Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
3~
. -1
This invention relates to certain novel analog~ of
the naturally occurring prostaglandins and to various novel
intermediates an~ reagents useful in their preparati~n. In
particular it relates to the preparation of novel ~-pentanor-
5 prostaglandins.
~ he pro~taglandins are C-20 unsaturated fatty acids
~hich exhibit diverse physiolsgical efects. F~r instance,
the prosta~landins of the E and A series are potent va~odi-
lators ~Bergstrom, et al., A _ ~ . 64:332-33,
1965 and ~erg~trom, et al., Life Sci. 6:449-455, 1967) and
lower sys~emia arterial blood pressure ~vasodepression~ on
intraven~us administration (Weeks and King, Fed
~:23:327, 1964; Bergstrom, et al., 1965, op. cit.; Carlson, at
al , A-t~ g~ 183O423-430p 1968; and Carlson, et alO,
Ac . 75:161-169, 1969). Another well kn~wn
phy iological action for PGE~ and PGE2 is as a bronchodilator
~Cuthbert, ~ 4:723-72~, 1969~.
~ 9till another important physilogical role for the
natur~l prostaglandins is in connection with the reproductive
2~ cycïe. PGE2 is known to possess the ability to induce labor
~Kar~m, et al., ~ . 77:20~-210,
197~), ko induce therapeutic abortion ~Bygdeman, et al.,
~, 4, 293 ~1971) and to be usefuï for contr~l of
fertility ~Karim~ ~ , 3, 173 (1971)). Patents
have been obtained f~r ~everal pro~taglandins o~ the E and F
; serie~ a~ i~ducers of labor in mammals (Belgian Patent
754,158 and West German Patent 2,034,641~, and on PGFl, F2
and ~3 or control of the reproductive cycle (South African
Pat~nt 69/6089).
:
. ~
l~ '
;; ~ . ,
3~
--2--
Still other known physiologi~al activities for PGE
are in the inhibition of gastric acid secretion ~Shaw and
Ramwell, In: W ~ , New York,
Wiley, 1968, p~ 55-64~ and also of platelet aggregation
tEmmons~ et al., ~ 2:468-472, 1967).
It is now known that such physiolsgical effects
will be produced in vivo for only a short period, following
the admin stration of a prostaglandinO A substantial body
of evidence indicates that the reason for this rapid cessa-
tion of activity is that the natural prostaglandins are
quickly and eficiently metabolically deactivated by B-
~xidation oE the carboxylic acid side-chain and by oxidation
of the 15a-hydroxyl group (Anggasrdt et al., A
Scan~ 396 (1971) and references cited therein~.
15It was, of course, cons~dered desirable to create
analogs of the prostaglandins which would have p~ysiological
activities equivalent to the natural compounds, but in which
the selectivity of action and the duration of the activi~y
would be increasedO Increased selectivity of action would
~e expecte~ to alleviate the s~vere side effects, particular-
ly gastroint2stinal side effects, frequently observed follow-
: ing systemic administration of the natural prostaglandins
~see Lancet, 536, 1971).
In accordance with the preqent invention there is
provided a process fur preparing a compound of ~he formula:~
W
-Ar
''OH ~..I
and the C15 epimer thereof; whexein Ar is phenyl; W is a
single bond or cis double bond; Z i5 a single bond or trans
,~ 0~
double bond; M is oxo, ~' or ~ ; Y and Q when taken
~ogether orm a single bond, or Q is ~-hydroxyl when Y is
hydrogen~ X is tetrazolyl; e group of the iormula -C-O-R'
..
,
. '.1 ' : '`. ~ ' : '
~ . .
.:. , "
5~3~
--3--
wherein Rq is hydroyen, alkyl of from 1 to 10 carbon atom~,
lower alkyl, phenyl or biphenyl, with the proviso that R' i~
lower alkyl, phenyl or biphenyl when W is a cls double bond
and Q is a-hydroxyl; or a group of the formula -QNHR wherein
R" is alkanoyl ~f from 2 to 10 carb~n atom~, aryoyl or alkyl-
sulfonyl of from 1 to 7 car330n atoms; and wherein M, Y and Q
are so selected as to complete the structure of a prosta-
glandin of the A, E or F series, the lower alkan~yl, ~ormyl
or ~enzoyl esters of any free hydr~xyl groups at the Cg-,
Cll- and C15-positions~ and the pharmaceutically-acceptable
salts of the compounds wherein X is COOH, which comprises:
~a) reacting a compound of the formula:
\X
THPO~ `O-Ar
"OT~P ...II
wherein Ar, M, ~, X an~ Z are as defined above and T~P ls
lS 2-tetrahydropyranyl, with a suitable acid, to f~rm the d~sir-
ed compound of Fo~mula I, wherein Q is a-hydroxy, Y 1
hydr~gen, and Ar, M, ~, X and Z are as defined above;
(b~ reacting a compound of Formula I, above, whereln Q
i8 a-hydr~xy and Y is hydrogen, M is oxo, and Ar, W, X and Z
2~ are as defined a~ve, with a suitable dehydrating agent, to
form the desired compound of Formula I wherein Q and Y taken
together form a single bon~, M i s oxo and Ar; W, X and Z are
as defined above;
~cl hydrogenating a compound of the Formula I, above,
wherei~ Q is a-hydroxy and Y is hydrogen, M is oxo, Ar, W,
X an~ Z are as defined above, to form the desired ¢ompound o
,H
Formula I, wherein Q is a-hydroxy, Y is hydrogen, M is ~,',
:~ or ~ and Ar, W and Z are as defined above, and, if
.,................ ~E~
desired, s~paxating the 9a- and 9B-isomers;
~d) catalytically hy~rogenating a campound of Formula I,
r
~ ~1
; ,. . -.
831
--4--
above, wherein Ar, M and X are as defined above, W i~ a
~ingle bond or Ci5 double bond when Z is a trans double bond
and Z is a single bond when W i9 a cls ~ouble bond, to form
the desire~ compound of Formula I wherein Q is a-h~droxy, Y
is hydrogen, Ar, M and X are as d~ined above, and W an~ Z
are ~ingle bonds;
~ e~ selective~y hydrogenating a compound of Formula I,
or the trialkylsilyl ester of a compound of Formula I, wherein
X is COOH, above, wherein Ar, X and M ~re a~ de~ined above
and ~ and Z are double bonds, to form the desired compound of
Formula I wherein Q is ~-hydroxy, Y i~ hydroyen, Ar, X and M
are as d~fined above, ~ i~ a single ~ond and Z i~ a trans
d~uble ~nd; and, when require~t con~erting those compounds
o~ Formula I wherein X i~ COO~ to esters or substituted amides,
as defined above, ~y reaction with suitable ~sterifying ~r
amidating reag~nt~, respectively; and, if desired, preparing
the 9~-, lla- and 15a-lower alkanoyl, formyl or benzoyl e^ter~
of any free ~dr~xyl groups by reac~ing the compounds wi~h
the appropriate acylating agent~ and, if desired, preparing
2~ tha pharmaceutically-acc~p~able ~alts o those aompound~
wharein x is COO~.
The inv~ntion al~o provides a process as de~cribe~
above for preparing a c~mpound of the ~Qrmula:
0~
,~"- ~ X
~O\' ~ ~ -~r
'O~ .~.IA
an~ the C15 epimer th~r~o~7 wher~in Ar, W, z and X are a~ ;
deined above, ~ich Gompri~e8:
~a) reaoting a compound o the formula:
0~
THPO' ~ -Ar
'OTHP r ~ ~IIA
3~
--s--
wherein Ar, W, X, Z and THP are as deined a~ove, with a
suitable acid;
~b) hydrogenating a compound of the formula:
~X
~ Ar ~..IB
wherein Ar, ~, X an~ Z are as aefined above, and then ~epa-
rating the 9~- and 9B~isomers;
~ c~ aatalytically hydrogenating a compound of Formula
IA, above, wherein Ar and X are as defined above, W is a
single bond or cis double bond when Z is a trans d~uble bond
and Z is a single bond when W is a cis double bond, to form
a compound o~ Formula IA, a~ove, wherein Ar and X are as
defined ab~ve, and ~ and Z are single bonds;
~ d) selectively cataly~ically hydrogenating the di-
methylisopropylsilyl derivative of a compound of Formula IA,
- 15 wherein X is COOH, Ar i5 as defined above, W is a cis double
bond and Z is a trans ~ouble bond, to form a compound o
F~rmula IA, above, wherein Ar is as defined above, ~ is a
~ingle bond and Z is a ~ double bond; and when re~ulred,
converting those compounds of Formula IA wherein X is COOH
to e~ters or substituted amides by reaction with suitable
e~teri~ying or amidating agentB, respeatively; and, if de-
: sired, preparing the 9a~ , and 15a-lower alkanoyl,
; formyl or benzoyl esters of any free hydr~xyl groups by re-
~: acting the compoun~s ~ith the appropriate acy~ating agents;
:-. 25 and, if desired, preparing the pharmaceutically-acceptable
salts of those compcunds wherein X is COOH~
The invention further provides a process as descrlb-
~d above for preparing a compound of the formula:
~ X
: HO ~O-Ar , O ~ I~
:
: . , : , :
`' - ';.,., ,,., " ~ ; . ;`' ~
~5~3~
--6--
and the C15 epimer thereo~, wherein Ar, W, Z an~ X are a~
define~ above, which comprises:
~a) reacting a compound of the formula:
~ ~ X
THPO~ t ~~O-Ar
'OT~IP , . . IIB
wherein Ar, THP~ W, X an~ Z are as defined above, with a
~uita~le acid;
~ b) catalytically hydrogenating a compound of Formula
I~, above, wherein Ar and X are a~ defined above, W is a
~inyle b~nd or a cis ~uble bon~ when Z is a tran~ double
bond and Z is a ~ingle ~ond when W i9 a cis double bond, to
a~ford a compound of Formula IB wherein Ar and X are a~
defined above, and W and Z are single bonds;
(c) sel2ctiv~1y catalytically hydrog~nating the di-
meth~lisopropylsilyl deriYative of a compound o~ Formula IB,
above, wher~in Ar and X are as ~efine~ above, W is a cls
double bond and Z is a trans double bond, to afford a com-
pound ~f Formula IB, ab~ve, whexein Ar and X are as de~ined
abova, W i~ a sin~le bond and ~ i; a trans double bond; and
when re~uired, converting those compounds of Formula IB
wherein X i~ COO~ to e~ter~ or sub3titute~ amides by reaction
with suitable esterifying or amidating agents, xe~pectively;
and, if de~i~e~, prepa~ing the lower alkanoyl, formyl or
b~oyl ester~ of any free 11- and 15-hydroxyl groups by r~-
a~ ing th~ a~mp~unds with the appropriate acylating agen~s;
~ 25 an~ e~ired, prepaxin~ ~he pharma~eutically-acGepta~le
.: aalts ~ tho~e compound~, wherein X i~ C00~.
The inv~nti~n ~till ~urkher provides a pro~e~s as
- descri~ed ab~ve for preparing a rompound of the formula:
~~ ~ x
" ~ ~-Ar
'~o~ ... IC
,.~
.
.; ~:
.
, . : : :. , , ;
, . . . . .. . . .
.. . . .
83~
-7
and the C~5 epimer th~reo~, wherein Ar, W, Z and X are A~
defined above, which compri~e~ reacting a compound of khe
formula:
X
' ~ , O-Ar
'O~ ...IB
with a ~uitable ~ehydra~ing agent; and, when re~uired, con
verting tho~e c~mpound~ of Formula IC wherein X i~ COO~ t~
e~ers or substltute~ amide~ by reaction wi h suitable
e~erifying or amldating r~agent~, respeotively, and, if ~e-
~ired, p~eparing the C15-lower alk~noyl, formyl or ben~oyl
1~ e~ter ~y reacting the c~mpound with an appropriate acylat$ng
agent; and, if de~ired, preparing the pharmaceutically-
a¢ceptabl~ 3alt8 of tho~e comp~und~ wherein X i9 CO~.
Th0 intermediate c~mpound of the formula:
0~
T~PO ~ ~ -Ar
~THP O,.IIA
and t~e C15 ~pim~r thar~Q~ ~ and the Cg and C15 epimer~
there~f~ wh~rein Ar i~ phenyl; ~P $~ 2-~etrahydropyranyl; W
i~ a singla bond or Ci8 double bon~3 ~ i8 a single bond or
tran~ ~uble b~nd; and X i~ tetrszolyl; a grQup o~ the
ormula - -O-R~ wherein Rl 1~ hydrogan, alkyl ~ ~rom 1 ~o
~: 2~ 1~ oarbon a~om~, lcwer ~lkyl, phonyl or biph~nyl when W i~ a
~ingl~ bond and Rl i~ lower alkyl, ~henyl or biphqnyl when W
i~ a ci~ ~oubl~ bon~; or d group o the ormula -~N~R" wh~rein
R" $~ alkanoyl o~ ~rom 2 to 1~ ~arbon atom~, aryoyl or ~lkyl~
~ulfonyl o~ ~rom 1 to 7 carbon atoms; may be prepared by a
25 ~roGe~s whl~h compri~
~,a~ r~aoting a oompourld o~ the formula:
. .
. , , , , ~
~,
.-. ~ ,
, . ,
ii8,~
~8~
0~
~1 z
~ ~3-Ar
~OTHP . . .VA
wherein Ar, TElP and Z are a~ de~ined above with ~n ylide of
~he f~3rmula s
~C61E5 ) 3P~ C~l2-c~2-cH;2-x
wherein X ls a~ defined a~ove with the provi30 that when
X~C02RI the c~mpound t3f Formula VA i~ first reacted with an
ylid~ ~f th~ formula:
~C6~I5) 3-P'C~-CH2CH2C}I2C~2~
an~ the re~ul~ing produc~ es~erifled if desired, to afford a
¢~mp~und ~f Formula IIA wherain Ar, X and ~ axe a~ defined
al~ov~ and W i8 a ais double bon~; and, wh~n re~uired, ~ub-
~ uently hydrogenatin~ the aompound thus ~ormed to a~ord
a compound of Formula IIA whsrain Ar, X and Z are as dein~d
above and W is a ~in~le bond,;
~b~ h~dr~3genatlng a compoun~ of F~3rmula IIA above,
whera~n Ar and X are a~ defined a~ova, W iB a ClB double
1:s3nd and Z i~ a trans ~ouble bo~d, to form a csmpound o~
Ft~mula IIA above wheraln Ar i8 as de~in~d ab~ve and W and
Z a~e ~ingle bon~ ~
.:.` 2~ ~6) ~aleotlvely hyda~c~yenatln~ a ct3mpound o Formula
II~ above, wheroln A~ and X ~ de~lned abovs, W i8 a ol~
~ouble bQ~d and Z i.~ a trans d~uble b~nd, to ~orm ~ c~mpound
o~ Fl3rmula II~ wher~in ~r an~ X a~ de1ned abov~, W i~
~ingle bon~ and Z i~ a tran~ d~ubl~ ~ond .
