CA1088931A - Preparation of 9-oxo tetrahydropyranyl substituted prostaglandin intermediates - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
The preparation of substituted .omega.-pentanorprostaglandins, of the Formula:

Description

:L0~3931 This i~ a divisio~al of Patent Application No.
185,274, file~ November 7, 1973.
This invention relates to the preparation o~ noval tetrahydropyranyl ether derivatives of pxostaglandins useful a~ intermediates in the prepara~i~n o~ ~ertain novel analogs of the naturall~ occurring prostaglandins, in partioular the novel ~-pentanorpro~taglandins di~clo~ed in Application No.
1~5,27~.
Tha prostaglandin6 are C 20 unsaturat0d fatty acids whioh exhibit ~iverse phy~iological effects. For in~tance, the pro~taglandins of the E and A seri~ are potant va~odil-ator~ ~Berg~trom, et al., A ~ 64:332~33, 19S5 and ~erg~trom, et al., Llfo 801. 6:449 455, 1967) and lower ~ystemic arterial blood pres~ure ~va~odepre~31On~ on intravenous administration ~Weeks and King, /~e~ati~n er~O.
23:327, 1964; 9ergstrom, et al., 1965, ~ .; Caxl on, et al " Acta Med. Scand, 183:423-435, 1~68; and Carlson, et al,, Ao ~ . 75:161-169, 1969). Another well known physiological a¢tion or PGEl and PGE2 i~ as a broncho- :

2~ dilator ~Cuthbert, ~rit. ~od. ~. 4:723-726, 1969).
S~ill another impor~an~ physiologioal rol~ ~or th~
~atural pro~taglandins i~ in connea~ion with the reprodu~t~ve cycle. PGE2 i~ known ~o pO~5~S~ the ab~lity t~ ~nduo~ labor ~Karim, et al., ~ . 77:2~0-210, 1970), to lnduce therapeutiG abortion ~Byg~eman, ~t al., , 4, 293 ~1971) and to be u~e~ul ~or aontrol of f~rtility ~Karim, ~ , 3, 173 tl971)~. Patents have be~n obtained for sever~l prostaglandins o~ the ~ and F
serie~ as indua~rs of labor in mammals tBelgian Pat~nt 39 754,158 an~ WQ~t Garman Patent 2,034,6ql~, and on PGF1, ~2 and F3 for ~ontrol of the reproduativ~ aycla tSouth African Patent 69/6089).

., ,~,.
.
.. . . . .
'.` "' ' ~. , ' , .
.. :

~ .
.

389;~

Still other known physiological activitie~ for PGE
are in the inhibition of ga~tric acid secretion (Shaw and Ramwell, In: Worcester Symp. on Prostaglandins, New York, Wiley, 1968, p. 55-64) and also of platelet aggregation ~Emmons, et al., ~rit. ~ed J. 2:468-472, 1967).
It is now known that such phy~iological ef~eot~
~ill be produaed _ vivo for only a short period, following the administration of a prostaqlandin, A substantial body of evidence indicates that the raason for this rapid oessa-tion of activity is that the natural prostaglandins arequickly and efficiently metabolically deactivated by B-oxidation of the carboxylic acid side-chain and by oxidation of the 15a-hydroxyl group ~Anggard~ et al., Scand., 81, 396 (1971~ and refere~ce~ cited thereln~.
It was, of course, con~i~ered desirable to create analog~ of the prostaglandin~ which would have physiologlcal ac~ivi~ie~ equivalent to th~ natural co~pounas, but in which the s~le~tivity of aGtion and the duration of the activity would be increased. Increase~ selectivity of action would be expected to alleviate the severe side effects, particular-ly gastrointestinal side effects, fre~uently ob~erved follow-in~ ayatemic administration o~ the natural prostaglandins ~see Lan~et, 536, 1971~.
.
In accordance with the present invention th~re is provided a process for preparing a c~mpound of the formula:
W

Q~f ~-Ar '/OH ,..I
and the C15 epimer thereof; wherein Ar i~ phenyl; W i8 a ~ingle bond or ci~ double bond; Z i~ a single bond or trans ,H 0~
double b~nd; M i~3 oxo, ~ or ~ ; Y and Q when ta~en "~OH '~'H
together form a si~gle bond, or Q is a-hydroxyl when Y is hydrogen7 X i8 tetrazolyl; a group of the formula -~-O-R' - , . . . .
. '' '' .' ' '' : - . , .
'. ' ': ' :
- : . , : .: .
,: .
, . ., :
': - . ' ' ~ ' ' ' .

.

wherein R' ia hydrogen, alkyl of from 1 to 10 carbon atoms, lower alkyl, phenyl or biphenyl, w:Lth khe provl~o tha~ R' is lower alkyl, phenyl or biphenyl when W is a cis double bond and Q is a-hydraxyl; or a group of the formula -~NHR" wherein ~" is alkanoyl of from 2 to 10 carbon atom6, aryoyl or alkyl-sulfonyl of from 1 to 7 carbon atom~; and wher~in M, Y and Q
are ~o selected as to complete the structure of a prosta-glandin of the A, E or F series, ~he lower alkanoyl, formyl or benzoyl e~ter~ of any free hydroxyl groups at the Cg~, Cll- and C15-~o itions, and ~he pharmaceutically-acceptable salts of the compound~ wherein X is COOH, which compxi~e~:
~a) reactlng.a compound of the formula:
jl , ~.L,'`,' x T~PQ' -Ar "OT~P ...II
wherein Ar, M, ~, X and Z are as defined above a~d T~P i6 2-tetrahydropyranyl, with a suitable acid, to form the de~ir-ed compound o Formula I, wherein Q is a-h~dr~y, Y
hydrogen, and Ar, M, W, X and Z are a~ de~ined abov~;
~ b) reacting a comp~und of Formula I, abcv~, wherein Q
i~ a-hydroxy~and Y is.hydrog2n, M is ~xo, an~ Ar, W, X and Z
are as defined above, with a suita~le dehydrating agent, to form the de~ired compound of Formula I ~herein Q and Y taken tog~ther form a single bond, M i8 OXO and Ar, W, X and Z are as defined above;
ac~ hydrogenating a comp~und of the Formula I, ~bov~, wherein Q is a~hydroxy and Y is hydrogen, ~ is oxo, Ar, W, X an~ ~ are as defined above, to form the desired aompound of Formula I, wherein Q i~ a-hydroxy, Y i~ hydrog2n, M is ,0~
or ~ and Ar, W and Z are as ~efined abo~e, and, if desirQd, ~epara~ the 9a- and 3B-isomers;
i~d~ oatalytlcally hydrogenatin~ a c~mpound of Formula I, `!, ~
.~ .
' ' ' , ~ ' .~. , ' . . ' . ~ .

--4~
above, wherein Ar, M and X are as deined above, W ia a single bond or cls double bond when Z i~ a trans double bond and Z is a single bond when W is a cis double bond, to ~orm the desired compound of Formula I wherein Q is a-hydroxy, Y
is hydrogen, Ar, M and X are as defined above, and W and Z
are aingle bonds;
~ e~ selectively hydrogenating a aompound of Formula I, or the trialkylsilyl e8ter of a ~ompound of Formula I, wherein X i8 COOH, abov~, wherein Ar, X ~ndl M ~re as de~in~d ~bove and ~ and ~ are doubla bond~, to form the d~sired compound o~
~ormula I whereln Q is a-hy~roxy, Y iB hydrogen, Ar, X and M
are as d~fin~d a~ove, W i~ a ~ingl~ ~ond and Z i~ a trAns doubls bond; and, wh~n required, oonverting tho~e compound~
of Formula I wherein X i~ COO~ to e~ters or sub~t$tutod ami~
~8 d~fined above, by reaction wi~h suitable ~storify~ng or amid~ting re~gents, r~8p~0tiv~1y; an~, if dQ~ , pr~paring the 9-, lla- and 15~-lower alkanoyl, formyl ~r benzoyl ~sters o~ any ~ee hyd~oxyl groups by reacting tha compounda wlth th~ ~pp~opriate a~yl~tin~ ag~nt~ ~nd, $f ~e ircd, prep~ring tha pharmaoeuklçally a¢o~ptabl~ ~al~8 o ~ho~ c~mpound~
~h~rein X i~ COO~.
~h~ inventi~n al80 provide~ a pro~es~ 8arl~ad abov2 ~or prcparing a c~mpound of tho f~rmul~:
0~ :
~`"' ~ ~X
~O~ Ar 'O~ ... IA
~nd th~ C15 oplm~r th~reo~ wh~r~ln Ar, ~, Z ~na x a~fin~d abovo, Yhich comp~
~a) ~aoting a com~ound o th~ ~o~mula:
0}~
~""~
I ~
-Ar 'OT~P ... IIA

~b .: .
.. . , .. . . . ~ .

' ~ , ! .
,. . ' ~ . .

~l~8l~3~.

wherein Ar, W, X, Z and THP are as defined above, with a suitable acid;
~b) hydrogenating a compound of the formula:
\X

~ Ar ,..IB

wherein Ar, ~, X and Z are as defined above, and th~n ~epa-rating the 9~- and 9B-isomers;
~ c) catalytically hydrogenating ~ compound of Formula IA, above, wherein Ar and X are as defined above, ~ i8 a single b~nd or cis-double bond when Z i~ a rans double bon~
and Z is a ~ingle bond when W i~ a ci~ double bond, to ~orm a compound of Formula IA, above, wherein Ar and X are a~
de~ined above, ~nd ~ and Z are single bo~dA;
~ d~ selectively catalytically hydrogenating the di-methyli~opropy}~ilyl derivativ~ of a ~ompound of Formula IA, wherein X i~ COOH, Ar i8 as defln~d above, W i~ a ci~ ~uble b~nd and Z i~ a rans double bond, to form a compound of Formula IA, above, wherein Ar i8 as d~fined above, W i~ a ~ingl~ bond and Z i6 a trans ~ouble bond; and when required, converting tho~e compounds of Formul~ IA wherein X ia CO~H
to e ters or sub~tituted amide~ by reacti~n with ~uitable e~terifying or amidating agen~, respectively; and, if de-sirad, preparing the 9a , lla-, and 15a-lower alkanoyl, formyl or b~nzoyl ester~ sf ~ny ~ree hydroxyl group~ by re ac~ing the compounds with the appropriate acylating agont~;
and, i~ ~e~ireq, pr~paring th~ pharmaceutically-ac~ptable salt~ ~f thcse compounds wh~rein x is COOH.
. The invention further provide~ a proce~s as d~crib-ed above ~or preparing a c~mpound of the formula:
p O-Ar "OH ~oI~

,~
~' . . . :
:, .. : . . . . . . . . ..
.: ~ , , . . :
' : ' ' , ' .

~88~3~

and the C15 epimer thereof, wher~in Ar, W, Z and X ~re as def ined above, which comprises:
~a) reacting a compound of the ~ormula:
X
THPOI W~O_Ar ~OT~P . . ~ I IB
5 wherein Ar, ~IP, ~, X and æ are as d~fined above, with a ~uitable acld;
~ b) catalytlcally hydrogen~ting a compound o~ Formula IB, abov~, wherein Ar and X ar~ a~ de~ined above, W i~ a ~ingle bond or a ¢i8 double bon~ whes~ Z i~ a trans ~~uol e lQ bond and Z i8 a ~ingle bos~ wh~3n W i3 a ci~ doubl~ bond, to af ~o~d a compound of Formula B wh~r ein Ar an~ X are as deflne~l abotv~, and W and Z are ~ingle 130r~
ctiv~ly cat~lyti¢ally h~drog~rlating the ~i-methyli~opropylsilyl darivat~ o~ ~ csmp~und o~ Formula IB, 15 above, wher~ln Ar and X ara a9 define~ ~bov~, W i~ a oi~
d~uble ~ond and Z i8 a tran~ doublo l~nd, to afford a ~om pound o~ Formula I~3, abc)ve, wh~3rein Ar and X ~r~ a8 d~lned above, W i~ ~ sin~le ~nd ~nd ~ i9 a tran~ ~oubla b~n~s an~
wh~n ro~uired, conve~tirlg tho~ compoun~ f Formula I~
20 o~h~r~in X i8 COO~ t:o ~aters or e~bstituted ~mid~la by r~o.Gtion with ~uitable 2aterl~ying sr am~ dating ag~nt~, respo~tivoly and, i~ ~o~ired, pr~pa~ing h~ low~ canoyl, fo~m~?l o~
bonsoyl ~tffr~ of any ~ree 11- ~n~ lS-hy~lroxyl group~ by r~-aotln~ the oompound~ with the appropriat~ acylatlng agento 25 and, i ~e~re~, pr~arlng th~ ~harma~eutlaally-~o~pt~bl-s~lt~ of ~ho~ compQund~, wh~r~ X i~ COO~.
~ ho inv~nti~r~ 3 tlll u~ther provid~s ~ pro~o~a a~
dea~rib~ abov~ Eor pre~aring s ~ompound ~ tha ~ormul~s X

-Ar ,,,O~ ,, ,IC

.. ~ .
:~ .
',~
~ ' ' :'.' ; , . , ~ .
' .. . . . .. . .
. .

lQ8~3~
-7~
and the C15 epimer thereo~, wherein Ar, ~, Z and X are as defined above, which comprises reacting a compound of the formula: o ~y~ x HO~ Ar 'OH ...IB
with a suitable dehydrating agent; and, when required, con-verting those compounds of Formula IC wherein X i8 COO~ to ~sters or substituted amides by reaction with suitable esterifying or amidating reagents, respectively, and, if de-sired, preparing the C15-lower alkanoyl, formyl or ben~oyl ester by reacting the compound with an appropriate acylating agent; and, if desired, preparing the pharmaceutically-acceptable salts of those compounds wher~in X is COOH.
This divisional application relates to a process . .
for preparing a compound of the ormula:
OH
X

THPO~ ~ O-Ar ~OTHP ... IIA
and the C15 epimer thereof, and the Cg and C15 epimers thereof: wherein Ar is phenyl; T~P is 2-tetrahydropyranyl;
W is a single bond or cis double bond; Z is a single bond or trans double bond; and X is tetrazolyl; a group of the O
formula -~-O-RI wherein R' is hy~rogen, alkyl of ~rom 1 to 10 carbon atoms, lower alkyl, phenyl or biphenyl when W is a single bond and R' is lower alkyl, phenyl or biphenyl ~hen W

is a cis dauble bond; or a group of the formula -~NHR" wherein R" is alkanoyl of from 2 to 10 carbon atoms, aryoyl or alkyl-sulfonyl ~f from 1 to 7 carbon atoms; whioh comprises:
~a) reacting a compound of the formula:

: . , . . ... , .... . .. .. : . .

