by addition of dry
diethyl ether. The addition proceeds dropwise over a per-
iod of 2-3 hours. Reaction progress is monitored by thin
layer chromatography (ethyl acetate and,Skellysolve B;
7:3). The addition of the potassium tri-sec-butyl boro-
hydride solution is terminated when the starting material
is consumed. The reaction is then quenched by addition of
10 ml. of oxygen-free methanol and 25 ml. of oxygen-free
water. The reaction mixture is then allowed to warm to
10-20 C. The formula Xlll lactone thereby,formed is used
in the steps below without further purification or charac-
terization.
C. To the reaction product of part B above is added
with stirring 9 ml. of oxygen-free 10 percent aqueous sod-
ium hydroxide. The reaction mixture is allowed to warm to
room temperature and the progress of the reaction is mon-
itored by thin layer cl-r~r~Lography to completion.
2~ ri-sec-butyl borane is then extracted from the
reaction product of part C above by adding 25 ml. of
oxygen^free water to the reaction mixture, shaking~ and
thereafter separating the lower aqueous phas,e. The organic
phase is then,washed once with a partially saturated sodium
chloride solution which is then added to the aqueous ex- '
-21-
3249
~6~
tract. The combined aqueous layers are then extracted with
diethyl ether. There results from this extraction three
layers: an aqueous layer, a tetrahydrofuran-containing
layer, and the ethereal layer. The ethereal layer is com- ~-
bined with the organic phase obtained above and this com-
bined organic phase is dried over magnesium sulfate and
evaporated to an oil under oxygen-free conditions. This
oil consists essentially of tri-sec-butyl borane, with some
contamination comprising diphenylurea.
E. The organic and tetrahydrofuran layers obtained
by the extraction of part D above are added to 4.2 9. of
sodium hydroxide. This mixture is then heated to 85 C.
for about 16-18 hours to achieve hydrolysis of the 11-
phenylurethane directing group. Progress of this reaction
is monitored conveniently by silica gel TLC.
The resulting mixture is then cooled to room temperature
and the pH adjusted to 9.0 by addition of 2 M phosphoric
acid. This mixture is then extracted twice with dichloro-
methane, thereafter discarding these dichloromethane ex-
tracts. The aqueous phase is then cooled to 0-5 C. and
carefully acidified to a pH of 4. The resulting acidic
solution is then saturated by addition of solid sodium
chloride. Thereafter this saturated aqueous solution is
extracted with 400 ml. of ethyl acetate and the organic
extracts so formed are washed twice with brine to remove
undesired by-products. The resulting organic phase is then
cooled and benzene is added to the mixture until the mixture
becomes turbid. This organic mixture is then dried over
sodium sulfate and the solvent evaporated at 30 C. under
vacuum. Crystallization of the formula XIV product occurs
-22-
3~4
~ 9SZ~ '
during this evaporation. Ethyl acetate is then added so as
to yield a volume of 20-30 ml. and the ethyl acetate mixture
is then cooled a~ 0 C. for 2 hours to complete crystalliza^
tion. The ethyl acetate is ~hen removed by filtration and
the filtrate is rlnsed with cold ethyl acetate. The re-
sulting crystals are then dried to constant weight, yield-
ing 3.13 9. o~ pure formula XVI product.
PreParation 1 Recycle of tri-sec-butyl borane to pOt-
assium tri-sec-butyl borohydride.
Tri-sec-butyl borane (as obtained from Example 1,
part D) is dissolved in 100 ml. of oxygen-free Skellysolve~
B (7so~ric hexanes). The diphenylurea present in this
mixture, being Insoluble in Skellysolve B, is separated~
The solvent is then evaporated under nitrogen atmosphere
and vacuum to yield tri-sec-butyl borane.
One and one-half grams of 57 percent potassium hydride
suspension in mineral oil is dissolved in 25 ml. of dry
oxygen-free tetrahydrofuran. The resulting slurry is cooled
~o 0 C. under nitrogen atmosphere. Trl-sec-butyl borane
(1.575 g.~, as obtalned above, in 5 ml. of tetrahydr~furan
Is added drapwlse over 10 min,
The resul~lng mixture is allowed to warm to room tem-
pera~re and thereafter stirred for 1 ho~r. The stirrtng
ts stopped and fine solids are allowed to settle ~vernlght.