The lntermediate compound of the ~ormula:
~ X
t ~ A~ "
JOT~IP ..3II~
as~d the C15 eplmer thereof; whareln Ar i8 phenyl; W i~ a
~'
:~ . . , . .,. ; . , .
- ,, ,, ,. ~ .
: - ~ - :. . ..
~L~85~331
g
sinyle bond or CL5 double bond; Z i~ a single bond or krans
double bond; and X is tekrazolyl; a yroup of the formula
- -O-R' wherein R' is hydrogen, alkyl of from 1 to 10 carbon
atoms; lQwer alkyl, phenyl or biphenyl when W is a single
bond and R' i5 lower alkyl, phenyL or biphenyl when W is a
GlS double bond; or a group of the formula _QNHR" wherein R"
is alkanoyl of from ~ to 10 carbon atoms, aryoyl or alkyl-
sulfonyl of from 1 to 7 carbon atoms; may be prepared by re-
acting a compound of khe formula:
OH
"" ~ X
TEP~ `~6' ~~Y~ ~`O-Ar
~OT~P ... IIA
wherein Ar, T~P, X, W and Z are as defined above with chromic
acid in aqueous sulfuric acid and acetone.
Additional intermediates u~ed in the process of
this inventi~n are those of Formulae III, IV, V and VI set
out hereinafter.
The intermediate compound of the formula:
/~
0
, \
1/~`""
~"1 . l
Q~ ~ ~ -Ar
d ~ . III
; wherein Ar is phenyl; 3,4-dime~hoxyphenyl, 3,4-methylene-
dioxyphenyli 3,4,5-t~imethoxyphenyl; a- or ~-naphthyl or
m~nosub~tituted phenyl wherein said substituent is halo,
trifluoromethyl, phenyl, lower alkyl or lower alkoxy; and
Q is ~-biphenylcarbonyl; may be prepared by reacting a com-
; pound of the formula:
~7
: ,
.~. . .. .
~: .
.`.... . ~
,, .: . :
83~
--10--
o_C
L
QO~ ~CHO
wherein Q is as ~efined above; with a compound of the formula:
lower alkyl-O
~-CH2-~-0-Ar
lower al~syl-O ~d
wherein Ar is as defined above.
The intermediate compound of the formula:
~ .
; 1~1"" .,;,
Q'o~ ~ ~ O-~r
~0 o~cIV
wherein Ar is phenyl; 3,4 dimethoxyphenyl; 3,4-methylene-
: di~xyphenyl; 3,4,5-trimethoxyphenyl; a- or ~-naphthyl or
monosubstituted phenyl wherein said substituent is halo, tri-
flu~romethyl, phenyl, lower alkyl or lower alkoxy and Q' is
hydrQgen ~r ~-biphenylcar~onyl; may be prepared by reducing
~: a compound of the Formula III:
- o
Q`~ ~O-Ar
O . ~ . III
wherein Ar and Q are as ~eined above to afford a compound
~f Formula IV, above, wherein Ar and Q are as defined above,
and, if desired, separating the 8a- and 8B-isomer~ and i~
desired, reacting a compound of Formula IV, above, wherein
Ar is as defined above an~ Q is biphen~lcarbonyl with K2C03
to afford a compound of Formula IV wherein Q is hydrogen;
~ .
.. ,. . : :
,
. : . ~ ;, .. .
' , ', . . '' ':
~;ID8~
and, if desired, separating the 8~ and 8~isomers~
The intermediate oompound of the formula:
0
' \
~"" Z
T~PO`~ ~ 4i' ~ ~ O-Ar
OTHP ... V
wherein Ar is phenyl; 3,4-dimethoxyp~enyl; 3,4-methylene-
dioxyphenyl; 3,4,5-trimethoxyphenyl; a~ or ~-naphthyl; mono-
substituted phenyl wherein said substituent iæ halo, tri-
1u~romethyl, phenyl, lower alkyl or lower alkoxy; THP is
~ 2-tetrahydropyranyl; Z i a single bond or a trans double
: bond; and Y is O or ~ ; may be prepared by reacting a
~0
10 compound of the Formula:
:,'` .~
~ ,~ ,.
~O ~ ~ ` O-Ar
,,IV
wherein Ar ~nd Z are as deflned above and Y is =O, with 2,3-
:~ dihydropyran in the presenae o~ an acid catalyst to afford
a compound of Formula V wherein Ar and Z are a~ defined above,
and Y is =O; reactin~ a compound of Formula V, above, whereinAr and Z are as defined above and Y is =O with diisobutyl-
aluminum hydride to afford a compound of Formula V whe~ein
~- - Ar and Z are as defined above and Y is ~ H ; by
: \O}I
`; catalytically reducing reducing a compound of Formula IV,
ab~ve, ~herein Ar is as defined above, 2 is a trans double
bond and Y is =O, to afford a compound of Formula V wherein
Ar is as defined above, Y is =O and 2 is a single bond.
The interm~diate compound of the formula:
.: . . :, -
' ~. ' ~ ;' : : . :
, ~ " " , ~ " ,, , ~, ,, . .t ' ~
31
~ o ~,OC~3
Ar-O~CH2~ -CH2 P~
OCH3 O. oVI
wherein Ar iB phenyl; 3,4-dimethoxyphenyl; 3,4-met~ylene-
diox~phenyl; 3,4,5-trimethoxyphenyl; a- or B~naphthyl or
mon~substituted phenyl wherein said substitu2nt is halo, tri-
fluoromethyl, phenyl, lower alkyl or lower alkoxy; may beprepared by reacting a lower alkyl aster of the formula:
. Ar-O-CH2~-O-lower alkyl
wherein Ar is as defined a~ove, with a dialkyl methyl phos-
phonate ~f the formul~:
(lower alkyl-0~2P-C~3
Preferred compounds prepared by the process of
this invention are 16~phenGxy PGE2 ~-biphenyl ester,
16-phenoxy PGF2~ ~biphenyl ester, and 16-phenoxy PGF2B ~-
biphenyl e~ter.
Preferred intermediate6 are the C9 epimers of the
- compounds of F~rmula II,
Other preferred prostag:Landins are as follows:
A c~mpound ~f Formula I wherein Ar is phenyl and
~: the pro~taglandin is PGE2.
A compound of Formula I wherein Ar i~ phenyl, ana
the prostaglan~ln is PGF2~o
A compound o Formula I wharein Ar is phenyl and
the prostaglandin is PGF23,
: Especially preferred prostaglandin~ are the
~5 following: -
; A compound according to Formula I whereln X is
-~-NHR", ~" is acetyl, W iæ a cis double bond, Ar is phenylO
A compound aocording to Formula I wherein X is
tetraæolyl, W is a cis double bond, 2 ig a trans double bond,
and Ar is phenyl.
A compound according t~ F3rmula I wherein X is
-~NHR", R" is methylsulfonyl, W is a cis d~uble bond, Z is
.w
.
~' ' ~ ,,
,. . . . .
Ei 3~
-13-
a trans double bond~ and Ar i~ phenyl.
compound according to Formula I wherein X is
R
-~-NHR", Rl' is methylsulfonyl, W is a C1S double bond, Z is
a trans d~uble bond, and Ar is m~methoxyphenyl.
_. _
A compou~d accordiny to Formula I whexein X is
_ ~-N~R", R" is acetyl, W is a oi8 double bond, Z is a trans
double bond, and Ar i~ m-methoxyphenyl.
Novel intermediates of the Formulae below may be
prepared by ~he processes described herein:
OH
~"' ~ ~,
p~c~l ~ ~ ~, O-Ar
"OTHP ... IIA'
,
T~PO` ~ ~ `O-Ar
~OT~P .O o IIB I
an~ the Cg an~ C15 epimer~ thereof; wh~rein Ar is phenyl;
; 3,4-dimethoxyphenyl; 3,4-methylenedioxyphenyl; 3,4,5-tri-
methoxyphenyl; a- or ~-naphthyl or monosubstituted phenyl
wherein said substituent is halo, trifluoromethyl, phenyl,
lower alkyl or lower alkoxy; THP i6 2-tetrahydropyranyl; W
is a sin~le band or a cis double bond; Z is a single bond
or trans double bond; and X is:
~a] a group of the formula -~-O-RI Whereln R~ is alkyl
2~ of from 1 to 10 carbon atQmS; aralkyl of from 7 to 9 carbon
atoms; cycloalkyl of from 3 to 8 carbon atoms; a~ or ~-
naphthyl; phenyl or mon~substituted phenyl, uherein the sub-
stituent is halo, lower alkyl or l~wer alkoxy;
(b) ~-phenyl-phenoxycarbonyl;
,,
: ' , , :'' ' : , '
t ' - ' ' '' ' . , :
: ' ' "' . . ,, , : ' ' :
'. '. ' ' .~ :
S~33~
~c) tetraæolyl; or
td) a group of the formula -INHR Where1n R 1~ A1kan-
~yl having from 2 t~ 10 carbon atoms, cycloalkanoyl havlng
from 4 to 8 carbon at~m~; aryoyl or su~stltuted aryoyl of
from 7 to 11 carbon atoms wherein the substituent is methyl,
halogen, or methoxy; alkylsulfonyl of rom 1 to 7 carbon
atoms; arylsul~onyl or substituted arylsulfonyl wherein the
substituent is methyl, halogen or methoxy.
The starting materials for the various novel com-
1~ pounds prepared by the proces~ of this invention are a~ail-
able commexcially or may be made by methods well known to
those skilled in the art. For example, to make dimethyl
2-~xo-3-phenoxypropylphosphonate, the starting material for
the ~yn~hesis of the 16-phenoxy prostaglandins, one cools
a $~1ution of dimethyl methylphosphonate in tetrahydrofuran
to -78 in a dry nitrogen atmosphere and then adds n butyl-
: lithium in hexane dropwise, slowly, After stirrin~, methyl-
; 2~phenoxy acetate is added dropwise. After 3 to ~ hours at
: -78~ the reaction mixture is warmed to ambient temperature,
neutralized with acetic acid and rotary evaporated to a
white gel. The gelatin~us matexial is taken up in water,
the aqueou~ phase is extracted in chloroform and the combin-
ed vrganiG extracts are backwashed, ~ried, an~ concentrated
to give the desired productO
~ make substituted 16-phenoxy prostaglandins, one
re~uires substituted phenoxy acetlc acids which are prepared
by condensation of appropriate phenol with a haloacetic acid
or ester in the presence of a kase as described by J,M.
Petersen, ~ , 5, 519 (1951) or M~ Beroza,
Ale ~ ,, 4, 49 ~1956~. Thu~ condensation of bromo-
methyl acetate with sesmol ln presence of sodium methoxide
gives the
Similarly, one may prepare ~ ~
3~4,5-trimethoxv~henoxY acetic acid and ~-phenylphenoxy
aceti~_acid
-
.
~S~3~
--lS
o
S'-~
o~ ~
:, o ~ o
~ N~ ;O
Il o \/ ~, U~l
: . :, ,. . : :,
. ', ~. ' ::, ~ ~ " !
33L
-15-
A~ shown in Scheme A, the first step :in ~he aoM-
plete synthesis (1 -~ 2) is the condensation oE the appropri-
ate ester with a dlalkyl methylphosphonate to produce oxo-
phosph~nate 2~ These es~ers are obtained as previously de-
scribe~
In 2 ~ 3 the oxophosphonate 2 is reacted with the
known [Corey et al., J A~ _ ,h~ c , 93, 1491 ~1971)~
aldehyde H to produce, after chromatography or crystalliæa-
ti~n, the enone 3~
The enone 3 may be reduced with zinc borohydride
or with a trialkylborohydride, such as lithium triethylboro-
hydride, to a mixture of alcohol , 4 and 5 which may be sepa-
rated by column chromato~r~phy~ In this reaction ethers
such as tetrahydrofuran ~r 1,2-dimethoxy ethane are usually
employe~ as solvPnts, although occasionally methanol is pre-
ferred to ensure specificity of reduction. Further trans-
formation~ of 4 are shown in Scheme B.
4 ~ 6 Is a base catalyzed transesterification in
which the ~-biphenyl-carbonyl protecting gr~up is removed.
This is most conveniently conducted with potassium carbon-
ate in methanol or methanol-tetrahydrofuran solvent. 6 ~ 7
Involves the protection of the two free hydroxyl groups with
an acid-la~ile pr~tecting group. Any sufficiently acid-
labile group is satis~actory; however, the most usual one is
tetrahydropyranyl, which can be incorporated in the molecule
~ reatment with ~ihydropyran and an acid catalyst in an
anhydrou~ medium. The catalyst is u~ually ~-toluenesulfonic
acid.
7 ~ 8 Is a reduction of the lactone 7 to the hemi-
acetal 8 using diisobutyl aluminum hydride in an inert s~lv-
ent~ Lo~ reaction temperatures are preferred and -60 to
-70~C. are usual. However, higher temperature may be em-
pl~yed if over~reduckion does not occur. 8 Is purified, if
~esired, by column chromatography.
8 ~ 9 Is a Wittig condensation in which hemiacetal
8 is reacted ~ith ~4-carb~xy-n-butyl)triphenylphosphonium
bromide in dimethyl sulfoxide, in the presence o~ sodium
~' .
`
.. . : , . . . .
.. ..
~5~3~
methylsulfinyl methide. 9 Xs purified as above~
The conversion 9 ~ 12 is an acidic hydrolysis of
the tetrahydropyranyl groups. Any acid may be used which
does not cause destruction of the molecule in the course of
the removal of the protecting group; ho~ever, this is
accomplished most o~ten by use of 65% aqueous acetic acid.
The product is purified as above.