.. , ., ., , - ; ~ ,''' . ' . ' ' . ' ~ ' ~ ' ' ,, ' ' ' ' . ' , ' . ' ' ' ' ; ' ' ' .

- , : . ' ~ .

~0~ 3 OH

T~o ~ ~ O-Ar OTHP . . .VA
wherei~ Ar, TEIP and Z are as defined above with an ylide of the formulas ~C6~I5) 3P3CH-c~2 C~2 C~2 X
wherein X i8 a~ ~afined above with the proviso that when XaC02R~ the compound of Formula VA i~ fir~t raa~ted wit}~ o.n ylide of ~he formula:
t~6~1s~ 3-PZ'cH-cH2cH~cH 2co2~
and the r~sultlns~ product e~teri1ed i~ dl3s:Lr6d~ to A~i~ord a compound of Formula IIA whers~n Ar, X and Z are ~ de~ined a~ove and 6~ is a ci~ doubl~ bond; and, when r~quir~d, ~ul;-~quently hydrogenating th~ compound thu~ fonned to a~g~oxd a compound of Formula IIA wherein Ar, X and Z ar~ a~ de~lnoa abov~ and S~ 1~ a single bon~;
~b) hydr~g~nating a comp~und o~ Formul~ IIA ~v~, wherein Ar ~r~d X ~re as dafine~ abov~ W i~ a ~i8 ~ubla bond arld Z i~ a trAn~ ~oubl~ l~ond, to form a compound ~
Formula IIA above wher2in Ar i~ a~ dei~in~d ab0ve and 11 and Z aro ~ingle bon~s 2~ ~¢) ~oleotiv~ly hydr~g~nating ~ comp~und of Fo~mul~
IIA a~ov~, whersi~ Ar and X ~Iro a8 ~fln~d abo~ a oi~
double bond and Z i~ a ~ran ublo b~nd, to form e. ~ompound of Formula IIA wher~ln Ar ~nd X ax~ aEI do~lnod abov~ W i~
a aingl~ bon~ ~nd Z 1~ a tr~n~ doubl~ bon~.
Tha int~rm~di~t~ oompoun~ o~ th~ fo~mul~:
~ X

THPO~ Ar ~ OT~P . . ,IIB
an~ the C15 ~plme~ th0reo~; wherein P.x i~ phenyl; W iB a ~d .

~: o ~08~3~331 g single bond or cls double bond; Z is a single bond or trans double bond; and X is tetraxolyl; a group of the formula -~-O-RI wherein R' is hydrogen, alkyl of Erom 1 to 10 carbor atoms; lower alkyl, phenyl or biphenyl when W i8 a ~ingla bond and R' is lower alkyl, phenyl or biphenyl when W i~ a cis double bond; or a group of the ormula - NHR" wherein R"
is alkanoyl of from 2 to 10 aarbon atom~, aryoyl or alkyl-sulfonyl of from 1 to 7 carbon atoms; may be prepared by re-acting a co~pound of the formula:
O~I
,' .~,.~' ~ X
Z
T~P~ Ar "OT~P ... IIA
wherein Ar, T~P, X, W and Z ~re a~ defined above with chrQmia acid in aqueous sulfuric acid and acetone.
Additional intermediates u~ed in the pr~c2ss of thi~ Lnvention are those of Formulae III, IV, V and VI set out hereinafter.
.; The intermediate compound of the formula:
.` /~

".

Q~ ~ -Ar 'd ~ . ~III
wherein Ar is phenyl; 3,4-dimethoxyphenyl, 3,~-methylene-dioxyphenyl; 3,4,5-trimethoxyphenyl; ~- or ~-naphthyl or mono~ubstituted phenyl wherein said ~ubstituent i~ halo, trifluoromethyl, phenyl, lower alkyl or lower alkoxy; and Q is ~-biphenylcarbo~yl; may be prepared by reacting a com-pound of the formula:
... ~: . .

:
~ ' . . ~' '-' ~;~
' - . . ., . ' ' : ~ ' ' : ' ' .
, . , ~ . ' ' ~ ' ' . . . ... . . .
, . :
.
.. ' . , .: ,, .
.
.

:

~0~ 931 ..

o C~

wherein Q is aæ defined above; with a compound of the formula:
lower alkyl-O
P-C}12-Cj-O-Ar lower alkyl-O
wherein Ar iB as defined above.
The intermediate ~ompound of the formula:
.o--~

Q~o ~ ~ ~ ~ ~ o-~r HO ...IV
wherein Ar is pheny~; 3,4-dimethoxyphenyl; 3,4-methylene-dioxyphenyl; 3,4,5-trimethoxyphenyl; ~- or ~-naphthyl or monosubstituted phenyl wherein said ~ubstituent i~ halo, ~ri-fluoromethyl, phenyl, low~r alkyl or l~wer alkoxy a~d Q' i8hydrogen or ~-biphenylca~bonyl; may be prapared by xeducing a compound of the Formula III:

` ~` ~ ~ ...III
wherein Ar and Q are as defin~d above to aford a compound of F~rmula IV, ~l~ove, wherein Ar and Q are a~ defined a~ove, and, if de~ired, ~eparating the 8a- and 8B-isomers~ and if desixed, reacting a compound of Formula IV~ above, wherein Ar i8 as defined above and Q i8 biphenylcarbonyl with K2C03 to ~ffo~d a compound of Formula IV wherein Q i~ hydrogen;

~,,,, '.
.. . . .

.. . . . . .
.. . ..
:. . . . :: . :.

~)8~931 and, if desired, separating the 8~- and 8~-isomers~
The intermediate compound of the formula:
0~ , THP0~` ~ ~ ~ 0-~r THP ...V
wherein Ar i5 phenyl; 3,4-dimethoxyphenyl; 3,4-methylene-dioxyphenyl; 3,4,5-trimethoxyphenyl; a- or ~-naphthyl; mono-substituted phenyl wherein said sub~tituent ia halo, tri-fluoromethyl, phenyl, lvwer alkyl or lower alkoxy; THR is 2-tetrahydropyranyl; Z is a single bond or a trans dcuble El ~ond; and Y i~ 0 ox ~ ; may be pr~pared by reacting a compound o~ the Formula:
0 ~
\

~10` ~O-Ar ~1 . . .IV
wh~rein Ar and Z are a~ defined ab~ve and Y is -0, with 2,3-dihydropyr~n in the prasenca of an acid catalys~ to afford a compound of Formula V wharein Ar and Z are as defined above, and Y is ~0; reacting a compound of Formula V, ab~ve, wherein Ar an~ Z are as defined above and Y i~ ~0 with dii~obutyl-aluminum hydride to afford a aompound of Formula V ~he~ein Ar and Z are a~ ~efined ab~ve and Y is ~ H -; by ~0~
catalytically redu¢ing reducing a compound of Formula IV, above, wh~rein Ar i8 aq defined above, Z i~ a tran~ double bond and Y i5 =~, to afford a compound of Formula V wh~rein Ar i~ as define.d above, Y i8 =0 and Z i~ a single bond.
The i.ntermediate compound of the formula:

...~
~ I
.
~ ' ''.- `' . . ~ ' ' .. . . . . .
.. . . . . . .
.. . : , . .
.

' ~ . ~

~ ~o' 3 Ar-O-CH2- -CH -P

wherein Ar is phenyl; 3,4-dimethoxyphenyl; 3,4-methylene-dioxyphenyl; 3,4,5-trimethoxyphen~l; a- or B-naphthyl or monosubstituted phenyl wherein sai.d substituent ~s halo, tri-fluoromethyl, phenyl, lower alkyl or lowex alkoxy; may beprepared by reacting a lower alkyl ester of the formula:

Ar-O-CH2~-O-low~r alkyl wherein Ar i8 as defined above, with a dialkyl methyl phos-phonate of the ~ormula:
O
~lower alkyl-O)2P-C~3 Pre~rred compoun~ prepared by the proc~s~ of this inventi~n are 16-phenoxy PGE2 ~-biphenyl ester, 16-phenoxy PGF2~ ~-biphenyl e~ter, and 16-phenoxy PGF2~ 2 biphenyl e~ter.
Preferred in~ermediates are the C9 epimers of the compounds o~ Formula II.
Other preferred prostaglandins are as follow~:
A compound of Formula I wherein Ar i8 phenyl and the prostaglandin i8 PGE2.
A compound of Formula I wherein Ar ia phenyl, and the prostaglandin is PGF2a.
A compound of Formula I wherein Ar i8 phenyl and the prostaslandin i8 PGF2B.
Especially pre~erred prostaglandins are the following:
A compound accordin~ to Formula I wherein X 1 ' -~-NHR", R" is a~etyl, W i~ a cis double bond, Ar is phenyl.
A compound according to Formula I wherein X i~
te~razolyl, W i~; a Ci6 double bond, æ is a trans ~ouble bond, an~ Ar is phenyl. I
A compound according ko Formula I wherein X is -~-NHR", R" is methyl~ulfo~yl, W iB a cis double bond, Z is ~1`
,~, . :., ....... . . ,, , : .
,, , ~' :
,: .
.

)8H931 a rans double bond, and Ar is phenyl.
~ compound according to Foxmula I wherein X is -~-NHR", R" is methyleulfonyl, W i~3 a ci~ double bond, Z is a trans double bond, and Ar is m-methoxyphenyl.
A compound according to Formula I wherein X i6 - -N~R", R" i~ acetyl~ W is a cis ~ouble bond, Z is a xan6 double bond, and Ar ia m-methoxyphe~yl.
Novel intexmediates ~f the Formulae below may be prepared by the processes de~Gribed herein:
o}~

T~PO` ~ O-Ax "OT~P ... IIA' 1~ ' , . .

~EPO ~ Q-Ar 'OT~P I ~.. IIBI
an~ th~ Cg and C15 Qpimers thereof; wherein Ax is phenyl;

3,4-dimethoxyph~nyl; 3,4-methylen~dioxyphenyl; 3,4,S-tri-methoxyphenyl; a- or B-~aphthyl or monosubstitut~ ph~nyl lS wherein ~aid 5ubstituent i~ halo, txi~luoromethyl, phenyl, lower alkyl ~r low~r alkoxy; T~P is 2-tetrahydropyr~nyl; W
is a ~inyle bond or a Ci8 double bond; Z i8 a single bond or trans double bond; and X i~:

~a) a group of the formula -~-O-~' wherein R' is alkyl 20 of from 1 to 10 carbon atom~; aralkyl of rom 7 to 9 carbon atoms; cycloalkyl of from 3 to 8 carbon atom~ or B-naph~hyl; phenyl or mon~3ub~titute~ phenyl, wherein the ~ub-BtitUent is halo, lower alkyl or lower alkoxy;
(b) ~-phenyl-phenoxycarbonyl;

~,:

: ~ :

(c) tetraæolyl; or (d~ ~ group of the formula --~ HR" wherein R" is alkan-oyl having from 2 to 10 carbon atoms, cycloalkanoyl having from 4 to 8 carbon atoms; aryoyl er ubstituted aryoyl of from 7 to 11 carbon atoms wherein the substituent is methyl, halogen, or methoxy; alkylsulfonyl of from 1 to 7 carbon atoms; axylsulfonyl or substituted arylsul~onyl wherein the subgtituent i8 methyl, halogen or methoxy.
The starti~g materials ~or the various novel com-pounds prepared by the process of this invention are avail-able commercially or may be made by methods welI known to those skilled in the art. For example, to make dimethyl 2-oxo-3-phenoxypropylphosphonate, the starting material for khe synthesis of the 16-phenoxy prostaglandins, one cool~
a solution of dimethy} methylphosphonate in tetrahydrofuran to 78 in a dry nitrogen atmo~phere and then adds n-butyl-lithium in hexanc dropwise, ~lowly. A~ter stirring, methyl-2-phenoxy acetate i8 ad~ed dropwi~e.. After 3 to 4 hours at -78 the reaction mixture i~ warmed to am~ient temperature, 2~ neutralized with acetic acid and r~tary evaporated to a white gel. The gelatinou6 material is taken up in water, the aqueou~ phase i8 extracted in ~hloroform and the combin-ed organic extracts are backwashed, dried, and concentrated to give the desired pro~uct.
To make substituted 16-phen~xy pro~taglandins, one requires substituted phenoxy aoetic acids which are prepared by cond~nsation of appropriate phenol with a haloacetic ~cid or ester in ~he precence Q~ a ba~e a~ described by ~.M.
Petersen, Acta Ch _ c-ndl~Avi~a, 5, 519 (1951) or M~ Beroza, A~ri. Food ~hem., 4, 49 ~1956~. ~hus condensation of bromo-methy~ acetate with se~mol in presence of ~odium methoxide gives the ~L~
Similarly, one may prepare ~ , 3f4~5 trimethoxy ~ and acetic acid.
..

.
, ' '' . . .,. ~'': ~' , '' ' ,'':
. . .
- . , ~ . ' ~ ' , .

93~

~Y. ~ ,~
~o ~

,f~

o N CC~

,..... ........ ... . .. .......... ,.. ~.... .. .... ~.......... . .

.... . ... . ...... .. .. ...... ... . . . .. . . .
. .
. . .
. . . . . .
..

.

893~

A~ shown in Scheme A, the firsk step in the com-plete synthesi5 (1 ~ 2) is the conden~ation of tha appropri-ate ester with a dialkyl methylpho~phonate to produce oxo-phosphonate 2. These esters are obtained as previou~ly de-ecribed.
In 2 ~ 3 the oxopho6phonate 2 is reacted with theknown ~Corey et al., J. Am. Chem., 80c.~ 93, 1491 (lg71)~
aldehyde H to produce, after chromatography or cry~talliza-tion, the enone 3.
The enone 3 may be reduced with zinc borohydride or with a trialkylborohydride, 9uch a~ lithium triethylboro-hydride, to a mix~ure of alcohols, ~ an~ 5 which may be sepa-rat~d by aolumn chromatography. In thi~ reacti~n ether~
such ~8 tetrahydxo~ura~ ox 1,2-dimethoxy etha~e are u~ually employe~ a~ ~olvent~, although ocoag~onally metha~ol is pre-ferred to ensure ~peci~icity of re~uction. Further ~rans-formation~ o~ 4 are ~h~wn in S¢h~me ~.