Z5 ~h~ resul~ing mlxture Is then flltered under nltrogen at-
mo~phere through a ftne slntared glass funnel yleldlng a
clear ltgh~ yellow solu~lon of the tltle compound.
P)~ ~ 2,3,4,5,6~Pentanor-PG~2~ prepared from 3a,-
~-dlhydroxy-2~(3-oxo trans-1-octenyl)-1~-
~0 cyclopentaneacet~c acld y laetone uslng a
,
~E3 ' '
3249
~ ~9 ~ 2V
diphenylcarbamate directing group.
A. At room temperature under nitrogen atmosphere the
formula Xl lactone starting material (5.0 9.) in 70 ml. of
tetrahydrofuran and ~.4 g. of diphenylcarbamoyl chloride
are mixed with stirring. Thereafter sodium hydride (~00
mg., as a 57 percent suspension in mineral oil) is slowly
added. Progress of the reaction is monitored by thin layer
chromatography, and when shown to be complete, about 3 hr.,
the reaction is quenched by slow dropwise addition of
acetic acid.
Thereafter the diphenylcarbamoyl derivative is puri-
fied by evaporation of the solvent, addition of ice water,
extraction with dichloromethane, and subjection of the
dichloromethane extract to washing, drying, and evapora-
tion of solvent. The melting point is 80-82 C. The
ultraviolet spectrum shows ~max. (ethanol) at 230 ~
(~ 22,528). Characteristic NMR absorptions are observed
at 4.0, 6.0, 6.6, and 7.25 ~. Characteristic infrared
absorptions are observed 1666, 1686, 1700, and 1775 ~.
B. The title product is obtained by subjecting the
reaction product of part A above successively to the pro-
cedures described in Example 1, parts B-E.
ExamPle 3 2,3,4,5,6-Pentanor-PGF1a prepared from 3a,-
5~-dihydroxy-2~ -oxo-trans-l-octenyl)-la
cyclopentaneacetic acid y lactone using a
p-tolylcarbamoyl directing group.
A. The formula Xl lactone, p-tolylisocyanate, and
triethylamine are stirred in freshly distilled tetrahydro-
furan at room temperature. When the resulting reaction is
~ shown to be complete by thin layer chromatography, the
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3249
Z~
tetrahydrofuran is removed by evaporation, and the result-
ing mixture combined with cold water and thereafter ex-
tracted with dichloromethane. The pure formula Xll p-tolyl-
urethane derivative is recovered by subjection to silica
gel chromatography and subsequent crystallization from
ethyl acetate and Skellysolve B (isomeric hexanes), The
melting point 80.5-82.5 C. The ultraviolet spectrum
) shows ~max. at 234 ~ (~ = 26,933). The NMR spec
trum shows characteristic absorptions at 5.05, 6.17, 6.8,
and 7.0-7.4 ~.
B. Using the reaction product of part A above, and
following the procedures described in Example 1, parts
B-E, the title compound is prepared.
ExamPle 4 2,3,4,5,6-Pentanor-PGF1a prepared from 3a,-
5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-1a-
cyclopentaneacetic acid y lactone using a
(2~5-dichlorophenyl)carbamoyldirectin9
group.
A. The formula Xl lactone starting material and 2,5-
dichlorophenylisocyanate are stirred together in dry pyri-
dine at room temperature. When the reaction is shown to
be complete by thin layer chromatography, isolation of the
product proceeds by addition of cold water and extraction
with ethyl acetate. The ethyl acetate extract is subjected
to silica gel chromatography and crystallization from ethyl
acetate and Skellysolve B to yield pure product. The pro-
duct shows thin layer chromatographic Rf of 0.11 (ethyl
acetate and Skellysolve B; 1:1) .
B. Using the reaction product of part A above and
following the procedure of Example 1, parts B-E, there is
-25-
~249
iO~g5~0
prepared the title compound.