9 ~ 10 Is an oxidation of the secondary alcohol 9
to the ketone 10. This may be accomplished using any oxidiz-
ing agent which does not attack double bonds; however, theJones' reagent is usually preferred. The product is puri-
fie~ as above.
10 ~ 11 Is carried out in the same manner as 9 ~ 12.
The product is purified as above.
lS ~1 ~ 15 Is an acid-catalyzed dehydration. Any acid
may be usecl for the process which does not cause extensive
decomposition of ~he product, but the most usual procedure
con~ists of dissolving 11 in an excess of 97% formic acid
f~llowed by dilution with ice water and extraction of the
product after the starting material has been consumed. The
product is purified as above.
~1
.. . .
. : . :
3~ .
--18~- r
SCHEME ~
HO' ~\~-Ar
6 H ~OH
~ ,0
THPO ~ ~O-Ar ~ ,.
TIIPO' ~\.~O-Ar
HO ~ ~ H OTHP
THPO L ~H\/~O ~ X
THPO ' ~~O-Ar
OH ~ lo OTHP
HO--" \~\~-Ar j~
12 H ûH ~ r~ =/ X
HO' ~ O-Ar
11 H OH
~X
~~/~ O-Ar l5
H OH
3~
--19-- ,.
~ s illustrated in Scheme C~ 5 may be substituted
fox 4 ln scheme ~ to provide prostaglandin derivatives 12',
ll' and 15'.
SCH
OH
~7 HO' ~\~O-Ar
HO ~I 12
1~
'~ X ,,
5 \ I I .
\ ~O~ ~ O-Ar
\ ~0
O-Ar
HO H 15' .
Scheme D illustrate~ the synthesis of precursors
to the 13,14-dihydro 15-substituted-~-pentanorprostaglandins.
In 3 ~19 + l9' the enone 3 i8 reduced to the
tetrahydro compound through the use of any of the complex
metal hydride reducing agenk~ LiAlH4, NaB~4, KB~4, LiBH4 and
Zn~B~4)2. Especially preferred i~ Na~4. The products,
1~ and l9', are separated from each other by column chroma-
tography.
Furthermore, the compounds 4 and 5 of Scheme A may
be r~duced catalytiaally with hy~rogen to 19 and 19' xespec-
ti~ely. The s~age at whioh the double bond is reduced is
not critical, and hydrogenation of 6 or 7 of Scheme ~ ~ill
al~o afford useful intermediate~ for the 13,14~dihydro
prostaglandin analogs of t~e pre6ent invention. This reduc-
.l'
,, : .~ - , . ;
:
', ' :,
~L~85i1~
-20-
tion may be achieved with eikher a homogenous cataly~t quch
a~ kris~triphenylphosphine~chlororhodium, or with a hekero~
geneous catalyst such as platinum, palladium or rhodium.
-r~ `
~
.
. . . ~ .
31 ~ 3~
--21--
o~
o
o~,~,~
~,~
~ '
~'
, :` :: `: :
. .::: ~ , , , , i
-2~
~he converslon of 19 and 19' to the.ir r~spect1ve
prostagland~n~ follows the route fihown in Scheme ~ when 4
is replaced by 19 and 19' to yield the 13,14-dihydro PGE2,
PGA2 and PGF2 series of prostaglandin dexivatives.
Scheme E illustrate~ the preparation of the various
reduced 15-substituted-~-pentanorprostaglandin precursors:
19 ~ 22 Is carried out as illustrated in Scheme B
for 4 ~ 9. 22 May be used as both a precursor to a 13,14-
dihydro-15-substituted-~-pen~anorprostaglandin of the "2-
series" or as an intermediate to 23, a precursor to a 13,14-
dihydro-15-substituted-~-pentanorprostaglandin of the "1-
series". 22 -~ 23 Is carried out by catalytic hydrog nation
using the catalyst described for the reduction of 4 ~ 19 of
Scheme D. Intermediates o $ha type 21 are prepared by
select~Ve hydrogenation of the 5,6-c~s double ~ond at low
temperatUre using ~atalysts such as those described for
4 ~ 19 and 17 ~ 23. EspecialIy preferred for this hydrogena-
ti~n is the use of palladium-on-carbon as a catalyst and a
reaction temperature of -20. Intermediates of the type 21
are n~t only p~ecursors to 15-substituted-~-pentanorprosta-
glandins o the "l-series" through the route 9 ~ 15 of Scheme
B, but also aR a precursor to compounds of the type 23
through the route alrPady dis~ussed for 22 ~ 23.
,'"" ' '
' '
, ' ' , ~ '
~8~3~
-23
~C
o P~
1 o
~1~<
E~ > ~ PZ
:
r~ ~ .
\
P~
E~ '
; , . : .. ,: , ,. .. . ~ . :
, ., :. : -: : ,
'.. : : ,. :: :, : ` : - . ', ~:'
.. . :.~ :..... .. .
3~
-2~-
Furthexmore, the 15-substituted~ pentanorprosta-
glandins of the El and Fl~ series may be obtained directly
from thP corresponding prostaglandin analog of the "2-series"
by first protecting the hydroxyl by introducing dimet~yl iso-
propyl silyl groups, reducing selectively the cis ~ouble bond,and removing the protecting group.
The introduction of the protecting group i8 u~ually
accompliqhed by treatment of the prostaglandin analog with
dimethyl isopropyl chloxosilane and triethylamine, the re-
duction is acaomplished a discussed above for 9 ~ 21 andremoval of the protecting group is accomplished by contact-
ing the re~uced protec~ed compound with 3:1 acetic acid:water
for la minutes or until reacti~n i~ substantially complete.
~he ClS epimers ~f 21, 22 and 23 may be used as
precursers to the 15-epi series of prostaglandin derivatives
des~ribed ab~v~.
In the foregoing procedures, where purification by
ch~omatography is desired~ appropriate chromatographic supports
in~lude neutral alumina and silica gel and 60-200 mes~ silica
gel i9 ~enerally preerred, The ~hromatography i6 suitably
conducted in reaction-inert solvents such as ether, ethyl
acetate, benzene, chloro~orm~ methylene chloride, cyclohexane
and n-hexane, aæ further illustratsd in th~ appended examples.
It ~ill be seen that the ~oregoing formulae depiot
optically aative aompoun~s. It will be alear, however, that
th~ corresponding racemat~ will exhibit valuable biological
activity by virtue of their content of the above-mentioned
biologically active optioal iso~er, and it i8 intended that
~uch raaemate~ al~o be embraced by the ~oregoing ~ormulae
herein an~ in ~he appended claims. The rac~mic mixtures are
readily prepared by ths same methods employed herein to
synthesize the optically active species, by mere substitution
o~ corresponding racemic precurs~r~ in place of optically
active starting materials~
In numerous in vivo and in vitro tests we have
demonstrated that the new prostaglandin analogs pos~ess
physiological activities comparable to those exhibited by the
~,
,
, ~
-25-
natural prost~glandins. These test~ include, among o~her~,
a test Eor e~fect on i~olated smooth muscle from guinea piy
uterus, guinea pig ileum and rat uterus, inhibition of hist-
amine-induced bronchospasm in the guinea pig, and effect on
dog blo~d pressure, inhibition o~ stress-induced ulceration
in the rat, inhibition o~ gastric acid and pepsin secretion
in rat and dog, inhibition of collagen or ADP-induced blood
platelet aggregation and abortifacient activity in rats and
guinea pigs by luteolykic and non-luteolytic mechanisms.
Th~ physiological responses observed in these tests
are useful in determining the utility of the test sub3tance
for the treatment of various natural and pathological condi-
tions. Such determined u~ilities include: antihypertensive
activity, bronchodilator activity, antithrombogenic activity,
antiulcer activity, smooth muscle activity ~useful as an
anti-fertility agent, for the induction of labor, and as an
abortifacientJ, and anti-fertility activity through a mechan-
ism not affecting smooth muscle, fQr example, luteolytic
mechanisms, and the synchronization of the estrous cycle in
farm animals.
The novel compounds prepared by the process of this
invention possess more seleotive aotivity profiles than the
corresponding naturally occurring prostaglandins, and in many
cases, exhibit a longer duration of action. For example,
16~phenoxy~tetranorprostaglandin E2 which exhibits smooth
muscle timulating activity comparable to PGE2, i~ inaativ~
in inhibition of histamine-induce~ bronchospasms in gui~ea
pigsO Furthermore, although the threshold dose of hypotensive
response of 16-phenoxy-~-tetran~r PGE2 in dogs is higher than
3~ that o PGE2, the duration of a¢tion is markedly prolonged
relative to PGE2. The 15-substituted ~-pentanorprostaglandins
of the PGEo, Fq~, Fl~, F2B, and 13,14-dihydro PFG2B exhibit
similar smooth muscle st~ant activity, whereas the corre-
sponding derivatives of the Ao~ Al, A2 and 13,14-dihydro PGA2
series have gastric antisecretory/antiulcer activity~
Particularly useful fox fertility c~ntrol, abortion
an~ induction of labor are the 16-phenoxy-~-tetranorprosta-
. .
- ~ ': . , ':
;
.
3~
-26~
glandins of the E2~ F2~ F2~ se~ies based on especially out-
s~anding smoo~h muscle stimulating activlty, and at the ~ame
time raduced blood pressure effects. Similarly, the substi-
tuted ~-pentanorprostaglandins of the PGEl, PGFoU, PGFl~,
and 13,14-dihydro PGF2~ series are useful for fextility con-
trol including abortion and induction of labor on the basis
of their smooth muscle stimulant activity. The novel 15-sub-
stituted ~-pentanorprostaglandin-13~14-dihydro-E2 analogs
may be employed in ~he treatment o~ peptic ulcers. The novel
prostaglandins with a ~-O~ at the 15-position are in general
less potent, although frequently more selective than the
corresponding a-hydroxyl epimers. Additionally, the prosta-
glandins having a ~-hy~roxyl at C-15 are valuable intermedi-
ates for prostaglandins having a ~-hydroxyl at C-15 through
a recycling process involving an oxidation and reduction at
C-15.
The new compounds prepared by the process of this
invention may be used in a variety of pharmaceutical formula-
tions which contain the compound, and they may be administer-
20 ed in the sama manner as natural prostaglandins by a varietyof routes, such as intravenous, oral, intravaginal, intra-
and extra-amniotic, among others.
For induction of abortion, tablets or an aqueous
suspension or alcoholic solution of 16-phenoxy-~-tetranor-
2S prostaglandin would appr~priately b~ administered at oraldoses of 0.1 to 20 mg., with 1 to 7 do6es per day being em-
ployed. Fox intravaginal administration a suitable formula-
tion would be lactoæe tablets or an impregnated tampon of
the same agent. For such treatments suitable doses would be
3~ from 0.1 to 20 mg./dose with 1 to 7 doses being employedO
For intra-amniotic administration a suitable formulation
would be an aqueous solution containing O.Q5 to 10 mg./dose
with 1 to 7 doses being employed. For extra-amniotic admin-
istration a suitable formulation would be an aqueous solu-
tion containing O~Q5 to 1 mg./dose with 1 to 5 doses beingemployed. Alternatively, the 16-phenoxy-~-tetranorprosta-
glandins of this invention may be infused intravenously for
,,
.. '
-: : ,
~583~
-27-
induction of abortion at doses of 0O05 to 50 ~Ig/minute ~or
a period of from 1 to 24 hours. For synchronizakion of the
estrous cycle in pigs, sheep, co~s or horses, a solution or
suspension containing 0.03 to 30 mg./day of 15-phenoxy-~-
tetranorprostaglandin is administered subcutaneously from 1to 4 days~
15-Substituted-~-pentanorprostaglandins of the A
series are useful gastric antisecretory and antiulcer agents,
as are the 15-substituted-~-pentanorprostaglandins of the E
series~ For treatment of peptic ulcers these compounds are
administered preferably orally in the form of capsules or
tablets at doses of 0.001 to 0.1 mg./kg./day.
To prepare any of the above dosage forms or any of
the numerous other forms possible, various reaction-inert
diluents, excipients or aarriers may be employed. Such sub-
stances inalude, for example, water, ethanol, gelatins, lac-
tose, starches, magnesium stearate, talc, vegetable oils,
benzyl alcohols, gums, polyalkylene glycols, petroleum jelly,
cholesterol, and other known carriers for medicaments. If
desired, these pharmaceutical compositions may contain
auxiliary substances such as preserving agents, wetting
agents, stabilizing agents, or other therapeutic agents such
as antibiotics.
Various modifications are possible on the upper
side chain of the prostaglanains prepared by the process of
this invePtion; æuch modifications do not, as a rule, alter
the basic biological activity of the prostaglandin, although
they may increase selectivity and duration of action further
and reduce toxicity. For example, a tetrazoyl group may be
33 placed at the Cl position. 16-Phenoxy-PGE2-tetrazoyl has the
same utility as 16-phenoxy PGE2 esters; namely, for induction
of labor or abortion, an~ for the inhibition of ga~tric acid
~ecretion and treatment of peptic ulcers.
Another upper side chain modification which may be
made in the prostaglandins of this invention is substitution
of the carboxylate group at the Cl position by a carboxamide
group. Alternatively, the novel compounds prepared by the
.
' ' . ~ , ~
.:
~s~
-28-
process of this invention represented by ~ormula I ~where X
is ~NHR" and wherein R" is as defined pre~iously~, may be
prepared from compounds 9 and 10 of Scheme B ~or the corre-
sponding 15-epimers Qr 15-lower alkyl derivatives of 9 and
10) by reaction with appropriate isocyanates, followed by
hy~rolysis with dilute acid. The utility of N-methylsulfonyl-
16-phenoxy PGE2 carboxamide, for example, is the same as
that o~ 16-phenoxy PGE2 esters.
One particularly beneficial ester is the p-biphenyl
ester. Such esters are prepared in the appended examples by
simply adding ~-phenylphenol to the prostaglandin in methyl-
en~ chloride in the presence of a dehydrating agent, for
example, dicyclohexylcarbodiimide, and stirring overnight.
Although not more p~tent in in vitro smooth muscle te6ts,
abortifacient evaluation of 16-phenoxy-~-tetranor PGE2 and
PGF2~ p-biphenyl esters demonstrated that these p-biphenyl-
e~ters possess physi~lo~ical activities markedly greater
than those of the free acids.