4 ~ 6 Is a ba~ c~aly~e~ tra~ste~ifi~ation in which the ~-biphenyl-carbonyl protectin~ group i~ removed.
Thi~ is most c~nveniently ~onducted with potas~lum carbon-ate in methanol or methan~l-t2trahydro~uran solvent. 6 ~ 7 In~olve~ ~h~ protection of the two fre~ hydroxyl groups with an acid-~a~ile protecting group. Any su~ficiently acid-labile group i~ 3ati5~acto~y; however, the most u~ual one ~ 5 tetrahydropyranyl, which can be incorporated in the molecule ~y treatment with dihydropyran a~d an acid catalyst in ~n anhydrou~ m~dium. The c~t~ly~t is u ually ~-toluenesulfoni~
aoid.
7 ~ 8 I~ a reduction o~ the lactone 7 t~ the h~mi-aoetal 8 u~in~ diisobutyl aluminum hydride in an inert ~olv-~nt. ~o~. reac~ion temp~rature~ are pre~erred and -6Q to -70C. are u~ual. Howeve~, higher tempera~ure may be em-ploye~ if ov~x-reduction do~s not occur. 8 Is purified, if d2sired, by ~olumn chrom~tography.
8 ~ 9 I~ a ~ittig condensation in wh1ch hemiacetal 8 ia reacted ~i~h ~4-ca~b~xy-n-butyl)triphenylphosphonium bromide in dimethyl ~ulfoxide, in tha presence of sod~um '~ ' . ~ : . : . . . ;
: ~ : , : , . : :

.. : . , , ~, : : .:
.
- .

-` ~0~38931 methylsulfinyl methide. 9 Is purified as above.
Tha conversion 9 ~ 12 is an acidic hydrolysis of the tetrahydropyranyl groups. Any acid may be u~ed which does not cause destruction of the molecule in the cour~e of S khe removal of the protecting group; ho~ever, this is accomplished most often by u~e of 65% aqueous acetic acid.
The product i8 purified a~ above.
9 > 10 I~ an oxidation of the ~econdary alcohol 9 to the ketone L0. Thi~ may be accompli~hed using any oxidiz-ing agent which does not attaçk d~uble bond~; however, theJones ' reagent is usually preferr~d. The product is puri-fied as above.
L0 ~ ll.Is carried out in the same manner as 9 ~ 12.
The product i8 purified as above.
11 ~ 15 I~ an acia-c~talyzed d~hydr~tion. Any ~id may be u~ed for the pro~es~ which does not cause e~ten~iv~
decomposition of the pr~duct, but the mo~t usual proce~ur~
consi~ts of dis~lving _ in an exce~ ~f 97% f~rmi~ a~id followed by diluti~n with ica water and extraction ~f the produc~ atex the s~artig mat~rial ha~ been consumed. The product is purified a~ above.

, . . .
. . .

8~3~313~

SCHEME B

f ~
HO' ~ ~ ~ -Ar 6 H `OH
~ \
~ ~ ~ o ~ OH

THPO~ ~ ~ ~ ~ O-Ar ~ ~, H OTHP 7 ~ l l po ~ ~ ~ ~ O-Ar / - H OTHP
HO
1~
f~ "' ~X
THPO ~ O-Ar ~ , H OTHP
THPO' ~ O-Ar O,H ~ lo OTHP

HO ~ ~ ~ -Ar 12 ~ OH

HO~ ~ O-Ar - H OH

~,"~ X
Il I
O-Ar l5 H OH

~'.~' . ,~
.. . . . .. . . . . . . . . . . . . .

' . ' ' ' .' ~ : : ' ' ~ : ' :' . ' : ' ~ '~" ' ~

8~g3~

As illustrated in Scheme C/ 5 may be ~ubsti~uted for 4 in scheme ~ to provide pro3taglandin dsrivatives 12', 11' and 15'.
SC~EME C
OH

HO' ~ ~ O-Ar HO H 12' I~
_ _ > ~"~'~ X' \ ~o~ ~ O-Ar ~0 }I
\~ R

~o ~
HO ~ l5l .
Scheme D illustratee he synthesis of precursors to the 13,14-dihydro-15-~ub~tituted-~-pent~norprostaglandins.
In 3-~19 + 19' the enone 3 i~ reduced to the tetrahydro compound through the us~ of any of the complex metal hydride r~ducing agents~ LiA1~4 9 NaB~4~ KB~4, LiB~4 and Zn~B~4~2. Especially preferred is Na~H4. The products, 19 and 19~, are ~eparated from each o~her by column chroma-tography.
Furthermore, the aompound~ 4 and 5 of Scheme A may be reduoed catalytically with hydxogen to 19 and 19' respec-tively. The tage at whioh the double bond is reduaed i6 not critical, and hydrogenation of 6 ox 7 of Scheme ~ will al~o afford useful intermediat~s for the 13,14-dihydro prostagla~din analogs of the present invention. This reduc-~"
, . . . . . .

.
, . ' ' .
, 3~

tion may be achieved with either a homogenous catalyst such as tris(triphenylphosphine~chlororhodium, or with a hetero-geneous catalyst such as platinum~ palladium or rhodium.

' ; , , .: . . . . . .
' :: ' : ' :, . , ': ,, .
. ~, ' ~, . ' ., 8~

~ .
~' .

0~ --~, , .
,,~
~'` ' ,.
~ I -- >
/ ~ ` .

o ~ .
4~
, ....... : . ,, . . . ~ , . ..
- . . ' ' 8893~

-2~-The conversion of 19 and 19' to their re~pective prostaglandins follows the route shown in Scheme B when 4 is replaced by 19 and 19' to yield the 13,14-dihydro PGE2, PGA2 and PGF2 æeries of prostaglandin derivatives.

s Scheme E illustrate~ the preparation o~ the variou~
reduced 15-substituted-~-pentanorprostaglandin precursors:
19 ~ 22 Is carried out as illustrat~d in Scheme B
for 4 ~ 9. 22 May be u6ed as both a precursor to a 13,14-dihydro-15-substitut2d-~-pentanorprostaglandin 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 hydrogenation using the catalyst desGribed or the reduction of 4 ~ 19 of Schem~ D. Interm~diate~ o~ th~ type 21 are prepared by ~5 selsct~e hydrog~nation of the 5,6-c~s double b~nd at low temperature u~ing catalyst~ such a8 tho~e d~scri~ed for 4 ~ 19 and 17 ~ 23. Especi~lly preferred for this hydrogena-tion i9 the u~e of palladium-o~-ca$bon as a cataly~t an~ a reaction temparature of -20~ Interm~diate~ of the type 21 are not only pxeQursors to 15-substituted-~-pentanorpro~ta-glandins of the "l-series" through the route 9 ~ 15 of Scheme B, but al80 as a precursor to c~mpounds of the type 23 through the ~oute already di3cuseed for 22 ~ 23.

.. . . . .
: . . , - : ' : . ~ ' ' .

.

- , . .
", : .
. . . .,; . .
.
.' ' : ' , : ' ':' ~Q~ 31 ~ `

o ~

;;, > ~ O

0~ >

:~ >~ .

<
o P~ ~
~O ~ .

Nl ~
~--a .

,~
D
T_ .

~ `~ 108~193 Furthermore, the 15-sub~tituted-~-pentanorprosta-glandins of the El and Fla ~eries may be obtained directly from the corresponding prostaglandin analog of the "2-Berie~"
by fir~t protecking the hydroxyl by introducing dimethyl iso-propyl ~ilyl groups, reducing ~electively the cis double bond,and removing the protecting group.
The intxoduction of the protecting group i3 u8Ually accomplished by treatment Qf the pro~tagiandin analog with dimethyl i~opropyl chlorosilane and triet~ylamine, tha re-duction is accompli3hed a di~au8~ed above for 9 ~ 21 andremoval o the protecting group i~ accomplished by contact-ing the reduced protected compoun~ with 3:1 acetic acid:water for 10 minut~s or.until rçaction i3 ~ubstantially omplet~.
The C15 epimers of 21, 22 and 23 may be u~ed aa precursors to the 15Depi serie8 of pro~taglandin derivativQs de cribed above.
In the foregoing prooedure~, wher~ purifiaat~on by chromatography i~ desired. appropriat~ chr~smat~graphi~ ~upport~
includ~ neutral alumlna and s~iica ~el and 60-200 m~h silica gel i8 ~enerally preferred. The chromat~graphy i~ ~uitably conducted in reaction-inert solvent~ ~uch as ether, ethyl acetate, benzene, chloro~orm~ methylene chloride, oyol~h~xane and n-hexane, ~8 further illu~trat~d in ths appended exdmplas.
It will be ~een khat the forogoing ~ormulae d~piot optically activs ~ompounds. It will be cle~r, however, that the corr~ponding racematoe wtll exhibit valuahla bi~logi¢al activity by virtu~ of th~ir contont of the abov~-m~ntlon~d biologically a~tiv~ optical iBomer, and it 1~ intended th~t ~uch r cemate~ ~lao be ~mbrw ~d by the for~going ~ormul~e 3~ herein and in the app~naed alaim~. The r~¢emic m~xture~ are readily prepar~d by the same method~ employed herein t~
synthesize the ~ptically active species, by mere substitution of corresponding racemio precur~or~ in place of optically active st~rting material~.
In numerous ln v~ vc~ and ln vitxo tests wa have demon~trated that th~ new pro~taglandin analogs p~sess physiological aativities comparable to those exhibited by the .~
i r~.
.. ..
~, ............. . . :
.

.:................................. ~ : :
.
' ~ .' .' . ' ' , ~ . . ~

- la~ss3~

natural prostaglandins. These test include, among others, a test for effect on isolated smooth mu~cle from guinea pig uterus, guinea pig ileum and rat uterus, inhibition of hist-amine-induced bronchospasm in th8 guinea pig, and eff2ct on dog blood pressure, inhibition o stress-induced ulceration in the rat, inhibition of ga~tric acid and pepsin ~ecretion in rat and dog, inhibition of collagen or ADP-induced blood platelet aggregation and abortifacient activity in rat~ and guinea pi~8 by luteolytic and non-luteolytic mechani~m~.
~he physiological r~sponses observed in these te~ts are useful in determining the utility of the test substance for the treatment of variou~ natural and pathological condi-tion~. Such determined utilitie~ include: antihyperten~iv2 activity, bronchodilator ac~ivity, ~ntithrombogenlc activity, antiulcer activity, sm~oth mu6cle actiYity ~useful as an anti-fertility agent, for th~ induction of labor, and a~ an abortifacient], and anti~ertility activity through a m~chan-i~m not affe~ting smooth mu~cle, for ~xample, lu~eolytic mechanisms, and the synohronization of the estrous cycle in farm animals.
The novel compound~ prepared by the pr~ces~ of this inventi~n po sess more seleotive aotivity profil~s than the corresponding naturally occu~ring pro~taglandins, and in many aases, exhibit a longer duration o ~ctlon. For example, 16 phenoxy-~-tetranorprostagland~n E2 which exhibit~ smooth muscle stimulating activity comparable to PGE2, iB inactiv~
in inhibition of histamine-~n~uced broncho~pa~ms in guinea pig8. Furthermore, although the threshold do~e o hypote~lve re~ponse o~ 16-phenoxy~ etranor PGE2 in dQgs i~ higher than that of PGE2, the duration of action iB markedly prolonged relative to PGE2. The 15-substituted-~-pentanorprostaglandin~
Eo~ FoB~ FlB, F2B, and 13,14-dihydro PFG2~ exhlbit similar mooth muscle st~ant activity, whereas the corre-sponding d~rivative~ of the Ao~ Al, A2 and 13,14-dihydro PGA2 ~eries have ga~tric antisecretory/antiulcer activity.
Particularly useful for fertility control, abortion and induction of labor are the 16-phenoxy-~-tetranorprosta-. .
.~ :

.

~1 ~81393~

glandins of the E2, F2~ F2B series ba6ed on especially out-standing smooth muscle stimulating activity, and at the ~ame time reduced blood pres~ure effect~3. Similarly, the substi-tuted ~-pentanorprostaglandins of the PGEl, PGFo~, PGFl~, and 13,14-dihydro PGF2~ series are use~ul for fertility con-trol including abortion and induct.ion of labor on the basis of their smooth muscle stimulant as~tivity. The novel 15-sub-stituted ~-pentanorprostaglandin-1:3~14-~ihydro-E2 analogs may be employed in the treatment of peptic ulcers. The novel prostaglandins with a ~-OH at the 15-position are in general lesa potent, although frequently more selective than the corresponding a-hydroxyl epimers. Additionally, ths prosta-glandins having a.B-hydroxyl at C-15 are valuable lntermedi-ate~ for prostaglandins having a ~-hydroxyl at C-15 through a re¢ycling process involving an oxldation and reduction at C-15.
The new compounds pr~pared by the process of thi~
inventio~ may be used in a variety of pharmaceutical formul~-tions which contain the compound, and they may be admini~ter-ed in the same manner as natur~l prostagl~ndin~ by a varietyof routes, such as intraven~us, oral, intravaginal, intra-and extra-amniotic, among other~O
For induction of abortion, tablets or an aqueous su~pension or alcoholic solution of 16-phenoxy-~-tetr~nor-prostaglandin would appropriately ~e administered at oraldose~ of 0~1 to 20 mg., with 1 to 7 doses per day being em-ployed. For intravaginal adm~ni~tration a suitabl2 formula-tion would be lactose tablets or an impregnated tampon o~
the same agent. For such trea~ments suitable dQses would be from O.1 to 20 mg./dose with 1 to 7 doses being employed.
For intra-amniotic admini~tration a suitable ~ormulation would be an a~ueous solution containing 0.05 to 10 mg./dose with 1 to 7 doses being employed. For extra-amniotic admin-istration a suitable formulation would ba an aqueous 501u-tion containing 0.0~5 to 1 mg./dose with 1 to S dose~ beingemployed. Alternatively, the 16-phenoxy-~-tetranorprosta-glandin~ o~ this invention may be $nfused intravenously for .