Example ~ 2,3,4,5,6-Pentanor-PGF1a prepared from 3~J-
5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-la-
cyclopentaneacetic acid y lactone using a
3-(p-bromophenyl)carbamoyl directing group.
A. Following the procedure of Example 4, part A, but
using in piace of 2,5-dichlorophenylisocyanate, p-bromo-
phenylisocyanate, there is prepared the corresponding 3-(p-
bromophenyl)urethane product.
B. Using the reaction product of part A above, and
following the procedure of Example 1J parts B-E, there is
prepared the title compound.
Example 6 2,3,4,5,6-Pentanor-PGFia prepared from 3a,-
5a-dihydroxy-2~-(3-oxo-trans-1-octenyl)-1a-
cyclopentaneacetic acid y lac~one using a
3-(p-ethoxyphenyl)carbamoyl directing group.
A. Following the procedure of Example 4, part A, but
using p-ethoxyphenylisocyanate in place of 2,5-dichloro-
phenylisocyanate there is prepared the corresponding 3-(p-
ethoxyphenyl)urethane derivative of the lactone starting
material. The melting point is 91-93 C.
B. Using the reaction product of part A above, and
following the procedure of Example 1J parts B-E, there is
prepared the title compound.
Following the procedure of any of Examples 1-6, but
using in place of potassium-tri-sec-butyl borohydride one
of the following potassium borohydrides:
tri-(3-hexyl),
tri-(4-octyl), or
tri-(5-dqcy~)
-26-
3249
~LO~i95~) :
there is obtained the formula XVI product.
Further, following the procedure of any of Examples
1-6, or following the procedure described in the preceding
paragraph, but replacing the lactone starting material
therein ~ith a 3~,5a-dihydroxy-1a-cyclopentaneacetic acid
y lactone which i5 substituted at the 2~-position with one
of the following substituents:
3-oxo-4-methyl-trans-1-octenyl;
3-oxo-4,4-dimethyl-trans-1-octenyl;
3-oxo-4-fluoro-trans-1-octenyl;
3-oxo-4,4-difluoro-trans-1-octenyl;
3-oxo-4-phenoxy-trans-1-butenyl;
3-oxo-4-(m-chlorophenoxy)-trans-1-butenyl;
3-oxo-4-(m-trifluoromethylphenoxy)-trans-1-butenyl;
3-oxo-4-(p-fluorophenoxy)-trans-1-butenyl;
3-oxo-4-phenoxy-trans-1-pentenyl;
3-oxo-4-(m-chlorophenoxy)-trans-1-pentenyl;
3-oxo-4-(m-trifluoromethylphenoxy)-trans-1-pentenyl;
3-oxo-4-(p-fluorophenoxy)-trans-1-pentenyl;
3-oxo-4-methyl-4-phenoxy-trans-1-pentenyl;
3-oxo-4-methyl-4-(m-chlorophenoxy)-trans-1-pentenyl;
3-oxo-4-methyl-4-(m-trifluoromethylphenoxy)-trans-1-
pentenyl;
3-oxo-4-methyl-4-(p-fluorophenoxy)-trans-1-pentenyl;
3-oxo-5-phenyl-trans-1-pentenyl;
3-oxo-5-(m-chlorophenyl)-trans-1-pentenyl;
3-oxo-5-(m-trifluoromethylphenoyl)-trans-1-pentenyl;
; 3-oxo-5-(p-fluorophenyl)-trans-1-pentenyl;
3-oxo-4-methyl-5-phenyl-trans-1-pentenyl;
3-oxo-4-phenyl-5-(m-chlorophenyl)-trans-1-pentenyl;
-27-
!