The following Examples are merely illu~trative,
and in no way limit th~ scope of the appended claims. In
these Examples it will be appreciated that all temperature6
are expre~sed in Cen~igrade, all melting and boiling points
are uncorrected.
~xaNpLE I
~
A solution of 33,2 g. ~268 mmoles) dimethyl methyl-
phosphonate (Aldrich~ in 360 ml. dry tetrahydro~uran was
cooled to -78 in a dry nitrogen atmosphere. To the stirred
phosphonate solution was added 118 ml. of 2.34 M n-butyl-
lithium in hexane solution ~Alfa Inorganics, Inc.) dropwiseover a period of 18 minutes at such a rate that the reaction
temperature never rose above -65. After an additional 5
minute~ stirring at -78, 22.2 g~ ~134 mmole~ methyl 2-
phenoxy acetate was added dropwise at a rate that kept the
reaction temperature less than -70 ~20 minutes~. After 3s5
hours at -78 the reaction mixture was all~wed to warm to
'~h'
)~Sii~3
29-
ambient temperature, neutralized with 14 ml. acetic acid and
rotary evaporated to a white gel. The gelatinou~ material
was taken up in 175 ml. water, the aqueous phase extracted
with 100 ml. portions of chloroform ~3x], the combinPd
organic extracts were ~ackwashed ~50 cc ~2~' dried ~MgSO4),
an~ c~ncentrated ~water a~pirator) to a crude residue and
distilled, b.p. 172-175 tO.5 mm) to give 24.6 g. dimethyl
2 oxo-3-phenoxypro~ylphosphonate.
The nmr spectrum tCDC13) sho~ed a doublet centered
at 3.75~ ~J = 11.5 cps, 6H) for ~C~3O)-~-, a singlet at 4.7
~2H) for C~H5O-C~2-CO-, a doublet centered at 3~24~ ~J = 23
cps, 2H) -~-C~2-P-, and a multiplet at 6.8-7.5~ ~5~) for the
aromatic protons.
EXAMPhE _
2-[3~ Phenylbenzoyloxy-5~-~ydroxy-2~-~3-oxo-4-Phenoxy-trans-
Dimethyl 2-oxo 3-phe~oxypropylpho~phonate ~5.4 g.),
(21 mmole) in 200 mlO anhydrous ether was treated with 7.9
ml. ~19 mmole) 2.5 M n-butyllithium in n-hexane ~Alfa In-
organics, Inc ) in a dry nitrogen atmosphere at room tempera-
ture~ After 5 min. of stirring, an additional 400 ml. of
anhydrous ether was added followed by 6.0 g. ~17 mmole) 2-
E 3~ phenylbenzoyloxy-5~-hydroxy-2~-formylcyclopentan-la-
yl]acetlc acid, y-lacto~e in one portion and 50 ml. anhydrous
ether, After 35 minutes the reaction mixture was quenched
with 5 ml. glacial acetic acid and washed with 100 ml.
~aturated sodium bicarbonate solution (4x), 100 ml. water
~2x), 100 ml. ~aturated brine ~lx), dried ~MgSO4~ and evapor-
ated to yiel~ 5.2 ~m 7 2-[3a-~-phenylbenzoyloxy 5a-hydroxy-
2B-~3-o~o-4-phenoxy-trans-1-buten-1-yl~cyclopent-la-yl]acetic
acid, ~-lactone as a solid after column ahromatography
~Silica gel~ Baker, 60-200 mesh); m.p. 112-114 after crystal-
lization from methylene ahloride-hexane.
The ir spectrum (~Br) of the product exhibited
absorption bands at 1775 cm 1 ~strong), 1715 cm 1 (strong),
1~75 cm 1 (medium) and 1630 cm 1 (medium) attributable to the
.
.-: :
.:
.. .
.
5~3~
-30-
carbonyl groups and at 970 cm 1 for the _rans double bond.
EXll MP ~E: I I I
2-[3a-p~Phenyl~enzoyloxy-5~-~ydroxy-2~-~3~-Hydroxy-4-Phenoxy-
trans-~Buten-l~yl~Cyclopent~ yl]acetic acid, ~-Lactone
To a solution of 5.1 g. (10~5 mmole) 2-~3~-~-phenyl-
benzoyloxy-5a-hydroxy-2~-(3-oxo-4-phenoxy-trans-l~buten-1-yl)-
cyclopent~ yl]acetic acid, ~-lactone in 30 ml. dry 1,2-
dimekho~yethane in a dry nitrogen atmosphere at ambient temp-
erature was added dropwise 11 ml. ~5.5 mmole~ of a 0.5 M zinc
borohydride solution. After stirring at xoom temperature for
2 hours, a saturated sodium bitartrate solution was added
dropui~e until hydrogen evolution ceased. The reaction mix-
ture was allowed to stir for 5 minutes at which time 250 ml.
dry methylene chloride was added. After drying ~MgS04) and
concentrating ~water aspirator) the resultant semi-solid was
purified ~y column ohromatography on silica gel (Baker
"Analyæed" Reagent* 60-200 mesh~ using ether as eluent. After
elution of less polar impurities a fraction con~aining 896
mg. 2-[3a-~-phenylbenæoyloxy-5~-hydroxy-2~-(3~-hydroxy-4-
phenoxy-trans-l-buten-l-yl~cyclopent-l~-yl~acetic acid, ~-
lactone, a 600 mg. fraction of mixed 4 and 5 and finally a
fraction ~1.5 gm.) of 2-[3a-~-phenylbenzoyloxy-5~-hydroxy-
2~-~3~-hydroxy-4-phenoxy-trans-1-huten-yl~cyclopent-la-yl]-
acetic acid, y-lactone.
; 25 The ir spectrum ~CHC13) of 4 had strong carbonyl
absorptions at 1770 and 1715 cm 1 and an absorption at 970
cm for the trans double bond.
EX~MPLE IV
2-[3a,5a-Dihydroxy-2~-~3~-hydroxy-4-phenoxy~trans-1-buten-1-
~
A heterogeneous mixture of 846 mg. (1.7 mmole) of
2-~3~-~-phenylbenzoyloxy-5~-hydroxy-2~-(3~-hydroxy-4 phenoxy~
trans-l-buten-l-yl)cyclopent-l~-yl]acetic acid, y-lactone,
10 ml~ of absolute methanol and 120 mg. of finely powdered,
anhydrous potassium carbonate was stirred at room temperature
for 20 hours, then cooled to 0. To the cooled solution was
added 1~75 ml. of l.ON aqueous hydrochloric acid. After
stirring at 0 for an additional 10 minutes, 10 ml~ of water
*Trademark
~r
~.
3~
wa added with concomitant formation of methyl p~phenyl-
ben~oate which was collected by filtration. The ~iltrate
was saturated with solid sodium chloride, extracted with
ethyl acetate (4 x 10 ml.), the combined organic extracts
were washed with saturated sodium bicarbonate ~10 ml.) dried
~MgSO~) and concentrated to give 445 mg. of viscous, oily
2-[3a,5a-dihydroxy 2B-~3a-hydroxy-4-phenoxy-trans-1-buten~
yl~cyclopent-la-yl]acetic acid, ~-lactone~
The ir spectrum ~CHC13) exhibited a strong absorp-
tion at 1772 cm 1 for the lactone carbonyl and medium absorp-
tion at 965 cm 1 for the trans double bond.
EXAMPLE V
2-[5a-Hydroxy 3a-(tetrahydropyran-2-yloxy-2~-t3a-tetrahydro-
pyran-2-yloxy-4-phenoxy-trans-1-buten-l~yl)cyclopent-la-yl]-
acetic acid, ~-lactone
To a solution of 445 mg. ~1.46 mmole) 2-r3a,5a-di-
hydroxy-2~-(3a-hydroxy-4-phenoxy-trans-1-buten-yl~cyalopent-
la-yl~acetic acid, y-lactone in 5 ml~ anhydrous methylene
chlorlde and 0.4 ml. of 2,3-dihydr~pyran at 0 in a dry
nitrogen atmosphçre ~as added 5 mg. p-toluenesul~oni~ acid,
monohydrate. After stirring for 15 minutes, the reaction
mixture was combined with 100 ml. ether, the ether solution
washed with saturated so~ium bicarbonate ~1 x 15 ml~l then
saturated brine ~1 x 15 ml.), dried ~MgSO4) and concentrated
t~ yield 752 mg. (~1~0%) crude 2-~5~-tetrahydropyran-2-yloxy-
4-phenoxy-trans-1-butsn-1-yl)cyclopent-la-yl~acetic acid, y-
__
lactone,
The ir (CHCl3) spectrum had a medium absorptlon at
970 cm 1 for the trans double bond, and at 1770 cm 1 for
lactone carbonyl.
EXAMæLE VI
2~5a-Hydr~xy-3a-(tetrahydrQpyran-2-yloxy)-2B-(3a-tetrahydro-
pyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl~cyclopent-1~-yl]-
acetaldehvde, y-hemiacetal
A s~lution of 590 mgO ~1.46 mmole~ 2-[5a-hydroxy-
3a-(tetrahydropyran-2-yloxy)-2B-~3a-tetrahydropyran-2-yloxy-
4-phenoxy-trans-1-buten-1-yl~cyclopent-la-yl]acetic acld, ~-
lactone in 8 ml. dry toluene was cooled to -78~ in a dry
~1
:. :
,:,
: . : ' : ' ::
'
5i 513~
-32--
nitrogen atmosphere~ To khis oooled ~olution was added 2.0
ml. of 20% diisobutylaluminum hydride in n-hexane (Alfa In-
organics) dropwise at ~uch a rate so that the internal temp-
erature never rose above -65 ~15 minutes~. After an addi-
tional 45 minutes of stirring at -784, anhydrous methanol
was added until gas evolution ceased and the reaction mix-
ture was allowed to warm to room temperatureO The reaction
mixture was combined ~ith 100 ml. ether, washed with 50
sodi~ potassium tartrate solution (4 x 20 ml.), dried
~Na2S04) a~d concentrated to yield 613 mgO 2-[5a-hydroxy-3~-
[tetrahydropyran-2-ylox~)~2~-(3~-tetrahydropyran-2-yloxy-4-
phenoxy-trans-l-buten-l-yl)cycl~pent-l-yl~acetaldehyde, y-
hemiacetal.
EXAMPLE VII
. . .
9a-~1ydroxy-11~,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-
cis-5-trans-13-~-tetranorprostadienoic acid
To a solution of 1.6 gm, ~3O6 mmole) (4-carboxy-n-
butyl)triphenylphosphonium bromide in a dry nitrogen atmo-
sphere in 6.0 ml. dry dimethyl sulfoxide ~as added 3.24 ml.
(6.5 mmole) of a 2.0M solution of sodium methylsulfinylmeth-
ide in dimethyl suloxide. To this red ylide solution was
added dropwise a solution o~ 613 mg. ~1.29 mmole) 2-~5~-
hydro~y-3a-~tetrahydropyran-2-yloxy)-2~-(3a-tetrahydropyran-
2-yloxy-4-phenoxy-trans-1-buten-l yl)cyclopent-1~-yl~acet-
aldehyde, y-hemiacetal in 5.0 ml. dry dimethyl sulfoxide
over a period of 20 minutes. Ater an additional 2 h~urs
stirring at r~om temperature, the reaction mixture was poured
onto ice water. The basic a~ueous solution was washed t~ice
with ethyl acetate ~2~ ml.~ and acidified to pX 3 with 10~
3~ aqueou~ hydrochloric acid. The acidic solution was extracted
with ethyl acetate (3 x 20 ml.) and the combined organic
extracts washed once with WateF ~10 mlO)~ dried (MgS04~ an~
evaporated to a solid residue, This solid residue was tri-
turated with ethyl acetate an~ the filtrate concentrated to
yield 754 mg. of 9~-hydroxy~ ,15~-bis-~tetrahydropyran-2~
yloxy)-16-phenoxy-cls-5-trans-13-~-tetranorprostadienoic acid
was collected. Infrared spectrum ~C~C13) displayed a strong
I,
.
' . ` : ~ . ,
i83~
-33-
band at 1720 cm 1 for the carboxyl group.
EXAMPLE VIII
9~Oxo~ ,15a-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-S-
trans-13-~-tetranorprostadienoic acid
~ _ _ _ _ _
To a solution cooled to ~1~ under nitrogen of 754
mg. (1.3 mmole~ 9~-hydroxy-lla,15a-bis-~tetrahydropyran-2-yl-
oxy~-16-phenoxy-cis-5-trans-13-~-tetranor-prostadienoic acid
in 13 ml. reagent grade acetone was added dropwise to 0.56
ml~ 41 mmole) of Jones' reagent. After 20 minutes at -109
~Q 0.260 ml~ 2-propanol was added and the reaction mixture was
allowed to stir an additional 5 minutes at which time it was
c~mbined with 75 ml. ethyl acetate, washed with water ~3 x
10 ml.), dried (MgSO4) and concentrated to give 752 mg. of
9-oxo-lla t 15a bis~(tetrahydropyran-2-yloxy)-16-phenoxy-cis-
5-trans-13-~-tetranorprostadienoic acid, which was chromato-
graphed on silica gel using ethyl acetate as eluent to afford
505 m~. of pure 10.
EX~UPLE IX
9-Oxo-lla,15a-dihydroxy-16-phenoxy-cls-5-trans-13-~-tetranor-
~rostadienoic acid
A solutio~ of 5~5 my. ~0.9 mmole) 9-oxo-lla,15~-
bis-~tetrahydropyran-2~yloxy)-16-phenoxy-cis-5-trans-13-~-
tetranorprostadienoic acid in 6.3 ml. of a 65:35 mixture of
glacial acetic acid:water was stirred under nitrogen at 25
for 18 hours then was concentrated by rotary evaporation.
The resultant crude oil was purified by c~lumn chromato-
graphy on silica gzl IMallinckrodt* CC 4 lQ0-2~0 mesh~ using
ethyl acetate as eluent. After elution of less polar Lmpur-
ities the oily 9-oxo-lla,15a-dihydroxy-16-phenoxy-c -5-trans-
13-~-tetranorprostadienoic acid weighing 210 mg, was collected.
Ir (CHC13) displayed a broad band at 1725 cm 1 for
carbonyl absorptions, and a band at 97~ cm 1 for the 13,14-
trans-double bond.