:' ~ ' ' . .
.
, - - 108~3~31 induction of abortion at doses o~ 0.05 to 50 ~g/minute ~or a period of from 1 to 24 hours. For synchronization of the estrous cycle in pigs, sheep, cows or hor~es, a s~lution or suspension containing 0.03 to 30 mg./day of 16-phenoxy-~-tetranorprostaglandin is administered subcutaneously from 1to 4 days.
15 Sub~tituted~-pentanorproskaglandins of the A
series are useful gastxic antisecretory and antiulcer ag~nts, as are the 15-aubQtitutQd-~-pentanorprostaglandins of the E
series. For trea~ment of peptic ulcers these compounds are admini~tered prefer~bly orally in the form o~ capsulas or tablets at doses of 0.001 to 0.1 mg.~kg./day.
To prepare any of the a~ove dosage form~ or any o f the numerous othex form~ po5sible, various reaction-inert diluents, excipients or carriers ma~ be employed, Such aub-stance8 include, for example, water, etha~ol, gelatin~ 13c-tose, starches, magnesium stearate, talc, vegetable oil~, benzyl alcohols, gums, polyalkylene glycols, petr~l~um ~llyO
cholesterol, and other known carriers for medicaments. If desired, theae pharmaceutical oompositions may contain auxiliary substances ~uch a~ preserving agents, wetting agents, stabilizing agent~, or other therapeutic agents ~uch as antibiotics.
Various modifications are po~ible on the upper 6ide chain of the pro~taglandins prepared by the proce~ of this invention; such modification8 d~ not, as a rule, alter the basic biol~gical activity of the prsstaglandin, although they may increase selectivity and dur~tion o~ action further and reduce toxicity. For example, a tetrazoyl group may be placad at th~ Cl po~ition. 16-Phenoxy-PGE2-tetrazoyl has the same utility as 16-phenoxy PGE2 e~t~rs; namely, for induotion of labor or abortion, and for the inhibition of gas~ria acid secretion and trea~ment of pep~ic ulcers.
Another upper side ahain modification which may be made in the pro8taglandin~ of this invention is su~stitution of the carboxylate group at the Cl po~ition by a carboxamide group. Alternatively, the novel compounds prepared by the .~

~Q8~3~31 proce s of this invention represented by Formula I ~where X

i~ ~N~R" and ~herein R" i5 as deiined previou~lyl, may be prepared from compounds 9 and 10 of Scheme B (or the corre-sponding 15-epimers or 15-lower alk~l derivatives of 9 and 10) by reaction with appropriate isocyanate~ followed by hydroly~is with dilute acid. The utility of N-methylsul~onyl~
16-phenoxy PGE2 carboxamide, for example, i8 the same as that of 16-phenoxy PGE2 esters.
One particularly beneficial ester ia the ~-biphenyl ester. ~uch esters are prep~red in the appended example~ by simply adding ~-phenylphenol to the pro~taglandin in methyl-ene chloride in the presence of a dehydrating agent t for example, dicyclohexylcar~odiimide, and stirring ov~rnigh~.
Although not more p~tent in in vitro smooth muscle t~Bt8, abortifacient evaluation of 16-phenoxy-~-tetranor PGE2 and PGF2~ p-biphenyl e~tex~ demon~trated that these p-biph~yl-esters po~sess physi~logical activities markedly greater than those of the free acids.
The following Examples are merely illu~trative, and in no way limit the scope ~f the appended clalms. In the~e Examples it vill be appreciated that all temperatures are expressed in Centigrade, all melting and boiling points are uncorrected.
EXAMP~E I
Dime~hyl 2-Oxo-3-Ph~noxypropyl~hosphonate A solution ~f 33,2 g. ~268 mmoles3 dimethyl methyl-phosphonate ~Aldrich) in 360 ml. dry tetrahydrofuran was cooled to -78 in a dry nitxogen ~tm~sp~ere. To the stirred phosphonate solution was add~d 118 ml. o~ 2.34 M n~butyl-lithium in hexane ~olution ~Alfa Inorganics, Inc.) dropwi~eover a period of 18 minute~ at such a rate that the xeaction temperature never roae above -65. After an additional 5 minutes stirring at -78, 22.2 g. ~134 mmole~ methyl 2-phenoxy acetate wa~ adde~ dropwi~e at a rate that kept the reaction temperature less than -70 ~20 minute~, Ater 3.5 hours at -78 the reaction mixture was allowed to warm to ~, . .
. . .
.
: .
.
~ .. ' :.: ' ' '' ' ,' :. , . ~' ..

~8893~

-2g--ambient temperature, neutralized with 14 ml. acetic acid and rotary evaporated to a white gel. The ~elatinous material was taken up in 175 ml. water, the aqueous phase extracted with 100 ml. portions of chloroform ~3x~, the combined organic extracts were backwashed t5~ cc ~2)~ dried ~MgSO4), and concentr~ted ~water aspirator~ to a crude re~idue and distilled, b.p. 172-175 ~0.5 mm) to give 24.6 g. dimethyl 2-oxo-3-phenoxypropylphosphona~e.
Th~ nmr spectrum tCDC13~ shewed a doublet centered at 3.75~ ~J = 11.5 cp~, 6~ for ~C~3O)-~ , a ~inglet at 4.7 (2H) for C6H5O-C~2-CO-, a doublet c~ntered at 3.24~ 23 cps, 2H) - -CH2-P-, and a multiplet at 6.8-7.S~ ~5~) for th~
aromat~c pro~ ns.

2-[3a-p-Phe~ylb~nzoyloxy-5a-~ydrox~-2~ ~3-oxo;4-Phonoxy-tran~-l-buten-l-vl)cvclo~ent-l~-vllAc~tio Aaid ~-~a~tone Dimethyl 2-oxo-3-phenoxypropylph~spho~at~ ~5.4 g,), ~21 mmole~ in 200 ml. anhydrou6 ethar W~8 treated with 7.9 ml. ~19 mmole) 2.5 M n-butyllithium in n-hexane l~lfa In-organ~c~, Inc.~ in a dry nitro~en ~tm~aphere at room tempe~-ture. After 5 min. of ~tirring, an add$tional 4bo ml. ~f anhydrou~ ~ther was added ~ollowed by 6.0 g. ~17 mm~lel 2-~3a-~-phenylbenzoyloxy-5a-hydroxy-2~-formylcyclop~nt~n-la-yl]aaet~c acid, ~-lactone in one portion and 50 ml. anhyd~ou~
ether. Aft~r 35 minuto~ the reaction mixtur~ W~8 queno~ed with 5 ml. glac~al acetic acid and wash~d with 100 ml.
saturat~d ~odium bicarbonate ~olution ~4x), 10~ ml. water ~2x), 100 ml. ~aturated brine ~lx), dried ~gSO4~ and ev~por-ated to yield 5.2 gm. 2-~3a-~-phenylbenzoyloxy-5a-hydroxy-2B-~3-oxo-4-phenoxy-tra~s-1-buten-1-yl)cyclopent-la-ylJacetic acid, y-lactone ~8 a solid ~fter 901umn chromatography ~Silica gel, Baker, 60-200 mesh); m.p. 112-114 after cry~tal-lization from methylene chlorlde~hex~ne.
The ir spectrum ~KBr) of ~he product exhibited ab~orption band~ at 1775 cm 1 ~trong), 1715 cm 1 (~treng), 16i5 cm 1 (medium) and 163Q Gm 1 ~medium) attributable to the '~'`1 .~,,~, .

.

,, --~ 3LQ~893 -3~-carbonyl groups and a~ 970 cm 1 for the trans double bond.
EX~MPLE III
2-[3~ Phenylbenzoyloxy-5a-~Ydrc)xy~2~-(3~-Hyd~oxy-4-Phenoxy-trans-I-Buten-l-yl)cyclopent-l~ acetic acid, y-Lactone To a solution of 5.1 g~, (10.5 mmole~ 2-~3a-~-phenyl-benzoyloxy-5a-hydroxy-2~-(3-oxo-4-phenoxy-trans-l-buten cyclopent-l~-yl]acetic acid, y-lactone in 30 ml, dry 1,2-dimethoxyethane in a dry nitrogen atmosphera at ambient temp-erature was added dropwi~e 11 ml. ~5.5 mmole) of a O.5 M zin~
borohydride solution. After stirring at room temperature for 2 hours, a saturated ~odium bit~xtrate s~lu~i~n was added dropwi~e until hydr~gen evolution cea~d. The rea~tion mix-ture was allowed to ~tir for 5 minute~ at which time 250 ml.
dry methylene chloride wa~ added. After ~rying ~MgSO4) and conoentratin~ ~water aspirator~ the resultant semi-sol~d wa8 purified by column chromatography o~ silioa gel ~aker "Analyz~d" Reagent* 60-200 meRh) u~ing eth~r a~ ~luent. A~er ~lu~on o~ le~8 polar impuritia~ a ~raction con~ain~ng 896 mg. 2-~3~ ph~nylben~oyloxyo5~-hydr~xy-2B-(3-hydroxy-4-phenoxy-tran~ buten-l-yl)cyclopent~ yl~acetic a~id, y-lactone, a 600 mg. fraction of mixed 4 and 5 and f~nally a ~ractio~ tl.5 ~m.) of 2-[3a-~-phe~ylbenzoyloxy~5~-hy~ro~y-2B-~3B-hydroxy-4-phenQxy-trans-l-but~n-yl)cycl~pent-la-yl~-acetic acid, y-lactone.:
The ir spectrum ~CHC13) of 4 had strong car~onyl absorptions at 1770 and 1715 cm 1 and an absorptiQn at 970 om ~0r the tran~ ~ouble bond .. . .
EXPXPL~ IV
2-[3a~5~-Dihydroxy-2B-~3a-hyd~oxy-4-phenoxy-trans-l-buten l~c clo ent-l-vl.lacetic a~id ~-lactQn0 ~ .
A heterogeneous mixtur0 of 846 mg. ~1.7 mmole) of 2-~3a~ hanylbenzoyloxy-~5~-hydroxy-2B-~3a-hydxoxy-4-ph0noxy-trans-l-buten-l-yl)cyc}opQnt-la-yl]acetic acid, ~-lactone, 1~ ml~ of absolut~ me hanol and 120 mg. o~ finely powdered, anhydrou~ pota,3sium carbonate was stirr~d at room ~emperature for 20 hour3~ then ~ooled to 0. To the oooled 501ution wa~
added 1.75 ml. o~ l.ON a~ueou~ hyd~ochloric acid. A~t~r ~tirring at ~ for an additional 10 minut~s, 10 ml. of water *Trad~mark ~' .
. , . . , : . .
: . .

,, .
:
. , was added with concomitant formation of methyl p-phenyl-benzoate which was collected by filtration. ~he filtrate 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 ~MgSO4) and concentrated to give 445 mg. of viscous, oily 2-13a,5a-dihydroxy-2B-~3~-hydroxy-4-phenoxy-trans-1-buten-1-yl)cyclopent-la-yl]acetic acid, y-lacton~.
The ir spectrum ~C~C13) 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.
BX~UPLE V
2-[Sa-Hydroxy-3a-(tetrahydropyran-2-yloxy-2~- (3a-tetrahydro-pyran-2-yloxy-4-phenoxy-tran~ buten-1-yl)cyclopent~ yl~-acetic acid ~-lactone To a solution of 445 mg. (1.4~ mmole) 2-l~a,5a~
hydroxy-2B-~3a-hydroxy-4-phenoxy-tran~-1-buten-yl~ cycl~pent-la-yl]acetic Acid, y-lactone in 5 ml. anhydrous methylene chlorid2 and 0.4 ml. of 2,3-~ihydr~pyran at 0~ ln a dry nitro~en atmo~phere ~as added 5 mg. p-toluene~ul~onia ~cid, monohydrate. After stirring for 15 minutes, the reaction mixture was combined with 10~ ml. ~ther, the ather solution washed with saturated sodium bicarbonate ~1 x 15 ml . ~ then saturated brine ~1 x 15 ml.), dried ~MgSO4) and cono~ntrated to yield 752 mg. ~>100%) crude 2-[5~-tetrahydr~pyran-2-yloxy-4-phenoxy- rans-l-buten-l-yl)cyclopent-la-yl~cetic acid, y-lactone.
The ir ~CHC13) spectrum had a me~ium abs~rption at 970 cm 1 for the tran8 double bond, and at 1770 cm 1 ~or 3~ lactone carbo~yl.
EXAMPLE VI
2~5a-Hydr~xy-3a-(tetrahydropyran-2-yloxy)-2B- (3a-tetrahydro-pyran-2-yloxy-4-phenoxy-trans-1-buten-1-yl) cyclopent-l~-yl]-~ h~mia~etal A 901ution o~ 690 mg. (1.46 mmole) 2-lSa-hy~roxy-3a ~t~trahydrcpyran-2-yloxy~-2B-~3a tetrahydropyran-2-yloxy-4-phenoxy- ran~ buten-l~yl)cy~lopent-la-yl]acetic acid, ~-lactone in 8 ml. dry toluene wa~ cooled to -78 in a dry ~.

nitrogen atmosphere, To thi~ aooled solution wa~ ~dded 2.0 ml. of 20% dii~obutylaluminum hydride in n hexane ~Alfa In-organics) dropwise at such a ratle 50 that the internal temp-erature never rose above -65 ~15 minutes~. A~ter an addi-

- 5 tional 45 minutes of stirring at -78, ~nhydrous methanol was add~d until gas evolution celased and the reaction mix-ture was allowed to warm to room temperature. The reaction mixture was combined with 100 ml. ether, wa~hed with 50%
~odium potassium tartrate solution (4 x 20 ml.), dried ~Na2S04) and concentrated to yield 613 mg. 2-~5a-hydroxy-3~-~tetrahydropy~an-2~yloxy)-2B-~3a-tetrahydropyran-2-yloxy-4-phenoxy-tran8-l-buten-l-yl)cyclop2nt-l-yl~acet~ldehyde, r-hemiacetal.
EXAMPL~ VII
9a-~ydroxy-lla,15a-bi~-~tetrahydropyran-2-yloxy)-16-ph~n~y-ci~-5-trans 13-~-tetranorprostadienoic acid ~ o a ~olution of 1.6 gm. ~3.6 mmole) ~4-carboxy-n-butyl)triphenylphosphonium b~omlde in ~ dry nitrogen a~mo-sphere in 6.0 ml. dry dimeth~l sulfoxide wa~ added 3.24 ml.
(6.5 mmole) of a 2.0M s~lUtion of sodiUm methyl8ulfinylmet~-ide in dimethyl sulfoxide. To ~hi6 red ylide solution wa~
added dropwise a solution of 613 mg. (1.29 mmole) 2-[5a-hydroxy-3~-~tetrahydropyran-2-yloxy)-2B-~3~-tetrahydropyran-2-yloxy-4-phenoxy- ran6-l-buten-l-yl)cyclopent-la-yl~acet-aldehyde, y-hemiacetal in 5.0 ml. dry dimethyl sulfQxide ov~r a period of 2g minutes. Aft~r an additi~nal 2 hour~
stirring at room tem~er~ture, th~ reaction mixtur~ wa~ pour~d onto ice water. The basic a~u~ous solution was ~a~hed twice with ethyl acetate ~2~ ml.) and acidified to p~ 3 with 10~
aqueou~ hydrochloric acid. ~he aci~ic ~olution was ex~racted wi~h ethyl ac~ta.e ~3 x 20 ml.) and t~e aombined organi~
extract~ washe~ once with wate~ ~10 ml.); dried (MgS04) and evaporated to a ~olid residue. This solid residue ~a~ tri~
turated with ethyl acetate and the filtrate concentrated to yield 754 mg. of 9a-hydroxy-lla,15~-bis-(te~rahydropyran-2-yloxy)-16-phenoxy-cls-5-tran~-13~-tetra~orpr~tadienoic acid was collected. Infrared spectrum ~CHC13) displayed a trong .. . . . ................................. . . .

. , : . : . . :
.
.