~249
~069S20
3-oxo-4-methyl-5-(m-trifluoromethylphenyl)-trans-1-
penteny !;
3-oxo-4-phenyl-5-(p-fluorophenyl)-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-phenyl-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-(m-chloropheny!)-trans-1-pentenyl;
3-oxo-4,4-dimethyl-5-(m-trifluoromethylphenyl)-trans-
1-pentenyl;
3-oxo-4,4-dimethyl-5-(p-fluorophenyl)-trans-1-pen-
tenyl;
3-oxo-4-fluoro-5-phenyl-trans-1-pentenyl;
3-oxo-4-fluoro-5-(m-chlorophenyl)-trans-1-pentenyl;
3-oxo-4-phenyl-5-(m-trifluoromethylphenyl)-trans-1-
pentenyl;
3-oxo-4-phenyl-5-(p-fluorophenylJ-trans-1-pentenyl;
3-oxo-4,4-difluoro-5-phenyl-trans-1-pentenyl;
3-oxo-4,4-difluoro-5-(m-chlorophenyl)-trans-1-pen-
tenyl;
3-oxo-4,4-difluoro-5-(m-trifluoromethyl)-trans-1-
pentenyl;
3-oxo-4,4-difluoro-5-(p-fluorophenyl)-trans-1-pen-
tenyl;
3-oxo-trans-1-cis-5-octadienyl-4-methyl-trans-1-cis-
5-octadienyl;
3-oxo-4,4-dimethyl-trans-1-cis-5-octadienyl;
3-oxo-4-fluoro-trans-1-cis-5-octadienyl; or
3-oxo-4,4-difluoro-trans-1-cis-5-octadienyl, there is
obtained respectively, the corresponding 2,3,4J5J6-penta-
nor-PGF~a-type cGmpoundJ as follows:
16-methyl;
16J16-dimethyl;
-28-
~249
9~ZO
16-fluoro;
16,16-difluoro;
16-phenoxy-17,18,19,20-tetranor;
16-(m-chlorophenoxy)-17,18,19,20-tetranor;
16-(m-trifluoromethylphenoxy)-17,18,19,20-tetranor;
16-(p-fluorophenoxy)-17918,19,20-tetranor;
16-phenoxy-18,19,20-trinor;
16-(m-chlorophenoxy)-18J19,20-trinor;
16-(m-trifluoromethylphenoxy)-18J19J20-trinor;
16-(p-fluorophenoxy)-18,19J20-trinor;
16-methyl-16-phenoxy-18J19J20-trinor;
16-methyl-16-(m-chlorophenoxy)-18J19J20-trinor;
. 16-methyl-16-(m-trifluoromethylphenoxy)-18J19J20-
trinor;
16-methyl-16-(p-fluorophenoxy)-18J19J20-trinor;
17-phenoxy-18,19J20-trinor;
17-(m-chlorophenyl)-18J19,20-trinor;
17-(m-trifluoromethylphenyl)-18J19J20-trinor;
17-(p-fluorophenyl)-18j19J20-trinor;
16-methyl-17-phenyl-18J19,20-trinor;
16-methyl-17-(m-chlorophenyl)-18,19,20-trinor;
16-methyl-17-(m-trifluoromethylphenyl)-18~19,20-trinor;
16-methyl-17-(p-fluorophenyl)-18J19,20-trinor;
16J16-dimethyl-17-phenyl-18J19J20-trinor;
16J16-dimethyl-17-(m-chlorophenyl)-18J19J20-trinor;
16,16-dimethyl-17-(m-trifluoromethyl)-18J19J20-trinor;
16J16-dimethyl-17-(p-fluorophenyl)-18J19J20-trinor;
16-fluoro-17-phenyl-18J19J20-trinor;
16-fluoro-17-(m-chlorophenyl)-18,19,20-trinor;
16-fluoro-17-(m-trifluoromethylphenyl)-18,19,20-trinor;
-29-
3249
10~9S'~
16-fluoro-17-(p-fluorophenyl)-18,19,20-trinor;
16,16-difluoro-17-phenyl-18,19,20-trinor;
16J16-difluoro-17-(m-chlorophenyl)-18,19,20-trinor;
16,16-difluoro-17-(m-trifluoromethylphenyl)-18,19,2Q-
trinor;
16,16-difluoro-17-(p-fluorophenyl)-18J19,20-trinor;
cis-17,18-didehydro;
16-methyl-cis-17,18-didehydro;
16-16-dimethyl-cis-17,18-didehydro;
16-fluoro-cis-17,18-didehydro; or
16,16-difluoro-cis-17,18-didehydro.
.~ .
5 0