EX~MPLE X
35 9a ,11~ ,15~-Trihydroxy-16-phenoxy-cis-5-trans-13-~-tetranor-
prostadienoic acid _ _ _ _
A mixture of 375 mg. ~Q.65 mmole) 9a-hydroxy-
11~,15a b -(tetrahydropyran-2~yloxy~-16-phenoxy-cls-5-trans-
*Trademark
'~ .
., : ,
3~
~ 34-
13 ~-tetranor-prostadienoic acid, acetic acid ~6.5 ml.) and
water ~3.5 ml.) was stirred under nitroyen at room tempera-
ture for 20 hours. The resultiny clear ~olution wa~ concen-
trated under reduced pressure ancl the residue ~380 mg.~ waR
dissolved in ethyl acetate. The ethyl acetate solution was
washed with brine (20 ml.~, dried ~NaSO~) and concentrated
to a clear oil. Chromatography on silica gel (Mallinckrodt*
CC-7) using chl4ro0rm and then ethyl acekate as eluent
afforded the desir~d product, 9a,11a,15a-trihydroxy-16-phen-
1~ oxy-cis 5-trans-13-~-tet~anorpro~tadianoic acid as a color-
less oil weighing ~8 mg.
EXAMPLE XI
9a-Hydroxy~ ,15~-bis-(~etrahydropyran-2-yloxy)-16-phenoxy-
~-tetranorprostanoic acid
A mixture of 190 mg. ~0.33 mmole) 9~-hydroxy 11~,15~-
bls-~tetrahydropyxan-2-yloxy~-16-phenoxy-cis-5-trans-13-~-
tetranorpro~tadienoic acid, 5% palladium-on-carbon ~150 mg.)
in methanol (10 ml.) is stirred under an atmosphere of hydro-
gen for 60 hours at r~om temperature. The mixture is filter-
2~ ed and concentraked to give 9~-hydroxy-lla,15a-bi~-~tetra-
hydropyranr2-yloxy)-16-phenoxy-~-tetranorprostanoic acid.
EXAMPLE XII
9~,11a,15~-Trihydroxy-16-phenoxy-~-tetranorprostanoic acid
Hydrolysis of 20 mg. 9a-hydroxy-lla,15~-bls-~tetra-
hydr~pyran-2-yloxy)-16-phenoxy-~-tetranorprostanoic acid is
carried out with acetic acid ~0.5 ml.) and water ~.3 ml.~
under nitrogen at room tempexature for 20 hours. Purifica-
~ion as descri~ed in Example X affords pure 9a,1Lu,15~-tri-
hydroxy-16-phenoxy-~tetranorprostanoic acid.
EX~MPLE XIII
9-Oxo~ ,15~-dihydroxy-16-phenoxy-~-tetranorprostanoic acid
A solution of 186 mg. ~0~3 mmole~ of the product of
Example XI in 3 ml. acetone is oxidized with 0.14 ml. ~0.35
mmole) o~ Jones' reagent as described in Example VIII. Isol-
ation of the product and hydrolysis with acetic acid and
water at room temperature as desaribed in Example IX gives
pure 9-oxo~ ,15~ dihydroxy-16-phenoxy-~ tetranorpro~tanolc
*Trademark
.
"
' ' :' :' .. ,. . :. ~,
:. . : , . .
' .,', ~ ., ;.
5~33~L
-35-
aa ld .
EXaMPLE XIV
9~0xo-15a-hydroxy-16-phenoxy-cis-5,10-trans-13-~tetranor-
urostatrienoic acid
A mixtUre of 52 mg. ~0.1 mmole~ 9-oxo-lla,15a-di-
hydroxy-16-phenoxy-cls-5 trans-13-~-tetranorpxo~tadienoic
acid with 0.2 ml. 97~ foxmic acid i8 stirred at 25 for 2.5
hours. About 5 ml. ice~ater is added to the reaction mix-
ture which is then ext~acted with ethyl acetate, dried
tNa2so4) and concentrated to give a crude oil. Chromatography
of the cru~e product on silica gel ~Mallinckrodt* CC-7) using
methylene chloridç-ethyl acetate as eluent gives the desirad
9~xo-15a-hydroxy-16-phenoxy~cis-5,10-trans=13-~-tetranor-
prostatrienoic acid.
~ EX~PLE XV
9~0xo-15a-hydroxy-16-phenoxy-~-tetranor-prost-10-enoic acid
9-Oxo~ , 15~-dihy~roxy-16-phenoxy-~-tetranorprosta-
noi~ acid is treated with 97~ formic acid as described in
Example XIV and c~nverted to colorless oily 9-oxo-15a-hydroxy-
16-phenoxy-~ tetranor-prost-10-enoic acid.
EXAMPLE XVI
2-[3a-~-Phenylben3oyloxy-5a-hydroxy-2B-(3-hydroxy-3-methyl-4
phenoxy-trans-l-buten-l-yl)cyclopent-la~yl~acetic acid, y-
lactone ~
~4 To a solution of 2-[3a-~-phenylbenzoyloxy-5~-
hydroxy-2~-(3-oxo-4-phenoxy-trans-1-buten-1-yl)~yclopent~
yl]acetic acid, y-lactone coole~ to -78 in ether-THF, is
added dropwise one equivalent of 2N solution o ~ethyl lithium
in ether. After stirring at -78 for 15 minutes the reaction
is quenched by addition of glacial acetic acid, sufficient to
brin~ p~I up to 7. The mixture is diluted with methylene
chloride, washed with water, saturated brine, dried ~Na2S04)
and concentrated to give the oily epimeric alcohols~ The
crude product is purified by column chromatography ~n silica
gel to give the desired 2-[3a-~-phenylbenæyloxy-5~-hydroxy-
2B-(3-hydroxy-3-methyl-4-phenoxy-trans-1-buten-1-yl)cyclopent-
l~-yl]acetic acid, y-lactone, which may be converted ~o give
17 and 17' through steps previously outlined for the prepara-
*Tra~emark
~7 ,~ ~
.
3~
36--
tion of 9-oxo-lla,15~-dihydxoxy-:l6--phenoxy-_s~5-trans-13-~-
tetranorprostadienoic acid.
EXAMPLE XVII
9~ ,15a-Trihydroxy-16-phenoxy-5-cis-13~tran~ tekranor-
S ~rostadienoic acid
To a solution of 50 mg. of 9-oxo~lla,15a-dihydroxy-
16-phenoxy-cis-5-trans-13-~-tetranor-prostadienoio acid in
2.5 ml. absolute methanol cooled to 0 i6 added dropwise a
solution of 25 mg. of sodium borohydride in 1 ml. absolute
methanol. The reaction mixture is s~irred under nitrogen at
~ for 2 hours and then concentrated. The residue is dis-
solved in methylene chloride, washed with brine, dried
(Na2S04), an~ is concentrated. Purification of the crud~
product by silica gel chromatography affords 16-phenoxy-P~
and the desired 9~,11a,15~-trihydroxy 16-phenoxy-5-cis-13-
trans-~-tetranorprostadienoio acid.
EXAMP~E XVIII
2-[3a ~-Ph~nylbenzyloxy-s~-hydroxy-2B-t3~-hydroxy-4-phenoxy-
but-l-yl)cyclopent-la-y~acetic acid~ y-lactone _ _
2~ ~ heterogenous solution of 2.5 g. of ~-~3~-~-phenyl-
benæoyloxy-5~-hydroxy-2~-t3a-hydroxy-4-phenoxy-trans-1-~uten-
l-yl~cyclopent-la-yl~acetic acid, ~-lactone and 0.25 g. of
5% palladium-on-charcoal in 30 ml. of absolute methanol is
stirred under 1 atmosphere of hydrogen for 4 hours. The mix-
ture is then filtered and concentrated to afford 2-[3a-~-
phenylbenzoyloxy-5a-hydroxy-2~-(3-oxo-4-phenoxy-but~l-yl)
cyclop~nt~ yl]acetic aci~, y-lactone.
To a solution of 1.9 g~ of the crude hyd~ogenation
product above in 20 ml. of absolute methanol is added excess
3G sodium borohydride and the ~olution is stirred at room temp-
erature under nitrogen ~or 2 hours, and then concentrated~
The ~esidue is diluted with 0.1 N hydrochloric acid and the
aqu~ous layer is extracted with ethyl acetate. The combined
organic extract6 are wa~hed with saturated brine, are dried
(Na2S04) f and are concentrated~ Purification of the crude
residue by silica gel chromatography af~ords 2-~3~-~-phenyl-
benzyloxy-5~-hydroxy-2~-l3~-hydr~xy-4-phenoxy-but-1-yl)cyclo-
pent~ yl]acetic aoid, ~-lac~one and the 3~-hydroxy epimer.
c~
. ~ .:. . ~. '
,:
.
: : . . : ., .:: i ..
, : :, -.. - :
: ; . ,.
-37-
This is conveLted to the 13,14~dihydro E2 and F~
compounds using methods ~nployed in Examples V throuyh IX
ExAMæLE XIX
_ _
9~-Hydroxy-lla,15~-bis-~tetrahydropyran-2 yloxy~ 16-phenoxy-
13-trans-~-tetranorprostenoic acid
A heterogeneous mixture of 800 mg. of 9~hydroxy-
lla,lS~bis-~tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-
13-~-tetranorprostadienoic acid and 80 mg. o~ 5% palladium-
on-charcoal in 10 ml. of absolute methanol is stirred under 1
atmosphere cf hydrogen at -22 f~r 5 hours. The mixture is
then filtered and the filtra~e is conoentrated to afford 9~-
hydroxy-lla,15~bis-~tetrahydropyran-2-yloxy)-16-phenoxy-13-
trans-~-tetranorprostenoic acid.
Hydrolysis with acetic acid and water in the usual
15 manner affor~s 16-phenoxy PGFl~.
EXAMPLE XX
9-~xo-lla,15a-dihydroxy-16-phenoxy-13-trans-~-tetranorpros-
t~noic acicl
_ _ ~_ _ _ _ __ __ _ _ __._
~ solution of 72 mg. 9-oxo-ll~,lS~-dihydroxy-16-
phenoxy-cls-S-trans-13-~-tetran~r-prostadienoic acid in 5 ml.
of anhydrous ether is treated with 450 mg. dimethylisopropyl
chlorosilane and 36 mg. of triethylamine at room temperature
und~r nitrogen for 48 hours. The reaction mixture i~ cooled
to 0, methanol is added, and the resulting solution is wa~h-
ed with water, drie~ (Na2SO4~, an~ is concentrated. Theresidue is di~-~olved in methanol ~6 ml.) and 3~ mg. of 5~
palladium-on-charcoal is added. The resulting mixture is
stirre~ at -22 under 1 atmo~phere of hydrogen for 4 hours.
After filtration and concentration of the filtrate, the
residue is stirred with a 65:35 mixture o acetic acid:water
for 10 minutes at room temperature. The mixture is diluted
with water, extracted with ethyl acetate, dried (Na~SO4~ and
concentrated to afford, a~ter purification by silica gel
chromatography, 9-Qxo-lla,15a-dihydroxy-16-phenoxy-13-trans-
~-tetranorprostenoic acid.
E~AMPLE XXI
A mixture of 5-bromovaler~nitrile ~16.2 g., 0 10
m~le), triphenylphosphine ~26.2 g., ~.10 mole~ and toluene
..
- ~ , . ..
-38-
(100 ml.) was heated to reflux with stir.ri.ng under nitroy~n
for 16 hours. The xesulting thick white suspension wa~ cool-
ed to room temperature and filtered. The residue ~7as washed
with benzene and air dried to give 33.~ g. of a white,
crystalline solid, m~p. 230-232~, which was 4-cyanobutyltrl-
phenylphosphonium bromide.
Anal.
_._
Calc~d for c23H23BrNp: C, 65.10; ~, 5.47; N, 3-30
Found: ~, 65.01; H, 5.40; N7 3.19.
A mixture of the phosphonium salt above ~10.0 g.,
23.5 ~moles), ammonium chloride (1.60 g,, 30.0 mmoles~,
lithium chloride (0.032 gO, 0.76 mmole), so~ium azide ~1.91
g., 29.3 mmoles~, and dimethylformamide ~50 ml.) was heated
to 127 ~oil bath) under nitrogen with stirring ~or 18 hours.
The re ulting suspension was cooled and filtered. The residue
wa~ washed with dimethylformamide and the combined filtrate
and wa~hin~s were concentrated ~aspirator pressure, ca~ 45).
The oily residue was crystallized from water at 0 and air
dried to give a white crystalline solid (8.11 ~.~, m.p. 100-
2~ 10~o The product was recry~ta}lized from methanol-ether to
give white prisms (7.18 g~). M.P. 197-206. An analytical
sample was prepared by recrystallization from 2-propanol to
give a white crystalline powder, m.p, 212-213, which was
4~(tetrazol-5-yl)butyltriphenylpho~phonium bromide.
25 Anal.
Calc'd for C23H24~PBr: C, 59.10; H, 5.17; N, 11.99
P, 6.63; Br, 17~09
Found: C, 59.35: H, 5.28; N, 12,31;
P, 6.78; Br, 17.26.
EXAMPLE XXII
l-~Tetrazol-5-yl) 9~-hydroxy-lla,15~-bis-~tetrahydropyran-2-
yloxy)-16-phenoxy-cis-5-trans-13~-tetranarprostadiene
To a solution of 4-~tetrazol-5-yl)butyltriphenyl
phosphonium bromide tl.49 gm.) in a dry nitrogen atmospher0
in 6.0 ml. dry DMSO is added 3.24 ml, of a 2.0 M solution of
sodium methylsulfinylmethide in DMSO. To this solution is
added dropwise a solution of ~15 mg. 2-~5~-hydroxy-3~-(tetra-
hydropyran~2-yloxy) 2~-~3~-tetrahydropyran-2-yloxy-4-phenoxy-
: `
. ~ .
:: :
'` ; :: ` '' ~ :
~ : :. ,. ,,: .,
. ~ : . : : . . " i ' .
51~3~
-39-
trans-l~buten-1 yl)cycl~pent-lu-y.lJacetaldehyde~ ~hem1acekal
in 5.0 ml. dry DMSO over a perio~ of 20 minutes. After an
additional 2 hours stirrin~ at room temperature the reackion
mixture is poured onto ice water. The basic aqueous solution
is acidifie~ with O.lN ~Cl and extracted with ethyl acetats.