1~88~31 band at 1720 cm for the carboxyl group.
EXA~LE VIII
9-Oxo-11~,15~-bis-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorprostadienoic acid ~
To a solution cooled to -10 under nitrogen of 754 mg. tl.3 mmole~ 9a-hydroxy-lla,15~-bis-~tetrahydropyran-2-yl-oxy~-16-phenoxy-cis-5-trans-13-~tetranor-pro~tadienoic acid in 13 ml. reagent grade acetone was added dropwise to 0.56 ml. ~1.41 mmole) of Jone~' reagent. AftPr 20 minute~ at -10 1~ 0.26~ ml. 2-propanol was added and the reaotion mlxture wa~
allowed to stir an additional 5 minutes at which time it was combined with 75 ml. ethyl acetate, wa5hed with water (3 x 10 ml~), dried ~MgSO4) and conoentrated to give 752 mg. of 9-oxo-lla~15a-bis-(tetrahydropyran-2-yloxy)-l6-phen~xy-ci~-5-tran~-13-~-tetranorpr~stadienoic acid, which was chromato--graphed on ~ilica gel using ~thyl acetate a~ elue~t to af~rd 505 mg. of pure 10.
EX~MP~E IX
9-Oxo~ ,15a-dihydrGxy-16-phenoxy-cis-5-trans 13-~-tetranor-Dro~tadienoic acid A s~lution of 5~5 mg. ~0.S mmole) 9-ox~ ,15~-bis-~tetrahydropyran-2-yloxy~-16-phanoxy-cts-5-trans-13-~-tetranorpr~stadienoic acid in 6.3 ml. of a 65:35 mixture of glacial acetic acid:water wa~ ~tirred und~r nitroyen ~t 25 for 18 hours then was conqentrated by rotary evaporation.
The resultant crude oil was purified by c~lumn chromat~-graphy on silica gel ~Mallinckrodt* CC-4 100-20~ m~sh~ u~ing ethyl acetate as eluent. After ~lution of le~ polar impur-ities the ~ily 9-oxo~ ,15a-dihydroxy-16-phenox~-ci~-5-trans-13-~-tetranorprostad~noic acld welghing 210 mg. was coll~ct~d.
Ir ~C~C13) display~d a broad band at 1725 cm 1 for carbonyl ab~orptionfi~ and a band at 970 cm 1 for the 13,14-tran~-double bond.
__ ExaMæLE X
9a,11~,15~-Trihydroxy-16-phenoxy ci~-5-tran~-13-~-tetranor-~roQtadienoic acid ~~ ~
A mixture of 375 mg. ~0.65 mmole) 9a hydroxy-11~,15a-bi~-~t~trahydropyran-2-yloxy)-16-ph~noxy-c~-S-trans-*Trad~mark .~
;' .
, .

~(~8893~

13-w-tetranor-prostadienoic aaid, acetic acid (6.5 ml.~ and water ~3.5 ml.) was stirred under nitrogen at room temp~ra-ture for 2~ hours. The re$ultin~ clear ~olution wa~ conc~n-trated under reduced pressure an~ the residue (38~ mg.) wa~
dissolved in ethyl acetate. The ethyl acetate ~olution wa washed with brine (20 ml.), dried ~NaSO4~ and conaentrated to a clear oil. Chromatography on silica gel ~Mallinckrodt*
CC-7) using chloroform and then ethyl acetate as eluent afforded the desired product, 9a,11~,15a-trihydro~y-16-ph2n-oxy-cis-5-trans-13-~-tetxanorprostadienoic acid as a color-les~ oil weighing 98 mg.
EXAMPLE XI
9a-Hydroxy-lla,lSa-bis-~tetrahydrOpyran-2-yloxy)-16-phenoxy-~-tetranorprostanolc acid ~ mixture of 190 mg. ~0.33 mmole) 9a-hy~roxy-lla,15a- .
bi~-(tetrahydropyran-2-ylox~i-16-phe~oxy-cis-5-trans-13-~-~tetranorprostadienoic ac$d, 5~ palladium-on-car~on ~15~ mg.~
in methanol ~10 ml.) i8 stirred under an atmosphere of hy~ro-gen or 60 hours ~t room temperature. The mixtur~ 1~ filte~-ed and concen~rate~ to give 9~-hydroxy~ ,15~-bi~-~tetra-hydropyran-2-yloxy)-16-phenoxy-~-tetranorprostanoic acid.
EXAYPLE XII
9a,11~,15a-Trihydroxy-16-phenoxy-~-tetranorprostanoic acid Hydrolysis of 20 mg. 9a-hydroxy-lla,15a-bis-~tetra-hydropyran-2-yloxy)-16-phenoxy-~ tetranorprostanoic acid iB
~arrie~ out with acetic acid ~0.5 ml.) and water ~.3 m~.) under nitrogen at room temperature for 20 hour~. Pur~fioa-tion as described i~ Example X affords pure 9~,11a,15a-tri-hydroxy-16~ph~noxy-~-tetranorpro~tanoic acid.
EXAMPLE XIII

A ~lutlon of 186 mg. ~.3 mmole) of the product o~
Example XI in 3 ml. acetone is ox~dized with 0.14 ml. ~0.35 mmole) of Jone~ r~agent a de~cribed in Example VIII. I~l ation of the product and hydroly3is with acetic acid and wa~er at room temperature a~ de~crib~d in Example IX gives pure 9-oxo-lla,15a-dihydroxy-16-phenoxy-~-tetranorpro~tanoic *Trademark ~'' ' ' ~' ', : , :, 1(~ 3~

acid.
EXAMPLE XIV
~ .
9-Oxo-15~-hydroxy-16-phenoxy-c~ S,10- rans-13-~-tetranor-~ro~tatrienoic acid A mixture of 52 mg. ~0.,1 mmole~ 9-oxo-lla,15~-di-hydroxy~ phenoxy-ols-5-trans-13-~-tetranorpro~tadienoi acid with 0.2 ml. 97% formic acicl ia stirred at 25 for 2.5 hours. About 5 ml. ice-water ls added to the reaction mix-ture which is then extracted with ethyl acetate, d~ied ~Na2S04) and concentrated to give a crude oil. Chromatography of the cruda product on silica gel (Mallinckrodt* CC-7) u~ing methylene chlorida-ethyl acetake as eluent give~ th~ desir~d 9-oxo-lSa-hydroxy-16-phenoxy-cis-5,1U-trans-13-~-tetranor-pro~tatrienoic acid.
EX~MPLE XV
.

9-Ox~ ,lSa-dihy~ro~y-16-phe~oxy-~-tetranorprosta-noi~ aci~ is treated with 97% fQ~mic a~i~ a~ d~cr~bed ~n Example XIV and conv~rted to colorles~ oily 9-oxo-15a-hydroxy-2~ 16-phenoxy-~-tetran~r-pro~t 10-enoic acid.
EXhK~LE XVI
~-[3a-~-Phenylbenzoyloxy-Sa-hydroxy-2~-(3-hydroxy-3-mekhyl-4-phanoxy-tran~-l-buten l-yl)cyclopent la-yl~asetic acid, y-lactone 24 To a solution of 2-[3~-p-phenylbenzoylQxy-5a hydrQxy-2B-(3-~xo-4-phenoxy-trans-1-buten-1-yl)cy~lopent~
yl]acetic acid, y-lactone cooled to 78 in ether-T~F, i3 added dropwi~e one equivalent o~ 2N ~olution o~ methyl lithium in ether. A~ter stirxin~ at ~78 ~or 15 minute~ the reaotion is quenched ~y addition of glacial acetic acid, su~ficient to bring p~ up to 7. The mixture is diluted with methylene ahloride, wash~d with water, saturated brine, dried (Na2S04) an~ concentrated t~ give the oily epimeric ~lcohol~. The arude product i~ pu~ d by column chromatography on silica gel to give the de~ired 2-~3~-~.phenylben~yloxy-5~-hydroxy-2B-~3-hydroxy-3-methyl-4-phenoxy-tran~ buten-1-yl)cyclopent-la-yl]acetic acid, y-lactonQ, which may be converted to givo 17 and 17' thr~ugh stsp~ previou81y outlined for the prepara-*Tra~emark , W~3~-36-tion o 9-oxo-lla,15a-dihydroxy-16-phenoxy cis-5-trans-13-~-tetranorprostadienoic acid.
EXaNPLE XVII
9~,11a,15a-Trihydroxy-16-phenoxy-5-cis-13-trans-~-tetranor-orostadienoic acid To a solution of 50 ~g. of 9-oxo-lla,15a-dihydroxy-16-phenoxy-cis~S-trans~13~-tetranor-prostadienoic acid in 2.5 ml. absolute m~thanol ~ooled to 0 i3 added dropwi~e a solution o~ 25 mg. of ~odium bo~hydride in 1 ml. ab~olute methanol. The reaotio~ mixture is ~ti~red under nitrogen at 0 for 2 hours and the~ concentrat~d. The residue i8 diB-solved in methyl~ne chloride, washçd with b~ine, dried ~Na2S04), and i~ concen~rat~d. Purifioation o~ ~he crud~
produ~t by silica ~el chromatography afford~ 16-phenoxy PFG
and the desir~d~9~,lla,15e-txihydroxy-16-phen~xy-S-ci~-13-tr~n~ ~-tetxanorprostadienoic aoid.
EX~PLE XVI T I
2-~3a ~-Phenylbenzyloxy-Sa~hydroxy-2B-~3a-hydrsxy-4-ph~noxy-but~l-vl)ovcl~ent Ia-Yl~ac~ a¢id Y-lactone A heterogenous solution of 2.5 g. ~f 2-~3a-~-phenyl-benzoyloxy-5a-hydroxy-2B-~3a-h~droxy-4-phe~xy-tran~ but~n-l-yl)cyclopent-la-yl]acetic acid, y-lactone and 0.25 g. of 5% palladium-on-charcoal in 30 ml. of absolute methan~l ia stirred under 1 atmo6phere of hydrogen for 4 hours. The mi~-ture is then ~iltered and concentrated to afford 2-[3a-~-phenylbenzoyloxy-5a-hyd~oxy-2B-~3-ox~-4-phenoxy~utrl-yl)- -cyclo~ent-la-yl~cetic acid, ~-lactone, To a ~oluti~n ~ 1.9 g. o~ ~he crude hydrog~nation product ab~ve in 20 ml. of ab olute methan~l is ~d~ed exces~ :
sodium borohydride and the ~oluti~n is ~irred ~t ro~m temp-erature u~d~r nitrogen for 2 hour6 t and th~n con~entrated.
The r~idue i~ diluted with 0.1 N hydrochloric acid and the agueou~ layer i8 extract~d with ethyl aca~ate. ~he combined organi~ extracts are wa~h~d wlth saturated br~:no, are dried ~Na2S04), ~nd are concentrated~ Purification o~ the crude .
re~idue by sil~ca gel chromatog~aphy afford~ 2-~3~ phenyl-benzyloxy-5a-hydr~xy-2B-~3a-hydr~xy-4-phenoxy-but-1-yl~yclo-pent-la-yl~ace1;ic acid, y~lactone and the 3~-hydroxy epimer.

~lLQ8~1931 This is converted to the 13,14-dihydro E2 and F2 compounds using methods employed in Examples V through IX, EXAMPLE XIX
9~-Hydroxy-11~15~-bis-(tetrahydroPYran-2-yloxy)-16-phenoxy-13-trans-~-tetranorprostenoic acid A heterogeneou9 mixture of 800 mg, o~ 9~-hydroxy-lla,15a-bis-~tetrahydropyran-2-ylox~)-16-phenoxy-cis-5-tranfi-13-~-tetranorprostadienoic acid and 80 mg. of 5~ palladium-on-charcoal in 10 ml. of absolute methanol is ~tirred under 1 atmosphere of hydrogen at -22 for 5 hours. The mixture i8 then filtered and the filtrate i8 conoentrated to a~ford 9~-hydroxy-lla,15a-bis-~tetrahydropyran-2-yloxy)-16-ph~noxy-13-trans-~-tetranorpro~tenoic acid.
~ydrolysis with acetic acid and water in th~ usual manner affords 16-phenoxy PGFl~.
EXAPPLE XX
9-Oxo-lla,15a-dihydroxy-16-phenoxy 13-trans-~-tetranorpro~-A s~lution of 72 mg. 9-oxo-11~,15~-dihydroxy-16 phenoxy-als-5-tran~-13-~-tetranor-pro~tadienoic acid in 5 ml.
of anhydrous ether i~ treated with 4S0 mg. dîmethyli~opropyl chloro~ilane and 36 mg. of triethylamine at room tempera~ure under nitrogen for 48 hour5. The reaction mixture is cooled to 0, methanol i8 a~ded, and the re9ulting ~olution i8 ~a3h-ed with watert dried ~Na2SO4), and i~ concentrated. There~idue i8 di~solved in methanol ~6 ml.) and 30 mg, o 5%
palladium-on-charcoal is added. The resulting mi~ure i8 stirred at -22 under 1 atmo~phere of hydrogen ~or 4 hours.
After filtration and concentration of the filtrate, the re~idue i~ ~tlrred with a 65:35 mixture of aaetio acid:~ater for 10 minute~ at room temperature. The mixture i6 diluted : with water, extracte~ with ethyl acetate, dried ~Na2SO4) and concentrated to afford, after purification by ~ilica gel chromatography, 9-oxo~ ,15a-dihydroxy-16-phenoxy-13-tr~ns-~-te~ranorpro6tenoic acid.
EX~MPLE XXI
~C
A mixture o~ 5-bromovaleronitrile ~16.2 g., 0 10 molet, triphenylpho~phine ~26.2 y., 0.10 mole~ and toluene B

.

93~

~100 ml.) was heated to reflux w:ith stirring undex nitrogen for 16 hour~. The resulting thiek white suspen ion was cool-ed to room temperature and filtered. The residue wa~ washed with benzene and air dried to give 33.9 g. of a white, crystalline solid, m~p. 230-232, which was 4-cyanobutyltri-phenylphosphonium bromide.
A _ .
Calc'd for C23H23BrNP: C, 65..L0; ~, 5-47; N, 3.30 Found: C, 65.~1; H, 5.40; N, 3.19.
10A mixture of the phosphonium salt above ~10.0 g., 23.5 mmole~l, ammonium chloride ~1.60 g., 30.0 mmoles~, lithium chloride (0.032 g~, 0.76 mmole), ~odium a~ide ~1.91 g., 29.3 mmoles), and dimethylformamlde ~50 ml.~ was heat~d to 127 ~oil bath) under nitrosen wlth stirring for 18 hour3.
The resulting suspension was cooled and filtered. Ths resi~ue wa~ wa~h~d wi~h dimethylformamide and the c~mbined filtrate -~
and washing5 were ~oncenkrat~d tasPirator prQssure, ca. 45).
The oily residue wa~ crystallize~ from water ~k ~ and air dri~d to give a white cryst~lline solid (8.11 g.), m.p. 100-20 102. The product was recrysta}lized from methanol-ether to give white prisms ~7 .18 g . ~ . M.P . 197-206 . An analytical sample was prepared by recrystallizat~ on ~rom 2-propanol to give a white crystalline powder, m.p. 212~213, ~hich was 4-(tetrazol-5-yl)butyltriphenylphosphonium brvmide.
Anal.
Calc'd for C23H24H4PBr: C, 59.10; H, 5-1~; N, 11.99 P, 6.63; Br, 17.09 Found: C, 59.35; ~, 5.28; N, 12.31;
P, 6.78; Br, 17.26.
EXAMPLE XXII
1- ~Tetrazol-5-yl) -9a-hydroxy~ ,15a-bis- (tet.rahydropyran-2-To a solution of 4-(tetrazol-5-yl) butyltriphenyl phosphonium bromide (1.49 gm.) in a dry nitrogen atmo~phere in 6.0 ml. dry DMSO i5 added 3 . 24 ml. of a 2.0 M solution of sodium methylsulfinylmethide in DMSO. To this solu~ion is added dropwise a solution of 615 mg. 2- ~5a-hydroxy~3~-~tekra-hydropyran-2-yloxy) -2B- ~3~ tetrahydropyran-2-yloxy-4-phenoxy-,~
. . .
~, - - .
, .

- ' ' ' ' '' ' ` ' . ' .
... . .
.. .

:lQ8~5~3i ` ~ .

tran~ buten-l-yl)cyclopent-l~ acataldehyde, y-hemiacetal in 5.0 ml. dry DM90 over a period of 20 minutes. After an additional 2 hours 5tirring at room temperature the reaction mixture i~ poured onto ice water. The basic aqueou~ Bolution is acidified with O.lN HCl and extracted with ethyl acetate, The residue obtained ater evaporation o~ the solvent is chromatographed, to give pure l-~tetrazol-5-yl)-9~-hydroxy-lla,15a-bis-~tetrahydropyran-2-yloxy~-16 phenoxy-cis-5-txan 13-~ tetranorprostadiene.
10 EXAMæLE XXIII
[4-~Methanesul~onylaminocarbonyl~butyl]~riphenylpho3phQnium bromide ~ mixture of 0.950 g. ~0.~1 mole) of methanesul~on-amid~ and 1.80 g. ~0.01 mol~) of S-bromovaleric acid chloride was heat~d on a steam bath until gas evolution cea~ed ~ca.
5 minutes). The brown reaction mixture wa~ allowe~d to c~
and was ~is~olved in methyl~ne chlorida. The methyl~ne chloride 301ution was treated with Darco, wa~ filtor~d, an~
wa6 diluted with hexane with cooling to a~ford the white, cry~talline N-methanesulfonyl-5-~rom~valeramide weighing 2.22 g. ~86.0~ yield) which melted at 88-89.
The nmr spectrum ~CDC13) showed a broad ~inglet at 4.26-3.95~ for the N-~, a multiplet at 3.66-3.23 ~r tha -CH2Br, a singlet at 3.31~ for the S02-C~3, a multiplst at 2.63-2~20~ for the -C~2C0, and a multiplet at 2.12 1.52~ ~r the CH2-C~2. Th~ ir ~pectrum ~C~C13) sh~wea a s~r~ng absorp-tion at 1720 cm 1 attributable to the caxbonyl group.
A solution of 2.20 g. ~8.57 mmoles) o~ the N-meth~nesul~nyl-5-bromovaleramide, pr~pared as above, 2.24 g.
3G ~8.57 mmola~) of triphenylpho~phine, and 20 ml. o~ aoeto-nitrile was heated to reflux under nitrogen overnight. ~he solution wa~ then ~oncentrate~ by rotary ev~poration and the re~ultant ~olld wa3 tritur~ted with hot benzene ~4~). The triturated solid wa8 reo~ystalliæed from ab601ute sthanol:-ether to afford the whlte, cry talline t4-(methan~3ulfonyl-amino~arbonyl)butyl~t~iphenylpho~phonium bromi~e weighing 2.80 g. (63.7% yield) meltin~ at 190-191.

.~
.
- . .

,. . . . : . .
, ~ . .

~ 3L()8~3~

The ir spectrum ~KBr) of the product exhibited a strong absorption at 5.85 ~ attributable to the carbonyl group. The nmr spectrum ~CDC13~ exhibited a complex multi-plet at 8.14-7.27~ for the aromatic pro~ons, a multiplet at 4.00-3.30~ for the -C~2P, a singlet at 3.12~ for the -S02C~3, a multiplet at 3.00-2.3~ for the C~2CO, and a multiplet at 2.23-1.38~ ~or the C~2CH2. A titration of the solid product indicated the pKa 1/2 to be 5.25.
EXAMP~E XXIV
-~-Biphenyl 9-oxo-lla,lSa-dihydroxy-16-phenoxy-cis-S-~ran~-I3-~tetranorpro~tadienoate To a solution of 50 mg. tO.13 mmole) of 9-oxo-11~,15~-dihydroxy-16-phenoxy-cis-5 tran~-13-~-tetranorpro~ta-dienoic acid and 63 mg, (0.4 mmole~ of p-phenylphenol in 10 ml. o~ dry methylene chloride wa~ add~d 8~5 mg. (0.4 mmole) of dicyclohexylcarbodiimide and th~ ~olution stirred ~ver-night at room temperature. Afk~r conce~tration, the crud~
product wa~ purifi~d by silica gel chromatography ~o give the des~red ~-biphenyl ester, m.p. 100-1~2.
Anal.
Calc'd fur C36~3~06: C, 75.53; ~ 71 Found: C, 75,65; H, 6.83.
EXAMP~E XXV
~-Biphenyl 9a,11~,15~-trihydroxy-16-phsnoxy-cis-5-trans-13-~-tetranor-prostadianoate To a solution o~ 106 mg. o~ 9a,11a,15a-trihydroxy-16- phenoxy-cis-5-trans-13-~-tetranorprostadien~$c aaid and 189 mgO of p-phenylphenol in 30 ml. dry methylens ahlorido waC added 6~0 mg. of dicyclohexylcarbodiimide and th0 ~olu-~ion sti~red overnight at room temperature. A~ter concentra-tion, the crud~ product was purified by silica gel chroma-tography to give 80 mg. pure ~-biphenyl e~ter, m.p. 101-103.
Anal -Calc d for C34~13306: C, 75.25; ~, 7.
35Founds C, 75.38; ~, 7.30.

.
~., .: . . , . . : : . . . . : -. .
, . . .
~.
.. . .. ..

.

lQ8~393~

EXAMPLE XXVI
Phenethyl 9-oxo-lla,15~-dihydroxyl-16-phenoxy-ci8-5-trans-13-~-tetranorprostadienoate A mixture of O-phenethy:L-N,N'-dicyclohexyl-isourea, prepared by reacting phenethyl al~ohol and dicyclohexylcarbo-diimide, and 9~oxo-11,15 dihydroxy-16-pheno~y cis-5-trans-13-~-tetranorpro~tadienoic acid in methylene chloxide and di-methylformamidQ is atirred o~erni~ht at room tempera~ure, Af~er filtration, concentra~ion and chromatography on ~ilio~
gel the pure phenethyl aster is obtained.
In a similar fashion ar~ prepared the benzyl, cyclopropyl and oyclooctyl e~ter8 u8ing benzyl alcohol, ayclopropanol and cyclooctanol, respectively.
XX~XPL~ XXVII
Methyl 9~ ,15a-trihYd~oxy-16-phenoxy-ols-5-tran~-13-~-te~ranor~rostadienoate ~ , , , . ,"..
To an ethereal solution of 100 mg, of ga,ll~,l5a-trihydroxy-16-phenoxy-ci~-5-trans-13-~-tel:ranorpr~t~di~noic acid i8 addea ~n excess of other~al diazomethane until a yellow color persists. Concentration affords pure m~thyl 9a,11a,15a-trihydroxy-16-ph~n~xy-ci~-5-trans-13-~-tQ ranor-pr~stadienoate.
Similarly, using diazodecane ~prepared by oxi~ation of dodecyl hydrazone) is prepared dod~yl 9~ ,15~-tri-hydroxy-16-phenoxy-cis-5-trans-13-~-tetranorprostadienoate.
~ XAUPL~ XXVIII
9~,11a,l5-Trihydroxy-16-ph~noxy~ 5-trans-13-~-tetranor-pro~tadienoic acid tris-hydroxyme~h~lamino methane 8alt ~o a ~oluti~n o~ 0.70 mmole of 9B,lla,15~-trihydr-3~ oxy-16-phenoxy~ 5-t~ans 13-~-t~tranorprostadienoic a¢id in 3S ml. o~ ~ry aceto~itrile, heated at 83 i~ added a ~olu-tion of 86 mg. (0.68 mmale~ o~ tris-hydroxymethylaminomekhane in 0.15 ml. of wat2r with vigor~u~ 9tirring. The mixture ia allowed to cool to roam t~mparature and 9~,11a,15~-trihydroxy-16-phenoxy-ci~-5-tr~n~-13-~-t~tranorprostadisnoic acid tri~-hydr~xym0thylamino methane ~alt i~ colle¢ted.

. . ~: : :
, .
.. . . . :
: . . . .
:,: ' , .., .: , ; :

.

93~

~XA~PLE XXIX
- .
9-Oxo~ 15a-bisformyloxy-16-phenoxy-CiS-5-trans-13-~-tetra-norprostadienoic acid_ .. . . .
To a solutio~ of 0.1 mmol~ of 9-~xo-11,15~-di-hydroxy-16-phenoxy-cls-5-tranS-l3-w-tetranorprostadienoic acid in 0.5 ml. of dry tetrahydrofuran is added 29 mg. ~0,33 mmole) o~ ~ormic acetic anhydrid~ and 35 mg. (0.33 mmola) of 2,6-1utidine. The solution i8 st:irred ~or 1 hour under nitrogen at room temperature thes~ 36 mg, of water is addod.
The mixture is ~tirred at room t~mperature for additional on~
hour and diluted ~ith ethyl ac~tate. The diluted Bolution is washed with O.lN HCl, watar and brine, ~hen drl~d ~Na2S04~.
Chromatography o~ the crude product on silica gel afford~
the desired bi~formyloxy compound.
EX~MPL~ XXX
.. -- . ...
9B,lla,15a-Tri~pivaloyloxy-16-phenoxy-c~s-5-tr~n#-13-~-t~tra-nor~rostadienoic acid To a solution of 0.2 mmole of 9B,lla,15otrihydroxy-16-phenoxy-ci~-S-tran3-13-~-totranorpro~tadienoi~ acld in 1 ml. of pyridine i8 added 120 mg. ~1.0 mmole) of pivaloyl chlorlde. The solution is ~tirred 4 hours at 45 und~r nitrog~n then iB ~ooled to room t~mperature. Wat~r ~40 mg,~
i8 added and the mixture stirrad 2 hourY ~t room tQmper~ture and dilutad with ethylacQtate. The diluted ~olution i~
wa~hed with dilut~ ~Cl, water and than brine. Co~centrat~o~
and purification by ~hromatogr~phy on silica gol g~ve ~e d~sir0d tri~pivaloyloxy acid.
EXa~}~ XXXI
l-t~tr~zol-5-yl)-9a-hydroxy-lla,15a-bis-(tetrahydropyran-2-~
To a s~lution o~ 4-(tetrazol-5-yl)bultyl~riphenyl pho~phonium ~romide ~1.49 g.) in a dry nitrogen a~mo~pher~
ln 6.0 ml. dry ~MSO w~ added 3.24 ml. of a 2.0M solut~o~ o~
~od~um m~thyl~ulfinylmothida in D~SO. To this solution w~
added dropwi-qe a solution of 615 mg. 2-~5-hydr~xy-3~-~tetra-hydropyra~-2-yloxy~-2~-~3a-~tstrahydropyran-2-yloxy)-4-ph~n-oxy-tran~-l buton-1-yl)cyclopent-1-yl~acotaldehyde, y-h~mi-acet~l in 5.0 ml~ dry DMSO over a period of 20 minut~. After '~.

'~,~

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. .
, . . , ~ , ,, . :

~ 38~3~

an additional 2 hour stirring ak room temperature, th~ re-action mixture ~as poured onto ice water. The basic aqueous solution was acidified with O.lN ~Cl and extracted ~ith ethyl acetate. The residue obtained after evaporation of the solv-ent was chromatographed to give 680 mg. pure colorlesæ oilyl-(tetrazol-5-yl)-9~-hydroxy~ ,15a-bis-(tetrahydropyran-2-yloxy)-16-phenox~-cls-5-tran -13-~ tetranorprost~diene, EXAMPLE XXXII
l-~Tetrazol-5-yl)-9a,11a,15~-trihydroxy-16-pheno~y-cls-5-trans-13-~-tetranorprostadiene lla,15a-bi ~tetr~hydropyran-2-yloxy~-16-phenoxy-c ~8- 5-tr~ns-13-~-te~ranor-pr~stadiene in 6 ml. of 65:35 mix~ure of glacial acetic acid:watar w~ stirred under nitrogon ~t 25~
for 18 hour~ and then w~s ~oncontr~ted by rot~ry avaporatlon.
The r~sultant crude oil ~a~ purifi~ by column c~romatogr~phy on ~ ca gel tMA~ ckrodt CC-7, 100-2Q~ m~h) u~ x-tur2s of chloroform:e~hyl ac~tat~ a~ ~lu~nt. A~t~r ~lution of le~ pol~r impurities the colorles~, oily 1-(t~tr~ol-5-yl)-20 9a, lla ,15~-trihydroxy-16-pbenoxy-cis-5-tran~-13-~ totranorD
prostadiene weighing 220 mg. ~80% yi~ld) ~a~ collect~d~
EXAMP~E XXXIII
l-(Tatrazol-5~yl)-9-oxo-lla,15-bih-(t~tr~hy~ropyr~n-2-yl~xy)-16-phenoxy-ci~-5-~rans-13-~-tetranorpro~tadi~nQ
~o a ~olution cool~d to 15 under ni~rog~n, of 600 mg~ 1-(t~r~zol-5-yl)-9a-hydroxy-lla,15a-~ t~*~ra~ydro-pyran 2~yloxy)-16-ph~noxy-~ic S-tran~-13-~-t~tr~no~pros~-diene in 12 ml. raagent grad~ ~etone was ~dd~d arOp~ 0.6 ml. of Jone~' reag~nt. A~ter 30 minut~s ~t -1~, 0.6 ~1.
2-propanol wa~ added and tho r~ction mLxtur~ allo~od to ~tir at ~ddit.ional 5 minute~ at which tlme it W~8 comb~n~
wl~h 75 ml. ethyl ac~tat~, washed with water ~3 x 10 ml.)~
dried (Na2SO4) and concentr~ted to giv~ 510 mg. o~ the oolor-le~5, olly 1-~tetrazol-5-yl)-9-oxo~ gl5~-bi~-ttetrahydro-35 pyran-2-yloxy)~ phQnoxy-ci8-5-trAn~ 3-~ t~trz~norpro8~:a-dione.