The residue obtained after evaporation of the sol~ent is
chromatograph~d, to give pure l-~tetrazol-5-yl) 9~-hydroxy-
lla,15a-bis-~tetrahydropyran-2-yloxy~-16-phenoxy-cis-5-trans-
13-~-tetran~rprosta~iene.
EXAMPLE XXIII
~4-~Methanesulfonylaminocarbonyl)butyl~triphenylphosphonium
bromide
A mixture of 0.950 g. ~0.01 mole) of methanesulfon-
amide an~ 1.80 y. (0.01 mole) of 5-bromovaleric acid chloride
was heated on a steam bath u~til gas evolution ceased (ca.
5 minutes). The brown reaction mixture was allowed to cool
and was dissolved in me~hylene chloride. The methylene
chloride solution was trea~ed with Darco, was ~iltered, and
was diluted with hexane with cooling to afford the white,
cry6talllne N-methanesulfonyl-5-bromovaleramide we~ghing 2.22
g . ~86 . ~% yield) which melted at 88-89.
The nmr spectrum ~CDC133 sho~ed a broad singlet at
4.26-3.95~ for the N-H, a multiplet at 3 66-3.23 ~or the
-CH2Br~ a singlet at 3.31~ for the SO2-C~3, a multiplet at
2.63-2.20~ for th~ -OEI2CO, and a multiplet at 2.12-1.52~ or
the CH2-CH2. The ir spectrum ~C~C13~ showed a strong absorp-
tion at 1720 cm 1 attributable t~ the carbonyl group.
A solution of 2.20 g. ~8.57 mmoles~ of the N-
methan sulf~nyl-5-bromovaleramide, prepared as above, 2.24 g~
~8.57 mmoles) of triphenylphosphine, and 20 ml. o~ aceto-
nitrile was heated to reflux u~der nitroyen overnight. The
s~lution was then concentrated by rGtary evaporation and the
r~ultant so~id was triturated with hot benzene (4x~. The
triturated solid was recrystallized from absolute ethanol:-
ether to afford the white, crystalline [4-~methan~sulfonyl-
aminocarbonyl)butyl~triphenylphosphonium bromide weighing
2.80 g. (63.7% yield) melting at 190-191.
. ~:
. . ~ . .
~01~5~33~
-40-
The ir spectrum ~KBr) of the product exhibited a
strong absorption at 5.85 ~ attributable to the car~onyl
group. The nmr spectrum (CDC13~ exhibited a complex multi-
plet at 8.14-7.27~ for the aromatic proton~, a multiplet at
4.00-3.30~ for the -CH2P, a singlet at 3.12~ for the -SO2CH3,
a multiplet at 3.00-2.38~ for the CH2CO, and a multiplet at
2.23-1.38~ for the CH2CH2. A titration of the solid product
indicated the pKa 1/2 to be 5.25.
EXAMPLE XXIV
~-Biphenyl 9-oxo~ ,15~-dihydroxy-16-phenoxy~cis-5-trans-
To a soluti~n of 50 mg. (0.13 mmole) of 9-oxo-
110~,15~-dihydroxy-16-phenoxy-cls-5-trans-13-~-tetranorprosta-
dienoic acid and 63 mg. (0.4 mmole) of ~-phenylph~nol in 10
ml. of dry methylene chloride w~s added 825 mg. (0.4 mmole~
of dicyalohexylca~bodiimide and the solution stirred over-
night at room temperature. After concentration, the crude
pro~uct was puri~ied by silica gel chromatography to give
the desired ~-biphenyl ester, m.p. 100-102.
Anal.
~` CalC`d f~ C36~366
Found: C, 75.65, H, 6.83.
EXAMPLE XXV
~-Biphenyl 9~ ,15~-trihydroxy-16-phenoxy-c~s~5-trans~13
w-tetranor-prostadienoate
To a solution of 106 mg. of 9~ ,15a-trihydroxy-
16 phenoxy-cis 5-trans-13-~-tetranorprostadienoic acid and
189 mg. of ~-phenylphen~l in 30 ml. dry methylene chloride
was added 600 mg. ~f dicyclohexylcarbodiimide and the solu~
; 3~ tion stirred overnight at room temperature. After concen~ra-
tion, the crude product was purified by silica gel chroma-
tography to give ~0 mg. pure ~biphenyl ester, m.p. 101-103.
Anal
Calc d for C34H386 C,
Found: C, 75.38; H, 7.30O
,.
: .
: . ....
.
.. ';.
: ' :
3~
-41-
EXAMPLE_XXVI
Phenethyl 9-oxo~ ,15a-dihydroxyl-16-phenoxy-cis~5-trans-13-
A mi~ture of O-phenethyl-N,N'-dicyclohexyl-isourea,
prepared by reacting phenethyl alcohol and dicyclohexylcarbo-
diimide, and 9-oxo-11,15-dihydroxy-16-phenoxy-cis-5-trans-13-
~-tetranorprostadienoic acid in methylene chloride and di-
methylformamide i~ stirred overnight at room temperatureO
After filtratio~, concentration and chromatography on silica
10 g~l the pure phenethyl ~ter is obtained. ~-
In a similar fashion are prepared the benzyl,
cyclopropyl and oyalooctyl esters using benzyl alcohol,
cyclopropanol and cyclooctanol, respectively.
Methyl ~a,lla,15a-trihydroxy-16-phenoxy-cis~5-trans-13-~-
~ostadlenoate _ _ _
To an ethereal solution of 100 mg. of 9a,11~,15~-
trihydroxy-16-phenoxy-cls-5-trans-13-~-tetranorprostadienoic
acid i~ added an excess o~ etheraal diazomethane u~til a
yellow color persists. Concentration affords pure methyl
~ 9~ ,15~-trihydroxy-16~phenoxy cis-5-trans-13-~-tetranor-
: prostadienoate.
Similarly, u~ing diazodecane ~prepared by oxidation
of dodecyl hydrazone) is prepared dodecyl 9a,11u,15~-tri-
hydroxy-16-phenoxy-cis-5-trans-13-~-tetranorprostadienoate.
9~ a-Trihydroxy-16-ph~noxy-ci~-5-trans-13-~-tetranor-
prostadienoic acid tris-hydroxyme~h~lamino methane salt
To a solution of 0.70 mmole o 9~,11a,15~-trihydr-
oxy-16-phenoxy-cis-5-t~ans-13-~-tetranorprostadienoic acid
in 35 ml. o~ dry acetonitrile, heated at 80 is added a solu-
tion of 86 mg. ~0.68 mmole) o~ tris-hydroxymethylaminomethane
in 0.15 ml. of wa~er with vigorous stirring. The mixture ~s
allowed to cool to room temperature and q~,lla,l5~-trihydroxy-
3S 16-ph~noxy-cis-5-trans-13-~-tetranorprostadienoic acid tris-
hydxoxymethylamino methane salt is collected.
~'
3 !L
-~2-
EXA XXI
9-Oxo~ ,15~-bisformyloxy-16-phenoxy~cis-5-tran~-13-~-tetra-
nor~rostadienoic acid
To a solution of 0.1 mmole of 9-oxo-11~,15~-di-
hy~roxy-16-phenoxy-ois-5~trans-13-~-tetranorprostadienoic
aoid in 0.5 ml. of dry ~ekrahydrofuran is addad 29 mg. ~.33
mmole) of formic acetic anhydride and 35 mg. ~0.33 mmole) of
2,6-lutidine. The solution is stirred for 1 hour under
~itrogen at room temperature then 36 mg. of water is added.
19 The mix~ure i~ stirred at room temperature for additional one
hour and diluted ~ith ethyl acetate. The diluted solution
is washed with O.lN HCl, ~ater and brine, then dried ~Na2S04).
Chromatography of the crude product on silica gel affords
the desired bisformyloxy compound.
: 15 Exa~pLE XXX
9B~ l5a-Tri6pivaloyloxy-l6-phenoxy cis-5-trans-13-~-tetra-
norpro~tadi noic ~cid _ _ _
To a solution of O.2 mmole of 9B,11~,15a-trihydroxy-
16-phenoxy-cis-5-trans-13-~-tetran~rprostadienoic acid in 1
ml. of pyridine is added 120 mg. ~1.0 mmole) of pivaloyl
chloride. The solution is stirred 4 hours at 45 under
~; nitrogen then is cooled to room temperature. Water ~40 mg,)
is added and the mixture stirred 2 hours at r~om temperature
and diluted with ethylaaetate. The diluted solution is
wa hed with dilute HCl, water an~ then brina. Concentration
and puri~ication by chromatography on silioa gel ga~e t~e
desired trispivaloylo~y acid.
EX~MPLE XXXI
l-~Tetrazol-5-yl)-9a-hy~roxy-11~,15a-bi~-(tetrahydropyran-2-
yloxy) 16-phenoxy-cis-5-trans-13-~--tetranorprostadiene
To a solution of 4-(tetrazol-5-yl)butyltriphenyl
phosphonium bromide (1.49 g.) in a dry nitrogen atmosphere
in 6.0 ml~ dry DMSO was added 3.24 mlO of a 2.0M solution of
sodium methylsulfinylmethide in DMSO. To this solution was
added dropwise a solution of 615 mg. 2-~5~ hydroxy-3~-(tetra-
h~dropyran-2-yloxy)-2B-(3a-~tetrahydropyran 2-yloxy)-4-phen-
oxy-trans-l-buten-l-yl)cyclopent~ yl]ace aldehyde, y-hemi-
__
acetal in 5.0 ml. dry DMSO over a period of 20 minutes~ After
3E .
.
.` ' .
. . : ..
. ... .. ::. .. ;
5~
-43
an additional 2 houx stirrlng ak room ternperature, the re~
action mixture ~as poured onto ice ~ater. The basic aqueous
solution was acidi~ied with ~.lN HCl and extxacted with ethyl
acetate, ~he residue obtained after evaporation of the solv-
ent ~as chromatographed to give 680 mg, pure colorless oilyl-(tetraæol-5-yl)-9a-hydroxy-lla,15a-bls-^ttetrahydropyran-2-
yloxy~-16-phenoxy-cis-5-tran~-13-~-tetranorprostadiene.
ExAMæ~E XXXII
l-(Tetrazol-5-yl)-9~,lla,15~-trihydroxy-16-phenox~-cis-5-
t~ans~l3-~-tçtranorprostadiene
A solution o~ 300 mg. 1 (tetrazol-$-yl~-9~-hydroxy-
lla t 15a-bisttetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-
13-~-tetranor-prostadiene in 6 ml. of 65:35 mixture of
glacial acetic acid:water was stirred under nitrogen at 25
lS for 18 hour~ and then was concentrated by rotary evaporation.
The resultant crude oil was ~urif ied by column chromatography
on silica gel (Mallinckrodt CC-7, 100-200 mesh) using mix-
`~ tures of chloroform:ethyl acetate as eluant. A~ter elution
of less p~lar impurities the colorless, oily l~ttetrazol-5-yl)-
20 9a,11~,15a-trihydroxy-16-phenoxy-cls-5-trans-13- -tetranor-
prostadiene weighing 220 mg. ~80% yield) was collected.
EXAMPLE XXXI I I
l-~Tetrazol-5~yl)-9-oxo-lla,15a-~is-~tetrahydropyran-2-yloxy)-
16-phenoxy-cis-5-trans-13-~-tetranorprostadiene
To a solution cooled to -15 under nitrogen, ~f
600 mg, 1-~tetrazol-5-yl)-9a-hyd~oxy-lla,15a-bls-(tetrahydrQ-
pyran~2-yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorprosta-
diene in 12 ml. reagent grade acetone ~as added dropwi~a 0,6
ml, of Jones' reagent. After 30 minutes at 10, 0,6 ml.
2-propanol was added and the reaction mixture was allo~ed to
stir at additional 5 minutes at which time it was combined
with 75 ml~ ethyl acetate, washed with water t3 x 10 ml,~,
dried ~Na2$O4) and ~oncentrated to give 510 mg. o~ the color-
less, oily l-(tetrazol 5-yl)-9-oxo-lla,15a-bls-(tetr~hydro-
pyran-2-yloxy)-16-phenoxy-cls~5-trans-13-~-tetranorprosta-
diene.
.
~5~3~
--~4--
EXANPLE XXXI~7
l-(Tetrazol-5-yl)-9-oxo~ /15a-dihydroxy~16-phenoxy-cis-5-
trans-13-~-tetranorproætadiene
A solution of 508 mg. 1-~tetrazol-5-yl~-9-oxo-
11~,15a-bls-(tetrahydropyran-2-yloxy~16-phenoxy-cis-5-trans-
13-~-tetranorpro$tadiene in 10 ml~ of a 65:35 mixture of
glaaial acetic acid:water was stirred under nitrog~n at 25
for 20 hours and then was concentrated ~y rotary evaporation.
The resultant crude oil was puriied by column chromatography
on silica gel (Mallinckrodt* CC-7 100~290 mesh~ using mix-
tures of chloroform:ethyl a~etate as eluants. After elution
of le~s p~lar impurities ~he colorless oily l-~tetrazol-5-
yl)-9~oxo-lla,15a-dihyd~oxy-16-phenoxy-cis-5-trans-13-~-
tetranorpro$ta~iene weighing 240 mg. was obtained.
EXAMPL~ XXXV
N-Methanesulfonyl-9~-hydroxy-11~,15~-bis-(tetrahydropyran-2
yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorprostadienamide
To a solution of 1O7 g. ~4-methanesulfonylamino-
carbonyl)-butyl~triphenylpho6phonium bromide in a dry nitro-
gen atmosphere in 6.0 ml. dry DMSO was added 3.2 ml. ~6O5mmole) of a 2.0 M solution of sodium methylsulfinylmethide
in DMSO. To this red ylid solution was added drop~ise a
solution of 610 mg. ~.29 mmole) 2-~5a-hydroxy-3~-(tetra-
hydropyran-2-yloxy~-2~-~3~-ttetrahydropyran-2-yloxy)-4-phen-
oxy-trans-l-buten-l-yl)cycIopent~ ylJacetaldehyde; y-heml-
acetal in 5 ml. dry D~SO over a period of 20 minutes. After
an ad~itional 2 hour stirring at room temperature, the re-
action mixtuxe poured onto ice water. The basic aqueous
s~lution ~as washed twice with ~thyl acetate t3 x 20 ml.)
and combined organic extracts washed once with water ~10 ml.),
dried ~Na2SO4~ and evaporated to an oil. Chromatography on
silica gel afforded 684 mg. pure oily N-methanesulonyl-9~-
hydroxy-11~,15~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-
5-trans~13-~-tetranorprostadienamide.