.... , .. , . . ~ : . , . . . . . . : ..

.
,. ~ . . .
. , : .

: , . :, , .

1~8~931 ~, EXAMPLE XXXIV
l-~Tetrazol-5-yl)-9-oxo~ ,15a-dihydroxy-16-phenoxy-cis-5-trans-13-~-tetranorprostadiene A ~olution o~ 508 mg. 1- ttetrazol-5-yl~-9-oxo-5 11~,15~-bl~-(tetrahydroPyran-2-yloxy)-l6-phenoxy-cl~-s-trar~
13-~-tetranorprostadiene in 10 ml. of a 65:35 mixtuxe of glacial acetic acid:water was stirred under nitrogen at 25 ~or 2~ hours and then was concentrated by rotar~ evaporation.
The resultant crude oil wa~ purif ied by column chromatography on 8ilioa gel (Mallin~krodt* CC 7 100-200 me~h) uaing mlx-ture~ of chloro~orm:ethyl acetate as eluants. A~ter elution af le~s polar impuritie~ the colorless oily l-~t~trazcl-5-Yl)~9-o~o~ s~-dihyd~oxy-l6-phenoxy~ 5-tra~s-l3 tetranorp~ostadiene weighing ~40 mg. wa~ obtained.
EXAMPL~ XXXV
N-Me~hanesulfonyl-9a-hydroxy-lla,15a-bia-~t~trahydropyran-2 T~ a ~Qlution of 1.7 g. ~-methanesulfonylamino-carbonyl~b~tyl~triph2nylpho~phonlum bromi.d~ in a d~y n~tro-gen atmosphere in 6.0 ml. dry DMSO was added 3.2 ml. ~6.5mmole3 ~f a 2.0 M solution ~ ~odium met~ylsulfinylmethi~2 in DMSO. To this red ylid solution was adde~ drop~ise a solution o~ 610 mg. tl.29 mmole) 2-~5~-hydroxy-3~-~t~tra-hydropyran-2-yloxy~-2B-~3~-~tetrahydropyran-2-yloxy)-4-phon-oxy-trans-l-but~n-l-yl)cyclopent-la-yl~acetaldehyde, y-hemi-acetal in 5 ml. dry D~SO ov~r a period of 20 minutes. Aftor an additional 2 hour ~tirrin~ at ro~m temperature, the r~-action mixtu~e poured onto ice water. The basic aqueous ~olution was wash~d twice with ethyl acetate (3 x 20 ml.) and comblned orga~ic ~xk~aot~ wa~hed on~e ~ith water ~10 ml.), dri~d ~Na2S~4) and evaporat~d ~o an oil. Chromatography on ~ilica gel a~orded 684 mg. pure oily N-methane~ul~onyl-9a-hyd~xy-lla,l~-bi3-(tetrahydropyran-2-yloxy)-16-phenoxy-~
5-tran~-13- -t2txanorprostadienamide.
~ E XXXVI
N-Methane~ulf~nyl-9~,lla,15a-trihydroxy-16-phenoxy~ois-5-tran~-13-~-tetranorprostadien~mide __ A solution of 250 mg. in 5 ml. of 65:35 mixture of *Trad~mark : -, ~ .

.

~0~38931 .

glacial acetic acid:~ater was stirred unde~ nitrogen at 25 for 18 hours and then was concentxated 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 polarimpurities the colorless oily N-methanesulfonyl-9~,lla,15~-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-~-tetranorprostadienamide _~ . . . ..
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 an additional 5 minutes at which time it was combined with 60 ml. ethyl acetate, washed with water (3 x L0 ml.), dried ~Na2SO4) and concentrated to afford 380 mg. o~ the colorless oily N-methanesulfonyl-9-oxo-lla,lSa-bis-~tetra-hydropyran-2-yloxy)-16-phenoxy-cls-5-trans-13-~-tetranorpxos-tadienamide.
EXAMPLE XXXVIII
N-Methanesulfonyl-9-oxo~ 5a-bis-dihydroxy-l6~phen 5-trans-13-~-tetranorprostadienamide A solution of 260 mg. in 6 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitroyen at 25~ for 20 hours and then was concentxated 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 impurities the colorless N-methanesulfonyl-9-oxo-ll~,lSa-bls-dihydroxy-16-phenoxy-cls-5-trans-13-~-tetranorprostadien-amide weighing 130 mg. was obtained. The product crystalliz-ed from ether as colorless crystals, m.p. 76 *Trademark .,~

,, .. : , ... .: ; '. ' . .. , : . , , ~ .
. . .

... . : .. ,.; . . . . .
, .

~ ,, ~"
--4~--E}~WPLE _XXXIX
9~ ,15~-Trihydroxy-16-phenoxy-cis-5-trans-13-~-tetranor-prostadienoic a~id _ __ To a stirred solution of 0.18 g. (0.47 mmole) 9-oxo-lla,15a-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 ~aO~ ~10 ml.). After 1 hour at 0, the reaction was quenched by addition of watex ~4 ml.) and con-centrated under reduced pr~ssure. The residue was acidified with 10% HCl to pH 3, extracted with ethyl acetate, dried ~Na2SO4) and concentrated. Chromatography on 20 g. silica gel ~CC-7*) and elution with methanol-ben2ene af~orded pure 9~ ,15~-trihydroxy-16-phenoxy-ci~-5-trans-13-~-tetranor-prostadienoic acid, as a colorless oil, homogenous on t.l.c., rf 0~25 ~C6H6-dioxan-HCO~H, 15:S:2).
~XAMoeLE XL
N-~enzoyl 9-oxo~ ,15a-dihydroxy~5-cls-13-trans-16-ph~noxy-~-tetranorprostadienamide To lo0 mmole of 9-oxo-lla,15a-b1s-~tetrahydropyran-2-yl-oxy)-16-phenoxy-c1s-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 0Ol molar benzoylisocyanate in T~F is added.
After a rurther hour of stirring, the reaction mixture is neutralize~ with acetic acid and the solvent removed by evaporation ~ln vacuo). The resultant residue i.s taken up in methylene c~oride and washed successively with water and sodium bicarbonate to yield, after drying and solvent evapora-tion, N-benzoyl 9-oxo-lla,15~-bis-~tetrahydropyran-2-yloxy)-30 16-phenoxy-c -5-trans-13-~-tetranorprostadienamide. This intermediate is th~n hydrolyzed overnight with acetic acid/-water (as in Example IX) and purified by column chromatography to give the desired N-benzoyl-9-oxo-lla,15~-dihydroxy-5-cls-13-trans-16-phenoxy-w-tetranorpro tadienamide.
EXAMPLE XLI
N-Methanesulfonyl 9-oxo-lla,15a-dihydroxy-5-cis-13-trans-16-phenoxy ~-tetranorprostadienamide To 1.0 mmole of 9-oxo-lla,15~-b1s-(tetrahydropyran-*Trademark ~ . .
, , ~ . - . , . : .
,.

., , , , , , , ~: , . . '' , 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.
A~ter a further hour of stirring, the reaction mixture is neutrali~ed with acetic acid and the solvent removed by evaporation ~ln vacuo~. The resul.tant residue is taken up in methylene chlorine and washed successively with water and sodium bicarbonat~ to yield, after drying and solvent evapor~
ation, ~-methanesulfonyl 9-oxo~ ,15a-bls-~tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorprostadienamide.
This intermediate is then hydroly2ed over~ight with acetic acid/water ~as in Example IX~ and purified by column chroma-tography to give the desired N-methanesulfonyl 9-oxo-lla,15a-dihydroxy-5-cis-13-tran~-16-phenoxy-~-tetranorprostadienamide.
EXAMPLE XLII
N-Acetyl-9a-hydroxy-lla,15a-bis-~tetrahydropyran-2-yloxy)-16-phenoxy-c~s-5-trans-13-~-tetranor-prostadienamide To a solution of 5.32 g. ~4-~acetamido carbonyl)-butylltriphenyl phosphonium bromide in a dry nitrogen atmo-sphere in 10 ml. dry DMSO was added t~,7 ml. of a 2.0 M solu-tion of so~ium methylsulfinyl methide in DMSO. To this red ylid solution was added dropwise a solution of 0.524 g. ~
mmoles) 2-~5-hydroxy-3a-~tetra~ydropyran-2-yloxy)-2~-~3~-~tetrahydropyran-2-yloxy)-4-phenoxy-trans-1-~uten-1-yl)cyclo-pent-la-yl]acetaldehyde, y-hemiacetal in 10 ml. dry DMSO
over a period of 20 minutes. After an additional 2 hours stirring, at room temperature, ~he reaction mixture was poured onto ice water. The basic aqueous solution was washed twice with ethyl acetate (3 x ~5 ml.) and combined organic extracts washed o~ce with water ~10 ml.), dried ~Na2SO4~ and evaporat-ed to an oil. Chromatography on silica gel afforded 0.66 ym.
pure oily N-acetyl-9a-hydroxy-11,15a-bls-(tetrahydropyran-2-yloxy)-16-phenoxy-cis-5-trans-13-~-tetranorpro3tadienamide.
EXAMPLE X~III
N-Acetyl-ga,lla,15a-trihydroxy-16-phenoxy~cls-5-trans-13-~-tetranorProstadienamide A solution of 0.39 g. of N-acetyl-9a-hydroxy-lla,15a-. . : . . : : . , . -: ', ' ' , ' ~ ! . . '. ' . , . ' . . ' . ' ' , ' ." ' ' ', '' " ' .
.' , ., ' ' ' . ' ' .

, 33l bis-~tetrahydropyran-2-yloxy~-16-phenoxy-cis-5-tran~-13-~-tetranorprostadienamide in 5 ml. of 65:35 ml~ture o~ glacial acetic acid:water ~as stirred under nitrogen at 25 ~or 18 hours and then was concentrated to a arude oil, ~hich was purified by column chromatography on silica gel ~CC-7*~, using mixtures of chloroform:et~yl acetate as eluant. After elution of less polar impuritie~3 the colorle~s oil N-acetyl-9a,11a,15a-trihydxoxy-16-phenoxy-cis-5-trans-13-~-tetranor-prostadienamide weighing 95 mg. was colleated.
EXAMPLE XLIV
__ N-Acetyl-9-Qxo-11~,15a-bis-~tetrahydropyran-2-yloxy)-16-phen-oxy-cis-5-trans-13-~-tetranorprostadi~namide To a solution cooled to -10 un~er nitrogen, of 394 mg. N-acetyl-9a-hydroxy-lla,15a-bi5-~tetrahydrOpyran-2-yloxy)-16 phenoxy-cls-S-trans-13~-tetran~rpxo~tadienamid~
in 10 ml. reagent grade acetone wa~ added dropwise 0.27 ml.
of Jone~' reagent. After 3~ minute~ 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 wa~ combined with 60 ml. ethyl acetate, washed with water (3 x lO ml.), ~ried ~Na2S04~ and concentrated to afford 390 mg. o~ col~r-less oily N-acetyl 9-oxo-lla,lSa-bis-~tetrahydrcpyran-2-yloxy)-16-phenoxy~ci~-5-trans-13-~-tetranorprostadienamide.

N-Acetyl-9-oxo-lla,15~-bi~-dihydroxy-16-phenoxy-ols-5-trans-13-~-tetranorprostadienamlde A ~olution of 390 mg. of N-a¢etyl-9-o~o-lla,15a-bis-~tetrahydropyran-2-yloxy)-16-phenoxy-ci~-S-tran3-13-~-tetranorprostadienamide in 8 ml. of a 65:35 mixture of glacial acetic acid:water was stirred under nitrogen at 25~ for 20 hour6 and then was concentrated to a crude oil ~hich was purified by column chromatography on sillca gel using mix-turee of chlorQform ethyl acetate as eluantsO After elution of le~ polar impurities the colorle~3 oily N-acetyl-9-oxo-lla,lSa-bis-dihydroxy-16-phenoxy-cls-5 tran~-13-~-tetranor-prostadienamide weighing 76 mg.

~Trademark ~88~3~

-S.D. 49-SUPPLEMENTARY DISCLOSURE

0~ 0 R s~
tq a~
g ~ ~ O ~ t~ ~ t~
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--S~Do 50~
SUPPLEMENTARY DISCLOSURE

O

O ~ ,q U
~1~ 8~ ,u ~"

O I` r~ c~ o o ~ rl C~ O rl U~ r~ C~
~ ~ ~ ~ ~ ~ H ~ ~ H ~ ~ ~ ~ H ~ ~ H ~ ~

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` ~8~93~

-S . D . 51-SUPPLEMEN~ARY DISCLOSURE
_ _ _ ~ U ~ o ~
t:~ U ~ 3 u ~ ~ G ~ rl h U o U~ o ' o o o U~ U~ ,1 ~ r7 ~ ,1 U~ ~ o p~o o ~1 _ Z 1` Ul u~ ~J Z ~ u~ i r1 G~ H _I ~ H ~I cr~ H r~

~: ' 31 ~ ~ N N
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~ ,, ,, ,, ~ .
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h 1~ X ~ ~

æ ~ ~ z ~ æ o x u z u z; u ~,~ .

. . : . .
, - ; . :
,, .

,, , ,: . ,,,.. . :

3~

S.D. 52-Thus, the pre~ent inve:ntion provide~ a proces~ for preparing a compound of ~he formula:
M

W ~~
I Z

Ar ~O~
5 and the C15 epimer thereof; wherein Ar i~ phenyl or mono-sub3tituted phenyl wherein the sub~tituent i~ halo, trifluor~-methyl, lower alkyl or lower alkoxy; ~ i~ a ~in~le bo~ or ci~ double bond; ~ is a ingle bond or tran~ double bond; ~5 i3 OXO, ~ or ~ ; Y and Q when taken ~og~ther form a ~ingle bond, or Q is ~-hydroxyl when Y i~ hydrogen; X i~

tetrazolyl; a group of the formula ~ R' wher~in R~ i~
hydr~gen, alkyl o~ from 1 to 19 ~arb~n atoms, l~wer alkyl phenyl or biphenyl, with the provi~ at Rl i~ low~ alkyl phenyl or blphenyl when W is a Ci8 dQuble bondi and Q i8 ~-hydroxyl; or a group of the f~r~ula -CN~R" whs~ein R" i~
alkanoyl of ~rom 2 to 10 aarbon atom~, aryoyl, alkyl~ulfony~
of from 1 to 7 car~on at~s, or aryl3ulfonyl; and whsr~in M, Y and Q are BO selected a~ to complot~ the ~ruature o a pro~taglandin of the A, E or F s~riea, the lower alkanoyl, formyl ~r benzoyl e~ter~ of any free hydroxyl ~roup~ at the Cg-, Cll- and C15-po8ition8, and the pha~maceutically-accept-able ba~s of the compounds wherein X is COOH, which compriBe~:
~a) r~acting a compoun~ of the formula:
M

T~PO~ ~ O-Ar O~HP

.
. .

~ .. . . .

: , -~ ~08~9;~

--S.D. 53--wherein Ar, M, W, X and Z are as defined above and T~P i~
2-tetrahydropyranyl, with a suitable acid, to form the de-sired compound o~ Formula I, wherein Q is a-hydroxy, Y is hydrogen, and Ar, M, W, X and Z ~re as de~ined above;
(b) reacting A compound of Formula I, above, ~herein Q is a-hydroxy and Y is hydrogen, M i~ oxo and Ar, N, X and Z ar~ as defin~d above, with a auitable dehydrating agent, to form the desired compound of Fo~mul~ I wherein Q and Y
taken ~ogether ~orm a single bond, ~ is oxo and Ar, W, X
and Z are as deflned above;
~ c) hyd~ogena~ing a compound o th~ Formula I, above, wherein Q is a-hydroxy and Y is hydrogen, M i~ ox~, Ar, W, X and 2 are as def ined above, to form the desired ~mpound of Formula I, whçrein Q i8 a-hy~roxy, Y i8 hydrogen, M i~
H OH
~ o~ ~ and Ar, W and Z are ~ d~ine~ above, and, if d~sired, separating the 9a- and 9~i90m~rs;
~ d) catalyti~211y hydrogenatinq a compound of Formula I, above, wherein Ar, M and X are a~ de~ined above, W is a ~ingle bond or cis double bond when Z i8 a trans ~ouble bond and Z i5 a ~ingle bond when ~ i8 a ci~ double bond to foxm the desired compound of Formula I wher0i~ Q is a-hydr~xy, Y
is hydrogen, Ar, M and X are a3 definad ~ove, and W and Z
ar~ ~ingle bonds~
~e) ~electively ~ydrogenating a compound Qf Formula I, or the trialkylsilyl ester o~ ~ compound of Formula I ~
wherein X i3 COO~, ~bov~, wher~in Ar~ X and M are as deined abo~e a~d ~ and Z are doub.le bond , to ~orm the desired comW
pound ~f Formula I wherein Q ls a-h~dr~xy, Y i8 hydrogen, ~r, X and M are as def ined above, W is a ~i~gle bond and Z i8 a tran~ double bond7 and when roquir~ onv~rting those com-pound6 o Formula I wherein X i~ COOH ~.o e~ter~ or ~ubstitut-ed amid~, a~ clefined above, by rea~ion with suitable es~ri~ying or amidating reagent~, r~pectively, and, if de-~ired, preparing the 9a-, lla- and 15a-lower alkanoyl, formyl or ~enzoyl e~ters of any free hydr~xyl groups by reac~ing the .
~;i 3~
-S.D. 54 compounds with the appropriate ac:ylating agent~, and, i~
deæired, preparing the pharmaceut:ically acceptable ~alts of those compounds whexein X i~ ~OO~I.
The inv~ntion al~o provide~ a proce~ a~ described above for preparing a compound oi. the ~ormula:
0~
~""~X
HO~ Ar ~OH , . . . IA
and the C15 epimer thereof; w~erein Ar, n, z and X are de~ined ab~ve, whlch ~omprises:
ta) reacting a compound o~ ~he formula:
~X

THPO~ ~ O-Ar 'OT~P ... IIA
wherein Ar, W, X, Z and ~HP are as de~ined a~ove, wl~h a ~ui~able acid;
~b) hydrogenat ng a compound of the formula~
~x ~l ~~O-Ar .IB
~herein Ar, ~, X and Z are a~ do~ined above, ~nd then Bepa-ratin~ the 9a- an~ 9~-i80m~r~;
~c~ catalytically hydrogenating a compound of the Formula IA, above, wherein Ar, and X a~e a~ defined above, 20 W is a single bond or ci3 double bond when Z i~ a tran~
double bond and Z i~ a ~ingle bond when W i~ a cis double bond, ~o ~orm a compound of Formula IA, above, wherein Ar, ~ .

~ .

~(18Eil931 -S.D. 55-SUPPLEMENTARY DISCLOSU~E
and X are as defined above, and W and Z are si~gle bonde;
~ d) selectively catalytically hydrogenating the di-methylisopropylsilyl derivative of a compound of Formula IA, wherein X is COO~, Ar i8 as de~ine~ above, W is a ~i8 double bond and Z i~ a trans double bondl, to form a compound o~
Formula IA, above wherein Ar is als defined above, W i~ a aingle bond and Z i~ a tran~ double bond~
and when required, converting those compounds ~f Formula IA wherein X is COOH ~o eater~ or substitut2d amid~s by reaction with suitable esteri~ying or amidati~g agent~, re~pectively; and, if desired, preparing the 9~ , and ~ low~r..alkanoyl, formyl o~ benzoyl es~ers of any free hydroxyl groups by reacting the compounds with the appropri-ate acylating agent3, and, if desir~d, pr2paring th~ pharma~ceutically acceptable ~alts of tho~e compound~ wh~r~in X,i8 COO~ .
The inYention furthex provide~ a proce~8 as des-cribed above for preparing a compound ~' the ~'ormula:

~ X

~O~\~ ~ O-~r "o~ ...IB
and the C15 epimer thereof; wherein Ar, W, X and Z ar~ ~B
deflned abo~.re, which compri~es:
~a) rzacting a compound of the for~ula:
fi ' ' ' ' ~X

THPO~ Ar ~OT~P ... II
~5 wherein Ar, THP, W, X and Z are a8 defined a'Dove, ~ith a suitable a~id;
~ b) catalytically hydrogenating ~ c~mpound of Formula IB, above, wherein Ar, and X are aa defined above, W i8 a ~.
: , , ' . . , . ;, , . ~ ' :

, : : :: , : . , ., . .
. ' . :, ~: .
:
.. . .

-S.D. 56-SUPPLEMENTARY DISCLOSURE
__ _ _ _, _ ~ingle bond or cia double bond wh~an Z is a trans doubla bond and Z is a single bond when W is a aia double bond, to afford a compound of Formula IB wherein Ax, and X are as defined above, and W and Z are sin~le bonds;
(c) selectively catalytical:ly hydrogenatlng the di-me~hylisopropylsilyl derivative o:E a compound of Formula IB, wherein Ar and X are as defined abo~e, ~ i~ a ci8 doubl~
bond and Z is a trans double bond, to af~ord a compound of Formula I~, abo~e wherein Ar and X are as defined abov~, W
is a single bond and Z i~ a trans double bond;
and when required, converting those compound~ o~
Formula IB wherein X i5 COOH to e~ters or ~ub~tituted amide~
by raaction with suitable esterifying or amidating agents, respectively; and, if d~sired, prep~ring the lower alkanoyl, formyl or benzoyl e~ter~ of any ~ree 11- and 15-hydroxyl group8 by xeacting the compounds with the appropriate acylat-ing agents, and, if desire~ preparing the pharmaaeutically acceptable salts of those compounds wherein X is CO~H.
The invention ~till further p~ovide8 a proces~
~e~cribed above for preparing a compound o~ the ~ormul~:
d~""~--~ -Ar . 0~
and the C15 epimer t~ereof; wherein Ar, W, Z an~ X are de~ined above, ~hich comprises reacting a compound o~ ~h~
25 formula: `
O
~ X

HO~ ~ -Ar O~ o~IB
with a ~uitable dehydrating agent; and, ~hen required, con-verting tho~e compounds o~ Formula IC wherein X is COO~ to ~lQ8~31 , ... . .

SUPPLEMENTARY DISCLOSURE
esters or substituted amides, by reaction with suitable esterifying or amidating reagents~ respectively, and, if desired, preparing the C15-lower alkanoyl, formyl or benzoyl ester by reacting the compound wi.th an appropriate acylating agent, and, if desired, preparincJ the pharmaceutically accept-able salts of those compounds wherein X is COOH.
This divisional application relates to a prqcess for preparing a compound of the formula:
OH
~ ~X
I I Z
THPO\ ~ O~Ar ~OTHP ... IIA
and the C15 epimer thereof and the Cg and C15 epimers thereof;
wherein Ar is phenyl; or monosubs~ituted phenyl wherein the substituent is halo, trifluor~methyl, low~r alkyl, or lower alkoxy; THP is 2-tetrahydropyranyl; ~ is a single bond or cis double bond; Z is a sin~le bond or trans double bond and X is tetrazolyl; a group of the formula l~ wherein R' - -O-R' is hydrogen, alkyl of from 1 to 10 carbon atoms, lower alkyl phenyl or biphenyl when W is a single bond and Rl i~ lower . .
alkyl phenyl or biphenyl when R' is a cis double bond; or a group of the formula -CNHR" wherein R" iS alkanoyl of rom 2 to 10 carbon atoms, aryoyl, alkylsulfonyl of from 1 to 7 carbon atoms or arylsulfonyl, which comprises:
(a) reacting a compound of the formula:
~OH

THPO\\\ ~ O-Ar ~OTHP . . . VA

~' : :
:, . ~:
,, ; : ' ': :
: . . . , ~ , ~ . : . ' - . . :: . . :
: :.

~ 10~3~9~

-S.D. 58--~UPPLEMENTARY DISCLOSURE
wherein Ar, THP and Z are as defined above with an ylids of the formula:
(C6H5) 3P=CH-CH2 C~I2 CH2 X
wherein X is as defined above, with the proviso that whan X
equals CO2R' the compound of Formula VA i~ ~irst reacted with an ylide of the formula:
(C6~5)3P=C~ CH2C~,~CH2CO2 and the resulting product esteriied if desired, to afford a compound of Formula IIA, wherein Ar, X and Z are a~ defined above and W is a ci5 double bond, and, when required, æub-se~uently hydrogenating the compound thus formed to afford a compound of Formula IIA, ~herein Ar, X and Z are a~ de~ned above and ~ is a single bond;
~b) hydrogenating a compound of Formula IIA, abovo wherein Ar, and X are a~ deined above, ~ is a cis double bond and Z i8 a tran8 double bond, to ~orm a compound o~
Formula IIA above wherein Ar i~ a~ definzd above and W an~ Z
are single bond~;
~c) ~electively hydrog~nating a compound o Formula IIA
above, wherein Ax and X are as d~fined above, W is ~ cis double bond and Z is a trans double bond, to ~rm ~ comp~und of Formula IIA, wherein Ar and X ar~ a3 ~efinod abov~, W la a single bond and Z is a trans double bond.
The intermediate compound of the formula:
O

T~PO~ ' ~ ~O-A~ ... IIB
OT~P
and the C15 epimer th~reo~; wh~rein Ar is phQnyl; or mono-~ubatituted phenyl whereln the sub~tituent is h~lo, trifluoro-m~thyl, lower alkyl, or lower alkoxy~ T~P i~ 2-tetrahydro-pyranyl; W is a single bond or ci8 double bond; Z is a single bond or trans double bond and X is tetrazolyls a group of th~

formula -C-O-R~ wherein R' i9 hydrogen, alkyl of from 1 to 10 ~(381~5~31 -S.D. 59-SUPPLEMENTARY DISCLOSURE
carbon atoms, lower alkyl phenyl or biphenyl when R' iB a single bond and R' i6 lower alkyl phenyl or biphenyl when R' is a cis double bond; or a group of the formula ~ wherein NHR"
5 R" is alkanoyl of from 2 to 10 carbon atom~, aryoyl, alkyl-sulfonyl of from 1 to 7 carbon atoms or arylsul~o~yl; may be prepared by reacting a compound of the formula:
OH
-~ X
THPo~ ~O-Ar ~T~P . ... I IA
wherein Ar, T}IP, x, W and z are as defin~d abe~e with 10 chromic acid in aqueous sul~uric acid and acetone.

~.' .:
.. . ..
.

.. . ..

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a compound of the formula:

...IIA
and the C15 epimer thereof, and the C9 and C15 epimers thereof; wherein Ar is phenyl; THP is 2-tetrahydropyranyl;
W is a single bond or cis double bond; Z is a single bond or trans double bond; and X is tetrazolyl; a group of the formula -?-O-R' wherein R' is hydrogen, alkyl of from 1 to 10 carbon atoms, lower alkyl phenyl or biphenyl when W is a single bond and R' is lower alkyl phenyl or biphenyl when W

is a cis double bond; or a group of the formula -CNHR" wherein R" is alkanoyl of from 2 to 10 carbon atoms, aryoyl or alkyl-sulfonyl of from 1 to 7 carbon atoms; which comprises:
(a) reacting a compound of the formula:

...VA
wherein Ar, THP and Z are as defined above with an ylide of the formula:
(C6H5)3P=CH-CH2-CH2-CH2-X
wherein X is as defined above with the proviso that when X=CO2R' the compound of Formula VA is first reacted with an ylide of the formula:
(C6H5)3-P=CH-CH2CH2CH2CO2H
and the resulting product estarified if desired, to afford a compound of Formula IIA wherein Ar, X and Z are as defined above and W is a cis double bond; and, when required, sub-sequently hydrogenating the compound thus formed 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 is 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.

CLAIM SUPPORTED BY SUPPLEMENTARY DISCLOSURE
SD-2. A process for preparing a compound of the formula:

...IIA
and the C15 epimer thereof and the C9 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 cis double bond; Z is a single bond or trans double bond and X is tetrazolyl; a group of the formula -?-O-R' wherein R' is hydrogen, alkyl of from 1 to 10 carbon atoms, lower alkyl phenyl or biphenyl when W is a single bond and R1 is lower alkyl phenyl or biphenyl when R' is a cis double bond; or a group of the formula -?NHR" wherein R" is alkanoyl of from 2 to 10 carbon atoms, aryoyl, alkyl-sulfonyl of from 1 to 7 carbon atoms or arylsulfonyl; which comprises:
(a) reacting a compound of the formula:

...VA

wherein Ar, THP and Z are as defined above with an ylide of the formula:
(C6H5)3P=CH-CH2-CH2-CH2-X
wherein X is as defined above, with the proviso that when X=CO2R' the compound of Formula VA is first reacted with an ylide of the formula:

(C6H5)3P=CH-CH2CH2CH2CO2H
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 cis double bond, and, when required, sub-sequently hydrogenating the compound thus formed 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, 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 is 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 com-pound of Formula IIA, wherein Ar and X are as defined above, W is a single bond and Z is a trans double bond.