EX2~MPLE XXXVI
N-Methanesulfonyl-9a,11~,15~-trihydroxy-16-phenoxy-cls-5-
trans-13-~-tetranorprostadienamide
A solution of 250 mg~ in 5 ml. of 65:35 mixture of
*Trademark
,~,,p
,
.. ~ '' "'~'' .
:: .. : ~:
;;
S83~ (
,. ,,,
-45-
glacial acetic acid:water was stirred under nitrogen at 25
for 18 hours and then was concentrated to a crude oil, which
was purified by column chromatography on silica gel
I (Mallinckrodt* CC-7~ 100-200 mesh~ using mixtures of chloro-
form:ethyl acetate as eluants. After elution of less polar
impurities the colorless oily N-methanesulfonyl-9a,11a,15a-
trihydroxy-16-phenoxy-cls-5-trans-13-~-tetranorprostadien-
amide weighing 180 mg. was collected. The product was shown
to be homogeneous by liquid-liquid chromatography.
EXAMPLE XXXVII
N-Methanesulfonyl 9~oxo-lla,15a-bis-(tetrahydropyran-2-yloxy)-
16-phenoxy-cis-5-trans-13-~-tetranorprostadieA-~id~
To a solution cooled to -10~ under nitrogen, of
400 mg. in 8 ml. reagent grade acetone was added dropwise
0.4 ml. of Jones' reagent. After 30 minutes at -10, 0.4 ml.
2-propanol was added and the reaction mixture was allowed to
stir a~ additional 5 minutes at which time it ~as combined
with 60 ml. ethyl acetate, washed with water (3 x 10 ml.),
dried ~Na2SO4) and concentrated to afford 380 mg. of the
colorless oily N-methanesulfonyl-9-oxo-lla,15~-bis-(tetra-
hydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorpros-
tadienamide.
EXAMPLE XXXVIII
N-Methanesulfonyl-9-oxO~ ,15~-bis-dihydroxy-16-phenoxy-cis-
5-trans-13-~-tetranorprostadienamide -
A solution of 260 mg. in 6 ml. of a 65:35 mixtureof glacial acetic acid:water was stirred under nitrogen at
25 for 20 hours and then was concentrated to a crude oil
which was purified by column chromatography on silica gel
(Mallinckrodt* CC-7, 100-200 mesh) using mixtures of chloro-
form:ethyl acetate as eluants. After elution of less polar
impurit~es the colorless N-methanesulfonyl-9-oxo-ll~,lSa-
bis-dihydroxy-16-phenoxy-cis-5-trans-13-~-tetranorprostadien-
amide weighing 130 mg. was obtained. The product crystalliz-
ed from ether as colorless crystals, m.p. 76
*Trademark
. - : . .: . , :
~6-
EXAMPLE XXXIX
__
9Br~l5a-Trihydroxy 16-phenoxy-c -5-trans-13- -tetranor-
~roskadienoic acid
To a stirred solution of 0ql8 g. (0.47 mmole) 9-oxo-
11~,15~-dihydroxy-16-phenoxy-cls-5-trans-13-~-tetranorprosta-
dienoic acid in MeO~ (20 ml.) at 0 was added a cold solution
of 0.06 g. NaB~4 in MeOE (10 ml.). After 1 hour at 0, the
reaction was quenched by addition of water (4 ml.) and con-
centrated under reduced pressure. The residue was acidified
with 10% HCl to p~ 3, extracted with ethyl acetate, dried
(Na2SO4) and concentrated. Chromatography on 20 g. silica
gel (CC-7*) and elution with methanol-benzene afforded pure
9~,11a,15~-trihydroxy-16-phenoxy-cis-5-trans-13-~-tetranor-
prostadienoic acid, as a colorless oil, homogenous on t.l.c.,
rf 0.25 (C6H6-dioxan-HCO2H, 15;5~
ExAMæLE XL
N-Benzoyl 9-oxo-lla,15a-dihydroxy-5-cls-13-trans-16-phenoxy-
~-tetranorprostadienamide
To lo0 mmole of 9-oxo-11~,15a-bis-~tetrahydropyran-
2-yl-oxy)-16-phenoxy-cis-5-trans-13-~-tetranorprostadienoic
acid (Example VIII) in 40 ml. THF is added 2 ml. triethyl-
amine. After 15 minutes of stirring at room temperature
10.0 ml. of 0.1 molar benzoylisocyanate in T~F is added.
After a further hour of stirring, the reaction mixture iB
neutrali~e~ with acetic acid and the solvent removed by
evaporation (ln vacuo). The resultant residue is taken up in
methylene chloride and washed successively with water and
sodium bicarbonate to yield, after drying and solvent evapora-
tion, N-benzoyl 9-oxo-lla,lSa-bis-(tetrahydropyran-2-yloxy)-
30 16-phenoxy-cis-5-trans-13-~-tetranorprostadienamide. This
intermediate i5 then hydrolyzed overnight wi~h acetic acid/-
water (as in Example IX) and purified by column chromatography
to give the desired N-benzoyl-9-oxo-ll,lS~-dihydroxy-S-cis-
13-trans-16-phenoxy~-tetranorprostadi~namide.
EXAMPLE X~I
N-Methanesulfonyl ~-oxo~ ,15a-dihydroxy-5-cis-13-trans-16
phenoxy-~-tetranorprostadienamide
_ _
To 1.0 mmole of 9-oxo-lla,15~-bis-(tetrahydropyran-
*Trademark
~i , .......... ...
~: , : . : , . .
33~ .
-47-
2-yl-oxy~-16-phenoxy-cis-5-trans 13-~-tetranorprostadienoic
acid ~Example VIII~ in 40 ml. THF is added 2 ml. triethyl-
amine~ After 15 minutes of stirring at room temperature 10.0
ml. of 0.1 molar methanesulfonylisocyanate in THF is added.
After a further hour of stirring, th~ reaction mixture is
neutralized with acetic acid and the solvent removed by
evaporation (in vacuo~ The resultant residue is taken up
in methylene chlorine and washed successively with water and
sodium bicarbonate to yield, after drying and solvent evapor-
ation, N-methanesulfonyl 9-oxo~ ,15~-bis-~tetrahydropyran-
2-yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorprostadienamide.
This intermediate is then hydrolyzed overnight with acetic
acid/water (as in Example IX) and purified by column chroma-
tography to give the desired N-methanesulfonyl 9-oxo~ ,15a-
dihydroxy-5-cls-13-trans-16-phenoxy-~-tetranorprostadienamide.
EX~MPLE XLI I
N-Acetyl-9a-hydroxy-lla,15a-biS-~tetrahydropyran-2-yloxy~-16-
phenoxy-cis-5-trans-13-~-tetranor-prostadienamide
To a solution of 5.32 gO t4-(acetamido carbonyl) -
butyl]triphenyl phosphonium bromide in a dry nitrogen atmo-
sphere in 1~ ml. ary DMSO was adde~ 17.7 ml. of a 2.0 M solu-
tion of sodium methylsulfinyl methicle in DMSO. To this red
ylid solution was added dropwise a solution of 0.524 g. ~1.1
mmoles) 2-t5~-hydroxy-3a-(tetrahydropyran-2-yl~xy)-2B-~3~
~tetrahydropyran-2-yloxy)-4-phenoxy-trans-1-buten-1-yl)cyclo-
pent-l~-yl]acetaldehyde, y-hemiacetal in 10 ml. dry DMSO
over a period of 20 minutes. After an additional 2 hours
stirring, at room temperature, the reaction mixture was poured
onto ice water. The basic aqueous solution was washed twice
with ethyl acetate (3 x 25 ml.) and combined organic extracts
washed once with water (10 ml.), dried (Na2SO4) and evaporat-
ed to an oil. Chromatography on silica gel afforded 0.66 gm.
pure oily N-acetyl-9~-hydroxy-11,15~-bis-(tetrahydropyran-2-
yloxy)-16-phenoxy cis-5-trans-13-~-tetranorprostadienamideD
EXAMPLE XLIII
I
N-Acetyl-9a,11a,15~-trihydroxy-16-phenoxy-cis-5-trans-13-~- 1
tetranor~rostadienamide
A solution of 0.39 g. of N-acetyl-9a-hydroxy-11,15~-
i
~ '. '. ;. ' .
-~8-
bis-(tetrahydropyran-2-yloxy~-16-phenoxy-cis-5-trans-13-~-
tetranorprostadienamide in 5 ml~ of 65:35 mixture o~ glacial
acetic acid:water was stirred under nitrogen at 25 or 18
hours and then was concentrated to a crude oil, ~hich was
puxified by column chromatography on silica gel (CC-7*~,
using mixtures of chloroform:ethyl acetate as eluant. After
elution of less polar impurities the colorless oil N-acetyl-
9a,11a,15~-trihydrox~-16-phenoxy-cis-5-trans-13-~-tetranor-
prostadienamide weighing 95 mg. was collected.
EXI~IPLE XLIV
N-Acetyl-9-oxo~ ,15a-bis-~tetrahydropyran-2-yloxy)-16-phen-
oxy-cis-5-trans-13-~-tetranorprostadienamide
_ _ _
To a solution cooled to -1~ under nitrogen, of
394 mg. N-acetyl-9awhydroxy~ ,15a-bis-~tetrahydropyran-2-
yloxy)-16 phenoxy-cls-5-trans-13-~-tetranorprostadienamide
in 1~ ml. reagent grade acetone was added dropwise 0.27 ml
of Jones' reagent. After 30 minutes at -10, 0.4 ml. 2-
propanol was added and the reaction mixture was allowed to
stir an additional 5 minutes at which time it was combined
with 60 ml. ethyl acetate, washed with water t3 x 10 ml.),
~ried ~Na2S04~ and concentrated to afford 390 mg. of color-
less oily N-acetyl 9-oxo~ ,15~-bls-~tetrahydropyran-2-yloxy)-
16-phenoxy-c~s-5-trans-13-~ tetranorprostadienamide.
EXAMPLE_XLV
N-Acetyl-9-oxo-lla~15a-bls-dihydroxy-16-phenoxy-cls-5-trans-
13-~tetranorprostadienamlde
_ _
A solution of 390 mg. of N-acetyl 9-oxo~ ,15a-
bls (tetrahydrc~pyran-2-yloxy~-16-phenoxy-cis-5-trans-13-~-
tetranorprostadienamide in 8 ml. of a 65:35 mixture of glacial
acetic acid:water was stirred under nitrogen at 25 for 20
h~urs and then was concentrated to a crude oil which was
purified by column chromatography on silica gel using mix-
tures of chloroform ethyl acetate as eluants. After elution
of less polar imp~ritiPs the colorless oily N-acetyl-9-oxo-
lla,15a-bis-dihydroxy-16-phenoxy-cls~5-trans-13-~-tetranor-
prostadienamide weighing 76 mg.
*Trademark
~1
,~
.. ,: :
' `.: ''''` ~ .
~L~135i~
-S.D. 49-
SUPPLEMENTAR~ DISCLOSURE
. ~
F
R ~: R ~:
,4 aJ R
I ~ 3 ~ N ~ O ~¦UN~ N
~1 U~ ~ m o u~ o ~ a~ ~ t) O -- ~ ~ t) O
D s-l¦ U O ~ O 'O a~ ~ tg
1 ~ _, _
O orl U~ rl O rl 1~ ~1 ~ O ~ O O U~ In o 1` ~ a~ D O
Q H ~1 ~) H _i ~n H Ul ~-1 H U~ _I æ 1~ u- ~ ~ z r~ ~ z; ,~ u~ u~
.~
~ ~q 31 ~ I ~ I h
U ~ o
Q, ~ ~ R ~:
o ~ 31 O ,~ o 3
~ ~ X
~Q I
::Ql X
s:: ~ ~ O O O O O O O O
o ~ ~ q, ~, ~ 4~ R
h
~1 ~ ~ ~Q ~ 0 u tn ~ ~n U ~n
X
R o ~ R ~ ~ ,¢ ~ ~ X
~ ~ ~ ~ o ~ ~ ~P~ ~ o
~ ~ ~
~ ~; Z ~1 z rd z ~: z O z ~
.. ,, ' ::; . , .
35~3~
-S.D. 50-
`: SUPPLEME~TARY DISCL :)SURE
:
~ o
o
o
O ~ Q
U ,4 U ,~ h ~:
l~ ~ o o o oQ~ O d O
O ~ d m ~ ~ .4~ I ~ ~ ~ O .4
a~ ~o ~ ~ ~ ~ ~
~1 0 ~ 5~ rl ~ ~ ~1~ ~1 ~ ~ ~1 ~ ~
ra ~ c) O ~I R ~I Q ~ ~ o 53
U~ V ~ C) ~
1 ~ o P:: o 5~ s~ o ~ o 5~ ~ o
~ ~.~ o ~ O
a ~ _i ~ ,, O ~ ,, ~ ~ ,
0~ 1`001 1 ~ ~ I ~ I ~ ~ I ~ ~ I _J ~
o h ~ ~3 ~ h ~ 13
0 , , o ~ ~ ~ ~ t) ,1 ~ U ~ O ,
t) I` ~ O ~ ,1 o,1 rl O ~ rl O
U:l Z 1` U~ Zt` ls) u7 t~J H r-l cn 1-1 Cl~ n H ~ H ~1 a~-
D ~ X ~ X
~ o s ~
~ o
I ~ ,¢ n~ N
, ~ 8
-- ~ ~ X ^ ~ 31 O
O ~1 o I ~:
:
~ ~ W~
In S~ O
I ~ 0
,~ o 1 ~ 1 0 a
o ~ ~ ~ ~ o ~ ~
N ~ N I ~ 31
d ~1 1 0 ~ d 31 1 1
I
X
a~ c o
I ~1 0 ~ ~ O
31 ~ X
I I ~ ~ ~ o
_ o ~3 0 .Q
I ~ w t~ w k I ~ ~ w
~ O ~ X
o ~: m h u~ o ~ ,1~n
~1 ~U O o 0 ~
0 ~ ~ o ~ ~ ~ o
V ~ ~ ~ X N
u~ ~ o
h o o~
c~ m
~ I ~ I I I oI a~ II n~ I
Z ~ ~ ~z; 3 ~ Z ~:N ~
'~`
.. .. ... . . ..
; ~
~ 5~3~
-S.D. 51-
SUPPLEMENTARY DISCLOSURE
~1 ~ Q ~
o ~o
R
~ ~ ~ a
U o ~ ~ ~ ~ ~ ~ ~ ~
~ ~ 1~ P ~Z ~ R ~ ~A R
O ~ ~ Z; 11 ~ ~ ~nlU ~ o a) ,~ o
~ ~ ~ I Z S~ S~ r~ n,~
,_ ~ ~ o Z;~ t)l U ~1 ~ V ~ } U ~I Q
~1 1 1 I P3 ~ ~ O ~ U O ::~ V O ~ O
rd ~) VC~ Z V ~~ V ~ ~ ~
a ~ --. o -- o ~ o
E~ ,~
u~ o c~ o I I n~ tl5 I ~ I I ~I nl I
1~ ~ U h ~ ~ ~ ~ ~ V
h ~ 1 0
O O ~r) O O O O ~ 10 ~ rl O
O ~ c~ ~ O O O
U~ ~ 1 Z I ~ H ~1 ~ H ~I c~ H ~
h
~0
h
I
31 $ ~' W
31 P ~4 ~ h
~ ~_ h ~
.¢ X ~ ~ 0
a
~1 ~ aJ a
I
0 31 31 31
~ ~ X ~ O
,~
N ~ ~ .¢ ~ ~
S~
r~
r~ ~ ~ 'I r~
~ ~ a.
~ 0~
~I ~ ~ 4~ r~
X ~ J 9Cr~ ~ r~
O Pi U~ O
e ,1 e ~ ~ ~ e
0 ~ ~ $ ~ x ~ x
tn ~ ~ ~ o a~ o ~ o
o s~ al ~ ~ R ,¢ ~ ~ ~
~ ~ ~ ,e ~
z ~ z ~ æU z~ æu æu
~ .
- , .. . . .. .
, ,, ;, . . . ..
. I .
-S.D. 52-
SUPPLEMENTARY DISCLOSURE
Thus, the present invention provides a process for
preparing a compound o~ the formula:
M
YJ~ ~~x
Q ~ `O-Ar
~O~ ...I
and the Cl5 epimer thereof; wherein Ar is phenyl or mono-
substituted phenyl wherein the substituent is halo, trifluoro-
methyl, lower alkyl or lower alkoxy; W is a single bon~ or
cls double bond; Z is a ~ingle bond or trans double bond; M
~ OH
is oxo, ~ or ~ ; Y and Q when taken together form
a single bond, or Q is ~-hydroxyl when Y is hydrogen; X is
tetrazolyl; a group of the formula -~-O-R' wherein R' is
hydrogen, alkyl of from l to 10 carbQn atoms, l~wer alkyl
phenyl or biphenyl, with the proviso that R' is lower alkyl
phenyl or blphenyl when W is a GiS double bond; and Q i~ ~-
hydroxyl; or a group of the ~ormula ~ R" wherein R" isalkanoyl of from 2 to 10 carbon atoms, aryoyl, alkylsulfonyl
o~ from l to 7 carbon atoms, or arylsulfonyl; and wherein M,
Y and Q axe so s~lecte~ as to complete the structure o~ a
prostaglandin of the A, E or F series, the lowex alkanoyl,
formyl or benzoyl esters of any free hydroxyl groups at the
Cg-, Cll- and Cl5-positions, and the pharmaceutically-accept-
able bases of the compounds wherein X is COOH~ which comprises:
~a) reacting a compound of the formula:
M
~ X
THPO~\ O-Ar
OTHP
, .',
. .
'', , ~
: : :.: .; . :
. : ,.:: :
i83~
S.D. 53~
wherein Ar, M, W, X and Z are as defined above and THP i8
2-tetrahydropyranyl, with a suitable acid, to form the de-
sired compound of Formula I, wherein Q is ~-hydroxy, Y is
h~drogen, and Ar, M, W, X and Z are as defined above;
~ b) reacting a compound of Formula I, above, ~herein
Q is a-hydroxy and Y is hydrogen, M is oxo and Ar, W, X and
Z are as defined above, with a suitable dehydrating agent,
to form the desired compound of Formula I wherein Q and Y
taken together form a single bond, M is oxo and Ar, ~, X
and Z are as defined above;
~ c) hydrogenating a compound of the Formula I, above,
wherein Q is a-hydroxy and Y is hydrogen, M i9 OXO, Ar, W,
X and Z are as defined above, to form the desired compound
of Formula I, wherein Q is a-hydroxy, Y is hydrogen, M is
H OH
~ or ~ and Ar, W and Z are as defined above, and,
if d~sired, separating the 9a- and 9B-isomers;
~ d) catalytically hyarogenating a compound of Formula
I, above, wherein Ar, M and X are as defined above, W is a
single bond or cis d~uble bond when Z is a trans double bond
and Z is a single bond when W is a cis double bond to form
the desired compound of Formula I wherein Q is a-hydxoxy, Y
is hydrogen, Ar, M and X are as defined above, and W an~ Z
are single bonds:
~e) selectively hydrogenating a aompound o~ Formula I,
ox the trialkylsilyl ester of a compound of Formula I,
wherein X is COO~, above, wherein Ar, X and M are as defined
above and W and Z are double bonds, to form the desired com-
pound of F~rmula I wherein Q is a-hydroxy, Y is hydrogen, Ar,
X and M are as defined above, W is a single bond and Z is a
trans double bond; and when required, converting those com-
pounds of Formula I wherein X is COO~ to esters or substi~ut-
ed amides, as defined above, by reaction with suitable
esterifying or amidating reagents, respectivPly, and, if de-
sired, preparing the 9~-, lla- and 15a-lower alkanoyl, formyl
or benzoyl esters of any free hydroxyl groups ~y reacting the
~3~
'' ' , ~
;' '
Si~3~
-S.~. 5~ -
compounds with the appropriate acylating agents, and, i~
desixed, preparing khe pharmaceutically acceptable salts of
those compounds wherein X is COOH.
The inventi~n also provides a process as described
above ~or pxeparing a compound of the formula:
OH
~ X
HO~` ~ O-Ar
~O~ ... IA
and the C15 epimer thereof; wherein Ar, W, Z and X are as
defined above, which comprises:
10~a) reacting a oompound of the formula:
IIH
`~ X
THPO`~ ~ O-Ar
~'OTEP ... IIA
wherein Ar, W, x, æ and THP are as de~ined above, with a
suitable acid;
~b) hydxogenating a compound o~ the formula:
x
15HO~I ~ O-Ar
OH ... IB
wherein Ar, W, X and Z are as defined above, and then sPpa-
rating the 9~- and 9~ mers;
~c) catalytically hydrogqnating a compound o~ the
Formula I~, above, wherein Ar, and X ar~ as defined above,
~ is a single bond or cls double bond when Z is a trans
double bond and Z is a single bond when W is a cls d~uble
bond, to form a comp~und o~ Formula IA, above, wherein Ar,
: ' '' .. ,
, . ..
3~
~ S.D. 55-
SUPPLEMENTARY DISCLOSURE
and X are as defined aboYe, and W and Z are single bonds;
td) selectively catalytically hydrogenating the di-
methylisopropylsilyl derivakive of a compound of Formula IA,
wherein X i~ COO~, Ar is as defined above, W is a Ci8 double
b~nd and Z is a trans double bond, to form a compound of
Formula IA, above wherein Ar is as defined above, W is a
single bond and Z is a trans double bond,
and when required, converting those compounds of
Formula IA wherein X is COOH to ester. or substituted amides
by reaction with suitable esteriying or amidating agents,
respectively; and, if desired, preparing the 9~ , and
~ ~lo~er alkanoyl, formyl or benzoyl esters of any free
hydro~yl groups by reacting the compound~ with the appropri-
ate acylating agents, and, if desired, preparing the pharma-
ceutically acceptable salts of those compounds wherein X is
COOH~
The invention further provides a process as des-
cribed above for preparing a compound of the formula:
~ x~
~O\ ~ O-Ar
"O~ c..IB
and the C15 epimer thereof; wherein Ar, W, X and Z ara as
de~ined above, whi~h comprises:
~ a) reacting a compound of the formula:
x
THPO~ Ar
OTHP ...II
wherein Ar, THP, W, X and Z are as defined above, with a
suitable acid;
~ b) catalytically hydrogenating a compound o~ Formula
IB, above, whexein Ar, and X are as defined above, W is a
~, ,.
' '' ''
~S~33~
-S.D. 56
5UPPLEMENTARY DISCLOSURE
single bond or cls double bond when Z is a trans double bond
and Z is a single bond when W is a cls dGuble bond, to
afford a compound o~ Formula IB wherein Ar, and X are as
defined above, and W and Z are single bonds;
(c) seleckively catalytically hydrogenating the di-
methylisopropylsilyl derivative of a compound o~ Formula IB,
wherein Ar and X are as defined above, ~ i9 a cl~ double
bond and Z is a trans double bond, to afford a compound of
Formula IB, above wherein Ar and X are as defined above, W
is a single bond and Z is a trans double bond;
and when required, converting those compounds of
Formula IB wherein X is COOH to esters or substituted amides
by reaction with suitable esterifying or amidating agents,
respectively; and, if desired, preparing the lower alkanoyl,
formyl or benzoyl esters of any free 11- and 15-hydroxyl
groups by reacting the compounds with th~ appropriate acylat-
ing agents, and, if desired, preparin~ the pharmaceutically
accepta~le salts of those compounds wherein X is COOH.
The invention still further provides a process as
described above for preparing a compound of the formula:
Il
t~~~X
Il I Z
O-Ax
OH ... IC
and the C15 epimer thereof; wherein ~r, ~, Z and X are as
defined above, which comprises reacting a compound of the
formula:
o
\X
HO` ~ , -Ar
OH ~..IB
with a suitable dehydrating agent; and, ~hen required, con-
verting t~ose compouncls of Formula IC wherein X is COOH to
~ 583~
-S.D. 57-
SUPPLEMENTARY DISCL05URE
esters or substituted amides, by reaction with suitable
esterifying or amidating reagents, respectively, and, i~
desired, preparing the C15-lower alkanoyl, formyl or benzoyl
ester by reacting the compound with an appropriate acylating
agent, and, if desired, preparing the pharmaceutically
accep~able salts of those aompounds wherein X is COOH.
The intermediate compound of the formula:
OH
~X
THPO~ ~ O-Ar
'OTHP ... IIA
and the C15 epimer thereof and the Cg and C15 epimers
thereof; wherein Ar is phenyl; or monosubstituted phenyl
wherein the substituent is halo, trifluoromethyl, lower alkyl,
or lower alkoxy; THP is 2-tetrahydropyranyl; W is a single
bond or c1s double bond; Z is a single bond or tran double
bond and X is tetrazolyI; a group of the formula q
-~ O-R'
wherein R' is hydrogen, alkyl of from 1 to 10 carbon atoms,
lower alkyl phenyl or biphenyl when ~ is a single bond and
R' is lower alkyl phenyl or biphenyl when R' is a cis double
bond; or a group of the formula R ~herein R" is
~~NHR"
alkanoyl of from 2 to 10 carbon atoms, aryoyl, alkylsulfonyl
of rom 1 to 7 carbon toms or arylsulfonyl~ may be prepared
by a process which comprises:
(a) reacting a compoun~ of the formula:
L 1 z
THPO~ -- ~O-Ar
OTHP ~oVA
..~
~.
;
,,-
3~
-S.D. 58-
SUPPLEMENTARY DISCLOSURE
_ _ _
wherein Ar, THP and Z are as defined above with an ylide of
the formula:
(C6H5) 3P=CE~-cH2 CH2 CH2
wherein X is as defined above, with the proviso that when X
equals CO2R' the compound of Formula VA is first reacted
with an ylide of the formula:
(~6H5)3P CH-CH2CH2CH2CO2~
and the resulting product esterified if desired, to afford
a compound of Formula IIA, wherein Ar, X and Z are as defined
above and W is a ClS double bond, and, when required, sub-
sequently hydrogenating the compound thus ~ormed to afford
a compound of Formula IIA, wherein Ar, X and Z are as defined
above and W is a single bond;
~b) hydrogenating a compound of Formula IIA, above
wherein Ar, and X are as defined above, W is a cis double
bond and Z is a trans double bond, to form a compound of
Formula IIA above wherein Ar i5 as defined above and W and Z
are single bonds;
(c) selectively hydrogenating a compound of Formula IIA
above, wherein Ar and X are as defined above, W is a cis
double bond and Z is a trans double bond, to form a compound
of Formula IIA, wherein Ar and X are as defined above, W is
a single bond and Z is a trans double bond.
The intermediate compound of the formula:
o
THPO~ Ar o~IIB
OTHP
and the C15 epimer thereof; wherein Ar is phenyl; or mono-
substituted phenyl wherein the substituent is halo, trifluoro-
methyl, lower alkyl, or lower alkoxy; THP is 2-tetrahydro-
pyranyl; W is a single bond or cis double bond; Z is a singlebond or tran~ double bond and X is tetrazolyl; a group of the
formula -C-O~R' wherein R' is hydrogen, alkyl of from 1 to 10
.
: "~ ' ' ~
, ~
: ... ..
3~
-S.D. 59-
SUPPLEMENTARY DISCLOSURE
__
carbon atoms, lower alkyl phenyl or biphenyl when R' is a
single bond and R' is lower alkyl phenyl or biphenyl when R'
is a cis double bond; or a group of the formula R wherein
-~NHR"
R" is alkanoyl of from 2 to 10 carbon atom~, aryoyl, alkyl~
sulfonyl of from 1 to 7 carbon a~oms or arylsulfonyl: may be
prepared by reactin~ a compound of the formula:
OH
~X
I Z
THPO~ ~ O-Ar
~OT~P ... IIA
wherein Ar, THP, X, W and Z are as defined above with
chromic acid in aqueous sulfuric acid and acetone.
.r
~.,
: ,
:.` '' ' :
: :
